United States
Environmental Protection
1=1 m m Agency
EPA/690/R-07/016F
Final
9-25-2007
Provisional Peer Reviewed Toxicity Values for
Dimethyl phthalate
(CASRN 131-11-3)
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
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p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
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
l^g
microgram
[j,mol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
DIMETHYL PHTHALATE (CASRN 131-11-3)
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
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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
Dimethyl phthalate (DMP) is a phthalate ester used in the manufacture of a variety of
products such as vinyl swimming pools and seats, safety glass, toothbrushes, toys and clothing; it
is also used as an ingredient of numerous nonplasticized products (NTP, 1995). DMP has the
empirical formula C10H10O4 (Figure 1).
0
II
kA,c
11
0
Figure 1. Dimethyl Phthalate Structure
och3
OCHj
The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System
(IRIS) (U.S. EPA, 2007) does not list a chronic oral reference dose (RfD), chronic inhalation
reference concentration (RfC), or derive an oral slope factor or inhalation unit risk for cancer,
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citing inadequate data. The IRIS weight of evidence assessment classifies DMP as a class D
carcinogen (not classifiable) (U.S. EPA, 2007).
Subchronic or chronic RfDs for DMP are not listed in the Health Effects Assessment
Summary Tables (HEAST) (U.S. EPA, 1997), or the Drinking Water Standards and Health
Advisories list (U.S. EPA, 2006). The Chemical Assessment and Related Activities (CARA) list
(U.S. EPA, 1991, 1994) includes a Health and Environmental Effects Profile (HEEP) (U.S.
EPA, 1987a), Drinking Water Criteria Document (DWCD) (U.S. EPA, 1987b), and Health
Effects Assessment (HEA) (U.S. EPA, 1987c) for phthalic acid esters, but RfDs, RfCs, or cancer
potency factors for DMP were not derived due to insufficient data. The American Conference of
Governmental Industrial Hygienists (ACGIH) (2006), the National Institute for Occupational
Safety and Health (NIOSH) (2006) and the Occupational Safety and Health Administration
(OSHA) (2006) all list an 8-hour time weighted average (TWA) occupational exposure limit of 5
mg/m3, set to control excess mist, not to protect against toxic or irritant effects. The Agency for
Toxic Substances Disease and Registry (ATSDR) (2006), International Agency for Research on
Cancer (IARC) (2006) and World Health Organization (WHO) (2006) have not produced
documents regarding DMP or phthalic acid esters. Safety assessments of phthalate esters
conducted by the Cosmetic Ingredient Review Expert Panel (CIREP) (CIREP, 1985, 2003) were
consulted for relevant information.
Literature searches for studies relevant to the derivation of provisional toxicity values for
DMP (CASRN 131-11-3) were conducted from 1965 to August 2007 in TOXLINE
(supplemented with BIOSIS and NTIS updates), MEDLINE, TSCATS, RTECS, CCRIS, DART,
EMIC/EMICBACK, HSDB, GENETOX and CANCERLIT and Current Contents.
REVIEW OF PERTINENT LITERATURE
Human Studies
No studies investigating the effects of subchronic or chronic oral or inhalation exposure
to DMP in humans were identified.
Animal Studies
Oral Exposure
Chronic Toxicity - The effect of chronic dietary exposure to DMP was investigated by
Lehman (1955). However, due to poor reporting of methods and results, data from this study
cannot be used to identify NOAEL or LOAEL values for adverse effects of chronic oral
exposure to DMP. According to the study report, groups of 10 female rats (strain not reported)
were fed diets containing 0, 2.0, 4.0 or 8.0% DMP for 2 years. Mortality rates in the DMP
treatment groups did not differ from the control group. Growth rate in the 4.0 and 8.0% groups
was slightly, but statistically, different (direction and magnitude of change not reported) from
controls, although methods used to assess growth rate were not reported. "Chronic nephritis"
was observed in rats treated with 8.0% DMP, but not in the other DMP treatment groups. No
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other effects of DMP treatment were noted. Comprehensive toxicity endpoints, such as
histopathology or standard biochemical and hematological endpoints, were not assessed in this
study. Additional chronic oral exposure studies of DMP to laboratory animals were not
identified.
