United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/024F
Final
9-30-2009
Provisional Peer-Reviewed Toxicity Values for
Commercial or Practical Grade Hexane
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
COMMERCIAL OR PRACTICAL GRADE HEXANE
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.
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
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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
Commercial hexane is a mixture of aliphatic hydrocarbons used as a solvent for
adhesives or to clean machinery (U.S. EPA, 2005a). Although the precise amount of each
constituent varies, slightly more than half (about 52%) of commercial hexane consists of
//-hexane. The remaining portion is a mixture of isomers and structurally related chemicals, such
as 3-methylpentane (16%), methylcyclopentane (16%), and 2-methylpentane (13%), as well as
some minor components such as cyclohexane and 2,4-dimethylpentane (U.S. EPA 2005a). In
order to ensure the comparability of the data included in this review, only studies of hexane
mixtures with similar composition were reviewed. Studies of mixtures with //-hexane content
less than 45% or greater than 55% were excluded from consideration.
No chronic or subchronic RfDs or RfCs or cancer assessment for commercial hexane are
available on IRIS (U.S. EPA, 2008), the Drinking Water Standards and Health Advisory list
(U.S. EPA, 2006), or in the Health Effects Assessment Summary Tables (HEAST;
U.S. EPA, 1997). No documents on commercial hexane are listed in the Chemical Assessments
and Related Activities (CARA) list (U.S. EPA 1991a, 1994a). The Occupational Safety and
Health Administration (OSHA), National Institute of Occupational Safety and Health (NIOSH),
and American Conference of Governmental Industrial Hygienists (ACGIH) have not derived
occupational exposure limits for commercial hexane (OSHA, 2008; NIOSH, 2008;
ACGIH, 2007). The ATSDR, World Health Organization (WHO), and the International Agency
for Research on Cancer (IARC) have not published documents on commercial hexane
(ATSDR, 2008; WHO, 2008; IARC, 2008). The National Toxicology Program (NTP, 2008) has
not performed toxicity or carcinogenicity assessments for //-hexane or commercial hexane, and
these compounds a not on the 11* Report on Carcinogens (NTP, 2005).
IRIS (U.S. EPA, 2008) reports a chronic RfC and cancer assessment for «-hexane. The
IRIS toxicological review for //-hexane (U.S. EPA, 2005a) includes a review of data on
commercial hexane; the IRIS review was used extensively for this report. Toxicological reviews
of this mixture by the Massachusetts Department of Environmental Protection (MADEP, 2003)
and the Total Petroleum Hydrocarbon Criteria Working Group (TPHCWG, 1997) were also
consulted for relevant information.
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To identify toxicological information pertinent to the derivation of provisional toxicity
values for commercial hexane, the IRIS toxicological review for //-hexane (U.S. EPA, 2005a)
was consulted for pertinent studies, as were MADEP (2003) and TPHCWG (1997). Update
literature searches to June 2008 were conducted using the following databases: MEDLINE,
TOXLINE, BIOSIS, TSCATS, CCRIS, DART/ETIC, GENETOX, HSDB, and Current Contents
to identify any studies of commercial hexane published since the IRIS review (U.S. EPA,
2005a). Appendix A provides additional detail on the literature search process.
REVIEW OF PERTINENT DATA
Human Studies
Oral Exposure
No studies examining the health effects of oral exposure to commercial hexane in
humans were identified.
Inhalation Exposure
U.S. EPA (2005a) reviewed the epidemiological data on human inhalation exposure to
mixtures containing //-hexane. The //-hexane content of the mixtures varied widely. A few of
the studies explicitly examined the effects of human exposure to commercial or technical grade
hexane. The summaries of these studies as reported by U.S. EPA (2005a) are represented below.
Passero et al. (1983) screened 654 workers in 44 shoe factories and 86 home
shops during a periodfrom 1973-1981. Evaluation by clinical and
electrodiagnostic examination identified 184 workers with some degree of
neurological abnormality. Of these 184 subjects, 9 had other neurological
disorders (the authors reported that the most common was radiculopathy due to
intervertebral disc disease), 77 displayed minimal changes and were considered
normal following repeated examination by the study authors and 98 manifested
overt polyneuropathy. The majority of the workplace solvent samples collected
contained commercial hexane. The commercial hexane was determined to
contain greater than 60% of total mass as hydrocarbons such as pentane,
2-methyl-pentane, 3-methyl-pentane, n-hexane, heptane, cyclopentane,
cyclohexane and methyl-cyclopentane. In 7/12 samples taken from workplaces of
individuals with the most severe polyneuropathy, over 99% of the total solvent
was composed of these hydrocarbons. No relationship was found between length
of exposure and severity of disease. In the cases ofpolyneuropathy, the
neurological pattern showed an insidious onset of loss of distal motor and
sensory function with marked reflex loss. General symptoms, such as nausea or
vomiting, epigastric pain and insomnia, preceded or accompanied the
neuropathy. Clinical symptoms were weakness, paresthesia (burning or tingling
sensation in limbs) and cramp-like pain with related motor impairment,
hypoesthesia (partial loss of sensation and/or diminished sensibility), changes in
tendon reflexes and muscle trophism and tone. These symptoms were usually
confined to distal portions of the limbs and occurred with varying degrees of
intensity depending on the extent of exposure. All 98 polyneuropathy cases
exhibited abnormal motor nerve action potentials (MAPs), regardless of severity.
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The occurrence of fibrillations, positive waves, fasciculations and slowing of
motor nerve conduction velocity (MCV) increased with disease severity. Several
of the most affected cases exhibited CNS involvement with alterations in
electroencephalogram or spasticity in the lower limbs and increased deep tendon
reflexes. The clinical course of these 98 cases was followedfor up to 8 years.
Except for the most severe cases, patients improved slowly when removedfrom
the affected environment. However, deterioration continuedfor some even after
exposure ceased.
Seppalainen et al. (1979) compared the visual evoked potentials (VEPs) and
electroretinograms (ERGs) of 15 workers to those of 10 healthy subjects with no
occupational exposure to solvents or other neurotoxic chemicals. The highest
recorded n-hexane levels in the two factories where the workers were exposed
rangedfrom 2000 to 3250 ppm. In both factories, exposure was to technical
grade hexane, which contains other aliphatic hydrocarbons with no known
neurotoxic effects. Maculopathy, color discrimination deficits, flatter VEPs and
diminished peak-to-peak amplitudes of the ERGs were more common among
cases than controls.
An earlier study by the same researchers described visual defects in this same
group of 15 workers (Raitta et al., 1978). The Farnsworth-Munsell (FM)-100 hue
test showed 12 of the 15 subjects to have impaired color vision, one of which was
probably due to a congenital abnormality. The other cases of color vision
impairment were acquired, mostly in the blue-yellow axis. In 11/15 subjects there
was evidence of associated maculopathy (damage of vessels in the eye that leak
fluid into the center of the retina causing loss of central vision), in most cases
characterized by pigment dispersion.
Animal Studies
The summaries of available studies of commercial hexane contained in the IRIS
Toxicological Review of //-hexane (U.S. EPA, 2005) are provided below with additional
information.
Oral Exposure
Krasavage et al. (1980) reported the results of a 90-day study in rats exposed to
commercial grade hexane via oral gavage. The //-hexane content of the mixture was reported to
be 40%. This study was not included in the review, as studies of mixtures with //-hexane content
less than 45% or greater than 55% were excluded from consideration.
Inhalation Exposure
MADEP (2003) identified two studies of commercial hexane (Miyagaki, 1967 and
IRDC, 1986) with //-hexane concentrations outside the limits established for this review
(45-55%)). The //-hexane content in the mixture studied by Miyagaki (1967) was reported to
range from 60-75%, while the «-hexane content in the commercial hexane used by IRDC (1986)
was 37-39%). These studies were not included in the review, as the results could not be reliably
considered comparable to mixtures containing ~50%> //-hexane.
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Subchronic Studies—Biodynamics (1989; also published as an abstract by
Duffy et al., 1991) conducted a 13-week inhalation toxicity study of commercial hexane in
F344 rats and B6C3F1 mice. Animals (10/sex/group) were exposed to target concentrations of
0-, 900-, 3,000-, or 9,000-ppm commercial hexane (51.7-53.5% «-hexane) for 6 hours/day,
5 days/week for 13 weeks. Animals were observed twice daily for mortality and clinical signs,
with weekly detailed clinical examinations. Body weights and food consumption were recorded
weekly. Ophthalmoscopic examinations were made before exposure began and just prior to
termination. Blood was collected for hematology (erythrocyte count [RBC], total and
differential leukocyte counts, platelet count, hematocrit [Hct], hemoglobin [Hgb], mean
corpuscular volume, mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin
concentration [MCHC]), and clinical chemistry (aspartate aminotransferase, alanine
aminotransferase, creatinine, blood urea nitrogen [BUN], glucose, total protein, alkaline
phosphatase [ALP], albumin, electrolytes, inorganic phosphorus, gamma glutamyl transferase
[GGT], total bilirubin, creatine phosphokinase, and lactic acid dehydrogenase [LDH]). In mice,
the clinical chemistry parameters were limited by the small quantities of serum. Gross necropsy
was performed on all animals at study termination, and selected organ weights (adrenals, ovaries,
testes with epididymides, kidneys, liver, brain, lungs, heart, and spleen) were recorded.
Comprehensive histopathology examinations (35 tissues) were made on all animals.
In rats, there were no changes in body weight, food consumption, or water intake and no
treatment-related mortality at any concentration (Biodynamics, 1989; Duffy et al., 1991). The
only treatment-related clinical sign of toxicity was lacrimation in high-concentration female rats
(in only 2/10 rats). Corneal dystrophic changes were observed in two high-concentration males;
no other ophthalmoscopic changes were reported. In high concentration-males, increased
platelet count (8% higher than controls) was observed. Clinical chemistry evaluation indicated
increases in creatinine, total protein, and albumin and decreased chloride in high-concentration
males. It was noted that these changes were within reference ranges for untreated rats
(Wolford et al., 1986). No statistically significant changes in hematology or clinical chemistry
were observed in female rats. At the high concentration, there were increases in relative kidney
and adrenal weights in males and an increase in relative adrenal weight in females.
Histopathological changes in these organs were limited to hydrocarbon nephropathy in the male
rats, as discussed in more detail below. Male rats exposed to 9,000 ppm displayed an increase in
absolute and relative liver weights (16 and 19% higher than controls,/? < 0.01). Slight
hemorrhage was observed in the livers of 3/10 high-concentration male rats, and acute/sub acute
inflammation of the liver was noted in 2/10 high-concentration males. These effects were not
observed in female rats or control or lower-concentration males. No histopathology was
observed in the nasopharyngeal tissues or larynx.
Adverse histopathological findings typical of hydrocarbon nephropathy were observed in
the kidneys of high-dose male rats, as described in the experimental pathology report of the study
(EPL, 1989). All male rats (controls and exposed) showed some evidence of hyaline droplet
formation and related nephropathy. However, this effect was more severe in male rats exposed
to commercial hexane compared with controls. The kidneys of high-concentration males showed
mild tubular dilatation, with granular material in the lumen and signs of epithelial regeneration
compared with controls. High-concentration males displayed mild-to-moderate degrees of
epithelial regeneration, a response that was minimal in controls and in animals receiving lower
concentrations of commercial hexane.
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A minimal LOAEL of 9,000 ppm was identified for rats based on liver effects (increased
liver weight, slight hemorrhage, and inflammation) in males, and a NOAEL of 3,000 ppm was
identified. Although the incidences of histopathological findings were not statistically
significant, the effects, especially hemorrhage, were clearly adverse, were not observed at lower
concentrations or in controls, and were correlated with liver-weight increases.
As with rats, there were no effects of treatment on body weight, food or water
consumption, or mortality in mice (Biodynamics, 1989; Duffy et al., 1991). Excessive
lacrimation was observed in both sexes of high-concentration mice (up to 7/10 animals at one
time point at 3,000 ppm and 10/10 at 9,000 ppm in males and 7/10, 9/10, and 9/10 in low-, mid-,
and high-concentration females, with increases over time); no control mice displayed this effect.
There were no treatment-related ophthalmoscopic findings in mice. Mean corpuscular volume
was increased relative to controls in high-concentration males, but no other hematology changes
were observed. Absolute and relative liver weights were significantly increased (8% and 9%,
p < 0.05) in high-concentration female mice, and relative liver weight was increased in
high-concentration males (12%,p< 0.01). There were no treatment-related histopathology
findings in mice. A minimal LOAEL of 900 ppm was identified for these data based on
excessive lacrimation, an indication of eye irritation, in female mice. The incidence of this effect
increased with time and concentration, was observed in males at higher concentrations, and was
not observed in control mice at any time. No NOAEL can be identified.
Bio-Research Laboratories (1990) conducted a 13-week study of the effects of
commercial hexane (51.5-53.3% //-hexane) in Sprague-Dawley rats (also reported in an abstract
by Soiefer et al., 1991). Groups of 12 rats/sex were exposed to 0-, 900-, 3,000-, or 9,000-ppm
commercial hexane for 6 hours/day, 5 days/week for 13 weeks. Clinical signs were monitored
twice daily, while body weight and food consumption were determined weekly. The animals
were evaluated in a functional observational battery (FOB) approximately 1-2 hours after the
first exposure and prior to exposure on Days 1, 7, 14, 35, 63, and 91. The FOB included
qualitative observations (in the chamber, during handling, and in an arena designed for this
purpose) as well as quantitative measures of grip strength (forelimb and hindlimb) and landing
foot splay. Motor activity was tested prestudy and on Days 34, 62, and 90. From each exposure
group, four rats/sex were given complete gross pathological examinations upon sacrifice. The
remaining eight animals/group were subjected to whole body perfusion and set aside for
neuropathology examination. In total, six animals/sex in each of the control and
high-concentration groups were assessed for histological signs of neuropathology in a large
number of nervous system tissues; tissues in other groups were not assessed because effects were
not noted in the high-concentration group.
Treatment with commercial hexane did not affect survival, body weight, or food
consumption (Bio-Research Laboratories, 1990; Soifer et al., 1991). A higher incidence of
staining of the muzzle/head and/or periorbital region was reported in treated animals; the authors
suggested that this reflected stress-induced porphyrhinitis. No treatment-related effects were
observed in the FOB or motor activity assessments of any treatment groups, nor was evidence of
neuropathology observed on examination of nervous system tissues in the high-concentration
group. A NOAEL of 9,000 ppm was identified for neurotoxicity/neuropathology in rats based on
these data.
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The International Research and Development Corporation (IRDC), sponsored by Phillips
Petroleum Co., continuously exposed male Sprague-Dawley rats to //-hexane and a C6-isomer
mixture consisting of //-hexane, methylcyclopentane, 3-methylpentane, and 2-methylpentane for
22 hours/day, 7 days/week for 6 months (IRDC, 1992a,b). This study was conducted in two
phases; Table 1 shows the exposure groups.
Table 1. Experimental Protocols for Phases I and II of a 6-Month Inhalation Study of
tt-Hexane and a Mixture Containing Hydrocarbon Isomers Plus n-Hexane in Male
Sprague-Dawley Rats3
Phase
Group
Treatment
Number of Animals Treated
I
I
Controls
24
II
125-ppm n-hexane
14
III
125-ppm /-/-hexane + 125 ppm C6 isomers'3
14
IV
125-ppm n-hexane + 375 ppm C6 isomers
14
V
125-ppm n-hexane + 1,375 ppm C6 isomers
14
VI
500-ppm //-hexane
24
II
VII
Controls
20
VIII
500-ppm C6 isomers
20
IX
500-ppm //-hexane + 500 ppm C6 isomers
20
X
500-ppm //-hexane
20
aIRDC (1992a,b).
bC6 isomers were a mixture of «-hexane-depleted C6 hydrocarbons containing methylcyclopentane,
3-methylpentane, and 2-methylpentane as major components.
For the purposes of this review, the relevant results are from Groups III and IX of the
10 treatment groups used in this study. These groups, but not the other treatment groups, were
exposed to C6 mixtures consisting of 50% //-hexane. This is the mixture most similar to the
composition of commercial hexane, which is 51-53% //-hexane. The other major components of
the C6 mixture were methylcyclopentane, 2-methylpentane, and 3-methylpentane (IRDC, 1992a,
b). For groups III and IX, the proportions of these three components were approximately
15%) each; these proportions are also similar to that of commercial hexane.
In both phases of this study, animals were examined daily for signs of clinical toxicity,
and body weights were monitored weekly (IRDC, 1992a,b). In Phase I, two controls and four
rats from Group VI (see Table 1) were taken from their exposure groups every month for the first
5 months. These animals, plus four from all groups exposed for 6 months, were examined
histopathologically for changes to the cervical spinal cord. All surviving animals (10/group)
were necropsied at study termination, and the weights of their major organs were recorded.
Excised pieces of tissue from a variety of organs and tissues were fixed for histopathological
examination, including all abnormal masses, adrenal gland, abdominal aorta, bone marrow,
brain, Zymbal's gland, esophagus, epididymides, eye and optic nerve, tongue, Harderian gland,
neuroganglia, liver, kidney, lung, lymph nodes, mammary gland, pancreas, parathyroid, pituitary,
prostate, salivary gland, skeletal muscle, skin, nasal turbinates, gonads, lacrimal gland, heart,
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thymus, thyroid, peripheral nerve, small intestine, large intestine, spinal cord, spleen, seminal
vesicle, stomach, and urinary bladder.
No treatment-related differences in survival, clinical signs, or body weight were noted in
Group III (125-ppm «-hexane and 125-ppm C6 isomers; see Table 1) compared with controls
(although body weights were slightly higher than controls) (IRDC, 1992a). None of the mixed
hexane treatment groups, including Group III, exhibited neuropathologic or myopathic changes
in Phase I of the study. Slight reductions in relative organ weights (compared with controls)
were attributable to the higher body weights in Group III animals. Gross necropsy findings in
Group III consisted of "tan or red raised, soft areas" in the livers of 2/10 rats, characterized as
mild-to-moderate in severity; there were no such findings in controls. Microscopic findings of
hepatocellular necrosis in 2/10 Group III rats were consistent with the gross findings. Necrosis
was also observed in the livers of rats of other treatment groups but was not observed in any
controls. Although the increased incidence was not statistically significant, the authors
considered the effect to be treatment-related based on the severity of the effect.
In Phase II of the study (see Table 1), five rats/group were sacrificed after 2 and 6 months
for neuropathology evaluation (IRDC, 1992b). The surviving animals (10/group) were sacrificed
after 6 months for complete necropsy, organ weight determinations, and histopathology
evaluations (see Phase I above for description). There were no treatment-related deaths in
Phase II. Beginning at Week 17, abnormal gait was observed in animals of Group IX
(500-ppm «-hexane and 500-ppm C6 isomers; see Table 1); the incidence and severity of this
effect increased with time. Body weight was significantly reduced in Group IX animals
beginning in Week 5; at study termination, the average body weight was 25% less than controls
(p < 0.01). Absolute and relative kidney weights were significantly increased (19% and 61%,
respectively; p < 0.01) in Group IX animals when compared with controls; other organ weight
changes were attributable to reductions in body weight. There were no gross necropsy findings
attributable to treatment. Histopathology findings in Group IX animals included axonal
degeneration, atrophy, and mononuclear cell infiltration in the tibial and/or sciatic nerves, mild
skeletal muscle atrophy, and chronic nephritis. Table 2 shows the incidences and severity of
these findings.
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Table 2. Incidences of Histopathology Findings for Phase II of a 6-Month Inhalation
Study of ft-Hexane and a Mixture Containing Hydrocarbon Isomers Plus n-Hexane in
Male Sprague-Dawley Ratsa
Target Organ/Cellular Response
Control
Group IX (500-ppm /i-hcxanc + 500-ppm
C6 Mixture)
Tibial and Sciatic Nerves (Combined)
Atrophy (Trace/Mild)
0/9
8/17
Axonal Degeneration (Trace)
0/9
2/17
Mononuclear Cell Infiltration (Trace/Mild)
0/9
3/17
Skeletal Muscle
Atrophy (Mild)
0/10
1/10
Kidney
Chronic Nephritis: Trace
Mild
Moderate
6/10
0/10
0/10
3/10
3/10
1/10
aIRDC (1992b).
In contrast to Phase I, neither gross liver abnormalities nor necrosis of hepatocytes was
observed in Phase II, despite the higher concentration of test material used (IRDC, 1992a,b). As
a result, the liver findings in Phase I are considered anomalous and not related to treatment.
Thus, these data are consistent with a NOAEL of 250-ppm mixed hexanes (containing
50% «-hexane) and a LOAEL of 1,000 ppm based on neuropathology, muscle atrophy, body
weight reductions, and increased severity of chronic nephritis in male rats. The authors indicated
that during exposure a brown oily material collected on the glass beads of the inhalation system
for each exposure group. Samples of this brown material were subjected to infrared
spectroscopy, which confirmed the presence of a phthalate ester-type compound. Although the
toxicological effects noted were consistent with the toxicity of //-hexane, some uncertainties
related to potential co-exposure exist.
Although other groups in this study (IRDC, 1992a,b) were exposed to pure //-hexane or to
mixtures that are not representative of commercial hexane, examination of the findings in these
groups is instructive in helping to distinguish effects that are attributable to //-hexane versus
mixed hexanes without «-hexane, as well as to give an indication of dose-response relationships.
To this end, Table 3 compares the effects observed in the different groups. In the table, observed
changes are shown under the three primary types of effects (neuropathy/myopathy, hepatic
effects, and renal effects) reported in the studies. The comparison of effects among the groups
shows the scattered nature of the liver changes (lack of dose-response relationship) in Phase I as
well as the absence of liver findings in Phase II, despite higher exposures. The table also
provides support for the suggestion that //-hexane may be largely responsible for the neuropathy
and myopathy findings, as groups exposed to mixtures with low (<500 ppm) or no //-hexane did
not exhibit evidence of these effects. Interpretation of the kidney findings is not as clear, as
groups exposed to pure //-hexane (Groups VI and X) or to hexanes without //-hexane
(Group VIII) exhibited varying degrees of kidney histopathology and/or weight changes.
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Chronic Studies—The American Petroleum Institute (API) sponsored two 2-year
carcinogenicity studies with commercial hexane: one in F344 rats (Biodynamics, 1993a) and the
other in B6C3F1 mice (Biodynamics, 1993b). The principal features and key findings of these
studies have been compiled into a single research report that was published in the peer-reviewed
literature (Daughtrey et al., 1999). In both studies, 50 animals/sex/group were exposed
6 hours/day, 5 days/week, to a commercial hexane preparation at targeted inhalation
concentrations of 0, 900, 3,000, or 9,000 ppm for 2 years. The commercial hexane preparation
used in the experiments consisted of 51.5% //-hexane, 16% methylcyclopentane, 16.1%
3-methylpentane, 12.9% 2-methylpentane, 3.3% cyclohexane, and trace amounts of other
hydrocarbons. Detailed physical examinations were given weekly. Body weight was recorded
weekly through Week 13 and monthly for the remainder of the study. All animals were given
ophthalmoscopic examinations before the study and at study termination. Differential leukocyte
count and erythrocyte morphology were evaluated on blood collected at Months 12, 18, and at
termination. Complete necropsies were performed on all animals, and histopathology of a
comprehensive list of tissues (>30) was evaluated in control and high-concentration animals, as
well as any animals that died prior to terminal sacrifice. Organ weights were not recorded.
There were no statistically significant differences in survival rates between control and
exposed rats of either sex (Biodynamics, 1993a; Daughtrey et al., 1999). Exposed animals
showed few clinical signs of toxicity in response to exposure to commercial hexane other than
lacrimation; this effect was observed in control animals as well, but at an increased incidence in
male rats of the mid- and high-concentration groups (incidence varied over time, with peak
incidences of 16/50, 26/50, and 30/50 in control, mid-, and high-concentration groups,
respectively). Body weights were significantly decreased (p < 0.05) in mid- and
high-concentration rats of both sexes. Terminal body weights were 7 and 11% lower than
controls in high-concentration males and females, respectively, with smaller reductions in the
mid-concentration group. Ophthalmoscopic findings were unremarkable, as were the limited
hematology analyses and gross necropsy observations. Histopathological lesions in the
respiratory passages were noted, especially in the nasal turbinates and larynx (see Table 4).
Specific findings consisted of hyperplasia of epithelial and goblet cells, chronic inflammation,
and increased incidence of intracytoplasmic eosinophilic material in all groups exposed to
commercial hexane. Chronic inflammation was also seen to some extent in controls. Low-,
mid-, and high-dose males and females displayed squamous metaplasia/hyperplasia of the
columnar epithelium in the larynges. Table 4 does not reflect the histologic examinations of the
larynx performed only on animals that died prior to terminal sacrifice in the low- and mid-dose
groups. There were no treatment-related necropsy findings in tissues located away from the
site-of-entry, and no treatment-related histopathological abnormalities in the sciatic nerves were
observed in any group of F344 rats exposed to commercial hexane in this study. There was no
treatment-related tumor formation at any tissue site in F344 rats. The histopathological lesions
of the respiratory tract that were evident, even in low-dose rats of both sexes, suggest that a
NOAEL cannot be derived from this study. A LOAEL of 900 ppm (lowest dose tested) is
identified based on the nasal and laryngeal lesions.
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Table 3. Comparison of Effects Among Groups of Rats Treated for 6 Months with Various Combinations
of tt-Hexane and Mixed Hexanesa

