United States
Environmental Protection
1=1 m m Agency
EPA/690/R-10/019F
Final
9-29-2010
Provisional Peer-Reviewed Toxicity Values for
4-Methylphenol (p-Cresol)
(CASRN 106-44-5)
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
Harlal Choudhury, DVM, Ph.D., DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
John C. Lipscomb, Ph.D., DABT, Fellow ATS
National Center for Environmental Assessment, Cincinnati, OH
Maureen R. Gwinn, Ph.D., DABT
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).
l

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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	iii
BACKGROUND	1
HISTORY	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	2
INTRODUCTION	2
REVIEW 01 PERTINENT DATA	4
HUMAN STUDIES	4
Oral Exposure	4
Inhalation Exposure	4
ANIMAL STUDIES	5
Oral Exposure	5
Subchronic Studies	5
Reproductive/Developmental Studies	17
Inhalation Exposure	21
Subchronic Studies	21
OTHER STUDIES	22
Toxicokinetics	22
Acute/Short-term Toxicity	23
Other Routes	23
Neurotoxicity	24
Immunotoxicity	24
Mechanistic	24
Genotoxicity	24
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD VALUES
I OR 4-METHYLPHENOL	25
SUBCHRONIC AND CHRONIC p-RfD	25
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR 4-METHYLPHENOL	28
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR 4-METHYLPHENOL	28
WEIGHT-OF -E VIDEN CE DESCRIPTOR	28
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK	29
REFERENCES	29
ii

