United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/043F
Final
9-28-2009
Provisional Peer-Reviewed Toxicity Values for
?7-Nonane
(CASRN 111-84-2)
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
n-NONANE (CASRN 111-84-2)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.S. EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1) U.S. EPA's Integrated Risk Information System (IRIS).
2) Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. EPA's Superfund
Program.
3) Other (peer-reviewed) toxicity values, including
~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~ California Environmental Protection Agency (CalEPA) values, and
~ EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in U.S. EPA's IRIS. PPRTVs are developed according to a
Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific
literature using the same methods, sources of data, and Agency guidance for value derivation
generally used by the U.S. EPA IRIS Program. All provisional toxicity values receive internal
review by two U.S. EPA scientists and external peer review by three independently selected
scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multiprogram consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all U.S. EPA programs, while PPRTVs are developed
specifically for the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
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and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. EPA programs or
external parties who may choose of their own initiative to use these PPRTVs are advised that
Superfund resources will not generally be used to respond to challenges of PPRTVs used in a
context outside of the Superfund Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the U.S. EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
No RfD, RfC, or carcinogenicity assessment for n-nonane is available on IRIS
(U.S. EPA, 2009). «-Nonane is not included on the Health Effects Assessment Summary Tables
(HEAST; U.S. EPA, 1997), the Drinking Water Standards and Health Advisory list (U.S. EPA,
2006), or the Chemical Assessments and Related Activities (CARA) list (U.S. EPA, 1991, 1994).
The Agency for Toxic Substances and Disease Registry (ATSDR) (2009) has not produced a
Toxicological Profile for //-nonane. Toxicological Profiles on mixtures containing //-nonane,
such as jet fuel JP-8 (ATSDR, 1998), and Total Petroleum Hydrocarbons (ATSDR, 1999), do not
derive oral or inhalation MRLs for any of the individual compounds. A chronic oral RfD of
1.017 mg/kg/day has been derived for //-nonane by Staats Creative Sciences (SCS) for the United
States Air Force (Staats, 1994) based on route-to-route extrapolation from an inhalation
concentration of 1600 ppm derived from a subchronic inhalation study in rats by Carpenter et al.
(1978). Although Staats (1994) used the 1600-ppm level as a NOAEL, Carpenter et al. (1978)
reported the NOAEL for subchronic inhalation of //-nonane vapor by rats to be 590 ppm based
on consistent suppression of weight gain and signs of toxic stress in rats exposed in the high-dose
group to 1600-ppm «-nonane vapor.
No Environmental Health Criteria Document is available for //-nonane from the World
Health Organization (WHO, 2009). The Occupational Safety and Health Administration
(OSHA, 2009) has not established a permissible exposure limit (PEL) for «-nonane. The
National Institute for Occupational Safety and Health (NIOSH, 2008) has set a recommended
exposure limit (REL) of 200 ppm (1,050 mg/m3) for «-nonane based on CNS effects, irritation of
the eyes, skin, nose, and throat and chemical pneumonitis (aspiration liquid). The American
Conference of Governmental Industrial Hygienists (ACGIH, 2007) recommends a threshold
limit value (TLV) of 200 ppm—also based on CNS effects. The carcinogenicity of «-nonane has
not been assessed by the International Agency for Research on Cancer (IARC, 2009) or the
National Toxicology Program (NTP, 2005, 2009).
To identify toxicological information pertinent to the derivation of provisional toxicity
values for //-nonane, literature searches were conducted in December 2007 using the following
databases: MEDLINE, TOXLINE (Special), BIOSIS, TSCATS 1/TSCATS2, CCRIS,
DART/ETIC, GENETOX, HSDB, RTECS, and Current Contents. A Voluntary Children's
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Chemical Evaluation Program (VCCEP) Tier 1 Pilot Submission on the //-Alkane Category from
the American Chemistry Council n-Alkane VCCEP Consortium (2004) was also reviewed for
relevant data. A final search for toxicological information was conducted for the period from
December 2007 and September 2009.
REVIEW OF PERTINENT DATA
Human Studies
No information was located regarding the subchronic or chronic oral or inhalation
toxicity of //-nonane in humans.
Animal Studies
Oral Exposure
Data on the subchronic oral effects of //-nonane in animals come from a single subchronic
study by Dodd et al. (2003). Dodd et al. (2003) treated groups of 10 male C57BL/6 mice and
10 female Fischer 344 rats with doses (neat) of 0, 100, 1000, or 5000 mg/kg-day of «-nonane
(99% purity) by gavage 7 days/week for 90 days. The test protocol required two rodent species
and both male and female animals. Because of a concern for the development of a-2u-globulin
nephropathy in male rats, only female rats were dosed. The study authors dosed only male mice.
The dosages were established based on a 7-day range-finding study conducted by the same
researchers, which are discussed in further detail below. Dodd et al. (2003) randomly assigned
mice and rats to dose groups (10/group). Due to unexpected mortality in the high-dose rats
during the first 4 days of dosing, two additional rats were assigned to this group. Animals were
allowed free access to food and water and were housed individually in plastic cages. Body
weights were determined and recorded immediately prior to the initiation of the study. Body
weights and food consumption were determined and recorded weekly thereafter. Animals were
fasted at least 12 hours prior to sacrifice following the 90-day exposure period.
Effects on general toxicity, neurobehavioral activity (grip strength and locomotor
activity), hematology (hematocrit [HCT], hemoglobin [HGB] concentration, erythrocyte count
[RBC], mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean
corpuscular hemoglobin concentration [MCHC], total and differential leukocyte count [WBC],
and platelet count), clinical chemistry (calcium, phosphorus, chloride, sodium, potassium,
glucose, alanine aminotransferase [ALT], aspartate aminotransferase [AST], y-glutamyl
transpeptidase, alkaline phosphatase [ALP], blood urea nitrogen [BUN], albumin, globulin, total
protein, creatinine, and total bilirubin), and organ weights (liver, kidneys, adrenals, gonads,
spleen, lungs, and brain) were evaluated in all animals (Dodd et al., 2003). In addition, a few
additional serum chemistry measurements of cholesterol, triglycerides, and magnesium were
made only in rats. Gross necropsy, including examination of the external surface of the body, all
the orifices, and the cranial, thoracic, and the abdominal cavities and their contents, were
conducted on each animal. Histopathologic examination of 32 tissues and organs, including any
gross lesions identified at necropsy, were conducted on all control and high-dose animals and on
"target" tissues from low- and mid-dose animals.
