United States
Environmental Protection
1=1 m m Agency
EPA/690/R-15/008F
Final
6-30-2015
Provisional Peer-Reviewed Toxicity Values for
Diundecyl Phthalate
(CASRN 3648-20-2)
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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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Senthilkumar Perumal-Kuppusamy, DVM, PhD, DABT
Oak Ridge Institute for Science and Education
DRAFT DOCUMENT PREPARED BY
National Center for Environmental Assessment, Cincinnati, OH
PRIMARY INTERNAL REVIEWERS
Q. Jay Zhao, PhD, MPH, DABT
National Center for Environmental Assessment, Cincinnati, OH
Ghazi Dannan, PhD
National Center for Environmental Assessment, Washington, DC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document 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).
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TABLE OF CONTENTS
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVs	1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER)	4
HUMAN STUDIES	8
Oral Exposures	8
Inhalation Exposures	8
Other Exposures	8
ANIMAL STUDIES	8
Oral Exposure	8
Short-term-Duration Studies	8
Chronic-Duration Studies	11
Reproductive/Developmental Studies	11
Reproductive Studies	12
Carcinogenicity Studies	12
Inhalation Exposure	12
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	12
Acute/Short-Term Study	15
Toxicokinetics	15
Genotoxicity	15
DERIVATION 01 PROVISIONAL VALUES	16
DERIVATION OF ORAL REFERENCE DOSES	17
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)	17
Derivation of a Chronic Provisional RfD (Chronic p-RfD)	20
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	20
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR	20
MODE-OF-ACTION DISCI SSION	21
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	21
APPENDIX A. SCREENING PROVISIONAL VALUES	22
APPENDIX B. DATA TABLES	23
APPENDIX C. BENCHMARK DOSE MODELING RESULTS	29
MODEL-FITTING PROCEDURE FOR CONTINUOUS DATA	29
INCREASED RELATIVE LIVER WEIGHT IN MALE F344 RATS TREATED
WITH DIUNDECYL PHTHALATE FOR 21 DAYS (Barber et al., 1987; BIBRA,
1986)	29
APPENDIX D. REFERENCES	35
in

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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
MN
micronuclei
ACGIH
American Conference of Governmental
MNPCE
micronucleated polychromatic

Industrial Hygienists

erythrocyte
AIC
Akaike's information criterion
MOA
mode of action
ALD
approximate lethal dosage
MTD
maximum tolerated dose
ALT
alanine aminotransferase
NAG
N-acetyl-P-D-glucosaminidase
AST
aspartate aminotransferase
NCEA
National Center for Environmental
atm
atmosphere

Assessment
ATSDR
Agency for Toxic Substances and
NCI
National Cancer Institute

Disease Registry
NOAEL
no-observed-adverse-effect level
BMD
benchmark dose
NTP
National Toxicology Program
BMDL
benchmark dose lower confidence limit
NZW
New Zealand White (rabbit breed)
BMDS
Benchmark Dose Software
OCT
ornithine carbamoyl transferase
BMR
benchmark response
ORD
Office of Research and Development
BUN
blood urea nitrogen
PBPK
physiologically based pharmacokinetic
BW
body weight
PCNA
proliferating cell nuclear antigen
CA
chromosomal aberration
PND
postnatal day
CAS
Chemical Abstracts Service
POD
point of departure
CASRN
Chemical Abstracts Service Registry
POD[adj]
duration-adjusted POD

Number
QSAR
quantitative structure-activity
CBI
covalent binding index

relationship
CHO
Chinese hamster ovary (cell line cells)
RBC
red blood cell
CL
confidence limit
RDS
replicative DNA synthesis
CNS
central nervous system
RfC
inhalation reference concentration
CPN
chronic progressive nephropathy
RfD
oral reference dose
CYP450
cytochrome P450
RGDR
regional gas dose ratio
DAF
dosimetric adjustment factor
RNA
ribonucleic acid
DEN
diethylnitrosamine
SAR
structure activity relationship
DMSO
dimethylsulfoxide
SCE
sister chromatid exchange
DNA
deoxyribonucleic acid
SD
standard deviation
EPA
Environmental Protection Agency
SDH
sorbitol dehydrogenase
FDA
Food and Drug Administration
SE
standard error
FEV1
forced expiratory volume of 1 second
SGOT
glutamic oxaloacetic transaminase, also
GD
gestation day

known as AST
GDH
glutamate dehydrogenase
SGPT
glutamic pyruvic transaminase, also
GGT
y-glutamyl transferase

known as ALT
GSH
glutathione
SSD
systemic scleroderma
GST
glutathione-S-transferase
TCA
trichloroacetic acid
Hb/g-A
animal blood-gas partition coefficient
TCE
trichloroethylene
Hb/g-H
human blood-gas partition coefficient
TWA
time-weighted average
HEC
human equivalent concentration
UF
uncertainty factor
HED
human equivalent dose
UFa
interspecies uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFS
subchronic-to-chronic uncertainty factor
IVF
in vitro fertilization
UFd
database uncertainty factor
LC50
median lethal concentration
U.S.
United States of America
LD50
median lethal dose
WBC
white blood cell
LOAEL
lowest-observed-adverse-effect level


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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
DIUNDECYL PHTHALATE (CASRN 3648-20-2)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (http://www.epa.eov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVs
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
Diundecyl phthalate (DUP) (CASRN 3648-20-2) is a widely used chemical intermediate
in the synthesis of various industrial chemicals. It is a primary plasticizer for polyvinyl chloride
formulations and is used in car interiors, perfumes, and cosmetics. It is listed as a high
production volume chemical (NLM 2009). DUP is a clear viscous fluid and stable under room
conditions. The chemical structure of DUP is depicted in Figure 1, and its molecular formula is
C6H4 1,2 [COO(CH2)ioCH3]2 or C30H50O4. Some physicochemical properties of DUP are
provided in Table 1.
o
vOCH2(CH2)9CH3
.OCH2(CH2)9CH3
o
Figure 1. Chemical Structure of Diundecyl Phthalate
Table 1. Physicochemical Properties of Diundecyl Phthalate (CASRN 3648-20-2)
Property (Unit)
Value3
Density (g/cm3)
0.955 at 20°C
Vapor pressure (mm Hg at 25°C)
1.22 x 10-9
Log octanol-water partition coefficient (unitless)
11.49
Henry's law constant (atm-m3/mol)
5.60 x 10"5
Solubility in water (mg/L at 20°C)
1.11
Molecular weight (g/mol)
474.72
aSource: NLM (2009). unless otherwise noted.
A summary of available toxicity values for DUP from U.S. EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for
Diundecyl Phthalate (CASRN 3648-20-2)
Source/Parameter3
Value
(Applicability)
Notes
Reference
Noncancer
ACGIH
NV
NA
ACGIH (2013)
ATSDR
NV
NA
ATSDR (2014)
Cal/EPA
NV
NA
(Cal/EPA): Cal/EPA (2015a): Cal/EPA (2014)
NIOSH
NV
NA
NIOSH (2010)
OSHA
NV
NA
OSHA (2011); OSHA (2006)
IRIS
NV
NA
(U.S. EPA)
DWSHA
NV
NA
U.S. EPA (2012a)
HEAST
NV
NA
U.S. EPA (1994)
CARA HEEP
NV
NA
U.S. EPA (1994)
NTP
NV
NA
NTP (2012)
WHO
NV
NA
(WHO)
Cancer
IRIS
NV
NA
(U.S. EPA)
HEAST
NV
NA
U.S. EPA (2011a)
IARC
NV
NA
IARC (2013)
NTP
NV
NA
NTP (2014)
Cal/EPA
NV
NA
(Cal/EPA): Cal/EPA (2015a): Cal/EPA (2011)
ACGIH
NV
NA
ACGIH (2013)
"Sources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; Cal/EPA = California Environmental Protection Agency; CARA = Chemical
Assessments and Related Activities; DWSHA = Drinking Water Standards and Health Advisories;
HEAST = Health Effects Assessment Summary Tables; HEEP = Health and Environmental Effects Profile;
IARC = International Agency for Research on Cancer; IRIS = Integrated Risk Information System;
NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; OSHA
Occupational Safety and Health Administration; WHO = World Health Organization.
NA = not applicable; NV = not available.
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Literature searches were conducted on sources published from 1900 through
December 2014 for studies relevant to the derivation of provisional toxicity values for diundecyl
phthalate, CASRN 3648-20-2. The following databases were searched by chemical name,
synonyms, or CASRN: ACGM, ANEUPL, AT SDR, BIOSIS, Cal/EPA, CCRIS, CD AT,
ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP, GENE-TOX,
HAPAB, HERO, HMTC, HSDB, IARC, INCHEM IPCS, IP A, ITER, IUCLID, LactMed,
NIOSH, NTIS, NTP, OSHA, OPP/RED, PESTAB, PPBIB, PPRTV, PubMed (toxicology
subset), RISKLINE, RTECS, TOXLINE, TRI, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA
HEEP, U.S. EPA OW, U.S. EPA's Declassified CBI database, and U.S. EPA
TSCATS/TSCATS2. The following databases were searched for toxicity values or exposure
limits: ACGIH, AT SDR, Cal/EPA, U.S. EPA IRIS, IARC, NIOSH, NTP, OSHA, and WHO.
REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3 A and 3B provide an overview of the relevant database for DUP and includes all
potentially relevant subchronic-duration studies. The principal study that is chosen to derive
provisional toxicity values is identified in bold. Following the table, important aspects of all the
studies listed are provided in the study summary section in the same order as in the table, and
reference can be made to details provided in Tables 3A and 3B. The phrase "statistical
significance," used throughout the document, indicates ap-value <0.05 unless otherwise
indicated.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Diundecyl Phthalate (CASRN 3648-20-2)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAELa
BMDLa
LOAEL1
Reference
(Comments)
Notesb
Human
1. Oral (mg/kg-d)a
No Data
2. Inhalation (mg/m3)a
No Data
Animal
1. Oral (mg/kg-d)a
Short termd
5/5, F344 rat, daily
diet for 21 d
0, 286,1,177, or 2,445 (M);
0, 284,1,101, or 2,086 (F)
(0, 0.3,1.2, or 2.5% DUP
in the diet in both sexes)
Increased absolute and
relative liver weights in both
sexes.
NA (M)
284 (F)
119.4 for
increased
absolute and
relative liver
weight in males
286 (M)
1,101 (F)
Barber et al.
TR,
PR,
PS
(1987). RIBMA
(1986)

