PUBLIC RELEASE DRAFT
July 2024
EPA Document# EPA-740-D-24-014
May 2024
Office of Chemical Safety and
Pollution Prevention
v=/EPA
United States
Environmental Protection Agency
Draft Human Health Hazard Assessment
for 1,2-Dichloroethane
Technical Support Document for the Draft Risk Evaluation
CASRN 107-06-2
ci
July 2024
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TABLE OF CONTENTS
SUMMARY 7
1 INTRODUCTION 12
1.1 Approach and Methodology 12
1.1.1 Identification and Evaluation of 1,2-Dichloroethane Hazard Data 13
1.1.2 Summary and Structure of the Draft Human Health Hazard Assessment 13
2 TOXICOKINETICS 14
2.1 Oral Route 14
2.2 Inhalation Route 17
2.3 Dermal Route 19
2.4 Parenteral Routes, In Vitro Studies, and Physiologically-Based Pharmacokinetic (PBPK)
Modeling Approach 20
2.4.1 Parenteral Routes 20
2.4.2 Studies 20
2.4.3 Physiologically-Based Pharmacokinetic (PBPK) Modeling Approach 21
2.5 Summary 22
3 NON-CANCER HAZARD IDENTIFICATION AND EVIDENCE INTEGRATION 23
3.1 Critical Human Health Hazard Outcomes 23
3.1.1 Renal Toxicity 23
3.1.2 Immunological/Hematological 24
3.1.3 Neurological/Behavioral 26
3.1.4 Reproductive/Developmental 27
3.1.5 Hepatic 29
3.1.6 Nutritional/Metabolic 31
3.1.7 Respiratory 31
3.1.8 Mortality 32
4 GENOTOXICITY HAZARD IDENTIFICATION AND EVIDENCE INTEGRATION 34
5 CANCER HAZARD IDENTIFICATION AND EVIDENCE INTEGRATION 39
6 DOSE-RESPONSE ASSESSMENT 42
6.1 Selection of Studies and Endpoints for Non-cancer Toxicity 42
6.1.1 Uncertainty Factors Used for Non-cancer Endpoints 42
6.1.2 Non-cancer PODs for Acute Exposures 43
6.1.3 Non-cancer PODs for Short-Term/Subchronic Exposures 50
6.1.4 Non-cancer PODs for Chronic Exposures 57
6.2 Summary of Studies Not Considered/Considered Suitable for POD Determination of 1,2-
Dichloroethane 64
6.3 Endpoint Derivation for Carcinogenic Dose-Response Assessment 79
6.3.1 Cancer Dose-Response Assessment 79
6.3.2 Summary of Continuous and Worker PODs 81
6.4 Weight of Scientific Evidence Conclusions for Human Health Hazard 82
6.4.1 Overall Confidence - Strengths, Limitations, Assumptions, and Key Sources of
Uncertainty in the Human Health Hazard Assessment 83
7 POTENTIALLY EXPOSED OR SUSCEPTIBLE SUBPOPULATIONS 85
8 PODS FOR NON-CANCER AND CANCER HUMAN HEALTH HAZARD ENDPOINTS.. 87
REFERENCES 95
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75 Appendix A CALCULATING DAILY ORAL HUMAN EQUIVALENT DOSES AND
76 HUMAN EQUIVALENT CONCENTRATIONS 108
77 A,1 Equations 108
78 A.l.l Air Concentration Unit Conversion 108
79 A. 1.2 Adjustment for Continuous Exposure 108
80 A. 1.3 Calculation of HEDs and HECs from Animal PODs 109
81 A. 1.4 Cancer Inhalation Unit Risk Ill
82 A. 1.5 Conversion of Continuous PODs to Occupational PODs Ill
83 A. 1.6 Summary of Continuous and Worker Non-cancer PODs Ill
84 Appendix B EVIDENCE INTEGRATION TABLES FOR NON-CANCER FOR 1,2-
85 DICHLOROETHANE 113
86 Appendix C EVIDENCE INTEGRATION TABLES FOR CANCER FOR 1,2-
87 DICHLOROETHANE 143
88 Appendix D LIST OF SUPPLEMENTAL DOCUMENTS 158
89 Appendix E HUMAN HEALTH HAZARD VALUES USED BY EPA OFFICES AND
90 OTHER AGENCIES 160
91 E.l Summary of Non-cancer Assessments of EPA Offices and Other Agencies 160
92 E,2 Summary of Cancer Assessments of EPA Offices and Other Agencies 166
93 Appendix F BENCHMARK DOSE ANALYSIS 167
94 F. 1 Non-cancer PODs for Acute Exposures for 1,2-Dichloroethane 167
95 F.2 Non-cancer PODs for Short/Intermediate-Term Exposures for 1,2-Dichloroethane 169
96 F.3 Non-cancer PODs for Chronic Exposures for 1,2-Dichloroethane 170
97
98 LIST of tables
99 Table 2-1. Tissue Levels and Time to Peak Tissue Level in Rats Exposed to 1,2-Dichloroethane by
100 Gavage in Corn Oil 15
101 Table 2-2. Tissue Levels and Time to Peak Tissue Level in Rats Exposed by Inhalation to 1,2-
102 Dichloroethane for 6 Hours 18
103 Table 2-3. 1,2-Dichloroethane Partition Coefficients Steady State Estimates 21
104 Table 2-4. 1,2-Dichloroethane Tissue: Air Partition Coefficients 21
105 Table 5-1. 1,2-Dichloroethane Oncologic Results 41
106 Table 5-2. 1,2-Dichloroethane Precursor Events 41
107 Table 6-1. Acute, Oral, Non-cancer POD-Endpoint Selection Table 46
108 Table 6-2. Acute, Inhalation, Non-cancer POD-Endpoint Selection Table 47
109 Table 6-3. Short-Term/Subchronic, Oral, Non-cancer POD-Endpoint Selection Table 52
110 Table 6-4. Short-Term/Subchronic, Inhalation, Non-cancer POD-Endpoint Selection Table 54
111 Table 6-5. Chronic, Oral, Non-cancer POD-Endpoint Selection Table 58
112 Table 6-6. Chronic, Inhalation, Non-cancer POD-Endpoint Selection Table 60
113 Table 6-7. Oral Studies Not Considered Suitable for PODs for 1,2-Dichloroethane 65
114 Table 6-8. Inhalation Studies Not Considered Suitable for PODs for 1,2-Dichloroethane 66
115 Table 6-9. Dermal Studies Not Considered Suitable for PODs for 1,2-Dichloroethane 68
116 Table 6-10. Summary of Studies Considered for Non-cancer Dose-Response Assessment of 1,2-
117 Di chl oroethane 68
118 Table 6-11. Summary of Candidate Acute, Non-cancer, Oral PODs for 1,2-Dichloroethane 70
119 Table 6-12. Summary of Candidate Short-Term/Intermediate, Non-cancer, Oral PODs for 1,2-
120 Dichloroethane 71
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Table 6-13. Summary of Candidate Acute, Non-cancer, Inhalation PODs for 1,2-Dichloroethane 73
Table 6-14. Summary of Candidate Short-Term/Intermediate, Non-cancer, Inhalation PODs for 1,2-
Dichloroethane 76
Table 6-15. Summary of Candidate Chronic, Non-cancer, Inhalation PODs for 1,2-Dichloroethane 78
Table 6-16. IUR Estimates for Tumor Data from Nagano et al. (2006) Study of 1,2-Dichloroethane
Using Linear Low-Dose Extrapolation Approach 80
Table 6-17. Summary of Cancer PODs for 1,2-Dichloroethane 82
Table 6-18. Confidence Summary for Human Health Hazard Assessment 84
Table 7-1. Summary of PESS Categories in the Draft Risk Evaluation and Remaining Sources of
Uncertainty 86
Table 8-1. PODs and Toxicity Values Used to Estimate Non-cancer Risks for Acute Exposure Scenarios
88
Table 8-2. PODs and Toxicity Values Used to Estimate Non-cancer Risks for Short-Term Exposure
Scenarios 90
Table 8-3. PODs and Toxicity Values Used to Estimate Non-cancer Risks for Chronic Exposure
Scenarios 92
Table 8-4. Cancer PODs for 1,2-Dichloroethane Lifetime Exposure Scenarios 94
LIST OF FIGURES
Figure 1-1. EPA Approach to Hazard Identification, Evidence Integration, and Dose-Response Analysis
for Human Health Hazard 12
Figure 2-1. Proposed Metabolic Scheme for 1,2-Dichloroethane (IPCS, 1995) 16
Figure 5-1. Hepatocellular Carcinomas Dose Response in Mice for 1,2-Dichloroethane (NTP (1978)). 40
LIST OF APPENDIX TABLES
Table Apx A-l. Summary of Non-cancer PODs for 1,2-Dichloroethane 112
TableApx B-l. 1,2-Dichloroethane Evidence Integration Table for Reproductive/Developmental
Effects 113
Table Apx B-2. 1,2-Dichloroethane Evidence Integration Table for Renal Effects 120
Table Apx B-3. 1,2-Dichloroethane Evidence Integration Table for Hepatic Effects 123
Table Apx B-4. 1,2-Dichloroethane Evidence Integration Table for Immune/Hematological Effects. 129
Table Apx B-5. 1,2-Dichloroethane Evidence Integration Table for Neurological/Behavioral Effects 131
Table Apx B-6. 1,2-Dichloroethane Evidence Integration Table for Respiratory Tract Effects 136
Table Apx B-7. 1,2-Dichloroethane Evidence Integration Table for Nutritional/Metabolic Effects.... 138
Table Apx B-8. 1,2-Dichloroethane Evidence Integration Table for Mortality 140
Table Apx C-l. 1,2-Dichloroethane Cancer Evidence Integration Table 143
Table Apx E-l. Non-cancer Human Health Hazard Values based on Exposure Duration and Route for
1,2-Dichloroethane 162
Table Apx E-2. 1,2-Dichloroethane Cancer Slope Factors and Inhalation Unit Risk of EPA Offices and
Other Agencies 166
Table Apx F-l. Relative Kidney Weights in Male Mice Exposed to 1,2-Dichloroethane Once by
Gavage 167
Table Apx F-2. Incidence of Nasal Lesions in Male and Female Rats (Combined) Exposed to 1,2-
Dichloroethane for 8 Hours 168
Table Apx F-3. Antibody-forming Cells per Spleen in Male Mice Exposed to 1,2-Dichloroethane by
Daily Gavage for 14 Days 169
Table Apx F-4. Sperm Concentration in Male Mice Exposed to 1,2-Dichloroethane for 4 Weeks 170
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KEY ABBREVIATIONS AND ACRONYMS
ADME
Absorption, distribution, metabolism, and elimination
AF
Assessment factor
ALT
Alanine transaminase
AMTIC
Ambient Monitoring Technology Information Center
AST
Aspartate aminotransferase (AST)
ATSDR
Agency for Toxic Substances and Disease Registry
BAF
Bioaccumulation factor
BALF
Bronchioalveolar lavage fluid
BCF
Bioconcentration factor
BMC
Benchmark concentration
BMD
Benchmark dose
BMR
Benchmark response
BUN
Blood urea nitrogen
CASRN
Chemical Abstracts Service Registry Number
ChV
Chronic value
CSF
Cancer slope factor
CWA
Clean Water Act
EPA
Environmental Protection Agency
GD
Gestation day
GSH
Glutathione
GST
Glutathione-S-transferase
HC05
Hazardous concentration for 5 percent of species
HEC
Human Equivalent Concentration
HED
Human Equivalent Dose
HERO
Health and Environmental Research Online (Database)
IRIS
Integrated Risk Information System
IUR
Inhalation unit risk
LCx
Lethal concentration at which (x) percent of test organisms die
LDH
Lactate dehydrogenase
LDx
Lethal dose at which (x) percent of test organisms die
LOD
Limit of detection
LOAEL
Lowest-adverse-effect-level
MOE
Margin of exposure
NATA
National Scale Air-Toxics Assessment
ND
Non-detect
NEI
National Emissions Inventory
NOAEL
No-adverse-effect-level
NTP
National Toxicology Program
OCSPP
Office of Chemical Safety and Pollution Prevention
OECD
Organisation for Economic Co-operation and Development
OPPT
Office of Pollution Prevention and Toxics
PBPK
Phy si ol ogi cally-b ased pharmacokineti c
PECO
Population, exposure, comparator, and outcome
PESS
Potentially exposed or susceptible subpopulations
POD
Point of departure
SD
Sprague-Dawley (rat)
SR
Systematic review
SSD
Species sensitivity distribution
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218
TLV
Threshold limit value
219
TRI
Toxics Release Inventory
220
TRV
Toxicity reference value
221
TSCA
Toxic Substances Control Act
222
TWA
Time-weighted average
223
UF
Uncertainty Factor
224
U.S.
United States
225
WOSE
Weight of scientific evidence
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SUMMARY
This technical support document for 1,2-dichloroethane describes the non-cancer and cancer hazards
associated with exposure to 1,2-dichloroethane and identifies the points of departure (PODs) to be used
to estimate risks from 1,2-dichloroethane exposures in the draft risk evaluation of 1,2-dichloroethane.
The Existing Chemicals Risk Evaluation Division (ECRAD) has received input from senior scientists
and technical experts from EPA's OCSPP and across the Agency. Specifically, ECRAD has received
input from the OCSPP Senior Science Advisors, OCSPP's Science Policy Council, and through the
intra-agency review process. The areas of analysis contained in this draft 1,2-dichloroethane human
health hazard assessment technical support document reflect some of the revisions received throughout
the review process and during scientific deliberations; however, there are some significant aspects of the
development of this draft 1,2-dichloroethane human health hazard assessment for which there is not
agreement between ECRAD and senior scientists and technical experts. In accordance with EPA's
Scientific Integrity Policy (https://www.epa.eov/scientific-inteeritY/epas-scientific-inteeritY-policy). the
areas of scientific disagreement are described in relevant charge questions and are intended to guide the
scientific peer review by the TSCA Science Advisory Committee on Chemicals (SACC). EPA is
requesting the SACC provide input on these science issues—including the differences of scientific
opinion—which relate specifically to 1,2-dichloroethane (and the concurrently released draft 1,1-
dichloroethane risk evaluation) but also more broadly in the application of risk assessment practices and
use of existing EPA and internally accepted guidance documents.
EPA evaluated the reasonably available information for human health hazards and identified hazard
PODs for adverse effects following acute, short-term/sub chronic, and chronic exposures. These PODs
represent the potential for greater biological susceptibility across subpopulations. The most biologically
relevant and sensitive PODs for non-cancer for 1,2-dichloroethane from among the human health
hazards identified—along with the corresponding Human Equivalent Dose (HED), the Human
Equivalent Concentration (HEC), and the total combined uncertainty factors (UF) for each route and
exposure duration—are summarized below (Table ES-1). The lack of adequate non-cancer data by the
dermal route for 1,2-dichloroethane required route-to-route extrapolation from oral PODs. The
following summarizes the key points of this section of the draft risk evaluation.
The most biologically relevant and sensitive PODs for cancer effects for 1,2-dichloroethane from among
the human health hazards identified—along with the corresponding cancer slope factor (CSF), dermal
slope factor, inhalation unit risk (MR), and drinking water unit risk—are also summarized below (Table
ES-2).
EPA identified kidney toxicity, immunotoxicity, and neurotoxicity as the most sensitive critical human
health hazard outcomes associated with 1,2-dichloroethane. These hazard outcome categories received
likely evidence integration conclusions, and sensitive health effects were identified for these hazard
outcomes. In the draft risk evaluation, renal toxicity forms the basis of the POD used for acute oral
exposure scenarios and immunotoxicity is the basis of the POD used for both short-term and chronic
oral exposure scenarios. Neurotoxicity is the basis of the POD used for acute inhalation exposure and
reproductive effects is the basis for short-term/sub chronic and chronic inhalation exposure scenarios.
Additionally, hazard identification and evidence integration of other toxicity outcomes are also outlined
to emphasize the systematic review process applied to identify potential POD with within the 1,2-
dichloroethane database.
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EPA is proposing a POD of 153 mg/kg-day (HED of 19.9 mg/kg-day) to estimate non-cancer risks from
oral exposure to 1,2-dichlorethane for acute durations of exposure in the draft risk evaluation for 1,1-
dichloroethane. The proposed POD was derived based on benchmark dose modeling of increased kidney
weight in male mice {i.e., the only sex tested). Increased blood urea nitrogen levels support the kidney
findings as both parameters were dose-responsive. The POD of 153 mg/kg-day is the 90 percent lower
confidence limit of the BMD associated with a benchmark response (BMR) of 10 percent. As presented
in Section 6.1.2 and Table 6-1, additional acute duration studies of 1,2-dichlorethane provide similar,
although less sensitive, candidate PODs, which further support EPA's proposal to use the selected HED
of 19.9 mg/kg-day for increased kidney weight. The Agency has performed 3/4 body weight scaling to
yield the HED of 19.9 mg/kg-day and is applying the animal to human extrapolation factor {i.e.,
interspecies extrapolation; UFa) of 3 x and a within human variability extrapolation factor {i.e.,
intraspecies extrapolation; UFh) of 10x. Thus, a total UF of 30x is applied for use as the benchmark
margin of exposure (MOE). Based on the strengths, limitations, and uncertainties discussed Section
6.4.1, EPA has robust overall confidence in the proposed POD based on increased kidney weight
for use in characterizing risk from exposure to 1,2-dichloroethane for acute oral exposure
scenarios.
EPA is proposing a POD of 48.9 mg/m3 (HEC of 10.14 ppm) to estimate non-cancer risks from
inhalation to 1,2-dichloroethane for acute durations of exposure in the draft risk evaluation for 1,1-
dichloroethane. The proposed POD was derived based on benchmark dose modeling of degeneration
with necrosis of the olfactory (nasal) mucosa in male and female mice. The POD of 48.9 mg/m3 is the
90 percent lower confidence limit of the BMD associated with a BMR of 10 percent. As presented in
Section 6.1.2 and Table 6-2, additional acute duration studies of 1,2-dichloroethane provide similar,
although less sensitive, candidate PODs, which further support EPA's proposal to use the selected POD
of 48.9 mg/m3 for degeneration with necrosis of the olfactory (nasal) mucosa. The Agency is applying
the animal to human extrapolation factor {i.e., interspecies extrapolation; UFa) of 3 / and a within
human variability extrapolation factor {i.e., intraspecies extrapolation; UFh) of 10x. Thus, a total UF of
30x is applied for use as the benchmark MOE. Based on the strengths, limitations, and uncertainties
discussed in Section 6.4.1, EPA has robust overall confidence in the proposed POD based on
degeneration with necrosis of the olfactory (nasal) mucosa for use in characterizing risk from
exposure to 1,2-dichloroethane for acute inhalation exposure scenarios.
EPA is proposing an adjusted lowest-observed-adverse effect level (LOAELadj) of 4.89 mg/kg-day
(HED of 0.890 mg/kg-day) from a high quality 14-day gavage study in male mice based on suppression
of immune response (antibody forming cells [AFCs] in the spleen) to estimate non-cancer risks from
oral exposure to 1,2-dichloroethane for short-term/chronic durations of exposure in the draft risk
evaluation of 1,1-dichloroethane. The study also demonstrated decreased leukocyte counts to support
immunosuppression. As presented in Sections 6.1.3 and 6.1.4 and Table 6-3 and Table 6-5, additional
short-term/chronic duration studies of 1,2-dichloroethane provide similar, although less sensitive,
candidate PODs, which further support EPA's proposal to use the selected POD of 4.89 mg/kg-day for
suppression of immune response (AFCs in the spleen). The Agency has performed 3/4 body weight
scaling to yield the HED of 0.890 mg/kg-day and is applying the animal to human extrapolation factor
{i.e., interspecies extrapolation; UFa) of 3x, a within human variability extrapolation factor {i.e.,
intraspecies extrapolation; UFh) of 10x and a LOAEL to extrapolate a no-observed-adverse-effect-level
(NOAEL) factor {i.e., UFl) of 3x. The use of a duration adjustment factor {i.e., short-term study to long-
term risk assessment, UFs) of 10x was applied for the chronic duration, specifically. Thus, a total
uncertainty factor (UF) of 100x is applied for use as the benchmark MOE for the short-term duration
and 1000x chronic duration, respectively. Based on the strengths, limitations, and uncertainties
discussed in Section 6.4.1, EPA has robust overall confidence in the proposed POD based on
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suppression of immune response for use in characterizing risk from exposure to 1,2-
dichloroethane for short-term/chronic oral exposure scenarios.
EPA is proposing a POD of 21.2 mg/m3 (HEC of 22.0 ppm) to estimate non-cancer risks from inhalation
to 1,2-dichloroethane for short-term/chronic durations of exposure in the draft risk evaluation for 1,1-
dichloroethane. The proposed POD was derived based on benchmark dose modeling of decreased sperm
concentration in male mice after a whole body, 4-week exposure. The POD of 21.2 mg/m3 is the 95
percent lower confidence limit of the BMD associated with a BMR of 5 percent due to a biological
significance and relevance at this level in humans.
As presented in Sections 6.1.3 and 6.1.4, as well as Table 6-4 and Table 6-6, additional short-term
duration studies of 1,2-dichloroethane provide less sensitive, candidate PODs, which further support
EPA's proposal to use the selected POD of 21.2 mg/m3 for decreased sperm concentration. The Agency
is applying the animal to human extrapolation factor {i.e., interspecies extrapolation; UFA) of 3x and a
within human variability extrapolation factor {i.e., intraspecies extrapolation; UFH) of 10x. The use of a
duration adjustment factor {i.e., short-term study to long-term risk assessment, UFS) of 10x was applied
for the chronic duration, specifically. Thus, a total UF of 30x is applied for use as the benchmark MOE
for the short-term duration and 300x chronic duration, respectively. Based on the strengths, limitations,
and uncertainties discussed Section 6.4.1, EPA has robust overall confidence in the proposed POD
based on decreased sperm concentration for use in characterizing risk from exposure to 1,2-
dichloroethane for short-term/chronic inhalation exposure scenarios.
No data were available for the dermal route identified based on systematic review that were suitable for
deriving route-specific PODs. Therefore, EPA used the acute, short-term, and chronic oral PODs to
evaluate risks from dermal exposure to 1,2-dichloroethane.
Systematic review identified two high-quality 1,2-dichloroethane cancer studies for cancer dose-
response. The oral cancer studies in mice performed by on 1,2-dichloroethane resulted in
tumor types or pre-cancerous lesions {i.e., hepatocellular carcinomas, endometrial polyps,
hemangiosarcomas, and mammary gland tumors). Therefore, EPA is proposing a CSF of 0.062 per
mg/kg-day for the oral/dermal exposure routes to 1,2-dichloroethane based on hepatocellular carcinomas
in male mice for both continuous {i.e., general population) and worker (occupational) scenarios. In
addition, EPA is proposing a drinking water (DW) unit risk of 1,8x 10"6 per [j,g/L based on an
extrapolation from the oral gavage data and further discussed in Section 6.3.1.
The 1,2-dichloroethane inhalation cancer study by Nagano et al. (2006) is the basis for the inhalation
unit risk (MR) as this study identified similar tumors as observed in the 1,2-dichloroethane oral cancer
study. EPA is therefore proposing an IUR of 7.1 x 10 6 per [j,g/m3 and 2/ 10 6 per [j,g/m3 for the inhalation
exposure route to 1,2-dichloroethane based on a combined tumor model (mammary gland adenomas,
fibroadenomas, and adenocarcinomas and subcutaneous fibromas) for the continuous and worker
scenarios, respectively (see Section 6.3.1).
Based on the strengths, limitations, and uncertainties discussed in Section 6.4.1, EPA has robust
overall confidence in the proposed CSF and IUR based on hepatocellular carcinomas and a
combined tumor model (in a miliary gland adenomas, fibroadenomas, and adenocarcinomas and
subcutaneous fibromas), respectively.
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370 Table ES-1. Non-cancer HECs and HEDs Used to Estimate Risks
Target
Organ
System
POD
(mg/kg-
day)
Worker
Continuous
Worker
Continuous
HED
(mg/kg-day)
Exposure
Scenario
Species
Du ration
Effect
HEC
(mg/m3)
| ppm ]
HEC
(mg/m3)
[ppm]
HED
(mg/kg-
day)
Benchmark
MOE
Reference
Acute -
Oral
Renal
Mice
(male)
Single
dose via
oral
gavage
BMDLio
= 153
mg/kg-day
BMD =
270 mg/kg
Increased
kidney weight
N/A
N/A
19.9
19.9
UFa" = 3
UFh = 10
Total UF =
30
Storeret al. (1984)
Acute -
Inhalation
Neurological
Rats
(males and
females
combined)
8-hours
(whole
body to
vapor)
BMCio =
48.9
mg/m3
[12.1 ppm]
Degeneration
with necrosis
of the
olfactory
mucosa
(41.1
mg/m3)
[10.14
ppm]
(9.78 mg/m3)
[2.42 ppm]
N/A
N/A
UFa = 3
UFh = 10
Total UF =
30
Dow Chemical
(2006b)
Short-term
and
Chronic -
Oral
Immune
System
Mice
(male)
14-days
via oral
gavage
LOAELadj
= 4.89
mg/kg
Suppression
of immune
response
(AFCs/
spleen)
N/A
N/A
0.890
0.636
Short-term:
UFa = 3
UFh = 10
UFl=3
Total UF =
100
Munson et al. (1982)
Chronic:
UFa = 3
UFh = 10
UFl=3
UFS= 10
Total UF =
1,000
Short-term
and
Chronic -
Inhalation
Reproductive
Mice
(male)
4-weeks
(6
hours/day
for 7
days/week
bmcl5=
21.2
mg/m3
[5.2 ppm]
Decreases in
sperm
concentration
(89.0
mg/m3)
[22.0
ppm]
(21.2 mg/m3)
[5.2 ppm]
N/A
N/A
Short-term:
UFa = 3
UFh = 10
Total UF =
30
Zhang et al. (2017)
whole
body to
vapor)
Chronic:
UFa = 3
UFh = 10
UFS= 10
Total UF =
300
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Exposure
Scenario
Target
Organ
System
Species
Du ration
POD
(mg/kg-
day)
Effect
Worker
HEC
(mg/m3)
[ppm]
Continuous
HEC
(mg/m3)
|ppm|
Worker
HED
(mg/kg-
day)
Continuous
HED
(mg/kg-day)
Benchmark
MOE
Reference
HEC = human equivalent concentration; HED = human equivalent dose; MOE = margin of exposure; NOAEL = no-observed-adverse-effect level; POD = point of
departure; SD = Sprague-Dawley; UF = uncertainty factor
" EPA used allometric bodv weisht scaling to the three-auarters PA) power to derive the HED. Consistent with EPA Guidance U.S. EPA (201 lb), the UFa was reduced
from 10 to 3.
371
372
373 Table ES-2. Cancer POPs for 1,2-Dichloroethane Lifetime Exposure Scenarios
Exposure
Assumption "
Oral Slope
Factor''
Dermal Slope Factor''
Inhalation Unit Risk'
Drinking Water
Unit Risk''
Extra Cancer Risk
Benchmark
Continuous Exposure
0.062 per
mg/kg/day
0.062 per mg/kg/day
7.1E-06 (per |ig/m3)
2.9E-02 (per ppm)
1.8E-06 per ug/L
1E-06 (general population)
Worker
0.062 per
mg/kg/day
0.062 per mg/kg/day
2.4E-06 (per |ig/m3)
9.5E-03 (per ppm)
1.8E-06 per ug/L
1E-04 (occupational)
" Cancer slope factor and unit risk will be derived based on continuous exposure scenarios. Due to the exposure averaging time adjustments incorporated into lifetime
exposure estimates, separate cancer hazard values for occupational scenarios are not required.
b The oral CSF for male mice based on hepatocellular carcinomas in male mice was 6.2><10~2 (per mu/ku-bw/dav) in a studv bv NTP (1978). Due to scarcity of data,
route-to-route extrapolation from the oral slope factor is used for the dermal route.
c Cancer inhalation PODs from 1,2-dichloroethane based on combined tumor model (mammary gland adenomas, fibroadenomas, and adenocarcinomas and subcutaneous
fibromas in female rats) Nagano et al. (2006)
' Therefore, the oral CSF for 1.2-dichloroethane from the reliable NTP mouse cancer studv NTP (1978) was selected for use in assessment of cancer risks associated
with exposure to 1,2-dichloroethane. This mouse CSF was used to calculate a drinking water unit risk of 1.8 E-06 per ug/L using a drinking water intake of 2 L/day and
body weight of 70 kg.
374
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1 INTRODUCTION
Following publication of the Final Scope of the Risk Evaluation for 1,2-Dichloroethane CASRN107-06-
2 (U.S. EPA. 2020). one of the next steps in the Toxic Substances Control Act (TSCA) risk evaluation
process is to identify and characterize the human health hazards of 1,2-dichloroethane and conduct a
dose-response assessment to determine the points of departure (PODs) to be used to estimate risks from
1,2-dichloroethane exposures. This technical support document for 1,2-dichloroethane summarizes the
non-cancer and cancer hazards associated with exposure to 1,2-dichloroethane and identifies the PODs
to be used to estimate risks from 1,2-dichloroethane exposures.
1.1 Approach and Methodology
To identify and integrate human epidemiologic data and animal data into the draft 1,2-Dichloroethane
Risk Evaluation, EPA first reviewed existing assessments of 1,2-dichloroethane conducted by regulatory
and authoritative agencies such as ATSDR (2022). as well as several systematic reviews of studies of
1,2-dichloroethane published by U.S. EPA Integrated Risk Information System (IRIS) programU.S.
EPA (1987b) and U.S. EPA Provisional Peer-Reviewed Toxicity Values U.S. EPA (2010). A summary
and evaluation of the toxicity values identified from these assessments are provided in Appendix E.
EPA used the general approach described in Figure 1-1 to evaluate and extract evidence for 1,2-
dichloroethane human health hazard and dose-response information. This approach is based on the Draft
Systematic Review Protocol Supporting TSCA Risk Evaluations for Chemical Substances (U.S. EPA.
2021) (hereafter referred to as the 2021 Draft Systematic Review Protocol), updates to the systematic
review processes presented in the Draft Risk Evaluation for 1,1-Dichloroethane - Systematic Review
Protocol (U.S. EPA. 2024b) (hereafter referred to as the 1,1-Dichloroethane Systematic Review
Protocol) and the Framework for Raman Health Risk Assessment to Inform Decision Making (U.S.
EPA. 2014).
Figure 1-1. EPA Approach to Hazard Identification, Evidence Integration, and Dose-Response
Analysis for Human Health Hazard
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1.1.1 Identification and Evaluation of 1,2-Dichloroethane Hazard Data
For the human health hazard assessment, EPA used a systematic review (SR) approach described in the
2021 Draft Systematic Review Protocol ( 21), to identify relevant studies of acceptable data
quality and integrate the pertinent data while evaluating the weight of scientific evidence. For identified
hazards and endpoints with weight of scientific evidence supporting an adverse outcome, studies were
considered for dose-response analysis. The 2021 Draft Systematic Review Protocol ( 21)
describes the general process of evidence evaluation and integration, with relevant updates to the
process presented in the 1,1-dichloroethane Systematic Review Protocol ( 24b).
For data quality evaluation, EPA systematically reviewed literature studies for 1,2-dichloroethane first
by reviewing screened titles and abstracts and then full texts for relevancy using population, exposure,
comparator, and outcome (PECO) screening criteria. Studies that met the PECO criteria were evaluated
for data quality using pre-established metrics as specified in the 1,2-Dichloroethane Systematic Review
Protocol ( )24b). Studies (based on the specified metrics) received overall data quality
determinations of either Uninformative, Low, Medium, or High. The results and details of the data
quality evaluation for 1,2-dichloroethane human health hazard are included in the Draft Risk Evaluation
for 1,1-Dichloroethane - Systematic Review Supplemental File: Data Quality Evaluation Information
for Human Health Hazard Epidemiology ( )24e). This supplemental file is hereafter referred
to as the 1,1-Dichloroethane Data Quality Evaluation Information for Human Health Hazard
Epidemiology. The results and details of the data quality evaluation for 1,2-dichloroethane animal
toxicity studies are included in the Draft Risk Evaluation for 1,1-Dichloroethane - Systematic Review
Supplemental File: Data Quality Evaluation Information for Human Health Hazard Animal Toxicology
( 2024d). This supplemental file is hereafter referred to as 1,1-Dichloroethane Data Quality
Evaluation Information for Human Health Hazard Animal Toxicology ( 024d) or OPPT SR
review ( 2024d).
Following data quality evaluation, EPA completed data extraction of the toxicological information from
each on topic study that met the PECO criteria. This data extraction included studies of all data quality
determinations including "uninformative." The results of data extraction for human and animal for 1,2-
dichloroethane toxicity studies are reported in the Draft Risk Evaluation for 1,1-Dichloroethane -
Systematic Review Supplemental File: Data Extraction Information for Environmental Hazard and
Human Health Hazard Animal Toxicology and Epidemiology ( 24c). This supplemental file
is hereafter referred to as the 1,1-Dichloroethane Data Extraction Information for Environmental Hazard
and Human Health Hazard Animal Toxicology and Epidemiology.
1.1.2 Summary and Structure of the Draft Human Health Hazard Assessment
EPA completed a hazard identification and evidence integration for 1,2-dichloroethane based on a
review and evaluation of the results of the SR process including data quality evaluation and data
extraction. The hazard identification and evidence integration completed for 1,2-dichloroethane are
provided in Section 2 for toxicokinetics, Section 3 for non-cancer human and animal study data
(stratified by organ system), Section 4 genotoxicity and evidence integration, Section 5 for cancer and
evidence integration, Section 6 for dose-response assessment, Section 7 for potentially exposed or
susceptible subpopulations, and Section 8 for PODs for non-cancer and cancer human health hazard
endpoints.
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2 TOXICOKINETICS
This section provides a summary on the absorption, distribution, metabolism, and elimination (ADME)
data available for 1,2-dichloroethane.
2.1 Oral Route
Case reports and experimental animal studies were identified that provided useful data in evaluating
absorption, distribution, metabolism, and excretion (ADME) of 1,2-dichloroethane for the oral route.
Human studies were not identified specifically regarding the absorption of 1,2-dichloroethane following
oral exposure, however, based on case studies that demonstrate the toxic effects (such as death) due to
intentional(Yodai ken and Babcocl r" <, < < chhead and Close. 1951) or accidental(Uucpcr and Smith.
1935) ingestion, it can be inferred that 1,2-dichloroethane is rapidly absorbed into systemic circulation.
With a Kowof 1.48, 1,2-dichloroethane is lipophilic and is anticipated to traverse mucosal membranes
within the gastrointestinal tract via passive diffusion (ATSDR. 2022). Experimental animal studies
further support this conclusion.
Oral absorption is rapid and complete according to Reitz et nl i I l)82)and Spreafico et al. (1980) as cited
in ATSDR (2022). In rats given a single gavage dose of 150 mg/kg of 1,2-dichloroethane in corn oil,
peak blood concentrations were reached within 15 minutes and approximately 94 percent of the
administered dose was absorbed within 48 hours Reitz et al. (1982). Spreafico et al. (1980) also
demonstrated rapid oral absorption, with peak blood levels occurring between 30 and 60 minutes in rats
given gavage doses of 25, 50, or 150 mg/kg of 1,2-dichloroethane in corn oil. Additionally, it is to be
noted that at 3.3 minutes and 6.4 minutes, half of the 25 and 150 mg/kg doses were absorbed,
respectively. This further emphasizes the rapid oral absorption of 1,2-dichloroethane. Examination of
the peak blood level curves at the different doses shows a linear curve up to 50 mg/kg 1,2-
dichloroethane and a decrease in steepness of the curve at 100 mg/kg, suggesting a relative saturation of
oral absorption at doses exceeding 100 mg/kg. Additionally, in a study by Withev et S3), rats
given a single gavage dose of 100 mg/kg of 1,2-dichloroethane in corn oil or water, peak blood
concentrations (Cmax) were approximately 4-fold higher and the time to reach Cmax was 3-fold faster
following administration in water compared to corn oil, thus implicating the choice of the vehicle in
affecting absorption rates. Similar findings regarding the rate of absorption were observed in rats given
doses of 43 mg/kg/day in water or 150 mg/kg/day in corn oil via oral gavage with Cmax values of 15 or
30 minutes in water and corn oil, respectively (Dow Chemical. 2006a). Based on these data from animal
studies and the available, though limited, human evidence exposure to 1,2-dichloroethane via drinking
water may be of concern to human health.
Distribution, based on experimental animal studies was also identified to be rapid following gavage
dosing, with concentrations peaking first in the liver at 6 to 7 minutes, followed by lung at 10 to 20
minutes and adipose tissue at 20 to 60 minutes (I )). Tissue levels were dose-dependent and the
highest peak tissue concentration at any dose was detected in fat. Similar mean peak tissue levels in liver
and lung were seen following 11 daily doses of 50 mg/kg, indicating that bioaccumulation does not
occur in these tissues with multiple doses. Bioaccumulation in adipose tissue is suggested by higher
peak adipose tissue levels after 11 gavage doses compared to a single gavage dose (Table 2-1).
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Table 2-1. Tissue Levels and Time to Peak Tissue Level in Rats Exposed to 1,2-Dichloroethane by
Gavage in Corn Oil
Organ/Peak
Concentration/Time to Peak
Concentration
Dose (mg/kg)
25 (Single)
50 (Single)
50 (11 Oral
Doses)
150 (Single)
Liver
J^g/g
30.02 ±3.29
55.00 ± 4.12
53.12 ± 3.87
92.10 ±7.58
Minutes
6
6
6
7.5
Lung
J^g/g
2.92 ±0.38
7.20 ±0.39
7.19 ± 0.59
8.31 ± 1.27
Minutes
10
20
15
20
Adipose
J^g/g
110.67 ±
6.98
148.92 ±
20.75
161.69 ±9.93
259.88 ±
25.03
Minutes
20
60
40
40
Source: (MCA. 1979)
In pregnant rats exposed to a single dose of 160 mg/kg radiolabeled [14C]-l,2-dichloroethane on
gestation day (GD) 12, the highest tissue concentrations were found in the liver and intestine after 48
hours (radiolabel was also detected in the stomach, kidney, and ovary) Pavan 5) as cited in
ATSDR (2022). Distribution across the placenta was also demonstrated by detection of the radiolabeled
1,2-dichloroethane in the developing fetus within 1 hour; the maximum concentration was detected 4
hours after exposure Pavan et; 5) as cited in ATSDR (2022). Administration of 160 mg/kg
14C-1,2-dichloroethane on GD 18 showed a greater degree of accumulation in the developing fetuses and
the placenta Pavan et al. (1995) as cited in ATSDR (2022).
No human studies on the metabolism of 1,2-dichloroethane were located via the oral route, so the
primary metabolic pathways for 1,2-dichloroethane was elucidated from in vitro studies and in vivo
studies in rats and mice that include cytochrome P450 (CYP) oxidation and glutathione (GSH)
conjugation (Figure 2-1) (IPCS. 1995). Metabolism by CYP results in an unstable gem-chlorohydrin that
releases hydrochloric acid, resulting in the formation of 2-chloroacetaldehyde. 2-Chloroacetaldehyde is
oxidized to form chloroacetic acid or reduced to form 2-chloroethanol, and these metabolites are
conjugated with GSH and excreted in the urine (IPC >). Metabolism via glutathione-S-transferase
results in formation of S-(2-chloroethyl)-glutathione, which rearranges to form a reactive episulfonium
ion. The episulfonium ion can form adducts with protein, DNA or RNA or interact further with GSH to
produce water soluble metabolites that are excreted in the urine (Figure 2-1) (IPCS. 1995). As depicted
in Figure 2-1, 1,2-dichloroethane is directly reactive and forms chloroaldehydes, which can form
persistent DNA cross-links (OECD. 2015).
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c,A/'
CytoOvoRW P 450
Gimaffuor* ¦ S tranOerasc
S-<2 -Chioroethyl glutathione
(Half-Mustard)
Ceflular
macromolecular
adducts
O NAOH
NAD*
2 -ChloroacetalcJehyde 2 -CWoroethanol
/\ /? ^ OH
c,/v C,/V
CI ~ GS ©
\
Glutathione eptsulfonium ion
OS A/
S-(2 -Hydroxyethyl >-gi utath tone
I Urine metabolites
Cellular
macromolecular
adducts
y\ SG
.A/
S-Cartxjxymethyl glutathione
o
° H NH2 O
S-Cartxwymethy4-L-cyste*iylglyane
GS
S.S4 Ethene bisgiutathione
S.S'-Ethene bis-L-cysteine
I Urine metabolites]
S-Cart>oxymethyl-L-cyste«e
Thiodiacetic aod
(thodiglycolic acid)
N-Acetyl-S-carboxymethyl-L-cysteine
Figure 2-1. Proposed Metabolic Scheme for 1,2-Dichloroethane ( PCS, 1995)
In male rats exposed to a single oral dose of 150 mg/kg 114C]-1,2-dichloroethane. 60 percent of the
administered dose was detected as urinary metabolites and 29 percent was released unchanged in
expired air, suggesting that metabolic saturation occurred at this dose (leitz et al.. 1982). Although
urinary metabolites were not characterized in this study, a decrease in hepatic non-protein sulfhydryl
content suggests that the glutathione (GSH) conjugation pathway was involved.
Animal studies were useful in demonstrating the elimination of 1,2-dichloroethane as being rapid
following oral exposure, primarily via urinary excretion of water-soluble metabolites and exhalation of
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unchanged compound or CO2 (Pavan et ai. 1995; Mi torn a et ai. 1985; Reitz et al. 1982) as cited in
ATSDR (2022). In rats given a single gavage dose of 150 mg/kg [14C]-1,2-dichloroethane, elimination
was 96 percent complete within 48 hours, with 60 percent of the radiolabel excreted as urinary
metabolites (70 percent thiodiacetic acid, 26-28 percent thiodiacetic acid sulfoxide), 29 percent exhaled
as unchanged 1,2-dichloroethane, 5 percent exhaled as CO2, and the remaining 6 percent recovered in
feces, carcass, and cage washes (Reitz et al.. 1982). The elimination kinetics were described as biphasic
with an initial elimination half-life (VA) of 90 minutes, followed by a t]A of approximately 20 to 30
minutes when blood levels were 5 to 10 |ig/mL (Reitz et al.. 1982).
In a study by Mitoma et al. (1985). rats and mice given gavage doses of 100 and 150 mg/kg [14C]-1,2-
dichloroethane, respectively, following pretreatment with unlabeled 1,2-dichloroethane 5 days/week for
4 weeks, resulted in a recovery of radiolabel in excreta (urine and feces) at 69.5 percent in rats and 81.9
percent in mice after 48 hours. Exhalation of the radiolabeled/non-radiolabeled 1,2-dichloroethane
compounds and CO2 accounted for 11.5 and 8.2 percent, respectively, in rats and 7.7 and 18.2 percent,
respectively, in mice. The recovery of radiolabel in the carcass was 7 percent of the administered dose in
rats and 2.4 percent of administered dose in mice (Mitoma et al.. 1985).
The excretion of thioglycolic acid and other thioether metabolites were measured in rat urine 24 hours
after gavage administration of 0.25, 0.5, 2.02, 4.04, or 8.08 mmol/kg (25, 50, 200, 400, or 800 mg/kg)
[14C]-1,2-dichloroethane (Pavan et al.. 1993). The total concentration of urinary metabolites increased
linearly with administered doses between 25 and 400 mg/kg; however, the percentage of the
administered dose excreted in the urine decreased with increasing dose level, likely due to metabolic
saturation and ranging from 63 to 7.4 percent (Payan et al.. 1993).
2.2 Inhalation Route
Case reports and experimental animal studies were identified that provided useful data in evaluating
absorption, distribution, metabolism, and excretion (ADME) of 1,2-dichlorethane for the inhalation
route. As 1,2-dichloroethane possesses a high vapor pressure of 79 mmHg at 20°C and a high blood/air
partition coefficient estimated to be 19.5 ± 0.7 in humans and 30.4 ± 1.2 in F344 rats the absorption of
1,2-dichloroethane may be attributed to passive diffusion across the alveolar membranes (Gargas et al..
1989). This has been demonstrated by the presence of 1,2-dichloroethane in the breast milk of nursing
women exposed to 15.6 ppm (63 mg/m3)of 1,2-dichloroethane in workplace air (with concurrent dermal
exposure) (Urusova. 1953). A fatal case report by Nouchi et al. (1984)identified a poisoning due to
exposure to 1,2-dichloroethane in an enclosed space for 30 minutes. Although the air concentrations
were not measured in this incidence, it can be inferred that the absorption of 1,2-dichloroethane occurred
rapidly thus providing support for absorption through the lungs. This rapid absorption by inhalation has
also been supported in animal studies. In studies by Reitz et al. (1982); Reitz et al. (1980) peak blood
levels approached a steady-state of 8 |j,g/mL within 1 to 2 hours after a 6 hour inhalation exposure to 150
ppm (607 mg/m3)of 1,2-dichloroethane. Furthermore, exposure to 50 ppm (202 mg/m3) of 1,2-
dichloroethane in a study by Spreafico et al. (1980) also identified similar peak blood levels. An
inhalation exposure of 250 ppm 1,2-dichloroethane in the same study by Spreafico et al. (1980) and in
Dow Chemical (2006a). however, did not reach a steady state until 3 hours post-exposure. In rats
exposed to 150 ppm (607 mg/m3) 14C-1,2-dichloroethane for 6 hours, approximately 93 percent
absorption occurred, based on recovery of radiolabel in urine and feces and as CO2 in expired air by 48
hours Reitz et al. (1982).
Distribution, based on reports in humans indicated that 1,2-dichloroethane was detected in the breath
(14.3 ppm/58 mg/m3) and breast milk (0.54-0.64 mg percent [per 100 mL]) of nursing mothers 1 hour
after leaving an occupational facility with exposure concentrations of 15.6 ppm (63 mg/m3) 1,2-
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dichloroethane LIrusova (1953) as cited in AT SDR (2022). It needs to be noted that this measurement
suggests a rapid distribution of 1,2-dichloroethane, yet these data can be attributed to prior exposures
prior to the sampling. Various animal studies have been identified that demonstrate the distribution
profile of 1,2-dichloroethane further. In a study in rats following a 6-hour inhalation exposure to 50 or
250 ppm (202 or 1011 mg/m3) 1,2-dichloroethane, it was observed that 1,2-dichloroethane was readily
distributed in various tissue in a concentration-dependent manner Spreafico et al. (1980). Additionally,
among the tissues evaluated by Spreafico et £ 0), peak tissue levels in liver and lung were lower
than concentrations in blood, but adipose tissue levels were 8 to 9 times higher than blood levels
Spreafico et al. (1980)(see Table 2-2). Furthermore, the distribution equilibrium occurred within 2 hours
and 3 hours of the 50 ppm and 250 ppm (202 and 1011 mg/m3) exposures, respectively.
Table 2-2. Tissue Levels and Time to Peak Tissue Level in Rats Exposed by Inhalation to 1,2-
Jichloroethane for 6 Hours
Organ/Peak Concentration/
Concentration (ppm)
Time to Peak Concentration
50
250
Blood
l^g/g
1.37 ±0.11
31.29 ± 1.19
Hours
6
6
Liver
l^g/g
1.14 ± 0.17
22.49 ± 1.12
Hours
4
6
Lung
l^g/g
0.42 ±0.05
14.47 ± 1.12
Hours
4
3
Adipose
l^g/g
11.08 ±0.77
273.32 ± 12.46
Hours
4
6
Source: Soreafico et al. (1980) as cited in ATSDR (2022)
A similar study in male rats exposed to 160 ppm (648 mg/m3) 1,2-dichloroethane for 6 hours showed the
highest tissue levels of 1,2-dichloroethane in abdominal fat Take et al. (2013).
As indicated in Section 2.1, due to no human studies on the metabolism of 1,2-dichloroethane being
available, the primary metabolic pathways for 1,2-dichloroethane via the inhalation route are also based
on in vitro and in vivo studies in rats and mice. Thus, the proposed metabolic pathways for the oral route
is also applicable to the inhalation route (see Figure 2-1). Additional studies also outline metabolism as
near complete in rats exposed to 150 ppm (607 mg/m3) of [14C]-1,2-dichloroethane for 6 hours, with 84
percent of radiolabel excreted as urinary metabolites and 2 percent released as unchanged compound in
expired air Reitz et 12). Urinary metabolites were not characterized; however, a decrease in the
hepatic non-protein sulfhydryl content suggest involvement of the GSH conjugation pathway. In a rat
inhalation study comparing blood concentrations resulting from exposure to 50 or 250 ppm (202 and
1011 mg/m3), peak blood levels of 1,2-dichloroethane were 22-fold higher at the higher concentration
Spreafico et al. (1980). Taken together, these results suggest that metabolic saturation occurs at a
concentration between 150 and 250 ppm (607 and 1011 mg/m3) for 1,2-dichloroethane, corresponding to
blood levels of 5 to 10 |ig/mL (Reitz et al.. 1982; Spreali-'c ^ l,}N0).
LIrusova (1953) showed that 1,2-dichloroethane was detected in expired air of women occupationally
exposed to 15.6 ppm (63 mg/m3) by inhalation. Similar findings were noted in women exposed by
dermal contact only in this study as well. In rats exposed via inhalation, elimination occurred by
excretion of metabolites in urine and exhalation of unchanged compound or CO: (Reitz et al.. 1982;
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Spreafico et ai. 1980). Following inhalation of 150 ppm (607 mg/m3) [14C]-1,2-dichloroethane for
6 hours, elimination from the blood was near complete by 48 hours, with 84 percent of the dose detected
as urinary metabolites (70 percent thiodiacetic acid, 26-28 percent thiodiacetic acid sulfoxide), 2 percent
excreted unchanged in feces, and 7 percent exhaled as CO: (Reitz et ai. 1982). The elimination kinetics
of 1,2-dichloroethane in rats were described as monophasic with t]A values of 12.7 and 22 minutes at
inhalation concentrations of 25 and 250 ppm (100 to 1011 mg/m3) 1,2-dichloroethane, respectively
(Spreafico et ai. 1980). Excretion was dose-dependent with the percentage exhaled as unchanged 1,2-
dichloroethane increased at the highest concentration; elimination from adipose tissue was slower than
elimination from blood, liver, or lungs (Spreafico et ai. 1980).
In male mice exposed to 25, 87, or 185 ppm (100, 350, or 700 mg/m3) 1,2-dichloroethane for 6 hours,
elimination was rapid, with clearance of parent compound from the blood near complete within 1 hour
after exposure (Zhong et ai. 2022). In a 28-day study in male mice also exposed to 25, 87, or 185 ppm
(100, 350, or 700 mg/m3) for 6 hours/day, 5 days/week, 2-chloroacetic acid was detected as the primary
metabolite in urine at concentrations of 300, 1,000, and 1,300 (.ig/L, respectively (Liang et ai. 2021).
2.3 Dermal Route
As no studies were located regarding distribution following dermal exposure to 1,2-dichloroethane in
animals and EPA was not able to identify neither human studies nor in vivo animal data that evaluated
metabolism of 1,2-dichloroethane following exposure by the dermal route, case reports and animal
studies did provide some useful information regarding the toxicokinetic profile of 1,2-dichloroethane via
the dermal route regarding absorption, distribution (in humans) and elimination.
In the study by LIrusova (1953). an increase in the presence of 1,2-dichloroethane was observed in the
breast milk of nursing women due to concurrent dermal and inhalation exposure within the workplace
with peak levels of 2.8 mg/100 mL within 1 hour. This observation by Uruso1 suggests that
percutaneous absorption to contaminated water or directly to the 1,2-dichlorethane may be a key route to
exposure in humans. Although the analytical methodology for this study were not provided in detail to
allow for a thorough assessment, other in vivo animal studies have demonstrated that 1,2-dichloroethane
is readily absorbed through the skin (Morgan et ai. 1991; Jakobson et ai. 1982; Tsuruta h>").
In guinea pigs dermally exposed to neat 1,2-dichloroethane, using a covered dermal cell on clipped
intact skin, blood concentrations rose rapidly during the first 30 minutes and continued to increase over
a 12-hour period (Jakobson et ai. 1982). Tsu estimated a percutaneous absorption rate of 480
nmol/minute/cm2 for 1,2-dichloroethane through the clipped, intact abdominal skin of mice following a
15-minute exposure using a closed dermal cell. Application of neat 1,2-dichloroethane to the shaved
backs of rats using covered dermal cells resulted in approximately 50 percent absorption of the applied
dose with the peak blood level measured at 24 hours (Morgan et ai. 1991). Dermal absorption was faster
and more complete for aqueous solutions of 1,2-dichloroethane, with peak blood levels measured within
1 to 2 hours and greater than 99 percent of the applied dose absorbed within the 24-hour exposure period
(Morgan et a [).
Additionally, 1,2-dichloroethane was detected in expired air of women occupationally exposed by
dermal contact only (gas masks were worn to prevent inhalation) (LIrusova. 1953).
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2.4 Parenteral Routes, In Vitro Studies, and Physiologically-Based
Pharmacokinetic (PBPK) Modeling Approach
2.4.1 Parenteral Routes
Although not identified as a key route of exposure to 1,2-dichloroethane, these studies can provide
information regarding the toxicokinetic profile. In mice administered a single intravenous injection
radiolabel 1,2-dichloroethane, high levels of radioactivity were identified in the nasal mucosa and
tracheobronchial epithelium within 1 minute of injection that continued through the 4 day observation
period of the study (Brittebo et al. 1989). Radioactivity to a lesser extent were found in the epithelia of
the upper alimentary tract, the eyelid, vagina, liver, kidney, adrenal cortex, and submaxillary salivary
gland (Brittebo et al.. 1989). The localization of the radioactivity found in the study by :ebo et al.
(19891 was considered to be of non-volatile metabolites of 1,2-dichloroethane formed within those
tissue rather than the parent chemical. In a study by Withev and Collir 3), rats that were dosed
with a single 15 mg/kg intravenous dose of 1,2-dichloroethane to investigate 1,2-dichloroethane kinetics
identified fat is the preliminary distribution site as compared to the other tissues that were evaluated
(brain, kidney, spleen, liver, lung, and heart).
2.4. 2 Studies
As mentioned earlier, due to no human studies on the metabolism of 1,2-dichloroethane being identified,
the primary metabolic pathways for 1,2-dichloroethane, were elucidated from in vitro studies and in vivo
studies in rats and mice. This section aims to focus on the in vitro studies identified to illustrate the
metabolic profile for 1,2-dichloroethane.
In vitro studies using rat and human liver microsomes have demonstrated that oxidative metabolism via
CYP2E1 results in the formation of 2-chloroacetaldehyde by dechlorination of an unstable chlorohydrin
molecule (Guengerich et al.. 1991; Casciola and Ivanetich. 1984; McCall et al.. 1983; Guengerich et al..
1980). GSH conjugation of 1,2-dichloroethane was demonstrated in primary rat hepatocytes resulting in
the formation of S-(2-hydroxyethyl) glutathione, S-(carboxymethyl) glutathione, and
S,S'-(l,2-ethanediyl)bis(glutathione), and GSH depletion was observed (Jean am ). The S-
(carboxymethyl) glutathione metabolite likely results from conjugation of 2-chloroacetic acid with GSH
(Johnson. 1967). This metabolite can be degraded to form glycine, glutamic acid, and S-
carboxymethylcysteine, which may be oxidized to yield thiodiglycolic acid (see Figure 2-1) (IPCS.
1995). Metabolic rate constants were determined using rat liver microsomes and substrate
concentrations between 50 |iM and 1 mM (Vmax = 0.24 nmol/minute per mg protein; Km = 0.14 mM)
(Salmon et al.. 1981).
In vitro studies using skin from humans, pigs, and guinea pigs have reported apparent partition
coefficients (Kp), steady-state flux (Jss) values, and lag time estimates {i.e., the time to achieve a steady-
state concentration) (see Table 2-3). In human skin, 0.1 to 0.2 percent of the applied dose was absorbed
over 24 hours, with the maximum flux occurring within 10 minutes of exposure (Gaiiar and Kasting.
2014). Evaporation from the skin surface accounted for the majority of applied dose in this study.
Specifically, it was determined that 0.21 percent of the lowest dermal administration of 7.9 mg/cm2 and
0.13 percent of the highest dose of 63.1 mg/cm2 was absorbed by the skin over a 24 hour period. The Kp
and lag time values for 1,2-dichloroethane were similar for human and guinea pig skin (Frasch and
Barbero. 2009); however, the dermal permeability rate was lower in pig skin (decreased Kp value; longer
lag time) (Schenk et al.. 2018). In guinea pig skin, the flux was lower in saturated aqueous solution
compared to the undiluted test substance (Frasch et al.. 2007). This result appears to differ from the in
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vivo study using the shaved skin of rats, which showed a higher percent absorption for an aqueous
solution of 1,2-dichloroethane compared to a neat application (Morgan et al. 1991).
