United States
Environmental Protection
1=1 m m Agency
EPA/690/R-11/031F
Final
6-16-2011
Provisional Peer-Reviewed Toxicity Values for
/>-Isopropyltoluene
(CASRN 99-87-6)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Chris Cubbison, PhD
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
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
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVS 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 4
HUMAN STUDIES 7
ANIMAL STUDIES 7
Oral Exposures 7
Inhalation Exposures 7
Sub chronic-duration Studies 7
Chronic-duration Studies 9
Developmental Studies 9
Reproductive Studies 9
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 10
Genotoxicity 15
Short-term Studies 15
Toxicokinetics 16
DERIVATION 01 PROVISIONAL VALUES 18
DERIVATION OF ORAL REFERENCE DOSES 19
Derivation of Subchronic Provisional RfD (Subchronic p-RfD) 19
Derivation of Chronic Provisional RfD (Chronic p-RfD) 19
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 19
Derivation of Subchronic Provisional RfC (Subchronic p-RfC) 19
Derivation of Chronic Provisional RfC (Chronic p-RfC) 19
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTION 19
MODE-OF-ACTION (MOA) DISCUSSION 21
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 21
Derivation of Provisional Oral Slope Factor (p-OSF) 21
Derivation of Provisional Inhalation Unit Risk (p-IUR) 21
APPENDIX A. PROVISIONAL SCREENING VALUES 22
APPENDIX B. DATA TABLES 23
APPENDIX C. BMD OUTPUTS 25
APPENDIX D. REFERENCES 26
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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
/7-ISOPROPYLTOLUENE (CASRN 99-87-6)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (www.epa.gov/iris), the respective PPRTVs are removed
from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
p-Isopropyl toluene, also known as p-cymene, is a naturally occurring aromatic organic
compound. It is classified as a hydrocarbon related to a monoterpene. Its structure consists of a
benzene ring/;c/ra-substituted with a methyl group and an isopropyl group (U.S. EPA, 2005a).
The empirical formula for/?-isopropyltoluene is C10H14 (see Figure 1). /?-Isopropyltoluene
occurs naturally in more than 200 foods such as butter, carrots, nutmeg, orange juice, oregano,
raspberries, and lemon oil, and almost every spice (U.S. EPA, 2005a) and is a constituent of a
number of essential oils, most commonly the oils of cumin and thyme. The consumption of
p-isopropyltoluene is derived predominantly from its presence in traditional foods. It has been
estimated that approximately 30,000 kg ofp-isopropyltoluene is consumed annually as a natural
component food (U.S. EPA, 2005a). /?-Isopropyltoluene is also a component of solvents used as
thinners for lacquers and varnishes (HSDB, 2000) and is used in the flavor and fragrance
industry (U.S. EPA, 2005a). There are two less common geometric isomers of
p-isopropyltoluene: o-isopropyltoluene, in which the alkyl groups are ortho-substituted, and
/77-isopropyl toluene, in which the alkyl groups are we to-substituted. p-Isopropyl toluene is the
only natural isomer. A table of physicochemical properties is provided below (see Table 1).
Figure 1. /7-Isopropyltoluene Structure
Table 1. Physicochemical Properties Table for
/7-Isopropyltoluene (CASRN 99-87-6)a
Property (unit)
Value
Boiling point (°C)
177
Melting point (°C)
-68
Density (g/cirf)
0.85
Vapor pressure (Pa at 25°C)
200
pH (unitless)
Not available
Solubility in water (mg/L)
0.002
Relative vapor density (air = 1)
4.62
Molecular weight (g/mol)
134.2
Flash point (°C)
Not available
Octanol/water partition coefficient (unitless)
4.1
aSource: IPCS (1997); NLM (2011)
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The IRIS database (U.S. EPA, 201 la) does not list a chronic oral reference dose (RfD), a
chronic inhalation reference concentration (RfC), or a cancer assessment for p-isopropyl toluene.
The HEAST (U.S. EPA, 201 lb) does not list subchronic or chronic RfDs or RfCs for
/?-isopropyltoluene. The Drinking Water Standards and Health Advisories list (U.S. EPA, 2009)
does not list any values for/?-isopropyltoluene, and the Chemical Assessments and Related
Activities (CARA) list (U.S. EPA, 1994) does not report any assessments forp-isopropyltoluene.
The CalEPA (2008, 2009) has not derived toxicity values for exposure top-isopropyltoluene.
No occupational exposure limits for/?-isopropyltoluene have been derived by the
American Conference of Governmental Industrial Hygienists (ACGIH, 2011), the National
Institute of Occupational Safety and Health (NIOSH, 2010), or the Occupational Safety and
Health Administration (OSHA, 2010). Russia and Sweden have assigned short-term
3 3
occupational exposure limits of 10 mg/m (skin) and 190 mg/m (inhalation), respectively, for
/>-isopropyltoluene. Denmark and Sweden have assignedp-isopropyltoluene a time-weighted
3 3
average threshold limit value (TWA-TLV) of 25 ppm (135 mg/m for Denmark and 140 mg/m
for Sweden) for a normal 8-hour workday (RTECS, 2008).
