United States FINAL DRAFT
Environmental Protection ECAO-CIN-P188
A8encv September. 1987
&EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS PROFILE FOR
PHTHALIC ACID ALKYL. ARYL AND ALKYL/ARYL ESTERS
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
document Is a preliminary draft. It has not been formally released
.S. Environmental Protection Agency and should not at this stage be
d to represent Agency policy. It Is being circulated for comments
schnlcal accuracy and policy Implications.
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DISCLAIMER
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
ECAO-CIN-P188
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PREFACE
Health and Environmental Effects Profiles (HEEPs) are prepared for the
Office of Solid Waste and Emergency Response by the Office of Health and
Environmental Assessment. The HEEPs are Intended to support listings of
hazardous constituents of a wide range of waste streams under Section 3001
of the Resource Conservation and Recovery Act (RCRA), as well as to provide
health-related limits for emergency actions under Section 101 of the Compre-
hensive Environmental Response, Compensation and Liability Act (CERCLA).
Both published literature and Information obtained from Agency program
office files are evaluated as they pertain to potential human health,
aquatic life and environmental effects of hazardous waste constituents. The
"literature searched and the dates of the searches are Included 1n the
section titled "Appendix: Literature Searched." The literature search
material Is current through November, 1985.
Quantitative estimates are presented provided sufficient data are
available. For systemic toxicants, these Include Reference doses (RfOs) for
chronic exposures. An RfO (formerly known as the ADI) is defined as the
amount of a chemical to which humans can be exposed on a dally basis over an
extended period of time (usually a lifetime) without suffering a deleterious
effect. In the case of suspected carcinogens, RfDs are not estimated in
this document series. Instead, a carcinogenic potency factor of q-|* is
provided. These potency estimates are derived for both oral and Inhalation
exposures where possible. In addition, unit risk estimates for air and
drinking water are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and carclno-
genlclty are derived. The RQ 1s used to determine the quantity of a hazard-
ous substance for which notification Is required in the event of a release
as specified under CERCLA. These two RQs (chronic toxkUy and carclnogen-
IcHy) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxldty and acute mammalian toxldty).
The first draft of this document was prepared by Syracuse Research
Corporation under EPA Contract No. 68-03-3228. The document was subse-
quently revised after reviews by staff within the Office of Health and
Environmental Assessment: Carcinogen Assessment Group, Reproductive Effects
Assessment Group, Exposure Assessment Group, and the Environmental Criteria
and Assessment Office In Cincinnati.
The HEEPs will become part of the EPA RCRA and CERCLA dockets.
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EXECUTIVE SUMMARY
The literature was broadly searched for Information pertaining to alkyl
and aryl phthalate esters. The only compounds for which appropriate
toxlcologlcal data were located Include d1(2-ethylhexylJphthalate, dlethyl
phthalate, d1-n-butyl phthalate, dimethyl phthalate, d1-n-octyl phthalate,
n-butylbenzyl phthalate and d11sononyl phthalate.
Alkyl and aryl phthalates are generally colorless and odorless compounds
(CEH, 1975). Most alkyl phthalates are liquids at ambient temperature. In
general, the phthalate esters are poorly soluble In water but soluble In
most organic solvents, Including acetone, benzene and ether (Hawley, 1981).
Phthalate plastldzers can undergo oxidation during plastic processing;
antloxldants are added to resins to Inhibit this reaction.
The alkyl and aryl phthalates are produced by reacting phthallc anhy-
dride with an excess amount of the corresponding alcohol(s) 1n the presence
of an esterlfIcatlon catalyst. The commercial products are usually >99%
pure {U.S. EPA, 1978b). Sixteen U.S. manufacturers produce one or more of
the 17 selected phthallc acid esters. Reported production figures and esti-
mated production volumes were available for each of the alkyl phthalates.
Total U.S. production volume of phthallc add esters amounted to 1179
million pounds 1n 1984 (USITC, 1985). Alkyl and aryl phthalates are used
predominantly as plastldzers for polyvlnyl chloride resins (U.S. EPA,
1978a,b). To a lesser extent, they are used as plastldzers for other vinyl
resins, cellulose ester plastics, synthetic elastomers and other polymers.
End-uses Include construction, home furnishing, consumer goods, packaging,
electrical uses, transportation, medical products and others (U.S. EPA,
1978a,b). Some alkyl esters have minor applications as dielectric fluid
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[d1(2-ethylhexyl)phthalate], active Ingredients 1n pesticides, resin
solvents, perfume fixatives, solvents and other uses (Hawley, 1981; U.S.
EPA, 1979).
Hydrolysis Is not expected to be a significant removal mechanism of
phthalate esters (Suffet et al., 1981). Mabey et al. (1981) estimated that
phthalate esters will not undergo significant oxidation In water. UV
absorption spectra for some phthalates Indicate that potential exists for
direct photolysis 1n the environment. The photolysis half-life of n-butyl
benzyl phthalate has been observed to be >100 days (Gledhlll et al., 1980).
Phthalate esters are reported to be metabolized 1n the aquatic environment
by a variety of pure microorganisms and degraded by mixed mlcroblal systems.
The mlcroblal degradation rates vary widely depending upon environmental
conditions such as temperature, pH, amount of oxygen present and the phtha-
late structure (HattoM et al., 1975). BlodegradablHty of phthalates In
freshwater decreases with Increasing size and complexity of the phthalate
ester chains (Hattorl et al., 1975; Johnson et al., 1984).
Results from river die-away tests and activated sludge studies Indicate
that phthalates, as a class, undergo rapid degradation by bacteria commonly
found In the environment (Saeger and Tucker, 1973a,b, 1976; Gledhlll et al.,
1980). For example, 1n a simulated lake microcosm Gledhlll et al. (1980)
observed >95X primary degradation of the complex ester n-butyl benzyl phtha-
late 1n 7 days. Under anaerobic conditions, blodegradatlon of short-chain
alkyl esters has been shown to be possible, but slower than under aerobic
conditions, while degradation of the long-chain esters has been shown to be
very slight or undetectable (Johnson et al., 1984; Johnson and Lulves, 1975;
Horowitz et al., 1982; Shelton et al., 1984). From the estimated Henry's
Law Constants for n-butyl benzyl, d1-n-butyl, d1(2-ethylhexyl), dlethyl,
dimethyl and d1-n-octyl phthalates, phthalate esters are predicted to not
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significantly volatilize from water (Lyman et al., 1982). D1-n-octyl phtha-
late may significantly volatilize from shallow rivers, although volatiliza-
tion from deeper waters should not be significant (Lyman et al., 1982). In
sea water, adsorption onto clay minerals and calclte appears to be a revers-
ible process, whereas adsorption onto sediments Is Irreversible (Sullivan et
al., 1982). This suggests that marine sediments may act as a final reposi-
tory of phthallc acid esters (Sullivan et al., 1982). Calculated sediment-
water partitioning coefficients Indicate adsorption Is likely for all phtha-
late esters, with adsorption tendency Increasing with the size and complex-
ity of the ester chain (Mabey et al., 1981). Complexatlon with the widely
occurring humlc and fulvlc substances causes solubH1zat1on of phthalate
esters In water, thus modifying their mobility (Hatsuda and Schnltzer,
1971). Phthalates have been Identified In living matter, and data collected
from field and laboratory studies Indicate that these compounds can bloaccu-
mulate 1n aquatic organisms (Callahan et al., 1979a).
In air, the phthalate esters, as a class, are predicted to react with
hydroxyl radicals, with a t of <1 day (U.S. EPA, 1986a). The actual
atmospheric t, ?, however, may be longer than the estimated values because
of adsorption onto airborne partlculate matter. Removal of atmospheric
phthalate by wet and dry deposition has also been observed (Kawamura and
Kaplan, 1983; Atlas and G1am, 1981; Karasek et al., 1978; Weschler, 1984).
Significant hydrolysis of phthalate esters 1n wet soils Is unlikely
(Wolfe et al., 1980; Gledhlll et al., 1980). Shanker et al. (1985) observed
mlcroblal degradation of d1-n-butyl, d1(2-ethylhexyl) and dimethyl phtha-
lates 1n garden soil. Results Indicate that soil mlcroflora significantly
degrade phthalates under aerobic conditions, and short-chain phthalates
degrade at a faster rate than the longer chain phthalates. The anaerobic
degradation of phthates was very slow compared with aerobic blodegradatlon.
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The water solubilities and K values of the phthalates suggest that
adsorption to soils 1s dependent on the size and complexity of phthalate
ester chains. Dimethyl phthalate should be reasonably mobile In soils,
whereas large or branched chain esters, Including dlphenyl phthalate, should
remain strongly adsorbed to soils. The mobility of phthalate esters 1n the
presence of fulvlc add should Increase. Since dimethyl phthalate 1s not
likely to adsorb to soils, volatilization from dry soil surfaces may be a
potential removal mechanism. Volatilization should be Insignificant for
other phthalates.
Phthalate esters are ubiquitous In the environment, they have been
Identified In surface waters In the United States and elsewhere 1n the
world. The maximum reported concentration of d1(2-ethylhexyl) phthalate 1n
any surface water was 600 ug/l, which was detected In Mississippi River
water (Corcoran, 1973). The average concentration of Individual phthalate
esters 1n surface water 1s <1 vq/i (Michael et al., 1984). Phthalate
esters have also been Identified 1n groundwater from contaminated sites; a
maximum of 100 yg/l of d1(2-ethylhexyl) phthalate was detected \n
groundwater from a landfill site In New Castle County, DE (DeWalle and
Chlan, 1981). Several phthalate esters have been Identified In drinking
water abstracted both from surface water and groundwater. The maximum
concentrations of dlethyl, d1-n-butyl, d1(2-ethylhexyl) and butyl benzyl
phthalates 1n 39 public water wells were reported to 4.6, 470, 170 and 38
vig/1, respectively (CEQ, 1980; 1981; Burmaster, 1982). The Science
Advisory Board of the U.S. EPA reviewed selected organic chemicals and
estimated that the distribution of the phthalate esters 1s -50% In U.S.
drinking waters, with an overall phthalate concentration of ~1 yg/5.
(U.S. EPA, 1978c). On the basis of these data and an average consumption
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rate of 2 I/day, dally phthalate exposure to a U.S. Individual from
Ingesting drinking water 1s estimated to be 2 pg.
Phthalate esters have been detected In ambient atmosphere. Probably the
biggest contributor to atmospheric phthalate 1s the Incineration of plastics
that contain the esters (Peakall, 1975). The concentrations of d1-n-butyl
and d1(2-ethylhexyl) phthalate 1n New York City's ambient air were 4.2
mg/m3 and 13.7 ng/m3, respectively (Bove et al.. 1978). In College
Station, TX, the corresponding values were reported to be 3.8 and 2.4
ng/m3 (Atlas and Glam, 1981). Until more air monitoring data become
available, 1t Is not possible to provide an average urban and rural levels
of phthalate esters. Consequently, Inhalation exposure of phthalate esters
to the U.S. population residing In urban, suburban and rural areas cannot be
estimated. Maximum exposure to phthalate esters 1s likely to occur under
occupational conditions. Concentrations of phthalate esters ranged from
1.7-40 mg/m3 1n a mixing area and from 10-66 mg/m3 In another area of a
company manufacturing artificial leather and films of PVC (U.S. EPA, 1980b).
NIOSH (1985) estimates that -2,406,700 workers are annually exposed to
dlethyl, d1-n-butyl and d1(2-ethylhexyl) phthalate In the United States.
Several authors have Identified phthalate esters In foods. D1(2-ethyl-
hexyl) phthalate was detected at a concentration of 6.50 mg/kg 1n mackerel
fillets (Muslal et al., 1981). The concentration of dl-n-butyl phthalate In
rainbow trout from the Great Lakes was reported to be 8.1 mg/kg (Glass et
al., 1977). In butter samples obtained from Japan, the concentration of
d1-n-butylphthalate was 4-11 mg/kg (Horlta et al., 1973). Instant vegetable
cream soup obtained from a Japanese market contained 6.35 mg/kg of
d1-n-butyl phthalate (Tomlta et al., 1977). No estimate of phthalate ester
exposure from food composites typically consumed by an Individual In the
United States 1s known.
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Phthalate esters can be absorbed through the skin during the use of many
cosmeUc products, Insect repellants and the water from PVC-Hned swimming
pools (U.S. EPA, 1980a). A special segment of the population 1s exposed to
phthalate esters during medical/surgical procedures, such as hemodlalysls
and Intravenous applications. No estimates on the dermal exposure of
phthalate esters to Individuals can be made from the data available In the
literature.
It Is difficult to draw conclusions about the relative toxkHy of
phthallc add esters to aquatic biota because of the larqe variability In
toxldty of each ester to different species. It Is also difficult to pick
out those species most sensitive to phthalates; however, Table 6-10 contains
the most and least sensitive species and toxic concentrations reported for
each ester. All of the esters listed 1n Table 6-10 caused toxic effects at
<3.2 mg/a,. The lowest concentration reported to cause toxic effects was
0.003 mg/1 dl(2-ethylhexyl) phthalate, which caused decreased production
of offspring by Daphnla magna (Mayer and Sanders, 1973).
Although there were large differences In species sensitivity among ma'jor
taxonomlc groups, none of these groups except bacteria were especially more
or less sensitive than other groups. Bacteria were clearly less sensitive
than other organisms to d1-n-butyl, dlallyl, dlethyl and dimethyl phthalates
(Sugatt and Foote, 1981). The available Information concerning freshwater
and saltwater species Indicated no difference 1n phthalate ester toxldty
between freshwater and saltwater environments.
Many Investigators have reported toxic effects of phthalates at concen-
trations greater than their aqueous solubility; however, the data Indicate
that all of the phthalates except dlhexyl, dlnonyl, d1-n-decyl and dllso-
decyl phthlates were toxic to at least one species at concentrations near or
below their solubility (Sugatt and Foote, 1981).
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Information concerning residues of phthallc add esters In aquatic biota
suggests that accumulation Is determined primarily by the degree to which
species can metabolize and eliminate them (Soedergren, 1982). F1sh gener-
ally have a well-developed mechanism In this regard and therefore do not
accumulate phthalates to a great extent.
Oral studies show that d1(2-ethylhexyl) phthalate, d1-n-butyl phthalate,
and d11sooctyl phthalate are absorbed from the gastrointestinal tract
(Williams and Blanchfleld, 1974, 1975; Daniel and Bratt, 1974; Ikeda et al.,
1978. 1980; Tanaka et al., 1978; Pollack et al., 1985a; Olshl and Hlraga,
1982; Telrlynck and Belpalre, 1985; Schmld and Schlatter, 1985). Pollack et
al. (1985a) demonstrated that uptake of IntraperHoneally administered d1(2-
ethylhexyl) phthalate Into the blood 1s poor In rats. Orally administered
phthallc add esters are primarily and largely converted to their monoester
derivatives by enzymes 1n the gastrointestinal tract before absorption
(Albro and Thomas, 1973; Rowland, 1974; Rowland et al., 1977; Lake et al.,
1977b; Carter et al., 1974; White et al., 1980; Pollack et al.. 1985a;
Telrlynck and Belpalre, 1985; Olshl and HUoga, 1982). Other tissues such
as the liver have also been shown to hydrolyze phthallc add esters (Carter
et al., 1974). In contrast, Intraperltoneally administered d1(2-ethylhexyl)
phthalate 1s taken up primarily as d1(2-ethylhexyl) phthalate, with only 1%
hydrolyzed to monoethylhexyl phthalate (Pollack et al., 1985a).
Oral and Intravenous studies Indicate that d1(2-ethylhexyl) phthalate,
d1-n-butyl phthalate and d11sooctyl phthalate are not retained for long 1n
the body (Tanaka et al., 1975, 1978; Williams and Blanchfleld, 1974, 1975;
Daniel and Bratt, 1974; 01sh1 and Hlraga, 1982; Telrlynck and Belpalre,
1985; Ikeda et al., 1978, 1980). In general, phthallc add esters and
metabolites distribute primarily to liver, kidneys, fat and the gastro-
intestinal tract. Metabolites have been found In almost every tissue; 1n
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particular a high concentration of monoethylhexyl phthalate, the hydrolytlc
derivative of d1(2-ethylhexy1) phthalate, has been observed In the testes of
rats (01sh1 and Hlraga, 1982). The distribution of d1(2-ethylhexyl) phtha-
late and metabolites In various tissues, particularly liver, kidneys and
fat, has been observed to vary with route of administration (diet, gavage,
parenteral), vehicle and dose (Thomas and Thomas, 1984; Pollack et al.,
1985a; Albro et al., 1982). In a dietary study on rats, radioactivity from
i«C-d1(2-ethy1hexy1) phthalate In the liver and fat declined with half-
lives of 1-2 and 3-5 days, respectively (Daniel and Bratt, 1974). In gavage
studies (Olshl and Hlraga, 1982), the disappearance of d1(2-ethylhexyl)
phthalate from tissues It.,,- ranging from 1.49-156 hours) was more rapid
than for that of monoethylhexyl phthalate (t, ._ ranging from 22.6-68
hours).
Although short-chain phthallc acid dlesters such as dimethyl phthalate
can be excreted unchanged 1n the urine, most phthallc add dlesters are
further metabolized before excretion. The first step of metabolism entails
hydrolysis of the parent compound to a monoester derivative. Once formed,
the monoester derivative can then be further hydrolyzed to phthallc add and
excreted, conjugated with glucuronlde then excreted, or oxidized and
excreted. The first alternative occurs primarily with short-chain phthallc
add esters (Albro and Thomas, 1973; Albro and Moore, 1974; Albro et al.,
1973). The second alternative Is the primary route of metabolism for
d1(2-ethylhexyl) phthalate and occurs 1n all spedes except the rat (Albro
et al., 1973, 1981, 1982; Kluwe, 1982a,b; Peck et al., 1978; Teirlynck and
Belpalre, 1985; Schmld and Schlatter, 1985; Williams and Blanchfleld, 1975;
Daniel and Bratt. 1974; Chu et al., 1981; Tanaka et al., 1975; Thomas and
Thomas, 1984); however, glucuronlde conjugates of d1-n-butyl phthalate have
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been observed 1n rats (Tanaka et a!., 1978; Foster et al., 1982; Kaneshlma
et al., 1978). The third route of metabolism has been observed In rats,
guinea pigs and hamsters (Williams and Blanchfleld, 1974, 1975; Tanaka et
al., 1978; Daniel and Bratt, 1974; Chu et al., 1981; Shuguenot et al.,
1975). The metabolism of phthallc add esters Is not qualitatively affected
by route of exposure (Kluwe, 1982).
Excretion of d11sooctyl phthalate, d1-n-butyl phthalate and d1(2-ethyl-
hexyl) phthalates has been studied (Ikeda et al., 1978, 1980; Schmld and
Schlatter, 1985; Telrlynck and Belpalre, 1985; Williams and Blanchfleld,
1974, 1975; Daniel and Bratt, 1974; Kaneshlma et al., 1978; Tanaka et al.,
19-75, 1978). These compounds and their metabolites are excreted 1n urine,
bile and feces; the relative Importance of the route of excretion depends
upon the compound and species, while the rate of excretion appears to be
rapid. Half-lives of 7.9 and 12 hours were reported for urinary excretion
of d1(2-ethylhexyl) phthalate 1n humans and rats, respectively (Schmld and
Shlatter, 1985"; Telrlynck and Belpalre, 1985). PharmacoklneMc data on aryl
or aryl/alkyl pthalates could not be located 1n the available literature as
cited 1n the Appendix.
D1(2-ethylhexyl) and n-butyl benzyl phthalates have been tested for
carcinogenic potential 1n feeding studies with F344 rats and B6C3F1 mice.
D1(2-ethylhexyl) phthalate was found to cause Increased Incidences of liver
neoplasms 1n both rats and mice (NTP, 1982b; Kluwe et al., 1982b). Using
EPA's we1ght-of-ev1dence classification system, this Is a group B2 chemical
meaning there 1s sufficient evidence In animals and thus DEHP 1s probably
carcinogenic 1n humans. n-Butyl benzyl phthalate caused an Increase 1n
myelomonocytlc leukemia In female F344 rats (NTP, 1982a). Because of high
background Incidence of myelomonocytlc leukemia In F344 rats and because
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dose-related and significant decreases 1n malignant lymphoma, all lymphoma,
and leukemia or lymphoma were observed In male B6C3F1 mice (NTP, 1982a),
there Is only limited evidence to conclude that n-butyl benzyl phthalate Is
carcinogenic. The EPA weight of evidence category Is group C, meaning that
the compound Is considered a possible human carcinogen.
The mutagenldty and genotoxIcHy of phthaUc acid esters have been
reviewed by Thomas and Thomas (1984) and Hopkins (1983). D1(2-ethylhexyl)
phthalate and metabolites have yielded mostly negative results In Ames tests
with ^. typhlmur 1um. and mixed results with J_n v1 tro and J_n y1 vo tests of
genotoxIcHy. Dlethyl phthalate, dimethyl phthalate, and dl-n-butyl phtha-
late were found to be mutagenlc 1n J_n vitro mlcroblal assays with S. typhl-
mur 1 urn (Kozumbo et al., 1982; Rubin et al., 1979; Seed, 1982).
Oral studies have shown that d1(2-ethylhexyl) phthalate, dl-n-butyl
phthalate, and d1-n-heptyl phthalate can produce adverse effects upon the
developing fetus when mice and rats are exposed during gestation (Wolkowskl-
Tyl, 1984a,b; Bell et al., 1979; Bell, 1980; Shlota and Mima, 1985; Shlota
and Nlshlmura, 1982; Shlota et al., 1980; Nakamura et al., 1979; Yagl et
al., 1978, 1980; TomHa et al., 1982b; Onda et al., 1974). Whether the
observed effects (reduced fetal weight, fetal mortality, gross external and
skeletal malformations) represent a primary effect of the compound In
question or whether they occur as a result of maternal toxkKy has yet to
be demonstrated unequivocally. Studies conducted by NTP (Wolkowskl-Tyl et
al., 1984a,b) Indicate that mice are more sensitive than rats.
NTP has recently conducted reproduction and fertility assessments on
CD-I mice for dlethyl phthalate (Reel et al., 1984) and dl-n-octyl phthalate
(Gulatl et al., 1985). Dietary d1-n-octyl phthalate had no effects on
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reproduction and fertility among parental or F-j mice. Dietary dlethyl
phthalate had no effects on reproduction and fertility In parental mice, but
dlethyl phthalate-exposed F mice had fewer pups/Utter than did controls,
as well as Increased liver weights (males and females). Increased prostate
weights, Increased pituitary weights (females only) and decreased sperm
concentrations. Booth et al. (1983) and Plasterer et al. (1985) reported
that dimethyl phthalate had no effects on reproduction In CD-I mice.
