United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/044F
Final
9-17-2009
Provisional Peer-Reviewed Toxicity Values for
^7-Pentane
(CASRN 109-66-0)
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
ft-PENTANE (CASRN 109-66-0)
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
//-Pentane is a high production volume (HPV) chemical mainly extracted from crude oil
or natural gas. //-Pentane is used as a solvent with in consumer and industrial products and, also,
as a component of gasoline and natural gas. Despite this potential for human exposures, no RfD,
RfC, or carcinogenicity assessment for //-pentane is available on IRIS (U.S. EPA, 2008). The
Health Effects Assessment Summary Tables (HEAST; U.S. EPA, 1997) states that subchronic
and chronic toxicity data for //-pentane were inadequate for quantitative risk assessment based on
a Health Effects Assessment (HEA) for //-pentane (U.S. EPA, 1987). //-Pentane was categorized
as a U.S. EPA Group D carcinogen in the HEA (U.S. EPA, 1987). w-Pentane is not included on
the Drinking Water Standards and Health Advisory list (U.S. EPA, 2006). The Chemical
Assessments and Related Activities (CARA) list includes only the above-mentioned HEA
(U.S. EPA, 1991, 1994a). The Agency for Toxic Substances and Disease Registry (ATSDR,
2008) has not produced a Toxicological Profile for //-pentane, and no Environmental Health
Criteria Document is available from the World Health Organization (WHO, 2008). The
American Conference of Governmental Industrial Hygienists (ACGIH, 2007) recommends a
threshold limit value (TLV) of 600 ppm (1,770 mg/m ) for //-pentane as an 8-hour time-weighted
average to protect against narcotic and irritation effects and possible peripheral neuropathy. The
National Institute of Occupational Safety and Health (NIOSH, 2008) has set a recommended
"3
exposure limit (REL) of 120 ppm (350 mg/m ) for //-pentane as an 8-hour time-weighted average
to protect against irritation of the eyes, skin, and nose, drowsiness, and narcosis. The
Occupational Safety and Health Administration (OSHA, 2008) permissible exposure level (PEL)
for «-pentane is 1,000 ppm (2,950 mg/m3). The carcinogenicity of «-pentane has not been
assessed by the International Agency for Research on Cancer (IARC, 2008) or the National
Toxicology Program (NTP, 2005, 2008).
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Literature searches were conducted from the 1960s through December 2007, and updated
in January 2009, for studies relevant to the derivation of provisional toxicity values for
«-pentane. Databases searched include MEDLINE, TOXLINE (Special), BIOSIS,
TSCATS1/TSCATS 2, CCRIS, DART/ETIC, GENETOX, HSDB, RTECS, and Current
Contents. A review by Galvin and Marashi (1999) was also examined for relevant studies.
REVIEW OF PERTINENT DATA
Human Studies
No information was located regarding the subchronic or chronic oral or inhalation
toxicity of //-pentane in humans.
Animal Studies
Oral Exposure
Available studies for repeated oral exposure consist of a reproductive study in rats
(McKee et al., 1998), and a rat subchronic nephrotoxicity study (API, 1985). Due to the high
volatility of //-pentane (the boiling point is roughly 36.1°C [95°F]), inhalation is expected as the
major pathway of human exposure. Despite the fact the the boiling point of //-pentane is below
the body temperature of a rat (roughly 37.5°C [99°F]), available repeated-dose oral studies
include both short-term (API, 1985) and developmental toxicity (McKee et al., 1998) gavage
studies.
As part of an oral nephrotoxicity screening study, API (1985) administered undiluted
«-pentane daily to groups of 10 male Fischer 344 rats at gavage doses of 0, 500, or
2,000 mg/kg-day 5 days/week for 4 weeks. Control animals received isotonic saline at a dose of
2,000 mg/kg-day. Dosing was carried out with two subgroups per exposure group (designated as
subgroups 'A' and 'B'). Each subgroup contained five rats dosed one day apart. Mortality and
clinical signs were noted during the treatment period. Body weights were determined prior to
dosing and at the time of scheduled euthanasia. Gross examination of tissues and organs was
conducted on all treated rats. Kidneys were the only organs examined microscopically. Twenty
percent of low-dose rats (2/10) and 40% of high-dose rats (4/10) died before the end of the study
period. Prior to death, these rats exhibited observable weight loss (Table 1). Other clinical
effects such as labored breathing, prostration, and coldness to touch were not specifically related
to //-pentane-treatment. API (1985) does not specifically report necropsy results for these
animals and does not discuss any further details regarding the potential cause of death. Thus, the
cause of death of these rats is unknown. Lesions consisting of raised, pale, white or dark foci
were found upon gross examination in the forestomach of treated rats, most notably among rats
from the high dose group.
