United States
Environmental Protection
Agency
EPA/690/R-09/032F
Final
9-30-2009
Provisional Peer-Reviewed Toxicity Values for
Midrange Aliphatic Hydrocarbon Streams
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 MIDRANGE
ALIPHATIC HYDROCARBON STREAMS
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,
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users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. EPA programs or
external parties who may choose of their own initiative to use these PPRTVs are advised that
Superfund resources will not generally be used to respond to challenges of PPRTVs used in a
context outside of the Superfund Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the U.S. EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
The midrange (i.e., medium carbon number range) hydrocarbon streams that are the
subject of this PPRTV document include isoparaffinic hydrocarbon-containing streams (IPH,
composed of isoparaffins or of isoparaffins with //-alkanes and naphthenes), dearomatized white
spirit (DAWS, composed of paraffins and naphthenes), and Stoddard Solvent IIC. The
hydrocarbons in these streams fall within the carbon number range of C9-C18, and the content
of aromatic compounds is <1.0%. Isoparaffinic hydrocarbons are branched chain alkanes and
naphthenes are cyclic alkanes.
No chronic or subchronic RfDs or RfCs or cancer assessment for IPH, DAWS, or
Stoddard Solvent IIC are available on IRIS (U.S. EPA, 2009), the Drinking Water Standards and
Health Advisory list (U.S. EPA, 2006), or in the HEAST (U.S. EPA, 1997). No documents for
these mixtures are listed in the Chemical Assessments and Related Activities (CARA) list
(U.S. EPA 1991a, 1994a). The Occupational Safety and Health Administration (OSHA), the
National Institute of Occupational Safety and Health (NIOSH), and the American Conference of
Governmental Industrial Hygienists (ACGIH) have not derived occupational exposure limits for
midrange aliphatic hydrocarbon streams of low aromatic content (OSHA, 2008; NIOSH, 2008;
ACGIH, 2007). An ATSDR (1995) toxicological profile for Stoddard solvent, a World Health
Organization (WHO, 1996) Environmental Health Criteria document on white spirit or Stoddard
solvent, and an International Agency for Research on Cancer (IARC, 1989) monograph on
petroleum solvents were reviewed for relevant information. However, with few exceptions, the
studies reviewed for these documents pertained to mixtures containing substantial aromatic
content (>10%) and were not relevant to this PPRTV document1. Pertinent information on these
mixtures was not located through the Petroleum High Production Volume (HPV) Testing Group
(2007) publications or the Organisation for Economic Co-operation and Development (OECD)
1 ATSDR, WHO, and IARC prepared general overviews on the toxicity of Stoddard solvent, white spirit, or
petroleum solvents and, thus, included information on formulations of these mixtures that included a significant
proportion of aromatic compounds. Because this document is intended to review mixtures that are representative of
the midrange aliphatic fraction of hydrocarbon compounds, those mixtures that contained a nontrivial proportion
(>1.0%) of aromatic compounds are not considered further.
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HPV Programme Screening Information Dataset (SIDS) documents (OECD/SIDS, 2007).
Reviews of these mixtures (IPH, DAWS, and Stoddard Solvent IIC) by the Massachusetts
Department of Environmental Protection (MADEP, 2003) and the Total Petroleum Hydrocarbon
Criteria Working Group (TPHCWG, 1997) were consulted for relevant information. In addition,
a review of the toxicology of IPH published by Mullin et al. (1990) was consulted. The National
Toxicology Program (NTP, 2004) has assessed the toxicity and carcinogenicity of Stoddard
Solvent IIC. Finally, the Voluntary Children's Chemical Evaluation Program (VCCEP) Peer
Consultation Meeting report on //-alkanes (decane, //-dodecane, and undecane) was reviewed for
studies of relevant mixtures.
One unpublished developmental toxicity study performed by Exxon Biomedical Sciences
could not be located, thus, the study information presented in this PPRTV document is based on
secondary sources (i.e., Mullin et al., 1990; VCCEP submission). In addition, partial copies of
the three oral studies (Anonymous, 1990, 1991a,b) were obtained from MADEP; important
sections including data tables and pathology appendices were missing. Efforts to obtain full
copies of these reports from MADEP, API, ExxonMobil Biomedical Sciences, and the USAF
were not successful.
To identify toxicological information pertinent to the derivation of provisional toxicity
values for IPH or DAWS and to identify studies published since the MADEP (2003) review,
updated literature searches (January 2002-July 2009) of the following databases were conducted:
MEDLINE, TOXLINE, BIOSIS, TSCATS, CCRIS, GENETOX, DART/ETIC, HSDB, and
Current Contents (last 6 months). Stoddard Solvent IIC was identified as a potentially relevant
mixture through screening of the initial searches. For this mixture, a comprehensive review of
previous data by NTP (2004) was used as a starting point for the literature search, and second
updated literature searches were conducted in March 2008 to identify studies published since the
review. A final updated literature was conducted in July 2009.
REVIEW OF PERTINENT DATA
Human Studies
Pederson and Cohr (1984a,b) conducted two studies of acute inhalation exposure to white
spirits with low aromatic content. In the first study (Pedersen and Cohr, 1984a), 12 volunteers
(average age 25 years) were exposed for 6 hours to 610 mg/m3 Shellsol TS (99% paraffins),
605 mg/m3 Exsol D 40 (52% paraffins and 48% naphthenes) or 610 mg/m3 Varnolene
(57%) paraffins, 25%> naphthenes, and 18%> aromatics). The same volunteers were exposed to
each of the three mixtures with a 1-week interval between exposures and served as their own
controls. After exposure, blood and urine were collected for serum chemistry (glucose,
triglycerides, cholesterol, urate, a-amylase, creatine kinase, orosomucoid [a measure of
inflammatory response], sodium, and potassium), and urine parameters (albumin and
132-microglobulin). In addition, lung function, echocardiogram (ECG), blood pressure, pulse,
and mucociliary function were assessed. Examination for neurological effects (Romberg's test
and nystagmus) was performed. No symptoms were reported by the volunteers. The only
statistically significant (p < 0.05) differences from preexposure values were decreases in serum
a-amylase (9%>) and potassium (9%>) 48 hours after exposure to Exsol D 40. A subsequent study
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published in the same paper (Pedersen and Cohr, 1984a) further evaluated exposure to Exsol D
40 at concentrations of 304, 611, or 1228 mg/m3 for 6 hours and observed the decreases in serum
a-amylase (7%; 6 hours after exposure began) and urate (4%; 48 hours after exposure began).
In the second study, seven of the same volunteers were exposed to 616 mg/m3 Shellsol
(99% paraffins), 6 hours/day, for 5 days (Pedersen and Cohr, 1984b). The remaining five
volunteers served as untreated controls. Blood samples were collected 24, 96, and 168 hours
after exposure began for measurement of serum levels of immunoglobulins, orosomucoid,
creatine kinase, and follicle stimulating hormone. Average creatine kinase was statistically
significantly (p < 0.05) increased above preexposure levels after 96 (59% higher) and 168 hours
(76%) higher). Follicle stimulating hormone was statistically significantly decreased (p < 0.05)
below baseline after 24 (11% decrease) and 96 hours (9%>). However, the authors noted marked
inter- and intraindividual variation in these parameters. For both of these studies, the
toxicological significance of the observed changes is uncertain.
Ernstgard et al. (2009a,b) conducted two studies of acute inhalation exposure to standard
white spirits (15-20%) aromatics; stdWS) and DAWS (0.002% aromatics). In the first study (i.e.,
Ernstgard et al, 2009a), the aim of the study was to identify thresholds (dose-finding) of irritation
and central nervous system (CNS) effects. Eight volunteers (four female and four male healthy
volunteers) were exposed to increasing levels of stdWS or DAWS in eight 10-min steps from
0.5 to 600 mg/m3. The study authors reported that the stdWS caused more severe effects of
irritation and CNS than that of DAWS. In the second study (i.e., Ernstgard et al, 2009b),
12 volunteers (6 female and 6 male healthy volunteers) were exposed on five occasions to 100 or
300 mg/m3 DAWS or stdWS (19%> aromatics), or to clean air (as a control group), for 4 hours at
rest. The study authors did not observe any exposure-related effects for DAWS but did note eye
irritation at the high stdWS exposure only—but not for the DAWS at any level. However, the
study authors (Ernstgard et al., 2009b) claimed that the slightly more irritating effects by stdWS
than DAWS could "not be confirmed by objective measurements." For both of these studies, the
toxicological significance of the observed effects in either irritation or CNS for DAWS is
uncertain. No effect levels are identified for DAWS.
No other human studies of exposure to midrange aliphatic compounds with low aromatic
content were identified. NTP (2004) reviewed case studies and human exposure studies of white
spirits with significant aromatic content (>10%); however, it is not possible to determine whether
the observed effects were attributable to the aliphatic or aromatic constituents. In addition,
NTP (2004) discussed a number of studies reporting neurological or neuropsychological effects
of occupational exposure to alkyd paints, but the nature of the exposures (e.g., composition of
the inhaled mixture) is not reported, so exposure to compounds or mixtures other than midrange
aliphatics cannot be discounted.
Animal Studies
Oral Exposure
There were three studies of oral exposure to midrange aliphatic hydrocarbon streams
(CI 1-C17, C9-C12, and C10-C13, respectively) that were identified in the searches
(Anonymous, 1990, 1991a,b). The copies of these three studies obtained for this review were
missing many tables and appendices and repeated efforts to obtain these studies from a variety of
sources were unsuccessful. As a result, the summaries of the studies contained herein rely on the
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information available in the text of the reports, as well as information provided by MADEP
(2003) and TPHCWG (1997) from their reviews of the complete reports. Limitations in the data
available for analysis of these studies increase the uncertainty associated with using these data
for toxicity assessment. No other oral studies of midrange aliphatic hydrocarbon streams were
located.
Subchronic Studies
A subchronic study of the oral toxicity of an isoparaffinic mixture (CI 1-C17, typical
aromatic content <0.05%) was conducted in Crl: CDBR (Sprague-Dawley) rats (Anonymous,
1990). Groups of 10 rats/sex/dose were given gavage doses of 0, 100, 500, or 1000 mg/kg-day
of the test material in corn oil 7 days/week for 13 weeks. Due to gavage deaths in the control
and 500 mg/kg-day group, 10 additional males were added to each of these groups. Most of the
deaths occurred prior to Day 12 of the study; however, the studies authors did not indicate when
the additional males were added. Control and high-dose-recovery groups of 10 animals/sex were
treated as above and then maintained for 28 days after treatment was terminated to evaluate
reversibility of effects. Daily mortality checks and clinical observations were made and both
body weights and food intake were recorded weekly. Ophthalmoscopic examinations were
performed on all rats prior to study initiation and at terminal sacrifice. Blood was collected on
Day 32, at terminal sacrifice and on Day 120 (for the recovery groups) for evaluation of
hematology (erythrocyte count, hematocrit [Hct], hemoglobin [Hgb], total and differential
leukocyte count, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean
corpuscular hemoglobin concentration [MCHC], platelet count, and reticulocyte count), and
serum chemistry (albumin, blood urea nitrogen [BUN], calcium, cholesterol, creatinine,
electrolytes, gamma glutamyl transferase [GGT], glucose, phosphorus, alanine aminotransferase
[ALT], aspartate aminotransferase [AST], total bilirubin, total protein, and triglycerides). All
animals were necropsied and selected organs (adrenals, kidneys, brain, liver, and ovaries/testes)
were weighed. Microscopic examination was performed on a comprehensive list of tissues (>35)
from control and high-dose animals, as well as any gross lesions, tissue masses, liver, lungs and
kidneys from low- and mid-dose groups. In the recovery group, comprehensive histopathology
examination was performed after the conclusion of the observation period.
There were no treatment-related differences in mortality, in the incidence of clinical
observations or in ophthalmoscopic findings (Anonymous, 1990). As noted earlier, a number of
deaths due to gavage errors occurred early in the study, prompting the investigators to add two
groups of 10 males (control and 500 mg/kg-day). Treated females had occasional dose-related
increases in body weight and food consumption, but the only statistically significant (p < 0.05)
difference was an increase in food consumption in high-dose females. Dose-related decreases in
hematology parameters were observed in male rats at both interim (Day 32) and terminal
evaluation. Statistically significant (p < 0.05) decreases in erythrocyte count, Hct, and Hgb were
noted in high-dose males at both time points, and mid-dose males had significantly lower
erythrocyte count and Hgb at study termination. At Day 32—but not at study termination—
low-dose males had lower erythrocyte counts and lower Hgb and MCHC levels than controls.
Data tables reflecting these endpoints were missing from the report, so statistical significance
and magnitude of change cannot be reported. Hematology was not affected by treatment at any
dose in female rats. The authors also noted a dose-related increase in platelet count. Statistically
significant differences in hematology parameters (increases in Hgb, MCHC, and MCH; p < 0.05)
in the recovery groups were considered to be within normal limits. In male rats, statistically
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significant (p < 0.05) serum chemistry changes at both interim and terminal evaluation were
reported to be within the range of normal variation, with the exception of decreased triglycerides
in high-dose males. The authors considered this effect to be treatment-related. The text of the
report indicated that triglycerides were statistically significantly increased at the mid-dose at
study termination (p < 0.05). In female rats, decreases in AST at both the mid- and high doses
were considered by the researchers to be potentially related to exposure. As with the
hematology, data tables are missing from the report.
Both absolute and relative liver weights were significantly increased (p < 0.05) over
control values in mid- and high-dose animals of both sexes (Anonymous, 1990). Absolute
kidney weight was increased in females of the mid- and high doses, but relative kidney weights
were not different from controls. No other treatment-related changes in organ weights were
noted. High-dose rats in the recovery group had lower relative liver weights than high-dose
animals terminated after 13 weeks. Data tables showing the organ weights were missing from
the report. There were no treatment-related findings on gross necropsy or histopathology
evaluation of any exposure group, nor were there any findings in the recovery group.
In the absence of data tables to support the observations in the text of the report, it is
difficult to identify effect levels with any degree of confidence. MADEP (2003) identified the
low-dose (100 mg/kg-day) as a NOAEL and the mid-dose (500 mg/kg-day) as a LOAEL based
on changes in serum chemistry and liver weight. In the absence of histopathology findings, the
biological significance of these effects is not clear as the liver weights were increased at the mid-
dose while serum chemistry indicated decreases in AST in females and decreased triglycerides in
males. However, the hematology findings provide a more consistent basis for identifying the
LOAEL. Decreases in erythrocyte count, Hct and Hgb at both the mid- and high-doses in male
rats were observed at both the interim (Day 32) and terminal evaluations. The authors
characterized the changes as trending toward anemia at the high-dose. Thus, a LOAEL of 500
mg/kg-day is identified based on hematology findings in male rats, with a NOAEL of 100
mg/kg-day.
A subchronic study of a related mixture was also conducted in rats (Anonymous, 1991a).
The mixture was characterized by MADEP (2003) as C10-C13 isoparaffins/naphthenes/
//-alkanes, with a typical aromatic content of 0.1%. In this study, groups of 10/sex/dose
Sprague-Dawley rats were given gavage doses of 0, 100, 500, or 1000 mg/kg-day of the mixture
in corn oil, 7 days/week for 13 weeks. A recovery group of 10 additional high-dose animals was
maintained for 28 untreated days after exposure was terminated. Toxicological evaluations were
