A fTfcJt United States
l*1"' r°"rn8n
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Lucina E. Lizarraga, PhD
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Dan D. Petersen, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
Scott C. Wesselkamper, PhD
National Center for Environmental Assessment, Cincinnati, OH
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the content 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).
li
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS iv
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 1
INTRODUCTION 2
REVIEW 01 POTENTIALLY RELEVANT DATA 6
HUMAN STUDIES 11
ANIMAL STUDIES 11
Oral Exposures 11
Inhalation Exposures 16
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 16
Short-Term-Duration Oral Studies with Considerable Limitations 16
Genotoxicity 16
Supporting Human Studies 19
Metabolism/Toxicokinetic Studies 26
Mode-of-Action/Mechanistic Studies 26
DERIVATION 01 PROVISIONAL VALUES 27
DERIVATION OF ORAL REFERENCE DOSES 28
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 29
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 29
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 30
Derivation of a Provisional Oral Slope Factor 30
Derivation of a Provisional Inhalation Unit Risk 30
APPENDIX A. SCREENING PROVISIONAL VALUES 31
APPENDIX B. DATA TABLES 46
APPENDIX C. TOXICOKINETICS AND DOSE-RESPONSE INFORMATION FOR
/y/-I)I)I) AND CANDIDATE SURROGATES 48
APPENDIX D. REFERENCES 61
iii p,p'- DDD
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COMMONLY USED ABBREVIATIONS AND ACRONYMS1
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
7V-acetyl-P-D-glucosaminidase
AR
androgen receptor
NCEA
National Center for Environmental
AST
aspartate aminotransferase
Assessment
atm
atmosphere
NCI
National Cancer Institute
ATSDR
Agency for Toxic Substances and
NOAEL
no-observed-adverse-effect level
Disease Registry
NTP
National Toxicology Program
BMD
benchmark dose
NZW
New Zealand White (rabbit breed)
BMDL
benchmark dose lower confidence limit
OCT
ornithine carbamoyl transferase
BMDS
Benchmark Dose Software
ORD
Office of Research and Development
BMR
benchmark response
PBPK
physiologically based pharmacokinetic
BUN
blood urea nitrogen
PCNA
proliferating cell nuclear antigen
BW
body weight
PND
postnatal day
CA
chromosomal aberration
POD
point of departure
CAS
Chemical Abstracts Service
PODadj
duration-adjusted POD
CASRN
Chemical Abstracts Service registry
QSAR
quantitative structure-activity
number
relationship
CBI
covalent binding index
RBC
red blood cell
CHO
Chinese hamster ovary (cell line cells)
RDS
replicative DNA synthesis
CL
confidence limit
RfC
inhalation reference concentration
CNS
central nervous system
RfD
oral reference dose
CPN
chronic progressive nephropathy
RGDR
regional gas dose ratio
CYP450
cytochrome P450
RNA
ribonucleic acid
DAF
dosimetric adjustment factor
SAR
structure activity relationship
DEN
diethylnitrosamine
SCE
sister chromatid exchange
DMSO
dimethylsulfoxide
SD
standard deviation
DNA
deoxyribonucleic acid
SDH
sorbitol dehydrogenase
EPA
Environmental Protection Agency
SE
standard error
ER
estrogen receptor
SGOT
serum glutamic oxaloacetic
FDA
Food and Drug Administration
transaminase, also known as AST
FEVi
forced expiratory volume of 1 second
SGPT
serum glutamic pyruvic transaminase,
GD
gestation day
also known as ALT
GDH
glutamate dehydrogenase
SSD
systemic scleroderma
GGT
y-glutamyl transferase
TCA
trichloroacetic acid
GSH
glutathione
TCE
trichloroethylene
GST
glutathione-S-transferase
TWA
time-weighted average
Hb/g-A
animal blood-gas partition coefficient
UF
uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFa
interspecies uncertainty factor
HEC
human equivalent concentration
UFc
composite uncertainty factor
HED
human equivalent dose
UFd
database uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFl
LOAEL-to-NOAEL uncertainty factor
IVF
in vitro fertilization
UFS
subchronic-to-chronic 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
Abbreviations and acronyms not listed on this page are defined upon first use in the PPRTV document.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
/>,/>-DICHLORODIPHENYLDICHLOROETHANE (p,p'-DDD) (CASRN 72-54-8)
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 at least two National Center for
Environment Assessment (NCEA) scientists and an independent external peer review by at least
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.
PPRTV assessments are eligible to be updated on a 5-year cycle to incorporate new data
or methodologies that might impact the toxicity values or characterization of potential for
adverse human-health effects and are revised as appropriate. Questions regarding nomination of
chemicals for update can be sent to the appropriate U.S. Environmental Protection Agency
(EPA) Superfund and Technology Liaison (https://www.epa.gov/research/fact-sheets-regional-
science).
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. 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.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVs
Questions regarding the content of this PPRTV assessment should be directed to the EPA
Office of Research and Development's (ORD's) NCEA, Superfund Health Risk Technical
Support Center (513-569-7300).
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INTRODUCTION
p,p -Dichlorodiphenyldichloroethane (/;,//-DDD), CASRN 72-54-8, belongs to the class
of compounds known as aryl halides. It was formerly used as an insecticide, but all use has been
banned in the United States due to concerns about human health, bioaccumulation, and toxicity
to the aquatic environment (HSDB. 2010). /;,//-DDD is listed as a Superfund hazardous
substance by the EPA and has been assigned a Comprehensive Environmental Response,
Compensation, and Liability Act (CERCLA) Reportable Quantity of 1 pound (U.S. EPA 2015).
as well as being listed on the 2015 CERCLA Substance Priority List (ATSDR 2016). It is also
included on The Proposition 65 List (Cal/EPA 2017a).
Commercial production ofp,p -DDD occurs by the condensation of dichloroacetaldehyde
with chlorobenzene (O'Neil. 2013) or by the chlorination of ethanol to give
2,2-dichloro-vinylethyl ether, which is then condensed with 2 moles of chlorobenzene (NLM,
2010).
The empirical formula forp,p'-DDD is C14H10CI4 (see Figure 1). Table 1 summarizes the
physicochemical properties ofp,p'-DDD. /;,//-DDD is a crystalline solid at room temperature
(NLM. 2010). p,p -DDD's vapor pressure indicates that it will exist in both the vapor and
particulate phases in the atmosphere. The estimated half-life of vapor phase p,p -DDD in air by
reaction with photochemically produced hydroxyl radicals is 2.5 days. p,p -DDD's Henry's law
constant indicates that it may volatilize from moist surfaces, although volatilization is expected
to be attenuated by adsorption to suspended solids and sediment in the water column. Its low
vapor pressure indicates thatp,p'-DDD is not expected to volatilize from dry soil surfaces. The
low water solubility and high soil adsorption coefficient forp,p -DDD indicate that it will be
immobile in soil, and it is therefore not expected to leach to groundwater or undergo runoff after
a rain event. Hydrolysis is not expected to be an important fate process, as measured half-lives
of 27 and 190 years have been reported at pH 7 and 3-5, respectively. Measured
bioconcentration factor (BCF) values from 2,710-51,000 forp,p -DDD suggest that
bioconcentration in aquatic organisms is very high, and no biodegradation has been observed in
screening and lab tests (NLM. 2010).
CI CI
Figure \.p,p'-DDD Structure
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Table 1. Physicochemical Properties ofp,p -DDD (CASRN 72-54-8)
Property (unit)
Value
Physical state
Solid3
Boiling point (°C)
350b
Melting point (°C)
109.5b
Density (at 20°C)
1.4763
Vapor pressure (mm Hg at 25 °C)
1.35 x 10-6b
pH (unitless)
NA
pKa (unitless)
NA
Solubility in water (mg/L at 25 °C)
0.09b
Octanol-water partition coefficient (log Kow)
6.02b
Henry's law constant (atm-m3/mol at 25°C)
6.60 x 10-6 b
Soil adsorption coefficient Koc (L/kg)
1.306 and 1.318 x 105 a
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
4.3 x 10 12 (estimated)13
Atmospheric half-life (d)
2.5 (estimated)13
Relative vapor density (air = 1)
lla
Molecular weight (g/mol)
320b
Flash point (closed cup in °C)
NV
"HSDB (2010).
bU.S. EPA (2012b).
NA = not applicable; NV = not available; p,p'-DDD = /?,//-dichlorodiphcnvldichlorocthanc.
A summary of available toxicity values for /;,//-DDD from EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for p,p -DDD (CASRN 72-54-8)
Source (parameter)3'b
Value (applicability)
Notes
Reference
Noncancer
IRIS
NV
NA
U.S. EPA (2017a)
HEAST
NV
NA
U.S. EPA (201 la)
DWSHA
NV
NA
U.S. EPA (2012a)
ATSDR
NV
NA
ATSDR (2017)
IPCS
NV
NA
IPCS (2017);
WHO (2017)
Cal/EPA
NV
NA
Cal/EPA (2014a):
Cal/EPA (2017a):
Cal/EPA (2017b)
OSHA
NV
NA
OSHA (2006):
OSHA (2011)
NIOSH
NV
NA
NIOSH (2016)
ACGIH
NV
NA
ACGIH (2016)
DOE (PAC)
PAC-1: 2.1 mg/m3;
PAC-2: 24 mg/m3;
PAC-3: 3,000 mg/m3
Based on TEELs
DOE (2015)
USAPHC (air-MEG)
1-hr critical: 500 mg/m3;
1-hr marginal: 250 mg/m3;
1-hr negligible: 35 mg/m3
Based on TEELs
U.S. APHC (2013)
USAPHC (water-MEG)
1-yr negligible: 041 mg/L
5 L intake rate; based on liver tumors
U.S. APHC (2013)
USAPHC (soil-MEG)
1-yr negligible: 5,160 mg/kg
Basis: cancer
U.S. APHC (2013)
Cancer
IRIS (WOE)
Classification B2: probable
human carcinogen
Based on an increased incidence of
lung tumors in male and female mice,
liver tumors in male mice, and
thyroid tumors in male rats.
p,p'-DDD is structurally similar to,
and is a known metabolite of,
p,p'-DUI, a probable human
carcinogen.
U.S. EPA (1988b)
IRIS (OSF)
0.24 (mg/kg-dr1
Based on liver tumors in male CF-1
mice (Tomatis et al.. 1974).
U.S. EPA (1988b)
HEAST
NV
NA
U.S. EPA (2011a)
DWSHA
NV
NA
U.S. EPA (2012a)
NTP
NV
NA
NTP (2014)
IARC
NV
NA
IARC (2017)
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Table 2. Summary of Available Toxicity Values for p,p -DDD (CASRN 72-54-8)
Source (parameter)3'b
Value (applicability)
Notes
Reference
Cal/EPA (IUR)
0.000069 (iig/m3)-1
Based on U.S. EPA ( 1988b)
Cal/EPA (2014b)
Cal/EPA (ISF)
0.24 (mg/kg-dr1
Based on U.S. EPA (1988b)
Cal/EPA (2014b)
Cal/EPA (OSF)
0.24 (mg/kg-dr1
Based on U.S. EPA (1988b)
Cal/EPA (2014b)
ACGIH
NV
NA
ACGIH (2016)
"Sources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; Cal/EPA = California Environmental Protection Agency;
DOE = U.S. Department of Energy; DWSHA = Drinking Water Standards and Health Advisories;
HEAST = Health Effects Assessment Summary Tables; IARC = International Agency for Research on Cancer;
IPCS = International Programme on Chemical Safety; IRIS = Integrated Risk Information System;
NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program;
OSHA = Occupational Safety and Health Administration; USAPHC = U.S. Army Public Health Command.
Parameters: ISF = inhalation slope factor; IUR = inhalation unit risk; MEG = military exposure guideline;
OSF = oral slope factor; PAC = protective action criteria; TEEL = temporary emergency exposure limit;
WOE = weight of evidence.
p,p'-DDD =p,p'-dichlorodiphenyldichloroethane; p,p'-DDT = /?,//-dichlorodiphcnvltrichlorocthanc: NA = not
applicable; NV = not available.
Non-date-limited literature searches were conducted in December 2015 and updated in
July 2017 for studies relevant to the derivation of provisional toxicity values for p,p -DDD
(CASRN 72-54-8). Searches were conducted using U.S. EPA's Health and Environmental
Research Online (HERO) database of scientific literature. HERO searches the following
databases: PubMed, TOXLINE (including TSCATS1), and Web of Science. The following
databases were searched outside of HERO for health-related data: American Conference of
Governmental Industrial Hygienists (ACGIH), Agency for Toxic Substances and Disease
Registry (ATSDR), California Environmental Protection Agency (Cal/EPA), U.S. EPA
Integrated Risk Information System (IRIS), U.S. EPA Health Effects Assessment Summary
Tables (HEAST),U.S. EPA Office of Water (OW),U.S. EPA TSCATS2/TSCATS8e,U.S. EPA
High Production Volume (HPV),U.S. EPA National pesticide Information Retrieval System
(NPIRS), European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), Japan
Existing Chemical Data Base (JECDB), European Chemicals Agency (ECHA), Organisation for
Economic Co-operation and Development (OECD) Screening Information Data Sets (SIDS),
OECD International Uniform Chemical Information Database (IUCLID), OECD HPV, National
Institute for Occupational Safety and Health (NIOSH), National Toxicology Program (NTP), and
Occupational Safety and Health Administration (OSHA).
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REVIEW OF POTENTIALLY RELEVANT DATA
Tables 3A and 3B provide overviews of the relevant noncancer and cancer databases,
respectively, forp,p -DDD and include all potentially relevant repeated short-term-, subchronic-,
and chronic-duration studies as well as reproductive and developmental toxicity studies. The
phrase "statistical significance," used throughout the document, indicates ap-value of < 0.05
unless otherwise specified. A carcinogenicity assessment for p,p'-DDD is available on IRIS
(U.S. EPA. 1988b); therefore, cancer data are not discussed in detail below.
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Table 3A. Summary of Potentially Relevant Noncancer Data forp,p'~DDD (CASRN 72-54-8)
Category3
Number of Male/Female, Strain,
Species, Study Type, Study
Duration, Reported Doses
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference (comments)
Notes0
Human
1. Oral (mg/kg-d)
Subchronic
One adult male volunteer, diet for
81 d. The pesticide was mixed with
vegetable oil, emulsified with gum
arabic and water, and taken with
meals (no further detail on dosing
was provided); reported dose: 5 mg/d
0.07d
No health effects noted in clinical
chemistry or hematology
parameters
NDr
NDr
Morgan and Roan (1974.
PR
1971)
(No NOAEL determination
due to limited endpoints,
limited experimental
details, and single subject)
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
Subchronic
8-12 M, Wistar rat, diet for 6 wk
followed by 2-wk recovery; reported
doses: 0 or 200 ppm
0, 18.4
Evidence of immunosuppression
(reduced humoral and
cell-mediated immunity) and
decreased relative spleen weight
NDr
18.4
Baneriee et al. (1996)
PR
(Limited endpoints
evaluated)
Subchronic
5 M/5 F, Osborne-Mendel rat, diet for
6 wk followed by 2-wk recovery;
reported doses: 0, 562, 1,000, 1,780,
3,160, or 5,620 ppm
0, 29.5, 52.5,
93.40, 165.8, or
294.9 (M);
0, 31.9, 56.7,
101.0, 179.2, or
318.7(F)
NDr
NDr
NDr
NCI (1978)
(Test article was 60% pure;
only body weight and
mortality were examined;
few details on experimental
results preclude the
determination of critical
effects and effect levels)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data forp,p'~DDD (CASRN 72-54-8)
Category3
Number of Male/Female, Strain,
Species, Study Type, Study
Duration, Reported Doses
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference (comments)
Notes0
Subchronic
5 M/5 F, B6C3Fi mouse, diet for
6 wk followed by 2-wk recovery;
reported doses: 0, 251, 398, 631,
1,000, or 1,590 ppm
0, 27.2, 43.1,
68.3, 108, or
172.1 (M);
0, 29.4, 46.6,
73.9, 117, or
186.1 (F)
NDr
NDr
NDr
NCI (1978)
(Test article was 60% pure;
only body weight and
mortality were examined;
few details on experimental
results preclude the
determination of critical
effects and effect levels)
PR
Subchronic
1 M, dog (breed not specified), diet
for 29-60 d (control left untreated for
100 d); reported doses: 0, 80, or
200 mg/kg-d
0, 80, or 200
No observed effects
NDr
NDr
Cueto et al. (1958)
(No NOAEL determination
due to limited endpoints
and low animal numbers)
PR
Chronic
50 M/50 F (20 controls/sex),
Osborne-Mendel rat, diet for 78 wk
followed by 34-35 wk of recovery;
reported doses: 0, 1,647, or
3,294 ppm (M); 0, 850, or
1,700 ppm (F)
0, 69.21,
138.4 (M);
0, 39.3,
78.66 (F)
Depression of body weight
(>10%) in both sexes
NA
39.3 (F)
NCI (1978)
(Test article was 60% pure.
