United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-07/008F
Final
7-03-2007
Provisional Peer Reviewed Toxicity Values for
2-Chlorophenol
(CASRN 95-57-8)
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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Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and
Liability Act of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
i.v.	intravenous
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
NAAQS	National Ambient Air Quality Standards
NOAEL	no-observed-adverse-effect level
NOAEL(ADJ)	NOAEL adjusted to continuous exposure duration
NOAEL(HEC)	NOAEL adjusted for dosimetric differences across species to a human
NOEL	no-observed-effect level
OSF	oral slope factor
p-IUR	provisional inhalation unit risk
p-OSF	provisional oral slope factor
p-RfC	provisional inhalation reference concentration
p-RfD	provisional oral reference dose
PBPK	physiologically based pharmacokinetic
ppb	parts per billion
ppm	parts per million
PPRTV	Provisional Peer Reviewed Toxicity Value
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RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Mg
microgram
(imol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
2-CHLOROPHENOL (CASRN 95-57-8)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
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circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
A chronic reference dose (RfD) value of 5E-3 mg/kg-day is available for 2-chlorophenol
on IRIS (U.S. EPA, 1988a) and in the Drinking Water Standards and Health Advisories list (U.S.
EPA, 2004). The HEAST (U.S. EPA, 1997) lists a subchronic RfD for 2-chlorophenol of 5E-2
mg/kg-day. Both RfD values were based on a no-observed-adverse-effect level (NOAEL) of 5
mg/kg-day for reproductive effects in a drinking water study that exposed rats to 2-chlorophenol
for 10 weeks prior to mating and during mating, gestation and weaning (Exon and Koller, 1982).
Uncertainty factors of 100 and 1000 were used to derive the subchronic and chronic RfDs,
respectively. The source documents for the RfD assessments included a Drinking Water Criteria
Document (DWCD) (U.S. EPA, 1986a), a Health Effects Assessment (HEA) (U.S. EPA, 1987a),
and two Health and Environmental Effects Documents (HEEDs) (U.S. EPA, 1987b, 1990). The
Chemical Assessments and Related Activities (CARA) lists (U.S. EPA, 1991, 1994) do not
include any additional relevant EPA documents. The Agency for Toxic Substances and Disease
Registry (ATSDR, 1999) and the World Health Organization (WHO, 1989) have assessed the
health effects of chlorophenols, but did not derive any oral risk assessment values specifically for
2-chlorophenol.
An RfC for 2-chlorophenol is not available on IRIS (U.S. EPA, 1988a) nor in the HEAST
(U.S. EPA, 1997). The Agency for Toxic Substances and Disease Registry (ATSDR) and the
World Health Organization (WHO) have not derived any inhalation risk assessment values for 2-
chlorophenol. Occupational exposure limits for 2-chlorophenol have not been derived by the
American Conference for Governmental Industrial Hygienists (ACGIH), the National Institute
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for Occupational Safety and Health (NIOSH) or the Occupational Safety and Health
Administration (OSHA).
A cancer assessment for 2-chlorophenol is not available on IRIS (U.S. EPA, 1988a). The
HEEDs (U.S. EPA, 1987b, 1990) assigned 2-chlorophenol to U.S. EPA (1986b) Cancer Group D
(not classifiable as to human carcinogenicity); this classification is also included in the Drinking
Water Standards and Health Advisories list (U.S. EPA, 2004). The carcinogenicity of 2-
chlorophenol has not been assessed by NTP or IARC.
Literature searches were conducted from the 1960's through August, 2006 for studies
relevant to the derivation of provisional toxicity values for 2-chlorophenol. Data bases searched
included: TOXLINE/TOXCENTER (including BIOSIS, NTIS and Chemical Abstracts subfiles),
MEDLINE (including PubMed cancer subset), TSCATS/TSCATS 2, CCRIS, DART/ETIC,
GENETOX, HSDB, RTECS, and Current Contents.
REVIEW OF PERTINENT DATA
Human Studies
Relevant information regarding the toxicity of 2-chlorophenol in humans was not located.
Animal Studies
Oral Exposure. In a 14-day study performed in conjunction with EPA, groups of 12
male and 12 adult female CD-I ICR mice were administered 2-chlorophenol in corn oil by
gavage in doses of 0, 35, 69 or 175 mg/kg-day (Borzelleca, 1983; Borzelleca et al., 1985). The
highest dose level was approximately 50% of the acute oral LD50 of 347 and 345 mg/kg in male
and female CD-I mice, respectively. Endpoints evaluated during the study included clinical
observations, body weight (days 1, 8 and 15), and food and water intake. Endpoints evaluated at
the end of the treatment period included hematology [red blood cells (RBC), total and
differential white blood cells (WBC), platelets, hematocrit (Hct), hemoglobin (Hgb) and
coagulation], serum chemistry [lactate dehydrogenase (LDH), alkaline phosphatase (ALP),
aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN),
bilirubin, protein, glucose, cholesterol, albumin/globulin, phosphorus, potassium, calcium,
sodium and chloride], hepatic microsomal activities (cytochrome P450, cytochrome bs, protein,
aminopyrine demethylase, aniline hydroxylase, and arylhydrocarbon hydroxylase), immune
response and behavioral measurements. The earlier report of the study (Borzelleca, 1983)
implies that the immunology endpoints included cell-mediated response (Delayed-type
hypersensitivity (DTH) response to sheep RBC, response to concanavalin A), humoral response
[splenic Immunoglobulin mu (IgM) antibody forming cells (AFC) to sheep RBC, serum antibody
levels to sheep RBC, lymphocyte response to lipopolysaccharide (LPS)], and reticuloendothelial
system (RES) function (vascular clearance and uptake of 51Cr sheep RBC). The Borzelleca
(1983) report also implies that the behavioral endpoints included inverted screen test, swimming
endurance, locomotor activity, pain sensitivity, olfactory sensitivity, passive avoidance learning,
and forepaw grip strength. Other endpoints included sister-chromatid exchange (bone marrow
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and/or testes, not otherwise specified), in vitro fertilization capability (penetration of ova,
fertilization, blastula formation), absolute and relative organ weights, and gross pathology.