Phase I
Phase II
Group
I
II
m
IV
V
VI
VII
VIII
IX
X
rt-hcxanc (ppm)
0
125
125
125
125
500
0
0
500
500
Mixed hexanes (ppm)
0
0
125
375
1375
0
0
500
500
0
Body weight (g)
535
602
609 b
572
528
444b
581
568
436°
407°
Neuropathic/myopathic Effects
Abnormal gaitd
0/14
0/14
0/14
0/14
0/14
7/14
0/15
0/15
8/15
8/15
Skeletal muscle atrophy
0/10
0/10
0/10
0/9
0/10
9/10
0/10
0/10
1/10
3/10
Tibial or sciatic nerve atrophy (trace/mild)
e
-
-
-
-
-
0/9
0/16
8/17
14/16
Tibial or sciatic nerve axonal degeneration
0/10
0/10
0/10
0/10
0/10
7/10
0/9
0/16
2/17
0/16
Tibial or sciatic nerve mononuclear cell infiltration
(trace/mild)
-
-
-
-
-
-
0/9
0/16
3/17
3/16
Spinal cord (thoracic/lumbar/sacral) axonal
degeneration
0/10
0/10
0/10
0/10
0/10
8/10
-
-
-
-
Spinal cord (thoracic/lumbar/sacral)
vacuolar change
0/10
0/10
0/10
0/10
0/10
1/10
-
-
-
-
Hepatic Effects
Gross liver discoloration
0/10
3/10
2/10
0/10
1/10
5/10
-
-
-
-
Mean absolute liver weight (g)
15.45
18.11
18.26
17.70
19.81°
14.65
-
-
-
-
Mean liver: body weight (%)
2.88
3.01
3.02
3.08
3.74°
3.31°
-
-
-
-
Panlobular necrosis (trace)
0/10
0/10
2/10
0/10
0/10
0/10
-
-
-
-
Panlobular necrosis (mild)
0/10
1/10
0/10
0/10
1/10
2/10
-
-
-
-
Panlobular necrosis (moderate)
0/10
2/10
0/10
0/10
0/10
0/10
-
-
-
-
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Table 3. Comparison of Effects Among Groups of Rats Treated for 6 Months with Various Combinations
of tt-Hexane and Mixed Hexanesa

