United States
Environmental Protection
1=1 m m Agency
EPA/690/R-07/01 OF
Final
8-13-2007
Provisional Peer Reviewed Toxicity Values for
p,p '-Dichlorodiphenyldichloroethane (p,p '-DDD)
(CASRN 72-54-8)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms and Abbreviations
bw
body weight
cc
cubic centimeters
CD
Caesarean Delivered
CERCLA
Comprehensive Environmental Response, Compensation and Liability Act

of 1980
CNS
central nervous system
cu.m
cubic meter
DWEL
Drinking Water Equivalent Level
FEL
frank-effect level
FIFRA
Federal Insecticide, Fungicide, and Rodenticide Act
g
grams
GI
gastrointestinal
HEC
human equivalent concentration
Hgb
hemoglobin
i.m.
intramuscular
i.p.
intraperitoneal
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
i.v.
intravenous
kg
kilogram
L
liter
LEL
lowest-effect level
LOAEL
lowest-observed-adverse-effect level
LOAEL(ADJ)
LOAEL adjusted to continuous exposure duration
LOAEL(HEC)
LOAEL adjusted for dosimetric differences across species to a human
m
meter
MCL
maximum contaminant level
MCLG
maximum contaminant level goal
MF
modifying factor
mg
milligram
mg/kg
milligrams per kilogram
mg/L
milligrams per liter
MRL
minimal risk level
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-ob served-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
1

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PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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8-13-2007
PROVISIONAL TOXICITY VALUES FOR
p,p '-DICHLORODIPHENYLDICHLOROETHANE 1)I)I)) (CASRN 72-54-8)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
1

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8-13-2007
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
No verified chronic reference dose (RfD) or reference concentration (RfC) forp,p '-
dichlorodiphenyldichloroethane (p,p '-DDD) is available on the U.S. Environmental Protection
Agency's (EPA) Integrated Risk Information System (IRIS) (U.S. EPA, 2007), Drinking Water
Standards and Health Advisories list (U.S. EPA, 2006) or Health Effects Assessment Summary
Tables (HEAST) (U.S. EPA, 1997). The U.S. EPA's Chemical Assessments and Related
Activities (CARA) list (U.S. EPA, 1991, 1994) does not indicate any documents relating to the
noncancer health effects ofp,p '-DDD. The Agency for Toxic Substances Disease and Registry
(ATSDR, 2002) prepared a toxicological profile for dichlorodiphenyltrichloroethane (DDT),
dichlorodiphenyldichloroethylene (DDE) and DDD. ATSDR did not develop any Minimal Risk
Levels (MRLs) forp,p '-DDD, but no explanation was provided. The American Conference of
Governmental Industrial Hygienist (ACGIH, 2006), Occupational Safety and Health
Administration (OSHA, 2006) and National Institute for Occupational Safety and Health
(NIOSH, 2006) have not adopted occupational exposure limits forp,p '-DDD. A NIOSH Special
Occupational Hazard Review document, two International Agency for Research on Cancer
monographs (IARC, 1974, 1991), the National Toxicology Program status report (NTP, 2006)
and two World Health Organization documents (WHO, 1979, 1989) were consulted for relevant
information.
A cancer weight-of-evidence classification and an oral slope factor for p,p '-DDD are
available on IRIS (U.S. EPA, 2007). The cancer assessment, verified in 1988, classifiesp,p '-
DDD in category B2 (probable human carcinogen) under U.S. EPA (1986) Guidelines for
Carcinogen Assessment, based on lung tumors in female mice, lung and liver tumors in male
2