For endpoints evaluated at
study termination,
prolonged observation
period may have allowed
for recovery from toxic
effects)
PR
Chronic
50 M/50 F (20 controls/sex), B6C3Fi
mouse, diet for 78 wk followed by
13-15 wk of recovery; reported
doses: 0, 411, or 822 ppm
0, 42.3,
84.6 (M);
0, 42.6,
85.2 (F)
Depression of body weight
(-14%) in females
42.6
85.2
NCI (1978)
(Test article was 60% pure.
For endpoints evaluated at
study termination,
prolonged observation
period may have allowed
for recovery from toxic
effects)
PR
Chronic
60 M/60 F, CF-1 mouse, diet for
123 wk; reported doses: 0 or 250 ppm
0, 45.0 (M); 0,
46.1 (F)
Depression of body weight
(>10%) in males
NDr
45.0
Tomatis et al. (1974)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data forp,p'-DDD (CASRN 72-54-8)
Category3
Number of Male/Female, Strain,
Species, Study Type, Study
Duration, Reported Doses
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference (comments)
Notes0
2. Inhalation (mg/m3)
ND
'Duration categories are defined as follows: subchronic = repeated exposure for >30 days <10% lifespan for humans (>30 days up to approximately 90 days in typically
used laboratory animal species); and chronic = repeated exposure for >10% lifespan for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S.
EPA. 2002).
'Dosimetry: Values are presented as ADDs (mg/kg-day) for /'./'-DDD, adjusted for purity of the administered material, where applicable [e.g., NCI (1978)1.
°Notes: PR = peer reviewed.
'Intake of 5 mg/day for a male volunteer. ADD was calculated assuming a reference body weight of 70 kg (U.S. EPA. 1988e).
ADD = adjusted daily dose; F = female(s); LOAEL = lowest-observed-adverse-effect level; M = male(s); NA = not applicable; ND = no data; NDr = not determined;
NOAEL = no-observed-adverse-effect level; /?,//-DDD = /j,//-dichlorodiphcnyldichlorocthane.
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Table 3B. Summary of Potentially Relevant Cancer Data for p,p -DDD (CASRN 72-54-8)
Number of Male/Female, Strain, Species,
Reference
Category
Study Type, Study Duration, Reported Doses
Dosimetry3
Critical Effects
(comments)
Notesb
Human
ND
Animal
1. Oral (mg/kg-d)
Carcinogenicity
50 M/50 F (20 controls/sex), Osborne-Mendel
0, 20.26, 40.52 (M);
Treatment-related increases in the
NCI (1978)
PR
rat, diet for 78 wk followed by 34-35 wk of
0, 10.73,21.48 (F)
incidence of thyroid follicular cell
(Test article was
recovery; reported doses: 0, 1,647, or
adenomas or carcinomas in males
60% pure)
3,294 ppm (M); 0, 850, or 1,700 ppm (F)
Carcinogenicity
50 M/50 F (20 controls/sex), B6C3Fi mouse, diet
0,6.43, 11.8 (M);
Nonsignificant increase in
NCI (1978)
PR
for 78 wk followed by 13-15 wk of recovery;
0, 6.39, 12.8 (F)
hepatocellular carcinomas in both
(Test article was
reported doses: 0, 411, or 822 ppm
sexes
60% pure)
Carcinogenicity
60 M/60 F, CF-1 mouse, diet for 123 wk;
0, 6.56 (M and F)
Significant increase in lung tumors in
Tomatis et al. (1974)
PR,
reported doses: 0 or 250 ppm
both sexes and liver tumors in males
IRIS
2. Inhalation (mg/m3)
ND
'Dosimetry: The units for oral exposures are expressed as HEDs (mg/kg-day) for />./>'-DDD. adjusted for purity of the administered material, where applicable [e.g., NCI
(1978)1. HED = animal dose (mg/kg-day) x (BWa ^ BWh)1/4, where D AF = dosimetric adjustment factor, BW„ = animal body weight, and BWh = human body weight
(U.S. EPA. 2011b). Reference body weights recommended by U.S. EPA (1988e) were used to calculate the DAFs: 70 kg for humans; 0.514 kg (M) and 0.389 kg (F) for
Osborne-Mendel rats in a chronic-duration study; 0.0373 kg (M) and 0.0353 kg (F) for B6C3Fi mice in a chronic-duration study; 0.134 kg (M). No strain-specific
reference body weights were available for CF-1 mice; instead, average rat body weights in a chronic-duration study were used (0.0317 kg for M and 0.02875 kg for F).
bNotes: IRIS = used by the Integrated Risk Information System (U.S. EPA. 1988b): PR = peer reviewed.
BW = body weight; F = female(s); HED = human equivalent dose; M = male(s); ND = no data; p,p'-DDD = /?,//-dichlorodiphcnvldichlorocthane.
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HUMAN STUDIES
Human studies ofp,p -DDD include one subchronic-duration study with a volunteer
(Morgan and Roan. 1974. 1971). and several epidemiological investigations of associations
between/>,//-DDD levels in biological media and adverse health effects (Tyagi et aL 2015;
Freire et al.. 2014; Guo et aL. 2014; Al-Saleh et aL. 2012; Boada et aL. 2012; Freire et al.. 2012;
Su et aL, 2012; Ociepa-Zawal et aL, 2010; Son et aL, 2010; Zumbado et aL, 2010; Boada et aL,
2007; Pant et aL, 2007; Asawasinsopon et aL, 2006; Damgaard et aL, 2006; Perry et aL, 2006;
Dalvie et aL, 2004a; Dalvie et aL, 2004b; Pant et aL, 2004; Pines et aL, 1987; Saxena et aL, 1983;
Saxena et al., 1981; Saxena et al.. 1980).
In a volunteer study of technical dichlorodiphenyltrichloroethane (T-DDT) and its
metabolites (includingp,p -DDD), an adult male ingested 5 mg/day ofp,p'-DDD for 81 days
(Morgan and Roan. 1971). The pesticide was mixed with vegetable oil, emulsified with gum
arabic and water, and taken with meals (no further detail on dosing was provided). Assuming a
reference body weight of 70 kg (U.S. EPA, 1988e), the intake of/>,//-DDD was 0.07 mg/kg-day.
Before, during, and after the treatment period, the man was given a battery of hematological and
clinical biochemical tests (frequency and nature of testing not reported). No abnormalities were
detected. Although no effects on hematological and clinical chemistry endpoints were observed,
details of the test endpoints, frequency, and results were not reported, other endpoints were not
assessed, and the study was conducted on a single volunteer with uncertain applicability to
others; thus, the administered dose cannot be considered a no-observed-adverse-effect level
(NOAEL).
ANIMAL STUDIES
Oral Exposures
Subchronic-Duration Studies
Baner jee el al. (1996)
The effects of dietary p,p -DDD exposure on humoral and cell-mediated immune
response were evaluated in Wistar rats. Groups of 8-12 male rats were given either the control
diet or a diet containing 200 ppm p,p -DDD (purity 99%) for 6 weeks (equivalent to
18.4 mg/kg-day2), during which general condition, food consumption, and body weights were
recorded weekly. Half of each group was immunized by subcutaneous administration of 3 mg
ovalbumin 3 weeks before the end of the exposure period; the other half was not challenged with
ovalbumin. At the end of the exposure period, rats were sacrificed and blood samples were
collected. The liver, spleen, and thymus from each animal were removed and weighed. The
humoral immune response was quantified by measuring immunoglobulin levels
(Immunoglobulin M [IgM] and Immunoglobulin G [IgG]), estimating the albumin:globulin
(A:G) ratio and measuring the ovalbumin antibody titer by enzyme-linked immunosorbent assay
(ELISA). Cell-mediated response was assessed in vivo, by quantifying the delayed type
hypersensitivity reaction (measuring footpad thickness after ovalbumin challenge), and in vitro
by measuring leukocyte and macrophage migration inhibition. The latter tests assess whether
chemical exposure results in suppression of lymphokine production.
Exposure top,p -DDD had no effect on mortality, food intake, body weight, or relative
liver or thymus weights, but significantly (p < 0.05) reduced relative spleen weight by 14%;
2Dose estimates were calculated using a reference body weight of 0.217 kg and a reference food consumption of
0.020 kg/day for male Wistar rats in a subchronic-duration study (U.S. EPA. 19886).
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absolute spleen weights were not reported (Baneriee et aL 1996). With regard to humoral
immune responses, treatment with p,p -DDD had no effect on the serum A: G ratio, but
significantly (p < 0.05) reduced the levels of IgG, IgM, and the titer of antiovalbumin antibody in
serum by 15, 24, and 35%, respectively, compared to controls. Treatment withp,p -DDD
significantly reduced cell-mediated immune responses; delayed type hypersensitivity reactions
(increase in footpad thickness) and tests of inhibition of migration of leucocytes and
macrophages were suppressed by 24, 24, and 25% (respectively) compared to controls.
The only dose tested (18.4 mg/kg-day) was identified as a lowest-observed-adverse-effect
level (LOAEL) for evidence of immunosuppression and potential effects on spleen weight in
rats; no NOAEL could be identified from these data.
NCI (1978)
In preparation for a chronic cancer bioassay, NCI (1978) conducted a range-finding
dietary toxicity study of DDD in Osborne-Mendel rats and B6C3Fi mice. Technical-grade DDD
(60%)p,p -DDD) in corn oil was mixed with feed and administered ad libitum to groups of
five male and five female rats per concentration for 6 weeks, followed by a 2-week observation
period. The test material contained 19 impurities contributing 40% of the total dose; none of the
impurities were identified. Diets containing 0, 562, 1,000, 1,780, 3,160, or 5,620 ppm
technical-grade DDD were fed to rats (corresponding top,p'-DDD doses of 0, 29.5, 52.5, 93.40,
165.8, or 294.9 mg/kg-day in males, and 0, 31.9, 56.7, 101.0, 179.2, or 318.7 mg/kg-day in
females3 after adjustment for 60% purity). Only mortality and body-weight changes were
evaluated; no animals were necropsied.
No deaths were observed in rats exposed top,p -DDD concentrations up to 3,160 ppm; no
information was reported on mortality at 5,620 ppm. Mean body weights were reduced in male
rats exposed to 1,780 ppm (9% lower than controls) and 3,160 ppm (10% lower), and in female
rats exposed to 1,000 ppm (39% lower) and 1,780 ppm (4% lower); neither statistical analysis
nor raw data were presented. No data on body-weight changes at other doses were reported.
This study included low animal numbers, examined few endpoints, and provided incomplete
reporting on body-weight changes, preventing the identification of potential target organ effects
and associated effect levels.
In the mouse study, groups of five male and five female mice were exposed to dietary
p,p -DDD for 6 weeks, followed by a 2-week observation period; test material and study protocol
were as described above for rats. Mice received diets containing 0, 251, 398, 631, 1,000, or
1,590 ppm (0, 27.2, 43.1, 68.3, 108, or 172.1 mg/kg-dayp,p -DDD in males, and 0, 29.4, 46.6,
73.9, 117, or 186.1 mg/kg-dayp,p'-DDD in females3 after adjustment for 60% purity). Mortality
was observed in male mice of all but the 631-ppm exposure group (data and details not reported);
no deaths occurred among control males. Mortality was also observed in female mice exposed to
1,000 and 1,590 ppm, but not in other groups (data not reported). p,p -DDD did not affect mean
body weights in the exposed mice; mean body-weight gain in male and female mice exposed to
'Dose estimates were calculated using reference values for food consumption and body weight (U.S. EPA. 19886).
Reference body weights for Osborne-Mendel rats in a subchronic-duration study: 0.263 kg (males) and 0.201 kg
(females). Reference food consumption for Osborne-Mendel rats in a subchronic-duration study: 0.023 kg/day
(males) and 0.019 kg/day (females). Reference body weights for B6C3Fi mice in a subchronic-duration study:
0.0316 kg (males) and 0.0246 kg (females). Reference food consumption for B6C3Fi mice in a
subchronic-duration study: 0.0057 kg/day (males) and 0.0048 kg/day (females).
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concentrations up to 631 ppm exceeded weight gain in controls (details not reported). Because
incidence data for mortality effects associated with p,p -DDD exposure were not reported and
few details were provided, reliable frank effect levels (FELs) cannot be established. The study
also suffers from deficiencies in protocol design (low animal numbers and few endpoints
examined) that preclude the identification other effect levels.
Cueto et al. (1958)
Technical-grade DDD was separated into different fractions and each fraction was tested
for adrenocorticolytic activity in male dogs (breed not specified) via dietary administration. A
single dog received 80 mg/kg-day of purified p,p'-DDD for 29 days, and another dog received
the same dose for 80 days; a third dog was treated with 200 mg/kg-day for 30 days, and a fourth
dog was left untreated for 100 days as a control. The endpoints examined included general
appearance, periodic tests of adrenal activity and, after necropsy, examination of adrenal
histopathology. No other organ system was evaluated. Treatment withp,p -DDD at either dose
level had no effect on the physical state of the dogs. In tests of adrenal activity administered
after 4 and 20 days of treatment, the dog treated with 200 mg/kg-day of p,p'-DDD and the
control dog exhibited the same effects in response to an injection of adrenocorticotropic
hormone: there were similar decreases in the eosinophil count and similar increases in the plasma
level of 17-hydroxycorticosteroids. At termination, no treated dogs showed evidence of adrenal
histopathology. This study is inadequate to establish effect levels due to limited endpoints
evaluated and very low animal numbers.
Chronic-Duration/Carcinogenicity Studies
NCI (1978)
A carcinogenicity bioassay of/>,//-DDD was conducted by NCI (1978) in
Osborne-Mendel rats and B6C3Fi mice. Technical-grade DDD (60%p,p'~DDD) in corn oil was
mixed with feed at varying concentrations and administered ad libitum. The test material
contained 19 impurities, contributing 40% of the total dose; none of the impurities were
identified. Nominal concentrations, durations of exposure at these concentrations, and weighted
average concentration and dose estimates over the 78-week exposure period are provided in
Table B-l. As the table indicates, the exposure concentration was increased once in rats and
twice in mice, as the animals tolerated the exposures well. Rats were observed for 34 or
35 weeks after exposure termination and prior to sacrifice. Mice were observed for 13-15 weeks
after the 78-week exposure period and prior to sacrifice. Time-weighted average technical-grade
DDD concentrations given to rats were 0, 1,647, or 3,294 ppm (corresponding top,p -DDD
doses of 0, 69.21, or 138.4 mg/kg-day4 after adjustment for 60% purity) in males and 0, 850, or
1,700 ppm (corresponding top,p -DDD doses of 0, 39.3, or 78.66 mg/kg-day4 after adjustment
for 60% purity) in females. Mice received weighted-average technical-grade DDD
concentrations of 0, 411, or 822 ppm (corresponding top,p -DDD doses of 0, 42.3, or
84.6 mg/kg-day in males and 0, 42.6, or 85.2 mg/kg-day in females4 after adjustment for
60% purity).
'Dose estimates were calculated using the reference values for food consumption and body weight (U.S. EPA.