Table 2-3.1,2-Dichloroethane Partition Coefficients Steady State Estimates
Partition Coefficients (K,,) Steady-State Flux (Jss) Estimates from In Vitro Dermal Absorption Studies
Species
Test
Material(s)
KP
(cm/hour)
Jss
(jig/cm2-hour)
Lag Time
(minutes)
Reference
Human
Neat
ND
37-193°
ND
Gajjar and Kastine (2014)
Human
Guinea pig
Neat
Neat
0.259
0.259
ND
ND
6
6
Frascfa and Barbero (2009)
Pig
Neat
1.9E-03
1,360
30.7
Schenk et al. (2018)
Guinea pig
Neat
Aqueous
ND
ND
6,280fe
1,076
ND
ND
Frascfa et al. (2007)
a Range of Jss values for applied doses of 7.9, 15.8, 31.5, or 63.1 mg/cm2.
b Also reported a Jss value of 3,842 ng/cm2-hour from a different laboratory.
ND = not derived
Tissue:air partition coefficients calculated using a vial equilibration method and tissues obtained from
male Fischer 344 rats suggest that 1,2-dichloroethane is preferentially distributed to highly perfused
tissues and will accumulate in fat (see Table 2-4) (Dow Chemical. 2006a; Gareas and Andersen. 1989).
Table 2-4.1,2-Dichloroethane Tissue:Air Partition Coefficients
Partition Coefficient
Blood:Air
Liver:Air
Muscle:Air
Fat:Air
Brain:Air
Kidney:Air
Testis:Air
Ovary:Air
30.4 ± 1.2"
35.7 ± 1.6a
23.4 ± 1.4a
344 ± 5fl
39.5 ± 2.89fe
44.89 ±6.77fe
31.14 ± 7.98fe
74.59 ±9.82fe
a Gareas and Andersen (1989).
b Dow Chemical (2006a).
2.4.3 Physiologically-Based Pharmacokinetic (PBPK) Modeling Approach
Two PBPK models were developed to describe the disposition of 1,2-dichloroethane. The D'Souza et al.
(1988); D'Souza et; 7)model used five compartments (lung, liver, richly perfused tissues, slowly
perfused tissues, and fat) and assumed that metabolism occurs only in the liver and lung. Metabolic
pathways included a saturable oxidation pathway and GSH conjugation. This PBPK model, which was
validated in rats and mice, predicted that inhalation produces less GSH-conjugate metabolites (measured
as GSH depletion in the liver) than gavage exposure.
Sweeney et al. (2008)extended and updated the D'Souza et .i. > s 18); D'Souza et s87) model by
adding two gastrointestinal compartments, a compartment for the kidney, and an additional metabolism
pathway for extrahepatic enzymes. Model parameter values that were revised included the oral
absorption rate, time delay constant for GSH synthesis following depletion, and GSH levels in liver and
lung tissue. Model predictions were compared to experimental rat data for intravenous, oral, and
inhalation routes, and the model performed well for single and repeated exposure. Because the model
has not been validated in humans, it is unclear whether this model would be useful for extrapolating
between rats and humans (ATSDR. 2022).
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2.5 Summary
Toxicokinetic data indicates that orally administered 1,2-dichloroethane is rapidly metabolized in the
body with the primary metabolic pathways mediated by cytochrome P450 and glutathione conjugation.
Upon absorption via the oral and inhalation routes, 1,2-dichloroethane is readily distributed to various
tissues, including breast milk, with the highest concentrations found in adipose tissue. Tissue
distribution patterns of 1,2-dichloroethane revealed that absorption from the gastrointestinal tract is
rapid with peak steady-state blood concentrations within one hour after oral exposure, 2-3 hours after
inhalation exposure and 1-2 hours after dermal exposure (for aqueous solutions).
Metabolites of 1,2-dichloroethane via inhalation are rapidly excreted as illustrated by animal studies
with almost complete elimination within 48 hours post-exposure primarily in urine in the form of the
metabolites thiodiglycolic acid and thiodiglycolic acid sulfoxide (84 percent) and to a lesser extent in
feces and expired air (7 percent as CO2). Specifically for oral exposure, 1,2-dichloroethane is excreted
via the urine and feces, however, a large percent (29 percent) is excreted unchanged in expired air.
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3 NON-CANCER HAZARD IDENTIFICATION AND EVIDENCE
INTEGRATION
The sections below describe adverse outcome and mechanistic data available as well as evidence
integration conclusions for each human health hazard outcome observed in 1,2-dichloroethane toxicity
studies. EPA identified very few epidemiological studies relevant to non-cancer endpoints. Therefore,
evidence is primarily based on available laboratory animal toxicity studies—exclusively via the oral and
inhalation routes.
The 2021 Draft Systematic Review Protocol ( 21) describes the general process of evidence
evaluation and integration, with relevant updates to the process presented in the 1,2-Dichloroethane
Systematic Review Protocol ( 2024b). Section 3.1 provides a detailed evaluation of the 1,2-
dichloroethane hazard outcomes and evidence integration conclusions. The analyses are presented as a
series of evidence integration tables in Appendix B for 1,2-dichloroethane (non-cancer) and Appendix C
for 1,2-dichloroethane (cancer).
3.1 Critical Human Health Hazard Outcomes
The sections below focus on hazard identification and evidence integration of kidney toxicity,
immunotoxicity, and neurotoxicity, which are the most sensitive critical human health hazard outcomes
associated with 1,2-dichloroethane. These hazard outcome categories received likely evidence
integration conclusions, and sensitive health effects were identified for these hazard outcomes. In the
risk evaluation, renal toxicity forms the basis of the POD used for acute oral exposure scenarios and
immunotoxicity is the basis of the POD used for short-term and chronic oral exposure scenarios. The
2022 ATSDR document for 1,2-dichloroethane confirmed that immunotoxicity is the most sensitive
endpoint (ATSDR. 2022). Neurotoxicity is the basis of the POD used for acute inhalation exposure and
reproductive effects is the basis for short-term/sub chronic and chronic inhalation exposure scenarios.
Due to a lack of adequate dermal studies, dermal hazard was based on route-to-route extrapolation from
oral exposure. Additionally, hazard identification and evidence integration of other toxicity outcomes
are also outlined to emphasize the integration of the identified health outcomes of 1,2-dichloroethane.
3.1.1 Renal Toxicity
Humans
EPA did not identify epidemiological studies that evaluated any potential renal hazards for 1,2-
dichloroethane.
Laboratory Animals
A review of high and medium quality acute, subchronic, and chronic studies identified studies that
indicated renal effects following 1,2-dichloroethane exposure.
Oral
B6C3F1. mice in the Storer et t 4) study that were administered a single oral gavage dose of 1,2-
dichloroethane at 0, 100, 200, 300, 400, 500, or 600 mg/kg-bw resulted in kidney weights increased at
300 mg/kg-bw doses and greater. In support, L-iditol dehydrogenase (IDH, 9-fold increase) and blood
urea nitrogen (BUN) indicated a trend increase at 200 mg/kg-bw and greater doses but was not
statistically significant due to the low number of animals tested (N = 5).
In the Morel et t 9) acute single exposure oral gavage study in male Swiss OF 1 mice treated with
0, 1,000, or 1,500 mg/kg-bw of 1,2-dichloroethane, a significant increase in damaged renal tubules (7.66
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vs. 0.32 percent in controls) was seen only seen in the highest dose group with the lowest dose already
above the limit dose.
In the subchronic 90 day (7 day/week for 13 weeks) oral gavage study by Daniel -n A male and
female Sprague-Dawley rats treated with 0, 37.5, 75, or 150 mg/kg-bw/day of 1,2-dichloroethane
resulted in increased relative kidney weights in both males and females (18 and 15 percent higher than
controls, respectively) at the 75 and 150 mg/kg-bw/day.
The subchronic 90-day oral gavage study in Wistar rats by van Esch et al. (1977) dosed at 0, 10, 30 or
90 mg/kg-bw/day of 1,2-dichloroethane resulted in a significant increase in relative kidney weight of 17
and 16 percent higher than controls in males and females in the 90 mg/kg-bw/day, respectively.
In the subchronic study by x oral gavage of 1,2-dichloroethane at the dosages of 0, 30, 60,
120, 240 or 480 mg/kg-bw/day for 13 weeks in male F344 rats, resulted in significant increases in
absolute kidney weights at 30, 60, and 120 mg/kg/day ( 9, 21 and 25 percent, respectively) and
significant increases in relative kidney weights at 60 and 120 mg/kg-bw/day doses (15 and 26 percent,
respectively). Female F344 rats dosed at 0, 18, 37, 75, 150, or 300 mg/kg/day at 5 days/week via oral
gavage for 13 weeks caused significant increases in absolute kidney weights (12 and 23 percent) and
relative kidney weights (10 and 21 percent) at 75 and 150 mg/kg-bw/day, respectively.
Inhalation
StorerciM i l°S4) identified increased serum BUN (85 percent) and relative kidney weight (12 percent)
in B6C3F1 male mice as compared to controls after a 4 hour exposure to 1,2-dichloroethnae vapor of
499 ppm (2,020 mg/m3). Increased mortality at concentrations greater than 499 ppm precluded a more
thorough evaluation of these effects in this study and subsequent dose-response analysis.
Mechanistic
EPA did not identify mechanistic studies that evaluated any potential renal hazards for 1,2-
dichloroethane.
Evidence Integration Summary
There were no human epidemiological nor mechanistic studies available for 1,2-dichlorethane and
therefore, there is indeterminate human evidence and mechanistic support to assess whether 1,2-
dichloroethane can cause renal changes in humans. The evidence in animal studies for 1,2-
dichloroethane is moderate based on several high- and medium-quality studies that found associations
between 1,2-dichloroethane exposure and increased kidney weights, BUN, and/or renal tubular
histopathology in rats (both sexes) and mice following inhalation, oral, dermal, and intraperitoneal
injection exposures.
Overall, EPA concluded that evidence indicates that 1,2-dichloroethane likely causes renal effects under
relevant exposure circumstances.
3,1.2 Immunological/Hematological
Humans
EPA did not identify epidemiological studies that evaluated any potential immunological/hematological
hazards for 1,2-dichloroethane.
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Laboratory Animals
A review of high- and medium-quality acute, subchronic, and chronic studies identified studies that
indicated immunological/hematological effects following 1,2-dichloroethane exposure.
Oral
Munson et al. (1982)—a study in male CD-I mice administered 1,2-dichloroethane by oral gavage for
14 days at doses of 0, 4.9, and 49 mg/kg-bw/day—resulted in decreased antibody-forming cells with
immunosuppression at adverse 25 and 40 percent levels at the 4.9 and 49 mg/kg-bw/day dose groups,
respectively. Suppression of cell-mediated immune responses were also indicated at both dosages. A
decrease in leukocytes at approximately 30 percent was reported in the highest dosage group. No effects
were observed regarding the organ weights of the liver, spleen, lungs, thymus, kidney, or brain.
Additionally, hepatic clinical chemistry also remained unchanged. It is important to note that the
ATSDR (2022) document concluded that the immune system was the most sensitive target, but it also
considered this 14-day study in the acute duration category, so it was not utilized for the subchronic or
chronic PODs.
Inhalation
In the study by Sherwood et al. (1987). female CD-I mice exposed to 1,2 dichloroethane for 3 hours at
5.4 ppm (22 mg/m3) resulted in mortality following streptococcal challenge but it is important to note
that the inoculation with the bacteria was unlikely representative of a human equivalent immunological
challenge. Male SD rats in the same study did not exhibit any effects to the streptococcal immunological
challenge after exposures up to 200 ppm (801 mg/m3). In addition, in Sherwood et al. (19871 identified
no effects in female CD-I mice or male SD rats due to streptococcal challenge after 1,2-dichloroethane
inhalation exposure for 5 or 12 days in the mice or rats, respectively.
Mechanistic
EPA identified mechanistic studies that indicated potential immunological/hematological hazards for
1,2-dichloroethane. Immunosuppression is a recognized characteristic of carcinogens and tumors were
reported for 1,2-dichloroethane in various studies. An in vitro study utilizing human Jurkat immune T
cells indicated cytotoxicity by 1,2-dichloroethane and other similar chlorinated solvents such as
trichloroethylene, perchloroethylene and dichloromethane McDermott and Heffron ( . Human
Jurkat T cell death at 5 and 10 percent responses occurred at concentrations of 157 and 379 micromolar,
respectively. Importantly, these 1,2-dichloroethane cytotoxic concentrations are similar to milk levels in
female workers {i.e., 283 micromolar) and blood levels in rats {i.e., 1.36 mM), both via dermal
exposures ( DR. 2022); McDermott and Heffron (2013). That study also reported increases in
reactive oxygen species and increased cellular calcium levels by 1,2-dichloroethane and other similar
chlorinated solvents such as trichloroethylene, perchloroethylene and dichloromethane. Cell death
caused by 1,2-dichloroethane and the other similar chlorinated solvents trichloroethylene,
perchloroethylene and dichloromethane was, however, inhibited by the antioxidant N-acetylcysteine.
Additionally, 1,2-dichloroethane possessing immunological/hematological effects is demonstrated in an
in vitro study that identified reduced phagocytic activity of mouse peritoneal macrophages to 76 percent
of control levels at a concentration of 200 mM (Utsumi et ai h">l>2). Cell-free and in vitro studies that
investigated 1,2-dichloroethane effects on human erythrocyte glutathione-S-transferase (GST) by
(Ansari et al.. 1987) resulted in dose-related reductions in the GST enzymatic activity.
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Evidence Integration Summary
There were no human epidemiological studies available for 1,2-dichloroethane and therefore, there is
indeterminate human evidence to assess whether 1,2-dichloroethane may cause immunological/
hematological changes in humans. Limited mechanistic evidence based on in vitro data that showed
reductions in macrophage phagocytic activity and erythrocyte GST activity after exposure to 1,2-
dichloroethane was also considered to be indeterminate.
Available toxicological studies based on high-quality inhalation and gavage studies of immune function
in mice indicated an association between 1,2-dichloroethane exposure and immunosuppression was
observed. A more limited inhalation study in rats and a longer-term drinking water study in mice that
was rated uninformative did not show any effects. Evidence from other studies showed only small
effects on hematology and no effects on relevant organ weights or histopathology. Based on this
information, evidence based on animal studies for 1,2-dichloroethane, suggests the immunological/
hematological effects as slight.
Overall, EPA concluded that robust weight of scientific evidence (WOSE) information indicates that
1,2-dichloroethane likely causes immune system suppression under relevant exposure conditions to both
animals and humans. This conclusion is supported by multiple lines of evidence such as the cytotoxicity
to human Jurkat T cells in vitro at relevant human tissue levels, the cell mediated immunosuppression in
mice at the lowest-observable-adverse-effect level (LOAEL) of 4.89 mg/kg/day, decreased leukocytes
count in mice. In support, the 1,2-dichloroethane AT SDR (2022) authoritative document concluded that
"the immune system was the most sensitive target for short-term exposure to 1,2-dichloroethane by both
the inhalation and oral routes in mice."
3.1.3 N eurological/Behavioral
Humans
Chlorinated aliphatic solvents are known to cause central nervous system depression, and respiratory
tract and dermal irritation in humans (ATSDR. 2015). Case reports of human exposure to 1,2-
dichloroethane by inhalation or ingestion indicated clinical signs of neurotoxicity (dizziness, tremors,
paralysis, coma) as well as histopathology changes in the brain at autopsy (ATSDR. 2022). Workers
exposed to 1,2-dichloroethane for extended periods were shown to develop cerebral edema and toxic
encephalopathy (ATSDR. 2022). A single study of Russian aircraft manufacturing workers noted
decreased visual-motor reaction and decreased upper extremity motor function, as well as increased
reaction making errors in workers exposed to 1,2-dichloroethane compared to those that were not,
however the results were only described qualitatively and no statistical analyses were conducted, and the
study was determined to be uninformative by systematic review (Kozik. 1957).
Laboratory Animals
A review of high and medium quality acute, subchronic, and chronic studies identified studies that
indicated neurological/behavioral effects following 1,2-dichloroethane exposure.
Oral
Male and female F344/N rats in the (NTP. 1991) study administered 1,2-dichloroethane at dosages of 0,
30, 60, 120, 240, or 480 mg/kg/day (males) and 0, 18, 37, 75, 150, or 300 mg/kg/day (females) in corn
oil via gavage, 5 days/week for 13 weeks in the resulted in death in all males in the 240 and 480
mg/kg/day groups and 9/10 of the females in the 300 mg/kg/day group, respectively, with the identified
presence of necrosis in the cerebellum at the highest dose group. In addition, clinical signs observed in
the 240 and 300 mg/kg/day groups of male and female rats included tremors and abnormal posture.
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Inhalation
Male SD rats exposed to 1.5 hours of 1,2-dichloroethane in Zhou et al. (2016) were shown to develop
histological changes in the brain as denoted by edema at 975.9 ppm (3,950 mg/m3).
Neurotoxicity and histological changes in the brains of SD rats exposed to 1,2-dichloroethane for 12
hours was seen in a study by Oin-li et al. (2010) at a LOAEL of 5,000 mg/m3 as indicated by abnormal
behavior and edema, however, details regarding the histological severity of edema were not provided.
In the acute Dow Chemical (2006b) inhalation study, histological changes and injury were identified in
the olfactory mucosa of F344/DUCRL rats exposed for 4 or 8 hours to 1,2-dichlorethane vapor at 100
and 200 ppm (405 and 809 mg/m3), respectively. The effect on the olfactory mucosa is also considered
neurological as this tissue is neuroepithelial in nature.
Mechanistic
EPA identified mechanistic studies that suggest 1,2-dichloroethane can result in brain edema due to a
downregulation of tight junction proteins (occludin and ZO-1) and mRNA, increase of free calcium,
decreased ATP content, and decrease ATPase activity in the brains of mice after an exposure of to 296
ppm (1,200 mg/m3) for 3.5 hours/day for 3 days (Wane et al.. 2018a; Wane et al.. 2014).
Evidence Integration Summary
Case reports document clinical signs of neurotoxicity and brain histopathology changes in humans
exposed to 1,2-dichloroethane by inhalation or ingestion as well as the ability of 1,2-dichloroethane to
downregulate tight junction proteins and energy production while also upregulating aquaporin and
matrix metalloproteinase in the brains of exposed mice. Based on these human epidemiological and
mechanistic data available for 1,2-dichloroethane, the evidence is slight for an association between 1,2-
dichloroethane and adverse neurological effects. Several high- and medium-quality studies using rats
exposed to 1,2-dichloroethane by inhalation or gavage or mice exposed by intraperitoneal injection
showed the occurrence of neurobehavioral changes, clinical signs of neurotoxicity, or changes in brain
histopathology. Therefore, EPA determined that the animal evidence for adverse neurological/behavioral
effects based on these data are moderate for the association between 1,2-dichloroethane and adverse
neurological/behavioral effects.
Overall, EPA concluded that evidence indicates that to 1,2-dichloroethane likely causes neurological/
behavioral effects under relevant exposure circumstances.
3,1.4 Reproductive/Developmental
Humans
EPA did not locate adequate human epidemiology studies for 1,2-dichloroethane that could be utilized
for a non-cancer dose response analysis and the overall non-cancer, 1,2-dichloroethane epidemiology
literature is considered indeterminate for non-cancer health effects. The Brender et al. (2 study
found associations between any exposure to 1,2-dichloroethane and neural tube defects and spina bifida;
however, exposure was estimated based on maternal residential proximity to industrial point sources of
emissions rather than using a measured level of exposure. Additionally, two studies of 1,2-
dichloroethane presence in drinking water and congenital anomalies found a relationship between 1,2-
dichloroethane detection and major cardiac defects in newborns, but the same relationship was not
significant when comparing odds of major cardiac defects between newborns with 1,2-dichloroethane
water concentrations above 1 ppb vs. equal to or below 1 ppb (Bo\ c I Bove et al.. 1995).
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Laboratory Animals
A review of high and medium quality acute, subchronic, and chronic studies identified studies that
indicated reproductive/developmental effects following 1,2-dichloroethane exposure.
Oral
Sprague-Dawley dams that were administered 1,2-dichloroethane by gavage at doses of 0, 1.2, 1.6, 2.0,
and 2.4 mmol/kg (corresponding to 0, 120, 160, 200, and 240 mg/kg-bw/day in the Pavan et al. (1995)
study during gestation day (GD) 6 to GD 21 resulted in increases in non-implantations and resorptions.
The increases in non-implants and resorptions are difficult to interpret given the significant maternal
toxicity (decreases in maternal body weight gain) observed at corresponding doses (30 and 49 percent at
200 and 240 mg/kg/day, respectively), and because there was no effect on the number of live fetuses per
litter despite changes in non-surviving implants/litter and resorption sites/litter.
Inhalation
Rao et al. (1980). a reproductive/developmental study in pregnant SD rats exposed to 1,2-dichloroethane
vapor at 0, 100, or 300 ppm (0, 405, 1214 mg/m3) or during GD 6 to 15, identified a significant decrease
in bilobed thoracic centra incidences. However, due to increased incidence in maternal mortality a dose-
response evaluation could not be performed on this effect. Additionally, a multi-generational evaluation
by Rao et al. (1980) also identified decreased body weight of F1B male weanlings as a result of
exposure to 150 ppm (613 mg/m3) for 6 hours/day for 7 weeks in utero.
Exposure to pregnant SD rats to 1,2-dichloroethane in Pavan et al. (1995) indicated a significant
decrease in pregnancy rate at 250 ppm (1,000 mg/m3); however, this effect was not seen at the highest
concentration of 300 ppm (1,200 mg/m3).
Zhang et al. (2017). a reproductive study that evaluated the effects of 1,2-dichloroethane on male Swiss
mice following a 4-week exposure period, resulted in changes in sperm morphology and concentration
along with decreased seminiferous tubules and the height of germinal epithelium at 25 ppm (102
mg/m3).
Mechanistic
Male mice treated with 86 ppm or 173 ppm (350 or 700 mg/m3) of 1,2-dichlorethane for 4 weeks
resulted in an inhibition of the cyclic adenosine monophosphate (cAMP)-response element binding
(CREB) protein and the cAMP-response element modulator (CREM), subsequently inducing apoptosis,
and resulting in reproductive toxicity in male mice as indicated by a decrease in sperm concentration of
greater than 25 percent (4.65 ± 0.52 vs. 3.30 ± 0.57 M/g) in the control vs. 700 mg/m3 treated animals,
respectively (Zhane et al.. 1 ).
Evidence Integration Summary
In high- and medium-quality studies, associations were observed between 1,2-dichloroethane exposure
and various birth defects (neural tube defects including spina bifida and heart defects of different types).
However, the effect sizes were small with associations that were weak and, in some cases, based on very
low group sizes. Results of the two available epidemiological studies were also not consistent (neural
tube defects/spina bifida in one study but not the other; different types of cardiac defects in the two
studies) and both studies were limited in various ways, including incomplete data on neural tube defects,
potential exposure misclassification, questionable temporality, and co-exposures to other chemicals that
were also associated with the same defects. Based on these evaluations, the evidence of reproductive/
developmental effects due to 1,2-dichloroethane was considered indeterminate for these effects.
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In high-quality studies, mice exposed to 1,2-dichloroethane by inhalation or intraperitoneal injection, but
not by drinking water, exhibited effects on testicular pathology and sperm parameters. Most of the data
in rats indicated no effect on the testes (or other reproductive organs); however, sperm parameters were
not evaluated in rats. Thus, the evidence for effects on the male reproductive tract was considered
moderate. Evidence was considered moderate based on inhalation studies in rats, oral studies in rats and
mice, and a dermal study in mice that all indicated no effects of 1,2-dichloroethane on female
reproductive organ weights or histopathology. With regard to developmental effects, a high-quality
study on 1,2-dichlorethane indicated sterility in male mice exposed by intraperitoneal injection. In
addition, evidence for effects on weanling pup body weight after 1,2-dchloroethane inhalation exposure
was considered weak and inconsistent. Thus, evidence was considered slight for developmental effects
due to 1,2-dichloroethane.
Mechanistic evidence for reproductive/developmental effects based on inhibition of CREM/CREB
signaling and the occurrence of apoptosis in testes of male mice exposed to 1,2-dichloroethane in vivo to
support observed effects on testes pathology, sperm morphology, and fertility in this species was
considered moderate.
Overall, EPA concluded that the evidence indicates that 1,2-dichloroethane likely causes effects on male
reproductive structure and/or function under relevant exposure conditions. The nature of the effect
chosen for calculating risks—changes in sperm morphology and concentration identified by Zhang et al.
(2 —is considered adverse, and the fertility of human males is known to be sensitive to changes in
sperm numbers and quality ( ). The evidence is, however, inadequate to determine
whether 1,2-dichloroethane may cause effects on the developing organism and there is no evidence that
1,2-dichloroethane causes effects on female reproductive structure and/or function.
3.1.5 Hepatic
Humans
A single study of liver damage markers in the blood of vinyl chloride workers showed abnormal levels
of aspartate aminotransferase (AST) and alanine transaminase (ALT) in the moderate 1,2-dichloroethane
exposure intensity group compared with the low 1,2-dichloroethane exposure intensity group; however,
all participants were also exposed to low levels of vinyl chloride monomer, which may also affect liver
enzyme levels (Cheng et al.. 1999).
Laboratory Animals
A review of high and medium quality acute, subchronic, and chronic studies identified studies that
indicated hepatic effects following 1,2-dichloroethane exposure.
Oral
In Cottalasso et al. (2002). a single gavage of 628 mg/kg-bw of 1,2-dichloroethane in female SD rats
after 16 hours of fasting resulted in increased ALT, AST, and lactate dehydrogenase (LDH) at 45, 44,
and 67 percent as compared to controls, respectively. Histological examination also identified moderate
steatosis.
In the 10-day oral gavage study by Daniel et al. (1994). male and female SD rats administered 0, 10, 30,
100, or 300 mg/kg-bw/day of 1,2-dichloroethane exhibited significantly increased relative liver weights
(14 percent relative to controls) and serum cholesterol levels in male rats alone at 100 mg/kg-bw/day.
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The short-term, 10-day oral gavage study in Wistar rats by van Esch e dosed at 0, 3, 10, 30,
100, or 300 mg/kg-bw/day 1,2-dichloroethane resulted in death of all animals in the 300 mg/kg-bw/day,
which upon subsequent histological evaluation showed extensive liver vacuolization and lipid droplets.
In the subchronic, 90-day (7 day/week for 13 weeks) oral gavage study by Daniel et al. (1994). male and
female SD rats treated with 0, 37.5, 75, or 150 mg/kg-bw/day of 1,2-dichloroethane resulted in a 20
percent increase in relative liver weights in only male rats at 75 mg/kg-bw/day.
The subchronic, 90-day oral gavage study in male Wistar rats by van Esch et al. (1977) dosed at 0, 10,
30, 90 mg/kg-bw/day resulted in a significantly increase in relative liver weight of 13 percent higher
than controls in females at the highest dose. However, this change was not accompanied by any changes
in serum enzymes or liver histopathology.
Inhalation
Exposure to 1,2-dichloroethane for 4 hours at 499 ppm (2,020 mg/m3) via inhalation in Storer et al.
(1984) identified increased serum ALT (2-fold) and SDH (1 1-fold) in B6C3F1 male mice as compared
to controls.
Absolute and relative liver weights in male Swiss mice at greater than or equal to 10 percent as
compared to controls was indicated in a 6 hours/day for 28 days study by Zeng et al. (2018) at a
concentration of 89.83 ppm (364 mg/m3) of 1,2-dichloroethane.
IRFJv 78). in a chronic 12-month study in both male and female SD rats, resulted in an increase of
ALT and LDH in both sexes when exposed to 50 ppm (200 mg/m3) of 1,2-dichloroethane.
Mechanistic
In the study by Storer et al. (1984), B6C3F1. mice were administered a single dose of 1,2-dichloroethane
at 100, 200, 300, or 400 mg/kg via oral gavage in corn oil or to 100, 150, 200, or 300 mg/kg by
intraperitoneal injection and euthanized 4 hours later. It was identified that a statistically significant
increase in DNA damage in hepatic nuclei was present in all dose groups via oral administration and at
doses greater or equal to 150 mg/kg via intraperitoneal injection, as characterized by single-strand
breaks, when compared to controls.
Evidence Integration Summary
There were no adequate human epidemiological studies available for 1,2-dichloroethane; therefore, there
is indeterminate human evidence to assess whether 1,2-dichloroethane may cause hepatic changes in
humans. The only human epidemiological study was considered inadequate due to confounding
associated with co-exposure to vinyl chloride. Limited in vitro data indicate that 1,2-dichloroethane may
increase DNA damage, cause oxidative stress, or impair glucose and/or lipid metabolism in mice and in
rat hepatocytes and liver slices; however, this information suggests that overall mechanistic evidence for
hepatic effects is indeterminate. Several high- and medium-quality studies in rats and mice found
associations between 1,2-dichloroethane exposure and increased liver weights, serum enzymes, or
histopathology changes following inhalation, oral, and intraperitoneal injection exposures. Based on
these studies, EPA determined that the animal evidence for adverse effects on the liver are moderate for
the association between 1,2-dichloroethane and adverse hepatic effects.
Overall, EPA concluded that evidence suggests, but is not sufficient to conclude, 1,2-dichloroethane can
cause hepatic toxicity under relevant exposure circumstances.
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3.1.6 Nutritional/Metabolic
Humans
EPA did not identify epidemiological studies that evaluated any potential nutritional/metabolic hazards
for 1,2-dichloroethane.
Laboratory Animals
A review of high- and medium-quality acute, subchronic, and chronic studies identified studies that
indicated nutritional/metabolic effects following 1,2-dichloroethane exposure.
Oral
In the study by Pavan et al. (1995). pregnant SD rats exposed to 1,2-dichloroethane via oral gavage
exhibited a decrease in absolute maternal body weight during GD 6 to 21 relative to controls. The short-
term NTP (1978). preliminary, dose-range finding study in male and female Osborne-Mendel rats
gavaged with 0, 40, 63, 100, 150 or 251 mg/kg-bw/day of 1,2-dichloroethane for 5 days/week for 6
weeks suggested body weight effects during exposure. However, due to the lack of quantitative data
provided in the study report, a thorough evaluation of the data could not be performed.
Inhalation
Male and female albino guinea pigs were exposed, whole body, to 1,2-dichloroethane vapor
concentrations of 100, 200, and 400 ppm (405, 809, or 1619 mg/m3) for 246 days (at 200 ppm/809
mg/m3) and up to 212 days (at 100 ppm/405 mg/m3) by (Spencer et al.. 1951) that demonstrated,
statistically significant reductions in final body weights were observed in males (16 percent) and females
(9 percent), compared with air-only controls at 200 ppm (809 mg/m3).
Mechanistic
EPA did not identify mechanistic studies that evaluated any potential nutritional/metabolic hazards for
1,2-dichloroethane.
Evidence Integration Summary
Because there were no human epidemiological or mechanistic studies available for 1,2-dichloroethane,
there is indeterminate human evidence and mechanistic support to assess whether 1,2-dichloroethane
can cause nutritional/metabolic changes in humans. The evidence is considered slight for animal studies
for 1,2-dichloroethane based on decreased body weight as reported in mice and guinea pigs exposed by
inhalation and rats and mice exposed orally to 1,2-dichloroethane in high- and medium-quality studies.
In addition, several high- and medium-quality studies in a few species via various routes of exposure
reported no effect on body weight, sometimes at lower exposure levels or shorter exposure durations to
1,2-dichloroethane.
Overall, EPA concluded that 1,2-dichloroethane may cause nutritional/ metabolic effects under relevant
exposure conditions.
3.1.7 Respiratory
Humans
EPA did not identify epidemiological studies that evaluated any potential respiratory hazards for 1,2-
dichloroethane.
Laboratory Animals
A review of high- and medium-quality acute, subchronic, and chronic studies identified that demonstrate
respiratory effects following 1,2-dichloroethane exposure.
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Oral
In the study by Salovsky et al. (2002). a single oral dose of 136 mg/kg-bw 1,2-dichloroethane in male
Wistar rats resulted in increased total number of cells in the bronchioalveolar lavage fluid (BALF) at 30
days after dosing. Non-inflammatory histological changes such as cyanosis, interstitial edema, vacuolar
changes, desquamative changes, atelectasis, and alveolar macrophage proliferation were also seen in the
lungs. Inflammatory histological such as macrophage proliferation that was mixed with a small number
of neutrophils and eosinophils) occurred in the peribronchial (mild degree on GD 5 and mild-moderate
on GDs 15 and 30), interstitial (mild-moderate on GDs 5 and 30 and moderate on GD 15), and
interbronchial (mild on GD 1 and mild-moderate on GD 5) regions. These histological data were only
presented qualitatively.
Inhalation
In the acute Dow Chemical (2006b) inhalation study, histological changes and injury were identified in
the olfactory mucosa of F344/DUCRL rats exposed for 4 or 8 hours to 1,2-dichloroethane vapor at 100
and 200 ppm (405 and 809 mg/m3), respectively.
Mechanistic
EPA did not identify mechanistic studies that evaluated any potential respiratory hazards for 1,2-
dichloroethane.
Evidence Integration Summary
Because there no human epidemiological or mechanistic studies are available for 1,2-dichloroethane,
there is indeterminate human evidence and mechanistic support to assess whether 1,2-dichloroethane
can cause respiratory tract changes in humans. In a high-quality study, an association between 1,2-
dichloroethane inhalation exposure and nasal lesions was observed in rats exposed to concentrations
greater or equal to 435 mg/m3 (>107.5 ppm). Although one medium-quality study reported lung lesions
in rats after a single gavage dose, high- and medium- quality studies of longer duration and higher doses,
as well as a high-quality study of acute inhalation exposure, did not show effects of 1,2-dichloroethane
on lower respiratory tract tissues of rats. Based on this, evidence from animal studies was considered
slight to moderate.
Overall, EPA concluded that the evidence suggests, but is not sufficient to conclude, that 1,2-
dichloroethane can cause lower respiratory tract effects under relevant exposure conditions.
3.1.8 Mortality
Humans
EPA identified two limited retrospective cohort studies that found no increase in mortality of workers
from either petrochemical or herbicide manufacturing plants with presumed exposure to 1,2-
dichloroethane relative to the general United States population (BASF. 2005; Teta et al.. 1991).
Laboratory Animals
A review of high-and medium-quality acute, subchronic, and chronic studies identified studies that
indicated mortality following 1,2-dichloroethane exposure.
Oral
The short-term, 10 day oral gavage study in male Wistar rats by van Esch dosed at 0, 3, 10,
30, 100, or 300 mg/kg-bw/day 1,2-dichloroethane resulted in death of all animals in the 300 mg/kg-
bw/day exposure group.
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Inhalation
In the study by Francovitch et al. (1986). male CD-I mice treated with 1,2-dichloroethane for 4 hours
via inhalation resulted in a dose-related increase in mortality beginning at a concentration of 1,000 ppm
(4,050 mg/m3).
Male SD rats exposed via inhalation to 1,2-dichloroethane for 7 hours/day for 5 days/weeks resulted in
the occurrence of mortality starting at 304 ppm (1,230 mg/m3) (lewe et al.. 1986b).
Female SD rats exposed to 300 ppm (1,210 mg/m3) 1,2-dichloroethane resulted in increased incidences
in mortality in dams when exposed for 10 days during GDs 6 to 15 (Rao et al.. 1980). Additionally, in
Rao et al. (1980). New Zealand white rabbits treated with 1,2-dichloroethane for 7 hours/day during the
13 days of GD 6 to 18 also showed increased incidences of maternal mortality beginning at the exposure
concentration of 100 ppm (405 mg/m3).
In the study by Pavan et al. (1995). female SD rats treated with 1,2-dichloroethane resulted in increased
incidence of maternal death at a LOAEL of 329 ppm (1,330 mg/m3).
Mechanistic
EPA did not identify mechanistic studies that evaluated any potential mortality hazards for 1,2-
dichloroethane.
Evidence Integration Summary
Limited epidemiological data show no increase in mortality among workers with presumed exposure to
1,2-dichloroethane but are insufficient to draw any broader conclusions. Therefore, there is
indeterminate human evidence to assess whether 1,2-dichloroethane may cause mortality in humans.
Because there are no mechanistic studies available for 1,2-dichloroethane, there is indeterminate
mechanistic support to assess whether 1,2-dichloroethane may cause mortality in humans. The evidence
is considered robust with regard to animal studies of 1,2-dichloroethane as treatment-related increases in
the incidence of mortality were observed in several animal species exposed to 1,2-dichloroethane via
inhalation, oral, or dermal exposure for acute, short-term/intermediate, or chronic durations in multiple
studies.
Overall, EPA concluded that the evidence indicates that 1,2-dichloroethane may cause death under
relevant exposure circumstances and lethal levels have been identified in animal studies.
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4 GENOTOXICITY HAZARD IDENTIFICATION AND EVIDENCE
INTEGRATION
1,2-Dichloroethane is considered a "probable human carcinogen" ( 37b) based on evidence
of tumorigenicity in animal studies, including significant increases in tumors of the mammary gland
(robust evidence), lung (moderate evidence), liver (slight-to-moderate evidence), circulatory system
(slight evidence) and other tissues (indeterminate evidence) in male and/or female rats and/or mice by
oral, inhalation, and/or dermal exposure (see Appendix C). The occurrence of tumors in multiple tissues
and treated groups is suggestive of a genotoxic mode of action, and most data relating to mode of action
for 1,2-dichloroethane carcinogenicity are assays for genetic toxicity. Recent comprehensive reviews
( ^ 1V»DR. 2022; Gwinn et al.. 201 I) were used to develop an overview of genotoxicity data for 1,2-
dichloroethane and the role of metabolism, which is presented below. Potential nongenotoxic modes of
action for rat mammary tumors were investigated in one study (Lebaron et al.. 2021). Brief discussions
of the information (both genotoxic and non-genotoxic mechanisms) that pertain to specific tumor sites
associated with 1,2-dichloroethane exposure (mammary gland, lung, liver, and circulatory system)
follow the general genotoxicity discussion.
Genotoxicity Overview
Evidence from in vivo studies using multiple animal species and routes of exposure and in vitro studies
using multiple test systems indicates that 1,2-dichloroethane and/or its metabolites can induce mutations,
chromosomal aberrations, DNA damage, and DNA adducts in certain test systems. The available data
show that biotransformation of 1,2-dichloroethane to reactive metabolites via a major CYP450-mediated
oxidative pathway and a minor glutathione conjugation pathway contributes to the observed effects.
There are species-, sex-, tissue-, and dose-related differences in the interactions between 1,2-
dichloroethane and/or its metabolites and DNA.
Evidence that 1,2-dichloroethane induces gene mutation is based largely on in vitro studies. Reverse
mutation studies in Salmonella typhimurium were predominantly positive, especially with metabolic
activation ( DR. 2022; Gwinn et al.. 2011). Mutagenicity was seen more consistently in Salmonella
strains that detect base-pair substitutions (e.g., TA1535) than those that detect frameshift mutations (e.g.,
TA97) (ATSDR. 2022; Gwinn et al..1 ). Mutations at the HGPRT locus were increased in Chinese
hamster ovary (CHO) cells in the presence of metabolic activation, both when 1,2-dichloroethane was
incorporated in media (Tan and Hsie. 1981) and when cells were exposed to 1,2-dichloroethane as a
vapor in a closed system (Zamora et a ?)• There are limited gene mutation data from in vivo
studies. Oral and inhalation studies assessing various types of mutations in Drosophila were generally
positive, but many of the studies were limited by lack of methodological details and/or the use of a
single exposure level (ATSDR. 2022; Gwinn et al..: ). A single study of lacZ mutations in the liver
and testis of Muta™ mice showed no increase in the mutation frequency after exposure to 1,2-
dichloroethane by oral or intraperitoneal administration at doses up to 150 or 280 mg/kg-bw,
respectively (Hachiya and Motohashi. 2000).
In vivo rodent studies showing clastogenic effects, DNA damage, and DNA adducts in the mammary
gland, lung, liver, and circulatory system tissues are discussed in the subsections below on potential
mechanisms for carcinogenicity in these tissues. A small number of in vivo studies of genotoxicity
endpoints in other tissue types showed evidence of DNA damage (Comet assay) in mouse kidney,
bladder, and brain (Sasaki et al.. 1998); and DNA binding or DNA adducts in mouse and rat stomach,
forestomach, and kidney (Watanabe et al.. 2007; Hellman a ndt. 1986; Inskeep et al.. 1986; Prodi
et al.. 1986; Arfellini et al.. 1984) after exposure by intraperitoneal injection.
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Role of Metabolism
Available data are not sufficient to determine whether metabolism of 1,2-dichloroethane is a necessary
first step in its genotoxic action. In vitro studies in bacteria have shown that exogenous metabolic
activation is either required for, or increases the mutagenic activity of, 1,2-dichloroethane (ATSDR.
2022; Gwinn et ai. ). In contrast, experiments in human lymphocytes cultured in vitro with 1,2-
dichloroethane showed increased micronucleus formation in the absence of S9, but not in the presence
of S9 (Tafazoli etai. 1998).
Evidence suggests that metabolism of 1,2-dichloroethane, especially via the glutathione pathway, does
lead to increased genotoxicity. Crespi et t 5) compared the genotoxicity of 1,2-dichloroethane in
human cell lines with differing metabolic capacities. Crespi et; 5) observed 25-fold higher
HGPRT mutation frequencies in AHH-1 compared with TK6 human lymphoblastoid cells. The study
authors measured 5-fold greater glutathione-S-transferase activity in the AHH-1 cells than the TK6 cells,
suggesting that the glutathione metabolic pathway increased the frequency of mutations induced by 1,2-
dichloroethane.
Several studies have inhibited or stimulated enzymes to elucidate the relative importance of the CYP450
and glutathione pathways in 1,2-dichloroethane genotoxicity. In Ames assays, supplementation of the
media with glutathione or glutathione-S-transferase increases the mutagenicity of 1,2-dichloroethane
( \ I SDR. 2022; Gwinn et ai. 1 I). Drosophila melanogaster pretreated with buthionine sulfoximine
(BSO, an inhibitor of glutathione synthesis) before inhalation exposure to 1,2-dichloroethane exhibited
reduced mutations (measured using somatic mutation and recombination tests [SMARTs]) compared
with those that were not pretreated (Romert et at.. 1990). Pretreatment of fruit flies with an inducer of
glutathione-S-transferase (phenobarbital) significantly increased mutation frequency (Romert et ai.
1990). In support of these findings, Chroust et ai (2001) observed increased mutagenicity in transgenic
fruit flies expressing human glutathione-S-transferase (AI subunit), an effect that was mitigated by
pretreatment with BSO.
Inhibition of CYP450 metabolism has been shown to potentiate DNA damage and increase DNA
binding from exposure to 1,2-dichloroethane. In rats exposed to piperonyl butoxide in addition to 1,2-
dichloroethane (via intraperitoneal injection), increased levels of hepatic DNA damage (measured with
alkaline DNA unwinding assay) were seen in comparison to the levels in rats treated with 1,2-
dichloroethane alone (Storer and Conolly. 1985). Similarly, increased DNA binding in the liver, kidney,
spleen, and testes was observed in rats exposed to 1,2-dichloroethane by inhalation with concurrent
dietary exposure to the CYP450 inhibitor disulfiram (relative to 1,2-dichloroethane exposure alone)
(U\\ e et ai. 1986a).
Mammary Gland Cancer Mechanisms
Lebaron et ai (2 conducted in vivo experiments to assess potential mechanisms of rodent mammary
tumors induced by 1,2-dichloroethane. The study authors exposed female F344 rats by inhalation to 0 or
200 ppm (809 mg/m3) 1,2-dichloroethane for 6 hours/day on at least 28 consecutive days. At sacrifice,
blood samples were obtained for assessment of serum prolactin, and mammary tissues were collected for
histopathology and assays of epithelial cell proliferation (Ki-67 immunohistochemistry), DNA damage
(Comet assay), and levels of glutathione, reduced glutathione, and oxidized glutathione. There was no
difference between exposed and control groups for any of these endpoints, nor was there an effect of
exposure on 8-oxo-2'-deoxyguanosine (8-OHdG) adduct levels, a marker of oxidative DNA damage.
Exposure to 1,2-dichloroethane did, however, induce a significant increase in S-(2-N7-guanylethyl)
glutathione DNA adducts, as also found in the liver in this and other studies. In vitro studies have shown
these adducts to be mutagenic (Gwinn et ai. ). Lebaron et ai (2021). however, argue that in vivo
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evidence does not support this conclusion and that these adducts should be considered biomarkers of
exposure, rather than mutagenic adducts.
No other data on potential mechanisms were located. The DNA adducts in mammary tissue resulting
from 1,2-dichloroethane exposure in vivo could plausibly be related to subsequent formation of
mammary tumors, although the role of these adducts in carcinogenicity of 1,2-dichloroethane has not
been conclusively demonstrated.
Lung Cancer Mechanisms
Studies relevant to carcinogenic mechanisms of 1,2-dichloroethane-induced lung cancers are limited to
measurements of DNA damage in the lung of mice exposed by intraperitoneal injection (Sasaki et al..
1998) and quantification of DNA adducts in the lungs of rats and mice also exposed by intraperitoneal
injection (Baertsch et al.. 1991; Prodi et a |). Increased DNA damage (measured by alkaline single
cell gel [SCG] assay and compared with measurement at time 0) was observed in the lungs of mice
when measured 3 or 24 hours after dosing with 200 mg/kg 1,2-dichloroethane (Sasaki et al.. 1998).
DNA binding in the lungs of female rats was observed after 12 hours of inhalation exposure to 14C-1,2-
dichloroethane (Baertsch et al.. 1991). Prodi 0 observed higher binding of 14C-1,2-
dichloroethane to DNA in the lungs of mice compared with rats, consistent with the susceptibility of
mice, but not rats, to 1,2-dichloroethane-induced lung tumors (Nagano et al.. 2006). Experiments on
binding of radiolabeled 1,2-dichloroethane to calf thymus DNA in the presence of microsomes and/or or
cytosol from mouse and rat lung indicated binding in the presence of lung-derived microsomes
(containing CYP450), but not cytosol (containing glutathione-S-transferase) (Prodi et al.. 1988).
In an in vitro experiment, Matsuoka et al. (1998) observed dose-related increases in chromosomal
aberrations in Chinese hamster lung fibroblast (CHL) cells when incubated with 1,2-dichloroethane in
the presence of S9. In the absence of S9, the results were judged to be equivocal (Matsuoka oi I h">l >8).
No other data on potential mechanisms were located. The observed genotoxic effects and DNA
binding/adduct formation in lung tissue following 1,2-dichloroethane exposure in vitro and in vivo could
plausibly be related to subsequent formation of lung tumors, although a direct connection between these
events and 1,2-dichloroethane-induced lung carcinogenesis has not been conclusively demonstrated.
Liver Cancer Mechanisms
One study evaluated potential mutations in the livers of animals exposed to 1,2-dichloroethane. Hachiya
and Motohashi (2000) measured the frequency of hepatic tissue lacZ mutations in the Muta™ Mouse
model 14 and 28 days after single gavage doses up to 150 mg/kg-bw or after repeated intraperitoneal
injections resulting in cumulative doses up to 280 mg/kg-bw. No increase in mutation frequency was
observed in the liver in any of the experiments.
When measured 3 and 24 hours after mice were exposed to 1,2-dichloroethane by intraperitoneal
injection, an increase in DNA damage in the liver was detected by alkaline SGC assay (when compared
to levels seen at time 0) (Sasaki et al.. 1998). Significant decreases in the percentage of double-stranded
DNA were observed in mice given single intraperitoneal doses of 300 mg/kg (Taningher et al.. 1991) or
2 and 3 mmol/kg (200 and 300 mg/kg) (Storer and Conolly. 1983). Storer et i 4) assessed route
differences in DNA damage in the livers of mice exposed by gavage (100-400 mg/kg), intraperitoneal
injection (100-300 mg/kg), and inhalation (4 hours at 150-2,000 ppm/607-8095 mg/m3). The fraction of
double stranded DNA was significantly decreased in a dose-related fashion at all doses (>100 mg/kg)
after gavage administration, at doses greater than or equal to 150 mg/kg after intraperitoneal injection,
and at concentrations greater than or equal to 1,000 ppm 4047 mg/m3) after inhalation exposure. While
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the lower doses producing DNA damage by oral and intraperitoneal exposure did not produce systemic
effects in parallel groups of similarly-treated mice, all concentrations producing DNA damage by
inhalation exposure were lethal to the similarly exposed mice (Storer et at.. 1984). In a study comparing
alkylation of hepatic DNA in rats and mice exposed to 1,2-dichloroethane by intraperitoneal injection,
higher levels of alkylation were observed in mice compared with rats (at least 40-fold higher in the first
30 minutes after dosing) (Baneriee. 1988).
Binding of 1,2-dichloroethane or its metabolites to hepatic DNA of rats and mice exposed in vivo has
been demonstrated in a number of studies (Lebaron et al. 2021; Watanabe et ai. 2007; Baertsch et al.
1991; Prodi et al.. 1988; Inskeep et al.. 1986). Available data show sex-, species-, and dose-related
differences in adduct levels. For example, an early study that compared DNA adduct levels in the livers
of male rats and mice exposed to 1,2-dichloroethane by intraperitoneal injection (127 |iCi/kg) showed
higher binding in mouse compared to rat (Prodi et al.. 1988). In contrast, in hepatic tissue from male and
female mice and male rats exposed by intraperitoneal administration of a much lower dose of 1,2-
dichloroethane (21 |iCi/kg, corresponding to 5 mg/kg), the highest levels of adducts were in female mice
(57 fmol/mg DNA), followed by male rats (46 fmol/mg DNA) and male mice (29 fmol/mg DNA)
(Watanabe et al.. 2007). In rats exposed by inhalation (50 ppm/202 mg/m3) for 2 years and then given a
single oral dose of radiolabeled 1,2-dichloroethane, no exposure-related difference in DNA adduct levels
was detected (Cheever et al.. 1990). Notably, this exposure level also failed to induce an increase in
tumors at any site.
DNA adducts from the glutathione metabolic pathway have been demonstrated to occur in the livers of
laboratory rodents exposed in vivo. In mice and rats administered 5 mg/kg 1,2-dichloroethane by
intraperitoneal injection, the primary adduct was S-(2-N7-guanylethyl) glutathione (Watanabe et al..
2007). Similarly, in rats given 150 mg/kg 14C-1,2-dichloroethane by intraperitoneal injection and
sacrificed 8 hours later, prominent adducts in the liver were identified by high-performance liquid
chromatography (HPLC) as S-[2-(N7-guanyl) ethyl jglutathi one and S-[2-(N7-
guanyl)ethyl]cysteinylglycine (Inskeep et al.. 1986). Also, after 28 days of inhalation exposure to 200
ppm (809 mg/m3) 1,2-dichloroethane, a significant increase in S-(2-N7-guanylethyl) glutathione DNA
adducts was detected in the livers of female rats (Lebaron et al.. 2021). As discussed above for
mammary tumors, there is some uncertainty as to the toxicological significance of these adducts. While
in vitro studies have shown these adducts to be mutagenic (Gwinn et al.. 2011). Lebaron et al. (2021)
argue that in vivo evidence does not support this conclusion and that these adducts should be considered
biomarkers of exposure, rather than mutagenic adducts.
One study was located presenting in vitro data pertaining to the genotoxicity of 1,2-dichloroethane in the
liver. In this study, 1,2-dichloroethane induced DNA repair in both rat and mouse primary hepatocytes
(MiImam et a I PssS).
No other data on potential mechanisms were located. The observed DNA damage and DNA
binding/adduct formation in liver tissue following exposure to 1,2-dichloroethane in vitro and in vivo
could plausibly be related to subsequent formation of liver tumors, although a direct connection between
these events and 1,2-dichloroethane-induced liver carcinogenesis has not been conclusively
demonstrated.
Circulatory System Cancer Mechanisms
Data pertaining to mechanisms of circulatory system cancers induced by 1,2-dichloroethane consist of
genotoxicity studies, including one in vivo study in rats (Lone et al.. 2016). three in vivo studies in mice
(Witt et al.. 2000; Sasaki et al.. 1998; Giri and Que Hee. 1988). and three in vitro experiments in human
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lymphoblastoid cells or lymphocytes (Tafazoli et al. 1998; Doherty et al. 1996; Crespi et ai. 1985).
Rats exposed by intraperitoneal injection to doses of 80.7, 161.4, or 242.1 mg/kg-bw exhibited
statistically significant, dose-related increases in the incidences of chromosomal aberrations and
micronuclei in bone marrow, as well as DNA damage (measured by alkaline comet assay) in blood cells
(Lone et al.. ). In mice exposed by intraperitoneal injection, significant increases in sister chromatid
exchange frequencies (Giri and Que Hee. 1988) and DNA damage (Sasaki et al.. 1998) were observed in
bone marrow. However, 90 days of drinking water exposure to 1,2-dichloroethane (up to 8000 mg/L)
did not increase the frequency of micronuclei in mice (Witt et al.. 2000). A study of workers exposed to
1,2-dichloroethane and vinyl chloride showed increased sister chromatid exchanges in the blood of those
exposed to moderate levels of 1,2-dichloroethane with low levels of vinyl chloride exposure (Cheng et
al. 2000).
Several in vitro genotoxicity experiments were conducted in cells of the circulatory system. Increases in
mutations (measured using the hypoxanthine-guanine phosphoribosyltransferase [HGPRT] assay) and
micronuclei were observed in human lymphoblastoid cells cultured with 1,2-dichloroethane (Doherty et
al.. 1996; Crespi et al.. 1985). Incubation with 1,2-dichloroethane resulted in increased micronuclei and
DNA damage (by Comet assay) in human peripheral lymphocytes in the absence of exogenous
metabolic activation (Tafazoli et al.. 1998).
No other data on potential mechanisms were located. The observed genotoxic effects of 1,2-
dichloroethane in hematopoietic cells and tissues in vitro and in vivo could plausibly be related to
subsequent formation of tumors, although a direct connection between these events and 1,2-
dichloroethane-induced circulatory system cancers has not been conclusively demonstrated.
Summary
1,2-Dichloroethane is likely to be carcinogenic to humans based on evidence of turnorigenicity in animal
studies, including multiple tumor sites in male and/or female rats and/or mice by oral, inhalation, and/or
dermal exposure. The occurrence of tumors in multiple tissues and treated groups is suggestive of a
genotoxic mode of action, and most data relating to mode of action for 1,2-dichloroethane
carcinogenicity are assays for genetic toxicity. Evidence from in vivo studies using multiple animal
species and routes of exposure and in vitro studies using multiple test systems indicates that 1,2-
dichloroethane and/or its metabolites can induce mutations, chromosomal aberrations, DNA damage,
and DNA binding/adduct formation in certain test systems. The available data also show that
biotransformation of 1,2-dichloroethane to reactive metabolites via a major CYP450-mediated oxidative
pathway and a minor glutathione conjugation pathway contributes to the observed effects. In vivo and in
vitro data showing genotoxicity and DNA binding/adduct formation in tissues where tumors associated
with 1,2-dichloroethane exposure have been observed (mammary gland, lung, liver, and circulatory
system) support that these effects could plausibly be related to formation of tumors in these tissues,
although a direct connection between these events and 1,2-dichloroethane-induced carcinogenesis has
not been conclusively demonstrated. Potential nongenotoxic modes of action were explored only in one
study of rat mammary tissue, and no supporting results were obtained.
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5 CANCER HAZARD IDENTIFICATION AND EVIDENCE
INTEGRATION
Evidence in Humans
The 1,2-dichloroethane human epidemiology literature is similarly indeterminate as to whether 1,2-
dichloroethane exposure causes cancer due to a lack of published studies. A few studies showed
significant relationships between 1,2-dichloroethane and certain types of cancers, however these
relationships existed in very specific subgroups and were not consistent across exposure groups, which
limits our ability to draw conclusions from their results. For example, although Niehoff et al. (2
found a slight increase in the risk for ER+ invasive breast cancer in the fourth quintile of exposure as
compared with the first, this relationship was not significant in the fifth quintile of exposure as
compared with the first. This study also did not find a significant relationship between 1,2-
dichloroethane exposure and overall incidence of breast cancer, which was consistent with the only
other study investigating this relationship (Garcia et ). Similarly, 1,2-dichloroethane exposure
was associated with a borderline significant increase in pancreatic cancer, but only among Black females
with low estimated exposure intensity (and not medium or high exposure intensity) (Kernan et al..
1999). Studies of brain cancer and kidney cancer showed no significant relationship with 1,2-
dichloroethane exposure (Dosemeci et al.. 1999; Austin and Schnatter. 1983).
Another study observed higher incidence of all-cause cancer than was expected in a cohort of workers
when compared to the general population, but the statistical significance of this result was not reported,
and the significance of all-cause cancer is not clear ( 35). This same study looked at many
specific cancer SIRs as well, but none were statistically significantly elevated except for prostate cancer,
which no other studies in the literature reported observing. Sob el et al. (1987) did not show a statistically
significant relationship between 1,2-dichloroethane exposure and soft-tissue sarcoma, but also had very
low statistical power with a sample size of seven 1,2-dichloroethane exposed participants. In general,
more studies would be needed to draw conclusions about the weight of evidence for the relationship
between 1,2-dichloroethane exposure and cancer from the epidemiologic literature, and none of the
existing studies measured exposure in a way that could be used to estimate a quantitative dose-response
relationship.