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Mice in the control, low-, and mid-dose groups did not exhibit any notable clinical signs
of toxicity during the 90-day exposure to //-nonane (Dodd et al., 2003). However, rats in the
control, low-, and mid-dose groups exhibited the occasional presence of dry red material around
the eyes. Both mice and rats in the high-dose group exhibited general signs of toxicity in the
form of wet urogenital/perianal areas, matted fur in the anal area, perianal alopecia,
perianal/hindlimb erythema, dark-colored urine, diarrhea, erythema/excreta at base of tail,
hunched posture, dry red material around the eyes and nose, lower jaw alopecia, and matted body
fur. In addition, mice at the high dose exhibited occasional redness and swelling of the penis and
scrotal area. Food consumption values and body-weight gains were not different from controls
for mice. Food consumption values were significantly (p < 0.01) decreased during the first two
weeks of the study for mid- and high-dose female rats. However, no significant differences in
body-weight gain compared to controls were observed. No statistical difference between
exposed and control animals in regard to grip strength was observed. There was a pattern of
decreased motor activity that was observed during the first 12 weeks of the study in male mice
and female rats dosed with //-nonane. A clear dose-response relationship, however, was not
observed.
Dodd et al. (2003) reported mortality in five high-dose rats within the first 10 days of the
study. Upon necropsy of these rats, gross and histologic lesions (pulmonary hemorrhage and
severe transmural hemorrhagic gastritis) were observed. The authors considered these lesions to
be caused by trauma during oral gavage. In addition, another high-dose rat died during Week 11,
and a mid-dose rat died during Week 13. These deaths were also attributed to dosing accidents.
Two high-dose mice, two mid-dose mice, and one control mouse also died before the end of the
90-day study. Again, hemorrhagic lesions were suggestive of dosing accidents.
Table 1 summarizes the statistically significant hematological changes observed in mice
and rats. Dodd et al. (2003) recognized that although statistically significant differences in two
hematology indices were observed among exposed animals compared to control animals, all the
values were well within normal limits for each species. Furthermore, Dodd et al. (2003) stated
that the occurrence of increased neutrophil percentage and corresponding decreased lymphocyte
percentage is consistent with the normal physiologic responses to stress and minor
inflammation—which, in turn, correlates with the histopathology alterations described below.
Statistically significant changes in serum chemistry in mice and rats are summarized in
Table 2. Similarly to the alterations in hematology, some changes in serum chemistry in exposed
animals were significantly different from control animals, but the values were well within normal
limits for each species and represent mild, clinically insignificant changes (Dodd et al., 2003).
Tables 3 and 4 summarize the mean absolute and relative organ weights for male mice
and female rats, respectively. As shown, absolute and relative (to body and to brain) liver
weights were significantly (p < 0.05) increased by 13-15% in female rats receiving
5000-mg/kg-day «-nonane and by 19-23% in male mice receiving 5000-mg/kg-day «-nonane.
Other noteworthy changes (p < 0.05), occurring only in female rats, were a 13-19% increase in
mean absolute and relative lung weight in the 5000-mg/kg-day group and smaller—but
apparently dose-related—changes (p < 0.05) in adrenal (11—24% increase) and ovary
(14-26%) decrease) weights in the 1000- and 5000-mg/kg-day groups.
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Table 1. Mean Hematologic Values of Male Mice and Female Ratsa
Parameter
0 mg/kg-day
100 mg/kg-day
1000 mg/kg-day
5000 mg/kg-day
Mice
Rats
Mice
Rats
Mice
Rats
Mice
Rats
RBC (106)
11.5 ± 1.2b
8.9 ±0.4
11.4 ±0.6
8.8 ±0.5
10.9 ±0.9
8.7 ±0.6
9.7 ± 1.5°
8.9 ±0.8
HGB (g/dl)
16.7 ±0.7
15.4 ±0.6
16 ±0.3
15.5 ±0.8
15.5 ±0.5
15.2 ± 1.0
14.5 ± 2.0d
15.5 ± 1.2
HCT (%)
53.7 ±5.1
47.2 ± 1.7
52.4 ±4.1
46.9 ±2.5
49.4 ±2.9
46.6 ±2.9
44.1 ±6.9d
47.2 ±3.8
WBC (103)
5.6 ± 1.3
6.8 ±0.8
7.1 ±2.6
8.7 ± 1.1°
5.9 ± 1.4
7.9 ± 1.5
7.6 ±2.0
9.6 ± 1.2°
Basophils (%)
1.2 ±2.0
0.1 ±0.1
0.6 ± 1.0
0.3 ±0.2
0.9 ± 1.4
0.2 ±0.2
0.5 ±0.6
0.8 ± 0.7°
Neutrophils (%)
9.6 ±5.5
21.1 ± 3.2
10.4 ± 8.1d
22.1 ±3.9
10.7 ± 5.5d
24.4 ±3.5
25.8 ± 10.9d
29.5 ± 7.3°
lymphocytes (%)
85.6 ±4.4
73.8 ±3.2
86.2 ±6.8
73.2 ±4
85.5 ±4.2
70.9 ±3.6
70.1 ± 14.5d
65.3 ± 6.9°
aDodd et al., 2003; C57BL/6 mice; Fisher 344 rats
bMean±SD
cp< 0.05 compared to control
dp < 0.01 compared to control
Table 2. Mean Serum Chemistry Values of Male Mice and Female Ratsa
Parameter
