United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/053F
Final
9-22-2009
Provisional Peer-Reviewed Toxicity Values for
1,1 '-Sulfonylbis(4-chlorobenzene)
(CASRN 80-07-9)
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
l,l'-SULFONYLBIS(4-CHLOROBENZENE) (CASRN 80-07-9)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.S. EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1)	U.S. EPA's Integrated Risk Information System (IRIS).
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. EPA's Superfund
Program.
3)	Other (peer-reviewed) toxicity values, including
•	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
•	California Environmental Protection Agency (CalEPA) values, and
•	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in U.S. EPA's IRIS. PPRTVs are developed according to a
Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific
literature using the same methods, sources of data, and Agency guidance for value derivation
generally used by the U.S. EPA IRIS Program. All provisional toxicity values receive internal
review by two U.S. EPA scientists and external peer review by three independently selected
scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multiprogram consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all U.S. EPA programs, while PPRTVs are developed
specifically for the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. EPA programs or
external parties who may choose of their own initiative to use these PPRTVs are advised that
Superfund resources will not generally be used to respond to challenges of PPRTVs used in a
context outside of the Superfund Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the U.S. EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
The chemical l,l'-sulfonylbis(4-chlorobenzene) is a monomer used in the plastics
industry for creating polysulfone plastics, which are approved for food-contact use by the
U.S. Food and Drug Administration (FDA) and a wide variety of other consumer plastics. They
are also used in polyethersulfone plastics and as a component in reactive dyes in the textile
industry. Despite the widespread potential exposures, no RfD, RfC, or cancer assessment for
l,l'-sulfonylbis(4-chlorobenzene) (see Figure 1 for chemical structure) is available on IRIS
(U.S. EPA, 2008), in the Health Effects Assessment Summary Tables (HEAST)
(U.S. EPA, 1997), or in the Drinking Water Standards and Health Advisories list
(U.S. EPA, 2006). No relevant documents were located in the Chemical Assessments and
Related Activities (CARA) list (U.S. EPA, 1991, 1994). The Agency for Toxic Substances and
Disease Registry (ATSDR, 2008) has not published a Toxicological Profile for
l,l'-sulfonylbis(4-chlorobenzene), and no Environmental Health Criteria Document is available
from the World Health Organization (WHO, 2008).
Neither the American Conference for Governmental Industrial Hygienists
(ACGIH, 2008), Occupational Safety and Health Administration (OSHA, 2008) nor the National
Institute of Occupational Safety and Health (NIOSH, 2008) has established occupational health
standards for l,l-sulfonylbis(4-chlorobenzene). The carcinogenicity of
l,l'-sulfonylbis(4-chlorobenzene) has not been assessed by the International Agency for
INTRODUCTION
Figure 1. Structure of l,l'-Sulfonylbis(4-chlorobenzene)
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Research on Cancer (IARC, 2008), and l,l-sulfonylbis(4-chlorobenzene) is not included in the
National Toxicology Program's (NTP) Report on Carcinogens (NTP, 2005)—although NTP has
evaluated the subchronic and chronic toxicity and carcinogenicity from oral exposure to
l,r-sulfonylbis(4-chlorobenzene) in both mice and rats (NTP, 2001).
Literature searches were conducted from the 1960s through November of 2008 and
updated in August 2009 for studies relevant to the derivation of provisional toxicity values for
l,r-sulfonylbis(4-chlorobenzene). Databases searched include MEDLINE, TOXLINE (with
NTIS), BIOSIS, TSCATS/ TSCATS2, CCRIS, DART, GENETOX, HSDB, RTECS, Chemical
Abstracts, and Current Contents (through August 2009).
REVIEW OF PERTINENT DATA
Human Studies
No studies regarding oral or inhalation exposure of humans to
l,l'-sulfonylbis(4-chlorobenzene) were located.
Animal Studies
Oral Exposure
Available subchronic and chronic oral studies of l,l'-sulfonylbis(4-chlorobenzene)
include a 14-week study in rats (Chhabra et al., 2001) and a 2-year study in rats and mice
(NTP, 2001). A short-term toxicity study evaluating limited endpoints in rats (Poon et al., 1999)
is discussed under Other Studies.
Subchronic Studies—In the subchronic toxicity study, F344 rats (10/sex/dose), were
exposed continuously to l,l'-sulfonylbis(4-chlorobenzene) (>99% pure) at 0, 30, 100, 300, 1000,
or 3000 ppm in the diet for 14 weeks (Chhabra et al., 2001; NTP, 2001). Average daily doses
were reported by the researchers to be approximately 0, 2, 6, 19, and 65 and 200 mg/kg-day in
both males and females. Clinical observations and body weights were evaluated weekly and at
the end of the study. A neurobehavioral screening battery that included tests for autonomic,
convulsive, excitability, neuromuscular, sensorimotor, and general motor activity was
administered on Week 12 to rats exposed to 0, 100, 300, or 1000 ppm. At study termination,
blood samples were collected for hematology (erythrocyte, platelet and leukocyte counts,
hematocrit, hemoglobin concentration, mean cell volume [MCV], mean cell hemoglobin [MCH]
and mean cell hemoglobin concentration [MCHC]), and clinical chemistry (urea nitrogen,
creatinine, total protein, albumin, alanine aminotransferase [ALT], alkaline phosphatase [ALP],
sorbitol dehydrogenase, creatine kinase, and total bile acids). At necropsy, selected organs
(heart, right kidney, liver, ovary, right testis, thymus, and uterus) were weighed. A complete
histopathological examination was conducted on control and high-dose rats, and target tissues
were examined microscopically in animals from all dose groups.
All rats survived the duration of the experiment and no clinical signs related to exposure
were observed (Chhabra et al., 2001; NTP, 2001). Tables 1 and 2 show the statistically
significant changes in males and females, respectively. At the end of the experiment, male and
female rats exposed to >300 ppm showed statistically significant, dose-related reductions in
weight body weight. Final body weights of rats in the 300- and 1000-ppm groups were
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approximately 96% and 91% of controls (respectively), while those in the 3000-ppm groups
were 82—85% of control values. Feed consumption was reduced (23—39% less than controls) in
the 3000-ppm group during the first week of the study, but it was similar to controls in all groups
by the end of the study. A neurobehavioral screening battery revealed no statistically significant
treatment-related effects in rats. A mild effect on the erythropoietic system was evidenced by
slight—but statistically significant—decreases in hemoglobin, MCH, and MCHC, as well as
significant increases in platelets, in both males (>1000 ppm) and females (>300 ppm). Clinical
chemistry changes included slight—but statistically significant—increases in albumin and total
protein concentrations in male and female rats exposed to >300 ppm and a dose-related decrease
in ALP activity in males from all dose groups and in females at >100 ppm. Significant increases
in sorbitol dehydrogenase activity were observed in rats of both sexes at 3000 ppm (83% and
45%) higher than controls in males and females, respectively). In addition, a statistically
significant increase in bile salt concentration was observed in 3000-ppm males (27% higher than
controls). ALT activity was not increased at any dose; decreased activity (relative to controls)
was observed in the lower dose groups. Slight—but statistically significant—increases in serum
creatinine were observed in high-dose rats of both sexes; blood urea nitrogen was increased in
high-dose males.
At necropsy, absolute and relative liver weights were significantly increased in a
dose-related fashion in both male and female rats at >100 ppm (Chhabra et al., 2001; NTP, 2001;
see Tables 1 and 2). In males, other significant organ weight changes were observed, primarily
at 300 ppm and above, including increases in absolute and/or relative kidney and testes weights
and decreased absolute and relative thymus weight. In females, relative—but not absolute—
kidney weights were significantly elevated compared to controls at >1000 ppm; decreased body
weight at these doses may have contributed to this change. There were no significant changes in
ovary or uterus weights at any dose level. No gross lesions of any organ were observed.
Histopathological examination of the liver revealed increased incidences of slight-to-mild
centrilobular hypertrophy in males at >100 ppm and females at >300 ppm. The increase in cell
size was reported to be due to both cytomegaly and karyomegaly (nuclear enlargement). In the
kidney, there was a statistically significant, dose-related increase in the incidence of nephropathy
in females at >1000 ppm (minimal severity in all dose groups) and a dose-related increase in the
severity of nephropathy in males at >300 ppm, from minimal in controls and low-dose groups to
marked in the high-dose group (9/10 controls and all treated males showed nephropathy). The
observed nephropathy is characterized by foci of regenerating renal tubules with associated
peritubular fibrosis and interstitial mononuclear inflammatory cell infiltration.