Evidence in Animals
Systematic review identified three high-quality 1,2-dichloroethane cancer studies available in animals.
The NTP (1978) cancer study for 1,2-dichloroethane in Osborne-Mendel rats and B6C3F1 mice
provides evidence of the carcinogenicity treated by oral gavage for 78 weeks. Male rats had significantly
increased incidence of forestomach squamous-cell carcinomas and circulatory system
hemangiosarcomas. Significant increases in mammary adenocarcinoma incidence in female rats and
mice were observed. Alveolar/bronchiolar adenomas developed in mice of both sexes and females
developed endometrial stromal polyps and sarcomas, while males developed hepatocellular carcinomas.
However, the rat study for 1,2-dichloroethane was not utilized for cancer slope factor derivation due to
the excessive animal deaths and pre-cancerous endometrial polyps in mice for 1,2-dichloroethane are not
considered for cancer slope factor analysis. In addition, the high incidence of death in the rat study
caused it to have an "uninformative" rating in systematic review, so cancer slope factors were not
modeled from this data set.
In contrast, the oral cancer study in mice performed by NTP (1978) on 1,2-dichloroethane resulted in
tumor types or pre-cancerous lesions {i.e., hepatocellular carcinomas, endometrial polyps,
hemangiosarcomas, and mammary gland tumors). The NTP (1978) oral study in 1,2-dichloroethane also
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showed an excellent dose response for hepatocellular carcinomas (Figure 5-1). As a result, the cancer
slope factor for 1,2-dichloroethane was selected from the NTP (1978) study in mice, which had a high
systematic review rating (see Table 8-4). An oral cancer slope factor of 6,2/ 10 2 (mg/kg)/day was
calculated and is in agreement with U.S. EPA (1987a) that also calculated a cancer slope factor on these
data from hepatocellular carcinomas in male mice treated with for 1,2-dichloroethane.
A 26-week (3 times/week) 1,2-dichloroethane study in CB6F1-Tg rasH2@Jcl (rasH2) mice by Suguro et
al. (2017) was considered for dermal exposure. In this study, mice dermally exposed to 126 mg (6300
mg/kg-bw/day based on the default body weight of 0.02 kg for a mouse) via shaved dorsal skin, resulted
in bronchioloalveolar adenomas and adenocarcinomas in both male and female mice with
bronchioloalveolar hyperplasia predominately in female mice. This study was not chosen for cancer
dose-response assessment as only this dose was tested. In addition, this strain of mouse is also highly
susceptible to cancer and due to severe clinical signs observed in the females, 5 of the 10 animals were
euthanized prior to the scheduled study duration at 18 weeks. Thus, the cancer slope factor from NTP
(1978) based on hepatocellular carcinomas was also utilized for dermal exposure.
Alkyl halides, such as 1,2-dichloroethane, are considered to be direct acting alkylating agents. Thus, it is
considered to be hypothetical the relevance of metabolic saturation of liver metabolic capacity for the
formation of oncogenic intermediates (OECD. 2002).
Additionally, the 1,2-dichloroethane inhalation cancer study by Nagano et al. (2006) produced similar
tumors as observed in the 1,2-dichloroethane oral cancer study. The cancer data from Nagano et al.
(2006) for 1,2-dichloroethane was utilized for the inhalation route. The highest estimated inhalation unit
risk (IUR) is 7,1 / 10 6 (per (J,g/m3) for combined mammary gland adenomas, fibroadenomas, and
adenocarcinomas and subcutaneous fibromas in female rats in the inhalation study.
Dose (niK/kg/day)
Figure 5-1. Hepatocellular Carcinomas Dose Response in Mice for 1,2-
Dichloroethane (NTP (1978))
The OncoLogic™ model developed by the EPA evaluates the carcinogenic potential of chemicals
following sets of knowledge rules based on studies of how chemicals cause cancer in animals and
humans. 1,2-dichloroethane was categorized as a moderate concern for carcinogenicity based on its
potential as a biological alkylating agent as vicinal alkyl halides such as 1,2-dichloroethane are
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1562 chemically reactive (Table 5-1). Table 5-2 outlines 1,2-dichloroethane associated precursor events to
1563 carcinogenicity.
1564
1565 Table 5-1.1,2-Dichloroethane Oncologic Results
Parameter
1,2-Dichloroethane
Classification for carcinogenicity
Medium Concern
Chemistry
Vicinal alkyl dihalide
Chemical reactivity
Geminal alkyl dihalide < vicinal alkyl dihalide
1566
1567 Table 5-2.1,2-Dichloroethane Precursor Events"
Parameter
1,2-Dichloroethane
Ames assay
+
DNA repair test rats
+
DNA repair test mice
+
Endometrial polyps
+
a Ames Assay positive with and without metabolic activation, Alkyl halides are directly reactive
1568
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6 DOSE-RESPONSE ASSESSMENT
According to the Draft Systematic Review Protocol Supporting TSCA Risk Evaluations for Chemical
Substances (U.S. EPA. 20211 hazard endpoints that receive evidence integration judgments of
demonstrates and likely are considered for dose-response analysis. Endpoints with suggestive evidence
can be considered on a case-by-case basis. Studies that received high or medium overall quality
determinations (or low-quality studies if no other data are available) with adequate quantitative
information and sufficient sensitivity can be compared.
Because the health effect with the most robust and sensitive POD among these suggestive outcomes
were derived from 1,2- dichloroethane, these data were used for risk characterization for each exposure
scenario to be protective of other adverse effects as described in the sections below.
Data for the dose-response assessment were selected from oral and inhalation toxicity studies in animals
specifically from 1,2-dichloroethane. Additionally, no usable PBPK models are available to extrapolate
between animal and human doses or between routes of exposure using 1,2-dichloroethane-specific
information. The PODs estimated based on effects in animals were converted to HEDs or cancer slope
factors (CSFs) for the oral and dermal routes and HECs or Inhalation Unit Risks (IURs) for the
inhalation route. For this conversion, EPA used guidance from U.S. EPA. (201 la) to allometrically scale
oral data between animals and humans. Although the guidance is specific for the oral route, EPA used
the same HEDs and CSFs for the dermal route of exposure as the oral route because the extrapolation
from oral to dermal routes is done using the human oral doses, which do not need to be scaled across
species. EPA accounts for dermal absorption in the dermal exposure estimates, which can then be
directly compared to the dermal HEDs.
For the inhalation route, EPA extrapolated the daily oral HEDs and CSFs to HECs and IURs using
human body weight and breathing rate relevant to a continuous exposure of an individual at rest. For
consistency, all HEDs and the CSF are expressed as daily doses and all HECs are based on daily,
continuous concentrations (24 hours/day) using a breathing rate for individuals at rest. Adjustments to
exposure durations, exposure frequencies, and breathing rates are made in the exposure estimates used to
calculate risks for individual exposure scenarios.
6.1 Selection of Studies and Endpoints for Non-cancer Toxicity
The following subsections provide a description of the selection of critical non-cancer PODs for acute,
short-term/sub chronic and chronic exposures for 1,2-dichloroethane. The sections provide a summary of
the evaluation of the possible PODs and the rationale for selection of the critical study (and POD) in a
series of tables. The tables are intended to streamline the text of the forthcoming draft risk evaluation.
6.1.1 Uncertainty Factors Used for Non-cancer Endpoints
For the non-cancer health effects, EPA applied specific uncertainty factors (UF) to identify benchmark
MOEs for acute, short term, and chronic exposure durations for each exposure route among studies that
are used to estimate risks. and further discuss use of UFs in human
health hazard dose-response assessment. A total uncertainty factor for each POD is calculated by
multiplication of each of the five individual uncertainty factors. In general, the higher the total
uncertainty factor applied to a POD to identify a benchmark MOE, the higher the uncertainty in the
hazard value. The following five individual UFs are considered for each of the PODs identified for use
in risk estimation. In the case of 1,1-dichloroethane, the database uncertainty factor was not used for any
of the PODs.
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1. Interspecies Uncertainty Factor (UFa) of 3
EPA uses data from oral toxicity studies in animals to derive relevant HEDs, and (
201 la) recommends allometric scaling (using the % power of body weight) to account for
interspecies toxicokinetics differences for oral data. When applying allometric scaling, EPA
guidance recommends reducing the UFA from 10 to 3. The remaining uncertainty is associated
with interspecies differences in toxicodynamics. EPA also uses a UFa of 3 for the inhalation
HEC that accounts for dosimetric adjustment and dermal HED values as these values are derived
from the oral HED.
2. Intraspecies Uncertainty Factor (UFh) of 10
EPA uses a default UFh of 10 to account for variation in sensitivity within human populations
due to limited information regarding the degree to which human variability may impact the
disposition of or response to, 1,2-dichloroethane.
3. LOAEL-to-NOAEL Uncertainty Factor (UFl) of 1 or 3
For the PODs chosen to calculate risks based on BMDL values, EPA used a UFl of 1. EPA
compared these values with other endpoints that were based on LOAELs, which used a UFl of 3
to account for the uncertainty inherent in extrapolating from the LOAEL to the NOAEL.
4. Subchronic-to-Chronic Duration Uncertainty Factor (UFs) of 10
EPA uses a default of 10 to account for extrapolating from data obtained in a study with less-
than-lifetime (subchronic) exposure to lifetime (chronic) exposure. A default value of 10 for this
UF is applied to the NOAEL/LOAEL or BMDL/BMCL from the subchronic study on the
assumption that effects from a given compound in a subchronic study occur at a 10-fold higher
concentration than in a corresponding (but absent) chronic study
5. Database Uncertainty Factor (UFd) of 1
EPA considers the application of a database UF to account for the potential for deriving an
under-protective POD due to an incomplete characterization of the chemical's toxicity. As the
database for 1,2-dichlorethane possesses data that informs several toxicological endpoints, a UFd
of 1 was applied.
6.1.2 Non-cancer PODs for Acute Exposures
Oral
Table 6-1 shows the recommended acute oral study and POD for 1,2-dichloroethane followed by co-
critical endpoints (PODs within the range of the recommended study) and other studies considered in
support of the recommended POD.
When examining the 1,2-dichloroethane study database, a number of toxicological endpoints were
identified. These studies were evaluated by systematic review and only four studies were considered for
the acute, oral, non-cancer dose assessment (Table 6-10). In Cheever et al. (1990). the authors noted that
a preliminary study on 4 month old Osborne-Mendel rats dosed with 150 mg/kg-bw by oral gavage of
radiolabeled 1,2-dichloroethane identified that 14C was almost completely eliminated within 24 hours
after administration. Elimination of 14C was found primarily in urine (49.7 to 51.5 percent) followed by
expired air (35.5 to 39.6 percent), with only a small portion was detected as 14C02 in feces. This
suggests that the kidneys are a potential target due to oral exposure to 1,2-dichloroethane.
In the Morel 9) acute, single exposure, oral gavage study in male Swiss OF1 mice treated with
0, 1,000, or 1,500 mg/kg-bw of 1,2-dichloroethane, a significant increase in damaged renal tubules (7.66
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vs. 0.32 percent in controls) was seen only seen in the highest dose group with the lowest dose already
above the limit dose. B6C3F1. mice in the Storer 4) study that were administered a single oral
gavage dose at 0, 100, 200, 300, 400, 500, 600 mg/kg-bw resulted in absolute kidney weights increased
at 300 mg/kg-bw doses and greater. Relative kidney weights in Storer |) were also increased
in the 300 mg/kg and higher dose groups along with serum BUN (serum BUN showed a trend increase
but the 300 mg/kg/day dose was not statistically significant to control at N = 5; however, the BMD
analysis using all data points together showed significance above 106 mg/kg/day). Thus, based on both
histological and clinical chemistry parameters, the Storer et 84) study based on mice kidney
weight was identified as the recommended candidate for the acute oral POD. To calculate risks for the
acute exposure duration in the risk evaluation, EPA used a daily HED of 19.9 mg/kg-bw (based on a
BMDLio of 153 mg/kg-bw) from Storer et al. (1984) and based on a significant (13 percent) increase in
relative kidney weight in male B6C3F1 mice administered a single dose of 1,2-dichloroethane at 100,
200, 300, or 400 mg/kg via oral gavage in corn oil. That study was given a high overall quality
determination and a, uncertainty factor (UF) of 30 was used for the benchmark margin of exposure
(MOE) during risk characterization (see Table 8-1).
Evaluation of the 1,2-dichloroethane studies also suggests the liver and respiratory system as targets of
oral 1,2-dichloroethane exposure. In the Munson et; 2) study, an acute, single oral gavage to 1-2-
dichloroethane in CD-I mice identified a LD50 of 413 and 489 mg/kg for female and male mice,
respectively. Upon necropsy of these animals, it was identified that the lungs and liver appeared to be
the primary target organs.
In support of liver toxicity, in the study by Storer et al. (1984). B6C3F1 mice were administered a single
dose of 1,2-dichloroethane at 100, 200, 300, or 400 mg/kg via oral gavage in corn oil and euthanized 4
hours later. It was identified that a statistically significant increase in DNA damage in hepatic nuclei was
present in all dose groups, as characterized by single-strand breaks, when compared to controls. The
study by Storer et al. (1984) also indicated increased IDH (also known as sorbitol dehydrogenase, SDH)
and AAT (alanine aminotransferase) serum levels were also increased at the 200 mg/kg and higher doses
in the B6C3F1. mice. In Cottalasso et al. (2002). a single gavage of 628 mg/kg of 1,2-dichloroethane in
female Sprague-Dawley rats resulted in increased ALT, AST, and LDH compared to controls.
Additionally, histological evaluation of the liver showed moderate steatosis. Increased malondialdehyde
(MDA), a marker of lipid peroxidation, was also seen in the treated animals when compared to controls.
Although clinical chemistry for liver enzyme-implicates liver injury due to 1,2-dichloroethane exposure,
gross pathology changes (e.g., in liver weight or quantified histological changes) were not identified.
With regard to the respiratory system, only the study by Salovsky et al. (2002). a single oral dose of 136
mg/kg-bw 1,2-dichloroethane in male Wistar rats resulted in increased total number of cells in the BALF
of male Wister rats at 30 days after dosing. Histological changes were only presented qualitatively.
Thus, this study was not identified as the POD due to limited quantitative data.
Inhalation
Table 6-2 shows the recommended acute inhalation study and POD for 1,2-dichloroethane followed by
co-critical endpoints (i.e., PODs within the range of the recommended study) and other studies
considered in support of the recommended POD.
A route-to-route extrapolation from the acute Storer 4) 1,2-dichloroethane oral study was not
conducted given the differences in absorption rates across routes, method of dosing effects on blood
levels and hazards (i.e., gavage bolus dose vs. slower inhalation dosing), the lack of a PBPK model, and
the inherent uncertainties when performing oral-to-inhalation route extrapolations for a volatile solvent
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{i.e., most of the oral dose is eliminated in expired air). An 8-hour inhalation study in male and female
rats exposed to 1,2-dichloroethane by Dow Chemical (2006b) was used identified. A BMCLio of 48.9
mg/m3 and BMD of 81.4 mg/m3 were identified based on degeneration with necrosis of the olfactory
mucosa. The acute inhalation HEC for occupational and continuous exposure of 10.14 ppm (41.1
mg/m3) and 2.42 ppm (9.78 mg/m3), respectively, with a benchmark MOE of 30, was used for risk
assessment of acute inhalation exposure (Table 8-1). The resulting RGDR value of 0.2 is the combined
value for male (0.25) and female (0.16) F344 rats used to calculate HEC continuous ( .).
Dermal
No acute exposure studies on 1,2-dichloroethane via the dermal route were identified. Therefore, the
acute oral HED of 19.9 mg/kg-bw/day was extrapolated for the dermal route, with a benchmark MOE of
30, and was used for risk assessment of acute dermal exposures (Table 8-1).
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Table 6-1. Acute, Oral, Non-cancer
'OD-Endpoint Selection Table
Chemical/
Endpoint
POD
(mjj/kjj/day)
Study Parameters
Comments
POD selected for risk evaluation of non-cancer for acute oral exposures
1,2-Dichloroclhanc
Kidney weight
BMDL = 153
BMD = 270
NOAEL = 200 mg/kg
LOAEL = 300 mg/kg
Gavase. SR I Iisli
B6C3F1 Mice -Male
Single exposure (0, 200, 300, 400, 500, or 600 mg/kg)
Single exposure study with a POD dose virtually identical to the
POD dose where resorptions were observed. This POD is
protective for other endpoints such as narcosis, BUN, IDH,
resorptions, etc.
Death started at 400 mg/kg; LD5o (males) = 450 mg/kg).
( o-crnical similes
1,2-Dichloroethane,
Blood urea nitrogen
(BUN)
NOAEL = 200
LOAEL = 300
Storeret al. (1984). Gavase. SRHish
B6C3F1 Mice-Male
Single exposure (0, 200, 300, 400, 500, or 600 mg/kg)
Adverse increase in BUN supporting kidney effects, not
statistically significant due to low N=5.
1,2 -Dichloroethane
L-iditol
dehydrogenase
(IDH)
NOAEL = 200
LOAEL = 300
Storeret al. (1984). Gavase. SRHieh
B6C3F1 Mice -Male
Single exposure (0, 200, 300, 400, 500, or 600 mg/kg)
Nine-fold adverse increase in IDH marker of tissue damage
(associated mostly with kidney and liver damage), not statistically
significant due to low N=5.
()llier studies end points considered
1,2 -Dichloroethane
Kidney
histopathology
NOAEL = 1,000
LOAEL = 1,500
Morel et al. (1999). Gavase. SRHieh
Swiss OF1 Mice - Male
(0, 1,000, 1,500 mg/kg)
Significant increase in damaged renal tubules but lowest dose
above the limit dose.
1,2 -Dichloroethane
Liver weight
LOAEL = 625
Moodv et al. (1981). Gavase. SR Medium
SD Rats - Male
Single exposure (0, 625 mg/kg)
Increased liver weight. Dose is not a sensitive endpoint.
1,2 -Dichloroethane
Liver clinical
chemistry
NOAEL = 134
Kitchin et al. (1993). Gavase. SRHish
SD Rats - Female
Single exposure (0, 134 mg/kg)
No effects reported. Inadequate dosing (too low).
1,2 -Dichloroethane
Fetal resorptions
NOAEL = 160
LOAEL = 200
(Data not amenable
for BMD modeling)
Pavan et al. (1995). Gavase
Pre-Natal Developmental, SR High
SD Rats - Female
Dosing GD 6-20 (0, 120, 160, 200, or 240 mg/kg)
The increases in non-implants and resorptions are difficult to
interpret given the significant maternal toxicity at corresponding
doses (30 and 49% at 200 and 240 mg/kg/day, respectively)
consisting of decreases in maternal body weight gain, and the fact
that there was no effect on the number of live fetuses per litter
despite the changes in non-surviving implants/litter and resorption
sites/litter. Therefore, cannot be used as POD.
1725
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1726 Table 6-2. Acute, Inhalation, Non-cancer POD-Endpoint Selection Table
Chemical/
Endpoint
POD
(mjj/m3)
Study Parameters
Comments
POD selected for non-cancer risk evaluation for acute inhalation exposures
1,2 -Dichloroethane
Neurological
BMDLio = 48.9 mg/m3
or 12.1 ppm
NOAEL = 202
I.OAF.I. = 405
Dow Chemical (2006b), SR High
F344 Rats - Male
8 hours/day 1 days (0, 50, 100, 150, 200, 600, 2000
ppm; 0, 202, 405, 607, 809, 2,428, 8,095 mg/m3)
Degeneration with necrosis of the olfactory neuroepithelial
mucosa.
( o-criHeal eudpoiuls
1,2 -Dichloroethane
Reproductive
toxicity/fetal
development
Reproductive/
Developmental
BMDLs = 25 pup BW
decreased at 613
BMDLio = 50 mg/m3
NOAEL = 305
LOAEL= 613
Rao et al. (1980). Vaoor. SR Medium
SD Rats - Both sexes
Inhalation. Prior to mating, during gestation, and
post-natally for two F1 generations (0, 25, 75, 150
ppm; 0, 102, 305 or 613 mg/m3
Decreased body weight of selected FIB male weanlings at 150
ppm
Study used for co-critical endpoints with BMDLio very close to
that from the recommended endpoint. Considering
NOAELs/LOAELs, using the recommended endpoint will be
protective of the decreases in pup body weight. Also, portal of
entry effects can be considered more sensitive than systemic
effects.
()llier siudies end points considered
1,2 -Dichloroethane
Prenatal
developmental
Reproductive/
Developmental Toxicity
NOAEL = 1,200
Maternal Toxicity:
NOAEL = 1,000
I.OAF.I. = 1,200
Pavan et al. (1995). Vaoor. SRHieh
SD Rats - Both sexes
Inhalation exposure for 2 weeks. GD 6-20. 6
hours/day 7 days/week, at 0, 150, 200, 250, 300
ppm; 0, 610, 820, 1,000, 1,200 mg/m3
Repro/Dev Toxicity: Pregnancy rate among females at 250 ppm
was significantly lower (p<0.05). This was not observed at the
highest concentration of 300 ppm. No other significant effects
reported.
Maternal Toxicity: 2/26 dams died at 300 ppm (highest dose).
Maternal body weight gain at GD 6-21 was significantly
decreased at 300 ppm. No mention of food consumption.
NOAEL/LOAEL higher than recommended endpoint.
Not amenable to BMD modeling.
1,2 -Dichloroethane
Prenatal
developmental
Reproductive/
Developmental
I.OAF.I. = 405
Maternal Toxicity:
NOAEL = 405
I.OAF.I. = 1,214
Rao et al. (1980). Vaoor. SR Medium
SD Rats - Female
Inhalation exposure for 10 days. GD 6-15. 7
hours/day 0, 100, 300 ppm (0, 405, 1,214 mg/m3)
Developmental Toxicity: A significant decrease in the incidence
of bilobed thoracic centra was seen at 100 ppm however study
essentially becomes a single dose study and not amenable to dose-
response modeling due to the high maternal toxicity at 300 ppm
(10/16 maternal rats died at 300 ppm). Therefore, this study is not
acceptable for POD derivation.
1,2 -Dichloroethane
Liver
NOAEL = 2,527
LOAF.L = 3.475
Brondeau et al. (1983). whole bodv inhalation
chamber, SR Medium
Significant increases in serum GLDH and SDH levels were seen
at >850 ppm (3,475 mg/m3); serum ALT and AST were
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Chemical/
Endpoint
POD
(mjj/m3)
Study Parameters
Comments
SD Rats - Male
0, 618, 850, 1056, 1304 ppm; 0, 2,527, 3,475, 4,318,
5,332 mg/m3
significantly increased at 850 ppm (3,475 mg/m3) but not at
higher concentrations. Dose-response analysis inadequate.
Histopathology and organ weight were not assessed.
1,2 -Dichloroethane
Liver, metabolic,
kidney, neurological
Liver, Metabolic and
Kidney (Organ Weight)
Overall study
NOAEL/LOAEL:
Metabolic (Body
Weight)
NOAEL = 809
I.OAF.I. = 2428
Dow Chemical (2006b). Vaoor. SRHieh
F344 Rats- Both sexes
4 or 8 hours:
(0, 50, 100, 150, 200, 600, or 2,000 ppm; 202, 405,
607, 809, 2,428 or 8,095 mg/m3)
Organ weight changes (liver, adrenal, kidney); histological
changes (liver, kidney, olfactory mucosa); multiple FOB changes,
bw changes were observed although most effects were
inconsistent or transient but supportive of liver and kidney
effects; the neurological effect (degeneration of the olfactory
neuroepithelial mucosa) from this study was used as the
recommended POD (see first entry above).
1,2 -Dichloroethane
Liver/kidney relative
organ weights
Liver (relative organ
weight):
NOAEL = 5,111
LOAEL = 6,134
Kidney (relative organ
weight):
NOAEL: N/A
LOAEL:4089
Francovitch et al. (1986). Vaoor. SR Medium
CD-I Mice - Male
4 hours:
(0, 1,000, 1,250, 1,500 ppm; 0, 4,089, 5,111 or
6,134 mg/m3)
Organ weight changes and histology (liver and kidney); however,
exposure group where these changes occurred, and negative
control data were not reported. While study is supportive of liver
and kidney effects, it is not suitable for dose-response analysis.
Observed effects are occurring at higher concentrations than the
recommended POD.
1,2 -Dichloroethane
Immunological/
streptococcal
infection challenge
CD-I (Female):
NOAEL = 9.21
LOAEL = 21.6
SD Rats (Male):
NOAEL: 801.2
Sherwood et al. (1987). Vaoor. SR Hish
CD-I Mice - Female
3 hour single exposure; 0, 2.3, 5.4, 10.8 ppm; 0,
9.21,21.6, 43.3 mg/m3
SD Rats - Male
3 or 5 hour single exposure; 0, 10, 20, 50, 100, 200
ppm; 0, 40.1, 80.1, 200.3, 400.6 and 801.2 mg/m3
Mice: Increased mortality from streptococcal challenge;
decreased bactericidal activity; no effects in cell counts or
phagocytic activity of alveolar macrophages; increased leucine
aminopeptidase (LAP) activity.
Rats: No effects observed
1,2 -Dichloroethane
Neurological
For 12 hours/day for 1
day:
NOAEL = 2,500
LOAEL = 5,000
2, 4, or 6 hours/day for
1 day:
Oin-li et al. (2010). Vaoor. SR Medium
SD Rats: Both sexes
12 hours/day for 1 day:
0, 2,500, 5,000, 10,000 mg/m3
12 hours/day for 1 day:
No mortality observed; signs of abnormal behavior; effects on
brain histology (edema corresponding with water content in the
cortex, no details on severity or dose-response).
2, 4, or 6 hours/day for 1 day:
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Chemical/
Endpoint
POD
(mjj/m3)
Study Parameters
Comments
I.OAF.I. = 5,000
2, 4, or 6 hours/day for 1 day:
0 or 5000 mg/m3
Effects on brain histology less severe than at 12 hours (edema
corresponding with water content of cortex, perineural and
perivascular spaces).
These effects no suitable for dose-response analysis but are
supportive of neurological effects seen in the recommended study
and POD.
1,2 -Dichloroethane
Neurological
For 1.5 or 4 hours:
NOAEL = 4,000
Zhou et al. (2016). Vaoor. SR Medium
SD Rats - Males
1.5 or 4 hours; 0, 4,000, or 12,000 mg/m3
Effects on the brain lesions with edema, and a significant
decrease in the number of fiber tracts were observed compared to
control. Study not suitable for dose- response analysis. Study
supports neurological effects seen in the recommended study and
POD.
1,2 -Dichloroethane
Liver/kidney clinical
chemistry
Liver Clinical
Chemistry:
NOAEL = 640
I.OAF.I. = 2,020
Kidney weight/BUN:
NOAEL = 640
I.OAF.I. = 2,020
Mortality:
NOAEL = 2,020
I.OAF.I. = 4,339
Storeret al. (1984). Gas. SRHieh
B6C3F1 Mice-Males
4 hours (0, 58, 499, 1072, and
1,946 ppm; 0, 640, 2,020, 4,339, and 7,876 mg/m3
Increased serum levels of IDH, ALT, and BUN; increased liver
and kidney weights; evidence of DNA damage; and increased
mortality (4/5 and 5/5 at >499 ppm) essentially reducing this
study to a single dose study and unsuitable for dose-response
analysis.
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6.1,3 Non-cancer PODs for Short-Term/Subchronic Exposures
Oral Short-Term/Subchronic
Table 6-3 shows the recommended short term/sub chronic oral study and POD for 1,2-dichloroethane
(followed by co-critical endpoints [PODs] within the range of the recommended study) and other studies
considered in support of the recommended POD.
For 1,2- dichloroethane, a total of four animal toxicity studies were available and three had acceptable
data quality for dose-response analysis and identification of the short-term/sub chronic oral duration
POD. There were no dermal data for the short-term/sub chronic duration exposure.
Using the 1,2-dichloroethane database, the selected critical study was Munson et al. (1982). In this 14-
day short-term study in CD1 mice of both sexes and dosed with 1,2-dichloroethane via oral gavage at
doses of 0, 4.9, 49 mg/kg. Endpoints evaluated included body weight, hematology, gross necropsy,
organ weights (liver, spleen, lungs, thymus, kidney, and brain), humoral immunity, and cell-mediated
immunity. The treatment-related effect observed in this study was immunosuppression based on
observed suppression of a cell-mediated immune response at doses 4.9 and 49 mg/kg/day. Co-critical
endpoints identified in this same Munson et t 2) study included an observed 30 percent decrease in
leukocytes at 49 mg/kg/day, and a dose-dependent trend of antibody forming cells/spleen towards
immune suppression with 25 and 40 percent suppression at 4.9 and 49 mg/kg/day, respectively.
N provided additional support for immunotoxicity. It was a 13-week oral gavage study of
F344/N rats dosed with 30, 60, 120, 240, or 480 mg/kg for males or 18, 37, 75, 150, or 300 for females
of 1,2-dichloroethane that observed possible dose-related incidences of thymus necrosis. Female rat
absolute thymus weight was decreased. The study quality was limited by lack of drinking water
consumption reporting that would ensure consistent dosing of test animals throughout the study and by
changes in thymus co-occurring with mortality. ] also reported a statistically significant
absolute and relative kidney weights at 60 and 120 mg/kg/day or 75 and 150 mg/kg/day in male or
female rats, respectively. Increased absolute kidney weight was initially seen at 30 mg/kg in male mice.
EPA's independent convergence on Munson 2) for the non-cancer, oral, short-term POD
selection is validated by the 2022 ATSDR Toxicological Profile for 1,2-Dichloroethane (ATSDR.
2022). which also identified immunosuppression as the most sensitive human health protective endpoint.
It is important to emphasize that immunotoxicity found in 1,2-dichloroethane databases is recognized as
a cancer mechanism (Hanahan and Weinberg. 2011). Specifically, inflammatory cell recruitment that
can actively promote tumor formation and was observed in Munson et 82) through cell-mediated
immune responses.
Several other studies were considered from across 1,2-dichloroethane databases, including changes in
kidney organ weight from a drinking water study from 1,2-dichloroethane (N ), as discussed;
reproductive/developmental outcomes following exposure to 1,2-dichloroethane, including fetal
resorptions and decreases in maternal body weight (Payan et al.. 1995) and likely confounded results for
fertility and implantation success for 1.2-dichloroethanel .anc et al. (1982).
Inhalation
A 4-week, short-term study in male mice exposed to 1,2-dichloroethane by Zhang et al. (2017) with a
BMCLs and BMC5 of 6.6 ppm (26.7 mg/m3) and 5.24 ppm (21.2 mg/m3), was identified based on
decreased sperm concentration. The short-term/sub chronic inhalation HEC for occupational and
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1776 continuous exposure of 22 ppm (89 mg/m3) and 5.2 ppm (21.2 mg/m3), with a benchmark MOE of 100,
1777 was used to assess short-term/subchronic inhalation exposure (see Table 8-2).
1778
1779 Dermal
1780 No short-term/subchronic exposure studies on 1,2-dichloroethane via the dermal route were located.
1781 Therefore, the short-term/subchronic oral HED for occupational and continuous exposures of 171 and
1782 239 mg/kg-bw/day was extrapolated for the dermal route, with a benchmark MOE of 100, and was used
1783 to assess short-term dermal exposure (see Table 8-2).
1784
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1785 Table 6-3. Short-Term/Subchronic, Oral, Non-cancer POD-Endpoint Selection Table
Chcmicsil/Enri point
POD fmg/kg/riiiy)
Study Parameters
Comments
l'( )l) selecled lor non-cancer risk e\ alualion lor shori-icrm suhchroinc oral exposures
1,2 -Dichloroethane
Decreased cell based immune
response
LOAELadj = 4.9
Munson et al. (1982). Gavaee. SRHieh
CD1 Mice - Both sexes
14 days (0, 4.9, 49 mg/kg-day)
ATSDR (2022) Report for 1,2-dichloroethane confirms that
immunosuppression is the most sensitive human health protective
endpoint, Other similar chlorinated solvents demonstrate
immuno toxicity.
( o-crilical eudpoiuls
1.2-1 )idiloroelhane
1 )ec leased leukocytes
I.OMI. 4>)
( i;i\ age. Sk 1 ligli
CD1 Mice - Both sexes
14 days (0, 4.9, 49 mg/kg-day)
Supports cell-based immunosuppression endpoiiii.
(Mlier siudies eudpoiuls considered
1,2 -Dichloroethane
Immune (thymus)
NOAEL=240
mg/kg-day
(males); 150
mg/kg-day
(females)
LOAEL= 480
mg/kg-day for
thymus necrosis in
males; 300 mg/kg-
day for thymus
necrosis in females
NTP (1991). Gavaee. SRHieh
F344 Rats - Both sexes
13 weeks (0, 30, 60, 120, 240, 480 mg/kg-
day (males); 0, 18, 37, 75, 150, 300
mg/kg/day (females)
Qualitatively supports immunosuppression. However, thymus
necrosis occurs at dosages where mortality was also occurring
therefore cannot be used as a POD.
1,2 -Dichloroethane
Kidney weight
LOAEL = 30
(males)
LOAEL = 75
(females)
NTP (1991). Gavaee. SRHieh
F344 Rats - Both sexes
13 weeks (0, 30, 60, 120, 240, 480 mg/kg-
day (males); 0, 18, 37, 75, 150, 300
mg/kg/day (females)
Study was considered for POD selection but not selected as this is
not the most sensitive endpoint compared to immunosuppression.
1,2-Dichloroethane,
Fetal resorptions
NOAEL=160
LOAEL=200
(Data were not
amenable for
BMD modeling)
Pavan et al. (1995). Gavaee
Pre-Natal Developmental, SR High
SD Rats - Female
Dosing GD6-20 (0, 120, 160, 200, or 240
mg/kg)
The increases in non-implants and resorptions are difficult to
interpret given the significant maternal toxicity at corresponding
doses (30 and 49% at 200 and 240 mg/kg/day, respectively)
consisting of decreases in maternal bw gain, and the fact that there
was no effect on the number of live fetuses per litter despite the
changes in non-surviving implants/litter and resorption sites/litter.
Therefore, cannot be used as POD.
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Chemical/End point
POD (mjj/kjj/day)
Study Parameters
Comments
1,2 -Dichloroethane
Decreases in maternal body
weight gain
NOAEL=160
LOAEL=200
(BMD = 99.1;
BMDL = 41.8)
Pavan et al. (1995). Gavaee
Pre-Natal Developmental, SR High
SD Rats - Female
Dosing GD6-20 (0, 120, 160, 200, or 240
mg/kg)
A dose-related reduction in adjusted (for gravid uterine weight)
maternal bodyweight gain during treatment occurred, with
statistical significance achieved at the two highest doses (30 and
49% reduction compared with controls, p < 0.05). However, this
POD is not as sensitive (LOAEL = 200; BMDL = 41.8) as the
Immunotoxicity Endpoint (LOAELadj = 4.9).
1,2 -Dichloroethane
Multigenerational/reproductive
pup weight
LOAEL= 50
Lane et al. (1982), Drinking Water, SR High
ICR Mice - Both Sexes
Multigenerational (0, 5, 15 or 50 mg/kg-day)
Drinking water not measured to confirm actual dosage, therefore
not reliable for a dose-response analysis. Also, not as sensitive
(LOAEL = 50) as the Immunotoxicity Endpoint identified in the
Munson et al. (1982), LOAELadj = 4.9.
Pup weight was biologically significantly (>5%) decreased at >0.09
mg/ml (50mg/kg/day) in Fl/B mice.
1,2 -Dichloroethane
Chronic 26-week dermal study
Decreased body weight in
females; increased distal
tubular mild karyomegaly (both
sexes); renal karyomegaly and
tubular degeneration (females)
LOAEL= 6,300
Sueiiro et al. (2017). Dermal. SRHieh
CB6F1- Tg rasH2@Jcl (rasH2) mice - Both
sexes
3 days/week 26 weeks (0, 126 mg; 0, 6,300
mg/kg-day
Not considered acceptable for dose response assessment as the
study used a single dose using transgenic mice.
1786
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1787 Table 6-4. Short-Term/Subchronic, Inhalation, Non-cancer POD-Endpoint Selection Table
Chemical F.ndpninKs)
POD (mjj/m3)
Study Parameters
C nmmcnts
l'( )l) sckvlcd li>r ikin-c;iik.vr risk e\ ;ilii;ilkiher sindies ciklpoiiiis considered
1,2 -Dichloroethane
Liver
LOAEL = 3,424
B rondeau et al. (1983). Vaoor. SR
Medium
SD Rats - Males
6 hours/day for 2 or 4 days; 0 or 3424
mg/m3
6 hours/day for 2 days:
Significant increases in serum ALT, GLDH, and SDH levels ; liver
histopathology and organ weight were not assessed.
6 hours/day for 4 days:
Serum SDH levels were significantly increased.
Liver histopathology and organ weight were not assessed.
1,2 -Dichloroethane
Liver
LOAEL = 619
I ewe et al. (1986c). Vaoor. SRHieh
SD Rats - Male
7 hours/day, 5 days/week, 4 weeks: 0,
153, 304, 455 ppm; 619, 1,230, and
1,842 mg/m3
Increased relative liver weight and 5'-NT. Absolute liver weight was not
reported. No changes in hepatic GST activity, hepatic DNA content, or
serum enzymes ALT or SDH were observed at any concentration.
1,2 -Dichloroethane
Liver/reproductive/
metabolic/mortality
Immune:
NOAEL = 1,842
Reproductive:
NOAEL = 1,842
I ewe et al. (1986c). Vaoor. SRHieh
SD Rats - Male
7 hours/day, 5 days/week, 30 days:
0, 153, 304, 455 ppm; 619, 1,230, and
1,842 mg/m3
Immune, Reproductive/Developmental: No effects on organ weight or
histopathology.
Liver: Increased relative liver weight, absolute liver weight was not
reported.
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Chemical End|)oint(s)
POD (mjj/m3)
Study Parameters
Comments
Liver:
LOAEL = 619
Mortality, Metabolic:
NOAEL = 619
LOAEL = 1,230
Mortality: Occurred in 1/12 and 2/12 animals in 1,230 and 1,842 mg/m3,
respectively
Metabolic: Decreased body weight.
NOAEL/LOAEL higher than recommended endpoint.
Not amenable to BMD modeling
1,2-Dichloroethane-
Reproductive/
developmental/
maternal toxicity
Reproductive/
Developmental
NOAEL = 1,200
Maternal Toxicity:
NOAEL = 1,000
LOAEL = 1,200
Pavan et al. (1995). Vaoor. SRHieh
SD Rats - Both Sexes
Inhalation exposure for 2 weeks. GD
6-20. 6 hours/day 7 days/week,
0, 150, 200, 250, 300 ppm; 0, 610,
820, 1,000, 1,200 mg/m3
Reproductive/Developmental Toxicity: Pregnancy rate among females at
250 ppm was significantly lower, but not at 300 ppm; no other
significant effects reported.
Maternal Toxicity: 2/26 dams died at 300 ppm (highest dose). Maternal
body weight gain at GD 6-21 was significantly decreased at 300 ppm.
No mention of food consumption.
NOAEL/LOAEL higher than recommended endpoint.
Not amenable to BMD modeling.
1,2 -Dichloroethane
Reproductive/
developmental; maternal
toxicity
Reproductive/
Developmental
LOAEL = 405
Maternal Toxicity:
NOAEL = 405
LOAEL = 1,214
Rao et al. (1980). Vaoor. SR Medium
SD Rats - Female
Inhalation exposure for 10 days. GD
6—15. 7 hours/day. 0, 100, 300 ppm
(0, 405, 1,214 mg/m3)
Developmental Toxicity: A significant decrease in the incidence of
bilobed thoracic centra was seen at 100 ppm however study essentially
becomes a single dose study and not amenable to dose-response
modeling due to the high maternal toxicity at 300 ppm (10/16 maternal
rats died at 300 ppm). Therefore, this study is not acceptable for POD
derivation.
1,2 -Dichloroethane
Immunological/
streptococcal infection
challenge
CD-I Mice:
NOAEL = 9.21
SD Rats:
NOAEL = 400.6
Sherwood et al. (1987). Vaoor. SR
High
CD-I Mice - Female
3 hours/day, 5 days/week, 5 days; 0,
2.3; 0,9.21 mg/m3
SD Rats - Male
5 hours/day, 5 days/week, 12 days; 0,
10, 20, 50, 100; 0, 40.1, 80.1, 200.3,
400.6 mg/m3
CD-I mice and SD rats showed no effects.
1,2 -Dichloroethane
Liver/metabolic
Liver:
NOAEL = 350
Metabolic:
NOAEL = 350
LOAEL = 700
Zeng et al. (2018), Aerosol, SRHigh
Swiss Mice: Male
6 hours/day, 7 days/week, 28 days
0, 350, 700 mg/m3
Liver: Increased absolute and relative liver weight, increased liver
concentrations of glycogen, triglycerides, and free fatty acids at all
concentrations; increased ALT (1.9-fold) at 700 mg/m3; increased
serum AST (1.3-fold to 1.7-fold), triglycerides, and free fatty acids;
decreased serum glucose at both exposure concentrations.
Metabolic: Body weight was significantly reduced at 700 mg/m3.
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Chemical End|)oint(s)
POD (mjj/m3)
Study Parameters
Comments
1,2 -Dichloroethane
Neurological,
Reproductive,
Immune/Hematological,
Liver, Mortality,
Metabolic, Kidney (Rat):
Respiratory:
NOAEL = 809
Liver, Metabolic and
Kidney (Guinea Pig):
NOAEL = 405
Spencer et al. (1951). Vaoor. SR
Medium
Wistar Rats - Both sexes
7 hours/day 5 days/week
212 days*, (0, 100, 200, 400 ppm; 0,
405, 809, 1,619 mg/m3)
*Although all exposure
groups were intended for chronic
duration exposures, animals at the
high exposure level died within 14
days (females) and 56 days (males).
Guinea Pigs - Both sexes
7 hours/day 5 days/week
248 days, (0, 100, 200, 400 ppm; 0,
405, 809, 1,619 mg/m3)
Rats: High mortality at 400 ppm starting at 2 weeks; no other effects
reported.
Guinea Pigs: High mortality at 400 ppm starting at 2 weeks; reductions
in body weight starting at 100 ppm; increases in liver weight; possible
liver histopathology and changes in kidney weight, but incidence not
reported.
1788
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6.1.4 Non-cancer PODs for Chronic Exposures
Oral
Table 6-5 shows the recommended chronic oral study and POD for 1,2-dichloroethane followed by co-
critical endpoints (PODs within the range of the recommended study) and other studies considered in
support of the recommended POD.
No studies of chronic oral exposure in laboratory animals were considered suitable for POD
determination (see Section F.3 for 1,2-dichloroethane). Therefore, the short-term/sub chronic POD
identified in Section 6.1.3 was also used for chronic exposure. The short-term/sub chronic continuous
HED was 0.636 mg/kg-bw/day and the worker HED was 0.890 mg/kg-bw/day (see Appendix F.2). The
benchmark MOE for this POD is 1,000 based on 3 for interspecies extrapolation when a dosimetric
adjustment is used, 10 for human variability, 3 for the use of a LOAEL to extrapolate a NOAEL (based
on the dose-response), and 10 for extrapolating from a subchronic study duration to a chronic study
duration for chronic exposures (see Table 8-3).
Inhalation
Table 6-6 shows the recommended chronic inhalation study and POD for 1,2-dichloroethane followed
by co-critical endpoints (PODs within the range of the recommended study) and other studies considered
in support of the recommended POD.
No chronic PODs were identified from studies for inhalation exposures to 1,2-dichloroethane. A 4-week
short-term study in male mice exposed to 1,2-dichloroethane by Zhang et al. (2017) was used. A
duration extrapolation from the 4-week short-term/sub chronic to a chronic duration was conducted in
order to account for uncertainty. A subchronic to chronic UF of 10 was thus applied for extrapolating
from a subchronic to chronic study duration. A BMCLs and BMCs of 6.6 ppm (26.7 mg/m3) and 5.24
ppm (21.2 mg/m3), were identified based on decreased sperm concentration. The short-term/sub chronic
inhalation HEC for occupational and continuous exposure of 22 ppm (89 mg/m3) and 5.2 ppm (21.2
mg/m3), respectively, with a benchmark MOE of 300, was used for risk assessment of chronic inhalation
exposure. Although an uncertainty regarding study duration may have been reduced by use of the
chronic (Nagano et al.. 2006) study that evaluated 1,2-dichloroethane, the study did not adequately
evaluate non-cancer effects, preventing the determination of a non-cancer chronic POD.
Dermal
No chronic studies on 1,2-dichloroethane via the dermal route were located. Therefore, the chronic oral
HED for occupational and continuous exposures of 0.89 and 0.636 mg/kg-bw/day, respectively, was
extrapolated for the dermal route, with a benchmark MOE of 1,000, and was used for risk assessment of
chronic dermal exposure (see Table 8-3).
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Table 6-5. Chronic, Oral, ]>
on-cancer POD-Endpoint Selection Table
Chemical Endpoint(s)
POD
(mjj/kg/day)
Study Parameters
Comments
POD selected for non-cancer risk evaluation for chronic oral exposures
1,2-Dichloroclhanc
Decreased cell based immune
response
LOAELadj — 4.9
Munson et al. (1982). Gavase
SR High
CD1 Mice - Both sexes
14 days (0, 4.9, 49 mg/kg-day)
; ; Report for 1.2-dichlorocthane confirms that
immunosuppression is the most sensitive human health
protective endpoint, Other similar chlorinated solvents
demonstrate immunotoxicity.
( o-crilical eudpoiuls
1,2-Dichloroe thane
Decreased leukocytes
i.o\i:i. 4<>
(ia\ aue
SR High
CD1 Mice - Both sexes
14 days (0, 4.9, 49 mg/kg-day)
Supports cell-based immunosuppression endpoint
()tlier studies considered
1.2-1 )iehloroelhane
Immune (thymus)
\()\i:i. 24u nig kg-dav
(males); 150 mg/kg-day
(females)
LOAEL = 480 mg/kg-day
for thymus necrosis in
males; 300 mg/kg-day for
thymus necrosis in females
. Uivaue. Sk Midi (VIP
1991)
F344 Rats - Both sexes
13 weeks (0, 30, 60, 120, 240, 480
mg/kg-day (males); 0, 18, 37, 75, 150,
300 mg/kg/day (females)
Qualitatively supports immunosuppression. However,
thymus necrosis occurs at dosages where mortality was also
occurring therefore cannot be used as a POD.
1,2 -Dichloroethane
Kidney weight
LOAEL = 30 (males)
LOAEL = 75 (females)
NTP (1991). Gavase. SRHish
F344 Rats - Both sexes
13 weeks (0, 30, 60, 120, 240, 480
mg/kg-day (males); 0, 18, 37, 75, 150,
300 mg/kg/day (females)
Study was considered for POD selection but not selected as
this is not the most sensitive endpoint compared to
immunosuppression.
1,2 -Dichloroethane
Fetal resorptions
NOAEL = 160
LOAEL = 200
(Data were not amenable to
modeling)
Pavan et al. (1995). Gavase
Prenatal Developmental, SR High
SD Rats - Female
Dosing GD6-20 (0, 120, 160, 200, or 240
mg/kg)
The increases in non-implants and resorptions are difficult to
interpret given the significant maternal toxicity at
corresponding doses (30 and 49% at 200 and 240 mg/kg/day,
respectively) consisting of decreases in maternal bw gain,
and the fact that there was no effect on the number of live
fetuses per litter despite the changes in non-surviving
implants/litter and resorption sites/litter. Therefore, cannot be
used as POD.
1,2-Dichloroethane,
NOAEL = 160
LOAEL = 200
Pavan et al. (1995). Gavase
Prenatal Developmental, SR High
A dose-related reduction in adjusted (for gravid uterine
weight) maternal bodyweight gain during treatment occurred,
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Chemical End|)oint(s)
POD
(mjj/kg/day)
Study Parameters
Comments
Decreases in maternal body
weight gain
(BMD = 99.1; BMDL =
41.8)
SD Rats - Female
Dosing GD 6-20 (0, 120, 160, 200, or
240 mg/kg)
with statistical significance achieved at the two highest doses
(30 and 49% reduction compared with controls, p < 0.05).
However, this POD is not as sensitive (LOAEL = 200;
BMDL = 41.8) as the Immunotoxicity Endpoint (LOAELadj
=4.9).
1,2 -Dichloroethane
Multigenerational/reproductive
pup weight
I.OAF.I. = 50
Lane et al. (1982), Drinking Water, SR
High
ICR Mice - Both Sexes
Reproductive Toxicity
(0, 5, 15 or 50 mg/kg-day)
Drinking water not measured to confirm actual dosage. Also,
not as sensitive (LOAEL=50) as the Immunotoxicity
Endpoint (LOAEL =4.9)
Pup weight was biologically significantly (>5%) decreased at
>0.09 mg/ml (50mg/kg/day) inFl/B mice.
1,2 -Dichloroethane
40-week chronic study
Body weight/lymphoma
I.OAF.I. = 150 (females)
Storeret al. (1995). Gavaee. SR Medium
ppG64 Mice - Both sexes
7 days/week for 40 weeks (0, 150, 300
mg/kg-day (female); 0, 100, 200
mg/kg/day (males)
Minimal endpoints evaluated, only non-cancer endpoints
were body weight and lymphoma at 150.
Doses adjusted due to substantial mortality females at 300
mg/kg/day. Clear dose-response could not be assessed.
1,2 -Dichloroethane
Chronic 26-week dermal study
I.OAF.I. = 6300
Decreased body weight in
females; increased distal
tubular mild karyomegaly
(both sexes); renal
karyomegaly &
tubular degeneration
(females)
Sueiiro et al. (2017). Dermal. SRHieh
CB6F1- Tg rasH2@Jcl (rasH2) mice -
Both sexes
3 days/week 26 weeks (0, 126 mg; 0,
6300 mg/kg-day
Single dosage using transgenic mice.
1828
1829
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1830 Table 6-6. Chronic, Inhalation, Non-cancer POD-Endpoint Selection Table
Chcmical-Endpoint
POD
(mjj/em3)
Study Parameters
Comments
POD selected for non-cancer risk evaluation for chronic inhalation exposures
1,2 -Dicliloroe thane
Male reproductive
BMDL5 = 21.2 nig/1113
NOAEL: 350
LOAEL: 700
zjihmk ci ai. (2u i /», 4 week morphological
analysis of sperm parameters, SR High
Swiss Mice - Male
6 hours/day 7 days/week 4
weeks (0, 100, 350, 700
mg/m3)
Decreases in sperm concentration.
( o-enHeal eudpoiiiis
1,2 -Dichloroethanc.
Fetal development
keprodueliv e
Developmental
BMDL5= 25 Pup BW
decreased at 613
BMDLio= 50 mg/m3
NOAEL: 305
LOAEL: 613
. \ apor. SR Medium
SD Rats - Both sexes
Inhalation. Prior to mating, rats were exposed for
60 days (6 hours/day, 5 days/week). The rest of the
time, exposed to 6 hours/day, 7 days/week, except
from gestational day 21-post natal day 4 maternal
exposure stopped to allow for delivery and rearing
of the young). Two F1 generations were evaluated,
0,25,75,150 ppm; 0, 102, 305 or 613 mg/m3
Decreased hods weight of selected I'll! male weanlings al I5(>
ppm.
Study used for co-critical endpoints with BMDL10 very close to
that from the recommended endpoint. Considering
NOAELs/LOAELs, using the recommended endpoint will be
protective of the decreases in pup body weight. Also, portal of
entry effects can be considered more sensitive than systemic
effects.
()lher studies considered
1,2 -Dichloroethane
Reproductive/
Developmental
NOAEL: 1,200
Pavan et al. (1995). Vaoor. SRHieh
SD Rats - Both Sexes
Repro/Dev Toxicity: Pregnancy rate among females at 250
ppm was significantly lower; not observed at the highest
concentration of 300 ppm; no other significant effects reported.
Maternal Toxicity:
NOAEL = 1000
LOAEL = 1,200
Inhalation exposure for 2 weeks. GD 6-20. 6
hours/day 7 days/week,
0, 150, 200, 250, 300 ppm; 0, 610, 820, 1,000,
1,200 mg/m3
Maternal Toxicity: 2/26 dams died at 300 ppm (highest dose).
Maternal body weight gain at GD 6-21 was significantly
decreased at 300 ppm. No mention of food consumption.
NOAEL/LOAEL higher than recommended endpoint.
Not amenable to BMD modeling.
1,2 -Dichloroethane
Reproductive/
Developmental
LOAEL = 405
Maternal Toxicity:
NOAEL = 405
LOAEL = 1214
Rao et al. (1980). Vaoor. SR Medium
SD Rats - Female
Inhalation exposure for 10 days. GD 6-15. 7
hours/day.0, 100, 300 ppm (0, 405, 1,214 mg/m3)
Developmental Toxicity: A significant decrease in the
incidence of bilobed thoracic centra was seen at 100 ppm
however study essentially becomes a single dose study and not
amenable to dose-response modeling due to the high maternal
toxicity at 300 ppm (10/16 maternal rats died at 300 ppm).
Therefore, this study is not acceptable for POD derivation.
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Chcmical-Endpoint
POD
(mjj/em3)
Study Parameters
Comments
1,2 -Dichloroethane
Hematological:
NOAEL = 202
LOAEL = 607
Liver:
LOAEL = 20
Kidney:
NOAEL = 202
LOAEL = 607
IRFMN (1978). Vaoor. SR Medium
SD Rats - Both sexes
7 hours/day, 5 days/week for 12
months: 0, 5, 10, 50, 150 ppm; 0, 20, 40, 202, 607
mg/m3
Hemoglobin levels were significantly decreased in both sexes
at 150 ppm; changes in hematocrit (increases rather than
decreases) were of questionable biological significance and did
not show a dose-response; decreases in cholesterol and calcium
levels at >10 ppm; clinical chemistry signs of liver toxicity but
did not show a dose-response, kidney BUN increases at 150
ppm; other kidney changes were male rat-specific and not
relevant to humans.
1,2 -Dichloroethane
Reproductive/Development
al, Mortality & Metabolic:
NOAEL: 204
Liver:
LOAEL: 204
Cheeveret al. (1990). Vaoor. SRHieh
SD Rats - Both sexes
7 hours/day 5 days/week
104 weeks (0, 50 ppm; 0, 204 mg/m3)
Gross testicular lesions were found in higher frequency in
exposed males (24%) compared to control (10%) (data not
shown and gross pathologic observations were not evaluated
statistically); mortality similar in both treatment and control
groups, survival rate in exposed rats (60 and 64%) was similar
to control (58 and 54%) in males and females, respectively;
absolute and relative liver weights were not different from
controls.
1,2 -Dichloroethane
Immunological/
Hematological, Liver, and
Kidney:
NOAEL = 809
IRFMN (1976). Vaoor. SR Medium
SD Rats - Both sexes
7 hours/day 5 days/week 24
weeks, (0, 5, 10, 50, 150, 250
ppm; 0, 20, 40, 202, 607, 1,012 mg/m3)*
*Animals in the highest exposure group were
exposed to 250 ppm for "a few weeks" and then
the exposure concentration was reduced to 150
ppm due to acute toxicity. A reliable TWA
concentration cannot be determined based on the
information available in this report, IRFMN (1978)
suggested that the change occurred after 12 weeks
of exposure. If this is accurate, then the TWA
exposure concentration for the high exposure
group was 200 ppm.
All observed hematological, serum chemistry, and
urinalysis changes observed either did not reach
statistical significance, showed no clear relation to
exposure concentration, and/or were not biologically
significant.
1,2 -Dichloroethane
Immunological/
Hematological, Liver, and
Kidney:
NOAEL = 607
IRFMN (1987). Vaoor. SR Medium
SD Rats - Both sexes
Significant decrease in segmented neutrophils in the high
exposure group in males; no other hematological changes were
observed; serum liver and kidney chemistry changes either did
not reach statistical significance, showed no clear relation to
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Chcmical-Endpoint
POD
(mjj/em3)
Study Parameters
Comments
7 hours/day 5 days/week 78
weeks, (0, 5, 10, 50, 150, 250
ppm; 0, 20, 40, 202, 607, 1012 mg/m3)*
exposure, concentration, and/or were not biologically
significant; no urinary changes were observed.
*Animals in the highest exposure group were
exposed to 250 ppm for "a few weeks" and then
the exposure concentration was reduced to 150
ppm due to acute toxicity. A reliable TWA
concentration cannot be determined based on the
information available in this report, IRFMN (1978)
suggested that the change occurred after 12 weeks
of exposure. If this is accurate, then the TWA
exposure concentration for the high exposure
group was 200 ppm.