0 mg/kg-day
100 mg/kg-day
1000 mg/kg-day
5000 mg/kg-day
Mice
Rats
Mice
Rats
Mice
Rats
Mice
Rats
Chloride
(mmol/1)
115 ±4b
98.7 ± 1.3
115 ± 2
98.8 ± 1.9
113 ± lc
99.7 ±0.9
111 ± 2d
98.3 ±2.1
Total Protein
(g/dl)
5 ±0.3
6.3 ±0.2
4.8 ±0.3
6.3 ±0.2
4.8 ±0.1
5.9 ± 0.2°
4.6 ±0.3
6.1 ±0.3
AST (IU/1)
64.1 ±4.4
85.6 ±23
52.3 ±5.4
78.5 ±8.2
54.5 ± 13.5
83.1 ± 15
50.6 ± 5.6°
97.3 ± 15.3
AIT (IU/1)
16.8 ±6.0
48.8 ±4.1
15.8 ±7.3
47.9 ±7.2
24.5 ± 14.5
44.7 ±5.8
19.3 ±9.1
61.8 ±5C
A1P (IU/1)
98.3 ± 15
127 ± 13
96 ± 17.4°
124 ±21
89.5 ± 7.7d
113 ± 11
65.5 ± 18d
157 ±53
Triglycerides
(mg/dl)
NAe
62.2 ± 14.8
NA
69.4 ± 18.3
NA
49.8 ±6.7
NA
37.2 ± 11.4d
Cholesterol
(mg/dl)
NA
77.9 ±7.5
NA
79.1 ±5.1
NA
72.7 ±3.2
NA
64.5 ± 6.6c
Albumin (g/dl)
2.6 ±0.2
3.6 ±0.1
2.5 ±0.1
3.6 ±0.1
2.4 ± 0.1°
3.2 ± 0.2°
2.2 ± 0.2d
3.2 ± 0.2°
Total Bilirubin
(mg/dl)
0.4 ±0.1
0.3 ±0.1
0.3 ±0.1
0.3 ±0.1
0.3 ±<0.1
0.3 ±0.1
0.2 ± 0.1°
0.3 ±0.1
aDodd et al, 2003; C57B1/6 mice; Fisher 344 rats
bMean±SD
cp< 0.05 compared to control
dp < 0.01 compared to control
eNA = not analyzed
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Table 3. Mean (%) Absolute and Relative Organ
Weights of Male Micea
Organ
Dose (mg/kg-day)
0
100
1000
5000
Absolute Weights
Liver
1.14 ± 0.04b
1.2 ±0.03
1.27 ±0.06
1.4 ± 0.08°
Kidneys
0.45 ±0.01
0.41 ±0.01
0.4 ± 0.01°
0.4 ± 0.02°
Lungs
0.34 ±0.01
0.31 ±0.02
0.29 ±0.02
0.28 ±0.02
Spleen
0.05 ±<0.01
0.06 ±<0.01
0.07 ±<0.01
0.12 ±0.04
Adrenals
0.006 ±0.001
0.007 ±0.001
0.005 ±0.001
0.005 ± 0.001
Testes
0.22 ±<0.01
0.2 ±0.01
0.21 ±0.01
0.2 ±0.01
Brain
0.43 ±<0.01
0.42 ±<0.01
0.42 ±<0.01
0.41 ±0.01
Body Weight
28.5 ±0.5
27.6 ±0.5
27.6 ±0.9
26.9 ±0.7
Relative to Body Weight
Liver
4.01 ±0.13
4.35 ±0.08
4.6 ± 0.11°
5.18 ± 0.2°
Kidneys
1.58 ±0.02
1.5 ±0.03
1.46 ± 0.02°
1.47 ±0.05
Lungs
1.21 ±0.03
1.13 ±0.07
1.04 ±0.06
1.04 ±0.04
Spleen
0.19 ±0.01
0.23 ±0.01
0.24 ±0.01
0.46 ±0.14
Adrenals
0.023 ± 0.004
0.025 ± 0.004
0.018 ±0.003
0.02 ± 0.003
Testes
0.78 ±0.02
0.74 ±0.03
0.77 ±0.03
0.76 ±0.03
Brain
1.51 ±0.03
1.54 ±0.02
1.53 ±0.06
1.54 ±0.04
Relative to Brain Weight
Liver
266 ± 10
283 ±7
304 ± 16°
339 ±21°
Kidneys
105 ±2
97.4 ± 1.4
95.8 ±3.4
96.1 ±4.9
Lungs
79.9 ± 1.9
73.4 ±4.6
68.6 ±5.5
67.7 ±3.6
Spleen
12.7 ±0.5
14.7 ±0.5
15.9 ± 1.1
30.4 ±9.6
Adrenals
1.5 ±0.25
1.61 ±0.26
1.22 ±0.25
1.31 ±0.19
Testes
51.9 ± 1.1
48.2 ± 1.7
50.4 ± 1.7
49.1 ± 1.6
aDodd et al., 2003; C57BL/6 mice
bMean ± SD, units are percent
cp <0.05 compared to control
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Table 4. Mean (%) Absolute and Relative Organ Weights of Female Rats3
Organ
Dose (mg/kg-day)
0
100
1000
5000
Absolute Weights
Liver
4.19 ± 0.1b
4.1 ±0.11
4.03 ±0.09
4.82 ± 0.18°
Kidneys
1.17 ±0.02
1.14 ±0.02
1.13 ±0.02
1.21 ±0.04
Lungs
1.32 ±0.12
1.25 ±0.07
1.21 ±0.09
2.28 ± 0.44°
Spleen
0.39 ±0.01
0.38 ±0.01
0.35 ±0.01
0.34 ± 0.02°
Adrenals
0.054 ± 0.003
0.053 ± 0.002
0.060 ± 0.002
0.066 ± 0.003
Ovaries
0.091 ±0.002
0.088 ± 0.002
0.076 ± 0.003°
0.067 ± 0.008°
Brain
1.69 ±0.02
1.67 ±0.01
1.64 ±0.03
1.67 ±0.02
Body Weight
163.3 ±2.5
161.9 ± 1.5
154 ±2.5
160.8 ±4.4
Relative to Body Weight
Liver
2.56 ±0.04
2.53 ±0.06
2.62 ± 0.04
3.0 ±0.06°
Kidneys
0.72 ±0.01
0.71 ±0.01
0.74 ±0.01
0.75 ±0.01
Lungs
0.8 ±0.07
0.77 ± 0.04
0.79 ±0.05
1.43 ±0.3°
Spleen
0.24 ±<0.01
0.23 ±0.01
0.23 ±<0.01
0.21 ±0.01°
Adrenals
0.033 ± 0.002
0.033 ±0.001
0.039 ±0.001c
0.041 ±0.001°
Ovaries
0.056 ±0.001
0.055 ±0.001
0.050 ± 0.002
0.041 ±0.004°
Brain
1.04 ±0.01
1.03 ±0.01
1.07 ±0.01
1.04 ±0.03
Relative to Brain Weight
Liver
248 ±5
245 ±6
246 ±4
289 ± 10°
Kidneys
69.3 ± 1
68.3 ±0.6
69.2 ±0.9
72.7 ±2.2
Lungs
77.5 ±6.4
75.1 ±4.8
73.8 ±5.1
138 ±28°
Spleen
22.9 ±0.5
22.5 ±0.5
21.2 ±0.4
20.4 ± 1
Adrenals
3.21 ±0.19
3.16 ±0.08
3.66 ± 0.13°
3.97 ±0.18°
Ovaries
5.41 ±0.09
5.28 ±0.13
4.65 ±0.18
4.0 ±0.45°
aDodd et al., 2003; Fisher 344 rats
bMean ± SD, units are percent
cp <0.05 compared to control
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Table 5 summarizes the tissue lesion incidence reported by Dodd et al. (2003) in exposed
animals. Lesions occurred primarily along the alimentary tract. Varying degrees of hyperplasia
and hyperkeratosis of the squamous epithelium were found in the nonglandular stomach
(forestomach) of mice and rats from all dose groups. Occasionally, erosion and ulceration of the
mucosa were also present. No lesions were observed in the glandular stomach of any treated
animal. Other lesions observed were mild inflammation in the proximal duodenum mucosa
(high-dose rats), perianal hyperplasia accompanied by hyperkeratosis often with mild
inflammation (mid- and high-dose mice and rats), and multifocal minimal-to-mild necrosis and
suppurative inflammation of the nasal turbinates (high-dose mice; low-, mid-, and high-dose
rats). In rats, the nasal lesions were often accompanied by pulmonary lesions (incidence not