the same as described above for the CI 1-C17 mixture.
Treatment did not result in statistically significant differences (p < 0.05) in survival, body
weight, food consumption, or ophthalmoscopic findings, nor were there treatment-related clinical
signs of toxicity (Anonymous, 1991a). The authors noted a trend toward reduced body weight in
males exposed at the mid- and high doses, but this trend apparently did not reach statistical
significance. Hematology analysis indicated a statistically significant (p < 0.01) increase in
platelet count in high-dose males evaluated at termination; no other treatment-related effects on
hematology parameters were noted. Serum chemistry changes noted at termination were
dose-related increases in BUN (p < 0.05 in mid- and high-dose males), creatinine (p < 0.05 in
low- and high-dose males), phosphorous (p < 0.01 in high-dose males), and ALT (p < 0.01 in
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high-dose males) in males and cholesterol (p < 0.05 in high-dose females) in females. The data
tables showing the magnitude of change were missing from the report; however, the authors
indicated that these changes were within normal physiological limits. At the interim blood
collection, a statistically significant decrease in AST levels was observed in the high-dose
females; at termination, this decrease persisted in the high-dose and AST was also decreased in
the mid-dose (p < 0.05). Glucose levels were decreased in mid- and high-dose animals of both
sexes (p < 0.05). Absolute and relative kidney weights were increased in mid- and high-dose
males (p < 0.05), as were relative liver weights, while relative testicular weights were increased
only at the high dose. In females, absolute and relative liver weights were increased at the high
dose (p < 0.01) and relative—but not absolute—liver weight was increased at the mid-dose
(p < 0.05). In the high-dose-recovery group, there was some evidence of return to normal in the
relative liver and kidney weights.
Histopathology evaluation indicated treatment-related effects on the kidneys (males only)
and livers (both sexes) (Anonymous, 1991a). Kidney changes were indicative of hyaline droplet
nephropathy. The changes included hyaline droplet accumulation, an increased incidence of
multifocal cortical tubular basophilia, degeneration and regeneration of tubular epithelium, and
dilated medullary tubules with granular casts. The incidence and severity were reported to
increase with dose, but additional details were not provided in the text, and the tables and
appendices were not available. The severity of this effect was reduced in the recovery group
rats, in which no hyaline droplets were observed, but granular casts and multifocal cortical
tubular basophilia persisted. No kidney histopathology was observed in female rats. In
high-dose male rats and mid- and high-dose females, centrilobular hepatocellular hypertrophy
(minimal to slight) was observed. Rats in the high-dose-recovery group did not show evidence
of this change.
The authors identified the low dose (100 mg/kg-day) as a NOAEL, but they did not
discuss the basis for choosing the NOAEL. MADEP (2003) likewise identified this dose as a
NOAEL, citing serum chemistry changes and liver weight increases as the critical effects.
Kidney histopathology in male rats was consistent with male-rat specific hyaline droplet
nephropathy—a condition that is not relevant to humans (U.S. EPA, 1991b) but a detailed
analysis of the mode of action has not been conducted. Therefore, this effect is considered
relevant to humans. Regarding liver effects, the authors suggested that the hepatocellular
hypertrophy was likely adaptive, but that it might account for mild serum chemistry changes
(increased ALT in males, increased cholesterol in females, and decreased glucose in both
sexes2). The authors also indicated that many of the statistically significant changes (p < 0.05) in
serum chemistry parameters were within normal physiological limits. Data showing the
magnitude of change in liver weights and serum chemistry parameters were not available;
therefore, the biological significance is difficult to discern. A LOAEL of 500 mg/kg-day is
identified based on liver effects (serum chemistry, liver weight and histopathology), with a
NOAEL of 100 mg/kg-day. These effect levels are subject to change upon examination of the
actual data tables and/or appendices that were not available at the time of this review.
2In the discussion of liver effects, the authors also cited increased bilirubin in males and increased triglycerides in
females, effects that had not been reported in the results section. Without the data tables and appendices, it is not
possible to determine whether these endpoints were also affected or not.
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In a third study, apparently conducted by the same organization as the other two, groups
of 10/sex Sprague-Dawley rats were given gavage doses of 0, 500, 2500, or 5000 mg/kg-day of a
hydrocarbon mixture (Anonymous, 1991b). MADEP (2003) characterized the mixture as
containing isoparaffins, //-alkanes, and naphthenes in the C9-C12 range and a typical aromatic
content of 0.1%. Doses were administered 7 days/week for 13 weeks. A high-dose recovery
group was observed for 28 days after exposure was terminated; this group consisted of 10 male
and 6 female rats. The numbers of females in the high-dose and high-dose-recovery groups were
14 and 6, respectively, although the section that was referenced as an explanation of why the
numbers of females differed in these groups was missing from the report. Evaluations were as
reported for the CI 1-C17 mixture with two exceptions: (1) there was no interim blood sampling
for hematology and serum chemistry, which were evaluated only at sacrifice and (2) in addition
to gross lesions, tissue masses, liver, lungs and kidney, the stomach was also examined
microscopically in all dose groups, as it was identified as a target organ in the high-dose group.
A number of gavage-related deaths occurred (1/10, 1/10, 4/14, and 3/6 in the control,
mid-dose, high-dose and high-dose-recovery females and 2/10 each in the control and
high-dose-recovery males). A second female death in the 2500 mg/kg-group was not explained.
The incidences of certain clinical signs (especially swollen anus, anogenital staining, emaciation,
and alopecia) were reported to be increased in the rats treated at 5000 mg/kg-day, while clinical
signs in the remaining groups were unremarkable. Occasional statistically significant (p < 0.05)
reductions (from control values) in body weight were noted in mid-dose males and persistent
reductions occurred in high-dose males between Day 49 and study termination (p < 0.01).
Female body weights were likewise reduced in both the mid- and high-dose groups at study
termination (p < 0.01). Data tables from which to estimate the magnitude of difference were
missing from the report and the authors did not note the magnitude in the text. Food
consumption was increased in mid- and high-dose animals of both sexes when compared with
control values. No treatment-related ophthalmoscopic findings were reported.
Hematology analysis indicated a dose-related increase in platelet count in both male and
female rats, with statistical significance reached at all doses in males and at the high dose in
females (p < 0.05). Leukocyte count was also reportedly increased with dose in males, and
segmented neutrophils were increased in high-dose and high-dose-recovery animals of both
sexes. However, additional information and statistical significance were not reported. No other
hematology changes were noted. Serum chemistry changes in males included dose-related
increases in BUN (statistically significantly different from control at mid- and high-doses,
p < 0.01), GGT (significant at high-dose only ,p< 0.01) and ALT (mid- and high doses,
p < 0.01), while cholesterol was increased in both sexes at doses of >2500 mg/kg-day (p < 0.01)
and bilirubin was increased in both sexes at the high dose (p < 0.05). Glucose levels were
decreased in all male treatment groups and in females at the mid- and high doses (p < 0.05). The
authors noted that hematology and serum chemistry analyses in recovery groups indicated
reversibility of some changes (data tables and appendices not available).
Organ weight changes were described in the text, but data tables supporting the
discussion were missing from the report (Anonymous, 1991b). Relative liver weights were
significantly (p < 0.05) increased over controls in mid- and high doses in animals of both sexes,
and absolute liver weights were increased in all treated female groups. Relative kidney weights
were increased in treated males and females at all doses (p < 0.01); absolute kidney weights were
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increased in all treated male groups. Absolute and relative adrenal weights were increased in
mid- and high-dose females and in high-dose males; relative adrenal weight was also increased
in mid-dose males. Finally, relative—but not absolute—testicular weights were increased in
high-dose males. Histopathologic findings in the livers and kidneys corroborated the organ
weight changes. Hepatocellular hypertrophy was noted at increased incidence in all treated
animals except the high-dose-recovery group. Kidney changes indicative of hyaline droplet
nephropathy (hyaline droplet accumulation, granular casts in medullary tubules, increased
basophilia of cortical tubules) occurred at increased incidence and severity in the treated males;
fewer of these changes were noted in the recovery-group males. In addition to the liver and
kidney changes, gross or microscopic evidence for gastrointestinal irritation was observed:
hyperplasia and hyperkeratosis of the nonglandular stomach, as well as irritation of the skin and
mucosa of the anus (necrosis, neutrophilic inflammatory cell infiltrations and pustule formation
of the anus). Although the text of the report did not clearly identify doses at which these irritant
effects were observed, TPHCWG (1997) and MADEP (2003) both reported that these effects
occurred in males and females of the mid- and high-dose groups. Effects in the stomach
persisted in 3/8 high-dose males in the recovery group but not in the females or the other five
males; no gross lesions of the anus were observed in recovery animals.
The authors indicated that a NOAEL could not be identified from these data, citing liver
and kidney effects in the low-dose groups. Effects at the low dose included increased absolute
liver weight in females, increased absolute and relative kidney weight in males and increased
relative kidney weight in females, hepatocellular hypertrophy in both sexes, and increased
incidence or severity of hyaline droplet nephropathy. The low dose (500 mg/kg-day) is
identified as a LOAEL based on these changes and no NOAEL is identified. These effect levels
are subject to change upon examination of the actual data tables and/or appendices that were not
available at the time of this review. Table 5 summarizes the available oral noncancer dose-
response information.
Table 5. Summary of Oral Noncancer Dose-Response Information
Species
Sex
Dose
(mg/kg-day)
Exposure
Regimen
NOAEL
(mg/kg-day)
LOAEL
(mg/kg-day)
Responses at the
LOAEL
Comments
Reference
Rat
M/F
0, 500, 2500,
5000
Gavage
7 d/wkfor 13
wks
NA
500
Increased liver and
kidney weights and
hepatocellular
hypertrophy.
C9-C12
Isoparaffins/n-
Alkanes/
Naphthenes (0.1%
aromatic)
Anonymous,
1991b
Rat
M/F
0, 100, 500,
1000
Gavage
7 d/wkfor 13
wks
100
500
Increased liver
weight, serum
chemistry changes,
hepatocellular
hypertrophy.
C10-C13
Isoparaffins/
Naphthenes/n-
Alkanes (0.1%
aromatic)
Anonymous,
1991a
Rat
M/F
0, 100, 500,
1000
Gavage
7 d/wkfor 13
wks
100
500
Hematology
changes trending
toward anemia.
Increased liver
weight and serum
chemistry changes
also occurred at
LOAEL.
C11-C17
Isoparaffinic
Solvent (<0.05%
aromatic)
Anonymous,
1990
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Inhalation Exposure
Subchronic Studies
Mullin et al. (1990) reviewed an unpublished study performed by the Phillips Petroleum
Company in 1986. According to the review, four rhesus monkeys received exposure to Soltrol
130 for 6 hours/day, 3 days/week, for 13 exposures at a mean concentration of 4200 mg/m3.
Mullin et al. (1990) did not provide any information on the exposure chamber or nature of the
exposure composition (e.g., vapor or aerosol, particle size, etc.). Soltrol 130 was reported to be a
mixture of C10-C13 hydrocarbons with an average molecular weight of 158 g/mol. Though the
review is unclear, it appears that there was no control group. The monkeys were examined for
behavioral changes and both body weight and food consumption were measured. Clinical
chemistry, urinalysis, gross necropsy, and histopathology were apparently evaluated, although
Mullin et al. (1990) provided no details of these examinations. The only effects noted were
lymphocytopenia and neutrophilia (characterized as slight by Mullin et al. [1990]) when
measured both at the midpoint and at the end of the study. In the absence of a control group, it is
not possible to assign effect levels from these data.
Shell Research Limited (1980) conducted a subchronic toxicity study of Shell Sol TD, a
mixture described as primarily isoparaffins in the C10-C12 range (-16% C10, 38.7% CI 1, and
44.4% C12). Groups of 18 male and female Wistar rats were exposed for 6 hours/day,
5 days/week, for 13 weeks to measured concentrations of 0, 2529, 5200, or 10,186 mg/m3 (200,
5200, or 1800 ppm). The exposure atmospheres were generated by completely evaporating the
test material via electrically heated quartz tubes. Solvent vapor was mixed with ventilating air,
and concentrations were quantified by flame ionization detection. Animals were observed daily,
and body weight, food consumption, and water intake were measured weekly. Prior to sacrifice,
blood was collected for hematology (Hgb, Hct, erythrocyte count, total and differential leukocyte
counts, MCV, MCH, MCHC, prothrombin time, and coagulation time) and serum chemistry
(protein, BUN, alkaline phosphatase [ALP], ALT, AST, electrolytes, chloride, albumin,
glucose). All animals received gross necropsies, and selected organs were weighed (brain, heart,
kidney, liver, spleen, testes). Animals of all but the low concentration group were evaluated for
histopathology (29 tissues including nasal cavity) and kidneys of low concentration males were
also examined microscopically.
Exposure to the high concentration induced lethargy in rats of both sexes for up to 1 hour
after the exposure time (Shell Research Limited, 1980). There was a statistically significant
(p < 0.05) reduction in the body weight of females at all concentrations and in males at the high
concentration during the first part of the study. In both sexes, body weight decrements never
exceeded 6% of control values. Food consumption was also reduced in males during the first
part of the study and occasionally in females throughout the study. High concentration males
consumed more water than controls—at times as much as 46% more. The authors reported that
all male rats exhibited low-grade anemia based on reductions in Hgb, Hct, and erythrocyte
counts (see Table 1); however, all of these measures were within reference ranges for rats
(Wolford et al., 1986). Leukocyte counts were also decreased (20% below controls; p < 0.01) at
the high concentration in males. Hematology changes in females were limited to small changes
in the differential leukocyte count. Serum chemistry changes included decreases in AST and
ALT in all exposed females and increases in protein and albumin at the highest concentration.
The toxicological significance of these changes is uncertain. In males, serum chemistry changes
were observed at the high concentration only and included increases in ALP, potassium,
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chloride, and albumin. Increased water consumption and changes in potassium, chloride, and
albumin may be related to kidney effects in male rats, as confirmed by histopathology (see
below). Statistically significant (p < 0.05) organ-weight changes were observed in both sexes, as
shown in Table 1. Liver weights were increased at all concentrations in males (8-36%) and at all
but the lowest concentration in females (13-42%). Spleen and heart weights were also increased
in high-concentration males; however, the magnitude of change is small (<10%) and the
toxicological significance of these changes is uncertain. Kidney weights were increased in all
treated males and in high-concentration females. Histopathology evaluation indicated kidney
changes in all treated male rats but no effects in female rats. Kidney changes were described as
hyaline intracytoplasmic inclusions, increased incidence of tubular degeneration and dilatation of
cortical tubules. The histopathology changes in male rats are consistent with the a2u-globulin
nephrotoxicity commonly observed in male rats; however, a mode of action analysis ws not
conducted. Therefore, this effect can be considered relevant to humans (U.S. EPA, 1991b).
Table 1. Selected Changes in
Rats Exposed to ShellSol TD via Inhalation for 13 Weeksa

