PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
EPA Document# EPA-740-R1-8014
January 2020, DRAFT
Office of Chemical Safety and
Pollution Prevention
vvEPA
United States
Environmental Protection Agency
Draft Risk Evaluation for
Carbon Tetrachloride
(Methane, Tetrachloro-)
CASRN: 56-23-5
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January 2020 DRAFT
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TABLE OF CONTENTS
ACKNOWLEDGEMENTS 10
ABBREVIATIONS 11
EXECUTIVE SUMMARY 15
1 INTRODUCTION 23
1.1 Physical and Chemical Properties 25
1.2 Uses and Production Volume 26
1.3 Regulatory and Assessment History 26
1.3.1 Regulatory History 26
1.4 Scope of the Evaluation 28
1.4.1 Conditions of Use Included in the Risk Evaluation 28
1.4.2 Subcategories Determined Not To Be Conditions of Use 28
1.4.2.1 Specialty Uses - Aerospace Industry 28
1.4.2.2 Manufacturing of Pharmaceuticals 29
1.4.2.3 Exclusions During Problem Formulation 29
1.4.3 Conceptual Models 35
1.5 Systematic Review 38
1.5.1 Data and Information Collection 38
1.5.2 Data Evaluation 44
1.5.3 Data Integration 44
2 EXPOSURES 44
2.1 Fate and Transport 45
2.1.1 Fate and Transport Approach and Methodology 45
2.1.2 Fate and Transport 45
2.2 Environmental Releases 49
2.3 Environmental Exposures 50
2.3.1 Environmental Exposures - Aquatic Pathway 50
2.3.1.1 Methodology for Modeling Surface water Concentrations from Facilities releases (E-
FAST 2014) 51
2.3.2 Terrestrial Environmental Exposure 51
2.4 Human Exposures 52
2.4.1 Occupational Exposures 52
2.4.1.1.1 Process Description 54
2.4.1.1.2 Number of Workers and ONUs 55
2.4.1.2 General Inhalation Exposure Assessment Approach and Methodology 56
2.4.1.3 General Dermal Exposure Assessment Approach and Methodology 59
2.4.1.4 Consideration of Engineering Controls and Personal Protective 61
Equipment 61
2.4.1.5 Regrouping of Conditions of Use for Engineering Assessment 64
2.4.1.6 Inhalation Exposure Assessment 68
2.4.1.6.1 Domestic Manufacturing 68
2.4.1.6.2 Import and Repackaging 70
2.4.1.6.3 Processing as a Reactant or Intermediate 73
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43 2.4.1.6.4 Specialty Uses - Department of Defense Data 75
44 2.4.1.6.5 Reactive Ion Etching 78
45 2.4.1.6.6 Industrial Processing Agent/Aid 79
46 2.4.1.6.7 Additive 81
47 2.4.1.6.8 Laboratory Chemicals 82
48 2.4.1.6.9 Disposal/Recycling 84
49 2.4.1.6.10 Summary of Occupational Inhalation Exposure Assessment 87
50 2.4.1.7 Dermal Exposure Assessment 92
51 2.4,2 Consumer Exposures 94
52 2.4.3 General Population Exposures 94
53 2.5 Other Exposure Considerations 95
54 2.5.1 Potentially Exposed or Susceptible Subpopulations 95
55 2.5.2 Aggregate and Sentinel Exposures 95
56 3 HAZARDS 95
57 3.1 Environmental Hazards 95
58 3.1.1 Approach and Methodology 96
59 3.1.2 Hazard Identification-Toxicity to Aquatic Organisms 97
60 3.2 Human Health Hazards 97
61 3.2.1 Approach and Methodology 97
62 3.2.2 Toxicokinetics 100
63 3.2.3 Hazard Identification 100
64 3.2.3.1 Non-Cancer Hazards 100
65 3.2.3.2 Epidemiological Data on Non-Cancer Toxicity 114
66 3.2.3.3 Genotoxicity and Cancer Hazards 115
67 3.2.3.3.1 Genotoxicity 115
68 3.2.3.3.2 Carcinogenicity 116
69 3.2.4 Weight of Scientific Evidence 120
70 3.2.4.1 Non-Cancer Hazards 120
71 3.2.4.1.1 Acute Toxicity 121
72 3.2.4.1.2 Chronic Toxicity 121
73 3.2.4,2 Genotoxicity and Cancer 122
74 3.2.4.3 MOA for Carcinogenicity 123
75 3.2.4.3.1 Mode of Action for Liver Tumors 123
76 3.2.4.3.2 Mode of Action for Pheochromocytomas (Adrenal Tumors) 127
77 3.2.5 Dose-Response Assessment 127
78 3.2.5.1 Selection of Studies for Dose-Response Assessment 127
79 3.2.5.1.1 Toxicity After Acute Inhalation Exposures in Humans 127
80 3.2.5.1.2 Toxicity from Chronic Inhalation Exposures 128
81 3.2.5.1.3 Toxicity from Dermal Exposures 129
82 3.2.5.2 Derivation of PODs and UF for Benchmark Margins of Exposure (MOEs) 130
83 3.2.5.2.1 PODs for Acute Inhalation Exposure 130
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84 3.2.5.2.2 PODs for Chronic Inhalation Exposure 130
85 3.2.5.2.3 PODs for Acute Dermal Exposures 132
86 3.2.5.2.4 PODs for Chronic Dermal Exposures 133
87 3.2.5.2.5 C ancer Inhal ati on Unit Ri sk and Dermal SI ope F actor 134
88 3.2.5.3 PODs for Human Health Hazard Endpoints and Confidence Levels 135
89 3.2.5.4 Potentially Exposed or Susceptible Subpopulations 137
90 4 RISK CHARACTERIZATION 138
91 4,1 Environmental Risk 138
92 4.1.1 Aquatic Pathway 139
93 4.1.2 Risk Estimation for Aquatic Environment 144
94 4.1,3 Risk Estimation for Sediment 144
95 4.1.4 Risk Estimation for Terrestrial 145
96 4.2 Human Health Risk 145
97 4.2.1 Risk Estimation Approach 145
98 4.2.2 Risk Estimation for Non-Cancer Effects Following Acute Inhalation Exposures 150
99 4.2.3 Risk Estimation for Non-Cancer Effects Following Chronic Inhalation Exposures 152
100 4.2.4 Risk Estimation for Non-Cancer Effects Following Acute Dermal Exposures 154
101 4.2.5 Risk Estimation for Non-Cancer Effects Following Chronic Dermal Exposures 154
102 4.2.6 Risk Estimation for Cancer Effects Following Chronic Inhalation Exposures 155
103 4.2.7 Risk Estimations for Cancer Effects Following Chronic Dermal Exposures 158
104 4.2.8 Summary of Non-cancer and Cancer Estimates for Inhalation and Dermal Exposures 159
105 4.3 Potentially Exposed or Susceptible Subpopulations 165
106 4.4 Assumptions and Key Sources of Uncertainty 166
107 4.4.1 Occupational Exposure Assumptions and Uncertainties 166
108 4.4.2 Environmental Exposure Assumptions and Uncertainties 168
109 4.4.3 Environmental Hazard Assumptions and Uncertainties 169
110 4.4.4 Human Health Hazard Assumptions and Uncertainties 170
111 4.5 Risk Characterization Confidence Levels 170
112 4.5.1 Environmental Risk 170
113 4.5.2 Human Health Risk 170
114 4,6 Aggregate or Sentinel Exposures 171
115 5 RISK DETERMINATION 172
116 5.1 Unreasonable Risk 172
117 5.1.1 Overview 172
118 5.1.2 Risks to Human Health 173
119 5.1.2.1 Determining Non-Cancer Risks 173
120 5.1.2.2 Determining Cancer Risks 174
121 5.1.3 Determining Environmental Risk 175
122 5.2 Risk Determination for Carbon Tetrachloride 175
123 5.3 Detailed Risk Determinations by Conditions of Use 179
124 5.3.1 Manufacture-Domestic manufacture 179
125 5.3.2 Manufacture-Import (includes repackaging and loading/unloading) 180
126 5.3.3 Processing-Processing as a reactant in the production of hydrochlorofluorocarbon,
127 hydrofluorocarbon, hydrofluoroolefin, and perchloroethylene 181
128 5.3.4 Processing- Processing as reactant/intermediate in reactive ion etching 182
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129 5.3.5 Processing - Incorporation into formulation, mixture or reaction products-Petrochemicals-
130 derived manufacturing, agricultural products manufacturing, and other basic organic and
131 inorganic chemical manufacturing 182
132 5.3.6 Processing-Repackaging of carbon tetrachloride for use in laboratory chemicals 184
133 5.3.7 Processing-Recycling 185
134 5.3.8 Distribution in Commerce 186
135 5.3.9 Industrial/ Commercial Use - Industrial Processing Aid - Manufacturing of petrochemical-
136 derived products and agricultural products 187
137 5.3.10 Industrial/Commercial Use - Other Basic Organic and Inorganic Chemical Manufacturing
138 (manufacturing of chlorinated compounds used in solvents for cleaning and degreasing,
139 adhesives and sealants, paints and coatings, asphalt, and elimination of nitrogen trichloride
140 in the production of chlorine and caustic) 188
141 5.3.11 Industrial/Commercial Use - Metal recovery 189
142 5.3.12 Industrial/Commercial Use - Use an additive 190
143 5.3.13 Industrial/Commercial Use-Specialty Uses Department of Defense 191
144 5.3.14 Industrial/Commercial Use - Laboratory Chemical 192
145 5.3.15 Disposal 193
146 6 REFERENCES 194
147 7 APPENDICES 211
148 Appendix A REGULATORY HISTORY 211
149 A.l Federal Laws and Regulations 211
150 A.2 State Laws and Regulations 218
151 A.3 International Laws and Regulations 219
152 Appendix B LIST OF SUPPLEMENTAL DOCUMENTS 222
153 Appendix C FATE AND TRANSPORT 223
154 Appendix D RELEASES TO THE ENVIRONMENT 238
155 Appendix E SURFACE WATER ANALYSIS FOR CARBON TETRACHLORIDE 239
156 Appendix F OCCUPATIONAL EXPOSURES 247
157 Appendix G ENVIRONMENTAL HAZARDS 248
158 G.l Systematic Review 248
159 G.2 Hazard Identification-Aquatic 270
160 G.3 Weight of Evidence 272
161 G.4 Concentrations of Concern 274
162 G.5 Hazard Estimation for Acute Exposure Durations 275
163 G.6 Hazard Estimation for Chronic Exposure Durations 275
164 G.l Hazard Estimation for Algal Toxicity 275
165 G.8 Summary of Environmental Hazard Assessment 276
166 Appendix H HUMAN HEALTH HAZARDS 277
167 Appendix I GENOTOXICITY 287
168 1,1 In vitro Genotoxicity and Mutation 287
169 1.2 In vivo Genotoxicity 291
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Appendix J EVIDENCE ON LINEARITY OF THE PBPK MODEL 294
Appendix K SUMMARY OF PUBLIC COMMENTS / RESPONSE TO COMMENTS 295
LIST OF TABLES
Table 1-1. Physical and Chemical Properties of Carbon Tetrachloride 25
Table 1-2. Production Volume of Carbon Tetrachloride in Chemical Data Reporting (CDR) Reporting
Period (2012 to 2015)a 26
Table 1-3. Assessment History of Carbon Tetrachloride 27
Table 1-4. Categories and Subcategories of Conditions of Use Included in the Scope of the Risk
Evaluation 32
Table 2-1. Environmental Fate Characteristics of Carbon Tetrachloride 48
Table 2-2. Assigned Protection Factors for Respirators in OSHA Standard 29 CFR § 1910.134 62
Table 2-3. Exposure Control Efficiencies and Protection Factors for Different Dermal 64
Table 2-4. Crosswalk of Subcategories of Use Listed in Table 1-4 and the Sections Assessed for
Occupational Exposure 65
Table 2-5. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride During
Manufacturing 69
Table 2-6. Summary of Worker Inhalation Exposure Monitoring Data for Manufacture of Carbon
Tetrachloride 70
Table 2-7. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride During Import
and Repackaging 72
Table 2-8. Summary of Exposure Modeling Results for Import and Repackaging 73
Table 2-9. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride During
Processing as a Reactant 75
Table 2-10. DoD Inhalation Monitoring Results 76
Table 2-11. Summary of Worker Inhalation Exposure Monitoring Data for Specialty Use of Carbon
Tetrachloride 78
Table 2-12. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride During Use as a
RIi: 79
Table 2-13. List of Approved Uses of Carbon Tetrachloride as a Process Agents in the MP Side
Agreement, Decision X/14: Process Agents1 80
Table 2-14. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride During Use as a
Processing Agent/Aid 81
Table 2-15. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride when used as
an Additive 82
Table 2-16. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride During Use as a
Laboratory Chemical 84
Table 2-17. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride During Waste
Handling 86
Table 2-18. Summary of Occupational Inhalation Exposure Assessment for Workers 88
Table 2-19. Summary and Ranking of Occupational Exposure of Carbon Tetrachloride for Various
Conditions of Use 89
Table 2-20. Estimated Dermal Acute and Chronic Retained Doses for Workers for All Conditions of Use
94
Table 3-1. Acute Inhalation Toxicity Study in Humans (Critical Study for NAC/AEGL-2 Values) 103
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Table 3-2. Acute Toxicity Oral study in Sprague-Dawley Rats with Acceptable Data Quality Not
Evaluated in Previous Hazard Assessments for Carbon Tetrachloride 104
Table 3-3. Developmental Toxicity Studies in Fisher 344 and Sprague-Dawley Rats with Acceptable
Data Quality 105
Table 3-4. Subchronic and Chronic Inhalation Studies in Various Experimental Animal Species with
Acceptable (High, Medium or Low) Data Quality 109
Table 3-5. Subchronic Oral Toxicity Studies in Rats and Mice with Acceptable Quality Data 112
Table 3-6. Acute Toxicity Dermal Studies in Guinea Pigs with Observations on Liver Toxicity and/or
Toxicity Progression Over Time 114
Table 3-7. Acceptable Epidemiological Studies for Non-Cancer Toxicity of Carbon Tetrachloride Not
Evaluated in Previously Published Hazard Assessments 115
Table 3-8. Acceptable Epidemiological Studies for Cancer Toxicity of Carbon Tetrachloride Not
evaluated in EPA IRIS Assessment 117
Table 3-9. Incidence of liver tumors in F344 rats exposed to carbon tetrachloride vapor for 104 weeks (6
hours/day, 5 days/week)3 119
Table 3-10. Incidence of liver and adrenal tumors in BDFi mice exposed to carbon tetrachloride vapor
for 104 weeks (6 hours/day, 5 days/week)3 120
Table 3-11. Cytotoxic MOA (key events as proposed by EPA-HQ-OPPT-2016-0733-0066 and EPA-
HQ-OPPT-2016-0733-0088) 124
Table 3-12. Combined MOA (non-cytotoxic at low dose and cytotoxic at high dose) 125
Table 3-13. PODs for Acute Inhalation Exposures based on Human Data 130
Table 3-14. PODs for Chronic Inhalation Exposures based on Animal data 132
Table 3-15. PODs for Acute Dermal Exposures (non-occluded) 133
Table 3-16. PODs for Chronic Dermal Exposures 134
Table 3-17. Summary of PODs for Evaluating Human Health Hazards from Acute and Chronic
Inhalation and Dermal Exposure Scenarios 136
Table 4-1. Concentrations of Concern (COCs) for Environmental Toxicity 140
Table 4-2. Modeled Facilities Showing Acute, Chronic, Algae Risk from the Release of Carbon
Tetrachloride; RQ Greater Than One are Shown in Bold 142
Table 4-3. Use Scenarios, Populations of Interest and Toxicological Endpoints for Assessing
Occupational Risks Following Acute Inhalation Exposures to Carbon Tetrachloride... 145
Table 4-4. Use Scenarios, Populations of Interest and Toxicological Endpoints for Assessing
Occupational Risks Following Chronic Inhalation Exposures to Carbon Tetrachloride 146
Table 4-5. Use Scenarios, Populations of Interest and Toxicological Endpoints for Assessing
Occupational Risks Following Acute Dermal Exposures to Carbon Tetrachloride 147
Table 4-6. Use Scenarios, Populations of Interest and Toxicological Endpoints for Assessing
Occupational Risks Following Chronic Dermal Exposures to Carbon Tetrachloride.... 147
Table 4-7. Risk Estimates for Acute Inhalation Exposures based on POD of 360 mg/m3 - 8hrs (=310
mg/m3-12 hrs); and Benchmark MOE of 10 151
Table 4-8. Risk Estimates for Chronic Inhalation Exposures based on POD of 31. lmg/m3- 8 hrs (= 26.4
mg/m3-12 hrs) and Benchmark MOE of 30 153
Table 4-9. Risk Estimates for Acute Dermal Exposures 154
Table 4-10. Risk Estimates from Chronic Dermal Exposures 155
Table 4-11. Risk Estimates for Cancer Effects from Chronic Inhalation Exposures for Workers Based on
IUR of 6 x 10"6 per [j,g/m3 and Benchmark Risk = 1 in 104 156
Table 4-12. Risk Estimates for Cancer Effects from Chronic Dermal Exposures for Workers; Benchmark
Risk = 1 in 104 159
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Table 4-13. Summary of Estimated Non-cancer and Cancer Risks from Inhalation and Dermal
Exposures1 161
Table 5-1. Summary of Unreasonable Risk Determinations by Condition of Use 178
LIST OF FIGURES
Figure 1-1. Carbon Tetrachloride Life Cycle Diagram 31
Figure 1-2. Carbon Tetrachloride Conceptual Model for Industrial/Commercial Activities and Uses:
Potential Exposures and Hazards 36
Figure 1-3. Carbon Tetrachloride Conceptual Model for Environmental Releases and Wastes: Potential
Exposures and Hazards 37
Figure 1-4. Key/Supporting Data Sources for Environmental Fate and Transport 40
Figure 1-5. Key/Supporting Data Sources for Releases and Occupational Exposures 41
Figure 1-6. Key/Supporting Sources for Environmental Exposures 42
Figure 1-7. Key/Supporting Sources for Environmental Hazards 42
Figure 1-8. Key/Supporting Data Sources for Human Health Hazards 43
Figure 2-1. General Process Flow Diagram for Import and Repackaging 71
Figure 2-2. General Laboratory Use Process Flow Diagram 83
Figure 2-3. Typical Waste Disposal Process 85
Figure 3-1. Hazard Identification and Dose-Response Process 98
Figure 4-1. Cancer Risk Estimates for Occupational Use of Carbon Tetrachloride in Manufacturing and
Processing as Reactant/Intermediate Based on Monitoring or Surrogate Monitoring Data
8 hr TWA 157
Figure 4-2. Cancer Risk Estimates for Occupational Use of Carbon Tetrachloride in Manufacturing and
Processing as Reactant/Intermediate Based on Monitoring or Surrogate Monitoring Data
12 hr TWA 157
Figure 4-3. Cancer Risk Estimates for Occupational Use of Carbon Tetrachloride in Import, Processing
Agent, Additive and Disposal/Recycling Based on Modeling 158
Figure 4-4. Cancer Risk Estimates for Occupational Use of Carbon Tetrachloride in Specialty Uses-DoD
Based on Monitoring Data 158
LIST OF APPENDIX TABLES
Table_Apx A-l. Federal Laws and Regulations 211
Table_Apx A-2. State Laws and Regulations 218
Table_Apx A-3. Regulatory Actions by Other Governments and Tribes 219
TableApx C-l. Biodegradation Study Summary for Carbon Tetrachloride 223
Table_Apx C-2. Photolysis Study Summary for Carbon Tetrachloride 225
Table_Apx C-3. Hydrolysis Study Summary for Carbon Tetrachloride 225
Table_Apx C-4. Sorption Study Summary for Carbon Tetrachloride 226
Table Apx C-5. Other Fate Endpoints Study Summary for Carbon Tetrachloride 236
Table Apx D-l. Summary of Carbon Tetrachloride TRI Releases to the Environment for from 2018
(lbs) 238
Table Apx G-l. Aquatic toxicity studies that were evaluated for Carbon Tetrachloride 248
Table Apx G-2. Aquatic toxicity studies that were evaluated for carbon tetrachloride 271
Table Apx H-l. Summary of Reviewed Human Health Animal Studies for Carbon Tetrachloride 277
Table Apx H-2. Summary of Reviewed Genotoxicity Studies for Carbon Tetrachloride 286
Table Apx 1-1. Bacterial mutagenesis data in systems believed relevant to detection of oxidative
damage to DNA - excerpted from EPA IRIS Assessment 289
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304 TableApx 1-2. Chromosomal changes in in vitro studies mammalian cells from liver, kidney or lung; or
305 cells with CYP2E1 genetic capability added - excerpted from EPA IRIS Assessment. 290
306 Table Apx J-l. Table Summarizing PBPK Model results in the IRIS Assessment Tables C-6 and C-10
307 294
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ACKNOWLEDGEMENTS
This report was developed by the United States Environmental Protection Agency (U.S. EPA), Office of
Chemical Safety and Pollution Prevention (OCSPP), Office of Pollution Prevention and Toxics (OPPT).
Acknowledgements
The OPPT Assessment Team gratefully acknowledges participation or input from Intra-agency
reviewers that included multiple offices within EPA, Inter-agency reviewers that included multiple
Federal agencies, and assistance from EPA contractors GDIT (Contract No. CIO-SP3,
HHSN316201200013W), ERG (Contract No. EP-W-12-006), Versar (Contract No. EP-W-17-006), ICF
(Contract No. EPC14001), and SRC (Contract No. EP-W-12-003).
Docket
Supporting information can be found in public docket: EPA-HQ-OPPT-2016-0733.
Disclaimer
Reference herein to any specific commercial products, process or service by trade name, trademark,
manufacturer or otherwise does not constitute or imply its endorsement, recommendation or favoring by
the United States Government.
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ABBREVIATIONS
°c
Degrees Celsius
AAL
Allowable Ambient Levels
ACGM
American Conference of Government Industrial Hygienists
ADC
Average Daily Concentration
AEC
Acute Exposure Concentration
AIA
Aerospace Industries Association
AIHA
American Industrial Hygiene Association
APF
Assigned Protection Factor
atm
Atmosphere(s)
ATSDR
Agency for Toxic Substances and Disease Registries
AWQC
Ambient Water Quality Criteria
BCF
Bioconcentration Factor
BLS
Bureau of Labor Statistics
BUN
Blood Urea Nitrogen
CAA
Clean Air Act
CASRN
Chemical Abstract Service Registry Number
CBI
Confidential Business Information
ecu
Carbon tetrachloride
CDR
Chemical Data Reporting
CEHD
Chemical Exposure Health Data
CERCLA
Comprehensive Environmental Response, Compensation and Liability Act
CFC
C hlorofluorocarb on
cm2
Square Centimeter(s)
cm3
Cubic Centimeter(s)
CPN
Chronic progressive nephropathy
CNS
Central Nervous System
coc
Concentration of Concern
CoRAP
Community Rolling Action Plan
CPSC
Consumer Product Safety Commission
cs2
Carbon Disulfide
CSATAM
Community-Scale Air Toxics Ambient Monitoring
CSCL
Chemical Substances Control Law
CSF
Cancer Slope Factor
CSM
Chlorosulphonated polyolefin
CYP450
Cytochrome P450
CWA
Clean Water Act
DMR
Discharge Monitoring Report
DNA
Deoxyribonucleic Acid
DoD
Department of Defense
DT50
Dissipation Time for 50% of the compound to dissipate
EC
European Commission
ECHA
European Chemicals Agency
EDC
Ethylene Dichloride
ELCR
Excess Lifetime Cancer Risk
EPA
Environmental Protection Agency
EPCRA
Emergency Planning and Community Right-to-Know Act
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384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
ESD
EU
FDA
FFDCA
FHSA
FIFRA
g
GS
HAP
HCFC
HC1
HFC
HFO
HSIA
HVLP
IBC
IDLH
IMAP
IRIS
ISHA
kg
km
L
LA DC
lb
LOD
log Koc
log Kow
3
m
MACT
MCL
MCLG
MEMA
mg
mmHg
MP
mPas
NAC/AEGL
NAICS
NATA
NATTS
NEI
NESHAP
NHANES
NIOSH
NPDES
NPDWR
NTP
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Emission Scenario Document
European Union
Food and Drug Administration
Federal Food, Drug and Cosmetic Act
Federal Hazardous Substance Act
Federal Insecticide, Fungicide, and Rodenticide Act
Gram(s)
Generic scenario
Hazardous Air Pollutant
Hy drochl orofluorocarb ons
Hydrochloric Acid
Hy drofluorocarb on
Hydrofluoroolefin
Halogenated Solvents Industry Alliance
High Volume, Low Pressure
Intermediate Bulk Containers
Immediately Dangerous to Life and Health
Inventory Multi-Tiered Assessment and Prioritisation
Integrated Risk Information System
Industrial Safety and Health Act
Kilogram(s)
Kilometer(s)
Liter(s)
Lifetime Average Daily Concentration
Pound
Limit of Detection
Logarithmic Soil Organic Carbon:Water Partitioning Coefficient
Logarithmic Octanol:Water Partition Coefficient
Cubic Meter(s)
Maximum Achievable Control Technology
Maximum Contaminant Level
Maximum Contaminant Level Goal
Motor and Equipment Manufacturer Association
Milligram(s)
Millimeter(s) of Mercury
Montreal Protocol
Millipascal(s)-Second
National Advisory Committee for Acute Exposure Guideline Levels
North American Industrial Classification System
National Air Toxics Assessment
National Air Toxics Trends Stations
National Emissions Inventory
National Emission Standards
National Health and Nutrition Examination Survey
National Institute for Occupational Safety and Health
National Pollutant Discharge Elimination System
National Primary Drinking Water Regulations
National Toxicology Program
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NWQMC
National Water Quality Monitoring Council
OARS
Occupational Alliance for Risk Science
OBOD
Open Burn/Open Detection
OCSPP
Office of Chemical Safety and Pollution Prevention
ODS
Ozone Depleting Substance
OECD
Organisation for Economic Co-operation and Development
OELs
Occupational Exposure Limits/Levels
ONU
Occupational Non-Users
OPPT
Office of Pollution Prevention and Toxics
OSHA
Occupational Safety and Health Administration
OW
Office of Water
PCE
Perchloroethylene
PDM
Probabilistic Dilution Model
PEL
Permissible Exposure Limit
PESS
Potentially Exposed or Susceptible Subpopulations
PF
Protection Factor
POD
Point of Departure
POTW
Publicly Owned Treatment Works
ppm
Part(s) per Million
PPE
Personal Protective Equipment
QC
Quality Control
REACH
Registration, Evaluation, Authorisation and Restriction of Chemicals
RCRA
Resource Conservation and Recovery Act
REL
Recommended Exposure Limit
RFI
Reporting Forms and Instructions
RIE
Reactive Ion Etching
SDS
Safety Data Sheet
SDWASafe Drinking Water Act
SIAP
Screening Information Dataset Initial Assessment Profile
SIDS
Screening Information Dataset
SOC
Standard Occupational Classification
STEL
Short-term Exposure Limit
STORET
STORage and RETrieval
SUSB
Statistics of US Businesses
SYR
Six-year Review
TCCR
Transparent, Clear, Consistent and Reasonable
TCLP
Toxicity Characteristic Leaching Procedure
TLV
Threshold Limit Value
TRI
Toxics Release Inventory
TSCA
Toxic Substances Control Act
TSDF
Treatment, Storage and Disposal Facilities
TURA
Toxic Use Reduction Act
TWA
Time-Weighted Average
UATMP
Urban Air Toxics Monitoring Program
UNEP
United Nations Environment Programme
U.S.
United States
USGS
United States Geological Survey
VOC
Volatile Organic Compounds
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Workplace Environmental Exposure Limit
470
WHO
World Health Organization
471
WQP
Water Quality Portal
472
Yderm
Weight fraction of the chemical of interest in the liquid phase
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EXECUTIVE SUMMARY
This draft risk evaluation for carbon tetrachloride was performed in accordance with the Frank R.
Lautenberg Chemical Safety for the 21st Century Act and is being disseminated for public comment and
peer review. The Frank R. Lautenberg Chemical Safety for the 21st Century Act amended the Toxic
Substances Control Act (TSCA), the Nation's primary chemicals management law, in June 2016. As per
EPA's final rule, Procedures for Chemical Risk Evaluation Under the Amended Toxic Substances
Control Act (82 FR 33726). EPA is taking comment on this draft, and will also obtain peer review on
this draft risk evaluation for carbon tetrachloride. All conclusions, findings, and determinations in this
document are preliminary and subject to comment. The final risk evaluation may change in response to
public comments received on the draft risk evaluation and/or in response to peer review, which itself
may be informed by the public comments. The preliminary conclusions, findings, and determinations in
this draft risk evaluation are for the purpose of identifying whether the chemical substance presents
unreasonable risk or no unreasonable risk under the conditions of use, in accordance with TSCA section
6, and are not intended to represent any findings under TSCA section 7.
TSCA § 26(h) and (i) require EPA to use scientific information, technical procedures, measures,
methods, protocols, methodologies and models consistent with the best available science and to base its
decisions on the weight of the scientific evidence. To meet these TSCA § 26 science standards, EPA
used the TSCA systematic review process described in the Application of Systematic Review in TSCA
Risk Evaluations document (U.S. EPA. 2018a). The data collection, evaluation, and integration stages of
the systematic review process are used to develop the exposure, fate, and hazard assessments for risk
evaluations.
Carbon tetrachloride [CASRN: 56-23-5] is a high production volume solvent. Previously, carbon
tetrachloride was a high production solvent in consumer and fumigant products, including as a solvent to
make refrigerants and propellants for aerosol cans, as a solvent for oils, fats, lacquers, varnishes, rubber
waxes, and resins, and as a grain fumigant and dry-cleaning agent. The Montreal Protocol and Title VI
of the Clean Air Act (CAA) Amendments of 1990 led to a phase-out of carbon tetrachloride production
in the United States for most non-feedstock domestic uses in 1996 and the Consumer Product Safety
Commission (CPSC) banned the use of carbon tetrachloride in consumer products (excluding
unavoidable residues not exceeding 10 ppm atmospheric concentration) in 1970. As a result of this
phase-out and ban, it is highly unlikely that there are any ongoing uses of carbon tetrachloride that could
be considered legacy uses, and no such uses have been evaluated. Currently, carbon tetrachloride is used
as a feedstock in the production of hydrochloro fluorocarbons (HCFCs), hydrofluorocarbons (HFCs) and
hydrofluoroolefins (HFOs). EPA has identified information on the regulated use of carbon tetrachloride
as a process agent in the manufacturing of petrochemicals-derived and agricultural products and other
chlorinated compounds such as chlorinated paraffins, chlorinated rubber and others that may be used
downstream in the formulation of solvents for degreasing and cleaning, adhesives, sealants, paints,
coatings, rubber, cement and asphalt formulations. The use of carbon tetrachloride for non-feedstock
uses (i.e., process agent, laboratory chemical) is regulated in accordance with the Montreal Protocol.
Carbon tetrachloride has been reportable to the Toxics Release Inventory (TRI) chemical under Section
313 of the Emergency Planning and Community Right-to-Know Act (EPCRA) since 1987. It is
designated a Hazardous Air Pollutant (HAP) under the Clean Air Act (CAA), and is a hazardous
substance under the Comprehensive Environmental Response, Compensation and Liability Act
(CERCLA). It is subject to National Primary Drinking Water Regulations (NPDWR) under the Safe
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Drinking Water Act (SDWA) and designated as a toxic pollutant under the Clean Water Act (CWA) and
as such is subject to effluent limitations.
Approach
EPA used reasonably available information (defined in 40 CFR 702.33 as "information that EPA
possesses or can reasonably generate, obtain, and synthesize for use in risk evaluations, considering
the deadlines ... for completing such evaluation") in a "fit-for-purpose" approach, to develop a risk
evaluation that relies on the best available science and is based on the weight of the scientific evidence.
EPA used previous analyses as a starting point for identifying key and supporting studies to inform the
exposure, fate, and hazard assessments. EPA also evaluated other studies that were published since these
reviews. EPA reviewed the information and evaluated the quality of the methods and reporting of results
of the individual studies using the evaluation strategies described in Application of Systematic Review in
TSCA Risk Evaluations (U.S. EPA. 2018a).
In the problem formulation document (U.S. EPA. 2018d). EPA identified the carbon
tetrachloride conditions of use and presented two conceptual models and an analysis plan for
this current draft risk evaluation. These have been updated in the draft risk evaluation to remove two
activities that are no longer considered conditions of use because they consist of outdated
industrial/commercial processes (see section 1.4.2). EPA has quantitatively evaluated the risk to the
environment and human health, using both monitoring data and modeling approaches, for the conditions
of use identified in section 1.4.1 of this draft risk evaluation. EPA quantitatively evaluated the risk to
aquatic species from exposure to surface water from water releases due to disposals of carbon
tetrachloride associated with its manufacturing, processing, use, or disposal carbon tetrachloride. EPA
also quantitatively evaluated the risk to workers, from inhalation and dermal exposures, and
occupational non-users (ONUs)1, from inhalation exposures, by comparing the estimated exposures to
acute and chronic human health hazards.
Exposures
EPA used environmental monitoring data to assess ambient water exposure to aquatic organisms. While
carbon tetrachloride is present in various environmental media, such as groundwater, surface water, and
air, EPA stated in the problem formulation that EPA did not expect to include in the risk evaluation
certain exposure pathways that are under the jurisdiction of other EPA-administered statutes, and stated
that EPA expected to conduct no further analysis beyond what was presented in the problem formulation
document for the environmental exposure pathways that remained in the scope of this draft risk
evaluation. Further analysis was not conducted for exposure to aquatic organisms from the suspended
soils or sediment pathway based on a qualitative assessment of the physical chemical properties and fate
of carbon tetrachloride in the environment. However, exposures to aquatic organisms from ambient
surface water were further analyzed in this draft risk evaluation to address a slight change in the
environmental hazard chronic COC and the calculation of a distinct algal COC during the data quality
evaluation process after the problem formulation phase. This assessment is used to inform the risk
determination. These analyses are described in sections 2.1, 2.3 and 4.1 and Appendix E.
EPA evaluated exposures to carbon tetrachloride in occupational settings for the conditions of use
included in the scope of the risk evaluation, listed in section 1.4 (Scope of the Evaluation). In
occupational settings, EPA evaluated acute and chronic inhalation exposures to workers and ONUs, and
1 ONUs are workers who do not directly handle carbon tetrachloride but perform work in an area where carbon tetrachloride
is present.
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acute and chronic dermal exposures to workers. EPA used inhalation monitoring data, where reasonably
available and that met data evaluation criteria, as well as, modeling approaches, where reasonably
available, to estimate potential inhalation exposures. There is uncertainty in the ONU inhalation risk
estimate since the data did not distinguish between worker and ONU inhalation exposure estimates.
While the difference between the exposures of ONUs and the exposures of workers directly handling the
carbon tetrachloride generally cannot be quantified, ONU inhalation exposures are expected to be lower
than inhalation exposures for workers directly handling the chemical. EPA considered the ONU
exposures to be equal to the central tendency risk estimates for workers when determining ONU risk
attributable to inhalation. While this is likely health protective as it assumes ONU exposure is greater
than that of 50% of the workers, this is highly uncertain, and EPA has low confidence in these exposure
estimates for ONUs. Dermal exposures are not expected because ONUs do not typically directly handle
the carbon tetrachloride, nor they are in the immediate proximity of carbon tetrachloride. Dermal doses
for workers were estimated in these scenarios because dermal monitoring data was not reasonably
available. These analyses are described in section 2.4 of this draft risk evaluation.
Hazards
EPA reviewed the environmental hazard data using the data quality review evaluation metrics and the
rating criteria described in the Application of Systematic Review in TSCA Risk Evaluations (U.S. EPA.
2018a). EPA concluded that carbon tetrachloride poses a hazard to environmental aquatic receptors with
amphibians being the most sensitive taxa for acute and chronic exposures. Algal endpoints are
considered separately from the other taxa and not incorporated into acute or chronic concentrations of
concern (COCs) because durations normally considered acute for other species (e.g., 48, 72, or 96 hours)
can encompass several generations of algae. A distinct COC is calculated for algal toxicity. The results
of the environmental hazard assessment are in section 3.1.
EPA evaluated reasonably available information for human health hazards and identified hazard
endpoints including acute and chronic toxicity for non-cancer effects and cancer. EPA used the
Framework for Human Health Risk Assessment to Inform Decision Making (U.S. EPA. 2014) to
interpret, extract, and integrate carbon tetrachloride's human health hazard and dose-response
information. EPA reviewed key and supporting information from previous hazard assessments [EPA
IRIS Toxicologic Review (U.S. EPA. 2010). an ATSDR Toxicological Profile (ATSDR. 2005) and
NAC Acute Exposure Guideline Levels (AEGL) (NRC. 2014) and other international assessments listed
in Table 1-3. EPA also screened and evaluated new studies that were published since these reviews (i.e.,
from 2010-2018).
EPA developed a hazard and dose-response analysis using endpoints observed in inhalation and oral
hazard studies, evaluated the weight of the scientific evidence considering EPA and National Research
Council (NRC) risk assessment guidance and selected the points of departure (POD) for acute and
chronic, non-cancer endpoints, and inhalation unit risk and cancer slope factors for cancer risk estimates.
Potential health effects of carbon tetrachloride exposure described in the literature include: effects on the
central nervous system (CNS), liver, kidney, as well as skin irritation, and cancer. EPA identified acute
PODs for inhalation and dermal exposures based on acute CNS effects observed in humans (Davis.
1934). The chronic POD for inhalation exposures are based on a study observing increased fatty changes
in rodent livers (Nagano et al.. 2007a). EPA identified a limited number of toxicity studies by the dermal
route that were adequate for dose-response assessment. Therefore, most of the dermal candidate values
were derived by route-to-route extrapolation from the inhalation PODs mentioned above. In accordance
with U.S. EPA (2005a) Guidelines for Carcinogen Risk Assessment, carbon tetrachloride is classified
"likely to be carcinogenic to humans" based on sufficient evidence in animals and limited supporting
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evidence in humans. EPA calculated cancer risk with a linear model using cancer slope factors for low
dose exposures of carbon tetrachloride, which is EPA's baseline approach to risk assessment when the
MOA is unknown. A general correspondence has been observed between hepatocellular cytotoxicity and
regenerative hyperplasia and the induction of liver tumors as a potential MOA. As indicated in (U.S.
EPA. 20101 this MOA appears to play a significant role at relatively high exposures above the POD,
driving the steep increase in liver tumors in this exposure range. Data to characterize MOA key events at
low-exposure levels, however, are limited, hence the use of the baseline linear approach. EPA
considered a nonlinear approach with exposures exceeding the POD (18 mg/m3) for continuous
exposure, because above this level, the fitted dose-response model better characterizes what is known
about the MOA of carcinogenicity of carbon tetrachloride at higher doses (U.S. EPA. 2010). The results
of these analyses are described in section 3.2.
Human Populations Considered in This Risk Evaluation
EPA assumed those who use carbon tetrachloride would be adults of either sex (>16 years old),
including pregnant women, and evaluated risks to individuals who do not use carbon tetrachloride but
may be indirectly exposed due to their proximity to the user who is directly handling carbon
tetrachloride.
The risk evaluation is based on potential central nervous system depression which can lead to workplace
accidents and which is a precursor to more severe central nervous system effects such as incapacitation,
loss of consciousness, and death, as well as liver toxicity and cancer as sensitive endpoints. The risk
evaluation also assesses the risk to other potentially exposed or susceptible subpopulations, including
people with pre-existing conditions and people with genetic variations that make them more susceptible.
Exposures that do not present risks based on sensitive toxicity endpoints are not expected to present
risks for other potential health effects of carbon tetrachloride because other health effects occur at higher
levels of exposure.
Risk Characterization
This draft risk evaluation characterizes the environmental and human health risks from carbon
tetrachloride under the conditions of use, including manufacture, processing, distribution, use and
disposal. This risk characterization identifies potential risks that are used in the identification of
unreasonable risks in the risk determination.
Environmental Risk: For environmental risk, EPA utilized a risk quotient (RQ) to compare the
environmental concentration to the effect level to characterize the risk to aquatic organisms. EPA
included a qualitive assessment describing carbon tetrachloride exposure from sediments and land-
applied biosolids. Carbon tetrachloride is not expected to accumulate in sediments, and could be mobile
in soil, and migrate to water or volatilize to air. The results of the risk characterization are in section 4.1,
including a table that summarizes the RQs for acute and chronic risks.
EPA determined that there are no acute or chronic environmental risks from the TSCA conditions of use
of carbon tetrachloride. Using conservative scenarios, EPA demonstrated that the surface water
concentrations did not exceed the acute or chronic COCs (i.e., RQs < 1) for aquatic species for all sites
except one site (i.e., acute RQ = 1.4). EPA determined there is not an acute aquatic concern for carbon
tetrachloride after further review of the site, which indicated that there was a one-
time elevated environmental release of carbon tetrachloride in 2014 due to an unexpected chemical
spill. Details of these estimates are in section 4.1.2.
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Human Health Risks: For human health risks to workers, EPA identified potential cancer and non-
cancer human health risks from chronic inhalation exposures. EPA did not identify risks from acute
exposures for central nervous system depression. For dermal exposures, EPA did not identify potential
risks for non-cancer liver effects but identified potential cancer risks for high-end chronic exposures.
For workers and ONUs, EPA estimated potential cancer risk from chronic exposures to carbon
tetrachloride using an inhalation unit risk value or dermal cancer slope factor multiplied by the chronic
exposure for each COU. For workers and ONUs, EPA also estimated potential non-cancer (liver) risks
resulting from acute or chronic inhalation or dermal exposures and used a Margin of Exposure (MOE)
approach. For workers, EPA estimated risks using several occupational exposure scenarios, which
varied assumptions regarding the expected use of personal protective equipment (PPE) for respiratory
and dermal exposures for workers directly handling carbon tetrachloride. More information on
respiratory and dermal protection, including EPA's approach regarding the occupational exposure
scenarios for carbon tetrachloride, is in section 2.4.1.1.
For workers, chronic non-cancer risks were indicated for high-end exposures and cancer risks were
indicated for both high-end and central tendency exposures for the manufacturing and processing
conditions if PPE was not used. For most industrial/commercial conditions of use, cancer risks were also
identified for high-end inhalation exposure scenarios if PPE was not used. With use of expected PPE
during relevant conditions of use (COUs), worker exposures were estimated to be reduced with MOEs
greater than benchmark MOEs and cancer risks below the benchmark cancer risk. EPA's estimates for
worker risks for each occupational exposure scenario are presented in section 4.2 and summarized in
Table 4-13. Cancer risks for workers were identified for high-end dermal exposures for all COUs (see
section 4.2.7). The dermal high-end exposures are reduced with the use of gloves (PF =5) resulting in
cancer risks below the benchmark. Risks were not identified for non-cancer liver effects for workers
from dermal exposures (see sections 4.2.4, 4.2.5)
For ONUs, cancer risks were indicated for inhalation occupational exposure scenarios for manufacturing
and processing carbon tetrachloride conditions of use. ONUs are not expected to be using PPE to reduce
exposures to carbon tetrachloride used in their vicinity. ONUs are not dermally exposed to carbon
tetrachloride and dermal risks to ONUs were not identified. EPA's estimates for ONU risks for each
occupational exposure scenario are presented in section 4.2 and summarized in Table 4-13
Strengths, Limitations and Uncertainties in the Risk Characterization
Key assumptions and uncertainties in the environmental risk estimation include the uncertainty around
modeled releases that have surface water concentrations greater than the highest concentration of
concern for aquatic organisms.
For the human health risk estimation, key assumptions and uncertainties are related to the estimates for
ONU inhalation exposures, because monitoring data were not readily available for many of the
conditions of use evaluated. Therefore, there is low confidence in the ONU inhalation exposure
estimates used in the risk calculations. An additional source of uncertainty in the dermal risk assessment
is the inhalation to dermal route-to-route extrapolations and use of the limited available dermal data in a
weight of evidence approach. Another source of uncertainty for the human health hazard is the evidence
in support of a mode of action (MOA) for carcinogenesis of carbon tetrachloride at low dose levels.
Therefore, a low dose linear cancer risk model for carbon tetrachloride was used to calculate cancer risk.
Assumptions and key sources of uncertainty are detailed in section 4.4.
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Potentially Exposed and Susceptible Subyoyidations fPESS)
TSCA § 6(b)(4) requires that EPA evaluate risk to relevant PESS. In developing the risk evaluation,
EPA analyzed the reasonably available information to ascertain whether some human receptor groups
may have greater exposure or greater susceptibility than the general population to the hazard posed by
carbon tetrachloride. EPA considered carbon tetrachloride exposures to be higher among workers using
carbon tetrachloride and ONUs in the vicinity of carbon tetrachloride use than the exposures
experienced by the general population. Additionally, variability of susceptibility to carbon tetrachloride
may be correlated with genetic polymorphism in its metabolizing enzymes. Factors other than
polymorphisms that regulate CYP2E1 induction may have greater influence on the formation of the
toxic metabolic product of carbon tetrachloride exposure. The CYP2E1 enzyme is easily induced by
many substances, resulting in increased metabolism. For example, moderate to heavy alcohol drinkers
may have increased susceptibility to carbon tetrachloride (NRC. 2014). To account for variation in
sensitivity within human populations intraspecies uncertainty factors (UFs) were applied for non-cancer
effects. The UF values selected are described in section 3.2.5.2.
Aggregate and Sentinel Exposures
Exposures to carbon tetrachloride were evaluated by inhalation and dermal routes separately. Inhalation
and dermal exposures are assumed to occur simultaneously for workers. EPA chose not to employ
additivity of exposure pathways at this time within a condition of use because of the uncertainties
present in the current exposure estimation procedures that may lead to an underestimate of aggregate
exposure. Other identified uncertainties for performing an aggregate exposure assessment of carbon
tetrachloride are discussed in section 4.6. Those uncertainties were also considered by EPA for
determining not to employ additivity of exposure pathways. In this risk evaluation, EPA considered
sentinel exposure the highest exposure given the details of the conditions of use and the potential
exposure scenarios.
Risk Determination
In each risk evaluation under TSCA section 6(b), EPA determines whether a chemical substance
presents an unreasonable risk of injury to health or the environment, under the conditions of use. The
determination does not consider costs or other non-risk factors. In making this determination, EPA
considers relevant risk-related factors including, but not limited to: the effects of the chemical substance
on health and human exposure to such substance under the conditions of use (including cancer and non-
cancer risks); the effects of the chemical substance on the environment and environmental exposure
under the conditions of use; the population exposed (including any potentially exposed or susceptible
subpopulations); the severity of hazard (including the nature of the hazard, the irreversibility of the
hazard); and uncertainties. EPA also takes into consideration the Agency's confidence in the data used
in the risk estimate. This includes an evaluation of the strengths, limitations, and uncertainties associated
with the information used to inform the risk estimate and the risk characterization. The rationale for the
preliminary risk determination is discussed in section 5.1.
Environmental Risks: EPA modeled industrial discharges of carbon tetrachloride to surface water to
estimate surface water concentrations. The estimated surface water concentrations did not exceed the
acute COC for aquatic species for all but one of the sites assessed, and the exceedance at that site was
due to an unexpected chemical spill. None of the sites analyzed had more than 20 days where the
chronic and algal COCs were exceeded. With respect to sediment-dwelling aquatic species, carbon
tetrachloride is not expected to partition to or be retained in sediment and is expected to remain in
aqueous phase due to its water solubility and low partitioning to organic matter. Consequently, EPA did
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not further assess exposure to sediment-dwelling aquatic organisms. Therefore, in this draft risk
evaluation, EPA does not find unreasonable environmental risk to aquatic species from the conditions of
use for carbon tetrachloride. As explained in section 2.5.3.2 of the problem formulation (U.S. EPA.
2018d), exposure to terrestrial organisms was removed from the scope of the evaluation. This exposure
pathway is considered to be covered under programs of other environmental statutes, administered by
EPA, which adequately assess and effectively manage exposures and for which long-standing regulatory
and analytical processes already exist. Therefore, EPA did not evaluate hazards and exposures to
terrestrial organisms in this draft risk evaluation, and there is no risk determination for terrestrial
organisms.
Risks of Injury to Health: EPA's preliminary determination of unreasonable risk for specific conditions
of use of carbon tetrachloride listed below are based on health risks to occupational non-users. As
described below, risks to workers, general population, consumers, and bystanders to consumer use either
were not relevant for these conditions of use or were evaluated and not found to be unreasonable.
Risks from acute exposures include central nervous system effects that are temporarily disabling, such
as dizziness. Risks from chronic exposures include liver toxicity and cancer.
Risk to Workers: EPA evaluated workers' acute and chronic inhalation and dermal occupational
exposures for cancer and non-cancer risks and preliminarily determined that these risks are not
unreasonable. This determination incorporates consideration of expected PPE (frequently estimated to
be a respirator of APF 10, 25 or 50). A full description of EPA's preliminary determination for each
condition of use is in section 5.3.
Risk to the General Population: EPA is not including in this draft risk evaluation exposure pathways
under programs of other environmental statutes, administered by EPA, which adequately assess and
effectively manage exposures and for which long-standing regulatory and analytical processes already
exist. The Office of Chemical Safety and Pollution Prevention works closely with EPA offices that
administer and implement the regulatory programs under these statutes. EPA believes this TSCA risk
evaluation should focus on those exposure pathways associated with TSCA uses that are not covered
under other environmental regulatory regimes administered by EPA because these pathways are likely to
represent the greatest areas of concern to EPA. As described in section 2.4.3 of this draft risk evaluation,
exposure pathways for carbon tetrachloride for human receptors (i.e., general population) already
addressed by these other statutory programs include ambient air, drinking water, ambient water,
biosolids, and disposal. Because there are no other exposure pathways impacting the general population,
EPA did not evaluate hazards or exposures to the general population in this risk evaluation, and there is
no risk determination for the general population.
Risks to Occupational Non-Users (ONUs): EPA evaluated ONU acute and chronic inhalation
occupational exposures for cancer and non-cancer risks and preliminarily determined whether any risks
indicated are unreasonable. Generally, risks identified for ONUs are linked to acute and chronic
inhalation exposures. The determinations reflect the hazards associated with the occupational exposures
to carbon tetrachloride and the expected absence of PPE for ONUs. The driver for EPA's determinations
of unreasonable risk for ONUs is cancer from chronic inhalation exposure. The determinations reflect
the severity of the hazards associated with the occupational exposures to carbon tetrachloride and the
expected absence of PPE for ONUs. For dermal exposures, because ONUs are not expected to be
dermally exposed to carbon tetrachloride, dermal risks to ONUs generally were not identified. ONU
inhalation exposures are expected to be lower than inhalation exposures for workers directly handling
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the chemical substance; however, the relative exposure of ONUs to workers in these cases cannot be
quantified. To account for the fact that the monitoring data or modeling did not distinguish between
worker and ONU inhalation exposure estimates, EPA considered the central tendency risk estimate
when determining ONU risk. Recognizing the significant uncertainty surrounding EPA's inhalation
exposure estimates for ONUs, EPA will continue to seek data on ONU inhalation exposures during the
public comment period on the draft risk evaluation. In addition, because EPA is preliminarily making a
finding that four COUs present an unreasonable risk for ONUs based on increased cancer risk estimate
of 4 x 10"4, EPA will further analyze this information to determine whether this four-fold difference
from the cancer risk benchmark falls within the range of uncertainty for these estimates. As noted
previously, EPA has low confidence in the exposure estimates for ONUs.
For ONUs, EPA preliminarily determined that the conditions of use that present unreasonable risks
include the domestic manufacture of carbon tetrachloride; the processing of carbon tetrachloride as a
reactant or intermediate in the production of hydrochlorofluorocarbons (HCFCs), hydrofluorocarbon
(HFC), hydrofluoroolefin (HFO), and perchloroethylene (PCE); processing for incorporation into
formulation, mixtures or reaction products (other basic organic and inorganic chemical manufacturing);
and industrial/commercial use in the manufacture of other basic chemicals (including chlorinated
compounds used in solvents, adhesives, asphalt, and paints and coatings). A full description of EPA's
preliminary determination for each condition of use is in section 5.3.
Risk to Consumers and Bystanders to Consumer Use: EPA did not include any consumer uses among
the conditions of use within the scope of the risk evaluation for carbon tetrachloride. The Consumer
Product Safety Commission (CPSC) banned the use of carbon tetrachloride in consumer products
(excluding unavoidable residues not exceeding 10 ppm atmospheric concentration) in 1970. While
carbon tetrachloride is used in the manufacturing of other chlorinated compounds that may be
subsequently added to commercially available products, EPA expects that consumer use of such
products would present only de minimis exposure to, or otherwise insignificant risk from, carbon
tetrachloride given the high volatility of carbon tetrachloride and the extent of reaction and efficacy of
the separation/purification process for purifying final products. Therefore, EPA did not evaluate hazards
or exposures to consumers or bystanders to consumer use in this risk evaluation, and there are no risk
determinations for these populations.
Summary of Risk Determinations:
EPA has preliminarily determined that the following conditions of use of carbon tetrachloride do not
present an unreasonable risk of injury to health. The details of these determinations are presented in
Table 5-1 and section 5.3.
Conditions of Use that Do Not Present an Unreasonable Risk
•
Import (including loading/unloading and repackaging)
•
Processing as a reactant/intermediate in reactive ion etching (i.e., semiconductor
manufacturing)
•
Processing for incorporation into formulation, mixtures or reaction products (petrochemicals-
derived manufacturing; agricultural products manufacturing)
•
Repackaging for use in laboratory chemicals
•
Recycling
•
Distribution in commerce
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Conditions of Use that Do Not Present an Unreasonable Risk
• Industrial/commercial use as an industrial processing aid in the manufacture of petrochemicals-
derived products and agricultural products
• Industrial/commercial use in metal recovery
• Industrial/commercial use as an additive
• Specialty uses by the Department of Defense
• Industrial/commercial use as a laboratory chemical
• Disposal
EPA has preliminarily determined that the following conditions of use of carbon tetrachloride present an
unreasonable risk of injury to health of occupational non-users. The details of these determinations are
presented in Table 5-1 and in section 5.3.
Manufacturing Use that Presents an Unreasonable Risk to ONUs
• Domestic manufacture
Processing Use that Presents an Unreasonable Risk to ONUs
• Processing as a reactant or intermediate in the production of hydrochlorofluorocarbons
(HCFCs), hydrofluorocarbon (HFCs) and hydrofluoroolefin (HFOs), and perchloroethylene
(PCE)
• Processing for incorporation into formulation, mixtures or reaction products (other basic
organic and inorganic chemical manufacturing)
Industrial/Commercial Use that Presents an Unreasonable Risk to ONUs
• Industrial/commercial use in the manufacture of other basic chemicals (including chlorinated
compounds used in solvents, adhesives, asphalt, and paints and coatings)
1 INTRODUCTION
This document presents for comment the draft risk evaluation for carbon tetrachloride under the Frank
R. Lautenberg Chemical Safety for the 21st Century Act. The Frank R. Lautenberg Chemical Safety for
the 21st Century Act amended the Toxic Substances Control Act, the Nation's primary chemicals
management law, in June 2016.
The Agency published the Scope of the Risk Evaluation for Carbon Tetrachloride (U.S. EPA. 2017e) in
June 2017, and the problem formulation in June 2018 (U.S. EPA. 2018d). which represented the
analytical phase of risk evaluation whereby "the purpose for the assessment is articulated, the problem is
defined, and a plan for analyzing and characterizing risk is determined" as described in Section 2.2 of
the Framework for Raman Health Risk Assessment to Inform Decision Making. EPA received comments
on the published problem formulation for carbon tetrachloride and has considered the comments specific
to carbon tetrachloride, as well as more general comments regarding EPA's chemical risk evaluation
approach for developing the draft risk evaluations for the first 10 TSCA Workplan chemicals.
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During problem formulation, EPA identified the carbon tetrachloride's conditions of use and presented
the associated conceptual models and an analysis plan. Based on EPA's analysis of the conditions of
use, physical-chemical and fate properties, environmental releases, and exposure pathways, the problem
formulations preliminarily concluded that further analysis was necessary for exposure pathways to
workers. Further analysis was not conducted for exposure to aquatic organisms from the suspended soils
or sediment pathway based on a qualitative assessment of the physical chemical properties and fate of
carbon tetrachloride in the environment. However, to address a slight change in the environmental
hazard chronic COC from 7 ppb to 3 ppb during the data quality evaluation process after the problem
formulation phase, EPA quantitatively evaluated risk to aquatic organisms from exposure to surface
water based on a conservative assessment of the available monitoring data for carbon tetrachloride to
adequately evaluate any potential environmental risk to aquatic organisms posed by carbon
tetrachloride.
EPA used reasonably available information consistent with the best available science for physical
chemical and fate properties, potential exposures, and relevant hazards according to the systematic
review process. For the human exposure pathways, EPA evaluated inhalation exposures to vapors and
mists for workers and occupational non-users, and dermal exposures via skin contact with liquids for
workers. EPA characterized risks to ecological receptors from exposures via surface water in the risk
characterization section of this draft risk evaluation based on the analyses briefly described above.
This document is structured such that the Introduction (Section 1) presents the basic physical-chemical
properties of carbon tetrachloride, and background information on its regulatory history, conditions of
use and conceptual models, with emphasis on any changes since the publication of the problem
formulation. This section also includes a discussion of the systematic review process utilized in this draft
risk evaluation. Exposures (Section 2) provides a discussion and analysis of both human and
environmental exposures that can be expected based on the conditions of use for carbon tetrachloride.
Hazards (Section 3) discusses environmental and human health hazards of carbon tetrachloride. The
Risk characterization (Section 4) integrates and assesses reasonably available information on human
health and environmental hazards and exposures, as required by TSCA (15 U.S.C 2605(b)(4)(F)). This
section also includes a discussion of any uncertainties and how they impact the draft risk evaluation. As
required under TSCA 15 U.S.C. 2605(b)(4), a determination of whether the risk posed by this chemical
substance is unreasonable is presented in the Risk Determination (Section 0).
As per EPA's final rule, Procedures for Chemical Risk Evaluation Under the Amended Toxic
Substances Control Act (82 Fed. Reg. 33726) (hereinafter "Risk Evaluation Rule"), this draft risk
evaluation is subject to both public comment and peer review, which are distinct but related processes.
EPA is providing 60 days for public comment, which will inform the EPA Science Advisory Committee
on Chemicals (SACC) peer review process. EPA seeks public comment on all aspects of this draft risk
evaluation, including all conclusions, findings, and determinations.
Peer review will be conducted in accordance with EPA's regulatory procedures for chemical risk
evaluations, including using the EPA Peer Review Handbook and other methods consistent with section
26 of TSCA (See 40 CFR 702.45). As explained in the Risk Evaluation Rule, the purpose of peer review
is for the independent review of the science underlying the risk assessment. Peer review will therefore
address aspects of the underlying science as outlined in the charge to the peer review panel such as
hazard assessment, assessment of dose-response, exposure assessment, and risk characterization.
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The final risk evaluation may change in response to public comments received on the draft risk
evaluation and/or in response to peer review, which itself may be informed by public comments. EPA
will respond to public and peer review comments received on the draft risk evaluation when it issues the
final risk evaluation.
EPA solicited input on the first 10 chemicals as it developed use dossiers, scope documents, and
problem formulations. At each step, EPA has received information and comments specific to individual
chemicals and of a more general nature relating to various aspects of the risk evaluation process,
technical issues, and the regulatory and statutory requirements. EPA has considered comments and
information received at each step in the process and factored in the information and comments as the
Agency deemed appropriate and relevant including comments on the published problem formulation of
carbon tetrachloride. Thus, in addition to any new comments on the draft risk evaluation, the public
should re-submit or clearly identify at this point any previously filed comments, modified as appropriate,
that are relevant to this risk evaluation and that the submitter feels have not been addressed. EPA does
not intend to further respond to comments submitted prior to the publication of this draft risk evaluation
unless they are clearly identified in comments on this draft risk evaluation.
1.1 Physical and Chemical Properties
Carbon tetrachloride is a colorless liquid at room temperature with a sweet, aromatic and ethereal odor
resembling chloroform (Merck. 1996); (U.S. Coast Guard. 1985). Carbon tetrachloride is expected to
volatilize based on its high vapor pressure (115 mm Hg at 25°C) (Lide. 1999). Carbon tetrachloride has
a log Kowvalue of 2.83 (Hansch et al.. 1995). indicating that this chemical is moderately miscible in
water. A summary of the physical and chemical properties of carbon tetrachloride are listed in Table 1-1.
Table 1-1. Physical and Chemical Properties of Carbon Tetrachloride
Property
Value3
References
Molecular formula
ecu
Molecular weight
153.82
Physical form
Colorless liquid with sweet odor
(Merck. 1996); (U.S.
Coast Guard, 1985)
Melting point
-23°C
(Lide. 1999)
Boiling point
76.8°C
(Lide. 1999)
Density
1.4601 g/cm3 at 20°C
(Lide. 1999)
Vapor pressure
115 mm Hg at 25°C
(Boublik et al., 1984)
Vapor density
5.3 (relative to air)
(Boublik et al., 1984)
Water solubility
793 mg/L at 25°C
(Horvath, 1982)
Octanol:water partition
coefficient (log Kow)
2.83
(Hansch et al., 1995)
Henry's Law constant
0.0276 atm m3/mole
(Leishton and Calo,
1981)
Flash point
None
(U.S. Coast Guard, 1985)
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Property
Value3
References
Autoflammability
Not flammable
(USCG, 1999)
Viscosity
2.03 mPas at -23°C
(Daubert and Danner,
1989)
Refractive index
1.4607 at 20°C
(Merck. 1996)
Dielectric constant
2.24 at 20°C
(Norbert and Dean, 1967)
a Measured unless otherwise noted.
1.2 Uses and Production Volume
Carbon tetrachloride is a high production volume solvent. Over one hundred forty two million pounds of
carbon tetrachloride were produced or imported in the U.S. in 2015 according to the EPA's Chemical
Data Reporting (CDR) database. The Montreal Protocol and Title VI of the Clean Air Act (CAA)
Amendments of 1990 led to a phase-out of carbon tetrachloride production in the United States for most
non-feedstock domestic uses in 1996 and the Consumer Product Safety Commission (CPSC) banned the
use of carbon tetrachloride in consumer products (excluding unavoidable residues not exceeding 10 ppm
atmospheric concentration) in 1970. Currently, carbon tetrachloride is used as a feedstock in the
production of hydrochlorofluorocarbons (HCFCs), hydrofluorocarbons (HFCs) and hydrofluoroolefins
(HFOs). As explained in the problem formulation (U.S. EPA. 2018d). EPA identified additional
information on the regulated use of carbon tetrachloride as a process agent (non-feedstock uses) in the
manufacturing of petrochemicals-derived and agricultural products and other chlorinated compounds
such as chlorinated paraffins, chlorinated rubber and others that may be used downstream in the
formulation of solvents for degreasing and cleaning, adhesives, sealants, paints, coatings, rubber, cement
and asphalt formulations. The use of carbon tetrachloride for non-feedstock uses (i.e., process agent,
laboratory chemical) is regulated in accordance with the Montreal Protocol.
The 2016 CDR (reporting period 2012 to 2015) reporting data for carbon tetrachloride are provided in
Table 1-2 for carbon tetrachloride from EPA's CDR database (U.S. EPA. 2017b).
Table 1-2. Production Volume of Carbon Tetrachloride in Chemical Data Reporting (CDR)
Reporting Period (2012 to 2015)a
Reporting Year
2012
2013
2014
2015
Total Aggregate
Production Volume (lbs)
129,145,698
116,658,281
138,951,153
142,582,067
a (U.S. EPA. 2017b). Internal communication. The CDR data for the 2016 reoortine oeriod is available via ChemView
(httt>s://iava.er>a.eov/chemview) (U.S. EPA. 2016d).
1.3 Regulatory and Assessment History
1.3.1 Regulatory History
EPA conducted a search of existing domestic and international laws, regulations and assessments
pertaining to carbon tetrachloride. EPA compiled this summary from data available from federal, state,
international and other government sources, as cited in Appendix A. EPA evaluated and considered the
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impact of existing laws and regulations (e.g., regulations on landfill disposal, design, and operations) in
the problem formulation step to determine what, if any, further analysis might be necessary as part of the
risk evaluation (see section 2.5.3.2 in (U.S. EPA. 2018dV).
Federal Laws and Regulations
Carbon tetrachloride is subject to federal statutes or regulations, other than TSCA, that are implemented
by other offices within EPA and/or other federal agencies/departments. A summary of federal laws,
regulations and implementing authorities is provided in Appendix A.
State Laws and Regulations
Carbon tetrachloride is subject to state statutes or regulations implemented by state agencies or
departments. A summary of state laws, regulations and implementing authorities is provided in
Appendix A.
Laws and Regulations in Other Countries and International Treaties or Agreements
Carbon tetrachloride is subject to statutes or regulations in countries other than the United States and/or
international treaties and/or agreements. A summary of these laws, regulations, treaties and/or
agreements is provided in Appendix A.
EPA identified numerous previous assessments conducted by Agency Programs and other organizations
(see Table 1-3). Since the publication of the problem formulation, an additional assessment by the
National Advisory Committee for Acute Exposure Guideline Levels for Hazardous
Substances (NAC/AEGL Committee) has been identified. Depending on the source, these assessments
may include information on conditions of use, hazards, exposures and potentially exposed or susceptible
subpopulations.
Table 1-3. Assessment History of Carbon Tetrach
oride
Authoring Organization
Assessment
EPA assessments
U.S. EPA, Office of Water (OW)
Update of Human Health Ambient Water Oualitv
Criteria: Carbon Tetrachloride 56-23-5, EPA-HO-
OW-2014-0135-0182 (2015)
U.S. EPA, Integrated Risk Information System
(IRIS)
Toxicological Review of Carbon Tetrachloride In
SuDDort of Summary Information on IRIS (2010)
U.S. EPA, Office of Water
Carbon Tetrachloride Health Advisory, Office of
Drinking Water US Environmental Protection
Agencv (1987)
National Advisory Committee for Acute Exposure
Guideline Levels for Hazardous
Substances (NAC/AEGL Committee)
Carbon Tetrachloride - Final AEGL Document
(2014)
Other U.S.-based organizations
Agency for Toxic Substances and Disease Registry
(AT SDR)
Toxicological Profile for Carbon Tetrachloride
(2005)
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Authoring Organization
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California Environment Protection Agency, Office
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Public Health Goal for Carbon Tetrachloride
(2000)
International
Health Canada
Guidelines for Canadian Drinkins Water Oualitv,
Guideline Technical Document, Carbon
Tetrachloride (2010)
Organisation for Economic Co-operation and
Development's Screening Information Dataset
(OECD SIDS), Co-CAM, 10-12
SIDS SIAP for Carbon Tetrachloride (2011)
World Health Organization (WHO)
Carbon Tetrachloride in Drinkins Water,
Background document for development of WHO
Guidelines for Drinkins -water Oualitv (2004)
National Industrial Chemicals Notification and
Assessment Scheme (Australia)
Environment Tier II Assessment for Methane,
Tetrachloro- (2017, last update) (2017)
1.4 Scope of the Evaluation
1.4.1 Conditions of Use Included in the Risk Evaluation
TSCA § 3(4) defines the conditions of use as "the circumstances, as determined by the Administrator,
under which a chemical substance is intended, known, or reasonably foreseen to be manufactured,
processed, distributed in commerce, used, or disposed of." The life cycle diagram is presented below in
Figure 1-1. The conditions of use are described below in Table 1-4.
Workplace exposures and releases have been evaluated in this draft risk evaluation for the following
industrial/commercial uses of carbon tetrachloride:
1. Manufacture: Manufacturing
2. Manufacture: Import (including repackaging)
3. Processing: Reactant/Intermediate: Feedstock for HCFC, HFCs, HFO and PCE
4. Processing: Reactant/Intermediate: Reactive Ion Etching
5. Processing: Incorporation into Formulation, Mixture or Reaction Products
6. Industrial/Commercial Use: DoD Specialty Uses
7. Industrial/Commercial Use: Laboratory Chemical,
8. Industrial/Commercial Use Processing agent/aid
9. Industrial/Commercial Use: Additive
10. Disposal: Waste Handling
1.4.2 Subcategories Determined Not To Be Conditions of Use
1.4.2.1 Specialty Uses - Aerospace Industry
EPA conducted public outreach and literature searches to collect information about carbon tetrachloride
conditions of use and has reviewed reasonably available information obtained or possessed by EPA
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concerning activities associated with carbon tetrachloride. As a result of that review, EPA has
determined uses of carbon tetrachloride that were previously thought to be a condition of use are no
longer used in current practices and are not reasonably foreseen to be resumed. Consequently, EPA will
not consider or evaluate these activities or associated hazards or exposures in the risk evaluation for
carbon tetrachloride. Specialty uses of carbon tetrachloride, specifically adhesives and cleaning
operations, were identified in the aerospace industry based on information provided by the Aerospace
Industries Association (AIA) (Riegle. 2017). However, upon reaching out to AIA for specific use
details, AIA replied with the following statement:
After additional investigation, usage identified by AIA companies were based upon products that
have been discontinued. There appear to be products that contain trace amounts of carbon
tetrachloride (< 1%) that might be a reaction by-product, contaminant or imperfect distillation of
perchloroethylene. Therefore, carbon tetrachloride is no longer an AIA concern. (AIA. 2019)
Based on all present information, EPA did not evaluate the use of carbon tetrachloride in cleaning
operations (vapor degreasing, etc.) or use as an adhesive in the aerospace industry as there are no data
supporting its use in the industry and there is no significant human exposure from products used in the
aerospace industry. Additionally, there are current regulatory actions (The Montreal Protocol and CAA
Title VI) that prohibit the direct use of carbon tetrachloride in the formulation of commercially available
products for industrial/commercial/consumer uses (including aerosol and non-aerosol
adhesives/sealants, paints/coatings, and cleaning/degreasing solvent products), except as a laboratory
chemical (Problem Formulation section 2.2.2.1) (U.S. EPA. 2018d).
1.4.2.2 Manufacturing of Pharmaceuticals
EPA had identified uses of carbon tetrachloride as a process agent in the manufacturing of
pharmaceuticals (i.e., ibuprofen) in the problem formulation (U.S. EPA. 2018d). In 1983, EPA presented
a report entitled Preliminary Study of Sources of Carbon Tetrachloride: Final Report. This report stated
that carbon tetrachloride was used as a solvent to dissolve solid reactants during the pharmaceutical
manufacturing process, which included ibuprofen (U.S. EPA. 1983). However, the Science History
Institute published an article titled, The Greening of Chemistry, which explains that ibuprofen was once
manufactured with the use of multiple solvents, one of which was carbon tetrachloride. It continues to
explain, ".. .in the early 1990s ibuprofen got a makeover. Using catalysts rather than excess reagents to
drive the reactions, chemists halved the number of stages in the ibuprofen manufacturing process and
eliminated carbon tetrachloride, a toxic solvent, from the process" (Hoag. 2016). EPA found no
evidence to suggest that the manufacturing of ibuprofen, or any other pharmaceuticals, still utilizes
carbon tetrachloride or that such use is reasonably foreseen to resume. Accordingly, EPA no longer
considers use as a process agent in the manufacturing of pharmaceuticals to be a condition of use of
carbon tetrachloride and does not evaluate it in this draft risk evaluation.
1.4.2.3 Exclusions During Problem Formulation
In problem formulation, EPA removed from the risk evaluation any activities and exposure pathways
that EPA concluded do not warrant inclusion in the risk evaluation. Consequently, EPA did not evaluate
these activities and conditions of use or associated hazards or exposures in the risk evaluation for carbon
tetrachloride. For example, for one activity that was listed as a "condition of use" in the scope document,
incorporation of carbon tetrachloride into an article, EPA had insufficient information following the
further investigations during problem formulation to find that it is a circumstance under which the
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chemical is actually "intended, known, or reasonably foreseen to be manufactured, processed,
distributed in commerce, used, or disposed of (U.S. EPA. 2018d).
In addition, there are conditions of use for which EPA had sufficient basis to conclude during problem
formulation would present only de minimis exposures or otherwise insignificant risks and that did not
warrant further evaluation or inclusion in the risk evaluation. These activities and conditions of use
consist of industrial/commercial/consumer uses of carbon tetrachloride in commercially available
aerosol and non-aerosol adhesives/sealants, paints/coatings, and cleaning/degreasing solvent products.
Based on information obtained by EPA, there are no approved consumer uses for carbon tetrachloride.
There are current regulatory actions that prohibit the direct use of carbon tetrachloride as a reactant or
additive in the formulation of commercially available products for industrial/commercial/consumer uses
(including aerosol and non-aerosol adhesives/sealants, paints/coatings, and cleaning/degreasing solvent
products), except as a laboratory chemical. The use of carbon tetrachloride (and mixtures containing it)
in household products has also been banned by CPSC since 1970, with the exception of "unavoidable
manufacturing residues of carbon tetrachloride in other chemicals that under reasonably foreseen
conditions of use do not result in an atmospheric concentration of carbon tetrachloride greater than 10
parts per million." 16 CFR 1500.17(a)(2).
The domestic and international use of carbon tetrachloride as a process agent is addressed under the
Montreal Protocol (MP) side agreement, Decision X/14: Process Agents (UNEP/Ozone Secretariat.
1998). This decision lists a limited number of specific manufacturing uses of carbon tetrachloride as a
process agent (non-feedstock use) in which carbon tetrachloride may not be destroyed in the production
process. Based on the process agent applications, carbon tetrachloride is used in the manufacturing of
other chlorinated compounds that may be subsequently added to commercially available products (i.e.,
solvents for cleaning/degreasing, adhesives/sealants, and paints/coatings). Given the high volatility of
carbon tetrachloride and the extent of reaction and efficacy of the separation/purification process for
purifying final products, EPA expects insignificant or unmeasurable concentrations of carbon
tetrachloride as a manufacturing residue in the chlorinated substances in the commercially available
products. In its regulations on the protection of stratospheric ozone at 40 CFR part 82, EPA excludes
from the definition of controlled substance the inadvertent or coincidental creation of insignificant
quantities of a listed substance (including carbon tetrachloride) resulting from the substance's use as a
process agent (40 CFR 82.3). These expectations and current regulations are consistent with public
comments received by EPA, EPA-HQ-QPPT-2016-0733-0005 and EPA-HQ-QPPT-2016-0733-0017.
stating that carbon tetrachloride may be present in a limited number of industrial products with
chlorinated ingredients at a concentration of less than 0.003% by weight.
Based on the information identified by EPA, carbon tetrachloride is not a direct reactant or additive in
the formulation of solvents for cleaning and degreasing, adhesives and sealants or paints and coatings.
Because industrial, commercial, and consumer use of such products (solvents for cleaning/degreasing,
adhesives/sealants, and paints/coatings) would present only de minimis exposure to or otherwise
insignificant risk from manufacturing residues of carbon tetrachloride in chlorinated compounds, EPA
determined during problem formulation that these conditions of use did not warrant evaluation, and EPA
has not considered or evaluated these conditions of use or associated hazards or exposures in the risk
evaluation for carbon tetrachloride.
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MFG/IMPORT PROCESSING INDUSTRIAL, COMMERCIAL USESa RELEASES and WASTE DISPOSAL
| | Manufacture (includes Import)
~ Processing
~ Industrial/commercial use
Recycling
Repackaging
(Volume not reported)
Manufacture
(includes import)
(142.6 Million lbs)
Laboratory Chemicals
e.g. extraction solvent
Incorporated into
Formulation, Mixture,
or Reaction Products
(Volume not reported)
Disposal b
Processing as
Reactant/lntermediate
(Volume CBI)
e.g. Intermediate for
refrigerant manufacture;
other chlorinated
compounds (PCE); reactive
ion etching
Other Basic Organic and Inorganic
Chemical Manufacturing
(Volume CBI or not reported)
e.g. Manufacturing of organic and inorganic
compounds as listed in MP Decision X/14
Directive), some of which can be used in
manufacturing of Solvents for Cleaning and
Degreasing, Adhesives, Sealants, Paints and
Coati ngs.
Petrochemical-derived and
Agricultural Products
Manufacturing
(Volume CBI or not reported)
[uses listed in Montreal Protocol's (MP)
Decision X/14 Directive).
Other Uses
e.g., metal recovery; specialty uses
Figure 1-1. Carbon Tetrachloride Life Cycle Diagram
The life cycle diagram depicts the conditions of use that are within the scope of the risk evaluation during various life cycle stages including
manufacturing, processing, use (industrial/commercial), distribution and disposal. The production volumes shown are for reporting year 2015
from the 2016 CDR reporting period (U.S. EPA. 2016d). Activities related to distribution (e.g., loading, unloading) will be considered
throughout the carbon tetrachloride life cycle, rather than using a single distribution scenario.
a See Table 1 -4 for additional uses not mentioned specifically in this diagram.
b Disposal refers to the following activities - Industrial pre-treatment, Industrial wastewater treatment, publicly owned treatment works (POTW), Underground injection
Municipal landfill. Hazardous landfill. Other land disposal. Municipal waste incinerator. Hazardous waste incinerator. Off-site waste transfer
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1114 Table 1-4. Categories and Subcategories of Conditions of Use Included in the Scope of the
1115 Risk Evaluation
Life Cycle Stage
Category3
Subcategoryb
References
Manufacture
Domestic
Manufacture
Domestic manufacture
(U.S. EPA. 2016d)
Import
Import
(U.S. EPA. 2016d)
Processing
Processing as a
Reactant/
Intermediate
Hy drochl orofluorocarb ons
(HCFCs), Hydrofluorocarbon
(HFCs) and
Hydrofluoroolefin (HFOs)
Use document, EPA-
HO-OPPT-2016-073 3-
0003; Public comments,
EP A-HO-OPPT-2016-
0733-0007. EPA-HO-
OPPT-2016-0733-0008.
EP A-HO-OPPT-2016-
0733-0016 and EPA-
HO-OPPT-2016-073 3-
0064; (U.S. EPA.
2016d)
Perchloroethylene (PCE)
Use document, EPA-
HO-OPPT-2016-073 3-
0003; Public comments,
EP A-HO-OPPT-2016-
0733-0007 and EPA-
HO-OPPT-2016-073 3-
0008; (U.S. EPA.
2016d)
Reactive ion etching (i.e.,
semiconductor
manufacturing)
Use document, EPA-
HO-OPPT-2016-073 3-
0003; Public comment,
EP A-HO-OPPT-2016-
0733-0063
Incorporation into
Formulation,
Mixture or Reaction
Products
Petrochemicals-derived
manufacturing; Agricultural
products manufacturing;
Other basic organic and
inorganic chemical
manufacturing.
(TJ.S. EPA. 2016d); Use
document, EPA-HO-
OPPT-2016-0733-0003;
(TJ.S. EPA. 2016b);
(TJNEP/Ozone
Secretariat, 1998);
Public comment, EPA-
HO-OPPT-2016-073 3-
0064
Processing -
repackaging
Laboratory Chemicals
(TJ.S. EPA. 2016b)
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Recycling
Recycling
(U.S. EPA. 2016d).
(U.S. EPA. 2016b)
Distribution in
commerce
Distribution
Distribution in commerce
(U.S. EPA. 2016b); Use
document, EPA-HO-
OPPT-2016-0733-0003.
Industrial/commercial
use
Petrochemicals-
derived Products
Manufacturing
Processing aid
Use document, EPA-
HO-OPPT-2016-073 3-
0003; (U.S. EPA.
2016d); OJNEP/Ozone
Secretariat, 1998)
Additive
Use document, EPA-
HO-OPPT-2016-073 3-
0003; Public comment,
EP A-HO-OPPT-2016-
0733-0012; (U.S. EPA.
2016b); OJNEP/Ozone
Secretariat, 1998)
Agricultural
Products
Manufacturing
Processing aid
(U.S. EPA. 2016d). Use
document, EPA-HO-
OPPT-2016-0733-0003;
Public comments, EPA-
HO-OPPT-2016-073 3-
0007 and EPA-HO-
OPPT-2016-0733-0008;
(XJNEP/Ozone
Secretariat, 1998)
Other Basic Organic
and Inorganic
Chemical
Manufacturing
Manufacturing of chlorinated
compounds used in solvents
for cleaning and degreasing
Use document, EPA-
HO-OPPT-2016-073 3-
0003; Public comments,
EP A-HO-OPPT-2016-
0733-0011. EPA-HO-
OPPT-2016-0733-0012
and EPA-HO-OPPT-
2016-0733-0015;
(XJNEP/Ozone
Secretariat, 1998)
Manufacturing of chlorinated
compounds used in adhesives
and sealants
Use document, EPA-
HO-OPPT-2016-073 3-
0003; Public comments,
EP A-HO-OPPT-2016-
0733-0011. EPA-HO-
OPPT-2016-073 3-0024.
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EP A-HO-OPPT-2016-
0733-0012. and EPA-
HO-OPPT-2016-073 3-
0015; (UNEP/Ozone
Secretariat, 1998)
Manufacturing of chlorinated
compounds used in paints
and coatings
Use document, EPA-
HO-OPPT-2016-073 3-
0003 Public comment,
EP A-HO-OPPT-2016-
0733-0024;
(UNEP/Ozone
Secretariat, 1998)
Manufacturing of inorganic
chlorinated compounds (i.e.,
elimination of nitrogen
trichloride in the production
of chlorine and caustic)
Public comment, EPA-
HO-OPPT-2016-073 3-
0027; (TJNEP/Ozone
Secretariat, 1998)
Manufacturing of chlorinated
compounds used in asphalt
Use document, EPA-
HO-OPPT-2016-073 3-
0003; (UNEP/Ozone
Secretariat, 1998)
Other Uses (i.e.,
Specialty Uses)
Processing aid (i.e., metal
recovery, DoD uses).
Use document, EPA-
HO-OPPT-2016-073 3-
0003
Laboratory
Chemicals
Laboratory chemical
Use document, EPA-
HO-OPPT-2016-073 3-
0003; (U.S. EPA.