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Table 1. Mean Body Weight Changes and Total Kidney
Weight in Rats with Orally Administered «-Pentanea
Dose
(mg/kg-day)
Initial Body Weight
(g)
Terminal Body Weight
(g)
Total Kidney Weight
(g)
0
179
234
1.75
500
180
197b
1.61b
2000
179
200b
1.59b
aAPI (1985).
bStatistically significantly lower than control at p< 0.05.
Significant decreases in body-weight gain compared to control rats were observed in both
low-dose and high-dose rats (API, 1985), as shown in Table 1. Over the 4-week study, control
rats gained 55 g, whereas treated rats gained only 17-21 g (a 62-69% depression in weight gain
compared to control rats). The effect on body weight does not demonstrate a clear dose-response
relationship because the effect is slightly lessened in high-dose rats compared to low-dose rats.
A slight dose-response relationship is observed, however, based on mean absolute kidney
weights, as shown in Table 1. Total kidney weight is significantly decreased in low-dose rats
(-8%) and high-dose rats (-9%) compared to control rats. The relative kidney weights are not
reported, but they can be calculated from the mean data. Relative (to body weight) kidney
weights are 0.75, 0.82, and 0.80% for the control, low-dose, and high-dose groups respectively.
Histopathological examination of the kidneys for hyaline droplet changes, regenerative
epithelium formation, and tubular dilatation is not remarkable.
Aside from the lesions observed in the forestomach of treated rats, as described above, no
other significant changes were noted in treated rats based on gross examination (API, 1985).
This study by API (1985) was designed as a screening study specifically for evaluating
nephrotoxicity in rats. The researchers observed overt effects (death, clinical signs, decreased
body weight relative to controls) in rats at both of the //-pentane doses tested but did not include
investigation of more sensitive systemic endpoints (other than kidney histopathology) and,
additionally, only evaluated male rats (no females) for 4 weeks. For these reasons, API (1985) is
deemed inadequate for risk assessment purposes.
In McKee et al., 1998, a range-finding developmental toxicity study, groups of
Sprague-Dawley rats (7 dams/group) were administered //-pentane (>95% purity) in corn oil at
gavage doses of 0, 250, 500, 750, or 1,000 mg/kg-day on days 6-15 of gestation. Gross
necropsies and uterine examinations (uterine weights, contents, and implantations) were
performed on dams at sacrifice on Gestation Day (GD) 21. All live fetuses were weighed, sexed
externally, and examined externally for gross malformations. The researchers reported that there
were no biologically significant external observations and no differences in fetal body weight or
sex ratio between treated and control rats.
In the full study from which a useful NOAEL could be found, groups of 25 mated
Sprague-Dawley dams were administered //-pentane (>95% purity) in corn oil at gavage doses of
0, 100, 500, or 1,000 mg/kg-day on GDs 6-15 (McKee et al., 1998). There was one control dam
and one low-dose dam that delivered prior to scheduled sacrifice. The littering data from these
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two animals was not used for further analysis by McKee et al. (1998). Body weights were
determined during the treatment period and clinical signs were noted. Gross necropsies and
uterine examinations were performed at sacrifice on GD 21. Live fetuses were weighed and
examined externally for gross malformations (stunted growth, cleft palate, micrognathia, short
tail). After sacrifice, the viscera of about 50% of the fetuses from each litter were examined by
fresh dissection. The heads of these fetuses were further examined microscopically for the
presence of abnormalities. The remaining fetuses were processed for skeletal staining and
examined for the presence of malformations and ossification variations.