19886). Reference body weights for Osborne-Mendel rats in a chronic-duration study: 0.514 kg (males) and
0.389 kg (females). Reference food consumption for Osborne-Mendel rats in a chronic-duration study: 0.036 kg/day
(males) and 0.030 kg/day (females). Reference body weights for B6C3Fi mice in a chronic-duration study:
0.0373 kg (males) and 0.0353 kg (females). Reference food consumption for B6C3Fi mice in a chronic-duration
study: 0.0064 kg/day (males) and 0.0061 kg/day (females).
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Body-weight and food-consumption measurements, clinical observations, and palpations
for masses were conducted weekly for 10 weeks and monthly thereafter; mortality checks were
performed daily (NCI. 1978). Necropsy was performed on all animals, but organ weights were
not recorded. Histopathologic examination was initially limited to control animals, animals with
visible tumors and at least 10 males and females with no gross pathological findings from each
group. Later in the study, the protocol was altered to include tissues from other animals;
however, the study authors did not indicate how the other animals were selected, how many were
included, or when the protocol change was initiated. Nearly 30 tissues were subjected to
microscopic examination. The study authors noted that tissues were not examined from some
animals that died early and that some animals were missing, cannibalized, or in an advanced
state of autolysis, precluding histopathologic examination. Incidence of lesions was reported
using the number of animals for which that specific tissue was examined as the number at risk,
except where lesions were observed grossly or could appear at multiple sites (e.g., lymphoma), in
which case, the number of animals necropsied was used.
The study authors reported that, beginning at Week 30 and continuing through
termination of the exposure period, treated rats (not further specified) exhibited a slightly greater
incidence of clinical signs of toxicity (hunched appearance and urine staining; data not reported)
(NC I. 1978). Prior to 30 weeks and during the recovery period, there was no treatment-related
effect on the incidence of clinical signs (data not reported), according to the study authors.
p,p -DDD treatment did not significantly affect probability of survival in either sex. There were
clear treatment-related reductions in body weight, but the study authors did not present statistical
comparisons of group mean body weights or raw data. Based on graphical presentation of the
data, the greatest differences from control weights occurred between Weeks 60 and 75, when the
mean body weights were about 10 and 20% lower than controls in low- and high-dose males
(respectively) and about 20 and 30% lower in low- and high-dose females. Treatment with
p,p -DDD had no significant effect on the incidence of non-neoplastic lesions in rats in any tissue
examined. A NOAEL cannot be determined from this study. The low dose (39.3 mg/kg-day in
females) is a LOAEL for biologically significant reductions (>10%) in mean body weight in
male and female rats.
An increased incidence of combined thyroid follicular-cell adenomas or carcinomas was
observed in exposed male rats compared to controls that reached statistical significance at the
low treatment dose. Based on the statistical analysis, the study authors reported an association
between increased incidence of thyroid tumors and p,p -DDD treatment. No other
treatment-related effects on tumor frequency were found. This study was evaluated as part of the
IRIS cancer assessment (U.S. EPA. 1988b). but was not used in deriving the oral slope factor
(OSF).
In mice, p,p -DDD treatment had no significant effect on probability of survival in either
sex. Clinical signs occurred with the same frequency in treated and control animals. Exposure
to p,p -DDD had no effect on male body weight throughout the treatment period, but dose-related
depression of body weight was observed in female mice after Week 30. The study authors did
not present statistical comparisons of group mean body weights or raw data. Based on graphical
presentation of the data, the body-weight reduction peaked at about 14% in the high-dose group
between Weeks 60 and 75; in the low-dose group, body-weight decrements appeared to be <10%
throughout the study. Treatment did not significantly increase the incidence of non-neoplastic
lesions in any tissue in either sex. The low dose of 42.3 mg/kg-day p,p -DDD is a NOAEL and
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the high dose of 84.6 mg/kg-day p,p -DDD is a LOAEL for body-weight depression in female
mice.
The study authors reported increases in the incidence of hepatocellular carcinomas in
mice treated withp,p -DDD; however, the increase was not statistically significant in either sex.
No other treatment-related effects on tumor frequency were observed. This study was evaluated
as part of the IRIS cancer assessment (U.S. EPA. 1988b). but was not used in deriving the OSF.
Tomatis et al. (1974)
The carcinogenicity of p,p -DDD was evaluated in CF-1 mice treated via the diet for a
lifetime. The study authors administeredp,p -DDD in the diet (250 ppm) to 60 male and
60 female mice (6-7 weeks old) for up to 123 weeks; 101 male and 97 female mice were
maintained on a control diet. The test compound was 99% pure and was dissolved in acetone
prior to being mixed with powdered food and converted to pellets. It is not clear whether the
control diet contained acetone. A dietary concentration of 250 ppm corresponds to an estimated
p,p -DDD dose of about 45.0 and 46.1 mg/kg-day for males and females, respectively.5 Groups
of four animals (sex not specified) were sacrificed either between Weeks 65 and 74 of treatment
or between Weeks 94 and 118 of treatment for analysis of p,p -DDD levels in the liver and
interscapular fat (and sometimes in liver tumors and kidney; details not provided). All animals
dying spontaneously or killed humanely were necropsied; remaining animals were sacrificed at
130 weeks of age. Histopathology evaluation was restricted to the lungs, heart, thymus, liver,
kidneys, spleen, brain, and any organs with gross abnormalities.
Survival was not affected by/>,//-DDD (Tomatis et al. 1974). Survival to 90 weeks was
76 and 72% in treated males and females, compared with 67 and 73% in control males and
females, respectively. There were no clinical signs of toxicity among mice treated with
p,p -DDD. The study authors reported neither a statistical comparison of body weights nor raw
data; however, based on visual evaluation of body-weight curves (covering the period from the
third to fourteenth month of age), body weights of the treated males were depressed by
>10%) relative to controls over the entire period of observation; body weights of treated females
were unaffected by treatment. The only other possible effect was a fivefold increase in the
incidence of myocardial necrosis in males, although the overall incidence was small (3/59 in
treated animals vs. 1/98 in controls) and not statistically significant (p-value = 0.15 in Fisher's
exact test performed for this review). The only dose ofp,p -DDD tested, 45.0 mg/kg-day, is a
LOAEL for body-weight depression in male mice.
The study authors noted that the incidence of lung tumors was increased over controls in
p,p -DDD-exposed mice of both sexes; in addition, the incidence of liver tumors (hepatomas)
was increased in male mice (Tomatis et al.. 1974). This study was used in the derivation of the
OSF for/;,//-DDD (U.S. EPA. 1988b).
5Based on reference values for food consumption and body weight (U.S. EPA. 1988e). No strain-specific reference
body weights were available for CF-1 mice; instead, average reference body weight for mice in a chronic-duration
study were used: 0.0317 kg (male) and 0.02875 kg (female). Average reference food consumption for mice in a
chronic-duration study were also used: 0.0057 kg/day (male) and 0.0053 kg/day (female).
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Inhalation Exposures
No studies on the effects in laboratory animals top,p -DDD exposure via inhalation have
been identified.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Short-Term-Duration Oral Studies with Considerable Limitations
Powers et al. (1974)
Eleven mongrel dogs and four purebred Beagle dogs were administered gelatin capsules
containing technical-grade DDD (characterized by the study authors as 90% p,p -DDD and
5-8% o,//-DDD, other impurities unspecified) dissolved in corn oil. The dogs were given daily
doses of 100 mg/kg for 6-day periods, or 200 mg/kg on alternative days for up to 30 days. In
total, dogs received doses ranging from 600 mg/kg (6 x 100 mg/kg) to 3,000 mg/kg
(15 x 200 mg/kg). Control groups (consisting of 6 mongrels and 2 Beagles) of various sizes
were maintained. Upon sacrifice, the adrenal glands were weighed (in some cases), and/or
examined with light and electron microscopy. The study authors reported histopathology
findings in the adrenals of treated dogs, including degenerative vacuolation, especially in the
inner cortex, mitochondrial swelling, cellular necrosis, and dilatation of smooth endoplasmic
reticulum. Because the test material in this study included the potent adrenocorticolytic DDD
isomer, o,p -DDD, and potentially other contaminants, it is not possible to determine whether
any of the adrenal effects are attributable to p,p -DDD exposure. The study is inadequate to
establish effect levels.
Genotoxicity
Genotoxicity data for />,//-DDD have been summarized by ATS PR (2002a), WHO
(20111 and I ARC (1991). />,//-DDD was negative in tests for reverse mutation in bacteria with
or without activation. p,p -DDD was also negative in tests for unscheduled deoxyribonucleic
acid (DNA) synthesis in primary rat, mouse, and hamster hepatocytes. Weak positive results
were found for chromosomal aberrations (CAs) in Chinese hamster B14F28 cells. Recent
studies evaluating the potential genotoxicity of p,p -DDD are limited to evaluations of DNA
damage and micronucleus formation in zebra mussel hemocytes and human peripheral blood
lymphocytes, and positive results were observed in both test systems (described in Table 4A and
summarized below).
DNA damage and micronuclei (MN) were reported in Dreissenapolymorpha (zebra
mussel) hemocytes following 48, 96, and 168 hours of exposure to p,p -DDD in water at 0.1, 2,
or 10 |.ig/L (Binelli et al.. 2008). Analysis using single cell gel electrophoresis (SCGE) alkaline
comet assay revealed a dose- and time-related increase in DNA breakage, measured using
tail-length-to-comet-head ratio (LDR) and tail intensity. MN were also induced in hemocytes
collected from exposed zebra mussels, increasing with both exposure time and concentration.
DNA damage and MN were also reported in assays conducted in human peripheral blood
lymphocytes following in vitro exposure to/>,//-DDD at 3.9 |ig/mL for 1, 6, or 24 hours (Geric et
al.. 2012). DNA strand breaks, detected in a standard comet assay, were significantly increased
after 24 hours of exposure. Oxidative DNA damage, as measured by
8-hydroxy-2'-deoxyguanosine (80HdG) formation in a modified comet assay, did not occur.
Significant increases in the frequency of MN, numbers of nucleoplasmic bridges, and nuclear
buds were reported after 24 hours, as analyzed using a cytokinesis-block micronucleus assay.
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Table 4A. Recent Studies ofp,p -DDD Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested3
Results
without
Activationb
Results
with
Activationb
Comments
Reference
Genotoxicity studies in nonmammalian eukaryotic organisms—in vivo exposure
Micronucleus test
Dreissena polymorpha (zebra mussel)
hemocytes; zebra mussel exposures were
conducted under semistatic conditions for
up to 168 hr. Hemolymph (100 |iL) was
extracted from the posterior adductor
muscle of 10 mussels at 48, 96, and 168 hr
after exposure initiation.
0 (untreated and
solvent controls),
0.1, 2, or 10 ng/L
+
+
MN frequency was significantly
increased >threefold over the
respective controls at each dose and
time period.
Binelli et al.
(2008)
DNA damage
(SCGE; comet assay)
D. polymorpha hemocytes; zebra mussel
exposures were conducted under
semistatic conditions for up to 168 hr.
Hemolymph (100 |iL) was extracted from
the posterior adductor muscle of
10 mussels at 48, 96, and 168 hr after
exposure initiation.
0 (untreated and
solvent controls),
0.1, 2, or 10 ng/L
+
+
DNA damage was significantly
increased in a dose- and
time-related manner and exhibited
progressive accumulation of DNA
damage over time.
Binelli et al.
(2008)
Genotoxicity studies in mammalian cells—in vitro exposure
DNA diffusion assay
Human peripheral blood lymphocytes
0 (control),
3.9 ng/mL for 1, 6,
or 24 hr
+
NDr
Cell viability was decreased from
25% of control at 1 and 6 hr, and to
-50% of control at 24 hr. Both
apoptosis and necrosis were
observed, but necrosis was the
primary form of cell death.
Geric et al.
(2012)
DNA damage
(alkaline comet assay)
Human peripheral blood lymphocytes
0 (control),
3.9 ng/mL for 1, 6,
or 24 hr
+
NDr
Tail intensity was increased after
24 hr of exposure; the percentage of
DNA in the tail was 9.28%
compared to 1.81% (control).
Geric et al.
(2012)
DNA damage
(FPG-modified comet
assay; 80HdG
formation)
Human peripheral blood lymphocytes
3.9 ng/mL for 1, 6,
or 24 hr
NDr
NA
Geric et al.
(2012)
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Table 4A. Recent Studies ofp,p -DDD Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested3
Results
without
Activationb
Results
with
Activationb
Comments
Reference
Cytokinesis-block
micronucleus assay
Human peripheral blood lymphocytes
3.9 ng/mL for 1, 6,
or 24 hr
+
NDr
p,p'-DDD induced significant
increases in the number of
micronucleated cells, and total
number ofMN, nucleoplasmic
bridges, and nuclear buds after 6
and 24 hr of exposure.
The CBPI was significantly
decreased by 15% only at the 24-hr
exposure.
Geric et al.
(2012)
aLowest effective dose for positive results; highest dose tested for negative results.
b+ = positive; - = negative.
80HdG = 8-hydroxy-2'-deoxyguanosine; CBPI = cytokinesis-block proliferation index; DNA = deoxyribonucleic acid; FPG = formamidopyrimidine-DNA glycosylase;
MN = micronuclei; NA = not applicable; NDr = not determined; p,p'-DDD = /?,//-dichlorodiphen\ idichloroethane; SCGE = single cell gel electrophoresis.
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Supporting Human Studies
Epidemiology studies evaluating the association between adverse health effects and
measurements ofp,p -DDD in biological fluids are described in detail in Table 4B. Maternal
blood and placental levels ofp,p -DDD were significantly higher in cases of spontaneous
abortion and preterm labor, but not the rate of still birth, when compared with full-term
deliveries (Tyagi et al.. 2015; Saxena et al.. 1983; Saxena et al.. 1981; Saxena et ai, 1980).
Decreased birth weight was associated with increased/>,//-DDD levels in cord blood serum (Gup
et al - 2014) and decreased birth length was correlated with placental />,//-DDD levels (Al-Saleh
et al., 2012). Serum levels of/>,//-DDD were also associated with changes in reproductive
hormones in adult males and females (F'reire et al.. 2014; Perry et al.. 2006; Dal vie et al.. 2004a).
Infertility in men was associated with higher serum and seminal fluid concentrations of
/>,//-DDD (Pant et al.. 2007; Pant et al.. 2004; Pines et al.. 1987). Sperm effects, however, were
not consistently observed in these studies (Pant et al.. 2007; Pant et al.. 2004; Pines et al.. 1987).
Other health outcomes that were reportedly associated with elevated serum p,p -DDD
concentrations include breast cancer (Boada et al.. 2012). altered thyroid hormone status (f'reire
et al.. 2012). decreased insulin-like growth factor-1 (IGF-I) (/umbado et al.. 2010; Boada et al..
2007). and Type 2 diabetes (Son et al.. 2010). Taken together, these studies suggest an
association between p,p -DDD exposure and reproductive or hormonal effects. However, in all
of these studies, the participants had measurable levels of other chlorinated compounds,
including DDE and DDT. Further, whenp,p -DDD levels in biological fluids are used as an
estimate for exposure, it is not possible to determine whether the levels result from direct
exposure to p,p -DDD or from metabolism of DDT. As a consequence, none of the available
human studies are suitable for use in deriving provisional toxicity values.
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Table 4B. Epidemiology Studies Evaluating Associations between Health Effects and p,p -DDD Levels in
Biological Fluids and Tissues
Study Population
Outcome
Levels of p,p -DDD in Biological Media3
Results and Notes
Reference
Pregnancy outcomes
India; case-control study;
pregnant women between
18-30 yr of age; 20 cases of
spontaneous abortion or
premature labor, 20 controls
(full-term delivery)
Spontaneous abortion and
preterm labor (12-32 wk of
gestation)
Maternal blood:
Controls = 6.5 ± 7.88 ppb;
Cases = 39.65 ± 19.85 ppb
Placenta:
Controls = 4.85 ± 9.28 ppb;
Cases = 16.72 ± 18.96 ppb
Maternal blood and placental levels
ofp,p'-DDD were significantly
(p < 0.001) higher in cases of
spontaneous abortion and preterm
labor when compared with full-term
deliveries.
Saxena et al.
