United States
Environmental Protection
Agency
Health Effects Support
Document for 1,1,2,2-
Tetrachloroethane
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Health Effects Support Document
for
1,1,2,2-Tetrachloroethane
U.S. Environmental Protection Agency
Office of Water (43 04T)
Health and Ecological Criteria Division
Washington, DC 20460
www.epa.gov/safewater/ccl/pdf/1122tetrachloroethane.pdf
EPA Document Number EPA-822-R-08-007
January, 2008
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FOREWORD
The Safe Drinking Water Act (SDWA), as amended in 1996, requires the Administrator
of the U.S. Environmental Protection Agency (U.S. EPA) to establish a list of contaminants to
aid the Agency in regulatory priority setting for the drinking water program. In addition, the
SDWA requires EPA to make regulatory determinations for no fewer than five contaminants by
August 2001 and every five years thereafter. The criteria used to determine whether or not to
regulate a chemical on the Contaminant Candidate List (CCL) are the following:
The contaminant may have an adverse effect on the health of persons.
The contaminant is 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.
• In the sole judgment of the Administrator, regulation of such contaminant presents a
meaningful opportunity for health risk reduction for persons served by public water
systems.
The Agency's findings for all three criteria are used in making a determination to
regulate a contaminant. The Agency may determine that there is no need for regulation when a
contaminant fails to meet one of the criteria. The decision not to regulate is considered a final
Agency action and is subject to judicial review.
This document provides the health effects basis for the regulatory determination for
1,1,2,2-tetrachloroethane. In arriving at the regulatory determination, data on toxicokinetics,
human exposure, acute and chronic toxicity to animals and humans, epidemiology, and
mechanisms of toxicity were evaluated. In order to avoid wasteful duplication of effort,
information from the following risk assessments by the U.S. EPA and other government
agencies were used in the development of this document.
ATSDR (Agency for Toxic Substances and Disease Registry). 1996, 2006 (draft).
Toxicological Profile for 1,1,2,2-Tetrachloroethane. U.S. Department of Health and
Human Services, Public Health Service, Atlanta, GA.
Cal EPA (California Environmental Protection Agency). 2003. Public health goal for
1,1,2,2-tetrachloroethane in drinking water. Office of Environmental Health Hazard
Assessment. Available from: .
U.S. EPA. 1989c. United States Environmental Protection Agency.
1,1,2,2-Tetrachloroethane Drinking Water Health Advisory. Office of Water.
1,1,2,2-Tetrachloroethane —January, 2008
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U.S. EPA (United States Environmental Protection Agency). 1986e. Integrated Risk
Information System (IRIS): 1,1,2,2-tetrachloroethane (cancer assessment 1986).
Available from: .
World Health Organization. 1998. Concise International Chemical Assessment
Document; 1,1,2,2-Tetrachloroethane. Geneva.
Information from the published risk assessments was supplemented with information
from the primary references for key studies and recent studies of 1,1,2,2-tetrachloroethane
identified by a literature search conducted in 2003 and updated in 2006 and 2008.
A Reference Dose (RfD) is provided as the assessment of long-term toxic effects other
than carcinogenicity. RfD determination assumes that thresholds exist for certain toxic effects,
such as cellular necrosis, significant body or organ weight changes, blood disorders, etc. It is
expressed in terms of milligrams per kilogram per day (mg/kg/day). In general, the RfD is an
estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure to
the human population (including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime.
The carcinogenicity assessment for 1,1,2,2-tetrachloroethane includes a formal hazard
identification and an estimate of tumorigenic potency when available. Hazard identification is a
weight-of-evidence judgment of the likelihood that the agent is a human carcinogen via the oral
route and of the conditions under which the carcinogenic effects may be expressed.
Development of these hazard identification and dose-response assessments for 1,1,2,2-
tetrachloroethane has followed the general guidelines for risk assessment as set forth by the
National Research Council (1983). EPA guidelines that were used in the development of this
assessment may include the following: Guidelines for the Health Risk Assessment of Chemical
Mixtures (U.S. EPA, 1986a), Guidelines for Mutagenicity Risk Assessment (U.S. EPA, 1986b),
Guidelines for Developmental Toxicity Risk Assessment ((3.$. EPA, 1991), Guidelines for
Reproductive Toxicity Risk Assessment (U.S. EPA, 1996a), Guidelines for Neurotoxicity Risk
Assessment (U.S. EPA, 1998a), Guidelines for Carcinogen Assessment (U.S. EPA, 2005a),
Recommendations for and Documentation of Biological Values for Use in Risk Assessment (U.S.
EPA, 1988), (proposed) Interim Policy for Particle Size and Limit Concentration Issues in
Inhalation Toxicity (U.S. EPA, 1994a), Methods for Derivation of Inhalation Reference
Concentrations and Application of Inhalation Dosimetry (U.S. EPA, 1994b), Use of the
Benchmark Dose Approach in Health Risk Assessment (U.S. EPA, 1995a), Science Policy
Council Handbook: Peer Review (U.S. EPA, 1998b, 2000a), Science Policy Council Handbook:
Risk Characterization (U.S. EPA, 2000b), Benchmark Dose Technical Guidance Document
(U.S. EPA, 2000c), Supplementary Guidance for Conducting Health Risk Assessment of
Chemical Mixtures (U.S. EPA, 2000d), and^4 Review of the Reference Dose and Reference
Concentration Processes (U.S. EPA, 2002a).
The chapter on occurrence and exposure to 1,1,2,2-tetrachloroethane through potable
water was developed by the Office of Ground Water and Drinking Water (OGWDW). It is
1,1,2,2-Tetrachloroethane — January, 2008 vi
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based primarily on unregulated contaminant monitoring (UCM) data collected under the SDWA.
The UCM data are supplemented with ambient water data, as well as data from the States, and
published papers on occurrence in drinking water.
1,1,2,2-Tetrachloroethane — January, 2008 vii
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1,1,2,2-Tetrachloroethane — January, 2008 viii
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ACKNOWLEDGMENT
This document was prepared under the U.S. EPA Contract No. 68c-02-009, Work
Assignment No. 3-54 with ICF Consulting, Inc. The Lead U.S. EPA Scientist is Joyce
Morrissey Donohue, Ph.D., Health and Ecological Criteria Division, Office of Science and
Technology, Office of Water.
1,1,2,2-Tetrachloroethane — January, 2008 ix
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1,1,2,2-Tetrachloroethane —January, 2008
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TABLE OF CONTENTS
FOREWORD v
ACKNOWLEDGMENT ix
LIST OF TABLES xv
LIST OF FIGURES xvii
1.0 EXECUTIVE SUMMARY 1-1
2.0 IDENTITY: CHEMICAL AND PHYSICAL PROPERTIES 2-1
3.0 USES AND ENVIRONMENTAL FATE 3-1
3.1 Production and Use 3-1
3.2 Environmental Release 3-1
3.3 Environmental Fate 3-3
3.4 Summary 3-5
4.0 EXPOSURE FROM DRINKING WATER 4-1
4.1 Introduction 4-1
4.2 Ambient Occurrence 4-1
4.2.1 Data Sources and Methods 4-1
4.2.2 Results 4-2
4.3 Drinking Water Occurrences 4-3
4.3.1 Data Sources and Methods 4-3
4.3.2 Derivation of the Health Reference Value 4-4
4.3.3 Results 4-5
4.4 Summary 4-17
5.0 EXPOSURE FROM MEDIA OTHER THAN WATER 5-1
5.1 Exposure from Food 5-1
5.1.1 Concentration in Non-Fish Food Items 5-1
5.1.2 Concentrations in Fish and Shellfish 5-1
5.1.3 Intake of 1,1,2,2-Tetrachloroethane from Food 5-1
5.2 Exposure from Air 5-1
5.2.1 Concentration of 1,1,2,2-Tetrachloroethane in Air 5-2
5.2.2 Intake of 1,1,2,2-Tetrachloroethane from Air 5-3
5.3 Exposure from Soil 5-3
5.3.1 Concentration of 1,1,2,2-Tetrachloroethane in Soil 5-3
5.3.2 Intake of 1,1,2,2-Tetrachloroethane from Soil 5-3
5.4 Other Residential Exposures 5-4
5.5 Occupational (Workplace) Exposures 5-4
1,1,2,2-Tetrachloroethane — January, 2008 xi
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5.5.1 Description of Industries and Workplaces 5-4
5.5.2 Types of Exposure (Inhalation, Dermal, Other) 5-5
5.5.3 Exposure in the Work Environment 5-5
5.6 Summary 5-5
6.0 TOXICOKINETICS 6-1
6.1 Absorption 6-1
6.2 Distribution 6-2
6.3 Metabolism 6-3
6.3.1 Metabolic Rate Constants 6-7
6.4 Excretion 6-8
7.0 HAZARD IDENTIFICATION 7-1
7.1 Human Effects 7-1
7.1.1 Short-Term Studies and Case Reports 7-1
7.1.2 Long-Term and Epidemiological Studies 7-2
7.2 Animal Studies 7-3
7.2.1 Acute Toxicity 7-3
7.2.2 Short-Term Studies 7-5
7.2.3 Subchronic Studies 7-7
7.2.4 Neurotoxicity 7-13
7.2.5 Developmental/Reproductive Toxicity 7-15
7.2.6 Chronic Toxicity 7-18
7.2.7 Carcinogenicity 7-20
7.3 Other Key Data 7-23
7.3.1 Mutagenicity and Genotoxicity 7-23
7.3.2 Immunotoxicity 7-26
7.3.3 Physiological or Mechanistic Studies 7-27
7.3.3.1 NoncancerEffects 7-27
7.3.3.2 Cancer Effects 7-28
7.3.3.3 Interactions with Other Chemicals 7-28
7.3.4 Structure-Activity Relationship 7-29
7.4 Hazard Characterization 7-29
7.4.1 Synthesis and Evaluation of Major Noncancer Effects 7-29
7.4.2 Synthesis and Evaluation of Carcinogenic Effects 7-31
7.4.3 Mode of Action and Implications in Cancer Assessment 7-32
7.4.4 Weight of Evidence Evaluation for Carcinogenicity 7-32
7.4.5 Potentially Sensitive Populations 7-33
8.0 DOSE-RESPONSE ASSESSMENT 8-1
8.1 Dose-Response for Noncancer Effects 8-1
8.1.1 RfD Determination 8-3
8.1.1.1 Benchmark Dose Approach 8-3
8.1.1.2 NOAEL/LOAEL Approach 8-8
8.1.2 RfC Determination 8-9
1,1,2,2-Tetrachloroethane — January, 2008 xii
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8.2 Dose-Response for Cancer Effects 8-9
8.2.1 Choice of Study 8-9
8.2.2 Dose-Response Characterization 8-10
8.2.3 Cancer Potency and Unit Risk 8-12
9.0 REGULATORY DETERMINATION AND CHARACTERIZATION OF RISK FROM
DRINKING WATER 9-1
9.1 Regulatory Determination for Chemicals on the CCL 9-1
9.1.1 Criteria for Regulatory Determination 9-1
9.1.2 National Drinking Water Advisory Council Recommendations 9-2
9.2 Health Effects 9-2
9.2.1 Health Criterion Conclusion 9-3
9.2.2 Hazard Characterization and Mode of Action Implications 9-3
9.2.3 Dose-Response Characterization 9-4
9.3 Occurrence in Public Water Systems 9-5
9.3.1 Occurrence Criterion Conclusion 9-6
9.3.2 Monitoring Data 9-6
9.3.3 Use and Fate Data 9-7
9.4 Risk Reduction 9-8
9.4.1 Risk Criterion Conclusion 9-8
9.4.2 Exposed Population Estimates 9-9
9.4.3 Relative Source Contribution 9-10
9.4.4 Sensitive Populations 9-10
9.5 Regulatory Determination Decision 9-10
10.0 REFERENCES 10-1
APPENDIX A: Abbreviations and Acronyms Appendix A-l
APPENDIX B: Benchmark Dose Modeling Results for Non-Cancer Endpoints . . Appendix B-l
APPENDIX C: Benchmark Dose Modeling Results for Cancer Risk Estimation . Appendix C-l
1,1,2,2-Tetrachloroethane — January, 2008 xiii
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LIST OF TABLES
Table 2-1 Chemical and Physical Properties of 1,1,2,2-Tetrachloroethane 2-2
Table 3-1 Environmental Releases of 1,1,2,2-Tetrachloroethane in the U.S., 1988-2001
(pounds) 3-3
Table 4-1 Summary UCM Occurrence Statistics for 1,1,2,2-Tetrachloroethane (Round 1)
4-7
Table 4-2 Summary UCM Occurrence Statistics for 1,1,2,2-Tetrachloroethane (Round 2)
4-8
Table 7-1 Doses and Effects from the NTP 14-Week Study (2004) in F-344 Rats 7-10
Table 7-2 Doses and Effects from the NTP 14-Week Study (2004) in B6C3F1 Mice . . 7-12
Table 7-3 Summary of Liver Tumor Incidence, 78-Week Study in Mice 7-21
Table 7-4 Experimental Metastasises in Athymic Mice Injected with Transformed BALB/c
3T3 Cells 7-23
Table 7-5 Genotoxicity of 1,1,2,2-Tetrachloroethane/w Vitro 7-24
Table 8-1 NOAEL/LOAEL Data for Oral Subchronic and Chronic Studies of 1,1,2,2 -
Tetrachloroethane 8-1
Table 8-2 Benchmark Modeling Results for Noncancer Endpoints in the NTP Study (2004)
With Rats 8-5
Table 8-3 Summary of Liver Tumor Incidence, 78-Week Study in Mice 8-11
Table 8-4 Factors Used to Derive the Oral Slope Factor 8-13
Table 9-1 Populations Exposed to 1,1,2,2-Tetrachloroethane at V* HRL or HRL 9-9
1,1,2,2-Tetrachloroethane —January, 2008
xv
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1,1,2,2-Tetrachloroethane — January, 2008 xvi
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LIST OF FIGURES
Figure 2-1 Chemical Structure of 1,1,2,2-Tetrachloroethane 2-1
Figure 4-1 Cross-section States for Round 1 (24 States) and Round 2 (20 States) 4-4
Figure 4-2 Geographic Distribution of 1,1,2,2-Tetrachloroethane Detections in Both Cross-
Section and Non-Cross-Section States (Combined UCM Rounds 1 and 2) . . 4-10
Figure 4-3 Geographic Distribution of 1,1,2,2-Tetrachloroethane Detections in Both Cross-
Section and Non-Cross-Section States (Above: UCM Round 1; Below: UCM
Round 2) 4-11
Figure 4-4 Geographic Distribution of 1,1,2,2-Tetrachloroethane Detection Frequencies in
Cross-Section States (Above: UCM Round 1; Below: UCM Round 2) 4-12
Figure 4-5 Geographic Distribution of 1,1,2,2-Tetrachloroethane FtRL Exceedance
Frequencies in Cross-Section States (Above: UCM Round 1; Below: UCM
Round 2) 4-13
Figure 4-6 Annual Frequency of 1,1,2,2-Tetrachloroethane Detections (above) and HRL
Exceedances (below), 1985-1997, in Select Cross-Section States 4-14
Figure 4-7 Distribution of 1,1,2,2-Tetrachloroethane Detections (above) and HRL
Exceedances (below) Among Select Cross-Section States 4-16
Figure 6-1 Postulated Metabolism of 1,1,2,2-Tetrachloroethane 6-5
Figure 8-1 BMD Modeling Results for Male Relative Liver Weight 8-6
Figure 8-2 Multistage Model Fit to Bioassay Tumor Data for Female Mice 8-12
1,1,2,2-Tetrachloroethane — January, 2008 xvii
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1.0 EXECUTIVE SUMMARY
1,1,2,2- Tetrachloroethane is one of a family of volatile, chlorinated, ethane and ethene
compounds with a variety of commercial uses. 1,1,2,2-Tetrachloroethane is presently no longer
manufactured in the United States. Some product continues to be released to the environment as
a by-product in the synthesis of other chlorinated chemicals. Data from the Toxic Release
Inventory (TRI) from show a total release of 5420 pounds in 2001 compared to a release of
17547 pounds in 1988. This change is indicative of the decline in production and use.
When considered in its totality, the data on the occurrence of 1,1,2,2-tetrachloroethane in
public potable water systems indicate that a positive regulatory determination is not justified at
this time. Although 1,1,2,2-tetrachloroethane is a likely carcinogen and has noncancer effects on
several organ systems, it does not occur widely in drinking water systems, and continued decline
of its commercial use and environmental release will further reduce the risk for source- and
drinking water contamination. 1,1,2,2-Tetrachloroethane does not occur in potable water
systems at levels of concern, and regulation would not provide a meaningful opportunity to
reduce risk for the population.
1,1,2,2-Tetrachloroethane is fairly stable in the environment, especially in the upper
atmosphere. Degradation by microbes is possible but appears to be slow. Prevalence in finished
and ambient water is low and has declined in concert with the decrease in U.S. production and
use. There are no data that demonstrate that it is present in the food supply, and there are no
recent data from monitoring of ambient air samples.
Data on the occurrence of 1,1,2,2-tetrachloroethane in drinking water were obtained from
the Unregulated Contaminant Monitoring program and represent two time periods: 1988 to 1992
(Round 1) and 1993 to 1997 (Round 2). Detection limits for the methods used by the states
varied from 0.01 to 10 |ig/L with a median value of 0.5 |ig/L. Some under-reporting of the
actual occurrence may have occurred as a result of the variability in the reporting limits. Results
from Round 2 are likely to be more accurate than those from Round 1 because the upper bond
for reporting decreased from 10 |ig/L to 2.5 |ig/L. Round 2 results are also more representative
of current production and use conditions. In Round 2, 0.07% of 24,800 systems reported at least
one detection of 1,1,2,2-tetrachloroethane at a level greater than the benchmark health reference
level (HRL) of 0.4 |ig/L. When extrapolated to a national level, an estimated 168,000 persons
could have been exposed to 1,1,2,2-tetrachloroethane at levels greater than the HRL at some
time during the reporting period.
Absorption of 1,1,2,2-tetrachloroethane by both the oral and inhalation routes is nearly
complete. The major site of metabolism is the liver where it is dechlorinated, apparently by way
of a cytochrome P450, and oxidized to dichloroacetic acid (DC A). There is some evidence for a
free radical intermediate in this process. DCA is metabolized by cytosolic GST zeta, ultimately
forming oxalate and carbon dioxide. Glycolate and glyoxalate are intermediates in this process
and provide a route for some of the carbons from 1,1,2,2-tetrachloroethane to become
incorporated in the synthesis of endogenously-formed intermediary metabolites like glycine and
serine. There are several variants of GST zeta in the human population which leads to
1,1,2,2-Tetrachloroethane — January, 2008 1-1
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differences in the amount of DCA that becomes metabolized. In addition, DCA is an inhibitor of
GST zeta, leading to increased serum levels when exposure is continuous rather than episodic.
Numerous studies in humans and animals implicate the liver as the primary target organ
and liver toxicity as the critical effect in dose-response analysis. 1,1,2,2-Tetrachloroethane also
has effects on hematology, the kidney, testes, and nervous system. The human data are limited
and often confounded by simultaneous exposure to other chemicals. Most human data apply to
occupational exposures and lack quantification of exposure concentration and dose.
Animal data are available for the inhalation and oral routes in several species. A 2004
subchronic study by the National Toxicology Program (NTP) using F-344 rats and B6C3F1 mice
provides the most comprehensive dose-response data on the noncancer effects of 1,1,2,2-
tetrachloroethane and serves as the basis for the reference dose (RfD) of 10 jig/kg/day. The RfD
was derived from a lower-bound limit on the dose (BMDL) associated with a one standard
deviation increase in relative liver weight in F-344 rats (10.71 mg/kg/day) and supported by
increased cytoplasmic vacuolization of hepatocytes in 7/10 males at the lowest tested dose plus
increased levels of serum levels of liver enzymes that are biomarkers for liver toxicity at BMDLs
of about 30 mg/kg/day. Rats were found to be more sensitive than mice to the noncancer effects
of 1,1,2,2-tetrachloroethane. The uncertainty factor for the RfD calculation was 1000 (10 for
intraspecies variability, 10 for interspecies variability, 3 for a duration adjustment from
subchronic to chronic, and 3 for database uncertainties). The data for the inhalation route of
exposure do not support the derivation of a reference concentration (RfC) at this time.
Range finding studies for developmental toxicity in rats and mice were conducted by
NTP and demonstrate a lack of developmental effects except at doses that were maternally toxic
and greater than the point of departure for the RfD calculation. The data on reproductive toxicity
are more limited, consisting of a one-generation study of inhalation exposure to 13.3 mg/m3 for 4
hours per day in 7 exposed male and 5 female rats. Although there were no effects on the
number of pups, pup weights, pup mortality or malformations, there is a need for a more
comprehensive study of reproductive toxicity using a range of doses, more animals per dose
group and a broader suite of monitored endpoints. The observation of effects on the testes and
decreases in sperm motility support the need for additional research on the reproductive effects
of 1,1,2,2-tetrachloroethane.
The National Cancer Institute conducted studies of the turnorigenicity of 1,1,2,2-
tetrachloroethane in Osborne-Mendel rats and B6C3F1 mice using gavage in corn oil as the
exposure route. Liver tumors were identified in both species; the finding for mice was judged to
be positive and that for rats, equivocal. These findings are consistent with those for DCA, its
principal metabolite, which also causes liver tumors in both rats and mice after oral exposure
with mice having the greater sensitivity.
Limited studies of the tumorigenic mode of action suggest that 1,1,2,2-tetrachloroethane
acts as a promoter for tumor development and that it also has a weak initiation activity.
Genotoxicity studies provide limited evidence for mutagenicity and stronger evidence for
chromosomal effects. 1,1,2,2-Tetrachloroethane is likely to be a human carcinogen based on the
1,1,2,2-Tetrachloroethane — January, 2008 1 -2
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NCI cancer data and the data demonstrating its potential as both an initiator and promoter. There
is a need for additional mode of action research on 1,1,2,2-tetrachloroethane and examination of
the similarities and differences that exist between it and DC A. DCA is also a likely human
carcinogen. IARC places 1,1,2,2-tetrachloroethane in Group 3 for inadequate human data and
limited data from animal studies.
The Office of Water quantified the cancer risk for 1,1,2,2-tetrachloroethane using the
multistage model of the Agency Benchmark Dose Software (version 3.1.2) following the 2005
cancer guidelines. The cancer slope factor is 8.5 x 10"2 (mg/kg/day)"1; the concentration
equivalent to a one-in-a-million risk is 0.4 |ig/L, a value that serves as the HRL benchmark used
in evaluating the occurrence data. This value differs from the 0.2 |ig/L value calculated for the
U.S. EPA Integrated Risk Information System (IRIS) under the 1986 cancer guidelines.
Differences between the two cancer assessments are mostly a function of policy differences
between the 1986 and 2005 guidelines.
There are several factors that could increase sensitivity to exposure to
1,1,2,2-tetrachloroethane. Continuous exposure to DCA from chlorinated water could increase
the toxicity of 1,1,2,2-tetrachloroethane, if the DCA concentrations were sufficient to inhibit
GST zeta activity and increase the production of free radical intermediates. Dietary deficiencies
of antioxidant nutrients would increase the opportunity for liver damage through a free
radical/lipid peroxidation mechanism, and preexisting damage to the liver or kidneys could
increase the risks for target organ damage.
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2.0 IDENTITY: CHEMICAL AND PHYSICAL PROPERTIES
At room temperature 1,1,2,2-tetrachloroethane is a heavy, pure, colorless to pale-yellow
liquid with a sweetish, pungent, chloroform-like odor. It is a corrosive substance that will attack
some forms of plastics, rubber, and coatings. 1,1,2,2-Tetrachloroethane is soluble in alcohol,
ether, acetone, and benzene; it is miscible with methanol, ethanol, petroleum ether, carbon
tetrachloride, chloroform, carbon disulfide, dimethylformamide, and some oils. Its solubility in
water is about 2.87 g/L at 20°C. Technical grade 1,1,2,2-tetrachloroethane is 98% pure. 1,1,1,2-
Tetrachloroethane is found as an impurity in technical grade 1,1,2,2-tetrachloroethane (HSDB,
2004).
Figure 2-1 Chemical Structure of l,l?2,2-Tetrachloroethane
The chemical structure of 1,1,2,2-tetrachloroethane is shown above (Figure 2-1). Its
physical and chemical properties are listed in Table 2-1, along with other reference information.
1,1,2,2-Tetrachloroethane — January, 2008 2-1
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Table 2-1 Chemical and Physical Properties of l,l;2,2-Tetrachloroethane
Property
Chemical Abstracts Registry
(CAS) No.
US EPA Pesticide Chemical
Code
Synonyms
Registered Trade Name(s)
Chemical Formula
Molecular Weight
Physical State
Boiling Point
Melting Point
Density (at 20°C)
Vapor Pressure:
At 20°C
At 25°C
Partition Coefficients:
Log Kow
Log Koc
Solubility in:
Water
Other Solvents
Conversion Factors
(at 25°C, 1 atm)
Information
79-34-5
078601
Acetylene tetrachloride;
sym-Tetrachloroethane; s-
Tetrachloroethane
Bonoform; Cellon; Westron
C2H2C14
167.85
liquid
146.1-146.5°C
-43.8°C
1.59g/mL
Not found
4.62 mmHg
2.39
1.68-2.38
2.87 g/L (20°C)
2.86 g/L (25°C)
Ethanol, Methanol, Ether,
Acetone, Benzene,
Petroleum, Carbon
tetrachloride, Chloroform,
Carbon disulfide, Dimethyl
formamide, oils
1 ppm= 6.98 mg/m3
1 mg/m3=0.14 ppm
Sources: ATSDR (1996, 2006); HSDB (2004)
1,1,2,2-Tetrachloroethane —January, 2008
2-2
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3.0 USES AND ENVIRONMENTAL FATE
This section summarizes information pertaining to the uses, manufacture, and
environmental fate of 1,1,2,2-tetrachloroethane.
3.1 Production and Use
Prior to the 1980s, 1,1,2,2-tetrachloroethane was commonly used in the production of
other chemicals, primarily trichloroethylene (TCE), tetrachloroethylene (PCE), and 1,2-
dichloroethylene (Archer, 1979). It was also used as a metal degreaser, an extractant for oils and
fats, and a component of paint removers, varnishes and lacquers, and photographic films
(Hawley, 1981). More recently 1,1,2,2-tetrachloroethane use has declined, leading to an end to
commercial production in the U.S. Some use of 1,1,2,2-tetrachloroethane in the production of
chlorinated ethanes and ethenes has remained (ATSDR, 2006). Formerly it was used as a
fumigant, insecticide, and weed killer but is not currently registered in the U.S. for such uses
(U.S. EPA, 2004a).
Approximately 440 million pounds of 1,1,2,2-tetrachloroethane were produced in 1967
(Konietzko, 1984). Production fell to 34 million pounds in 1974, and production for commercial
uses ceased in the U.S. by the late 1980s. 1,1,2,2-tetrachloroethane is no longer produced as a
commercial product in the United States. The last production plant was Specialty Materials
Division of Eagle-Picher Industries in Lenexa, Kansas (SRI, 1988). By the late 1980s, this
facility was sold to the Vulcan Materials Company, and production was discontinued
(Montgomery and Welkom, 1990; SRI, 1993). Imports are also thought to be minimal (ATSDR,
2006).
3.2 Environmental Release
Although 1,1,2,2-tetrachloroethane is no longer generated as a commercial product, it is
still generated as an intermediate product and/or by-product in the manufacturing of other
synthetic chemicals, including trichloroethylene, 1,1,2-trichloroethane, 1,2-dichloroethene,
tetrachloroethylene, vinyl chloride, ethylene dichloride, and 1,1,1-trichloroethane. It can occur
as a trace contaminant in these and other manufactured chemicals, and in the waste stream of
facilities that produce them. ATSDR (2006) lists 95 facilities that produce 1,1,2,2-
tetrachloroethane as a by-product or use it as an intermediate product; the list is likely not
exhaustive.
1,1,2,2-Tetrachloroethane is listed as a Toxic Release Inventory (TRI) chemical. The
EPA established the TRI in 1987 in response to Section 313 of the Emergency Planning and
Community Right-to-Know Act (EPCRA). EPCRA requires the U.S. EPA and the states to
collect annual information on toxic chemical releases and transfers from industrial facilities and
to make this information available to the public through TRI. TRI details not only the types and
quantities of toxic chemicals released to the air, water, and land by facilities, but also provides
information on the quantities of chemicals sent to other facilities for further processing. The
scope of TRI was expanded in 1990 by the Pollution Prevention Act requiring additional
1,1,2,2-Tetrachloroethane — January, 2008 3-1
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information to be reported on waste management and source reduction activities. The purpose of
TRI is to educate the public on releases and transfer so that they can make informed decisions on
the consequences of those actions. The increased transparency has also forced industries to pay
closer attention to their use of toxic chemicals, resulting in internally-motivated reductions in use
(U.S. EPA, 2003a).
Facilities are required to report releases or transfers of chemicals if they manufacture,
process, or otherwise use more than established threshold quantities of these chemicals
(currently 25,000 pounds for manufacture and process and 10,000 pounds for use). Both the
number and type of facilities required to report has increased over time so that in 2002 over
24,000 industrial and federal facilities submitted in excess of 93,000 reports on toxic releases
(U.S. EPA, 2002b). In 2000, special thresholds were added for persistent bioaccumulative toxic
chemicals, for example dioxin and dioxin-like compounds. Today, TRI reports on releases of
nearly 670 chemicals (U.S. EPA, 2002b).
Although TRI can provide a general idea of release trends, it is far from exhaustive and
has significant limitations. For example, small facilities (those with fewer than 10 full-time
employees, and those that do not exceed manufacture and use limits) are not required to report
releases. In addition, the reporting threshold for the manufacturing and processing of TRI
chemicals changed between 1987 and 1989, dropping from 75,000 pounds per year in 1987 to
50,000 in 1988 to the current 25,000 in 1989; this creates the potential for misleading data trends
over time (U.S. EPA, 1996b). Finally, TRI data are meant to reflect releases and should not be
used to estimate general public exposure to a chemical (U.S. EPA, 2002b).
TRI data for 1,1,2,2-tetrachloroethane (see Table 3-1) are reported for the years 1988 to
2001 (U.S. EPA, 2004b). Air emissions constitute most of the on-site releases. Reported air
releases peaked in 1991 and then generally declined. Surface water discharges ranged in the
thousands of pounds until the mid-1990s, and then dropped off significantly. There is no
detectable pattern in on-site underground injections or releases to land. Reported off-site
releases were most significant in the first year of reporting, and then generally declined, with an
aberrant peak in 1998 and a rising trend in the last few recorded years.
The TRI data for 1,1,2,2-tetrachloroethane were reported from nineteen states (AK, CT,
CO, FL, KS, KY, LA, MI, MO, NC, NE, NJ, NY, OH, PA, SC, TN, TX, and VA), but no more
than 11 states reported in a given year. Louisiana and Texas were the only states to report every
year. Louisiana consistently discharged the most pounds per year to the environment, but that
state's reported releases dropped off considerably from 112,445 Ibs. in 1988 to 2,367 Ibs. in
2001 (U.S. EPA, 2004b).
1,1,2,2-Tetrachloroethane — January, 2008 3 -2
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Table 3-1 Environmental Releases of 1,1,2,2-Tetrachloroethane in the U.S., 1988-2001
(pounds)
Year
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
On-Site Releases
Air Emissions
3,462
4,461
5,202
7,299
13,614
15,488
8,275
12,484
28,203
48,899
64,251
44,796
35,611
43,865
Surface Water
Discharges
56
13
1
269
0
130
2,222
1,517
2,930
5,164
2,113
3,529
5,429
1,903
Underground
Injection*
0
5
0
5
0
0
0
26
0
0
0
80
283
0
Releases
to Land
961
0
15
0
0
0
0
0
1
0
0
495
18
29
Off-Site
Releases
941
631
30
6,503
511
7
7
52
80
273
262
771
15,209
128,750
Total On- &
Off-Site
Releases
5,420
5,110
5,248
14,076
14,125
15,625
10,504
14,079
31,214
54,336
66,626
49,671
56,550
174,547
Source: U.S. EPA, 2004b
3.3 Environmental Fate
1,1,2,2-Tetrachloroethane may be found primarily in the troposphere, where it is not
expected to react readily with photochemically produced hydroxyl radicals. It can be expected
to diffuse slowly into the stratosphere where it will degrade rapidly by photodissociation. Half-
life estimations have been derived using structure-activity models. In one case, Singh, et al.
(1981) suggested a half-life of >2 years in the troposphere. Another estimate, however,
assumed first order kinetics and suggested a half-life of approximately 53 days (Atkinson, 1987).
The half-life in the troposphere is sufficiently long to suggest that 1,1,2,2-tetrachloroethane will
distribute throughout the atmosphere.
1,1,2,2-Tetrachloroethane that reaches the stratosphere via diffusion will photodegrade
rapidly due to the shorter wavelengths of ultraviolet radiation. Chlorine radicals are produced.
The chlorine radicals may react with ozone, and perhaps deplete the stratospheric ozone layer.
Based on an estimated half-time and a tropospheric-to-stratospheric turnover time of 30 years
(U.S. EPA, 1979), it has been predicted that less than 1% of tropospheric
1,1,2,2-tetrachloroethane would eventually reach the stratosphere. The ozone depletion potential
for 1,1,2,2-tetrachloroethane is 0.001 relative to CFC-11 (trichlorofluoromethane), based on the
method developed by Nimitz and Skaggs (1992).
Due to the moderate vapor pressure of 5.95 mm Hg at 25°C, some
1,1,2,2-tetrachloroethane in surface water is expected to volatilize to ambient air. The
volatilization half-life of 1,1,2,2-tetrachloroethane is estimated to be 6.3 hours (Thomas, 1982).
This is based on a calculated Henry's law constant of 4.7xlO"4 atm-m3/mol (Mackay and Shiu,
1981), and a model river 1 m deep, flowing at 1 m/s, with a wind velocity of 3 m/sec. First-order
decay kinetics is assumed.