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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMD
benchmark dose
BMCL
benchmark concentration lower bound 95% confidence interval
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
POD
point of departure
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
4-METHYLPHENOL (P-CRESOL) (CASRN 106-44-5)
BACKGROUND
HISTORY
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1)	EPA's Integrated Risk Information System (IRIS)
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in EPA's Superfund
Program
3)	Other (peer-reviewed) toxicity values, including
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR);
~	California Environmental Protection Agency (CalEPA) values; and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's IRIS. PPRTVs are developed according to a Standard
Operating Procedure (SOP) and are derived after a review of the relevant scientific literature
using the same methods, sources of data, and Agency guidance for value derivation generally
used by the EPA IRIS Program. All provisional toxicity values receive internal review by a
panel of six EPA scientists and external peer review by three independently selected scientific
experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram
consensus review provided for IRIS values. This is because IRIS values are generally intended
to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund
Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
DISCLAIMERS
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
An RfD for 4-methylphenol (p-cresol) is not available on IRIS (U.S. EPA, 2008) or the
Drinking Water and Health Advisories list (U.S. EPA, 2006). The Health Effects Assessment
Summary Tables (HEAST; U.S. EPA, 1997) lists a chronic RfD of 0.005 mg/kg-day for/?-cresol
that was originally derived in a 1991 Health and Environmental Effects Document (HEED) for
4-methylphenol (U.S. EPA, 1991a). The critical effects were symptoms of overt maternal
toxicity (respiratory distress, cyanosis, ocular discharge, hypoactivity, and death) at
50 mg/kg-day or higher in a gavage developmental toxicity study in rabbits (BRRC, 1988a). The
RfD was derived by applying a UF of 1000 (10 for extrapolation to chronic exposure, 10 for
extrapolation from animals to humans, and 10 for human variability) to the NOAEL of
5 mg/kg-day for maternal effects. Confidence in the RfD was considered medium. In the
HEAST (U.S. EPA, 1997), the chronic RfD was also adopted as the subchronic RfD. In addition
to the previously mentioned HEED, the Chemical Assessments and Related Activities (CARA)
list (U.S. EPA, 1991b, 1994) references a Health Effects Assessment (HEA) (U.S. EPA, 1984)
and a Health and Environmental Effects Profile (HEEP) for Cresols (U.S. EPA, 1985).
However, at the time those documents were produced, the oral data were not adequate for use in
deriving toxicity values.
The Agency for Toxic Substances and Disease Registry (ATSDR, 2006) recently released
a public comment draft update toxicological profile for cresols in which an intermediate-duration
oral MRL of 0.1 mg/kg-day was derived for m/p-cresol from a BMDLio of 13.94 mg/kg-day for
nasal lesions in a 13-week dietary study of an m/p-cresol (60:40) mixture in rats. ATSDR (2006)
concluded that the MRL for mlp-cresol should also be protective for exposures to the individual
isomers (i.e., can be adopted for o-, m- and />cresol). ATSDR (2006) considered only dietary
studies in deriving this MRL based on the conclusion that gavage studies showed markedly
different effects than dietary studies and the premise that dietary exposure is more relevant than
gavage with regard to human exposure. Due to a lack in chronic oral data, a chronic oral MRL
was not derived. As presented in an Environmental Health Criteria document for cresols (WHO,
1995), the World Health Organization derived an acceptable daily intake (ADI) of
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0.17 mg/kg-day for all three cresol isomers (o- m-, and />cresol) based on a NOAEL of
50 mg/kg-day in (unspecified) subchronic studies. The California Environmental Protection
Agency (CalEPA, 2005a) has not derived a chronic oral REL for 4-methylphenol.
No RfC values for 4-methylphenol are reported in IRIS (U.S. EPA, 2008) or the HEAST
(U.S. EPA, 1997). ATSDR declined to derive inhalation MRLs due to limitations in the
available inhalation data (ATSDR, 2006). CalEPA (2005a, 2005b) derived a chronic inhalation
"3
REL of 600 |ig/m (100 ppb) for cresol mixtures. The REL is based on oral subchronic toxicity
data and was adopted for p-cresol (4-methylphenol) and the other cresol isomers.
Based on the limited data that were available, the National Institute for Occupational
Safety and Health (NIOSH) established a recommended exposure limit-time weighted average
(REL-TWA) of 2.3 ppm (10 mg/m3) (NIOSH, 1978, 2005). The American Conference of
Governmental Industrial Hygienists (ACGIH) took a different approach and recommended a
-3
threshold limit value-time weighted average (TLV-TWA) of 5 ppm (22 mg/m ) with a skin
notation, based on analogy to phenol (ACGIH, 2001, 2007). The Occupational Safety and
Health Administration permissible exposure limit-time weighted average (OSHA PEL-TWA) is
5 ppm (22 mg/m3) with a skin notation (OSHA, 2008).
A carcinogenicity assessment for 4-methylphenol is available on IRIS (U.S. EPA, 2008).
This assessment is derived from the 1985 HEEP for Cresols (U.S. EPA, 1985). 4-Methylphenol
was assigned to cancer weight-of-evidence Group C, possible human carcinogen based on an
increased incidence of skin papillomas in mice in a dermal initiation-promotion study (Boutwell
and Bosch, 1959). Supporting data from genotoxicity tests include positive results from an
unpublished study of induction of unscheduled DNA synthesis in human lung fibroblasts (with
metabolic activation) treated with 4-methylphenol and positive results in a number of other
genotoxicity tests using a mixture of 2-, 3-, and 4-methylphenol isomers. Limited anecdotal data
from occupationally exposed individuals were considered to be inadequate. The HEAST
(U.S. EPA, 1997) reports the availability of the weight-of-evidence assessment on IRIS but
contains no additional information. The International Agency for Research on Cancer (IARC)
has not evaluated 4-methylphenol for carcinogenicity (IARC, 2007). The National Toxicology
Program (NTP, 2006) has not tested the chronic toxicity/carcinogenicity of 4-methylphenol
(p-cresol), but a 2-year study of mixed w/^-cresol (60:40) isomers in rats and mice was recently
completed and the results are available in a preliminary report. NTP (2005) did not include
4-methylphenol in the 11th Report on Carcinogens. CalEPA (2002) has not derived a cancer
potency factor for 4-methylphenol.
Literature searches were conducted from 1960s through January 2010 for studies relevant
to the derivation of provisional toxicity values for 4-methylphenol. The following databases
were searched: MEDLINE, TOXLINE (Special), BIOSIS, TSCATS 1/TSCATS 2, CCRIS,
DART/ETIC, GENETOX, HSDB, RTECS, and Current Contents.
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REVIEW OF PERTINENT DATA
Human Studies
An English abstract of a study published in Japanese reported the presence of fecal
4-methylphenol in 8/8 colonic carcinoma patients and 28/30 rectal carcinoma patients
(Kubo, 1990). The authors stated these findings in cancer patients differed significantly
(p < 0.01) from healthy controls, suggesting a possible association between increased excretion
of 4-methylphenol and cancer. The source of the 4-methylphenol1, and whether or not
4-methylphenol is a causal agent or a by-product of a carcinogenic process, was not determined.
Renwick et al. (1988) found high variability in the excretion of 4-methylphenol and
phenol in 32 patients with histologically confirmed carcinoma of the urinary bladder and in a
group of sex- and age-matched controls. Their findings suggest that endogenously produced
phenols—including 4-methylphenol—do not contribute significantly to the development of
bladder cancer in humans. However, a more recent study by Schepers et al. (2007) discussed
briefly in the "Mechanistic" section, indicates that a metabolite of 4-methylphenol, rather than
the parent compound, could be responsible for increasing pro-inflammatory vascular damage that
subsequently leads to development of urinary system pathology.
Oral Exposure
No information was located concerning health effects in humans following oral exposure
to 4-methylphenol (p-cresol) alone. Case studies of individuals who drank cresol-containing
disinfectants report irritation of mouth and throat, abdominal pain, and vomiting (summarized by
ATSDR, 2006; WHO, 1995). Primary targets of ingested cresols appear to be the central
nervous system (reduced consciousness, coma), blood (methemoglobinemia, hemoglobinemia,
hemoglobinuria, reduced erythrocyte glutathione levels), and kidneys (irritation, tubular
degeneration). There is also some indication of toxicity in lungs, heart, and liver.
Inhalation Exposure
No studies regarding the effects of inhalation exposure to 4-methylphenol in humans
were identified. Due to its low vapor pressure, exposure to methylphenols is not likely to occur
except under conditions where aerosols are formed or at high temperatures. A few studies that
discuss effects associated with exposure to other methylphenol isomers and mixtures are
summarized briefly.
"3
Uzhdavini et al. (1972) reported that 8/10 volunteers exposed to 6 mg/m of a
vapor/aerosol mixture of 2-methylphenol complained of throat irritation and nasal constriction
-3
and dryness. The duration of exposure is not reported, but 6 mg/m appears to be the threshold
concentration for mucosal irritation. Molodkina et al. (1985) observed circulatory disturbances
and minor hematological changes (decreased RBC, WBC, and platelets; decreased
glucose-6-phosphatase dehydrogenase activity and sulfhydryl group concentrations within
erythrocytes; and reduced life span of erythrocytes) in female workers exposed to tricresol (a
mixture of 2-, 3-, and 4-methylphenol) while producing enameled wire. Mean exposure
3	3
concentrations of 1.4 mg/m and maximum concentrations of 3.6-5.0 mg/m were recorded. Of
the 96 women included in the study, 70% were exposed for 10 years or more. In another study,
1 4-methylphenol is an endogenous byproduct of metabolism as well as an environmental contaminant.
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reproductive disorders (hormonal shifts, menstrual problems, high perinatal mortality, and
abnormal development of children) were reported among female workers exposed to tricresol
during the production of enameled wire (Syrovadko and Malysheva, 1977). Pashkova (1973)
also reported an increased incidence of menstrual disturbances in women workers exposed to
tricresol (along with phosphoryl chloride and tricresylphosphate). These incidences were related
to increased estrogen and decreased progesterone activity resulting from ovarian dysfunction. It
is uncertain whether the workers in these studies were exposed to other chemicals and whether
dermal exposure was an important factor.
Animal Studies
Oral Exposure
Subchronic Studies—Sprague-Dawley rats (30/sex/group) were given 4-methylphenol
(99.9% pure) in corn oil by gavage at doses of 0, 50, 175, or 600 mg/kg-day, once daily, for
13 weeks (MBA, 1988). Clinical signs were observed twice daily. Body weights were recorded
on the first day of dosing and weekly thereafter, and weekly food consumption was noted. Rats
were subjected to weekly physical examinations. Ophthalmologic examinations were performed
prior to treatment initiation and during treatment Week 13. Subgroups (10/sex/dose) were
sacrificed during Week 7 for interim evaluation of hematology and urinalysis. Hematology and
urinalysis were evaluated again just prior to study termination. Complete gross necropsy was
conducted on all rats in the study. All major tissues and organs from all control and high-dose
animals sacrificed at study termination as well as those that died during the study were examined
microscopically. Individual organ weights (heart, spleen, brain, kidneys, gonads, adrenals, and
thyroid/parathyroid) were recorded from animals surviving until terminal sacrifice.
The authors noted death in 3/30 high-dose female rats within the first 3 days of dosing
(MBA, 1988). Two of the females that died had tremors or convulsions, and both were comatose
prior to death. The third female died without manifesting clinical signs. Of the surviving rats,
clinical signs were observed throughout the 13 weeks of the study only in high-dose rats. The
most common clinical signs were excessive salivation and lethargy, with occasional tremors;
these signs disappeared within 1 hour postdosing. The authors reported no deaths or clinical
signs of toxicity in mid- or low-dose groups. Significantly (p < 0.05) reduced food consumption
was apparent in the high-dose males and females and in the mid-dose males during early weeks
of dosing. The high-dose male and female rats had significantly (p < 0.05) lower final mean
body weights (15 and 8%, respectively) and reduced mean body-weight gains (21 and 13%,
respectively), relative to controls. Effects on body weight in mid- and low-dose rats were seen
during the first few weeks of dosing, but were no longer apparent by study termination. At study
termination, dose-related reductions in red blood cell count, hemoglobin concentration, and
hematocrit were seen in mid- and high-dose female (but not male) rats. Table 1 summarizes the