2016d\ Public
comments, EPA-HO-
OPPT-2016-0733-0007;
EP A-HO-OPPT-2016-
0733-0013 andEPA-
HO-OPPT-2016-073 3-
0063
Disposal
Disposal0
Industrial pre-treatment
CU.S. EPA. 2017a)
Industrial wastewater
treatment
CU.S. EPA. 2017a)
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Publicly owned treatment
works (POTW)
(U.S. EPA. 2017a)
Underground injection
(U.S. EPA. 2017a)
Municipal landfill
(U.S. EPA. 2017a)
Hazardous landfill
(U.S. EPA. 2017a)
Other land disposal
(U.S. EPA. 2017a)
Municipal waste incinerator
(U.S. EPA. 2017a)
Hazardous waste incinerator
(U.S. EPA. 2017a)
Off-site waste transfer
(U.S. EPA. 2017a)
aThese categories of conditions of use appear in the Life Cycle Diagram, reflect CDR codes and broadly represent
conditions of use of carbon tetrachloride in industrial/commercial settings.
bThese subcategories reflect more specific uses of carbon tetrachloride.
Disposal subcategories were evaluated for workplace exposures.
1116
1117 1.4.3 Conceptual Models
1118 EPA considered the potential for hazards to human health and the environment resulting from
1119 exposure pathways outlined in the preliminary conceptual models of the carbon tetrachloride
1120 scope document (U.S. EPA. 2017e). The preliminary conceptual models were refined in the
1121 problem formulation document (U.S. EPA. 2018d). Based on review and evaluation of
1122 reasonably available data for carbon tetrachloride, EPA determined in the problem formulation
1123 that no further analysis of the environmental release pathways outlined in the conceptual models
1124 was necessary due to a qualitative assessment of the physical chemical properties and fate of
1125 carbon tetrachloride in the environment, and a quantitative comparison of hazards and exposures
1126 for aquatic organisms.
1127
1128 Upon further evaluation of the reasonably available hazard data of carbon tetrachloride after the
1129 problem formulation phase, EPA decreased the environmental hazard chronic COC from 7 |ig/L
1130 to 3 |ig/L and conducted further analysis of the aquatic pathway to evaluate potential risk to
1131 aquatic organisms from carbon tetrachloride. The conceptual models for this risk evaluation are
1132 shown below in Figure 1-2 and Figure 1-3.
1133
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INDUSTRIAL AND COMMERCIAL EXPOSURE PATHWAY EXPOSURE ROUTE
ACTIVITIES / USES
Manufacturing
Processing:
As reactant/ intermediate
Repackaging
Liquid Contact
Dermal
Recycling
Hazards Potentially Associated with
Acute and/or Chronic Exposures
Workers
Inhalation
Petrochemical-derived
and Agricultural Products
Manufacturing
Fugitive
Emissionsa
Occupational
Outdoor Air
Other Basic Organic and
InorganicChemical
Manufacturing
Other Uses
Laboratory Chemicals
~ Pathways that are analyzed in the risk evaluation.
~ Pathways that are in the risk evaluation with no further analysis.
Waste Handling,
Treatment and Disposal
Wastewater, Liquid Wastes
Figure 1-2. Carbon Tetrachloride Conceptual Model for Industrial/Commercial Activities and Uses: Potential Exposures and
Hazards
The conceptual model presents the exposure pathways, exposure routes and hazards to human receptors from industrial/commercial
activities and uses of carbon tetrachloride.
"¦Fugitive air emissions include fugitive equipment leaks from valves, pump seals, flanges, compressors, sampling connections, open-ended lines; evaporative
losses from surface impoundment and spills; and releases from building ventilation systems.
includes possible vapor intrusion into industrial/commercial facility from carbon tetrachloride ground water; exposure to mists is not expected for ONU.
°Receptors include PESS.
dWhen data and information are available to support the analysis, EPA also considers the effect that engineering controls and/or personal protective equipment
have on occupational exposure levels.
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1145
RELEASES AND WASTES FROM EXPOSURE PATHWAY RECEPTORS HAZARDS
INDUSTRIAL / COMMERCIAL USES
discharge
Aquatic
Species
Water,
Sediment
POTW
Wastewater or
Liquid Wastes
Indirect discharge
Industrial Pre-
Treatment or
Industrial WWT
Hazards Potentially Associated with
Acute and Chronic Exposures
KEY:
Pathways that are included in the risk evaluation.
1147
1148 Figure 1-3. Carbon Tetrachloride Conceptual Model for Environmental Releases and Wastes: Potential Exposures and
1149 Hazards
1150 The conceptual model presents the exposure pathways, exposure routes and hazards to environmental receptors from environmental
1151 water releases of carbon tetrachloride.
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1.5 Systematic Review
TSCA requires EPA to use scientific information, technical procedures, measures, methods,
protocols, methodologies and models consistent with the best available science and base
decisions under TSCA section 6 on the weight of scientific evidence. Within the TSCA risk
evaluation context, the weight of the scientific evidence is defined as "a systematic review
method, applied in a manner suited to the nature of the evidence or decision, that uses a pre-
established protocol to comprehensively, objectively, transparently, and consistently identify and
evaluate each stream of evidence, including strengths, limitations, and relevance of each study
and to integrate evidence as necessary and appropriate based upon strengths, limitations, and
relevance" (40 C.F.R 702.33).
To meet the TSCA science standards, EPA will be guided by the systematic review process
described in the Application of Systematic Review in TSCA Risk Evaluations document (U.S.
EPA. 2018a). The process complements the risk evaluation process in that the data collection,
data evaluation and data integration stages of the systematic review process are used to develop
the exposure and hazard assessments based on reasonably available information. EPA defines
"reasonably available information" to mean information that EPA possesses, or can reasonably
generate, obtain and synthesize for use in risk evaluations, considering the deadlines for
completing the evaluation (40 C.F.R. 702.33).
EPA is implementing systematic review methods and approaches within the regulatory context
of the amended TSCA. Although EPA will make an effort to adopt as many best practices as
practicable from the systematic review community, EPA expects modifications to the process to
ensure that the identification, screening, evaluation and integration of data and information can
support timely regulatory decision making under the aggressive timelines of the statute.
1.5.1 Data and Information Collection
EPA planned and conducted a comprehensive literature search based on key words related to the
different discipline-specific evidence supporting the risk evaluation (e.g., environmental fate and
transport; engineering releases and occupational exposure; environmental exposure; and
environmental and human health hazard). EPA then developed and applied inclusion and
exclusion criteria during the title and abstract screening to identify information potentially
relevant for the risk evaluation process. The literature and screening strategy as specifically
applied to carbon tetrachloride is described in the Application of Systematic Review in TSCA Risk
Evaluations (U.S. EPA. 2018a) and results of screening were published in Carbon tetrachloride
(CASRN 56-23-5) Bibliography: Supplemental File for the TSCA Scope Document (U.S. EPA.
2017a).
For studies determined to be on-topic (or relevant) after title and abstract screening, EPA
conducted a full text screening to further exclude references that were not relevant to the risk
evaluation. Screening decisions were made based on eligibility criteria documented in the form
of the populations, exposures, comparators, and outcomes (PECO) framework or a modified
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framework.2 Data sources that met the criteria were carried forward to the data evaluation stage.
The inclusion and exclusion criteria for full text screening for carbon tetrachloride are available
in Appendix F of the Problem Formulation of the Risk Evaluation for Carbon Tetrachloride
(U.S. EPA. 2018d).
In addition to the comprehensive literature search and screening process described above, EPA
leverage the information presented in previous assessments,3 when identifying relevant key and
supporting data,4 and information for developing the carbon tetrachloride risk evaluation. This is
discussed in the Strategy for Conducting Literature Searches for Carbon Tetrachloride:
Supplemental Document to the TSCA Scope Document (EPA-HQ-QPPT-2016-0733-0050). In
general, many of the key and supporting data sources were identified in the comprehensive
Carbon tetrachloride (CASRN 56-23-5) Bibliography: Supplemental File for the TSCA Scope
Document (U.S. EPA. 2017a). However, there were instances that EPA missed relevant
references that were not captured in the initial categorization of the on-topic references. EPA
found additional relevant data and information using backward reference searching, which was a
technique that will be included in future search strategies. This issue was discussed in section 4
of the Application of Systematic Review for TSCA Risk Evaluations (U.S. EPA. 2018a). Other
relevant key and supporting references were identified through targeted supplemental searches to
support the analytical approaches and methods in the carbon tetrachloride risk evaluation (e.g., to
locate specific information for exposure modeling) or to identify new data and information
published after the date limits of the initial search.
EPA used previous chemical assessments to quickly identify relevant key and supporting
information as a pragmatic approach to expedite the quality evaluation of the data sources, but
many of those data sources were already captured in the comprehensive literature search as
explained above. EPA also considered newer information not taken into account by previous
chemical assessments as described in the Strategy for Conducting Literature Searches for
Carbon Tetrachloride: Supplemental Document to the TSCA Scope Document (EPA-HQ-OPPT-
2016-0733-0050). EPA then evaluated the confidence of this information rather than evaluating
the confidence of all the underlying evidence ever published on carbon tetrachloride's fate and
transport, environmental releases, and environmental and human exposure and hazard potential.
Such a comprehensive evaluation of all of the data and information ever published for a chemical
substance would be extremely labor intensive and could not be achieved under the TSCA
statutory deadlines for most chemical substances, especially those that have a data rich database.
EPA also considered how this approach to data gathering would change the conclusions
presented in the previous assessments.
2 A PESO statement was used during the full text screening of environmental fate and transport data sources. PESO stands for
Pathways and Processes, Exposure, Setting or Scenario, and Outcomes. A RESO statement was used during the full text
screening of the engineering and occupational exposure literature. RESO stands for Receptors, Exposure, Setting or Scenario,
and Outcomes.
3 Examples of existing assessments are EPA's chemical assessments (e.g. previous work plan risk assessments, problem
formulation documents), ATSDR's Toxicological Profiles, EPA's IRIS assessments and ECHA's dossiers. This is described in
more detail in the Strategy' for Conducting Literature Searches for Carbon Tetrachloride: Supplemental File for the TSCA
Scope Document fEPA-HO-OPPT-2016-0733-005Q'i.
4 Key and supporting data and information are those that support key analyses, arguments, and/or conclusions in the risk
evaluation.
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Using this pragmatic approach, EPA maximized the scientific and analytical efforts of other
regulatory and non-regulatory agencies by accepting for the most part, the relevant scientific
knowledge gathered and analyzed by others, except for influential information sources that may
impact the weight of the scientific evidence underlying EPA's findings. This influential
information (i.e., key/supporting studies) came from a smaller pool of information sources
subjected to the rigor of the TSCA systematic review process to ensure that the best available
science is incorporated into the weight of the scientific evidence used to support the carbon
tetrachloride draft risk evaluation.
The literature flow diagrams shown in Figure 1-4, Figure 1-5, Figure 1-6, Figure 1-7 and Figure
1-8 highlight the results obtained for each scientific discipline based on this approach. Each
diagram provides the total number of references considered at the start of each systematic review
stage (i.e., data search, data screening, data evaluation, data extraction/data integration) and those
excluded based on criteria guiding EPA's screening and data quality evaluation decisions.
EPA made the decision to bypass the data screening step for data sources that were highly
relevant to the draft risk evaluation as described above. These data sources are depicted as
"key/supporting data sources" in the literature flow diagrams. Note that the number of
"key/supporting data sources" were excluded from the total count during the data screening stage
and added, for the most part, to the data evaluation stage depending on the discipline-specific
evidence. The exception was the engineering releases and occupational exposure data sources
that were subject to a combined data extraction and evaluation step (Figure 1-5).
Data Integration (n=37) I
Data Extraction,1'
Data Screening (n=5,093)
D ata Search Results (n=5,093)
Data Evaluation (n=39)
*Key' Supp orting
Data Sources (n=l)
Excluded References
(n=5,055)
Excluded: Ref that are
unacc eptable based on the
evaluation criteria (rF=2)
*These are key and supporting studies from existing assessments (e.g., EPA IRES assessments, ATSDR assessments,
ECHA dossiers) that were highly relevant for the TSCArisk evaluation. These studies bypassed the data screening
step and moved directly to the data evaluation step. Data sources identified relevant to physical-chemical
properties were not included in this literature flow diagram. The data quality evaluation of physical-chemical
properties studies can be found in the supplemental document. Data Quality Evaluation of Physical-Chemical
Properties Studies (Docket: ERA-HQ- OPPT-2019-0499) and the extracted data are presented in Table 1-1.
Figure 1-4. Key/Supporting Data Sources for Environmental Fate and Transport
The number of publications considered in each step of the systematic review of the carbon
tetrachloride's fate and transport literature is summarized in Figure 1-4. Literature on the
environmental fate and transport of carbon tetrachloride were gathered and screened as described
in Appendix C of the Application of Systematic Review in TSCA Risk Evaluations (U.S. EPA.
2018a). Additional information regarding the literature search and screening strategy for carbon
tetrachloride is provided in EPA's Strategy for Conducting Literature Searches for Carbon
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Tetrachloride: Supplemental File for the TSCA Scope Document (EPA-HQ-QPPT-2016-0733-
0050). The results of this screening are published in the Carbon tetrachloride (CASRN 56-23-5)
Bibliography: Supplemental File for the TSCA Scope Document (U.S. EPA. 2017a).
Data Search Results (n=5,143)
n=i4!
Key/supporting
data sources
(n=9)
Excluded References (n=5.002)
"Data Sources that were not
integrated (n=47)
Excluded Ref that are
unacceptable based on
evaluation criteria (n=94)
Data Integration (n=9)
Data Extraction/Data Evaluation (n=150)
Data Screening (n=5,143)
"The quality of data in these sources (n=47) were acceptable for risk assessment purposes, but they were ultimately
excluded from further consideration based on EPAs integration approach for environmental release and occupational
exposure data/information EPAs approach uses a hierarchy of preferences that guide decisions about what types of
data/information are included for further analysis, synthesis and integration into the environmental release and
occupational exposure assessments EPA prefers using data with the highest rated quality among those in the higher
level of the hierarchy of preferences (i e, data > modeling > occupational exposure limits or release limits) If warranted
EPA may use data/information of lower rated quality as supportive evidence in the environmental release and
occupational exposure assessments
Figure 1-5. Key/Supporting Data Sources for Releases and Occupational Exposures
As shown in Figure 1-5, the literature search strategy for carbon tetrachloride's environmental
releases and occupational exposures yielded 5,143 data sources. Of these data sources, 141 were
determined to be relevant to the risk evaluation through the data screening process. These
relevant data sources were entered to the data extraction/evaluation phase. After data
extraction/evaluation, EPA identified several data gaps and performed a supplemental targeted
search to address these gaps (e.g. to locate information needed for exposure modeling). The
supplemental search yielded 9 relevant data sources that bypassed the data screening step and
were evaluated and extracted in accordance with Appendix D of Data Quality Criteria for
Occupational Exposure and Release Data of th q Application of Systematic Review in TSCA Risk
Evaluations (U.S. EPA. 2018a). Of the 150 sources from which data were extracted and
evaluated, 94 sources only contained data that were rated as unacceptable based on flaws
detected during the evaluation. Of the 56 sources forwarded for data integration, data from 9
sources were integrated, and 47 sources contained data that were not integrated (e.g., lower
quality data that were not needed due to the existence of higher quality data, data for release
media that were removed from scope after data collection).
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Key/supporting
data sources
(n= 0)
Excluded References (n=393)
Data Search Results (n=393
Excluded: Ref that are
unacceptable based on
evaluation criteria (n=0)
Data Extraction/Data Integration (n=0>
Data Evaluation (n =0 )
Data Screening (n=393
"These are key and supporting data sources from existing assessments (e.g.. EPA IRIS assessments. ATSDR
assessments, ECHA dossiers) that were highly relevant for the TSCA risk evaluation. These studies bypassed
the data screening step and moved directly to the data evaluation step.
Figure 1-6. Key/Supporting Sources for Environmental Exposures
The number of data and information sources considered in each step of the systematic review of
carbon tetrachloride literature on environmental exposure is summarized in Figure 1-6. The
literature search results for environmental exposures yielded 393 data sources. Of these data
sources, none were determined to be relevant to the draft risk evaluation through the data
screening process.
(n *'
Data Extraction I Data Integration (n -14)
Evaluation (n = 75)
Full Text Screening (n = 628)
Data Search Results (n ¦ 10469 )
Title /Abstract Screening (n »10469)
Figure 1-7. Key/Supporting Sources for Environmental Hazards
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The environmental hazard data sources were identified through literature searches and screening
strategies using the ECOTOX Standing Operating Procedures. For studies determined to be on-
topic after title and abstract screening, EPA conducted a full text screening to further exclude
references that were not relevant to the risk evaluation. Screening decisions were made based on
eligibility criteria as documented in the ECOTOX User Guide (U.S. EPA. 2018c). Additional
details can be found in the Strategy for Conducting Literature Searches for Carbon
Tetrachloride: Supplemental Document to the TSCA Scope Document, EPA-HQ-OPPT-2016-
0733-0050. During problem formulation, EPA made refinements to the conceptual models
resulting in the exclusion of the terrestrial species exposure pathways and studies that are not
biologically relevant from the scope of the risk evaluation. The terrestrial species exposure
pathways were considered to be covered under programs of other environmental statues
administered by EPA, which adequately assess and effectively manage such exposures
(e.g., RCRA, CAA). Therefore, environmental hazard data sources on terrestrial organisms and
on metabolic endpoints were excluded from data quality evaluation. The "Key/Supporting
Studies" box represents data sources typically cited in existing assessments and considered
highly relevant for the TSCA risk evaluation because they were used as key and supporting
information by regulatory and non-regulatory organizations to support their chemical hazard and
risk assessments. These citations were found independently from the ECOTOX process. These
studies bypassed the data screening step and moved directly to the data evaluation step.
n=15
Key/supporting
data sources
(n = 18)
Excluded References (n = 6454)
Data Search Results (n = 6.489
Excluded: Ref that are
unacceptable based on
evaluation criteria (n = 4)
Data Extraction/Data Integration (n = 29)
Data Evaluation (n = 33)
Data Screening (n = 6,471 )
Figure 1-8. Key/Supporting Data Sources for Human Health Hazards
The literature search strategy used to gather human health hazard information for carbon
tetrachloride yielded 6,489 studies. This included 18 key and supporting studies (identified from
previous regulatory assessments) that skipped the initial screening process and proceeded
directly to the data evaluation phase. Of the 6,489 studies identified for carbon tetrachloride
6,454 were excluded as off topic during the title and abstract screening phase. The remaining 15
human health hazard studies advanced to full text screening; a total of 29 studies were
determined to be relevant to the draft risk evaluation. These relevant data sources were evaluated
and extracted in accordance with the process described in Appendix G of the Application of
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Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018a). Additional details can be found
in EPA's Strategy for Strategy for Conducting Literature Searches for Carbon Tetrachloride:
Supplemental Document to the TSCA Scope Document (EPA-HQ-QPPT-2016-0733-0050).). The
results of this screening process are published in the Carbon tetrachloride (CASRN 56-23-5)
Bibliography: Supplemental File for the TSCA Scope Document (U.S. EPA. 2017a).
1.5.2 Data Evaluation
During the data evaluation stage, EPA typically assesses the quality of the data sources using the
evaluation strategies and criteria described in Application of Systematic Review in TSCA Risk
Evaluations (U.S. EPA. 2018a). EPA evaluated the quality of the all data sources that passed
full-text screening. Each data source received an overall confidence rating of high, medium, low
or unacceptable.
The results of these data quality evaluations are provided in sections 1.1 (Physical and Chemical
Properties), 2.1 (Fate and Transport) and 2.5.2 (Hazards). Supplemental files 1A - 1H (see list of
supplemental files in Appendix B) also provide details of the data evaluations including
individual metric scores and the overall study score for each data source.
1.5.3 Data Integration
During data integration and analysis, EPA considers quality, consistency, relevancy, coherence
and biological plausibility to make final conclusions regarding the weight of the scientific
evidence. As stated in Application of Systematic Review in TSCA Risk Evaluations (U.S. EPA.
2018a). data integration involves transparently discussing the significant issues, strengths, and
limitations as well as the uncertainties of the reasonably available information and the major
points of interpretation (U.S. EPA. 2018e).
EPA used previous assessments to identify key and supporting information and then analyzed
and synthesized available evidence regarding carbon tetrachloride's chemical properties,
environmental fate and transport properties and its potential for exposure and hazard. EPA's
analysis also considered recent data sources that were not considered in the previous assessments
(section 1.5.1) as well as reasonably available information on potentially exposed or susceptible
subpopulations.
The exposures and hazards sections describe EPA's analysis of the relevant lines of evidence that
were found acceptable for the risk evaluation based on the data quality reviews provided in the
supplemental files.
2 EXPOSURES
This section describes EPA's approach to assessing environmental and human exposures. First,
the fate and transport of carbon tetrachloride in the environment is characterized. Then, carbon
tetrachloride's environmental releases are assessed. This information is then integrated into an
assessment of environmental exposures. Last, occupational exposures (including potentially
exposed or susceptible subpopulations) are assessed. For all exposure-related disciplines, EPA
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screened, evaluated, extracted and integrated reasonably available empirical data. In addition,
EPA used models to estimate exposures. Both empirical data and modeled estimates were
considered when selecting values for use in the exposure assessment.
2.1 Fate and Transport
2.1.1 Fate and Transport Approach and Methodology
EPA gathered and evaluated environmental fate information according to the process described
in the Application of Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018a).
Reasonably available environmental fate data were selected for use in the current evaluation.
Furthermore, EPA used previous regulatory and non-regulatory chemical assessments to inform
the environmental fate and transport information discussed in this section and Appendix C. EPA
had confidence in the information used in the previous assessments to describe the
environmental fate and transport of carbon tetrachloride and thus used it to make scoping
decisions.
EPA conducted a comprehensive search and screening process as described in section 1.5. Using
this pragmatic approach, EPA evaluated the confidence of the key and supporting data sources of
previous assessments as well as newer information instead of evaluating the confidence of all the
underlying evidence ever published on environmental fate and transport for carbon tetrachloride.
This allowed EPA to maximize the scientific and analytical efforts of other regulatory and non-
regulatory agencies by accepting for the most part the scientific knowledge gathered and
analyzed by others except for influential information sources. Those exceptions would constitute
a smaller pool of sources subject to the rigor of the TSCA systematic review process to ensure
that the risk evaluation uses the best available science and the weight of the scientific evidence.
Other fate estimates were based on modeling results from EPI Suite™ (U.S. EPA. 2012a). a
predictive tool for physical/chemical and environmental fate properties. The data evaluation
tables describing their review can be found in the supplemental document, Risk Evaluation for
Carbon Tetrachloride, Systematic Review Supplemental File: Data Quality Evaluation of
Environmental Fate and Transport Studies (U.S. EPA. 2019c).
The carbon tetrachloride environmental fate characteristics and physical-chemical properties
used in fate assessment are presented in Table 2-1. EPA used EPI Suite™ estimations and
reasonably available fate data to characterize the environmental fate and transport of carbon
tetrachloride. Please note that this section and Appendix C may also cite other data sources as
part of the reasonably available evidence on the fate and transport properties of carbon
tetrachloride. EPA did not subject these other data sources to the later phases of the systematic
review process (i.e., data evaluation and integration) based on the approach explained above.
2.1.2 Fate and Transport
Environmental fate includes both transport and transformation processes. Environmental
transport is the movement of the chemical within and between environmental media.
Transformation occurs through the degradation or reaction of the chemical with other species in
the environment. Hence, knowledge of the environmental fate of the chemical informs the
determination of the specific exposure pathways and potential human and environmental
receptors EPA considered in the risk evaluation. Table 2-1 provides environmental fate data that
EPA identified and considered in developing the scope for carbon tetrachloride. This information
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has not changed from that provided in the scope and problem formulation documents (U.S. EPA.
2018d).
During problem formulation, EPA considered volatilization during wastewater treatment,
volatilization from lakes and rivers followed by upward diffusion in the troposphere,
biodegradation rates, and soil organic carbon:water partition coefficient (log Koc) when making
changes to the conceptual models, as described in section 2.5.3.1 of the problem formulation
document (U.S. EPA. 2018d).
EPI Suite™ (U.S. EPA. 2012a) modules were used to predict volatilization of carbon
tetrachloride from wastewater treatment plants, lakes, and rivers. The EPI Suite™ module that
estimates chemical removal in sewage treatment plants ("STP" module) was run using default
settings to evaluate the potential for carbon tetrachloride to volatilize to air or adsorb to sludge
during wastewater treatment. The STP module estimates that about 90% of carbon tetrachloride
in wastewater will be removed by volatilization and 2% by adsorption. This estimation can be
confirmed with a wastewater treatment removal study showing that carbon tetrachloride
partitioned to the water column for greater than 99% and the range of <10 to 0.1% was
distributed in sludge (Chen et al.. 2014).
The EPI Suite™ module that estimates volatilization from lakes and rivers ("Volatilization"
module) was run using default settings to evaluate the volatilization half4ife of carbon
tetrachloride in surface water. The volatilization module estimates that the half4ife of carbon
tetrachloride in a model river will be about 1.3 hours and the half-life in a model lake will be
about 5 days.
The EPI Suite™ module that predicts biodegradation rates ("BIOWIN" module) was run using
default settings to estimate biodegradation rates of carbon tetrachloride under aerobic conditions.
Three of the models built into the BIOWIN module (BIOWIN 1, 2 and 6) estimate that carbon
tetrachloride will not rapidly biodegrade in aerobic environments. However, BIOWIN 5 shows
moderate biodegradation under aerobic conditions. On the other hand, the model that estimates
anaerobic biodegradation (BIOWIN 7) predicts that carbon tetrachloride will biodegrade
moderately under anaerobic conditions.
In water, under aerobic conditions, a negative result has been reported for a ready
biodegradability test according to OECD TG 301C MITI (I) (Ministry of International Trade and
Industry, Japan) test method. This test method, however, uses high concentrations of the test
substance so that toxicity to aerobic bacteria may have occurred, which may have prevented or
limited biodegradation (ECHA. 2012). The overwhelming evidence suggests that aerobic
biodegradation is very slow and anaerobic biodegradation is moderate to rapid (ECHA. 2012;
OECD. 2011; AT SDR. 2005; CalEPA. 2000).
Based on the available environmental fate data, carbon tetrachloride is likely to biodegrade
slowly under aerobic conditions with pathways that are environment- and microbial population-
dependent. Anaerobic degradation has been observed to be faster than aerobic degradation under
some conditions with acclimated microbial populations. Anaerobic biodegradation could be a
significant degradation mechanism in soil and ground water.
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The log Koc reported in the carbon tetrachloride scoping document were measured values in the
range of 1.69 - 2.16, while the estimated value range using EPI Suite™ is 1.6 - 2.5. These
values are supported by the basic principle of environmental chemistry which states that the Koc
is typically within one order of magnitude (one log unit) of the octanol: water partition coefficient
(Kow). Indeed, the log Kow reported for carbon tetrachloride in Table 2-1 is a measured value of
2.83, which is within the expected range. Further, the Koc could be approximately one order of
magnitude larger than predicted by EPI Suite™ before sorption would be expected to
significantly impact the mobility of carbon tetrachloride in groundwater. The log Koc and log
Kow reported in previous assessments of carbon tetrachloride were in the range of 1.69 - 2.16
and 2.64 - 2.83, respectively (ECHA. 2012; OECD. 2011; ATSDR 20051 while measured
values found in studies via the process of systematic review of highly rated literatures are in the
range of 1.11 - 2.43 for various surface soil types; 0.79 - 1.93 for aquifer sediments; 1.67 for
marine and estuary sediments (Riley et al.. 2010; Roose et al.. 2001; Zhao et al.. 1999; Duffy et
al.. 1997; Rogers and McFarlane. 1981). and these values are associated with low sorption to soil
and sediment.
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1478 Table 2-1. Environmental Fate Characteristics of Carbon Tetrachloride
Property or Endpoint
Value3
References
Direct photodegradation
Minutes (atmospheric-stratospheric)
(OECD. 2011)
Indirect photodegradation
>330 years (atmospheric)
(OECD. 2011);
(Cox et al., 1976)
Hydrolysis half4ife
7000 years at 1 ppm
(OECD. 2011);
(Mabev and Mill, 1978)
Abiotic soil degradation
5 days (autoclaved soils)
(Anderson et al., 1991)
Biodegradation
6 to 12 months (soil - estimated)13
7 days to 12 months (aerobic water, based
on multiple studies)
3 days to 4 weeks (anaerobic water, based
on multiple studies)
13 days to 19 months (anaerobic
wastewater treatment, based on multiple
studies)
7 days (aerobic wastewater treatment)
(OECD. 2011);
(ECHA. 2012);
(ATSDR. 2005);
(HSDB. 2005);
(Van Eekert et al.. 1998);
(Bouwer and McCartv,
1983);
(Doons and Wu, 1992);
(Tabak et al.. 1981); (de
Best et al., 1997)
Wastewater Treatment
Mass distribution/partition:
Water - >99%
Sludge->10-0.1%
(Chen et al., 2014)
Bioconcentration factor
(BCF)
30 bluegill sunfish
40 rainbow trout
(OECD. 2011)
Bioaccumulation factor
(BAF)
19 (estimated)
(U.S. EPA. 2012a)
Soil organic carbon:water
partition coefficient (log Koc)
1.11- 2.43 (from various soil types)
0.79 - 1.93 (aquifer sediments)
1.67 (marine and estuary sediments)
(ECHA. 2012);
(OECD. 2011); (Duffv et
al., 1997); (Rosers and
McFarlane, 1981)(Roose
et al., 2001); (Zhao et al.,
1999); (Rilev et al.. 2010)
"¦Measured unless otherwise noted.
bThis figure (6 to 12 months) represents a half-life estimate based on the estimated aqueous aerobic biodegradation half-life
of carbon tetrachloride.
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1480 Carbon tetrachloride shows minimal susceptibility to indirect photolysis by hydroxyl radicals in
1481 the troposphere, where its estimated tropospheric half-life exceeds 330 years. Ultimately, carbon
1482 tetrachloride diffuses upward into the stratosphere where it is photodegraded to form the
1483 trichloromethyl radical and chlorine atoms (OECD. 2011). Carbon tetrachloride is efficiently
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degraded by direct photolysis under stratospheric conditions and the DT50 (Dissipation Time for
50% of the compound to dissipate) value is in the order of minutes. However, the troposphere to
the stratosphere migration of carbon tetrachloride is very long and this migration time limits the
dissipation. The rate of photodegradation increases at altitudes >20 km and beyond.
Carbon tetrachloride dissolved in water does not photodegrade or oxidize in any measurable
amounts, with a calculated hydrolysis half-life of 7,000 years based on experimental data at a
concentration of 1 ppm (OECD. 2011). Removal mechanisms from water could include
volatilization due to the Henry's Law constant and anaerobic degradation in subsurface
environment.
Estimated and measured BCF and BAF values ranging from 19-40 indicate that carbon
tetrachloride has low bioaccumulation potential in fish (U.S. EPA. 2012a; OECD. 2011).
2.2 Environmental Releases
Releases to the environment from the conditions of use (e.g., industrial/commercial processes or
commercial uses resulting in down-the-drain releases) are one component of potential exposure
and may be derived from reported data that are obtained through direct measurement,
calculations based on empirical data and/or assumptions, and models.
Under the Emergency Planning and Community Right-to-Know Act (EPCRA) section 313 rule,
carbon tetrachloride is a Toxics Release Inventory (TRI)-reportable substance effective January
1, 1987. The TRI database includes information on disposal and other releases of carbon
tetrachloride to air, water, and land, in addition to how it is being managed through recycling,
treatment, and burning for energy recovery. Facilities are required to report if they manufacture
(including import) or process more than 25,000 pounds of carbon tetrachloride, or if they
otherwise use more than 10,000 pounds of carbon tetrachloride.
TRI reporting by subject facilities is required by law to provide information on releases and other
waste management activities of Emergency Planning and Community Right-to-Know Act
(EPCRA) Section 313 chemicals (i.e., TRI chemicals) to the public for informed decision
making and to assist the EPA in determining the need for future regulations. Section 313 of
EPCRA and Section 6607 of the Pollution Prevention Act (PPA) require certain industrial
facilities to report release and other waste management quantities of TRI-listed chemicals
annually when a reporting threshold is triggered, but these statutes do not impose any monitoring
burden for determining the quantities.
TRI data are self-reported by the subject facility where some facilities are required to measure or
monitor emission or other waste management quantities due to regulations unrelated to the TRI
Program, or due to company policies. These existing, readily available data are often used by
facilities for TRI reporting purposes. When measured (e.g., monitoring) data are not "readily
available," or are known to be non-representative for TRI reporting purposes, the TRI
regulations require that facilities determine release and other waste management quantities of
TRI-listed chemicals by making "reasonable estimates." Such reasonable estimates include a
variety of different approaches ranging from published or site-specific emission factors (e.g.,
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AP-42), mass balance calculations, or other engineering estimation methods or best engineering
judgement. TRI reports are then submitted directly to EPA on an annual basis and must be
certified by a facility's senior management official that the quantities reported to TRI are
reasonable estimates as required by law.
Based on 2018 TRI (U.S. EPA. 2018f). 49 facilities reported almost 252 thousand pounds of
carbon tetrachloride released into the environment. Of these environmental releases, the largest
releases of over 176 thousand pounds were to air (fugitive and point source air emissions), less
than 2 thousand pounds were released to water (surface water discharges), over 73 thousand
pounds were released to land (of which disposal to Resource Conservation and Recovery Act
(RCRA) Subtitle C landfills is the primary disposal method), and under 146 pounds were
released in other forms such as indefinite storage. Carbon tetrachloride migration to groundwater
from RCRA Subtitle C landfills regulated by the state/local jurisdictions will likely be mitigated
by landfill design (double liner, leachate capture) and requirements to adsorb liquids onto solid
absorbant and containerize prior to disposal. See Appendix D for a TRI summary table on the
2018 releases of carbon tetrachloride to various media.
2.3 Environmental Exposures
In the problem formulation (U.S. EPA. 2018d). EPA presented an analysis and preliminary
conclusions on environmental exposures to aquatic species based on releases to surface water,
and from sediments and suspended biosolids. No additional information regarding environmental
exposures was received or identified by the EPA following the publication of the problem
formulation that would alter the preliminary conclusions about environmental exposures
presented in the problem formulation (U.S. EPA. 2018d). As reviewed during problem
formulation, carbon tetrachloride is present in environmental media such as groundwater, surface
water, and air. EPA conducted analysis of the environmental release pathways to aquatic
receptors based on a qualitative assessment of the fate and transport properties of carbon
tetrachloride in the environment (described in section 2.1), and a quantitative comparison of
hazards and exposures for aquatic organisms as described in section 2.5.3.2 of the problem
formulation (U.S. EPA. 2018d). which has been updated in section 4.1.2 below.
2.3.1 Environmental Exposures - Aquatic Pathway
As explained in section 2.5.3.1 of the Problem Formulation document (U.S. EPA. 2018d). EPA
conducted a qualitative assessment of carbon tetrachloride exposures to aquatic species from
sediments and suspended solids and determined that it was not necessary to further analyze these
exposures quantitatively. The qualitative assessment explains that due to the log Koc (1.7 - 2.16)
and high solubility of 793 mg/L at 25°C, sorption of carbon tetrachloride to sediments and
suspended solids is unlikely. The fate information on carbon tetrachloride identified in the
systematic review confirmed the validity of the fate values used for concluding that risk to
aquatic species from sediments and solid do not need further analysis.
After publication of the problem formulation, EPA identified additional data on ecological
hazards requiring an update of the analysis of carbon tetrachloride releases and surface water
concentrations. In order to update this analysis, EPA modeled industrial discharges to surface
water to estimate surface water concentration using five years (2014 through 2018) EPA NPDES
permit Discharge Monitoring Report (DMR) data on the top highest carbon tetrachloride
releasing facilities based on the reported annual loadings (lbs/year). EPA used the Probabilistic
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Dilution Model (PDM) within EPA's Exposure and Fate Assessment Screening Tool, version
2014 (E-FAST 2014) to estimate surface water concentrations resulting from facilities' reported
annual release/loading amounts. Further information on the releases of carbon tetrachloride to
surface water and the estimated surface water carbon tetrachloride concentrations for acute and
chronic scenarios based on E-FAST can be found in Table 4-2 and Appendix E.
2.3.1.1 Methodology for Modeling Surface water Concentrations from
Facilities releases (E-FAST 2014)
Surface water concentrations resulting from wastewater releases of carbon tetrachloride from
facilities that use, manufacture, or process the chemical were modeled using EPA's E-FAST,
Version 2014 (U.S. EPA. 2007). As appropriate, two scenarios were modeled per release: release
of the annual load over an estimated maximum number of operating days (250 days/year) to
model a chronic aquatic exposure scenario and over 20 days/year to model acute aquatic
exposure. E-FAST 2014 is a model that estimates chemical concentrations in water to which
aquatic life may be exposed using upper percentile and/or mean exposure parametric values,
resulting in possible conservative exposure estimates. Advantages to this model are that it
requires minimal input parameters and it has undergone extensive peer review by experts outside
of EPA. To obtain more detailed information on the E- FAST 2014 tool from the user
guide/background document, visit this web address: https://www.epa.gov/tsca-screening-tools/e-
fast-exposure-and-fate-assessment-screening-tool-version-2014.
In some ways, the E-FAST estimates are overestimating aquatic exposure, because carbon
tetrachloride is a volatile chemical and E-FAST does not take volatilization into consideration;
and for static water bodies, E-FAST does not take dilution into consideration.
Overall Confidence in Estimated Water Surface Concentrations
EPA has medium confidence in the estimated water surface concentrations because the modeled
estimates are based on conservative assumptions and parameters explained above (i.e., top
discharging facilities), which could result in overestimation of the water concentrations, in
addition to the uncertainties associated with the E-FAST model and DMR dataset (see section
4.4.2).
2.3.2 Terrestrial Environmental Exposure
Terrestrial species populations living near industrial/commercial facilities using carbon
tetrachloride may be exposed to the chemical through environmental media. Terrestrial species
populations living near industrial/commercial facilities using carbon tetrachloride may be
exposed via multiple routes such as ingestion of surface waters and inhalation of outdoor air. As
described above, carbon tetrachloride is present and measurable through monitoring in a variety
of environmental media including ambient air, surface water and ground water.
During problem formulation EPA determined that carbon tetrachloride present in various media
pathways (i.e., air, water, land) fall under the jurisdiction of existing regulatory programs and
associated analytical processes carried out under other EPA-administered statutes and that these
existing programs and processes adequately assess and effectively manage the exposures (see
section 2.5.3.2 of the problem formulation document) (U.S. EPA. 2018d). Therefore, these
exposure pathways were excluded from the scope of this risk evaluation, and terrestrial
environmental exposure data were not analyzed as part of this risk evaluation.
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2.4 Human Exposures
2.4.1 Occupational Exposures
Occupational exposures could be direct or indirect and the magnitude of exposure for an
occupational worker could be a function of duration, proximity and intensity of exposures. The
duration of exposure, which partially depends on worker mobility, could vary for different
employee groups. EPA considers workers at the facility who neither directly perform activities
near the carbon tetrachloride source area nor regularly handle carbon tetrachloride to be
occupational non-users (ONU). Workers that are directly handling carbon tetrachloride and/or
perform activities near sources of carbon tetrachloride are in the near field and are called workers
throughout this report. The near-field is reported to be conceptualized as a volume of air within
one-meter in any direction of the worker's head and the far-field comprised the remainder of the
room (Tielemans et al.. 2008). The source area/exposure zone could be judged by several factors
such as the chemical inventory, ventilation of the facility, vapor pressure and emission potential
of the chemical, process temperature, size of the room, job tasks, and modes of chemical
dispersal from activities (Leblanc et al.. 2018). Corn and Esmen (1979) indicated that the
assignment of zones is a professional judgment and not a scientific exercise.
The job classifications for ONUs could be dependent on the conditions of use. For example,
ONUs for manufacturing include supervisors, managers, and tradesmen that may be in the
manufacturing area, but do not perform tasks that result in the same level of exposures as
production workers. It could be challenging to characterize direct and indirect exposures for
some conditions of use since it is not uncommon for employees at a facility to perform multiple
types of tasks throughout the work day. Workers could perform activities that bring them into
direct contact with carbon tetrachloride and also perform additional tasks as ONUs. The
groupings of employees are not necessarily distinct as workers perform a variety of tasks over
the course of the day that could result in direct exposure and indirect exposure. Indirect
exposures of employees working near contaminants could be difficult to separate due to
overlapping tasks that makes it difficult to delineate exposures of workers and ONUs.
EPA assessed occupational exposures following the analysis plan published in section 2.6.1.2 of
the problem formulation document (U.S. EPA. 2018d). EPA evaluated acute and chronic
inhalation exposures to workers and ONUs in association with carbon tetrachloride
manufacturing, import and repackaging, its use in industrial applications as a reactant/
intermediate and process agent, laboratory chemicals and disposal. Appendix F of the problem
formulation document (U.S. EPA. 2018d) provides additional detail on the mapping of the
conditions of use to the Occupational Exposure Scenario (OES) groups used in this risk
evaluation. EPA used inhalation monitoring data when available and that met data evaluation
criteria (see section 1.5); and modeling approaches to estimate potential inhalation exposures
when inhalation monitoring data were not reasonably available. Specific inhalation assessment
methodology is described in further detail below for each type of assessment.
EPA also estimated dermal doses for workers in these scenarios since dermal monitoring data
was not reasonably available. EPA modeled dermal doses using the EPA Dermal Exposure to
Volatile Liquids Model which improves upon the existing EPA 2-HandDermal Exposure model
by accounting for the effect of evaporation on dermal absorption for volatile chemicals and the
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potential exposure reduction due to glove use. More information about this model and how it was
used may be found in section 2.4.1.4 and Appendix F. EPA does not expect dermal exposures for
occupational non-users due to no direct contact with the chemical.
Components of the Occupational Exposure Assessment
The occupational exposure assessment of each condition of use comprises the following
components:
• Process Description: A description of the condition of use, including the role of the
chemical in the use; process vessels, equipment, and tools used during the condition of
use.
• Number of Sites: The sites that use the chemical for the given condition of use.
• Worker Activities: Descriptions of the worker activities, including an assessment for
potential points of worker exposure and environmental releases.
• Number of Workers and Occupational Non-Users: An estimate of the number of sites,
number of workers and occupational non-users potentially exposed to the chemical for
the given condition of use. Unless mentioned otherwise in this report, the total number of
workers and ONUs are number of personnel per site per day. See Appendix A of the
supplemental document Risk Evaluation for Carbon Tetrachloride, Supplemental
Information on Releases and Occupational Exposure Assessment (U.S. EPA. 2019b) for a
discussion of EPA's approach for determining an estimation for the number of affected
workers.
• Inhalation Exposure: Central tendency and high-end estimates of inhalation exposure to
workers and occupational non-users. See Appendix B and Appendix C of the
supplemental document Risk Evaluation for Carbon Tetrachloride, Supplemental
Information on Releases and Occupational Exposure Assessment (U.S. EPA. 2019b).
• Dermal Exposure: It estimates for multiple scenarios, accounting for simultaneous
absorption and evaporation, and different protection factors of glove use. A separate
dermal exposure section (2.4.1.8) is included that provides estimates of the dermal
exposures for all the assessed conditions of use. EPA assessed dermal exposure to
workers using the Dermal Exposure to Volatile Liquids Model. The dermal exposure
scenarios consider impact of glove use. Dermal exposure assessment is described in more
detail Appendix E of the document Risk Evaluation for Carbon Tetrachloride,
Supplemental Information on Releases and Occupational Exposure Assessment (U.S.
EPA. 2019b).
The OSHA Personal Protective Equipment (PPE) Standard, 29 CFR § 1910.132, requires that
employers conduct a hazard assessment of the workplace to identify all the hazards that exist and
determine what methods to use to protect workers from these identified hazards. PPE is one of
the options that may be utilized to protect employees from hazardous exposures based on the
findings of the hazard assessment. The OSHA determines the technological and economic
feasibility of implementing engineering controls to meet different concentration benchmarks. If
the employer determines that exposures are not hazardous, OSHA does not require controls such
as PPE. Conversely if the employer identifies a hazardous exposure, OSHA requires control
measures.
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The OSHA respirator protection standard, 29 CFR § 1910.134(a)(1), recommends employers
utilize the hierarchy of controls for reducing or removing chemical hazards. Based on the
hierarchy of controls, the most effective controls are elimination, substitution, or engineering
controls. These are followed by administrative controls and finally the use of PPE. The
respiratory protection standard requires the use of feasible engineering controls as the primary
means to control air contaminants. Respirators are required when effective engineering controls
are not feasible. They are the last means of worker protection in the hierarchy of controls. When
effective engineering and administrative controls are not feasible to adequately protect workers
and maintain compliance with other OSHA statutory and regulatory requirements under 29 CFR
§ 1910.1000, employers should utilize respirator protective equipment. (29 CFR §
1910.134(a)(1)).
If information and data indicate that use or handling of a chemical cannot, under worst-case
conditions, release concentrations of a respiratory hazard above a level that would trigger the
need for a respirator or require use of a more protective respirator employees would not be
assumed to wear them. Employers also use engineering or administrative controls to bring
employee exposures below permissible exposure limits for airborne contaminants, respirators
would be used to supplement engineering and administrative controls only when these controls
cannot be feasibly implemented to reduce employee exposure to permissible levels.
Occupational Exposures Approach and Methodology
To assess inhalation exposure, EPA reviewed workplace inhalation monitoring data collected by
government agencies such as OSHA and NIOSH, monitoring data submitted by industry
organizations through public comments, and monitoring data found in published literature (i.e.,
personal exposure monitoring data and area monitoring data). Studies were evaluated using the
evaluation strategies laid out in the Application of Systematic Review in TSCA Risk Evaluations
(U.S. EPA. 2018a).
For several conditions of use, the EPA modeled exposure in occupational settings. The models
were used to either supplement existing exposure monitoring data or to provide exposure
estimates where data are insufficient. For example, the EPA developed the Tank Truck and
Railcar Loading and Unloading Release and Inhalation Exposure Model to estimate worker
exposure during container and truck unloading activities that occur at industrial facilities.
• Using the time-weighted average (TWA) exposure concentrations obtained from
monitoring data or modeling, EPA calculated the Acute Concentration (AC), Average
Daily Concentrations (ADC) and Lifetime Average Daily Concentration (LADC) to
assess risk. The AC, ADC, and LADC equations are described in Risk Evaluation for
Carbon Tetrachloride, Supplemental Information on Releases and Occupational
Exposure Assessment (U.S. EPA. 2019b).
See Appendix E of the supplemental document Risk Evaluation for Carbon Tetrachloride,
Supplemental Information on Releases and Occupational Exposure Assessment (U.S. EPA.
2019b) for a discussion of EPA's statistical analysis approach for assessing dermal exposure.
2.4.1,1 Process Description
EPA performed a literature search to find descriptions of processes involved in each condition of
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use to identify worker activities that could potentially result in occupational exposures. Where
process descriptions were unclear or not available, EPA referenced relevant Emission Scenario
Documents (ESD's) or Generic Scenarios (GS's). Process descriptions for each condition of use
can be found in section 2.4.1.3.
2.4.1,2 Number of Workers and ONUs
Where available, EPA used CDR data to provide a basis to estimate the number of workers and
ONUs. EPA supplemented the available CDR data with U.S. economic data using the following
method:
1. Identify the North American Industry Classification System (NAICS) codes for the
industry sectors associated with these uses by reviewing Chemical Data Reporting (CDR)
data, Toxics Release Inventory (TRI) data, and EPA Generic Scenarios (GS's) and
Organisation for Economic Co-operation and Development (OECD) Emission Scenario
Documents (ESDs) for the chemical.
2. Estimate total employment by industry/occupation combination using the Bureau of
Labor Statistics' Occupational Employment Statistics data (BLS Data).
3. Refine the Occupational Exposure Scenarios (OES) estimates where they are not
sufficiently granular by using the U.S. Census' Statistics of US Businesses (SUSB) data
(SUSB Data) on total employment by 6-digit NAICS.
4. Use market penetration data to estimate the percentage of employees likely to be using
carbon tetrachloride instead of other chemicals. If no market penetration data were
available, estimate of the number of sites using carbon tetrachloride from given NAICS
code and multiply by the estimated workers and ONUs/site provided in BLS data.
5. Combine the data generated in Steps 1 through 5 to produce an estimate of the number of
employees using carbon tetrachloride in each industry/occupation combination, and sum
these to arrive at a total estimate of the number of employees with exposure.
There are a few uncertainties surrounding the estimated number of workers potentially exposed
to carbon tetrachloride, as outlined below. Most are unlikely to result in a systematic
underestimate or overestimate and could result in an inaccurate estimate. There are inherent
limitations to the use of CDR data as they are reported by manufacturers and importers of carbon
tetrachloride. CDR may not capture all sites and workers associated with any given chemical.
There are also uncertainties with BLS data. First, BLS' OES employment data for each
industry/occupation combination are only available at the 3-, 4-, or 5-digit NAICS level, rather
than the full 6-digit NAICS level. This lack of granularity could result in an overestimate of the
number of exposed workers if some 6-digit NAICS are included in the less granular BLS
estimates but are not likely to use carbon tetrachloride for the assessed applications. EPA
addressed this issue by refining the OES estimates using total employment data from the U.S.
Census' SUSB. However, this approach assumes that the distribution of occupation types (SOC
codes) in each 6-digit NAICS is equal to the distribution of occupation types at the parent 5-digit
NAICS level. If the distribution of workers in occupations with carbon tetrachloride exposure
differs from the overall distribution of workers in each NAICS, then this approach could result in
inaccuracy. The judgments about which industries (represented by NAICS codes) and
occupations (represented by SOC codes) are associated with the uses assessed in this report are
based on EPA's understanding of how carbon tetrachloride is used in each industry. Designations
of which industries and occupations have potential exposures is nevertheless subjective, and
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some industries/occupations with few exposures might erroneously be included, or some
industries/occupations with exposures might erroneously be excluded. This would result in
inaccuracy but would be unlikely to systematically either overestimate or underestimate the
count of exposed workers.
2.4,1.3 General Inhalation Exposure Assessment Approach and Methodology
EPA provided occupational exposure results representative of central tendency conditions and
high-end conditions. A central tendency could be representative of occupational exposures in the
center of the distribution for a given condition of use. For risk evaluation, EPA may use the 50th
percentile (median), mean (arithmetic or geometric), mode, or midpoint values of a distribution
as representative of the central tendency scenario. EPA's preference is to provide the 50th
percentile of the distribution. However, if the full distribution is not known, the mean, mode, or
midpoint of the distribution represents the central tendency depending on the statistics available
for the distribution.
A high-end could be representative of occupational exposures that occur at probabilities above
the 90th percentile but below the exposure of the individual with the highest exposure (U.S. EPA.
1992a). For risk evaluation, EPA provided high-end results at the 95th percentile. If the 95th
percentile is not available, EPA may use a different percentile greater than or equal to the 90th
percentile but less than or equal to the 99.9th percentile, depending on the statistics available for
the distribution. If the full distribution is not known and the preferred statistics are not available,
EPA may estimate a maximum or bounding estimate in lieu of the high-end.
For occupational exposures, EPA may use measured or estimated air concentrations to calculate
exposure concentration metrics required for risk assessment, such as average daily concentration
and lifetime average daily concentration. These calculations require additional parameter inputs,
such as years of exposure, exposure duration and frequency, and lifetime years. EPA may
estimate exposure concentrations from monitoring data, modeling, or occupational exposure
limits.
For the final exposure result metrics, each of the input parameters (e.g., air concentrations,
working years, exposure frequency, lifetime years) may be a point estimate (i.e., a single
descriptor or statistic, such as central tendency or high-end) or a full distribution. EPA will
consider three general approaches for estimating the final exposure result metrics:
• Deterministic calculations: EPA will use combinations of point estimates of each
parameter to estimate a central tendency and high-end for each final exposure metric
result. EPA will document the method and rationale for selecting parametric
combinations to be representative of central tendency and high-end.
• Probabilistic (stochastic) calculations: EPA will pursue Monte Carlo simulations using
the full distribution of each parameter to calculate a full distribution of the final exposure
metric results and selecting the 50th and 95th percentiles of this resulting distribution as
the central tendency and high-end, respectively.
• Combination of deterministic and probabilistic calculations: EPA may have full
distributions for some parameters but point estimates of the remaining parameters. For
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example, EPA may pursue Monte Carlo modeling to estimate exposure concentrations,
but only have point estimates of working years of exposure, exposure duration and
frequency, and lifetime years. In this case, EPA will document the approach and rationale
for combining point estimates with distribution results for estimating central tendency
and high-end results.
EPA follows the following hierarchy in selecting data and approaches for assessing inhalation
exposures:
1. Monitoring data:
a. Personal and directly applicable
b. Area and directly applicable
c. Personal and potentially applicable or similar
d. Area and potentially applicable or similar
2. Modeling approaches:
a. Surrogate monitoring data
b. Fundamental modeling approaches
c. Statistical regression modeling approaches
3. Occupational exposure limits:
a. OSHA PEL
b. Company-specific OELs (for site-specific exposure assessments, e.g., there is only one
manufacturer who provides to EPA their internal OEL but does not provide monitoring
data)
c. Voluntary limits (ACGIH TLV, NIOSH REL, Occupational Alliance for Risk Science
(OARS) workplace environmental exposure level (WEEL) [formerly by AIHA])
Exposures are calculated from the datasets provided in the sources depending on the size of the
dataset. For datasets with six or more data points, central tendency and high-end exposures were
estimated using the 50th percentile and 95th percentile. For datasets with three to five data points,
central tendency exposure was calculated using the 50th percentile and the maximum was
presented as the high-end exposure estimate. For datasets with two data points, the midpoint was
presented as a midpoint value and the higher of the two values was presented as a higher value.
Finally, data sets with only one data point presented the value as a what-if exposure. EPA cannot
determine the statistical representativeness of the values for the small sample size. For datasets
including exposure data that were reported as below the limit of detection (LOD), EPA estimated
the exposure concentrations for these data, following EPA's Guidelines for Statistical Analysis of
Occupational Exposure Data (U.S. EPA. 1994) which recommends using the ^=- if the
geometric standard deviation of the data is less than 3.0 and if the geometric standard
deviation is 3.0 or greater. Specific details related to each condition of use can be found in
section 2.4.1.7. For each condition of use, these values were used to calculate chronic (non-
cancer and cancer) exposures. Equations and sample calculations for chronic exposures can be
found in the supplemental document Risk Evaluation for Carbon Tetrachloride, Supplemental
Information on Releases and Occupational Exposure Assessment (U.S. EPA. 2019b).
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EPA used exposure monitoring data and exposure models to estimate inhalation exposures for all
conditions of use. Specific details related to the use of monitoring data for each condition of use
can be found in section 2.4.1.7.
A summary of the key occupational acute and chronic inhalation exposure concentration models
for carbon tetrachloride are presented below. The supplemental document Risk Evaluation for
Carbon Tetrachloride, Supplemental Information on Releases and Occupational Exposure
Assessment (U.S. EPA. 2019b) provides detailed discussion on the values of the exposure
parameters and air concentrations input into these models.
Acute and Chronic Inhalation Exposure Concentrations Models
A key input to the acute and chronic models for occupational assessment is 8-hr time-weighted
average air concentration (TWA). The 8-hr TWA air concentrations are time averaged to
calculate acute exposure, average daily concentration (ADC) for chronic, non-cancer risks, and
lifetime average daily concentration (LADC) for chronic, cancer risks.
Acute workplace exposures are assumed to be equal to the contaminant concentration in air (8-hr
TWA), per Equation A-l.
Equation 2-1
C X ED
AEC = —
acute
Where:
AEC = acute exposure concentration [mg/m3]
C = contaminant concentration in air (8-hour TWA) [mg/m3]
ED = exposure duration [hr/day]
ATacute = acute averaging time [hr/day]
ADC and LADC are used to estimate workplace chronic exposures for non-cancer and cancer
risks, respectively. These exposures are estimated as follows:
Equation 2-2
C x ED x EF x WY
ADC or LADC = — —
AT or ATc
Where:
ADC = average daily concentration (8-hr TWA) used for chronic non-cancer risk
calculations
LADC = lifetime average daily concentration (8-hr TWA) used for chronic cancer risk
calculations
C = contaminant concentration in air (8-hr TWA)
ED = exposure duration (8 hr/day)
EF = exposure frequency (250 days/yr)
WY = exposed working years per lifetime (tenure values used to represent: 50th
percentile = 31; 95th percentile = 40)
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AT = averaging time, non-cancer risks (WY x 250 days/yr x 8 hr/day)
ATC = averaging time, cancer risks (lifetime (LT) x 365 days/year x 24 hr/day; where
LT= 78 years)
2.4.1.4 General Dermal Exposure Assessment Approach and Methodology
Dermal exposure data were not readily available for the conditions of use in the assessment.
Because carbon tetrachloride is a volatile liquid, the dermal absorption of carbon tetrachloride
depends on the type and duration of exposure. Where exposure is without gloves, only a fraction
of carbon tetrachloride that comes into contact with the skin will be absorbed as the chemical
readily evaporates from the skin. Specific details used to calculate the dermal exposure to carbon
tetrachloride can be found in section 2.4.1.8.
A summary of the key occupational dermal dose models for carbon tetrachloride are presented
below. The supplemental document Risk Evaluation for Carbon Tetrachloride, Supplemental
Information on Releases and Occupational Exposure Assessment (U.S. EPA. 2019b) provides
detailed discussion on the values of the exposure parameters input into these models.
Key Dermal Exposure Dose Models
Current EPA dermal models do not incorporate the evaporation of material from the dermis. The
dermal potential dose rate, Dexp (mg/day), is calculated as (U.S. EPA. 2013a):
Equation 2-3
Dexp — S x Qu x Yfierm x FT
Where:
S is the surface area of contact: 535 cm2 (central tendency) and 1,070 cm2 (high end),
representing the total surface area of one and two hands, respectively (note that EPA has no
data on actual surface area of contact for any OES).
Qu is the quantity remaining on the skin: 1.4 mg/cm2-event (central tendency) and 2.1 mg/cm2-
event (high end). These are the midpoint value and high end of range default value,
respectively, used in the EPA's dermal contact with liquids models.
Ydenn is the weight fraction of the chemical of interest in the liquid: EPA will assess a unique
value of this parameter for each occupational scenario or group of similar occupational
scenarios (0 < Yderm < 1).
FT is the frequency of events (integer number per day; 1 event/day).
Here Qu does not represent the quantity remaining after evaporation, but represents the quantity
remaining after the bulk liquid has fallen from the hand that cannot be removed by wiping the
skin (e.g., the film that remains on the skin).
One way to account for evaporation of a volatile solvent would be to add a multiplicative factor
to the EPA model to represent the proportion of chemical that remains on the skin after
evaporation,/abs (0
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Equation 2-4
Dexp — S X (_ Qu X f abs) X Yderm X FT
This approach simply removes the evaporated mass from the calculation of dermal uptake.
Evaporation is not instantaneous, but the EPA model already has a simplified representation of
the kinetics of dermal uptake. More information about this approach is presented in the
supplemental document Risk Evaluation for Carbon Tetrachloride, Supplemental Information on
Releases and Occupational Exposure Assessment (U.S. EPA. 2019b).
Safety equipment manufacturers recommend Silver Shield®/4H®, Viton (synthetic rubber and
fluoropolymer elastomer), Viton/Butyl and Nitrile for gloves and DuPont Tychem® BR and LV,
Responder® and TK; ONESuit® TEC; and Kappler Zytron® 300, 400, and 500 as protective
materials for clothing. Most nitrile gloves have a breakthrough time of only a few minutes and
thus offer little protection when exposed to carbon tetrachloride. For operations involving the use
of larger amounts of carbon tetrachloride, when transferring carbon tetrachloride from one
container to another or for other potentially extended contact, the only gloves recommended are
Viton. The gloves should not be assumed to provide full protection. Regarding glove use, data
about the frequency of effective glove use - that is, the proper use of effective gloves - is very
limited in industrial settings. Initial literature review suggests that there is unlikely to be
sufficient data to justify a specific probability distribution for effective glove use for a chemical
or industry. Instead, the impact of effective glove use should be explored by considering
different percentages of effectiveness (e.g., 25% vs. 50% effectiveness).
EPA also made assumptions about glove use and associated protection factors. Where workers
wear gloves, workers are exposed to carbon tetrachloride-based product that may penetrate the
gloves, such as seepage through the cuff from improper donning of the gloves, and if the gloves
occlude the evaporation of carbon tetrachloride from the skin. Where workers do not wear
gloves, workers are exposed through direct contact with carbon tetrachloride.
Gloves only offer barrier protection until the chemical breaks through the glove material. Using a
conceptual model, Cherrie (2004) proposed a glove workplace protection factor - the ratio of
estimated uptake through the hands without gloves to the estimated uptake though the hands
while wearing gloves: this protection factor is driven by flux, and thus varies with time. The
European Centre For Ecotoxicology and Toxicology of Chemicals Targeted Risk Assessment
(ECETOC TRA) model represents the protection factor of gloves as a fixed, assigned protection
factor equal to 5, 10, or 20 (Marquart et al.. 2017). where, similar to the APR for respiratory
protection, the inverse of the protection factor is the fraction of the chemical that penetrates the
glove. Dermal doses without and with glove use are estimated in the occupational exposure
sections below and summarized in Table 2-20.
For most scenarios, EPA did not find enough data to determine statistical distributions of the
actual exposure parameters and concentration inputs to the inhalation and dermal models
described above. Within the distributions, central tendencies describe 50th percentile or the
substitute that most closely represents the 50th percentile. The high-end of a distribution
describes the range of the distribution above 90th percentile (U.S. EPA. 1992b). Ideally, EPA
would use the 50th and 95th percentiles for each parameter. Where these statistics were unknown,
the mean or median (mean is preferable to median) served as substitutes for 50th percentile and
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the high-end of ranges served as a substitute for 95th percentile. However, these substitutes were
highly uncertain and not ideal substitutes for the percentiles. EPA could not determine whether
these substitutes were suitable to represent statistical distributions of real-world scenarios.
2.4.1.5 Consideration of Engineering Controls and Personal Protective
Equipment
OSHA and NIOSH recommend employers utilize the hierarchy of controls to address hazardous
exposures in the workplace. The hierarchy of controls strategy outlines, in descending order of
priority, the use of elimination, substitution, engineering controls, administrative controls, and lastly
PPE. The hierarchy of controls prioritizes the most effective measures first which is to eliminate
or substitute the harmful chemical (e.g., use a different process, substitute with a less hazardous
material), thereby preventing or reducing exposure potential. Following elimination and
substitution, the hierarchy recommends engineering controls to isolate employees from the
hazard, followed by administrative controls, or changes in work practices to reduce exposure
potential (e.g., source enclosure, local exhaust ventilation systems, temperature). Administrative
controls are policies and procedures instituted and overseen by the employer to protect worker
exposures. The respirators do not replace engineering controls and they are implemented in
addition to feasible engineering controls (29 CFR § 1910.134(a)(1). The PPE (e.g., respirators,
gloves) could be used as the last means of control, when the other control measures cannot
reduce workplace exposure to an acceptable level.
Respiratory Protection
OSHA's Respiratory Protection Standard (29 CFR § 1910.134) requires employers in certain
industries to address workplace hazards by implementing engineering control measures and, if
these are not feasible, provide respirators that are applicable and suitable for the purpose
intended. Engineering and administrative controls must be implemented whenever employees are
exposed above the PEL. If engineering and administrative controls do not reduce exposures to
below the PEL, respirators must be worn. Respirator selection provisions are provided in §
1910.134(d) and require that appropriate respirators are selected based on the respiratory
hazard(s) to which the worker will be exposed and workplace and user factors that affect
respirator performance and reliability. Assigned protection factors (APFs) are provided in Table
1 under § 1910.134(d)(3)(i)(A) (see below in Table 2-2) and refer to the level of respiratory
protection that a respirator or class of respirators could be provided to employees when the
employer implements a continuing, effective respiratory protection program. Implementation of
a full respiratory protection program requires employers to provide training, appropriate
selection, fit testing, cleaning, and change-out schedules in order to have confidence in the
efficacy of the respiratory protection.
The United States has several regulatory and non-regulatory exposure limits for carbon
tetrachloride. The OSHA Permissible Exposure Limit (PEL) is 10 ppm time-weighted average
(TWA) and the Ceiling limit is 200 ppm as a maximum peak. The short-term exposure limit
(STEL) is 25 ppm for five minutes once every four hours. The NIOSH Recommended Exposure
Limit (REL) is 2 ppm (12.6 mg/m3) for a 60-minute Short-term Exposure Limit (STEL) (OSHA.
2017). NIOSH indicates that carbon tetrachloride has an immediately dangerous to life and
health (IDLH) value of 200 ppm (ATSDR 2017) based on acute inhalation toxicity data in
humans. OSHA's other occupational safety and health standards that would apply to carbon
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tetrachloride exposures that exceed these levels include hazard assessment, exposure monitoring,
and control measures such as engineering controls and respiratory protection (29 CFR
1910.1000).
Respirators should be used when effective engineering controls are not feasible as per OSHA's
29 CFR § 1910.134. Knowledge of the range of respirator APFs is intended to assist employers
in selecting the appropriate type of respirator, based on exposure monitoring data, that could
provide a level of protection needed for a specific exposure scenario. Table 2-2 lists the range of
APFs for respirators. The APFs are not to be assumed to be interchangeable for any condition of
use, workplace, worker or ONU. Employers should first consider elimination, substitution,
engineering, and administrative controls to reduce exposure potential and, if exposures remain
over a regulatory limit, employers are required to institute a respiratory protection program and
provide employees with NIOSH-certified respirators. Where other hazardous agents could exist
in addition to carbon tetrachloride, consideration of combination cartridges would be necessary.
Table 2-2 can be used as a guide to show the protectiveness of each category of respirator; EPA
took this information into consideration as discussed in section 4.2.1. Based on the APF,
inhalation exposures may be reduced by a factor of 5 to 10,000 when employers implement an
effective respiratory protection program.
Table 2-2. Assigned Protection Factors for Respirators in OSHA Standard 29 CFR §
1910.134
Type of Respirator
Quarter
Mask
Half
Mask
Full
Facepiece
Helmet/
Hood
Loose-
fitting
Facepiece
1. Air-Purifying Respirator
5
10
50
-
-
2. Power Air-Purifying Respirator (PAPR)
-
50
1,000
25/1,000
25
3. Supplied-Air Respirator (SAR) or Airline Respirator
• Demand mode
-
10
50
-
-
• Continuous flow mode
-
50
1,000
25/1,000
25
• Pressure-demand or other positive-
pressure mode
/-
50
1,000
-
-
4. Self-Contained Breathing Apparatus (SCBA)
• Demand mode
-
10
50
50
-
• Pressure-demand or other positive-
pressure mode (e.g., open/closed
circuit)
-
-
10,000
10,000
-
Source: 1910.134(d)(3)(i)(A)
The National Institute for Occupational Safety and Health (NIOSH) and the U.S. Department of
Labor's Bureau of Labor Statistics (BLS) conducted a voluntary survey of U.S. employers
regarding the use of respiratory protective devices between August 2001 and January 2002. The
survey had a 75.5% response rate (NIOSH. 2003). A voluntary survey may not be representative
of all private industry respirator use patterns as some establishments with low or no respirator
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use could have chosen to not respond to the survey. Therefore, results of the survey could
potentially be biased towards higher respirator use. NIOSH and BLS estimated about 619,400
establishments used respirators for voluntary or required purposes (including emergency and
non-emergency uses). About 281,800 establishments (45%) were estimated to have had
respirator use for required purposes in the 12 months prior to the survey. The 281,800
establishments estimated to have had respirator use for required purposes were estimated to be
approximately 4.5% of all private industry establishments in the U.S. at the time (NIOSH. 2003).
The survey found that the establishments that required respirator use had the following respirator
program characteristics (NIOSH. 2003):
• 59% provided training to workers on respirator use;
• 34% had a written respiratory protection program;
• 47% performed an assessment of the employees' medical fitness to wear respirators;
• 24% included air sampling to determine respirator selection.
The survey report does not provide a result for respirator fit testing or identify if fit testing was
included in one of the other program characteristics. Of the establishments that had respirator use
for a required purpose within the 12 months prior to the survey, NIOSH and BLS found (NIOSH.
2003):
• Non-powered air purifying respirators are most common, 94% overall and varying from
89% to 100% across industry sectors
o A high majority use dust masks, 76% overall and varying from 56% to 88% across
industry sectors of the establishments;
o A varying fraction use half-mask respirators, 52% overall and varying from 26% to
66% across industry sectors;
o A varying fraction use full-facepiece respirators, 23% overall and varying from 4% to
33% across industry sectors.
• Powered air-purifying respirators represent a minority of respirator use, 15% overall and
varying from 7% to 22% across industry sectors;
• Supplied air respirators represent a minority of respirator use, 17% overall and varying
from 4% to 37% across industry sectors.
In a more recent article, the University of Pittsburgh, CDC, and RAND Corporation used the
OSHA data base to examine all inspections in manufacturing in 47 states from 1999 through
2006 (Mendeloff et al.. 2013); the examination starts with 1999 because an expanded OSHA
respiratory program standard became effective in late 1998. The article identified inspections and
establishments at which respiratory protection violations were cited, and it compares the
prevalence of violations by industry with the prevalence reported in the BLS survey of respirator
use. The pattern of noncompliance across industries mostly mirrored the survey findings about
the prevalence of requirements for respirator use. The probability of citing a respiratory
protection violation was similar across establishment size categories, except for a large drop for
establishments with over 200 workers. The presence of a worker accompanying the inspector
increased the probability that a respiratory program violation could be cited; the presence of a
union slightly decreased it. Thus, the likelihood of respirator use may not be widespread or
effective.
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Dermal Protection
Based on a hazard assessment, employers must also determine whether employees are exposed to
skin hazards (1910.32(d). The Hand Protection section of OSHA's Personal Protective
Equipment Standard (29 CFR § 1910.138(a)) requires employers to select and require workers to
wear gloves to prevent exposure to harmful substances identified in the hazard assessment. As
with respirators, gloves are used to prevent employee exposures to skin hazards. Employers base
selection of gloves on the type of hazardous chemical(s) encountered, conditions during use,
tasks performed and factors that affect performance and wear ability. Gloves, if proven
impervious to the hazardous chemical, and if worn on clean hands and replaced when
contaminated or compromised, could provide employees with protection from hazardous
substances. As described earlier, EPA is using glove protection factors developed by a
conceptual model developed by Cherie et al. in this risk evaluation. Table 2-3 shows these glove
protection factors (PF) and the dermal protection strategies. These values could vary depending
on the type of gloves used and the presence of employee training program.
Table 2-3. Exposure Control Efficiencies and Protection Factors for Different Dermal
Protection Strategies
Dermal Protection Characteristics
Affected User Group
Efficiency
Protection
Factor
a. Any glove without permeation data and without
employee training
Industrial/Commercial
Uses
0
1
b. Gloves with available permeation data
indicating that the material of construction offers
good protection for the substance
80
5
c. Chemically resistant gloves (i.e., as b above)
with "basic" employee training
90
10
d. Chemically resistant gloves in combination with
specific activity training (e.g., procedure for glove
removal and disposal) for tasks where dermal
exposure could occur
Industrial Uses
95
20
2.4.1.6 Regrouping of Conditions of Use for Engineering Assessment
EPA assessed the conditions of use in Table 1-4; however, several of the categories and/or
subcategories were regrouped and assessed together due to similarities in their processes and
exposures. This regrouping minimized repetitive assessments and representative of the potential
exposure for the specified process category. Additionally, each condition of use may be assessed
at the category or subcategory level depending on the specifics of the processes and the exposure
potential for each category/subcategory. For example, import is listed under the manufacture life
cycle stage in Table 1-4, however, in the engineering assessment it is analyzed with the
processing - repackaging category due to the similar processing steps and worker interactions
with carbon tetrachloride that occur during both the importing and repacking of carbon
tetrachloride. Similarly, the subcategory reactive ion etching (i.e., semiconductor manufacturing)
is listed under the processing as a reactant/ intermediate category, however, it is assessed
separately because it is a specialized process that uses small quantities of carbon tetrachloride in
a controlled, clean room environment. This category could be different from the use of carbon
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tetrachloride as a reactant to produce large quantities of another chemical. Exposure from the use
of carbon tetrachloride in reactive ion etching would be inaccurately captured if it was included
in the assessment for the use of carbon tetrachloride as a reactant.
Similarly, the categories and subcategories originally listed in the problem formulation document
(U.S. EPA. 2018d) for incorporation into formulation are regrouped to either the use of carbon
tetrachloride as a reactant to manufacturing a chlorinated compound that is subsequently
formulated into a product or as a processing aid/agent used to aid in the manufacture of
formulated products (agricultural chemicals, petrochemicals-derived products, and any other
basic organic and inorganic chemical manufacturing). The former case is evaluated in the
reactant section and the latter in the processing aid section.
A crosswalk of all the conditions of use listed in Table 1-4 to the conditions of use assessed for
occupational exposures is provided in Table 2-4 below.
Table 2-4. Crosswalk of Subcategories of Use Listed in Table 1-4 and the Sections Assessed
for Occupational Exposure
Life Cycle
Stage
Category
Reported in
Table 1-4
Subcategory
Reported in
Table 1-45
Category in Current
Engineering Assessment
Manufacture
Domestic
manufacture
Domestic
manufacture
Domestic Manufacturing
(Section 2.4.1.7.1)
Import
Import
Import and Repackaging
(Section 2.4.1.7.2)
Processing
Processing as a
reactant/
intermediate
Hy drochl orofluorocar
bons (HCFCs),
Hydrofluorocarbon
(HFCs) and
Hydrofluoroolefin
(HFOs)
Processing as a Reactant or
Intermediate (Section
2.4.1.7.3)
Perchl oroethyl ene
(PCE)
Reactive ion etching
(i.e., semiconductor
manufacturing)
Reactive Ion Etching (Section
2.4.1.7.5)
Incorporation
into
Formulation,
Mixture or
Reaction
products
Petrochemicals-
derived
manufacturing;
Agricultural products
manufacturing; Other
basic organic and
Industrial Processing
Agent/Aid (Section 2.4.1.7.6)
Additive (Section 2.4.1.7.7)
5 These subcategories reflect more specific uses of carbon tetrachloride.
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Life Cycle
Stage
Category
Reported in
Table 1-4
Subcategory
Reported in
Table 1-45
Category in Current
Engineering Assessment
inorganic chemical
manufacturing.
Processing as a Reactant or
Intermediate (Section
2.4.1.7.3)
Processing -
repackaging
Laboratory
Chemicals
Import and Repackaging
(Section 2.4.1.7.2)6
Recycling
Recycling
Disposal/Recycling (Section
2.4.1.7.9)
Distribution in
commerce
Distribution
Distribution in
commerce
Exposures from distribution
are assessed within all
conditions of use
Industrial/comm
ercial use
Petrochemicals-
derived products
manufacturing
Processing aid
Industrial Processing
Agent/Aid (Section 2.4.1.7.6)
Additive
Additive (Section 2.4.1.7.7)
Agricultural
products
manufacturing
Processing aid
Industrial Processing
Agent/Aid (Section 2.4.1.7.6)
Other Basic
Organic and
Inorganic
Chemical
Manufacturing
Manufacturing of
chlorinated
compounds used in
solvents for cleaning
and degreasing
Processing as a Reactant or
Intermediate (Section
2.4.1.7.3)
Other Basic
Organic and
Inorganic
Chemical
Manufacturing
Manufacturing of
chlorinated
compounds used in
adhesives and
sealants
Processing as a Reactant or
Intermediate (Section
2.4.1.7.3)
Other Basic
Organic and
Inorganic
Chemical
Manufacturing
Manufacturing of
chlorinated
compounds used in
paints and coatings
Processing as a Reactant or
Intermediate (Section
2.4.1.7.3)
6 Repackaging is assessed, but not specifically for the use of laboratory chemicals. EPA expects exposures from
repackaging of carbon tetrachloride to be similar regardless of the end-use function of carbon tetrachloride.
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Life Cycle
Stage
Category
Reported in
Table 1-4
Subcategory
Reported in
Table 1-45
Category in Current
Engineering Assessment
Other Basic
Organic and
Inorganic
Chemical
Manufacturing
Manufacturing of
inorganic chlorinated
compounds (i.e.,
elimination of
nitrogen trichloride in
the production of
chlorine and caustic)
Processing as a Reactant or
Intermediate (Section
2.4.1.7.3)
Other Basic
Organic and
Inorganic
Chemical
Manufacturing
Manufacturing of
chlorinated
compounds used in
asphalt
Processing as a Reactant or
Intermediate (Section
2.4.1.7.3)
Other uses
Processing aid (i.e.,
metal recovery).
Industrial Processing
Agent/Aid (Section 2.4.1.7.6)
Specialty uses (i.e.,
DoD uses)
Specialty Uses - DoD Data
(Section 2.4.1.7.4)
Laboratory
chemicals
Laboratory chemical
Laboratory Chemicals (Section
2.4.1.7.8)
Disposal
Disposal
Industrial pre-
treatment
Disposal/Recycling (Section
2.4.1.7.9)7
Industrial wastewater
treatment
Publicly owned
treatment works
(POTW)
Underground
injection
Municipal landfill
Hazardous landfill
Other land disposal
Municipal waste
incinerator
7 Each of the conditions of use of carbon tetrachloride may generate waste streams of the chemical that are collected
and transported to third-party sites for disposal, treatment, or recycling. Industrial sites that treat, dispose, or directly
discharge onsite wastes that they themselves generate are assessed in each condition of use assessment. This section
only assesses wastes of carbon tetrachloride that are generated during a condition of use and sent to a third-party site
for treatment, disposal, or recycling.
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Life Cycle
Stage
Category
Reported in
Table 1-4
Subcategory
Reported in
Table 1-45
Category in Current
Engineering Assessment
Hazardous waste
incinerator
Off-site waste
transfer
The following sections contain process descriptions and the specific details (worker activities,
analysis for determining number of workers, and exposure assessment approach and results) for
the assessment for the regrouped conditions of use. The following sections provide a summary of
the engineering assessments focusing on results. Additional details on how EPA arrived at the
results can be found in the supplemental Risk Evaluation for Carbon Tetrachloride,
Supplemental Information on Releases and Occupational Exposure Assessment (U.S. EPA.
2019b).
2.4.1.7 Inhalation Exposure Assessment
The following sections present inhalation exposure estimates for each condition of use.
2.4.1.7.1 Domestic Manufacturing
Process Description
Currently, most carbon tetrachloride is manufactured using one of three methods:
1. Chlorination of Hydrocarbons or Chlorinated Hydrocarbons
2. Oxychlorination of Hydrocarbons
3. CS2 Chlorination (Hoibrook. 2000)
EPA assessed the import of carbon tetrachloride separate from domestic manufacturing (see
2.4.1.7.2) in order to account for differences in the expected industrial operations and the
associated worker activities which would otherwise be inaccurately captured if included in
this scenario.
Worker Activities
Worker activities at manufacturing facilities may involve manually adding raw materials or
connecting/disconnecting transfer lines used to unload containers into storage or reaction vessels,
rinsing/cleaning containers and/or process equipment, collecting and analyzing quality control
(QC) samples, manually loading carbon tetrachloride product, or connecting/disconnecting
transfer lines used to load carbon tetrachloride product into containers.
ONUs for manufacturing include supervisors, managers, and tradesmen that may be in the same
area as exposure sources but may not perform tasks that result in the same level of exposures as
workers. The presence and motions of the worker or ONUs near/far away from the source or the
performance of ventilation units could have a considerable influence on the flow field around the
person and thus on the dispersion of the chemical from the source to the breathing zone.
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Number of Workers and Occupational Non-Users
The CDR Rule under TSCA (40 CFR Part 711) requires that U.S. manufacturers and importers
provide EPA with information on chemicals they manufacture (including imports). For the 2016
CDR cycle, data collected for each chemical include the company name, volume of each
chemical manufactured/imported, the number of workers employed at each site, and information
on whether the chemical is used in the commercial, industrial, and/or consumer sector. Based on
activity information reported in the 2016 CDR and 2016 TRI, EPA identified seven sites that
domestically manufacture CCU
To determine the total number of workers and ONUs, EPA used the average worker and ONUs
estimates from the BLS analysis based on each site's reported NAICS code in TRI (U.S. BLS.
2016). EPA used the average worker and ONUs estimates from the BLS analysis based on the
reported NAICS codes (or 325199 when not available) in TRI. To determine the total number of
workers and ONUs, EPA used the average worker and ONUs estimates from the BLS analysis
based on each site's reported NAICS code in TRI (U.S. BLS. 2016). EPA used the average
worker and ONUs estimates from the BLS analysis based on the reported NAICS codes (or
325199 when not available) in TRI.
EPA used the seven sites reported as domestic manufacturers in the 2016 CDR and/or 2017 TRI
and the average worker and ONUs estimates from the BLS analysis and TRI reported NAICS
codes to determine the total number of workers and ONUs. This resulted in 5 sites being
classified under 325199 and 2 sites under 325180. There is a total of 243 workers and 115 ONUs
(see Table 2-5).
Table 2-5. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride
During Manufacturing
Number of
Sites
Total Exposed
Workers
Total Exposed
Occupational
Non-Users
Total Exposed
7
243
115
358
Inhalation Exposure
EPA assessed inhalation exposures during manufacturing using identified monitoring data. Table
2-6 summarizes 8-hr and 12-hr TWA samples obtained from data submitted by the Halogenated
Solvents Industry Alliance (HSIA) via public comment for two companies (HSIA. 2019). For
additional details on the methodology and approach for data analysis that produced the following
results, refer to Risk Evaluation for Carbon Tetrachloride, Supplemental Information on
Releases and Occupational Exposure Assessment (U.S. EPA. 2019b)
HSIA (2019) provided monitoring data for carbon tetrachloride collected by two companies
listed as "Company A" and "Company B". The data were collected between 2005 and 2018 with
full-shift data collected over 8 to 12 hours during which workers engaged in a variety of
activities including collecting catch samples; performing filter changes; line and equipment
opening; loading and unloading; process sampling; and transferring of hazardous wastes (HSIA.