1,2 -Dichloroethane
Mortality (Rats):
NOAEL = 654
Mortality (Mice):
NOAEL = 368
Nagano et al. (2006)
F344 Rats - Both sexes
6 hours/day 5 days/week 104 weeks total, (0, 10,
40, 160 ppm; 0, 41, 164 or 654 mg/m3)
Crj:BDFl Mice - Both sexes
6 hours/day 5 days/week 104 weeks total, 0, 10,
30, 90 ppm; 0, 41, 123 or 368 mg/m3)
Endpoints evaluated included mortality, clinical signs of
toxicity, body weight, food consumption, hematology, blood
biochemistry, urinalysis, organ weight, gross necropsy of
organs and histopathology. No significant effects reported.
1,2 -Dichloroethane
Immune/Hematological
Nutritional/Metabolic,
Liver, Mortality, and
Kidney
(Rats/Rabbits/Guinea
Pigs/Cats):
NOAEL = 405
Hofmann et al. (1971). Vaoor. SR Medium
SD Rats - Both sexes
Bunte Rabbits - Both sexes
Pirbright - White Guinea Pigs - Both sexes
Cats - Both sexes
6 hours/day 5 days/week 17
weeks, (0, 100 ppm; 0, 405 mg/m3)
The endpoints evaluated included mortality, body weights,
hematological effects (blood counts, not further specified),
liver effects (serum AST and ALT, liver weight, and liver
histology), and renal effects (BUN and serum creatinine,
urinary status - not further specified, kidney weight, and
kidney histology); bromsulphthalein test in rabbits & cats does
not indicate liver effects.
Rats, cats, and guinea pigs: No significant effects reported.
One of 4 rabbits showed increased BUN and kidney histology
(not further specified); the observation of these effects in 1
rabbit was not considered adverse (or of questionable
adversity).
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Chcmical-Endpoint
POD
(mjj/em3)
Study Parameters
Comments
1,2 -Dichloroethane
Neurological, Liver, and
Mortality (Rabbits):
Not determined
Hematological, Kidney,
Liver, and Mortality
(Monkeys):
NOAEL = 405
Spencer et al. (1951). Vapor. SR Medium
Rabbit - Both sexes
7 hours/day 5 days/week
248 days*, (0, 100, 400 ppm; 0, 405, 1,619
mg/m3)
*The exact duration of exposure is unclear. At 400
ppm rabbits "tolerated" exposure for 232 days"
and at 100 ppm, rabbits "tolerated" exposure for
248 days without signs of adverse effects; the time
of termination is not specified.
Monkeys - Males
7 hours/day 5 days/week
212 days*, (0, 100, 400 ppm; 0, 405, 1619 mg/m3)
*At 400 ppm both Monkeys were killed in a
moribund state after 8 and 12 exposures,
respectively. The duration noted above applies
only to the 100 ppm group.
Wistar Rats - Both sexes
7 hours/day 5 days/week
212 days*, (0, 100, 400 ppm; 0, 405, 1619 mg/m3)
*Although all exposure groups were intended for
chronic duration exposures, animals at the high
exposure level died within 14 days (females) and
56 days (males).
Guinea Pigs - Both sexes
7 hours/day 5 days/week
248 days, (0, 100, 200, 400 ppm; 0, 405, 809,
1,619 mg/m3)
No significant effects reported in rabbits; histopathological
changes reported in the liver and kidney in monkeys; mortality
observed in rats and guinea pigs; uncertain signs of body
weight changes, and possible signs of liver and kidney toxicity
in guinea pigs but the data either did not show dose-response,
or quantal data for these endpoints or incidence values and a
statement whether any control animals exhibited these changes
were not included.
1831
1832
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6.2 Summary of Studies Not Considered/Considered Suitable for POD
Determination of 1,2-Dichloroethane
According to )21) Draft Systematic Review Protocol, hazard endpoints that receive
evidence integration judgments of demonstrates and likely would generally be considered for dose-
response analysis. Endpoints with suggestive evidence can be considered on a case-by-case basis.
Studies that received high or medium overall quality determinations (or low-quality studies if no other
data are available) with adequate quantitative information and sufficient sensitivity can be compared.
The only hazard outcome for which evidence demonstrates that 1,2-dichloroethane causes the effect was
mortality. For neurological/behavioral effects, EPA's evidence integration judgment was likely. For
nutritional/metabolic, renal/kidney, hepatic/liver, lung/respiratory, immune/hematological, and
reproductive effects, EPA's evidence integration conclusion was that the evidence was suggestive.
Finally, EPA concluded that the available evidence was inadequate to determine whether 1,2-
dichloroethane induces developmental effects.
No human studies provided adequate information for POD determination. Animal studies of oral,
inhalation, or dermal exposure that received high or medium quality determinations for one or more of
these health outcomes were considered for dose-response information, with some exceptions. Studies
that identified a NOAEL at the highest dose/concentration tested were not considered for dose-response
assessment but were considered as part of evidence integration for the relevant health outcomes. In
addition, acute lethality studies that did not include untreated or vehicle-treated controls, or other studies
that did not present sufficient information to determine a NOAEL or LOAEL were not considered.
Finally, only studies in intact, wild-type laboratory animal strains were considered for dose-response
assessment. A small number of studies using partially-hepatectomized animals or transgenic models
were excluded from consideration, as shown in the tables.
Table 6-7, Table 6-8 and Table 6-9 show the animal studies of oral, inhalation, and dermal exposure
(respectively) that were excluded from consideration for dose-response assessment along with the reason
for excluding each. Table 6-10 summarizes studies that were considered for dose-response assessment
for 1,2-dichloroethane. Table 6-11, Table 6-12, Table 6-13, Table 6-14, and Table 6-15 summarize
candidate PODs for acute, short-term/sub chronic, or chronic durations via for oral or inhalation
exposure.
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Table 6-7. Oral Studies Not Considered Suitable for
'ODs for 1,2-Dich
oroethane
Duration
Category
Reference
HERO ID
Species
Specific
Route
Rationale
Acute
Cottalasso et al. (1995)
200280
Rat
Gavage
Not suitable for POD due to
dosing uncertainties
Acute
Dow Chemical (2006a)
625286
Rat
Gavage
Freestanding NOAEL"
Acute
Kettering Laboratory (1943)
4528351
Rabbit
Gavage
Uninformative
Acute
Kitchin et al. (1993)
6118
Rat
Gavage
Freestanding NOAEL"
Acute
Mellon Institute (1948)
5447301
Rat
Gavage
Uninformative
Acute
Mellon Institute (1948)
5447301
Mouse
Gavage
Uninformative
Acute
Mellon Institute (1948)
5447301
Rabbit
Gavage
Uninformative
Acute
Moodv et al. (1981)
18954
Rat
Gavage
Not suitable for POD; evaluation
limited to liver weight and data
not shown
Acute
Munson et al. (1982)
62637
Mouse
Gavage
Low
Acute
Stauffer Cliem Co (1973)
6569955
Rat
Gavage
Not suitable for POD; no control
group
Acute
Milman et al. (1988)
200479
Rat
Gavage
Study of partially
hepatectomized animals
Short-term
Dow Chemical (2006a)
625286
Rat
Gavage
Freestanding NOAEL"
Short-term
NTP (1978)
5441108
Mouse
Gavage
Freestanding NOAEL"
Subchronic
Milman et al. (1988)
200479
Rat
Gavage
Study of partially
hepatectomized animals
Subchronic
Aluinot et al. (1976)
194588
Rat
Diet
Freestanding NOAEL" (for 5-
week female and 13-week male
growth studies)
not suitable for POD due to
dosing uncertainties (for 5- to 7-
week preliminary study)
Subchronic
NTP (1991)
1772371
Rat
Drinking
water
Uninformative
Subchronic
NTP (1991)
1772371
Mouse
Drinking
water
Uninformative
Subchronic
Munson et al. (1982)
62637
Mouse
Drinking
water
Uninformative
Chronic
Aluinot et al. (1976)
194588
Rat
Diet
Uninformative
Chronic
Klaunig et al. (1986)
200427
Mouse
Drinking
water
Not suitable for POD due to
reporting limitations
Chronic
Storeret al. (1995)
200612
Mouse
Gavage
Study of transgenic mice
predisposed to cancer
Chronic
NTP (1978)
5441108
Mouse
Gavage
Not suitable for POD due to
confounding by tumors
Chronic
NTP (1978)
5441108
Rat
Gavage
Uninformative
Reproduction/
Developmental
Lane et al. (1982)
62609
Mouse
Drinking
water
Freestanding NOAEL"
Reproduction/
WIL Research (2015)
7310776
Rat
Drinking
Uninformative
Developmental
water
Reproduction/
Aluinot et al. (1976)
194588
Rat
Diet
Uninformative
Developmental
" No effects observed at highest dose tested for all apical health outcomes rated Low or higher.
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Table 6-8. Inhalation Studies Not Considered Suitab
e for PC
»Ds for 1,2-Dichloroethane
Duration
Category
Reference
HERO ID
Species
Rationale
Acute
Brondeau et al. (1983)
200247
Rat
Not suitable for POD due to limited
evaluations
Acute
Dow Chemical (2005)
10699112
Rat
Not suitable for POD determination; no
control group
Acute
Dow Chemical (2017)
10699356
Rat
Not suitable for POD determination; no
control group
Acute
Sherwood et al. (1987)
200590
Rat
Freestanding NOAEL"
Acute
Guo and Niu (2003)
200352
Rat
Uninformative
Acute
Jin et al. (2018a): Jin et al.
(2018b)
5431556,
5557200
Mouse
Uninformative
Acute
Mellon Institute (1948)
5447301
Rat
Uninformative
Acute
Mellon Institute (1948)
5447301
Rabbit
Uninformative
Acute
Mellon Institute (1948)
5447301
Mouse
Uninformative
Acute
Spencer et al. (1951)
62617
Rat
Not suitable for POD determination; no
control group
Acute
Zhang et al. (2011)
734177
Rat
Uninformative
Short-term
Brondeau et al. (1983)
200247
Rat
Not suitable for POD due to limited
evaluations
Short-term
Dow Chemical (2014)
10609985
Rat
Freestanding NOAEL"
Short-term
Jin et al. (2018a): Jin et al.
(2018b)
5431556,
5557200
Mouse
Uninformative
Short-term
Li et al. (2015)
4492694
Rat
Uninformative
Short-term
Pane et al. (2018)
4697150
Rat
Uninformative
Short-term
Sherwood et al. (1987)
200590
Rat
Freestanding NOAEL3
Short-term
Sherwood et al. (1987)
200590
Mouse
Freestanding NOAEL"
Short-term
Spencer et al. (1951)
62617
Rat
Uninformative
Short-term
Spencer et al. (1951)
62617
Guinea
Pig
Uninformative
Short-term
Sun et al. (2016c)
4451633
Mouse
Uninformative
Short-term
Wane et al. (2013)
1522109
Mouse
Uninformative
Short-term
Wane et al. (2014)
4453007
Mouse
Uninformative
Short-term
Zhane and Jin (2019)
5556105
Mouse
Uninformative
Subchronic
Hofmann et al. (1971)
1937626
Rat
Uninformative
Subchronic
Hofmann et al. (1971)
1937626
Guinea
Pig
Uninformative
Subchronic
Hofmann et al. (1971)
1937626
Cat
Not suitable for POD due to reporting
limitations and small group size6
Subchronic
Hofmann et al. (1971)
1937626
Rabbit
Uninformative
Subchronic
Kettering Laboratory (1943)
4528351
Rabbit
Uninformative
Chronic
Cheeveret al. (1990)
12097
Rat
Freestanding NOAEL"
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Duration
Category
Reference
HERO ID
Species
Rationale
Chronic
Hofmann et al. (1971)
1937626
Rat
Freestanding NOAEL" (17- and 26-week
experiments)
Chronic
Hofmann et al. (1971)
1937626
Rabbit
Freestanding NOAEL" (17- and 26-week
experiments)
Chronic
Hofmann et al. (1971)
1937626
Guinea
Pig
Freestanding NOAEL3 (17- and 26-week
experiments)
Chronic
Hofmann et al. (1971)
1937626
Cat
Freestanding NOAEL" (17-week experiment);
Uninformative (26-week experiment)
Chronic
IRFMN (1976)
5447359
Rat
Freestanding NOAEL"
Chronic
IRFMN (1987)
94773
Rat
Freestanding NOAEL"
Chronic
IRFMN (1987)
94773
Mouse
Freestanding NOAEL"
Chronic
IRFMN (1987)
5447260
Rat
Freestanding NOAEL"
Chronic
Mellon Institute (1947)
1973131
Rat
Uninformative
Chronic
Mellon Institute (1947)
1973131
Dog
Not suitable for POD due to reporting
limitations and small group size6
Chronic
Nagano et al. (2006)
200497
Rat
Freestanding NOAEL"
Chronic
Nagano et al. (2006)
200497
Mouse
Not suitable for POD due to confounding by
tumors
Chronic
Spencer et al. (1951)
62617
Rat
Not suitable for POD due to variable exposure
durations and reporting limitations
Chronic
Spencer et al. (1951)
62617
Guinea
Pig
Not suitable for POD due to variable exposure
durations and reporting limitations
Chronic
Spencer et al. (1951)
62617
Rabbit
Not suitable for POD due to variable exposure
durations, reporting limitations, and small
group size6
Chronic
Spencer et al. (1951)
62617
Monkey
Not suitable for POD due to variable exposure
durations, reporting limitations, and small
group size6
Reproduction/
Developmental
Rao et al. (1980)
5453539
Rat
Freestanding NOAEL" (one-generation
reproduction study)
Reproduction/
Developmental
Zhao et al. (1997)
77864
Rat
Uninformative
Reproduction/
Developmental
Zhao et al. (1989)
200708
Rat
Uninformative
Reproduction/
Developmental
Zhao et al. (1989)
200708
Mouse
Uninformative
" No effects observed at highest dose tested for all apical health outcomes rated Low or higher.
h Group size of 1-2 per exposure level.
1867
1868
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1869 Table 6-9. Dermal Studies Not Considered Suitable for POPs for 1,2-Dichloroethane
Du ration
Category
Reference
HERO ID
Species
Rationale
Acute
Kronevi et al (1981)
58151
Guinea pig
Uninformative
Acute
Van Diiuren et al. (1979)
94473
Mouse
Uninformative
Acute
Dow Chemical (1956)
725343
Rabbit
Low (no control; LD5o study)
Acute
Kettering Laboratory (1943)
4528351
Rabbit
Uninformative
Acute
Dow Chemical (1962)
5447286
Cattle
Low (no sex, strain or n/group reported)
Acute
Mellon Institute (1948)
5447301
Rabbit
Uninformative
Acute
Stauffer Cliem Co (1973)
6569955
Rabbit
Negative for skin and eye irritation
Chronic
Van Duuren et al. (1979)
94473
Mouse
Uninformative
Chronic
Sueiiro et al. (2017)
4451542
Mouse
Study of transgenic mice predisposed to
cancer
1870
1871
1872 Table 6-10. Summary of Studies Considered for Non-cancer Dose-Response Assessment of 1,2-
1873 Dichloroethane
Reference
Duration Category
(Duration)
Species, Strain, and Sex
Study Rating for Non-
cancer Endpoints
Oral
Storeret al. (1984)
Acute (once by gavage)
Mouse (B6C3F1, male)
High
Morel et al. (1999)
Acute (once by gavage)
Mouse (Swiss OF1, male)
High
Cottalasso et al. (2002)
Acute (once by gavage)
Rat (Sprague-Dawley, female)
Medium
Salovskv et al. (2002)
Acute (once by gavage)
Rat (Wistar, male)
Medium
Daniel et al. (1994)
Short-term (10 days by
daily gavage)
Rat (Sprague-Dawley, males and
female)
High
Munson et al. (1982)
Short-term (14 days by
daily gavage)
Mouse (CD-I, male)
High
van Esch et al. (1977)
Short-term (2 weeks by
gavage 5 days/week)
Rat (Wistar, male)
High
NTP (1978)
Short-term (6 weeks by
gavage 5 days/week)
Rat (Osborne-Mendel, males and
female)
Medium
Daniel et al. (1994)
Subchronic (90 days by
daily gavage)
Rat (Sprague-Dawley, males and
female)
High
van Esch et al. (1977)
Subchronic (90 days by
gavage 5 days/week)
Rat (Wistar, males and female)
High
NTP (1991)
Subchronic (13 weeks by
gavage, 5 days/week)
Rat (F344, males and female)
High
Pavan et al. (1995)
Repro/Dev (15 days, GDs
6-20 by daily gavage)
Rat (Sprague-Dawley, female)
High
Inhalation
;ovitch et al. (1986)
Acute (4 hours)
Mouse (CD, male)
Medium
Storeret al. (1984)
Acute (4 hours)
Mouse (B6C3F1, male)
High
Dow Chemical (2006b)
Acute (4 or 8 hours)
Rat (F344/ DUCRL, male and
female)
High
Sherwood et al. (1987)
Acute (3 hours)
Mouse (CD-I, female)
High
Zhou et al. (2016)
Acute (1.5 or 4 hours)
Rat (Sprague-Dawley, male)
Medium
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Reference
Duration Category
Species, Strain, and Sex
Study Rating for Non-
(Duration)
cancer Endpoints
Gin-li et al. (2010)
Acute (12 hours)
Rat (Sprague-Dawley, male and
female)
Medium
I ewe et al. (1986b)
Short-term (30 days;
5 days/week; 7 hours/day)
Rat (Sprague-Dawley, male)
High
Zhang et al. (2017)
Short-term (1 or 4 weeks;
6 hours/day)
Mouse (Swiss, male)
High
Zeng et al. (2018)
Short-term (28 days;
6 hours/day)
Mouse (Swiss, male)
High
IRFMN (1978)
Chronic (12 months;
5 days/week; 7 hours/day)
Rat (Sprague-Dawley, male and
female)
Medium
Rao et al. (1980)
Repro/Dev (10 days;
7 hours/day; GDs 6-15)
Rat (Sprague-Dawley, female)
Medium
Rao et al. (1980)
Repro/Dev (13 days; 7
hours/day; GDs 6-18)
Rabbit (New Zealand White,
female)
Medium
kepro l)e\ (15 da\s. (¦
kal (Sprauue-Daw lev. female)
1 hull
hours da>. (il)s <> 2<>i
Dermal
No data
No dermal exposure studies of 1,2-dichloroethane were considered suitable for use in determining a
POD. Table 6-11 through Table 6-15 summarize the NOAELs and LOAELs identified from the oral
(acute and short-term/sub chronic) and inhalation (acute, short-term/sub chronic, and chronic) studies,
respectively. Only the endpoint with the lowest LOAEL for a given study was included in the table (if
the lowest LOAEL was for multiple endpoints, all were included in the table). Each NOAEL and
LOAEL was converted to reflect continuous exposure (NOAELCOntinuous and LOAELCOntinuous) using
EquationApx A-3 and EquationApx A-4. After adjustment for continuous exposure, each oral
NOAEL and LOAEL was converted to a HED using Equation Apx A-5 and each inhalation NOAEL
and LOAEL was converted to a HEC using Equation Apx A-6 (for extrarespiratory effects) or
Equation Apx A-7 (for nasal effects).
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1885 Table 6-11. Summary of Candidate Acute, Non-cancer, Oral POPs for 1,2-Dichloroethane
Target
Organ/
System
Species (Strain,
Sex, n/Group)
Exposure
NOAEL
(mg/kg-bw)
LOAEL
(mg/kg-bw)
Basis for
NOAEL/LOAEL
Candidate PODb
(mg/kg-bw)
(POD Tvpe)
Reference
Study Rating for
Target
Organ/System
Renal/Kidney
{evidence
suggests)
Mouse (B6C3F1,
5 males/group)
Once
(gavage)
NOAEL = 200
NOAELhed =
26.0
LOAEL = 300
LOAELhed = 39.0
Significantly increased
relative kidney weight
(13 percent higher than
controls)
19.9
(BMDLiohed for
kidney weight)
Storer et al.
(1984)
High
Mouse
(Swiss OF1, 10
males/group)
Once
(gavage)
NOAEL = 1,000
NOAELhed = 130
LOAEL = 1,500
LOAELhed = 195
Increased percentage of
damaged proximal
tubules
130
(NOAELhed)
Morel et al.
(1999)
High
Hepatic/Liver
{evidence
suggests)
Rat (Sprague-
Dawley; 10
females/group)
Once
(gavage)
ND
LOAEL = 628
LOAELhed = 151
Significantly increased
ALT, AST, and LDH (45,
44, and 67% higher than
controls, respectively)
and liver steatosis
151
(LOAELhed)
Cottalasso et
al. (2002)
Medium
Respiratory
{evidence
suggests)
Rat (Wistar, 4-6
males/group)
Once
(gavage)
ND
LOAEL = 136
LOAELhed = 32.6
Significantly increased
total number of cells in
BALF; inflammatory and
noninflammatory
histological changes in
lung (data reported
qualitatively)
32.6
(LOAELhed)
Salovskv et
al. (2002)
Medium
1886
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1887 Table 6-12. Summary of Candidate Short-Term/Intermediate, Non-cancer, Oral POPs for 1,2-Dichloroethane
Target Organ/
System
Species (Strain,
Sex, n/Group)
Exposure
NOAEL
(mg/kg-bw/day)
LOAEL
(mg/kg-bw/dav)
Basis for
NOAEL/LOAEL
Candidate POD h
(mg/kg-bw/day)
(POD Type)
Reference
Study Rating
for Target
Organ/System
Mortality
(evidence
demonstrates)
Rat (SPF Wistar,
6 males/group)
2 weeks
(gavage, 5
days/week)
NOAEL = 100
NOAELcontinuous
71.4
NOAELhed =
7.1
LOAEL = 300
LOAELcontinuous
214
LOAELhed =
51.4
Mortality in all animals
(6/6 animals by day 5)
17.1
(NOAELhed)
van Escli et al.
(1977)
High
Nutritional/
Metabolic
(evidence
suggests)
Rat (Sprague-
Dawley; 25-26
females/group)
15 days
GDs 6-20
(daily
gavage)
NOAELcontinuous
158
NOAELhed =
37.9
LOAELcontinuous
198
LOAELhed = 47.5
Decreased absolute
maternal body weight gainc
on GDs 6-21 (reduced >30
percent relative to controls)
10.0
(BMDLiohed for
maternal body
weight)
Pavan et al.
(1995)
High
Rat (Osborne-
Mendel,
5/sex/group)
6 weeks
(gavage, 5
days/week)
ND
LOAEL =40
LOAELcontinuous
29
LOAELhed = 7.0
Decreased body weights
(10 percent) in females
7.0
(LOAELhed)
NTP (1978)
Medium
Hepatic/Liver
(evidence
suggests)
Rat (Sprague-
Dawley;
10/sex/group)
10 days
(gavage,
daily)
NOAELcontinuous
30
NOAELhed = 7.2
LOAELcontinuous
100
LOAELhed = 24
Significantly increased
relative liver weights (14
percent relative to controls)
and serum cholesterol
levels (data not shown) in
males
7.2
(NOAELhed)
Daniel et al.
(1994)
High
Rat (Sprague-
Dawley;
10/sex/group)
90 days
(gavage,
daily)
NOAELcontinuous
37.5
NOAELhed =
9.00
LOAELcontinuous
75
LOAELhed =18
Significantly increased
relative liver weight (20
percent higher than
controls) and serum ALP
(data not shown) in males
9.00
(NOAELhed)
Daniel et al.
(1994)
High
Rat (SPF Wistar,
10/sex/group)
90 days
(gavage, 5
days/week)
NOAEL = 30
NOAELcontinuous
21
NOAELhed = 5.0
LOAEL = 90
LOAELcontinuous
64
LOAELhed =15
Significantly increased
relative liver weight (13
percent higher than
controls) in females
5.0
(NOAELhed)
van Escli et al.
(1977)
Medium
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Target Organ/
System
Species (Strain,
Sex, n/Group)
Exposure
NOAEL
(mg/kg-bw/day)
LOAEL
(mg/kg-bw/dav)
Basis for
NOAEL/LOAEL
Candidate POD h
(mg/kg-bw/day)
(POD Type)
Reference
Study Rating
for Target
Organ/System
Rat (Sprague-
Dawley;
10/sex/group)
90 days
(gavage,
daily)
NOAELcontinuous
37.5
NOAELhed =
9.00
LOAELcontinuous
75
LOAELhed =18
Significantly increased
relative kidney weights in
males and females (18 and
15 percent higher than
controls, respectively)
9.00
(NOAELhed)
Daniel et al.
(1994)
High
Renal/
Kidney
(evidence
suggests)
Rat (SPF Wistar,
10/sex/group)
90 days
(gavage, 5
days/week)
NOAEL = 30
NOAELcontinuous
21
NOAELhed = 5.0
LOAEL = 90
LOAELcontinuous
64
LOAELhed =15
Significantly increased
relative kidney weight (17
and 16 percent higher than
controls in males and
females, respectively)
5.0
(NOAELhed)
van Escli et al.
(1977)
Medium
Rat (F344;
10/sex/group)
13 weeks
(gavage, 5
days/week)
ND
LOAEL = 30
LOAELcontinuous
21
LOAELhed = 5
Significantly increased
absolute kidney weights in
males (9 percent higher
than controls)
3.4
(BMDLiohed for
absolute kidney
weight)
NOAEL = 37
NOAELcontinuous
26
NOAELhed = 6.2
LOAEL = 75
LOAELcontinuous
54
LOAELhed =13
Increased absolute and
relative kidney weights in
females (12 and 10 percent
higher than controls,
respectively)
6.2 (NOAELhed)
NTP (1991)
High
Immune/
Hematological
(evidence
suggests)
Mouse (CD-I;
10-12
males/group)
14 days
(daily
gavage)
ND
LOAELcontinuous
4.89
LOAELhed =
0.636
Suppression of humoral and
cell-mediated immune
responses
0.636 (LOAELhed)
Munson et al.
(1982)
High
1888
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1889 Table 6-13. Summary of Candidate Acute, Non-cancer, Inhalation POPs for l,2-Dichloroethanea
Target Organ/
System
Species
(Strain, Sex,
n/Group)
Exposure
NOAEL
LOAEL
Basis for
NOAEL/LOAEL
Candidate
POD1'
(POD Type)
Reference
Study Rating
for Target
Organ/System
Mortality
(evidence
demonstrates)
Mouse (CD-
1, 10-15
males/group)
4 hours
ND
LOAEL =
4,050 mg/m3
(1,000 ppm)
LOAELcontinuous
LOAELhec =
675 mg/m3
(167 ppm)
Dose-related increase
in mortality compared
with controls
(quantitative data not
reported)
675 mg/m3
or 167 ppm
(LOAELhec)
Francovitch
et al. (1986)
Medium
Renal/Kidney
(evidence
suggests)
Mouse
(B6C3F1, 5
males/group)
4 hours
NOAEL=
639 mg/m3
(158 ppm)
NOAELcontinuous
NOAELhec =
107 mg/m3
(26.3 ppm)
LOAEL=
2,020 mg/m3
(499 ppm)
LOAELcontinuous
LOAELhec =
337 mg/m3
(83.2 ppm)
Significantly
increased serum BUN
and relative kidney
weight (85 and 12
percent higher than
controls, respectively)
207 mg/m3 or
51.1 ppm
(BMCLiohec
for relative
kidney
weight)
Storer et al.
(1984)
High
Hepatic/Liver
(evidence
suggests)
Mouse
(B6C3F1, 5
males/group)
4 hours
NOAEL=
639 mg/m3
(158 ppm)
NOAELcontinuous
NOAELhec =
107 mg/m3
(26.3 ppm)
LOAEL=
2020 mg/m3
(499 ppm)
LOAELcontinuous
LOAELhec =
337 mg/m3
(83.2 ppm)
Increased serum ALT
(2-fold higher than
controls [ns]) and
SDH (11-fold higher
than controls; p <
0.05)
107 mg/m3 or
26.3 ppm
(NOAELhec)
Storer et al.
(1984)
High
Lung/
Respiratory
(evidence
suggests)
Rat (F344/
DUCRL,
5/sex/group)
4 hours
NOAEL=
212 mg/m3
(52.4 ppm)
NOAELcontinuous
35.3 mg/m3
(8.73 ppm)
NOAELhec =
7.06 mg/m3
(1.74 ppm)
LOAEL=
794.9 mg/m3
(196.4 ppm)
LOAELcontinuous
132.5 mg/m3
(32.73 ppm)
LOAELhec =
26.50 mg/m3
(6.547 ppm)
Histological changes
to the olfactory
mucosa in males and
females
1.75 mg/m3 or
0.432 ppm
(BMCLiohec
for
degeneration
with necrosis
in males and
females)
Dow
Chemical
(2006b)
High
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Target Organ/
System
Species
(Strain, Sex,
n/Group)
Exposure
NOAEL
LOAEL
Basis for
NOAEL/LOAEL
Candidate
POD11
(POD Type)
Reference
Study Rating
for Target
Organ/System
Rat (F344/
DUCRL,
10/sex/group)
4 hours
ND
LOAEL =
794.9 mg/m3
(196.4 ppm)
LOAELcontinuous
132.5 mg/m3
(32.73 ppm)
Histological changes
to the olfactory
mucosa in males and
females
4.636 mg/m3
or 1.145 ppm
(BMCLiohec
for
regeneration
in males and
females)
Dow
Chemical
(2006b)
High
Lung/
Respiratory
LOAELhec =
26.50 mg/m3
(6.547 ppm)
(evidence
suggests)
Rat (F344/
DUCRL,
5/sex/group)
8 hours
NOAEL
214 mg/m3
(52.8 ppm)
NOAELcontinuous
71.3 mg/m3
(17.6 ppm)
NOAELhec =
14.3 mg/m3
(3.52 ppm)
LOAEL=
435.1 mg/m3
(107.5 ppm)
LOAELcontinuous
145.0 mg/m3
(35.83 ppm)
LOAELhec =
29.01 mg/m3
(7.166 ppm)
Histological changes
to the olfactory
mucosa in males and
females
9.78 mg/m3 or
2.42 ppm
(BMCLiohec
for
degeneration
with necrosis
in males and
females)
Dow
Chemical
(2006b)
High
Immune/
Hematological
(evidence
suggests)
Mouse (CD-
1, 140
females/
group)
3 hours
NOAEL=
9.3 mg/m3
(2.3 ppm)
NOAELcontinuous
NOAELhec =
1.2 mg/m3
(0.29 ppm)
LOAEL=
22 mg/m3
(5.4 ppm)
LOAELcontinuous
LOAELhec =
2.8 mg/m3
(0.68 ppm)
Mortality following
streptococcal
challenge
1.2 mg/m3 or
0.29 ppm
(NOAELhec)
Sherwood et
al. (1
High
(Note: Mice
inhaled -2E04
aerosolized
streptococci
1 hour after
exposure. This
is unlikely to
represent
typical
immunological
challenges in
humans).
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Target Organ/
System
Species
(Strain, Sex,
n/Group)
Exposure
NOAEL
LOAEL
Basis for
NOAEL/LOAEL
Candidate
POD11
(POD Type)
Reference
Study Rating
for Target
Organ/System
Rat (Sprague-
Dawley, 6
males/group)
1.5 hours
ND
LOAEL =
3,950 mg/m3
(975.9 ppm)
Changes in brain
histopathology
246.9 mg/m3
or 61.00 ppm
(LOAELhec)
Zhou et al
(2016)
Medium
Neurological/
Behavioral
LOAELcontinuous
LOAELhec =
246.9 mg/m3
(61.00 ppm)
(evidence
likely)
Rat (Sprague-
Dawley,
12/sex/group)
12 hours
NOAEL=
2,500 mg/m3
(617.7 ppm)
NOAELcontinuous
NOAELhec =
1,250 mg/m3
(308.9 ppm)
LOAEL=
5,000 mg/m3
(1,240 ppm)
LOAELcontinuous
LOAELhec =
2,500 mg/m3
(620 ppm)
Clinical signs of
neurotoxicity and
changes in brain
histology
1250 mg/m3
or 308.9 ppm
(NOAELhec)
Oin-li et al.
(2010)
Medium
" BMCLs are presented as HECs for comparison with other candidate PODs. BMCL1SD = BMCL for benchmark response of 1 standard deviation change from control
mean. BMCLio = BMCL for benchmark response of 10 percent relative deviation from control mean. BMCLio = BMCL for benchmark response of 10 percent extra
risk.
1890
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Table 6-14. Summary of Cant
idate Short-Term/Intermediate, Non-cancer,
nhalation PODs for 1,2-Dichloroethane"
Target Organ/
System
Species (Strain,
Sex, n/Group)
Exposure
NOAEL
LOAEL
Basis for
NOAEL/LOAEL
Candidate
POD11
(POD Type)
Reference
Study Rating
for Target
Organ/System
Mortality
(evidence
demonstrates)
Rat (Sprague-
Dawley, 12
males/group)
30 days
5 days/week
7 hours/day
NOAEL =
619 mg/m3
(153 ppm)
NOAELcontinuous
NOAELhec =
129 mg/m3
(31.9 ppm)
LOAEL =
1,230 mg/m3
(304 ppm)
LOAELcontinuous
LOAELhec =
256 mg/m3
(63.3 ppm)
Mortality
(1/12 animals)
154 mg/m3 or
38.0 ppm
(BMCLiohec for
mortality)
I ewe et al.
(1986b.
1986c)
High
Rat (Sprague-
Dawley, 16-30
females/group)
10 days
7 hours/day
GD 6-15
NOAEL=
405 mg/m3
(100 ppm)
NOAELcontinuous
NOAELhec =
118 mg/m3
(29.2 ppm)
LOAEL=
1,210 mg/m3
(300 ppm)
LOAELcontinuous
LOAELhec =
353 mg/m3
(87.5 ppm)
Mortality
(10/16 animals)
118 mg/m3 or
29.2 ppm
(NOAELhec)
Rao et al.
(1980)
Medium
Rat (Sprague-
Dawley, 26
females/ group)
15 days
6 hours/day
GD 6-20
NOAEL=
1,030 mg/m3
(254 ppm)
NOAELcontinuous
NOAELhec =
258 mg/m3
(63.5 ppm)
LOAEL=
1,330 mg/m3
(329 ppm)
LOAELcontinuous
LOAELhec =
333 mg/m3
(82.3 ppm)
Mortality
(2/26 dams)
258 mg/m3 or
63.5 ppm
(NOAELhec)
Pavan et al.
(1995)
High
Rabbit (New
Zealand White,
19-21 females/
group)
13 days
7 hours/day
GD 6-18
ND
LOAEL=
405 mg/m3
(100 ppm)
LOAELcontinuous
LOAELhec =
118 mg/m3
(29.2 ppm)
Mortality
(4/21 animals)
59.4 mg/m3 or
14.7 ppm
(BMCLiohec for
mortality)
Rao et al.
(1980)
Medium
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Target Organ/
System
Species (Strain,
Sex, n/Group)
Exposure
NOAEL
LOAEL
Basis for
NOAEL/LOAEL
Candidate
POD11
(POD Type)
Reference
Study Rating
for Target
Organ/System
Hepatic/Liver
(evidence
suggests)
Mouse (Swiss,
10 males/
group)
28 days
6 hours/day
ND
LOAEL =
363.58 mg/m3
(89.830 ppm)
LOAELcontinuous
LOAELhec =
90.895 mg/m3
(22.457 ppm)
Increased absolute
and relative liver
weights (>10 percent
higher than controls)
51.720 mg/m3 or
12.778 ppm
(BMCLiohec for
relative liver
weight)
Zeng et al.
(2018)
High
Reproductive/
Developmental
(evidence
suggests)
Mouse (Swiss,
5-15 males/
group)
4 weeks
6 hours/day
ND
LOAEL=
102.70 mg/m3
(25.374 ppm)
LOAELcontinuous
LOAELhec =
25.675 mg/m3
(6.3435 ppm)
Changes in sperm
parameters
(increased total,
sperm head, body,
and tail
abnormalities;
decreased sperm
concentration;
decreased height of
seminiferous tubules
and height of
germinal epithelium)
21.240 mg/m3 or
5.2500 ppm
(BMCLshec for
sperm
concentration)
18.815 mg/m3 or
4.6486 ppm
(BMCLisdhec
for seminiferous
tubule height)
8.6304 mg/m3 or
2.1323 ppm
(BMCLisdhec
for germinal
epithelium
height)
Zhang et al.
(2017)
High
" BMCLs are presented as HECs for comparison with other candidate PODs. BMCLi Sd = BMCL for benchmark response of 1 standard deviation change from control
mean. BMCLio = BMCL for benchmark response of 10 percent relative deviation from control mean. BMCLiohec = BMCL for benchmark response of 5 percent relative
deviation from control mean. BMCLio = BMCL for benchmark response of 10 percent extra risk.
1892
1893
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1894 Table 6-15. Summary of Candidate C
PUBLIC RELEASE DRAFT
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ironic, Non-cancer, Inhalation POPs for 1,2-Dichloroethane
Target Organ/
System
Speeies
(Strain, Sex,
n/Group)
Exposure
NOAEL
LOAEL
Basis for
NOAEL/LOAEL
Candidate POD"
(POD Type)
Refcrcnee
Study Rating
for Target
Organ/System
Hepatic/Liver
(evidence
suggests)
Rat (Sprague-
Dawley, 8-
10/sex/group)
12 months
5 days/week
7 hours/day
NOAEL = 40 mg/m3
(10 ppm)
NO A E LConi mi ioi is
NOAELhec = 8.3
mg/m3
(2.1 ppm)
LOAEL = 200 mg/m3
(50 ppm)
LOAELcontinuous
LOAELhec = 42
mg/m3
(10 ppm)
Increased ALT
(>2-fold higher
than controls) and
LDH (18 percent
higher than
controls) in males
8.3 mg/m3 or
2.1 ppm
(NOAELhec)
IRFMN
Medium
NOAEL = 40 mg/m3
(10 ppm)
NOAELcontinuous
NOAELhec =
8.3 mg/m3
(2.1 ppm)
LOAEL = 200 mg/m3
(50 ppm)
LOAELcontinuous
LOAELhec =
42 mg/m3
(10 ppm)
Increased ALT
(>2-fold higher
than controls) and
LDH (25 percent
higher than
controls) in
females
1.7 mg/m3
or 0.42 ppm
(BMCLi sdhec for
LDH in females)
(1978)
" BMCLs are presented as HECs for comparison with other candidate PODs. BMCLisd = BMCL for benchmark response of 1 standard deviation change from control
mean. BMCLio = BMCL for benchmark response of 10 percent relative deviation from control mean. BMCLio = BMCL for benchmark response of 10 percent extra risk.
1895
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6.3 Endpoint Derivation for Carcinogenic Dose-Response Assessment
EPA used the oral cancer slope factors from 1,2-dichloroethane, based on hepatocellular carcinomas in
male mice NTP (1978). The inhalation unit risk for 1,2-dichloroethane was based on read-cross from an
inhalation study for 1,2-dichloroethane by Nagano et al. (2006). EPA conducted BMD modeling on
these data as described below.
The BMD modeling of cancer incidence data was conducted with the EPA's BMD software (BMDS,
version 3.3). Modeled concentrations were in units of ppm. For these data, the Multistage model was fit
to the incidence data using a BMR of 10 percent ER. The Multistage cancer model was run for all
polynomial degrees up to n-1 (where n is the number of dose groups including control). Adequacy of
model fit was judged based on the chi-square 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 BMDL from the model with the lowest AIC was selected if the BMDLs were
sufficiently close (< 3-fold); if the BMDLs were not sufficiently close (> 3-fold), model-dependence is
indicated, and the model with the lowest reliable BMDL was selected.
Where applicable, the MS Combo model was used to evaluate the combined cancer risk of tumors
observed in multiple tissues in a test group, assuming that the tumors in the different tissues occurred
independently. MS Combo was run using the incidence data for the individual tumors and the
polydegrees identified in the model runs for the individual tumors.
6.3.1 Cancer Dose-Response Assessment
IUR for Inhalation Exposures
In 1987, EPA's Integrated Risk Information System (IRIS) program derived an IUR of 2.6x 10~5 (per
|ig/m3) based on route-to-route extrapolation from the oral CSF derived at the same time. The inhalation
cancer bioassay by Nagano et al. (2006) was not available at the time of the IRIS assessment.
IUR estimates based on the tumor data sets in Nagano et al. (2006) were calculated using the following
equation (Equation 6-1):
Equation 6-1.
IUR = BMR/HEC
Where:
BMR = Benchmark response
HEC = Human equivalent concentration in |ig/m3
A BMR of 10 percent extra risk was selected for all data sets. HECs were calculating using the ratio of
blood/gas partition coefficients, as shown in Gargas and Andersen (1989). estimated blood/air partition
coefficients for 1,2-dichloroethane of 19.5 and 30.4 in humans and rats, respectively. Because the rat
partition coefficient is greater than the human partition coefficient, the default ratio of 1 is used in the
calculation in accordance with 94) guidance. A blood/air partition coefficient for mice was
not available from the literature reviewed; thus, the default ratio of 1 was used to calculate HECs for
data in mice.
Details of the BMD modeling are provided in Draft Risk Evaluation for 1,1-Dichloroethane -
Supplemental Information File: Benchmark Dose Modeling ( 324a) and a summary of the
BMCL, HEC, and IUR estimate for each data set are shown in Table 6-16.
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1943 Table 6-16. IUR Estimates for Tumor Data from Nagano et ai. (2006) Study of 1,2-Dichloroethane
1944 Using Linear Low-Dose Extrapolation Approach
Species
and Sex
Tumor Tvpc
Selected Model
BMCLio
(ppm)
BMCLio
(jig/m3)
HEC
(jig/m3)
IUR
Estimate
(^ji/m3)"1
Subcutaneous fibroma
Multistage 1-degree
7
28,332
28,332
3.5E-06
Mammary gland
fibroadenomas
Multistage 1-degree
17
68,807
68,807
1.5E-06
Male rats
Mammary gland
fibroadenomas and adenomas
combined
Multistage 3-degree
15
60,712
60,712
1.6E-06
Peritoneal mesothelioma
Multistage 3-degree
19
76,901
76,901
1.3E-06
Combined mammary gland,
subcutaneous, and peritoneum
tumors
MS Combo
5
20,237
20,237
4.9E-06
Subcutaneous fibroma
Multistage 1-degree
17
68,807
68,807
1.5E-06
Mammary gland adenomas
Multistage 1-degree
9
36,427
36,427
2.7E-06
Mammary gland
fibroadenomas
Multistage 1-degree
8
32,380
32,380
3.1E-06
Female
Mammary gland
fibroadenomas and adenomas
combined
Multistage 1-degree
5
20,237
20,237
4.9E-06
rats
Mammary gland
adenocarcinoma
Multistage 3-degree
23
93,091
93,091
1.1E-06
Mammary gland
fibroadenomas adenomas, and
adenocarcinomas combined
Multistage 1-degree
4
16,190
16,190
6.2E-06
Combined mammary gland
and subcutaneous tumors
MS Combo
4
16,190
16,190
6.2E-06
Bronchiolo-alveolar adenomas
Multistage 3-degree
9
36,427
36,427
2.7E-06
Bronchiolo-alveolar
Multistage 2-degree
14
56,664
56,664
1.8E-06
carcinomas
Bronchiolo-alveolar adenomas
and carcinomas combined
Multistage 2-degree
7
28,332
28,332
3.5E-06
Female
mice
Mammary gland
adenocarcinomas
Multistage 3-degree
10
40,474
40,474
2.5E-06
Hepatocellular adenomas
Multistage 3-degree
11
44,522
44,522
2.2E-06
Hepatocellular adenomas and
carcinomas combined
Multistage 2-degree
10
40,474
40,474
2.5E-06
Combined lung, mammary
gland, and liver tumors3
MS Combo
5
20,237
20,237
4.9E-06
" In addition to the tumor types shown in the table, EPA conducted BMD modeling on the combined incidence of lung,
mammary gland, and liver tumors and endometrial stromal polyps to evaluate whether including the polyps would result in
a lower BMCLio. The BMCLio for combined tumors with polyps was 5 ppm (20 |ig/m3). unchanged from the BMCLio
without the polyps.
1945
1946 The highest estimated IUR is 6.2x 1CT6 (per (J,g/m3) for combined mammary gland adenomas,
1947 fibroadenomas, and adenocarcinomas and subcutaneous fibromas in female rats in the inhalation study
1948 by Nagano et al. (2006).
1949
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CSF for Oral Exposures
The IRIS program derived an oral CSF of 9.1 x 10~2 (per mg/kg-bw/day) for 1,2-dichloroethane in 1987
based on the incidence of hemangiosarcomas in male rats in the chronic bioassay by 0,
however, this study did not pass EPA systematic review. The IRIS CSF was derived using time-to-tumor
modeling to account for intercurrent mortality of the rats in the NT 8) study. No updates to the
time-to-tumor modeling approach have been made since the 1987 assessment. Hemangiosarcomas in
male rats were determined to be the most sensitive species, strain, and site, however this study was
deemed unacceptable by EPA systematic review. Although CSF does not account for other tumor types
induced by 1,2-dichloroethane in the male rat, there is currently no time-to-tumor modeling approach
available that accounts for multiple tumor types.
The IRIS program also derived an oral CSF for male mice based on hepatocarcinomas of 6,2/ 10 2 (per
mg/kg-bw/day) also from the NTP (1978) study. No oral cancer bioassays of 1,2-dichloroethane have
been published since the IRIS assessment. Therefore, the oral CSF for 1,2-dichloroethane from the NTP
(1978) mouse study was selected for use in assessment of cancer risks associated with exposure to 1,2-
dichloroethane. This mouse CSF was also used to calculate a drinking water unit risk of 1.8x 10"6 per
ug/L using a drinking water intake of 2 L/day and body weight of 70 kg.
CSF for Dermal Exposures
There are no reliable dermal cancer studies of 1,2-dichloroethane; thus, the CSF for 1,2-dichloroethane
was obtained from route-to-route extrapolation using oral data. There are uncertainties associated with
extrapolation from both oral and inhalation. Use of an oral POD for dermal extrapolation may not be
preferred for chemicals known to undergo extensive liver metabolism because the "first-pass effect" that
directs intestinally absorbed chemicals directly to the liver applies only to oral ingestion. In contrast, the
accuracy of extrapolation of inhalation toxicity data for dermal PODs is dependent on assumptions about
inhalation exposure factors such as breathing rate and any associated dosimetric adjustments. Whole-
body inhalation studies may also already be incorporating some level of dermal absorption. Given these
competing uncertainties, in the absence of data to support selection of either the oral CSF or inhalation
IUR, the method resulting in the most protective dermal CSF was selected. The value of the oral CSF is
6.2xl0~2 (per mg/kg-bw/day). For comparison, a CSF of 3,3/10 2 (per mg/kg-bw/day) was obtained
using route-to-route extrapolation from the IUR of 6,0/ 10 6 per [j,g/m3 (6,0/10 3 per mg/m3) per
Equation 6-2 as follows:
Equation 6-2.
Dermal CSF (per mg/kg-bw/day) = 6.0xl0~3 (per mg/m3) x (80 kg/14.7 m3/day)
= 3.3 x 10~2 (per mg/kg-bw/day)
The more protective value of 6.2x 10~2 per mg/kg-bw/day based on the oral CSF was selected for the
dermal CSF.
6.3.2 Summary of Continuous and Worker PODs
The continuous IUR was adjusted for occupational scenarios using equations provided in Equation Apx
A-13. Table 6-17 provides a summary of the cancer PODs for both continuous and occupational
exposure scenarios.
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1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
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Table 6-17. Summary of Cancer PODs
or 1,2-Dichloroethane
Route
Continuous POD
Worker POD
Reference
Inhalation
6.0E-06 (per |ig/m3)
2.1E-06 (per |ig/m3)
Nagano et al. (2006)
Oral
6.2E-02 (per mg/kg-bw/day)
Same as continuous
NTP (1978)
Dermal
6.2E-02 (per mg/kg-bw/day)
Same as continuous
Route-to-route extrapolation from oral
6.4 Weight of Scientific Evidence Conclusions for Human Health Hazard
The weight of scientific evidence supporting the human health hazard assessment is based on the
strengths, limitations, and uncertainties associated with the hazard studies identified. The weight of
scientific evidence is summarized using confidence descriptors: robust, moderate, slight, or
indeterminate. This approach is consistent with the Draft Systematic Review Protocol Supporting TSCA
Risk Evaluations for Chemical Substances (U. 2021). When weighing and integrating evidence
to estimate the potential that 1,2-dichloroethane may cause a given non-cancer or cancer health hazard
endpoint (e.g., immune system, reproductive, and hepatocarcinomas), EPA uses several factors adapted
from Sir Bradford Hill (Hill. 1965). These elements include consistency, dose-response relationship,
strength of the association, temporal relationship, biological plausibility, and coherence among other
considerations.
EPA considered evidence integration conclusions from Sections 3, 4, 5 and additional factors when
choosing studies for dose-response modeling and for each exposure scenario (acute, short-
term/sub chronic, and chronic), as described in Section 6. Additional considerations pertinent to the
overall hazard confidence levels include evidence integration conclusions, selection of the critical
endpoint and study, relevance to the exposure scenario, dose-response considerations and PESS
sensitivity.
Weight of Scientific Evidence Conclusions
For complete details on weight of scientific evidence conclusions within evidence streams, see the
evidence profile tables for each organ domain in Appendix B. For a more detailed description of the
hazard database and weight of scientific evidence evaluation see Draft Systematic Review Protocol
Supporting TSCA Risk Evaluations for Chemical Substances (U, ) for details on the process
of evidence evaluation and integration.
PESS
Relevant data on lifestages and target organs were evaluated to identify potentially susceptible
subpopulations exposed to 1,2-dichloroethane. An evaluation of 1,2-dichloroethane in animals identified
non-cancer effects such as (1) increased kidney weight (reported by Storer et al. (1984)); (2)
degeneration with necrosis of the olfactory mucosa (reported by Dow Chemical (2006b)); (3)
suppression of immune response (reported by Munson et al. (1982)); and (4) decreases in sperm
concentrations (reported by Zhang et ); and cancer effects such as (5) liver cancer (based on
hepatocarcinomas in male mice (NTP. 1978); and (4) combined mammary gland adenomas,
fibroadenomas, and adenocarcinomas and subcutaneous fibroin as Nagano et al. (2006). These effects
were considered as representative of the potential for greater biological susceptibility across
subpopulations. In addition, significant decreases in maternal body weight gain were observed in a
prenatal developmental toxicity study by Pavan et al. (1995). which could support the pregnant female
as having greater biological susceptibility.
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Although information on other considerations potentially impacting greater biological susceptibility
(such as pre-existing disease, lifestyle activities, sociodemographic factors, nutritional status, genetic
predispositions, or other chemical co-exposures and non-chemical stressors), was sparse, there is some
information on 1,2-dichloroethane as impacting greater biological susceptibility. For example,
individuals with impaired renal function based on evidence that 1,2-dichloroethane is nephrotoxic in
animals, people with compromised immune systems may be particularly susceptible to exposure to 1,2-
dichlorethane based on evidence that 1,2-dichloroethane is immunotoxic, individuals with chronic
respiratory disease because of the effects on the olfactory mucosa induced by 1,2-dichloroethane, and
finally, impacts on male reproduction based on evidence that 1,2-dichloroethane causes decreases in
sperm concentration in animals.
For PESS, specifically susceptibility, across the database for 1,2-dichloroethane, uncertainty exists
based on limited number of studies, and the differences in results and comprehensiveness of endpoints
assessed towards specific health outcomes across studies.
6,4,1 Overall Confidence - Strengths, Limitations, Assumptions, and Key Sources of
Uncertainty in the Human Health Hazard Assessment
1,2-dichloroethane lacked adequate data by the dermal route for any exposure duration. Therefore, EPA
used a route-to-route extrapolation approach from the available 1,2-dichloroethane oral data to fill in the
dermal data gap. EPA also has high confidence in this approach. Since both oral and dermal routes are
similar metabolically and by-pass first pass metabolism through the liver, and since oral ADME studies
showed that most of the 1,2-dichloroethane oral dose was eliminated unchanged in expired air, oral
PODs were used for extrapolation via the dermal route.
EPA has high confidence in the human health hazard database for 1,2-dichloroethane and in the
selection of the critical PODs. This is based on several reasons. First, all studies used to assess the
hazards for 1,2-dichloroethane were rated high to medium in SR. Second, critical non-cancer effects that
were ultimately selected as PODs for quantitative risk estimates (kidney toxicity, neurotoxicity,
immunotoxicity, and reproductive toxicity), were considered the most sensitive and biologically relevant
effects, supported by multiple lines of evidence that spanned across species, routes, and durations of
exposure (see Section 6.1 and endpoint selection tables: Table 6-1, Table 6-2, Table 6-3, Table 6-4,
Table 6-5, and Table 6-6).
While EPA has high confidence in the hazard identification of PODs used for quantitative risk estimates,
there are some uncertainties in the 1,2-dichloroethane database. For example, while there were several
studies via the chronic exposure duration for both oral and inhalation exposures, none of those studies
were selected for the chronic POD for a variety of reasons including the identified NOAELs/LOAELs
were higher than the recommended endpoint, or there were limited endpoints evaluated, or other
methodological issues (see endpoint selection tables: Table 6-5 and Table 6-6). As a result, subchronic
data was used for the chronic POD and an uncertainty factor (UFS) of 10 was applied to account for the
use of a short-term study for long-term (chronic) assessment.
Table 6-18 presents a summary of confidence for each hazard endpoint and relevant exposure duration
based on critical human health hazards considered for the acute, short-term/intermediate, chronic, and
lifetime exposure scenarios used to calculate risks.
EPA considered evidence integration conclusions from Sections 3, 4, 5 and additional factors listed
below when choosing studies for dose-response modeling and for each relevant exposure scenario
(acute, short-term/intermediate, and chronic), as described in Section 6.4.
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2085 Table 6-18. Confidence Summary for Human Health Hazard Assessment
Hazard Domain
Evidence
Integration
Conclusion
Selection of Most
Critical
Endpoint and
Studv
Relevance to
Exposure
Scenario
Dose-Response
Considerations
PESS
Scnsitivitv
Overall
Hazard
Confidence
\aile iinii-c;iik.vi
Oral
Kid iic\
kohusl
Inhalation
\CMI\iUi\ICII\
kohnsl
SlKiii-k'ini iiiiemialmie iinii-ciiiiccr
Oral
lininiiik>u>\ial\
kohnsi
I ii I i;i l;il K)i i
Reproductive
+++
+++
Rohnsl
( limine iku>\ial\
knhusi
Inhalation
kepi\'diicli\ c
knhusi
( aikx
Cancer' ^
Rubusl
2086
2087
+ + + Robust confidence suggests thorough understanding of the scientific evidence and uncertainties. The supporting
weight of the scientific evidence outweighs the uncertainties to the point where it is unlikely that the uncertainties could
have a significant effect on the hazard estimate.
+ + Moderate confidence suggests some understanding of the scientific evidence and uncertainties. The supporting
scientific evidence weighed against the uncertainties is reasonably adequate to characterize hazard estimates.
+ Slight confidence is assigned when the weight of the scientific evidence may not be adequate to characterize the
scenario, and when the assessor is making the best scientific assessment possible in the absence of complete information.
There are additional uncertainties that may need to be considered.
" Degeneration with necrosis of olfactory mucosa
b Oral based on hepatocellular carcinomas
c Inhalation based on combined tumors (mammary gland adenomas, fibroadenomas, and adenocarcinomas and
subcutaneous libromas)
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7 POTENTIALLY EXPOSED OR SUSCEPTIBLE
SUBP OPUL ATION S
EPA considered PESS throughout the exposure assessment and throughout the hazard identification and
dose-response analysis. EPA has identified several factors that may contribute to a group having
increased exposure or biological susceptibility. Examples of these factors include lifestage, preexisting
disease, occupational and certain consumer exposures, nutrition, and lifestyle activities.
For the 1,2-dichloroethane draft risk evaluation, EPA accounted for the following PESS groups: infants
exposed to drinking water during formula bottle feeding, subsistence and Tribal fishers, pregnant
women and people of reproductive age, individuals with compromised immune systems or neurological
disorders, workers, people with the aldehyde dehydrogenase-2 mutation which is more likely in people
of Asian descent, lifestyle factors such as smoking cigarettes or secondhand smoke, and communities
who live near facilities that emit 1,2-dichloroethane.
Table 7-1 summarizes how PESS were incorporated into the risk evaluation and the remaining sources
of uncertainty related to consideration of PESS.
Additional information on other factors that could possibly impact greater biological susceptibility
following exposure to 1,2-dichloroethane—such as more comprehensive information on pre-existing
diseases in humans, lifestyle activities, nutritional status, or other chemical co-exposures and non-
chemical stressors—was limited.
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2109 Table 7-1. Summary of PESS Categories in the Draft Risk Evaluation and Remaining Sources of Uncertainty
PESS Categories
Potential Sources of Biological Susceptibility Incorporated into Hazard Assessment
Lifestage
Direct evidence of a reproductive/developmental effect was the basis for the chronic inhalation POD used for risk estimation. Other
reproductive/developmental data was difficult to interpret across the chemical databases, including fetal resorptions. 1,2-dichloroethane
partitions in the milk of women exposed dermallv (ATSDR. 2022; Urusova. 1953)
Children in households that smoke cisarettes. receiving secondhand smoke, mav be exposed to hieher levels of 1.2-dichloroethane (ATSDR.