McKee et al. (1998) did not observe any clinical signs among treated dams. Based on the
figure presented by McKee et al. (1998), it is apparent that all control and treated dams exhibited
increases in body weight over their initial values during gestation, and the difference in mean
body weights between the control and treated dams was minimal. No significant differences in
food consumption or uterine weights were observed between treated and control animals (data
not shown). McKee et al. (1998) did not observe any significant changes upon necropsy of
treated dams. Data on uterine implantation and fetal parameters showed no evidence of an effect
of //-pentane on numbers of viable fetuses, resorptions, implantations, pre- or postimplantation
loss, or corpora lutea; fetal body weight; Nor was there evidence of total or individual variations
or malformations (external, visceral or skeletal) on either a per-fetus or per-litter basis. Although
the data are not shown, the authors also reported no statistically significant difference between
treated and control groups in number of skeletal ossification sites. Based on the absence of
maternal or developmental toxicity, the highest dose of 1,000 mg/kg-day is identified as a
freestanding NOAEL for maternal and developmental toxicity.
Inhalation Exposure
Available studies for repeated inhalation exposure consist of a subchronic study in rats
(McKee et al., 1998), two independent subchronic neurotoxicity studies (Takeuchi et al., 1980,
1981; Frontali et al., 1981), and a range-finding developmental toxicity study (Hurtt and
Kennedy, 1999; E.I. Dupont De Nemours & Co., 1994).
McKee et al. (1998) (the key study in this document) exposed groups of Sprague-Dawley
rats (10/sex/concentration) to //-pentane vapors (>95% purity) via whole-body inhalation to
target concentrations of 0, 5,000, 10,000, or 20,000 mg/m3, 6 hours/day, 5 days/week, for
"3
13 weeks. The highest concentration tested (20,000 mg/m ) is one-half the lower explosive limit
of //-pentane (McKee et al., 1998). The mean measured concentrations were 0, 5,097 ± 79,
"3
10,203 ±151 and 20,483 ± 734 mg/m . Concentrations were chosen based on no apparent
effects seen at the same concentration levels during a 5-day range finding study. Exposure was
continued into the 14th week to ensure that each animal was exposed on the day prior to sacrifice.
Control rats were exposed to air only. All rats were evaluated for survival, body-weight changes,
clinical signs, ophthalmoscopic examination, hematology (specific endpoints not identified),
clinical chemistry (specific endpoints not specified), and organ weights (adrenals, brain,
epididymis, kidneys, liver, lungs, trachea, prostate, seminal vesicles, spleen, testes or ovaries,
thymus, and uterus). All tissues from rats of the high-exposure group, including the brain, liver,
kidneys, heart, respiratory tissues, reproductive tissues, gastrointestinal tissues, and any gross
lesions were examined microscopically. Respiratory tract tissues and gross lesions from the
mid- and low-exposure groups were also subject to microscopic examination.
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No rats died during treatment through the 90-day study (McKee et al., 1998). Incidental
clinical signs (not described) were not considered by the researchers to be related to treatment
with //-pentane. Based on a figure presented by the researchers, all rats grew normally
throughout the 90-day study. A small (<10%) but statistically significant (p < 0.05) increase in
"3
mean body weight was observed among male rats exposed to 5000 mg/m //-pentane from
Day 36 to Day 92 compared to control rats, but this is not considered treatment related, as similar
increases were not seen among the higher exposure groups. McKee et al. (1998) reported slight
statistically significant increases (p < 0.05) in food consumption and body-weight gain among
some treated rats compared to control rats, but the researchers noted that the differences were
sporadic and not related to treatment level.
McKee et al. (1998) reported that there were no treatment-related changes in hematology
or clinical chemistry among treated rats (data not shown). Increased absolute liver weight
"3
among male rats exposed to 5,000 mg/m was the only significant difference (p < 0.05) observed
based on organ weights among treated rats compared to control rats. Similar increases were not
observed among the higher exposure groups, indicating this effect is not related to exposure. No
notable changes were observed as part of the ophthalmological investigation or at necropsy upon
gross examination (McKee et al., 1998). McKee et al. (1998) did not provide specific details on
the types of lesions that were observed following microscopic examination, but the researchers
did report that the microscopic changes observed were known to occur spontaneously and
concluded that neither incidence nor type of lesion were related to exposure. In the absence of
biologically significant systemic effects following inhalation of //-pentane, the highest
concentration tested, 20,483 mg/m3 for a 90-day exposure, is identified as a freestanding
NOAEL for systemic toxicity.