reported) consistent with aspiration of foreign material, ranging from peribronchial histiocytic
infiltrates to necrohemorrhagic bronchopneumonia. Based on the pathology of these lesions and
the pulmonary foreign body response observed in rats, Dodd et al. (2003) suggest that the lesions
in the nasal turbinates resulted from direct contact with the gavaged test agent—rather than from
specific xenobiotic targeting of nasal mucosa. Based on the lesions observed in the forestomachs
of both rats and mice at all dose levels, the lowest dose tested of 100 mg/kg-day is identified as a
LOAEL for the purposes of this review. A NOAEL is not identified in this study.
Table 5. Incidence of Tissue Lesionsa
Lesion
Dose (mg/kg-day)
0
100
1000
5000
Mice
Rats
Mice
Rats
Mice
Rats
Mice
Rats
Stomach (nonglandular)—squamous
epithelial hyperplasia/ hyperkeratosis
0/9
0/10
6/10
8/10
7/8
10/10
8/8
10/11
Proximal Duodenum—inflammation
(mild)
0/7
0/10
0/10
0/10
0/10
0/10
0/10
2/10
Rectum—perianal hyperplasia,
hyperkeratosis and inflammation
0/9
0/10
0/10
0/10
2/10
5/10
8/10
9/11
Nasal Turbinates—rhinitis
0/9
0/10
0/10
1/9
0/10
7/10
4/10
9/10
'Dodd et al., 2003; C57BL/6 mice; Fisher 344 rats
Inhalation Exposure
Data on the subchronic inhalation effects of //-nonane in animals come from a single
study by Carpenter et al. (1978). Carpenter et al. (1978) exposed groups of 25 male
Harlan-Wistar rats intermittently to 0-, 360-, 590-, or 1600 ppm (0-, 1888-, 3095-, or
8393 mg/m3) of //-nonane (98.4% purity) for 6 hours per day, 5 days per week, for 13 weeks
(total of 63 exposure days). The study authors selected the concentrations based on results of an
acute 4-hour inhalation study and preliminary repeated inhalation trials performed during a
preliminary investigation, as summarized further below (Carpenter et al., 1978). Eight to nine
rats from each dose group were sacrificed after 63 exposure days, while the remaining rats were
exposed for an additional 2 days and then sacrificed. Exposed rats were monitored for changes
in general appearance and behavior, body-weight gain, hematology (HCT, RBC, reticulocyte
count, total and differential WBC), clinical chemistry (ALP, ALT [SGOT], AST [SGPT], and
BUN), and urinalysis (specific measurements not described). In addition, three rats from each
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exposure group were sacrificed for histopathologic examination of tissues (adrenal, brain,
pituitary, trachea, bifurcation of the trachea, thyroid, parathyroid, lung, heart, liver, kidney,
spleen, stomach, duodenum, pancreas, ileum, jejunum, colon, skeletal muscle, sciatic nerve, and
bone marrow) after 19 and 38 days of exposure.
Carpenter et al. (1978) reported that two rats from the low-dose group died during the
study. These rats demonstrated suppurative bronchopneumonia upon necropsy. No deaths
occurred in the mid-dose group, but two rats in the high-dose group died during the first day of
exposure. Necropsy revealed lung congestion and hemorrhage in these rats, but no other
significant lesions were found. Carpenter et al. (1978) concluded that mortality was not
dose-related and the deaths were not related to treatment by //-nonane. Rats in the low- and
mid-dose groups did not demonstrate any changes in appearance or behavior, while rats in the
high-dose group exhibited salivation, mild coordination loss, and fine tremors throughout the
first 4 days of exposure, and continued to exhibit salivation and lacrimation throughout the
13-week study. High-dose rats also had statistically significantly (p < 0.01) decreased
body-weight gain throughout the study, and significantly (p < 0.05) reduced mean final body
weight, in comparison to control animals, as shown in Tables 6 and 7 below. Although
statistically significant (p < 0.05), the deficit in terminal body weight is small (7% decrease) and
less than what is generally considered biologically significant (10% decrease).
Carpenter et al. (1978) noted that no significant differences were observed in urinalysis
comparisons—although data are not reported. Blood chemistry values appeared normal for all
parameters evaluated in treated rats except for a small, transitory, statistically significant
elevation in AST in high-dose rats within the first 4 weeks of exposure (p < 0.05). Similar
increases in AST levels were not observed after 8 or 13 weeks of exposure. All hematological
parameters in treated rats appeared normal except for statistically significant increases in
eosinophil counts after 8 weeks of exposure (p < 0.05) among rats from the mid-dose group.
This effect was not observed after 13 weeks and did not demonstrate a dose-response
relationship, as similar effects were not observed in rats from the high-dose group. In general,
the only effects observed based on clinical chemistry and hematology were small, transient, and
not dose-related.
