United States
Environmental Protection
1=1 m m Agency
EPA/690/R-10/011F
Final
10-01-2010
Provisional Peer-Reviewed Toxicity Values for
1,2-Dichloroethane
(CASRN 107-06-2)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Janet Hess-Wilson, Ph.D.
National Center for Environmental Assessment, Cincinnati, OH
CONTRIBUTORS
Harlal Choudhury, DVM, Ph.D., DABT
National Center for Environmental Assessment, Cincinnati, OH
Dan D. Petersen, Ph.D., DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Q. Jay Zhao, Ph.D., M.P.H., DABT
National Center for Environmental Assessment, Cincinnati, OH
Martin W. Gehlhaus, III, M.H.S
National Center for Environmental Assessment, Washington, DC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300)
li

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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	iv
BACKGROUND	1
HISTORY	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	2
INTRODUCTION	2
REVIEW 01 PERTINENT DATA	4
HUMAN STUDIES	4
Oral Exposure	4
Inhalation Exposure	4
ANIMAL STUDIES	8
Oral Exposure	8
Subchronic Studies	8
Chronic Studies	19
Reproductive/Developmental Studies	21
Inhalation Exposure	23
Subchronic Studies	23
Chronic Studies	23
Reproductive/Developmental Studies	28
OTHER STUDIES	32
Toxicokinetics	32
Immunotoxicity	33
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD VALUES
I OR 1,2-DICHLOROETHANE	34
SUBCHRONIC p-RfD	37
CHRONIC p-RfD	38
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC INHALATION RfC
VALUES I OR 1,2-DICHLOROETHANE	38
SUBCHRONIC p-RfC	43
CHRONIC p-RfC	44
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR 1,2-DICHLOROETHANE	46
REFERENCES	46
APPENDIX A. DETAILS OF BENCHMARK DOSE MODELING FOR SUBCHRONIC
RfD	52
APPENDIX B. DERIVATION OF CHRONIC RfD SCREENING VALUE	55
APPENDIX C. DETAILS OF BENCHMARK DOSE MODELING FOR CHRONIC RfC	57
in

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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMD
benchmark dose
BMCL
benchmark concentration lower bound 95% confidence interval
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
POD
point of departure
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
iv