6/0, S-D rat, daily
gavage for 28 d
0 or 500
Sdcrm effects: Decreased SDcrm
counts, sperm motility, sperm
curvilinear velocity, sperm
straightness, and sperm linearity
Serum chemistrv: Increased
alkaline phosphatase, and
glutamate oxaloacetate
NA
NDr
500
Kwack et al.
(2009)
PR
Chronicf
ND
Developmental
toxicity
0/20-22, S-D rat,
daily gavage GD 6-20
0, 250, 500, or 1,000
Maternal: NA
Maternal:
Maternal: NDr
Maternal:
Saillenfait et al.
PR
Fetal: Increased fetal
malformation (supernumerary
14th rib)
1,000
Fetal: 250
Fetal: NDr
NA
Fetal:
500
(2013)
(LOAEL with
minimal
significance)
Carcinogenicity
ND
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Table 3A. Summary of Potentially Relevant Noncancer Data for Diundecyl Phthalate (CASRN 3648-20-2)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAEL3
BMDL3
LOAEL3
Reference
(Comments)
Notesb
2. Inhalation (mg/m3)a
Subchronic6
ND
Chronicf
ND
Reproductive/
Developmental
ND
Carcinogenicity
ND
aDosimetry: NOAEL, BMDL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-d) for oral noncancer effects.
bNotes: PS = principal study, indicated by bold text; PR = peer reviewed; TR = technical report.
cAcute = exposure for <24 h (U.S. EPA. 20021.
•'Short-term = repeated exposure for >24 h < 30 d (U.S. EPA. 20021.
"Long-term (Subchronic) = repeated exposure for >30 d < 10% lifespan for humans (more than 30 days up to approximately 90 days in typically used laboratory animal
species). fU.S. EPA. 20021.
'Chronic = repeated exposure for >10% lifespan for humans (more than approximately 90 days to 2 years in typically used laboratory animal species). (U.S. EPA. 20021.
GD = Gestation Day; NA = not applicable; ND = no data; NDr = not determined; S-D = Sprague-Dawley.
M and F in the parentheses denote male and female, respectively.
1
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Table 3B. Summary of Potentially Relevant Cancer Data for Diundecyl Phthalate (CASRN 3648-20-2)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry
Critical Effects
NOAEL
BMDL
LOAEL
Reference
(Comments)
Notes
Human
1. Oral (mg/kg-d)
Carcinogenicity ND
2. Inhalation (mg/m3)
Carcinogenicity ND
Animal
1. Oral (mg/kg-d)
Carcinogenicity ND
2. Inhalation (mg/m3)
Carcinogenicity ND
ND = no data.
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HUMAN STUDIES
Oral Exposures
No studies have been identified.
Inhalation Exposures
No studies have been identified.
Other Exposures
Medeiros et al. (1999) evaluated the skin sensitization response to DUP in an irritation
test and human repeated insult patch test (HRIPT) using the modified Draize procedure (Draize.
1959). The irritation test was conducted after a single 24 hours occluded patch exposure to DUP
in 15 subjects (14 females and 1 male). Evaluations were conducted 30 minutes and 24 hours
after patch removal. No significant irritation was observed in any of the subjects. The HRIPT
test was conducted after repeated applications (up to nine times) of DUP to the same skin site
with a contact period of 24 hours per application. Following a 10- to 17-day rest period, the
challenge phase was initiated on the 6th week, and DUP was again applied for 24 hours. Dermal
reactions were scored 48 and 72 hours after each application. Out of a 128 total test subjects
(both males and females) enrolled in the study, only 104 test subjects (both males and females)
completed the study. No evidence of dermal irritation or sensitization was observed, indicating
the lack of skin sensitization potential for DUP.
ANIMAL STUDIES
Oral Exposure
Short-term-Duration Studies
The short-term database includes two studies: a 21 -day study in rats (Barber et al.. 1987;
BIBRA. 1986) and a 28-day study in rats (Kwack et al.. 2009).
Barber et al. (1987): BIBRA (1986)
DUP (purity unknown) was fed to a group of five male and five female F344 rats at
dietary levels of 0 % (control), 0.3 % (low dose), 1.2 % (mid dose), or 2.5% (high dose) for
21 days (doses of 0, 286, 1,177, or 2,445 mg/kg-day, respectively, in males and 0, 284, 1,101, or
2,086 mg/kg-day, respectively, in females are calculated based on body weight and food intake
measurements provided in the study) (Barber et al.. 1987; BIBRA. 1986). All rats were weighed
individually 3 days before the start of treatment (Day -3), on the day treatment began (Day 0),
and subsequently twice weekly until the end of the treatment period. Food intakes were
measured over the period of days from Day -3 to 0, and continuous intakes were then measured
at twice-weekly intervals until the day preceding necropsy. The rats were sacrificed after an
overnight fast and blood was collected to determine serum triglyceride and cholesterol levels.
The liver, kidneys, and testes were weighed and preserved for histological examination. In
addition, samples of liver were processed for electron microscopy examination of the
peroxisomes; for histochemical demonstration of neutral fat; and for biochemical determination
of cyanide-insensitive palmitoyl-CoA oxidation, microsomal lauric acid 11- and
12-hydroxylation, and total and microsomal protein levels.
No variations in behavior and food intake were observed that could be considered
treatment related throughout the experimental period. The male rats in the high-dose group
showed a statistically and biologically (>10% change) significant reduction in body weight,
whereas males in the other two treatment groups did not show any statistically significant
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changes compared to control. Female rats in the mid- and high-dose groups showed a
statistically significant reduction (but less than 10% change) in body weight compared to control
(see Table B-l).
In the mid-dose group males, three rats had pale livers, and in high-dose group males,
two rats had a pale liver. In the female rats, an enlarged liver was seen in one rat each in the
mid-dose and high-dose group. Both sexes showed a statistically and biologically (>10%
change) significant increase in absolute and relative liver weights in the mid-dose and high-dose
groups. Although no statistically significant increase of absolute and relative liver weights were
observed in the low-dose groups of both sexes, DUP treated male rats showed more than 10%
change in both absolute and relative liver weights compared to control. In male rats, absolute
kidney weights were statistically and biologically (>10% change) significantly lower in the
mid- and high-dose groups, whereas no statistically significant difference in relative kidney
weights was observed in any of the treated male groups (see Table B-l). In female rats, no
statistically significant difference was observed in the absolute kidney weights of any of the
treated females, but relative kidney weights were statistically significantly higher in the mid- and
high-dose groups. The high-dose treated group showed a more than 10% increase compared to
control (see Table B-l). Since there is no change in the absolute kidney weight of females, the
increase in relative kidney weights of females could be due to a decrease in mean body weights.
No statistically significant difference was found in the absolute testes weights of any of the
treated groups, but relative testes weights were statistically significantly higher in the mid- and
high-dose groups (see Table B-l). The change in relative testes weights (and not in the absolute
testes weights) could also be due to a decrease in mean body weights.
In the high-dose group of both sexes, there was a moderate increase in peroxisomes in
both periportal and centrilobular areas of the liver (low- and mid-dose groups were not
examined). This was accompanied by changes in peroxisome associated parameters (i.e.,
increased activities of palmitoyl-CoA oxidation and lauric acid hydroxylation and decreased
concentrations of serum triglycerides and cholesterol). A dose-related, statistically significant
increase in cyanide-insensitive palmitoyl-CoA oxidation in the mid- and high-dose group of both
sexes was observed (see Table B-2). Statistically significant increases in lauric acid 11- and
12-hydroxylase activities were observed at all doses of DUP in males but only at the high dose in
females (see Table B-2). Serum triglyceride and total cholesterol concentrations were
statistically significantly lower in the mid- and high-dose group in males. In females, however,
no statistically significant difference was observed in the treated groups (see Table B-2). Total
hepatic protein concentrations were statistically significantly higher in the mid- and high-dose
group female rats (biological significance is unknown), but these values in males were similar to
control.
In the liver of mid- and high-dose males, an increase in individual cell necrosis and
vacuolization of centrilobular hepatocytes were observed (see Table B-3). In the high-dose
males, there was also a distention of both smooth and rough endoplasmic reticulum in the
centrilobular area. These findings, suggest that DUP is hepatotoxic in the mid- and high-dose
groups of male rats. In females, the only effect seen was a deposit of neutral lipid in the
centrilobular areas at high dose.
The degree of cytoplasmic basophilia in the liver was reduced in the mid- and high-dose
group of both sexes. The study authors considered this change in staining characteristics likely
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due to a change in the organelle component and metabolic status of the cell and noted that
alterations of this kind have been produced by other compounds that result in increases in
