United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/019F
Final
9-29-2009
Provisional Peer-Reviewed Toxicity Values for
Diphenyl sulfone
(CASRN 127-63-9)
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
DIPHENYL SULFONE (CASRN 127-63-9)
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.
INTRODUCTION
No RfD, RfC, or cancer assessment for diphenyl sulfone (chemical structure shown in
Figure 1) is available on IRIS (U.S. EPA, 2009), in the 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, 1994,
1991a). ATSDR (2009) has not published a Toxicological Profile for diphenyl sulfone and no
Environmental Health Criteria Document is available (WHO, 2009). The American Conference
of Governmental Industrial Hygienists (ACGIH, 2008), the Occupational Safety and Health
Administration (OSHA, 2009), and the National Institute for Occupational Safety and Health
(NIOSH, 2009) have not established occupational health standards for diphenyl sulfone. The
carcinogenicity of diphenyl sulfone has not been assessed by the International Agency for
Research on Cancer (IARC, 2009) or the National Toxicology Program (NTP, 2009, 2005).
Figure 1. Chemical Structure of Diphenyl Sulfone
Literature searches were conducted from the 1960s through August 2009 for studies
relevant to the derivation of provisional toxicity values for diphenyl sulfone. Databases searched
include MEDLINE, TOXLINE (with NTIS), BIOSIS, TSCATS/TSCATS2, CCRIS, DART,
GENETOX, HSDB, RTECS, Chemical Abstracts, and Current Contents.
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REVIEW OF PERTINENT DATA
Human Studies
No human data having the ability to inform the derivation of either inhalation or oral
exposure toxicity values for diphenyl sulfone have been located.
Animal Studies
Oral Exposure
One relevant animal toxicity study was located. Groups of CD Sprague-Dawley rats
(15/sex/group) were fed diets containing 0, 100, 200, or 2,000 ppm of diphenyl sulfone (purity at
least 99.5%) for 13-14 weeks (HLE, 1981). Because of the logistics of processing, the
medium- and low-dose male rats—and some of the control males—were sacrificed after
14 weeks of treatment, rather than the target of 13 weeks. The study authors calculated the
intake of diphenyl sulfone as 0, 8, 16, or 164 mg/kg-day in males and 0, 9, 19, or 206 mg/kg-day
in females. Animals were observed daily for clinical signs of toxicity. Body weights and food
consumption were recorded weekly. The eyes of all animals were examined with an
ophthalmoscope before treatment, and the examination was repeated in control and high-dose
animals during Weeks 6 and 13. Blood samples were collected from five males and five females
per group during Weeks 1 and 12 to measure diphenyl sulfone concentrations in plasma (pooled
by sex and group). In addition, after 0, 5, and 12 weeks, 16-hour fasting blood and urine samples
were collected from 10 rats per sex in the control and high-dose groups for standard hematology
and clinical chemistry analyses and urinalysis. The same numbers of medium and low-dose rats
were also fasted. Although fluids were not routinely collected from these animals, certain
investigations were extended to these groups to elucidate changes observed in the high-dose rats.
At termination, each animal was necropsied. The final organ weights of the adrenal, brain, heart,
kidneys, liver, lungs, pituitary, ovaries/testes, spleen, and thyroids were measured.
Histopathological examination of the liver and kidneys was conducted on all animals, and
34 other tissues were examined in animals in the control and high-dose groups. In six animals
per sex in the high-dose, medium-dose, and control groups, liver samples were examined by
electron microscopy; in six animals per sex in all groups, liver homogenates were measured for
aminopyrine-iV-demethylase (APDM) activity, which is a biomarker of hepatic metabolic status.
According to the HLE (1981), no treatment-related deaths were observed. Treatment
with diphenyl sulfone reportedly had no significant effect on the incidence of clinical signs.