In a supportive study, Takeuchi et al. (1980, 1981) conducted a neurotoxicity study in
rats evaluating the effects of //-pentane. A group of 7 male Wistar rats was exposed to vapors of
//-pentane (99% purity) via whole-body inhalation at a target concentration of 3,000 ppm
"3
(8,853 mg/m ) for 12 hours/day, 7 days/week for 16 weeks. This concentration was chosen
based on previous experiments with //-hexane (Takeuchi et al., 1980, 1981). A group of
7 control rats were exposed to air only. The measured mean vapor concentration at the end of
the study was 3,080 ± 200 ppm (9,089 mg/m3). Takeuchi et al. (1980, 1981) evaluated
neurotoxicity by measuring the conduction velocity of the peripheral nerve and distal (tail)
latency to electrical stimulation. Body weights, motor nerve conduction velocity, distal latency,
and mixed nerve conduction velocity were measured prior to treatment and again after 4, 8, 12,
and 16 weeks of exposure. Gross and microscopic examination was performed on one rat
following the 16-week exposure to //-pentane. The researchers minimized artifacts in the
fixation for the microscopic examination by fixing tissues while under anesthesia. The rats were
perfused from the left ventricle with a fixative containing paraformaldehyde and glutaraldehyde. Tissue
was fixed in the same fixative and then postfixed with osmium tetroxide. Specifically, the
gastrocnemius and soleus muscles, the dorsal trunk of the tail nerve, and the tibial nerve were
examined microscopically in this rat.
Takeuchi et al. (1980, 1981) did not observe any statistically significant treatment-related
effects on nerve conduction, body weight, or distal latency. Microscopic examination revealed
slight swelling of the mitochondria and sarcoplasmic reticulum and a slight dilatation of
myofilament bundles in the gastrocnemius and soleus muscles. Takeuchi et al. (1980, 1981)
tested only one concentration of //-pentane using a small number of male rats, examined only
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endpoints for evaluating peripheral neuropathy, and examined only one rat microscopically.
Based on these limitations of the study and the absence of effects, the data of
Takeuchi et al. (1980, 1981) are of limited usefulness for risk assessment.
In an additional supportive study, Frontali et al. (1981) also investigated the neurotoxic
effects in rats following inhalation of //-pentane vapors. Frontali et al. (1981) exposed male
Sprague-Dawley rats (6-9 rats) to //-pentane vapors (99% purity) via whole-body inhalation at a
"3
target concentration of 3,000 ppm (8,853 mg/m ) for 9 hours/day, 5 days/week, for 30 weeks.
Control rats were exposed to air only. Body weights were recorded intermittently throughout the
study, although it is unclear if weights were recorded at weekly or monthly intervals.
Additionally, all rats were subjected intermittently throughout the study (at the same time
intervals for measuring body weight) to a physiological test of neuromuscular function based on
the measure of hindlimb spread on landing after falling from 32 cm height. After 30 weeks of
exposure to //-pentane vapors, rats were euthanized for histological examination of the tibial
nerves, optic nerves, and medulla oblongata. Frontali et al. (1981) did not observe any signs of
neuropathy in treated rats. Absolute body weight values were analyzed by two statistical means:
two-way analysis of variance and Student's Mest for the comparison of two slopes. Treated rats
demonstrated a significant decrease in body weight (p < 10 x 10"5) based on two-way analysis of
variance. However, based on a Student's Mest, significance was not attained (p = 0.092).
Although these results are contradictory, Frontali et al. (1981) suggest that the results from the
Mest were the result of dispersion of data. The deviation in slope from the control curve in the
/-test was of the same order of magnitude as in other treatments (//-hexane, 2-methylpentane),
where significant differences were attained using the Student's Mest (p < 0.05). No alterations
in nervous tissues were observed by microscopic examination. Frontali et al. (1981) examined a
small number of male rats per concentration and only examined neurological endpoints.
Although this study does provide evidence that //-pentane is not neurotoxic, based on the
limitations of the study as listed above and the absence of effects, the data of Frontali et al.
(1981) are of limited usefulness for the derivation of an RfC.