Histopathological examinations were not performed. The results of this study are qualitatively
reported in tabular summaries. Effects included 100% mortality at 175 mg/kg-day, hyperactivity
at 35 and 69 mg/kg-day, reduced body weight at 69 mg/kg-day, and reduced brain, liver and
spleen weights (effect levels not indicated); additional information on these effects was not
reported. No biologically or statistically significant compound-related adverse effects were
reported for the other endpoints as indicated by the authors. The 100% mortality in the high-
dose animals indicates that 175 mg/kg-day was a FEL for short-term repeated gavage exposures
in mice. The authors (Borzelleca et al., 1985) referred to the effects at the lower doses as "slight
toxic effects", but apparently concluded that they were not biologically significant, indicating
that 69 mg/kg-day was a NOAEL. Results of acute studies reported by Borzelleca et al. (1985)
include an ED50 of 63 mg/kg for reversible motor impairment in mice exposed to a single oral
dose of 2-chlorophenol; additional information was not provided.
Gavage studies (10-day and 90-day) of 2-chlorophenol in Sprague-Dawley rats were
conducted by the EPA (Daniel et al., 1993). In the 10-day study, groups of 10 male and
10 female 8-week-old Sprague-Dawley rats were administered 2-chlorophenol in corn oil by
daily gavage at doses of 0, 13, 64, 129 or 257 mg/kg-day. The highest dose level was
approximately 38% of the reported acute LD50 of 670 mg/kg for a rat. Endpoints evaluated
during the study included clinical signs (observed for physiological and behavioral responses and
mortality), body weight and food and water consumption. Evaluations at the end of the exposure
period included hematology [RBC, WBC, Hct, Hgb and mean corpuscular volume (MCV)],
serum chemistry (ALP, AST, ALT, LDH, cholesterol, BUN, creatinine, glucose, and calcium),
absolute and relative organ weights (brain, liver, spleen, lungs, thymus, kidneys, adrenal glands,
heart, and gonads), and gross pathology. Comprehensive histological examinations were
performed in the control and high-dose groups; target organs were also histologically evaluated
at the lower dose levels. Tissues that were examined included liver, kidneys, urinary bladder,
heart, aorta, skin, skeletal muscle, bone, sciatic nerve, spleen, thymus, lymph nodes, respiratory
tract (nasal turbinates, trachea, lung with bronchi), gastrointestinal tract (esophagus, stomach,
duodenum, jejunum, ileum, cecum, colon, rectum), endocrine system (adrenals, pancreas,
pituitary, thyroid/parathyroid), and reproductive system (testes, epididymis, seminal vesicles,
prostate, preputial gland, ovaries, uterus, clitoral gland).
There were no treatment-related deaths, significant clinical observations or significant
changes in food or water consumption or body weight gain (Daniel et al., 1993). The
hematology evaluations found significantly (p<0.05) increased RBC count (12% higher than
controls) and Hct (28% higher than controls) in the high-dose (257 mg/kg-day) males; these
effects were not clearly dose-related and there were no significant changes in hematologic values
in females. Serum chemistry changes that were statistically significant included increased
glucose levels in females at 129 and 257 mg/kg-day (45 and 42% higher than controls,
respectively) and males at 257 mg/kg-day (21% higher than controls); decreased ALP in females
at 129 and 257 mg/kg-day (15 and 16% lower than controls); and decreased AST, cholesterol,
and LDH in males at 257 mg/kg-day (25, 27 and 55% lower than controls, respectively). Serum
LDH values were significantly decreased in females at 64 and 129 mg/kg-day, but not at 257
mg/kg-day. The only serum chemistry changes that appeared to be dose-related were the
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increased glucose and decreased ALP in female rats, but the authors reported that these values
were within the normal ranges for laboratory rats. Statistically significant organ weight changes
consisted of decreases in absolute kidney and heart weights in females at 129 mg/kg-day, but not
at other dose levels, and decreases in absolute and relative lung weights in females at all dose
levels; quantitative data were not reported. Necropsy findings included enlarged mandibular
lymph nodes, reddened lungs and reduced thymus size in all groups of both sexes; these were
minimal to mild changes not considered to be treatment-related by the authors. The histological
examinations similarly showed lymphoid hyperplasia, mild congestion of the lungs, and mild
thymic atrophy in all groups; these effects did not appear to be treatment-related to the authors
because they were not significant in severity or incidence (data not reported). Histopathological
changes in kidneys, heart, lungs or other tissues were not reported. The lack of any clear
treatment-related or biologically significant hematology, clinical chemistry, organ weight or
pathological changes indicates that the highest dose level, 257 mg/kg-day, is aNOAEL for 10-
day gavage exposure in male and female rats although it is difficult to ascertain the significance
of the reported effects due to a lack of data reporting.