1,1,2,2-Tetrachloroethane —January, 2008
3-3
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In wastewater treatment plants, aeration towers are used to remove 1,1,2,2-
tetrachloroethane. The contaminated water is cascaded over trickling towers, and streams of air
to create aerosolized droplets that accelerate the volatilization processes. In stripping, as
opposed to ordinary volatilization, the liquid and gas phases are dispersed. Stripping was able to
remove 96% of the 1,1,2,2-tetrachloroethane in tests performed with activated sludge reactors
(Kincannon et al., 1983). The half-life for 1,1,2,2-tetrachloroethane removal by air stripping was
0.3 hour.
Chlorinated hydrocarbons are degraded through one or more of three possible
degradation pathways all of which accomplish reductive dechlorination: hydrogenolysis,
dichloroelimination, and dehydrochlorination (O'Loughlin et al., 1999). Hydrogenolysis is the
sequential replacement of chlorine atoms by hydrogen atoms (i.e., 1,1,2,2-tetrachloroethane -•
1,1,2-trichloroethane). This is usually driven by microbial activity. Dichloroelimination is an
abiotic reaction where there is a simultaneous release of two chlorine atoms and a hydrogen,
which forms an alkene (i.e., 1,1,2,2-tetrachloroethane -+ cis/trans 1,2-dichloroethene).
Dehydrochlorination is an abiotic elimination reaction (i.e., 1,1,2,2-tetrachloroethane -+
trichloroethene). Studies have shown that the biotic reactions found in natural systems can
effectively degrade 1,1,2,2-tetrachloroethane levels to below detection limits (Lorah et al.,
2003).
In some studies, 1,1,2,2-tetrachloroethane was reported to undergo a base-catalyzed
hydrolysis in water (25°C and pH=7.0 ). Its calculated half-life is 102 days when assuming a
second order rate reaction (Cooper et al., 1987). Solutions of lower ionic strength, which are
more typical of groundwater, had half-lives of 573 days for 1,1,2,2-tetrachloroethane removal at
pH=6.05 and 36 days at pH=7.01 (Haag and Mill, 1988). In a sterile, anaerobic solution of pH
7.0, after 28 days, 25% of the chemical had degraded (Klecka and Gonsior, 1983).
1,1,2,2-Tetrachloroethane underwent hydrolysis in pore-water extracted from sediments (low-
carbon sandy material) with a half-life of 29.1 days at pH values between 7.0 and 7.5 (Haag and
Mill, 1988). In an anoxic sediment-water system (pH unreported) the half-life of
1,1,2,2-tetrachloroethane with both chemical hydrolysis and biotic degradation was 6.6 days
(Jafvert and Wolfe, 1987).
In early studies, aerobic biodegradability tests results were conflicting. A study with 5
and 10 parts per million (ppm) 1,1,2,2-tetrachloroethane incubated with sewage seed for 7 days,
followed by 3 successive 7-day subcultures, found no significant degradation (Tabak et al.,
1981). Other investigators (Mudder and Musterman, 1982) found that in an unacclimated
biodegradability test when the initial concentration of 1,1,2,2-tetrachloroethane was 4.4 ppm, it
degraded by 41% in 24 days. There was no degradation over 5 days at an initial 1,1,2,2-
tetrachloroethane concentration of 0.85 ppm using acclimated microbes. A river die-away test
yielded 19% loss after 5 days using an acclimated system with an initial concentration of 17.3
ppm. None of the other chlorinated ethanes and ethenes in the study were found to be
biodegradable. Many researchers attribute most 1,1,2,2-tetrachloroethane loss associated with
sewage treatment to air-stripping processes and not biodegradation (Kincannon et al., 1983).
1,1,2,2-Tetrachloroethane — January, 2008 3 -4
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Current studies conducted by the Air Force investigated the redox chemistry of humic
substances under anoxic conditions. Humic materials have electron-donating and terminal
electron-accepting properties which in the presence on nickel ions can accelerate redox reactions
(O'Loughlin et al., 2003). 1,1,2,2-Tetrachloroethane undergoes a p-elimination or
dichloroelimination to c/V/fram'-l,2-dichloroethene under anoxic conditions with humic acid and
nickel. The half-life for this reaction was 61 minutes; with titanium and nickel, the half-life was
4 hours and with nickel alone the half-life was 23 hours, demonstrating the high redox potential
of humic acid.
1,1,2,2-Tetrachloroethane is expected to volatilize from moist soil surfaces because of its
vapor pressure, Henry's Law constant, low adsorption to soil, and a log Kocof 1.66 (Chiou et al.,
1979) or 2.38 (Valsaraj et al., 1999). The Koc of 1,1,2,2-tetrachloroethane is 46 in a silt loam
soil (Chiou et al., 1979). These chemical factors suggest that 1,1,2,2-tetrachloroethane will not
adsorb appreciably to soil, suspended solids, or sediment.
A measured aqueous hydrolysis rate constant, Kb (also referred to as the ionization
constant of a base), of 2.3x107 L/moles-yr, corresponds to a half-life of 1.1 days at pH 9 (Rolling
et al., 1987). Samples were incubated for six weeks under anaerobic conditions after inoculation
with a microorganism culture, consisting of primarily of anaerobic microorganisms that were
obtained from an anaerobic digester of a municipal wastewater treatment facility. The products
formed were: 1,1,2-trichloroethane, trichloroethene, c/5-l,2-dichloroethene,
rram--l,2-dichloroethene, 1,1-dichloroethene, and vinyl chloride (Hallen et al., 1986).
Bioconcentration is not expected to occur with 1,1,2,2-tetrachloroethane, because only
bioconcentration factors (BCF) of values greater than 500-1000 are considered significant. The
BCF in bluegill sunfish was found to be 8 after 16 days (Barrows et al., 1980). A
bioconcentration factor of 2.0 is predicted for fathead minnows (ASTER, 1995). These BCF
values are in agreement with those estimated by regression analysis using Kow. The estimated
values are between 21 and 36 (Veith et al., 1980).
3.4 Summary
1,1,2,2-Tetrachloroethane once was used to produce various chlorinated chemicals;
however, its production for this purpose has declined. Other uses included cleaning/degreasing
solvent for metals, paint remover, varnishes and lacquers, photographic film, and fats /oils
extractant. It now is found primarily as an intermediate during the manufacture of some
chlorinated chemicals and is no longer produced commercially in the United States. The TRI
data on releases to the environment confirm the decline in production and use during the past
decade.
1,1,2,2-Tetrachloroethane is found in the troposphere where it is stable. At higher
atmospheric levels, it can be photodegraded releasing chlorine radicals. Its half-life in the
tropospheric atmosphere has been estimated to be between 53 days to >2 years. The chlorine
radicals that are formed by photodegradation may react with ozone leading to its depletion.
1,1,2,2-Tetrachloroethane — January, 2008 3-5
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Due to its moderate vapor pressure, 1,1,2,2-tetrachloroethane in surface water is expected
to volatilize to the atmosphere. The volatilization half-life is estimated to be about 6.3 hours.
1,1,2,2-Tetrachloroethane can hydrolyze in water (25°C, pH=7.0). Its half-life in water is
pH-dependent. In experimental studies with solutions that had ionic strengths similar to
groundwater, 1,1,2,2-tetrachloroethane's half-life was between 36 and 573 days at pH levels
between 6.05 and 7.01. When incubated under anaerobic conditions in the presence of a culture
of primarily anaerobic microorganisms, the products formed included 1,1,2-trichloroethane,
trichloroethene, c/5-l,2-dichloroethene, ^rami-l,2-dichloroethene, 1,1-dichloroethene, and vinyl
chloride. Aerobic biodegradability test results are conflicting, and range from none to 41%
degradation with various concentrations of 1,1,2,2-tetrachloroethane, and the presence or
absence of acclimated microbes. Most 1,1,2,2-tetrachloroethane loss associated with sewage
treatment is attributable to air-stripping processes and not biodegradation.
1,1,2,2-Tetrachloroethane is not expected to bioconcentrate in fish and, subsequently, to
higher life forms. BCFs, when estimated, range between 2 and 36; when measured in bluegill
sunfish, the BCF was 8.
1,1,2,2-Tetrachloroethane — January, 2008 3-6
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4.0 EXPOSURE FROM DRINKING WATER
4.1 Introduction
EPA used data from several sources to evaluate the potential for occurrence of 1,1,2,2-
tetrachloroethane in Public Water Systems (PWSs). The primary source of drinking water
occurrence data for 1,1,2,2-tetrachloroethane was the Unregulated Contaminant Monitoring
(UCM) program. The Agency also evaluated ambient water quality data from the United States
Geological Survey (USGS).
4.2 Ambient Occurrence
4.2.1 Data Sources and Methods
USGS instituted the National Water Quality Assessment (NAWQA) program in 1991 to
examine ambient water quality status and trends in the United States. NAWQA is designed to
apply nationally consistent methods to provide a consistent basis for comparisons among study
basins across the country and over time. These occurrence assessments serve to facilitate
interpretation of natural and anthropogenic factors affecting national water quality. For more
detailed information on the NAWQA program design and implementation, please refer to Leahy
and Thompson (1994) and Hamilton and colleagues (2004).
Study Unit Monitoring
The NAWQA program conducts monitoring and water quality assessments in significant
watersheds and aquifers referred to as "study units." NAWQA's sampling approach is not
"statistically" designed (i.e., it does not involve random sampling), but it provides a
representative view of the nation's waters in its coverage and scope. Together, the 51 study units
monitored between 1991 and 2001 include the aquifers and watersheds that supply more than
60% of the nation's drinking water and water used for agriculture and industry (NRC, 2002).
NAWQA monitors the occurrence of chemicals such as pesticides, nutrients, volatile organic
compounds (VOCs), trace elements, and radionuclides, and the condition of aquatic habitats and
fish, insects, and algal communities (Hamilton et al., 2004).
Monitoring of study units occurs in stages. Between 1991 and 2001, approximately one-
third of the study units at a time were studied intensively for a period of three to five years,
alternating with a period of less intensive research and monitoring that lasted between five and
seven years. Thus, all participating study units rotated through intensive assessment in a ten-
year cycle (Leahy and Thompson, 1994). The first ten-year cycle was called "Cycle 1."
Summary reports are available for the 51 study units that underwent intensive monitoring in
Cycle 1 (USGS, 2001). Cycle 2 monitoring is scheduled to proceed in 42 study units from 2002
to 2012 (Hamilton et al., 2004).
1,1,2,2-Tetrachloroethane — January, 2008 4-1
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VOC National Synthesis
Through a series of National Synthesis efforts, the USGS NAWQA program is preparing
comprehensive analyses of data on topics of particular concern. These data are aggregated from
the individual study units and other sources to provide a national overview.
The VOC National Synthesis began in 1994. The most comprehensive VOC National
Synthesis reports to date are one random survey and one focused survey funded by the American
Water Works Association Research Foundation (AwwaRF) and carried out by USGS in
collaboration with the Metropolitan Water District of Southern California and the Oregon Health
& Science University. The random survey (Grady, 2003) targeted surface and ground waters
used as source water by community water systems (CWSs). Samples were taken from the source
waters of 954 CWSs in 1999 and 2000. The random survey was designed to be nationally
representative of CWS source water. In the focused survey (Delzer and Ivahnenko, 2003), 134
CWS source waters were monitored for VOCs between 1999 and 2001. These surface and
ground waters were chosen because they were suspected or known to contain methyl tertiary-
butyl ether (MTBE). The focused survey was designed to provide insight into temporal
variability and anthropogenic factors associated with VOC occurrence. Details of the
monitoring plan for these two studies are provided by Ivahnenko and colleagues (2001).
Additional products of the VOC National Synthesis include a compilation of historical
VOC monitoring data from multiple studies (Squillace et al., 1999). The data, collected from
2948 wells between 1985 and 1995 by local, state, and federal agencies, were reviewed to ensure
they met data quality criteria. Most of the data were from early study unit monitoring. The
samples represent both urban and rural areas, and both drinking water and non-drinking water
wells. A full analysis of 10 years of study unit monitoring data has not yet been performed by
the VOC National Synthesis.
4.2.2 Results
Random and Focused VOC Surveys
The national random survey and focused survey both found no detections of 1,1,2,2-
tetrachloroethane at the reporting level of 0.2 |ig/L (Grady, 2003; Delzer and Ivahnenko, 2003).
In addition, the focused survey provided results for 1,1,2,2-tetrachloroethane below the reporting
level. At levels as low as the method detection limit (0.26 |ig/L), no detections of 1,1,2,2-
tetrachloroethane were found (Delzer and Ivahnenko, 2003).
Compilation of Historical VOC Monitoring Data
Multiple investigators collected 1,1,2,2-tetrachloroethane samples from 204 urban wells
and 1267 rural wells. At a reporting level of 0.2 |ig/L, there were no detections of 1,1,2,2-
tetrachloroethane (Squillace et al., 1999).
1,1,2,2-Tetrachloroethane — January, 2008 4-2
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4.3 Drinking Water Occurrences
4.3.1 Data Sources and Methods
In 1987, EPA initiated the UCM program to fulfill a 1986 SDWA Amendment that
required monitoring of specified unregulated contaminants to gather information on their
occurrence in drinking water for future regulatory decision-making purposes. EPA implemented
the UCM program in two phases or rounds. The first round of UCM monitoring generally
extended from 1988 to 1992 and is referred to as UCM Round 1 monitoring. The second round
of UCM monitoring generally extended from 1993 to 1997 and is referred to as UCM Round 2
monitoring.
UCM Round 1 monitored for 34 volatile organic compounds (VOCs), including 1,1,2,2-
tetrachloroethane (52 FR 25720, July 8, 1987). UCM Round 2 monitored for the same 34
VOCs, plus 13 synthetic organic compounds (SOCs) and sulfate (57 FR 31776, July 17, 1992).
The UCM Round 1 database contains contaminant occurrence data from 38 States, Washington,
DC, and the U.S. Virgin Islands. The UCM Round 2 database contains data from 34 States and
several Tribes. Due to incomplete State data sets, national occurrence estimates based on raw
(unedited) UCM Round 1 or Round 2 data could be skewed to low-occurrence or
high-occurrence settings (e.g., some States only reported detections). To address potential biases
in the data1, EPA developed national cross-sections from the UCM Round 1 and Round 2 State
data using an approach similar to that used for EPA's 1999 Chemical Monitoring Reform
(CMR), the first Six Year Review, and the first CCL Regulatory Determinations. This national
cross-section approach was developed to support occurrence analyses and was supported by
scientific peer reviewers and stakeholders. Because UCM Round 1 and Round 2 data represent
different time periods and include occurrence data from different States, EPA developed separate
national cross-sections for each data set.
The UCM Round 1 national cross-section consists of data from 24 States, with
approximately 3.3 million total analytical data points from approximately 22,000 unique PWSs.
The UCM Round 2 national cross-section consists of data from 20 States, with approximately
3.7 million analytical data points from slightly more than 27,000 unique PWSs. The two
national cross-sections represent significantly large samples of national occurrence data. Within
each cross-section, the number of systems and analytical records for each contaminant varies.
EPA constructed the national cross-sections in a way that provides a balance and range of States
with varying pollution potential indicators, a wide range of the geologic and hydrologic
conditions, and a very large sample of monitoring data points. While EPA recognizes that some
limitations exist, the Agency believes that the national cross-sections provide a reasonable
estimate of the overall distribution and the central tendency of contaminant occurrence. See
Figure 4-1 for a listing of States in each national cross-section. Further details on the UCM
program and the construction of cross-sections can be found in other documents (U.S. EPA,
2000e).
1 The potential biases in the raw UCM data are due to lack of representativeness (since not all States
provided UCM data) and incompleteness (since some States that provided data had incomplete data sets).
1,1,2,2-Tetrachloroethane — January, 2008 4-3
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Figure 4-1 Cross-section States for Round 1 (24 States) and Round 2 (20 States)
Round 1
Alabama
Alaska*
Arizona
California
Florida
Georgia
Hawaii
Illinois
Indiana
Iowa
Kentucky*
Maryland*
Minnesota*
Montana
New Jersey
New Mexico*
North Carolina*
Ohio*
South Dakota
Tennessee
Utah
Washington*
West Virginia
Wyoming
Round 2
Alaska*
Arkansas
Colorado
Kentucky*
Maine
Maryland*
Massachusetts
Michigan
Minnesota*
Missouri
New Hampshire
New Mexico*
North Carolina*
North Dakota
Ohio*
Oklahoma
Oregon
Rhode Island
Texas
Washington*
* Cross-section state in both Round 1 and Round 2
4.3.2 Derivation of the Health Reference Value
To evaluate the systems and populations exposed to 1,1,2,2-tetrachloroethane through
PWSs, the monitoring data were analyzed against the Minimum Reporting Level (MRL) and a
benchmark value for health that is termed the Health Reference Level (HRL). Two different
approaches were used to derive the HRL, one for chemicals that cause cancer and exhibit a linear
response to dose and the other applies to noncarcinogens and carcinogens evaluated using a non-
linear approach.
For those contaminants considered to be likely or probable human carcinogens, EPA
evaluated data on the mode of action of the chemical to determine the method of low dose
extrapolation. When the mode of action analysis indicated that a linear low dose extrapolation
was needed or when data on the mode of action were lacking, a default low dose linear
extrapolation was used to calculate the risk-specific dose equivalent to a one cancer in a million
1,1,2,2-Tetrachloroethane —January, 2008
4-4
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(10"6) risk. The risk-specific dose was combined with adult body weight and drinking water
consumption data to estimate the drinking water concentration equivalent to a one-in-a-million
(10"6) cancer risk and this value was used as the HRL for likely or probable carcinogens.
For those chemicals not considered to be carcinogenic to humans, EPA generally
calculates a reference dose (RfD). An RfD is an estimate (with uncertainty spanning perhaps an
order of magnitude) of a daily oral exposure to the human population (including sensitive
subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.
The RfD can be derived from either a "no observed adverse effect level" (NOAEL), a "lowest
observed adverse effect level" (LOAEL), or a benchmark dose, with uncertainty factors applied
to reflect limitations of the data used. EPA derived the HRLs for noncarcinogens using the RfD
approach as follows:
HRL = [(RfD x BW)/DWI] x RSC
Where:
RfD = Reference Dose
BW = Body Weight for an adult, assumed to be 70 kilograms (kg)
DWI = Drinking Water Intake, assumed to be 2 L/day (90th percentile)
RSC = Relative Source Contribution, or the level of exposure believed to result from
drinking water when compared to other sources (e.g., food, ambient air). In all
cases a 20 percent RSC is used for HRL derivation because it is the lowest and
most conservative RSC used in the derivation of an MCLG for drinking water.
In the case of 1,1,2,2-tetrachloroethane, the HRL is based on the concentration in
drinking water equivalent to a one-in-a million risk (10"6) of cancer above back ground
calculated as follows:
Concentration at 10"6 Risk = (Risk x Body Weight)/(Slope Factor x Drinking Water Intake)
= (0.000001 x 70 kg)/(0.085 (mg/kg/day)'1 x 2 L/day)
= 4.12 x 10"4 mg/L (0.4 |ig/L rounded to one significant figure)
The cancer assessment for 1,1,2,2-tetrachloroethane is found in section 8.2 of this document.
4.3.3 Results
Tables 4-1 and 4-2 show the results from the Round 1 and Round 2 cross-sections.
Results from all states, including those with incomplete and less reliable data, are also presented
for the sake of comparison. Results are analyzed at the level of simple detections (at or above the
minimum reporting level, or >MRL), exceedances of the health reference level (>HRL or >0.4
|ig/L), and exceedances of one half the value of the HRL (>/^HRL or >0.2 |ig/L). MRLs for
1,1,2,2-Tetrachloroethane — January, 2008 4-5
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1,1,2,2-tetrachloroethane were not uniform. They varied from 0.01 |ig/L to 10 |ig/L in the first
round, and from 0.01 |ig/L to 2.5 |ig/L in the second round. The modal (most common) MRL in
both rounds was 0.5 |ig/L. Because the MRL was often higher than the HRL and /^HRL, it is
likely that the sampling failed to capture some HRL and ^HRL exceedances at the participating
systems, and that the HRL and ^HRL analyses underestimate actual 1,1,2,2-tetrachloroethane
occurrence.
In Round 1 cross-section states, 1,1,2,2-tetrachloroethane was detected at approximately
0.45% of PWSs, affecting 1.86% of the population served, equivalent to approximately 4.0
million people nationally. Exceedances of one-half the value of the HRL were found at 0.22%
of PWSs, affecting 1.69% of the population served, equivalent to approximately 3.6 million
people nationally. HRL exceedances were found at 0.20% of PWSs, affecting 1.63% of the
population served, equivalent to approximately 3.5 million people nationally.
When all Round 1 results are included in the analysis, including results from states with
incomplete or less reliable data, 1,1,2,2-tetrachloroethane detection frequencies appear to be
slightly higher than the cross-section data indicate. Detections affect 0.48% of PWSs and 2.16%
of the population served; exceedances of the /^HRL benchmark affect 0.26% of PWSs and
1.99% of the population served; and HRL exceedances affect 0.24% of PWSs and 1.90% of the
population served.
In Round 2 cross-section states, 1,1,2,2-tetrachloroethane was detected at 0.08% of
PWSs, affecting 2.61% of the population served, equivalent to approximately 5.6 million people
nationally. The ^HRL benchmark was exceeded in 0.07% of PWSs (18 of 24,800), affecting
0.51% of the population served, equivalent to approximately 1.1 million people nationally. The
HRL benchmark was exceeded in 0.07% of PWSs (17 of 24,800 - one fewer than the ^HRL
benchmark), affecting 0.08% of the population served, equivalent to approximately 0.2 million
people nationally. Round 2 generally shows lower occurrence of 1,1,2,2-tetrachloroethane than
Round 1. One apparently contradictory indicator, the strikingly high proportion of the
population served by PWSs with detections in Round 2, is due to the unusually large size of one
of the relatively few contaminated surface water systems.
Including Round 2 results from all reporting states in the analysis does not substanially
change the picture of 1,1,2,2-tetrachloroethane occurrence. Detections affect 0.08% of PWSs
and 2.23% of the population served; ^HRL exceedances affect 0.07% of PWSs and 0.44% of the
population served; and HRL exceedances affect 0.06% of PWSs and 0.08% of the population
served.
1,1,2,2-Tetrachloroethane — January, 2008 4-6
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Table 4-1 Summary UCM Occurrence Statistics for 1,1^2,2-Tetrachloroethane (Round 1)
Frequency Factors
Total Number of Samples
Percent of Samples with Detections
99th Percentile Concentration (all samples)
Health Reference Level (HRL)
Minimum Reporting Level (MRL) - Range
- (modal value)
Maximum Concentration of Detections
99 Percentile Concentration of Detections
Median Concentration of Detections
Total Number of PWSs
Number of GW PWSs
Number of SW PWSs
Total Population
Population of GW PWSs
Population of SW PWSs
Occurrence by System
PWSs with detections (> MRL)
Range across States
GW PWSs with detections
SW PWSs with detections
PWSs > 1/2 HRL
Range across States
GW PWSs > 1/2 HRL
SW PWSs > 1/2 HRL
PWSs > HRL
Range across States
GW PWSs > HRL
SW PWSs > HRL
Occurrence by Population Served
Population served by PWSs with detections
Range across States
Pop. Served by GW PWSs with detections
Pop. Served by SW PWSs with detections
Population served by PWSs > 1/2 HRL
Range across States
Pop. Served by GW PWSs > 1/2 HRL
Pop. Served by SW PWSs > 1/2 HRL
Population served by PWSs > HRL
Range across States
Pop. Served by GW PWSs > HRL
Pop. Served by SW PWSs > HRL
24 State
Cross-Section
67,688
0.16%
ViHRL, and PWSs >HRL= percentages of PWS with at least one sampling result greater
than or equal to the MRL, exceeding the !/iHRL benchmark, or exceeding the HRL benchmark; Percentages of Population Served by PWSs with Detections, by PWSs > !/iHRL, and by PWSs
>HRL = percentages of the population served by PWSs with at least one sampling result greater than or equal to the MRL, exceeding the !/iHRL benchmark, or exceeding the HRL benchmark.
Notes:
-Only results at or above the MRL were reported as detections. Concentrations below the MRL are considered non-detects.
-Because some systems were counted as both ground water and surface water systems and others could not be classified, GW and SW figures might not add up to totals.
-Due to differences between the ratios of GW and SW systems with monitoring results and the national ratio, extrapolated GW and SW figures might not add up to extrapolated totals..
1,1,2,2-Tetrachloroethane —January, 2008
4-7
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Table 4-2 Summary UCM Occurrence Statistics for 1,1^2,2-Tetrachloroethane (Round 2)
Frequency Factors
Total Number of Samples
Percent of Samples with Detections
99 Percentile Concentration (all samples)
Health Reference Level (HRL)
Minimum Reporting Level (MRL) - Range
- (modal value)
Maximum Concentration of Detections
99 Percentile Concentration of Detections
Median Concentration of Detections
Total Number of PWSs
Number of GW PWSs
Number of SW PWSs
Total Population
Population of GW PWSs
Population of S W PWSs
Occurrence by System
PWSs with detections (> MRL)
Range across States
GW PWSs with detections
SW PWSs with detections
PWSs > 1/2 HRL
Range across States
GW PWSs > 1/2 HRL
SW PWSs > 1/2 HRL
PWSs > HRL
Range across States
GW PWSs > HRL
SW PWSs > HRL
Occurrence by Population Served
Population served by PWSs with detections
Range across States
Pop. Served by GW PWSs with detections
Pop. Served by SW PWSs with detections
Population served by PWSs > 1/2 HRL
Range across States
Pop. Served by GW PWSs > 1/2 HRL
Pop. Served by SW PWSs > 1/2 HRL
Population served by PWSs > HRL
Range across States
Pop. Served by GW PWSs > HRL
Pop. Served by SW PWSs > HRL
20 State
Cross- Section1
98,911
0.02%
'/zHRL, and PWSs >HRL= percentages of PWS with at least one sampling result greater
than or equal to the MRL, exceeding the '/zHRL benchmark, or exceeding the HRL benchmark; Percentages of Population Served by PWSs with Detections, by PWSs > '/zHRL, and by PWSs
>HRL = percentages of the population served by PWSs with at least one sampling result greater than or equal to the MRL, exceeding the '/4HRL benchmark, or exceeding the HRL benchmark.
Notes:
-Only results at or above the MRL were reported as detections. Concentrations below the MRL are considered non-detects.
-Due to differences between the ratios of GW and SW systems with monitoring results and the national ratio, extrapolated GW and SW figures might not add up to extrapolated totals.
1,1,2,2-Tetrachloroethane —January, 2008
4-8
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Regional Patterns
Each of the following maps focuses on a somewhat different aspect of the geographical
distribution of 1,1,2,2-tetrachloroethane occurrence. Figure 4-2 identifies all states with at least
one PWS with a detection of 1,1,2,2-tetrachloroethane in Round 1 or Round 2. All states are
included in this analysis, including both cross-section states with reliable data and non-cross-
section states with less reliable data, in order to provide the broadest assessment of possible
1,1,2,2-tetrachloroethane occurrence. Figure 4-3 presents the same information (identifying
states with detections, regardless of whether they were included in the cross-sections) separately
for Round 1 (1988-1992) and Round 2 (1993-1999), to reveal temporal trends.
Figure 4-4 illustrates the geographic distribution of states with different detection
frequencies (percentage of PWSs with at least one detection), and Figure 4-5 illustrates the
geographic distribution of different HRL exceedance frequencies (percentage of PWSs with at
least one HRL exceedance). Only cross-section states, which have the most complete and reliable
occurrence data, are included in these two analyses. In each figure, Round 1 data are presented in
the upper map and Round 2 data are presented in the lower map to reveal temporal trends.
In each map, two color categories represent states with no data. Those in white do not
belong to the relevant Round or cross-section, and those in the lightest category of shading were
included in the Round or cross-section but have no data for 1,1,2,2-tetrachloroethane. The darker
shades are used to differentiate occurrence findings in states with 1,1,2,2-tetrachloroethane data.
The number of Northeastern, Mid-Atlantic, Great Lakes, and Southwestern states,
reporting at least one detection, especially in Round 1, suggests a possible regional pattern to the
environmental release. However, states with detections are distributed from the east to the west
coast, and from the Canadian to the Mexican borders. Even the states with the highest proportion
of PWSs with detections are generally distributed across the United States.
1,1,2,2-Tetrachloroethane — January, 2008 4-9
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Figure 4-2 Geographic Distribution of l,l?2,2-Tetrachloroethane Detections in Both Cross-
Section and Non-Cross-Section States (Combined UCM Rounds 1 and 2)
States Not in Round 1 or 2
States with No Data for Contaminant
States with No Detections
States with Detections
1,1,2,2-Tetrachloroethane —January, 2008
4-10
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Figure 4-3 Geographic Distribution of l,l?2,2-Tetrachloroethane Detections in Both
Cross-Section and Non-Cross-Section States (Above: UCM Round 1; Below:
UCM Round 2)
Q States Not in Round 1
I I States with No Data for Contaminant
I I States with No Detections
11 States with Detections
HI
I I States Not in Round 2
I I States with No Data for Contaminant
I I States with No Detections
• States with Detections
1,1,2,2-Tetrachloroethane —January, 2008
4-11
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Figure 4-4 Geographic Distribution of 1,1^2,2-Tetrachloroethane Detection Frequencies
in Cross-Section States (Above: UCM Round 1; Below: UCM Round 2)
NY
1H* p R.I. U
CONN. Q
__,-/ > ! NJ. F
-TPWD0N .
^-•s^f^n DEL n
> J
/'-'—^^^^B, I MI). |
I I States Not in Round 2 Cross-section
I I States with No Data for Contaminant
O States with No Detections (> MRL)
DU States with 0.01 - 0.49% PWSs > MRL
I States with 0.50 - 4.14% PWSs > MRL
I • States with 4.15 - 11.64% PWSs > MRL
1,1,2,2-Tetrachloroethane —January, 2008
4-12
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Figure 4-5 Geographic Distribution of 1,1^2,2-Tetrachloroethane HRL Exceedance
Frequencies in Cross-Section States (Above: UCM Round 1; Below: UCM
Round 2)
I I States Not in Round 1 Cross-section
I | States with No Data for Contaminant
I 1 States with No HRL Exceedances
• States with 0.01 - 0.64% PWSs > HRL
H States with 0.65 - 2.76% PWSs > HRL
I I States Not in Round 2 Cross-section
I j States with No Data for Contaminant
I I States with No HRL Exceedances
• States with 0.01 - 0.64% PWSs > HRL
• States with 0.65 - 2.76% PWSs > HRL
1,1,2,2-Tetrachloroethane —January, 2008
4-13
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Temporal Patterns
Eight states (Alaska, Kentucky, Maryland, Minnesota, New Mexico, North Carolina,
Ohio, and Washington) contributed 1,1,2,2-tetrachloroethane data to both the Round 1 and Round
2 cross-sections. While these states are not necessarily nationally representative, they enable a
preliminary assessment of temporal trends in 1,1,2,2-tetrachloroethane occurrence. Figures 4-6
and 4-7 suggest that detections in those states were most common in 1988-1990, and again in
1994. HRL exceedances were also most common in 1988 and 1994. Only three of the eight
states had detections in both Rounds, and only one state (Ohio) had HRL exceedances in both
Rounds.
Figure 4-6 Annual Frequency of 1,1,2,2-Tetrachloroethane Detections (above) and HRL
Exceedances (below), 1985-1997, in Select Cross-Section States
Percent PWSs > MRL
r-i
1985 1986 1987 198
r^
n
n
-
n n
8 1989 1990 1991 1992 1992 1993 1994 1995 1996 1997
DRoundl lRound2
1,1,2,2-Tetrachloroethane —January, 2008
4-14
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0.23% "
Percent PWSs>HRL
1985 1986 1987
-
n
n
PI
1988 1989 1990 1991 1992 1992 1993 1994 1995 1996 1997
D Round 1 • Round 2
Notes: Data are from AK, KY, MD, MN, NC, NM, OH, and WA. (These eight states are the only states in both
the Round 1 cross-section and the Round 2 cross-section.) Both Round 1 and Round 2 have data for 1992;
1992 results from each Round are presented separately. The HRL for 1,1,2,2-tetrachloroethane is 0.4 jug/L.
1,1,2,2-Tetrachloroethane —January, 2008
4-15
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Figure 4-7 Distribution of l,l?2,2-Tetrachloroethane Detections (above) and HRL
Exceedances (below) Among Select Cross-Section States
AK
Percent PWSs > MRL
KY
MD
MN
NC
NM
OH
WA
D Round 1 • Round 2
.60%
.jUyo
U.4Uyo
0.30%
.2(J/o
.10%
.UUyo
Percent PWSs > HRL
n
i j
AK KY MD MN NC NM OH WA
D Round 1 • Round 2
Notes: These eight states are the only states in both the Round 1 cross-section and the Round 2 cross-section.
The HRL for 1,1,2,2-tetrachloroethane is 0.4 jug/L.
1,1,2,2-Tetrachloroethane —January, 2008
4-16
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4.4 Summary
The available data for the occurrence of 1,1,2,2-tetrachloroethane in drinking water are
consistent with the decrease in production and use within the United States over the past three
decades. Between Round 1 (1987-1992) and Round 2 (1992-1997) of drinking water monitoring,
the 99th percentile concentration for detections for all reporting states declined from 112 |ig/L to 2
|ig/L and the percent of systems with detections declined from 0.45% to 0.08%. The Round 2
monitoring is likely to be more reflective of current conditions based on the release data presented
in Chapter 3 and the lower upper limit on the method detection capabilities. During Round 2,
2.61% of the population of the cross-section states was exposed to 1,1,2,2-tetrachloroethane at
least once during the monitoring period. The exposed population served by surface water systems
was far larger than that served by ground water systems (4.06% vs. 0.09%, respectively, for the
cross-section states. When looking at the systems with detections in Round 2 monitoring, the
numbers also decline compared to Round 1 although the total population exposed increased. The
increase in the exposed population can be explained by one particularly large surface water
system, serving 1.5 million people, that had a detection above the MRL but below the /^ the HRL
and HRL benchmarks in Round 2.
The decline in the percent of PWSs with concentrations higher than the /^HRL and HRL
benchmarks between Rounds 1 and 2 suggests a decline in environmental levels of 1,1,2,2-
tetrachloroethane that correlates with the decline in releases over the same period (see Chapter 3).