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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
1,2-DICHLOROETHANE (CASRN 107-06-2)
BACKGROUND
HISTORY
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1)	EPA's Integrated Risk Information System (IRIS)
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in EPA's Superfund
Program
3)	Other (peer-reviewed) toxicity values, including
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR);
~	California Environmental Protection Agency (CalEPA) values; and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's IRIS. PPRTVs are developed according to a Standard
Operating Procedure (SOP) and are derived after a review of the relevant scientific literature
using the same methods, sources of data, and Agency guidance for value derivation generally
used by the EPA IRIS Program. All provisional toxicity values receive internal review by a
panel of six EPA scientists and external peer review by three independently selected scientific
experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram
consensus review provided for IRIS values. This is because IRIS values are generally intended
to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund
Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
DISCLAIMERS
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
The compound 1,2-dichloroethane (1,2-DCA), also known as ethylene dichloride (EDC),
is a chlorinated solvent and degreaser with a molecular weight of 98.96 g/mol (Hazardous
Substances Data Bank [HSDB], 2008). Figure 1 shows its chemical structure.
IRIS (U.S. EPA, 2008) does not include RfD or RfC values for 1,2-DCA. No RfD or
RfC values are listed in the HEAST (U.S. EPA, 1997). Relevant documents on the Chemical
Assessments and Related Activities (CARA) list (U.S. EPA, 1991, 1994a) include a Health
Effects Assessment (HEA) (U.S. EPA, 1984), a Health and Environmental Effects Profile
(HEEP) (U.S. EPA, 1985a), and a Health Assessment Document (HAD) (U.S. EPA, 1985b).
None of these documents attempted to derive RfD or RfC values because 1,2-DCA had been
demonstrated to be carcinogenic. A drinking water Quantification of Toxicological Effects
(QTE) (U.S. EPA, 1985c) presented interim RfD derivations based on an oral multigeneration
study by Lane et al. (1982) and on inhalation data. However, a subsequent Drinking Water
Health Advisory (U.S. EPA, 1987) concluded that no appropriate data were available for
determining an RfD, and no RfD value appears on the Drinking Water Standards and Health
Advisories list (U.S. EPA, 2006).
ATSDR (2001) derived an intermediate-duration oral minimal risk level (MRL) of
0.2 mg/kg-day from a 13-week drinking water study in rats (National Toxicology Program
[NTP], 1991) in which a lowest-observed-adverse-effect level (LOAEL) of 58 mg/kg-day for
increased kidney weight was identified. Uncertainty factors (UFs) used in the MRL derivation
INTRODUCTION
Figure 1. Chemical Structure of 1,2-Dichloroethane
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were 3 for use of a minimal LOAEL, 10 for interspecies extrapolation, and 10 for human
variability. No chronic oral MRL was derived due to the lack of adequate data. ATSDR (2001)
derived an MRL of 0.6 ppm for chronic-duration inhalation exposure (>365 days) to 1,2-DCA
based on a no-observed-adverse-effect level (NOAEL) of 50 ppm from a study with rats exposed
for 7 hours/day, 5 days/week for 2 years (Cheever et al., 1990). The UF comprised factors of
3 for interspecies extrapolation after dosimetric adjustment, 10 for human variability, and 3 for
database deficiencies. Although only one dose was tested in the source study, other studies in
the database support the NOAEL.
California EPA (CalEPA, 2000, 2008a,b) lists a chronic inhalation recommended
exposure limit (REL) of 0.4 mg/m3 (0.1 ppm) for 1,2-DCA based on a NOAEL of 10 ppm and
LOAEL of 50 ppm for hepatotoxicity (increased serum liver enzymes) in rats exposed
7 hours/day, 5 days/week for 12 months (Spreafico et al., 1980). The World Health Organization
(WHO, 1987, 1995) has published environmental health criteria documents for 1,2-DCA and a
companion health and safety guide (WHO, 1991); the health and safety guide concludes that it
was not possible to derive a NOEL for noncarcinogenic effects on the basis of available human
data, but that a NOEL of 400 mg/m3 could be established on the basis of animal toxicity data.
No oral values for drinking water were derived by WHO (1991).
There are occupational exposure limits for 1,2-DCA. The American Conference of
Governmental Industrial Hygienists (ACGIH, 2007) posts a threshold limit value-time weighted
average (TLV-TWA), dating from 1977, of 10 ppm to protect against liver damage and nausea,
with an A4 designation (not classifiable) for human carcinogenicity. In contrast, the National
Institute of Occupational Safety and Health (NIOSH, 2008) lists 1,2-DCA as an occupational
carcinogen with a recommended exposure limit-time weighted average (REL-TWA) of 1 ppm
(4 mg/m3) and a short-term exposure limit of 2 ppm (8 mg/m3). The Occupational Safety and
Health Administration (OSHA, 2008) permissible exposure limit (PEL) is 50 ppm as TWA,
100 ppm as a ceiling, and 200 ppm as an acceptable maximum peak above the acceptable ceiling
concentration for an 8-hour shift (not to exceed 5 minutes in any 3 hours).
IRIS (U.S. EPA, 2008) classifies 1,2-DCA as a Group B2 (probable human) carcinogen
based on the induction of several tumor types in rats and mice treated by gavage and on
observation of lung papillomas in mice after topical application. IRIS (U.S. EPA, 2008) posts an
OSF of 9.1 x 10" per mg/kg-day derived from linearized multistage modeling of
hemangiosarcomas in male Osborne-Mendel rats treated with 1,2-DCA by gavage (National
Cancer Institute [NCI], 1978). This corresponds to a Drinking Water Unit Risk of 2.6 x 10"6 per
[j,g/L and a risk level of 10"4 at a drinking water concentration of 0.040 mg/L. The latter level is
included in the Drinking Water Standards and Health Advisories list (U.S. EPA, 2006). IRIS
also posts an Inhalation Unit Risk Factor (IUR) of 2.6 x 10"5 per |ig/m3 based on extrapolation
from the oral data for hemangiosarcoma in male rats (NCI, 1978).
NTP (2008) has assessed the toxicity (NTP, 1991: 13-week study) and carcinogenicity of
1,2-DCA (NCI, 1978), and this compound is included in the 11th Report on Carcinogens (NTP,
2005), which concludes that 1,2-DCA is Reasonably Anticipated to Be a Human Carcinogen
based on sufficient evidence of carcinogenicity in experimental animals (NCI, 1978). The
International Agency for Research on Cancer (IARC, 1979, 1987, 1999, 2008) classifies
1,2-DCA as Group 2B (Possible Human Carcinogen) based on sufficient evidence of
carcinogenicity in animals and inadequate evidence of carcinogenicity in humans. Oral studies
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1	2
in mice and rats conducted by NCI (1978) were considered adequate. Inhalation studies with
rats and mice were not considered to be adequate. CalEPA (2002) lists a cancer IUR factor of
2.1 x 10"5 (|ig/in3)"' and an OSF of 7.2 x 10"2 (mg/kg-day)"1 for 1,2-DCA. Environment Canada
(1994)	categorized 1,2-DCA as Group II (Probably Carcinogenic to Humans), with estimates of
carcinogenic potency (TDo.os) ranging from 6.2 to 297 mg/kg-day. The present document does
not contain a cancer assessment for 1,2-DCA, as one is available on IRIS (U.S. EPA, 2008).
Literature searches were conducted from 1960s through January 2010 in the following
databases for studies relevant to the derivation of provisional toxicity values for 1,2-DCA:
TOXLINE, MEDLINE, TSCATS1/2, RTECS, CCRIS, DART, HSDB, GENETOX, CCRIS,
CHEMABS, BIOSIS, and Current Contents (last 6 months). An Organisation for Economic
Co-operation and Development Screening Information Dataset (OECD SIDS) Initial Assessment
Report (OECD, 2002) was also consulted for relevant information.
REVIEW OF PERTINENT DATA
HUMAN STUDIES
Oral Exposure
Information concerning the toxic effects of ingested 1,2-DCA in humans is largely
limited to case reports of individuals who accidentally or intentionally ingested 1,2-DCA. These
case reports generally describe findings in single individuals exposed acutely to 1,2-DCA and
give only crude estimates of ingested dose, further limiting the value of the data. Available
reviews (ATSDR, 2001; IARC, 1999; WHO, 1995) reported that symptoms of acute 1,2-DCA
intoxication include cardiac arrhythmia, bronchitis, hemorrhagic gastritis and colitis,
hepatocellular damage, renal tubular necrosis and calcification, and CNS depression. WHO
(1995)	reported the estimated lethal dose in humans to be 20-50 mL based on these case reports;
these intakes correspond to doses of 25-62 g3, or 350-890 mg/kg based on a reference body
weight of 70 kg. Ecological epidemiological studies (Bove, 1996; Bove et al., 1995;
Croen et al., 1997, all cited in ATSDR, 2001) have reported an association between 1,2-DCA in
drinking water supplies and major birth defects, but lack of individual exposure information and
concurrent exposures to other compounds limits the usefulness of these studies for establishing
an association or evaluating the dose-response relationship. Both oral and inhalation exposures
were likely in these studies.
Inhalation Exposure
Fatal and nonfatal outcomes have resulted from acute occupational exposure to 1,2-DCA
(U.S. EPA, 1985b). In most occupational cases, the exposures were poorly characterized and
consisted of a mixture of solvents. Generally, inhalation of 1,2-DCA vapor first affects the CNS
(with symptoms of headache, dizziness, lethargy, feelings of drunkenness, unconsciousness) and
causes irritation and inflammation of the respiratory tract, which is characteristic of chlorinated
aliphatic hydrocarbon toxicity (U.S. EPA, 1985b). Other signs and symptoms of inhalation
1 Significant increases in benign and malignant tumors of the lung, malignant lymphomas, hepatocellular
carcinomas, and mammary and uterine adenocarcinoma.
2Forestomach carcinomas in males, benign and malignant mammary tumors in females, and hemangiosarcomas in
both sexes.
3Assuming specific gravity of 1.235 (HSDB, 2008).
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exposure included eye irritation, cyanosis, epigastric tenderness, hepatomegaly, and jaundice
(U.S. EPA, 1985b; WHO, 1995). WHO (1995) reported damage to the liver, kidneys, and lungs.
Quantitative data pertinent to the effects of repeated inhalation of 1,2-DCA by humans are
limited and derived chiefly from foreign reports lacking controls and providing inadequate
information about duration of exposure and/or number of subjects exposed (U.S. EPA, 1985b).
Case reports of repeated exposures to unknown concentrations describe nervousness, irritability,
tremors, depressed reflexes, and irritation of the skin and mucous membranes in exposed
workers (U.S. EPA, 1985b). EPA (1985b) reviewed a number of older case reports and
occupational health studies; selected case reports and studies (those providing semiquantitative
information and/or clear identification of target organs) are described below, as are newer studies
of inhalation exposure to 1,2-DCA in humans.
A case study reported by Nouchi et al. (1984) detailed the clinical effects, blood
chemistry, and autopsy findings of a 51-year-old man who died after being exposed to 1,2-DCA
vapor for 30 minutes while removing 1,2-DCA residue from the hold of an oil tanker. Exposure
is likely to have occurred by both the inhalation and dermal routes. No estimate of the exposure
concentration was available, although exposure conditions were described as a "thick vapor of
dichloroethane." An autopsy revealed congestion of the lungs, degenerative changes in the
myocardium, liver necrosis, renal tubular necrosis, and smaller nerve cells in the brain.
In a summary of studies of 100 Russian workers from different (unspecified) industries
"3
who were exposed to <25 ppm (-100 mg/m ) of 1,2-DCA for 6 months to 5 years, Rosenbaum
(1947; as cited in U.S. EPA, 1985a,b) reported that the following signs and symptoms occurred
in "many" of the workers: heightened responses of the autonomic nervous system, improved
muscular tonus, bradycardia, increased perspiration, and increased frequency of fatigue,
irritability, and sleeplessness.
Agricultural workers in Poland were exposed to 1,2-DCA during its transportation,
distribution, and application (use as a fumigant on agricultural fields) (Brzozowski et al., 1954;
as cited in U.S. EPA, 1984). The exposure was believed to be primarily via dermal contact, but
air concentrations were estimated to range from 4-60 ppm (-16-240 mg/m ) depending on the
activity. Among 118 of these workers, 90 had clinical findings, including conjunctival
congestion (82/118), weakness (54/118), reddening of the pharynx (50/118), bronchial symptoms
(43/118), metallic taste (40/118), dermographism (37/118), nausea (31/118), cough (30/118),
liver pain (29/118), irritation of the conjunctiva (24/118), rapid pulse (21/118), and dyspnea after
effort (21/118).
Cetnarowicz (1959) studied a small number of Polish oil refinery workers exposed to
vapor from a solvent containing 80% 1,2-DCA and 20% benzene for -6 months. All
"3
10 centrifuge workers exposed to levels of 1,2-DCA ranging from 250 to 800 mg/m reported
eye irritation and lacrimation, and 6 complained of dryness of the mouth, gastrointestinal
disturbances (nausea, vomiting, loss of appetite), dizziness, and fatigue. Of the 10, 3 complained
of epigastric pain. Upon clinical examination, palpation revealed liver tenderness with slight
enlargement in 4/10 workers. Only 1/6 workers exposed to lower concentrations
(40 to 150 mg/m3) of 1,2-DCA complained of symptoms similar to those reported by the
centrifuge-exposure subgroup. Additional physical examination of all 16 workers revealed no
eye or upper or lower respiratory tract damage but provided additional evidence of liver effects
(altered liver function tests) and gastrointestinal effects (X-ray observable gastritis in 6/16, with
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pyloric spasms in 3/16); distribution of these additional findings among the two subgroups was
not reported. This study is limited by coexposure to benzene and the lack of a control group.
Kozik (1957) reported the results of a study of Russian aircraft industry employees (glue
shop workers) exposed to 1,2-DCA. In this study, morbidity and temporary loss of working
capacity was examined during the period from 1951 to 1955. No information on the length of
employment or the duration of exposure was reported. For 70-75% of the work shift, the
"3
ambient concentration of 1,2-DCA was <50 mg/m ; for the remaining 25-30%, the levels ranged
up to 150 mg/m3. Upon reviewing the data on the ambient air concentrations, NIOSH (1976)
estimated that the TWA concentration in the breathing zone was about 61 mg/m3 (15 ppm4).
The incidences of morbidity and the number of days lost from work due to acute gastrointestinal
diseases, liver and gallbladder disease, neuritis and radiculitis, and other disorders were higher in
the glue shop workers than in other workers in the plant, but a statistical analysis of the data was
not reported. Respiratory tract disease or irritation was not mentioned. Examination of 83 of the
gluers revealed that 19 had liver and gallbladder diseases, 13 had neuritis, 11 had hypotension,
and 10 had goiter and hyperthyroidism. Examination of unexposed workers was not performed.
The authors noted that diseases of the muscles, tendons, and ganglia were considered to be
associated with the many repetitive motions the workers had to make when applying the glue.
Results of neurobehavioral testing in a group of 17 gluers revealed impaired visual-motor
reactions on 2/3 tests when compared with a group of 10 controls (machinists in the same
factory). The test methods were poorly described but involved the determination of reaction
time and error rate in the performance of a simple reaction, complex reaction (differentiation of
color), and "alternation of the complex reaction." The mean rates for all three reactions (speed
of reaction) before and after work were not significantly different between the two groups. The
number of workers making errors and the percentage error were higher in gluers than in controls
for the complex reaction and the alternation of complex reaction. Errors occurred only at the end
of the work day. The authors reported that 4/10 machinists made errors, while 15/17 gluers
made errors (p = 0.01 by Fisher's exact test performed for this review). This study has several
limitations, including the lack of statistical analysis of morbidity data, lack of medical
examination of nonexposed workers, examination of a limited number of toxicity endpoints, and
the lack of control of potentially confounding factors, such as alcohol intake. Because the only
endpoint that was evaluated in both an exposed and a referent group was the neurobehavioral
testing, these data are used to define effect levels. For the purpose of this review, the TWA
exposure concentration of 61 mg/m3 estimated by NIOSH (1976) is considered to represent a
LOAEL based on neurobehavioral effects in gluers. This LOAEL is uncertain given the poor
quality of the study and reporting, limited numbers of subjects, and lack of control for potential
confounders.
A number of recent studies of hazardous waste workers exposed to 1,2-DCA report
effects on memory and other neurobehavioral parameters (Dilks et al., 2005, 2007; Bowler et al.,
2003; Novakovic-Agopian and Bowler, 2001). Dilks et al. (2005, 2007) reported that
61 hazardous waste workers (59 men and 2 women) exposed to 1,2-DCA for 2 years and
examined 4 years later exhibited statistically significant memory impairments when compared
4In its summary of this study, NIOSH (1976) estimated a TWA of 15 ppm and provided some information on the
basis for this estimate. In its derivation of the recommended standard, NIOSH (1976) gave the exposure estimate as
a range from 10-15 ppm, without any reference to the basis for the range. For the purpose of this review, the TWA
estimate of 15 ppm is used.
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with 48 workers without exposure to petrochemicals. A follow-up study of 12 of the male
workers showed that the memory impairments persisted 8 years after the end of exposure. This
study is limited by the lack of information on the nature and magnitude of exposure to 1,2-DCA,
lack of information on other exposures sustained by the hazardous waste workers, lack of control
for potential confounders, strong potential for selection bias (if the hazardous waste workers
believed themselves to be impaired), and poor reporting.
Bowler et al. (2003; Novakovic-Agopian and Bowler, 2001) examined
neuropsychological effects in 221 hazardous waste workers exposed to 1,2-DCA. The clinical
evaluations were conducted as part of a lawsuit and were funded by the plaintiffs; however, they
were peer reviewed and published in a publically available journal. This study reported some
details of the exposure setting, but did not include any information on the magnitude of
exposures. Based on the description of the exposure setting (cleanup of a spill of 1,2-DCA from
a damaged pipeline), both dermal and inhalation exposures were likely. Bowler et al. (2003)
reported subjective symptoms, as well as the results of a battery of neuropsychological tests
(including intelligence, memory, motor speed, grip strength, visual function, and mood). There
was no control group. The authors reported that the workers exhibited lower processing speed,
attention, cognitive flexibility, motor coordination and speed, and impairments of verbal
memory, verbal fluency, visuo-spatial ability, vision, and mood. Lack of a control group,
absence of exposure information, and potential selection bias (due to the litigation) limit the
usefulness of this study.
Cheng et al. (1999) examined serum chemistry parameters (alanine aminotransferase
[ALT], aspartate aminotransferase [AST], and gamma glutamyl transpeptidase [GGT]) indicative
of liver toxicity in 251 male workers at four vinyl chloride manufacturing plants. The workers
were exposed to both vinyl chloride and 1,2-DCA. Using job descriptions and measurements of
vinyl chloride and 1,2-DCA in various jobs, the authors defined three exposure groups: low
1,2-DCA (median of 0.32-0.44 ppm, range from 0.16 to 0.72 ppm) with moderate vinyl chloride
(median of 0.44-1.63 ppm, range from 0.15 to 41.04 ppm); moderate 1,2-DCA (median of
0.77-1.31 ppm, range from 0.17 to 333.7 ppm) with low vinyl chloride (median of
0.18-0.27 ppm, range from 0.18 to 0.34 ppm); and low 1,2-DCA (median from 0.26-0.35 ppm;
range from 0.17 to 0.52 ppm) with low vinyl chloride (median from 0.29-0.39 ppm; range from
0.25-2.46 ppm). Each exposure is presented as a median and range because multiple jobs were
included in each category. The average duration of employment in the workers was 13.1 years.
Using a logistic regression analysis in which abnormal AST was defined as a serum
concentration >37 IU/L (international units per liter) and abnormal ALT was defined as
>41 IU/L, the authors observed statistically significant increases in the odds of having abnormal
AST (OR = 2.2, 95% CI = 1.0-5.4,/? < 0.05) and ALT (OR = 2.1, 95% CI = 1.1-4.2,/? < 0.05)
levels in workers exposed to moderate levels of 1,2-DCA and low levels of vinyl chloride,
compared with low 1,2-DCA and low vinyl chloride. Moderate vinyl chloride and low 1,2-DCA
was not significantly associated with abnormal AST or ALT. No association between 1,2-DCA
exposure and changes in GGT was seen in any exposure group. This study is limited by strong
potential for exposure misclassification, as the median exposures to both 1,2-DCA and vinyl
chloride were similar among all groups. Potential confounding by coexposure to vinyl chloride,
a potent hepatotoxicant, also limits the utility of this study.
Zhao et al. (1989) conducted a retrospective survey of the reproductive history of
98 workers (44 males, 54 females) that had contact with 1,2-DCA at a synthetic fiber factory or a
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Beijing chemical plant that produced 1,2-DCA (98.5% purity). The control group comprised
349 workers (136 males, 213 females) from a clothing factory or a computer factory having no
1,2-DCA contact but having similar medical and living conditions as the 1,2-DCA-exposed
group. The 1,2-DCA concentrations were estimated based on the records of periodic tests
performed at the plants during previous years. A large variation range of 1.5-1,534 mg/m was
reported for 1,2-DCA concentrations in the factories. The results of the survey indicated that
female workers from the 1,2-DCA contact group and the wives of male workers in the contact
group had statistically significant higher rates of premature births than the control group
(p < 0.05). The rates of pregnancy, miscarriages, and fetal deaths prior to or at birth were
comparable between the 1,2-DCA-contact and control groups. There were no physical
deformities and no obvious effects on the body weights of the newborns. Because
1,2-DCA-contact workers were exposed to other chemicals concurrent with their 1,2-DCA
exposure, no conclusions regarding the reproductive effects of 1,2-DCA could be reached.
ANIMAL STUDIES
Oral Exposure
Subchronic Studies—There are three subchronic studies in the literature: two in rats,
and one in mice and rats. In the first study, Van Esch et al. (1977) exposed Wistar rats of both
sexes (10/sex/dose) to 1,2-DCA (99% pure) via gavage administration at 0, 10, 30, or
90 mg/kg-day, 5 days/week for 90 days. The dose selections were based on the results of a
range-finding study in which groups of six male rats were dosed with 3, 10, 30, 100, or
300 mg/kg-day, 5 days/week for 2 weeks. In the range-finding study, all high-dose rats died;
histology on these animals revealed fatty degeneration of the liver. In the 90-day subchronic
study, body weights and food consumption were measured (frequency not reported). At 4 and
8 weeks of exposure, blood was collected for serum chemistry (ALT, alkaline phosphatase
[ALP]; eight males/dose group), and glucose-6-phosphatase, aryl hydrocarbon hydroxylase
(AH), and aminopyrene demethylase (APDM) activity, and triglyceride levels were measured in
the livers (four males/dose group). At the end of exposure, liver function was assessed using the
bromosulphophthalein retention test on six animals/sex/group. Hematology parameters
(hematocrit [Hct], hemoglobin [Hgb], red blood cells [RBC], total and differential white blood
cells [WBC], mean cell volume [MCV], mean cell hemoglobin [MCH], and mean cell
hemoglobin concentration [MCHC]) were assessed on blood collected at the end of exposure
from all animals. Upon sacrifice at the end of exposure, organs (brain, heart, liver, spleen,
kidneys, thymus, pituitary, thyroid, adrenals, ovaries, testes, and uterus) from all animals were
weighed, and histopathology of these and 16 other tissues was assessed in control and high-dose
animals. Liver and kidneys from low- and mid-dose groups were examined microscopically.
Additionally, in the subchronic study, Van Esch et al., 1977 observed slightly lower
weight gain (3—7% less than controls) in females in all dose groups and in mid- and high-dose
males; statistical analysis or data with which to perform statistical analyses were not reported
(Van Esch et al., 1977). Increased relative kidney weight (14—17% higher than controls)
occurred in both sexes at the high dose, and increased relative liver (13%) and brain (9%)
weights were also seen in the females at this dose; absolute weights were not reported. Based on
data reported in the paper, relative weights of other organs were not affected by treatment.
Reduced body weights in the high-dose animals may have contributed to the increases in relative
kidney, liver, and brain weights. Clinical chemistry parameters did not differ between exposed
and control animals; based on data shown in the report, sporadic hematological changes were
seen in females, but the changes were not dose-related. There were no treatment-related
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histopathological lesions. The authors identified a no-effect level of 30 mg/kg-day. The
increases in relative liver and kidney weights at 90 mg/kg-day are considered the LOAEL based
on the following observation by the authors: liver toxicity at higher doses (fatty degeneration at
300 mg/kg-day in the range-finding study), the consistent finding of increased kidney weights in
other studies of rats and mice exposed orally to 1,2-DCA (NTP, 1991; Daniel et al., 1994), and
the observation of renal histopathology in mice and some strains of rats exposed to higher doses
of 1,2-DCA (NTP, 1991; Daniel et al., 1994). The NOAEL is 30 mg/kg-day.
In the second subchronic study, which was chosen as the critical study, groups of F344/N
rats, Sprague-Dawley rats, Osborne-Mendel rats, and B6C3F1 mice (10 animals/sex) were
exposed to drinking water containing 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm of 1,2-DCA
(>99% pure) for 13 weeks (NTP, 1991). The high concentration was close to the solubility limit
for 1,2-DCA in water. The authors estimated the daily doses in mg/kg-day shown in Table 1
based on drinking water consumption and average body weights.
Table 1. Estimated Average Daily Doses (mg/kg-day) of 1,2-DCA in Animals Exposed via
Drinking Water for 13 Weeks3
Concentration in
Water (ppm)
Rats
Mice
F344/N
Sprague-Dawley
Osborne-Mendel
B6C3F1
Male
Female
Male
Female
Male
Female
Male
Female
500
49
58
60
76
54
82
249
244
1,000
86
102
99
106
88
126
448
647
2,000
147
182
165
172
146
213
781
1,182
4,000
259
320
276
311
266
428
2,710
2,478
8,000
515
601
518
531
492
727
4,207
4,926
aNTP (1991)
Additional groups of F344/N rats (10/sex) were administered 1,2-DCA (>99% pure) in
corn oil by gavage on 5 days/week for 13 weeks to compare toxicity resulting from bolus
administration with that of the continuous exposure in drinking water (NTP, 1991). Gavage
doses were 0, 30, 60, 120, 240, or 480 mg/kg-day in the male rats and 0, 18, 37, 75, 150, or
300 mg/kg-day in the female rats. In all groups (drinking water and gavage), signs of toxicity
were assessed twice daily, while body weight and food and water consumption were recorded
weekly. Separate groups of 10 male rats/strain were exposed to 0, 2,000, 4,000, or 8,000 ppm in
drinking water or 0, 120, 240, or 480 mg/kg-day by gavage and used for evaluation of
hematology (RBC, WBC, Hgb, Hct, MCV, MCH, MCHC, differential leukocyte count, platelets,
reticulocytes, and erythrocyte morphology) and serum chemistry (sorbitol dehydrogenase [SDH],
creatine kinase, ALT, ALP, and blood urea nitrogen [BUN]) on Days 3, 7, 14, 45, and 90.
Hematology and serum chemistry parameters were also evaluated on animals of the core groups
at study termination. Upon sacrifice at the end of exposure, organ weights (liver, right kidney,
brain, heart, thymus, lung, and right testis) were recorded, and gross necropsy was performed.
Histological examinations were completed on control and high-dose animals of all species and
strains, as well as on 4,000-ppm female mice, male rats exposed by gavage to 120 or
240 mg/kg-day, and on female rats exposed by gavage to 150 mg/kg-day.
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None of the rats given 1,2-DCA in drinking water died, and no treatment-related clinical
signs were observed (NTP, 1991). Dose-related decreases in water consumption, likely
reflecting poor palatability of the compound, occurred in all treated groups; decreases were
4-44% in F334/N males, 5-42% in F334/N females, 14-56%) in male Sprague-Dawley males,
25-70%) in Sprague-Dawley females, 17-60%) in Osborne-Mendel male rats, and 21-58%) in
Osborne-Mendel female rats. Dose-related reductions in body weight in most groups were
considered by the researchers to result from dehydration. Several hematology and serum
chemistry changes, including increases in RBC, Hct, or Hgb, mild decreases in MCV, and
increases in BUN (all observed in males) were also attributed by the researchers to dehydration
resulting from decreased water consumption. Sporadic, statistically significant (p < 0.05)
decreases in ALP and ALT levels were observed in treated male animals evaluated for serum
chemistry; the toxicological significance of these changes is uncertain. Creatine kinase activity
was unaffected in male rats of all three strains. SDH activity was significantly increased at
8,000 ppm on Days 14 and 45 in F344/N males and at 8,000 ppm on Day 14 in Sprague-Dawley
males (statistical significance of (p< 0.05) but was unaffected in Osborne-Mendel males.
In all three strains, absolute and/or relative kidney and liver weights were increased by
exposure; Tables 2 and 3 show the organ-weight changes in males and females, respectively
(NTP, 1991). Absolute kidney weights were significantly (p < 0.01) increased at >1,000 ppm in
male F344/N rats; absolute kidney weights were not affected by treatment in male
Sprague-Dawley or Osborne-Mendel rats. Relative kidney weights were significantly increased
at >1,000 ppm in F344/N males, at >4,000 ppm in Osborne-Mendel males, and at 1,000, 4,000,
and 8,000 ppm in Sprague-Dawley males (p < 0.05). Absolute kidney weights were significantly
(p < 0.05) increased at all drinking water exposure levels in female rats of all strains; relative
kidney weights were also increased at all exposure concentrations in female Sprague-Dawley and
Osborne-Mendel rats, and at >1,000 ppm in female F344/N rats. In male rats of all strains,
absolute liver weight changes were either not statistically significant or not dose-related; relative
liver weights were increased at all exposure concentrations in male Sprague-Dawley rats and at
>2,000 ppm in male F344/N rats but did not increase with dose. Neither absolute nor relative
liver weights exhibited dose-related changes in male or female Osborne-Mendel rats. In female
F344/N rats, there were sporadic increases in absolute liver weight, but the changes did not
exhibit clear dose-dependence; relative liver weights were increased at >4,000 ppm. In female
Sprague-Dawley rats, relative liver weight was increased at the highest drinking water
concentration; there were no changes in absolute liver weight (see Table 3).
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Table 2. Significant Changes in Male Rats Treated with 1,2-DCA in Drinking Water for 13 Weeks3
Parameter Evaluated
Concentration in Water (ppm)
Control
500
1,000
2,000
4,000
8,000
F344/N
Dose (mg/kg-day)
0
49
86
147
259
515
Final body weight (g)
358 ± 4b
359 ±7
358 ±5
358 ±3
329 ±3C
302 ± 4°
Water consumption (g/day)
25
24
21
18
15
14
Organ weights
Absolute kidney weight (mg)
1,232 ±48
1,345 ±38
1,433 ± 28°
1,523 ± 15°
1,451 ± 18°
1,377 ± 22°
Relative kidney weight (mg/g)
3.4 ±0.16
3.8 ±0.08
4.0 ± 0.09°
4.3 ± 0.04°
4.4 ± 0.06°
4.6 ± 0.07°
Absolute liver weight (mg)
15,450 ± 660
16,500 ± 540
16,960 ± 570
17,840 ± 250d
16,050 ±330
14,760 ± 340
Relative liver weight (mg/g)
42.9 ±2.17
46.5 ±0.95
47.7 ± 1.37
50.2 ± 0.49°
49.1 ± 0.79d
49.2 ± 0.85d
Sprague-Dawley
Dose (mg/kg-day)
0
60
99
165
276
518
Final body weight (g)
457 ±11
452 ±7
439 ±6
436 ± 12
440 ±8
418 ±9d
Water consumption (g/day)
43
37
30
25
21
19
Organ weights
Absolute kidney weight (mg)
1,871 ±74
1,943 ±59
1,954 ±58
1,856 ±74
2,000 ± 52
2,008 ± 55
Relative kidney weight (mg/g)
4.2 ±0.14
4.4 ± 0.11
4.5 ± 0.08d
4.3 ± 0.11
4.6 ± 0.1 ld
4.9 ± 0.11°
Absolute liver weight (mg)
18,480 ± 790
20,080 ± 590
18,810 ±570
20,100 ±790
19,970 ± 490
19,230 ±560
Relative liver weight (mg/g)
41.1 ± 1.03
45.0 ± 1.15d
43.6 ± 0.75d
46.5 ± 1.11°
45.9 ± 0.82°
46.5 ± 1.20°
Osborne-Mendel
Dose (mg/kg-day)
0
54
88
146
266
492
Final body weight (g)
452 ± 15
482 ± 13
468 ± 17
435 ± 14
399 ± 12
382 ±lld
Water consumption (g/day)
42
35
28
22
19
17
Organ weights
Absolute kidney weight (mg)
1,506 ±36 (n = 9)
1,600 ±41
1,751 ±40c
1,656 ±59
1,613 ±44
1,507 ± 68
Relative kidney weight (mg/g)
3.7 ± 0.28 (n = 9)
3.4 ±0.09
3.8 ± 0.14
3.8 ±0.09
4.1 ± 0.13°
4.0 ± 0.18d
Absolute liver weight (mg)
16,230 ± 810 (« = 9)
17,830 ±610
21,080 ±840c
19,310 ±800
15,190 ±510
15,900 ± 800
Relative liver weight (mg/g)
39.2 ±2.01 (n = 9)
37.4 ±0.85
45.4 ± 0.90d
44.6 ± 1.24d
38.8 ± 1.45
41.9± 1.59
aNTP (1991)
bMean ± standard error; n = 10 per group unless noted otherwise
cp < 0.01
dSignificantly dilferent from control at p< 0.05
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Table 3. Significant Changes in Female Rats Treated with 1,2-DCA in Drinking Water for 13 Weeks3
Parameter Evaluated
Concentration in Water (ppm)
Control
500
1,000
2,000
4,000
8,000
F344/N
Dose (mg/kg-day)
0
58
102
182
320
601
Final body weight (g)
202 ± 2b
204 ±3
207 ±2
199 ±3
195 ± 1
187 ±2
Water consumption (g/day)
19
18
16
14
12
11
Organ weights
Absolute kidney weight (mg)
739 ± 26
814 ± 16°
885 ±16d
845 ±17d
932 ±15d
923 ± 15d
Relative kidney weight (mg/g)
3.8 ± 0.13
4.1± 0.07
4.2 ± 0.17°
4.3 ± 0.07d
4.8 ± 0.09d
5.0 ± 0.04d
Absolute liver weight (mg)
6,829 ± 154
7,268 ± 179
7,627 ± 177d
7,278 ± 165
7,551 ± 171°
7,134 ± 147
Relative liver weight (mg/g)
35.3 ±0.85
36.6 ±0.60
36.3 ± 1.57
37.2 ±0.75
39.2 ± 0.94d
38.5 ± 0.61d
Histopathology (incidence)
Renal tubular regeneration
0/10
0/10
1/10
2/10
3/10
9/10e
Sprague-Dawley
Dose (mg/kg-day)
0
76
106
172
311
531
Final body weight (g)
281 ±6
291 ±8
290 ±5
276 ±5
270 ±7
257 ±5
Water consumption (g/day)
44
33
23
18
16
13
Organ weights
Absolute kidney weight (mg)
1,030 ±36
1,160 ±27c
1,221 ±28d
1,211 ± 33d
1,208 ± 50d
1,342 ± 16d
Relative kidney weight (mg/g)
3.8 ± 0.11
4.1 ± 0.09°
4.3 ± 0.13°
4.5 ± 0.1 ld
4.6 ± 0.16d
5.2 ± 0.10d
Absolute liver weight (mg)
11,140 ±350
11,890 ±530
12,200 ± 680
10,990 ±310
11,500 ±370
11,950 ±450f
Relative liver weight (mg/g)
41.2 ± 1.07
42.0 ± 1.49
42.7 ± 2.60
40.6 ± 1.32
43.5 ± 1.37
46.6 ± 1.41°'f
Osborne-Mendel
Dose (mg/kg-day)
0
82
126
213
428
727
Final body weight (g)
278 ± 12
277 ±6
275 ±5
261 ±4
275 ±7
258 ±5
Water consumption (g/day)
43
34
26
23
22
18
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Table 3. Significant Changes in Female Rats Treated with 1,2-DCA in Drinking Water for 13 Weeks3
Parameter Evaluated
Concentration in Water (ppm)
Control
500
1,000
2,000
4,000
8,000
Organ weights
Absolute kidney weight (mg)
894 ± 28
1,017 ± 15d
1,041 ±22d
1,020 ± 24d
1,096 ± 37d
1,094 ± 33d
Relative kidney weight (mg/g)
3.3 ± 0.11
3.7 ± 0.06°
3.9 ± 0.06d
4.0 ± 0.16d
4.1 ± 0.14d
4.2 ± 0.26d
Absolute liver weight (mg)
10,390 ±450
11,580 ±360
10,810 ±230
10,390 ±430
10,750 ± 300
10,100 ±410
Relative liver weight (mg/g)
37.9 ± 1.04
41.5 ±0.96
40.0 ±0.81
41.0 ±2.39
39.8 ±0.73
38.6 ±2.49
aNTP (1991)
bMean ± standard error; n = 10 per group unless noted otherwise
Significantly different from control at p< 0.05
d/?<0.01
ep < 0.01, Fisher's exact test performed for this review
fn = 9 per group
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No lesions attributable to 1,2-DCA were observed in the livers of any strain or sex of rat.
The only histopathology finding was minimal-to-mild renal tubular regeneration, which occurred
at similar incidence and severity in all groups of treated and control male and female rats, except
female F344/N rats. In female F344/N rats, there was a dose-related increase in the incidence of
mild renal tubular regeneration; the increase was significantly different from control in the
8,000-ppm group. Information on possible functional renal deficits in this group was lacking, as
serum chemistry analyses were only performed in male rats. A LOAEL of 58 mg/kg-day
(500 ppm), the lowest dose tested, is identified for increased absolute kidney weight (>10%) in
female F344/N rats. The increased kidney weight is considered to be an early stage adverse
effect because a dose-related increase in the incidence of renal tubular regeneration (indicative of
previous tubular injury with subsequent repair) was observed at higher doses in the same strain
of rats. A NOAEL was not identified.
In the F344/N rat gavage study, all males exposed to 240 or 480 mg/kg-day and
9/10 females exposed to 300 mg/kg-day died; clinical signs preceding death included tremors,
salivation, emaciation, abnormal postures, ruffled fur, and dyspnea (NTP, 1991). The deaths
occurred throughout the exposure period. Pathology evaluation of moribund/dead animals
showed necrosis in the thymus and cerebellum, as well as hyperplasia, inflammation, and
mineralization in the forestomach mucosa. No deaths occurred at other doses, and there were no
effects on growth at sublethal doses. Statistically significant differences from control values
were observed in various hematological (decreased Hgb) and serum chemistry (increased ALT
and SDH) measures in males dosed at 120 mg/kg-day, but these changes were not observed
consistently throughout the study. Hematology and serum chemistry were not evaluated in
females. As with the drinking water studies, both kidney and liver weights were affected by
gavage treatment with 1,2-DCA (see Table 4) at sublethal doses. In male F344/N rats exposed
via gavage, absolute kidney weights were significantly increased over controls at all doses, while
relative kidney weights were higher at >60 mg/kg-day. In females, both absolute and relative
kidney weights were significantly increased at >75 mg/kg-day. Absolute and relative liver
weights were significantly increased in males at 120 mg/kg-day and in females at all doses. No
liver lesions were reported in any group exposed via gavage. Renal tubular regeneration was
observed in all dosed groups, but incidence was comparable to that of vehicle controls. These
experiments identified a (Frank Effect Level) FEL of 240 mg/kg-day for mortality in male
F344/N rats. A LOAEL of 75 mg/kg-day is identified based on increased absolute kidney
weights in females. This determination is supported by the finding of renal histopathology in the
same strain and sex of rat (female F344/N rats) exposed to higher doses of 1,2-DCA in the
associated drinking water study (NTP, 1991). Increases in absolute and relative kidney weights
were noted in males at lower doses in this study, but these changes were not associated with any
histopathology in either this or the drinking water study. As such, the increases in kidney
weights were not considered to be adverse in male rats. Increased liver weights were also noted
at lower doses (i.e., >18 mg/kg-day in females); however, the increase in liver weight is
considered to be nonadverse due to the lack of accompanying histopathology in this and other
studies. Based on these considerations, the LOAEL for this study is 75 mg/kg-day based on
increased kidney weight in females, and the NOAEL is 37 mg/kg-day.
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Table 4. Significant Changes in F344/N Rats Treated with 1,2-DCA Via Gavage for 13 Weeks"
Parameter Evaluated
Dose (mg/kg-day)
Control
30
60
120
240
480
Males
Final body weight (g)
333 ±4b
346 ±5
349 ±9
338 ±9
No survivors
No survivors
Organ weights
Absolute kidney weight (mg)
1,324 ±29
1,441 ±26c
1,600 ± 54d
1,653 ± 47d