Subchronic/Developmental/Reproductive Toxicity - Subchronic oral toxicity studies
evaluating comprehensive toxicological endpoints were not identified, although several studies
assessing developmental effects of gestational exposure to DMP have been conducted (Gray et
al., 2000; Field et al., 1993; NTP, 1989; Hardin et al., 1987; Plasterer et al., 1985; Booth et al.,
1983). Although gestational exposure studies also include preliminary, short-term dose-ranging
studies designed to identify test doses for evaluation of developmental effects, comprehensive
toxicological endpoints were not examined. Studies investigating the testicular toxicity of DMP
exposure have also been conducted (Gray et al., 2000; Foster et al., 1980; Oishi and Hiraga,
1980).
The developmental effects of exposure to dietary DMP were assessed in Sprague Dawley
(CD) rats (NTP, 1989). The study consisted of a preliminary dose-ranging study and a "full
developmental" study. Results of the developmental study were also reported in a peer-reviewed
publication by Field et al. (1993). For the dose-ranging study, groups of 8 pregnant rats were
exposed to dietary DMP at concentrations of 0, 0.25, 0.5, 1.0, 2.5 or 5.0% (equivalent to 200,
400, 800, 2,000 or 4,000 mg/kg-day, based on a projected average body weight of 275 g and an
anticipated average daily food intake 22 g food/day) on gestational days (GD) 6 through 15.
Throughout the treatment period, rats were examined twice daily for signs of toxicity. On GD
20, all animals were sacrificed and uteri were examined for implantation sites. Maternal body
weight and selected organ weights (kidneys, liver) were assessed at the end of the treatment
period. Fetal body weight was measured and dead and live fetuses were examined for external
malformations. No maternal mortalities or clinical signs of toxicity were observed in any
treatment group. Based on decreased maternal food consumption and weight gain, maternal
toxicity was observed in the 5% DMP group. Food consumption in the 5% DMP group was
significantly decreased compared to control during GD 6 through 9. Maternal weight gain over
the entire treatment period was reduced by 33% (p<0.01) in the 5.0% DMP group, compared to
controls, but not in the other DMP groups. Relative left kidney weight was significantly
increased by 15, 20, 19, 14 and 21% in the 0.25, 0.5, 1.0, 2.5, or 5.0% DMP groups, respectively;
absolute left kidney weight was significantly increased by 24, 19, 13 and 19% in the 0.5, 1.0,
2.5, or 5.0%) DMP groups, respectively. No consistent changes in absolute or relative right
kidney weight were observed. The biological significance of increased relative left kidney
weight in DMP treatment groups was not established. Pregnancy rates in DMP groups were
similar to control. No effect of DMP on fetal development was observed, based on fetal
viability, body weight and the incidence of external malformations or variations.
Based on results of the dose-ranging study showing limited toxicity in dams at the highest
exposure level, dietary concentrations of 0, 0.25, 1.0 and 5.0% were selected for the full
developmental study (Field et al., 1993; NTP, 1989). The full developmental study followed the
same protocol as the dose-ranging study, except with 29-30 animals per treatment group and
additional assessments for fetal visceral and skeletal malformations. Based on weight and food
consumption measured during the exposure period, the study authors calculated the daily dose of
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DMP to be 0, 200, 800 and 3600 mg/kg-day in the 0, 0.25, 1.0 and 5.0% groups, respectively.
No maternal mortalities or treatment-related signs of toxicity were observed during the study in
any DMP groups. In the 5% group, maternal body weight gain was reduced by 28% (p<0.01)
compared to control over the treatment period (GD 6-15), but did not differ significantly from
control over the full gestation period (with or without correction for gravid uterine weights).
