United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-12/007F
Final
11-26-2012
Provisional Peer-Reviewed Toxicity Values for
2-Chloroethanol
(CASRN 107-07-3)
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
Chris Cubbison, PhD
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Geniece M. Lehmann, PhD
National Center for Environmental Assessment, Research Triangle Park, NC
Susan Makris, MS
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).
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	iv
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVs	1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)	3
HUMAN STUDIES	7
Oral Exposures	7
Inhalation Exposures	7
ANIMAL STUDIES	8
Oral Exposure	8
Subchronic Studies	8
Chronic Studies	10
Developmental and Reproduction Studies	10
Reproductive Studies	11
Carcinogenic Studies	11
INHALATION EXPOSURE	11
OTHER STUDIES	11
SHORT-TERM TOXICITY STUDIES	11
Human Studies	11
Animal Studies	14
Studies Involving Exposure Routes Other Than Oral or Inhalation	14
Genotoxicity Studies	16
Metabolism and Toxicokinetic Studies	17
Mode-of-Action and Mechanistic Studies	20
DERIVATION 01 PROVISIONAL VALUES	31
DERIVATION OF ORAL REFERENCE DOSE	31
Derivation of Subchronic and Chronic Provisional RfDs	31
Derivation of Chronic Provisional RfD (Chronic p-RfD)	33
DERIVATION OF INHALATION REFERENCE CONCENTRATION	34
Derivation of Subchronic or Chronic Provisional RfCs (Subchronic or Chronic
p-RfCs)	34
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR	34
MODE OF ACTION	35
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	35
Derivation of Provisional Oral Slope Factor (p-OSF)	35
Derivation of Provisional Inhalation Unit Risk (p-IUR)	35
APPENDIX A. DERIVATION OF SCREENING VALUES	36
APPENDIX B. DATA TABLES	37
APPENDIX C. BMD MODELING OUTPUTS FOR 2-CHLOROETHANOL	38
APPENDIX D. REFERENCES	39
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMCL
benchmark concentration lower bound 95% confidence interval
BMD
benchmark dose
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
POD
point of departure
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
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
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
2-CHLOROETHANOL (CASRN 107-07-3)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (http://www.epa.eov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVs
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
2-Chloroethanol is also known as ethylene chlorohydrin and by 42 other synonyms. It
occurs as a colorless, glycerine-like liquid, described as having a sweet, pleasant, faintly
ether-like odor (HSDB, 2005). It is an intermediate in the synthesis of ethylene oxide and
ethylene glycol and in the production of indigo, dichloroethyl formal (an intermediate for the
production of polysulfide elastomers), and thiodiethylene glycol (used in textile printing). It is
also an industrial solvent, a preemergent plant growth stimulator, and an extractant for textile
printing dyes. The principal use of 2-chloroethanol was formerly in the production of ethylene
oxide. Before 1972, as much as one billion pounds of 2-chloroethanol was used for this purpose
(NTP, 1985a,b,c). The empirical formula for 2-chloroethanol is C2H5CIO, and the molecular
structure of 2-choloroethanol is presented in Figure 1. Some physicochemical properties of
2-chloroethanol are provided in Table 1. In this document, "statistically significant" denotes a
/>value of <0.05, unless otherwise noted. The most common routes of exposure to toxic levels
of 2-chloroethanol are expected to be dermally or by inhalation (NTP, 1985a,b,c).
2-Chloroethanol is quite stable and persistent and has been found in foods, medical supplies, and
medical devices (Andrews et al., 1983).
.OH
CI ^
Figure 1. 2-Chloroethanol Structure
Table 1. Physicochemical Properties Table for 2-Chloroethanol (CASRN 107-07-3)a
Property (unit)
Value
Boiling point (°C)
128-130
Melting point (°C)
-67.5
Density (g/cm3 at 20°C)
1.197
Vapor pressure (mm Hg at 20°C)
4.9
Solubility in water (g/L at 25°C)
infinitely
Relative vapor density (air =1)
2.78
Molecular weight (g/mol)
80.51
Octanol/water partition coefficient (log Kow, unitless)
-0.06
aValues were obtained from HSDB (2005).
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No RfD, RfC, or cancer assessment for 2-chloroethanol is included on EPA's Integrated
Risk Information System (IRIS) (U.S. EPA, 2012b) or on the Drinking Water Standards and
Health Advisories List (U.S. EPA, 2006). No RfD or RfC values were reported in the Health
Effects Assessment Summary Tables (HEAST) (U.S. EPA, 2012a). The Chemical Assessments
and Related Activities (CARA) list (U.S. EPA, 1994) does not include a Health and
Environmental Effects Profile (HEEP) for 2-chloroethanol. The toxicity of 2-chloroethanol has
not been reviewed by the Agency for Toxic Substances and Disease Registry (ATSDR, 2008) or
the World Health Organization (WHO, 2010). The California Protection Agency (CalEPA,
2008) has not derived toxicity values for exposure to 2-chloroethanol.
Regulatory standards are reported in the Hazardous Substance Data Bank (HSDB, 2005)
for 2-chloroethanol (CASRN 107-07-3). The OSHA Permissible Exposure Limit (PEL) for
general, construction, and maritime industries is a 5-ppm (16 mg/m3) 8-hour time weighted
average (OSHA, 2010). The American Conference of Governmental Industrial Hygienists
(ACGIH) has set a Ceiling Threshold Limit Value (TLV-C) to skin of 1 ppm (3.3 mg/m3)
(ACGIH, 2010, 2001). The NIOSH recommended exposure limit is a ceiling value of 1 ppm
(3.3 mg/m3) to skin (NIOSH, 2010). The NIOSH Immediately Dangerous to Life or Health
Concentration (IDLH) is 7 ppm. The Chemical Assessments and Related Activities (CARA) list
(U.S. EPA, 1994) does not include any health and environmental assessment documents for
2-chloroethanol.
Literature searches were conducted on sources published from 1900 through
November 2011 for studies relevant to the derivation of provisional toxicity values for
2-chloroethanol (CASRN 107-07-3). Searches were conducted using EPA's Health and
Environmental Research Online (HERO) database of scientific literature. HERO searches the
following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane Library;
DOE: Energy Information Administration, Information Bridge, and Energy Citations Database;
EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing Office;
Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics
& Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through the National
Service Center for Environmental Publications [NSCEP] and National Environmental
Publications Internet Site [NEPIS] database); PubMed: MEDLINE and CANCERLIT databases;
SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET (Toxicology Data Network):
ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP,
GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search,
NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI; and TSCATS; Virtual Health Library; Web
of Science (searches Current Content database among others); World Health Organization; and
Worldwide Science. The following databases outside of HERO were searched for health
information: ACGIH, ATSDR, CalEPA, EPA IRIS, EPA HEAST, EPA HEEP, EPA OW, EPA
TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 2 provides information for all of the potentially relevant studies. Entries for the
principal studies are bolded.
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Table 2. Summary of Potentially Relevant Data for 2-Chloroethanol (CASRN 107-07-3)
Category
Number of Male/Female,
Strain Species, Study
Type, Study Duration
Dosimetry"
Critical effects at LOAEL
NOAEL"
BMDL/
BMCLa
LOAEL3
Reference
(Comments)
Notesb
Human
1. Oral (mg/kg-day)a
Subchronic
None
Chronic
None
Developmental
None
Reproductive
None
Cancer
None
2. Inhalation (mg/m3)a
Subchronic
None
Chronic
None
Developmental
None
Reproductive
None
Cancer
2174 males, occupational
epidemiological study,
mean duration and
follow-up not reported
Not known
Increased risk for leukemia and
pancreatic cancer with
increasing time on the job
Not
applicable
Not run
Not
applicable
Greenberg et al.
(1990)
PR
Cancer
278 males, occupational
epidemiological study,
mean duration 5.9 years,
mean follow-up 36.5 years
Not known
Increased risk for total cancer,
pancreatic cancer, all lymphatic
and hematopoietic cancers, and
leukemia with increasing time
on the job
Not
applicable
Not run
Not
applicable
Benson and Teta
(1993)
PR
Cancer
1361 males, occupational
epidemiological study,
duration 0.1-35 years,
follow-up 8-44 years
Not known
No increased risk for
pancreatic, lymphopoietic, and
hematopoietic cancers
Not
applicable
Not run
Not
applicable
Olsen et al.
(1997)
PR
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Table 2. Summary of Potentially Relevant Data for 2-Chloroethanol (CASRN 107-07-3)
Category
Number of Male/Female,
Strain Species, Study
Type, Study Duration
Dosimetry"
Critical effects at LOAEL
NOAEL"
BMDL/
BMCLa
LOAEL3
Reference
(Comments)
Notesb
Animal
1. Oral (mg/kg-day)a
Subchronic
25/25 FDRL rat, 6 weeks
administered daily in diet
followed by 12 weeks
daily gavage
0,30, 45, or 67.5
Increased moribundity,
decreased body weight, and
death (17/25 males,
19/25 females) at the high
dose
45
Not run
67.5
Oser et al.
(1975a)
PS, PR
Subchronic
5 male, strain not specified
rat, daily in diet, 220 days
0, 9, 18, 36, 72, 108,
144, or 216,
(calculated by
U.S. EPA, 1988)
Decreased body-weight gain
72
Not run
108
Ambrose (1950)
PR
Subchronic
4/4 beagle dog,
administered daily in diet,
15 weeks
Estimated at 13.3,
18.3, and 18.4 in
males and 16.9,
19.3, and 20.3 in
females
Severe emesis prevented
consistent dose retention in all
but the lowest doses in males
and females
13.3/16.9 in
males/
females
Not run
Not
identified
Oser et al.
(1975b); no
adverse effects
observed in any
dose group, but
severe emesis
complicates
dosimetry
PR
Subchronic
2/2 Rhesus monkey,
administered daily in diet,
12 weeks
0, 30, 45, or
62.5 mg/kg-day
None observed
62.5
Not run
Not
identified
Oser et al.
(1975c)
PR
Chronic
None
Developmental
12 female CD-I mouse,
gavage, administered on
GDs 6-16
0, 50, 100, or 150;
additional control
group treated with
86.5 ethanol
Dams: decreased body-weight
gain
Fetuses: decreased body weight
50
50
Not run
100
100
Courtney et al.
(1982a)
PR
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Table 2. Summary of Potentially Relevant Data for 2-Chloroethanol (CASRN 107-07-3)
Category
Number of Male/Female,
Strain Species, Study
Type, Study Duration
Dosimetry"
Critical effects at LOAEL
NOAEL3
BMDL/
BMCLa
LOAEL3
Reference
(Comments)
Notesb
Developmental
Dose groups included 16,
3,3,4, and 13 female
CD-I mice, drinking water,
administered on GDs 6-16
0, 16, 43,77, or 227
Dams: none observed
Fetuses: none observed
227
227
Not run
Not
identified
Courtney et al.
(1982b)
PR
Reproductive
None
Carcinogenic
None
2. Inhalation (mg/m3)a
Subchronic
None
Chronic
None
Developmental
None
Reproductive
None
Carcinogenic
None
dosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-day) for oral noncancer effects. All long-term exposure
values (4 weeks and longer) are converted from a discontinuous to a continuous (weekly) exposure. Values from animal developmental studies are not adjusted to a
continuous exposure.
bPS = principal study, NPR = not peer reviewed, PR = peer reviewed.
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HUMAN STUDIES
Oral Exposures
No oral studies on the subchronic, chronic, developmental, or reproductive toxicity or on
the carcinogenicity of 2-chloroethanol in humans were identified.
Inhalation Exposures
No inhalation studies were found on the subchronic, chronic, developmental, or
reproductive toxicity of 2-chloroethanol in humans. The carcinogenic potential of
2-chloroethanol was evaluated in three epidemiological studies (Greenberg et al., 1990; Benson
and Teta, 1993; Olsen et al., 1997). None of the three studies determined exposure levels of
2-chloroethanol. Further, the studies do not conclusively identify the causative agent, thus
precluding their use in a quantitative assessment.