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Table 1. Changes in Male Rats Exposed to l,l'-Sulfonylbis(4-chlorobenzene)
Via the Diet for 14 Weeks"
Parameter
Dietary Concentration in ppm (Dose in mg/kg-d)
0
30
(2 mg/kg-d)
100
(6 mg/kg-d)
300
(19 mg/kg-d)
1000
(65 mg/kg-d)
3000
(200 mg/kg-d)
Terminal body weight (g)
369 ± 4b
378 ±7
366 ±4
350 ±4C
340 ± 6d
304 ± 8d
Hematology
Hemoglobin (g/dL)
16.5 ±0.2
16.6 ±0.1
16.2 ±0.2
16.3 ±0.2
15.6 ± 0.1d
15.8 ± 0.2d
Reticulocytes (10'/|iL)
0.11 ±0.01
0.11±0.01
0.12 ±0.01
0.13 ±0.01
0.14 ±0.01
0.15 ± 0.02°
MCH (pg)
17.4 ±0.1
17.8 ±0.1
17.6 ±0.1
17.6 ±0.1
17.3 ±0.1
16.9 ± 0.3°
MCHC (g/dL)
34.0 ±0.2
34.0 ±0.1
33.9 ±0.2
34.0 ±0.2
33.5 ±0.2
32.6 ± 0.3d
Platelets (lo VjiL)
754.7 ± 15.0
793.6 ±56.5
769.1 ±22.8
761.1 ± 13.3
837.8 ±20.4d
948.8 ±21.0d
Serum chemistry
Albumin (g/dL)
4.9 ±0.1
4.9 ±0.1
5.1 ±0.1
5.4 ± 0.1d
5.1 ± 0.0d
5.3 ± 0.1d
Total protein (g/dL)
7.4 ±0.1
7.4 ±0.2
7.7 ±0.1
8.2 ± 0.1d
8.2 ± 0.1d
8.6 ± 0.1d
ALP (U/L)
602 ± 11
509 ± 27d
460 ± 7d
474 ± 9d
402 ± 8d
421 ±8d
Sorbitol dehydrogenase
(U/L)
23 ±2
24 ±2
20 ± 1
23 ±3
27 ±2
42 ± 4d
ALT (U/L)
73 ±6
53 ± 4°
50 ± 3d
61 ± 6
63 ±5
73 ±6
Bile salts (|imol/L)
25.2 ±2.4
23.6 ± 1.4
27.8 ±2.9
25.0 ±0.8
26.2 ±0.5
32 ± 1.3d
Urea nitrogen (mg/dL)
20.5 ±0.3
18.2 ±0.5
19.8 ±0.4
21 ±0.3
21 ±0.3
24 ± 0.3d
Creatinine (mg/dL)
0.68 ±0.01
0.7 ±0.02
0.69 ±0.01
0.69 ±0.01
0.71 ±0.02
0.76 ± 0.02d
Organ weights
Absolute kidney weight
(g)
1.38 ±0.03
1.37 ±0.04
1.42 ±0.03
1.43 ±0.04
1.63 ± 0.04d
1.56 ± 0.03d
Relative kidney weight
(g/g-bw)
0.35 ±0.005
0.35 ±0.005
0.37 ± 0.006°
0.39 ± 0.007d
0.46 ± 0.007d
0.50 ± 0.005d
Absolute liver weight (g)
15.5 ±0.37
15.6 ±0.5
18.2 ± 0.48d
20.1 ± 0.36d
25.0 ± 0.6d
26.4 ± 0.46d
Relative liver weight
(g/g-bw)
3.96 ±0.08
4.03 ±0.07
4.77 ± 0.12d
5.48 ± 0.06d
7.08 ± 0.09d
8.47 ± 0.16d
Absolute R. testis weight
(g)
1.49 ±0.02
1.48 ±0.04
1.51 ±0.02
1.50 ±0.01
1.57 ± 0.01°
1.54 ± 0.02°
Relative R. testis weight
(g/g-bw)
0.38 ±0.005
0.38 ±0.006
0.40 ± 0.008
0.41 ± 0.005d
0.45 ± 0.009d
0.49 ± 0.011d
Absolute thymus weight
(g)
0.35 ±0.02
0.30 ±0.02
0.31 ±0.02
0.28 ± 0.01d
0.25 ± 0.01d
0.23 ± 0.02d
Relative thymus weight
(g/g-bw)
0.088 ±
0.005
0.078 ±
0.003
0.081 ±
0.005
0.075 ±0.003c
0.070 ±
0.003d
0.072 ± 0.004d
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Table 1. Changes in Male Rats Exposed to l,l'-Sulfonylbis(4-chlorobenzene)
Via the Diet for 14 Weeks"
Parameter
Dietary Concentration in ppm (Dose in mg/kg-d)
0
30
(2 mg/kg-d)
100
(6 mg/kg-d)
300
(19 mg/kg-d)
1000
(65 mg/kg-d)
3000
(200 mg/kg-d)
Histopathology
Centrilobular
Hypertrophy (liver)
0/10e
0/10
7/10d (l.l)f
10/10d (2.0)
10/10d (2.0)
10/10d (2.0)
Nephropathy (kidney)
9/10 (1.0)
10/10 (1.0)
10/10 (1.0)
10/10 (1.9)
10/10 (2.9)
10/10 (3.8)
aChhabra et al. (2001).
bValues are presented as means ± SE.
Significantly different from control (p < 0.05).
dSignificantly different from control (p < 0.01).
"Number of animals affected/number examined.
fAverage severity grades of lesions in affected animals (1, minimal; 2, mild; 3, moderate; 4, marked) in parentheses.
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Table 2. Changes in Female Rats Exposed to l,l'-Sulfonylbis(4-chlorobenzene)
Via the Diet for 14 Weeks"
Parameter
Dietary Concentration in ppm (Dose in mg/kg-d)
0
30
(2 mg/kg-d)
100
(6 mg/kg-d)
300
(19 mg/kg-d)
1000
(65 mg/kg-d)
3000
(200 mg/kg-d)
Terminal body weight (g)
204 ± 2b
201 ±2
200 ±2
196 ± 3C
185 ±2d
174 ± 3d
Hematology
Hemoglobin (g/dL)
15.8 ±0.2
16.1 ±0.1
15.7 ±0.1
15.6 ±0.2
15.0 ± 0.2d
14.8 ± 0.2d
Mean cell volume (fL)
55.2 ±0.2
55.9 ±0.2
55.6 ±0.2
55.1 ±0.2
54.4 ± 0.2°
54.1 ± 0.4d
MCH (pg)
19.2±0.1
19.4±0.1
19.2±0.1
18.7±0.1d
17.9±0.1d
17.8±0.1d
MCHC (g/dL)
34.9 ±0.2
34.6 ±0.2
34.5 ±0.3
33.9 ± 0.3°
32.9 ± 0.2d
32.8 ± 0.2d
Platelets (10 7|iL)
736.4 ± 11.5
783.9 ± 14.9°
772.7 ±23.2
790.4 ± 12.4°
843.9 ± 14.3d
826.9 ± 16.8d
Serum chemistry
Albumin (g/dL)
5.1 ±0.1
5.3 ± 0.1°
5.1 ±0.1
5.4 ± 0.1d
6.0 ± 0.1d
6.1 ± 0.1d
Total protein (g/dL)
7.2 ±0.1
7.6 ± 0.1d
7.5 ± 0.1d
8.0 ± 0.1d
9.1 ± 0.1d
9.5 ± 0.2d
ALP (U/L)
447 ± 16
432±125
368 ±14d
339 ±15d
225 ± 8d
243 ± 9d
Sorbitol dehydrogenase
(U/L)
20 ±2
20 ± 1
20 ±2
21 ± 1
27 ±4
29 ± 4°
ALT (U/L)
52 ±3
44 ± 1
41 ± 2°
40 ± r
48 ±6
47 ±4
Bile acids (|imol/L)
48.5 ±5.3
54.2 ±6.1
59.1 ±5.1
72 ± 10.3
42.2 ±2.4
49.4 ±5.8
Urea nitrogen (mg/dL)
19.3 ±0.6
18.7 ±0.8
18.2 ±0.5
19.6 ± 1
18.6 ±0.5
21.8 ±0.6
Creatinine (mg/dL)
0.67 ± 0.02
0.71 ±0.02
0.68 ±0.01
0.68 ±0.01
0.68 ±0.01
0.73 ± 0.02°
Organ Weights
Absolute kidney weight
(g)
0.75 ± 0.02
0.76 ±0.01
0.77 ±0.01
0.74 ± 0.02
0.79 ±0.01
0.78 ±0.02
Relative kidney weight
(g/g-bw)
0.35 ±0.006
0.37 ±0.005
0.37 ±0.006
0.37 ±0.006
0.42 ± 0.004d
0.44 ± 0.007d
Absolute liver weight (g)
7.5 ±0.17
7.7 ±0.14
8.2 ± 0.10°
9.3 ± 0.26d
12.2 ± 0.27d
14.7 ± 0.24d
Relative liver weight
(g/g-bw)
3.23 ±0.04
3.72 ±0.06
4.00 ± 0.04d
4.61 ±0.08d
6.47 ± 0.12d
8.32 ± 0.15d
Histopathology
Centrilobular hypertrophy
(liver)
0/10e
0/10
0/10
10/10d(1.0)f
10/10d (1.9)
10/10d (1.9)
Nephropathy (kidney)
0/10
0/10
1/10(1.0)
2/10 (1.0)
5/10° (1.0)
9/10d (1.0)
aChhabra et al. (2001).