The toxicity of/>-isopropyltoluene has not been reviewed by the Agency for Toxic
Substances and Disease Registry (ATSDR, 2011). The World Health Organization (WHO,
2006) evaluated the safety of/?-isopropyltoluene for use as a flavoring agent and stated that
p-isopropyloluene did not present a safety concern at the current estimated intake (approximately
1100 |ig of p-isopropyltoluene/person in Europe and 470 |igp-isopropyltoluene/person in the
United States). This evaluation is based on the available toxicity and metabolism data of
/?-isopropyltoluene, which were reviewed by the WHO (2006). /Msopropyl toluene is also
recognized as "Generally Recognized as Safe" (GRAS) for its intended use in food by the United
States Food and Drug Administration (Hall, 1960, as cited in U.S. EPA, 2005a).
The HEAST (U.S. EPA, 201 lb) does not report any cancer values for p-isopropyltoluene.
The International Agency for Research on Cancer (IARC, 2011) has not reviewed the
carcinogenic potential of/>-isopropyltoluene, and the compound is not included in the
11th Report on Carcinogens (NTP, 2005). CalEPA (2008) has not prepared a quantitative
estimate of the carcinogenic potential for p-isopropyltoluene.
Literature searches were conducted on sources published from 1900 through
June 4, 2011, for studies relevant to the derivation of provisional toxicity values for
/?-isopropyltoluene, CAS No. 99-87-6. Searches were conducted using EPA's Health and
Environmental Research Online (HERO) database of scientific literature. HERO searches the
following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane Library;
DOE: Energy Information Administration, Information Bridge, and Energy Citations Database;
EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing Office;
Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics
& Statistics and Life Sciences; NSCEP/NEPIS (U.S. EPA publications available through the
National Service Center for Environmental Publications (NSCEP) and National Environmental
Publications Internet Site (NEPIS) database); PubMed: MEDLINE and CANCERLIT databases;
SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET (Toxicology Data Network):
ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP,
GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search,
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NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI, and TSCATS; Virtual Health Library; Web
of Science (searches Current Content database among others); World Health Organization; and
Worldwide Science. The following databases outside of HERO were searched for risk
assessment values: ACGM, AT SDR, CalEPA, EPA IRIS, EPA HEAST, EPA HEEP, EPA OW,
EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 2 provides an overview of the relevant database for /?-isopropyltoluene and
includes all potentially relevant repeated short-term-, subchronic-, and chronic-duration studies.
NOAELs, LOAELs, and BMDLs/BMCLs are provided in HED/HEC units for comparison
except that oral noncancer values are not converted to HEDs and are identified in parentheses as
(Adjusted) rather than HED/HECs. Principal studies are identified. Following the table,
important aspects of all the studies are provided in the same order as the table. Reference is
made to details provided in Table 2. The phrase, "statistical significance" used throughout the
document, indicates ap-walue of <0.05.
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Table 2. Summary of Potentially Relevant Data for /j-Isopropyltoluene (CASRN 99-87-6)
Notes3
Category
Number of
Male/Female, Strain
Species, Study Type,
Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELbc
Reference
(Comments)
Human
1. Oral (mg/kg-day)b
Subchronic
ND
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
2. Inhalation (mg/m3)b
Subchronic
ND
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
Animal
1. Oral (mg/kg-day)b
Subchronic
ND
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
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Table 2. Summary of Potentially Relevant Data for />-Isopropyltoluene (CASRN 99-87-6)
Notes3
Category
Number of
Male/Female, Strain
Species, Study Type,
Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELbc
Reference
(Comments)
2. Inhalation (mg/m3)b
PR
Subchronic
7-12/0, Long-Evans
Rat, 6 h/d, 5 d/wk, 4 wk,
8-wk recovery period
0, 49, or 245
No signs of overt toxicity were
observed.
Some statistically-significant changes
in the synaptosomal fraction of
homogenized brain: decreased yield of
synaptosomal protein, and increased
concentrations of synaptosomal
noradrenaline (NA) and dopamine
(DA) were reported.
245
Not run
NA
Lam et al.
(1996)
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenic
ND
aNotes: IRIS = Utilized by IRIS, date of last update; PS = Principal study, PR = Peer Reviewed, NPR = Not peer reviewed.
bDosimetry: Exposure and NOAEL values are converted to human equivalent concentration (HEC in mg/m3) units using the following equation:
HECexresp = (ppm x MW ^ 24.45) x (hours per day exposed ^ 24) x (days per week exposed ^ 7) x blood gas partition coefficient.
°NA = not applicable, ND = No data, NDr = Not determined, NR = Not reported, NR/Dr = Not reported by the study author, but determined from data.
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HUMAN STUDIES
No studies investigating the effects of oral or inhalation exposure to /?-isopropyltoluene in
humans have been identified.
ANIMAL STUDIES
Oral Exposures
No studies investigating the health effects of short-term-, subchronic-, or
chronic-duration, developmental, or reproductive oral exposure to/?-isopropyltoluene in animals
have been identified. Data on/?-isopropyltoluene-induced toxicity in animals exposed orally are
limited to a single acute toxicity study (Jenner et al., 1964, see "Other Data" section below).
Inhalation Exposures
The effects of inhalation exposure of animals to />-isopropyltoluene have been evaluated
in one subchronic-duration study (Lam et al., 1996). Two acute inhalation studies are available
for/>-isopropyltoluene (MacDonald, 1962a,b, as cited in U.S. EPA, 2005a; see "Other Data"
section below).