Greenberg et al. (1990) performed a retrospective cohort study examining mortality in
2174 men, potentially exposed to 2-chloroethanol at two chemical production plants between
1940 and 1978. These workers had duties in a department that used or produced ethylene oxide,
a known alkylating agent that is genotoxic and carcinogenic in rats and mice. The study cohort
was drawn from a pool of 29,139 male workers who had ever been employed at either of the two
production facilities and an associated technical center during the same period. There were no
statistically significant increases in deaths due to any cause; however, 7 deaths were attributed to
leukemia with 3.0 deaths expected, and 7 deaths were attributed to pancreatic cancer with
4.1 deaths expected. Investigations revealed that four of the seven leukemia victims and six of
the seven pancreatic cancer victims had worked in the "chlorohydrin department," an area that
produced ethylene chlorohydrin (2-chloroethanol) and/or propylene chlorohydrin. Further, the
relative risk of death from these diseases was "strongly related to duration of assignment to that
department." Potential exposure to ethylene oxide in this department was low, suggesting an
association between exposure to ethylene chlorohydrin and/or propylene chlorohydrin and
increased death due to leukemia and pancreatic cancer.
Benson and Teta (1993) subsequently performed a 10-year update on 278 men who had
worked in the "chlorohydrin unit" to verify the increases in mortality due to leukemia and
pancreatic cancer observed by Greenberg et al. (1990). Standardized mortality ratios (SMRs; the
relative measure of the difference in risk between exposed and unexposed populations in a cohort
study) were calculated, and duration-response trends were assessed for this group. Two
additional cases of pancreatic cancer were noted, along with cases of non-Hodgkin's lymphoma
and multiple myeloma. The authors concluded that "pronounced increases in risk were seen for
total cancer, pancreatic cancer, all lymphatic and hematopoietic cancers, and leukemia with
increasing durations of assignment to the "chlorohydrin unit." However, there were insufficient
data to conclusively identify the causative agent(s).
Olsen et al. (1997) performed another epidemiological study on a cohort of 1361 men
who worked at chemical manufacturing facilities at different locations than in the previous two
studies to determine whether a similar increased risk in mortality from pancreatic,
lymphopoietic, and hematopoietic cancers occurred. The subjects were exposed during their
employment to ethylene chlorohydrin and propylene chlorohydrin. Calculation of the SMR did
not indicate an increased risk of the previously reported cancers; however, the authors did
conclude that "an additional five to ten years of follow-up of the cohort are necessary to ensure
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comparable latency periods" with the previous studies. No follow-up studies were identified in
the literature search for this assessment.
In summary, these epidemiological studies were not able to determine a causative agent,
and there are no conclusive data to support that 2-chloroethanol is carcinogenic in humans at this
time.
ANIMAL STUDIES
Oral Exposure
The effects of oral exposure of animals to 2-chloroethanol have been evaluated in
subchronic (Oser et al., 1975a,b,c; Ambrose, 1950) and developmental (Courtney et al., 1982a,b)
studies. Oser et al. (1975) is a journal article containing studies performed on three different
species (i.e., rat, dog, and monkey). To differentiate between the studies, the designation of
Oser et al. (1975a) is used for the rat study, Oser et al. (1975b) is used for the dog study, and
Oser et al. (1975c) is used for the monkey study. Courtney et al. (1982a,b) is a journal article
containing the results of studies performed using two routes of exposure; Courtney et al. (1982a)
is used for the gavage study, and Courtney et al. (1982b) is used for the drinking water study.
Subchronic Studies
The study by Oser et al. (1975a) is selected as the principal study for deriving the
subchronic and chronic p-RfDs. In a peer-reviewed study, Oser et al. (1975a) administered
2-chloroethanol (purity not provided) in the diet to 25 FDRL rats/sex/dose group at
concentrations intended to provide 0, 30, 45, or 67.5 mg/kg-day daily for 6 weeks. After
6 weeks, the method of administration was changed to gavage due to a lack of stability of the
compound in the diet. At this point, body-weight gains were similar in all groups and in both
sexes, and no differences were noted in the clinical signs. Thereafter, the rats were fasted
overnight, allowed a 1-hour feeding period, and dosed by daily gavage for an additional
12 weeks (10-mL/kg dose volume) with freshly prepared aqueous solutions at 0, 30, 45, or
67.5 mg/kg-day. Food (Purina Laboratory Chow) remained available until the end of each work
day; water was provided ad libitum. The rats were housed individually in raised-bottom cages
(no further husbandry information was provided). At Weeks 6 and 12 from the start of gavage
dosing, urine was collected from 10 rats/sex/dose group for urinalysis; blood was collected from
these rats and analyzed for hemoglobin, hematocrit, total and differential leukocyte counts,
prothrombin time, blood urea nitrogen, blood glucose, serum glutamic-oxaloacetic transaminase,
and serum alkaline phosphatase. The rats were sacrificed and necropsied after 12 weeks of
gavage treatment. The liver, kidneys, heart, gonads, adrenals, thyroids, and pituitary were
weighed. Tissue samples were taken from 26 organs (i.e., liver, kidney, lung, heart, and other
organs unspecified in the report) from 10 rats/sex/dose in the control and 67.5-mg/kg-day groups
and evaluated histologically. Additionally, tissue samples from the liver and kidney were
evaluated for all dose groups. This study was conducted prior to the adoption of Good
Laboratory Practice (GLP) standards (40 CFR Part 160; November 29, 1983). Statistical
analyses were not performed, and insufficient data were provided to allow the reviewers to
perform statistical analyses. It was not stated whether the stability of the compound in the
aqueous solutions was verified, although solutions were prepared fresh prior to dosing.
However, the following information is known from the Hazardous Substance Data Bank (HSDB,
2005): the test compound is miscible with water and degrades in water at high temperature
(100°C); the National Fire Protection Association (NFPA) Hazard Classification of reactivity for
2-chloroethanol is 0 (it is not reactive with water); the aquatic fate of the compound when
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released into water may be biodegradation; 2-chloroethanol is not expect to volatize from surface
waters, adsorb to sediment, bioconcentrate in fish, photolyze, or hydrolyze. A National
Toxicology Program (NTP, 1985a,b,c) study demonstrated the stability of the compound in
70% aqueous ethanol for 21 days at room temperature. Thus, together, this information suggests
that 2-chloroethanol may be stable in water at room temperature. Consequently, risk assessment
proceeds on the assumption that the test compound is stable in water. Considering that the actual
dose received during the first 6 weeks (dietary formulations) is unknown due to test compound
instability, total exposure of these animals is also unknown.
During the first 3 weeks after gavage administration was begun, food consumption was
decreased (see Table B. 1), and labored breathing was observed in the majority of the
67.5-mg/kg-day rats (Oser et al., 1975a). These animals became moribund and were sacrificed;
only 8 of 25 males and 6 of 25 females survived to the end of the 12-week dosing period.
Overall (Weeks 1-12 of gavage dosing) body-weight gain was decreased by 34% in the
surviving 67.5-mg/kg-day males. No other adverse effect was reported for any examined
parameter, except in the decedents. The following gross pathological findings were noted in the
decedents: dark livers with alternate pale and granular areas; reddened and/or bloody
gastrointestinal tissues; hemorrhagic adrenal and pituitary glands; and red or dark red lungs. The
following qualitative histological findings were noted in the decedents: subacute myocarditis
(frequently, both sexes), colloid depletion in the thyroid (one male, four females), fatty changes
in the liver (one male, five females), thyroid congestion (four males), and congestive pulmonary
changes (frequently, both sexes). Based on a lack of observed toxicological effects, the study
authors defined 45 mg/kg-day as the NOAEL. Frank effects (i.e. moribundity) were observed in
rats treated at the next (highest) level (67.5 mg/kg-day). Consequently, the LOAEL is also the
study FEL (Frank Effects Level).
Ambrose (1950) administered 2-chloroethanol in the diet at concentrations of 0, 0.01,
0.02, 0.04, 0.08, 0.12, 0.16, or 0.24% (equivalent to 0, 9, 18, 36, 72, 108, 144, or 216 mg/kg-day,
respectively, calculated by the U.S. EPA [1988]) daily to five male rats/dose group (strain not
specified) for approximately 220 days. Stability of the test compound in the diet was not
reported. Because the stability of the test compound in the diet is unknown in this study and
2-chloroethanol was shown to be unstable in the diet (Oser et al., 1975), this study is considered
unacceptable for calculating a p-RfD and is only briefly summarized. Body-weight gain was
decreased at doses of 108 mg/kg-day and above, and food consumption was decreased at doses
of 144 mg/kg-day and above. Autopsy and histological examination revealed no
treatment-related effects. The study authors did not define a NOAEL or LOAEL. Rats dosed at
72 mg/kg-day showed no treatment-related effects; therefore, this dose level is considered the
NOAEL. The LOAEL is 108 mg/kg-day, based on decreased body-weight gain.
Oser et al. (1975b) administered 2-chloroethanol (purity not provided) in the diet to four
beagle dogs/sex/dose group for up to 15 weeks at estimated daily mean doses of 13.3, 18.3, and
18.4 mg/kg-day in males and 16.9, 19.3, and 20.3 mg/kg-day in females. Approximately
20 mg/kg-day seemed to be the maximum dose tolerated without a severe emetic response.
Doses were administered initially as a wet mash at concentrations up to 1350 ppm (4445 mg/kg),
but these concentrations were reduced in several stages to ensure retention. The levels of
2-chloroethanol were gradually increased as long as the doses were retained; however, only the
lowest dose was consistently retained. Husbandry and study design/methodology were the same
as previously described in Oser et al. (1975a). Stability of the compound in the diet was not
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reported, but it was stated that the diets were freshly prepared. It was unclear how the estimated
daily mean dose could be accurately determined due to the reported emetic response. The mid-
and high-dose groups received approximately the same dose. Statistical analyses were not
reported. No adverse effects were reported for any dose group. The study authors did not define
a NOAEL or LOAEL; however, the highest dose that was consistently retained by the dogs
(13.3/16.9 mg/kg-day in males/females) showed no effects; therefore, the 13.3/16.9 mg/kg-day is
considered a NOAEL in males and females, respectively, and a LOAEL is not identified.
Oser et al. (1975c) administered 2-chloroethanol (purity not provided) orally by syringe
in an apple sauce vehicle to two Rhesus (Macaca mulatto) monkeys/sex/dose group for up to
12 weeks at daily doses of 0, 30, 45, or 62.5 mg/kg-day. Dose formulations were "freshly
prepared," but stability of the compound in the vehicle was not reported. Each animal was
housed individually in a raised-bottom cage and was fed Rockland Farms Monkey Chow and
fresh fruit (no further husbandry information was provided). The study design/methodology was
the same as previously described in Oser et al. (1975a). No adverse effects were reported for any
dose group, and an n of 2 precludes meaningful statistical analyses. The study authors did not
define a NOAEL or LOAEL; however, the highest dose (62.5 mg/kg-day) showed no effects.
Thus, 62.5 mg/kg-day is considered a NOAEL; a LOAEL is not identified.
Chronic Studies
No studies regarding the effects of chronic oral exposure to 2-chloroethanol in animals
were identified.
Developmental and Reproduction Studies
In a developmental toxicity study, Courtney et al. (1982a) administered 2-chloroethanol
(99% purity) in water by gavage to 12 presumed pregnant CD-I mice/dose group at doses of 0,
50, 100, or 150 mg/kg-day in a volume of 0.1 mL/mouse/day on Gestation Days (GDs) 6-16.