2019). EPA assessed two exposure scenarios: 1) 8-hr TWA exposures; and 2) 12-hr TWA
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exposures. Both sets of manufacturing monitoring data were determined to have a "high"
confidence rating through EPA's systematic review process.
Table 2-6. Summary of Worker Inhalation Exposure Monitoring Data for Manufacture of
Carbon Tetrachloride
Exposure Calculation
Number of
Samples
Central
Tendency
(mg/m3)
High-End
(mg/m3)
Confidence Rating of
Associated Air
Concentration Data
8-hr TWA Results for Company A and B
Full-Shift TWA
0.76
4.0
AC
127
0.76
4.0
High
ADC
0.76
4.0
LADC
0.069
0.47
12-hr TWA Results for Company A and B
Full-Shift TWA
0.50
4.8
AC
246
0.50
4.8
High
ADC
0.50
4.8
LADC
0.069
0.83
Equations and parameters for calculation of the ADC and LADC are described in supplemental document Risk
Evaluation for Carbon Tetrachloride, Supplemental Information on Releases and Occupational Exposure
Assessment flJ.S. EPA. 2019b).
2.4.1.7.2 Import and Repackaging
Domestic production and importation of carbon tetrachloride is currently prohibited under
regulations implementing the Montreal Protocol (MP) and CAA Title VI, except when
transformed (used and entirely consumed, except for trace quantities, in the manufacture of other
chemicals for commercial purposes), destroyed (including destruction after use as a catalyst or
stabilizer), or used for essential laboratory and analytical uses. (40 CFR Part 82, 60 FR 24970,
24971 (May 10, 1995)). Therefore, once imported or manufactured, carbon tetrachloride will be
handled again either on-site or by another facility for the identified uses described in detail in the
following sections.
The import and repackaging scenarios cover only those sites that purchase carbon tetrachloride
from domestic and/or foreign suppliers and repackage the carbon tetrachloride from bulk
containers into smaller containers for resale (i.e., laboratory chemicals). It does not include sites
that import carbon tetrachloride and either: (1) store the chemical in a warehouse and resell
directly without repackaging; (2) act as the importer of record for carbon tetrachloride but carbon
tetrachloride is never present at the site8; or (3) import the chemical and process or use the
chemical directly at the site. In case #1, there is little or negligible opportunity for exposures or
releases as the containers are never opened. In case #2, the potential for exposure and release is
at the site receiving carbon tetrachloride, not the "import" site and exposures/releases at the site
8 In CDR, the reporting site is the importer of record which may be a corporate site or other entity that facilitates the
import of the chemical but never actually receives the chemical. Rather, the chemical is shipped directly to the site
processing or using the chemical.
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receiving carbon tetrachloride are assessed in the relevant scenario based on the condition of use
for carbon tetrachloride at the site. Similarly, for case #3, the potential for exposure and release
at these sites are evaluated in the relevant scenario depending on the condition of use for carbon
tetrachloride at the site.
Process Description
EPA assessed the import and repackaging of carbon tetrachloride together because both uses
share similar operations and worker activities that are expected to result in similar exposures.
In general, commodity chemicals are imported into the United States in bulk via water, air, land,
and intermodal shipments (Tomer and Kane. 2015). These shipments take the form of
oceangoing chemical tankers, railcars, tank trucks, and intermodal tank containers. Chemicals
shipped in bulk containers may be repackaged into smaller containers for resale, such as drums
or bottles. Domestically manufactured commodity chemicals may be shipped within the United
States in liquid cargo barges, railcars, tank trucks, tank containers, intermediate bulk containers
(IBCs)/totes, and drums. Both import and domestically manufactured commodity chemicals may
be repackaged by wholesalers for resale; for example, repackaging bulk packaging into drums or
bottles.
For this risk evaluation, EPA assesses the repackaging of carbon tetrachloride from bulk
packaging to drums and bottles at wholesale repackaging sites (see Figure 2-1).
Unloaded from
larger containers
and loaded into
smaller containers
Smaller containers
shipped to
customers for use
Carbon tetrachloride
received in rail cars,
tanks, or totes
Figure 2-1. General Process Flow Diagram for Import and Repackaging
Worker Activities
Based on EPA's knowledge of the chemical industry, worker activities at import and
repackaging sites are potentially exposed while connecting and disconnecting hoses and transfer
lines to containers and packaging to be unloaded (e.g., railcars, tank trucks, totes), intermediate
storage vessels (e.g., storage tanks, pressure vessels), analyzing QC samples, and final packaging
containers (e.g., drums, bottles).
ONUs for repackaging include supervisors, managers, and tradesmen that may be in the
repackaging area but do not perform tasks that result in the same level of exposures as
repackaging workers.
Number of Workers and Occupational Non-Users
Upon review of CDR data, EPA determined one import site. None of the CDR submissions
reported a repackaging activity in the industrial processing and use section. The number of
potentially exposed workers was estimated based on data from the BLS for NAICS code 424690
(U.S. BLS. 2016; U.S. Census Bureau. 2015).
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In the 2017 TRI data (U.S. EPA. 2018f). one submission reported an import activity and one
submission reported a repackaging activity. The site reporting import in the 2017 TRI also
reported use of carbon tetrachloride as a processing aid and is included in the assessment of use
of carbon tetrachloride as a processing aid. The TRI entry marked for repackaging has primary
NAICS code 562211, Hazardous Waste Treatment and Disposal, and is most likely a waste
disposal facility so it is included in the waste handling/recycling assessment.
Based on the information reported in the 2016 CDR and 2017 TRI, EPA assesses one possible
import/repackaging site for carbon tetrachloride (U.S. EPA. 2017h. 2016c). EPA identified the
NAICS code 424690, Other Chemical and Allied Products Merchant Wholesalers, as the code
could include sites importing and repackaging carbon tetrachloride. EPA assesses the number of
potentially exposed workers based on data from the BLS for NAICS code 424690 and related
SOC codes. There is a total of one potentially exposed workers and one ONU for sites under this
NAICS code (see Table 2-7) (U.S. BLS. 2016; U.S. Census Bureau. 2015).
Table 2-7. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride
During Import and Repackaging
Number of
Sites
Total Exposed
Workers
Total Exposed
Occupational
Non-Users
Total Exposed
1
1
1
2
Inhalation Exposure
EPA did not identify any inhalation exposure monitoring data related to the repackaging of
carbon tetrachloride. Therefore, EPA assessed inhalation exposures during repackaging using the
Tank Truck and Railcar Loading and Unloading Release and Inhalation Exposure Model,
conservatively assuming carbon tetrachloride is present at 100 percent concentration when
imported or repackaged. The model estimates the potential concentration of carbon tetrachloride
in air when it is unloaded or loaded at an industrial facility. The model accounts for the
displacement of saturated air containing the chemical of interest as the container/truck is filled
with liquid, emissions of saturated air containing the chemical of interest that remains in the
loading arm, transfer hose and related equipment, and emissions from equipment leaks from
processing units such as pumps, seals, and valves. More details included in the model
calculations and methodology are discussed in the Risk Evaluation for Carbon Tetrachloride,
Supplemental Information on Releases and Occupational Exposure Assessment (U.S. EPA.
2019b).
EPA calculated 8-hr TWA exposures to workers during loading activities. The 8-hr TWA
exposure is the weighted average exposure during an entire 8-hr shift, assuming zero exposures
during the remainder of the shift.
presents a summary of the exposure modeling results. The model estimates a central tendency
exposure of 0.057 mg/m3 8-hr TWA and a high-end exposure of 0.30 mg/m3 8-hr TWA.
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Table 2-8. Summary of Exposure Modeling Results for Import and Repackaging
Exposure
Calculation
Central Tendency
(mg/m3)
High-End
(mg/m3)
Confidence
Rating of
Associated Air
Concentration
Data
Full-Shift TWA
0.057
0.30
N/A - Modeled
Data
AC
0.057
0.30
ADC
0.057
0.30
LADC
0.0052
0.035
2.4.1.7.3 Processing as a Reactant or Intermediate
Process Description
Processing as a reactant or intermediate is the use of carbon tetrachloride as a feedstock in the
production of another chemical product via a chemical reaction in which carbon tetrachloride is
consumed. Carbon tetrachloride is a reactant used in the manufacturing of both inorganic and
organic chlorinated compounds. In the past, carbon tetrachloride was mainly used as feedstock
for the manufacture of chlorofluorocarbons (CFCs) (Marshall and Pottenger. 2016). However,
due to the discovery that CFCs contribute to stratospheric ozone depletion, the use of CFCs was
phased-out by the year 2000 to comply with the Montreal Protocol (Holbrook. 2000). One of the
primary CFC replacements was the HFCs. Most HFCs, do not require carbon tetrachloride for
their manufacture. However, carbon tetrachloride is used as a feedstock to produce HFC-245fa
and HFC-365mfc. The production of hydrofluorocarbons HFC-245fa and HFC-365mfc
accounted for 71% and 23%, respectively, of total carbon tetrachloride consumption in 2016
(MacRov. 2017).
Currently, carbon tetrachloride is used as a reactant to manufacture a variety of chlorinated
compounds including:
HCFCs
HFCs
Hydrofluoroolefins (HFO)s
• Vinyl Chloride
• Ethylene Dichloride (EDC)
• Perchloroethylene (PCE)
• Chloroform
• Hafnium Tetrachloride
Thiophosgene
Methylene Chloride (Krock. 2017; U.S. EPA. 2017d; Marshall and Pottenger.
2016; Weil et al.. 2006; Holbrook. 2003).
The listed chlorinated compounds may then be used in solvents for cleaning and degreasing,
adhesives and sealants, paints and coatings, and asphalt.
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Worker Activities
Similar to when manufacturing carbon tetrachloride, workers are potentially exposed while
connecting and disconnecting hoses and transfer lines to containers and packaging to be
unloaded (e.g., railcars, tank trucks, totes) and manually adding raw materials into intermediate
storage vessels (e.g., storage tanks, pressure vessels) when processing carbon tetrachloride as a
reactant.
ONUs for processing as a reactant include supervisors, managers, and tradesmen that may be in
the same area as exposure sources but do not perform tasks that result in the same level of
exposures as workers.
Number of Workers and Occupational Non-Users
The number of workers and occupational non-users potentially exposed to carbon tetrachloride at
sites processing carbon tetrachloride as a reactant were assessed using 2016 CDR data, 2017 TRI
data, BLS Data and SUSB Data. From the 2016 CDR data, seven submitters reported eight
records of processing carbon tetrachloride as a reactant with each record reporting fewer than 10
sites that process carbon tetrachloride as a reactant. However, five of the eight CDR records are
also reported manufacture locations of carbon tetrachloride. EPA assessed these five records
among the manufacturing section (Section 2.4.1.7.1). EPA assesses the remaining three reports
from CDR in this section. Upon review of 2017 TRI, EPA found eight sites reported using
carbon tetrachloride as a reactant (U.S. EPA. 2017h). and five of these sites are reported
manufacturers of carbon tetrachloride in CDR. This falls within the range reported for number of
sites from the 2016 CDR. EPA assessed three of the listed TRI submissions that use carbon
tetrachloride as a reactant. Between CDR and TRI, EPA assessed a range of six to thirty sites.
To determine the high-end total number of workers and ONUs, EPA used the high-end of ranges
reported for number of sites (nine sites) in the three 2016 CDR reports. Then, EPA assessed
using the corresponding number of workers from BLS analysis that are associated with the
primary NAICS codes for those entries (U.S. BLS. 2016; U.S. EPA. 2016c). For the other three
TRI submissions, the average worker and ONUs estimates from the BLS analysis were used
based on their NAICS codes (U.S. BLS. 2016).This resulted in an estimated 911 workers and
429 ONUs (see Table 2-9).
To determine the low-end total number of workers and ONUs, EPA used the low-end of ranges
reported for number of sites in the three CDR reports. Then, EPA assessed using the
corresponding number of workers from BLS analysis that are associated with the primary
NAICS codes for those entries (U.S. BLS. 2016; U.S. EPA. 2016c). For the remaining three TRI
sites, EPA used the average worker and ONUs estimates from the BLS analysis and TRI reported
NAICS codes (U.S. EPA. 2017h; U.S. BLS. 2016).This resulted in an estimated 182 workers and
86 ONUs (see Table 2-9).
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Table 2-9. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride
During Processing as a Reactant
Number of
Sites
Total Exposed
Workers
Total Exposed
Occupational
Non-Users
Total Exposed
High-End
911
429
1,340
Low-End
182
86
268
Inhalation Exposure
EPA identified one source for inhalation exposure monitoring data related to the use of carbon
tetrachloride as a reactant; however, the discrete sample values as well as the number of samples
taken were not available to estimate exposure concentrations. The manufacturing setting and
associated worker activities are similar for both the manufacture and use as a reactant or
intermediate of carbon tetrachloride. Therefore, the exposure sources, exposure routes, and
exposure levels for the manufacture of carbon tetrachloride will be used to assess the inhalation
exposure during the use of carbon tetrachloride as a reactant or intermediate.9
The manufacturing monitoring data were determined to have a "high" confidence rating through
EPA's systematic review process. Although these data are not directly applicable to processing
of carbon tetrachloride as a reactant, EPA expects a high degree of overlap of worker tasks at
both manufacturing sites and sites processing carbon tetrachloride as a reactant. Based on this
expectation and the strength of the monitoring data, EPA has a medium to high level of
confidence in the assessed exposures. See section 2.4.1.7.2 for the assessment of worker
exposure from chemical manufacturing activities.
2.4.1.7.4 Specialty Uses - Department of Defense Data
EPA reached out to the Department of Defense (DoD) for monitoring data for the first 10
chemical substances that are the subject of the Agency's initial chemical risk evaluations. The
DoD provided monitoring data from its Defense Occupational and Environmental Health
Readiness System - Industrial Hygiene (DOEHRS-IH), which collects occupational and
environmental health risk data from each service branch. The DoD provided inhalation
monitoring data for three branches of the military: The Army, Air Force, and Navy (Defense
Occupational and Environmental Health Readiness System - Industrial Hygiene (DOEHRS-IH).
2018). These data are not distinguished among the three branches.
The following subsections provide an overview of the DoD data. EPA only used the Open
Burn/Open detection (OBOD) clean-up data in this assessment as these were the only data EPA
could use to assess 8-hr TWA exposures. The sampling results for the remaining six processes
9 Chlorinated hydrocarbon use means a process that produces one or more of the following products using
chloroform, carbon tetrachloride, chlorinated paraffins, Hypalon®, oxybisphenoxarsine/l,3-diisocyanate,
polycarbonate, polysulfide rubber, and symmetrical tetrachloropyridiene (Federal Register, Vol. 57, No. 252,
December 31, 1992,62765)
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were measured over a period less than 50 percent of the duration of the process (or an 8-hr shift
if the process duration was not specified). No extrapolation of data was performed to estimate 8-
hr TWA exposure using those data that were sampled only a fraction of the process time (or an
8-hr shift).
Data Overview
The data provided by DoD includes 105 data points for carbon tetrachloride from samples taken
during seven processes:
1. OBOD Clean-Up
2. Detonation Chamber
3. Mobile Detonation Test Facility
4. Plastics/Modeling (Thermoforming)
5. Solvent Extraction of Explosive Samples
6. Glue Sound Dampening Material to Torpedo Body
7. Spray Painting - High Volume, Low Pressure (HVLP) Spray Gun
The provided personal breathing zone samples for all of the DoD activities are summarized in
Table 2-10. All sample results are indicated as less than a value, which is considered to be the
limit of detection (LOD). The DoD data stated that all workers monitored worked an 8-hr shift.
For some processes, the DoD data do not provide the process duration.
Table 2-10. E
»oD Inhalation Monitoring E
Lesults
Process
Worker
Activity
Description
Worker
Activity
Frequency
Process
Duration
(hours)
Min.
Sample
Result
(mg/m3)
Max.
Sample
Result
(mg/m3)
Number
of
Samples
Sample
Duration
(min)
Sample
Date
OBOD
Clean-Up
Cleaning and
sampling
residual metal
and ash
1-2 hours
1-2 hours
< 1.261
-
3
140
Jan. 27,
2015
Detonation
Chamber
Destruction of
munition and
storage of
resulting
liquid waste
Special
Occasions
>10 hours
<2.9
<30
95
14-140
2011
Mobile
Detonation
Test
Facility
Destruction of
munition and
storage of
resulting
liquid waste
Special
Occasions
>10 hours
<3.8
< 17
3
24-116
June
15,
2011
Plastics/
Modeling
(Thermof
orming)
None
Provided
2-3 Times/
Month
-
<5000
PPb
-
1
104
Dec. 4,
2015
Solvent
Extraction
of
Explosive
Samples
Sampling of
energetics
with solvent
Weekly
6-8 hours
<5.52
-
1
60
Sept.
22,
1993
Glue Sound
Dampening
Material to
None
Provided
Special
Occasions
-
<0.217
-
1
221
June
22,
2011
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Process
Worker
Activity
Description
Worker
Activity
Frequency
Process
Duration
(hours)
Min.
Sample
Result
(mg/m3)
Max.
Sample
Result
(mg/m3)
Number
of
Samples
Sample
Duration
(min)
Sample
Date
Torpedo
Body
Spray
Painting -
High
Volume,
Low
Pressure
(HVLP)
Spray Gun
None
Provided
Weekly
-
<3.2
-
1
0
June 5,
2016
1 All three samples provided were listed as < 0.2 ppm (1.26 mg/m3)
OBOD Clean-Up Process Description
During the OBOD clean-up process, employees clean up residual metal and ash. Small metal
pieces and ash are drummed and stored. Once drum(s) are full, personnel perform sampling to
determine disposal requirements. Larger pieces of metal can be sold for recycling once deemed
inert. Clean-up is performed in steel toe boots, coveralls, and respiratory protection (powered air-
purifying respirator [PAPR] with tight-fitting facepiece and organic vapor and HEPA cartridge).
A self-contained breathing apparatus (SCBA) is available for emergencies and as needed for
clean-up (Defense Occupational and Environmental Health Readiness System - Industrial
Hygiene (DOEHRS-HD. 2018V
Inhalation Exposure
As the exposure values are reported to be below the LOD, EPA assessed the data as a range from
0 to 1.26 mg/m3 using the midpoint (0.68 mg/m3) to calculate the central tendency 8-hr TWA
and the maximum value (1.26 mg/m3) to calculate the high end 8-hr TWA. Additionally, the
DoD data indicates that OBOD clean-up has a duration of one to two hours. The sampling
duration of the January 27, 2015 monitoring was 140 minutes (approximately 2.3 hours). The
workers' exposures are zero for the remainder of an 8-hr shift. Therefore, EPA averaged the 140-
minute midpoint and maximum sample results over eight hours to calculate the 8-hr TWA
exposure.
DoD reported the process frequency for the OBOD cleaning as every 2-3 weeks. EPA
incorporated this data and adjusted the exposure frequency to reflect the limited work exposure
time when calculating the central tendency and high-end ADC and LADC. The central tendency
ADC and LADC are calculated using the midpoint of the process frequency range, 2.5 weeks
(125 days/year), and the high-end ADC and LADC are calculated using maximum of the process
frequency range, 3 weeks (150 days/year). Results are displayed in Table 2-11.
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Table 2-11. Summary of Worker Inhalation Exposure Monitoring Data for Specialty Use of
Carbon Tetrachloride
Exposure
Calculation
Number of
Samples
Central
Tendency
(mg/m3)
High-End
(mg/m3)
Confidence Rating of
Associated Air
Concentration Data
8-hr TWA Results for OBOD Clean-Up
Full-Shift TWA
3
0.18
0.37
High
AC
0.18
0.37
ADC
0.092
0.22
LADC
0.0083
0.026
Equations and parameters for calculation of the ADC and LADC are described in supplemental document Risk
Evaluation for Carbon Tetrachloride, Supplemental Information on Releases and Occupational Exposure
Assessment (U.S. EPA. 2019b).
2.4.1.7.5 Reactive Ion Etching
Process Description
Reactive ion etching (RIE) is a microfabrication technique used in miniature electronic
component manufacture. Ion bombardment and a reactive gas, such as carbon tetrachloride, are
used to selectively etch wafers (U.S. EPA. 2017d).
Typically, a clean environment is essential for manufacturing the miniature electronic
components (primarily semiconductors) that require RIE. Flaws in the wafer surface or
contamination of the materials used can result in "opens" or "shorts" in the transistor circuits,
causing them to be unusable (OECD. 2010). Therefore, current semiconductor fabrication
facilities (i.e., 'fabs') are built to Class-1 cleanroom specifications, which means there is no more
than one particle larger than 0.5-micron in one cubic foot of air. In addition, cleaning operations
precede and follow most of the manufacturing process steps. Wet processing, during which
wafers are repeatedly immersed in or sprayed with solutions, is commonly used to minimize the
risk of contamination. In addition, many processes operate within a positive pressure
environment (OECD. 2010).
EPA assessed the use of carbon tetrachloride in reactive ion etching separately from processing
as a reactant or intermediatejo account for differences in the work environments, the industrial
processes, and the quantities of carbon tetrachloride used which would otherwise be inaccurately
captured if reactive ion etching was included in the reactant scenario.
Worker Activities
Specific worker activities for RIE were not identified, but EPA utilized the worker activities
listed in the Emission Scenario Document (ESD) on Photoresist Use in Semiconductor
Manufacturing because worker activities will be similar for RTF, as they are for using
photoresists. According to the ESD on Photoresist Use in Semiconductor Manufacturing, there
are two main worker activity groups at a facility that utilizes RIE that include: equipment
operators and equipment maintenance/waste management technicians. Equipment operators'
main role is to change-out the liquid etching containers containing carbon tetrachloride.
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Equipment maintenance/waste management technicians clean empty containers, clean/maintain
equipment, and change-out the excess solvent collection containers (OECD. 2010).
When workers must enter the cleanroom environment to perform their duties, the worker is
required to wear full-body coveralls (i.e., "space suits"), respirators, face shields, and gloves.
Additionally, wafers are often manipulated robotically within the closed system, or transferred
within "micro" enclosures between process steps to limit worker exposure. However, some sites
have separate work areas outside the wafer processing area (e.g., "chemical kitchens") in which
the photoresist and other chemical containers and supply lines are connected. If workers handle
the photoresist bottles and other chemical containers in a separate area, such as the chemical
kitchen, they will likely be wearing solvent-resistant gloves, aprons, goggles, and respirators
with organic vapor cartridges to minimize exposure (OECD. 2010).
Number of Workers and Occupational Non-Users
Based on information in the ESD on Photoresist Use in Semiconductor Manufacturing, EPA
identified the NAICS code 334413, Semiconductor and Related Device Manufacturing, as the
NAICS code could include sites using carbon tetrachloride as a RIE (OECD. 2010). EPA
estimated the number of workers and ONUs for this NAICS code using Bureau of Labor
Statistics' OES data and the U.S. Census' SUSB (U.S. BLS. 2016; U.S. Census Bureau. 2015).
This analysis resulted in an average of 50 workers and 45 ONU per site. EPA does not have data
to estimate the number of sites using carbon tetrachloride as a RIE; therefore, only the per site
data are presented in Table 2-12.
Table 2-12. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride
During Use as a RIE
Exposed Workers per
Site
Exposed Occupational
Non-Users per Site
Total Exposed Per
Site
50
45
95
Inhalation Exposure
The worker exposures to carbon tetrachloride during RIE are negligible. Due to the performance
requirements of products typically produced via RIE, carbon tetrachloride could be applied in
small amounts in a highly controlled work area, thus eliminating or significantly reducing the
potential for exposures. EPA anticipates that carbon tetrachloride is used in RIE applications in
limited quantities and among limited facilities. This is consistent with assumptions for similar
industry processes provided in the ESD on Chemical Vapor Deposition in the Semiconductor
Industry and ESD on Photoresist Use in Semiconductor Manufacturing (OECD. 2015. 2010).
2.4.1.7.6 Industrial Processing Agent/Aid
Process Description
According to the TRI Reporting Forms and Instructions (RFI) Guidance Document, a processing
aid is a "chemical that is added to a reaction mixture to aid in the manufacture or synthesis of
another chemical substance but is not intended to remain in or become part of the product or
product mixture". Examples of such chemicals include, but are not limited to, process solvents,
catalysts, inhibitors, initiators, reaction terminators, and solution buffers (U.S. EPA. 2018g).
Additionally, processing agents are intended to improve the processing characteristics or the
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operation of process equipment, but not intended to affect the function of a substance or article
created (U.S. EPA. 2016b).
The domestic and international use of carbon tetrachloride as a process agent is addressed under
the MP side agreement, Decision X/14: Process Agents (UNEP/Ozone Secretariat 1998). This
decision lists a limited number of specific manufacturing uses of carbon tetrachloride as a
process agent (non-feedstock use) in which carbon tetrachloride may not be reacted or destroyed
in the production process. Approved uses of carbon tetrachloride as a process agent are listed
below in Table 2-13.
Table 2-13. List of Approved Uses of Carbon Tetrachloride as a Process Agents in the MP
Side Agreement, Decision X/14: Process Agents1
1
Elimination of nitrogen trichloride in the
production of chlorine and caustic
10
Manufacture of chlorinated paraffin
2
Recovery of chlorine in tail gas from
production of chlorine
11
Production of pharmaceuticals -
ketotifen, anticol and disulfiram
3
Manufacture of chlorinated rubber
12
Production of tralomethrine (insecticide)
4
Manufacture of endosulphan (insecticide)
13
Bromohexine hydrochloride
5
Manufacture of isobutyl acetophenone
(ibuprofen - analgesic)
14
Diclofenac sodium
6
Manufacture of 1-1, Bis (4-chlorophenyl)
2,2,2- trichloroethanol (dicofol
insecticide)
15
Cloxacilin
7
Manufacture of chlorosulphonated
polyolefin (CSM)
16
Phenyl glycine
8
Manufacture of poly-phenylene-terephtal-
amide
17
Isosorbid mononitrate
9
Manufacture of styrene butadiene rubber
18
Omeprazol
'EPA found no evidence to suggest that the manufacturing of ibuprofen, or any other pharmaceuticals, still utilizes carbon tetrachloride or that
such use is reasonably foreseen to resume. Accordingly, EPA no longer considers use as a process agent in the manufacturing of pharmaceuticals
to be a condition of use of carbon tetrachloride and does not evaluate it in this draft risk evaluation. See section 1.4.2.2
EPA has identified uses of carbon tetrachloride as a process agent in the manufacturing of
petrochemical-derived products, agricultural products, inorganic compounds (i.e., chlorine), and
chlorinated compounds that are used in the formulation of solvents for cleaning and degreasing,
adhesive and sealants, paints and coatings and asphalt (U.S. EPA. 2017d). A current example of
using carbon tetrachloride as a process agent in petrochemicals-derived product manufacturing is
the manufacture of chlorinated rubber resins. The resulting resins are thermoplastic, odorless,
and non-toxic. Carbon tetrachloride is preferred in this process as it is the only solvent not
attacked by chlorine (U.S. EPA. 2017d).
Worker Activities
During processing, workers are primarily exposed while connecting and disconnecting hoses and
transfer lines to containers and packaging to be unloaded (e.g., railcars, tank trucks, totes, drums,
bottles) and intermediate storage vessels (e.g., storage tanks, pressure vessels).
ONUs for use of carbon tetrachloride used as a processing agent/aid include supervisors,
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managers, and tradesmen that may be in the same area as exposure sources but do not perform
tasks that result in the same level of exposures as workers.
Number of Workers and Occupational Non-Users
Using 2016 CDR data and 2017 TRI data, EPA confirmed three sites that use carbon
tetrachloride as a processing agent/aid.
To determine the total number of workers and ONUs, EPA used the average worker and ONUs
estimates from the BLS analysis based on their NAICS codes (U.S. BLS. 2016). This resulted in
an estimated 67 workers and 32 ONUs (see Table 2-14).
Table 2-14. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride
During Use as a Processing Agent/Aid
Number of
Sites
Total Exposed
Workers
Total Exposed
Occupational
Non-Users
Total Exposed
3
67
32
99
Inhalation Exposure
EPA did not find any exposure monitoring data for use of carbon tetrachloride as a processing
agent/aid; therefore, exposures were assessed with the Tank Truck and Railcar Loading and
Unloading Release and Inhalation Exposure Model.
See section 2.4.1.7.2 for the assessment of worker exposure from chemical unloading activities.
The exposure sources, routes, and exposure levels are similar to those at an import/repackaging
facility, where unloading and handling are the key worker activities. Inhalation exposure
assessment for processing carbon tetrachloride as a processing agent/aid is estimated by the Tank
Truck and Railcar Loading and Unloading Release and Inhalation Exposure Model used in the
import/repackaging scenario.
2.4.1.7.7 Additive
Process Description
Additives are chemicals combined with a chemical product to enhance the properties of the
product. Additives typically stay mixed within the finished product and remain unreacted.
This section includes the assessment of the use of carbon tetrachloride as an additive for
petrochemicals-derived products manufacturing and agricultural products manufacturing.
Specific uses of carbon tetrachloride as an additive include both an additive used in plastic
components used in the automotive industry (HSIA. 2017) and a fuel additive (U.S. EPA.
2017d).
Worker Activities
Similar to manufacturing facilities, worker activities use of carbon tetrachloride as an additive
may involve manually adding raw materials or connecting/disconnecting transfer lines used to
unload containers into storage or reaction vessels, rinsing/cleaning containers and/or process
equipment, collecting and analyzing quality control (QC) samples, and packaging formulated
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products into containers and tank trucks. The exact activities and associated level of exposure
will differ depending on the degree of automation, presence of engineering controls, and use of
PPE at each facility.
ONUs for use of carbon tetrachloride as an additive include supervisors, managers, and
tradesmen that may be in the same area as exposure sources but do not perform tasks that result
in the same level of exposures as workers.
Number of Workers and Occupational Non-Users
Upon review of the 2017 TRI data, EPA found that one site reported the use of carbon
tetrachloride as a formulation component (U.S. EPA. 2018f). EPA determined the number of
workers using the related SOC codes from BLS analysis that are associated with the primary
NAICS code, 325211, listed in TRI. This resulted in an estimated 27 workers and 12 ONUs
potentially exposed at sites using carbon tetrachloride as an additive (see Table 2-15).
Table 2-15. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride
when used as an Additive
Number of
Sites
Total
Exposed
Workers
Total
Exposed
Occupational
Non-Users
Total
Exposed
1
27
12
39
Inhalation Exposure
EPA did not find any exposure monitoring data for use of carbon tetrachloride as an additive;
therefore, exposures from use of carbon tetrachloride as an additive were assessed with the Tank
Tr uck and Railcar Loading and Unloading Release and Inhalation Exposure Model.
See section 2.4.1.7.2 for the assessment of worker exposure from chemical unloading activities.
The exposure sources, routes, and exposure levels are similar to those at an import/ repackaging
facility, where unloading and handling are the key worker activities. Inhalation exposure
assessment for the use of carbon tetrachloride as an additive is estimated by the Tank Truck and
Railcar Loading and Unloading Release and Inhalation Exposure Model used in the
import/repackaging scenario.
2.4.1.7.8 Laboratory Chemicals
Process Description
Carbon tetrachloride is used in a variety of laboratory applications, which include, but are not
limited to, the following:
• Chemical reagent;
• Extraction solvent; and
• Reference material or solvent in analytical procedures, such as spectroscopic
measurements (U.S. EPA. 2017d).
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Specific process descriptions for how carbon tetrachloride is used in each of these applications is
not known. In general, carbon tetrachloride is typically received in small containers and used in
small quantities on a lab bench in a fume cupboard or hood. After use, waste carbon tetrachloride
is collected and disposed or recycled. Figure 2-2 depicts this general process.
CCI4 received in small
containers
CCI4 used in small quantities
for various lab uses
Waste CCI4 collected and
disposed of or recycled
CCI4 = carbon tetrachloride
Figure 2-2. General Laboratory Use Process Flow Diagram
EPA assessed the repackaging of carbon tetrachloride separately (see section 2.4.1.7.2) in order
to account for differences in the industrial processing methods, processing quantities, and the
associated worker interaction which would otherwise be inaccurately captured if included in this
scenario.
Worker Activities
Specific worker activities for using laboratory uses were not identified, but the workers could be
potentially exposed to carbon tetrachloride in laboratories during multiple activities, including
unloading of carbon tetrachloride from the containers in which they were received, transferring
carbon tetrachloride into laboratory equipment (i.e., beakers, flasks, other intermediate storage
containers), dissolving substances into carbon tetrachloride or otherwise preparing samples that
contain carbon tetrachloride analyzing these samples, and discarding the samples.
ONUs include employees that work at the sites where carbon tetrachloride is used, but they do
not directly handle the chemical and are therefore could have lower inhalation exposures and
would not have dermal exposures. ONUs for this condition of use include supervisors, managers,
and other employees that may be in the laboratory but do not perform tasks that result in the
same level of exposures as those workers that engage in tasks related to the use of carbon
tetrachloride.
Number of Workers and Occupational Non-Users
Using 2016 CDR data and 2017 TRI data, EPA confirmed one industrial use of carbon
tetrachloride as a laboratory chemical for fewer than ten sites (U.S. EPA. 2018f 2016a). EPA
determined the number of workers using the related SOC codes from BLS analysis that are
associated with the primary NAICS code, 541380, Testing Laboratories.
To determine the high-end total number of workers and ONUs, EPA used the high-end number
of sites from CDR (nine sites) and the BLS OES data to estimate number of workers per site.
This resulted in a total of 87 exposed workers and ONUs (see Table 2-16).
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To determine the low-end total number of workers and ONUs, EPA used the low-end number of
sites from CDR (one site) and the BLS OES data to estimate workers per site listed for these
industrial use sites. This resulted in a total of ten exposed workers and ONUs (see Table 2-16).
Table 2-16. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride
During Use as a Laboratory Chemical
Total
Exposed
Workers
Total
Number of
Sites
Exposed
Occupational
Non-Users
Total
Exposed
High-End
9
9
78
87
Low-End
1
1
9
10
Inhalation Exposure
EPA does not have monitoring data to assess worker exposures to carbon tetrachloride during
laboratory use. Following workplace safety protocols for the use of chemicals in laboratories,
carbon tetrachloride is generally handled in small amounts as required for reactions or analyses.
Carbon tetrachloride is handled under a fume hood as per good laboratory practices, thus
reducing the potential for inhalation exposures
2.4.1.7.9 Disposal/Recycling
This scenario is meant to include sites like hazardous waste treatment sites (TSDFs), including
incinerators, landfills, other forms of treatment, and solvent or other material reclamation or
recycling. These are sites largely covered under RCRA (e.g., RCRA permitted TSDFs) but also
include municipal waste combustors and landfills.
Process Description
Each of the conditions of use of carbon tetrachloride may generate waste streams of the chemical
that are collected and transported to third-party sites for disposal, treatment, or recycling.
Industrial sites that treat or dispose onsite wastes that they themselves generate are assessed in
each condition of use assessment in sections 2.4.1.7.1 to 2.4.1.7.8. Wastes of carbon tetrachloride
that are generated during a condition of use and sent to a third-party site for treatment, disposal,
or recycling may include the following:
• Wastewater: carbon tetrachloride may be contained in wastewater discharged to POTW
or other, non-public treatment works for treatment. Industrial wastewater containing
carbon tetrachloride discharged to a POTW may be subject to EPA or authorized NPDES
state pretreatment programs.
• Solid Wastes: Solid wastes are defined under RCRA as any material that is discarded by
being: abandoned; inherently waste-like; a discarded military munition; or recycled in
certain ways (certain instances of the generation and legitimate reclamation of secondary
materials are exempted as solid wastes under RCRA). Solid wastes may subsequently
meet RCRA's definition of hazardous waste by either being listed as a waste at 40 CFR
§§ 261.30 to 261.35 or by meeting waste-like characteristics as defined at 40 CFR §§
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261.20 to 261.24. Solid wastes that are hazardous wastes are regulated under the more
stringent requirements of Subtitle C of RCRA, whereas non-hazardous solid wastes are
regulated under the less stringent requirements of Subtitle D of RCRA.
o Carbon tetrachloride is both a listed and a characteristic hazardous waste. Carbon
tetrachloride is a non-specific-source listed hazardous waste under waste number
F001 (spent halogenated degreasing solvents) [40 CFR § 261.31] and a source-
specific listed hazardous waste under waste number K016 (heavy ends or
distillation residues from the production of carbon tetrachloride, which may
contain residual carbon tetrachloride) [40 CFR §261.32], Discarded, commercial-
grade carbon tetrachloride is a listed hazardous waste under waste number U211
40 CFR § 261.33.
o Carbon tetrachloride is a toxic contaminant under RCRA with waste number
DO 19. A solid waste can be a hazardous waste due to its toxicity characteristic if
its extract following the Toxicity Characteristic Leaching Procedure (TCLP) (or
the liquid waste itself if it contains less than 0.5% filterable solids) contains at
least 0.5 mg/L of carbon tetrachloride [40 CFR § 261.24],
• Wastes Exempted as Solid Wastes under RCRA: Certain conditions of use of carbon
tetrachloride may generate wastes of carbon tetrachloride that are exempted as solid
wastes under 40 CFR § 261.4(a). For example, the generation and legitimate reclamation
of hazardous secondary materials of carbon tetrachloride may be exempt as a solid waste.
2016 TRI data lists off-site transfers of carbon tetrachloride to land disposal, wastewater
See Figure 2-3 for a
Recycling
o
Treatment
/ g
n
. Disposal
liir4
Figure 2-3. Typical Waste Disposal Process
Source: (J.S. EPA. 2017c)
treatment, incineration, and recycling facilities ( J.S. EPA. 2017b. f).
general depiction of the waste disposal process.
Hazardous Waste
Generation
Hazardous Waste
Transportation
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Worker Activities
At waste disposal sites, workers are potentially exposed via dermal contact with waste containing
carbon tetrachloride or via inhalation of carbon tetrachloride vapor. Depending on the
concentration of carbon tetrachloride in the waste stream, the route and level of exposure may be
similar to that associated with container unloading activities. At municipal waste incineration
facilities, there may be one or more technicians present on the tipping floor to oversee
operations, direct trucks, inspect incoming waste, or perform other tasks as warranted by
individual facility practices. At landfills, typical worker activities may include operating refuse
vehicles to weigh and unload the waste materials, operating bulldozers to spread and compact
wastes, and monitoring, inspecting, and surveying a landfill site [California Department of
Resources Recycling and Recovery (CalRecvcle. 2018)1.
Number of Workers and Occupational Non-Users
The 2016 CDR uses did not show any submissions for waste handling, so EPA reviewed the
2017 TRI data and found twelve sites reported using carbon tetrachloride during waste handling
(U.S. EPA. 2018f. 2017b. 2016d).
EPA determined the number of workers using the related SOC codes from BLS analysis that are
associated with the primary NAICS codes listed in TRI (U.S. BLS. 2016). This analysis resulted
in 125 workers and 63 ONUs potentially exposed at sites using carbon tetrachloride as a
processing agent/aid (see Table 2-17).
Table 2-17. Estimated Number of Workers Potentially Exposed to Carbon Tetrachloride
During Waste Handling
Number of
Sites
Total Exposed
Workers
Total Exposed
Occupational
Non-Users
Total Exposed
12
125
63
188
Inhalation Exposure
EPA did not find any exposure monitoring data for waste handling of carbon tetrachloride;
therefore, exposures from waste handling activities were assessed with the Tank Truck and
Railcar Loading and Unloading Release and Inhalation Exposure Model. The following
subsections detail the results of EPA's occupational exposure assessment for waste handling are
based on modeling.
See section 2.4.1.7.2 for the assessment of worker exposure from chemical unloading activities.
The exposure sources, routes, and exposure levels are similar to those at an import/repackaging
facility, where unloading and handling are the key worker activities. Inhalation exposure
assessment for the disposal of carbon tetrachloride is estimated by the Tank Truck and Railcar
Loading and Unloading Release and Inhalation Exposure Model used in the import/repackaging
scenario.
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2.4.1.7.10 Summary of Occupational Inhalation Exposure
Assessment
Table 2-18 presents the occupational exposure assessment summary for the conditions of use
described by the previous sections of this draft risk evaluation.
For additional information on the developmental details, methodology, approach, and results of
any part of the occupational exposure determination process, refer to the supplemental document
Risk Evaluation for Carbon Tetrachloride, Supplemental Information on Releases and
Occupational Exposure Assessment (U.S. EPA. 2019b).
The summary and ranking of occupational exposure of carbon tetrachloride indicating strengths,
challenges, whether modelling or monitoring preformed, representativeness and confidence of
data assessed, hierarchy of data, and overall rating for various conditions of use are shown in
Table 2-19.
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2880 Table 2-18. Summary of Occupational Inhalation Exposure Assessment for Workers
Condition of Use
8-Hour or 12-
Hour TWA
Exposures
Acute Exposures
Chronic, Non-
Cancer Exposures
Chronic,
Cancer
Exposures
TWA
Data
Points
Data
Type
8 or 12-hi' TWA
(mg/m3)
AC twa (mg/m3)
ADC twa (mg/m3)
LADC twa
(mg/m3)
High-
End
Central
Tendency
High-
End
Central
Tendency
High-End
Central
Tendency
High-
End
Central
Tendency
Manufacturing - 8-hr
TWA
4.0
0.76
4.0
0.76
4.0
0.76
0.47
0.069
127
Monitoring
Data
Manufacturing - 12-
hr TWA
4.8
0.50
4.8
0.50
4.8
0.50
0.83
0.069
246
Monitoring
Data
Import/Repackaging
0.30
0.057
0.30
0.057
0.30
0.057
0.035
0.0052
N/A
Model
Processing as
Reactant/Intennediate
- 8-hr TWA
4.0
0.76
4.0
0.76
4.0
0.76
0.47
0.069
127
Surrogate
Monitoring
Data
Processing as
Reactant/Intennediate
- 12-hr TWA
4.8
0.50
4.8
0.50
4.8
0.50
0.83
0.069
246
Surrogate
Monitoring
Data
Specialty Uses -
Department of
Defense Data
0.37
0.18
0.37
0.18
0.22
0.092
0.026
0.0083
3
Monitoring
Data
Reactive Ion Etching
Negligible - Highly controlled work areas with small quantities applied
Industrial Processing
Aid
0.30
0.057
0.30
0.057
0.30
0.057
0.035
0.0052
N/A
Model
Additive
0.30
0.057
0.30
0.057
0.30
0.057
0.035
0.0052
N/A
Model
Laboratory
Chemicals
No data - exposure is low as laboratory typically uses small quantities on a lab bench under a fume cupboard or hood.
Waste Handling
0.30
0.057
0.30
0.057
0.30
0.057
0.035
0.0052
N/A
Model
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2881
Table 2-19. Summary and Ranking of Occupational Exposure of Carbon Tetrachloride for Various Conditions of Use
Occupational
Exposure
Scenario
Inhalation Exposure
Manufacturing
Import and
Repackaging
Processing as a
Reactant or
Intermediate
Strength
PBZ sampling
High data quality
Source of
information
available directly
from
manufacturer
CDR provided
employee counts
for specific
manufacturing
site
Data from
multiple facilities
CDR provided
employee counts
for specific
Import and
Repackaging sites
Model uses
published EPA
emission factors
PBZ sampling
415 data points
Challenge
Data is provided
from one source
Monitoring
Modeling
Representativeness
Dermal
Exposure Overall
Modeling" Rating
for
Worker ONU Wolkersb
Data (#) Surrogate Worker ONU Worker ONU
Many data points
were at or below
the limit of
detection
No Monitoring
Data
EPA models are
not specific to
Import and
Repackaging
Relies on process
and protection
assumptions
May
underestimate
worker exposure
No monitoring
data for this CoU;
Surrogate data
from
manufacturing
(373)
~
(373)
~
Routine monitoring
data available for work
environment
Assesses exposure
based on loading and
unloading only.
Assumes controlled and
closed systems for all
other operations.
Routine monitoring
data available for work
environment
~
~
Higher
Lower
Higher
Lower
Higher
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Dermal
Occupational
Exposure Strength
Scenario
Source of
information
available directly
from
manufacturer
Data is provided
from one source
Lower
CDR provided
employee counts
for specific
manufacturing
site
Data from
multiple facilities
Many data points
were at or below
the limit of
detection
Specialty Uses
(Department of
Defense)
PBZ sampling
All data points are
at or below the
limit of detection
Only 3 data points
s
(3)
3C
~
3C
3C
3C
Routine monitoring
data available for work
environment
—
H
L
Industrial
Processing
Agent/Aid
CDR provided
employee counts
for specific
industrial
processing
agent/aid sites
No Monitoring
Data
EPA models are
not specific to use
as Industrial
Processing
Agent/Aid
X
3C
3C
3C
3C
Assesses exposure
based on loading and
unloading only.
Assumes controlled and
closed systems for all
other operations.
—
H
L
Model uses
published EPA
emission factors
Relies on process
and protection
assumptions
May
underestimate
worker exposure
Inhalation Exposure
Monitoring
Modeling
Representativeness
Exposure
Modeling"
Worker ONU
Data (#) Surrogate Worker ONU Worker ONU
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Occupational
Exposure
Scenario
Inhalation Exposure
Additive
Disposal /
Recycling
Strength
CDR provided
employee counts
for specific
additive sites
Model uses
published EPA
emission factors
CDR provided
employee counts
for specific
disposal/recycling
sites
Model uses
published EPA
emission factors
Challenge
No Monitoring
Data
Monitoring
Modeling
EPA models are
not specific to use
as an additive
Relies on process
and protection
assumptions
No Monitoring
Data
EPA models are
not specific to
disposal/recycling
Relies on process
and protection
assumptions
Data (#) Surrogate Worker ONU Worker ONU
Representativeness
Assesses exposure
based on loading and
unloading only.
Assumes controlled and
closed systems for all
other operations.
Dermal
Exposure Overall
Modeling'1 Rating
for
Worker ONU Workersb
Assesses exposure
based on loading and
unloading only.
Assumes controlled and
closed systems for all
other operations.
2882 'Dermal exposure estimates, which are based on high-end/central tendency parameters and commercial/industrial settings, have medium level of confidence.
2883 bONU exposure estimates, which are based on central tendency paraments, have low levels of confidence.
Hieher
Lower
Higher
Lower
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2.4.1.8 Dermal Exposure Assessment
Because carbon tetrachloride is a volatile liquid, the dermal absorption of carbon tetrachloride
depends on the type and duration of exposure. Where exposure is without gloves, only a fraction
of carbon tetrachloride that comes into contact with the skin will be retained as the chemical
readily evaporates from the skin. However, dermal exposure may be significant in cases of
occluded exposure, repeated contacts, or dermal immersion. For example, work activities with a
high degree of splash potential may result in carbon tetrachloride liquids trapped inside the
gloves, inhibiting the evaporation of carbon tetrachloride and increasing the exposure duration.
Specific methodology for dermal exposure estimation is detailed in Appendix E of the document
Risk Evaluation for Carbon Tetrachloride, Supplemental Information on Releases and
Occupational Exposure Assessment (U.S. EPA. 2019b).
Table 2-20 presents the estimated dermal retained dose for workers in various exposure
scenarios, focusing on what-if scenarios for glove use. The dose estimates assume one exposure
event (applied dose) per work day and that approximately four percent of the applied dose is
absorbed through the skin during industrial settings. The conditions of use for carbon
tetrachloride are industrial uses that occur in closed systems where dermal exposure is likely
limited to chemical loading/unloading activities (e.g., connecting hoses) and taking quality
control samples. Across all types of uses, the maximum possible exposure concentration (Yderm)
exists during industrial uses that generally occur in closed systems. Therefore, all conditions of
use for carbon tetrachloride are assessed at the maximum Yderm, or 1. In addition to the what-if
scenarios for glove use, EPA considered the potential for occluded dermal exposures; however,
based on the worker activities for the condition of use for carbon tetrachloride, EPA determined
occluded exposures to be unlikely. Occluded scenarios are generally expected where workers are
expected to come into contact with bulk liquid carbon tetrachloride during use in open systems
(e.g., during solvent changeout in vapor degreasing and dry cleaning) and not expected in closed
systems (e.g., during connection/disconnection of hoses used in loading of bulk containers in
manufacturing). For further description of the applicable scenarios, see Appendix E of Risk
Evaluation for Carbon Tetrachloride, Supplemental Information on Releases and Occupational
Exposure Assessment (U.S. EPA. 2019b). EPA assesses the following what-if glove use
scenarios for all conditions of use of carbon tetrachloride for workers:
No gloves used: Operators in these industrial uses, while working around closed-system
equipment, may not wear gloves or may wear gloves for abrasion protection or gripping that are
not chemical resistant.
• Gloves used with a protection factor of 5, 10, and 20: Operators may wear
chemical-resistant gloves when taking quality control samples or when
connecting and disconnecting hoses during loading/unloading activities. The
gloves could offer a range of protection, depending on the type of glove and
employee training provided.
• Scenarios not assessed: EPA does not assess occlusion as workers in these
industries are not likely to come into contact with bulk liquid carbon tetrachloride
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that could lead to chemical permeation under the cuff of the glove or excessive
liquid contact time leading to chemical permeation through the glove.
The skin is a very complex and dynamic human organ composed of an outer epidermis and inner
dermis with functions well beyond that of just a barrier to the external environment. Dermal
absorption depends largely on the barrier function of the stratum corneum, the outermost
superficial layer of the epidermis, and is modulated by factors such as skin integrity, hydration,
density of hair follicles and sebaceous glands, thickness at the site of exposure assessment,
physiochemical properties of the substance, chemical exposure concentration, and duration of
exposure. The workplace protection factor for gloves is based on the ratio of uptake through the
unprotected skin to the corresponding uptake through the hands when protective gloves are worn.
The exposure assessments were conducted considering vapor pressure and other physical-
chemical properties, of carbon tetrachloride. The key barrier of the skin is located in the
outermost layer of the skin, the stratum corneum, which consists of corneocytes surrounded by
lipid regions. Due to increased area of contact and reduced skin barrier properties, repeated skin
contact with chemicals could have even higher than expected exposure if evaporation of the
chemical occurs and the concentration of chemical in contact with the skin increases. In the
workplace the wearing of gloves could have important consequences for dermal uptake. If the
worker is handling a chemical without any gloves, a splash of the liquid or immersion of the
hand in the chemical may overwhelm the skin contamination layer so that the liquid chemical
essentially comprises the skin contamination layer. If the material is undiluted, then uptake could
proceed rapidly as there will be a large concentration difference between the skin contamination
layer and the peripheral blood supply. Conversely, if the contaminant material is in a dilute form,
there will be relatively slow uptake. If the worker is wearing a glove the situation will be
different. In case the chemical comes into contact with the outer glove surface, there will be no
flux into the inner glove contamination layer until the chemical breaks through. The chemical
could partition into the glove and then diffuse towards the inner glove surface; then it could
partition into the skin contamination layer. Diffusion through the stratum corneum is dependent
on the concentration. The glove protection factor is unlikely to be constant for a glove type but
could be influenced by the work situation and the duration of the exposure as glove performance
and pass/fail criteria are also dependent on cut, puncture and abrasion resistance; chemical
permeation and degradation; holes; heat and flame resistance; vibration, and dexterity of
operation and operator.
As shown in Table 2-20 the calculated retained dose is low for all dermal exposure scenarios as
carbon tetrachloride evaporates quickly after exposure. Dermal exposure to liquid is not expected
for occupational non-users, as they do not directly handle carbon tetrachloride.
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Table 2-20. Estimated Dermal Acute and Chronic Retained Doses for Workers for All
Conditions of Use10
Category
Exposure Level
Acute
Potential
Dose Rate
Acute
Retained
Dose
Chronic
Retained Dose,
Non-Cancer
Chronic
Retained Dose,
Cancer
APDRexp
(mg/day)
ARD
(mg/kg-
day)
CRD
(mg/kg-day)
CRD
(mg/kg-day)
Worker, No Gloves
High End
90
1.1
1.1
0.39
Central Tendency
30
0.37
0.37
0.10
Worker with
Gloves; PF =
5
High End
18
0.22
0.22
0.079
Central Tendency
6.0
0.075
0.075
0.020
Worker with
Gloves; PF =
10
High End
9.0
0.11
0.11
0.039
Central Tendency
3.0
0.037
0.037
0.010
Worker with
Gloves; PF =
20
High End
4.5
0.056
0.056
0.020
Central Tendency
1.5
0.019
0.019
0.0051
2.4.2 Consumer Exposures
As explained in section 1.4.1, there are no consumer uses of carbon tetrachloride within the
scope of the risk evaluation. No additional information was received by EPA following the
publication of the problem formulation that would update the problem formulation conclusion
that carbon tetrachloride is expected to be present in consumer products at trace levels resulting
in de minimis exposures or otherwise insignificant risks and therefore that consumer uses do not
warrant inclusion in the risk evaluation. Accordingly, EPA did not analyze consumer exposures
in the risk evaluation for carbon tetrachloride.
2.4.3 General Population Exposures
As explained in sections 1 and 2.5 of the problem formulation document (U.S. EPA. 2018d).
EPA is not including in this draft risk evaluation exposure pathways under programs of other
environmental statutes, administered by EPA, which adequately assess and effectively manage
exposures and for which long-standing regulatory and analytical processes already exist.
Therefore, based on information obtained by EPA and presented in section 2.5.3.2 of the
problem formulation document (U.S. EPA. 2018d). EPA is not evaluating any exposure
pathways to human receptors (i.e., general population) from environmental releases and waste
streams associated with industrial/commercial activities for carbon tetrachloride which result in
releases to the following pathways: ambient air pathway (carbon tetrachloride is listed as a
Hazardous Air Pollutant (HAP) in the Clean Air Act (C AA)), drinking water pathway (National
Primary Drinking Water Regulations (NPDWRs) are promulgated for carbon tetrachloride under
the Safe Drinking Water Act (SDWA)), ambient water pathways (carbon tetrachloride is a
priority pollutant with recommended water quality criteria for protection of human health under
the Clean Water Act (CWA)), biosolids pathways (carbon tetrachloride in biosolids is currently
being addressed in the CWA regulatory analytical process), and disposal pathways (carbon
tetrachloride disposal pathways are subject to regulation under the RCRA, SDWA, and CAA).
111 Calculation are described in Appendix E of Risk Evaluation for Carbon Tetrachloride, Supplemental Information
on Releases and Occupational Exposure Assessment (U.S. EPA. 2019b).
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Because there are no other exposure pathways impacting the general population, EPA did not
analyze general population exposures in the risk evaluation for carbon tetrachloride.
2.5 Other Exposure Considerations
2.5.1 Potentially Exposed or Susceptible Subpopulations
TSCA § 6(b)(4)(A) requires that a risk evaluation "determine whether at chemical substance
presents an unreasonable risk of injury to health or the environment, without consideration of
cost or other non risk factors, including an unreasonable risk to a potentially exposed or
susceptible subpopulation identified as relevant to the risk evaluation by the Administrator,
under the conditions of use." TSCA § 3(12) states that "the term 'potentially exposed or
susceptible subpopulation' means a group of individuals within the general population identified
by the Administrator who, due to either greater susceptibility or greater exposure, may be at
greater risk than the general population of adverse health effects from exposure to a chemical
substance or mixture, such as infants, children, pregnant women, workers, or the elderly."
In developing the draft risk evaluation, the EPA analyzed the reasonably available information to
ascertain whether some human receptor groups may have greater exposure or susceptibility than
the general population to the hazard posed by a chemical. During problem formulation, the EPA
identified the following potentially exposed or susceptible subpopulations based on their greater
exposure to carbon tetrachloride: workers and occupational non-users. Accordingly, EPA has
assessed potential risks to these two subpopulations in this draft risk evaluation. Section 3.2.5.2
describes the hazard information identifying susceptibility to the toxic effects of carbon
tetrachloride in individuals with histories of alcohol usage.
2.5.2 Aggregate and Sentinel Exposures
As a part of risk evaluation, Section 2605(b)(4)(F)(ii) of TSCA requires EPA to describe whether
aggregate or sentinel exposures were considered under the identified conditions of use and the
basis for their consideration. EPA has defined aggregate exposure as "the combined exposures to
an individual from a single chemical substance across multiple routes and across multiple
pathways." (40 C.F.R. 702.33). EPA defines sentinel exposure as "exposure to a single chemical
substance that represents the plausible upper bound relative to all other exposures within a broad
category of similar or related exposures." (40 C.F.R. 702.33). EPA considered sentinel exposure
in the form of high-end estimates for occupational exposure scenarios which incorporate dermal
and inhalation exposure, as these routes are expected to present the highest exposure potential
based on details provided for the manufacturing, processing and use scenarios discussed in the
previous section. The exposure calculation used to estimate dermal exposure to liquid is
conservative for high-end occupational scenarios where it assumes full contact of both hands and
no glove use. See further information on aggregate and sentinel exposures in section 4.6.
3 HAZARDS
3.1 Environmental Hazards
EPA conducted comprehensive searches for data on the environmental hazards of carbon
tetrachloride, as described in the Strategy for Conducting Literature Searches for Carbon
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Tetrachloride: Supplemental File for the TSCA Scope Document (EPA-HQ-QPPT-2016-0733-
0050). Based on an initial screening, EPA analyzed the hazards of carbon tetrachloride identified
in this risk evaluation document. The relevance of each hazard endpoint within the context of a
specific exposure scenario was judged for appropriateness. For example, hazards that occur only
as a result of chronic exposures may not be applicable for acute exposure scenarios. This means
that it is unlikely that every identified hazard was analyzed for every exposure scenario.
Further, EPA focused in the risk evaluation process on conducting timely, relevant, high-quality,
and scientifically credible risk evaluations. See 82 FR 33726, 33728 (July 20, 2017). Each risk
evaluation is "fit-for-purpose," meaning the level of refinement will vary as necessary to
determine whether the chemical substance presents an unreasonable risk. Given the nature of the
evidence, for the conditions of use of the specific chemical substance, and when information and
analysis are sufficient to make a risk determination using assumptions, uncertainty factors, and
models or screening methodologies, EPA may decide not to refine its analysis further (40 CFR
702.41(a)(6), (7); see also 82 FR at 33739-40).
3.hi Approach and Methodology
As part of the problem formulation, EPA reviewed and characterized the environmental hazards
associated with carbon tetrachloride (see section 2.5.3.1. of the problem formulation document)
(U.S. EPA. 2018d). EPA identified the following sources of environmental hazard data for
carbon tetrachloride: ECHA (2017). OECD SIDS Initial Assessment Profile (SIAP) (2011). and
Australia's 2017 National Industrial Chemicals Notification and Assessment Scheme (NICNAS).
In addition, scientific studies were identified in a literature search for carbon tetrachloride
{Carbon tetrachloride (CASRN 56-23-5) Bibliography: Supplemental File for the TSCA Scope
Document, EPA-HQ-OPPT-2016-0733) and were evaluated based on data quality evaluation
metrics and rating criteria described in the Application of Systematic Review in TSCA Risk
Evaluations (U.S. EPA. 2018a) and Strategy for Assessing Data Quality in TSCA Risk
Evaluation (U.S. EPA. 2018e). Since only studies with data quality evaluation results of 'high'
and 'medium' quality ratings were available to characterize the environmental hazards, no
studies with 'low" ratings were used. The Agency attempted but was not able to obtain the full
scientific publications listed in ECHA, SIAP, and NICNAS. As a result, these data could not be
systematically reviewed and were not used in the risk evaluation. Even if the Agency had
obtained the full studies and considered them acceptable, EPA determined that the ecotoxicity
values presented in ECHA, SIAP, and NICNAS would not have resulted in a more conservative
environmental hazard assessment. The robust summary endpoints from these sources align with
the dataset EPA used to assess the hazards of carbon tetrachloride. Furthermore, the acute and
chronic COCs for carbon tetrachloride were based on the lowest toxicity value in the dataset.
Of the 75 on-topic environmental hazard sources identified by the ECOTOX process, 61
citations were considered out of scope and/or unacceptable in data quality based on the data
quality evaluation metrics and the rating criteria described in the Application of Systematic
Review in TSCA Risk Evaluations (U.S. EPA. 2018a). The data quality evaluation results for the
remaining 14 on-topic studies for carbon tetrachloride environmental hazard are presented in the
document Risk Evaluation for Carbon Tetrachloride, Systematic Review Supplemental File:
Data Quality Evaluation of Environmental Hazard Studies (U.S. EPA. 2019e). Relevant test data
from the screened literature are summarized in 7Appendix G as ranges (min-max).
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3.1.2 Hazard Identification-Toxicity to Aquatic Organisms
EPA identified and evaluated carbon tetrachloride environmental hazard data for fish, aquatic
invertebrates, amphibians, and algae across acute and chronic exposure durations. During
problem formulation, terrestrial species exposure pathways were considered to be covered under
programs of other environmental statues administered by EPA, which adequately assess and
effectively manage such exposures (e.g., RCRA and CAA). Thus, environmental hazard data
sources on terrestrial organisms and on metabolic endpoints were considered out of scope and
excluded from data quality evaluation.
As a result of a screening-level comparison of the reasonably available environmental hazard
data with exposure concentrations, it was determined that no further hazard analyses were
necessary (see section 2.5.3.1. of the problem formulation document) (U.S. EPA. 2018d). Upon
further evaluation of the reasonably available hazard data of carbon tetrachloride after the
problem formulation phase, EPA decreased the environmental hazard chronic COC from 7 |ig/L
to 3 |ig/L. Consequently, EPA assessed the risk of aquatic organisms in this draft risk evaluation.
The derived acute COC (62 |ig/L) and chronic COC (3 |ig/L) are based on environmental
toxicity endpoint values (e.g., ECso) from Brack and Rottler (1994) and (Black et al.. 1982; Birge
et al.. 1980). respectively. The data represent the lowest bound of all carbon tetrachloride data
available in the public domain and provide the most conservative hazard values. Further details
about the environmental hazards of carbon tetrachloride are available in Appendix G.
Previously, algal endpoints were considered together with data from other taxa in the acute and
chronic COC calculations. Now, algal endpoints are considered separately from the other taxa
and not incorporated into acute or chronic COCs because durations normally considered acute
for other species (e.g., 48, 72, or 96 hours) can encompass several generations of algae. A
distinct COC is calculated for algal toxicity.
Overall Confidence in COCs
After evaluating all available carbon tetrachloride test data, EPA has high confidence in the
environmental hazard data for carbon tetrachloride and high confidence that the data incorporates
the most conservative (highest toxicity)/environmentally-protective acute and chronic
concentrations of concern (as described above).
3.2 Human Health Hazards
3.2.1 Approach and Methodology
EPA used the approach described in section 1.5 to evaluate, extract and integrate carbon
tetrachloride's human health hazard and dose-response information. Figure 3-1 presents the steps
for the hazard identification and dose response process used by EPA in this risk evaluation draft.
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WOE
Narrative by
Adverse
End point
(Section 3.2.4)
Stud>' Quality
Summary
Table '
Summarv of
Results and
PODs
(Section 3.2.5)
Human Health Hazard Assessment
Risk Characterization
Data
Extraction
Extract data from
key. supporting
and new studies
Risk Characterization
Analysis
Determine the qualitative
and or quantitative human
health risks and include, as
appropriate, a discussion of
• Uncertainty and variability
¦ Data quality
• PESS
• Alternative interpretations
Data Integration
Integrate hazard information by considering quality (i.e.,
strengths, limitations), consistency, relevancy, coherence and
biological plausibility
Hazard ID
Confirm potential
hazards identified
during
scoping problem
formulation and
identify- new hazards
from new literature (if
applicable)
Dose-Response
Analysis
Benchmark dose
modeling for
endpoints with
adequate data:
Selection of PODs
Data Evaluation
After full-text screening,
apply pre-determined data
quality evaluation criteria
Systematic to assess the confidence of
Review key and supporting studies
Stage identified from previous
assessments as well as
new studies not
considered in the previous
assessments
Output of
Systematic
Review
Stage
Figure 3-1. Hazard Identification and Dose-Response Process
The new on-topic studies and key and supporting studies from previous hazard assessments were
screened against inclusion criteria in the PECO statement. Relevant studies were further
evaluated using the data quality criteria in the Application of Systematic Review in TSCA Risk
Evaluations (U.S. EPA. 2018a).
In the data evaluation step (Step 1), the key and supporting studies from previous hazard
assessments and new on-topic studies were evaluated using the data evaluation criteria for
human, animal, and in vitro studies described in the Application of Systematic Review in TSCA
Risk Evaluations (U.S. EPA. 2018a). Specifically, EPA reviewed key and supporting information
from previous EPA hazard assessments, such as U.S. EPA (2010). the ATSDR Toxicological
Profile (2005) and previous assessments listed in Table 1-3 as a starting point. EPA also
screened and evaluated new studies that were published since these assessments, as identified in
the literature search conducted by the Agency for carbon tetrachloride (Carbon tetrachloride
(CASRN 56-23-5) Bibliography: Supplemental File for the TSCA Scope Document, EPA-HQ-
QPPT-2016-0733 ).
In data extraction (Step 2), data is evaluated for consistency and relevance and summarized
according to each endpoint in an evidence table, which can be found in the supplemental files for
this risk evaluation draft. In data integration (Step 3), the strengths and limitations of the data are
evaluated for each endpoint and a weight of the scientific evidence narrative is developed. In the
dose-response analysis (Step 4), data for each selected hazard endpoint is modeled to determine
the dose-response relationship. The results are summarized, and the uncertainties are presented in
section 3.2.5.
EPA considered new studies with information on acute, non-cancer and cancer endpoints if the
study was found to meet the quality criteria with an overall data quality rating of high, medium,
or low. Studies found to be acceptable and rated high, medium or low were used for hazard
identification. EPA has not developed data quality criteria for all types of relevant information
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(e.g., toxicokinetics data). Therefore, EPA is using these data to support the risk evaluation.
Information that was rated unacceptable was considered in the risk evaluation under a weight of
evidence approach, when necessary to fulfill data gaps. Information on human health hazard
endpoints for all acceptable studies (with high, medium or low scores) evaluated is presented in
Appendix H.
Adverse health effects associated with exposure to carbon tetrachloride were identified by
considering the quality and weight of the scientific evidence to identify the most sensitive
hazards or key endpoints. Based on the systematic review of the reasonably available data, EPA
narrowed the focus of the carbon tetrachloride hazard characterization to liver toxicity,
neurotoxicity, kidney toxicity, reproductive/ developmental toxicity, and cancer. In addition, a
summary of key studies and endpoints carried forward in the draft risk evaluation can be found
in Appendix H, including the no-observed- or lowest-observed-adverse-effect levels (NOAEL
and LOAEL) for health endpoints by target organ/system, the corresponding benchmark dose
lower confidence limits (BMDLs), when available, and the corresponding human equivalent
concentrations (HECs), and uncertainty factors (UFs).
These key studies provided the dose-response information necessary for selection of points of
departure (PODs). The EPA defines a POD as the dose-response point that marks the beginning
of a low-dose extrapolation. This point can be the lower bound on the dose for an estimated
incidence, or a change in response level from a dose-response model (e.g., benchmark dose or
BMD), a NOAEL value, or a lowest-observed-adverse-effect level (LOAEL) for an observed
incidence, or a change in the level (i.e., severity) of a given response. PODs were adjusted as
appropriate to conform to the specific exposure scenarios evaluated.
The potential mode of action (MOA) for cancer was evaluated according to the framework for
MOA analysis described in the EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA.
2005b). The evidence for genotoxicity is summarized in Appendix I.
The dose-response assessment used for selection of PODs for cancer and non-cancer endpoints
and the benchmark dose analysis used in the draft risk evaluation are found in section 3.2.5.
Development of the carbon tetrachloride hazard and dose-response assessments considered
principles set forth in various risk assessment guidances/guidelines issued by the National
Research Council and the EPA.
Given that the inhalation and dermal routes of exposure are the routes of concern for this risk
evaluation, studies conducted via these routes of exposure were considered for POD derivation in
this assessment. Nevertheless, oral exposure data are presented herein below for weight of
evidence support in the selection of hazard endpoints and PODs. No acceptable toxicological
data are available by the dermal route and physiologically based pharmacokinetic/
pharmacodynamic (PBPK/PD) models that would facilitate route-to-route extrapolation to the
dermal route have not been identified for carbon tetrachloride. Therefore, inhalation PODs were
extrapolated for use via the dermal route using assumptions about absorption in this risk
evaluation.
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The EPA consulted EPA's Guidelines for Developmental Toxicity Risk Assessment (U.S. EPA.
1991) when making the decision to use developmental toxicity studies to evaluate risks that may
be associated with acute exposure to carbon tetrachloride during occupational exposure
scenarios. This decision is based on the EPA's policy, which is based on the health-protective
assumption that a single exposure during a critical window of fetal development may produce
adverse developmental effects. The EPA guidelines state that for developmental toxic effects, a
primary assumption is that a single exposure at a critical time in development may produce an
adverse developmental effect, i.e., repeated exposures is not a necessary prerequisite for
developmental toxicity to be manifested (U.S. EPA. 1991). However limited evidence from
gestational exposure studies for carbon tetrachloride in rats suggest that developmental effects
are likely associated with the sustained lower maternal weight over gestation days 6-15 rather
than the result of exposure to carbon tetrachloride on a single day of the study (NRC. 2014) (see
sections 3.2.5.1 and 3.2.4.1.1).
A summary table which includes all endpoints considered for this assessment, the no-observed-
or lowest-observed-adverse-effect levels (NOAEL and LOAEL) for health endpoints by target
organ/system and the results of the data evaluation is provided in Appendix H. The sections
below present the analysis, synthesis and integration of the hazard information resulting from
those data sources that have low, medium or high overall data quality.
3.2.2 Toxicokinetics
The toxicokinetics of carbon tetrachloride have been comprehensively described in previous
toxicological assessments (see Table 1-3). In summary, the IRIS assessment describes that
carbon tetrachloride is rapidly absorbed by any route of exposure. Once absorbed, carbon
tetrachloride is widely distributed among tissues, especially those with high lipid content,
reaching peak concentrations in <1-6 hours, depending on exposure concentration or dose.
Animal studies show that volatile metabolites are released in exhaled air, whereas nonvolatile
metabolites are excreted in feces and to a lesser degree, in urine.
The metabolism of carbon tetrachloride has been extensively studied in in vivo and in vitro
mammalian systems. Carbon tetrachloride is metabolized in the body, primarily by the liver, but
also in the kidney, lung, and other tissues containing CYP450. Based on reasonably available
information, the initial step in biotransformation of carbon tetrachloride is reductive
dehalogenation: reductive cleavage of one carbon-chlorine bond to yield chloride ion and the
trichloromethyl radical. Biotransformation of carbon tetrachloride to reactive metabolites,
including the trichloromethyl radical, is hypothesized to be a key event in the toxicity of carbon
tetrachloride. The fate of the trichloromethyl radical depends on the availability of oxygen and
includes several alternative pathways for anaerobic or aerobic conditions (i.e., anaerobic
dimerization to form hexachloroethane, aerobic trapping by oxygen to form a trichloromethyl
peroxy radical).
3.2.3 Hazard Identification
3.2.3.1 Non-Cancer Hazards
For non-cancer hazard characterization, EPA reviewed the reasonably available information on
acute, subchronic, and chronic exposure to carbon tetrachloride via the inhalation, dermal and
oral routes and evaluated the identified hazard endpoints. Studies were evaluated according to
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the Application of Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018a. b). The
results of the data quality evaluation for the non-cancer studies are described here and included
in the data extraction summary table in Appendix H.
Toxicity Following Acute Exposure
Overall, the database evaluating the acute toxicity of carbon tetrachloride is limited to numerous
case reports on acute inhalation exposure of humans to carbon tetrachloride, most without
adequate exposure characterization, in addition to a small number of animal studies. Human case
reports following acute exposures identify liver as a primary target organ of toxicity and the
kidney as an additional primary target organ of toxicity. Neurotoxicity indicated as central
nervous system (CNS) depression is another primary effect of carbon tetrachloride in humans
following acute exposures, with examples of neurotoxic effects including drowsiness, headache,
dizziness, weakness, coma and seizures. Gastrointestinal symptoms such as nausea and vomiting,
diarrhea and abdominal pain are considered another initial acute effect (U.S. EPA. 2010;
ATSDR. 2005). Unmetabolized carbon tetrachloride is expected to depress the CNS, while most
other toxic effects of carbon tetrachloride are related to its biotransformation products catalyzed
by CYP-450 enzymes (ATSDR 2005).
The National Advisory Committee for Acute Exposure Guideline Levels for hazardous
substances (NAC/AEGL) (NRC. 2014) describe case reports of human fatalities resulting from
acute exposure to carbon tetrachloride, which provide a clinical picture of dizziness, nausea,
abdominal pain, oliguria, anuria, and death being attributed to renal failure and hepatotoxicity.
NAC/AEGL has concluded that although data on lethality in humans following acute exposures
to carbon tetrachloride are available, exposure concentration and duration information are
lacking.
Hazard Effects from Acute Inhalation Exposures - Human Data
The EPA IRIS Assessment (U.S. EPA. 2010) concluded that the CNS depression is an
immediate effect in acute toxicity studies in animals exposed by inhalation to relatively high
concentrations of carbon tetrachloride.
Similar conclusions were reached by NAC/AEGL (NRC. 2014) based on human data.
NAC/AEGL developed acute exposure guideline levels-2 (AEGL-2) (NRC. 2014) for carbon
tetrachloride based on CNS effects observed in humans. AEGL-2 values are defined as the
airborne concentrations of a substance above which it is predicted that the general population,
including susceptible individuals, could experience irreversible or other serious, long-lasting
adverse health effects or an impaired ability to escape.11
NAC/AEGL evaluated a series of experiments conducted by Davis (1934)(data quality rating =
low) to determine their suitability to derive AEGL-2 values for carbon tetrachloride. In one
study, three human subjects were exposed to carbon tetrachloride at 317 ppm (concentration
11 Similarly, AEGL-3 values (i.e., airborne concentration above which it is predicted that the general population, including
susceptible individuals, could experience life-threatening health effects or death) were also developed on a 1-h LCoi (lethal
concentration, 1% lethality) of 5,135.5 ppm on the basis of data from multiple studies in laboratory rats. AEGL-1 concentration
values for notable discomfort, irritation, or certain asymptomatic, non-sensory (non-disabling, transient) effects were not
established for carbon tetrachloride.
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calculated on the basis of room volume and amount of carbon tetrachloride) for 30 min. CNS
effects, including nausea, vomiting, dizziness, and headaches, were reported by the subjects but
clinical assessments (urinalysis, blood count, hemoglobin levels, blood pressure, and heart rate)
remained normal for up to 48 h post-exposure (Davis. 1934). Similar effects were reported by
subjects exposed at 1,191 ppm for 15 min, with the exception that one of the four subjects found
the exposure to be intolerable after 9 min (i.e., the subject experienced headache, nausea,
vomiting). Exposures at 2,382 ppm for 3-7 min produced these effects in addition to dizziness,
listlessness, and sleepiness. The observed CNS effects were apparently not long-lasting but were
considered severe enough to impair escape or normal function and, therefore, a conservative end
point (i.e., hazard effect) for deriving AEGL-2 values by NAC/AEGL.
In the second experiment, four subjects (ages 35, 48, 22, and 30; gender not specified) were
exposed to a carbon tetrachloride at 76 ppm for 2.5 h. There were no symptoms or signs of
toxicity in any of the subjects. In a third experiment, the same subjects in the second experiment
were exposed 24 hours later to carbon tetrachloride at 76 ppm for 4 h and did not have signs or
symptoms. Davis (1934) also reported that renal effects were observed in a worker
experimentally exposed to carbon tetrachloride at 200 ppm for 8 h with renal function returning
to near normal 2 months after exposure.
The AEGL-2 values were derived on the basis of the highest no-effect level of 76 ppm for CNS
effects in humans exposed carbon tetrachloride for 4 h (Davis. 1934). The AEGL-2 values are
derived using an interspecies uncertainty factor of 1 because the study was conducted in humans,
and an intraspecies uncertainty factor of 10 to account for individuals who may be more
susceptible to the toxic effects of carbon tetrachloride, including greater potential of carbon
tetrachloride-induced toxicity in individuals with histories of alcohol usage.
Hazard Effects from Acute Inhalation and Oral Exposures - Animal Data
IRIS, ATSDR and AEGL have identified and evaluated a small number of available acute animal
studies for carbon tetrachloride. Systematic review for this risk evaluation found that two of the
main acute animal studies in those previous hazard assessments have unacceptable data quality:
Hayes et al., (1986) acute study, which has an ECHA reliability = 4 and Adams et al., (1952)
acute study (ECHA reliability score not available). Nevertheless, the EPA IRIS Assessment
(U.S. EPA. 2010) and ATSDR profile (ATSDR. 2005) provide a weight of evidence evaluation
on the effects observed in animal studies after acute oral and inhalation exposure to carbon
tetrachloride. In animals acutely exposed to carbon tetrachloride, the liver appears to be the
primary target organ; damage to the kidney occurs at slightly higher doses. Hepatic toxicity is
frequently demonstrated by significant increases in serum enzyme activities that peak between
24 and 48 hours after dosing (U.S. EPA. 2010). Similarly, ATSDR (2005) evaluated the acute
toxicity database for carbon tetrachloride and determined that hepatotoxicity appeared to be the
critical effect from acute duration exposure. However, ATSDR (2005) did not derive an MRL for
acute-duration inhalation exposure to carbon tetrachloride due in part to data limitations. A more
recent and comprehensive review of both acute epidemiological data and animal studies by
NAC/AEGL (NRC. 2014) concluded that animal inhalation toxicity data for carbon tetrachloride
affirm hepatotoxic and renal effects, as well as anesthetic-like effects, as primary end points; and
that findings from animal studies are consistent with those associated with human exposures.
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In addition to acute toxicity data evaluated by IRIS, AEGL and ATSDR, the systematic review
identified an additional study evaluating liver toxicity of carbon tetrachloride after single dose
administration with high overall quality based on the quality criteria in the Application of
Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018a). In this additional study by Sun
et al., (2014) (data quality rating = high), a total of 30 male Sprague-Dawley rats (5 rats/group)
were given single oral gavage doses of carbon tetrachloride at 0, 50, or 2000 mg/kg. Rats were
then sacrificed at either 6- or 24-hours post-dosing (5/group/time point). An additional group of
male rats (5/group) were given oral doses of vehicle (corn oil) or carbon tetrachloride for 3-days
at the same doses and sacrificed 24-hours after the third dose (72 hours). Rats lost weight 24-
hours after a single exposure to 2,000 mg/kg (or after 3 daily doses at 2,000 mg/kg). Control and
low-dose animals gained weight normally. Food consumption was also decreased in high-dose
rats. Significant, dose-related increases in serum ALT (30-114%), AST (15-213%), and ALP
(37-137%) were observed in both dose groups following exposure for 3 days. Twenty-four
hours after exposure, ALT was significantly increased by 15% at 50 mg/kg, but not 2000 mg/kg.
ALP was significantly increased by 78% at 2000 mg/kg after 24 hours. Other significant
potentially exposure-related findings were limited to the high-dose group and included a 26-49%
increase in BUN 6- or 24-hours after a single exposure, a 24-33% decrease in cholesterol, and a
59-69% decrease in triglycerides 24-hours after one or three exposures, and a 12-23% decrease
in glucose 6- or 24-hours after a single exposure. No other consistent clinical chemistry findings
were observed. No significant changes were observed in liver triglyceride levels.
Centrilobular necrosis, centrilobular degeneration, and cytoplasmic vacuolization were observed
at 6- and 24-hours post-dose in all animals given a single dose of 2,000 mg/kg. In animals given
3 doses of 2,000 mg/kg carbon tetrachloride, 80% were observed with centrilobular
degeneration, while 100% were observed with centrilobular necrosis and cytoplasmic
vacuolization. Mean severity scores for centrilobular necrosis and degeneration were highest 24-
hours after a single exposure, whereas severity scores for cytoplasmic vacuolization were highest
after 3 exposures. Six hours after a single exposure to 50 mg/kg, 40% of animals (n=2) showed
minimal centrilobular necrosis. Hepatic lesions were not observed at other time points following
exposure to 50 mg/kg. No hepatic lesions were observed in control groups at any time point. No
exposure-related kidney lesions were observed in any group (Sun et al.. 2014).
Table 3-1 and Table 3-2 present a summary of acute toxicity studies in humans by the inhalation
route and in rats by the oral route of exposure, which are either a critical study identified for
establishing AEGL values or a study published after the completion of the IRIS assessment (U.S.
EPA. 2010) and NAC/AEGL (NRC. 2014).
Table 3-1. Acute Inhalation Toxicity Study in Humans (Critical Study for NAC/AEGL-2
Values)
Subjects
Exposure
Route
Doses/
Concentrations
Duration
Effect Dose
Effect
Reference
Data Quality
Evaluation
Four subjects
(ages 35,48, 22,
and 30; gender
not specified)
Inhalation
76 ppm
2.5 hrs, 4
hrs
NOAEC=
76 ppm
NoCNS
symptoms or
signs of
toxicity
(Davis.
1934)
low; basis for
AEGL-2
Note: information on associated human studies from (Davis. 1934) can be found in text.
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Table 3-2. Acute Toxicity Oral study in Sprague-Dawley Rats with Acceptable Data
Quality Not Evaluated in Previous Hazard Assessments for Carbon Tetrachloride
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Effect Dose
Effect
Reference
Data Quality
Evaluation
Rat, Sprague-
Dawley, M
(n=5/group)
Oral,
gavage
(com oil
vehicle)
0, 50, or 2000
mg/kg-bw/day
6, 24, hours
(the 72 hrs
exposure is
categorized
as
subchronic)
LOAEL = 50
mg/kg-
bw/day
Weight loss;
increased ALP;
decreased
cholesterol,
triglycerides,
and glucose;
liver
histopathology;
increased BUN
(Sun et al..