Control
2529 m «/m3
5200 in «/m3
10,186 mg/m3
Males
Hematology
Hemoglobin (g/dL)
15b
14.6°
14.3d
14.4d
Hematocrit (%)
41
40d
39d
39d
/ 'j
Erythrocyte count (10 /mm )
7.79
1.5T
7.46d
7.46d
Leukocyte count (103/mm3)
4.5
4.6
4.0
3.6d
Clinical Chemistry
Alkaline phosphatase (IU)
86
87
92
100c
Organ Weightse
Liver weight (g)
15.4
16.59d
17.40d
21.00d
Kidney weight (g)
2.77
3.33d
3.45d
3.83d
Heart weight (g)
1.17
1.22
1.22
1.27d
Spleen weight (g)
0.79
0.82
0.82
0.86c
Females

Control
2529 in «/m3
5200 in «/m3
10,186 mg/m3
Clinical Chemistry
ALT (IU)
27
(21)M
(21)ct
19d
AST (IU)
54
43d
43d
37d
Organ Weightse
Liver weight (g)
8.92
9.29
10.09d
12.67d
Kidney weight (g)
1.78
1.87
1.88
2.06d
aShell Research Limited, 1980
bMean reported; group-wise variability not given
Significantly different from control atp< 0.05
d/?<0.01
"Organ weights as given in the report after adjustment for terminal body weight
fAuthors did not provide simple means for these values, but rather statistically modified estimates (Williams means,
shown in parentheses).
The study authors stated that changes in hematology parameters in all treated males were
within reference ranges and, thus, not considered toxicologically significant. Signs of liver
toxicity included increased liver weight in all exposed males and in mid- and high-concentration
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females, as well as increased ALP (males at 10,186 mg/m3) and decreased ALT and AST (all
exposed females). Changes in ALP, ALT, and AST included a 16% increase in ALP and -30%
decrease in ALT and AST, and there were no histopathology findings in the livers of treated
animals. The serum chemistry changes and increased liver weights were observed in the females
at higher concentration levels (5200 and 10,186 mg/m3). A LOAEL of 5200 mg/m3 is identified
based on these effects. In addition, at the highest concentration (10,186 mg/m3), rats of both
sexes exhibited lethargy for up to 1 hour after exposure. The NOAEL is 2529 mg/m3.
Phillips and Egan (1984a) evaluated the subchronic toxicity of two midrange aliphatic
hydrocarbon streams: dearomatized white spirit (DAWS) and isoparaffinic hydrocarbons (IPH).
DAWS was characterized as containing 58% paraffins (straight chain alkanes), 42% naphthenes,
and <0.5%) aromatics, with hydrocarbons in the CI 1-C12 range. IPH was characterized as
consisting entirely of isoparaffins of the C10-C11 range. Sprague-Dawley rats
(35/sex/concentration) were exposed for 6 hours/day, 5 days/week, for up to 12 weeks at
concentrations of 1970 or 5610 mg/m3 DAWS or 1910 or 5620 mg/m3 IPH, with a common
chamber control group. The test materials were flash evaporated from heated flasks and then
mixed with intake air to obtain the exposure concentrations. During exposure days, the chamber
concentrations were measured using infrared spectroscopy, and the hydrocarbon compositions
were verified by gas chromatography analysis after 8 and 11 weeks on study. Daily checks for
clinical signs of toxicity were made and body weights were measured weekly. Interim sacrifices
of 10 rats/sex/group were made after 4 and 8 weeks of exposure; the remaining rats were
sacrificed after 12 weeks. After 12 weeks of exposure, blood was collected for hematology
(Hgb, Hct, erythrocyte count, clotting time, MCV, and total and differential leukocyte count) and
serum chemistry (BUN, glucose, ALT, and ALP). Upon sacrifice, the kidneys, liver, lungs,
brain, adrenals, and gonads were weighed. All animals were examined for histopathology of
23 tissues; no tissues of the respiratory tract were examined.
Because of a malfunctioning thermostat, the low-concentration DAWS group was
inadvertently exposed to combustion products of DAWS and was replaced with another group
with a concurrent chamber control group (Phillips and Egan, 1984a). The authors indicated that
this event occurred early in the study, but they did not provide further details. Exposure to
DAWS did not affect survival, but it did result in significant reductions in the body weight of
male rats at the high concentration beginning in Week 5. Based on graphical presentation of the
data, the terminal body weights in this group appeared to be reduced by about 7% from control
values. Hematology parameters did not appear to be affected by treatment with DAWS, as
statistically significant (p < 0.05) differences from control values (Hgb and erythrocyte count)
were only observed at the low concentration and not at the high concentration. At Weeks 4 and
8, serum glucose levels were significantly (p < 0.05) decreased (10—16% below controls) in both
males and females exposed to the high concentration of DAWS; however, no difference from
control values was apparent at 12 weeks. No other treatment-related effects on serum chemistry
were observed. Relative liver and kidney weights were significantly (p < 0.05) increased
(14-20% higher than control for liver and 12-18% for kidney) at all time points in male rats
exposed to 5610 mg/m3 DAWS; absolute kidney weight was also increased (12%) at Week 4
only. In male rats exposed to 1970 mg/m3 DAWS, the only organ weight change was an
increase (12%) in relative kidney weight at Week 8. As with males, relative liver weights were
significantly (p < 0.01) increased (10-18%) higher than controls) at all time points in female rats
exposed to 5610 mg/m3 DAWS. At Week 12, absolute liver weights were increased in female
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rats at both concentrations (10 and 25% for low and high concentration, respectively; p < 0.05).
Kidney weights in female rats were unaffected by treatment with DAWS.
The only histopathology findings observed after DAWS treatment were in the kidneys of
male rats and consisted of increased incidence of regenerative epithelium in the cortex and
dilated tubules containing proteinaceous casts in the corticomedullary areas (Phillips and Egan,
1984a). These changes were observed at both 1970 and 5610 mg/m3 exposures of DAWS as
early as the 4-week sacrifice and the severity of the lesions increased with time. The authors did
not report the incidences or severity ratings of these lesions. The lesions were described as
similar to those observed early in the development of chronic progressive nephropathy (CPN), an
age-related phenomenon commonly observed in rats. Data from oral studies of similar mixtures
(Anonymous, 1991a,b), as well as a mechanistic study of kidney effects after inhalation exposure
to isoparaffinic hydrocarbons (Viau et al., 1986, described below under Other Studies), coupled
with the lack of effects in female rats, suggest that the kidney lesions could be related to male
rat-specific hyaline droplet nephropathy (U.S. EPA, 1991b). However, a mode of action analysis
was not conducted, thus this effect can be considered relevant to humans. The high
concentration (5610 mg/m3 DAWS) is considered a NOAEL. The only changes observed at this
concentration were (1) mild (<10%) body weight reduction in males and (2) increased relative—
but not absolute—liver weight in both sexes and transient decreases in glucose levels. The body
weight reductions were not biologically significant. No changes in ALT or ALP were observed.
There were no effects of IPH treatment on survival, but significant (p-value not reported)
reductions in the body weight of male rats were observed at both concentrations; reductions were
significant beginning during Week 5 (Phillips and Egan, 1984a). Based on graphical
presentation of the data, the terminal body weights were reduced by about 5-7% from control
values. Erythrocyte count was significantly (p < 0.05) decreased (~5 % relative to controls) in
males exposed to both concentrations of IPH; no other hematology parameters were affected.
The only serum chemistry parameter that differed from controls was serum glucose, which was
reduced (8—14%) in males of both exposure groups at 8 weeks and in females of both groups at
4 weeks. Relative kidney weight was significantly (p < 0.05) increased at all time points in male
rats exposed to both concentrations of IPH; absolute kidney weight was increased only at
Week 8 in the high concentration group. Relative kidney weight increases (over control values)
at the low concentration of IPH ranged from 11—12% while increases at the high concentration
were from 13-19%. In females, absolute and relative kidney weights were increased at Week 8
but not at Weeks 4 or 12. Significant (p < 0.05) increases in absolute and relative liver weight
were observed after exposure at the high concentration in both sexes. In males, absolute and
relative liver weights were increased (15 and 14% higher than controls, respectively) at Week 4,
and relative weight was increased (8%) at Week 12. In females, relative liver weight was
increased at Week 4 and Week 8 (13 and 8%, respectively), and absolute liver weight was
increased (9%) at Week 8. Liver weights in females did not differ from controls at study
termination. The study authors indicated that other organ weight changes were sporadic and not
considered treatment-related.
As with DAWS, histopathology findings after IPH treatment were limited to the kidneys
of male rats (regenerative epithelium in the cortex and dilated tubules containing proteinaceous
casts) and were described as similar to age-related CPN (Phillips and Egan, 1984a). The authors
reported these findings at both 1910 and 5620 mg/m3 exposures of IPH beginning at the 4-week
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sacrifice, with increasing severity over time. Incidence data were not reported. As discussed for
the study of DAWS, the kidney changes observed after IPH exposure may be related to male rat-
specific hyaline droplet nephropathy (U.S. EPA, 1991b); however, a mode of action analysis was
not conducted, thus this effect is considered relevant to humans. The high concentration of IPH
(5620 mg/m3) is considered a NOAEL. The only changes observed at this concentration were
small (<10%) reductions in body weight in males, slight decreases in erythrocyte count and
serum glucose, as well as increases in liver and kidney weights in both sexes. At study
termination, the only statistically significant (p < 0.05) organ weight changes were increased
relative kidney weight in males at both exposure levels, and a small (8%) increase in relative
liver weight in high-concentration males.
In preparation for chronic studies, NTP (2004) conducted subchronic inhalation studies of
Stoddard Solvent IIC in F344/N rats and B6C3F1 mice. The test material was characterized as a
mixture of ^-paraffins, isoparaffins, and cycloparaffins with 10-13 carbons; the aromatic content
was measured as <1.0%. Stoddard Solvent IIC vapor was generated by pumping the material
through a preheater and into a heated glass column; heated nitrogen resulted in vaporization of
the mixture as it left the generator, and the line transporting the vapor to the exposure chamber
was heated to prevent condensation. A particle detector used during the 2-week and 3-month
studies confirmed that the test material was present as a vapor and not an aerosol in the exposure
chamber. Exposure concentrations were verified by gas chromatography during the studies.
Exposure concentrations were selected based on the results of 2-week studies in both species, in
which exposure concentrations ranging from 138-2200 mg/m3 were used. Neither survival nor
body weights of either species were affected at concentrations up to 2200 mg/m3 in the 2-week
studies. In male rats, relative liver weights were increased at exposures to 550 mg/m3 and
greater; in female rats, absolute liver and kidney weight increases occurred at concentrations of
275 mg/m3 and above. Minimal diffuse cytoplasmic vacuolization of hepatocytes occurred in all
female rats exposed to 2200 mg/m3 and only one control. In mice, absolute and relative liver
weights were increased in both sexes at 275 mg/m3 and above and kidney weights were
increased in females exposed to 1100 mg/m3 and greater. Liver cytomegaly occurred in all male
and female mice exposed to 2200 mg/m3 in the 2-week studies (NTP, 2004).
The same exposure concentrations were used in the subchronic studies (NTP, 2004).
Groups of 10/sex/species were exposed to vapor concentrations of 0, 138, 275, 550, 1100, or
2200 mg/m3 for 6 hours/day, 5 days/week, for 14 weeks. Chamber concentrations were verified
by GC analysis throughout the study. Animals were observed twice daily and body weights and
clinical signs were recorded weekly. Prior to sacrifice, blood was collected from mice for
hematology (Hct, packed cell volume, Hgb, erythrocyte count, platelet count, total and
differential leukocyte count, reticulocyte count, nucleated erythrocyte/1 eukocyte ratios, MCV,
MCH, and MCHC); clinical chemistry was not performed on blood samples from mice.
Hematology (detailed previously) and clinical chemistry evaluations (BUN, creatinine, total
protein, albumin, globulin, albumin/globulin ration, ALT, ALP, creatine kinase, sorbitol
dehydrogenase, bile acids, and hemolysis) were performed on blood samples collected
intermittently from groups of 10 rats/sex/dose used for clinical pathology and from all rats at
termination. Sperm count and motility were evaluated in male rats and mice from the
550-, 1100-, and 2200-mg/m3 groups and vaginal cytology and estrous cyclicity were evaluated
in females of the same groups. All animals were necropsied at sacrifice and the heart, right
kidney, liver, lung, right testis, and thymus were weighed. A large number of tissues (>31) from
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control and high concentration animals were examined microscopically. In addition, the larynx,
lung, nose, and trachea of all groups in both species were examined, as were the kidneys of rats
and the spleens of female mice of all groups.
There were no deaths among rats of either sex (NTP, 2004). The incidence of clinical
signs was not affected by treatment. Mean terminal body weights of female rats were higher
than controls in all exposure groups, but the difference was statistically significant (p < 0.01)
only in the group exposed to 275 mg/m3. Male body weights were comparable to controls in all
exposure groups. Exposure to Stoddard Solvent IIC resulted in concentration-related decreases
in ALT levels in both sexes (see Table 2) and an increase (albeit not persistent) in serum bile
acid in exposed females at all concentrations. The authors attributed increases in creatinine
(males and females), total protein (males), and albumin (males) in rats exposed to levels of
550 mg/m3 or more to a decrease in plasma volume. Decreases in Hct, Hgb, and erythrocyte
counts were recorded among high-concentration males, but the study authors did not consider the
changes to be toxicologically relevant. Relative kidney, liver, and testes weights were
significantly (p < 0.05) increased in all exposed male groups (see Table 2). Absolute kidney
weights were also increased in males exposed to concentrations of 550 mg/m3 and higher, but
absolute liver and testes weights were not different from controls. Female organ weights were
not affected by treatment at any concentration. Sperm motility was reduced at all the exposure
levels evaluated for this endpoint (>550 mg/m3). Estrous cyclicity and vaginal cytology were not
affected by treatment.
Histopathology changes considered by the authors to be indicative of a2U-globulin
nephropathy were observed in male rats exposed to concentrations of 550 mg/m3 and greater
(NTP, 2004). The changes consisted of increased incidence of renal tubule granular casts and
increased severity of hyaline droplet accumulation and renal tubular regeneration. No
microscopic changes were observed in the kidneys of female rats at any exposure level. Both
male and female rats exhibited increased incidences of goblet cell hypertrophy of the nasal
respiratory epithelium when exposed to higher concentrations of Stoddard Solvent IIC
(>1100 mg/m3 in females and at 2200 mg/m3 in males). The incidences and severity scores are
shown in Table 2.
NTP (2004) did not identify effect levels. The kidney changes reported in male rats,
including kidney weight increases and histopathology, are considered indicative of a2U-globulin
nephropathy; however a mode of action analysis was not conducted, thus this effect is considered
relevant to humans. (U.S. EPA, 1991b). Statistically significant (p < 0.05) decreases in sperm
motility were observed at concentrations of 550 mg/m3 and higher, but the maximum decrease
was only 12%. It is unclear whether a decrease in sperm motility of this magnitude will affect
fertility. NTP (2004) reported that studies in mice indicate little or no effect on fertility until
sperm motility is reduced by 40% or more; there are no corresponding studies in rats to inform
this question. Relative testes weights were increased in all exposed males, but the toxicological
significance of this finding is uncertain. Relative—but not absolute—liver weights were
increased (up to 13%) in males at all exposure levels, and decreases in ALT were observed in
both sexes at 550 mg/m3 and higher concentrations. Exposure-related increases in the incidence
of nasal goblet cell hypertrophy were observed in both sexes (at 2200 mg/m3 in males and >1100
mg/m3 in females). This endpoint may reflect an irritant property of the test material. For the
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Table 2. Selected Changes in Rats Exposed to Stoddard Solvent IIC via Inhalation for 13 Weeksa