data.
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Table 1. Significant Results for Rats at Study Termination Following Gavage
Administration of 4-Methylphenol (p-Cresol) for 13 Weeksa
Variable
0 mg/kg-day
50 mg/kg-day
175 mg/kg-day
600 mg/kg-day
Females (n = 10 unless noted otherwise)
RBC (x 106 mm3)
8.83 ±0.48
8.44 ±0.44
8.18 ± 0.50b
8.09 ± 0.54b
Hgb (g/dL)
16.3 ±0.7
15.9 ± 0.7
15.3 ± 0.8b
15.1 ±0.7b
HCT (%)
46.4 ±2.3
44.4 ±2.0
42.9 ± 2.1b
42.1 ± 1.8b
ALT (iu/L)
32 ± 17
38 ±29
39 ± 12
158 ± 195b
AST(iu/L)
79 ± 15
90 ±35
79 ± 17
189 ± 64b
Cholesterol (mg/dL)
96.1 ± 14.0
95.2 ± 14.3
109.5 ±22.4
139.0 ±43.4b
Males (n = 10 unless noted otherwise)
Phosphate (mg/dL)
10.0 ±2.0
8.9 ±0.9
9.9 ± 1.3 (9)
8.4 ± 1.0b
Total Protein (g/dL)
6.8 ±0.30
7.0 ±0.30
7.3 ± 0.4b
7.6 ± 0.6b
aMBA, 1988; values are mean± SD.
bStatistically significant from controls, p < 0.05, Analysis of Variance, Dunnett's test.
Mean serum ALT was significantly elevated in high-dose females at the interim
evaluation (MBA, 1988). Both ALT and AST were significantly elevated in high-dose females
(but not males) at the end of the study. The elevated ALT and AST values can be attributed to
unusually high values in 4/10 females, two of which also had chronic hepatic inflammation.
Other changes in clinical chemistry variables were noted at study termination and included
increased serum cholesterol in high-dose females, decreased total phosphate in high-dose males,
and increased total protein (mostly globulins) in mid- and high-dose males. Table 1 summarizes
these clinical chemistry values. The increases in ALT, AST, and cholesterol can be attributed to
treatment-related effects on the liver. The increase in serum protein could be due to nutritional
status and/or metabolic derangement; liver and kidney pathology is usually accompanied by
decreases, rather than increases, in serum proteins. The decrease in phosphate at the high dose
lacks biological relevance and appears to be an artifact of statistical testing.
Significant changes in organ weights that were considered to be treatment-related
included elevated relative kidney weights (increased by approximately 17 and 10% in high- and
mid-dose males, respectively and 11% in high-dose females) and elevated relative (6% higher)
but decreased absolute (10% lower) liver weight in high-dose males only (MBA, 1988). Other
typically slight, but significant (p < 0.05) changes in organ weights were noted for the heart and
testes of high-dose males, brain of high-dose males and females, ovaries of high-dose females,
and spleen of low-dose females. In the high-dose groups, at least some of these changes in
relative organ weights were attributed to depressed body-weight gain. In male rats, a slight—but
statistically significant (p < 0.05)—increase in the incidence of minimal-to-mild nephropathy
was noted in low-dose (11/20) and high-dose (12/20) male rats compared with 4/20 in controls;
at mid-dose, the incidence (7/20) did not reach statistical significance. Incidences of
nephropathy in the control groups of male rats used in o-cresol and m-cresol studies conducted
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concurrently by the same laboratory were 10/20 and 7/20, respectively. Due to the variable
incidence of this lesion (even among controls), the absence of a dose-related increased incidence
or severity and the absence of nephropathy in female rats, the observed nephropathy in male rats
is considered to be an equivocal treatment-related effect. Trachea-epithelial metaplasia was
noted in 10/20 high-dose males and 9/20 high-dose females versus none in sex-matched controls.
The NOAEL for the study is 50 mg/kg-day. The LOAEL for the study is 175 mg/kg-day, based
on anemia (reduced RBC count, hemoglobin, and hematocrit) in female rats.
In a subchronic neurotoxicity study, CD rats (10/sex/group) were exposed to
4-methylphenol in corn oil by gavage once daily at doses of 50, 175, or 600 mg/kg-day for
13 weeks (TRL, 1986). Groups of 20 male and 20 female rats served as vehicle controls. Body
weights and food consumption were recorded weekly. Clinical observations were made at least
twice daily throughout the study. Observations for signs of neurotoxicity were made once during
the pretreatment period, 1- and 6-hours postdosing on Day 1 and prior to dosing on Days 2, 7,
14, 30, 60, and 90. Each animal was observed for respiration, salivation, urination, tremors,
piloerection, diarrhea, pupil size, pupil response, lacrimation, hypothermia, vocalization,
exophthalmos, palpebral closure, and convulsions, followed by tests for positional passivity, wire
maneuverability, forelimb grip strength, positive geotropism, extensor thrust, limb rotation, tail
pinch, toe pinch, and hind-limb splay. Randomly selected animals from each test group received
neuropathological examinations as follows. The brain and spinal cord of 10 controls per sex and
5 per sex of each treatment group were grossly examined for signs of treatment-related toxicity.
Microscopic exams of forebrain, center of cerebrum, midbrain, cerebellum, pons, medulla
oblongata, cervical and lumbar portions of the spinal cord, dorsal root ganglia, ventral root
fibers, Gasserian ganglia, proximal sciatic nerve, sural nerve, tibial nerve, and eye and optic
nerve were conducted for an additional 10 male and 10 female controls and for 5 rats per sex of
each treatment group. Gross pathological examinations were performed on the contents of
cranial, thoracic, and peritoneal cavities of animals found dead during the course of the study.
Esophagus, stomach, lungs with trachea, and some gross lesions taken from animals succumbing
early were prepared for microscopic evaluation.
Mortality was noted in 4/10 high-dose rats of each sex (TRL, 1986). Of these eight
deaths, seven were considered to be directly compound-related (five were associated with
respiratory distress). There were no deaths in any of the other study groups. Compound-related
mortality was greatest during the first few treatment weeks. Treatment-related effects on body
weight or food consumption were confined to the high-dose groups and consisted of significant
(p < 0.05) lower mean body weight in males during the first week of the study only and reduced
mean food consumption in males and females during the initial portion of the study. Clinical
signs were dose-related in incidence and include salivation, myotonus, tremors, urine wet
abdomen, hypoactivity, rapid respiration, myoclonus, low body posture, and labored respiration.
Convulsions were also reported to occur in a few high-dose animals. Incidences of salivation,
myotonus, tremors, and urine-wet abdomen increased or remained the same throughout the
study. The tables that summarize the detailed incidence data for the clinical signs reported in the
study narrative are not in the report (TRL, 1986), and, therefore, are not presented here.
However, available clinical symptoms discussed in this report are clear indications of
neurotoxicity endpoint and considered relevant for development of toxicity values. Myotonus
was observed only among high-dose animals. The incidences of hypoactivity and rapid
respiration appeared to increase during the first few weeks of treatment and all dose groups were
affected in a dose-related manner. Dose-related incidences of myoclonus, low body posture, and
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labored respiration (mid- and high-dose groups only), noted only in a few rats, were greatest
during the first week of treatment and sporadic thereafter. The study authors indicated that the
50 mg/kg-day dose level appeared to be an "adverse effect level" for clinical signs related to
neurotoxicity, although diminished response with repeated dosing indicated that there might have
been some degree of adaptation to exposure to 4-methylphenol. The results of neurobehavioral
tests and neuropathological examinations were negative. The NOAEL for this study is
50 mg/kg-day. The LOAEL is 175 mg/kg-day, and it is based on clinical signs of neurotoxicity.
Hirose et al. (1986) fed groups of 15 male Syrian golden hamsters 0 or 1.5%
4-methylphenol (25% of the LD50) of >98%) purity in the diet for 20 weeks (equivalent to
1500 mg/kg-day). Three animals of each group were dosed intraperitoneally with radiolabeled
thymidine before sacrifice and evaluated for increased thymidine uptake in the epithelium of the
glandular stomach and bladder. Increased thymidine uptake is indicative of an increase in
mitosis that could be a precursor to proliferative changes such as cancer. The liver, kidneys,
lungs, cheek pouch, esophagus, stomach, pancreas, and urinary bladder were removed from all
animals. Livers and kidneys were weighed and fixed in formalin. Sections of the forestomach,
glandular stomach, and urinary bladder were evaluated histologically. Data for body weight,
liver weight, forestomach histopathology, and thymidine uptake in the forestomach, pyloric
region, and urinary bladder are shown in the report.
4-Methylphenol induced small and nonsignificant increases of mean thymidine uptake in
the forestomach and pyloric region (1.5 times that of controls), and a large—but nonsignificant
(3.5 times)—increase in the urinary bladder (Hirose et al., 1986). The lack of statistical
significance in the latter effect is likely due to the large standard deviation in the treatment group
(0.28 ± 0.39 versus 0.08 ± 0.14 in controls). Statistically significant (p < 0.05) mild
(15/15 treated versus 7/15 controls) to moderate hyperplasia (10/15 treated versus 1/15 controls)
was observed without papillomatous lesions in the forestomach of treated hamsters. Exposure
was not continued long enough to determine whether the forestomach lesions would progress to
neoplasia or whether the increased mitosis in the bladder could have been a precursor to tumor
formation. The LOAEL for this study is 1500 mg/kg-day (only dose tested).
Forestomach hyperplasia was not observed in male and female Wistar rats following
dietary exposure to 4-methylphenol at a concentration of 2%> (2000 mg/kg-day, assuming a food
factor of 0.1 for subchronic or shorter duration in rats) for an unspecified period of time
(Altmann et al., 1986). The purpose of this investigation was to compare the effects of
3-tert-butyl-hydorxyanisole (BHA) on the forestomach with a variety of structurally similar
compounds. No further details were provided with regard to 4-methylphenol.
NTP (1992a) fed groups of F344/N rats and B6C3Fi mice (5/sex/species) diets containing
0, 300, 1000, 3000, 10,000, or 30,000 ppm of 4-methylphenol (>98%> pure) for 28 days. Based
on data presented by the authors, mean doses of 4-methylphenol were 0, 25, 87, 256, 835, and
2180 mg/kg-day in male rats; 0, 25, 83, 242, 770, and 2060 mg/kg-day in female rats; 0, 50, 163,
469, and 1410 mg/kg-day in male mice; and 0, 60, 207, 564, and 1590 mg/kg-day in female
mice. Doses at the high concentration in mice were not calculated due to 100%> early mortality.
Food consumption was recorded twice weekly. Animals were observed twice daily for clinical
signs of toxicity. Body weights were recorded weekly. Necropsy was performed on all animals.
Organ weights were recorded for brain, heart, right kidney, liver, lungs, thymus, and right testis.
Complete histopathologic examinations were performed on all control animals, all rats in the
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highest-dose group and all mice in the two highest-dose groups (inclusive of early deaths).
Target organs and tissues (nasal epithelium and bone marrow of male and female rats and mice;
uterus of female rats; liver, kidney, and lymphoid organs of male and female mice) and gross
lesions were examined in lower-dose groups to establish a no-effect level.
Survival was 100% in rats (NTP, 1992a). Relative to controls, higher-dose male and
female rats had significant decreases (p < 0.05) in mean final body weight (29 and 16% lower in
males and females, respectively) and mean body-weight gains (58 and 46% lower in males and
females, respectively). The authors stated that food consumption was depressed by as much as
75%) and 79% in high-dose males and females, respectively, during the first week of the study,
but they did not show food consumption data. Clinical signs of toxicity observed in all
high-dose rats during the first week included hunched posture, rough hair coat and thin
appearance. Significant treatment-related organ-weight changes (data not shown) included
increased relative liver weights (>835 mg/kg-day in males and >242 mg/kg-day in females) and
kidney weights (>835 mg/kg-day in males and at 2060 mg/kg-day in females). Other organ
(brain and testes) weight changes were considered by the investigators to be the result of reduced
body-weight gain. No gross lesions were seen at necropsy. Table 2 summarizes the author's
observations of histopathologic lesions in bone marrow, nasal epithelium, and the uterus. The
small numbers of animals in each dose group preclude meaningful statistical analysis. The nasal
lesions may be due to inhalation exposure via 4-methylphenol vapors released from the food
and/or to direct nasal contact with 4-methylphenol during feeding. The NOAEL for rats in this
study is 87 mg/kg-day. The LOAEL for rats is 242 mg/kg-day on the basis of nasal respiratory
epithelial hyperplasia.
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Table 2. Incidence (Mean Severity) of Relevant Histopathological Findings for Rats
Fed 4-Methylphenol (p-Cresol) for 28 Daysa
Male Rats