Body weights on Week 13 at the end of the study were significantly reduced by 11% in males
and 9% in females of the high-dose group, and they were reduced—but not significantly—in
males at the medium dose (see Table 1). Food consumption was about 5% lower than controls in
high- and medium-dose males, but it was similar to controls in females. The study authors
calculated that the efficiency of food conversion was reduced in high-dose animals throughout
most of the study. From this, they concluded that the adverse effect on weight gain in high-dose
rats was a primary effect of diphenyl sulfone rather than a palatability effect. Plasma
measurements of diphenyl sulfone verified dose-related increases in absorption. No
treatment-related ocular changes were observed. Statistically significant reductions were found
for red cell hematological parameters: hemoglobin (Hgb) levels in high-dose males (Week 13)
and females (Week 13), red blood cell (RBC) counts in high dose males (Week 13), and packed
blood cell volumes (PCV) in high-dose males and females at Week 13 and medium-dose males
at Week 14 (see Table 1). However, the study authors considered these changes to be within the
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range of normal values. The study authors reported that no significant changes were observed in
other hematological parameters (total and differential white cell counts, prothrombin clotting
time, or activated partial thromboplastin coagulation time) (data not shown). Statistically
significant changes in two clinical chemistry parameters were observed in high-dose rats:
elevations in plasma cholesterol in males (Week 13), and reductions in plasma alkaline
phosphatase (ALP) in males (Week 13); slight increases in cholesterol and triglycerides and a
decrease in plasma ALP were observed in females, but they were not statistically significantly
different from control (see Table 1). Furthermore, the biological significance of these changes is
uncertain. The study authors reported that no other significant changes were observed in blood
chemistry parameters (plasma glucose, blood urea nitrogen [BUN], albumin, total protein,
sodium, potassium, cholesterol, alanine aminotransferase [ALT], or aspartate aminotransferase
[AST]) (data not shown). The only treatment-related change in urinalysis parameters reported by
the study authors was a slight increase in ketones and reducing substances in the urine of
high-dose males and females. Treatment was reported to have no effect on urine pH or urine
levels of bilirubin, urobilinogen, protein, glucose, or cells, or other solid constituents. The
urinalysis data are not provided in the report.
According to HLE (1981), no gross treatment-related lesions were observed at necropsy.
Liver and kidney weights were elevated in treated rats compared to controls (see Table 1);
statistically significant elevations occurred in absolute liver and kidney weights in high-dose rats
of both sexes, in relative liver weights in high- and mid-dose rats of both sexes, and in relative
kidney weights in high- and mid-dose males and high- and low-dose females. Mean relative
brain weights were significantly elevated in high-dose animals of both sexes compared to
controls. The study authors reported no changes in the weights of other organs (data not shown).
Histopathology was observed in the liver, kidney, and spleen (see Table 1). Lesions in the
kidney, which were observed only in male rats, were characterized by the study authors as
"tubular degeneration/regeneration and eosinophilic droplet formation in the proximal kidney
tubules." Eosinophilic droplets were seen in all male groups including controls, but these
droplets increased in incidence and severity with dose. Tubular degeneration and regeneration
were observed only in high-dose male rats. The study authors stated that the accumulation of
eosinophilic droplets (possibly reabsorbed protein) in kidney tubules of male rats was of
uncertain toxicological significance because it commonly occurred in control males and the
observed increases could have been adaptive responses to treatment. Considering
sex-specificity, the proximal tubule location of droplet formation and the progression to tubular
degeneration are consistent with hyaline droplet nephropathy associated with alpha 2U-globulin
accumulation, which is specific to male rats (U.S. EPA, 1991b). However, there is no
confirming evidence that the male renal pathology in this study was related to alpha 2U-globulin.
Hemosiderosis in the spleen of high-dose rats is consistent with the hematological changes
observed in this group, but it was considered incidental to treatment by the study authors. In the
liver, hepatocellular hypertrophy was a dose-related finding. Ultrastructural analysis of the liver
revealed a proliferation of smooth endoplasmic reticulum in livers from high-dose males (6/6)
and females (6/6) and minimal changes in a third of the medium-dose males (2/6) examined.
