United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/015F
Final
9-28-2009
Provisional Peer-Reviewed Toxicity Values for
4,4' -Dichlorobenzophenone
(CASRN 90-98-2)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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COMMONLY USED ABBREVIATIONS
BMD
Benchmark Dose
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
RfC
inhalation reference concentration
RfD
oral reference dose
UF
uncertainty factor
UFa
animal to human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete to complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL to NOAEL uncertainty factor
UFS
subchronic to chronic uncertainty factor
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
4,4'-DICHLOROBENZOPHENONE (CASRN 90-98-2)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.S. EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	U.S. EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in U.S. EPA's IRIS. PPRTVs are developed according to a
Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific
literature using the same methods, sources of data, and Agency guidance for value derivation
generally used by the U.S. EPA IRIS Program. All provisional toxicity values receive internal
review by two U.S. EPA scientists and external peer review by three independently selected
scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multiprogram consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all U.S. EPA programs, while PPRTVs are developed
specifically for the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
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and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. EPA programs or
external parties who may choose of their own initiative to use these PPRTVs are advised that
Superfund resources will not generally be used to respond to challenges of PPRTVs used in a
context outside of the Superfund Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the U.S. EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
No RfD, RfC, or cancer assessment for 4,4'-dichlorobenzophenone (chemical structure
shown in Figure 1) is available on IRIS (U.S. EPA, 2009), the Drinking Water Standards and
Health Advisories list (U.S. EPA, 2006), or in the HEAST (U.S. EPA, 1997). The Chemical
Assessments and Related Activities (CARA) list (U.S. EPA, 1994, 1991) does not include any
documents pertaining to 4,4'-dichlorobenzophenone. ATSDR (2009) has not published a
toxicological profile for 4,4'-dichlorobenzophenone, and neither the World Health Organization
(WHO, 2009) nor CalEPA (2009a, b) has assessed the toxicity of 4,4'-dichlorobenzophenone.
Occupational exposure limits have not been established by the American Conference of
Governmental Industrial Hygienists (ACGIH, 2008), the National Institute for Occupational
Safety and Health (NIOSH, 2009), or the Occupational Safety and Health Administration
(OSHA, 2009). The carcinogenicity of 4,4'-dichlorobenzophenone has not been assessed by the
International Agency for Research on Cancer (IARC, 2009) or the National Toxicology Program
(NTP, 2009, 2005).
o
Figure 1. Chemical Structure of 4,4'-Dichlorobenzophenone
Literature searches were conducted from the 1960s through September 2009 for studies
relevant to provisional toxicity values for 4,4'-dichlorobenzophenone. The databases searched
include RTECS, HSDB, TSCATS, MEDLINE, TOXLINE, DART, CCRIS, GENETOX,
CHEMABS, BIOSIS, and Current Contents (last 6 months).
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REVIEW OF PERTINENT DATA
Human Studies
No studies were located regarding oral or inhalation exposure of humans to
4,4' -di chl orob enzophenone.
Animal Studies
Oral Exposure
In an unpublished subchronic toxicity study, Wistar rats (15/sex/dose) were administered
4,4'-dichlorobenzophenone (purity not reported) at 0, 100, or 1,250 ppm in the diet for 13 weeks
and then sacrificed (Ambrose and Borzelleca, 1965). Doses of 0, 7, or 86 mg/kg-day for males
and 0, 7, or 90 mg/kg-day for females were estimated for this assessment1. Body weights were
recorded weekly. Average daily food consumption was measured based on 3-day observations
during the fourth and thirteenth weeks. Hematological analyses, including hematocrit,
hemoglobin concentration, and total and differential white blood cell counts were performed
using blood samples collected from five rats/sex/dose in the fourth and thirteenth weeks. Urine
samples collected from five rats of each sex at each dose were pooled at Weeks 4 and 13 to
determine pH and the concentrations of protein and reducing substances. Average organ weights
and organ-to-body weight ratios of the heart, liver, spleen, kidney, adrenal glands, and testes
were recorded at 90-day sacrifice. Histopathological evaluations of the heart, lung, liver, spleen,
kidney, urinary bladder, gastroenteric system, skeletal muscle, bone marrow, skin, brain,
pituitary gland, thyroid, pancreas, adrenal glands, and gonad were performed.