Carpenter et al. (1978) reported that no treatment-related histopathologic lesions occurred
in rats exposed to //-nonane. Although there were no remarkable changes in blood, urine, or
tissues from rats repeatedly exposed to //-nonane vapor, the rats exposed to the highest level did
demonstrate clinical signs of toxicity throughout the study (salivation and lacrimation; also mild
coordination loss and fine tremors early in the study). The high-exposure rats also exhibited a
decreased body-weight gain and slightly decreased terminal body weights (-7%) compared to
control animals. The high exposure level of 8393 mg/m3 is identified as a LOAEL based on
-3
clinical signs and body-weight changes in rats exposed to //-nonane vapor. The 3095 mg/m
exposure level is aNOAEL.
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Table 6. Mean Final Body Weight3
Concentration
Body Weightb
(mg/m3)
(grams)
0
523.9 ±56.4
1889
548.1 ±37.6
3095
532.0 ±58.1
8393
484.8 ±61.2C
aCarpenter et al., 1978; Harlan-Wistar rats
bMean± SD
°0.05 >p> 0.01
Table 7. Body-Weight Gain Throughout the Study3
Days of Exposure
Concentration (mg/m3)
0
8393
4
23.0 ± 11.9b
10.4 ± 12c
18
139.6 ±23.3
105.3 ±27.1c
33
217.1 ±34.7
183.8 ±33.4d
47
274.7 ±41.1
222.3 ± 47.5d
62
297.4 ±62.1
267.7 ±55.4
aCarpenter et al., 1978; Harlan-Wistar rats
bMean ± SD; units are in grams
><0.001
d0.01 >/? >0.001
Other Studies
Acute/Short-term Toxicity
As mentioned above, Dodd et al. (2003) conducted a 7-day range-finding study, whereby
male C57BL/6 mice (5/group) and female F-344 rats (5/group) were treated with 0, 700, 1800, or
3600 mg/kg-day n-nonane (neat) for 7 consecutive days. The exposed animals were evaluated
for general toxicity, neurotoxicity, body weights, gross necropsy, and changes in organ weights.
Mice from the high-dose group demonstrated increased liver and spleen weights compared to
controls, and mice in the 1800-mg/kg-day dose group demonstrated increased liver weights.
Rats from the high-dose group demonstrated decreased body weights compared to controls and
signs of irritation in the perianal area. Neurobehavioral tests were inconclusive.
Carpenter et al. (1978) exposed groups of 16 male Harlan-Wistar rats to 4000, 8000,
16,000, or 32,000 mg/m3 (measured concentrations of 1330, 4600, 11,000, or 23,000 mg/m3)
//-nonane (98.4% purity) vapors for 4 hours. Ten rats were randomly selected for LC50
determination. Mortality occurred at 11,000 mg/m3 (1/10) and at 23,000 mg/m3 (8/10), which
resulted in an acute 4-hour LC50 of 17,000 (14,000-21,000) mg/m3. Micropathological
examination of tissues taken from six rats 14 days after each of the single 4-hour inhalation
periods revealed no lesions attributable to //-nonane vapor inhalation.
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In addition, Carpenter et al. (1978) exposed 10 female albino Harlan-Wistar rats to
12,000 mg/m3 (measured concentration of 9200 mg/m3) «-nonane vapor for 2 consecutive days.
Within 3 hours of exposure on both days, rats exhibited poor coordination, tremors, and clonic
spasms. Carpenter et al. (1978) exposed another group of 10 female Harlan-Wistar rats to
10,000 mg/m //-nonane vapors for 3 consecutive days, 6 hours/day. The rats were rested for a
weekend and then subjected to the same exposure for an additional 4 days. The mean measured
concentration for the 7 days was 8100 mg/m //-nonane vapor. The study authors documented
minor coordination loss, mild tremors, and slight irritation of the eyes and extremities in exposed
rats on Exposure Day 2. Similar effects were observed throughout the 7-day exposure period.
No lesions attributable to //-nonane exposure were found during necropsy.
Nilsen et al. (1988) exposed male Sprague-Dawley rats to 12,663-, 18,675-, 23,281-, or
27,698-mg/m3 //-nonane (>99% purity) vapors for a single 8-hour exposure. Mortality rates by
exposure were 0/10, 1/10, 4/10, and 9/10, respectively. Necropsy revealed dilation of the
sinusoids and marked pulmonary edema in the animals that died during treatment. The 8-hour
"3
LC50 for «-nonane was 23,733 mg/m .
Additional information, that falls outside the scope of the provisional values documents,
is available from studies not discussed here. Toxicokinetic inhalation studies in rats
(Zahlsen et al., 1990; Zahlsen et al., 1992; and Lof et al., 1999) reveal the accumulation of
«-nonane in adipose tissues but not in blood or in the target tissues. Metabolism of «-nonane is
discussed by Serve et al. (1995), Mortsen et al. (2000), and Edwards et al. (2005). Finally,
Robinson (1999) developed a physiologically based pharmacokinetic (PBPK) model for inhaled
«-nonane in the rat.
Other Routes
A series of reports by Khan et al. (1980a, 1980b, 1985) evaluated the effects in rats
following an intraperitoneal (i.p.) dose of 1.0 mL/kg-day //-nonane for up to 7 days. Decreased
body weight, increased relative liver weight, increased phenobarbital-induced sleeping times,
and altered activities of hepatic and serum enzymes were observed.
Genotoxicity
Data on the genotoxic potential of //-nonane are limited, but they suggest that the
potential for //-nonane to induce any significant mutagenic or cytogenetic activity is low.
//-Nonane did not cause mutations in vitro in mutagenicity assays with S. typhimurium at
concentrations up to 10 mg/plate with or without metabolic activation (Zeiger et al., 1992).
Rivedal et al. (1992) demonstrated that //-nonane did not induce morphological transformation in
Syrian hamster embryo cells, nor did it reduce intercellular communication in Syrian hamster
embryo cells.
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DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR n-NONANE
Subchronic p-RfD
Data on the subchronic oral toxicity of //-nonane come from a single study by Dodd et al.
(2003). Dodd et al. (2003) reported proliferative forestomach lesions with varying degrees of
hyperplasia and hyperkeratosis of the squamous epithelium among all groups of rats and mice
with a LOAEL of 100 mg/kg-day. A NOAEL could not be determined.