Control
138 m «/m3
275 in «/m3
550 in «/m3
1100 in «/m3
2200 in «/m3
Males
Clinical Chemistry
ALT (IU/L)
80 ± 5b
73 ±6
71 ±4
62 ± 6d
46 ± ld
42 ± 2d
Organ Weights
Right kidney weight (g)
0.917 ±
0.021
0.958 ±
0.016
0.967 ±
0.025
0.984 ± 0.026c
1.022 ±0.022d
1.020 ±0.024d
Right kidney / body weight
(mg/g)
2.747 ±
0.045
2.901 ±
0.042c
2.911 ±
0.040d
2.972 ±0.041d
3.073 ±0.029d
3.235 ±0.050d
Liver / body weight (mg/g)
28.6 ±0.4
30.1 ±0.5C
30.2 ± 0.4C
30.4 ± 0.4d
30.8 ± 0.5d
32.4 ± 0.4d
Right testis / body weight (g)
4.076 ±
0.081
4.258 ±
0.059c
4.294 ±
0.053c
4.332 ±0.047d
4.285 ±0.068d
4.459 ± 0.040d
Reproductive Evaluations
Epididymal sperm motility (%)
90.28 ± 1.40
Not
evaluated
Not
evaluated
77.27 ± 3.99c
80.38 ±2.62c
79.44 ± 1.59c
Histopathology
Nasal Goblet Cell, Respiratory
Epithelial Hypertrophy
2/10e (1.0)f
2/10 (1.0)
2/10(1.0)
2/10 (1.0)
4/10(1.5)
7/10° (1.9)
Females