In the 90-day study, groups of 10 male and 10 female 8-week-old Sprague-Dawley rats
were administered 2-chlorophenol in corn oil by daily gavage at doses of 0, 17, 50, or 150
mg/kg-day (Daniel et al., 1993). Study endpoints were the same as in the 10-day study
summarized above; evaluations included clinical signs, body weight, food and water
consumption, hematology, serum chemistry (with the addition of triglycerides, total protein,
albumin and globulin), organ weights and gross pathology in all groups, and histopathology in
the control and high-dose groups. There were no clinical signs of toxicity, unscheduled deaths,
or significant changes in food or water consumption or body weight gain. Hematology changes
that were statistically significant included increased RBC count in females at 17 and 150 mg/kg-
day (3 and 6% higher controls), but not at 50 mg/kg-day; increased Hct in females at 150 mg/kg-
day (5% higher than controls); and increased MCV in males at 150 mg/kg-day (3% higher than
controls). Serum chemistry changes that were statistically significant included decreased ALP in
males at 50 and 150 mg/kg-day (31 and 28% less than controls), decreased AST in males at 50
and 150 mg/kg-day (22 and 19% less than controls), decreased ALT in males at 50 and 150
mg/kg-day (18 and 18% less than controls), and increased glucose at 50 mg/kg-day (16% higher
than controls; similar increases occurred at 17 and 150 mg/kg-day but were not statistically
significant). Although statistically significant changes were observed for these and several other
hematology and clinical chemistry indices, no responses were clearly dose-related, consistent
between sexes or, according to the authors, outside normal ranges or biologically significant.
There were no clear effects on organ weights; the only statistically significant changes were
increased relative liver weight in females at 17 mg/kg-day, increased absolute spleen weight in
males at 17 and 50 mg/kg-day, and increased absolute brain weight in males at 50 mg/kg-day;
quantitative data were not reported. There were no gross or histopathological changes in either
sex. The lack of any clear treatment-related or biologically significant hematology, clinical
chemistry or organ weight changes, as well as the lack of any pathological effects, indicates that
the highest dose level, 150 mg/kg-day, is a NOAEL for 90-day gavage exposure in rats.
The oral toxicity of 2-chlorophenol was also assessed in 18-day studies with preweanling
rats and in 14- and 28-day studies with juvenile rats (Hasegawa et al., 2005). Preweanling
Sprague-Dawley SPF rats were administered 2-chlorophenol in olive oil by gavage on postnatal
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days (PNDs) 4-21 in dose-finding and main studies. In the 18-day dose-finding study with
preweanling rats, groups of 4 males and 4 females were exposed to dose levels of 0, 20, 100 or
500 mg/kg-day. General behavior and body weight were evaluated during the study, and
hematology, blood chemistry, gross pathology and organ weights were evaluated on PND 22;
histopathology was not assessed. Although not specifically reported, it is assumed that the scope
of these evaluations was the same as in the main study with newborn rats summarized below.
Effects were limited to 100% mortality by the 9th day of dosing at 500 mg/kg-day; clinical signs
were not observed at 20 and 100 mg/kg-day, and no other results were reported. This study
identified a FEL of 500 mg/kg-day for lethality in preweanling rats. The next lowest dose level
of 100 mg/kg-day is a NOAEL based on the lack of clinical signs and systemic effects, but
confidence in this effect level is low due to the small numbers of animals and lack of histological
examinations.
In the main 18-day study with preweanling rats, groups of 12 male and 12 female
Sprague-Dawley SPF rats were administered 2-chlorophenol in olive oil by gavage in doses of 0,
8, 50 or 300 mg/kg-day on PNDs 4-21 (Hasegawa et al., 2005). Half of the animals were
sacrificed on PND 22, and the remaining 6 rats/sex/group were observed without treatment for
the following 9 weeks and then sacrificed (on PND 85). Endpoints evaluated during the study
included general behavior, body weight and postnatal developmental parameters, including
surface righting and visual placing reflex for reflex ontogeny, fur appearance, incisor eruption
and eye opening for external development, and preputial separation, vaginal opening and estrous
cycle for sexual development. Comprehensive hematology and blood biochemistry evaluations
were conducted at the end of the treatment period on PND 22 (6 rats/sex/dose) and end of the
observation period on PND 85 (6 rats/sex/dose). Hematology indices included RBC, Hct, Hgb,
MCV, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, total and
differential WBC, platelet count, and reticulocyte count. Blood biochemistry indices included
total protein, albumin, albumin/globulin ratio, glucose, total cholesterol, triglycerides,
phospholipid, total bilirubin, BUN, creatinine, AST, ALT, ALP, y-glutamyl transpeptidase,
calcium, inorganic phosphorus, sodium, potassium and chloride. Prothrombin time, activated
thromboplastin time, and urine indices (color, pH, occult blood, protein, glucose, ketone bodies,
bilirubin, urobilinogen, sediment, volume and osmotic pressure) were evaluated only at the end
of the observation period. Organ weights (brain, pituitary, thymus, thyroids, heart, lungs, liver,
spleen, kidneys, adrenals, testes, epididymides, ovaries and uterus) and histopathology (organs
that were weighed as well as macroscopically abnormal organs) were evaluated on PND 22 (6
rats/sex/dose); it was not indicated if these evaluations were performed on PND 85.