Dose for (mg/kg-day)
Organ/Effect
0
25
87
256
835
2180
Bone marrow hypocellularity
0/5
NE
0/5
1/5 (2.0)
1/5 (2.0)
5/5 (3.0)
Nasal
Olfactory epithelium atrophy
0/5
NE
0/5
0/5
0/5
5/5 (2.0)
Respiratory epithelium






Hyperplasia
0/5
NE
0/5
1/5 (2.0)
4/5 (2.7)
5/5 (2.8)
Squamous metaplasia
0/5
NE
0/5
0/5
0/5
2/5 (2.0)
Female Rats

Dose for (mg/kg-day)
Organ/Effect
0
25
83
242
769
2060
Bone marrow hypocellularity
0/5
NE
0/5
0/5
1/5 (2.0)
3/5 (2.7)
Nasal
Olfactory epithelium atrophy
0/5
NE
0/5
1/5 (1.0)
0/5
4/5 (1.7)
Respiratory epithelium






Hyperplasia
0/5
NE
0/5
1/5 (1.0)
3/5 (3.0)
3/5 (2.3)
Squamous metaplasia
0/5
NE
0/5
0/5
1/5 (2.0)
0/5
Uterus: Endothelium, atrophy
0/5
0/1
0/1
0/1
0/5
3/5
aNTP, 1992a: severity ratings, given in parentheses, are on a scale of 1-4 where 1 = minimal, 2 = mild,
3 = moderate and 4 = marked.
NE = Not examined.
All mice exposed to the highest concentration (30,000 ppm), one male at the next highest
concentration (10,000 ppm), and one control male died or were sacrificed in moribund condition
(NTP, 1992a). Compared to controls, mean final body weight and mean body-weight gain were
significantly (p < 0.05) lower (17 and 83%, respectively) in 1410 mg/kg-day (10,000 ppm)
males; food consumption was depressed for 1410 mg/kg-day males and 1590 mg/kg-day
(10,000 ppm) females throughout most of the first 2 treatment-weeks. Clinical signs (hunched
posture, labored breathing, lethargy, rough hair coat, hypothermia, and/or thin appearance) were
observed in 469- and 1410-mg/kg-day males and 1590-mg/kg-day females. Significant
treatment-related organ weight changes (data not shown) included increased relative liver weight
(1410 mg/kg-day males and >564 mg/kg-day females), kidney weight (>469 mg/kg-day males),
and heart weight (1410 mg/kg-day males). No gross lesions were noted at necropsy. Table 3
summarizes the incidences of relevant histopathological lesions. The small numbers of animals
in each dose group preclude meaningful statistical analysis.
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Table 3. Incidence (Mean Severity) of Relevant Histopathological Findings for Mice
Fed 4-Methylphenol (p-Cresol) for 28 Daysa
Male Mice

Dose for (mg/kg-day)
Organ/Effect
0
50
163
469
1410
Ndb
Bone marrow hypocellularity
0/5
NE
NE
NE
0/5
2/5 (1.5)
Kidney: Renal tubule necrosis
0/5
NE
NE
NE
0/5
4/5 (1.7)
Liver
Centrolobular atrophy
0/5
NE
NE
NE
0/5
1/5 (3.0)
Centrolobular necrosis
0/5
NE
NE
NE
0/5
1/5 (2.0)
Necrosis
0/5
NE
NE
NE
0/5
2/5 (3.0)
Nasal
Respiratory epithelium






Atrophy
0/5
0/5
0/5
0/5
0/5
1/5 (2.0)
Hyperplasia
0/5
0/5
3/5 (1.0)
5/5 (1.8)
5/5 (2.0)
1/5 (2.0)
Olfactory epithelium






Atrophy
0/5
0/5
0/5
0/5
0/5
1/5 (2.0)
Necrosis
0/5
0/5
0/5
0/5
0/5
2/5 (2.5)
Squamous metaplasia
0/5
0/5
0/5
0/5
1/5 (2.0)
1/5 (3.0)
Female Mice

Dose for (mg/kg-day)