In a range-finding developmental toxicity study, groups of Crl:CD®BR rats
(7-8 dams/concentration) were exposed to //-pentane vapors (99.6% purity) via whole-body
inhalation at target concentrations of 0, 1,000, 3,000, or 10,000 ppm (0, 2,951, 8,853, or
29,509 mg/m3), for 6 hours/day, from GDs 6 to 15 (Hurtt and Kennedy, 1999; E.I. Dupont De
Nemours & Co., 1994). Control dams were exposed to air only. GD 0 was assigned on the day a
copulatory plug was detected. This study was previously described by E.I. Dupont De
Nemours & Co. (1994), although the day when copulation was confirmed was previously
designated GD 1. Body weights and food consumption were monitored and recorded on GDs 0,
6, 8, 10, 12, 14, 16, and 21. Clinical signs were recorded each morning throughout the study and
each afternoon during the exposure period. Dams were euthanized on GD 21. Following
sacrifice, gross pathologic examination was made on the thoracic and abdominal cavities.
Gravid uteri were weighed and examined for the number of corpora lutea observed per ovary and
the number and position of all live, dead, and resorbed fetuses. Fetuses were weighed, sexed,
and examined for gross malformations.
Hurtt and Kennedy (1999) did not observe any mortality, unusual clinical signs, or
changes in food consumption among treated dams. Hurtt and Kennedy (1999) report tabular
summaries of maternal body-weight changes and effects on reproduction parameters in dams
exposed to //-pentane by inhalation. The results do not indicate any significant exposure-related
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effects of //-pentane exposure on maternal body weights, number of pregnant females, mean
number of viable fetuses, or mean number of implantations. Though mean resorptions per litter
at the two highest concentrations tested are increased compared to controls, as shown in Table 2,
these changes are not statistically significant (p > 0.05) and do not appear to be exposure related.
Though the fetal weights are slightly lower in all treatment groups when compared to controls,
the differences are not statistically significant, (p > 0.05) nor is there an exposure-related trend.
No external malformations among the pup fetuses were observed (data not shown). Based on
these negative findings, Hurtt and Kennedy (1999) did not conduct a full-spectrum
developmental toxicity study in rats.
Table 2. Reproductive Parameters in Dams Exposed to n-Pentane by Inhalation51

Exposure Group (ppm)
0
1,000
3,000
10,000
No. pregnant/No. treated
8/8
8/8
7/8
7/8
Implants/litter
17.6 ± 0.5b
17.8 ±0.4
17.7 ±0.3
17.1 ± 1
Resorptions/litter
0.8 ±0.3
0.8 ±0.2
1.3 ±0.5
1.1 ± 0.5
Live fetuses/litter
16.9 ±0.4
17 ±0.5
16.4 ±0.6
16 ± 1.2
Fetal body weight
5.37 ±0.1
5.22 ±0.1
5.17 ± 0.1
5.23 ±0.1
aHurtt & Kennedy (1999)
bValues are presented as means ± SE
The findings by Hurtt and Kennedy (1999) support the findings by McKee et al. (1998)
described above for oral exposure, suggesting that the developing fetus is not a sensitive target of
//-pentane in rats. Based on the absence of maternal or developmental toxicity, the high
"3
concentration of 10,000 ppm (29,509 mg/m ) is identified as aNOAEL for maternal and
developmental toxicity. However, the small group sizes and lack of detailed examination for
skeletal and visceral variations limit the usefulness of this study for risk assessment purposes.
Other Studies
Acute/Short-term Toxicity
//-Pentane does not appear to be acutely toxic following oral or inhalation exposure, as
summarized below.
Eastman Kodak Company (1966) reported an acute oral LD50 for rats of
400-3200 mg/kg. Similarly, an acute oral LD50 value of >2,000 mg/kg was reported in rats by
McKee et al. (1998). Human volunteers exposed to 5000-ppm (14,755 mg/m3) «-pentane for
10 minutes did not exhibit any adverse symptoms and, in particular, did not demonstrate mucous
membrane irritation (Carreon, 2001). Phillips Petroleum Company (1982) was unable to induce
"3
upper airway irritancy in mice exposed to 74,000 mg/m «-pentane vapors for 2 minutes.