Four rats died during the course of the experiment; two were control females, and two
were low-dose males (Ambrose and Borzelleca, 1965). The data showed no dose-related effects
on average body weights, food consumption, or hematological or urinalysis values after
treatment with 4,4'-dichlorobenzophenone (only mean values were shown; no statistical analyses
were reported). The only statistically significant finding reported was a reduction
(-18% decrease) in the heart-to-body weight ratio in males administered the high dose of
4,4'-dichlorobenzophenone. Neither a/>value nor the statistical test used to establish
significance was provided by the authors; a t-test specifically performed for this document
showedp < 0.02. Absolute heart weight did not differ considerably from controls in this group.
There was no effect of treatment on absolute or relative heart weight in females at any dose.
Because no treatment-related histopathological changes were detected in the heart or any other
tissue in either sex, this response for the decreased heart-to-body weight ratio is not considered
biologically significant, and therefore, a LOAEL is not identified. For the purpose of this
review, the highest dose tested of 86 mg/kg-day is identified as a NOAEL for subchronic toxicity
in rats; however, confidence in this value is low due to incomplete reporting of methods and
results.
Calculated by multiplying the dietary concentration (in ppm [mg chemical/kg food]) by the time weighted average
(TWA) daily food consumption rate (normalized for body weight) for each dose. TWA daily food intake was
calculated as the sum for all samples taken during an interval and divided by the total sampling time of values
reported for the fourth and thirteenth weeks. For example, in low-dose females, the dose was calculated to be
0.073 kg food/kg-bw ([0.097 x 4 + 0.063 x9]t 13) x 100 mg chemical/kg food = 7 mg/kg-day.
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Inhalation Exposure
No studies were located regarding inhalation exposure of animals to
4,4'-dichlorobenzophenone.
Other Studies
Genotoxicity
Limited genotoxicity testing of 4,4'-dichlorobenzophenone in vitro has produced
negative results. 4,4'-Dichlorobenzophenone did not significantly increase the number of
His+ revertants in several strains of Salmonella typhimurium with or without metabolic activation
(DeFlora et al., 1984; Bartsch et al., 1980; Planche et al., 1979) or significantly impair DNA
repair in Escherichia coli (DeFlora et al., 1990).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR 4,4'-DICHLOROBENZOPHENONE
Because the toxicity data based on the unpublished study (Ambrose and Borzelleca,
1965) are not peer reviewed, no provisional chronic or subchronic RfDs are developed.
However, the Appendix of this document contains screening chronic and subchronic p-RfD
values that may be useful in certain instances. Please see the attached Appendix for details.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR 4,4'-DICHLOROBENZOPHENONE
Provisional RfC values for 4,4'-dichlorobenzophenone cannot be derived because of the
lack of human or animal inhalation data.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR 4,4' -DICHLOROBENZOPHENONE
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 4,4'-dichlorobenzophenone.
No human or animal carcinogenicity data are available. A limited data set based on in vitro
studies in S. typhimurium and E. coli suggests that 4,4'-dichlorobenzophenone is not likely to be
genotoxic.
Quantitative Estimates of Carcinogenic Risk
Derivation of quantitative estimates of cancer risk for 4,4'-dichlorobenzophenone is
precluded by the lack of data.
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REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2008) Threshold limit
values for chemical substances and physical agents and biological exposure indices. Cincinnati,
OH.
Ambrose, A.M., Borzelleca, J.F. (1965) Toxicological study on the effect of adding
dichlorobenzophenone to the diet of rats for a period of three months. Conducted by the Medical
College of Virginia, Department of Pharmacology for Rohm and Haas. Unpublished study.
ATSDR (Agency for Toxic Substances and Disease Registry). (2009) Toxicological profile
information sheet. U.S. Department of Health and Human Services, Public Health Service.