smooth endoplasmic reticulum and associated structures. The study authors considered this
change in cytoplasmic staining represents evidence of an adaptive change rather than a toxic
effect. No pathological abnormalities were detected in the testes (males) or in the kidneys of
either sex.
A lowest-observed-adverse-effect level (LOAEL) of 286 mg/kg-day is identified based
on increased absolute and relative liver weights in male rats. A no-observed-adverse-effect level
(NOAEL) was not identified.
Kwack et al. (2009)
In a 28-day study, DUP (purity unknown) was administered to six male Sprague-Dawley
rats daily by gavage (corn oil was used as vehicle) at 0 (control) or 500 mg/kg-day (Kwack et al..
2009). The control group received only corn oil. The animals were observed for immediate
signs of toxicity and examined once a day throughout the experimental period to record any
delayed acute effects and mortality. All rats were weighed on Days 0, 3, 6, 9, 12, 15, 18, 21, 24,
and 28. Food consumption was measured at the beginning of treatment and twice per week
during the 28-day treatment period. The rats were sacrificed under anesthesia, and heart, lung,
liver, kidneys, adrenal glands, spleen, thymus, thyroid glands, testes, and epididymis were
weighed, and organ-to-body-weight ratios were calculated. During sacrifice, blood was collected
for hematology analysis while serum separated from the collected blood was used for serum
biochemistry analysis. Hematology analysis included red blood cell count, hemoglobin
concentration, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, platelet
count, and white blood cell count. Serum biochemistry parameters included calcium, potassium,
sodium, albumin, blood urea nitrogen, triglyceride, creatinine, glucose, total cholesterol, total
bilirubin, total protein, alkaline phosphatase (ALP), glutamate pyruvate transaminase (GPT),
glutamate oxaloacetate transaminase (GOT), and /-glutamyl transferase (GGT). Urinalysis
included occult blood, pH, protein, urobilinogen, glucose, nitrite, bilirubin, ketone bodies,
leukocytes, and urine specific gravity. The right cauda epididymis was used for sperm count
analysis, and the left cauda epididymis was used to evaluate sperm motility. The sperm motion
parameters included percentage of motile sperm, average path velocity (VAP), straight-line
velocity (VSL), curvilinear velocity (VCL), amplitude of the lateral head displacement (ALH),
beat cross frequency (BCF), straightness (STR), and linearity (LIN).
No treatment-related statistically significant reductions in body weight, relative organ
weights, or food consumption were observed throughout the experiment. Also, no statistically
significant changes in any of the hematological parameters and urinalysis were observed. A
statistically significant increase in serum total protein (biological significance is unknown),
GOT, and ALP levels (9%, 50%, and 80%, respectively) in the treatment group compared to the
control group was observed. A statistically significant decrease in the mean sperm count, mean
sperm motility, VCL, STR, and LIN (28%, 63%, 17%, 19%, and 20%, respectively) in the
treatment group compared to the control group was observed (see Table B-4).
The dose of 500 mg/kg-day is a LOAEL for decreased sperm counts, sperm motility
VCL, STR, and LIN as well as increased serum ALP, and GOT levels in rats exposed by gavage
for 28-days. A NOAEL was not identified in this study.
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Chronic-Duration Studies
No studies have been identified.
Reproductive/Developmental Studies
Saillenfait et al. (2013)
Reproductive and developmental toxicity were evaluated in Sprague-Dawley rats.
Groups of 20-24 female rats were housed overnight with adult males. The presence of sperm in
the vaginal smear was considered to be GD 0. Groups of 20-22 pregnant rats were gavaged
once daily with 0, 250 (low dose), 500 (mid dose), or 1,000 (high dose) mg/kg-day of DUP
(>98% purity) in olive oil between Gestation Days (GD) 6-20 (Saillenfait et al.. 2013). The
animals were observed daily for any obvious signs of toxicity. Food consumption was recorded
every 3 days starting on GD 6. Maternal body weights were recorded on GD 0, 6, 9, 12, 15, 18,
and 21. Dams were sacrificed on GD 21 and the uterine horns were removed, and weighed. The
number of implantation sites, resorptions, dead and live fetuses from the uterus, and the number
of corpora lutea in each ovary were recorded. All live fetuses were individually weighed, sexed,
evaluated for external anomalies, and measured for anogenital distance (AGD). Half of the live
fetuses from each litter were examined for internal soft tissue changes and the other half was
examined for skeletal malformations.
No treatment-related clinical signs, mortalities, or statistically significant changes in
mean maternal body weights, gravid uterine weights, or maternal food consumption were
observed throughout the study (see Table B-5). No statistically significant differences were
observed in the number of corpora lutea or incidence of preimplantation loss. The numbers of
implants were statistically significantly lower than the control at the low and mid doses but not at
the high dose (see Table B-6). However, no effects on postimplantation loss, resorptions, live
fetuses, fetal sex ratio (percent male fetuses per litter), or fetal body weights were observed.
No statistically significant changes in AGD were observed in any of the treatment groups
of either sex. However, after adjustment with the cubic root of fetal body weight, a statistically
significant decrease was observed in the mid-dose group of male fetuses. Isolated cases of
malformations occurred in one fetus at low dose (omphalocele), in one fetus at mid dose (club
foot) and in one fetus at high dose (diaphragmatic hernia). The study authors considered these
cases incidental and not treatment related (see Table B-7). A statistically significant increase in
the number of fetuses with incidence of supernumerary 14th ribs was observed in the mid-, and
high-dose groups. The mean percentage of affected fetuses per litter in the control, low-, mid-,
and high-dose group was 10.3, 20.8, 46.6, and 25.4, respectively. The study authors reported
that the historical olive oil control groups have a range from 6.8 to 19.4% of affected fetuses per
litter (no further details were provided in the study). A statistically significant increase in the
number of litters with incidence of supernumerary 14th ribs was also observed in the mid-dose
group. Among the types of supernumerary 14th ribs, long supernumerary ribs (more than one
third of the length of the preceding rib) were observed in one fetus in the low-dose group and in
one fetus in the high-dose group. The remaining supernumerary 14th ribs were either pin-point
ossification sites (78-88%) or short (less than one third of the length of the preceding rib) in both
control and treated groups. These pin-point ossification sites and short supernumerary ribs are
transient and tends to disappear in subsequent development, and therefore the incidence of
supernumerary 14th ribs observed in this study may not be considered as strong evidence for a
developmental toxic endpoint. In addition, although no clear dose-response relationship was
observed, the study authors pointed out that a relationship to treatment cannot be ruled out
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(see Table B-7). No statistically significant changes in the incidences of any other skeletal
variations were observed. The elevated number of ossified caudal vertebral centra in the
DUP-treated groups compared to control was not considered toxicologically meaningful by the
study authors. These data indicate a maternal NOAEL of 1,000 mg/kg-day; a maternal LOAEL
was not identified. The developmental NOAEL is 250 mg/kg-day, with a LOAEL (with minimal
biological significance) of 500 mg/kg-day, based on the increased incidence of the
supernumerary 14th ribs in rats.
Reproductive Studies
No studies have been identified.
Carcinogenicity Studies
No studies have been identified.
Inhalation Exposure
No studies have been identified.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Tables 4A and 4B summarize other studies conducted with DUP that are not appropriate
for selection of a point of departure (POD) for derivation of a provisional RfD (p-RfD) but
provide supportive data.
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Table 4A. Summary of Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute/Short-term study
0 or 0.5 mL DUP (purity not reported) applied
to the trunk and lateral areas of intact skin of
male albino rabbits (6/group) for 24 h.
Observations were made after 24 and 48 h of
application
Mild to very slight erythema and no
edema was observed after 24 and
48 h
DUP produced mild to no
skin irritation
DuPont (1983)
Metabolism/Toxicokinetics
14C-labeled Dimethyl, diethyl, di-n-butyl,
di-n-octyl, di-(2-ethylhexyl), and dicyclohexyl
phthalates were incubated with small intestinal
mucosal cells and hepatic cells of human (no
sex mentioned), male S-D rats, male albino
ferrets, and male olive baboons for evaluation of
esterase activities of phthalate diesters
All phthalate diesters were
hydrolyzed in both small intestinal
mucosal cells and hepatic cells of
all four species
Phthalate diesters undergo
hydrolysis in the
gastrointestinal tract with
subsequent absorption and
further metabolism of the
resultant monoester and
alcohol moieties in the liver
Lake et al. (1977);
Albro and Moore (1974);
Albro et al. f 1973)