Some high-dose males (2/6) and females (1/6) also showed increased lipid vacuolization in
hepatocytes. In addition, high-dose males and females showed significant elevations in liver
aminopyrine-/V-demethylase activity.
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Table 1. Changes in Sprague-Dawley Rats Fed Diets Containing
Diphenyl Sulfone for 13-14 Weeks"

Dietary concentration (ppm)
Control
100
200
2,000
Males
Dose (mg/kg-day)
0
8
16
164
Number of animals examined
15
15
15
15
Body weight (Week 13)
464 ± 52b
467 ± 45
438 ±56
411 ±27°
Hematology
Hgb (g/dL, Week 13)
16.8
--
--
15.6d
Hgb (g/dL, Week 14)
15.4
15.0
14.8
~
RBC (mil/cmm, Week 13)
8.53
--
--
7.85d
RBC (mil/cmm, Week 14)
7.97
7.71
7.72
~
PCV (%, Week 13)
44
--
--
40d
PCV (%, Week 14)
41
40
39°
~
Clinical chemistry (Week 13)
Cholesterol (mg/dL)
44
--
--
-o
00
00
Triglycerides (mg/dL)
78
--
--
75
ALP (IU/L)
271
--
--
153d
Organ weights
Liver (g)
13.82
14.32
14.45
21.56d
Kidney (g)
2.42
2.63
2.51
3.57d
Brain (g)
1.96
2.00
1.97
2.02
Relative organ weights (% of body weight)
Liver
3.001
3.100
3.330d
5.258d
Kidney
0.529
0.570
0.584°
0.869d
Brain
0.432
0.436
0.463
0.494d
Histopathology findings
Kidneys (tubular degeneration/
regeneration/
0/15e
—
~
15/15®
(slight-to -moderate)
Kidneys (eosinophilic droplet
formation/
8/15
(minimal)
12/15
(minimal-to -slight)
14/15®
(slight)
15/15®
(moderate-to-marked)
Liver (cellular hypertrophy/
6/15
(minimal)
11/15
(minimal-to -slight)
13/15®
(minimal-to -slight)
15/15®
(slight-to -moderate)
Spleen (hemosiderosis)
2/15
--
--
9/15®
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Table 1. Changes in Sprague-Dawley Rats Fed Diets Containing
Diphenyl Sulfone for 13-14 Weeks"

Dietary concentration (ppm)
Control
100
200
2,000
Females
Dose (mg/kg-day)
0
9
19
206
Number of animals examined
15
15
15
15
Body weight (Week 13)
258 ± 27b
261 ±28
250 ± 18
235 ±22
Hematology (Week 13)
Hgb (g/dL)
16.3
--
--
15.3d
RBC (mil/cmmj
8.10
--
--
7.94
PCV (%)
43
--
--
41°
Clinical chemistry (Week 13)
Cholesterol (mg/dL)
66
--
--
93
Triglycerides (mg/dL)
66
--
--
70
ALP (IU/L)
132
--
--
112
Organ weights
Liver (g)
7.79
8.70
8.90
13.16d
Kidney (g)
1.39
1.53°
1.47°
1.60d
Brain (g)
1.79
1.82
1.81
1.82
Relative organ weights (% of body weight)
Liver
3.131
3.443
3.610°
5.608d
Kidney
0.561
0.610°
0.598
0.680d
Brain
0.726
0.731
0.742
0.779°
Histopathology findings
Kidneys (tubular degeneration/
regeneration/eosinophilic
droplet formation/
0/15°
—
—
0/15
Liver (cellular hypertrophy/
6/15
(minimal)
14/15®
(minimal-to -slight)
14/15®
(minimal-to -slight)
15/15®
(moderate-to-marked)
Spleen (hemosiderosis)
9/15
—
—
12/15
aHLE (1981).
bMean ± standard deviation (standard deviations reported only for body weight data in original study).
Significantly different from control atp< 0.05 (ANOVA, Students t-test).
d/?<0.01.
"Number affected/number examined.
fData from source Table 7, as superseded by source Tables 8-10 and source text p. A34-35.