However, these values may underestimate actual exposure because not all systems were able to
detect 1,1,2,2-tetrachloroethane at concentrations as low as the HRL or /^HRL. Round 2 results
are more certain than those from Round 1 since the upper bound of the range of MRLs decreased
from 10 |ig/L to 2.5 |ig/L. The cross-section states with reported exceedances of the HRL in
Round 2 were Maine, Massachusetts, Michigan, North Carolina, Ohio, Oklahoma, and Texas.
States with detections are distributed from the east to the west coast, and from the Canadian to the
Mexican borders. No national patterns are evident from ^HRL and HRL exceedances.
1,1,2,2-Tetrachloroethane — January, 2008 4-17
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1,1,2,2-Tetrachloroethane — January, 2008 4-18
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5.0 EXPOSURE FROM MEDIA OTHER THAN WATER
5.1 Exposure from Food
There was no information found in the literature reviewed concerning the exposure of
1,1,2,2-tetrachloroethane from food. It is not included in the Food and Drug Administration
(FDA) database on direct and indirect additives approved for use in the United States (U.S. FDA,
2004).
5.1.1 Concentration in Non-Fish Food Items
There was no information found in the literature reviewed concerning the concentration of
1,1,2,2-tetrachloroethane in non-fish food items.
5.1.2 Concentrations in Fish and Shellfish
There is a lack of information concerning the occurrence of 1,1,2,2-tetrachloroethane in
fish. In 1996, 1,1,2,2-tetrachloroethane was detected in tissue samples from fish at a National
Priority List (NPL) site in the Ashtabula River watershed, Ohio. An advisory was in effect for all
species offish on the lower Ashtabula River as determined from the EPA's Fish Consumption
Advisory Database (U.S. EPA, 1995b).
5.1.3 Intake of l,l?2,2-Tetrachloroethane from Food
There was no information found in the literature reviewed concerning the intake of
1,1,2,2-tetrachloroethane from food. Any exposure would be due to accidental contamination and
would likely be episodic and rare. The related compounds, tetrachloroethene and 1,1,1,2-
tetrachloroethane, were present in food samples collected and analyzed for volatile organic
compounds (VOCs) during the FDA Total Diet Study Program (Fleming-Jones and Smith, 2003;
U.S. FDA, 2003). Although tetrachloroethene was present at low levels in a wide variety of
foods, very few of the foods collected had any detectable concentrations of 1,1,1,2-
tetrachloroethane. No detection of 1,1,2,2-tetrachloroethane was reported.
5.2 Exposure from Air
1,1,2,2-Tetrachloroethane can be released into the air during the process of manufacturing
trichloroethylene or during its uses as a solvent, degreaser, intermediate, or cleaning solvent
(Verschueren, 1983). 1,1,2,2-Tetrachloroethane may be emitted from hazardous landfills
(Harkov et al., 1987). It was one of the ten most prevalent chlorinated chemicals found in solvent
wastes that were incinerated each year prior to 1980 (Travis et al., 1986).
1,1,2,2-Tetrachloroethane — January, 2008 5-1
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5.2.1 Concentration of l,l?2,2-Tetrachloroethane in Air
Much of the data on the concentrations of 1,1,2,2-tetrachloroethane present in ambient and
indoor air come from sampling programs conducted in the 1980s or earlier. 1,1,2,2-
Tetrachloroethane production in this country, and its use by the chemical industry, has declined
since the late 1980s (see Table 3-1). The decline in production and use should be considered in
evaluating the monitoring data discussed below.
Concentrations of 1,1,2,2-tetrachloroethane were detected in the troposphere at levels that
ranged between 0.1 to 0.4 parts per trillion (ppt) (Class and Ballschmiter, 1986). Data collected
in the late 1970s to early 1980s at 853 urban/suburban sites in the United States, revealed a
median concentration of 1,1,2,2-tetrachloroethane of 5.4 ppt, with values ranging from less than
detection limits to a maximum of 4800 ppt. Two rural areas sampled did not have detectable
levels of 1,1,2,2-tetrachloroethane (Brodzinsky and Singh, 1982). Shah and Heyerdahl (1988)
supplemented this database by monitoring an additional 158 sites. The total number of monitoring
sites between the two studies was 1011. The overall median levels of 1,1,2,2-tetrachloroethane
were at or below the lower detection limit; 75% of the samples showed concentrations less than or
equal to 8ppt. About 25% of the samples collected from 25 sites in Minnesota between 1991 and
1998 had detections of 1,1,2,2-tetrachloroethane. The mean, median and maximum
concentrations were 0.84, 4.2 and 962 ppt respectively. All samples collected from 13 sites in
Louisiana. New Jersey, Texas and Vermont by Mohamed et al. (2002) had concentrations of
1,1,2,2-tetrachloroethane less than 1 ppb.
Air samples from several New Jersey cities were analyzed in the summer of 1981. Levels
of 1,1,2,2-tetrachloroethane were detected in 9 of 38 samples from Newark; 1 of 37 samples from
Elizabeth; and 4 of 35 samples from Camden (Harkov et al., 1983). Additionally, it was detected
in 4 out of 105 samples from the same 3 cities in the winter of 1982 (Harkov et al., 1987). Mean
concentrations of 1,1,2,2-tetrachloroethane in major U.S. cities listed in other reports ranged from
trace levels below detection limits to 57 parts per billion (ppb) (Harkov et al., 1981, 1983; Lioy et
al., 1985; Singh etal., 1981, 1982).
Indoor levels of 1,1,2,2-tetrachloroethane were detected in air samples from eight homes
in Knoxville, Tennessee during the winter (Gupta et al., 1984). The mean concentration was 13.0
|lg/m3 (1.8 ppb) in 10/16 samples (detection limits were not reported). The source was not
investigated, but the levels may be attributed to consumer products used in the home or out
gassing of the chemical from construction materials or household furnishings.
A survey of 1159 common household products was performed by the EPA in an effort to
identify the potential for household products to pollute indoor air (Sack et al., 1992). Two-
hundred and sixteen of the products contained 1,1,2,2-tetrachloroethane. Trace amounts were
commonly found in adhesives, oils, greases, and lubricants. Concentrations in the products were
uniformly near detection limits (detection limits not reported); thus, Sack et al. (1992) concluded
that 1,1,2,2-tetrachloroethane has a low potential to pose unacceptable human exposure risks in
indoor air.
1,1,2,2-Tetrachloroethane — January, 2008 5 -2
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1,1,2,2-Tetrachloroethane was detected in air at five National Priorities List (NPL)
Superfund hazardous waste sites in New Jersey. The mean levels reported ranged from 0.01-0.59
ppb, and the maximum levels ranged from 0.17-11.38 ppb. An urban landfill receiving municipal
waste and non-hazardous industrial waste had a mean of 0.01 ppb and the maximum was 0.19 ppb
(LaRegina et al., 1986). Air samples from the Kin-But waste disposal site near Edison, New
Jersey contained up to 2.1 ppb of 1,1,2,2-tetrachloroethane. Air concentrations of 0.226 ppb of
1,1,2,2-tetrachloroethane were found in Iberville Parish, Louisiana, along the Mississippi River,
where many organic chemical production and storage facilities are located (Pellizzari, 1982).
5.2.2 Intake of l,l?2,2-Tetrachloroethane from Air
There was no information found in the literature reviewed concerning current average
levels of 1,1,2,2-tetrachloroethane in ambient or indoor air. Accordingly it is not possible to
estimate a current exposure level for the general population. In the most recent measurement of
ambient air (Shah and Heyerdahl, 1988), the median concentration measured was less than the
detection limit.
5.3 Exposure from Soil
1,1,2,2-Tetrachloroethane is released to soil when it is disposed of in landfills or from
accidental spills of products or wastes containing 1,1,2,2-tetrachloroethane. 1,1,2,2-
Tetrachloroethane released to soils and landfills may be mixed wastes; therefore, estimation of the
overall releases to the soil is limited. 1,1,2,2-Tetrachloroethane's volatility and biodegradation
suggest that it will not accumulate in the soil.
5.3.1 Concentration of l,l?2,2-Tetrachloroethane in Soil
Relatively little information was available on general background or monitoring data of
1,1,2,2-tetrachloroethane in soil. Most studies are about hazardous waste sites. An analysis of
test wells around Resources Conservation and Recovery Act (RCRA) disposal sites, determined
that 25 of 479 sites had levels above the 1,1,2,2-tetrachloroethane detection limit (Plumb, 1991). A
waste disposal site in Pennsylvania had 2.4 ppm 1,1,2,2-tetrachloroethane in soil (Sable and
Clark, 1984).
Sediment monitoring data from rivers, lakes, and other aquatic systems from the U.S.
EPA's national STORET database illustrate that less than 1% of the samples contained 1,1,2,2-
tetrachloroethane levels above the detection limit of approximately 5 |ig/kg (Staples et al., 1985).
Based on ATSDR's HazDat database (HazDat, 2006), at least 135 of 1678 current or past NPL
sites with 1,1,2,2-tetrachloroethane contamination had the chemical in its soil or sediment.
5.3.2 Intake of l,l?2,2-Tetrachloroethane from Soil
Humans are unlikely to be exposed to 1,1,2,2-tetrachloroethane through soils. Exposure
by inhalation of airborne soil particles, by ingestion of household dust, or by direct ingestion of
soil might be possible for those living near a hazardous waste site contaminated with 1,1,2,2-
tetrachloroethane. Infants and toddlers ingest soil and household dust by hand-to-mouth transfer
1,1,2,2-Tetrachloroethane — January, 2008 5-3
-------
during everyday activities. They may therefore be exposed to higher levels than adults living in
the same contaminated environment. However, in most locations 1,1,2,2-tetrachloroethane is not
likely to be present in soils. The TRI release data for land disposal (Table 3-1) show no releases
for all but three of the last ten years. There was a large reported discharge to land (941 pounds) in
2001; the other reported releases were 1 and 15 pounds.
5.4 Other Residential Exposures
1,1,2,2 tetrachloroethane can be introduced into household air from cigarette smoke. Bi et
al (2005) found that 3-6 jig tetrachloroethane/cigarette were released into the atmosphere from
smoking.
5.5 Occupational (Workplace) Exposures
The National Institute for Occupational Safely and Health (NIOSH) conducted a field
survey of 4,490 facilities to estimate the exposure of chemicals in the workplace (1981-1983).
This was a nationwide survey based on a statistical sample of virtually all workplace
environments in the United States where 8 or more persons are employed. The survey was based
on all Standard Industrial Classification (SIC) code workplace types except mining and
agriculture (Sieber et al., 1991). The National Occupational Exposure Survey (NOES) estimated
that 4,145 workers were potentially exposed to 1,1,2,2-tetrachloroethane in the United States.
They also estimated that 3666 workers were in occupations involving work in chemical research
and development laboratories, and the other exposures involved jobs in industrial chemical plants
(NIOSH, 2006). The NOES database does not contain information on the frequency,
concentration, or duration of exposure; the survey provides only estimates of the number of
workers potentially exposed to chemicals in the workplace. This survey was conducted prior to
the decrease in production and use of 1,1,2,2-tetrachloroethane in the United States.
According to the Occupational Safety and Health Administration (OSHA) (1998), the
current 8-hour time-weighted average (TWA) permissible exposure level (PEL) for 1,1,2,2-
tetrachloroethane is 5 ppm (35 mg/m3). The prior standard of 1 ppm (7 mg/m3) was abandoned,
however, it is reported that several states continue to follow this guideline (HSDB, 2004).
According to NIOSH, the recommended exposure level for a 10-hour TWA is 1 ppm (7 mg/m3)
1,1,2,2-tetrachloroethane (HSDB, 2004).
5.5.1 Description of Industries and Workplaces
The NOES estimated that workers potentially exposed to 1,1,2,2-tetrachloroethane in the
U. S. were in occupations involving work in chemical research and development laboratories and
in industrial chemical plants (NIOSH, 2006).
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5.5.2 Types of Exposure (Inhalation, Dermal, Other)
1,1,2,2-Tetrachloroethane is a volatile substance with a vapor pressure of about 6 mm Hg
at 25°C. Accordingly, most workplace exposure is likely to result from inhalation, except for
those working directly with 1,1,2,2-tetrachloroethane. Some dermal exposure could result from
direct contact, if proper industrial hygiene practices were not followed.
5.5.3 Exposure in the Work Environment
Information concerning other sources of occupational exposure to
1,1,2,2-tetrachloroethane was not found in the literature reviewed.
5.6 Summary
Exposures are possible for individuals who smoke cigarettes and those living near waste
disposal facilities where 1,1,2,2-tetrachloroethane site contamination has occurred. Higher
inhalation exposures also would occur for workers at chemical plants where 1,1,2,2-
tetrachloroethane is still produced as a chemical intermediate. Other populations with higher
exposures could include people living close to NPL or other waste sites where leachates or runoff
from contaminated soils could affect groundwater used for drinking water. Little or no 1,1,2,2-
tetrachloroethane was found in foods or ambient air.
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6.0 TOXICOKINETICS
6.1 Absorption
There are relatively few quantitative data for absorption of 1,1,2,2-tetrachloroethane by
the gastrointestinal or respiratory tracts in humans or animals. 1,1,2,2-Tetrachloroethane is a
small lipophilic molecule (log Kow = 2.39) (ATSDR, 2006) and would be able to diffuse through
the lipid matrix of cell membranes. Data from studies that administered radiolabeled compound
and measured its presence in tissue and excretory products, along with the adverse health effects
observed after exposure, demonstrate absorption for all routes of exposure.
Oral Exposure
The recovery of radioactivity in the expired air and urine from rats and mice administered
150 mg/kg oral doses of the 1,1,2,2-tetrachloroethane by gavage in corn oil was 65% to 73% for
both species after 72 hours; 4 to 6% was recovered in the feces with the remainder in the skin and
carcass (20 to 30%). This indicates that the compound is almost completely absorbed orally
(Dow, 1988). Another study showed that rats given an oral dose of 100 mg/kg of radiolabeled
1,1,2,2-tetrachloroethane by gavage metabolized approximately 80% of the dose within 48 hours
while mice given a 200 mg/kg dose metabolized approximately 70% (Mitoma et al., 1985). The
percent metabolized was determined by adding the amounts of label in expired carbon dioxide,
excreta, and that remaining in the carcass. These data are supportive of the conclusion that a
large fraction of an oral dose of 1,1,2,2-tetrachloroethane is absorbed. Since absorption is likely
to be diffusion-limited, the percent of the dose absorbed would be higher at low environmental
doses than at the higher doses used in the experimental studies.
Inhalation Exposure
A study in human volunteers was carried out in which a bulb containing 38C1-labeled
1,1,2,2-tetrachloroethane was inserted into their mouths. The volunteers immediately inhaled
deeply, held their breath for 20 seconds, and then exhaled through a trap containing granulated
charcoal. The excretion of the radiolabel in the exhaled breath, and the partition coefficients
between blood and air were measured. The study indicated that 97% of a single breath of 1,1,2,2-
tetrachloroethane was absorbed systemically (Morgan et al., 1970).
The recovery of radiolabeled 1,1,2,2-tetrachloroethane from rats and mice exposed to a
vapor concentration of 10 ppm (70 mg/m3) for 6 hours was 52 to 60% in expired air and urine and
29 to 42% in the skin and carcass. Only 5 to 6% was found in the feces indicating nearly
complete absorption (Dow, 1988).
Dermal Exposure
Up to 1 mL (1.6 mg based on a density of 1.595 at 20°C) of 1,1,2,2-tetrachloroethane
applied to the skin of mice or guinea pigs was absorbed or adsorbed within one-half hour
(Jakobson et al., 1982; Tsuruta, 1975). The application site was sealed to prevent evaporation.
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6.2 Distribution
No studies of the systemic distribution of 1,1,2,2-tetrachloroethane in humans were
identified for any exposure route. Available data from animal studies for oral and inhalation
exposures generally lacked quantitative measurements in individual tissues. There were no
distribution data in animals for the dermal route of exposure (ATSDR, 2006).
Oral Exposure
Hepatic protein-binding was seen in rats and mice administered 1,1,2,2-tetrachloroethane
by gavage for five days per week for five weeks, followed by a single dose of 14C-1,1,2,2-
tetrachloroethane (Mitoma et al., 1985). The doses in rats were 25 or 100 mg/kg, while those
given to mice were 50 and 200 mg/kg. These doses are equivalent to the maximum tolerated dose
(MTD) and one quarter of the MTD used in the National Cancer Institute (NCI, 1978) bioassays
of 1,1,2,2-tetrachloroethane. The protein binding in rats was generally comparable to that for
mice and was directly related to dose. The protein binding in rats receiving doses of 25 or 100
mg/kg was 3.31 and 12.93 nmol eq/mg purified liver protein at the low and high dose,
respectively, while the binding in mice receiving doses of 50 or 200 mg/kg was 7.22 and 25.09
nmol eq/mg, respectively. The presence of the radiolabel in protein could represent either binding
to the protein or incorporation of the radiolabeled carbon from dechlorinated 1,1,2,2-
tetrachloroethane into nonessential amino acids.
The binding of label from inhaled 1,1,2,2-tetrachloroethane to liver proteins after
inhalation exposure to 10 ppm for 6 hours was also examined (Dow, 1988). Samples of
precipitated protein were subjected to acid hydrolysis to determine if the label was bound to the
protein through a hydrolyzable bond. About 85 to 90 percent of the label was found to be
incorporated into the protein and was not removed by acid hydrolysis. This suggests
incorporation of some of the DCA metabolites (possibly glycine or serine; see Figure 3-1) into the
protein structure. The amount of label present in the proteins from mice was 1.9 times greater
than that for rats.
Mitoma et al. (1985) examined the radiolabel remaining in the carcass 48 hours after
administration of radiolabeled 1,1,2,2-tetrachloroethane. The data were only reported for the 100
mg/kg dose in rats and the 200 mg/kg dose in mice. The amount of radiolabel remaining in the
carcass was 31% for the rats and 27% for the mice.
Adverse effects were observed following oral exposures in the liver, kidney, and testes in
mice and rats indicating distribution to these tissues (NCI, 1978; NTP, 1996, 2004). No data were
identified that provided measurements of 1,1,2,2-tetrachloroethane concentrations in these or
other tissues.
Inhalation Exposure
No studies were located regarding distribution in humans or animals following inhalation
exposure to 1,1,2,2-tetrachloroethane. However, adverse effects have been observed in liver and
kidney for animals exposed via inhalation (Deguchi, 1972; Horiuchi et al., 1962; Price et al. 1978;
Schmidt et al., 1980b) demonstrating systemic distribution of inhaled 1,1,2,2-tetrachloroethane.
1,1,2,2-Tetrachloroethane — January, 2008 6-2
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Other Routes of Exposure
Three days after an intraperitoneal dose of 0.21 to 0.32 g/kg of 14C-1,1,2,2-
tetrachloroethane, a mean of 15.5% of the administered radiolabel was present in the carcass of
female albino mice (Yllner, 1971). This finding supports a possible mechanism for the retention
of the radiolabel, through binding of 1,1,2,2-tetrachloroethane metabolites to tissue
macromolecules or incorporation of the label into other compounds. The results were similar
after intravenous injection of 14C-1,1,2,2-tetrachloroethane into female C57B1 mice. Bound
radiolabel was identified by autoradiography in the olfactory and tracheobronchial mucosa, oral
cavity, nasopharynx, esophagus, forestomach, liver, biliary bladder, adrenal cortex, and testes
between 1 and 4 hours after injection (Eriksson and Brittebo, 1991).
6.3 Metabolism
When administered by the oral or inhalation routes, 1,1,2,2-tetrachloroethane appears to
be extensively metabolized although quantitative data that identify metabolites are limited. In the
72 hours after a gavage exposure to a dose of 150 mg/kg, 9.39% was recovered from expired air
as unmetabolized 1,1,2,2-tetrachloroethane in Osborne-Mendel rats and 0.68% of the dose was
recovered in B6C3F1 mice. After inhalation exposure for 6 hours to 10 ppm
l,l,2,2,tetrachloroethane, 7.73% was recovered unmetabolized from expired air in Osborne-
Mendel rats and 1.78% in B6C3F1 mice 72 hours later (Dow, 1988). Additional, unmetabolized
1,1,2,2-tetrachloroethane could have been distributed to the adipose tissues and retained in the
carcass.
The initial stages of metabolism are believed to involve cytochrome (CYP) P450, but the
specific isoforms involved have not been identified. Biotransformation reactions were increased
by chronic ethanol consumption and fasting, preconditions that are known to induce the levels of
cytochrome P-450 isoform CYP 2E1 (Johansson et al., 1988; Soucek and Gut, 1992). Sapigni et
al. (1992) found a seven-fold induction of hepatic CYP 2B1 following gavage treatment of groups
of 6 CD1 mice for 3 days with doses of 6.5%, 12%, 25%, or 50% of the LD50 in corn oil. The
degree of enhancement was not dose-related, but may indicate a role for CYP 2B1 in 1,1,2,2-
tetrachloroethane metabolism. Conversely, in vitro responses of hepatic microsomes from CD1
mice after exposure to a single dose of either 300 or 600 mg/kg 1,1,2,2-tetrachloroethane (20% or
40% of the LD50) were indicative of reduced activities for CYPs 1A1, 1A2, 2B1, 2E1, and 3A; the
CYP1 Al isoform was affected the least (-26.6%) and the CYP 3A isoform the most (-57.5%)
(Paolini et al., 1992). Eriksson and Brittebo (1991) found that metabolite binding to liver tissue
slices was decreased by about 60% when metyrapone, an inhibitor of CYP 3A4 was added to the
culture medium, but only about 15% when a-naphthoflavone a CYP 1 Al inhibitor was added to
the culture medium, implicating CYP 3A4 in the metabolic activation of 1,1,2,2-
tetrachl oroethane.
It has been hypothesized that the first step in the metabolism of 1,1,2,2-tetrachloroethane
is the loss of a chlorine generating a 1,2,2-trichloroethyl free radical. A carbon-centered radical
was detected in lipid extracts from the livers of mice treated with a single dose of 600 mg/kg
1,1,2,2-tetrachloroethane by Paolini et al. (1992). Tomasi et al. (1984) found evidence of a free
radical intermediate in rats. A free radical can combine with oxygen to form a peroxide free
1,1,2,2-Tetrachloroethane — January, 2008 6-3
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radical and subsequently react with the unsaturated bonds of membrane lipids diverting some of
the 1,1,2,2-tetrachloroethane from further catabolic reactions. Paolini et al. (1992) were able to
measure cis-trans and trans-trans diene hydroperoxide products in microsomes from animals
exposed to 300 and 600 mg/kg 1,1,2,2-tetrachloroethane. In addition, Halpert (1982) reported the
formation of dichloroacetylated protein adducts. The reactive moiety in this instance was
postulated to be dichloroacetyl chloride formed by oxidation of the free radical carbon.
Dichloroacetic acid (DCA) appears to be the major metabolite of 1,1,2,2-tetrachloroethane
(Yllner, 1971). This suggests loss of a second chlorine from carbon 1 of the parent compound
which would be consistent with a reactive acyl chloride intermediate. Dichloroacetic acid is
metabolized by cytosolic glutathione-S-transferase zeta (GSTZ) forming glyoxylate, glycolate,
and oxalate; transamination of glycolate produces glycine (U.S. EPA, 2003b). Complete
oxidation of the chlorine free intermediates produces carbon dioxide (Figure 6-1).
Among humans there are known polymorphisms in GSTZ which may account for
differences in the ability to metabolize DCA and other halogenated compounds. The GSTZ
variants are designated GSTZla-la, GSTZlb-lb, GSTZlc-lc, GSTZld-ld, and GSTZle-le
(Blackburn et al., 2000, 2001; Tzeng et al., 2000). Analysis of blood samples from 128
Caucasian, Australians of European origin showed a variant distribution of 0.086, 0.285, 0.473,
0.156 and 0 for GSTZ la-la, GSTZlb-lb, GSTZlc-lc, GSTZld-ld, and GSTZle-le,
respectively. GSTZla-la has been demonstrated to have 4-5-fold higher activity toward DCA
than the other variants. However, excluding the GSTZ le-le variant it has the lowest frequency
in the population studied by Blackburn et al. (2001). The most common variant, GSTZlc-lc, had
the highest activity toward the isomerization of maleylacetoacetate and lower activity toward
DCA as a substrate.
The most comprehensive metabolite study was conducted by Yllner (1971). Individual
female albino mice were given single doses of 210 to 320 mg/kg 14C-labeled and unlabeled
1,1,2,2-tetrachloroethane in olive oil by intraperitoneal injection. Urine, feces and exhaled air
were collected over 72 hours in three 24-hour aliquots; label recovery was almost complete.
Trapped carbon dioxide accounted for 37 to 51% of the label in the first 24-hours, 5 to 6% of the
label in the second 24 hours and 2 to 4% in the last 24-hours. Unmetabolized 1,1,2,2-
tetrachloroethane and other volatile chlorinated hydrocarbons accounted for 3 to 4% of the dose
for the first 24 hours and negligible amounts thereafter. The total 72-hour collected urine
accounted for 23 to 34% of the label with about 90% of that total excreted in the first 24 hours.
In a separate study, 24-hour urine samples were collected from mice given intraperitoneal
doses of from 160 to 320 mg/kg (Yllner, 1971). The urinary metabolites were identified by paper
chromatography. Dichloroacetic acid was the primary metabolite identified, accounting for about
27% of the labeled urinary metabolites. Trichloroethanol (10%), oxalic acid (7%), glycolic acid
(0.9%), trichloroacetic acid (4%)and urea (2%) were also found to contain the radiolabel. Almost
half of the urinary activity was not identified.
1,1,2,2-Tetrachloroethane — January, 2008 6-4
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Figure 6-1 Postulated Metabolism of l,l?2,2-Tetrachloroethane
Cl Cl
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Cl Cl
1.1,12-TetracMDroethaiue
Cl Cl
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Cl Cl
lipid peroxidatiDn^
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i 1 •
~*f |
Cl OH
1, 1,2,2- TetTicMoroethyl radical
1. l,--TQcMoiuetliylpeiDxy radical
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Dichloraacelyl clitoride
CQ.+NH4+
THF
The authors hypothesized that much of the residual label in the carcass after 72 hours
represented glycine formed as a metabolite of DC A. Accordingly, three mice were given
intraperitoneal doses of 1,1,2,2-tetrachloroethane (200-310 mg/kg; 35.8 -52.1 jimol) and 156
jimol sodium benzoate. The reaction of glycine with benzoate produces hippuric acid which is
excreted in urine. Under these conditions about 50% of the 1,1,2,2-tetrachloroethane dose was
present in the urine after 24 hours as opposed to about the 23% to 34% excreted in the absence of
1,1,2,2-Tetrachloroethane —January, 2008
6-5
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benzoate. The authors estimated that 20 to 23% of the 1,1,2,2-tetrachloroethane had been
converted to glycine. Some of the glycine derived from DC A may become incorporated into
proteins as glycine or serine (See Figure 6-1).
Studies by Dow (1988) found only a slight decrease in hepatic level of non-protein
sulfhydryl groups in B6C3F1 mice in the 12-hour period after oral exposure to a dose of 500
mg/kg 1,1,2,2-tetrachloroethane. The reduction in sulfhydryl groups was 10 to 15% in the first
hour after dosing and returned to a level the same or slightly higher than that observed in controls.
Eriksson and Brittebo (1991) demonstrated that radiolabeled 1,1,2,2-tetrachloroethane is
metabolized in mice by cytochrome P-450 to products that bind to the epithelium of the
respiratory and upper alimentary tracts following intravenous administration (3 mg/kg) to mice.
High levels of radiolabel were also identified in the liver and gallbladder. The bound metabolites
and the modified membrane constituents (phospholipids or proteins) were not identified in the
study. However, there was a dose-related decrease in hepatic binding in tissue slices when
glutathione was added to the medium. This is consistent with the dichloroacetic acid route of
metabolism, since this pathway requires glutathione. It is also consistent with the formation a
peroxide free radical since reduced glutathione participates in free radical detoxification.
Small quantities of trichloroethanol and trichloroacetic acid have been identified as
1,1,2,2-tetrachloroethane metabolites (Ikeda and Ohtsuji, 1972; Mitoma et al., 1985; Yllner,
1971). Production of a trisubstituted number 2 carbon in trichloroacetic acid from the
disubstituted carbons of 1,1,2,2-tetrachloroethane would require rearrangement of the chlorine
substituents during metabolism. Yllner (1971) found that an aqueous solution of 1,1,2,2-
tetrachloroethane at pH=7 when heated to body temperature (37°C) in sealed ampules was
dehydrohalogenated to form trichloroethylene (12%) over a 24-hour period. Hydration of
trichloroethylene to form trichloroethanol followed by oxidation could account for the presence of
both trichloroethylene and trichloroacetic acid in urine after exposure to 1,1,2,2-
tetrachloroethane.
An alternate source of trichloroethanol and trichloroacetic acid in urine after exposure to
1,1,2,2-tetrachloroethane would be the presence of its isomer, 1,1,1,2-tetrachloroethane, as an
impurity in the 1,1,2,2-tetrachloroethane used for dosing. The purity of commercially available
1,1,2,2-tetrachloroethane ranges from 97 to 99.5% (Aldrich Handbook, 1994). The analysis of
the 1,1,2,2-tetrachloroethane used in the NTP study (2004) by gas chromatography found one
major impurity and four minor unidentified impurities even though the sample was reported to be
99% 1,1,2,2- tetrachloroethane. The presence of 1,1,1,2-tetrachloroethane as an impurity in the
dosed material could account for some of the trichloroacetic acid in the urine.
Unfortunately there is no study of 1,1,2,2-tetrachloroethane that examined metabolism
after repeated dosing. Based on the single dose study of metabolism conducted by Yllner (1971)
and supported by studies that looked at respiratory elimination of unmetabolized
tetrachloroethane and labeled carbon dioxide, it can be concluded that, in a naive mouse, there is
complete metabolism of about 50 to 60% of the dose to carbon dioxide, DC A and its intermediary
metabolites (glycine, glyoxylic acid and oxalate) account for 25 to 30%. Small amounts 1-2% are
1,1,2,2-Tetrachloroethane — January, 2008 6-6
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exhaled as unmetabolized 1,1,2,2-tetrachloroethane. A small fraction of the dose and may be
slowly converted to trichloroethylene through spontaneous dehydrohalogenation and be further
metabolized to trichloroethanol and trichloroacetic acid. Some unmetabolized parent compound
may partition to adipose tissues and some may become bound to macromolecules as a result of
free radical reactions. Rats exhaled a larger portion (10%) of the dose as unmetabolized 1,1,2,2-
tetrachloroethane than mice (Dow, 1988).
Based on studies of DC A, the amounts of DC A that does not become metabolized should
increase as the dose and/or duration of exposure increases because of GSTZ inhibition (U.S. EPA
2003b). The amount of unmetabolized parent compound is small in a naive animal but may
increase as dose and duration of exposure increases.
6.3.1 Metabolic Rate Constants
Gargus and Anderson (1989) used the level of exhaled 1,1,2,2-tetrachloroethane from rats
in conjunction with a physiologically-based pharmacokinetic (PBPK) model to determine
metabolic kinetic constants for inhalation exposure. Two rats were exposed to 350 ppm (2243
mg/m3) 1,1,2,2-tetrachloroethane in an inhalation chamber for 6 hours. The animals were then
placed in a special chamber where the exhaled air was collected over an 18-hour period and the
1,1,2,2-tetrachloroethane concentration measured. The levels of 1,1,2,2-tetrachloroethane in
exhaled air were fit using a PBPK model which had been developed from rat blood:air,
liverblood, muscle:blood, and fatblood partition coefficients.
The PBPK model was fit to the data on the concentrations in exhaled air to determine the
Michaelis-Menton constant (Km) and maximum velocity (Vmax) for the metabolism of 1,1,2,2-
tetrachloroethane. A portion of the 1,1,2,2-tetrachloroethane in the exposure chamber adhered
onto the fur, causing an initial spike in measured post-exposure chamber air concentrations when
it was released that could not be predicted by the model. This effect disappeared after 3 hours.
The optimized metabolic rate (Vmax) for 1,1,2,2-tetrachloroethane was estimated as 12.9
mg/kg/hour and the Km was 0.8 mg/L. The Vmax was higher than that for other tri- through hexa-
chloroethanes studied. The reaction was classified as high affinity by the authors based on the
Km, and they concluded that hepatic metabolism would be subject to flow-limited behavior at low
concentrations as would be expected based on intrinsic hepatic clearance characteristics.
However, it is important to remember that these estimations are based on whole animal data and a
single 6-hour exposure. Thus, the model does not account for the changes that would occur when
continued exposure led to enzyme inhibition nor for the fact that there may be more than one
metabolic pathway for 1,1,2,2-tetrachloroethane.
1,1,2,2-Tetrachloroethane — January, 2008 6-7
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6.4 Excretion
No data were available regarding the excretion of 1,1,2,2-tetrachloroethane or its
metabolites from studies of human exposure for oral and dermal routes of exposure. A single
human inhalation study was identified (ATSDR, 2006), as described in the Inhalation Exposure
section below.
Oral Exposure
The excretion of 1,1,2,2-tetrachloroethane was followed for 72 hours after oral
administration of a 150-mg/kg single radiolabeled dose to rats and mice (Dow, 1988). More than
90% of the dose was metabolized or excreted unchanged in both species. In rats, 41% was
excreted in breath (9% as unmetabolized tetrachloroethane and 32% as CO2), 23% in urine, and
4% in feces. Thirty percent was retained in the skin and carcass. In mice, 51% was excreted in
breath (1% as unmetabolized tetrachloroethane and 50% as CO2), 22% in urine, and 6% in feces.
Twenty percent was retained in the skin and carcass.