Both diesters and monoesters of14 C-labeled
Dimethyl, di-n-butyl, and di-(2-ethylhexyl)
phthalates were incubated in an everted gut sac
preparation of male S-D rat for evaluation of
metabolism and absorption of phthalate diesters
All phthalate diesters were
hydrolyzed in the small intestinal
mucosa to monoesters. Monoesters
were absorbed in significantly
greater quantity than corresponding
diesters
Phthalate diesters undergo
hydrolysis to monoesters and
absorbed in the rat small
intestine
White et al. (1980)
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Table 4B. Summary of Diundecyl Phthalate (CASRN 3648-20-2) Genotoxicity
Endpoint
Test System
Dose Concentration
Results
Comments
References
Without
Activation3
With
Activation3
Genotoxicity studies in prokaryotic organisms
Reverse mutation
(Ames test)
Salmonella typhimurium
strains TA 98, 100, 1535,
and 1537 in the presence or
absence of S9
10-10,000 ng/plate


No positive results were
observed
Zeiger et al. (1985);
NTP (1983)
Genotoxicity studies in mammalian eukaryotic cells—in vitro
Forward mutation
L5178Y mouse lymphoma
cells in vitro
1,000-8,000 ng/mL
(with activation);
2,000-10,000 ng/mL
(without activation)


No positive results were
observed
Hazleton
Biotechnologies
Company (1986)
Cell transformation
Balb/3T3 mouse cells in
vitro
4,000-40,000 ng/mL