Maternal weight gain was similar to control in the 0.25 and 1.0% groups. Correspondingly,
significant decreases in food consumption were seen in the 5.0% group on GD 6-9 (28%
decrease) and GD 9-12 (14% decrease), but not later, and the difference from control over the
full gestation period was not statistically significant. Food consumption was similar to control in
the 0.25 and 1.0% groups. Relative liver weight was increased by 5.8% (p<0.01) in the 5%
DMP group, but not the 0.25 or 1% DMP groups, compared to control (NTP, 1989).
Histopathological evaluation of the liver was not conducted. No effects were observed on
absolute liver weight or absolute or relative left and right kidney weight in any DMP group.
Pregnancy weights were similar in DMP groups compared to control. Treatment with DMP had
no effect on any reproductive or developmental parameter, including number of implantation
sites, number of resorptions, fetal viability, live and dead fetuses per litter, fetal body weight or
fetal growth. The incidence of external, visceral and skeletal malformations was similar in the
DMP treatment groups compared to control. Based on results of the full developmental study,
the authors identified NOAEL and LOAEL values for maternal toxicity of 1.0% (800 mg/kg-
day) and 5.0% (3600 mg/kg-day), respectively, for decreased body weight gain and increased
relative liver weight. For fetal effects, a NOAEL of 5% (3600 mg/kg-day) was reported; a
LOAEL was not identified.
Plasterer et al. (1985) assessed the effects of gestational exposure to the maximum
tolerated dose (MTD) of DMP on the development of CD-I mice. Results were also reported in
an unpublished study (Booth et al., 1983). Initially, to identify the MTD (defined as the dose "at
or just below the threshold for adult lethality"), an 8-day screening study was performed in non-
pregnant female mice (67-71 days old). Groups of 10 mice were administered daily oral doses of
0, 875, 1750, 3500, 7000 or 11,890 mg/kg DMP in corn oil. No mortalities were observed in the
control, 875 or 1750 mg/kg-day groups. Percent mortality in the 3500, 7000, and 11,890 mg/kg
groups was 10, 50 and 100%, respectively. The average weight of surviving mice in DMP
treatment groups was not different relative to control. No additional information on effects of
DMP exposure was reported. The MTD was identified as 3500 mg/kg-day. Pregnant CD-I mice
(n=36) were administered 3500 mg/kg DMP in corn oil by gavage on GD 7 through 15; the
control group of 40 mice was treated with corn oil. Gestational day 1 was defined as the day on
which a seminal plug was identified. No treatment-related mortalities were observed in the DMP
group. Maternal survival, weight gain and the number of rats delivering litters in the DMP group
did not differ from control. No effect of DMP treatment was observed on the number of live and
dead young per litter or on average pup weight. No gross congenital abnormalities were
observed in the control or DMP groups.
No effects were observed in a gestational exposure study in mice (Hardin et al., 1987). A
preliminary, 8-day, oral (gavage) dose-ranging study in non-pregnant female CD-I mice was
conducted to determine the LDio value for DMP (5000 mg/kg-day), the exposure level selected
for evaluation of developmental effects. Parameters assessed in the dose-ranging study were
body weight, signs of toxicity and mortality. No additional information on methods or results of
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the dose-ranging study was reported. The developmental effects of DMP were evaluated in two
tests. In one test, pregnant mice were administered corn oil vehicle (n=50) or 3500 mg/kg-day
DMP (n=49); in the second test, pregnant mice were administered corn oil vehicle (n=43) or
5000 mg/kg-day DMP (n=43). Mice were examined daily for signs of toxicity and body weights
were recorded on GD 6 and 17. Following completion of delivery (postnatal day 1), the number
of live and dead pups and pup weight were recorded and pups. On postnatal day (PND) 3,
maternal and live pup weights were recorded. No systematic effort was made to examine either
live or dead pups for malformations. Twelve dams (28%) in the 5000 mg/kg-day DMP group
died during the treatment period (cause of death not reported); no mortality was observed in mice
treated with 3500 mg/kg-day DMP or in controls. Maternal weight gain and the number of
viable litters were similar between the DMP groups and matched controls. The number of
liveborn per litter, percentage survival to postnatal day 3, birth weight and postnatal weight gain
in the treated groups and matched controls were similar. Although not specifically assessed, no
external malformations were noted in the DMP groups. This study found no effects on the
measured reproductive parameters, even at a dose (5000 mg/kg-day) overtly toxic to the dams.