Mice given an oral dose of 200 mg/kg radiolabeled 1,1,2,2-tetrachloroethane excreted
about 10% of the dose unchanged or as volatile metabolites in the breath. Ten percent of the dose
was metabolized and excreted in the breath as CO2. The amount excreted in the urine and feces,
measured together, was 30% after 48 hours. The remainder was retained in the carcass (27%)
suggesting deposition in adipose tissues or metabolism and incorporation into or binding to
biological molecules, such as proteins or lipids (Mitoma et al., 1985). When the same protocol
was applied to rats given a dose of 100 mg/kg radiolabeled compound, the exhaled 1,1,2,2-
tetrachloroethane and volatile metabolites accounted for 7% of the dose, while 46% of the dose
was found in the excreta. Only 2% was exhaled as CO2.
Inhalation Exposure
A study with human volunteers showed that 3% of inhaled chlorine-labeled 1,1,2,2-
tetrachloroethane was excreted in the breath within one hour, and that the urinary excretion rate
was 0.015% of the absorbed dose/min (Morgan et al., 1970).
The excretion of 14C-1,1,2,2-tetrachloroethane was tracked for 72 hours following
exposure of rats and mice to vapor concentrations of 10 ppm (70 mg/m3) of the radiolabeled
chemical for 6 hours (Dow, 1988). More than 90% of the absorbed dose was metabolized in both
species. The percentage of the recovered radioactivity in rats was 33% in breath (8% as
unmetabolized tetrachloroethane and 25% as CO2), 19% in urine, and 5% in feces. In mice the
amounts were 34% in breath (2% as unmetabolized tetrachloroethane and 32% as CO2), 26% in
urine, and 6% in feces.
Dermal Exposure
A study describing the elimination of 1,1,2,2-tetrachloroethane in guinea pigs
demonstrated that the half-life of the 1,1,2,2-tetrachloroethane in the blood was about two hours
following dermal absorption (Jakobson et al., 1982).
1,1,2,2-Tetrachloroethane — January, 2008 6-8
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Other Exposure Routes
Following intraperitoneal injections of doses ranging from 210 to 320 mg/kg 14C-labeled
1,1,2,2-tetrachloroethane in rats and mice, about 4% of the radioactivity was expired unchanged
in the breath after 72 hours and 50% was expired as CO2. Another 28% of the radioactivity was
excreted in the urine, 1% was in the feces, and 16% remained in the carcass (Yllner, 1971).
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7.0 HAZARD IDENTIFICATION
7.1 Human Effects
7.1.1 Short-Term Studies and Case Reports
Intentional and Accidental Acute Ingestion
There are several case study reports of individuals who committed suicide by ingesting
1,1,2,2-tetrachloroethane. The amount consumed varied among individuals, making a lethal dose
difficult to determine. The approximate lethal doses were estimated to be 4100 mg/kg (Hepple,
1927), 357 mg/kg (Lilliman, 1949), 1100 to 9600 mg/kg (Mant, 1953). Death following suicidal
ingestion of 1,1,2,2-tetrachloroethane generally occurred within 3 to 20 hours. The presence of
food in the gastrointestinal tract appeared to increase the time to death. Subjects usually lost
consciousness within about an hour of exposure. Postmortem examination showed congestion in
the lungs along with epicardial- and endocardial- anoxic hemorrhaging in some cases (ATSDR,
2006). In one situation (Lilliman, 1949), there was slight congestion of the liver tissues.
Several men and women were accidentally given oral doses (approximately 70 to 117
mg/kg) of undiluted 1,1,2,2-tetrachloroethane as a treatment for intestinal parasites (round
worms) in an African clinic. The subjects lost consciousness within an hour. While unconscious
they experienced shallow breathing, a faint pulse, and pronounced lowering of blood pressure
(60/46) (Sherman, 1953; Ward, 1955). There were no fatalities and the subjects, understandably,
refused further treatment at the clinic.
Acute and Short-Term Inhalation Exposure
A study was conducted during which two volunteers inhaled 1,1,2,2-tetrachloroethane
vapors in a chamber at concentrations of 20, 30, or 90 mg/m3 for 10 minutes; 800 mg/m3 for 20
minutes; 900 mg/m3 for 10 minutes; 1000 mg/m3 for 30 minutes; 1800 mg/m3 for 10 minutes, and
2300 mg/m3 for 10 minutes (Lehmann and Schmidt-Kehl, 1936). After 10 minutes,
1,1,2,2-tetrachloroethane odor was detectable at concentrations of 20 mg/m3 and above. Mild
nausea and vomiting were observed at the lowest exposure concentration (20 mg/m3) after 20
minutes. At concentrations of 90 mg/m3 and above, minor respiratory effects were experienced.
Dizziness and eye irritation were reported at concentrations of 800 mg/m3 and above. The study
lacks detail on the sequencing of exposure episodes. Ideally, adequate recovery periods would
have been allowed between exposures to each increasing 1,1,2,2-tetrachloroethane concentration.
This experimental detail was not reported.
Gastrointestinal and neurological distresses were reported following occupational
exposure (inhalation and most likely dermal) to a cellulose acetate varnish with
1,1,2,2-tetrachloroethane as the solvent while covering fabric airplane wings during the early
years of aviation (Willcox et al., 1915). Although most workers recovered, at least 4 of 14
workers later became confused, delirious, comatose, and finally died. Autopsies revealed extreme
liver damage including areas of fatty degeneration. Fatty degeneration and congestion of the
kidney were found in one female who died after a 2-3 month exposure. The levels of 1,1,2,2-
tetrachloroethane in the air were not measured, so inhaled concentrations and total exposures are
not known.
1,1,2,2-Tetrachloroethane — January, 2008 7-1
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One worker was exposed to an unknown amount of 1,1,2,2-tetrachloroethane by a
combination of the inhalation and dermal routes while cleaning up a spill. The exposure proved
to be fatal. The subject experienced nausea, vomiting, loss of appetite, headache, fatigue and
jaundice within six days of the incident. He died 20 days after exposure despite treatment.
Autopsy records demonstrated liver cirrhosis and inflamation, enlargement of the heart and
spleen, and bleeding in the gastrointestinal tract (Coyer, 1944).
7.1.2 Long-Term and Epidemiological Studies
Several occupational case reports and epidemiology studies of human exposures to
1,1,2,2-tetrachloroethane have been published. Most of them provide limited exposure data.
Humans exposed to 1,1,2,2-tetrachloroethane in the workplace developed gastric distress
including pain, nausea, vomiting, loss of appetite, loss of body weight, jaundice, and an enlarged
liver (Horiguchi et al., 1964; Jeney et al., 1957; Koelsch, 1915; Willcox et al., 1915). However, it
was not possible to correlate specific adverse effects with specific exposure levels. Clinical signs
generally disappeared when the workers changed employment.
Norman et al. (1981) retrospectively studied mortality records of a group of 1,099 white
male civilians who worked for the army during World War II and were exposed dermally and/or
by inhalation to tetrachloroethane solvent vapors in chemical processing plants where clothing
was impregnated with N,N-dichlorohexachlorodiphenylurea for protection against mustard gas.
The exposed workers were compared to 1319 non-exposed workers (i.e., individuals working in
chemical processing plants using a water-based solvent instead of tetrachloroethane). Exposure
levels were not measured; the exposure durations ranged from about 5 weeks to 1 year, with an
average of about 5 months. The period between exposure and the epidemiology study was 31
years (1946-1976).
The exposed group showed a very slight, non-significant increase in the incidence of
deaths due to genital cancers (relative risk [RR] =4.56), leukemia (RR=1.77), and other lymphatic
cancers (RR=5.19), when compared to similar workers not exposed. The increased incidences
were not statistically significant. Overall, cancer mortality for exposed workers was 1.26 times
that of unexposed workers. There were no significant increases of death from liver cirrhosis.
Several confounding factors may have influenced the study results (i.e., exposure to the N,N-
dichlorohexachlorodiphenylurea and dry cleaning solvents), and there were no occupational
histories recorded for the 31-year period after exposure. The authors concluded that the results
are difficult to interpret, and the observed incidences of cancer may not have been due to
tetrachloroethane exposure. This information is inconclusive as to whether tetrachloroethane
causes cancer in humans.
Jeney et al. (1957) studied a group of about 50 penicillin plant workers who used
1,1,2,2-tetrachloroethane as an extractant for 3 years. During the first year, air concentrations
were reported to range from 2.3 to 247 ppm (16 to 1724 mg/m3) for most of the work shift.
Approximately half of the workers developed hepatitis (diagnosed by palpation and liver function
tests). Liver dysfunction occurred at a lower frequency and severity. Liver enlargement was
found in 5% of the workers, urobilinogenuria in 12%, and increased serum bilirubin in 7.6%.
1,1,2,2-Tetrachloroethane — January, 2008 7-2
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Exposure-related neurological or hematological changes were not reported. It is not clear
whether the workers had direct dermal contact with the 1,1,2,2 tetrachloroethane in addition to the
inhalation exposure. There was no control group for this study.
Lobo-Mendonca (1963) studied 380 workers who were exposed to
1,1,2,2-tetrachloroethane during the manufacture of bracelets from waste cellulose acetate film at
23 factories in Bombay, India. Eighty-five of the workers had dermal contact with a 1:1 liquid
mixture of 1,1,2,2-tetrachloroethane and acetone, 107 had dermal contact with undiluted
1,1,2,2-tetrachloroethane, and 188 were exposed only by inhalation of vapor. Average breathing
zone concentrations of 1,1,2,2-tetrachloroethane ranged from 9 to 98 ppm (63 to 684 mg/m3),
with most samples ranging between 20 and 65 ppm (140 and 454 mg/m3). Neurological signs
were reported to occur in exposed workers, primarily finger tremors (in 35% of the exposed
workers), and appeared to be dose-related. Controls were not evaluated and the reported air
concentrations may not have been representative of actual exposures (WHO, 1998).
An increase in the number of large mononuclear cells, white blood cells, and platelets, and
slight anemia were found in workers in an artificial silk factory who were exposed both dermally
and via inhalation of 1,1,2,2-tetrachloroethane vapors (Minot and Smith, 1921). Neurological
symptoms, including fatigue, irritability and headache were also observed. Accurate measures of
exposure concentrations were not available.
7.2 Animal Studies
7.2.1 Acute Toxicity
Oral Exposure
Estimates of the oral LD50 of 1,1,2,2-tetrachloroethane in rats fall in a narrow range
(ATSDR, 2006): 319 mg/kg (Smyth et al., 1969), 250 mg/kg (Gohlke et al., 1977), and 330 mg/kg
(Schmidt et al., 1980a). However, the LD50 identified by Paolini, et al. (1992) using gavage
exposures to groups of six CD-I mice gave a considerably higher value of 1,476 mg/kg.
Ten male Wistar rats that received a single oral dose of 100 mg/kg of
1,1,2,2-tetrachloroethane in peanut oil were found to have hepatic necrosis and fatty
degeneration 20 to 22 hours after exposure, but no changes in relative liver weight or body
weight. Levels of liver serum leucine aminopeptidase, ascorbic acid, and triglyceride were
increased (Schmidt et al., 1980a). In another study, single doses of 143.5, 287, 574, or 1148
mg/kg were administered by gavage in corn oil to groups of male Sprague-Dawley rats. The
animals were sacrificed 24 hours later and the liver excised for analysis. Levels of aspartate
amino transferase (AST) and alanine amino transferase (ALT) were significantly elevated at
doses of 287 mg/kg and above (Cottalasso et al., 1998). When the levels of AST and ALT were
evaluated at different time points (5, 15, 30, or 60 minutes) after administration of the 574-mg/kg
dose, the increases reached a level of significance (p<0.05) 30 minutes after dosing (n=4-6).
Significant increases in liver triglycerides also were seen at this same dose.
A lethal dose of 300 mg/kg-day was identified when groups of male Osborne-Mendel rats
were exposed for 4 days to doses of 0, 25, 75, 150, or 300 mg/kg/day by gavage in corn oil (Dow,
1,1,2,2-Tetrachloroethane — January, 2008 7-3
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1988). After sacrifice, enlargement of hepatic cells in the centrilobular region and hyperplasia
were seen at doses of 75 mg/kg/day and above. Body weight was depressed at doses of 150
mg/kg/day and above, reaching a 16% difference in the highest dose group. The animals in the
highest dose group exhibited central nervous system depression which could have contributed to
the death of some rats in this dose group. When groups of male B6C3F1 mice were exposed
under the same conditions, there were no deaths (Dow, 1988). Centrilobular hepatic swelling was
noted at doses of 75 mg/kg/day and hepatic mitosis was observed at the highest dose. The no
observed adverse effect level (NOAEL) in this study was the 25-mg/kg/day doses for both mice
and rats and the lowest observed adverse effect level (LOAEL) was the 75-mg/kg/day dose.
Inhalation Exposure
Concentrations of 1,1,2,2-tetrachloroethane in air that cause death in rats following 4- to
6-hour exposures have been consistently reported to be near 1000 ppm (6980 mg/m3) (Carpenter
et al., 1949; Deguchi, 1972; Schmidt et al., 1980b; Smyth et al., 1969).
Groups of 10 rats and 10 guinea pigs were exposed to concentrations of 0, 576 ppm (3951
mg/m3), 5050 ppm (32,249 mg/m3), or 6310 ppm (44,044 mg/m3) for 30 minutes. Three of the
rats died at the 5050-ppm concentration; labored respiration and eye irritation were observed.
Post mortem evaluations did not reveal any lesions of the livers or kidneys. Myocardial damage
was found in 1 of 10 rats following the 30-minute exposure to 6310 ppm. There were three
deaths in the guinea pigs at the highest dose; labored respiration became apparent at the 5050-
ppm dose and above and lacrimation was observed at the 576-ppm dose and above. Histological
changes in the liver, kidney, and heart were not observed in the guinea pigs (Price et al., 1978).
Adult male Wistar rats (6/group) exposed to 0, 10, 100, or 1000 ppm (equivalent to 0, 70,
700, 7000 mg/m3, respectively) 1,1,2,2-tetrachloroethane for 6 hours showed a dose-related
increased serum AST levels 24 to 72 hours after exposure when compared with controls
(Deguchi, 1972). There were no trends found in serum ALT over a 120-hour period after
exposure. No pathological changes were observed in the liver, kidney, brain, heart, spleen, or
bone marrow after the 6-hour exposure to 100 ppm. Four of the 6 rats exposed to 1000 ppm died
within 18 hours following exposure.
Schmidt et al. (1980b) observed fine droplet fatty degeneration in the liver when groups of
5 to 10 male Wistar rats were exposed to concentrations of 0, 0.41, 0.7, 1.03, 2.10, or 4.2 mg/L
(410, 700, 1030, 2000, or 4200 mg/m3) 1,1,2,2-tetrachloroethane vapor for 4 hours and sacrificed
after 24 hours. There was a concentration-related increase in liver triglycerides and liver ascorbic
acid at doses >700 mg/m3 when measurements were taken 24 hours after the exposure. The
serum triglycerides appeared to decrease compared to controls but the decrease was not
concentration-related. Alkaline phosphatase and succinic dehydrogenase were increased in the
liver at the highest exposure concentration. Fine droplets of fat were seen in the liver at the 700-
mg/m3 concentration. The histological effects at the highest concentration were manifest as
inflamation and necrotic cells with tiny fat droplets and ceroid pigments. Histological results
were reported only for the 700 and 4200 mg/m3 exposure concentrations.
In mice, the acute exposures that caused death were reported to be approximately 5000 to
6000 ppm (i.e., 34,900 to 41,880 mg/m3) (Horiuchi et al., 1962; Lazarew, 1929; Pantelitsch,
1,1,2,2-Tetrachloroethane — January, 2008 7-4
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1933). In animals surviving more than a few days, fatty degeneration of the liver was seen at
necropsy (Horiuchi et al., 1962). Mice exposed to 600 or 800 ppm (i.e., 4188 to 5584 mg/m3)
1,1,2,2-tetrachloroethane for 3 hours had increased levels of hepatic triglycerides (Tomokuni,
1969, 1970).
Dermal/Ocular Exposure
The dermal LD50 reported for 1,1,2,2-tetrachloroethane in rabbits was 6360 mg/kg (Smyth
et al., 1969). Direct application of 514 mg/cm2 1,1,2,2-tetrachloroethane for 16 hours damaged
the skin of guinea pigs, causing karyopyknosis (compaction of the chromatin observed after cell
death) and pseudoeosinophilic infiltration (Kronevi et al., 1981). Application of
1,1,2,2-tetrachloroethane (concentration not reported) to the shaved abdomen of rabbits caused
hyperemia, edema, and severe blistering (Dow, 1944).
Guinea pigs were found to be more sensitive to ocular irritation from 1,1,2,2-
tetrachloroethane vapors than rats (Price et al., 1978). Five minutes after exposure to a 576-ppm
concentration, eye squinting, and closure were observed; lacrimation had begun by 15 minutes of
exposure. Rats did not exhibit these responses until the exposure concentration had reached 5050
ppm and above.
7.2.2 Short-Term Studies
Oral Exposure
The NTP study (2004) conducted a 15-day range finding study of 1,1,2,2-
tetrachloroethane in F344/N rats and B6C3F1 mice using a dietary route of exposure. The
chemical was administered through microcapsules incorporated in the feed. The microcapsules
were made from a combination of corn starch and sucrose granules. Groups of 5 male and female
rats or mice were fed dietary levels of 0, 3325, 6650, 13,300, 26,600, or 53,200 ppm in their food.
The animals were examined for clinical signs. Body weights were recorded initially, on day 8,
and at the end of the dosing period. Food consumption was measured for the two highest dose
groups at on days 1, 8, 11, and 15. At termination, the animals were subjected to gross necropsy
and histopathological examination of any lesions identified. Selected major organ weights (heart,
liver, lung, thymus, right kidney, and right testes) were recorded. Controls were either
completely untreated or received diets with the tetrachloroethane-free microcapsules.
All of the rats in the two highest dose groups were sacrificed on day 11 of the study
because of their poor physical condition and were not evaluated for changes in body weight or
organ weights. Weight gain in all surviving animals was significantly less than that of the
controls; all animals except the males in the 3325-ppm low dose group lost weight during the
study. Relative liver weights were significantly increased among the surviving animals in the
lowest dose group but not at higher doses. Relative kidney weights were significantly increased
in all dose groups except the low dose females; relative thymus weights were significantly
decreased in the highest two dose groups. A small number of animals in each dose group,
including the untreated controls, had hepatodiaphragmatic nodules and mild or moderate
centrilobular degeneration. The LOAEL in this study was 3325 ppm (273 mg/kg/day for females
and 326 mg/kg/day for males based on food consumption and initial body weights). The initial
weights were used for the dose calculation because all animals except the low dose males lost
1,1,2,2-Tetrachloroethane — January, 2008 7-5
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weight over the 15-day period and no information was given for the weight loss time course. The
effects associated with the LOAEL were increased relative liver weight, increased kidney weight,
and body weight loss for the females; there was no NOAEL.
In mice, all animals receiving the highest dose and the males in the penultimate dose
group died or were sacrificed before the end of the study and were not evaluated for body weights
or organ weights. Body weights for all surviving animals were significantly lower than the
controls and all groups, except the low-dose females that lost weight during the study. Relative
liver weights were significantly increased in all surviving males and the females receiving the
13,300 and 26,000 ppm. Relative kidney weights were significantly increased and thymus
weights were decreased for females receiving concentrations > 13,300 ppm.
All exposed animals had mottled livers with cellular swelling, cytoplasmic rarefaction,
single paranuclear vacuoles, and hepatocellular necrosis. The extent of liver damage increased
with dose. There was some pooling of sinusoidal erythrocytes and infiltration with mononuclear
cells. The lowest dose (579 mg/kg/day in males and 623 mg/kg/day for females based on food
intake and initial body weights) was an LOAEL in mice. There was considerable scattering of
feed, especially at the higher doses, preventing an accurate measure of food intake. Accordingly,
the calculated dose is only an estimate of the actual dose. The effects associated with the LOAEL
were decreased body weight, increased relative liver weight (males), decreased relative thymus
weight (females), and histopathological lesions of the liver; there was no NOAEL in the study.
In a study examining the potential renal toxicity of orally administered halogenated
ethanes, groups of five male F344/N rats received 0, 0.62, or 1.24 mmol/kg-day 1,1,2,2-
tetrachloroethane in corn oil (0, 104, 208 mg/kg/day) by gavage daily for 21 days (NTP, 1996).
All animals were examined for body weights, clinical signs, urinalysis, organ weights, and gross
pathology. Histology was conducted on the liver and right kidney. Gross lesions were examined
histopathologically. Rats in the high-dose group died or were killed before the end of the study.
Clinical observations among the high-dose animals included an emaciated appearance and
lethargy (5/5 animals), diarrhea (4/5 animals), abnormal breathing (3/5 animals), and ruffled fur
(3/5 animals). In the low-dose group, no effects on survival, body weight gain, urinalysis,
absolute and relative kidney weights, or kidney histopathology were observed. Absolute and
relative liver weights of all dosed groups were greater than those for the controls. Mild to
moderate cytoplasmic vacuolization (multifocal areas of hepatocytes with clear droplets within
the cytoplasm) was observed among all rats in the low-dose group. The NTP did not consider the
cytoplasmic vacuolization observed at 104 mg/kg/day to be an adverse effect. However, the 104
mg/kg/day dose could be regarded as a marginal LOAEL in rats exposed to 1,1,2,2-
tetrachloroethane for 21 days based on the increased liver weights and hepatocyte vacuolization.
The 208-mg/kg/day dose was a frank effect level (PEL).
The National Cancer Institute (NCI, 1978) conducted range-finding studies in rats and
mice. In this study, groups of five male and five female Osborne-Mendel rats received gavage
doses of 0 (vehicle control group), 56, 100, 178, 316, and 562 mg/kg of 1,1,2,2-tetrachloroethane
in corn oil 5 days/week for 6 weeks followed by a 2-week observation period. Groups of five
male and five female B6C3F1 mice were similarly exposed to 0, 32, 56, 100, 178, and 316 mg/kg
of 1,1,2,2-tetrachloroethane. Mortality and body weight gain were the only endpoints used to
1,1,2,2-Tetrachloroethane — January, 2008 7-6
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assess toxicity. In the rats, mortality was observed in one male exposed to 100 mg/kg, and all
five females exposed to 316 mg/kg (mortality rates in the 562-mg/kg group were not provided).
Decreases in body weight gain were observed in the rats at the 56, 100, and 178 mg/kg doses; the
differences were 3, 9, and 38% for the males and 9, 24, and 41% for the females compared to the
controls. No deaths were observed in the mice and there were no significant alterations in body
weight gain. The limited number of endpoints examined in this study precludes identifying
NOAELs and/or LOAELs.
Inhalation Exposure
Hepatic effects (fine-droplet fatty degeneration, inflammatory changes in the liver, and
necrotic foci) were described in a study in which male rats were exposed to 2 ppm (14 mg/m3)
1,1,2,2-tetrachloroethane for 4 hours per day, for a total of 8 exposures in 10 days (Gohlke and
Schmidt, 1972). This study, however, had a number of limitations, including maintaining the rats
at elevated room temperatures, a lack of a defined dose-response or duration-response
relationships, and inconsistencies in the reported results (ATSDR, 2006).
7.2.3 Subchronic Studies
Oral Exposure
In a subchronic study conducted for the NTP (2004), groups of 10 male and 10 female
F344 rats were fed diets containing microencapsulated 1,1,2,2-tetrachloroethane for 14 weeks at
concentrations of 0, 268, 589, 1180, 2300, and 4600 ppm. One control group was untreated and a
second received food containing the starch microcapsules. The estimated doses based on food
intake and body weights were 0, 20, 40, 80, 170, or 320 mg/kg/day for males and females.
Satellite groups of 10 males and 10 females received the same doses as the core group and were
used for collection of blood samples.
The animals were examined for clinical signs daily. Body weights and food consumption
were recorded weekly. Blood samples were collected on days 5 and 21, and week 13 for
hematology and serum biochemistry measurements. A "Functional Observational Battery" (FOB)
was given to the core study animals from the three lowest dose groups and controls during weeks
4 and 13. FOB results are reported in Section 7.2.4. Sperm motility and vaginal examinations
and measurements of estrus cycles were conducted at the end of the study. The sperm and
vaginal results are reported in Section 7.2.5. After sacrifice, all animals were subjected to gross
necropsy. Complete histopathological examinations were conducted for the animals in the high
dose group and for the liver, spleen, bone, and bone marrow in the lower dose groups. The testes
and prostate in males and ovaries and clitoral gland in females were examined for all dose groups.
Statistically-significant decreases in final body weight were observed in the males and the
females from the highest three dose groups (> 1180 ppm). Animals in the highest dose group lost
weight across the duration of the study, but all animals survived. Food consumption was notably
decreased among the animals in the highest dose group (4600 ppm) and slightly decreased among
animals in the 2300-ppm dose group. The maximum tolerated dose was exceeded for males and
females in the 2300- and 4600-ppm dose groups and for females in the 1800-ppm dose group,
since final body weights were more than 10% lower than that for the controls. For this reason, the
1,1,2,2-Tetrachloroethane — January, 2008 7-7
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observations from the 2300- and 4600-ppm dose groups are not included in Table 7-1, the
summary of the observed effects in the F-344 rats.
The blood samples taken on days 5 and 21 had a variety of statically significant changes in
various red blood cell and other hematological parameters, especially at doses of 1800 ppm and
greater. At the end of the study, dose groups exposed to concentrations >589 ppm had
hematological changes indicative of a microcytic anemia. A lack of an increase in reticulocyte
counts suggested that the anemia did not elicit an erythropoietic response. Some groups showed
decreases in platelet counts early in the study (> 1800 ppm for males and >598 ppm for females).
However, by the end of the study platelet counts were significantly decreased only in the >2300-
ppm dose groups. Decreased leucocyte counts were seen in these same dose groups.
A number of significant changes were observed in serum biochemical parameters during
the study; most were dose-related. ALT and sorbitol dehydrogenase (SDH) levels were
significantly increased in males at doses >2300 ppm and in females at doses > 1800 ppm. These
parameters along with others are indicative of hepatic toxicity. [There was a significant increase
of SDH in males at the lowest dose but the increase at the next higher dose was not significant.]
Significant increases in bile acids, alkaline phosphatase, and 5'-nucleotidase were indicative of
cholestasis (obstructed outflow of bile from the liver) at concentrations >2300 ppm. On day 5,
cholesterol levels were significantly decreased in all dose groups but by the end of 14-weeks the
levels were significantly decreased in females only at levels > 1180 ppm and only in the highest
dose group for males. At the early time points, there was evidence of hypoproteinuria
accompanied by elevated levels of albumin and increased levels of creatinine kinase, suggesting
muscle injury in the two highest dose groups. These conditions had resolved by the end of the
study.
Among the animals in the lower dose groups (< 1180 ppm) relative liver weights were
increased in a dose-related fashion. Decreased absolute organ weights at the higher doses were
likely a consequence of exceeding the maximum tolerated dose.
Gross and histopathologic observations, combined with the clinical biochemistry
parameters discussed above, implicate the liver as the primary target organ for 1,1,2,2-
tetrachloroethane in this 14-week study. Hepatocyte vacuolization was seen in all dose groups.
The number and type of liver lesions increased with dose. Necrosis and altered cell foci were
observed at doses of >2300 ppm. Cell foci appeared as basophilic, eosinophilic, mixed cell,
and/or clear cell clusters of cellular alterations. Bile duct hyperplasia and pigmentation appeared
only in the highest dose group for the males but in the two highest dose groups for females. In
males, atrophy of the spleen, bone, bone marrow, and male reproductive organs (prostate, seminal
vesicle, and testes) were apparent only for the 4600-ppm dose group, but in the females, changes
were observed in both the 2300- and 4600-ppm dose groups. The reproductive organs examined
in females were the uterus, ovary, and clitoral gland. Organ atrophy was attributed to the body
weight deficits in the affected groups. The results of the tests of sperm motility and estrus cycle
are reported in section 7.2.5.
According to the authors, the 589-ppm dose level (40 mg/kg/day for males and females)
was the LOAEL for systemic effects in this study. The only observed effect in the 268-ppm
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group was hepatocyte cytoplasmic vacuolization of minimal severity in 7/10 males (p<0.05) but
not in females. As mentioned earlier, the SDH levels in the 268-ppm males was significantly
increased but the increase for the 589-ppm dose group was not significant. These minimal effects
were not considered adverse by the authors. The effects that contributed to the identification of
589 ppm as the LOAEL were on hepatocyte cytoplasmic vacuolization (mild severity) in 9/10
males and 10/10 females (compared to 0/20 controls), increased relative liver weight, plus
significantly decreased hemoglobin in males and hematocrit in females. It also is possible to
classify the 268-ppm dose (20 mg/kg/day) as a marginal LOAEL for the male rats based on the
cytoplasmic vacuolization in 7/10 male rats.
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Table 7-1 Doses and Effects from the NTP 14-Week Study (2004) in F-344 Rats
Concentration
in Diet ( ppm)
0
268
589
1,180
Dose - Males
(mg/kg/day)
0
20
40
80
Significant Effects
Increased SDH
Increased hepatocyte
cytoplasmic vacuolization
(1.3)1
Decreased hemoglobin
Increased SDH (not significant)
Increased hepatocyte
cytoplasmic vacuolization
(2.0)1
Increased relative liver weight
Decreased sperm motility
Decreased body weight gain
(5%)
Increased ALT
Increased SDH
Decreased hemoglobin
Decreased manual hematocrit
Increased relative liver weight
Increased relative kidney
weight
Increased hepatocyte
cytoplasmic vacuolization
(1.9)1
Spleen pigmentation
Decreased epididymal sperm
motility
Decreased left epididymis
weight
Dose - Females
(mg/kg/day)
0
20
40
80
Significant Effects
No observed effects
Decreased manual
hematocrit
Increased hepatocyte
cytoplasmic
vacuolization (1. 7) '
Increased relative liver
weight
Decreased body weight
gain (8%)
Decreased manual
hematocrit
Decreased hemoglobin
Decreased mean cell
volume
Decreased mean cell
hemoglobin
Decreased cholesterol
Increased hepatocyte
cytoplasmic
vacuolization (2.2)1
Increased relative liver
weight
Higher doses not shown because they clearly exceed the maximum tolerated dose
1. Severity scale for hepatocyte cytoplasmic vacuolization 1 = minimal; 2 = mild; 3 = moderate; 4 = severe
The protocol used for the NTP study (2004) in rats with slight modifications was used to
study groups of 10 male and 10 female B6C3F1 mice. The dietary concentrations used for the
mice were 0, 589, 1120, 2300, 4550, or 9100 ppm. These corresponded to doses of 0, 100, 200,
370, 700, and 1360 mg/kg/day for the males and 0, 80, 160, 300, 600, and 1400 mg/kg/day for the
females. There were no measurements of hematology in mice; measurement of serum
biochemical parameters were only conducted at the end of the study.
There was a significant difference from vehicle controls in body weight gain among mice
for all exposure concentrations >2300 ppm, but as with the rats, there was no mortality. The
exposed animals had final body weights that were more than 10% lower than the controls for each
of the doses >4550 ppm, indicating that the maximum tolerated dose had been exceeded. For this
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7-10
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reason the effects observed in the two highest dose groups are not included in Table 7-2 on the
effects observed in the NTP study (2004) of B6C3F1 mice.
The clinical signs of liver toxicity in mice were similar to those in rats. There was a dose-
related increase in ALT in all female dose groups, which became significant at concentrations
> 1120 ppm. In males, the concentration of ALT did not begin to increase until the 1120 dose and
became significant for concentrations >2300 ppm. SDH results were similar except that the
increases attained significance at concentrations >589 ppm in females and > 1120 ppm in males.
Bile acids, alkaline phosphatase, and 5'-nucleotidase indicated cholestasis at concentrations of
> 1120 ppm in females and >2300 ppm in males. Serum protein levels were significantly
decreased at doses of >2300 ppm, and cholesterol levels in females were significantly decreased
at concentrations of > 1120 ppm. The dose-related downward trend in cholesterol levels was
reversed at the highest dose, but the cholesterol level still remained significantly lower than the
controls.
On necropsy, the livers for all females and males were pale at concentrations >2300 ppm.
One male had pale kidneys in each of the two highest dose groups. Relative liver weights were
significantly elevated for all exposed female groups and males receiving the 1120- and 2300-ppm
concentrations. Absolute and relative kidney weights were decreased in males at concentrations
of >2300 ppm, and absolute thymus weights were decreased in males and females at the highest
dose. The decreased absolute organ weights among the animals in the higher dose groups may be
due to the deficits in body weight gain. An increase in focal lymphocyte cellular infiltration of
the lung was observed in the female mice exposed to 4550 or 9100 ppm; however, the number of
infiltrates was within the normal range and was not considered to be related to 1,1,2,2-
tetrachloroethane exposure.
Hepatocyte hypertrophy was evident in males and females receiving concentrations > 1120
ppm. Pigmentation and bile duct hyperplasia were significantly increased at concentrations
>2300 ppm. A significant increase in liver necrosis was observed in males at concentrations
>2300 ppm and in females for concentrations >4550 ppm. Based on observations of significant
changes in the parameters measured, the 1120-ppm concentration (a dose of 160 mg/kg/day in
females and 200 mg/kg/day in males) was a clear LOAEL for this study and the 589-ppm
concentration (80 mg/kg/day for females and 100 mg/kg/day for males) was the NOAEL.
There was a significant dose-related increase in SDH levels for females at doses of 589
ppm and higher that could indicate that the 589-ppm concentration is a marginal LOAEL, rather
than a true NOAEL. The authors of the study did not identify an NOAEL and/or LOAEL for the
mice because of the tumor response that was seen in mice in a cancer study conducted by NCI
(see Sections 7.2.6 and 7.2.7).