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8-13-2007
mice, and thyroid tumors in male rats after dietary exposure. IRIS (U.S. EPA, 2007) reports an
oral slope factor of 0.24 per mg/kg-day, and drinking water unit risk of 6.9 E-6 per |ig/L, based
on liver tumors in male mice exposed via the diet by Tomatis et al. (1974). The IRIS
carcinogenicity assessment forp,p '-DDD is derived from the Hazard Assessment Report on
DDT, DDD and DDE (U.S. EPA, 1980) and Carcinogen Assessment Group's Calculation of the
Carcinogenicity of Dicofol (Kelthane), DDT, DDE, and DDD (TDE) (U.S. EPA, 1985a). IRIS
does not report an inhalation unit risk forp,p '-DDD. p,p '-DDD is not included in the NTP's 11th
Report on Carcinogens (NTP, 2005). IARC (1991) classifies DDT and associated compounds
(includingp,p -DDD) in Group 2B (possibly carcinogenic to humans), citing inadequate
evidence in humans, but sufficient evidence in animals for the carcinogenicity of DDT. The
present document does not include a cancer assessment forp,p '-DDD, as one is available on
IRIS.
To identify toxicological information pertinent to the derivation of provisional toxicity
values for p,p '-DDD, references from the 2002 ATSDR Toxicological Profile for DDT, DDE
and DDD were screened for publications pertinent to the toxicity ofp,p '-DDD. Update searches
were conducted in January, 2007 for literature dating from 2001 to 2007 using the following
databases: MEDLINE, TOXLINE Special, and DART/ETIC (2001-2007); BIOSIS (2000-2007);
TSCATS, CCRIS, GENETOX, HSDB, RTECS (not date limited); and Current Contents
(previous 6 months).
REVIEW OF PERTINENT DATA
Human Studies
Human studies of p,p '-DDD include one subchronic study with a human volunteer
(Morgan and Roan, 1971), several studies of occupational exposure to technical grade DDT,
which containsp,p '-DDD (Kolmodin et al., 1969; Laws et al., 1967, 1973; Morgan and Lin,
1978; Morgan et al., 1980; Ortelee, 1958; Poland et al., 1970; Wong et al., 1984), and several
investigations of associations between reproductive effects andp,p '-DDD levels in biological
fluids (Saxena et al., 1980, 1981, 1983; Pines et al., 1987; Dalvie et al., 2004; Pant et al., 2004;
Perry et al., 2006). Due to the low number of study subjects, concurrent exposures to other
chemicals, and difficulty in distinguishing between biological levels ofp,p '-DDD resulting from
exposure and levels resulting from human metabolism of DDT or DDE, data from the available
human studies were not considered useful for derivation of provisional toxicity values.
In a study of the toxicokinetics of DDT and its metabolites (including p,p -DDD), an
adult male volunteer 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, 1988a), the intake ofp,p '-DDD was 0.071 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. 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 more than 4 ppm in adipose (based on visual
3