Doses were calculated based on GD 6 body weights. It was not stated whether the test
compound stability was confirmed in the vehicle, and frequency of preparation of the dosing
solutions was not provided. All mice were sacrificed on GD 17. Upon sacrifice, the fetuses
were weighed as a litter and examined, and half of each litter was stored in Bouin's solution until
examined by dissection. The remaining fetuses were stained with alizarin red S for skeletal
examination. In addition, the fetuses selected for alizarin staining were weighed individually,
and their livers were removed and weighed. Parameters reported also included maternal
body-weight gain, relative liver weight, implants/litter, fetus mortality, fetuses/litter, fetal weight,
number and type of anomalies, fetal liver weight (absolute and relative), placenta weight, and
number of litters and fetuses. At 150 mg/kg-day, 75% of the maternal mice died, usually after
2-4 treatments, and the remaining 25% were not pregnant. At 100 mg/kg-day, maternal
body-weight gain was decreased (p < 0.05) by 61%, and fetal body weight was decreased
(p < 0.05) by 14%). At 100 mg/kg-day, absolute and relative liver weights of the fetuses were
decreased (p < 0.05) by 19% and 9%, respectively. These findings were considered to reflect the
decreased fetal body weight. A minor decrease (p < 0.05) of 6% was also noted in relative liver
weight in the 50-mg/kg-day fetuses; this finding was not considered biologically relevant. The
study authors did not define a NOAEL or LOAEL. Maternal mice dosed at 50 mg/kg-day
showed no treatment-related effects; therefore, this dose level is considered the maternal
NOAEL. The maternal LOAEL is 100 mg/kg-day, based on decreased maternal body-weight
gain. Fetuses dosed at 50 mg/kg-day showed no treatment-related effects; therefore, this dose
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level is considered the developmental NOAEL. The developmental LOAEL is 100 mg/kg-day,
based on decreased fetal body weight.
In a companion developmental toxicity study, Courtney et al. (1982b) administered
2-chloroethanol (99% purity) in the drinking water of presumed pregnant CD-I mice at nominal
doses of 0, 10, 25, 50, or 200 mg/kg-day on GDs 6-16. Actual intake, reported by the study
authors, was 0, 16, 43, 77, or 227 mg/kg-day, and the numbers of pregnant mice for which data
were reported were 16, 3, 3, 4, and 13 per dose group, respectively. It was not stated whether the
test compound stability was confirmed in the vehicle, and frequency of preparation of the dosing
solutions was not provided. All mice were sacrificed on GD 17. Upon sacrifice, the fetuses
were weighed as a litter and examined, and half of each litter was stored in Bouin's solution until
examined by dissection. The remaining fetuses were stained with alizarin red S for skeletal
examination. Total liver triglycerides of the dams in the high-dose group and the concurrent
control mice were determined. Parameters reported also included maternal body-weight gain,
relative liver weight, implants/litter, fetus mortality, fetuses/litter, fetal weight, and number and
type of anomalies. There were no significant differences in the maternal or fetal parameters at
any dose level in the drinking water, and no teratogenic effect could be attributed in either group
to the compound. The gavage arm of the study (Courtney et al., 1982a) probably produced
higher transient blood levels of the compound than did the drinking water study (Courtney et al.,
1982b), possibly resulting in more severe effects. The study reviewers identified a maternal and
developmental NOAEL of 227 mg/kg-day (the highest dose tested); a LOAEL is not identified.
Reproductive Studies
No studies regarding the effects of oral exposure to 2-chloroethanol on reproduction in
animals were identified.
Carcinogenic Studies
No studies regarding the effects of oral exposure to 2-chloroethanol on carcinogenicity in
animals were identified.
Inhalation Exposure
No inhalation studies on the subchronic, chronic, developmental, or reproductive toxicity
or carcinogenicity of 2-chloroethanol in animals were identified.
OTHER STUDIES
Short-Term Toxicity Studies
Human Studies
Several studies detailing the acute or short-term toxicity of 2-chloroethanol in humans
were found (Deng et al., 2001; Miller et al., 1970; Bush et al., 1949; Goldblatt and Chiesman,
1944). Because the effects in humans are of particular concern, these studies are detailed below
(and in Table 3), even though the information cannot be used to quantify subchronic or chronic
RfD or RfC values.
Deng et al. (2001) conducted a retrospective analysis to evaluate patients with
2-chloroethanol poisoning reported to the Taiwan Poison Control Center during 1985-1998.
There were 17 patients (11 male and 6 female) ranging from 2-70 years of age. Five patients
attempted or committed suicide, nine patients were exposed unintentionally, and three patients
were occupationally exposed. Ingestion via the mouth was the most common route of exposure
(14 patients), while three patients were exposed through the dermal and/or oral route, and one
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patient was exposed by inhalation. Seven out of 17 patients died within 24 hours after exhibiting
severe symptoms such as metabolic acidosis, respiratory failure, shock, and/or coma. The
estimated dose resulting in patient death was in excess of 330 mg/kg. An estimated dose of
742 mg/kg-day resulted in severe toxicity to a 7-year-old male; however, this patient improved
upon receiving ethanol therapy soon after admission and for the next 4 days. Although shown to
have a protective effect on 2-chloroethanol toxicity (Bonitenko et al., 1981), ethanol therapy was
insufficient to rescue a 2-year-old male who ingested an estimated 396-792 mg/kg dose. The
benefit of ethanol therapy was unclear for two other cases where only mild or moderate toxicity
was observed. Doses of less than 100 mg/kg resulted in mild toxicity (transient signs and
symptoms). All but one patient developed symptoms within 2 hours after exposure. Patients
with mild-to-moderate poisoning had mild gastrointestinal, cardiovascular, respiratory, or
neurologic effects (nine patients); vomiting (five patients); tachycardia, tachypnea, and
weakness/lethargy (three patients); nausea, transient confusion, and sore throat/oral discomfort
(two patients); and dizziness, chest tightness, transient hypertension, chilliness, hypokalemia,
and slightly impaired renal function (one patient). See the Metabolism and Toxicokinetic Studies
section and Figure 2 for additional information on mechanism of ethanol therapy.
Miller et al. (1970) presented a case study in which a 23-month-old male patient ingested
approximately 2 mL of Cinecol, a photographic film cement containing 1-2 mL of
chloroethanol. The patient became pale and cyanotic and showed respiratory difficulty. General
convulsions, fluctuating systolic blood pressure, and varying pulse rate were observed 5-7 hours
later. His temperature and pulse rate increased, while his blood pressure decreased. The patient
vomited, became apnoeic, and had a cardiac arrest resulting in his death in less than 12 hours
after ingestion. At necropsy, the following findings were noted: edematous and congested lungs;
pulmonary hemorrhage; petechiae in the subepicardium, thymus, and beneath the liver capsule;
toxic follicular pattern in the spleen; and agonal intussusceptions in the small bowel.
Microscopically, early necrosis of the liver parenchyma with nuclear vacuolation, cytoplasmic
swelling, and small foci of polymorph infiltration, kidney tubular swelling, widespread neuronal
enlargement in the brain, damaged Purkinje cells, and swollen endothelial lining of some
cerebral blood vessels were observed. Neither 2-chloroethanol nor chloroacetic acid were found
in the blood or tissues.
Bush et al. (1949) described the poisoning of employees at a large seed potato supply
firm in Bakersfield, CA. Exposure of seed Irish potatoes to 2-chloroethanol can reduce their
dormancy period from 90 days to only a few days. Workers were exposed by both the dermal
and inhalation routes. One worker suffered nausea and dizziness followed by vomiting,
abdominal pain, weakness, and diminished vision. He seemed to recover an hour and a half after
the symptoms were first noticed; however, he collapsed and became comatose after two more
hours. He was deeply cyanotic, his heart tones were imperceptible, his skin was cold and
clammy, and his blood pressure could not be measured. He was treated with caffeine and
sodium benzoate, atropine sulfate, morphine sulfate, picrotoxin, nikethamide solution, methylene
blue, and epinephrine. He died 8 hours after the initial onset of symptoms. Findings in the
patient included albuminuria, fatty infiltration of the liver, brain edema, lung congestion/edema,
dilatation of the chambers of the right side of the heart, spleen congestion, cloudy swelling and
hyperemia of the kidneys, fatty degeneration of the myocardium, swollen and hyperemic renal
glomeruli, swollen epithelial cells occluding the renal convoluted tubules, pulmonary alveoli
dilated and filled with blood, and hyperemia in the spleen. These findings may have been
confounded by the drugs that were administered therapeutically. Five coworkers survived but
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suffered from nausea, vomiting, and dizziness. There were varying complaints of "burning
sensation of the nose, irritation of the eyes, diminished vision, and numbness of the hands and
fingers." A significant fall in blood pressure was noticed in two patients. One patient required
76 days for complete recovery, while a second patient required almost a month. The other three
patients recovered within hours to days after exposure.
Eleven cases of poisoning observed in workers involved in the manufacture of
2-chloroethanol were described by Goldblatt and Chiesman (1944). In two of these cases, the
patient died. A foreman was exposed to high concentrations of 2-chloroethanol and ethylene
dichloride (quantitative dose unknown) for approximately 1.5 hours. The findings included
vomiting, restlessness, unsteadiness, weak pulse, pupils varying in size, sluggish tendon reflexes,
blood pressure immeasurable, profuse perspiration, petechial hemorrhages in the pericardium,
cerebral cortex congestion, cerebral hemisphere edema, lung collapse and edema, extravasation
of blood into the alveoli, areas of degenerative change in the liver, fatty degeneration in the liver,
loss of cellular outlines and nuclei disappearance in liver, and cross striations in heart not visible.
The author stated that the second mortality may be attributed to individual susceptibility
(idiosyncratic response). This patient was exposed for some 2 months to concentrations
(quantity unknown) of 2-chloroethanol (probably mixed with some sym-dichloroethane) and
died 11 weeks and 2 days after starting work. The patient would collapse while walking in the
street. He complained of headache, dizziness, and vomiting. His mental condition was called
"very muddled." At autopsy, the following findings were noted: congested, slightly hyperplastic
spleen, congested kidney, damaged renal convoluted tubules, and degenerative changes and
edema of the basal ganglia.
A summary of the signs and symptoms in the nine nonfatal cases of human exposure
described by Goldblatt and Chiesman (1944) included
•	digestive system—nausea, epigastric pain, repeated vomiting (bile may
appear), and bulky offensive stools;
•	circulatory system—depressor action on the circulation, and signs of shock in
severe cases;
•	nervous system—headache, giddiness, incoordination, confusion, and mild
narcotic effects;
•	urinary system—slight albuminuria (disappearing on recovery) and polyuria;
•	respiratory system—cough may be present and rhonchi; and
•	skin—erythema on skin of arms and trunk in severe cases.
The authors further stated that "symptoms and signs were worse in men of poor physical
standard. Recovery in these nonfatal cases was complete; and in all except one, it was rapid."
From the nature of the work (Goldblatt and Chiesman, 1944), it is certain that the route of
absorption was the respiratory tract. The vapor absorbed was a mixture of 2-chloroethanol and
ethylene dichloride, but the very minor narcotic effects observed lead the authors to believe that
the latter was not the principal cause of the symptoms. The possibility of summation of toxic
effects cannot be ruled out, and the contribution of ethylene dichloride to the observed toxicity is
not known. Concentrations of 2-chloroethanol and ethylene dichloride were measured at seven
different sampling points during the night shift, and steps were taken to effectively reduce these
concentrations. Concentrations of 2-chloroethanol ranged from 2-49 ppm (mean of 21 ppm or
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"3
69 mg/m ), and concentrations of ethylene dichloride were 2-152 ppm (mean of 70 ppm or
230 mg/m3). When these concentrations were lowered to 0-5 ppm (mean of 2.5 ppm or
3	3
8 mg/m ) 2-chloroethanol and 12-48 ppm (mean of 30 ppm or 99 mg/m ) ethylene dichloride,
there was also a corresponding decrease in symptoms in the workers.
Animal Studies
The NTP (1985a,b,c) study is subdivided for clarity. The NTP (1985a) section addresses
acute toxicity of 2-chloroethanol in a variety of species. The NTP (1985b) section addresses
chronic dermal toxicity and carcinogenicity in rats while the NTP (1985c) refers to similar
studies with mice. Only a brief synopsis is presented because these data are not pertinent to
deriving subchronic and chronic RfD or RfC values. The LD50 is 1357 and 1813 mg/kg in male
and female Swiss mice, and the LD50 is 395 mg/kg) in both male and female F344/N rats.