1,1,2,2-Tetrachloroethane — January, 2008 7-11
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Table 7-2 Doses and Effects from the NTP 14-Week Study (2004) in B6C3F1 Mice
Concentration
in Diet ( ppm)
0
589
1120
2300
Dose - Males
(mg/kg/day)
0
100
200
370
Significant Effects
No significant effects
Decreased total protein
Increased SDH
Hepatocyte hypertrophy1
(l.O)1
Decreased body weight
gain (13%)
Decreased total protein
Increased ALT
Increased AP
Increased SDH
Increased 5' nucleotidase
Increased bile acids
Hepatocyte hypertrophy
(2.2)1
Hepatocyte necrosis
Focal liver pigmentation
Bile duct hyperplasia
Increased relative liver
weight
Dose-
Females
(mg/kg/day)
0
80
160
300
Significant Effects
Increased SDH
Increased relative liver weight
Increased ALT
Increased SDH
Increased 5' nucleotidase
Increased bile acids
Decreased cholesterol
Hepatocyte hypertrophy (l.O)1
Increased relative liver weight
Decreased total protein
Increased ALT
Increased AP
Increased SDH
Increased bile acids
Decreased cholesterol
Hepatocyte hypertrophy (1.9)1
Focal liver pigmentation
Bile duct hyperplasia
Increased relative liver weight
Increased relative heart weight
Higher doses not shown because they clearly exceed the maximum tolerated dose
1. Severity scale for hepatocyte hypertrophy 1 = minimal; 2 = mild; 3 = moderate; 4 = severe
1,1,2,2-Tetrachloroethane —January, 2008
7-12
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Inhalation Exposure
Fifty-five female rats were exposed to 130 ppm (907 mg/m3) 1,1,2,2-tetrachloroethane for
5 hours/day, 5 days/week for 15 weeks. They exhibited increased relative liver weight and signs
of hyperplasia (including increased numbers of binuclear cells), granulation, and vacuolization of
the liver cells. Histological examination of the lungs revealed no treatment-related lesions
(Truffert et al., 1977). The rats also showed slightly decreased hematocrit levels, but statistical
significance was not reported.
Exposure to 1,1,2,2-tetrachloroethane at 50 mg/m3 four hours/day, 5 days/ week, or 130
mg/m3 for 15 minutes, 5 times/day and 5 days/week, both for approximately 5 weeks, resulted in
alterations in biochemical parameters and organ weights in male rats (strain and number not
specified). Although no "morphological changes" were noted upon examination, the nature and
extent of the histopathological examination were not specified (Schmidt et al., 1975).
Brown, Norway and Wistar rats were exposed to 516 ppm (3602 mg/m3)
1,1,2,2-tetrachloroethane for 5 hours/day, 5 days/week for 13 weeks. The animals had depressed
body weights compared with controls. There were small glomerular lesions in the kidneys and
the levels of protein in the urine were lower than those for controls (Danan et al., 1983).
7.2.4 Neurotoxicity
There have been a number of indications of neurotoxicity in humans exposed to 1,1,2,2-
tetrachloroethane by the inhalation route. Human volunteers who inhaled 800 mg/m3
1,1,2,2-tetrachloroethane for 20 minutes or >900 mg/m3 for 10 minutes reported being dizzy.
These effects did not occur when the exposure was 90 mg/m3 for 10 minutes (Lehmann and
Schmidt-Kehl, 1936).
Humans exposed to 1,1,2,2-tetrachloroethane vapors in the workplace showed symptoms
such as headache, tremors, dizziness, numbness, and drowsiness (Hamilton, 1917; Jeney et al.,
1957; Lobo-Mendonca, 1963; Minot and Smith, 1921; Parmenter, 1921). Length of exposure was
not noted, but the reports seem to indicate that the exposures generally were for a period of about
18 months or less. Exposure levels were noted in only one study, and these ranged from 9 to 98
ppm (63 to 684 mg/m3), with significant skin exposure in addition to the inhalation exposure
(Lobo-Mendonca, 1963). The incidence of tremors was higher among factory workers exposed to
higher concentrations, suggesting a dose-response relationship. Workers in an artificial silk plant
experienced fatigue, irritability, headache, and coma (Minot and Smith, 1921). Exposure levels
were not reported. The data from the occupational studies are limited because most do not
provide information on whether or not there might have been co-exposures to other chemicals
with neurotoxic properties.
There are a variety of reports of short term inhalation exposures of rodents to 1,1,2,2-
tetrachloroethane that are indicative of adverse effects on the central nervous system after short-
term exposures. In acute duration experiments, rats showed a decrease in spontaneous motor
activity after being exposed to 360 ppm (2513 mg/m3) for 6 hours (Horvath and Frantik, 1973),
and mice showed a loss of reflexes after being exposed to 1091 ppm (7615 mg/m3) for 2 hours
(Lazarew, 1929). As the concentration or duration of exposure to 1,1,2,2-tetrachloroethane
1,1,2,2-Tetrachloroethane — January, 2008 7-13
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increased, mice, rats, and guinea pigs showed some combination of a loss of reflexes, loss of
spontaneous motor activity, ataxia, prostration, and narcosis (Lazarew, 1929; Pantelitsch, 1933;
Price et al., 1978). Rats exposed to 9000 ppm (62,820 mg/m3) for 2 hours/day, twice a week for 4
weeks exhibited hyperactivity, ataxia, and then unconsciousness (Horiuchi et al., 1962).
Narcosis also was observed in a cat exposed to 8300 ppm (57934 mg/m3) 1,1,2,2-
tetrachloroethane for 5 hours (Lehmann, 1911). One monkey was exposed to
1,1,2,2-tetrachloroethane for 2 hours/day, 6 days/week for 9 months (190 exposures). For the
first 20 exposures, the concentrations were 2000-4000 ppm (13960-27920 mg/m3); for the next
140 exposures, the concentrations were 1000-2000 ppm (6980-13960 mg/m3); and for the last 30
exposures, the concentrations were 3000-4000 ppm (20,940-27,920 mg/m3). The monkey was
rendered unconsciousness 20 to 60 minutes after each 2-hour exposure, starting with the fifteenth
exposure (Horiuchi et al., 1962).
Rats receiving a single oral 50-mg/kg dose displayed significantly decreased avoidance
learning. This effect was not detected at a dose of 25 mg/kg (Wolff, 1978). A single oral dose of
50 mg/kg body weight increased levels of several neurotransmitters in the brain of rats (Kanada et
al., 1994). Rats receiving doses of 300 mg/kg-day for 3 to 4 days experienced significant central
nervous system depression and debilitation (Dow, 1988).
During the 14-week NTP study (2004), F-344 rats in the 0-, 268-, 589-, and 1180-ppm
exposure groups and B6C3F1 mice in the 0-, 1120-, 2300-, and 4550-ppm groups were given a
FOB to examine the neurotoxic potential of 1,1,2,2-tetrachloroethane during weeks 4 and 13 of
the study. The test battery included observations of general behavior, gait, coordination,
movement patterns, convulsions, tremors, fighting, licking behavior, as well as piloerection,
lacrimation, chromodacryorrhea (reddish corneal discharge without the presence of red blood
cells), vocalization, diarrhea, and urination patterns. No significant dose-response increase in the
incidence of any of these parameters were noted among the animals in any dose group.
Edefors and Ravn-Jonsen (1992) examined the effects of a variety of nonpolar
halogenated and nonhalogenated solvents, including 1,1,2,2-tetrachloroethane, on the activity of
the Ca2+/Mg2+ ATPase from freshly isolated rat synaptosomal membrane preparations. The
enzyme activity was monitored through the amount of ATP produced relative to the concentration
of the dissolved solvent in the buffer solution. In the case of 1,1,2,2-tetrachloroethane, the
maximum activity (105%) was observed with the 25% solution. The ATPase activity with the
12.5% solution was about 80% of the maximum, and that for the 50% solution was about 60% of
the maximum. The biphasic response showed initial excitation (higher levels of ATP) as the
concentration increased from 12.5% to 25% followed by a depression (lower levels of ATP) at
concentrations greater than 25%. 1,1,2,2-Tetrachloroethane had no significant impact on the
fluidity of the synaptosomal membrane.
1,1,2,2-Tetrachloroethane — January, 2008 7-14
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7.2.5 Developmental/Reproductive Toxicity
No studies were located regarding reproductive or developmental effects in humans
following exposure to 1,1,2,2-tetrachloroethane. In addition, there have been no standard
multigeneration reproductive studies of 1,1,2,2-tetrachloroethane in animals. There are data from
a limited single generation study (Schmidt et al., 1972) and a developmental study (Schmidt,
1976) using protocols that are now nonstandard. The NTP study (2004) examined the
reproductive organs in males and females and measured sperm production in male rats. The data
from these studies are reported below.
The data from animals studies on developmental toxicity are more complete, since studies
have been completed in two species. The studies were conducted in pregnant Sprague-Dawley
rats and CD-I Swiss mice by Environmental Research and Testing, Inc. for NTP (1991a,b) but
are more consistent with a range-finding methodology than a full developmental study.
Reproductive Effects
Oral Exposure
As part of the NTP study (2004), epididymal sperm samples were collected from rats
receiving concentrations of 0, 589, 1180, or 2300 ppm 1,1,2,2-tetrachloroethane in their diets
after 14 weeks. The left cauda, left epididymus, and left testis were weighed. In females, vaginal
smears were collected for 12 days prior to the end of the study for vaginal cytology examinations.
The percentage of time spent in various estrous stages and estrous cycle length were evaluated.
There was a decrease in sperm motility at concentrations of 589 ppm and greater. The left
epididymus weight was decreased at concentrations of > 1180 ppm, and the weight of the left
cauda epididymus was increased for the 2300-ppm concentration. Estrus cycles were altered in
females receiving the 2300-ppm concentration. These females spent more time is the diestrus
phase of the cycle and less time in other phases.
Mice receiving dietary 1,1,2,2-tetrachloroethane concentrations of 0, 1120, 4550, or 9100
ppm in the NTP study (2004) were examined using the same parameters described for the rats
above. The results in mice were comparable to those in rats but occurred at a higher dose. In
mice, with the exception of the weight of the left testis which was decreased in the group
receiving the 4550-ppm concentration, changes in all measured parameters were significant for
only the 9100-ppm concentration.
Longer-term oral gavage exposures of male or female rats or mice produced no gross or
histological alterations in the reproductive organs in the chronic study by NCI (1978; see Section
7.2.6). In these 78-week gavage studies, male rats were dosed at levels up to 108 mg/kg-day,
female rats were dosed at levels up to 76 mg/kg-day, and mice (both sexes) were dosed at levels
up to 284 mg/kg-day.
Testicular effects were found in groups of 10 rats dosed by gavage at doses on 0, 3.2, or 8
mg/kg-day, 82 times in 120 days (Gohlke et al., 1977). A high incidence of interstitial edema of
the testes, clumped sperm, and epithelial cells in the tubular lumen were observed. Partial
necrosis and totally atrophied tubules, giant cells, and two-row germinal epithelial cells with
1,1,2,2-Tetrachloroethane — January, 2008 7-15
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disturbed spermatogenesis also were observed (the incidence was not reported). Some of these
changes (details not provided) persisted during the 2-week follow-up observation period. No
other reproductive indices were examined. This study had a number of limitations, including an
unusual experimental design in which the rats were exposed in the presence and absence of an
elevated air temperature (35°C). Effects were observed at both 1,1,2,2-tetrachloroethane doses.
Inhalation Exposure
In a limited one-generation inhalation study, male rats were exposed to 13.3 mg/m3
1,1,2,2-tetrachloroethane, 4 hours/day (days/ week not specified) for a 9-month period. One week
before the end of the exposure period, groups of 7 exposed males and control males were mated
with 5 unexposed females. Exposure of the males continued during the mating period. The Fx
generation was observed for 12 weeks postpartum. There were no statistically significant
differences in the percentage of females having offspring (77.1% in controls vs. 62.9% in
exposed), number of pups per litter, average birth weight, gestation length, sex ratio, offspring
mortality at postnatal days 1, 2, 7, 14, 21, and 84, or average weight on postnatal day 84. No
macroscopic malformations were observed (Schmidt et al., 1972).
In rats, no effects on the testes, epididymis, ovaries, or uteruses were seen after inhalation
exposure for 30 minutes to 6310 ppm (44,044 mg/m3) 1,1,2,2-tetrachloroethane (Price et al.,
1978). In female rats, exposure to 130-ppm (907 mg/m3) 1,1,2,2-tetrachloroethane vapors for 15
weeks (5-6 hours/day; 5 days/week) also had no effect on the histology of the reproductive organs
(Truffert et al., 1977). Inhalation of 1,1,2,2-tetrachloroethane for 9 months to a TWA
concentration of 1974 ppm (13,779 mg/m3) produced no pathological changes in the testes of one
monkey (Horiuchi et al., 1962).
Developmental Effects
Groups of 8 to 9 pregnant female Sprague-Dawley rats were exposed to doses of 0, 34,
98, 180, 278, or 330 mg/kg/day 1,1,2,2-tetrachloroethane (98% pure) through microcapsules
incorporated in the diet starting on gestation day (gd) 4 in a range finding study (NTP, 199la).
The doses were estimated by the study authors based on the concentrations in the diet and food
consumption. Gestation day 0 was defined as the day of mating. Food consumption, body
weights and clinical signs were observed during treatment. The animals were sacrificed on gd 20.
Live and dead pups, implantation sites, resorption sites, and fetal body weights were recorded.
There were no maternal deaths during the study. Clinical signs of toxicity (rough hair
coat) were observed in the two highest dose groups and 3 of 9 rats from the highest dose group
developed a hunched posture as well. Weight gain during treatment and weight gain corrected for
gravid uteri weight were significantly decreased in all but the lowest dose group. Average feed
consumption was significantly lower in the exposed animals than in the controls and
demonstrated a dose-related pattern. The 34-mg/kg/day dose appeared to be an NOAEL for
maternal toxicity. There was a significant difference in maternal body weight on gd 16 but not at
other time points. In all other dose groups differences in body weight were significantly lower at
all time points from day 9 to day 20.
1,1,2,2-Tetrachloroethane — January, 2008 7-16
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At sacrifice, total pup resorption was seen in one animal from the 98-mg/kg/day dose
group and 4 of 9 animals in the 330 mg/kg/day dose group. Significant decreases in average fetal
body weights were observed for all dose groups except the 34-mg/kg/day group. The 98-
mg/kg/day dose group was the LOAEL for fetal toxicity based on decreased fetal weights but
confounded by maternal toxicity in the dams which was manifest as decreased weight gain during
pregnancy. The NOAEL for the pups was 34 mg/kg/day based on the parameters evaluated.
There was no evaluation for external, visceral or skeletal abnormalities.
NTP (1991b) conducted two studies, comparable to that described above, in Swiss CD-I
mice. In the first study, the doses (4 to 10% of the diet) the doses were lethal to the pregnant
animals and, thus, a second study was conducted using lower doses. The target doses for the
second study (0.5 to 3% of the diet) were 0, 987, 2120, 2216, or 4575 mg/kg/day. All animals in
the 3% dose group died early in the study and, thus, a dose was not calculated for this group.
Dose groups each included 5 to 10 pregnant animals.
Maternal mortality and clinical signs of toxicity were present in all but the lowest dose
group. Daily feed consumption was significantly increased compared to controls in the 2216
mg/kg/day dose group for gd 6-11 but was lower than that for controls for gd days 11-16. Body
weight gain and body weights were decreased at doses of 2120 mg/kg/day and above, but not in a
dose-related pattern. The livers of the dams were discolored and enlarged for all dose groups
except the lowest. The 987-mg/kg dose was an NOAEL for the dams based on an absence of
clinical signs of toxicity, effects on body weight, and liver histopathology. The 2120-mg/kg/day
dose group was the LOAEL.
The maternal mortality in the 2216- and 4575-dose groups made it difficult to evaluate the
fetal toxicity in mice. There was only one dam left in the 2216-mg/kg dose group at sacrifice on
day 17 and two in the 4575-mg/kg/day dose group. Embryos were completely resorbed in one
dam in each dose group. Total resorptions were seen for 2 of 8 dams in the 2120-mg/kg/day dose
group, but were not seen in the 987-mg/kg/day dose group. Accordingly, 987 mg/kg/day was
determined to be an NOAEL for maternal and fetal toxicity in Swiss CD-I mice based on the
parameters evaluated. There was no evaluation for external, visceral or skeletal abnormalities.
In AB or DBA mice, single intraperitoneal injections of 700 mg/kg
1,1,2,2-tetrachloroethane in corn oil on day gd 9 or 400 mg/kg/injection on gd days 7 through 14
were not embryotoxic. However, injections of 300 mg/kg on gd 1 through 14 were embryolethal
for the DBA strain. In the DBA mice the incidence of deformities (skeletal or visceral) in the
1,1,2,2-tetrachloroethane exposed mice was 3-5% compared to 2% for the corn oil exposed
controls. The highest percentage of fetal malformation (9.39%) was seen when a 700 mg/kg ip.
dose was administered on gd 9 to the AB mice. There is generally a low (< 2%) incidence of
developmental abnormalities (exencephaly, cleft palate, anophthalmia, and fused ribs and
vertebrae) in this strain (Schmidt, 1976).
1,1,2,2-Tetrachloroethane — January, 2008 7-17
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7.2.6 Chronic Toxicity
Oral Exposure
NCI (1978) conducted a chronic study of the tumorigenic potential of 1,1,2,2-
tetrachloroethane in groups of 50/sex/species Osborne-Mendel rats (7 weeks old at initiation) and
B6C3F1 mice (5 weeks old at initiation). The animals were administered technical grade 1,1,2,2-
tetrachloroethane (purity >90%) in corn oil via gavage, 5 days/week for 78 weeks. The doses
were adjusted several times during the study.
In the male rats, the doses increased from an initial 50 mg/kg/day to 65 mg/kg/day after
14-weeks for the low-dose group. For the male high dose group the doses were raised from 100
mg/kg/day to 130 mg/kg/day. For the female rats in the low dose group the doses were lowered
from 50 to 40 mg/kg/day after 25 weeks and from 100 to 80 mg/kg/day for the high dose group.
the doses The 5 days/week time-weighted average doses were calculated as 62 or 108 mg/kg/day
for male rats, 43 or 76 mg/kg/day for female rats. NCI (1978) did not normalize the doses for a 7
days/week exposure. The exposure period was followed by a 32-week period in which the rats
were not exposed to 1,1,2,2-tetrachloroethane. The vehicle and untreated control groups
included 20 animals/sex/species.
A statistically significant association between increased mortality and dose was observed
in the female rats; 10 of the high-dose females died during the first 5 weeks of the study. The
incidence of chronic murine pneumonia in the low- and high-dose female rats (8/20, 34/50,
38/50, respectively) was significantly increased compared to the controls (p<0.05, Fisher Exact
Test). Eight of the 10 females that died had pneumonia; NCI (1978) considered the deaths to be
related to 1,1,2,2-tetrachloroethane exposure. No significant effects of 1,1,2,2-tetrachloroethane
on survival were observed in the low-dose female rats and in both male dose groups.
Clinical signs observed in the exposed rats, but not in the controls, included a hunched
appearance in the high-dose females and squinted or reddened eyes. The investigators noted that
there was a low or moderate incidence of labored breathing, wheezing, and/or nasal discharge in
exposed and control animals during the first year of the study. Near the end of the study, these
respiratory signs were observed more frequently in the 1,1,2,2-tetrachloroethane-exposed animals
than in the controls; no additional information on this effect was provided.
Dose-related differences in body weight gain were observed in the rats; the differences
between body weights of the vehicle control rats and the low- and high-dose rats were less than
10% for the low-dose group and 20% to 25% for the high-dose male and female rats, respectively.
No significant increases in tumor incidence were observed in the rats. The tumor data are
presented in Section 7.2.7. This study identifies an LOAEL of 43 mg/kg/day (31 mg/kg/day when
normalized to account for a 7 day exposure per week) for an increased incidence of chronic
murine pneumonia in female rats exposed to gavage doses of 1,1,2,2-tetrachloroethane for 78
weeks and an FEL of 76 mg/kg/day (55 mg/kg/day when normalized for the 7 days/week
exposure).
The NCI (1978) protocol for the rats described above was also used for the B6C3F1 mice.
The time weighted average doses were 0, 142, or 283 mg/kg for both male and female mice dosed
1,1,2,2-Tetrachloroethane — January, 2008 7-18
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for 5 days/week. As was the case for the rats, the doses were adjusted during the study. At the
low dose, the initial level was 100 mg/kg/day. The dose was increased to 150 mg/kg/day and then
to 200 mg/kg/day; at 26 weeks it was lowered to 150 mg/kg/day. The high dose was initially 200
mg/kg/day. It was raised to first 300 mg/kg/day and then 400 mg/kg/day; after 26 weeks it was
lowered to 300 mg/kg/day once more. The post-treatment observation period for the mice was 12
weeks.
A statistically significant association between mortality and dose was noted. There was a
considerable decrease in survival after 45 weeks of exposure in the high-dose male and female
mice. Acute toxic tubular nephrosis was determined to be the apparent cause of death in 33 high-
dose males dying between weeks 69 and 70. There was a high incidence (95%) of pronounced
abdominal distension among the high-dose animals beginning in week 60 and continuing
throughout the recovery period, which was probably related to the liver tumors. The tumors
could also have contributed to the early deaths among the females.
A slight decrease in body weight gain (less than 10%) was observed in the high dose male
mice; no other effects on body weight gain were observed. Significant increases in the incidence
of hepatocellular carcinoma were observed in the low- and high-dose male and female mice.
Additional details on the tumorigenic effects of 1,1,2,2-tetrachloroethane are reported in Section
7.2.7. Increases in the incidence of nonneoplastic lesions were limited to hydronephrosis in the
high-dose groups (0/20, 0/46, 16/46) and chronic inflammation in the kidneys of high-dose
females (0/20, 0/46, and 5/46). This study identifies an NOAEL of 142 mg/kg for noncancer
effects and a frank effect level of 283 mg/kg in mice exposed to 1,1,2,2-tetrachloroethane for 78
weeks. After applying a duration adjustment to normalize the 5-days/week exposure over a
seven-day week, the NOAEL becomes 101 mg/kg/day and the LOAEL 202 mg/kg/day.
Inhalation Exposure
Schmidt et al. (1972) exposed groups of 105 male rats (strain not specified) to 0 or 13.3
mg/m3 four hours/day for up to 325 days. Interim sacrifices of 7 animals per group were
conducted on days 110 and 265 and at termination of exposure. After exposures ceased, the
remaining animals were kept until they died naturally. The parameters evaluated at each sacrifice
time were not consistent making it difficult to determine if there were any trends related to the
duration of exposure.
At 110 days, body weight was decreased by 5% compared to the controls, a decrease that
was reported as significant (p< 0.01). Leucocyte levels and P! globulins were significantly
increased (p<0.025 and p<0.02 respectively ) and adrenocorticotrophic hormone (ACTH)
concentration in the pituitary was decreased (p<0.001). The change in ACTH was the only
endpoint that was measured at each sacrifice point. The difference between the exposed and
control animals decreased with time and was only slightly lower than controls at 325 days
(p<0.02). At the 265 day-sacrifice, the fat content of the liver, segmented neutrophils and
lymphocytes were measured in addition to ACTH. The fat content of the liver was increased
(p<0.05) as were the segmented neutrophils (p<0.05). The percent lymphocytes was decreased
(p<0.01). The only parameter measured at 235 days in addition to ACTH was y-globulins which
were slightly increased (p<0.05).
1,1,2,2-Tetrachloroethane — January, 2008 7-19
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No histolopathological lesions were found in the lungs or heart of a monkey exposed to a
time-weighted average of 1974-ppm (13,779 mg/m3) 1,1,2,2-tetrachloroethane vapors 2
hours/day, 6 days/week for 9 months (Horiuchi et al., 1962). The monkey was reported to
experience transient diarrhea and anorexia, and sporadic changes in hematocrit, red blood cell,
and white blood cell counts, although these changes showed no clear dose-response trend
(Horiuchi et al., 1962). Only one monkey was studied, and a control was not included.
Rabbits were exposed to 0.3, 1.5, or 15 ppm (equivalent to 2, 11, and 105 mg/m3)
1,1,2,2,-tetrachloroethane for 3 to 4 hours daily for 7 to 11 months. The 15-ppm exposure group
showed early signs (unspecified) of liver degeneration at necropsy (Navrotskiy et al., 1971).
7.2.7 Carcinogenicity
Oral Exposure
A highly significant dose-related trend in the incidence of hepatocellular carcinomas was
observed in groups of 50 male and female B6C3F1 mice administered technical-grade
1,1,2,2-tetrachloroethane in corn oil by gavage (NCI, 1978). Full details of this study can be
found in Section 7.2.6. The-5 days/week, time-weighted average daily doses were 142 or 283
mg/kg/day for 78 weeks followed by a 12-week recovery period. The doses were normalized by
NCI for a 5-days/week exposure rather than for a 7 day exposure. When normalized for a 7-day
per week exposure these doses are equivalent to doses of 101 or 202 mg/kg/day. Effects in the
treatment groups compared to the control are summarized in Table 7-3. The increased
hepatocellular incidences were statistically significant at both dose levels compared with vehicle
controls. Tumors also appeared earlier in mice administered the higher dose than those given the
low-dose. The first tumor in the high does male mice occurred on week 52 while that in the low
dose occurred on week 84. For the female mice the first high-dose tumor occurred at 53 weeks
and the first low-dose tumor at 58 weeks. Between week 69 and 70 of the study 33 of the high
dose males died; all but one had tumors. Between week 52 and week 90, 34 of the female mice
died. Tumors were considered to be the cause for most on the premature animal deaths.
The hepatocellular tumors in the mice were varied in appearance. Some were clusters of
well-differentiated cells with a uniform arrangement of cords. Others were composed of
anaplastic cells with large hyperchromic nuclei, vacuolated pale cytoplasm, many with
eosinophilic inclusions. Mitotic figures were often present. Some tumors had a combined
morphology where anaplastic areas were identified within well differentiated tumors.
There was no significant increase in the incidence of any type of neoplastic or
preneoplastic lesions in groups of 50 male or 50 female Osborne-Mendel rats similarly
administered technical-grade 1,1,2,2-tetrachloroethane in corn oil by gavage (NCI, 1978). The
normalized time-weighted average doses (for 5 days/week) were 44 or 77 mg/kg/day (males) and
31 or 54 mg/kg/day (females) for 78 weeks. The control groups (untreated and vehicle) each
consisted of 20 animals/sex. There were two high-dose males with hepatocellular carcinomas and
one with a hepatic preneoplastic nodule, but these results were not significant. None-the-less,
NCI considered the results in male rats to be equivocal because hepatocellular carcinomas are
rare tumors in Osborne-Mendel rats. One papilloma and one carcinoma of the stomach were also
observed in the high-dose males.
1,1,2,2-Tetrachloroethane — January, 2008 7-20
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Table 7-3 Summary of Liver Tumor Incidence, 78-Week Study in Mice
Male
Female
Normalized Time Weighted
Average Doses Dose1
(mg/kg/day)
0 (untreated)
0 (vehicle)
101
202
0 (untreated)
0 (vehicle)
101
202
Liver Tumor Incidence
2/182
1/18
13/503
44/493
!/202
0/20
30/483
43/473
Source: NCI (1978)
1. Doses were derived from the data in the NCI report (Table 2) and duration adjusted to accommodate the 5 out of 7
day weekly exposure. The calculation of the high dose exposure using the formula given by NTP with Table 2 and
data in exposures and durations indicated that the high dose exposure before 5-days/week normalization was 283.3
mg/kg/day rather than 284 mg/kg/day as indicated in Table 6 of the NCI report or 282 mg/kg/day as indicated in the
NCI study summary.
2. The data on the numbers of animals with tumors were obtained from Tables 6 and 7 of the NCI report and differ
for the male and female untreated control group from the values given in the NCI study summary. Any animals that
died prior to the appearance of the first tumor are not included in the statistical evaluation.
3. Significantly increased compared to control, p < 0.05.
In an initiation/promotion assay, groups of 10 male Osborne-Mendel rats were
administered a gavage dose of 100 mg/kg body weight in corn oil followed by dietary exposure to
phenobarbital for 7 weeks and were sacrificed a week later. 1,1,2,2-Tetrachloroethane caused a
significant (p < 0.05) increase in the formation of y-glutamyl transpeptidase-positive (GGT+)
foci in the liver (a preneoplastic indicator) when compared to the corn oil control but not the
phenobarbital control. When 1,1,2,2-tetrachloroethane was administered for 7 weeks after
diethylnitrosamine initiation, the number of GGT+ foci (4.4 ±0.8) were greater than those that
formed when the tetrachloroethane was administered as the initiator (1.2 ±0.4). Accordingly, the
data suggest that 1,1,2,2-tetrachloroethane may act as a weak initiator of GGT± foci and as a
stronger promoter for foci initiated by a different chemical (Story et al., 1986).
Other Routes of Exposure
The development of pulmonary tumors in groups of 20 male Strain A mice following
intraperitoneal administration of 80, 200, or 400 mg/kg-day of 1,1,2,2-tetrachloroethane in
tricaprylin three times per week for up to 8 weeks was studied by Theiss et al. (1977).
Tricaprylin served as the vehicle control and urethane as a positive control. The number of
injections was as follows: 5 injections for the 80-mg/kg/day group, 18 injections for the 200-
mg/kg/day group, and 16 injections for the 400-mg/kg/day group. Preliminary testing identified
the highest dose as a maximally tolerated dose. The animals were sacrificed at 24 weeks and the
1,1,2,2-Tetrachloroethane —January, 2008
7-21
-------
number of surface lung-adenomas was evaluated. A marginally significant increase (p=0.059) in
pulmonary tumors in mice was reported at 400 mg/kg-day, but not at lower doses. Mortality,
however, was high in this study. Only 5 of 20 mice survived to the end of the study in the 400-
mg/kg dose group. Animal deaths also occurred in the low-dose (10/20) and mid-dose (5/20)
groups.
Colacci et al. (1993) used BALB/c 3T3 cells that had been transformed in vitro through
exposure to 1,1,2,2-tetrachloroethane (see Section 7.3.1) and injected them subcutaneously into
groups of 5 athymic Charles River CD1/BR mice. The BALB/c 3T3 cell line is derived from the
mouse embryo and is fibroblast-like in its properties. It is used in tumorigenicity and viral
transformation assays (HyperCLDB, 2004). Two concentrations were tested. In the absence of
S9, a concentration of 1000 |lg/mL was necessary to achieve transformation while in the presence
of S9, a concentration of 500 |ig/mL was sufficient. Separate pools of cells were prepared for the
transformation assay, two without S9 (pools A and B) and two with S9 (pools C and D).
Transformed cells were injected subcutaneously at concentrations of 1 x 106 or 5 x 106
transformed cells. The mice were observed weekly for tumor formation for up to 4 months. All
animals injected with the higher concentration of transformed cells (19/19) and 8 of 9 animals
receiving the lower concentration developed tumors within 3 months. At 3 months there were no
tumors in the controls injected with untreated BALB/c 3T3 cells; after 4 months there were
tumors in 3 of 10 controls.
In a second phase of this same study, transformed cells (5 x 105) were injected
intravenously into groups of 8 or 9 mice. The control group received untreated BALB/c 3T3
cells. After 8 weeks the animals were sacrificed; 25% of the controls had pulmonary nodules
while the incidence among the 4 treated groups ranged from 55.5% to 88.9%. Table 7-4
summarizes the tumors and metastasises observed in each group. Cells transformed with 1,1,2,2-
tetrachloroethane in the presence and absence of S9 had increased tumors and metastasises. The
authors concluded that 1,1,2,2-tetrachloroethane was able to transform weakly tumorigenic
BALB/c 3T3 cells to fully tumorigenic and invasive cells and that both genotoxic and
nongenotoxic events may have been involved with this change (Colacci et al., 1993).
1,1,2,2-Tetrachloroethane — January, 2008 7-22
-------
Table 7-4 Experimental Metastasises in Athymic Mice Injected with Transformed
BALB/c 3T3 Cells
Test Material
BALB/c 3T3 cells
1,1,2,2-Tetrachloroethane; 1000 |J,g/mL -
no S9 - Pool A
1,1,2,2-Tetrachloroethane; 1000 [ig/mL -
no S9 - Pool B
1,1,2,2-Tetrachloroethane; 500 |J,g/mL with
S9 - Pool C
1,1,2,2-Tetrachloroethane; 500 |J,g/niL with
S9 - Pool D
Animals with
Tumors
4/16
7/8
8/9
7/8
5/9
Range of Observed
Metastasises per Mouse
0-10
1-17
0-7
0-8
0-56
Median for
Metastasises
0
8
2
5
1
Adapted from Colacci et al. (1993)
Note: There seems to be an error in the Table in the published paper from which these data are abstracted. The
transformed cell pools with S9 are identified as Pool A and B. The methodology section clearly identifies these as
pools C and D. Accordingly they are identified as such in this table.
7.3 Other Key Data
7.3.1 Mutagenicity and Genotoxicity
1,1,2,2-Tetrachloroethane has shown mixed results in assays for gene mutation,
chromosomal aberration, DNA repair and synthesis, and cell transformation.
Results of selected in vitro studies are summarized in Table 7-5. Predominantly negative
results have been reported for the induction of gene mutation in prokaryotic systems with or
without metabolic activation, whereas both positive and negative results have been observed for
gene conversions in yeast and fungi. 1,1,2,2-Tetrachloroethane induced sister chromatid
exchange but not chromosomal aberrations, DNA repair, or unscheduled DNA synthesis in
mammalian cells in vitro. In vivo micronucleus results in mice were positive in both males and
females.
Studies using Salmonella typhimurium strains that detect base pair (TA100 and TA1535)
and frame shift (TA98, TA1537, and TA1538) mutations were negative in almost all assays
(Haworth et al., 1983; Milman et al., 1988; Nestmann et al., 1980) using concentrations that range
from those with no associated cytotoxicity to those high enough to cause cytotoxicity. Exceptions
to the negative results are the studies by Mersch-Sundermann (1989a) and Brem et al. (1974).
Mersch-Sundermann (1989a) obtained positive results in TA97 and TA98 in the absence of
microsomal activation; Brem et al. (1974) reported positive results in TA1530 and TA1535 in the
presence of microsomal activation.
1,1,2,2-Tetrachloroethane —January, 2008
7-23
-------
Inhalation exposure to 1,1,2,2-tetrachloroethane at 349 mg/m3 (51 ppm) for 5 days did not
induce dominant lethal mutations in rats, and results for chromosomal aberrations in rat bone
marrow cells were equivocal. This concentration did not induce cytotoxicity (McGregor, 1980).
1,1,2,2-Tetrachloroethane did not induce unscheduled DNA synthesis in hepatocytes of mice
exposed to doses of 200, 500, or 600 mg/kg body weight by gavage. Results for the induction of
S-phase synthesis (an indicator of chemically induced cell proliferation) were negative in
hepatocytes from male mice dosed with 200 or 600 mg/kg and were equivocal in female mice
dosed with 500 mg/kg (Mirsalis et al., 1989).