(1980)
India; case-control study;
pregnant women between
18-32 yr of age; 10 cases of
spontaneous abortion, 15 cases of
preterm labor, 25 controls
(full-term delivery)
Spontaneous abortion and
preterm labor (weeks of
gestation not specified)
Maternal blood:
Controls = 6.9 ± 7.9 ppb;
Preterm labor cases =15.2±12.5 ppb;
Spontaneous abortion
cases = 65.5 ± 129.4 ppb
Placenta (also fetus for spontaneous abortion
cases):
Controls = 4.9 ± 8.3 ppb;
Preterm labor cases = 10.7 ± 10.7 ppb;
Spontaneous abortion
cases = 20.6 ± 22.8 ppb
Maternal blood and placental levels
ofp,p'-DDD were significantly
(p < 0.001) higher in cases of
preterm labor and spontaneous
abortion when compared with
full-term deliveries.
Saxena et al.
(1981)
India; case-control study;
pregnant women (age not
reported); 9 cases of stillbirth,
27 controls (full term delivery)
Stillbirth
Maternal blood:
Controls = 5.3 ppb (SD not reported);
Cases = 3.6 ppb
Placenta:
Controls = 5.0 ppb;
Cases = 7.6 ppb
Cord blood:
Controls = 6.2 ppb;
Cases = 4.1 ppb
Maternal blood, placental, and cord
blood levels ofp,p'-DDD were
similar for stillbirth cases and
controls.
Saxena et al.
(1983)
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Table 4B. Epidemiology Studies Evaluating Associations between Health Effects and p,p -DDD Levels in
Biological Fluids and Tissues
Study Population
Outcome
Levels of p,p -DDD in Biological Media3
Results and Notes
Reference
Saudi Arabia; cross-sectional
study of 1,578 mother-newborn
pairs (mean maternal age of
28 yr)
Neonatal anthropometric
measures
Maternal blood = 0.002 ± 0.030 ^g/L
Cord blood = 0.005 ± 0.135 ^ig/L
Placenta (ng/kg dry wt.) = 7.042 ± 18.030;
Placenta (ng/kg wet wt.) = 42.357 ± 110.792
Placentalp,p'-DDD levels were
correlated with decreased
crown-heel length in neonates
(regression analysis adjusted for
many continuous and categorical
variables).
Al-Saleh et al.
(2012)
China; cross-sectional study of
81 mother-infant pairs (median
maternal age of 29 yr)
Birth weight
Median serum (ng/g lipid):
Maternal = 1.42;
Cord = 0.73
A decrease in birth weight was
associated with increasedp,p'-DDD
levels in cord blood serum (not
statistically significant; multivariate
linear regression adjusted for
maternal age, maternal BMI at
delivery, infant gender, and week of
gestation).
C iuo et al.
(2014)
India; case-control study;
pregnant women with a mean
maternal age of 23 yr old;
50 cases of preterm birth (<37 wk
gestation) and 50 controls
(gestation of >37 wk)
Preterm birth (<37 wk
gestation), placental weight,
baby weight, period of
gestation
Maternal blood (ppb):
Controls = 1.13 ±0.041;
Cases = 1.74 ±0.895
Placenta:
Controls = 5.780 ± 4.8055;
Cases = 7.663 ± 5.5670
Maternal blood levels of p,p'-DDD
were significantly (p = 0.016) higher
in cases of preterm labor; no
significant correlation was observed
between/?,/)-DDD concentration
and placental weight, baby weight,
or gestation period.
Tvaei et al.
(2015)
Sexual differentiation measures
Denmark and Finland; nested
case-control study of
mother-child pairs (maternal age
between 29-31 yr); 62 cases of
cryptorchidism, 68 healthy
controls
Cryptorchidism in male
offspring
Breast milk (ng/g lipid):
Controls (median) = 0.34;
Cases (median) = 0.36
Breast milk concentrations of
p,p'-DDD were similar between
cryptorchidism cases and controls.
Damgaard et al.
(2006)
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Table 4B. Epidemiology Studies Evaluating Associations between Health Effects and p,p -DDD Levels in
Biological Fluids and Tissues
Study Population
Outcome
Levels of p,p -DDD in Biological Media3
Results and Notes
Reference
Reproductive hormone levels
South Africa; cross-sectional
study of 50 male malaria control
workers (mean age of 45 yr)
Hormone levels before and
after gonadotropin-releasing
hormone challenge (LH, FSH,
E2, testosterone inhibin)
Serum level (|ig/g lipid): 0.91 ± 0.68
A significant positive association
was observed between serum
p,p'-DDD levels, and baseline levels
of testosterone and E2 (linear
regression adjusted for age and basal
SHBG).
Dalvie et al.
(2004a)
China; prospective cohort study;
287 women between 20-34 yr of
age
Levels of progesterone
(measured as urinary PdG) and
estrogen (measured as urinary
estrone conjugates or EiC)
Serum range (ng/g): 0.07-0.96
Higher serump,p'-DDD levels were
associated with lower log (PdG)
levels across all phases of the
menstrual cycle and lower EiC
levels during periovulation, and the
luteal period (linear regression
adjusted for age, age squared, BMI,
BMI squared, education, shift work,
stress, passive smoke, noise, and
dust exposure).
Perrv et al.
(2006)
Brazil; cross-sectional study;
304 men and 300 women (mean
age of 39 yr)
Serum levels of testosterone in
men and E2, progesterone,
prolactin, LH, and FSH in
females
Median concentration in serum (ng/mL):
Men= 0.61;
Premenopausal women (n = 223) = 0.59;
Peri/postmenopausal women
(n = 77) = 0.87
A significant negative association
was observed between serum
p,p'-DDD levels, and LH and FSH
concentrations in
peri/postmenopausal women
(multivariate regression adjusted for
age, ethnicity, years at location,
BMI, breastfeeding, smoking, and
serum cholesterol and triglycerides).
Freire et al.
(2014)
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Table 4B. Epidemiology Studies Evaluating Associations between Health Effects and p,p -DDD Levels in
Biological Fluids and Tissues
Study Population
Outcome
Levels of p,p -DDD in Biological Media3
Results and Notes
Reference
Male reproductive effects (fertility, semen analysis)
Israel; case-control study; men
between 25-45 yr of age;
29 cases of infertility (>5 yr
history, sperm effects);
14 controls (fertile with at least
one child <2 yr old)
Male fertility, semen analysis
(sperm count, motility, and
morphology)
Serum (ng/g):
Control = 2.23 ± 3.0;
Cases = 4.35 ± 4.74
Serump,p'-DDD was significantly
higher in infertile men compared to
controls; no association between
serum levels and sperm effects was
noted.
Pines et al.
(1987)
South Africa; cross-sectional
study of 60 male malaria control
workers (mean age of 45 yr)
Semen analysis (sperm count,
density and motility)
Serum levels were not reported
No significant association between
serum p,p'-DDD and semen
parameters was observed.
Dalvie et al.
(2004b)
India; case-control study of men;
45 cases of infertility (>1 yr
history, mean age 31 yr);
45 controls (fertile; mean age of
29 yr)
Male fertility; semen analysis
for fructose concentration
(marker of seminal vesicle
secretion), and activity of acid
phosphatase and y-glutamyl
transpeptidase (markers of
prostate function)
Seminal fluid concentration (|ig/L):
Controls = 12.1 ± 1.36 (SEM);
Cases = 21.38 ± 2.12 (SEM)
The semen level of p,p'-DDD was
significantly higher in infertile men
compared to controls; in infertile
men, p,p'-DDD levels in semen
were significantly correlated with
higher levels of fructose.
Pant et al.
(2004)
India; case-control study of men;
50 cases of infertility (>1 yr
history, mean age 30 yr);
50 controls (fertile, mean age of
29 yr)
Semen analysis (sperm count
and motility)
Seminal fluid concentration (|ig/L):
Controls = 13.4 ± 1.09 (SEM);
Cases = 20.74 ± 1.92 (SEM)
The semen level of p,p'-DDD was
significantly higher in infertile men
compared to controls; in infertile
men, p,p'-DDD levels in semen
were significantly correlated with
decreased sperm count.
Pant et al.
(2007)
Breast cancer
Poland; case-control study of
women between 37-87 yr of age
(mean age of 58); 54 cases of
breast cancer; 23 healthy controls
Breast cancer stage and grade
Breast adipose tissue (mg/kg fat):
Controls = 0.025 ± 0.032;
Cases = 0.031 ±0.037
Levels of p,p'-DDD did not differ
between cases and controls; no
significant correlation was observed
between breast adipose levels of
p,p'-DDD and breast cancer stage or
grade.
Ociera-Zawal et
al. (2010)
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Table 4B. Epidemiology Studies Evaluating Associations between Health Effects and p,p -DDD Levels in
Biological Fluids and Tissues
Study Population
Outcome
Levels of p,p -DDD in Biological Media3
Results and Notes
Reference
Spain; case-control study of
women; 121 cases of breast
cancer (mean age of 58);
103 healthy controls (mean age of
45)
Breast cancer risk
Serum (ng/g lipid):
Controls = 21.8 ± 131.2;
Cases = 440.3 ± 412.7
The serum level of p,p'-DDD was
significantly higher in women with
breast cancer compared to controls;
breast cancer risk was slightly
elevated (adjusted OR 1.008:
95% CI 1.001-1.015,/) = 0.024;
adjusted for age, BMI, menopausal
status, lactation, and smoking
habits).
Boada et al.
(2012)
Thyroid hormone status
Thailand; cross-sectional study of
39 mother-infant pairs (full term,
normal delivery)
Thyroid hormone status in
infants (measured in umbilical
cord blood)
Serum (ng/g lipid):
Maternal = 139 ± 115;
Cord = 105 ±63.0
No correlation was found between
p,p'-DDD and thyroid hormone
levels in cord serum.
Asawasinsooon
et al. (2006)
Brazil; cross-sectional study of
193 children (<15 yr old)
Thyroid hormone status in
children
Serum (ng/mL):
Mean of levels above detection limit = 24.2
Total T3 levels and free T4 levels
were positively associated with
serum concentrations of p,p'-DDD
(regression adjusted for age, gender,
triglycerides, and cholesterol).
Freire et al.
(2012)
Insulin-like growth factor-I (IGF-I)
Spain; cross-sectional study of
176 men (mean age of 43 yr) and
247 women (mean age of 43 yr)
Serum concentrations of IGF-I
Median serum (ng/g fat):
Men = 0.0 (19.3% of samples above the
detection limit);
Women = 0.0 (19.8% of samples above the
detection limit)
IGF levels were lower in women
aged 36-50 with detectable
p,p'-DDD concentrations, compared
to women of the same age group
with nondetectable levels of
p,p'-DDD (p = 0.03; IGF levels
were adjusted for age, BMI, and
IGFBP-3).
Boada et al.
(2007)
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Table 4B. Epidemiology Studies Evaluating Associations between Health Effects and p,p -DDD Levels in
Biological Fluids and Tissues
Study Population
Outcome
Levels of p,p -DDD in Biological Media3
Results and Notes
Reference
Spain; cross-sectional study of
children (ages 6-12 in females;
6-15 in males) and adolescents
(ages 13-19 in females; 15-19 in
males); 81 boys and 79 girls
Serum concentrations of IGF-I
Median serum (25th-75th percentile)
(ng/gfat):
Male children = 0.0 (0.0-0.0);
Male adolescents = 0.0 (0.0-132.9);
Female children = 0.0 (0.0-0.0);
Female adolescents = 0.0 (0.0-0.0)
Detectable levels ofp,p'-DDD in
prepubertal male children were
inversely associated with IGF-I
levels (p = 0.049) (multivariate
analysis adjusted for age, height,
weight, and IGFBP-3; a categorical
variable was included to account for
the large number of samples with
p,p'-DDD concentrations below the
detection limit).
Zumbado et al.
(2010)
Gallstone disease
China; case-control study;
150 patients with gallstones,
150 age- and gender-matched
controls
Gallstone disease
Median serum concentrations (|ig/L):
Controls = 0.369;
Cases = 0.381
p,p'-DDD concentrations were
similar between cases and controls;
percent detectability was slightly
higher in cases vs. controls
(100 vs. 94.7%).
Su et al. (2012)
Type 2 diabetes
Korea; case-control study;
40 diabetic patients (53% men,
mean age of 57 yr) and 40 healthy
controls (53% men, mean age of
57 yr)
Type 2 diabetes
Serum (ng/g lipid):
Controls = 5.7 ± 3.7;
Cases = 6.6 ±3.6
p,p'-DDD concentrations were
similar between cases and controls;
association between serum
concentration and Type 2 diabetes
was observed at the highest tertile of
exposure after adjusting for age, sex,
BMI, alcohol consumption, and
smoking (adjusted OR 3.6;
95% CI 0.08-16.3).
Son et al. (2010)
"Values represent mean± SD unless otherwise indicated.
BMI = body mass index; CI = confidence interval; E2 = estradiol; FSH = follicle stimulating hormone; IGF = insulin-like growth factor; IGFBP-3 = IGF binding
protein-3; LH = luteinizing hormone; OR = odds ratio; PdG = pregnanediol-3-glucuronide; p,p'-DDD = /?,//-dichlorodiphcnyldichlorocthanc: SD = standard deviation;
SEM = standard error of the mean; SHBG = sex hormone binding globulin; T3 = triiodothyronine; T4 = thyroxine.
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Metabolism/Toxicokinetic Studies
In a study of the toxicokinetics of DDT and its metabolites (includingp,p'-DDD), an
adult male volunteer ingested 5 mg/day of/>,//-DDD for 81 days (Morgan and Roan. 1974.
1971). The pesticide was mixed with vegetable oil, emulsified with gum arabic and water, and
taken with meals (no further detail on dosing was provided). Serum and adipose levels of
p,p -DDD rose steadily during the exposure period, peaking at exposure termination at almost
80 ppb in serum and >4 ppm in adipose (based on visual examination of data presented
graphically). Twenty-four percent of the ingested dose was stored in adipose tissue over the
exposure period. After exposure was withdrawn, levels in both serum and adipose declined
rapidly. Measurements taken 160 days after exposure termination showed no detectable
p,p -DDD in serum and levels reduced to almost 1 ppm in adipose. Approximately 68% of the
total administered dose was excreted in the urine during the first year of the study (urine
concentrations were measured monthly). p,p -DDD has been detected in adipose tissue, breast
milk, and placenta from many study populations of environmental exposure (Xu et al.. 2015;
Hernik et al.. 2014; Man et al.. 2014; Bedi et al.. 2013; Sons et al.. 2013; Bergkvist et at.. 2012;
Cok et al.. 2012; Wane et al.. 2011; A/eredo et al.. 2008; Shen et al.. 2008; Bouwman et al..
2006).
The metabolism and excretion ofp,p -DDD have been studied in experimental animals.
The primary urinary metabolite ofp,p -DDD in rats, mice, and hamsters is
2,2-A/'.s(4'-ch 1 oropheny 1) acetic acid (DDA) (Gold and Brunk. 1984, 1983, 1982; Peterson and
Robison. 1964). The intermediary metabolites (i.e., between/>,//-DDD and DDA) appear to
differ by species. Studies in rats suggest thatp,p -DDD is rapidly detoxified to DDA through the
following intermediates: 1 -chloro-2,2-/?/.s(4'-chlorophenyl)ethene (DDMU),
1 -chloro-2,2-/?/.s(4'-chlorophenyl)ethane (DDMS), 1,1 -/?/.s(4'-chlorophenyl)ethene (DDNU),
2,2-/?/.s(4'-chlorophenyl)ethanol (DDOH), and 2,2-/?/.s(4'-chlorophenyl)ethanal (DDCHO)
(Peterson and Robison, 1964). Metabolism occurs in both the liver and kidney, and
DDMU-epoxide is postulated as a possible reactive intermediate of p,p -DDD in rats. Studies in
mice and hamsters suggest thatp,p -DDD is preferentially metabolized to
2,2-A/.s(4'-chlorophenyl)acetyl chloride (DDA-C1), which is hydrolyzed to DDA (Gold and
Brunk. 1984. 1983. 1982). Formation of DDMU and DDMU-epoxide appears to be a minor
pathway in mice and hamsters.