Not carried out
No positive results were
observed
Barber et al. (2000);
Hazleton
Biotechnologies
Company (1986)
"(+) = positive; (-) = negative
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Acute/Short-Term Study
DuPoni (1983)
Application of 0.5 mL DUP (purity unknown) for 24 hours on the intact skin of trunk and
lateral areas of male albino rabbits (6/group) produced only mild to no skin irritation after 24 and
48 hours of treatment (DuPont. 1983).
Toxicokinetics
Lake etal. (1977); Albro and Moore (1974); Albro et al. (1973); White et al. (1980)
There are no data on the toxicokinetics of DUP. However, a few studies are available on
the toxicokinetics of other phthalate diesters. In general, phthalate diesters undergo partial
hydrolysis in the gastrointestinal tract with subsequent absorption and further metabolism of the
resultant monoester and alcohol moieties. This was demonstrated in an in vitro study using
hepatic and intestinal preparations from human, rat, baboon, and ferret (Lake et al.. 1977; Albro
and Moore. 1974; Albro et al. 1973). Esterases within the mucosal epithelium actively
hydrolyse phthalate diesters to the monoesters; thus, very little intact diester is thought to reach
the systemic circulation as demonstrated using an everted gut-sac preparation from the rat small
intestine (White et al.. 1980).
Genotoxicity
Hazleton Biotechnologies Company (1986); Barber et al (2000)
DUP did not induce a statistically significant increase in the mutant frequency in an in
vitro L5178Y cell mouse lymphoma assay when incubated with DUP concentrations between
1,000 and 8,000 ng/mL in culture media with S9 metabolic activation and between 2,000 and
10,000 (.ig/mL of culture media without S9 metabolic activation system (Hazleton
Biotechnologies Company. 1986). DUP did not induce a statistically significant increase in the
numbers of transformation foci of BALB/3T3 cells when incubated in DUP concentrations
between 4,000 and 40,000 (.ig/mL of culture media without S9 metabolic activation (Barber et
al.. 2000; Hazleton Biotechnologies Company. 1986).
Zeiser et al (1985); NIP (1983)
DUP was not mutagenic in Salmonella typhimurium strains TA 98, TA 100, TA 1535,
and TA 1537 both in the presence and absence of S9 metabolic activation when incubated with
DUP at concentrations up to 10,000 (.ig/plate (Zeiger et al, 1985; NTP, 1983).
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DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present a summary of noncancer reference and cancer values, respectively. IRIS data are indicated in the table, if
available.
Table 5. Summary of Noncancer Reference Values for Diundecyl Phthalate (CASRN 3648-20-2)
Toxicity Type (Units)
Species/Sex
Critical Effect
p-Reference Value
POD Method
PODhed
UFc
Principal Study
Subchronic p-RfD (mg/kg-d)
Rat/M
Increased relative liver
weight in male rats
3 x 10-2
BMDLio
28.7
1,000
(Barberet al. (1987);
BIBRA (1986V)
Chronic p-RfD (mg/kg-d)
NDr
Subchronic p-RfC (mg/m3)
NDr
Chronic p-RfC (mg/m3)
NDr
NDr = not determinable.
Table 6. Summary of Cancer Values for Diundecyl Phthalate (CASRN 3648-20-2)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
NDr
p-IUR (mg/m3)
NDr
NDr = not determinable.
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DERIVATION OF ORAL REFERENCE DOSES
The animal studies provide sufficient information to derive a subchronic provisional
reference dose (p-RfD) for DUP. The oral toxicity database consists of two short-term-duration
studies in rats and one reproductive/developmental study in rats. Table 3 A summarizes the
noncancer exposure-response data from available oral studies.
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
The short-term-duration studies (Kwack et al.. 2009; Barber et al.. 1987; BIBRA. 1986).
and the reproductive/developmental study (Sail ten fait et at., 2013) are considered as potential
key studies on which to base the subchronic p-RfD for DUP.
A LOAEL of 286 mg/kg-day for increased absolute and relative liver weights in male rats
was identified in the 21 -day dietary study (Barber et al.. 1987; BIBRA. 1986). A LOAEL of
500 mg/kg-day for decreased sperm counts, sperm motility, VCL, STR, and LIN as well as
increased serum ALP, and GOT was identified in the 28-day gavage study Kwack et al. (2009).
Although a LOAEL of 500 mg/kg-day for supernumerary 14th ribs was observed in the
Saillenfait et al. (2013) reproductive/developmental study, the supernumerary 14th ribs tend to
disappear in subsequent development. However, the study authors mentioned that a relationship
to treatment cannot be ruled out. Therefore, 500 mg/kg-day is considered as a LOAEL with
minimal biological significance, and 250 mg/kg-day as aNOAEL.
The BIBRA (1986) and Barber et al. (1987) studies exposed both sexes of rats to multiple
doses of DUP, analyzed multiple organs, and provided adequate information for performing
BMD modeling. Although, the changes in liver weights are identified as the most sensitive
effect, these studies did not analyze sperm parameters, which were reported by Kwack et al.
(2009). The Kwack et al. (2009) study exposed male rats to a single dose of DUP and analyzed
multiple organs. Changes in liver enzymes (e.g., significant increase in serum ALP, and GOT)
and sperm parameters (e.g., significant decrease in sperm count, motility, VCL, STR, and LIN)
are identified as the most sensitive effects for this study. However, the Kwack et al. (2009) study
utilized only one test dose (thereby precluding BMD modeling) in one sex, which is not an
optimal study design for assessment purposes.
Alterations in liver (NRC. 2008; Gannina et al.. 1984) and sperm parameters (Pant et al..
2011; NRC. 2008; Fredricsson et al.. 1993) as sensitive endpoints have been reported for several
other phthalate esters in both laboratory animals and humans. However, it should be noted that
DUP is structurally related to diisononyl phthalate (DINP) and diisodecyl phthalate (DIDP),
which are reported to be primarily hepatotoxic (CPSC. 2010a. b; Lington et al.. 1997; Lake et al..
1991). In addition, the BIBRA (1986). Barber et al. (1987). and Kwack et al. (2009) studies all
identified liver changes as sensitive effects. Furthermore, from the available dose response
information, BMD modeling could only be performed for liver effects and not for sperm
parameters data. Based on the available hazard and dose response information, the liver seems to
be the most consistent and sensitive target organ observed following oral exposure to DUP.
Benchmark dose (BMD) modeling using the U.S. EPA's BMDS (Version 2.2.1) software
was conducted for increased absolute and relative liver weights of both sexes from the 21-day rat
study (Barber et al.. 1987; BIBRA. 1986). Table 7 summarizes NOAEL, LOAEL, BMD and
benchmark dose lower confidence limit (BMDL) for these endpoints as well as their PODs.
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Table 7. Candidate PODs for Multiple Noncancer Effects Following Subchronic Oral
Exposure to Diundecyl Phthalate11 (CASRN 3648-20-2)
Effect
Dose (mg/kg-d)
NOAEL
LOAEL
BMR
BMD
BMDL
POD
Increased absolute liver weight (M)
NA
286
10%
554.8b
356.9b
356.9
Increased relative liver weight (M)
NA
286
10%
223.4
119.4
119.4
Increased absolute liver weight (F)