2014)
High
Hazard Effects from Oral and Inhalation Exposures During Gestation
Developmental effects from carbon tetrachloride exposures are more extensively studied by the
oral route than any other route of exposure. The lowest adverse effect level for developmental
hazards from oral exposures was identified in the EPA IRIS Assessment (U.S. EPA. 2010) in
Narotsky (1997) (data quality rating = high). In this study, groups of 12-14 timed-pregnant F344
rats received carbon tetrachloride at doses of 0, 25, 50, or 75 mg/kg-day in either corn oil or an
aqueous emulsion (10% Emulphor) on GDs 6-15. Dose-related piloerection was observed in
dams at >50 mg/kg-day for both vehicles but was seen in more animals and for longer periods in
the corn oil groups. Dams exposed to 75 mg/kg-day in corn oil also exhibited kyphosis (rounded
upper back) and statistically significant weight loss. Dams exposed to 50 and 75 mg/kg-day in
aqueous emulsion showed only significantly reduced body weight gain. Full-litter resorption
occurred with an incidence of 0/13, 0/13, 5/12 (42%), and 8/12 (67%) in the control through
high-dose corn oil groups and 0/12, 0/12, 2/14 (14%), and 1/12 (8%) in the respective aqueous
groups. The difference between vehicles was statistically significant at the highest dose. Among
the surviving litters, there were no effects on gestation length, prenatal or postnatal survival, or
pup weight or morphology. The 25 mg/kg-day dose was a NOAEL for developmental and
maternal toxicity and the 50 mg/kg-day dose a LOAEL for full-litter resorption and maternal
toxicity (i.e., reduced maternal weight gain, piloerection) with either corn oil or aqueous vehicle,
although these effects were more pronounced with the corn oil vehicle. EPA (2010) noted that
the NOAEL in this developmental study (25 mg/kg-day) exceeds the POD for the RfD based on
liver effects by over 6-fold and the LOAEL (50 mg/kg-day) by 13-fold and is consistent with
developmental toxicity endpoints as less sensitive than measures of hepatotoxicity.
The IRIS assessment identified Schwetz et al. (1974) (data quality rating = high) as the most
detailed inhalation exposure developmental toxicity study available. In the Schwetz et al. (1974)
study, groups of pregnant Sprague-Dawley were exposed whole-body by inhalation to 0, 300, or
1,000 ppm carbon tetrachloride vapor for 7 hours/day on days 6-15 of gestation. A significant
increase in the serum glutamic-pyruvic transaminase activity was observed in rats exposed to
300 and 1000 ppm by the end of the exposure period. This effect was no longer observed by day
6 post exposure. The developmental effects at the LOAEC of 300 ppm consisted of decreased
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fetal body weight (7%) and decreased crown-rump length (3.5%). The same effects were
observed at 1,000 ppm (i.e., 14% decreased fetal body weight, 4.5% decreased crown-rump
length) in addition to increases in sternebral anomalies (13% at 1,000 ppm vs 2% in controls).
Maternal toxicity was observed at 300 and 1,000 ppm. Food consumption and body weight were
significantly reduced in treated dams compared with controls. Hepatotoxicity was indicated by
significantly elevated serum ALT, gross changes in liver appearance (pale, mottled liver), and
significantly increased liver weight (26% at 300 ppm and 44% at 1,000 ppm).
The systematic review process for this risk evaluation did not identify additional developmental
toxicity data by the inhalation or oral routes for carbon tetrachloride. Table 3-3 presents the
developmental toxicity studies with acceptable data quality.
Table 3-3. Developmental Toxicity Studies in Fisher 344 and Sprague-Dawley Rats with
Acceptable Data Quality
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Effect Dose
Effect
Reference
Data
Quality
Evaluation
Rat F344, F
(n=12-14/
group)
Oral,
gavage
(corn oil
vehicle or
10%
Emulphor
vehicle)
0, 25,50 or 75
mg/kg-bw/day
GDs 6-15
NOAEL= 25
mg/kg-
bw/day (F),
LOAEL= 50
mg/kg-
bw/day (F)
Piloerection;
markedly
increased
full-litter
resorption
(Narotskv
et al..
1997)
high
Rat, Sprague-
Dawley, F
(11=24-28/
group)
Inhalation
(whole
body)
0, 300, or 1,000
ppm for 7
hours/day
GDs 6-15
LOAEC=
300 ppm;
NOAECnot
determined
Decreased
fetal body
weight and
crown-rump
length;
increased
sternebral
anomalies
(Schwetz
et al..
1974)
high
Subchronic and Chronic Hazards front Inhalation and Oral Exposures
Consistent with human data, toxicity assays in animals exposed orally or by inhalation of sub-
chronic or chronic duration identify the liver as the major target organ. While the liver appears to
be the primary target organ from exposure to carbon tetrachloride by both the oral and inhalation
routes, the kidney is also a target organ for carbon tetrachloride exposure.
All the key and supporting inhalation and oral studies in the EPA IRIS Assessment (U.S. EPA.
2010) were rated acceptable with low, medium or high overall quality data using the quality
criteria in the Application of Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018a).
Those acceptable studies are briefly described in this section and Appendix H. The systematic
review process for this risk evaluation did not identify additional subchronic and chronic toxicity
data for carbon tetrachloride.
Inhalation
The IRIS assessment concluded that the liver and kidney are the most prominent targets of
carbon tetrachloride in subchronic and chronic inhalation toxicity studies in animals. Renal
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damage was reported less frequently in these animal studies and generally at higher
concentrations than those causing liver damage. The key and supporting subchronic and chronic
inhalation studies in the IRIS assessment are summarized below.
The IRIS RfC is based on the findings from bioassays conducted by Nagano (2007a) (data quality
rating = high). In one of the subchronic inhalation studies in rats, F344/DuCij rats (10/sex/group)
were subjected to whole body exposure of carbon tetrachloride vapor (Purity: 99.8%)
concentrations of 0, 10, 30, 90, 270, or 810 ppm (0, 63, 189, 566, 1,700, or 5,094 mg/m3) for 6
hours/day, 5 days/week for 13 weeks. The lowest exposure concentration of 10 ppm was a
LOAEC for rats for hepatic effects including increased liver weight and histopathological effects
ranging from slight fatty change, cytological alteration, and granulation to ceroid deposits,
fibrosis, pleomorphism, proliferation of bile ducts and cirrhosis. While small fatty droplets were
not evident in male rats at any concentration, large droplets were significantly elevated at > 30
ppm in both male and female rats. Different types of significantly altered cell foci (acidophilic,
basophilic, clear cell, and mixed cell foci) was evident at 810 ppm in male rats and 270 ppm in
female rats. A NOAEC was not identified.
A similar whole body exposure to carbon tetrachloride (99.8%) vapor was conducted in mice
(Nagano et al.. 2007b) (data quality rating = high) where groups of Crj: BDF1 mice
(10/sex/group) were exposed at concentrations of 0, 10, 30, 90, 270, or 810 ppm (0, 63, 189,
566, 1,700, or 5,094 mg/m3) for 6 hours/day, 5 days/week for 13 weeks. A similar set of end
points as that of the rat study were measured in mice. However, the incidence of altered cell foci
was not significantly elevated in male mice at < 270 ppm and was not noted in female mice.
Additional liver lesions observed include: nuclear enlargement with atypia and altered cell foci
(>270 ppm) and collapse (possibly resulting from the necrotic loss of hepatocytes) at (>30 ppm).
The lowest exposure level of 10 ppm is a LOAEC for hepatic effects (slight cytological
alterations) in male mice. Hepatic effects (i.e., fatty change, fibrosis and cirrhosis) were observed
in female mice exposed to (>30 ppm).
Significant increases were observed in liver weights (>10 ppm for males and >30 ppm for female
rats) and kidney weights (>10 ppm for male rats and >90 ppm for female rats). Statistically
significant, exposure-related decreases in hemoglobin and hematocrit were observed at >90 ppm in
both males and females. At 810 ppm, red blood cell count was also significantly decreased in both
sexes. Serum chemistry changes included large, statistically significant, and exposure-related
increases in ALT, AST, LDH, ALP, and LAP (leucine aminopeptidase) in males at >270 ppm and
females at >90 ppm. In general, female mice were less sensitive to hematological alterations than
male mice. Nephrotoxicity was observed at higher concentrations than toxicity to the liver,
although kidney weights were increased significantly at 10 ppm in male rats and > 90ppm in
female rats. Glomerulosclerosis was observed only at the highest concentration (810 ppm) of
exposure in rats. No histopathological changes were observed in the nasal cavity, larynx, trachea
or lungs of any carbon tetrachloride-exposed mouse or rat groups.
Nagano et al., (2007a) (data quality rating = high) conducted studies with groups of F344/DuCij
rats (50/sex/group) exposed whole body to 0, 5, 25, or 125 ppm (0, 31.5, 157, or 786 mg/m3) of
carbon tetrachloride (99.8% pure) vapor for 6 hours/day, 5 days/week for 104 weeks. An
increase in the severity of proteinuria in rats of both sexes was observed at the low exposure
concentration of 5 ppm; however, interpretation of the observed proteinuria and the renal lesions
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in the F344 rat is difficult because this strain has a high spontaneous incidence of renal lesions.
Increases in the incidence and severity of nonneoplastic liver lesions (fatty change, fibrosis,
cirrhosis) were seen at 25 and 125 ppm in both males and females. Therefore, 5 ppm was
considered a NOAEC based on liver toxicity at 25 and 125 ppm evidenced by serum chemistry
changes (including significant increases in ALT, AST, LDH, LAP, and GGT) and
histopathologic changes (fatty change, fibrosis, and cirrhosis). Kidney effects described above
were also considered for determining the NOAEC value, which is the basis of the EPA IRIS
RfC.
A similar 2-year (104 week) study was conducted by the same group in Cij: BDF1 mice (Nagano
et al.. 2007a) (data quality rating = high). Groups of 50/sex were exposed to 0, 5, 25, or 125 ppm
(0, 31.5, 157, or 786 mg/m3) of carbon tetrachloride (99% pure) vapor for 6 hours/day, 5
days/week for 104 weeks. The 25ppm concentration was a LOAEC in this study for effects on
the liver (increased weight, serum chemistry changes indicative of damage, and lesions), kidney
(serum chemistry changes and lesions), and spleen (lesions); decreased growth; and reduced
survival. The 5-ppm level was a NOAEC.
Benson and Springer (1999) (data quality rating = high) exposed groups of F344/Crl rats, B6C3F1
mice, and Syrian hamsters (10 males/species) by nose only inhalation to 0, 5, 20 or 100 ppm of
carbon tetrachloride for 6 hours per day, 5 days per week for 1, 4 or 12 weeks. The chamber
concentrations were monitored throughout the exposure. According to study authors, the
objectives of the study were 3-fold. The first objective was to evaluate the metabolism of carbon
tetrachloride to get an estimate of species sensitivity. These studies were conducted as either
whole-body exposures (for in vivo metabolism) or nose only exposures (for toxicokinetic
studies). In vitro studies using human liver microsomes were also conducted. The second
objective was to assess the genotoxic or non-genotoxic mechanisms of liver tumors for carbon
tetrachloride exposure. The third objective is to compare in vitro and in vivo metabolism studies
to revise the model for uptake, fate and metabolism of carbon tetrachloride to provide an
estimate for a human metabolic rate constant. Cell proliferation was evaluated in these animals
by implanting a minipump containing BrdU (bromodeoxyuridine) in each animal prior to
necropsy. At sacrifice, blood was collected for ALT and SDH determinations, and liver sections
were collected for histopathological examination and BrdU detection. In summary, Benson and
Springer (1999) used in vitro data on metabolism of carbon tetrachloride by human liver
microsomes, together with in vitro and in vivo rodent data, to estimate the in vivo human
metabolic rate constants and generated experimental information that allowed expanding the rat
PBPK model of Paustenbach et al., (1988) to include parameters for the hamster.
Following repeated carbon tetrachloride inhalation exposure in the Benson and Springer (1999)
studies, hepatocellular proliferation was reported along with necrosis and regenerative cell
proliferation at 20 and 100 ppm in mice. In rats, liver microsomal protein levels were increased
by 45% and 63% following 5-day inhalation exposure at 5 ppm without any change in the 12-
week exposure group. In hamsters, following carbon tetrachloride inhalation exposure (100 ppm)
microsomal protein levels were decreased by 33% and 54% in both the 5-day and the 12-week
exposure groups. Mice did not exhibit any decrease in microsomal protein content at any
concentration of exposure. Significant increases in percent BrdU positive cells in the cell
proliferation assays were apparent at 20 and 100 ppm in mice and at 100 ppm in hamsters. Serum
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levels of ALT and SDH were significantly increased in mice at >20 ppm and in rats and hamsters at
100 ppm.
Cytochromes CYP2E1 and CYP2B, which are the primary enzymes responsible for
biotransformation of carbon tetrachloride in rodents, were measured in all exposed and control
animals in the metabolic studies (Benson and Springer. 1999). In all species, microsomal
measurement of these enzymes indicated that while enzyme induction increased several fold as
dose increased, catalytic activity was not significantly altered.
The rate of carbon tetrachloride metabolism was measured in rat, mouse and hamster species.
The metabolic rate of carbon tetrachloride did not vary more than 2-fold between the three
species. A NOAEC of 5ppm and a LOAEC of 20 ppm for hepatotoxicity was identified for mice.
Hamsters and rats were less sensitive than mice, with NOAEC of 20 ppm and LOAEC of 100
ppm, respectively.
Adams et al., (1952) (data quality rating = low) conducted studies with Wistar-derived rats (15-
25/sex), outbred guinea pigs (5-9/sex), outbred rabbits (1-2/sex), and Rhesus monkeys (1-2 of
either sex) exposed to carbon tetrachloride vapor (>99% pure), 7 hours/day, 5 days/week for 6
months at concentrations of 5, 10, 25, 50, 100, 200, or 400 ppm (31, 63, 157, 315, 630, 1,260, or
2,520 mg/m3). Matched control groups included unexposed and air exposed. Animals were
observed frequently for appearance and general behavior and were weighed twice weekly.
Selected animals were used for hematological analyses periodically throughout the study.
Moribund animals and those surviving to scheduled sacrifice were necropsied. The lungs, heart,
liver, kidneys, spleen, and testes were weighed, and sections from these and 10 other tissues
were prepared for histopathological examination. Serum chemistry analyses were performed in
terminal blood samples and part of the liver was frozen and used for lipid analyses. In this study,
the primary target of carbon tetrachloride in all species was the liver. In guinea pigs, liver effects
progressed from a slight, statistically significant increase in relative liver weight in females at 5
ppm to slight-to-moderate fatty degeneration and increases in liver total lipid, neutral fat, and
esterified cholesterol at 10 ppm, and cirrhosis at 25 ppm. However, the effect at the 5-ppm dose
was not considered adverse, as there were no histopathological changes in the liver at 5 ppm. In
the kidney, slight tubular degeneration was observed at 200 ppm and increased kidney weight
was noted at 400 ppm. Mortality was increased at >100 ppm. A similar progression of effects
was seen in rats, (no effects at 5 ppm, mild liver changes at 10 ppm, cirrhosis at 50 ppm, and
liver necrosis, kidney effects, testicular atrophy, growth depression, and mortality at 200 ppm
and above). In rabbits, 10 ppm was without effect, 25 ppm produced increase in liver weight and
mild liver changes (mild fatty degeneration and(in) by histological examinations, 50 ppm
produced moderate liver changes, and 100 ppm produced growth depression. Monkeys were the
least sensitive species tested, with evidence of adverse effects (mild liver lesions and increased
liver lipid) only at 100 ppm, the highest concentration tested. This study identified NOAEL and
LOAEL values, respectively, of 5 and 10 ppm in rats and guinea pigs, 10 and 25 ppm in rabbits,
and 50 and 100 ppm in monkeys, all based on hepatotoxic effects.
Table 3-4 presents a summary of subchronic and chronic inhalation studies in various
experimental animal species for carbon tetrachloride with acceptable data quality.
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Table 3-4. Subchronic and Chronic Inhalation Studies in Various Experimental Animal
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Effect Dose
Effect
Reference
Data Quality
Evaluation
Rat,
F344/DuCij
(SPF), M/F
(n=100/group)
Inhalation,
vapor,
whole
body
0,31, 157 or 786
nig/ni3 (0, 5,25
or 125 ppm)
6 hours/ day,
5 days/ week
for 104 weeks
NOAEC= 31
nig/ni3,
LOAEC= 157
nig/ni3
Increased AST,
ALT, LDH, GPT,
BUN, CPK;
lesions in the liver
(fatty changes,
fibrosis)
(Naeano et
al.. 2007a)
High
Mouse,
Crj:BDFl
(SPF), M/F (n=
100/group)
Inhalation,
vapor,
whole
body
0,31, 157 or 786
nig/ni3 (0, 5,25
or 125 ppm)
6 hours/ day,
5 days/ week
for 104 weeks
NOAEC=31
nig/ni3 (M)
Reduced survival;
increased ALT,
AST, LDH, ALP,
protein, total
bilirubin, and
BUN; decreased
urinary pH;
increased liver
weight; spleen
and liver lesions
(Naeano et
al.. 2007a)
High
Mouse, BDF1,
M/F (n=20/
group)
Inhalation,
vapor,
whole
body
0, 63, 189, 566,
1699, or 5096
nig/ni3 (0, 10,
30, 90, 270, or
810 ppm)
6 hours/ day,
5 days/ week
for 13 weeks
LOAEC= 63
nig/ni3
Slight cytological
alterations in the
liver; Cytoplasmic
globules
(Naeano et
al.. 2007b)
High
Rat, F344, M/
F (n=20/
group)
Inhalation,
vapor,
whole
body
0, 63, 189, 566,
1699, 5096
nig/ni3 (0, 10,
30, 90,270,810
ppm)
6 hours/ day,
5 days/ week
for 13 weeks
NOAEC= 63
nig/ni3 (F),
LOAEC=189
nig/ni3 (F)
Increased liver
weight; Large
droplet fatty
change in liver
(Nasano et
al.. 2007b)
High
Mouse,
B6C3F1, M
(n=10/ group)
Inhalation,
whole
body
0,31, 126, or
629 nig/ni3 (0, 5,
20 or 100 ppm)
6 hours/ day,
5 days/ week
for 12 weeks
NOAEC= 31
nig/ni3 (M),
LOAEC= 126
nig/ni3 (M)
Increased ALT,
SDH; necrosis
and cell
prolileration in
liver
(Benson and
Sorinser.
1999)
Low
Hamster,
Syrian, M
(n=10/ group)
Inhalation,
whole
body
0,31, 127 or 636
nig/ni3 (0, 5,20
or 100 ppm)
6 hours/ day,
5 days/ week
for 12 weeks
NOAEC= 126
nig/ni3 (M),
LOAEC= 629
nig/ni3 (M)
Increased ALT,
SDH; necrosis
and cell
proliferation in
liver
(Benson
and
Sorinser.
1999)
Low
Rat Wistar-
derived, M/ F
(n=30-50
group)
Inhalation,
vapor,
whole
body
0,31,63, 157,
315,629, 1258
or 2516 nig/ni3
(0,5,10,25, 50,
100,200 or 400
ppm)
7 hours/ day,
5 days/ week
for 6 months
NOAEC= 31
nig/ni3,
LOAEC= 63
nig/ni3
Increased liver
weight; fatty
degeneration in
liver
(Adams et
al.. 1952)
Low
Guinea pig, M/
F (n=10-18
group)
Inhalation,
vapor,
whole
body
0,31,63, 157,
315,629, 1258
or 2516 nig/ni3
(0,5,10,25, 50,
100,200 or 400
ppm)
7 hours/ day,
5 days/ week
for 6 months
NOAEC= 31
nig/ni3,
LOAEC= 63
nig/ni3
Increased liver
weight; fatty
degeneration in
liver
(Adams et
al.. 1952)
Low
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Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Effect Dose
Effect
Reference
Data Quality
Evaluation
Rabbit, albino,
M/F (n=2-4/
group)
Inhalation,
vapor,
whole
body
0,31,63, 157,
315,630, 1260
or 2520 nig/ni3
(0,5,10,25, 50,
100,200 or 400
ppm)
7 hours/ day,
5 days/ week
for 6 months
NOAEC= 63
nig/ni3,
LOAEC= 157
nig/ni3
Increased liver
weight; fatty
degeneration and
slight cirrhosis in
liver
(Adams et
al.. 1952)
Low
Monkey,
rhesus, M/ F
(n=2-4/ group)
Inhalation,
vapor,
whole
body
0,31,63, 157,
315 or 630 mg/
m3 (0, 5, 20, 25,
50 or 100 ppm)
7 hours/ day,
5 days/ week
for 6 months
NOAEC= 315
nig/ni3,
LOAEC= 629
nig/ni3
Slight fatty
degeneration and
increased lipid
content in liver
(Adams et
al.. 1952)
Low
Oral
U.S. EPA (2010) identifies the following subchronic oral gavage studies
as supporting studies in the derivation of the RfD for carbon tetrachloride, Condie et al. (1986).
Allis et al. (1990) and Hayes et al. (1986). Bruckner et al. (1986) was the principal study.
Consistent with human data, toxicity assays in animals (i.e., rats, mice) exposed orally identify
the liver to be the major target organ, with oral NOAELs between 0.71 and 0.86 mg/kg.
Subchronic oral studies that also examined non-hepatic endpoints (Bruckner et al.. 1986; Haves
et al.. 1986) did not observe effects in the kidneys or other organs. These studies are summarized
below as follows.
In a subchronic study by Bruckner et al. (1986) (data quality rating = high) groups of 15-16 adult
male Sprague-Dawley rats were given doses of 0, 1, 10, or 33 mg/kg of analytical-grade carbon
tetrachloride by oral gavage in corn oil 5 days/week (time-weighted average doses of 0, 0.71,
7.1, or 23.6 mg/kg-day) for 12 weeks. Body weight gain in this group was significantly reduced
by 6% after 30 days and 17% after 90 days in the high dose group. In the high dose group (23.6
mg/kg-day) liver enzymes including ALT (up to 34 times control levels), SDH (up to 50 times
control levels), and OCT (up to 8 times control levels) were significantly elevated from week 2
through the end of exposure. In addition, significantly increased relative liver weight and
degenerative lesions were observed. Reported liver lesions included lipid vacuolization, nuclear
and cellular polymorphism, bile duct hyperplasia, and periportal fibrosis. Severe degenerative
changes, such as Councilman-like bodies (single-cell necrosis), deeply eosinophilic cytoplasm,
and pyknotic nuclei, were occasionally noted as well. No evidence of nephrotoxicity was
observed. At lower doses moderate effects were seen in animals. At 7.1 mg/kg-day only a
significant (two- to threefold) elevation of SDH during the second half of the exposure period
and the presence of mild centrilobular vacuolization in the liver was observed. Serum ALT and
SDH levels returned towards control levels in both mid- and high-dose rats following a 2-week
recovery period although hepatic lesions of less severity with the exception of fibrosis and bile
duct hyperplasia were still present in both groups. No effects were observed in rats exposed to
0.71 mg/kg-day. This study identified aNOAEL of 0.71 mg/kg-day and a LOAEL of 7.1 mg/kg-
day for carbon tetrachloride-induced liver toxicity.
A subchronic study conducted by Condie (1986) (data quality rating = high) compared the
effects of two different gavage vehicles on the toxicity of carbon tetrachloride in mice. CD-I
mice (12/sex/group) were treated with 0, 1.2, 12, or 120 mg/kg of carbon tetrachloride by oral
gavage in either corn oil or 1% Tween-60 aqueous emulsion 5 days/week for 12 weeks (average
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daily doses of 0, 0.86, 8.6, or 86 mg/kg-day) (Condie et al.. 1986). Fifteen deaths occurred
during the study (6 in male mice, 9 in female mice). Of the total deaths, 8 were attributed to
gavage (4 male and 4 female mice). These deaths did not appear to influence the study outcome.
In the high-dose group (86 mg/kg-day) relative liver weight was significantly elevated. In
addition, liver enzymes were significantly increased (ALT (77-89 times control levels in corn oil
and 10-19 times control levels in Tween-60), AST (14-15 times control levels in corn oil and 3-
4 times control levels in Tween-60), and LDH (12-15 times control levels in corn oil and 2-3
times control levels in Tween-60). Histopathological findings include increased incidence and
severity of hepatocellular vacuolization, inflammation, hepatocytomegaly, necrosis, and portal
bridging fibrosis. The only difference between oral gavage vehicles observed at 86 mg/kg-day
was a greater incidence and severity of necrosis in mice given carbon tetrachloride in corn oil.
The difference between vehicles was more apparent at the middle dose of 8.6 mg/kg-day. This
dose produced significantly elevated ALT and mild-to-moderate liver lesions in mice gavaged
with corn oil but was identified as a NOAEL for mice gavaged with Tween-60. The low dose of
0.86 mg/kg-day was identified as the NOAEL for mice gavaged with corn oil. In general, both
sexes responded similarly, with severity of histopathologic changes in males slightly greater than
females.
A subchronic study in mice was conducted at higher doses by Hayes (1986) (data quality rating =
medium). CD-I mice (20/sex/group) received daily oral gavage doses of 0, 12, 120, 540, or
1,200 mg/kg-day of carbon tetrachloride in corn oil for 90 days (Haves et al.. 1986). An
untreated control group of 20 male and 20 female mice was maintained as well. Dose-related
effects including increases in serum LDH, ALT, AST, ALP, and 5'-nucleotidase and a decrease
in serum glucose were observed in both sexes. Treatment-related lesions were observed in the
liver, including fatty change, hepatocytomegaly, karyomegaly, bile duct hyperplasia, necrosis,
and chronic hepatitis associated with increases in absolute and relative liver weight. Other
changes in organ weight include increases in spleen and thymus weights. No treatment-related
lesions were observed in the kidney. No changes were found in urinalysis or hematology
parameters. It should be noted that, compared with untreated controls, vehicle controls had
significantly elevated serum LDH and ALT, altered organ weights, and increased incidence of
liver lesions (e.g., necrosis in 5/19 in vehicle controls versus 0/20 in untreated controls and 20/20
in the 12 mg/kg-day group). This study failed to identify a NOAEL; the low dose of 12 mg/kg-
day was a LOAEL for hepatic effects.
Allis (1990)(data quality rating = medium) conducted a study to investigate the ability of rats to
recover from toxicity induced by subchronic exposure to carbon tetrachloride. Groups of 48 60-
day-old male F344 rats were given 0, 20, or 40 mg/kg of carbon tetrachloride 5 days/week for 12
weeks (average daily doses of 0, 14.3, or 28.6 mg/kg-day) by oral gavage in corn oil. One day
after the end of exposure, significant dose-related changes were found for relative liver weight,
serum ALT, AST, and LDH (all increased), and liver CYP450 (decreased) in both dose groups.
In addition, serum ALP and cholesterol were increased in the high-dose group only. In the low-
dose group, histopathological examination of the liver revealed cirrhosis in 2/6 rats and vacuolar
degeneration and hepatocellular necrosis in 6/6 rats; in the high-dose group, histopathological
examination revealed cirrhosis (as well as degeneration and necrosis) in 6/6 rats. Serum enzyme
levels and CYP450 returned to control levels within 8 days of the end of exposure. Severity of
microscopic lesions declined during the postexposure period, but cirrhosis persisted in the high-
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dose group through the end of the experiment. Relative liver weight decreased during the
postexposure period but did not reach control levels in the high-dose group even after 22 days.
Neither of the radiolabeled tracer techniques detected a decreased functional capacity in cirrhotic
livers, a finding that could not be explained by the investigators. The low dose of 14.3 mg/kg-
day was a LOAEL for hepatic toxicity in this study. Table 3-5 presents the subchronic oral
toxicity studies with acceptable data quality.
Table 3-5. Subchronic Oral Toxicity Studies in Rats and Mice with Acceptable Quality
)ata
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose
Effect
Reference
Data Quality
Evaluation
Mouse, CD-I,
M/F (n=40/
group)
Oral, gavage
(com oil
vehicle)
0, 12, 120, 540 or
1200 mg/kg-
bw/day
7 days/
week for 90
days
LOAEL= 12
mg/kg-
bw/day
Increased liver
weight, ALT,
AST, ALP,
LDH, 5'-
nucleotidase;
fatty change,
hepato-
cytomegaly,
necrosis, and
hepatitis
(Haves et
al.. 1986)
Medium
Rat,
Sprague
Dawley, M
(11=15-16/
group)
Oral,
gavage
(com oil
vehicle)
0,1, 10 or 33
mg/kg-bw/day
5 days/
week for
12 weeks
NOAEL= 1
mg/kg-
bw/day
(M), '
LOAEL=
10 mg/kg-
bw/day (M)
Two- to three-
fold increase
in SDH; mild
centrilobular
vacuolization
in liver
(Bruckne
r et al..
1986)
High
Rat, F344,
M (n=48/
group; 6/
group and
sacrifice
time;
sacrificed at
intervals
from 1 to 15
days post
exposure)
Oral,
gavage
(com oil
vehicle)
0,20 or 40
mg/kg-bw/day
5 days/
week for
12 weeks
LOAEL=
20 mg/kg-
bw/day (M)
Increased
liver weight,
ALT, AST,
LDH; reduced
liver
CYP450;
cirrhosis,
necrosis, and
degeneration
in liver
(Allis et
al.. 1990)
Medium
Mouse, CD-
1, M/F
(n=24/
group)
Oral,
gavage
(com oil
vehicle)
0,1.2, 12 or 120
mg/kg-bw/day
5 days/
week for
12 weeks
NOAEL=
1.2 mg/kg-
bw/day,
LOAEL=
12 mg/kg-
bw/day
Increased
ALT; mild to
moderate
hepatic
lesions
(hepato-
cytomegaly,
necrosis,
inflammation)
(Condie
et al..
1986)
High
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Species/
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(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose
Effect
Reference
Data Quality
Evaluation
Mouse, CD-
1, M/F
(n=24/
group)
Oral,
gavage
(1%
Tween-60
vehicle)
0,1.2, 12 or 120
mg/kg-bw/day
5 days/
week for
12 weeks
NOAEL=
12 mg/kg-
bw/day,
LOAEL=
120 mg/kg-
bw/day
Increased
liver weight,
ALT, AST,
LDH; hepato-
cytomegaly,
vacuolation,
inflammation,
necrosis, and
fibrosis in
liver
(Condie
et al..
1986)
High
Hazard Effects from Dermal Exposures
Primary irritation hazard in rabbits and guinea pigs from acute dermal exposures has been
identified for carbon tetrachloride (ATSDR. 2005). Guinea pigs also exhibited degenerative
change in epidermal cells and edema (ATSDR 2005). In the murine local lymph node assay,
carbon tetrachloride showed weak dermal sensitization potential (OECD. 2011).
The limited number of animal studies by the dermal route, which have been cited in the previous
assessments for carbon tetrachloride (see Table 1-3) were found to be acceptable with low,
medium or high overall quality data based on the quality criteria in the Application of Systematic
Review in TSCA Risk Evaluations (U.S. EPA. 2018a). Those acceptable studies are briefly
described in Appendix H. The systematic review process for this risk evaluation did not identify
additional dermal toxicity data for carbon tetrachloride.
Among the few dermal studies, Kronevi (1979) (data quality rating = unacceptable due to lack of
negative controls and small number of animals) is the only available animal dermal study that
includes histopathological observations of the liver and kidney in addition to skin tissue. In this
study, guinea pigs weighing 440 and 570 g were dermally exposed to a single application of 1
mL of carbon tetrachloride in a 3.1 cm2 skin depot (513 mg/cm2)12 for 15 minutes, 1 hour, 4
hours, or 16 hours. Changes in liver morphology were observed from carbon tetrachloride
exposure only in the 16 hour exposure group. At 16 hours, the study authors reported marked
hydropic changes in the central two-thirds of each lobule of hepatocytes. These changes were
characterized by large clear cytoplasmic spaces. There also was a tendency to necrotic lesions
characterized by homogenous, slightly eosinophilic, and slightly PAS-positive structures within
the cytoplasm of most of these hepatocytes. The glycogen was absent all over the specimens and
the nuclei showed a tendency to degeneration. Animals exposed to the same dose levels of
carbon tetrachloride for 15 minutes, 1 hr or 4 hr did not show liver morphology alterations.13
12 This exposure concentration is reported in the ATSDR profile for carbon tetrachloride. The concentration estimate is based on
a density value of 1.59 g/mL for carbon tetrachloride.
13 Hie study authors reported marked hydropic changes in the central two-thirds of each lobule of hepatocytes. These changes
were characterized by large clear cytoplasmic spaces. There also was a tendency to necrotic lesions characterized by
homogenous, slightly eosinophilic, and slightly PAS-positive structures within the cytoplasm of most of these hepatocytes. The
glycogen was absent all over the specimens and the nuclei showed a tendency to degeneration.
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There were no reported kidney changes from dermal exposures to carbon tetrachloride in this
study.
In Wahlberg and Boman (1979) (data quality rating = medium), guinea pigs (20 animals/dose)
were exposed to carbon tetrachloride by a single application of 0.5 or 2.0 ml to a 3.1 cm2 area of
skin. Application area was occluded to prevent inhalation and ingestion. Dermal contact with
carbon tetrachloride occurred for 5 consecutive days to the single applied dose under occluded
exposure conditions. For animals exposed to 0.5 ml, mortality was observed from day 3 (1 out of
20 animals died) to day 14. Five animals died by the end of the observation period. Among
animals exposed to 2.0 mL, mortality was observed from day 1 (1 out of 20 animals died) to day
21. A total of 13 animals died in the 2.0 mL dose group by the end of the observation period.
Besides the few animal studies with dermal exposures, information on the toxicity of carbon
tetrachloride following dermal exposure is mostly based on anecdotal evidence. For instance, the
IRIS assessment describes one case report of carbon tetrachloride- induced toxicity that can at
least partially be attributed to absorption across the skin (Farrell and Senseman. 1944). The
worker was exposed 8 hours/day by using a fine spray of carbon tetrachloride to saturate a cloth
wrapped around the fingers. Although some exposure is likely to have occurred by inhalation,
absorption through the skin of the hands was considered as the primary route of exposure. After
an unspecified period of time at this job, the worker showed weakness, pain in the limbs, and
loss or reduction of certain reflexes. The patient lost 8 pounds in the month between onset of
illness and hospitalization. The signs and symptoms of neurotoxicity reversed after several
months without exposure.
presents acute toxicity dermal studies in guinea pigs with experimental observations in liver
toxicity and/or toxicity progression over time.
Table 3-6. Acute Toxicity Dermal Studies in Guinea Pigs with Observations on Liver
Toxicity and/or Toxicity Progression Over Time
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations*
Duration
Effect
Dose
Effect
Reference
Data Quality
Evaluation
Guinea pig,
albino (n=20,
gender not
specified)
Dermal
1 mL
15 minutes
to 16 hours
LOAEL
= 513
mg/ cm2
(1 mL)
Hydropic
changes, slight
necrosis at 16
hrs exposure
(Kronevi
et al..
1979)
Unacceptable
(i.e., lack of
negative
controls and
small number
of animals)
Guinea pig
(n=20, gender
not specified)
Dermal
0.5 or 2.0 mL
Single
application;
contact for 5
days
LOAEL
= 260
mg/ cm2
(0.5 mL)
5 of 20 animals
died at 0.5 ml;
13 of 20
animals died at
2.0 ml. (first
animal death on
dayl at 2.0 ml)
(Wahlbere
and
Boman.
1979)
Medium
*As reported by study authors: mL of highly pure carbon tetrachloride solution.
3.2.3.2 Epidemiological Data on Non-Cancer Toxicity
Epidemiological data on non-cancer effects of carbon tetrachloride published prior to 2010 have
been evaluated in previous assessments (see Table 1-3). For instance, the occupational study by
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Tomenson et al., (1995) (data quality = medium) was considered by EPA IRIS as the basis for
the RfC derivation. The study was not selected as the basis for the RfC because exposures for
almost two-thirds of the workers were estimated, so that there is some uncertainty in the study
NOAEL and LOAEL values.
Tomenson et al., (1995) conducted a cross-sectional study of hepatic function in 135 carbon
tetrachloride-exposed workers in three chemical plants in northwest England and in a control
group of 276 unexposed workers. The exposure assessment was based on historical personal
monitoring data for various jobs at the three plants. Subjects were placed into one of three
exposure categories—low (<1 ppm), medium (1.1-3.9 ppm), or high (>4 ppm)—according to
their current jobs. Overall, this study suggests an effect of occupational carbon tetrachloride
exposure on the liver at exposures in the range of >1-3.9 ppm (6.3-24.5 mg/m3); this exposure
range is considered a LOAEL. The low exposure category in this study (<1 ppm or <6.3 mg/m3)
is a NOAEL.
Table 3-7presents human epidemiological studies published on or after 2010 that have acceptable
data quality according to the systematic review for this risk evaluation. As shown in the table, the
studies do not suggest significant association between carbon tetrachloride exposure and
Parkinson's Disease or autism.
Table 3-7. Acceptable Epidemiological Studies for Non-Cancer Toxicity of Carbon
etrachloride Not Evaluated in Previously Pub
ished Hazard Assessments
Outcome/
Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
Parkinson's Disease
(PD)
99 male twin pairs 35-84
years of age from US
National Academy of
Sciences/National
Research Council World
War II Veteran Twins
Registry, 1993-1995
Self-reported
exposure to carbon
tetrachloride
A positive, non-significant
association was observed
between Parkinson Disease
and exposure to carbon
tetrachloride
(Goldman
et al.. 2012)
High
Autism Spectrum
Disorder
Nurses' Health Study II
children 3-18 years (US;
325 cases/22101 controls).
Carbon tetrachloride
air concentrations at
mother's location at
birth
Carbon tetrachloride
exposure was not
significantly associated
with Autism Spectrum
Disorder.
(Roberts et
al.. 2013)
High
3.2.3.3 Genotoxicity and Cancer Hazards
3.2.3.3.1 Genotoxicity
A substantial body of publications have studied genotoxic effects of carbon tetrachloride as
documented in the EPA IRIS Toxicological Review of carbon tetrachloride (U.S. EPA. 2010).
The results of this review, as further supported in data summaries provided in Appendix
KAppendix I indicate:
• There is little direct evidence that carbon tetrachloride induces intragenic or point
mutations in mammalian systems.
• Multiple studies have characterized the formation of endogenously produced DNA
adducts, chromosomal aberrations, and micronucleus formation. The presence of cellular
toxicity in a number of studies, complicates the evaluation of the database.
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• Lipid peroxidation products generate compounds (e.g., reactive aldehydes) that may
covalently bind to DNA.
• Measurement of genetic damage to DNA has not been well characterized at or below
doses at which tumors are observed.
The systematic review did not identify additional genetic toxicity studies with carbon
tetrachloride rated of medium or high overall quality based on the quality criteria in the
Application of Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018a).
The in vitro and in vivo genotoxicity databases for carbon tetrachloride, including their
limitations are described in Appendix I.
3.2.3.3.2 Carcinogenicity
Under the Guidelines for Carcinogen Risk Assessment (U.S. EPA. 2005b). EPA classifies carbon
tetrachloride as "likely to be carcinogenic to humans" based on: "(1) inadequate evidence of
carcinogenicity in humans and (2) sufficient evidence in animals by oral and inhalation exposure,
i.e., hepatic tumors in multiple species (rat, mouse, and hamster) and pheochromocytomas (adrenal
gland tumors) in mice."
Epidemiological Data on Carcinogenicity
The 2010 EPA IRIS assessment concluded that the evidence in humans was inadequate to show an
association between exposure to carbon tetrachloride and carcinogenicity. There was some limited
evidence for certain types of cancer in occupational populations thought to have had some
exposure to carbon tetrachloride, including non-Hodgkin's lymphoma, lymphosarcoma and
lymphatic leukemia, esophageal and cervical cancer, breast cancer, astrocytic brain cancer, and
rectal cancer (U.S. EPA. 2010).
Table 3-8 presents epidemiological studies published after completion of the EPA IRIS
assessment that have been found to be of acceptable data quality in the systematic review for this
risk evaluation. Among the 11 studies, there was one study of breast cancer, one study of
head/neck cancer, one study of kidney cancer, two studies of lung cancer, two studies of
lymphohematopoietic cancers, and four studies of cancers of the nervous system.
Combining these with the several studies noted in the IRIS assessment, there was little evidence
of an association between carbon tetrachloride exposure and the lymphohematopoietic cancers
(non-Hodgkin lymphoma, lymphosarcoma, lymphatic leukemia, multiple myeloma, and mycosis
fungoides - the most common form of cutaneous T-cell lymphoma), breast cancer, head/neck
cancer, kidney cancer, or lung cancer. However, four of these newer studies report results for
cancers of the nervous system - as did one study from the IRIS assessment (Heineman et al..
1994). Three of these were specific to astrocytic brain tumors which include astrocytoma,
glioma, and glioblastoma and occur in adults. The fourth was a study of neuroblastoma - a
childhood cancer of the nervous system.
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3795 Table 3-8. Acceptable Epidemiological Studies for Cancer Toxicity of Carbon
Tetrachloride >
ot evaluated in EPA IRIS Assessment
Cancer Endpoint
Study Population
Exposure
Results
Reference
Data
Quality
Evaluation
Brain
(Neuroblastoma)
Children (75 cases,
14602 controls), ages
<6 years bom in 1990-
2007 in California
within 5 km of
exposure monitoring
stations, cases from
California Cancer
Registry.
Carbon tetrachloride
(0.105 ppbV) in
ambient air. pollution
monitoring stations
used to estimate
maternal exposure
during pregnancy from
birth certificate
address.
Significant positive association between
risk of neuroblastomas per interquartile
increase in carbon tetrachloride exposure
(OR=2.55; 95% CI: 1.07. 6.53) within a
5 km radius and (OR=7.87; 95% CI:
1.37. 45.34) within a 2.5 km radius of
monitors. Significant positive
association for the highest quartile of
carbon tetrachloride exposure compared
to the lowest (OR=8.85; 95% CI: 1.19.
66.0).
(Heck et
al.. 2013)
Medium
Brain
(Glioblastoma)
8,006 men of Japanese
descent from the
Honolulu
Heart Program (HHP)
and Honolulu-Asia
Aging Study
(HAAS) cohorts, aged
45-68 at initial
examination (1965-
1968) and followed
through 1998. 9
glioblastoma cases.
Usual occupation with
no. low-medium, or
high exposure to
carbon tetrachloride,
based on professional
judgement; no
quantification of
exposure available.
Rate ratio of exposed vs unexposed was
10.09 (p=0.012). A positive, statistically
significant association was found
between glioblastoma and high
occupational exposure vs. no exposure to
carbon tetrachloride (OR=26.59; 95%
CI: 2.9. 243.50).
(Nelson et
al.. 2012)
Medium
Brain
(Glioma)
489 glioma cases, 197
meningioma cases,
and 799 controls from
three USA hospitals in
Arizona,
Massachusetts and
Pennsylvania.
Occupational exposure
to carbon tetrachloride
via self-reported
occupational history
and industrial
hygienist assigned
level of exposure.
Carbon tetrachloride was associated with
a significant increase in risk of gliomas
with higher average weekly exposure
(OR=7!l; 95% CL 1.1. 45.2; p-value =
0.04) and when further controlling for
lead and magnetic fields (OR=60.2; 95%
CI: 2.4. 1533.8).
(Neta et
al.. 2012)
High
Brain
(Glioma)
Non-farm workers
from the Upper
Midwest Health Study
(798 cases and 1141
controls from Iowa,
Michigan, Minnesota,
and Wisconsin 1995-
1997).
Carbon tetrachloride
use (self-reported
occupational history
through 1992. using a
bibliographic database
of published
exposure). Of798
glioma cases. 360
interviews were
conducted with
proxies because the
cases were deceased.
Excluding proxy-only interviews: "Ever"
vs. "never" having carbon tetrachloride
exposure was not associated with a risk
of glioma (OR=0.82; 95% CI: 0.64.
1.06) and cumulative exposure was
associated with decreased risk of
gliomas per ppm-year with borderline
significance (OR=0.98; 95% CI: 0.96.
1.00).
Including proxy-only interviews: "Ever"
vs. "never" having carbon tetrachloride
exposure was significantly associated
with a decreased risk of glioma
(OR=0.79; 95% CI: 0.65^ 0.97) and
cumulative exposure was associated with
a small but significant decrease in risk of
gliomas per ppm-year (OR=0.98; 95%
CI: 0.96. 0.99).
(Ruder et
al.. 2013)
High
Breast
Participants in the
California Teacher
Study. 1995-2011.
(n=112,378 women)
National-Scale Air
Toxics Assessment
modeled air
concentrations
Borderline significant increase in risk of
breast cancer incidence associated with
5th quintile carbon tetrachloride exposure
compared to 1st quintile exposure.
Significant trend across quintiles.
(Garcia et
al.. 2015)
High
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Cancer Endpoint
Study Population
Exposure
Results
Reference
Data
Quality
Evaluation
Head/Neck
Case-control, women
only, 296 cases, 775
controls, diagnosed
2001-2007, general
population, 18-85
years, subset of
ICARE cohort
Carbon tetrachloride,
exposure qualitatively
stated as ever (job
with likely exposure
>lmonth) or never
No significant association between
carbon tetrachloride and head/neck
cancers
(Carton et
al.. 2017)
Medium
Kidney
General population
case-control study of
kidney cancer (1217
cases; 1235 controls).
Detroit (2002 - 2007)
and Chicago (2003).
Job exposure matrix
was used to determine
years exposed,
average weekly
exposure and
cumulative hours
exposed, to carbon
tetrachloride
No significant associations observed
between exposure to carbon tetrachloride
and kidney cancer.
(Purdue et
al.. 2016)
High
Lymphohematopoietic
(Multiple myeloma)
180 cases of multiple
myeloma (diagnosed
between January 1,
2000 and March 21.
2002; 35-74 years old)
and 481 controls (35-
74 years old).
Exposure to carbon
tetrachloride estimated
with job exposure
matrix. Individual
cumulative exposure
scores were calculated
by multiplying the
midpoint of the
intensity (in ppm) by
the midpoint of the
frequency (in
hours/week) by the
number of years
worked in each
exposed job.
Primary analysis: non-significant
increase risk of multiple myeloma
(OR=l.l; 95% CI: 0.7. 1.8). When
individuals with reported exposure rated
as "low confidence" were considered
unexposed, a non-significant increased
risk of multiple myeloma was observed
in individuals ever exposed to carbon
tetrachloride (OR=1.6; 95% CI: 0.8.
3.0). A significant exposure-related
trend (p = 0.01) was observed for
duration of exposure. The risks of
myeloma were not increased with
cumulative exposure score (with and
without a 10-year lag).
(Gold et
al.. 2010)
High
Lymphohematopoietic
(Mycosis Fungoides)
100 patients with
Mycosis Fungoides
and 2846 controls, 35-
69 years of age, from
Denmark, Sweden,
France, Germany,
Italy, and Spain. 1995-
1997.
Occupational exposure
to carbon tetrachloride
assessed with job
exposure matrix.
A positive, non-significant association
was observed between Mycosis
Fungoides and subjects with exposure to
carbon tetrachloride >= median of
control exposure vs. unexposed subjects
(Morales-
Suarez-
Varela et
al.. 2013)
High
Lung
Investigation of
occupational and
environmental causes
or respiratory cancers
(ICARE) study
subjects, population-
based case-control
study in France 2001-
2007 (622 women
cases and 760 women
controls).
Cumulative Exposure
Index based on self-
reported job histories
and probability,
intensity, and
frequency of exposure
to carbon tetrachloride
based on jobs.
Carbon tetrachloride was not
significantly associated with lung cancer
in women.
(Mattei et
al.. 2014)
Medium
Lung
Lung cancer cases and
randomly selected
population-based
controls frequency
matched by sex and
age in Montreal
Canada
Carbon tetrachloride
exposure (any or
substantial) was
assessed by a team of
industrial chemists and
hygienists based on
self-reported job
histories.
Increase in OR for any exposure to
carbon tetrachloride in Study II only;
significant increased OR for substantial
exposure in Study II and pooled analysis
(Vizcava
et al..
2013)
Medium
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3799 The EPA IRIS assessment concludes that carbon tetrachloride has been shown to be a liver
3800 carcinogen in rats, mice, and hamsters in eight bioassays of various experimental design by oral
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and inhalation exposure. Carbon tetrachloride has also been shown to induce
pheochromocytomas in mice by oral and inhalation exposure. Information on the carcinogenic
effects of carbon tetrachloride via the dermal route in humans and animals is limited or absent.
The IRIS assessment (U.S. EPA. 2010) identifies the (Nagano et al.. 2007a) bioassay of carbon
tetrachloride by the inhalation route described in section 3.2.3.1 (data quality = high) as a
bioassay that provides data adequate for dose-response modeling. In this bioassay, carbon
tetrachloride produced a statistically significant increase in hepatocellular adenomas and
carcinomas in rats and mice of both sexes, and adrenal pheochromocytomas in mice of both
sexes.
Tumor incidence data for rats in the 104-week inhalation study in F344/DCR rats described
above are presented in Table 3-9 (Nagano et al.. 2007a). The incidence of hepatocellular
adenomas and carcinomas was statistically significantly increased in male and female rats at 125
ppm. The incidence of hepatocellular carcinomas in female 25-ppm rats (6%) was not
statistically elevated compared with the concurrent control but did exceed the historical control
range for female rats (0-2%). The increase in liver carcinoma over historical control (2/1,797)
was statistically significant (based on Fisher's exact test; two-tailed p-value = 0.0002). No other
tumors occurred with an increased incidence in treated rats. Incidences of foci of cellular
alteration (preneoplastic lesions of the liver), including clear, acidophilic, basophilic, and mixed
cell foci, were significantly increased in the 25-ppm female rats; in males, only the incidence of
basophilic cell foci was increased at 125 ppm.
Tumor incidence data in mice are presented in Table 3-10. The incidences of liver tumors in
control mice (18% in males and 4% in females for hepatocellular adenomas and 34% in males
and 4% in females for hepatocellular carcinomas) were similar to historical control data for liver
tumors in Cij :BDF1 mice in 20 studies at JBRC. The gender differences in unexposed mice are
thought to be related to inhibition of liver tumor formation by female estrogen levels. The
incidences of hepatocellular adenomas and carcinomas were significantly elevated in both sexes
at >25 ppm. At 5 ppm, the incidence of liver adenomas in female mice (8/49 or 16%) was
statistically significantly elevated compared to the concurrent control group and exceeded the
historical control range (2-10%). The incidence of benign adrenal pheochromocytomas was
significantly increased in males at 25 or 125 ppm and females at 125 ppm.
Table 3-9. Incidence of liver tumors in F344 rats exposed to carbon tetrachloride vapor for
104 weeks (6 hours/day, 5 days/week)3
Tumor
Male
Female
0 ppm
5 ppm
25 ppm
125 ppm
0 ppm
5 ppm
25 ppm
125 ppm
Hepatocellular
adenoma
0/50b
1/50
1/50
21/50°
0/5 0b
0/50
0/50
40/50°
Hepatocellular
carcinoma
l/50b
0/50
0/50
32/50°
0/5 0b
0/50
3/50d
15/50°
Hepatocellular
adenoma or
carcinoma
l/50b
1/50
1/50
40/50°
0/5 0b
0/50
3/50d
44/50°
aThe exposure concentrations adjusted to continuous exposure (i.e., multiplied by 5/7 x 6/24) = 0.9, 4.5, and
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22.3 ppm.
Statistically significant trend for increased tumor incidence by Peto's test (p < 0.01).
Tumor incidence significantly elevated compared with that in controls by Fisher's exact test (p < 0.01).
Statistically significant (p < 0.001 by Fisher's exact test) in comparison to the historical control
incidence (2/1,797). Sources: (Nagano et al.. 2007a)
Table 3-10. Incidence of liver and adrenal tumors in BDFi mice exposed to carbon
tetrachloride vapor for 104 weeks (6 hours/day, 5 days/week)3
Tumor
Male
Female
0 ppm
5 ppm
25 ppm
125 ppm
0 ppm
5 ppm
25 ppm
125 ppm
Hepatocellular adenoma
9/5 0b
10/50
27/50c
16/50
2/5 0b
8/49d
17/50°
5/49
Hepatocellular
carcinoma
17/50b
12/50
44/50°
47/50°
2/5 0b
1/49
33/50°
48/49°
Hepatocellular adenoma
or carcinoma
24/50b
20/50
49/50°
49/50°
4/5 0b
9/49
44/50°
48/49°
Adrenal
pheochromocytoma0
0/5 0b
0/50
16/50°
32/50°
0/5 0b
0/49
0/50
22/49°
The exposure concentrations adjusted to continuous exposure (i.e., multiplied by 5/7 x 6/24) = 0.9, 4.5, and
22.3 ppm.
Statistically significant trend for increased tumor incidence by Peto's test (p < 0.01).
Tumor incidence was significantly elevated compared with controls by Fisher's exact test (p < 0.01).
dTumor incidence was significantly elevated compared with controls by Fisher's exact test (p < 0.05).
eAll pheochromocytomas in the mouse were benign with the exception of one malignant pheochromocytoma in
the 125-ppm male mouse group. Sources: (Nagano et al„ 2007a)
The systematic review did not identify additional cancer studies with carbon tetrachloride with
acceptable data quality based on the quality criteria in the Application of Systematic Review in
TSCA Risk Evaluations (U.S. EPA, 2018a).
3.2,4 Weight of Scientific Evidence
The following sections describe the weight of the scientific evidence for both non-cancer and
cancer hazard endpoints. Factors considered in weighing the scientific evidence included
consistency and coherence among human and animal studies, quality of the studies (such as
whether studies exhibited design flaws that made them unacceptable) and biological plausibility.
Relevance of data was considered primarily during the screening process but may also have been
considered when weighing the evidence.
3.2.4.1 Non-Cancer Hazards
The following sections consider and describe the weight of the scientific evidence of health
hazard domains discussed in section 3.2.3.1. These domains include: toxicity from acute
exposure; liver effects; nervous system effects; kidney effects; and reproductive and
developmental effects.
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3.2.4.1.1 Acute Toxicity
EPA is basing the evidence integration for the acute toxicity of carbon tetrachloride on the
conclusions of the AEGL program. NAC/AEGL evaluated reports describing nonlethal effects of
acute exposure of humans to carbon tetrachloride in addition of relevant animal data to derive
AEGL values. The AGL-2 values are based on observations of CNS effects (Davis. 1934). (i.e.,
nausea, vomiting, dizziness, and headaches) despite normal clinical assessments (i.e., urinalysis,
blood count, hemoglobin levels, blood pressure, and heart rate) for individuals exposed to 317
ppm carbon tetrachloride for 30 min. The observed effects were apparently not long4asting but
are considered severe enough to impair escape or normal function. The same study also reported
notable renal effects in a worker experimentally exposed to carbon tetrachloride at 200 ppm for 8
hrs.
Testing for developmental toxicity by the inhalation route is limited to one study in the rat that
found effects only at high, maternally toxic exposure concentrations. Reduced fetal body weight
and crown-rump length was reported in the single inhalation study (Schwetz et al.. 1974) at a
concentration that also produced toxicity in the dam (i.e., hepatoxicity reflected by increase in
serum glutamic-pyruvic transaminase activity). This inhalation developmental toxicity study has
been reviewed in the ATSDR, IRIS, and AEGL assessments. NAC/AEGL (NRC. 2014)
determined that these results were inconclusive for identifying any fetal end points for deriving
AEGL (acute) values. NAC/AEGL further concluded that these developmental effects are likely
associated with the sustained lower maternal weight over gestation days 6-15 rather than the
result of exposure to carbon tetrachloride on a single day of the study (see section 3.2.5.1).
The systematic review did not identify additional developmental toxicity studies with carbon
tetrachloride with acceptable data quality based on the quality criteria in the Application of
Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018a).
Limited available acute animal studies by the dermal route, described above, provide evidence of
mortality and liver changes from single, continuous (>19 hrs) dermal exposure conditions. The
systematic review did not identify additional dermal acute toxicity studies with carbon
tetrachloride with acceptable data quality based on the quality criteria in the Application of
Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018a).
3.2.4.1.2 Chronic Toxicity
Limited evidence from gestational exposure studies in animals suggest that developmental
toxicity is not an acute effect (see section 3.2.4.1.1) nor the most sensitive effect for carbon
tetrachloride. Developmental toxicity has been observed at doses accompanied by some degree
of maternal toxicity. Increased resorptions were observed in developmental toxicity studies
following maternal exposure to doses >50 mg/kg-day during pregnancy (Narotsky et al.. 1997).
which were attributed to maternally-mediated effects, including reduced progesterone and
luteinizing hormone levels in dams. EPA (2010) concluded that the most detailed developmental
toxicity study by inhalation exposure (Schwetz et al.. 1974) suggests that developmental effects
of carbon tetrachloride occur at concentrations toxic to the mother and at exposure
concentrations higher than those associated with liver and kidney toxicity. EPA (2010) notes that
the LOAEL for developmental effects (in the presence of maternal toxicity) in this study (300
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ppm) was 66-fold higher than the NOAEL (5 ppm) for liver toxicity from chronic inhalation
exposures identified by IRIS for the development of the RfC.
The EPA IRIS Assessment (U.S. EPA. 2010) identified the liver as the target organ for carbon
tetrachloride after repeated inhalation and oral exposure in animals and humans. Limited
available dermal exposure data suggest that liver changes can be induced by exposure to carbon
tetrachloride through the skin in animals.
Primary animal evidence on the liver toxicity from inhalation exposures is from the chronic (104
week) inhalation toxicity study in F344/DuCij rats (Nagano et al.. 2007a). Increased incidence
and severity of nonneoplastic liver lesions (fatty change, fibrosis, cirrhosis) were seen at 25 and
125 ppm in both male and female rats in this study. Fatty change in the liver of rats was selected
by EPA IRIS as the specific endpoint indicative of cellular damage and most sensitive endpoint
among the histopathologic changes observed in the 25-ppm group rats in the study. This critical
effect is the basis for the derivation of the IRIS Inhalation Reference Concentration (RfC).
Kidney toxicity was identified as a target for carbon tetrachloride toxicity after repeated
inhalation exposure (U.S. EPA. 2010). Similar to the evidence for liver toxicity, the primary
evidence for kidney toxicity is the chronic (104 week) inhalation toxicity study in F344/DuCrj
rats (Nagano et al.. 2007a). increased severity of glomerulonephrosis, accompanied by evidence
of impaired glomerular function, including increases in serum BUN, creatinine, inorganic
phosphorus and proteinuria were observed following exposure to >25 ppm. The interpretation of
the observed proteinuria in the F344 rat, a strain with a high spontaneous incidence of renal
lesions, was deemed problematic and not an appropriate basis for the RfC in the IRIS
assessment.
The kidney was not identified as a critical target for carbon tetrachloride toxicity following oral
exposure. In oral gavage studies, no exposure-related kidney effects were observed in Sprague-
Dawley rats exposed to doses up to 2,000 mg/kg-day for 1-3 days (Sun et al.. 2014). Sprague-
Dawley rats exposed to doses up to 33 mg/kg-day for 12 weeks (Bruckner et al.. 1986). or CD-I
mice exposed to doses up to 1,200 mg/kg-day for 90 days (Haves et al.. 1986).
The systematic review did not identify additional chronic toxicity studies with carbon
tetrachloride with acceptable data quality based on the quality criteria in the Application of
Systematic Review in TSCA Risk Evaluations (U.S. EPA. 2018a).
3.2.4.2 Genotoxicity and Cancer
The available data for carbon tetrachloride do not support a conclusion that this compound
induces cancer though a mutagenic mode of action, however, there are important limitations to
the database. While there is little direct evidence that carbon tetrachloride induces intragenic or
point mutations in mammalian systems, studies have characterized formation of DNA adducts
and chromosomal damage. Lipid peroxidation products (e.g., reactive aldehydes) may contribute
to observed effects. The presence of cellular toxicity complicates the evaluation of the database
and genetic damage has not been well studied at or below the doses at which tumors are
observed.
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The EPA IRIS assessment of carbon tetrachloride classifies this compound as "likely to be
carcinogenic to humans" based on sufficient evidence in animals by oral and inhalation
exposure, i.e., hepatic tumors in multiple species (rat, mouse, and hamster) and
pheochromocytomas (adrenal gland tumors) in male and female mice exposed by oral and
inhalation exposures (U.S. EPA. 2010).
The systematic review did not identify additional genotoxicity studies with carbon tetrachloride
with acceptable data quality based on the quality criteria in the Application of Systematic Review
in TSCA Risk Evaluations (U.S. EPA. 2018a).
3.2.4.3 MOA for Carcinogenicity
This section summarizes available information on mode of action (MOA) for carbon
tetrachloride carcinogenicity based on the MOA analysis performed in the 2010 EPA IRIS
assessment (U.S. EPA. 2010) and additional information made available since 2010. The
Guidelines for Carcinogen Risk Assessment (U.S. EPA. 2005a) identifies steps for determining
whether a hypothesized MOA is operative. The steps include an outline of the sequence of events
leading to cancer, identification of the key events, and determination of whether there is a causal
relationship between events and cancer. The EPA IRIS assessment reviewed MOA information
for liver tumors and pheochromocytomas. IRIS described evidence in support of several
potential mechanisms of action (described below) but concluded that "the overall MOA for
carbon tetrachloride carcinogenicity across all levels of exposure is unknown at this time" (U.S.
EPA. 2010). The IRIS assessment did not review information on potential MO As for brain
cancers and the MOA for brain cancer is also unknown.
3.2.4.3.1 Mode of Action for Liver Tumors
EPA has qualitatively evaluated the weight of evidence for several proposed MO As for liver
carcinogenicity using the framework outlined in EPA cancer risk guidelines (U.S. EPA. 2005a).
This analysis considers the MOA analysis previously conducted by the IRIS program (U.S. EPA.
2010). more recent evidence, and information submitted to EPA through public comment (see
Appendix K) to evaluate supporting and counterfactual evidence for proposed MOAs.
A general correspondence has been observed between hepatocellular cytotoxicity and
regenerative hyperplasia and the induction of liver tumors. At lower exposure levels, this
correspondence is less consistent (U.S. EPA. 2010). A hypothesized carcinogenic MOA for
carbon tetrachloride-induced liver tumors has been proposed and includes the following key
events:
(1) metabolism to the trichloromethyl radical by CYP2E1 and subsequent formation of the
trichloromethyl peroxy radical,
(2) radical-induced mechanisms leading to hepatocellular cytotoxicity, and
(3) sustained regenerative and proliferative changes in the liver in response to hepatotoxicity.
This MOA appears to play a significant role at relatively high exposures, driving the steep
increase in liver tumors in this exposure range. Data to characterize key events at low-exposure
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levels, however, are limited. Therefore, EPA also considered an alternate MOA that combines
cytotoxic mechanisms at high doses with alternate, non-cytotoxic mechanisms as lower doses.
Based on information in the IRIS assessment and public comments EPA-HQ-OPPT-2016-0733-
0066 and EPA-HQ-QPPT-2016-0733-0088. the following potential MOAs, including evidence
for key events, are evaluated in Table 3-11 and Appendix K.
• Liver cytotoxic MOA (Lipid peroxidation and cytotoxicity as proposed in comments
submitted by ACC)
• Combined MOA (non-cytotoxic at low dose and cytotoxic at high dose)
Table 3-11. Cytotoxic MOA (key events as proposed by EP A-HQ-OPPT-2016-0733-0066
and EPA-HO-QPPT-2016-0733-0088)
Key Events
Supporting Evidence
Counterfactual Evidence
Data Gaps/limitations
Metabolism
There is well documented
evidence in IRIS assessment
and other assessments listed in
Table 1-3 on the metabolism of
carbon tetrachloride to the
trichloromethyl radical by
CYP2E1 and subsequent
formation of the
trichloromethyl peroxy radical
No significant evidence
No significant gaps
Lipid peroxidation and
attack of cellular
membranes
From EPA-HO-OPPT-2016-
0733-0066 and EPA-HO-
OPPT-2016-073 3-0088:
Studies of radical scavengers
that are not necessarily specific
to trichloromethyl peroxy or
lipid peroxidative free radicals
have shown that these agents
confer protection against
carbon tetrachloride induced
liver toxicity, while another
study demonstrated
administration of a-tocopherol.
Vitamin E antioxidant, had
been shown to reduce lipid
peroxidation (Gee et al.. 1981).
Numerous studies have
demonstrated lipid
peroxidation following carbon
tetrachloride exposure by the
detection of conjugated dienes
in liver lipids, increased
exhalation of ethane and
pentane (end degradation
products of peroxidized
polyunsaturated fatty acids) or
malondialdehyde and 4-HNE.
Hartlev et al.. (1999)
demonstrated the temporal
No significant evidence
From information in
Appendix I: Collectively,
the data indicate that
carbon tetrachloride
exposure can result in the
formation of DNA adducts
in response to two distinct
pools of reactive oxygen
species 1) those formed as
a result of exposure to
carbon tetrachloride itself
or reactive metabolites
thereof and 2) those
formed as a result of lipid
peroxidation. However, the
relative contribution of
each of these pathways to
the overall carcinogenic
potential carbon
tetrachloride is currently
uncertain.
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Key Events
Supporting Evidence
Counterfactual Evidence
Data Gaps/limitations
relationship between carbon
tetrachloride exposure-initiated
lipid peroxidation, liver
damage and formation of 4-
HNE and MDA protein
adducts.
Cytotoxicity due to
loss of calcium
homeostasis
From EP A-HO-OPPT -2016-
0733-0066 and EPA-HO-
OPPT-2016-073 3-0088:
Studies have reported 100-fold
or more increases in cytosolic
concentrations of calcium
following exposure to carbon
tetrachloride.
Studies have demonstrated that
effect of carbon tetrachloride
on membrane integrity and the
active transport that may be by
the NADPH-cytochrome P-
450 electron-transport chain in
liver endoplasmic reticulum, a
distance away from the
nucleus (Mccav et al.. 1984;
Slater and Sawver. 1977;
Recknaeel and Glende. 1973).
which appear to be secondary
to lipid peroxidation.
Low-dose exposed female
mice displayed an increase
incidence of liver
adenomas that occurred in
the absence of
hepatocellular
cytotoxicity, suggesting
that more than one
mechanism may be
responsible for carbon
tetrachloride-induced liver
carcinogenesis
It is uncertain if disruption
of calcium homeostasis is a
major driver of
carcinogenesis.
Regenerative
Proliferation
Increased hepatocellular
toxicity in animals occurred
with a concomitant increase in
regenerative cellular
proliferation to compensate for
necrotic or damaged tissue.
No significant evidence
No significant gaps
Liver tumors
EPA IRIS assessment (U.S.
EPA. 2010) summarizes a
variety of studies describing
liver tumor formation in rats,
mice, and hamsters by both
oral and inhalation exposure
No significant evidence
No significant gaps
Table 3-12. Combined MOA (non-cytotoxic at
ow dose and cytotoxic at high dose)
Key Events
Supporting Evidence
Counterfactual Evidence
Data Gaps/limitations
Metabolism
There is well documented
evidence in EPA IRIS
assessment and other
assessments listed in Table 1-3
on the metabolism of carbon
tetrachloride to the
trichloromethyl radical by
CYP2E1 and subsequent
formation of the
trichloromethyl peroxy radical
No significant evidence
No significant gaps
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Key Events
Supporting Evidence
Counterfactual Evidence
Data Gaps/limitations
radical-induced
mechanisms (driven
by non-cytotoxic
mechanisms at low
doses and cytotoxic
mechanisms at high
doses)
Multiple studies have
characterized the formation of
endogenously produced DNA
adducts, chromosomal
aberrations, and micronucleus
formation.
Lipid peroxidation products
generate compounds (e.g.
reactive aldehydes) that may
covalently bind to DNA
Low-dose exposed female
mice displayed an increase
incidence of liver adenomas
that occurred in the absence of
hepatocellular cytotoxicity,
suggesting that more than one
mechanism may be responsible
for carbon tetrachloride-
induced liver carcinogenesis.
Carbon tetrachloride lias
consistently been negative
in studies using
Salmonella and certain
strains of E. coli, at high
exposure concentrations.
Measurement of genetic
damage to DNA has not
been well characterized at
or below doses at which
tumors are observed.
Technical challenges for
the evaluation the
genotoxicity of carbon
tetrachloride are
summarized in Appendix I.
It is unknown what are the
major radical-induced
mechanisms driving
carcinogenesis.
Regenerative
Proliferation after
cytotoxicity at high-
dose exposures only
Increased hepatocellular
toxicity in animals occurred
with a concomitant increase in
regenerative cellular
proliferation to compensate for
necrotic or damaged tissue for
high- dose exposed animals.
Low-dose exposed female
mice displayed an increase
incidence of liver
adenomas that occurred in
the absence of
hepatocellular
cytotoxicity, suggesting
that more than one
mechanism may be
responsible for carbon
tetrachloride-induced liver
carcinogenesis.
No significant gaps
Liver tumors
The IRIS Toxicological
Review of carbon tetrachloride
(U.S. EPA. 2010) summarizes
a variety of studies describing
liver tumor formation in rats,
mice, and hamsters by both
oral and inhalation exposure
No significant evidence
No significant gaps
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4020 Based on the qualitative MO A WOE for the alternative MO As, there are significant data
4021 limitations to assess within certainty the causal considerations (i.e., biological plausibility,
4022 essentiality, dose-response concordance, consistency) for the postulated non-cytotoxic and
4023 cytotoxic key events that are expected to occur after carbon tetrachloride metabolism. The
4024 available data suggest that cytotoxicity is one major mechanism in the MOA of carcinogenesis at
4025 high exposures, however data also indicate that carbon tetrachloride can induce tumors in the
4026 absence of cytotoxicity, i.e., tumorigenesis in low dose female mice. There is limited information
4027 about mechanisms at lower doses.
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3.2.4.3.2 Mode of Action for Pheochromocytomas (Adrenal
Tumors)
EPA has reviewed the available literature and concludes that the MOA by which carbon
tetrachloride induces pheochromocytomas in mice is unknown. Animal and in vitro evidence
suggests that metabolism is an important contributor to the toxicity of carbon tetrachloride in the
adrenal gland ((U.S. EPA. 2010) (see page 168)).
Pheochromocytomas are relatively rare in people. Only a small number of chemicals have been
associated with pheochromocytomas in mice, and there does not appear to be a common
mechanism shared across these chemicals (U.S. EPA. 2010). Several potential MO As for
induction of pheochromocytomas in mice have been hypothesized but not experimentally
supported, including endocrine disturbances, uncoupling of oxidative phosphorylation,
disturbances in calcium homeostasis, impaired mitochondrial function, and hepatoxicity (Greim
et al.. 2009).
3.2.5 Dose-Response Assessment
3.2.5.1 Selection of Studies for Dose-Response Assessment
EPA evaluated data from studies described in sections 3.2.3 and 3.2.4 to characterize the dose-
response relationships of carbon tetrachloride and selected studies and endpoints to quantify risks
for specific exposure scenarios. The selected studies had adequate information to select PODs.
3.2.5.1.1 Toxicity After Acute Inhalation Exposures in
Humans
Acute inhalation exposures to carbon tetrachloride above the AEGL-2 values are expected to
induce immediate and temporary CNS effects, which consist of escape-impairing symptoms in
occupational settings (i.e., dizziness). Acute inhalation human data were used by the AEGL
program for the identification of a NOAEL for transient CNS effects of 76 ppm in humans
exposed carbon tetrachloride for 4 h (Davis. 1934). EPA considers that the acute NOEL
identified by the AEGL program is adequate for assessing acute effects in inhalation
occupational exposure scenarios for TSCA conditions of use of carbon tetrachloride. EPA
reviewed the acute dose-response information in the AEGL report (NRC. 2014) including the
identification of the PODs and uncertainty factors identified for CNS effects but did not conduct
further dose-response analysis.
The endpoint and effect level identified by NAC/AEGL for the AEGL-2 values are considered to
provide both a relevant effect and robust POD because the values represent the concentration
above which it is predicted that irreversible or other serious, long-lasting adverse health effects
or an impaired ability to escape can be experienced by workers. On the other hand, the AEGL-3
values protect from life-threatening health effects or death, which are appropriate for emergency
or accidental releases of the chemical.
Developmental toxicity studies were also considered in the derivation of acute toxicity values as
adverse effects in the fetus related to the unique susceptibility of the fetus at discrete times
during gestation (U.S. EPA. 1991). Therefore, EPA conservatively assumes that the adverse fetal
effects observed in a developmental toxicity study that includes exposures across multiple days
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of embryonic or fetal development, or even throughout gestation, could have occurred as the
result of exposure on a single day of the study (U.S. EPA. 1991). Among the reasonably
available developmental toxicity data for carbon tetrachloride, Schwetz et al., (1974) is the only
developmental study by the inhalation route with acceptable data quality. This inhalation
developmental study has been reviewed in the ATSDR, IRIS, and AEGL assessments. ATSDR,
IRIS, and AEGL describe that the developmental effects (decreased fetal body weight and
crown-rump length) occur at the same LOAEL that results in maternal toxicity (a NOAEL was
not identified). ATSDR categorized these effects as less serious. The maternal effects were
reduced body weight (decreased food consumption), increased liver weight and ALT. Based on
this consideration as well as experimental variability over the 3-fold dose range, AEGL
determined that these results were inconclusive for identifying any fetal end points for deriving
AEGL values. They further concluded that these developmental effects are likely associated with
the sustained lower maternal weight over gestation days 6-15 rather than the result of exposure to
carbon tetrachloride on a single day of the study.
The oral developmental studies by Narotsky et al., (1997). which were rated of high quality in
the systematic review, identified a developmental NOAEL of 25 mg/kg-d based on observed
full-litter resorption at 50 mg/kg-d. However oral exposures to carbon tetrachloride undergo
first-pass metabolism in the liver, the organ with the highest concentration of CYP2E1 enzymes
involved in the generation of carbon tetrachloride's toxic metabolites.14 This major difference in
the metabolism of carbon tetrachloride between oral and inhalation routes of exposure limits the
usefulness of extrapolating a developmental inhalation POD from the oral developmental study,
given that different developmental toxicity processes may be involved between the two routes of
exposure.
3.2.5.1.2 Toxicity from Chronic Inhalation Exposures
EPA's systematic review process rated as high the overall quality of the 13-week and 104-week
inhalation studies by Nagano et al., (2007a; 2007b). The IRIS assessment concluded that among
the animal studies for carbon tetrachloride the most robust inhalation study was the 104-weeks
(2-year) inhalation study with F344/DuCrj rats in which the lowest exposure concentration in
this study, 5 ppm, was considered a NOAEL based on liver and kidney toxicity at >25 ppm. A
human PBPK model was used in the IRIS Assessment to estimate continuous HECs (in mg/m3)
that would result in values for the internal dose metrics, equal to the BMDLio values for fatty
changes of the liver. The BMDLio based on male rat data was calcirfated as 14.3 mg/nf for
continuous exposures.
14 Hie EPA IRIS assessment (U.S. EPA. 2010) indicates that among the PBPK models developed for carbon tetrachloride, the
model by (Yoon et al.. 2007) is the only one that addressed extrahepatic metabolism of carbon tetrachloride. (Yoon et al..
2007) reported that no metabolic activity was detected in the fat, brain, or skin. The proportion of liver metabolism estimated for
the lung and kidney was quite small, 0.79 and 0.93%, respectively, based on the microsomal studies. The EPA IRIS assessment
also indicates that the human kidney has been reported by multiple laboratories to not express any detectable CYP2E1 protein.
Considerations taken for determining the subchronic to chronic UF in the EPA IRIS assessment included the observation of early
onset of toxicity following oral exposure. For instance, assessment reviewers commented that oral exposure leads to first pass
metabolism in the liver resulting in peak exposure at the target site after oral exposures while more opportunity for extrahepatic
targeting is expected from inhalation exposures.
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The systematic review conducted did not identify information that challenges the observations or
conclusions from this critical study used in the IRIS assessment to derive a reference
concentration and inhalation unit risk for carbon tetrachloride.
3.2.5.1.3 Toxicity from Dermal Exposures
Kronevi et. al., (1979) (data quality rating = unacceptable due to lack of negative controls and
small number of animals) is the only available animal dermal study that includes
histopathological observations of liver and kidney in addition to skin. In the study guinea pigs
dermally exposed to a single application of 1 mL of carbon tetrachloride in a 3.1 cm2 skin depot
(513 mg/cm2)15 for 16 hours showed hydropic changes and necrosis in liver cells. Animals
exposed to the same dose levels for 15 minutes, 1 hr or 4 hr did not show liver morphology
alterations. The study provides suggestive evidence on the lower systemic availability of carbon
tetrachloride from dermal exposures in comparison with other routes of exposure. The results of
Kronevi et al., (1979) can be considered in conjunction with the findings from Wahlberg and
Boman, (1979). in which guinea pigs exposed to a higher dose level of 1 mL with a similar size
skin depot as Kronevi et al., (1979) did not show mortality during the first 2 days of continuous
dermal exposure. Collectively, these studies provide evidence suggesting that the induction of
liver toxicity in animals dermally exposed for 4 hrs to 0.5 mL carbon tetrachloride from a skin
depot of 3.1 cm2 is unlikely.
A study briefly described in the IRIS assessment: Tsuruta, (1975) (Klimisch score = 4: 'Not
assignable') reports a percutaneous absorption rate for carbon tetrachloride in mice of 53.6 ± 9.3
nmoles/ minute/cm2. This study, which is equivalent in design to OECD Guideline 427 (Skin
Absorption: In Vivo Method)16 is considered to provide an underestmation of the skin absorption
rate for occluded exposures because of the possibility of carbon tetrachloride volatilization
during dose preparation or application. The aspect of volatilization is not considered in this study
to address potential loss of the analyte. In addition, the IRIS assessment states that Morgan et al.,
(1991) (Klimisch Score =3: 'Not reliable') showed that approximately one quarter of an applied
volume (i.e., 0.54 mL of neat carbon tetrachloride application) was absorbed in a 24-hour period
under occluded conditions.
The systematic review did not identify additional information for refining the skin absorption
rate for carbon tetrachloride. Therefore, the available dermal toxicity information, with its
uncertainties and limitations has been used under a weight of evidence approach in the derivation
of dermal PODs for liver toxicity from acute dermal exposures.
Due to the lack of repeated-dose dermal toxicity data and the irritating properties of carbon
tetrachloride (i.e., irritation is associated with increased dermal absorption for repeated dermal
exposures), the limited acute dermal data with histopathology observations and information on
dermal absorption rate were used in the derivation of PODs for chronic dermal exposures for the
chemical.
15 This exposure concentration is reported in the ATSDR profile for carbon tetrachloride. The concentration estimate is based on
a density value of 1.59 g/niL for carbon tetrachloride.
10 Equivalency based on information in ECHA dossier for carbon tetrachloride; ECHA reliability score =4.
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PODs for chronic dermal exposures were derived using reasonably available inhalation data.
Extrapolation from oral exposure data is not recommended due to differences in the
biotransformation process between the oral and other routes of exposures for carbon
tetrachloride. First-pass metabolism and activation of carbon tetrachloride in the liver is only a
metabolic step for oral exposures to the chemical.
3.2.5.2 Derivation of PODs and UF for Benchmark Margins of Exposure
(MOEs)
3.2.5.2.1 PODs for Acute Inhalation Exposure
The AEGL Program identified a NOEL of 76 ppm (480 mg/m3) for CNS effects (i.e., dizziness)
in humans exposed to carbon tetrachloride for 4 hrs.17 The resulting AEGL-2 value is 7.6 ppm
(48 mg/m3) for 4 hrs and 5.8 ppm (36 mg/m3) for 8 hrs based on a UFh of 10 to account for
individuals who may be more susceptible to the toxic effects of carbon tetrachloride (e.g.,
variability in metabolism and disposition from alcohol usage).
Based on AEGL program recommendations for carbon tetrachloride, the POD for acute
inhalation exposures in this risk evaluation is 360 mg/m3 - 8 hr for disabling effects (CNS effects
such as dizziness) from elevated, but short inhalation exposures. For 12-hrs of exposure, the
acute inhalation POD is 310 mg/m3 (49 ppm) based on temporal scaling using the equation Cn x t
= k, where an empirical value of n was determined to be 2.5 on the basis of rat lethality data
(NRC, 2014). A benchmark MOE of 10 is used for intraspecies variability to account for
susceptible individuals, such as moderate to heavy alcohol users, in agreement with the AEGL
program conclusions. NRC (2014) explains that the intraspecies uncertainty factor of 10 was
retained for protection of susceptible individuals due to the known variability in the metabolic
disposition of carbon tetrachloride that may result in an altered toxic response.
Table 3-13. PODs for Acute Inhalation Exposures based on Human Data
Study
Study
Details
Endpoint
POD
UFs/Dose Metric
Benchmark MOE
Acute: CNS (temporarily disabling effects) protective of heavy alcohol users
(Davis,
1934)
Human
Data
CNS
360 mg/m3-8 h^
UFh 10
10
310 mg/m3-12 hr
310 mg/m3-12 hr
Temporal scaling was performed using the equation Cn x t = k (TenBerge et al.. 1986). where an empirical value of
n was determined to be 2.5 on the basis of rat lethality data (NRC. 2014).
3.2.5.2.2 PODs for Chronic Inhalation Exposure
The basis for the chronic inhalation PODs is the 104-weeks (2-year) inhalation study with
F344/DuCrj rats (Nagano et al.. 2007b). in which the lowest exposure concentration in this study,
5 ppm, was considered a NOAEC based on liver and kidney toxicity at >25 ppm. A human
17 Transient kidney effects were also reported for acute exposures, but at higher exposure concentrations (see
Section 3.2.3.1).
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PBPK model was used in the IRIS Assessment to estimate HEC (in mg/m3) consisting of
calculated BMDLio for fatty changes of the liver of 14.3 mg/m3 for continuous exposures.
Because the relationship between the PBPK-estimated internal dose metric and the external
concentration is linear, a periodic time adjustment of the 24-hour chronic HEC would produce a
nearly equivalent result as running the PBPK model assuming periodic exposures. While
additional nonlinearities in the model can be introduced when simulating periodic (as opposed to
continuous) exposures, the difference is small for chemicals that are rapidly absorbed and cleared
from the body. Such is the case with carbon tetrachloride. The linearity of the PBPK model was
determined by analysis of Tables C-6 and C-10 of the IRIS assessment (see Appendix J, below).
These tables presented the external:internal dose ratios for the human PBPK model over a span
of concentrations, using the model assumptions adopted by the IRIS assessment (model
parameter VmaxC = 1.49 mg/hr/kg BW0 70, continuous 24 hour/day, 7 days/week exposure).