No effects on male sexual differentiation were observed following gestational exposure
of rats to DMP (Gray et al., 2000). Pregnant Sprague Dawley rats were administered 0 or 750
mg/kg-day DMP in corn oil from GD 14 to PND 3. There were 19 control litters and 4 treated
litters with live pups. Male offspring were assessed during the postnatal period through the onset
of puberty. For all males, evaluations included: body weights and anogenital distance (AG) (on
PND 2); examination of the inguinal region for hemorrhagic testes (on PND 9-10); examination
for the presence of areolas/nipples (on PND 13); and examination for the onset of puberty, as
indicated by preputial separation (daily after weaning). On PND 2, one male was randomly
selected from each liter for necropsy, including paired testes weights and testicular histology. At
3-5 months of age, surviving males were sacrificed for blood collection (for measurement of
serum testosterone) and necropsy (measurement of organ weights, examination for external and
internal abnormalities of reproductive tissues). The number of males examined for
malformations in the DMP group was 21 and in the control group was 80. For all parameters
assessed, DMP-exposed animals did not differ from controls.
Serum testosterone levels were decreased in male rats exposed to dietary DMP for 1
week (Oishi and Hiraga, 1980). Young (5-weeks old) JCL:Wistar rats were fed diets containing
0 (n=20) or 2% (n=10) DMP for 1 week. Using average body weight and average daily food
consumption for a weanling rat (U.S. EPA, 1988), the daily dose of DMP was calculated as 302
mg/kg-day. Body weight and food consumption were measured daily. At sacrifice after 1 week
of treatment, blood samples were analyzed for serum zinc and testosterone and selected organs
(testes, liver and kidneys) were analyzed for weight and zinc content. Body weight and food
consumption between the groups was similar during the treatment period. Absolute and relative
liver weights were increased by 17% (p<0.05) and 15% (p<0.05), respectively, compared to
control. No treatment-related effects on absolute and relative weights of testes and kidneys were
observed. Concentrations of testosterone in serum and testes and dihydrotestosterone in serum
were significantly (p<0.05) reduced compared to control. Since data were presented graphically
with poor resolution, the magnitude of change can only be approximated as a reduction of about
50%. Zinc content of serum, testes, liver and kidneys was unchanged compare to control.
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A study on testicular effects of oral DMP exposure in young rats found no treatment-
related effects (Foster et al., 1980). Groups of 12 young Sprague Dawley rats (weighing 70-90 g,
age not reported) were administered 0 or 7.2 mmol/kg-day (equivalent to 1400 mg/kg-day) by
gavage for 4 days. Body weight and food consumption were assessed throughout the exposure
period. One day after administration of the final dose, testicular weight was measured and testes
were examined for histopathological changes. No significant differences were observed in food
intake, body weight gain or weight of the testes between the control and DMP groups.
Histopathological assessment of testes from DMP-treated rats showed no lesions or evidence of
atrophy.
Inhalation Exposure
Subchronic or chronic inhalation toxicity studies of DMP in animals were not identified.
Supporting Studies
Dermal Tumor Initiation/Promotion Studies - Studies assessing the carcinogenicity of
oral or inhaled DMP were not identified. However, the NTP (1995) conducted a study on the
dermal exposure to DMP in a 1-year initiation/promotion study in mice. In the initiation study,
mice were dosed dermally with DMP to evaluate its activity as a skin tumor initiator, with and
without the known skin tumor promoter 12-6>-tetradecanoylphorbol-1 2-acetate (TPA). In the
promoter study, mice were dosed dermally to evaluate the activity of DMP as a skin tumor
promoter with and without the known skin tumor initiator 7,12-dimethylbenzanthracene
(DMBA). Groups of 50 male Swiss (CD-I) mice were dermally administered various
initiation/promotion treatments. Comparative control groups included vehicle control
(acetone/acetone), initiation/promotion control (DMBA/TPA), initiator control
(DMBA/acetone), and promoter control (acetone/TPA). Treatment groups included DMP
initiation (DMP/TPA) and DMP promotion (DMBA/DMP). DMP (0.12 g) was applied 1 time
per week in the initiation study and 5 times per week in the promoter study. Based on the
incidence of skin neoplasms, DMP did not exhibit activity as an initiator or promoter for skin
carcinogenesis.