Stadler et al. (2001) exposed male Crl:CD BR rats to //-pentane vapors via whole-body
inhalation at target concentrations of 0, 1,000, 3,000, or 10,000 ppm (0, 2,951, 8,853, or
29,509 mg/m3), respectively, for 6 hours/day, 5 days/week, for 2 weeks. Five rats from each
exposure group were observed postexposure over a 14-day recovery period. Stadler et al. (2001)
did not observe any unusual clinical signs among the treated rats, and body weights were not
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altered. No unusual behavior response was observed among the treated rats subjected to
behavioral assessments. Significant increases in serum calcium and phosphorus concentrations
"3
were observed among rats exposed to 8,853 and 29,509 mg/m n-pentane, but these changes are
slight; the phosphorus values are within the range of historical control values, and they are
reversible (levels returned to normal following the 2-week recovery period). Stadler et al. (2001)
suggested that the combination of increased calcium and phosphorus may indicate potentially
adverse alterations in mineral metabolism or homeostasis but noted that these effects could be
part of background variation and not related to //-pentane exposure. No other clinical pathology
changes were observed, and there is no indication of //-pentane toxicity based on tissue
pathology. Based on these findings, the highest concentration tested, 29,509 mg/m3, is identified
as the NOAEL for systemic effects in rats following repeated inhalation of //-pentane vapors over
2 weeks.
As mentioned previously McKee et al. (1998) conducted a 5-day range-finding study
whereby Sprague-Dawley rats (5/sex/concentration) were exposed to //-pentane vapors via
"3
whole-body inhalation at target concentrations of 0, 5,000, 10,000, or 20,000 mg/m for
6 hours/day on 5 consecutive days. No apparent effects are noted at any concentration. These
"3
data suggest the LC50 for //-pentane is >20,000 mg/m for acute exposures (6 hours/day for
5 days) (approximately 6,778 ppm). Lazarew (1929) found that exposure to
"3
200,000-300,000 mg/m «-pentane vapors caused mice to lie on their side. Studies summarized
in a review by Galvin and Marashi (1999), demonstrate that in single acute exposures, large
quantities of //-pentane act as an anesthetic and as an asphyxiant at high concentrations
(>300,000 mg/m3).
Toxicokinetics
The toxicokinetic literature on //-pentane is not robust, but there are some conclusions
that can be drawn. Frommer et al. (1970) showed that the initial step of metabolism was a P450
mediated hydroxylation to 2-pentanol and 3-pentanol in a 2:1 ratio. Subsequent work in other
laboratories demonstrated further metabolism to 2-pentanone. Filser et al. (1983) developed a
pharmacokinetic model that demonstrates a half-time for elimination/excretion of 0.13 hours.
Considering the rapid metabolism (to pentanol and pentanone) and excretion, there is little
potential for tissue accumulation (McKee et al., 1998).
Genotoxicity
Genotoxicity studies indicate that the potential for //-pentane to induce any significant
mutagenic activity is low, as summarized below. //-Pentane was not mutagenic in a Salmonella
gene mutagenicity assay that was modified for low-volatility materials (Kirwin et al., 1980). An
increasing, dose-related trend (p < 0.01) has been observed in the percentage of aberrant cells in
an in vitro chromosome aberration test with Chinese hamster ovary (CHO) cells during a 20-hour
repeat harvest in the presence of metabolic activation (McKee et al., 1998). However, as the
highest concentrations tested may have exceeded a level at which artifacts can be produced
(10 mM) and since similar increases of aberrant cells were not observed in the initial 20-hour
treatment, the increase in chromosomal aberrations during the repeated treatment is not
considered biologically important. //-Pentane did not induce micronuclei formation and did not
produce cytotoxicity in the bone marrow of rats exposed in vivo to 5,000, 10,000, or
"3
20,000 mg/m (McKee et al., 1998). w-Pentane was not mutagenic in male mice in a dominant
lethal study following injection of 48-666 mg/kg into the peritoneum (Epstein et al., 1972).
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FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR n-PENTANE
Oral studies of //-pentane are limited to short-term (API, 1985) and developmental
toxicity (McKee et al., 1998) gavage studies. API (1985) demonstrated significant decreases in
body weights and absolute kidney weights of male rats at both doses of //-pentane tested (500 or
2,000 mg/kg-day). No signs of nephrotoxicity were observed based on histopathology. In
addition, though API (1985) reported 20% mortality among low-dose rats and 40% mortality
among high-dose rats, the researchers did not provide enough information to ascertain the cause
of death. As described above, this study is of limited usefulness for risk assessment based on
poor reporting of study details, limited assessment of endpoints, and evaluation of only male rats
over short exposure duration. Contrary to the results reported by API (1985), McKee et al.