Dimethyl phthalate was administered by gavage on days 7-15 of gestation.
The fertility of Sherman rats was not affected by dietary administration of
dl(2-ethylhexyl) phthalate (up to 0.4%) for 1-2 years (Carpenter et al.,
1953).
Orally administered dl (2-ethylhexyl), d1-n-butyl, n-butyl benzyl,
d1-n-pentyl, dllsobutyl and dl-n-heptyl phthalates have been shown to cause
testlcular atrophy In rats to mice (Gray et al., 1977, 1982; Shaffer et al.,
1945; Gangolll, 1982; Olshl and Hlraga, 1980a, 1983; Gray and Butterworth,
1980; Mangham et al., 1981; Olshl, 1985; Agarwal et al., 1985; Foster et
al., 1980). D1-n-octyl, dimethyl, dlethyl, dlpropyl and dl-n-heptyl phtha-
lates did not cause testlcular atrophy In rats (Gray and Butterworth, 1980;
Foster et al., 1980). Species differences In phthalTc add ester-promoted
testlcular atrophy have been observed. Gray et al. (1982) failed to observe
testlcular atrophy 1n hamsters gavaged with d1-n-butyl, d1-(2-ethylhexyl)
and dl-n-pentyl phthalates at doses equlmolar to those that caused atrophy
In rats. In the same study, mice gavaged with equlmolar doses of
dl-n-butyl, d1(2-ethylhexyl) and dl-n-pentyl phthalates had only slight
focal atrophy.
Chronic or subchronlc oral studies have been conducted with d1(2-ethyl-
hexyl), d1-n-butyl, dimethyl, dUsononyl, n-butyl benzyl and d1-n-octyl
phthalates (Carpenter et al., 1953; Harris et al., 1955; Nlkonorow et al.,
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1973; Gray et al., 1977; Gangolll, 1982; NTP, 1982a,b; Kluwe et al., 1982b;
Shaffer et al., 1945; Popp et al., 1985; Canning et al., 1985; Nagasaki et
al., 1974; Ota et al., 1974; Lake et al., 1976, 1977a; Haslenko, 1968; Food
Research Laboratories, 1955; Brown et al., 1978; Smith, 1953; Lefaux, 1968;
Plekacz, 1971; LeBreton, n.d.; Bornmann et al., 1956; Lehman, 1955; Living-
ston, 1971; Monsanto, 1972; Plekacz, 1971). Liver, kidneys and testes
appear to be target organs. Occupational exposure to phthalate esters has
been associated w1h polyneuropathy (Mllkov et al., 1973; GlUoll et al.,
1978).
Acute oral LO s have been reported for d1(2-ethylhexyl), dimethyl,
d1-n-butyl, dlethyl, n-butyl benzyl, d1-n-octyl, dlhexyl, dlnonyl and
dldecyl phthalates. These values are summarized In Table 5-11.
An Interim q * of 8.36xlO"3 (mg/kg/day)~1 was derived for
d1(2-ethylhexyl) phthalate based on the Incidence of hepatocellular
carcinoma or adenoma In male mice In the NTP (1982b) study. This value Is
considered Interim pending additional analysis of potential 1nterspec1es
differences In metabolism. The concentrations 1n water associated with risk
levels of 10"s, 10~* and 10"7 are 4.19xlO"2, 4.19xlO~3 and
4.19x10"* mg/i, assuming that a 70 kg human consumes 2 l/day.
Additional metabolic factors need to be considered before a value 1s
proposed.
The RfD of 0.75 mg/kg/day (52.5 mg/day) was derived for dlethyl
phthalate, based on a subchronlc oral rat NOEL of 159 mg/kg/day In the study
by Brown et al. (1978) and using an uncertainty factor of 1000. An RfD of
0.13 mg/kg/day (8.75 mg/day) for d1-n-butyl phthalate 1s derived based on a
52-week oral rat NOAEL of 125 mg/kg/day In the study by Smith (1953) and
using an uncertainty factor of 1000. The U.S. EPA (1980b) derived an RfD of
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10 mg/kg/day (700 mg/day) for dimethyl phthalate based on a chronic rat
NOAEL of 1000 mg/kg/day In the study by Lehman (1955) using an uncertainty
factor of 100. A revaluation of the Lehman (1955) study suggests that the
data, as presented In this paper are Inadequate for development of an RfD.
An RfD was not derived for d1-n-octyl phthalate based on Inadequate
data. An RfD of 0.16 mg/kg/day (11.1 mg/day) could be derived for n-butyl
benzyl phthalate based on a subchronlc rat NOEL of 159 mg/kg/day In the NTP
(1985) study. However, this RfD would not be protective for potential
carcinogenic effects of butyl benzyl phthalate.
CSs were calculated for dl(2-ethylhexyl) phthalate, dlethyl phthalate,
dl-n-butyl phthalate, dimethyl phthalate, d1-n-octyl phthalate, n-butyl
benzyl phthalate and d11sononyl phthalate (Table 9-7). In each case, the
data that resulted 1n the highest CS, are recommended as the basis for the
RQs (Tables 9-8 to 9-14). The RQ for each of the phthalate esters listed
are >1000. Data were not sufficient for deriving an RQ for the other
phthalate esters discussed 1n this document.
An F factor of 5.14xlO~2 (mg/kg/day)"1 was calculated for d1(2-
ethylhexyl) phthalate, placing this chemical In Potency Group 3. Because
the evidence for cardnogenldty 1n animals was sufficient, d1 (2-ethylhexyl)
phthalate 1s placed 1n EPA Group B2. An EPA Group B2 chemical In Potency
Group 3 has a low hazard ranking under CERCLA. The evidence for
cardnogenldty of n-butyl benzyl phthalate 1n the NTP (1982a) study was
limited, Implying an EPA Group C classification, possible human carcinogen,
while no data regarding the cardnogenldty of other phthalate esters were
available; therefore, these chemicals are placed In EPA Group D.
xv1
-------
TABLE OF CONTENTS
Page
1. INTRODUCTION 1-1
1.1. STRUCTURE AND CAS NUMBER 1-1
1.2. CHEMICAL AND PHYSICAL PROPERTIES 1-1
1.3. PRODUCTION DATA 1-1
1.4. USE DATA 1-8
1.5. SUMMARY 1-13
2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES 2-1
2.1. WATER 2-1
2.1.1. Hydrolysis 2-1
2.1.2. Oxidation 2-1
2.1.3. Photolysis 2-2
2.1.4. Mlcroblal Degradation 2-2
2.1.5. Volatilization 2-6
2.1.6. Adsorption 2-6
2.1.7. B1oaccumulat1on 2-8
2.2. AIR 2-8
2.2.1. Chemical Degradation 2-8
2.2.2. Physical Removal 2-8
2.3. SOIL 2-9
2.3.1. Chemical Degradation. ' 2-9
2.3.2. Mlcroblal Degradation 2-9
2.3.3. Volatilization 2-11
2.3.4. Adsorption 2-11
2.4. SUMMARY 2-12
3. EXPOSURE 3-1
3.1. WATER 3-1
3.2. AIR 3-11
3.3. FOOD 3-15
3.4. DERMAL 3-15
3.5. SUMMARY 3-18
4. PHARMACOKINETCS 4-1
4.1. ABSORPTION 4-1
4.2. DISTRIBUTION 4-4
4.3. METABOLISM 4-7
4.4. EXCRETION 4-8
4.5. SUMMARY 4-11
xv11
-------
TABLE OF CONTENTS (cont.)
5. EFFECTS 5-1
5.1. CARCINOGEN1CITY 5-1
5.1.1. n-Butyl Benzyl Phthalate 5-1
5.1.2. D1-2(ethylhexyl) Phthalates 5-5
5.2. MUTAGENICITY 5-9
5.3. TERATOGENICITY 5-12
5.4. OTHER REPRODUCTIVE EFFECTS 5-18
5.5. CHRONIC AND SUBCHRONIC TOXICITY 5-24
5.5.1. D1-2(ethylhexyl) Phthalates 5-24
5.5.2. Olethyl Phthalate 5-29
5.5.3. Dl-n-butyl Phthalate 5-32
5.5.4. Dimethyl Phthalate 5-32
5.5.5. Dllsononyl Phthalate 5-36
5.5.6. n-8utyl Benzyl Phthalate 5-36
5.5.7. D1-n-octyl Phthalate 5-^
5.5.8. Human Studies 5-3^
5.6. OTHER RELEVANT INFORMATION 5-"3S
5.7. SUMMARY 5-40
6. AQUATIC TOXICITY 6-1
6.1. ACUTE 6-1
6.2. CHRONIC 6-12
6.3. PLANTS 6-15
6.4. RESIDUES 6-15
6.5. SUMMARY 6-24
7. EXISTING GUIDELINES AND STANDARDS 7-1
7.1. HUMAN 7-1
7.2. AQUATIC 7-1
8. RISK ASSESSMENT 8-1
8.1. DI(2-ETHYLHEXYL) PHTHALATE 8-1
8.2. DIETHYL PHTHALATE 8-7
8.3. DI-n-BUTYL PHTHALATE 8-7
8.4. DIMETHYL PHTHALATE 8-9
8.5. DI-n-OCTYL PHTHALATE 8-9
8.6. n-BUTYL BENZYL PHTHALATE 8-10
8.7. DIISONONYL PHTHALATE 8-11
8.8. SUMMARY 8-12
XV111
-------
TABLE OF CONTENTS (cont.
9. REPORTABLE QUANTITIES 9-1
9.1. REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC
TOXICITY 9-1
9.1.1. D1(2-ethylhexyl) Phthalate 9-1
9.1.2. Dlethyl Phthalate 9-2
9.1.3. 01-n-butyl Phthalate 9-3
9.1.4. Dimethyl Phthalate 9-5
9.1.5. Dl-n-octyl Phthalate 9-5
9.1.6. n-Butyl Benzyl Phthalate 9-6
9.1.7. Dllsononyl Phthalate 9-6
9.1.8. 01-n-heptyl Phthalate 9-7
9.1.9. Summary 9-7
9.2. HEIGHT OF EVIDENCE AND POTENCY FACTOR (F=1/E010)
FOR CARCINOGENICITY 9-16
9.2.1. DM2-ethylhexyl) Phthalate 9-16
9.2.2. n-Butyl Benzyl Phthalate 9-t*
9.2.3. Other Phthalate Esters 9-19
10. REFERENCES 10-1
APPENDIX: LITERATURE SEARCHED A-l
x1x
-------
LIST OF TABLES
No. Title Page
1-1 General Information on Selected Dlalkyl Phthalates 1-2
1-2 Chemical and Physical Properties 1-6
1-3 Manufacturers of Alky! and Aryl Pthtalates 1n the
United States 1-9
1-4 Annual United States Production Volume of Alkyl and
Aryl Phthalates 1-11
2-1 Blodegradatlon Screening of Some Alkyl and Aryl
Phthalates 2-4
2-2 Blodegradatlon of Phthalates In Garden Soil 2-10
3-1 Concentrations of n-Butyl Benzyl Phthalate 1n United
States Haters Near Industrial Sites 3-5
3-2 Median Concentration of Phthalate Esters 1n Industrial
Effluents and Ambient Water 1n the United States
Compiled from STORET Stations 3-8
3-3 Concentrations of Commonly Reported Phthalate Esters
Detected In Drinking Waters 1n the United States 3-9
3-4 Percentage Occurrence of Phthalates by Water Source 3-10
3-5 Atmospheric Levels of a Few Phthalate Esters Measured
Throughout the World 3-13
3-6 Concentrations of Phthalate Esters 1n Some Foods 3-16
4-1 Biological Half-Lives of 01{2-ethylhexyl) Phthalate and
Monoethylhexyl Phthalate In Rats After a Single Oral
Dose of 01 (2-ethylhexyl) Phthalate 4-6
4-2 Excretion of Phthallc Add Esters 4-10
5-1 Inadequate Cancer Studies 5-2
5-2 Hematopoletlc Neoplasms In F344/N Rats and B6C3F1 Mice
Fed n-Butyl Benzyl Phthalate In the Diet for 103 Weeks. ... 5-4
5-3 Liver Neoplasms 1n F344/N Rats and B6C3F1 Mice Fed
D1(2-ethy1hexyl) Phthalate 1n the Diet for 103 Weeks 5-6
5-4 Summary of Oral TeratogenlcHy Studies with D1(2-ethyl-
hexyl) Phthalate 5-14
xx
-------
LIST OF TABLES (cont.)
No. Title Page
5-5 Summary of Oral Teratogenld ty Studies for Phthallc
Add Esters Other than D1 (2-ethylhexyl) Phthalate 5-17
5-6 Orally Administered Phthalate Esters Causing Testlcular
Atrophy \n Rats 5-21
5-7 Oral ToxkHy Summary for D1(2-ethylhexyl) Phthalate 5-25
5-8 Oral ToxkHy Summary for Dlethyl Phthalate 5-30
5-9 Oral ToxkHy Summary for D1-n-butyl Phthalate 5-33
5-10 Oral ToxkHy Summary for Miscellaneous Phthalate Esters. . . 5-34
5-11 Acute Oral ToxkUy of Phthalate Esters 5-33'
6-1 Acute ToxkHy of Phthallc Acid Esters to Aquatic
Vertebrates 6-2
6-2 Acute ToxkHy of Phthalk Add Esters to Aquatic
Invertebrates 6-7
6-3 Range of Acute LC50 and EC50 Values for Phthalate Esters. . . 6-11
6-4 Chronic ToxkHy of Phthalk Add Esters to Aquatic
Vertebrates 6-13
6-5 Chronk ToxkHy of Phthalk Add Esters to Aquatk
Invertebrates 6-14
6-6 Acute ToxkHy of Phthalate Esters to Aquatic Plants
and Bacteria 6-16
6-7 Data from Uptake and Elimination Studies with Phthalk
Add Esters In Aquatk Biota 6-19
6-8 Data from Model Ecosystem Studies Concerning Phthalate
Residues 6-22
6-9 MonHoMng Data for Phthalk Add Esters In Aquatk
Organisms 6-23
6-10 Range of Spedes Sensitivity for Algae, Invertebrates
and Vertebrates to Phthalate Esters 6-26
7-1 Existing AOIs/RfOs for Phthalk Add Esters 7-2
8-1 Cancer Data Sheet for Derivation of q-|* 8-3
8-2 Cancer Data Sheet for Derivation of q^* 8-4
xxl
-------
LIST OF TABLES (cont.)
No. Title Page
8-3 Cancer Data Sheet for Derivation of q-j* 8-5
8-4 Cancer Data Sheet for Derivation of q-]* 8-6
9-1 Summary of RQs Derived for Phthallc Add Esters 9-8
9-2 D1(2-ethylhexyl) Phthalate: Minimum Effective Dose (MED)
and Reportable Quantity (RQ) 9-9
9-3 Dlethyl Phthalate: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 9-10
9.4 D1-n-butyl Phthalate: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 9-11
9-5 Dimethyl Phthalate: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 9-12
9_6 Dl-n-octyl Phthalate: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 9-13
9-7 n-Butyl Benzyl Phthalate: Minimum Effective Dose (MED)
and Reportable Quantity (RQ) 9-14
9-8 Dllsononyl Phthalate: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 9-15
9-9 Derivation of Potency Factor (F). Agent: D1(2-ethyl-
hexyl) Phthalate 9-18
xx11
-------
LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AP Add phosphatase
ADC Area under curve
B8P n-Butyl benzyl phthalate
BCF B1oconcentrat1on factor
BOD Biological oxygen demand
bw Body weight
CAS Chemical Abstract Service
CHO Chinese hamster ovary
CS Composite score
DAP Olallyl phthalate
DBP 01-n-butyl phthalate
DEHP D1(2-ethylhexyl) phthalate
DEP Olethyl phthalate
DHP Olhexyl phthalate
DHeP Dlheptyl phthalate
OIBP Dllsobutyl phthalate
DIDP (D1DP) Dllsodecyl phthalate
DINP Dllsononyl phthalate
DIOP (D10P) D11sooctyl phthalate
DMP Dimethyl phthalate
DMSO Dimethyl sulfoxlde
DNA Deoxyr1bonucle1c acid
DNP Dlnonyl phthalate
OOP D1-n-octyl phthalate
DPep D1-n-pentyl phthalate
XX111
-------
LIST OF ABBREVIATIONS (cont.)
OUP Dlundecyl phthalate
ECso Concentration effective to 50% of recipients
PEL Frank-effect level
Koc Soil sorptlon coefficient
Kow Octanol/water partition coefficient
LCso Concentration lethal to 50% of recipients
1050 Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
MEHP Monoethylhexyl phthalate
HTO Maximum tolerated dose
NOAEL No-observed-adverse-effect level
NOEC No-observed-effect concentration
NOEL No-observed-effect level
ppm Parts per mil Hon
ppt Parts per thousand
PVC Polyvlnyl chloride
RQ Reportable quantity
RV(j Dose-rating value
RVe Effect-rating value
SCE Sister chromatld exchange
SGOT Serum glutamlc oxaloacetlc transamlnase
SGPT Serum glutamlc pyruvlc transamlnase
SS Saturated solution
TWA Time-weighted average
UV Ultraviolet
HS Hater solubility
xxlv
-------
1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
The synonyms, CAS number, structure, empirical formula and molecular
weight for each of the phthallc add alkyl and aryl esters discussed In this
report are presented In Table 1-1.
1.2. CHEMICAL AND PHYSICAL PROPERTIES
Alkyl and aryl phthalates are generally colorless and substantially
odorless compounds (CEH, 1975). Most alkyl phthalates are liquids at
ambient temperature. In general, the phthalate esters are poorly soluble 1n
water but soluble 1n most organic solvents Including acetone, benzene and
ether (Hawley, 1981).
Alkyl phthalates undergo the typical reactions of carboxyllc esters, for
example, saponlf1cat1on by strong bases, hydrolysis In the presence of
strong aqueous adds, reduction to alcohols by the action of hydrogen, ester
Interchange and conversion to amides by reaction with ammonia.
Commercially, phthalate plastldzers can undergo oxidation during
plastics processing, forming peroxides which later decompose with develop-
ment of colored and odorous compounds. Ant1ox1dants such as blsphenol A are
added to the resin to Inhibit this reaction (U.S. EPA, 1978b).
Selected physical properties of a few phthalate esters are listed In
Table 1-2. The data on the physical properties of phthalate esters varies
to a great extent from one source to another. The most recent and appar-
ently reasonable values for these parameters are given.
1.3. PRODUCTION DATA
Alkyl and aryl phthalates are formed by reacting phthallc anhydride with
an excess amount of the corresponding alcohol(s) 1n the presence of an
esterlfkatlon catalyst (for example, sulfurlc add or p-toluenesulfonlc
0779p 1-1 06/05/86
-------
TABIF 1-1
General Information on Selected Dlalkyl Phthalates
<£>
•o
i
oj
CAS Number
85-68-7
85-69-8
84-74-2
Chemical Name
n-Butyl benzyl
phthalate
n-Butyl ?-ethyl-
hexyl phthalate
Ot-n-butyl
phthalate
Synonyms*
1.2-benzenedlcarboxyllc
acid, butyl phenylmethyl
ester; BBP; benzyl n-
butyl phthalate
1 .2-benzenedlcarboxyl Ic
acid, butyl 2-ethyl-
hexyl ester
1 ,2-benzenedtcarboxyllc
acid, dlbutyl ester;
Chemical Molecular Structure
Formula Uelqht
C19H?00« 312.37 9,
II
^J:-0-C,N,
(oT /-^
^^^c-o-CMj-^N
0
C20H30°4 334.50 0
II
^v^^C-O-C^Ht
COJL
^^^ C-0-CH,CM(CjH, )C4Mt
II
0
Cl6H22°4 278.35 g
II
84-77-5
117-81-7
o
tn
oo
DBP; n-butyl phthalate
01 -n-decylphthalate
1,2-benrenedlcarboxy 1Ic
acid, dldecyl ester; OOP;
decyl phthalate
C28H46°4
"8.6?
Dl(2-ethylhexyl)
phthalate
1,?-benzenedlcarboxy lie
acid. bls(?-ethyl
hexyl) ester; OfHP;
OOP; dloctyl phthalate;
octyl phthalate
390.57
C-0 CH,CH(C,M,)C4Ht
C-0-CM,CH(C,H$)C«H,
0
-------
TABU 1-1 (cont.)
CAS Number Chemkal Name
0
-o
vD
"° 84-66-2 Dtethyl phthalate
Synonyms*
1 ,2-ben7ened1carboxyl1c
actd, dlethyl ester;
DfP; dlethyl-o-
phenylene-dt acetates
Chemical Molecular Structure
Formula Weight
^^^ C-Q-CjH4
II
0
i
CJ
3648-?! -3
84-75-3
Dlheptyl phthalate
Dlhexyl phthalate
1 ,?-ben?ened\carboxyUc
actd. dlheptyl ester;
heptyl phthaUte; OHeP
1 ,?-benienedtcarboxyl Ic
actd. dlhexyl ester; DHP
C?3H34°4
36?. Sb
C-0-C,H,s
0
C-O-CtH,,
0
o
tn
PO
^H
CO
26761-40-0
285S3-12-3
Dllsodecyl phthalate
Dltsononyl phthalate
1,?-beniened1car boxy 1 tc
actd, dttsodecylester;
D10P
1 ,?-ben?enedlcarboxyl )c
acH. dl Isonony Jester ;
OINP
446.68
418 68
C 0-CH(CM,)CiM,,
C-0-CH(CH,)C»H|7
0
0
II
C-0-CH(CH,)CfM,s
C-0-CH(CH,)C,Hlf
0
-------
TABlf 1-1 (cont.)
CAS Number
Chemical Name
Synonyms'
Chemical
Formula
Molecular
Weight
Structure
o
in
27554-26-3
131-11-3
84-76-4
117-84-0
84-62-8
Dtlsooctyl phthalate
Dimethyl phthalate
Dlnonyl phthalate
Dl-n-octyl phthalate
Olphenyl phthalate
1,2-benzenedtcarboxyllc
acid; DIOP
1,2-benienedlcarboxyllc
acid, dimethyl ester; DNP
1,2-benienedlcarboxylIc
acid, dlnonyl ester; DMP
1 ,?-ben7enedtearboxy 1tc
acid, dl-n-octyl ester;
OOP; DNOP; n-octyl
phthalate
1, 2-benzenedlcarboxylIc
acid, dlphenyl ester;
DPP; phenylphthalate
C?4«38°4
ClOH10°4
C?0HH04
390.62
194.19
418.68
390.6?