Mode-of-Action/Mechanistic Studies
A number of studies have investigated the hormonal activities of DDT and related
compounds. When Gellert et al. (1972) injected groups of 1 1 or 12 mature ovariectomized
Sprague-Dawley (S-D) rats with 0.1 or 10 mg/day of p,p'-DDD in dimethyl sulfoxide (DMSO)
for 7 days, there was no effect on uterine weight, uterine histology, cytology of vaginal smears,
serum levels of luteinizing hormone, or follicle stimulating hormone. In castrated male Brl Han:
WIST Jcl (GALAS) rats treated with 8, 40, or 200 mg/kg-day /;,//-DDD via gavage for 10 days,
either with or without testosterone propionate, treatment with 200 mg/kgp,p'-DDD and
testosterone propionate resulted in statistically significant decreases in seminal vesicle and
bulbocavernosus/levator ani muscles, indicating antiandrogenic activity (Yamasaki et al.. 2004).
In in vitro assays, p,p -DDD did not competitively inhibit binding of 17P-estradiol to the estrogen
receptor (ER), but competitively inhibited binding of a synthetic androgen (R1881) to the rat
androgen receptor (AR) (Kelce et al.. 1995). In in vitro assays using yeast reporter gene systems,
p,p -DDD was unable to activate expression of the ER gene or the AR gene at concentrations
<10 4 M (Gaido et al.. 1997). Using an in vitro human hepatoma cell reporter gene system,
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Maness et al. (1998) found that p,p'~DDD did not stimulate expression of the human androgen
receptor (hAR) gene, but did inhibit androgen-dependent expression of the hAR gene. p,p'-DDD
gave positive results in an AR binding assay (Yamasaki et al.. 2004). The results of these
experiments suggest thatp,p -DDD possesses antiandrogenic activity.
Limited evidence suggests thatp,p -DDD binds to lung tissues and can be cytotoxic to
lung cells. When Lund et al. (1989) intravenously (i.v.) injected radiolabeled/>,//-DDD into
mice, autoradiography of solvent-extracted, whole-body sections revealed specific covalent
binding in the alveoli of the lung, in the lateral nasal gland, and in the salivary glands. The
results of the in vivo study suggest that pulmonary binding of p,p -DDD can occur after i.v.
exposure. An in vitro experiment in the same paper demonstrated thatp,p -DDD irreversibly
bound to protein following incubation with S-9 fractions from murine lung or liver. The study
authors concluded that covalent binding of p,p -DDD in the lung was the result of in situ
bioactivation. In an in vitro study, Nichols et al. (1992) incubated lung cells isolated from
rabbits withp,p -DDD, with or without 1-aminobenzotriazole (1-ABT, a suicide substrate
inhibitor of cytochrome P450 [CYP450] monooxygenases). Cytotoxicity ofp,p -DDD to Clara
cells especially, and to alveolar type II cells and alveolar macrophages to a lesser degree, was
dependent on the presence of functional CYP450. Subsequently, Nichols et al. (1995) evaluated
potential mechanisms for bioactivation of p,p -DDD in cultured Clara cells of rabbits and a
transformed human bronchial epithelial cell line (BEAS-2B). Both cell types were vulnerable to
p,p -DDD-mediated cytotoxicity and were protected by coincubation with 1-ABT, the inhibitor
to CYP450. In another experiment, Nichols et al. (1995) found that cytotoxicity was reduced
when human BEAS-2B cells, rabbit Clara cells, or rabbit pulmonary microsomes were incubated
withp,p -DDD that had a deuterium substitution at the C-l position. The results indicated that
the cytotoxicity ofp,p -DDD may be caused by its oxidation at C-l mediated by CYP450 in the
lung.
DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present summaries of noncancer and cancer references values,
respectively.
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Table 5. Summary of Noncancer Reference Values for p,p -DDD (CASRN 72-54-8)
Toxicity Type
(units)
Species/Sex
Critical
Effect
p-Reference
Value
POD
Method
POD
UFc
Principal Study
Screening
subchronic p-RfD
(mg/kg-d)
Rat/M, F
Liver
lesions
3 x 1(T5
NOAEL
(HED)
0.01
(based on
surrogate POD)
300
Laug et al. (1950)
as cited in ATSDR
f2002a) and U.S.
EPA (1988d)
Screening chronic
p-RfD (mg/kg-d)
Rat/M, F
Liver
lesions
3 x 10-5
NOAEL
(HED)
300
Laug et al.(1950)
as cited in ATSDR
(2002a) and U.S.
EPA (1988d)
Subchronic p-RfC
(mg/m3)
NDr
Chronic p-RfC
(mg/m3)
NDr
F = female(s); HED = human equivalent dose; M = male(s); NDr = not determined;
NOAEL = no-observed-adverse-effect level; POD = point of departure;
p,p'-DDD =p,p'-dichlorodiphenyldichloroethane; p-RfC = provisional reference concentration;
p-RfD = provisional reference dose; UFC = composite uncertainty factor.
Table 6. Summary of Cancer Reference Values for p,p -DDD (CASRN 72-54-8)
Toxicity Type (units)
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-d) 1
An OSF of 0.24 (mg/kg/dav) 1 is available on IRIS (U.S. EPA. 1988b)
p-IUR (mg/m3)-1
NDr
IRIS = Integrated Risk Information System; NDr = not determined; p-IUR = provisional inhalation unit risk;
p-OSF = provisional oral slope factor; p,p'-DDD =p,p'-dichlorodiphenyldichloroethane.
DERIVATION OF ORAL REFERENCE DOSES
None of the human studies of p,p -DDD are suitable for deriving provisional reference
doses (p-RfDs). The human database includes an oral subchronic-duration study in a single male
volunteer exposed to 0.07 mgp,p -DDD/kg-day, with the study lacking detailed information on
toxicity endpoints and experimental results (Morgan and Roan. 1974. 1971). Several
epidemiological studies are available evaluating the potential association between biological
measurements ofp,p -DDD, and reproductive or hormonal outcomes (see Table 4B). However,
it is not possible to clearly attribute any effects reported in these studies to direct exposure to
p,p -DDD, due to confounding effects from concomitant exposure to other organochlorine
compounds, and also because it is not possible to determine whetherp,p -DDD measured in
biological tissues resulted from exposure top,p -DDD or from metabolism of DDT top,p'-DDD
in the human body.
Animal studies relevant to the derivation of p-RfD values include 6-week dose
range-finding studies in rats and mice (NCI. 1978). a 6-week immunotoxicity study in rats
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(Baneriee ct al.. 1996). a sub chronic-duration adrenal toxicity study in dogs (Cucto et al.. 1958).
and chronic-duration studies in rats and mice (NCI. 1978; Tomatis et al. 1974) (see Table 3A).
The usefulness of the data from the NCI (1978) subchronic- and chronic-duration studies
is compromised by the low purity of the technical-grade DDD tested. Only 60% of the product
wasp,p -DDD and at least 19 impurities (unspecified) were present in the remaining 40%. In the
subchronic dose range-finding studies, mortality was reported in exposed rats and decreases in
body weight were noted in some exposed mice; however, low number of animals were included,
limited endpoints were examined (body weight and mortality) and results were poorly reported,
precluding the determination of critical effects and effect levels. The chronic-duration data are
further compromised by the substantial adjustments in administered dietary level during the
study and by the long post-treatment observation period, during which recovery from or reversal
of effects could have occurred. Therefore, chronic-duration LOAELs (39.3-85.2 mg/kg-day)
based on decreased body weights in rats and in female mice are not considered sufficiently
reliable for the p-RfD derivation. Tomatis et al. (1974) also found reductions in body weight in
male mice at a LOAEL of 45.0 mg/kg-day. The study was designed primarily as a
carcinogenicity bioassay with sparse detail on noncancer effects, limiting its use for the
assessment of long-term noncancer toxicity.
The 6-week immunotoxicity study by Baneriee et al. (1996) reported significant
decreases in relative spleen weight and reduced humoral and cell-mediated immunity in male
rats at a LOAEL of 18.4 mg/kg-day. In the absence of information on absolute organ-weight
changes or spleen histopathology, the biological significance of the observed decreases in
relative spleen weight are unknown. The study included relevant immune function assays
(i.e., delayed-type hypersensitivity [DTH] reaction and ovalbumin-specific IgG and IgM
measurements) indicative of an immunosuppressive effect, as well as, more general immune
system tests (i.e., macrophage and lymphocyte migration) that provide equivocal evidence of
immunotoxicity. However, the study suffers from methodological issues, such as the evaluation
of limited endpoints and the use of one treatment dose, one species, and one sex (males). In the
absence of additional supporting information, the findings of immunotoxicity with p,p -DDD
exposure are inconclusive. Therefore, the Baneriee et al. (1996) study, by itself, does not qualify
as the basis for either a subchronic or chronic p-RfD. Finally, the adrenal toxicity study in dogs
(Cueto et al.. 1958) is not suitable for the p-RfD derivation due to the small number of animals
used and few endpoints examined.
As a result of the limitations in the available oral toxicity data for p,p -DDD, subchronic
and chronic p-RfDs were not derived directly. Instead, screening subchronic and chronic p-RfDs
are derived in Appendix A using an alternative surrogate approach.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
The absence of relevant inhalation data precludes derivation of provisional reference
concentrations (p-RfCs) forp,p'-DDD directly. An alternative surrogate approach was
attempted, but screening p-RfCs could not be derived due to a lack of inhalation toxicity values
for potential surrogates (see Appendix A).
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
A B2 cancer classification (probable human carcinogen) is available forp,p -DDD on
IRIS (U.S. EPA. 1988b).
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DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of a Provisional Oral Slope Factor
An OSF of 0.24 (mg/kg/day) 1 is available for/>,//-DDD on IRIS (U.S. EPA. 1988b).
Derivation of a Provisional Inhalation Unit Risk
Derivation of quantitative estimates of cancer risk following inhalation exposure to
p,p -DDD is precluded by the absence of inhalation data for this compound.
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APPENDIX A. SCREENING PROVISIONAL VALUES
For the reasons noted in the main Provisional Peer-Reviewed Toxicity Value (PPRTV)
document, provisional toxicity values forp,p -dichlorodiphenyldichloroethane (p,p -DDD) could
not be derived. 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 main 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 Heath Risk Technical
Support Center.
APPLICATION OF AN ALTERNATIVE SURROGATE APPROACH FOR
NONCANCER VALUES
The surrogate approach allows for the use of data from related compounds to calculate
screening values when data for the compound of interest are limited or unavailable. Details
regarding searches and methods for surrogate analysis are presented in Wane et al. (2012).
Three types of potential surrogates (structural, metabolic, and toxicity-like) are identified to
facilitate the final surrogate chemical selection. The surrogate approach may or may not be
route-specific or applicable to multiple routes of exposure. All information was considered
together as part of the final weight-of-evidence (WOE) approach to select the most suitable
surrogate both toxicologically and chemically.
Structural Surrogates (Structural Analogs)
An initial surrogate search focused on the identification of structurally similar chemicals
with toxicity values from the Integrated Risk Information System (IRIS), PPRTV, Agency for
Toxic Substances and Disease Registry (ATSDR), or California Environmental Protection
Agency (Cal/EPA) databases to take advantage of the well-characterized chemical-class
information. Under Wang et al. (2012). structural similarity for analogs is typically evaluated
using U.S. EPA's DSSTox database (DSSTox. 2016). and the National Library of Medicine's
(NLM's) ChemlDplus database (C'hemll)plus. 2017). The Organisation for Economic
Co-operation and Development (OECD) Toolbox was also used to calculate structural similarity
using the Tanimoto method (a similar quantitative method used by ChemlDplus and DSSTox).
Three structural analogs top,p -DDD were identified with available oral toxicity values and
>50% similarity scores from at least two of the structure activity relationship (SAR) databases
consulted: p,p -dichlorodiphenyltrichloroethane (/>,//-DDT) (ATSDR. 2002a; U.S. EPA. 1988d).
p,p -dichlorodiphenyldichloroethylene (/>,//-DDE) ( ATSDR. 2002a). and
p,p -di methoxydi phenyl tri chl oroethane (methoxychlor) (ATSDR. 2002b; U.S. EPA. 1988c). No
structural analogs with inhalation toxicity values were identified; therefore, the current surrogate
analyses are specific to the assessment of repeated-exposure toxicity via the oral route.
Table A-l summarizes the analogs' physicochemical properties and similarity scores.
Overall, the structural similarity scores derived from ChemlDplus, DSSTox, and the OECD
31
p,p'~ DDD
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quantitative structure-activity relationship (QSAR) Toolbox were consistently highest for
p,p -DDT (71-96%) and lowest for methoxychlor (36-64.6%); structural similarity scores for
p,p -DDE were intermediate (56-67%). p,p'-DDD and the candidate surrogates are
organochlorine compounds that share a basic chemical structure, consisting of a diphenylalkane
structure containing three or more chlorine atoms. The para substitutions in the phenyl rings are
important in determining the physicochemical properties and insecticidal activity of these
compounds (Coats, 1990). In the case of/>,//-DDT, />,//-DDD, and/>,//-DDE, the para
substituents are occupied by chlorine atoms. Conversely, these moieties are replaced by
methoxy groups in the methoxychlor compound, contributing to the less bioaccumulative
properties of methoxychlor in animals and in the environment, compared to p,p -DDT,
/>,//-DDD, andp,p'~DDE (Kapoor et al.. 1970).
In general, physicochemical properties for all four organochlorine compounds are similar
(see Table A-l). Although water solubility is considered low (i.e., <1 mg/L), /;,//-DDD and the
structural analogs are expected to be bioavailable by the oral route. These compounds exhibit
moderate volatility (i.e., Henry's law constant of 10 3 to 10 7) and low vapor pressure; however,
they are expected to be bioavailable when inhaled (as a vapor or particulate matter).
Surrogate Summary and Evaluation
Based on comparable structural and physicochemical properties, p,p -DDT andp,p'-DDE
are considered suitable structural surrogates forp,p -DDD. On the other hand, methoxychlor is a
less suitable surrogate based on functional group differences (i.e., presence ofp,p -methoxy
groups) that could affect the toxicokinetic properties and toxicity of this compound compared to
p,p -DDD and the structurally related /},//-chlorinated analogs (p,p'-DDT andp,p -DDE).
32
p,p'~ DDD
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Table A-l. Physicochemical Properties ofp,p -DDD (CASRN 72-54-8) and Candidate Surrogates"
Chemical
p,p -Dichlorodiphenyl
dichloroethane
(DDD)
p,p '-Dichlorodiphenyl
trichloroethane
(DDT)
p,p '-Dichlorodiphenyl
dichloroethylene
(DDE)
p,p '-Dimethoxydiphenyl
trichloroethane
(Methoxychlor)
Structure
. .cr'tx.
jQh(X
.xy*xx
\
o
fi
o
/
CASRN
72-54-8
50-29-3
72-55-9
72-43-5
Molecular weight
320
354
318
346
ChemlDplus similarity score (%)b
100
77
67
64.6
DSSTox similarity score (%)
100
96
61
52.1
OECD QSAR Toolbox similarity score (%)°
100
71
56
36
Melting point (°C)
109.5
108.5
89
87
Boiling point (°C)
350
260
336
346
Vapor pressure (mm Hg at 25°C)
1.35 x 10-6
1.6 x 10-7 (20°C)
6 x io 6 (extrapolated)
4.2 x 10 5 (estimated)
Henry's law constant (atm-m3/mole at 25°C)
6.60 x 10-6
8.32 x 10-6
4.16 x 10"5
2.03 x IO"7
Water solubility (mg/L)
0.09
0.0055
0.04
0.1
Log Kow
6.02
6.91
6.51
5.08
pKa
NA
NA
NA
NA
'Data were gathered from PHYSPROP for each respective compound unless otherwise specified (U.S. EPA. 2012b').
'ChemlDplus Advanced, similarity scores (ChemlDnliis. 2017).
"OECD (2016).
NA = not applicable; OECD = Organisation for Economic Co-operation and Development; QSAR = quantitative structure-activity relationship.