0
60
207
564
1590
Ndc
Bone marrow hypocellularity
0/5
NE
NE
NE
0/5
3/5 (2.0)
Kidney: Renal tubule necrosis
0/5
NE
NE
NE
0/5
3/5 (1.7)
Liver
Centrolobular necrosis
0/5
NE
NE
NE
0/5
1/5 (2.0)
Nasal






Olfactory epithelium






Atrophy
0/5
0/5
0/5
1/5 (1.0)
0/5
0/5
Necrosis
0/5
0/5
0/5
0/5
0/5
3/5 (2.0)
Respiratory epithelium






Hyperplasia
0/5
1/5 (1.0)
2/5 (1.0)
4/5 (1.7)
5/5 (1.6)
1/5 (1.0)
''NTP. 1992a: severity ratings are on a scale of 1-4 where 1 = minimal, 2 = mild, 3 = moderate and 4 = marked.
bNot determined due to 100% mortality at the highest dietary concentration (30,000 ppm).
NE = Not examined.
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NTP (1992a) concluded that the renal tubule and hepatic necrosis and minimal-to-mild
bone marrow hypocellularity, all limited to the high-dose group with 100% mortality
(30,000 ppm), were possibly the direct result of 4-methylphenol toxicity. The nasal lesions may
be indicative of inhalation exposure via 4-methylphenol vapors released from the food and/or
direct nasal contact with 4-methylphenol during feeding. Other lesions not shown in Table 3 but
seen in high-dose mice (lymphoid necrosis and depletion in various lymphoid tissues including
the spleen) were considered secondary to mortality. The NOAEL for the study with mice is not
established. Nasal epithelial hyperplasia observed in females in all groups may possibly be
unrelated to systemic effects via oral exposure.
NTP (1992a) conducted similar 28-day dietary studies with 2-methylphenol (o-cresol),
3-methylphenol (m-cresol) and /«//>cresol and 13-week studies with o- and /«//>cresol and
concluded that the toxicity of the individual isomers was generally equivalent in both qualitative
and quantitative terms. In general, the toxicity observed following 28-day administration of
/«//;-cresol could be accounted for by results observed following administration of either m- or
^-isomers alone. For example, in rats, the increased relative organ weights (brain, liver, kidney,
testes), bone marrow histopathology, and nasal epithelial changes were observed at identical
doses following either p-cresol or /??//;-cresol exposure. Changes observed in rats following
exposure to mlp-cresol that were not observed following exposure to />cresol alone were
increased colloid in thyroid follicular cells (>3000 ppm) and an increased incidence of
forestomach hyperplasia (>10,000 ppm). In mice, there were several findings observed
following administration of /??//>cresol that were not observed following administration of the
individual isomers. Increased incidences of bronchiolar hyperplasia (both sexes) and hyperplasia
of the forestomach and esophagus (males only) were observed at the highest dietary
concentration (30,000 ppm). Critical dose-response data for the studies with isomers other than
/>cresol are summarized in Table 4, along with results for /;-cresol, and are considered further in
the dose-response assessment.
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Table 4. Summary of Oral Noncancer Dose-Response Information
Species/
isomer
Sex
Dose
(mg/kg-day)
Exposure
Duration
NOAEL
(mg/kg-day)
LOAEL
(mg/kg-day)
Responses at the
LOAEL
Comments
Reference
Subchronic Dietary Exposure
Hamster
/?-cresol
M
0 or 1.5% in diet
(approx. 1500
mg/kg-day)
20 weeks
none
1500
Moderate
hyperplasia of the
forestomach (10/15
treated vs. 1/15
controls)

Hirose et al.,
1986
Rat
/?-cresol
M
0, 25/25, 87/83,
256/242, 835/769,
or 2180/2060
mg/kg-day
(male/female)
28 days
87
242
Nasal respiratory
epithelial hyperplasia
No forestomach hyperplasia
NTP, 1992a
Rat
mlp-cresol
M/F
0, 26/27, 90/95,
261/268, 877/886,
or 2600/2570
mg/kg-day
(male/female)
28 days
27
95
Nasal respiratory
epithelial hyperplasia
Thyroid follicular cell colloid in
males/females at >261/268 mg/kg-day,
epithelial hyperplasia and
hyperkeratosis of esophagus and/or
forestomach in males/females at
>261/268 mg/kg-day
NTP, 1992a
Rat
mlp-cresol
M/F
0, 123/131,
241/254, 486/509,
991/1024, or
2014/2050
mg/kg-day
(male/female)
13 weeks
none (M)
123 (M)
Nasal respiratory
epithelial hyperplasia
Thyroid follicular cell colloid in
females/males at >509/991 mg/kg-day
NTP, 1992a
Mouse
/?-cresol
F
0, 50/60, 163/207,
469/564, or
1410/1590
mg/kg-day
(male/female)
28 days
none
60
Nasal respiratory
epithelial hyperplasia
The NOAEL/LOAEL for this effect in
males is 50/163 mg/kg-day
NTP, 1992a
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Table 4. Summary of Oral Noncancer Dose-Response Information
Species/
isomer
Sex
Dose
(mg/kg-day)
Exposure
Duration
NOAEL
(mg/kg-day)
LOAEL
(mg/kg-day)
Responses at the
LOAEL
Comments
Reference
Mouse
mlp-cresol
M/F
0, 50/65, 161/200,
471/604,
1490/1880, or
4530/4730
mg/kg-day
(male/female)
28 days
200 (F)
604 (F)
Nasal respiratory
epithelial hyperplasia

NTP, 1992a
Mouse
m/p-cresol
M/F
0, 96/116,
194/239, 402/472,
776/923, or
1513/1693
mg/kg-day
(male/female)
13 weeks
none (M)
96 (M)
Nasal respiratory
epithelial hyperplasia

NTP, 1992a
Subchronic Gavage Exposure
Rat
/?-cresol
F
0, 50, 175, or 600
13 weeks
50
175
Reductions in red
blood cell count,
hemoglobin
concentration and
hematocrit
Tremors, convulsions, mortality, and
tracheal-epithelial metaplasia were
observed in both sexes at
600 mg/kg-day
MBA, 1988
Rat
/?-cresol
M
0, 50, 175, or 600
13 weeks
50
175
Clinical signs of
neurotoxicity but no
effects on
neurobehavioral
performance or
neurohistopathology
Neurotoxicity study;
mortality at high dose
TRL, 1986
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Table 4. Summary of Oral Noncancer Dose-Response Information
Species/
isomer
Sex
Dose
(mg/kg-day)
Exposure
Duration
NOAEL
(mg/kg-day)
LOAEL
(mg/kg-day)
Responses at the
LOAEL
Comments
Reference
Chronic Dietary Exposure (no chronic gavage studies were identified)
Rat
mlp-cresol
(60:40)
M
0, 70, 230, or 720
105 weeks
none
70
Nasal respiratory
epithelial and goblet
cell hyperplasia
>230: Respiratory epithelial squamous
metaplasia
720: Reduced body weight, increased
renal pelvis epithelial hyperplasia,
marginally increased renal tubule;
respiratory epithelial inflammation
NTP, 2007
Mouse
mlp-cresol
(60:40)
F
0, 100, 300, or
1040
106-107
weeks
none
100
Lung: bronchiolar
hyperplasia;
Thyroid: follicular
degeneration
>300: Reduced body weight, nasal
respiratory epithelial hyperplasia
1040: Increased forestomach squamous
cell papilloma
NTP, 2007
Reproductive/Developmental Toxicity (all are gavage studies except mouse reproduction study by NTP)
Rat
reproductive
/?-cresol
M,F
0, 30, 175, or 450
to both sexes
Two
generations
30 (parental
toxicity)
450
(reproductive
toxicity)
175 (parental
toxicity)
none
(reproductive
toxicity)
Clinical signs of
toxicity immediately
following dosing
Reduced body weight gain at
450 mg/kg-day in F0 and F1 males and
F1 females; perinatal body-weight gain
reduced in F2 pups at 450 mg/kg-day.
No reproductive toxicity
BRRC, 1989
Rat,
developmental
/?-cresol
F
0, 30, 175, or 450
GDs 6-15
175
(maternal)
175
(fetal)
450
(maternal)
450
(fetal)
Maternal toxicity:
clinical signs of
neurotoxicity and
mortality.
Developmental
toxicity: skeletal
variations and
decreased fetal body
weight

BRRC, 1988b
Rat
developmental
p-cresol
F
0, 100, 333, 667,
or 1000
GD 11
1000
none

No maternal or fetal toxicity was
observed
Kavlock,
1990
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Table 4. Summary of Oral Noncancer Dose-Response Information
Species/
isomer
Sex
Dose
(mg/kg-day)
Exposure
Duration
NOAEL
(mg/kg-day)
LOAEL
(mg/kg-day)
Responses at the
LOAEL
Comments
Reference
Rabbit
developmental
(range-finding
study)
/?-cresol
F
0, 50, 150, 300,
500
GDs6-11
none
(maternal)
150
(fetal)
50 (maternal)
300
(fetal)
Respiratory distress
(maternal)
Forelimb and pelvic
girdle variations
were seen in
300 mg/kg-day
fetuses but not in
other groups