318.33
C-0-CM(CM,)C,M|,
C-0-CH(CH,)C,H,,
0
0
II
C-O-CH,
C-O-CH,
0
0
II
C-0 C,H,,
C-0-C,M,,
0
C-O-CiM,,
C-O-C.M,,
0
0
i'-o -
CO
cr>
-------
TABLE 1-1 (cont.)
o
—j
CAS Number
Chemical Name
Synonyms*
Chemical
Formula
Molecular
Height
Struc lure
2119-06-2
OUrldecyl phthalate
1,2-benzenedlcarboKyUc
acid, dltrldecylester;
OIDP
C34"S9°4
S30.9?
3648-20-2
Olundecyl phthalate
1 ,?-benzenedtcarboxyl Ic C30H50°4
acid, dlundecyl ester; DUP
474.80
0
0
C 0-C..H,,
0
*SANSS. 1985
O
tn
03
CT-
-------
TABLE 1-2
Chemical and Physical Properties3
— 1
•o
CAS Number
85-68-7
85-69-8
84-74-2
84-77-5
117-81-7
84-66-2
3648-21-3
84-75-3
26761-40-0
28553-12-3
27554-26-3
131-11-3
84-76-3
§> 117-84-0
O
en
Chemical Name
n-Butyl benzyl
phthalate
n-Butyl 2-ethyl-
hexyl phthalate
Dl-n-butyl
phthalate
Dl-n-decyl
phthalate
01(2-ethyl-
hexyl) phthalate
Dlethyl phthalate
Otheptyl phthalate
01-n-hexyl
phthalate
Dllsodecyl
phthalate
Dl Isononyl
phthalate
Ollsooctyl
phthalate
Dimethyl phthalate
Dlnonyl phthalate
Dl -n-octyl
phthalate
Melting
Point
CC)
-35
-37b
-40
-37C
-46b
-40.5
NA
-33b
-50b
<-50
-46b
0
NA
-25
Bol ling
Point
CC)
370
224
(5 mm Hg)
335
261
(5 mm Hg)
236
(5 ram Hg)
296
NA
210
(5 mm Hg)
250-257
(4 mm Hg)
222-230
(5 mm Hg)
370
283
413
220-240°
(4 mm Hg)
Vapor Pressure
8.6x10"* mm Hg
(20')
NA
1.06x10-* mm Hg
(25-C)
NA
0.62x10'' mm Hg
(25-C)
3.45xlO"« mm Hg
(20-C)
NA
NA
0.3 mm
(200'C)
NA
NA
4.19xlO-'d mm Hg
(20°C)
NA
1.44xlO~-
(25»)
Water Solubility
2.9 mg/l
NA
13 mg/l
(25-C)
0.33 »g/lc
(24-C)
0.29 mg/l (20*C)
0.40 mg/l (25*C)
129 mg/l (20*C)
896 mg/l (25*C)
NA
NA
0.28 n»q/ic
(24-C)
NA
NA
4.32x10* mg/l
(25-C)
3 n>g/i
(25°C)
3.0 mg/l
(25-C)
Log KOH
4.91
7.61
4.72
NA
9.64
2.47
NA
7.74
11.80
10.50
9.64
1.56
10.98
5.22
Specific
Gravity
1.113-1.121
(25/25-C)
0.9941
(25-C)
1.047
(20/4-C)
0.9675
(20/20-C)
0.986
(20/20-C)
1.123
(25/4-C)
NA
1.008
(20°C)
0.966
(20/20'C)
0.982
(25-C)
0.986
(20°C)
1.189
(25/25-C)
0.972
(25-C)
0.978
(20°C)
Refractive
Index
1.535-1.540
(25')
1.4868
(25-C)
1.4915
(25-C)
NA
1.4830-1.4859
(20-C)
1.5002
(25-C)
NA
1.491
(20"C)
1.484
(20°C)
NA
1.484
(20-)
1 . 5 1 38
(25«)
1.4871
(20°C)
1.482
(25°C)
CD
-------
TABLE 1-2 (cont.)
CAS Number
84-62-8
119-06-2
3648-20-2
Chemical Name
Olphenyl phthalate
Dltrldecyl
phthalate
Dtundecyl
phthalate
Melting Boiling
Point Point Vapor Pressure
(•C) CC)
68-70 405*C NA
-37b 240 NA
(2 on Hg)
2e NA NA
Water Solubility
0.082 ng/l
(25'C)
0.34 ng/tc
(24-C)
NA
Specific
Log Kow Gravity
NA 1.28
(20*C)
15.10 0.951
(20/20'C)
13.14 0.954
(25'C)
Refractive
Index
1.572
(74-C)
1.484
(20-C)
1.481
(25-C)
aSources: Agranoff. 1985; Dobbs and Cull. 1982; Claw et al.. 1980; Grayson and Fosbraey. 1982; Hansch and Leo. 1985; Hawley. 1981; 1ARC.
1982; Holllfleld. 1979; Leyder and Boulanger. 1983; Habey et al.. 1981; Scala and Banerjee. 1982; Schwarz. 1980; U.S. EPA. 1978c. 1980a,b;
Verschueren. 1983; Wolfe et al.. 1980
bPour point
cMultIcomponent nlxture
dCalculated
eFreeztng point
NA ^ Not available
OS
-------
acid). Many of these products are Isomerlc mixtures of alcohols derived
from the oxo reaction of olef1ns--a reaction that results 1n the formation
of alcohols with varying amounts of branching. In addition, some producers
offer an ester made from a mixture of two or more alcohols. Thus, d1-
(heptylnonyl) phthalate may consist of dlheptyl phthalate, dlnonyl phthalate
and heptylnonyl phthalate. The commercially available products are usually
>99% pure with a residual maximum acidity of 0.01X (presumably monoalkyl
phthalates containing one carboxyllc add group). The remaining Impurities
could be dlesters of 1so-phthal1c acid, terephthallc acid or malelc
anhydride (U.S. EPA, 1978b).
Table 1-3 lists the primary manufacturers and production sites of alkyl
and aryl phthalate esters. Reported production data and estimates of
production for these phthalates are presented In Table 1-4.
1.4. USE DATA
Alkyl and aryl phthalates are used as plastldzers primarily for PVC
resins and less often for other vinyl resins, cellulose ester plastics,
synthetic elastomers and other polymers. Plastldzer end uses are wide
ranging and Include construction, home furnishings, consumer goods, packag-
ing, electrical uses, transportation and medical products (U.S. EPA, 1978b).
n-Butyl benzyl phthalate Is used exclusively as a plastldzer, predomi-
nantly 1n vinyl flooring. The second most common use 1s In polyvlnyl
acetate emulsions used as adheslves (I.e., 1n the packaging Industry). It
has also been used as a plastldzer 1n acrylic resins, ethyl cellulose,
polyvlnyl forma! and polyvlnyl butyral resins (IARC, 1982).
D1-n-butyl phthalate Is used mostly as a plastldzer In polyvlnyl
acetate emulsions for surface coatings, adheslves, and paper and textile
treating (U.S. EPA, 19785). This compound 1s a registered active Ingredient
0779p 1-8 06/05/86
-------
TABLE 1-3
Manufacturers of Alkyl and Aryl Phthalates In the United States3
Phthalate
Manufacturer/Location
n-Butyl benzyl
Butyl(2-ethy1hexyl)
D1-n-butyl
D1-n-decylb
D1(2-ethylhexyl)
Dlethyl
01heptylc
01hexylb
DUsodecyl
D11sononyl
Monsanto Co., NJ
Hatco Chemical Corp., Fords, NJ
Badlsche Corp., Kearny, NJ
Eastman-Kodak, TN
Hatco Chemical Corp., Fords, NJ
Nuodex Chemical Inc., Chestertown, MD
Union Camp Corp., Dover, OH
U.S. Steel Corp., Neville Island, PA
Continental 011 Co., Aberdeen, NJ
Eastman-Kodak, NY
Tenneco Chemical Inc., Chestertown, MD
Badlsche Corp.; Kearny, NJ
B.F. Goodrich Co., Avon Lake, OH
Eastman-Kodak, TN
Hatco Chemical Corp., Fords, NJ
Monsanto Co., TX
Nuodex Chemical Inc., Chestertown, MD
Teknor Apex Co., Hebronvllle, MA
U.S. Steel Corp., Neville Island, PA
DynamH Nobel of America, Stony Point, NJ
Eastman-Kodak, TN
Morfex Chemical Co., Greensboro, NC
Monsanto Co., TX
Continental 011 Co., Aberdeen, NJ
U.S. Steel Corp., Neville Island, PA
Badlsche Corp., Kearny, NJ
Exxon Corp., Baton Rouge, LA
Hatco Chemical Corp., Fords, NJ
Nuodex Chemical Inc., Chestertown, MD
ReUhold Chemicals, Inc., Carteret, NJ
Teknor Apex Co., Hebronvllle, MA
U.S. Steel Corp., Neville Island, PA
Exxon Corp., Baton Rouge, LA
U.S. Steel Corp., Neville Island, PA.
0779p
1-9
06/05/86
-------
TABLE 1-3 (cont.)
Phthalate
Manufacturer/Locate on
Dllsooctyl
Dimethyl
Dlnonyl
D1-n-octylb
Dlphenyl13
DUrldecyl
D1undecyld
Relchold Chemicals, Inc., Carteret, NJ
Teknor Apex Co., Hebronvllle, MA
DynamH Nobel of America, Inc., Stony Point, NJ
Eastman-Kodak, TN
Morfex Chemical Co., Greensboro, NC
Sybron Corp., Lyndhurst, NJ
Monsanto Co., TX
Relchold Chemicals, Inc., Carteret, NJ
Tenneco Chemical Inc., Chestertown, MD
Eastman-Kodak, NY
Tenneco Chemical Inc., Chestertown, MD
Monsanto Co., MO
Exxon Corp., Baton Rouge, LA
Nuodex Chemical Inc., Chestertown, MD
Relchold Chemicals, Inc., Carteret, NJ
Teknor Apex Co., Hebronville, MA
U.S. Steel Corp., Neville Island, PA
Monsanto Co., TX
aSRI. 1985
bU.S. EPA, 1985b
cManufactured as the mixture d1(heptyl, nonyl, undecyl) phthalate
^Manufactured as the mixture d1(heptyl, nonyl, undecyl) phthalate and as
dlundecyl phthalate alone
0779p
1-10
08/31/87
-------
TABLE 1-4
Annual United States Production Volume of Alky! and Aryl Phthalates
Chemical
n-Butyl benzyl phthalate
Total butyloctyl phthalates
[Include butyl(2-ethylhexyl )
phthalate]
CMbutyl phthalates
(Include d1-n-butyl phthalate)
Dldecyl phthalate
D1(2-ethylhexyl) phthalate
Dlethyl phthalate
Dlheptyl phthalate
Dlhexyl phthalate
Dllsodecyl phthalate
Dllsononyl phthalate
Dllsooctyl phthalate
Dimethyl phthalate
Dloctyl phthalates
[Include 01-n-octyl phthalate,
exclude D1 (2-ethylhexyl )
phthalate]
Dlphenyl phthalate
DHrldecyl phthalate
Dlundecyl phthalate
Volume Produced Year
(ml H1on pounds)
101-510
12.28
22.21
1-10
251.1
17.75
10-50
0.2-2.0
145.82
<0.001
1-10
8.64
301.12
0.1-1.0
21.79
10-50
1977
1982
1984
1977
1982
1984
1977
1977
1984
1977
1977
1984
1984
1977
1984
1977
Reference
U.S. EPA, 1985b
USITC, 1983
USITC, 1985
U.S. EPA, 1985b
USITC, 1983
USITC, 1985
U.S. EPA, 1985b
U.S. EPA, 1985b
USITC, 1985
U.S. EPA, 1985b
U.S. EPA, 1985b
USITC, 1985
USITC, 1985
U.S. EPA, 1985b
USITC, 1985
U.S. EPA, 1985b
0779p
1-11
08/31/87
-------
1n pesticides and 1s used as an Insect repellant for textiles (U.S. EPA,
1979). Other uses are as a perfume solvent and fixative, and as a resin
solvent (Hawley, 1981).
D1(2-ethylhexyl)phthalate Is used 1n wire Insulation, cloth coatings,
elastomerlc molded materials, extruded and calendered compositions, food
packaging and 1n blomedkal applications. The only significant non-PVC use
Is as a dielectric fluid 1n capacitors (IARC, 1982).
Olethyl phthalate Is used almost entirely as a plastldzer for cellulose
ester plastic films and sheets (photographic, blister packaging and tape
applications) and molded and extruded articles (consumer articles such as
toothbrushes, automotive components, tool handles and toys). This compound
Is also used as a solvent for nitrocellulose and cellulose acetate, In
Insecticide sprays and mosquito repellants, as a camphor substitute and as a
perfume fixative and solvent (U.S. EPA, 1978a,b; Hawley, 1981).
Dlhexyl phthalate Is used In plastlsols for carpetback coating (U.S.
EPA, 1978a,b).
D1-1sodecyl phthalate 1s used In automotive upholstery, PVC and urethane
foams and 1n wire cable Insulation with dllsononyl, dltrldecyl and dl-noctyl
phthalates (U.S. EPA, 1978a,b).
Dllsononyl phthalate 1s used mainly as a plastldzer and has minor use
as a dielectric fluid In capacitors (U.S. EPA, 1978a,b).
Dimethyl phthalate 1s used 1n solid rocket propellants, lacquers,
plastics, safety glasses, rubber coating agents, molding powders and In
Insect repellants {Hawley, 1981) and 1s a registered active Ingredient In
pesticides (U.S. EPA, 1979).
Olnonyl phthalate 1s used mainly as a plastldzer and the pure grade Is
used as stationary liquid phase 1n chromatography (Hawley, 1981).
0779p 1-12 10/15/87
-------
D1-n-octyl phthalate 1s used In plastlsols for carpetback coating (U.S.
EPA, 1978b) and Is also a registered active Ingredient In pesticides (U.S.
EPA, 1979).
Dlphenyl phthalate Is used primarily as a plastlclzer, but 1s also a
registered active Ingredient 1n pesticides (U.S. EPA, 1979).
Phthalates based on C^-C,, alcohols are used heavily 1n PVC resins
for automotive applications and to a lesser extent 1n plastlsols, dispersion
coatings, and In other film, sheeting, coated fabric and extrusion applica-
tions (U.S. EPA, 1978b).
1.5. SUMMARY
Alkyl and aryl phthalates are generally colorless and odorless compounds
(CEH, 1975). Most alkyl phthalates are colorless liquids at ambient
temperature. In general, the phthalate esters are poorly soluble 1n water
but soluble In most organic solvents, Including acetone, benzene and ether
(Hawley, 1981). Phthalate plastldzers can undergo oxidation during plastic
processing; antloxldants are added to resins to Inhibit this reaction.
The alkyl and aryl phthalates are produced by reacting phthallc anhy-
dride with an excess amount of the corresponding alcohol(s) In the presence
of an esterlfIcatlon catalyst. The commercial products are usually >99%
pure (U.S. EPA, 1978b). Sixteen U.S. manufacturers produce one or more of
the 17 selected phthallc add esters. Reported production figures and esti-
mated production volumes were available for each of the alkyl phthalates.
Total U.S. production volume of phthallc add esters amounted to 1179
million pounds 1n 1984 (USITC, 1985). Alkyl and aryl phthalates are used
predominantly as plastldzers for polyvlnyl chloride resins (U.S. EPA,
1978a,b). To a lesser extent, they are used as plastldzers for other vinyl
resins, cellulose ester plastics, synthetic elastomers and other polymers.
0779p 1-13 10/15/87
-------
End-uses Include construction, home furnishing, consumer goods, packaging,
electrical uses, transportation and medical products (U.S. EPA, 1978a,b).
Some alkyl esters have minor applications as dielectric fluid [d1(2-ethyl-
hexyl)phthalate], active Ingredients in pesticides, resin sqlvents, perfume
fixatives, solvents and other uses (Hawley, 1981; U.S. EPA, 1979).
0779p 1-14 10/15/87
-------
2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES
2.1. WATER
2.1.1. Hydrolysis. Limited data regarding the hydrolysis of the phthallc
acid esters were located In the available literature as cited In the
Appendix. Gledhlll et al. (1980) observed <5X hydrolysis of 1 mg/l
n-butyl benzyl phthalate 1n 28 days. Wolfe et al. (1980) estimated second-
order rate constants for alkaline hydrolysis of phthalates at pH 10-12 and
30°C.
Rate constants varied with the size and complexity of the phthalates and
ranged from l.lxlO"4 M"1 sec"1 fo.r dl (2-ethyhexyl) phthalate to
6.9xlO~2 M"1 sec'1 for dimethyl phthalate. Thus, corresponding
estimated half-lives at pH 7 range from 3.2-2000 years, respectively. The
hydrolysis half-lives of dlphenyl and d1-t-butyl phthalates at a pH of 7 are
estimated to be 35 days and 12,000 years, respectively (Suffet et al.,
1981). Hydrolysis may not result 1n significant degradation of most phtha-
late esters compared with other mechanisms such as mlcroblal degradation.
2.1.2. Oxidation. No experimental data pertaining to the oxidation of
alkyl and aryl phthalates In water were located In the available literature
as cited In the Appendix. Mabey et al. (1981) calculated R0? radical
reaction rate constants for phthalate esters, which become larger with
Increasing size and complexity of the phthalate ester chains. Values range
from 0.05 M"1 sec"1 for dimethyl phthalate to 7.2 M'1 sec'1 for
d1(2-ethylhexyl) phthalate and 280 M"1 sec"1 for n-butyl benzyl phtha-
late. Assuming an ambient RO radical concentration of 10~9 M, (Mill et
al., 1980), oxidation half-lives were calculated to be >3 years for the
alkyl phthalates. A significantly shorter half-life of -29 days was calcu-
lated for n-butyl benzyl phthalate using data from Mabey et al. (1981).
0780p 2-1 08/26/86
-------
Habey et al. (1981) predicted that reaction of phthalates with singlet
oxygen would not be environmentally Important.
The Interaction of alkyl phthalates with OH radicals present In normal
ambient water 1s considered to be too slow to be of Importance (Callahan et
al., 1979a).
2.1.3. Photolysis. GledhUl et al. (1980) studied the photolysis of
aqueous n-butyl benzyl phthalate In sealed tubes. The photolysis half-life
was >100 days. Experimental data regarding the photolysis of alkyl phtha-
lates 1n water were not located In the available literature as dted 1n the
Appendix; however, the UV absorption spectra for d1-n-butyl, d1(2-ethyl-
hexyl), dlethyl, dimethyl and d1-n-octyl phthalates In organic solvents
Indicates slight absorption at wavelengths of 290nm. The absorption becomes
even less significant at longer wavelengths and no absorption occurs above
310 nm (Sadtler, n.d.). This Information Indicates that although the poten-
tial for direct photolysis exists, the photolysis of phthalates In ambient
waters may not be significant.
2.1.4. M1crob1al Degradation. Phthalate esters have been reported to be
metabolized In water by pure cultures of microorganisms, mixed microorgan-
isms and 1n natural water. The rates of degradation vary widely depending
upon environmental conditions, such as temperature, pH, amount of dissolved
oxygen and the structure of phthalate (HattoM et al., 1975). The degrada-
tion of phthalate esters by pure culture Isolated from natural water, acti-
vated sludge and soil have been studied by several Investigators (Taylor et
al., 1981; Kurane et al., 1979a,b; Engelhardt et al., 1975, 1977; Engelhardt
and Wallnofer, 1978; Klausmeler and Jones, 1960; Perez et al., 1977; Ohta
and Nakamoto, 1979). Several authors have studied the blodegradatlon of
phthalate esters by mixed microorganisms. Thus, activated sludge, domestic
0780p 2-2 08/26/86
-------
wastewater and natural river water have been used as mlcroblal Inoculum to
study the blodegradatlon of phthalate esters (O'Grady et a!., 1985; Saeger
and Tucker, 1973b, 1976; Sasaki, 1978; Sugatt et al., 1984). Tabak et al.
(1981) observed 100X degradation of dimethyl, dlethyl, dl-n-butyl and butyl
benzylphthalate In 7 days with unaccllmated microorganisms from domestic
wastewater. On the other hand, b1s-(2-ethylhexyl) phthalate and d1-n-octyl
phthalate needed 21 days of acclimatization before a blodegradatlon of >90%
In 7 days were observed (Tabak et al., 1981). Similarly, the mineralization
of >85X occurred with various phthalates In 28 days with both activated
sludge and river water (Saeger and Tucker, 1976; Sugatt et al., 1984). The
metabolic pathway data Indicate that phthalate esters first undergo
enzymatic hydrolysis to form the monoester, followed by further hydrolysis
to phthallc acid. The phthallc add 1s further degraded to carbon dioxide
and water (U.S. EPA, 1978b; Saeger and Tucker, 1976).
Results of various river die-away studies using a few phthalate esters
are presented In Table 2-1. Saeger and Tucker (1973a,b, 1976) and Gledhlll
et al. (1980) concluded from their river die-away and activated sludge
studies that phthalate plastldzers, as a class, undergo rapid primary
degradation and mineralization by bacteria commonly found In the environ-
ment. In a simulated lake microcosm, Gledhlll et al. (1980) observed >95%
primary degradation of n-butyl benzyl phthalate In 7 days (Cn=l mg/i).
The blodegradatlon half-life for n-butyl benzyl phthalate In this natural
water system was <4 days. The length and configuration of the alkyl ester
chains significantly influences the blodegradatlon rate of phthalates 1n
freshwater ecosystems, whereas acclimation of microbes appears to have
IHtle effect (HattoM et al., 1975; Johnson et al., 1984). In freshwater
systems, phthalates such as dimethyl and dlethyl phthalate are expected to
0780p 2-3 08/26/86
-------
o
en
00
TABLE 2-1
Blodegradatlon Screening of Some Alkyl and Aryl Phthalates3
03
•o
Phthalate
n-Butyl benzyl
D1(2-ethylhexyl)
D1(hexyl, nonyl,
undecyl)
i. D1(hexyl, octyl,
nonyl, decyl, undecyl)
Dlundecyl
River Die-Away.
X Primary
Degradation1*
100
40
55
NA
20
Unaccl
(weeks
1.3
5.0
5.0
NA
5.0
Imated System
tl/2c
) (weeks)
0.2
2.5
NA
3.0
2.5
River Dte-Away.
% Primary
Degradation
100
NA
NA
NA
NA
Unaccl Imated
t
(days)
9
NA
NA
NA
NA
Systemd
M/2
(days)
2
NA
NA
NA
NA
aln1t1al concentrations = 1 mg/i
DSaeger and Tucker, 1973a
cSaeger and Tucker, 1973b
dGledh111 et al., 1980
NA = Not available
-------
degrade faster than the larger and more complex phthalate esters (Johnson et
al., 1984; HattoM et al., 1975). Hattorl et al. (1975) observed 100%
decomposition of dlethyl phthalate after 6 days and 100% decomposition of
dimethyl phthalate after 8-11 days In river water Initially spiked with 25
mg/i of the ester. D1 (2-ethylhexyl) phthalate degraded only -40% after 2
weeks In river water. In relatively clean ocean water, -14-20% degradation
of dlethyl and dimethyl phthalate was measured after 14 days, while the
larger phthalates were decomposed >30% during the same period. The degrada-
tion of all the phthalate esters were much higher with polluted ocean water.