"2-Chloroethanol is highly irritating to mucous membranes but produces little if any reaction
upon contact with rabbit skin. It is not a sensitizer in the guinea pig test. Toxic amounts can be
absorbed through the skin without causing dermal irritation."
Studies Involving Exposure Routes Other Than Oral or Inhalation
While not useful for deriving provisional toxicity values, the following studies may be
helpful under some circumstances. Chronic toxicity/carcinogenicity studies were performed by
dermal exposure in rats (NTP, 1985b) and mice (NTP, 1985c). Carcinogenicity studies were
performed in mice by intravenous injection (Homburger, 1968), rats by subcutaneous injection
(Mason et al., 1971), and mice by subcutaneous injection (Dunkelberg, 1983a,b). A subchronic
study was performed in rats by intraperitoneal injection (Lawrence et al., 1971). Cardio toxicity
was examined in rat heart tissue (Chen et al., 2011) and developmental studies were performed
in mice (Jones-Price et al., 1985a) and rabbits (Jones-Price et al., 1985b) by intravenous
injection.
In a dermal chronic toxicity/carcinogenicity study (NTP, 1985b), 2-chloroethanol in
70% aqueous ethanol was applied to the shaved skin of 50 F344N rats/sex/dose at dose levels of
0, 50, or 100 mg/kg-day, 5 days/week during a 103-week period. No adverse effects were
reported, and no evidence of carcinogenic potential was noted. In a companion dermal chronic
toxicity/carcinogenicity study (NTP, 1985c), 2-chloroethanol in 70% aqueous ethanol was
applied to the shaved skin of 50 Swiss CD-I mice/sex/dose at dose levels of 0, 7.5, or
15 mg/kg-day daily for 5 days/week during a 104-week period. In males, survival at
15 mg/kg-day was 12/50 compared to 26/50 in the controls. In the mice that died, local
inflammation and ulceration were observed, as well as lung congestion, inflammation, or
hemorrhage. No evidence of carcinogenic potential was found. The results of these studies were
confounded by the use of ethanol as a vehicle. Bonitenko et al. (1981) demonstrated that the
simultaneous administration of ethanol provides a protective effect against 2-chloroethanol
toxicity regardless of route (oral or dermal), increasing the LD50, reducing the incidence of
hepatic and renal necrotic lesions, and raising the blood concentration of 2-chloroethanol. Blair
and Vallee (1966) demonstrated that 2-chloroethanol is a substrate for the purified cytoplasmic
alcohol dehydrogenase of human liver, and Sood and O'Brien (1994) showed that
2-chloroacetaldehyde (CAA)-induced cytotoxicity in isolated hepatocytes was enhanced
markedly if hepatocyte alcohol- or aldehyde-dehydrogenase were inhibited prior to CAA
administration. Despite the confounding factor that the choice of vehicle introduces, it is
noteworthy that male mice were treated with up to toxic levels (as indicated by increased
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mortality) without evidence of carcinogenic potential (NTP, 1985c). See the Metabolism and
Toxicokinetic Studies section and Figure 2 for additional information.
Homburger (1968) evaluated tumor incidence in mice over a 12-month period following
a single 1.2-mg intravenous dose of 2-chloroethanol. No increase in tumor incidence was
observed; however, a small increase in alveolar/bronchiolar adenomas (5/18 treated vs.
2/18 controls) was noted when the same dose was administered once per month for 7 months.
Mason et al. (1971) evaluated tumor incidence in F344 rats following subcutaneous
injections of 2-chloroethanol in saline at dose levels of 0, 0.3, 1, 3, or 10 mg/kg-day twice each
week for 52 weeks followed by observation without treatment for 26 weeks. It was stated that
pituitary gland adenomas were observed in 7/100 female rats dosed with 2-chloroethanol (all
dose groups combined) compared to 1/50 controls. Data were not presented to allow verification
of a dose-dependent effect. This study is considered inappropriate for the development of
chronic toxicity values due to the route of administration, and dosing only twice a week.
Dunkelberg (1983a) evaluated tumor incidence in female NMRI mice following weekly
subcutaneous injection of 0.3, 1, or 3 mg of 2-chloroethanol in tricaprylin for approximately
70 weeks. No carcinogenic effect was noted. In the companion arm of the study, Dunkelberg
(1983b) also evaluated tumor incidence in rats (number, strain, and sex not specified in abstract)
following a single gavage dose at 2.5 or 10.0 mg/kg in salad oil; no carcinogenic effect was
noted. Both studies were presented in German, and an English translation was unavailable for
review.
Lawrence et al. (1971) administered 2-chloroethanol to groups of 12 male
Sprague-Dawley rats by intraperitoneal injection at dose levels of 0, 12.8, or 32.0 mg/kg-day
three times per week for 12 weeks. Six of the 12 rats dosed at 32.0 mg/kg-day and four of the
12 rats dosed at 12.8 mg/kg-day died early in the study. The study was repeated with doses of
6.4 and 12.8 mg/kg-day; all rats survived. A third phase, in which 12 rats/dose group were
administered daily doses of 2-chloroethanol at 0, 6.4, or 12.8 mg/kg-day for 30 days, was
conducted. Seven of 12 rats given daily doses of 12.8 mg/kg-day died during the study.
Chen et al. (2011) compared the ability of both 2-chloroethanol and chloroacetaldehyde
(CAA) to cause cardiotoxicity in vitro in heart tissue (atria) from male Sprague-Dawley rats. A
trial tissue was isolated from groups of 5 rats and cultured with 2-chloroethanol or 2-CAA (0, 1,
5, and 10 mM), and the contractile tension was measured for 60 minutes with a force
displacement transducer. Cardiotoxicity was measured by the ability of the chemicals to reduce
or arrest tension in the atrial tissue. 2-Chloroethanol significantly reduced atrial tension in a
dose-dependent manner but did not induce (cardiac) arrest after 60 minutes. 2-CAA also
significantly reduced the atrial tension but to a greater (2-fold) degree and caused tension arrest
in the tissues after approximately 23 minutes. The authors concluded that the CAA metabolite of
2-chloroethanol was likely responsible for the observed cardiotoxicity in humans (Deng et al.,
2001) or cardiac arrest reported by Miller et al. (1970). In a developmental toxicity study
(Jones-Price et al., 1985a), 2-chloroethanol in 5% dextrose was administered daily by
intravenous injection in a volume of 1 mL/kg body weight to timed-pregnant CD-I mice at doses
of 0, 60, or 120 mg/kg-day on GDs 4-6, 6-8, 8-10, or 10-12. At sacrifice on GD 17, a total of
34-54 dams (i.e., confirmed-pregnant females) per treatment group from each exposure period
were evaluated. Administration at 60 mg/kg-day did not result in any statistically significant
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expression of maternal toxicity, regardless of the period of administration. Evidence of
embryotoxicity in the 60-mg/kg-day group was observed only following exposure on GDs 8-10,
a treatment that significantly decreased the average fetal body weight per litter. No statistically
significant change in the incidence of malformed fetuses per litter was observed for any exposure
period at 60 mg/kg-day. At 120 mg/kg-day, decreased maternal and fetal body weights were
noted, as well as increased maternal mortality. An increase in the incidence of malformed
fetuses was only seen at one exposure period (GDs 8-10). In a companion developmental
toxicity study (Jones-Price et al., 1985b), 2-chloroethanol in 5% dextrose was administered daily
by intravenous injection in a volume of 0.3 mL/kg of body weight to artificially inseminated
New Zealand white rabbits at doses of 0, 9, 18, or 36 mg/kg-day on GDs 6-14. At sacrifice on
GD 30, a total of 15 to 21 does (i.e., confirmed-pregnant females) per treatment group were
evaluated. There was no evidence of a fetotoxic or teratogenic effect at any dose.
Genotoxicity Studies
The genotoxicity of 2-chloroethanol was reviewed and summarized in the NTP
(1985a,b,c) study. It was found that the compound can cause gene mutations in Salmonella
typhimurium, Klebsiella pneumonia, Escherichia coli, and Aspergillus nidulans. It is a
direct-acting base-pair substitution mutagen in S. typhimurium strains TA1530, TA1535, and
TA100, and the addition of rat liver S9 enhances the mutagenic effect. It can cause DNA
damage to Escherichia coli and human fibroblasts, and it causes chromosome aberrations in
Allium and rat bone marrow. However, no genotoxicity was noted in many other eukaryote tests.
No evidence of genotoxicity was noted in the following tests: gene mutation in
Schizosaccharomyces pom he.f Drosophila melanogaster, mouse lymphoma, or Chinese hamster
(V79); chromosomal aberrations in Saccharomyces cerevisiae or Glycine max; DNA damage in
human (HeLa); and micronucleus, heritable translocations, and dominant lethal tests in the
mouse. Since this report was published, 2-chloroethanol has been shown to be genotoxic in
other tests. For example, it causes the induction of prophage lambda in E. coli (DeMarini and
Brooks, 1992).
Kitchin et al. (1992) developed an assay using battery of short-term in vitro tests to
predict carcinogenicity in 111 chemicals. The complementary tests were designed to detect
cytotoxicity, promotion, and carcinogenesis in Sprague-Dawley rats that were treated with
2-chloroethanol at doses of 18 or 54 mg/kg-day. The first dose was given 21 hours before
sacrifice, and the second dose was given 4 hours before sacrifice by an unreported route of
administration. Rat serum alanine aminotransferase activity (a measure of cell damage), hepatic
DNA damage as determined by alkaline elution (potential carcinogenesis), hepatic ornithine
decarboxylase activity (possible promotion), and hepatic cytochrome P450 content (possible
promotion) were measured. This study evaluated 111 chemicals of known rodent
carcinogenicity (49 carcinogens and 62 noncarcinogens). Using data from these short-term
assays, the suggested technique achieved 73% concordance with its predicted carcinogenic
potential for these chemicals and the known carcinogenic potential of these chemicals. The
sensitivity of the technique was 56%, and the specificity was 84%. This concordance ratio is
superior to the Ames test (51%) and structural alerts (46%). This study predicts that
2-chloroethanol is carcinogenic, which is noteworthy in the absence of a suitable animal
carcinogenicity study.
Allavena et al. (1992) developed another battery of in vivo assays to confirm the results
of in vitro assays or as an alternative to in vitro assays to predict carcinogenic potential. These
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tests included the micronucleus assay, induction of unscheduled DNA synthesis (UDS), and
induction of rat hepatocyte DNA damage. Two protocols were used. The first protocol involved
administration of 2-chloroethanol in 1% aqueous carboxymethylcellulose by gavage to male
Sprague-Dawley rats at one-half the LD50 value 20 hours after a two-thirds hepatectomy. The
animals were sacrificed 48 hours later, and micronucleated cells in the liver and bone marrow
were assayed. In the second protocol, rats were administered 2-chloroethanol 30 and 6 hours
before termination. "The bone marrow was examined for the frequency of micronuclei in
polychromatic erythrocytes; hepatocyte primary cultures were prepared from the liver for the
subsequent evaluation of the amount of DNA fragmentation, carried out at 4 and 20 hours, and of
UDS, measured 20 hours after seeding." The results of these tests indicated that 2-chloroethanol
was not genotoxic.
Rannug et al. (1976) evaluated potential mutagenicity by testing the ability of
2-chloroethanol, and other metabolites of vinyl chloride, to directly cause base-pair substitution
in Salmonella typhimurium TA1535 bacteria without S-9 metabolic activation. No effects were
observed at 0, 0.1, 0.5, or 1.5 mM (0.008, 0.043, or 0.128 mg/L). 2-Chloroethanol was retested
at higher concentrations of 0, 1 mM, and 1 M (0, 80.5 mg/L, and 80.5 g/L). 2-Chloroethanol was
only faintly toxic (details not reported for the highest doses) and only weakly mutagenic (data
not available). The authors concluded that the mutagenicity observed for vinyl chloride could
not be attributed to 2-chloroethanol.
McCann et al. (1975) evaluated the potential mutagenicity of 2-chloroethanol by testing
its ability to cause the reversion of S. typhimurium, strains TA100 and TA1535 with and without
S-9 activation, using S-9 fraction from both rat liver microsomes and also human liver extracts.