Genotoxicity Studies - Results of in vitro assays of mutagenicity of DMP are
summarized in Table 1. In bacterial (NTP, 1995; Kozumbo et al., 1982; Kozumbo and Rubin,
1991; Agarwal et al., 1985; Zeigler et al., 1985, 1982) and mammalian cells (Barber et al., 2000;
Hazleton Biotechnologies, 1986a,b), negative results were observed for gene mutation without
the addition of exogenous metabolic activation. Conflicting results were observed in gene
mutation studies in bacterial cells with metabolic activation, with positive results observed in
reports by Kozumbo et al. (1982), Kozumbo and Rubin (1991) and Agarwal et al. (1985).
Results of gene mutation studies in mouse lymphoma cell lines were positive with metabolic
activation (Hazleton Biotechnologies, 1986a,b). Positive results were obtained for effects of
DMP on sister chromatid exchange with, but not without, metabolic activation (NTP, 1995;
Loveday et al., 1990). DMP tested negative with and without metabolic activation for
chromosomal aberrations in Chinese hamster ovary cells (NTP, 1995; Loveday et al., 1990) and
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Table 1. Genotoxicity of Dimethyl Phthalate In Vitro
Test System
Endpoint
Results"
Reference
With
Activation
Without
Activation
Salmonella typhimurium (reverse
mutation)
Gene mutation
—
—
NTP, 1995
S. typhimurium (reverse
mutation)
Gene mutation
+
—
Kozumbo et al.,
1982; Kozumbo and
Rubin, 1991
S. typhimurium (reverse
mutation)
Gene mutation
+
—
Agarwal et al., 1985
S. typhimurium (reverse
mutation)
Gene mutation
—
—
Zeigler et al., 1982,
1985
Mouse lymphoma cells
Gene mutation
+
—
Barber etal., 2000
Mouse lymphoma cells
Gene mutation
+
—
Hazleton
Biotechnologies,
1986a
Mouse lymphoma cells
Gene mutation
+
—
Hazleton
Biotechnologies,
1986b
Chinese hamster ovary cells
Sister chromatid exchange
+
—
NTP, 1995
Chinese hamster ovary cells
Sister chromatid exchange
+
—
Loveday et al., 1990
Chinese hamster ovary cells
Chromosomal aberrations
—
—
NTP, 1995
Chinese hamster ovary cells
Chromosomal aberrations
—
—
Loveday et al., 1990
Balb/3T3 cells
Cell transformation
—
X
Barber etal., 2000
Balb/C-3T3
Cell transformation
—
X
Litton Bionetics, Inc.,
1986
Balb/C-3T3
Cell transformation
—
X
Litton Bionetics, Inc.,
1985
a - = negative; + = positive
X: Test with exogenous metabolic activation was not conducted
for cell transformation in Balb/3T3 cells (Barber et al., 2000; Litton Bionetics, Inc., 1985, 1986).
Additional studies assessing the genotoxic effects of DMP in vivo were not identified.