The Benchmark Dose (BMD) approach was applied to the incidence data for forestomach
lesions in mice and rats (see Table 5). Appendix B contains details of the modeling and a plot of
the best-fitting model. For rats, a BMD of 9.62 mg/kg-day and Benchmark Dose Lower Bound
(BMDL) of 3.55 mg/kg-day were calculated, although there is little confidence in these values
due to irregularities in the model output (see Appendix B). For mice, the BMD is
8.43 mg/kg-day and the BMDL is 3.13 mg/kg-day. The BMDL of 3.13 mg/kg-day for mice was
selected as the point of departure (POD) for derivation of the subchronic p-RfD.
A subchronic p-RfD is derived for «-nonane by dividing the BMDL of 3.13 mg/kg-day
by an UF of 1000, as shown below:
Subchronic p-RfD = BMDL UF
= 3.13 mg/kg-day ^ 1000
= 0.003 or 3 x 10 3 mg/kg-day
The UF of 1000 is composed of the following:
• UFa: A factor of 10 is applied for animal-to-human extrapolation to account for
potential pharmacokinetic and pharmacodynamic differences between animals
and humans.
• UFr: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating susceptible human response are
limited.
• UFd: A factor of 10 is applied for database limitations. Although a subchronic
oral study is available for //-nonane that evaluated effects in two species
(Dodd et al., 2003), data for evaluating developmental and reproductive toxicity
are limited and might have identified adverse effects at lower levels.
Confidence in the principal study (Dodd et al., 2003) is medium because, despite the
investigation of sensitive endpoints, the sample sizes are relatively small (10 per dose) and only
one sex of each species was tested. Confidence in the database is low because the data set is
limited to a single subchronic study and acute animal studies. Reflecting medium confidence in
the principal study and low confidence in the database, confidence in the subchronic p-RfD is
low.
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Chronic p-RfD
No oral chronic studies on //-nonane are available. Although a subchronic study is
available (Dodd et al., 2003), the study is not extrapolated to estimate the effects due to chronic
exposure because of the high level of uncertainty (i.e. Composite UF of 3000) associated with
the subchronic p-RfD. However, the Appendix A of this document contains a screening value
that may be useful in certain instances. Please see the attached Appendix A for details.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR n-NONANE
Subchronic p-RfC
Data on the subchronic inhalation toxicity of //-nonane come from a single study by
Carpenter et al. (1978). Carpenter et al. (1978) observed clinical signs (salivation and
lacrimation) and marginally depressed body weight (-7%) in rats exposed to the LOAEL of
3 3
8393 mg/m for 6 hours per day, 5 days per week, for 13 weeks. The NOAEL is 3095 mg/m .
BMD modeling of the body-weight data is not possible because group sizes for this
endpoint are not reported. Due to interim sacrifices and occasional deaths during the study,
group sizes were less than the initial 25 per group. However, reporting of study methods and
results is not sufficiently detailed to develop estimated values. Likewise, incidence data for
clinical signs are not reported. Therefore, a NOAEL/LOAEL approach is used to identify the
NOAEL of 3095 mg/m3 as the POD for deriving the p-RfC values.
-3
To calculate the subchronic p-RfC for //-nonane, the NOAEL of 3095 mg/m in male rats
(Carpenter et al., 1978) is first adjusted for continuous exposure (NOAEL[adj]) as recommended
by U.S. EPA (1994). The NOAEL[ADj] is calculated as follows (U.S. EPA, 1994):
NOAEL[adj] = (NOAEL) (# hours/24 hours) (# days/7 days)
= (3095 mg/m3) (6 hours/24 hours) (5 days/7 days)
= 553 mg/m3
The human equivalent concentration (NOAEL[Hec]) based on the NOAEL[Adj] is
calculated for systemic effects (clinical signs and decreased body weight) of a Category 3 gas
(relatively low solubility and low reactivity) by multiplying the NOAEL[Adj] by the ratio of the
blood:gas (air) partition coefficient of //-nonane for the laboratory animal species to the human
value ([Hb/g]A/[Hb/g]H). Blood:air partition coefficients of 5.8 and 50 have been estimated in rats
(Smith et al., 2005) and humans (Imbriani et al., 1985), respectively. Using these reported
partition coefficients, a NOAEL[Hec] of 66.4 mg/m3 is calculated as follows:
NOAEL[hec] = NOAEL[adj] x (Hb/g)A/(Hb/g)H
= 553 mg/m3 x 0.12
= 66.4 mg/m3
"3
A subchronic p-RfC for «-nonane, based on the NOAEL[Hec] of 66.4 mg/m in male rats
(Carpenter et al., 1978), is derived as follows:
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Subchronic p-RfC = NOAEL[hec] ^ UF
= 66.4 mg/m3 300
= 2 x 10-1 mg/m3
The UF of 300 is composed of the following:
• UFa: A partial UF of 3 (10°5) is applied for interspecies extrapolation to account
for potential pharmacodynamic differences between rats and humans. Converting
the rat data to human equivalent concentrations by the dosimetric equations
accounts for pharmacokinetic differences between rats and humans; thus, it is not
necessary to use the full UF of 10 for interspecies extrapolation.
• UFr: A 10-fold UF for intraspecies differences is applied to account for
potentially susceptible individuals in the absence of quantitative information or
information on the variability of response in humans.
• UFd: An UF of 10 is included for database limitations. A single subchronic
inhalation toxicity study in one animal species (rat) is available (Carpenter et al.,
1978). The database lacks supporting systemic studies, multigenerational
reproduction studies, and developmental toxicity studies.
Confidence in the principal study (Carpenter et al., 1978) is low-to-medium. The
13-week study in rats uses adequate numbers of animals, a wide variety of endpoints (including
comprehensive histopathologic examinations) and appropriate controls. However, only male rats
were tested, histopathologic examinations were limited to three animals per exposure group at
two time points before the end of the study (at 19 and 38 days), and reporting of study methods
and results is incomplete. Confidence in the database is low because the database lacks adequate
studies of neurotoxicity, developmental toxicity, and reproductive toxicity (including
multigeneration reproductive toxicity). Reflecting low-to-medium confidence in the principal
study and low confidence in the database, confidence in the subchronic p-RfC is low.
Chronic p-RfC
To derive the chronic p-RfC, an additional 10-fold uncertainty factor for exposure
duration is applied to the POD, resulting in a total uncertainty factor of 3000. The chronic
p-RfC for «-nonane is derived below:
Chronic p-RfC = NOAEL[hec] ^ UF
= 66.4 mg/m3 - 3000
= 2 x 10"2 mg/m3
The UF of 3000 is composed of the following:
• UFa: A partial UF of 3 (10°5) is applied for interspecies extrapolation to account
for potential pharmacodynamic differences between rats and humans. Converting
the rat data to human equivalent concentrations by the dosimetric equations
accounts for pharmacokinetic differences between rats and humans; thus, it is not
necessary to use the full UF of 10 for interspecies extrapolation.