BRRC, 1987
Rabbit
developmental
/?-cresol
F
0, 5, 50, or 100
GDs 6-18
5 (maternal)
100
(fetal)
50
(maternal)
none
(fetal)
Mortality and
clinical signs:
hypoactivity,
respiratory distress,
ocular irritation
No developmental toxicity was
observed at any dose
BRRC,
1988a.
Mouse
dietary
reproductive
mlp-cresol
(60:40)
M, F
0, 362, 1390, or
1682 (average of
mean M and F
doses)
Two
generations
1390
1682
Increased cumulative
day to fifth litter and
decreased number of
live pups/litter in F1
generation
Continuous breeding protocol
NTP, 1992b
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Chronic Studies—No chronic oral studies conducted with 4-methylphenol alone have
been identified. NTP (2007) reports preliminary findings from chronic dietary studies conducted
with mixed mlp-cresols (60/40) in rats and mice. As of May 2008, the report has not been
finalized, but the draft abstract, pathology data, and survival and growth data are available on the
NTP Web site. The only details currently available for this study are presented below.
F344/N rats (50 males/dose) were fed mixed mlp-cresol isomers (60/40) in the diet at
concentrations of 0, 1500, 5000, or 15,000 ppm (equivalent to 0, 70, 230, or 720 mg/kg-day) for
105 weeks (NTP, 2007). There were no treatment-related effects on survival, and body weights
were comparable between controls and all but high-dose rats throughout the study. Body weight
was significantly reduced in the high-dose rats throughout the study. At study termination, body
weight of the high dose male group was 85% of the control weight. Significant nonneoplastic
lesions were observed in the highest dose groups in the kidney (increased incidence and severity
of hyperplasia of the transitional epithelium of the renal pelvis [0/50, 0/50, 2/50, and 8/50] and
liver [eosinophilic focus: 14/50, 14/50, 13/50, and 23/50]). Increased incidences of nasal lesions
were observed at all doses. Goblet cell hyperplasia was observed at incidences of 23/50, 40/50,
42/50, and 47/50 for 0, 70, 230, and 720 mg/kg-day, respectively. Respiratory epithelium
hyperplasia was observed at incidences of 3/50, 17/50, 31/50, and 47/50 for 0, 70, 230, and
720 mg/kg-day, respectively. Significantly (p < 0.05) increased incidences of metaplasia of the
respiratory epithelium were observed in the mid-and high-dose groups, and the incidence of
inflammation was significantly (p < 0.05) increased in the high-dose group. There were no
statistically significant treatment-related neoplastic changes. However, there was an increased
incidence of renal tubule adenomas in high-dose males (3/50 regular tissue slices; 4/50 when
regular and extended examinations are combined) in comparison with controls (0/50), low
(0/50), and mid-dose (0/50) groups. The incidence of renal tubule adenomas in high-dose males
was outside the historical control range and was considered to provide equivocal evidence of
carcinogenicity in male rats. As reported for mice (NTP, 1992a), the nasal effects in rats may
possibly be unrelated to systemic effects via oral exposure. No NOAEL was established.
B6C3F1 mice (50 females/dose) were fed mixed mlp cresol isomers (60/40) in the diet at
concentrations of 0, 1000, 3000, or 10,000 ppm (0, 100, 300, or 1040 mg/kg-bw/day) for
106-107 weeks (NTP, 2007). Survival was comparable among treatment groups. Body weight
was significantly lower than controls in mid- and high-dose mice, but food consumption was
reduced only in the high-dose group. Significantly increased incidences of nonneoplastic lesions
were observed in the thyroid (follicular degeneration at all doses), lung (bronchiolar hyperplasia
at all doses), nose (epithelial hyperplasia at the mid-and high-doses), and liver (eosinophilic
focus at the high-dose). The LOAEL for nonneoplastic effects in the mouse study is
100 mg/kg-day (lowest dose tested) for follicular degeneration of thyroid and bronchiolar
hyperplasia. No NOAEL was established. The incidence of squamous cell papilloma of the
forestomach was significantly increased in high-dose mice with respect to controls (0/50, 1/50,
1/49, 10/50 at 0, 100, 300, 1040 mg/kg-day, respectively). NTP (2007) considered the latter
observation to provide some evidence of potential carcinogenicity to humans.
Reproductive/Developmental Studies—In a reproductive toxicity study (BRRC, 1989),
Sprague-Dawley rats (25/sex/group) were administered 4-methylphenol (98.93% pure) in corn
oil by gavage at doses of 0 (vehicle only), 30, 175, or 450 mg/kg-day, 5 days/week for
10-11 weeks premating. Males and females were dosed daily through mating, and females were
also dosed daily during gestation and lactation. Groups of F1 rats were treated in the same
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manner as the parental generation to produce the F2 generation. Clinical signs, body weight, and
food consumption were monitored. All animals were subjected to gross pathological
examination. All control and high-dose animals received histopathological examination of the
pituitary, vagina, uterus, ovaries, testes, epididymides, seminal vesicles, prostate, and other
tissues with gross lesions identified as being potentially treatment related. Additionally, any of
the above tissues or organs in other dose groups that showed gross alterations were evaluated
microscopically. Gross and histopathological examinations were conducted for any parental
animals that died during the study. Gross pathological examinations were also performed on F1
or F2 pups that appeared abnormal or died during the study. Reproductive variables (mating
success, fertility, number of females with live litters, number of live pups at birth, lactation index
4-, 7-, 14-, and 21-day survival indices) were assessed in F0 and F1 rats.
Significant (p < 0.05) mortality was observed in high-dose adult F0 and F1 male
(28-36%) and female (32-40%) rats (BRRC, 1989). Treatment-related decreases in body
weight and body-weight gains were observed primarily in high-dose F0 and F1 males and F1
females during prebreeding treatment. For example, F0 males in the high-dose group weighed
approximately 13% less than their control counterparts on Week 13 of the study and gained only
9.5 ± 6.02 grams (n = 25) in comparison with controls who gained 17.6 ± 5.43 grams (n = 25)
from the 12th to 13th week of exposure. The decreases in body weight (8% less than controls at
greatest point of deviation) and body weight gain were less in F1 females than in males, and
were significant only during the first 4 weeks of treatment. Decreased food consumption was
also noted in high-dose male and female rats and was more pronounced early in the treatment
period. Clinical signs of toxicity were observed in high-dose males and females during exposure
and/or within 15 minutes following exposure and included hypoactivity, ataxia, twitches,
tremors, prostration, urine stains, audible respiration, and perioral wetness. Perinasal
encrustation and urogenital wetness were also seen in F0 females. Increased incidences of
perioral wetness (salivation/drooling) were observed in F0 and F1 males and females of the
175 mg/kg-day dose group. There were no clear signs of treatment-related perinatal toxicity in
F1 pups. No treatment-related gross or histologic lesions were observed in rats that survived to
sacrifice. Gross and histologic findings in rats that died prior to scheduled sacrifice mainly
involved color changes in lungs, crusted or stained skin, and lung congestion. There were no
treatment-related adverse reproductive effects. Based on clinical signs of toxicity observed in
mid- and high-dose parental rats (175 and 450 mg/kg-day dose groups, respectively), the
NOAEL for parental toxicity in this study is 30 mg/kg-day. The LOAEL for parental toxicity is
175 mg/kg-day for clinical signs of toxicity following dosing. The NOAEL for reproductive
toxicity is 450 mg/kg-day (highest dose tested).
In a developmental toxicity study (BRRC, 1988b), groups of 25 mated Sprague-Dawley
rats were treated with 4-methyphenol (99.7% pure) in corn oil by gavage at doses of 30, 175, or
450 mg/kg-day on Gestation Days (GD) 6-15. A group of 50 mated dams served as vehicle
controls. Clinical observations were made twice daily during treatment and once per day
otherwise. Food consumption was measured throughout gestation. Maternal body weights were
recorded on GDs 0, 6, 11, and 15 and at terminal sacrifice on GD 21, at which time dams were
also evaluated for liver and gravid uterine weights, number of corpora lutea, resorptions, and
dead and live fetuses. All live fetuses were weighed and examined for external malformations
and variations. Approximately one-half of the live fetuses from each litter were examined for
visceral and craniofacial malformations; the other half was examined for skeletal abnormalities.
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Maternal and fetal effects were limited to the 450-mg/kg-day dose group (BRRC, 1988b).
Death was noted in three high-dose dams and two others were removed from the study, due to
dosing error. Significantly increased incidences of clinical signs of treatment-related toxicity
included hypoactivity, ataxia, tremors, twitches, prone positioning, urogenital area wetness,
labored and audible respiration, gasping, perinasal encrustation, perioral wetness and
encrustation, and red fluid expelled from the mouth. Food consumption during treatment was
approximately 24% lower than controls. Mean body weight on GD 15 and body-weight gain
during the treatment period were significantly lower than controls (reduced approximately 7 and
40%, respectively). There were no treatment-related effects on gestational parameters or on the
incidence of external, soft tissue, or skeletal malformations. The incidences of bi-lobed cervical
centrum #6, reduced number of ossified caudal segments, and unossified sternebrae #5 were
significantly increased in fetuses of the 450-mg/kg-day dose group, relative to controls. There
were no other significant dose-related adverse skeletal effects. Fetal body weight per litter was
significantly lower (approximately 6%>) in the high-dose fetuses in comparison with controls.
The NOAEL for maternal toxicity in this study is 175 mg/kg-day. Mortality and clinical signs of
toxicity (hypoactivity, respiratory distress, signs of central nervous system toxicity) were
observed at 450 mg/kg-day. The NOAEL for fetal effects in this study is 175 mg/kg-day. The
LOAEL for fetal effects (skeletal variations, depressed fetal body weight) is 450 mg/kg-day.
Groups of 14 mated New Zealand white rabbits were exposed to 4-methylphenol
(99.7%) pure) in corn oil by gavage at doses of 5, 50, or 100 mg/kg-day on GDs 6-18
(BRRC, 1988a). A group of 28 mated females served as vehicle controls. Clinical observations
were made twice daily during treatment and once per day otherwise. Food consumption was
measured throughout gestation. Maternal body weights were recorded on GD 0, then every
6 days until terminal sacrifice on GD 29, at which time does were also evaluated for liver and
gravid uterine weights, number of corpora lutea, resorptions, and dead and live fetuses. All live
fetuses were weighed and examined for external malformations and variations and then prepared
for visceral examination. The sex ratios were noted for each litter, and approximately one-half
of the live fetuses in each litter were examined for soft tissue craniofacial malformations. All
fetuses were examined for skeletal abnormalities.
One dose each from the mid- and high-dose groups was removed from the study due to
dosing error (BRRC, 1988a). Death prior to scheduled necropsy was noted in 5/14 high-dose
and 2/13 mid-dose does and was considered to be due to 4-methylphenol toxicity. Clinical signs
of treatment-related maternal toxicity in the mid- and high-dose groups included hypoactivity,
respiratory distress (gasping, cyanosis, labored and audible rapid breathing), and ocular
discharge. No clinical signs of toxicity were noted in the low-dose group. Food consumption
was not significantly affected by 4-methylphenol treatment. There were no significant
dose-related adverse effects on maternal body weight, gravid uterine weight, or liver weight.
There were no signs of treatment-related gross maternal lesions at necropsy. No significant
treatment-related effects were observed with respect to numbers of corpora lutea, implantation
sites, live and dead fetuses, sex ratio, or fetal malformations. The NOAEL for maternal toxicity
is 5 mg/kg-day. Mortality and clinical signs of toxicity (hypoactivity, respiratory distress, and
ocular irritation) were observed at 50 mg/kg-day, making 50 mg/kg-day the LOAEL for maternal
toxicity. The NOAEL for fetal effects is 100 mg/kg-day (highest dose tested).
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In a range-finding developmental toxicity study (BRRC, 1987) to determine the doses to
be used in the main study reported above (BRRC, 1988a), groups of eight mated New Zealand
white rabbits were exposed to 4-methylphenol in corn oil by gavage during Days 6 through 18 of
gestation. Vehicle controls consisted of 16 mated does. Mortality was noted in 0/8, 2/8, 4/8, and
7/8 rabbits in the 50-, 150-, 300-, and 500-mg/kg-day dose groups, respectively. Significantly
reduced food consumption during GDs 6-11 was observed in does at >300 mg/kg-day.
Significantly depressed mean body-weight gain was seen in the 150 mg/kg-day group during
Days 6-12 of gestation and in the 300 mg/kg-day group throughout gestation. Clinical signs of
central nervous system and cardiopulmonary toxicity were noted in does at >300 mg/kg-day.
Respiratory distress was observed in a few of the does in the 50 mg/kg-day dose group. The
only apparent treatment-related adverse fetal effects were forelimb and pectoral girdle variations
in the 300 mg/kg-day dose group. No adverse fetal effects were observed in the 500 mg/kg-day
dose group, but this observation is not reliable due to the small sample size of this dose group
(only one dam at this dose group survived to produce a litter). The LOAEL for maternal toxicity
is 50 mg/kg-day (lowest dose tested) on the basis of respiratory distress. The NOAEL for fetal
toxicity is 150 mg/kg-day because the forelimb and pectoral girdle variations were seen at the
next higher dose (LOAEL = 300 mg/kg-day).
Sprague-Dawley rats (13/group) were treated by gavage to a single dose of
4-methylphenol at 100, 333, 667, or 1000 mg/kg on Day 11 of gestation (Kavlock, 1990). A
group of 17 pregnant dams served as vehicle controls. Rats were weighed on Days 10, 11, 12,
14, 17, and 21 of gestation. Rats were observed for clinical signs of toxicity for several hours
postdosing and were allowed to deliver at term. Body weight and viability of the neonates was
assessed on Postpartum Days 1, 3, and 6. Overt malformations were examined, perinatal loss