284
1,101
10%
371.9
303.1
303.1
Increased relative liver weight (F)
284
1,101
10%
NF
NF
284
"Barber et al. (19871: BIBRA (19861.
bAn adequate fit was achieved when the high dose group was removed.
M and F in the parenthesis denotes male and female respectively.
BMD input data are presented in Appendix B. The curves and BMD output text for increased relative liver weight
in male rats are provided in Appendix C.
NA = not applicable, NF = no acceptable model fit.
Based on the modeling results for liver weight changes, the lowest POD is increased
relative liver weight in male rats with a BMDLio of 1 19.4 mg/kg-day. The BIBRA (1986) and
Barber et al. (1987) studies are selected as the principal studies and the BMDLio of
119.4 mg/kg-day based on increased relative liver weight in male rats is chosen as the POD
for the derivation of the subchronic p-RfD.
In Recommended Use of Body Weight4 as the Default Method in Derivation of the Oral
Reference Dose (U.S. EPA. 2011b). the Agency endorses a hierarchy of approaches to derive
human equivalent oral exposures from data from laboratory animal species, with the preferred
approach being physiologically based toxicokinetic modeling. Other approaches may include
using some chemical-specific information, without a complete physiologically based
toxicokinetic model. In lieu of chemical-specific models or data to inform the derivation of
human equivalent oral exposures, U.S. EPA endorses body-weight scaling to the 3/4 power
(BW3/4) as a default to extrapolate toxicologically equivalent doses of orally administered agents
from all laboratory animals to humans for the purpose of deriving an RfD under certain exposure
conditions. More specifically, the use of BW3 4 scaling for deriving an RfD is recommended
when the observed effects are associated with the parent compound or a stable metabolite but not
for portal-of-entry effects.
A validated human physiologically based pharmacokinetic (PBPK) model for DUP is not
available for use in extrapolating doses from animals to humans. In addition, the selected POD
of 119.4 mg/kg-day is based on liver effects, which is not a portal-of-entry or developmental
effect. Therefore, scaling by BW3/4 is relevant for deriving human equivalent doses (HEDs) for
this effect.
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Following U.S. EPA (2011b) guidance, the POD is converted to a HED through the
application of a dosimetric adjustment factor (DAF1) derived as follows:
DAF	=	(BWa1/4 - BWh1/4)
Where:
DAF	=	dosimetric adjustment factor
BWa	=	animal body weight
BWh	=	human body weight
Using a BW„ of 0.25 kg for rats and a default BWh of 70 kg for humans (U.S. EPA.
1988). the resulting DAF is 0.24. Applying this DAF to the BMDLio identified in the 21 -day rat
study yields a PODhed as follows:
PODhed = BMDLio (mg/kg-day) x DAF
= BMDLio (mg/kg-day) x 0.24
= 119.4 (mg/kg-day) x 0.24
= 28.7 mg/kg-day
A subchronic p-RfD for DUP is derived by applying an uncertainty factor (UF) of 1,000
to the PODhed of 28.7 mg/kg-day as follows:
Subchronic p-RfD = PODhed ^ UFc
= 28.7 mg/kg-day ^ 1,000
= 3 x 10"2 mg/kg-day
Table 8 summarizes the UFs for the subchronic p-RfD for DUP.
:As described in detail in Recommended Use of Body Weight4 as the Default Method in Derivation of the Oral
Reference Dose flJ.S. EPA. 2011b). rate-related processes scale across species in a manner related to both the direct
(BWm) and allometric scaling (BW3/4) aspects such that BW3'4 ^ BW1 1 = BW ' converted to a
DAF = BWa"4 - BWi,1'4.
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Table 8. UFs for Subchronic p-RfD for Diundecyl Phthalate (CASRN 3648-20-2)
UF
Value
Justification
UFa
3
A UFa of 3 (100 5) is applied to account for remaining uncertainty such as the toxicodynamic
differences between rats and humans following oral exposure to DUP. The toxicokinetic
uncertainty has been accounted for by calculation of a human equivalent dose (HED) as
described in the RfD methodology (U.S. EPA. 2011b).
UFh
10
A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of DUP in humans.
UFl
1
A UFl of 10 is not applied because the POD is a BMDL.
UFS
3
A UFS of 3 is applied because the duration of the principal study is limited to 21 d.
UFd
10
A UFd of 10 is applied because there are only two short term-duration studies in rats and one
developmental toxicity study in rats. However, no subchronic studies and two generation
reproductive studies were identified.
UFC
1,000
UFC = UFa x UFh x UFl x UFs x UFd
The confidence of the subchronic p-RfD for DUP is low as explained in Table 9.
Table 9. Confidence Descriptor for Subchronic p-RfD for
Diundecyl Phthalate (CASRN 3648-20-2)
Confidence Categories
Designation3
Discussion
Confidence in study
L
Confidence in the orincioal study is low because BIBRA (1986)
and Barber et al. (1987) used a medium numbers of animals, and
used a short term-duration exposure.
Confidence in database
L
Confidence in the database is low because it includes only two
short term-duration studies in rats that are limited in duration
and one developmental toxicity study in rats. No two-generation
reproductive toxicity studies were identified.
Confidence in subchronic p-RfD
L
The overall confidence in the subchronic p-RfD is low.
aL = Low
Derivation of a Chronic Provisional RfD (Chronic p-RfD)
Because no chronic-duration studies exist for DUP and only limited sub chronic-duration
studies are available, it is inappropriate to derive a chronic p-RfD.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
No suitable published studies investigating the effects of subchronic or chronic inhalation
toxicity of diundecyl phthalate in humans or animals have been identified.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Table 10 identifies the cancer WOE descriptor for diundecyl phthalate.
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Table 10. Cancer WOE Descriptor for Diundecyl Phthalate (CASRN 3648-20-2)
Possible WOE
Descriptor
Designation
Route of Entry
(Oral, Inhalation,
or Both)
Comments
"Carcinogenic to
Humans "
NS
NA
No human carcinogenicity data were
identified.
"Likely to Be
Carcinogenic to Humans "
NS
NA
No animal carcinogenicity studies were
identified.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
No animal carcinogenicity studies were
identified.
"Inadequate Information
to Assess Carcinogenic
Potential"
Selected
Both
This descriptor is selected due to the lack
of any information on the carcinogenicity
of DUP.
"Not Likely to Be
Carcinogenic to Humans "
NS
NA
Although the genotoxicity studies were
negative, there are no data to indicate that
DUP is not carcinogenic.
NA = not applicable; NS = not selected.
MODE-OF-ACTION DISCUSSION
The Guidelines for Carcinogen Risk Assessment (U.S. EPA. 2005) define mode of action
as "a sequence of key events and processes starting with interaction of an agent with a cell,
proceeding through operational and anatomical changes, and resulting in cancer formation"
(p. 1-10). Examples of possible modes of carcinogenic action for a given chemical include
"mutagenicity, mitogenesis, inhibition of cell death, cytotoxicity with reparative cell
proliferation, and immunologic suppression" (p. 1-10).
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