bValues are presented as means ± SE.
Significantly different from control (p < 0.05).
dSignificantly different from control (p < 0.01).
"Number of animals affected/number examined.
fAverage severity grades of lesions in affected animals (1, minimal; 2, mild; 3, moderate; 4, marked) in parentheses.
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The authors identified a NOAEL of 30 ppm (2 mg/kg-day) for this study
(Chhabra et al., 2001; NTP, 2001). Effects observed at the next higher dose (100 ppm or
6 mg/kg-day) include increased absolute and relative liver weights, increased incidence of
hepatocellular hypertrophy (males), decreased ALP and ALT, increased total serum protein
(females), and a nonsignificant increase in the incidence of nephropathy (females). For the
purpose of this review, the 100-ppm (6 mg/kg-day) dose is considered a LOAEL based on
increased incidence of centrilobular hypertrophy and increased liver weight in male rats. Given
the magnitude of the liver weight changes, the statistical significance of these changes, the
accompanying histopathology, the serum chemistry changes (increased serum levels of bile salts,
total protein, and sorbitol dehydrogenase) observed at the high dose in this study, this is viewed
as a toxic effect. Additionally, the evidence for liver toxicity in the chronic study (see below) of
rats (bile-duct hyperplasia in female rats; Chhabra et al., 2001; NTP, 2001) further supports these
effects of early indicators of subsequent pathology. Evidence for liver toxicity was also
observed in mice chronically exposed to l,l'-sulfonylbis(4-chlorobenzene); hepatocellular
necrosis was seen after subchronic exposure, and increased incidence of eosinophilic foci was
seen after chronic exposure (Chhabra et al., 2001; NTP, 2001).
In the 14-week study in mice, groups of 10/sex/dose were fed diets containing 0, 30, 100,
300, 1000, or 3000 ppm of (> 99% pure) l,l'-sulfonylbis(4-chlorobenzene), which the
researchers estimated to be equivalent to 0, 3.5, 15, 50, 165, or 480 mg/kg-day in both males and
females (Chhabra et al., 2001; NTP, 2001). The same study procedures described above for rats
were followed for mice—except the neurobehavioral assessment was conducted during Week 12
for female mice exposed to 0, 300, 1000, or 3000 ppm, and blood samples were only analyzed
for hematology and not clinical chemistry. All mice survived to the end of the study and no
clinical signs related to exposure were noted. Significant changes are reported in Table 3.
Body-weight gain was significantly reduced in treated males and females at >300 ppm. Final
body weight was 91-92% of control in the 300-ppm groups and 85-87%) of controls in the
1000- and 3000-ppm groups. Feed consumption was 47-52%) lower than controls in the
3000-ppm groups during the first week of the study but similar to controls in all groups by
Week 14. The neurological assessment found no effects in mice at any level. Hematological
analyses revealed minimal changes in platelet counts and red cell indices that the authors
indicated were within physiological ranges and, consequently, not biologically significant.
Both absolute and relative liver weights were statistically significantly increased in a
dose-related manner in male and female mice (see Table 3) at >300 ppm (Chhabra et al., 2001;
NTP, 2001). In addition, relative—but not absolute—organ-weight changes (testis and kidney in
males, and ovary, uterus, and kidney in females) were statistically significantly increased at
>1000 ppm; however, these changes were likely attributable to reduced body weights in these
groups. Absolute—but not relative—thymus weight was statistically significantly decreased
(20%o less than controls,/? < 0.01) in high-dose females. There was a statistically significant,
dose-related increase in the incidence of centrilobular hypertrophy among male mice at
>100 ppm and female mice at >1000 ppm. The lesions were morphologically similar to those in
rats (described above) and increased in severity in relation to dose. In addition, hepatic necrosis
(minimal severity) was seen in males at >100 ppm and females at >1000 ppm. The increase in
incidence was statistically significant in males at >1000 ppm. Hepatic necrosis in these mice is
characterized by multiple, randomly scattered small foci of coagulative necrosis. No other
histological changes are reported in mice. The study authors did not identify effect levels for
mice. For the purposes of this review, a NOAEL of 30 ppm (3.5 mg/kg-day) and a LOAEL of
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100 ppm (15 mg/kg-day) are identified based on increased incidence of centrilobular
hypertrophy in male mice. A nonsignificant increase in the incidence of hepatocellular necrosis
(1/10 males) was also observed at this dose; this finding increased with dose and was not
observed in control animals or those exposed to the NOAEL. Centrilobular hypertrophy is
considered a sensitive indicator of toxicity for this chemical, given the available evidence for
more explicitly toxic liver effects also occurring in both mice and rats. In the mouse, there were
dose-related increase in liver cell necrosis in the subchronic study and eosinophilic foci in the
chronic study and in the rats the serum chemistry findings in subchronic study and bile-duct
hyperplasia in the chronic study. Serum chemistry was not analyzed in either the subchronic or
chronic studies (see below) in mice, so there are no serum chemistry data to inform the
assessment of liver toxicity in mice.
Chronic Studies—In the chronic study in rats (Chhabra et al., 2001; NTP, 2001), groups
of 50 male and 50 female F344 rats were fed diets containing 0, 10 (males only), 30, 100, or
300 (females only) ppm of l,l'-sulfonylbis(4-chlorobenzene) (>99% purity) for 2 years. The
researchers reported average daily doses of 0, 0.5, 1.5, or 5 mg/kg-day in males and 1.6, 5.4, or
17 mg/kg-day in females. Survival and signs of illness were monitored twice daily; clinical
observations were recorded monthly. Body weights were measured weekly for the first
13 weeks and monthly thereafter and at study termination. Blood samples were collected at
approximately 2 weeks and 3, 12, and 18 months for determination of
l,l'-sulfonylbis(4-chlorobenzene); hematology was not assessed. At necropsy, a comprehensive
set of organs and tissues were examined for grossly visible and microscopic lesions. Clinical
pathology and organ weights are not assessed.
Survival was similar in control and treated rats, and no clinical findings were attributed to
exposure (Chhabra et al., 2001; NTP, 2001). Feed consumption in treated groups was similar to
controls. Body weights of mid- and high-dose males and females were less than controls for
much of the study but remained within 10% of the control group for all but the high-dose
females, which exhibited a >10% decrease in body weights compared to controls (based on
graphical presentation of data; statistical analysis was not reported). Histopathology lesions
related to treatment were found only in the liver. Statistically significant increased incidences of
minimal-to-mild centrilobular hypertrophy (males and females), minimal bile-duct hyperplasia
(females only), and minimal-to-mild centrilobular degeneration (females) were observed at
>100 ppm (see Table 4). Hepatocyte hypertrophy was characterized by increased size of the
centrilobular hepatocytes and fine cytoplasmic vacuolization accompanied by eosinophilic or
basophilic stippling. Bile-duct hyperplasia was characterized by increased bile duct profiles
within the portal areas. Centrilobular degeneration was noted to be only observed in those
animals that had mononuclear cell leukemia in the liver; NTP (2001) suggested that this lesion
was most likely a manifestation of anoxia due to large numbers of mononuclear leukemic cells
infiltrating the centrilobular sinusoids. However, mononuclear cell leukemias are common in
aging F344 rats, and the NTP data show high levels of these leukemias in the control rats as well.