Available online at http://www.atsdr.cdc.gov/toxpro2.html.
Bartsch, H.C.; Malaveille, A. Camus, G. et al. (1980) Validation and comparative studies on
180 chemicals with S. typhimurium strains and v79 Chinese hamster cells in the presence of
various metabolizing systems. Mutat Res 76:1-50.
CalEPA (California Environmental Protection Agency). (2009a) Search chronic RELs. Office of
Environmental Health and Hazard Assessment. Available online at http://www.oehha.ca.gov/air/
chronic rels/index.html.
CalEPA (California Environmental Protection Agency). (2009b) Search toxicity criteria
database. Office of Environmental Health and Hazard Assessment. Available online at
http://www.oehha.ca.gov/risk/ChemicalDB/index.asp.
DeFlora, S. Zanacchi, P. Camoirano, A.; et al. (1984) Genotoxic activity and potency of
135 compounds in the Ames reversion test and in a bacterial DNA-repair test. Mutat Res
133:161-198.
DeFlora, S., Zanacchi, P. Bennicelli, C. et al. (1990) Genotoxicity biotransformations and
interactions of marine pollutants as related to genetic and carcinogenic hazards. In: Grandjean,
E. ed. Advances in applied biotechnology series, Vol. 5. Carcinogenic, mutagenic, and
teratogenic marine pollutants: Impact on human health and the environment, pp. 3-31.
IARC (International Agency for Research on Cancer). (2009) Search IARC monographs.
Available online at http://monographs.iarc.fr/ENG/Monographs/allmonos90.php.
Moudgal C.J., Venkatapathy, R. Choudhury, H. Bruce RM, Lipscomb J.C. (2003) Application of
QSTRs in the selection of a surrogate toxicity value for a chemical of concern. Environ Sci
Technol. 37:5228-5235.
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. Available online at http://ntp-server.niehs.nih.gov.
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NTP (National Toxicology Program). (2009) Management status report. Available online at
http://ntp. niehs.nih.gov/index.cfm? obi ectid=78CC7E4C-F 1F6-975E-72940974DE301C3F.
OSHA (Occupational Safety and Health Administration). (2009) OSHA Standard 1910.1000
Table Z-l. Part Z, toxic and hazardous substances. Available online at
https://www.osha.eov/pls/oshaweb/owadisp.show document?p table standards&p id=9992.
Planche, G., Croisy, A. Malaveille, C. et al. (1979) Metabolic and mutagenicity studies on DDT
and 15 derivatives. Detection of l,l-bis(p-chlorophenyl)-2,2-dichloroethane and
l,l-bis(p-chlorophenyl)-2,2,2-trichloroethyl acetate (kelthane acetate) as mutagens in Salmonella
typhimurium and of l,l-bis(p-chlorophenyl)ethylene oxide, a likely metabolite, as an alkylating
agent. Chem Biol Interact 25:157-176.
U.S. EPA (Environmental Protection Agency). (1989) Integrated Risk Information System
(IRIS). IRIS Summary of Chlorobenzilate (CASRN 510-15-6). Office of Research and
Development, National center for Environmental Assessment, Washington, DC. Available online
at http://www.epa.gov/iris/.
U.S. EPA (Environmental Protection Agency). (1991) Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
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 and 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. U.S. Environmental Protection Agency, Risk Assessment Forum, Washington, DC.
EPA/630/P-03/001B. Available online at http://www.thecre.com/pdf/20050404 cancer.pdf.
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.
Available online at 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. Available online at http://www.epa.gov/iris/ (Accessed February 2009).
WHO (World Health Organization). (2009) Online catalogs for the Environmental Health
Criteria series. Available online at http://www.who.int/ipcs/publications/ehc/ehc alphabetical/
en/index.html.