2-Chloroethanol was weakly mutagenic in the TA1535 strain but showed clear activity
(1 revertant colony per 0.6 |iM) in the TA100 strain with S-9 activation. The testing of
chloroacetaldehyde yielded similar results using S-9 activation with strains TA100 and TA1535.
The authors suggest that chloroacetaldehyde may be the active metabolite of 2-chloroethanol,
which supports the hypothesis that chloroacetaldehyde may cause the toxicity attributed to
2-chloroethanol (Johnson, 1967).
In summary, 2-chloroethanol is known to be genotoxic in some tests, particularly in
bacterial systems. It has only sometimes been shown to be genotoxic in eukaryote systems.
Conflicting data exist in short term in vivo assays regarding its genotoxicity; however, one
system, which may correctly predict carcinogenic potential 73% of the time, suggests that
2-chloroethanol may be carcinogenic.
Metabolism and Toxicokinetic Studies
The NTP (1985a,b,c) summarized the proposed metabolic pathway of 2-chloroethanol as
follows (see Figure 2):
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C1CH2CH20H + NAD+
(I)
I
C1CH2CH0 + NADH + H+
(II)
C1CH2CH0 + GSH
I
gs-ch2cho+h + cr
(in)
GS-CH2CHO + NAD+ + H20
I
gs-ch2cho
(III)
gs-ch2cooh
av)
I
I
I
HOOCCH(NH2)CH2-S-CH2COOH
(V)
o
t
HOOCCH2-S-CH2COOH
(VII)
I
HOOCCH2-S-CH2COOH
(VI)
GS-CH2COOH + NADH + H+
(IV)
Figure 2a,b. Metabolic Pathway of 2-Chloroethanol
Source: NTP (1985a,b,c).
Johnson (1967) suggested that the toxicity of 2-chloroethanol (I) was due to the
formation of chloroacetaldehyde (II) by the test animal in amounts greater than
could be detoxified by glutathione (GSH). Both ethanol and 2-chloroethanol are
known to be substrates for the purified cytoplasmic alcohol dehydrogenase of
human liver, rat liver, or yeast. Co-administration with ethanol reduces the
toxicity of 2-chloroethethanol, presumably by competition for the alcohol
dehydrogenase. Johnson (1967) demonstrated the in vivo and in vitro formation
of S-carboxymethyl-GSH (IV) in livers of rats dosed with 2-chloroethanol;
S-carboxymethyl-GSH (IV) is presumably formedfrom GSH and
chloroacetaldehyde, the dehydrogenation product of 2-chloroethanol;
S-formylmethyl-GSH is the presumed intermediate. Grunow andAltmann (1982)
reportedfinding thiodiacetic acid (VI) and thionyldiacetic acid in the urine of rats
given an oral dose of 2-chloroethanol; both these compounds are derivable from
S-carboxymethylcysteine, the hydrolysis and deamination product of
S-carboxymethyl-GSH. Thiodiacetic acid has been shown to be a metabolite of
compounds that have the general property of being converted to
chloroacetaldehyde (II); these compounds include vinyl chloride,
1,2-dichloroethanol, and vinylidene chloride.
Chen et al. (2010) performed a metabolism study in male Sprague-Dawley rats (group
size not reported) injected once intraperitoneally with saline or 120 mg/kg of 2-chloroethanol.
Thirty minutes before 2-chloroethanol administration, the animals were treated with saline,
5-mg/kg fomepizole (an inhibitor or alcohol dehydrogenase with very high affinity), or 75-mg/kg
disulfiram (an inhibitor of acetaldehyde dehydrogenase). Another group was treated with
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400-mg/kg-day A-acetylcysteine (used to augment glutathione reserves) for 4 days, followed by
one dose of 5 mg/kg of fomepizole and 120 mg/kg of 2-chloroethanol. Animals were sacrificed
1 hour after 2-chloroethanol treatment, and blood, liver, and kidneys were collected.
Chloroacetaldehyde was measured in the plasma, and glutathione was measured in the liver and
kidneys. The study authors also determined LD50 values for 2-chloroethanol. The addition of
fomepizole reduced the conversion of 2-chloroethanol to chloroacetaldehyde (CAA) and the
resulting toxicity of 2-chloroethanol was reduced. Treatment with disulfiram increased the
concentration of CAA with an increase in 2-chloroethanol toxicity. Glutathione levels were
significantly less than the control group in the liver after treatment with 2-chloroethanol. This
research corroborates the proposed metabolic pathway described above.
Hung et al. (2006) evaluated 4-methylpyrazole (4-MP) as an antidote to 2-chloroethanol
toxicity by pretreatment of rats (number and strain not specified) with 4-MP or saline control
followed by ip injection with several doses (not specified) of 2-chloroethanol. 4-MP is a potent
inhibitor of alcohol dehydrogenase which catalyses the conversion of 2-chloroethanol to CAA.
The blood concentration of CAA in the treated group was 42.7% lower than in the untreated
controls. Treatment with 4-MP also increased the LD50 from 58 mg/kg (control value) to
180 mg/kg. The Hung et al. (2006) study is available only as an abstract with few details.
Bonitenko et al. (1981) demonstrated that the simultaneous administration of ethanol
provides a protective effect against 2-chloroethanol toxicity regardless of route (oral or dermal),
increasing the LD50, reducing the incidence of hepatic and renal necrotic lesions, and raising the
blood concentration of 2-chloroethanol. Blair and Vallee (1966) demonstrated that
2-chloroethanol is a substrate for the purified cytoplasmic alcohol dehydrogenase of human liver,
and Sood and O'Brien (1994) showed that 2-chloroacetaldehyde (CAA)-induced cytotoxicity in
isolated hepatocytes was enhanced markedly if hepatocyte alcohol or aldehyde dehydrogenase
were inhibited prior to CAA administration. Consequently, ethanol has been used as a specific
treatment for 2-chloroethanol toxicity (Deng et al., 2001).
Grunow and Altman (1982) conducted a toxicokinetic study in which male Wistar rats
were dosed orally by gavage using [l,2-14C]-chloroethanol (99% radiochemical purity) in water.
The study was conducted in three parts: elimination studies, distribution studies, and
identification of urinary metabolites. In the elimination study, six rats received single doses of
approximately 5 mg/kg, and three rats received doses of about 50 mg/kg. After dosing, the
animals were placed in metabolism cages. Urine and feces were collected separately at 24-hour
intervals. Expired air was also collected. After 4 days, the animals were euthanized. Blood and
select organs (adipose tissue, adrenal, bone, brain, heart, intestine, kidney, liver, lung, muscle,
skin, spleen, stomach, testes, and thyroid) were collected. In a distribution study, single doses of
5 mg/kg were given to eight rats, and these animals were sacrificed after 0.5, 1, 2, 4, 6, or
8 hours. Radioactivity was determined in the blood, liver, and kidney. For the isolation and
identification of urinary metabolites, unlabelled 2-chloroethanol was administered in doses of
50 mg/kg.
The authors described the results as follows:
At both dose levels, the radioactivity was rapidly eliminated, mainly in the urine.
On the first day after application of 5 mg/kg, 77.2% of the dose was found in the
urine, 1.7% in the feces, and 1.0% as carbon dioxide in the expired air. Only
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2.8% were [sic] excreted by these routes during the following 3 days. The
residual radioactivity remaining in the tissues after 4 days was almost equally
distributed and amounted to about 0.4% of the dose in the liver and 3% in the
whole organism. At the higher dose level, excretion rates and tissue
concentrations were similar. Examination of the urine by anion exchange
chromatography on DEAE-Sephadex revealed two metabolites which were
identified by GC/MS analysis as thiodiacetic acid and thionyldiacetic acid. These
metabolites represented almost all of the urinary radioactivity. They were
excreted in approximately equal amounts at the low dose whereas the thiodiacetic
acid predominated with about 70% of the urinary radioactivity at the high dose.
Thiodiacetic acid can be formed from the GSH conjugate of chloroacetaldehyde or
chloroacetic acid by hydrolysis and subsequent deamination and decarboxylation of the
intermediate product S-carboxymethylcysteine. Thionyldiacetic acid is formed by oxidation of
thiodiacetic acid.
Mode-of-Action and Mechanistic Studies
Friedman et al. (1982) evaluated the effects of 2-chloroethanol on rat tissue following in
vitro and in vivo exposure in a series of eight tests. 2-Chloroethanol (99% purity) in 0.9% saline
was administered by gavage to Osborne-Mendel (FDA strain) rats (4-8/sex/dose group
depending on the experiment). In Test 1, rats (6 males/dose group) were treated with
2-chloroethanol at 0 or 54.8 mg/kg, and the GSH concentrations were determined in the liver and
red blood cells. In Test 2, rats (7 males/dose group) were treated with 0, 5, 10, 20, or 40 mg/kg
2-chloroethanol. After 2 hours, they were given [ 4C]orotic acid (12.5 |iCi/kg) and [3H]leucine
(50.0 |iCi/kg) via i.p. injection and sacrificed 1 hour later. The amount (mg/g) of RNA and
protein and the radioactivity (dpm/mg x 103) were quantified, as were concentrations of DNA
(mg/g) and GSH (|imol/g). In Test 3, rats (8 males/dose group) were treated with
2-chloroethanol at 0, 10, 20, or 50 mg/kg. After 2 hours, they were given [14C]leucine
"3
(12.5 |iCi/kg) and [ HJleucine (50 |iCi/kg) and sacrificed 1 hour later. Protein synthesis was
measured by quantifying [3H]leucine and [14C]leucine. In Test 4, rats (8 males/dose group) were
treated with 2-chloroethanol at 0, 10, 20, or 40 mg/kg. After 2 hours, they were given
[14C]glycine (19.2 |iCi/kg) and [3H]leucine (76.9 |iCi/kg) and sacrificed 1 hour later.
Unincorporated radioactivity (3H and 14C) and protein synthesis ([3H]leucine and [14C]glycine)
were measured. In Test 5, rats (6 males/dose group) were treated with 2-chloroethanol at
"3
30 mg/kg. At either 0, 1, 2, 3, 5, or 6.5 hours after treatment, the rats were given [ HJleucine
(50 |iCi/kg) and sacrificed 30 minutes later. RNA, DNA, fat, and protein were quantified
(mg/g), as was GSH (|imol/g). In Test 6, rats (7/sex/dose group) were treated with
2-chloroethanol at 0, 15, 20, or 30 mg/kg. After 2 hours, they were given [14C]orotic acid
(12.5 |iCi/kg) and [ HJleucine (25.0 |iCi/kg) and sacrificed 1 hour later. Liver samples were
taken from both sexes, and kidney samples were taken from males. GSH was measured in the
liver (|imol/g), and RNA and protein levels were determined by measuring radioactivity
(dpm/mg x 103). In Test 7, one male rat was administered [14C]leucine (12.5 |iCi/kg)
intraperitoneally 2 hours before sacrifice. The liver was removed, rapidly prepared, and
incubated with 2-chloroethanol at 0, 1.5, 3, 6, 12, 24, or 48 mg/mL in triplicate. The liver slices
were homogenized, and protein was isolated and analyzed for radioactivity. In Test 8, rats
(6 males/dose group) were treated with 2-chloroethanol by gavage at 0 or 20 mg/kg immediately
after receiving saline, cysteine HC1 (200 mg/kg), or diethyl maleate (1000 mg/kg) by
intraperitoneal injection. After 2 hours, they were given [3H]leucine (30 |iCi/kg) and sacrificed
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1 hour later. Protein synthesis (dpm/mg x 103) and GSH (|imol/g) were quantified, and the
percentage change was reported. Further details of the methodology, including the preparation
of samples and their analysis, are provided in the cited report. This series of experiments
provides insight on several modes of action of 2-chloroethanol, briefly summarized as follows:
At concentrations as low as 2.5 mg/ml, protein synthesis in liver slices was
inhibited; at concentrations of 25 mg/ml and above, RNA synthesis and
respiration were also impaired. Single oral doses of 2-chloroethanol to young
adult rats at doses of 15 40 mg/kg body weight depressed liver nonprotein
sulfhydryl (GSH) concentration and liver protein but not RNA synthesis. Liver
lipid was increased by 7 hr after a single oral dose of 30 mg/kg. The time courses
and dose-response relationship for GSH depletion and restoration andfor protein
synthesis inhibition and recovery were similar. The livers of female rats were
more sensitive than the livers of male rats to the effects of 2-chloroethanol.