For example, while 33% of dlbutyl phthalate and 14% of dlethyl phthalate
degraded 1n clean ocean water 1n 14 days, the degradation was 100% 1n 5 days
for dlbutyl phthalate and 68% 1n 14 days for dlethyl phthalate with polluted
ocean water. The higher degradation 1n polluted water was attributed to the
presence of higher concentrations and nutrients In polluted water. Longer
chain phthalate esters decomposed faster than dimethyl and dlethylphthalates
1n clean ocean water, a finding not further explained (Hattorl et al., 1975).
In aquatic sediments under anaerobic conditions, blodegradatlon of short
chain alkyl esters appears to be slow and degradation of the longer chain
esters has been observed to be very slight or undetectable (Johnson et al.,
1984; Johnson and Lulves, 1975; Horowitz et al., 1982; Shelton et al.,
1984). Johnson and Lulves (1975) observed 61 and 98% anaerobic mineraliza-
tion of dl-n-butyl phthalate In 14 and 30 days, respectively. Under the
same conditions, no detectable degradation of dl(2-ethylhexyl) phthalate was
measured after 30 days. Johnson et al. (1984) measured 10% anaerobic
mineralization of radlolabeled d1 (2-ethylhexyl) phthalate after 28 days and
<1% mineralization of dllsononyl and dllsooctyl phthalates. Optimal degra-
dation of long chain phthalates occurred at high concentrations In nutrient-
rich aquatic sediments with temperatures above 22°C. Such environmental
0780p 2-5 08/26/86
-------
conditions are typical of sewage treatment ponds, wetlands, eutrophlc lakes
and enriched streams during summer. Winter conditions, particularly at
northern latitudes and environmentally realistic (low, <1 yg/l) concen-
trations would adversely affect blodegradatlon (Johnson et al., 1984).
2.1.5. Volatilization. No significant volatility losses (O.5X/24 hours)
were observed for n-butyl benzyl, d1(2-ethylhexyl), d1(hexylt nonyl,
undecyl) and dlundecyl phthalates during blodegradatlon studies with
activated sludge (Saeger and Tucker, 1976). Atlas et al. (1982) measured
the mass-transfer coefficient of dl-n-butyl phthalate to be 0.104 cm/hour In
stirred (200-300 rpm) seawater free of Interfering organic contaminants at
23°C. At a depth of 4.5 cm, the volatilization half-life of d1-n-butyl
phthalate has been calculated to be 30 hours following the method of DHUng
(1977).
Henry's Law constants for some phthalate add esters, calculated using
vapor pressure and water solubility data from Table 1-2 are as follows:
dl-methyl phthalate 2.5xlO~7 atm.mVmol
dl-ethyl phthalate 7.8xlO"7 atm-rnVmol
dl-n-butyl phthalate 2.2x10"* atm-rnVmol
dl-n-octyl phthalate 2.4xlO"s atm«m3/mol
d1-(2-ethylhexyl)phthalate l.lxlO"7 atm-rnVmol
n-butyl benzyl phthalate 1.2x10"' atm-mVmol
This Information also suggests that volatilization would not be a
significant removal process for these phthalate esters, except dl-n-octyl
phthalate, which could volatilize significantly from shallow rivers (Lyman
et al., 1982). The evaporation half-life of d1(2-ethylhexyl) phthalate from
bodies of water has been estimated to be 15 years (Callahan et al., 1979a).
2.1.6. Adsorption. Sullivan et al. (1982) studied the adsorption of
d1-n-butyl and d1(2-ethylhexyl) phthalates onto clay minerals, caldte and
sediment samples from seawater. Results Indicate that adsorption Increases
0780p 2-6 08/26/86
-------
with Increased salinity or decreased solubility of phthalates. Adsorption
onto the clay minerals and calclte appeared to be a reversible process,
whereas adsorption onto sediments was Irreversible. This suggests that
marine sediments may act as a final repository of phthallc acid esters
(Sullivan et a!., 1982). Mabey et al. (1981) calculated sediment-water
partition coefficients for phthalates, Indicating adsorption 1s likely for
all phthalate esters with adsorption tendency Increasing with size and
branching of the ester chain. Sediment adsorption coefficients range from
98 for dimethyl phthalate to >150,000 for d1-n-butyl phthalate and the
larger phthalate esters Including n-butyl benzyl phthalate. Gledhlll et al.
(1980) observed significant partitioning of n-butyl benzyl phthalate to
sediments In a simulated lake microcosm. The average ratio of this compound
measured In sediments versus water was 571:1.
The contention that phthalates will be adsorbed significantly onto sedi-
ments In aquatic ecosystems Is supported by the observation that phthalates
are commonly found In bottom sediments from both streams and seas (Callahan
et al., 1979a).
Evidence suggests that complexatlon of phthalates In natural water with
organic substances may be one mode of transport of phthalates (Khan, 1980;
Ogner and Schnltzer, 1970; Matsuda and Schnltzer, 1971). Phthalate esters
have been observed readily Interacting with fulvlc acid, a widely occurring
humlc substance found 1n soils and waters. The phthalates appear to adsorb
to the surface of the fulvlc add molecule rather than react with It. The
fulvlc acld-phthalate complex Is very soluble 1n water; thus, mobility of
otherwise Insoluble phthalate esters Is modified. Extent of solub1llzat1on
appears to vary with phthalate size. Equivalent quantities of fulvlc add
will solublUze 4 times as many equivalents of d1(2-ethylhexyl) phthalate as
of d1-n-butyl phthalate (Matsuda and Schnltzer, 1971).
0780p 2-7 08/26/86
-------
2.1.7. B1oaccumulat1on. Phthalate esters have been Identified In living
matter, and data collected from field and laboratory studies Indicate that
these compounds can be taken up and bloaccumulated In a variety of organ-
Isms. The majority of data 1s on d1(2-ethylhexyl) phthalate (Callahan et
al.. 1979a). Host phthalates have relatively high KW values (>250),
suggesting I1poph1llc1ty and potential for bloconcentratlon. Studies
pertaining to the uptake and bloaccumulatlon of phthalate esters In aquatic
organisms are discussed In Chapter 6.
2.2. AIR
2.2.1. Chemical Degradation. Limited data regarding the degradation of
the phthalate esters 1n the atmosphere are available In the literature as
dted In the Appendix. The HO radical reaction half-life of gaseous
dimethyl, d1-n-butyl, d1(2-ethylhexyl) and n-butyl benzyl phthalates at 25°C
have been estimated to be 23.80, 18.44, 11.86 and 14.29 hours, respectively,
by the GEMS programming method (U.S. EPA, 1986a).
The same GEMS programming method predicts that reaction of phthalates
with atmospheric ozone Is not a significant process (U.S. EPA, 1986a).
The UV absorption spectra for dl-n-butyl, dl(2-ethylhexyl), dlethyl,
dllsodecyl and d1-n-octyl phthalate reveal slight absorption of UV light at
wavelengths >290 nm although no absorption occurs at wavelengths >310 nm
(Sadtler, n.d.). These data suggest that although there Is a potential for
photodegradatlon In the atmosphere, the process 1s probably not a signifi-
cant one.
2.2.2. Physical Removal. Monitoring data reveal that phthalate esters
can be removed from the atmosphere by wet and dry deposition (Kawamura and
Kaplan, 1983; Atlas and G1am, 1981; Karasek et al., 1978; Weschler, 1984).
0780p 2-8 08/31/87
-------
Average measured ratios of the concentration In precipitation to air are
3.56x10* and 3.93x10* for d1-n-butyl phthalate and d1(2-ethylhexyl}
phthalate, respectively (Atlas and Glam, 1981). This Indicates significant
removal of atmospheric phthalates through precipitation. The probability of
removal of an atmospheric pollutant through adsorption on atmospheric
aerosols and subsequent precipitation 1s reasonable for chemicals with
saturation vapor pressures of <10~T mm Hg (CupHt, 1980). Since the vapor
pressures of all the phthalates, listed 1n Table 1-2, with the exception of
d1(2-ethyl hexyl) phthalate, are <10~7 mm Hg, they are not likely to be
removed significantly by this mechanism. 01(2-ethylhexyl) phthalate, on the
other hand, may be significantly removed.
2.3. SOIL
2.3.1. Chemical Degradation. Pertinent data regarding the chemical
degradation of phthalate esters In soil could not be located In the avail-
able literature as cited In the Appendix. Considering data presented In
Section 2.1., hydrolysis In wet soils (excluding dlphenyl phthalate) and
photolysis at soil surfaces would not be Important degradation mechanisms.
2.3.2. M1crob1a1 Degradation. Shanker et al. (1985) observed mlcroblal
degradation of d1-n-butyl, dl(2-ethylhexyl) and dimethyl phthalates In
garden soil. Results of this study are listed In Table 2-2. This Investi-
gation Indicates soil mlcroflora significantly degraded phthalates under
aerobic conditions, and shorter chain phthalates degraded at a faster rate
than the compounds with longer chains. The anaerobic degradation of phtha-
lates was much slower than the aerobic degradation. In various other
studies, a considerable number of widely occurring microorganisms capable of
degrading phthalate esters, such as Nocardla. Arthrobacter. Pseudomonas and
the fungus Penlcllllum Illadntum. have been Isolated from soils and other
0780p 2-9 05/13/86
-------
GO
0
•o
TABLE 2-2
Blodegradatlon of Phthalates In Garden Solla'b
Dimethyl Phthalate
Incubation
Tine
(days)
0
5
10
15
1, 20
o
30
Autoclaved
control
Aerobic
DHP
468 O 6
18001
43*9
0
0
0
465*6
PA
0
9*0.5
8i0.5
0
0
0
traces
Anaerobic
OMP
47102
410*8
376^6
302OO
245.6
178^2
467*8
PA
0
8*1.1
lOiO.5
240. 7
90.1
3*1.0
0
Dl-n-butyl
Aerobic
DNBP
47204
11003
40*6
0
0
0
465*10
PA
0
8i0.6
6±0.6
0
0
0
traces
Phthalate
D1(2-ethylhexyl)phthalate
Anaerobic
DNBP
470O7
402*9
348^8
30 U 9
239*9
159*4
463*9
PA
0
12O.1
14*2.9
29^3.5
22*2.3
15O.7
0
Aerobic
DEHP
480*9
430.8
320 Ol
NA
120*4
40^8
471.4
PA
0
8*1.1
7*1.1
NA
11*0.6
5±0.6
0
Anaerobic
DEHP
478^9
460^8
439*6
NA
389*5
318*7
478*7
PA
0
traces
2*0
NA
8*1.1
Ill0.6
0
aSource: Shanker et al., 1985
''Each value Is the meatuSE of triplicate samples In
PA = Phthallc acid
NA = Not available
compound recovered/g soil
o
tn
CD
-------
natural sources (Kurane et al., 1977; Ohta and Nakamoto, 1979; Englehardt
and Wallnofer, 1978; Englehardt et al., 1977; Williams and Dale, 1983; Lewis
et al., 1984; Klausmeler and Jones, 1960). In view of this Information as
well as the aquatic blodegradatlon data (see Section 2.1.4.), significant
removal of phthalate esters may be possible under aerobic conditions;
however, anaerobic degradation may be a very slow removal mechanism.
2.3.3. Volatilization. Pertinent data regarding the volatilization of
alkyl and aryl phthallc acid esters from soil surfaces could not be located
1n the available literature as cited In the Appendix. Considering the
tendency of the larger phthalates to adsorb to soils (Section 3.2.4.) as
well as their relatively low vapor pressures, volatilization will probably
not be an Important removal mechanism. Since dimethyl phthalate Is not
likely to adsorb to soils, volatilization from dry soil surfaces may be a
potential removal mechanism for this compound.
2.3.4. Adsorption. Pertinent data regarding the adsorption of alkyl and
aryl phthalates to soils could not be located In the available literature as
cited In the Appendix. Wide ranging water solubilities and K values
suggest that adsorption to soils by the phthalate esters Is dependent upon
the size and complexity of the phthalate ester chains. Mobility of phtha-
lates 1n soil has been categorized using adsorption coefficients obtained
from the following equation (Kenaga, 1980): log K = 3.64-0.55 log WS.
From this equation, dimethyl phthalate should predictably be highly mobile
1n soils (K =44). n-Butyl benzyl, d1-n-butyl, d1-n-octyl and dlnonyl
phthalates should be low to slightly mobile (K 890-2400), while larger
or branch-chained compounds, Including dlphenyl phthalate, should remain
strorgly adsorbed to soils (K >5000). Data presented In Section 2.1.
Indicate that the mobility of phthalates Is affected, and expectably
enhanced, by the presence of fulvlc add In soils.
0780p 2-11 06/06/86
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2.4. SUMMARY
Hydrolysis Is not expected to be a significant removal mechanism of
phthalate esters (Suffet et al., 1981). Mabey et al. (1981) estimated that
phthalate esters will not undergo significant oxidation In water. UV
absorption spectra for some phthalates In nonaqueous solvents Indicate that
potential exists for direct photolysis In the environment. The photolysis
half-life of n-butyl benzyl phthalate has been observed to be >100 days
(Gledhlll et al., 1980). Phthalate esters are reported to be metabolized In
the aquatic environment by a variety of pure microorganisms and degraded by
mixed mlcroblal systems. The mlcroblal degradation rates vary widely
depending upon environmental conditions such as temperature, pH, amount of
oxygen present and the phthalate structure (Thomas et al., 1984; Hattorl et
al., 1975). Blodegradablllty of phthalates In freshwater decreases with
Increasing size and complexity of the phthalate ester chains (Hattorl et
al., 1980; Johnson et al., 1984).
Results from river die-away tests and activated sludge studies Indicate
that phthalates, as a class, undergo rapid degradation by bacteria commonly
found 1n the environment (Saeger and Tucker, 1973a,b, 1976; Gledhlll et al.,
1980). For example, In a simulated lake microcosm Gledhlll et al. (1980)
observed >95X primary degradation of the complex ester n-butyl benzyl phtha-
late In 7 days. Under anaerobic conditions, btodegradatlon of short-chain
alkyl esters has been shown to be possible, but slower than under aerobic
conditions, while degradation of the long-chain esters has been shown to be
very slight or undetectable (Johnson et al., 1984; Johnson and Lulves, 1975;
Horowitz et al., 1982; Shelton et al., 1984). From the estimated Henry's
Law Constants for n-butyl benzyl, ch-n-butylt d1(2-ethylhexyl), dlethyl,
dimethyl and d1-n-octyl phthalates, phthalate esters are predicted to not
0780p 2-12 08/26/86
-------
significantly volatilize from water (Lyman et al., 1982). Dl-n-octyl phtha-
late may significantly volatilize from shallow rivers, although volatiliza-
tion from deeper waters should not be significant (Lyman et al., 1982). In
seawater, adsorption onto clay minerals and calclte appears to be a revers-
ible process, whereas adsorption onto sediments 1s Irreversible (Sullivan et
al., 1982). This suggests that marine sediments may act as a final reposi-
tory of phthallc acid esters (Sullivan et al., 1982). Calculated sediment-
water partitioning coefficients Indicate adsorption 1s likely for all phtha-
late esters, with adsorption tendency Increasing with the size and complex-
ity of the ester chain (Habey et al., 1981). Complexatlon with the widely
occurring humlc and fulvlc substances causes solub1!1zat1on of phthalate
esters In water, thus modifying their mobility (Matsuda and SchnHzer,
1971). Phthalates have been Identified 1n living matter, and data collected
from field and laboratory studies Indicate that these compounds can bloaccu-
mulate 1n aquatic organisms (Callahan et al.. 1979a).
In air, the phthalate esters, as a class, are predicted to react with
hydroxyl radicals, with a t,/2 of <1 day (U.S. EPA, 1986a). The actual
atmospheric t, ._, however, may be longer than the estimated values because
of adsorption onto airborne partlculate matter. Removal of atmospheric
phthalate by wet and dry deposition has also been observed (Kawamura and
Kaplan, 1983; Atlas and Glam, 1981; Karasek et al., 1978; Weschler, 1984).
Significant hydrolysis of phthalate esters In wet soils 1s unlikely
(Wolfe et al., 1980; Gledhlll et al., 1980). Shanker et al. (1985) observed
mlcroblal degradation of dl-n-butyl, d1(2-ethylhexyl) and dimethyl phtha-
lates 1n garden soil. Results Indicate that soil mlcroflora significantly
degrade phthalates under aerobic conditions, and short-chain phthalates
degrade at a faster rate than the longer chain phthalates. The anaerobic
0780p 2-13 08/31/87
-------
degradation of phthalates was very slow compared with aerobic blodegrada-
tlon. The water solubilities and K values of the phthalates suggest
that adsorption to soils Is dependent on the size and complexity of phtha-
late ester chains. Dimethyl phthalate should be reasonably mobile 1n soils,
whereas large or branched chain esters, Including dlphenyl phthalate, should
remain strongly adsorbed to soils. The mobility of phthalate esters 1n the
presence of fulvlc add should Increase. Since dimethyl phthalate Is not
likely to adsorb to soils, volatilization from dry soil surfaces may be a
potential removal mechanism. Volatilization will be Insignificant for other
phthalates.
0780p 2-14 06/06/86
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3. EXPOSURE
Phthalate esters are ub1qu1t1ous 1n the environment. They have been
found In underground and drinking waters, surface waters, soil, oil, food,
plants, fish, animals and humans (Callahan et a!., 1979a). There Is some
evidence that phthalate esters occur naturally In certain plants and organ-
Isms {Callahan et al., 1979a; Peakall, 1975; Mathur, 1974). The environ-
mental contribution of phthalate esters from anthropogenic sources, however,
far exceeds Us contribution from natural sources. The disposal of plastic
materials containing phthalate esters In disposal sHes constitutes the
major reservoir of these compounds In the environment (Mathur, 1974;
Peakall, 1975). All these environmental media containing phthalate esters
may directly or Indirectly cause human exposure to these compounds. The
leaching of phthalate esters from the hemodlalysls tubing and the PVC bags
containing Intravenous solutions can be sources of exposure to these
compounds for a special segment of the population. A considerable body of
research has been done In this area (Ono et al., 1975; Corley et al., 1977;
Pollack et al., 1985b; Fayz et al., 1977). The levels of these compounds In
water, air and food and possible human exposure to phthalate esters from
these sources are discussed 1n the following sections.
3.1. WATER
Phthalate esters have been detected In Industrial effluents by several
Investigators. Jungclaus et al. (1976) reported the presence of dlethyl
phthalate at a concentration of 60 yg/l (60 ppb) 1n the wastewater from
a tire manufacturing plant. In a survey of effluents from the petroleum
refining Industry, Snider and Manning (1982) reported the detection of
0781p 3-1 05/13/86
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dimethyl, dlethyl, dl-n-butyl, d1(2-ethylhexyl) and n-butyl benzyl phtha-
lates 1n both the blotreatment effluents and final effluents of the treated
wastewaters. The concentrations of dimethyl, dlethyl and n-butyl benzyl
phthalates In the final effluents were always <20 ^g/j, (ppb), but final
effluents from one type of refinery wastewater had a d1-n-butyl phthalate
concentration In the range of 2-32 yg/8.. In another class of refinery,
the concentration range of d1{2-ethylhexyl) phthalate In the final effluents
was reported to be <0.1-2000 wg/s. (Snider and Manning, 1982). HHes and
Lopez-Avlla (1980) reported the presence (concentration not quantified) of
dloctyl and d1(2-ethylhexyl) phthalates In wastewaters from an unspecified
specialty chemical manufacturing plant. The average concentrations of
dlethyl, d1(2-ethylhexyl), dl-n-octyl, d1-n-butyl and n-butyl benzyl phtha-
lates In 76 sources of pollution Into the Influent of sewage treatment
plants of two cH1es were reported to range from 16.2-22.0, 19-46, 33-62.5
and 16-17 vg/4, respectively (Callahan et al., 1979b). Other authors
have detected dimethyl, dlethyl, dlbutyl, dllsobutyl and dloctyl phthalates
In the treated effluents from pulp and paper manufacturers (Voss, 1984;
Brownlce and Strachan, 1977; Fox, 1977). The concentrations of dlethyl,
dlbutyl and dloctyl phthalates In the effluents were reported to be 50, 70
and 15 yg/l, respectively (Brownlee and Strachan, 1977; Voss, 1984).
Phthalate esters were also Identified In the Influents and effluents of
sewage treatment plants (Thomson et al., 1981; McCarty and Relnhard, 1980;
Ellis et al., 1982; HHes, 1979; Callahan et al., 1979b). The concentra-
tions of dimethyl, dlethyl, d1-n-butyl, dllsobutyl, d1(2-ethylhexyl) and
n-butyl benzyl phthalates In sewage Influent were reported to be as high as
6.0, 17, 50, 3.0, 200 and 40 yg/l, respectively (Callahan et al., 1979b;
McCarty and Relnhard, 1980; HHes, 1979). The removal of the phthalate
0781p 3-2 05/13/86
-------
esters as a result of treatment of wastewater evidently depends on the
nature of treatment. For example, Callahan et al. (1979a) reported almost
complete removal of dlethyl, d1 (2-ethylhexyl), n-octyl and n-butyl benzyl
phthalates in the effluent from a sewage treatment plant. Other Investi-
gators have observed partial removal or, In some cases, Increases In the
concentrations of phthalate esters In the effluent from sewage treatment
plants (Young et al., 1983; HHes, 1979; McCarty and Relnhardt, 1980).
Thus, although the concentration of d1 (2-ethylhexyl) phthalate 1n the Influ-
ent water of the Los Angeles County sewage treatment plant was 42 yg/8.,
the treated effluent had a reported concentration of 420 ^g/l (Young et
al., 1983). Other Investigators have Identified the presence of dlethyl,
d1-n-butyl and d1(2-ethylhexyl) phthalates In the wastewater from a poultry
plant, which had undergone wastewater treatment and reclamation, and In
wastewater from a dining hall, laboratory and dormitory of a Japanese
university (Shlbuya, 1979; Andelman et al., 1984).