8Significantly different from control at p< 0.05 (Fisher Exact test performed for this review).
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In summary, the HLE (1981) study revealed a number of significant effects following
diphenyl sulfone exposure. Body weights at the end of the study were significantly reduced
(9-11%) in the high-dose group due to a reduction in efficiency of food conversion. However,
no significant reduction in body weight was observed in the low- or mid-dose treated rats.
Dose-related renal effects were observed in male rats—including increased organ weight and
eosinophilic droplet formation in corticotubular epithelium at >16 mg/kg-day and tubular
degeneration/regeneration at 164 mg/kg-day. The available evidence suggests these changes
were probably associated with alpha 2U-globulin nephropathy, which is specific to male rats
(U.S. EPA, 1991b)—although this was not conclusively demonstrated. While increased kidney
weight was observed in female rats at doses down to 9 mg/kg-day, the lack of associated renal
histopathology in females at any dose suggests that the kidney weight changes in females were
not toxicologically significant. Although no overt signs of liver damage (e.g., increases in serum
biomarkers of hepatotoxicity, histological signs of liver degeneration) were observed at any
exposure level, several dose-related hepatic effects (e.g., increased absolute and/or relative organ
weights, hepatocellular hypertrophy, lipid vacuolization, proliferation in smooth endoplasmic
reticulum, hepatic aminopyrine-A-demethylase activity) were observed in males and females
following subchronic exposure to >16 mg/kg-day of diphenyl sulfone in the diet. For the
purpose of this review, a LOAEL of 16 mg/kg-day and a NOAEL of 8 mg/kg-day are identified
from the HLE (1981) study based on increased relative liver weight in male rats. Although the
study initially appeared to have been generally well designed, an incident in which a control
female escaped, became pregnant, littered, and was subsequently returned to the study raises
some uncertainty regarding implementation of standard procedures.
Inhalation Exposure
No relevant data have been located regarding the toxicity of diphenyl sulfone to animals
following inhalation exposure.
Other Studies
Diphenyl sulfone was tested for mutagenicity in a Sa/mone/la/Microsome assay. Briefly,
diphenyl sulfone was applied at concentrations of up to 5000 |ig/plate to cultures of Salmonella
typhimurium strains TA1535, TA100, TA1537, and TA98, in the presence or absence of
S9 fraction. Diphenyl sulfone concentrations up to—and including—5000 |ig did not induce
mutagenic activity in any strain tested with or without metabolic activation (Bayer AG, 1991).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR DIPHENYL SULFONE
Limited information is available on the oral toxicity of diphenyl sulfone, and only one
study, the HLE (1981) 13-week rat study, is of a duration relevant for assessing effects
associated with this compound. However, based upon current standard operating procedure,
unpublished principal or influential studies must be peer-reviewed before they can be considered
for reference-value derivation. Since the HLE (1981) study is an unpublished TSCA submission,
it is not known if the information has been peer-reviewed. As such, while subchronic and
chronic oral reference values cannot be derived here, "screening-level" evaluations of oral
diphenyl sulfone toxicity are provided in Appendix A.
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FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR DIPHENYL SULFONE
A provisional RfC cannot be derived for diphenyl sulfone because inhalation toxicity data
are not available in humans or animals.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR DIPHENYL SULFONE
Weight-of-Evidence Descriptor
Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is
"Inadequate Information to Assess [the] Carcinogenic Potential' of diphenyl sulfone. Studies
evaluating the carcinogenic potential of oral or inhalation exposure to diphenyl sulfone in
humans or animals were not identified in the available literature.
Quantitative Estimates of Carcinogenic Risk
Derivation of quantitative estimates of cancer risk for diphenyl sulfone is precluded by
the lack of suitable data.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2008) Threshold limit
values for chemical substances and physical agents and biological exposure indices. Cincinnati,
OH.
ATSDR (Agency for Toxic Substances and Disease Registry). (2009) Toxicological profile
information sheet. U.S. Department of Health and Human Services, Public Health Service.
Online, http://www.atsdr.cdc.gov/toxprofiles/index.asp.