• 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.
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• UFr: A 10-fold UF for intraspecies differences is applied to account for
potentially susceptible individuals in the absence of quantitative information or
information on the variability of response in humans.
• UFd: An UF of 10 is included for database limitations. A single subchronic
inhalation toxicity study in one animal species (rat) is available (Carpenter et al.,
1978). The database lacks supporting systemic studies, multigenerational
reproduction studies, and developmental toxicity studies.
Confidence in the subchronic toxicity study used to derive the chronic p-RfC is
low-to-medium as discussed in the subchronic p-RfC derivation. Confidence in the database is
low due to the lack of a chronic study and for the reasons discussed in the subchronic p-RfC
derivation. Reflecting low-to-medium confidence in the principal study and low confidence in
the database, confidence in the chronic p-RfC is low.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR n-NONANE
Weight-of-Evidence Descriptor
Studies evaluating the carcinogenic potential of oral or inhalation exposure to //-nonane
in humans or animals have not been located in the available literature. Genotoxicity data suggest
that the potential for //-nonane to induce any significant mutagenic or cytogenetic activity is low.
Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is
"Inadequate Information to Assess [the] Carcinogenic Potential' of n-nonane.
Quantitative Estimates of Carcinogenic Risk
A lack of suitable data precludes derivation of quantitative estimates of cancer risk for
«-nonane.
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Dodd, D.R., Wolfe, R.E., Pollard, D.L., Merrill, E.A., Sterner, T.R., Bekkedal, M-Y-V., English,
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rats and male C57BL/6 mice. United States Air Force Research Laboratory, AFRL-HE-WP-TR-
2002-0137.
Edwards, J.E., Rose, R.L. and Hodgson, E. 2005. The metabolism of nonane, a JP-8 jet fuel
component, by human liver microsomes, P450 isoforms and alcohol dehydrogenase and
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for some industrially important substances. Giornale Italiano diMedicina del Lavoro,
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Khan, S. and Pandya, K.P. 1980a. Biochemical studies on the toxicity of //-octane and
//-nonane. Environmental Research, 22:271-276.
Khan, S., Mukhtar, H., and Pandya, K.P. 1980b. //-Octane and //-nonane induced alterations in
xenobiotic metabolizing enzyme activities and lipid peroxidation of rat liver. Toxicology,
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Khan, S. and Pandya, K.P. 1985. Hepatotoxicity in albino rats exposed to //-octane and
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(1,2,4-trimethylcyclohexane) hydrocarbons in the rat after repeated inhalation. Pharmacology
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APPENDIX A. DERIVATION OF SCREENING VALUE FOR n-NONANE
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for //-nonane. 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.
Screening Chronic p-RfD
Data on the subchronic oral toxicity of //-nonane come from a single study by Dodd et al.
(2003). Dodd et al. (2003) reported proliferative forestomach lesions with varying degrees of
hyperplasia and hyperkeratosis of the squamous epithelium among all groups of rats and mice
with a LOAEL of 100 mg/kg-day. A NOAEL could not be determined.
The Benchmark Dose (BMD) approach was applied to the incidence data for forestomach
lesions in mice and rats (see Table 5). Appendix B contains details of the modeling and a plot of
the best-fitting model. For rats, a BMD of 9.62 mg/kg-day and Benchmark Dose Lower Bound
(BMDL) of 3.55 mg/kg-day were calculated, although there is little confidence in these values
due to irregularities in the model output (see Appendix B). For mice, the BMD is
8.43 mg/kg-day and the BMDL is 3.13 mg/kg-day. The BMDL of 3.13 mg/kg-day for mice was
selected as the POD for derivation of the screening chronic p-RfD.
No oral chronic studies on //-nonane are available. Using the BMDL of 3.13 mg/kg-day
for mice based on incidence of forestomach lesions following subchronic oral exposure to
//-nonane, a screening chronic p-RfD is derived as follows:
Screening Chronic p-RfD = BMDL UF
= 3.13 mg/kg-day ^ 10,000
= 0.0003 or 3 x 10"4 mg/kg-day
The UF of 10,000 is composed of the following:
• UFa: A factor of 10 is applied for animal-to-human extrapolation to account for
potential pharmacokinetic and pharmacodynamic differences between animals
and humans
• UFr: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation, because data for evaluating susceptible human response are
limited.
• UFs: A factor of 10 is applied for using data from a subchronic study to assess
potential effects from chronic exposure, because data chronic exposure might
have identified additional effects from longer exposure.
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• UFd: A factor of 10 is applied for database limitations. Although a subchronic
oral study is available for nonane that evaluated effects in two species, data for
evaluating developmental and reproductive toxicity are limited and might have
identified effects at lower levels.
Confidence in the subchronic toxicity study used to derive the screening chronic p-RfD is
medium, as discussed in the subchronic p-RfD derivation. Confidence in the database is low due
to the lack of a chronic study and for the reasons discussed in the subchronic p-RfD derivation.
Reflecting medium confidence in the principal study and low confidence in the database,
confidence in the screening chronic p-RfD is low.
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APPENDIX B. DETAILS OF BENCHMARK DOSE MODELING
FOR SUBCHRONIC RfD
Model-Fitting Procedure for Quantal Data:
The incidence data were analyzed using all available models for quantal data in the
benchmark dose software (BMDS) program (version 2.1) developed by the U.S. EPA. Risk was
calculated as extra risk. Confidence bounds were automatically calculated by the BMDS using a
maximum likelihood profile method.
Output from the BMDS program was evaluated using the criteria described in U.S. EPA
(2000). Goodness-of-fit was evaluated using the chi-square statistic calculated by the BMDS
program. Acceptable global goodness-of-fit is indicated by a p-value greater than or equal to
0.1. Models that did not meet this criterion were eliminated from consideration. Local fit is
evaluated visually on the graphic output by comparing the observed and estimated results at each
data point. BMDLio estimates that are within a factor of 3 are considered to show no model
dependence and are ranked using the Akaike Information Criteria (AIC) reported by the BMDS
program. The model with the lowest AIC is considered to provide a superior fit. When the
BMDLio estimates vary by greater than a factor of 3, the lowest BMDLio value is selected as the
conservative estimate for the POD.