The lack of data on the carcinogenicity of DUP precludes the derivation of quantitative
estimates for either oral (p-OSF) or inhalation (p-IUR) exposure.
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APPENDIX A. SCREENING PROVISIONAL VALUES
No screening values are presented.
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APPENDIX B. DATA TABLES
Table B-l. Body Weights and Organ Weights of F344 Rats Treated with Diundecyl Phthalate (CASRN 3648-20-2) by Diet for
21 Days"
Parameters
Male (mg/kg-d)
Female (mg/kg-d)
0
286
1,177
2,445
0
284
1,101
2,086
Mean body weight (g)
222 ±4.5
224 ±5.6
(0.90%)b
211 ± 3.1
(-4.95%)
194 ±4.5
*** (-12.6%)
144 ± 1.5
141 ±3.4
(-2.08%)
134 ± 1.3
***
(-6.94%)
133 ±2.4
*** (-7.64%)
Absolute liver weight (g)
7.24 ± 0.22
8.05 ±0.41
(11.2%)
8.94 ±0.40
** (23.5%)
8.42 ±0.35
* (16.3%)
4.36 ±0.07
4.48 ±0.11
(2.75%)
5.80 ±0.24
*** (33.0%)
6.53 ±0.36
*** (49.8%)
Relative liver weight (g/100 g
body weight)
3.26 ±0.10
3.59 ±0.10
(10.1%)
4.24 ±0.18
*** (30.1%)
4.34 ±0.10
*** (33.1%)
3.02 ±0.06
3.18 ±0.06
(5.30%)
4.32 ±0.15
*** (43.0%)
4.92 ±0.23
*** (62.9%)
Absolute kidney weight (g)
1.50 ±0.04
1.50 ±0.06
(0.00%)
1.34 ±0.03
* (-10.7%)
1.29 ±0.03
** (-14.0%)
1.03 ±0.01
0.99 ±0.02 (-
3.88%)
1.03 ±0.04
(0.00%)
1.04 ±0.02
(0.97%)
Relative kidney weight (g/100 g
body weight)
0.68 ±0.01
0.67 ± 0.02 (-
1.47%)
0.64 ±0.01
(-5.88%)
0.67 ±0.01 (-
1.47%)
0.71 ±0.01
0.71 ±0.02
(0.00%)
0.77 ± 0.02
* (8.45%)
0.79 ±0.01
** (11.3%)
Absolute testes weight (g)
2.60 ± 0.07
2.67 ±0.05
2.65 ± 0.05
2.66 ±0.05
-
-
-
-
Relative testes weight (g/100 g
body weight)
1.17 ±0.03
1.20 ±0.02
1.26 ±0.02
*
1.38 ±0.03
***
-
-
-
-
aBarber et al. (1987): BIBRA (1986)
Percentage change compared to control. Figures are the means ± standard error for groups of five rats.
* Significantly different from the control at p< 0.05.
**Significantly different from the control at/? < 0.01.
***Significantly different from the control atp< 0.001.
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Table B-2. Selected Changes in F344 Rats Treated with Diundecyl Phthalate by (CASRN 3648-20-2) Diet for 21 Days3
Parameters
Male (mg/kg-d)
Female (mg/kg-d)
0
286
1,177
2,445
0
284
1,101
2,086
Serum triglycerides (mmol/L)
0.93 ±0.11
0.77 ±0.03
0.45 ±0.03
***
0.46 ± 0.04
***
0.59 ±0.08
0.45 ±0.02
0.50 ±0.05
0.50 ±0.03
Total cholesterol (mmol/L)
2.00 ±0.13
1.64 ±0.05
1.34 ±0.17
***
1.30 ±0.10
***
2.06 ±0.05
1.84 ± 0.11
1.85 ±0.04
1.99 ±0.08
Palmitoyl-CoA oxidation levels in liver
(mol/min/mg homogenate protein)
4.0 ±0.34
5.3 ±0.18
8.3 ±0.60
***
14.5 ±0.62
***
5.8 ±0.47
6.1 ± 0.31
11.3 ±0.81
***
19.2 ±0.47
***
Laurie acid 11-hydroxylase in liver
(mol/min/mg microsomal protein)
0.6 ±0.04
0.9 ±0.03
**
1.0 ±0.10
***
1.2 ±0.07
***
0.4 ±0.07
0.5 ±0.03
0.7 ± 0.11
1.3 ±0.21
***
Laurie acid 12-hydroxylase in liver
(mol/min/mg microsomal protein)
1.1 ±0.15
2.5 ±0.14
***
3.6 ±0.25
***
4.4 ±0.24
***
0.8 ±0.07
0.7 ±0.05
1.2 ±0.21
2.5 ±0.20
***
Total hepatic protein (mg/g liver)
236 ±4.3
237 ±3.2
247 ± 7.7
239 ±4.5
215 ±2.1
225 ±3.9
233 ±3.4
***
240 ±3.6
***
Microsomal protein (mg/g liver)
25.5 ± 1.14
24.4 ±0.63
23.3 ±0.61
22.7 ± 1.05
21.2 ±0.65
19.6 ±0.77
20.1 ±0.92
19.6 ±0.98
'Barber et al. (1987): BI6RA (1986)
Figures are the means ± standard error for groups of five rats.
* Significantly different from the control at p< 0.05.
**Significantly different from the control atp< 0.01.
***Significantly different from the control at p< 0.00
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Table B-3. Selected Incidence of Histological Liver Changes in F344 Rats Treated with
Diundecyl Phthalate by (CASRN 3648-20-2) Diet for 21 Days"
Parameters
Male (mg/kg-d)
Female (mg/kg-d)
0
286
1,177
2,445
0
284
1,101
2,086
Slight increase individual cell necrosis
0/5b
0/5
4/5*
5/5*
0/5
0/5
0/5
0/5
Slight cell vacuolization
0/5
0/5
2/5
4/5*
1/5
0/5
0/5
0/5
Moderate cell vacuolization
0/5
0/5
5/5*
3/5
0/5
0/5
0/5
0/5
Reduced cytoplasmic basophilia
0/5
0/5
5/5*
5/5*
0/5
0/5
4/5*
4/5*
"Barber et al. (1987): BIBRA (1986)
bNumber of animals with lesions/number of animals observed.
* Significantly different from the control at p< 0.05.
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Table B-4. Selected Changes in Serum and Sperm of
Male Sprague-Dawley Rats Following Treatment with
Diundecyl Phthalate (CASRN 3648-20-2) by Gavage for 28 Days"
Parameters
Controlb
DUP (500 mg/kg-d)
Serum
Total protein (g/dL)
7.03 ±0.28
7.67 ±0.46*
Glutamate oxaloacetate transaminase (IU/L)
75.67 ±7.81
113.83 ± 15.58*
Alkaline phosphatase (IU/L)
347.0 ±49.78
626.5 ± 55.83*
Sperm
Count (106/g)
2,568.0 ± 154.9
1,851.67 ±214.49*
Motility (%)
74.67 ±4.51
27.50 ±6.66*
Curvilinear velocity (|im/s)
261.3 ± 17.94
217.3 ± 18.59*
Straightness (%)
71.33 ±3.33
57.67 ±8.39*
Linearity (%)
31.50 ± 1.76
25.17 ±2.48*
"Kwack et al. (2009).
bControl group received only corn oil.
Figures are the means ± standard deviation for groups of six rats.
* Significantly different from the control at p< 0.05.
Table B-5. Selected Maternal Findings in Female Sprague-Dawley Rats Treated with
Diundecyl Phthalate (CASRN 3648-20-2) by Gavage from GD 6 to 20a
Parameters
Exposure Group (mg/kg-d)
0
250
500
1,000
Number of dead/treated
0/22
0/21
0/21
0/22
Number (%) pregnant
22 (100)
21 (100)
21 (100)
20 (90.9)
Body weight (g) GD 0
230 ± 13b
229 ±11
229 ± 13
231 ± 13
Body weight (g) GD 21
414 ±25
407 ± 25
405 ± 47
408 ± 27
Food consumption (g/d)
GD 0-21
22 ± 1
23 ±2
23 ±3
23 ±2
Gravid uterine weight (g)
107 ± 13
98 ±23
96 ±29
103 ± 15
aSaillenfait et al. (2013).
bMean± SD.
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Table B-6. Selected Reproductive Findings in Female Sprague-Dawley Rats Treated with
Diundecyl Phthalate (CASRN 3648-20-2) by Gavage from GD 6 to 20a
Parameters
Exposure Group (mg/kg-d)
0
250
500
1,000
All littersb
22
21
21
20
No. corpora lutea
15.7 ± 1.5°
14.7 ±2.0
14.9 ± 1.8
15.3 ± 1.7
% Preimplantation loss per litter
3.0 ±4.8
10.4 ± 17.7
8.4 ± 13.7
5.9 ± 10.2
No. Implantation sites per litter
15.2 ± 1.8
13.2 ±3.3*
13.4 ±2.9*
14.3 ± 1.7
% Postimplantation loss per litterd
6.4 ± 10.8
2.5 ±5.9
8.0 ±21.4
5.6 ±5.7
% Resorptions per litter
6.1 ± 10.7
2.2 ±4.4
7.7 ±21.5
3.7 ±7.2
Live litters6
22
21
20
20
No. live fetuses per litter
14.2 ± 1.9
12.9 ±3.3
13.2 ±2.7
13.8 ±3.0
Fetal body weight (g)—All fetuses
5.52 ±0.31
5.58 ±0.36
5.60 ±0.21
5.53 ±0.27
Fetal body weight (g)—Male fetuses
5.69 ±0.31
5.75 ±0.34
5.78 ±0.25
5.69 ±0.30
Fetal body weight (g)—Female fetuses
5.37 ±0.32
5.37 ±0.39
5.48 ±0.19
5.39 ±0.28
AGD—Male fetuses
2.96 ±0.12
2.95 ±0.15
2.85 ±0.11
2.86 ±0.15
AGD—Female fetuses
1.04 ±0.06
1.06 ±0.06
1.07 ±0.06
1.09 ±0.06
AGD/(body weight)1'3—Male fetuses
1.65 ±0.08
1.65 ±0.08
1.59 ±0.05*
1.60 ±0.09
AGD/(body weight)1'3—Female fetuses
0.59 ±0.03
0.60 ±0.03
0.61 ±0.03
0.62 ±0.04
aSaillenfait et al. (2013).
includes all pregnant females at euthanization.
°Mean± SD.
d[(No. of resorptions + dead fetuses) ^ No. implantations] x 100.
"Includes all animals with live fetuses at euthanization.
* Significantly different from the control at p< 0.05.
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Table B-7. Selected Fetal Malformations and Variations Following Treatment of
Female Sprague-Dawley Rats with
Diundecyl Phthalate (CASRN 3648-20-2) by Gavage from GD 6 to 20a