2022); (Wane 2012). The increase in susceptibility due to secondhand smoke is not known and is a source of uncertainty in part reliant on
proximity to the smoker, space ventilation, and frequency of smoking/number of cigarettes smoked.
Evidence in mice revealed a statistically significant increase in benign uterine endometrial stromal polyps in high-dose analog 1,2-
dichloroethane females which may have implications for women of childbearing age, or fertility challenges. Evidence also from mice showed
changes in sperm parameters in decreases in sperm count following short-term exposures to the analog 1,2-dichloroethane.
Potential susceptibility of older adults due to toxicokinetic differences was addressed through a UF of 10 for human variability.
Pre-existing Disease
Indirect evidence suggesting chronic liver disease may delay detoxification was addressed qualitatively and through the UF of 10 for human
variability. (ATSDR. 2022) indicates concern for individuals with compromised immune systems exposed to 1.2-dichloroethane.
Observed impaired motor activity and CNS depression, from evidence in rats following 1,2-dichloroethane exposure, have potential
implications for greater susceptibility in people with Parkinson's Disease, other neurological disorders.
The increase in susceptibility due to pre-existing disease is not known and is a source of uncertainty.
Lifestyle Activities
People that smoke cigarettes may be exposed to higher levels of 1,2-dichloroethane. Mean concentration of 0.32 |ig/m3 (0.079 ppb) in homes
of smokers vs. the home of nonsmokers of 0.03 ^g/m3 (0.007 ppb) (ATSDR, 2022).
Occupational
Exposures
EPA did not identify occupational exposures that influence susceptibility.
Sociodemographic
EPA did not identify sociodemographic factors that influence susceptibility.
Geography and site-
specific
EPA did not specifically identify geography and/or site-specific factors that influence susceptibility.
Nutrition
EPA did not identify nutritional factors that influence susceptibility.
Genetics/ Epigenetics
Indirect evidence that genetic variants may increase susceptibility of the target organ was addressed through a UF of 10 for human variability.
However, a known metabolite of 1,2-dichloroethane is the reactive 2-chloroacetaldehyde supporting that a PESS group are people with the
aldehyde dehydrogenase-2 mutation which is more likely in people of Asian descent which have increased rates of cancer due to decreased
reactive aldehyde clearance, which is not addressed by the UFH (~28-54 percent incidence in Asians, ~7 million in the United States). Cancer
studies in animals with the aldehyde dehydrogenase-2 clearance enzyme mutation are not available to quantitatively assess this PESS group.
Other Unique
Activities
EPA did not identify unique activities that influence susceptibility.
Aggregate Exposures
Not relevant to susceptibility.
Other Chemical and
Nonchemical Stressors
EPA did not identify other chemical and nonchemical stressors that influence susceptibility.
2110
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2111 8 PODS FOR NON-CANCER AND CANCER HUMAN HEALTH
2112 HAZARD ENDPOINTS
2113 Table 8-1, Table 8-2, and Table 8-3 list the non-cancer PODs and corresponding HECs, HEDs, and UFs
2114 that EPA used in the draft 1,2-dichloroethane risk evaluation to estimate risks following acute, short-
2115 term/sub chronic, and chronic exposure, respectively. Table 8-4 provides the cancer PODs for evaluating
2116 lifetime exposure.
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2117 Table 8-1. POPs and Toxicity Values Used to Estimate Non-cancer Risks for Acute Exposure Scenarios"
Target
Orjjan/
System "
Species/
Gender
Du ration/
Route
Study
POD/Tvpe
Effect
Worker
HEC b
(mg/m3)
|ppm|
Continuous
HEC*
(mjj/m3)
|ppm|
Worker
HED'
(m«/k«-
bw/day)
Continuous
HED'
(mji/kji-
bw/day)
Uncertainty
Factors4'
Total
Uncertainty
Factors
Reference
Data
Quality
Renal
Mice
(male)
Oral
1-day oral gavage
BMDLio
= 153
mg/kg
BMD =
270 mg/kg
Increased
kidney
weight
N/A
N/A
19.9
19.9
UFa = 3
UFh = 10
UFl = 1
UFS= 1
UFD= 1
30 d
Storer et al.
(1984)
High
Neurological
Rats
(males and
females
combined)
Inhalation
8-hour inhalation
BMCio =
48.9
mg/m3 or
12.1 ppm
Degeneration
with necrosis
of the
olfactory
mucosa
(41.1
mg/m3)
[10.14
ppm]
(9.78
mg/m3)
[2.42 ppm]
N/A
N/A
UFa = 3
UFh = 10
UFl = 1
UFS= 1
UFd= 1
30 e
Dow
Chemical
(2006b)
High
Renal
Mice
(male)
Dermal
(extrapolated
from oral)
1-day oral gavage
BMDLio
= 153
mg/kg
BMD=270
mg/kg
Increased
kidney
weight
N/A
N/A
19.9
19.9
UFa = 3
UFh = 10
UFl = 1
UFS= 1
UFd= 1
30 f
Storer et al.
(1984)
High
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Target
Orjjan/
Svstcm "
Species/
Gender
Du ration/
Route
Study
POD/Type
Effect
Worker
HEC''
(mg/m3)
[ppm]
Continuous
HEC''
(mjj/m3)
[ppm]
Worker
HED'
(mji/k«-
bw/dav)
Continuous
HED'
bw/day)
Uncertainty
Factors4'
Total
Uncertainty
Factors
Reference
Data
Quality
2118
2119
" See Section 3 for details.
b BMCLio of 48.9 mg/m3 continuous adjusted x RGDR value (0.2) = 9.78 mg/m3 for the HEC for continuous (adjusted for 24 hours). The HEC for the worker is the
HECcont x 4.2 (hours in a week divided by the # of working hours in a week; 168/40) = 60.1 mg/m3. Both HEC worker and continuous were converted to ppm by
dividing by a factor of 4.05 (based 24.45/MW).
c BMDLio of 153 x DAF (0.13 BW3'4 for mice) = 20.3 mg/kg. All oral PODs were first adjusted to 7 days/week and inhalation PODs adjusted to 24 hours/day, 7
days/week (continuous exposure). All continuous oral PODs were then converted to HEDs using DAFs. Dermal PODs were set equal to the oral HED. It is often
necessary to convert between ppm and mg/m3 due to variation in concentration reporting in studies and the default units for different OPPT models. Therefore, EPA
presents all inhalation PODs in equivalents of both units to avoid confusion and errors. PODs converted for use in worker exposure scenarios were adjusted to 8
hours/day, 5 days/week and converted to HECs.
d POD identified from acute exposure by the oral route to 1,2-dichloroethane. An acute-duration oral HED for both worker and continuous exposure of 5.56 mg/kg-
bw/day was used for risk assessment of acute oral exposure, with a total uncertainty factor of 30, based on a combination of uncertainty factors: 3 for interspecies
extrapolation when a dosimetric adjustment is used and 10 for human variability.
' POD identified from acute exposure by the inhalation route to 1,2-dichloroethane. An acute-duration inhalation HEC of 10.14 ppm for worker and 2.42 ppm for
continuous exposures was used for risk assessment of acute inhalation exposure, with a total uncertainty factor of 30, based on a combination of uncertainty factors: 3
for interspecies extrapolation when a dosimetric adjustment is used and 10 for human variability.
' No PODs were identified from acute exposure by the dermal route to 1,2-dichloroethane; therefore, route-to-route extrapolation from the oral route was used to
identify a POD. An acute-duration dermal HED for both worker and continuous exposure of 5.56 mg/kg-bw/day was used for risk assessment of acute dermal exposure,
with a total uncertainty factor of 30, based on a combination of uncertainty factors: 3 for interspecies extrapolation when a dosimetric adjustment is used and 10 for
human variability.
g UF = uncertainty factor; UFA = extrapolation from animal to human (interspecies); UFH = potential variation in sensitivity among members of the human population
(intraspecies); UFL = use of a LOAEL to extrapolate a NOAEL; UFS = use of a short-term study for long-term risk assessment; UFD = to account for the absence of key
data (i.e., lack of a critical study).
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Table 8-2.
'ODs and Toxicity Values Uset
to Estimate Non-cancer Risks for Short-Term Exposure Scenarios"
Target
Organ
System
Species
Duration/
Route
Study
POD/
Type
Effect
Worker
HEC b
(ppm)
|mg/m3|
Continuous
HEC b
(ppm)
|mg/m3|
Worker
HED c
(mg/kg-
bw/day)
Continuous
IIII)
(mg/kg-
bw/day)
Uncertainty
Factors 8
Total
Uncertainty
Factors
Reference
Data
Quality
Immune
System
Mice
(male)
Oral 1,2-
dichloroethane
data
14-days oral
gavage
LOAELadj
= 4.89
mg/kg
Suppression
of immune
response
(AFCs/spleen)
N/A
N/A
0.890
0.636
UFa = 3
UFh = 10
UFl = 3
UFS= 1
UFd= 1
100rf
Munson et al.
(1982)
High
Reproductive
Mice
(male)
Inhalation 1,2-
dichloroethane
data
4-week
morphological
analysis of
sperm
parameters/
inhalation
BMCLs =
21.2
mg/m3
Decreases in
sperm
concentration
(89.0
mg/m3)
[22.0
ppm]
(21.2
mg/m3)
[5.2 ppm]
N/A
N/A
UFa = 3
UFh = 10
UFl = 1
UFS= 1
UFd= 1
30®
Zhang et al. (2017)
High
Immune
System
Mice
(male)
Dermal
(extrapolated
from oral)
1,2-
dichloroethane
data
14-days oral
gavage
LOAELadj
= 4.89
mg/kg
Suppression
of immune
response
(AFCs/spleen)
N/A
N/A
0.890
0.636
UFa = 3
UFh = 10
UFl = 3
UFS= 1
UFd= 1
10(/
Munson et al.
(1982)
High
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Target
Orjjan
Svstcm
Species
Duration/
Route
Study
POD/
Type
Effect
Worker
HEC h
(ppm)
|mjj/m3]
Continuous
HEC h
(ppm)
[mj*/m3|
Worker
HED'
(mj;/k»-
bw/day)
Continuous
HED'
(mji/kji-
bw/day)
Uncertainty
Factors4'
Total
Uncertainty
Factors
Reference
Data
Quality
2121
2122
" See Section 3 for details.
'' BMCLs = 21.2 mg/m3 was adjusted to continuous adjusted (with no respiratory effects, there is no RGD; the blood:air ratio = 1, based on Equation Apx A-7; therefore,
the HECcont is the same as the adjusted POD of 21.2 mg/m3. The HEC worker is the HECCOnt x 4.2 (hours in a week divided by the # of working hours in a week; 168/40)
= 89.0 mg/m3. Both HEC worker and continuous converted to ppm divided by a factor of 4.05 (based 24.45/MW).
c All oral PODs were first adjusted to 7 days/week. All continuous oral PODs were then converted to HEDs using DAFs. Dermal PODs were set equal to the oral HED. It
is often necessary to convert between ppm and mg/m3 due to variation in concentration reporting in studies and the default units for different OPPT models. Therefore,
EPA presents all PODs in equivalents of both units to avoid confusion and errors. PODs converted for use in worker exposure scenarios were adjusted to 8 hours/day, 5
days/week and converted to HECs.
d POD identified from short-term/subchronic exposure by the oral route to 1,2-dichloroethane. A short-term/subchronic-duration oral HED for worker of 0.890 mg/kg-
bw/day and a HED for continuous exposure of 0.636 mg/kg-bw/day was used for risk assessment of short-term/subchronic oral exposure, with a total uncertainty factor
of 100, based on a combination of uncertainty factors: 3 for interspecies extrapolation when a dosimetric adjustment is used, 10 for human variability, and 3 for use of a
LOAEL to extrapolate a NOAEL (based on the dose-response).
e POD identified from short-term/subchronic exposure by the inhalation route to 1,2-dichloroethane. A short-term/subchronic-duration inhalation HEC for worker
exposure of 89.0 mg/m3, and a HEC for continuous exposure of 21.2 mg/m3, was used for risk assessment of short-term/subchronic inhalation exposure, with a total
uncertainty factor of 30, based on a combination of uncertainty factors: 3 for interspecies extrapolation when a dosimetric adjustment is used and 10 for human
variability.
' No PODs were identified from short-term/subchronic exposure by the dermal route to 1,2-dichloroethane; therefore, route-to-route extrapolation from the oral route
was used to identify a POD. A short-term/subchronic-duration dermal HED for worker of 0.890 mg/kg-bw/day and a HED for continuous exposure of 0.636 mg/kg-
bw/day was used for risk assessment of short-term/subchronic dermal exposure, with a total uncertainty factor of 100, based on a combination of uncertainty factors: 3
for interspecies extrapolation when a dosimetric adjustment is used, 10 for human variability, and 3 for use of a LOAEL to extrapolate a NOAEL (based on the dose-
response).
g UF = uncertainty factor; UFA = extrapolation from animal to human (interspecies); UFH = potential variation in sensitivity among members of the human population
(intraspecies); UFL = use of a LOAEL to extrapolate a NOAEL; UFS = use of a short-term study for long-term risk assessment; UFD = to account for the absence of key
data (i.e., lack of a critical study).
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Table 8-3.
'ODs and Toxicity Values Used to
Estimate Non-cancer Risks for Chronic Exposure Scenarios"
Target
Organ
System
Species
Duration/
Route
Study
POD/
Type
Effect
Worker
HEC b
(ppm)
|mg/m3|
Continuous
HEC*
(ppm)
|mg/m3|
Worker
HED c
(mg/kg-
bw/day)
Continuous
HED c
(mg/kg-
bw/day)
Uncertainty
Factors g
Total
U nccrtaintv
Factors
Reference
Data
Quality
Immune
System
Mice
(male)
Oral
1,2-dichloroethane
data
14-days oral gavage
LOAELadj =
4.89 mg/kg
Suppression
of immune
response
(AFCs/spleen)
N/A
N/A
0.890
0.636
UFa = 3
UFh = 10
UFl=3
UFS = 10
UFd= 1
1,000^
Munson et
al. (1982)
High
Reproductive
Mice
(male)
Inhalation
1,2-dichloroethane
data
4-week
morphological
analysis of sperm
parameters/
inhalation
bmcl5=
21.2
mg/m3
Decreases in
sperm
concentration
(89.0
mg/m3)
[22.0
ppm]
(21.2
mg/m3)
[5.2 ppm]
N/A
N/A
UFa = 3
UFh = 10
UFl = 1
UFS = 10
UFd= 1
300®
Zhang et al.
£2
High
Immune
System
Mice
(male)
Dermal
(extrapolated from
oral)
1,2-dichloroethane
data
14-days oral gavage
LOAELadj =
4.89 mg/kg
Suppression
of immune
response
(AFCs/spleen)
N/A
N/A
0.890
0.636
UFa = 3
UFh = 10
UFl = 3
UFS = 10
UFd= 1
1,00(/
Munson et
al (1982)
High
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Target
Organ
Svstcm
Species
Duration/
Route
Study
POD/
Type
Effect
Worker
HEC h
(ppm)
|mg/m3|
Continuous
HEC h
(ppm)
|mg/m3|
Worker
HED<
(m<;/k«-
Im/day)
Continuous
HED'
(mg/kg-
bw/day)
Uncertainty
Factors*
Total
Uncertainty
Factors
Reference
Data
Quality
" See Section 3 for details.
'' BMCLs = 21.2 mg/m3 was adjusted to continuous adjusted (with no respiratory effects, there is no RGD; the blood/air ratio = 1, based on Equation Apx A-7; therefore,
the HECcont is the same as the adjusted POD of 21.2 mg/m3. The HEC worker is the HECCOnt x 4.2 (hours in a week divided by the # of working hours in a week; 168/40)
= 89.0 mg/m3. Both HEC worker and continuous converted to ppm divided by a factor of 4.05 (based 24.45/MW).
c All oral PODs were first adjusted to 7 days/week. All continuous oral PODs were then converted to HEDs using DAFs. Dermal PODs were set equal to the oral HED.
It is often necessary to convert between ppm and mg/m3 due to variation in concentration reporting in studies and the default units for different OPPT models. Therefore.
EPA presents all PODs in equivalents of both units to avoid confusion and errors. PODs converted for use in worker exposure scenarios were adjusted to 8 hours/day, 5
days/week and converted to HECs.
d POD identified from chronic exposure by the oral route to 1,2-dichloroethane. A chronic-duration oral HED for worker of 0.890 mg/kg-bw/day and a HED for
continuous exposure of 0.636 mg/kg-bw/day was used for risk assessment of chronic oral exposure, with a total uncertainty factor of 1000, based on a combination of
uncertainty factors: 3 for interspecies extrapolation when a dosimetric adjustment is used, 10 for human variability, 3 for the use of a LOAEL to extrapolate a NOAEL
(based on the dose-response), and 10 for extrapolating from a subchronic study duration to a chronic study duration.
e POD identified from chronic exposure by the inhalation route to 1,2-dichloroethane. The chronic-duration inhalation HEC for worker exposure of 89.0 mg/m3, and a
HEC for continuous exposure of 21.2 mg/m3, was used for risk assessment of chronic inhalation exposure, with a total uncertainty factor of 300, based on a combination
of uncertainty factors: 3 for interspecies extrapolation when a dosimetric adjustment is used, 10 for human variability, and 10 for extrapolating from a subchronic study
duration to a chronic study duration.
' No PODs were identified from chronic exposure by the dermal route to 1,2-dichloroethane; therefore, route-to-route extrapolation from the oral route was used to
identify a POD. A chronic-duration dermal HED for worker of 0.890 mg/kg-bw/day and a HED for continuous exposure of 0.636 mg/kg-bw/day was used for risk
assessment of chronic dermal exposure, with a total uncertainty factor of 1000, based on a combination of uncertainty factors: 3 for interspecies extrapolation when a
dosimetric adjustment is used, 10 for human variability, 3 for the use of a LOAEL to extrapolate a NOAEL (based on the dose -response), and 10 for extrapolating from
a subchronic study duration to a chronic study duration.
g UF = uncertainty factor; UFA = extrapolation from animal to human (interspecies); UFH = potential variation in sensitivity among members of the human population
(intraspecies); UFL = use of a LOAEL to extrapolate a NOAEL; UFS = use of a short-term study for long-term risk assessment; UFDb = to account for the absence of key
data (i.e., lack of a critical study).
2124
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2125 Table 8-4. Cancer POPs for 1,2-Dichloroethane Lifetime Exposure Scenarios
Exposure
Assumption"
Oral Slope
Factor''
Dermal Slope
Factor''
Inhalation Unit
Risk'
Drinking Water
Unit Risk''
Extra Cancer Risk
Benchmark
Continuous
Exposure
0.062 per
mg/kg/day
0.062 per
mg/kg/day
7.1E-06 (per ng/m3)
2.9E-02 (per ppm)
1.8E-06 per ug/L
1E-06 (general
population)
Worker
0.062 per
mg/kg/day
0.062 per
mg/kg/day
2.4E-06 (per ng/m3)
9.5E-03 (per ppm)
1.8E-06 per ug/L
1E-04 (occupational)
" Cancer slope factor and unit risk will be derived based on continuous exposure scenarios. Due to the exposure averaging
time adjustments incorporated into lifetime exposure estimates, separate cancer hazard values for occupational scenarios are
not required.
b The oral CSF for male mice based on heratocarcinomas was 6.2x10-3 (oer mu/ku-bw/dav) in a reliable studv NTP (1978).
Cancer PODs from 1.2-dichloroethane based on hepatocellular carcinomas in male mice NTP {1978). Due to scarcity of data,
route-to-route extrapolation from the oral slope factor is used for the dermal route.
c Cancer inhalation PODs from 1,2-dichloroethane based on based on combined mammary gland adenomas, fibroadenomas,
and adenocarcinomas and subcutaneous fibromas in female rats Nagano et al. (2006).
' Therefore, the oral CSF for 1.2-dichloroethane from the reliable NTP mouse cancer studv NTP (1978) was selected for use
in assessment of cancer risks associated with exposure to 1,2-dichloroethane. This mouse CSF was used to calculate a
drinking water unit risk of 1.8 E-06 per ug/L using a drinking water intake of 2 L/day and body weight of 70 kg.
2126
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REFERENCES
Alumot E; Nachtomi. E; Man del. E; Holstein. P. (1976). Tolerance and acceptable daily intake of
chlorinated fumigants in the rat diet. Food Cosmet Toxicol 14: 105-111.
http://dx.doi.ore 10 101 c-00l- >264(76)80:^: 0
Ansai> \ v >Hgh. SV: Gan. JC: Awasthi V' (1987). Human erythrocyte glutathione S-transferase: A
possible marker of chemical exposure. Toxicol Lett 37: 57-62. http://dx.doic >/0378-
4274(87)90167-6
Arfellini. 0 s 10
Borzellet ;hman. RA. (1982). Effects of selected organic drinking water contaminants on male
reproduction. Richmond, Va: Medical College of Virginia.
https://search.proqiiest.com/docview/135436777accoun I.
Bove. FX (1996). Public drinking water contamination and birthweight, prematurity, fetal deaths, and
birth defects. Toxicol Ind Health 12: 255-266.
Bove. i 1 mer. MC: Klot Esiikh'i J. Dufficv. EM: Savriii h (1995). Public drinking water
contamination and birth outcomes. Am J Epidemiol 141: 850-862.
http://dx.doi.ore/10.1093/oxfordiournals.j I I % I
Brender. ID: Shinde. Mil: Zha ig. X: Lanelois. PH. (2014). Maternal residential proximity to
chlorinated solvent emissions and birth defects in offspring: A case-control study. Environ
Health 13: 96. http://dx.doi.ors 86/1476-069X-13-96
Brittebo. EB: Kowalski r% 4iantous. t i Brandt. 1. (1989). Epithelial binding of 1,2-dichloroethane in
mice. Toxicology 56: 35-45. http://dx.doi.on 10 101 0300-483X(89)902 10 J
Brondeau. MT: Bonnet. P: Guenier. IP: De. CI. (1983). Short-term inhalation test for evaluating
industrial hepatotoxicants in rats. Toxicol Lett 19: 139-146. http://dx.doij 178-
4274(83)90274-6
Casciola. LAF: Ivanetich. KM. (1984). Metabolism of chloroethanes by rat liver nuclear cytochrome P-
450. Carcinogenesis 5: 543-548. http://dx.doi.ore/10.1093/carcin/5.5.543
Page 95 of 171
-------
2176
2177
2178
2179
2180
2181
2182
2183
2184
2185
2186
2187
2188
2189
2190
2191
2192
2193
2194
2195
2196
2197
2198
2199
2200
2201
2202
2203
2204
2205
2206
2207
2208
2209
2210
2211
2212
2213
2214
2215
2216
2217
2218
2219
2220
2221
2222
2223
PUBLIC RELEASE DRAFT
July 2024
Cheever. KL; Cholakis. JM; El-Hawaii. AM; Kovatch. R.M; Weisburger. EK. (1990). Ethylene
dichloride: The influence of disulfiram or ethanol on oncogenicity, metabolism, and DNA
covalent binding in rats. Toxicol Sci 14: 243-261. http://dx.doi.ore )272~
0590(90)90205~X
Chen ?hou. PY; Huang. ML; Du. CL; Wong. RH; Chen. PC. (2000). Increased lymphocyte sister
chromatid exchange frequency in workers with exposure to low level of ethylene dichloride.
Mutat Res 470: 109-114. http://dx.doi.on §1383-5742(00)00045-4
Cheng. TJ; Huang. ML; You. NC; Du. CL; Chan. TT. (1999). Abnormal liver function in workers
exposed to low levels of ethylene dichloride and vinyl chloride monomer. J Occup Environ Med
41: 1128-1133. http://dx.doi.org/10.1097/00Q i I C^M.OOOOOOIN
Chroust. K; Jowett. T; Farid-Waiidi. MF; Huang ova. M; Wolf. R; Holoubek. I. (2001).
Activation or detoxification of mutagenic and carcinogenic compounds in transgenic Drosophila
expressing human glutathione S-transferase. Mutat Res 498: 169-179.
http://dx.doi.org/i0J016/S I 'A i - I v QI KV280-7
Cottalasso. D; Barisione. G; Fontana. L; Domenicotti. C; Pronzato. MA; Nanni. G. (1994). Impairment
of lipoglycoprotein metabolism in rat-liver cells induced by 1,2-dichloroethane. Occup Environ
Med 51: 281-285. http://dx.doi.org/10.H36/oem 81
Cottalasso P. Pomenicotti. C; Travel ,s Picozato. M; Naron (2002). Influence of chronic
ethanol consumption on toxic effects of 1,2-dichloroethane: glycolipoprotein retention and
impairment of dolichol concentration in rat liver microsomes and Golgi apparatus. Toxicology
178: 229-240. http://dx.doi.on »0300~483X(02)00235~4
Cottalasso P. I'omana. L; Gazzo. P; Dapino. D; Domeniconi 1. Piciizato. MA; Nanni. G. (1995).
Effects of 1,2-dichloroethane intoxication on dolichol levels and glycosyltransferase activities in
rat liver microsomes and Golgi apparatus. Toxicology 104: 63-71.
http://dx.doi.orE >300~483X(95)03130-8
Crebelli. R; Carina \ 1 ^tpardi. P; Conti 1 i jssio. F; Raited I', H;irone P, ("iliutti. P; Cinelli. S;
Verk (1999). Evaluation of 10 aliphatic halogenated hydrocarbons in the mouse bone
marrow micronucleus test. Mutagenesis 14: 207-215. http://dx.doi.org riutage/14.2.207
Crespi. CL; Seixas. GM; Turner. TR; Ryan. CG; Penma (1985). Mutagenicity of 1,2-
dichloroethane and 1,2-dibromoethane in two human lymphoblastoid cell lines. Mutat Res 142:
133-140. http://dx.doi.c 5/0165-7992(85)90053-3
D'Souza. RW; Francis. WR; Andersen. ME. (1988). Physiological model for tissue glutathione depletion
and increased resynthesis after ethylene dichloride exposure. J Pharmacol Exp Ther 245: 563-
568.
D'Souza. RW; Francis. \\ K Kt\t.v kO \ii4ersen. ME. (1987). Physiologically based pharmacokinetic
model for ethylene dichloride and its application in risk assessment. In Pharmacokinetics in risk
assessment: V 8, drinking water and health. Washington, DC: National Academy Press.
Daigle. JH.J; Colo PN, Carlson i « \\ K Wilson. V.L. (2009). Ethylene Dichloride Disruption of
Fertility in Male Mice. The Open Toxicology Journal 3: 39-46.
http://dx.doi.orE 874340400903010039
Panici t Tn Kohinson. M; Olson K \ K 1 ondie. LW. (1994). Ten and ninety-day toxicity
studies of 1,2-dichloroethane in Sprague-Dawley rats. Drug Chem Toxicol 17: 463-477.
http://dx.doi. org/10.3109/014805494(
Davis. B (2012). Endometrial stromal polyps in rodents: Biology, etiology, and relevance to disease in
women [Review], Toxicol Pathol 40: 419-424. http://dx.doi.org/10.1177/019262
Dohe lard. S; Parry. EM; Parry. JM. (1996). An investigation into the activation and
deactivation of chlorinated hydrocarbons to genotoxins in metabolically competent human cells.
Mutagenesis 11: 247-274. http://dx.doi.org/10.1093/mutage/11.3.247
Page 96 of 171
-------
2224
2225
2226
2227
2228
2229
2230
2231
2232
2233
2234
2235
2236
2237
2238
2239
2240
2241
2242
2243
2244
2245
2246
2247
2248
2249
2250
2251
2252
2253
2254
2255
2256
2257
2258
2259
2260
2261
2262
2263
2264
2265
2266
2267
2268
2269
2270
2271
2272
PUBLIC RELEASE DRAFT
July 2024
Dosemeci. M; Cocco. P; Chow. WH. (1999). Gender differences in risk of renal cell carcinoma and
occupational exposures to chlorinated aliphatic hydrocarbons. Am J Ind Med 36: 54-59.
http://dx.doi.ore 10 100 J ; sicfl 10° 0. hi 0 > -6:1 <54:: ai d-aj i m 8>3.0. co;2-0
Dow Chemical. (1956). Results of skin absorption studies on carbon tetrachloride, ethylene dichloride,
tetrachloroethylene, trichloroethylene, and chlorothene [TSCA Submission], (OTS0515981. 86-
870002191. TSCATS/309536).
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/OTS0515981 .xhtml
Dow Chemical. (1962). Topical application of various solvents and solutions to evaluate dermal
irritation [TSCA Submission], (OTS0515970. 86-870002180. TSCATS/309514).
https://ntrl.ntis.gOv/NTRL/dashboard/searchResults/titleDetail/OTS0515970.xhtml
Dow Chemical. (1989). Comparison of the acute lethality of selected hydrocarbons via intratracheal and
oral routes (final report) with attachments, cover sheets and letter dated 061989 [TSCA
Submission], (Laboratory Project Study ID T2.02-194-000-002. OTS0520615. 86-890000576.
TSCATS/404074).
Dow Chemical. (2005). Ethylene dichloride: Acute vapor inhalation toxicity study in Fischer 344 rats.
(041089). Millwood, VA: HAP Task Force for Ethylene Dichloride.
Dow Chemical. (2006a). 1,2-Dichloroethane (EDC): Limited pharmacokinetics and metabolism study in
Fischer 344 rats. (041093). Millwood, VA: HAP Task Force.
Dow Chemical. (2006b). Re: Testing consent order for ethylene dichloride; final report (docket no .
OPPT-2003-0010) [TSCA Submission], (Study ID No. 041115. 40060000065). HAP Task Force
for Ethylene Dichloride.
Dow Chemical. (2014). [Redacted] Investigation of the mode of action for 1,2-dichloroethane-induced
mammary tumors in female F344/DuCrl rats. (121180).
Dow Chemical. (2017). [Redacted] 1,2-Dichloroethane: Acute vapor inhalation toxicity study in
F344/DuCrl rats. (171002). Brussels, Belgium: ReachCentrum S.A.
Francovitch. RJ; Schor. NA; George. WJ. (1986). Effects of SKF 525A, phenobarbital, and 3-
methylcholanthrene on ethylene dichloride toxicity following inhalation exposure. Int J Toxicol
5: 117-126. http://dx.doi.ofg/10.3109/10915818t
Frasch. HF; Barbero. AM. (2009). A paired comparison between human skin and hairless guinea pig
skin in vitro permeability and lag time measurements for 6 industrial chemicals. Cutan Ocul
Toxicol 28: 107-113. http://dx.doi.org/i0J080/1556952090295Q474
Frasch. HF; Bar chkar. H; Mcdougal. IN. (2007). Skin penetration and lag times of neat
and aqueous diethyl phthalate, 1,2-dichloroethane and naphthalene. Cutan Ocul Toxicol 26: 147-
160. http://dx.doi.org/10.1080/15569520' 274
Gaiiar. RM; Kasting. GB. (2014). Absorption of ethanol, acetone, benzene and 1,2-dichloroethane
through human skin in vitro: a test of diffusion model predictions. Toxicol Appl Pharmacol 281:
109-1 17. http://dx.doi.oi ^ 10 101 5/i.taap..01 I 0° 01 '<
Garcia. E; Hurley. S; Nelson. DO; Hertz. A; Reynolds. P. (2015). Hazardous air pollutants and breast
cancer risk in California teachers: A cohort study. Environ Health 14: 14.
http://dx.doi.ore 10 I 186/1476-06^ \ I i I i
Gargas. ML; Andersen. ME. (1989). Determining kinetic constants of chlorinated ethane metabolism in
the rat from rates of exhalation. Toxicol Appl Pharmacol 99: 344-353.
http://dx.doi.ore 10 101 00 II 008X(89)900M>1
Gargas. "K li r^vrge;-v k < \ »nsard. 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. http://dx.doi.org/i 0 J 0 i 6/00 11 008x(89VV I
Giri. AK; Que Hee. SS. (1988). In vivo sister chromatid exchange induced by 1,2-dichloroethane on
bone marrow cells of mice. Environ Mol Mutagen 12: 331-334.
http://dx.doi.org/10.1002/em.2860120307
Page 97 of 171
-------
2273
2274
2275
2276
2277
2278
2279
2280
2281
2282
2283
2284
2285
2286
2287
2288
2289
2290
2291
2292
2293
2294
2295
2296
2297
2298
2299
2300
2301
2302
2303
2304
2305
2306
2307
2308
2309
2310
2311
2312
2313
2314
2315
2316
2317
2318
2319
2320
PUBLIC RELEASE DRAFT
July 2024
Guengerich. FP; Crawford. WM. In Domoradzki A . Mcdonald. TL; Watanabe. PG. (1980). In vitro
activation of 1,2-dichloroethane by microsomal and cytosolic enzymes. Toxicol Appl Pharmacol
55: 303-317. http://dx.dou 6/0041 -008X(80)90092-7
Guengerich. FP; Kim. DH; Iwasaki. M. (1991). Role of human cytochrome P-450 IIE1 in the oxidation
of many low molecular weight cancer suspects. Chem Res Toxicol 4: 168-179.
http://dx.doi.ore x00020a008
Guo. XL; Ni (2003). [The relationship between excitatory amino acids and acute intoxicated
encephalopathy induced by 1,2-dichloroethane], Zhonghua Laodong Weisheng Zhiyebing Zazhi
21: 83-85.
Gwinn. MR; Johns. DO; Bateson. tyton. KZ. (2011). A review of the genotoxicity of 1,2-
dichloroethane (EDC) [Review], Mutat Res 727: 42-53.
http://dx.doi.ore 10 101 i.mrrev.-0 I I 01 001
Hachiya. N; Motohashi. Y. (2000). Examination of lacZ mutant induction in the liver and testis of
Muta(TM)Mouse following injection of halogenated aliphatic hydrocarbons classified as human
carcinogens. Ind Health 38: 213-220. http://dx.doi.org/10.2486/indhealth.38.213
Han ah an. D; Weinberg. RA. (2011). Hallmarks of cancer: The next generation [Review], Cell 144: 646-
674. http://dx.dt > ^ so /j.cell.201 I 0J.013
Hellman. indt. I. (1986). Effects of carcinogenic halogenated aliphatic hydrocarbons on
[3H]thymidine incorporation into various organs of the mouse. A comparison between 1,2-
dibromoethane and 1,2-dichloroethane. Mutat Res 163: 193-199. http://dx.doi.org/10.1016/0027-
190048-5
Heppel. LA; Ne; rin. TL; Endicott. KM; Porterfield. VT. (1945). The toxicology of 1,2-
dichloroethane (ethylene). III. Its acute toxicity and the effect of protective agents. J Pharmacol
Exp Ther 84: 53-63.
Heppel. LA; Ne; rin. TL; Endicott. KM; Porterfield. VT. (1946). The toxicology of 1,2-
dichloroethane (ethylene dichloride): V. The effects of daily inhalations. J Ind Hyg Toxicol 28:
113-120.
H (1965). The environment and disease: Association or causation? Proc R Soc Med 58: 295-300.
http://dx.doi.ore 10 I I 00 505800503
Hofmann. HT; Birnstiel. H; Jobst. P. (1971). On inhalation toxicity of 1,1- and 1,2-dichloroethane. Arch
Toxikol 27: 248-265. http://dx.doi.on 07/BF00315048
H.otchkist \minis. AK; Johnson, i \ i rieger. SM; Woolhiser. MR; Maurissen. JP. (2010). Acute
toxicologic and neurotoxic effects of inhaled 1,2-dichloroethane in adult Fischer 344 rats. Food
Chem Toxicol 48: 470-481. http://dx.doi.org/10.1016/i .fct.2009.10.039
Hueper. WC; Smith. C. (1935). Fatal ethylene dichlorid poisoning. Am J Med Sci 189: 778-784.
< Hie Hee. SS; Wagner. AN O (1986a). Effect of disulfiram pretreatment on the tissue
distribution, macromolecular binding, and excretion of [U-l,2-14C]dichloroethane in the rat.
Drug Metab Dispos 14: 65-72.
Igw^ < Hie Hee. SS; Wagner. AN O (1986b). Interaction between 1,2-dichloroethane and disulfiram.
I. Toxicologic effects. Fundam Appl Toxicol 6: 733-746. http://dx.doi.off )272~
0590(86)90186-7
Igw^ oi < Hie Hee. SS; Wagner \N D (1986c). Interaction between 1,2-dichloroethane and
tetraethylthiuram disulfide (disulfiram). II. Hepatotoxic manifestations with possible mechanism
of action. Toxicol Appl Pharmacol 86: 286-297. http://dx.doi.c >/0041~008X(86)90059-
I
Inskeep. PB; Koga. N; Cmarik. JL; Guengerich. FP. (1986). Covalent binding of 1,2-dihaloalkanes to
DNA and stability of the major DNA adduct, S-[2-(N7-guanyl)ethyl]glutathione. Cancer Res 46:
2839-2844.
Page 98 of 171
-------
2321
2322
2323
2324
2325
2326
2327
2328
2329
2330
2331
2332
2333
2334
2335
2336
2337
2338
2339
2340
2341
2342
2343
2344
2345
2346
2347
2348
2349
2350
2351
2352
2353
2354
2355
2356
2357
2358
2359
2360
2361
2362
2363
2364
2365
2366
2367
PUBLIC RELEASE DRAFT
July 2024
IPCS. (1995). 1,2-Dichloroethane (Second edition) [WHO EHC], Geneva, Switzerland: World Health
Organization, http://www.inchem.ore/documents/ehc/ehc/e htm
IRFMN. (1976). Clinical chemistry results after 6 months inhalatory exposure to ethylene dichloride
[TSCA Submission], (OTS0515738. 86-870001662. TSCATS/309048). Shell Oil Company.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/OTS0515738.xhtml
IRFMN. (1978). Clinical chemistry results in adult rats exposed to ethylene dichloride by inhalation for
12 months [TSCA Submission], (OTS0515737. 86-870001661). Shell Oil Company.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/OTS0515737.xhtml
IRFMN. (1987). Report on the clinical chemistry results after 18 months inhalatory exposure - ethylene
dichloride [TSCA Submission], (OTS0517059. 86-870002269. TSCATS/309692). Dow
Chemical. https://ntrl.ntis.eov/NTRL/dashboard/searchResiilts/titleDetail/OTS0517059.xhtml
Jakob son. I; Wahlberg. IE; Holmt lansson. G (1982). Uptake via the blood and elimination of
10 organic solvents following epicutaneous exposure of anesthetized guinea pigs. Toxicol Appl
Pharmacol 63: 181-187. http://dx.doi.ore/10.1016/00 11 008X(82)90039-4
Jean, \ W,v4 OJ (1992). Utilization of glutathione during 1,2-dihaloethane metabolism in rat
hepatocytes. Chem Res Toxicol 5: 386-391. http://dx.doi.ore/10.1021/tx00027a011
Jin. X; Liao. Y; Tan \ no. J: Wang hao. F; Jin. Y. (2018a). Involvement of the p38 MAPK
signaling pathway in overexpression of matrix metalloproteinase-9 during the course of brain
edema in 1,2-dichloroethane-intoxicated mice. Neurotoxicology 69: 296-306.
http://dx.doi.ore/10.1016/i .neuro.2018.07.022
Jlii \ 1 u<« \ i jti \ buc t tin. Y. (2018b). Involvement of CYP2E1 in the course of
brain edema induced by subacute poisoning with 1,2-dichloroethane in mice. Front Pharmacol 9:
1317. http://dx.doi.ore/10.3389/fphar
Johnson. MK. (1967). Metabolism of chloroethanol in the rat. Biochem Pharmacol 16: 185-199.
http://dx.doi.orE >006-2952(67)90199-2
Kanada. M: Miyaeawa. M: Sato. M; Haseeawa. H; Honma. T. (1994). Neurochemical profile of effects
of 28 neurotoxic chemicals on the central nervous system in rats (1) Effects of oral
administration on brain contents of biogenic amines and metabolites. Ind Health 32: 145-164.
http: //dx. doi. or e/10.2486/in dh ealt
Kern; semeci. M; Silverman. DT; Balbus. J: Zahm. SH. (1999). Occupational risk
factors for pancreatic cancer: A case-control study based on death certificates from 24 U.S.
states. Am J Ind Med 36: 260-270. http://dx.doi. >10)1097-
9908)36:2<260::AID-AJIM5>3.0.CO:2-P
Kettering Laboratory. (1943). The physiological effects upon rabbits of exposure to 1,2-dichloroethane
and 1,2-dibromoethane [TSCA Submission], (OTS0516127. 86-870001224. TSCATS/400132 ).
University of Cincinnati.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/OT xhtml
Kitchin. I i rMown. JL; Kulkami \P (1993). Predicting rodent carcinogenicity of halogenated
hydrocarbons by in vivo biochemical parameters. Birth Defects Res B Dev Reprod Toxicol 13:
167-184. http://dx.doi.c 2/tcm. 1770130403
Klaunig. JE; Ruch. RJ; Pereira. MA. (1986). Carcinogenicity of chlorinated methane and ethane
compounds administered in drinking water to mice. Environ Health Perspect 69: 89-95.
http://dx.doi.org 39/ehp.866989
Kozil (1957). [Problems of occupational hygiene in the use of dichloroethane in the aviation
industry]. Gig TrProfZabol 1: 31-38.
Kronf t I' WaMbet\ h Molmb''^ <' (1981). Skin pathology following epicutaneous exposure to
seven organic solvents. Int J Tissue React 3: 21-30.
Page 99 of 171
-------
2368
2369
2370
2371
2372
2373
2374
2375
2376
2377
2378
2379
2380
2381
2382
2383
2384
2385
2386
2387
2388
2389
2390
2391
2392
2393
2394
2395
2396
2397
2398
2399
2400
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2405
2406
2407
2408
2409
2410
2411
2412
2413
2414
2415
PUBLIC RELEASE DRAFT
July 2024
Lane. RW: Riddle HI . Uorzelleca 11 (1982). Effects of 1,2-dichloroethane and 1,1,1-trichloroethane
in drinking water on reproduction and development in mice. Toxicol Appl Pharmacol 63: 409-
421. http://dx.doi.org/10.1016/0041 4)08X(82)90270-8
Lebaron. Ml; Hotchkist- 'hang i:'. Koehler. MW; Boverhof DR. (2021). Investigation of potential
early key events and mode of action for 1,2-dichloroethane-induced mammary tumors in female
rats. J Appl Toxicol 41: 362-374. http://dx.doi.ore/10.1002/iat.4048
Li. W; Chen. L; Su. Y; Yin. H. ua; Pane. Y; Zhuang. Z. (2015). 1,2-Dichloroethane induced
nephrotoxicity through ROS mediated apoptosis in vitro and in vivo. Toxicology Research 4:
1389-1399. http://dx.doi.ore/10.1039/c5tx00056d
Liang «' hone \ \\ ane 1 ti} 1 1 i 1 X; Huam \ I ki. M; Zham «' Mene. H; Jiang. L;
Jiane. J: Wti. J; Zhang. Y; Rot ,g. X; Huang. Z. (2021). 1,2-Dichloroethane induces
apoptosis in the cerebral cortexes of NIH Swiss mice through microRNA-182-5p targeting
phospholipase D1 via a mitochondria-dependent pathway. Toxicol Appl Pharmacol 430: 15728-
15728. http://dx.doi.ore/10.1016/i.taap.20. ill _ |
Livesev. JC. (1982) Studies on the metabolism and toxicity of 1,2-dihaloethanes. (Doctoral
Dissertation). University of Minnesota, Minneapolis, MN. Retrieved from
https://login.libpdb.d.umn.edu:2443/login?url=
Lochhead. HB; Close. HP. (1951). Ethylene dichloride plastic cement: A case of fatal poisoning. JAMA
146: 1323. http://dx.doi.on 10 1001 iama.1951.636 01 1001 101 Hi
Lone. MI; Nazam. N: Hussain. \ * mgh. SK; Dai Vtj a K \ M ^ ihtani. Mil, \hmad. W.
(2016). Genotoxicity and immunotoxic effects of 1,2-dichloroethane in Wistar rats. J Environ Sci
Health C Environ Carcinog Ecotoxicol Rev 34: 169-186.
http://dx.doi.Org/10.1080/10590501.2
Maltoni. ('. \ ;tlgimigli. L; Scamatc t (1980). Long-term carcinogenic bioassays on ethylene
dichloride administered by inhalation to rats and mice. In B Ames; P Infante; R Reitz (Eds.),
Ethylene dichloride: A potential health risk? (pp. 3-29). Cold Spring Harbor, NY: Cold Spring
Harbor Laboratory.
Matsuoki avashi. M; Sofuni. T. (1998). In vitro clastogenicity of 19 organic chemicals found in
contaminated water and 7 structurally related chemicals. Environmental Mutagen Research 20:
159-165.
MCA. (1979). Third report on distribution and metabolism of 1,2-dichloroethane (EDC) in experimental
animals with attachments and cover letter dated 041179 [TSCA Submission] (pp. 21).
(OTS0516163. 86-870001582. TSCATS/400204). Institute of Pharmacology.
https://ntrl.ntis.eov/NTRL/dashboard/searchResiilts/titleDetail/OT xhtml
McCall. SN; Jurgens. P; Ivanetich. KM. (1983). Hepatic microsomal metabolism of the dichloroethanes.
Biochem Pharmacol 32: 207-213. http://dx.doix >/0006~2952(83)90545~2
McDermott. C; Heffron. JJA. (2013). Toxicity of Industrially Relevant Chlorinated Organic Solvents In
Vitro. Int J Toxicol 32: 136-145. http://dx.doi.or S2006
Mellon Institute. (1947). Repeated exposure of rats and dogs to vapors of eight chlorinated hydrocarbons
[TSCA Submission], (OTS0515559. 86-870001397. TSCATS/308690). Carbide and Carbon
Chemicals Corporation.
https://ntrl.ntis.eov/NTRL/dashboard/searchResults/titleDetail/OTS0^i2^^ xhtml
Mellon Institute. (1948). The toxicity of ethylene dichloride [TSCA Submission], (Report 11-40.
OTS0515565. 86-870001403). Union Carbide Corporation.
Milman. HA; Story. PL; Riccio. ES; Sivc Williams. GM; Tone. C; Tyson. CA. (1988). Rat
liver foci and in vitro assays to detect initiating and promoting effects of chlorinated ethanes and
ethylenes. Ann N Y Acad Sci 534: 521-530. http://dx.doi.o
6632.1988.tb30143.x
Page 100 of 171
-------
2416
2417
2418
2419
2420
2421
2422
2423
2424
2425
2426
2427
2428
2429
2430
2431
2432
2433
2434
2435
2436
2437
2438
2439
2440
2441
2442
2443
2444
2445
2446
2447
2448
2449
2450
2451
2452
2453
2454
2455
2456
2457
2458
2459
2460
2461
2462
2463
PUBLIC RELEASE DRAFT
July 2024
Mi torn a. C; Steeeer. T; Jackson. SE; Wheeler. KP; Rogers. JH; Milman. HA. (1985). Metabolic
disposition study of chlorinated hydrocarbons in rats and mice. Drug Chem Toxicol 8: 183-194.
http://dx.doi.org/10.3109/014805485Q8999169
Mood\ IH i.tines, il . Ciawson. GA; Smuckler. EA. (1981). Correlations among the changes in
hepatic microsomal components after intoxication with alkyl halides and other hepatotoxins. Mol
Pharmacol 20: 685-693.
More an. M; Hettich. D; Huguet. N. (1999). Role of SAM-dependent thiol methylation in the renal
toxicity of several solvents in mice. J Appl Toxicol 19: 47-54.
http://dx.doi.org 10 1002/(SICD1099-1263(199901 /0.)r K47::AID-JAT536>3.0.CO;2-L
Morgan. PL; Bucher. JR.; Elwell. MR; Lilia. HS: Mtirtfa (1990). Comparative toxicity of ethylene
dichloride in F344/N, Sprague-Dawley and Osborne-Mendel rats. Food Chem Toxicol 28: 839-
845. http://dx.doi.oiv tOtOt /0278-6915(90)90*' I
Morgan. PL; Coopt k. PL; Sykora. II; Sutton. B; Mattie. PR; McPougal. IN. (1991).
Dermal absorption of neat and aqueous volatile organic chemicals in the Fischer 344 rat. Environ
Res 55: 51-63. http://dx.doi.orv 10 101 'S0013-- •» 1,0-^0140-9
Munson. AE; Sanders. VM; Douglas. lin. LE; Kauffmann. BM; White Jr.. KL. (1982). In vivo
assessment of immunotoxicity. Environ Health Perspect 43: 41-52.
http://dx.doi.org/10.1289/ehp.824341
Nagano. K; Umeda. Y; Senoh. H; Gotoh. to. H; Yamamoto. S; Matsushima. T. (2006).
Carcinogenicity and chronic toxicity in rats and mice exposed by inhalation to 1,2-
dichloroethane for two years. J Occup Health 48: 424-436. http://dx.doi.oiv 10 I ^ ''!/ioh IN IJ I
Niehoff. NM; Gammon. MP; Keit. AP; Nichols. > < ngel. LS; Sandler. PP; Wlnu' \< (2019).
Airborne mammary carcinogens and breast cancer risk in the Sister Study. Environ Int 130:
104897. http://dx.d0i.0rg/l /i.envint.2019.06.007
Nouchi. T; Miura. H; Kanavama. M; Mizuguchi. O; Takano. T. (1984). Fatal intoxication by 1,2-
dichloroethane - a case report. Int Arch Occup Environ Health 54: 111-113.
http://dx.doi.org/10.1007/BF0Q37
NTP. (1978). Bioassay of 1,2-dichloroethane for possible carcinogenicity [NTP], In National Cancer
Institute carcinogenesis technical report series, no 55. (TR 55). Bethesda, Maryland: U.S.
Pepartment of Health and Human Services, National Institutes of Health, National Cancer
Institute, https://ntp.niehs.nih.gov/sites/defaiilt/files/ntp/htdocs/tt rpts/tr055.pdf?vw
NTP. (1991). Toxicity studies of 1,2-dichloroethane (ethylene bichloride) (CAS No. 107-06-2) in
F344/N rats, Sprague Pawley rats, Osborne-Mendel rats, and B6C3F1 mice (drinking water and
gavage studies). (NTP TOX 4; NIH Publication No. 91-3123). Research Triangle Park, NC.
https://ntp.niehs.nih.gov/piiblications/reports/tox/000s/tox004
OECP. (2002). SIPS initial assessment report for SI AM 14. 1,2-Pichloroethane (CAS no: 107-06-2)
[OECP SIPS], Paris, France: UNEP Publications.
https://hpvchemicats.oecd.ofg/UI/handtef.axd?id=95fM194-732a-4cc9-b59b-839ed3b 18732
OECP. (2015). Fundamental and guiding principles for (Q)SAR analysis of chemical carcinogens with
mechanistic considerations. (ENV/JM/MONO(2015)46). Paris, France.
http://www.oecd. org/officialdocuments/publicdisplaydocumentpdf/?cote=env/im/mono(2015)46
&doclanguage=en
Ott. MG; Teta. J; Greenberg. HL. (1989). Lymphatic and hematopoietic tissue cancer in a chemical
manufacturing environment. Am J Ind Med 16: 631-644.
http://dx.doi.ors 32/aiim .4700160603
Pang. ig. S; Zhou. Y; Li. W. (2018). 1,2-Pichloroethane induced hepatotoxicity and
apoptosis by inhibition of ERK 1/2 pathways. Can J Physiol Pharmacol 96: 1119-1126.
http://dx.doi.ors ;jpp-2017-0677
Page 101 of 171
-------
2464
2465
2466
2467
2468
2469
2470
2471
2472
2473
2474
2475
2476
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2478
2479
2480
2481
2482
2483
2484
2485
2486
2487
2488
2489
2490
2491
2492
2493
2494
2495
2496
2497
2498
2499
2500
2501
2502
2503
2504
2505
2506
2507
2508
2509
2510
PUBLIC RELEASE DRAFT
July 2024
Paolini. M; Mesirca. R; Pozzetti. L; Sapo a. GL; Trieff. NM; Cantelli-Forti. G. (1994).
Correlation between murine liver cytochrome P450 2B1 induction by halogenated hydrocarbons
and toxicity. Toxicol Environ Chem 44: 55-64. http://dx.doi.org/10.1080/02772249409358Q43
Pavan. IP; Bevdon. D: Fabi \ ^ Brondeau. MT: Ban. M; de Ceaurritz. J C1993). Urinary thiodiglvcolic
acid and thioether excretion in male rats dosed with 1,2-dichloroethane. J Appl Toxicol 13: 417-
422. http://dx.doi.ore/10.1002/iat.2550130608
Pavan. IP; Saillenfait. AM; Bonnet P; Fabry. IP: Lamgomme. I; Sab ate. IP. (1995). Assessment of the
developmental toxicity and placental transfer of 1,2-dichloroethane in rats. Toxicol Sci 28: 187-
198. http://dx.doi.ore/!0.1006/faat. 19
Prodi. G; Arfellini. G; Colacci. \ tilli. S; Mazzullo. M. (1986). Interaction of halocompounds with
nucleic acids. Toxicol Pathol 14: 438-444. http://dx.doi.ore/10.1177/019262338601400409
Prodi. G; Cotact > \ > dU. S; Lattan: > Mazzullo. M; Turiru P (1988). Comparison of the covalent
binding of various chloroethanes with nucleic acids. In F Feo; P Pani; A Columbano; R Garcea
(Eds.), Chemical carcinogenesis (pp. 93-102). Boston, MA: Springer.
http://dx.doi.ore 10 100 •_> s I i - <\ 40 10
Qin-1 ao. N; Lai-vu. L; Li-iun. Y; Xiao-li. G; Jian-xun. H; Lin-pine. W; You-xin. L. (2010). Toxic
encephalopathy induced by occupational exposure to 1,2-dichloroethane and toxicological effect
on animal model. In Proceedings of the 5th International Academic Conference on
Environmental and Occupational Medicine. Shanghai, China: Journal of Environmental &
Occupational Medicine.
Que. SSH; lewe. OI; Boyle. IR. (1988). Elemental alterations during the exposure of 1,2-dichloroethane
(EDC), disulfiram (DSF), and EDC-DSF to male Sprague-Dawley rats. Biol Trace El em Res 18:
9-28. http://dx.doi.ore/ 917485
Rao. KS; Murray. IS; Deacon. MM; John pun. IX; Youne. IT. (1980). Teratogenicity and
reproduction studies in animals inhaling ethylene dichloride. In B Ames; P Infante; RReitz
(Eds.), Banbury report: Ethylene dichloride: A potential health risk (pp. P149-P166). Cold
Spring Harbor, NY: Cold Spring Harbor Laboratory.
Rfu lev 1 h ; Domorad: 11 < Hiast. J I', 1 nnevardt. P; Watanabe. PG. (1980).
Pharmacokinetics and macromolecular interactions of ethylene dichloride: Comparison of oral
and inhalation exposures. In B Ames; P Infante; R Reitz (Eds.), Ethylene dichloride: A potential
health risk? (pp. 135-148). Cold Spring Harbor Laboratory: Cold Spring Harbor, NY.
Rfu tc\ 1 h ; Ramse\ 1 » V:im ,11', 1 ;inevardt. PW; Watanabe. PG. (1982). Pharmacokinetics
and macromolecular interactions of ethylene dichloride in rats after inhalation or gavage. Toxicol
Appl Pharmacol 62: 190-204. http://dx.doi.oi >- 10 101 /0041-008X(82)901 I \
Romert. L; Maenusson. I; Ramel. C. (1990). The importance of glutathione and glutathione transferase
for somatic mutations in Drosophila melanogaster induced in vivo by 1,2-dichloroethane.
Carcinogenesis 11: 1399-1402. http://dx.doi.ora 10 i 0''3/carcin II s
Salmon. AG; Jones. [ackrodt. WC. (1981). Microsomal dechlorination of chloroethanes:
Structure-reactivity relationships. Xenobiotica 11: 723-734.
http://dx.doi.ore/10.3109/00498258109045876
Salovsky. P; Shopova. V; Danche1 ianov. Y; Marinov. E. (2002). Early pneumotoxic effects
after oral administration of 1,2-dichloroethane. J Occup Environ Med 44: 475-480.
http://dx.doi.ore/10.1097/00043764-200205000-00016
Sasaki \ I Sae>i \ \l .raka. M; Ishibashi. v N >^faida. K; Su. YQ; Matsusai j x lvuda. S. (1998).