Effects included tremors in 11/12 males and 12/12 females at 300 mg/kg-day; the tremors
appeared within 5 minutes of dosing and disappeared within 4 hours in most animals. At 50
mg/kg-day, 1/12 females showed tremors once from 15-30 minutes following dosing on
treatment day 9. No tremors were observed in males at 50 mg/kg-day or in either sex at 0 or 8
mg/kg-day. The only other reported effects occurred at 300 mg/kg-day; these consisted of other
signs of neurotoxicity (hypoactivity in 2/12 males and 3/12 females and abnormal gait in 1/12
males and 1/12 females), transiently decreased body weight in both sexes (additional information
not reported), and histological changes in the kidneys (slight to moderate basophilic renal tubules
in 4/6 males and 5/6 females) with increases in relative kidney weight (8% in males and 4% in
females). The biological significance of the basophilic renal tubular changes was not discussed.
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No results were reported for the 9-week observation period. The 300 mg/kg-day dose is a FEL
for preweanling rats based on the occurrence of tremors in 23/24 of the exposed males and
females; other signs of neurotoxicity (hypoactivity and abnormal gait) were also observed at this
dose level. The next lowest dose of 50 mg/kg-day is a NOAEL because tremors were only
observed in 1/12 females once on exposure day 9; the incidence is not statistically different from
the control group (0/12) and the occurrence was isolated. Additionally, there were no clinical
signs of neurotoxicity in the males exposed to 50 mg/kg-day, or in the 4 males and 4 females
exposed to 100 mg/kg-day in the dose-finding study summarized above.
The studies with juvenile rats included a 14-day dose-finding study and a 28-day main
study (Hasegawa et al., 2005). In the 14-day dose-finding study, 5-week-old male and female
Sprague-Dawley SPF rats were administered 2-chlorophenol in olive oil by gavage in doses of 0,
100, 200 or 500 mg/kg-day; group sizes were 3 per sex at 500 mg/kg-day and were not reported
for the other dose levels. General behavior, body weight and food consumption were evaluated
during the study, and hematology, blood chemistry, gross pathology and organ weights were
evaluated the day after the last treatment; histopathology was not assessed. Although not
specifically reported, it is assumed that the scope of these evaluations was the same as in the
study with newborn rats summarized above. The only information regarding the results is a
statement that no toxic signs were observed, indicating that 500 mg/kg-day is a NOAEL in
juvenile rats. Confidence in this effect level is low due to the apparent small numbers of animals
and lack of histological examinations.
In the 28-day main study, groups of 12 male and 12 female 5- to 6-week old Sprague-
Dawley SPF rats were exposed to 2-chlorophenol in olive oil by gavage in doses of 0, 8, 40, 200
or 1000 mg/kg-day (Hasegawa et al., 2005). It appears that half of the animals were sacrificed
following the last treatment and the remaining 6 rats/sex/group were observed without treatment
for the following 2 weeks and then sacrificed. Evaluations included general behavior, body
weight, food consumption, urinalysis, hematology, blood biochemistry, gross pathology, organ
weights and histopathology. Although not specifically reported, it is implied that the scope and
schedule of these evaluations are the same as in the 18-day study with preweanling rats
summarized above. The only effects in this study were clinical signs of neurotoxicity and
histological changes in the liver in most animals only at 1000 mg/kg-day. The clinical signs
occurred sporadically in both sexes within 3 hours of dosing and included tremors (4/12 males
and 5/12 females), hypoactivity (8/12 males and 5/12 females) and abnormal gait (4/12 males
and 7/12 females). The liver effects consisted of slight centrilobular hypertrophy of hepatocytes
(6/6 males and 5/6 females); the authors indicated that this suggested a compensatory response
for hepatic metabolism. None of the animals showed basophilic renal tubules as observed in the
preweanling rats exposed to 300 mg/kg-day on PNDs 4-21 (see above). No results were reported
for the 2-week observation period. This study identified a FEL of 1000 mg/kg-day based on the
clinical signs of neurotoxicity; the NOAEL is 200 mg/kg-day.
Additional information on effects of repeated oral exposures to 2-chlorophenol is
available from a series of reproductive toxicity, immunotoxicity and carcinogenicity studies in
Sprague-Dawley rats that were exposed prenatally, postnatally, or both pre- and postnatally to
concentrations of 0, 5, 50 or 500 ppm 2-chlorophenol in drinking water (Exon and Koller, 1982,
1983a,b, 1985). Offspring produced in the reproductive study were used in the immunotoxicity
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and carcinogenicity studies. In the reproductive study, groups of 12-14 females were exposed to
the treated drinking water from 3 weeks of age through breeding (to untreated males) at 90 days
of age and subsequently until 3 weeks post-parturition (Exon and Koller, 1982, 1983b, 1985).