Phthalate esters have been Identified In surface waters throughout the
United States. The presence of dimethyl phthalate In surface waters around
the contaminated area 1n Love Canal, Niagara Falls, NY, was reported by
Hauser and Bromberg (1982). The concentrations of dlbutyl, dl(2-ethylhexyl)
and n-butyl benzyl phthalates 1n Delaware River water 2 miles downstream
from a Philadelphia wastewater treatment plant were reported to be 0.6, 1.0
and 0.6 vg/l, respectively (HHes, 1979). Oewalle and Chlan (1978) also
Identified dlbutyl, dlethyl and hexyl esters and an unidentified phthalate
In Delaware River water and Us major tributaries; dlethylhexyl phthalate
occurred 1n these waters with a 90X frequency. The concentrations of phtha-
late esters 1n Delaware River water between Marcus Hook, PA, and Trenton,
NJ, was reported to be higher In winter than 1n summer (Sheldon and HHes,
0781p 3-3 06/06/86
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1978). The reported concentration ranges for dlbutyl, dloctyl and butyl
benzyl phthalates In this Mverwater during the winter of 1976-1977 were
0.2-0.6, 3.0-5.0 and 0.4-1.0 vg/l, respectively. Goodley and Gordon
(1976) reported the presence of dlethyl, dl-n-butyl and d1-n-octyl phtha-
lates In lower Tennessee River water near Calvert CHy, KY. Corcoran (1973)
reported the concentration of d1(2-ethylhexyl ) phthalate In Mississippi
River water to be (tentatively) as high as 600 wg/l. The concentration
further downstream In the water of Escambla Bay, FL, was much less (not
quantified), and the concentration was even less (not quantified) 1n the
water of the Gulf Stream. Murray et al. (1981) Identified d1(2-ethylhexyl )
phthalate In the water from Galveston Bay, TX, at a mean concentration of
0.6 yg/l. Other Investigators have Identified dlbutyl, dlethyl and
dloctyl phthalates 1n water from lower Fox River, WI (Peterman et al.,
1980). Results of an extensive survey designed to determine the levels of
butyl benzyl phthalate In surface waters near various Industrial sites In
the United States are reported 1n Table 3-1.
Phthalate esters also have been Identified 1n river waters In other
countries, Including the Rhine, Ijssel, Mense and Waal rivers 1n the Nether-
lands (Schouten et al.,' 1979; Meljers and VanderLeer, 1976), in the Kiel
Bright In Germany (Ehrhardt and Derenbach, 1980), In the Caronl River,
Trinidad (Moore and Karasek, 1984), and 1n the River Glatt, Switzerland
(Zuercher and G1ger, 1976). The maximum reported concentrations of
d1-n-butyl phthalate and dl (2-ethylhexyl ) phthalate 1n these foreign waters
were 2.8 yg/J. (Ijssel River) and 4.1 ^g/l (Mense River), respec-
tively (Schouten et al., 1979).
Rainwater collected from West Los Angeles, CA, during 1981-1982 con-
tained a maximum of 9.0 »q/i of total phthalate esters (Kawamura and
0781p 3-4 06/06/86
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TABLE 3-1
Concentrations of n-8utyl Benzyl Phthalate In United States
Haters Near Industrial Sites*
Concentration In Hater
Sampling Site
1980 1981 1982
Alabama River, Mobile, AL
Baltimore Harbor, Sparrow1 s. Point, MO
Charles River, Boston, MA
Chesapeake Bay, Fisherman IS, MA
Delaware Bay, Lewes, DE
Delaware River, Port Penn, DE
Delaware River, Wilmington, DE
Detroit River, Gllwater, MI
Illinois River, 3ol1et, IL
Kanawha River, NHro, HV
Kanawha River, Hlnfleld Dam, HV
Lake Erie, Erie, PA
Lake Huron, Saglnaw Bay, MI
Lake Michigan, Charlevolx, MI
Lake Michigan, Calumet, IL
Lake Onelda, Verona Beach, NY
Lake Ontario, Four Mile Creek, NY
Lake Superior, Sault St. Marie, MI
Mississippi River, St. Paul, MN
Mississippi River, above St. Lonls, MO
Mississippi River, below St. Louis, HO
Mississippi River, Memphis, TN
Missouri River, St. Louis, MO
Mobile Bay, Ft. Morgan, AL
Niagara River, Sandy Beach, NY
Ohio River, GalUpolls Ferry, OH
Ohio River, Plttsburg, PA
Potamac River, Popes Creek, MD
Saglnaw River, Bay City, MI
San Francisco Bay, Brooks Island, CA
NO
NS
NS
NO
NO
ND
NO
NS
NS
NS
NS
ND
ND
ND
ND
NS
NS
ND
ND
ND
NS
ND
ND
ND
NS
NS
NS
ND
NS
ND
NS
NS
ND
ND
ND
ND
NS
NS
0.6-0.9
NS
NS
ND
ND
ND
ND
ND
NS
ND
ND
ND
NS
ND
ND
NS
NS
NS
NS
ND
NS
NS
ND
ND
NS
ND
ND
ND
ND
ND-0.35
NS
ND-0.3
ND
NS
ND
ND
ND
NS
ND
ND-0.45
NS
ND
ND-0.85
ND
ND
NS
NO
ND
ND-0.3
NS
ND
ND-0.3
*Source: Michael et al., 1984
NS = Not sampled
ND = Not detected with the detection limits being 0.5, 0.5 and 0.3
In 1980, 1981 and 1982, respectively.
0781p 3-5 05/13/86
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Kaplan, 1983). Dimethyl, dlethyl, dl-n-butyl, d1-n-octyl, d1(2-ethylhexyl)
and n-butyl benzyl phthalate esters have been Identified In urban runoff
waters at concentration ranges of 2-10, 0.5-11.0, 0.4-1, 7-39 and 10.0
vg/l, respectively (Cole et al., 1984). From their survey of contamina-
tion of Japanese rivers, Takana et al. (1978) concluded that only 10% of the
phthalate ester load In river waters Is attributable to atmospheric precipi-
tation and 90X to wash off following periods of rain.
Phthalate esters have also been Identified In groundwater from contami-
nated sites. In a system developed to study the trace organic removal effi-
ciency by an Infiltration site In Phoenix, AZ, Tomson et al. (1981) reported
complete removal of dimethyl phthalate from sewage water (0.023 pg/9.
Initial cone.) passed through a 60-foot deep Infiltration basin. The
removal of dlethylphthalate was -93%, but dlbutyl phthalate concentration
was observed to Increase as a result of Infiltration. Francis et al. (1980)
specified dlbutyl, dlethyl and several unidentified phthalates In leachates
from radioactive waste disposal sites at Maxey Flats, KY, and at West
Valley, NY. Dunlap et al. (1976a,b) detected several phthalate esters In
groundwater from a landfill site near Norman, OK; concentrations of
dlethyl, dllsobutyl and dloctyl phthalates were 4.1, 0.1 and 2.4 yg/a,
respectively (Dunlap et al., 1976a,b). Groundwater samples from a well at
General ElectMc's capacitor manufacturing facility 1n Ft. Edward, NY,
contained d1(2-ethylhexyl) phthalate (Welch, 1982). Hutchlns et al. (1983)
Identified dimethyl, dlethyl, dlbutyl and d1(2-ethylhexyl) phthalates In
groundwaters at Infiltration sites of secondary effluents at Ft. Devens, MA;
Boulder, CO; Lubbock, TX; and Phoenix, AZ. The maximum reported concentra-
tions of dimethyl, dlethyl, dlbutyl and dl(2-ethylhexyl) phthalates In these
groundwaters were 0.19, 0.87, 2.38 and 1.40 yg/i, respectively. DeHalle
0781p 3-6 06/06/86
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and Chlan (1981) reported cMbutyl and d1(2-ethylhexyl) phthalates at concen-
trations up to 1 and 100 yg/t In groundwaters from a landfill site In
New Castle County, DE. Leachate from a landfill site In Broome County, NY,
contained various phthalate esters, Including dlethyl phthalate at 15
pg/l (Russell and McDuffle, 1983). Dlethyl phthalate at 0.3 Mg/i
concentration was Identified In groundwater from a contaminated site In the
Netherlands (Zoeteman et al., 1981).
The concentrations of several phthalate esters In effluents and ambient
waters are given In Table 3-2.
Several phthalate esters have been Identified In drinking water
abstracted from groundwater and surface water In the United States and
elsewhere. The concentrations of four most frequently occurring phthalate
esters detected In the U.S. drinking waters are given In Table 3-3. It Is
evident from Table 3-3 that even the most frequently occurring phthalate
esters do not occur In all U.S. drinking waters. In a National Organlcs
Reconnaissance Survey of drinking waters from 10 U.S. cities (Seattle, HA;
New York, NY; Miami, PL; Tuscon, AZ; Ottumwa, IA; Grand ForKe, ND; Cincin-
nati, OH; Lawrence, MA; Philadelphia, PA; and Terrebonne Parish, LA), both
dl-n-butyl and dlethyl phthalate occurred In 60% of those waters (Bedding et
al., 1982). The Science Advisory Board of U.S. EPA reviewed selected
organic chemicals and estimated that the distribution of the phthalate
esters 1s -50% In U.S. drinking waters, with an overall phthalate concentra-
tion of -0.1 Mg/l (U.S. EPA, 1975).
Levins et al. (1979) reported In a survey of water from Cincinnati, St.
Louis, Atlanta and Hartford that the following percentages of samples from
each category contained the designated phthalates (Table 3-4).
0781p 3-7 08/26/86
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TABLE 3-2
Median Concentration of Phthalate Esters 1n Industrial
Effluents and Ambient Hater In the United States
Compiled from STORE! Stat1onsa«b
Phthalate
Dimethyl phthalate
Dlethyl phthalate
D1(2-ethylhexyl) phthalate
n-Butyl benzyl phthalate
Dimethyl phthalate
Dlethyl phthalate
D1(2-ethy1hexyl) phthalate
n-Butyl benzyl phthalate
Median
Concentration
(ng/l)
EFFLUENTS
<10.0
<10.0
10.0
<6.0
AMBIENT WATERS
<10.0
<10.0
10.0
<10.0
Number
of
Samples
1255
1286
1385
1337
836
862
901
1220
Frequency of
Occurrence
(X)
2.8
9.9
38.9
7.2
0.6
3.0
24.0
3.0
aSource: Staples et al., 1985
bThe authors used U.S. EPA STORET data only from the 1980s because better
quality control practices were used to develop the data at that time.
0781p
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06/06/86
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—J
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o
OD
ISi
CD
1ABLE 3-3
Concentrations of Commonly Reported Phthalate Esters Detected In Drinking Haters In the United States
•a
Location
Thirty-nine public water wells In
New York State
Maters from Torresdale Treatment
Plant In Philadelphia, PA
District of Columbia drinking water
CarrolUon Water Plant In New
Orleans. LAC
Jefferson fl Mater Plant In New
Orleans. LAC
Jefferson f? Mater Plant In New
-------
o
oo
TABLE 3-4
Percentage Occurrence of Phthalates by Hater Source
Residential Commercial Industrial Tap Water
to Total number of samples 47 42 21 12
i
0 Dlethyl phthalate 49 36 8
Dl-n-butyl phthalate 34 43 57 25
DEHP/d1-n-octyl phthalate 23 38 24 17
Influent
18
50
67
22
o
CD
en
-------
Levins et al. (1979) also reported tap water concentrations of phtha-
lates for each of the four cH1es. Dlethyl phthalate was detected only In
Cincinnati at a concentration of 3.3 vg/l. D1-n-butyl phthalate was
detected In Cincinnati at 14.3 an In Hartford at 3.8 wg/i. Butyl benzyl
phthalate was not detected In tap water for any of the four cH1es while
DEHP was found In Cincinnati only, at a concentration of 16.5 ng/l.
Phthalate esters are reportedly present In drinking water 1n other parts
of the world. Dl-n-butyl phthalate at concentrations up to 1 jjg/l has
been detected In drinking water In Shlzuoka, Japan (Shlbuya, 1979). Several
esters Including d1-n-butyl and dlethyl phthalate have been Identified In
several water supplies In England* (Fielding et al., 1981; Crathorne et al.,
1984; Packham et al., 1981). Morlta et al. (1974) Identified d1-n-butyl and
d1(2-ethylhexyl) phthalate In Tokyo tap water at mean concentrations of 2.3
and 1.3 yg/i, respectively. Shlralsh! et al. (1985) Identified
dl(2-ethylhexyl) phthalate In tap water from Tsukuba, Japan. Tap water from
Kltakyushu, Japan, was reported to contain dlethyl, d1-n-butyl and
d1(ethylhexyl) phthalates at maximum concentrations of 0.021, 0.24 and 0.24
vg/l, respectively (Aklyama et al., 1980; Shlnohara et al., 1981).
On' the basis of an overall average phthalate drinking water concentra-
tion of 1 pg/l (U.S. EPA, 1975) and a consumption rate of 2 l/day, the
dally exposure to phthalate ester by an Individual In the United States Is
-2 Mg.
3.2. AIR
It Is difficult to estimate the magnitude of different sources In
contributing to the atmospheric level of phthalate esters. Phthalate esters
used for nonplastlclzer purposes, such as pesticide carriers, cosmetics,
fragrances and Insect repellant, are subject to direct evaporation and may
0781p 3-11 08/26/86
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contribute substantially to the atmospheric burden of these compounds
(Peakall, 1975). The release of phthalates Into the atmosphere from various
plastics used In weather stripping, furniture, auto upholstery, wall cover-
Ings and other household materials will add to this. Reportedly, a new room
with PVC flooring may contain 0.15-0.26 mg/m3 of phthalates (Peakall,
1975). Klselev et al. (1983) have shown that the use of certain plastics as
household Items can result In the release of dlethyl, dimethyl, dlbutyl and
dloctyl phthalates Into the atmosphere. Probably the largest amount of
atmospheric phthalate esters originate from the Incineration of the plastics
containing phthalate esters. Peakall (1975) estimated that -2% of total
phthalate-contalnlng plastics used In the United States vaporizes Into the
atmosphere during Incineration. Several Investigators have Identified
phthalate esters In fly ash from municipal Incinerators, Including dimethyl,
dlethyl, dlbutyl, dloctyl, dllsooctyl and n-butyl benzyl phthalates (long et
al., 1984; Vlau et al., 1984; Elceman et al., 1979, 1981). The concentra-
tions of dimethyl, dlbutyl and dloctyl phthalates In the fly ash from an
electrostatic predpltater of a coal-fired power station In Frultland, NH,
were reported to be 46 ppb (371 vg/m3}, 140 ppb (1620 yg/m3) and 45
ppb (731 pg/m3), respectively (Harrison et al., 1985). Esters Including
dlethyl, dllsobutyl, dlbutyl and d! (2-ethylhexyl) phthalates were Identified
In the emissions from combination coal/refuse combustion (Vlck et al.,
1978). Similarly, phthalate esters were Identified In the emissions of a
wire-reclamation Incinerator (Hryhorczuk et al., 1981).
The presence of atmospheric phthalate esters were reported by several
Investigators (Wauters et al., 1979; Karasek et al., 1978; Meyers and HHes,
1982; Weschler, 1980) and quantitative worldwide levels are presented In
Table 3-5. These data for different urban and rural locations are greatly
0781p 3-12 08/26/86
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TABLE 3-5
Atmospheric Levels of a Few Phthalate Esters Measured Throughout the World
Concentrations of
Phthalate Esters (mq/m3)
Location
Chacaltaya, Bolivia (background level)
Antwerp, Belgium
Atmosphere of Gulf of Mexico
Atmosphere of Gulf of Mexico
Atmosphere of North Atlantic
Barrow, AK
Atmosphere of Enewetak Atoll,
North Pacific Ocean (background)
College Station. TX
Pigeon Key, FL
New York City. NY
Sterling Forest. NY
Indoor air, Wichita, KS
Outdoor air, Wichita, KS
Indoor air, Lubbock, TX
Outdoor air, Lubbock, TX
Hamilton, Ontario, Canada
DEP
0.66
4.4
NR
NR
NR
0.2
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
DBP
28
50
1.30
0.3
1.0
1.0
0.87
3.8
18.5
14.2
1.1
NR
NR
0.2
0.2
700*
DEHP
19
70
1.16
0.4
2.9
-20
1.4
2.4
16.6
13.7
2.8
55
2.2
20
2.0
300*
Reference
Cautreels et a)., 1977
Cautreels et al.. 1977
Glam et al. , 1980
Glam et al., 1978
Glam et al.. 1978
Weschler. 1981
Atlas and Glam. 1981
Atlas and Glam, 1981
Atlas and G1am. 1981
Bove et al.. 1978
Bove et al.. 1978
Weschler, 1984
Weschler, 1984
Weschler. 1984
Weschler, 1984
Thomas. 1973
*These values are much higher because the sampling site was adjacent to a municipal Incinerator.
NR = Not reported
-------
varied. For example, the sum of d1-n-butyl and d1(2-ethylhexyl) phthalate
concentrations In New York CUy was <20 ng/m3 (Bove et al., 1978), while
the value for the sum of the same two compounds was -120 ng/m3 for
Antwerp, Belgium (Cautreels, et al., 1977). There Is also a large differ-
ence 1n the reported levels of phthalate esters for remote areas and 1n some
cases the phthalate concentrations In remote areas reported by one author
exceeds the urban phthalate level reported by another author. Obviously,
unless more air monitoring data are developed In the United States, 1t will
not be possible to provide an average urban and rural levels for the phtha-
late esters. The Great Lakes Science Advisory Board (1980) estimates that a
total of -95 metric tons of airborne d1-n-buty1 and d1(2-ethylhexyl) phtha-
0
lates are deposited Into the Great Lakes every year.
Maximum exposure to phthalate esters 1s likely to be under occupational
conditions. The National Occupational Hazard Survey (NIOSH, 1985) estimates
that -2,406,700 workers are annually exposed to dlethyl, d1-n-butyl and
d1(2-ethylhexyl) phthalates 1n the United States. U.S. EPA (1980a) reported
that the concentration of phthalate esters ranged from 1.7-40 mg/m3 1n one
area and from 10-66 mg/m3 In another area of a company that manufactured
artificial leather and PVC films. The level of dlethyl phalate 1n the
vulcanization area of a shoe-sole factory was reported to vary between 0 and
120 ng/m3 (Cocheo et al., 1983). Concentrations of d1-n-butyl, dllso-
butyl and d1(2-ethylhexyl) phthalate In the vulcanization area of a tire
retreading factory were 10-2500, 5-500 and 0-2 yg/m3, respectively
(Cocheo et al., 1983).
American published reports on the levels of phthalate esters 1n occupa-
tional atmosphere are rare. The exposure of phthalate esters to the U.S.
population residing In urban, suburban and rural areas cannot be estimated
because of the lack of reliable monitoring data.
0781p 3-14 08/26/86
-------
3.3. FOOD
Many of the packaging materials and tubings used to produce foods and
beverages are plastics that contain phthalate esters. These esters may
migrate from the plastics to the food during contact. Two 1 m PVC tubings,
one containing 47.2% dlnonyl phthalate and the other containing 5.5X
d1(2-ethylhexyl) phthalate, when kept In contact with 100 ml milk for a
period of 24 hours at a temperature of 38°C, leached out 46 and 20 mg/l of
the two respective compounds Into the milk (HUdbrett, 1973). It Is also
reported that cheese and lard kept In contact with plastic films for 1 month
at ?5°C were contaminated with phthalate esters, at concentrations <2 ppm
(U.S. EPA, 1980a). Since commercial vegetable oils are often sold In
plastic containers, Williams (1973b) analyzed one corn oil and several soy
oil samples for d1(2-ethylhexyl) phthalate, but did not detect It In any of
these oils. Several authors have Identified phthalate esters In foods,
particularly aquatic foods; levels and their food sources are given In
Table 3-6.
It Is evident that phthalate esters are present In a variety of foods
consumed by humans. Estimates, however, of human consumption of these
compounds from foods requires the foreknowledge of phthalate levels In such
foods. In the absence of such data, It Is not possible to estimate the
phthalate exposure from food sources.
3.4. DERMAL
Phthalate esters can be absorbed through the skin during the use of many
cosmetic products, Insect repellants and the water from PVC-Hned swimming
pools. Hemod1alys1s tubing and PVC bags containing Intravenous solutions
also can be sources of exposure to these compounds for a special segment of
the population. U.S. EPA (1980a) describes phthalate ester exposure from
0781p 3-15 08/26/86
-------
o
«J
oo
TABlt 3-6
Concentrations of Phthalate Esters tn Some foods
CO
i
o
oo
CO
cr
Concentration of Phthalate (mq/kq)
Food
Perch (Perca f luvlatllls) muscle
Pike (Esox hlclus) muscle
Clams
Herring (fillets)
Mackerel (fillets)
Plaice (fillets)
Redflsh (fillets)
Spade fish (muscle)
Croaker (muscle)
Trout (muscle)
Shark (muscle)
Catfish (muscle)
Shrimp (whole)
Sting ray (muscle)
Eel (whole)
Blue crab (muscle)
Rainbow trout (whole)
Whole milk
Skim milk
Butter
Bourbon whiskey
Unprocessed eel
Unprocessed catfish
Unprocessed pickerel
Unprocessed pickerel
a
Canned tuna
Canned salmon
Canned shrimp
Source
South Coast of Finland
South Coast of Finland
Portland. ME
Gulf of St. Lawrence
Gulf of St. Lawrence
Gulf of St. Lawrence
Gulf of St. Lawrence
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Gulf of Mexico
Tokoyo. Japan
Tokoyo. Japan
Tokoyo, Japan
Tokoyo. Japan
Imported to Japan
Canada
Lake St. Pierre
Lake Huron
Lake Ontario
Canada
Canada
Canada
DBP
NR
NR
0.07
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
0.6
O.OS
0.2
4-11
0.06
ND
ND
ND
NQ
0.078
0.037
NO
01 HP
0-0.1
0
0.14
4.71
6.50
<0.010
<0.010
0.011
0.003
0.004
0.00?
ND
0.008
0.012
0.002
0.003
NR
NR
NR
NR
NR
0.104
NO
NO
NO
0.160
0.089
ND
Reference
Persson et al, . 1978
Persson et al. . 1978
Ray et al.. 1983
Muslal et al.. 1981
Muslal et al., 1981
Muslal et al.. 1981
Muslal et al.. 1981
Gtam et a).. 19/5
Glam et al.. 1975
Glam et al.. 1975
Glam et al.. 1975
Gtam et al.. 1975
Glam et al. , 1975
Glam et a).. 1975
Glam et al. . 1975
Gtam et al.. 1975
Mortta et al.. 19/3
Morlta et al.. 1973
Horlta et al.. 1973
Morlta et al.. 1973
Salto et al. . 1980
Williams. 1973a
Williams. 1973a
Williams. 1973a
Williams. 1973d
Williams. 1973d
Williams. 1973a
Williams, 1973d
-------
TABLE 3-6 (cont. )
— 1
CO
•o Food
Frozen rainbow trout
Frozen ocean perch
Frozen mackerel
Hatchery-reared Juvenile
Atlantic salmon (commercial)
Egg white
Salad oil3
Lard
Soft margarine3
Mayonnaise3
Instant vegetable cream soup
Instant corn cream soup
OS
j_, Fried cake
•^ Wheat flour3
Bread crumbs3
Rice powder
Hashed potatoes
Sugar
Table salt3
Soy sauce
Worcestershire sauce
Honey
Pickles
Rainbow trout
Long-nose sucker
Whlteflsh (fillet)
o
Source
Canada
Canada
Canada
Atlantic Ocean
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Japan
Great Lakes
Great Lakes
Great Lakes
Concentrat Ion of
OBP
ND
ND
ND
NR
0.098
0.11
0.09
3.1?