There appears to be no significant relationship between the chemical and these leukemias. No
treatment-related nonneoplastic lesions were seen at 30 ppm. The authors identified a NOAEL
of 30 ppm (1.5-1.6 mg/kg-day) (Chhabra et al., 2001; NTP, 2001) based on liver effects seen at
higher doses. A LOAEL of 100 ppm (5-5.4 mg/kg-day) is identified based on increased
incidences of bile-duct hyperplasia (females) and centrilobular hypertrophy (in males and
females).
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Table 3. Changes in Mice Exposed to l,l'-Sulfonylbis
(4-chlorobenzene) Via the Diet for 14 Weeks"
Parameter
Dietary Concentration in ppm
(Dose in mg/kg-d)
0
30
(3.5 mg/kg-d)
100
(15 mg/kg-d)
300
(50 mg/kg-d)
1000
(165 mg/kg-d)
3000
(480 mg/kg-d)
Males
Terminal body weight
(g)
33.7 ± 0.5b
36.0 ±0.5
33.5 ±0.8
30.9 ± 0.4°
28.9 ± 0.4°
28.5 ± 0.3°
Organ weights
Absolute liver weight
(g)
1.71 ±0.03
1.86 ±0.04
1.79 ±0.05
1.95 ± 0.04°
2.39 ± 0.06°
2.95 ± 0.06°
Relative liver weight
(g/g-bw)
4.85 ±0.09
4.93 ±0.11
5.02 ±0.08
5.89 ± 0.10°
7.65 ± 0.10°
9.91 ± 0.17°
Histopathology
Centrilobular
hypertrophy
0/10d
0/10
6/10e (1.0)f
10/10e (2.0)
10/10e (3.0)
10/10e (3.0)
Hepatocellular
necrosis
0/10
0/10
1/10 (1.0)
3/10(1.0)
7/10e (1.0)
8/10e(1.0)
Females
Terminal body weight
(g)
27.7 ±0.7
29.3 ±0.8
28.5 ±0.6
25.3 ± 0.4e
24.1 ±0.5e
23.9 ± 0.2e
Organ weights
Absolute liver weight
(g)
1.25 ±0.04
1.34 ±0.04
1.34 ±0.02
1.56 ± 0.05e
1.80 ± 0.05e
2.30 ± 0.04e
Relative liver weight
(g/g-bw)
4.39 ±0.07
4.47 ±0.08
4.75 ± 0.09e
6.04 ± 0.13e
7.14 ± 0.12e
9.09 ± 0.10e
Histopathology
Centrilobular
hypertrophy
0/10
0/10
0/10
0/10
10/10e (1.0)
10/10e (2.0)
Hepatocellular
necrosis
0/10
0/10
0/10
0/10
1/10 (1.0)
2/10 (1.5)
aChhabra et al. (2001).
bValues are presented as means ± SE.
Significantly different from control (p < 0.01).
dNumber of animals affected/number examined.
"Significantly different from control (p < 0.05).
fAverage severity grades of lesions in affected animals (1, minimal; 2, mild; 3, moderate; 4, marked) in parentheses.
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Table 4. Incidence of Nonneoplastic Liver Lesions in Rats Fed
l,l'-Sulfonylbis(4-chlorobenzene) for 2 Years"
Dietary concentration in ppm
(dose in mg/kg-d)
Centrilobular
Hypertrophy
Bile-Duct
Hyperplasia
Centrilobular
Degeneration
Males
0
0/50b
46/50 (1.7)
18/50 (2.0)
10 (0.5 mg/kg-d)
1/50 (1.0)
47/50 (1.5)
15/50 (2.1)
30 (1.5 mg/kg-d)
3/50 (1.0)
44/50 (1.8)
20/50 (2.1)
100 (5.0 mg/kg-d)
16/50° (1.3)
48/50 (1.9)
23/50 (2.2)
Females
0
0/50
5/50 (1.4)
1/50 (1.0)
30 (1.6 mg/kg-d)
2/50 (1.5)
12/50(1.1)
5/50 (2.0)
100 (5.4 mg/kg-d)
24/50° (1.3)
21/50° (1.0)
10/50° (2.2)
300 (17 mg/kg-d)
38/50° (1.7)
32/50° (1.0)
7/50d (1.7)
aChhabra et al. (2001).
bNumber of animals affected/number examined. Average severity grades of lesions in affected animals (1,
minimal; 2, mild; 3, moderate; 4, marked) in parentheses.
Significantly different from control (p < 0.01).
dSignificantly different from control (p < 0.05).
In the 2-year study in mice, groups of 50 male and 50 female B6C3Flmice were fed diets
containing l,r-sulfonylbis(4-chlorobenzene) (>99% pure) at 0, 30, 100, or 300 ppm,
corresponding to doses of 0, 4, 13, or 40 mg/kg-day in males and 0, 3, 10, or 33 mg/kg-day in
females (Chhabra et al., 2001; NTP, 2001). Endpoints examined in the mouse study were the
same as those in the corresponding rat study. Survival of treated mice was similar to controls,
and no clinical signs related to treatment were observed. Feed consumption was similar to
controls in all groups, but mean body weights among high-dose mice were less than the controls
throughout most of the study; terminal body weights appeared to be within 10% of controls for
male—but not female—mice based on data presented graphically (statistical analysis was not
reported). Statistically significant, dose-related increases in the incidence of centrilobular
hypertrophy in the liver were found in male mice at >30 ppm and female mice at >100 ppm (see
Table 5). The lesions were morphologically similar to those in rats (described above) and
increased in severity in relation to dose. The only other nonneoplastic lesion noted was a
significant increase in eosinophilic foci in the livers of female mice treated with 300 ppm (see
Table 5). The study authors did not identify effect levels for mice (Chhabra et al., 2001;
NTP, 2001). A LOAEL of 30 ppm ( 4 mg/kg-day) is identified based on increased incidence of
centrilobular hypertrophy in male mice; a NOAEL cannot be determined. Liver cell hypertrophy
is considered adverse given the evidence for eosinophilic foci in female mice exposed
chronically and liver cell necrosis in male and female mice exposed subchronically to
1, l'-sulfonylbis(4-chlorobenzene).
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Table 5. Incidence of Nonneoplastic Liver Lesions in Mice Fed
l,l'-Sulfonylbis(4-chlorobenzene) for 2 Years"
Dietary concentration in ppm
(dose in mg/kg-d)
Centrilobular
Hypertrophy
Eosinophilic Focus
Males
0
1/50b (1.0)
5/50
30 (4 mg/kg-d)
24/50° (1.0)
9/50
100 (13 mg/kg-d)
43/50° (1.4)
7/50
300 (40 mg/kg-d)
45/50° (2.8)
8/50
Females
0
0/50
2/50
30 (3 mg/kg-d)
0/50
1/50
100 (10 mg/kg-d)
9/50° (1.0)
4/50
300 (33 mg/kg-d)
29/50° (1.4)
14/50°
aChhabra et al. (2001).
bNumber of animals affected/number examined. Average severity grades of lesions in affected animals (1,
minimal; 2, mild; 3, moderate; 4, marked) in parentheses.
Significantly different from control (p < 0.05).
No statistically significant increases in tumor incidence related to
l,r-sulfonylbis(4-chlorobenzene) treatment were found in any dose group (rats or mice) during
the 2-year studies (Chhabra et al., 2001; NTP, 2001). The NTP concluded that there was no
evidence of carcinogenic activity of l,l'-sulfonylbis(4-chlorobenzene) in rats or mice in this
study.
Inhalation Exposure
No animal studies examining the effects of subchronic or chronic inhalation exposure to
l,l'-sulfonylbis(4-chlorobenzene) were located.