Table 1 shows the statistically significant reproductive endpoints that were reported by Exon and
Koller (1982). The values found in Exon and Koller (1983b, 1985) agree with each other but are
slightly different from those found in Exon and Koller (1982), and differ in their statistical
evaluation. The reason for the differences is unknown. Maternal and pup weight, percent
conception, litter size, and number of stillbirths were evaluated at parturition. Pup survival, body
weight and hematology (red and white cell counts, hemoglobin, packed cell volume, and mean
corpuscular volume) were evaluated at weaning.
Table 1. B
Reproductive effects of 2-Chlorophenol in Rats
Effect
Dose (ppm)
0
5
50
500
Litter Size
(mean ± SD)
11.4 ± 1.2
n=12
11.7 ± 3.5
n=12
10.1 ±2.3
n=12
9.2 ± 4.3b
n=14
Stillborn
(incidence)
0/91
2/105
0/91
6/110b
a Female rats were exposed to 2-chlorophenol in drinking water from 3 weeks of age through mating
at 90 days of age and subsequently through pregnancy and lactation.
bSignificantly different from control group (p<0.05).
Source: Exon and Koller (1982)
Statistically significant (p<0.05) changes included 19% reduced mean litter size (live and
stillborn pups) at 500 ppm (9.2 ± 4.3 compared to 11.4 ± 1.2 in controls) and 5% increased
incidence of stillbirths at 500 ppm (6/110 compared to 0/91 in controls) (Exon and Koller, 1982).
Based on the evidence of decreased litter size and an increase in stillbirth incidence, this
study identified a NOAEL of 50 ppm and a LOAEL of 500 ppm for reproductive toxicity. The
conversion factor for converting the amount of 2-chlorophenol ingested in drinking water (ppm)
to a dose (mg/kg-day) was calculated by dividing the reference water consumption of 0.031
L/day for female Sprague Dawley rats in a subchronic study by the corresponding reference body
weight in female Sprague Dawley rats (0.031 L/day/0.204 kg = 0.15 L/kg-day) (U.S. EPA,
1988b). Thus, the 5, 50 and 500 ppm doses correspond to estimated drinking water doses of
0.75, 7.5 and 75 mg/kg-day, respectively, and the NOAEL and LOAEL correspond to 7.5 and 75
mg/kg-day, respectively.
In the immunotoxicity studies, offspring from female rats described in the above studies
that were exposed to 0, 5, 50 or 500 ppm 2-chlorophenol in drinking water from 3 weeks of age
through mating at 90 days until 3 weeks post-parturition were continued on treatment for 10
weeks (Exon and Koller, 1983a) or 15 weeks (Exon and Koller, 1985), at which time immune
responses were evaluated. Tests were conducted for humoral immunity (measured as the ratio of
serum Immunoglobulin gamma (IgG) antibody levels to bovine serum albumin or keyhole limpet
hemocyanin), cell-mediated immunity (measured as delayed-type hypersensitivity response in
ears injected with oxazolone), and macrophage function (measured as the ability of peritoneal
exudate cells to phagocytize sheep red blood cells in vitro) in 4 male and 4 female offspring from
each exposure group. Body, liver, spleen, and thymus weights were also evaluated in these
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offspring. There were no statistically significant (p<0.05) differences between the treated and
control groups for any of the immune responses or other end points, indicating that a NOAEL of
500 ppm was identified. Using conversion factors of 0.14 and 0.15 L/kg-day based on
subchronic values for water consumption and body weight in male and female Sprague Dawley
rats (U.S. EPA, 1988b), respectively, the NOAEL of 500 ppm identified in these studies
corresponds to estimated drinking water doses of 70 mg/kg-day in males and 75 mg/kg-day in
females.
In the carcinogenicity studies (Exon and Koller, 1983b, 1985), groups of 24-32 male and
24-28 female rats received combined pre- and postnatal exposures to 0, 5, 50 or 500 ppm of 2-
chlorophenol in drinking water. Three-week-old females were exposed continuously through
mating (90 days of age), pregnancy and lactation, and the offspring received treated drinking
water from weaning for 24 months. All rats were observed daily for gross signs of morbidity,
and moribund or tumor-bearing rats were sacrificed. Body weight was measured monthly in all
rats, and hematology (RBC, WBC, Hct, Hgb and MCV) was evaluated every 2 weeks (Exon and
Koller, 1983b) or every 2 months (Exon and Koller, 1985) in 5 males and 5 females per group.
Gross and microscopic examinations of major organs and tumor tissues were conducted in all
animals. There were no effects on body weight at 15 weeks (Exon and Koller, 1985) or 7
months (Exon and Koller 1983b), the only times for which data were reported. A significant
decrease in body weight (p<0.10) was observed at 7 months in females at doses of 5 and 500ppm
(7.6 and 5.2% less than controls respectively). Exon and Koller (1985) noted that red blood cell
count, packed cell volume and blood hemoglobin concentrations were "generally increased" in
both sexes at 500 ppm. These effects were most evident after 14 months of exposure, when the
RBC, packed cell volume (PCV) and hemoglobin values were 15, 19 and 16% higher than
controls (p<0.05), respectively; no other quantitative hematology data were reported. In an
earlier report of interim (15-month) findings, however, Exon and Koller (1983b) indicated that 2-
chlorophenol did not affect any of the measured hematology parameters. Noncancer
histopathologic observations were not reported. Although there were no clear treatment-related
or biologically significant body weight or hematology changes, the lack of noncancer
histopathology data precludes identification of a NOAEL or LOAEL for chronic toxicity. There
were no statistically significant (p<0.10) differences between exposed and control groups in
tumor incidence, latency or type in either sex. Incidences of total tumors in the 0, 5, 50 and 500
ppm groups were 13, 17, 8 and 18% in males, and 5, 0, 13, and 18% in females, respectively; no
other incidence data were reported.