1.25
6.35
0.17
0.64
?.47
0.77
0.03
0.09
0.16
1.41
0.03
0.17
0.11
0. 16
5.4
8.1
NR
Phthalate (mq/kq)
DC HP
NO
NQ
NQ
)3-)6b
0.18?
0.15
0.10
O.b5
ND
ND
0.49
1 .57
0.03
0.33
0.05
0.01
0.04
o.o;
0.08
0.17
0.37
NK
NR
7-1
Reference
Williams. 1973a
Williams. I9?3a
Williams. 1973d
Zltko. 1973
Ishlda et al.. 1981
Tomlta et al.. 1977
Tomlta et al.. 1977
Tomlta et al.. 1977
Tomlta et al. . 1977
Tomlta et al. . 1977
Tomlta et al. . 1977
Tomlta et al.. 1977
Tomlta et al.. 197?
Tomlta et al.. 1977
Tomlta et al.. 197?
Tomlta et al.. 1977
Tomlta et al.. 1977
Tomlta et al. . 1977
Tomlta et al., 1977
Tomlta et al., 1977
Tomlta et al. , 1977
lomlta et al. . 197/
Glass et al.. 1977
Glass et al. , 1977
Glass et a). . 1977
ro aThese are the highest reported values
CD bTh1s represents concentration range In the llptd
NR = Not reported; NQ = compound Identified but not quantified; NO -- not detected
-------
other medical sources. Several authors have measured the levels of phtha-
late esters In serum from surgical patients (Chlng et al., 1981) and in
human adipose tissues (Mes and Campbell, 1976; Mes et al., 1974), although
the latter concentrations probably represent exposure from Inhalation,
Ingestlon and dermal exposure sources.
3.5. SUMMARY
Phthalate esters are ubiquitous In the environment. They have been
Identified 1n surface waters In the United States and elsewhere In the
world. The maximum reported concentration of dl(2-ethylhexyl) phthalate 1n
any surface water was 600 yg/a, which was detected In Mississippi River
water (Corcoran, 1973). The average concentration of Individual phthalate
esters in surface water Is <1 vq/l (Michael et al., 1984). Phthalate
esters have also been Identified In groundwater from contaminated sites; a
maximum of 100 ug/l of d1(2-ethylhexyl) phthalate was detected In
groundwater from a landfill site In New Castle County, DE (DeWalle and
Chlan, 1981). Several phthalate esters have been Identified In drinking
water abstracted both from surface water and groundwater. The maximum
concentrations of dlethyl, d1-n-butyl, d1(2-ethylhexyl) and butyl benzyl
phthalates In 39 public water wells were reported to 4.6, 470, 170 and 38
wg/t, respectively (CEQ, 1980, 1981; Burmaster, 1982). The Science
Advisory Board of the U.S. EPA reviewed selected organic chemicals and
estimated that the distribution of the phthalate esters Is -50% In U.S.
drinking waters, with an overall phthalate concentration of ~1 yg/l
(U.S. EPA, 1978c). On the basis of these data and an average consumption
rate of 2 l/day, dally phthalate exposure to a U.S. Individual from
Ingesting drinking water Is estimated to be 2 vg.
0781p 3-18 08/26/86
-------
Phthalate esters have been detected In ambient atmosphere. Probably the
biggest contributor to atmospheric phthalate Is the Incineration of plastics
that contained the esters (Peakall, 1975). The concentrations of dl-n-butyl
and dl (2-ethylhexyl) phthalate -In New York City's ambient air were 4.2
mg/m3 and 13.7 ng/m3, respectively (Bove et al., 1978). In College
Station, TX, the corresponding values were reported to be 3.8 and 2.4
ng/rn3 (Atlas and G1am, 1981). Until more air monitoring data become
available. It Is not possible to provide average urban and rural levels of
phthalate esters. Consequently, Inhalation exposure of phthalate esters to
the U.S. population residing In urban, suburban and rural areas cannot be
estimated. Maximum exposure to phthalate esters Is likely to occur under
occupational conditions. Concentrations of phthalate esters ranged from
1.7-40 mg/m3 1n a mixing area and from 10-66 mg/m3 In another area of a
company manufacturing artificial leather and films of PVC (U.S. EPA, 1980b).
NIOSH (1985) estimates that -2,406,700 workers are annually exposed to
dlethyl, d1-n-butyl and d1(2-ethylhexyl) phthalate 1n the United States.
Several authors have Identified phthalate esters In foods. D1(2-ethyl-
hexyl) phthalate was detected at a concentration of 6.50 mg/kg In mackerel
fillets (Huslal et al., 1981). The concentration of d1-n-butyl phthalate In
rainbow trout from the Great Lakes was reported to be 8.1 mg/kg (Glass et
al., 1977). In butter samples obtained from Japan, the concentration of
d1-n-butyl phthalate was 4-11 mg/kg (Morlta et al., 1973). Instant
vegetable cream soup obtained from a Japanese market contained 6.35 mg/kg of
dl-n-butyl phthalate (TomHa et al., 1977). No estimates of phthalate ester
exposure from food composites typically consumed by an Individual In the
United States are available.
0781p 3-19 08/26/86
-------
Phthalate esters can be absorbed through the skin during the use of many
cosmetic products, Insect repellants and the water from PVC-Hned swimming
pools (U.S. EPA, 1980a). A special segment of the population 1s exposed to
phthalate esters during medical/surgical procedures, such as hemodlalysl's
and Intravenous applications. No estimates on the dermal exposure of
phthalate esters to Individuals can be made from the data available 1n the
literature as dted In the Appendix.
0781 p 3-20 08/26/86
-------
4. PHARMACOKINETICS
The pharmacoklnetlcs of phthalate esters has been reviewed by Kluwe
(1982), Albro et al. (1982), Thomas and Thomas (1984), and U.S. EPA (1978b,
1980b, 1985a). The majority of studies have focused on d1(2-ethylhexyl)
phthalate. Information on the pharmacoklnetlcs of aryl or aryl/alkyl esters
of phthallc add could not be located 1n the available literature as cited
1n the Appendix.
4.1. ABSORPTION
In general, excretion profiles Indicate that alkyl phthallc acid esters
and their degradation products are probably well absorbed from the gastro-
intestinal tract.
When d1(2-ethylhexyl) phthalate (10 or 2000 ppm) was administered to
rats In the diet, >90% of the administered dose was excreted as metabolites
In the urine; the remainder was excreted In the feces (Williams and Blanch-
field. 1974). When d1(2-ethylhexyl) phthalate was administered to rats by
gavage (3 or 1000 mg/kg, vehicle = corn oil), 42-54% of the administered
dose was excreted as metabolites 1n the urine, while 24-57% was excreted as
metabolites In the feces within 1-4 days (Williams and BlanchHeld, 1974;
Daniel and Bratt, 1974). In humans, 10-15% of a single oral dose of
d1(2-ethylhexyl) phthalate was excreted In the urine within 24 hours of
administration (Schmld and Schlatter, 1985). Absorption of d1(2-ethylhexyl)
phthalate and degradation products may be greater than urinary levels of
metabolites would Indicate, since substantial biliary excretion has been
observed 1n rats, dogs and miniature pigs (Daniel and Bratt, 1974; Ikeda et
al., 1980).
0782p 4-1 06/06/86
-------
Gastrointestinal absorption of d1-n-butyl phthalate can be Inferred from
observations that >90% of a single dose of d1-n-butyl phthalate administered
to rats by gavage (60, 270 or 2310 mg/kg, vehicles = corn oil, DMSO) was
excreted as metabolites In the urine within 2 days; the remainder was
excreted In the feces (Tanaka et al.. 1978; Williams and BlanchMeld, 1975).
Substantial biliary excretion of d1-n-butyl phthalate metabolites (30-60% of
60 mg/kg dose within 2 days) was also observed (Tanaka et al., 1978).
Ikeda et al. (1978) observed that metabolites of d11sooctyl phthalate
were excreted In the urine, feces and bile of dogs, rats and miniature pigs
exposed orally to dllsooctyl phthalate (21-28 days In feed, then single
gavage dose of l4C-d1 Isooctyl phthalate In corn oil), qualitatively
Indicating that gastrointestinal absorption of dllsooctyl phthalate or Its
degradation products occurs In each of these species.
Apparent hydrolytlc activity toward d1 (2-ethylhexyl ) phthalate 1n
pancreatic homogenates led Albro and Thomas (1973) to hypothesize that very
little, 1f any. Intact phthalate dlester Is absorbed from the gastrointes-
tinal tract. Further studies have shown that phthalate esters d1(2-ethyl-
hexyl) phthalate, dimethyl phthalate, d1-n-butyl phthalate, d1-n-octyl
phthalate) are readily hydrollzed to their monoester derivatives by enzymes
In Intestinal mucosal cells (Rowland, 1974; White et al., 1980) and other
tissues (Carter et al., 1974), and by extracellular enzymes present In the
Intestinal contents of rats, ferrets and baboons (Rowland, 1974; Rowland et
al., 1977; Lake et al., 1977b).
Recent gavage studies on rats demonstrated that d1 (2-ethylhexyl )
phthalate was hydrolyzed to monoethylhexyl phthalate, which was subsequently
absorbed (TeUlynck and Belpalre, 1985; Olshl and Hlraga, 1982). Telrlynck
and Belpalre (1985) reported that plasma concentrations of 8.8^1.7
0782p 4-2 06/06/86
-------
d1(2-ethylhexyl) phthalate and 63.2^8.7 pg/mi monoethylhexyl phthalate
were reached within 3 hours after a single oral dose of d1(2-ethylhexyl)
phthalate {2.8 g/kg 1n corn oil). These observations raise concern about
the validity of using route-to-route extrapolation In either quantitative or
qualitative assessment of risk associated with 1ngest1on, since It appears
that the d'alkyl esters are largely hydrolyzed to monoester derivatives
before absorption from the gastrointestinal tract. In a recent study on
rats, Pollack et al. (1985a) found that 80% of a single oral (gavage In corn
oil) dose of d1(2-ethylhexyl) phthalate was hydrolyzed to Us monoester
derivative (monoethylhexyl phthalate) and subsequently absorbed; 13% of the
dose was absorbed as d1(2-ethylhexyl) phthalate. The ratio of the AUCs for
monoethylhexyl phthalate to dl(2-ethylhexyl) phthalate was -1. Repetitive
oral dosing did not affect the extent of absorption. In contrast, uptake of
d1(2-ethylhexyl) phthalate and Us derlvatlve(s) Into the bloodstream from
the peritoneal cavity was poor. Only IX of an equivalent Intraperltoneal
dose was hydrolyzed to monoethylhexyl phthalate; 5.2% was taken up as
d1(2-ethylhexyl) phthalate. The ratio of the AUC for monoethylhexyl phtha-
late to d1(2-ethylhexyl) phthalate after either Intraperltoneal or Intra-
arterlal administration was <0.4. Furthermore, repetitive Intraperltoneal
administration of d1(2-ethylhexyl) phthalate led to an apparent decrease 1n
the rate and extent of uptake. Poor Intraperltoneal uptake Into the blood
was attributed to the fact that d1(2-ethylhexyl) phthalate 1s UpophlUc and
distributed Into the peritoneal fat. U.S. EPA (1980b) and Thomas and Thomas
(1984) state that phthallc add esters may not be readily taken Into the
bloodstream from the peritoneal cavity, and both sources question whether
Intraperltoneal studies are useful 1n oral risk assessment.
0782p 4-3 06/06/86
-------
4.2. DISTRIBUTION
Several studies have shown that d1(2-ethylhexyl) phthalate and d1-n-
butyl phthalate, administered either orally or Intravenously, are cleared
rapidly from the body, largely within 24 hours of exposure (Tanaka et al.,
1975, 1978; Williams and Blanchfleld, 1974, 1975; Ikeda et al., 1980; Daniel
and Bratt, 1974; Olshl and Hlraga, 1982; Telrlynck and Belpalre, 1985). The
same observation holds true for orally administered d11sooctyl phthalate
(Ikeda, et al., 1978). The parent compound and metabolites are distributed
primarily to plasma, liver, kidney, the gastrointestinal tract and fat.
Metabolites have also been found In almost every other tissue. In particu-
lar, a high concentration of monoethylhexyl phthalate, the hydrolytlc
derivative of d1(2-ethylhexyl) phthalate, has been found 1n the testes of
rats (Olshl and Hlraga, 1982). Concentrations of d1(2-ethylhexyl) phthalate
and metabolites In various tissues, particularly liver, kidney and fat, vary
with route of administration (diet, gavage, parenteral), vehicle and dose
(Thomas and Thomas, 1984; Polla.ck et al., 1985a; Albro et al., 1982).
In a dietary study on rats, Daniel and Bratt (1974) reported that
steady-state tissue concentrations of radioactivity from l4C-d1(2-ethyl-
hexyl } phthalate were proportional to dietary concentrations and reached
maximum values 1n liver and fat within 1 and 2 weeks of treatment, respec-
tively. When dietary d1(2-ethylhexyl) phthalate was removed, radioactivity
1n the liver and fat declined, with half-lives of 1-2 days and 3-5 days,
respectively.
The distribution and retention of d1(2-ethylhexyl) phthalate and Us
monoester derivative, monoethylhexyl phthalate, were examined 1n gavage
studies on rats. Telrlynck and Belpalre (1985) reported that maximum
concentrations of monoethylhexyl phthalate and d1(2-ethylhexyl) phthalate
0782p 4-4 05/13/86
-------
were reached In the plasma within 3 hours of a single dose of d1(2-ethyl-
hexyl) phthalate (2.8 g/kg In corn oil). The ratio of the AUCs for mono-
ethylhexyl phthalate to d1(2-ethylhexyl) phthalate was 16.1^6.1. Monoethyl-
hexyl phthalate disappeared from the plasma with a t. . of 5.2+.0.5 hours.
The concentration of dl (2-ethylhexyl) phthalate 1n the plasma was considered
too low for accurate estimation of t,/7- Repetitive dosing with
d1(2-ethylhexyl) phthalate (2.8 g/kg/day In corn oil for 7 days) produced no
accumulation of either monoethylhexyl phthalate or d1(2-ethylhexyl) phtha-
late In the plasma.
Olshl and Hlraga (1982) reported that maximum concentrations of
d1(2-ethylhexyl) phthalate and monoethylhexyl phthalate were observed In the
blood and tissues of rats within 6-24 hours after a single oral dose of
d1(2-ethylhexyl) phthalate of 25 mmol/kg (9.8 g/kg) In corn oil. In
general, the disappearance of monoethylhexyl phthalate from the tissues was
slower than that of d\(2-ethylhexy1) phthalate; half-lives for monoethyl-
hexyl phthalate ranged from 22.6-68 hours, while half-lives for d1(2-ethyl-
hexyl) phthalate In several tissues ranged from 1.49-156 hours (Table 4-1).
The ratio of monoethylhexyl phthalate/d1(2-ethylhexyl) phthalate, measured 6
hours after dosing, was 113+23, 79*.!?, 210i4.8, 46*.0.57 and 87*24 In blood,
liver, testes, heart and epldldymal fat, respectively. In this study,
concentrations of d1(2-ethylhexyl) phthalate and monoethylhexyl phthalate In
the kidneys were very low.
Little Is known about the ability of phthallc acid esters to cross the
placenta (Kluwe, 1982). Using perfuslon techniques, Klhlstrom (1983) showed
that Intravenously administered dl(2-ethylhexyl) phthalate Is transported
across the placenta of guinea pigs and appears In the fetal circulation.
0782p 4-5 05/13/86
-------
TABLE 4-1
Biological Half-Lives of 01(2-ethylhexyl) Phthalate and Honoethylhexyl
Phthalate 1n Rats After a Single Oral Dose of D1(2-ethylhexyl)
Phthalate (25 imnol/kg In Corn 01l)a
Tissue
Blood
Liver
Testes
Heart
Spleen
Lung
Ep1d1dymal fat
M/2
MEHP
23.8
31.9
49.9 (6 < t < 48)
28.8
22.6
NO
67.6 (24 < t < 96)
(hours)b
DEHP
18.6
28.4
8.28 (24 < t < 96)
15.2
NO
1.49 (1 < t < 6)
25.3 (6 < t < 96)
156 (48 < t < 96)
aSource: 01sh1 and Hlraga, 1982
bB1olog1cal t]/2 calculated from least-squares fit of data during 6-96
hours except for tlmeframes Indicated for testes, lung and fat.
NO = No data
0782p 4-6 05/13/86
-------
Singh et al. (1975) demonstrated that radioactivity from l4C-d1ethyl
phthalate and 14C-d1(2-ethylhexyl) phthalate (position of label not
reported) administered IntrapeM toneal ly to rats on either day 5 or 10 of
gestation was found In the placentas, amnlotlc fluid and fetal tissue
throughout gestation. The relevance of these findings to orally Ingested
phthallc add esters Is unclear.
4.3. METABOLISM
Kluwe et al. (1982a) states that, In general, the metabolism of alkyl
phthallc add esters 1s not qualitatively affected by route of administra-
tion. The first step of metabolism entails hydrolysis to a monoester
derivative (Kluwe, 1982); the location and extent to which this occurs Is
route-dependent (Pollack et al., 1985a). Ingested phthallc add esters are
converted to their monoester derivatives by enzymes 1n the gastrointestinal
tract before absorption (see Section 4.1.). Since other tissues contain
enzymes capable of hydrolyzlng phthallc add esters (Carter et al., 1974),
parenterally administered phthallc add esters can also be hydrolyzed.
Once formed, the monoester derivative can then be further hydrolyzed to
phthallc add and excreted; conjugated to glucuronlde and excreted; or
oxidized and excreted (Kluwe, 1982).
Short-chain phthallc add esters, such as d1-n-butyl phthalate and
dimethyl phthalate can be excreted as parent compound, their monoester
derivatives and pthallc add. In rats, only small quantities of monoester
derivatives from longer-chain phthallc add esters, such as d1 (2-ethylhexyl)
phthalate or dllsooctyl phthalate are converted to phthallc add before
excretion (Albro and Thomas, 1973; Albro and Moore, 1974; Albro et al.,
1973).
0782p 4-7 06/06/86
-------
In all mammalian species tested but the rat, glucuronlde conjugates of
monoethylhexyl phthalate are the major urinary metabolites of d1(2-ethyl-
hexyl) phthalate (Albro et al., 1982; Kluwe, 1982). Species that form
glucuronlde conjugates of monoethylhexyl phthalate Include humans, hamsters,
green monkeys, guinea pigs and mice (Albro et al., 1981, 1982; Peck et al.,
1978; Telrlynck and Belpalre, 1985; Schmld and Schlatter, 1985). The
absence of conjugates of dM2-ethylhexyl) phthalate metabolites has been
confirmed In 3 strains of rat (Williams and Blanchfleld, 1975; Daniel and
Bratt, 1974; Chu et al., 1981; Tanaka et al., 1975; Albro and Moore, 1974;
Albro et al., 1973; Albro et al., 1982; Kluwe, 1982; Thomas and Thomas,
1984). In contrast, a glucuronlde conjugate of the dl-n-butyl phthalate
monoester derivative (mono-butyl phthalate) has been Identified as a major
urinary metabolite In rats, In hamsters and guinea pigs (Tanaka et al.,
1978; Foster et al., 1982; Kaneshlma et al., 1978).
Oxidation of monoester derivatives of dlalkyl phthallc acid esters has
been observed 1n rats, guinea pigs and hamsters (Williams and Blanchfleld,
1974, 1975; Tanaka et al., 1978; Daniel and Bratt, 1974; Chu et al., 1981;
Lhuguenot et al., 1985). In general, the terminal or next-to-last carbon
atom 1n the monoester derivative 1s oxidized to an alcohol. Aldehydes,
ketones and carboxyllc adds are formed by successive oxidations. Compounds
with alkyl chains containing six or more linear carbons may undergo
B-ox1dat1on (Kluwe, 1982; Albro and Moore, 1974; Albro et al., 1973).
4.4. EXCRETION
Excretion of dllsooctyl phthalate, d1-n-butyl phthalate and d1(2-ethyl-
hexyl) phthalate and their metabolites has been studied. Routes of excre-
tion for these compounds Include urine, feces and bile; the relative Impor-
tance of route of excretion depends upon the compound and species, while the
0782p 4-8 06/06/86
-------
rate of excretion appears to be rapid despite those considerations. The
available studies are summarized In Table 4-2.
Half-lives of 7.9 and 12 hours have been reported for excretion of
d1 (2-ethylhexyl) phthalate and metabolites 1n rats (Telrlynck and Belpalre,
1985) and humans (Schmld and Schlaffer, 1985), respectively. Excretion
half-lives of 1.2 and 5.4 hours have been reported for dllsooctyl phthalate
and metabolites In dogs and miniature pigs, respectively (Ikeda et al.,
1978).
Comparative studies with 14C-dnsooctyl phthalate (Ikeda et al.. 1978)
have shown that urinary excretion prevails In mlnlplgs, fecal excretion
prevails In dogs, and rats excrete approximately equal quantities of radio-
activity 1n urine and feces. Early biliary excretion (4-24 hours after
dosing) was shown to be substantial 1n dogs, but low 1n rats and mlnlplgs.
In rats, d1-n-butyl phthalate 1s primarily excreted In the urine (-90X),
with the balance excreted In the feces (Tanaka et al., 1978; Williams and
Blanchfleld, 1975). Substantial biliary excretion has been shown to occur
from within a few hours to 5 days after dosing {Tanaka et al., 1978;
Kaneshlma et al., 1978).
It Is difficult to generalize about patterns of excretion of d1(2-ethyl-
hexyl) phthalate In rats, althrough the reasons for apparent discrepancies
are unclear. In a recent comparative study where rats, dogs and mlnlplgs
were fed a diet containing d1(2-ethylhexyl) phthalate (equivalent to 50
mg/kg/day) for 21-28 days then treated by gavage with a single dose of
14C-d1(2-ethy'lhexyl) phthalate (50 mg/kg), urinary excretion was the major
route In mlnlplgs only. Rats and dogs, 1n particular, excreted radioactiv-
ity primarily In the feces. Biliary excretion was shown to be substantial
In dogs and minimal 1n mlnlplgs and rats (Ikeda et al., 1980).