was calculated, and litters were maintained until weaning, at which time they were examined for
previously undetected external malformations. There were no treatment-related deaths. Mid-
and high-dose dams lost body weight (-3 and -10 g, respectively; statistically significant only for
the highest dose) during the first 24 hours of exposure, but they had weight gains that were not
statistically different from controls by the 72-hour weigh-in. There were no significant
differences between any treatment group and controls with regard to litter size, perinatal loss,
mean pup weight, and litter biomass. No other adverse maternal or fetal effects were assessed or
reported. The NOAEL for maternal and fetal toxicity is 1000 mg/kg-day (highest dose tested).
Reproductive effects following a continuous breeding protocol were examined in mice
(8 per gender) exposed to a 60:40 mixture of mlp-cresol in the diet at concentrations of 0, 0.25,
1.0, and 1.5% (equivalent to doses of 0, 362, 1390, or 1682 mg/kg-day; page 50, Table 2-8,
average of male and female values for Task 2) for two generations (NTP, 1992b). Endpoints
examined in the study include clinical signs, body weight, food consumption, gross necropsy,
reproductive performance, vaginal cytology, sperm variables, and testicular histopathology. The
NOAEL for parental and reproductive toxicity in this study is equivalent to an average dose of
1390 mg/kg-day. Reduced body weight and food consumption and parallel changes in various
organ weights were observed at the higher dose. An increased cumulative day to production of
the fifth litter (difference of 3 days in comparison with controls) and decreased number of live
pups/litter in the F1 generation (10.1 ± 0.6, n = 19 high-dose; versus 12.7 ± 0.4, n = 21 control)
were also observed at the highest dose (1682 mg/kg-day). The LOAEL for parental and
reproductive toxicity is, therefore, 1682 mg/kg-day.
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Inhalation Exposure
The inhalation database is composed of translations of studies from the Russian literature
that are lacking in details relevant to methods and results.
Subchronic Studies—Pereima (1975) exposed female rats (strain and numbers not
-3
reported) to 4-methylphenol aerosols at 10 mg/m for 4 months followed by a 2-month
observation period. Clinical signs of toxicity, including loss of appetite, emaciation, and reduced
locomotor activity, were noted. Body-weight gain was reduced and remained depressed
throughout the observation period. Dystrophic changes were observed in the lung and liver
accompanied by a decrease in lung weight and an increase in liver weight. Hemorrhagic
inflammation of the nasal mucosa and conjunctiva and inflammation of the skin and
subcutaneous tissue were noted during the exposure period and remained evident throughout the
recovery period. Exposed animals also developed oliguria that persisted through the recovery
period. No further details are reported.
Cresol isomers other than 4-methylphenol have been tested in laboratory animals.
Results for the relevant studies involving 2-methylphenol, 3-methylphenol, and cresol mixtures
(dicresol and tricresol) are discussed below.
Mice were exposed to a combination of 2-methylphenol (o-cresol) aerosol and vapor at
an average concentration of 50 mg/m3, 3 hours/day, 6 days/week) for 1 month (Uzhdavini et al.,
1972). No mortality was observed. Clinical signs of toxicity (respiratory irritation and
hypoactivity), slightly reduced body-weight gain, respiratory tract lesions (edema, cellular
proliferation, and small hemorrhages in the lung), and degenerative lesions in heart, liver,
kidney, and CNS tissue were reported. No further details are reported.
"3
Rats were exposed to an average concentration of 9 mg/m of 2-methylphenol vapor
4-6 hr/day, 5 days/week for 4 months (Uzhdavini et al., 1972). Respiratory lesions (irritation
and inflammation of the upper respiratory tract and edema and perivascular sclerosis in the
lungs), hematological changes (increased leukocytes in blood, decreased erythropoietic elements
in bone marrow), increased duration of hexanol narcosis (possibly indicating decreased liver
function), and accelerated loss of a conditioned defense reflex were reported. Guinea pigs
exposed under the same protocol had only minor hematological effects and a slight change in
echocardiogram (Uzhdavini et al., 1972). No further details are reported.
"3
Female rats were exposed to 10 mg/m of 2-methylphenol aerosols for 4 months
(Pereima, 1975). The effects observed in this study were almost identical to those reported
above for 4-methylphenol. 3-Methylphenol (w-cresol) was also tested in this study, but the only
effects observed are reduced body-weight gain, transient oliguria, and dystrophic changes in the
lung and liver (Pereima, 1975). No further details are reported.
"3
Rats exposed to 5 mg/m of dicresol (a mixture of 3- and 4-methylphenol) for 4 months
(4 hours/day, 5 days/week) had decreased growth, hematological changes (increased
erythrocytes, decreased neutrophils), altered electrocardiogram, organ weight changes (increased
kidney weight, decreased uterus weight), tissue lesions (fatty liver, dystrophic changes in the
lungs, myocardium, kidney, and CNS), and altered adrenal cortical function. Only minor effects
"3
were reported for rats exposed similarly to 1.45 mg/m (Uzhdavini et al., 1976). No further
details are reported.
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"3
Rats exposed continuously to 0.05 mg/m of tricresol (a mixture of 2-, 3-, and
4-methylphenol) vapor for 3 months had reduced growth, increased CNS excitability, structural
changes in blood proteins, decreased gamma globulins in blood serum and microscopic lesions in
the lung and liver, while rats exposed to 0.005 mg/m3 did not show these effects
(Kurlyandskiy et al., 1975; Uzhdavini and Gilev, 1976). No further details were reported.
Other Studies
Toxicokinetics—Methylphenols, including 4-methylphenol, are naturally occurring in
humans due to amino acid metabolism by intestinal microflora. There is little toxicokinetic
information regarding the absorption, distribution, and elimination of the methylphenols in
animals or humans. Absorption is inferred from the observation of toxicity following oral,
dermal, and inhalation administration (ATSDR, 2006). The following values were reported
following intravenous administration of a 3 mg/kg dose of 4-methylphenol to rats:
ty2 (blood) =1.5 hours; total clearance from the blood = 23.2 mL/min/kg; and renal clearance
= 4.8 mL/min/kg (Lesaffer et al., 2001). The authors suggested that processes such as exsorption
(off-gassing from the blood), biotransformation, or biliary excretion may be responsible for the
observed discrepancy between renal clearance and blood clearance.
Conjugation with glucuronic acid and inorganic sulfates is the primary metabolic
pathway for all cresol isomers, and all isomers are eliminated primarily in the urine in conjugated
form. All isomers undergo enterohepatic circulation (OECD-SIDS, 2003). />Cresylsulfate is the
primary metabolite of 4-methylphenol (Schepers et al., 2007). Oxidation to a reactive quinone
methide intermediate has been proposed for 4-methylphenol based on in vitro studies with rat
liver (Thompson et al., 1996). Another metabolic pathway involving aromatic oxidation of
4-methylphenol to 4-methyl-ortho-hydroquinone and the formation of
4-methyl-ortho-benzoquinone has recently been proposed following in vitro experiments with
human liver microsomes (Yan et al., 2005).
The type of oral exposure may affect the types of toxic effects caused by 4-methylphenol
and the doses at which they occur. Bray et al. (1950) observed greater toxicity in rabbits given
/>cresol by gavage on an empty stomach than in rats given food 1-2 hours prior to dosing,
suggesting that food might retard absorption of />cresol. Further evidence for the idea that
gavage exposure might result in a greater dose absorbed than dietary or drinking water exposure
comes from examination of acute toxicity values. LD50 values for rats are 7-9 times lower
following undiluted administration by gavage than those following administration of
4-methylphenol diluted in oil (Bray et al., 1950).
Morinaga et al. (2004) observed that a single gavage dose of m/p-cresol (to rats) in soap
quickly disappeared from stomach contents, with 50% gone within 15 minutes and all gone
within 8 hours. Conjugated derivatives were all gone from the blood within 4 hours. One
interesting finding of these studies is that the liver and spleen had higher concentrations of
unconjugated cresols than the blood over an 8-hour period. The authors suggested that these
findings could be explained by the hypothesis that a gavage bolus could diffuse through the
stomach and intestinal walls to nearby tissue. If true, this hypothesis could potentially explain
some of the differences in toxicity observed in comparing the results of gavage versus dietary
studies.
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The toxicokinetic database for the methylphenol isomers does not include studies with
dietary administration nor detailed information to make comparisons on the basis of total
absorbed dose (e.g., area under the curve calculations) or peak blood concentrations.
Acute/Short-term Toxicity—WHO (1995) and OECD-SIDS (2003) summarize the
available oral acute toxicity studies for o-, m-, and /?-cresol. No studies are available for
mixtures of the isomers. In general, o-cresol is the most toxic, followed by />cresol and
m-cresol. Administration of undiluted cresols resulted in lower LD50 values than when a vehicle
was used. The LD50 values that are reported following undiluted administration of the test
substance to rats are 121 mg/kg for o-cresol, 207 mg/kg for /J-cresol, and 242 mg/kg for
m-cresol. The LD50 values that are reported for rats following administration of the test
substance in oil (10%) are 1350-1470 mg/kg for o-cresol, 1430-1800 mg/kg for/?-cresol, and
2010-2020 for w-cresol. Mice are more sensitive than rats with LD50 values 3-4 times lower.
The LD50 values for the test substance administered to mice in oil (10%) are 344 mg/kg for
o-cresol, 344-440 mg/kg for /;-cresol, and 600-828 for w-cresol. Following administration of
undiluted isomers to rats, the clinical signs that preceded death (all three isomers except as
noted) included hypoactivity, lethargy, excess salivation, dyspnea, hemorrhagic rhinitis (p-cresol
only), lack of coordination, prostration, muscle twitches, tremors, convulsions, and coma.
Gastrointestinal inflammation and hemorrhage and hyperemia of the lungs, liver, and kidney
were noted upon necropsy of rats dying before study termination. Gastrointestinal inflammation
was the only pathological finding in survivors and was limited to rats exposed to />cresol. No
gross pathological findings were noted in surviving rats treated with o- or m-cresol.
"3
Pereima (1975) reported mean lethal concentrations of 29 mg/m for both o- and
^-cresols following acute inhalation exposures of rats. OECD-SIDS (2003) reports that no
mortality, no clinical signs of toxicity, and no gross pathological changes were noted in 6 male
-3
rats exposed to />cresol at a concentration of 710 mg/m for 1 hour.
Other Routes—WHO (1995) reports dermal toxicity values as follows. Dermal LD50
values in rabbits are 890, 2830, 300, and 2000 mg/kg for o-, m-,p-, and mixed cresols,
respectively. Dermal LD50 values in rats were 620, 1100, 750, and 825 mg/kg for o-cresol,
m-cresol, /?-cresol, and dicresol (a mixture of m- and /^-cresols), respectively.
4-Methylphenol is corrosive to the skin and causes severe eye irritation and damage in
animals (OECD-SIDS, 2003). 4-Methylphenol (4% in petrolatum) did not cause sensitization in
25 human volunteers who participated in a dermal maximization test (OECD-SIDS, 2003).
Boutwell and Bosch (1959) conducted initiation-promotion studies with a number of
chemicals—including methylphenols. Female Sutter mice (27-29/group; 2-3 months of age)
received a single dermal application of 25 [j,L of 0.3% dimethylbenzanthracene (DMBA) in
acetone as the initiator, followed 1 week later by 25 [xL of 20% by volume (v/v) o-, m-, or
/>cresol in benzene twice weekly for 12 weeks. Skin papillomas were evaluated at 12 weeks.
Many of the cresol-treated mice died—presumably of cresol toxicity. There was no mortality or
evidence of skin papillomas in the benzene control group (benzene weekly after DMBA
initiation). The numbers of surviving mice that developed skin papillomas at 12 weeks are as
follows: 10/17, o-cresol; 7/14, m-cresol, and 7/20,^-cresol. None of the 12 mice in the benzene
control group died or developed skin papillomas.
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In another experiment, groups of 20 mice received a single dose (25 |iL) of 0.3% DMBA
in acetone, followed by twice-weekly applications of 5.7% w-cresol in benzene or 5.7%p-cresol
in benzene for 20 weeks. No skin papillomas were observed in the 18 surviving benzene control
mice; 4/17 w-cresol-, and 4/14 /?-cresol-treated mice developed skin papillomas (Boutwell and
Bosch, 1959).
These two experiments indicate that cresols can promote tumor formation by polycyclic
aromatic hydrocarbons and are used to support a Group C, possible human carcinogen,
weight-of-evidence finding for the carcinogenicity of 4-methylphenol verified on IRIS.
Neurotoxicity—As discussed in previous sections, clinical signs of toxicity including
salivation, tremors, convulsions, and ataxia have been observed in the acute and subchronic oral
studies conducted with 4-methylphenol. Despite the appearance of clinical signs, no adverse
behavioral effects or neuropathology was observed in a subchronic gavage study specifically
designed to investigate the neurotoxicity of 4-methylphenol (TRL, 1986). The study identifies a
NOAEL of 50 mg/kg-day and a LOAEL of 175 mg/kg-day based on clinical signs (TRL, 1986).
Immunotoxicity—Oxidative burst activity is a marker for the inflammatory status of
leukocytes. Baseline activation of leukocytes has been associated with vascular damage, which,
in turn, has been associated with renal insufficiency in patients with kidney disease
(Schepers et al., 2007). Schepers et al. (2007) demonstrated that />cresylsulfate, a primary
metabolite of 4-methylphenol, increased the oxidative burst activity of unstimulated leucocytes
in whole blood drawn from healthy human volunteers.
Mechanistic—The metabolism of 4-methylphenol involves the formation of several
intermediates that have been proposed as potential agents of toxicity. Schepers et al. (2007)
demonstrated that /?-cresyl sulphate, a primary metabolite of 4-methylphenol, increased the
pro-inflammatory activity of unstimulated leucocytes in blood drawn from healthy humans. This
observation is congruent with the hypothesis that/?-cresylsulfate causes vascular damage and