Protein synthesis was also depressed in kidneys of 2-chloroethanol-treated male
rats but at higher doses than those needed for this effect to occur in livers of the
same animals. Liver polysome disaggregation also occurred after oral
2-chloroethanol doses of 20 mg/kg and greater. The effects of 2-chloroethanol on
ribosome profiles and protein synthesis were at least partially reversed by
concurrent intraperitoneal administration of cysteine.
Andrews et al. (1983) evaluated the effects of 2-chloroethanol on fatty acid synthesis.
Cornish x White Rock crossbred chicks (6-8/dose group) received a gavage dose of 60-mg/kg
2-chloroethanol (99% purity) as a 10% aqueous solution, 200-mg/kg ethanol as a 10% aqueous
solution, or 200-mg/kg undiluted carbon tetrachloride. Another group of 6-8 chicks was treated
with eight consecutive daily doses of 40-mg/kg-day 2-chloroethanol as a 10% aqueous solution.
Control groups received gavage treatment with water. Eighteen hours after the last treatment,
blood samples were collected, the chicks were sacrificed, and the livers were harvested. The
chicks and livers were weighed. Livers were homogenized. Fatty acid synthesis, mitochondrial
fatty acid elongation, protein content, cytochrome c oxidase activity, isocitrate dehydrogenase
activity, and tissue triglyceride levels were measured in the homogenates. Plasma trigyceride
levels were also measured. Histological examination of the liver tissue was also performed.
Further details of the procedures used in quantifying the parameters are detailed in the cited
publication. Briefly, the results were reported as follows:
Mitochondrial elongation of fatty acids was decreased significantly while fatty
acid sythetase activity was not significantly affected by 2CE treatment.
Cytochrome c oxidase activity in fresh whole liver homogenate was significantly
higher in chicks subjected to acute exposure with 2CE when compared to the
controls. Upon freezing and thawing of homogenates, cytochrome c oxidase
activity increased significantly in the control group, but was unchanged in the
2CE group, which suggests that the mitochondrial membrane integrity is
compromised by 2CE treatment. Serum and liver triglyceride levels were
significantly elevated in both the single and multiple 2CE dose groups. Liver to
body weight ratios were significantly higher in both treatment groups when
compared to their controls. Histological examination of the liver of the 2CE
chicks showed cytoplasmic clearing of the cells, but no vacuolization or
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centrilobular necrosis. Serum isocitrate dehydrogenase levels were significantly
higher in the multiple treatment 2CE group than in the control group.
Greater than 70% inhibition of mitochondrial fatty acid elongation activity was observed
in this study. This inhibition could have a serious impact on organs, such as the heart, which
relies entirely on this synthetic system for fatty acid production.
Feuer et al. (1977) evaluated the effect of 2-chloroethanol on hepatic microsomal
enzymes in the rat. 2-Chloroethanol in saline was given by daily subcutaneous injection (sc) to
rats at a dose level of 0 or 20 mg/kg-day in females and 0, 3, 10, or 20 mg/kg-day in males for
7 days. The rats were sacrificed after the last dose. One additional group of males was given a
single subcutaneous dose of 50 mg/kg and sacrificed 3 hours later. Liver homogenates and
postlysosomal fractions containing microsomes were prepared. Activities of aminopyrine
A'-demethylase, coumarin 3-hydroxylase, glucose 6-phosphatase, and inosine diphosphatase were
assayed, and protein content was determined. Enzyme levels were determined in homogenates
to obtain the total and in microsomes to identify the localization of the enzyme in this fraction.
2-Chloroethanol caused an impairment of microsomal drug-metabolizing enzymes and
phosphatases in the liver of rats. Briefly, the results were reported as follows:
A significant reduction in activities of drug-metabolizing enzymes (aminopyrine
N-demethylase, coumarin 3-hydroxylase) and a marked decrease of glucose
6-phosphatase were seen in both sexes given dose levels of 20 mg/kg sc daily for
7 days. Inosine diphosphatase activity remained unaltered. In male rats given 3
or 10 mg/kg, a trend in the inhibition of drug metabolism was found. A single
dose of 50 mg/kg caused no apparent change in the activities of the enzymes
measured.
Kaphalia and Ansari (1989) treated Sprague-Dawley male rats (4/dose group) with a
single daily gavage dose of 2-chloroethanol (purity not reported) in mineral oil at
0 or 50 mg/kg-day for 5 days. The rats were then sacrificed. Hepatic microsomal lipids were
extracted, and the fatty acid esters were separated by thin-layer chromatography. The ester
fraction was further purified by HPLC and analyzed by ammonia chemical ionization mass
spectrometry. 2-Chloroethyl palmitate, 2-chloroethyl oleate, and 2-chloroethyl stearate were
isolated. The authors concluded that the administration of 2-chloroethanol could cause hepatic
fatty acid conjugation.
Bhat et al. (1991) investigated the effect of 2-chloroethanol on rat liver mitochondrial
respiration. Rat liver mitochondria were isolated, and mitochondrial respiration was determined
with an oxygen electrode. The results were as follows:
With succinate as the respiratory substrate and using chloroethanols (purity =
99%; 150 mM), 2-chloroethanol stimulated respiration by 28% and
2,2-dichloroethanol by 203%. 2-Chloroethanol showed maximum stimulation at
600 mM (98%). Respiratory stimulation was independent of mitochondrial
protein concentration. Chloroethanols (optimal concentrations for respiratory
stimulation with succinate) inhibited mitochondrial respiration when
glutamate-malate was used as the respiratory substrate. Estimation of ATP
showed that chloroethanols inhibited the synthesis of ATP. These results indicate
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that chloroethanols stimulate mitochondrial respiration by uncoupling oxidative
phosphorylation and that the uncoupling potency is proportional to the extent of
chlorination at the fi-position of haloethanol.
In summary, these studies demonstrate cardiotoxicity as well as the following findings in
the liver that result from 2-chloroethanol treatment: inhibited protein synthesis, impaired RNA
synthesis and respiration, depressed nonprotein sulfhydryl (GSH) concentration, increased lipid
levels, polysome disaggregation, decreased mitochondrial elongation of fatty acids, increased
cytochrome c oxidase activity, compromised mitochondrial membrane integrity, elevated
triglyceride levels, increased liver-to-body-weight ratios, cytoplasmic clearing of the cells,
hepatic fatty acid conjugation, stimulation of mitochondrial respiration by uncoupling oxidative
phosphorylation, and decreased aminopyrine iV-demethylase, coumarin 3-hydroxylase, and
glucose 6-phosphatase activities. The livers of female rats were more sensitive than the livers of
male rats to at least some of these effects.
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Table 3. Other Studies for 2-Chloroethanol (CASRN 107-07-3)
Tests
Materials and Methods
Results
Conclusions
References
Short-Term Toxicity Studies
Human poisoning
cases
Poison cases of 11 males and 6 females (ages
from 2 to 70 years) were detailed. Exposure
route was typically oral.
Signs and symptoms ranged from mild
gastrointestinal and neurologic effects to
metabolic acidosis, respiratory failure,
and death.
The compound is acutely toxic and
potentially fatal to humans.
Deng et al.
(2001)
Toddler ingestion
case
23-Month-old male ingested approximately
1-2 mL of 2-chloroethanol
Signs included cyanosis, respiratory
difficulty, convulsions, shock, and death.
Necropsy findings were also reported.
The compound can be fatal in small doses
to children.
Miller et al.
(1970)
Employee poisoning
cases
Six workers were exposed dermally and by
inhalation while working at a large seed
potato supply firm.
Signs and symptoms ranged from mild
gastrointestinal and neurologic effects to
coma and death. Necropsy findings were
also reported. Recovery for survivors
was usually within a few days.
Following OSHA mandates is needed to
protect workers.
Bush et al.
(1949)
Employee poisoning
cases
Eleven cases of poisoning observed in
workers involved in the manufacture of the
compound are described. The exposure route
was by inhalation.
The compound has effects on the
digestive, circulatory, nervous, urinary,
and respiratory systems, as well as the
skin. Effects can be fatal; otherwise,
recovery is typically rapid and complete.
Following OSHA mandates is needed to
protect workers.
Goldblatt and
Chiesman
(1944)
Acute dermal
toxicity in animals
LD50, and other acute effects from single
dose skin painting exposure are very briefly
reported for rats and mice.
The LD50 is approximately 395 mg/kg in
both male and female F344/N rats and the
LD50 is approximately 1357 mg/kg in
male- and 1813 mg/kg in female Swiss
CD-I mice.
The compound is acutely toxic.
NTP (1985a)
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Table 3. Other Studies for 2-Chloroethanol (CASRN 107-07-3)
Tests
Materials and Methods
Results
Conclusions
References
Studies Involving Exposure Routes Other Than Oral or Inhalation
Chronic toxicity/
carcinogenicity
study-dermal
exposure
2-Chloroethanol was applied in 70% aqueous
ethanol to the shaved skin of 50 F344/N
rats/sex/dose at dose levels of 0, 50, or
100 mg/kg-day, 5 days/week during a
103-week period.
No adverse effect was observed.
The results of this study were confounded
by the vehicle used.
NTP (1985b)
Chronic toxicity/
carcinogenicity
study-dermal
exposure
2-Chloroethanol was applied in 70% aqueous
ethanol to the shaved skin of 50 Swiss CD-I
mice/sex/dose at dose levels of 0, 7.5, or
15 mg/kg-day, 5 days/week during a
104-week period.
Increased mortality was observed at
15 mg/kg-day, but no evidence of
carcinogenic potential was observed.
The results of this study were confounded
by the vehicle used.
NTP (1985c)
Carcinogenicity
study
Mice were injected intravenously with a
single 1.2-mg dose, and evaluated for tumors
after one year.
No effect on tumor incidence was
observed.
Study is not useful for this assessment.
Homburger
(1968)
Carcinogenicity
study
Rats were injected subcutaneously at dose
levels of 0, 0.3, 1, 3, or 10 mg/kg twice each
week for 12 months and observed untreated
for an additional 6 months.
A possible increase in pituitary adenomas
in females was noted, but could not be
confirmed.
Study is not useful for this assessment.
Mason et al.
(1971)
Carcinogenicity
study
Mice were injected subcutaneously once
weekly at dose levels of 0.3, 1, or 3 mg/kg in
tricaprylin.
No carcinogenic effect was noted.
Study is not useful for this assessment.
Article is in German
Abstract only.
Dunkelberg
(1983a,b)
Subchronic study
Rats were treated by intraperitoneal injection
3 times weekly at doses of 0, 6.4, 12.8, and
32 mg/kg-day for 12 weeks. In a second
experiment, rats received 0, 6.4, and 12.8
mg/kg-day daily for 30 days.
No adverse effect was observed.
Study is not useful for this assessment.
Lawrence et
al. (1971)
Cardiotoxicity
Cardiotoxicity was demonstrated in isolated
Sprague-Dawley rat atrial tissue exposed to
2-chloroethanol or CAA in vitro.
Spontaneous atrial tissue tension was
significantly reduced in a dose-dependent
manner by 2-chloroethanol after 60
minutes. Chloroacetaldehyde also caused
a dose-dependent reduction
approximately 2-fold greater than 2-
chloroethanol and caused tension arrest
after 23 minutes.
Chloroacetaldehyde treatment resulted in
greater cardiac toxicity in isolated heart
tissue than 2-chloroethanol.
Chen et al.