Exposure Group (mg/kg-d)
Parameters
0
250
500
1,000
Total No. of fetuses (litters) examined13
External
312 (22)
270 (21)
264 (20)
275 (20)
Visceral
156 (22)
135 (21)
132 (20)
138 (0)
Skeletal
156 (22)
135 (21)
132 (20)
137 (20)
Malformations
Omphalocele
0
1(1)
0
0
Diaphragmatic hernia
0
0
0
1(1)
External variations
Club foot (unilateral)
0
0
1(1)
0
Skeletal variations
Supernumerary 14th ribs (any
type: includes pin-point
ossification sites, short, and
long ribs)
17(10)
29 (13)
60##(17)*
32#(12)
Supernumerary 14th ribs
(only long ribs °)
0
1(1)
0
1(1)
No. of ossification centers
Caudal vertebral centra
6.12 ± 0.37d
6.59 ± 0.705
6.70 ±0.57^5
6.67 ±0.65^
aSaillenfait et al. (2013).
bThe incidence of individual defect is presented as number of fetuses (number of litters).
°More than one third of the length of the preceding rib.
dMean± SD.
* Significantly different from the control at p< 0.05 (Fisher's test).
"Significantly different from the control at p< 0.05 (Mann-Whitney test).
""Significantly different from the control atp< 0.01 (Mann-Whitney test).
Significantly different from the control at p< 0.05 (Dunnett's test).
§§Significantly different from the control at p< 0.01 (Dunnett's test).
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APPENDIX C. BENCHMARK DOSE MODELING RESULTS
MODEL-FITTING PROCEDURE FOR CONTINUOUS DATA
The benchmark dose (BMD) modeling of continuous data was conducted with
U.S. EPA's BMDS (Version 2.2.1). For these data, all continuous models available within the
software were fit using a benchmark response (BMR) of 1 standard deviation (SD) relative risk.
For changes in liver, body, and kidney weights, a BMR of 10% for weight changes relative to
control was used. An adequate fit was judged based on the goodness-of-fit p-walue (p> 0.1),
magnitude of the scaled residuals in the vicinity of the BMR, and visual inspection of the model
fit. In addition to these three criteria forjudging adequacy of model fit, a determination was
made as to whether the variance across dose groups was homogeneous. If a homogeneous
variance model was deemed appropriate based on the statistical test provided in BMDS
(i.e., Test 2), the final BMD results were estimated from a homogeneous variance model. If the
test for homogeneity of variance was rejected (p< 0.1), the model was run again while modeling
the variance as a power function of the mean to account for this nonhomogeneous variance. If
this nonhomogeneous variance model did not adequately fit the variance data (i.e., Test 3;
p-w alue < 0.1), the data set was considered unsuitable for BMD modeling. Among all models
providing adequate fit, the lowest benchmark dose lower confidence limit (BMDL) was selected
if the BMDLs estimated from different models varied greater than threefold; otherwise, the
BMDL from the model with the lowest Akaike's information criterion (AIC) was selected as a
potential point of departure (POD) from which to derive the RfD.
In addition, in the absence of a mechanistic understanding of the biological response to a
toxic agent, data from exposures much higher than the study lowest-observed-adverse-effect
level (LOAEL) do not provide reliable information regarding the shape of the response at low
doses. However, such exposures can have a strong effect on the shape of the fitted model in the
low-dose region of the dose-response curve in some cases. Thus, if lack of fit is due to
characteristics of the dose-response data for high doses, then the U.S. EPA Benchmark Dose
Technical Guidance document allows for data to be adjusted by eliminating the high-dose group
(U.S. EPA. 2012b). Because the focus of BMD analysis is on the low dose region of the
response curve, eliminating the high-dose group is deemed reasonable.
INCREASED RELATIVE LIVER WEIGHT IN MALE F344 RATS TREATED WITH
DIUNDECYL PHTHALATE FOR 21 DAYS (Barber et a).. 1987; BIBRA. 1986)
Following the above procedure, continuous-variable models in the U.S. EPA BMDS
(Version 2.1.1) were fit to the data shown in Table B-l for increased relative liver weight in male
rats (Barber et al.. 1987; BIBR A. 1986). For increased relative liver weight, a BMR of a
10% change relative to the control mean was used. The homogeneity variance (Test 2) p-w alue
of greater than 0.1 indicates that constant variance is the appropriate variance model. As
assessed by the goodness-of-fit test and visual inspection, the exponential model 4 provided the
best fit model (see Table C-l and Figure C-l) resulting in a BMDio of 223.4 mg/kg-day and
BMDLio of 119.4 mg/kg-day.
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Table C-l. Model Predictions for Increased Relative Liver Weight in Male F344 Rats"
Model
BMDio
BMDLio
/7-Value Test 2b
/7-Value Test 3b
Goodness-of-Fit
/>-Valucb
AIC
Scaled Residual of
Interest
Conclusion
Exponential (M2)
910.0
701.8
0.373
0.373
0.006
-19.67
2.241
Goodness-of-fit p-valuc <0.1
Exponential (M3)
910.0
701.8
0.373
0.373
0.006
-19.67
2.241
Goodness-of-fit p-valuc <0.1
Exponential (M4)
223.4
119.4
0.373
0.373
0.502
-27.47
-0.4055
Goodness-of-fit p-valuc >0.1
Exponential (M5)
282.8
126.3
0.373
0.373
N/A
-25.92
-1.54 x 10-8
Goodness of fit not available
Hill
283.6
115.3
0.373
0.373
NA
-25.92
1.39x 10~8
Goodness of fit not available
Linear
803.0
599.0
0.373
0.373
0.010
-20.74
2.14
Goodness-of-fit p-valuc <0.1
Polynomial
803.0
599.0
0.373
0.373
0.010
-20.74
2.14
Goodness-of-fit p-valuc <0.1
Power
803.0
599.0
0.373
0.373
0.010
-20.74
2.14
Goodness-of-fit p-valuc <0.1
;'(Barber et al. (1987): BIBRA (1986)1.
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
AIC = Akaike's information criterion.
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Exponential Model 4 with 0.95 Confidence Level
4.5
4
3.5
3
Exponential
BMDL
BMD
500	1000	1500	2000	2500
dose
19:04 02/28 2014
Figure C-l. Fit of Exponential Model with Homogenous Variance and Restricted Power to
Data on Relative Liver Weight in Male Rats (Barber et al.. 1987; BIBRA, 1986)
Text Output for Exponential BMD Model for Relative Liver Weight in Male Rats
(Barber et al.. 1987: BIBRA. 1986)
Exponential Model. (Version: 1.7; Date: 12/10/2009)
Input Data File: C:/US EPA/BMDS220/Data/SessionFiles/DIUP/exp_BIBRA-M-
relative liver wt-TW_PKS-ExpoConti.(d)
Gnuplot Plotting File:
Fri Feb 28 19:04:37 2014
BMDS Model Run
The form of the response function by Model:
Model 2
Model 3
Model 4
Model 5
Y[dose]	= a	*	exp{sign *	b * dose}
Y[dose]	= a	*	exp{sign *	(b * dose)Ad)
Y[dose]	= a	*	[c-(c-l) *	exp{-b * dose}]
Y[dose]	= a	*	[c-(c-l) *	exp{-(b * dose)Ad}]
Note: Y[dose] is the median response for exposure
sign = +1 for increasing trend in data;
sign = -1 for decreasing trend.
dose;
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Model
2
is
nested
within
Models 3 and 4
Model
3
is
nested
within
Model 5.
Model
4
is
nested
within
Model 5.
Dependent variable = Mean
Independent variable = Dose
Data are assumed to be distributed: normally
Variance Model: exp(lnalpha +rho *ln(Y[dose]))
rho is set to 0.
A constant variance model is fit.
Total number of dose groups = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
MLE solution provided: Exact
Initial Parameter Values
Variable
lnalpha
rho(S)
a
b
c
d
Model 4
-2.79623
0
3. 097
0. 000883305
1. 47142
1
(S)
Specified
Parameter Estimates
Variable	Model 4
lnalpha	-2.77371
rho	0
a	3.2382
b	0.00146636
c	1.35801
d	1
Table of Stats From Input Data
Dose	N	Obs Mean	Obs Std Dev
0	5	3.26	0.22
286	5	3.59	0.22
1177	5	4.24	0.4
2445	5	4.34	0.22
Estimated Values of Interest
Dose	Est Mean	Est Std	Scaled Residual
0	3.238	0.2499	0.1951
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286
1177
2445
3. 635
4.191
4.365
0.2499
0.2499
0.2499
-0.4055
0.4374
-0.2269
Other models for which	likelihoods are calculated:
Model A1:	Yij	= Mu(i) + e(ij)
Var{e(ij)}	= SigmaA2
Model A2:	Yij	= Mu(i) + e(ij)
Var{e(ij)}	= Sigma(i)^2
Model A3:	Yij	= Mu(i) + e(ij)
Var{e(ij)}	= exp(lalpha + log(mean(i)) * rho)
Model R:	Yij	= Mu + e(i)
Var{e(ij)}	= Sigma^2
Model
A1
A2
A3
R
4
Likelihoods of Interest
Log (likelihood)	DF
17.96226	5
19.52481	8
17.96226	5
3.357581	2
17.73712	4
AIC
-25.92452
-23.04961
-25.92452
-2.715162
-27.47423
Additive constant for all log-likelihoods =	-18.38. This constant added to the
above values gives the log-likelihood including the term that does not
depend on the model parameters.
Test
1:
Test
2 :
Test
3:
Explanation of Tests
Does response and/or variances differ among Dose levels? (A2 vs. R)
Are Variances Homogeneous? (A2 vs. Al)
Are variances adeguately modeled? (A2 vs. A3)
Test 6a: Does Model 4 fit the data? (A3 vs 4)
Test
Test 1
Test 2
Test 3
Test 6a
Tests of Interest
-2*log(Likelihood Ratio)
32.33
3.125
3.125
0.4503
D. F.
6
3
3
1
p-value
< 0.0001
0.3727
0.3727
0.5022
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose
levels, it seems appropriate to model the data.
The p-value for Test 2 is greater than .1. A homogeneous
variance model appears to be appropriate here.
The p-value for Test 3 is greater than .1. The modeled
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variance appears to be appropriate here.
The p-value for Test 6a is greater than .1. Model 4 seems
to adequately describe the data.
Benchmark Dose Computations:
Specified Effect = 0.100000
Risk Type = Relative deviation
Confidence Level = 0.950000
BMD
223.389
BMDL
119.425
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