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examination of data presented graphically). After exposure was withdrawn, levels in both serum
and adipose declined rapidly. Measurements taken 180 days after exposure termination showed
no detectablep,p '-DDD in serum and levels reduced to almost 1 ppm in adipose. Although no
adverse effects on hematological and clinical chemistry endpoints were observed, details of the
test endpoints, frequency, and results were not reported, and other endpoints were not assessed;
thus the administered dose cannot be considered a NOAEL. Furthermore, the study was
conducted on only one volunteer, limiting the usefulness of the data.
Several epidemiology studies of workers exposed to technical grade DDT were located
(Kolmodin et al., 1969; Laws et al., 1967, 1973; Morgan and Lin, 1978; Morgan et al., 1980;
Ortelee, 1958; Poland et al., 1970; Wong et al., 1984). Technical grade DDT consists of a
mixture ofp,p -DDT (77.1%), o,p '-DDT (14.9%), p,p '-DDE (4.0%), p,p '-DDD (0.3%), o,p '-
DDE (0.1%), o,p '-DDD (0.1%) and unidentified compounds (3.5%) (U.S. EPA, 1980).
Exposure was primarily via the inhalation and dermal routes, but some oral exposure probably
occurred as well. In most of the studies, workers were exposed to a variety of other compounds
in addition to technical grade DDT. Because of the mixed exposures, these studies do not
provide any useful information on health effects ofp,p '-DDD in humans.
Measurements ofp,p '-DDD in biological fluids have been used to evaluate potential
effects on female reproductive function. Saxena et al. (1980, 1981, 1983) studied the levels of
organochlorine insecticides in maternal blood and placenta in cases of stillbirth, premature labor
and delivery, spontaneous abortion, and normal full-term delivery among patients in India. The
levels ofp,p '-DDD in maternal blood, placentas and cord blood of stillbirths were not
significantly different from the levels in normal full-term deliveries (Saxena et al., 1983);
however, there were few participants in this study (9 stillbirths and 27 full-term deliveries).
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; levels ofp,p '-
DDT, p,p '-DDE, lindane, and aldrin were also significantly higher (Saxena et al., 1980, 1981).
However, due to the small numbers of study participants (<25 cases and <25 controls) and the
confounding role of other pesticides, a causal relationship betweenp,p '-DDD and reproductive
effects cannot be established from these data. As reported in an abstract, Perry et al. (2006)
evaluated the association between serum levels of DDT and its metabolites (not specified) with
urinary levels of progesterone and estrogen, and menstrual cycle characteristics in 287 newly-
married women who were trying to conceive. Data were collected from each woman for 1 year
or until conception. After adjustment for potential confounders, increased serump,p '-DDD
levels were associated with decreased urinary levels of pregnanediol-3-glucuronide across all
menstrual cycle days; however, the authors did not present statistical analysis of the results. No
other associations withp,p '-DDD were reported in the abstract. In these studies (Saxena et al.,
1980, 1981, 1983; Perry et al., 2006), it is not known whether thep,p '-DDD detected in the
subjects was derived from direct exposure to p,p '-DDD or from metabolism of DDT or DDE. In
addition, since the subjects in these studies also had detectable levels of other compounds
(including DDT and its other metabolites), the degree to which the observed effects can be
attributed top,p '-DDD is uncertain.
Because there are indications thatp,p '-DDD may have antiandrogenic effects, several
studies have examined the association between male reproductive function and p,p '-DDD in
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biological fluids. Pines et al. (1987) studied the possible associations between organochlorine
insecticide exposures and reproductive function in men by comparing concentrations of these
compounds in the serum of 29 infertile and 14 fertile men from the general Israeli population.
Serum concentrations ofp,p '-DDD alone or in combination with p,p '-DDT and p,p '-DDE were
statistically significantly (p<0.05) higher in infertile men than in fertile men. Correlations
between semen characteristics (sperm count, motility, morphology) and the serum concentrations
of these compounds, however, were not significant. Dalvie et al. (2004a) evaluated the effects of
DDT and its metabolites on semen, fertility and sexual function in a cross-sectional study of 60
anti-malaria workers in South Africa. There were no statistically significant associations
between serum levels ofp,p '-DDD and sperm count, density or morphology; self-reported
problems with sexual function; prevalence of genital abnormalities on physical examination; or
number of pregnancies fathered. In a companion study, Dalvie et al. (2004b) reported that levels
of estradiol and testosterone were significantly (p<0.05) increased with higher serum levels of
p,p '-DDD. Pant et al. (2004) compared levels ofp,p '-DDD and other chlorinated pesticides in
the semen of 45 fertile and 45 infertile men in India. Levels ofp,p -DDD, p,p '-DDE, total DDT
and various isomers of hexachlorocyclohexane (HCH) were significantly (p<0.05) higher in the
semen of infertile than fertile men. Semen levels of p,p '-DDD were 78% higher in infertile men.
Correlation analysis showed that p,p '-DDD levels in semen of infertile men were significantly
correlated with higher levels of fructose (a marker for seminal vesicle secretion). Infertile men
had higher levels of fructose than fertile men and the authors suggested that the higher fructose
was indicative of underutilization of fructose due to biochemical defects. As with other studies
using biological levels of p,p '-DDD as a measure of exposure, it is not possible to associate any
of the observed effects on male reproductive function with exposure to p,p '-DDD.
In summary, the available human studies do not provide conclusive evidence for an
association between p,p '-DDD exposure and reproductive or hormonal effects. 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 a surrogate for
exposure, it is not possible to determine whether the levels result from direct exposure top,p '-
DDD or from metabolism of DDT and/or DDE. As a consequence, none of the human studies is
suitable for use in deriving provisional toxicity values.
Animal Studies
Oral Exposure
Subchronic Exposure — In preparation for a chronic cancer bioassay, NCI (1978)
conducted a range-finding dietary toxicity study of DDD in Osborne-Mendel rats and B6C3F1
mice. Technical grade DDD (60%p,p '-DDD) in corn oil was mixed with feed and administered
ad libitum to groups of 5 male and 5 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. The major analytical peak comprising 60% of the
test material was assumed to bep,p '-DDD. Diets containing 0, 562, 1000, 1780, 3160 or 5620
ppm technical grade DDD were fed to rats (corresponding top,p '-DDD doses of 0, 29, 52, 93,
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166 or 295 mg/kg-day in males, and 0, 32, 57, 101, 179 or 319 mg/kg-day in females1 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 3160 ppm; no
information was reported on mortality at 5620 ppm (NCI, 1978). Mean body weights were
reduced in male rats exposed to 1780 ppm (9% lower than controls) and 3160 ppm (10% lower),
and in female rats exposed to 1000 ppm (39% lower) and 1780 ppm (4% lower); neither
statistical analysis nor raw data were presented. No data on body weight changes at other doses
were reported. This study did not provide sufficient information to establish effect levels.
Groups of 5 male and 5 female mice were exposed to dietary p,p '-DDD for 6 weeks,
followed by a 2-week observation period (NCI, 1978); test material and study protocol were as
described above for rats (NCI, 1978). Mice received diets containing 0, 251, 398, 631, 1000 or
1590 ppm (0, 27, 43, 68, 108 or 172 mg/kg-day p,p '-DDD in males, and 0, 29, 47, 74, 117 or 186
mg/kg-day p,p '-DDD in females2 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 (NCI, 1978). Mortality was also observed in female mice
exposed to 1000 and 1590 ppm but not in other groups (data not reported). p,p '-DDD did not
affect body weights in the exposed mice; mean body weight gain in male and female mice
exposed to concentrations up to 631 ppm exceeded weight gain in controls (details not reported).
This study did not provide sufficient information to establish effect levels.
Baneijee et al. (1996) evaluated the effects of dietary p,p '-DDD exposure on humoral and
cell-mediated immune response in Wistar rats. Groups of 8-12 male rats were given either the
control diet or a diet containing 200 ppmp,p '-DDD (99% pure) for 6 weeks (equivalent to about
18 mg/kg-day3), 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 three weeks before the end of the exposure period; the other half was left
unstimulated. At the end of the exposure period, rats were sacrificed and blood samples
collected. The liver, spleen and thymus from each animal were removed and weighed. The
humoral immune response was quantified by measuring immunoglobulin levels (IgM and IgG),
estimating the albumin/globulin ratio and measuring the ovalbumin antibody titer by 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%;
absolute spleen weights were not reported (Banerjee et al., 1996). With regard to humoral
1	Based on reference values for food consumption and body weight (U.S. EPA, 1988a); doses given are for pure
p,p '-DDD after adjustment for 60% purity.
2	Based on reference values for food consumption and body weight (U.S. EPA, 1988a); doses given are for pure
p,p '-DDD after adjustment for 60% purity.
3	Based on reference values for food consumption and body weight (U.S. EPA, 1988a).
6