Control
138 in «/m3
275 in «/m3
550 in «/m3
1100 in «/m3
2200 in «/m3
Clinical Chemistry
ALT (IU/L)
52 ±3
55 ±3
56 ±4
42 ± 2°
46 ±3
39 ± 2d
Histopathology
Nasal Goblet Cell, Respiratory
Epithelial Hypertrophy
0/10
1/10 (2.0)
1/10(1.0)
0/10
4/10C (1.0)
9/10d (1.7)
aNTP, 2004
bMean ± standard deviation
"Significantly different from control atp< 0.05
d/?<0.01
"Number affected/number examined
f Severity score in parentheses (1 = minimal, 2 = mild, 3 = moderate, 4 = marked)
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purpose of this review, a LOAEL is established at 1100 mg/m3 based on nasal goblet cell
hypertrophy in females. The NOAEL is 550 mg/m3.
In mice, one male in the lowest exposure group was sacrificed prematurely due to
moribund condition, but no other effects on survival were observed (NTP, 2004). There were no
statistically significant (p < 0.01) effects on body weight; however, exposed males were reported
to appear thin. Exposure to Stoddard Solvent IIC did not affect other clinical signs or
hematology findings. Absolute liver weight was increased (11% higher than control, p < 0.01) in
males at the highest concentration and relative liver weight was increased in males at 1100 and
2200 mg/m3 (8% and 14%, respectively). No other organ weight changes were observed. Sperm
motility was reduced (10% below controls; p < 0.05) at the highest concentration only. Female
reproductive evaluations were not affected by treatment. The only histopathology finding was an
increase (p < 0.01 by Fisher's exact test performed for this review) in the incidence of
hematopoietic cell proliferation in the spleens of all exposed females (1/10, 8/10, 7/10, 7/10, 9/9,
9/10 in control through high-concentration groups). The authors did not consider this effect to be
toxicologically significant. Although sperm motility was reduced at the high concentration
(10%) decrease), NTP (2004) reported that studies in mice indicate little or no effect on fertility
until sperm motility is reduced by 40% or more; thus, this effect is not considered as the basis for
a LOAEL determination. Clinical chemistry was not evaluated in mice. The high concentration
(2200 mg/m3) is considered a LOAEL in the mice study, based on statistically significantly
increased absolute and relative liver weight.
Chronic Studies
Lund et al. (1996) evaluated the neurotoxicity of DAWS (carbon range and aromatic
content not reported) in groups of 36 male Mol:Wist rats exposed to concentrations of 0, 2339, or
4679 mg/m3 for 6 hours/day, 5 days/week, for 6 months. The authors did not describe the
inhalation exposure conditions or equipment. After the exposure period, animals were followed
for 70-80 untreated days before neurophysiological and neurobehavioral testing was conducted.
Body weights were recorded weekly and water consumption was measured for the last 5 weeks
of exposure and first 6 weeks postexposure. After exposure was terminated, groups of
10 rats/exposure were placed in metabolism cages for 24-hour urine collection, after which blood
was collected for serum chemistry (ALT, ALP, glucose, creatinine, urea, protein, phosphate, and
uric acid). After two unexposed months, neurobehavioral testing was initiated, including motor
activity (control and high-exposure groups only), functional observational battery, passive
avoidance test, eight-arm radial maze test, and Morris water maze (with and without
scopolamine [an anticholinergic agent] challenge). Another 10 rats/group were used for
electrophysiological measurements, including visual flash evoked potentials (FEP),
somatosensory evoked potentials (SEP), and auditory brainstem response (ABR) 3 months after
exposure concluded. After 6 untreated months, 10 animals/group were sacrificed for necropsy,
organ weight measurements (liver, kidneys, adrenals, heart, spleen, and testes), and
histopathology of these organs together with the sciatic nerve.
The authors reported that exposed rats showed "signs of discomfort" at both exposure
levels (Lund et al., 1996). Lacrimation and bloody nasal discharge were noted, as was a narcotic
effect during the first 2 weeks of exposure, but incidences and difference from controls were not
described. Body weights were not affected by exposure, but water consumption was increased
relative to controls when measured during the last 5 weeks of exposure. Urine output was
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increased in rats exposed to the high concentration of DAWS and serum levels of uric acid were
increased; no other changes in urine or serum chemistry parameters were noted. Dose-dependent
increases in the amplitude of early latency peaks were observed during measurements of FEP,
SEP, and ABR, as shown in Table 3. Early latency peak-to-peak amplitudes (both FEP and SEP)
were significantly (p < 0.05) larger than controls at both concentrations of DAWS and
later-latency amplitude (FEP only) was increased at the high concentration. No treatment-related
differences in FOB parameters were noted. Motor activity was significantly lower than controls
in the high-concentration group at various time points, but was not consistently affected at each
evaluation. No effects of treatment were noted on other neurobehavioral tests (passive
avoidance, Morris water maze, radial arm maze) or on histopathology findings. A LOAEL of
2339 mg/m3 for clinical signs of toxicity (lacrimation and bloody nasal discharge) and
neurophysiological changes is identified. No NOAEL can be identified.
Table 3. Significant Changes in Rat Neurophysiological Measures (Evoked
Potentials) 3 Months after Exposure to DAWS for 6 Monthsa
Endpoint and Measurement
Control
2339 mg/m3
(400 ppm)
4679 mg/m3
(800 ppm)
Flash Evoked Potential
N1P2 peak to peak amplitude (|iV)
124.5 ±
33.2
163.5 ±25.lb
179.2 ± 54.7b
N2P3 peak to peak amplitude (|iV)
47.2 ±22.1
53.9 ± 18.0
83.4 ± 32.2b
Somatosensory Evoked Potential
PI amplitude (|iV)
18.8 ±8.8
37.3 ± 14. lb
43.9 ± 21.2b
Root Mean Square (RMS) voltage (|iV)
19.0 ±8.1
23.0 ± 8.5
30.4 ± 8.9C
Auditory Brainstem Response
4 kHz la amplitude (|iV)
4.4 ± 1.1
5.8 ±2.1
6.4 ± 1.3b
4 kHz Root Mean Square (RMS) voltage
(HV)
6.6 ± 1.1
9.2 ± 2.1c
8.2 ± 1.3°
8 kHz la amplitude (|iV)
6.5 ± 1.4
8.3 ±2.9
8.8 ± 2. lc
8 kHz IV amplitude (|iV)
15.2 ±3.1
19.6 ± 5.2
18.5 ±2.5C
8 kHz Root Mean Square (RMS) voltage
(HV)
7.9 ± 1.4
10.8 ± 2.9C
9.7 ± 1.3°
16 kHz la amplitude (|iV)
6.1 ± 1.1
7.3 ±2.6
7.7 ± 1.6°
aLundetal., 1996
bSignificantly different from control by one-way ANOVA, p < 0.01
cp < 0.05
Chronic inhalation studies of Stoddard Solvent IIC (mixture of //-paraffins, isoparaffins
and cycloparaffins with 10-13 carbons; aromatic content <1.0%) were performed by NTP (2004)
in F344/N rats and B6C3F1 mice. Groups of 50 animals/sex/species were exposed to vapor
concentrations of 0, 138 (male rats only), 550, 1100, or 2200 (male and female mice and female
rats only) mg/m3 for 6 hours/day, 5 days/week, for 2 years. Chamber concentrations were
verified by GC analysis throughout the study. Animals were observed twice daily and body
weights and clinical signs were recorded weekly through the first month, monthly until Week 89
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and biweekly thereafter. All animals were necropsied at sacrifice; organ weights were not
recorded. Comprehensive histopathology evaluations (>31) were performed on all treated
animals. A separate study evaluating the role of a2U-globulin nephropathy in rats was conducted;
this study is discussed under Mechanistic Studies (page 28) below.
In rats, survival was significantly (p < 0.01) reduced at 138 and 1100 mg/m3 (but not at
550 mg/m3) in males and at 2200 mg/m3 in females. The mean body weights and incidences of
clinical signs in exposed rats were comparable to controls. Male rats exhibited increases in the
incidence of renal tubule hyperplasia, transitional epithelial hyperplasia of the renal pelvis and
renal papillary mineralization. With the exception of increased renal papillary mineralization,
which occurred at all concentrations, these effects were restricted to the mid- and
high-concentration groups. Based on the constellation of renal findings in male rats, coupled
with the results of the satellite kidney toxicity study (discussed below under Mechanistic
Studies), the kidney effects were attributed to a2u-globulin nephropathy (NTP, 2004); however, a
mode of action analysis was not conducted. Thus, this endpoint is considered relevant to human
health (U.S. EPA, 1991b). In female rats exposed to 2200 mg/m3 and in male rats exposed to
138 mg/m3 Stoddard Solvent IIC, the incidences of olfactory epithelial hyaline degeneration
were increased (females: 28/50 exposed vs. 12/49 controls; males: 8/50 exposed vs. 2/50
controls). However, NTP (2004) considered this effect to be of questionable biological
significance because this lesion is commonly observed in the nasal passages of rats, especially
during inhalation studies. Nonneoplastic lesions attributed to Stoddard Solvent IIC exposure
included an increased incidence of adrenal medullary hyperplasia in males at the mid
concentration but not at the high concentration (see Table 4). The LOAEL is established at 550
mg/m3 based on the increase in adrenal medullary hyperplasia in male rats, and the NOAEL is
138 mg/m3. The apparent lack of dose-response trend at the highest concentration treatment
group (decreased incidence at the highest dose; 15/50 at 1100 mg/m3 vs. 23/50 at 550 mg/m3)
may be related to other unknown (and perhaps more serious effects) at the same level of
exposure. It is unclear whether the incidence of hyperplasia is part of cancer progression
(increased tumor incidences at higher levels) or an independent event itself. Since there is no
incidence of hyperplasia in the subchronic study (NTP, 2004) under the same experimental
conditions, and because there is high background level in the chamber control group (12/50) in
the chronic study, it is not possible to determine if this effect is a precursor event (preneoplastic
change) based on the limited information.
The incidences of renal tubular adenoma and/or carcinoma were not statistically
significantly increased over controls in rats of either sex at any exposure level (NTP, 2004). A
nonsignificant increase in renal adenoma incidence was observed at the highest concentration
(7/50 vs. 3/50 in controls in extended histopathology evaluations). The incidence of clitoral
gland adenoma was significantly (p < 0.05) increased at 1100 and 2200 mg/m3 and the incidence
of clitoral gland adenoma or carcinoma was significantly increased at the high concentration.
However, the incidences at all exposure levels were reported to be within historical control
ranges for chamber controls. Based on this observation, along with the absence of exposure-
related increases in clitoral gland hyperplasia or carcinoma (clitoral adenoma is part of a
morphologic continuum from hyperplasia to carcinoma), NTP (2004) concluded that the clitoral
gland adenomas were not treatment-related. The incidences of benign and benign or malignant
(combined) pheochromocytoma of the adrenal glands were increased over both chamber controls
and over historical control incidences in males exposed to 550 and 1100 mg/m3 (see Table 4).
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Table 4. Incidence of Neoplastic and Nonneoplastic Changes in the Adrenal Medulla of
Male Rats Exposed to Stoddard Solvent IIC for 2 Yearsa
Lesion
Chamber
Control
Historical
Control
138 mg/m3
550 mg/m3
1100 mg/m3
Hyperplasia
12/50 (2.5)b
Not reported
14/50 (2.6)
23/50d(2.6)
15/50(2.2)
Benign
pheochromocytoma
5/50
42/298
(14%)
9/50
13/50c
17/50d
Benign or
malignant
(combined)
pheochromocytoma
6/50
48/298
(16%)
9/50
13/50c
19/50d
"NTP. 2004
bNumber affected/number examined; severity score in parentheses (l=minimal, 2=mild, 3=moderate, 4=marked)
Significantly different from chamber control at p< 0.05
d/?<0.01
Significant (p < 0.001) concentration-related trends were also evident in both the benign and
combined incidence rates. NTP (2004) noted that, although some studies have demonstrated a
correlation between the severity of nephropathy and adrenal pheochromocytoma, correlation
analysis performed on the Stoddard Solvent IIC data failed to indicate a similar correlation,
suggesting that the increase in adrenal tumors was not explained by kidney toxicity. The
observation of increased incidences of adrenal neoplasms served as the basis for a finding of
some evidence of carcinogenic activity for Stoddard Solvent IIC in male rats (NTP, 2004).
Survival of mice in the 2-year study was not affected by treatment (NTP, 2004). Clinical
signs were comparable among all groups including control and the body weights of male mice
were unaffected. Mean body weights of all exposed female mice were increased over controls
(6-12% higher); statistical comparisons of the differences were not reported, nor were data with
which to perform such comparisons. Nonneoplastic histology findings were restricted to the
liver. The incidences of basophilic and eosinophilic foci were increased in males exposed to
1100 mg/m3 but not in those exposed to 2200 mg/m3; thus, the relationship to exposure is
uncertain. The incidence of eosinophilic foci in female mice was significantly (p < 0.05)
increased at the high concentration (4/50, 9/50, 6/50, 11/50 in control through high
concentration). This lesion was considered mild in all groups including controls. For the
purpose of this PPRTV document, the high concentration (2200 mg/m3) is considered a LOAEL
for the increased incidence of eosinophilic foci of the liver in female mice and 1100 mg/m3 is a
NOAEL.
Statistically significant (p < 0.05) increases in the incidences of multiple hepatocellular
adenoma (males and females) and hepatocellular adenoma (females only) were observed in the
high concentration group, but there was no difference in the rate of hepatocellular carcinoma
formation (NTP, 2004). The increase in multiple adenomas in males was not considered to be
exposure-related, as the incidence of all adenomas was not increased in males at any exposure
level. Thus, NTP (2004) concluded that there was no evidence of carcinogenic activity in male
mice. Since liver tumors in this strain of mouse are affected by body weight, NTP (2004)
conducted a statistical analysis to evaluate the relationship between liver neoplasm incidence and
body weight in the female mice and concluded that the increase in liver tumors was primarily
due to the increased body weights in the exposed females. NTP (2004) concluded that there was
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equivocal evidence of carcinogenic activity of Stoddard Solvent IIC in female mice. It should be
noted that the maximum exposure concentration in this study was not a Maximum Tolerated
Dose, but rather was limited by the maximum vapor concentration that could be attained.
Reproductive/Developmental Studies—Both Mullin et al. (1990) and TPHCWG (1997)
reviewed an unpublished study performed by Exxon Corporation (1988) on the developmental
toxicity of IPH. The test material was Isopar G, which was characterized by Mullin et al. (1990)
as a mixture of predominantly C10-C11 hydrocarbons with an average molecular weight of
149 g/mol. No information on the exposure conditions or equipment was provided. According
to the review, mated CD rats were exposed to 0, 300, or 900 ppm Isopar G for 6 hours/day on
gestation days (GD) 6-15, followed by sacrifice on GD 21. Based on the reported average
molecular weight, these exposures (300 and 900 ppm) are estimated to be equivalent to 1828 and
5485 mg/m3, respectively. Parameters evaluated included live and dead fetuses, early and late
resorptions, implantation sites, number of corpora lutea, fetal weight, length, and sex, in addition
to external, visceral, and skeletal malformations. Mullin et al. (1990) reported that there were no
effects on any of these parameters; thus, the high concentration of 900 ppm (5485 mg/m3) was a
developmental NOAEL. While Mullin et al. (1990) did not address maternal toxicity
parameters, TPHCWG (1997) reported that no maternal toxicity was observed; thus, the high
concentration is apparently a maternal NOAEL as well. Given the reliance on secondary
sources, these effect levels should be considered with caution.
Hass et al. (2001) evaluated the neurobehavioral effects of gestational exposure to
DAWS (<0.4 wt. % aromatic, carbon range not specified) in Mol:WIST rats. The authors did not
describe the inhalation exposure conditions or equipment. Groups of time-mated rats were
exposed to 0 or 4679 mg/m3 of DAWS for 6 hours/day on GD 7-20. While group sizes were not
explicitly noted, there were 14 litters in the controls and 13 in the exposed group. Maternal body