(1998) did not observe any statistically significant treatment-related effects on maternal body
weights or survival of rats exposed to //-pentane concentrations up to 1,000 mg/kg-day via
gavage during the gestation period. One factor potentially contributing to the differences
between the API (1985) study and the McKee et al. (1998) study is the dosing vehicle: the API
study used saline while the McKee study used corn oil. Finally, McKee et al. (1998) did not
observe any significant changes in reproductive parameters in dams or any adverse effects on
fetal development of pups. The available data are not sufficient for derivation of a provisional
subchronic or chronic RfD for //-pentane because systemic toxicity has not been adequately
studied.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR n-PENTANE
Subchronic p-RfC
Data on the subchronic inhalation toxicity of //-pentane come from a subchronic study in
rats (McKee et al., 1998), three subchronic neurotoxicity studies (Takeuchi et al., 1980, 1981;
Frontali et al., 1981) and a range-finding developmental toxicity study (Hurtt and Kennedy,
1999; E.I. Dupont De Nemours & Co., 1994) were used to calculate the NOAELadj and
NOAELhec values. McKee et al. (1998) did not observe any significant treatment-related effects
"3
in rats exposed to concentrations of //-pentane up to 20,483 mg/m for 6 hours per day, 5 days
per week, for 13 weeks. The neurotoxicity studies (Takeuchi et al., 1980, 1981; Frontali et al.,
1981) are of limited usefulness for risk assessment based on small sample sizes and evaluation of
a limited number of endpoints. However, the results from these studies (Takeuchi et al., 1980,
1981; Frontali et al., 1981) show that //-pentane does not induce neurotoxic (changes in
conduction velocity or microscopic changes) effects in rats exposed to concentrations up to
"3
9,089 mg/m . The developmental toxicity study by Hurtt and Kennedy (1999) found that
//-pentane exposure did not induce developmental effects in rat fetuses from dams exposed to
"3
//-pentane vapor during gestation up to the highest concentration tested (29,509 mg/m ), although
the usefulness of the study is limited because group sizes are small and complete fetal
examinations were not performed.
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The NOAEL, NOAELadj, and NOAELhec values from McKee et al. (1998), Takeuchi
et al. (1980, 1981), Frontali et al., (1981), and Hurtt and Kennedy (1999) are given in Table 3.
The NOAEL for each study (the highest concentration tested in each study) has been adjusted for
continuous exposure (NOAELadj), and the human equivalent concentrations (NOAELhec) have
been subsequently calculated, as recommended by U.S. EPA (1994b). The NOAELadj values
have been calculated as follows:
NOAELadj = (NOAEL) (# hours dosed/24) (# days dosed/7)
3,657.7 = 20,483 x (6/24) x (5/7)
Table 3. NOAELadj and NOAELhec Values for ft-Pentane Inhalation Studies
Study
NOAEL (mg/m3)
NOAELadj
(mg/m3)
NOAELhec
(mg/m3)
McKee etal. (1998)
20,483
3,658
3,658
Takeuchi et al. (1980, 1981)
9,089
4,545
4,545
Frontali et al. (1981)
8,853
2,371
2,371
Hurtt and Kennedy (1999)
29,509
7,377
7,377
The NOAELhec values shown in Table 3 are based on the NOAELadj values and were
calculated for remote effects (extrarespiratory) of a Category 3 gas by multiplying the
NOAELadj values by the ratio of the blood:gas (air) partition coefficient of n-pentane for the
laboratory animal species to the human value ([Hb/g]A/[Hb/g]H)- Blood:air partition coefficients of
1.48 and 0.38 have been estimated in rats (Meulenberg and Vijverberg, 2000) and humans
(Perbellini et al., 1985), respectively. The reliability of the rat value reported above is uncertain
because it is a predicted value based on a model using knowledge of empirical relations between
olive oil (Poil:air), saline (Psaline:air), and tissue partition coefficients (Ptissue:air) for rat tissues
(Meulenberg and Vijverberg, 2000). In accordance with U.S. EPA (1994b), the value of 1.0 is
used for the ratio of [Hb/g]A/[Hb/g]H when [Hb/g]A > [Hb/g]H- The resulting NOAELhec values are
listed in Table 3.