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immune responses, treatment with p,p '-DDD had no effect on the serum albumin/globulin ratio,
but significantly (p<0.05) reduced the levels of IgG, IgM and the titer of anti-ovalbumin
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. In
this study, the only dose tested (18 mg/kg-day) is a minimal LOAEL for evidence of
immunosuppression and potential effects on spleen weight in rats; no NOAEL can be identified
from these data. The LOAEL is considered minimal because the impact of the observed changes
on immune function is not certain.
Chronic Exposure — Tomatis et al. (1974) evaluated the carcinogenicity ofp,p '-DDD
(and p,p '-DDE separately) in CF-1 mice treated via the diet for a lifetime. The 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 43 mg/kg-day
(for both males and females) based on reference values for food consumption and body weight of
mice (U.S. EPA, 1988a). 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 p,p '-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 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 3rd
through 14th month of age), body weights of the treated males were depressed by more than 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 5-fold 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). No statistical analysis was presented by the authors. A post-hoc Fisher's
Exact test was performed on the response data with a p-value of 0.15. Although not statistically
significant by standard definitions, the 5-fold increase is still suggestive of an effect. The only
dose ofp,p '-DDD tested, 43 mg/kg-day, is a LOAEL for body weight depression and suggestive
of myocardial necrosis in male mice in this study.
The 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 hepatomas was increased in male
mice (Tomatis et al., 1974). This study was used in the derivation of the oral slope factor for
p,p '-DDD (U.S. EPA, 2007).
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NCI (1978) conducted a carcinogenicity bioassay of p,p '-DDD in Osborne-Mendel rats
and B6C3F1 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 are given in Table 1. 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 to 15 weeks after the 78-week exposure period and prior to
sacrifice. Weighted average exposure concentrations shown in Table 1 are averaged over the 78-
week exposure period and do not take into account the post-exposure observation period.
Weighted average dose estimates shown in the table are doses ofp,p '-DDD after adjustment for
purity.
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 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 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
cases the number of animals necropsied was used.
The authors reported that, beginning during week 30 and continuing through termination
of the exposure period, treated rats exhibited a slightly greater incidence of clinical signs of
toxicity (hunched appearance and urine staining; data not reported) (NCI, 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 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 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 withp,p '-DDD had no
significant effect on the incidence of nonneoplastic lesions in rats in any tissue examined. A
NOAEL cannot be determined from this study. The low dose (39 mg/kg-day in females) is a
LOAEL for depression of body weight gain and clinical signs of toxicity. The LOAEL is for the
mixture. A LOAEL forp,p '-DDD cannot be established from this study.
8