weights were recorded on GD 11, 15, 17, and 21. Dams were allowed to give birth, at which
time pups were counted, sexed and examined grossly and maternal and pup weights were
recorded. Pup body weights were also measured on PND 1, 2, 3, 6, 10, 14, 19, and 21. Upon
weaning on postnatal (PND) 21, one rat/sex/litter was tested for neuromotor ability (Rotarod
testing on 2 consecutive days at 16 weeks of age), motor activity in an open field (on
2 consecutive days at age 17 weeks), learning and memory (Morris Water Maze, in which a
hidden platform must be located, beginning at age 3 weeks and testing periodically up to age
19 weeks). The remaining pups were sacrificed and necropsied at this time. Reflex ontogeny
and sexual maturation of the offspring selected for testing were recorded. All dams were
sacrificed and necropsied at PND 21 and uterine implantation sites were counted.
Exposure to DAWS resulted in reduced maternal body-weight gain during the exposure
period (26% below controls,/? = 0.007) (Hass et al., 2001). While litter sizes were smaller and
postimplantation loss higher in the exposed rats than in controls, neither change was statistically
significant. Birth weight of exposed pups was higher than controls, but there were no
body-weight differences during lactation or postweaning. Reflex development and sexual
maturation occurred normally in exposed rats, and neither neuromotor ability nor motor activity
was significantly affected (p < 0.05) by treatment. In the tests of learning and memory, however,
significant differences between exposed and control offspring were observed. When rats were
tested at age 2 months for recall of maze information learned at age 1 month, exposed male rats
took longer to locate a hidden platform (p = 0.022). When reversal learning was tested (platform
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relocated), latency (time to find the hidden platform) and path length (distance traveled to hidden
platform) were significantly higher in exposed female rats (p < 0.05). Finally, when rats were
tested for memory of the water maze at age 19 weeks, both sexes (when combined) showed
significantly increased latency (p = 0.019); when analyzed separately by sex, the difference was
borderline significant in females and not significant in males. The exposure concentration in this
study (4679 mg/m3) is both a maternal and a developmental LOAEL based on decreased
body-weight gain in dams and effects on memory and learning in offspring. No NOAEL can be
identified from this study.
Other Studies
Genotoxicity—Stoddard Solvent IIC was not mutagenic in Salmonella typhimurium
strains TA97, TA98, TA100, and TA1535, with and without rat or hamster S9 mix (NTP, 2004).
This mixture did not induce an increase in the frequency of micronucleated peripheral blood
erythrocytes in B6C3F1 mice exposed for 3 months to concentrations from 138 to 2200 mg/m3.
In its review of other genotoxicity assays, NTP (2004) did not provide any other data on white
spirit/Stoddard Solvent of low aromatic content.
In their review of industry studies of isoparaffinic hydrocarbons, Mullin et al. (1990)
reported that Isopar L, Isopar G, and Soltrol 1303 were not mutagenic in S. typhimurium strains
TA98, TA100, TA1535, TA1537, or TA1538 with or without S9. In addition, Isopar G gave
negative results in tests for DNA damage in Pol A -Escherichia coli and for mutagenicity in
E. coli strain WP2. Isopar G did not induce micronuclei in erythrocytes of mice treated
intraperitoneally and was not mutagenic in rats in a dominant lethal test. Soltrol 130 tested
negative in the mouse lymphoma assay for forward mutations and in an assay for sister
chromatid exchanges in Chinese hamster ovary (CHO) cells (reviewed by Mullin et al., 1990).
Mechanistic Studies—Lam et al. (1992) observed dose-related increases in levels of
reduced glutathione in brain tissue removed from male Wistar rats after 3 weeks of inhalation
exposure (6 hours/day, 7 days/week) to DAWS (<0.4% aromatic) at concentrations of 2339 or
4679 mg/m3. Increased generation of reactive oxygen species was observed in hippocampal
fractions from rats exposed to the higher concentration. These findings suggest a possible
mechanism for neurotoxicity of DAWS.
To further evaluate the kidney effects they observed after exposing rats to isoparaffinic
hydrocarbons, Phillips and Egan (1984b) and Phillips and Cockrell (1984) exposed groups of
50 male and female F344 rats to concentrations of 0, 1830, or 5480 mg/m3 via inhalation for
6 hours/day, 5 days/week, for up to 8 weeks. Kidney function was assessed through urinalysis,
hematology, serum chemistry, creatinine clearance, urine-concentrating ability and kidney
weights, and both light and electron microscopy of the kidneys. Ability to concentrate urine was
reduced in male rats at both exposure levels after 4 and 8 weeks of exposure and in
high-exposure males after the 4-week recovery period; females were not affected. At both
exposure concentrations, increases in urinary levels of glucose and protein were observed in
males after 4 and 8 weeks of exposure, but not after the recovery period. Excretion of epithelial
cells in the urine was markedly increased in male rats exposed to both concentrations after 4 and
8 weeks of exposure, but not after the 4-week recovery. Creatinine clearance rates were reduced
3Mullin et al. (1990) indicated a carbon range of C10-C11 for Isopar G, CI 1-C13 for Isopar L, and C10-C13 for
Soltrol 130. Aromatic content was not reported.
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only in the high-concentration group in male rats exposed for 8 weeks. Statistically significant
(p < 0.05) concentration- and time-related changes in serum chemistry parameters (reduced
glucose, increased BUN and creatinine) were observed in male—but not female—rats after both
4 and 8 weeks of exposure. Clinical chemistry parameters were comparable to controls in treated
rats after 4 weeks of recovery.
Relative kidney weights were increased over controls in both groups of treated males
throughout the study, while absolute kidney weights were increased in high-concentration males
only (Phillips and Egan, 1984b; Phillips and Cockrell, 1984). The increase in relative kidney
weight persisted through the recovery period in high-concentration males. In females, relative
kidney weights were increased at the high concentration after 8 weeks. Microscopic examination
of kidneys revealed increased incidence and severity of regenerative epithelium, tubular
dilatation with intratubular protein, and protein droplets in male rats; the severity increased with
time among treated males. Exposure-related changes in these findings were not observed in
females. Treated male rats also exhibited tubular nephrosis, lymphoid infiltration of the renal
interstitium, and thickening of the tubular basement membranes. Electron microscopy of the
protein droplets showed electron dense, angular, crystalline structures surrounded by remnants of
membrane-bound phagolysosomes. Focal loss of brush border and degeneration and sloughing
of necrotic cells were also shown.
In a series of experiments aimed at exploring the nature of the renal effects of
isoparaffinic hydrocarbons, Viau et al. (1986) exposed Sprague-Dawley rats to Shell Sol TD
(consisting of C10-C12 isoparaffins) for 8 hours/day, 5 days/week, for up to 16 months.
Exposure concentrations were 0, 580 or 6500 mg/m3. In one experiment, groups of 24 male rats
were exposed to 0 or 6500 mg/m3 for 46 or 68 weeks. In a second experiment, 12 rats/sex were
exposed to these concentrations for 13 weeks followed by a 6-week recovery period. A third
experiment involved exposure of groups of 12 male rats to 0 or 580 mg/m3 for 16 weeks.
Finally, groups of 6 male and 5-6 castrated male rats were exposed to 0 or 6500 mg/m3 for
5.5 weeks. Urine was collected at study intermittently for evaluation of enzymes
(B-N acetyl-D-glucosaminidase and lactate dehydrogenase [LDH]) and proteins (a2U-globulin and
albumin). Tests of renal function (urinary concentration, acidification, sodium retention, and
glomerular filtration rate) were performed. Histopathology evaluation was performed on animals
exposed for 5.5, 46 weeks or 68 weeks of exposure, including Mallory-Heidenhain (M-H)
staining for hyaline droplets. Subgroups of rats treated for 68 weeks were treated with
3H-thymidine for evaluation of kidney cortex labeling index.
All male rats—except the castrated ones—exposed at the high concentration showed a
marked increase in the urinary excretion of lactate dehydrogenase (LDH) (Viau et al., 1986).
Albuminuria was also observed in male rats, but the difference from control declined over time
due to the effect of age-related chronic progressive nephrosis in the controls. Functional tests
showed that exposure at the high concentration decreased the ability to concentrate urine and
reduced capacity to reduce sodium loss during reduced sodium intake. Glomerular filtration rate
was slightly reduced (6% less than controls,/? < 0.05) in intact males exposed to the high
concentration. While urinary clearance and reabsorption of a2U-globulin were unaffected by
exposure in all male rats, serum and kidney concentrations of this protein were much higher
noncastrated exposed male rats than in unexposed controls. After exposure for 5.5, 46, or
68 weeks, numerous hyaline droplets were observed in intact male rats using M-H staining.
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Kidney histopathology (zones of tubular dilatation filled with granular material at the
cortico-medullary junction) was observed in the male rats treated at the high concentration for
5.5 weeks but not in the rats exposed for longer durations. The kidney cortex labeling index was
not different in the animals treated for 46 or 68 weeks.
In the NTP (2004) chronic study, a separate study of renal toxicity in rats was performed,
in which 10 rats/sex were exposed to 0, 138, 550, or 1100 mg/m3 Stoddard Solvent IIC
(NTP, 2004). At sacrifice after 13 weeks, the kidneys were weighed and examined
microscopically, and the a2U-globulin and protein content of the right kidneys was measured.
Cell proliferation in the left kidney was measured as BrdU uptake. Significant, exposure-related
increases in both number of labeled cells and labeling index were observed in male rats exposed
to 550 or 1100 mg/m3 but not in females at any concentration. Overall soluble protein content
was not changed in an exposure-related fashion, but the a2U-globulin content was significantly
increased over controls in the mid- and high-exposure males and in high-exposure females.
Histopathology examination of treated males indicated concentration-related increases in the
severity of hyaline droplets and increased incidences of granular casts (550 and 1100 mg/m3),
cortical tubule degeneration (1100 mg/m3) and cortical tubule regeneration (550 and
1100 mg/m3). These changes were not observed in females. The study authors considered the
renal changes to be characteristic of male-rat specific a2U-globulin nephropathy; however, a
mode of action analysis was not conducted.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL
RfD VALUES FOR MIDRANGE ALIPHATIC HYDROCARBON STREAMS
Because the toxicity data based on the three unpublished studies (Anonymous, 1990,
1991a,b) are not peer-reviewed, no provisional chronic or subchronic RfDs are developed.
However, the Appendix of this document contains screening chronic and subchronic p-RfD
values that may be useful in certain instances. Please see the attached Appendix A for details.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION p-RfC VALUES FOR MIDRANGE ALIPHATIC HYDROCARBON
STREAMS
Inhalation studies available for use in developing subchronic and/or chronic provisional
RfCs (p-RfC) for midrange aliphatic hydrocarbon streams include chronic bioassays of Stoddard
Solvent IIC in rats and mice (NTP, 2004); a chronic study of neurophysiological and
neurobehavioral effects in rats exposed to DAWS (Lund et al., 1996); subchronic toxicity studies
of Stoddard Solvent IIC in rats and mice (NTP, 2004); a subchronic toxicity study of DAWS and
IPH in rats (Phillips and Egan, 1984a); an unpublished subchronic study of ShellSol TD in rats
(Shell Research Limited, 1980); and a developmental neurobehavioral toxicity study of DAWS
in rats (Hass et al., 2001). An unpublished developmental toxicity study by Exxon Corp.
identified a freestanding NOAEL for maternal and developmental effects (5485 mg/m3);
however, the original study was not located and the available information is derived from
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secondary sources, precluding it for use in p-RfC derivation. All of the remaining studies were
generally well conducted, with adequate numbers of animals and appropriate reporting. Table 6
summarizes the available inhalation noncancer dose-response information.
To provide a basis for comparing the studies, LOAEL and NOAEL values were adjusted
for continuous exposure and then converted to human equivalent concentrations (HEC). The
mixtures were treated as Category 3 gases if the observed toxicological effect was
extrarespiratory and as Category 1 gases if the observed effect was in the respiratory tract
(U.S. EPA, 1994b). Only one study (NTP, 2004 subchronic study in rats) documented
respiratory tract effects (nasal goblet cell hypertrophy) at the lowest concentration and is selected
as the critical effect for the derivation of the subchronic p-RfD. For this LOAEL and NOAEL,
the HEC was derived by multiplying the adjusted animal effect level by an interspecies
dosimetric adjustment for effects in the extrathoracic area of the respiratory tract, according to
the following calculation (U.S. EPA, 1994b):
RGDR(ET) = (M Va - SWMV. - S,)
where
RGDR(ET)	= regional gas dose ratio for the extrathoracic area of the respiratory tract
MVa	= animal minute volume (rat = 0.167 L/min)
MVh	= human minute volume (13.8 L/min)
Sa	= surface area of the extrathoracic region in the animal (rat =15 cm2)
Sh	= surface area of the extrathoracic region in the human (200 cm2).
Using default values for surface area and human minute volume, along with the rat
minute volume estimated using the female rat body weight and recommended algorithm (all
provided in U.S. EPA, 1994b), the RGDR(ET) = 0.16 for nasal effects in rats, calculated as
follows:
RGDR(ET) = (MVa - Sa)/(MVh - Sh)
= (0.167 L/min 15 cm2) / (13.8 L/min 200 cm2)
= 0.011 L/min-cm2 0.069 L/min-cm2
= 0.16
All of the other studies identified extrarespiratory effects and the dosimetric adjustments
were made using the ratio of blood:gas partition coefficients. Blood:gas partition coefficients for
the pertinent mixtures were not located. In a pharmacokinetic model of white spirit,
Hissink et al. (2007) identified //-decane as the predominant nonaromatic compound in white
spirit and reported blood:gas partition coefficients of 21 and 37 for rats and humans,
respectively. Other coefficients for //-decane were also located. Imbriani et al. (1985) reported a
human blood:gas partition coefficient of 84 for humans. Meulenberg and Vijverberg (2000)
reported a value of 17 for decane in rats, citing a 1994 study. The values reported by
Hissink et al. (2007) were chosen over the other options because the estimations for humans and
rats were made using the same protocols; the resulting ratio of partition coefficients was
0.57 (21/37). This ratio was selected to represent the partitioning of Stoddard Solvent IIC and
DAWS, as both mixtures are white spirits with low aromatic content. The composition of
Shell Sol TD contained a greater proportion of higher carbon-range constituents (-16% C10,
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Table 6. Summary of Inhalation Noncancer Dose-Response Information
Species
Sex
Exposure
Concentration
(mg/m3)
Exposure
Regimen
NOAEL
(mg/m3)
LOAEL
(mg/m3)
Responses
Comments
Reference
Subchronic
Rat
M/F
0, 138, 275, 550,
1100 or 2200
6 hr/d,
5 d/wk
for
14 weeks
550
1100
Nasal goblet cell hypertrophy in
females
Stoddard Solvent IIC (//-paraffins,
isoparaffins and cycloparaffins;
C10-C13; <1.0% aromatic).
Minimal LOAEL.
NTP, 2004
Rat
M/F
0, 2529, 5200,
10,186
6 hr/d,
5 d/wk
for
13 weeks
2529
5200
Lethargy at highest
concentration in both sexes;
serum chemistry changes and
increased liver weights in
females
Shell Sol TD (primarily
isoparaffins; -16% C10, 38.7%
Cll and 44.4% C12).
Shell Research
Limited, 1980
Rat
M/F
0, 1970, 5610
6 hr/d,
5 d/wk
for
12 weeks
5610
NA
None
Dearomatized white spirit (58%
paraffins, 42% naphthenes;
C11-C12; <0.5% aromatics).
Phillips and
Egan, 1984a
Rat
M/F
0, 1910, 5620
6 hr/d,
5 d/wk
for
12 weeks
5620
NA
None
Isoparaffinic hydrocarbons
(isoparaffins; C10-C11).
Phillips and
Egan, 1984a