Table C-6 presented PBPK model results for the MCA (mean arterial concentration) internal
dose metric, while Table C-10 presented results for the MRAMKL (mean rate of metabolism in
the liver) internal dose metric. An adaptation of these tables is presented in Appendix J. The
MRAMKL dose metric was used for RfC derivation in the IRIS assessment. For the inhalation
unit risk derivation, the MCA dose metric was used. For the MRAMKL internal dose metric, the
external: internal dose ratio remains relatively constant (within 10% of the value estimated at the
lowest simulated concentration) at external concentrations (ECs) below 95 mg/m3. The value of
the (24-hour continuous) HEC (BMDLio) used for RfC derivation was 14.3 mg/m3, and thus is
within the linear range. This supports the use of the Haber's law equation, Cn x t = k with n=l to
estimate HEC values for non-continuous exposures.
U.S. EPA (2002) notes that extrapolation from longer to shorter time durations will result in a
higher extrapolated exposure concentration value when using downward slope equations such as
Cn x t = k, especially when n = 1 or 0.8. When n = 3 in the equation, the downward slope is less
appreciable than for n = 1 or 0.8. For instance, the slope for the equation with n = 2.5 (equation
for carbon tetrachloride) is -0.1, while the slopes for the equations with n = 3 and n = 1 are -0.07
and -2, respectively based in a k value of 343. The slope of -0.1 for n = 2.5 suggests that the
extrapolated concentrations of carbon tetrachloride for shorter times of exposure are less shifted
to higher values because they are influenced by a much lower downward slope.
Conservatively, the BMDLio value for continuous exposures was extrapolated to shorter
exposure durations using the equation Cn x t = k, where an empirical value of n was determined
to be 2.5 on the basis of rat lethality data (Ten Berge et al.. 1986).
A benchmark MOE of 30 (based on UFh 10 and UFa 3) is used to evaluate risk for workers and
ONUs.
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Table 3-14.
PODs for C
ironic Inhalation Exposures based on Animal data
Study
Study
Details
Endpoint
POD
UFs/Dose Metric
Benchmark MOE
(Nasano et
al.. 2007a)
Chronic
inhalation
rat
Fatty
changes in
the liver
BMCLio[hec]: 14.3
mg/m3 for continuous
exposures, which is
equivalent to 31.1 mg/m3
for 8 hrs/d and 5 days
per week of exposure
and 26.4 mg/m3 for 12
hrs/d and 5 days per
week*
UFh 10
UFa 3
30
*Time adjustments based on Cn x t = k, where n = 2.5 and adjustment for 5 days/week exposures
3.2.5.2.3 PODs for Acute Dermal Exposures
Given the limited information on non-cancer effects after acute dermal toxicity from carbon
tetrachloride, the POD for acute dermal exposures is based on the only reasonably available
acute toxicity study with histopathological information on liver and kidney tissues (Kronevi et
al.. 1979). The study was found to be unacceptable in the systematic review due to the lack of
negative controls and small number of animal per dose group. However, the study findings
provide a rough comparison of liver and kidney changes from acute dermal exposure to carbon
tetrachloride during different time periods (i.e., 4 hrs, 19 hrs). The use of the study findings in
conjunction with findings from another dermal toxicity study with similar experimental
conditions and acceptable quality data (i.e., (Wahlberg and Boman. 1979)) were used to derive a
POD for acute dermal exposures. An alternative approach, in which the POD for acute dermal
exposures is extrapolated from the POD for chronic inhalation exposures results in a similar
POD for acute exposures (2,450 mg/kg vs 2,750 mg/kg).18 Extrapolation of the acute dermal
POD from acute inhalation POD was not performed because the critical acute inhalation effects
of neurotoxicity are influenced by the accessibility to brain tissue by inhaled carbon
tetrachloride.
Based on the assumption that induction of liver toxicity is unlikely for animals dermally exposed
for 4 hrs to 0.5 mL carbon tetrachloride from a skin depot of 3.1 cm2 (see section 3.2.5.1), an
acute dose for occluded conditions, which is associated with non-adverse liver effects was
estimated. Dose for occluded exposures = [(260 mg/cm2 x 3.1 cm2) / 0.440 kg ] - 4 hrs or 1,832
mg/kg - 4 hrs
A NOAEL value for the acute dermal exposure dose was then obtained by estimating how much
of the acute dose is absorbed in 4 hrs under by using the reasonably available dermal absorption
information for carbon tetrachloride. The available information includes a (underestimated)
percutaneous absorption rate for carbon tetrachloride in mice of 53.6 ± 9.3 nmoles/ minute/cm2
(Tsuruta. 1975). which shows dermal absorption of carbon tetrachloride has linear dependency to
18 presents a POD for chronic dermal exposures of 245 mg/kg-d based on inhalation exposure information.
Extrapolation of a POD for acute dermal exposures by multiplying the derived POD for chronic dermal exposures
by a factor of 10 results in a POD for acute dermal exposures of 2,450 mg/kg.
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the time and area of exposure and the experimental observations from Morgan et al., (1991)
showing that about 25% of a total dose was absorbed in a 24-hr period under occluded conditions
were used to extrapolate NOAEL for retained/absorbed carbon tetrachloride for acute dermal
exposures.
By considering the reasonably available animal evidence on dermal absorption (i.e., 25% of a
dermal dose is absorbed in 24 hrs, and linear time dependency for dermal absorption), a
conservative assumption of 6% of an applied dose of carbon tetrachloride under occluded dermal
conditions been absorbed in 4 hrs, was used to account for experimental underestimation.
Therefore, the estimated NOAEL for acute (retained/absorbed) for occluded dermal exposures =
1,832 mg/kg x 0.06 = 110 mg/kg-d.
This NOAEL for acute (retained/absorbed) occluded exposures can be adjusted to a larger
NOAEL value for non-occluded exposures to account for volatilization of carbon tetrachloride
during non-occluded dermal exposures. Loss of carbon tetrachloride from volatilization in non-
occluded scenarios results in the need for a higher amount of applied dose to reach effect levels.
The supplemental file (U.S. EPA. 2019b) explains that because carbon tetrachloride is a volatile
liquid, its dermal absorption depends on the type and duration of exposure. Where exposure is
not occluded, only a fraction of carbon tetrachloride that comes into contact with the skin will be
absorbed as the chemical readily evaporates from the skin. The default fraction of applied mass
that is absorbed for carbon tetrachloride is 0.04. This fractional absorption factor is estimated
based on a theoretical framework by Kasting and Miller (2006).
The NOAEL for non-occluded retained doses of carbon tetrachloride is estimated by dividing the
NOAEL of 110 mg/kg-d for occluded dermal exposures by the default absorbed fraction factor
of 0.04. Therefore, a NOAEL for acute non-occluded retained doses of 2,750 mg/kg was
estimated.
Table 3-15. POPs for Acute Dermal Exposures (non-occluded)
Study
Study
Details
Endpoint
POD
UFs/Dose
Metric
Benchmark MOE
(Kronevi et
al.. 1979:
Wall 1 be re
Acute
dermal
studies in
guinea
pigs
Histopathological
changes in the
liver
2,750 mg/kg-d
(estimated
retained/ab sorb ed
dose per day)
UFh 10
UFa 10
100
and Boman.
1979)
3.2.5.2.4 PODs for Chronic Dermal Exposures
The chronic inhalation HEC was converted to a dermal HED for non-occluded retained doses by
using a modified equation based on (Jongeneel. 2012) equation (Equation 3-1) for transposing an
inhalation Occupational exposure level (OEL) to a dermal OEL. In the modified equation a
dermal absorption factor is not used, which allows the estimation of the absorbed dermal dose
instead of the OEL. This modification is necessary because dermal exposures in 2.4.1.8 are
retained doses.
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Equation 3-1. HEDDermal HEChuman,respiratory ^ Vrate ^ T ^ ftbsOFptlOIl (inhalation)/
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In summary, the MS-combo model could not be applied because the dose metric is
different for the two different tumor types, and even if they could be combined, the risk
estimates would not change.
2- nonlinear approach with exposures exceeding the POD (18 mg/m3, lower 95% bound
on exposure associated with 10% extra risk) for continuous exposure, because above this
level, the fitted dose-response model better characterizes what is known about the
carcinogenicity of carbon tetrachloride. This threshold approach is used in this risk
evaluations for high exposures based on a benchmark MOE of 30 (UFh =10 and UFa =
3).
Cancer Slope Factor for Dermal Exposures
To avoid uncertainties related to the first-pass biotransformation of carbon tetrachloride from
oral exposures, a cancer slope factor for dermal exposures was derived using the IUR of
6 x 10"6 per [j,g/m3 and similar approach presented in section 3.2.5.2.4.
Starting with time adjusted IUR of 6x 10"6 per [j,g/m3
• Adjusting for a default worker ventilation rate of 1.25 m3 per hour for light activities for
8 hrs/day (10 m3/day).
o 6 x 10"6 per [j,g/m3 x 1 day/10 m3 = 6 x 10"7 per [j,g/d
• Adjusting for average worker bodyweight of 80 kg
o 6 x 10"7 per [j,g/d x 80 kg = 5 x 10"5 per [j,g/kg-d or 5 x 10"2 per mg/kg-d
• Adjusting for absorption: 63% inhalation absorption.
o Dermal Cancer Slope Factor = (5 x 10"2per mg/kg-d) (1/63) = 8 x 10"4per mg/kg-
d
3.2.5.3 PODs for Human Health Hazard Endpoints and Confidence Levels
Section 3.2.5.2 summarizes the PODs derived for evaluating human health hazards from acute
and chronic inhalation scenarios, acute dermal scenarios and PODs extrapolated from inhalation
studies to evaluate human health hazards from chronic dermal scenarios. EPA has also
determined confidence levels for the acute, non-cancer chronic and cancer chronic values used in
the risk evaluation. These confidence levels consider the data quality ratings of the study chosen
as the basis of dose-response modeling and also consider the strengths and limitations of the
body of evidence including the strengths and limitations of the human, animal and MOA
information to support the endpoint both qualitatively and quantitatively.
Confidence Levels
NAS/AEGL considered several reports providing data on nonlethal effects of acute exposure of
humans to carbon tetrachloride to establish an AEGL-2 value. Some of the reports include Davis
(1934). which includes a series of controlled exposure experiments that allowed the
determination of a no-effect level for non-lasting CNS effects (i.e., dizziness). The data set was
determined to provide suitable data to derive AEGL-2 values by NAS/AEGL. Overall, there is
high confidence in this endpoint because the quantitative dataset consists of a series of controlled
exposure experiments that identify a no-effect level for CNS effects in humans. EPA found that
this study is an acceptable study with low data quality based upon our review using the
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systematic review protocol. Further information on the data quality evaluation of this study can
be found in the Draft Risk Evaluation for Carbon Tetrachloride, Systematic Review
Supplemental File: Data Quality Evaluation of Epidemiological Studies. Docket EPA-HO-
OPPT-2019-0499 (U.S. EPA, 2019g).
For the chronic non-cancer endpoint, confidence in the Nagano et al., (2007a) the principal study
is high. According to EPA (2010) and systematic review for this risk evaluation, this chronic
study was well conducted, using two species and 50 animals/sex/group. The chronic study was
preceded by a 13-week subchronic study, and an extensive set of endpoints was examined in
both studies. Thus, EPA has high confidence in the chronic non-cancer endpoint based on liver
effects.
For the chronic cancer endpoint, the same high-quality chronic cancer bioassay in rats and mice
provided data adequate for dose-response modeling. The IUR is based on pheochromocytomas
observed in only one of the rodent species, mice. Furthermore, the cancer MOA for carbon
tetrachloride is not fully elucidated, especially at low doses. Thus, EPA has medium confidence
in the chronic cancer endpoint and dose-response model used in this risk evaluation.
Table 3-17. Summary of PODs for Evaluating Human Health Hazards from Acute and
Chronic Inhalation and Dermal Exposure Scenarios
Exposure
Route
Hazard
Endpoint
Value
Hazard
POD/HEC
Units
Benchmark
MOE
Basis for
Selection
Key Study
Temporary
CNS effects
4 hrs-single
exposure
360
mg/m3-8hr
10
(UFh 10)
Study duration and
endpoint relevant to
worker acute
exposures; in
agreement with
AEGL acute
exposure guidelines
(Davis. 1934)
Inhalation
Non-cancer
Extrapolated
BMCLio[hec]
31.1
mg/m3 - 8
hrs
30
(UFh 10; UFa 3)
POD relevant for
liver effects; in
agreement with
IRIS non-cancer
conclusions
(Naaano et al..
2007a)
Cancer
Inhalation
Unit Risk
(IUR)
6 x 10"6
(Hg/m3)"1
1 in 104 for
occupational risk
In agreement with
IRIS cancer
conclusions for
carbon tetrachloride
(Naaano et al.,
2007a)
Short term-
Liver
effects
Single
exposure
2,750
mg/kg-d
100
(UFh 10; UFa
10)
POD relevant for
liver effects
(Kronevi et al..
1979)
(Wahlbera and
Boman, 1979)
Dermal
Non-cancer
Extrapolated
Human
Equivalent
Dose (HED)
245
mg/kg-d
30
(UFh 10;
UFa 3)
POD relevant for
liver effects
(Naaano et al..
2007a)
Cancer
Cancer Slope
Factor (CSF)
8 x 10"4
(derived from
IUR)
(mg/kg-d)"1
1 in 104 for
occupational risk
In agreement with
IRIS cancer
conclusions for
carbon tetrachloride
(Naaano et al..
2007a)
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Uncertainty Factors = LTF a = interspecies LTF; UFh = intraspecies UF
3.2.5.4 Potentially Exposed or Susceptible Subpopulations
EPA evaluated reasonably available information to identify human subpopulations that may have
greater susceptibility to carbon tetrachloride than the general population. Because the scope of
this human health assessment is limited to workers and ONUs, this section focuses on identifying
subpopulations within workers and ONUs who may be have greater susceptibility to carbon
tetrachloride. This hazard assessment does not address factors that may make non-
workers/ONUs more susceptible to carbon tetrachloride. Based on reasonably available
information, some individuals in the workplace may be more biologically susceptible to the
effects of carbon tetrachloride due to age, alcohol consumption, nutritional status, pre-existing
disease (e.g. diabetes or liver disease), exposure to other chemicals, and genetic variation.
Metabolism of carbon tetrachloride to reactive metabolites by cytochrome p450 enzymes
(particularly CYP2E1 and CYP3A) is hypothesized to be a key event in the toxicity of this
compound. Differences in the metabolism due to alcohol consumption, exposure to other
chemicals, age, nutritional status, genetic variability in CYP expression, or impaired liver
function due to liver disease can increase susceptibility to carbon tetrachloride (U.S. EPA. 2010).
For example, alcohol is known to induce CYP2E1 expression. Cases of acute toxicity from
occupational exposures indicate that heavy drinkers are more susceptible to carbon tetrachloride
and this observation has been verified in numerous animal studies. Exposure to other chemicals
that induce p450 enzymes, including isopropanol, methanol, acetone, methyl ethyl ketone,
methyl isobutyl ketone, 2-butanone, phenobarbital, methamphetamine, nicotine,
trichloroethylene, polychlorinated and polybrominated biphenyls, DDT, mirex, and chlordecone
have also been shown to potentiate carbon tetrachloride liver toxicity (U.S. EPA. 2010; AT SDR.
2005).
Age can influence susceptibility to carbon tetrachloride due to differences in metabolism,
antioxidant responses, and reduced kidney function in older adults. While lower CYP expression
may reduce susceptibility of older adults to carbon tetrachloride in some tissues, reduced kidney
function and increased CYP3A activity in the liver (indicated by animal studies) suggest that
older populations could be at greater risk of carbon tetrachloride-associated kidney damage (U.S.
EPA. 2010).
Nutrition has also been shown to influence susceptibility to carbon tetrachloride in animals. Food
restriction has been shown to increase liver toxicity of carbon tetrachloride. Diets low in
antioxidants increase lipid peroxidation and liver damage in following carbon tetrachloride
exposure (reversed with antioxidant supplementation) and zinc deficient diets increase carbon
tetrachloride-induced liver toxicity (U.S. EPA. 2010).
The AEGL-2 values (See section 3.2.3.1), which are the basis for the PODs for acute inhalation
exposures in this draft risk evaluation, were derived using an intraspecies uncertainty factor of 10
to account for individuals who may be more susceptible to the toxic effects of carbon
tetrachloride, including greater potential of carbon tetrachloride-induced toxicity in individuals
with histories of alcohol usage. Susceptibility to carbon tetrachloride due to elevated (i.e.,
moderate-high) alcohol use is in agreement with the known dispositional potentiation of carbon
tetrachloride toxicity by inducers of cytochrome CYP2E1 enzymes. The AEGL document states
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that the variability in response to carbon tetrachloride is emphasized by the fact that an estimated
exposure at 63 ppm-h was fatal in a heavy drinker whereas controlled exposures at 190 ppm-h
were without effect for individuals not categorized as heavy drinkers.
4 RISK CHARACTERIZATION
4.1 Environmental Risk
EPA integrated fate, exposure, and environmental hazard information when characterizing the
environmental risk of carbon tetrachloride. As stated in section 2.1, carbon tetrachloride is not
expected to bioconcentrate in biota or accumulate in wastewater biosolids, soil, sediment, or
biota. Releases of carbon tetrachloride to the environment are likely to volatilize into the
atmosphere, where it will photodegrade under stratospheric conditions. It may migrate to
groundwater, where it will slowly hydrolyze. Section 2.1 also explains that the bioconcentration
potential of carbon tetrachloride is low. EPA modeled environmental exposure with surface
water concentrations of carbon tetrachloride ranging from 4.9E-05 |ig/L to 1.3E+02 |ig/L for
acute exposures and 4.1E-06 |ig/L to 1.0E+01 |ig/L for chronic exposures from facilities
releasing the chemical to surface water. The modeled data represents estimated concentrations
near facilities that are actively monitoring and reporting carbon tetrachloride releases to surface
receiving water via EPA's Discharge Monitoring Reports as required under the National
Pollutant Discharge Elimination System (NPDES) permitting rules.
EPA concludes that carbon tetrachloride poses a hazard to environmental aquatic receptors
(section 3.1). Amphibians are the most sensitive taxa for acute and chronic exposures,
respectively. For acute exposures, a hazard value of 0.9 mg/L was established for amphibians
using data on teratogenesis leading to lethality in frog embryos and larvae. For acute exposures,
carbon tetrachloride also has hazard values for fish as low as 10.4 mg/L and for freshwater
aquatic invertebrates as low as 11.1 mg/L. For chronic exposures, carbon tetrachloride has a
hazard value for amphibians of 0.03 mg/L based on teratogenesis and lethality in frog embryos
and larvae. For chronic exposures, carbon tetrachloride also has hazard values as low as 1.97
mg/L for fish and 1.1 mg/L (acute to chronic ratio of 10) for aquatic invertebrates. In algal
studies, carbon tetrachloride has hazard values ranging from 0.07 to 23.59 mg/L.
EPA considered the biological relevance of the species that the COCs were based on when
integrating the COCs with surface water concentration data to produce risk quotients (RQs). For
example, life-history and the habitat-use influence the likelihood of exposure above the hazard
benchmark in an aquatic environment. In general, amphibian distribution is typically limited to
freshwater environments. Larvae of the amphibian species (Lithobates sp. and Rana sp.)
evaluated for hazards from chronic exposure (see Appendix G.2) can occupy a wide range of
freshwater habitats including wetlands, lakes, springs, and streams throughout development and
metamorphosis. However, as adults these species are semi-aquatic and may interact with surface
water for fewer days per year. In contrast, fish occupy a wide range of freshwater habitats
throughout their entire life cycle. If hazard benchmarks are exceeded by both larval amphibians
and fish from a modeled and estimated chronic exposure, it provides additional evidence that the
site-specific releases could affect that specific aquatic environment.
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A total of 14 aquatic environmental hazard studies were reviewed and determined to have
acceptable data quality for carbon tetrachloride. EPA's evaluation of these studies was either
high or medium during data quality evaluation (Appendix G). The document Risk Evaluation for
Carbon Tetrachloride, Systematic Review Supplemental File: Data Quality Evaluation of
Environmental Hazard Studies. EPA, (2019e) presents details of the data evaluations for each
study, including scores for each metric and the overall study score.
For this risk evaluation, EPA conducted a multi-year analysis of 21 facilities that released the
highest concentration of carbon tetrachloride from 2014-2018 as reported in the EPA Discharge
Monitoring Reports. Given carbon tetrachloride's conditions of use under TSCA outlined during
problem formulation (U.S. EPA. 2018d). EPA determined that significant environmental
exposures are not expected to exceed the acute and chronic COCs for aquatic species, as
presented in section 3.1.2. Environmental releases of carbon tetrachloride occur through disposal
from industrial/commercial facilities as well as from POTWs. Sources of carbon tetrachloride
from POTWs releases may not be tied to a specific condition of use given that POTWs may have
multiple release sources. However, EPA is confident that the risks from releases of carbon
tetrachloride include all conditions of use considered within the scope of the risk evaluation
because EPA is using the worst-case, high end exposures and modeled surface water
concentrations.
At problem formulation, EPA made refinements to the conceptual models resulting in the
elimination of the sediment exposure pathway from further analysis. Based on physical chemical
and fate properties of carbon tetrachloride, EPA did not conduct a full quantitative assessment to
further evaluated exposure to sediment-dwelling aquatic organisms through the sediment. There
is no data to suggest that sediment-dwelling aquatic organisms are exposed to carbon
tetrachloride.
During problem formulation, exposure pathways to terrestrial species (e.g., through soil, land-
applied biosolids, and ambient air) were determined to be adequately assessed and effectively
managed under programs of other environmental statutes administered by EPA. These pathways
were excluded from the scope of this risk evaluation. Thus, environmental hazard data sources
on terrestrial organisms were excluded from data quality evaluation.
4.1.1 Aquatic Pathway
The purpose of the environmental risk characterization is to determine whether there are risks to
the aquatic environment from levels of carbon tetrachloride found in surface water based on the
fate properties, relatively high potential for release, and the availability of environmental
monitoring data and hazard data. Although EPA did not calculate risks to the aquatic
environment at problem formulation, EPA conducted further analysis of the environmental
release pathway in this risk evaluation during data quality evaluation. Due to the physical,
chemical, and fate properties of carbon tetrachloride in the environment (e.g., volatility, water
solubility) and a quantitative comparison of hazards and exposures for aquatic organisms, EPA
has high confidence that there are no environmental risks to the aquatic species posed by carbon
tetrachloride under the conditions of use within the scope of the risk evaluation. The results of
the analyses are presented in Appendix E and Appendix G.
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The environmental risk of carbon tetrachloride is characterized by calculating risk quotients or
RQs (U.S. EPA. 1998). The RQ is defined as:
RQ = Environmental Concentration / Effect Level
An RQ equal to 1 indicates that the exposures are the same as the concentration that causes
effects. If the RQ is above 1, the exposure is greater than the effect concentration. If the RQ is
below 1, the exposure is less than the effect concentration. The Concentrations of Concern
(COCs) for aquatic organisms shown in Table 4-1 were used to calculate RQs. The
environmental concentration for surface water is determined based on experimental test data of
carbon tetrachloride (Appendix E and Appendix G).
Table 4-1. Concentrations of Concern (COCs) for Environmental Toxicity
Environmental
Toxicity
Most Sensitive Test
Assessment
Factor**
Concentration of
Concern (COC)*
Acute Toxicity,
aquatic
organisms
9-day amphibian LCso
10
90 |ig/L
Chronic
Toxicity,
aquatic
organisms
9-day amphibians LCio
10
3 |ig/L
Algae
72-hour algal ECio
10
7 Hg/L
*The Concentration of Concern is derived from the most sensitive acute, chronic, and algal toxicity values (hazard
values) divided by an assessment factor of 10.
**Assessment factors are applied to account for variation within and across taxa.
As described in Appendix E and Appendix G, EPA used model exposure data that was calculated
from E-FAST, monitored data from Discharge Monitoring Reports (DMR), and aquatic COCs
from the available hazard data to determine the risk of carbon tetrachloride to aquatic species
using the RQ method.
EPA quantitatively evaluated risk to aquatic organisms from exposure to surface water and
assessed the available monitoring data for carbon tetrachloride to adequately evaluate any
potential environmental risk to aquatic organisms posed by carbon tetrachloride. The results of
the review are summarized in Appendix E. All facilities were modeled in E-FAST. Facilities
with an RQ > 1 for the acute COC, or an RQ > 1 and 20 days or more of exceedance for the
chronic and algal COCs suggest the potential for environmental risks posed by carbon
tetrachloride.
EPA used the acute COC (90 |ig/L), chronic COC (3 |ig/L), and algal COC (7 |ig/L) based on
environmental toxicity LCso from (Brack and Rottler. 1994). LCio from (Black et al.. 1982; Birge
et al.. 1980). and ECio from (Brack and Rottler. 1994) endpoint values, respectively, to represent
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the lowest bound of all carbon tetrachloride data available in the public domain and provide the
most conservative hazard values.
EPA estimated carbon tetrachloride concentrations in surface water resulting from individual
industrial direct discharges as well as from indirect discharges that receive and treat wastewater
from multiple facilities and sources such as the municipal Publicly-Owned Treatment Works
(POTWs). EPA compiled five years of carbon tetrachloride NPDES permit Discharge
Monitoring Report (DMR) release data (2014 through 2018). This expanded data set provides a
range of facilities and a range of discharge amounts for this time period within the United States.
EPA used the Probabilistic Dilution Model (PDM) in E-FAST to estimate site-specific receiving
water concentrations of carbon tetrachloride at the point of discharge. Based on carbon
tetrachloride physical-chemical properties, EPA anticipates that in surface waters, carbon
tetrachloride will dissipate and volatilize. The E-FAST model, however, did not include these
processes in surface water estimates, thereby providing conservative estimates. The largest
releases of carbon tetrachloride were modeled for releases over 20 days and 250 days per year as
estimates of releases that could lead to chronic risk. The 20-day time frame was derived from
partial life cycle tests (e.g., daphnid chronic and fish early life stage tests) that typically range
from 21 to 28 days in duration and the 250-day time frame represents annual full-time industrial
operations. The surface water concentrations are summarized in Table 4-2 below.
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4574 Table 4-2. Modeled Facilities Showing Acute, Chronic, Algae Risk from the Release of Carbon Tetrachloride; RQ Greater
4575 Than One are Shown in Bold
NPDES
Facility
Name
Amount
Discharged
for 20 days
(kg/day)
20 Day
Stream
Cone.
(fig/L)
Days
Acute
COCa
Exceeded
(PDM)
RQ for
Amphibian
Acute COC
(90 Jig/L)
RQ for
Algae
COC
(7 ng/L)
Amount
Discharged
for 250 days
(kg/day)
250 Day
Stream
Cone.
(fig/L)
Days
Chronic
COCb
Exceeded
(PDM)
RQ for
Amphibian
Chronic
COC
(3 ng/L)
RQ for
Algae
COC
(7 ng/L)
TX0021458
Fort Bend
County
WCID2
N/A
N/A
N/A
N/A
N/A
0.10
1.0E+01
0
3.4E+00
1.5E+00
AL0001961
AKZO
Chemicals,
Inc.
5.7
3.1E-01
0
3.4E-03
4.4E-02
0.46
2.5E-02
0
8.3E-03
3.5E-03
LA0000329
Honeywell,
Baton Rouge
0.20
8.1E-04
0
9.0E-06
1.2E-04
0.02
6.5E-05
0
2.2E-05
9.3E-06
LA0005401
ExxonMobil,
Baton Rouge
0.01
4.0E-04
0
4.5E-06
5.7E-05
0.01
3.2E-05
0
1.1E-05
4.6E-06
OH0029149
Gabriel
Performance
0.19
45
0
5.0E-01
6.4E+00
0.02
3.6
2
1.2E+00
5.1E-01
WV0004359
Natrium Plant
0.29
3.4E-02
0
3.8E-04
4.9E-03
0.02
2.9E-03
0
9.5E-04
4.1E-04
CA0107336
Sea World,
San Diego0
OH0007269
Dover
Chemical
Corp
1.8
1.3E+2
0
1.4E+00d
1.8E+01
0.14
10
15
3.3E+00
1.4E+00
LA0006181
Honeywell,
Geismar
0.18
7.3E-04
0
8.1E-06
1.0E-04
0.02
6.1E-05
0
2.0E-05
8.7E-06
LA0038245
Clean
Harbors,
Baton Rouge
0.33
1.3E-03
0
1.5E-05
1.9E-04
0.03
1.0E-04
0
3.5E-05
1.5E-05
TXO119792
Equistar
Chemicals LP
0.68
4.4
0
4.9E-02
6.3E-01
0.05
3.5E-01
0
1.2E-01
5.0E-02
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NPDES
Facility
Name
Amount
Discharged
for 20 days
(kg/day)
20 Day
Stream
Cone.
(fig/L)
Days
Acute
COCa
Exceeded
(PDM)
RQ for
Amphibian
Acute COC
(90 Jig/L)
RQ for
Algae
COC
(7 jig/L)
Amount
Discharged
for 250 days
(kg/day)
250 Day
Stream
Cone.
(Hg/L)
Days
Chronic
COCb
Exceeded
(PDM)
RQ for
Amphibian
Chronic
COC
(3 jig/L)
RQ for
Algae
COC
(7 jig/L)
WV0001279
Chemours
Chemicals
LLC
0.11
1.1E0-
02
0
1.2E-04
1.6E-03
0.01
8.0E-04
0
2.7E-04
1.2E-04
TX0007072
Eco Services
Operations
0.26
49
0
5.4E-01
7.0E+00
0.02
3.9
2
1.3E+00
5.6E-01
KY0024082
Barbourville
STP
N/A
N/A
N/A
N/A
N/A
0.01
3.5E-01
0
1.2E-01
5.0E-02
WA0030520
Central
Kitsap
WWTP
0.06
7.0E+01
N/A
7.76E-01
10.0E+0
0
0.01
5.8E-01
0
1.9E-01
8.3E-02
M00002526
Bayer Crop
Science
0.05
5.9E-01
0
6.56E-03
8.4E-02
0.0
4.7E-02
0
1.6E-02
6.7E-03
KY0027979
Eddyville
STP
N/A
N/A
N/A
N/A
N/A
0.01
1.0
1
3.4E-01
1.5E-01
KY0103357
Richmond
Silver Creek
STP
N/A
N/A
N/A
N/A
N/A
0.0
3.1E-01
0
1.0E-01
4.4E-02
KY0003603
Arkema Inc.
0.02
9.5E-04
0
1.1E-05
1.4E-04
0.0
8.7E-05
0
2.9E-05
1.2E-05
KY009161
Caveland
Enviromnenta
1 Auth
0.03
8.4E-02
0
9.3E-04
1.2E-02
0.0
5.6E-03
0
1.9E-03
8.0E-04
LA0002933
Occidental
Chem Corp,
Geismar
0.01
4.9E-05
0
5.4E-07
6.9E-06
0.0
4.0E-06
0
1.4E-06
5.8E-07
4576 a Acute COC = 90 ng/L: acute RQs for POTW facilities were N/A because the days of the releases were assumed to be over 20 days.
4577 bClironic COC = 3 ng/L
4578 °San Diego Sea World facility (CA0107336) was not included in the analysis since the reported level is above permit discharge limits; noncompliance and spills
4579 are not in the scope of this risk evaluation.
4580 dAlthough the acute RQ = 1.4, the days of exceedances is zero because of the 20-day averaging period for acute exposures.
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4584
4585
4586
4587
4588
4589
4590
4591
4592
4593
4594
4595
4596
4597
4598
4599
4600
4601
4602
4603
4604
4605
4606
4607
4608
4609
4610
4611
4612
4613
4614
4615
4616
4617
4618
4619
4620
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4.1.2 Risk Estimation for Aquatic Environment
To characterize potential risk from exposures to carbon tetrachloride, EPA calculated RQs based
on modeled data from E-FAST for sites that had surface water discharges according to carbon
tetrachloride DMR data (Appendix E).
All facilities assessed in this risk evaluation were modeled in E-FAST. The RQs and days of
exceedance that indicate risk for aquatic organisms (facilities with an RQ > 1 for the acute COC,
or an RQ > 1 and 20 days or more of exceedance for the chronic and algal COCs) for all facilities
analyzed in this risk evaluation are presented in Table 4-2.
Using conservative scenarios, EPA concluded that the surface water concentrations did not
exceed the acute COC (i.e., acute RQs < 1) for aquatic species for all sites except one site at
Dover Chemical Corp (i.e., worst-case scenario; RQ = 1.4), as summarized in Table 4-2. EPA
determined there is not an acute aquatic concern for carbon tetrachloride after further review of
the Dover Chemical Corp site (see Section 2).
The predicted exposure concentrations in surface water of carbon tetrachloride (from 4.9E-05
|ig/L to 1.3E+02 |ig/L for acute exposures and 4.1E-06 |ig/L to 1.0E+1 |ig/L for chronic
exposures; see 7Appendix E) were based on conservative assumptions, including 0% removal of
carbon tetrachloride by the waste water treatment facility. As explained in section 2.1, the EPI
Suite™ STP module estimates that about 90% of carbon tetrachloride in wastewater will be
removed by volatilization and 2% by adsorption. Also due to its physical-chemical properties,
carbon tetrachloride is not anticipated to bioaccumulate in fish (BCF 30- 40) thus there is no
bioconcentration or bioaccumulation concern. Although the chronic COC was exceeded by four
facilities ranging from 1.2 to 3.4 (i.e., worst-case scenario; RQ = 3.4) and the algae COC was
exceeded by four facilities ranging from 6.4 to 18 based on the 20-day stream concentration and
by two facilities ranging from 1.4 to 1.5 based on the 250-day stream concentration, these carbon
tetrachloride releases are not continuously released over time (i.e., chronic exposure). Frequency
and duration of exposure also affects potential for adverse effects in aquatic organisms,
especially for chronic exposures. Therefore, the number of days that a COC was exceeded was
also calculated using E-FAST. The days of exceedance modeled in E-FAST are not necessarily
consecutive and could occur sporadically throughout the year. For carbon tetrachloride,
continuous aquatic exposures are more likely for the longer exposure scenarios (i.e., 100-365
days/yr of exceedance of a COC), and more of an interval or pulse exposure for shorter exposure
scenarios (i.e., 1-99 days/yr of exceedances of a COC). Due to the volatile properties of carbon
tetrachloride, it is more likely that a chronic exposure duration will occur when there are long-
term consecutive days of release versus an interval or pulse exposure which would more likely
result in an acute exposure duration. For all the sites analyzed in this risk evaluation of carbon
tetrachloride, all of the release sites had < 20 days of exceedance of the chronic COC.
Consequently, EPA determined there is not an acute, chronic, algal concern of carbon
tetrachloride from the conditions of use for aquatic organisms.
4.1.3 Risk Estimation for Sediment
EPA did not quantitatively estimate sediment-bound carbon tetrachloride exposure to sediment-
dwelling aquatic organisms. On-topic hazard studies for sediment exposures are not available in
the scientific literature (and would not be expected due to the physical, chemical, and fate
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4627
4628
4629
4630
4631
4632
4633
4634
4635
4636
4637
4638
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4640
4641
4642
4643
4644
4645
4646
4647
4648
4649
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
properties of the chemical). Carbon tetrachloride is not expected to partition to or be retained in
sediment and is expected to remain in aqueous phase due to its water solubility (793 mg/L) and
low partitioning to organic matter (log Koc = 0.79 - 1.93 (aquifer sediments) and 1.67 (marine
and estuary sediments)) (see section 2.1). According to this reasonably available information,
carbon tetrachloride is likely to be in pore water and not adsorbed to the sediment organic matter
because the chemical has low partitioning to organic matter. Thus, qualitatively, sediment-bound
carbon tetrachloride exposure concentrations are expected to be low. Consequently, EPA
determined there is not an acute or chronic sediment-bound concern of carbon tetrachloride from
the COUs and did not further analyze exposure pathways to ecological sediment-dwelling
species in the risk evaluation.
4.1.4 Risk Estimation for Terrestrial
During problem formulation, EPA made refinements to the conceptual models resulting in the
elimination of the terrestrial exposure pathway. As explained in section 2.5.3.2 of the problem
formulation (U.S. EPA. 2018d). exposure to terrestrial organisms was removed from the scope of
the evaluation. This exposure pathway is under programs of other environmental statutes,
administered by EPA, which adequately assess and effectively manage exposures and for which
long-standing regulatory and analytical processes already exist.
4.2 Human Health Risk
4.2.1 Risk Estimation Approach
Development of the carbon tetrachloride hazard and dose-response assessment used for the
selection of PODs for non-cancer and cancer endpoints and the benchmark dose analyses used in
the risk characterization are found in section 3.2.5.2.
The use scenarios, populations of interest and toxicological endpoints that were selected for
determining potential risks from acute and chronic exposures are presented in Table 4-3, Table
4-4, Table 4-5 and Table 4-6.
Table 4-3. Use Scenarios, Populations of Interest and Toxicological Endpoints for Assessing
Occupational Risks Following Acute Inhalation Exposures to Carbon Tetrachloride
Populations and Toxicological Approach
Occupational Use Scenarios of Carbon
Tetrachloride
Population of Interest and Exposure
Scenario:
Occupational Users:
Adult worker (>16 years old) exposed to carbon tetrachloride
for a single 8-hr exposure.
Occupational Non-users:
Adult (>16 years old) exposed to carbon tetrachloride
indirectly by being in the same work area of building.
Health Effects of Concern, Concentration
and Time Duration
Non-Cancer Health Effects: CNS
1. Non-Cancer Hazard values or Point of Departures
(PODs): 58 ppm-8 hr (or 360 mg/m3 - 8 lir) for temporary
disabling CNS effects;
Cancer Health Effects: Cancer risks folio wins acute
exposures were not estimated. Relationship is not known
between a single short-term exposure to carbon tetrachloride
and the induction of cancer in humans.
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4656
4657
4658
4659
4660
4661
4662
4663
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Populations and Toxicological Approach
Occupational Use Scenarios of Carbon
Tetrachloride
Uncertainty Factors (UF) used in Non-
Cancer Margin of Exposure (MOE)
calculations
UFh= 10 (based on human data and susceptibility from
alcohol consumption)
Total UF=Benchmark MOE= 10
Notes:
Adult workers (>16 years old) include both healthy female and male workers.
LTFH=intraspecies UF
Table 4-4. Use Scenarios, Populations of Interest and Toxicological Endpoints for Assessing
Occupational Risks Following Chronic Inhalation Exposures to Carbon Tetrachloride
Populations and Toxicological Approach
Occupational Use Scenarios of Carbon
Tetrachloride
Population of Interest and Exposure
Scenario:
Occupational Users:
Adult worker (>16 years old) exposed to carbon
tetrachloride for the entire 8-hr workday for 250 days per
year for 40 working years.
Occupational Non-users:
Adult worker (>16 years old) repeatedly exposed to indirect
carbon tetrachloride exposures by being in the same work
area of building.
Health Effects of Concern, Concentration
and Time Duration
Non-Cancer
1. Non-cancer health effects: Fatty changes in the liver
2. Non-Cancer Hazard values or Point of Departure (POD):
BMCLio[HEC]: 14.3 mg/m3 for continuous exposures,
which is equivalent to 31.1 mg/m3 for 8 lirs, EPA IRIS
Assessment (U.S. EPA. 2010)
Cancer
1. Cancer health effects: carbon tetrachloride is classified as
"likely to be carcinogenic to humans"
2. Cancer Inhalation Unit Risk (IUR): 6 x 10~6per |ig/m3 for
lifetime continuous exposure
Uncertainty Factors (UF) Used in Non-
Cancer Margin of Exposure (MOE)
calculations
(UFh= 10) x(UFa=3) = 30
Total UF=Benchmark MOE=30
Cancer Benchmark
1 in 104 cancer risk for worker populations
Notes: Adult workers (>16 years old) include both healthy female and male workers. UFH=intraspecies UF;
UFA=interspecies UF
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4668
4669
4670
Table 4-5. Use Scenarios, Populations of Interest and Toxicological Endpoints for Assessing
Populations and Toxicological Approach
Occupational Use Scenarios of Carbon
Tetrachloride
Population of Interest and Exposure
Scenario:
Occupational Users:
Adult worker (>16 years old) exposed to carbon tetrachloride
for a single 8-hr exposure.
Health Effects of Concern, Concentration
and Time Duration
Non-Cancer Health Effects: CNS
1. Non-Cancer Hazard values or Point of Departures
(PODs): 2,750 mg/kg-d for liver effects
Cancer Health Effects: Cancer risks folio wins acute
exposures were not estimated. Relationship is not known
between a single short-term exposure to carbon tetrachloride
and the induction of cancer in humans.
Uncertainty Factors (UF) used in Non-
Cancer Margin of Exposure (MOE)
calculations
(UFh= 10) x (UFa = 10) = 100
Total UF=Benchmark MOE=100
Notes:
Adult workers (>16 years old) include both healthy female and male workers.
UFH=intraspecies UF; UFA=interspecies UF
Table 4-6. Use Scenarios, Populations of Interest and Toxicological Endpoints for Assessing
Populations and Toxicological Approach
Occupational Use Scenarios of Carbon
Tetrachloride
Population of Interest and Exposure Scenario:
Occupational Users:
Adult worker (>16 years old) exposed to carbon
tetrachloride for the entire 8-hr workday for 250 days per
year for 40 working years.
Health Effects of Concern, Concentration and
Time Duration
Non-Cancer
1. Non-cancer health effects: Fatty changes in the liver
2. Non-Cancer POD: 245 mg/kg-d based on route to
route extrapolation from BMCLio[hec]: 14.3 mg/m3 for
continuous exposures.
Cancer
1. Cancer health effects: carbon tetrachloride is
classified as "likely to be carcinogenic to humans"
2. Cancer Slope factor derived from Inhalation Unit Risk
(IUR) of 6 x 10"6per |ig/m3 for lifetime continuous
exposure
Uncertainty Factors (UF) Used in Non-Cancer
Margin of Exposure (MOE) calculations
(UFh= 10) x (UFa =3) = 30
Total UF=Benchmark MOE=30
Cancer Benchmark
1 in 104 cancer risk for worker populations
Notes: Adult workers (>16 years old) include both healthy female and male drinking workers. The risk evaluation
for repeated exposures focused on the most sensitive life stage in humans, which is alcohol drinkers (see section
3.2.3.1) UFH=intraspecies UF; UFA=interspecies.
UFH=intraspecies UF; UFA=interspecies UF
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4674
4675
4676
4677
4678
4679
4680
4681
4682
4683
4684
4685
4686
4687
4688
4689
4690
4691
4692
4693
4694
4695
4696
4697
4698
4699
4700
4701
4702
4703
4704
4705
4706
4707
4708
4709
4710
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EPA used a Margin of Exposure (MOE) approach to identify potential non-cancer risks. The
MOE is the ratio of the non-cancer POD divided by a human exposure dose, which is then
compared to a benchmark MOE. If the calculated MOE is less than the benchmark MOE, this
indicates potential risk to human health, whereas if the calculated MOE is equal to or greater
than the benchmark MOE, it suggests that the risks are negligible.
Acute or chronic MOEs (MOEaCute or MOEchronic) were used in this assessment to estimate non-
cancer risks using Equation 4-1.
Equation 4-1. Equation to Calculate Non-Cancer Risks Following Acute or Chronic
Exposures Using Margin of Exposures
MOEacute or chronic — Non-cancer Hazard value (POD)
Human Exposure
Where:
MOE
Hazard value (POD)
Human Exposure
= Margin of exposure (unitless)
= NOAEC or HEC (mg/m3)
= Exposure estimate (in mg/m3) from occupational
exposure assessment
The Acute Exposure Concentration (AEC) was used to estimate acute/short-term inhalation risks,
whereas the Average Daily Concentration/Dose (ADC)/D) was used to estimate chronic non-
cancer inhalation/dermal.
EPA used MOEs19 to estimate acute and chronic risks for non-cancer based on the following:
1. the HECs/HEDs identified for the highest quality studies within each health effects domain;
2. the endpoint/study-specific UFs applied to the HECs/HEDs per the review of the EPA
Reference Dose and Reference Concentration Processes (U.S. EPA. 2002): and
3. the exposure estimates calculated for carbon tetrachloride conditions under the conditions
of use (see section 2.4).
MOEs allow for the presentation of a range of risk estimates. The occupational exposure
scenarios considered both acute and chronic exposures. Different adverse endpoints were used
based on the expected exposure durations. For occupational exposure calculations, the 8 hr and
12 hr TWAs was used to calculate MOEs for risk estimates for acute and chronic exposures. The
occupational inhalation exposure scenarios considered both acute and chronic exposures. For
non-cancer effects, risks for transient CNS effects were evaluated for acute (short-term)
exposures, whereas risks for toxicity to the liver was evaluated for repeated (chronic) exposures
to carbon tetrachloride because of their human relevance and relevance to occupational
exposures as discussed in section 3.2.3.
19 Margin of Exposure (MOE) = (Non-cancer hazard value, POD) (Human Exposure) Equation 4-1. The
benchmark MOE is used to interpret the MOEs and consists of the total UF.
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4713
4714
4715
4716
4717
4718
4719
4720
4721
4722
4723
4724
4725
4726
4727
4728
4729
4730
4731
4732
4733
4734
4735
4736
4737
4738
4739
4740
4741
4742
4743
4744
4745
4746
4747
4748
4749
4750
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The total UF for each non-cancer POD was the benchmark MOE used to interpret the MOE risk
estimates for each use scenario. The MOE estimate was interpreted as human health risk if the
MOE estimate was less than the benchmark MOE (i.e., the total UF). On the other hand, the
MOE estimate indicated negligible concerns for adverse human health effects if the MOE
estimate exceeded the benchmark MOE. Typically, the larger the MOE, the more unlikely it is
that a non-cancer adverse effect would occur.
To determine the level of personal protection needed by workers to reduce the high-end exposures
to below the level of concern for non-cancer risks, EPA evaluated the impact of respirator use.
Typical APF values of 10, 25 and 50 were compared to the calculated MOE and the benchmark
MOE to determine the level of APF required to reduce exposure so that risk is below the level of
concern for noncancer risks (i.e., calculated MOE > benchmark MOE).
EPA estimated potential cancer risks from chronic exposures to carbon tetrachloride using
probabilistic approaches, which consisted of calculating the added cancer risk. Each of these
approaches is discussed below.
Added cancer risks for repeated exposures to carbon tetrachloride were estimated using Equation
4-2. Estimates of added cancer risks should be interpreted as the incremental probability of an
individual developing cancer over a lifetime as a result of exposure to the potential carcinogen
(i.e., incremental or added individual lifetime cancer risk).
Equation 4-2. Equation to Calculate Cancer Risks
Inhalation Cancer Risk = Human Exposure x IUR
or
Dermal Cancer Risk = Human Exposure x CSF
Where:
Risk = Added cancer risk (unitless)
Human exposure = Occupational exposure estimate (LADC in ppm)
IUR = Inhalation unit risk (6 x 10"6 per |ig/m3 for continuous exposures)
CSF = Inhalation unit risk adjusted for 0.8% dermal absorption
For carbon tetrachloride, EPA, consistent with OSHA (878 F.2d 389, 392 (D.C. Cir. 1989) and
2017 NIOSH guidance NIOSH [2017] Current intelligence bulletin 68: NIOSH chemical
carcinogen policy, available at https://www.cdc.gov/niosh/docs/2017-100/pdf/2017-10Q.pdf..
used 1 x 10"4 as the benchmark for the purposes of this risk determination for individuals in
industrial/commercial work environments subject to Occupational Safety and Health Act
(OSHA) requirements. It is important to note that 1 x 10"4 is not a bright line and EPA has
discretion to find unreasonable risks based on other benchmarks as appropriate based on
analysis. It is important to note that exposure related considerations (duration, magnitude,
population exposed) can affect EPA's estimates of the added cancer risk.
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4753 4.2.2 Risk Estimation for Non-Cancer Effects Following Acute Inhalation
4754 Exposures
4755 Non-cancer risk estimates for acute inhalation exposures to carbon tetrachloride were derived for
4756 occupational scenarios for the TSCA conditions of use. The risk estimates for acute inhalation
4757 exposures are based on CNS effects that are temporarily disabling (NRC. 2014) and focus on the
4758 high-end (95th percentile) and 50th percentile (central tendency). Non-cancer risk estimates for
4759 acute occupational exposure scenarios are presented in Table 4-7, below. Risk estimates were
4760 calculated for the occupational inhalation exposure scenarios described in section 2.4.1.7. The
4761 calculated MOEs without respirators are greater than the benchmark MOE of 10 for the high-end
4762 and central tendency exposures for all the conditions of use.
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Table 4-7. Risk Estimates for Acute Inhalation Exposures based on POD of 360 mg/m3 - 8hrs (= 310 mg/m3-12 hrs); and
benchmark MOE of 10
EXPOSURE
Calculated MOE without
Calculated MOE with Respirator (Worker)*
ADC (mg/m3)
Respirator (Worker and ONU)
APF =10
APF
=25
APF =50
Condition of Use
High-End
(Worker)
Central
Tendency
(Worker and
ONU)
MOE High-
End
MOE Central
Tendency
MOE High-
End
MOE
Central
Tendency
MOE High-
End
MOE
Central
Tendency
MOE
High-
End
MOE
Central
Tendency
Manufacturing -
8-hr TWA
4.0
0.76
90
474
900
4,740
2,250
11,850
4,500
23,700
Manufacturing -
12-hr TWA
4.8
0.50
65
620
650
6,200
1,625
15,500
3,250
31,000
Import/
Repackaging
0.30
0.057
1,200
6,316
12,000
63,160
30,000
157,900
60,000
315,800
Processing as
Reactant/Intermed
iate - 8-hr TWA
4.0
0.76
90
474
900
4,740
2,250
11,850
4,500
23,700
Processing as
Reactant/Intermed
iate - 12-hr TWA
4.8
0.50
65
620
650
6,200
1,625
15,500
3,250
31,000
Industrial
Processing Aid
0.30
0.057
1,200
6,316
12,000
63,160
30,000
157,900
60,000
315,800
Additive
0.30
0.057
1,200
6,316
12,000
63,160
30,000
157,900
60,000
315,800
Disposal: Waste
Handling
0.30
0.057
1,200
6,316
12,000
63,160
30,000
157,900
60,000
315,800
Specialty Uses-
DoD Data
0.367
0.183
981
1,967
9,810
19,670
24,525
49,175
49,050
98,350
Reactive Ion
Etching
Negligible - Highly controlled work areas with small quantities applied
Laboratory
Chemicals
No data - exposure is low as laboratory typically uses small quantities inside a fume hood.
4765 * MOEs with respirator use were calculated by multiplying the MOE without a respirator by the respirator APF. OSHA's occupational safety and health standards for carbon
4766 tetrachloride include respiratory protection recommendations starting with APF =10 (any supplied-air respirator) up to APF =10,000 for emergency or planned entry into unknown
4767 concentrations.
Page 151 of 301
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4768
4769
4770
4771
4772
4773
4774
4775
4776
4777
4778
4779
4780
4781
4782
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
4.2.3 Risk Estimation for Non-Cancer Effects Following Chronic Inhalation
Exposures
Chronic non-cancer risk estimates for inhalation exposures to carbon tetrachloride were derived
for occupational scenarios using estimated inhalation average daily concentrations (ADCs). The
risk estimates for chronic non-cancer health effects are based on the BMCLio[HEC] for liver
effects: 14.3 mg/m3 for continuous exposures, which is equivalent to 31.1 mg/m3 for 8 hrs of
exposure and 26.4 mg/m3 for 12 hrs.20 Non-cancer risk estimates for chronic exposures for each
occupational use scenario are presented in Table 4-8 below.
The calculated MOEs are greater than the benchmark MOEs of 30 for the high-end and central
tendency exposures for most conditions of use without respirator use, except for the high-end
exposures for manufacturing and processing as reactant/intermediate (8 hr and 12 hr TWA)
COUs. The high-end exposures with MOEs below the benchmark MOE have exposure
reductions during use of respirator with APF 10 that result in MOEs greater than the benchmark
MOE.
211 Time adjustment from continuous exposure to 5 days per week and to 8 or 12 hrs/day
Page 152 of 301
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Table 4-8. Risk Estimates for Chronic Inhalation Exposures based on POD of 31.1mg/m3- 8 hrs (= 26.4 mg/m3-12 hrs) and
benchmark MOE of 30
EXPOSURE
Calculated MOE without
Calculated MOE with Respirator (Worker)*
ADC (mg/m3)
Respirator (Worker and ONU)
APF =10
APF
=25
APF =50
Condition of Use
High-End
(Worker)
Central
Tendency
(Worker and
ONU)
MOE High-
End
MOE Central
Tendency
MOE High-
End
MOE
Central
Tendency
MOE High-
End
MOE
Central
Tendency
MOE
High-
End
MOE
Central
Tendency
Manufacturing -
8-hr TWA
4.0
0.76
8
41
80
410
200
1,025
400
2,050
Manufacturing -
12-hr TWA
4.8
0.50
6
53
60
530
150
1,325
300
2,650
Import/
Repackaging
0.30
0.057
104
546
1.040
5,460
2,600
13,650
5,200
27,300
Processing as
Reactant/Intermed
iate - 8-hr TWA
4.0
0.76
8
41
80
410
200
1,025
400
2,050
Processing as
Reactant/Intermed
iate — 12-hr TWA
4.8
0.50
6
53
60
530
150
1,325
300
2,650
Industrial
Processing Aid
0.30
0.057
104
546
1,040
5,460
2,600
13,650
5,200
27,300
Additive
0.30
0.057
104
546
1,040
5,460
2,600
13,650
5,200
27,300
Disposal: Waste
Handling
0.30
0.057
104
546
1,040
5,460
2,600
13,650
5,200
27,300
Specialty Uses-
DoD Data
0.22
0.09
141
346
1,040
5,460
2,600
13,650
5,200
27,300
Reactive Ion
Etching
Negligible - Highly controlled work areas with small quantities applied
Laboratory
Chemicals
No data - exposure is low as laboratory typically uses small quantities inside a fume hood.
4785 Bold: Calculated MOEs were below the benchmark MOE. * MOEs with respirator use were calculated by multiplying the MOE without a respirator by the respirator APF.
4786 OSHA's occupational safety and health standards for carbon tetrachloride include respiratory protection recommendations starting with APF =10 (any supplied-air respirator) up to
4787 APF =10,000 for emergency or planned entry into unknown concentrations.
Page 153 of 301
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4788
4789
4790
4791
4792
4793
4794
4795
4796
4797
4798
4799
4800
4801
4802
4803
4804
4805
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
4.2.4 Risk Estimation for Non-Cancer Effects Following Acute Dermal
Exposures
Results from dermal studies with guinea pigs (Kronevi et al.. 1979; Wahlberg and Boman. 1979)
were used in conjunction with dermal absorption information for carbon tetrachloride to derive a
POD for acute dermal exposures of 2,750 mg/kg (see section 3.2.5.2.3). Table 4-9 outlines the
non-cancer dermal risk estimates to workers with and without the use of gloves for all conditions
of use.
Table 4-9. Risk Estimates for Acute Dermal Exposures
Condition
of
Use
Health Effect,
Endpoint and Study
POD
(mg/kg-
day)
Exposure
Level
Acute
Retained
Dose
(mg/kg-
day)
Benchmark
MOE
(= Total UF)
Worker
MOE, No
Gloves
Worker
MOE with
Gloves: 5
Manufacture
Import and
repackaging
Additive
Processing as
a Reactant
Processing
Agent/ Aid
Recycling
Waste
disposal
Liver
Liver toxicity for non
to light alcohol users
- Histopathological
changes in the liver
(guinea pigs)
(Kronevi et al.. 1979;
Wahlbere and
Boman. 1979)
2750
High End
1.1
100
2,500
12,500
Laboratory
Chemicals
Specialty
Uses -
Department
of Defense
Data
Central
Tendency
0.37
100
7,432
37,160
Reactive Ion
Etching
Negligible - Highly controlled work areas with small quantities applied
4.2.5 Risk Estimation for Non-Cancer Effects Following Chronic Dermal
Exposures
The HEDDermai of 245 mg/kg-d for non-occluded exposures was extrapolated from the chronic
inhalation BMCLio[hec]: 14.3 mg/m3 for continuous exposures, which was derived in the EPA
IRIS assessment (U.S. EPA. 2010) using data from Nagano et al., (2007a).
Table 4-10 outlines the non-cancer dermal risk estimates to workers for endpoints with and
without the use of gloves.
Page 154 of 301
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4806
4807
4808
4809
4810
4811
4812
4813
4814
4815
4816
4817
4818
4819
4820
4821
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Table 4-10. Risk Estimates from Chronic Dermal Exposures
Condition
of
Use
Health Effect,
Endpoint and
Study
HEP
(mg/kg-
day)
Exposure
Level
Chronic
Retained
Dose
(mg/kg-
day)
Benchmark
MOE
(= Total UF)
Worker
MOE,
No
Gloves
Worker
MOE
with
Gloves: 5
Manufacture
Import and
repackaging
Additive
Liver
Liver toxicity for
non to light
alcohol users -
Histopathological
changes in the
liver (guinea
pigs)
(Kroncvi et al..
1979: Wahlbere
High
1.1
30
223
1,115
Processing
as a
Reactant
End
Processing
Agent/ Aid
245
Recycling
Waste
disposal
Laboratory
Chemicals
and Boman
1979)
Central
Tendency
0.37
30
662
3,310
Specialty
Uses -
Department
of Defense
Data
Reactive Ion
Etching
Negligible - Highly controlled work areas with small quantities applied
4.2.6 Risk Estimation for Cancer Effects Following Chronic Inhalation
Exposures
EPA estimated the added cancer risks associated with chronic exposures to carbon tetrachloride
in the workplace. The added cancer risk estimation for carbon tetrachloride was calculated by
multiplying the occupational scenario-specific estimates (i.e., LADC) for both workers and
occupational non-users by EPA's inhalation unit risk (IUR) to estimate the added cancer risk.
Added cancer risks were expressed as number of cancer cases per million. Table 4-11 outlines
the cancer risk estimates to workers from inhalation exposures for the conditions of use for
carbon tetrachloride.
In general terms, the exposure frequency (i.e., the amount of days per year for workers or
occupational non-users exposed to carbon tetrachloride) was considered to be 250 days per year
and the occupational exposure duration was 40 years over a 70-year lifespan. It is recognized that
these exposure assumptions are likely yielding conservative cancer risk estimates, but EPA does
not have additional information for further refinement.
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Table 4-11. Risk Estimates for Cancer Effects from Chronic Inhalation Exposures for Workers Based on IUR of 6 x 10~6 per
Condition of Use
Chronic, Cancer Exposures
Calculated Cancer Risk
Calculated Cancer Risk with Respirator (Worker)*
LADC (mg/m3)
without Respirator
(Worker and ONU)
APF =10
APF =25
APF =50
High-End
(Worker)
Central Tendency
(Worker and ONU)
High-End
Central
Tendency
High-End
Central
Tendency
High-End
Central
Tendency
High-
End
Central
Tendency
Manufacturing - 8-hr
TWA
0.47
0.07
3E-03
4E-04
3E-04
4E-05
1E-04
2E-05
6E-05
8E-06
Manufacturing - 12-hr
TWA
0.83
0.07
5E-03
4E-04
5E-04
4E-05
2E-04
2E-05
1E-04
8E-06
Import/Repackaging
0.035
0.005
2E-04
3E-05
2E-05
3E-06
8E-06
1E-06
4E-06
6E-07
Processing as
Reactant/Inteimediate
- 8-hr TWA
0.47
0.07
3E-03
4E-04
3E-04
4E-05
1E-04
2E-05
6E-05
8E-06
Processing as
Reactant/Inteimediate
- 12-In TWA
0.83
0.07
5E-03
4E-04
5E-04
4E-05
2E-04
2E-05
1E-04
8E-06
Industrial Processing
Aid
0.035
0.005
2E-04
3E-05
2E-05
3E-06
8E-06
1E-06
4E-06
6E-07
Additive
0.035
0.005
2E-04
3E-05
2E-05
3E-06
8E-06
1E-06
4E-06
6E-07
Disposal: Waste
Handling
0.035
0.005
2E-04
3E-05
2E-05
3E-06
8E-06
1E-06
4E-06
6E-07
Specialty Uses-DoD
Data
0.026
0.008
2E-04
5E-05
2E-05
5E-06
8E-06
2E-06
4E-06
1E-06
Reactive Ion Etching
Negligible - Highly controlled woik areas with small quantities applied
Laboiatoiy Chemicals
No data - exposure is low as laboiatoiy typically uses small quantities inside a fume hood.
4824 Bold: Calculated extra-cancer risk are greater than the benchmark cancer risk or MOEs are below the benchmark MOE. Extra cancer risk was calculated as follows: "Central
4825 Tendency LADC (|ig/m3)" or "High-end LADC (|ig/m3)" x IUR (i.e., 6 x 10"6 per ng/m3)
4826 *Cancer risks with respirator use were calculated by dividing the cancer risk without a respirator by the respirator APF; MOEs with respirator use were calculated by multiplying
4827 the MOE without a respirator by the respirator APF. OSHA's occupational safety and health standards for carbon tetrachloride include respiratory protection recommendations
4828 starting with APF =10 (any supplied-air respirator) up to APF = 10,000 for emergency or planned entry into unknown concentrations.
4829
Page 156 of 301
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4830
4831
4832
4833
4834
4835
4836
4837
4838
4839
4840
4841
4842
4843
4844
4845
4846
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Figure 4-1 through Figure 4-4 present the incremental individual lifetime cancer risks for the 95th
percentile/high-end and 50th percentile/central tendency exposures to carbon tetrachloride
occurring in occupational exposure scenarios. The figures consist of graphical representations of
the cancer risks presented in Table 4-11 by COU.
1X 7 l.E 6 1.E S l.E-4 l.E 3 I E 2 1-E-l IjE+O
WoriwrSSlti PcrcctHilr
: SOlli Percentile
¦ Cancer ft*sk with APF of 50
¦ Cancer ffcfc
Excess Cancer Kisk*
Figure 4-1. Cancer Risk Estimates for Occupational Use of Carbon Tetrachloride in
Manufacturing and Processing as Reactant/Intermediate Based on Monitoring or
Surrogate Monitoring Data 8 hr TWA
l.E+0
Worker 95th Percentife
¦ Cancer Risk with APF of 50
¦ Cancer Risk
Worker 50th Percentile
Figure 4-2. Cancer Risk Estimates for Occupational Use of Carbon Tetrachloride in
Manufacturing and Processing as Reactant/Intermediate Based on Monitoring or
Surrogate Monitoring Data 12 hr TWA
Page 157 of 301
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4847
4848
4849
4850
4851
4852
4853
4854
4855
4856
4857
4858
4859
4860
4861
4862
4863
4864
4865
4866
4867
4868
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
LE-7 LE-6 l.E-5 l.E-4 l.E-3 1E-2 LE-1 l.E+O
Worker 95th Percentife
¦ Cancer Risk with APF of 50
¦ Cancer Risk
Worker 5Cth Percentile
Excess Cancer Risk*
Figure 4-3. Cancer Risk Estimates for Occupational Use of Carbon Tetrachloride in
Import, Processing Agent, Additive and Disposal/Recycling Based on Modeling
Worker 95th Peres ntife
¦ Cancer Risk with APF of 50
¦ Cancer Risk
Worker 50th Perce ntife
Figure 4-4. Cancer Risk Estimates for Occupational Use of Carbon Tetrachloride in
Specialty Uses-DoD Based on Monitoring Data
4.2.7 Risk Estimations for Cancer Effects Following Chronic Dermal Exposures
EPA estimated the added cancer risks associated with chronic dermal exposures to carbon
tetrachloride in the workplace. The added cancer risk estimation for carbon tetrachloride was
calculated by multiplying the occupational scenario-specific dermal exposure estimates for
workers by the derived CSFDemiai to estimate the added cancer risk. The CSFDemiai was
extrapolated from the EPA's inhalation unit risk (IUR) of 6 x 10"6 per [j,g/m3 for continuous
lifetime exposure resulting in a derived CSFDemiai of 8 x 10"4per mg/kg for non-occluded
exposures (see section 3.2.5.2.4). Table 4-12 outlines the non-cancer dermal risk estimates to
workers for endpoints with and without gloves.
Page 158 of 301
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4869
4870
4871
4872
4873
4874
4875
4876
4877
4878
4879
4880
4881
4882
4883
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Table 4-12. Risk Estimates for Cancer Effects from Chronic Dermal Exposures for
Workers; Benchmark Risk = 1 in 104
Conditions of Use
Exposure
Level
No Gloves
Gloves: 5
Manufacture
Import and
repackaging
Additive
Processing as a
Reactant
Processing
Agent/Aid
High End
3E-4
6E-5
Recycling
Waste disposal
Laboratory
Chemicals
Specialty Uses -
Department of
Defense Data
Manufacture
Import and
repackaging
Additive
Processing as a
Reactant
Processing
Agent/Aid
Central
Tendency
8E-5
2E-5
Recycling
Waste disposal
Laboratory
Chemicals
Specialty Uses -
Department of
Defense Data
Reactive Ion
Etching
Negligible
Highly controlled work areas with small quantities
applied
4.2,8 Summary of Non-cancer and Cancer Estimates for Inhalation and Dermal
Exposures
Table 4-13 presents a summary of the MOEs and estimated cancer risks for the inhalation
exposures from the conditions of use for carbon tetrachloride. The high-end chronic inhalation
exposures for manufacturing and processing (8hr and 12hr TWA) COUs have MOEs below the
benchmark MOE and cancer risks greater than the benchmark cancer risk. The central tendency
chronic inhalation exposures for the same COUs have cancer risks greater than the benchmark.
However, all those inhalation exposures are reduced with respirator use (APF 10, 25 or 50)
resulting in MOEs greater than benchmark MOEs and cancer risks below the benchmark cancer
risk.
There are cancer risks above the cancer risk benchmark for the high-end exposures for the
additive, processing agent/aid, import and repackaging, specialty uses-DoD and
Page 159 of 301
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4884 disposal/recycling COUs. Those high-end exposures are reduced with respirator use (APF 10)
4885 resulting in cancer risks below the benchmark.
4886
4887 The calculated MOEs for all the occupational dermal exposures without gloves are greater than
4888 the benchmark MOEs. The calculated cancer risks are lower than the benchmark cancer risk for
4889 the central tendency dermal exposures from all the COUs for carbon tetrachloride. The
4890 calculated cancer risks for the high-end dermal exposures for all COUs is higher than the
4891 benchmark cancer risk without the use of gloves. Those dermal high-end exposures are reduced
4892 with the use of gloves (PF =5) resulting in cancer risks below the benchmark.
Page 160 of 301
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Table 4-13. Summary of Estimated Non-cancer and Cancer Risks from Inhalation and Dermal Exposures1
Risk estimates for No-PPE
Risk estimates with PPE**
Life Cycle
Stage
Category
Assessed Condition
of Use
Population
Exposure
Type
Exposure
Levels
Acute Non-
cancer
(inhalation
benchmark
MOE = 10;
dermal
benchmark
MOE=100)
Chronic
Non-
cancer
(inhalation
/dermal
benchmark
MOE = 30)
Cancer Risk
(cancer risk
benchmark
1 in 104)
Acute Non-
cancer
(inhalation
benchmark
MOE = 10;
dermal
benchmark
MOE=100)
Chronic
Non-cancer
(inhalation/
dermal
benchmark
MOE = 30)
Cancer Risk
of 1 in 104
Manufacture
Domestic
Manufacture
Domestic
Manufacture
Worker
(high-end
and central
8-hr
TWA
Central
Tendency
474
41
4E-04
N/A
N/A
4E-05
(APF =10)
tendency
exposures)
High -End
90
8
3E-03
N/A
80
(APF =10)
1E-04
(APF =25)
ONU
(central
tendency
12-hr
TWA
Central
Tendency
620
53
4E-04
N/A
N/A
4E-05
(APF =10)
inhalation
exposures)
High -End
65
6
5E-03
N/A
60
(APF = 10)
1E-04
(APF =50)
Dermal
Central
Tendency
7.432
662
8E-05
N/A
N/A
N/A
High -End
2.500
223
3E-04
N/A
N/A
6E-05
(PF =5)
Import
Import and
Repackaging
Worker
(high-end
and central
tendency
exposures)
8 hr-TWA
Central
Tendency
6.316
546
3E-05
N/A
N/A
N/A
High -End
1.200
104
2E-04
N/A
N/A
2E-05
(APF =10)
ONU
(central
tendency
inhalation
exposures)
Dermal
Central
Tendency
7.432
662
8E-05
N/A
N/A
N/A
High -End
2.500
223
3E-04
N/A
N/A
6E-05
(PF =5)
Process-
ing
Processing as a
reactant/
intermediate for
manufacturing of
HCFCs, HFCs.
Processing as
Reactant/
Intermediate*
Worker
(high-end
and central
tendency
exposures)
8-hr
Central
Tendency
474
41
4E-04
N/A
N/A
4E-05
(APF =10)
TWA
High -End
90
8
3E-03
N/A
80
(APF =10)
1E-04
(APF =25)
HFOs and PCE
12-hr
TWA
Central
Tendency
620
53
4E-04
N/A
N/A
4E-05
(APF =10)
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Life Cycle
Stage
Category
Assessed Condition
of Use
Population
Exposure
Type
Exposure
Levels
Risk estimates for No-PPE
Risk estimates with PPE**
Acute Non-
cancer
(inhalation
benchmark
MOE = 10;
dermal
benchmark
MOE=100)
Chronic
Non-
cancer
(inhalation
/dermal
benchmark
MOE = 30)
Cancer Risk
(cancer risk
benchmark
1 in 104)
Acute Non-
cancer
(inhalation
benchmark
MOE = 10;
dermal
benchmark
MOE=100)
Chronic
Non-cancer
(inhalation/
dermal
benchmark
MOE = 30)
Cancer Risk
of 1 in 104
ONU
(central
tendency
inhalation
exposures)
High -End
65
6
5E-03
N/A
60
(APF = 10)
1E-04
(APF =50)
Dermal
Central
Tendency
7.432
662
8E-05
N/A
N/A
N/A
High -End
2.500
223
3E-04
N/A
N/A
6E-05
(PF =5)
Reactive ion
etching
(i.e., semi-
conductor
manufacturing)
Reactive ion etching
(i.e., semi-conductor
manufacturing)
Negligible - Highly controlled work areas with small quantities applied
Distribution in
commerce
Distribution
Activities related to
distribution (e.g.,
loading, unloading)
Activities related to distribution (e.g., loading, unloading) are considered throughout the life cycle, rather than using a single
distribution scenario
Industrial/com
mercial use
Manufacturing of
Petrochemicals-
derived products
and agricultural
products
Industrial
Processing Agent/
Aid)*
Worker
(high-end
and central
tendency
exposures)
ONU
(central
tendency
inhalation
exposures)
8 hr TWA
Central
Tendency
6.316
546
3E-05
N/A
N/A
N/A
High -End
1.200
104
2E-04
N/A
N/A
2E-05
(APF =10)
Dermal
Central
Tendency
7.432
662
8E-05
N/A
N/A
N/A
High -End
2.500
223
3E-04
N/A
N/A
6E-05
(PF =5)
Additive
Worker
(high-end
and central
tendency
exposures)
8 hr TWA
Central
Tendency
6.316
546
3E-05
N/A
N/A
N/A
High -End
1.200
104
2E-04
N/A
N/A
2E-05
(APF =10)
Dermal
Central
Tendency
7.432
662
8E-05
N/A
N/A
N/A
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Life Cycle
Stage
Category
Assessed Condition
of Use
Population
Exposure
Type
Exposure
Levels
Risk estimates for No-PPE
Risk estimates with PPE**
Acute Non-
cancer
(inhalation
benchmark
MOE = 10;
dermal
benchmark
MOE=100)
Chronic
Non-
cancer
(inhalation
/dermal
benchmark
MOE = 30)
Cancer Risk
(cancer risk
benchmark
1 in 104)
Acute Non-
cancer
(inhalation
benchmark
MOE = 10;
dermal
benchmark
MOE=100)
Chronic
Non-cancer
(inhalation/
dermal
benchmark
MOE = 30)
Cancer Risk
of 1 in 104
ONU
(central
tendency
inhalation
exposures)
High -End
2.500
223
3E-04
N/A
N/A
6E-05
(PF =5)
Other Basic
Organic and
Inorganic
Chemical
Manufacturing
(i.e., chlorinated
products used in
solvents for
cleaning and
degreasing.
adhesives. sealants,
paints, coatings,
asphalt)
Processing as a
Reactant or
Intennediate
Worker
(high-end
and central
tendency
exposures)
ONU
(central
tendency
inhalation
exposures)
8-hr
TWA
Central
Tendency
474
41
4E-04
N/A
N/A
4E-05
(APF =10)
High -End
90
8
3E-03
N/A
80
(APF =10)
1E-04
(APF =25)
12-hr
TWA
Central
Tendency
620
53
4E-04
N/A
N/A
4E-05
(APF =10)
High -End
65
6
5E-03
N/A
60
(APF = 10)
1E-04
(APF =50)
Dermal
Central
Tendency
7.432
662
8E-05
N/A
N/A
N/A
High -End
2.500
223
3E-04
N/A
N/A
6E-05
(PF =5)
Specialty LTses-DoD
Data
Worker
(high-end
and central
tendency
exposures)
ONU
(central
tendency
inhalation
exposures)
8 hr TWA
Central
Tendency
1.967
346
5E-05
N/A
N/A
N/A
High -End
981
141
2E-04
N/A
N/A
2E-05
(APF =10)
Dermal
Central
Tendency
7.432
662
8E-05
N/A
N/A
N/A
High -End
2.500
223
3E-04
N/A
N/A
6E-05
(PF =5)
Laboratory
chemicals
Laboratory
Chemicals
No data - exposure is low as laboratory typically uses small quantities inside a fume hood.
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Life Cycle
Stage
Category
Assessed Condition
of Use
Population
Exposure
Type
Exposure
Levels
Risk estimates for No-PPE
Risk estimates with PPE**
Acute Non-
cancer
(inhalation
benchmark
MOE = 10;
dermal
benchmark
MOE=100)
Chronic
Non-
cancer
(inhalation
/dermal
benchmark
MOE = 30)
Cancer Risk
(cancer risk
benchmark
1 in 104)
Acute Non-
cancer
(inhalation
benchmark
MOE = 10;
dermal
benchmark
MOE=100)
Chronic
Non-cancer
(inhalation/
dermal
benchmark
MOE = 30)
Cancer Risk
of 1 in 104
Disposal
Disposal
Di sposal/Recycling
Worker
(high-end
and central
tendency
exposures)
ONU
(central
tendency
inhalation
exposures)
8 hr TWA
Central
Tendency
6.316
546
3E-05
N/A
N/A
N/A
High -End
1.200
104
2E-04
N/A
N/A
2E-05
(APF =10)
Dermal
Central
Tendency
7.432
662
8E-05
N/A
N/A
N/A
High -End
2.500
223
3E-04
N/A
N/A
6E-05
(PF =5)
4894 'This table presents a summary of the risks for inhalation and dermal exposures by combining the risk findings for the COUs listed in Table 4-7 to Table 4-11 and the associated lifecycle stages as listed
4895 in Table 1-4 and Figure 1-1.
4896 *Incorporation into Reaction, Mixture and Reaction Products was regrouped and accessed under Industrial Processing Agent/Aid and Processing as a Reactant or Intermediate (see section 1.4.1, Table
4897 1-4 and section 2.4.1.6)
4898 "Risk estimates were calculated for the respirator with the lowest APF that reduces exposure to levels with MOEs greater than benchmark MOE or cancer risk lower than benchmark cancer risk.
4899
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4.3 Potentially Exposed or Susceptible Subpopulations
TSCA requires that the determination of whether a chemical substance presents an unreasonable
risk include consideration of unreasonable risk to "a potentially exposed or susceptible
subpopulation identified as relevant to the risk evaluation" by EPA. TSCA § 3(12) states that
"the term 'potentially exposed or susceptible subpopulation'' means a group of individuals within
the general population identified by the Administrator who, due to either greater susceptibility or
greater exposure, may be at greater risk than the general population of adverse health effects
from exposure to a chemical substance or mixture, such as infants, children, pregnant women,
workers, or the elderly."
In developing the exposure assessment for carbon tetrachloride, EPA analyzed reasonably
available information to identify groups that may have greater exposure or susceptibility than the
general population to the hazard posed by carbon tetrachloride. Exposures of carbon
tetrachloride could be higher amongst workers and ONUs who use or are exposed to carbon
tetrachloride as part of typical processes.
The scope of this human health assessment is limited to workers and ONUs. Thus, this section
focuses on identifying subpopulations within workers and ONUs who may have greater
susceptibility to carbon tetrachloride. Assessment of susceptible subpopulations does not include
children or non-workers/non-ONUs.
Some workers and ONUs may be more biologically susceptible to the effects of carbon
tetrachloride due to age, alcohol consumption, nutritional status, pre-existing disease (e.g.,
diabetes or liver disease), exposure to other chemicals, and genetic variation (described in more
detail in section 3.2.5.4).
Metabolism of carbon tetrachloride to reactive metabolites by cytochrome p450 enzymes
(particularly CYP2E1 and CYP3A) is hypothesized to be a key event in the toxicity of this
compound. Differences in the metabolism due to alcohol consumption, exposure to other
chemicals, age, nutritional status, genetic variability in CYP expression, or impaired liver
function due to liver disease can increase susceptibility to carbon tetrachloride (U.S. EPA. 2010).
For example, alcohol is known to induce CYP2E1 expression. Cases of acute toxicity from
occupational exposures indicate that heavy drinkers are more susceptible to carbon tetrachloride
and this observation has been verified in numerous animal studies. Exposure to other chemicals
that induce p450 enzymes, including isopropanol, methanol, acetone, methyl ethyl ketone,
methyl isobutyl ketone, 2-butanone, phenobarbital, methamphetamine, nicotine,
trichloroethylene, polychlorinated and polybrominated biphenyls, DDT, mirex, and chlordecone
have also been shown to potentiate carbon tetrachloride liver toxicity (U.S. EPA. 2010; AT SDR.
2005).
Age can influence susceptibility to carbon tetrachloride due to differences in metabolism,
antioxidant responses, and reduced kidney function in older adults. While lower CYP expression
may reduce susceptibility of older adults to carbon tetrachloride in some tissues, reduced kidney
function and increased CYP3A activity in the liver (indicated by animal studies) suggest that
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older populations could be at greater risk of carbon tetrachloride-associated kidney damage (U.S.
EPA. 2010V
Nutrition has also been shown to influence susceptibility to carbon tetrachloride in animals. Food
restriction has been shown to increase liver toxicity of carbon tetrachloride. Diets low in
antioxidants increase lipid peroxidation and liver damage in following carbon tetrachloride
exposure (reversed with antioxidant supplementation) and zinc deficient diets increase carbon
tetrachloride-induced liver toxicity (U.S. EPA. 2010).
EPA identified groups of individuals with greater inhalation exposure as workers in occupational
scenarios. EPA examined worker exposures in this risk evaluation for several occupational
scenarios (see section 2.4.1 for these exposure scenarios).
To account for variation in sensitivity within human populations intraspecies UFs were applied
for non-cancer effects. The UF values selected are described in section 3.2.5.2.
4.4 Assumptions and Key Sources of Uncertainty
The characterization of assumptions, variability and uncertainty may raise or lower the
confidence of the risk estimates. This section describes the assumptions and uncertainties in the
exposure assessment, hazard/dose-response and risk characterization.
4.4.1 Occupational Exposure Assumptions and Uncertainties
EPA addressed variability in models by identifying key model parameters to apply a statistical
distribution that mathematically defines the parameter's variability. EPA defined statistical
distributions for parameters using documented statistical variations where available. Uncertainty
is "the lack of knowledge about specific variables, parameters, models, or other factors" and can
be described qualitatively or quantitatively (U.S. EPA. 2001). The following sections discuss
uncertainties in each of the assessed carbon tetrachloride use scenarios.
Number of Workers
There are a number of uncertainties surrounding the estimated number of workers potentially
exposed to carbon tetrachloride, as outlined below.
First, BLS' OES employment data for each industry/occupation combination are only available
at the 3-, 4-, or 5-digit NAICS level, rather than the full 6-digit NAICS level. This lack of
granularity could result in an overestimate of the number of exposed workers if some 6-digit
NAICS are included in the less granular BLS estimates but are not, in reality, likely to use
carbon tetrachloride for the assessed applications. EPA addressed this issue by refining the OES
estimates using total employment data from the U.S. Census' SUSB. However, this approach
considers that the distribution of occupation types (SOC codes) in each 6-digit NAICS is equal to
the distribution of occupation types at the parent 5-digit NAICS level. If the distribution of
workers in occupations with carbon tetrachloride exposure differs from the overall distribution of
workers in each NAICS, then this approach will result in inaccuracy.
Second, EPA's judgments about which industries (represented by NAICS codes) and
occupations (represented by SOC codes) are associated with the uses assessed in this report are
based on EPA's understanding of how carbon tetrachloride is used in each industry. Designations
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of which industries and occupations have potential exposures is nevertheless subjective, and
some industries/occupations with few exposures might erroneously be included, or some
industries/occupations with exposures might erroneously be excluded. This would result in
inaccuracy but would be unlikely to systematically either overestimate or underestimate the
count of exposed workers.
Occupational non-users (ONUs)
EPA evaluated inhalation risks for acute and chronic exposures for ONUs. However, EPA did
not separately calculate inhalation risk estimates for ONUs and workers. There is uncertainty in
the ONU inhalation risk estimate since the data did not distinguish between worker and ONU
inhalation exposure estimates. While the difference between the exposures of ONUs and the
exposures of workers directly handling the chemical generally cannot be quantified, ONU
inhalation exposures are expected to be lower than inhalation exposures for workers directly
handling the chemical. EPA considered the ONU exposures to be equal to the central tendency
risk estimates for workers when determining ONU risk attributable to inhalation. While this is
likely health protective as it assumes ONU exposure is greater than that of 50% of the workers,
this is highly uncertain, and EPA has low confidence in these exposure estimates for ONUs.