Relative kidney weight (mg/g)
3.9 ±0.06
4.1 ± 0.10
4.5 ± 0.08d
4.9 ± 0.07d


Absolute liver weight (mg)
17,000 ± 440
17,960 ±510
(n = 9)
18,270 ± 540
19,400 ± 660°
(« = 9)


Relative liver weight (mg/g)
50.2 ±0.87
50.9 ±0.97
(n = 9)
51.7 ±0.92
57.4 ± 0.83d (n = 9)


Females

Control
18
37
75
150
300
Final body weight (g)
193 ±2
193 ±2
197 ±3
199 ±3
194 ±3
177
Organ weights
Absolute kidney weight (mg)
800 ± 16
717 ±70
798 ± 20
898±23d
984 ± 9d
No data
Relative kidney weight (mg/g)
4.2 ±0.08
3.8 ±0.37
4.1 ±0.09
4.6 ± 0.08°
5.1 ± 0.08d
No data
Absolute liver weight (mg)
7,345 ± 120
8,000 ± 20lc
7,920 ± 191°
8,577 ± 197d
9,775 ± 151d
No data
Relative liver weight (mg/g)
38.7 ±0.54
42.1 ± 0.87d
40.8 ± 0.61°
43.6 ± 0.69d
51.0 ± 1.08d
No data
aNTP, 1991
bMean ± standard error; n = 10 per group unless noted otherwise
Significantly different from control at p< 0.05
d/?<0.01
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In the mouse drinking water study, 9/10 female mice exposed to 8,000 ppm died before
the end of the study; there were no deaths in other treatment groups (NTP, 1991). No
treatment-related clinical signs were observed at any dose, and water consumption, while
variable, was similar between treated and control animals. Terminal body weights were lower in
all treated groups of mice relative to controls (-5-10%); a decrease of 10% was observed only in
males exposed to 8,000 ppm. Hematological and serum chemical analyses were not performed
on mice. Table 5 shows organ-weight changes, limited to the kidney and liver. Significantly
(p < 0.05) increased absolute and relative kidney weights occurred in males exposed to
>1,000 ppm and in all treated females. The difference from controls increased with dose in
males but not in females. Increased relative liver weight was observed in all treated males;
absolute liver weight was increased only at >4,000 ppm in males. In females, relative liver
weight was increased at >1,000 ppm, while absolute liver weight was significantly increased
only at >4,000 ppm. A dose-related increase in the incidence of renal tubular regeneration
(minimal-to-moderate) occurred in males (statistically significant versus controls in the
4,000- and 8,000-ppm groups,/* < 0.01). Other renal lesions, including karyomegaly, dilatation,
protein casts, and mineralization occurred in males at the highest dose but not in any other
treated or control groups. Renal tubular regeneration was observed in 1/10 females at
4,000 ppm; no other renal lesions were reported in females. Treatment-related histopathology
was not observed in other tissues. A NOAEL and LOAEL of 249 and 448 mg/kg-day (500 and
1,000 ppm), respectively, are identified for increased kidney weight in male mice. The increased
kidney weight in male mice is considered to be an early stage adverse effect based on the
dose-related increase in the incidence of renal histopathology observed at higher doses.
Although increased kidney weights were observed in female mice exposed to 500-ppm 1,2-DCA,
this change in females was not clearly adverse, as there was no further increase in kidney weight
with dose and the weight change was not accompanied by histopathology at any dose.
In the third subchronic study, Daniel et al. (1994) exposed Sprague-Dawley rats
(10/sex/dose) to 1,2-DCA (purity not reported; verified by gas chromatograph/mass spectrometry
[GC/MS] to contain "no detectable impurities") in corn oil by gavage at doses of 0 (vehicle
control), 37.5, 75, or 150 mg/kg-day for 90 consecutive days. Signs of toxicity were assessed
daily, and body weight was measured weekly. Food and water intake were measured twice
weekly. Ophthalmoscopy was evaluated before and after the exposure period. Urine samples
collected during the last week of the study were analyzed for pH, protein, glucose, bilirubin,
urobilinogen, and occult blood analyses. Prior to euthanization, blood was collected for
hematology (WBC, RBC, Hgb, and Hct) and serum chemistry (BUN, creatinine, ALP, AST,
ALT, lactate dehydrogenase, total bilirubin, total protein, albumin, calcium, sodium, and
potassium). Comprehensive gross examinations were conducted at necropsy; the brain, liver,
spleen, lungs, thymus, kidneys, adrenals, heart, and gonads were weighed. Comprehensive
histopathology examinations were performed on control and high-dose animals, as well as on
target tissues in other dose groups.
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Table 5. Significant Changes in B6C3F1 Mice Treated with 1,2-DCA in Drinking Water for 13 Weeks3
Parameter Evaluated
Concentration in Water (ppm)
Control
500
1,000
2,000
4,000
8,000
Males
Dose (mg/kg-day)
0
249
448
781
2,710
4,207
Final body weight (g)
31.4 ± ,06b
28.9 ±0.6
29.3 ±0.5
29.4 ±0.8
28.6 ±0.7
25.9 ±0.7
Organ weights
Absolute kidney weight (mg)
305 ±7
301 ±8
323 ± T
358 ±8d
385 ±9d
379 ±12d
Relative kidney weight (mg/g)
10.2 ±0.22
10.8 ±0.12
11.4 ± 0.12d
12.4 ± 0.33d
13.8 ± 0.40d
15.0 ± 0.54d
Absolute liver weight (g)
1,455 ±55
1,490 ± 42
1,519 ±55
1,571 ±56
1,628 ± 54°
1,598 ±78c
Relative liver weight (mg/g)
48.5 ± 1.06
53.6 ± 0.91d
53.4 ± 1.18d
54.3 ± 1.46d
57.6 ± 1.10d
62.8 ± 2.13d
Kidney histopathologye
Tubular regeneration
0/10
1/10
2/10
2/10
8/10d
9/10d
Karyomegaly
0/10
0/10
0/10
0/10
0/10
10/10d
Dilatation
0/10
0/10
0/10
0/10
0/10
5/10°
Protein casts
0/10
0/10
0/10
0/10
0/10
8/10d
Mineralization
0/10
0/10
0/10
0/10
0/10
5/10°
Females
Dose (mg/kg-day)
0
244
647
1,182
2,478
4,926
Final body weight (g)
25.9 ±0.6
24.7 ±0.5
23.2 ±0.6
23.7 ±0.5
23.8 ±0.6
23.4f
Organ weights
Absolute kidney weight (mg)
191 ± 4
225 ± 6d
211 ± 5d
212 ±7d
215 ±7d
217
Relative kidney weight (mg/g)
8.0 ±0.23
9.4 ± 0.21d
9.4 ± 0.17d
9.3 ± 0.24d
9.3 ± 0.22d
9.4
Absolute liver weight (g)
1,258 ±39
1,258 ±52
1,263 ± 34
1,314 ±56
1,383 ±29c
1,391
Relative liver weight (mg/g)
52.5 ±0.85
51.5 ±0.95
56.0 ± 0.67°
56.1 ± 1.18°
59.7 ± 1.0ld
60.5
aNTP (1991)
bMean ± standard error; n = 10 per group unless noted otherwise
Significantly different from control at p< 0.05
d/?<0.01
"Number affected/number examined
fOnly one mouse survived to termination
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There were no treatment-related deaths or clinical signs of toxicity in any groups
(Daniel et al., 1994). Table 6 shows significant changes in body weight, hematology, and organ
weights. Terminal body weight and food consumption were significantly decreased at
150 mg/kg-day in males (body weight was 17% less than controls; p < 0.05; food consumption
data not shown) but comparable to controls in all other groups. No effects were observed upon
ophthalmoscopic examination in any group. Hematology changes occurred in both male and
female rats. In males, hemoglobin was significantly decreased (compared with controls) at the
two highest doses (p < 0.05), while hematocrit was significant decreased at 75 mg/kg-day
(p < 0.05) but increased at 150 mg/kg-day (p < 0.05). Platelets were also significantly (p < 0.05)
increased in the high-dose group (see Table 6). In females exposed to the highest dose, red
blood cells, lymphocytes, hemoglobin, and hematocrit were significantly (p < 0.05) decreased
while platelets, white blood cells, neutrophils, and monocytes were significantly (p < 0.05)
increased; however, the values reported are within reference ranges for these parameters
(Wolford et al., 1986). Few serum chemistry changes were noted; in females, potassium levels
were increased, and albumin levels decreased at >75 mg/kg-day, while in males, ALP was
increased at these doses (data not shown in original manuscript). According to the authors,
urinalysis data were unremarkable (data not shown). Changes in relative organ weights were
observed at the mid- and high doses; absolute organ weights were not reported. In males,
relative brain, kidney, and liver weights were significantly (p < 0.05) increased at doses of
>75 mg/kg-day; increases in relative testes and adrenal weights occurred at 150 mg/kg-day, but
were probably attributable to the body-weight decrements at this dose. In females, relative
kidney weight was increased at >75 mg/kg-day (up to 22%) and relative liver weight at
150 mg/kg-day (32%); no other organ weight changes occurred in females. None of the few
gross or microscopic lesions observed were considered by the researchers to be related to
treatment (no further details reported). A LOAEL of 75 mg/kg-day is identified for these data
based on increases in relative liver weights in males at this dose; the NOAEL is 37.5 mg/kg-day.
Although the liver weight changes were not associated with any histopathology,
Daniel et al. (1994) reported increased ALP levels in male rats, potentially indicative of
hepatotoxicity, at doses of >75 mg/kg-day. Other changes at the LOAEL were increases in
relative kidney weights, decreases in Hgb and Hct (and RBC in females), and increases in
platelets in male and female rats.
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Table 6. Significant Changes in Sprague-Dawley Rats Treated
with 1,2-DCA by Gavage for 90 Days3