Inhalation Exposure. Relevant information regarding the inhalation toxicity of 2-chlorophenol
in animals was not located.
Other Studies
Co-carcinogenicity and Tumor Promotion. In a co-carcinogenicity study (Exon and Koller,
1983b, 1985), groups of 24-32 male and 24-28 female Sprague-Dawley rats were exposed
prenatally, postnatally, or both pre- and postnatally to 0, 5, 50 or 500 ppm 2-chlorophenol in
drinking water, with prenatal exposure to the known carcinogen ethylnitrosourea (ENU).
Comparison groups received prenatal exposure to ENU alone; comparisons were not made to
offspring unexposed to ENU or 2-chlorophenol. Rats were exposed to ENU as its precursors,
9

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ethylurea (0.316% in feed) and sodium nitrite (1 ppm in drinking water), on days 14-21 of
gestation. Prenatal exposure to 2-chlorophenol involved exposing 3-week-old females through
mating (90 days of age) and pregnancy; the dams were not exposed during lactation, and the
offspring were observed without treatment from weaning for 24 months. Postnatal exposure to
2-chlorophenol involved exposing offspring from unexposed dams to the treated water from
weaning for 24 months. Combined pre- and postnatal exposure to 2-chlorophenol involved
exposing 3-week-old females continuously through mating (90 days of age), pregnancy and
lactation, and subsequent exposure of the offspring to the treated water from weaning for 24
months. Histological examinations were performed on major organs and grossly observed
tumors, but data were only reported for total tumors.
Male offspring of rats treated with ENU and combined pre- and postnatal exposure to 2-
chlorophenol, at all treatment levels, had significantly (p<0.10) increased incidences of total
tumors when compared to the group exposed to ENU alone (Table 2). Significantly higher
incidences of total tumors also occurred in male offspring exposed to ENU and 2-chlorophenol
given prenatally at 5 and 500 ppm (but not 50 ppm), male offspring exposed to ENU and 2-
chlorophenol given postnatally at 5 ppm, and female offspring exposed to ENU and 2-
chlorophenol given prenatally or postnatally at 500 ppm. Tumor latency (mean days to tumor)
was significantly decreased in rats exposed to ENU with combined pre- and postnatal exposure
to 2-chlorophenol at all treatment levels when compared to the group exposed to ENU alone.
Although total tumor incidence was increased and time-to-tumor latency was decreased in all
groups of male rats with combined pre- and postnatal exposure to 2-chlorophenol compared with
those exposed to ENU alone, interpretation of the findings is complicated by a high tumor
incidence in the group exposed to ENU alone, lack of a dose-response relationship, and lack of
similar effects in females (Table 2). The authors concluded that the results suggest that 2-
chlorophenol may act as a co-carcinogen or promoter of carcinogenesis.
Table 2. Tumor Incidence and Latency in Rats Exposed Pre- and Postnatally to 2-
Chlorophenol with Prenatal Exposure to ENU (Exon and Koller, 1983b)
2-Chlorophenol (ppm)
(Pre-and Postnatal +
ENU)
Total Tumor Incidence (%)
No. Rats/Group
Days to
Tumor
(mean ± SE)
Total
Male
Female
Male
Female
Unexposed
3
7
0
30
30
422 ± 40
ENU only
58
54
63
28
24
302 ± 16
5
85a
92a
79
24
24
245 ±14a
50
63
75a
50
24
24
256±17a
500
68
IT
60
30
30
259±14a
ap<0.10 compared to ENU positive control group by chi-square test (incidence data) or analysis of variance
(least-square means) (latency data).
The skin tumor-promoting ability of 2-chlorophenol was assessed in 2- to 3-month old
female albino Sutter mice (Boutwell and Bosch, 1959). When 25|il of a 20% solution of 2-
chlorophenol in benzene was applied to shaved back skin twice weekly for 15 weeks following
initiation with a single 25|il application of 0.3% DMBA (9,10-dimethyl-l,2-benz[a]anthracene)
in benzene, 31/35 mice survived compared to 15/20 similarly initiated vehicle control mice. Of
the survivors, 61% had skin papillomas compared to 7% in controls, and 10% had skin
10

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carcinomas compared to 0% in controls. When 2-chlorophenol was applied as a 20% solution in
dioxane to uninitiated mice twice weekly for 12 weeks, 28/30 mice survived; 46% of the
survivors had papillomas and 0% developed carcinomas. A dioxane-treated vehicle control
group was not reported.