Analysis of Exposure Monitoring Data
This draft risk evaluation uses existing worker exposure monitoring data to assess exposure to
carbon tetrachloride during manufacturing. Some data sources may be inherently biased. For
example, bias may be present if exposure monitoring was conducted to address concerns
regarding adverse human health effects reported following exposures during use.
Some scenarios have limited exposure monitoring data in literature, if any. Where there are few
data points available, it is unlikely the results will be representative of worker exposure across
the industry.
In cases where there was no exposure monitoring data, EPA used monitoring data from similar
conditions of use as surrogate (i.e., monitoring data from manufacturing were used as surrogate
monitoring data for the processing COUs). While these conditions of use have similar worker
activities contributing to exposures, it is unknown whether the results will be fully representative
of worker exposure across different conditions of use.
Where sufficient data were available, the 95th and 50th percentile exposure concentrations were
calculated using available data. The 95th percentile exposure concentration is intended to
represent a high-end exposure level, while the 50th percentile exposure concentration represents
typical exposure level. The underlying distribution of the data, and the representativeness of the
available data, are not known. Where discrete data was not available, EPA used reported
statistics (i.e., median, mean, 90th percentile, etc.). Since EPA could not verify these values,
there is an added level of uncertainty.
EPA generally calculated ADC and LADC values assuming a high-end exposure duration of 250
days per year over 40 years and a typical exposure duration of 250 days per year over 31 years.
This assumes the workers and occupational non-users are regularly exposed during their entire
working lifetime, which likely results in an overestimate. Individuals may change jobs during the
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course of their career such that they are no longer exposed to carbon tetrachloride, resulting in
actual ADC and LADC values that are lower than the estimates presented.
Modeling Dermal Exposures
To assess dermal exposure, EPA used a modified equation from the EPA/OPPT 2-Hand Dermal
Exposure to Liquids Model to calculate the dermal absorbed dose for both non-occluded and
occluded scenarios. The modified equation incorporates a "fraction absorbed (fabs)" parameter
to account for the evaporation of volatile chemicals and a "protection factor (PF)" to account for
glove use. PF values will vary depending on the type of glove used and the presence of employee
training program.
The model considers an infinite dose scenario and does not account for the transient exposure
and exposure duration effect, which likely overestimates exposures. The model assumes one
exposure event per day, which likely underestimates exposure as workers often come into repeat
contact with the chemical throughout their work day. Surface areas of skin exposure are based on
skin surface area of hands from EPA's Exposure Factors Handbook, but actual surface areas with
liquid contact are unknown and uncertain for all occupational exposure scenarios. For many
scenarios, the assumption of contact over the full area of two hands likely overestimates
exposures. Weight fractions are usually reported to CDR and shown in other literature sources as
ranges, and EPA assessed only upper ends of ranges. While the glove protection factors are
based on the ECETOC TRA model as described in section 2.4.1.5 they are "what-if
assumptions and are highly uncertain. EPA does not know the actual frequency, type, and
effectiveness of glove use in specific workplaces of the occupational exposure scenarios. Except
where specified above, it is unknown whether most of these uncertainties overestimate or
underestimate exposures. The representativeness of the modeling results toward the true
distribution of dermal doses for the occupational scenarios is uncertain.
More details on the dermal methodology are discussed in the supplemental document Risk
Evaluation for Carbon Tetrachloride, Supplemental Information on Releases and Occupational
Exposure Assessment (U.S. EPA. 2019b).
4.4.2 Environmental Exposure Assumptions and Uncertainties
As described in Appendix E and section 2.3.1, a screening4evel aquatic exposure assessment
was undertaken to evaluate ecological exposures in the U.S. that may be associated with releases
of carbon tetrachloride to surface waters. This assessment was intended as a first-tier, or
screening-level, evaluation. The top ten (by annual release/discharge amount) facilities as
reported in EPA's Discharge Monitoring Reports (DMRs) were selected for use in exposure
modeling for each of five years from 2014 through 2018. Thus, not all reporting sites were
modeled, and the selected sites were not cross-walked with the conditions of use included in the
occupational engineering assessment.
For the purposes of this assessment, the number of release days were either 20 days or 250 days.
The reported annual release amounts from DMR were divided by these numbers of release days
to obtain the necessary kg/site-day release input. These assumptions are not based on associated
industry-specific data or standards, but on the assumptions to capture conservative environmental
concentrations for acute and chronic release scenarios. The 20 days of release is the assumption
for a chronic scenario, appropriate for comparison against a chronic COC, whereas 250 days of
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release may be more typical for facilities that operate and release effluent frequently, such as
POTWs or treatment plants.
Uncertainties in the modeled surface water concentration estimates include the variable amount
of releases of carbon tetrachloride captured in the DMR database and regulated by the Office of
Water's NPDES permitting process.
Lastly, some facilities releasing carbon tetrachloride, such as POTWs, may not be associated
with a TSCA condition of use covered in this risk evaluation. Use of facility data to estimate
environmental exposures is constrained by a number of other uncertainties including: the
heterogeneity of processes and releases among facilities grouped within a given sector;
assumptions made regarding sector definitions used to select facilities covered under the scope;
and fluctuations in the level of production and associated environmental releases incurred as a
result of changes in standard operating procedures. Nevertheless, it is important to note that the
DMR dataset is based on the most comprehensive, best reasonably available data at a nationwide
scale. DMR is based on representative pollutant monitoring data at facility outfalls and
corresponding wastewater discharges. Any exceedances of permit levels are referred to EPA's
Enforcement and Compliance.
4.4.3 Environmental Hazard Assumptions and Uncertainties
While the EPA has determined that sufficient data are available to characterize the overall
environmental hazards of carbon tetrachloride, uncertainties exist. To begin, while reasonable
attempts were made, the Agency was not able to obtain all of the full scientific reports listed in
ECHA, SIAP, and NICNAS on carbon tetrachloride due to challenges that include ownership of
the studies by foreign sources. EPA did not use its information collection authority to obtain the
full scientific reports or translate foreign language studies listed in ECHA, SIAP, and NICNAS
because the robust summary endpoints from these sources align with the dataset EPA used to
assess the hazards of carbon tetrachloride. Additionally, EPA has successfully obtained the full
study reports for the most conservative endpoint values in the scientific literature that are driving
the acute and chronic concentrations of concern.
Furthermore, EPA used sub-chronic data, measuring a developmental effect in embryo and
larvae, to calculate the amphibian chronic COC, which introduces some uncertainty about
whether EPA is overestimating or underestimating chronic risk. Assessment factors (AFs) were
used to calculate the acute and chronic concentrations of concern for carbon tetrachloride. As
described in Appendix G, AFs account for differences in inter- and intra-species variability, as
well as laboratory-to-field variability and are routinely used within TSCA for assessing the
hazard of new industrial chemicals (with very limited environmental test data). Some
uncertainty may be associated with the use of the specific AFs used in the hazard assessment.
There is no way of knowing exactly how much uncertainty to account for in the AFs. Therefore,
there is uncertainty associated with the use of the specific AFs used in the hazard assessment.
For example, a standard AF has not been established for amphibians by the EPA under TSCA,
because there are few amphibian studies for industrial chemicals. It is unclear whether using an
assessment factor of 10 to calculate the acute COC value for amphibians using the sub-chronic
embryo-larvae test data is sufficiently protective or is overly protective of amphibian exposures
to carbon tetrachloride. There are additional factors that affect the potential for adverse effects in
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aquatic organisms. Life-history factors and the habitat of aquatic organisms influences the
likelihood of exposure above the hazard benchmark in an aquatic environment.
4.4.4 Human Health Hazard Assumptions and Uncertainties
Toxicity data are limited for dermal exposures to carbon tetrachloride and for developmental
toxicity by the inhalation route. The available developmental toxicity by the inhalation route
suggests that carbon tetrachloride does not induce developmental effects from single exposures
during gestation (see section 3.2.4.1.1). The available dermal data were used in a weight of
evidence approach to derive points of departures (POD) for occupational dermal exposures and
estimates of dermal absorption.
The main source of uncertainty for the human health hazard is the lack of evidence in support of
a mode of action (MOA) for carcinogenesis of carbon tetrachloride at low dose levels. Therefore,
a low dose linear cancer risk model for carbon tetrachloride was used to calculate cancer risk,
which is EPA's baseline approach to risk assessment when the MOA is unknown or not
sufficiently supported by the evidence.
Several uncertainties affected the dermal risk assessment. Evaporation from skin could occur (if
in an aqueous solution, evaporation may be less likely). Route-to-route extrapolation was used to
calculate a human equivalent dermal dose for chronic exposures based on an equation in
Jongeneel (2012). Inhalation to dermal route-to-route extrapolation assumes that the inhalation
route of exposure is most relevant to dermal exposures, as carbon tetrachloride undergoes first-
pass bioactivation in the liver for oral exposures.
The BMDLio value for continuous inhalation exposures was extrapolated to shorter exposure
durations using the equation Cn x t = k, where an empirical value of n was determined to be 2.5
based on rat lethality data (Ten Berge et al.. 1986). The validity of this extrapolation is supported
by similar time scaling processes conducted in the generation of AEGL values. Uncertainties
associated to this extrapolation are discussed in U.S. EPA, (2002) (see section 3.2.5.2.2).
4.5 Risk Characterization Confidence Levels
4.5.1 Environmental Risk
EPA has high confidence that there are no identified ecological risks from the TSCA conditions
of use and exposure pathways within the scope of the risk evaluation for carbon tetrachloride.
This is based on EPA using conservative, high end exposures and modeled surface water
concentrations and the most conservative (highest toxicity)/environmentally-protective acute and
chronic COC.
4.5.2 Human Health Risk
There is medium to high confidence in the risk estimates for inhalation exposures. The PODs for
non-cancer and cancer effects from acute or chronic exposures are rated with at least medium
confidence (see section 3.2.5.3). Exposure estimates from monitoring/surrogate monitoring data
(i.e., manufacturing and processing COUs) are based on a robust monitoring dataset (i.e., > 100
data points), reflecting high confidence in resulting exposure estimates. Exposure estimates for
all the other COUs are based on modeling or monitoring data with limited datapoints (i.e.,
OBOD cleanup process in DoD). There is congruency between the exposure estimates based on
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the limited monitoring data for the OBOD cleanup (i.e., a process that last 1-2 hrs/day) and
estimates based on the Tank Truck and Railcar Loading and Unloading Release and Inhalation
Exposure Model that estimates worker exposure during container and truck unloading activities
that occur at industrial facilities. The fact that there is congruency in the resulting exposure
estimates suggest at least medium confidence in those exposure estimates.
There is low confidence in the risk estimates for dermal exposures. The lack of quantitative data
on dermal absorption for carbon tetrachloride affects the derivation of accurate dermal PODs and
the modeling of dermal exposures. The conservative assumptions used to derive the PODs and
exposure estimate are likely to result in risk overestimations.
4.6 Aggregate or Sentinel Exposures
Section 6(b)(4)(F)(ii) of TSC A requires the EPA, as a part of the risk evaluation, to describe
whether aggregate or sentinel exposures under the conditions of use were considered and the
basis for their consideration. The EPA has defined aggregate exposure as "the combined
exposures to an individual from a single chemical substance across multiple routes and across
multiple pathways" (40 CFR § 702.33). In this risk evaluation exposure is limited to exposure to
carbon tetrachloride by both inhalation and dermal contact only. Inhalation exposure is specified
by the air concentration encountered as a function of time during the work-day. Dermal contact
is characterized by the surface area of skin (hands) exposed, and the duration of the dermal
exposure. For workplace exposures inhalation and dermal exposures are assumed to be only
simultaneous (both end at the end of the task, shift, or work day).
Quantitative information on the dermal absorption of carbon tetrachloride is limited. This data
limitation hinders the accuracy of estimated internal doses from dermal exposures. On the other
hand, carbon tetrachloride is a skin irritant and sensitizer, which suggests that workers are
persuaded on their own (in addition to the workplace industrial hygiene program and OSHA
regulations) to wear gloves when handling the chemical. Based on this assumption, the
occurrence of aggregate exposures including dermal exposures without gloves is expected to be
highly unlikely especially for chronic aggregate exposures. Aggregate exposures including
dermal exposures with gloves are expected to be greatly influenced by the higher inhalation
exposures (see retained absorbed doses from dermal exposures with gloves in Table 2-20). This
greater influence by the inhalation route of exposure is also suggested by the high inhalation
absorption for carbon tetrachloride and the number of activities that may generate fugitive
emissions in the COUs (see section 2.4.1.7).
The EPA defines sentinel exposure as "the exposure to a single chemical substance that
represents the plausible upper bound of exposure relative to all other exposures within a broad
category of similar or related exposures (40 CFR § 702.33)." In this risk evaluation, the EPA
considered sentinel exposure the highest exposure given the details of the conditions of use and
the potential exposure scenarios - for example, workers who perform activities with higher
exposure potential, or certain physical factors like body weight or skin surface area exposed.
EPA characterized high-end exposures in evaluating exposure using both monitoring data and
modeling approaches. Where statistical data are available, EPA typically uses the 95th percentile
value of the available dataset to characterize high-end exposure for a given condition of use.
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Greater inhalation exposures to carbon tetrachloride are estimated for the Domestic
Manufacturing and Processing as Reactant/Intermediate COUs than all the other COUs in this
draft risk evaluation (see Table 2-18, Table 4-7 and Table 4-8).
5 Risk Determination
5.1 Unreasonable Risk
5.1.1 Overview
In each risk evaluation under TSCA section 6(b), EPA determines whether a chemical substance
presents an unreasonable risk of injury to health or the environment, under the conditions of use.
These determinations do not consider costs or other non-risk factors. In making these
determinations, EPA considers relevant risk-related factors, including, but not limited to: the
effects of the chemical substance on health and human exposure to such substance under the
conditions of use (including cancer and non-cancer risks); the effects of the chemical substance
on the environment and environmental exposure under the conditions of use; the population
exposed (including any potentially exposed or susceptible subpopulations (PESS)); the severity
of hazard (including the nature of the hazard and the irreversibility of the hazard); and
uncertainties. EPA also takes into consideration the Agency's confidence in the data used in the
risk estimate. This includes an evaluation of the strengths, limitations and uncertainties
associated with the information used to inform the risk estimate and the risk characterization.
This approach is in keeping with the Agency's final rule, Procedures for Chemical Risk
Evaluation Under the Amended Toxic Substances Control Act (82 FR 33726).21
Under TSCA, conditions of use are defined as the circumstances, as determined by the
Administrator, under which the substance is intended, known, or reasonably foreseen to be
manufactured, processed, distributed in commerce, used, or disposed of. TSCA §3(4).
An unreasonable risk may be indicated when health risks under the conditions of use are
identified by comparing the estimated risks with the risk benchmarks and where the risks affect
the general population or PESS, identified as relevant. For workers (which are one example of
PESS), an unreasonable risk may be indicated when risks are not adequately addressed through
expected use of workplace practices and exposure controls, including engineering controls or use
of personal protective equipment (PPE). An unreasonable risk may also be indicated when
environmental risks under the conditions of use are greater than environmental risk benchmarks.
The risk estimates contribute to the evidence EPA uses to determine unreasonable risk.
EPA uses the term "indicates unreasonable risk" to indicate EPA concern for potential
unreasonable risk. For non-cancer endpoints, "less than MOE benchmark" is used to indicate
potential unreasonable risk; this occurs if an MOE value is less than the benchmark MOE (e.g.,
MOE 0.3 < benchmark MOE 30). For cancer endpoints, EPA uses the term "greater than risk
benchmark" to indicate potential unreasonable risk; this occurs, for example, if the lifetime
21 This risk determination is being issued under TSCA section 6(b) and the terms used, such as unreasonable risk,
and the considerations discussed are specific to TSCA. Other statutes have different authorities and mandates and
may involve risk considerations other than those discussed here.
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cancer risk value is greater than 1 in 10,000 (e.g., cancer risk value is 5 x 10"2 which is greater
than the standard range of acceptable cancer risk benchmarks of 1 x 10"4 to 1 x 10"6). For
environmental endpoints, to indicate potential unreasonable risk EPA uses a risk quotient (RQ)
value "greater than 1" (i.e., RQ >1). Conversely, EPA uses the term "does not indicate
unreasonable risk" to indicate that it is unlikely that EPA has a concern for potential
unreasonable risk. More details are described below.
The degree of uncertainty surrounding the MOEs, cancer risk or RQs is a factor in determining
whether or not unreasonable risk is present. Where uncertainty is low, and EPA has high
confidence in the hazard and exposure characterizations (for example, the basis for the
characterizations is measured or monitoring data or a robust model and the hazards identified for
risk estimation are relevant for conditions of use), the Agency has a higher degree of confidence
in its risk determination. EPA may also consider other risk factors, such as severity of endpoint,
reversibility of effect, or exposure-related considerations, such as magnitude or number of
exposures, in determining that the risks are unreasonable under the conditions of use. Where
EPA has made assumptions in the scientific evaluation, whether or not those assumptions are
protective will also be a consideration. Additionally, EPA considers the central tendency and
high-end scenarios when determining the unreasonable risk. High-end risk estimates (i.e., 95th
percentile) are generally intended to cover individuals or sub-populations with greater exposure
(PESS) and central tendency risk estimates are generally estimates of average or typical
exposure.
EPA may make a no unreasonable risk determination for conditions of use where the substance's
hazard and exposure potential, or where the risk-related factors described previously, lead EPA
to determine that the risks are not unreasonable.
EPA's general approach to determining unreasonable risks to health or the environment is
described in more detail in sections 5.1.2 and 5.1.3; these are not chemical-specific
considerations and the examples listed may not necessarily be evaluated or considered for this
chemical substance.
5.1.2 Risks to Human Health
5.1.2.1 Determining Non-Cancer Risks
Margins of exposure (MOEs) are used in EPA's risk evaluations as a starting point to estimate
non-cancer risks for acute and chronic exposures. The non-cancer evaluation refers to potential
adverse health effects associated with health endpoints other than cancer, including to the body's
organ systems, such as reproductive/developmental effects, cardiac and lung effects, and kidney
and liver effects. The MOE is the point of departure (POD) (an approximation of the no-
observed adverse effect level (NOAEL) or benchmark dose level (BMDL)) for a specific health
endpoint divided by the exposure concentration for the specific scenario of concern. The
benchmark for the MOE that is used accounts for the total uncertainty in a POD, including, as
appropriate: (1) the variation in sensitivity among the members of the human population (i.e.,
intrahuman/intraspecies variability); (2) the uncertainty in extrapolating animal data to humans
(i.e., interspecies variability); (3) the uncertainty in extrapolating from data obtained in a study
with less-than-lifetime exposure to lifetime exposure (i.e., extrapolating from subchronic to
chronic exposure); and (4) the uncertainty in extrapolating from a lowest observed adverse effect
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level (LOAEL) rather than from a NOAEL. MOEs can provide a non-cancer risk profile by
presenting a range of estimates for different non-cancer health effects for different exposure
scenarios and are a widely recognized point estimate method for evaluating a range of potential
non-cancer health risks from exposure to a chemical.
A calculated MOE that is less than the benchmark MOE indicates the possibility of risk to
human health. Whether those risks are unreasonable will depend upon other risk-related factors,
such as severity of endpoint, reversibility of effect, exposure-related considerations (e.g.,
duration, magnitude, frequency of exposure, population exposed), and the confidence in the
information used to inform the hazard and exposure values. If the calculated MOE is greater than
the benchmark MOE, generally it is less likely that there is risk.
Uncertainty factors (UFs) also play an important role in the risk estimation approach and in
determining unreasonable risk. A lower benchmark MOE (e.g., 30) indicates greater certainty in
the data (because fewer of the default UFs relevant to a given POD as described above were
applied). A higher benchmark MOE (e.g., 1000) would indicate more uncertainty in risk
estimation and extrapolation for the MOE for specific endpoints and scenarios. However, these
are often not the only uncertainties in a risk evaluation.
5.1.2.2 Determining Cancer Risks
EPA estimates cancer risks by determining the incremental increase in probability of an
individual in an exposed population developing cancer over a lifetime (excess lifetime cancer
risk (ELCR)) following exposure to the chemical under specified use scenarios. Standard cancer
benchmarks used by EPA and other regulatory agencies are an increased cancer risk above
benchmarks ranging from 1 in 1,000,000 to 1 in 10,000 (i.e., 1 x 10"6 to 1 x 10"4) depending on
the subpopulation exposed. Generally, EPA considers 1 x 10"6 to 1 x 10"4 as the appropriate
benchmark for the general population, consumer users, and non-occupational PESS.22
For the subject chemical substance, the EPA, consistent with case law and 2017 NIOSH
guidance,23 used 1 x 10"4 as the benchmark for the purposes of this risk determination for
individuals in industrial/commercial work environments subject to Occupational Safety and
Health Act (OSHA) requirements. It is important to note that 1 x 10"4 is not a bright line and
EPA has discretion to make risk determinations based on other benchmarks as appropriate. It is
22 As an example, when EP A's Office of Water in 2017 updated the Human Health Benchmarks for Pesticides, the
benchmark for a "theoretical upper-bound excess lifetime cancer risk" from pesticides in drinking water was
identified as 1 in 1,000,000 to 1 in 10,000 over a lifetime of exposure (EPA. Human Health Benchmarks for
Pesticides: Updated 2017 Technical Document. January 2017. https://www.epa.gov/sites/production/files/2015-
10/documents/hh-benchmarks-techdoc.pdf). Similarly, EPA's approach under the Clean Air Act to evaluate residual
risk and to develop standards is a two-step approach that includes a "presumptive limit on maximum individual
lifetime [cancer] risk (MIR) of approximately 1 in 10 thousand" and consideration of whether emissions standards
provide an ample margin of safety to protect public health "in consideration of all health information including the
number of persons at risk levels higher than approximately 1 in 1 million, as well as other relevant factors" (54 FR
38044, 38045, September 14, 1989).
23 International Union UAW v. Pendergrass, 878 F.2d 389 (D.C. Cir. 1989), citing Industrial Union Department,
AFL-CIO v. American Petroleum Institute, 448 U.S. 607 (1980) ("Benzene decision"), in which it was found that a
lifetime cancer risk of 1 in 1,000 was found to be clearly significant; and NIOSH (2016). Current intelligence
bulletin 68: NIOSH chemical carcinogen policy, available at https://www.cdc.gov/niosh/docs/2017-100/pdf/2017-
100.pdf.
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important to note that exposure-related considerations (duration, magnitude, population exposed)
can affect EPA's estimates of the excess lifetime cancer risk.
5.1.3 Determining Environmental Risk
To assess environmental risk, EPA generally identifies and evaluates environmental hazard data
for aquatic, sediment-dwelling, and terrestrial organisms exposed under acute and chronic
exposure conditions. The environmental risk includes any risks that exceed benchmark values to
the aquatic and terrestrial environment from levels of the evaluated chemical found in the
environment (e.g., surface water, sediment, soil, biota) based on the fate properties, relatively
high potential for release, and the availability of environmental monitoring data and hazard data.
Environmental risks are estimated by calculating a RQ. The RQ is defined as:
RQ = Environmental Concentration / Effect Level
An RQ equal to 1 indicates that the exposures are the same as the concentration that causes
effects. If the RQ is greater than 1, the exposure is greater than the effect concentration and there
is potential for risk presumed. If the RQ is less than 1, the exposure is less than the effect
concentration and unreasonable risk is not likely. The Concentrations of Concern (COC) or
hazard value for certain aquatic organisms are used to calculate RQs for acute and chronic
exposures. For environmental risk, EPA is more likely to determine that there is unreasonable
risk if the RQ exceeds 1 for the conditions of use being evaluated. Consistent with EPA's human
health evaluations, the RQ is not treated as a bright line and other risk-based factors may be
considered (e.g., exposure scenario, uncertainty, severity of effect) for purposes of making a risk
determination.
5.2 Risk Determination for Carbon Tetrachloride
EPA's preliminary determinations of unreasonable risk for specific conditions of use of carbon
tetrachloride listed below are based on health risks to occupational non-users (ONUs) during
occupational exposures.
As described in section 4, significant risks associated with more than one adverse effect (e.g.
liver toxicity and cancer) were identified for particular conditions of use. In Table 5-1 and
section 5.3 below, EPA identifies cancer as the driver endpoint for the conditions of use that
EPA has determined present unreasonable risks. This is the effect that is most sensitive, and it is
expected that addressing risks for this effect would address other identified risks.
• Occupational non-users (ONUs): EPA evaluated inhalation risks for acute and chronic
exposures for occupational non-users (ONUs). However, EPA did not separately calculate
inhalation risk estimates for ONUs and workers. There is uncertainty in the ONU inhalation
risk estimate since the data did not distinguish between worker and ONU inhalation exposure
estimates. While the difference between the exposures of ONUs and the exposures of
workers directly handling the chemical generally cannot be quantified, ONU inhalation
exposures are expected to be lower than inhalation exposures for workers directly handling
the chemical. EPA considered the ONU exposures to be equal to the central tendency risk
estimates for workers when determining ONU risk attributable to inhalation. While this is
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likely health protective as it assumes ONU exposure is greater than that of 50% of the
workers, this is highly uncertain, and EPA has low confidence in these exposure estimates for
ONUs. Recognizing the significant uncertainty surrounding EPA's inhalation exposure
estimates for ONUs, EPA will continue to seek data on ONU inhalation exposures during the
public comment period on the draft risk evaluation. In addition, because EPA is preliminarily
making a finding that four COUs present an unreasonable risk for ONUs based on an
increased cancer risk estimate of 4 * 10"4, EPA will further analyze this information to
determine whether this four-fold difference from the cancer risk benchmark falls within the
range of uncertainty for these estimates. Dermal exposures are not expected because ONUs
do not typically directly handle the carbon tetrachloride, nor they are in the immediate
proximity of carbon tetrachloride. Estimated numbers of occupational non-users are
in section 2.4.1.
As described below, risks to workers, general population, consumers, bystanders to consumer
use, and the environment either were not relevant for these conditions of use or were evaluated
and not found to be unreasonable. For the conditions of use where EPA found no unreasonable
risk, EPA describes the estimated risks in section 4.2 (Table 4-7, Table 4-8, and Table 4-11)
• Workers: EPA evaluated workers' acute and chronic inhalation and dermal occupational
exposures for cancer and non-cancer risks and determined whether any risks indicated are
unreasonable. For all applicable conditions of use, acute and chronic inhalation and dermal
exposure scenarios resulted in calculated MOEs and cancer risk levels that did not indicate
risk (Table 4-7, Table 4-8, Table 4-9, Table 4-10, Table 4-11,Table 4-12) with expected PPE. As
a result, EPA does not find unreasonable risks of injury to health of workers from acute and
chronic inhalation and dermal exposures to carbon tetrachloride. EPA expects there is
compliance with federal and state laws, such as worker protection standards, unless case-
specific facts indicate otherwise, and therefore existing OSHA regulations for worker
protection and hazard communication will result in use of appropriate PPE consistent with
the applicable SDSs in a manner adequate to protect employees. Estimated numbers of
workers are in section 2.4.1.
• General population: The Office of Chemical Safety and Pollution Prevention works closely
with the offices within EPA that administer and implement the regulatory programs under
these statutes. EPA believes that the TSCA risk evaluation should focus on those exposure
pathways associated with TSCA uses that are not subject to the regulatory regimes discussed
above because these pathways are likely to represent the greatest areas of concern to EPA.
Examples of exposure pathways covered by other statutes for carbon tetrachloride such as:
the ambient air pathway (i.e., carbon tetrachloride is listed as a Hazardous Air Pollutant in
the Clean Air Act (CAA)), the drinking water pathway (i.e., National Primary Drinking
Water Regulations (NPDWRs) are promulgated for carbon tetrachloride under the Safe
Drinking Water Act), ambient water pathways (i.e., carbon tetrachloride is a priority
pollutant with recommended water quality criteria for protection of human health under the
CWA), the biosolids pathway (i.e., the biosolids pathway for carbon tetrachloride is currently
being addressed in the CWA regulatory analytical process), and disposal pathways (i.e.,
carbon tetrachloride disposal is managed and prevented from further environmental release
by RCRA and SDWA regulations). In addition, the Montreal Protocol and Title VI of the
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CAA Amendments of 1990 led to a phase-out of carbon tetrachloride production in the
United States for most non feedstock domestic uses in 1996.
• Consumers and bystanders to consumer use: EPA did not include any consumer uses
among the conditions of use within the scope of the risk evaluation for carbon tetrachloride.
The CPSC banned the use of carbon tetrachloride in consumer products (excluding
unavoidable residues not exceeding 10 ppm atmospheric concentration) in 1970. Therefore,
EPA did not evaluate hazards or exposures to consumers or bystanders to consumer use in
this risk evaluation, and there are no risk determinations for these populations.
• Environmental risks: EPA concluded that the surface water concentrations did not exceed
the acute COC (i.e., acute RQs < 1) for aquatic species for all but one of the sites assessed
(see Table 4-2). EPA determined there is not an acute aquatic concern for carbon tetrachloride
after further review indicated that the one site had a one-time increased environmental
release of carbon tetrachloride in 2014 due to an unexpected chemical spill. With respect to
the chronic COC, due to the volatile properties of carbon tetrachloride, EPA determined that
it is more likely that a chronic exposure duration will occur when there are long-term
consecutive days of release versus an interval or pulse exposure, which would more likely
result in an acute exposure duration. For all sites analyzed, none had more than 20 days
where the chronic COC was exceeded (see Table 4-2). Consequently, EPA determined there
is not an acute or chronic aquatic concern for carbon tetrachloride from the conditions of use.
With respect to algae, no sites had more than 20 days where the algal COC was exceeded
(see Table 4-2). Due to the quick regeneration time of many algae species, impacts to algae
populations would be most likely to over long-term consecutive days of release (i.e., > 20)
versus an interval or pulse exposure. Consequently, EPA determined there is not a concern
for carbon tetrachloride exposure to algae from the conditions of use. With respect to
sediment-dwelling aquatic species, carbon tetrachloride is not expected to partition to or be
retained in sediment and is expected to remain in aqueous phase due to its water solubility
and low partitioning to organic matter, so EPA did not further evaluate exposure to sediment-
dwelling organisms. Therefore, EPA does not find unreasonable environmental risks to
aquatic species from the conditions of use for carbon tetrachloride (see section 4.1). Also, as
explained in section 2.5.3.2 of the problem formulation (U.S. EPA. 2018d). exposure to
terrestrial organisms was removed from the scope of the evaluation. This exposure pathway
is considered to be covered under programs of other environmental statutes administered by
EPA (e.g., CWA, RCRA, and CAA) which adequately assess and effectively manage
exposures and for which long-standing regulatory and analytical processes already exist.
Therefore, EPA did not evaluate hazards and exposures to terrestrial organisms in this risk
evaluation, and there is no risk determination for terrestrial organisms.
Table 5-1 below presents an overview of risk determinations by condition of use. An in-
depth explanation of each determination follows the table, in section 5.3.
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5461 Table 5-1. Summary of Unreasonable Risk Determinations by Condition of Use
Condition of Use
Unreasonable Risk Determination
Domestic manufacture
Presents an unreasonable risk of injury to health (occupational non-users)
Import (including loading/unloading and repackaging)
Does not present an unreasonable risk of injury to health or the environment
Processing as a reactant in the production of
hydrochlorofluorocarbons, hydrofluorocarbon,
hydrofluoroolefin, and perchloroethylene
Presents an unreasonable risk of injury to health (occupational non-users)
Processing as a reactant/intermediate in reactive ion etching
(i.e., semiconductor manufacturing)
Does not present an unreasonable risk of injury to health or the environment
Processing for incorporation into formulation, mixtures or
reaction products (petrochemicals-derived manufacturing;
agricultural products manufacturing; other basic organic and
inorganic chemical manufacturing)
Presents an unreasonable risk of injury to health (occupational non-users) (other
basic organic and inorganic chemical manufacturing).
Does not present an unreasonable risk of injury to health or the environment
(petrochemicals-derived manufacturing; agricultural products manufacturing)
Repackaging for use in laboratory chemicals
Does not present an unreasonable risk of injury to health or the environment
Recycling
Does not present an unreasonable risk of injury to health or the environment
Distribution in commerce
Does not present an unreasonable risk of injury to health or the environment
Industrial/commercial use as an industrial processing aid in the
manufacture of petrochemicals-derived products and
agricultural products.
Does not present an unreasonable risk of injury to health or the environment
Industrial/commercial use in the manufacture of other basic
chemicals (including chlorinated compounds used in solvents,
adhesives, asphalt, and paints and coatings)
Presents an unreasonable risk of injury to health (occupational non-users)
Industrial/commercial use in metal recovery
Does not present an unreasonable risk of injury to health or the environment
Industrial/commercial use as an additive
Does not present an unreasonable risk of injury to health or the environment
Specialty uses by the Department of Defense
Does not present an unreasonable risk of injury to health or the environment
Industrial/commercial use as a laboratory chemical
Does not present an unreasonable risk of injury to health or the environment
Disposal
Does not present an unreasonable risk of injury to health or the environment
5462
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5.3 Detailed Risk Determinations by Conditions of Use
5.3.1 Manufacture-Domestic manufacture
Section 6(b)(4)(A) unreasonable risk determination for domestic manufacture of carbon
tetrachloride:
• Presents an unreasonable risk of injury to health (occupational non-users
(ONUs)).
• Does not present an unreasonable risk of injury to health (workers).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Unreasonable risk driver - ONUs:
• Cancer from chronic inhalation exposure.
Driver benchmark - ONUs:
• Cancer: Benchmark = 1 x 10"4
Risk estimate - ONUs:
Cancer: Chronic inhalation risk estimate 4 x 10"4and 5 x 10"3 (12-hr TWA) (central tendency and
high end) (Table 4-11)
Risk Considerations: EPA assessed inhalation exposures using submitted monitoring data
containing information on 8-hour and 12-hour shifts for this and other conditions of use for
which this occupational exposure scenario is relevant. The unreasonable risk determination was
based on the submitted monitoring data for 12-hour shifts. The submitted data cover two
companies and are summarized in Table 2-6. There is uncertainty in the ONU risk estimate since
the data did not distinguish between worker and ONU inhalation exposure estimates. To account
for this uncertainty, EPA considered the central tendency estimate when determining ONU risk.
As noted previously, EPA has low confidence in the exposure estimates for ONUs. For the
purpose of making a risk determination for workers, EPA considered the high-end estimates.
While those risk estimates for this condition of use indicate risk in the absence of PPE, the risk
estimates for these pathways do not indicate risk for workers when expected use of PPE, a
respirator with an APF of 50, was considered (Table 4-8 and Table 4-11). EPA's unreasonable
risk determination for ONUs reflects the hazards associated with chronic exposure to carbon
tetrachloride and is based on an expected absence of PPE for ONUs.
Life Cycle Stage
Category
Subcategory
Manufacture
Domestic Manufacture
Domestic manufacture
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5.3.2 Manufacture- Import (includes repackaging and loading/unloading)
Section 6(b)(4)(A) unreasonable risk determination for import of carbon tetrachloride:
• Does not present an unreasonable risk of injury to health (workers and ONUs).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Exposure scenario with highest risk estimate - workers and ONUs:
• Liver toxicity from chronic inhalation exposure and cancer from chronic dermal
exposure.
Benchmarks - workers and ONUs:
• Liver toxicity: Benchmark MOE = 30.
• Cancer: Benchmark = 1 x 10"4.
Risk estimates - workers:
• Liver toxicity: Chronic inhalation MOE 104 (high end) (Table 4-8).
• Cancer: Dermal risk estimate 6 x 10"5 (high end) with PPE (gloves PF 5) (Table 4-12).
Risk estimates - ONUs:
• Liver toxicity: Chronic inhalation MOEs 546 and 104 (central tendency and high end)
(Table 4-8).
• Cancer: Chronic inhalation risk estimates 3 x 10"5 and 2 x 10"4 (central tendency and high
end) (Table 4-11).
Risk Considerations: Risk estimates for workers and ONUs for acute and chronic inhalation and
forworkers, chronic dermal do not indicate risk. While high-end risk estimates for this condition
of use indicate risk in the absence of PPE, risk estimates for these pathways do not indicate risk
for workers when expected use of PPE, a respirator with an APF of 10 and gloves with a PF of 5,
was considered (Table 4-8, Table 4-11 and Table 4-12). EPA did not separately calculate risk
estimates for ONUs and workers. ONU inhalation exposures are expected to be lower than
inhalation exposures for workers directly handling the chemical substance; however, the relative
exposure of ONUs to workers in these cases cannot be quantified. To account for this
uncertainty, EPA considered the central tendency estimate when determining ONU risk. EPA's
risk determination for ONUs is based on an expected absence of PPE. Dermal exposures are not
expected for ONUs.
Life Cycle Stage
Category
Subcategory
Manufacture
Import
Import
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5.3.3 Processing-Processing as a reactant in the production of
hydrochlorofluorocarbon, hydrofluorocarbon, hydrofluoroolefin, and
perchloroethylene
Section 6(b)(4)(A) unreasonable risk determination for processing carbon tetrachloride as a
reactant in the production of hydrochlorofluorocarbon. hydrofluorocarbon. hydrofluoroolefin.
and perchloroethylene:
• Presents an unreasonable risk of injury to health (ONUs).
• Does not present an unreasonable risk of injury to health (workers).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Unreasonable risk driver - ONUs:
• Cancer from chronic inhalation exposure.
Driver benchmark - ONUs:
• Cancer: Benchmark = 1 x 10"4
Risk estimate - ONUs:
• Cancer: Chronic inhalation risk estimates 4 x 10"4 and 5 x 10"3 (12-hr TWA) (central
tendency and high end) (Table 4-11)
Risk Considerations: EPA assessed inhalation exposures using submitted monitoring data
containing information on 8-hour and 12-hour shifts for this and other conditions of use for
which this occupational exposure scenario is relevant. The unreasonable risk determination was
based on the submitted monitoring data for 12-hour shifts. The submitted data cover two
companies and are summarized in Table 2-6. There is uncertainty in the ONU risk estimate since
the data did not distinguish between worker and ONU inhalation exposure estimates. To account
for this uncertainty, EPA considered the central tendency estimate when determining ONU risk.
As noted previously, EPA has low confidence in the exposure estimates for ONUs. For the
purpose of making a risk determination for workers, EPA considered the high-end estimates.
While those risk estimates for this condition of use indicate risk in the absence of PPE, the risk
estimates for these pathways do not indicate risk for workers when expected use of PPE, a
respirator with an APF of 50, was considered (Table 4-8 and Table 4-11). EPA's unreasonable
risk determination for ONUs reflects the hazards associated with chronic exposure to carbon
tetrachloride and is based on an expected absence of PPE for ONUs.
Life Cycle Stage
Category
Subcategory
Processing
Processing as a Reactant/
Intermediate
Hydrochlorofluorocarbons (HCFCs),
Hydrofluorocarbon (HFCs) and
Hydrofluoroolefin (HFOs)
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5591
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5593
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5598
5599
5600
5601
5602
5603
5604
5605
5606
5607
5608
5609
5610
5611
5612
5613
5614
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Life Cycle Stage
Category
Subcategory
Perchloroethylene (PCE)
5.3.4 Processing- Processing as reactant/intermediate in reactive ion etching
Section 6(b)(4)(A) unreasonable risk determination for processing of carbon tetrachloride as a
reactant/intermediate in reactive ion etching (e.g.. semiconductor manufacture):
• Does not present an unreasonable risk of injury to health (workers and ONUs).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Risk Considerations: A quantitative evaluation of the occupational exposures attributable to this
condition of use is not included in the risk evaluation because EPA estimates that worker
exposures to carbon tetrachloride during reactive ion etching are negligible. Due to the
performance requirements of products typically produced using this technique, carbon
tetrachloride is typically applied in small quantities under a fume hood and/or inside a highly
controlled work area (a Class 1 clean room), thus eliminating or significantly reducing the
potential for exposures (section 2.4.1.7.5).
Life Cycle Stage
Category
Subcategory
Processing
Processing as a Reactant/
Intermediate
Reactive ion etching (i.e.,
semiconductor manufacturing)
5.3.5 Processing - Incorporation into formulation, mixture or reaction
products-Petrochemicals-derived manufacturing, agricultural products
manufacturing, and other basic organic and inorganic chemical
manufacturing
Section 6(b)(4)(A) unreasonable risk determination for processing carbon tetrachloride to
incorporate into a formulation, mixture or reaction product (other basic organic and inorganic
chemical manufacturing):
• Presents an unreasonable risk of injury to health (ONUs).
• Does not present an unreasonable risk of injury to health (workers).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Unreasonable risk driver - ONUs:
• Cancer from chronic inhalation exposure
Driver benchmark - ONUs:
• Cancer: Benchmark = 1 * 10"4
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5629
5630
5631
5632
5633
5634
5635
5636
5637
5638
5639
5640
5641
5642
5643
5644
5645
5646
5647
5648
5649
5650
5651
5652
5653
5654
5655
5656
5657
5658
5659
5660
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5662
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Risk estimate - ONUs:
• Cancer: Chronic inhalation risk estimates 4 * 10"4 and 5 * 10"3 (central tendency and
high end) (Table 4-11)
Risk Considerations: EPA assessed inhalation exposures using submitted monitoring data
containing information on 8-hour and 12-hour shifts for this and other conditions of use for
which this occupational exposure scenario is relevant. The unreasonable risk determination was
based on the submitted monitoring data for 12-hour shifts. The submitted data cover two
companies and are summarized in Table 2-6. There is uncertainty in the ONU risk estimate since
the data did not distinguish between worker and ONU inhalation exposure estimates. To account
for this uncertainty, EPA considered the central tendency estimate when determining ONU risk.
As noted previously, EPA has low confidence in the exposure estimates for ONUs. For the
purpose of making a risk determination for workers, EPA considered the high-end estimates.
While those risk estimates for this condition of use indicate risk in the absence of PPE, the risk
estimates for these pathways do not indicate risk for workers when expected use of PPE, a
respirator with an APF of 50, was considered (Table 4-8, Table 4-11). EPA's unreasonable risk
determination for ONUs reflects the hazards associated with chronic exposure to carbon
tetrachloride and is based on an expected absence of PPE for ONUs.
Section 6(b)(4)(A) unreasonable risk determination for processing carbon tetrachloride to
incorporate into a formulation, mixture or reaction product (petrochemicals-derived
manufacturing, agricultural products manufacturing):
• Does not present an unreasonable risk of injury to health (workers, ONUs).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Exposure scenario with highest risk estimate - workers and ONUs:
• Liver toxicity from chronic inhalation exposure and cancer from chronic dermal
exposure.
Benchmarks - workers and ONUs:
• Liver toxicity: Benchmark MOE = 30.
• Cancer: Benchmark = 1 * 10"4.
Risk estimates - workers:
• Liver toxicity: Chronic inhalation MOE 104 (high end) (Table 4-8).
• Cancer: Chronic dermal risk estimate 6 * 10"5 (high end) with PPE (gloves PF 5) (Table
4-12).
Risk estimates - ONUs:
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5672
5673
5674
5675
5676
5677
5678
5679
5680
5681
5682
5683
5684
5685
5686
5687
5688
5689
5690
5691
5692
5693
5694
5695
5696
5697
5698
5699
5700
5701
5702
5703
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
• Liver toxicity: Chronic inhalation MOEs 546 and 104 (central tendency and high end)
(Table 4-8).
• Cancer: Chronic inhalation risk estimates 3 * 10"5 and 2 * 10"4 (central tendency and high
end) (Table 4-11).
Risk Considerations: Risk estimates for workers and ONUs for acute and chronic inhalation and
for workers, chronic dermal do not indicate risk. While high-end risk estimates for this condition
of use indicate risk in the absence of PPE, risk estimates for these pathways do not indicate risk
for workers when expected use of PPE, a respirator with an APF of 10 and gloves with PF of 5,
was considered (Table 4-8, Table 4-11 and Table 4-12). EPA did not separately calculate risk
estimates for ONUs and workers. ONU inhalation exposures are expected to be lower than
inhalation exposures for workers directly handling the chemical substance; however, the relative
exposure of ONUs to workers in these cases cannot be quantified. To account for this
uncertainty, EPA considered the central tendency estimate when determining ONU risk. EPA's
risk determination for ONUs is based on an expected absence of PPE. Dermal exposures are not
expected for ONUs.
Life Cycle Stage
Category
Subcategory
Processing
Incorporation into
Formulation, Mixture or
Reaction Products
Petrochemicals-derived manufacturing;
Agricultural products manufacturing;
Other basic organic and inorganic
chemical manufacturing.
5.3.6 Processing-Repackaging of carbon tetrachloride for use in laboratory
chemicals
Section 6(b)(4)(A) unreasonable risk determination for repackaging of carbon tetrachloride for
use in laboratory chemicals:
• Does not present an unreasonable risk of injury to health (workers and ONUs).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Exposure scenario with highest risk estimate - workers and ONUs:
• Liver toxicity from chronic inhalation exposure and cancer from chronic dermal
exposure.
Benchmarks - workers and ONUs:
• Liver toxicity: Benchmark MOE = 30.
• Cancer: Benchmark = 1 x 10"4.
Risk estimates - workers:
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5713
5714
5715
5716
5717
5718
5719
5720
5721
5722
5723
5724
5725
5726
5727
5728
5729
5730
5731
5732
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5734
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5737
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
• Liver toxicity: Chronic inhalation MOE 104 (high end) (Table 4-8).
• Cancer: Chronic dermal risk estimate 6 x 10"5 (high end) with PPE (gloves PF 5) (Table
4-12).
Risk estimates - ONUs:
• Liver toxicity: Chronic inhalation MOEs 546 and 104 (central tendency and high end)
(Table 4-8).
• Cancer: Chronic inhalation risk estimates 3 x 10"5 and 2 x 10"4 (central tendency and high
end) (Table 4-11).
Risk Considerations: Risk estimates for workers and ONUs for acute and chronic inhalation and
for workers, chronic dermal do not indicate risk. While high-end risk estimates for this condition
of use indicate risk in the absence of PPE, risk estimates for these pathways do not indicate risk
for workers when expected use of PPE, a respirator with an APF of 10 and gloves with PF of 5,
was considered (Table 4-8, Table 4-11 and Table 4-12). EPA did not separately calculate risk
estimates for ONUs and workers. ONU inhalation exposures are expected to be lower than
inhalation exposures for workers directly handling the chemical substance; however, the relative
exposure of ONUs to workers in these cases cannot be quantified. To account for this
uncertainty, EPA considered the central tendency estimate when determining ONU risk. EPA's
risk determination for ONUs is based on an expected absence of PPE. Dermal exposures are not
expected for ONUs.
Life Cycle Stage
Category
Subcategory
Processing
Processing - repackaging
Laboratory Chemicals
5.3.7 Processing-Recycling
Section 6(b)(4)(A) unreasonable risk determination for recycling of carbon tetrachloride:
• Does not present an unreasonable risk of injury to health (workers and ONUs).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Exposure scenario with highest risk estimate - workers and ONUs:
• Liver toxicity from chronic inhalation exposure and cancer from chronic dermal
exposure.
Benchmarks - workers and ONUs:
• Liver toxicity: Benchmark MOE = 30.
• Cancer: Benchmark = 1 x 10"4.
Risk estimates - workers:
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5751
5752
5753
5754
5755
5756
5757
5758
5759
5760
5761
5762
5763
5764
5765
5766
5767
5768
5769
5770
5771
5772
5773
5774
5775
5776
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5778
5779
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
• Liver toxicity: Chronic inhalation MOE 104 (high end) (Table 4-8).
• Cancer: Chronic dermal risk estimate 6 x 10"5 (high end) with PPE (gloves PF 5) (Table
4-12).
Risk estimates - ONUs:
• Liver toxicity: Chronic inhalation MOEs 546 and 104 (central tendency and high end)
(Table 4-8).
• Cancer: Chronic inhalation risk estimates 3 x 10"5 and 2 x 10"4 (central tendency and high
end) (Table 4-11).
Risk Considerations: Risk estimates for workers and ONUs for acute and chronic inhalation and
for workers, chronic dermal do not indicate risk. While high-end risk estimates for this condition
of use indicate risk in the absence of PPE, risk estimates for these pathways do not indicate risk
for workers when expected use of PPE, a respirator with an APF of 10 and gloves with PF of 5,
was considered (Table 4-8, Table 4-11 and Table 4-12). EPA did not separately calculate risk
estimates for ONUs and workers. ONU inhalation exposures are expected to be lower than
inhalation exposures for workers directly handling the chemical substance; however, the relative
exposure of ONUs to workers in these cases cannot be quantified. To account for this
uncertainty, EPA considered the central tendency estimate when determining ONU risk. EPA's
risk determination for ONUs is based on an expected absence of PPE. Dermal exposures are not
expected for ONUs.
Life Cycle Stage
Category
Subcategory
Processing
Recycling
Recycling
5.3.8 Distribution in Commerce
Section 6(b)(4)(A) unreasonable risk determination for distribution of carbon tetrachloride:
• Does not present an unreasonable risk of injury to health (workers and ONUs).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Risk Considerations: A quantitative evaluation of the distribution of carbon tetrachloride was not
included in the risk evaluation because exposures and releases from distribution were considered
within each condition of use.
Life Cycle Stage
Category
Subcategory
Distribution in commerce
Distribution
Distribution in commerce
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5789
5790
5791
5792
5793
5794
5795
5796
5797
5798
5799
5800
5801
5802
5803
5804
5805
5806
5807
5808
5809
5810
5811
5812
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5820
5821
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
5.3.9 Industrial/ Commercial Use - Industrial Processing Aid - Manufacturing
of petrochemical-derived products and agricultural products
Section 6(b)(4)(A) unreasonable risk determination for use of carbon tetrachloride as an
industrial processing aid in the manufacture of petrochemicals-derived products and agricultural
products:
• Does not present an unreasonable risk of injury to health (workers and ONUs).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Exposure scenario with highest risk estimate - workers and ONUs:
• Liver toxicity from chronic inhalation exposure and cancer from chronic dermal
exposure.
Benchmarks - workers and ONUs:
• Liver toxicity: Benchmark MOE = 30.
• Cancer: Benchmark = 1 x 10"4.
Risk estimates - workers:
• Liver toxicity: Chronic inhalation MOE 104 (high end) (Table 4-8).
• Cancer: Chronic dermal risk estimate 6 x 10"5 (high end) with PPE (gloves PF 5) (Table
4-12).
Risk estimates - ONUs:
• Liver toxicity: Chronic inhalation MOEs 546 and 104 (central tendency and high end)
(Table 4-8).
• Cancer: Chronic inhalation risk estimates 3 x 10"5 and 2 x 10"4 (central tendency and high
end) (Table 4-11).
Risk Considerations: Risk estimates for workers and ONUs for acute and chronic inhalation and
for workers, chronic dermal do not indicate risk. While high-end risk estimates for this condition
of use indicate risk in the absence of PPE, risk estimates for these pathways do not indicate risk
for workers when expected use of PPE, a respirator with an APF of 10 and gloves with a PF of 5,
was considered (Table 4-8, Table 4-11 and Table 4-12). EPA did not separately calculate risk
estimates for ONUs and workers. ONU inhalation exposures are expected to be lower than
inhalation exposures for workers directly handling the chemical substance; however, the relative
exposure of ONUs to workers in these cases cannot be quantified. To account for this
uncertainty, EPA considered the central tendency estimate when determining ONU risk. EPA's
risk determination for ONUs is based on an expected absence of PPE. Dermal exposures are not
expected for ONUs.
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5834
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5836
5837
5838
5839
5840
5841
5842
5843
5844
5845
5846
5847
5848
5849
5850
5851
5852
5853
5854
5855
5856
5857
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Life Cycle Stage
Category
Subcategory
Industrial/commercial
use
Petrochemicals-derived Products
Manufacturing
Processing aid
Agricultural Products Manufacturing
Other Basic Organic and Inorganic
Chemical Manufacturing
5.3.10 Industrial/Commercial Use - Other Basic Organic and Inorganic
Chemical Manufacturing (manufacturing of chlorinated compounds used
in solvents for cleaning and degreasing, adhesives and sealants, paints and
coatings, asphalt, and elimination of nitrogen trichloride in the production
of chlorine and caustic)
Section 6(b)(4)(A) unreasonable risk determination for use of carbon tetrachloride in the
manufacture of other basic chemicals:
• Presents an unreasonable risk of injury to health (ONUs).
• Does not present an unreasonable risk of injury to health (workers).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Unreasonable risk driver - ONUs:
• Cancer from chronic inhalation exposure.
Driver benchmark - ONUs:
• Cancer: Benchmark = 1 x 10"4
Risk estimate - ONUs:
• Cancer: Chronic inhalation risk estimates 4 x 10"4 and 5 x 10"3 (12-hr TWA) (central
tendency and high end) (Table 4-11)
Risk Considerations: EPA assessed inhalation exposures using submitted monitoring data
containing information on 8-hour and 12-hour shifts for this and other conditions of use for
which this occupational exposure scenario is relevant. The unreasonable risk determination was
based on the submitted monitoring data for 12-hour shifts. The submitted data cover two
companies and are summarized in Table 2-6. There is uncertainty in the ONU risk estimate since
the data did not distinguish between worker and ONU inhalation exposure estimates. To account
for this uncertainty, EPA considered the central tendency estimate when determining ONU risk.
As noted previously, EPA has low confidence in the exposure estimates for ONUs. For the
purpose of making a risk determination for workers, EPA considered the high-end estimates.
While those risk estimates for this condition of use indicate risk in the absence of PPE, the risk
estimates for these pathways do not indicate risk for workers when expected use of PPE, a
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respirator with an APF of 50, was considered (Table 4-8 and Table 4-11). EPA's unreasonable
risk determination for ONUs reflects the hazards associated with chronic exposure to carbon
tetrachloride and is based on an expected absence of PPE for ONUs.
Life Cycle Stage
Category
Subcategory
Industrial/commercial
use
Other Basic Organic and
Inorganic Chemical
Manufacturing
Manufacturing of chlorinated
compounds used in solvents for
cleaning and degreasing
Manufacturing of chlorinated
compounds used in adhesives and
sealants
Manufacturing of chlorinated
compounds used in paints and coatings
Manufacturing of inorganic chlorinated
compounds (i.e., elimination of
nitrogen trichloride in the production of
chlorine and caustic)
Manufacturing of chlorinated
compounds used in asphalt
5.3.1 l_Industrial/Commercial Use - Metal recovery
Section 6(b)(4)(A) unreasonable risk determination for use of carbon tetrachloride in metal
recovery:
• Does not present an unreasonable risk of injury to health (workers and ONUs).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Exposure scenario with highest risk estimate - workers and ONUs:
• Liver toxicity from chronic inhalation exposure and cancer from chronic dermal
exposure.
Benchmarks - workers and ONUs:
• Liver toxicity: Benchmark MOE = 30.
• Cancer: Benchmark = 1 x 10"4.
Risk estimates - workers:
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5892
5893
5894
5895
5896
5897
5898
5899
5900
5901
5902
5903
5904
5905
5906
5907
5908
5909
5910
5911
5912
5913
5914
5915
5916
5917
5918
5919
5920
5921
5922
5923
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5925
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
• Liver toxicity: Chronic inhalation MOE 104 (high end) (Table 4-8).
• Cancer: Chronic dermal risk estimate 6 x 10"5 (high end) with PPE (gloves PF 5) (Table
4-12).
Risk estimates - ONUs:
• Liver toxicity: Chronic inhalation MOEs 546 and 104 (central tendency and high end)
(Table 4-8).
• Cancer: Chronic inhalation risk estimates 3 x 10"5 and 2 x 10"4 (central tendency and high
end) (Table 4-11).
Risk Considerations: Risk estimates for workers and ONUs for acute and chronic inhalation and
for workers, chronic dermal do not indicate risk. While high-end risk estimates for this condition
of use indicate risk in the absence of PPE, risk estimates for these pathways do not indicate risk
for workers when expected use of PPE, a respirator with an APF of 10 and gloves with a PF of 5,
was considered (Table 4-8, Table 4-11 and Table 4-12). EPA did not separately calculate risk
estimates for ONUs and workers. ONU inhalation exposures are expected to be lower than
inhalation exposures for workers directly handling the chemical substance; however, the relative
exposure of ONUs to workers in these cases cannot be quantified. To account for this
uncertainty, EPA considered the central tendency estimate when determining ONU risk. EPA's
risk determination for ONUs is based on an expected absence of PPE. Dermal exposures are not
expected for ONUs.
Life Cycle Stage
Category
Subcategory
Industrial/commercial
use
Other Uses
Processing aid (i.e., metal recovery).
5.3.12 Industrial/Commercial Use - Use an additive
Section 6(b)(4)(A) unreasonable risk determination for the use of carbon tetrachloride as an
additive:
• Does not present an unreasonable risk of injury to health (workers and ONUs).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Exposure scenario with highest risk estimate - workers and ONUs:
• Liver toxicity from chronic inhalation exposure and cancer from chronic dermal
exposure.
Benchmarks - workers and ONUs:
• Liver toxicity: Benchmark MOE = 30.
• Cancer: Benchmark = 1 x 10"4.
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5937
5938
5939
5940
5941
5942
5943
5944
5945
5946
5947
5948
5949
5950
5951
5952
5953
5954
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5957
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Risk estimates - workers:
• Liver toxicity: Chronic inhalation MOE 104 (high end) (Table 4-8)
• Cancer: Chronic dermal risk estimate 6 x 10"5 (high end) with PPE (gloves PF 5) (Table
4-12).
Risk estimates - ONUs:
• Liver toxicity: Chronic inhalation MOEs 546 and 104 (central tendency and high end)
(Table 4-8).
• Cancer: Chronic inhalation risk estimates 3 x 10"5 and 2 x 10"4 (central tendency and high
end) (Table 4-11).
Risk Considerations: Risk estimates for workers and ONUs for acute and chronic inhalation and
for workers, chronic dermal do not indicate risk. While high-end risk estimates for this condition
of use indicate risk in the absence of PPE, risk estimates for these pathways do not indicate risk
for workers when expected use of PPE, a respirator with an APF of 10 and gloves with a PF of 5,
was considered (Table 4-8, Table 4-11 and Table 4-12). EPA did not separately calculate risk
estimates for ONUs and workers. ONU inhalation exposures are expected to be lower than
inhalation exposures for workers directly handling the chemical substance; however, the relative
exposure of ONUs to workers in these cases cannot be quantified. To account for this
uncertainty, EPA considered the central tendency estimate when determining ONU risk. EPA's
risk determination for ONUs is based on an expected absence of PPE. Dermal exposures are not
expected for ONUs.
Life Cycle Stage
Category
Subcategory
Industrial/commercial
use
Petrochemicals-derived
Products Manufacturing
Additive
5.3.13 Industrial/Commercial Use - Specialty Uses - Department of Defense
Section 6(b)(4)(A) unreasonable risk determination for the specialty uses of carbon tetrachloride
by the Department of Defense:
• Does not present an unreasonable risk of injury to health (workers and ONUs).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Exposure scenario with highest risk estimate - workers and ONUs:
• Liver toxicity from chronic inhalation exposure and cancer from chronic dermal
exposure.
Benchmarks - workers and ONUs:
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5977
5978
5979
5980
5981
5982
5983
5984
5985
5986
5987
5988
5989
5990
5991
5992
5993
5994
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• Liver toxicity: Benchmark MOE = 30.
• Cancer: Benchmark = 1 x 10"4.
Risk estimates - workers:
• Liver toxicity: Chronic inhalation MOE 141 (high end) (Table 4-8).
• Cancer: Chronic dermal risk estimate 6 x 10"5 (high end) with PPE (gloves PF 5) (Table
4-12).
Risk estimates - ONUs:
• Liver toxicity: Chronic inhalation MOEs 346 and 141 (central tendency and high end)
(Table 4-8).
• Cancer: Chronic inhalation risk estimates 3 x 10"5 and 2 x 10"4 (central tendency and high
end) (Table 4-11).
Systematic Review confidence rating (hazard): High.
Systematic Review confidence rating (inhalation exposure): High
Risk Considerations: Risk estimates for workers and ONUs for acute and chronic inhalation and
for workers, chronic dermal do not indicate risk. While high-end risk estimates for this condition
of use indicate risk in the absence of PPE, risk estimates for these pathways do not indicate risk
for workers when expected use of PPE, a respirator with an APF of 10 and gloves with a PF of 5,
was considered (Table 4-8, Table 4-11 and Table 4-12). EPA did not separately calculate risk
estimates for ONUs and workers. ONU inhalation exposures are expected to be lower than
inhalation exposures for workers directly handling the chemical substance; however, the relative
exposure of ONUs to workers in these cases cannot be quantified. To account for this
uncertainty, EPA considered the central tendency estimate when determining ONU risk. EPA's
risk determination for ONUs is based on an expected absence of PPE. Dermal exposures are not
expected for ONUs.
Life Cycle Stage
Category
Subcategory
Industrial/commercial
use
Other Uses
Specialty uses (i.e., Department of
Defense Data
5.3.14 Industrial/Commercial Use - Laboratory Chemical
Section 6(b)(4)(A) unreasonable risk determination for the use of carbon tetrachloride as a
laboratory chemical:
• Does not present an unreasonable risk of injury to health (workers and ONUs).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
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6013
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6015
6016
6017
6018
6019
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6021
6022
6023
6024
6025
6026
6027
6028
6029
6030
6031
6032
6033
6034
6035
6036
6037
6038
6039
6040
6041
6042
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Risk Considerations: As discussed in section 2.4.1.7.8, EPA does not have data to assess worker
exposures to carbon tetrachloride during laboratory use. However, due to the expected safety
practices when using this chemical in a laboratory setting, carbon tetrachloride is applied in
small quantities under a fume hood, thus reducing the potential for inhalation exposures.
Life Cycle Stage
Category
Subcategory
Industrial/commercial
use
Laboratory chemicals
Laboratory chemical
5.3.15 Disposal
Section 6(b)(4)(A) unreasonable risk determination for disposal of carbon tetrachloride:
• Does not present an unreasonable risk of injury to health (workers and ONUs).
• Does not present an unreasonable risk of injury to the environment (aquatic, sediment
dwelling and terrestrial organisms).
Exposure scenario with highest risk estimate - workers and ONUs:
• Liver toxicity from chronic inhalation exposure and cancer from chronic dermal
exposure.
Benchmarks - workers and ONUs:
• Liver toxicity: Benchmark MOE = 30.
• Cancer: Benchmark = 1 x 10"4.
Risk estimates - workers:
• Liver toxicity: Chronic inhalation MOE 104 (high end) (Table 4-8).
• Cancer: Chronic dermal risk estimate 6 x 10"5 (high end) with PPE (gloves PF 5) (Table
4-12).
Risk estimates - ONUs:
• Liver toxicity: Chronic inhalation MOEs 546 and 104 (central tendency and high end)
(Table 4-8).
• Cancer: Chronic inhalation risk estimates 3 x 10"5 and 2 x 10"4 (central tendency and
high end) (Table 4-11).
Risk Considerations: Risk estimates for workers and ONUs for acute and chronic inhalation and
for workers, chronic dermal do not indicate risk. While high-end risk estimates for this condition
of use indicate risk in the absence of PPE, risk estimates for these pathways do not indicate risk
for workers when expected use of PPE, a respirator with an APF of 10 and gloves with a PF of 5,
was considered (Table 4-8, Table 4-11 and Table 4-12). EPA did not separately calculate risk
estimates for ONUs and workers. ONU inhalation exposures are expected to be lower than
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inhalation exposures for workers directly handling the chemical substance; however, the relative
exposure of ONUs to workers in these cases cannot be quantified. To account for this
uncertainty, EPA considered the central tendency estimate when determining ONU risk. EPA's
risk determination for ONUs is based on an expected absence of PPE. Dermal exposures are not
expected for ONUs.
Life Cycle Stage
Category
Subcategory
Pisposal
Pisposal
Industrial pre-treatment
Industrial wastewater treatment
Publicly owned treatment works (POTW)
Underground injection
Municipal landfill
Hazardous landfill
Other land disposal
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23-5); Reporting Year 2016. Washington, DC. https://www.epa.gov/chemical-data-
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and Toxics. Retrieved from https://www.epa.gov/chemical-data-reporting
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hazardous-waste
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U.S. EPA. (2017e). Scope of the risk evaluation for Carbon Tetrachloride (methane, tetrachloro-
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U.S. EPA. (2017f). Toxics Release Inventory (TRI) Program. Basic Plus Data Files: Carbon
Tetrachloride (CAS # 56-23-5) Reporting Year 2016. Washington, DC: U.S.
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https://www.epa.gov/toxics-release-inventorv-tri-program/tri-data-and-tools
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1.0. (740P18001). Washington, D.C.: U.S. Environmental Protection Agency, Office of
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Occupational Risk Calculations.
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on Releases and Occupational Exposure Assessment.
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Supplemental File: Data Quality Evaluation of Environmental Fate and Transport
Studies.
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Supplemental File: Updates to the Data Quality Criteria for Epidemiological Studies.
(Docket # EPA-HQ-OPPT-2019-0236).
U.S. EPA. (2019e). Draft Risk Evaluation for Carbon Tetrachloride, Systematic Review
Supplemental File: Data Quality Evaluation of Ecological Hazard Studies.
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Supplemental File: Data Quality Evaluation of Environmental Releases and Occupational
Exposure Data Common Sources.
U.S. EPA. (2019g). Draft Risk Evaluation for Carbon Tetrachloride, Systematic Review
Supplemental File: Data Quality Evaluation of Epidemiological Studies.
U.S. EPA. (2019h). Draft Risk Evaluation for Carbon Tetrachloride, Systematic Review
Supplemental File: Data Quality Evaluation of Human Health Hazard Studies - Animal
and Invitro Studies.
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6763 7 APPENDICES
6764
6765 Appendix A REGULATORY HISTORY
6766
6767 A.l Federal Laws and Regulations
6768 Table Apx A-l. Federal Laws and Regulations
Statutes/Regulations
Description of Authority/Regulation
Description of Regulation
EPA Regulations
TSCA - Section 6(b)
EPA is directed to identify and begin
risk evaluations on 10 chemical
substances drawn from the 2014 update
of the TSCA Work Plan for Chemical
Assessments.
Carbon tetrachloride is on the
initial list of chemicals to be
evaluated for unreasonable risk
under TSCA (81 FR 91927,
December 19, 2016).
TSCA - Section 8(a)
The TSCA section 8(a) CDR Rule
requires manufacturers (including
importers) to give EPA basic exposure-
related information on the types,
quantities and uses of chemical
substances produced domestically and
imported into the United States.
Carbon tetrachloride
manufacturing (including
importing), processing and use
information is reported under
the CDR Rule (76 FR 50816,
August 16, 2011).
TSCA - Section 8(b)
EPA must compile, keep current and
publish a list (the TSCA Inventory) of
each chemical substance manufactured,
processed, or imported in the United
States.
Carbon tetrachloride was on
the initial TSCA Inventory and
therefore was not subject to
EPA's new chemicals review
process under TSCA section 5
(60 FR 16309, March 29,
1995).
TSCA - Section 8(d)
Provides EPA with authority to issue
rules requiring producers, importers
and (if specified) processors of a
chemical substance or mixture to
submit lists and/or copies of health and
safety studies.
Two submissions received
(1947-1994) (U.S. EPA,
ChemView. Accessed April
13, 2017).
TSCA - Section 8(e)
Manufacturers (including imports),
processors and distributors must
immediately notify EPA if they obtain
information that supports the
conclusion that a chemical substance or
mixture presents a substantial risk of
injury to health or the environment.
Three submissions received
(1992-2010) (U.S. EPA,
ChemView. Accessed April
13, 2017).
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Statutes/Regulations
Description of Authority/Regulation
Description of Regulation
TSCA - Section 4
Provides EPA with authority to issue
rules and orders requiring
manufacturers (including importers)
and processors to test chemical
substances and mixtures.
Seven section 4 notifications
received for carbon
tetrachloride: two acute aquatic
toxicity studies, one
bioaccumulation report and
four monitoring reports
(1978-1980) (U.S. EPA,
ChemView. Accessed April
13, 2017).
EPCRA- Section 313
Requires annual reporting from
facilities in specific industry sectors
that employ 10 or more full time
equivalent employees and that
manufacture, process, or otherwise use
a TRI-listed chemical in quantities
above threshold levels.
Carbon tetrachloride is a listed
substance subject to reporting
requirements under 40 CFR
372.65 effective as of January
1, 1987.
Federal Insecticide,
Fungicide, and
Rodenticide Act
(FIFRA) - Sections 3
and 6
FIFRA governs the sale, distribution
and use of pesticides. Section 3 of
FIFRA generally requires that pesticide
products be registered by EPA prior to
distribution or sale. Pesticides may only
be registered if, among other things,
they do not cause "unreasonable
adverse effects on the environment."
Section 6 of FIFRA provides EPA with
the authority to cancel pesticide
registrations if either (1) the pesticide,
labeling, or other material does not
comply with FIFRA; or (2) when used
in accordance with widespread and
commonly recognized practice, the
pesticide generally causes unreasonable
adverse effects on the environment.
Use of carbon tetrachloride as
a grain fumigant was banned
under FIFRA in 1986 (51 FR
41004, November 12, 1986).
Federal Food, Drug,
and Cosmetic Act
(FFDCA) - Section
408
FFDCA governs the allowable residues
of pesticides in food. Section 408 of the
FFDCA provides EPA with the
authority to set tolerances (rules that
establish maximum allowable residue
limits), or exemptions from the
requirement of a tolerance, for all
residues of a pesticide (including both
active and inert ingredients) that are in
or on food. Prior to issuing a tolerance
EPA removed carbon
tetrachloride from its list of
pesticide product inert
ingredients used in pesticide
products in 1998 (63 FR
34384, June 24, 1998).
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Statutes/Regulations
Description of Authority/Regulation
Description of Regulation
or exemption from tolerance, EPA must
determine that the tolerance or
exemption is "safe." Sections 408(b)
and (c) of the FFDCA define "safe" to
mean the Agency has a reasonable
certainty that no harm will result from
aggregate exposures to the pesticide
residue, including all dietary exposure
and all other exposure (e.g., non-
occupational exposures) for which there
is reliable information. Pesticide
tolerances or exemptions from
tolerance that do not meet the FFDCA
safety standard are subject to
revocation. In the absence of a
tolerance or an exemption from
tolerance, a food containing a pesticide
residue is considered adulterated and
may not be distributed in interstate
commerce.
CAA - Section 112(b)
This section lists 189 HAPs that must
be addressed by EPA and includes
authority for EPA to add or delete
pollutants. EPA may, by rule, add
pollutants that present, or may present,
a threat of adverse human health effects
or adverse environmental effects.
Lists carbon tetrachloride as a
HAP (70 FR 75047, December
19, 2005).
CAA - Section 112(d)
Directs EPA to establish, by rule,
National Emission Standards
(NESHAPs) for each category or
subcategory of major sources and area
sources of HAPs. The standards must
require the maximum degree of
emission reduction that EPA
determines is achievable by each
particular source category. This is
generally referred to as maximum
achievable control technology
(MACT).
There are a number of source-
specific NESHAPs for carbon
tetrachloride, including:
Rubber tire manufacturing (67
FR 45588, July 9, 2002)
Chemical Manufacturing Area
Sources (74 FR 56008,
October 29, 2009)
Organic HAP from the
Synthetic Organic Chemical
Manufacturing and Other
Processes (59 FR 19402, April
22,1994),
Halogenated solvent cleaning
operations (59 FR 61801,
December 2, 1994)
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Statutes/Regulations
Description of Authority/Regulation
Description of Regulation
Wood Furniture
Manufacturing Operations (60
FR 62930, December 7,1995)
Group 1 Polymers and Resins
(61 FR 46906, September 5,
1996)
Plywood and Composite Wood
Products (69 FR 45944, July
30, 2004)
CAA - Sections
112(d) and 112(f)
Risk and technology review (RTR) of
section 112(d) MACT standards.
Section 112(f)(2) requires EPA to
conduct risk assessments for each
source category subject to section
112(d) MACT standards, and to
determine if additional standards are
needed to reduce remaining risks.
Section 112(d)(6) requires EPA to
review and revise the MACT standards,
as necessary, taking into account
developments in practices, processes
and control technologies.
EPA has promulgated a
number of RTR NESHAP
(e.g., the RTR NESHAP for
Group 1 Polymers and Resins
(76 FR 22566; April 21,
2011)) and will do so, as
required, for the remaining
source categories with
NESHAP.
CAA - Section 604
Establishes a mandatory phase-out of
ozone depleting substances.
The production and import of
carbon tetrachloride for non-
feedstock domestic uses was
phased out in 1996 (58 FR
65018, December 10, 1993).
However, this restriction does
not apply to production and
import of amounts that are
transformed or destroyed. 40
CFR 82.4. "Transform" is
defined as "to use and entirely
consume (except for trace
quantities) a controlled
substance in the manufacture
of other chemicals for
commercial purposes." 40
CFR 82.3.
CWA - Section
304(a)(1)
Requires EPA to develop and publish
ambient water quality criteria (AWQC)
reflecting the latest scientific
knowledge on the effects on human
In 2015, EPA published
updated AWQC for carbon
tetrachloride, including
recommendations for "water +
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Statutes/Regulations
Description of Authority/Regulation
Description of Regulation
health that may be expected from the
presence of pollutants in any body of
water.
organism" and "organism
only" human health criteria for
states and authorized tribes to
consider when adopting
criteria into their water quality
standards.
CWA - Sections
301(b), 304(b), 306,
and 307(b)
Requires establishment of Effluent
Limitations Guidelines and Standards
for conventional, toxic, and
non-conventional pollutants. For toxic
and non-conventional pollutants, EPA
identifies the best available technology
that is economically achievable for that
industry after considering statutorily
prescribed factors and sets regulatory
requirements based on the performance
of that technology.
CWA - Section 307(a)
Establishes a list of toxic pollutants or
combination of pollutants under the
CWA. The statute specifies a list of
families of toxic pollutants also listed in
the Code of Federal Regulations at 40
CFR 401.15. The "priority pollutants"
specified by those families are listed in
40 CFR part 423, Appendix A. These
are pollutants for which best available
technology effluent limitations must be
established on either a national basis
through rules, see section 301(b),
304(b), 307(b), 306, or on a case-by-
case best professional judgment basis in
NPDES permits. CWA 402(a)(1)(B).
Carbon tetrachloride is
designated as a toxic pollutant
under section 307(a)(1) of the
CWA and as such is subject to
effluent limitations.
SDWA- Section 1412
Requires EPA to publish a non-
enforceable maximum contaminant
level goals (MCLGs) for contaminants
which 1. may have an adverse effect on
the health of persons; 2. are known to
occur or there is a substantial likelihood
that the contaminant will occur in
public water systems with a frequency
and at levels of public health concern;
and 3. in the sole judgment of the
Administrator, regulation of the
Carbon tetrachloride is subject
to National Primary Drinking
Water Regulations (NPDWR)
under SDWA and EPA has set
a MCLG of zero and an
enforceable MCL of 0.005
mg/L (56 FR 3526 January 30,
1991).
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Statutes/Regulations
Description of Authority/Regulation
Description of Regulation
contaminant presents a meaningful
opportunity for health risk reductions
for persons served by public water
systems. When EPA publishes an
MCLG, EPA must also promulgate a
National Primary Drinking Water
Regulation (NPDWR) which includes
either an enforceable maximum
contaminant level (MCL), or a required
treatment technique. Public water
systems are required to comply with
NPDWRs.
Comprehensive
Environmental
Response,
Compensation and
Liability Act
(CERCLA) - Sections
102(a) and 103
Authorizes EPA to promulgate
regulations designating as hazardous
substances those substances which,
when released into the environment,
may present substantial danger to the
public health or welfare or the
environment. EPA must also
promulgate regulations establishing the
quantity of any hazardous substance the
release of which must be reported under
Section 103. Section 103 requires
persons in charge of vessels or facilities
to report to the National Response
Center if they have knowledge of a
release of a hazardous substance above
the reportable quantity threshold.
Carbon tetrachloride is a
hazardous substance under
CERCLA. Releases of carbon
tetrachloride in excess of
10 pounds must be reported
(40 CFR 302.4).
RCRA - Section 3001
Directs EPA to develop and promulgate
criteria for identifying the
characteristics of hazardous waste, and
for listing hazardous waste, taking into
account toxicity, persistence, and
degradability in nature, potential for
accumulation in tissue, and other
related factors such as flammability,
corrosiveness, and other hazardous
characteristics.
Carbon tetrachloride is
included on the list of
hazardous wastes pursuant to
RCRA 3001. Two categories
of carbon tetrachloride wastes
are considered hazardous:
discarded commercial
chemicals (U211) (40 CFR
261.31(a)), and spent
degreasing solvent (F001) (40
CFR 261.33(f)) (45 FR 33084
May 19, 1980).
RCRA solid waste that leaches
0.5 mg/L or more carbon
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Statutes/Regulations
Description of Authority/Regulation
Description of Regulation
tetrachloride when tested using
the TCLP leach test is RCRA
hazardous (DO 19) under 40
CFR 261.24 (55 FR 11798
March 29, 1990).
In 2013, EPA modified its
hazardous waste management
regulations to conditionally
exclude solvent-contaminated
wipes that have been cleaned
and reused from the definition
of solid waste under RCRA
(40 CFR 261.4(a)(26)) (78 FR
46447, July 31, 2013).
Other Federal Regulations
Federal Hazardous
Substance Act (FHSA)
Requires precautionary labeling on the
immediate container of hazardous
household products and allows the
Consumer Product Safety Commission
(CPSC) to ban certain products that are
so dangerous or the nature of the hazard
is such that required labeling is not
adequate to protect consumers.
Use of carbon tetrachloride in
consumer products was banned
in 1970 by the CPSC (16 CFR
1500.17).
FFDCA
Provides the U.S. Food and Drug
Administration (FDA) with authority to
oversee the safety of food, drugs and
cosmetics.
The FDA regulates carbon
tetrachloride in bottled water.
The maximum permissible
level of carbon tetrachloride in
bottled water is 0.005 mg/L
(21 CFR 165.110).
All medical devices containing
or manufactured with carbon
tetrachloride must contain a
warning statement that the
compound may destroy ozone
in the atmosphere (21 CFR
801.433).
Carbon tetrachloride is also
listed as an "Inactive
Ingredient for approved Drug
Products" by FDA (FDA
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Statutes/Regulations
Description of Authority/Regulation
Description of Regulation
Inactive Ingredient Database.
Accessed April 13, 2017).
OSHA
Requires employers to provide their
workers with a place of employment
free from recognized hazards to safety
and health, such as exposure to toxic
chemicals, excessive noise levels,
mechanical dangers, heat or cold stress,
or unsanitary conditions.
Under the Act, OSHA can issue
occupational safety and health
standards including such provisions as
permissible exposure limits (PELs),
exposure monitoring, engineering and
administrative control measures, and
respiratory protection.
In 1970, OSHA issued
occupational safety and health
standards for carbon
tetrachloride that included a
PEL of 10 ppm TWA,
exposure monitoring, control
measures and respiratory
protection (29 CFR
1910.1000).
OSHA prohibits all workplaces
from using portable fire
extinguishers containing
carbon tetrachloride (29 CFR
1910.157(c)(3)).
Atomic Energy Act
The Atomic Energy Act authorizes the
Department of Energy to regulate the
health and safety of its contractor
employees.
10 CFR 851.23, Worker Safety
and Health Program, requires
the use of the 2005 ACGIH
TLVs if they are more
protective than the OSHA
PEL. The 2005 TLV for
carbon tetrachloride is 5 ppm
(8hr Time Weighted Average)
and 10 ppm Short Term
Exposure Limit (STEL).
6769
6770
6771 A.2 State Laws and Regulations
6772 Table Apx A-2. State Laws and Regulations
State Actions
Description of Action
State agencies of interest
State permissible exposure limits
California PEL: 12.6 mg/L (Cal Code Regs. Title
8, section 5155), Hawaii PEL: 2 ppm (Hawaii
Administrative Rules section 12-60-50).
State Right-to-Know Acts
Massachusetts (454 Code Mass. Regs, section
21.00), New Jersey (8:59 N.J. Admin. Code
section 9.1), Pennsylvania (34 Pa. Code section
323).
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State Actions
Description of Action
State agencies of interest
State air regulations
Allowable Ambient Levels (AAL): Rhode Island
(12 R.I. Code R. 031-022), New Hampshire
(RSA 125-1:6, ENV-A Chap. 1400).
State drinking water standards and guidelines
Arizona (14 Ariz. Admin. Register 2978, August
1, 2008), California (Cal Code Regs. Title 26,
section 22-64444), Delaware (Del. Admin. Code
Title 16, section 4462), Connecticut (Conn.
Agencies Regs, section 19-13-B102), Florida
(Fla. Admin. Code R. Chap. 62-550), Maine (10
144 Me. Code R. Chap. 231), Massachusetts (310
Code Mass. Regs, section 22.00), Minnesota
(Minn R. Chap. 4720), New Jersey (7:10 N.J
Admin. Code section 5.2), Pennsylvania (25 Pa.
Code section 109.202), Rhode Island (14 R.I.
CodeR. section 180-003), Texas (30 Tex.
Admin. Code section 290.104).
Other
In California, carbon tetrachloride was added to
the Proposition 65 list in 1987 (Cal. Code Regs.
Title 27, section 27001).
Carbon tetrachloride is on the MA Toxic Use
Reduction Act (TURA) list of 1989 (301 Code
Mass. Regs, section 41.03).
6773
6774 A.3 International Laws and Regulations
6775 Table Apx A-3. Regulatory Actions by Other Governments and Tribes
Country/Organization
Requirements and Restrictions
Regulatory Actions by other Governments and Tribes
Montreal Protocol
Carbon tetrachloride is considered an ozone depleting substance
(ODS) and its production and use are controlled under the 1987
Montreal Protocol on Substances That Deplete the Ozone Layer and
its amendments (Montreal Protocol Annex B - Group II).
Canada
Carbon tetrachloride is on the Canadian List of Toxic Substances
(CEPA 1999 Schedule 1). Other regulations include:
Federal Halocarbon Regulations, 2003 (SOR/2003-289).