33
p,p'~ DDD
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Metabolic Surrogates
Table C-l summarizes available toxicokinetic data for /;,//-DDD and the structurally
similar compounds identified as potential surrogates.
Absorption
No data on the rate and extent of oral absorption are available for p,p -DDD or p,p -DDE;
however, bothp,p -DDD andp,p'-DDE were detected in serum and adipose tissue from human
volunteers ingesting 5 mg daily for 81 or 92 days, respectively, confirming that absorption did
occur (Morgan and Roan, 1974, 1971). Additionally, oral absorption of/>,//-DDD and/>,//-DDE
can be infered by the detection of parent chemicals and corresponding metabolites in excreta of
exposed animals (see "Metabolism" discussion below). The maximum serum concentration
(Cmax) ofp,p'-DDT was detected 3 hours after ingestion of a 20-mg dose by a volunteer,
indicating that absorption was rapid (Morgan and Roan. 1974). The oral absorption of both
p,p -DDT and methoxychlor was confirmed in animal studies to be rapid and near complete
(see Table C-l). Oral bioavailability is anticipated to be similar for the target compound and
each of the potential surrogates based on comparable physicochemical properties (i.e., water
solubility, Kow).
Distribution
p,p'-DDD,p,p -DDT, andp,p'-DDE have been detected in adipose tissue, breast milk,
and the placenta of environmentally exposed humans (Xu et aL 2015; Hernik et aL 2014; Man
et al„ 2014; Bedi et al.. 2013; Song et aL 2013; Bergkvist et aL 2012; Cok et aL 2012; Wang et
aL 2011; A/.eredo et aL 2008; Shen et aL 2008; Bouwman et aL 2006; AT SDR, 2002a). Data
in human volunteers indicate thatp,p-DDD,/\p -DDT, andp,p'-DDE persist in adipose tissue
for several months to years following exposure (see Table C-l). Transplacental and lactational
transfer of/>,//-DDT and/>,//-DDE have been demonstrated in laboratory animal studies (You et
al.. 1999; Woolley and Talens. 1971). Methoxychlor was detected in rat breast milk, but does
not persist in rat adipose tissue (no human data are available) (Chapin et al. 1997; Harris et aL
1974; Kunz.e et al.. 1950).
Metabolism
The primary metabolic pathway forp,p'-DDT involves initial dechlorination top,p'-DDD
orp,p'-DDE in the liver, although metabolism ofp,p -DDT via/;>,//-DDD, proceeds faster than
via the/>,//-DDE pathway (Morgan and Roan. 1971; Peterson and Robison. 1964). />,//-DDD is
further metabolized to 2,2-/?/.s(/;-chlorophenyl ) acetic acid (DDA), which is the primary urinary
metabolite detected following exposure to eitherp,p -DDT or /;,//-DDD in humans, rats, mice,
and hamsters (Gold and Brunk. 1984. 1983. 1982; Roan et al. 1971; Peterson and Robi son.
1964). Table A-2 compares excreted metabolites in rodents for/>,//-DDD and the candidate
surrogates. Metabolic disposition patterns in the mouse reveal remarkable similarities in the
metabolism ofp,p -DDT and/;,//-DDD, providing further support for the suitability ofp,p'-DDT
as a metabolic surrogate ofp,p -DDD. Although possible reactive metabolites
(e.g., 2,2-/?/.s[4'-chlorophenyl]acetyl chloride [DDA-C1] and
1 -chloro-2,2-/?/.s[/;-chloro-phenyl]ethene [DDMU]-epoxide) can result from the
biotransformation ofp,p'-DDT to DDA, viap,p'-DDD (see Table C-l), this metabolic pathway is
considered, for the most part, a detoxification pathway (Gold and Brunk, 1983).
p,p -DDE is less metabolically active than /;,//-DDD and /;,//-DDT, as evidenced by the
presence ofp,p -DDE as the major component in excreta fromp,p -DDE-exposed animals
34
p,p'- DDD
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(see Table A-2) and as the only urinary product recovered in a human subject exposed to
p,p -DDE (5 mg daily for 92 days) (Morgan and Roan. 1974). The inefficiency ofp,p'-DDE
metabolism appears to be related to the greater affinity of this compoud for fat storage in relation
to/>,//-DDD and/>,//-DDT (Morgan and Roan. 1971). Nevertheless, metabolism of/>,//-DDE to
DDA has been demostrated in rats with intraperitoneal (i.p.) injection (see Table A-2).
Methylsulfonyl metabolites ofp,p -DDE (2- and 3-methylsulfonyl-DDE) have also been
identified in humans and marine animals, and could represent an important metabolic pathway
for/;,//-DDE (see Table C-l).
Table A-2. Summary of Metabolites forp,p'-DDD and Candidate Surrogates
Chemical
Route
Species
Metabolites and Other Excreted Products (%)
Reference
PjP '-DDD
Oral:
100 mg/kg
Mouse
DDA (95%), parent compound (4%), 2-OH-DDA (1%),
DDOH (<1%), DDE (<1%), and DDMU (<1%) in urine
within 72 ha
Gold and
Brutik (1982)
p,p'- DDT
Oral:
500 mg/kg
Mouse
DDA (86%), DDE (9%), DDD (3%), 2-OH-DDA (1%),
parent compound (<1%), DDMU (<1%), and DDOH
(<1%) in urine within 72 ha
Gold and
Bnmk (1982)
p,p'- DDE
Oral: 20 mg/kg
i.p.: 200 mg/kg
Mouse
Rat
Mostly excreted as parent compound in urine and feces
within 72 h. Primary metabolite: 3'-OH-DDE
Unchanged DDE was the major component in feces.
Primary fecal metabolites: ring-hydroxylated products of
DDE (3'-OH-DDE and 2'-OH-DDE), followed by DDA
and DBP
Gold and
Bnmk (1986)
Fawcett et al.
(1987)
Methoxychlor
Oral: 50 mg/kg
Rat
Mono-hydroxy methoxychlor (30%),
/>/.v-hydroxy-nictlioxychlor (23%),
/j/.v-hydroxy-diphcnylacctic acid and
h/.v-liy droxy -ben/oplienone (11%), parent compound
(8%), /)/.v-liydroxy-dichloroctliylcnc (1%) in urine and
feces over an 11-d periodb
Kanoor et al.
(1970);
ATSDR
(2002b)
Expressed as percent of excreted dose.
bExpressed as percent of the administered dose.
DBP = />/.y(4'-ch 1 oroplienv 1)kctonc; DDA = 2.2-/)/.v(4'-cliloroplicm l)acctic acid;
2-OH-DDA = 2-livdroxy-2.2-/)/.v(4'-chloroplicnvl)acctic acid;
2'-OH-DDE = 1, l,-dichloro-2-(4'-chlorophenyl)-2-(2"-hydroxy-4"-chlorophenyl)ethene;
3'-OH-DDE = l,l,-dichloro-2-(4'-chlorophenyl)-2-(3 "-hydroxy-4"-chlorophenyl)ethene;
DDMU = 1 -cliloro-2.2-/)/.v(4'-cliloroplicnyl)ctlicnc: DDOH = 2.2-/);.v(4'-cliloroplicnvl)cthanol; i.p. = intraperitoneal;
p,p'-DDD = p,p '-dichlorodiphenyldichloroethane; p,p'-DDE = /j,//-dichlorodiphcnyldichlorocthylcnc.
Contrary top,p -DDD, the primary metabolic pathway of methoxychlor in mice involves
sequential O-demethylation, leading to the production of mono-hydroxy and A/.s-hydroxy
methoxychlor (see Table A-2). The demethylated metabolites are believed to be involved in the
reproductive effects of methoxychlor resulting from interaction of these compounds with steriod
hormone receptors such as the estrogen and androgen receptors (Sumida et aL 2001; Charles et
al.. 2000; Maness et aL 1998; Bulger et aL 1978). Alternatively, dechlorination of
methoxychlor results in the formation of A/.s-hydroxydiphenyl acetic acid,
35
p,p'~ DDD
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/?/.s-hydroxybenzophenone, and A/.s-hydroxy-dichloroethylene, which constitutes a minor
metabolism pathway for this compound (see Table A-2).
Excretion
Excretion ofp,p'-DDD andp,p -DDT metabolites following oral exposure in humans
occurs primarily through the urine (i.e., as DDA) (see Table C-l) and substantial urinary
excretion has also been detected in animals (see Table A-2). p,p'-DDT may also be eliminated in
feces, breast milk, and semen (as the parent compound and/or metabolites) (ATSDR. 2002a). In
the rat, />,//-DDE is excreted mostly unchanged via the urine and feces after oral exposure (Gold
and Brunk. 1986). but preferential elimination via the feces has been documented after
intravenous (i.v.) injection (34% of administered dose) (Miihlebach et ai. 1991). Importantly,
analysis of adipose tissue and urinary excretion in human volunteers with repeated-dose
exposure to p,p'-DDD,p,p -DDT, or p,p'-DDE showed slow rates of elimination of these
compounds (see Table C-l). In contrast, methoxychlor and its metabolites were rapidly
eliminated in mice via the feces (Kapoor et al, 1970).
Surrogate Summary and Evaluation
p,p'-DDT is a suitable metabolic surrogate forp,p'-DDD due to the fact that the primary
metabolic pathway forp,p -DDT is dechlorination top,p -DDD, as well as similarities in the rate
and route of elimination (both materials persist in the body and are eliminated primarily as the
shared downstream metabolite DDA in the urine). The other candidate surrogates are less
suitable. Metabolism ofp,p -DDE is less efficient compared top,p'-DDD and/;,//-DDT, in part,
due to the greater capacity ofp,p'-DDE for fat storage. Contrary top,p'-DDT and the other
candidate surrogates, methoxychlor appears to be efficiently metabolized and cleared from the
body. In addition, the major metabolic pathway ((9-demethylation) and pattern of metabolites
for methoxychlor differ fromp,p'~DDD and elimination is primarily via the feces.
Toxicity-Like Surrogates
Table A-3 summarizes available oral toxicity values for /;>,//-DDD and the compounds
identified as potential surrogates. Acute toxicity data forp,p -DDD are limited to reported
median lethal dose (LD50) values of 113 mg/kg-day in rats and >5,000 mg/kg in hamsters; no
further information was provided (Chemll)plus. 2017). Lethality data in hamsters were similar
forp,p -DDD, /;,//-DDT, and /;,//-DDE (LD50 >5,000 mg/kg). In rats, /;,//-DDD andp,p'-DT>T
displayed similar potency (LD50 = 113 and 87 mg/kg, respectively), butp,p'-DDE and
methoxychlor were less acutely toxic (LD50 = 880 and 1,855 mg/kg, respectively).
As discussed in the main body of this document and shown in Table 3A, repeated-dose
oral toxicity data forp,p'-DDD provide only limited information due to evaluation of few
endpoints and/or use of a low-purity test compound (Baneriee et al.. 1996; NCI. 1978; Tomatis et
al.. 1974; Cueto et al.. 1958). Due to these limitations, sensitive target organs of toxicity could
not be identified. Oral toxicity values forp,p -DDT andp,p'-DDE are based on liver effects in
rats, while oral toxicity values for methoxychlor are derived from reproductive effects in rats and
rabbits (see Table A-3). These endpoints are discussed below, and a comparison of the
dose-response data in experimental animals for these effects following oral exposure to
p,p -DDD and all potential surrogates is provided in Figures C-l to C-l.
Among the candidate surrogates, the liver is a sensitive target organ of toxicity for
p,p -DDT andp,p'-DDE (see Figures C-l and C-2). Non-neoplastic liver effects following
36
p,p'- DDD
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exposure top,p -DDT andp,p'~DDE include increased liver weight and hepatic lesions ranging
from hepatocellular hypertrophy to fatty degeneration and necrosis. Liver toxicity has also been
observed with methoxychlor exposure (see Figures C-l and C-2); however, these effects
(primarily increased liver weight and changes in serum and/or liver enzymes) occurred at high
doses often associated with lethality (ATSDR. 2002b). Overall, potency for liver toxicity was
/;,//-DDT > /;,//-DDE > methoxychlor. The only available study ofp,p'-DDD that provided
results for non-neoplastic endpoints was the chronic NCI (1978) cancer bioassay. This study
found no effect on the incidence of liver lesions, but was limited by design as a cancer bioassay
(e.g., treated rats and mice had respective 35- and 15-week untreated observation periods prior to
necropsy; senescent changes in both species and liver tumors in mice may have obscured
non-neoplastic changes). Nevertheless,/?,/?'-DDD,p,p -DDT, andp,p'-DDE all produced liver
tumors in experimental animals (see Figure C-3) and displayed similar carcinogenic potency
based on estimated oral slope factors (OSFs) (see Table A-3). Conversely, evidence of liver
carcinogenicity for methoxychlor was inconclusive (U.S. EPA. 1988c). Although a mode of
action (MOA) for the liver tumors has not been established and it is unclear how the observed
non-neoplastic liver effects may be related to development of tumors following p,p -DDT and
p,p -DDE exposure, these findings suggest that the liver is a relevant target organ of toxicity for
thep,p -chlorinated chemicals (/;,//-DDD, /;,//-DDT, andp,p'-DDE).
Reproductive effects are produced by all three candidate surrogates, including decreased
fertility, altered male sexual differentiation, and precocious puberty in females (see Figures C-4,
C-5, and C-6). An increase in adverse pregnancy outcomes was also found forp,p'-DDT and
methoxychlor, but not forp,p'-DDE (see Figure C-7). Potency was highest forp,p'-DDT. No
reproductive or pregnancy outcomes data were available forp,p'-DDD. The mechanism of
toxicity for the observed reproductive effects could be related to the endocrine disruption
properties of these compounds. p,p'-DDD,p,p -DDT, and p,p'-DDE are competitive inhibitors of
the androgen receptor (AR) (Kelce et al., 1995) and may also possess weak estrogenic activity
via interaction with the estrogen receptor (ER) (Soto et aL 1997; Singhal et al.. 1970; Welch et
al.. 1969). Mechanistic studies suggest that hydroxylated metabolites of methoxychlor
(e.g., mono- and A/.v-hydroxymethoxychlor and A/.v-hydroxy-dichloroethylene) are more potent
agonists of the ER than the parent chemical (Sumida et al.. 2001; Charles et al.. 2000; Bulger et
al.. 1978; Bulger and Kupfer. 1978) and exert stronger antagonism towards the AR than
methoxychlor (Maness et al.. 1998). Thus, metabolic activation is thought to be important for
the endocrine disrupting activity of this compound (ATSDR. 2002b).
Surrogate Summary and Evaluation
Based on comparisons of available toxicity data, p,p'-DDT andp,p'-DDE are potential
toxicity-like surrogates ioxp,p -DDD. The /^//-chlorinated chemicals share similarities in
overall toxicity profile, including LD50 values, long-term toxicity target organ (liver),
carcinogenic potencies (OSFs), and a putative pathway for reproductive toxicity via modulation
of steroid hormone receptors (e.g., ER and AR). Unlikep,p -DDD and the other candidate
surrogates, the major metabolic route ((9-demethylation) for methoxychlor constitutes a
bioactivation pathway for the critical effects of this compound (reproductive toxicity); therefore,
methoxychlor is excluded from consideration as a potential toxicity-like surrogate forp,p -DDD.