Subchronic-duration Studies
Lam etal., 1996
In a peer-reviewed study, Lam et al. (1996) studied the effects of inhalation exposure of
rats to/?-isopropyltoluene for 4 weeks. It was not stated whether the study was performed under
Good Laboratory Practice standards, but the study appears scientifically sound. Groups of 7 to
12 Long-Evans male rats were exposed to 0, 50, or 250 ppm (v/v) (equivalent to HECexresp of 0,
"3
49 or 245 mg/m ) of/?-isopropyltoluene (purity greater than 99%) for 6 hours/day, 5 days/week,
for 4 weeks with an 8-week recovery period. The animals were housed (two per cage) in
stainless-steel wire cages and were kept on a 12:12-hour light-dark cycle. Exposure to
/?-isopropyltoluene vapor took place during the dark cycle. During the study, body weight was
determined weekly. This study was designed to specifically examine the neurotoxic potential of
inhaled/>-isopropyltoluene, with a focus on examining the following neurochemical parameters:
global, regional, and subcellular rat brain concentrations of the CNS neurotransmitters
noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) and their metabolism.
Although the study authors stated that a variety of general toxicity parameters were also
monitored, no information was given on general toxicity endpoints measured. After the 8-week
recovery period, rats were sacrificed by decapitation, and the cerebellum was removed, weighed,
and homogenized. The remainder of the brain was also weighed and homogenized.
Synaptosomes were isolated from the rat forebrain and prepared using gradient centrifugation.
The two homogenates and the synaptosomes were processed for neurotransmitter analyses (i.e.,
determination of NA, DA, and 5-HT), and an aliquot of each homogenate and synaptosomes was
reserved for determination of enzyme activities (lactate dehydrogenase [LDH],
acetylcholinesterase [AChE], and butylcholinesterase [BuChE]) and protein analysis. The study
authors performed statistical analysis of the neurochemical data by analysis of variance (PROC
ANOVA/GLM) followed by Dunnett's two-tailed /-test.
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The study authors stated that no treatment-related deaths or abnormal clinical signs were
observed, although no information about clinical observations was reported. The study authors
reported that there were no effects on body weight or terminal weight of the brain, cerebellum, or
whole brain in any treatment groups (data were not given in the study). The study authors also
reported that there was no effect on regional enzyme activities, regional protein synthesis, or
regional neurotransmitter concentrations. The relative yield and total amount of synaptosomal
protein were significantly reduced at 49 and 245 mg/m , and according to the study authors, they
were reduced in a concentration-related manner (see Table B.l). The relative activities of LDH,
AChE, and BuChE (defined as U/mg synaptosomal protein where U = 1 uM min"1) were
"3
significantly increased at 49 and 245 mg/m (see Table B.2). Total activity of LDH, AChE, and
BuChE (defined as U in the synaptosomal fraction per whole brain minus cerebellum) was
unaffected (data were not reported in the study). In relation to total LDH activities, a
cytoplasmatic marker enzyme, the relative synaptosomal choline esterase activities (AChE and
BuChE), and synaptosomal concentrations of NA, DA, and 5-HT were unaffected by
/?-isopropyltoluene exposure (see Table B.3). Relative to synaptosomal protein, the NA and DA
-3
concentrations were significantly increased at 49 and 245 mg/m , whereas 5-HT was unaffected
(see Table B.4). Conversely, the total amount of NA and DA in the synaptosomal fraction was
unaffected by treatment, whereas, the total amount of 5-HT was statistically significantly
decreased at 245 mg/m3 (see Table B.5). According to the study authors, these findings suggest
that noradrenergic and dopaminergic neurons may be vulnerable to/?-isopropyltoluene exposure,
giving rise to the hypothesis that the density and total number of synapses is reduced by
/?-isopropyltoluene, which is functionally compensated for by increased NA and DA
neurotransmitter release from noradrenergic and dopaminergic neurons. This compensation
could also be linked to a reduced potential for serotonergic activity. The study authors also
addressed whether or not these changes "implicate toxicity" as follows: "No generally accepted
parameter or test system is as yet established to document or predict central nervous system
neurotoxicity from neurochemical, electrophysiological, pathological, or behavioral approaches.
The present effects of/?-isopropyltoluene following four weeks of exposure and an exposure free
period of 8 weeks are long-lasting effects present at a time where/?-isopropyltoluene is supposed
to be eliminated from the body. It is not possible to conclude that these long-lasting effects are
truly irreversible" (Lam et al., 1996, p. 229). The study authors stated that the pattern of changes
induced by /?-isopropyltoluene may be a reflection of "first stage organic affective syndrome," in
which the pathophysiology is unclear, the time period is days to weeks without sequelae, and the
clinical manifestations are depression, irritability, and loss of interest in daily activities.
In summary, inhalation exposure of rats for 4 weeks to/>-isopropyltoluene resulted in
long-lasting changes in synaptosomal neurochemistry (yield of synaptosomal protein was
decreased, while synaptosomal NA and DA concentrations were increased) (Lam et al., 1996).
These changes were reported to be unaccompanied by clinical signs of toxicity. The study
authors considered that, with the present state of knowledge, it was impossible to conclude
whether or not these changes in synaptosomal neurochemistry were indicative of any
neurotoxicity. The study authors did not identify a NOAEL or LOAEL from the study.
"3
However, EPA (2005a) identified a NOAEL of 245 mg/m from this study based on the lack of
overt toxicity. EPA and the study authors, therefore, do not consider the changes to the
neurochemical parameters to be an adverse treatment-related effect.