(2011)
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Table 3. Other Studies for 2-Chloroethanol (CASRN 107-07-3)
Tests
Materials and Methods
Results
Conclusions
References
Developmental study
Mice were treated by daily intravenous
injections of 0, 60, or 120 mg/kg-day in 5%
dextrose on GDs 4-6, 6-8, 8-10, or 10-12.
Evidence of embryotoxicity in the
60-mg/kg-day group was observed only
following exposure on GDs 8-10, a
treatment that significantly decreased the
average fetal body weight per litter. At
120 mg/kg-day, decreased maternal and
fetal body weights were noted, as well as
increased maternal mortality. An
increase in the incidence of malformed
fetuses was seen only at GDs 8-10.
Study is not useful for this assessment.
Jones-Price et
al. (1985a)
Developmental study
Rabbits were treated by daily intravenous
injections of 0, 9, 18, or 36 mg/kg-day in 5%
dextrose on GDs 6-14.
There was no evidence of a fetotoxic or
teratogenic effect at any dose.
Study is not useful for this assessment.
Jones-Price et
al. (1985b)
Genotoxicity Studies
Review of genetic
toxicity
Provides an overview of genetic toxicity
studies up to 1985.
The compound is mutagenic in bacteria.
Other forms of genotoxicity were also
noted. The compound demonstrated
genotoxicity in some eukaryote cell tests,
but not in others.
There is evidence that the compound is
genotoxic, particularly in bacteria.
NTP
(1985a,b,c)
Genotoxicity study
Evaluated whether the compound causes
induction of prophage lambda in E. coli.
Induction of prophage lambda was
observed.
The compound is genotoxic in E. coli.
DeMarini and
Brooks (1992)
Genotoxicity study
A battery of short-term in vitro tests (DNA
damage and enzyme assays) in rats was used
to predict carcinogenicity. This study
evaluates 111 chemicals for carcinogenicity
using the test battery and achieved a 73%
concordance with in vivo rodent tests.
This study predicted 2-chloroethanol is a
carcinogen.
This test battery could be useful as a
replacement or a supplementary study to
the Ames Assay.
Kitchin et al.
(1992)
Genotoxicity study
A battery of short-term in vivo tests in rats
was used to predict carcinogenicity. These
tests included the micronucleus assay,
induction of unscheduled DNA synthesis,
and induction of DNA damage.
No significant difference from controls.
These tests suggest that the compound
may not be genotoxic in rats.
Allavena et al.
(1992)
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Table 3. Other Studies for 2-Chloroethanol (CASRN 107-07-3)
Tests
Materials and Methods
Results
Conclusions
References
Genotoxicity study
Ames bacterial assay using Salmonella
typhimurium strain TA1535 for base-pair
substitution mutagenesis at concentrations of
0.1 mM to 1 M (0.008 mg/L to 80.5 g/L).
Chloroethanol was weakly mutagenic at
the highest dose
Weak mutagenic activity supports
potential carcinogenicity.
Rannug et al.
(1976)
Genotoxicity study
Ames bacterial assay using Salmonella
typhimurium strains TA100 (histidine
reversion) and TA1535 (frameshift
mutations) with and without S-9 activation at
concentrations of 0, 1, 5, and 21 mg/plate.
S-9 activated chloroethanol is clearly
mutagenic at the high dose (TA100) but
weakly mutagenic in TA1535.
Mutagenic activity supports potential
carcinogenicity. Results with
2-chloroethanol were similar to results
with chloroacetaldehyde and supports
conclusion (Johnson, 1967) that toxicity
associated with 2-chloroethanol is caused
by chloroacetaldehyde.
McCann et al.
(1975)
Genotoxicity study
The Bhas 42 cell transformation assay is a
short-term system using a clone of the
BALB/c 3T3 cells transfected with an
oncogenic murine ras gene (v-Ha-rav) that
detects initiators and also promoters. Cells
exposed to 0, 10, 30, 100, 300, 1,000 mM of
2-chloroethanol with MCA used as initiator
and TPA as a promoter.
Cells were not transformed by
2-chloroethanol after initiation nor were
cells promoted by TPA.
2-chloroethanol was not an initiator or a
promoter in this assay.
Sakai et al.
(2010)
Genotoxicity study
2-chloroethanol vs Chloroacetaldehyde
(CAA) tested in vitro for ability to cause
chromosome aberrations in CHO cells at 0, 5,
7.5, and 10 mM. In vivo tests with ICR mice
given 0, 10, 20, and 40 mM 2-chloroethanol
or CAA via i.p. injection for ability to induce
micronucleus formation.
Neither chemical caused chromosome
aberrations without S-9 activation. With
S-9, CAA caused aberrations while
2-chloroethanol did not.
CAA did but 2-chloroethanol did not
induce micro nuclei in mice.
CAA but not 2-chloroethanol caused
chromosome aberrations and
micronucleus formation. Supports the
hypothesis that 2-chloroethanol
metabolite, CAA, is responsible for the
observed mutagenicity of 2-chloroethanol
Liao et al.
(2011)
Metabolism and Toxicokinetic Studies
Metabolism study
This study summarizes what is known
concerning the metabolism of the compound.
The compound is a substrate for alcohol
dehydrogenase. Glutathione is used in
the metabolism of the compound. The
ultimate products of the metabolism are
thiodiacetic acid and thionyldiacetic acid.
As with other alcohols, the metabolism of
this compound is affected by the
availability of alcohol dehydrogenase.
NTP
(1985a,b,c)
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Table 3. Other Studies for 2-Chloroethanol (CASRN 107-07-3)
Tests
Materials and Methods
Results
Conclusions
References
Metabolism study
This study investigated the effects of
fomepizole (alcohol dehydrogenase
inhibitor), disulfiram (an inhibitor of
acetaldehyde dehydrogenase) and
iV-acetylcysteine (to augment glutathione
reserves) on 2-chloroethanol toxicity.
Acetylcysteine slightly decreased
toxicity. Fomepizole significantly
decreased toxicity. The two agents
combined were even more effective.
Disulfiram increased the toxicity of
2-chloroethanol thus confirming CAA as
the toxic metabolite of 2-chloroethanol.
Supports the pathway detailed in the NTP
study above.
Chen et al.
(2010)
Metabolism study
This study investigated the effect of
4-methylpyrazole (aldehyde dehydrogenase
inhibitor) on 2-chloroethanol toxicity.
4-Methylpyrazole decreased toxicity of
2-chloroethanol.
Supports the pathway detailed in the NTP
study above.
Abstract only
Hung et al.
(2006)
Metabolism study
The effect of simultaneous administration of
ethanol with 2-chloroethanol was compared
to the administration of 2-chloroethanol only.
Ethanol increases the LD50, reduces the
incidence of hepatic and renal necrotic
lesions, and raises the blood
concentration of 2-chloroethanol.
Ethanol has a protective effect against
2-chloroethanol toxicity.
Bonitenko
et al. (1981)
Metabolism study
Human liver alcohol dehydrogenase catalytic
activity was tested in vitro on several
substrates including 2-chloroethanol
Demonstrated that 2-chloroethanol is a
substrate for the purified cytoplasmic
alcohol dehydrogenase of human liver
Supports the pathway detailed in the NTP
study above.
Blair and
Vallee (1966)
Metabolism study
The effect of ethanol or aldehyde
dehydrogenase inhibition in isolated
hepatocytes on 2-chloroacetaldehyde-induced
cytotoxicity was examined.
Ethanol or aldehyde dehydrogenase
inhibition markedly enhanced
2-chloroacetaldehyde-induced
cytotoxicity. Hepatocyte glutathione and
ATP depletion was noted, as well as
enhanced lipid peroxidation.
2-Chloroacetaldehyde metabolites were
less toxic than the parent.
Alcohol or aldehyde dehydrogenase
inhibition increases the toxicity of
2-chloroethanol. 2-Chloroacetaldehyde
can result in oxidative stress and its
cytotoxicity depends on cellular redox
homeostasis and cellular energy supply.
Sood and
O'Brien
(1994)
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Table 3. Other Studies for 2-Chloroethanol (CASRN 107-07-3)
Tests
Materials and Methods
Results
Conclusions
References
Toxicokinetic study
Male Wistar rats were dosed orally by
gavage using [l,2-14C]-chloroethanol in
water. In elimination studies, 6 rats received
single doses of approximately 5 mg/kg, and
3 rats received doses of about 50 mg/kg.
After dosing, animals were placed in
metabolism cages. Urine and feces were
collected separately at 24-hour intervals.
Expired air was also collected. After 4 days,
the animals were terminated. Blood and
selected organs were collected. In a
distribution study, single doses of 5 mg/kg
were given to 8 rats, and these animals were
sacrificed after 0.5, 1, 2, 4, 6, and 8 hours.
Radioactivity was determined in the blood,
liver, and kidney. For the isolation and
identification of urinary metabolites,
unlabelled 2-chloroethanol was administered
in doses of 50 mg/kg. Radioactivity was
quantified through liquid scintillation
counting, and metabolites were identified by
GC-MS.
At both dose levels, the radioactivity was
rapidly eliminated, mainly in the urine.
On the first day after application of
5 mg/kg, 77.2% of the dose was found in
the urine. The residual radioactivity
remaining in the tissues after 4 days was
almost equally distributed and amounted
to about 3% in the whole organism. Two
urinary metabolites were identified as
thiodiacetic acid and thionyldiacetic acid,
and they represented almost the whole
urinary radioactivity.
Elimination is rapid, through the urine,
and mainly as thiodiacetic acid and
thionyldiacetic acid. The identification
of these metabolites supports the
metabolic pathway proposed above.
Grunow and
Altaian (1982)
Mode-of-Action and Mechanistic Studies
Mode/mechanistic
action study
A series of tests were conducted to elucidate
the mode of action and provide insight into
the mechanism of action of 2-chloroethanol.
In male and female rats.
There was a dose-related decrease in
RNA, protein synthesis, GSH, in male
and female liver slices and an increase in
fat content.
These studies demonstrated that, in the
liver, 2-chloroethanol can inhibit protein
synthesis, impair respiration, depress
nonprotein sulfhydryl (GSH)
concentration, increase lipid levels, and
result in polysome disaggregation. The
livers of female rats were more sensitive
than the livers of male rats to at least
some of these effects.
Friedman
etal. (1982)
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Table 3. Other Studies for 2-Chloroethanol (CASRN 107-07-3)
Tests
Materials and Methods
Results
Conclusions
References
Mode of action study
Chicks were treated by gavage, and their
livers were collected, weighed, and
homogenized. Fatty acid synthesis,
mitochondrial fatty acid elongation, protein
content, cytochrome c oxidase activity,
isocitrate dehydrogenase activity, and tissue
triglyceride levels were measured in the
homogenates. Plasma triglyceride levels
were measured, and histological examination
of the liver tissue was performed.
2-Chloroethanol decreased mitochondrial
elongation of fatty acids, increased
cytochrome c oxidase activity,
compromised mitochondrial membrane
integrity, elevated triglyceride levels,
increased liver-to-body-weight ratios.
Inhibition of mitochondrial fatty acid
elongation activity could have serious
impact on organs, such as the heart,
which relies entirely on this synthetic
system for fatty acid production
Andrews et al.
(1983)
Mode of action study
2-Chloroethanol in saline was given by daily
subcutaneous injection to rats at various
doses for 7 days or as a single dose. Liver
homogenates and postlysosomal fractions
containing microsomes were prepared.
Activities of aminopyrine \ -dcmcthvlasc.
coumarin 3-hydroxylase, glucose
6-phosphatase, and inosine diphosphatase
were assayed, and protein content was
determined.
2-Chloroethanol	treatment decreased
aminopyrine Y-dcmcthvlasc. coumarin
3-hydroxylase,	and glucose
6-phosphatase activities.
2-Chloroethanol decreases the activity of
microsomal drug-metabolizing enzymes
and phosphatases in the liver of rats.
Feuer et al.
(1977)
Mode of action study
Male rats were treated by gavage and
sacrificed, hepatic microsomal lipids were
extracted, and fatty acid esters were isolated
and identified.
2-Chloroethyl palmitate, 2-chloroethyl
oleate, and 2-chloroethyl stearate were
identified.