Bayer AG. (1991) Final report: salmonella/microsome test with cover letter dated 4/23/92.
Submitted under TSCA; EPA Document No. 86-920000908; NTIS No. OTS0535645.
HLE (Hazleton Laboratories Europe, Ltd.). (1981) Initial submission: diphenyl sulfone: 13-week
feeding study in rats with cover letter dated 8/29/92. Submitted under TSCA; EPA Document
No. 88-920006821; NTIS No. OTS0543826.
IARC (International Agency for Research on Cancer). (2009) Search IARC monographs.
Online, http://monoeraphs.iarc.fr/.
NIOSH (National Institute for Occupational Safety and Health). (2009) NIOSH pocket guide to
chemical Hazards. Index by CASRN.
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-server.niehs.nih.eov/.
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NTP (National Toxicology Program). (2009) Testing status of agents atNTP. Online.
http://ntp.ni ehs.nih. gov: 8080/index.html?col=010stat.
OSHA (Occupational Safety and Health Administration). (2009) OSHA Standard 1915.1000 for
air contaminants. Part Z, Toxic and hazardous substances. Online, http://www.osha.gov/pls/
oshaweb/owadisp.show document?p tabie=STANDARDS&p id=9992.
U.S. EPA (Environmental Protection Agency). (1991a) Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
U.S. EPA (Environmental Protection Agency). (1991b) Alpha2U-globulin: association with
chemically induced renal toxicity and neoplasia in the male rat. Risk Assessment Forum,
Washington, DC; EPA/625/3-91/019F.
U.S. EPA (Environmental Protection Agency). (1994) Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
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; EPA/540/R-97/036. NTIS PB97-921199.
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/cancereuidelines/.
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. Online.
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf.
U.S. EPA (Environmental Protection Agency). (2009) Integrated Risk Information System
(IRIS). Office of Research and Development, National Center for Environmental Assessment,
Washington, DC. Online, http://www.epa.gov/iris/.
WHO (World Health Organization). (2009) 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. DERIVATION OF A SUBCHRONIC AND CHRONIC ORAL
SCREENING VALUE FOR DIPHENYL SULFONE (CASRN 127-63-9)
For reasons noted in the main PPRTV document, it is inappropriate to derive a
subchronic or chronic oral p-RfD for diphenyl sulfone based on the HLE (1981) 13-week rat
study. Specifically, as an unpublished, presumably nonpeer-reviewed TSCA submission, any
useful data provided in such a reference is currently deemed inappropriate for the derivation of
provisional toxicity values. However, the qualitative and quantitative information in the
HLE (1981) study may be used to support derivation of provisional oral screening values for
diphenyl sulfone (CASRN 127-63-9) that may be of use to risk assessors. In such cases, the
Superfund Health Risk Technical Support Center summarizes available information in an
Appendix. Information contained in an appendix receives 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 values in an appendix to a PPRTV
assessment should understand that there is considerably more uncertainty associated with the
derivation of an appendix screening 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 Subchronic Oral p-RfD
Limited information is available on the oral toxicity of diphenyl sulfone and only one
study, the HLE (1981) 13-week rat study, is available for evaluation of diphenyl sulfone effects.
This is a comprehensive subchronic study in which male and female rats were administered
diphenyl sulfone via diet in doses of 0, 8, 16, or 164 mg/kg-day and 0, 9, 19, or 206 mg/kg-day,
respectively for 13-weeks. The study examined a broad spectrum of gross, histological,
hematological, and clinical chemistry parameters/endpoints and identifies aNOAEL of
8 mg/kg-day and LOAEL of 16 mg/kg-day based on significantly increased relative liver weight
in exposed male rats, compared to control (female rats also exhibited a dose-dependent increase
in relative liver weight with a NOAEL of 9 mg/kg-day and LOAEL of 19 mg/kg-day). Increased
kidney weight was also observed in male and female rats; however, this observation was not
dose-dependent in females (Table 1). Kidney histopathology consistent with alpha 2U-globulin
nephropathy was observed in male rats. Conversely, no histopathology was observed in the
kidneys of female rats at the highest dose tested (206 mg/kg-day). Thus, kidney effects are not
considered further. High incidences of liver hypertrophy were observed in male and female rats
at all diphenyl sulfone doses tested; however, there was a 40% incidence of this cellular
phenotype in untreated controls of both sexes. As such, liver hypertrophy is not further
considered. Other observations include hepatic changes indicative of increased metabolic
activity, and hematological and splenic changes considered not to be treatment-related by the
study authors. Therefore, increased relative liver weight has been selected as the critical effect.