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Chronic-duration Studies
No chronic-duration inhalation studies were identified for p-isopropyltoluene.
Developmental Studies
No developmental inhalation studies were identified for/>-isopropyltoluene.
Reproductive Studies
No reproductive inhalation studies were identified for/?-isopropyltoluene.
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OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
A few studies on genotoxicity, short-term toxicity, metabolism, and toxicokinetics of/>-isopropyltoluene are available. These are
summarized in Tables 3 and 4.
Table 3. Summary of /7-Isopropyltoluene Genotoxicity
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With
Activation
Genotoxicity studies in prokaryotic organisms
Reverse mutation
Salmonella typhimurium TA98, TA100
0.05-100 mL/plate
NT
-
None
Rockwell and
Raw(1979)
Salmonella typhimurium TA98, TA100
0.5 ml
NT
The urinary solutions isolated
from rats given 0.5 mL of
p-isopropyltolucnc were
tested in this part of the study
Rockwell and
Raw(1979)
Escherichia coli Sd-4-73
NR
NT
~
None
Szybalski (1958,
as cited inU.S
EPA, 2005a)
SOS repair induction
ND
Genotoxicity studies in nonmammalian eukaryotic organisms
Mutation
ND
Recombination induction
ND
Chromosomal abberation
ND
Chromosomal
malsegregation
ND
Mitotic arrest
ND
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Table 3. Summary of />-Isopropyltoluene Genotoxicity
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without With
Activation Activation
Genotoxicity studies in mammalian cells—in vitro
Mutation
ND
Chromosomal aberrations
ND
Sister chromatid exchange
(SCE)
ND
DNA damage
ND
DNA adducts
ND
Genotoxicity studies in mammals—in vivo
Chromosomal aberrations
ND
Sister chromatid exchange
(SCE)
ND
DNA damage
ND
DNA adducts
ND
Mouse biochemical or
visible specific locus test
ND
Dominant lethal
ND
Genotoxicity studies in subcellular systems
DNA binding
ND
aLowest effective dose for positive results, highest dose tested for negative results.
b+ = positive, ± = equivocal or weakly positive, - = negative, T = cytotoxicity, ND = no data, NR = Not reported, NT = Not tested.
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Table 4. Other Studies
Tests
Materials and Methods
Results
Conclusions
References
Short-term Studies
Groups of five young adult male and five
female Osborne-Mendel rats were
administered a single dose of
/Msopropyltoluene by gavage. The doses
tested were not provided in the study.
Animals were observed for 12 days after
dosing.
Depression (which was exhibited soon
after dosing), coma, bloody lacrimation,
diarrhea, and irritability and scrawny
appearance were observed in the treated
animals. Oral LD50 = 4750 mg/kg-day.
/?-1 so propyl toluene has low acute oral
toxicity.
Jenner et al.
(1964)
Short-term Studies
Acute toxicity studies on
/Msopropyltoluene following inhalation
exposure. Unpublished studies were
summarized in a secondary source
(U.S. EPA, 2005a). Rats, guinea pigs,
and mice were tested with a single dose of
/Msopropyltoluene at an atmospheric
concentration of 9.7 mg/L (5 hours).
Mortality was observed in mice, but not
in rats and guinea pigs. Necropsy in
mice revealed hyperemic lungs, mottled
liver, and pale kidneys.
/?-1 so propyl toluene has low acute
inhalation toxicity.
MacDonald
(1962a,b, as cited
inU.S EPA,
2005a)
Short-term Studies
Acute toxicity studies on
/Msopropyltoluene in rabbits following
dermal exposure. Unpublished study that
was summarized in a secondary source
(U.S. EPA, 2005a).
Unpublished study where insufficient
data were reported in the secondary
source. Dermal median lethal dose
>5000 mg/kg.
p-Isopropyltolucnc has low acute dermal
toxicity.
Moreno (1973, as
cited in
U.S. EPA, 2005a)
Toxicokinetic
A single male Japanese white rabbit was
administered p-isopropyltolucne as a
single oral dose (gavage) at 670 mg/kg.
Urine was collected daily for 3 days after
chemical administration and stored at
0-5°C until time of analysis.
Within 72 hours after administration,
20% of the administered dose was
eliminated in the urine as neutral or
acidic metabolites. The main
metabolites identified in the urine were
/?-cvmcn-9-ol and /?-cvmcn-8-ol (50%
and 28%, respectively, of the neutral
metabolites). In total, seven metabolites
were identified.
Hydroxylation at the three possible
aliphatic sites of /?-i so propyl toluene
contributes to the metabolite formation
in this species. However the methyl
group oxidation makes a minor
contribution compared with that shown
by hydroxylation of the isopropyl group.
Ishida et al.
(1981)
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Table 4. Other Studies
Tests
Materials and Methods
Results
Conclusions
References
Toxicokinetic
Male Wistar rats or Dunkin Hartley
guinea pigs were administered
/>-isopropyltoluene orally or by inhalation
at a dose of 100 mg/kg.
Urine was collected for analysis.
Within 48 hours after administration,
approximately 60-80% of the
administered dose was excreted in the
form of extractable metabolites in the
urine. Similar urinary metabolites were
identified in both species but in different
quantities.