ODS Regulations, 1998 (SOR/99-7).
European Union (EU)
Carbon tetrachloride was evaluated under the 2012 Community
rolling action plan (CoRAP) under regulation (European Commission
[EC]) No 1907/2006 - REACH (Registration, Evaluation,
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Country/Organization
Requirements and Restrictions
Authorisation and Restriction of Chemicals) ECHA database.
Accessed April 18, 2017).
Carbon tetrachloride is restricted by regulation (EC) No 2037/2000 on
substances that deplete the ozone layer.
Australia
Carbon tetrachloride was assessed under Environment Tier II of the
Inventory Multi-Tiered Assessment and Prioritisation (IMAP), and
there have been no reported imports of the chemical as a feedstock in
the last 10 years (National Industrial Chemicals Notification and
Assessment Scheme, NICNAS, 2017, Environment Tier II Assessment
for Methane, Tetrachloro-. Accessed April, 18 2017).
Japan
Carbon tetrachloride is regulated in Japan under the following
legislation:
• Industrial Safety and Health Act (ISHA)
• Act on the Evaluation of Chemical Substances and Regulation
of Their Manufacture, etc. (Chemical Substances Control Law
(CSCL))
• Act on Confirmation, etc. of Release Amounts of Specific
Chemical Substances in the Environment and Promotion of
Improvements to the Management Thereof
• Poisonous and Deleterious Substances Control Act
• Act on the Protection of the Ozone Layer through the Control
of Specified Substances and Other Measures
• Air Pollution Control Law
• Water Pollution Control Law
• Soil Contamination Countermeasures Act
(National Institute of Technology and Evaluation (NITE) Chemical
Risk Information Platform (CHIRP). Accessed April 13, 2017).
Australia, Austria,
Belgium, Canada,
Denmark, EU, Finland,
France, Germany, Ireland,
Israel, Japan, Latvia, New
Zealand, People's
Republic of China,
Poland, Singapore, South
Korea, Spain, Sweden,
Switzerland, United
Kingdom
Occupational exposure limits (OELs) for carbon tetrachloride.
(GESTIS International limit values for chemical agents (Occupational
exposure limits, OELs) database. Accessed April 18, 2017).
Basel Convention
Halogenated organic solvents (Y41) are listed as a category of waste
under the Basel Convention-Annex I. Although the United States is
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Country/Organization
Requirements and Restrictions
not currently a party to the Basel Convention, this treaty still affects
U.S. importers and exporter.
OECD Control of
Transboundary
Movements of Wastes
Destined for Recovery
Operations
Halogenated organic solvents (A3150) are listed as a category of
waste subject to The Amber Control Procedure under Council
Decision C (2001) 107/Final.
6776
6777
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6778
6779
6780
6781
6782
6783
6784
6785
6786
6787
6788
6789
6790
6791
6792
6793
6794
6795
6796
6797
6798
6799
6800
6801
6802
6803
6804
6805
6806
6807
6808
6809
6810
6811
6812
6813
6814
6815
6816
6817
6818
6819
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Appendix B LIST OF SUPPLEMENTAL DOCUMENTS
1. Associated Systematic Review Data Quality Evaluation and Data Extraction Documents-
Provides additional detail and information on individual study evaluations and data
extractions including criteria and scoring results.
a. Draft Risk Evaluation for Carbon Tetrachloride, Systematic Review Supplemental
File: Data Quality Evaluation of Environmental Fate and Transport Studies.
DocketEPA-HO-OPPT-2019-0499 (U.S. EPA, 2019q
b. Draft Risk Evaluation for Carbon Tetrachloride, Systematic Review Supplemental
File: Data Quality Evaluation of Physical Chemical Properties Studies Docket
EPA-HO-OPPT-2019-0499 (U.S. EPA. 20190.
c. Draft Risk Evaluation for Carbon Tetrachloride, Systematic Review Supplemental
File: Data Quality Evaluation of Environmental Releases and Occupational
Exposure Data Common Sources. Docket EPA-HO-OPPT-2019-0499 (U.S. EPA.
2019a
d. Draft Risk Evaluation for Carbon Tetrachloride, Systematic Review Supplemental
File: Data Quality Evaluation of Ecological Hazard Studies. Docket EPA-HO-
OPPT-2019-0499 (U.S. EPA, 2019e).
e. Draft Risk Evaluation for Carbon Tetrachloride, Systematic Review Supplemental
File: Data Quality Evaluation of Human Health Hazard Studies - Animal and
Invitro Studies. Docket EPA-HO-OPPT-2019-0499 (U.S. EPA. 2019h).
f. Draft Risk Evaluation for Carbon Tetrachloride, Systematic Review Supplemental
File: Data Quality Evaluation of Epidemiological Studies. Docket EPA-HO-
OPPT-2019-0499 (U.S. EPA. 2019u).
g. Draft Risk Evaluation for Carbon Tetrachloride, Systematic Review Supplemental
File: Updates to the Data Quality Criteria for Epidemiological Studies. Docket
EPA-HO-OPPT-2019-0499 (U.S. EPA, 2019d).
2. Draft Risk Evaluation for Carbon Tetrachloride, Supplemental Information on Releases and
Occupational Exposure Assessment Docket. EPA-HO-OPPT-2019-0499 (U.S. EPA. 2019bV
provides additional details and information on the environmental release and occupational
exposure assessment, including process information, estimates of number of sites and
workers, summary of monitoring data, and exposure modeling equations, inputs and outputs.
3. Draft Risk Evaluation for Carbon Tetrachloride, Supplemental Excel File on Occupational
Risk Calculations. Docket EPA-HO-OPPT-2019-0499 (U.S. EPA. 2019a).
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6820 Appendix C FATE AND TRANSPORT
6821
6822 TableApx C-l. Biodegradation Study Summary for Carbon Tetrachloride
Study Type
(year)
Initial
Concentration
Inoculum
Source
(An)aerobic
Status
Duration
Result
Comments
Affiliated
Reference
Data Quality
Evaluation
Results of
Full Study
Report
Water
Anaerobic
biodegradation
using unadapted
methanogenic
granular sludge
both with and
without a co-
substrate.
<7.5 |imol/L
activated
sludge,
industrial,
nonadapted
anaerobic
15 days
Biodeeradation
oarameter: percent
removal: 100%/5-
1 Id in unadapted
sludge;
100%/5-8d in
unadapted sludge +
cosubstrate;
100%/15-16d in
autoclaved sludge
The
reviewer
agreed with
this study's
overall
quality
level.
(Van
Eekert et
al.. 1998)
High
Other
<149 (ig/L
activated
sludge,
adapted
anaerobic
54 days
Biodeeradation
oara meter: Dcrccnt
removal bv
radiolabel:
100%/16d
The
reviewer
agreed with
this study's
overall
quality
level.
(Bouwer
and
McCartv.
1983)
High
Other
<16 ng/L
activated
sludge,
adapted
anaerobic
19 months
Biodeeradation
parameter:
concentration in
column effluent
(initial
concentration: 16
ue/L. liauid
retention: 2 davs):
<0.1 ug/L
The
reviewer
agreed with
this study's
overall
quality
level.
(Bouwer
and
McCartv.
1983)
High
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Study Type
(year)
Initial
Concentration
Inoculum
Source
(An)aerobic
Status
Duration
Result
Comments
Affiliated
Reference
Data Quality
Evaluation
Results of
Full Study
Report
Static-culture,
flask-screening
method
5 mg/L
sewage,
domestic,
non-
adapted
Aerobic
7 days, then
three
additional 7-
day periods
for
"subcultures"
(total test
time was 28
days)
Biodeeradation
oarameter: percent
removal:
Avg. 89%/7 days
The
reviewer
agreed with
this study's
overall
quality
level.
(Tabak et
al.. 1981)
High
Transformation
under sulfate
reducing
conditions in an
anaerobic
continuously fed
packed-bed
reactor
2.5-56.6
|imol/L
anaerobic
micro-
organisms
anaerobic
13 days
(variable
electron
donors); 27
days to 30
weeks(inliibit
ion - variable
concentration
)
Biodeeradation
parameter: percent
removal via
dechlorination:
100%/30 weeks;
transformation
products included
chloroform and
dichloro-methane.
The
reviewer
agreed with
this study's
overall
quality
level.
(de Best et
al.. 1997)
High
Soil
Other
100 mg/kg
Microbial
colonies on
agar plates
revealed
that
autoclave
controls
were
devoid of
microbial
activity.
not specified
7 days
Biodeeradation
parameter: half-
life:
50%/5 days
The
reviewer
agreed with
this study's
overall
quality
level.
(Anderson
et al..
1991)
Medium
6823
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6824 TableApx C-2. Photolysis Study Summary for Carbon Tetrachloride
Study Type (year)
Wavelength
Range
Duration
Result
Comments
Affiliated
Reference
Data Quality
Evaluation Results
of Full Study
Report
Air
Calculation
195 - 225 nin
Not reported
Photodeeradation
Daramctcr: atmospheric
lifetime or residence time:
30-50 years
The reviewer
agreed with this
study's overall
quality level.
(Molina and
Rowland. 1974)
High
Photochemical oxidation
using photolysis of nitrous
acid in air as a source of
hydroxyl radicals
360 nin
Not reported
Photodeeradation
Daramctcr: TroDOSDhcric
lifetime: >330 vears
The reviewer
agreed with this
study's overall
quality level.
(Cox et al..
1976)
High
Absorption
160-275
700 seconds
Photodeeradation
Daramctcr: absolution:
threshold wavelength =
253 mn
The reviewer
agreed with this
study's overall
quality level.
(Hubrich and
Stuhl. 1980)
High
Water
Reductive dechlorination
in aqueous solution with
ferrous and sulfide ions in
the absence and presence
of light
Visible light;
530±20 lux
33 days
Photodeeradation
Daramctcr: Dcrccnt
transformation via
reductive dechlorination:
84%/33d (Ferrous; dark);
99.9%/33d (Ferrous; light)
The reviewer
agreed with this
study's overall
quality level.
(Doone and Wu.
1992)
High
6825
6826 Table Apx C-3. Hydrolysis Study Summary for Carbon Tetrachloride
Study Type (year)
pH
Temperature
Duration
Results
Comments
Affiliated
Reference
Data Quality
Evaluation
Results of Full
Study Report
Calculation; Review
paper including
calculated kh and t(l/2)
at 298K and pH 7 for
carbon tetrachloride
7
298K
Not reported
Hvdrolvsis
Daramctcr: half-
life (298Kand
loom):
7000 years.
The reviewer
agreed with this
study's overall
quality level.
(Mabev and
Mill. 1978)
Medium
6827
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6828
6829 Table Apx C-4. Sorption Study Summary for Carbon Tetrachloride
Data
Study Type (year)
Sorbent Source
Sorbent
Qualities
(clay/silt/sand,
OC, pH)
Duration
Results
Comments
Affiliated
Reference
Quality
Evaluation
Results of
Full Study
Report
Partitioning based on
measurements in
sediments of Scheldt
Estuary and water
Southern North Sea
Water salinity
range 1.45-20.8
g/L
Scheldt estuary
and Belgian
continental shelf
sediments
Not reported
Sorption parameter: loe
Koc(sw.ea.):
1.67
The reviewer agreed
with this study's overall
quality level.
(Roosc et
al.. 2001)
High
Breakthrough
curves measured
under water-
saturated, steady-
flow conditions
Equilibrium and two-
site models applied to
field and laboratory
experiments to
determine transport
behavior (including
Kd)
in glass columns
with aquifer
material from site
at Borden.
Ontario and
synthetic
groundwater
prepared from
organic-free
water; field
experiments at
site in Borden.
Ontario
organic carbon
0.018-0.020
wt%, pH 8.2-
8.3
Sorotion parameter: Kd:
0.019-0.168 (g/g);
Retardation factors
obtained from column
experiments conducted at
high velocities were
lower than those obtained
at low velocities
The reviewer agreed
with this study's overall
quality level.
(Ptacek and
Gillham.
1992)
High
Sorption isotherms in
lignite and peat soil
lignite sample
collected from
Oberlausitz area
in Saxony,
Germany;
Carbon content
lignite: 53.5%
peat 46.1%;
moisture
content
Sorotion parameter: loe
Kf: lienite and neat,
respectively: 2.29. 1/n =
0.916 and 1.59, l/n =
0.879
The reviewer agreed
with this study's overall
quality level.
(Endo et
al.. 2008)
High
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Data
Study Type (year)
Sorbent Source
Sorbent
Qualities
(clay/silt/sand,
OC, pH)
Duration
Results
Comments
Affiliated
Reference
Quality
Evaluation
Results of
Full Study
Report
Pahokee peat soil
11.1±0.4%
purchased from
International
10.2±0.2%
Humic
Substances
Society
Column sorption of
Carbon tetrachloride
Sandy soil
samples sieved
through a 0.425-
mm sieve
and retained by a
0.250-mm sieve
97.6% sand
2.4% clay; OC
below the
detection limit
of 0.03%
So rot ion parameter: Kd:
0.39 L/kg; retardation
factor (Rf) 2.64
The reviewer agreed
with this study's overall
quality level.
(Zhao et
al.. 1999)
High
No guideline cited;
batch equilibrium soil
sorption study
McLaurin sandy
Loam from Stone
County, MS. Air
dried and sieved
to 2 mm
0.66±0.04%,
pH 4.43 +/-
0.03
Sorotion parameter: Koc:
48.89+/-16.16; Sorotion
parameter: Kb:
0.323 +/-0.107
The reviewer agreed
with this study's overall
quality level. Study
reported in ECHA
(ECHA.
AdsorDtion/desorDtion:
Carbon tetrachloride.
2017.)
(Walton et
al.. 1992)
High
Wastewater
solids collected
Sorption on
wastewater solids
(isotherm test)
from three
different
municipal
WWTP near
Cincinnati OH,
Volatile
Not applicable
Sorotion parameter: loe
Kd: Drimarv sludse.
mixed-liauor solids and
disested. sludse.
respectively: 2.66. 2.80.
2.49
The reviewer agreed
with this study's overall
quality level.
(Dobbs et
al.. 1989)
High
suspended solids
ranged from 65-
85%
No guideline cited;
batch equilibrium soil
sorption study
Captina silt loam
from Roane
County, TN. Air
1.49±0.06%,
pH 4.97±0.08
Sorotion parameter: Koc:
143.6 +/-32.11;
Sorotion parameter: Kb:
The reviewer agreed
with this study's overall
quality level. Study
(Walton et
al.. 1992)
High
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Study Type (year)
Sorbent Source
Sorbent
Qualities
(clay/silt/sand,
OC, pH)
Duration
Results
Comments
Affiliated
Reference
Data
Quality
Evaluation
Results of
Full Study
Report
dried and sieved
to 2 mm
2.140+/-0.478
reported in ECHA
CECHA.
AdsorDtion/desorDtion:
Carbon tetrachloride.
2017.)
Column desorption
study using
contaminated aquifer
sediments
T17; T18; T19: 3
sediment cores
from aquifer in
Hanford known
to contain' and
CHC13; samples
were stored at
4degC; OC
determined using
ASTM standard
procedure;
groundwater from
Hanford site
T17; T18; T19:
OC 0.059%,
0.017%,
0.088%; gravel
58.97%,
1.85%, 8.16%;
Sand 25.6%,
835.%, 9.53%;
silt 6.02%,
10.2%, 45.5%;
clay: 1.97%,
4.42%, 36.7%,
respectively
So rot ion parameter: Kd:
T17 core sample and T18
core sample, respectively:
0.367, 1.44
The reviewer agreed
with this study's overall
quality level.
(Rilev et
al.. 2010)
High
Batch equilibration
studies in a
stratigraphic column
for the determination
of sorption
coefficients Koc and
Kd in soils
representing three
horizons
Soil samples
from University
of Nebraska's
South Central
Research and
Extension Center
in Clay County,
NE; hasting
series: fine,
montmorillonitic,
mesic Udic
Argiustoll
% silt and sand
not reported.
Total clay
content (g/kg)
= 265.7±22.6
Modern A
horizon
330.4±16.2
Buried A,
273.7±30.4
Loess C
horizon.
Organic carbon
(g/kg):
14.9±2.6
Modern A,
Sorption parameter: los
Koc: Modern A horizon
Buried A and Loess C
horizon sites,
respectively: 1.74
(±0.04), 1.89 (±0.10),
2.43 (±0.18)
The reviewer agreed
with this study's overall
quality level.
(Duffy et
al.. 1997)
High
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Study Type (year)
Sorbent Source
Sorbent
Qualities
(clay/silt/sand,
OC, pH)
Duration
Results
Comments
Affiliated
Reference
Data
Quality
Evaluation
Results of
Full Study
Report
5.3±0.6 Buried
A, 1.4±0.5
Loess C
Vapor sorption of
carbon tetrachloride in
high organic soils
Peat reference
sample from
International
Humic
Substances
Society collected
from Everglades
Fl; extracted peat
from 0.1M NaOH
extraction of
reference peat
soil; muck soil
from Michigan
State University
Research Farm
Lainsburg, MI
Carbon content
(from cited
source):
extracted peat
64.0%, peat
57.1%, muck
53.1%,
cellulose
44.4%; oxygen
content:
extracted peat
28.9%, peat
33.9%, muck
37.5%,
cellulose
49.4%; ash
content:
extracted peat
15.0%, peat
13.6%, muck
18.5%
Solution Daramctcr:
Kom: oeat and muck
respectively:
44.6, 27.8
The reviewer agreed
with this study's overall
quality level. A previous
study was cited for
several details, HERO
ID 3566467,
Rutherford, D. W., et al.
(1992). "Influence of
soil organic matter
composition on the
partition of organic
compounds."
(Rutherford
and Cliiou.
1992)
High
Sorption of Carbon
tetrachloride in high
organic soil and
cellulose
Peat reference
sample from
International
Humic
Substances
Society collected
from Everglades,
Fl; extracted peat
from 0.1M NaOH
extraction of
Carbon
content:
extracted peat
64.0%, peat
57.1%, muck
53.1%,
cellulose
44.4%; oxygen
content:
extracted peat
Solution Daramctcr:
Kom: ueat. neat. muck,
and cellulose
respectively:
73.5, 44.6, 27.8, and 1.75
The reviewer agreed
with this study's overall
quality level.
(Rutherford
et al..
1992)
High
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Study Type (year)
Sorbent Source
Sorbent
Qualities
(clay/silt/sand,
OC, pH)
Duration
Results
Comments
Affiliated
Reference
Data
Quality
Evaluation
Results of
Full Study
Report
reference peat
soil; muck soil
from Michigan
State University
Research Farm
Lainsburg, MI;
cellulose from
Aldrich
28.9%, peat
33.9%, muck
37.5%,
cellulose
49.4%; ash
content:
extracted peat
15.0%, peat
13.6%, muck
18.5%,
cellulose 0.0%
ASTM, 1993.
Standard Test Method
for Determining a
Sorption Constant
(Koc) for an Organic
Chemical in Soil
and Sediments
Sediments
collected from a
chloroform and
carbon
tetrachloride
contaminated
sandy aquifer in
Schoolcraft
Michigan
Silty/fine sand;
Medium sand;
Coarse sand;
Very coarse
sand
So rot ion parameter: Kd:
Siltv/fine sand. Medium
sand. Coarse sand, and
Verv coarse sand.
respectively:
0.162,0.233,0.494,
0.376
The reviewer agreed
with this study's overall
quality level.
(Zhao et
al.. 2005)
High
Sorption on aquifer
materials
Column with low
organic carbon
aquifer materials
Rabis, Vejen, and
Vasby;
groundwater from
municipal
drinking water
plant in Demnark
spiked influent
CT cone 26 ug/L
OC 0.007-
0.025%; 63-
90% coarse
sand; 8-34%
fine sand; 0-
2% silt; 1-2%
clay
Sorption parameter: Kd:
0.02 -0.11;Rf= 1.10-
1.46
The reviewer agreed
with this study's overall
quality level. The
reviewer noted:
Quantitative Kd data for
carbon tetrachloride was
not reported; however,
the Rf was reported.
(Larson et
al.. 1992)
High
Adsorption/desorption
in soil
EPA standard soil
(FW
Enviresponse,
OC 0.8%; sand
56.4% clay
Sorption parameter:
Monolayer adsorption
capacity Xm:
The reviewer agreed
with this study's overall
quality level.
(Thibaud et
al.. 1992)
High
Page 230 of 301
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Study Type (year)
Sorbent Source
Sorbent
Qualities
(clay/silt/sand,
OC, pH)
Duration
Results
Comments
Affiliated
Reference
Data
Quality
Evaluation
Results of
Full Study
Report
Inc.) sieved to
210-250 um
analyzed by Soil
Testing
Laboratory of
Texas A&M
University
28.9%, silt
14.7%
7.3;
Sorption parameter:
adsorption capacity at
saturation Xa:
39.2
Forced gradient test
Sand aquifer in
Borden Ontario
composed of fine
to medium
grained sand;
aquifer is
unconfined, water
table fluctuates
over the year;
aquifer is 10 m
thick underlain
by thick silty clay
aquitard, within
2-3m of the
aquifer is a plume
of contaminants
silty clay
Sorption parameter: Kd:
0.03-0.24, Rf: .2-2.3
The reviewer agreed
with this study's overall
quality level.
(Mackav et
al.. 1994)
High
Calculation; Carbon
tetrachloride
concentrations in air
and soil gas for
determination of soil
flux and partial
atmospheric lifetime
Site
characteristics:
boreal, temperate,
and tropical
forests, temperate
grasslands
Not reported
2 weeks
monitorin
g data
Sorption parameter: x-soil
(partial lifetime of
atmospheric CT due to
soil removal):
90 years
The reviewer agreed
with this study's overall
quality level; partial
lifetime calculation
based on 2 weeks
monitoring data from
several different
regions.
(Happell
and Roche.
2003)
High
Calculation; Carbon
tetrachloride
concentrations in air
boreal forest soil
in Alberta,
Canada; sub-
Not reported
Sorption parameter: x-soil
(partial lifetime of
The reviewer agreed
with this study's overall
quality level.
(Happell et
al.. 2014)
High
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Study Type (year)
Sorbent Source
Sorbent
Qualities
(clay/silt/sand,
OC, pH)
Duration
Results
Comments
Affiliated
Reference
Data
Quality
Evaluation
Results of
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Report
and soil gas for
determination of soil
flux
tropical forest
soil in South
Florida, tropical
forest soil in
Puerto Rico
atmospheric CT due to
soil removal):
245 years
Determination of
Freundlich sorption
constants in silty loam
clay
Hastings silty
clay loams;
Overton silty clay
loams
1% sand, 31%
clay, 2.6% OC
(Hastings);
15% sand, 34%
clay, 1.8% OC
(Overton)
Sorption parameter: Koc:
45: Sorotion parameter:
Ml
0.62 (Hastings);
1.18 (Overton)
The reviewer agreed
with this study's overall
quality level.
(Roeers
and
McFarlane.
1981)
Medium
Batch sorption using
aquifer solids to
determine equilibrium
distribution coefficient
Kd
Site Moffett
Field, CA: core
material from
heterogeneous
aquifer composed
of sand and
gravel with
interspersed
layers of silts and
clays
organic carbon
content, foe:
0.08-0.16%
Sorotion oarameter: Kd:
1.0 ± 0.2, Rf = 6 ± 1.0
The reviewer agreed
with this study's overall
quality level.
(Harmon et
al.. 1992)
Medium
Adsorption isotherms
obtained from batch
methods
A: Black soil I,
B: Black soil II,
C: Gray soil, D:
Brown soil I, E:
Brown soil II
A: 4.9%, B:
3.2%, C: 0.5%,
D: 0.4%, E:
0.1%
Sorotion parameter:
Henrv's partition
coefficient k (amount
adsorbed/eaui-librium
concentration): Black soil
I. Black soil II. Grav soil.
Brown soil I. Brown soil
II. respectively:
0.7,0.4, 0.1, <0.05, <0.05
The reviewer agreed
with this study's overall
quality level.
(Urano and
Murata.
1985)
Medium
Other
Eglin-Florida Soil
OC 1.6%;
91.7% sand.
Sorotion parameter:
Henrv's isotherm constant
K:
The reviewer
downgraded this study's
overall quality rating.
(Pens and
Dural.
1998)
Low
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Study Type (year)
Sorbent Source
Sorbent
Qualities
(clay/silt/sand,
OC, pH)
Duration
Results
Comments
Affiliated
Reference
Data
Quality
Evaluation
Results of
Full Study
Report
6.3% silt 2.0%
clay, pH 4.7
1.123
Solution Daramctcr:
normalized isotherm
constant Ki:
0.375
They noted: No controls
or analytical details
were reported.
Times Beach
Missouri Soil
OC 2.4%;
11.4% sand,
35.2% silt,
33.4% clay, pH
6.9
Solution Daramctcr:
Henrv's isotherm constant
K
1.695
Solution Daramctcr:
normalized isotherm
constant Ki:
0.301
The reviewer
downgraded this study's
overall quality rating.
They noted: No controls
or analytical details
were reported.
(Pens and
Dural.
1998)
Low
Sorption/partitioning
experiments using
water and soil
32 normal soils
from diverse
geographic
regions in US and
China; soil
samples collected
from A horizon
and lm below
land surface
Organic
carbon: 0.16-
6.09% for soils
Sorption Daramctcr: Koc:
45-74 (range);
60±7 (avg.)
The reviewer
downgraded this study's
overall quality rating.
They noted: Limited
data was reported; no
details on specific GC
methods, extraction
efficiency, mass balance
or controls.
(Kile et al..
1995)
Low
Other
Visalia-California
Soil
OC 1.7%;
45.1% sand,
35.2% silt,
21.7% clay, pH
8.1
Solution Daramctcr:
Henrv's isotherm constant
K
1.483
Solution Daramctcr:
normalized isotherm
constant Ki:
0.459
The reviewer
downgraded this study's
overall quality rating.
They noted: No controls
or analytical details
were reported.
(Pens and
Dural.
1998)
Low
Sorption/partitioning
experiments using
water and suspended
river solids
5 river
suspended-solid
samples collected
from locations in
Organic
carbon: 0.38-
2.87%
Sorption Daramctcr: Koc:
49-89
The reviewer
downgraded this study's
overall quality rating.
They noted: Limited
(Kile et al..
1995)
Low
Page 233 of 301
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Study Type (year)
Sorbent Source
Sorbent
Qualities
(clay/silt/sand,
OC, pH)
Duration
Results
Comments
Affiliated
Reference
Data
Quality
Evaluation
Results of
Full Study
Report
Illinois River IL,
Mississippi River
MO, and Yellow
River China
data was reported; no
details on specific GC
methods, extraction
efficiency, mass balance
or controls.
Sorption/partitioning
experiments using
water and suspended
river solids
4 contaminated
bed sediment and
soil samples
collected from
locations in LA,
MA, and MN
Organic
carbon: 1.56-
5.27%
Sorption parameter: Koc:
133-665
The reviewer
downgraded this study's
overall quality rating.
They noted: Limited
data was reported; no
details on specific GC
methods, extraction
efficiency, mass balance
or controls.
(Kile et al..
1995)
Low
Sorption/partitioning
experiments using
water and sediment
36 bed sediments
from diverse
geographic
regions in US and
China; sediments
collected from
rivers, freshwater
lakes, and
marine/bay
harbors
Organic
carbon: 0.11-
4.73% for bed
sediment
Sorotion parameter: Koc:
66-119 (range); 102±11
(avg.)
The reviewer
downgraded this study's
overall quality rating.
They noted: Limited
data was reported; no
details on specific GC
methods, extraction
efficiency, mass balance
or controls.
(Kile et al..
1995)
Low
Partitioning in clays
clay:water
Sorotion parameter: Kem
(adsorotion eauilibrium
constant eas/mineral):
90 at 0%RH; 3.6 at
80%RH
The reviewer agreed
with this study's overall
quality level.
(Cabbar et
al.. 1998)
Low
Vapor sorption of CT
using synthetic clay
pellets
Synthetic clay:
montmorillonite-
type natural clay
and humic acid
Sorotion oarameter:
coefficient that considers:
(1) adsorotion from the
vanor ohasc to the Dure
mineral surface: (2)
The reviewer
downgraded this study's
overall quality rating.
They noted: Study
details were not
(Cabbar.
1999)
Low
Page 234 of 301
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Study Type (year)
Sorbent Source
Sorbent
Qualities
(clay/silt/sand,
OC, pH)
Duration
Results
Comments
Affiliated
Reference
Data
Quality
Evaluation
Results of
Full Study
Report
adso rot ions on the
surface of a water film
that is adsorbed on the
mineral: (3) dissolution
into an adsorbed water
film and soil oreanic
carbon:
39.9(5%); 9.7(20%);
5.8(40%); 4.8(60%);
3.6(80%) for pure clay;
36.3(0%), 21.6(5%);
9.95(20%); 6.32(40%);
5.05(60%); 3.38(80%)
for 2%humic acid-clay
pellet; 21.8(0%),
15.65(5%); 9.49(20%);
7.21(40%); 5.49(60%);
3.50 (80%) for 2% humic
acid-clay pellet
provided, and results
were not
environmentally
relevant.
Sorption/desorption of
organic vapors on
single particles using
an electrodynamic
thermo gravimetric
analyzer
Spherocarb,
mo ntmorillonite,
and Carbopack
particles
0.63,0.62,0.95
g/cm3
Sorotion Daramctcr: The
isothermal adsorption and
desorption of organic
vapors on a single soil
particle was studied. Xa
amount of contaminant
adsorbed per gram of soil
was reported. Xa = 0.012
-0.347
The test method was not
relevant to conceptual
model for this
compound.
(Toenotti et
al.. 1991)
Unacceptab
le
6830
6831
6832
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
6833 Table Apx C-5. Other Fate Endpoints Study Summary for Carbon Tetrachloride
System
Study Type (year)
Results
Comments
Affiliated Reference
Data Quality Evaluation
Results of Full Study Report
Non-guideline;
Sorption/desorption in
Biomass: Air-biomass
and water-biomass
(wood) partitioning
Partitioning measured
using tree cores and
tree cuttings from
hybrid poplar tree
trunks; Kaw:
Partitioning between
air and biomass
(organic matter from
trees); Klw:
partitioning between
water (internal
aqueous solution) and
biomass (dry wood)
Parameter: Kaw(L/e):
air:tree-core (solution):
0.055±0.008; aintree-
cuttins (sorption):
0.042±0.007; aintree-
cuttins (dcsorotion):
0.072±0.008;
Parameter: Klw(L/e):
watenbiomass:
0.0593±0.0066
(measured) 0.0239
(calculated)
The reviewer agreed
with this study's
overall quality level.
(Ma and Burken.
2002)
High
Non-guideline; Lab-
scale batch
experiments using a
bioreactor to simulate
the fate of VOCs in
wastewater treatment
plants (WWTP) and
fugacity model
predictions of VOCs
in WWTP
Concentrations in air,
water and sludge
phases analyzed under
four different
operational
circumstances
evaluating single and
combined effects of
aeration and sludge
addition on phase
distributions; sludge
added prior to
experiments; aeration
3rd-10thhr.
Parameter: rartitionine:
The concentrations of
the VOCs
in the air, water, and
sludge phases of the
bioreactor were
analyzed regularly.
Mass distributions
indicated that carbon
tetrachloride was
mainly present in the
water phase throughout
the four treatment
stages; less than 0.1% of
the total mass was
subject to biological
sorption and/or
degradation by the
sludge; water aeration
resulted in increased
partitioning to the air
phase with a negative
impact on biological
The reviewer agreed
with this study's
overall quality level.
(Chen etal.. 2014)
High
Page 236 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
System
Study Type (year)
Results
Comments
Affiliated Reference
Data Quality Evaluation
Results of Full Study Report
removal; carbon
tetrachloride mass
distribution throughout
the 4 stages: >99%
water, >10 - 0.1%
sludge
Measurement of
organic chemical
effect on soil
microbial respiration
and correlation to
structure activity
analysis
Over a 7-day period
soils were examined
for chemical effects
on microbial
respiration; soils
moistened with DI
water for an 80% base
saturation; no
amendments were
added
Parameter: effect on soil
microbial respiration:
No difference in the silt
loam; no effect on the
C02 efflux from soils in
the silt loam; observed
decrease in C02 efflux
from the sandy loam
soils during the course
of the 6-day period but
no significant difference
on the final day of the
experiment. SAR
analysis showed no
linear correlation with
log Kow, water
solubility, vapor
pressure, HLC, or acute
tox to chemical effects
on soil microbial
respiration
The reviewer
downgraded this
study's overall
quality rating. They
noted: Study details
not reported (i.e..
Analytical
methodology)
limited study
evaluation. Study
results not relevant
to a
specific/designated
Fate endpoint.
(Walton etal.. 1989)
Low
Anaerobic abiotic
transformation in the
presence of sulfide
and sulfide minerals
Time-series
experiment under
aseptic conditions in
flame-sealed glass
ampules; temp
dependence assessed
at 37.5, 50.0, and
62.7degC; pH effect
was observed over pH
6-10
Parameter: abiotic
dechlorination (50 °C):
75% conversion to
carbon dioxide; 20%
conversion to
chloroform
Testing conditions
were not reported,
and data provided
were insufficient to
interpret results.
Figures referenced
in the text were not
provided.
(Krieeman-Kine and
Reinhard. 1991)
Unacceptable
6834
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6835
6836
6837
6838
6839
Appendix D RELEASES TO THE ENVIRONMENT
TableApx D-l. Summary of Carbon Tetrachloride TRI Releases to the Environment for
'rom 2018 (lbs
Number
of
Facilities
Air Releases
Water
Releases
Land Disposal
Other
Releases"
Total On-
and Off-Site
Disposal or
Other
Releasesb'c
Stack Air
Releases
Fugitive
Air
Releases
Class I
Under-
ground
Injection
RCRA
Subtitle C
Landfills
All other
Land
Disposal"
Totals
2018
49
116,710
59,355
1,704
15,088
29,140
29,532
146
251,674
176,065
73,760
Data source: 2018 TRI Data OJ.S. EPA. 2018f).
a Terminology used in these columns may not match the more detailed data element names used in the TRI public data and analysis access
points.
b These release quantities do include releases due to one-time events not associated with production such as remedial actions or earthquakes.
c Counts release quantities once at final disposition, accounting for transfers to other TRI reporting facilities that ultimately dispose of the
chemical waste.
6840
6841
Page 238 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
6842 Appendix E SURFACE WATER ANALYSIS FOR CARBON
6843 TETRACHLORIDE
6844
6845 EPA identified additional data on ecological hazards requiring an update of the analysis of
6846 carbon tetrachloride releases and surface water concentrations (see Appendix H). In order to
6847 update the analysis, EPA expanded the release data as reported by facilities in the Discharge
6848 Monitoring Reports (in EPA's ECHO) to five years of releases (2014 through 2018) and
6849 expanded the number of facilities releasing carbon tetrachloride in any given year in order to
6850 capture the range and variability of releases.
6851
6852 Table E-l. Releases of Carbon Tetrachloride to Surface Waters3
NPDES
Facility Name
Total Pounds Discharged Per Year (lbs/yr)
2014
2015
2016
2017
2018
5yr
Mean
5yr
Median
TX0021458
Fort Bend County
WCID2
81
134
25
19
21
56
61
AL0001961
AKZO Chemicals,
Inc.
56
110
115
280
700
250
320
LA0000329
Honeywell, Baton
Rouge
20
24
0
0
0
8.8
0
LA0005401
ExxonMobil,
Baton Rouge
0
22
0
0
0
4.4
0
OH0029149
Gabriel
Performance
14
21
1.2
2.4
3.7
8.5
3.7
WV0004359
Natrium Plant
13
14
12
12
14
13
13
CA0107336
Sea World, San
Diego
0
14b
0
0
0
—
—
OH0007269
Dover Chemical
Corp
320°
13
19
48
0
79
19
LA0006181
Honeywell,
Geismar
0
9.8
9.8
11
9.9
8.1
9.8
LA0038245
Clean Harbors,
Baton Rouge
0
8.9
17
26
21
15
17
TXO119792
Equistar
Chemicals LP
0
0
78
16
56
30
16
WV0001279
Chemours
Chemicals LLC
0
0
0
0
23
4.7
0
Page 239 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Total Pounds Discharged Per Year (lbs/yr)
NPDES
Facility Name
2014
2015
2016
2017
2018
5yr
Mean
5yr
Median
TX0007072
Eco Services
Operations
3.6
5.5
18
9.1
22
12
9.1
KY0024082
Barbourville STP
0
0
0
0
19
3.9
0
WA0030520
Central Kitsap
WWTP
0
0
0
0
13
2.6
0
M00002526
Bayer Cropscience
0
0
0
0
11
2.2
0
KY0027979
Eddyville STP
0
0
0
5.0
9.7
2.9
0
KY0103357
Richmond Silver
Creek STP
0
0
0
0
7.0
1.4
0
KY0003603
Arkema Inc.
0
0
0
0
4.9
0.98
0
KY009161
Caveland
Environmental
Auth
0
0
0
2.4
4.2
1.3
0
LA0002933
Occidental Chem
Corp, Geismar
0
0
0
0
2.6
0.52
0
6853 a2014 to 2018 data from the EPA ECHO website
6854 bSan Diego Sea World facility (CA0107336) was not included in the analysis since the reported level is
6855 above permit discharge limits; noncompliance and spills are not in the scope of this risk evaluation.
6856 °A 2014 accidental spill/release of carbon tetrachloride likely contributed to the larger release of the
6857 chemical compared to the following 4 years; noncompliance and spills are not in the scope of this risk
6858 evaluation, (https://www.timesreporter.com/article/20140716/news/140719487)
6859
6860
6861
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6862 Table E-2. Surface Water Carbon Tetrachloride Concentrations for Acute (20 day) and Chronic (250 day) Scenarios and
6863 Amphibian Concentration of Concern Comparisons
NPDES
Facility Name
Amount
Discharged
for 20 days
(kg/day)
20 Day
Stream
Cone.
(Jig/L)
Days
Acute
COCa
Exceeded
(PDM)
Amount
Discharged
for 250 days
(kg/day)
250 Day
Stream
Cone.
(Jig/L)
Days Chronic
COCb
Exceeded
(PDM)
TX0021458
Fort Bend County
WCID2
N/A
N/A
N/A
0.10
10
0
AL0001961
AKZO Chemicals,
Inc.
5.7
3.1E-01
0
0.46
2.5E-02
0
LA0000329
Honeywell, Baton
Rouge
0.20
8.1E-04
0
0.02
6.5E-05
0
LA0005401
ExxonMobil, Baton
Rouge
0.01
4.0E-04
0
0.01
3.2E-05
0
OH0029149
Gabriel Performance
0.19
45
0
0.02
3.6
2
WV0004359
Natrium Plant
0.29
3.4E-02
0
0.02
2.9E-03
0
CA0107336
Sea World, San
Diego0
OH0007269
Dover Chemical Corp
1.8
1.3E+2
0
0.14
10
15
LA0006181
Honeywell, Geismar
0.18
7.3E-04
0
0.02
6.1E-05
0
LA0038245
Clean Harbors, Baton
Rouge
0.33
1.3E-03
0
0.03
1.0E-04
0
TXO119792
Equistar Chemicals
LP
0.68
4.4
0
0.05
3.5E-01
0
WV0001279
Chemours Chemicals
LLC
0.11
1.1E0-02
0
0.01
8.0E-04
0
Page 241 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
NPDES
Facility Name
Amount
Discharged
for 20 days
(kg/day)
20 Day
Stream
Cone.
(Jig/L)
Days
Acute
COCa
Exceeded
(PDM)
Amount
Discharged
for 250 days
(kg/day)
250 Day
Stream
Cone.
(Jig/L)
Days Chronic
COCb
Exceeded
(PDM)
TX0007072
Eco Services
Operations
0.26
49
0
0.02
3.9
2
KY0024082
Barbourville STP
N/A
N/A
N/A
0.01
3.5E-01
0
WA0030520
Central Kitsap
WWTP
0.06
7.0E+01
N/A
0.01
5.8E-01
0
M00002526
Bayer Cropscience
0.05
5.9E-01
0
0.0
4.7E-02
0
KY0027979
Eddyville STP
N/A
N/A
N/A
0.01
1.0
1
KY0103357
Richmond Silver
Creek STP
N/A
N/A
N/A
0.0
3.1E-01
0
KY0003603
Arkema Inc.
0.02
9.5E-04
0
0.0
8.7E-05
0
KY009161
Caveland
Environmental Auth
0.03
8.4E-02
0
0.0
5.6E-03
0
LA0002933
Occidental Chem
Corp, Geismar
0.01
4.9E-05
0
0.0
4.0E-06
0
6864 aAcute COC = 90 |ig/L
6865 bChronic COC = 3 |ig/L
6866 cSan Diego Sea World facility (CA0107336) was not included in the analysis since the reported level is above permit discharge limits;
6867 noncompliance and spills are not in the scope of this risk evaluation.
6868
6869
6870
6871
Page 242 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
6872 Table E-3. Surface Water Carbon Tetrachloride Concentrations for Acute (20 day) and Chronic (250 day) Scenarios and Algal
6873 Concentration of Concern Comparisons
NPDES
Facility Name
Amount
Discharged
for 20 days
(kg/day)
20 Day
Stream
Cone.
(Jig/L)
Days
Algal
COCa
Exceeded
(PDM)
Amount
Discharged
for 250 days
(kg/day)
250 Day
Stream
Cone.
(Jig/L)
Days
Algal
COCa
Exceeded
(PDM)
TX0021458
Fort Bend County
WCID2
N/A
N/A
N/A
0.10
10
0
AL0001961
AKZO Chemicals,
Inc.
5.7
3.1E-01
0
0.46
2.5E-02
0
LA0000329
Honeywell, Baton
Rouge
0.20
8.1E-04
0
0.02
6.5E-05
0
LA0005401
ExxonMobil, Baton
Rouge
0.01
4.0E-04
0
0.01
3.2E-05
0
OH0029149
Gabriel Performance
0.19
45
2
0.02
3.6
2
WV0004359
Natrium Plant
0.29
3.4E-02
0
0.02
2.9E-03
0
CA0107336
Sea World, San
Diegob
OH0007269
Dover Chemical
Corp
1.8
1.3E+2
8
0.14
10
3
LA0006181
Honeywell, Geismar
0.18
7.3E-04
0
0.02
6.1E-05
0
LA0038245
Clean Harbors,
Baton Rouge
0.33
1.3E-03
0
0.03
1.0E-04
0
TXO119792
Equistar Chemicals
LP
0.68
4.4
1
0.05
3.5E-01
0
Page 243 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
NPDES
Facility Name
Amount
Discharged
for 20 days
(kg/day)
20 Day
Stream
Cone.
(Jig/L)
Days
Algal
COCa
Exceeded
(PDM)
Amount
Discharged
for 250 days
(kg/day)
250 Day
Stream
Cone.
(Jig/L)
Days
Algal
COCa
Exceeded
(PDM)
WV0001279
Chemours
Chemicals LLC
0.11
1.1E0-02
0
0.01
8.0E-04
0
TX0007072
Eco Services
Operations
0.26
49
2
0.02
3.9
0
KY0024082
Barbourville STP
N/A
N/A
N/A
0.01
3.5E-01
0
WA0030520
Central Kitsap
WWTP
0.06
7.0E+01
N/A
0.01
5.8E-01
0
M00002526
Bayer Cropscience
0.05
5.9E-01
0
0.0
4.7E-02
0
KY0027979
Eddyville STP
N/A
N/A
N/A
0.01
1.0
0
KY0103357
Richmond Silver
Creek STP
N/A
N/A
N/A
0.0
3.1E-01
0
KY0003603
Arkema Inc.
0.02
9.5E-04
0
0.0
8.7E-05
0
KY009161
Caveland
Environmental Auth
0.03
8.4E-02
0
0.0
5.6E-03
0
LA0002933
Occidental Chem
Corp, Geismar
0.01
4.9E-05
0
0.0
4.0E-06
0
6874 aAlgal COC = 7 |ig/L
6875 bSan Diego Sea World facility (CA0107336) was not included in the analysis since the reported level is above permit discharge limits;
6876 noncompliance and spills are not in the scope of this risk evaluation.
6877
Page 244 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
6878 Table E-3. Surface Water Carbon Tetrachloride Concentrations for Acute (20 day) and Chronic (250 day) Scenarios and Algal
6879 Concentration of Concern Comparison
NPDES
Facility Name
Amount
Discharged
for 20 days
(kg/day)
20 Day
Stream
Cone.
(Jig/L)
Days
Algae
COCa
Exceeded
(PDM)
Amount
Discharged
for 250 days
(kg/day)
250 Day
Stream
Cone.
(Jig/L)
Days
Algae
COCb
Exceeded
(PDM)
TX0021458
Fort Bend County
WCID2
N/A
N/A
N/A
0.10
10
0
AL0001961
AKZO Chemicals,
Inc.
5.7
3.1E-01
0
0.46
2.5E-02
0
LA0000329
Honeywell, Baton
Rouge
0.20
8.1E-04
0
0.02
6.5E-05
0
LA0005401
ExxonMobil, Baton
Rouge
0.01
4.0E-04
0
0.01
3.2E-05
0
OH0029149
Gabriel Performance
0.19
45
2
0.02
3.5
0
WV0004359
Natrium Plant
0.29
3.4E-02
0
0.02
2.9E-03
0
CA0107336
Sea World, San
Diego0
OH0007269
Dover Chemical
Corp
1.8
1.3E+2
8
0.14
10
3
LA0006181
Honeywell, Geismar
0.18
7.3E-04
0
0.02
6.7E-05
0
LA0038245
Clean Harbors,
Baton Rouge
0.33
1.3E-03
0
0.03
1.05E-
04
0
TXO119792
Equistar Chemicals
LP
0.68
4.4
1
0.05
3.5E-01
0
Page 245 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
NPDES
Facility Name
Amount
Discharged
for 20 days
(kg/day)
20 Day
Stream
Cone.
(Jig/L)
Days
Algae
COCa
Exceeded
(PDM)
Amount
Discharged
for 250 days
(kg/day)
250 Day
Stream
Cone.
(Jig/L)
Days
Algae
COCb
Exceeded
(PDM)
WV0001279
Chemours
Chemicals LLC
0.11
1.1E-02
0
0.01
8.0E-04
0
TX0007072
Eco Services
Operations
0.26
49
2
0.02
3.9
0
KY0024082
Barbourville STP
N/A
N/A
N/A
0.01
3.5E-01
0
WA0030520
Central Kitsap
WWTP
N/A
N/A
N/A
0.01
5.8E-01
0
M00002526
Bayer Cropscience
0.05
5.9E-01
0
0.0
4.7E-02
0
KY0027979
Eddyville STP
N/A
N/A
N/A
0.01
1.0
0
KY0103357
Richmond Silver
Creek STP
N/A
N/A
N/A
0.0
3.1E-01
0
KY0003603
Arkema Inc.
0.02
9.5E-04
0
0.0
8.7E-05
0
KY009161
Caveland
Environmental Auth
0.03
8.4E-02
0
0.0
5.6E-03
0
LA0002933
Occidental Chem
Corp, Geismar
0.01
4.9E-5
0
0.0
4.0E-06
0
6880 abAlgal COC = 7 |ig/L
6881 cSan Diego Sea World facility (CA0107336) was not included in the analysis since the reported level is above permit discharge limits;
6882 noncompliance and spills are not in the scope of this risk evaluation
6883
6884
6885
6886
Page 246 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
6887 Appendix F OCCUPATIONAL EXPOSURES
6888
6889 For additional information on the developmental details, methodology, approach, and results of
6890 any part of the occupational exposure determination process, refer to the supplemental document
6891 Risk Evaluation for Carbon Tetrachloride, Supplemental Information on Releases and
6892 Occupational Exposure Assessment (U.S. EPA. 2019b).
Page 247 of 301
-------
6893
6894
6895
6896
6897
6898
6899
6900
6901
6902
6903
6904
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Appendix G ENVIRONMENTAL HAZARDS
G.l Systematic Review
EPA reviewed ecotoxicity studies for carbon tetrachloride according to the data quality
evaluation criteria found in the Application of Systematic Review in TSCA Risk Evaluations (U.S.
EPA. 2018a). The detailed data quality evaluation results of the 14 on-topic studies for carbon
tetrachloride environmental hazard are presented in the document Risk Evaluation for Carbon
Tetrachloride, Systematic Review Supplemental File: Data Quality Evaluation of Environmental
Hazard Studies (U.S. EPA. 2019e). The data quality extraction results for carbon tetrachloride
environmental hazard are presented in Table Apx G-l.
Table Apx G-l. At
uatic toxicity studies that were evaluated for Carbon Tetrachloride
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Fish
Rainbow trout
(Oncorhynchus
mvkiss)
Fresh
24-hour
LD50 -
4.75
inL/kg
body
weight
1.6-5.0 inL/kg
Intra-
peritoneal,
Nominal
Mortality
(Weber et
al.. 1979)
High
Rainbow trout
('Oncorhynchus
mvkiss)
Fresh
24-hour
LOAEL
= 0.2
inL/kg
body
weight
0, 0.2, 2.0 inL/kg
Intra-
peritoneal,
Nominal
Plasma
clearance of
sulfobromoph
thalein
(Weber et
al.. 1979)
High
Rainbow trout
('Oncorhynchus
mvkiss)
Fresh
48-hour
LOAEL
= 2
inL/kg
body
weight
0, 2.0 inL/kg
Intra-
peritoneal,
Nominal
Plasma
clearance of
sulfobromoph
thalein
(Weber et
al.. 1979)
High
Rainbow trout
('Oncorhynchus
mvkiss)
Fresh
96-hour
LOAEL
= 2
inL/kg
body
weight
0, 2.0 inL/kg
Intra-
peritoneal,
Nominal
Plasma
clearance of
sulfobromoph
thalein
(Weber et
al.. 1979)
High
Rainbow trout
('Oncorhynchus
mvkiss)
Fresh
24-hour
LOAEL
= 1
inL/kg
body
weight
0, 1.0, 2.0 inL/kg
Intra-
peritoneal,
Nominal
Glutamic
pyruvic
transaminase
activity
(Weber et
al.. 1979)
High
Rainbow trout
('Oncorhynchus
mvkiss)
Fresh
48-hour
LOAEL
= 1
inL/kg
body
weight
0, 1.0, 2.0 inL/kg
Intra-
peritoneal,
Nominal
Glutamic
pyruvic
transaminase
activity
(Weber et
al.. 1979)
High
Rainbow trout
('Oncorhynchus
mvkiss)
Fresh
24-hour
LOAEL
= 1
inL/kg
body
weight
0, 1.0, 2.0 inL/kg
Intra-
peritoneal,
Nominal
Increased
body weight
gain
(Weber et
al.. 1979)
High
Page 248 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Rainbow trout
Fresh
24-hour
NOAEL
0, 2.0 mL/kg
Intra-
Plasma
(Weber et
High
(Oncorhynchus
mvkiss)
= 2
mL/kg
body
weight
peritoneal,
Nominal
osmolality
al.. 1979)
Rainbow trout
Fresh
24-hour
LOAEL
0, 2.0 mL/kg
Intra-
Plasma
(Weber et
High
('Oncorhynchus
mvkiss)
= 2
mL/kg
body
weight
peritoneal,
Nominal
protein
concentration
al.. 1979)
Rainbow trout
Fresh
24-hour
LOAEL
0, 2.0 mL/kg
Intra-
Rate of
(Weber et
High
('Oncorhynchus
mvkiss)
= 2
mL/kg
body
weight
peritoneal,
Nominal
urinary
excretion
al.. 1979)
Rainbow trout
Fresh
23-day
LCso =
0, 0.024, 0.070,
Flow-
Mortality
(Black et
High
('Oncorhynchus
mvkiss)
2.02 mg
AI/L
1.11,5.61, 10.9,
45.8 mg/L
through,
Measured
al.. 1982)
Rainbow trout
Fresh
27-day
LCso =
0, 0.024, 0.070,
Flow-
Mortality
(Black et
High
('Oncorhynchus
mvkiss)
1.97 mg
AI/L
1.11,5.61, 10.9,
45.8 mg/L
through,
Measured
al.. 1982)
Rainbow trout
Fresh
23-day
LCioo =
0, 0.024, 0.070,
Flow-
Mortality
(Black et
High
('Oncorhynchus
mvkiss)
45.8 mg
AI/L
1.11,5.61, 10.9,
45.8 mg/L
through,
Measured
al.. 1982)
Rainbow trout
Fresh
27-day
LCioo =
0, 0.024, 0.070,
Flow-
Mortality
(Black et
High
('Oncorhynchus
mvkiss)
10.9 mg
AI/L
1.11,5.61, 10.9,
45.8 mg/L
through,
Measured
al.. 1982)
Rainbow trout
Fresh
16-day
NOAEL
0, 8 mg/L
Renewal,
Lipid
(Bauder et
High
('Oncorhynchus
mvkiss)
= 8mg
AI/L
Nominal
peroxidation
al.. 2005)
Rainbow trout
Fresh
4-day
LOAEL
0, 0.04 mg/L
Static,
Induction of
(Koskinen
High
(Oncorhynchus
= 0.04
Nominal
genes for
et al.. 2004)
mvkiss)
mg AI/L
lipid-binding
proteins and
enzymes of
glycolysis
and energy
metabolism
Rainbow trout
Fresh
3-month
NOAEL
0 (blank control).
Intra-
Hepatic
(Kotsanis
High
(Oncorhynchus
mvkiss)
= 1
mL/kg
body
weight
0 (solvent
control), 1 mL/kg
body weight
(one injection
every 21 days)
peritoneal,
Nominal,
Solvent:
DMSO
lesions
and
Metcalfe.
1988)
Rainbow trout
Fresh
6-mo nth
NOAEL
0 (blank control).
Intra-
Hepatic
(Kotsanis
High
(Oncorhynchus
mvkiss)
= 1
mL/kg
body
weight
0 (solvent
control), 1 mL/kg
body weight
(one injection
every 21 days)
peritoneal,
Nominal,
Solvent:
DMSO
lesions
and
Metcalfe.
1988)
Page 249 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Rainbow trout
(Oncorhvnchus
mykiss)
Fresh
6-mo nth
NOAEL
= 1
mL/kg
body
weight
0 (blank control),
0 (solvent
control), 1 mL/kg
body weight
(one injection
every 21 days)
Intra-
peritoneal,
Nominal,
Solvent:
DMSO;
Partial
hepatecto
my at 4
months
Hepatic
lesions
(Kotsanis
and
Metcalfe.
1988)
High
Common carp
(Cyprinus
carpio)
Fresh
3-day
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Lactate
dehydrogenas
e activity
(Jia et al..
2013)
High
Common carp
(Cyprinus
carpio)
Fresh
3-day
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Serum total
protein
(Jia et al..
2013)
High
Common carp
(Cyprinus
carpio)
Fresh
3-day
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Serum
albumin
(Jia et al..
2013)
High
Common carp
(Cyprinus
carpio)
Fresh
3-day
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Superoxide
dismutase
activity
(Jia et al..
2013)
High
Common carp
(Cyprinus
carpio)
Fresh
3-day
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Catalase
activity
(Jia et al..
2013)
High
Common carp
(Cyprinus
carpio)
Fresh
3-day
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Glutathione
peroxidase
activity
(Jia et al..
2013)
High
Page 250 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Common carp
(Cvprinus
carpio)
Fresh
3-day
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Total
antioxidant
capacity
(Jia et al..
2013)
High
Common carp
(Cvprinus
carpio)
Fresh
3-day
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Concentration
of reduced
glutathione in
blood
(Jia et al..
2013)
High
Common carp
(Cvprinus
carpio)
Fresh
3-day
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Concentration
of
malondialdeh
yde in blood
(Jia et al..
2013)
High
Common carp
(Cvprinus
carpio)
Fresh
3-day
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Liver weight
(relative to
body weight)
(Jia et al..
2013)
High
Common carp
(Cvprinus
carpio)
Fresh
3-day
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Glutamic
pyruvic
transaminase
activity
(Jia et al..
2013)
High
Common carp
(Cvprinus
carpio)
Fresh
3-day
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Glutamic-
oxaloacetic
transaminase
activity
(Jia et al..
2013)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Total
antioxidant
capacity
(Jia et al..
2014)
High
Page 251 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Superoxide
dismutase
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Glutathione
peroxidase
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Catalase
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Concentration
of reduced
glutathione in
blood
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Concentration
of
malondialdeh
yde in blood
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Cytochrome
P450 2E1
level in liver
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Toll-like
receptor 4
protein level
in liver
(Jia et al..
2014)
High
Page 252 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Glutamic-
oxaloacetic
transaminase
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Glutamic
pyruvic
transaminase
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Liver
histopatholog
y
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Nuclear
factor-KB
cREL subunit
gene
expression
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Tumor
necrosis
factor gene
expression
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Inducible
nitric oxide
synthase gene
expression
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Interleukin 1
beta gene
expression
(Jia et al..
2014)
High
Page 253 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Interleukin 6
gene
expression
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 0.5
mL/kg
body
weight
(30% v/v
solution)
0, 0.5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Arachis
oil
Interleukin
12b gene
expression
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
16-hour
LOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Hepatocyte
viability
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
0-hour
NOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Hepatocyte
viability
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
2-hour
NOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Hepatocyte
viability
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
1-hour
NOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Hepatocyte
viability
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Hepatocyte
viability
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
8-hour
LOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Hepatocyte
viability
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
0-hour
NOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 3
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
1-hour
NOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 3
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
2-hour
LOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 3
activity
(Jia et al..
2014)
High
Page 254 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Common carp
(Cvprinus
carpio)
Fresh
8-hour
NOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 3
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 3
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
16-hour
NOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 3
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
0-hour
NOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 8
activity
(Jia et al..
2014) k
High
Common carp
(Cvprinus
carpio)
Fresh
1-hour
NOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 8
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
2-hour
LOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 8
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 8
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
8-hour
LOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 8
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
16-hour
NOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 8
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
0-hour
NOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 9
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
1-hour
NOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 9
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
2-hour
LOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 9
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 9
activity
(Jia et al..
2014)
High
Page 255 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Common carp
(Cvprinus
carpio)
Fresh
8-hour
LOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 9
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
16-hour
NOAEL
1,230.56
mg AI/L
0, 1230.56 mg/L
In vitro.
Nominal
Caspase 9
activity
(Jia et al..
2014)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,845.84
mg AI/L
0, 1,845.84 mg/L
In vitro.
Nominal
Adenosine
triphosphate
in liver
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,845.84
mg AI/L
0, 1,845.84 mg/L
In vitro.
Nominal
Glutamic
pyruvic
transaminase
activity
(Liu et al..
2015) k
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,845.84
mg AI/L
0, 1,845.84 mg/L
In vitro.
Nominal
Glutamic-
oxaloacetic
transaminase
activity
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,845.84
mg AI/L
0, 1,845.84 mg/L
In vitro.
Nominal
Alkaline
phosphatase
activity
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,845.84
mg AI/L
0, 1,845.84 mg/L
In vitro.
Nominal
Lactate
dehydrogenas
e activity
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,845.84
mg AI/L
0, 1,845.84 mg/L
In vitro.
Nominal
Malondialdeh
yde content in
liver
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,845.84
mg AI/L
0, 1,845.84 mg/L
In vitro.
Nominal
Superoxide
dismutase
activity
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,845.84
mg AI/L
0, 1,845.84 mg/L
In vitro.
Nominal
Glutathione
peroxidase
activity
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,845.84
mg AI/L
0, 1,845.84 mg/L
In vitro.
Nominal
Glutathione
S-transferase
activity
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,845.84
mg AI/L
0, 1,845.84 mg/L
In vitro.
Nominal
Catalase
activity
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,845.84
mg AI/L
0, 1,845.84 mg/L
In vitro.
Nominal
Concentration
of reduced
glutathione in
liver
(Liu et al..
2015)
High
Page 256 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Common carp
(Cvprinus
carpio)
Fresh
4-hour
LOAEL
1,845.84
mg AI/L
0, 1,845.84 mg/L
In vitro.
Nominal
Total
antioxidant
capacity
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 5
mL/kg
body
weight
(30% v/v
solution)
0, 5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Olive oil
Catalase
activity
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 5
mL/kg
body
weight
(30% v/v
solution)
0, 5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Olive oil
Total
antioxidant
capacity
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 5
mL/kg
body
weight
(30% v/v
solution)
0, 5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Olive oil
Superoxide
dismutase
activity
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 5
mL/kg
body
weight
(30% v/v
solution)
0, 5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Olive oil
Malondialdeh
yde content in
liver
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 5
mL/kg
body
weight
(30% v/v
solution)
0, 5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Olive oil
Glutathione
peroxidase
activity
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 5
mL/kg
body
weight
(30% v/v
solution)
0, 5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Olive oil
Glutamic-
oxaloacetic
transaminase
activity
(Liu et al..
2015)
High
Page 257 of 301
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 5
mL/kg
body
weight
(30% v/v
solution)
0, 5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Olive oil
Lactate
dehydrogenas
e activity
(Liu et al..
2015)
High
Common carp
(Cvprinus
carpio)
Fresh
72-hour
LOAEL
= 5
mL/kg
body
weight
(30% v/v
solution)
0, 5 mL/kg body
weight
(30% v/v solution)
Intra-
peritoneal,
Nominal,
Solvent:
Olive oil
Glutamic
pyruvic
transaminase
activity
(Liu et al..
2015)
High
Bluegill
(Lepomis
macrochirus)
Fresh
21-day
BCF =
30
0.0523 mg AI/L
Flow-
through,
Measured,
Solvent:
Acetone
Residue,
whole body
(Barrows et
al.. 1980)
High
Bluegill
(Lepomis
macrochirus)
Fresh
24-hour
LCso =
38 mg/L
Not reported
Static,
Nominal,
Solvent:
Not
specified
Mortality
(Buccafusc
o et al..
1981)
Medium
Bluegill
(Lepomis
macrochirus)
Fresh
96-hour
LCso =
27 mg/L
Not reported
Static,
Nominal,
Solvent:
Not
specified
Mortality
(Buccafusc
o et al..
1981)
Medium
Fathead
minnow
(Pimephales
promelas)
Fresh
96-hour
LCso =
41.4 mg
AI/L
<1.70, 8.62-9.2,
12.5-15,21.3-
29.6, 36.2-46.3,
81.8-84.9 mg/L
Flow-
through,
Measured
Mortality
(Geiser et
al.. 1990)
High
Fathead
minnow
(Pimephales
promelas)
Fresh
96-hour
ECso =
20.8 mg
AI/L
<1.70, 8.62-9.2,
12.5-15,21.3-
29.6, 36.2-46.3,
81.8-84.9 mg/L
Flow-
through,
Measured
Loss of
equilibrium
(Geiser et
al.. 1990)
High
Fathead
minnow
(Pimephales
promelas)
Fresh
96-hour
LCso =
43.3 mg
AI/L
(Rep 1)
0, 9.7, 10.5, 19.6,
37.1,73.2, 181.0
mg/L
Flow-
through,
Measured
Mortality
(Kimball.
1978)
High
Fathead
minnow
(Pimephales
promelas)
Fresh
96-hour
LCso =
42.9 mg
AI/L
(Rep 2)
0, 9.7, 10.5, 19.6,
37.1,73.2, 181.0
mg/L
Flow-
through,
Measured
Mortality
(Kimball.
1978)
High
Fathead
minnow
(Pimephales
promelas)
Fresh
>7 days
NOAEL
= 37.1
mg AI/L
0, 9.7, 10.5, 19.6,
37.1,73.2, 181.0
mg/L
Flow-
through,
Measured
Mortality
(Kimball.
1978)
High
Page 258 of 301
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Fathead
minnow
(Pimephales
promelas)
Fresh
>7 days
LOAEL
= 73.2
mg AI/L
0, 9.7, 10.5, 19.6,
37.1,73.2, 181.0
mg/L
Flow-
through,
Measured
Mortality
(Kimball.
1978)
High
Fathead
minnow
(Pimephales
promelas)
Fresh
>7 days
MATC =
52.1 mg
AI/L
0, 9.7, 10.5, 19.6,
37.1,73.2, 181.0
mg/L
Flow-
through,
Measured
Mortality
(Kimball.
1978)
High
Fathead
minnow
(Pimephales
promelas)
Fresh
>7 days
LCioo =
73.2 mg
AI/L
0, 9.7, 10.5, 19.6,
37.1,73.2, 181.0
mg/L
Flow-
through,
Measured
Mortality
(Kimball.
1978)
High
Fathead
minnow
(Pimephales
promelas)
Fresh
96-hour
LCso =
10.4 mg
AI/L
Not reported
Static,
Measured
Mortality
(Brooke.
1987) k
High
Fathead
minnow
(Pimephales
promelas)
Fresh
96-hour
LCso =
41.4 mg
AI/L
Not reported
Flow-
through,
Measured
Mortality
(Brooke.
1987)
High
Fathead
minnow
(Pimephales
promelas)
Fresh
5-day
LCioo =
62.8 mg
AI/L
0,0.015,0.065,
0.72, 9.32, 24.2,
45.0, 62.8 mg/L
Flow-
through,
Measured
Mortality
(Black et
al.. 1982)
High
Fathead
minnow
(Pimephales
promelas)
Fresh
9-day
LCioo =
62.8 mg
AI/L
0,0.015,0.065,
0.72, 9.32, 24.2,
45.0, 62.8 mg/L
Flow-
through,
Measured
Mortality
(Black et
al.. 1982)
High
Fathead
minnow
(Pimephales
promelas)
Fresh
5-day
LCso =
16.25 mg
AI/L
0,0.015,0.065,
0.72, 9.32, 24.2,
45.0, 62.8 mg/L
Flow-
through,
Measured
Mortality
(Black et
al.. 1982)
High
Fathead
minnow
(Pimephales
promelas)
Fresh
9-day
LCso = 4
mg AI/L
0,0.015,0.065,
0.72, 9.32, 24.2,
45.0, 62.8 mg/L
Flow-
through,
Measured
Mortality
(Black et
al.. 1982)
High
Japanese
medaka
(Oryzias
latipes)
Fresh
10-day
LCso =
96 mg
AI/L
0, 58, 70, 84, 101,
121, 145 mg/L
Renewal,
Nominal
Mortality
(Schell,
1987)
High
Japanese
medaka
(Oryzias
latipes)
Fresh
10-day
LCioo =
145 mg
AI/L
0, 58, 70, 84, 101,
121, 145 mg/L
Renewal,
Nominal
Mortality
(Schell,
1987)
High
Japanese
medaka
(Oryzias
latipes)
Fresh
10-day
NOEC =
70 mg
AI/L;
LOEC =
84 mg
AI/L
0, 58, 70, 84, 101,
121, 145 mg/L
Renewal,
Nominal
Mortality
(Schell,
1987)
High
Page 259 of 301
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Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Mozambique
tilapia
(Oreochromis
mossambicus)
Fresh
24-hour
LOAEL
= 9 mg/L
0, 9 mg/L
Static,
Nominal
Malondialdeh
yde content in
liver
(dc Vera
and
Pocsidio.
1998)
High
Mozambique
tilapia
('Oreochromis
mossambicus)
Fresh
48-hour
NOAEL
= 9 mg/L
0, 9 mg/L
Static,
Nominal
Malondialdeh
yde content in
liver
(dc Vera
and
Pocsidio.
1998)
High
Mozambique
tilapia
{Oreochromis
mossambicus)
Fresh
72-hour
NOAEL
= 9 mg/L
0, 9 mg/L
Static,
Nominal
Malondialdeh
yde content in
liver
(dc Vera
and
Pocsidio.
1998)
High
Mozambique
tilapia
{Oreochromis
mossambicus)
Fresh
96-hour
LOAEL
= 9 mg/L
0, 9 mg/L
Static,
Nominal
Malondialdeh
yde content in
liver
(de Vera
and
Pocsidio.
1998)
High
Mozambique
tilapia
{Oreochromis
mossambicus)
Fresh
168-hour
LOAEL
= 9 mg/L
0, 9 mg/L
Static,
Nominal
Malondialdeh
yde content in
liver
(de Vera
and
Pocsidio.
1998)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Hematocrit
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Red blood
cell count
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Muscle water
content
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Sodium
concentration
in blood
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Potassium
concentration
in blood
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Sodium/potas
sium ratio in
blood
(Chen et
al.. 2004)
High
Page 260 of 301
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Nile tilapia
(Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Chloride
concentration
in blood
(Chen et
al.. 2004)
High
Nile tilapia
('Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the gill, sum
(Chen et
al.. 2004)
High
Nile tilapia
('Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the gill,
circulatory
disturbance
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the gill,
regenerative
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the gill,
proliferation
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the trunk
kidney,
inflammation
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the trunk
kidney, sum
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the trunk
kidney,
circulatory
disturbance
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the liver,
regenerative
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the trunk
kidney,
proliferation
(Chen et
al.. 2004)
High
Page 261 of 301
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Nile tilapia
(Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the liver,
inflammation
(Chen et
al.. 2004)
High
Nile tilapia
('Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the liver, sum
(Chen et
al.. 2004)
High
Nile tilapia
('Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Calcium
concentration
in blood
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Magnesium
concentration
in blood
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Bicarbonate
concentration
in blood
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Phosphate
concentration
in blood
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Iron
concentration
in blood
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Total iron
binding
capacity
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Percent
saturation of
iron binding
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Anion gap
(Chen et
al.. 2004)
High
Page 262 of 301
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Nile tilapia
(Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Total protein
(Chen et
al.. 2004)
High
Nile tilapia
('Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Glucose
(Chen et
al.. 2004)
High
Nile tilapia
('Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Cholesterol
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Bilirubin
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Alanine
transaminase
activity
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Aspartate
aminotransfer
ase activity
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Alkaline
phosphatase
activity
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Creatine
kinase
activity
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the liver,
circulatory
disturbance
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the liver,
proliferation
(Chen et
al.. 2004)
High
Page 263 of 301
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Nile tilapia
(Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the spleen,
inflammation
(Chen et
al.. 2004)
High
Nile tilapia
('Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Body weight
(Chen et
al.. 2004)
High
Nile tilapia
('Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the spleen,
circulatory
disturbance
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the spleen,
regenerative
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the spleen,
proliferation
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the gill,
inflammation
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL /kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the spleen,
sum
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the head
kidney,
circulatory
disturbance
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the head
kidney,
regenerative
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the trunk
kidney,
regenerative
(Chen et
al.. 2004)
High
Page 264 of 301
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Nile tilapia
(Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the head
kidney,
proliferation
(Chen et
al.. 2004)
High
Nile tilapia
('Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the head
kidney,
inflammation
(Chen et
al.. 2004)
High
Nile tilapia
('Oreochromis
niloticus)
Fresh
42-44-
hour
LOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the head
kidney, sum
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the intestine,
regenerative
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the intestine,
circulatory
disturbance
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the intestine,
proliferation
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the intestine,
inflammation
(Chen et
al.. 2004)
High
Nile tilapia
{Oreochromis
niloticus)
Fresh
42-44-
hour
NOAEL
= 1.12
mL/kg
body
weight
0, 1.12 mL/kg
body weight
Intra-
peritoneal,
Nominal
Histological
changes in
the intestine,
sum
(Chen et
al.. 2004)
High
Tidewater
silversides
{Menidia
berylUna)
Salt
96-hour
LCso =
150
mg/L
0, 75, 100, 125,
200, 320 mg/L
Static,
Nominal,
Solvent:
Not
specified
Mortality
(Dawson et
al.. 1977)
Medium
Bluegill
{Lepomis
macrochirus)
Fresh
96-hour
LCso =
125
mg/L
0, 75, 100, 125,
200, 320 mg/L
Static,
Nominal,
Solvent:
Not
specified
Mortality
(Dawson et
al.. 1977)
Medium
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Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Fish (species
not reported)
Not
reporte
d
48-hour
LCso =
38 mg
AI/L
Not reported
Static,
Measured
Mortality
(Freitae et
al.. 1994)
High
Aquatic Invertebrates
Water flea
Fresh
24-hour
LCso -
Not reported
Static,
Mortality
(LeBlanc.
High
(Daphnia
magna)
35 mg
AI/L
Nominal,
Solvent:
Unknown
1980)
Water flea
Fresh
48-hour
LCso =
Not reported
Static,
Mortality
(LeBlanc.
High
(Daphnia
magna)
35 mg
AI/L
Nominal,
Solvent:
Unknown
1980)
Water flea
(Daphnia
magna)
Fresh
48-hour
NOEC =
7.7 mg
AI/L
Not reported
Static,
Nominal,
Solvent:
Unknown
Mortality
(LeBlanc.
1980) k
High
Water flea
Fresh
0.25-
NOAEL
0, 2.34375,
Static,
Phototactic
(Martins et
High
(Daphnia
magna)
hour
= 37.5
mg AI/L
LOAEL
= 75 mg
AI/L
4.6875, 9.375,
18.75,37.5,75
mg/L
Nominal
response
al.. 2007a)
Water flea
Fresh
3.5-hour
NOAEL
0, 2.34375,
Static,
Phototactic
(Martins et
High
(Daphnia
magna)
= 37.5
mg AI/L
LOAEL
= 75 mg
AI/L
4.6875, 9.375,
18.75,37.5,75
mg/L
Nominal
response
al.. 2007a)
Water flea
Fresh
24-hour
LOAEL
0, 2.34375,
Static,
Phototactic
(Martins et
High
(Daphnia
magna)
= 2.3 mg
AI/L
4.6875, 9.375,
18.75,37.5,75
mg/L
Nominal
response
al.. 2007a)
Water flea
Fresh
48-hour
NOAEL
0, 2.34375,
Static,
Phototactic
(Martins et
High
(Daphnia
magna)
= 18.75
mg AI/L
LOAEL
= 37.5
mg AI/L
4.6875, 9.375,
18.75,37.5,75
mg/L
Nominal
response
al.. 2007a)
Water flea
Fresh
3.5-hour
LCo = 75
0, 75 mg/L
Static,
Mortality
(Martins et
High
(Daphnia
magna)
mg AI/L
Nominal
al.. 2007b)
Water flea
Fresh
3.5-hour
NOAEL
0, 75 mg/L
Static,
Oxygen
(Martins et
High
(Daphnia
magna)
= 75 mg
AI/L
Nominal
consumption
al.. 2007b)
Water flea
Fresh
15-
NOAEL
0, 75 mg/L
Static,
Oxygen
(Martins et
High
(Daphnia
magna)
minute
= 75 mg
AI/L
Nominal
consumption
al.. 2007b)
Water flea
Fresh
24-hour
ECso =
Not reported
Static,
Immobilizatio
(Freitae et
High
(Daphnia
magna)
20 mg
AI/L
Measured
n
al.. 1994)
Page 266 of 301
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Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Scud
(Gammarus
pseudolimnaeus
)
Fresh
96-hour
LCso =
11.1 mg
AI/L
Not reported
Flow-
through,
Measured
Mortality
(Brooke.
1987)
High
Ostracod
(Cypris
subglobosa)
Fresh
24-hour
ECso =
301 mg
AI/L
Not reported
Renewal,
Nominal
Immobilizatio
n
(Khanearot
High
and Das.
2009)
Ostracod
0Cvpris
subglobosa)
Fresh
48-hour
ECso =
181 mg
AI/L
Not reported
Renewal,
Nominal
Immobilizatio
n
(Khanearot
High
and Das.
2009)
Flatworm
(Dugesia
japonica)
Fresh
7-day
LCso =
0.2 mg
AI/L
Not reported
Renewal,
Nominal
Mortality
(Yoshioka
et al.. 1986)
Unacceptable
Flatworm
(Dugesia
japonica)
Fresh
7-day
ECso =
1.5 mg
AI/L
Not reported
Renewal,
Nominal
Abnormal
regeneration
(Yoshioka
et al.. 1986)
Unacceptable
Ciliate
(Tetrahymena
pvriformis)
Fresh
24-hour
ECso =
830 mg
AI/L
Not reported
Static,
Nominal,
Solvent:
unknown
Population
growth rate
(Yoshioka
et al.. 1985)
Unacceptable
Midge
(Chironomus
tentans)
Fresh
24-hour
LOAEL
= 0.02
mg AI/L
0, 0.02, 0.2, 2
mg/L
Static,
Nominal,
Solvent:
acetone
Gene
expression -
heat shock
protein and
hemoglobin
(Lee et al..
2006)
High
Midge
(Chironomus
tentans)
Fresh
48-hour
NOAEL
= 2mg
AI/L
0, 0.02, 0.2, 2
mg/L
Static,
Nominal,
Solvent:
acetone
Body fresh
weight
(Lee et al..
2006)
High
Midge
(Chironomus
tentans)
Fresh
48-hour
NOAEL
= 0.2 mg
AI/L
LOAEL
= 2mg
AI/L
0, 0.02, 0.2, 2
mg/L
Static,
Nominal,
Solvent:
acetone
Body dry
weight
(Lee et al..
2006)
High
Yellow fever
mosquito
(Aedes aegvpti)
Fresh
24-hour
LCso =
224 mg
AI/L
Not reported
Static,
Nominal
Mortality
(Richie et
al.. 1984)
High
Yellow fever
mosquito
(Aedes aegvpti)
Fresh
0.5-hour
LCso =
467 mg
AI/L
Not reported
Static,
Nominal
Mortality
(Richie et
al.. 1984)
High
Yellow fever
mosquito
(Aedes aegvpti)
Fresh
1-hour
LCso =
375 mg
AI/L
Not reported
Static,
Nominal
Mortality
(Richie et
al.. 1984)
High
Algae
Green algae
(Chlamvdomon
as reinhardtii)
Fresh
72-hour
ECso =
0.25 mg
AI/L
Not reported
Static,
Measured
Biomass
(Brack and
Rottler.
1994)
High
Green algae
(Chlamvdomon
as reinhardtii)
Fresh
72-hour
ECio =
0.07 mg
AI/L
Not reported
Static,
Measured
Biomass
(Brack and
Rottler.
1994)
High
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Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Green algae
(Pseudokirchne
riella
subcapitata)
Fresh
48-hour
ECso =
23.59 mg
AI/L
Not reported
Static,
Nominal
Growth
(Tsai and
Chen.
2007)
High
Algae
(Desmodesmus
subspicatus)
Fresh
72-hour
ECso =
21 mg/L
Not reported
Static,
Measured
Inhibition
(Freitae et
al.. 1994)
High
Marine
bacterium
(Photobacteriu
Salt
15-
minute
ECso = 5
mg/L
Not reported
Static,
Measured
Bioluminesce
nee
(Freitae et
al.. 1994)
Medium
phosphoreum)
Activated
sludge
microorganisms
Fresh
5-day
ECso >
1000
mg/L
Not reported
Static,
Measured
o2
consumption
(Freitae et
al.. 1994)
High
Amphibians
Bullfrog (Rana
catesbeiana)
Fresh
4-day
LCso -
1.5 mg
AI/L
0, 0.026, 0.060,
1.18,7.81,65.7
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
Bullfrog (Rana
catesbeiana)
Fresh
8-day
LCso =
0.9 mg
AI/L
0, 0.026, 0.060,
1.18,7.81,65.7
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
Bullfrog {Rana
catesbeiana)
Fresh
4-day
LCioo =
65.7 mg
AI/L
0, 0.026, 0.060,
1.18,7.81,65.7
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
Bullfrog {Rana
catesbeiana)
Fresh
8-day
LCioo =
7.81 mg
AI/L
0, 0.026, 0.060,
1.18,7.81,65.7
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
Pickerel frog
{Lithobates
palustris)
Fresh
4-day
LCso =
3.62 mg
AI/L
0, 0.020, 0.032,
0.69,4.98, 92.5
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
Pickerel frog
{Lithobates
palustris)
Fresh
8-day
LCso =
2.37 mg
AI/L
0, 0.020, 0.032,
0.69,4.98, 92.5
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
Fowler's toad
{Anaxvrus bufo)
Fresh
3-day
LCso >92
mg AI/L
0, 0.020, 0.032,
0.69,4.98, 92.5
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
Fowler's toad
{Anaxvrus bufo)
Fresh
7-day
LCso =
2.83 mg
AI/L
0, 0.020, 0.032,
0.69,4.98, 92.5
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
Bullfrog {Rana
catesbeiana)
Fresh
8-day
LCio =
0.113 mg
AI/L
0, 0.026, 0.060,
1.18,7.81,65.7
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
Bullfrog {Rana
catesbeiana)
Fresh
8-day
LCoi =
0.0236
mg AI/L
0, 0.026, 0.060,
1.18,7.81,65.7
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
Pickerel frog
{Lithobates
palustris)
Fresh
8-day
LCio =
0.4357
mg AI/L
0, 0.020, 0.032,
0.69,4.98, 92.5
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
Pickerel frog
{Lithobates
palustris)
Fresh
8-day
LCoi =
0.1096
mg AI/L
0, 0.020, 0.032,
0.69,4.98, 92.5
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
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Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Pickerel frog
(Lithobates
palustris)
Fresh
4-day
LCioo =
92.5 mg
AI/L
0, 0.020, 0.032,
0.69,4.98, 92.5
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Birse et
al.. 1980)
High
Pickerel frog
(Lithobates
palustris)
Fresh
8-day
LCioo =
92.5 mg
AI/L
0, 0.020, 0.032,
0.69,4.98, 92.5
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
Fowler's toad
(Anaxvrus bufo)
Fresh
7-day
LCioo =
92.5 mg
AI/L
0, 0.020, 0.032,
0.69,4.98, 92.5
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Biree et
al.. 1980)
High
Bullfrog (Rana
catesbeiana)
Fresh
8-day
LOEC =
0.060 mg
AI/L
0, 0.026, 0.060,
1.18,7.81,65.7
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Birse et
al.. 1980)
High
Pickerel frog
(Lithobates
palustris)
Fresh
8-day
LOEC =
92.5 mg
AI/L
0, 0.020, 0.032,
0.69,4.98, 92.5
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Birse et
al.. 1980)
High
Fowler's toad
(Anaxvrus bufo)
Fresh
7-day
LOEC =
92.5 mg
AI/L
0, 0.020, 0.032,
0.69,4.98, 92.5
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Birse et
al.. 1980)
High
Pickerel frog
(Lithobates
palustris)
Fresh
4.5-day
LCso =
3.62 mg
AI/L
Not reported
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
Pickerel frog
(Lithobates
palustris)
Fresh
8.5-day
LCso =
2.37 mg
AI/L
Not reported
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
Fowler's toad
(Anaxvrus bufo)
Fresh
3-day
LCso >
92 mg
AI/L
Not reported
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
Fowler's toad
(Anaxvrus bufo)
Fresh
7-day
LCso =
2.83 mg
AI/L
Not reported
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
European
common frog
(Rana
temporaria)
Fresh
9-day
LCso =
1.16 mg
AI/L
0,0.010,0.076,
0.67, 10.7, 24.0,
41.2 mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
European
common frog
(Rana
temporaria)
Fresh
9-day
LCioo =
41.2 mg
AI/L
0,0.010,0.076,
0.67, 10.7, 24.0,
41.2 mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
European
common frog
(Rana
temporaria)
Fresh
9-day
LCio =
0.025 mg
AI/L
0,0.010,0.076,
0.67, 10.7, 24.0,
41.2 mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
European
common frog
(Rana
temporaria)
Fresh
9-day
LCoi =
0.0011
mg AI/L
0, 0.010, 0.076,
0.67, 10.7, 24.0,
41.2 mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
European
common frog
(Rana
temporaria)
Fresh
5-day
LCso =
4.56 mg
AI/L
0,0.010,0.076,
0.67, 10.7, 24.0,
41.2 mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
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6916
6917
6918
6919
6920
6921
6922
6923
6924
6925
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Test Species
Fresh/
Salt
Water
Duration
End-
point
Concentration(s)
Test
Analysis
Effect(s)
References
Data Quality
Evaluation
Leopard frog
(Lithobates
pipiens)
Fresh
9-day
LC50 =
1.64 mg
AI/L
0,0.010,0.076,
0.67, 10.7, 24.0,
41.2 mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
Leopard frog
(Lithobates
pipiens)
Fresh
9-day
LC10 =
0.0339
mg AI/L
0,0.010,0.076,
0.67, 10.7, 24.0,
41.2 mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
Leopard frog
(Lithobates
pipiens)
Fresh
9-day
LC01 =
0.0014
mg AI/L
0,0.010,0.076,
0.67, 10.7, 24.0,
41.2 mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
Leopard frog
(Lithobates
pipiens)
Fresh
5-day
LC50 =
6.77 mg
AI/L
0,0.010,0.076,
0.67, 10.7, 24.0,
41.2 mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
Northwestern
salamander
(Ambvstoma
gracile)
Fresh
5.5-day
LC50 =
9.01 mg
AI/L
0,0.010,0.076,
0.67, 10.6, 24.2,
41.8 mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
Northwestern
salamander
(Ambvstoma
gracile)
Fresh
9.5-day
LC50 =
1.98 mg
AI/L
0,0.010,0.076,
0.67, 10.6, 24.2,
41.8 mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
African clawed
frog (Xenopus
laevis)
Fresh
2-day
LC50 >
27 mg
AI/L
0, 0.004, 0.073,
0.60, 10.5, 27.2
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
African clawed
frog (Xenopus
laevis)
Fresh
6-day
LC50 =
22.42 mg
AI/L
0, 0.004, 0.073,
0.60, 10.5, 27.2
mg/L
Flow-
through,
Measured
Teratogenesis
Leading to
Mortality
(Black et
al.. 1982)
High
G.2 Hazard Identification- Aquatic
Relevant data from the screened literature are summarized below (TableApx G-2) as ranges
(min-max). Studies with data quality evaluation results of 'medium' to 'high' were used to
characterize the environmental hazards of carbon tetrachloride. Table Apx G-2 provides the
species, media, duration, endpoint, effects, etc. for the acceptable acute toxicity studies that were
evaluated.