Mechanism of Action Studies - Testicular toxicity, including underdeveloped or absent
reproductive organs, hypospadias, cryptorchidism, decreased anogenital distance, and decreased
sperm production have been observed following gestational exposure of rats to some phthalate
esters (dibutyl phthalate, diethylhexyl phthalate) (Liu et al. 2005), although no evidence of
developmental toxicity to the male reproductive system has been observed following gestational
exposure of rats to dimethyl phthalate (Gray et al., 2000). Results of a toxicogenomics study by
Liu et al. (2005) suggest that phthalate ester-induced toxicity to the male reproductive system
may be mediated through altered expression of testicular genes. Oral exposure of pregnant
Sprague-Dawley rats (on GD12-19) to phthalate esters (500 mg/mg-day in corn oil by gavage)
with known effects on male reproductive organ development (dibutyl phthalate, diethylhexyl
phthalate, dipentyl phthalate, and benzyl butyl phthalate) produced significant alterations in
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expression of 391 of 30,000 genes in fetal testes (Liu et al., 2005). Gene pathways affected by
exposure included those involved in Sertoli cell development and in communication between
Sertoli cells and gonocytes. However, no significant changes in gene expression were observed
in fetal testes following oral administration of DMP (500 mg/kg-day) in corn oil to pregnant
dams on GD 12-19 (Liu et al., 2005). Results of the study by Lui et al., (2005) provide
supportive evidence that gestational exposures to dimethyl phthalate may not be toxic to
developing male reproductive organs.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR DIMETHYL PHTHALATE
Studies investigating the effects of subchronic or chronic oral exposure in humans to
DMP were not identified. Oral exposure studies in animals are limited to a poorly reported
chronic study in rats (Lehman, 1955), several gestational exposure studies in rats and mice (Gray
et al., 2000; Field et al., 1993; NTP, 1989; Hardin et al., 1987; Plasterer et al., 1985; Booth et al.,
1983) and short-term (e.g., 1 week or less) studies investigating the potential effects of DMP on
the male reproductive system in rats (Gray et al., 2000; Foster et al., 1980; Oishi and Hiraga,
1980). Results of gestational exposure studies indicate that DMP does not produce adverse
effects on reproductive outcome or fetal development, even at doses producing maternal toxicity.
However, assessments of maternal toxicity in both dose-ranging and developmental portions of
gestational exposure studies were based on only a few parameters (signs of toxicity, body weight
gain and weights of selected organs). Since comprehensive toxicological endpoints were not
assessed, the available studies are not suitable for use in derivation of subchronic and chronic p-
RfDs for DMP. However, a "screening" level value for oral DMP exposure is provided in the
Appendix.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR DIMETHYL PHTHALATE
No studies investigating the effects of subchronic or chronic inhalation exposure to DMP
in humans or animals were identified. The lack of suitable data precludes derivation of
subchronic and chronic p-RfCs for DMP.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR DIMETHYL PHTHALATE
Weight-of-Evidence Descriptor
Studies evaluating the carcinogenic potential of oral or inhalation exposure to DMP in
humans were not identified in the available literature. Cancer bioassays for DMP have not been
conducted in animals for either oral or inhalation exposure. DMP did not exhibit activity as an
initiator or promoter for skin carcinogenesis in a 1-year dermal initiation/promotion study in
mice conducted by NTP (1995). The available studies on the mutagenic potential of DMP are
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equivocal. The current IRIS assessment (9/07/1988) indicates that the human carcinogenic
potential is not classifiable (classification of D) under the 1986 Guidelines for Carcinogen Risk
Assessment (U.S.EPA, 1986). Under the 2005 Guidelines for Carcinogen Risk Assessment(U.S.
EPA, 2005), inadequate information is available to assess the carcinogenic potential of DMP.
Quantitative Estimates of Carcinogenic Risk
Derivation of quantitative estimates of cancer risk for DMP is precluded by the lack of
suitable data.