Oxidation of both the methyl and
isopropyl groups of p-isopropyltolucne
contributed to the metabolite formation
in both species. No ring-hydroxylation
of p-isopropyltolucnc was detected in
rats, but trace amounts of the ring
hydroxylation metabolites were detected
in the urine in guinea-pigs. Ring
hydroxylation in guinea pigs only
occurred ortho to the methyl group.
Walde et al.
(1983)
Metabolism
Four rabbits (2F/2M) were given
/Msopropyltolucnc orally at a dose of
1000 mg/kg. The study was designed to
identify the stereochemistry of
/>-isopropyltoluene metabolites.
Urine was collected 3 days after dosing.
Different hydroxylated and carboxylated
metabolites were recovered in the urine.
Four were optically active, and three
were optically inactive.
The cytochrome p450 enzymes
responsible for the oxidation of
p-isopropyltolucnc seem to have
different regioselective properties.
The enzymatic oxidation of
p-isopropyltolucnc occurred
stereoselective^.
Matsumoto et al.
(1992)
Metabolism
A variety of species (rat, brushtail
possum, greater glider and ringtail
possum) were administered
/>-isopropyltoluene orally at doses
equivalent to 50 and 200 mg/kg.
Urine and feces were collected for two
24-hour periods.
64% of the administered dose was
excreted in urine within 48 hours for all
of the species.
Differences were observed between the
species in the urinary metabolic
disposition of p-isopropyltoliicnc. The
rat and brushtail possum excreted
metabolites containing all degrees of
oxidation (one to four oxygen atoms
added) but predominantly a
monooxygenated metabolite. The
greater glider and ringtail possum
excreted metabolites containing three or
four oxygen atoms. A conjugation
reaction with glycine, glucuronic acid, or
glutathione was observed in the rat and
the brushtail possum.
All these species exhibit a complex
metabolic pattern with extensive
oxidation of the methyl and isopropyl
groups of p-isopropyltolucnc.
Boyle et al.
(1999)
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Table 4. Other Studies
Tests
Materials and Methods
Results
Conclusions
References
Metabolism
/>-isopropyltoluene (purity = 99%)
incubated in vitro with human
recombinant p450 enzymes followed by
GC-MS analysis.
Single human volunteer swallowed
35 tablets containing 1% tea tree oil
containing /j-isopropyltoluene among
other monoterpenes (dose not further
discussed).
Thymol (2-isopropyl-5-methylphenol),
/?-isopropylbcnzyl alcohol,
/?, a a-1 ri me t In 1 be nz v 1 alcohol, and
/?-isopropylbenzaldehyde were identified
in the extract.
Thymol was recovered from both blood
and urine while other monoterpenes were
detected in urine.
One predicted metabolite from in vitro
study (thymol) was found in human
blood and urine following oral dosing
with tea tree oil containing p-
isopropyltoluene.
Meesters et al.
(2009)
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Genotoxicity
The genotoxic effects of/>-isopropyltoluene were assessed in vitro in bacterial reverse
mutation assays. /Msopropyl toluene gave negative results in the Ames mutagenicity test using
Salmonella typhimurium strains TA98 and TA100 in the presence of metabolic activation
systems (Rockwell and Raw, 1979). Also, /?-isopropyltoluene produced no increase in the
frequency of mutations when tested in Sd-4-73 Escherichia coli (Szybalski, 1958, as cited in
U.S. EPA, 2005a).
In a study designed to investigate the mutagenicity of the urinary metabolites of a number
of food additives, two Sprague-Dawley rats were given a single dose of 0.5 mL of
/?-isopropyltoluene (approximately 1706 mg/kg bw) by gavage, and their urine was collected for
24 hours. To assess the genotoxic potential of urinary metabolites, the urine was assayed
directly or extracted with ether after dilution in a phosphate buffer and treatment with
P-glucuronidase to hydrolyse glucuronide conjugates. Accordingly, three types of urine samples
were tested in the Ames assay with S. typhimurium strains TA98 and TA100 with metabolic
activation: 24-hour urine samples (500 (j,L), ether extracts of the urine, and aqueous fractions of
the extracts. No evidence of mutagenicity was observed for isopropyltoluene in this study
(Rockwell and Raw, 1979).
Short-term Studies
Several studies have evaluated the acute toxicity of /^-isopropyl toluene in animals
following oral, inhalation, or dermal exposure (Jenner et al., 1964; MacDonald, 1962a,b, as cited
in U.S. EPA, 2005a; Moreno, 1973, as cited in U.S. EPA, 2005a).
Jenner et al. (1964) evaluated the acute oral toxicity of ^-isopropyl toluene in rats in a
study designed to investigate the acute toxicity of food flavorings in animals. Groups of five
young adult male and five female Osborne-Mendel rats were given single doses of
/^-isopropyltoluene (purity was not provided in the study) by gavage. The doses tested were not
provided in the study. The animals were fasted for approximately 18 hours prior to treatment,
and, after dosing, the animals were observed for mortality and clinical signs of toxicity. The
observation was continued for 12 days until the animals appeared normal and showed weight
gain. The main clinical signs observed in the rats included depression (which was exhibited soon
after dosing), coma, bloody lacrimation, diarrhea, and irritability and scrawny appearance. The
acute oral LD50 ofp-isopropyltoluene in rats was identified as 4750 mg/kg-day, with confidence
limits of 3720-6060 mg/kg-day, calculated by the method of Litchfield and Wilcoxon (1949).