Table 7-5 Genotoxicity of l,l;2,2-Tetrachloroethane In Vitro
Species (test system)
Saccharomyces cerevisiae
D7
Saccharomyces cerevisiae
D7
XV185-14C
Salmonella typhimurium
TA1530, TA1535
TA1538
Salmonella typhimurium TA
98, TA 100, TA1535, TA
1537, TA 1538
Salmonella typhimurium TA
98, TA 100, TA 1535, TA
1537
Salmonella typhimurium
TA98, TA100, TA1535,
TA1537
Salmonella typhimurium
TA100
Salmonella typhimurium
TA 97, TA 98
TA 100, TA 102
Salmonella tvphimurium
End-point
Mitotic gene conversion
Recombination
Gene conversion and
reversion
Reverse mutations
Reverse mutations
Reverse mutations
Reverse mutations
Reverse mutations
Reverse mutations
Forward mutations
With
activation
nt
nt
nt
nt
nt
nt
+
-
-
Without
activation
+
+
-
+
-
-
-
-
Reference
Callenetal., 1980
Nestmann and Lee,
1983
Bremetal., 1974
Nestmann et al.,
1980
Milman et al., 1988
Haworth et al., 1983
Warner etal., 1988
Mersch-Sundemann
etal., 1989a
Roldan-Arjona et al,
1,1,2,2-Tetrachloroethane — January, 2008
7-24
-------
Species (test system)
BA13/BAL13
Escherichia coli (polymerase
deficient pol A+/pol A-)
Escherichia coli PQ37
Escherichia coli
Aspergillus nidulans
Chinese hamster ovary cells
Chinese hamster ovary cells
BALB/c3T3 cells (mouse)
Mouse hepatocytes
Mouse hepatocytes
Rat hepatocytes
Rat hepatocytes
Human embryonic intestinal
cells
End-point
DNA damage
Gene mutation
Induction of prophage
lambda
Mitotic malsegregation
Chromosomal
aberrations
Sister chromatid
exchange
Sister chromatid
exchange
DNA growth, repair, or
synthesis
DNA repair
DNA growth, repair, or
synthesis
DNA repair
Unscheduled DNA
synthesis
With
activation
nt
"
+
nt
+
+
nt
nt
nt
nt
Without
activation
+
"
"
+
+
+
-
-
Reference
1991
Bremetal., 1974
Mersch-Sundemann
etal., 1989b
DeMarini and
Brooks, 1992
Crebelli et al., 1988
Galloway etal.,
1987
Galloway etal.,
1987
Colacci et al., 1992
Williams, 1983
Milmanetal., 1988
Williams, 1983
Milmanetal., 1988
McGregor, 1980
nt = not tested
Radio label from 1,1,2,2-Tetrachloroethane has been reported to bind to or become
incorporated into cellular macromolecules (DNA, RNA, and/or proteins) from several organs in
rodents, following in vivo exposure (Mitoma et al., 1985; Colacci et al., 1987; Eriksson and
Brittebo, 1991). Results for cell transformation in mammalian cells have been mixed, with
positive results (Colacci et al., 1992, 1993) and negative results (Little, 1983; Tu et al., 1985;
Milman et al., 1988) reported. 1,1,2,2-Tetrachloroethane did not induce sex-linked recessive
lethal mutations or mitotic recombination in Drosophila melanogaster in three studies
(McGregor, 1980; Woodruff et al., 1985; Vogel andNivard, 1993).
An in vivo mouse micronucleus test was conducted for NTP (2004) using dietary levels of
1,1,2,2-tetrachloroethane equivalent to those employed in the subchronic study. Groups of 5 male
1,1,2,2-Tetrachloroethane —January, 2008
7-25
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and 5 female mice were used for each of the five dose groups. There was a dose-related increase
in the number of micronucleated normochromatic erythrocytes per thousand cells and a
significant difference from controls for the males and females. Accordingly the test results were
considered positive.
Colacci et al. (1992) concluded that 1,1,2,2-tetrachloroethane was able to initiate genetic
changes in an in vitro two-stage BALB/c 3T3 cell culture. The cells were treated with
subeffective or transforming concentrations of 1,1,2,2-tetrachloroethane (31.25 to 500 |lg/mL) in
the presence of an S9 activating system and in the absence or presence of tetradecanoylphorbol
acetate (TPA), a promoter. In the level I analysis, the number of transformed foci were double
those of the controls for concentrations of 62.5 |ig/mL and above in the absence of TPA, but
lower than the benzo(a)pyrene used as a positive control. In the presence of TPA, the difference
between the 1,1,2,2-tetrachloroethane and controls was increased and the number of transformed
foci were similar to the benzo(a)pyrene positive control. The level II analysis examined the
potential for amplification of the response through a replating of the transformed cells allowing
for additional rounds of cell division. In the level II analysis, all 1,1,2,2-tetrachloroethane
concentrations tested showed statistically significant increases in the mean number of
transformations per plate in both the presence and absence of TPA.
Colacci et al (1992) also examined the ability of 1,1,2,2-tetrachloroethane to induce
chromosomal aberrations in BALB/c 3T3 cells using 500 |lg/mL in the absence of S9 and 1000
|lg/mL in the presence of S9. DMSO (1%) was the solvent control and 3-methylcholanthrene
and benzo(a)pyrene were the positive controls. Responses for the 1,1,2,2-tetrachloroethane were
comparable to the positive controls in both cases.
The in vitro studies of mutagenicity suggest that 1,1,2,2-tetrachloroethane either does not
alter DNA structure or, is at best, a weak mutagen. The mouse micronucleus results in
conjunction with the in vitro tests for sister chromatid exchange indicate that 1,1,2,2-
tetrachloroethane can have clastogenic effects.
7.3.2 Immunotoxicity
Rabbits exposed to 1.5 ppm of 1,1,2,2-tetrachloroethane vapor 3 hours/day for 8 months
and then immunized with a typhoid vaccine showed a decrease in antibody liters and an increase
in the electrophoretic mobility of the specific antibodies when compared to rabbits that were not
exposed to 1,1,2,2-tetrachloroethane (Shmuter, 1977).
The elevated incidence of chronic murine pneumonia among treated female rats (40%,
68%, and 76% for control, low dose, and high dose animals, respectively) in the NCI (1978)
cancer study, along with the elevated white cell counts (90% higher than controls) seen by
Schmidt et al. (1972) after 110 days of exposure to 13.3 mg/m3, are suggestive of possible effects
on the immune system. In the NTP studies (2004), significantly decreased relative thymus
weights were observed in female rats at the highest dose, but not in male rats or male or female
mice.
1,1,2,2-Tetrachloroethane — January, 2008 7-26
-------
7.3.3 Physiological or Mechanistic Studies
7.3.3.1 Noncancer Effects
ImpairedHeme Synthesis. There are limited mechanistic data that relate to the effects of
1,1,2,2-tetrachloroethane on heme synthesis. The data come from a study conducted to determine
if heme effects may have contributed to decreased levels of CYP P450 enzymes. Paolini et al.
(1992) treated groups of 6 male and female Swiss albino mice with doses of 0, 300, or 600 mg/kg
1,1,2,2-tetrachloroethane in corn oil. The animals were fasted for 16 hours before dosing, and
sacrificed 24 hours after exposure. The livers were removed and analyzed for the activity of y-
aminolevulinic acid (ALA) synthetase (a critical enzyme for heme synthesis) and heme
oxygenase (a critical enzyme for heme degradation). The activity of ALA synthetase was
decreased by 35% at the lower dose and by almost 60% at the higher dose. The lower dose had
no significant effect on heme oxygenase activity, but activity was increased by about 35% at the
higher dose. At the 600-mg/kg dose, the total heme content of the liver was reduced by about
33%. The authors concluded that the decrease in heme level in the liver was, in part, responsible
for a decrease in the levels of CYP 450 (58-73%) observed during other portions of this same
study (see Section 6.3).
Decreased hemoglobin or hematocrit levels were identified in several short term studies of
1,1,2,2-tetrachloroethane (NTP, 2004; Minot and Smith, 1921). The study of hepatic heme
synthesis by Paolini et al. (1992) did not examine the impact of 1,1,2,2-tetrachloroethane on
hematopoiesis. Accordingly the results are not directly applicable to the observation of decreased
red-blood cell parameters measured in the whole animal studies.
Lipid Per oxidation. Paolini et al. (1992) used electron spin resonance spectroscopy in
conjunction with a spin trapping agent to determine if free radicals were formed in the liver of 5
male mice exposed to a single intraperitoneal dose of 600 mg/kg 1,1,2,2-tetrachloroethane and
sacrificed 24 hours later. The observed signal was interpreted as being evidence for the presence
of a CHC12CHC1 free radical. Mice treated with 180 mg/kg phenyl-T-butylnitrone served as a
positive control. In addition, lipid extracts from the treated mouse livers gave spectroscopic
evidence that conjugated dienes and hydroperoxides from lipid peroxidation of polyunsaturated
fatty acids were present in the endoplasmic reticulum.
Dolichols are long chain polyisoprenoid units found in mammalian tissues in their free
form or esterified to phosphate or fatty acids. They are located in the endoplasmic reticulum and
Golgi apparatus and function in the glycosylation of glycoproteins and in the process of
membrane translocation of activated glycosyl units. Cottalasso et al. (1998) hypothesized that the
dolichols would be substrates for attack by free radicals produced in the metabolism of 1,1,2,2-
tetrachloroethane and that their inactivation would impact the glycoslylation of secretory proteins,
particularly the very low density lipoproteins. Accordingly, this study investigated whether
1,1,2,2-tetrachloroethane affects glycosylation mechanisms by changing the dolichol levels and
distribution in rat liver microsomes and Golgi apparatus. Analysis for free-radical modified or
peroxidized dolichols was not a component of the protocol.
1,1,2,2-Tetrachloroethane — January, 2008 7-27
-------
Male Sprague-Dawley rats received a single dose of 0 or 574 mg/kg
1,1,2,2-tetrachloroethane in mineral oil and groups of 5 animals were sacrificed 5, 15, 30, and 60
minutes later. Samples of the endoplasmic reticulum (microsomes) and Golgi apparatus (three
fractions) were collected from homogenized liver samples and analyzed for their total dolichol,
free dolichol and dolichol phosphate concentrations. Total dolichol levels decreased in all
organelle samples at 60 minutes after dosing. The decreases were greatest in microsomes and the
secretory fraction of the Golgi apparatus (a decrease of 56% and 57%, respectively). There was a
continual decrease in both free dolichol and dolichol phosphate in microsomes at all time points.
Decreases were significant in the 15-minute and later samples. If this phenomenon were linked to
the assembly of very low density lipoproteins (VLDLs), it could help to explain the
hypocholesteremic effects of 1,1,2,2-tetrachloroethane in rats and mice. VLDLs are responsible
for the systemic transport of endogenous cholesterol from the liver to other tissues.
7.3.3.2 Cancer Effects
As part of a study to determine if BALB/c 3T3 cells exposed to 1,1,2,2-tetrachloroethane
were capable of inducing tumor formation in treated mice, Colacci et al. (1993) examined the
invasive properties of the transformed cells using a reconstituted basement membrane matrigel
derived from an Engelbrecht-Holm-Swarm tumor. In order to become invasive and metastasize,
most tumor types must be able to cross basement membranes. Very few control BALB/c 3T3
cells were able to cross the membrane matrigel. However, a large number of the transformed
cells were able to penetrate the membrane barrier. The transformed cells were also able to
display invasive growth in a three dimensional gel formed from the reconstituted membrane.
7.3.3.3 Interactions with Other Chemicals
In an in vitro study of the synergistic effects of 15 xenobiotic chemicals with 2,4-D,
1,1,2,2-tetrachloroethane was one of the materials evaluated. The toxicity of the 2,4-D was
enhanced when a no effect concentration (NOEC) of 1,1,2,2,-tetrachloroethane was combined
with it. In one study, Jacobi et al. (1995) found that there was a decrease in the concentration of
2,4-D that caused a 20% growth inhibition in human fibroblasts when it was combined with the
no effect concentration of 1,1,2,2-tetrachloroethane. In a second study, the binary combination of
an NOEC concentration of 1,1,2,2,-tetrachloroethane with 2,4-D decreased DNA synthesis by
48% in cultured fibroblasts compared to 2,4-D alone (Jacobi et al., 1996). The authors
hypothesize that lipophilic substances like 1,1,2,2,-tetrachloroethane are synergistic in
combination with a hydrophylic compound like 2,4-D at much lower concentrations than
hydrophilic chemicals because of their capacity to damage membranes and enhance cellular
uptake of both compounds.
1,1,2,2-Tetrachloroethane — January, 2008 7-28
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7.3.4 Structure-Activity Relationship
1,1,2,2-Tetrachloroethane is one of a series of chlorinated ethanes that have been studied
for their toxicity. Most of them (1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane,
1,1,1,2-tetrachloroethane, and hexachloroethane), like 1,1,2,2-tetrachloroethane, are associated
with tumor development in at least one species (U.S. EPA, 1986d,e,f, 1987, 1989a,b). All of
them have caused liver precancerous nodules, adenomas, and/or carcinomas in mice; 1,1-
dichloroethane and 1,2-dichloroethane also caused mammary tumors and hemangiosarcomas in
female rats. Hepatic toxicity, and in some cases, renal toxicity, are characteristics of many of
these related chlorinated ethanes and were often identified as the critical effects that provided the
basis for the their IRIS RfD values. A number of these chlorinated alkanes and alkenes also share
common metabolites (i.e., DCA and TCA). DCA has been demonstrated to cause tumors in both
rats and mice (mice are more sensitive) and TCA has caused tumors in mice.
7.4 Hazard Characterization
7.4.1 Synthesis and Evaluation of Major Noncancer Effects
Human exposure data for 1,1,2,2-tetrachloroethane consist of one experimental inhalation
study, case reports of suicidal or accidental ingestion, and occupational studies. Many of the
occupational reports are dated and complicated by uncertainties in levels of exposure to
1,1,2,2-tetrachloroethane and other chemicals. The human case studies suffer from similar
deficiencies in the quantification of exposure and the reporting of effects. Autopsy findings in
suicide cases included congestion and edema in the lungs, mucosal congestion of the esophagus
and upper stomach, and epicardial- and endocardial- anoxic hemorrhaging (ATSDR, 2006).
Respiratory, mucosal, and eye irritation, nausea, vomiting, and dizziness were reported by
humans volunteers exposed to 1,1,2,2-tetrachloroethane vapors under controlled chamber
conditions (Lehmann and Schmidt-Kehl, 1936). In a few occupational situations, death resulted
from inhalation exposure to 1,1,2,2-tetrachloroethane. The subjects who died had fatty
degeneration and necrosis of the liver as well as effects on the kidney, spleen, and heart (Coyer,
1944; Willcox et al., 1915). Effects from non-lethal occupational exposures included gastric
distress (including pain, nausea and vomiting), loss of appetite, and loss of body weight (Jeney et
al., 1957; Lobo-Mendonca 1963; Minot and Smith 1921). There also were increases in the number
of white blood cells, jaundice, an enlarged liver, cirrhosis, and neurological symptoms such as
headache, tremors, dizziness, numbness, and drowsiness.
There have been a variety of animal studies in rats and mice using both the inhalation and
oral exposure routes. Some of the early work does not follow current standards for good
laboratory practices. Several of these studies were reported in German and the study descriptions
were obtained from translation of the German papers or from secondary sources (ATSDR, 2006;
Cal EPA, 2003). Studies by the NTP (2004) provide a detailed evaluation of the short-term and
subchronic oral toxicity of 1,1,2,2-tetrachloroethane and confirm many of the early observations.
In rats and mice exposed orally, the liver appears to be the principal target organ. Effects
on the liver were seen in subchronic studies and included: histopathological alterations consisting
1,1,2,2-Tetrachloroethane — January, 2008 7-29
-------
of basophilic, eosinophilic, mixed cell, and/or clear cell foci of cellular alterations; hepatocyte
necrosis; mitotic alterations in hepatocytes; liver pigmentation; bile duct hyperplasia; hepatocyte
hypertrophy; cytoplasmic vacuolization and increased liver weight (NTP, 2004; Schmidt et al.,
1980a). Biomarkers of the damage to the liver include elevated serum levels of ALT and/or SDH
(NTP, 2004). Data on hepatic effects after short-term exposures (Dow, 1988; NTP, 1996, 2004:
Schmidt et al., 1980a) are limited, but are consistent with the observations following subchronic
oral exposure. Rats seem to exhibit these effects at lower doses than mice.
In addition to effects on the liver, rats exposed to 1,1,2,2-tetrachloroethane exhibited
decreased leucocyte counts and changes in red blood cell parameters indicative of a microcytic
anemia (NTP, 2004). Effects on the kidney were suggested by increased relative kidney weights
in rats and mice in short-term and/or subchronic studies (NTP, 1996, 2004) and acute tubular
nephrosis in mice after chronic exposures (NCI, 1978). Decreased relative thymus weights in
female rats at high doses (NTP, 2004) suggested the possibility of immunological effects. In mice,
there were no hematological effects and kidney weights were decreased at doses above 2300 ppm
in males (NTP, 2004). Significant non-neoplastic effects in the NCI (1978) studies were limited to
the kidney in mice.
Death was a frequent consequence of high-dose exposure of animals to 1,1,2,2-
tetrachloroethane. In such instances, the animals exhibited clear clinical signs of distress. Weight
gain was impeded and, in some cases, weight loss was observed (NTP, 2004). In short-term high
dose studies, the distressed animals became emaciated, had a poor quality coat and some showed
patches of hair loss (NTP, 1996, 2004). Neurological effects occurred primarily after inhalation
exposures and included decreased motor activity, loss of reflexes, ataxia, prostration, and narcosis
(Horvath and Frantek, 1973; Lazarew, 1929; Price et al., 1978).
Information on the reproductive effects of 1,1,2,2-tetrachloroethane is limited. There is a
single one-generation study that does not follow a standard methodology and examined a small
number of animals (5 females and 7 exposed males) exposed via inhalation to one dose (13
mg/m3). There were no statistically-significant differences in the percentage of females having
offspring (77.1% in controls vs. 62.9% in exposed animals), number of pups per litter, average
birth weight, gestation length, sex ratio, offspring mortality at postnatal days 1, 2, 7, 14, 21, and
84, or average weight on postnatal day 84. No macroscopic malformations were observed
(Schmidt et al., 1972).
There was a decrease in sperm motility in the NTP study (2004) following an oral 14-week
exposure at concentrations of 27 mg/kg/day and greater. At higher doses (> 149 mg/kg/day) the
left epididymus weight was decreased and the weight of the left cauda epididymus was increased.
Similar effects were seen in mice, although, at higher doses (1525 mg/kg/day).
Range-finding studies for developmental toxicity conducted for NTP (199la, b) found that
1,1,2,2-tetrachloroethane was toxic to the dams and pups of Sprague-Dawley rats and CD-I Swiss
mice. Rats were more sensitive than mice. The NOAEL in the rats for both maternal toxicity and
associated fetal toxicity was 34 mg/kg/day with an LOAEL of 98 mg/kg/day for decreased
maternal weight gain and decreased fetal body weight (NTP, 199la). In mice the NOAEL was
987 mg/kg/day and the LOAEL was 2120 mg/kg/day for mortality and fetal resorptions (NTP,
1,1,2,2-Tetrachloroethane — January, 2008 7-30
-------
1991b). These studies did not include evaluations of the pups for visceral or skeletal
abnormalities.
7.4.2 Synthesis and Evaluation of Carcinogenic Effects
There is only one study that examined the relationship between 1,1,2,2-tetrachloroethane
and cancer in humans. An epidemiological study on the relationship between occupational
exposure of soldiers to 1,1,2,2-tetrachloroethane during World War II and subsequent development
of tumors over the 30+ year period after the exposure was carried out by Norman et al. (1981). It
showed a weak correlation between inhalation exposure to 1,1,2,2-tetrachloroethane and
development of genital tumors and leukemia. The soldiers were exposed to other chemicals in
addition to 1,1,2,2-tetrachloroethane during their military service and there were no post-military
records on employment, so no definite conclusions could be drawn from the study.
The ability of 1,1,2,2-tetrachloroethane to induce cancer in animals was tested in an oral
gavage study and an intraperitoneal injection study. NCI (1978) looked for tumors in B6C3F1
mice and Osborne-Mendel rats following oral gavage administration of 1,1,2,2-tetrachloroethane
in corn oil for 78 weeks, followed by 32 weeks of observation for the rats and 12 weeks for the
mice. A significant increase in the incidence of hepatocellular carcinomas in B6C3F1 mice was
reported. Rats had no significant increase in tumor incidence, but there were two males with
hepatocellular carcinomas and one with a preneoplastic hepatic nodule in the high-dose group.
According to (NCI, 1978), these are rare tumors for Osborne-Mendel rats. The 7-days/week,
normalized time-weighted average doses were 44 and 78 mg/kg/day for male rats, 31 and 55
mg/kg/day for female rats, and 101 and 202 mg/kg/day for both male and female mice.
Haseman (1984) reported that an increased incidence of hepatocellular carcinomas in
B6C3F1 mice is not unusual because many chemicals increase the spontaneous rate of such tumors
in these mice, but do not produce them in other sites in mice or in rats. Since this species of mouse
has a high rate of spontaneous incidence of liver tumors, the data may not be indicative of
carcinogenic risk in humans (ATSDR, 1996). Osborne-Mendel rats have been shown to have a
low incidence of liver tumors when treated with carbon tetrachloride as a positive control (NCI,
1978). This indicated to the study authors that rats may not be sensitive enough to detect tumors
caused by 1,1,2,2-tetrachloroethane.
The second study that resulted in carcinogenic effects in animals focused on the
development of pulmonary tumors in male Strain A mice following intraperitoneal administration
of 80 to 400 mg/kg-day of 1,1,2,2-tetrachloroethane for 2 to 6 weeks (Theiss et al., 1977). A
marginally significant increase in pulmonary tumors in mice was reported at 400 mg/kg/day, but
not at lower doses (Theiss et al., 1977). The results from this study were confounded by a small
number of animals in each dose group (20 males) and high mortality during the study.
1,1,2,2-Tetrachloroethane — January, 2008 7-31
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7.4.3 Mode of Action and Implications in Cancer Assessment
Story et al. (1986) examined the effect of 1,1,2,2-tetrachloroethane in a rat liver GGT+ foci
assay for its initiating and promoting potential in male rats. The results indicated that 1,1,2,2-
tetrachloroethane was a weak initiator and a somewhat stronger tumor promoter. Colacci et al.
(1992, 1993) confirmed tumor initiation by 1,1,2,2-tetrachloroethane using an in vitro two-stage
BALB/c 3T3 cell transformation assay combined with an in vivo phase which demonstrated the
tumorigenic impact of the injected transformed cells in athymic CD1/BR mice. The results of
these studies suggest that 1,1,2,2-tetrachloroethane can act as a complete carcinogen, although it
seems to have a stronger influence as a promoter of tumors initiated by other factors.
7.4.4 Weight of Evidence Evaluation for Carcinogenicity
Evidence of carcinogenicity was seen in male and female mice in a study conducted by the
NCI (1978). The evidence for tumorigenicity in male rats in the same study was equivocal.
Mechanistic studies of initiation and promotion using the production of GGT + foci in the livers of
male Osborne-Mendel rats and an in vitro two-stage BALB/c3T3 cell transformation assay in
athymic CD1/BR mice indicate that 1,1,2,2-tetrachloroethane is a weak initiator that also can
function as a tumor promoter (see Section 7.4.3 above). Studies of gene mutation in Salmonella
have mostly been negative, but a few positive results were observed. Results with Saccharomyces
cerevisiae and Escherichia coli were also mixed. The mouse micronucleus assay (NTP, 2004) was
positive for males and females as were in vitro assays for sister chromatid exchange (Galloway et
al., 1987; Colacci etal., 1992).
Following the U.S. EPA (2005a) guidelines for carcinogen risk assessment, 1,2,2,2-
tetrachloroethane can be classified as likely to be carcinogenic to humans. Information from
animal studies is adequate, but supporting data from human studies are lacking. The IRIS
classification for 1,1,2,2-tetrachloroethane (U.S. EPA, 1986e) under the U.S. EPA (1986c)
guidelines for cancer assessment is Group C. However, the IRIS assessment is presently being
updated through the IRIS program. The International Agency for Research on Cancer (IARC,
1999) classifies 1,1,2,2-tetrachloroethane in Group 3. The data in humans are inadequate and
there is limited evidence for carcinogenicity in experimental animals. The Agency IRIS
assessment for DC A, the principal 1,1,2,2-tetrachloroethane metabolite classified DC A as likely to
be carcinogenic to humans (U.S. EPA, 2005a).
1,1,2,2-Tetrachloroethane — January, 2008 7-32
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7.4.5 Potentially Sensitive Populations
No populations with unusual susceptibility to the health effects of 1,1,2,2-tetrachloroethane
could be identified based on the available literature. Factors that could increase individual
susceptibility include chronic alcohol consumption, diabetes, and fasting (Soucek and Gut, 1992).
Individuals with pre-existing liver and kidney damage would likely be sensitive to 1,1,2,2-
tetrachloroethane exposure. Low intake of antioxidant nutrients (Vitamin E, Vitamin C, and
selenium) would be a predisposing factor for liver damage if free radicals play a role in the hepatic
toxicity of 1,1,2,2-tetrachloroethane.
No data were available that could be used to evaluate sensitivity to children. Fetotoxicity
observed during pregnancy appeared to be a consequence of maternal toxicity (NTP, 1991a,b). In
the NTP studies (2004), males appeared to demonstrate hepatic toxicity at lower doses than those
affecting females.
Dichloroacetic acid (DCA) is the principal metabolite of 1,1,2,2-tetrachloroethane and also
causes hepatic toxicity and liver tumors. DCA is a disinfection by-product that is often present in
disinfected potable water. If continuous exposure to DCA in disinfected water inhibited GSTZ, it
could increase the toxicity of the 1,1,2,2-tetrachloroethane.
Populations differ in their ability to convert DCA to oxalic acid. Five separate isozymes of
the rate controlling enzyme (GSTZ) with differing catalytic capabilities have been identified (e.g.,
GSTZla-la, GSTZlb-lb, GSTZlc-lc, GSTZld-ld, and GSTZle-le) (U.S. EPA, 2003b).
Differences in GST zeta activity could render some populations more sensitive to 1,1,2,2-
tetrachloroethane than others. However, it will be necessary to have a more complete
understanding of the mode of action for DCA and 1,1,2,2-tetrachloroethane hepatic toxicity in
order to predict how differing GST isozymes might influence sensitivity.
1,1,2,2-Tetrachloroethane — January, 2008 7-33
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1,1,2,2-Tetrachloroethane — January, 2008 7-34
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8.0 DOSE-RESPONSE ASSESSMENT
8.1 Dose-Response for Noncancer Effects
The derivation of the reference dose (RfD) for 1,1,2,2-tetrachloroethane is described
below. The RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a
daily oral exposure to the human population (including sensitive subgroups) that is likely to be
without an appreciable risk of deleterious effects during a lifetime. Table 8-1 summarizes the
available dose-response data for oral subchronic and chronic animal studies of 1,1,2,2-
tetrachloroethane. The available data indicate that the liver seems to be the principal target organ
and rats are more susceptible to the noncancer effects of 1,1,2,2-tetrachloroethane than mice after
oral exposures (NCI, 1978; NTP, 2004). The NTP subchronic study (2004) provides the most
complete data set for noncancer effects and is the study that identified the lowest LOAEL.
Accordingly, this study was selected for use in derivation of the RfD. The NCI (1978) study is an
inadequate basis for the development of an RfD because it did not examine a full range of
noncancer endpoints and lacked an NOAEL. The LOAELs were the same or greater than the
LOAELs in the NTP study (2004) .
Table 8-1 NOAEL/LOAEL Data for Oral Subchronic and Chronic Studies of 1,1,2,2 -
Tetrachloroethane
Species
Rats
Mice
Rats
Mice
Rats
Mice
Study
Duration
14 weeks
14 weeks
6 weeks
6 weeks
78 weeks
78 weeks
NOAEL
(mg/kg/day)
20 (M, F)
100 (M)
80 (F)
100 (M)
56 (F)
316
None
None
LOAEL
(mg/kg/day)
40 (M, F)
200 (M)
160 (F)
178 (M)
100 (F)
None
31 (M)
101 (M/F)
Critical Effect(s)
Hepatocyte cytoplasmic
vacuolization, Increases in SDH,
increased relative liver weight,
decreased hemoglobin (males),
decreased hematocrit (females),
decreased sperm motility.
Hepatocyte hypertrophy, increased
relative liver weight
Decreased body weight gain;
Decreased body weight gain
Increased incidence of chronic
murine pneumonia
Liver tumors
Reference
NTP, 2004
NTP, 2004
NCI, 1978
NCI, 1978
NCI, 1978
NCI, 1978
In the NTP study (2004), groups of male and female F344 rats (10/sex) were fed diets
containing microencapsulated 1,1,2,2-tetrachloroethane for 14 weeks at concentrations of 0, 268,
589, 1180, 2300, and 4600 ppm. One control group was untreated and a second received food
containing the starch microcapsules. Doses were 0, 20, 40, 80, 170, or 320 mg/kg/day for the
males and females. Statically significant decreases in body weight gain were observed in the
1,1,2,2-Tetrachloroethane —January, 2008
8-1
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males from the two highest dose groups and the females from the three highest dose groups
(> 1,180 ppm for females and >2,300 ppm in males). Animals in the highest dose group lost
weight across the duration of the study, but all animals survived. Doses of 2300 and 4600 ppm
exceeded the maximum tolerated dose based on changes in body weight.
The blood samples taken on days 5 and 21 had a variety of statistically significant changes
in various red blood cell and other hematological parameters, especially at doses > 1800 ppm. At
the end of the study, dose groups exposed to concentrations >589 ppm had hematological changes
indicative of a microcytic anemia. Some groups showed decreases in platelet counts early in the
study (> 1800 ppm for males and >598 ppm for females). However, by the end of the study,
platelet counts were significantly decreased only in the >2300-ppm dose groups. Decreased
leucocyte counts were seen in these same dose groups.
A number of significant changes were observed in serum biochemical parameters during
the study; most were dose-related. ALT and/or SDH levels were increased in males at doses >268
ppm and in females at doses > 1800 ppm (in most cases increases were significant). Significant
increases in bile acids, alkaline phosphatase, and 5'nucleotidase were indicative of cholestasis
(obstructed outflow of bile from the liver) at concentrations >2300 ppm. Significant dose-related
hypocholesterolemia was present in male and female rats receiving concentrations of >589 ppm
during the early stages of exposure; however, by the end of 14 weeks, the levels were significantly
decreased only at the doses > 1180 ppm in the females and at the highest dose in the males. At the
early time points, there was evidence of hypoproteinuria accompanied by elevated levels of
albumin and increased levels of creatinine kinase (suggesting possible muscle injury) in the two
highest dose groups. These conditions had resolved by the end of the study. There were no
neurological effects identified in the exposed animals using a FOB evaluation.
Among the animals in the lower dose groups, absolute and relative liver weights were
increased in a dose-related fashion. For animals in the 1180 ppm and greater dose groups, the
absolute liver weights decreased, but the relative weights were elevated. Relative kidney weights
were significantly increased in the 2300- and 4600-dose groups and relative thymus weights in
females were decreased for the 4600-ppm dose group. Decreased absolute organ weights at the
higher doses were evidently a consequence of the decreased weight gain in the 2300-ppm group
and weight loss in the 4600-ppm group. Gross and histopathologic observations revealed
hepatocyte vacuolization in all dose groups. The number and severity of liver lesions increased
with dose. Necrosis and altered cell foci were observed at doses of >2300ppm. Cell foci
appeared as basophilic, eosinophilic, mixed cell, and/or clear cell clusters of cellular alterations.
According to the authors, the 589-ppm dose group (27 mg/kg/day for males and 31
mg/kg/day for females) was the LOAEL for systemic effects in this study. The only observed
effect in the 268-ppm group was hepatocyte cytoplasmic vacuolization in 7/10 males but not
females and a significant increase in SDH for the males that did not remain significant at the next
highest dose. The hepatic vacuolization was not considered adverse by the authors because the
changes were considered to be mild (severity grade 1.3) but were regarded by EPA as a marinal
LOAEL. The effects that contributed to the identification of the 589-ppm dose as the LOAEL
included: hepatocyte cytoplasmic vacuolization in 9/10 males and 10/10 females (compared to
0/20 control; severity grade 2.0); increased relative liver weight and significantly decreased
1,1,2,2-Tetrachloroethane—January, 2008 8-2
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hemoglobin in males and hematocrit in females; and decreased sperm motility. There was a dose-
related trend towards increased levels of ALT and SDH at 14 weeks in male rats, which reached
significance for the 1180 ppm concentration.
There are no adequate data on reproductive toxicity for 1,1,2,2-tetrachloroethane. The
studies of the male and female reproductive organs and estrus cycling included in the NTP study
(2004) all showed effects only at dose levels above the LOAEL for liver and hematological effects
(doses of > 1180 ppm for males and >2300 ppm for females). Sperm motility was significantly
decreased at doses greater than or equal to the LOAEL. There was a limited one-generation
inhalation study using 7 males and 5 females exposed to 13.3 mg/m3 1,1,2,2-tetrachloroethane for
4 hours/day for an unspecified number of times over a nine-month period (Schmidt et al., 1972).
There were no statistically significant differences in the percentage of females having offspring
(77.1% in controls versus 62.9% in exposed groups), number of pups per litter, average birth
weight, gestation length, sex ratio, offspring mortality at postnatal days 1, 2, 7, 14, 21, and 84, or
average weight on postnatal day 84. No macroscopic malformations were observed .
The NTP (1991a,b) conducted range-finding studies of developmental toxicity in rats and
mice using 10 pregnant females per dose group. The animals were exposed orally through
microcapsules in feed starting on gd 4 and continuing until sacrifice on gd 20 for rats and gd 17 for
mice. Both studies identified an NOAEL that was greater than the LOAEL in the NTP subchronic
study (2004) . In both cases, embryo/fetotoxicity was accompanied by maternal toxicity. There
was no evaluation of the pups for visceral or skeletal abnormalities.