Genotoxicity. A limited amount of information is available on the genotoxicity of 2-
chlorophenol. 2-Chlorophenol did not induce reverse mutations in Salmonella typhimurium
strains TA98, TA100, TA1535 and TA1537 when tested with or without exogenous metabolic
activation (Haworth et al., 1983). 2-Chlorophenol did not induce DNA-repairing genes
(umuDC) in S. typhimurium TA1535/pSK1002 (Ono et al., 1992), or DNA damage in
Escherichia coli as shown by the induction of prophage lambda (DeMarini et al., 1990), when
tested with or without exogenous metabolic activation. Sister-chromatid exchanges were not
increased in mice that were exposed to 2-chlorophenol in corn oil by gavage in doses of 35-175
mg/kg-day for 14 days (Borzelleca et al., 1985); bone marrow and testicular cells (specific cell
types not indicated) were examined.
DERIVATION OF A PROVISIONAL SUBCHRONIC ORAL RfD
FOR 2-CHLOROPHENOL
Subchronic RfD
Information relevant to the derivation of a subchronic oral RfD for 2-chlorophenol is
available from one 14-day study in mice (Borzelleca, 1983; Borzelleca et al., 1985) and several
studies in rats ranging in exposure duration from 10 days to approximately 16-21 weeks (Daniel
et al., 1993; Exon and Koller, 1982, 1983a, 1985; Hasegawa et al., 2005). The preponderance of
these studies used gavage exposure and showed frank toxic effects, particularly mortality and
clinical signs of neurotoxicity, as summarized in Table 3. The gavage studies identified FELs of
175 mg/kg-day for mortality in mice exposed for 14 days (Borzelleca, 1983; Borzelleca et al.,
1985), 300 mg/kg-day for overt neurotoxicity (tremors) and 500 mg/kg-day for mortality in
preweanling rats exposed for 18 days on PNDs 4-21 (Hasegawa et al., 2005), and 1000 mg/kg-
day for overt neurotoxicity (tremors, hypoactivity and abnormal gait) in rats exposed for 28 days
(Hasegawa et al., 2005). Although these are generally well-designed studies with comprehensive
evaluations that included clinical signs, body weight, hematology, clinical chemistry, organ
weights, histology and, in the study with preweanling rats, postnatal developmental indices, they
did not identify more subtle indicators of toxicity and actual data were not supplied in some
instances. NOAELs in the gavage studies were 69 mg/kg-day in mice exposed for 14 days
(Borzelleca, 1983; Borzelleca et al., 1985), 50 and 100 mg/kg-day in preweanling rats exposed
for 18 days on PNDs 4-21 (Hasegawa et al., 2005), 150 mg/kg-day in rats exposed for 90 days
(Daniel et al., 1993), and 200 mg/kg-day in rats exposed for 28 days (Hasegawa et al., 2005).
11

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Table 3. Summary of Effect Levels from Oral Toxicity Studies of 2-Chlorophenol
Species
Exposure
Duration
NOAEL'
LOAEL'
FELa
Effects
Reference
mouse
14 days
(gavage)
69
ND
175
100% mortality at 175 mg/kg-
day. No biologically
significant effects at 69 mg/kg-
dayb'°.
Borzelleca,
1983;
Borzelleca et
al., 1985
rat
10 days
(gavage)
257
ND
ND
No clear treatment-related or
biologically significant
effects'3.
Daniel et al.,
1993
rat
90 days
(gavage)
150
ND
ND
No clear treatment-related or
biologically significant
effectsbd
Daniel et al.,
1993
rat
18 days
(PND 4-21)
(gavage)
100
ND
500
100% mortality at 500 mg/kg-
day. No effects at 100 mg/kg-
day but small numbers of rats
were tested. Dose-finding
study with no histologyb.
Hasegawa et al.,
2005
rat
18 days
(PND 4-21)
(gavage)
50e
ND
300
Tremors in 23/24 males and
females at 300 mg/kg-day. No
clear treatment-related effects
at 50 mg/kg-dayb'd.
Hasegawa et al.,
2005
rat
14 days
(gavage)
500
ND
ND
No clinical signs or other
effects but small numbers of
rats were tested. Dose-finding
study with no histologyb.
Hasegawa et al.,
2005
rat
28 days
(gavage)
200
ND
1000
Tremors, hypoactivity,
abnormal gait and centrilobular
hepatocellular hypertrophy at
1000 mg/kg-day. No reported
effects at 200 mg/kg-daybd.
Hasegawa et al.,
2005
rat
16 weeks'
(drinking
water)
7.5
75
ND
Reduced litter size (19%) and
increased incidence of
stillbirths.
Exon and
Koller, 1982,
1985
rat
16-21
weeks8
(drinking
water)
75
ND
ND
No effects on immune
responses'1 or body, liver,
spleen or thymus weights.
Other endpoints not evaluated.
Exon and
Koller, 1983a,
1985
ND = not determined
amg/kg-day
bEndpoints included clinical signs, body weight, hematology, serum chemistry, organ weights and gross pathology.
cEndpoints included immune responses and behavioral tests.
dEndpoints included histopathology.
eThe only reported effect was tremors in 1/12 females that occurred once on treatment day 9.
fFemale rats were exposed from 3 weeks of age through mating to untreated males at 90 days of age and subsequently through
pregnancy and lactation.
BOffspring of female rats that were exposed from 3 weeks of age through mating to untreated males at 90 days of age and
subsequently through pregnancy and lactation were continued on treatment for 10-15 weeks.
hTests for humoral immunity, cell-mediated immunity and macrophage function were conducted.