Dose (mg/kg-day)
Control
37.5
75
150
Males
No. animals examined
10
10
10
10
Terminal body weight
597 ± 30b
590 ±30
562 ± 44
495 ± 39°
Hematology
Hemoglobin (g/dL)
16.2 ±0.6
16.0 ±0.6
15.4 ± 0.5°
15.2 ± 0.7°
Hematocrit (%)
46.0 ±2.1
45.4 ± 1.8
46.7 ± l.lc
43.0 ± 2.0°
Platelets x 103
1,179 ± 188
1,219 ± 125
1,252 ±91
1,394 ±208c
Organ weights
Brain (%)
0.40 ±0.03
0.40 ± 0.02
0.43 ± 0.03°
0.49 ± 0.04°
Kidneys (%)
0.62 ± 0.06
0.66 ± 0.06
0.73 ± 0.05°
0.84 ± 0.07°
Liver (%)
2.59 ±0.21
2.69 ±0.16
3.10 ± 0.42°
3.40 ± 0.36°
Females
No. animals examined
10
10
10
10
Terminal body weight
304 ± 31b
311 ± 33
284 ± 23
294 ±35
Hematology
Hemoglobin (g/dL)
15.9 ±0.6
15.9 ±0.7
15.2 ±0.8
14.8 ± 0.7°
Hematocrit (%)
45.0 ± 1.7
45.2 ±2.3
43.5 ± 1.7
41.6 ± 1.9°
Platelets x 103
1,119 ± 65
1,130 ± 115
1,235 ± 165
1,410 ± 156°
Red blood cells x 106
8.3 ±0.03
8.4 ±0.04
8.1 ±0.3
7.7 ± 0.3°
White blood cells x 103
5.0 ±2.0
5.6 ± 1.2
5.8 ± 1.0
7.9 ± 2.2c
Neutrophils (%)
20.0 ± 13.2
21.4 ± 11.8
22.4 ±8.8
26.6 ± 14.4°
Lymphocytes (%)
76.0 ±28.4
76.8 ±20.2
75.9 ± 16.6
68.4 ± 12.9°
Monocytes (%)
2.0 ± 1.8
0.0 ±0.9
1.7 ± 1.9
2.2 ± 1.1°
Organ Weights
Kidneys (%)
0.67 ±0.09
0.70 ± 0.06
0.77 ± 0.07°
0.82 ± 0.09°
Liver (%)
2.75 ±0.17
2.85 ±0.17
3.02 ±0.35
3.64 ± 0.36°
"Daniel etal. (1994)
bMean ± standard error
Significantly different from control at p< 0.05
Chronic Studies—There are two chronic studies: one in rats, and one in rats and mice.
In the first study, Alumot et al. (1976) conducted a 2-year study of dietary exposure to 1,2-DCA
in which liver function was the primary evaluation. A preliminary study was conducted in which
rats were fed dietary levels of 0, 300, or 600 ppm (about 30 or 60 mg/kg-day) 1,2 DCA (purity
not specified) for 5 weeks or 1,600 ppm (about 160 mg/kg-day) 1,2-DCA for 7 weeks and liver
weight, total liver fat content, and liver triglycerides were measured. Gross and histological
examinations were not performed. In the group exposed to 1,600 ppm for 7 weeks, significant
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(p < 0.05) increases in total liver fat (13% higher than controls) and total liver triglycerides
(75% higher) were observed, but liver weight was not different from control. Other groups did
not exhibit differences from control values. In the 2-year study, groups of rats (18/sex/dose) of
unspecified strain were fed a feed mash fumigated with 1,2-DCA (purity not reported) that
resulted in measured feed concentrations of 0, 250, or 500 ppm (Alumot et al., 1976). The
researchers estimated that 60-10% of the residue initially present in the feed was consumed.
Body weight and food intake were recorded weekly for the first 3 months and biweekly
thereafter. Based on typical body weights and food consumption, the authors estimated the doses
consumed to be approximately 25 and 50 mg/kg-day. The animals were mated for evaluation of
reproductive effects; these findings are discussed below under Reproductive and Developmental
Studies. During mating periods of 10 days each, the animals were fed control diets. At sacrifice,
blood was collected for analysis of total protein, albumin, glucose, urea, cholesterol, uric acid,
ALT, and AST. Liver samples were analyzed for total fat, triglycerides, and phospholipids. No
gross or microscopic examinations were performed. Survival of all groups, especially males,
was affected by respiratory disease after 14 months; few males (<22%) of any group (including
controls) survived to study termination. The authors reported that there were no
treatment-related effects on survival, growth, food consumption, or serum chemistry indices
(data were shown for survival, body weight, and serum chemistry but not food consumption in
the study report). In addition, the authors indicated that there were no fatty livers in the treated
animals (no further information provided). Due to the uncertainty in dose estimates and
limitations in the toxicological evaluations, effect levels were not determined.
In the second chronic study, which was used as the critical study, NCI (1978)
carcinogenicity study, Osborne-Mendel rats (50/sex/group) were treated with 1,2-DCA
(>90%) pure) in corn oil by gavage at variable doses administered 5 days/week for 78 weeks.
NCI (1978) estimated TWA doses (averaged over the 78-week treatment period, but not
converted to equivalent continuous, 7-day per week doses) of 47 or 95 mg/kg-day for 78 weeks.
B6C3F1 mice (50/sex/group) were also treated for 78 weeks with TWA doses of 97 or
195 mg/kg-day (males) and 149 or 299 mg/kg-day (females), 5 days/week. Untreated and
vehicle controls (20/sex/group) of both species were maintained concurrently. Signs of toxicity,
body weight, and food consumption were recorded weekly, and animals were palpated for tissue
masses at the same time. Hematological and clinical chemistry determinations were not
conducted. Observation continued for 13 weeks after the dosing period. Comprehensive gross
and histological examinations were performed upon moribund condition, death, or sacrifice at
the end of the bioassay.
In rats, mortality was significantly (p < 0.001) increased in both sexes exposed to
95 mg/kg-day when compared with controls but was not significantly affected in the low-dose
group (NCI, 1978). Survival of male and female rats treated with 95 mg/kg-day was 50%> at
Weeks 55 and 57, respectively. For rats treated with 47 mg/kg-day, survival was reported as
52%o at 82 weeks for male rats and 50%> at 85 weeks in female rats. Of the vehicle controls,
50%o of male and female rats survived at least 72 and 88 weeks, respectively, while 50 and 60%>
of untreated male and female control rats survived until the end of the study. The study authors
attributed the high mortality in the rats to toxic effects and bronchopneumonia rather than to
cancer. Several rats (number not reported) in both the 47- and 95-mg/kg-day dose groups had a
hunched appearance and transient labored breathing beginning during the 6t week of treatment.
Although one or two control rats (untreated or vehicle not specified) started to show these signs,
the incidence was reported to be substantially higher in the treated groups than in the control
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groups. Other treatment-related clinical signs observed during the first year included abdominal
urine stains, cloudy or squinted eyes, and reddish crust on the eyes (incidence and affected doses
not reported). Based on data shown in the report, there were no effects on body weight. The
only treatment-related nonneoplastic lesion found upon microscopic examination was splenic
hematopoiesis in female rats. Splenic hematopoiesis occurred in 0/20 untreated controls,
1/20 vehicle controls, and 0/50 low-dose and 16/50 high-dose females; the incidence at the high
dose was statistically significantly different from controls (p < 0.05 by Fisher's exact test
conducted for this review). A number of neoplasms were observed at increased incidence in
male and/or female rats, including squamous cell carcinoma of the forestomach,
hemangiosarcoma of the spleen and other sites, adenocarcinoma of the mammary gland, and
subcutaneous fibroma. For noncancer effects, a LOAEL of 47 mg/kg-day, the lowest dose
tested, is identified for clinical signs of labored breathing and hunched appearance in both sexes
of rats. A NOAEL was not identified. However, the quality of this study was limited by dosage
adjustments and poor survival; in addition, the clinical signs observed after Week 6 in this study
were not seen in subchronic studies of rats exposed via gavage or drinking water to much higher
doses (NTP, 1991).
Female mice treated with 299 mg/kg-day also had significantly increased mortality, but
mortality was not affected in the other groups of mice (NCI, 1978). These deaths may have been
tumor-related as 25/36 (69%) had one or more tumors. For male mice, there was no statistically
significant association between 1,2-DCA dosage and mortality. Clinical signs in treated groups
were unremarkable compared with controls. Body weight was not affected by treatment in male
mice or low-dose female mice. Body weight in high-dose female mice became significantly
depressed around 30 weeks and was reduced by >45% of control weight at 90 weeks. The
incidence of chronic murine pneumonia was dose-related in mice; present in 0/17 untreated
control, 0/19 vehicle control, 5/46 low-dose, and 11/47 high-dose males, and in 0/19 untreated
control, 0/20 vehicle control, 1/50 low-dose and 6/48 high-dose females. However, only the
incidence in high-dose males was statistically significantly different from controls (p < 0.05 by
Fisher's exact test conducted for this review). No other treatment-related nonneoplastic lesions
were found in mice. Increases in the incidences of hepatocellular carcinomas,
alveolar/bronchiolar adenomas, mammary adenocarcinomas, endometrial tumors, and squamous
cell carcinomas were observed in male or female mice. For noncancer effects, a NOAEL and
LOAEL of 97 and 195 mg/kg-day, respectively, are identified for a significant increase in the
incidence of chronic murine pneumonia in male mice.
Reproductive/Developmental Studies—There was one developmental and one
multigenerational reproductive study in the literature. Reproductive function was assessed in the
2-year study conducted by Alumot et al. (1976). Groups of rats (18/sex/dose; strain not reported)
were given feed fumigated with 1,2-DCA (purity not reported) to produce measured feed
concentrations of 0, 250, or 500 ppm. The authors calculated doses of approximately 25 and
50 mg/kg-day based on typical body weight and food consumption. In addition to assessments
of mortality, growth, and serum chemistry, the animals were mated periodically (first mating
after 6 weeks of exposure) to assess reproductive function (pregnancy rate, birth rate, litter size,
and pup survival and body weight at birth and at weaning). During mating periods of 10 days
each, the animals were fed control diets; as a result, the overall doses received by the animals are
somewhat uncertain. No differences were found in any of the parameters assessed (number of
pregnancies and litters, litter size, mortality of young at birth and weaning, and the body weight
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of young at birth and at weaning). Limitations in the reporting of this study and uncertainty in
dose estimates preclude the determination of effect levels.
Mated female Sprague-Dawley rats (25-26/group) were given 0 (vehicle control),
1.2, 1.6, 2.0, or 2.4 mmol/kg-day 1,2-DCA (>99% pure) dissolved in corn oil (equivalent to
0, 119, 158, 198, or 238 mg/kg-day) by gavage on Gestation Days (GD) 6-20 (15 days)
(Payan et al., 1995). Maternal body weights were measured on GD 0 and every 3 days during
treatment. Dams were sacrificed on GD 21 for assessment of uterine weight and examination of
uterine contents. Numbers of implantations, resorptions, and live and dead fetuses were noted.
Live fetuses were weighed, sexed, and examined for external malformations. Half of the live
fetuses were prepared for skeletal examination and the remainder for visceral examination. No
maternal deaths occurred. A dose-related reduction in adjusted (for gravid uterine weight)
maternal body-weight gain during treatment occurred, with statistical significance achieved at
the two highest doses (30 and 49% reduction compared with controls,/? < 0.05). Pregnancy rates
were similar in all groups. However, three dams exposed to the highest dose of 1,2-DCA
delivered their litters a day earlier than expected, and the litters were excluded from analysis due
to the possibility that cannibalization of part of the litter may have occurred. Treatment with
1,2-DCA did not result in significant changes to the mean numbers of implantation sites and live
fetuses, fetal sex ratio, or fetal weights. There was a slight but significant (p < 0.05) dose-related
trend for increased resorptions (2.48 ± 0.89; 2.19 ± 0.84; 5.86 ± 2.55; 7.08 ± 1.49; and
13.30 ± 7.05 percent for control through high-dose); the difference from controls in pair-wise
tests reached statistical significance (p < 0.05) only at >198 mg/kg-day. While the mean
percentage of resorptions was increased at 238 mg/kg-day, the difference from controls was not
statistically significant, apparently due to the smaller group size and larger variability.
Incidences of external, visceral, and skeletal variations and malformations were similar in all
groups. A developmental NOAEL and LOAEL of 158 and 198 mg/kg-day, respectively, are
identified for increased resorptions. The maternal toxicity NOAEL and LOAEL are also 158 and
198 mg/kg-day, respectively for decreased body-weight gain during treatment.
In the multigeneration reproduction study, Lane et al., 1982 treated male and female ICR
Swiss mice continuously with drinking water (ad libitum) containing 30, 90, or 290 ppm of
1,2-DCA (>99% pure), giving nominal daily doses of 0, 5, 15, or 50 mg/kg-day (Lane et al.,
1982). Both vehicle (1% Emulphor) and untreated control groups were included. The parental
(F0) generation was maintained on the exposure regimen for 35 days before the first mating
period. Two weeks after the weaning of the F1A litters, the F0 parents were remated to produce
the FIB litters. In a third mating of the F0 parents, the males were used in a dominant lethal
study, while the females were used for a teratology study (F1C). Randomly selected pups from
the FIB litters were mated at 14 weeks of age and then remated after weaning of the F2A litters,
producing the final F2B litters. As with the F1C litters, the F2B litters were also used for
dominant lethal and teratology studies. Among parents of the F0 and FIB generations, body
weight was measured weekly, and fluid intake was recorded biweekly. After 24 or 25 weeks of
dosing, the F0 and FIB parents were sacrificed and subjected to gross necropsy. Fertility and
gestation indices were calculated from all matings. Litter observations included 21-day survival;
litter size on Postnatal Days (PND) 0, 4, 7, 14, and 21; litter weights on PND 7 and 14; pup
weights on PND 21; and viability and lactation indices. Pups from all generations were
sacrificed and given gross necropsy after PND 21.
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In the dominant lethal studies, treated males were mated with untreated females
(Lane et al., 1982). After 14 days from the midpoint of the mating period, the females were
sacrificed for examination of uterine contents. Numbers of implantations, early and late
resorptions, and viable fetuses were counted. In the teratology studies, treated females were
mated with untreated males and examined daily for a vaginal plug. On GD 18, the females were
sacrificed, and uterine contents were examined; numbers of implantations, resorptions, and
viable and nonviable male and female fetuses were recorded. Each fetus was weighed and
evaluated for external malformations. If no external malformations were found, each third fetus
was prepared for evaluation of visceral malformations, and the remainder were prepared for
assessment of skeletal malformations. Due to a preparation error, the F1C fetuses were not
examined for skeletal malformations.
No parental treatment-related effects were observed in F0 and FIB generations as judged
by mortality rates, fluid intake, body-weight gain, and gross pathology (data shown;
Lane et al., 1982). Furthermore, there were no significant differences between treated and
control groups for gestation or fertility indices, weight gain, numbers of implantations,
resorptions, or live fetuses, or on 4- and 21-day survival in any of the matings (data shown for all
but weight gain). There was also no evidence of dominant lethality in treated males mated to
untreated females. Finally, based on data shown in the report, no significant increase in gross,
visceral, or skeletal anomalies or any fetotoxic effects were observed in the teratology studies.
This study identifies a NOAEL of 50 mg/kg-day, the highest dose tested, for both parental and
offspring toxicity.
Inhalation Exposure
Subchronic Studies—In the sole subchronic inhalation study, Nagano et al. (2006)
conducted a subchronic dose range-finding study in preparation for a chronic
toxicity/carcinogenicity bioassay of 1,2-DCA. Little information was provided on the
range-finding study. Groups of F344/DuCij rats and Cij:BDFl mice of both sexes (number not
reported) were exposed via inhalation to 1,2-DCA (>99% pure) for 13 weeks. Endpoints were
limited to mortality, clinical signs, and body weight. The authors observed 100% mortality in
"3
rats exposed to 320 ppm (1,295 mg/m ) 1,2-DCA, but no mortality, clinical signs, or body-
weight changes at 160 ppm (648 mg/m3). In the range-finding study of mice, 6/10 female mice
exposed to 160 ppm (648 mg/m ) 1,2-DCA died, while 7—9% body-weight reductions were
observed in males and females exposed to 80 ppm (324 mg/m3); no other mortality or signs of
toxicity were reported. This study identifies FELs of 1,295 and 648 mg/m (320 and 160 ppm)
for rats and mice, respectively.
Chronic Studies—There are six chronic inhalation studies: three in rats, one in rats and
mice, and two in multiples species. In the first chronic study, Heppel et al. (1946) exposed
several species, including dogs, cats, guinea pigs, rabbits, rats, mice, and monkeys (strains not
reported) to 420, 730, 1,540, or 3,900 mg/m3 of commercial 1,2-DCA (purity not reported)
7 hours/day, 5 days/week for up to 8 months. Not all species were exposed to all concentrations.
The duration of exposure varied with the exposure level and species, and group size and sex ratio
were variable. Each exposure level was accompanied by control animals, but not all exposed
species were represented by controls at each level. Toxicological evaluations varied with species
and exposure level; mortality, clinical signs, and gross and microscopic pathology were
evaluated in at least some animals in most experiments. Treatment-related mortality was
3	3
observed in guinea pigs and rats exposed to >730 mg/m , in rabbits exposed to >1,540 mg/m ,
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"3
and in dogs, cats, and monkeys exposed to 3,900 mg/m . Necropsy of animals that died often
revealed pulmonary congestion, myocarditis, and/or fatty degeneration of the liver, kidney,
and/or heart. Only rats, mice, and guinea pigs were exposed to the lowest concentration of
420 mg/m3; the duration of exposure was 4 months. No compound-related deaths were observed
at this level, but the guinea pigs of both control and exposed groups suffered from growth
depression, disease, and some deaths unrelated to treatment. The female rats were bred, and the
litter survival rates were characterized as "satisfactory" (data not shown). Evaluation of mice
was limited to body weight, which was not affected at this exposure (data not shown). Gross and
"3
microscopic examinations (not specified) of selected rats and guinea pigs exposed to 420 mg/m
were unremarkable (data not shown). This study identified a FEL of 730 mg/m3 (180 ppm)
based on significant mortality in rats and guinea pigs. Limitations in study design (variable
exposure protocols, group sizes, and toxicological evaluations) and reporting (strains and sexes
not reported, results not reported quantitatively) preclude the identification of reliable effect
levels from this study.
In the second chronic study, Spencer et al. (1951) exposed groups of Wistar rats
(15/sex/group) for 212 days (30 weeks, up to 151 exposures), randomly bred guinea pigs
(8/sex/group) for 162-246 days (23-35 weeks, up to 180 exposures), randomly bred rabbits
(2 male and 1 female per group) for 232-248 days (33 to 35 weeks, up to 178 exposures), and
rhesus monkeys (2/males/group) for up to 240 days (34 weeks, up to 178 exposures) to
0 (unexposed), 0 (chamber-exposed), 405, 810, or 1,620 mg/m3 of 1,2-DCA (99.7% pure)
7 hours/day, 5 days/week. Rabbits and monkeys did not receive the mid-level exposures.
Endpoints examined included body weight and food consumption, hematologic (not specified,
but included prothrombin clotting time) and serum chemistry (BUN, nonprotein nitrogen,
phosphatase) parameters, lipid content of liver (total, phospholipid, neutral fat, and free and
esterified cholesterol), organ weights (lung, heart, liver, kidneys, spleen, and testes), and gross
and histologic examination of the major organs and tissues (not specified). At 1,620 mg/m3, the
highest concentration, all rats, guinea pigs, and monkeys died or were killed in extremis within
56 (rats), 32 (guinea pigs), or 12 days (monkeys). Mortality was accompanied by weight loss
(rats and guinea pigs), fatty livers (rats), fatty liver degeneration (guinea pigs and monkeys),
cloudy swelling of the kidney tubular epithelium (guinea pigs), renal tubule degeneration with
cast formation (monkeys), and increased liver and kidney weights (guinea pigs). There were no
effects in rabbits at this concentration. At 810 mg/m3, there was no mortality in either rats or
guinea pigs (the only species tested). Rats exposed at this concentration exhibited no
treatment-related effects on growth, organ weights, hematology, clinical chemistry, or
"3
histopathology. Both male and female guinea pigs showed poorer growth at 810 mg/m , but
final body weight was significantly (p = 0.001) depressed only in males (16% less than controls).
"3
At 810 mg/m , half the guinea pigs of both sexes had parenchymatous liver degeneration with fat
vacuoles. No effects on any of the parameters evaluated were observed in any of the four species
exposed to 405 mg/m3 of 1,2-DCA. A NOAEL and LOAEL of 405 and 810 mg/m3,
respectively, are identified for liver lesions (both sexes) and reduced body weight (males) in
-3
guinea pigs. The high concentration (1,620 mg/m ) is a FEL for significant mortality in rats,
guinea pigs, and monkeys.
In the third chronic study, Maltoni et al. (1980; Spreafico et al., 1980) exposed groups of
male and female Sprague-Dawley rats and Swiss mice (90/sex/species/group) to concentrations
of 5, 10, 50, or 150-250 ppm (20, 40, 202, or 607-1,012 mg/m3) of 1,2-DCA (99.8% pure)
7 hours/day, 5 days/week for up to 18 months starting at age 11-12 weeks. Two control groups
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of 180 rats (one chamber control and one untreated) and one group of 249 untreated mice were
examined. After several days of exposure, the highest exposure level was decreased from 250 to
150 ppm because of severe toxicity (not further described). Body weights of all animals were
recorded every 2 weeks during exposure. Interim sacrifices of 8-10 rats were made after 3, 6, or
18 months of exposure. At each interim sacrifice, hematology (Hgb, Hct, MCV, RBC, total and
differential WBC, and platelet count) and serum chemistry (glucose, ALP, AST, ALT, GGT,
albumin, bilirubin, cholesterol, lactic acid dehydrogenase [LDH], creatine phosphokinase, BUN,
total proteins, uric acid, and electrolytes), and urinalysis (pH, proteins, bilirubin, glucose, Hgb,
RBC, WBC, epithelial cells, casts, crystals, mucus, and microorganisms) were evaluated (rats
only). Additional groups of 8-10 rats were started at age 14 months and exposed for 12 months
to the same concentrations for evaluation of hematology and serum chemistry (only). Animals
that were not sacrificed early were followed until natural death, whereupon gross necropsy was
performed, along with microscopic examination of >18 tissues (including the lungs, liver,
kidneys, and gonads).
Spreafico et al. (1980) reported methods and results of the blood analyses (most results
reported only qualitatively), while Maltoni et al. (1980) reported the survival findings and
neoplastic histopathology endpoints; nonneoplastic histopathology findings, if any, were not
reported. No information was provided in either report on the nature or extent of the toxicity at
3	3
1,012 mg/m that led to the reduction in exposure concentration to 607 mg/m in the
high-exposure group; it is not clear whether this toxicity included mortality. No concentration
-3
related effect on mortality was observed in the rats exposed to concentrations up to 607 mg/m .
Sporadic statistically significant (statistical analyses and p value not reported by authors)
changes in hematology, serum chemistry, and urinalysis parameters were observed in rats
exposed to 1,2-DCA for 3, 6, or 18 months; however, evaluation of the data showed that these
changes did not exhibit clear dose- or time-dependence. In rats that were exposed for 12 months
beginning at age 14 months, some significant dose-related alterations in clinical chemistry values
were observed, as shown in Table 7. Marked increases in ALT were observed in both sexes at
the two highest concentrations (from 2- to 8-fold higher than controls). GGT was increased
96-111% over controls in females exposed to the two highest concentrations, although this
change was not statistically significant. Serum uric acid and glucose (data not shown) were
"3
significantly higher than controls in rats exposed to 202-607 mg/m ; however, these parameters
were unusually low in control animals at this time point when compared with other time points,
potentially inflating the difference associated with treatment. Nonneoplastic pathology data were
not reported. The incidences of tumors were not different between the treatment and control
groups. The clinical chemistry data from the rats exposed for 12 months beginning at age
14 months are suggestive of liver and possibly kidney toxicity and indicate a NOAEL and
"3
LOAEL of 40 and 202 mg/m (10 and 50 ppm), respectively. The fact that these effects were not
observed in younger rats exposed to the same concentrations suggests the possibility that aged
animals may be more susceptible to the hepatic and/or renal toxicity of 1,2-DCA.
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Table 7. Significant Serum Chemistry Changes in
Sprague-Dawley Rats Treated with
1,2-DCA via Inhalation for 12 Months Beginning at 14 Months of Age3