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Gray, L.E., J. Ostby, M. Price et al. 2000. Perinatal exposure to the phthalates DEHP, BBP, and
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NTP (National Toxicology Program). 1989. Developmental toxicity evaluation of dimethyl
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APPENDIX
Derivation of a Screening Value for Dimethyl Phthalate (CASRN 131-11-3)
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for dimethyl phthalate (DMP). However, information is available for this
chemical which, although insufficient to support derivation of a provisional oral reference dose
(p-RfD), under current guidelines, may be of use to risk assessors. In such cases, the Superfund
Health Risk Technical Support Center summarizes available information in an Appendix and
develops a "Screening Value." Appendices receive the same level of internal and external
scientific peer review as the PPRTV documents to ensure their appropriateness within the
limitations detailed in the document. In some cases, as for DMP, a screening vale was developed
and included in an Appendix as a result of comments received during external review. Thus, the
information in this appendix has not undergone external peer review but is a result of
recommendations made by reviewers regarding the limited dataset available for DMP. In the
OSRTI hierarchy, Screening Values are considered to be below Tier 3, "Other (Peer-Reviewed)
Toxicity Values."
Screening Values are intended for use in limited circumstances when no Tier 1, 2, or 3
values are available. Screening Values may be used, for example, to rank relative risks of
individual chemicals present at a site to determine if the risk developed from the associated
exposure at the specific site is likely to be a significant concern in the overall cleanup decision.
Screening Values are not defensible as the primary drivers in making cleanup decisions because
they are based on limited information. Questions or concerns about the appropriate use of
Screening Values should be directed to the Superfund Health Risk Technical Support Center.
The available toxicity database reveals a paucity of reliable data for DMP. Studies
investigating the effects of subchronic or chronic exposure to DMP in humans were not
identified. Oral exposure studies in animals were limited to a poorly reported chronic duration
study in rats (Lehman, 1955), and several short-term studies (10 days or less), to include
gestational exposures, in mice or rats. Results of the gestational and short-term studies indicate
that DMP does not produce adverse effects on reproductive outcome or fetal development in
rodents. There are maternal effects (e.g. decreased body weight gain, increased relative liver
weight) reported in pregnant rat dams exposed orally to DMP at high doses. However, such
findings should be considered with caution as there was a palatability issue, with an associated
decrease in body weight, observed in animals exposed to high doses of DMP (e.g. NTP, 1989;
Field et al., 1993). Although DMP did not appear to be fetotoxic or teratogenic (NTP, 1989;
Field et al., 1993; Plasterer et al., 1985; Hardin et al. 1987; Gray et al., 2000), or display
evidence of gene alterations in fetal testes (Liu et al., 2005), changes indicative of exposure to
some phthalate esters were observed in male weanling rats (5 weeks of age) exposed to oral
DMP for one week at a dose of 302 mg/kg-day (Oishi and Hiraga, 1980). These effects included
a significant increase in absolute and relative liver weight, and a statistically significant decrease
in serum and testicular testosterone levels (approximately 50% compared to controls). It should
be noted that the available chronic study (Lehman, 1955), did not evaluate downstream effects
that could arise as a result of decreased testosterone levels. In addition, the short duration and
exposure to only one dose in the Oishi and Hiraga (1980) study, does not inform the dose-
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response or persistence of the effects. Thus, this study is considered inappropriate for derivation
of a p-RfD in the primary portion of this PPRTV document. An oral subchronic reference
screening level value of 1.0E-1 mg/kg-day DMP, based on a free-standing LOAEL for
increased absolute and relative liver weight and decreased serum and testicular testosterone in
male rats, is derived as follows:
Male Rat LOAEL = 302 mg/kg-day
DMP oral subchronic reference screening value = 302 mg/kg-day / 3000
= 0.1 mg/kg-day or 1.0E-1 mg/kg-day
The aggregate uncertainty of 3000 consists of a factor of 10 each for human interindividual
variability (UFH), interspecies variability (UFA), and extrapolation from a LOAEL to NOAEL
(UFl). A factor of three is included to account for deficiencies in the database which includes
developmental toxicity studies but does not include standard subchronic bioassays of toxicity,
studies of potential reproductive effects from exposure to DMP in male rats and mice, or two-
generation reproductive toxicity studies. Exposure to multiple phthalate esters in the
environment should be taken into consideration when conducting a risk assessment for DMP.
Studies have shown that several phthalate esters may have a common endpoint of toxicity related
to developmental and reproductive effects.
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