Detection in vivo genotoxicity of haloalkanes and haloalkenes carcinogenic to rodents by the
alkaline single cell gel electrophoresis (comet) assay in multiple mouse organs. Mutat Res 419:
13-20. hi11*. dvdoi.ore/10.10I6/S138 '< - IS(98)001 I S¦ S
Page 102 of 171
-------
2511
2512
2513
2514
2515
2516
2517
2518
2519
2520
2521
2522
2523
2524
2525
2526
2527
2528
2529
2530
2531
2532
2533
2534
2535
2536
2537
2538
2539
2540
2541
2542
2543
2544
2545
2546
2547
2548
2549
2550
2551
2552
2553
2554
2555
2556
2557
PUBLIC RELEASE DRAFT
July 2024
Schenk. L; Rauma." isson. MN: Johanson. G. (2018). Percutaneous absorption of thirty-eight
organic solvents in vitro using pig skin. PLoS ONE 13: e0205458.
http://dx.doi.ore jurnal. pone. 0205458
Sherwood. K.L; O'Shea. W; Thornier K.tiaicz.tl U\ \unvi. €; Graham. JA. (1987). Effects of
inhalation of ethylene dichloride on pulmonary defenses of mice and rats. Toxicol Appl
Pharmacol 91: 491-496. http://dx.doi.org/10 J 016/00 11 008X(87)90071-8
Sob el. W; Bond. GG: Skowronski. r%> r%rownsoii n • ook. RR (1987). A soft tissue sarcoma case
control study in a large multi-chemical manufacturing facility. Chemosphere 16: 2095-2099.
http://dx.doi.ore €45-6535(87)90214-1
Spencer. HC: Rowe. VK; Adams. EM; McCollister. DP; Irish. DP. (1951). Vapor toxicity of ethylene
dichloride determined by experiments on laboratory animals. Arch Ind Hyg Occup Med 4: 482-
493.
Spreaftco T, "ticcato. E; Marcucci r, Sironi. M; Paglialunea. S: Madonna. M; Mussini. E. (1980).
Pharmacokinetics of ethylene dichloride in rats treated by different routes and its long-term
inhalatory toxicity. In B Ames; P Infante; R Reitz (Eds.), Ethylene dichloride: A potential health
risk? (Banbury Report 5 ed., pp. 107-133). Cold Spring Harbor, NY: Cold Spring Harbor
Laboratory.
Stauffer Chem Co. (1973). Acute oral toxicity and eye and skin irritation properties of ethylene
dichloride [TSCA Submission], In Toxicological studies of 1,2-dichloroethane with attachments
and cover letter dated 072387. (Toxicology Labaoratory Report T-4408. OTS0515133. 86-
870000606).
Storer RP, Cnrtwrieht. ME; Cook. WO; Sop-n U \ ichols, WW (1995). Short-term carcinogenesis
bioassay of genotoxic procarcinogens in PIM transgenic mice. Carcinogenesis 16: 285-293.
http://dx.doi.ore/10.1093/carcin/l 6.2.285
Storei oily. RB. (1983). Comparative in vivo genotoxicity and acute hepatotoxicity of three
1,2-dihaloethanes. Carcinogenesis 4: 1491-1494. http://dx.doi.Hv 10 KVs3/carciri I I I I l°l
Storei l i molly KM (1985). An investigation of the role of microsomal oxidative metabolism in
the in vivo genotoxicity of 1,2-dichloroethane. Toxicol Appl Pharmacol 77: 36-46.
http://dx.doi.ore 10 101 00 II 008X(85)90265~0
Storer. RP; Jackson. NM; Conoll\ (1984). In vivo genotoxicity and acute hepatotoxicity of 1,2-
dichloroethane in mice: Comparison of oral, intraperitoneal, and inhalation routes of exposure.
Cancer Res 44: 4267-4271.
Story. PL; Meierhei rson. CA; Milman. HA. (1986). Differences in rat liver enzyme-altered
foci produced by chlorinated aliphatics and phenobarbital [Review], Toxicol Ind Health 2: 351-
362. http://dx.doi.oi ^074823378600200402
Sueuro. M; Numano « i awabe. M; Poi. Y; Imai. N; Mera. Y; Tamano. S. (2017). Lung tumor
induction by 26-week dermal application of 1,2-dichloroethane in CB6F1-Tg rasH2 mice.
Toxicol Pathol 45: 427-434. http://dx.doi.ore '192623317701003
Sun. Q; Liao. Y; Wane. T; Tang. H; Warn lu<> i >m. Y. (2016a). 2-Chloroethanol Induced
Upregulation of Matrix Metalloproteinase-2 in Primary Cultured Rat Astrocytes Via MAPK
Signal Pathways. Frontiers in Neuroscience 10: 593. http://dx.doi.org/10.3389/fnins.
Sun. Q; Liao. Y; Wang. T; Wang. G; Zha n. Y. (2016b). Alteration in mitochondrial function and
glutamate metabolism affected by 2-chloroethanol in primary cultured astrocytes. Toxicol In
Vitro 37: 50-60. http://dx.doi.oiv 10 101 5/i.tiv.201 0'" 005
Sun. Q; Wang G, liao. L; > b> 1 « H \ 1 \ \ (2016c). Roles of CYP2el in 1,2-dichloroethane-
induced liver damage in mice. Environ Toxicol 31: 1430-1438.
http: //dx. doi. or e/10.1002/tox .22148
Page 103 of 171
-------
2558
2559
2560
2561
2562
2563
2564
2565
2566
2567
2568
2569
2570
2571
2572
2573
2574
2575
2576
2577
2578
2579
2580
2581
2582
2583
2584
2585
2586
2587
2588
2589
2590
2591
2592
2593
2594
2595
2596
2597
2598
2599
2600
2601
2602
2603
2604
2605
PUBLIC RELEASE DRAFT
July 2024
Suzuki. T; Nezu. K; Sasaki. H; Miyazawa I Nhio. H. (1994). Cytotoxicity of chlorinated
hydrocarbons and lipid peroxidation in isolated rat hepatocytes. Biol Pharm Bull 17: 82-86.
http://dx.doi.ore 10 I _ l\ bj.4. I i2
Sweeney. LM; Sag! rgas. ML. (2008). Physiologically based pharmacokinetic model
development and simulations for ethylene dichloride (1,2-dichloroethane) in rats. Regul Toxicol
Pharmacol 51: 311-323. http://dx.doi.org/10.1016/i.yrtph.20Q8.Q5.QQ2
Tafazoli. M; Baetem ;erlings. P; Kirsch-Volders. M. (1998). In vitro mutagenicity and genotoxicity
study of a number of short-chain chlorinated hydrocarbons using the micronucleus test and the
alkaline single cell gel electrophoresis technique (Comet assay) in human lymphocytes: a
structure-activity relationship (QSAR) analysis of the genotoxic and cytotoxic potential.
Mutagenesis 13: 115-126. http://dx.doi.org/10.1093/mintage/13.2.115
Take. M; Takanobu. K; Takeuchi. T; Haresaku. M; Matsumoto. M; Nagano. K; Yamamoto. S:
Fukushima. S. (2013). Distribution of blood and tissue concentrations in rats by inhalation
exposure to 1,2-dichloroethane. J Environ Sci Health A Tox Hazard Subst Environ Eng 48:
1031-1036. http://dx.doi.org/10.1080/lQc 73765
Tan. EL; Hsie. AW. (1981). Mutagenicity and cytotoxicity of haloethanes as studied in the
CHO/HGPRT system. Mutat Res 90: 183-191. http://dx.doi.on 10 101 01 - I _ I V8D9QQ81-1
Taningher. M; Parodi. S: Grilli. S: Colact lazzullo. M; Bordone. R; Santi. L. (1991). Lack of
correlation between alkaline DNA fragmentation and DNA covalent binding induced by
polychloroethanes after in vivo administration. Problems related to the assessment of a
carcinogenic hazard. Cancer Detect Prev 15: 35-39.
Teta. MI; Ott. MG; Schnat (1991). An update of mortality due to brain neoplasms and other
causes among employees of a petrochemical facility. J Occup Med 33: 45-51.
http://dx.doi.ore 10 10'* 000 I > I I — 101000 0001 '<
Thomas. L; Defi /lariani. MF; van Rossum. GD. (1989). Comparison of metabolic effects of
carbon tetrachloride and 1,2-dichloroethane added in vitro to slices of rat liver. Toxicol In Vitro
3: 59-68. http://(ix.doi.< 5/0887-2333(89)90025-8
Tomasi. A; Alb an o. E; Bini. A; Botti. B; Slatn i I \ onnini. V. (1984). Free radical intermediates
under hypoxic conditions in the metabolism of halogenated carcinogens. Toxicol Pathol 12: 240-
246. http://dx.doi.oiv 10 I I /Q19261 - im.i'Q3Q6
T suruta. H. (1975). Percutaneous absorption of organic solvents: 1) comparative study of the in vivo
percutaneous absorption of chlorinated solvents in mice. Ind Health 13: 227-236.
http: //dx. doi. or g/10.2486/in dh ealth. 13.22 7
(1987a). 1,2-Dichloroethane: IRIS summary. U.S. Environmental Protection Agency.
(1987b). Integrated Risk Information System (IRIS) chemical assessment summary: 1,2-
dichloroethane; CASRN: 107-06-2. Washington, DC: U.S. Environmental Protection Agency,
National Center for Environmental Assessment.
https://cfpub.epa.gov/ncea/iris/iris documents/documents/subs nmarv.pdf
(1990). Integrated Risk Information System (IRIS) chemical assessment summary: 1,1-
dichloroethane; CASRN 75-34-3. Washington, DC: U.S. Environmental Protection Agency,
National Center for Environmental Assessment.
https://cfpub.epa.gov/ncea/iris/iris docum ents/docum ents/ sub st/Q4Q9 summary.pdf
(1993). Reference Dose (RfD): description and use in health risk assessments background
document 1A, March 15, 1993. Washington, DC: U.S. Environmental Protection Agency,
Integrated Risk Information System, https://www.epa.gov/iris/reference-dose-rfd-description-
and-use-health-risk-assessments
(1994). Methods for derivation of inhalation reference concentrations and application of
inhalation dosimetry [EPA Report], (EPA600890066F). Research Triangle Park, NC.
Page 104 of 171
-------
2606
2607
2608
2609
2610
2611
2612
2613
2614
2615
2616
2617
2618
2619
2620
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2622
2623
2624
2625
2626
2627
2628
2629
2630
2631
2632
2633
2634
2635
2636
2637
2638
2639
2640
2641
2642
2643
2644
2645
2646
2647
2648
2649
2650
2651
2652
2653
2654
PUBLIC RELEASE DRAFT
July 2024
https://cfpub.epa.gov/ncea/risk/recordisplav.cfm?deid=71993<£ 829& CF T OKEN=2
5006317
(1996). Guidelines for reproductive toxicity risk assessment [EPA Report], (EPA/630/R-
96/009). Washington, DC: U.S. Environmental Protection Agency, Risk Assessment Forum.
https://nepis.epa. gov/Exe/ZyPURL.cgi?Dockey=3 0004YQB.txt
U.S. EPA. (2002). A review of the reference dose and reference concentration processes [EPA Report],
(EPA630P02002F). Washington, DC. https://www.epa.gov/sites/production/files/2014-
)cum ents/ rfd-final.p df
U.S. EPA. (2006). Provisional peer-review toxicity values for 1,1-dichloroethane (CASRN 75-34-3).
Cincinnati, OH: U.S. Environmental Protection Agency, National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center.
https://hhpprtv.ornl.gov/issue papers/Dichloroethan f
U.S. EPA. (2010). Provisional peer-reviewed toxicity values for dichloroethane, 1,2. (EPA/690/R-
10/01 IF). Washington, DC. https://cfpub.epa.gov/ncea/pprtv/documents/Dichloroethanel2.pdf
(2011a). Exposure factors handbook: 2011 edition [EPA Report], (EPA/600/R-090/052F).
Washington, DC: U.S. Environmental Protection Agency, Office of Research and Development,
National Center for Environmental Assessment.
https://nepis.epa. gov/Exe/ZyPURL.cgi?Dockev=P 100F2QS.txt
U.S. EPA. (201 lb). Recommended use of body weight 3/4 as the default method in derivation of the
oral reference dose. (EPA100R110001). Washington, DC.
https://www.epa.gov/sites/prodiiction/files/2013-09/dociiments/recommended-iise-of-bw34.pdf
U.S. EPA. (2012a). Advances in inhalation gas dosimetry for derivation of a reference concentration
(RfC) and use in risk assessment (pp. 1-140). (EPA/600/R-12/044). Washington, DC.
https://cfpub.epa.gov/ncea/risk/recordisplav.cfm?deid=244650 > , CFTOKEN=
U.S. EPA. (2012b). Benchmark dose technical guidance [EPA Report], (EPA 100R12001). Washington,
DC: U.S. Environmental Protection Agency, Risk Assessment Forum.
https://www.epa.gov/risk/benchmark-dose-technical-guidance
U.S. EPA. (2014). Framework for human health risk assessment to inform decision making. Final [EPA
Report], (EPA/100/R-14/001). Washington, DC: U.S. Environmental Protection, Risk
Assessment Forum, https://www.epa.gov/risk/framework-human-health-risk-assessment-inform-
decisi on-making
U.S. EPA. (2020). Final scope of the risk evaluation for 1,2-dichloroethane; CASRN 107-06-2. (EPA
740-R-20-005). Washington, DC: Office of Chemical Safety and Pollution Prevention.
https://www.epa.gov/sites/defaiilt/files/2020-09/dociiments/casm 107-06-2 12-
dichloroethane final scope.pdf
U.S. EPA. (2021). Draft systematic review protocol supporting TSCA risk evaluations for chemical
substances, Version 1.0: A generic TSCA systematic review protocol with chemical-specific
methodologies. (EPA Document #EPA-D-20-031). Washington, DC: Office of Chemical Safety
and Pollution Prevention. https://www.regiilations.gov/dociiment/EPA-HQ-OPPT-2'
0005
U.S. EPA. (2024a). Draft Risk Evaluation for 1,1-Dichloroethane - Supplemental Information File:
Benchmark Dose Modeling. Washington, DC: Office of Pollution Prevention and Toxics, Office
of Chemical Safety and Pollution Prevention.
U.S. EPA. (2024b). Draft Risk Evaluation for 1,1-Dichloroethane - Systematic Review Protocol.
Washington, DC: Office of Pollution Prevention and Toxics, Office of Chemical Safety and
Pollution Prevention.
U.S. EPA. (2024c). Draft Risk Evaluation for 1,1-Dichloroethane - Systematic Review Supplemental
File: Data Extraction Information for Environmental Hazard and Human Health Hazard Animal
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Toxicology and Epidemiology. Washington, DC: Office of Pollution Prevention and Toxics,
Office of Chemical Safety and Pollution Prevention.
U.S. EPA. (2024d). Draft Risk Evaluation for 1,1-Dichloroethane - Systematic Review Supplemental
File: Data Quality Evaluation Information for Human Health Hazard Animal Toxicology.
Washington, DC: Office of Pollution Prevention and Toxics, Office of Chemical Safety and
Pollution Prevention.
U.S. EPA. (2024e). Draft Risk Evaluation for 1,1-Dichloroethane - Systematic Review Supplemental
File: Data Quality Evaluation Information for Human Health Hazard Epidemiology. Washington,
DC: Office of Pollution Prevention and Toxics, Office of Chemical Safety and Pollution
Prevention.
Umezu. T; Shibata. Y. (2014). Different behavioral effect dose-response profiles in mice exposed to
two-carbon chlorinated hydrocarbons: influence of structural and physical properties. Toxicol
Appl Pharmacol 279: 103-1 12. http://dx.dou ^ 10 101 | taap.201 I 0^ 01 J
Union Carbide. (1989). Lymphatic and hematopoietic tissue cancer in a chemical manufacturing
environment with attached tables and cover letter dated 022189 [TSCA Submission],
(OTS0513414-2. 8EHQ-0289-0698. 89-890000005. TSCATS/311144).
https://ntrl.ntis.gOv/NTRL/dashboard/searchResults/titleDetail/OTS05134172.xhtml
Urusova. TP. (1953). [Possibility of penetration of dichloroethane into milk in mothers exposed to
preparation in industry]. Gig Sanit 60: 36-37.
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. http://dx.doi.org/10.2166/wst. 1992.0309
Van Duuren. BL; Goldscht wengart. G; Smith. AC; Melchionne. S: Seidman. I; Roth. D
(1979). Carcinogenicity of halogenated olefinic and aliphatic hydrocarbons in mice. J Natl
Cancer Inst 63: 1433-1439.
van Esch. GJ; Kroes. R; van Logten. MI; den Tonkelaar. EM. (1977). Ninety-day toxicity study with
1,2-dichloroethane (DCE) in rats. (Report 195/77 Alg.Tox). Bilthoven, the Netherlands: National
Institute of Public Health and Environmental Protection.
Warn i H \ do, L; L> <\ \ \ ^ (2013). Effects of subacute exposure to 1,2-
dichloroethane on mouse behavior and the related mechanisms. Hum Exp Toxicol 32: 983-991.
http://dx.doi.ore 10 I I 0960 I I: I 0270
Warn ih \ .(> 1 < an. X; Yam hao. F; Jin. Y. (2018a). Disruption of Intracellular ATP
Generation and Tight Junction Protein Expression during the Course of Brain Edema Induced by
Subacute Poisoning of 1,2-Dichloroethane. Frontiers in Neuroscience 12: 12.
http://dx.doi.org/10.3389/fnins.2018.00Q12
Wane ^ \\uit \ bang. J; Gao. L; Tan \ \ j
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Webb. WW; Elf )ster. KD; Thom. RE; Anders. MW. (1987). Role for an episulfonium ion
in S-(2-chloroethyl)-DL-cysteine-induced cytotoxicity and its reaction with glutathione.
Biochemistry 26: 3017-3023. http://dx.doi.ore/10.1021 /bt00385aO 10
WIL Research. (2015). An extended one-generation drinking water reproductive toxicity study of
ethylene dichloride in rats [TSCA Submission], (Sec4-15-0042. WIL-417007). Millwood, VA:
HAP Task Force.
Withev. JR; Collins. BT. (1980). Chlorinated aliphatic hydrocarbons used in the foods industry: the
comparative pharmacokinetics of methylene chloride, 1,2 dichloroethane, chloroform and
trichloroethylene after I.V. administration in the rat. J Environ Pathol Toxicol 3: 313-332.
Withev. JR; Collins. BT; Collins. PG. (1983). Effect of vehicle on the pharmacokinetics and uptake of
four halogenated hydrocarbons from the gastrointestinal tract of the rat. J Appl Toxicol 3: 249-
253. http://dx.doi.org/10.1002/iat.25500305Q6
Witt. KL; Knapton. A; Wehr. CM; Hook. GJ; Mirsalis. J; Shelby. MP; Macereec (2000).
Micronucleated erythrocyte frequency in peripheral blood of B6C3F(1) mice from short-term,
prechronic, and chronic studies of the NTP carcinogenesis bioassay program. Environ Mol
Mutagen 36: 163-194. http://dx.doi.org/10.1002/1098-2280(2000B6:3<163::AID-
EM1>3.0.CO;2-P
Yodaiken. RE; Bab cock. JR. (1973). 1,2-dichloroethane poisoning. Arch Environ Occup Health 26: 281 -
284. http://dx.doi.org/10.1080/00039896.1973.10666277
Z am or a. PO; Benson. JM; Li. AP; Brook! (1983). Evaluation of an exposure system using cells
grown on collagen gels for detecting highly volatile mutagens in the CHO/HGPRT mutation
assay. Environ Mutagen 5: 795-801. http://dx.doi.org/10.1002/em.28600506Q4
Zeng. N; Jiang. H; Fan. O; Wang. T; Rom \\ It I i \u I? no. T; Warn t eng. L; Huang.
M; Zhen en. W; Hu. O; Huang. Z; Wang. Q. (2018). Aberrant expression of mi R-
451a contributes to 1,2-dichloroethane-induced hepatic glycerol gluconeogenesis disorder by
inhibiting glycerol kinase expression in NIH Swiss mice. J Appl Toxicol 38: 292-303.
http://dx.doi.ore 32/iat.3526
Zhang. L; Jii (2019). Toxic effects of combined treatment of 1,2-dichloroethane and ethanol on
mouse brain and the related mechanisms. J Biochem Mol Toxicol 33: 1.
http://dx.doi.ore 32/ibt.22294
Zhang. O; « M * I \ \ aig. L; Guo. XL; H.uam 1 \ Wang. LP; Li am \ \ (2011). Establishment
of a poisoned animal model of toxic encephalopathy induced by 1,2-dichloroethane. Int J
Immunopathol Pharmacol 24: 79S-83S.
Zhang \ . 1 i. G; Zhong. Y; Huang. M; Wu. J; Zheng. J; Ro^ \\ ng. L; Yin. \ i u S \t^ \u.
1 * Liii < *
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Appendix A CALCULATING DAILY ORAL HUMAN
EQUIVALENT DOSES AND HUMAN EQUIVALENT
CONCENTRATIONS
For 1,2-dichloroethane, all data considered for PODs are obtained from oral animal toxicity studies in
rats and mice. Because toxicity values for 1,2-dichloroethane are from oral and inhalation animal
studies, EPA must use an extrapolation method to estimate human equivalent doses (HEDs) and human
equivalent concentrations (HECs). The preferred method would be to use chemical-specific information
for such an extrapolation. However, there are no 1,2-dichloroethane-specific PBPK models, and EPA
did not locate other 1,2-dichloroethane information to conduct a chemical-specific quantitative
extrapolation. In the absence of such data, EPA relied on the guidance from I v « « \ * 201 lb), which
recommends scaling allometrically across species using the three-quarter power of body weight (BW3/4)
for oral data. Allometric scaling accounts for differences in physiological and biochemical processes,
mostly related to kinetics.
A.l Equations
This section provides equations used in calculating non-cancer PODs, including air concentration
conversions (ppm to mg/m3 and the converse), adjustments for continuous exposure, calculation of
human equivalent concentrations (HECs) and human equivalent doses (HEDs), and route-to-route
extrapolation calculations. All PODs were initially derived for continuous exposure scenarios
(7 days/week, and 24 hours/day for inhalation). See Appendix A. 1.5 for the calculated continuous
exposure PODs as well as PODs converted for use in occupational exposure scenarios (8 hours/day,
5 days/week).
A.l.l Air Concentration Unit Conversion
It is often necessary to convert between ppm and mg/m3 due to variation in concentration reporting in
studies and the default units for different OPPT models. Therefore, EPA presents all PODs in
equivalents of both units to avoid confusion and errors. Equation Apx A-l presents the conversion of
the HEC from ppm to mg/m3 and EquationApx A-2 shows the reverse conversion.
EquationApx A-l. Converting ppm to mg/m3
HECcontinuous(mg/m3) = HECcontinuous (ppm) * (molecular weight/24.45)
Equation Apx A-2. Converting mg/m3 to ppm
HECcontinuous (ppm) = HECcontinuous (mg/m3 ) * (2AAS/molecular weight)
For 1,2-dichloroethane, the molecular weight used in the equations is 98.96 mg/mmol.
A.1.2 Adjustment for Continuous Exposure
Non-cancer PODs for oral studies are adjusted from the exposure scenario of the original study to
continuous exposure following Equation Apx A-3.
Equation Apx A-3. Adjusting Non-cancer Oral POD for Continuous Exposure
P0Dcontinuous PO^study ^ (days Weeks^u(iy/days WeekContinous)
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Where:
days weekCOntinuous ~ 7 days
Non-cancer PODs for inhalation studies are adjusted from the exposure scenario of the original study to
continuous exposure following EquationApx A-4.
EquationApx A-4. Adjusting Non-cancer Inhalation POD for Continuous Exposure
P O D continuous
PODS{UCiy x (hours day study/hours day continous) ^ ([days
W66kstuciy j days weekcontin0us)
Where:
houvs daycontinous — 24 hours
days weekCOntin0us ~ 7 days
A. 1.3 Calculation of HEDs and HECs from Animal PODs
Consistent with guidance, oral PODs from animal studies are scaled to HEDs using
Equation Apx A-5.
Equation Apx A-5. Calculation of Continuous HED from Continuous Animal Oral POD
RFD — PDD v DAF
iiiji/continous — 1 '-'^continous ^ unl
Where:
HEDcontinous = human equivalent dose for continuous exposure (mg/kg-day)
PODcontinous = oral POD assuming daily doses (mg/kg-day)
DAF = dosimetric adjustment factor (unitless)
DAFs for scaling oral animal PODs to HEDs are calculated using Equation Apx A-6.
Equation Apx A-6. Calculating DAF for Oral HED Calculation
1
Where:
DAF = dosimetric adjustment factor (unitless)
BWi = body weight of species used in toxicity study (kg)
BW// = body weight of adult human (kg)
presents DAFs for extrapolation to humans from several species. However, because
those DAFs used a human body weight of 70 kg, EPA has updated the DAFs using a human body
weight of 80 kg from the EPA Exposure Factors Handbook ( ). EPA used the body
weights of 0.025 and 0.25 kg for mice and rats, respectively, as presented in . The
resulting DAFs for mice and rats are 0.13 and 0.24, respectively. For guinea pigs, EPA used a body
weight of 0.43 kg, resulting in a DAF of 0.27.
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guidance was used to convert animal inhalation PODs to HECs. Effects in animals
exposed to 1,2-dichloroethane by inhalation consisted of systemic (extrarespiratory) effects. Therefore,
consistent with 4) guidance, the HEC for extrarespiratory effects is calculated by
multiplying the animal POD by the ratio of the blood/gas partition coefficients in animals and humans.
EquationApx A-7 shows the HEC calculation for extrarespiratory effects.
EquationApx A-7. Calculation of HEC from Animal Inhalation POD
(—)
upr — pnn v 9 a
— 1 w ucontinuous ^ (HB\
vg~)H
Where:
(t)
hb,a = blood/air partition coefficient for animals (A) to humans (H)
~)H
Blood/air coefficients for 1,2-dichloroethane were 19.5 in humans and 30 in rats ("Gar gas et al. 1989).
Blood/air partition coefficients for other species were not located. When the animal blood/air partition
coefficient is greater than the human blood/air partition coefficient, the default ratio of 1 is used in the
calculation in accordance with 94) guidance.
Nasal effects were observed in one study of F344 rats exposed by inhalation to 1,2-dichloroethane (Dow
Chemical. 2006b). For nasal effects, in accordance with guidance, the HEC was
calculated using the regional gas dose ratio for extrathoracic effects (RGDRet) using Equation Apx A-8.
Equation Apx A-8. Calculating HEC Using Animal Inhalation POD and RGDRet
HEC continuous — P 0 D continuous X R G DRgj*
Where:
HECcontinuous = human equivalent concentration for continuous exposure (mg/m3)
PODcontinuous = animal POD for continuous exposure (mg/m3)
RGDRet = regional gas dose ratio for extrathoracic effects (unitless)
The RGDRet for nasal effects in F344 rats was calculated as shown in Equation Apx A-9.
Equation Apx A-9. Calculating RGDRet in Rats
Vp ,VFh
RGDRET = —^/—
SAa/SAh
Where:
RGDRet = regional gas dose ratio for extrathoracic effects (unitless)
VEa = ventilation rate for male and female F344 rats = 0.211 L/minute ( )
SAa = surface area of the extrathoracic region in rats =15 cm2 ( )
VEh = ventilation rate for humans =13.8 L/minute ( )
SAh = surface area of the extrathoracic region in humans = 200 cm2 ( 4)
The RGDRet for nasal effects in F344 rats calculated using the equation above is 0.2.
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A.1.4 Cancer Inhalation Unit Risk
For cancer risk assessment, an Inhalation Unit Risk (IUR.) can be converted to a Cancer Slope Factor
(CSF) using the exposure parameters described above for non-cancer conversions, as in EquationApx
A-10.
Equation Apx A-10. Calculating CSF from IUR
BWh
CSF = IUR X —!-
/ Ro
Where:
CSF = oral cancer slope factor based on daily exposure (per mg/kg-day)
IUR = inhalation unit risk based on continuous daily exposure (per mg/m3)
BWh = body weight of adult humans (kg) = 80
IRr = inhalation rate for an individual at rest (m3/day) = 14.7
A.1.5 Conversion of Continuous PODs to Occupational PODs
All PODs were initially derived for continuous exposure, and then converted to an equivalent POD for
occupational exposure for convenience in risk calculations. Equation Apx A-l 1 and Equation Apx
A-12 were used to convert from continuous to occupational exposure scenarios for oral and inhalation
non-cancer PODs, respectively.
Equation Apx A-ll. Adjusting Non-cancer Oral POD from Continuous to Occupational Exposure
PODoccupational PODcontinuous ^ days/WBBk*)
Equation Apx A-12. Adjusting Non-cancer Inhalation POD from Continuous to Occupational
Exposure
PODoccupational P^^continuous ^ (24/8 hoUTS / day^ X (7/5 days/WBBk^
To adjust a continuous IUR for occupational scenarios, Equation Apx A-13 was used (days per week
adjustment is not required because it is already accounted for in the Lifetime Average Daily
Concentration).
Equation Apx A-13. Adjusting Continuous IUR For Occupational Scenarios
IU ^occupational ~ W ^continuous ^ (hoUTS — day 0CCUpati0nal / hours — day continuous^
A.1.6 Summary of Continuous and Worker Non-cancer PODs
Each of the continuous non-cancer PODs described in the preceding sections was converted to an
equivalent POD for occupational exposure for convenience in risk calculations. Equations used to
convert from continuous to occupational exposure scenarios for oral and inhalation exposure,
respectively are provided in A.1.5. Table Apx A-l provides a summary of the non-cancer PODs for
both continuous and occupational exposure scenarios for 1,2-dichloroethane.
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Table Apx A-l. Summary of
\on-cancer PODs
'or 1,2-Dichloroethane
Route
Duration
Continuous POD
Worker POD
Benehmark
MOE
Reference
Oral
Acute
19.9 mg/kg-bw/day
19.9 mg/kg-bw/day
30
Storeret al. (1984)
Short/intermediate-
term
0.636 mg/kg-bw/day
0.890 mg/kg-bw/day
100
Munson et al. (1982)
Chronic
0.636 mg/kg-bw/day
0.890 mg/kg-bw/day
1,000
Munson et al. (1982)
Inhalation
Acute
9.78 mg/m3
41 mg/m3
30
Dow Chemical (2006b)
Short/intermediate-
term
21.2 mg/m3
89 mg/m3
30
Zhang et al. (2017)
Chronic
21.2 mg/m3
89 mg/m3
300
Zhang et al. (2017)
Dermal
(Route-to-
Route
Extrapolation
from Oral)
Acute
19.9 mg/kg-bw/day
19.9 mg/kg-bw/day
30
Storeret al. (1984)
Short/intermediate-
term
0.636 mg/kg-bw/day
0.890 mg/kg-bw/day
100
Munson et al. (1982)
Chronic
0.636 mg/kg-bw/day
0.890 mg/kg-bw/day
1,000
Munson et al. (1982)
2930
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2931 Appendix B EVIDENCE INTEGRATION TABLES FOR NON-CANCER FOR 1,2-
2932 DICHLOROETHANE
2933
Table Apx B-l. 1,2-Dichloroethane Evidence Integration Ta
)le for Reproductive/Developmental Effects
Database Summary
Factors that Increase
Strength
Factors that Decrease
Strength
Summary of Key Findings
and Within-Strcam
Strength of the Evidence
Judgement
Inferences across
Evidence Streams and
Overall WOSE
Judgement
1 v idcucc iiHcmaUou siiiiiniars indue mail on ivpmducliN c dc\ cK
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Database Summary
Factors that Increase
Strength
Factors that Decrease
Strength
Summary of Key Findings
and Within-Strcam
Strength of the Evidence
Judgement
Inferences across
Evidence Streams and
Overall WOSE
Judgement
1 !\ ideik.
ITkvlsiin male reproduceeoieaus
• Positive associations were
found in high and medium
quality studies.
e li'iim apical eudpoiuls in in vi\i
• No significant associations
were observed between 1,2-
dichloroethane exposure in
public water supplies and
neural tube defects, septal
heart defects, or total
cardiac defects.
Bioloeical plausibility and
human relevance:
• There was limited evidence
of temporality (exposure
prior to outcome) in either
study.
In both studies, subjects had
multiple overlapping
exposures, and positive
associations with spina
bifida or neural tube defects,
heart defects, and other
defects were found for many
of the other chemicals
considered in the analyses
mammalian annual studies
effects based on human
evidence:
• Indeterminate
• An inhalation study in rats evaluated
testis weight and gross and
microscopic pathology of the testes
after 30 davs exposure CI ewe et aL
1986b) Studv aualitv: Hieh
• An inhalation study in a single dog
evaluated testis histopathology after 6
months exposure (Mellon Institute.
1947) Study quality: Medium
• An inhalation study in mice evaluated
testis and epididymis weight, sperm
parameters and morphology, histology
of the testis, seminiferous tubules, and
Bioloeical eradient/dose-
rcsDonsc:
• In mice exposed by
inhalation for one week,
decreased sperm
concentration and motility,
increased sperm
abnormalities, and occasional
testicular and epididymal
histopathology changes)
were seen at 700 mg/m3.
After 4 weeks, effects seen at
> 350 mg/m3 included more
pronounced sperm changes,
Oualitv of the database:
• No studies of sperm
parameters in any species
other than mice were
available.
Consistency:
• No testicular
histopathology changes
were observed in mice
exposed by drinking water
for subchronic duration.
• No testicular
histopathology changes
Key findings'.
In high-quality studies, mice
exposed to 1,2-dichloroethane
by inhalation or
intraperitoneal injection, but
not by drinking water,
exhibited effects on testicular
pathology and sperm
parameters. Most of the data
in rats indicated no effect on
the testes (or other
reproductive organs);
however, sperm parameters
were not evaluated in rats.
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Database Summary
Factors that Increase
Strength
Factors that Decrease
Strength
Summary of Key Findings
and Within-Strcam
Strength of the Evidence
Judgement
Inferences across
Evidence Streams and
Overall WOSE
Judgement
caput epididymis, and plasma and
testis hormone levels after 1- or 4-
week exposure (Zhang et al. 2017)
Study quality: High
• An inhalation study in rats and guinea
pigs evaluated weight and gross and
microscopic pathology of the testes
after up to 212 and 246 days of
exposure, respectively (Spencer et al.
1951) Study quality: Medium
• A one-generation reproduction study
in rats exposed by inhalation
evaluated histopathology of F0 testes
after 176 davs of exposure (Rao et al..
1980) Study quality: Medium
• An inhalation cancer bioassay in rats
evaluated gross pathology of the
accessory sex organs, testes, and
seminal vesicles and histopathology
of the prostate and testes after 2 years
exposure (Cheeveret al. 1990) Studv
quality: High
• Gavage studies in rats evaluated testes
weights, gross pathology of the testes,
and histopathology (testes, seminal
vesicles, prostate, and preputial gland)
after 10- or 90-dav exposures (Daniel
et al. 1994) Studv aualitv: Hish
• A gavage study in rats evaluated
testes weights and histopathology of
the testes, epididymis, seminal
vesicles, and prostate after 13 weeks
exposure (NTP. 1991) Studv aualitv:
High
• A gavage cancer bioassay in mice
evaluated comprehensive
histopathology after 78 weeks
more extensive/severe
histological effects, and
increases in plasma and
testicular testosterone and
LH and testicular GnRH.
Consistency:
• Mice exposed to >5
mg/kg/day by daily
intraperitoneal injection for
5 days exhibited reduced
spermatogenesis, loss of
spermatogonia,
histopathology changes in
the testes, and sterility.
were observed in rats,
guinea pigs, or a single dog
exposed by inhalation for
durations between 30 and
246 days.
• No testicular
histopathology changes
were observed in rats
exposed by intraperitoneal
injection for 30 days or by
gavage for subchronic
durations.
Overall WOSE judgement for
male reproductive tract
effects based on animal
evidence:
• Moderate
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Judgement
exposure (NTP. 1978) Studv aualitv:
High
• A drinking water study in mice
evaluated testes weights and
histopathology of the testes,
epididymis, seminal vesicles, and
prostate after 13 weeks exposure
(NTP. 1991) Studv aualitv: Hish
• A dermal cancer bioassay in
transgenic mice susceptible to cancer
evaluated testes weights and
histopathology of the prostate,
seminal vesicle, and epididymis after
26 weeks exposure (Sueuro et al.
2017) Study quality: High
• An intraperitoneal injection study in
mice evaluated histopathology of the
testes 8 to 46 days after a 5-day
exposure and histopathology and
fertility for up to 9 months after a 5-
day exposure plus 45 days recovery
for sDermatouenesis turnover (Daiele
et al. 2009) Studv aualitv: Hish
• An intraperitoneal injection study in
rats evaluated testis weight and gross
and microscopic pathology of the
testes after 30 davs exposure CI ewe et
al. 1986b) Studv quality: Medium
ITkvlsim female ivpinducli\ e oruaus
• An inhalation study in female rats
evaluated serum prolactin levels and
morphometry and histopathology of
mammary tissue after at least 28 days
exposure (Dow Chemical. 2014)
Study quality: High
• A one-generation reproduction study
in female rats exposed by inhalation
evaluated histopathology of F0
Consistencv:
• Several high- and medium-
quality studies of rats and
mice exposed by inhalation,
gavage, drinking water,
and/or dermal contact
reported no treatment-
related changes in
Key findings'.
Inhalation studies in rats, oral
studies in rats and mice, and a
dermal study in mice
observed no effects of 1,2-
dichloroethane on female
reproductive organ weights or
histopathology.
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Inferences across
Evidence Streams and
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Judgement
ovaries and uterus after 176 days of
exposure (Rao et a.L 1980) Studv
quality: Medium
• An inhalation cancer bioassay in
female rats evaluated gross and
microscopic pathology of the
mammary tissue, ovaries, and uterus
after 2 vears exposure (Cheever et al.
1990) Study quality: High
• Gavage studies in rats evaluated ovary
weights, gross pathology of the
ovaries, and histopathology (ovaries,
uterus, clitoral gland, and mammary
gland) after 10- or 90-day exposures
(Daniel et al. 1994) Studv aualitv:
High
• A gavage cancer bioassay in mice
evaluated comprehensive
histopathology after 78 weeks
exposure (NTP. 1978) Studv aualitv:
High
• A drinking water study in mice and a
gavage study in rats evaluated
histopathology of the uterus,
mammary gland, clitoral gland, and
ovaries after 13 weeks exposure
(NTP. 1991) Studv aualitv: Hish
• A dermal cancer bioassay in
transgenic mice susceptible to cancer
evaluated ovary weights and
histopathology of the uterus,
mammary gland, and vagina after 26
weeks exposure (Sueiiro et al. 2017)
Study quality: High
reproductive organ weights
or histopathology.
Overall WOSE judgement for
female reproductive tract
effects based on animal
evidence:
• Moderate evidence of no
effect.
1-Heels on reproduction orol'I'spriim
• An inhalation study in male and
female rats evaluated numbers of live
and dead pups; and pup weight, sex,
Bioloeical eradient/dose-
rcsDonsc:
Magnitude and precision:
• The apparent body weight
decrease in selected male
Key findings'.
In a high-quality study,
sterility was observed in male
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Judgement
gross pathology, liver and kidney
weights, and liver and kidney
histopathology after one generation
exposure (Rao et al. 1980) Studv
quality: Medium
• Inhalation studies in female rats and
rabbits evaluated numbers of corpora
lutea; numbers of live, dead, and
resorbed fetuses; fetal weight, length,
and sex; external and skeletal
alterations; and cleft palate after
gestational exposure (Rao et al. 1980)
Study quality: Medium
• Inhalation and gavage studies in
female rats evaluated pregnancy
outcomes and fetal external, skeletal,
and visceral examinations after
gestational exposure (Pavan et al.
1995) Study quality: High
• A drinking water study in male and
female mice evaluated fertility and
gestation indices, numbers of
implantations and resorptions,
viability and lactation indices, litter
size, pup weight, and teratology after
multieenerational exposure (Lane et
al. 1982) Studv aualitv: Hish
• An intraperitoneal injection study in
male mice evaluated male fertility for
up to 9 months after a 5-day exposure
plus 45 days recovery for
SDermatouenesis turnover (Daiele et
L 2009) Studv qualitv: High
• An apparent decrease in
necropsy body weight was
observed at the high
concentration of 150 ppm in
a small subset of male FIB
weanling rats exposed by
inhalation in a one-
generation study.
• Male mice exposed by daily
intraperitoneal injection at >
10 mg/kg-d for 5 days
exhibited permanent sterility
(defined as sterility for 6
months or longer).
FIB weanlings at 150 ppm
was based on only 5 male
weanlings per group, was
not statistically
significantly different from
controls, was not seen in
female weanlings, and is
not supported by the study
authors' analysis of the full
data set, which showed no
effect on neonatal body
weight or growth of pups to
weaning in either F1A or
FIB litters.
mice exposed by
intraperitoneal injection.
Evidence for effects on
weanling pup body weight
after inhalation exposure is
weak and inconsistent.
Overall WOSE judgement for
developmental effects based
on animal evidence:
• Slight
1 !\ idcucc mi mcdiaiiisiic sludics
• \ii in vivn inhalation sluds in male rals
evaluated elemental content in the
testes after 30 davs exposure (One et
al. 1988).
P.ioloeical eradicui dosc-
rcsDonsc:
• Inhalation exposure to 1,2-
dichloroethane did not alter
likiki'jical nlausihiliis and
human relevance:
Key findings:
Evidence for inhibition of
CREM/ CREB signaling and
apoptosis in testes of male
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Judgement
• An in vivo inhalation study in male
mice evaluated mRNA expression in
the testis and genetic damage in
spermatozoa after 1- or 4-week
exposure (Zhang et aL 2017)
• An in vivo study in mice exposed by
intratesticular injection evaluated
testicular DNA synthesis (Borzelleca
and Carolinian, 1982).
zinc concentration in the
testes. Statistically
significant changes in other
element concentrations
included decreased Al, Hg,
and S and increased Ca and
P at the highest tested
concentration (1840 mg/m3
or 455 ppm)
• Expression consistent with
inhibition of CREM/ CREB
signaling and the induction
of apoptosis was observed in
the testis of mice.
• Intratesticular injection of
1,2-dichloroethane resulted
in a 53% decrease in
testicular DNA synthesis in
mice at the highest dose
tested (250 mg/kg) but not at
doses <100 mg/kg.
• The biological relevance of
the altered element content
in the testes is uncertain.
• The human relevance of
intratesticular injection
exposure is uncertain.
mice exposed to 1,2-
dichloroethane in vivo support
observed effects on testes
pathology, sperm
morphology, and fertility in
this species.
Overall WOSE judgement for
reproductive/developmental
effects based on mechanistic
evidence:
• Moderate
2935
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2936 Table Apx B-2.1,2-Dichloroethane Evidence Integration Table for Renal Effects
Database Summarv
Factors that Increase Strength
Factors that Decrease Strength
Summarv of Key
Findings and Within-
Strcam Strength of the
Evidence Judgement
Inferences across
Evidence Streams
and Overall WOSE
Judgement
I!\ idence liHcmaUon Siiiiiiikii'n IikIuciiiciii on Renal ITIccls
I !\ idcncc from hiini;iii studies
I !\ itlcncc Ironi apical cudpoiuls in
Indelenniiuie
in;iinin;iIi;i11 ;inini;il studies
Studies evaluating histopathology in
conjunction with other renal endpoints:
» Acute inhalation studies in male and female
rats and male mice evaluated kidney
histopathology and weight after a single 4-
hour exposure (Dow Chemical 2006b');
Study quality: High. (Francovitch et at.
1986): Study quality: Medium.
» A short-term inhalation study in male rats
evaluated kidney histopathology and weight
and after 30 days of exposure (Iewe et at.
1986b): Study quality: High.
» A chronic inhalation study in F0 male and
female rats evaluated kidney histopathology
and weight after exposure in a reproduction
study from pre-breeding through the
generation of 2 litters (Rao et at. .1.980).
Study quality: Medium.
» Chronic inhalation studies in male and
female rats evaluated kidney histopathology,
kidney weight, and/or clinical chemistry
after 212 days or 17-weeks of exposure
(Spencer et at. .1.951). (Hofinann et at.
IM I); Study quality: Medium.
Chronic inhalation studies in a single dog,
guinea pigs, and rabbits evaluated kidney
histopathology, kidney weight, and/or
clinical chemistry after 6 months, 212 days,
or 17 weeks of exposure (Mellon Institute.
.1.947). (Spencer et at. .1.951). (Hofinann et
at. .1.971): Study quality: Medium.
Short-term and subchronic gavage studies in
male and female rats evaluated kidney and
Biological gradient/dose-
response:
• In acute inhalation studies:
o Rats exhibited significantly
increased incidences of
basophilia of the renal
tubular epithelium (males)
or degeneration/ necrosis
(females) in addition to
significantly increased
absolute and relative
kidney weights (>10%,
both sexes) at 8212 mg/m3
(2029 ppm).
o Male mice exhibited
significantly increased
kidney weights (>10%) and
BUN (86%) at >2,020
mg/m3 (>499 ppm).
o In a chronic inhalation
study in rats, a statistically
significant increase in BUN
(-50%) was reported at 607
mg/m3 (150 ppm).
o In acute gavage studies,
male mice exhibited
significant increases in
relative kidney weight
(>10%) at >300 mg/kg and
significantly increased
percentage of damaged
renal proximal tubules at
1,500 mg/kg.
Biological gradient/dose
response:
• High-quality short-term and
chronic inhalation studies
found no treatment-related
effects on kidney weight or
histopathology in rats exposed
up to 647 mg/m3 (159.7 ppm)
or mice exposed up to 368
mg/m3 (89.8 ppm)
• High-quality short-term
gavage studies found no
treatment-related effects on
kidney histopathology, kidney
weight, or BUN in rats (both
sexes) exposed up to 300
mg/kg-day or on kidney
weight or gross pathology in
mice (both sexes) exposed up
to 49 mg/kg-day.
• High-quality subchronic
gavage studies in male and
female rats found no
treatment-related
histopathology changes at
doses up to 150 mg/kg-day.
• A high-quality chronic gavage
cancer bioassay in mice found
no treatment-related effects on
kidney histopathology at doses
up to 299 mg/kg-day.
Key findings'.
Several high- and
medium-quality studies
found associations
between 1,2-
dichloroethane exposure
and increased kidney
weights, BUN, and/or
renal tubular
histopathology in rats
(both sexes) and mice
following inhalation, oral,
dermal, and
intraperitoneal injection
exposures.
Overall WOSE judgement
for renal effects based on
animal evidence:
• Moderate
Overall WOSE
judgement for renal
ejjects based on
integration of
information across
evidence streams:
Evidence indicates
that 1,2-
dichloroethane likely
causes renal effects
under relevant
exposure
circumstances.
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and Overall WOSE
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bladder histopathology, kidney weight,
and/or clinical chemistry, and/or urinary
chemistry after 10 or 13 weeks of exposure
(Daniel et al. 1994). (NTP. 1991): Studv
quality: High.
• A subchronic drinking water study in male
and female mice evaluated kidney
histopathology, weight of kidney and
urinary bladder, and BUN after 13 weeks of
exposure (NTP. 1991): Studv aualitv: Hish.
• A dermal cancer bioassay in male and
female transgenic mice susceptible to cancer
evaluated kidney histopathology and weight
after 26 weeks exposure (Sueiiro et al.
2017): Studv aualitv: Hish.
• A short-term intraperitoneal injection study
in male rats evaluated kidney
histopathology, kidney weight, and/or
clinical chemistry after 30 days of exposure
(lewe et al. 1986b): Studv aualitv: Medium.
Studies evaluating histopatholoev onlv:
• An acute inhalation study in rats, mice,
rabbits, and guinea pigs evaluated
microscopic kidney pathology after 1.5- to
7-hour exposures (HeoDel et al. 1945):
Study quality: Medium.
• Subchronic and chronic inhalation studies in
rats, rabbits, guinea pigs, and dogs evaluated
kidney histopathology after 13 to 35 weeks
of exposure (HeoDel et al. 1946): Studv
quality: Low or Medium.
• Inhalation cancer bioassays in male and
female rats and mice evaluated
histopathology of the kidney and urinary
bladder after 2 vears exposure (Cheever et
al. 1990). (Nagano et al.. 2006): Studv
quality: High.
o In subchronic gavage
studies, rats exhibited
significantly increased
kidney weights (>10%,
both sexes) at >30 mg/kg-
day and increased BUN
(20%, males) at 120 mg/kg-
day.
o In a subchronic drinking
water study, mice exhibited
significantly increased
incidences of tubular
regeneration (males) at
>781 mg/kg-day and
significantly increased
kidney weights (>10%,
both sexes) at 244-448
mg/kg-day.
o In an acute intraperitoneal
injection study in male
mice, a statistically
significant increase in
relative kidney weight was
observed at >400 mg/kg
reaching >10% at 500
mg/kg.
Consistencv:
• Renal histopathology changes
were also reported in studies
that were limited by lack of
reporting on control findings.
These included:
o Degeneration of renal
tubular epithelium in rats
and rabbits after acute
inhalation exposure,
o Increased severity of renal
tubular damage in mice
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• An acute gavage study in male mice
evaluated kidney immunohistochemistry
after a sinsle c\ do sure (Morel et al. 1999).
Study quality: High.
• A gavage cancer bioassay in male and
female mice evaluated kidney
histopathology after 78 weeks of exposure
(NTP. 19781: Studv aualitv: Hish.
Studies evaluating kidnev weisht. sross
after acute inhalation
exposure,
o Moderate fatty
degeneration of the kidney
in guinea pigs after
chronic inhalation
exposure,
o Mild karyomegaly of
distal tubules and tubular
degeneration in transgenic
mice after chronic dermal
exposure.
Biolosical plausibility and
human relevance:
• Metabolism of 1,2-
dichloroethane via
glutathione-S-transferase is
believed to yield a reactive
episulfonium ion which can
form the potent nephrotoxic
conjugate S-(2-chloroethyl)-
DL-cysteine.
ratholosv. and/or clinical chemistry:
• An acute inhalation study in mice evaluated
kidney weight and BUN levels after a 4-
hour exposure (Storer et al. 1984); Studv
quality: High.
• Chronic inhalation studies in male and
female rats evaluated serum chemistry and
urinalysis parameters after 6, 12, or 18
months of exposure (IRFMN, 1987, 1978,
1976); Studv aualitv: Medium.
• An acute gavage study in male mice
evaluated kidney weight and BUN after a
sinsle exposure (Storer et al. 1984); Studv
quality: High.
• A short-term gavage study in male and
female mice evaluated kidney weight and
gross pathology after 14 days exposure
(Munson et al. 1982); Studv aualitv: Hish.
• Acute intraperitoneal injection studies in
male rats and mice evaluated kidney weight
and serum chemistry parameters after a
sinsle exposure (Livesev. 1982). (Storer and
Conollv. 1985). (Storer et al. 1984): Studv
aualitv: Hish; (Storer and Conollv. 1983);
Study quality: Medium.
• A short-term intraperitoneal injection study
in male mice evaluated kidney gross
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ratholoev after 5 davs of exposure (NTP.
19781: Studv qualitv: High.
1 !\ ideuce in mechanistic studies iiiouei
• Indeterminate
2937
2938
2939 Table Apx B-3.1,2-Dichloroethane Evidence Integration Table for Hepatic Effects
Database Summary
Factors that Increase Strength
Factors that Decrease
Strength
Summary of Key Findings
and within-Stream
Strength of the Evidence
Judgement
Inferences across
Evidence Streams
and Overall WOSE
Judgement
1 !\ ideuce integration summars judgement on hepatic effects
1 !\ ideuce from human studies
Overall WOSE
judgement for hepatic
effects based on
integration of
information across
evidence streams:
Evidence suggests,
but is not sufficient to
conclude, that 1,2-
dichloroethane may
cause hepatic effects
under relevant
exposure conditions.
• A cohort study of 251 male workers
from 4 vinyl chloride monomer
(VCM) manufacturing plants
evaluated associations between
exposure to airborne 1,2-
dichloroethane (in conjunction with
low exposure to VCM) and serum
AST, ALT, and GGT. Personal and
area air sampling were used to
determine VCM and 1,2-
dichloroethane exposures and group
participants by job category into low
1,2-dichloroethane (job medians of
0.26-0.44 ppm) or moderate 1,2-
dichloroethane (job medians of 0.77-
1.31 ppm) plus low VCM (job
medians of 0.18-0.39 ddui). (Cheng
et al.. 1999). Studv qualitv: Medium
Biological gradicnt/dosc-resDonse:
• Increased odds of abnormal serum
AST (>37 IU/L) and ALT (>41IU/L)
were observed when comparing the
moderate-1,2-dichloroethane/low-
VCM group with the low-1,2-
dichloroethane/low-VCM group (OR
= 2.2, 95% CI = 1.0-5.4 for abnormal
AST; OR = 2.1, 95% CI = 1.1-4.2 for
abnormal ALT).
Magnitude/precision:
• Exposure concentrations in
the low- and moderate-1,2-
dichloroethane groups were
overlapping.
Biological Dlausibilitv/luiman
relevance:
• All subjects were also
exposed to vinyl chloride
monomer, a known liver
toxicant.
Key findings'.
In a medium-
quality study, increased
odds of abnormal serum
liver enzyme levels were
observed among workers
with higher exposure to
1,2-dichloroethane, in a
cohort with co-exposure to
vinyl chloride.
Overall WOSE judgement
for hepatic effects based on
human evidence:
Indeterminate
1 !\ ideuce lioni apical eudpoiuis in in viva mammalian animal studies
Studies evaluating historatholosv in
Biological gradicnt/dosc-rcsDonsc:
Consistencv:
Key findings'.
Several high- and medium-
quality studies in rats and
mice found associations
between 1,2-dichloroethane
coniunction with other liver
endDoint(s):
• Acute inhalation studies in male and
female rats and male mice evaluated
• In an acute inhalation study, rats
exhibited minimal histological
changes in the liver at 8212.3 mg/m3
• In a high-quality short-term
inhalation study in rats, no
treatment-related effects on
liver weight, serum chemistry
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liver weight and histopathology after
single 4- and/or 8- hour exposures
(Dow Chemical 200651: Study
quality: High. (Franeoviteh et at.
1986): Study quality: Medium
A short-term inhalation study in male
rats evaluated serum chemistry
(ALP, SDH, and 5'NT), liver weight,
and histopathology after 30 days
exposure (Iewe et at. 1986b. c)
Study quality: High
Subchronic and chronic inhalation
studies in male and female rats,
rabbits, cats, and guinea pigs
evaluated serum chemistry (ALT and
AST), bromsulphthalein retention,
liver weight and/or histopathology
after up to 17 weeks exposure
(Hofmann et at. .1.97.1.) Study quality:
Medium.
Chronic inhalation studies in male
and female rats and guinea pigs,
male monkeys, and a single dog
evaluated hepatic lipids/cholesterol,
liver function, liver weight, and/or
histopathology after 170-248 days
exposure (Spencer et at. .1.95.1.) Study
quality: Medium. (Mellon Institute.
.1.947) Study quality: Medium.
Chronic inhalation cancer bioassays
in male and female rats and mice
evaluated liver weight and
histopathology after 2 years exposure
(Nagano et at. 2006: Cheever et at.
.1.990) Study quality: High.
A one-generation inhalation
reproduction study in rats evaluated
parental liver weight and
(2029.0 ppm). Liver weight changes
were small (<10%) and inconsistent.
• In an acute inhalation study, male
mice exhibited a significant increase
in relative liver weight (>10%) at
6071 mg/m3 (1500 ppm). Histological
observations in the liver included
hepatocyte swelling, swollen nuclei,
fat accumulation, and occasional
small areas of necrosis (incidence and
severity were not reported)
• In a chronic inhalation cancer
bioassay, male (but not female) rats
exhibited increased absolute (but not
relative) liver weight (>10%) at 204
mg/m3 (50 ppm)
• In a short-term gavage study, male
(but not female) rats had significantly
increased relative liver weight (>10%)
and serum cholesterol at 100 mg/kg-
day in the absence of histopathology
changes.
• In subchronic gavage studies, male
and female rats exhibited significantly
increased relative liver weights
(>10%) at >75 mg/kg-day in the
absence of biologically significant
serum chemistry changes or
treatment-related histopathology
changes.
• In a subchronic drinking water study,
male and female mice exhibited
significantly increased (>10%)
absolute and relative liver weights at
> 2,478 mg/kg-day in the absence of
treatment-related histopathology
changes.
Consistency:
or histopathology were
observed in rats at
concentrations up to 1840
mg/m3 (455 ppm).
• In high-quality chronic
inhalation cancer bioassays
in rats and mice, no
significant effects on liver
weight or histology were
observed at concentrations up
to 646.4 mg/m3 (159.7 ppm
and 363 mg/m3 (89.8 ppm),
respectively.
exposure and increased
liver weights, serum
enzymes, and/or
histopathology changes
following inhalation, oral,
and intraperitoneal
injection exposures.
Overall WOSE judgement
for hepatic effects based on
animal evidence:
• Moderate
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histopathology after up to 176 days
exposure (Rao et al. 1980) Studv
quality: Medium.
• An acute gavage study in female rats
evaluated serum chemistry (ALT,
AST, and LDH) and histopathology
after a sinsle dose (Cottalasso et al.
2002) Studv aualitv: Medium.
• Short-term and subchronic gavage
studies in male and female rats
evaluated serum chemistry, liver
weight, and liver histopathology after
10-day and 13-week exposures
(Daniel et al. 1994; NTP. 1991):
Study quality: High.