Concentration (mg/m3)
Parameter Evaluated
Control
20
40
202
607
Males
ALT (milliunits/mL)
22.9 ± 2.3b
28.8 ±3.6
23.2 ±3.5
90.0 ± 9.3°
111.0 ± 13.4
Uric acid (mg %)
0.80 ±0.1
1.05 ±0.1
0.95 ±0.1
1.50 ± 0.1°
1.90 ± 0.1°
Females
ALT (milliunits/mL)
15.7 ± 1.0
23.4 ±3.1
28.2 ±4.5
143.0 ± 11.7°
110.1 ± 10.7°
GGT (milliunits/mL)
0.83 ±0.3
0.63 ±0.2
0.65 ±0.4
1.63 ±0.4
1.75 ±0.2
Uric acid (mg %)
0.94 ±0.1
1.08 ±0.1
1.25 ±0.1
1.63 ± 0.1°
3.41 ±0.3C
aSpreafico etal. (1980)
bPresumed to be mean ± SD; report does not specify; number of animals was 8-10/group
Significantly different from control atp< 0.05
The only toxicological information available on treated mice was survival and incidence
of neoplasms (Maltoni et al., 1980; Spreaftco et al., 1980); statistical analysis of survival rates
was not reported. Body weight was reportedly measured, but no data were provided on this
endpoint. Female high-concentration mice appeared to have slightly increased mortality during
the first 80 weeks. Survival of high-concentration females at 78 weeks of age was 48.9% versus
56.8% in control females. Survival of other groups was comparable to controls. The incidences
of tumors in mice were not different between the treatment and control groups. Effect levels
cannot be determined from this study due to the limited toxicological evaluations performed.
In the fourth chronic study, groups of 50 male and 50 female Sprague-Dawley rats were
exposed to 0 (chamber-filtered air exposed control) or 50 ppm (202 mg/m ) of 1,2-DCA
(>99% pure), 7 hours/day, 5 days/week for 2 years (Cheever et al., 1990). Signs of toxicity were
noted twice daily, and body weight was measured weekly for 8 weeks and then monthly for the
duration of the study. Food and water consumption were measured periodically during the study
(frequency not reported). Hematology and clinical chemistry were not assessed. Organ weights
(not specified) were recorded, and comprehensive gross and histological examinations (including
the respiratory tract) were performed on animals found dead or sacrificed moribund or at the end
of the exposure period. Survival, body weights, food consumption, and water consumption of
exposed animals were comparable to control values, and clinical signs were unremarkable.
Absolute and relative liver weights were not affected by treatment. Gross necropsy revealed a
marginal increase in the incidence of testicular lesions in male rats (12/50 exposed versus
5/50 controls, p = 0.054 by Fisher's exact test conducted for this review). The lesions were not
further described but may have been tumor-related in some animals (interstitial cell tumors of the
testes were observed in three treated males and two control males). Histopathological
examination did not reveal any differences in the testes between treated and control animals.
Exposed female rats were reported to exhibit a slight increase in the incidence of unspecified
basophilic focal cellular changes in the pancreas (data not shown, and no further detail provided).
No other nonneoplastic lesions were reported. In addition, there were no exposure-related
increases in the incidences of any tumors. The only exposure concentration tested, 202 mg/m3
(50 ppm), is a NOAEL for systemic toxicity.
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In the fifth chronic study, Nagano et al. (2006) conducted a chronic
toxicity/carcinogenicity bioassay of 1,2-DCA (>99% pure) using F344/DuCrj rats and Cij:BDFl
mice exposed via inhalation. Exposure concentrations were selected on the basis of a subchronic
dose range-finding study described earlier. In the chronic study, groups of 50 animals/sex were
exposed to target concentrations of 0, 10, 40, or 160 ppm (rats) or 0, 10, 30, or 90 ppm (mice)
continuously for 2 years. Daily observations for mortality and clinical signs were performed.
Food intake and body weight were recorded weekly for the first 14 weeks and monthly for the
remainder of the study. The toxicological evaluations were performed at the end of exposure and
included hematology, serum chemistry, and urinalysis (parameters not specified), gross
necropsy, selected organ weights (organs not specified), and comprehensive histopathology
(tissues not specified). The authors reported that the study was "conducted with reference to"
OECD Guideline 453 (Chronic Toxicity/Carcinogenicity Studies). Based on Guideline 453
(OECD, 2008), serum chemistry parameters likely included total protein; albumin; ALP, AST,
and/or ALT; GGT; and ornithine decarboxylase. Average measured concentrations of 1,2-DCA
were 0, 10.0 ± 0.1, 39.8 ± 0.6, and 159.7 ±2.1 ppm for the exposed rats (0, 40, 162, or
648 mg/m3), and 0, 10.0 ±0.2, 30.0 ± 0.4, and 89.8 ±1.2 ppm for exposed mice (0, 40, 121, or
-3
364 mg/m ) (Nagano et al., 2006). As shown by data presented in the report, there were no
significant treatment-related effects on survival or body weight in rats and mice. The study
authors also reported that there were no significant treatment-related effects on food
consumption, hematology, serum chemistry, urinalysis, or incidence of nonneoplastic
histopathology changes (data not shown). Survival was significantly reduced (p < 0.01
compared with controls) in female mice exposed to 30 ppm; however, survival was not
significantly different from controls at the high concentration. The authors attributed the deaths
at 30 ppm to malignant lymphoma and reported that neither reduced survival nor the incidences
of malignant lymphoma were related to exposure to 1,2-DCA. This study indicates a NOAEL of
648 mg/m3 (160 ppm) for noncancer effects in rats. Although no treatment-related nonneoplastic
"3
changes were observed in mice exposed to concentrations up to 364 mg/m (90 ppm), mortality
from tumors in female mice exposed to 121 mg/m3 limits the conclusions that can be drawn from
"3
the mouse study. The low concentration (40 mg/m ) is considered a NOAEL for noncancer
effects in mice.
Nagano et al. (2006) observed concentration-related increases in the incidences of
subcutaneous fibroma (both sexes of rat), mammary gland fibroadenoma (both sexes of rat),
mammary gland fibroma (female rats), mammary gland adenocarcinoma (female rats and mice),
peritoneal mesothelioma (male rats), bronchiole-alveolar adenoma and carcinoma (female mice),
endometrial stromal polyp (female mice), and hepatocellular adenoma (female mice).
In the sixth chronic study, Hofmann et al. (1971) exposed groups of randomly bred cats
(2/sex/group), randomly bred "colored" rabbits (2/sex/group), Pirbright-White guinea pigs
(5/sex/group), and Sprague-Dawley rats (5/sex/group) to 0, 100, or 500 ppm (0, 405, or
2,024 mg/m3) of 1,2-DCA (>99% pure) 6 hours/day, 5 days/week for up to 17 weeks. The
animals were observed for signs of toxicity, and their body weights were measured throughout
exposure (frequency not reported). In all species but the guinea pigs, hematology (unspecified),
urinalysis (unspecified), and serum chemistry (ALT, AST, urea, and creatinine) were analyzed
repeatedly (frequency not reported). Liver function was assessed in rabbits and cats using the
bromosulphophthalein test. Upon sacrifice, liver and kidney weights were recorded, and these
"3
and other "selected" organs were examined microscopically. At 2,024 mg/m , 3/4 rabbits died
after 10-17 exposures, 9/10 guinea pigs after 4-14 exposures, and all rats after 1-5 exposures.
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Necropsy of animals at this exposure level revealed dilatation of the heart (cats and rabbits),
hyperemia with some edema of the lungs (rats and guinea pigs), fatty degeneration with necrosis
of the myocardium and liver (rats and guinea pigs), and lipoid nephrosis and disgorgement of the
adrenals (rats and guinea pigs). Increased serum urea was noted in cats exposed to 2,024 mg/m3;
-3
no mortality was observed in this species. At 405 mg/m , there were no compound-related
effects on clinical signs, body weight, clinical chemistry, liver or kidney weights, or
histopathology. Hence, a NOAEL 405 (100 ppm) is identified for rabbits, guinea pigs, and rats.
The high concentration (2,024 mg/m3, or 500 ppm) is a FEL for mortality in rabbits, guinea pigs,
and rats but is a NOAEL in cats.
Reproductive/Developmental Studies—There are six reproductive/developmental
studies in the literature. In the first, groups of pregnant Sprague-Dawley rats (16-30/group) and
New Zealand White rabbits (19-21/group) were exposed to 0 (control), 100, or 300 ppm (0, 405,
or 1,214 mg/m3) of 1,2-DCA (99.9% pure) for 7 hours/day on GDs 6-15 (rats) or GDs 6-18
(rabbits) (Rao et al., 1980). Maternal animals were examined daily, and their body weight
recorded at intervals (unspecified) during treatment. The animals were sacrificed on GD 21 or
29 for rats or rabbits, respectively, corpora lutea were counted, and uteri were examined for
resorption sites and live and dead fetuses. Fetuses were weighed, measured for length, sexed,
and examined for external abnormalities, soft tissue alterations (1/3 of animals/group examined),
and skeletal abnormalities.
-3
In rats, maternal toxicity at 1,214 mg/m was severe, with 10 deaths among 16 treated
rats. Rao et al. (1980) did not report cause and timing of deaths. Prior to dying, rats showed
lethargy, ataxia, decreased body weight and food consumption, and some evidence of vaginal
"3
bleeding. No fetuses survived from the 1,214 mg/m group (there was only 1 litter at the high
exposure level, and it was totally resorbed). No maternal signs of toxicity were observed at the
405 mg/m3 1,2-DCA level. Exposure to 405 mg/m3 of 1,2-DCA did not affect mean litter size,
the incidence of resorptions, fetal body measurements, or sex ratio. Data provided in the report
showed that the incidences of external, visceral, and skeletal malformations were not increased
relative to controls at this exposure level. The incidence of a minor skeletal variation, bilobed
thoracic centra, was significantly decreased relative to controls among litters from 405 mg/m
rats. A maternal and developmental NOAEL of 405 mg/m3 (100 ppm) and FEL of 1,214 mg/m3
(300 ppm) for maternal mortality and failure to produce offspring are defined in rats.
In rabbits, the maternal mortality incidence was 0/20, 4/21, and 3/19 among control,
low-exposure, and high-exposure groups, respectively (Rao et al., 1980). The researchers
considered these deaths to be treatment-related. Exposure did not affect the rate of pregnancy,
number of implantation sites/doe, resorption incidence, litter size, sex ratio, or fetal
measurements in surviving rabbits. Further, the incidences of external, visceral, and skeletal
malformations were not increased among litters of treated rabbits compared with controls.
A significant decrease in minor skeletal alterations (extra ribs or lumbar spurs) was reported
"3
among treated litters. The lowest exposure level, 405 mg/m (100 ppm) is a FEL for maternal
mortality in rabbits. The high exposure level of 1,214 mg/m3 (300 ppm) is a NOAEL for
developmental effects.
In the one-generation reproductive toxicity study, Rao et al. (1980) exposed groups of
20 Sprague-Dawley rats of each sex to 0 (control; 30/sex), 25, 75, or 150 ppm (0, 101, 304, or
607 mg/m3) of 1,2-DCA (99.9% pure) 6 hours/day, 5 days/week for 60 days. Rats were mated
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after a 60-day exposure period, one-to-one within the treatment groups, to produce the F1A
generation. Exposure was continued during gestation (6 hours/day, 7 days/week), discontinued
from GD 21 to PND 4 and resumed until the second breeding cycle. A week after the F1A litters
were sacrificed (at age 21 days), the parental rats were remated to produce the FIB generation.
Male rats were exposed from the start of the experiment, initially on a 5 days/week (for 60 days)
schedule, then for 7 days/week. The rats were examined daily, and body weight and food
consumption were recorded weekly. Upon delivery, live and dead pups were counted; pup
survival was recorded again on PND 1,7, 14, and 21. Litter weights were measured on PND 1,
7, 14, and 21, while individual pup weights were measured on PND 21. Parental animals were
sacrificed and necropsied after weaning of the FIB litters. Liver and kidney weights of all
parental animals were recorded, and these organs, along with the ovaries, uterus, and testes were
examined microscopically in 10 rats/sex from the control and high-exposure groups. Pups from
both litters were sacrificed and necropsied at PND 21. Liver and kidney weights were measured
in five randomly selected pups/sex/group.
A few deaths occurred (one control female and one male and one female at 101 mg/m )
but were not related to exposure (Rao et al., 1980). No treatment-related clinical signs or gross
or microscopic pathology were observed among parents at any exposure level. Sporadic changes
in food consumption were observed but were not attributed to treatment (data not shown).
Data regarding fertility and reproduction from the F1A and FIB litters showed no
concentration-related effects. Fetal survival through weaning was comparable between all
treatment groups and controls. Exposure to 1,2-DCA did not affect neonatal body weight or
growth to weaning in the F1A or FIB generations. There were no treatment-related changes in
organ weights or histopathologic changes in the kidneys or livers of the F1 generations. In this
study, the highest exposure level of 607 mg/m3 (150 ppm) is a systemic and reproductive
NOAEL for 1,2-DCA in rats.
In the second study, Payan et al. (1995) exposed pregnant Sprague-Dawley rats
(26/group) for 6 hours/day to measured average concentrations of 0, 150, 194, 254, or 329 ppm
(0, 607, 785, 1,028, or 1,332 mg/m3) of 1,2-DCA (>99% pure) on GDs 6-20. Body weights of
maternal animals were recorded on GDs 0, 6, 13, and 21, and the animals were sacrificed on
GD 21 for examination of uterine contents. Numbers of implantations, resorptions, and live and
dead fetuses were noted. Live fetuses were weighed, sexed, and examined for external and oral
malformations. Half were then examined for visceral anomalies, and the remainder were
examined for skeletal anomalies. Among the 26 females exposed to the highest concentration,
two died during exposure; cause and timing of deaths were not reported. No deaths occurred in
"3
any of the other groups. At the high concentration of 1,332 mg/m , maternal body weight during
GDs 6-21 was significantly less than that of the control group (reduced 24%,p< 0.05). At
"3
<1,028 mg/m of 1,2-DCA, maternal body weight was unaffected. The pregnancy rate among
females inhaling 1,028 mg/m3 of 1,2-DCA was statistically significantly lower than control;
however, no effect on pregnancy rate was observed at the highest exposure level, so the change
is unlikely to be related to treatment. The data showed no significant differences between treated
and control groups in reproductive parameters, fetal body weights or sex ratio, or in the
incidences of external, skeletal, or visceral malformations or variations. A maternal NOAEL and
LOAEL of 1,028 and 1,332 mg/m3 (254 and 329 ppm), respectively, are identified for
significantly reduced body weight and low mortality at the high concentration. The highest
exposure level, 1,332 mg/m3 (329 ppm), is a developmental NOAEL in rats.
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In the third study, pregnant Wistar rats were exposed to 0, 6.1, or 51.3 ppm (0, 24.8, or
207.6 mg/m3) of 1,2-DCA (98.5% purity) for 6 hours/day, from 2 weeks before mating until
sacrifice on GD 20 (Zhao et al., 1989, 1997). The uteri were removed and implantation sites,
resorptions, and dead fetuses were recorded. Live fetuses were sexed and weighed. Half of the
fetuses were examined for external anomalies and the remaining for internal soft tissue
abnormalities. There were no obvious differences in body-weight gain, impregnation rates, RBC
counts, blood protein content, and urine protein in the treated dams compared to controls. ALT
and AST were higher, but not significantly, in both treated groups compared to control.
Preimplantation loss was significantly increased (31.0% compared to 10.2% in controls) in
female rats (number unspecified) that were exposed to 51.3 ppm during the entire pregnancy
period. Fetal survival rates in the treated groups were comparable to the control group. The
body weight of male fetuses from the low-dose group was significantly lower than controls
(3.9 g compared to 4.4 g in controls); however, no dose-relationship was evident, as no
significant effect on body weight was reported in high-dose rats. The incidences of gross
skeletal and visceral malformations in treated groups were not significantly different from the
control group. In the two treated groups, male rat neonates showed a significant increase in open
field measurements (times standing up and times of excretion) compared to the control group;
however, the significance of this finding is unclear.
Male dominant lethality testing was also performed in rats (Zhao et al., 1989, 1997).
Groups of male rats were exposed to 0, 6.2, or 198 ppm (0, 25, or 800 mg/m3) of 1,2-DCA for
4 hours/day for 1, 2, 3, or 4 weeks prior to mating. The impregnation rate was significantly
lower and the preimplantation loss significantly greater in females mated to high-dose males
exposed for 2 weeks compared to concurrent controls. However, these differences were likely
anomalies, as significant differences did not result in any other high-dose groups (1-, 3-, or
4-week exposures), and the impregnation rate and preimplantation loss in the 2-week controls
comprised the high and low ends of their respective ranges within the four control groups. This
study suggests aNOAEL and LOAEL of 6.1 and 51.3 ppm (24.8 and 207.6 mg/m3),
respectively, for reproductive effects in rats in the initial experiment (Zhao et al., 1989, 1997).
However, confidence in these assessments is limited because the translation contained
inconsistencies regarding species, group sizes were not reported, and the type of statistical test
was not indicated. Furthermore, other studies with more reliable reporting (Rao et al., 1980;
Payan et al., 1995) did not confirm the findings of Zhao et al., 1989, 1997.
In the fourth study, Zhao et al. (1984) exposed pregnant Swiss hybrid mice
(15-19/group) to 0, 25, or 250 mg/m3 of 1,2-DCA (98.5% pure) by breathing tube for
"3
4 hours/day on GDs 6-15. Another group of mice was exposed to 1,000 mg/m of 1,2-DCA for
4 hours/day on GDs 9 and 10. Maternal toxicity evaluations were not reported. Upon sacrifice
on GD 18, the numbers of implantations, resorptions, and live and dead fetuses were recorded.
Fetuses were examined for external, skeletal, and visceral anomalies; however, the preparation
and examination techniques were not reported. Although the details of the study design are
poorly reported in this paper, it appears that additional groups of mice received the same
treatments and were allowed to give birth. Offspring survival was recorded on PND 4 and 21,
and body weight was measured periodically for 2 months after birth. Developmental milestones
(appearance of hair and teeth, eye and ear opening, as well as some poorly described
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neurobehavioral milestones5) were noted. After 2 months, some of the offspring (numbers not
reported) were sacrificed and necropsied, and the heart, spleen, kidneys, and brains were
weighed. Other groups of treated and control offspring (Fl) were mated to evaluate effects in
the second generation. Pregnancy rates, and body weight and survival of offspring (F2) were
recorded.
In the first group of mice sacrificed on GD 18, there were no deaths, and body weight
was not affected by treatment (Zhao et al., 1984). The data showed no significant
treatment-related effects on number of implantations, resorptions, or live or dead fetuses, nor on
fetal weight, length, or incidence of external, visceral, or skeletal malformations. Similarly,
there were no exposure-related effects on offspring survival, body weight, and growth, or
developmental milestones in the Fl offspring reared for 2 months. Necropsy results and organ
weight data showed no effects of 1,2-DCA treatment on the Fl offspring. Finally, neither
survival nor body weight of F2 offspring showed any relationship to treatment (body weight data
not shown). Based on the lack of developmental or reproductive effects, the high concentration
"3
(250 mg/m ) may represent a NOAEL; however, poor reporting limits the reliability of this
study.
In the fifth study, published in Russian with a brief English abstract, Vozovaya (1974)
assessed the reproductive and developmental toxicity of inhaled 1,2-DCA in rats. This study was
reviewed by Barlow and Sullivan (1982); the study summary herein is based on information
provided in the review. According to the review, 28 female rats were exposed to 14 ppm
"3
(57 mg/m ) of 1,2-DCA for 4 hours/day, 6 days/week for 6 months prior to mating with
untreated males, and during pregnancy and rearing of the young. A group of 26 control rats were
exposed to air on the same schedule. Toxicological evaluations were not described in the
English abstract or the review. During the premating exposure period, the average length of the
estrous cycle was increased (prolonged diestrus), but females did not become infertile. Treated
females took more days with males before becoming pregnant, compared with controls.
According to Barlow and Sullivan (1982), maternal toxicity was not evident. The average litter
size of treated dams was significantly reduced (n = 6.5± 1.1) compared with controls
(n = 9.7± 0.6), but it could not be determined if reduced litter sizes were due to reproductive
effects in females or increased embryo and/or fetal death. An increased incidence of stillbirths
(23.1% in treated dams versus 5.1% in controls) suggests a fetotoxic effect. Birth weight of
treated pups was also reduced by 20% compared to controls. Mortality during the first month
after birth (exposure was continued) was 20% in treated pups and only 3% in controls. The
postweaning growth rate of treated female offspring was decreased compared with controls,
while males were unaffected (no details provided). Maturation and development (assessed by
noting timing of incisor eruption, hair growth, eye and ear opening) of offspring exposed in utero
were otherwise normal. According to Barlow and Sullivan (1982), Vozovaya (1974) assessed
central nervous system and liver function, muscular endurance, and limited hematology
(leukocytes counts and neutrophil phagocytic activity) in the offspring at 2, 4, and 6 months of
age, but no treatment-related changes were observed. Prolonged estrous was also noted in
female offspring exposed to 1,2-DCA (1.32 ± 0.07 days in treated offspring versus
1.02 ± 0.01 days in controls). At 3 months of age, the female offspring exposed in utero and
continuously after birth were mated with untreated males. Fertility of the Fl females was not
5Reported in the translation as "the initial establishing times for the baby mice to flip over on a flat surface or in the
air and the times for cross-section avoidance reflection and moving straight forward."
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affected, but neonatal mortality was 18% in treated litters compared with 7% in controls. Barlow
and Sullivan (1982) reported that microscopic examination of the ovaries, uterus, and fallopian
tubes of treated female offspring sacrificed at 6 months of age did not reveal evidence of
histopathology. These data suggest a LOAEL of 57 mg/m3 for increased estrous cycle and
prolonged time-to-pregnancy in maternal animals and for reduced litter size, increased number of
stillbirths, decreased birth weight, and decreased neonatal survival in offspring. However,
because the available information on this study is derived from a review of the original study,
and the original data were not examined, the reliability of this LOAEL is uncertain. In addition,
later, well-described developmental and reproductive toxicity studies in rats observed no effects
on litter size, pre and postnatal survival, or birth weight at higher exposure concentrations
(Rao et al., 1980; Payan et al., 1995), calling into question the findings of Vozovaya (1974).
The sixth study (Vozovaya, 1977), reviewed by WHO, (1995) was published in Russian
without an English summary. According to WHO (1995), exposure of rats (number and strain
not specified) to 15 mg/m3, 4 hours/day, 6 days/week for 4 months prior to and after the mating
period produced an increased estrous cycle and an increase in embryo mortality (27% in exposed
animals versus 11% in controls) (Vozovaya, 1977, as cited in WHO, 1995). The review
indicated that preimplantation losses were five times greater in treated animals compared with
controls. WHO (1995) reported that there were no fetal abnormalities other than hematomas of
the head, neck, and anterior extremities (incidences not reported). The available information was
not sufficient to determine effect levels. Further, as noted earlier, the effects observed by
Vozovaya (1974,1977) could not be reproduced in later developmental and reproductive toxicity
studies in rats exposed to higher concentrations of 1,2-DCA (Rao et al., 1980; Payan et al.,
1995).
OTHER STUDIES
Toxicokinetics
The toxicokinetics of 1,2-DCA have been extensively studied in rodents although not in
humans (ATSDR, 2001). Available information suggests that 1,2-DCA is readily absorbed after
oral, inhalation, and dermal exposure and is distributed throughout the body (ATSDR, 2001).
This compound is metabolized via mixed-function oxidases and glutathione conjugation;
products of mixed-function oxidases include chloroacetaldehyde, 2-chloroethanol, and
2-chloroacetic acid (ATSDR, 2001). ATSDR (2001) reported that metabolism of 1,2-DCA
appears to be saturable at gavage doses >25 mg/kg and after inhalation of concentrations of
>150 ppm. The saturation of metabolic pathways may be responsible for the greater toxicity
observed with bolus doses of 1,2-DCA compared with drinking water exposures (NTP, 1991).
The toxicokinetics of other halocarbons have been widely assessed, and it is recognized that
rodents have a greater capacity than humans to metabolically activate 1,2,3-trichloropropane,
trichloroethylene, perchloroethylene, and l,2-dibromo-3-chloropropane (U.S. EPA, 1985b).
However, no such information is available for 1,2-DCA.
Sweeney et al. (2008) published an updated PBPK model for 1,2-DCA in rats. The
model provided good fit to pharmacokinetic data obtained after inhalation, gavage, and
intravenous exposure in Osborne-Mendel, Sprague-Dawley, Wistar, and F344/N rats.
Sweeney et al. (2008) determined that their model is most appropriately used for conducting
route-to-route extrapolations for acute and repeated-exposure toxicity studies in rats. Currently,
the limited human metabolism and kinetic data for 1,2-DCE preclude the development of a
human model.
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Immunotoxicity
There were two immunotoxicity studies: one oral mouse study and one inhalation study
in rats and mice. In the oral study evaluating the immunotoxicity of 1,2-DCA, male CD-I mice
(32/group) were treated with drinking water containing 0, 20, 200, or 2,000 mg/L of 1,2-DCA
(purity not specified) (0, 3, 24, or 189 mg/kg-day, as calculated by the authors using measured
fluid consumption) for 90 days (Munson et al., 1982). Body weight and fluid consumption were
measured at unspecified intervals. Immunotoxicology analyses included antibody response to
sheep erythrocytes (antibody forming plaques in the spleen and antibody titers in blood), delayed
hypersensitivity response to sheep erythrocytes, and lymphocyte response to the mitogens LPS
(lipopolysaccharide from S. typhosa 0901) and concanavalin A. Blood was collected
(presumably at sacrifice, although the report is not clear) for hematology analysis (RBC, WBC
and platelet counts; Hgb, Hct, prothrombin time, and fibrinogen). The function of the
reticuloendothelial system was assessed in separate groups of mice by measuring the vascular
clearance and tissue uptake of radiolabeled sheep erythrocytes injected into exposed mice prior
to sacrifice. Necropsies were performed on all animals at sacrifice at the end of exposure; brain,
liver, spleen, lungs, thymus, kidneys, and testes were weighed. Reduced water consumption,
probably indicating an organoleptic effect of 1,2-DCA, was seen at 24 and 189 mg/kg-day (5.0,
5.5, 4.2, and 2.8 mL/mouse/day in control through high-dose groups). In addition, an
appreciable decrease in growth was seen in the high-dose group (about 10% lower terminal body
weight, based on data presented graphically and without statistical analysis). The reduction in
body weight at the high dose was most likely a result of dehydration from markedly lower water
intake. No significant treatment-related effects were seen on absolute or relative organ weights,
hematological parameters, or immunological function. A dose-dependent decrease in
hemagglutination titers was observed, but the change from control was not statistically
significant at any dose. Histological examination of organs and tissues was not conducted. The
NOAEL for this study would be the highest dose tested, 198 mg/kg-day.
In the second study, the immunotoxic effects of inhaled 1,2-DCA in young male
Sprague-Dawley rats and young female CD-I mice were examined by Sherwood et al. (1987).
"3
Rats were exposed for 3 or 5 hours nominally to 0, 100, or 200 ppm (0, 405, or 810 mg/m ) of
1,2-DCA or, in multiple exposure experiments, to 0, 10, 20, 50, or 100 ppm (0, 41, 81, 202, or
405 mg/m ) of 1,2-DCA (purity not reported) 5 hours/day, 5 days/week for 12 exposures. Mice
were exposed to 0 or 2.3 ppm (0 or 9.3 mg/m3) of 1,2-DCA 3 hours/day for 5 days. Additional
mice were exposed to 0, 2.3, 5.4, 10.8, or 100 ppm (0, 9.3, 21.9, 43.7, or 405 mg/m3) of 1,2-DCA
for a single 3-hour period. Testing was conducted after the conclusion of the single exposure or
repeated exposure periods. The number of animals/species/exposure level varied with the test,
ranging from 5 for alveolar macrophage cytostasis in rats to 140 for mortality from streptococcal
pneumonia in mice. In rats, no effects were observed on pulmonary bactericidal activity to
inhaled Klebsiella pneumonia, in vitro phagocytotic activity of alveolar macrophages, cytostatic
and cytolytic capacity of alveolar macrophages, alveolar macrophage ectoenzymes activity, or
mitogenic stimulation of lymphocytes from lung-associated, mesenteric, or popliteal lymph
-3
nodes. In mice, a single 3-hour exposure to 21.9 or 43.7 mg/m of 1,2-DCA significantly
increased mortality (monitored over a 14-day postexposure period) in a dose-related manner,
relative to controls, due to exposure to an aerosol of viable Streptococcus zooepidemicus
[~2 x 104 streptococci]). However, a single exposure or repeated exposures to 9.3 mg/m3 had no
"3
significant effects. An exposure level of 43.7 mg/m of 1,2-DCA significantly decreased
bactericidal activity towards inhaled K. pneumonia (p < 0.01); lower exposure levels were
without effect. Single exposure to 43.7 or 405 mg/m of 1,2-DCA did not affect the total
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numbers or differential counts of cells recovered by pulmonary lavage or the phagocytic or
cytostatic ability of the alveolar macrophages in vitro. Sherwood et al. (1987) suggested that the
evident interspecies differences in immunotoxic susceptibility argue against extrapolating from
animals to humans; given that mice and rats responded differentially, it is difficult to extrapolate
the response to humans. In addition, the massive streptococcal challenge to mice, consisting of
whole-body, 30-minute exposures to aerosols of bacteria for an estimated challenge exposure of
2 x 104 inhaled viable streptococci, is unlikely to be relevant to normal human immunological
challenge.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD
VALUES FOR 1,2-DICHLOROETHANE
Table 8 summarizes the studies available for use in deriving provisional oral toxicity
values for 1,2-DCA; these studies include subchronic gavage studies in rats (Van Esch et al.,
1977; NTP, 1991; Daniel et al., 1994); subchronic drinking water studies in rats and mice (NTP,
1991); a subchronic immunotoxicity study in mice (Munson et al., 1982); chronic gavage studies
in rats and mice (NCI, 1978); a developmental toxicity study in rats (Payan et al., 1995); and a
multigeneration reproductive toxicity study in mice (Lane et al., 1982). An additional chronic rat
study examining a small number of hepatotoxicity and reproductive toxicity endpoints
(Alumot et al., 1976) was also located. However, poor reporting, substantial limitations in the
toxicological evaluations, and great uncertainty in the dose estimates precluded both
determination of reliable effect levels from this study and the use of this study for POD
determination. Table 8 shows oral exposures and effect levels associated with the remaining
studies. The available information suggests that rats are more sensitive than mice to the effects
of 1,2-DCA exposure, and that gavage administration results in effects at lower doses than that
observed following drinking water administration in rats. Gavage doses of 240 mg/kg-day,
5 days/week (equivalent to 171 mg/kg-day continuously) for up to 13 weeks were lethal in rats
(NTP, 1991); in a chronic study, doses of 95 mg/kg-day, 5 days/week (equivalent to
68 mg/kg-day) increased mortality. In contrast, rats survived 13 weeks of exposure to higher
doses (-500 mg/kg-day) administered in drinking water (NTP, 1991). No rats consuming any
dose of 1,2-DCA in their water died, while all or most all male and female rats succumbed to the
higher bolus doses with noted pathological changes, serum clinical chemistry, and hematological
alterations often seen. These changes were not observed in any animal receiving 1,2-DCA via
drinking water.
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Table 8. Summary of Oral Noncancer Dose-Response Information
Species and
Study Type
Exposure
NOAEL
(mg/kg-day)
LOAEL
(mg/kg-day)
Duration-
Adjusted"
NOAEL
(mg/kg-day)
Duration-
Adjusted"
LOAEL
(mg/kg-day)
Responses at the
LOAEL
Comments
Reference
Subchronic
Wistar Rat
10/sex/dose
Gavage
0, 10, 30, or
90 mg/kg-day, 5 d/wk
for 90 days
30
90
21
64
Increased relative
kidney and liver
weights