Studies available on acute inhalation and dermal exposure to ^-isopropyltoluene are
unpublished studies (MacDonald, 1962a,b) that were summarized in a secondary source
(U.S. EPA, 2005a). The acute inhalation toxicity (5 hours) ofp-isopropyltoluene at an
atmospheric concentration of 9.7 mg/L was studied in a number of laboratory animal species,
including rats, guinea pigs (MacDonald, 1962a, as cited in U.S. EPA, 2005a), and mice
(MacDonald, 1962b, as cited in U.S. EPA, 2005a). In rats and guinea pigs, no deaths were
observed at this concentration and period of exposure, but ^-isopropyltoluene was reported to be
irritating to the animals (no further details were reported as to the type of irritation). Also,
transient clonic convulsions were reported within 15 minutes in rats and 90 minutes in guinea
pigs. These effects were fully reversible by the following morning. In mice, similar effects as
those observed in rats and guinea pigs were reported; however, mortality was observed (two
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mice died during the exposure period, and a third mouse died during the night after the
exposure). Gross necropsy in mice revealed hyperemic lungs, mottled liver, and pale kidneys.
The inhalation LC50 values forp-isopropyltoluene were not identified in the secondary source.
Moreno (1973, as cited in U.S. EPA, 2005a) reported a dermal median lethal dose for
/?-isopropyltoluene of >5,000 mg/kg-bw in rabbits (additional details regarding this study are not
available).
Toxicokinetics
Studies in animals (rats, rabbits, guinea pigs, and marsupials [possum and greater glider])
have shown that/>-isopropyltoluene is well absorbed from the gastrointestinal tract, widely
distributed in the body, metabolized, and excreted mainly in the urine (Ishida et al., 1981;
Walde et al., 1983; Matsumoto et al., 1992; Boyle et al., 1999). Walde et al. (1983) administered
a single dose of 100 mg/kg to rats and guinea pigs by either oral (gavage) or inhalation exposure;
"3
the equivalent dose in mg/m administered by inhalation was not provided in the study), 60-80%
of the administered dose was excreted as metabolites in the urine within 48-72 hours of dosing.
Eighteen urinary metabolites were identified. Most of the remaining dose was either excreted
via the feces or as unextractable metabolites in the urine (Walde et al., 1983). Ishida et al. (1981)
administered/?-isopropyltoluene (670 mg/kg) via gavage to one male rabbit and identified seven
metabolites. Matsumoto et al. (1992) also identified seven metabolites after oral administration
of/?-isopropyltoluene (10 g) in rabbits. In a study in marsupials (possum and greater glider) and
rats,/>-isopropyltoluene (0.37 and 1.49 mmol/kg; equivalent to 50 and 200 mg/kg) was
administered orally to the animals (Boyle et al., 1999), with nine metabolites identified in rats,
eight in brushtail possum, four in ringtail possum, and three in greater glider (all in the urine).
Recovery of the metabolites in the urine ranged from 52-74% of the administered dose. No
metabolites were identified in the feces.
In an in vitro metabolism study, Meesters et al. (2009) incubated/?-isopropyltoluene with
human recombinant p450 enzymes and identified the following products: thymol (2-isopropyl-
5-m ethyl phenol), />isopropylbenzyl alcohol, /;,a, a-tri methyl benzyl alcohol, and
/>isopropylbenzaldehyde. In the same study (Meesters et al., 2009), only thymol was recovered
from the blood and urine of a single human subject orally dosed with />isopropyltoluene. The
results of the in vivo metabolism studies demonstrated that /?-isopropyltoluene undergoes
extensive oxidation of the methyl substituent and isopropyl side-chain to yield polar oxygenated
metabolites (see Figure 2). The main metabolites include monohydric alcohols, diols, mono- and
dicarboxylic acids, and hydroxyacids. No ring-hydroxylation was identified. These metabolites
are either excreted unchanged in the urine or undergo conjugation with glucuronic acid and/or
glycine, followed by excretion in the urine.
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OH
HO..
HO.
- (p-toly l)-2-propanol p-Cy meiie 2-(p-toly I) -1 -propanol
2- (p- to ly I) -:2- pr op an oic
acid
OH
0.\
OH
O, .--OH
0-, .OH
OH ^
HO,
p- (1 - liy droxy -1 -methy 1
ethyl)benzoic acid
p-isopropylbenzoic
acid
p- (2-liy droxy -1 -rnetliy 1
etliyl)beiizoicacid
p - (-1 - c arb oxyethy I)
benzoic acid
Figure 2. /j-Isopropyltoluene Metabolism
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DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present a summary of noncancer and cancer reference values, respectively.
Table 5. Summary of Noncancer Reference Values for />-Isopropyltoluene (CASRN 99-87-6)
Toxicity Type (units)
Species/Sex
Critical Effect
/;-Reference Value
POD Method
POD
UFc
Principal Study
Subchronic />RfD (mg/kg-day)
None
None
None
None
None
None
None
Chronic />RfD (mg/kg-day)
None
None
None
None
None
None
None
Subchronic p-RfC (mg/m3)
None
None
None
None
None
None
None
Chronic />RfC (mg/m3)
None
None
None
None
None
None
None
Table 6. Summary of Cancer Reference Values for />-Isopropyltoluene (CASRN 99-87-6)
Toxicity Value
Reference Value
Tumor Type or
Precursor Effect
Species/Sex
Principal Study
p-OSF
None
None
None
None
p-IUR
None
None
None
None
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DERIVATION OF ORAL REFERENCE DOSES
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
A subchronic p-RfD was not derived forp-isopropyltoluene due to inadequate data.