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p,p'~ DDD
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Table A-3. Comparison of Available Oral Toxicity Values for p,p -DDD (CASRN 72-54-8) and Potential Surrogates
Name
PjP '-DDD
/>,/>'-DDT
PjP '-DDE
Methoxychlor
Structure
Ci
xnx
\
O
O
/
CASRN
72-54-8
50-29-3
72-55-9
72-43-5
Subchronic oral toxicity values
POD (mg/kg-d)
ND
0.05
1
5
POD type
ND
NOAEL
LOAEL (HED)
LOAEL
Subchronic UFC
ND
100 (UFa, UFh)
3,000 (UFa, UFd, UFh, UFl)
1,000 (UFa, UFh, UFl)
Subchronic
p-RfD/MRL
(mg/kg-d)
ND
5 x 10-4
3 x 10-4
5 x lO-3
Critical effects3
ND
Liver lesions (centrilobular
hepatocellular hypertrophy,
cytoplasmic oxyphilia, and
peripheral basophilic cytoplasmic
granules)
Increased relative liver weight in
adult male offspring exposed during
gestation and via lactation
Precocious puberty in females
(i.e., accelerated vaginal opening)
Other effects
(in principal study)
ND
None (only liver and kidney
histopathology were evaluated)
Effects at 50 mg/kg-d: Increased
relative liver weight in exposed
dams; decreased number of pups
alive, and decreased weaning index
at PND 21; delayed preputial
separation in male offspring and
early vaginal opening in female
offspring; reductions in copulation
index and fertility index in
F1 generation; increases in relative
adrenal weight and liver weight in
F1 adult females
Females: Irregular or absent estrous
cycles, decreased fertility, decreased
gravid uterine weight,
histopathological lesion in the
ovaries (cysts), uterus (hyperplasia,
metaplasia) and vagina (hyperplasia
and cornification) at >50 mg/kg-d;
decreased number of live pups per
litter at 150 mg/kg-d
Males: Delayed preputial separation
and weight of testes and epididymis
at >50 mg/kg-d
38
p,p'~ DDD
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Table A-3. Comparison of Available Oral Toxicity Values for p,p -DDD (CASRN 72-54-8) and Potential Surrogates
Name
PjP '-DDD
/>,/>'-DDT
PjP '-DDE
Methoxychlor
Structure
Ci
xnx
\
O
o
/
CASRN
72-54-8
50-29-3
72-55-9
72-43-5
Species
ND
Rat
Rat
Rat
Duration
ND
27 wk
GD 6-PND 20
GD 14-PND 42
Route (method)
ND
Diet
Gavage
Gavage
Source
ND
ATSDR (2002a): U.S. EPA (1988d)
U.S. EPA (2017b)
ATSDR (2002b)
Chronic oral toxicity values
POD (mg/k-d)
ND
0.05
1
5.01
POD type
ND
NOAEL
LOAEL (HED)
NOAEL
Chronic UFC
ND
100 (UFa, UFh)
3,000 (UFa, UFd, UFh, UFl)
1,000 (UFa, UFd, UFh)
Chronic RfD
(mg/kg-d)
ND
5 x 10-4
3 x 10 4 (screening p-RfD)
5 x 10-3
Critical effects3
ND
Liver lesions (centrilobular
hepatocellular hypertrophy,
cytoplasmic oxyphilia, and
peripheral basophilic cytoplasmic
granules)
Increased relative liver weight in
adult male offspring exposed as
neonates
Excessive litter loss
(i.e., spontaneous abortion)
Other effects
(in principal study)
ND
See above
See above
Decreased maternal body-weight
gain and increased clinical signs of
toxicity (not specified) at
>35.5 mg/kg-d
Species
ND
Rat
Rat
Rabbit
Duration
ND
27 wk
GD 6-PND 20
GDs 7-19
Route (method)
ND
Diet
Gavage
Gavage
Source
ND
U.S. EPA (1988d)
U.S. EPA (2017b)
U.S. EPA (1988c)
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p,p'~ DDD
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Table A-3. Comparison of Available Oral Toxicity Values for p,p -DDD (CASRN 72-54-8) and Potential Surrogates
Name
PjP '-DDD
PjP '-DDT
PjP '-DDE
Methoxychlor
Structure
Ci
xnx
\
O
O
/
CASRN
72-54-8
50-29-3
72-55-9
72-43-5
Carcinogenicity assessment
Classification
B2; probable human carcinogen
B2; probable human carcinogen
B2; probable human carcinogen
D; not classified as to human
carcinogenicity
OSF
24 x 10-1
3.4 x 10-1
3.4 x 10-1
ND
Tumor type
Liver
Liver
Liver
ND
Species
Mouse
Mouse and rat
Mouse and hamster
ND
Route (method)
Diet
Diet
Diet
ND
Source
U.S. EPA ( 1988b)
U.S. EPA fl988d)
U.S. EPA f 1988a)
U.S. EPA (1988c)
Oral acute lethality data
Rat LD50 (mg/kg)
113
87
880
1,855
Hamster LD50
(mg/kg)
>5,000
>5,000
>5,000
ND
Source
ChemlDplus (2017)
ChemlDplus (2017)
ChemlDplus (2017)
ChemlDplus (2017)
'Exposure-response arrays were prepared to illustrate the dose-response relationship for liver and reproductive effects across the candidate surrogate compounds
(see Figures C-l to C-7).
GD = gestation day; HED = human equivalent dose; LD5o = median lethal dose; LOAEL = lowest-observed-adverse-effect level; MRL = minimal risk level; ND = no
data; NOAEL = no-observed-adverse-effect level; OSF = oral slope factor; /?,/?'-DDD = /?,//-dichlorodiphcnyldichlorocthanc:
p,p '-DDE =p,p '-dichlorodiphenyldichloroethylene; p,p'-DDT = /j,//-dichlorodiphcnyltrichlorocthanc; PND = postnatal day; POD = point of departure;
p-RfD = provisional reference dose; RfD = oral reference dose; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty
factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor.
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p,p'- DDD
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Weight-of-Evidence Approach
A WOE approach is used to evaluate information from potential candidate surrogates as
described by Wang et al. (2012). Commonalities in structural/physicochemical properties,
toxicokinetics, metabolism, toxicity, or MOA between potential surrogates and chemical(s) of
concern are identified. Emphasis is given to toxicological and/or toxicokinetic similarity over
structural similarity. Surrogate candidates are excluded if they do not have commonality or
demonstrate significantly different physicochemical properties, and toxicokinetic profiles that set
them apart from the pool of potential surrogates and/or chemical(s) of concern. From the
remaining potential surrogates, the most appropriate surrogate (most biologically or
toxicologically relevant analog chemical) with the highest structural similarity and/or most
conservative toxicity value is selected.
The WOE approach used to select the surrogate compound forp,p -DDD is based
primarily on metabolic considerations, with supporting evidence from structural and toxicity
surrogate analyses. As such, p,p -DDT is identified as the final surrogate forp,p'-DDD based on
the following WOE rationale:
1) p,p -DDT is a metabolic precursor forp,p -DDD, and both compounds exhibit
similarities in metabolism pathways and in the rate and route of elimination (both
materials persist in the body and are eliminated primarily as the shared downstream
metabolite DDA in the urine).
2) p,p -DDT is a toxicity-like surrogate for /;,//-DDD based on overall similarities in the
toxicity profile of these compounds, including LD50 values, long-term toxicity target
organ (liver), carcinogenic potencies (OSFs), and a putative pathway for reproductive
toxicity via modulation of steroid hormone receptors (e.g., ER and AR).
3) p,p -DDT displays the highest structural similarity (71-96%) to /;>,//-DDD, according
to structure-activity relationship evaluations from ChemlDplus, DSSTOX, and OECD
Toolbox.
4) p,p -DDE and methoxychlor are less suitable surrogate candidates for /;,//-DDD,
p,p -DDE is less metabolically active than /;,//-DDD andp,p -DDT, which is related to
its greater affinity for fat storage. Metabolism and elimination pathways for
methoxychlor are different from p,p -DDD, in part, due to the presence of
/;,//-methoxy groups that allow for its efficient metabolism and clearance from the
body. Furthermore, in contrast top,p -DDT and /;>,//-DDD, metabolism of
methoxychlor via O-demethylation is known to be a bioactivation pathway for the
reproductive effects that form the basis of the oral toxicity values for this compound;
therefore, methoxychlor is not considered an appropriate toxicity-like surrogate for
/;,//-DDD.
ORAL TOXICITY VALUES
Derivation of a Screening Subchronic Provisional Reference Dose
Based on the overall surrogate approach presented in this PPRTV assessment, p,p -DDT
was selected as the surrogate for p,p -DDD for derivation of a screening subchronic p-RfD. The
study used to derive the ATSDR intermediate minimal risk levels (MRLs) and the IRIS chronic
oral reference dose (RfD) (ATSDR, 2002a; U.S. EPA, 1988d) was a 27-week dietary study in
41
p,p'~ DDD
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09-20-2017
rats [Laug et al. (1950) as cited in ATS PR (2002a) "I. ATS PR (2002a) described the study as
follows:
Experimental design: Groups of male andfemale Osborne-Mendel rats
(15/sex/group) were administered technical DDT (dissolved in corn oil) added to
the diet at dosage levels of 0, 1, 5, 10, or 50ppm for 15-27 weeks. This study was
essentially designed to examine whether DDT accumulates in adipose tissue and
to what extent, how age and dose level affect accumulation, and how rapidly it is
eliminated. Seventy-seven rats were usedfor microscopic evaluation of only the
liver and kidney. This was based on findings from a previous study from the same
group (Fitzhugh and Nelson 1947) in which higher dietary levels of DDT had
been used. Based on the previous findings, only the liver was expected to show
microscopic changes. Although not explicitly stated, it is assumed that
morphologic evaluations were conducted at the times when DDT levels in fat
were determined (after 15, 19, 23, and 27 weeks of treatment).
Effects noted in study and corresponding doses: These dose ranges were
calculated as shown below in the discussion of conversion factors. There were no
morphologic alterations in the kidneys. Liver alterations were noticed at the
5 ppm (0.25-0.5 mg/kg/day) dietary level of DDT and higher, but not at 1 ppm
(0.05-0.09 mg/kg/day). Liver changes consisted of hepatic cell enlargement,
especially in central lobules, increased cytoplasmic oxyphilia with sometimes a
semihyaline appearance, and more peripheral location of the basophilic
cytoplasmic granules. Necrosis was not observed. The severity of the effects was
dose-related, and males tended to show more hepatic cell changes than females.
Changes seen at the 5ppm level (0.25-0.5 mg/kg/day) were considered by the
authors as "minimal"; changes seen at the 50ppm level (2.5-4.6 mg/kg/day)
were slight, sometimes moderate; the authors do not comment about what they
saw in the 10 ppm (0.5-0.9 mg/kg/day) group, presumably the results were
intermediate to the doses above and below. The results from the kinetic studies
revealed that accumulation of DDT in fat occurred at all dietary levels tested and
that females stored more DDT than males; storage reached a maximum at 19
23 weeks; age did not affect the rate of DDT-accumulation; about 50-75% of
DDT stored in fat remained after a 1-month DDT-free diet, and 25% remained
after 3 months.
The critical effect in this study was liver lesions in male and female rats exposed to
technical-grade DDT (81% p,p -DDT and 19% o,//-DDT); the NOAEL of 1 ppm
(0.05 mg/kg-day) was used at the point of departure (POP) for />,//-PPT in ATS PR (2002a) and
U.S. EPA (1988d). and is adopted as the surrogate POP for/>,//-PPP.
For the current assessment, the NOAEL of 0.05 mg/kg-day was converted to a human
equivalent dose (HEP) according to current (U.S. EPA. 2011b) guidance. In Recommended Use
of Body Weight3''4 as the Default Method in Derivation of the Oral Reference Dose (U.S. EPA.
2011b). the Agency endorses body-weight scaling to the 3/4 power (i.e., 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 RiD from effects that are not portal-of-entry
effects.
42
p,p'~ PPP
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09-20-2017
Following U.S. EPA (2011b) guidance, the POD for liver effects in male and female rats
is converted to an HED through the application of a dosimetric adjustment factor (DAF) derived
as follows:
DAF = (BWa1/4 - BWh1/4)
where
DAF = dosimetric adjustment factor
BWa = animal body weight
BWh = human body weight
Using average reference BWa values of 0.514 and 0.389 kg for Osborne-Mendel male
and female rats, respectively, in a chronic-duration study and a reference BWh of 70 kg for
humans (U.S. EPA. 1988e), the resulting DAFs are 0.29 for males and 0.27 for females. The
female DAF of 0.27 was applied to the NOAEL of 0.05 mg/kg-day because it yields the most
health-protective POD (HED):
POD (HED) = NOAEL (mg/kg-day) x DAF
= 0.05 mg/kg-day x 0.27
= 0.01 mg/kg-day
In deriving a screening subchronic p-RfD for /;,//-DDD, an interspecies uncertainty
factor (UFa) of 3 is applied because cross-species dosimetric adjustment was performed, and
10-fold uncertainty factors are applied to account for intraspecies variability (UFh) and database
deficiencies (UFd) that reflect the lack of adequate repeated-dose toxicity data for /;,//-DDD,
Thus, a composite uncertainty factor (UFc) of 300 is used in the derivation of the screening
subchronic p-RfD forp,p'~DDD.
Screening Subchronic p-RfD = Surrogate POD (HED) ^ UFc
= 0.01 mg/kg-day -^300
= 3 x 10"5 mg/kg-day
Table A-4 summarizes the uncertainty factors for the screening subchronic p-RfD for
/;,//-DDD.
43
p,p'~ DDD
-------
FINAL
09-20-2017
Table A-4. Uncertainty Factors for the Screening Subchronic p-RfD for
p,p'-DDD (CASRN 72-54-8)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rats and humans followingp,p'-DDD exposure. The
toxicokinetic uncertainty has been accounted for by calculating an HED through application of a
DAF as outlined in the EPA's Recommended Use of Body WeightB/4 as the Default Method in
Derivation of the Oral Reference Dose ('U.S. EPA. 20 lib).
UFd
10
A UFd of 10 is applied to reflect absence of adequate repeated-dose oral toxicity studies for
p,p'-DDD.
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 p,p'-DDD in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because the principal study selected is a 27-wk study.
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS
DAF = dosimetric adjustment factor; HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect
level; NOAEL = no-observed-adverse-effect level; POD = point of departure;
p,p'-DDD = p,p'-dichlorodiphenyldichloroethane; p-RfD = provisional reference dose; UF = uncertainty factor;
UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic
uncertainty factor.
Derivation of a Screening Chronic Provisional Reference Dose
p,p -DDT was also selected as the surrogate for /;>,//-DDD for the derivation of a
screening chronic p-RfD. The principal study and POD for the IRIS chronic assessment for
p,p -DDT (U.S. EPA. 1988d) is the same used in the ATSDR (2002a) intermediate-duration
MRL derivation (Laug et ai. 1950) and the above derivation of a screening subchronic p-RfD for
p,p -DDD. Consistent findings of liver lesions induced by p,p'-DDT from a 2-year chronic
dietary study in rats cited in the IRIS assessment (U.S. EPA. 1988d) provide further support for
the use of the Laug et al. (1950) study to derive a surrogate chronic value for />,//-DDD. Thus,
the surrogate POD (HED) of 0.01 mg/kg-day identified in the 27-week rat study by Laug et al.
(1950) is similarly adopted for the derivation of the screening chronic p-RfD for />,//-DDD.
Similar to the screening subchronic p-RfD derived above, a UFc of 300 is applied.
Screening Chronic p-RfD = Surrogate POD (HED) ^ UFc
= 0.01 mg/kg-day -^300
= 3 x 10"5 mg/kg-day
Table A-5 summarizes the uncertainty factors for the screening chronic p-RfD for
p,p'~DDD.
44
p,p'~ DDD
-------
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09-20-2017
Table A-5. Uncertainty Factors for the Screening Chronic p-RfD for
p,p'-DDD (CASRN 72-54-8)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rats and humans followingp,p'-DDD exposure. The
toxicokinetic uncertainty has been accounted for by calculating an HED through application of a
DAF as outlined in the EPA's Recommended Use of Body WeightB/4 as the Default Method in
Derivation of the Oral Reference Dose ('U.S. EPA. 20 lib).
UFd
10
A UFd of 10 is applied to reflect absence of adequate repeated-dose oral toxicity studies for
p,p'-DDD.
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 p,p'-DDD in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because the principal study selected for the chronic assessment is considered
of chronic duration (>~90 d to 2 yr in typically used laboratory animal species).
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS
DAF = dosimetric adjustment factor; HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect
level; NOAEL = no-observed-adverse-effect level; POD = point of departure;
p,p'-DDD = p,p'-dichlorodiphenyldichloroethane; p-RfD = provisional reference dose; UF = uncertainty factor;
UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic
uncertainty factor.
