United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/030F
Final
9-15-2009
Provisional Peer-Reviewed Toxicity Values for
Methylcyclopentane
(CASRN 96-37-7)
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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COMMONLY USED ABBREVIATIONS
BMD
Benchmark Dose
IRIS
Integrated Risk Information System
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 inhalation reference concentration
p-RfD
provisional oral reference dose
RfC
inhalation reference concentration
RfD
oral reference dose
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
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
METHYLCYCLOPENTANE (CASRN 96-37-7)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.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)	U.S. EPA's Integrated Risk Information System (IRIS).
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. 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 U.S. 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 U.S. EPA IRIS Program. All provisional toxicity values receive internal
review by two U.S. 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 U.S. 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 U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. 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 U.S. EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
Methylcyclopentane is a normal constituent of gasoline and other petroleum distillates. It
is also a constituent (approximately 15%) of commercial hexane. There is a paucity of toxicity
data associated with the chemical. No RfD, RfC, or carcinogenicity assessment is available on
IRIS (U.S. EPA, 2008). Methyl cycl op entane is not included on the HEAST (U.S. EPA, 1997),
the Drinking Water Standards and Health Advisory list (U.S. EPA, 2006) or the CARA list
(U.S. EPA, 1991, 1994). ATSDR (2008) has not produced a Toxicological Profile for
methylcyclopentane, and no Environmental Health Criteria Document is available (WHO, 2008).
The carcinogenicity has not been assessed by IARC (2008) or NTP (2005, 2008).
ACGIH (2007), OSHA (2008), and NIOSH (2005) have not established occupational health
standards for methylcyclopentane. CalEPA (2002, 2005a, 2005b) has also not derived risk
values for methylcyclopentane.
Literature searches were conducted from 1960s through May 2008, and updated in
April 2009 for studies relevant to the derivation of provisional toxicity values for
methylcyclopentane. Databases searched included: MEDLINE, TOXLINE (Special), BIOSIS,
TSCATS 1/TSCATS 2, CCRIS, DART/ETIC, GENETOX, HSDB, RTECS, and Current
Contents.
REVIEW OF PERTINENT LITERATURE
Human Oral Studies
The literature search did not identify any studies related to oral dosing of humans.
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Animal Oral Studies
The literature search identified two animal studies of oral exposure to
methylcyclopentane, a 4-week nephrotoxicity screening study in rats (Borriston Laboratories,
1985; Haider et al., 1985) that is used as the critical study, and an 8 week peripheral neuropathy
study in rats (Ono et al., 1981).
In a nephrotoxicity screening study of unleaded gasoline components, groups of 10 male
Fischer 344 rats were administered 0.5 or 2.0 g/kg (500 or 2000 mg/kg) of undiluted
methylcyclopentane (98% purity) by gavage, once daily, 5 days/week, for 4 weeks (Borriston
Laboratories, 1985; Haider et al., 1985). A negative control group received isotonic saline at a
dose of 2.0 g/kg-day (2000 mg/kg-day). Animals were observed twice daily for mortality and
clinical signs of toxicity. Body weights were measured prior to dosing on Day 1, and at the time
of the scheduled sacrifices. Gross necropsies were performed on all animals following moribund
condition, death, or terminal sacrifice. Only the kidney was evaluated histopathologically.
In the high dose group, 4/10 rats died. One of the 10 low dose rats died; no clinical signs
were observed in the surviving low dose rats. No deaths or clinical signs were reported among
control rats. Terminal body weight was significantly reduced 16% in the high dose group and
8%> in the low dose group. Absolute kidney weight was similar to controls in both groups. Gross
necropsy findings not observed in controls included, in the high dose group, prominent lobular
liver patterns in 2/10, speckled patterns on the kidney cortex in 2/10, and a raised pale area in a
nonglandular section of stomach in 1/10 animals, and in both low and high dose groups, spotted
lung in 1/10 from each group, and discolored pancreas in 1/10 animals from each group.
Histological examinations of the kidney did not indicate any significant
methylcyclopentane-related nephropathy. Stomach irritation (observed during gross necropsy)
or other portal-of-entry effects were not verified since these tissues were not examined
histologically. For the purposes of this review, the 500 mg/kg dose is considered a NOAEL and
the 2000 mg/kg dose a LOAEL for the body weight endpoint.