Phase I
Phase II
Group
I
II
III
IV
V
VI
VII
VIII
IX
X
Renal Effects
Mean absolute kidney weight (g)
2.98
3.32
3.32
3.65c
4.140
3.15
3.08
3.49b
3.68c
3.40
Mean kidney: body weight (%)
0.56
0.55
0.55
0.65b
0.78 c
0.710
5.32
6.16
8.56c
8.44c
Mean kidney: brain weight (%)
-
-
-
-
-
-
1.46
1.69b
1.990
1.750
Degeneration/regeneration (trace)
(mild)
0/10
0/10
0/10
0/10
0/10
0/10
6/10
2/10
5/10
5/10
4/10
0/10
-
-
-
-
Chronic nephritis (trace)
(mild)
(moderate)
"
"
"
"
"
"
6/11 0/11
0/11
5/10
3/10
0/10
3/10
3/10
1/10
2/10
7/10
1/10
aIRDC (1992a,b).
bSignificantly different from controls (p < 0.05).
><0.01.
incidence at Week 25.
"Effect not present (for quantal endpoints) or not changed by exposure (organ weights).
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Table 4. Incidence of Nasal and Laryngeal Lesions in Male and Female F344 Rats
Exposed to Commercial Hexane for 2 Yearsa


Target Concentration of Commercial Hexane (ppm)
Target Organ/Cellular Response
0
900
3,000
9,000
Nasal Mucosa
Males
Goblet Cell Hypertrophy/Hyperplasia
29/48
37/50b
43/50°
41/50°
Epithelial Hyperplasia
2/48
19/50°
36/50°
43/50°
Intracytoplasmic Eosinophilic Material
21/48
49/50°
46/50°
46/50°
Inflammation
9/48
8/50
10/50
23/50
Females
Goblet Cell Hypertrophy/Hyperplasia
33/50
43/50°
43/50°
46/50°
Epithelial Hyperplasia
6/50
34/50°
38/50°
42/50°
Intracytoplasmic Eosinophilic Material
41/50
47/50°
48/50°
49/50°
Inflammation
8/50
6/50
4/50
13/50
Larynx
Males
Columnar Epithelial Hyperplasia/Metaplasia
4/49
d
-
11/50
Females
Columnar Epithelial Hyperplasia/Metaplasia
1/48
-
-
7/48
aDaughtrey et al. (1999); Biodynamics (1993a).
bSignificantly different (p < 0.05) from controls, as calculated by the authors using ordinal logistic regression.
><0.01.
dLaryngeal tissue not examined in all animals of these groups.
There were no statistically significant differences in survival between controls and
exposed mice of either sex (Biodynamics, 1993b; Daughtrey et al., 1999). There were no
differences in clinical signs of toxicity, ophthalmoloscopic findings, or hematology. Body
weight changes in commercial hexane-exposed mice were generally similar to those in controls.
Statistically significant (p < 0.05) body weight depression was noted in females exposed to
9,000 ppm after Week 29. On week 53 body weights were decreased by 14% below controls,
however by study termination, body weights in this group only differed from controls by 3%.
No nonneoplastic histopathology findings were affected by treatment; however, it should be
noted that the nasal turbinates were not examined for histopathology in mice. A minimal
LOAEL of 9,000 ppm (lowest dose tested) is identified from these data based on body weight
reductions in females; although body weights returned to normal by study termination, the
decrease compared with controls persisted for nearly half of the 2-year study. The NOAEL is
3,000 ppm.
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In female mice, there was a dose-related increase in the incidence of hepatocellular
neoplasms (Biodynamics, 1993b; Daughtrey et al., 1999). When benign and malignant tumors
were combined, the incidence reached statistical significance in the high-concentration group.
There was also an increased incidence of pituitary adenomas and adenocarcinomas in exposed
females (see Table 5). For these tumors there was a significantly elevated incidence at each
exposure concentration. Commercial hexane was associated with decreased severity and
incidence of cystic endometrial hyperplasia of the uterus among high-dose females compared
with controls.
Table 5. Incidence of Liver and Pituitary Tumors in Male and Female B6C3F1 Mice
Exposed to Commercial Hexane for 2 Years3