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Drinking water studies (Exon and Koller, 1982, 1983a and b, 1985) investigated
reproductive and immunological toxicity in rats. There were no effects on immune function in
rats that were exposed to 75 mg/kg-day via maternal drinking water during gestation and
lactation and subsequently by direct consumption for 10-15 weeks (Exon and Koller, 1983a,
1985). Exposure to 75 mg/kg-day in drinking water during pregnancy and lactation significantly
(p<0.05) affected litter size (19% reduced) and stillbirths (5% increased) in rats (Exon and Koller
1982, 1985); no effects on litter size occurred at 7.5 mg/kg-day. Therefore, reproductive toxicity
as evidenced by decreased litter size and an increase incidence in stillbirths was chosen for the
development of the subchronic RfD for 2-chlorophenol based on a NOAEL of 7.5 mg/kg-day
(Exon and Koller, 1982).
The NOAEL of 7.5 mg/kg-day is divided by a composite uncertainty factor of 1000 to
derive a provisional subchronic RfD of 8E-3 mg/kg-day, as follows:
sRfD	= NOAEL / UF
= 7.5 mg/kg-day / 1000
= 0.0075 or 8E-3 mg/kg-day
The composite UF of 1000 includes a factor of 10 for animal-to-human extrapolation, 10
for interindividual variability and 10 for database deficiencies.
1/2
The animal-to-human UF of 10 reflects a factor of three (10 ) for pharmacokinetic
differences across species and a factor of three (10 /2) for pharmacodynamic considerations.
The intraspecies UF of 10 is used to account for variation in sensitivity within human
populations because there is limited information on the degree to which humans of varying
gender, age, health status or genetic makeup might vary in the disposition of, or response to, the
chemical.
An UF for extrapolation from a LOAEL to a NOAEL is not necessary because a NOAEL
was chosen for the point of departure for the derivation for the sRfD.
The UF of 10 for database deficiencies is applied due to the lack of comprehensive
reproductive and developmental toxicity studies, including a two-generation reproductive
toxicity study and a subchronic study in mice (see below).
Confidence in the key study is low because a limited number of reproductive/
developmental endpoints (maternal and pup weight, percent conception, litter size and number of
stillborn) were evaluated and the adequacy of the reporting is marginal. Confidence in the
database is also low. The database includes 18-day, 28-day and 90-day studies in rats that
assessed systemic toxicity and postnatal developmental toxicity at doses that include the range of
those tested in the key study. Deficiencies in the database include the lack of comprehensive
reproductive and developmental toxicity studies (especially important because reproductive
effects have been identified as critical for this chemical) and a subchronic toxicity study longer
than 14 days in duration in mice, which appeared to be more sensitive than rats to the subchronic
effects of the chemical. In addition, a two-generation reproductive toxicity study is not
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available. Considering the levels of confidence in the key study and data base and the lack of
supporting data for the critical effects, confidence in the provisional RfD is low.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR 2-CHLOROPHENOL
No information is available on the subchronic or chronic inhalation toxicity of 2-
chlorophenol, precluding derivation of RfC values for this chemical.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR 2-CHLOROPHENOL
Weight-of-evidence Classification
Information regarding the carcinogenicity of 2-chlorophenol mainly consists of the
negative results of a drinking water study in which rats were exposed to 0, 5, 50 or 500 ppm via
maternal consumption during pregnancy and lactation and subsequently by direct consumption
for 24 months (Exon and Koller 1983b, 1985). There were no significant increases in tumor
incidence, latency or type in either sex, but a definitive conclusion regarding carcinogenicity is
precluded by the use of marginal numbers of animals for a cancer bioassay (24-32/sex/dose
level) and the apparent lack of a MTD, because the only observed effects (body weight and
hematology changes) were not clearly treatment-related or biologically significant.
The ability of 2-chlorophenol to act as a promoter or co-carcinogen was investigated in a
study with the known carcinogen ENU (Exon and Koller 1983b, 1985). Male rats that were
exposed to 0, 5, 50 or 500 ppm of 2-chlorophenol in drinking water via maternal consumption
during pregnancy and lactation and subsequently by direct consumption for 24 months,
combined with prenatal exposure to ENU, had increased total tumor incidences and decreased
time-to-tumor latencies compared to rats exposed to ENU alone. Another study found that
dermal application of 2-chlorophenol promoted the formation of DMBA-initiated skin tumors in
mice (Boutwell and Bosch, 1959).
2-Chlorophenol has been studied in several short term in vitro and in vivo animal studies.
2-Chlorophenol did not induce reverse mutations or DNA-repair in S. typhimurium (Haworth et
al., 1983; Ono et al., 1992), DNA damage in E. coli (DeMarini et al., 1990), or sister-chromatid
exchanges in orally-exposed mice (Borzelleca et al., 1985).
In accordance with current EPA cancer guidelines (U.S. EPA, 2005), the available data
are inadequate for an assessment of human carcinogenic potential.
Quantitative Estimates of Carcinogenic Risk
Derivation of quantitative estimates of cancer risk for 2-chlorophenol is precluded by the
lack of data demonstrating carcinogenicity associated with 2-chlorophenol exposure.
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7-3-2007
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