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APPENDIX A. DERIVATION OF A SCREENING VALUE FOR
4,4'-DICHLOROBENZOPHENONE (CASRN 90-98-2)
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for 4,4'-dichlorobenzophenone. However, information is available for this
chemical which, although insufficient to support derivation of a provisional toxicity value, under
current guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health
Risk Technical Support Center summarizes available information in an Appendix and develops a
"screening value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
Superfund Health Risk Technical Support Center.
The NOAEL of 86 mg/kg-day (highest dose tested) in an unpublished 90-day study
(Ambrose and Borzelleca, 1965) could serve as a basis for development of screening subchronic
and chronic p-RfDs.
Oral Toxicity Values
Screening Subchronic p-RfD
Oral data for 4,4'-dichlorobenzophenone are limited to a single subchronic study in rats
(Ambrose and Borzelleca, 1965) in which no biologically significant effects were found after
treatment with 4,4'-dichlorobenzophenone at the highest dose tested. The highest dose tested
and identified from this study (i.e., 86 mg/kg-day) serves as a NOAEL for the derivation of the
screening subchronic p-RfD.
Using the NOAEL of 86 mg/kg-day from the subchronic study in rats (Ambrose and
Borzelleca, 1965) as the point of departure (POD), a screening subchronic p-RfD is derived for
4,4'-dichlorobenzophenone as follows:
Screening Subchronic p-RfD = NOAEL UF
= 86 mg/kg-day ^ 1,000
= 0.09 or 9 x 10"2 mg/kg-day
The composite uncertainty factor (UF) of 1,000 is composed of the following UFs:
	UFh: A factor of 10 is applied to account for intraspecies variability, including
variability in susceptibility in human populations and life-stages.
	UFa: A factor of 10 is applied for animal-to-human extrapolation, as data for
evaluating toxicokinetic or toxicodynamic differences are insufficient.
	UFd: A factor of 10 is applied for database inadequacies, as data for evaluating
developmental and reproductive toxicity are not available.
Confidence in the principal study (Ambrose and Borzelleca, 1965) is low because
reporting of methods and results was incomplete, particularly with regard to standard deviations
and statistical tests for body weight, food intake, and hematology values. Confidence in the
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database is low because supporting subchronic data were unavailable and developmental and
reproductive effects were not evaluated. Confidence in the subchronic p-RfD is accordingly low.
Screening Chronic p-RfD
Oral data for 4,4'-dichlorobenzophenone are limited to a single subchronic study in rats
(Ambrose and Borzelleca, 1965); no chronic studies are available. In the absence of adequate
chronic data, the POD used to derive the subchronic p-RfD was also used to derive a screening
chronic p-RfD. A screening chronic p-RfD for 4,4'-dichlorobenzophenone is derived as
follows:
Screening Chronic p-RfD = NOAEL UF
= 86 mg/kg-day ^ 10,000
= 0.009 or 9 x 10 3 mg/kg-day
The composite UF of 10,000 is composed of the following UFs:
	UFr: A factor of 10 is applied to account for intraspecies variability, including
variability in susceptibility in human populations and life-stages.
	UFa: A factor of 10 is applied for animal-to-human extrapolation, as data for
evaluating toxicokinetic or toxicodynamic differences are insufficient.
	UFd: A factor of 10 is applied for database inadequacies, as data for evaluating
developmental and reproductive toxicity are not available.
	UFS: A factor of 10 is applied for using data from a subchronic study to assess
potential effects from chronic exposure, as data for evaluating response after
chronic exposure are not available.
As discussed for the subchronic p-RfD, confidence is low in the principal study
(Ambrose and Borzelleca, 1965), the database, and the overall assessment. Additionally, a
surrogate study for 4,4'-dichlorobenzophenone (Moudgal et al., 2003) based on structural
similarity (structural surrogates) and toxicokinetics (metabolic surrogates) has suggested the use
of the IRIS chronic RfD for chlorobenzilate, of 2 x 10"2 mg/kg-day (U.S. EPA, 1989), as an
alternate RfD for 4,4'-dichlorobenzophenone. This alternate RfD, which differs by
approximately a factor of 2, is in support of the screening chronic p-RfD.
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