0782p 4-9 05/13/86
-------
TABLE 4-?
Excretion of Phthallc Acid Esters
0
-J
CD
•o
_^
1
0
98/90/90
Compound Species tj/?
(hours)
DEHP human
human
rat
rat
rat
rat
rat
rat
dog
mlnlplg
DBP rat
rat
rat
rat
OIOP rat
dog
dog
mlnlplg
mlnlplg
aVeh1cle = corn oil for
bD1etary administration
12
NR
7.9
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR.
1.2
1.2
5.4
5.4
gavage
for 21
Route3
oral (single dose)
oral (4 doses)
gavage
gavage
diet or gavage
d1et/gavageb
diet
l.v.
dlet/gavageb
d1et/gavageb
gavage or l.v.
gavage
gavage
l.v.
d1et/gavageb
dlet/gavageb
d1et/gavageb
dlet/gavageb
d1et/gavageb
studies
-28 days, fasted overnight
X Dose
Time
2 days
2 days
72 hours
48-192 hours
48 hours
4 days
NR
7 days
4 days
4 days
48 hours
48 hours
5 hours
5 hours
4 days
4-21 days
4-24 hours
4-21 days
4-24 hours
. then by gavage
Urine
10-15
10-25
19.3
-60
42-57
27-37
91-98
49
1?-21
79
>90
80-90
NR
NR
41-57
23-28
9
65-86
15-49
with
Feces
NR
NR
balance
-40
38-57
53-56
2-8
28
5S-75
26
-8
balance
NR
NR
38-45
69-80
41
13-32
0-0.13
14C-Ester
Bile
NR
NR
NR
NR
9-14
<1
NR
NR
7-10
0.01-1.2
32-57 (gavage only)
NR
4.5
10
<1
trace-0.29
6-13
trace-0.01
0.25-0.73
In corn ol 1 .
Reference
Schmld and Schlatter, 1985
Schmld and Schlatter. 1985
Telrlynck and
Williams
and
Bel pa Ire,
Blanchf leld
1985
. 1974
Daniel and Bratt. 1974
Ikeda et
Williams
Tanaka et
Ikeda et
Ikeda et
Tanaka et
Williams
al..
and
al.
al..
al..
al.
and
Kaneshlma et
Kaneshtma et
Ikeda et
Ikeda et
Ikeda et
Ikeda et
Ikeda et
al..
al..
a)..
al..
al..
1980
Blanchf leld
. 1975
1980
1980
. 1978
Blanchf leld
al.. 1978
al.. 1978
1978
1978
19/8
1978
1978
. 1974
. 1975
HR = Not reported
-------
Daniel and Bratt (1974) observed substantial biliary excretion (9-1454)
In rats when d1(2-ethylhexyl) phthalate was administered 1n the diet for 7
days or as a single dose by gavage. The dose of d! (2-ethylhexyl) phthalate
(2.6 mg/kg bw) was considerably lower than the dose applied by Ikeda et al.
(1980) (50 mg/kg bw). The reason for the discrepancy remains unclear.
Other oral studies (gavage and diet) on rats Indicate that either fecal
and urinary excretion are approximately equal (Williams and BlanchMeld,
1974; Daniel and Bratt, 1974) or that fecal excretion prevails (Telrlynck
and Belpalre, 1985). In a dietary study on rats, Williams and BlanchMeld
(1974) showed that regardless of concentration [10 or 2000 ppm d1(2-ethyl-
hexyl) phthalate], urinary excretion prevailed (91-98% of administered
dose). In humans, only 10-1554 of a single oral dose or 10-2554 of four dally
oral doses of d1(2-ethylhexyl) phthalate were recovered as metabolites 1n
the urine within 48 hours of administration (Schmld and Schlatter, 1985).
4.5. SUMMARY
Oral studies show that d!(2-ethylhexyl) phthalate, d1-n-butyl phthalate,
and dllsooctyl phthalate are absorbed from the gastrointestinal tract
(Williams and Blanchfleld, 1974, 1975; Daniel and Bratt, 1974; Ikeda et al.,
1978, 1980; Tanaka et al., 1978; Pollack et al., 1985a; 01shl and Hlraga,
1982; Telrlynck and Belpalre, 1985; Schmld and Schlatter, 1985). Pollack et
al. (1985a) demonstrated that uptake of 1ntraper1toneally administered
d1(2-ethylhexyl) phthalate Into the blood Is poor 1n rats. Orally adminis-
tered phthallc add esters are primarily and largely converted to their
monoester derivatives by enzymes In the gastrointestinal tract before
absorption (Albro and Thomas, 1973; Rowland, 1974; Rowland et al., 1977;
Lake et al., 1977; Carter et al., 1974; White et al., 1980; Pollack et al.,
1985; Telrlynck and Belpalre, 1985; 01sh1 and Hlroga, 1982). Other tissues
0782p 4-11 06/06/86
-------
such as the Hver have also been shown to hydrolyze phthallc acid esters
(Carter et al., 1974). In contrast, IntrapeMtoneally administered
d1(2-ethylhexyl) phthalate Is taken up primarily as d1(2-ethylhexyl) phtha-
late, with only 1% hydrolyzed to monoethylhexyl phthalate (Pollack et al.,
1985a).
Oral and Intravenous studies Indicate that d1(2-ethylhexyl) phthalate,
dl-n-butyl phthalate and dllsooctyl phthalate are not retained for long 1n
the body (Tanaka et al.. 1975, 1978; Williams and Blanchfleld, 1974, 1975;
Daniel and Bratt, 1974; OUhl and Hlraga, 1982; Telrlynck and BelpaUe,
1985; Ikeda et al., 1978, 1980). In general, phthallc acid esters and
metabolites distribute primarily to liver, kidneys, fat and the gastro-
intestinal tract. Metabolites have been found In almost every tissue; 1n
particular a high concentration of monoethylhexyl phthalate, the hydrolytlc
derivative of d1(2-ethylhexyl) phthalate, has been observed In the testes of
rats (OIsM and Hlraga, 1982). The distribution of d1(2-ethylhexyl) phtha-
late and metabolites 1n various .tissues, particularly liver, kidneys and
fat, has been observed to vary wHh route of administration (diet, gavage,
parenteral), vehicle and dose (Thomas and Thomas, 1984; Pollack et al.,
1985a; Albro et al., 1982). In a dietary study on rats, radioactivity from
l4C-d1(2-ethylhexyl) phthalate In the liver and fat declined with half-
lives of 1-2 and 3-5 days, respectively (Daniel and Bratt, 1974). In gavage
studies (Olshl and Hlraga, 1982). the disappearance of d1(2-ethylhexyl)
phthalate from tissues (t,,~ ranging from 1.49-156 hours) was more rapid
than for that of monoethylhexyl phthalate (t,/? ranging from 22.6-68
hours).
0782p 4-12 05/13/86
-------
Although short-chain phthallc acid cHesters such as dimethyl phthalate
can be excreted unchanged In the urine, most phthallc add dlesters are
further metabolized before excretion. The first step of metabolism entails
hydrolysis of the parent compound to a monoester derivative. Once formed,
the monoester derivative can then be further hydrolyzed to phthallc add and
excreted, conjugated with glucuronlde then excreted, or oxidized and
excreted. The first alternative occurs primarily with short-chain phthallc
add esters (Albro and Thomas, 1973; Albro and Moore, 1974; Albro et al.,
1973). The second alternative Is the primary route of metabolism for
d1 (2-ethylhexyl J phthalate and occurs In all spedes except the rat (Albro
et al., 1973, 1981, 1982; Kluwe et al., 1982a,b; Peck et al., 1978;
Telrlynck and Belpalre, 1985; Schmld and Schlatter, 1985; Williams and
BlanchMeld, 1975; Daniel and Bratt, 1974; Chu et al., 1978; Tanaka et al.,
1975; Thomas and Thomas, 1984); however, glucuronlde conjugates of
dl-n-butyl phthalate have been observed In rats (Tanaka et al., 1978; Foster
et al., 1982; Kaneshlma et al., 1978). The third route of metabolism has
been observed In rats, guinea pigs and hamsters (Williams and BlanchHeld,
1974, 1975; Tanaka et al., 1978; Daniel and Bratt, 1974; Chu et al., 1981;
Shuguenot et al., 1975). The metabolism of phthallc add esters Is not
qualitatively affected by route of exposure (Kluwe, 1982).
Excretion of dllsooctyl phthalate, dl-n-butyl phthalate and d1(2-ethyl-
hexyl) phthalates has been studied (Ikeda et al., 1978, 1980; Schmld and
Schlatter, 1985; Telrlynck and Belpalre, 1985; Williams and BlanchMeld,
1974, 1975; Daniel and Bratt, 1974; Kaneshlma et al., 1978; Tanaka et al.,
1975, 1978). These compounds and their metabolites are excreted In urine,
bile and feces; the relative Importance of the route of excretion depends
upon the compound and species, while the rate of excretion appears to be
0782p 4-13 06/06/86
-------
rapid. Half-lives of 7.9 and 12 hours were reported for urinary excretion
of d1(2-ethylhexyl) phthalate In humans and rats, respectively (Schmld and
Shlatter, 1985; Telrlynck and Belpalre, 1985). Pharmacoklnetlc data on aryl
or aryl/alkyl pthalates could not be located In the available literature as
cited In the Appendix.
0782p 4-14 05/13/86
-------
5. EFFECTS
5.1. CARCINOGENICITY
D1(2-ethylriexyl) and n-butyl benzyl phthalates have been tested for
oncogenlcity In NTP-dlrected feeding studies on rats and mice. Wllbourn
and Montesano (1982) reviewed other studies on dl(2-ethylhexyl), n-butyl
benzyl and d1-n-butyl phthalates, which were conducted before the NIP bio-
assays, and concluded that they were Insufficient to assess the carcinogenic
potential of phthalate esters because of design and reporting limitations;
U.S. EPA (1985a) concurred with this assessment. These studies are listed
In Table 5-1. The NTP studies, though not flawless, provide the only
reasonable tests of oncogenlclty, and are reported as follows.
5.1.1. n-Butyl Benzyl Phthlate. n-Butyl benzyl phthalate (0, 6000 or
12,000 ppm) was fed to groups of 50 male and 50 female F344/N rats and 50
male and 50 female B6C3F1 mice for 28 weeks (male rats only) or 103 weeks
(mice and female rats) (NTP, 1982a). Control mice and female rats were
killed after 106 weeks on test. Because of high mortality, high-dose male
rats and male controls were killed after 29 weeks on test. Male and female
mice and female rats exposed to n-butyl benzyl phthalate were killed after
104-106 weeks. Endpolnts monitored Include body weight, food consumption,
mortality, clinical signs of toxlclty, and gross and microscopic pathology.
When treated animals were compared with controls, a number of compound-
related effects were observed. Increased mortality associated with "unex-
plained Internal hemorrhaglng" was observed In n-butyl benzyl phthalate-
exposed male rats beginning at the 14th week of exposure. Consequently, the
study on male rats was terminated after week 28 of exposure.
0783p 5-1 06/06/86
-------
TABLE 5-1
Inadequate Cancer Studies
Species
Rats, dogs,
guinea pigs
Rats
Mice
Mice
Rats
Mice
Compound
DEHP
DEHP
DEHP
BBP
BBP
DBP
Route
oral (diet)
oral (diet)
1ntraper1toneal
IntraperHoneal
NR
1ntraper1toneal
Reference
Carpenter et al
Harris et al . ,
OmoM, 1976
Thelss et al.,
Anonymous, 1968
Omorl, 1976
., 1953
1955
1977
NR = Not reported
0783p
5-2
05/14/86
-------
Survival curves were comparable for treated and control mice and female
rats. Reduced body weights were observed 1n all rats and mice fed n-butyl
benzyl phthalate. The reduction was slight In female rats but substantial
in male and female mice. Food consumption was reduced 70-80% In treated
female rats, but data on food consumption were not reported for mice and
male rats. A statistically significant Increase (p=0.011. Fisher Exact
test) In mononuclear cell leukemia was observed In high-dose female rats
(Table 5-2) and was frequently accompanied by splenomegaly and hepatomegaly.
A statistically significant Increase In leukemia or lymphoma was also
observed In high-dose female rats (p=0.007, Fisher Exact test). No other
compound-related Increases In neoplastlc or nonneoplastlc lesions were
observed 1n female'rats. The study on male rats was too brief to provide
meaningful analysis of the data. No compound-related Increases 1n the
Incidences of neoplastlc or nonneoplastlc lesions were observed in mice of
either sex. Dose-related and significant decreases In mammary gland
adenomas (female rats), alveolar/bronchlolar adenomas or carcinomas (male
mice), lymphomas (male mice), and lymphomas or leukemia (male mice) were
observed (see Table 5-2).
NTP (1982a) concluded that n-butyl benzyl phthalate was "probably
carcinogenic for female F344/N rats. In a separate report, Kluwe et al.
(1982a), however, concluded that since the background Incidence of myelo-
monocytlc leukemia 1s normally high In F344/N rats (8-15X and 9-24% In
females and males, respectively), results presented In NTP (1982a) provide
only equivocal evidence of n-butyl benzyl phthalate-lnduced cancer In female
rats. Furthermore, the fact that significant and dose-related decreases In
Incidences of malignant lymphoma, all lymphoma, and lymphoma or leukemia
were observed In male mice contributes to the uncertainty that n-butyl
0783p 5-3 05/14/86
-------
CO
TO
TABLE 5-2
Hematopoletlc Neoplasms In F344/N Rats and B6C3F1 Mice Fed n-Butyl Benzyl Phthalate
In the Diet for 103 Weeks3
LTI
1
Incidence (p-value)^
Species Sex
Tumor Type
Rat F mononuclear cell
leukemia
House H mal
all
Ignant
leukemia
or lymphoma
1 ymphoma
lymphoma s
lymphoma s
F mal
all
Ignant
or leukemia
lymphoma
lymphoma s
lymphoma
or leukemia.
Control
7/49
7/49
12/50
13/50
14/50
15/50
17/50
17/50
(0
(0
(0
(0
(0
.006)
.004)
.024N)C
.015N)C
.008N)C
(NS)
(NS)
(NS)
Low Dose
(6000 ppm)
7/49
7/49
10/49
11/49
11/49
14/50
16/50
16/50
(NS)
(NS)
(NS)
(NS)
(NS)
(NS)
(NS)
(NS)
High Dose
(12,000 ppm)
18/50
19/50
4/50
4/50
4/50
15/50
17/50
18/50
(0.011)
(0.007)
(0.027N)C
(0.016N)C
(0.009N
(NS)
(NS)
(NS)
)c
CD
aSource: NTP, 1982a
bp-Values next to the control Incidences Indicate the probability level for the Cochran-Armltage test; p-
values next to dosed-group Incidences Indicate the probability level for the Fisher Exact Test.
CN Indicates a negative trend, that Is, the Incidence for dosed groups Is lower than for controls.
NS = Not significant; p-value >0.05
-------
benzyl phthalate may cause leukemia 1n humans. IARC (1982) concluded that
the NTP (1982a) studies were Insufficient to assess the carcinogenic poten-
tial of n-butyl benzyl phthalate. U.S. EPA (1985a) Is currently reviewing
this Issue.
5.1.2. 01(2-ethylhexyl) Phthalates. 01(2-ethylhexyl) phthalate was fed
to groups of 50 male and 50 female F344 rats at levels of 0, 6000 or 12,000
ppm, and to groups of 50 male and 50 female 86C3F1 mice at levels of 0, 3000
or 6000 ppm for 103 weeks (NTP, 1982b; Kluwe et al., 1982b). Average doses
calculated from data on food consumption and body weight were 322 and 674
mg/kg/day for low- and high-dose male rats, 394 and 774 mg/kg/day for low-
and high-dose female rats, 672 and 1325 mg/kg/day for low- and high-dose
male mice, and 799 and 1821 mg/kg/day for low- and high-dose female mice,
respectively. Throughout the study, food consumption, body weight, mortal-
ity and clinical signs of toxldty were monitored. Animals surviving 103
weeks on test were maintained for an additional 1-2 weeks after treatment,
then evaluated by necropsy and hlstopathology. Animals that died before 103
weeks were evaluated similarly.
There were no compound-related effects on survival. A number of
compound-related effects were observed when treated animals were compared
with controls. A moderate decrease In body weight was observed 1n
d1(2-ethylhexyl) phthalate-treated female mice, but was not accompanied by a
reduction In food consumption. Body weight was also reduced moderately In
low- and high-dose male and high-dose female rats, but food consumption was
also slightly reduced. A significantly higher Incidence (Fisher Exact test)
of hepatocellular carcinoma was observed 1n high-dose female rats, mlddle-
and high-dose female mice and high-dose male mice (Table 5-3). A signifi-
cantly greater Incidence (Fisher Exact test) of hepatocellular carcinoma or
0783p 5-5 06/06/86
-------
TABLE 5-3
Liver Neoplasms In F344/N Rats and B6C3F1 Hlce Fed 01(2-ethylhexyl) Phthalate
CO
GO
XJ
In the Diet for 103 Weeks3
Incidence
Species Sex Tumor Type
Rat H hepatocellular
hepatocellular
or neoplastlc
F hepatocellular
en
^ hepatocellular
or neoplastlc
House H hepatocellular
hepatocellular
or adenoma
F hepatocellular
hepatocellular
or adenoma
care
Inoma
carcinoma
nodule
care
Inoma
carcinoma
nodule
care
care
care
care
Inoma
Inoma
Inoma
Inoma
Control
1/50
3/50
0/50
0/50
9/50
14/50
0/50
1/50
(0.
(0.
(0.
(
-------
TABLE 5-3 (cont.)
CD
CO
•o
o
\
o
CO
cr>
QUALITY OF EVIDENCE
Strengths of Study: Lifetime study of both sexes of two species; adequate number of animals tested at
MTD; relevant route of exposure; appropriate statistical analysis; comprehensive
hlstologlcal examination.
Overall adequacy: Adequate
aSource: NTP. 1982b
p-value next to the control Incidence Indicates the probability level for the Cochran-Armltage lest;
the p-value next to the dosed group Incidence Indicates the probability level for the Fisher Exact lest.
cRats were given dietary concentrations of 6000 and 12,000 ppm; mice were given 3000 and 6000 ppm.
NS = Not significant; p-value >0.05
-------
neoplastlc nodules was observed In high-dose male rats, middle- and high-
dose female rats and a significantly greater Incidence of hepatocellular
carcinoma or adenoma was observed In middle- and high-dose male and female
mice [see Table 5-3). Significantly decreased Incidences of Interstitial
cell tumors of the testes, pituitary carcinoma or adenoma and thyroid C-cell
carcinoma or adenoma were also observed 1n high-dose male rats. Significant
compound-related Increases In seminiferous tubule degeneration (rats and
mice) and hypertrophy of cells In the anterior pHultary (male rats) were
also observed.
NTP (1982b), Kluwe et al. (1982b), U.S. EPA (1985a) and IARC (1982)
concluded that these results provide sufficient evidence of d1(2-ethylhexyl)
phthalate-lnduced cardnogenlclty 1n rats and mice. This conclusion,
however, Is disputed. Northrup et al. (1982) claim that the NTP (1982b)
results are equivocal since the MTO was exceeded In some treatment groups,
Incidences of liver tumors varied within different control groups of the
same species and sex, and treated animals may have been malnourished.
Northrup et al. (1982) also claimed that the rodent data cannot be used to
predict carcinogenic risk In humans because d1(2-ethylhexyl) phthalate 1s
metabolized differently 1n rats than 1n humans. In response, Kluwe et al.
(1983) noted that MTD was not technically exceeded since there were no
compound-related effects on survival, the Incidence of liver tumors was
Increased 1n d1(2-ethylhexyl) phthalate-treated animals regardless of the
control data used and the differences 1n metabolism between rodents and
humans would not affect the carcinogenic response 1n rodents. More
recently, Turnbull and Rodrlcks (1985) concluded that using NTP (1982b) data
to estimate d1(2-ethylhexyl) phthalate-lnduced carcinogenic risk to humans
will probably overestimate actual risk. This conclusion was based on the
0783p 5-8 06/06/86
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differences between rodents and primates In the metabolism of dl(2-ethyl-
hexyl) phthalate, a nonlinear relationship between the administered dose of
d1(2-ethylhexyl) phthalate to the dose of the "proximate carcinogenic
species" in rodents, the fact that the "proximate carcinogenic species,"
which Is hypothesized to Induce cancer, Is produced to a greater extent In
rodents than In primates and that there are differences 1n target-site
sensH1v1ty between humans and rodents for liver tumors 1n general.
In conclusion, results of NTP bloassays Indicate that d1(2-ethylhexyl)
phthalate 1s carcinogenic for B6C3F1 mice and F344 rats of both sexes but
are only limited to assess the carcinogenic potential of n-butyl benzyl
phthalate. The relevance of these studies to the carcinogenic potential of
pthalate esters tn humans .1s questionable. Pertinent data regarding the
carclnogenldty of phthalates In humans could not be located In the avail-
able literature as dted In the Appendix. Adequate cancer bloassays have
not been conducted for other pthalate esters.
5.2. MUTAGENICITY
Thomas and Thomas (1984) and Hopkins (1983) reviewed the mutagenlclty
and genotoxldty of d1 (2-ethylhexyl) phthalate, Us metabolites and other
phthallc add esters. D1-2(ethylhexyl) phthalate and Us metabolites,
monoethylhexyl phthalate and 2-ethylhexanol, have been tested extensively In
Ames assays with Salmonella typhlmurlum with and without metabolic activa-
tion. Negative results have been reported by Zelger et al. (1982), K1rby et
al. 1983, Kozumbo et al. (1982), Ruddlck et al. (1981), Simmon et al.,
(1977), Warren et al. (1982), and Yoshlkawa et al. (1983). D1{2-ethylhexyl)
phthalate was also found not to cause reverse mutation In EscheMchla coll
with and without S9 (Toralta et al., 1982a; Yoshlkawa et al., 1983). Kozumbo
et al. (1982) and Rubin et al. (1979) reported that dimethyl and dlethyl
0783p 5-9 08/31/87
-------
phthalates were mutagenlc In strain TA100 of S. typhlmurlum but only 1n the
absence of 59. Seed (1982) reported that dimethyl, dlethyl (with and
without S9) and d1-n-butyl phthalates (without, but not with, S9), but not
d1(2-ethylhexyl), d1-n-octyl, dllsodecyl and dllsobutyl phthalates, were
found to cause mutation to 8-azaguan1ne resistance 1n bacterial suspension
assays with S. typhlmurlum; the d1(2-ethylhexyl) phthalate metabolite,
2-ethylhexanol, was found to be mutagenlc without S9. TomHa et al. (1982a)
reported that monoethylhexyl, but not d1(2-ethylhexyl), phthalate yielded
positive results 1n rec assays with Bacillus subtllls.