2-Chloroethanol can cause hepatic fatty
acid conjugation.
Kaphalia and
Ansari (1989)
Mechanistic study
Rat liver mitochondria were isolated and
used in vitro to evaluate mitochondrial
respiration following 2-chloroethanol
treatment. Succinate or glutamate maleate
were used as respiratory substrates.
2-Chloroethanol stimulates respiration
with succinate and inhibits respiration
with glutamate maleate. 2-Chloroethanol
inhibits ATP synthesis.
2-Chloroethanol stimulates mitochondrial
respiration by uncoupling oxidative
phosphorylation.
Bhat et al.
(1991)
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DERIVATION OF PROVISIONAL VALUES
Table 4 presents a summary of noncancer reference values. Table 5 presents a summary
of cancer values.
Table 4. Summary of Noncancer Reference Values for
2-Chloroethanol (CASRN 107-07-3)
Toxicity Type
(Units)3
Species/
Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFc
Principal Study
Subchronic
p-RfD
(mg/kg-day)
Rat/MF
Absence of any
toxicological effects
and frank effects
2 x KT1
NOAEL
45
300
Oseretal. (1975a)
Chronic p-RfD
(mg/kg-day)
Rat/MF
Absence of any
toxicological effects
and frank effects
2 x 1(T2
NOAEL
45
3000
Oseretal. (1975a)
Subchronic
p-RfC (mg/m3)
None
Chronic p-RfC
(mg/m3)
None
ND = Not Determined
Table 5. Summary of Cancer Values for 2-Chloroethanol (CASRN 107-07-3)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
None
p-IUR
None
DERIVATION OF ORAL REFERENCE DOSE
Derivation of Subchronic and Chronic Provisional RfDs
There are four subchronic-duration and two developmental studies involving oral
exposure to 2-chloroethanol (see Table 2). The subchronic-duration rat study by Oser et al.
(1975a) is selected as the principal study for derivation of a subchronic p-RfD. In this study, the
study authors administered 2-chloroethanol (0, 30, 45, and 67.5 mg/kg-day) to male and female
FDRL rats, 25/sex/dose, for 6 weeks in the diet followed by 12 weeks of gavage treatment at the
same doses. The study authors conducted urinalysis, hematology, and histology of tissues from
26 organs (though incompletely reported). The highest dose (67.5 mg/kg-day) caused high
mortality (17/25 males; 19/25 females), thus constituting a FEL in both sexes. There were no
observed effects of treatment at the next lower dose (45 mg/kg-day). This study was reported in
a peer-reviewed journal and was performed prior to implementation of GLP standards.
However, this study generally met the standards of study design and performance with regard to
numbers of animals, examination of potential toxicity endpoints, and presentation of information.
The selected study had some minor deficiencies, particularly in the reporting of the results.
These details are provided in the "Review of Potentially Relevant Data" section. Benchmark
dose (BMD) analysis is not appropriate because the highest dose is a FEL, and there were no
observed effects at the next lower dose. The other acceptable studies performed in dogs and
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monkeys (also reported in the publication by Oser et al., 1975a) did not identify any
toxicological effects at the highest doses tested (20.3 and 62.5 mg/kg-day, respectively).
The developmental toxicity study by Courtney et al. (1982a) could possibly be used to
derive p-RfDs. In that study, pregnant CD mice (12/dose group) were administered 0, 50, 100,
or 150 mg/kg-day of 2-chloroethanol on GDs 6-16 followed by sacrifice on GD 17. The study
authors examined litter and fetus weight, implants/litter, fetus mortality, number of fetuses/litter,
and the number and type of fetal anomalies. The maternal NOAEL was 50 mg/kg-day based on
a decrease in maternal body weight at a dose of 100 mg/kg-day. The fetal NOAEL was
50 mg/kg-day based on a biologically significant reduction in relative (9%) and absolute (19%)
fetal liver weight and a 14% reduction in body weight at 100 mg/kg-day. Although the
Courtney et al. (1982a) study provides a NOAEL and a LOAEL, the NOAELs (50 mg/kg-day,
fetal and maternal) are greater than that from Oser et al. (1975a). Thus, based on the absence of
any observable toxicological effects, the rat study by Oser et al. (1975a) provides the lowest
POD (a NOAEL of 45 mg/kg-day) for developing a subchronic p-RfD.
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
Adjusted for daily exposure:
The following dosimetric adjustments were made for each dose in the principal study for
dietary treatment.
NOAELadj = NOAELoseretai., 1975a x [conversion to daily dose]
= 45 mg/kg-day x (days of week dosed ^ 7 days in week)
= 45 mg/kg-day x 7 ^ 7
= 45 mg/kg-day
The subchronic p-RfD for 2-chloroethanol, based on the NOAEL of 45 mg/kg-day (POD)
in male and female rats (Oser et al., 1975a), is derived as follows:
Subchronic p-RfD = NOAELadj ^ UFc
= 45 mg/kg-day -^300
= 2 x 10-1 mg/kg-day
Table 6 summarizes the uncertainty factors (UFs) for the subchronic p-RfD for
2-chloroethanol.
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Table 6. Uncertainty Factors for Subchronic p-RfD of 2-Chloroethanol (CASRN 107-07-3)a
UF
Value
Justification
UFa
10
A UFa of 10 is applied for interspecies extrapolation to account for potential toxicokinetic and
toxicodynamic differences between rats and humans.
ufd
3
A UFd of 3 is applied because the database includes two acceptable developmental studies in mice
but no acceptable two-generation reproduction studies. Additionally, neurotoxicity studies may be
relevant based on data in humans (short-term exposure).
UFh
10
A UFh of 10 is applied for intraspecies differences to account for potentially susceptible individuals
in the absence of information on the variability of response in humans.
ufl
1
A UFl of 1 is applied because the POD was developed using a NOAEL.
UFS
1
A UFS of 1 is applied because a subchronic-duration study (Oser et al., 1975a) was utilized as the
principal study.
UFC
300

aOser et al. (1975a).
Derivation of Chronic Provisional RfD (Chronic p-RfD)
The study by Oser et al. (1975a) is selected as the principal study for derivation of a
chronic p-RfD in the absence of an acceptable chronic toxicity test in animals. The selection of
this study is detailed under the "Derivation of Subchronic p-RfD." Similar to the subchronic
p-RfD, the POD is a NOAEL of 45 mg/kg-day.
Adjusted for daily exposure:
The following dosimetric adjustments were made for each dose in the principal study for
dietary treatment.
NOAELadj = NOAELoseretai., 1975a x [conversion to daily dose]
= 45 mg/kg-day x (days of week dosed ^ 7 days in week)
= 45 mg/kg-day x 7 ^ 7
= 45 mg/kg-day
The chronic p-RfD for 2-chloroethanol, based on the NOAEL of 45 mg/kg-day (POD) in
male and female rats (Oser et al., 1975a), is derived as follows:
Chronic p-RfD = NOAELadj UFc
= 45 mg/kg-day 3000
= 2 x 10~2 mg/kg-day
Table 7 summarizes the UFs for the chronic p-RfD for 2-chloroethanol.
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Table 7. Uncertainty Factors for Chronic p-RfD of 2-Chloroethanol (CASRN 107-07-3)a
UF
Value
Justification
UFa
10
A UFa of 10 is applied for interspecies extrapolation to account for potential toxicokinetic and
toxicodynamic differences between rats and humans.
ufd
3
A UFd of 3 is applied because the database includes 2 acceptable developmental studies in mice but
no acceptable two-generation reproduction studies. Additionally, neurotoxicity studies may be
relevant based on data in humans (short-term exposure).
UFh
10
A UFh of 10 is applied for intraspecies differences to account for potentially susceptible individuals
in the absence of information on the variability of response in humans.
ufl
1
A UFl of 1 is applied because the POD was developed using a NOAEL.
UFS
10
A UFS of 10 is applied because a subchronic-duration study (Oser et al., 1975a) was utilized as the
principal study.
UFC
3000

aOser et al. (1975a).
DERIVATION OF INHALATION REFERENCE CONCENTRATION
Derivation of Subchronic or Chronic Provisional RfCs (Subchronic or Chronic p-RfCs)
No published studies investigating the effects of subchronic or chronic inhalation
exposure to 2-chloroethanol in humans or animals were identified that were acceptable for use in
derivation of subchronic or chronic p-RfCs.
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Table 8 identifies the cancer WOE descriptor for both oral and inhalation exposure to
2-chloroethanol as "Inadequate Information to Assess Carcinogenic PotentialNo
carcinogenicity dose-response studies in humans via the oral or inhalation routes were found.
Three epidemiological studies investigating the potential for 2-chloroethanol to cause cancer in
humans were located; however, the results were contradictory. Furthermore, these
epidemiological studies were insufficient to establish a causal relationship due to human
exposure to multiple chemical compounds. No animal carcinogenicity studies (oral or
inhalation) were located, regardless of route of administration. The most informative study
available was NTP (1985b,c), in which rats and mice were treated with 2-chloroethanol by
dermal application; however, this study was confounded because the 2-chloroethanol was
applied in a 70% aqueous ethanol vehicle. Ethanol protects against 2-chloroethanol toxicity. It
is noteworthy that male mice in this study were exposed to a FEL (increased mortality) without
any evidence of increased neoplastic incidence. Consequently, the WOE for carcinogenicity is
"Inadequate Information to Assess Carcinogenic Potential."
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Table 8. Cancer WOE Descriptor for 2-Chloroethanol (CASRN 107-07-3)
Possible WOE
Descriptor
Designation
Route of Entry
(Oral, Inhalation,
or Both)
Comments
"Carcinogenic to
Humans "
Not Selected
N/A
No definitive human studies are available.
"Likely to be
Carcinogenic to
Humans "
Not Selected
N/A
There are no animal carcinogenicity studies
via oral or inhalation routes.
"Suggestive
Evidence of
Carcinogenic
Potential"
Not Selected
N/A
There are no animal carcinogenicity studies
via oral or inhalation routes.
"Inadequate
Information to
Assess
Carcinogenic
Potential"
Selected
Both
There is inadequate human and animal
evidence of carcinogenicity via the oral
or inhalation route. Available
epidemiological studies provide
conflicting results regarding the possible
involvement of 2-chloroethanol in
increased cancer risk. Case studies do
not provide evidence to inform the
assessment of carcinogenic potential.
There are no animal carcinogenicity
studies via the oral or inhalation route.
"Not Likely to be
Carcinogenic to
Humans "
Not Selected
N/A

MODE OF ACTION
There are insufficient data to determine the mode of carcinogenic action.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of Provisional Oral Slope Factor (p-OSF)
No human or animal studies examining the carcinogenicity of 2-chloroethanol following
oral exposure were identified. Therefore, derivation of a p-OSF is precluded.
Derivation of Provisional Inhalation Unit Risk (p-IUR)
No human or animal studies examining the carcinogenicity of 2-chloroethanol following
inhalation exposure were identified. Therefore, derivation of a p-IUR is precluded.
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APPENDIX A. DERIVATION OF SCREENING VALUES
No screening values are presented.
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APPENDIX B. DATA TABLES
Table B.l. Mean Body-Weight, Food Efficiency, and Survival in Rats Exposed to
2-Chloroethanol via Gavage for 12 Weeksa'b
Parameter
Exposure Group (mg/kg-day)
0
30
45
67.5
Males
Mean body weight (g)
111
91
94
73
Food Efficiency (BWG in g/100 g food)
5.8
5.9
6.6
5.4
Survival (%)
100
100
100
32
Females
Mean body weight (g)
51
49
49
46
Food Efficiency (BWG in g/100 g food)
3.7
4.3
4.0
4.0
Survival (%)
96
100
96
24
"Oscr et al. (1975a). Data were obtained from Table 1 on page 314 of the cited publication.
''Means only, variations were not reported; statistical analyses were not performed.
BWG = body-weight gain.
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APPENDIX C. BMD MODELING OUTPUTS FOR 2-CHLOROETHANOL
There are no BMD modeling outputs for 2-chloroethanol.
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