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Table 1. Group Sizes, Dietary Concentrations and Dose Estimates for NCI (1978) Cancer
Bioassay forp,p'-DDD
Group
Group
Size
Nominal
Concentration
(mg/kg)
Duration at
this
Concentration
(weeks)
Untreated
Duration
(weeks)
Weighted
Average
Concentration
Technical
grade DDDa
(mg/kg)
Weighted
Average
Daily Dose
/>,/>-DDDb
(after
adjustment
for purity)
(mg/kg-day)
Male Rats
Control
20
0

111

0
Low Dose
50
1400
1750
0
23
55
34
1647
69
High Dose
50
2800
3500
0
23
55
35
3294
138
Female Rats
Control
20
0

111

0
Low Dose
50
850
0
78
35
850
39
High Dose
50
1700
0
78
35
1700
79
Male Mice
Control
20
0

90

0
Low Dose
50
315
375
425
0
5
11
62
13
411
42
High Dose
50
630
750
850
0
5
11
62
14
822
85
Female Mice
Control
20
0

90

0
Low Dose
50
315
375
425
0
5
11
62
14
411
43
High Dose
50
630
750
850
0
5
11
62
15
822
85
" Calculated by the authors as the sum of concentration x time averaged over 78 weeks.
b Calculated using weighted average concentration and reference values for body weight and food consumption from
U.S. EPA (1988a); doses adjusted for 60% purity.
Source: NCI, 1978.
9