Ono et al. (1981) conducted a comparative neurotoxicity study of commercial hexane
components (each >99% pure) in which a group of 5-7 male Wistar rats was treated with
methylcyclopentane by daily gavage in olive oil for 8 weeks at doses of 0.4 mL for the first
4 weeks, 0.6 mL for the next 2 weeks, and 1.2 mL for the final 2 weeks of the study. Taking into
account the average increase in body weight over the 8 weeks of the study, methylcyclopentane
doses can be estimated as 800, 1050, and 2020 mg/kg-day for Weeks 1-4, 5-6, and 7-8,
respectively. A group of 5-7 control animals was administered olive oil alone. Peripheral nerve
activity was measured in the tail of unanesthetized animals. Motor nerve conduction velocity,
motor distal latency, and mixed nerve conduction velocity were measured. Body weights and
conduction velocities were measured at the start of the experiment, and then every 2 weeks until
termination.
No mortality or clinical signs of toxicity were observed. Body weight gain in treated
animals was similar to controls. Motor nerve conduction velocity and mixed nerve conduction
velocity (proximal, but not distal, portion of tail nerve) were significantly reduced in treated rats
at 8 weeks. Distal latency was not affected at any time. The researchers characterized these
proximal effects as a slight, though significant, difference from control (p < 0.05) in the
impairment of peripheral nerve function by methylcyclopentane.
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Human Inhalation Studies
In a study by Lehmann et al., 2002, investigators passively sampled the air in the homes
of newborns as part of a larger German Lifestyle-Immune System-Allergy (LISA) study. A
random sample of 85 newborns (43 boys, 42 girls) was selected from the pool of 976 in the
larger study. Umbilical cord-blood samples were taken at delivery, and T-cell function was
assayed using intracellular cytokine staining. In vitro stimulated cells were fixed and stained
with monoclonal antibodies against T-cell surface antigen CD-3, the cytokines INF-gamma,
TNF-alpha, IL-2 and IL-4. Fluorescent-labeled cells were analyzed by flow cytometry. Volatile
organics were sampled passively in the homes for 4 weeks after birth using 3M monitors, and
adsorbed compounds were extracted and analyzed by GC-MS. Statistic associations were
determined using STATISTICA 5.1. For the logistic regression model, T-cell functions were
categorized by quartiles, where percentages of cytokine-producing cells below the 25th percentile
were categorized as reduced, while those over the 75th percentile were considered enhanced.
Indoor concentrations of VOCs differed widely among the children's dwellings.
Significant associations between elevated VOC levels in homes and changes in
cytokine-producing T-cells were observed for 10 chemicals (including methylcyclopentane). In
the regression model, significant associations were found with only naphthalene,
methylcyclopentane and tetrachloroethylene. Of the children in the group most exposed to
methylcyclopentane, 40.9% of the children had an increased amount of IL-4 producing T-cells,
compared to 19.3% in the least exposed group. Thep-value for the association wasp < 0.03.
The most prominent risk factor was new carpeting in the infants' bedroom (Odds Ratio 4.6;
Confidence Interval 1.11-19.3).
It is not known if the changed cytokine or T-lymphocyte levels are of any clinical
significance, therefore it is difficult to call theses effects adverse. The interpretational issue with
the complex chemical mixtures found in the various homes remains problematic.
Animal Inhalation Studies
No studies investigating the effects of subchronic or chronic inhalation exposure to
methylcyclopentane in animals was identified.
Genotoxicity Studies
The results with the Ames test with methylcyclopentane were uniformly negative in
strains TA100, TA98, TA135, TA1535, and TA97, with or without metabolic activation.
Neurotoxicity Studies
The Ono et al. study (1981) cited previously, points to a neurological endpoint for
methylcyclopentane. Concern exists because of the theoretical possibility that metabolism may
lead to ring-opening of methylcyclopentane to form //-hexane, a known neurotoxin, or other
branched hexanes. In the case of //-hexane, further metabolic activation is required which
generates the ultimate toxicant 2,5-hexanedione. This diketone reacts with protein amino groups
to form an imine in an initial reversible step, and then to cyclize irreversibly to form a pyrole.