Target Concentration of Commercial Hexane (ppm)
Target Organ/Cellular Response
0
900
3,000
9,000
Liver
Males
Adenomas
10/49
5/50
7/50
10/50
Carcinomas
7/49
11/50
10/50
3/50
Combined adenomas and carcinomas
17/49
16/50
17/50
13/50
Females
Adenomas
4/50
6/50
4/49
10/50
Carcinomas
3/50
2/50
5/49
6/50
Combined adenomas and carcinomas
7/50
8/50
9/49
16/50b'0
Pituitary
Males
Hyperplasia
0/46
0/11
0/6
1/46
Adenomas
1/46
0/11
0/6
0/46
Adenocarcinomas
0/46
0/11
0/6
0/46
Total neoplasms
1/46
0/11
0/6
0/46
Females
Hyperplasia
2/45
4/48
4/48
6/49
Adenomas
0/45
6/48b
7/48d
5/49b
Adenocarcinomas
0/45
0/48
1/48
0/49
Total neoplasms
0/45
6/48b
8/4 8 d
5/49b
aDaughtrey et al. (1999); Biodynamics (1993b).
bSignificantly different (p < 0.05) from controls, as calculated by the authors using Fisher's Exact test.
Significant dose-related trend; Cochrane-Armitage test, p < 0.05.
Significantly different (p < 0.01) from controls, as calculated by the authors using Fisher's Exact test.
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Reproductive/Developmental Studies—API sponsored two reproductive studies in
laboratory rats and mice exposed to commercial hexane (BRRC, 1989a,b). The first study was a
range-finding study in which pregnant Sprague-Dawley rats (8/group) and CD-I mice (8/group)
were exposed to inhaled commercial hexane for 6 hours/day at target concentrations of 0, 900,
3,000, or 9,000 ppm on Gestation Days (GDs) 6-15 (BRRC, 1989a). The mixture composition
was not reported. Pregnant rats were terminated on GD 21 and pregnant mice on GD 18.
Maternal body weight gain was monitored intermittently and at termination. Uterine weights,
number of ovarian corpora lutea, implantation sites, and viable and nonviable implants were
evaluated. All live fetuses were weighed, sexed, and examined for external and visceral
malformations and skeletal variations. None of the dams of either species displayed overt
maternal toxicity during the course of the experiment. There appeared to be a slight increase in
body weight gain in the high-dose rats in parallel with increased food and water consumption in
this group. The only sign of reproductive or developmental toxicity was a reduction in mean
fetal weight per litter (11% below controls,/? < 0.05) in the progeny of pregnant mice exposed to
9,000-ppm commercial hexane. No treatment-related malformations or variations were observed
in either the rat or mouse fetuses. This study identifies a developmental LOAEL of 9,000 ppm
for reduced fetal weight in mice, with a developmental NOAEL of 3,000 ppm and maternal
NOAEL of 9,000 ppm in mice. In rats, a developmental and maternal NOAEL of 9,000 ppm
(the highest dose tested) is identified.
In the full study, BRRC (1989b) exposed pregnant Sprague Dawley rats (25/group) to 0-,
900-, 3,000-, or 9,000-ppm commercial hexane (containing 53% «-hexane) for 6 hours/day on
GDs 6-15 and sacrificed the animals on GD 21. Maternal body weights and food and water
consumption were recorded on GDs 0, 6, 9, 12, 15, 18, and 21, and the weights of liver, kidney,
and uterus were measured at sacrifice. As in the range finding study, numbers of ovarian corpora
lutea, implantation sites, resorptions, and live and dead fetuses were evaluated. Fetuses were
examined for external and visceral abnormalities and for skeletal variations. There were no
treatment-related effects on reproductive, developmental, or teratological parameters in any of
the groups of rats in the study. Among maternal effects, body weight gain was reduced in
high-concentration dams throughout exposure (19% below controls,/? < 0.05, during GDs 6-15)
and in the mid-concentration group for a portion of the exposure period (29% below controls,
p < 0.05, during GDs 9-12). Food consumption was reduced in the high-concentration dams but
not in the mid-concentration dams. In dams exposed to the high concentration, an increased
incidence of pulmonary color change (6/21, compared with 0/23 controls; p < 0.05) was
observed at necropsy. A minimal maternal LOAEL of 3,000 ppm is identified based on body
weight reductions during gestation, with a maternal NOAEL of 900 ppm in rats. The reduction
in body-weight gain at this concentration was transient, occurring during GDs 9-12 only, and
there was no statistically significant reduction in body-weight gain over the entire exposure
period or gestational period. No reduction in body weight gain was reported in the range-finding
study in rats (BRRC, 1989a), or in the Fo generation in the two-generation reproductive toxicity
study (BRRC, 1991; Daughtrey et al., 1994, described below). Decreased body weight was
observed, however, in the Fi and F2 pups in the two-generation study (BBRC, 1991; Daughtrey
et al., 1994), in rats in a subchronic study (IRDC, 1992b), and female mice in the chronic
inhalation study (Biodynamics, 1993b; Daughtrey et al., 1999) discussed previously. Taking into
consideration that U.S. EPA regards body weight depression >10% to be adverse, that the effect
was transient in the 3,000-ppm dams but more pronounced in the 9,000-ppm dams in the BBRC
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(1989b) study, and that a body weight effect also was seen in some (but not other) studies, the
LOAEL of 3,000 ppm is considered close to the threshold for this effect. Thus, a developmental
NOAEL of 9,000 ppm applies to these data.
In addition, pregnant CD-I mice (30/group) were exposed to the same regimen as that
described for the Sprague-Dawley rats (BRRC, 1989b), and the same evaluations were
performed. There were no treatment-related effects on maternal body-weight gain, no changes in
food and water consumption, and no other clinical signs of toxicity among the exposed groups
compared with controls. Gestational parameters, including the numbers of viable and nonviable
implantations/litter and sex ratio, were unaffected by exposure to commercial hexane. However,
gross necropsy revealed a dose-dependent increase in the incidence of discoloration of the lungs
(0/27, 0/27, 2/25, and 12/29 in control through high-concentration groups). The incidence at
9,000 ppm was significantly different from controls (p < 0.01). In addition, dark brown foci
were evident in the lungs of 4/29 high-dose and 2/25 mid-dose dams; these incidences were not
statistically different from controls.
Fetal body weights were unchanged among the groups, and there were no significant
changes in the incidence of individual malformations or pooled external, visceral, or skeletal
malformations (BRRC, 1989b). However, there were treatment-related increases in the
incidences of two individual skeletal variations in high-dose pups. Comparing the incidences of
these effects between controls and high-dose groups by litter, the numbers were 0/26 versus 6/26
for bilateral bone islands at the first lumbar arch and 20/26 versus 26/26 for all unossified
intermediate phalanges (statistically significant atp< 0.05, Fisher's Exact test as calculated by
the study authors). Based on these skeletal variations, a developmental NOAEL of 3,000 ppm
and LOAEL of 9,000 ppm were identified. The only effect observed in dams was discoloration
of the lungs in mid- and high-dose animals, some of which also had dark brown foci on the
lungs. These effects were not observed in mice exposed to the same concentrations in the
range-finding study (BRRC, 1989a) and for a much longer duration in a chronic study
(Biodynamics, 1993b; Daughtrey et al., 1999). Pulmonary effects were not observed in rats
exposed to the same concentrations in subchronic, chronic, reproductive, or developmental
toxicity studies. Finally, it is not clear that discoloration of the lungs represents an adverse
effect. Thus, the high concentration (9,000 ppm) (the highest dose tested) is considered a
NOAEL for maternal effects.
BRRC (1991) carried out a two-generation reproductive/developmental toxicity study in
which, prior to breeding, 25 Sprague-Dawley rats/sex/group (Fo generation) were exposed to
concentrations of 0-, 900-, 3,000-, or 9,000-ppm inhaled commercial hexane for 6 hours/day,
5 days/week for 10 weeks. The study was published in the peer-reviewed literature by
Daughtrey et al. (1994). Clinical signs of toxicity were monitored daily, and food consumption
and body-weight data were recorded weekly. After 10 weeks, males and females were mated,
and these mating pairs were exposed to commercial hexane at the same doses for 6 hours/day,
7 days/week for 21 days. Cohabitation was maintained only long enough for pregnancy to be
achieved (copulation plug present). For the dams, exposure was continued through GD 19,
discontinued until Postnatal Day (PND) 4, and then reinstituted until weaning on PND 28, at
which point the F0 animals were sacrificed. On PND 4, the pups were culled to 4/sex/litter; then,
on PND 28, 25 Fi rats/sex/group were randomly selected for exposure to commercial hexane for
8-11 weeks. Subjects were then mated as described for the F0 generation. All F2 rats were
sacrificed on PND 28.
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Among the reproductive indices evaluated were survival, mating, fertility, gestation, live
births, and lactation (BRRC, 1991). All subjects were necropsied, and excised pieces of liver,
kidney, pituitary, and upper and lower respiratory tract, and any obvious lesions were examined
for histopathology. Reproductive organs and tissues taken for histopathology included the
vagina, uterus, ovary, testis, epididymis, seminal vesicles, and prostate.
In the F0 generation, there were no dose-related changes in body weight gain and no
clinical signs of toxicity resulting from exposure to commercial hexane at any concentration
(BRRC, 1991). Hyaline droplet nephropathy was visible histopathologically in the high-dose
Fo males. There were no changes in any of the mating indices, fertility, gestation, live
pups/litter, or pup viability at PND 28. A treatment-related effect of commercial hexane was a
reduction of mean body weight in the Fi pups of the high-dose dams, an effect that became
apparent at PND 14 and beyond. The mean body weight of the Fi pups remained lower than
controls throughout their prebreeding period. The group-specific means were significantly
decreased (by approximately 7%) on PND 21 (38.9 ± 4.0 g in high-dose pups versus
41.9 ± 3.95 g in control pups).
There were no overt signs of clinical toxicity and no other signs of reproductive
performance deficits in the Fi generation (BRRC, 1991). Similarly, no lesions in male
reproductive organs were apparent at necropsy and histopathological examination. Hyaline
droplet nephropathy was observed in Fi high-dose males (statistically significant). The numbers
of pups born to exposed Fi rats were not statistically different compared with controls. F2 pup
body weights in the high-concentration group were reduced by 6-9% compared with controls
after PND 7. The viability of F2 pups did not differ between the groups. A LOAEL of
9,000 ppm (31,579 mg/m ) is identified based on reduced body weights in the Fi and F2 pups
after PNDs 14 and 7, respectively. The NOAEL is 3,000 ppm (10,526 mg/m3). The high
concentration (9,000 ppm or 31,579 mg/m ) is a NOAEL for effects on reproduction.
Other Studies
Genotoxicity
In the few studies that have addressed the genotoxicity/mutagenicity of a mixture
containing approximately 50% //-hexane, no gene reversion or chromosomal aberrations in
Chinese hamster ovary (CHO) cells (with or without activation) or chromosomal aberrations in
Chinese hamster lung (CHL) cells were seen in vitro (Microbiological Associates, 1989, 1990).
In addition, in vivo, no chromosomal aberrations were induced in male and female
Sprague-Dawley rat bone marrow cells after nose-only inhalation exposure to commercial
hexane for 6 hours/day on 5 consecutive days at concentrations of 876, 3,249, and 8,715 ppm
(Microbiological Associates, 1990).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR COMMERCIAL HEXANE
No usable information was obtained to develop oral toxicity values (subchronic or
chronic p-RfDs) for commercial hexane.
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DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC INHALATION
p-RfC VALUES FOR COMMERCIAL HEXANE
A total of three epidemiological studies of human inhalation exposure to commercial or
practical grade hexane (Passero et al., 1983; Seppalainen et al., 1979; Raitta et al., 1978) were
reviewed by U.S. EPA (2005a). None of these studies reported exposure in terms of
concentration of commercial hexane which rendered them useless to derive inhalation toxicity
values for commercial hexane.
Inhalation studies of commercial hexane in laboratory animals of potential use in
developing subchronic p-RfCs are presented in Table 6.
In the subchronic mouse studies (Biodynamics, 1989; Duffy et al., 1991), increased
lacrimation occurred in a dose-related fashion at concentrations >900 ppm and was selected by
the authors as the basis for the LOAEL. However, increased lacrimation did not occur during
chronic exposure of mice to the same or higher concentrations (up to 9,000 ppm; Biodynamics,
1993b; Daughtrey et al., 1999). The subchronic mouse study was excluded as a potential basis
for the subchronic p-RfC because the biological significance of the lacrimation is uncertain
given this inconsistency. In addition to the subchronic, reproductive, and developmental toxicity
studies, chronic studies in rats and mice are available (Biodynamics, 1993a,b; Daughtrey et al.,
1999).
To facilitate comparison of the studies, effect levels were first adjusted to equivalent
continuous exposure concentrations. The NOAELs and LOAELs from each of the studies were
converted to human equivalent concentrations (NOAELhec and LOAELhec) based on U.S. EPA
(1994b). Available data on commercial hexane indicate that chronic exposure results in irritation
effects (specifically, nasal histopathology in rats) at low concentrations (900 ppm; Biodynamics,
1993a; Daughtrey et al., 1999), while subchronic exposure to concentrations as high as
9,000 ppm does not (Biodynamics, 1989; IRDC, 1992a,b) suggesting that exposure duration is
an important factor in the genesis of the nasal lesions. Thus, the effect levels for nasal lesions in
the chronic rat study were converted to equivalent continuous exposure. The U.S. EPA (2002)
also recommends adjusting for continuous exposure in developmental toxicity studies. Thus, the
effect levels in the developmental toxicity studies were also adjusted for continuous exposure.
The human equivalent concentration was then calculated using the dosimetric adjustment
appropriate to the observed effect, either airway or systemic toxicant (U.S. EPA, 1994b).
With the exception of studies by Biodynamics (1993a); Daughtrey et al, 1999), discussed
below, for all other potentially relevant studies, commercial hexane was treated as a Category 3
gas (systemic toxicant) since significant extrarespiratory effects but no significant airway effects
were observed in these studies. The ratio of blood:gas partition coefficients were used to make
this dosimetric adjustment. For //-hexane, the major constituent of commercial hexane, values
reported in the literature for blood:gas partition coefficients are 2.29 in F344 rats (Gargas et al.,
1989) and 0.8 in humans (Perbellini et al., 1985). However, the U.S. EPA (1994b) recommends
using a value of one as a maximum which is utilized in this case. The blood:gas partition
coefficient for mice was not located; the default value of one was also used for the mouse
studies.
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Table 6. Available Inhalation Noncancer Dose-Response Information for Commercial Hexane
Mixture or
Compound
Species
and Sex
Exposure
Concentration
(ppm)
Exposure
NOAEL
(ppm)
LOAEL
(ppm)
Responses
Comments
Reference
Subchronic
Commercial
hexane
(51.5-53.3%
//-hexane)
SD Rat
(M/F)
0, 900, 3,000,
9,000
6 hr/d, 5
d/wk, for
13 wks
9,000
NA
No effect on mortality,
clinical condition, body
weight, food intake, gross
pathology, FOB, motor
activity, or histology of
nervous system tissues