Mouse
M/F
0, 138, 275, 550,
1100 or 2200
6 hr/d,
5 d/wk
for
14 weeks
NA
2200
Increased absolute and relative
liver weight (>10 %)
Stoddard Solvent IIC (//-paraffins,
isoparaffins and cycloparaffins;
C10-C13; <1.0% aromatic).
NTP, 2004
Chronic
Rat
M/F
0, 138 550, 1100
(M); 0, 550, 1100
or 2200 (F)
6 hr/d,
5 d/wk
for
2 years
138
550
Adrenal medullary hyperplasia
in males
Stoddard Solvent IIC (//-paraffins,
isoparaffins and cycloparaffins;
C10-C13; <1.0% aromatic).
NTP, 2004
Rat
M
0, 2339, 4679
6 hr/d,
5	d/wk
for
6	months
NA
2339
Neurophysiological changes
(increased amplitude of evoked
potentials and auditory brainstem
response)
Dearomatized white spirit.
Carbon range and aromatic
content not specified. Effects
evaluated 3 months after exposure
concluded.
Lund et al., 1996
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Table 6. Summary of Inhalation Noncancer Dose-Response Information
Species
Sex
Exposure
Concentration
(mg/m3)
Exposure
Regimen
NOAEL
(mg/m3)
LOAEL
(mg/m3)
Responses
Comments
Reference
Mouse
M/F
0,550, 1100 or
2200
6 hr/d,
5 d/wk
for
2 years
1100
2200
Increased incidence of
eosinophilic foci in females
Stoddard Solvent IIC (//-paraffins,
isoparaffins and cycloparaffins;
C10-C13; <1.0% aromatic).
NTP, 2004
Reproductive/Developmental
Rat
F
0, 1828, 5485
6 hr/d on
GD 6-15
5485
NA
No maternal or developmental
effects
Isopar G (C10-C11). Unpublished
data. Summary based on reviews
by Mullin et al. (1990) and
TPHCWG (1997). Inadequate
data for use in p-RfC derivation.
Unpublished
study by Exxon
Corp., 1988;
reviewed by
Mullin et al.,
1990
Rat
F
0, 4679
6 hr/d on
GD 7-20
NA
4679
Decreased body-weight gain in
dams and neurobehavioral
effects in offspring
Dearomatized white spirit
(<0.4% aromatic). Carbon range
not specified.
Hass et al., 2001
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38.7% CI 1, and 44.4% C12) than white spirits and no data were found on the partitioning of CI 1
or C12 compounds; the default ratio of 1.0 was used for this mixture. In the absence of a
blood:gas partition coefficient for mice, the default ratio of 1.0 was used to perform the
dosimetric adjustment for the NTP (2004) study in mice. Table 7 shows the NOAEL and
LOAEL values from the pertinent studies along with the NOAELrec and LOAELrec
calculations.
Subchronic p-RfC
Among the subchronic and developmental toxicity studies, the lowest LOAELrec
(31 mg/m3; see Table 7 for calculation) was identified for nasal lesions (goblet cell hypertrophy)
in rats exposed subchronically (NTP, 2004). Goblet cell hypertrophy was significantly increased
in both male and female rats in a dose-related fashion in the subchronic NTP study. Nasal goblet
cells in mammals, including humans, produce mucous in the upper airways, and effects on the
nasal mucociliary system, including goblet cell hypertrophy and/or hyperplasia, are believed to
be sensitive indicators of toxicity or injury (Harkema et al., 2006; Schwart et al., 1994).
Hypertrophy of these cells may represent an early response to an inhaled irritant. Although an
increased incidence of nasal goblet cell hypertrophy was not observed in the chronic NTP study
of Stoddard Solvent IIC, this does not mean the observations in the subchronic study are not
relevant. The absence of this effect after chronic exposure may reflect the development of
tolerance to the chemical insult, or this effect could be concentration-dependant rather as
time-dependent. Alternatively, in a chronic study that spans the lifetime of the animal tested,
age-related changes may mask treatment-related effects that may be evident in a subchronic
study. Consequently, the nasal effects in rats observed in the subchronic study (NTP, 2004) were
considered relevant for use in deriving the subchronic p-RfC.
To select a POD for subchronic p-RfC derivation, the incidence of goblet cell
hypertrophy in female rats (see Table 2) was modeled using U.S. EPA's Benchmark Dose
Software (v. 1.4.1c). Appendix B provides details of the modeling effort and the selection of the
best fitting model. The best-fitting model, as assessed by AIC (model with lowest AIC after
excluding an outlier [BMCLio of 131 mg/m3]) was the logistic model. The BMCio and BMCLio
predicted by this model for the nasal lesion data are 597 and 410 mg/m3, respectively. The
BMCLio was adjusted to an equivalent continuous exposure concentration as follows:
BMCLioadj = BMCLio x 6/24 hours x 5/7 days
= 410 mg/m3 x 6/24 x 5/7
= 73 mg/m3
The BMCLiohec was then calculated using the RGDR value of 0.16 calculated earlier for
the nasal effects in rats. The BIVICLiohec ^vas thus calculated as BIVICLioadj (73 mg/m3) x 0.16
= 12 mg/m3. The BMCLiohec (12 mg/m3) was used as the POD for the subchronic p-RfC.
The subchronic p-RfC for midrange aliphatic hydrocarbon streams is derived as follows:
Subchronic p-RfC = BMCLiohec ^ UF
= 12 mg/m3 -100
= 0.1 or 1 x 10"1 mg/m3
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Table 7. Calculation of Human Equivalent Concentrations
Study
Species
Effect
Effect Level
(mg/m3)
Duration-Adjusted
Effect Level3
(mg/m3)
Dosimetric
Adjustment
Human Equivalent
Concentration13
(mg/m3)
Subchronic Exposure
NTP, 2004
Rat
Nasal goblet cell
hypertrophy in females
LOAEL = 1100
NOAEL = 550
LOAELADj = 196
NOAELadj = 98
0.16°
LOAELhec =31
NOAELhec = 16
Shell Research Limited, 1980
Rat
Lethargy at highest
concentration in both
sexes; serum chemistry
changes and increased
liver weights in females
LOAEL = 5200
NOAEL = 2529
LOAELadj = 929
NOAELadj = 452
1.0d
LOAELhec =929
NOAELhec =452
Chronic Exposure
NTP, 2004
Rat
Adrenal medullary
hyperplasia in males
LOAEL = 550
NOAEL = 138
LOAELadj — 98
NOAELadj = 25
0.57d
LOAELhec — ^6
NOAELhec = 14
Lund et al., 1996
Rat
Neurophysiological
changes (increased
amplitude of evoked
potentials and auditory
brainstem response)
LOAEL = 2339
No NOAEL
LOAELadj = 418
0.57d
LOAELhec =238
NTP, 2004
Mouse
Increased incidence of
eosinophilic foci in
females
LOAEL = 2200
NOAEL = 1100
LOAELadj = 393
NOAELadj = 196
1.0d
LOAELhec =393
NOAELhec = 196
Reproductive/Developmental Toxicity
Hass et al., 2001
Rat
Decreased body-weight
gain in dams and
neurobehavioral effects
in offspring
LOAEL = 4679
No NOAEL
LOAELadj = 1170
0.57d
LOAELhec ~~ 667
aAdjusted for continuous exposure using exposure regimen shown in Table 6 (example: LOAELadj =196 mg/m3 = 1100 mg/m3 x 6 hrs/24 hrs x 5
days/7 days)
bProduct of duration-adjusted effect level and dosimetric adjustment factor (example: LOAELhec = 31 mg/m3 =196 mg/m3 x 0.16)
°RGDR for extrathoracic respiratory tract effects; see text for details
dRatio of blood:gas partition coefficients for extrarespiratory effects; see text for details
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The composite UF of 100 is composed of the following:
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating variability in human populations are
lacking.
•	UFa: An UF of 3 (10°5) is applied to account for interspecies extrapolation
(toxicodynamic portion only) because a dosimetric adjustment was made.
•	UFd: An UF of 3 (10°5) is applied for database deficiencies. The database for
these mixtures includes subchronic and chronic toxicity studies in two species, a
chronic neurotoxicity study in rats, a developmental neurotoxicity study in rats,
and limited information on a developmental toxicity study in rats. The database
lacks a multigeneration reproductive toxicity study. Evidence that subchronic
exposure to Stoddard Solvent IIC affects sperm motility in rats and mice and
testes weight in rats (NTP, 2004) highlights the need for additional study of
potential reproductive effects.
Confidence in the principal study (NTP, 2004) is high. The study used adequate numbers
of animals, employed a wide range of exposure concentrations, and measured a variety of
endpoints. Confidence in the database is medium because there are no multigenerational
reproductive toxicity studies and there are limited developmental toxicity data. Confidence in
the subchronic p-RfC is medium.
Chronic p-RfC
Among all of the available toxicity studies, the lowest LOAELrec (31 mg/m3) is
identified for nasal goblet cell hypertrophy in rats exposed subchronically (NTP, 2004). The
LOAELrec for adrenal hyperplasia in male rats exposed chronically was only slightly higher
(56 mg/m3). To determine whether the adrenal effects in chronically exposed male rats would
result in a lower POD for the chronic p-RfC derivation, the incidence of adrenal hyperplasia in
male rats (see Table 4) was modeled using U.S. EPA's Benchmark Dose Software (v. 1.4.1c).
As noted earlier in the description of the chronic rat study (NTP, 2004), the incidence of adrenal
hyperplasia in male rats of the highest exposure group (1100 mg/m3) was not increased over
controls, and the incidence at this concentration was lower than that observed at 550 mg/m3.
Because the highest dose is not part of the dose-response relationship (the effect levels were
determined at the lower dose levels) or is not based on the treatment-related effect, this exposure
group (1100 mg/m3) is not included in the dose-response modeling. Appendix B provides details
of the modeling effort and the selection of best-fitting model. The logistic model provided the
best fit according to model selection guidance given by U.S. EPA (2000). The BMCio and
BMCL io predicted by this model for the adrenal hyperplasia data are 210 and 144 mg/m3,
respectively. The BMCLio was first adjusted to an equivalent continuous exposure concentration
as follows:
BMCLioadj = BMCLio x 6/24 hours x 5/7 days
= 144 mg/m3 x 6/24 x 5/7
= 26 mg/m3
The BMCLiohec was then calculated using the ratio of blood:gas partition coefficients
(0.57) calculated earlier for rats. The BMCLiohec was, thus, calculated as BMCLioadj
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(26 mg/m3) x 0.57 =15 mg/m3. This value is similar to the BMCLiohec calculated for nasal
goblet cell hypertrophy in rats exposed sub chronically (12 mg/m3). These two values of
BMCL iohec from the subchronic (12 mg/m ) and chronic (15 mg/m ) studies are potential PODs.
Because the lower value (12 mg/m3) is considered to be a more sensitive indicator of midrange
aliphatic hydrocarbon streams exposure, and is not likely to be time-independent, the POD is
chosen as 12 mg/m3 based on the nasal effect for the derivation of chronic p-RfC. Use of the
lower value ensures that the resulting p-RfC is protective for both nasal and adrenal lesions. The
chronic p-RfC for midrange aliphatic hydrocarbon streams is derived as follows:
Chronic p-RfC = BMCLiohec UF
= 12 mg/m3 - 100
= 0.1 or 1 x 10"1 mg/m3
The composite UF of 100 was composed of the following:
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for variability in human populations are lacking.
•	UFa: An UF of 3 (10°5) is applied to account for interspecies extrapolation
(toxicodynamic portion only) because a dosimetric adjustment was made.
•	UFd: An UF of 3 (10°5) for database deficiencies is applied. The database for
these mixtures includes subchronic and chronic toxicity studies in two species, a
chronic neurotoxicity study in rats, a developmental neurotoxicity study in rats,
and limited information on a developmental toxicity study in rats. The database
lacks a multigenerational reproductive toxicity study. Evidence that subchronic
exposure to Stoddard Solvent IIC affects sperm motility in rats and mice and
testes weights in rats (NTP, 2004) highlights the need for additional study of
potential reproductive effects.
•	UFS: An UF of 1 for subchronic-to-chronic extrapolation is applied. Although the
POD was derived from a subchronic study, no UF is included for extrapolation
from subchronic-to-chronic exposure because nasal goblet cell hypertrophy was
not observed in rats exposed under equivalent conditions in a chronic study
(NTP, 2004). No duration extrapolation is necessary for this critical effect.
As stated in the derivation of subchronic p-RfC, confidence in the principal study
(NTP, 2004) is high. Confidence in the database is medium because there are no
multigenerational reproductive toxicity studies and there are limited developmental toxicity data.
Confidence in the chronic p-RfC is medium as for the subchronic p-RfC.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
MIDRANGE ALIPHATIC HYDROCARBON STREAMS
Weight-of-Evidence Classification
Under EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is
"Suggestive Evidence for the Carcinogenic PotentiaF of Stoddard Solvent IIC and "Inadequate
Information to Assess the Carcinogenic PotentiaF of other mixtures described in this review.
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NTP (2004) tested Stoddard Solvent IIC in chronic inhalation carcinogenicity assays using
F344 rats and B6C3F1 mice. NTP (2004) concluded that there was "some evidence " of
carcinogenic activity for Stoddard Solvent IIC in male rats based on the dose-related increase in
adrenal pheochromocytomas and "equivocal evidence " of carcinogenic activity in female mice
based on a slightly increased incidence of hepatocellular adenomas. Testing of Stoddard Solvent
IIC for genotoxicity has given uniformly negative results (NTP, 2004).
Mode-of-Action Discussion
The U.S. EPA (2005) Guidelines for Carcinogen Risk Assessment defines mode of action
(MO A) 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 MOA. Examples of
possible modes of carcinogenic action include mutagenic, mitogenic, antiapoptotic (inhibition of
programmed cell death), cytotoxic with reparative cell proliferation and immunologic
suppression.
Very little information is available on the potential mode by which Stoddard Solvent IIC
increases the incidence of adrenal tumors in male rats. No effects on the adrenal glands were
reported in the one available subchronic toxicity study in rats (NTP, 2004). While there are
studies that suggest an association between nephropathy and the formation of adrenal
pheochromocytomas (NTP, 2004), statistical analysis for a correlation between these effects in
the study of Stoddard Solvent IIC failed to indicate such a relationship in this case. The slightly
increased incidence of hepatocellular adenomas in female mice was associated with body-weight
increases in the exposed females. No other information on potential mode of liver
carcinogenesis was identified. These limited data do not provide any basis for potential key
events in the MOA for either adrenal or hepatocellular tumors induced by Stoddard Solvent IIC.
Derivation of Provisional Cancer Values
Provisional Oral Slope Factor Derivation
There are no oral studies of Stoddard Solvent IIC; thus, a quantitative estimate of cancer
risk from oral exposure cannot be derived.
Provisional Inhalation Unit Risk Derivation
The data are considered adequate to develop a quantitative estimate of cancer risk from
inhalation exposure. However, because the WOE indicates "Suggestive Evidence for the
Carcinogenic Potential, " there is some uncertainty associated with the quantification. For these
reasons, Appendix A of this document contains a screening p-IUR that may be useful in certain
instances. Please see the attached Appendix for details.
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ATSDR (Agency for Toxic Substances and Disease Registry). 1995. Toxicological profile for
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Ernstgard, L., Iregren, A., Juran, S., Sjogren, B., van Thriel, C., Johanson, G. 2009b. Acute
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Hissink, A.M., J. Kruse, B.M. Kulig et al. 2007. Model studies for evaluating the
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Imbriani, M., S. Ghittori, G. Pezzagno et al. 1985. Urine/air partition coefficients for some
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Lam, H.R., A. Lof and O. Ladefoged. 1992. Brain concentrations of white spirit components
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Lund, S.P., L. Simonsen, U. Hass et al. 1996. Dearomatized white spirit inhalation exposure
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MADEP (Massachusetts Department of Environmental Protection). 2003. Updated petroleum
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sl c. gov/O sh Std_data/1915 1000. html.
Pedersen, L.M. and K.H. Cohr. 1984a. Biochemical pattern in experimental exposure of
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55:317-324.
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Pedersen, L.M. and K.H. Cohr. 1984b. Biochemical pattern in experimental exposure of
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Phillips, R.D. and V.Y.Y. Cockrell. 1984. Kidney structural changes in rats following
inhalation exposure to Cio - Cn isoparaffinic solvent. Toxicology. 33:261-273.
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white spirit and Cio - Cn isoparaffinic hydrocarbon in Sprague-Dawley rats. Fund. Appl.
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Phillips, R.D. and G.F. Egan. 1984b. Effect of C10-C11 isoparaffinic solvent on kidney
function in Fischer 344 rats during eight weeks of inhalation. Toxicol. Appl. Pharmacol.
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Schwartz L.W., F.F. Hahn, K.P. Keenan, et al. 1994. Proliferative lesions of the rat respiratory
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Shell Research Limited. 1980. The inhalation toxicity of Shellsol TD to rats following 13
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U.S. EPA. 1997. Health Effects Assessment Summary Tables (HEAST). FY-1997 Update.
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APPENDIX A. DERIVATION OF A SCREENING VALUE FOR
MIDRANGE ALIPHATIC HYDROCARBON STREAMS
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for mid range aliphatic hydrocarbon streams. However, information is available
for this chemical, 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 PPRTV documents 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.
Three screening values are presented in this Appendix: subchronic and chronic p-RfDs,
and an IUR. The NOAEL of 100 mg/kg-day identified in the two unpublished 90-day studies
(Anonymous 1990, 1991a) serve as the basis for development of screening subchronic and
chronic p-RfD. The BMCLiohec of 22 mg/m3 after duration and dosimetry adjustments from the
POD indentified in the NTP (2004) study serve as the basis for development of screening IUR.
Oral Toxicity Values
Subchronic Screening p-RfD
Available oral toxicity information on midrange aliphatic hydrocarbon streams is limited
to three unpublished studies on three different mixtures (Anonymous, 1990, 1991a,b). The
reports of these studies obtained for this review were missing data tables and appendices
reporting details of the findings described in the reports. Repeated efforts to obtain the complete
reports through a variety of sources were unsuccessful. In the absence of other studies with
which to assess the oral toxicity of midrange aliphatic hydrocarbon streams, the limited
unpublished studies were used for this Appendix; however, uncertainty in the resulting screening
values must be acknowledged.
Effect levels for these studies were identified based on tentative interpretations of the
effects described in the text, which, in turn, are supported by interpretations prepared by
MADEP (2003) and TPHCWG (1997) based on their reviews of the original reports. In
addition, because quantitative results were not available, BMD modeling of critical effects was
not possible for any of the studies.
As shown in Table 5, the LOAELs identified for all three studies were the same (500
mg/kg-day), and the effects are similar for the three mixtures (liver and/or kidney weight
increases, serum chemistry changes, hematology changes and/or hepatocellular hypertrophy).
Since Anonymous (1991b) failed to identify a NOAEL, Anonymous (1990, 1991a) are
considered as cocritical studies and the NOAEL (100 mg/kg-day) identified by Anonymous
(1990, 1991a) was selected as the POD. The screening subchronic p-RfD for midrange
aliphatic hydrocarbon streams is derived as follows:
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Screening Subchronic p-RfD = NOAEL UF
= 100 mg/kg-day 1000
= 0.1 or 1 x 10"1 mg/kg-day
The composite UF of 1000 is composed of the following UFs:
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating variability in human populations are
limited.
•	UFa: A factor of 10 is applied for animal-to-human extrapolation because data for
evaluating relative interspecies sensitivity are limited.
•	UFd: A factor of 10 is applied for database inadequacies because data for
evaluating developmental and reproductive toxicity for oral exposure are not
available.
Confidence in the critical studies is low, stemming in large part from the lack of data
tables and appendices necessary for an independent review of the study quality and findings.
Information in the studies indicates that adequate numbers of animals were used and thorough
toxicological evaluations were conducted; however, gavage errors occurred in two of the studies
(Anonymous, 1990, 1991b). Confidence in the database is low, reflecting the limited subchronic
toxicity data and developmental and reproductive toxicity studies. Confidence in the subchronic
p-RfD is low.
Chronic Screening p-RfD
The screening chronic p-RfD for midrange aliphatic hydrocarbon streams is derived
below:
Screening Chronic p-RfD = NOAEL UF
= 100 mg/kg-day ^ 10,000
= 0.01 or 1 x 10"2 mg/kg-day
The composite UF of 10,000 is composed of the following UFs:
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation as data for evaluating variability in human populations are limited.
•	UFa: A factor of 10 is applied for animal-to-human extrapolation because data for
evaluating relative interspecies sensitivity are limited.
•	UFd: A factor of 10 is applied for database inadequacies, as data for evaluating
developmental and reproductive toxicity for oral exposure are not available.
•	UFs: A factor of 10 is applied for using data from a subchronic study to assess
potential effects from chronic exposure because data for evaluating response after
chronic exposure are not available.
Confidence in the critical studies is low as stated in the derivation of a subchronic p-RfD.
Confidence in the database is low, reflecting the limited subchronic toxicity data, and lack of
chronic toxicity data and developmental and reproductive toxicity studies. Confidence in the
chronic p-RfD is low.
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Inhalation Cancer Risk
Screening Inhalation Unit Risk
The WOE for midrange aliphatic hydrocarbon streams is characterized as "Suggestive
Evidence of Carcinogenic Potential". The inhalation data are sufficient to derive a quantitative
estimate of cancer risk using BMD. Male F344 rats exhibited increased incidences of benign or
benign and malignant (combined) pheochromocytomas of the adrenal glands in a chronic
bioassay (NTP, 2004). The incidences of benign or benign and malignant tumors were
significantly increased at the mid- and high-exposure levels (550 and 1100 mg/m3). While the
incidence of hepatocellular adenomas was increased in female mice exposed in the companion
study (NTP, 2004), the increase was statistically significant only at the highest concentration
(2200 mg/m3). Because adrenal tumors in male rats were induced at a much lower concentration
(550 mg/m3), the IUR is derived using the adrenal tumor data.
The MOA for adrenal tumors produced by Stoddard Solvent IIC has not been fully
elucidated. Although the available genotoxicity data do not suggest a direct genotoxic action, the
contribution of a linear MOA to induction of adrenal tumors cannot be ruled out based on
available data; thus, a linear approach was applied. The dose-response data used in the
quantitative cancer assessment are shown in Table A-l.
Table A-l. Dose-Response Data for Adrenal Tumors in Male F344 Ratsa
Exposure Concentration (mg/m3)
Incidence of Benign or Malignant
Pheochromocytomas
0
6/50
138
9/50
550
13/50
1100
19/50
aNTP, 2004
Dose-response modeling of the data in Table A-l was performed to obtain a point of
POD for a quantitative assessment of cancer risk. The POD is an estimated dose (expressed in
human-equivalent terms) near the lower end of the observed range that marks the starting point
for extrapolation to lower doses. Appendix C provides details of the modeling effort and the
selection of the best fitting model. The multistage-cancer model with 1-degree polynomial was
selected based on U.S. EPA (2000) guidance. The BMCio and BMCLio predicted by this model
for the adrenal tumor data are 340 and 216 mg/m3, respectively. The BMCLio (216 mg/m3) was
used as the POD for the screening IUR. The BMCLio of 216 mg/m3 was first adjusted to an
equivalent continuous exposure concentration (216 mg/m3 x 6/24 hours x 5/7 days = 39 mg/m3).
The adjusted concentration was then converted to a human equivalent concentration. Because
adrenal tumors represent extrarespiratory effects, the mixture was treated as a Category 3 gas and
the ratio of blood:gas partition coefficients was used to make the dosimetric adjustment. As
noted earlier, blood:gas partition coefficients for n-decane (21 and 37 for rats and humans,
respectively) published by Hissink et al. (2007) were used to represent the partitioning of
Stoddard Solvent IIC; the ratio of coefficients was 0.57. The resulting BMCLiohec is 22 mg/m3
(39 mg/m3 x 0.57). The Screening p-IUR for midrange aliphatic hydrocarbon streams is
derived below:
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Screening p-IUR = 0.1BMCLiohec
= 0.1+22 mg/m3
= 4.5 x 10 3 (mg/m3)1
The IUR for Stoddard Solvent IIC should not be used with exposures exceeding the POD
(BMCLiohec = 22 mg/m3) because above this level the fitted dose-response model better
characterizes what is known about the carcinogenicity of Stoddard Solvent IIC.
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APPENDIX B: DETAILS OF BENCHMARK DOSE MODELING
FOR SUBCHRONIC AND CHRONIC p-RfCs
Subchronic p-RfC
Modeling Procedure for Dichotomous Data
The benchmark dose (BMD) modeling for dichotomous data was conducted with the
EPA's BMD software (BMDS version 2.1). For all the dichotomous data, the original data were
modeled with all the dichotomous models (i.e., Gamma, Multistage, Logistic, Log-logistic,
Probit, Log-Probit, Weibull, and Quantal linear models) available within the software with a
default benchmark response (BMR) of 10% extra risk. An adequate fit was judged based on the
goodness of fit p value (p > 0.1), scaled residual at the range of benchmark response (BMR), and
visual inspection of the model fit. Among all the models providing adequate data fit, the lowest
BMDL will be selected if the BMDLs estimated from different models if the range is not
sufficiently close; otherwise, the BMDL from the model with the lowest Akaike's Information
Criterion (AIC) would be considered appropriate for the data set.
Model-Fitting Results for Nasal Goblet Cell Hypertrophy in Female Rats Exposed for
13 Weeks (NTP\ 2004)
The data on nasal goblet cell hypertrophy in female rats are shown in Table 2 on page 19.
Exposure concentrations as reported in the study were used in the dose-response modeling.
Applying the modeling protocol outlined above, all models in the software provided adequate fits
to the data for the incidence of goblet cell hypertrophy in female rats (% p > 0.1) (see Table B-l).
Even though the BMCL values are not sufficiently close, the BMCL of 131 mg/m3 from either
the quantal linear or multistage (degree of polynomial = 1) model is considered as an outlier.
Excluding the BMCL of 131 mg/m3, the best-fitting model, as assessed by AIC (model with
lowest AIC) was the logistic model. The fit of the logistic model to the data is shown in Figure
B-l. The BMC cind BMCLio cissoci&ted with this model cire 597 cind 410 m^/m , respectively.
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Table B-l. Model Predictions for Nasal Goblet Cell Hypertrophy in Female Ratsa
Model
Degrees of
Freedom
x2
X2 Goodness
of Fit
/7-Value
AIC
BMC10
(mg/m3)
BMCL10
(mg/m3)
Logistic
4
2.84
0.58
40.96
596.65
409.76
Probit
4
3.01
0.56
41.11
546.12
378.87
Log-probit (slope >1)
3
2.29
0.51
42.19
801.84
502.66
Log-logistic (slope >1)
3
2.40
0.49
42.37
795.39
459.27
Gamma (power >1)
3
2.47
0.48
42.47
788.64
398.64
Weibull (power > 1)
3
2.73
0.43
42.95
720.44
285.42
Quantal Linear
5
5.78
0.33
43.65
198.21
130.87
Multistage (degree of
polynomial = l)b
5
5.78
0.3281
43.65
198.21
130.87
Multistage (degree of
polynomial = 2)b
4
3.24
0.52
41.74
516.08
200.19
Multistage (degree of
polynomial = 3)b
3
2.74
0.44
42.93
649.00
201.85
Multistage (degree of
polynomial = 4)b
3
2.74
0.44
42.93
649.00
191.83
Multistage (degree of
polynomial = 5)b
3
2.74
0.44
42.93
649.00
188.14
Quantal Linear
Invalid model choice per BMDS software
aNTP, 2004
'Degree of polynomial initially set to (n-1) where n = number of dose groups including control. Betas restricted
to >0.
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Logistic Model with 0.95 Confidence Level
Logistic
BMD Lower Bound
1
0.8
0.6
0.4
0.2
0
BMDL
BMD
0
500
1000
1500
2000
13:47 07/06 2000	Dose
BMCs and BMCLs indicated are associated with an extra risk of 10% and are in units of mg/m3.
Figure B-l. Fit of Logistic Model to Data on Goblet Cell Hypertrophy in Female Rats
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Logistic Model. (Version: 2.12; Date: 05/16/2008)
Input Data File: C:\USEPA\BMDS21Beta\Temp\2tmpl57D.(d)
Gnuplot Plotting File: C:\USEPA\BMDS21Beta\Temp\2tmpl57D.plt
Wed Jul 08 13:47:53 2009
BMDS Model Run
The form of the probability function is:
P[response] = 1/[1+EXP(-intercept-slope*dose)]
Dependent variable = Incidence
Independent variable = Dose
Slope parameter is not restricted
Total number of observations = 6
Total number of records with missing values = 0
Maximum number of iterations = 25 0
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
background =	0 Specified
intercept =	-2.86336
slope = 0.00208246
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
intercept	slope
intercept	1	-0.82
slope	-0.82	1
Interval
Variable
Limit
intercept
1.99765
slope
0.00389347
Parameter Estimates
95.0% Wald Confidence
Estimate	Std. Err.	Lower Conf. Limit Upper Conf.
-3.48793	0.760362	-4.97821
0.00261023	0.000654725	0.001327
Model
Analysis of Deviance Table
Log(likelihood) # Param's Deviance Test d.f. P-value
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FINAL
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Full model -16.4826
6