Other Studies
Acute/Short-term Studies
A short-term toxicity study evaluating hepatic enzyme induction was conducted by
Poon et al. (1999). Groups of six weanling male Sprague-Dawley rats were exposed to
0 (4% corn oil), 10, 100, or 1000 ppm of l,l'-sulfonylbis(4-chlorobenzene) (>99% purity) in the
diet for 28 days. The authors reported that these dietary concentrations corresponded to doses of
0, 0.8, 8.1, or 75.6 mg/kg-day. Additional control and 1000-ppm exposure groups (6/group)
were included for evaluation after 1, 2, and 3 weeks of exposure. Body weights and changes in
food consumption were monitored weekly and clinical observations were made daily. Urine
samples were collected weekly and analyzed for N-acetylglucosaminidase (NAG) activity,
protein, and ascorbic acid. At termination at the end of exposure, blood was collected for
hematology (erythrocyte count, hematocrit, MCV, MCH, platelet count, and total and differential
white blood cell counts) and clinical chemistry (inorganic phosphate, total protein, ALP,
aspartate aminotransferase [AST], bilirubin, calcium, cholesterol, glucose, uric acid, creatinine,
and blood urea nitrogen). Lavage fluid from the lung was collected for analysis of NAG and
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total protein, both biochemical markers for lung injury (Poon et al., 1999). The brain, heart,
thymus, liver, kidney, and spleen were excised and weighed. Liver homogenates were collected
for enzyme analyses (UDP-glucuronosyltransferase [UDPGT] activity, benzyloxyresorufin
O-dealkylase [BROD], methoxyresorufin O-dealkylase [MROD], pentoxyresorufin O-dealkylase
[PROD], ethoxyresorufin O-deethylase [EROD], glutathione S-transferase [GST] activity, and
thiobarbituric acid-reactive substances [TBARS]), and parts of the liver, spleen, kidneys, brain,
lungs, and abdominal fat were collected for analysis of l,r-sulfonylbis(4-chlorobenzene).
All animals survived to the end of the experimental period without clinical signs of
toxicity, although hematuria was observed in one animal from each of the 1-, 3-, and 4-week
groups exposed to 1000 ppm (Poon et al., 1999). After 4 weeks, body weight was statistically
significantly reduced by about 7% in the high-dose group (relative to controls,/? < 0.05), and
there was a significant corresponding decrease in feed consumption in this group. Hematology
analysis revealed a statistically significant increase in platelet count among high-dose rats;
however, the authors reported that the levels were within the normal range of variation in rats.
No significant changes were observed in total protein or NAG activity in lavage fluid or in urine
samples.
Exposure to l,l'-sulfonylbis(4-chlorobenzene) resulted in a number of hepatic effects,
including serum chemistry changes, increased microsomal enzyme activities, and increased liver
weight (Poon et al., 1999), as shown in Table 6. Serum chemistry findings included a
statistically significant increase in cholesterol at 1000 ppm (nearly 3-fold increase over controls),
and decrease in lactate dehydrogenase at >100 ppm. Marked increases in BROD and PROD
activity were observed in all dose groups, and UDPGT and GST activities were increased more
than 3-fold among high-dose rats. In contrast, MROD activity was significantly decreased in
high-dose rats, and EROD activity was not affected by treatment. In addition, urinary ascorbic
acid, a biomarker of hepatic enzyme induction in rats, was significantly elevated in all exposure
groups. Other serum and urine chemistry parameters were not statistically significantly affected
by exposure. After 4 weeks of exposure, relative liver weight was increased by 33% and 97% in
the 100-ppm and 1000-ppm groups, respectively. The time-course study revealed that while
liver weight and UDPGT and GST activities were maximally increased after 1 week of
treatment, BROD and PROD levels tended to increase from Week 1 to Week 4. The only other
statistically significant organ weight change was an increase in relative kidney weight in
high-dose rats (20% higher than controls, p < 0.05).
Residue analysis showed that the highest levels of l,l'-sulfonylbis(4-chlorobenzene)
residues were in adipose tissue, followed by the liver and kidneys; low levels of
l,l'-sulfonylbis(4-chlorobenzene) were measured in the lungs (Poon et al., 1999). The kidney
was the only organ that demonstrated increased l,l'-sulfonylbis(4-chlorobenzene) accumulation
over time during the time-course study.
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Table 6. Hepatic Enzyme Induction and Related Effects in Male Rats Treated with
l,l-Sulfonylbis(4-chlorobenzene) Via Diet for 28 Days"

Dose in mg/kg-d
Controlb
0.8b
8.1b
75.6b
Clinical chemistry
Serum cholesterol (mg/dL)
58.0 ±6.6
61.3 ±9.8
73.5 ± 11.2
161.8 ± 31.7°
Serum lactate dehydrogenase (IU/L)
2179 ±775
1714 ±638
1333 ± 500°
1234 ± 328°
Urinary ascorbic acid
(mg/g creatinine)
84 ±55
913 ±445c
1929 ± 346°
1403 ± 651°
Hepatic enzyme activities
BROD
0.09 ±0.01
0.41 ± 0.15°
9.07 ±5.33°
6.04 ± 2.07°
PROD
0.04 ±0.01
0.16 ± 0.07°
0.62 ± 0.36°
1.0 ± 0.23°
EROD
0.07 ±0.01
0.08 ±0.02
0.06 ± 0.02
0.04 ± 0.02
MROD
0.07 ±0.01
0.07 ± 0.02
0.05 ±0.03
0.02 ±0.01c
UDPGT
1.74 ±0.85
2.83 ±0.95
5.83 ± 1.31°
11.06 ± 2.13°
GST
943 ± 169
1223 ±217
2734 ± 510°
4237 ± 757°
TBARS (nmol/mg protein)
0.44 ± 0.22
0.39 ±0.10
0.47 ±0.30
1.35 ± 0.40°
Organ weights
Relative liver weight (% body weight)
3.52 ±0.18
3.8 ±0.36
4.68 ± 0.23°
6.92 ± 0.46°
"Poonetal. (1999).
bMean ± standard deviation.
Significantly different from control atp< 0.05.
BROD = benzyloxyresorufin O-dealkylase; PROD = pentoxyresorufin O-dealkylase; EROD = ethoxyresorufin
O-deethylase; MROD = methoxyresorufin O-dealkylase; UDPGT = UDP-glucuronosyltransferase;
GST = glutathione S-transferase; TBARS = thiobarbituric acid-reactive substances.
Genotoxicity
No evidence of mutagenicity was observed in Salmonella typhimurium strains TA97,
TA98, TA100, TA1535, 1537, or 1538 (DuPont, 1991; NTP, 2001), or in CHO/HGPRT cells
(Microbiological Associates, Inc., 1991a; NTP, 2001) tested with or without metabolic
activation. Evidence of weak mutagenic activity was observed in the mouse lymphoma L5178Y
assay when tested without metabolic activation—but not with metabolic activation (Inveresk
Research International, 1994). Tests for sister chromatid exchanges or chromosomal aberrations
in CHO cells treated with l,l'-sulfonylbis(4-chlorobenzene) gave equivocal and negative results
(respectively; NTP, 2001). Conflicting results were observed in mouse micronucleus assays
performed in vivo; l,l'-sulfonylbis(4-chlorobenzene) induced a weak positive response in mice
injected (intraperitoneally) with 200-800 mg/kg for 3 consecutive days (NTP, 2001) but a
negative response in male and female mice given a single intraperitoneal injection of 196 to
1960 mg/kg (Microbiological Associates Inc., 1991b).
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DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD
VALUES FOR l,l'-SULFONYLBIS(4-CHLOROBENZENE)
Oral studies of l,r-sulfonylbis(4-chlorobenzene) include subchronic and chronic studies
in mice and rats, all conducted by NTP (2001) and published by Chhabra et al. (2001). Table 7
summarizes the available oral dose-response information. A short-term (28-day) study that
focused on hepatic enzyme induction (Poon et al., 1999) provides supplemental information.