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8-13-2007
The authors reported treatment-related increases in the incidence of thyroid follicular-cell
neoplasms in rats treated withp,p '-DDD (NCI, 1978). No other treatment-related effects on
neoplasm frequency were observed. This study was evaluated as part of the IRIS cancer
assessment, but was not used in deriving the oral slope factor.
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 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 less
than 10% throughout the study. Treatment did not significantly increase the incidence of
neoplastic or nonneoplastic lesions in any tissue in either sex. The low dose of 42 mg/kg-day
p,p '-DDD is a NOAEL and the high dose of 85 mg/kg-day p,p '-DDD is a LOAEL for body
weight depression in female mice.
Inhalation Exposure
There are no data on the effects in laboratory animals ofp,p '-DDD exposure via
inhalation.
Other Studies
Adrenal Effects — Cueto and Brown (1958) fractionated technical grade DDD and
tested the fractions and isolates, delivered in gelatin capsules, for adrenocorticolytic activity in
male dogs (breed not specified). A single dog received 80 mg/kg-day of purified p,p '-DDD for
29	days and another 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 with p,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.
In a similar study, Powers et al. (1974) fed technical grade DDD (characterized by the
authors as 90%p,p '-DDD and 5-8% o,p '-DDD, other impurities unspecified) dissolved in corn
oil and administered in gelatin capsules to mixed groups of mongrel and purebred beagle dogs.
The dogs were given doses of either 100 or 200 mg/kg for varying time periods up to 30 days.
Control groups (mongrels and 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 authors reported histopathology findings in the adrenals of treated dogs,
including degenerative vacuolation, especially in the inner cortex, mitochondrial swelling,
10

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cellular necrosis and dilatation of smooth endoplasmic reticulum. Because the test material in
this study included o,p '-DDD and potentially other contaminants, it is not possible to determine
whether any of the adrenal affects are attributable to p,p '-DDD exposure.
Mechanistic — A number of studies have investigated the hormonal activities of DDT
and related compounds. When Gellert et al. (1972) injected groups of 11 or 12 mature
ovariectomized Sprague-Dawley rats with 0.1 or 10 mg/day ofp,p '-DDD in DMSO for 7 days,
there was no effect on uterine weight, uterine histology, cytology of vaginal smears or 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 p,p '-DDD via gavage for 10 days, either
with or without testosterone propionate, treatment with 200 mg/kg p,p '-DDD and testosterone
propionate resulted in 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, but competitively
inhibited binding of a synthetic androgen (R1881) to the rat androgen receptor (Kelce et al.,
1995). In in vitro assays using yeast reporter gene systems, p,p '-DDT was unable to activate
expression of the estrogen receptor gene or the androgen receptor gene at concentrations below
10"4 M (Gaido et al., 1997). Using an in vitro human hepatoma cell reporter gene system,
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 androgen receptor binding assay (Yamasaki et al., 2004). The results
of these experiments suggest that p,p '-DDD has antiandrogenic activity, but no estrogenic
activity.
Limited evidence suggests thatp,p '-DDD binds to lung tissues and can be cytotoxic to
lung cells. When Lund et al. (1989) intravenously injected radiolabeledp,p '-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 the salivary glands. The results of the in
vivo study suggest that pulmonary binding of p,p '-DDD can occur after intravenous exposure.
An in vitro experiment in the same paper demonstrated that p,p '-DDD irreversibly bound to
protein following incubation with S-9 fractions from murine lung or liver. The 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 P-450 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 cytochrome P-450. 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 co-incubation with 1-ABT, the inhibitor to
cytochrome P-450. 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
cytochrome P-450 in the lung.
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DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR 1) I) I)
None of the human studies of p,p '-DDD are suitable for derivation of provisional oral
RfD values. The database includes several epidemiological studies of workers exposed to
technical grade DDT (a mixture that includes a small percentage ofp,p -DDD), as well as studies
evaluating the potential association between biological measurements ofp,p '-DDD and
reproductive or hormonal effects. It is not possible to clearly attribute any effects reported in
these studies to direct exposure top,p '-DDD due to the confounding effects of concomitant
exposure to other organochlorine compounds (especially DDT and its other metabolites), and
because it is not possible to determine whetherp,p '-DDD measured in biological tissues resulted
from exposure to p,p '-DDD or from metabolism of DDT or DDE to p,p '-DDD in the human
body.
There are no suitable long-term general toxicity animal studies for derivation of a
provisional RfD. The Tomatis et al. (1974) study is designed primarily as a carcinogenicity
bioassay, with very sparse detail on noncancer effects. Furthermore, the LOAEL of 43 mg/kg-
day is very high compared to closely-related compounds. Chronic LOAELs for related
compounds are 0.25 mg/kg-day ip,p'~DDT; U.S. EPA, 1985b), 4.0 mg/kg-day (Cueto and
Brown, 1958) and 12 mg/kg-day (NCI, 1978), with the latter two being FELs (mortality). Given
the low LOAELs and FELs for closely related compounds, the potential is high that a well-
designed p,p '-DDT chronic study would produce a much lower LOAEL. As a result, the
Tomatis study is judged to be inadequate for assessment of long-term noncancer toxicity.
Studies suitable for use in deriving provisional RfD values include a chronic study in
mice (Tomatis et al., 1974) and a 6-week immunotoxicity study in rats (Banerjee et al., 1996).
Summaries of these studies and comparisons with the LOAEL values from the chronic NCI
(1978) study are shown in Table 2. The usefulness of data from the NCI (1978) subchronic and
chronic feeding studies for p-RfD derivation is compromised by the low purity of the technical
grade DDD tested. Only 60% of the product was p,p '-DDD and at least 19 impurities
(unspecified) were present in the remaining 40%. The chronic 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. The two studies in dogs (Cueto and Brown, 1958; Powers et al., 1974) are not suitable
for p-RfD derivation due to the small number of animals used, limited endpoints evaluated and,
in some cases, post-treatment observation periods allowing for reversal of effects.
The only remaining study, Banerjee et al. (1996), is a 6-week immunotxicity study that
does not cover the required general toxicity endpoints. Although the study was adequate for its
purpose and establishes the lowest LOAEL forp,p '-DDD, by itself, it does not qualify as the
basis for either a subchronic or chronic p-RfD. The oral noncancer database is inadequate for
derivation of p-RfDs. Neither of the two studies available for p-RfD derivation included more
than one dose level, precluding benchmark dose modeling of the effects.
12