Soiefer et al., 1991;
Bio-Research
Laboratories, 1989
Commercial
hexane
(51.7-53.5%
//-hexane)
F344 Rat
(M/F)
0, 900, 3,000,
9,000
6 hr/d,
5 d/wk, for
13 wks
3,000 (M)
9,000 (M)
Slight hemorrhage and
inflammation of liver and
kidney in few males (not
significantly different
from controls)
Increased severity of
hyaline droplet
nephropathy in treated
males
Duffy et al., 1991;
Biodynamics, 1989;
EPL, 1989
Mixed
hexanes (50%
//-hexane)
SD Rat
(M)
0, 250, 1,000
22 hr/d,
7 d/wk, for
6 mos
250
1,000
Abnormal gait; decreased
body weight; mild atrophy
of sciatic and/or tibial
nerve and skeletal muscle
Slight increase in
incidence and severity of
chronic nephritis;
potentially confounded by
coexposure to
phthalate-ester compound
IRDC, 1992a,b
Chronic
Commercial
hexane
(51.5%
//-hexane)
F344 Rat
(M/F)
0, 900, 3,000,
9,000
6 hr/d,
5 d/wk, for
2 yrs
NA
900
Histologic evidence of
mucosal irritation in nasal
turbinates and larynx in
both sexes
No histopathological
abnormalities of sciatic
nerve
Biodynamics, 1993a;
Daughtrey et al.,
1999
Commercial
hexane
(51.5%
//-hexane)
B6C3F1
Mouse
(M/F)
0, 900, 3,000,
9,000
6 hr/d,
5 d/wk, for
2 yrs
3,000
9,000
Body weight depression
in females. Minimal
LOAEL
Dose-related increase in
incidence of liver and
pituitary tumors in
females. Nasal turbinates
not examined in mice
Biodynamics,
1993b;
Daughtrey et al.,
1999
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Table 6. Available Inhalation Noncancer Dose-Response Information for Commercial Hexane
Mixture or
Compound
Species
and Sex
Exposure
Concentration
(ppm)
Exposure
NOAEL
(ppm)
LOAEL
(ppm)
Responses
Comments
Reference
Reproductive/Developmental
Commercial
hexane
SD Rat
(M/F)
0, 900, 3,000,
9,000
6 hr/d,
5 d/wk, for
2 generations
3,000
(offspring)
9,000
(reproductive)
9,000
(offspring)
NA
(reproductive)
Reduced body weight in
F, weanlings and F2 pups
after PND 7
Hyaline droplet
nephropathy in 9,000-ppm
F0 and F, males
Daughtrey et al.,
1994; BRRC, 1991
Commercial
hexane
SD Rat
(F)
0, 900, 3,000,
9,000
6 hr/d on
GDs 6-15
9,000
(maternal)
9,000
(develop-
mental)
NA (maternal)
NA (develop-
mental)
None
Range-finding study
BRRC, 1989a
Commercial
hexane
SD Rat
(F)
0, 900, 3,000,
9,000
6 hr/d on
GDs 6-15
900
(maternal)
9,000
(develop-
mental)
3,000
(maternal)
NA (develop-
mental)
Reduced body weight
gain during GD 9-12

BRRC, 1989b
Commercial
hexane
CD-I
Mouse
(F)
0, 900, 3,000,
9,000
6 hr/d on
GDs 6-15
9,000
(maternal)
3,000
(develop-
mental)
NA (maternal)
9,000
(develop-
mental)
Reduced fetal weights
Range-finding study
BRRC, 1989a
Commercial
hexane
CD-I
Mouse
(F)
0, 900, 3,000,
9,000
6 hr/d on
GDs 6-15
9,000
(maternal)
3,000
(develop-
mental)
NA (maternal)
9,000
(develop-
mental)
Increased incidence of
two skeletal variations

BRRC, 1989b
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For the rat study reported by Biodynamics (1993a; Daughtrey et al., 1999), respiratory
effects (nasal irritation) were observed. As recommended by U.S. EPA (1994b), commercial
hexane was treated as a Category 1 gas, and the Regional Gas Dose Ratio (RGDR) was
calculated in order to determine the HEC for respiratory effects from this study. For nasal
effects reported in Biodynamics (1993a; Daughtrey et al., 1999), RGDRet (extrathoracic) values
of 0.24 (for males) and 0.16 (for females) were calculated as indicated below (U.S. EPA, 1994b).
RGDRet = (Vf/SArt)^
(Ve/SAetX uman
= 0.24 for males
= 0.16 for females
Where
VE
Minute volume (L/min)
0.254 L/min for male F344 rats, 0.167 L/min for female
F344 rats, and 13.8 L/min for humans
SAet = Surface area of the extrathoracic region (cm )
= 15 cm2 for rats, 200 cm2 for humans
Table 7 shows the LOAELhec and NOAELhec values.
Subchronic p-RfC Derivation
As Table 7 indicates, the lowest LOAELhec values from the subchronic, reproductive,
and developmental toxicity studies (not chronic studies) were obtained in the IRDC (1992a,b)
"3
subchronic rat study (3,217 mg/m ) and the BRRC (1989b) developmental toxicity study in rats
(2,632 mg/m3). Effects observed by IRDC (1992a,b) included clinical and histopathological
signs of neuropathy as well as decreased body weight gain. Histopathological findings
consistent with the mode of action of //-hexane were observed in axons (peripheral nervous
tissue); these findings were consistent with the observed clinical signs that included altered gait.
The IRDC (1992a,b) study included two exposure groups, but the study was conducted in two
phases with different experimental protocols; thus, benchmark dose modeling of the data is not
practical. The NOAEL/LOAEL method was applied to derive the subchronic p-RfC. The
NOAELhec (804 mg/m3) associated with the lowest LOAELhec (3,217 mg/m3) identified in the
13-week subchronic study in rats (IRDC, 1992a,b) was selected as the point of departure (POD)
for derivation of the subchronic p-RfC.
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Table 7. Calculation of LOAELhec and NOAELhec Values for Subchronic p-RfC Derivation
Study
Species
Effect
Effect Level
(ppm)
Effect Level3
(mg/m3)
Duration-Adjusted
Effect Levelb
(mg/m3)
Dosimetric
Adjustment0
Human Equivalent
Concentration11
(mg/m3)
Subchronic
Duffy et al., 1991;
Biodynamics, 1989;
EPL, 1989
Rat
Slight hemorrhage and
inflammation of liver and
kidney in few males
LOAEL = 9,000
NOAEL = 3,000
LOAEL = 31,579
NOAEL = 10,526
LOAELadj= 5,639
NOAELadj= 1,880
1.0
LOAELhec = 5,639
NOAELhec = 1,880
IRDC, 1992a,b
Rat
Abnormal gait; decreased
body weight; mild atrophy
of sciatic and/or tibial nerve
and skeletal muscle
LOAEL = 1,000
NOAEL = 250
LOAEL = 3,510
NOAEL = 877
LOAELadj= 3,217
NOAF.I = 804
1.0
LOAELhec = 3,217
NOAELhec = 804
Chronic
Biodynamics,
1993a; Daughtrey et
al., 1999
Rat
Histologic evidence of
mucosal irritation in nasal
turbinates and larynx in
both sexes
LOAEL = 900
No NOAEL
LOAEL = 3,158
LOAELadj= 564
0.24 (M),
0.16(F)
(extrathoracic
RGDR for F344
rats)
LOAELhec = 135 (M)
LOAELhec = 90 (F)
Biodynamics,
1993b; Daughtrey et
al., 1999
Mouse
Body weight depression in
females. Minimal LOAEL
LOAEL = 9,000
NOAEL = 3,000
LOAEL = 31,579
NOAEL = 10,526
LOAELadj= 5,639
NOAF.I,-,|,j = 1,880
1.0
LOAELhec = 5,639
NOAELhec = 1,880
Reproductive/Developmental
Daughtrey et al.,
1994; BRRC, 1991
Rat
Reduced body weight in F,
weanlings and F2pups after
LD 7
LOAEL = 9,000
NOAEL = 3,000
LOAEL = 31,579
NOAEL = 10,526
LOAELadj= 5,639
NOAELadj =1,880
1.0
LOAELhec = 5,639
NOAELhec = 1,880
BRRC, 1989a
Mouse
Reduced fetal weights
LOAEL = 9,000
(developmental)
NOAEL = 3,000
(developmental)
LOAEL = 31,579
NOAEL = 10,526
LOAELadj= 7,895
NOAELadj =2,632
1.0
LOAELhec = 7895
NOAELhec = 2,632
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Table 7. Calculation of LOAELhec and NOAELhec Values for Subchronic p-RfC Derivation
Study
Species
Effect
Effect Level
(ppm)
Effect Level3
(mg/m3)
Duration-Adjusted
Effect Levelb
(mg/m3)
Dosimetric
Adjustment0
Human Equivalent
Concentration11
(mg/m3)
BRRC, 1989b
Rat
Reduced body weight gain
during GDs 9-12
LOAEL = 3,000
(maternal)
NOAEL = 900
(maternal)
LOAEL = 10,526
NOAEL = 3,158
LOAELadj= 2,632
NOAELadj = 789
1.0
LOAELhec = 2,632
NOAELhec =789
BRRC, 1989b
Mouse
Increased incidence of two
skeletal variations
LOAEL = 9,000
(developmental)
NOAEL = 3,000
(developmental)
LOAEL = 31,579
NOAEL = 10,526
LOAELadj= 7,895
NOAELadj =2,632
1.0
LOAELhec = 7,895
NOAELhec = 2,632
aEffect level converted from ppm to mg/m according to Equation 4-lb (mg/m = ppm x MW/24.45) of U.S. EPA (1994b). A weighted average (weighted by the
proportions of each constituent) MW of 85.79 g/mol was used for commercial hexane. A weighted average MW of 85.81 was used for IRDC (1992a,b) because the
proportions in the hexane mixture differed slightly from those of commercial hexane.
bTable 6 shows adjusted to equivalent continuous exposure concentration based on exposure regimen, using this equation:
NOAELadj = NOAEL x exposure hours/24 hours x exposure days/7 days.
°Except where noted, the dosimetric adjustment is the ratio of blood:gas partition coefficients; see text for additional information on dosimetric adjustments.
Calculated as shown in this equation: NOAELhec = NOAEL x dosimetric adjustment.
LD = luteinizing day.
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To derive the subchronic p-RfC for commercial hexane, a composite uncertainty factor
(UF) of 30 is applied to the NOAELhec as follows:
Subchronic p-RfC = NOAELhec ^ UF
= 804 mg/m3 ^ 30
= 26 8 or 27 x 10° mg/m3
The composite UF of 30 was composed of the following:
•	A default UF of 10 for intraspecies differences is used to account for potentially
susceptible individuals in the absence of information on the variability of
response in humans.
•	A partial UF of 3 (10°5) is used to account for interspecies extrapolation
(toxicodynamic portion only) because a dosimetric adjustment was made.
•	An UF of 1 for database uncertainty is applied. The database for commercial
hexane includes three subchronic toxicity studies in two species, two chronic
studies in two species, four developmental toxicity studies in two species, and a
two-generation reproductive toxicity study in rats. In addition, the database for
commercial hexane is supported in part by a large body of toxicity data for
//-hexane, the primary component of commercial hexane.
Confidence in the principal study used to derive the subchronic p-RfC (IRDC, 1992a,b) is
medium. The principal study (IRDC, 1992a,b) was designed and performed according to
standards for these types of studies at two exposure levels, and appropriate neurotoxicological
endpoints were evaluated. However, confidence in the database is reduced due to the lack of an
adequate continuous exposure study of neurotoxicity. Specifically, the differences between
intermittent and continuous exposure raises the possibility that the adjustment of intermittent
exposure concentrations to equivalent continuous exposure concentrations does not fully account
for neurotoxic potency during continuous exposure. This may be due to saturation of
metabolism during high-concentration intermittent exposure such that the potentially neurotoxic
metabolite(s) of //-hexane and other components of this mixture do not accumulate to the level
that may occur during lower-concentration continuous exposure. Thus, the lack of an exposure
study produces some uncertainty. Medium confidence in the subchronic p-RfC follows.
Chronic p-RfC Derivation
Among the studies available for use in deriving a chronic p-RfC for commercial hexane
(see Tables 6 and 7), the chronic study in rats (Biodynamics, 1993a; Daughtrey et al., 1999) has
the lowest LOAELhec (135 mg/m3 for males and 90 mg/m3 for females) for histologic evidence
-3
of nasal/laryngeal irritation). The next highest LOAELhec (2,632 mg/m ) is more than 20-fold
higher
In addition, the NOAELhec values for all of the remaining studies exceeded the
LOAELhec values from the chronic rat study (see Table 7). Because nasal irritation appears to
be the most sensitive effect in the available studies, the chronic study in rats was selected as the
basis for the chronic p-RfC. Table 4 presents data on the incidence of the critical effect (nasal
and laryngeal irritation) as reported by the authors (Biodynamics, 1993a; Daughtrey et al., 1999).
The incidence of laryngeal lesions, while increased at the high concentration, was not
statistically distinguishable from controls. In contrast, as the Table 4 shows, the incidences of
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three nasal lesions (goblet cell hyperplasia, epithelial hyperplasia, and intracytoplasmic
eosinophilic material) were significantly increased in both male and female rats at all exposure
concentrations. The authors did not report the cumulative incidence of nasal lesions. To identify
a POD for chronic p-RfC derivation, benchmark dose modeling was conducted on the incidences
of goblet cell and epithelial cell hyperplasia in both male and female rats. As shown in Table 4,
the incidence of intracytoplasmic eosinophilic material was high in the control groups (44% in
males and 82% in females) and increased to a near-maximal response at the lowest exposure
concentration; consequently, this endpoint was not considered suitable for benchmark dose
modeling.
Because the exposure regimen used by Biodynamics (1993a; Daughtrey et al., 1999) was
not continuous, BMD modeling was performed using doses adjusted for continuous exposure
followed by conversion to HECs. Available information indicates that duration of exposure is an
important factor in the development of nasal lesions; these effects were observed with chronic
exposure to 900 ppm (Biodynamics, 1993a; Daughtrey et al., 1999), but not with subchronic
exposure to concentrations up to 9,000 ppm (Biodynamics, 1989). Appendix B provides details
of the modeling results and exposure duration adjustments. All available dichotomous models in
the U.S. EPA BMDS (version 2.1) were fit to the incidence data on goblet cell and epithelial cell
hyperplasia in male and female rats (see Table 4). As assessed by the % goodness-of-fit test, the
log-logistic model provided the best fit to the data on each of these two endpoints in male rats
(% P> 0.1). The BMCiohec and BMCLiohec associated with goblet cell hyperplasia in males
"3
were 81.86 and 31.43 mg/m , respectively. The BMCiohec and BMCLiohec associated with
epithelial cell hyperplasia in males were 28.20 and 17.59 mg/m3, respectively. Efforts to model
the data on goblet cell and epithelial cell hyperplasia in females were unsuccessful, even when
the high dose group was dropped. The lower BMCLiohec 17.59 mg/m3), estimated for epithelial
cell hyperplasia in male rats, was selected as the POD for the chronic p-RfC.
The chronic p-RfC for commercial hexane was calculated as the BMCLiohec of
"3
17.59 mg/m (See Appendix B) divided by a composite UF of 30 as follows:
Chronic p-RfC = BMCLiohec UF
= 17.59 mg/m3-30
= 0.58 or 6 x 10_1 mg/m3
The composite UF of 30 was composed of the following:
•	An UF of 10 for intraspecies differences is used to account for potentially
susceptible individuals in the absence of information on the variability of
response in humans.
•	A partial UF of 3 (10°5) is used to account for interspecies extrapolation
(toxicodynamic portion only) because a dosimetric adjustment was made.
•	An UF of 1 for database uncertainty is applied. The database for commercial
hexane includes three subchronic toxicity studies in two species, two chronic
studies in two species, four developmental toxicity studies in two species, and a
two-generation reproductive toxicity study in rats. In addition, the database for
commercial hexane is supported in part by a large body of toxicity data for
//-hexane, the primary component of commercial hexane.
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Confidence in the principal study used to derive the chronic p-RfC (Biodynamics 1993a;
Daughtrey et al., 1999) is high. The study was adequate in terms of standards of these types of
animal studies and an appropriate range of exposure levels. Toxicological evaluations are
consistent with current practices and included comprehensive histopathology examinations,
including respiratory tract tissues and the sciatic nerve. Confidence in the database is medium.
As noted previously, the toxicological database for inhalation of commercial hexane includes
chronic toxicity studies in two species, subchronic toxicity studies in rats, developmental toxicity
studies in two species, and a multigeneration reproductive toxicity study in rats. Confidence in
the database is reduced due to uncertainty in the relevance of neuropathy observed in rats in the
IRDC (1992a,b) study, when other studies did not observe neuropathy at higher concentrations.
This inconsistency contributes to the database uncertainty. Medium confidence in the chronic
p-RfC follows.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR COMMERCIAL HEXANE
Weight-of-Evidence Descriptor
Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005b), there is
"Suggestive Evidence for [the] Carcinogenic Potential" of commercial hexane in humans.
There are no data on carcinogenicity of commercial hexane in humans. A 2-year carcinogenicity
bioassay in mice and rats exposed to commercial hexane showed an increased incidence of liver
tumors (combined hepatocellular adenomas and carcinomas) in female mice
(Daughtrey et al., 1999; Biodynamics, 1993a,b). No increase in liver tumor incidence was
observed in treated male mice or in either sex of F344 rats exposed to commercial hexane under
the same conditions. The study authors also identified a statistically significant increase in the
incidence of pituitary tumors in female mice. Available data on the genotoxicity of commercial
hexane are limited; no gene reversion or chromosomal aberrations in mammalian cells and no
chromosomal aberrations in the bone marrow of rats exposed in vivo were observed in the only
tests conducted.
Mode of Action Information
The U.S. EPA (2005b) Guidelines for Carcinogen Risk Assessment defines mode of
action as a sequence of key events and processes, starting with the interaction of an agent with a
cell, proceeding through operational and anatomical changes and resulting in cancer formation.
Toxicokinetic processes leading to the formation or distribution of the active agent (i.e., parent
material or metabolite) to the target tissue are not part of the mode of action. Examples of
possible modes of carcinogenic action include mutagenic, mitogenic, anti-apoptotic (inhibition of
programmed cell death), cytotoxic with reparative cell proliferation, and immunologic
suppression.
There are few mechanistic data to support a mode of action determination for commercial
hexane. Available genotoxicity data are inadequate to determine whether commercial hexane
interacts directly with DNA. No significant liver histopathology has been observed in mice after
subchronic or chronic exposure to commercial hexane (Biodynamics, 1989; Biodynamics,
1993b; Daughtrey et al., 1999), indicating that it probably does not cause liver cell toxicity at
doses that were tumorigenic in the females studied by Daughtrey et al. (1999). Evidence for
26