Table 7. Summary of Subchronic and Chronic Oral Toxicity Studies of
l,l'-Sulfonylbis(4-chlorobenzene)
Species,
sex,
number
Dose
(mg/kg-d)
Exposure
Regimen
NOAEL
(mg/kg-d)
LOAEL
(mg/kg-d)
Responses at the LOAEL
Reference
Rat,
10/sex/
dose
0, 2, 6, 19, 65,
200
Diet for
14 wk
2
6
Increased incidence of
centrilobular hypertrophy
and increased liver weight
in males
Chhabra et al.,
2001; NTP, 2001
Mouse,
10/sex/
dose
0, 3.5, 15, 50,
165, 480
Diet for
14 wk
3.5
15
Increased incidence of
centrilobular hypertrophy in
males
Chhabra et al.,
2001; NTP, 2001
Rat,
50/sex/
dose
0,0.5, 1.5,5
(M)
0, 1.6, 5.4, 17
(F)
Diet for
2 yr
1.5-1.6
5-5.4
Increased incidence of
bile-duct hyperplasia
(females) and centrilobular
hypertrophy (both sexes)
Chhabra et al.,
2001; NTP, 2001
Mouse,
50/sex/
dose
0, 4, 13, 40
(M)
0, 3, 10, 33
(F)
Diet for
2 yr
NA
4
Increased incidence of
centrilobular hypertrophy in
males
Chhabra et al.,
2001; NTP, 2001
The available studies suggest that the liver is the most sensitive target for
l,l'-sulfonylbis(4-chlorobenzene). Poon et al. (1999) showed that induction of hepatic drug
metabolizing enzymes occurs at the lowest doses that have been tested (0.8 mg/kg-day). At
higher doses, l,l'-sulfonylbis(4-chlorobenzene) produces liver lesions that increase in incidence
and severity with dose—including hepatocellular hypertrophy characterized by both cytomegaly
and karyomegaly, bile-duct hyperplasia, eosinophilic foci, and necrosis (Chhabra et al., 2001;
NTP, 2001). Increased liver weight was observed in all studies, and serum chemistry changes
indicative of hepatotoxicity (increased sorbitol dehydrogenase and bile acids) were found at
higher doses in the subchronic rat study (the only study that analyzed serum chemistry).
Subchronic p-RfD
Table 7 shows a summary of the subchronic rat and mouse data. In rats, a NOAEL and
LOAEL of 2 and 6 mg/kg-day, respectively, have been identified based on increased liver weight
and hepatocellular hypertrophy in males. In mice, a NOAEL and LOAEL of 3.5 and
15 mg/kg-day, respectively, have been identified based on hypertrophy in males
(Chhabra et al., 2001; NTP, 2001). The data on hepatocellular hypertrophy in both species are
not amenable to benchmark dose (BMD) modeling. This is primarily due to the shapes of the
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dose-response curves where the large increase in incidence (from 0/10 to 7/10 in male rats, and
0/10 to 6/10 in male mice) between the control and the low-dose and a subsequent plateau in
response levels at higher doses. That resulted in poor fits with the models in the EPA BMDS
software package. Also, relative liver weight changes in male rats are not modeled because the
data are confounded by decreases in body weight at the higher doses. While reduced overall
body weights may have had some impact on absolute liver weights, any such impact is expected
to be mitigated by the determination of the effect on relative liver weight, where body weight is
actually used in the calculation to normalize for such variations. BMD modeling was conducted
for increases in absolute liver weight in male rats (see Table 1).
Appendix A provides details of the modeling efforts and the selection of best fitting
models. The 2-degree polynomial model with homogenous variance provides the best fit to the
data on absolute liver weight in male rats after the three highest dose groups were dropped (no
model fit was achieved with more dose groups); the BMDisd and BMDLisd associated with this
endpoint were 4.21 and 3.56 mg/kg-day, respectively. This BMDLisd was selected as a suitable
point of departure for derivation of the subchronic p-RfD. While comparisons have no weight
programmatically, the BMDLisd of 3.56 mg/kg-day for increased absolute liver weight in male
rats is below the LOAELs for hypertrophy in both rats (6 mg/kg-day) and mice (15 mg/kg-day).
Physiologically based pharmacokinetic models as constructed by Matthews et al. (1996)
and Parham et al. (2002) were of inadequate applicability to reduce the uncertainty factor used
for animal to human extrapolation.
A subchronic p-RfD is derived by dividing the BMDL of 3.56 mg/kg-day by a UF of
1000, as shown below:
Subchronic p-RfD = BMDL UF
= 3.56 mg/kg-day ^ 1000
= 0.004 mg/kg-day or 4 x 10 3 mg/kg-day
The UF of 1000 is composed of the following:
•	UFr: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating susceptible human response are
insufficient.
•	UFa: A factor of 10 is applied for animal-to-human extrapolation because data for
evaluating relative interspecies sensitivity are insufficient.
•	UFd: A factor of 10 is applied for database inadequacies because data for
evaluating developmental and reproductive toxicity are lacking. The database for
l,l'-sulfonylbis(4-chlorobenzene) includes comprehensive subchronic and
chronic oral toxicity studies conducted by the NTP using both sexes of two
species (Chhabra et al., 2001; NTP, 2001), as well as a limited short-term study in
rats (Poon et al., 1999).
Confidence in the principal study (Chhabra et al., 2001; NTP, 2001) is high. Groups of
10 rats/sex/dose were used, a wide range of doses was tested, both a NOAEL and LOAEL were
identified, and comprehensive toxicological endpoints were evaluated (body weight, clinical
signs, neurobehavioral screening, hematology, clinical pathology, organ weights, and gross and
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histological pathology). Confidence in the database is medium. Although comprehensive
subchronic and chronic studies were conducted in rats and mice of both sexes by NTP,
developmental and reproductive toxicity have not been evaluated. Medium confidence in the
subchronic p-RfD follows.
Chronic p-RfD
Effects were observed at similar doses in mice and rats exposed chronically to
l,l'-sulfonylbis(4-chlorobenzene); the NOAEL and LOAEL in rats were ~2 and 5 mg/kg-day,
while the LOAEL in male mice (a NOAEL was not identified) was 4 mg/kg-day
(Chhabra et al., 2001; NTP, 2001). The data for centrilobular hypertrophy and bile-duct
hyperplasia in female rats, and centrilobular hypertrophy in male mice were considered for use in
the chronic p-RfD derivation. Although the incidence of centrilobular hypertrophy was also
increased in male rats exposed at the LOAEL, the incidence of this effect in males was lower
than in females exposed to the same dose. BMD modeling of the data on incidences of
centrilobular hypertrophy and bile-duct hyperplasia in female rats (see Table 4) was conducted.
The centrilobular hypertrophy data in male mice (see Table 5) are not amenable to BMD
modeling; the data results in inadequate model fits due to the large increase in incidence (from
1/50 to 24/50) between controls and the lowest dose, and, additionally, there were no data points
with response levels near the default benchmark response of 10% for quantal data.
Appendix B provides details of the modeling efforts and selection of best fitting models.
The log-probit model provided the best fit to the data on centrilobular hypertrophy in female rats;
the BMDio and BMDLio associated with this endpoint were 1.97 and 1.62 mg/kg-day,
respectively. The log-logistic model provided the best fit to the data on bile-duct hyperplasia in
female rats; the BMDio and BMDLio associated with this endpoint were 1.17 and
0.79 mg/kg-day, respectively. The lower BMDLio for bile-duct hyperplasia was selected as the
point of departure for derivation of the chronic p-RfD. This value is somewhat lower than the
LOAEL of 4 mg/kg-day for centrilobular hypertrophy in male mice.
A chronic p-RfD is derived by dividing the BMDLio of 0.79 mg/kg-day by a UF of
1000, as shown below:
Chronic p-RfD = BMDLio UF
= 0.79 mg/kg-day 1000
= 0.0008 mg/kg-day or 8 x 10"4
The UF of 1000 is composed of the following:
•	UFr: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating susceptible human response are
insufficient.
•	UFa: A factor of 10 is applied for animal-to-human extrapolation because data for
evaluating relative interspecies sensitivity are insufficient.
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• UFd: A factor of 10 is applied for database inadequacies because data for
evaluating developmental and reproductive toxicity are lacking. The database for
l,r-sulfonylbis(4-chlorobenzene) includes comprehensive subchronic and
chronic oral toxicity studies conducted by the NTP using both sexes of two
species (Chhabra et al., 2001; NTP, 2001), as well as a limited short-term study in
rats (Poon et al., 1999).