Model-Fitting for Incidence of Forestomach Lesions in Mice and Rats (Dodd et al., 2003):
Following the above procedure, quantal models were fit to the data shown in Table 5 for
incidence of forestomach lesions in mice and rats. The results are shown in Tables B-l (rats) and
B-2 (mice). Although the gamma model appeared to fit the rat data adequately (p = 0.61) and
benchmark values were calculated (BMDio = 9.62; BMDLio = 3.55), the AIC was extremely
high in relation to the other models and messages were contained in the output indicating that the
model did not converge. Therefore, there is little confidence in this result. No other models fit
the rat data adequately. For the mouse data, the log-logistic model fit the data adequately
(BMDio = 8.44; BMDLio = 3.13). Figures B-l (rat) and B-2 (mouse) show the fits of the models
to the data.
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Table B-l. Model Predictions for Forestomach Lesions in Rats
Model
Degrees of
Freedom
x2
X2 Goodness of
Fit />-Valuc
AIC
BMD10
(mg/kg-day)
BMDL10
(mg/kg-day)
Gamma (power > l)b
2
1
0.6065
1434.01
9.62
3.55
Log-logistic (slope >1)
3
11.8
0.0081
22.97
3.88
1.14
Logistic
2
19.78
0.0001
47.01
280.31
136.75
Multistage (betas > 0)°
2
21.07
0
44.99
136.80
64.06
Log-probit (slope > 1)
3
3274
0
35.95
24.65
13.34
Probit
2
19.8
0.0001
47.58
359.89
212.55
Weibull (power > 1)
2
21.07
0
44.99
136.80
64.06
Quantal-Linear
2
21.07
0
44.99
136.80
64.06
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
bModel selected for POD
°One degree polynomial shown. Higher degree polynomials default back to one degree.
Table B-2. Model Predictions for Forestomach Lesions in Mice
Model
Degrees of
Freedom
x2
X2 Goodness of
Fit />-Valuc
AIC
BMD10
(mg/kg-day)
BMDL10
(mg/kg-day)
Gamma (power > 1)
3
7.96
0.0469
26.77
26.98
15.58
Log-logistic (slope > l)b
3
0.52
0.9137
22.07
8.44
3.13
Logistic
2
6.52
0.0384
32.07
105.67
55.26
Multistage (betas > 0)°
3
7.96
0.0469
26.77
26.98
15.58
Log-probit (slope > 1)
3
7.9
0.0482
25.01
30.94
17.05
Probit
2
6.59
0.0371
32.10
109.93
66.28
Weibull (power > 1)
3
7.96
0.0469
26.77
26.98
15.58
Quantal-Linear
3
7.96
0.0469
26.77
26.98
15.58
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
bModel selected for POD.
°One degree polynomial shown. Higher degree polynomials default back to one degree.
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Gamma Multi-Hit Model with 0.95 Confidence Level
"O
=1
Total number of observations = 4
Total number of records with missing values = 0
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Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial (and Specified) Parameter Values
Background = 0.0454545
Slope = 0.0146706
Power = 1.3
the user,
Slope
Power
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background
have been estimated at a boundary point, or have been specified by
and do not appear in the correlation matrix )
Slope Power
NA NA
NA NA
NA - This parameter's variance has been estimated as zero or less.
THE MODEL HAS PROBABLY NOT CONVERGED!!!
Interval
Variable
Limit
Background
Slope
NA
Power
NA
Parameter Estimates
Estimate
0
0.0196736
1.24722
Std. Err.
NA
NA
NA
At least some variance estimates are negative.
THIS USUALLY MEANS THE MODEL HAS NOT CONVERGED!
Try again from another starting point.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
NA
NA
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
AIC:
Log(likelihood)
-8 .35732
-715.714
-25.6112
1435.43
# Param's Deviance Test d.f.
4
2 1414.71 2
1 34.5077 3
P-value
6.2934391e-308
<.0001
Goodness of Fit
Dose Est._Prob. Expected Observed Size
0.0000 0.0000 0.000 0.000 10
Scaled
Residual
0. 000
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100.0000 0.8000 8.000 8.000 10 0.000
1000.0000 1.0000 10.000 10.000 10 0.000
5000.0000 1.0000 11.000 9.999 11 -1.001
Chi^2 = 1.00 d.f. = 2 P-value = 0.6059
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 9.62447
BMDL = 3.55 095
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Log-Logistic Model with 0.95 Confidence Level
Log-Logistic
0 1000 2000 3000 4000 5000
Dose
13:45 09/23 2009
Figure B-2. Fit of Log-logistic Model to Incidence Data for Forestomach Lesions in Mice
(Dodd et al., 2003)
BMDs and BMDLs indicated are associated with an extra risk of 10% and are in units of mg/kg-day.
Logistic Model. (Version: 2.12; Date: 05/16/2008)
Input Data File: C:\USEPA\BMDS2l\Data\lnldiacotomice922Loglogist0922mice.(d)
Gnuplot Plotting File:
C:\USEPA\BMDS21\Data\lnldiacotomice922Loglogist0922mice.pit
Wed Sep 23 13:45:18 2009
BMDS Model Run
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-siope*Log(dose))]
Dependent variable = Percent
Independent variable = Dose
Slope parameter is restricted as slope >= 1
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
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Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial Parameter Values
background = 0
intercept = -5.38
slope = 1
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background -slope
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
intercept
intercept 1
Parameter Estimates
Interval
Variable
Limit
background
intercept
slope
Estimate
-4.32976
1
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
Indicates that this value is not calculated.
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Log(likelihood)
-9.74428
-10.0346
-23.5554
22.0692
# Param's
4
1
1
Deviance Test d.f.
0.580634
27.6223
P-value
0.9009
<.0001
Dose
Goodness of Fit
Est._Prob. Expected Observed Size
Scaled
Residual
0.0000
100.0000
1000.0000
5000.0000
0.0000
0.5684
0.9294
0.9850
0.000
5 . 684
7.435
7.880
0.000
6.000
7.000
8.000
9
10
0. 000
0.202
-0.601
0.349
Chi^2 = 0.52
d.f. = 3
P-value = 0.9137
Benchmark Dose Computation
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Specified effect
Risk Type
Confidence level
BMD
BMDL
FINAL
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o.i
Extra risk
0. 95
8.43622
3.12858
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