Fitted model -18.4789
2
3.99258
4

Reduced model -33.7401
1
34.515
5
<. i
AIC: 40.9578




Goodness of
Fit






Scaled
Dose Est. Prob. Expected
Observed
Size

Residual
0.0000 0.0297 0.297
0. 000
10

-0.553
138.0000 0.0420 0.420
1. 000
10

0.915
275.0000 0.0590 0.590
1. 000
10

0.551
550.0000 0.1138 1.138
0. 000
10

-1.133
1100.0000 0.3505 3.505
4.000
10

0.328
2200.0000 0.9050 9.050
9. 000
10

-0.054
0.407
Chi^2 =2.84
d.f. = 4
P-value
0.5848
Benchmark Dose Computation
Specified effect =
Risk Type	=
Confidence level =
BMD =
BMDL =
0.1
Extra risk
0.95
596.652
409.761
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Chronic p-RfC
Model-Fitting Results for Adrenal Medullary Hyperplasia in Male Rats Exposed for 2 Years
(NTP; 2004)
The data on adrenal hyperplasia in male rats exposed chronically to Stoddard Solvent IIC
are shown in Table 4. According to the study, exposure concentrations were used in the
dose-response modeling. As noted earlier in the description of the chronic rat study (i.e.,
NTP, 2004), the incidence of adrenal hyperplasia in male rats of the highest-exposure group (i.e.,
1100 mg/m3) was not increased over controls, and the incidence at this concentration was lower
than that observed at 550 mg/m3. Because the highest dose is not part of the dose-response
relationship (the effect levels were determined at the lower dose levels), or because it is not
based on the treatment-related effect, this exposure group (1100 mg/m3) is not included in the
dose-response modeling. Applying the modeling protocol outlined earlier, all of these models
provided adequate fit to the data for the incidence of adrenal hyperplasia in male rats (% p > 0.1)
(see Table B-2). The best-fitting model, as assessed by AIC, was the logistic model. The fit of
the logistic model to the data is shown in Figure B-2. The BMCio and BMCLio associated with
this model are 210 and 144 mg/m3, respectively.
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Table B-2. Model Predictions for Adrenal Hyperplasia in Male Rats
Model
Degrees
of
Freedom
2
X
2
X
Goodness
of Fit
/7-Value
AIC
BMCio
(mg/m3)
BMCL10
(mg/m3)
Logistic
1
0.01
0.9202
187.408
210.35
144.25
Probit
1
0.01
0.9062
187.412
205.74
139.53
Log-probit (slope >1)
1
0.06
0.8082
187.457
270.25
170.72
Multistage
(degree = l)a
1
0.08
0.7783
187.477
169.15
96.07
Log-logistic
(slope >1)
0b
0.00
NA
189.398
223.25
77.71
Gamma (power >1)
0b
0.00
NA
189.398
225.39
96.73
Weibull (power > 1)
ob
0.00
NA
189.398
227.56
96.73
Quantal Linear
Invalid model choice per BMDS software
aDegree of polynomial initially set to (n-1) where n = number of dose groups including control; model selected is
lowest degree model providing adequate fit. Betas restricted to >0.
bToo few dose groups to apply these models.
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Logistic Model with 0.95 Confidence Level
Logistic
0.6
0.5
0.4
0.3
0.2
BMDL
BMD
0.1
100
200
300
400
500
0
Dose
13:16 03/04 2008
BMCs and BMCLs indicated are associated with an extra risk of 10% and are in units of mg/m3.
Figure B-2. Fit of Logistic Model to Data on Adrenal Hyperplasia in Male Rats
Logistic Model. (Version: 2.12; Date: 05/16/2008)
Input Data File: C:\USEPA\BMDS21Beta\Temp\2tmpl67B.(d)
Gnuplot Plotting File: C:\USEPA\BMDS21Beta\Temp\2tmpl67B.plt
Wed Aug 12 16:05:55 2009
BMDS Model Run
The form of the probability function is:
P[response] = 1/[1+EXP(-intercept-slope*dose)]
Dependent variable = Incidence
Independent variable = Dose
Slope parameter is not restricted
Total number of observations = 3
Total number of records with missing values = 0
Maximum number of iterations = 25 0
Relative Function Convergence has been set to: le-008
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Parameter Convergence has been set to: le-008
Default Initial Parameter Values
background =	0 Specified
intercept =	-1.14386
slope = 0.00178243
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
intercept	slope
intercept 1	-0.74
slope -0.74	1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable	Estimate	Std. Err.	Lower Conf. Limit Upper Conf.
Limit
intercept	-1.17301	0.262986	-1.68845
0.657565
slope	0.00183216	0.000744182	0.000373592
0. 00329073
Model
Full model
Fitted model
Reduced model
Analysis of Deviance Table
#
Log(likelihood)
-91.6989
-91.7039
-94.7689
Param's
3
2
1
Deviance Test d.f.
0.0100324
6.14015
P-value
0.9202
0.04642
AIC:
187.408
Goodness of Fit
Scaled
Dose	Est._Prob. Expected Observed	Size	Residual
0.0000	0.2363	11.816 12.000	50	0.061
138.0000	0.2849	14.246 14.000	50	-0.077
550.0000	0.4588	22.938 23.000	50	0.018
Chi^2 = 0.01	d.f. = 1	P-value = 0.9202
Benchmark Dose Computation
Specified effect =	0.1
Risk Type	=	Extra risk
49

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Confidence level
BMD
BMDL
FINAL
9-30-2009
0.95
210.347
144.253
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APPENDIX C: DETAILS OF BENCHMARK DOSE MODELING
FOR INHALATION UNIT RISK
Model-Fitting Procedure for Cancer Incidence Data
The model-fitting procedure for dichotomous cancer incidence data is as follows. The
multistage-cancer model in the EPA Benchmark Dose (BMD) Software (version 2.1) is fit to the
incidence 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 selected, per U.S. EPA (2000) guidance. Goodness-of-fit is
assessed by the % test; adequate fit is indicated by ap-value greater than 0.1. In accordance with
U.S. EPA (2000) guidance, BMDs and lower one-sided confidence limits on the BMD (BMDLs)
associated with an extra risk of 10% are calculated.
Model-Fitting Results for Adrenal Tumors in Rats (NTP, 2004)
The incidence of benign and malignant adrenal pheochromocytomas in male rats exposed
for 2 years was modeled. The data on adrenal tumors in male rats are shown in Table 4 and
Table A-l. Exposure concentrations as reported in the study were used in the dose-response
modeling. Applying the modeling protocol outlined above, the multistage model with 1-degree
polynomial was the lowest degree polynomial providing adequate fit to the tumor data
(X P ^ 0.1) (see Table C-l). The fit of this model to the data is shown in Figure C-l. The
BMCio and BMCLio associated with this model are 340 and 216 mg/m3, respectively.
Table C-l. Model Predictions for Adrenal Tumors in Male Rats3
Model
Degrees
of
Freedom
2
X
2
1
Goodness
of Fit
p-Value
AIC
BMC10
(mg/m3)
BMCL10
(mg/m3)
Multistage (degree = l)b
2
0.12
0.94
211.66
339.95
215.68
Multistage (degree = 2)b
2
0.12
0.94
211.66
339.95
215.68
Multistage (degree = 3)b
2
0.12
0.94
211.66
339.95
215.68
aNTP, 2004
'Degree of polynomial initially set to (n-1) where n = number of dose groups including control. Betas restricted
to >0.
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Multistage Cancer Model with 0.95 Confidence Level
Multistage Cancer
Linear extrapolation
BMD Lower Bound
0.5
0.4
0.3
0.2
1
BMDL
BMD
0	200	400	600	800	1000
Dose
15:14 07/06 2009
BMCs and BMCLs indicated are associated with an extra risk of 10% and are in units of mg/m3.
Figure C-l. Fit of Multistage-Cancer Model (1-Degree Polynomial) to Data on Adrenal
Tumors in Male Rats
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Multistage Cancer Model. (Version: 1.7; Date: 05/16/2008)
Input Data File: C:\USEPA\BMDS21Beta\Data\3MulMidMul.(d)
Gnuplot Plotting File: C:\USEPA\BMDS21Beta\Data\3MulMidMul.plt
Wed Jul 08 15:14:06 2009
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
The parameter betas are restricted to be positive
Dependent variable = Incidence
Independent variable = Dose
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
Maximum number of iterations = 25 0
Relative Function Convergence has been set to: 2.22045e-016
Parameter Convergence has been set to: 1.49012e-008
****	We are sorry but Relative Function and Parameter Convergence	****
****	are currently unavailable in this model. Please keep checking	****
****	the web sight for model updates which will eventually	****
****	incorporate these convergence criterion. Default values used.	****
Default Initial Parameter Values
Background =	0.129941
Beta (1) = 0.00030685
Asymptotic Correlation Matrix of Parameter Estimates
Background	Beta(l)
Background	1	-0.69
Beta (1)	-0.69	1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable	Estimate	Std. Err.	Lower Conf. Limit Upper Conf.
Limit
Background	0.12 87 67	*	*	*
Beta (1)	0.00030993	*	*	*
* - Indicates that this value is not calculated.
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Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-103.772
-103.832
-109.05
Param's
4
2
1
Deviance Test d.f.
0.119374
10.5551
P-value
0.9421
0.01439
AIC:
211.663
Dose
Est. Prob.
Goodness of Fit
Expected
Observed
Size
Scaled
Residual
0.0000
138.0000
550.0000
1100.0000
0.1288
0.1652
0.2653
0.3805
6. 438
8.262
13.266
19.023
6. 000
9. 000
13.000
19.000
50
50
50
50
-0.185
0.281
-0.085
-0.007
Chi^2
0.12
d.f. = 2
P-value
0.9415
Benchmark Dose Computation
Specified effect =	0.1
Risk Type =	Extra risk
Confidence level =	0.95
BMD =	339.94 9
BMDL =	215.677
BMDU =	714.34
Taken together, (215.677, 714.34 ) is a 90	% two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 0.000463657
54

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