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8-13-2007
Table 2. Summary of Available Oral Noncancer Dose-Response Information Suitable for p-RfD Derivation and
Comparison with LOAELs from NCI (1978) Chronic Studies
Species
Sex
Dose
(mg/kg-day)
Exposure
Duration
NOAEL
(mg/kg-day)
LOAEL
(mg/kg-day)
Responses
Comments
Reference
Rats
M
0, 18 mg/kg-
day
6 weeks
NA
18
Immunosuppression
(reduced humoral and cell-
mediated immunity) and
decreased relative spleen
weight. Minimal LOAEL.
Endpoints included clinical
signs, body weight, selected
organ weights, and
immunotoxicity parameters.
Baneijee et al.,
1996
Mice
M,F
0, 43 mg/kg-
day
123 weeks
NA
43
Body weight depression in
males.
Endpoints included survival,
clinical signs, body weight,
and histopathology of selected
organs.
Tomatis, 1974
Rats
M,F
0, 69, 138
mg/kg-day
(M) or 0,39,
79 mg/kg-
day (F)
78 weeks,
followed by
34-35 weeks
observation
NA
39
Depression of body weight
gain and clinical signs of
toxicity in females.
Test article only 60% pure.
Prolonged observation period
may have allowed for
recovery from toxic effects.
Not suitable for p-RfD
derivation.
NCI, 1978
Mice
M,F
0, 42, 85
mg/kg-day
(M) or
0, 43, 85
mg/kg-day
(F)
78 weeks,
followed by
13-15 weeks
observation
42
85
Depression of body weight
gain in females.
Test article only 60% pure.
Prolonged observation period
may have allowed for
recovery from toxic effects.
Not suitable for p-RfD
derivation.
NCI, 1978
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8-13-2007
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION p-RfC VALUES FOR1) I) I)
No studies specifically investigating the effects of inhaled p,p '-DDD in humans or
animals were located. Thus, provisional RfCs were not derived forp,p '-DDD.
DERIVATION OF A PROVISIONAL CARCINOGENICITY
ASSESSMENT FORp,p'-DDD
A cancer assessment, including an oral slope factor, is available forp,p '-DDD on IRIS
(U.S. EPA, 1988b).
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