8.1.1 RfD Determination
8.1.1.1 Benchmark Dose Approach
The NTP study (2004) provided dose-response information for the hematological,
biochemical, body weight, organ weight, and histological effects. Based on the data provided and
the clear indication that the liver was the primary target organ for 1,1,2,2-tetrachloroethane, three
liver-related data sets were selected for modeling using the benchmark dose approach:
• Relative liver weights
• ALT levels
• SDH levels
Each of these endpoints are reflective of hepatic toxicity and are early indicators for possible
necrosis.
ALT is a vitamin B-6-requiring enzyme that functions in the transfer of the amino
functional group from an amino acid to pyruvate, forming alanine. This is an important reaction in
the catabolic pathway for amino acids and in the synthesis of nonessential amino acids. In general,
increases in serum activities of ALT are considered to be a liver-specific event in rodents and can
be used as a marker of hepatocellular necrosis or increased cell membrane permeability (Clampitt
1,1,2,2-Tetrachloroethane—January, 2008 8-3
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and Hart, 1978; Boyd, 1983). SDH is the enzyme that converts sorbitol (the alcohol sugar formed
by reduction of glucose and fructose) to glucose. It is a cytosolic enzyme with a more limited
tissue distribution than ALT. Accordingly, it also is an appropriate indicator for damage to liver
cells. Serum levels of both of these enzymes showed a dose-related trend towards increased
levels, especially in male rats, which made them appropriate candidates for benchmark dose
(BMD) modeling. Travelose et al. (1996) found that there was a treatment-related association
between increases in either or both enzymes and the presence of histopathological changes in the
liver at study termination by examining the data from 61 NTP 13-week toxicity studies. SDH had
higher predictive properties than ALT when only one enzyme was considered. Increases in the
activity of both enzymes were more predictive than either enzyme independently.
There was some evidence of cytoplasmic vacuolization in hepatocytes in 7of 10 male rats
but no females at the lowest dose. However, this endpoint was never graded at a level of greater
than mild in any dose group, even those with marked hepatocellular necrosis, and was not
considered at lexicologically relevant by the NTP pathology work group. Accordingly, this
endpoint was felt to be inappropriate as a point of departure.
Relative liver weight was also increased in both males and females. Increases in relative
liver weight, when unaccompanied by other signs of toxicity, is generally not considered adverse.
In this study, however, the increase in relative weight was accompanied by increased levels of
SDH in males and vacuolization of the hepatocytes in males and females. Increased relative liver
weight also is one of the hallmarks of DC A toxicity in animals studies and is attributed to
glycogen accumulation in the liver (U.S. EPA, 2003b). Although most 1,1,2,2-tetrachloroethane
studies did not examine the liver for glycogen deposits, an increase was observed in the short term
study in rats conducted by Dow (1988).
Hemoglobin levels and decreased sperm motility were also modeled. Hematological
effects have been reported in humans and several rodent studies in addition to the NTP study
(2004). There was a dose-related decrease in hemoglobin levels across all male dose groups at the
end of the study which reached statistical significance for the animals receiving the 589-ppm
dietary concentration. There was a similar trend in females which became statistically significant
for the animals receiving the 1180-ppm concentration. Significant dose-related decreases in sperm
motility were reported in the NTP study (2004) and effects on the testes were seen in the oral 27-
week study by Gohlke et al. (1977).
The data for each of the endpoints discussed above are continuous. They were modeled
using the U.S. EPA Benchmark Dose Software (BMDS) Version 1.3.2 (U.S. EPA, 2003c) and
options appropriate for continuous data, namely the linear, polynomial, power, and Hill models.
Data for the two highest dose groups were not included in the modeling because the differences in
body weights compared to controls indicated that the maximum tolerated dose had been exceeded.
The BMD levels were determined using a difference of one standard deviation from the control
mean.
The BMD and BMDL for those models that adequately fit the data (Chi-square, p>0.10)
with the lowest Akaike's Information Criterion (AIC) values are summarized in Table 8-2. Based
on Agency guidelines for the use of continuous data, the results for a change of one standard
1,1,2,2-Tetrachloroethane—January, 2008 8-4
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deviation in the relative liver weight for males was selected as the point of departure for
determination of the RfD. Figure 8-1 shows the model fit to the relative liver weight data. The
full modeling results are provided in Appendix B.
Table 8-2 Benchmark Modeling Results for Noncancer Endpoints in the NTP Study
(2004) With Rats
Endpoint
Model
Sex
BMD
BMDL
One Standard Deviation Change
ALT
ALT
SDH
SDH
Relative Liver Weight
Relative Liver Weight
Hemoglobin
Hemoglobin
Sperm motility
Polynomial
Polynomial
Linear
Linear
Linear
Polynomial
Linear
Polynomial
No models fit
male
female
male
female
male
female
male
female
male
46.61
86.31
45.73
167.33
13.08
24.21
45.47
48.69
-
29.13
76.13
31.69
67.40
10.71
16.09
31.56
29.74
-
The modeling results indicate that the increase in relative liver weight is the most sensitive
indicator of liver damage in male rats (BMDL of 10.71 mg/kg/day). The use of increased relative
liver weight as a biomarker for liver damage is supported by the increase in ALT and AST and
hematological effects at BMDL values about three-fold higher than the relative liver weight
BMDL and vacuolization of the cytoplasm in 7/10 male rats at the lowest dose tested (20
mg/kg/day). The leakage of ALT and SDH from the hepatic cells is a biomarker for a breakdown
in the cytoplasmic membrane, which is an early stage in the progression to cellular necrosis. They
are highly predictive (>75%) individually and combined for histopathological changes in the liver
(Travelos et al., 1996).
The BMD/BMDL values for the females suggest that they are more resistant to the
hepatotoxic effects of 1,1,2,2-tetrachloroethane than the male rats. The BMDL for increased
relative liver weight is 16.09 mg/kg/day in females, and the BMDL values for increases in ALT
and SDH are 76.13 mg/kg/day and 76.40 mg/kg/day, respectively. The BMDL for the decreased
hemoglobin value in females is 29.74 mg/kg/day.
1,1,2,2-Tetrachloroethane —January, 2008
8-5
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Figure 8-1 BMD Modeling Results for Male Relative Liver Weight
Linear Model with 0.95 Confidence Level
48
46
44
CD
Q: 40
c
CO
38
36
34
Linear
BMD
0 10
09:54 08/02 2006
20
30
40
dose
50
60
70
80
The liver endpoints were also modeled in male and female mice. Model fits were achieved
for ALT in males and ALT and SDH in females. In all cases, the BMDL values in mice (from 92
to 170 mg/kg/day) were greater than those for the rats.
The RfD is calculated from the BMDL for a one standard deviation change in relative liver
weight as follows:
RfD =10.71 mg/kg/dav = 0.01071 mg/kg/day = rounded to 10 |ig/kg/day
1000
where:
10.71 mg/kg/day
1000
The BMDL value for an increase in relative liver weight
The net uncertainty factor (UF) developed according to EPA
guidelines (Dourson and Stara, 1983; U.S. EPA, 2002a).
1,1,2,2-Tetrachloroethane —January, 2008
8-6
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The net uncertainty factor was derived as follows:
UFH A tenfold factor was applied allowing for differences in sensitivity among the human
population. 1,1,2,2-Tetrachloroethane is at least partially metabolized by the CYP P450
system. There are known genetic differences within the populations for specific CYP P450
isoforms and the activity of the CYP P450 isoforms is influenced by diet and other lifestyle
practices introducing greater diversity in human response. In addition, dichloroacetic acid
is an intermediate in the metabolism of 1,1,2,2-tetrachloroethane. There are four to five-
fold population differences in the activity of the five human GSTZ isoforms that are
responsible for the metabolism of dichloroacetic acid to glyoxylate.
UFA A tenfold factor was applied to account for differences between animals and humans.
There is little to no dose-response data from studies where adverse effects have been
observed in humans. High-dose acute case studies of accidental or suicide exposures to
1,1,2,2-tetrachloroethane identify the liver as a target tissue in humans. Lacking
quantitative data on the responses of humans, a full adjustment for interspecies differences
have been applied.
UFL An uncertainty factor of 1 is applied for NOAEL/LOAEL extrapolation. The point of
departure lower is the bound dose for a one standard deviation increase in relative liver
weight, an early biomarker for liver damage. Evidence that these effects are not purely
adaptive is provided by the increase in serum ALT and SDH at a BMDL that is only three-
fold higher than the point of departure for the increase in liver weight. The increases in
ALT and SDH are indicative of damage to the hepatocellular membrane. Given the fact
that the BMDL for the increase in relative liver weight occurs early in the progression of
liver effects and has been determined using the BMD approach, a UFL adjustment is not
necessary.
UFS An uncertainty factor of 3 is applied for extrapolation from a subchronic to a chronic
duration. There are data from a 78-week exposure study in male and female Osborne-
Mendel rats (NCI, 1978) using higher dose levels that indicate that the liver damage did not
proceed to cirrhosis or other major liver problems. However, the NCI (1978) study did
find two rare liver tumors and one preneoplastic nodule in the livers of male Osborne-
Mendel rats and did not monitor for hematological effects. Significant decreases in
hemoglobin were observed after 14 weeks in Fischer-344 male rats in the subchronic NTP
study (2004) . Accordingly, an UF of 3 is justified for the subchronic to chronic
adjustment, because of the differences in the rat strains used in the subchronic and chronic
studies and the limited monitoring of effects in the chronic study.
UFD An uncertainty factor of 3 was applied for database deficiencies. There is no adequate
study of reproductive toxicity, although a very limited one-generation inhalation study with
exposure to 13.3 mg/m3 did not identify reproductive effects in rats. The NTP study
(2004) demonstrated a significant decrease in sperm motility at the LOAEL but the data
demonstrate that the RfD will be protective of this effect. Range-finding developmental
studies in rats and mice indicated that 1,1,2,2-tetrachloroethane only causes embryo or
1,1,2,2-Tetrachloroethane—January, 2008 8-7
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fetotoxicity at doses that are maternally toxic. However, these studies are limited because
there was no evaluation for skeletal and visceral abnormalities.
8.1.1.2 NOAEL/LOAEL Approach
It is also possible to determine an RfD using the NOAEL/ LOAEL approach. The LOAEL
from the NTP study (2004) was the 20 mg/kg/day (268 ppm) dose for the males based on increased
cytoplasmic vacuolization and a significant increase in SDH. However, the authors of the NTP
study considered that dose to be an NOAEL because the SDH increase was not significant at the
next higher dose and the cytoplasmic vacuolization was mild and could have reflected a variety of
changes that were not necessarily adverse. If the 20-mg/kg/day dose is accepted as an NOAEL,
the uncertainty factor used for the benchmark dose-RfD above is appropriate. The RfD would be
calculated as follows:
RfD = 20 mg/kg/dav = 0.020 mg/kg/day (rounded to 20 |ig/kg/day)
1000
where:
20 mg/kg/day = The NOAEL for adverse effects on the liver in male rats
1000 = The net uncertainty factor (UF) developed according to EPA
guidelines (Dourson and Stara, 1983; U.S. EPA, 2002a).
An alternate interpretation of the data would be to consider the 268-ppm concentration (20-
mg/kg/day dose) as a marginal LOAEL. Under those circumstances, the uncertainty factor for the
calculation would increase by a factor of 3 for the UFL uncertainty, and the RfD would be
calculated as follows:
RfD = 20 mg/kg/dav = 0.00666 mg/kg/day (rounded to 7 |ig/kg/day)
3000
where:
20 mg/kg/day = The LOAEL for adverse effects on the liver in male rats
1000 = The net uncertainty factor (UF) developed according to EPA
guidelines (Dourson and Stara, 1983; U.S. EPA, 2002a). A three-
fold factor (UFL) was used fo the NOAEL/LOAEL adjustment
because the effects observed and the LOAEL were of marginal
toxicologic significance.
EPA prefers the benchmark dose approach for derivation of the RfD because it uses the
dose-response properties for increased relative liver weight. The increase in liver weight is
supported by two enzyme biomarkers for liver damage (ALT and SDH) at slightly higher BMDL
values and mild cytoplasmic vacuolization seen in almost all (7/10) of the exposed animals in the
20-mg/kg dose group. Each of these factors increases the confidence that liver toxicity is the
1,1,2,2-Tetrachloroethane—January, 2008 8-8
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critical effect and that the BMDL for the increase in relative liver weights should be used as the
basis for the RfD.
8.1.2 RfC Determination
The reference concentration (RfC) is an estimate of the daily inhalation exposure to the
human population that is likely to be without appreciable risk of deleterious effects over a lifetime.
The U.S. EPA has not developed an RfC for 1,1,2,2-tetrachloroethane because the available data
are inadequate. There are no studies in human populations that provided quantification of the
concentration in air associated with adverse effects. However, early occupational reports indicate
that 1,1,2,2-tetrachloroethane is associated with nausea, dizziness, headache, fatigue, eye irritation,
vomiting, mild anemia, and elevated white cell and platelet counts (Jeney et al., 1957; Lehman and
Schmidt-Kehl, 1936; Lobo-Mendonca, 1963; Minot and Smith, 1921; Willcox et al., 1915). Some
subjects that were occupationally exposed had enlargement of the liver or cirrhosis (Jeney et al.,
1957). In a controlled human exposure study (Lehman and Schmidt-Kehl, 1936), using two
volunteers, a 20-minute exposure to a concentration of 20 mg/m3 was sufficient to cause mild
nausea and vomiting.
There are no chronic inhalation data for 1,1,2,2-tetrachloroethane and the few studies of
subchronic duration (Danan et al., 1973; Schmidt et al., 1975; Truffert et al., 1977) are inadequate
for determination of an RfC because they examined only a single dose and did not provide
complete information on study design and observed effects. The lowest subchronic dose tested
was 50 mg/m3.
8.2 Dose-Response for Cancer Effects
8.2.1 Choice of Study
NCI (1978) found significant, dose-related increases in the incidence of hepatocellular
carcinomas in groups of 50 male and 50 female B6C3F1 mice exposed to 5 days/week, time-
weighted average concentrations of 142 or 282 mg/kg-day 1,1,2,2-tetrachloroethane in corn oil
administered via gavage for 78 weeks followed by a 12-week observation period. These doses are
equivalent to 101 and 202 mg/kg/day, respectively, when normalized over a 7-days/week period.
NCI (1978) did not find any significant increases in the incidence of neoplasms in Osborne-
Mendel rats similarly exposed to 5 days/week time-weighted average doses of 44 or 77 mg/kg-day
(males) or 31 and 54 mg/kg-day (females) when normalized for a 7-days/week exposure.
However, there were two male rats with hepatocellular carcinomas in the high dose group and one
with a hepatic preneoplastic nodule. Because these tumors are rare in Osborne-Mendel rats, the
NCI considered the results in male rats to be equivocal.
1,1,2,2-Tetrachloroethane—January, 2008 8-9
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Based on the results of available in vivo and in vitro assays, 1,1,2,2-tetrachloroethane has,
at most, a weak mutagenic potential. Studies of mutagenicity in Salmonella typhimurium,
Escherichia coli and Saccharomyces cerevisiae were predominantly negative but some positive
results were observed both with and without activation (see Table 7-5). Several studies (Colacci et
al., 1992; Galloway et al., 1987) found positive results for sister chromatic exchange both with and
without S9 activation, and a mouse micronucleus assay was positive for males and females (NTP,
2004).
1,1,2,2-Tetrachloroethane was a stronger promoter than an initiator of GGT+ foci in the
liver of rats (Story et al., 1986). Additional support for the classification of 1,1,2,2-
tetrachloroethane as a weak initiator was provided by the results of Colacci et al. (1992, 1993)
using an in vitro two-stage BALB/c 3T3 cell transformation assay and implantation of the
transformed cells into athymic CD1/BR mice. In both the GGT+ and cell transformation assays
the promotion potential of 1,1,2,2-tetrachloroethane was stronger than its initiation potential. This
profile for tumor induction by 1,1,2,2-tetrachloroethane is similar to that of dichloroacetic acid, its
primary metabolite (U.S. EPA, 2003b).
The critical study for quantification of the tumor dose response is the mouse study by NCI
(1978).
8.2.2 Dose-Response Characterization
Groups of male and female B6C3F1 mice (50/sex/dose) were administered technical-grade
1,1,2,2-tetrachloroethane in corn oil by gavage at normalized, 7 days/week, time-weighted average
daily doses of 101 or 202 mg/kg body weight for 78 weeks. The doses were not normalized
beyond the actual exposure period because of the variations in the doses across the duration of the
study and the link between DC A and 1,1,2,2 tetrachloroethane. DC A carcinogenicity appears to
be related to the inhibition of GSTZ in some, yet to be defined, fashion. Modeling of DC A
toxicokinetics in mice indicates that for drinking water exposures, the area under the curve (AUC)
for liver DCA is nonlinear (Barton et al., 1999). In animals pre-treated with DC A, the modeled
liver AUC was about 8-fold higher than in the naive animals with drinking water concentrations of
0.01 to about 0.8 g/L reflecting the impact of the enzyme inhibition. At higher doses, the
difference between the naive and pre-treated animals increased rapidly. Accordingly, the
magnitude of the dose at the time it is given may play a role in the carcinogenic potency of DCA
and 1,1,2,2-tetrachloroethane. For this reason artificially lowering the administered dose, beyond
the normalization for the irregular dosing pattern and the 5-day per week normalization did not
seem appropriate. Uncertainty introduced by the decreases and increases in the doses given during
the actual period of compound administration is most likely greater than any uncertainty
introduced by a failure to normalize for the estimated full life span of the animals.
Effects in treated animals were compared to the untreated- and vehicle control animals. A highly
significant dose-related trend in the incidence of hepatocellular carcinomas was observed in males
and females that received the chemical when compared to the respective controls (Table 8-3).
These tumors also appeared earlier in mice administered the higher dose. Slightly decreased body
weight gain and increased mortality also were observed in exposed mice; there were no increases
in the incidences of non-neoplastic lesions (NCI, 1978).
1,1,2,2-Tetrachloroethane — January, 2008 8-10
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Table 8-3 Summary of Liver Tumor Incidence, 78-Week Study in Mice
Male
Female
Normalized doses1
(mg/kg/day)
0
101
202
0
101
202
Liver Tumor Incidence2
3/36 (sum of 2 control groups)
13/50*
44/49*
1/40 (sum of 2 control groups)
30/48*
43/47*
Source: NCI (1978)
* Significantly increased compared to control, p < 0.05
1. Doses were derived from the dose duration data in the NCI report (Table 2) and calculated according to the NCI
formula. The doses were normalized to accommodate the 5 out of 7 day weekly exposure. The calculation indicated
that the high dose exposure was 283.3 mg/kg/day rather than 284 mg/kg/day shown in NCI Table 6 or 282 mg/kg/day
as indicated in the NCI study summary. Animals that died prior to 52 weeks, the time at which the first tumor was
observed were not included in the statistical analysis of the data.
2. The data on the numbers of animals with tumors were obtained from NCI Tables 6 and 7 and differ for the male and
female untreated control groups from the values given in the NCI summary.
1,1,2,2-Tetrachloroethane —January, 2008
8-11
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Figure 8-2 Multistage Model Fit to Bioassay Tumor Data for Female Mice
Multistage Model with 0.95 Confidence Level
0.8
T3
| °'6
M—
| 0.4
o
co
LJ_
0.2
Mjltistage
BIVD Lower Bound
-j/7
BMDL B|VD
0
15:5305/172005
50
100
dose
150
200
8.2.3 Cancer Potency and Unit Risk
U.S. EPA used the ED10 of 15 mg/kg/day and LED10 of 8 mg/kg/day for the tumor response
in female mice to derive a slope factor from both the point of departure and its lower bound for
1,1,2,2-tetrachloroethane. The rodent ED10 and LEd10 values were converted to human equivalent
doses (HED) by using a body weight to the 3/4 power scaling factor as required by the U.S. EPA
Guidelines for Carcinogen Risk Assessment Guidelines (2005a). This resulted in HED ED10 and
HED LED10 values of 2.08 and 1.17 mg/kg/day. The point of departure and lower bound slope
factor estimates for tumorigenicity are calculated from these values as follows:
Slope Factor Based on the Point of Departure
Slope Factor (SF) = Response = 0.1
, = 4.8x 10'2 (mg/kg/day)-
BMD10 2.08 mg/kg/day
Slope Factor Based on the Lower Bound Estimate for the Point of Departure
Slope Factor = Response =.
0.1
. = 8.5x 10-2(mg/kg/day)-
BMDL10 1.17 mg/kg/day
1,1,2,2-Tetrachloroethane —January, 2008
8-12
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The lower bound value is in fairly good agreement with the central tendency and lower
bound slope factors for the principal metabolite, dichloroacetic acid, which has a slope factor of
1.5 x ID'2 (mg/kg/day)4 and 7 x 10'2 (mg/kg/day)'1, respectively (U.S. EPA, 2003b).
The Health Reference Level (HRL) serves as the benchmark for examining the occurrence
data for 1,1,2,2-tetrachloroethane in the Regulatory Determination process. It is the concentration
in drinking water equivalent to a one-in-a million risk (10"6) of cancer above background. For
1,1,2,2-tetrachloroethane, the concentration equivalent to a 10"6 risk is calculated as follows:
Lower Bound Estimate
10 risk = risk x body weight
0.000001x70 kg
SF x drinking water intake 0.085 (mg/kg/day)"1 x 2L/day
The HRL is rounded to one significant figure and becomes 0.4 |ig/L.
= 4.12x 10-4mg/L
Point of Departure Estimate
10"6risk= risk x body weight
0.000001x70 kg
= 7.29xlO-4mg/L
SF x drinking water intake 0.048 (mg/kg/day)"1 x 2L/day
The Point of Departure Estimate rounded to one significant figure is 0.7 |ig/L
Prior Cancer Slope Factor
EPA evaluated the carcinogenicity for 1,1,2,2-tetrachloroethane under the Guidelines for
Cancer Risk Assessment (U.S. EPA, 1986c) using the linearized multistage model (U.S. EPA,
1986e). The oral slope factor using this approach is 2.0 x 10"1 per (mg/kg-day) using administered
doses that were adjusted for frequency and length of exposure, and human equivalent dose based
on body weight using a 2/3 power scaling factor (U.S. EPA, 1986e; see Table 8-4). The HRL
calculated from the IRIS slope factor is 0.2 |ig/L. The IRIS documentation for 1,1,2,2-
tetrachloroethane is currently being updated by the Agency.
Table 8-4 Factors Used to Derive the Oral Slope Factor
Administered Dose
(mg/kg/day)
0
142
284
Administered Dose,
Adjusted1
(mg/kg/day)
0
87
174
Human Equivalent Dose2
(mg/kg/day)
0
6.56
13.12
Tumor Incidence
(Female mice)
0/20
30/483
43/473
Source: U.S. EPA (1986e)
1. Adjusted for frequency (5/7 days) and length of exposure (546 days of an assumed life span of 637 days).
2. Human Equivalent Dose = Administered Dose x (0.03kg/70kg)1/3; 0.03 kg = Assumed Animal Weight.
3. Increase is statistically significant compared to controls, p O.05.
1,1,2,2-Tetrachloroethane —January, 2008
8-13
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The U.S. EPA (1986e) assessment on IRIS differs from the revised assessment presented in this
document in a number of respects, most related to application of the 2005 cancer guidelines. The
differences in the approach are summarized as follows:
The 1986 Human Equivalent Dose (HED) was determined using a 2/3 power scaling factor
for body weight as required by the EPA Guidelines for Cancer Risk Assessment (U.S.
EPA, 1986c). The new assessment uses a 3/4 power scaling factor for body weight as
required by the EPA Revised Guidelines for Carcinogen Risk Assessment (U. S. EPA,
2005a).
• The control values for the 1986 assessment were those for the untreated controls. The new
assessment combined the untreated and vehicle controls. There was one tumor in the
vehicle control group.
• The highest dose for the 1986 assessment was 284 mg/kg/day as indicated in the NCI
(1978) reports. The revised assessment used 283 mg/kg/day as the highest dose since that
is the result from using the NCI dose and duration information and the equation provided
by NCI for obtaining the time-weighted average doses.
The 1986 IRIS Assessment normalized doses to adjust for the 5 of 7 days weekly exposure
pattern and then also adjusted the dose for exposures for 546 days out of a 637-day life
span. The revised assessment normalized for the 7-days/week exposure but did not do the
lifetime normalization. The raising and lowering of dose levels during the study are
problematic. Studies of 1,12,2-tetrachloroethane indicate that it is at best a weak tumor
initiator. This also is true for its principle metabolite DC A. In the case of DCA, the
tumorigenic appears to be multifaceted but does not rely on a hyperplastic response of the
liver to tissue damage. For both 1,1,2,2-tetrachloroethane and DCA it is possible that
enzyme inhibition of GST zeta may be an important feature of the mode of action.
Accordingly, artificially lowering the doses by normalizing for a lifetime longer that the
period of exposure may not be appropriate.
• The linearized multistage model used for the IRIS assessment derived a slope by fitting the
dose-response data to a straight line that passes through the zero point for the X and Y
axises. The Revised Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a)
determine the slope factor by drawing a straight line from the lower bound on the 10
percent response level to zero.
Despite the difference in cancer risk assessment approaches listed above, the responses are
remarkably similar. The revised and original IRIS slope factors are 8.5 x 10"2 and 2 x 10"1
(mg/kg/day)"1 (mg/kg/day)"1, respectively. The revised and original IRIS HRL values are 0.4 |ig/L
and 0.2 |ig/L respectively.
1,1,2,2-Tetrachloroethane—January, 2008 8-14
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9.0 REGULATORY DETERMINATION AND CHARACTERIZATION OF RISK
FROM DRINKING WATER
9.1 Regulatory Determination for Chemicals on the CCL
The SDWA, as amended in 1996, required the EPA to establish a list of contaminants to
aid the Agency in regulatory priority setting for the drinking water program. EPA published a
draft of the first Contaminant Candidate List (CCL) on October 6, 1997 (62 FR 52193, U.S. EPA,
1997). After review of and response to comments, the final CCL was published on March 2, 1998
(63 FR 10273, U.S. EPA, 1998c).
On July 18, 2003, EPA announced final Regulatory Determinations for one microbe and 8
chemicals (68 FR 42897, U.S. EPA, 2003d) after proposing those determinations on June 3, 2002
(67 FR 38222, U.S. EPA, 2002c). The remaining 40 chemicals and ten microbial agents from the
first CCL became CCL 2 and were proposed in the Federal Register (FR) on April 2, 2004 (69 FR
17406, U.S. EPA 2004c) and finalized on February 24, 2005 (70FR:9071, U.S. EPA, 2005b).
EPA proposed Regulatory Determinations for 11 chemicals from CCL2 on May 1, 2007
(72FR 24016) (U.S. EPA, 2007). Determinations for all 11 chemicals were negative based on a
lack of national occurrence at levels of health concern. The Agency is given the freedom to
determine that there is no need for a regulation if a chemical on the CCL fails to meet one of three
criteria established by the SDWA and described in section 9.1.1. After review of public comments
and submitted data, the negative determinations for the 11 contaminants have been retained. Each
contaminant will be considered in the development of future CCLs if there are changes in health
effects and/or occurrence.
9.1.1 Criteria for Regulatory Determination
These are the three criteria used to determine whether or not to regulate a chemical on the
CCL:
The contaminant may have an adverse effect on the health of persons.
The contaminant is 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.
• In the sole judgment of the Administrator, regulation of such contaminant presents a
meaningful opportunity for health risk reduction for persons served by public water
systems.
The findings for all criteria are used in making a determination to regulate a contaminant.
As required by the SDWA, a decision to regulate commits the EPA to publication of a Maximum
Contaminant Level Goal (MCLG) and promulgation of a National Primary Drinking Water
Regulation (NPDWR) for that contaminant. The Agency may determine that there is no need for a
1,1,2,2-Tetrachloroethane — January, 2008 9-1
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regulation when a contaminant fails to meet one of the criteria. A decision not to regulate is
considered a final Agency action and is subject to judicial review. The Agency can choose to
publish a Health Advisory (a nonregulatory action) or other guidance for any contaminant on the
CCL, independent of the regulatory determination.
9.1.2 National Drinking Water Advisory Council Recommendations
In March 2000, the EPA convened a Working Group under the National Drinking Water
Advisory Council (NDWAC) to help develop an approach for making regulatory determinations.
The Working Group developed a protocol for analyzing and presenting the available scientific data
and recommended methods to identify and document the rationale supporting a regulatory
determination decision. The NDWAC Working Group report was presented to and accepted by
the entire NDWAC in July 2000.
Because of the intrinsic difference between microbial and chemical contaminants, the
Working Group developed separate but similar protocols for microorganisms and chemicals. The
approach for chemicals was based on an assessment of the impact of acute, chronic, and lifetime
exposures, as well as a risk assessment that includes evaluation of occurrence, fate, and dose-
response. The NDWAC protocol for chemicals is a semi-quantitative tool for addressing each of
the three CCL criteria. The NDWAC requested that the Agency use good judgment in balancing
the many factors that need to be considered in making a regulatory determination.
The EPA modified the semi-quantitative NDWAC suggestions for evaluating chemicals
against the regulatory determination criteria and applied them in decision-making. The
quantitative and qualitative factors for 1,1,2,2-tetrachloroethane that were considered for each of
the three criteria are presented in the sections that follow.
9.2 Health Effects
The first criterion asks if the contaminant may have an adverse effect on the health of
persons. Because all chemicals have adverse effects at some level of exposure, the challenge is to
define the dose at which adverse health effects are likely to occur and estimate a dose at which
adverse health effects are either not likely to occur (threshold toxicant), or have a low probability
for occurrence (non-threshold toxicant). The key elements that must be considered in evaluating
the first criterion are the mode of action, the critical effect(s), the dose-response for critical
effect(s), the RfD for threshold effects, and the slope factor for nonthreshold effects.
A full description of the health effects associated with exposure to 1,1,2,2-
tetrachloroethane is presented in Chapter 7 of this document and summarized below in Section
9.2.2. Chapter 8 and Section 9.2.3 present dose-response information.
1,1,2,2-Tetrachloroethane — January, 2008 9-2
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9.2.1 Health Criterion Conclusion
The available toxicological data indicate that 1,1,2,2-tetrachloroethane has the potential to
cause adverse health effects in humans and animals. Liver effects are the most common
manifestation of 1,1,2,2-tetrachloroethane toxicity. Dose information is lacking in almost all of
the human studies or case reports. The HRL (0.4 |ig/L) for 1,1,2,2-tetrachloroethane is based on
the occurrence of liver tumors in mice following chronic exposures (NCI, 1978). The RfD (10
|ig/kg/day) is based on evidence for liver damage, decreased hemoglobin levels, and decreased
sperm motility in male rats after subchronic exposures (NTP, 2004). Inhalation, but not oral
exposures, are associated with neurological effects (e.g., headaches dizziness, fatigue, tremors).
Based on these considerations, the evaluation of the first criterion for 1,1,2,2-tetrachloroethane is
positive: 1,1,2,2-tetrachloroethane may have an adverse effect on human health.
9.2.2 Hazard Characterization and Mode of Action Implications
Data on the toxicity of 1,1,2,2-tetrachloroethane in humans are limited, consisting of one
experimental inhalation study, a few case reports of suicidal or accidental ingestion, and dated
occupational studies. In most cases, there was no quantification of the exposure. Respiratory,
mucosal, eye irritation, nausea, vomiting, and dizziness were reported by human volunteers
exposed to 1,1,2,2-tetrachloroethane vapors under controlled chamber conditions (Lehmann and
Schmidt-Kehl, 1936). Effects from non-lethal occupational exposures included gastric distress
(i.e., pain, nausea, vomiting), headache, loss of appetite, an enlarged liver, and cirrhosis (Jeney et
al., 1957; Lobo-Mendonca 1963; Minot and Smith 1921).
There have been a variety of animal studies in rats and mice using both the inhalation and
oral exposure routes. Recent studies by the National Toxicology Program (NTP, 2004) provide a
detailed evaluation of the short-term and subchronic oral toxicity of 1,1,2,2-tetrachloroethane and
confirm many of the observations from earlier studies. In rats and mice exposed orally, the liver
appears to be the principal target organ.
A National Cancer Institute (1978) bioassay of 1,1,2,2-tetrachloroethane found evidence of
carcinogenicity in male and female B6C3F1 mice based on a dose-related statistically significant
increase in liver tumors. There was equivocal evidence for carcinogenicity in Osborne-Mendel
rats because of the occurrence of a small number of rare-for-species neoplastic and preneoplastic
lesions in the livers of the high dose animals.
Information on the reproductive effects of 1,1,2,2-tetrachloroethane is limited. There is a
single one-generation study that does not follow a standard methodology and examined a small
number of animals (five females and seven males) exposed via inhalation to one dose (13.3
mg/m3). There were no statistically significant differences in the percentage of females having
offspring, number of pups per litter, average birth weight, sex ratio, or post natal offspring
mortality (Schmidt et al., 1972). Effects on sperm in male rats were seen after oral exposure
(27mg/kg/day; NTP, 2004)
Developmental range-finding studies conducted for NTP (1991a,b) found that
1,1,2,2-tetrachloroethane was toxic to the dams and pups of Sprague Dawley rats and CD-I Swiss
1,1,2,2-Tetrachloroethane — January, 2008 9-3
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mice. Rats were more sensitive than mice. The NOAEL in the rats for both maternal toxicity and
associated fetal toxicity was 34 mg/kg/day with an LOAEL of 98 mg/kg/day. In mice, the
NOAEL was 987 mg/kg/day and the was LOAEL 2120 mg/kg/day.
EPA also evaluated whether health information is available regarding the potential effects
on children and other sensitive populations. Individuals with preexisting liver and kidney damage
would likely be sensitive to 1,1,2,2-tetrachloroethane exposure. Low intake of antioxidant
nutrients (e.g., Vitamin E, Vitamin C, and selenium) could be a predisposing factor for liver
damage. In addition, individuals with a genetically low capacity to metabolize dichloroacetic acid
(a principal metabolite of 1,1,2,2-tetrachloroethane) may be at greater risk than the general
population as a result of 1,1,2,2-tetrachloroethane exposure. There are no data that can inform
whether or not children would be more sensitive to the effects of 1,1,2,2-tetrachloroethane than the
general population.