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liver weight increases in rats and mice exposed subchronically to commercial hexane
(Biodynamics, 1989) raises the possibility that commercial hexane may induce cell proliferation
in the livers of female mice; however, no mechanistic data are available to support this
hypothesis. Organ weights were not measured in the chronic study (Biodynamics, 1993b;
Daughtrey et al., 1999).
Quantitative Estimates of Carcinogenic Risk
Oral Exposure
No oral quantitative estimate is derived because there are no oral carcinogenicity studies
of commercial hexane.
Quantitative Estimates of Carcinogenic Risk
Inhalation Exposure
Because the cancer descriptor designated here is "Suggestive Evidence for Carcinogenic
Potential," a quantitative IUR is provided as a screening value in Appendix C.
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U.S. EPA. 2008. Integrated Risk Information System (IRIS). Online. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http ://www. epa. gov/iris/.
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Wolford, ST., R.A. Schroer, F.X. Gohs et al. 1986. Reference range data base for serum
chemistry and hematology values in laboratory animals. J. Toxicol. Environ. Health.
18:161-188.
WHO (World Health Organization). 2008. Online Catalogs for the Environmental Criteria
Series. Online, http://www.who.int/pcs/pubs/pub ehc alph.htm.
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APPENDIX A. DESCRIPTION OF LITERATURE SEARCH PROCESS
The IRIS toxicological review (U.S. EPA, 2005a) contained a thorough review of toxicity
data on commercial hexane, so searches were limited to studies published since 2002. Studies
included in the U.S. EPA (2005a) review that pertained to commercial hexane were obtained.
The search for more recent studies of commercial hexane was combined with searches for
//-hexane and included terms to identify human exposure studies (epidemiologic, occupational),
animal studies, toxicodynamic and toxicokinetic studies, mode-of-action studies, and in vitro and
in vivo studies for all relevant endpoints (cancer and noncancer) and durations. The search
included health effects and toxicity information available from the U.S. EPA (IRIS), ATSDR,
and other relevant federal, state, or international governmental or quasi-governmental agencies,
including, but not limited to ACGIH, NIOSH, OSHA, NTP, IARC, WHO, and CalEPA. In
addition, electronic databases, including: CURRENT CONTENTS, MEDLINE, TOXLINE,
BIOSIS/TOXCENTER, TSCATS/TSCATS2, CCRIS, DART/ETIC, GENETOX, HSDB, and
RTECS were searched. Table A-l shows results of the electronic searches of these databases.
An electronic listing of all results of the gross literature review (including titles, references, and
abstracts) and a tabular summary of the search results were provided to U.S. EPA.
A toxicologist screened the literature searches based on review of abstracts and titles for
studies pertaining to the health effects from exposure to commercial hexane in humans and
animals. Decisions about whether to further consider a particular citation were based on the
scientific judgment of the toxicologist, based on reading the abstract provided in the literature
search output. Studies that were not considered pertinent were not retrieved. Citations may also
have been excluded after retrieval and review of the article by the toxicologist. A study may
have been excluded if its scope was outside the scope of the use under consideration, if it was not
relevant or appropriate, if its study design was inadequate, or if the study showed inadequacy of
quality control or flaws in the interpretation of results.
Following the literature search and screening process, a table of studies considered likely
to have data suitable for derivation of provisional toxicity values was prepared for U.S. EPA
review. The table identified each reference, title, a brief description of the study and findings,
and a conclusion as to whether the study was likely to be useful for provisional toxicity value
derivation. The initial determination of relevance was based on readily available information
(i.e., titles and abstracts, if available). U.S. EPA approval of the selected studies based on review
of the table preceded development of the PPRTV document.
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Table A-l. Summary of Electronic Database Searches for «-Hexane and Commercial Hexane
Chemical/
CASRN
PUBMED
TOXLINE
Special
(on
TOXNET)
BIOSIS (STN)
update
TSCATS2
CCRIS
DART/
ETIC
(not Pub
Med)
GENE-
TOX
HSDB
RTECS
Current
Contents
Dates
Searched
Entry date from
2003 on
200212:20070
9 [em]
UP >19991231
AND
PY > 2002
TSCATS 2
only
>01/01/2000
receipt date
Not date
limited
2003 on
Not date
limited
Not date
limited
Not date
limited
Last 6 months
Hexane
110-54-3
62
(45 + 17 in
process) with
hexane in title
51 records (33
+ 18 NTIS)
5 full cites
downloaded
limited to animal with
hexane in title
80 titles downloaded
limited to human and
removed cites with
EXTRACT*
0 records
1
0 since
2003
0
1
1
8 titles
downloaded
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APPENDIX B. DETAILS OF BENCHMARK DOSE MODELING FOR
THE PROVISIONAL CHRONIC RfC
Model Fitting Procedure for Dichotomous Data
All available dichotomous models in the EPA BMDS (version 2.1) are fit to the data
using the extra risk option. The multistage model is run for all polynomial degrees up to n-1
(where n is the number of dose groups including control); the lowest degree polynomial
providing adequate fit is used for comparison with the other models, per U.S. EPA (2000)
guidance. Adequacy of model fit is judged based on the % goodness-of-fit p-\alue (p> 0.1),
magnitude of scaled residuals in the vicinity of the benchmark response (BMR), and visual
inspection of the model fit. Among all the models providing adequate fit, the BMDL from the
model with the lowest Akaike's Information Criterion (AIC) is selected as a potential POD from
which to derive the p-RfC. When several models have the same AIC, the model resulting in the
lowest BMDL is selected. In accordance with U.S. EPA (2000) guidance, benchmark doses
(BMDs) and lower bounds on the BMD (BMDLs) associated with a BMR of 10% extra risk are
calculated for all models.
Results of Model Fitting
All available dichotomous models in the EPA BMDS (version 2.1) were fit to the
incidence data on goblet cell and epithelial cell hyperplasia in male and female rats
(Biodynamics, 1993a; Daughtrey et al., 1999; see Table 4). Because the exposure regimen used
by Biodynamics (1993a; Daughtrey et al., 1999) was not continuous, BMD modeling was
performed using doses adjusted for continuous exposure followed by conversion to HECs. As
assessed by the % goodness-of-fit test, the log-logistic model provided the best fit to the data for
either endpoint in males (x p> 0.1; see Tables B-l and B-2 and Figures B-l and B-2). The
BMCiohec and BMCLiohec associated with goblet cell hyperplasia in males are 81.86 and
-3
31.43 mg/m , respectively. The BMCiohec and BMCLiohec associated with epithelial cell
hyperplasia in males are 28.20 and 17.59 mg/m3, respectively (Table B-5).
Efforts to model the data on goblet cell and epithelial cell hyperplasia in females were
unsuccessful, even when the high dose group was dropped from the analysis. The software
failed to execute completely with any model.
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Table B-l. Input Data Used for Chronic p-RfC Derivation for Commercial Hexane
(51.1% w-Hexane) for the Incidence of Goblet Cell Hypertrophy/Hyperplasia in
Male Ratsa
PPM
(mg/m3)a
Daily Average
Concentration
(mg/m 3)c
HEC
(mg/m3)"
Total Neoplasms
Response
Number of Subjects
0
0
0
0
29
48
900
3168
565.7
136
37
50
3000
10560
1885.7
453
43
50
9000
31680
5657.1
1358
41
50
'Daughtrcy et al. (1999); Biodynamics (1993a).
bPPM conversion: C(mg/m3) = PPM x MW/24.45 = (PPM x 86.177 g/mol)/24.45 = 3.52 x PPM.
0 Average daily concentration = C(mg/m3) x (hours exposure/24hours) x (days exposure/7 days a week) =
C(mg/m3) x (6/24 x 5/7).
dHEC = (PPM conversion) x (average daily concentration) x RGDR. The critical effect: respiratory effects (nasal
irritation), Category 1 gas, extrathoracic (ET) and the RGDRET = (VE/SAET)rat/(VE/SAET)human = 0.24 for males.
Table B-2. BMD Modeling Results Based on Goblet Cell Hypertrophy/Hyperplasia in
Male Ratsa
Model
X2/'-Value
AIC
BMCiohec (mg/m3)
BMCLiohec (mg/m3)
Gamma (power >1)
0.0769
218.736
179.571
94.6424
Logistic
0.0677
219.007
211.022
119.216
Log-logistic
0.1348
217.388
81.8615
31.43
Log-probit (slope >1)
0.0380
220.163
345.465
167.467
Multistage (degree = 3)
0.0769
220.268
167.663
90.9906
Probit
0.0641
219.125
226.245
132.60
Weibull
0.0769
218.736
179.573
94.6424
Quantal linear
0.0769
218.736
179.573
94.6424
aDaughtrey et al. (1999); Biodynamics (1993a).
bDegree of polynomial initially set to (n-1) where n = number of dose groups including control; no model provided
adequate fit. Betas restricted to >0.
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Log-Logistic Model with 0.95 Confidence Level
Log-Logistic
0.9
0.7
0.6
0.5
IBMDL
BMD
0
200
400
600
800
1000
1200
1400
Dose
10:49 09/09 2009
Figure B-l. Dose-Response Modeling for Incidence of Goblet Cell
Hypertrophy/Hyperplasia in Male Rats
Logistic Model. (Version: 2.12; Date: 05/16/2008)
Input Data File:
C:\USEPA\BMDS21\Data\lnlGoblethypetrophyhyperplastiammaleloglostic.(d)
Gnuplot Plotting File:
C:\USEPA\BMDS21\Data\lnlGoblethypetrophyhyperplastiammaleloglostic.pit
Wed Sep 09 10:49:49 2009
BMDS Model Run
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-siope*Log(dose))]
Dependent variable = Percent
Independent variable = Dose
Slope parameter is restricted as slope >= 1
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
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User has chosen the log transformed model
Default Initial Parameter Values
background =	0.604
intercept =	-6.31119
slope =	1
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -slope
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
background intercept
background	1	-0.75
intercept	-0.75	1
Interval
Variable
Limit
background
intercept
slope
Parameter Estimates
Estimate
0.654013
-6.60225
1
Std. Err.
Indicates that this value is not calculated.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-104.696
-106.694
-109.673
# Param's	Deviance	Test d.f.	P-value
4
2	3.9964	2	0.1356
1	9.95448	3	0.01896
AIC:
217.388
Dose
Est. Prob.
Goodness of Fit
Expected
Observed
Size
Scaled
Residual
0.0000
136.0000
453.0000
1358.0000
0.6540
0.7079
0.7857
0. 8783
31.393
35.396
39.287
43.916
28.992
37.000
43.000
41.000
48
50
50
50
-0.728
0. 499
1.280
-1.261
ChiA2
4.01
d.f.
P-value
0.1348
Benchmark Dose Computation
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Specified effect
Risk Type
Confidence level
HMD
BMDL
0.1
Extra risk
0. 95
81.8615
31.43
Table B-3. Input Data Used for Chroninc p-RfC Derivation for Commercial Hexane
(51.1% M-Hexane) for the Incidence of Epithelial Hyperplasia in Males Ratsa
PPM
(mg/m3)a
Daily Average
Concentration
(mg/m3)c
HEC (mg/m3)d
Total Neoplasms
Response
Number of
Subjects
0
0
0
0
2
48
900
3168
565.7
136
19
50
3000
10560
1885.7
453
36
50
9000
31680
5657.1
1358
43
50
aDaughtrey et al. (1999); Biodynamics (1993a).
bPPM conversion: C(mg/m3) = PPM x MW/24.45 = (PPM x 86.177 g/mol)/24.45 = 3.52 x PPM.
0 Average daily concentration = C(mg/m3) x (hours exposure/24hours) x (days exposure/7 days a week) =
C(mg/m3) x (6/24 x 5/7).
dHEC = (PPM conversion) x (average daily concentration) x RGDR. The critical effect: respiratory effects (nasal
irritation), Category 1 gas, extrathoracic (ET) and the RGDRET = (VE/SAET)rat/(VE/SAET)human = 0.24 for males.
Table B-4. BMD Modeling Results Based on Epithelial Hyperplasia in Male Rats"
Model
AIC
x2
/7-Value
BMCiohec (mg/m3)
BMCL1()hec (mg/m3)
Gamma (power >1)
194.941
0.0072
52.6794
42.3999
Logistic
212.945
0.0000
137.593
111.172
Log-logistic0
188.687
0.5456
28.2021
17.5851
Log-probit (slope >1)
188.843
0.4713
29.7984
8.05051
Multistage (degree = 3)
189.538
0.0041
50.6871
41.2042
Probit
214.179
0.0000
144.716
121.314
Weibull
194.941
0.0072
52.6794
42.3999
Quantal linear
194.941
0.0072
52.6794
42.3999
aDaughtrey et al. (1999); Biodynamics (1993a).
bDegree of polynomial initially set to (n-1) where n = number of dose groups including control; no model provided
adequate fit. Betas restricted to >0.
The lowest AIC, withp> 0.1 and lowest residual.
38