• A subchronic drinking water study in
male and female mice evaluated liver
weight and histopathology after 13
weeks exposure (NTP. 1991) Studv
quality: High.
• A chronic dermal cancer bioassay in
male and female transgenic mice
evaluated liver weights and
histopathology after 26 weeks
exposure (Sueuro et al. 2017) Studv
quality: High.
Studies evaluating liver historatholoev
• Hepatic histopathology changes and
liver weight increases were also
reported in low- and medium-quality
studies that were limited by lack of
quantitative data reporting and
variable exposure regimens. The
lesions included:
o Congestion, fatty degeneration,
and/or necrosis in rats, mice,
rabbits, and guinea pigs after acute
to short-term inhalation exposures
that were sometimes lethal,
o Cloudy swelling, fatty
degeneration, necrosis, and/or
occasional fat vacuoles in rats and
guinea pigs after subchronic to
chronic inhalation exposure,
o Moderate steatosis in rats without
biologically significant changes in
AST or ALT after a single gavage
dose.
• In studies that did not evaluate
histopathology, findings included:
o Biologically and/or statistically
significant increases in serum SDH
and ALT in mice exposed for 4
hours by inhalation,
o Increased serum ALT, SDH and/or
glutamate dehydrogenase in rats
after single or repeated inhalation
exposures,
o Increased liver weight in mice
exposed by inhalation for 28 days,
o Increased ALT and AST in rats
after single gavage dose,
o Increased relative liver weight and
biologically significant increases
in serum SDH and ALT in mice
onlv:
• Acute inhalation studies in rats,
mice, rabbits, and guinea pigs
evaluated gross and microscopic
liver pathology after 1.5- to 7-hour
exposures (HeoDel et al. 1945).
Study quality: Medium
• Subchronic- and chronic inhalation
studies in male and/or female rats,
rabbits, guinea pigs, dogs, and cats
evaluated liver histopathology after 5
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to 35 weeks of exposure ffleooel et
al. 1946): Studv aualitv: Medium or
Low.
• A chronic gavage cancer bioassay in
male and female mice evaluated liver
histopathology after 78 weeks of
exposure (NTP. 1978) Studv aualitv:
High.
Studies evaluating onlv liver weight.
after a single gavage or
intraperitoneal dose.
gross rathologv and/or clinical
chemistrv:
• An acute inhalation study in male
mice evaluated liver weight and
serum chemistrv CStorer et al. 1984)
Study quality: High.
• Acute- and short-term inhalation
studies in male rats evaluated serum
chemistrv 03rondeau et al., 1983)
Study quality: Medium.
• A short-term inhalation study in male
mice evaluated liver weight and
serum chemistrv (Zeng et al. 2018)
Study quality: High.
• Chronic inhalation studies in male
and female rats evaluated serum
chemistrv ORFMN. 1987. 1978.
1976) Studv aualitv: Medium.
• Acute gavage studies in male and
female rats evaluated serum
chemistry and/or liver weight
CKitcfain et al.. 1993): Studv aualitv:
High. (Cottalasso et al. 1995) Studv
quality: Medium.
• An acute gavage study in male mice
evaluated liver weight and serum
chemistrv CStorer et al. 1984) Studv
quality: High.
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• A short-term gavage study in male
and female mice evaluated liver
weieht and sross ratholoev (Munson
et al. 1982s) Studv aualitv: Hish.
• A subchronic dietary study in rats
evaluated serum chemistry (Aluinot
et al. 1976). Studv aualitv: Medium
• Acute, short-term, and subchronic
intraperitoneal injection studies in
male rats and male mice evaluated
liver weight, serum chemistry, and/or
sross ratholoev (Storer and Conollv.
1985; Storeret al.. 1984; Livesev.
1982); Studv quality; Hish. (Daiele
et al. 2009; I ewe et al.. 1986b;
Storer and Conollv. 1983") Studv
quality: Medium.
1 v idence in mcdiaiiislic sludics
• An in vivo inhalation study in male
rats evaluated elemental content in
the liver after 30 days exposure (One
et al.. 1988).
• An in vivo inhalation study in male
mice evaluated hepatic micro-RNA
(miR) expression and
sluconeosenesis (Zeng et al. 2018).
• In vivo genotoxicity tests were
conducted in the liver of male mice
after single inhalation, oral, and
intraperitoneal exposures (Storer et
al. 1984).
o An in vivo intraperitoneal
injection study in male mice
evaluated hepatic enzyme
induction (Pacini! et al.. 1994).
o A series of studies in vivo in rats
and in vitro in rat hepatocytes
evaluated effects on
Biological aradicnt/dosc-rcsdonsc:
Bioloeical eradient/dose-
Key findings'.
Available data on liver
toxicity mechanisms are
limited and nonspecific.
Hepatic enzyme induction
was demonstrated in mice
exposed by intraperitoneal
injection. Limited in vitro
data indicate that 1,2-
dichloroethane may
increase oxidative stress or
impair glucose and/or lipid
metabolism in mice and in
rat hepatocytes and liver
slices.
Overall WOSEjudgement
for hepatic effects based on
mechanistic evidence:
• Indeterminate
• 1,2-Dichloroethane induced DNA
damage after oral and intraperitoneal
(but not inhalation) exposure.
• 1,2-Dichloroethane induced a dose-
related increase in PROD activity (a
probe for CYP450 2B1) in mice.
Oxidative stress:
• Incubation of rat liver slices with 1,2-
dichloroethane (up to 10 mM for up to
30 minutes) resulted in dose-and time-
dependent increases in MDA
production.
• Levels of GSH were significantly
decreased in rat hepatocytes cultured
with 4.4 to 6.5 mM 1,2-dichloroethane
for up to 1 hour.
• Free radicals were detected in rat
hepatocytes cultured with 1,2-
rcsDonsc:
• Rat hepatocytes exposed to
1,2-dichloroethane for 1
hour at 1.2 mM did not
show significantly
decreased GSH.
Consistency:
• Rat hepatocytes cultured
with 10 mM 1,2-
dichloroethane for 2 hours
did not show evidence of
lipid peroxidation (i.e.,
increased PCOOH or
PEOOH levels).
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glycolipoprotein metabolism
(Cottalasso et al. 2002;
Cottalasso et al. 1995;
Cottalasso et al. 1994).
o In vitro studies in rat
hepatocytes or rat liver slices
evaluated oxidative stress
parameters (Cottalasso et al.
1994; Suzuki et al. 1994; Jean
and Reed, 1992; Thomas et al.,
1989; To mas i et al.. 1984).
o An in vitro study in rat
hepatocytes incubated with the
cysteine S conjugate of 1,2-
dichloroethane, S-(2-
chloroethyl)-DL-cysteine
(CEC), evaluated cytotoxicity
related to oxidative stress (Webb
et al. 1987).
dichloroethane under anaerobic (but
not aerobic) conditions.
• The cysteine S conjugate of 1,2-
dichloroethane was cytotoxic and
depleted GSH in hepatocytes; co-
treatment with antioxidants and GSH
precursors mitigated these effects.
Effects on gluconeogenesis and
glycolipoprotein metabolism:
• Inhalation exposure increased miR-
451a expression and decreased
glycerol gluconeogenesis in the liver
of exposed mice.
• Rats treated with 1,2-dichloroethane
via gavage showed impairment of
glycoprotein biosynthesis.
• 1,2-dichloroethane treatment
increased retention and decreased
secretion of glycolipoproteins in rat
hepatocytes.
" Based on a density for 1,2-dichloroethane of 1.25 g/cm3.
5'-NT = 5'-nucleotidase; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; F = female; GGT = gamma-glutamyl
transferase; GLDH = glutamate dehydrogenase; GSH = glutathione; LDH = lactate dehydrogenase; M = male; MDA = malondialdehyde; ODC = orinithine
decarboxylase activity; PCOOH = phosphatidylcholine hydroperoxide; PEOOH = phosphatidylethanolamine hydroperoxide; PROD = pentoxyresorufin dealkylation;
SDH = sorbitol dehydrogenase.
2940
2941
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2942 Table Apx B-4.1,2-Dichloroethane Evidence Integration Table for Immune/Hematological Effects
Database Summarv
Factors that Increase
Strength
Factors that Decrease Strength
Summarv of Key
Findings and Within-
Strcam Strength of the
Evidence Judgement
Inferences across
Evidence Streams
and Overall WOSE
Judgement
I !\ idonce inleunilioii suiiimars iiiducmciil on immune hematological ell eels
I !\ idence Iioiii human studies i none)
I !\ ideuce from apical eudpoiuls in in vi<
IlldclCI'IIIIIKIk
11i;i11111i;iIi;i11 ;iiiiin;il studies
Studies of immune function:
• An inhalation study evaluated mortality from
Streptococcus zooepidemicus aerosol
challenge in female mice and lymphocyte
stimulation, alveolar macrophage inhibition,
and pulmonary bactericidal activity against
Klebsiella pneumoniae in female mice and
male rats after exposure once or for 5 (mice)
or 12 (rats) days (Sherwood et at. .1.987)
Study quality: High
• An oral gavage study in male mice evaluated
hematology (including coagulation), humoral
immunity (spleen cell antibody response),
cell-mediated immunity (delayed
hypersensitivity response), spleen and thymus
weight, and gross necropsy after 14 days
(Miinson et at. .1.982) Study quality: High
Studies of hematology, organ weights, and
histopathology:
• Inhalation studies in rats, mice, rabbits, and
guinea pigs (sex not specified) evaluated
gross pathology and histopathology of the
spleen after acute exposures (Heppel et at.
.1.945). Study quality: Medium
• An inhalation study in male rats evaluated
spleen weight, gross pathology, and
histopathology after 30 days exposure (Iawe
et at. 1986b) Study quality: High
• Inhalation studies in rats, rabbits, guinea pigs,
monkeys, cats and a single dog evaluated
hematology (and/or clotting parameters or
IgM) and/or spleen histopathology after 5 to
35 weeks of exposure (Heppel et at. .1.946)
Biological gradient/dose-
response:
• Female mice exposed by
inhalation for 3 hours
exhibited a concentration-
related increase in mortality
due to S. zooepidemicus
infection at concentrations
>22 mg/m3 (5.4 ppm).
Mortality incidences were
1.5 and 2.1-fold higher than
controls at 22 and 43.7
mg/m3, respectively. Female
mice also exhibited a small
decrease in bactericidal
activity against K.
pneumoniae at 43.7 mg/m3
(10.8 ppm).
• In a gavage study, decreased
humoral and cell-mediated
immune responses were
observed in male mice after
14 days exposure to >4.89
mg/kg-day; decreased
leukocyte counts were
observed at 48.9 mg/kg-day.
• In a gavage study in rats,
small decreases in
erythrocyte count,
hemoglobin, and hematocrit
were observed in both sexes
along with increased
platelets (both sexes) and
Consistency:
• Male rats exhibited no effects
in the K. pneumoniae
challenge assays after
exposures up to 810 mg/m3 for
5 hours or up to 405 mg/m3 for
12 days.
• In a study rated uninformative
due to decreased drinking
water intake at the high dose
of 189 mg/kg-day, no effect
on humoral or cell-mediated
immune responses or
leukocyte counts were
observed in mice exposed to
doses of 3, 24, or 189 mg/kg-
day via drinking water for 90
days.
» No treatment-related changes
in hematology were observed
in a gavage study of male rats
exposed to doses up to 120
mg/kg-day for 13 weeks, or in
studies of several species
exposed by inhalation for
durations from 5 weeks to 2
years.
• Multiple studies of several
species exposed by inhalation
or oral administration for
acute, subchronic, or chronic
durations showed no effects
Key findings'.
In high-quality inhalation
and gavage studies of
immune function in mice,
an association between
1,2-dichloroethane
exposure and
immunosuppression was
observed; a more limited
inhalation study in rats
and a longer-term
drinking water study in
mice rated Uninformative
did not show any effects.
Evidence from other
studies showed only small
effects on hematology and
no effects on relevant
organ weights or
histopathology.
Overall WOSE judgement
for immune/hematological
effects based on animal
evidence:
• Moderate
Overall WOSE
judgement for
immune/hematologic
al effects based on
integration of
information across
evidence streams:
Evidence indicates
that 1,2-
dichloroethane likely
causes immune
system suppression
under relevant
exposure conditions.
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(Mellon Institute, 1947) (Spencer et aL 1951)
leukocytes (females only)
after 90 days at 150 mg/kg-
day.
• In a subchronic gavage
study, increased incidences
of thymus necrosis were
observed in male and female
rats that died prematurely
(>240 mg/kg-day in males
and at 300 mg/kg-day in
females).
on relevant organ weights or
histopathology.
Biolosical olausibilitv and
human relevance:
• In the mouse inhalation study,
mice were exposed for 30
minutes to aerosols of
streptococcal bacteria (~2x 104
inhaled viable streptococci).
The relevance of this immune
challenge to typical human
bacterial exposures is
uncertain.
(IRFMN. 1987. 1978. 1976) (Hofmann et aL.
1971) Study quality: Low to Medium
• Inhalation cancer bioassays in male and
female rats and mice evaluated hematology
and/or comprehensive histopathology after 2
vears exposure (Cheever et aL. 1990)
(Nagano et aL. 2006) Studv aualitv: Hish
• A drinking water study in male and female
mice evaluated comprehensive
histopathology after 13 weeks exposure
(NTP. 1991) Studv aualitv: Hish
• Gavage studies in male and female rats
evaluated hematology, spleen and/or thymus
weights, and comprehensive histopathology
after 10- and/or 90-dav exposures (Daniel et
aL. 1994) (NTP. 1991) Studv aualitv: Hish
• A gavage cancer bioassay in male and female
mice evaluated comprehensive
histopathology after 78 weeks exposure
(NTP. 1978) Studv aualitv: Hish
• A gavage cancer bioassay in male and female
transgenic mice susceptible to cancer
evaluated hematology and histopathology of
the thymus, spleen, lymph nodes, and bone
marrow after 40 weeks exposure (Storer et
aL. 1995) Studv aualitv: Medium
• A dermal cancer bioassay in male and female
transgenic mice susceptible to cancer
evaluated thymus and spleen weights and
histopathology of the lymph nodes, thymus,
and bone marrow after 26 weeks exposure
(Sueiiro et aL. 2017) Studv aualitv: Hish
Studies Rated Uninformative:
• An oral study in male mice evaluated
hematology, humoral immunity (spleen cell
antibody response), cell-mediated immunity
(delayed hypersensitivity response), spleen
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cell response to mitogens, function of the
reticuloendothelial system, spleen and
thymus weight, and gross necropsy after 90
davs drinking water exposure. (Munson et al.
)
1 v idciicc mi mcdiaiiisiic siudics
• An in vitro study investigated phagocytic
activity of mouse peritoneal macrophages
incubated with 1.2-dichloroethane (TJtsuini et
al. 1992).
• Cell-free and in vitro studies investigated 1,2-
dichloroethane effects on erythrocyte
ulutathione-S-transfera.se (GST) (Ansari et al.
1987)
• An inhalation study in rats evaluated
elemental content in the spleen after 30 days
exposure to 1.2-dichloroethane COue et al.
1988).
Bioloeical eradient/dose-
resDonse:
• 1,2-Dichloroethane induced
dose-related reductions in
erythrocyte GST activity in
both the cell-free experiment
and in human erythrocytes in
vitro.
• 1,2-Dichloroethane reduced
macrophage phagocytic
activity to 76% of control
levels at a concentration of
200 mM.
Key findings'.
Limited in vitro data
showed reductions in
macrophage phagocytic
activity and erythrocyte
GST activity after
exposure to 1,2-
Dichloroethane.
Overall WOSEjudgement
for immune/hematological
effects based on
mechanistic evidence:
• Indeterminate
2943
2944
Table Apx B-5.1,2-Dichloroethane Evidence Integration Table for
Neurological/Behavioral Effects
Database Summary
Factors that Increase Strength
Factors that Decrease
Strength
Summary of Key
Findings and Within-
Strcam Strength of the
Evidence Judgement
Inferences across
Evidence Streams
and Overall WOSE
Judgement
1 !\ idcucc iuieuralKiii summars jiidueiiieui on iicumlomcal lvlia\ loial el Tec Is
1 !\ idcncc from human studies
Overall If OSE
judgement for
neurological/behavi
oral effects based on
integration of
information across
evidence streams:
• Case reports of human exposure to 1,2-
dichloroethane by inhalation or ingestion
indicated clinical signs of neurotoxicity
(dizziness, tremors, paralysis, coma) as
well as histopathology changes in the
brain at autopsy (ATSDR 2022).
• Workers exposed to 1,2-dichloroethane for
extended periods have developed cerebral
Key findings'.
Case reports document
clinical signs of
neurotoxicity and brain
histopathology changes in
humans exposed to 1,2-
dichloroethane by
inhalation or ingestion.
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and Overall WOSE
Judgement
edema and toxic encephalopathy (ATSDR
2022).
Overall WOSEjudgement
for
neurological/behavioral
effects based on human
evidence:
• Slight
Evidence indicates
that 1,2-
dichloroethane
likely causes
neurological/
behavioral effects
under relevant
exposure
circumstances.
1 !\ i do nee from apical eudpoiuis in in \ i\n mammalian animal studies
Studies e\aliialiim neiii\
7,706 mg/m3 (1904 ppm) one hour
after exposure but not at
subsequent times up to 15 days
later.
• In rats exposed by inhalation for >
1.5 hours to > 4000 mg/m3 brain
edema was seen, and
microstructural alterations were
detected by diffusion MRI 3 days
after exposure.
• In rats exposed by inhalation to >
5,000 mg/m3, increased water
content in the cortex was observed
after >2-hour exposure and edema
and histopathological changes in
the brain were observed by light
and transmission electron
microscopy at the end of > 6-hour
exposure.
• In animals of several species
exposed by inhalation for up to 12
hours, clinical signs including
hyperactivity, weakness, sedation,
• No treatment-related brain
weight or histopathology
changes were seen in
nervous system tissues 15
days after single 4-hr
exposure up to 8,212.3
mg/m3 (2,029.0 ppm).
• No histopathology changes
were observed in the brain,
sciatic nerve, or spinal cord
of rats exposed by inhalation
for 204 mg/m3 (50.4 ppm)
for 2 years in a cancer
bioassay.
• No clinical signs of toxicity
or histopathology changes in
the brain or sciatic nerve
were observed in rats
exposed by gavage to up to
300 mg/kg-d for 10 days or
150 mg/kg-d for 90 days.
• No histopathology changes
were observed in the brain,
sciatic nerve, or spinal cord
of mice exposed via drinking
water for 13 weeks, by
gavage for 78 weeks in a
cancer bioassay, or in
transgenic mice exposed by
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and electron microscopy, and water
content of the brain after 2-, 4-, 6-, or 12-
hour exposures CGin-li et al. 2010)
Study quality: Medium
• An inhalation cancer bioassay in male
and female rats evaluated brain, sciatic
nerve, and spinal cord gross and/or
microscopic pathology after 2 years
exposure (Cheeveret al. 1990) Studv
quality: High
• A gavage study in male and female rats
evaluated clinical signs, brain weight,
and gross and/or microscopic pathology
of the brain and sciatic nerve after 10- or
90-dav exposure (Daniel et al.. 1994)
Study quality: High
• A gavage study in male and female rats
evaluated clinical signs, brain weight,
and histopathology of the brain, sciatic
nerve, and spinal cord after 13 weeks
exposure (NTP. 1991) Studv aualitv:
High
• A drinking water study in male and
female mice evaluated clinical signs,
brain weight, and histopathology of the
brain, sciatic nerve, and spinal cord after
13 weeks exposure (NTP. 1991) Studv
quality: High
• A gavage cancer bioassay in male and
female mice evaluated clinical signs and
histopathology of the brain/meninges
after 78 weeks exposure (NTP, 1978)
Study quality: Medium
• A dermal cancer bioassay in male and
female transgenic mice evaluated clinical
signs, brain weights, and brain, spinal
cord, and sciatic nerve histopathology
dysphoria, and/or trembling were
reported.
• In rats exposed by gavage for 13
weeks, clinical signs of
neurotoxicity (including tremors
and abnormal posture) and
necrosis in the cerebellum were
observed at >240 mg/kg-day.
Consistencv:
• Mice exposed by intraperitoneal
injection showed a dose-related
decrease in response rate in lever-
pressing operant behavior test at >
62.5 mg/kg but no effects on other
tests.
dermal application for 40
weeks in a cancer bioassay.
• Exposure to 1,2-
dichloroethane did not alter
brain weights of rats exposed
by gavage for up to 90 days
or in mice exposed by
gavage for 14 days or
drinking water for 90 days.
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and Overall WOSE
Judgement
after 26 weeks exposure (Sueuro et al.
2017) Study quality: High
Studies evaluating clinical sisns. brain
weieht. and/or sross patholoev:
• Inhalation studies in rats, mice, rabbits,
and guinea pigs evaluated clinical signs
of neurotoxicity after 1.5- to 7-hour
exposures ffleooel et al.. 1945) Studv
quality: Medium
• An inhalation study in male and female
rats and guinea pigs and male monkeys
evaluated clinical signs and/or brain
histology after up to 35 weeks exposure
(Spencer et al. 1951) Studv aualitv:
High
• A gavage study in male rats evaluated
clinical signs and gross pathology after a
sinsle exposure (Stauffer Cliem Co.
1973) Study quality: Medium
• A gavage study in male and female mice
evaluated brain weight and gross
pathology after 14-day exposure
(Munson et al. 1982) Studv aualitv:
High
• An intraperitoneal (intraperitoneal)
injection study of fertility in male mice
evaluated gross pathology of the brain
after 5-dav exposure (Daiele et al.. 2009)
Study quality: Medium
1 !\ idciicc mi mcdiaiiisiic Mudics
• In vivo inhalation studies in mice aimed at
identifying mechanisms of brain edema
induced by 1,2-dichloroethane evaluated
aquaporin and matrix metalloproteinases
protein expression or ATP generation and
tight junction protein expression after 1-,
2-. or 3-dav exposure (Wane et al. 2018a:
Wane et al.. 2014).
Bioloeical eradient/dose-response:
• Exposure to 1,2-dichloroethane
upregulated the mRNA and/or
protein expression of aquaporin
and a matrix metalloproteinase
(MMP9).
• Exposure to 1,2-dichloroethane
resulted in decreased expression of
Key findings'.
1,2-dichloroethane may
downregulate tight
junction proteins and
energy production and
upregulate aquaporin and
a matrix metalloproteinase
in the brains of exposed
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Judgement
• An in vivo oral study in rats evaluated
neurotransmitter levels in the brain after a
sinsle exposure (Kanada et al. 1994).
• In vitro studies in rat astrocytes exposed to
2-chloroethanol (metabolite of 1,2-
dichloroethane) evaluated the roles of
mitochondrial function, glutamate
metabolism, matrix metalloproteinases,
and MAPK cell signaling in cerebral
edema induced by 1,2-dichloroethane
(Wang et al., 2018b; Wane et al., 2017;
Sun et al, 2016a; Sun et al, 20165).
tight junction proteins (occludin
and ZO-1) and mRNA, increased
free calcium, decreased ATP
content, and decreased ATPase
activity in the brains of mice.
Consistency:
• Exposure to 2-chloroethanol in
vitro resulted in decreased ATPase
activity, mitochondrial function
(membrane potential), and
glutamate metabolism (expression
of enzymes involved in glutamate
metabolism) in rat astrocytes.
Exposure also upregulated matrix
metalloproteinases (MMP2 and
MMP9) via increased p38 MAPK
signaling. Pretreatment with the
antioxidant N-acetyl-l-cysteine
mitigated effects on p38 and MMP
levels, suggesting a role for
oxidative stress.
mice.
Overall WOSEjudgement
for
neurological/behavioral
effects based on
mechanistic evidence:
• Slight
2946
2947
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2948 Table Apx B-6. 1,2-Dichloroethane Evidence Integration Table for Respiratory Tract Effects
Database Summarv
Factors that Increase
Strength
Factors that Decrease Strength
Summarv of Key
Findings and Within-
Strcam Strength of the
Evidence Judgement
Inferences across
Evidence Streams
and Overall WOSE
Judgement
I !\ idciicc ink'unilKiii suiiimars judgement i'ii iv^pir;iU'i"\ liacl effects
L\ idence I'mm human studies (ikHie)
I !\ ideuce li'oili apical endpoinls in in \i\n ni;inini;ili;in ;inini;il studies
• I udelcruii uale
Studies examining upper and lower respirator/
tract:
• An acute inhalation study in male and female
rats evaluated BAL, lung weight, and
histopathology of the respiratory tract
including nasal cavity 24 hours after 4- or 8-
hour exposures (Hotchkiss et at.. 20.1.0: Dow
Chemical 200651. Study quality: High
• An inhalation cancer bioassay in male and
female rats evaluated histopathology of the
respiratory tract including nasal cavity after
104 weeks of exposure (Cheever et at.. 1990").
Study quality: High
• Two gavage studies in rats evaluated lung
weight and histopathology of the lungs and
nasal cavity and turbinates after 10 and 90
days of exposure (Daniel et at. .1.994). Study
quality: High
• A gavage study in male and female rats
evaluated histopathology of the respiratory
tract including nasal cavity and turbinates,
after 13 weeks of exposure (NTP. .1.991).
Study quality: High
• A drinking water study in male and female
mice evaluated histopathology of the
respiratory tract including nasal cavity and
turbinates, after 13 weeks of exposure (NTP,
.1.99.1.). Study quality: High
» A dermal cancer bioassay in male and female
transgenic mice susceptible to cancer
evaluated lung weight and histopathology of
the nasal cavity, trachea, and lungs after 26
Biological gradient/dose-
response:
• In a high-quality study, dose-
related increased incidences
and/or severity of
degeneration/ necrosis of the
nasal olfactory mucosa
occurred in male and female
rats after inhalation
exposures >795 mg/m3
(>196.4 ppm) for 4 hours or
> 435 mg/m3 (>107.5 ppm)
for 8 hours. Regeneration of
the olfactory epithelium was
seen in groups sacrificed 15
days after a 4-hour exposure
to 795 mg/m3 (196.4 ppm).
• Lung effects including a
transient decrease in ALP in
BALF and histopathology
changes (edema, vacuolar
changes, desquamation,
atelectasis, macrophage
proliferation, and
inflammation) were reported
in rats after a single gavage
dose of 136 mg/kg.
Biological gradient/dose-
response:
• No treatment-related nasal
lesions were observed in
cancer bioassays of rats
exposed by inhalation up to
654 mg/m3 (160 ppm) for 2
years.
• High-quality studies in rats
did not show effects of 1,2-
dichloroethane on the lung
after gavage exposure up to
150 mg/kg/day for 90 days.
Magnitude and precision:
• Group sizes were small
(5/sex) in the acute inhalation
study that observed nasal
lesions.
Consistency:
• High- and medium-quality
studies in rats did not show
effects of 1,2-dichloroethane
on the lung after chronic
inhalation exposure up to 810
mg/m3 (200 ppm) for 212
days or up to 654 mg/m3 (160
ppm) for 2 years.
• High-quality studies in mice
did not show effects of 1,2-
dichloroethane on the lungs
after 14 days of gavage
exposure up to 49 mg/kg/day
or 13 weeks of drinking water
Key findings'.
In a high-quality study, an
association between 1,2-
dichloroethane inhalation
exposure and nasal lesions
was observed in rats
exposed to concentrations
>435 mg/m3 (>107.5
ppm). Although one
medium-quality study
reported lung lesions in
rats after a single gavage
dose, high- and medium-
quality studies of longer
duration and higher doses,
as well as a high-quality
study of acute inhalation
exposure, did not show
effects of 1,2-
dichloroethane on lower
respiratory tract tissues of
rats.
Overall WOSE judgement
for respiratory effects
based on animal
evidence:
• Slight to moderate
Overall WOSE
judgement for
respiratory tract
effects based on
integration of
information across
evidence streams:
Evidence suggests,
but is not sufficient to
conclude, that 1,2-
dichloroethane may
cause nasal effects
under relevant
exposure conditions.
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Database Summary
Factors that Increase
Strength
Factors that Decrease Strength
Summary of Key
Findings and Within-
Strcam Strength of the
Evidence Judgement
Inferences across
Evidence Streams
and Overall WOSE
Judgement
weeks of exposure (Sueuro et al. 2017s). Studv
quality: High
Studies examining onlv lower respiratory tract:
• An inhalation cancer bioassay in male and
female rats and mice evaluated lung weight
and histopathology after 104 weeks of
exposure (Nagano et al. 2006). Studv aualitv:
High
• An inhalation study in male and female rats
and guinea pigs evaluated lung weight and
historatholoev after-170 - 246 davs (Spencer
et al.. 1951). Studv aualitv: Medium
• A gavage study in male rats evaluated BALF,
lung weight, and lung histopathology 1 to 30
davs after a sinsle dose (Salovskv et al.
2002). Study quality: Medium
• A gavage study in mice evaluated lung weight
and gross pathology after 14 days of exposure
(Miinson et al. 1982). Studv aualitv: Hish
• A gavage study in male and female mice
evaluated the lungs, bronchi, and trachea for
histopathology after 78 weeks of exposure
(NTP. 1978). Studv aualitv: Hieh
• An intraperitoneal injection study in male rats
evaluated lung weight and histopathology
(Iewe et al. 1986b). Studv aualitv: Medium
• An intratracheal injection lethality study in
rats (sex NS) evaluated gross pathology of the
lungs at death or 3 days after a single dose
(Dow Chemical. 1989). Studv aualitv:
Medium
exposure up to 4926
mg/kg/day.
• A medium-quality study in
guinea pigs did not show
effects of 1,2-dichloroethane
on the lungs after exposure up
to 1620 mg/m3 (400 ppm) for
246 days.
• BAL parameters, lung weight,
and lung histopathology were
not affected in rats exposed by
inhalation up to 8212.26
mg/m3 (2029.0 ppm) for 4
hours.
Oualitv of the database:
• Lung histopathology data in
the acute gavage study that
reported lung effects were
presented qualitatively.
Bioloeical plausibility and human
relevance:
• Lung tumors are associated
with chronic inhalation or
gavage exposure in mice and
with subchronic dermal
exposure in susceptible
transgenic mice. Increases in
lung weight and preneoplastic
lesions, such as hyperplasia, in
some of these studies are
related to tumor development
and not indicative of a
separate nonneoplastic effect
on the lung.
Ivideuce mi niecliaiiisiic studies i uouei
• Indeterminate
2949
2950
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2951 Table Apx B-7. 1,2-Dichloroethane Evidence Integration Table
'or Nutritional/Metabolic Effects
Database Summarv
Factors that Increase Strength
Factors that Decrease Strength
Summarv of Key
Findings and Within-
Strcam Strength of the
Evidence Judgement
Inferences across
Evidence
Streams and
Overall WOSE
Judgement
Evidence integration summitry judgement on nutritional/metabolic effects
Evidence from human studies (none)
• liHlckTimiialc
I !\ idence Ironi apical cudpniiiis in in \'i\ >> mammalian animal studies
I'mds \u
was e\alnaled in the
following studies:
• Acute inhalation studies in male and
female rats (Dow Chemical 2006b');
Study quality: High.
• Short-term inhalation studies in male
mice (Zeng et at.. 20.1.8: Zhang et at,
20.1.7'); Study quality: High.
• A short-term inhalation study in
female rats (Dow Chemical 2014);
Study quality: High.
• Short-term, subchronic, and chronic
inhalation studies in male and/or
female rats, mice, rabbits, dogs,
guinea pigs, monkeys, and cats
(Spencer et al. .1.951; Heppel et al.
.1.946); Study quality: Medium or
Low.
• A one-generation inhalation
reproduction study in rats (Rao et al.
.1.980); Study quality: Medium.
• Chronic inhalation cancer bioassays
in male and female rats (Nagano et
al. 2006; Cheeveret al. .1.990); Study
quality: High.
• An acute oral gavage study in male
rats (Moody et al. 1981): Study
quality: Medium.
• A gavage study in female rats
exposed during gestation (Payan et
al. .1.995); Study quality: High.
I'lK'k'gical uiadieni dusc-rcsnmisc
Treatment-related adverse" effects
on body weight occurred in high or
medium quality studies of (species,
route, exposure level and duration):
• Mouse inhalation:
o >707 mg/m3 (175 ppm),
males, 4 weeks
• Guinea pig inhalation:
o 405 mg/m3 (100 ppm) in
females and 809 mg/m3 (200
ppm) in males, up to 246 d
• Rat gavage:
o >40 mg/kg-day, females, 6
weeks
o 150 mg/kg-day, males, 13
weeks
o 198 mg/kg-day, maternal
weight gain, GD 6-20
• Mouse drinking water:
o 4,207 mg/kg-day in males and
>647 mg/kg-day in females,
13 weeks
Consistency:
• Decreased body weight was
observed in male transgenic mice
exposed to 200 mg/kg-day by
gavage for 40 weeks.
lik'U'gical uiadienl dusc-iysnmisc
No treatment-related adverse effects on
body weight occurred in high or medium
quality studies of (species, route,
exposure level, and duration):
• Rat inhalation:
o <8,212 mg/m3 (2029 ppm), males
and females, 4 hours
o 832 mg/m3 (205 ppm), females, 4
weeks
o <809 mg/m3 (200 ppm), males
and females, up to 212 d
o <648 mg/m3 (160 ppm), males
and females, 2 years
• Monkey inhalation:
o 405 mg/m3 (100 ppm), males, up
to 212 days
• Rat gavage:
o 625 mg/kg-day, males, single
dose
o <300 mg/kg-day, males, and
females, 10 d
o <100 mg/kg-day, males, 2 weeks
o <90 mg/kg-day, males, and
females, 13 weeks
o <120 mg/kg-day in males and
<150 mg/kg-day in females, 13
weeks
Consistency:
• Body weight was not affected in low
quality inhalation studies of female
dogs exposed to 1,540 mg/m3 (380.5
Key findings'.
Decreased body weight
was reported in mice
and guinea pigs
exposed by inhalation
and rats and mice
exposed orally to 1,2-
dichloroethane in high-
and medium-quality
studies. Several high-
and medium-quality
studies in a few species
via various routes of
exposure reported no
effect on body weight,
sometimes at lower
exposure levels and/or
shorter exposure
durations.
Overall WOSE
judgement for
nutritional/metabolic
effects based on animal
evidence:
• Slight
Overall WOSE
judgement for
nutritional/
metabolic effects
based on
integration of
information
across evidence
streams:
Evidence suggests
that 1,2-
dichloroethane
may cause
nutritional/
metabolic effects
under relevant
exposure
conditions.
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Database Summary
Factors that Increase Strength
Factors that Decrease Strength
Summary of Key
Findings and Within-
Strcam Strength of the
Evidence Judgement
Inferences across
Evidence
Streams and
Overall WOSE
Judgement
• A short-term gavage study in male
and female mice (Munson et al.
1982); Study quality: High.
• Short-term and subchronic gavage
studies in male and female rats
(Daniel et al. 1994; NTP. 1991: van
Escli et al. 1977^); Studv aualitv:
Hieh. (NTP. 19781: Studv aualitv
Medium.
• A subchronic drinking water study in
male and female mice (NTP, 1991);
Study quality: High.
• A subchronic dietary study in rats
(Aluinot et al. 1976); Studv aualitv:
Medium.
• A multigenerational drinking water
studv in mice (Lane et al., 1982);
Study quality: High.
• Chronic gavage and dermal studies in
transgenic mice susceptible to cancer
(Sueiiro et al. 2017; Storeret al.
1995); Study quality: High.
• Short-term intraperitoneal injection
studies in male rats and male mice
(Daiele et al. 2009); Studv aualitv:
Hish; (lewe et al. 1986b): Studv
quality: Medium.
ppm) for 34-35 weeks or male rabbits
exposed to 730 mg/m3 (180 ppm) for
13-25 weeks.
• Body weight was not affected in rats
given feed fumigated with 1,2-
dichloroethane in a 13-week study
with dose uncertainties.
• Body weight was not affected in male
transgenic mice exposed to dermal
doses up to 6,300 mg/kg-day for 26
weeks.
• Body weight was not affected after
intraperitoneal administration in male
rats given 150 mg/kg-day for 30 days
or in male mice given 40 mg/kg-day
for 5 days.
Ividcucc mi iiiecliamslic studies i iionei
• Indeterminate
" In adult animals, decreases in body weight of at least 10% change from control are considered adverse unless the changes are attributable to food or drinking water
intake decreases due to palatability. Statistically significant decreases (relative to controls) in maternal body weight gain during gestation are considered adverse. Effects
on body weight of offspring at ages up to sexual maturity are considered developmental effects.
2952
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2953 Table Apx B-8. 1,2-Dichloroethane Evidence Integration Table for Mortality
Database Summary
Factors that Increase Strength
Factors that Decrease
Strength
Summary of Key Findings
and within-Strcam
Strength of the Evidence
Judgement
Inferences across
Evidence Streams
and Overall WOSE
Judgement
1 !\ idence iiHcmaUon Minimais luducmciil on nioil;ilil\
1 v kIciicc lioin hiini;iii sludics
Overall WOSE
judgement for
mortality effects
based on integration
of information across
evidence streams:
Evidence indicates
that 1,2-
dichloroethane may
cause death under
relevant exposure
circumstances and
lethal levels have
been identified in
animal studies.
• A retrospective cohort mortality study
evaluated all-cause mortality in 7849
white male petrochemical plant workers
followed from 1950 to 1983. SMRs were
calculated using age-, race-, and
calendar year-specific mortality rates of
males in the United States (Teta et al.
1991). Studv duality: Medium
• A retrospective cohort mortality study
evaluated all-cause mortality in
251 employees of an herbicide
manufacturing facility between 1979 and
1987, followed until 2003. SMRs were
calculated using age- and gender-
specific mortality rates in the United
States. (BASF. 2005). Studv duality:
Medium
Bioloeical olausibilitv and
human relevance:
• Two limited retrospective
cohort studies found no
increase in mortality of
workers with presumed
exposure to 1,2-
dichloroethane (and other
chemicals) relative to the
general U.S. population.
Key findings'.
Limited epidemiological data
show no increase in mortality
among workers with
presumed exposure to 1,2-
dichloroethane but are
insufficient to draw any
broader conclusions.
Overall WOSE judgement for
mortality effects based on
human evidence:
• Indeterminate
Evidence from apical cndpoinls in in vivo mammalian animal studies
• Acute-duration inhalation studies
evaluated mortality in rats, mice, and
euinea Dies (Dow Chemical. 2017.
2006b; Storeret al.. 1984; Spencer et al.,
1951). Studv quality: Hieh.(Oin-li et al.
2010; Francovitch et al., 1986; Heppel et
al. 1945). Studv duality: Medium
• Short-term- and subchronic-duration
inhalation studies evaluated mortality in
rats, guinea pigs, mice, rabbits, dogs,
and cats (Dow Chemical. 2014; Pay an et
al. 1995; lewe et al. 1986b). Studv
duality: Hieh. (Rao et al. 1980; Heppel
et al. 1946). Studv dualitv: Medium
• Chronic-duration inhalation studies
evaluated mortality in rats, mice, rabbits,
Bioloeical eradient/dose-
rcsDonsc:
Treatment-related deaths" or
effects on survival occurred in
studies of (species, route,
exposure, and intended duration):
• Rat inhalation:
o 10,200 mg/m3 (2,520 ppm),
4 hours
o 4,050 mg/m3 (1,000 ppm),
7 hours
o 1,230 mg/m3 (455 ppm),
30 d
o >730 mg/m3 (0.73 mg/L),
6 weeks
Bioloeical eradient/dose-
rcsDonsc:
No treatment-related1
deaths/effects on survival were
seen in studies of (species,
route, exposure, duration):
• Rat inhalation:
o <8,212 mg/m3 (2,029
ppm), 4 hours
o 5,000 mg/m3, 2-6 hours
o 630.6 mg/m3 (155.8 ppm),
8 hours
o 10,000 mg/m3, 12 hours
o 404 mg/m3, 17 weeks
o <646.4 mg/m3 (158 ppm),
2 years
Key findings'.
Treatment-related increases
in the incidence of mortality
were observed in several
animal species exposed to
1,2-dichloroethane via
inhalation, oral, or dermal
exposure for acute, short-
term/intermediate, or chronic
durations in multiple studies.
Overall WOSE judgement for
mortality effects based on
animal evidence:
• Robust
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Summary of Key Findings
Inferences across
Database Summary
Factors that Increase Strength
Factors that Decrease
and within-Strcam
Evidence Streams
Strength
Strength of the Evidence
and Overall WOSE
Judgement
Judgement
guinea pigs, dogs, monkeys, and cats
o 1,214 mg/m3 (300 ppm),
• Mouse inhalation:
(Nagano et aL 2006; Cheeveret aL
gestational exposure
o <700 mg/m3, 1 week
1990). Studv quality: Hish. (Hofmann et
• Mouse inhalation:
o 420 mg/m3, 4 weeks
al.. 1971: Spencer etaL. 195 1). Studv
o >4,339 mg/m3 (1,072 ppm),
o <363 mg/m3 (89.8 ppm),
duality: Medium; (HeoDel et al.. 1946).
4 hours
2 years
Studv aualitv: Low or Medium; (Mellon
o 6,071 mg/m3 (1,500 ppm),
• Rabbit, guinea pig, and cat
Institute. 1947). Studv duality: Low
7 hours
inhalation:
• Acute-duration gavage studies evaluated
• Rabbit inhalation:
o 404 mg/m3, 17 weeks
mortality in rats and mice (Kitchin et al.
o 12,100 mg/m3 (3,000 ppm),
• Rat gavage:
1993; Storeret al. 1984; Moody et al.
7 hours
o 625 mg/kg, once
1981). Studv quality: Hish; (Stauffer
o 6,071 mg/m3 (1,500 ppm),
o 150 mg/kg-day, 90 days
Cliem Co. 1973). Studv duality: Medium
5 d
o 240 mg/kg-day,
• Short-term- and subchronic-duration
o 1,980 mg/m3 (490 ppm),
gestational exposure
gavage studies evaluated mortality in
6 weeks
• Mouse drinking water:
rats (Daniel et al. 1994; NTP. 1991).
o 1,540 mg/m3 (1.54 mg/L),
o 2,710 mg/kg-day, 90 days
Study quality: High
20 weeks
(male)
• Chronic-duration gavage studies
o >405 mg/m3 (100 ppm),
• Mouse intraperitoneal:
evaluated mortality in wild type and
gestational exposure
o 600 mg/kg, once
transgenic mice (Storeret al.. 1995;
• Guinea pig inhalation:
NTP. 1978). Studv duality: Hish
o 6,071 mg/m3 (1,500 ppm),
• A subchronic drinking water study
7 hours
evaluated mortality in mice (NTP.
o 3,900 mg/m3 (3.9 mg/L), 4 d
1991). Study quality: High
o 730 mg/m3 (0.73 mg/L),
• Chronic-duration drinking water studies
25 weeks
evaluated mortality in mice (Klaunig et
• Dog inhalation:
al, 1986; Lane et al, 1982). Studv
o 3,900 mg/m3 (3.9 mg/L),
quality: High
5 weeks
• An acute-duration dermal exposure
• Cat inhalation:
study evaluated mortality in rabbits
o 3,900 mg/m3 (3.9 mg/L),
(Dow Chemical. 1956). Studv duality:
11 weeks
Medium
• Rat gavage:
• A chronic-duration dermal exposure
o >1,000 mg/kg, once
study evaluated mortality in transgenic
o >240 mg/kg-day, 90 days
mice (Sueiiro et aL. 2017). Studv
• Mouse gavage:
quality: High
o >400 mg/kg, once
• A single dose intratracheal exposure
o 150 mg/kg-day, 40 weeks
study evaluated mortality in rats (Dow
(female transgenic)
Chemical. 1989). Studv quality: Medium
• Mouse drinking water:
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Database Summary
Factors that Increase Strength
Factors that Decrease
Strength
Summary of Key Findings
and within-Strcam
Strength of the Evidence
Judgement
Inferences across
Evidence Streams
and Overall WOSE
Judgement
• Single dose intraperitoneal injection
studies evaluated mortality mice (TJmezu
and Shibata. 2014; Storer et al. 1984).
Studv duality: Hieh: (Storer and
Conollv. 1983). Studv duality: Medium;
(Crebelli et al.. 1999). Studv duality:
Low
o 4,926 mg/kg-day, 90 days
(female)
• Rabbit dermal:
o 2,800 mg/kg (LD50), 24
hours
• Rat intratracheal:
o 120 mg/kg, once
• Mouse intraperitoneal:
o 486 mg/kg (LD50), once
l!\idciii_v mi mechanistic studies (none)
• Indeterminate
" Apart from chronic bioassays, most studies did not report statistical significance of mortality incidences. For the purpose of hazard identification, deaths were
considered to be related to treatment if they occurred at a higher incidence than in controls, occurred at the highest dose tested or with a relationship to dose, and were
not attributed to factors unrelated to treatment (accident or disease). For chronic-duration studies, only statistically significant, treatment-related effects on survival were
included.
2954
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2955 Appendix C EVIDENCE INTEGRATION TABLES FOR CANCER FOR 1,2-
2956 DICHLOROETHANE
2957
2958 Table Apx C-l. 1,2-Dichloroethane Cancer Evidence Integration Table
Database Summary
Factors that Increase Strength
Factors that Decrease Strength
Summarv of Key Findings
and within-Strcam
Strength of the Evidence
Judgement
Inferences across
Evidence Streams
and Overall WOSE
Judgement
1 !\ idcik.v iiilemnlioii smiiiiii;ii> jiiilucinciil oil c;inccr cllccls
1 !\ lllCMCC ll'OIII llllllKIII s| Mil ICS
P>i'c;N c;mcci'
Overall ll'OSli
judgement for cancer
effects based on
integration of
information across
evidence streams:
Evidence indicates
that 1,2-
dichloroethane likely
causes cancer under
relevant exposure
circumstances.
• A prospective study of women from
the California Teacher Study Cohort,
for which the U.S. EPA's National-
Scale Air Toxics Assessment (NATA)
was used to estimate exposure,
evaluated the association between 1,2-
dichloroethane exposure and the
incidence of invasive breast cancer
(Garcia et al. 2015). Studv aualitv:
High
• A prospective study of women from
the Sister Study Cohort, for which the
U.S. EPA's NATA was used to
estimate exposure, evaluated the
association between 1,2-
dichloroethane and the incidence of
invasive breast cancer and/or ductal
carcinoma in situ (Niehoff et al,
2019). Study quality: Medium
Bioloeical eradient/dose-resoonse:
• The risk for ER+ invasive breast
cancer was slightly, but
significantly, increased in
quintile 4 (but not quintile 5) of
exposure relative to quintile 1 in
the medium-quality study.
Magnitude and precision:
• The study used quantitative
exposure estimates and
accounted for covariate
information on individual breast
cancer risk factors.
Bioloeical eradicnt/dosc-rcsDonsc:
• The overall risk for breast cancer
(both studies) and ER- invasive
breast cancer (medium-quality
study) was not significantly
increased in 1,2-dichloroethane-
exposed women.
• Analyses based on quintiles of
exposure did not show an
exposure-response relationship
between 1,2-dichloroethane
exposure and ER+ invasive breast
cancer.
Maenitude and precision:
• The significant effect estimate for
ER+ invasive breast cancer was
small (hazard ratio = 1.17).
• Exposure estimates based on
modeling of emissions data
and/or at the census tract level
may have contributed to exposure
misclassification.
Key findings'.
In a medium-quality study,
an association between 1,2-
dichloroethane exposure and
ER+ invasive breast cancer
was observed, but it was
small and did not show a
clear exposure-response
relationship.
Overall WOSEjudgement
for cancer effects based on
human evidence:
• Indeterminate
('irciilaloiA sicin cancer
• A nested case-control study of male
workers from three Union Carbide
facilities, for which job assignment
and history of departmental use were
Bioloeical eradient/dose-resoonse:
Bioloeical eradicnt/dosc-rcsDonsc:
Key findings'.
Significant limitations in the
available studies preclude
conclusions regarding
• In the medium-quality study,
there was a nonsignificant
increase in the OR for
• In the medium-quality study,
exposure levels of 1,2-
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Database Summary
Factors that Increase Strength
Factors that Decrease Strength
Summary of Key Findings
and within-Strcam
Strength of the Evidence
Judgement
Inferences across
Evidence Streams
and Overall WOSE
Judgement
taken to estimate exposure
(ever/never), evaluated the association
between 1,2-dichloroethane exposure
and the incidence of hematopoietic
tissue cancer COtt et al. 1989; Union
Carbide. 1989). Studv aualitv:
Medium
Studv aualitv ranked as Uninformative:
• A retrospective cohort study of male
workers " from one Union Carbide
facility COtt et al.. 1989; Union
Carbide. 1989). for which exposure
(ever/never) was based on the history
and/or duration of work in the
chlorohydrin unit (which produced
1,2-dichloroethane as a byproduct),
evaluated the association between
chemical exposure and the risk of
mortality due to lymphopoietic
cancers (Benson and Teta, 1993).
nonlymphocytic leukemia
(NLL) in 1,2-dichloroethane-
exposed workers, which was
higher in those working more
than 5 years.
• In a study ranked as
Uninformative owing to lack of
an appropriate comparison
group and lack of 1,2-
dichloroethane exposure levels,
work in the chlorohydrin unit
was significantly associated
with mortality from lymphatic
and hematopoietic cancers.
dichloroethane were not
provided.
Magnitude and precision:
• In the medium-quality study,
there was potential for
confounding because covariates
were not considered (race,
smoking status, concurrent
exposure to other chemicals).
• In the medium-quality study,
statistical power was limited
because cancer case numbers
were low (n = 5 for NLL).
• In the medium-quality study,
statistical methods were not
specified and ORs were provided
without CIs.
Consistencv:
• In the Uninformative study,
analysis was conducted based on
work department rather than
specific chemicals.
associations between 1,2-
dichloroethane exposure in
humans and circulatory
system cancers.
Overall WOSEjudgement
for cancer effects based on
human evidence:
• Indeterminate
lJaiiacalie cancer
• A case-control study of men and
women from 24 states, which
estimated intensity and probability of
1,2-dichloroethane exposure (low,
medium, high) based on listed
occupation and industry (from death
certificates) and a job exposure matrix
(JEM), evaluated the association
between 1,2-Dichloroethane exposure
and the risk of pancreatic cancer
(Kernan et al. 1999). Studv aualitv:
High
Studv aualitv ranked as Uninformative:
• A retrospective cohort study of male
workers b from a Union Carbide
Bioloeical aradicnt/dosc-rcsDonsc:
• In the high-quality study, 1,2-
dichloroethane exposure was
associated with a slight, but
borderline significant, increased
OR for pancreatic cancer among
Black females with low
estimated exposure intensity.
• In a study ranked as
Uninformative owing to lack of
an appropriate comparison
group and lack of 1,2-
dichloroethane exposure levels,
work in the chlorohydrin unit
was significantly associated
Bioloeical eradient/dose-resoonse:
• In the high-quality study, the risk
for pancreatic cancer in Black
females was not increased in
groups with medium or high
intensity exposure.
Consistencv:
• In the high-quality study, 1,2-
dichloroethane exposure was not
associated with an increased risk
of pancreatic cancer in Black
males, White females, or White
males.
• In the Uninformative study,
analysis was conducted based on
Key findings'.
In a high-quality study, a
slight, but significant,
association between low
intensity 1,2-dichloroethane
exposure and pancreatic
cancer was observed in
Black females, but the
association did not show an
exposure-response
relationship, and no
association was observed in
Black males or White males
or females.
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facility, for which exposure
(ever/never) was based on the history
and/or duration of work in the
chlorohydrin unit (which produced
1,2-dichloroethane as a byproduct),
evaluated the association between
chemical exposure and the risk of
mortality due to pancreatic cancer
(Benson and Teta. 1993).
with mortality from pancreatic
cancer.
work department rather than
specific chemicals.
Magnitude and precision:
• In the high-quality study, the
effect estimate in Black females
was small (OR = 1.2, 95% CI
1.0-1.4).
• In the high-quality study, there
was the potential for exposure
misclassification based on the
occupation and industry data
captured on death certificates.
Overall WOSEjudgement
for cancer effects based on
human evidence:
• Indeterminate
Kid lies cancer
• A populaUoii-babed, cas>o-a»iiuul
study of men and women from the
Minnesota Cancer Surveillance
System (cases) and the general
population of Minnesota or the Health
Care Financing administration
(controls), for which exposure was
estimated based on occupational
history and JEMs, evaluated the
association between 1,2-
dichloroethane exposure and the risk
for renal cell carcinoma (Dosemeci et
a.L 1999). Studv aualitv: Medium
1 iiolouical aradicnt/dosc-rcsDonse
I'.iolosical aradicnt/dosc-rcsDonse
Key findings:
In a medium-quality stud}.
no significant association
between 1,2-dichloroethane
exposure in humans and
renal cell carcinoma was
observed; however, the
number of exposed subjects
in the study population was
small.
Overall WOSE judgement
for cancer effects based on
human evidence:
• Indeterminate
• The risk of renal cell carcinoma
was significantly increased in
women exposed to all organic
solvents combined and all
chlorinated aliphatic
hydrocarbons combined.
Magnitude and precision:
• The use of a priori assessment of
exposure to solvents (including
1,2-dichloroethane) using JEMs
reduced recall bias among men
and women and cases and
controls.
• No significant increase in the risk
of renal cell carcinoma was
observed based on exposure to
1,2-dichloroethane among men,
women, or all participants.
Magnitude and precision:
• The number of participants
exposed to 1,2-dichloroethane
(40 cases and 48 controls) may
have been too low to detect
effects associated with 1,2-
dichloroethane exposure.
Oualitv of the database:
• Only one medium-quality study
was available to assess risk of
renal cancer due to 1,2-
dichloroethane exposure.
h'oslale cancer
• A retrospective cohort study
evaluated cancer incidence in
251 employees of an herbicide
manufacturing facility (bentazon unit)
between 1979 and 1987, followed
Biological aradicnt/dosc-rcsDon^.
Magnitude and precision:
Key findings:
In a medium-quality study,
an association between work
in bentazon production and
prostate cancer was
• A statistically significant
association was observed
between employment in the
bentazon unit and prostate
• The study did not directly assess
the association between exposure
to 1,2-dichloroethane and
prostate cancer. Other chemicals
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until 2003. SMRs were calculated
using age-, gender-, and race-specific
cancer incidence rates in South
Louisiana. (BASF. 2005). Studv
quality: Medium
cancer incidence (SIR = 2.2,
95% CI = 1.1-3.9)
were also used in the bentazon
unit.
observed; however, the
association with 1,2-
dichloroethane was not
directly assessed.
Overall WOSEjudgement
for cancer effects based on
human evidence:
Indeterminate
1 !\ idonce from apical eiklpoinis in in \ i\n mammalian animal Mudics
liivasi cancer
• A gavage study in male and female
mice examined the mammary gland
for neoplasms after 78 weeks of
exposure (NTP. 1978). Studv aualitv:
High
• Two inhalation studies in male and
female rats (Nagano et aL 2006;
Cheever et aL 1990) and one
inhalation study in male and female
mice (Nagano et aL. 2006) examined
the mammary gland for neoplasms
after 104 weeks of exposure. Study
quality: High
• A dermal study in male and female
transgenic mice susceptible to cancer
examined the mammary gland for
neoplasms after 26 weeks of exposure
(Sugiiro et aL. 2017). Studv aualitv:
High
Studv aualitv ranked as Uninformative:
• A gavage study in male and female
rats d examined the mammary gland
for neoplasms after 78 weeks of
exposure (NTP. 1978).
• An inhalation study in male and
female rats and mice® examined the
mammary gland for neoplasms at
Bioloeical eradient/dose-resoonse:
Consistencv:
Key findings'.
Mammary gland tumors
were observed in male and
female rats and in female
mice exposed to 1,2-
dichloroethane orally or via
inhalation in high-quality
studies.
Overall WOSE judgement
for breast cancer effects
based on animal evidence:
• Robust
• A significant dose-related trend
for increased incidence of
mammary gland
adenocarcinomas was observed
in female mice in the 78-week
gavage study using pooled
vehicle controls c; pairwise
comparisons showed significant
increases at both doses.
• Significant dose-related trends
for increased mammary gland
adenomas, fibroadenomas,
and/or adenocarcinomas were
observed in male and female rats
after 104 weeks of inhalation
exposure; pairwise comparisons
showed significant increases at
the highest exposure.
• A significant dose-related trend
for increased incidence of
mammary gland
adenocarcinoma was observed
in female mice after 104 weeks
of inhalation exposure.
• In a study ranked as
Uninformative due to high
mortality from pneumonia,
• The incidence of mammary gland
tumors was not increased in a 26-
week dermal study in transgenic
mice.
Magnitude and precision:
• Pairwise comparisons were not
significant for increased
incidence of mammary gland
adenocarcinoma in female mice
after 104 weeks of inhalation
exposure.