This leads to a retrograde distal axonopathy presenting initially as peripheral parasthesias
(U.S. EPA, 2008). There is, however, no direct evidence that the cyclopentane ring of
methylcyclopentane is cleaved in vivo, and the neuropathy observed by methylcyclohexane was
not an exact mimic of «-hexane.
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DERIVATION OF A PROVISIONAL SUBCHRONIC RfD FOR
METHYLCYCLOPENTANE
The reduction in body weight gain in subchronic exposures Haider et al., 1985 remains a
plausible subchronic endpoint, with reductions of 8% at 500 mg/kg and 16% at 2000 mg/kg
compared to controls. The reduction in body weight gain at the low dose was considered to be
minimal, therefore, the low dose was considered a NOAEL. The NOAEL was first adjusted to
continuous exposure from the 5 days/week dosing schedule. The NOAELadj was calculated as
the study NOAEL x 5/7 (500 mg/kg-day x 5/7 = 357 mg/kg-day). The NOAELadj was used as
the POD to derive a provisional sRfD for methylcyclopentane of 0.4 mg/kg-day as follows:
The composite uncertainty factor of 1000 is composed of the following:
•	A full UF of 10 was applied for inter-species extrapolation to account for
potential pharmacokinetic and pharmacodynamic differences between rats and
humans.
•	A full UF of 10 for intra-species differences was used to account for potentially
susceptible individuals in the absence of information on the variability of
response in humans.
•	A database UF of 10 was employed. The toxicological database for oral exposure
to methylcyclopentane is composed of two subchronic studies. The database
lacks developmental toxicity studies and a multigeneration reproduction study.
•	An uncertainty factor for LOAEL to NOAEL extrapolation was not needed as a
NOAEL was used to derive the subchronic p-RfD.
Confidence in the study is low. Dosimetry is suspect, given the potential volatilization of
the test chemical; however, this would result in a conservative value for toxicity. Confidence in
the database is low, since there were no chronic studies, no two-generational reproductive studies
and no developmental studies. Consequently, the confidence in the value is also low.
The studies by Borriston Laboratories (1985; Haider et al., 1985) are considered
inappropriate for deriving a chronic RfD because of the short duration of the dosing regimens.
Additionally, based on data from Ono et al. and Krasavage et al., the overt neurological endpoint
identified in Ono et al. may require significantly more than 4 weeks of exposure before it
becomes apparent in rodents. Thus, extension of the subchronic results to chronic exposures
(even with an additional uncertainty factor) may not be warranted.
Subchronic p-RfD = NOAELadj UF
0.4 or 4 x 10" mg/kg-day
DERIVATION OF A PROVISIONAL CHRONIC RfD
FOR METHYLCYCLOPENTANE
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DERIVATION OF A PROVISIONAL RfC
FOR METHYLCYCLOPENTANE
The study by Lehmann et al., 2002 is inappropriate for use in defining an RfC because of
limited dose-response information (only the data from the lowest and highest quartiles was
published), the lack of clear clinical significance for the potential endpoint, and the problem of
varying chemical mixtures with no controls.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
METHYLCYCLOPENTANE
Because of a lack of carcinogenic data in humans or animals, under the 2005 Guidelines
for Carcinogen Risk Assessment (U.S. EPA, 2005), this review classifies methylcyclopentane as
having "Inadequate Information to Assess the Carcinogenic Potential."
FEASIBILITY OF DERIVING A PROVISIONAL ORAL SLOPE FACTOR OR
INHALATION UNIT RISK FOR METHYLCYCLOPENTANE
Neither a provisional oral slope factor nor a provisional inhalation unit risk could be
derived for methylcyclopentane because of the lack of suitable human or animal, oral or
inhalation data.
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values for chemical substances and physical agents and biological exposure indices. Cincinnati,
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ATSDR (Agency for Toxic Substances and Disease Registry). 2008. Toxicological Profile
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Borriston Laboratories. 1985. Four-Week Oral Nephrotoxicity Screening Study in Male F344
Rats. #FYI-AX-0884-0280, EPA/OTS0000280-2.
CalEPA (California Environmental Protection Agency). 2002. Hot Spots Unit Risk and Cancer
Potency Values. Online, http://www.oehha.ca.gov/air/hot spots/pdf/TSDlookup2002.pdf.
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healthy at/chroni c. pdf.
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CalEPA (California Environmental Protection Agency). 2005b. Air Chronic Reference
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