VanEschetal.,
1977
Sprague-Dawley Rat
10/sex/dose
Gavage
0, 37.5, 75, or
150 mg/kg-day for
90 consecutive days
37.5
75
37.5
75
Increased relative
liver weight and
increased serum
ALP

Daniel etal.,
1994
F344/N Rat
10/sex/dose
Gavage
0, 30, 60, 120, 240, or
480 mg/kg-day (M);
0, 18, 37, 75, 150,
300 mg/kg-day (F),
5 d/wk for 13 wks
37
75
26
54
Increased absolute
kidney weight in
females

NTP, 1991
F344/N Rat
10/sex/dose
Drinking water
0, 49, 86, 147, 259, or
515 mg/kg-day (M);
0, 58, 102, 182, 320, or
601 mg/kg-day (F) for
13 wks
NA
58
NA
58
Increased absolute
kidney weight in
females
Dose-related increases
in renal regeneration in
females at higher doses
NTP, 1991
Sprague-Dawley Rat
10/sex/dose
Drinking water
0, 60, 99, 165, 276, or
518 mg/kg-day (M);
0, 76, 106, 172, 311, or
531 mg/kg-day (F) for
13 wks
NA
76
NA
76
Increased absolute
and relative kidney
weight in females

NTP, 1991
Osborne-Mendel Rat
10/sex/dose
Drinking water
0, 54, 88, 146, 266, or
492 mg/kg-day (M);
0, 82, 126, 213, 428, or
727 mg/kg-day (F) for
13 wks
NA
82
NA
82
Increased absolute
and relative kidney
weight in females

NTP, 1991
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Table 8. Summary of Oral Noncancer Dose-Response Information
Species and
Study Type
Exposure
NOAEL
(mg/kg-day)
LOAEL
(mg/kg-day)
Duration-
Adjusted"
NOAEL
(mg/kg-day)
Duration-
Adjusted"
LOAEL
(mg/kg-day)
Responses at the
LOAEL
Comments
Reference
B6C3F1 Mouse
10/sex/dose
Drinking water
0, 249, 448, 781, or
2,710 mg/kg-day (M);
0, 244, 647, 1,182, or
2,478 mg/kg-day (F) for
13 wks
249
448
249
448
Increased kidney
weight in males
Dose-related increases
in renal histopathology
in males at higher
doses
NTP, 1991
CD-I Mouse
Immunotoxicity
Drinking water
0, 3, 24, or 189 mg/kg-
day for 90 days
189
NA
189
NA
None
Limited evaluations
Munson etal.,
1982
Chronic
Osborne-Mendel Rat
Gavage
TWA doses of 0, 47, or
95 mg/kg-day, 5 d/wk
for 78 weeks
NA
47
NA
34
Clinical signs
Study limited by dose
adjustments and poor
survival
NCI, 1978
B6C3F1 Mouse
Gavage
TWA doses of 0, 97, or
195 mg/kg-day (M);
0, 149, or 299 mg/kg-day
(F), via gavage in corn
oil 5d/wk for 78 weeks
97
195
69
139
Increased incidence
of chronic murine
pneumonia in males
Study limited by dose
adjustments
NCI, 1978
Reproductive/Developmental
Sprague-Dawley Rat
Developmental
25-26 F/dose
0, 119, 158, 198, or 238
mg/kg-day via gavage on
GDs6-20
158
(maternal
and develop-
mental)
198
(maternal
and develop-
mental)
158
(maternal
and develop-
mental)
198
(maternal
and develop-
mental)
Decreased body-
weight gain in
dams; increased
resorptions

Payan etal.,
1995
ICR Swiss Mouse
Multigeneration
reproduction
10 M and 30 F/dose
0, 5, 15, or 50 mg/kg-day
in drinking water for two
generations
50 (parental
and
offspring)
NA
50
(parental and
offspring)
NA
None

Lane etal., 1982
a Adjusted to continuous exposure based on exposure regimen shown in table
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The available studies as a whole suggest the liver and kidney as target organs for
1,2-DCA toxicity via oral exposure. Evidence of toxicity to these organs includes increases in
liver and kidney weights in all of the subchronic animal oral studies (Daniel et al., 1994; NTP,
1991; Van Esch et al., 1977), clinical chemistry changes indicative of potential liver toxicity in
an oral study (Daniel et al., 1994), and dose-related kidney histopathology in both female rats
and male mice in subchronic drinking water studies (NTP, 1991). At lethal doses in rats, fatty
degeneration of the liver has been reported (Van Esch et al., 1977). Liver and kidney effects of
1,2-DCA have also been shown in at least one human exposed to 1,2-DCA; autopsy on a man
acutely poisoned with 1,2-DCA via inhalation exposure revealed hepatocellular and renal tubular
necrosis (Nouchi et al., 1984).
SUBCHRONIC p-RfD
Among the subchronic and reproductive or developmental toxicity studies of oral
exposure to 1,2-DCA, the lowest duration-adjusted LOAEL values (54 and 58 mg/kg-day) were
based on increased absolute kidney weights in female F344/N rats exposed via drinking water or
gavage (both reported by NTP, 1991). In order to select a point of departure (POD) for the
derivation of the subchronic p-RfD, data on both absolute and relative kidney weights in the
drinking water study were considered for benchmark dose (BMD) modeling; these data are
shown in Table 3. Although the gavage study resulted in a similar LOAEL, the drinking water
study was selected as the basis for the subchronic p-RfD because this exposure is more relevant
to likely human exposures.
The data on absolute and relative kidney weights in female F344/N rats exposed via
drinking water (NTP, 1991) were modeled using the continuous data models in the EPA
Benchmark Dose Software (BMDS) (v. 2.0). Appendix A describes the modeling approach and
results. In the absence of a biologically relevant benchmark response level (BMR), a default
BMR of 1 standard deviation (SD) from the control mean was used. No model fit was achieved
with any continuous data model, even when the high-dose groups were sequentially dropped
from the analysis. As a result, the LOAEL from the NTP (1991) study (>10% increase in
absolute kidney weights in female F344/N rats) was selected as the POD for the subchronic
p-RfD (a NOAEL was not identified).
A provisional subchronic RfD of 2 x 10" mg/kg-day for 1,2-DCA was derived by
applying an UF of 3,000 to the rat LOAEL of 58 mg/kg-day as follows:
Subchronic p-RfD = LOAEL UF
= 58 mg/kg-day ^ 3,000
= 0.02 or 2 x 10"2 mg/kg-day
The composite UF of 3,000 was composed of the following UFs:
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating susceptible human responses are
insufficient.
•	UFa: A factor of 10 is applied for animal-to-human extrapolation because data for
evaluating relative interspecies sensitivity are insufficient.
•	UFd: The database for oral 1,2-DCA includes subchronic gavage studies in rats
(Van Esch et al., 1977; Daniel et al., 1994; NTP, 1991); subchronic drinking
water studies in rats and mice (NTP, 1991); a subchronic immunotoxicity study in
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mice (Munson et al., 1982); chronic gavage studies in rats and mice (NCI, 1978);
a developmental toxicity study in rats (Payan et al., 1995), and a multigeneration
reproductive toxicity study in mice (Lane et al., 1982). Despite the relatively
complete database, a factor of 3 (i.e., 10°5) is applied for database inadequacies.
Human case reports and limited epidemiology (reviewed by ATSDR, 2001 and
WHO, 1995) have suggested that 1,2-DCA may result in neurotoxicity, but data
for evaluating potential neurotoxicity are inadequate.
• UFl: A factor of 10 is applied for using a LOAEL as the POD.
Confidence in the key study (NTP, 1991) is medium. Adequate numbers of animals were
used, and a range of toxicological endpoints were evaluated; in addition, three different strains of
rats were tested along with two methods of administration (gavage and drinking water) with
generally consistent findings; however, a NOAEL was not identified for F344/N rats.
Confidence in the database for oral 1,2-DCA, which includes subchronic gavage studies in rats
(Van Esch et al., 1977; Daniel et al., 1994; NTP, 1991), subchronic drinking water studies in rats
and mice (NTP, 1991), a subchronic immunotoxicity study in mice (Munson et al., 1982),
chronic gavage studies in rats and mice (NCI, 1978), a developmental toxicity study in rats
(Payan et al., 1995), and a multigeneration reproductive toxicity study in mice (Lane et al., 1982)
is also medium. The database lacks an assessment of potential neurotoxicity. Potential
neurotoxic effects of 1,2-DCA have been suggested by human case reports and limited
epidemiology (reviewed by ATSDR, 2001 and WHO, 1995). Medium confidence in the
provisional subchronic RfD follows.
CHRONIC p-RfD
Two chronic oral studies of 1,2-DCA were located in the literature searches:
Alumot et al. (1976) and NCI (1978). Poor reporting, considerable limitations in the
toxicological evaluations, and highly uncertain dose estimates precluded determination of
reliable effect levels for Alumot et al. (1976). In the gavage study conducted by NCI (1978),
LOAELs of 34 and 139 mg/kg-day were identified in rats and mice for clinical signs and an
increased incidence of chronic murine pneumonia (respectively). The quality of the rat study
was limited by poor survival at the high dose and the use of a variable dosing regimen. Further,
the clinical signs observed in rats were not seen in any of the subchronic studies of various rat
strains exposed via gavage or drinking water to much higher doses.
In the absence of suitable chronic data, the POD from the subchronic p-RfD could be
used to derive the chronic p-RfD; however, the composite UF would include the additional UFs
of 10 for applying data from a subchronic study to assess potential effects from chronic
exposure. This would result in the large composite UF of greater than 3,000, thereby relegating
this derivation of the chronic p-RfD to an appendix screening value (see Appendix B).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR 1,2-DICHLOROETHANE
Table 9 summarizes the available studies of inhaled 1,2-DCA. The inhalation toxicology
database for 1,2-DCA, while it contains several high-quality chronic toxicity studies, lacks clear
information on the critical effects of inhalation exposure. Of the few human inhalation studies,
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one occupational study (Kozik, 1957) provided adequate exposure information to identify a
tentative LOAEL of 61 mg/m3 based on neurobehavioral effects; although useful, this study was
limited by poor reporting, lack of information on exposure duration, small numbers of subjects,
and failure to control for potential confounding factors. However, animal data are also limited.
Developmental toxicity studies by Vozovaya (1974, 1977) and Zhao et al. (1984, 1989, 1997) are
not useful for toxicity value derivation due to limitations in the reporting and/or translation.
Further, the findings in these studies could not be reproduced in later developmental and
reproductive toxicity studies (Rao et al., 1980; Payan et al., 1995). Among a number of chronic
toxicity studies in several species, subchronic range-finding studies in two species,
developmental toxicity studies in two species, and a multigeneration reproductive toxicity study,
only two studies (Spreafico et al., 1980; Spencer et al., 1951) contained data to define LOAELs
for nonlethal effects (increased liver enzymes in aged rats, and liver lesions and reduced body
weight in guinea pigs, respectively). However, these studies suffered from a number of
limitations; Spreafico et al., 1980 provided only limited toxicological evaluation and mostly
qualitative reporting; Spencer et al., 1951 reported FELs for significant mortality at the
high-dose in some species (e.g., rats, guinea pigs, monkeys); however, no effects of any kind at
the same dose in other species (i.e., rabbits), and no observable effects in any species at the
mid-dose. The available information does suggest a steep dose-response curve for the effects of
inhaled 1,2-DCA; several studies (e.g., Spencer et al. [1951] study of rats; Nagano et al. [2006]
range-finding studies of rats and mice; Payan et al. [1995]; Rao et al. [1980]) identified FELs
based on lethality at concentrations approximately 2- to 3-fold higher than no-effect levels. The
database also suggests some degree of species differences in sensitivity, at least with respect to
mortality. Studies in mice (Nagano et al., 2006, subchronic range-finding study) and rabbits
(Rao et al., 1980) suggest that these species are more susceptible to the lethal effects of 1,2-DCA
3	3
(mortality FELs of 648 and 405 mg/m ) than rats, guinea pigs, or cats (FELs >1,214 mg/m ;
Nagano et al., 2006; Spencer et al., 1951; Payan et al., 1995; Rao et al., 1980; Hofmann et al.,
1971).
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Table 9. Summary of Inhalation Noncancer Dose-Response Information
Species and
Study Type
(«/sex/group)
Exposure
NOAEL
(mg/m3)
LOAEL
(mg/m3)
Responses at the LOAEL
Comments
Reference
Human studies
Human Occupational
TWA concentration
of ~61 mg/m3
NA
61
HECa: 22
Impaired neurobehavioral function
Limited by poor reporting, small
numbers of subjects, failure to control
for potential confounders; exposure
duration unknown
Kozik, 1957;
NIOSH, 1976
Subchronic studies
F344/N Rat
Number not
specified/sex/group
648 or 1,295 mg/m3
for 13 wks
NA
1,295 (FEL)
100% mortality
Briefly described study; insufficient
information to define NOAEL or
calculate HEC
Nagano etal.,
2006
BDF1 Mouse
Number not
specified/sex/group
324 or 648 mg/m3
for 104 wks
NA
648 (FEL)
50% mortality
Briefly described study; insufficient
information to define NOAEL or
calculate HEC
Nagano etal.,
2006
Chronic studies
F344/N Rat
50/sex/group
0, 40, 162, or
648 mg/m3, 6 hr/d,
5 d/wk for 104 wks
648
HECb: 116
NA
None

Nagano etal.,
2006
BDF1 Mouse
50/sex/group
0, 40, 121, or 364
mg/m3, 6 hr/d,
5 d/wk for 104 wks
40
HEC: 7
NA
Tumor-related mortality at
>121 mg/m3

Nagano etal.,
2006
Sprague-Dawley Rat
50/sex/group
0 or 202 mg/m3,
7 hr/d, 5 d/wk for
2yrs
202
HEC: 42
NA
Marginal increase in gross testicular
lesions (not further described) at
NOAEL, with no corresponding
histological findings
Limited endpoints evaluated.
Cheever etal.,
1990
Sprague-Dawley Rat
90/sex/group
0, 20, 40, 202,
607-1,012 mg/m3,
7 hr/d, 5 d/wk, up to
78 wks
40
HEC: 8
202
HEC: 42
Serum chemistry changes indicative
of liver and possibly kidney toxicity
in rats treated from 14 months to
26 months of age
High concentration reduced to from
1,012 to 607 mg/m3 after several days
due to high toxicity
Maltoni etal.,
1980;
Spreafico et al.,
1980
Rats, Rabbits, Guinea
Pigs,
2-5/sex/group
0, 405, 2,024 mg/m3,
6 hr/d, 5 d/wk for up
to 17 wks
405
HEC: 72
2,024 (FEL)
HEC: 361
Mortality
Small numbers of animals
Hofmann etal.,
1971
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Table 9. Summary of Inhalation Noncancer Dose-Response Information
Species and
Study Type
(«/sex/group)
Exposure
NOAEL
(mg/m3)
LOAEL
(mg/m3)
Responses at the LOAEL
Comments
Reference
Cats
2/sex/group
0, 405, 2,024 mg/m3,
6 hr/d, 5 d/wk for
6 (low conc.) and
17 (high conc.) wks
2,024
HEC: 361
NA
Slight increase in BUN at NOAEL.
Small numbers of animals
Hofmann etal.,
1971
Rats
15/sex/group
0, 405, 810,
1,620 mg/m3, 7 hr/d,
5 d/wk, up to 30 wks
810
HEC: 169
1,620 (FEL)
HEC: 338
Mortality

Spencer etal.,
1951
Guinea Pigs
8/sex/group
0, 405, 810,
1,620 mg/m3, 7 hr/d,
5 d/wk, up to 35 wks
405
HEC: 84
810
HEC: 169
Liver lesions and reduced body
weight
Small numbers of animals
Spencer etal.,
1951
Rabbits
2M, lF/group
0, 405, 1,620 mg/m3,
7 hr/d, 5 d/wk,
33-35 wks
1,620
HEC: 338
NA

Small numbers of animals
Spencer etal.,
1951
Monkeys
2M/group
0, 405, 1,620 mg/m3,
7 hr/d, 5 d/wk, up to
30 wks
405
HEC: 84
1,620 (FEL)
HEC: 338
Mortality
Small numbers of animals
Spencer etal.,
1951
Reproductive/Developmental Studies
Sprague-Dawley Rat
One-generation
reproduction
20/sex/group
0, 101, 304,
607 mg/m3, 6 hr/d,
5	d/wk for 60 d prior
to breeding, then
6	hr/d, 7 d/wk
thereafter
607
HEC: 108
NA
None

Rao etal., 1980
Sprague-Dawley Rat
Developmental
26F/group
0, 607, 1,028, or
1,332 mg/m3, 6 hr/d,
GDs 6-20
1,028
HEC: 257
(maternal)
1,332
HEC: 333
(develop-
mental)
1,332 (FEL)
HEC: 333
(maternal)
NA
(develop-
mental)
Low maternal mortality; decreased
body weight