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natural death after 78 weeks of
exposure (Maltoni et al. 1980).
significant dose-related trends
for increased mammary gland
adenocarcinomas or
adenocarcinomas and
fibroadenomas were observed in
female rats in the 78-week
study; pairwise comparisons
showed a significant increase at
the high dose for
adenocarcinomas and at both
doses for combined tumors.
• In a study ranked uninformative
due to lack of inhalation
exposure details, the incidence
of mammary gland fibromas and
fibroadenomas was significantly
increased in rats after 78 weeks
of inhalation exposure.
Oualitv of the database:
• Evidence of mammary gland
tumors in rats and mice was
observed in high-quality studies.
1 .in or cancer
• A gavage study in male and female
mice examined the liver for
neoplasms after 78 weeks of exposure
(NTP. 1978s). Studv aualitv: Hieh
• Two inhalation studies in male and
female rats (Nagano et al.. 2006;
Cheever et al. 1990) and one
inhalation study in male and female
mice (Nagano et al. 2006) examined
the liver for neoplasms after
104 weeks of exposure. Study quality:
High
• A dermal exposure study in male and
female transgenic mice susceptible to
cancer examined the liver for
Bioloeical eradient/dose-resoonse:
• A significant dose-related trend
for increased incidence of
hepatocellular carcinomas was
observed in male (but not
female) mice in the 78-week
gavage study using pooled and
matched vehicle controls ' and
the pairwise comparison to
pooled vehicle controls showed
a significant increase at the high
dose.
• A significant dose-related trend
for increased incidence of
hepatocellular adenomas and
Consistency:
• The incidence of liver tumors was
not increased in transgenic mice
following 26 weeks of dermal
exposure.
Magnitude and precision:
• In female mice, incidences of
hepatocellular adenomas and
adenomas or carcinomas in the
104-week inhalation study were
not significantly increased based
on pairwise comparisons to
controls.
Key findings'.
In high-quality studies,
increased liver tumor
incidence was observed in
male or female mice
following exposure via
gavage or inhalation,
respectively.
Overall WOSEjudgement
for liver cancer effects
based on animal evidence:
• Slight to Moderate
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neoplasms after 26 weeks of exposure
CSueuro et al. 2017s). Studv aualitv:
High
• Nine-week gavage studies in male rats
evaluated the potential for tumor
initiation and/or promotion in the liver
based on numbers of gamma-
glutamytranspeptidase (GGT)-
positive foci (Milman et al.. 1988;
Stow et al. 1986). Studv aualitv:
High
Studv aualitv ranked as Uninformative:
• A gavage study in male and female
rats g examined the liver for
neoplasms after 78 weeks of exposure
(NTP. 1978).
adenomas or carcinomas was
observed in female (but not
male) mice following 104 weeks
of inhalation exposure.
Oualitv of the database:
• Evidence of increased liver
tumor incidence was observed in
high-quality studies.
• A cancer bioassay and a tumor
promotion assay in male mice h
assessed the incidence of liver
adenomas and/or carcinomas after 52
weeks drinking water exposure
(Klaunig et al., 1986). An inhalation
study in male and female rats and
mice1 examined the liver for
neoplasms at natural death after 78
weeks of exposure (Maltoni et al.
1980).
• A dermal exposure study in female
mice ' examined the liver for
neoplasms after up to 85 weeks of
exposure (Van Diiuren et al. 1979).
I.mmu cancer
• A gavage study in male and female
mice examined the lung for
neoplasms after 78 weeks of exposure
(NTP. 1978). Studv aualitv: Hieh
Biological eradient/dose-resoonse:
• Significant trends and pairwise
comparisons for increased
incidence of
alveolar/bronchiolar adenomas
Magnitude and precision:
• Pairwise comparisons did not
show a significant increase in the
incidence of lung tumors in
Key findings'.
In high-quality studies,
increased lung tumor
incidence was observed in
male and/or female mice
following gavage,
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• Two inhalation studies in male and
female rats (Nagano et al. 2006;
Cheever et al. 1990) and one
inhalation study in male and female
mice (Nagano et al. 2006) examined
the lung for neoplasms after
104 weeks of exposure. Study quality:
High
• A dermal exposure study in male and
female transgenic mice susceptible to
cancer examined the lung for
neoplasms after 26 weeks of exposure
(Sugiiro et al. 2017). Studv duality:
High
Studv aualitv ranked as Uninformative:
• A gavage study in male and female
ratsA' examined the lung for
neoplasms after 78 weeks of exposure
(NTP. 1978).
• A cancer bioassay and a tumor
promotion assay in male mice '
assessed the incidence of lung
adenomas and/or carcinomas after 52
weeks of drinking water exposure
(Klaunig et al., 1986).
• An inhalation study in male and
female rats and miceexamined the
lungs for neoplasms at natural death
after 78 weeks of c\do sure (Maltoni
et al. 1980).
• A dermal exposure study in female
mice " reported neoplasms in the lung
(not routinely examined) after up to
82 weeks of exposure (Van Duuren et
al. 1979).
were observed in male and
female mice in the 78-week
gavage study.
• Significant trends for increased
incidence of bronchiolo-alveolar
carcinomas and carcinomas or
adenomas were observed in
female mice following 104
weeks of inhalation exposure.
• Significant increases in the
incidence and multiplicity of
bronchiolo-alveolar adenomas
and adenocarcinomas were
observed in both sexes in the
dermal study using transgenic
mice.
Consistency:
female mice in the 104-week
study.
inhalation, or dermal
exposure.
Overall WOSEjudgement
for lung cancer effects based
on animal evidence:
• Moderate
• In the dermal study ranked as
Uninformative due to the use of
methods that did not account for
the volatility of 1,2-
dichloroethane, a significantly
increased incidence of benign
lung papillomas was observed
in female mice.
Oualitv of the database:
• Evidence of lung tumors was
observed in three high-quality
studies.
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Judgement
\1csoihcliom;i ol lhc pcnuniciini
• A gavage study in male and female
mice conducted comprehensive
histopathological examination after
78 weeks of exposure (NTP, 1978).
Study quality: High
• Two inhalation studies in male and
female rats (Nagano et aL 2006;
Cheever et aL 1990) and one
inhalation study in male and female
mice (Nagano et aL. 2006) conducted
comprehensive histopathological
examination after 104 weeks of
exposure. Study quality: High
• A dermal exposure study in male and
female transgenic mice susceptible to
cancer conducted comprehensive
histopathological examination after
26 weeks of exposure (Sugiiro et al..
2017). Study quality: High
Studv aualitv ranked as Uninformative:
• A gavage study in male and female
rats ° conducted comprehensive
histopathological examination after
78 weeks of exposure (NTP, 1978).
• An inhalation study in male and
female rats and mice p conducted
comprehensive histopathological
examination at natural death after 78
weeks of exposure (Maltoni et aL.
1980).
Biological gradicnt/dosc-rcsDonsc:
• A significant trend for increased
incidence of mesothelioma of
the peritoneum was observed in
male rats following 104 weeks
of inhalation exposure.
Oualitv of the database:
• Evidence of mesothelioma of the
peritoneum was observed in a
high-quality study.
Magnitude and precision:
• Pairwise comparisons did not
show a significant increase in the
incidence of mesothelioma of the
peritoneum in male rats in the
104-week inhalation study.
Consistency:
• There was no significant increase
in incidence of mesothelioma of
the peritoneum in female rats
following 104 weeks of
inhalation exposure.
• The incidence of mesothelioma
of the peritoneum was not
increased in transgenic mice
following 26 weeks of dermal
exposure.
Key findings'.
In a high-quality study, a
trend for increased
incidence of mesothelioma
of the peritoneum was
observed in male mice
following inhalation
exposure; no significant
increase was noted in
pairwise comparison, and no
increase was seen in female
mice.
Overall WOSEjudgement
for mesothelioma of the
peritoneum based on animal
evidence:
• Indeterminate
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Liidnmcli'ial s|i'om;il puisps
• A gavage study in female mice
conducted histopathological
examination of the uterus after 78
weeks of exposure (NTP, 1978).
Study quality: High
• Two inhalation studies in female rats
(Nagano et aL 2006; Cheeveret aL
1990) and one inhalation study in
female mice (Nagano et aL 2006)
conducted histopathological
examination of the uterus after 104
weeks of exposure. Study quality:
High
• A dermal exposure study in female
transgenic mice susceptible to cancer
conducted histopathological
examination of the uterus after 26
weeks of exposure (Sugiiro et aL.
2017). Study quality: High
Studv aualitv ranked as Uninformative:
• A gavage study in female rats q
examined the uterus for neoplasms
after 78 weeks of c\do sure (NTP.
1978).
Bioloeical eradient/dose-resnonse:
• A significant trend for increased
incidence of endometrial stromal
polyps or sarcomas was
observed in female mice in the
78-week gavage study using
pooled vehicle controls ' . and
the pairwise comparison showed
a significant increase at both
doses.
• A significant trend for increased
incidence of endometrial stromal
polyps was observed in female
mice following 104 weeks of
inhalation exposure.
Oualitv of the database:
• Evidence of endometrial stromal
polyps in mice was observed in
high-quality oral and inhalation
studies.
Bioloeical eradicnt/dosc-rcsDonsc:
• The incidence of endometrial
stromal polyps in female mice
was not significantly increased in
a 26-week dermal exposure study
in transgenic mice.
Maenitude and precision:
• Pairwise comparisons using
matched controls did not show a
significant increase in the
incidence of stromal polyps or
sarcomas, and the incidence of
sarcomas (alone) was not
significantly increased in female
mice in the 78-week gavage
study.
• Pairwise comparisons did not
show a significantly increased
incidence in stromal polyps in
female mice in the 104-week
inhalation study.
Bioloeical olausibilitv and human
relevance:
The relevance to humans of
endometrial stromal polyps in mice
is uncertain due to differences in
etiology and hormone sensitivity
(Davis, 2012)
Key findings'.
In high-quality oral and
inhalation studies, the
incidence of endometrial
stromal polyps was
increased in female mice.
The relevance of these
findings to humans is
uncertain due to differences
in etiology and hormone
sensitivity among rodents
and humans. In addition,
there is uncertainty within
the scientific community
whether endometrial stromal
polyps should be considered
benign tumors or
nonneoplastic lesions.
Overall WOSEjudgement
for uterine cancer effects
based on animal evidence:
• Indeterminate
( uvulaliiiA s\sicm cancer
• A gavage study in male and female
mice subjected animals to
comprehensive histological
examinations for neoplasms after 78
weeks of exposure (NTP, 1978).
Study quality: High
Bioloeical eradient/dose-resnonse:
• Significant pairwise increases in
the incidence of
hemangiosarcoma in the liver
were observed in male mice at
the two highest exposure
Bioloeical eradicnt/dosc-rcsDonsc:
• There was not a significant dose-
related trend for increased
hemangiosarcomas of the liver in
male mice following 104 weeks
of inhalation exposure.
Key findings'.
In medium- and high-quality
studies, the incidence of
circulatory system tumors
(e.g., hemangiosarcomas)
was increased in mice
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Judgement
• A gavage study in female transgenic
mice susceptible to cancer subjected
animals to histological examinations
after 40 weeks of c\do sure (Storer et
al. 1995s). Studv aualitv: Medium
• Two inhalation studies in male and
female rats (Nagano et al.. 2006;
Cheever et al. 1990) and one
inhalation study in male and female
mice (Nagano et al. 2006) subiected
animals to comprehensive histological
examinations for neoplasms after 104
weeks of exposure. Study quality:
High
• A dermal study in transgenic mice
susceptible to cancer subjected
animals to comprehensive histological
examinations for neoplasms after 26
weeks of exposure (Sugiiro et al.
2017). Study quality: High
Studv aualitv ranked as Uninformative:
• A gavage study in male and female
rats v subjected animals to
comprehensive histological
examinations for neoplasms after 78
weeks of exposure (NTP, 1978).
concentrations following 104
weeks of inhalation exposure.
• A significantly increased
incidence of malignant
lymphoma was observed in
female transgenic mice in a 40-
week gavage study.
• In a study ranked as
Uninformative due to high
mortality from pneumonia, there
was a significant trend for
increased hemangiosarcomas in
male and female rats in a
78-week gavage study using
pooled vehicle controls and the
pairwise comparison showed a
significant increase at both
doses.
Oualitv of the database:
• Increased incidences of
circulatory system cancers were
observed in medium- and high-
quality studies.
• The incidence of circulatory
system cancers was not increased
in mice in a 78-week gavage
study. There was a significant
trend for decreased malignant
lymphomas of the hematopoietic
system in females using matched
vehicle controls.
• No hemangiomas or
hemangiosarcomas were observed
in male or female transgenic mice
in a 26-week dermal study.
Magnitude and precision:
• In the 78-week gavage study
ranked Uninformative, the trends
for increased hemangiosarcomas
in male and female rats were not
significant using matched
controls.
following inhalation and
dermal exposure.
Overall WOSEjudgement
for circulatory system
cancer effects based on
animal evidence:
• Slight
• A gavage study in male transgenic
mice " susceptible to cancer examined
the incidence of malignant
lymphomas after 40 weeks of
exposure (Storer et al. 1995).
• An inhalation study in male and
female rats and mice v examined
animals for neoplasms at natural death
after 78 weeks of exposure (Maltoni
et al.. 1980).
(mMmiiilcMiiial iracl cancer
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Judgement
• A gavage study in male and female
mice examined the gastrointestinal
tract for neoplasms after 78 weeks of
exposure (NTP. 1978). Studv aualitv:
High
• Two inhalation studies in male and
female rats (Nagano et aL 2006;
Cheever et aL 1990) and one
inhalation study in male and female
mice (Nagano et aL. 2006) examined
the gastrointestinal tract for
neoplasms after 104 weeks of
exposure. Study quality: High
• A dermal exposure study in male and
female transgenic mice susceptible to
cancer examined the gastrointestinal
tract for neoplasms after 26 weeks of
exposure (Sugiiro et aL. 2017). Studv
quality: High
Studv aualitv ranked as Uninformative:
• A gavage study in male and female
rats v examined the gastrointestinal
tract for neoplasms after 78 weeks of
exposure (NTP. 1978).
• An inhalation study in male and
female rats and mice ¦' examined the
stomach and intestines for neoplasms
at natural death after 78 weeks of
exposure (Maltoni et al.. 1980).
• A dermal exposure study in female
mice z examined the stomach for
neoplasms after up to 85 weeks of
exposure (Van: n et aL. 1979).
Bioloeical eradient/dose-response:
Bioloeical eradient/dose-response:
Key findings'.
In high-quality and
Uninformative gavage
studies, increased incidences
of gastrointestinal tract
tumors were observed in
female mice and male rats.
The effect appears to be
route-specific because
several high-quality studies
did not identify
gastrointestinal tumors
following inhalation or
dermal exposure.
Overall WOSEjudgement
for gastrointestinal cancer
effects based on animal
evidence:
• Indeterminate
• A significant trend for increased
incidence of squamous-cell
carcinomas in the stomach was
observed in female mice in the
78-week gavage study using
pooled vehicle controls.
• In a study ranked as
Uninformative owing to high
mortality from pneumonia, a
significant trend for increased
incidence of squamous-cell
carcinomas in the stomach was
observed in male rats in the 78-
week gavage study using pooled
and matched vehicle controls " :
the pairwise comparisons
showed a significant increase at
the highest dose.
• The incidence of gastrointestinal
tumors (forestomach tumors) was
not increased in rats or mice
following 104 weeks of inhalation
exposure.
• The incidence of gastrointestinal
tumors was not increased in two
dermal studies, including a study
in transgenic male and female
mice treated for 26 weeks, and an
85-week study in female mice
ranked as Uninformative due to
the use of methods that did not
account for the volatility of 1,2-
dichloroethane.
Maenitude and precision:
• The trend for increased incidence
of squamous-cell carcinomas in
female mice in the 78-week
gavage study was not significant
using matched controls, and the
pairwise comparisons using
pooled and matched controls
were not significant.
Siibciilaiicous fibromas
• A gavage study in male and female
mice conducted comprehensive
histopathological examination after 78
Bioloeical eradient/dose-response
• A significant trend for increased
incidence subcutaneous fibroma
was observed in male and
Maenitude and precision:
• A significant dose-related trend
for increased incidence of
subcutaneous fibromas was not
Key findings:
In a high-quality study, an
increased incidence of
subcutaneous fibromas in
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Inferences across
Evidence Streams
and Overall WOSE
Judgement
weeks of exposure (NTP, 1978).
Study quality: High
• Two inhalation studies in male and
female rats (Nagano et aL 2006;
Cheever et aL 1990) and one
inhalation study in male and female
mice (Nagano et aL. 2006) conducted
comprehensive histopathological
examination after 104 weeks of
exposure. Study quality: High
• A dermal exposure study in male and
female transgenic mice susceptible to
cancer conducted comprehensive
histopathological examination after 26
weeks of exposure (Sugiiro et aL.
2017). Study quality: High
Studv aualitv ranked as Uninformative:
• A gavage study in male and female
ratsconducted comprehensive
histopathological examination after 78
weeks of exposure (NTP, 1978).
• An inhalation study in male and
female rats and mice hh conducted
comprehensive histopathological
examination at natural death after 78
weeks of exposure (Maltoni et aL.
80).
female rats following 104 weeks
of inhalation exposure; pairwise
comparisons showed a
significant increase at the high
dose in female rats only.
• In a study ranked as
Uninformative due to high
mortality from pneumonia, a
significant dose-related trend for
increased incidence of
subcutaneous fibromas was
observed in male rats in the 78-
week gavage study using pooled
vehicle controls dd; pairwise
comparisons showed significant
increases at both doses.
Oualitv of the database:
• Evidence of subcutaneous
fibroma was observed in a high-
quality study.
observed in male rats in the 78-
week gavage study using
matched vehicle controls.
Consistency:
• The incidence of subcutaneous
tumors was not increased in
transgenic mice following 26
weeks of dermal exposure.
male and female rats was
seen following inhalation
exposure.
Overall WOSEjudgement
for subcutaneous fibromas
based on animal evidence:
• Indeterminate
1 !\ idcucc mi mcdiaiiisiic sludics
(jenoloxicilA.
• Two recent authoritative reviews
(ATSDR. 2022; Gwinn et aL. 2011)
were the primary sources used to
provide an overview of the database
of genotoxicity studies available for
11,2 dichloroethane, including
numerous studies of gene mutation in
Salmonella typhimurium; gene
mutation in fruit flies; gene mutation,
( OllslsleilCN .
• In most of the available studies,
1,2 dichloroethane induced
mutations in S. typhimurium in
the presence of metabolic
activation. Many of these
studies also reported positive
results without metabolic
activation.
OualilN of llie database.
• Alternative modes of action were
investigated only for mammary
gland tumors and not for other
tumor types induced by 1,2-
dichloroethane.
Key findings:
1,2-dichloroethane has
induced mutations,
clastogenic effects, DNA
damage, and DNA
binding/adduct formation in
vitro and in vivo. The
preponderance of the
substantial database consists
of positive results. While
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and Overall WOSE
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micronucleus formation, DNA
damage, and DNA binding/adduct
formation in mammalian cells/tissue
isolates in vitro; and clastogenicity,
DNA damage, and DNA
binding/adduct formation in mammals
in vivo.
Other mechanisms:
• A 28-day inhalation exposure
experiment in female rats evaluated
cell proliferation in mammary tissue
and serum prolactin levels (Lebaron et
al. 202I).
• 1,2 dichloroethane induced gene
mutations in multiple studies of
fruit flies.
• 1,2 dichloroethane yielded
positive results in gene mutation
assays in Chinese hamster ovary
cells and human lymphoblastoid
cells in vitro.
• 1,2 dichloroethane produced
clastogenic effects including
micronuclei in human
lymphocytes in vitro and
micronuclei, chromosomal
aberrations, and sister chromatid
exchanges in rat and mouse
bone marrow in vivo.
• DNA damage was observed in
human lymphocytes and rat and
mouse hepatocytes exposed to
1,2 dichloroethane in vitro and
in multiple tissues from rats and
mice exposed in vivo.
• DNA binding/adduct formation
after 1,2 dichloroethane
exposure was observed in vitro
and in multiple tissues from rats
and mice in vivo.
Bioloeical plausibility and human
relevance:
• Several metabolites of
1,2-dichloroethane, particularly
those from the glutathione
conjugation pathway, have been
shown to bind DNA and induce
DNA damage in vivo, and to
induce mutations in S.
typhimurium in vitro.
Oualitv of the database:
these effects could plausibly
be related to formation of
tumors, a direct connection
between these events and
1,2 dichloroethane induced
carcinogenesis has not been
conclusively demonstrated.
Few mechanistic data
examining alternative modes
of carcinogenic action are
available.
Overall WOSEjudgement
for cancer effects based on
mechanistic evidence:
• Moderate
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and Overall WOSE
Judgement
The genotoxicity database
includes numerous in vitro and
in vivo studies evaluating a wide
variety of genotoxic endpoints
in multiple test systems.
" The study was ranked as Uninformative because SMRs were calculated based on expected deaths from a reference population matched on sex, but not age, and exposure
was assessed based on duration of work in the facility; no information was provided on levels of exposure to 1,2-dichlororethane.
b The study was ranked as Uninformative because SMRs were calculated based on expected deaths from a reference population matched on sex and exposure was
assessed based on duration of work in the facility; no information was provided on levels of exposure to 1,2-dichloroethane.
c Pooled controls from several bioassays were used based on data for the same strain, tested by the same laboratory no more than 6 months apart, and diagnosed by the
same pathologist.
d The study in male and female rats was considered Uninformative due to high mortality from pneumonia in all groups (including controls).
e Pending evaluation.
' Pooled controls from several bioassays were used based on data for the same strain, tested by the same laboratory no more than 6 months apart, and diagnosed by the
same pathologist
g The study in male and female rats was considered Uninformative due to high mortality from pneumonia in all groups (including controls).
h The study in male mice was considered Uninformative due to inadequate study duration (52-week cancer bioassay) and a high tumor response rate in the initiation-only
control group (tumor promotion assay).
1 This chronic inhalation study was ranked Uninformative due to lack of information on the inhalation exposure methodology.
' The study in female mice was considered Uninformative because methods used to conduct the study did not account for volatility of the test substance.
k The study in male and female rats was considered Uninformative due to high mortality from pneumonia in all groups (including controls).
' The study in male mice was considered Uninformative due to inadequate study duration (52-week cancer bioassay) or a high tumor response rate in the initiation-only
control group (tumor promotion assay).
This chronic inhalation study was ranked Uninformative due to lack of information on the inhalation exposure methodology.
" The study in female mice was considered Uninformative because methods used to conduct the study did not account for volatility of the test substance.
° The study in male and female rats was considered Uninformative due to high mortality from pneumonia in all groups (including controls).
p This chronic inhalation study was ranked Uninformative due to lack of information on the inhalation exposure methodology.
q The study in female rats was considered Uninformative due to high mortality from pneumonia in all groups (including controls).
' Pooled controls from several bioassays were used based on data for the same strain, tested by the same laboratory no more than 6 months apart, and diagnosed by the
same pathologist.
v The study in male and female rats was considered Uninformative due to high mortality from pneumonia in all groups (including controls).
' Pooled controls from several bioassays were used based on data for the same strain, tested by the same laboratory no more than 6 months apart, and diagnosed by the
same pathologist.
" The study in male transgenic mice was considered Uninformative because the duration of the study was potentially inadequate for tumor development and no tumors
were observed (the same study in female transgenic mice was considered Informative because tumors were observed).
v This chronic inhalation study was ranked Uninformative due to lack of information on the inhalation exposure methodology.
" Pooled controls from several bioassays were used based on data for the same strain, tested by the same laboratory no more than 6 months apart, and diagnosed by the
same pathologist.
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and Overall WOSE
Judgement
2959
v The study in male and female rats was considered Uninformative due to high mortality from pneumonia in all groups (including controls).
¦' Pending evaluation.
z The study in female mice was considered Uninformative due to the use of methods that did not account for the volatility of 1,2-dichloroethane.
"" The study in male and female rats was considered Uninformative due to high mortality from pneumonia in all groups (including controls).
bb This chronic inhalation study was ranked Uninformative due to lack of information on the inhalation exposure methodology.
cc Including experiments reviewed by Gwinn et at. (20.1.1). and/or ATSDR (2022) that were not flagged as inconsistent with OECD guidance on genotoxicity testing, as
well as the one study published subsequently (Lone et at. 20.1.6).
dd Pooled controls from several bioassays were used based on data for the same strain, tested by the same laboratory no more than 6 months apart, and diagnosed by the
same pathologist.
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Appendix D LIST OF SUPPLEMENTAL DOCUMENTS
Appendix D incudes a list and citations for all supplemental documents included in this Draft Human
Health Hazard Assessment for 1,2-Dichloroethane. See Docket EPA.-H.Q-OPI for all
publicly released files associated with peer review and public comments.
Associated Systematic Review Protocol and Data Quality Evaluation and Data Extraction
Documents - Provide additional detail and information on systematic review methodologies used as
well as the data quality evaluations and extractions criteria and results.
Draft Risk Evaluation for 1,1-Dichloroethane - Systematic Review Protocol ( 24b)
- In lieu of an update to the Draft Systematic Review Protocol Supporting TSCA Risk
Evaluations for Chemical Substances, also referred to as the "2021 Draft Systematic Review
Protocol" (Is S 1 'P \ 2021). this systematic review protocol for the Draft Risk Evaluation for
1,1-Dichloroethane describes some clarifications and different approaches that were
implemented than those described in the 2021 Draft Systematic Review Protocol in response to
(1) SACC comments, (2) public comments, or (3) to reflect chemical-specific risk evaluation
needs. This supplemental file may also be referred to as the "1,1-Dichloroethane Systematic
Review Protocol."
Draft Risk Evaluation for 1,1-Dichloroethane - Systematic Review Supplemental File: Data
Quality Evaluation Information for Human Health Hazard Epidemiology • ( ?24e) -
Provides a compilation of tables for the data quality evaluation information for 1,2-
dichloroethane. Each table shows the data point, set, or information element that was evaluated
from a data source that has information relevant for the evaluation of epidemiological
information. This supplemental file may also be referred to as the "1,1-Dichloroethane Data
Quality Evaluation Information for Human Health Hazard Epidemiology."
Draft Risk Evaluation for 1,1-Dichloroethane - Systematic Review Supplemental File: Data
Quality Evaluation Information for Human Health Hazard Animal Toxicology (U.S. EPA.
2024d) - Provides a compilation of tables for the data quality evaluation information for 1,2-
dichloroethane. Each table shows the data point, set, or information element that was evaluated
from a data source that has information relevant for the evaluation of human health hazard
animal toxicity information. This supplemental file may also be referred to as the "1,1 -
Dichloroethane Data Quality Evaluation Information for Human Health Hazard Animal
Toxicology."
Draft Risk Evaluation for 1,1-Dichloroethane - Systematic Review Supplemental File: Data
Extraction Information for Environmental Hazard and Human Health Hazard Animal
Toxicology and Epidemiology ( >24c) - Provides a compilation of tables for the data
extraction for 1,2-dichloroethane. Each table shows the data point, set, or information element
that was extracted from a data source that has information relevant for the evaluation of
environmental hazard and human health hazard animal toxicology and epidemiology
information. This supplemental file may also be referred to as the "1,1 -Dichloroethane Data
Extraction Information for Environmental Hazard and Human Health Hazard Animal Toxicology
and Epidemiology."
Associated Supplemental Information Documents - Provide additional details and information on
exposure, hazard, and risk assessments.
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3008 Draft Risk Evaluation for 1,1-Dichloroethane - Supplemental Information File: Benchmark
3009 Dose Modeling ( >024aV
3010
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Appendix E HUMAN HEALTH HAZARD VALUES USED BY EPA
OFFICES AND OTHER AGENCIES
Historically, offices across EPA and other agencies (ATSDR), have developed their own assessments
for 1,2-dichloroethane. A comparison of these assessments is outlined in TableApx E-l for non-cancer
based on exposure duration and route.
E.l Summary of Non-cancer Assessments of EPA Offices and Other
Agencies
EPA first reviewed existing assessments of 1,2-dichloroethane conducted by regulatory and authoritative
agencies such as ATSDR (2022). as well as several systematic reviews of studies of 1,2-dichloroethane
published by U.S. EPA Integrated Risk Information System (IRIS) program( 7b) and U.S.
EPA Provisional Peer-Reviewed Toxicity Values (U.S. EPA. 2010).
Upon evaluation of the AT 1022) Toxicological Profile for 1,2-Dichloroethane and U.S. EPA
Provisional Peer-Reviewed Toxicity Values for 1,2-Dichloroethane (U.S. EPA. 2010). the studies
identified for minimal risk level (MRL) and provisional values, respectively, by these assessments were
evaluated by the Draft Systematic Review Protocol Supporting TSCA Risk Evaluations for Chemical
Substances (U.S. EPA. 2021). While there are many areas of agreement with these assessments, both the
ATSDR (2022) and 0 v <1 P \ . ' i ') assessments used studies that were identified as "Uninformative"
based on systematic review for the subchronic duration scenarios.
More specifically for both ATSDR (2022) and (I v << \ -V10). the 13-week study by (NTP. 1991) in
male and female F344/N, Sprague Dawley, and Osborne-Mendel rats as well as B6C3F1 mice exposed
to 1,2-dichloroethane in drinking water was used. A significant dose-related increase in kidney weight
and the kidney-body-ratio of female F344 rats was identified at 58 mg/kg/day among the three rat
strains. This study was considered as a potential candidate for POD derivation, however, the daily intake
doses were estimated on a mg/kg body weight basis and not measured throughout the duration of
exposure. The means by which the dosage estimates were calculated was by dividing the mean water
consumption over the 13-week study by the initial and final body weights of ten animals. Additionally,
weight gain depression was seen in males and females in the two higher dose groups throughout the
study and was likely caused by dehydration due to poor palatability of the formulated drinking water.
The study also indicated that water consumption was substantially decreased with increasing dose.
According to the study, a decrease of as much as 60 percent in water intake was also seen in both male
and female Osborne-Mendel rats at the highest concentration of 8000 ppm (a range of 500 -725
mg/kg/day) that indicates that the dose received by all exposed animals was less than the target dose.
The authors indicate that as water intake was reduced at most exposure levels, equivalent exposure did
not, however, occur at different dose levels within a strain. Due to the uncertainty regarding the
delivered dose and the inherit volatility associated with 1,2-dichloroethane, it was not recommended
using this drinking water study for this dose-response assessment.
(NTP. 1991). however, also included a 13-week gavage study that was rated high by systematic review
and considered for a POD for subchronic exposures based on kidney weight (30 mg/kg/day LOAEL
males; 75 mg/kg/day LOAEL females), however, the study had a higher POD via oral gavage, and was
not ultimately selected as the use of the most sensitive endpoint, immunosuppression, from Munson et
al. (1982) (LOAEL 4.9 mg/kg-day), was considered instead. In support, the 1,2-dichloroethane ATSDR
(2022) authoritative document also concluded that "the immune system was the most sensitive target for
short-term exposure to 1,2-dichloroethane by both the inhalation and oral routes in mice."
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With regard to identification of a subchronic provisional reference concentration (p-RfC) in (
2010) for 1 ,-2-dichloroethane, the occupational (Kozik. 1957) study used identified in this assessment
was rated "Uninformative" by systematic review based on a number of limitations (poor data and test
method reporting, lack of description of the analytical methodology, limited quantitative data and
statistical analyses, unstated criteria for diagnosis of disease, limited number of study participants and no
matched control group, lack of control for potential confounding, lack of exposure duration
information). Furthermore, (Kozik. 1957) did not report any data that could be used for BMD modeling.
Additionally, PPRTV also commented on the confidence of the study as well as confidence in the
calculated p-RfC as being very low. This study was also used for the chronic p-RfC irrespective of this
low confidence with additional uncertainty factor of 10 for the duration adjustment.
Therefore, studies only studies that received a rating of high and medium by systematic review were
considered for POD as outlined in Section 6.1 with study evaluation and selection rationale.
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3071 Table Apx E-l. Non-cancer Human Health Hazard Values based on Exposure Duration and Route for 1,2-Dichloroethane
Exposu rc
Solvent
Oral
Inhalation
Dermal
Comments
Acute
1,2-
Dichloroethane
POD BMDLio
= 153 mg/kg based on
increased kidney weight via
savase (Storer et al. 1984).
UF = 30
POD BMCio= 48.9 mg/m3
or 12.1 ppm based on
olfactory necrosis (Dow
Chemical 2006b).
UF = 30
POD BMDLio
= 153 mg/kg based on
increased kidney weight
((Storeret al. 1984).
UF = 30
Subchronic
1,2-
Dichloroethane
POD = I.OAF.1,,1, = 4.89
mg/kg based on
immunosuppression in a 14-
dav savase studv (Munson et
al.. 1982).
UF = 100
pod = bmcl5=
21.2 mg/m3 based on
decreases in sperm
concentration (Zhang et al.
2017).
UF = 30
POD = LOAELadj = 4.89
mg/kg based on
immunosuppression in a
14-day gavage study
(Munson et al.. 1982).
UF = 100
(ATSDR. 2022) identified
immunosuppression as the most sensitive
endpoint - however, ATSDR characterized
the Munson et al. (1982) studv as an acute
study and therefore it was excluded from
derivation of MRLs for subchronic and
chronic exposures.
Chronic
1,2-
Dichloroethane
POD = I.OAF.1,,1, = 4.89
mg/kg based on
immunosuppression in a 14-
day gavage
studv (Munson et al.. 1982).
UF = 1,000 "
pod = bmcl5=
21.2 mg/m3 based on
decreases in sperm
concentration (Zhang et al..
2017).
UF = 300
POD = LOAELadj = 4.89
mg/kg based on
immunosuppression in a
14-day gavage study
(Munson et al.. 1982).
UF = 1,000
A standard default of a UFS of 10 was added
for use of subchronic data for chronic
duration.
(ATSDR. 2022) identified
immunosuppression as the most sensitive
endpoint - however, ATSDR characterized
the Munson et al. (1982) studv as an acute
study and therefore it was excluded from
derivation of MRLs for subchronic and
chronic exposures.
IklSi i
Acute
1,2-
Dichloroethane
Not assessed under IRIS
Not assessed under IRIS
Not assessed under IRIS
Subchronic
1,2-
Dichloroethane
Not assessed under IRIS
Not assessed under IRIS
Not assessed under IRIS
Chronic
1,2-
Dichloroethane
Not assessed under IRIS
Not assessed under IRIS
Not assessed under IRIS
IWI'Vi )
Acute
1,2-
Dichloroethane
Did not derive a provisional
value
Did not derive a provisional
value
Did not derive a
provisional value
Database considered inadequate
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Exposu rc
Solvent
Oral
Inhalation
Dermal
Comments
Subchronic
1,2-
Dichloroethane
1,2-Dichloroethane animal
data was used. Database is
lacking human data by the
oral route.
RfD = 0.02 mg/kg-day based
on increased kidney weights
(NTP. 1991): (Morgan et al.
1990), 90-day drinking water
(DW)
UF = 3000
In context, the OPPT MRL is
0.049 mg/kg/day based on
the Munson et al. (1982)
immunotoxicity POD of 4.89
mg/kg/day and a total UF of
100.
1,2-Dichlorothane animal
data was not used - human
data was selected as the only
feasible study for
subchronic durations.
RfC = 0.07 mg/m3based on
neurobehavioral impairment
(Kozik. 1957)
UF = 300
In context, based on
decreased sperm count in
the Zhang et al. (2017) studv
with the UF of 30, the OPPT
RfC = 0.71 mg/m3.
Did not derive a
provisional value
For the oral route:
PPRTV used a UFD of 3 to account for
database inadequacies. OPPT/ECRAD did not
use the (NTP. 1991)/(Morgan et al. 1990)
DW study as it rated "Uninformative" in our
SR due to a reported 59% decrease in dose at
the end of each day, as well as noted
dehydration due to decreased water
consumption. Kidney effects could be due to
dehydration and not direct result of chemical
exposure. PPRTV made no mention of the
limitations of the DW study.
PPRTV makes no mention of the gavage
portion of the (NTP, 1991)/ (Morgan et al,
1990).
Note: OPPT/ECRAD h
PPRTV commentedc
For the inhalation route:
OPPT/ECRAD did not use the (Kozik. 1957)
study because it rated as "Uninformative" in
our SR based on a number of limitations
(poor data and test method reporting, lack of
description of the analytical methodology,
limited quantitative data and statistical
analyses, unstated criteria for diagnosis of
disease, limited number of study participants
and no matched control group, lack of control
for potential confounding, lack of exposure
duration information). (Kozik, 1957) did not
report any data that could be used for BMD
modeling.
PPRTV commented d
Chronic
1,2-
Dichloroethane
Did not derive a provisional
value.
RfC = 0.007 mg/m3based
on neurobehavioral
impairment (Kozik, 1957)
UF = 3,000
Did not derive a
provisional value.
For the RfD:
PPRTV commented
For the RfC:
Same study and conclusions as for the
subchronic duration only added an additional
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Exposu rc
Solvent
Oral
Inhalation
Dermal
Comments
In context, based on
decreased sperm count in
the Zhang et al. (2017) studv
with the UF of 300, the
OPPT RfC = 0.071 mg/m3
UF of 10 for use of subchronic study for
chronic duration to yield a total UF = 3,000.
YISDki )
Acute
1,2-
Dichloroethane
Did not derive an MRL
0.3 ppm based on
Degeneration, with necrosis,
olfactory epithelium in rats
(Dow.QiejiiiciiL
2006b):(Hotchkiss et al..
2010)
BMCLio = 57
(BMCLhec = 9.2)
UF = 30
In context, OPPT
determined an MRL of 0.3
ppm
Did not derive an MRL
AT SDR did not use the Munson et al. (1982)
gavage study because of a difference in
classification of acute and subchronic
between ATSDR and EPA. ATSDR classifies
a 14-day study as "acute," and therefore it
was not used by them for subchronic or
chronic POD derivation.
Subchronic
1,2-
Dichloroethane
0.2 mg/kg/day based on
kidnev weight in rats (NTP,
1991V (Morgan et al. 1990).
90-day drinking water (DW)
LOAEL = 58
UF = 300
In context, the OPPT MRL is
0.049 mg/kg/day based on
the Munson immunotoxicity
POD of 4.89 mg/kg/day and
a total UF of 100
Did not derive an MRL
Did not derive an MRL
OPPT/ECRAD did not use the drinking water
portion of either the Munson et al. (1982) or
(NTP. 1991)/(Morean et al. 1990) studies for
identification of a POD. The (NTP,
1991)/(Morean et al. 1990) studv identified
kidney weight as a POD via DW (58 mg/kg).
The DW portion of the study rated
"Uninformative" in our SR. The rationale for
that rating is based on up to a 59% loss of
concentration at the end of each day, with a
60% decrease in water consumption which
lead to dehydration and therefore the kidney
effects could likely be artifacts of
dehydration.
Chronic
1,2-
Dichloroethane
Did not derive an MRL
Did not derive an MRL
Did not derive an MRL
According to ATSDR, data were insufficient
to derive an acute-duration provisional oral
MRL due to uncertainty about the validity of
results at the lowest effect level based on
differences in effect between gavage doses
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Exposu rc
Solvent
Oral
Inhalation
Dermal
Comments
and drinking water doses. Data were
insufficient for the derivation of a chronic-
duration provisional oral MRL as the most
sensitive endpoint was represented by a
serious effect (such as death). ATSDR
concluded that the inhalation database was
inadequate for derivation of intermediate- and
chronic-duration inhalation MRLs.
" Per EPA RfC/RfD Guidance Document (U.S. EPA, 2002), UF's of up to 3,000 are acceptable. In the case of the RfC, the maximum UF would be 3,000, whereas the
maximum would be 10,000 for the RfD.
b OPPT/ECRAD used the savage portion of the Munson et al. (1982) studv to derive an oral POD for subchronic duration, as opposed to the gavase portion of the (NTP.
1991V (Morgan et al. 1990) studv. as it represented a more biologically relevant and sensitive POD. PPRTVbrieflv mentions the Munson et al. (1982) studv.
c PPRTV commented confidence in the studv (NTP. 1991V (Morgan et al. 1990) is medium (a UFD of 3 was used in their total UF calculation), and overall confidence
in the calculation of the provisional RfD is medium.
d PPRTV commented confidence in the studv (Kozik. 1957) is very low (and a UFD of 3 was used in their total UF calculation), and overall confidence in the
calculation of the provisional RfC is low.
' PPRTV commented "In the absence of suitable chronic data, the POD from the subchronic (NTP, 1991) p-RfD could be used to derive the chronic p-RfD; however,
the composite UF would include the additional UFs of 10 for applying data from a subchronic study to assess potential effects from chronic exposure. This would result
in the large composite UF of greater than 3,000, thereby relegating this derivation of the chronic p-RfD to an appendix screening value."
3072
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3073 E.2 Summary of Cancer Assessments of EPA Offices and Other Agencies
3074 Historically, offices across EPA and other agencies (OW, OLEM, CalEPA), have developed their own
3075 cancer assessments for 1,2-dichloroethane. The IRIS assessment of carcinogenic potential of 1,2-
3076 dichloroethane was considered to be 'supportive' of 1,2-dichloroethane carcinogenic potential. A
3077 comparison of the cancer slope factors across other program offices for 1,2-dichloroethane can be seen
3078 in Table_Apx E-2.
3079
3080 TableApx E-2.1,2-Dichloroethane Cancer Slope Factors and Inhalation Unit Risk of EPA Offices
3081 and Other Agencies
EPA Program
Oral Slope Factor
Inhalation Unit Risk
OPPTRE
Continuous Exposure
• 0.062 per mg/kg/day
• Mouse (NTP. 1978)
• Hepatocellular carcinoma data
• High OPPT SR rating
• 7.1E-06 per ng/m3
• Rat inhalation (Nagano et aL 2006)
• Combined tumors in females
• High OPPT SR rating
IRIS 1987
Assessment
U.S.I 11 a)
• 0.091 per mg/kg/day
• Rat hemangiosarcoma data (using a time to
death analysis) (NTP. 1978)
• Rat study rated Uninformative OPPT SR
• 2.6E-5 per |ig/m3
• Rat oral hemangiosarcoma data (using a
time to death analvsis) (NTP. 1978)
• Rat study rated Uninformative OPPT SR
OW
• 0.091 oer me/ke/dav based on (U.S. EPA.
1987a)
• Rat hemangiosarcoma data (using a time to
death analysis) (NTP. 1978)
• Rat study rated Uninformative OPPT SR
• Not reported
OAR
• Not reported
• 2.6E-5 per ue/m3 based on (U.S. EPA.
1987a)
• Rat oral hemangiosarcoma data (using a
time to death analvsis) (NTP. 1978)
• Rat study rated Uninformative OPPT SR
OLEM
• 0.091 oer me/ke/dav based on (U.S. EPA.
1987a)
• Rat oral hemangiosarcoma data (using a time
to death analvsis) (NTP. 1978)
• Rat study rated Uninformative OPPT SR
• 2.6E-5 per ue/m3 based on (U.S. EPA.
1987a)
• Rat oral hemangiosarcoma data (using a
time to death analvsis) (NTP. 1978)
• Rat study rated Uninformative OPPT SR
Cal EPA
• 0.072 per mg/kg/day
• Rat oral hemangiosarcoma data (using a
Weibull model) (NTP. 1978)
• Rat study rated Uninformative OPPT SR
• 2.1E-05 per |ig/m3
• Derived from oral rat data
• Rat study rated Uninformative OPPT SR
3082
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Appendix F BENCHMARK DOSE ANALYSIS
As described in the Draft Risk Evaluation for 1,1-Dichloroethane - Supplemental Information File:
Benchmark Dose Modeling ( 024a). all studies that were identified and considered as
candidate non-cancer PODs are indicated for each exposure duration and route. Those specific to 1,2-
dichloroethane can be found in Section 2.1 of )24a). Appendix F provides a summary of
those studies that were identified as the non-cancer PODs for 1,2-dichloroethane and used for
HED/HEC calculations. Section 2.2 in 324a) provides all studies that were identified and
considered for cancer dose-response.
F.l Non-cancer PODs for Acute Exposures for 1,2-Dichloroethane
Oral
The acute-duration oral POD for 1,2-dichloroethane was based on increased relative kidney weight in
male mice given a single gavage dose of 1,2-dichloroethane (Storer et ai. 1984). For this study, a
NOAEL of 200 mg/kg-bw/day and a LOAEL of 300 mg/kg-bw/day were identified for kidney weight
effects. To obtain a POD, BMD modeling was conducted on the relative kidney weight data using U.S
EPA's Benchmark Dose Software (BMDS; v. 3.3). TableApx F-l shows the relative kidney weights
corresponding to each dose. BMD modeling was conducted using a benchmark response (BMR) of 10
percent relative deviation from the control mean ( )).
Table Apx F-l. Relative Kidney Weights in Male Mice Exposed to 1,2-Dichloroethane
Once by Gavage
Dose
(mg/kg-day)
Number of Mice
Mean
(g/100 g body weight)
Standard Deviation
0
5
1.50
0.09
200
5
1.58
0.19
300
5
1.69
0.09
400
3
1.75
0.08
500
r
1.82
N/A
600
r
1.61
N/A
Source: Storer et V)
a 4/5 mice died in this group.
Following (U .S. EPA. 2012b) guidance, the polynomial 2-degree model with constant variance was
selected for these data. The BMDio% and BMDLio values for this model were 270 and 153 mg/kg-
bw/day, respectively. The BMDLio of 153 mg/kg-bw/day was selected as the POD.
The BMDLio of 153 mg/kg-bw/day was converted to a HED of 19.9 mg/kg-bw/day using the DAF of
0.13 for mice (see Appendix A. 1.3) and EquationApx F-l, as shown below:
EquationApx F-l.
HED = 153 mg/kg x 0.13 = 19.9 mg/kg
The HED of 19.9 mg/kg-bw/day does not need to be adjusted for occupational exposure. The benchmark
MOE for this POD is 30 (3 for interspecies extrapolation when a dosimetric adjustment is used and 10
for human variability).
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Inhalation
The acute-duration inhalation POD for 1,2-dichloroethane was based on nasal lesions in rats exposed
once by inhalation for 8 hours (Dow Chemical. 2006b). For this study, a NOAEL of 71.3 mg/m3 and
LOAEL of 145 mg/m3 were identified for increased incidences of degeneration with necrosis in the
olfactory mucosa of the nasal passages in male and female rats. To obtain a POD, BMD modeling was
conducted using EPA's BMDS (v. 3.3.2) on the incidence of these nasal lesions in male and female rats
(combined). The male and female data were combined for modeling because incidences were similar in
both sexes and the combined data set provided increased statistical power relative to the sex-specific
data sets. Prior to modeling, the exposure concentrations in the (Dow Chemical. 2006b) rat 8-hour study
were adjusted from the exposure scenario of the original study to continuous (24 hours/day) exposure
using EquationApx A-4. TableApx F-2 shows the nasal lesion incidences corresponding to each
exposure concentration. BMD modeling was conducted on the incidences using the continuous
equivalent concentrations and the default BMR for quantal data of 10 percent extra risk (
2012b).
Table Apx F-2. Incidence of Nasal Lesions in Male and Female Rats (Combined) Exposed to 1,2-
Dichloroethane for 8 Hours
Unadjusted Exposure
Concentration
(mg/m3)
Adjusted (Continuous) Exposure
Concentration
(mg/m3)
Incidence of Degeneration with
Necrosis of the Olfactory Mucosa
0
0
0/10
214
71.3
0/10
435.1
145.0
4/10
630.6
210.2
9/10
Source: Dow Chemical (2006b)
Following 012b) guidance, the multistage 3-degree model was selected for these data. The
BMCio and BMCLio for this model were 81.4 and 48.9 mg/m3, respectively. The BMCLio of 48.9
mg/m3 was selected as the POD.
guidance was used to convert the BMCLio of 48.9 mg/m3 to a HEC. For nasal lesions,
the RGDRet in rats is used. The RGDRet of 0.2 was calculated using Equation Apx A-8 (
1994).
The BMCLio (48.9 mg/m3) was multiplied by the RGDRet (0.2) to calculate the HEC, as shown in the
Equation Apx A-9.
The resulting HEC is 9.78 mg/m3 for continuous exposure. The continuous HEC of 9.78 mg/m3 is
converted to an equivalent worker HEC using Equation Apx A-12. The resulting POD for workers is
41.1 mg/m3. The benchmark MOE for this POD is 30 (3 for interspecies extrapolation when a dosimetric
adjustment is used and 10 for human variability).
EPA presents all inhalation PODs in equivalents of both mg/m3 and ppm to avoid confusion and errors.
Equation Apx A-2 was used with the molecular weight of 1,2-dichloroethane (98.96 mg/mmol) to
convert the continuous and worker PODs (9.78 and 41.1 mg/m3, respectively) to 2.42 and 10.2 ppm,
respectively.
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Dermal
No PODs were identified from acute studies of dermal exposure to 1,2-dichloroethane. Therefore, the
acute oral HED of 19.9 mg/kg-bw/day with benchmark MOE of 30 was used for risk assessment of
acute dermal exposure for both continuous and worker exposure scenarios. As noted in Section M.3.1.4,
when extrapolating from oral data that incorporated BW3 4 scaling to obtain the oral HED, EPA uses the
same HED for the dermal route of exposure. The same uncertainty factors are used in the benchmark
MOE for both oral and dermal scenarios.
F.2 Non-cancer PODs for Short/Intermediate-Term Exposures for 1,2-
Dichloroethane
Oral
The short-term/subchronic-duration oral POD for 1,2-dichloroethane was based on decreased immune
response in mice exposed to 1,2-dichloroethane by gavage for 14 days (Munson et ai. 1982). In this
study, a dose-related significant decrease in the number of antibody-forming cells per spleen
(AFC/spleen) was observed at all doses; the LOAEL was 4.89 mg/kg-bw/day. Using EPA's BMDS (v.
3.3), BMD modeling was conducted on the AFC/spleen data. The mice in the study by Munson et al.
(1982) were exposed 7 days/week, so no adjustment for continuous exposure was needed. TableApx
F-3 shows the AFC/spleen corresponding to each dose.
Table Apx F-3. Antibody-forming Cells per Spleen in Male Mice Exposed to 1,2-Dichloroethane
by Daily Gavage for 14 Days
Dose
(mg/kg-bw/day)
Number of Mice
Mean Number AFC/Spleen (xlO')
Standard Error
0
12
3.00
0.3
4.89
10
2.20
0.2
48.9
10
1.80
0.1
Source: Munson et al. (1982)
None of the models provided adequate fits to the means either assuming constant or non-constant
variance. Therefore, the LOAEL (lowest dose tested) was used as the POD.
The LOAEL of 4.89 mg/kg-bw/day was converted to a HED of 0.636 mg/kg-bw/day using the DAF of
0.13 for mice (see Section A. 1.3) and EquationApx A-5.
The continuous HED of 0.636 mg/kg-bw/day was converted to a worker HED of 0.890 mg/kg-bw/day
using Equation Apx A-l 1. The benchmark MOE for this POD is 100 based on a combination of
uncertainty factors: 3 for interspecies extrapolation when a dosimetric adjustment is used, 10 for human
variability, and 3 for use of a LOAEL to extrapolate a NOAEL (based on the dose-response) for short-
term and subchronic exposures.
Inhalation
The short-term/subchronic-duration inhalation POD for 1,2-dichloroethane was based on decreased
sperm concentration in mice exposed to 1,2-dichloroethane by inhalation for 4 weeks (Zhang et al..
2017). In this study, a concentration-related decrease in sperm concentration was observed, reaching
statistical significance (relative to controls) at 707.01 mg/m3. Using EPA's BMDS (v. 3.3.2), BMD
modeling was conducted on the sperm concentrations using mouse exposure concentrations. The mice in
the study by Zhang et a were exposed for 6 hours/day, 7 days/week. Prior to BMD modeling,
the exposure concentrations in the Zhang et al. C study were adjusted from the exposure scenario of
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the original study to equivalent continuous (24 hours/day) exposure concentrations using EquationApx
A-4. Table Apx F-4 shows the sperm concentrations corresponding to each exposure concentration.
BMD modeling was conducted on these data using a BMR of 5 percent relative deviation from controls.
Table Apx F-4. Sperm (
Concentration in Male Mice Exposed to 1,2-
Jichloroethane for 4 Weeks
Unadjusted Exposure
Concentration
(mg/m3)
Adjusted (Continuous)
Exposure Concentration
(mg/m3)
Number of
Animals
Mean Sperm
Concentration
(M/g)
SD
(M/g)
0.30
0.075
10
4.65
0.52
102.70
25.675
10
4.36
0.40
356.04
89.010
10
3.89
0.47
707.01
176.75
10
3.30
0.57
Source: Zhang et al. ('.
Following 012b) guidance, the exponential 3 model with constant variance was selected for
these data. The BMC 5 and BMCLs for this model were 26.735 and 21.240 mg/m3, respectively. The
BMCLs of 21.240 mg/m3 was selected as the POD.
guidance was used to convert animal inhalation PODs to HECs. For systemic
(extrarespiratory) effects, the HEC is calculated by multiplying the animal POD by the ratio of the
blood/gas partition coefficients in animals and humans, as shown in Equation Apx A-7.
A human blood/air partition coefficient of 19.5 ± 0.7 has been reported for 1,2-dichloroethane (Gareas et
ai. 1989). No blood/air partition coefficient for mice was identified in the literature reviewed. In the
absence of a blood/air partition coefficient for mice, the default ratio of 1 is used in the calculation, in
accordance with guidance. Therefore, the POD of 21.240 mg/m3 is multiplied by 1 to
give the HEC.
The resulting POD is 21.240 mg/m3 for continuous exposure. The continuous POD of 21.240 mg/m3 is
converted to an equivalent worker POD using Equation Apx A-13. The resulting POD for workers is
89.208 mg/m3. The benchmark MOE for this POD is 30 based on a combination of uncertainty factors: 3
for interspecies extrapolation when a dosimetric adjustment is used and 10 for human variability for
short-term and subchronic exposures.
Dermal
No PODs were identified from short-term or subchronic studies of dermal exposure to 1,2-
dichloroethane. Therefore, the short-term/subchronic oral HED of 0.636 mg/kg-bw/day and worker
HED of 0.890 mg/kg-bw/day with benchmark MOE of 100 were used for risk assessment of
short/intermediate-term dermal exposure. As noted in Appendix M.3.1.4, when extrapolating from oral
data that incorporated BW314 scaling to obtain the oral HED, EPA uses the same HED for the dermal
route of exposure. The same uncertainty factors are used in the benchmark MOE for both oral and
dermal scenarios.
F.3 Non-cancer PODs for Chronic Exposures for 1,2-Dichloroethane
Oral
No studies of chronic oral exposure in laboratory animals were considered suitable for POD
determination (see Table 6-7). Therefore, the short-term/subchronic POD was also used for chronic
exposure. The short-term/subchronic continuous HED was 0.636 mg/kg-bw/day and the worker HED
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was 0.890 mg/kg-bw/day (see Appendix F.2). The benchmark MOE for this POD is 1,000 based on 3
for interspecies extrapolation when a dosimetric adjustment is used, 10 for human variability, 3 for the
use of a LOAEL to extrapolate a NOAEL (based on the dose-response), and 10 for extrapolating from a
subchronic study duration to a chronic study duration for chronic exposures.
Inhalation
Only one study of chronic inhalation exposure in laboratory animals (IRFMN. 1978) was considered
suitable for POD determination (see Table 6-10). However, the 12-month study by IRFM'N (1978)
evaluated limited endpoints (serum chemistry changes only) and identified a higher LOAEL than the
study of sperm parameters by Zhang et al. (2017) that was used as the basis for the short-
term/sub chronic POD. Therefore, the POD from Zhang et al. (1 was also used for chronic exposure.
The resulting POD is 21.240 mg/m3 for continuous exposure. The continuous POD of 21.240 mg/m3 is
converted to an equivalent worker POD using Equation Apx A-12. Equation Apx A-2 was used with
the molecular weight of 1,2-dichloroethane (98.96 mg/mmol) to convert the continuous and worker
short-term/subchronic/chronic PODs (21.240 and 89.208 mg/m3, respectively) to 5.2478 and 22.041
ppm, respectively. The resulting POD for workers is 89.208 mg/m3 (see Table Apx A-l). The
benchmark MOE for this POD is 300 based on 3 for interspecies extrapolation when a dosimetric
adjustment is used, 10 for human variability, and 10 for extrapolation from a 4-week study to chronic
exposure duration for chronic exposures.
Dermal
No PODs were identified from chronic-duration studies of dermal exposure to 1,2-dichloroethane.
Therefore, the oral HEDs of 0.636 mg/kg-bw/day (continuous) and 0.890 mg/kg-bw/day (for workers)
with benchmark MOE of 1,000 were used for risk assessment of chronic-duration dermal exposure. As
noted in Section A. 1.3, when extrapolating from oral data that incorporated BW3/4 scaling to obtain the
oral FLED, EPA uses the same FLED for the dermal route of exposure. The same uncertainty factors are
used in the benchmark MOE for both oral and dermal scenarios.
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