Toxicity to Aquatic Organisms
For the aquatic environment, the hazard endpoint for fish, from acute exposure durations (24-
96-h LCso) to carbon tetrachloride, ranges from 10.4 - 150 mg/L (data quality evaluation scores
for each citation are in the parenthesis) (Freitag et al.. 1994) (high); (Schell. 1987) (high);
(Brooke. 1987) (high); (Kimball 1978) (high); (Geiger et al.. 1990) (high); (Buccafusco et al..
1981) (medium); and (Dawson et al.. 1977) (medium). The hazard endpoint for aquatic
invertebrates, from acute exposure durations (24-48-h L/EC50) to carbon tetrachloride, ranges
from 11.1 - 181 mg/L (LeBlanc. 1980) (high); (Freitag et al.. 1994) (high); (Brooke. 1987)
(high); (Khangarot and Das. 2009) (high); and (Richie et al.. 1984) (high). The hazard endpoint
for aquatic plants, from acute exposure durations (72-hr EC50) to carbon tetrachloride, ranges
from 0.25 - 23.59 mg/L (Brack and Rottler. 1994) (high); (Freitag et al.. 1994) (high); and
(Tsai and Chen. 2007) (high).
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There were no chronic studies that encompassed amphibian metamorphoses and adult
reproductive stages of the amphibian life-cycle. However, amphibian embryo and larvae were
the most sensitive life stages to sub-chronic exposures of carbon tetrachloride in the aquatic
environment. In two sub-chronic studies that EPA assigned an overall quality level of high,
amphibian embryos and larvae were exposed to carbon tetrachloride for 2 to 9 days under flow-
through conditions (Black et al.. 1982; Birge et al.. 1980). The study authors combined embryo-
larval lethality and teratogenesis effect concentrations to establish a 10% impairment value
(LCio). The LCio hazard endpoint for amphibian embryo-larval stages, from sub-chronic
exposure durations to carbon tetrachloride, ranges from 0.025 to 0.436 mg/L (Birge et al..
1980); and (Black et al.. 1982).
The hazard endpoint for fish, from chronic exposure durations (27-day LCso) to carbon
tetrachloride, is 1.97 mg/L (Black et al.. 1982) (high). The hazard endpoint for aquatic
invertebrates, from chronic exposure durations to carbon tetrachloride, is 1.1 mg/L. This is
calculated by applying an acute to chronic ratio (ACR) of 10 to the lowest acute aquatic
invertebrate endpoint value (11.1 mg/L (Brooke. 1987) (high)). The hazard endpoint for algae,
from chronic exposure durations (72-hr ECio) to carbon tetrachloride, is 0.07 mg/L (Brack and
Rottler. 1994) (high).
Table Apx G-2. Aquatic toxicity studies that were evaluated for carbon tetrachloride
Exposure
Duration
Test
organism
Endpoint
Hazard
value3
Units
Effect Endpoint
References'3
Acute
Fish
LCso
10.40-
150.0
mg/L
Mortality
(Brooke, 1987)
(high); (Freitag et al.,
1994) (high); (Schell,
1987) (high);
(Kimball. 1978)
(high); (Geiger et al.,
1990) (high);
(Buccafusco et al.,
1981) (medium);
(Dawson et al., 1977)
(medium)
Aquatic
invertebrates
L/EC50
11.10 —
224.0
mg/L
Mortality/
immobilization
(Brooke, 1987)
(high); (LeBlanc,
1980) (high); (Freitag
et al., 1994) (high);
(Khangarot and Das,
2009) (high); (Richie
et al., 1984) (high)
Amphibians
LC50
0.900 -
22.42
mg/L
Teratogenesis
Leading to
Mortality0
(Birge et al., 1980)
(high); (Black et al.,
1982) (high)
Acute COC
0.09
mg/L
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Exposure
Duration
Test
organism
Endpoint
Hazard
value3
Units
Effect Endpoint
References'3
Chronic
Fish
LCso
1.970
mg/L
Mortality
(Black et al.. 1982)
(high)
Aquatic
invertebrates
Chronic
value
1.100
(ACR10)
mg/L
Growth and
reproduction
(Brooke, 1987) (hiah)
Amphibians
LC10
0.025-
0.436
mg/L
Teratogenesis
Leading to
Mortality
(Birae et al., 1980)
(hiah); (Black et al.,
1982) (hiah)
Chronic
coc
0.003
mg/L
Algae
EC10
0.070
mg/L
Biomass
(Brack and Rottler,
1994) (hiah)
EC50
0.250-
23.59
mg/L
Biomass/growth
rate
(Brack and Rottler,
1994) (hiah); (Freitaa
et al., 1994) (hiah);
(Tsai and Chen, 2007)
(hiah)
Algae COC
0.007
mg/L
aValues in bold were usee
bData quality evaluation s
°The study authors define<
debilitating abnormalities
to derive the COC.
cores for each citation are in the parenthesis.
i embryo4arval teratogenesis as the percent of survivors with gross and
likely to result in eventual mortality.
6947
6948 Toxicity to Sediment and Terrestrial Organisms
6949 The limited number of environmental toxicity studies for carbon tetrachloride on sediment and
6950 terrestrial organisms were determined to contain data or information not relevant (off-topic) for
6951 the risk evaluation. No relevant (on-topic) toxicity data were available for carbon tetrachloride to
6952 birds. Hazard studies for sediment and terrestrial organisms are not likely to be conducted
6953 because exposure to carbon tetrachloride by these organisms is not expected due to the physical,
6954 chemical, and fate properties of the chemical.
6955 G.3 Weight of Evidence
6956 During the data integration stage of systematic review, EPA analyzed, synthesized, and
6957 integrated the data/information. This involved weighing scientific evidence for quality and
6958 relevance, using a Weight of Evidence (WoE) approach (U.S. EPA. 2018a).
6959
6960 During data evaluation, studies were rated high, medium, low, or unacceptable for quality based
6961 on the TSCA criteria described in the Application of Systematic Review in TSCA Risk
6962 Evaluations (U.S. EPA. 2018a). Only data/information rated as high, medium, or low for quality
6963 was used for the environmental risk assessment (unless otherwise noted). Any information rated
6964 as unacceptable was not used. While integrating environmental hazard data for carbon
6965 tetrachloride, EPA gave more weight to relevant data/information rated high or medium for
6966 quality. The ecological risk assessor decided if data/information were relevant based on whether
6967 it has biological, physical/chemical, and environmental relevance (U.S. EPA. 1998):
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6969
6970
6971
6972
6973
6974
6975
6976
6911
6978
6979
6980
6981
6982
6983
6984
6985
6986
6987
6988
6989
6990
6991
6992
6993
6994
6995
6996
6997
6998
6999
7000
7001
7002
7003
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• Biological relevance: correspondence among the taxa, life stages, and processes
measured or observed and the assessment endpoint.
• Physical/chemical relevance: correspondence between the chemical or physical agent
tested and the chemical or physical agent constituting the stressor of concern.
• Environmental relevance: correspondence between test conditions and conditions in the
region of concern (U.S. EPA. 1998).
This WoE approach was used to assess hazard data (Appendix H.2) and develop COCs as
described in Appendix H.4. Where high or medium quality studies were available for a
taxonomic group, low quality studies were not used to derive COCs. Additionally, where
multiple toxicity values were reported within a study for the same species (e.g., multiple EC50s
with different durations), they were summarized as ranges (min-max) in the Appendix Table H-2
and the higher quality or more relevant citation was used. If quality and relevance were equal,
the lowest toxicity endpoint value for acute and chronic exposures were used to derive acute and
chronic COCs.
Certain environmental studies on carbon tetrachloride were of high quality but were not
biologically relevant for purposes of environmental hazard assessment due to the reported
endpoints (e.g., glutamic pyruvic transaminase activity, serum total protein, catalase activity,
sodium concentration in blood, whole body residue). These studies (Chen et al.. 2004): (de Vera
andPocsidio. 1998): (Barrows et al.. 1980): (Liu et al.. 2015): (Jia et al.. 2013): (Kotsanis and
Metcalfe. 1988): (Weber et al.. 1979): (Koskinen et al.. 2004): (Bauder et al.. 2005): (Martins et
al.. 2007a): (Lee et al.. 2006)) are contained within the on-topic data evaluation section of
Appendix H.2, but were not used within the risk evaluation process. During risk evaluation, EPA
made refinements to the conceptual models resulting in the elimination of the terrestrial exposure
pathway and studies that are not biologically relevant from further analysis. Thus, environmental
hazard data sources on terrestrial organisms and on metabolic endpoints were considered out of
scope and excluded from data quality evaluation.
Environmental test data are reported from the Japanese Ministry of the Environment (MOE).
EPA obtained the Japanese MOE test data in Japanese (not English). Since studies in a foreign
language are generally excluded from evaluation (although there are exceptions on a case-by-
case basis) and the Japanese test data are not driving the environmental assessment, EPA decided
not to translate the Japanese test data into English or use the test data in this risk evaluation. EPA
acknowledges the studies exist and are included in carbon tetrachloride's docket.
To assess aquatic toxicity from acute exposures, data for four taxonomic groups were available:
amphibians, fish, aquatic invertebrates, and algae. For each taxonomic group, data were available
for multiple species, and were summarized in Appendix Table G-2 as ranges (min-max).
There were no chronic studies that encompassed amphibian metamorphoses and adult
reproductive stages of the amphibian life-cycle. However, amphibian embryo and larvae were
the most sensitive life stages to sub-chronic exposures of carbon tetrachloride in the aquatic
environment. In two sub-chronic studies that EPA assigned an overall quality level of high,
amphibian embryos and larvae were exposed to carbon tetrachloride for 2 to 9 days under flow-
through conditions (Black et al.. 1982: Birge et al.. 1980). The study authors combined embryo-
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7013
7014
7015
7016
7017
7018
7019
7020
7021
7022
7023
7024
7025
7026
7027
7028
7029
7030
7031
7032
7033
7034
7035
7036
7037
7038
7039
7040
7041
7042
7043
7044
7045
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larval lethality and teratogenesis effect concentrations to establish a 10% impairment value
(LCio) in Lithobatespalustris (Birge et al.. 1980) and Rana temporaria and Lithobatespipiens
(Black et al.. 19821 at carbon tetrachloride concentrations ranging from 0.010 - 92.5 mg/L.
EPA considered the sub-chronic hazard LCsos and LCios for amphibians for teratogenicity
leading to mortality to estimate acute and chronic hazard values for amphibians, respectively. To
assess aquatic toxicity from acute and chronic exposures, EPA used and rounded the lowest LCso
to 0.09 mg/L and LCio to 0.03 mg/L, respectively, from two high quality 9-days amphibian
studies (Black et al.. 1982; Birge et al.. 1980). When comparing these values to the other acute
and chronic data from fish and aquatic invertebrates, amphibians were again the most sensitive
taxonomic group. Therefore, the amphibian 9-day lowest LCso of 0.09 mg/L and LCio of 0.03
mg/L were used to derive an acute COC in Appendix Section G.5 and chronic COC in Appendix
Section G.6. These values were from two scientific articles that EPA assigned an overall quality
level of high and represents three species of amphibians.
The 72-hour algal ECio of 0.0717 mg/L represented the most sensitive toxicity value derived
from the available algal toxicity data to carbon tetrachloride and this value was used to derive an
algal COC as described in Appendix Section 7G.7. This value is from one algal study that EPA
assigned an overall quality of high.
G.4 Concentrations of Concern
EPA calculated screening-level acute and chronic COCs for aquatic species based on the
environmental hazard data for carbon tetrachloride, using EPA methods (U.S. EPA. 2012b);
(U.S. EPA. 2013b). While there was data representing amphibians, fish, aquatic invertebrates,
and aquatic plants, the data were not robust enough to conduct a more detailed species sensitivity
distribution analysis. Therefore, EPA chose to establish the COC as protective cut-off standards
above which exposures to carbon tetrachloride are expected to cause effects for each taxonomic
group in the aquatic environment. The acute, chronic, and algal COCs for carbon tetrachloride
are based on the lowest toxicity value in the dataset. For the aquatic environment, EPA derived
acute and a chronic COCs for amphibians as well as a COC for algae to serve as representative
COCs for all aquatic taxa.
After weighing the scientific evidence and selecting the appropriate toxicity values from the
integrated data to calculate COCs, EPA applied an assessment factor (AF) according to EPA
methods (U.S. EPA. 2012b); (U.S. EPA. 2013b). when possible. The application of AFs provides
a lower bound effect level that would likely encompass more sensitive species not represented by
the available experimental data. AFs also account for differences in inter- and intra-species
variability, as well as laboratory-to-field variability. These assessment factors are dependent
upon the availability of datasets that can be used to characterize relative sensitivities across
multiple species within a given taxa or species group. The assessment factors are standardized in
risk assessments conducted under TSCA, since the data available for most industrial chemicals
are limited. For fish and aquatic invertebrates (e.g., Daphnia sp.), the acute hazard values were
divided by an AF of 5 and the chronic hazard values were divided by an AF of 10. For algal
species, the hazard values were divided by an AF of 10. For amphibians, EPA does not have a
standardized AF. The greater level of uncertainty (i.e., unknown inter-species variability)
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7059
7060
7061
7062
7063
7064
7065
7066
7067
7068
7069
7070
7071
7072
7073
7074
7075
7076
7077
7078
7079
7080
7081
7082
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associated with the sub-chronic endpoints in the amphibian studies necessitates the use of a more
protective AF of 10. As such, for the acute and chronic COCs derived from amphibian data, an
AF of 10 is used (U.S. EPA. 2013b. 2012b).
G.5 Hazard Estimation for Acute Exposure Durations
The lowest acute toxicity value for aquatic organisms (i.e., most sensitive species) for carbon
tetrachloride is from a 9-day amphibian toxicity study where the LCso is 0.9 mg/L (Black et al..
1982; Birge et al.. 1980). The lowest value was then divided by the AF of 10.
Acute COC
The acute COC = (0.9 mg/L) / (AF of 10) = 0.09 mg/L x 1,000 = 90 |ig/L or 90 ppb
The acute COC of 90 |ig/L, derived from experimental amphibian endpoint, is used as the
conservative (screening-level) hazard level in this risk evaluation for carbon tetrachloride.
G.6 Hazard Estimation for Chronic Exposure Durations
The lowest chronic toxicity value for aquatic organisms (i.e., most sensitive species) for carbon
tetrachloride is from a 9-day amphibian toxicity study where the LCio is 0.03 mg/L (Black et al..
1982). The chronic COC was derived from the lowest chronic toxicity value from the amphibian
LC io (for developmental effects and mortality in frogs). Throughout the systematic review
process, these two studies were both assigned a quality level of high (Black et al.. 1982; Birge et
al.. 1980). The LCio was then divided by an assessment factor of 10, and then multiplied by
1,000 to convert from mg/L to |ig/L, or ppb.
Chronic COC
The chronic COC = (0.03 mg/L) / (AF of 10) = 0.003 mg/L x 1,000 = 3 |ig/L or ppb
The amphibian chronic COC for carbon tetrachloride is 3 |ig/L is used as the lower bound hazard
level in this risk evaluation for carbon tetrachloride.
G.7 Hazard Estimation for Algal Toxicity
Given that the hazard endpoints for aquatic plants (72-hr ECio/NOEC)) exposed to carbon
tetrachloride ranges from ranges from 0.0717 - 2.2 mg/L (Brack and Rottler. 1994). the chronic
COC is derived by dividing the 72-hr algal ECio of 0.0717 mg/L (the lowest chronic value in the
dataset) by an assessment factor of 10:
Algal Toxicity COC
The 72-hr algal toxicity value = (0.0717 mg/L) / AF of 10 = 0.007 mg/L or 7 |ig/L.
The chronic COC of 7 |ig/L, derived from experimental algal endpoint, is used as the lower
bound hazard level for algal toxicity in this risk evaluation for carbon tetrachloride.
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7105
7106
7107
7108
7109
7110
7111
7112
7113
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7115
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G.8 Summary of Environmental Hazard Assessment
The derived amphibian acute COC (90 |ig/L) and chronic COC (3 |ig/L) are based on
environmental toxicity endpoint values from (Black et al.. 1982; Birge et al.. 1980) and algal
COC (7 |ig/L) is based on environmental toxicity endpoint values from (Brack and Rottler.
1994). The data represent the lowest bound of all carbon tetrachloride data available in the public
domain and provide the most conservative hazard values. The full study reports for all on-topic
citations in this risk evaluation were systematically reviewed and described in the Risk
Evaluation for Carbon Tetrachloride, Systematic Review Supplemental File: Data Quality
Evaluation of Environmental Hazard Studies (U.S. EPA. 2019e).
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7130 Appendix H HUMAN HEALTH HAZARDS
7131 This appendix provides a high-level summary of the human health animal and in vitro (genotoxicity) studies that were evaluated in the
7132 systematic review process. The appendix summarizes and presents study findings in Tables.
7133
7134 TableApx H-l. Summary of Reviewed Human Health Animal Studies for Carbon Tetrachloride
7135
Target
Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)2
Exposure
Route
Doses/
Concentrations3
Duration4
Effect Dose or
Concentration
(Sex)
Effect6
Reference
Data
Quality
Evaluation8
Mortality
Chronic
Mouse,
Crj:BDFl
(SPF).M/F
(n=100/
group)
Inhalation.
vapor,
whole body
0, 32, 160, 801
mg/m3 (0, 5, 25,
125 ppm)
6 hours/
day,
5 days/
week for
104 weeks
NOAEL=32
mg/m3 (F),
LOAEL=160
mg/m3 (F)
Reduced
survival late in
study (because
of liver
tumors)
(Nasano
et al..
2007a)
High
Mortality
Short-term
(1-30 days)
Rat, Wistar,
M
(n=10/group)
Inhalation
0, 63,80 mg/kg-
bw/day
6
hours/day,
5
days/week
for 4 weeks
NOAEL= 80
mg/m3
No effect on
general
condition of
rats; no
significant
effects on
body weight
that were
considered
treatment-
related.
(Civo
Institute
Tno,
1985)
High
Mortality
Other
Guinea pig
(n=20)
Dermal
0.5 or 2.0 mL
(260 mg/ cm3)
Once;
contact for
5 days
LOAEL= 260
mg/ cm3 1
5 of 20
animals died
(Wahlbere
and
Bomau
1979)
Medium
Mortality
Other
Guinea pig.
Hartley, M
(n=~4/ group)
Dermal
(intact and
abraded
skin)
0.5 mL undiluted
(15,000 mg/kg)
Once
LD50= 15,000
mg/kg-bw/day
Reduced
survival
(Roudabus
h et al..
1965)
Unacceptable
Mortality
Other
Rabbit,
white, M/ F
(n=~4/ group)
Dermal
(abraded
skin)
0.5 mL undiluted
(15,000 mg/kg)
Once
LD50= 15,000
mg/ kg-day111
Reduced
survival
(Roudabus
h et al..
1965)
Unacceptable
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Target
Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)2
Exposure
Route
Doses/
Concentrations3
Duration4
Effect Dose or
Concentration
(Sex)
Effect6
Reference
Data
Quality
Evaluation8
Hepatic
Chronic
Mouse,
Inhalation.
6 hours/
NOAEL= 32
Incidence of
(Naeano
High
Cij:BDFl
(SPF).M/F
(n=100/
vapor,
whole body
0, 32, 160, 801
mg/m3 (0, 5, 25,
125 ppm)
day,
5 days/
week for
mg/m3,
LOAEL= 160
mg/m3
hepatocellular
adenoma or
carcinoma
et al..
2007a)
group)
104 weeks
Hepatic
Chronic
Rat,
Inhalation.
0, 32, 160, 801
6 hours/
NOAEL= 160
Incidence of
(Naeano
High
F344/DuCij
(SPF),M/F
vapor,
whole body
mg/m3 (0, 5, 25,
125 ppm)
day,
5 days/
mg/m3,
LOAEL= 125
hepatocellular
adenoma or
et al..
2007a)
(n=100/group
)
week for
104 weeks
ppm
carcinoma
Hepatic
Chronic
Rat,
Inhalation.
0, 31, 157 or 786
6 hours/
NOAEL= 31
Increased AST,
(Naeano
High
F344/DuCij
(SPF),M/F
(n=100/group
)
vapor,
whole body
mg/m3 (0, 5, 25
or 125 ppm)
day,
5 days/
week for
104 weeks
mg/m3,
LOAEL= 157
mg/m3
ALT, LDH,
GPT, BUN,
CPK; lesions in
the liver (fatty
changes, fibrosis)
et al..
2007a)
Hepatic
Chronic
Mouse,
Inhalation.
0, 31, 157 or 786
6 hours/
LOAEL=31
Reduced
(Naeano
High
Cij:BDFl
(SPF), M/F
(n=
vapor,
whole body
mg/m3 (0, 5, 25
or 125 ppm)
day,
5 days/
week for
mg/m3 (M)
survival late in
study (because
of liver
et al..
2007a)
100/group)
104 weeks
tumors);
increased
ALT, AST,
LDH, ALP,
protein, total
bilirubin, and
BUN;
decreased
urinary pH;
increased liver
weight; lesions
in the liver
(degeneration)
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Target
Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)2
Exposure
Route
Doses/
Concentrations3
Duration4
Effect Dose or
Concentration
(Sex)
Effect6
Reference
Data
Quality
Evaluation8
Hepatic
Chronic
Mouse,
BDF1.M/F
(n=20 / group)
Inhalation.
vapor,
whole body
0, 63, 189, 566,
1699, or 5096
mg/m3 (0, 10,
30, 90, 270, or
810 ppm)
6 hours/
day,
5 days/
week for
13 weeks
LOAEL= 63
mg/m3
Slight
cytological
alterations in
the liver;
Cytoplasmic
globules
(Naeano
et al..
2007b)
High
Hepatic
Chronic
Rat, F344, M/
F(n=20/
group)
Inhalation.
vapor,
whole body
0, 63, 189, 566,
1699, 5096
mg/m3 (0, 10,
30, 90, 270, 810
ppm)
6 hours/
day,
5 days/
week for
13 weeks
NOAEL= 63
mg/m3 (F),
LOAEL=189
mg/m3 (F)
Increased liver
weight; Large
droplet fatty
change in liver
(Naeano
et al..
2007b)
High
Hepatic
Chronic
Rat, F344, M/
F(n=20/
group)
Inhalation.
vapor,
whole body
0, 63, 189, 566,
1699, or 5096
mg/m3 (0, 10,
30, 90, 270, or
810 ppm)
6 hours/
day,
5 days/
week for
13 weeks
LOAEL= 63
mg/m3
Increased liver
weight; fatty
change in liver
(Naeano
et al..
2007b)
High
Hepatic
Chronic
Rat, albino,
M/F(n=30-
50/ group)
Inhalation.
vapor,
whole body
0, 31,63, 157,
315,629, 1258
or 2516 mg/m3
(0, 5, 10, 25, 50,
100, 200 or 400
ppm)
7 hours/
day,
5 days/
week for 6
months
NOAEL= 31
mg/m3,
LOAEL= 63
mg/m3
Increased liver
weight; fatty
degeneration
in liver
(Adams et
al.. 1952)
Low
Hepatic
Chronic
Guinea pig,
M/F(n=10-
18 group)
Inhalation.
vapor,
whole body
0, 31,63, 157,
315,629, 1258
or 2516 mg/m3
(0, 5, 10, 25, 50,
100, 200 or 400
ppm)
7 hours/
day,
5 days/
week for 6
months
NOAEL= 31
mg/m3,
LOAEL= 63
mg/m3
Increased liver
weight; fatty
degeneration
in liver
(Adams et
al.. 1952)
Low
Hepatic
Chronic
Rabbit,
albino, M/ F
(n=2-4/
group)
Inhalation.
vapor,
whole body
0, 31,63, 157,
315,630, 1260
or 2520 mg/m3
(0, 5, 10, 25, 50,
100, 200 or 400
ppm)
7 hours/
day,
5 days/
week for 6
months
NOAEL= 63
mg/m3,
LOAEL= 157
mg/m3
Increased liver
weight; fatty
degeneration
and slight
cirrhosis in
liver
(Adams et
al.. 1952)
Low
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Target
Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)2
Exposure
Route
Doses/
Concentrations3
Duration4
Effect Dose or
Concentration
(Sex)
Effect6
Reference
Data
Quality
Evaluation8
Hepatic
Chronic
Monkey,
rhesus, M/ F
(n=2-4 /
group)
Inhalation.
vapor,
whole body
0, 31,63, 157,
315 or 630 mg/
m3 (0, 5, 20, 25,
50 or 100 ppm)
7 hours/
day,
5 days/
week for 6
months
NOAEL= 315
mg/m3,
LOAEL= 629
mg/m3
Slight fatty
degeneration
and increased
lipid content in
liver
(Adams et
al.. 1952)
Low
Hepatic
Chronic
Mouse, CD-
LM/F
(n=40/ group)
Oral,
gavage
(corn oil
vehicle)
0, 12, 120, 540
or 1200 mg/kg-
bw/day
7 days/
week for
13 weeks
LOAEL= 12
mg/kg-bw/day
Increased liver
weight, ALT,
AST, ALP,
LDH, 5'-
nucleotidase;
fatty change,
hepato-
cytomegaly,
necrosis, and
hepatitis
(Haves et
al.. 1986)
Medium
Hepatic
Subchronic
Mouse, CD-
LM/F
(n=40/ group)
Oral,
gavage
(corn oil
vehicle)
0, 625, 1250,
2500 mg/kg-
bw/day
7 days/
week for
90 days
LOAEL= 625
mg/kg-bw/day
Increased liver
weight, ALT,
AST, ALP,
LDH, 5'-
nucleotidase;
fatty change,
hepato-
cytomegaly,
necrosis, and
hepatitis
(Haves et
al.. 1986)
Medium
Hepatic
Subchronic
Rat, F344/
Crl, M (n=10/
group)
Inhalation,
whole body
0,31, 126, or
629 mg/m3 (0, 5,
20 or 100 ppm)
6 hours/
day,
5 days/
week for
12 weeks
NOAEL= 126
mg/m3 (M),
LOAEL= 629
mg/m3 (M)
Increased
ALT, SDH;
necrosis in
liver
(Benson
and
Sorineer.
1999)
High
Hepatic
Subchronic
Mouse,
B6C3F1, M
(n=10/ group)
Inhalation,
whole body
0,31, 126, or
629 mg/m3 (0, 5,
20 or 100 ppm)
6 hours/
day,
5 days/
week for
12 weeks
NOAEL= 31
mg/m3 (M),
LOAEL= 126
mg/m3 (M)
Increased
ALT, SDH;
necrosis and
cell
proliferation in
liver
(Benson
and
Sorineer.
1999)
High
Page 280 of 301
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Target
Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)2
Exposure
Route
Doses/
Concentrations3
Duration4
Effect Dose or
Concentration
(Sex)
Effect6
Reference
Data
Quality
Evaluation8
Hepatic
Subchronic
Hamster,
Inhalation.
0,31, 127 or 636
6 hours/
NOAEL= 126
Increased
(Benson
High
Syrian, M
(n=10/ group)
whole body
mg/m3 (0, 5, 20
or 100 ppm)
day,
5 days/
week for
12 weeks
mg/m3 (M),
LOAEL= 629
mg/m3 (M)
ALT, SDH;
necrosis and
cell
proliferation in
liver
and
Sorineer.
1999)
Hepatic
Subchronic
Rat, Sprague
Dawley, M
(n=15-16/
group)
Oral,
gavage
(corn oil
vehicle)
0, 1, 10 or 33
mg/kg-bw/day
5 days/
week for
12 weeks
NOAEL= 1
mg/kg-bw/day
(M), LOAEL=
10 mg/kg-
bw/day (M)
Two- to three-
fold increase
in SDH; mild
centrilobular
vacuolization
in liver
(Bruckner
et al..
1986)
High
Hepatic
Subchronic
Rat, F344, M
Oral,
0, 20 or 40
5 days/
LOAEL= 20
Increased liver
(Allis et
Medium
(n=48/ group;
6/ group and
sacrifice
gavage
(corn oil
vehicle)
mg/kg-bw/day
week for
12 weeks
mg/kg-bw/day
(M)
weight, ALT,
AST, LDH;
reduced liver
al.. 1990)
time;
CYP450;
sacrificed at
cirrhosis.
intervals
necrosis, and
from 1 to 15
days post
exposure)
degeneration
in liver
Hepatic
Subchronic
Mouse, CD-
Oral,
0, 1.2, 12 or 120
5 days/
NOAF.L= 1.2
Increased
(Condie et
High
LM/F
(n=24/ group)
gavage
(corn oil
vehicle)
mg/kg-bw/day
week for
12 weeks
mg/kg-bw/day,
LOAEL= 12
mg/kg-bw/day
ALT; mild to
moderate
hepatic lesions
(hepato-
cytomegaly,
necrosis,
inflammation)
al.. 1986)
Hepatic
Subchronic
Rat, Sprague-
Oral,
0, 50, or 2000
72 hours
LOAEL = 50
increased
(Sun et
High
Dawley, M
(n=5/group)
gavage
(corn oil
vehicle)
mg/kg-bw/day
mg/kg-bw/day
ALT, AST,
and ALP
al.. 2014)
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Target
Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)2
Exposure
Route
Doses/
Concentrations3
Duration4
Effect Dose or
Concentration
(Sex)
Effect6
Reference
Data
Quality
Evaluation8
Hepatic
Acute
Guinea pig,
albino (n=20)
Dermal
513 mg/cin2
15 minutes
to 16 hours
LOAEL= 513
mg/ cm2
(ATSDR)
Hydropic
changes, slight
necrosis
(Kronevi
et al..
1979)
Unacceptable
Hepatic
Acute
Rat, Sprague-
Dawley, M
(n=5/group)
Oral,
gavage
(corn oil
vehicle)
0, 50, or 2000
mg/kg-bw/day
6 hours, 24
hours
NOAEL= 50
mg/kg-bw/day
Weight loss;
increased
ALP;
decreased
cholesterol,
triglycerides,
and glucose;
liver
histopathology
(centrilobular
necrosis and
degeneration;
cytoplasmic
vacuolization);
increased
BUN
(Sun et
al.. 2014)
High
Renal
Chronic
Rat, F344, M/
F(n=20/
group)
Inhalation
vapor,
whole body
0, 63, 189, 566,
1699, 5096
mg/m3 (0, 10,
30, 90, 270, 810
ppm)
6 hours/
day,
5 days/
week for
13 weeks
NOAEL=1699
mg/m3,
LOAEL=5096
mg/m3
Histopathologi
cal lesions,
kidney
glomeruloscler
osis
(Naeano
et al..
2007b)
High
Renal
Chronic
Rat,
F344/DuCij
(SPF),M/F
(n=100/
group)
Inhalation
vapor,
whole body
0,31, 157 or 786
mg/m3 (0, 5, 25
or 125 ppm)
6 hours/
day,
5 days/
week for
104 weeks
NOAEL= 31
mg/m3
LOAEL= 157
mg/m3
Lesions in the
kidney
(progressive
glomerulo-
nephrosis)
(Naeano
et al..
2007a)
High
Page 282 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Target
Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)2
Exposure
Route
Doses/
Concentrations3
Duration4
Effect Dose or
Concentration
(Sex)
Effect6
Reference
Data
Quality
Evaluation8
Renal
Chronic
Mouse,
Crj:BDFl
(SPF).M/F
(n=100/
group)
Inhalation
vapor,
whole body
0,31, 157 or 786
mg/m3 (0, 5, 25
or 125 ppm)
6 hours/
day,
5 days/
week for
104 weeks
NOAEL= 31
mg/m3,
LOAEL= 157
mg/m3
Increased
ALT, AST,
LDH, ALP,
protein, total
bilirubin and
BUN; lesions
in the kidney
(protein casts);
benign
pheochro-
mocytoma
(males)
(Nasano
et al..
2007a)
High
Renal
Acute (<24
lir)
Rat, Sprague-
Dawley, M
(n=5/group)
Oral,
gavage
(corn oil
vehicle)
Oral, gavage
(corn oil vehicle)
Not
Reported
NOAEL= 50
mg/kg-bw/day
Weight loss;
increased
ALP;
decreased
cholesterol,
triglycerides,
and glucose;
liver
histopathology
(centrilobular
necrosis and
degeneration;
cytoplasmic
vacuolization);
increased
BUN
(Sun et
al.. 2014)
High
Skin
Other
Guinea pig,
albino (n=20)
Dermal
513 mg/cm2
15 minutes
to 16 hours
LOAEL= 513
mg/ cm2
Karyopynosis,
spongiosis,
perinuclear
edema
(Kronevi
et al..
1979)
Unacceptable
Skin
Other
Guinea pig.
Hartley, M
(n=6/ group)
Dermal
(intact and
abraded
skin)
120 mg/kg-
bw/day
Once, 24
hours
LOAEL= 120
mg/kg-bw/day
Primary
irritation
(Roudabus
h et al..
1965)
Unacceptable
Page 283 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Target
Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)2
Exposure
Route
Doses/
Concentrations3
Duration4
Effect Dose or
Concentration
(Sex)
Effect6
Reference
Data
Quality
Evaluation8
Skin
Other
Rabbit,
white, M/ F
(n=6 / group)
Dermal
(intact and
abraded
skin)
120 mg/kg-
bw/day
Once, 24
hours
LOAEL= 120
mg/kg-bw/day
Primary
irritation
(Roudabus
h et al..
1965)
Unacceptable
Develop-
mental
Effects
Developme
ntal
Rat, F344, F
(n=12-14/
group)
Oral,
gavage
(corn oil
vehicle)
0, 25,50 or 75
mg/kg-bw/day
GDs 6-15
NOAEL= 25
mg/kg-bw/day
(F).
LOAEL= 50
mg/kg-bw/day
(F)
Piloerection;
markedly
increased full-
litter
resorption
(Narotskv
et al..
1997)
High
Develop-
mental
Effects
Developme
ntal
Rat, F344, F
(n=12-14/
group)
Oral,
gavage
(10%
Emulphor
vehicle)
0, 25,50 or 75
mg/kg-bw/day
GDs 6-15
NOAEL= 25
mg/kg-bw/day
(F).
LOAEL= 50
mg/kg-bw/day
(F)
Piloerection;
markedly
increased full-
litter
resorption
(Narotskv
et al..
1997)
High
Body
weight
Chronic
Rat,
F344/DuCij
(SPF),M/F
(n=100/group
)
Inhalation
vapor,
whole body
0, 32, 160, 801
mg/m3 (0, 5, 25,
125 ppm)
6 hours/
day,
5 days/
week for
104 weeks
NOAEL= 32
mg/m3,
LOAEL=160
mg/m3
Reduced body
weight gain
(Naeano
et al..
2007a)
High
Body
weight
Chronic
Mouse,
Cij:BDFl
(SPF), M/F
(n=
100/group)
Inhalation
vapor,
whole body
0, 32, 160, 801
mg/m3 (0, 5, 25,
125 ppm)
6 hours/
day,
5 days/
week for
104 weeks
NOAEL= 32
mg/m3,
LOAEL=160
mg/m3
Reduced body
weight gain
(Naeano
et al..
2007a)
High
Body
Weight
Subchronic
Rat, Sprague-
Dawley, M
(n=5/group)
Oral,
gavage
(corn oil
vehicle)
0, 50, or 2000
mg/kg-bw/day
72 hours
NOAEL= 50
mg/kg-bw/day
Weight loss
(Sunet al..
2014)
High
Page 284 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Target
Organ/
System1
Study
Type
Species/
Strain/Sex
(Number/
group)2
Exposure
Route
Doses/
Concentrations3
Duration4
Effect Dose or
Concentration
(Sex)
Effect6
Reference
Data
Quality
Evaluation8
Body
Subchronic
Rat, Wistar,
Inhalation
0, 63,80 mg/kg-
6
NOAF.L = 80
No effect on
(Civo
High
Weight
M
(n=10/group)
bw/day
hours/day,
5
days/week
for 4 weeks
mg/m3
general
condition of
rats; no
significant
effects on
body weight
that were
considered
treatment-
related.
Institute
Tno,
1985)
Body
Acute (<24
Rat, Sprague-
Oral,
0, 50, or 2000
6 hours, 24
NOAEL= 50
Weight loss;
(Sunet al..
High
Weight
hr)
Dawley, M
(n=5/group)
gavage
(corn oil
vehicle)
mg/kg-bw/day
hours
mg/kg-bw/day
increased
ALP;
decreased
cholesterol,
triglycerides,
and glucose;
liver
histopathology
(centrilobular
necrosis and
degeneration;
cytoplasmic
vacuolization);
increased
BUN
2014)
Immune
Chronic
Mouse,
Inhalation
0, 32, 160, 801
6 hours/
NOAEL= 160
Lesions in the
(Nasano
High
Crj:BDFl
vapor.
mg/m3 (0, 5, 25,
day.
mg/m3.
spleen (extra
et al..
(SPF), M/F
whole body
125 ppm)
5 days/
LOAEL= 801
medullary
2007a)
(n=
week for
mg/m3
hemato-
100/group)
104 weeks
poiesis)
7136
7137
7138
Page 285 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
7139 Table Apx H-2. Summary of Reviewed Genotoxicity Studies for Carbon Tetrachloride
Target
Organ/
System
Study
Type
Species/Strain/C
ell Type
(Number/group
if relevant)
Exposure
Route
Doses /
Concentrations
Duration
Effect
Concentration/
Result
Effect Measured
Reference
Data Quality
Evaluation
Genotoxi
city
Acute
Mouse
lymphoma
L5178/TK+/-
cells
In vitro
0,4.38, 6.55,8.76
mmol/L (+S9)
3 hours
Positive at 6.55
and 8.76 mmol/La
(at relative
toxicities of 6%
and 16%,
respectively)
Alkaline
unwinding of
DNA (ratio of
ssDNA and
dsDNA); cell
viability
(Garbers et
al.. 1988)
Unnacep
table
Genotoxi
city
Acute
Salmonella
tvphimurium
strains TA 98,
TA 100, TA
1535, TA 1537
<3 reolicates
/aroiiD
In vitro
0, 0.005, 0.01, 0.05,
0.1,0.2,0.5, 1,2,
5% (± S9)b
24 hours
Weakly positive0
in TA 98 (-S9) at
> 1%; negative in
TA 98 (+S9);
negative in TA
100, TA 1535,
and TA 1537 (±
S9)
Reverse mutation
(gas exposure
method)
(Araki et al..
2004)
High
Genotoxi
city
Acute
Escherichia coli
strains
WP2/wvr,4/pKM
101,
WP2/pKM101
<3 replicates
/group
In vitro
0,0.005,0.01,0.05,
0.1,0.2,0.5, 1,2,
5% (±S9)b
24 hours
Weakly positive0
at 2% in
WP2/wvr,4/pKMl
01 (±S9); positive
at > 0.1% (-S9)
and > 0.2% (+S9)
in WP2/pKM 101d
Reverse mutation
(gas exposure
method)
(Araki et al..
2004)
High
aThe test substance was positive at toxic concentrations only. However, the criteria for a positive response in this assay included increases in the relative fraction of ssDNA that is
greater than the increase in relative toxicity (at toxicities of 5% to 50%), if this occurs at 2 or more concentrations.
bTests were also conducted with glutathione-supplemented S9 mix.
CA result was considered positive if a two-fold increase in the number of revertants was observed.
dData ioxE.coli strain WP2/pKM101 were based on < 3 measurements (statistical analyses were not performed).
7140
7141
7142
7143
7144
Page 286 of 301
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7145
7146
7147
7148
7149
7150
7151
7152
7153
7154
7155
7156
7157
7158
7159
7160
7161
7162
7163
7164
7165
7166
7167
7168
7169
7170
7171
7172
7173
7174
7175
7176
7177
7178
7179
7180
7181
7182
7183
7184
7185
7186
7187
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Appendix I GENOTOXICITY
The in vitro and in vivo genotoxicity databases for carbon tetrachloride, including their
limitations are described below.
1.1 In vitro Genotoxicity and Mutation
The in vitro genotoxicity database for carbon tetrachloride, while large in number of studies, it is
not diverse in the type of assays contained to examine carbon tetrachloride's genotoxicity
potential. The studies identified below, while not definitive provide indications of mutational or
chromosomal changes that may be relevant to the mode of action of carbon tetrachloride
carcinogenesis.
Bacterial mutagenicity with reference to strains more capable to detect oxidative damage.
Many experiments have tested carbon tetrachloride for mutagenesis in standard salmonella
revers mutation assays. Eastmond (2008) observes: "While carbon tetrachloride has consistently
been negative in studies using Salmonella and certain strains of E. coli, at high exposure
concentrations, it has been reported to produce differential DNA repair and mutations in the
WP2 strain of E. coli, a strain that is particularly sensitive to oxidative mutagens (Araki et al..
2004; De Flora et al.. 1984) EPA IRIS (U.S. EPA. 2010) further notes that because the WP2
strains of E. coli have an AT base pair at the critical mutation site within the trpE gene, they have
been recommended for screening oxidizing mutagens (Martinez et al.. 2000; Gatehouse et al..
1994). "In contrast, using E. coli strains that are more sensitive to oxidative mutagens, increases
in DNA repair were reported by De Flora (1984) and increases in reverse mutation were reported
by Araki (2004) and Norpoth (1980). In the De Flora (1984) study, carbon tetrachloride was
more toxic to the E. coli strain CM871 (uvrA- recA- lexA-) than it was to the isogenic repair-
proficient WP2 strain or WP67 (uvrA- polA-). Although a similar pattern was seen in the
presence of metabolic activation, carbon tetrachloride was more active in the absence of
activation.
Bacterial test strains
Although carbon tetrachloride has been evaluated many times in the standard Salmonella test
strains, it has not been tested in either TA102 or TA104 and only a few times in the E. coli WP2
strains, the strains that would be the most sensitive to the oxidative DNA damage likely to be
generated during carbon tetrachloride toxicity.
Based on OECD relevant guidance as to selection of bacterial strains, standard Salmonella test
strains "may not detect certain oxidizing mutagens, cross4inking agents, and hydrazines. Such
substances may be detected by E.coli WP2 strains or S. typhimurium TA102..OECD's
recommended combination of strains includes E. coli WP2 strains or S. typhimurium TA102.
(OECD Guideline for Testing of Chemicals. Bacterial Reverse Mutation Test. Report 471,
adopted 21 July 1997.) Additionally, a statistically significant but well less than a twofold
increase for E. coli WP2uvrA was reported by Norpoth (1980) at high levels (about 25,000 ppm)
in another gas-phase exposure study."
Page 287 of 301
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7188
7189
7190
7191
7192
7193
7194
7195
7196
7197
7198
7199
7200
7201
7202
7203
7204
7205
7206
7207
7208
7209
7210
7211
7212
7213
7214
7215
7216
7217
7218
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
In vitro genotoxicity studies for carbon tetrachloride in mammalian cells
As discussed below, in vitro studies of carbon tetrachloride genotoxic effects in metabolically
competent liver cells will be of most importance. Studies in lung and kidney cells may provide
supplemental information, while studies in other cell types may not allow for metabolism
believed to be necessary for carbon tetrachloride toxicity/carcinogenicity.
Metabolism induction
According to EPA IRIS Assessment (U.S. EPA. 2010). "when standard inducing procedures
(Arochlor 1254 or the combination of phenobarbitone and beta-naphthoflavone) have been used,
the levels of CYP2E1 in the rat liver are markedly suppressed (Burke et al.. 1994). This would
lead to a decrease in CYP2E1 in the S9 used for the test and could potentially contribute to the
observed negative results." However, mammalian cell test strains using lymphocytes, ovary
cells, lung cells, or kidney cells may not closely resemble liver cells in the ability to metabolize
carbon tetrachloride. The kidney and lung do have P450 metabolic capability that has been
evaluated for carbon tetrachloride and this has been used in the development of PBPK models.
Using in vitro measurements with p-nitrophenol as a reference compound, (Yoon et al.. 2007)
has estimated CYP2E1 activity (Vmax - nmole/min/g) in the lung and kidney as approximately
6% and 5% of that in the liver. Accordingly, cells from these other tissues may not be similar to
liver cells in the metabolism of carbon tetrachloride.
Mammalian cell mutagenesis tests
There are no mutagenesis tests identified in mammalian liver, kidney or lung cells in vitro.
OECD now recommends in vitro mammalian cell gene mutation tests using the hprt or xprt
genes (OECD TG 476). The OECD cited tests include lung cell lines (V79 and CHL) that could
be examined for CYP2E1 competence.
Chromosomal changes
In the absence of mutation studies, the current review focuses on chromosomal aberration and
micronucleus studies in mammalian cells in vitro - using cells from (1) liver, (2) kidney, or lung
which also show some CYP2E1 activity, or (3) cells with CYP2E1 capability is added. These are
extracted from EPA IRIS Assessment (U.S. EPA. 2010) below.
Page 288 of 301
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7219
7220
7221
7222
7223
7224
7225
7226
7227
7228
7229
7230
7231
7232
7233
7234
7235
7236
7237
7238
7239
7240
7241
7242
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Table_Apx 1-1. Bacterial mutagenesis data in systems believed relevant to detection of oxidative damage to DNA - excerpted from
EPA IRIS Assessment
Test system
Endpoint
Test conditions
Results
with
metabolic
activation
Results
without
metabolic
activation
Reference
Escherichia coli WP2«/vrA/pKM101
Reverse mutation
Gas phase exposure in a gas
sampling bag for 24 lirs
±
±
10,000 ppm
(Araki et al.. 2004)
EE. coli WP2/pKM101
Reverse mutation
Gas phase exposure in a gas
sampling bag for 24 lirs
+
+e
5,000 ppm
(Araki et al.. 2004)
E. coli WPluvrA
Reverse mutation
Gas phase exposure in a
desiccator
ND
±
25,000 ppm
(Norooth et al..
1980)
+: positive results; -: negative results; ± : equivocal or weakly positive; T: Toxicity; ND: No Data
e Results similar with or without GSH added to the S9 mix. Positive response is based on the magnitude of response as statistical analyses were not performed.
Page 289 of 301
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PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
7243 Table_Apx 1-2. Chromosomal changes in in vitro studies mammalian cells from liver, kidney or lung; or cells with CYP2E1 genetic
7244 capability added - excerpted from EPA IRIS Assessment
Test system
Endpoint
Test conditions
Results
with
metabolic
activation
Results
without
metabolic
activation
Reference
RLi cultured cell line derived from rat
liver
Chromosomal
aberrations
Assay conducted in sealed
flasks
-
ND
0.02 |ig/mL in
DMSOd
(Dean and Hodson-
Walker. 1979)
V79 Chinese hamster lung cell line
Aneuploidy
3-Hr incubation
+
ND
246 iig/mL
(Onfelt. 1987)
V79 Chinese hamster lung cell line
c-Mitosis (spindle
disturbance)
30-Min incubation
±(T)
ND
492 ng/mL
(Onfelt. 1987)
li2El cell line (cDNA for CYP2E1)
Micronucleus
formation
Immunofluorescent labeling
of kinetochore proteins
+e (T)
ND
308 |ig/mL
(Dohertv et al..
1996)
Studv in CYP2E1 competent cells. Ouotins EPA (2010): Dohertv et al. (1996) reported that carbon tetrachloride induced micronuclei in two human
lymphoblastoid cell lines—one expressing CYP2E1 (li2El) and the other expressing CYP1A2, 2A6, 3A4, and 2E1 and microsomal epoxide hydrolase (MCL-
5)—but not the CYP1A1-expressing AHH-1 cell line. Treatment of the cells with 10 mM carbon tetrachloride resulted in five- and nine-fold increases in
micronucleated cells in the li2El and the MCL-5 cell lines, respectively. The increases occurred mostly in kinetochore-positive micronuclei, indicating an
origin from chromosome loss. Smaller increases (-two- to fourfold) in micronuclei originating from chromosomal breakage (kinetochore-negative) were also
seen." At the 10 mM high concentration, there was indication of substantial toxicity, but this study indicates a dose response trend town to 1 mM concentration,
where toxicity was less evident.
MCL-5 cell line (cDNA for CYPs
1A2, 2A6, 3A4, and 2E1, and epoxide
hydrolase)
Micronucleus
formation
Immunofluorescent labeling
of kinetochore proteins
+e(T)
ND
308 |ig/mL
(Dohertv et al..
1996)
See comment above
7245 positive results; -: negative results; ± : equivocal or weakly positive; T: Toxicity; ND: No Data
7246 e Results similar with or without GSH added to the S9 mix. Positive response is based on the magnitude of response as statistical analyses were not performed.
7247 d Results for the individual donors are presented.
Page 290 of 301
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7248
7249
7250
7251
7252
7253
7254
7255
7256
7257
7258
7259
7260
7261
7262
7263
7264
7265
7266
7267
7268
7269
7270
7271
7272
7273
7274
7275
7276
7277
7278
7279
7280
7281
7282
7283
7284
7285
7286
7287
7288
7289
7290
7291
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1.2 In vivo Genotoxicity
Assessment of potential genotoxic effects of carbon tetrachloride should focus first on effects in the in
vivo liver - CYP2E1 activity largely resides in the liver. Data from other tissues (lung and kidney) may
supplement the liver data to a degree as these tissues have lesser but maybe relevant CYP2E1
capability.24 It is not apparent that data for other tissues will reflect the CYP2E1 metabolism of CT.
The carbon tetrachloride database is sparse for in vivo tests studies of mutation and chromosomal
changes in liver tissue (and such tests appear unavailable for the kidney and lung). Available studies as
cited in EPA IRIS Assessment (U.S. EPA. 2010).
Mutation studies
Three studies using the lacL or lacZ genes in the liver in transgenic mice are available and reported
negative or inconclusive results. These studies use single or in one case five exposures to carbon
tetrachloride, a limitation for a study methodology in which longer term exposures are generally
recommended. Additionally, two studies reported an increase in mutation frequency after single
exposures, increases that while limited in magnitude, indicate a need for more definitive studies.
Chromosomal studies
Two studies reported positive results in micronucleus experiments, while two others were negative.
Two studies of chromosomal aberration or damage after single high dose carbon tetrachloride exposures
were negative. Use of maximal doses may not increase (or even reduce) sensitivity due to reduction of
CYP2E1 activity with high carbon tetrachloride doses.
DNA breakage
A number of in vivo comet and other DNA breakage assays have been performed with rodent liver cell
lines and appear mostly, but not uniformly, negative. These studies were primarily conducted using high
single dose injection or gavage dosing. There are general reservations about interpreting DNA breakage
data in toxicity. OECD Test Guideline 489 notes that "Fragmentation of the DNA can be caused not
only by chemically-induced genotoxicity, but also during the process of cell death, i.e., apoptosis and
necrosis. It is difficult to distinguish between genotoxicity and apoptosis/necrosis by the shape of the
nucleus and comet tail after electrophoresis.
UDS
A number of rodent experiments assessed unscheduled DNA synthesis (UDS) in the liver generally after
single oral or injection exposures. Test results were generally, but not uniformly, negative. OECD test
guideline 486 notes that the UDS test responds positively only to substances that induce DNA damage
that is repaired by nucleotide excision repair. It is not clear that this is a sensitive test for potential
carbon tetrachloride induced DNA damage, including oxidative damage. The OECD guideline also
comments that "The UDS test should not be considered as a surrogate test for a gene mutation test."
Summary of in vivo genotoxicity evidence
Optimal in vivo studies of carbon tetrachloride mutagenesis or chromosomal alterations are not
available. While the available in vivo database dose not on balance demonstrate carbon tetrachloride
genotoxicity, neither does is represent a fully sensitive body of studies to test for such effects.
24 Yoon (2007) lias estimated CYP2E1 activity (Vmax - nmole/min/g) in the lung and kidney as approximately 6% and 5%
of that in the liver.
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7292 Table_Apx 1-3. In vivo mutation and chromosomal change studies for carbon tetrachloride in liver tissue - excerpted from EPA IRIS
7293 Assessment
Test system
Endpoint
Test conditions
DNA adducts
IRIS (2010) descriptor3
Doseb
Reference
Mouse (B6C3Fi, lacl
transgenic; Big Blue™, male)
Mutations in lacl
transgene in liver
The target lacl gene is
recovered from genomic DNA
after five daily doses and the
animals sacrificed 7 d after the
first dose
IRIS: - (T)
35 mg/kg-day
(5 times)
(Mirsalis et al..
1994)
Comment: Original article not reviewed. This non-positive test used 5 administrations of a relevant dose of CT (a much lower dose than used in many shorter
term in vivo experiments. The sensitivity of this experiment could have been strengthened if CT were administered for a longer period.
Mouse (CD2Fi lacZ transgenic,
Mutamouse™, male)
Mutations in the
Inez transgene in
liver
The target Inez gene is
recovered from genomic DNA
after a single dose with the
animals being sacrificed 14 d
later
IRIS: - (T)
80 mg/kg by
oral gavage in
corn oil
(Tombolan et al..
1999)
Comment: The carbon tetrachloride data was generated as a adjuct of a study with a differenet research focus, and were thus limited in scope. CT mutation
frequesncy exceeded controls by 60% which was not indicated as significant, se of only a single test administration limits the sensitivity of these results. This
study should not be judged as a specificlly negative finding.
Mouse (CD2Fi lacZ transgenic,
Mutamouse™, male)
Mutations in the
Inez transgene in
liver
The target Inez gene is
recovered from genomic DNA
after dosing with the animals
being sacrificed 7, 14, or 28 d
later
IRIS: - (T)
1,400 mg/kg
by oral gavage
(Hachiva and
Motohashi. 2000)
Comment: Increases in mutation frequency, some more that twice the control rate were seen in some test groups. While the author inferred that the
results"were not biologically significant", this study is not a "negative" result. Use of only a single test administration limits the sensitivity of these results.
The high dose used may not contribute to sensitivity as CYP2E1 activity can be degreaded at high dose.
Mouse (DC-1, male)
Chromosomal
fragments and
bridges in liver
Anaphase analysis of squash
preparations prepared 72 hrs
after dosing
~
8,000 mg/kg
(Curtis and Tillev.
1968)
Rat (F344, male)
Chromosomal
aberrations in liver
Analyzed primary hepatocytes
cultured for 48 hrs from rats
sacrificed 0-72 hrs after
dosing
1,600 mg/kg
by oral gavage
in corn oil
(Sawada et al..
1991)
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Test system
Endpoint
Test conditions
DNA adducts
IRIS (2010) descriptor3
Doseb
Reference
Rat (F344, male)
Micronucleus
formation in liver
Analyzed primary hepatocytes
cultured for 48 lirs from rats
sacrificed 0-72 lirs after
dosing
1,600 mg/kg
by oral gavage
in corn oil
(Sawada et al..
1991)
Rat (Wistar, male)
Micronucleus
formation in liver
Analyzed primary hepatocytes
harvested 72 lirs after dosing,
an optimal time to detect
micronuclei.
±(T)
3,200 mg/kg
by oral gavage
in corn oil
(Van Goethem et al..
1993)
Rat (Wistar, male)
Micronucleus
formation in liver
Analyzed primary hepatocytes
harvested 72 lirs after dosing,
an optimal time to detect
micronuclei. Increase was in
both centromere-lacking (5.5-
fold) and centromere-
containing (3.6-fold)
micronuclei.
+ (T)g
3,200 mg/kg
by oral gavage
in corn oil
(Van Goethem et al..
1995)
Mouse (CBAxC575BL/6,
male)
Micronucleus
formation and
ploidy levels in
liver
Analyzed primary hepatocytes
from rats sacrificed 5 d after
dosing and compared with a
partially hepatectomized
control.
15-Min
inhalation at
0.05-
0.1 mL/5 L
(Urwaeva and
Delone. 1995)
7294 a+ = positive, ± = equivocal or weakly positive, - = negative, (T) = toxicity
7295 b i.m. = intramuscular, i.p. intraperitoneal, i.g. = intragastric gavage, s.c. = subcutaneous.
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7301 Appendix J EVIDENCE ON LINEARITY OF THE PBPK MODEL
7302 The appendix table below presents the external:internal dose ratios for the human PBPK model over a
7303 span of concentrations, using the model assumptions adopted by the IRIS assessment (model parameter
7304 VmaxC = 1.49 mg/hr/kg BW0 70, continuous 24 hour/day, 7 days/week exposure), including PBPK
7305 model results for the MCA (mean arterial concentration) internal dose metric and results for the
7306 MRAMKL (mean rate of metabolism in the liver) internal dose metric. This appendix table is a
7307 modification of Tables C-6 and C-10 in the IRIS assessment.
7308
7309 TableApx J-l. Table Summarizing PBPK Model results in the IRIS Assessment Tables C-6 and
7310 C-10
EC
(PPm)
EC
(mg/m3)
MCA
(jimol/L)
EC/MCA
%
change
MRAMKL
(jumol/hr/kg
liver)
EC/
MRAMKL
% change
0.1
0.6290
0.007827
80.37
—
—
—
—
0.2
1.258
0.01566
80.35
-0.02
—
—
—
0.3
1.887
0.02349
80.33
-0.05
—
—
—
0.4
2.516
0.03133
80.31
-0.07
—
—
—
0.5
3.145
0.03917
80.29
-0.10
—
—
—
0.6
3.774
0.04702
80.27
-0.12
—
—
—
0.7
4.403
0.05487
80.25
-0.15
—
—
—
0.8
5.032
0.06272
80.23
-0.17
—
—
—
0.9
5.661
0.07058
80.21
-0.20
—
—
—
1
6.290
0.07844
80.19
-0.22
1.3834
4.547
—
2
12.58
0.1573
79.99
-0.47
2.749
4.577
0.66
3
18.87
0.2365
79.80
-0.71
4.095
4.608
1.34
4
25.16
0.3161
79.60
-0.96
5.423
4.640
2.05
5
31.45
0.3962
79.39
-1.22
6.731
4.672
2.75
6
37.74
0.4766
79.19
-1.47
8.020
4.706
3.50
7
44.03
0.5575
78.98
-1.73
9.289
4.740
4.24
8
50.32
0.6388
78.78
-1.98
10.537
4.776
5.04
9
56.61
0.7205
78.57
-2.24
11.764
4.812
5.83
10
62.90
0.8027
78.36
-2.50
12.971
4.850
6.66
20
125.8
1.650
76.24
-5.14
23.832
5.279
16.10
30
188.7
2.545
74.16
-7.73
32.48
5.810
27.78
40
251.6
3.482
72.26
-10.09
39.11
6.434
41.50
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Appendix K SUMMARY OF PUBLIC COMMENTS / RESPONSE
TO COMMENTS
COMMENTS ON MOA FOR CARCINOGENICITY
EPA has received public comments from the American Chemistry Council (ACC) that provide a
different evaluation scheme of the mode of action for liver tumors induced by carbon tetrachloride. This
submission illustrates a recently developed quantitative MOA weight of evidence (WOE) scoring
approach (EP A-HQ-OPPT-2016-0733-0066) by providing a case example for the identification of the
likely operative MOA for carbon tetrachloride induced rodent liver tumor. The submission states that the
case example is not intended to be a complete discussion of all available and relevant studies and an in-
depth systematic review of the available literature was not conducted. The ACC submitted case example
reaches a different conclusion of the carbon tetrachloride MOA, evaluating the cytotoxicity MOA to
have a high positive score in their framework, while a mutagenicity MOA to have a highly negative
score, which supports a threshold cytotoxicity MOA.
The quantitative MOA weight of evidence (WOE) scoring approach is intended to be a competitive
evaluation of alternative MOA proposals stated in detail. In the case of carbon tetrachloride this
involves a proposed sequence of events for causation of cancer by carbon tetrachloride cytotoxicity and
alternately a proposed sequence of events for carbon tetrachloride cancer induction by direct
mutagenicity alone. ACC states: "This approach enables a side-by-side comparison of numerical WOE
confidence scores for each MOA to determine which MOA is more likely to be operative."
This approach for carbon tetrachloride does not address other important possibilities and areas of
uncertainty identified in the IRIS assessment including:
carbon tetrachloride cancer indication involves contributions from both cytotoxicity and
mutagenicity. As oxidative damage to DNA has been implicated in carcinogenesis, we believe
there is direct potential for this compound to contribute to both of these processes.
Other processes not evaluated in the process may be key to carbon tetrachloride carcinogenicity.
Such processes could include: oxidative damage to DNA resulting from carbon tetrachloride
metabolism and reactivity; epigenetic events related to carbon tetrachloride effects on DNA
methylation; or other as yet unidentified effects of carbon tetrachloride
EPA's (U.S. EPA. 2010) assessment concluded: (1) the MOA was unknown and (2) that there
was potential for a MOA that included both low dose genotoxic effects and higher dose
cytotoxicity. The submitted approach does not allow for consideration of these possibilities.
EPA uses a Bradford-Hill based evidence approach for MOA evaluation under its cancer guidelines.
Similarly, the submitted approach utilizes Bradford Hill considerations. However, the submitted scoring
system does not provide an appropriate evaluation system for datasets showing extensive areas of
uncertainty from confounding toxicity mechanisms:
I. Evaluation of the cytotoxicity MOA
A. "Essentiality"
This criterion addresses the extent that the available experimental data challenge and support the
proposed causal key steps for cancer causation.
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The submission cites the following experimental data as supporting qualitative evaluation of the
proposed MO A (paraphrased for succinctness):
(1) Metabolism of carbon tetrachloride has been demonstrated to produce free radicals including
CC13*, which has been detected in spin trapping studies with the liver in vivo, isolated liver
cells, and microsomal preparations.
(2) Studies using a variety of methodologies show that carbon tetrachloride exposures can cause
lipid peroxidation in the liver.
(3) A study in CYP2E1 knockout mice found that these animals avoided liver toxicity. Other
studies using CYP450 inhibitors indicate that prevention of carbon tetrachloride metabolism
also prevents liver toxicity. Studies with co-administration of free radical scavengers with
carbon tetrachloride have reduced liver toxicity. Conversely, there is increased carbon
tetrachloride cytotoxicity in hepatocyte cell lines that over express P450.
(4) Studies using free radical scavengers or antioxidants in conjunction with carbon tetrachloride
administration have shown reduced liver toxicity or lipid peroxidation. Co-administration of
antioxidants (vitamin E) with carbon tetrachloride have reduced liver peroxidation.
(5) Cytosolic calcium levels have been strongly increased by carbon tetrachloride treatment.
(6) CT administration increases cell replication in liver tissue. A lx administration of 40 mg/kg
carbon tetrachloride increased BrdU uptake by cells in the peri-portal zone at within one day,
plateauing at 3 days.
(7) Altered hepatic foci [of the GST-P form that are believed to be indicative of carcinogenic
processes] were increased by 12 weeks carbon tetrachloride treatment. [Such foci are
observed at the 25 ppm and 125 ppm inhalation exposures in Tsujimura (2008). but not
significantly elevated at 5 ppm or 1 ppm.]
(8) "Hepatocellular carcinomas appear only at the high dose in rats and mid and high doses in
mice, with an all or none response."
However, while these study findings inform our understanding of carbon tetrachloride
carcinogenesis, much uncertainty also remains.
(1) Metabolism of carbon tetrachloride to free radicals, at least substantially by CYP2E1, is
responsible for observed lipid peroxidation and liver toxicity of this compound but this does
not establish relative role of cytotoxicity or genotoxicity in a cancer MOA - both processes
could be driven by carbon tetrachloride metabolites and/or peroxidation products.
(2) These results suggest a hypothesis that lipid peroxidation is a specific cause of observed liver
toxicity, but it is not apparent that this hypothesis has been specifically challenged. Direct
liver toxicity from carbon tetrachloride metabolites is also possible. Also, importantly, a
recently discovered process termed ferroptosis describes cell death elicited by lipid
peroxidation as being "genetically, biochemically, and morphologically distinct from other
cell death modalities, including apoptosis, unregulated necrosis, and necroptosis" (Yang and
Stockwell, 2016, Ferroptosis: Death by Lipid Peroxidation. Trends Cell Biol. 26(3): 165-176).
As carbon tetrachloride toxicity studies have identified liver "necrosis", the above suggests
that this necrosis may be distinct from a lipid driven process. On the other hand, if ferroptosis
plays a role in (some) observed CT cell death, the effects of such cell death may not fit with a
regenerative hyperplasia (necrosis) driven MOA for cancer. A study by Siegers et al (1988)
provides substantial evidence that an iron mediated lipid peroxidation process is involved in
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carbon tetrachloride liver toxicity. Pretreatment of rodents with the iron binding agent
deferrioxamine before carbon tetrachloride administration reduced both the liver toxicity
(indicated by plasma GPT and SDH activity levels) and reduced lipid peroxidation (as
indicated by exhaled ethane levels) (Siegers et al.. 1988). The CT analogue
bromotrichloromethane showed the same pattern of results, while several other hepatotoxic
agents did not show a reduction of liver toxicity or lipid peroxidation following
deferrooxamine treatment. This suggests that the response observed was specifically relevant
to carbon tetrachloride's toxic mode of action.
(3) The submission proposes that lipid peroxidation-induced cell death drives cellular
proliferation-induced liver cancer. This conclusion ignores the carcinogenic potential of steps
leading up to lipid peroxidation, including oxygen and lipid based radical reactions resulting
from carbon tetrachloride metabolism, derangement of cellular calcium levels, potential
enhanced cellular iron availability to catalyze oxygen-radical induced lipid peroxidation, and
depletion of cellular glutathione and consequent inhibition of enzymes responsible for repair
of lipid peroxides.
(4) Changes in cytosolic calcium levels occur during carbon tetrachloride toxicity, but it is not
apparent that the hypothesis that elevation of cellular calcium concentrations causes toxicity
has been experimentally challenged.
(5) Cell replication is increased early, but not immediately, in the process of carbon tetrachloride
toxicity (i.e., at two days). Such proliferation is proposed to be due to tissue regeneration,
however other processes might also be involved.
(6) Cytotoxic processes (considered holistically) or increased cell replication specifically can be
proposed as causes of carbon tetrachloride carcinogenicity. However, these hypotheses are
proposed based on broader biological considerations and not directly supported or tested by
data on carbon tetrachloride.
(7) The observed tumorigenicity data have mostly shown steep dose response patterns that are
interpreted in the submission as indicative of thresholds. However, the study authors of the
inhalation cancer bioassay (Nagano et al.. 2007a) and EPA's IRIS assessment provide a more
nuanced characterization of the tumor data as being indicative of responses at some of the
lower dose levels.25
(8) Data on carbon tetrachloride increased GST-P liver foci in male rate are observed in
intermediate term experiments in male rats and follow a dose response pattern similar to, but
distinct from, the tumor dose response seen in male rats. (Foci were statistically elevated at
an inhaled concentration of 25 ppm, while a tumor response was not observed at that dose.)
In other studies, this GST-P foci protocol has been suggested as an practical indicator for
carcinogenicity by either genotoxic or non-genotoxic pathways. Thus, the observation of
25
In a visual examination of the data from the Nagano (2007a) inhalation study, the male F344 rat data is strongly nonlinear
with a high response at 125 ppm but no apparent response at 25 ppm. The female F344 rats also indicate a steep increase
between these doses, but an apparent increase in the carcinomas at 25 ppm suggests non-threshold behavior. In male BDF1
mice, there is a strong (essentially complete) tumor response at 25 and 125 ppm without observed increase at 5 ppm.
However, the high control tumor response observed in these male mice (approximately 50 % combined adenoma and
carcinoma risk) prevents sensitive determination potential compound response at low dose. In the female BDF1 mice, there
was likewise a high adenoma plus carcinoma tumor risk at the 25 ppm and 125 ppm doses, however, in this case there was
also a statistically significant increased incidence of tumors (primarily adenomas) at the subtoxic 5 ppm dose level -
indicating no apparent threshold for tumorigenic response in the female mice.
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these foci thus provides qualitative supporting evidence for carbon tetrachloride
carcinogenicity and also support for an upward curving (but not necessarily threshold) dose
response relationship in male rats. The role of this data in supporting a cytotoxic versus an
alternative MO A for carbon tetrachloride is not apparent. The occurrence of liver foci after
carbon tetrachloride treatment - without prior treatment by an initiating agent or use of a
partial hepatectomy may be interpreted to indicate that carbon tetrachloride is a "complete
carcinogen" (i.e., a compound that contributes to both tumor induction and promotion.)
The "Essentiality" criterion is scored in the submission as maximally high for all steps in their
proposed MOA. The resulting score contributes strongly to the highly positive ranking they assign to
the cytotoxicity MOA for tumors. However, a scoring problem is present in this methodology.
Specifically, the "essentiality" score for each proposed key event in a pathway is assigned "the
highest score achieved by any one of the unique Key Events in the pathway". This is a problematic
approach because a MOA may (and usually does) involve varied events with different degrees of
experimental support. Assigning the maximum score to all such events over states the available
evidence. In the case of the carbon tetrachloride, this numeric process leads to strongly over-scoring
the degree of experimental evidence for the cytotoxic MOA.
B. Dose-response concordance
The submission states: "Because the earlier key events are demonstrated via in vitro assays, the
concentrations do not align with the longer term in vivo studies. It is clear, however, that the doses
for the earlier key events are lower than those needed to elicit liver tumors ... for dose concordance
the precursor key events must occur earlier and at lower doses than the tumorigenic dose."
This quote does not provide a strong argument in favor of a cytotoxicity MOA. First, it is not clear to
the reader that doses at which early events have been demonstrated are lower than the experimental
tumorigenic doses. While it is difficult to compare in vitro and in vivo systems, with the available
PK predictions, the authors could have undertaken some comparisons between molar concentrations
of carbon tetrachloride in liver tissue and those used in the in vitro experiments they are referring to.
It is logically correct that precursor key events (if measured with sufficient sensitivity) must occur
doses at least as low as tumorigenic doses. Violation of this pattern can be strong evidence against a
MOA proposal. Such an example is presented in EPA (2010): namely tumors were observed in the
female mouse inhalation bioassay at a lower concentration (25 ppm) than where substantial toxicity
was observed. This provides evidence against cytotoxic effects alone providing an explanation for
observed tumors.
Secondly, a showing that precursor events occur at lower doses than tumors sets a rather low bar for
evaluating this dose response concordance. A range of diverse biological responses may occur at
doses below those that cause frank toxicity. Knowing that a given effect occurs at a subtoxic dose is
not in itself evidence that the two are related. Stronger evidence for a MOA would come from
demonstrating a reasonable quantitative functional relationship between increasing levels of the
proposed precursor response and increased incidence of apical toxic response26. The ACC materials
do not present such an analysis.
26 However, biological changes that are not directly related may show a common increasing relationship over a studied dose
range. This could result when diverse secondary events share a common antecedent (e.g., changes in metabolic patterns) or
simply because an agent has multiple biological effects within the experimental dose range.
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The submitted example case scored dose response concordance as providing "moderate" support
most of the proposed key events in the cytotoxicity MOA. In my evaluation, the evidence is
somewhat weaker. The data as assembled do not reveal unambiguous relationships between
increasing cytotoxicity and increasing tumorigenicity. EPA (2010) has also judged that the
inhalation study tumor response in the low dose (5 ppm) female mice occurred in the absence of
substantial observed toxicity.
C. Temporal concordance
Temporal relationships can provide important evidence for causal relationships, as reflected in
Bradford Hill's criterion: "The effect has to occur after the cause (and if there is an expected delay
between the cause and expected effect, then the effect must occur after that delay)" However, in
evaluating mechanistic data, it is also true that an agent can cause a variety of biological
perturbations resulting from short term exposure. That is many biological effects may occur much in
advance of chronic apical effects such as cancer. The observation that a proposed precursor occurs
rapidly (or even at subchronic duration) does not in itself provide much evidence for a causal
relationship between the two. Specific to carbon tetrachloride, ACC's concordance table shows
metabolism of carbon tetrachloride to reactive radicals, lipid peroxidation, loss of calcium
homeostasis, and initial cytotoxicity all occurring within 24 hours; cellular proliferation is observed
after two days, and liver tumors are observed at 2 years. This pattern of shorter term versus longer
term findings may simply reflect the expected time scales for (1) prompt events of metabolism and
initial chemical tissue interactions, (2) acute toxicological changes, and (3) chronic toxicity. This
pattern in itself doesn't provide much information to support a MOA.
The submitted example case cites Cabre et al., (2000) as showing liver fibrosis, changes in
glutathione pathways, and observation of products of lipid peroxidation at time periods before the
occurrence of cirrhosis. These earlier events may have a role in carbon tetrachloride carcinogenesis,
however, this study doesn't seem to provide evidence of a cancer MOA.
The MOA scoring process attributed maximum scores for "temporal concordance" for all five
hypothesized key events in the cytotoxicity pathway, contributing heavily to high overall score
assigned to the MOA. However, we believe the cited data on temporal patterns for carbon
tetrachloride effects provides only marginal insight for evaluating the MOA for this compound.
II. ACC evaluation of a mutagenicity MOA
This MOA as constructed calls for direct mutagenicity by carbon tetrachloride metabolites to account for
the observed cancer findings. As noted above, this inference does not agree with the conclusions about a
carbon tetrachloride MOA as described by EPA (2010). The IRIS assessment suggested a multi-step
MOA that may involve both mutagenicity and promotion by cytotoxic effects. Such mutagenic effects of
carbon tetrachloride need not be direct (in the sense of a direct metabolite of carbon tetrachloride
binding to DNA). A multistep MOA may involve oxidative DNA adducts derived through lipid
peroxidation resulting from carbon tetrachloride metabolism. Such effects need not be limited to
situations with carbon tetrachloride toxicity, as chemical interactions leading to ROS formation may
occur in the absence of toxicity. The presence of cytotoxicity may quantitatively alter the dose response
for production of DNA oxidation, however the specific effects of toxicity processes is unknown. High
doses of carbon tetrachloride may not produce maximal adduct response, as: (1) High carbon
tetrachloride doses can impair CYP2E1 metabolism to species causing lipid peroxidation (2) cell killing
at high doses will cause birth of cells not exposed to initial carbon tetrachloride doses - or prior
background conditions. While there are positive studies showing increased oxidative binding following
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carbon tetrachloride exposure, this database is complex and sometimes inconsistent. However, with the
present state of knowledge, carbon tetrachloride induced oxidative adducts may be an important
contributor to carbon tetrachloride's MOA for cancer. Feasible, studies using modern methods and
quality assurance procedures could substantially resolve these questions.
The submitted example case statement of a mutagenicity MOA is specific and calls for proof at several
stages for mutagenic processes:
(1) Metabolism of carbon tetrachloride to a reactive intermediate that leads to the formation of
carbon tetrachloride - induced pro-mutagenic DNA adducts
(2) Insufficient or mis- repair of carbon tetrachloride -induced DNA Adducts
(3) Early Mutations induced in cancer critical genes
(4) Clonal Expansion/Cell Proliferation to form Pre-neoplastic AHF
(5) Progression and late mutations
(6) Hepatocellular Carcinoma
Given the current lack of resolution on the potential for carbon tetrachloride mutagenicity at bioassay
and human relevant exposure levels (see below) the resultant scoring for this MOA was low. However,
the score derived by ACC was driven by the choice of steps included above. Note that step (1) includes
both metabolism and production of pro-mutagenic DNA adducts. This compound step would demand
much evidence to satisfy. This contrasts with the accompanying hypothesized cytotoxicity MOA where
step 1 was purely metabolic: "Metabolism via CYP2E1 and formation of trichloromethyl peroxy
radical". Requiring that both metabolism and DNA lesions be established in a first step for the
mutagenic MOA reduces the scoring for this MOA. The decision to separately include step (2) -
establishing that DNA repair is inadequate - seems both experimentally challenging and somewhat
beside the point as step (3) calls for specific data on completed mutations. Note also that step (3)
specifically addresses mutations in cancer critical genes, data that is rarely available from chemical
mutagenesis studies.
The practical challenge for evaluating a mutagenic MOA (or a role for mutation in a multi-step MOA) is
assessing the available data on mutagenesis. The attachments to this paper excerpt key data from EPA
(2010) for in vivo and in vitro genotoxicity toxicity studies. These tables seek to show that while there is
a large database of genotoxicity studies on carbon tetrachloride, there are also major limitations in the
database. In particular there are very limited in vitro data that applicable to oxidative damage to DNA by
carbon tetrachloride (i.e., positive but limited findings in E coli strains) and very limited in vivo
mutagenesis data for carbon tetrachloride metabolizing tissues. The submitted example case has judged
the carbon tetrachloride database as essentially demonstrating lack of a mutagenic effect. By comparison
EPA (2010) emphasized the available data do not allow characterization of the genotoxicity at low
carbon tetrachloride exposure levels or the role of such genotoxicity in a cancer MOA.
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7563
7564 TableApx K-l. Summary of Reviewed Genotoxicity Studies for Carbon Tetrachloride
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Target
Organ/
System
Study
Type
Species/Strain/
Cell Type
(Number/group if
relevant)
Exposure
Route
Doses /
Concentrations
Duration
Effect
Concentration/
Result
Effect Measured
Reference
Data Quality
Evaluation
Genotoxicity
Acute
Mouse lymphoma
L5178/TK+/- cells
In vitro
0, 4.38, 6.55, 8.76
mmol/L (+S9)
3 hours
Positive at 6.55 and
8.76 mmol/La (at
relative toxicities
of 6% and 16%,
respectively)
Alkaline unwinding
of DNA (ratio of
ssDNA and dsDNA);
cell viability
(Garbers et
al.. 1988)
Unnaceptable
Genotoxicity
Acute
Salmonella
tvphimurium strains
TA 98, TA 100, TA
1535, TA 1537
<3 reolicates /erouo
In vitro
0, 0.005, 0.01, 0.05,
0.1,0.2,0.5, 1,2, 5%
(± S9)b
24 hours
Weakly positive0 in
TA 98 (-S9) at >
1%; negative in TA
98 (+S9); negative
in TA 100, TA
1535, and TA 1537
(± S9)
Reverse mutation
(gas exposure
method)
(Araki et
al.. 2004)
High
Genotoxicity
Acute
Escherichia coli
strains
WPHuvrA /pKM 101,
WP2/pKM101
<3 replicates /group
In vitro
0, 0.005, 0.01, 0.05,
0.1,0.2,0.5, 1,2, 5%
(±S9)b
24 hours
Weakly positive0 at
2% in
WP2/wvr,4/pKM10
1 (±S9); positive at
> 0.1% (-S9) and>
0.2% (+S9) in
WP2/pKM101d
Reverse mutation
(gas exposure
method)
(Araki et
al.. 2004)
High
aThe test substance was positive at toxic concentrations only. However, the criteria for a positive response in this assay included increases in the relative fraction of ssDNA that is greater
than the increase in relative toxicity (at toxicities of 5% to 50%), if this occurs at 2 or more concentrations.
bTests were also conducted with glutathione-supplemented S9 mix.
CA result was considered positive if a two-fold increase in the number of revertants was observed.
dData for E.coli strain WP2/pKM101 were based on < 3 measurements (statistical analyses were not performed).
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