Payan etal., 1995
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Table 9. Summary of Inhalation Noncancer Dose-Response Information
Species and
Study Type
(«/sex/group)
Exposure
NOAEL
(mg/m3)
LOAEL
(mg/m3)
Responses at the LOAEL
Comments
Reference
Sprague-Dawley Rat
Developmental
16-30F/group
0, 405, or
1,214 mg/m3, 7 hr/d,
GDs 6-15
405
HEC: 118
(maternal and
develop-
mental)
1,214 (FEL)
HEC: 354
(maternal and
develop-
mental)
Maternal mortality; there was only
1 litter at the high exposure level
and it was totally resorbed
High maternal mortality at high
exposure level only
Rao etal., 1980
Rabbit
Developmental
19-21F/group
0, 405, or
1,214 mg/m3, 7 hr/d,
GDs 6-18
NA
(maternal)
1,214
HEC: 354
(develop-
mental)
405 (FEL)
HEC: 118
(maternal)
NA
(develop-
mental)
Maternal mortality
Low maternal mortality in both dose
groups did not increase with dose, but
was considered treatment-related by
the researchers
Rao etal., 1980
Calculated assuming inhalation of 10/20 m3 (10 m3 in 8-hour work day and 20 m3 in 24 hours), 5/7 days/week
bHEC calculated as follows: NOAELheC = NOAEL x exposure hours/24 hours x exposure days/7 days x dosimetric adjustment
For systemic effects, the dosimetric adjustment is the ratio of the animal:humanblood:gas partition coefficients for 1,2-dichloroethane (because the coefficient in
animals was greater than that in humans, a default value of 1 was used)
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The NOAELs and LOAELs from the available studies were converted to continuous
exposure human equivalent concentrations (NOAELhec and LOAELhec) based on the guidance
provided in Methods for Derivation of Inhalation Reference Concentrations (RfCs) and
Application of Inhalation Dosimetry (U.S. EPA, 1994b). Each effect level was first adjusted to
an equivalent continuous exposure concentration based on the exposure regimen reported in the
study. The human equivalent concentration was then calculated using the appropriate dosimetric
adjustment (U.S. EPA, 1994b). As all of the observed effects were extrarespiratory (systemic)
effects, 1,2-DCA was treated as a Category 3 gas, and the ratio of blood:gas partition coefficients
was used to make the dosimetric adjustment. Abraham et al. (2005) reported human and rat
blood:gas partition coefficients of 20 and 30, respectively, for 1,2-DCA. Because
(Hb/g)A > (Hb/g)H, a default value of 1 was used for the rat-to-human blood:gas ratio in accordance
with EPA (1994b) guidance. In the absence of blood:gas partition coefficients for other species,
the default ratio of 1.0 was used. Table 9 includes the NOAELhec and LOAELhec values
calculated for each of the studies.
SUBCHRONIC p-RfC
The studies available for defining a subchronic p-RfC for 1,2-DCA include the
occupational health study (Kozik, 1957)6, subchronic range-finding studies in rats and mice
(Nagano et al., 2006), a multigeneration reproductive toxicity study in rats (Rao et al., 1980), and
developmental toxicity studies in rats and rabbits (Payan et al., 1995; Rao et al., 1980). The
lowest LOAELhec in the animal studies was a FEL for maternal mortality in rabbits (118 mg/m3,
the lowest concentration tested) in the developmental toxicity study by Rao et al. (1980). The
LOAEL identified by Kozik (1957) for neurobehavioral impairment in humans was considerably
"3
lower (LOAELhec = 22 mg/m ). Although Kozik (1957) suffered from a number of limitations
(i.e., lack of description of the analytical methodology used, limited quantitative data and
statistical analyses, unstated criteria for diagnosis of disease, and lack of matched control
subjects), it was selected as the only feasible basis for the subchronic p-RfC derivation. The
"3
LOAELhec of 22 mg/m was chosen as the POD; Kozik (1957) did not report any data that could
be used for BMD modeling.
"3
For the subchronic p-RfC derivation, the LOAELhec of 22 mg/m was divided by a UF of
300, as shown below:
Subchronic p-RfC = LOAELhec ^ UF
22 mg/m3 - 300
= 0.07 mg/m3 or 7 x 10"2 mg/m3
The composite UF of 300 was composed of the following UFs:
•	UFa: A factor of 1 is applied for animal-to-human extrapolation because a human
study served as the basis for the p-RfC.
•	UFd: The toxicological database for inhaled 1,2-DCA includes a number of
chronic toxicity studies in several species, developmental toxicity studies in two
species, and a reproductive toxicity study; however, no high quality studies
identified LOAELs based on nonlethal effects. A factor of 3 (10° ) is applied for
database inadequacies, specifically, the lack of a comprehensive animal bioassay
6 Kozik (1957) did not explicitly report the length of time that subjects in the study were exposed; it was assumed
for the purpose of this review that the exposure was subchronic (<7 years for humans).
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of potential neurotoxicity in light of neurobehavioral effects identified in Kozik
(1957) and other human studies, and the acute neurotoxic effects reported in
Dilks et al. (2005) as well as the lack of a high quality key study (Dilks et al.,
2007).
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating susceptible human responses are
insufficient.
•	UFl: A factor of 10 is applied for using a LOAEL POD because data for
establishing a NOAEL are insufficient.
Confidence in the key study (Kozik, 1957) is very low. Although the study assessed
sensitive toxicological endpoints (neurobehavioral changes) and saw morbidity for liver disease
(comparable to this endpoint seen in animal bioassays), it suffered from a number of limitations,
including poor reporting, small number of subjects, lack of control for confounding, and
uncertain exposure assessment. Confidence in the database is medium; it includes chronic
toxicity studies in several species, developmental toxicity studies in two species, and a
reproductive toxicity study; however, no high quality studies identified clear LOAELs. In
addition, the database lacks a high quality assessment of neurotoxicity. Low confidence in the
provisional subchronic RfC follows.
CHRONIC p-RfC
Studies available for use in defining a chronic p-RfC for 1,2-DCA include the
occupational health study used to derive the subchronic p-RfC (Kozik, 1957) and chronic
toxicity studies in several species (Nagano et al., 2006; Cheever et al., 1990;
Spreafico et al., 1980; Maltoni et al., 1980; Hofmann et al., 1971; Spencer et al., 1951). Only
two chronic studies identified nonlethal LOAELs (Spreafico et al., 1980 and Spencer et al.,
"3
1951). The LOAELhec of 169 mg/m (for liver lesions and reduced body weight in guinea pigs)
identified by Spencer et al. (1951) exceeds the FEL for mortality in rabbits (Rao et al., 1980), so
this study is not useful for p-RfC derivation. Spreafico et al. (1980) identified a LOAELhec of
42 mg/m3 for increases in ALT (4- to 9-fold higher than controls) and GGT (~2-fold higher) in
rats exposed to 1,2-DCA from 14 months to 26 months of age. Changes in serum liver enzymes
were not observed in rats exposed to HEC concentrations up to 116 mg/m3 for 2 years in the only
other rat study that examined clinical chemistry (Nagano et al., 2006). However, the liver has
been identified as a critical target organ for oral exposure to 1,2-DCA as well as for exposure to
related chlorinated solvents such as 1,1-dichloroethylene (U.S. EPA, 2008). BMD modeling of
the ALT and GGT data reported by Spreafico et al. (1980) was conducted in order to determine
whether these data would result in a lower POD than the LOAEL identified by Kozik (1957) and
used to derive the subchronic p-RfC.
BMD modeling was performed on the changes in serum ALT in male rats and GGT in
female rats exposed for 12 months (see Table 7) using the nominal exposure concentrations.
While both enzymes were increased in both sexes, only the ALT in males and GGT in females
exhibited monotonic increases with exposure concentration, so these were selected for modeling.
Appendix C provides details of the modeling and results. The recommended Benchmark
Response (BMR) of 1 SD from the control mean (U.S. EPA, 2000) was used in the absence of a
biologically-based benchmark response level. No model fit was achieved with the male ALT
data (even when the high exposure group was dropped from the analysis) or with the full data set
for GGT in females. After dropping the high exposure group, adequate fit was achieved with the
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female GGT data. For this data set, the test for homogenous variance indicated adequate fit to
the variance data, and the 2-degree polynomial, 3-degree polynomial, and power models
provided adequate fit to the means. The BMCL values from the models that fit were within a
factor of 3, so the model with the lowest Akaike Information Criterion (AIC) (3-degree
polynomial) was chosen. The BMCisd and BMCLisd associated with this model are 142 and
130 mg/m3, respectively. After adjustment for continuous exposure and calculation of the
human equivalent concentration, the BMCLisdhec is 27 mg/m . This value is comparable to the
LOAELhec (22 mg/m3) identified by Kozik (1957). The LOAELhec of 22 mg/m3 (Kozik, 1957)
was used as the POD because it is lower and is based on human data. Furthermore, given that
Kozik (1957) also assessed liver disease in the occupationally exposed individuals and found the
neurobehavioral effects more sensitive, the choice of this POD would be protective against liver
effects in humans.
"3
For the chronic p-RfC derivation, the LOAELhec of 22 mg/m was divided by a UF of
3,000, as shown below:
Chronic p-RfC = LOAELhec ^ UF
22 mg/m3 - 3,000
= 0.007 mg/m3 or 7 x 10 3 mg/m3
The composite UF of 3,000 was composed of the following UFs:
•	UFa: A factor of 1 is applied for animal-to-human extrapolation because a human
study served as the basis for the p-RfC.
•	UFd: The toxicological database for inhaled 1,2-DCA includes a number of
chronic toxicity studies in several species, developmental toxicity studies in two
species, and a reproductive toxicity study; however, no high quality studies
identified LOAELs based on nonlethal effects. A factor of 3 (10° ) is applied for
database inadequacies, reflecting the absence of clear LOAELs and the lack of a
comprehensive study of potential neurotoxicity in light of neurobehavioral effects
identified in Kozik (1957) and other human studies.
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating susceptible human responses are
insufficient.
•	UFl: A factor of 10 is applied for using a LOAEL POD because data for
establishing a NOAEL are insufficient.
•	UFs: A factor of 10 is applied for using data from a subchronic study to assess
potential effects from chronic exposure because data for evaluating response after
chronic exposure are insufficient.
As noted earlier, confidence in the key study (Kozik, 1957) is very low, and confidence
in the cocritical study (Spreafico et al., 1980) is also low because the results were not confirmed
in the chronic study conducted by Nagano et al. (2006). Confidence in the database is medium;
it includes chronic toxicity studies in several species, developmental toxicity studies in two
species, and a reproductive toxicity study; however, no high quality studies identified clear
LOAELs. In addition, the database lacks a high quality assessment of neurotoxicity. Low
confidence in the provisional chronic RfC follows.
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PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR 1,2-DICHLOROETHANE
A provisional carcinogenicity assessment was not prepared for 1,2-DCA because IRIS
(U.S. EPA, 2008) includes a cancer assessment for this compound.
REFERENCES
Abraham, M.H., A. Ibrahim A and W.E. Acree, Jr. (2005) Air to blood distribution of volatile
organic compounds: A linear free energy analysis. Chem. Res. Toxicol. 18(5):904—911.
ACGIH (American Conference of Governmental Industrial Hygienists). (2007) TLVs® and
BEIs®: Threshold Limit Values for Chemical Substances and Physical Agents, Biological
Exposure Indices. ACGIH, Cincinnati, OH.
Alumot, E., E. Nachtomi, E. Mandel et al. (1976) Tolerance and acceptance daily intake of
chlorinated fumigants in the rat diet. Food Cosmet. Toxicol. 14:105-110.
ATSDR (Agency for Toxic Substances and Disease Registry). (2001) Toxicological Profile for
1,2-Dichloroethane, September, 2001. U.S. Department of Health and Human Services, Public
Health Service, Atlanta, GA. Online, www.atsdr.cdc.gov/toxpro2.html.
Barlow S.M. and Sullivan F.M. (1982) Reproductive Hazards of Industrial Chemicals : an
Evaluation of Animal and Human Data. London New York: Academic Press, pp. 310-315.
Bove, F.J. (1996) Public drinking water contamination and birthweight, prematurity, fetal deaths,
and birth defects. Toxicol. Ind. Health. 12:255-266.
Bove, F.J., M.C. Fulcomer, J.B. Klotz, J. Esmart, E. Dufficy and J. Savrin. (1995) Public
drinking water contamination and birth outcomes. Am. J. Epidemiol. 141(9):850-862.
Bowler, R.M., S. Gysens, E. Diamond, A. Booty, C. Hartney and H.A. Roels. (2003)
Neuropsychological effects of ethylene dichloride exposure. Neurotoxicology.
24(4-5):553-562.
Brzozowski, J., J. Czajka, T. Dutkiewicz et al. (1954) Work hygiene and the health condition of
workers occupied in combating the Leptinotarsa decemlineata with HCH and dichloroethane.
Med. Pr. 5:89-98. (As cited in U.S. EPA, 1984).
CalEPA (California Environmental Protection Agency). (2000) Determination of Noncancer
Chronic Reference Exposure Levels Batch 2A December 2000. Chronic Toxicity Summary
Ethylene Dichloride (1,2-Dichloroethane) CAS Registry Number: 107-06-2. Online.
http://www.oehha.ca.gov/air/chronic rels/pdf/107062.pdf.
CalEPA (California Environmental Protection Agency). (2002) Hot Spots Unit Risk and Cancer
Potency Values. Online, http://www.oehha.ca.gov/air/hot spots/pdf/TSDlookup2002.pdf.
46
1,2-Dichloroethane

-------
FINAL
10-1-2010
CalEPA (California Environmental Protection Agency). (2008a) Air Chronic Reference
Exposure Levels Adopted by OEHHA. Online, http://www.oehha.ca.gov/air/chronic_rels/
AllChrels.html.
CalEPA (California Environmental Protection Agency). (2008b) OEHHA/ARB Approved
Chronic Reference Exposure Levels and Target Organs. Online, http://www.arb.ca.gov/
toxics/healthval/chroni c.pdf.
Cetnarowicz, J. (1959) Experimental and clinical investigations into the action of dichloroethane.
Folia Med. Cracov. 1:169-192.
Cheever, K.L., J.M. Cholakis, A.M. El-Hawari et al. (1990) Ethylene dichloride: The influence
of disulfiram or ethanol on oncogenicity, metabolism, and DNA covalent binding in rats.
Fundam. Appl. Toxicol. 14:243-261.
Cheng, T.-J., M.-L. Huang, N.-C. You et al. (1999) Abnormal liver function in workers exposed
to low levels of ethylene dichloride and vinyl chloride monomer. J. Occup. Environ. Med.
41(12): 1128-1133.
Croen, L.A., G.M. Shaw, L. Sanbonmatsu et al. (1997) Maternal residential proximity to
hazardous waste sites and risk for selected congenital malformations. Epidemiology.
8:347-354.
Daniel, F.B., M. Robinson, G.R. Olson et al. (1994) Ten and ninety-day toxicity studies of
1,2-dichloroethane in Sprague-Dawley rats. Drug Chem. Toxicol. 17(4):463-477.
Dilks, L., D. Matzenbacher et al. (2005) A longitudinal study of memory impairments secondary
to ethylene dichloride exposure. Neurotoxicol. Teratol. 27(6):909-910.
Dilks, L., J. Marceaux, S. Dilks et al. (2007) The long term effects of ethylene dichloride
exposure on memory functioning. Am. J. Psychol. Res. 3(1):63—71.
Environment Canada. (1994) Canadian Environmental Protection Act Priority Substances List
Assessment Report. 1,2-Dichloroethane. Government of Canada, Environment Canada, Health
Canada.
Heppel, L.A., P.A. Neal, T.L. Perrin et al. (1946) The toxicology of 1,2-dichloroethane (ethylene
dichloride). J. Ind. Hyg. Toxicol. 28(4): 113-120.
Hofmann, H.T.H., H. Birnstiel and P. Jobst. (1971) On the inhalation toxicity of 1,1-and
1,2-dicholoroethane. Arch. Toxicol. 27:248-265.
HSDB (Hazardous Substances Data Bank). (2008) 1,2-Dichloroethane. Hazardous Substances
Data Bank. National Library of Medicine. Online, http://toxnet.nlm.nih.gov.
IARC (International Agency for Research on Cancer). (1979) Some Halogenated Hydrocarbons.
IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 20.
Lyon, France: International Agency for Research on Cancer. 609 pp.
47
1,2-Dichloroethane

-------
FINAL
10-1-2010
IARC (International Agency for Research on Cancer). (1987) Overall Evaluations of
Carcinogenicity. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans, Supplement 7. Lyon, France: International Agency for Research on Cancer. 440 pp.
IARC (International Agency for Research on Cancer). (1999) Re-evaluation of Some Organic
Chemicals, Hydrazine, and Hydrogen Peroxide. IARC Monographs on the Evaluation of
Carcinogenic Risk of Chemicals to Humans, vol. 71. Lyon, France: International Agency for
Research on Cancer. 1,589 pp.
IARC (International Agency for Research on Cancer). (2008) Search IARC Monographs.
Online. http://monoeraphs.iarc.fr/ENG/Monoeraphs/allmonos90.php.
Kozik, I.V. (1957) Problems of industrial hygiene in using dichloroethane in the aircraft
industry. Gig. Tr. Prof. Zabol. 1:31-38. (Translated from Russian).
Lane, R.W., B.L. Riddle and J.F. Borzelleca. (1982) Effects of 1,2-dichloroethane and
1,1,1-trichloroethane in drinking water on reproduction and development in mice. Toxicol.
Appl. Pharmacol. 63:409-421.
Maltoni, C., L. Valgimigli and C. Scarnato. (1980) Long-term carcinogenic bioassays of ethylene
dichloride administered by inhalation to rats and mice. Banbury Rep. 5:3-33.
Munson, A.E., V. M. Sanders, K A. Douglas et al. (1982) In vivo assessment of immunotoxicity.
Environ. Health Perspect. 43:4-52.
Nagano, K., Y. Umeda, et al. (2006) Carcinogenicity and chronic toxicity in rats and mice
exposed by inhalation to 1,2-dichloroethane for two years. J. Occup. Health. 48(6):424-36.
NCI (National Cancer Institute). (1978) Bioassay of 1,2-Dichloroethane for Possible
Carcinogenicity (CAS No. 107-06-2). Technical Report Series No 55. DHEW (NIH)
Publication No. 78-1361. Bethesda, MD: National Institute of Health. 64 pp.
NIOSH (National Institute for Occupational Safety and Health). (1976) Criteria For A
Recommended Standard. Occupational Exposure to Ethylene Dichloride (1,2-Dichloroethane).
National Institute of Occupational Safety and Health, Cincinnati OH; Public Health Service,
U.S. Department of Health, Education, and Welfare.
NIOSH (National Institute for Occupational Safety and Health). (2008) NIOSH Pocket Guide to
Chemical Hazards. Index by CASRN. Online, http://www2.cdc.gov/nioshtic-2/nioshtic2.htm.
Nouchi, T., H. Miura, M. Kanayama et al. (1984) Fatal intoxication by 1,2-dichloroethane- a
case report. Int. Arch. Occup. Environ. Health. 54:111-113.
Novakovic-Agopian, T. and R. Bowler. (2001) Attentional deficits in hazardous waste workers
following ethylene dichloride exposure. Neurotoxicology. 22(4):517-518.
48
1,2-Dichloroethane

-------
FINAL
10-1-2010
NTP (National Toxicology Program). (1991) Toxicity studies of 1,2-dichloroethane (ethylene
dichloride) (CAS No. 107-06-2) in F344/N rats, Sprague-Dawley rats, Osborne-Mendel rats, and
B6C3F1 mice (drinking water and gavage studies). NTP TOX 4., DHHS Publ. No. (NIH)
91-3123. NTIS PB91-185363.
NTP (National Toxicology Program). (2005) 11th Report on Carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Online, http://ntp-server.niehs.nih.eov/.
NTP (National Toxicology Program). (2008) Testing Status of Agents at NTP. Online.
http://ntp.niehs.nih.gov:8080/index.html?col=010stat.
OECD (Organisation for Economic Co-operation and Development Screening Information Data
Set). (2002) 1,2-Dichloroethane. SIDS Initial Assessment Report for 14th SIAM. Paris, France,
March 2002. Online. http://www.chem.unep.ch/irptc/sids/OECDSIDS/.
OECD (Organisation for Economic Co-operation and Development Screening Information Data
Set). (2008) Test guideline 453: Combined chronic toxicity/carcinogenicity studies. Online.
http://www.oecd.Org/document/55/0.3343.en 2649 34377 2349687 1 1 1 LOO.html.
OSHA (Occupational Safety and Health Administration). (2008) OSHA Standard 1915.1000 for
Air Contaminants. Part Z, Toxic and Hazardous Substances. Online, http://www.osha.gov/
pis/oshaweb/owadisp.show docunient?p table STAN'DARDS&p id=9992.
Payan, J.P., A.M. Saillenfait, P. Bonnet, J.P. Fabry, I. Langonne and J.P. Sabate. (1995)
Assessment of the developmental toxicity and placental transfer of 1,2-dichloroethane in rats.
Fundam. Appl. Toxicol. 28(2): 187-198.
Rao, K.S., J.S. Murray, M.M. Deacon, J.A. John, L.L. Calhoun and J.T. Young. (1980)
Teratogenicity and reproduction studies in animals inhaling ethylene dichloride. Banbury Rep.
5:149-166.
Rosenbaum, N.D. (1947) Ethylene dichloride as an industrial poison. Gig. Sanit. 12:17-21.
(As cited in U.S. EPA, 1985a,b).
Sherwood, R.L., W. O'Shea, P.T. Thomas, et al. (1987) Effects of inhalation of ethylene
dichloride on pulmonary defenses of mice and rats. Toxicol. Appl. Pharmacol. 91: 491-496.
Spencer, H.C., V.K. Rowe, E.M. Adams et al. (1951) Vapor toxicity of ethylene dichloride
determined by experiments on laboratory animals. Arch. Ind. Hyg. Occup. Med. 4:482-493.
Spreafico, F., E. Zuccato, F. Marcucci et al. (1980) Pharmacokinetics of ethylene dichloride in
rats treated by different routes and its long term inhalatory toxicity. In: Banbury Report 5.
Ethylene Dichloride: A Potential Health Risk? B. Ames, P. Infante and R. Reitz., Ed. Cold
Spring Harbor, NY: Cold Spring Harbor Laboratory, pp. 107-129.
Sweeney, L.M., S.A. Saghir et al. (2008) Physiologically based pharmacokinetic model
development and simulations for ethylene dichloride (1,2-dichloroethane) in rats. Regul.
Toxicol. Pharmacol. 51(3):311—23.
49
1,2-Dichloroethane