Confidence in the principal study (Chhabra et al., 2001; NTP, 2001) is medium. Groups
of 50 rats/sex/dose were used, three dose levels were tested, and both a NOAEL and LOAEL are
identified, but the endpoints examined are limited to survival, body weight, and comprehensive
gross and histological pathology. Confidence in the database is medium. Although
comprehensive subchronic and chronic studies were conducted in rats and mice of both sexes by
NTP (2001), developmental and reproductive toxicity have not been evaluated. Medium
confidence in the chronic p-RfD follows.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR l,l'-SULFONYLBIS(4-CHLOROBENZENE)
No data are available on the effects of l,l'-sulfonylbis(4-chlorobenzene) in humans or
animals exposed via inhalation; derivation of provisional RfC values for
l,l'-sulfonylbis(4-chlorobenzene) is precluded by the absence of data.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR 1,1' -SULFONYLBIS(4-CHLOROBENZENE)
Weight-of-Evidence Descriptor
Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is
"Inadequate Information to Assess [the overall] Carcinogenic Potential' of
1, l'-sulfonylbis(4-chlorobenzene). This is primarily because of the lack of information on a
second route of exposure. It should be noted that l,l'-sulfonylbis(4-chlorobenzene) may be
considered "Not Likely to be Carcinogenic to Humans" by the oral route of exposure based on
animal evidence demonstrating a lack of carcinogenic effect in both sexes in well-designed and
well-conducted studies in two appropriate animal species (U.S. EPA, 2005). These were large
studies (50/species/sex) conducted by NTP (2001) in both sexes of two species, using 3 dose
levels plus controls in each study. Survival was high in all treated and control groups; at study
termination, 20-45 animals remained available for tumor evaluation in the various groups. Dose
levels were selected based on subchronic studies, and changes in body weight and liver lesions
(described above) suggest that the high dose in each study approached the MTD (maximum
tolerated dose). There are no data on the potential carcinogenicity of
l,l'-sulfonylbis(4-chlorobenzene) in humans exposed orally.
Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is
"Inadequate Information to Assess [the] Carcinogenic potential' of
1, l'-sulfonylbis(4-chlorobenzene) by the inhalation route of exposure. There are no data on the
potential carcinogenicity of l,l'-sulfonylbis(4-chlorobenzene) in humans exposed via inhalation,
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and no inhalation bioassays are available. Genotoxicity data on this compound are limited, but
generally, the data resulted in equivocal or negative findings. Some evidence suggests that
l,l'-sulfonylbis(4-chlorobenzene) has the potential for induction of chromosomal damage in the
form of breakage or aneuploidy in vivo (NTP, 2001). Thus, while
l,l'-sulfonylbis(4-chlorobenzene) may be considered "not likely" by the oral route of exposure,
the "inadequate" determination from the inhalation route yields an overall "Inadequate
Information to Assess [the overall] Carcinogenic Potential' descriptor.
Quantitative Estimates of Carcinogenic Risk
Derivation of quantitative estimates of cancer risk for l,l'-sulfonylbis(4-chlorobenzene)
is precluded by the lack of data showing a carcinogenic effect.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2008. Threshold Limit
Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH,
Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2008. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service.
Online, http://www.atsdr.cdc.gov/toxprofiles/index.asp.
Chhabra, R.S., R.A. Herbert, J.R. Buchner et al. 2001. Toxicology and carcinogenesis studies of
p,p'-dichlorodiphenyl sulfone in rats and mice. Toxicol. Sci. 60:28-37.
DuPont. 1991. Studies on l,r-sulfonylbis(4-chlorobenzene). Performed by Haskell
Laboratories. Submitted by E.I. duPont de Nemours & Co. to U.S. EPA. OTS0533718.
IARC (International Agency for Research on Cancer). 2008. Search IARC Monographs.
Online, http://www.iarc.fr/.
Inveresk Research International. 1994. 4,4'-Dichlorodiphenyl sulphone mouse lymphoma
mutation assay. Performed by Inveresk Research Intl., Scotland. Submitted U.S. EPA by
Amoco Corporation, Chicago, IL. OTS0557565.
Matthews, J.M., S.L. Black, andH.B. Matthews. 1996. p,p'-Dichlorodiphenyl sulfone
metabolism and disposition in rats. Drug Metabolism and Disposition. 24(5):579-587.
Microbiological Associates, Inc. 1991a. CHO/HGPRT mutation assay with confirmation. Test
article: 4,4'-dichlorodiphenyl sulfone. Performed by Microbiological Associates, Rockville MD.
Submitted to U.S. EPA by Amoco Corporation, Chicago, IL. OTS053422.
Microbiological Associates, Inc. 1991b. Micronucleus cytogenetic assay in mice. Amended
final report. 4,4'-Dichlorodiphenylsulfone. Performed by Microbiological Associates, Rockville
MD. Submitted to U.S. EPA by Amoco Corporation, Chicago, IL. OTS0534323.
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NIOSH (National Institute for Occupational Safety and Health). 2008. NIOSH Pocket Guide to
Chemical Hazards. Index by CASRN. Online, http://www.cdc.gov/niosh/npe/.
NTP (National Toxicology Program). 2001. NTP Technical Report on the Toxicology and
Carcinogenesis Studies of p,p'-Dichlorodiphenyl Sulfone (CAS No. 80-07-9) in F344/N Rats
and B6C3F1 Mice (Feed Studies). National Toxicology Program, Research Triangle Park, NC.
September 2001. NTP TR501.
NTP (National Toxicology Program). 2005. 11th Report on Carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Online, http://ntp.niehs.nih.eov/ntp/roc/tocl 1 .htm.
OSHA (Occupational Safety and Health Administration). 2008. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Online.
https://www.osha.gov/pls/oshaweb/owadisp.show document?!) table standards&p id=9992.
Parham, F.M., H.B. Matthews, and C.J. Portier. 2002. Toxicology and Applied Pharmacology
181:153-163
Poon, R., P. Lecavelier, I. Chu et al. 1999. Effects of bis(4-chlorophenyl) sulfone on rats
following 28-day dietary exposure. J. Toxicol. Environ. Health. 56:185-198.
U.S. EPA (Environmental Protection Agency). 1991. Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April.
U.S. EPA (Environmental Protection Agency). 1994. Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
December.
U.S. EPA (Environmental Protection Agency). 1997. Health Effects Assessment Summary
Tables. FY-1997 Update. Prepared by the Office of Research and Development, National
Center for Environmental Assessment, Cincinnati OH for the Office of Emergency and Remedial
Response, Washington, DC. July. EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA (Environmental Protection Agency). 2000. Benchmark Dose Technical Guidance
Document. External Review Draft. Risk Assessment Forum. EPA/630/R-00/001. October.
U.S. EPA (Environmental Protection Agency). 2005. Guidelines for Carcinogen Risk
Assessment. Risk Assessment Forum, National Center for Environmental Assessment,
Washington, DC. EPA/630/P-03/001F. Online, http://www.epa.gov/cancerguidelines/.
U.S. EPA (Environmental Protection Agency). 2006. 2006 Edition of the Drinking Water
Standards and Health Advisories. Office of Water, Washington, DC. EPA/822/R-06/013.
Washington, DC. Online, http://water.epa.gov/drink/standards/hascience.cfm.
U.S. EPA (Environmental Protection Agency). 2008. Integrated Risk Information System
(IRIS). Online. Office of Research and Development, National Center for Environmental
Assessment, Washington, DC. http://www.epa.gov/iris/.
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WHO (World Health Organization). 2008. Online catalogs for the Environmental Health
Criteria Series. Online.
http://www.who.int/ipcs/publications/ehc/ehc alphabetical/en/index.html.
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APPENDIX A. DETAILS OF BENCHMARK DOSE MODELING
FOR SUBCHRONIC RfD
Model-Fitting Procedure for Continuous Data:
The model-fitting procedure for continuous data is as follows. The simplest model
(linear) is first applied to the data while assuming constant variance (EPA BMDS version 2.0).
If the data are consistent with the assumption of constant variance (p> 0.1), then the fit of the
linear model to the means is evaluated and the polynomial, power, and Hill models are fit to the
data while assuming constant variance. Adequate model fit is judged by three criteria:
goodness-of-fit p-value {p > 0.1), visual inspection of the dose-response curve, and scaled
residual at the data point (except the control) whose dose is closest to the BMD corresponding to
the predefined BMR. Among all the models providing adequate fit to the data, the lowest
BMDL is selected as the POD when the difference between the BMDLs estimated from these
models are more than 3-fold; otherwise, the BMDL from the model with the lowest AIC is
chosen. If the test for constant variance is negative, the linear model is run again while applying
the power model integrated into the BMDS to account for nonhomogenous variance. If the
nonhomogenous variance model provides an adequate fit (p > 0.1) to the variance data, then the
fit of the linear model to the means is evaluated and the polynomial, power, and Hill models are
fit to the data and evaluated while the variance model is applied. Model-fit and POD selection
proceed as described earlier. If the test for constant variance is negative and the nonhomogenous
variance model does not provide an adequate fit to the variance data, then the data set is
unsuitable for modeling.