Although limited in various ways, the neurotoxicity studies (Takeuchi et al., 1980, 1981;
Frontali et al., 1981) and the developmental toxicity study (Hurtt and Kennedy, 1999) support
the negative findings made by McKee et al. (1998) in rats exposed to «-pentane vapors for
90 days. The NOAELhec of 3,658 mg/m3 from McKee et al. (1998) is suitable for use as the
point of departure (POD) for derivation of subchronic and chronic p-RfC values because this
study evaluates both male and female rats based on a number of endpoints including physical
changes, clinical chemistry and hematology, and gross and microscopic examination of target
organs. A lack of adverse effect levels precludes the use of benchmark dose analysis in this
study. As no significant effects are seen in any of the subchronic studies, the threshold for toxic
effects of //-pentane is not established. Note however, that higher concentrations would
approach the lower explosive level, and it would not be rational to do so. Information from acute
studies shows that at extremely high concentrations (>200,000 mg/m3), //-pentane exposure may
act as an anesthetic (Lazarew, 1929; McKee et al., 1998; Galvin and Marashi, 1999).
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-2
A subchronic p-RfC of 10 mg/m for «-pentane, based on the NOAELhec of
3,658 mg/m3 in rats (McKee et al., 1998), is derived as follows:
Subchronic p-RfC = NOAEL[heci UF
= 3,658 mg/m - 300
= 10 or 1 x 101 mg/m3
The UF of 300 is composed of the following:
•	A partial UF of 3 (10°5) is applied for interspecies extrapolation to account for
potential pharmacodynamic differences between rats and humans. Converting the
rat data to human equivalent concentrations by the dosimetric equations accounts
for pharmacokinetic differences between rats and humans; thus, it is not necessary
to use the full UF of 10 for interspecies extrapolation.
•	A 10-fold UF for intraspecies differences is used to account for potentially
susceptible individuals in the absence of information on the variability of
response in humans.
•	A UF of 10 is included for database insufficiencies. The database includes only
freestanding NOAEL values, and it lacks a supporting systemic study and a
multigenerational reproduction study. While only one range-finding
developmental toxicity study by the inhalation route is available, an oral study in
the same species suggests that developmental toxicity is not a sensitive endpoint
for //-pentane; however, a second species has not been tested by either route of
exposure.
Confidence in the principal study (McKee et al., 1998) is medium. The study evaluated
10 animals per gender per dose and assessed a wide variety of potential endpoints. However, no
LOAEL was determined in the principal study and some data were not reported beyond the
authors stating that no effects were seen (hematology, serum chemistry, microscopic changes).
Confidence in the database is low because the database is limited to freestanding NOAEL values
and lacks adequate supporting systemic, multigenerational reproduction and developmental
toxicity studies. Reflecting medium confidence in the principal study and low confidence in the
database, confidence in the provisional subchronic RfC is low.
Chronic p-RfC
To derive the chronic p-RfC, a 10-fold UF for exposure duration is applied to the
NOAELhec, resulting in a total UF of 3,000. Although the exposure duration in the critical study
was only 90 days, a UF of 10 for exposure duration is considered appropriate because of the
toxicokinetic data showing that the half-life of //-pentane is 0.13 hours. Considering the rapid
metabolism (to pentanol and pentanone) and excretion, there is little potential for tissue
accumulation (McKee et al., 1998). As no significant effects are seen in any of the subchronic
studies, the threshold for toxic effects of //-pentane is not established, and the value derived
below is likely quite conservative, as there is no evidence of chronic toxicity. The chronic
p-RfC of 1 mg/m3 for //-pentane is derived below:
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Chronic p-RfC = NOAELrec - UF
= 3,658 mg/m3 - 3,000
= 1 or 1 x 10° mg/m3
Confidence in the subchronic toxicity study used to derive the chronic p-RfC is medium,
as discussed in the subchronic p-RfC derivation. Confidence in the database is low due to the
lack of a chronic study and for the reasons discussed in the subchronic p-RfC derivation. Low
confidence in the chronic p-RfC follows.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR n-PENTANE
Weight-of-Evidence Descriptor
Studies evaluating the carcinogenic potential of oral or inhalation exposure to //-pentane
in humans or animals were not identified in the available literature. Genotoxicity data suggest
that the potential for //-pentane to induce any significant mutagenic or cytogenetic activity is low.
Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is
'Inadequate Information to Assess [the] Carcinogenic Potential' of //-pentane.
Quantitative Estimates of Carcinogenic Risk
The lack of suitable data precludes derivation of quantitative estimates of cancer risk for
//-pentane.
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