Derivation of Chronic Provisional RfD (Chronic p-RfD)
A chronic p-RfD was not derived forp-isopropyltoluene due to inadequate data.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Derivation of Subchronic Provisional RfC (Subchronic p-RfC)
There is limited information on the inhalation toxicity of/>-isopropyltoluene in humans
and animals. Only one short-term inhalation study was identified (Lam et al., 1996). In this
study, rats were exposed to/?-isopropyltoluene for 4 weeks. Therefore, this is the only study that
can be considered as the principal study for derivation of the subchronic p-RfC.
Although this study is presented in a peer-reviewed journal and is defined by the EPA
(2005a) as an acceptable and well-documented publication that meets basic scientific principles,
it is considered inadequate with respect to the examination of potential toxicity endpoints. This
study focused on only a few neurochemical parameters: global, regional, and subcellular rat
brain concentrations of the CNS neurotransmitters NA, DA, and 5-HT and their metabolism.
These parameters provide supportive evidence for neurotoxicity, but, without additional
information, these parameters cannot be used to detect or assess neurotoxicity. This study lacks
the examination of other toxicity endpoints, which are needed to fully assess the toxicity of
/?-isopropyltoluene. The study authors stated that there was no difference in body weight
between the groups of animals during the study, but no data were provided on this endpoint. In
addition, the study authors reported that there were no clinical signs of overt toxicity, but no
additional information was provided on the endpoints examined to support this statement. In
summary, this study is considered of limited usefulness for two reasons: (1) it is not known if
toxic levels of /?-isopropyltoluene were achieved based on the limited number of endpoints for
which data were presented and (2) there is no scientific basis established for interpreting the
biological significance of the neurochemical effects induced by p-isopropyltoluene. The only
changes observed in rats exposed to inhaled/?-isopropyltoluene for 4 weeks were a decrease in
the synaptosomal protein yield and an increase in synaptosomal NA and DA concentrations at
both exposure levels. The study author stated that these effects were not accompanied with
clinical signs of overt toxicity, and they were unable to predict if these effects are indicative of
toxic effects on CNS functioning. There are a great many uncertainties involved in interpreting
the results from this study, and, therefore, the derivation of a subchronic p-RfC for
/?-isopropyltoluene is not recommended due to the inability to identify the target organ and
critical effect from this study.
Derivation of Chronic Provisional RfC (Chronic p-RfC)
Chronic-duration toxicity studies for inhaled/?-isopropyltoluene are not available.
Derivation of a chronic p-RfC based on Lam et al. (1996) is not recommended due to the study
limitations described above.
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTION
The EPA has not assigned a carcinogenicity classification to/?-isopropyltoluene under the
Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005b). In accordance with these
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guidelines, data are inadequate for an assessment of the human carcinogenic potential of
/?-isopropyltoluene (see Table 5). This WOE determination is based on the fact that no adequate
data, such as reliable human epidemiological studies or well-conducted long-term animal studies,
are available to perform a carcinogenicity assessment for/?-isopropyltoluene.
There is some evidence that suggests that/>-isopropyltoluene is unlikely to be a human
carcinogen. /Msopropyltoluene is a naturally occurring component of food that has been used as
a food additive for many years. This use has been reviewed by the FDA, and/?-isopropyltoluene
was granted GRAS status (Hall, 1960, as cited in U.S. EPA, 2005a). Moreover, in a review of
the safety of/?-isopropyltoluene for use as a flavoring agent performed by the WHO (2006), it
was concluded that/?-isopropyltoluene did not present a safety concern at the current estimated
intake (approximately 1100 |ig of p-isopropyltoluene/person in Europe and 470 |ig
p-isopropyl toluene/person in the United States). In addition, /;-isopropyltoluene does not appear
to be metabolized to any highly reactive chemical species. p-Isopropyl toluene appears to be
analogous to cumene in terms of its metabolism, and cumene was classified as a carcinogen
category D ('Wo/ Classifiable as to Human Carcinogenicity "), indicating inadequate or no
human or animal data, according to the 1986 Guidelines for Carcinogen Risk Assessment
(U.S. EPA, 1986).
Table 7 identifies the cancer WOE descriptor for /?-isopropyltoluene.
Table 7. Cancer WOE Descriptor for />-Isopropyltoluene
Possible WOE
Descriptor
Designation
Route of Entry (Oral,
Inhalation, or Both)
Comments
"Carcinogenic to
Humans "
N/A
N/A
"Likely to Be
Carcinogenic to
Humans "
N/A
N/A
"Suggestive Evidence of
Carcinogenic Potential"
N/A
N/A
"Inadequate
Information to Assess
Carcinogenic Potential"
Selected
N/A
No adequate information
available to assess the
carcinogenic potential by the
inhalation or oral routes of
exposure.
"Not Likely to Be
Carcinogenic to
Humans "
N/A
N/A
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MODE-OF-ACTION (MOA) DISCUSSION
The Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005b) define MOA ".. .as a
sequence of key events and processes, starting with interaction of an agent with a cell,
proceeding through operational and anatomical changes, and resulting in cancer formation."