45
p,p'~ DDD
-------
FINAL
09-20-2017
APPENDIX B. DATA TABLES
Table B-l. Group Sizes, Dietary Concentrations, and Dose Estimates for NCI (1978) Cancer Bioassay for v.v -DDD
Group
Group Size
Nominal Concentration
(ppm)
Duration at This
Concentration (wk)
Untreated
Duration (wk)
Weighted Average Concentration
Technical-Grade DDDa (ppm)
Weighted ADD />,/>'-DDDb
(adjusted for purity) (mg/kg-d)
Male rats
Control
20
0
111
0
Low dose
50
1,400
1,750
0
23
55
34
1,647
69.21
High dose
50
2,800
3,500
0
23
55
35
3,294
1384
Female rats
Control
20
0
111
0
Low dose
50
850
0
78
35
850
39.3
High dose
50
1,700
0
78
35
1,700
78.66
Male mice
Control
20
0
90
0
Low dose
50
315
375
425
0
5
11
62
13
411
42.3
High dose
50
630
750
850
0
5
11
62
14
822
84.6
46
p,p'~ DDD
-------
FINAL
09-20-2017
Table B-l. Group Sizes, Dietary Concentrations, and Dose Estimates for NCI 11978) Cancer Bioassay for v.v -DDD
Nominal Concentration
Duration at This
Untreated
Weighted Average Concentration
Weighted ADD />,/>'-DDDb
Group
Group Size
(ppm)
Concentration (wk)
Duration (wk)
Technical-Grade DDDa (ppm)
(adjusted for purity) (mg/kg-d)
Female mice
Control
20
0
90
0
Low dose
50
315
5
411
42.6
375
11
425
62
0
14
High dose
50
630
5
822
85.2
750
11
850
62
0
15
aCalculated by the study authors as the sum of concentration x time averaged over 78 weeks.
' Calculated using weighted average concentration, reference values for body weight, and food consumption from U.S. EPA (1988e): doses adjusted for 60% purity.
ADD = adjusted daily dose; p,p'-DDD = /?,//-dichlorodiphcnyldichlorocthanc.
47
p,p'~ DDD
-------
FINAL
09-20-2017
APPENDIX C. TOXICOKINETICS AND DOSE-RESPONSE INFORMATION
FORp,p -DDD AND CANDIDATE SURROGATES
Table C-l. ADME Data forp,p -DDD (CASRN 72-54-8) and Candidate Surrogates
Chemical
PjP '-DDD
/>,/>'-DDT
/J,//-DDE
Methoxychlor
Structure
.oV.
CI
.liuu
CASRN
72-54-8
50-29-3
72-55-9
72-43-5
Absorption
Rate and extent of oral
absorption
Human (oral): Detected in serum
and adipose tissue from a single
volunteer ingesting 5 mg of
p,p'-DDD daily for 81 d (rate and
extent of absorption were not
reDorted) (Morgan and Roaa 1974.
1971)
Human (oral): Cmax was
reached 3 hr after ingestion
(Morgan and Roaa 1974)
Rat (oral): 70-100% of dose
was absorbed in rats (vegetable
oil vehicle) over 24-48 hr
(Keller and Yearv. 1980: Rothe
etaL 1957s)
Human (oral): Detected in serum
and adipose tissue from a single
volunteer ingesting 5 mg of
p,p'-DDE daily for 92 d (rate and
extent of absorption were not
reported) (Morgan and Roaa 1974.
1971)
Mouse (oral): Rapid, >90% of oral
dose absorbed (kaixmr et al.. 1970)
48
p,p'~ DDD
-------
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Table C-l. ADME Data forp,p -DDD (CASRN 72-54-8) and Candidate Surrogates
Chemical
PjP '-DDD
/>,/>'-DDT
PjP '-DDE
Methoxychlor
Distribution
Extent of distribution
Human (oral): Detected in adipose
tissue, breast milk, and placenta
from many study populations of
environmental exposure (ATSDR.
Human (oral): Widespread
distribution; many study
populations of environmental
exposure demonstrate adipose
tissue storage, detection in
breast milk and placental
transfer (detected in cord
blood') fATSDR. 20023*): data
from two volunteers ingesting
7.7 or 15.4 mg ofp,p'-DDT
daily for 183 d indicated that
54 or 68% of the dose was
stored in adipose tissue,
respectivelv (Morgan and
Roaa 1971)
Rat (oral): Widespread
distribution to multiple organs;
crosses the placenta; lactational
transfer from dam to pup;
stored in adipose tissue
(Woollev and Talens. 1971)
Human (oral): Many study
populations of environmental
exposure demonstrate adipose tissue
storage, detection in breast milk,
and placental transfer (detected in
cord blood) (ATSDR. 2002a): in a
volunteer, 91% of the ingested dose
was stored in adipose tissue (dosing
described above) (Morgan and
Roaa 1971)
Rat (oral): Crosses the placenta;
lactational transfer from dam to pup;
stored in adipose tissue (You et al..
1999)
Rat (oral): Widespread distribution;
not stored in adipose tissue; found in
breast milk CChapin et al.. 1997:
Harris et al.. 1974: Kunze et al..
20023): in a volunteer. 24% of the
ingested dose was stored in adipose
tissue (dosing described above)
(Morgan and Roan. 1971)
1950)
49
p,p'~ DDD
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09-20-2017
Table C-l. ADME Data forp,p -DDD (CASRN 72-54-8) and Candidate Surrogates
Chemical
/>,/>'-DDD
/>,/>'-DDT
PiP '-DDE
Methoxychlor
Metabolism
Metabolic pathways
and metabolites
Human, rat, mouse, and hamster
(oral): Major urinary metabolite is
DDA
0- ,OH
Intermediary metabolites
(i.e., betweenp,p'-DDD and DDA)
may differ by species
(see "Metabolism/Toxicokinetic
Studies" section)
Possible reactive intermediates
include: DDA-C1 (formed by
hydroxylation of chlorinated ethane
side chain carbon in mice and
hamsters)
Human, rat, mouse, and
hamster (oral): Reductive
dechlorination to p,p'-DDD
occurs at a faster rate than
dehydrodechlorination to
/?,//-DDE (Morgan and Roan
1971: Peterson and Robison
1964)
Further metabolism of
p,p'-DDD by hydroxylation or
oxidation yields DDA as the
primary urinary metabolite of
p,p'-DDT (see "/?,//-DDD"
column for further details)
Human (oral): DDA was not
detected in a human subject exposed
top,p'-DDE (Morgan and Roan.
1971)
Rat (i.v): Metabolism of p,p'-DDE
to DDA occurs in the following
sequence:
DDE—>DDMU —>DDNU —>DDOH
(Datta. 1970)
Multiple mammalian species
including human: 2- and
3-methylsulfonyl-DDE are formed
following CYP450 oxidation to an
arene oxide, GSH conjugation,
excretion into bile, cleavage by
microbial C-S lyase, methylation of
thiols, reabsorption in the gut, and
oxidation to form methyl sulfones
that are distributed in the blood
Representative structure of
3 -methy lsulfonyl-DDE
(Linderholm et al„ 2007: Chu et al„
2003: Bergman et al„ 1994: Bakke
et al„ 1982: Jensen and Jansson
1976)
Mouse (oral): Sequential CYP450
demethylation to mono-hydroxy
methoxychlor (1) and />/.v-4-hydroxy
methoxychlor (2) (primary
metabolites); />/.v-4-hydro\y
methoxychlor may undergo ring
hydroxylation to give tris-hydroxy
methoxychlor (3)
(1)
50
p,p'- DDD
-------
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09-20-2017
Table C-l. ADME Data forp,p -DDD (CASRN 72-54-8) and Candidate Surrogates
Chemical
/>,/>'-DDT
PiP '-DDE
Methoxychlor
Continued:
Continued:
0^K-CI
cu^cl
DDMU-epoxide (formed by
dehydrodeclilorination followed by
oxidation in rats, mice, and
hamsters)
cu
(Gold and Brunk. 1984. 1983.
1982; Morsan and Roan 1971;
Peterson and Robison. 1964)
Continued:
Continued:
Continued:
Metabolites resulting from
dechlorination of methoxychlor:
6/s-hydroxy-dichloroethylene (4),
/>/.V-hydro\y-diplienv 1 acetic acid (5)
and /> /.v-1 n dro \ v bc nzo plie no nc (6)
(4)
ci^ci
(5)
o m
(6)
0
ho-^O^OIoh
(ATSDR 2002b: Kaooor et al..
1970)
51
p,p'- DDD
-------
FINAL
09-20-2017
Table C-l. ADME Data forp,p -DDD (CASRN 72-54-8) and Candidate Surrogates
Chemical
PjP '-DDD
/>,/>'-DDT
PjP '-DDE
Methoxychlor
Excretion
Rate of excretion
Human (oral): Detectable in urine
within 24 hr of oral dosing (Morgan
and Roan. 1971); adipose tissue
analysis from a single volunteer
(see dosing described above)
showed complete elimination from
fat within 9 mo of the termination
of dosins (Morgan and Roan. 1971)
Human (oral): Detectable in
urine within 24 hr of oral
dosing (Morgan and Roaa
1971); reduction in DDT
adipose storage occurs for at
least 3.5 yr following the first
dose (four human subjects who
ingested 5, 10, or 20 mg/d of
technical-grade DDT for up to
186 d) (Morgan and Roan.
1971)
Comparison of elimination
rates from fat showed the
slowest elimination from
humans, followed by monkeys,
dogs, and rats (Morgan and
Roaa 1974)
Human (oral): Adipose tissue
analysis from a single volunteer
(see dosing described above)
showed minimal elimination of
p,p'-DDE from lipid stores 8 mo
after discontinuation of dosing
(Morgan and Roan. 1971)
Rat (i.v.):
The total body burden tVi was 120 d
(Miihlebach et al.. 1991)
Mouse (oral): >90% of oral dose was
excreted within 48 hr (kanoor et al..
1970)
52
p,p'~ DDD
-------
FINAL
09-20-2017
Table C-l. ADME Data forp,p -DDD (CASRN 72-54-8) and Candidate Surrogates
Chemical
PjP '-DDD
/>,/>'-DDT
PjP '-DDE
Methoxychlor
Excretion routes
Human (oral): Urinary excretion of
69% of the total administered dose
within a year of the first dose in a
single volunteer (5 mg ofp,p'-DDD
daily for 81 d, urine concentrations
were measured monthly) (Morgan
aiKl Roan. 1971s)
Human and rat (oral): Urine
(major route), also feces (via
bile), semen, and breast milk
(not quantified) CATSDR.
2002a): urinary excretion of ud
to 10% of the total
administered dose within 3.5 yr
of the initial dose (20 mg of
p,p'-DDT daily for 183 d, urine
concentrations were measured
monthly) (Morganand Roan.
1971)
Human (oral): No urinary excretion
was measured for up to 1 yr after
the first dose in a single volunteer
(5 mg ofp,p'-DDE daily for 92 d,
urine concentrations were measured
monthly) (Morgan and Roan. 1971)
Rat (i.v.): 34% of the administered
dose was excreted in feces and 1%
in urine (14 d after dosing); 10% of
the excreted radioactivity was
unchangedp,p'-DDE in the feces;
no unchangedp,p'-DDE was
detected in the urine (Mflhlebach et
al.. 1991)
Mouse (oral): 90% in feces; 10% in
urine (kanoor et al.. 1970)
ADME = absorption, distribution, metabolism, and excretion; Cmax = maximum serum concentration; CYP450 = cytochrome P450;
DDA = 2.2-/)/.v(4'-chlorophenvl)acetic acid; DDA-C1 = 2,2-bis(4'-chlorophenyl)acetyl chloride; DDMU = 1 -chloro-2.2-/)/.v(4'-chlorophcnyl)cthcne:
DDNU = 1.1 -/)/.v(4'-chlorophcnyl)cthane: DDOH = 2,2-/)/.v(4'-chlorophcnvl)ethanol: GSH = glutathione; i.v. = intravenous;
p,p'-DDD = p,p '-dichlorodiphenyldichloroethane; /),/:»'-DDE = /?,//-dichlorodiphenyldichlo methylene: /;,//-DDT = /?,//-dichlorodiphcn\itrichlorocthane.
53
p,p'- DDD
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09-20-2017
• Dose above LOAEL
¦ LOAEL
~ NOAEL
O Dose below NOAEL
1000
t AST. ALT.1
& ALP .
-g———D-
"A
O
10
:
¦a dr
X
4, serum
albumin
Basis for DDE
subchronic
and r.hronir
oral p-RfDs
Short-term
MXC
Subchronic
Increased Liver Weight
Chronic
Short-
term
MXC
Subchronic
DDT
Chronic
Altered Clinical Chemistry
Figure C-l. Increased Liver Weight and Altered Liver Clinical Chemistry Following Oral Exposure to DDE, DDT,
or Methoxychlor (MXC)
54
p,p -DDD
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09-20-2017
Fatty degeneration;
centri obu ar necrosis
Centri obu ar
hypertrophy; Hepatocyte Fatty
fatty change hypertrophy metamorphosis
Centri lobular
necrosis
hypertrophy
hypertrophy
ratty change;
tocal necrosis
Necrasi
Vacuolation;
rt ro p h
-ocal hepatocellulai
net am orphosis
necrosis, hypertrophy
Amyloidosis
Hepatocyte
Vacuo ation
nfla(rimation
|—i hypertrophy, &
cell margi nation
eosiriiophilia;
hemorrhage
Centri I obul ar hypertrophy
cytoplasmicoxyphilia;
peripheral basophilic
cytoplasm icgranules
~/Basis for DDT
Dose above LOAEL
LOAEL
~ NOAEL
O Dose below NOAEL
chronicora RfD
and intermediateMRL
DDT MXC
Short-term
DDE DDT
Subchronic
Chronic
Figure C-2. Non-neoplastic Histopathological Changes in the Liver Following Oral Exposure to DDD, DDE, DDT,
or Methoxychlor (MXC)
55
p,p'- DDD
-------
FINAL
09-20-2017
1000
• Dose above CEL
~ CEL
ON0EL
O Dose below NOEL
100
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E
o
o
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of DDT IRIS OSF
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dprivafinn nf
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DDD IRIS OSF
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i
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Lactational
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exposure
tfO 1^0
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si/ fertility across generations
Figure C-4. Decreased Fertility Following Oral Exposure to DDE, DDT, or Methoxychlor (MXC)
57
p,p -DDD
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FINAL
09-20-2017
1000
100
• Dose above the LOAEL
¦ LOAEL
~ NOAEL
O Dose be low the NOAE L
Histologi cal
dyrriygy
n|/ agd
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i
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Figure C-5. Altered Male Sexual Differentiation Following Oral Exposure to DDE, DDT, or Methoxychlor (MXC)
58
p,p'- DDD
-------
FINAL
09-20-2017
1000
100
J 10
• Dose above the LOAEL
¦ LOAEL
~ NOAEL
O Dose below the NOAEL
I
Basis for MXC
intermediate oral MRL
0.1
DDE DDT
Gestation +/- Lactation
DDT
MXC
Pre mating +
gestation/lactation
DDT
Multigenerational
MXC
Pubertal +/- Post-pubertal
Figure C-6. Precocious Puberty in Females Following Oral Exposure to DDE, DDT, or Methoxychlor (MXC)
59
p,p -DDD
-------
FINAL
09-20-2017
1000
100
CO
-X.
E
o
Q
10
0.1
Dose above the LOAEL
LOAEL
~ NOAEL
O Dose below the NOAEL
4/ littererre-
T Resorptions^
si/ gestational age
vj/ pup weight
4/ pup weight
XII OSS /
CoropleteUtterloss -4M
^rpup-wefght
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chronicora RfD
'X Pre-implantatloalols
1s Resorption
survival
L^J
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gestation/lactaction
Gestation
Lactation
Figure C-7 Adverse Pregnancy Outcomes Following Oral Exposure to DDE, DDT, or Methoxychlor (MXC)
60
p,p -DDD
-------
FINAL
09-20-2017
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