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Log-Logistic Model with 0.95 Confidence Level
0	200	400	600	800 1000 1200 1400
Dose
11:19 09/09 2009
Figure B-2. Dose-Response Modeling for Incidence of Epithelial Hyperplasia in Male Rats
Logistic Model. (Version: 2.12; Date: 05/16/2008)
Input Data File:
C:\USEPA\BMDS21\Data\lnlEpithelialhyhyperplastiamEpLoglogm.(d)
Gnuplot Plotting File:
C:\USEPA\BMDS21\Data\lnlEpithelialhyhyperplastiamEpLoglogm.pit
Wed Sep 09 11:19:54 2009
BMDS Model Run
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-siope*Log(dose))]
Dependent variable = Percent
Independent variable = Dose
Slope parameter is restricted as slope >= 1
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
39

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User has chosen the log transformed model
Default Initial Parameter Values
background =	0.04
intercept =	-5.59407
slope =	1.03257
Asymptotic Correlation Matrix of Parameter Estimates
background	intercept
background 1	-0.13
intercept -0.13	1
slope 0.087	-0.99
slope
0.087
-0. 99
1
Parameter Estimates
Interval
Variable
Limit
background
intercept
slope
Estimate
0.0395001
-5.73192
1. 05848
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-91.1604
-91.3433
-137.235
# Param's	Deviance	Test d.f.	P-value
4
3	0.365824	1	0.5453
1	92.1485	3	<.0001
AIC:
188.687
Dose
Goodness of Fit
Est. Prob.
Expected
Observed
Size
Scaled
Residual
0.0000
136.0000
453.0000
1358.0000
ChiA2 =0.37
0.0395
0.3949
0.6901
0.8754
d.f. = 1
1.896 1.920	48	0.018
19.747 19.000	50	-0.216
34.505 36.000	50	0.457
43.772 43.000	50	-0.331
P-value = 0.5456
Benchmark Dose Computation
Specified effect =	0.1
Risk Type	=	Extra risk
40

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Confidence level =	0.95
HMD =	28.2021
BMDL =	17.5851
Selection of Model and POD
Table B-5. BMD Models with Acceptable Fit
Effect
Model
x2
/7-Value
AIC
BMCio(mg/m3)
BMCLio (mg/m3)
Goblet cell
Log logistic
0.138
217.388
81.8615
31.43
Epithelial cell
Log logistic
0.5456
188.687
28.2021
17.5851
Epithelial cell
Log probit
0.4713
188.843
29.7984
8.0 5051
For the epithelial cell data, the log-logistic model was selected based on the lowest AIC
3	3
(17.5851 mg/m ). In comparison to the goblet cell data of 31.43 mg/m , this lower value was
selected for the POD (SMCL^fc™ = 17.5851 mg/m3)
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APPENDIX C. DETAILS OF BENCHMARK DOSE MODELING FOR THE
SCREENING PROVISIONAL INHALATION UNIT RISK (IUR)
For the reasons noted in the main document, it is inappropriate to derive a provisional
IUR. However, information is available which, although insufficient to support derivation of a
provisional toxicity value, under current guidelines, may be of limited use to risk assessors. In
such cases, the Superfund Health Risk Technical Support Center summarizes available
information in an Appendix and develops a "Screening Value." Appendices receive the same
level of internal and external scientific peer review as the main document to ensure their
appropriateness within the limitations detailed in the document. Users of screening toxicity
values in an appendix to a PPRTV assessment should understand that there is considerably more
uncertainty associated with the derivation of an appendix screening toxicity value than for a
value presented in the body of the assessment. Questions or concerns about the appropriate use
of Screening Values should be directed to the Superfund Health Risk Technical Support center.
Model Fitting Procedure for Cancer Data
The Multistage cancer model for dichotomous data (EPA BMDS (version 2.1) was fit to
the incidence data using the extra risk option according to U.S. EPA (2000). Goodness-of-fit is
assessed by the % goodness of fit test (required >0.1).
Selection of Data for BMD Input:
According to the 2005 Cancer Guidelines, with the data from Biodynamics, 1993b;
Daughtrey et al., 1999 in Table 5, the appropriate input of tumor data for BMD analysis is:
1)	Combined adenoma and adenocarcinoma in pituitary of male mice. The data, even with
the highest dose removed, would not produce an acceptable fit.
2)	Combined adenoma and adenocarcinoma in pituitary of female mice with all doses
included. This data, did not satisfy the % goodness of fit test (required >0.1) test. See
Table C-l and Figure C-l
3)	Combined adenoma and adenocarcinoma in pituitary of female mice with the highest
dose removed. See Table C-2 and Figure C-2
4)	Combined hepatocellular adenomas and carcinomas in male mice. The data failed to
produce an acceptable fit.
5)	Combined hepatocellular adenomas and carcinomas in female mice (Biodynamics,
1993b; Daughtrey et al., 1999) See Table C-3 and Figure C-3.
Data used for development of the screening p-IUR are represented in Table 5
(Biodynamics, 1993b; Daughtrey et al., 1999). According to the 2005 Cancer Guidelines
(U.S. EPA, 2005), BMD modeling was performed using the BMD Cancer Multistage Model on
combined data for both pituitary and hepatic tumors for both males and females. Only the
female data, without the high dose, provided an adequate fit for the pituitary tumors. For the
liver tumors, only the full data set for females only provided an adequate fit.
42