Dose-response modeling of the relative liver weight data is not possible because there are no
variance data provided with the mean values in the HLE (1981) study (individual animal data are
not available either). As such, the NOAEL of 8 mg/kg-day for significantly increased relative
liver weight in male rats is selected as the point of departure for derivation of the subchronic oral
screening value.
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FINAL
9-29-2009
A screening subchronic oral p-RfD for diphenyl sulfone is derived by dividing the
NOAEL of 8 mg/kg-day by a UF of 1000 as shown below:
Screening Subchronic Oral p-RfD = NOAEL UF
= 8 mg/kg-day ^ 1000
= 0.008 or 8 x 10 3 mg/kg-day
The composite UF of 1000 is composed of the following:
A 10-fold UF for laboratory animal-to-human interspecies differences (UFa) is applied to
account for the variability in extrapolating from rats to humans. No information is available on
toxicokinetic or toxicodynamic differences or similarities for diphenyl sulfone in animals and
humans. In the absence of data to quantify specific toxicokinetic and toxicodynamic differences,
a default factor of 10 is applied.
A 10-fold UF for intraspecies differences (UFH) is applied to account for variability in
susceptibility in human populations. The default value of 10 is selected in the absence of
information indicating the degree to which humans may vary in susceptibility to diphenyl
sulfone toxicity.
A 10-fold UF for deficiencies in the diphenyl sulfone database (UFD) is applied because
the database for diphenyl sulfone includes only a single subchronic animal study, and no chronic
oral toxicity studies in any species. Furthermore, the database lacks any information concerning
reproductive and developmental endpoints following diphenyl sulfone exposure.
Screening Chronic Oral p-RfD
Derivation of the chronic oral screening value involves dividing the same subchronic
NOAEL of 8 mg/kg-day for significantly increased liver weight (FILE, 1981) by a composite
uncertainty factor (UF) of 10,000. The screening chronic oral p-RfD for diphenyl sulfone is
calculated as follows:
Screening Chronic Oral p-RfD = NOAEL UF
= 8 mg/kg-day ^ 10,000
= 0.0008 or 8 x 10"4 mg/kg-day
The composite UF of 10,000 includes component factors of 10 for extrapolation from rats to
humans, 10 for human variability, 10 for extrapolation from subchronic to chronic duration, and
10 for database insufficiencies, as explained below.
A 10-fold UF for laboratory animal-to-human interspecies differences (UFa) is applied to
account for the variability in extrapolating from rats to humans. No information is available on
toxicokinetic or toxicodynamic differences or similarities for diphenyl sulfone in animals and
humans. In the absence of data to quantify specific toxicokinetic and toxicodynamic differences,
a default factor of 10 is applied.
A 10-fold UF for intraspecies differences (UFH) is applied to account for potentially
susceptible human subpopulations. In the absence of information on the variability in response
of humans to diphenyl sulfone, the full value of 10 is applied.
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FINAL
9-29-2009
A 10-fold UF is applied for using data from a subchronic study to assess potential effects
from chronic exposure (UFS), as data for evaluating response after chronic exposure are not
available.
A 10-fold UF for deficiencies in the diphenyl sulfone database (UFD) is applied because
the database for diphenyl sulfone includes only a single subchronic animal study, and no chronic
oral toxicity studies in any species. Furthermore, the database lacks any information concerning
reproductive and developmental endpoints following diphenyl sulfone exposure.
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