-------
FINAL
10-1-2010
U.S. EPA. (1984) Health Effects Assessment (HEA) for 1,2-Dichloroethane (Ethylene
Dichloride). Prepared by the Office of Health and Environmental Assessment Office, Research
Triangle Park, NC for the Office of Air Quality Planning and Standards, Research Triangle Park,
NC.
U.S. EPA. (1985a) Health and Environmental Effects Profile (HEEP) for Dichloroethanes.
Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of
Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. (1985b) Health Assessment Document (HAD) for 1,2-Dichloroethane. Prepared by
the Environmental Criteria and Assessment Office, Research Triangle Park, North Carolina.
U.S. EPA. (1985c) Quantification of Toxicological Effects of 1,2-Dichloroethane [Includes
Health Effects Assessment (HEA) for 1,2-Dichloroethane], Prepared by the Office of Drinking
Water, Criteria and Standards Division, Washington, DC. NTIS PB86-118080.
U.S. EPA. (1987) 1,2-Dichloroethane Health Advisory. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Drinking Water, Washington, DC.
U.S. EPA. (1991) Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. (1994a) Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. (1994b) Methods for Derivation of Inhalation Reference Concentrations (RfCs) and
Application of Inhalation Dosimetry. U.S. Environmental Protection Agency, Office of Research
and Development, Office of Health and Environmental Assessment, Washington, DC.
EPA/600/8-90/066F.
U.S. EPA. (1997) Health Effects Assessment Summary Tables (HEAST). FY-1997 Update.
Prepared by the Office of Research and Development, National Center for Environmental
Assessment, Cincinnati, OH, for the Office of Emergency and Remedial Response, Washington,
DC. July. EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA. (2000) Benchmark Dose Technical Guidance Document. External Review Draft.
Risk Assessment Forum. EPA/630/R-00/001. October.
U.S. EPA. (2006) Drinking Water Standards and Health Advisories. Office of Water,
Washington, DC. Summer 2006. Online, http://www.epa.gov/waterscience/criteria/
drinking/dwstandards.pdf.
U.S. EPA. (2008) Integrated Risk Information System (IRIS). Online. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http ://www. epa. gov/iris/.
Van Esch, G.J., R. Kroes, M.J. van Logtenen et al. (1977) Ninety-day toxicity study with
1,2-dichloroethane (DCE) in rats. Utrecht: Rijks Instituut voor de Volksgezondheid.
50
1,2-Dichloroethane

-------
FINAL
10-1-2010
Vozovaya, M.A. (1974) [Development of posterity of two generations obtained from females
subjected to the action of dichloroethane]. Gig. Sanit. 39:25-28. (Article in Russian; as cited
by Barlow and Sullivan, 1982).
Vozovaya, M. (1977) [The effect of dichloroethane on the sexual cycle and embryogenesis of
experimental animals], Akush. Ginekol. 2:57-59. (As cited by WHO, 1995).
WHO (World Health Organization). (1987) International Programme on Chemical Safety.
Environmental Health Criteria 62: 1,2-Dichloroethane. Online, http://www.who.int/
ipcs/publications/ehc/ehc alphabetical/en/index.html.
WHO (World Health Organization). (1991) IPCS International Programme on Chemical Safety.
Health and Safety Guide No. 55: 1,2-Dichloroethane. Online, http://www.who.int/ipcs/
publications/ehc/ehc alphabetical/en/index.html.
WHO (World Health Organization). (1995) Programme on Chemical Safety. Environmental
Health Criteria 176: 1,2-Dichloroethane (2nd ed.). Online, http://www.who.int/ipcs/
publications/ehc/ehc alphabetical/en/index.html.
Wolford, S.T., R.A. Schroer, F.X. Gohs et al. (1986) Reference range data base for serum
chemistry and hematology values in laboratory animals. J. Toxicol. Environ. Health.
18:161-188.
Zhao, S.F., X.C. Zhang and Y.S. Bao. (1984) [The study on the effects of 1,2-dichloroethane on
the development of mice], Chinese J. Ind. Hyg. Occup. Dis. 2:343-346. (Article in Chinese
with English translation).
Zhao, S.F., X.C. Zhang and Y.S. Bao. (1989) The study on the effects of 1,2-dichloroethane on
the development on reproductive function. Chinese J. Prevent. Med. 23:199-202.
Zhao, S.F., X.C. Zhang, L.F. Zhang, et al. (1997) The evaluation of developmental toxicity of
chemicals exposed occupationally using whole embryo culture. Int. J. Dev. Biol. 41:275-282.
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APPENDIX A. DETAILS OF BENCHMARK DOSE MODELING
FOR SUBCHRONIC RfD
MODEL FITTING PROCEDURE FOR CONTINUOUS DATA
The model fitting procedure for continuous data is as follows. The simplest model
(linear) is first applied to the data while assuming constant variance. If the data are consistent
with the assumption of constant variance (p> 0.1), then the fit of the linear model to the means is
evaluated, and the polynomial, power, and Hill models are fit to the data while assuming
constant variance. Adequate model fit is judged by three criteria: goodness-of-fit />value
(p > 0.1), visual inspection of the dose-response curve, and scaled residual at the data point
(except the control) closest to the predefined benchmark response (BMR). Among all the
models providing adequate fit to the data, the lowest BMDL is selected as the point of departure
(POD) when the difference between the BMDLs estimated from these models are more than
3-fold; otherwise, the BMDL from the model with the lowest Akaike Information Criterion
(AIC) is chosen. If the test for constant variance is negative, the linear model is run again while
applying the power model integrated into the Benchmark Dose Software (BMDS) to account for
nonhomogenous variance. If the nonhomogenous variance model provides an adequate fit
(p> 0.1) to the variance data, then the polynomial, power, and Hill models are fit to the data and
evaluated while the variance model is applied. Model fit and POD selection proceed as
described earlier. If the test for constant variance is negative and the nonhomogenous variance
model does not provide an adequate fit to the variance data, then the data set is considered
unsuitable for modeling.
MODEL FITTING RESULTS FOR ABSOLUTE AND RELATIVE KIDNEY WEIGHT
IN FEMALE F344/N RATS EXPOSED VIA DRINKING WATER (NTP, 1991)
Data on female rat absolute and relative kidney weights were modeled according to the
procedure outlined above using BMDS version 2.0 with default parameter restrictions. In the
absence of data regarding a biologically meaningful change in kidney weight, the BMR was
chosen to be 1 standard deviation (SD) from the control mean, as recommended by EPA (2000).
Tables A-l and A-2 show the modeling results for absolute and relative kidney weights
(respectively). The constant variance model provided adequate fit to the variance data for
absolute kidney weight. However, none of the available models provided adequate fit to the
means for this endpoint, even when higher dose groups were sequentially dropped from the
analysis. For the relative kidney weight data, neither the constant nor nonconstant variance
models provided adequate fit to the variance data, even when higher dose groups were
sequentially dropped from the analysis. As a result, the data sets for absolute and relative kidney
weights are considered unsuitable for modeling.
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Table A-l. Model Predictions for Absolute Kidney Weight in Female F344/N Rats"
Model
Variance
7?-Valueb
Means
7?-Valueb
AIC
bmd1sd
(mg/kg-day)
BMDLisd
(mg/kg-day)
All dose groups
Linear (constant variance)0
0.3842
<0.0001
572.805
266.40
202.02
Polynomial, 5-degree
(constant variance)0
0.3842
<0.0001
572.805
266.40
202.02
Polynomial, 4-degree
(constant variance)0
0.3842
<0.0001
572.805
266.40
202.02
Polynomial, 3-degree
(constant variance)0
0.3842
<0.0001
572.805
266.40
202.02
Polynomial, 2-degree
(constant variance)0
0.3842
<0.0001
572.805
266.40
202.02
Power (constant variance)d
0.3842
<0.0001
572.805
266.40
202.02
Hill (constant variance)d
Failed




Without high-dose group
Linear (constant variance)0
0.3291
0.00014
477.788
296.36
217.62
Polynomial, 4-degree
(constant variance)0
0.3291
0.00014
477.788
296.36
217.62
Polynomial, 3-degree
(constant variance)0
0.3291
0.00014
477.788
296.36
217.62
Polynomial, 2-degree
(constant variance)0
0.3291
0.00014
477.788
296.36
217.62
Power (constant variance)d
0.3291
0.00014
477.788
296.36
217.62
Hill (constant variance)d
Failed




Without 2 high-dose groups
Linear (constant variance)0
0.2923
0.0015
383.358
113.21
76.46
Polynomial, 3-degree
(constant variance)0
0.2923
0.0015
383.358
113.21
76.46
Polynomial, 2-degree
(constant variance)0
0.2923
0.0015
383.358
113.21
76.46
Power (constant variance)d
0.2923
0.0015
383.358
0.2923
0.0015
Hill (constant variance)d
Failed




Without 3 high-dose groups
Linear (constant variance)0
0.2247
0.000817
293.385
117.55
77.30
aNTP (1991)
bValues <0.10 fail to meet conventional goodness-of-fit criteria
Coefficients restricted to be positive
dPower restricted to >1
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Table A-2. Model Predictions for Relative Kidney Weight in Female F344/N Rats"
Model
Variance
7?-Valueb
Means
7?-Valueb
AIC
bmd1sd
(mg/kg-day)
BMDLisd
(mg/kg-day)
All dose groups
Linear (constant variance)0
0.0002374
0.06744
-64.750
173.34
140.05
Linear (nonconstant variance)0
0.007694
0.02877
-70.617
272.28
193.84
Without high-dose group
Linear (constant variance)0
0.01131
0.6615
-50.864
119.00
91.54
Linear (nonconstant variance)0
0.01146
0.6494
-50.754
139.93
100.38
Without 2 high-dose groups
Linear (constant variance)0
0.008005
0.5135
-35.777
136.28
87.08
Linear (nonconstant variance)0
0.04308
0.04865
-34.600
172.27
91.72
Without 3 high-dose groups
Linear (constant variance)0
0.02777
0.6331
-20.204
98.32
56.55
Linear (nonconstant variance)0
0.00995
0.8735
-18.929
83.97
46.00
aNTP (1991)
bValues <0.10 fail to meet conventional goodness-of-fit criteria
Coefficients restricted to be positive
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APPENDIX B. DERIVATION OF CHRONIC RfD SCREENING VALUE
CHRONIC p-RfD
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for 1,2-dicholoroethane (1,2-DCA). However, information is available for this
chemical which, although insufficient to support derivation of a provisional toxicity value, under
current guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health
Risk Technical Support Center summarizes available information in an Appendix and develops a
"screening value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
Superfund Health Risk Technical Support Center.
Two chronic oral studies of 1,2-DCA were located in the literature searches:
Alumot et al. (1976) and National Cancer Institute [NCI] (1978). Poor reporting, limitations in
the toxicological evaluations, and uncertainty in the dose estimates precluded determination of
reliable effect levels for Alumot et al. (1976). In the gavage study conducted by NCI (1978),
lowest-observed-adverse-effect levels (LOAELs) of 34 and 139 mg/kg-day were identified in
rats and mice for clinical signs and an increased incidence of chronic murine pneumonia
(respectively). The quality of the rat study was limited by poor survival at the high dose and the
use of a variable dosing regimen. Further, the clinical signs observed in rats were not seen in any
of the subchronic studies of various rat strains exposed via gavage or drinking water to much
higher doses.
To derive the chronic p-RfD in the absence of suitable chronic data, the point of
departure (POD) from the subchronic p-RfD is used. Thus, the LOAEL of 58 mg/kg-day for a
>10% increase in absolute kidney weights in female F344/N rats that was used as the POD for
the subchronic p-RfD was also used as the POD for the screening-level chronic p-RfD.
A provisional screening chronic RfD for 1,2-DCA was derived by applying an
uncertainty factor (UF) of 10,000 to the subchronic rat LOAEL of 58 mg/kg-day as follows:
Screening Chronic p-RfD = LOAEL UF
= 58 mg/kg-day ^ 10,000
= 0.006 or 6 x 10 3 mg/kg-day
A calculated composite UF of 30,000 is composed of the UFs shown below. Assigning
this screening chronic p-RfD to an appendix emphasizes the high uncertainty associated with this
p-RfD derivation. Further, a composite UF of 30,000 is unrealistic given that there is evidence
that responses to chronic exposure are of similar magnitude to subchronic responses (see
discussion of UFs below). Therefore, a maximum UF of 10,000 is used to derive the screening
chronic p-RfD.
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UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating susceptible human responses are
insufficient.
UFa: A factor of 10 is applied for animal-to-human extrapolation because data for
evaluating relative interspecies sensitivity are insufficient.
UFd: The database for oral 1,2-DCA includes subchronic gavage studies in rats
(Van Esch et al., 1977; Daniel et al., 1994; National Toxicology Program [NTP],
1991), subchronic drinking water studies in rats and mice (NTP, 1991), a
subchronic immunotoxicity study in mice (Munson et al., 1982), chronic gavage
studies in rats and mice (NCI, 1978), a developmental toxicity study in rats
(Payan et al., 1995), and a multigeneration reproductive toxicity study in mice
(Lane et al., 1982). Despite the relatively complete database, a factor of 3 (i.e.,
10°5) is applied for database inadequacies. Human case reports and limited
epidemiology (reviewed by Agency for Toxic Substances and Disease Registry
[ATSDR], 2001 and World Health Organization [WHO], 1995) have suggested
that 1,2-DCA may result in neurotoxicity, but data for evaluating potential
neurotoxicity are inadequate.
UFl: A factor of 10 is applied for using a LOAEL as the POD.
UFs: A factor of 10 is applied for using data from a subchronic study to assess
potential effects from chronic exposure. Data for evaluating response after
chronic exposure are available, though limited. The chronic rat study identified a
LOAEL of 34 mg/kg-day (NCI, 1978) for clinical signs of toxicity. This LOAEL
is of similar magnitude to that of the subchronic study used to derive the p-RfD,
however, the available chronic data were limited and of poor quality.
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APPENDIX C. DETAILS OF BENCHMARK DOSE MODELING
FOR CHRONIC RfC
MODEL FITTING PROCEDURE FOR CONTINUOUS DATA
The model fitting procedure for continuous data is as follows. The simplest model
(linear) is first applied to the data while assuming constant variance. If the data are consistent
with the assumption of constant variance (p> 0.1), then the polynomial, power, and Hill models
are fit to the data while assuming constant variance. Adequate model fit is judged by three
criteria: goodness-of-fit p-walue (p > 0.1), visual inspection of the dose-response curve, and
scaled residual at the data point (except the control) closest to the predefined benchmark
response (BMR). Among all the models providing adequate fit to the data, the lowest BMDL is
selected as the point of departure (POD) when the difference between the BMDLs estimated
from these models are more than 3-fold; otherwise, the BMDL from the model with the lowest
Akaike Information Criterion (AIC) is chosen. If the test for constant variance is negative, the
linear model is run again while applying the power model integrated into the Benchmark Dose
Software (BMDS) to account for nonhomogenous variance. If the nonhomogenous variance
model provides an adequate fit (p> 0.1) to the variance data, the polynomial, power, and Hill
models are fit to the data and evaluated while the variance model is applied. Model fit and POD
selection proceed as described earlier. If the test for constant variance is negative and the
nonhomogenous variance model does not provide an adequate fit to the variance data, then the
data set is considered unsuitable for modeling.
MODEL FITTING RESULTS FOR SERUM ALT IN MALE RATS (Spreafico et al., 1980)
Data on serum ALT levels in male rats exposed for 1 year beginning at 14 months of age
(see Table 7) were modeled according to the procedure outlined above using BMDS version 2.0
with default parameter restrictions. Nominal exposure concentrations were used in the modeling.
In the absence of data regarding a biologically meaningful change in ALT, the BMR was chosen
to be 1 standard deviation (SD) from the control mean, as recommended by EPA (2000).
Table C-l shows the modeling results. While the nonconstant variance model in the software
provided adequate fit to the variance data, none of the available models provided adequate fit to
the means for this endpoint, even when higher dose groups were sequentially dropped from the
analysis.
MODEL FITTING RESULTS FOR SERUM GGT IN FEMALE RATS (Spreafico et al.,
1980)
Data on serum GGT levels in female rats exposed for 1 year beginning at 14 months of
age (see Table 7) were modeled according to the procedure outlined above using BMDS
version 2.0 with default parameter restrictions. Nominal exposure concentrations were used in
the modeling. In the absence of data regarding a biologically meaningful change in GGT, the
BMR was chosen to be 1 SD from the control mean, as recommended by EPA (2000).
Table C-2 shows the modeling results. Using the full data set, neither the constant nor
nonconstant variance models in the software provided adequate fit to the variance data. When
the high-dose group was dropped, the constant variance model provided adequate fit to the
variance data, and the polynomial (2- and 3-degree models) and power models provided
adequate fit to the means data. The BMC values from the models that fit were within a factor of
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3, so the model with the lowest AIC (3-degree polynomial) was chosen. Figure C-l shows the fit
of the 3-degree polynomial to the data on serum GGT in female rats. The BMCisd and
"3
BMCLisd associated with this model are 142 and 130 mg/m , respectively.
Table C-l. Model Predictions for Serum ALT in Male Sprague-Dawley Rats3
Model
Variance
p-V alueb
Means
p-V alueb
AIC
bmc1sd
(mg/m3)
bmcl1sd
(mg/m3)
All dose groups
Linear (constant variance)0
<0.0001
<0.0001
306.902
114.26
93.99
Linear (nonconstant variance)0
0.6935
<0.0001
322.201
163.18
4.80
Polynomial, 2-degree
(nonconstant variance)0
0.6935
<0.0001
379.201
Failed
Failed
Polynomial, 3-degree
(nonconstant variance)0
0.6935
<0.0001
346.199
387.55
4.01
Polynomial, 4-degree
(nonconstant variance)0
0.6935
<0.0001
346.283
386.90
4.08
Power (nonconstant variance)d
0.6935
<0.0001
267.87
16.68
12.18
Hill (constant variance)d
Failed




Without high-dose group
Linear (constant variance)0
0.000116
<0.0001
186.408
21.45
17.69
Linear (nonconstant variance)0
0.4871
<0.0001
186.203
30.23
8.79
Polynomial, 2-degree
(nonconstant variance)0
0.4871
<0.0001
162.298
51.19
33.65
Polynomial, 3-degree
(nonconstant variance)0
0.4871
<0.0001
161.394
78.52
37.53
Power (constant variance)d
0.4871
<0.0001
160.606
168.79
57.11
Hill (constant variance)d
Failed




Without 2 high-dose groups
Linear (constant variance)0
0.3647
<0.0001
108.50
539.70
47.08
aSpreafico et al. (1980)
bValues <0.10 fail to meet conventional goodness-of-fit criteria
Coefficients restricted to be positive
dPower restricted to >1
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Table C-2. Model Predictions for Serum GGT in Female Sprague-Dawley Rats3
Model
Variance
p-V alueb
Means
p-V alueb
AIC
bmc1sd
(mg/m3)
bmcl1sd
(mg/m3)
All dose groups
Linear (constant variance)0
0.08897
<0.0001
-33.496
213.82
165.79
Linear (nonconstant variance)0
0.04454
<0.0001
-31.502
219.18
124.02
Without high-dose group
Linear (constant variance)0
0.1736
0.03846
-34.377
72.24
54.87
Polynomial, 2-degree
(constant variance)0
0.1736
0.2688
-38.266
119.50
104.82
Polynomial, 3-degree
(constant variance)0
0.1736
0.333
-38.694
142.50
130.63
Power (constant variance)d
0.1736
0.1454
-36.773
187.03
81.52
Hill (constant variance)d
Failed




aSpreafico et al. (1980)
bValues <0.10 fail to meet conventional goodness-of-fit criteria
Coefficients restricted to be positive
dPower restricted to >1
Polynomial Model wth 0.95 Confidence Level
2
1.8
1.6
1.4
I
8. 1.2
CO
0
a.
ro	1
0
0.8
0.6
0.4
Polynomial
BMDL
0	50	100	150	200
Dose
13:30 12/31 2008
Figure C-l. Fit of Polynomial Model (3-degree) to Data on Serum GGT in Female Rats
Exposed to 1,2-DCA for 1 year (Spreafico et al., 1980)
BMC and BMCL indicated are associated with a change of 1 SD from the control and are in units of mg/m3.
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