subsequent renal insufficiency in humans with kidney disease. Thompson et al. (1996)
demonstrated that substituted cresols—including 4-methylphenol—are toxic to rat liver slices
(measured as loss of intracellular potassium as a proxy for cell viability) and are metabolized to
quinone methide intermediates in rat liver slices and rat microsomes (measured as glutathione
conjugate formation). Modifications to the parent compound (e.g., deuteration, ring-substitution)
that affected the rate of metabolism and the stability of the quinone methide were correlated with
observed toxicity (i.e., toxicity proportional to the presence of quinone methide), suggesting that
the quinone methide is the reactive metabolite associated with liver toxicity.
Genotoxicity—U.S. EPA's weight-of-evidence classification for 4-methylphenol takes
into account genotoxicity information for all of the individual cresol isomers as well as mixtures
of isomers. Cresols (o-, m-, and p-) are not mutagenic in various strains of Salmonella
typhimurium or Escherichia coli either in the presence or absence of mammalian liver
homogenates (Crowley and Margard, 1978; Litton Bionetics, 1980a, 1981a; Florin et al., 1980;
Douglas et al., 1980; Pool and Lin, 1982; Haworth et al., 1983; NTP, 2007).
A mixture of the three isomers was mutagenic in a mouse lymphoma forward mutation
assay with mammalian liver homogenates, while o-cresol was not mutagenic with or without
liver homogenates (Litton Bionetics, 1980b, 1981b). No isomer, when tested individually,
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induced sister chromatid exchanges (SCEs) in vivo, but the mixture of the three isomers induced
SCEs in Chinese hamster ovary (CHO) cells in vitro (Litton Bionetics, 1980c). Only o-cresol
induced SCEs in human lung fibroblasts (Cheng and Kligerman, 1984) and CHO cells
(Litton Bionetics, 1981c). In a screening test for putative carcinogens, infectious virus particles
were produced from SV40-transformed weanling Syrian hamster kidney cells exposed to
m-cresol (Moore and Coohill, 1983).
Studies on the induction of unscheduled DNA synthesis showed />cresol to be positive in
human lung fibroblast cells in the presence of hepatic homogenates (Crowley and Margard,
1978), the mixture of the three isomers to be weakly positive in primary rat hepatocytes,
(Litton Bionetics, 1980d) and o-cresol to be negative in rat hepatocytes (Litton Bionetics,
1981e).
In cell-transformation assays using BALB/3T3 cells, a mixture of three cresol isomers
was positive (Litton Bionetics, 1980e, 198Id) and o-cresol was negative. Positive mutagenic
responses were found at noncytotoxic doses (Litton Bionetics, 1980e). In another cell
transformation assay using /;-cresol, negative results were obtained with the mouse fibroblast cell
line C3H10T1/2 (Crowley and Margard, 1978).
4-Methylphenol inhibited semiconservative DNA synthesis (25% inhibition compared
with controls) and DNA repair (21% inhibition compared with controls) in human peripheral
lymphocytes (Daugherty and Franks, 1986) and inhibited DNA synthesis (measured by
radioactive thymidine incorporation) in V79 Chinese Hamster cells with a median inhibitory
concentration (IC50) of 0.15 mM (Richard et al., 1991). The latter result placed 4-methylphenol
into a "moderate" category when compared with other phenolic compounds (e.g., /;-nitrophenol
considered inactive with an IC50 >3 mM; phenol considered low, with an IC50 of 2.4 mM;
/?-aminophenol considered high with an IC50 of 0.0018 mM).
4-Methylphenol gave a positive result in an in vitro carcinogenicity test using a bovine
papillomavirus DNA-carrying mouse embryo fibroblast cell line (Tl). The lowest effective
concentration was 0.01 mg/mL (Kowalski et al., 2001).
4-Methylphenol did not increase the incidence of dominant lethal mutations in the germ
cells of male mice given single oral doses of 4-methylphenol in corn oil at concentrations up to
550 mg/kg. Toxicity was noted at an initially tested high dose of 650 mg/kg (Hazleton Lab.,
1989a). 4-Methylphenol was negative in a sex-linked recessive lethal test with Drosophila
melanogaster SLRL following oral feeding of adult males with 0, 60, 300, or 600 [j,g/mL for
3 days (Hazleton Lab, 1989b).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD
VALUES FOR 4-METHYLPHENOL
Subchronic and Chronic p-RFD
Table 4 summarizes the critical dose-response data for 4-methylphenol. In general, the
observed toxicity following exposure to 4-methylphenol (p-cresol) is qualitatively and
quantitatively similar to that of m/p-cresol (NTP, 1992a). The most sensitive endpoints
following gavage exposure are clinical signs of neurotoxicity and mortality in pregnant rabbits
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(BRRC, 1988a). While clinical signs of toxicity were observed, there were no treatment-related
effects of cresol exposure on behavioral or neuropathological endpoints following subchronic
gavage exposure (TRL, 1986). Clinical signs of neurotoxicity were not observed in any of the
dietary studies. Nasal epithelial hyperplasia and other respiratory tract lesions are the most
sensitive endpoints following dietary exposure. Nasal lesions were not observed in any of the
gavage studies, suggesting the possibility that off-gassing from the food—either prior to
ingestion or in the mouth during mastication—could be causing inhalation exposure and/or
portal-of-entry irritation.
The critical study (i.e., BRRC, 1988a) identifies aNOAEL of 5 mg/kg-day and a FEL of
50 mg/kg-day, based on maternal toxicity (clinical signs of hypoactivity, respiratory distress,
ocular irritation, and death) in New Zealand white rabbits exposed to 4-methylphenol by gavage
during gestation. Support for choosing the NOAEL of 5 mg/kg-day as a possible point of
departure (POD) for deriving a p-RfD comes from additional developmental toxicity studies in
rabbits (i.e., BRRC, 1987) and rats (i.e., BRRC, 1988b), reproductive toxicity studies in rats
(i.e., BRRC, 1989), a reproductive toxicity study with m/p-cresol in mice (i.e., NTP, 1992b), and
subchronic toxicity studies in rats and mice (i.e., MBA, 1988; NTP, 1992a; TRL, 1986).
Subchronic rodent studies reported clinical signs of neurotoxicity and hematopoietic effects at
doses of 175 mg/kg-day and higher (TRL, 1986) and other toxic effects, such as reduced spleen
weight and clinical symptoms of neurotoxicity in all exposed animals (50, 175, and
600 mg/kg-day, MBA, 1988). Furthermore, a rabbit dose-finding study (BRRC, 1987) to
determine doses for the main developmental study (BRRC, 1988a) indicated both maternal and
fetotoxicity at 50 mg/kg-day. Many of these studies reported similar effects as observed in the
maternal rabbits, and all had higher effect levels. Preliminary results from chronic dietary
exposure studies of male rats and female mice exposed to a 60/40 mixture of mlp-cresol (NTP,
2007) support previous findings from the existing subchronic and developmental toxicity studies
conducted with 4-methylphenol alone and would not affect selection of the POD from which to
derive an RfD for 4-methylphenol. NOAELs were not identified in the NTP (2007) chronic
studies of mlp-cresol. A LOAEL of 70 mg/kg-day was identified for male rats on the basis of
nasal lesions and a LOAEL of 100 mg/kg-day was identified for female mice on the basis of
thyroid follicular degeneration and bronchiolar hyperplasia. Comparable effect-levels are
derived from the 28-day studies with p-cresol (No NOAEL; LOAEL = 60 mg/kg-day for female
mice based on nasal lesions). Effect levels in the NTP (1992a, 2007) studies exceed the NOAEL
in the BRRC (1988a) study by more than an order of magnitude. BMD modeling of the sensitive
endpoints from the NTP (2007) and NTP (1992a) studies is possible, but it does not yield BMDL
values low enough to result in the derivation of a p-RfD lower than one derived on the basis of
the NOAEL of 5 mg/kg-day.
ATSDR (2006) has raised the issue that dietary studies may be more appropriate than
gavage studies as the basis for quantitative toxicity benchmarks for cresols and chose to
eliminate gavage studies from consideration in the derivation of MRLs. The argument is based
on the following observations: different toxic effects are observed following gavage versus
dietary exposure; the doses at which toxic effects occur following gavage exposure are much
lower than doses producing toxicity following dietary exposure; toxicity (measured as mortality)
was less when gavage doses were administered to recently fed rabbits than to fasted rabbits
(Bray et al., 1950); and dietary exposure is more relevant than gavage with respect to potential
human exposure. A similar approach was taken by the U.S. EPA in the derivation of the RfD for
phenol currently available on IRIS. However, the toxicokinetic database for phenol is more
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complete than the database for cresols, including drinking water and gavage data. Furthermore,
available data indicated that toxicity was correlated with peak blood concentrations rather than
total dose. While the database for cresols suggests some similarities to phenol regarding the
influence of gavage versus "natural" routes of oral exposure, the detailed comparative
toxicokinetic data are lacking. As such, gavage studies were chosen for the derivation of
provisional toxicity values. The rabbit maternal NOAEL of 5 mg/kg-day from the study by
(BRRC, 1988a) was recommended as the POD for deriving subchronic p-RfD values.
The available data for the BRRC (1988a) study are not amenable to benchmark dose
modeling as discussed in the study section. The subchronic p-RfD is derived by dividing the
NOAEL of 5 mg/kg-day by an UF of 300 as follows:
Subchronic p-RfD = 5 mg/kg-day 300
= 0.0166
= 0.02 or 2 x 10"2 mg/kg-day
The subchronic p-RfD is based on maternal toxicity, and, although the effects were
observed during the gestational period, the duration of exposure in the maternal animals is
treated as subchronic. Furthermore, lack of chronic dose-response studies and uncertainties in
the available subchronic studies precludes derivation of a chronic p-RfD.
The composite UF of 300 includes the following factors:
A full UF of 10 is applied for interspecies extrapolation to account for potential
pharmacokinetic and pharmacodynamic differences between rats and humans.
A full UF of 10 is applied for intraspecies differences in an effort to account for
potentially susceptible individuals in the absence of information on the variability of
response in humans.
A partial database uncertainty factor of 3 (10°5) is applied. The toxicological
database includes developmental toxicity studies on two species and a two-generation
reproduction study in rats. However, the database lacks a subchronic or chronic study
for the sensitive species (rabbits) where effects were observed.
Confidence in the key study is medium. Although the critical study (BRRC, 1988a) was
not of sufficient duration to be considered subchronic for maternal exposure, the NOAEL of
5 mg/kg-day is the highest NOAEL below all LOAELs. The NOAEL values identified in the rat
subchronic studies (MBA, 1988; TRL, 1986) were equal to the LOAEL identified in the key
study (BRRC, 1988a). The critical study identifies both a LOAEL and a NOAEL for maternal
toxicity using an appropriate protocol. Confidence in the database is medium. Studies for
subchronic toxicity, neurotoxicity, reproductive toxicity, and developmental toxicity have been
conducted for 4-methylphenol. However, chronic studies for 4-methylphenol (alone) are not
available and rabbits, which appear to be more sensitive than rodents on the basis of
developmental toxicity studies, were not tested in subchronic studies. Therefore, confidence in
the subchronic p-RfD is medium.
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FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR 4-METHYLPHENOL
None of the available studies regarding the inhalation toxicity of 4-methylphenol or the
other methylphenol isomers or mixtures are reported with enough detail to be useful for
quantitative toxicity assessment. Although limited, the available data suggest that
4-methylphenol and the other methylphenols are respiratory irritants and that portal-of-entry
effects are likely to be important in determining quantitative toxicity values for these
compounds. Therefore, extrapolation from the oral data is not recommended to derive inhalation
toxicity values. The toxicity of methylphenol isomers following inhalation exposure is
considered similar to that of phenol by ACGIH (2001). As such, ACGIH established a TLV for
methylphenols based on the TLV for phenol. However, there currently is no verifiable RfC for
phenol on IRIS that could serve as the basis for an RfC for 4-methylphenol. IRIS declined to
derive an RfC for phenol due to the lack of appropriate data (U.S. EPA, 2008).
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR 4-METHYLPHENOL
Weight-of-Evidence Descriptor
IRIS (U.S. EPA, 2008) lists a weight-of-evidence classification of Group C, possible
human carcinogen, for 4-methylphenol on the basis of inadequate data in humans, limited data in
animals (promotion of increased skin papillomas in mice; Boutwell and Bosch, 1959), and the
supporting data from assays for mutagenicity conducted with individual cresols and mixtures of
isomers. The data are not sufficient for quantitative toxicity assessment; therefore, no slope
factor is derived. The study by Kubo (1990), in which 4-methylphenol was detected in the feces
of colorectal cancer patients is suggestive of a possible relationship between 4-methylphenol
excretion and cancer, but it is of no value in establishing that exposure to exogenous
4-methylphenol causes cancer. Forestomach hyperplasia and epithelial mitosis of the bladder
were observed in hamsters exposed to one dose level of 4-methylphenol for 20 weeks
(Hirose et al., 1986). However, due to the lack of higher exposure doses and the short duration
of exposure, it is unknown whether these proliferative changes would progress to tumor
formation. Preliminary results of the NTP (2007) chronic dietary study of mlp-cresols support
the finding of possible carcinogenicity, providing equivocal evidence in rats and some evidence
in mice as follows. An increased incidence of squamous cell papilloma in the forestomach was
observed in female mice (0/50, 1/50, 1/49, and 10/50 at 0, 1000, 3000, and 10,000 ppm,
respectively), and a nonsignificant increase in kidney renal tube adenoma was observed in male
rats (0/50, 0/50, 0/50 and 4/50 at 0, 1500, 10,000, and 15,000 ppm, respectively).
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Quantitative Estimates of Carcinogenic Risk
Limitations in the available data preclude derivation of quantitative estimates of cancer
risk for 4-methylphenol.
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