9.2.3 Dose-Response Characterization
The results from the NTP subchronic study (2004) in F-344 rats were chosen to serve as
the basis of the RfD for 1,1,2,2-tetrachloroethane. The preponderance of the animal data indicates
that rats are more sensitive than mice to the noncancer effects of 1,1,2,2-tetrachloroethane and the
subchronic NTP data (2004) provide the best available dose-response data for a variety of
important endpoints. The LOAEL of 40 mg/kg/day was identified based on an increased incidence
of hepatocyte hypertrophy, increased relative liver weight, reduced hemoglobin levels and
decreased sperm motility in male rats at the end of the 14-week study. There was also a dose-
related trend towards increased levels of ALT and SDH, biomarkers for liver necrosis, that reached
statistical significance at higher doses. The NOAEL was 20 mg/kg/day. Because there was a mild
increase in hepatocyte vacuolization at the NOAEL that was not seen in the controls, it is possible
that the NOAEL is a marginal LOAEL, an early sign of liver effects, rather than simply an
adaptive response. Female rats were found to be less sensitive to adverse effects from 1,1,2,2-
tetrachloroethane than the males.
Changes in relative liver weight, ALT and SDH levels, hemoglobin, and sperm motility
were modeled using the EPA Benchmark Dose Software Version 1.3.2. Cytoplasmic
vacuolization of the hepatocytes was not modeled because of the weak dose-response for the
severity of the effect and the high response (7 of 10 animals at the NOAEL and 10 of 10 animals at
the LOAEL). The severity of the response at the NOAEL was considered by the NTP to be mild
and nonadverse. The dose-response data for the selected endpoints were modeled as continuous
end points using a change of one standard deviation from the controls to identify the BMD and
BMDL. The data from the highest two dose groups were not used for the modeling because the
maximum tolerated dose was clearly exceeded in both dose groups.
The BMDL for a one standard deviation change in relative liver weight provided the most
conservative estimate for the point of departure (10.71 mg/kg/day) and was used for the derivation
of the RfD. The models were not able to obtain an adequate fit for the sperm effects. The RfD
(10.71 jig/kg/day rounded to 10 jig/kg/day) for 1,1,2,2-tetrachloroethane was calculated using a
1000-fold uncertainty factor. The composite uncertainty factor (1000) included consideration of
intraspecies variability (10), interspecies variability (10), database deficiencies (3), and an
1,1,2,2-Tetrachloroethane — January, 2008 9-4
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adjustment for extrapolating from a subchronic to a chronic exposure (3). The 3-fold duration
adjustment was justified based on the results from the NCI (1978) cancer bioassay which did not
show a distinct worsening of liver effects in rats with age. The NCI study did not examine a full
array of noncancer endpoints and used a different rat strain from NTP, justifying the 3-fold UF for
the duration adjustment.
The dose-response assessment for the cancer effects of 1,1,2,2-tetrachloroethane utilized
the tumor data from the NCI (1978) study in B6C3F1 mice. The tumor incidences for male and
female mice were modeled using the multistage model from the EPA Benchmark Dose Software
Version 1.3.2. The tumor data for both the untreated and vehicle controls were combined for the
assessment. The data for the male mice did not achieve adequate model fit. The ED10 and LED10
for female mice were 15 mg/kg/day and 8 mg/kg/day respectively. After converting the doses to
HEC values, the slope factors were 4.8 10"2 (mg/kg/day)"1 and 8.5 10"2 (mg/kg/day)"1, respectively.
The concentration equivalent to a one-in-a-million risk level (10"6) (0.4 |ig/L) calculated from the
lower bound slope factor was used as the HRL in the analysis of the 1,1,2,2-tetrachloroethane
occurrence data.
9.3 Occurrence in Public Water Systems
The second criterion asks if the contaminant is known to occur or if there is a substantial
likelihood that the contaminant will occur in public water systems with a frequency and at levels
of public health concern. In order to address this question, the following information was
considered:
• Monitoring data from public water systems
• Ambient water concentrations and releases to the environment
• Environmental fate
Data on the occurrence of 1,1,2,2-tetrachloroethane in public drinking water systems were
the most important determinant in evaluating the second criterion. EPA looked at the total number
of systems that reported detections of 1,1,2,2-tetrachloroethane, as well those that reported
concentrations of 1,1,2,2-tetrachloroethane above an estimated drinking water health reference
level (URL). For noncarcinogens, the estimated URL level was calculated from the RfD assuming
that 20% of the total exposure would come from drinking water. For carcinogens, the HRL was
the 10"6 risk level (i.e., the probability of 1 excess tumor in a population of a million people). The
HRLs are benchmark values that were used in evaluating the occurrence data while the risk
assessments for the contaminants were being developed. The HRL for 1,1,2,2-tetrachloroethane is
0.4 |ig/L based on the c equivalent to a one-in-a-million extra risk for tumors.
The available monitoring data, including indications of whether or not the contaminant is a
national or a regional problem, are included in Chapter 4 of this document and summarized below.
Additional information on production, use, and fate are found in Chapters 2 and 3.
1,1,2,2-Tetrachloroethane—January, 2008 9-5
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9.3.1 Occurrence Criterion Conclusion
The available data for 1,1,2,2-tetrachloroethane production, use, and environmental
releases all show a downward trend. Between Round 1 (1987-1992) and Round 2 (1992-1997) of
drinking water monitoring, the 99th percentile concentration for detections for Cross Section
reporting states declined from 112 jig/L to 2 jig/L and the percent of systems with detections
declined from 0.45% to 0.08%. 1,1,2,2-Tetrachloroethane was not detected in ambient U. S.
surface waters in two surveys of VOCs in ground water at a level of detection that was lower than
the HRL. The physicochemical properties of 1,1,2,2-tetrachloroethane suggest that concentrations
in surface water will volatilize to the atmosphere where it is relatively stable. In soils and ground
water, acclimatized bacteria are able to metabolize 1,1,2,2-tetrachloroethane to simpler
compounds. Based on these data, it is unlikely that 1,1,2,2-tetrachloroethane will occur in public
water systems at frequencies or concentration levels that are of public health concern. Thus, the
evaluation for the second criterion is negative.
9.3.2 Monitoring Data
Occurrence data for 1,1,2,2-tetrachloroethane were collected through the unregulated
contaminant monitoring (UCM) program from 1987 to 1997. In Round 1, the percent of public
20,407 PWS with detections of 1,1,2,2-tetrachloroethane was 0.45% for cross section states. For
Round 2 monitoring, 0.08% of 24,800 systems reported detections for the cross section states.
Unfortunately for some states, the analytical method reporting limit (MRL) was greater than the
HRL of 0.4 |ig/L. MRL values reported for the states ranged from 0.01 to 10 |ig/L for Round 1
and 0.01 to 2.5 |ig/L for Round 2. The modal value in both cases was 0.5 |ig/L. The median
concentration for the detections in both cases was also 0.5 |ig/L. The 99th percentile concentration
for Round 1 was 112 |ig/L for the cross section states. In Round 2, the 99th percentile
concentrations for detections were 2 jig/L for the cross section states. The data show a decline in
the occurrence of 1,1,2,2-tetrachloroethane in finished water between Round 1 and Round 2. The
decline is supported by the fact that the MRL maximum for Round two was lower than that for
Round lincreasing the confidence in the Round 2 results.
Because of the variable MRL values, the number of systems reporting concentrations
exceeding the HRL must be viewed with some caution because not all systems and states were
able to detect 1,1,2,2-tetrachloroethane at the HRL. Accordingly, estimates based on the HRL
may under report the actual occurrence. Detections greater than the HRL occurred in
approximately 0.2% of PWS in cross section states in Round 1. In Round 2, there were detections
greater than the HRL in 0.07% of the PWS in the cross section states. Despite the limitation of the
MRL, the trend toward decreased occurrence of 1,1,2,2-tetrachloroethane in finished water
between Round 1 and Round 2 is clear.
Although 1,1,2,2-tetrachloroethane appears to occur in finished water at least occasionally
throughout the U.S., it does not currently appear to have a distinct geographic pattern. Twenty-
five of 47 States had at least one public water system with at least one analytical detection of this
contaminant. There is also no apparent geographic trend among the States with the highest
proportion of analytical detections. The state with the highest number of detections in Round 2
(the most representative of current conditions) was North Carolina. The States with HRL
1,1,2,2-Tetrachloroethane — January, 2008 9-6
-------
exceedances in Round 2 were Maine, Massachusetts, Michigan, North Carolina, Ohio, Oklahoma,
and Texas. Ohio was the only state that had HRL exceedances in both Round 1 and Round 2.
1,1,2,2-Tetrachloroethane was monitored through the U.S. Geological Service (USGS)
National Water Quality Assessment (NAWQA) program in two separate studies of VOC
occurrence. One survey (Grady, 2003), sampled source waters for community water systems
between 1999 and 2000. The levels of detection (0.2 |ig/L) were less than the HRL. 1,1,2,2-
Tetrachloroethane was not detected in any of the samples. The second survey (Delzer and
Ivahnenko, 2003) was conducted during the same time period and focused on source waters that
might be contaminated with methyl tertiary-butyl ether (MtBE). Samples were also analyzed for
other VOCs. Again, no 1,1,2,2-tetrachloroethane was detected.
9.3.3 Use and Fate Data
Prior to the 1980s, 1,1,2,2-tetrachloroethane was commonly used in the production of other
chemicals, primarily TCE, PCE, and 1,2-dichloroethylene (ATSDR, 2006). It was also used as a
metal degreaser and solvent. Production of 1,1,2,2-tetrachloroethane fell from approximately 440
million pounds in 1967 to 34 million pounds in 1974 and commercial production ceased in the
United States by the late 1980s; imports are thought to be minimal (ATSDR, 2006).
Although 1,1,2,2-tetrachloroethane is no longer produced as a commercial product in the
United States, it is still used as an intermediate and/or by-product in the manufacturing of other
synthetic chemicals. It can occur as a trace contaminant in these and other chlorinated alkanes, and
in the waste stream of facilities that produce them. Reports of environmental releases from the
Toxic Release Inventory show a major decline between 1988 and 2001 (U.S. EPA, 2004b). The
reported total releases to the environment in 1988 were 175,000 Ibs, while in 2001 the releases
totaled 5240 Ibs. In all years, releases to the atmosphere exceeded those for land and water. In
2001, only 56 Ibs were reported to be released to surface water.
There is little current information on the levels of 1,1,2,2-tetrachloroethane in
environmental media. The monitoring data from finished water are supportive of a decline in its
presence in the environment. Most of the monitoring data on ambient air are from periods of more
wide-spread use of this material as a solvent. A low log Koc indicates that 1,1,2,2-
tetrachloroethane does not accumulate in sediments. Half-life measurements and biodegradation
information suggest that anthropogenic releases of 1,1,2,2-tetrachloroethane from decades ago
have likely been degraded and do not constitute a current problem.
DC A is the primary intermediary metabolite in the mammalian metabolism of 1,1,2,2-
tetrachloroethane. DCA also is a disinfection byproduct in finished water treated with chlorine-
containing disinfectants. Thus, the presence of 1,1,2,2-tetrachloroethane in water that also
contains DCA would increase the total endogenous exposure (internal dose) of DCA. To the
extent that other chlorinated two carbon compounds such as trichloroethylene, 1,1,2-
trichloroethane, tetrachloroethylene, and 1,1, dichloroethane produce DCA during metabolism,
they too would increase endogenous exposure were they to co-occur with 1,1,2,2-
1,1,2,2-Tetrachloroethane — January, 2008 9-7
-------
tetrachloroethane. However, given the low levels of 1,1,2,2-tetrachloroethane found in finished
water, it is unlikely to be a major contributor to total internal DCA exposure.
9.4 Risk Reduction
The third criterion asks if, in the sole judgment of the Administrator, regulation presents a
meaningful opportunity for health risk reduction for persons served by public water systems. In
evaluating this criterion, EPA looked at the total exposed population, as well as the population
exposed to levels above the estimated HRL. Estimates of the populations exposed and the levels
to which they are exposed were derived from the monitoring results. These estimates are included
in Chapter 4 of this document and summarized in Section 9.4.2 below.
In order to evaluate risk from exposure through drinking water, EPA considered the net
environmental exposure in comparison to the exposure through drinking water. For example, if
exposure to a contaminant occurs primarily through ambient air, regulation of emissions to air
provides a more meaningful opportunity for EPA to reduce risk than does regulation of the
contaminant in drinking water. In making the regulatory determination, the available information
on exposure through drinking water (Chapter 4) and information on exposure through other media
(Chapter 5) were used to estimate the fraction that drinking water contributes to the total exposure.
The EPA findings are discussed in Section 9.4.3 below.
In making its regulatory determination, EPA also evaluated effects on potentially sensitive
populations, including the fetus, infants, and children. Sensitive population considerations are
discussed in Section 9.4.4.
9.4.1 Risk Criterion Conclusion
Approximately 5.6 million people were served by systems with detections greater than the
MRL for 1,1,2,2-tetrachloroethane based on the national extrapolations of the results from Round
2 cross section monitoring. A detection in one large system serving a population of 1.5 million
contributed to this total. An estimated 168,000 of these individuals were served by systems with
detections greater than the HRL on at least one occasion.
Drinking water is probably the largest contributor to total exposure in situations where
1,1,2,2 tetrachloroethane is present. Recent levels detected in ambient air have been very low and
it has not been detected in foods. However, even its presence in water is relatively rare. On the
basis of these observations, the impact of regulating 1,1,2,2-tetrachloroethane concentrations in
drinking water on health risk reduction is likely to be small. Thus, the evaluation of the third
criterion is negative.
1,1,2,2-Tetrachloroethane—January, 2008 9-8
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9.4.2 Exposed Population Estimates
The variability in the MRL values for both Round 1 and Round 2 data indicate that the
monitoring results must be viewed with some caution and that the Round 2 results are more likely
to give a clearer picture of current occurrence than the Round 1 results. In Round 2, 2.61% of the
population of the cross section states was exposed to 1,1,2,2-tetrachloroethane at least once during
the monitoring period. The exposed population served by surface water systems was far larger
than that served by ground water systems (4.06% vs. 0.09% respectively for the cross sections
states. When extrapolated to a national exposure these results equate to 5 million people exposed
by way of surface water systems and 80 thousand people exposed from ground water systems. A
detection on 1,1,2,2-tetrachloroethane in one large system serving 1.5 million people contributed
substantially to the surface water total.
When looking at the population exposed at concentrations greater than either /^ the HRL or
the HRL in Round 2 monitoring, the numbers decline (Table 9-1). As mentioned previously, these
values have to be viewed with caution because the modal MRL is slightly above the HRL. The
decline in the populations exposed at /^ the HRL and the HRL in Round 1 versus Round 2 is
additional evidence of the decline in the environmental levels of 1,1,2,2-tetrachloroethane. In
Round 1, the estimated population exposed at 1A the HRL was about 4 million people the cross
section states, compared to approximately 1 million in Round 2. The Round 1 estimate for
exposure above the HRL in the cross section states was 3.5 million people compared to 168
thousand people in Round 2.
Table 9-1 Populations Exposed to 1,1,2,2-Tetrachloroethane at 1A HRL or HRL
System Type
Cross Section
States
%
All States
%
National Extrapolation
Cross Section States
National
Extrapolation All
States
1/2 HRL
All PWS
Surface Water
Groundwater
0.51
0.75
0.09
0.44
0.63
0.11
1,082,000
950,000
80,000
936,000
803,000
94,000
HRL
All PWS
Surface Water
Groundwater
0.08
0.07
0.09
0.08
0.06
0.11
168,000
90,000
80,000
166,000
76,000
94,000
1,1,2,2-Tetrachloroethane —January, 2008
9-9
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9.4.3 Relative Source Contribution
A Relative Source Contribution (RSC) analysis compares the magnitude of exposure
expected via drinking water to the magnitude of exposure from intake of 1,1,2,2-tetrachloroethane
in other media, such as food, air, and soil. In situations where 1,1,2,2-tetrachloroethane occurs in
drinking water, the water is likely to be the major source of exposure, unless there is also
contamination at a local hazardous waste site. There are no national data for occurrence in foods
and ambient air levels have declined in concert with the decline in production and use based on
TRI data. Lack of recent quantitative monitoring data for air, foods, and soils would lead to a
default 20% RSC as described by U.S. EPA (2000f), were a lifetime Health Advisory (HA) to be
developed for noncancer effects.
9.4.4 Sensitive Populations
There are no data that indicate that the fetus is affected by oral exposure to 1,1,2,2-
tetrachloroethane at levels below those that have maternal effects or to inform an evaluation on
whether or not infants or children would be more sensitive than adults. Individuals with
preexisting liver and kidney damage would likely be more sensitive than the general population to
1,1,2,2-tetrachloroethane exposure. To the extent that lipid peroxidation plays a role in the liver
damage caused by 1,1,2,2-tetrachloroethane, low intake of antioxidant nutrients (Vitamin A,
Vitamin E, Vitamin C, and selenium) could be a predisposing factor for liver damage. Individuals
with a genetically low capacity to metabolize dichloroacetic acid might also be at greater risk than
the general population as a result of 1,1,2,2-tetrachloroethane exposure.
9.5 Regulatory Determination Decision
As stated in Section 9.1.1, a positive finding for all three criteria is required in order to
make a determination to regulate a contaminant. In the case of 1,1,2,2-tetrachloroethane, only the
finding for the criterion on health effects is positive. 1,1,2,2-tetrachloroethane may have an
adverse effect on the health of people. Based on monitoring conducted between 1987 to 1997,
1,1,2,2-tetrachloroethane was detected at least once in some PWS, but the number of detections
and the concentrations detected have declined as many of the commercial uses of 1,1,2,2-
tetrachloroethane have been phased out. Accordingly, it appears that 1,1,2,2-tetrachloroethane
does not occur in public water systems at a frequency and at levels of public health concern at the
present time. Based on the low occurrence of 1,1,2,2-tetrachloroethane in the potable water and in
the environment, regulation of 1,1,2,2-tetrachloroethane does not present a meaningful opportunity
for health risk reduction for persons served by public water systems at this time.
1,1,2,2-Tetrachloroethane — January, 2008 9-10
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contaminants in public water systems: an initial assessment. EPA Report 815-P-00-001. Office of
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ambient water quality criteria for the protection of human health. Office of Water, Office of
Science and Technology.
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U.S. EPA (United States Environmental Protection Agency). 2002c. Announcement of preliminary
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1,1,2,2-Tetrachloroethane — January, 2008 10-16
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1,1,2,2-Tetrachloroethane — January, 2008 10-18
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APPENDIX A: Abbreviations and Acronyms
ACTH adrenocorticotropic hormone
AIC Akaike's Information Criterion
ALA Y'amm°levulmic acid (ALA)
ALT alanine amino transferase
AST aspartate amino transferase
ASTER Assessment Tools for the Evaluation of Risk
ATSDR Agency for Toxic Substances and Disease Registry
BCF bioconcentration factor
BMC benchmark concentration
BMCL benchmark concentration lower confidence limit
BMD benchmark dose
BMDL benchmark dose lower confidence limit
BMDS Benchmark Dose Software
CAS Chemical Abstracts Registry
CCL Contaminant Candidate List
CYP cytochrome
DCA dichloroacetic acid
EC20 effective concentration for a 20% effect
EPCRA Emergency Planning and Community Right-to-Know Act
FDA Food and Drug Administration
FEL frank effect level
FOB functional observation battery
FR Federal Register
gd gestation day
GGT+ y§lutamyl transpeptidase-positive
GR green rusts
GST glutathione-S-transferase
HA Health Advisory
HED human equivalent dose
HRL health reference level
IARC International Agency for Risk of Carcinogens
IRIS Integrated Risk Information System
LD50 lethal dose for 50% of tested animals
LOAEL lowest observed adverse effect level
MRL analytical method reporting limit
MTD maximum tolerated dose
MtBE methyl turt-butyl ether
NCI National Cancer Institute
NOAEL no observed adverse effect level
NOEC no effect concentration
NOES National Occupational Exposure Survey
NIOSH National Institute for Occupational Safety and Health
NPL National Priorities List
NTP National Toxicology Program
1,1,2,2-Tetrachloroethane —January, 2008
Appendix A-1
-------
NAWQA National Water Quality Assessment
NOEC no effect concentration
OGWDW Office of Ground Water and Drinking Water
OSHA Occupational Safety and Health Administration
PBPK physiologically-based pharmacokinetic
PCE tetrachloroethylene
PEL permissible exposure level
ppb parts per billion
ppm parts per million
ppt parts per trillion
PWS public water systems
RCRA Resources Conservation and Recovery Act
RfC reference concentration
RfD reference dose
RR relative risk
RSC relative source contribution
SDWA Safe Drinking Water Act
SDH sorbitol dehydrogenase
SIC Standard Industrial Classification
TCE trichloroethylene
TWA time-weighted average
UF uncertainty factor
UCM unregulated contaminant monitoring
USGS U.S. Geological Service
U.S. EPA U.S. Environmental Protection Agency
VLDL very low density lipoprotein
VOC volatile organic compound
1,1,2,2-Tetrachloroethane —January, 2008
Appendix A-2
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APPENDIX B: Benchmark Dose Modeling Results for Non-Cancer Endpoints
Benchmark dose (BMD) modeling was performed to identify potential critical effect levels for
derivation of the RfD for 1,1,2,2-trichloroethane. The modeling was conducted according to draft
EPA guidelines (U.S. EPA, 2000c) using Benchmark Dose Software Version 1.3.2 (BMDS),
which is available from EPA (U.S. EPA, 2002). The BMD modeling results are summarized in
Tables C-l through C-3, with selected output following. The table include results for all the
endpoints and models for which (1) the BMDS model converged correctly, and (2) for which
BMDL and BMDL estimates were successfuly generated.
BMD models were fit for all of the endpoints from the 14-week feeding study (NTP, 2004)
that showed dose-related patterns of severity in rats and/or mice. These included serum alanine
aminotransferase (ALT) and sorbitol dehydrogenase (SDH), as well as blood hemoglobin
concentration, relative liver weight, and sperm motility in male rats. For BMD modeling, we
excluded data from high-dose groups that showed significant body weight differences from
controls and lower dose groups. This was done to exclude the potential that lower food
consumption, generalized systemic effects, or acute toxicity might effect the dose-response
relationships for the critical effects. For rats, this meant excluding all dose groups above 80
mg/kg-day. For female mice, all dose groups above 300 mg/kg-day were excluded, and for male
mice, data from dose groups above 370 mg/kg-day were excluded.
Because the endpoints are continuous variables, the continuous models available with
BMDS (linear, polynomial, power) were used. Because of the small number of data points
available (four for most of the data sets, three for the male mice, the Hill Model was not used to fit
data from the rat and mouse studies. For all of the modeling conducted, the BMR was defined as
an excess risk of 1.0 control standard deviation, the default for continuous data (U.S. EPA, 2000c).
It can be seen from the data in Tables B1-B3, that the rat is the more sensitive species, as
indicated by the lower BMD and BMDL values for rats as compared to mice, and that male rats
seem to be more sensitive than females. For this reason, as noted in Section 8.1.1, the most
sensitive endpoint in male rats (increase in relative liver weight, BMD) was selected as the point
of departure for RfD Derivation. The best-fitting (Linear) model generates a BMD estimate of
13.1 mg/kg and a BMDL estimate of 10.7 mg/kg. Relative liver weight is also the most sensitive
endpoint for female rats (BMDL = 24.2, BMDL = 16.1 with the best-fitting model.)
1,1,2,2-Tetrachloroethane — January, 2008 Appendix B-1
-------
Table B-l Benchmark Dose Modeling Summary for For Male Rats (NTP, 2004)
Table B-2
EndDoint(a)
ALT
ALT
ALT
SDH
SDH
SDH
RLW
RLW
RLW
HEMO
HEMO
HEMO
MOT
Model
Polynomial
Power
Linear
Linear
Polynomial
Power
Linear
Polynomial
Power
Linear
Polynomial
Power
Linear
D - value
0.965
0.944
0.089
0.261
0.101
0.101
0.148
0.059
0.051
0.709
0.526
0.407
0.0038
AIC
200.09
202.09
202.92
157.19
159.19
161.19
92.26
94.02
96.26
-7.36
-5.65
-3.36
156.32
BMD
46.6
46.5
26.7
45.7
45.7
45.7
13.1
11.8
13.1
45.5
36.2
45.5
49.2
BMDL
29.1
29.5
20.5
31.7
31.7
31.7
10.7
8.5
10.7
31.6
17.9
31.6
32.8
(a) ALT = alanine amino transferase, SDH = sorbitol dehydrogenase, RLW = relative liver weight,
HEMO = hemoglobin, and MOT = sperm motility
Benchmark Dose Modeling Summary for Female Rats (NTP, 2004)
EndDoint(a)
ALT
ALT
ALT
ALT
SDH
SDH
RLW
RLW
RLW
HEMO
HEMO
HEMO
Model
Polynomial
Linear
Power
Polynomial
(restricted)
Linear
Power
Polynomial
Power
Linear
Linear
Polynomial
Power
D - value
0.96
0.01
0.03
0.01
0.44
0.52
0.198
0.138
0.003
0.068
0.205
0.211
AIC
180.83
188.74
183.37
185.90
156.17
156.93
69.89
72.43
77.56
-28.76
-30.54
-28.58
BMD
86.3
125.7
79.8
83.1
167.3
82.4
24.2
26.0
13.3
29.4
48.7
46.0
BMDL
76.1
59.3
79.8
63.2
67.4
74.8
16.1
17.6
10.9
22.3
29.7
29.5
(a) See note to Table C-l.
1,1,2,2-Tetrachloroethane — January, 2008
Appendix B-2
-------
Table B-3 Benchmark Dose Modeling Summary for Male and Female Mice (NTP, 2004)
MALE
Endnoint(a)
ALT
SDH
RLW
Model
Linear
Linear
Linear
D - value
0.591
0.0004
0.089
AIC
253.03
172.39
98.64
BMD
770
76.5
58.9
BMDL
169
54.1
43.7
FEMALE
Endpoint
ALT
ALT
ALT
SDH
SDH
SDH
RLW
RLW
RLW
Model
Power
Polynomial
Linear
Linear
Power
Polynomial
Polynomial
Linear
Power
p - value
0.627
0.513
0.061
<0001
0.948
0.912
0.027
0.001
0.000
AIC
369.098
367.290
370.455
319.403
300.954
298.962
137.941
145.446
149.446
BMD
206
194
114.1
56.6
126
127
34.0
73.2
73.2
BMDL
132
126
86.0
46.0
95.0
91.7
25.4
58.4
58.4
(a) See note to Tabled.
1,1,2,2-Tetrachloroethane —January, 2008
Appendix B-3
-------
BMDS Model Output for Critical Non-Cancer Effect (Relative Liver Weight in Male Rats)
Polynomial Model. Revision: 2.2 Date: 9/12/2002
Input Data File: C:\BMDS DOCS\RE-ENTERED\MALE_RAT.(d)
Gnuplot Plotting File: C:\BMDS DOCS\RE-ENTERED\MALE_RAT.plt
MonJul 17 13:45:462006
BMDS MODEL RUN
The form of the response function is:
Y[dose] = beta_0 + beta_l*dose + beta_2*doseA2 + ...
Dependent variable = MEAN
Independent variable = DOSE
rho is set to 0
Signs of the polynomial coefficients are not restricted
A constant variance model is fit
Total number of dose groups = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
alpha = 3.375
rho = 0 Specified
beta_0 = 34.646
beta_l = 0.139757
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit
alpha 3.34192 0.747275 1.87728 4.80655
beta_0 34.646 0.447789 33.7683 35.5237
beta_l 0.139757 0.00977156 0.120605 0.158909
Asymptotic Correlation Matrix of Parameter Estimates
alpha beta_0 beta_l
alpha 1 le-012 -l.le-012
beta_0 le-012 1 -0.76
beta 1 -l.le-012 -0.76 1
1,1,2,2-Tetrachloroethane — January, 2008 Appendix B-4
-------
Table of Data and Estimated Values of Interest
Dose N Obs Mean Obs Std Dev Est Mean Est Std Dev ChiA2
Res.
0
20
40
80
10
10
10
10
34.8
36.7
41
45.6
1.3
1.4
2.7
1.6
34.6
37.4
40.2
45.8
1.83
1.83
1.83
1.83
0.249
-1.25
1.37
-0.375
Model Descriptions for likelihoods calculated
Model Al: Yij = Mu(i) + e(ij)
Var{e(ij)} = SigmaA2
Model A2: Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma(i)A2
Model R: Yi = Mu + e(i)
Var{e(i)} = SigmaA2
Likelihoods of Interest
Model Log(likelihood) DF AIC
Al -42.220696 5 94.441392
A2 -38.513709 8 93.027417
fitted -44.130893 2 92.261785
R -80.848861 2 165.697722
Test 1: Does response and/or variances differ among dose levels (A2 vs. R)
Test 2: Are Variances Homogeneous (Al vs. A2)
Test 3: Does the Model for the Mean Fit (Al vs. fitted)
Tests of Interest
Test -2*log(Likelihood Ratio) Testdf p-value
Test 1
Test 2
Test3
84.6703
7.41397
3.82039
6
3
2
<0001
0.05981
0.1481
The p-value for Test 1 is less than .05. There appears to be a difference between response and/or
variances among the dose levels. It seems appropriate to model the data
The p-value for Test 2 is greater than .05. A homogeneous variance model appears to be
appropriate here
1,1,2,2-Tetrachloroethane — January, 2008 Appendix B-5
-------
The p-value for Test 3 is greater than .05. The model chosen appears
to adequately describe the data
Benchmark Dose Computation
Specified effect = 1
Risk Type = Estimated standard deviations from the control mean
Confidence level =
0.95
BMD
13.0805
BMDL
10.7147
48
46
44
42
40
38
36
34
Linear Model with 0.95 Confidence Level
o>
§
Q.
03
o>
Linear
BMDL BMD
10
20
30
40
dose
50
60
70
80
11:36 08/02 2006
1,1,2,2-Tetrachloroethane —January, 2008
Appendix B-6
-------
APPENDIX C: Benchmark Dose Modeling Results for Cancer Risk Estimation
Benchmark dose (BMD) modeling was performed to identify a point of departure (POD) for
derivation of the cancer risk estimates for 1,1,2,2-trichloroethane. The modeling was conducted
according to EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a) and draft EPA
BMD guidelines (U.S. EPA, 2000c) using Benchmark Dose Software Version 1.3.2 (BMDS),
which is available from EPA (U.S. EPA, 2002). The BMD modeling results are summarized in
Table D-l, with selected output following. A brief discussion of the modeling results is presented
below. Based upon current EPA policy, only the multistage model was used, with the BMR
defined as a 10% increased incidence over control.
The increased incidence of liver tumors in female B6C3F1 mice given 1,1,2,2-
trichloroethane in feed for 78 weeks (NCI, 1978) was chosen as the endpoint to model. These
results are summarized in Table D-l. Fitting the 2-stage multistage model resulted in a BMD of
14.58 mg/kg-day and a BMDL of 8.22 mg/kg-day.
Table C-l
Benchmark Dose Estimates from NTP (2004) Male Rat Serum ALT
Activity
Model
Multistage (2)
BMD
14.58
BMDL
8.22
Chi-square
/j-value
0.31
AIC2
106
2Akaike's Information Criterion (AIC) = -2L + 2p, where L is the log-likelihood at the maximum likelihood
estimates for the parameters, and p is the number of model degrees of freedom. This can be used to compare models
with different numbers of parameters using a similar fitting method (for example, least squares or a binomial
maximum likelihood). Although such methods are not exact, they can provide useful guidance in model selection.
1,1,2,2-Tetrachloroethane —January, 2008
Appendix C-l
-------
Benchmark Dose Modeling Output For 1122-TCE Cancer Endpoint
Multistage Model. SRevision: 2.1 $ $Date: 2000/08/21 03:38:21 $
Input Data File: E:\BMDS\DATAYTCE-HEPCARC.(d)
Gnuplot Plotting File: E:\BMDS\DATA\TCE-HEPCARC.plt
TueJun 14 11:02:532005
BMDS MODEL RUN
The form of the probability function is:
P[response] = background + (l-background)*[l-EXP(
-betal*doseAl-beta2*doseA2)]
The parameter betas are restricted to be positive
Dependent variable = fmouse_hepcarc
Independent variable = fmouse_dose
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.0253206
Beta(l)= 0.00684418
Beta(2)= 2.5872e-005
Asymptotic Correlation Matrix of Parameter Estimates
Background Beta(l) Beta(2)
Background 1 -0.41 0.23
Beta(l) -0.41 1 -0.93
Beta(2) 0.23 -0.93 1
1,1,2,2-Tetrachloroethane — January, 2008 Appendix C-2
-------
Multistage Model with 0.95 Confidence Level
0.8
T3
CD
o 0.6
I
~ 0.4
CO
Ll_
0.2
Multistage
BMD Lower Bound
BMDL BMP
0
11:0206/142005
50
100
dose
Parameter Estimates
Variable Estimate
Background 0.025
Beta(l) 0.00684906
Beta(2) 2.58559e-005
Std. Err.
0.156125
0.00579368
3.45846e-005
150
200
Analysis of Deviance Table
Model Log(likelihood) Deviance TestDF P-value
Full model -49.4055
Fitted model -50.1115 1.41194 1 0.2347
Reduced model -92.948 87.085 3 <.0001
AIC: 106.223
Goodness of Fit
Dose Est._Prob. Expected Observed Size ChiA2 Res.
i: 1
0.0000 0.0250 0.500 1 20 1.026
1,1,2,2-Tetrachloroethane —January, 2008
Appendix C-3
-------
0.0000 0.0250 0.500 0 20 -1.026
i: 3
101.0000 0.6250 30.000 30 48 0.000
202.0000 0.9149 43.000 43 47 0.000
Chi-square = 1.03 DF = 1 P-value = 0.3112
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD= 14.5806
BMDL = 8.22427
1,1,2,2-Tetrachloroethane — January, 2008 Appendix C-4
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