Examples of possible modes of carcinogenic action include ".. .mutagenicity, mitogenesis,
inhibition of cell death, cytotoxicity with reparative cell proliferation, and immune suppression"
(p. 1-10).
There are no studies available that examine the carcinogenic activity of
/?-isopropyltoluene. However, the metabolic pathways of this compound have not been shown to
involve any suspect reactive species. Also, based on in vitro bacterial assays, there is some
evidence that suggests that p-isopropyltoluene is not genotoxic, and, therefore, it is unlikely that
the genotoxic mode-of-action would be applicable for />isopropyltoluene.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of Provisional Oral Slope Factor (p-OSF)
No p-OSF can be derived due to a lack of carcinogenicity data.
Derivation of Provisional Inhalation Unit Risk (p-IUR)
No p-IUR can be derived due to a lack of carcinogenicity data.
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APPENDIX A. PROVISIONAL SCREENING VALUES
Appendix A is not applicable.
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APPENDIX B. DATA TABLES
Table B.l. Yield of Protein in the Synaptosomal Fraction of the
Whole Brain Minus Cerebellum in Rats3'
0 m «/m3
49 in«/m3
245 in«/m3
Relative yield0
16.4 ±3.1 (7)
9.20 ± 2.11* (11)
8.62 ± 1.71* (12)
Total amount0
29.1 ± 5.8 (7)
16.4 ±3.6* (11)
15.1 ±3.0* (12)
"Lametal. (1996).
bResults are mean ± 1 standard deviation, with number of rats in parentheses.
Synaptosomal protein (mg)/whole brain-cerebellum (g).
*p < 0.05 between values from control and exposed rats .
Table B.2. Relative Enzyme Activities in the Synaptosomal Fraction of
Whole Brain-Cerebellum in Ratsa'b
0 in «/m3
49 in«/m3
245 in«/m3
LDH°
2.70 ± 0.40 (7)
4.87 ±0.87* (11)
5.33 ±0.61* (12)
AChEc
159 ±30 (7)
291 ±66* (11)
288± 52* (12)
BuChEc
209 ± 36 (7)
386 ±93* (11)
358 ±74* (12)
"Lametal. (1996).
bResults are mean ± 1 standard deviation, with number of rats in parentheses.
cmU/mg synaptosomal protein.
*p < 0.05 between values from control and exposed rats.
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Table B.3. Relative Concentration of Noradrenaline, Dopamine, and
5-Hydroxytryptamine and of Esterase Activities in the Synaptosomal
Fraction of Whole Brain-Cerebellum in Ratsa'b
0 m «/m3
49 in«/m3
245 in«/m3
AChE/LDHc
58.9 ±6.0 (7)
59.6 ±6.1 (11)
54.5 ± 10.3 (12)
BuChE/LDHc
77.5 ±8.3 (7)
78.9 ±9.1 (11)
67.8 ± 13.8 (12)
NA/LDHd
6.86 ±0.75 (7)
7.07 ±0.85 (11)
5.89 ± 1.09(12)
DA/LDH d
7.31 ± 1.18 (7)
7.79 ± 0.82 (11)
6.93 ± 1.09(12)
5-HT/LDHd
3.39 ±0.91 (7)
2.55 ±0.69 (11)
2.46 ± 1.05 (12)
"Lametal. (1996).
bResults are mean ± 1 standard deviation, with number of rats in parentheses.
°Esterase Activity (mU)/LDH Activity (U).
dpmol/U LDH.
Table B.4. Relative Concentration of Noradrenaline, Dopamine, and 5-Hydroxytryptamine
in the Synaptosomal Fraction of Whole Brain-Cerebellum in Ratsa'b
0 in «/m3
49 in«/m3
245 in«/m3
NAC
18.4 ±3.0 (7)
34.4 ±7.2* (11)
31.3 ±6.2* (12)
DAC
19.8 ±4.6 (7)
38.0 ± 8.8* (11)
36.8 ±6.5* (12)
5-HTc
8.98 ±2.32 (7)
12.4 ±4.2 (11)
13.1 ±5.9 (12)
"Lametal. (1996).
bResults are mean ± 1 standard deviation, with number of rats in parentheses.
°pmol/mg synaptosomal protein.
*p < 0.05 between values from control and exposed rats.
Table B.5. Total Amount of Noradrenaline, Dopamine, and 5-Hydroxytryptamine in the
Synaptosomal Fraction of Whole Brain-Cerebellum in Ratsa'b
0 in «/m3
49 in«/m3
245 in«/m3
NAC
522 ± 36 (7)
544 ±82 (11)
461 ±75 (12)
DAC
553 ± 27 (7)
600 ±86 (11)
541 ±62(12)
5-HTc
255 ± 53 (7)
194 ±44 (11)
189 ±63* (12)
"Lametal. (1996).
bResults are mean ± 1 standard deviation, with number of rats in parentheses.
°pmol/whole brain-cerebellum.
*p < 0.05 between values from control and exposed rats.
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APPENDIX C. BMD OUTPUTS
Appendix C is not applicable.
25
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Litchfield, JT, Jr.; Wilcoxon, F. (1949) A simplified method of evaluating dose-effect
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Matsumoto, T; Ishida, T; Yoshida, T; et al. (1992) The enantioselective metabolism of
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Meesters, RJW; Duisken, M; Hollender, J. (2009) Cytochrome P450-catalysed arene-
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