Model-Fitting Results for Changes in Absolute Liver Weight in Male Rats (NTP, 2001):
The default benchmark response of one standard deviation from the control mean was
used. Applying the procedure outlined above to the data for absolute liver weight in male rats,
no model fit was achieved with the full data set, so the high dose groups were sequentially
dropped from the analysis in an effort to achieve model fit. Adequate fits to the means and
variance data were achieved with the linear and polynomial models (constant variance) after the
three highest dose groups were dropped. Table A-l shows the results. BMDLisds from models
providing adequate fit differed by less than 3-fold. In accordance with U.S. EPA (2000)
guidance, the BMDLisd associated with the lowest AIC was selected from among the models
providing adequate fit. The 2-degree polynomial model had the lowest AIC; this model resulted
in BMDisd and BMDLisd values of 4.21 and 3.56 mg/kg-day, respectively.
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Table A-l. Model Predictions for Changes in Absolute Liver Weight in Male Rats"
Model
Variance
/7-Valueb
Means
/7-Valueb
AIC
bmd1sd
(mg/kg-d)
BMDL1sd
(mg/kg-d)
All dose groups
Hill, (constant variance)0
0.5878
0.04755
117.3108
4.27011
2.55666
Linear, Polynomial, and Power Models
generate identical results (constant
variance)d
0.5878
<0001
182.4915
51.858
42.5989
Without high dose group
Hill (constant variance)0
NA
Linear and polynomial (all degrees) yield
identical results (constant variance/
0.4448
0.000578
108.2518
12.0538
10.011
Power (constant variance)0
NA
Without two high dose groups
Hill (constant variance)0
NA
Linear and polynomial (all degrees) yield
identical results (constant variance/
0.6114
0.01782
75.19208
5.85109
4.57678
Power (constant variance)0
NA
Without three high dose groups
Hill (constant variance)0
NA
Linear and 1-degree polynomial (constant
variance/
0.5906
0.1453
56.92811
2.96167
2.09017
2-degree polynomial (constant variance/
0.5906
0.7309
54.92518
4.20852
3.56358
Power (constant variance)0
NA
aNTP, 2001.
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
°Power restricted to >1.
Coefficients restricted to be positive.
AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration
associated with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the
BMD/BMC; NA = Models generated errors, produced unusable outputs; SD = standard deviation.
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Polynomial Model with 0.95 Confidence Level
Dose
13:22 02/24 2009
Figure A-l. Fit of 2-Degree Polynomial (Constant Variance) Model to Data for Changes in
Absolute Liver Weight in Male Rats (NTP, 2001)
BMDs and BMDLs indicated are associated with a change of 1 SD from the control, and are in units of mg/kg-day.
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APPENDIX B. DETAILS OF BENCHMARK DOSE MODELING
FOR CHRONIC RfD
Model-Fitting Procedure for Quantal Noncancer Data:
The model-fitting procedure for dichotomous noncancer data is as follows. All available
dichotomous models in the EPA BMDS (version 2.0) are 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). Adequate model fit is judged by three criteria:
goodness-of-fit p-value (p > 0.1), visual inspection of the dose-response curve, and scaled
residual at the data point (except the control) closest to the predefined BMR. Among all the
models providing adequate fit to the data, the lowest BMDL is selected as the point of departure
when the difference between the BMDLs estimated from these models are more than 3-fold;
otherwise, the BMDL from the model with the lowest AIC is chosen. In accordance with
U.S. EPA (2000) guidance, benchmark doses (BMDs) and lower bounds on the BMD (BMDLs)
associated with an extra risk of 10% are calculated for all models.
Model-Fitting Results for the Incidence of Centrilobular Hypertrophy in Female Rats
(NTP, 2001):
Applying the procedure outlined above to the data for centrilobular hypertrophy in female
rats, adequate model fit was achieved with the log-logistic, log-probit, 1-degree multistage, and
quantal linear models. Table B-l shows the results. BMDLs from models providing adequate fit
differed by less than 3-fold. In accordance with U.S. EPA (2000) guidance, the model with the
lowest AIC was selected from among the models providing adequate fit. For this data set, the
log probit model was selected, resulting in a benchmark dose (BMDio) and associated 95% lower
confidence limit (BMDLio) of 1.97 and 1.62 mg/kg-day, respectively. Figure B-l shows the
model fit of the log probit model to the data.
Model-Fitting Results for the Incidence of Bile-Duct Hyperplasia in Female Rats
(NTP, 2001):
Applying the procedure outlined above to the data for bile-duct hyperplasia in female
rats, adequate model fit was achieved with all but the logistic and probit models. Table B-l
shows the results for the data. BMDLs from models providing adequate fit differed by less than
3-fold. In accordance with U.S. EPA (2000) guidance, the lowest AIC was selected from among
models providing adequate fit. For this data set, the log-logistic model was selected resulting in
a benchmark dose (BMDio) and associated 95% lower confidence limit (BMDLio) of 1.17 and
0.79 mg/kg-day, respectively. Figure B-2 shows the model fit of the log-logistic model to the
data.
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Table B-l. Model Predictions for Centrilobular Hypertrophy in Female Rats Exposed to
l,l'-Sulfonylbis(4-chlorobenzene) Via Diet for 2 Years"
Model
Degrees of
Freedom
x2
X2 Goodness
of Fit
/7-Valueb
AIC
BMD10
(mg/kg-d)
BMDL10
(mg/kg-d)
Gamma (power > 1)
2
5.88
0.05
151.36
1.62
1.00
Logistic
2
23.89
0.00
172.18
3.59
2.93
Log logistic (slope > 1)
2
3.46
0.18
148.79
1.82
1.14
Log probit (slope > 1)
3
3.01
0.39
146.17
1.97
1.62
Multistage (degree = I,
betas > 0)
3
5.93
0.11
150.19
1.20
0.97
Multistage (degree = 2,
betas > 0)
2
5.95
0.05
152.19
1.20
0.97
Multistage (degree = 3,
betas > 0)
2
5.95
0.05
152.19
1.20
0.97
Probit
2
22.96
0.00
170.33
3.43
2.85
Weibull (power > 1)
2
6.03
0.05
151.72
1.48
0.99
Quantal linear
3
5.93
0.11
150.19
1.20
0.97
aNTP (2001).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration
associated with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the
BMD/BMC; NA = Not applicable; SD = standard deviation.
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LogProbit Model with 0.95 Confidence Level
Dose
16:29 02/23 2009
Figure B-l. Fit of Log Probit Model to Data on Centrilobular Hypertrophy (NTP, 2001)
BMDs and BMDLs indicated are associated with an extra risk of 10%, and are in units of mg/kg-day.
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Table B-2. Model Predictions for Bile-Duct Hyperplasia in Female Rats Exposed to
l,l'-Sulfonylbis(4-chlorobenzene) Via Diet for 2 Years"
Model
Degrees of
Freedom
x2
X2 Goodness
of Fit
/7-Valueb
AIC
BMD10
(mg/kg-d)
BMDL10
(mg/kg-d)
Gamma (power > 1)
2
1.68
0.43
226.67
1.79
1.33
Logistic
2
5.35
0.07
230.63
3.60
2.93
Log logistic (slope > 1)
2
0.19
0.91
225.18
1.17
0.79
Log probit (slope >1)
2
4.64
0.10
229.73
3.27
2.39
Multistage (all degrees yield
identical results, betas > 0)
Weibull (power > 1) & quantal
linear yield identical results
2
1.68
0.43
226.67
1.79
1.33
Probit
2
5.10
0.08
230.33
3.45
2.83
aNTP (2001).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
AIC = Akaike Information Criterion; BMD/BMC = maximum likelihood estimate of the dose/concentration
associated with the selected benchmark response; BMDL/BMCL = 95% lower confidence limit on the
BMD/BMC; NA = Not applicable; SD = standard deviation.
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Log-Logistic Model with 0.95 Confidence Level
Dose
17:03 02/23 2009
Figure B-2. Fit of Log-Logistic Model to Data on Bile-Duct Hyperplasia (NTP, 2001)
BMDs and BMDLs indicated are associated with an extra risk of 10%, and are in units of mg/kg-day
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