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Table C-l. Input Data for Combined Pituitary Adenomas and Adenocarcinomas in
Female B6C3F1 Mice3
PPM
(mg/m3)b
Daily Average
Concentration
(mg/m3)c
Multiplier"1
HEC (mg/m3)'
Total
Neoplasms
Response
Number of
Subjects
0
0
0
1
0
0
45
900
3168
565.7
1
565.7
6
48
3000
10560
1885.7
1
1885.7
8
48
9000
31680
5657.1
1
5657.1
5
49
aDaughtrey et al. (1999); Biodynamics (1993b).
bPPM conversion: C(mg/m3) = PPM x MW/24.45 = (PPM x 86.177 g/mol)/24.45 = 3.52 x PPM.
0 Average daily concentration = C(mg/m3) x (hours exposure/24hours) x (days exposure/7 days a week) =
C(mg/m3) x (6/24 x 5/7).
dBlood gas partition coefficient = [(H(b/g))A] / [(H(b/g))H] - A default value of 1.0 was used because both partition
coefficients were not available.
eHEC: Human equivalent concentration (HEC) for Extra-respiratory effects (Cat 3 Gas) = Daily average
concentration x Blood gas partition coefficient.
BMD analysis of combined pituitary adenomas and adenocarcinomas in female mice.
1) Full data set:
The complete data set (4 values) for combined adenoma and adenocarcinoma in pituitary
of female mice did not adequately fit the data (x /rvalue <0.1).
Table C-l. BMD Modeling Results for Combined Pituitary Adenomas and
Adenocarcinomas in Female Mice B6C3F1 Mice for 2 Years (Full Set of Points)"
Model
x2
/7-Value
AIC
BMCio (mg/m3)
BMCL10hec
(mg/m3)
Multistage cancer
0.0136
122.643
16038.6
3162.62
aDaughtrey et al. (1999); Biodynamics (1993b).
43

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"O
0
H—'
o
0
o
CO
0.3
0.25
0.2
0.15
0.1
0.05
FINAL
9-30-2009
Multistage Cancer Model with 0.95 Confidence Level
Multistage Cancer
Linear extrapolation
BMDL
BMD
2000 4000 6000 8000 10000 12000 14000 16000
10:21 09/10 2009
Dose
Figure C-l. Dose-Response Modeling for Combined Pituitary Adenomas and
Adenocarcinoma of Female B6C3F1 Mice for 2 Years (Full Set of Points)
Multistage Cancer Model. (Version: 1.7; Date: 05/16/2008)
Input Data File:
C:\USEPA\BMDS21\Data\mschexaneunitriskwithlastpointhexaneunitriskwithlastpoint.(d)
Gnuplot Plotting File:
C:\USEPA\BMDS21\Data\mschexaneunitriskwithlastpointhexaneunitriskwithlastpoint.pit
Thu Sep 10 09:40:32 2009
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2) ]
The parameter betas are restricted to be positive
Dependent variable = Percent
Independent variable = Dose
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 3
44

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Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.0877332
Beta(l) = 7.85063e-006
Beta(2) =	0
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Beta(2)
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Background	Beta(l)
Background	1	-0.7 6
Beta (1)	-0.76	1
Parameter Estimates
Interval
Variable
Limit
Background
Beta(1)
Beta(2)
Estimate
0. 0828151
6.5 692e-00 6
0
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-56.3582
-59.3215
-62.4223
# Param's
4
2
1
Deviance Test d.f.
5.92663
12.1283
P-value
0. 05165
0.006956
AIC:
122.643
Dose
Est. Prob.
Goodness of Fit
Expected Observed	Size
Scaled
Residual
0.0000
566.0000
1886.0000
5657.0000
0.0828
0.0862
0.0941
0.1163
3.727
4.139
4	.517
5	. 697
0.000
6.240
8.160
4.900
45
48
48
49
-2.016
1. 081
1.801
-0.355
45

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ChiA2 =8.60	d.f. = 2	P-value = 0.0136
Benchmark Dose Computation
Specified effect =	0.1
Risk Type	=	Extra risk
Confidence level =	0.95
BMD =	16038.6
BMDL =	3162.62
BMDU did not converge for BMR = 0.100000
BMDU calculation failed
BMDU = Inf
2) Limited Data Set:
According to BMD Guidance (2000) the model fit was next tested with the highest concentration
point omitted. Results are shown in Table C-2, and the curve in Figure C-2.
Table C-2. BMD Modeling Results for Incidence of Combined Pituitarv Adenomas and
Adenocarcinomas in Female B6C3F1 Mice for 2 Years (with High Dose Omitted)3
Model
x2
p-Value
AIC
BMCiohec (mg/m3)
BMCLiohec
(mg/m3)
Multistage cancer
0.2048
83.8129
809.461
536.985
aDaughtrey et al. (1999); Biodynamics (1993b).
The Inhalation unit risk for combined pituitary tumor is provided by the BMDS
p-IUR = Multistage Cancer slope factor from BMDS = 0.000186255 or 1.9 E-4 mg/m3
Note: Default BMR is 0.1, or p-IUR = BMR BMCLiohec = 0.1 536.985 = 2 x 10 4 mg/m3
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Multistage Cancer Model with 0.95 Confidence Level
"O
0
-i—1
O
CD
o
CO
0.3
0.25
0.2
0.15
0.1
0.05
Multistage Cancer
Linear extrapolation
BMDL
BMD
500
1000
1500
14:39 09/09 2009
Dose
Figure C-2. Dose-Response Modeling for Combined Pituitary Adenomas and
Adenocarcinoma of Female B6C3F1 Mice for 2 Years (with High Dose Omitted)
Multistage Cancer Model. (Version: 1.7; Date: 05/16/2008)
Input Data File:
C:\USEPA\BMDS21\Data\mschexaneunitriskhexaneunitriskwithlastpointout.(d)
Gnuplot Plotting File:
C:\USEPA\BMDS21\Data\mschexaneunitriskhexaneunitriskwithlastpointout.pit
Wed Sep 09 14:39:21 2009
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2) ]
The parameter betas are restricted to be positive
Dependent variable = Percent
Independent variable = Dose
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
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Degree of polynomial
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.03 62 474
Beta(1) = 8.7614e-005
Beta(2) =	0
the user,
Beta(1)
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background -Beta(2)
have been estimated at a boundary point, or have been specified by
and do not appear in the correlation matrix )
Beta(1)
1
Parameter Estimates
Interval
Variable
Limit
Background
Beta(1)
Beta(2)
Estimate
0.000130161
0
Std. Err.
Indicates that this value is not calculated.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Log(likelihood)
-40.4291
-40.9064
-46.4923
83.8129
# Param's
3
1
1
Deviance Test d.f.
0. 954683
12.1265
P-value
0.6204
0.002327
Dose
Goodness of Fit
Est._Prob. Expected Observed	Size
Scaled
Residual
0.0000
566.0000
1886.0000
Chi^2 =3.17
0.0000
0.0710
0.2177
d.f. = 2
0.000	0.000	45
3.409	6.240	48
10.448	8.160	48
P-value = 0.2048
0. 000
1.591
-0.800
Benchmark Dose Computation
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FINAL
9-30-2009
Specified effect =	0.1
Risk Type	=	Extra risk
Confidence level =	0.95
BMD =	8 09.4 61
BMDL =	536.985
BMDU =	1632.44
Taken together, (536.985, 1632.44) is a 90	% two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 0.000186225
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FINAL
9-30-2009
BMD Analysis of combined liver adenomas and adenocarcinomas in female mice.
The complete data set (4 values ) for combined hepatocellular adenomas and carcinomas
in female mice was adequately simulated by the BMD multistage model
Table C-3. Input Data for Combined Liver Adenomas and Adenocarcinomas in Female
B6C3F1 Mice Exposed to Commercial «-Hexane for 2 Years"
PPM
(mg/m3)a
Daily Average
Concentration
(mg/m 3)c
Mutiplierd
for HECs
HEC
(mg/m3)'
Total Neoplasms
Response
Number of
Subjects
0
0
0
1
0
7
50
900
3168
565.7
1
362.5
8
50
3000
10560
1885.7
1
1875
9
49
9000
31568
5657.1
1
5625
16
50
aDaughtrey et al. (1999); Biodynamics (1993b).
bPPM conversion: C(mg/m3) = PPM x MW/24.45 = (PPM x 86.18 g/mol)/24.45 = 3.52 x PPM
0 Average daily concentration = C(mg/m3) x (hours exposure/24hours) x (days exposure/7 days a week) =
C(mg/m3) x (6/24 x 5/7).
dBlood gas partition coefficient = [(H(b/g))A] / [(H(b/g))H]. A default value of 1.0 was used because both partition
coefficients were not available.
eHEC: Human equivalent concentration (HEC) for Extra-respiratory effects (Cat 3 Gas) = Daily average
concentration x Blood gas partition coefficient.
Table C-4. BMD Modeling Results for Incidence of Combined
Liver Adenomas and Adenocarcinomas in Female B6C3F1 Mice Exposed to Commercial
n-Hexane for 2 Years."
Model
x2
/7-Value
AIC
BMCiohec (mg/m3)
BMCL1()hec (mg/m3)
Multistage cancer
0.8902
199.908
3263.62
1447.45
aDaughtrey et al. (1999); Biodynamics (1993b).
The Inhalation unit risk for combined liver adenomas and adenocarcinomas is provided by
the BMDS
p-IUR = Multistage Cancer slope factor from BMDS = 7 x 10~5 mg/m3
Note: Default BMR is 0.1, thus p-IUR = BMR BMCLiohec = 0.1 1447.45 = 7 x 10 5 mg/m3
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FINAL
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0.5
0.45
Multistage Cancer Model with 0.95 Confidence Level
Multistage Cancer
Linear extrapolation
"O
CD
tj
0
o
'tS
BMDL
15:08 09/09 2009
Figure C-3. Dose-Response Modeling for Incidence of Combined Liver Adenomas and
Adenocarcinomas in Female B6C3F1 Mice Exposed to Commercial «-Hexane for 2 Years3
Multistage Cancer Model. (Version: 1.7; Date: 05/16/2008)
Input Data File:
C:\USEPA\BMDS21\Data\mscHexaneunitrisklivertumorHexaneunitrisklivertumor.(d)
Gnuplot Plotting File:
C:\USEPA\BMDS21\Data\mscHexaneunitrisklivertumorHexaneunitrisklivertumor.pit
Wed Sep 09 15:08:06 2009
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2) ]
The parameter betas are restricted to be positive
Dependent variable = Percent
Independent variable = Dose
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
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FINAL
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Degree of polynomial
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background =	0.143625
Beta(l) = 2.02065e-005
Beta(2) = 3.62707e-009
Asymptotic Correlation Matrix of Parameter Estimates
Background	Beta(l)	Beta(2)
Background	1	-0.71	0.61
Beta (1)	-0.71	1	-0.97
Beta (2)	0.61	-0.97	1
Parameter Estimates
Interval
Variable
Limit
Background
Beta(1)
Beta(2)
Estimate
0.143332
2.07799e-005
3.52476e-009
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
* - Indicates that this value is not calculated.
Warning: Likelihood for the fitted model larger than the Likelihood for the full
model.
Error in computing chi-sguare; returning 2
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Log(likelihood)
-96.968
-96.9539
-99.8788
199.908
# Param's	Deviance	Test d.f.
4
3	-0.0281741	1
1	5.82161	3
P-value
2
0.1206
Dose
Goodness of Fit
Est._Prob. Expected Observed	Size
Scaled
Residual
0.0000
566.0000
1886.0000
5657.0000
Chi^2 =0.02
0.1433
0.1543
0.1865
0.3196
d.f. = 1
7.167 7.000	50	-0.067
7.715 8.000	50	0.111
9.139 9.016	49	-0.045
15.979 16.000	50	0.006
P-value = 0.8902
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FINAL
9-30-2009
Benchmark Dose Computation
Specified effect =	0.1
Risk Type	=	Extra risk
Confidence level =	0.95
BMD =	32 63.62
BMDL =	1447.45
BMDU =	8572.34
Taken together, (1447.45, 8572.34) is a 90	% two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 6.9087e-005
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Selection of IUR for Commercial Hexane
Table C-5. p-IURs for Pituitary and Liver Tumors in Female B6C3F1 Mice for 2 Years
Tumor Database
p-IUR
Combined pituitary adenomas and adenocarcinomas
2 x 10 4 mg/m3
Combined liver adenomas and adenocarcinomas
7 x 1(T5 mg/m3
The screening provisional IUR was selected from the greatest slope:
Screening p-IUR = 2 x 10~4 per mg/m3 or 2 x 10~7 per (ig/m3
54

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