With two exceptions, jjn v1tro genotoxlclty assays have yielded negative
results. 01-2(ethylhexyl) phthalate failed to cause an Increase In chromo-
somal aberrations In human lymphocytes (Turner et al., 1974), 1n Chinese
hamster Mbroblasts (Abe and Sasaki, 1977; Ishldate and Odashlma, 1977), and
In CHO cells (Phillips et al., 1982). D1-2(ethylhexyl) phthalate did not
cause aneuploldy In human fetal lung cells (Stenchever et al., 1976).
D1(2-ethylhexyl) phthalate and Us metabolites (monoethylhexyl and 2-ethyl-
hexanol) failed to Induce unscheduled DNA synthesis 1n primary rat hepato-
cytes (Hodgson et al., 1982). Monoethylhexyl phthalate was reported to
cause an Increase In chromosomal aberrations and SCE 1n Chinese hamster V79
embryonic cells (TomHa et al., 1982a) and CHO cells (Phillips et al., 1982).
Chromosomal aberrations were observed 1n embryonic cells 1n a study 1n
which Syrian golden hamsters were treated orally with 3.75-15 g/kg
d1(2-ethylhexyl) phthalate on day 11 of gestation (TomHa et al., 1982a).
Putman et al. (1983) failed to observe significant Increases In clastogenlc
changes In bone marrow cells taken from male F344 rats treated by gavage
with d1(2-ethylhexyl) phthalate (0.5-5 g/kg/day) or monoethylhexyl phthalate
0783p 5-10 06/06/86
-------
(0.01-0.14 g/kg/day) for 5 days. PosHWe results were observed 1n a domi-
nant/lethal study on ICR mice, where d1(2-ethylhexyl) phthalate was adminis-
tered as a single 1ntraper1tonea1 dose (2/3 LD5Q) (Singh et al., 1974).
Agarwal et al. (1985b) evaluated the ant1fert1lHy and mutagenlc effects
of DEHP In ICR mice. In the first phase of the study, eight male mice per
group were given DEHP by s.c. Injection at doses of 0.99, 1.97, 4.93 and
9.86 gAg on days 1, 5 and 10 of the experiment. Sixteen control animals
were gWen saline by s.c. Injection. On day 21, each male was housed with a
female for 7 days.
In phase two, five groups of 10 male mice each were Injected with 0,
0.99, 1.93, 4.93 and 9.86 mg/kg DEHP on days 15 and 10 of the experiment.
One untreated female mouse was housed with each male at each treatment
Interval. After the last dose, females were replaced at 5-day Intervals for
the first 21 days and at 7-day Intervals through a total of 8 weeks from the
start of the experiment.
The females were sacrificed 13 days from the middle of their respective
periods of cohabitation. The uterine horns and ovaries were examined for
total number of corpora lutea, Implantations, early fetal deaths and viable
fetuses. The difference between the number of corpora lutea and the number
of Implantations was calculated to reflect prelmplantatlon loss. The data
for all endpolnts were evaluated In three time frames: the first 3 weeks of
the study, the final 5 weeks and the totals for the 8 weeks.
HutagenlcHy was evaluated utilizing two Indices: prelmplantatlon
loss/Implants per pregnancy and early fetal deaths/Implants per pregnancy.
In the phase I study there was a reduction In the Incidence of preg-
nancies. Although prelmplantatlon loss appeared to be somewhat greater In
the treated groups, none of these differences were significant (p<0.05).
0783p 5-11 08/29/86
-------
In contrast, early fetal death was significantly Increased In all treated
groups. The numbers of viable fetuses were significantly reduced 1n the
lowest and highest dose groups only. Both of the mutagenlclty Indices were
Increased In all of the treated groups (statistics not reported).
In the phase II study, there was no effect of DEHP on the Incidence of
pregnancies. The number of Implantations were reduced In the 1.93 and 9.86
g/kg groups In the day 2 to 21 Interval, but not 1n the 4- to 8-week
Interval. Combining across weeks (1-8) there was a reduction 1n Implanta-
tions for the high dose alone. Prelmplantatlon loss was Increased In all
dose groups for the early study Interval and for the total 8-week period.
Early deaths were Increased for all dose groups for all three time
Intervals. The number of viable fetuses was significantly decreased during
the first study segment and for the total 8 weeks. The prelmplantatlon loss
mutagenldty Index was significantly Increased during the early study
segment In the 0.99, 1.97 and 0.86 mg/kg groups and for the overall study
(weeks 1-8) In the 1.97, 4.93 and 0.86 mg/kg dose groups. The early death
Index was significantly Increased for all doses at all study segments.
In experiments with F344 rats, Albro et al. (1982) showed that radio-
labeled d1(2-ethylhexyl) phthalate and monoethylhexyl phthalate (but not
ethylhexanol) associated strongly with DNA. Covalent binding, however, was
not demonstrated.
5.3. TERATOGENICITY
A number of oral studies have shown that exposure to d1(2-ethylhexyl),
d1-n-butyl and dl-n-heptyl phthalates during gestation can have adverse
effects upon the developing fetus. Whether the observed effects (reduced
fetal weight, fetal mortality, gross external and skeletal malformations)
0783p 5-12 08/26/86
-------
represent a primary effect of the compound 1n question or whether they occur
as a result of maternal toxlclty has yet to be demonstrated unequivocally.
Oral studies concerning d1 (2-ethylhexyl) phthalate are summarized In
Table 5-4.
D1-2(ethylhexyl) phthalate-lnduced fetotoxlc and teratogenlc effects
have been reported 1n rats and mice (Wolkowsk1-Tyl et al., 1984a,b; Bell et
al., 1979; Bell, 1980; Shlota and Mima, 1985; Shlota and Nlshlmura, 1982;
SMota et al., 1980; Nakamura et al., 1979; Yag1 et al., 1978, 1980; ToraUa
et al., 1982b; Onda et al., 1974; Nlkonorow et al., 1973). Studies con-
ducted by NTP (Wolkowsk1-Tyl et al., 1984a,b) Indicate that mice are more
sensitive to d1(2-ethylhexyl) phthalate than rats. The studies that show
effects at the lowest level of exposure and In the absence of maternal
toxlclty report a significantly Increased Incidence of percent of malformed
fetuses/lHter In CD-I mice whose dams were fed 91 mg/kg/day throughout
gestation (Ho1kowsk1-Tyl et al., 1984b); significantly decreased fetal body
weight In ddY-SlcXCBA mice whose dams were gavaged with 0.05 ml/kg (49
mg/kg) on day 7 of gestation (TomUa et al., 1982b); and the formation of
renal cysts In the F and F generations of mice exposed orally (not
specified) to 10 or 100 mg/kg/day for 3 generations (Onda et al., 1974); (no
other details provided). The decreased fetal body weights observed by
TomHa et al. (1982b) were not observed In ICR or CD-I mice treated at
somewhat higher (0.05X diet or -65 mg/kg/day) or lower (44 mg/kg/day) doses
throughout gestation (Wolkowskl-Tyl et al., 1984b; Shlota et al., 1980;
Shlota and Nlshlmura, 1982). The study conducted by Holkowsk1-Tyl et al.
(1984b) Is thorough and well-reported, and provides a NOEL of 44 mg/kg/day
and a LOAEL of 91 mg/kg/day for d1(2-ethylhexyl) phthalate-promoted terato-
genlc effects.
0783p 5-13 08/26/86
-------
TABLE 54
Summary of Oral Teratogenlclty Studies with 01(2-ethylhexyl) Phthalate
" Species/
03 Strain
co
•o
Dose. Vehicle and
Duration of Treatment
Endpolnts Monitored
Maternal Response
Fetal Response
Reference
Rat/F344
Rat/NR
Rat/Sprague-
Oawley
Rat/Sprague-
Dawley
Rat/Sprague-
Dawley
Rat/Wlstar
Mouse/CD-I
o
CO
CO
0. 0.5. 1.0. 1.5 or
2% diet (0. 356.7.
666.4. 856.5 or
1054.8 ng/kg/day) on
days 0-20 of gesta-
tion
2.5 or 5.0 ml/kg on
days 7-13 of gesta-
tion (vehicle NR)
0. 0.5 or IX diet on
last 16 days of ges-
tation and throughout
lactation
0. 0.5 or IX diet for
5-10 days after mating
0. 0.5X diet on days
5-18 of gestation
0. 0.34 or 1.7 g/kg/
day In olive oil for
3 months before
mating or 0. 0.34 or
1.7 g/kg/day In olive
oil on days 0-21 of
gestation
0. 0.025. 0.05. 0.1
or 0.15X diet (0.
44. 91. 191 or 292
mg/kg/day) on days
0-18 of gestation
standard NTP
teratology study
NR
sterologenesls In
livers of pups 8 days
after birth
sterologenesls In
brain and liver of
18-day fetuses
sterologenesls In livers
of fetuses and dams
day 21 of gestation:
number live fetuses;
number dead fetuses;
number resorptlons;
fetal body weight.
placental body weight.
skeletal examination of
fetuses; placental weight
standard NTP
teratology study
dose-related decrease
In bw. significant at
>1X; significant dose-
related Increase In
absolute and relative
liver weight, signifi-
cant at all doses;
significant dose-
related decrease In
gravid uterine weight,
significant at 2%
NR
NR
NR
reduced sterologenesls
NR
Dose-related decrease
In body weight, signi-
ficant at 0.1 and O.I5X;
dose-related Increase In
related liver weight,
significant at 0.1 and
0.1 SX
Dose-related Increase In X resorptIons/ Wolkowskl-Tyl
litter. X nonlive/litter (dead and resorbed). et al.. 1984a
and number of affected fetuses/litter (non-
live and malformed),significant at ?X; dust--
related decrease In bw. significant at all
doses; significant dose-related Increase In
X malformed fetuses/litter but no statisti-
cally significant palrwtse differences
No teratogenlc effects; 50X resorptIon of Nakayama,
Implants at ?.5 ml/kg; no other details 1968
(Both doses) significant reduced sterolo- Bell et a).,
genesis; significant reduced body weight; 1979
significant Increased related liver weight
(Both doses) significant reduced sterolo- Bell et al.,
genesis In brain and liver 1919
Reduced sterologenesls (not statistically Bell, 1980
significant)
No effects when administered before ges- Nlkonorow
tatlon; significantly reduced fetal body et al.. 1973
weight when administered during gestation
(high dose); significantly reduced placental
weight (both doses); Increased number of
resorptlons (high dose); no skeletal effects
dose-related Increase In X resorptlons/ Wolkowskl-lyl
litter, dead/litter, nonl1ve/11tter (dead et al.. 1984b
nd resorbed). and affected fetuses/Utter
(dead and malformed), significant at 0.1
and 0.1SX; significant decrease In fetal
body weight at 0.15X; significant Increases
In X malformed fetuses/litter at O.OS. 0.1
and 0.15X (external, visceral and skeletal
defects)
-------
TABLE 5-4 (cont.)
oo
CO
•o
Species/ Dose, Vehicle and
Strain Duration of Treatment
Endpolnts Honltored
Maternal Response
Fetal Response
Reference
Wouse/S/C-ICR
Mouse/ICR
tn
i
House/random
strain ddY-
Slc x CBA
House/ddY-
Slc x CBA
0. 250. 500. 1000 or
2000 mg/kg In olive
oil on days 7-9 of
gestation
0. 0.05. 0.1. 0.?.
0.4 or IX diet on
days 0-18 of gesta-
tion
0, 0.05. 0.1 or 1
til/kg on day 7 of
gestation (no vehicle)
various doses on day
6, 7. 8. 9 or 10 of
gestation (gestation
day 6) 2.5 mt/kg
(7) 1. 2.5 or 5 mt/kg
(8) 7.5 or 10 nt/kg
(9) 7.5, 10 or 30
mt/kg (10) 10 or 30
mt/kg (no vehicle)
day 18 of gestation:
number of abortions,
maternal mortality.
resorptlons. Implants,
dead fetuses, fetal
body weight, gross
external anomalies
day 18 of gestation:
maternal body weight;
number resorptlons;
number Implants; number
dead fetuses; fetal
body weight; gross
external, skeletal and
visceral anomalies
day 18 of gestation:
maternal body weight,
number Implants, early
and late resorptlons,
number live, gross
external and skeletal
malformations
day 18 of gestation:
maternal body weight,
number Implants,
number early and late
resorptlons, number
live fetuses wMh gross
external or skeletal
anomalles
3/11 aborted and 1/11
died at ?000 mg/kg;
abortions and mortality
were not observed at
any other level
significant decreased
body weight at 0.?,
0.4 and IX
(1 ml/kg) slight
decrease In body weight
on day 14 of gestation
decreased body weight
at all doses given on
days 6, 7 or 8 of
gestation
(1000 and 2000 mg/kg) significant Increases Shlota and
In X resorptlons and dead fetuses, and X Mima. 1985
malformed fetuses (exencephaly/anencephaly;
tall anomalies); decreased fetal body weight
100X early resorptlon (all Implants) at 0.4 Shlota and
and IX; significant Increased X resorptlons Nlshlraura.
at 0.1 and 0.?X; significant Increased X 198?; Shlota
fetuses with gross external malformations et al.. 1980
(neural tube defects) at 0.2, 0.4 and IX
(1 mt/kg) increased Incidence of gross and Nakamura
skeletal anomalies (elongated and fused ribs, et al., 1979
absence of tall and leg bones) (0.1 and 1
mt/kg) significant Increased fetal mortality
Significant reduced fetal body weight at all Yagl el al.,
doses on all days; Increased fetal mortallly 1978. 1980;
and resorptlons al all doses on days 7 and 8 Tomlla
of gestation; dose-related Increase In Incl- et a)., 1982a
dences of gross external and skeletal anom-
alies on days 7 and 8 of gestation (all
doses); some external anomalies but no
skeletal anomalies on days 9 or 10 of gesta-
tion (10 and 30 mt/kg on day 9. 30 mt/kg on
day 10); no resorptlons. dead fetuses, or
gross or skeletal anomalies were observed
In controls
oo
\
ro
^v
CO
House/ddy-
Slc x CBA
Mouse/ddy-
JCL and ICR
0. 0.05, 0.1 or 1
ml/kg on day 7 of
gestation (no vehicle)
0. 10 or 100 mg/kg/
day for 3 generatIons
(vehicle NR)
same as above
NR
decreased body weight
at 1 mt/kg
Significant reduced fetal body weight at all 1 omit a
doses; significant Increase In Incidences of el al., 1982b
gross and skeletal anomalies at IX; decreased
X live fetuses at 0.1 and IX
Formation of renal cysts In t\ and f? Onda et al.,
(both doses) 1974
NR = Not reported
-------
Studies concerning phthallc add esters other than d1 (2-ethylhexyl)
phthalate are summarized In Table 5-5. In separate reports of the same
study, Booth et al. (1983) and Plasterer et al. (1985) reported that di-
methyl phthalate had no effects on reproduction In CD-I mice. Groups of 50
female mice were gavaged with 0 or the MTD of dimethyl phthalate (3500 mg/kg
In corn oil) on days 7-15 of gestation, and allowed to deliver naturally.
There were no significant effects on survival, body weight, birth weight of
pups, or average number live/Utter, average number dead/Utter, or average
weight of pups on days 1 and 3 postpartum. The pups were not examined for
malformations.
Shlota et al. (1980) and SMota and Nlshlmura (1982) reported terato-
genlc and fetotoxlc effects In mice caused by d1-n-butyl phthalate, but only
at a dietary concentration (1%) that also produced a significant depression
of maternal weight gain. No effects on the fetuses or dams were observed In
mice fed <0.4X dl-n-butyl phthalate throughout gestation. In a 3-generat1on
study, Onda et al. (1974) observed renal cyst formation In the F. and F
generations of mice exposed orally (not specified) to 10 or 100 mg dl-n-
butyl phthalate/kg/day; however, no other details were given. An Increased
number of resorpUons and significantly reduced fetal body weights were
observed 1n rats gavaged with 600 mg d1-n-butyl phthalate/kg/day throughout
gestation (Nlkonorow et al., 1973); reduced placental weights were observed
In mice gavaged with 120 or 600 mg d1-n-butyl phthalate/kg/day. Unfortu-
nately, this study did not randomly select test animals and did not examine
gross or visceral malformations.
It Is difficult to define a dose-response relationship for d1-n-heptyl
phthalate. The only study, Nakashlma et al. (1977), Is poorly reported.
0783p 5-16 08/26/86
-------
Summary of Oral Teratogentclty Studies for Phthallc Acid Esters Other Than Dl (?-e thylhexyl) Phthalate
OD
CO
Species/ Dose. Vehicle and
Strain Duration of Treatment
Endpolnts Monitored
Maternal
Response
fetal Response
Reference
DIMETHYL PHTHALATE
Mouse/CD-I 0 or 3SOO mg/kg/day on
days 7-15 of gestation
en
I
Rat/Wlstar 0, 0.12 or 0.60 g/kg/day
In olive oil for 3 months
prior to mating or 0. 0.12
or 0.60 g/kg/day In olive
oil on days 0-21 of gesta-
tion
House/lCR 0. 0.05. 0.1. 0.2. 0.4 or
IX diet on days 0-18 of
gestation (0. 80. 180. 370.
660 or 2100 mg/kg/day)
dams were allowed to deliver; no effect
dams observed for survival and
body weight, pups observed for
birth weight, number of live/
Utter. dead/Utter, average
weight on day 1 or 3 post par turn
DI-n-BUTYL PHTHALATE
day 21 of gestation: number live NR
fetuses; number resorptlons;
fetal body weight, placental
body weight; skeletal examina-
tion of fetuses; placental
weight
day 18 of gestation: maternal significant
body weight, number resorpttons. decreased
number Implants, number dead body weight
fetuses, fetal body weight. at IX
gross external, skeletal and
visceral anomalies
No effects; pups were not examined for
ma 1 format tons
Booth et al..
1983;
Plasterer
et al.. 1985
No effects when D8P was administered Nlkonorow
prior to gestation; significantly reduced et al.. 1973
fetal body weight when administered
during gestation (0.6 g/kg/day); In-
creased number resorpttons (0.6 g/kg/day);
significant reduced placental weight
(both doses); no skeletal effects
Significant Increase In number of resorp- Shlota
tlons and dead fetuses at IX; significant et al.. 1980;
Increase In Incidence of gross external Shlota and
Malformations at IX; significant decreased Nlshlmura.
number of ossified coccygla at all levels 1982
of treatment
Mouse/ddY/JCL
and 1CR
0. 10 or 100 mg/kg/day for
3 generations (vehicle NR)
NR
NR
Dl-n-HEPTYL PHTHALATE
Formation of renal cysts
(no other details)
In
and fp
Onda et al.
1974
Mouse/ICR:JCL administered various doses
on either day 7. 8. 9. 10
or 11 of gestation (day 7)
0.94. 1.88 or 3.75 ml/kg
(8) 1.50. 2.50 or 7.50 ml/kg
(10) 7.50. 11.3 ml/kg
(11) 7.50. 11.3 ml/kg
O
co
CD
embryo/fetotoxlclty (NOS) gross NR
external and skeletal anomalies
Dose-response relationships not clearly
presented; high Incidence of gross
external anomalies on days 7 and 8 of
gestation at ?.S and 7.5 ml/kg; embryo/
fetotoxtclty highest on days 7 and 8;
100% resorptlons at 7.5 mt/kg (no other
Information); high Incidence of skeletal
anomalies on day 8, 100X with fused ribs
at 2.5 mt/kg (no other Information);
gross anomalies Included open eyelid.
cleft palate and olIgodactyl la on day 9.
exencephaly on day 8. and tall anomaly,
ollgodactyl la and hematoma on days 10 and 11
Nakashlma
et al.. 1977
NOS = Not otherwise specified; NR = not reported
-------
Fetotoxlc and teratogenlc effects were observed, but the study seemed to
focus on which days of gestation the mice were more likely to be sensitive
to exposure, and there was no consistent effort to report which effects
occurred at each particular dose. Furthermore, maternal effects were not
reported.
A recent study Indicates that phthallc acid esters may cause adverse
effects when transported to the developing organism by milk. Parmar et al.
(1985) observed a decrease In weight gain and changes In enzyme "levels
Indicative of liver damage in 21-day-old rat pups whose dams were gavaged
with 2000 mg dl(2-ethylhexyl) phthalate/kg throughout lactation.
A number of IntraperHoneal studies have been conducted with phthallc
add esters on rats (Singh et al., 1972). Given the route-dependent differ-
ences In absorption, distribution and excretion of phthallc add esters, the
relevance of IntraperHoneal studies to oral risk assessment 1s uncertain.
Singh et al. (1972) reported that parenterally administered dimethyl
phthalate (0.38-1,125 ml/kg), dlethyl phthalate (0.506-1.686 ml/kg),
dl-n-octyl phthalate (5, 10 ma/kg), d1(2-ethylhexyl) phthalate (10
ml/kg) and d1-n-buty1 phthalate (0.3-1.017 mi/kg) caused fetotoxlc or
teratogenlc effects when administered to rats on days 5, 10 and 15 of
gestation.
5.4. OTHER REPRODUCTIVE EFFECTS
NTP recently conducted reproduction and fertility assessments on CD-I
mice for dlethyl phthalate (Reel et al., 1984) and dl-n-octyl phthalate
(Gulat! et al., 1985), using a new protocol, "fertility assessment by con-
tinuous breeding." The protocol consists of four tasks: 1) a range-fIndlng
study to determine maximum tolerated dose; 2) a continuous breeding study
entailing exposure during 7 days before mating, followed by 98 days of
cohabHat^on and 21 days of segregation; 3} a crossover breeding study to
0783p 5-18 08/26/86
-------
determine the affected sex; and 4) a reproductive performance assessment of
control and high-dose Utters from Task 2. Task 3 Is performed only If
adverse effects are detected In Task 2. If no adverse effects are detected
In Task 2, then Task 4 1s performed.
Based on the range-finding studies, dietary concentrations of 0, 0.25,
1.25 and 2.5% dlethyl phthalate and 0, 1.25, 2.5 and 5% dl-n-octyl phthalate
were chosen for Task 2. No adverse compound-related effects (number of
pairs able to produce at least one litter, number of litters/pair, propor-
tion of pups born alive, sex of pups born alive, live pup weight) were
observed for either dlethyl phthalate or dl-n-octyl phthalate; Task 4 was
therefore performed for bojih compounds. Endpolnts monitored for Task 4
Include body weight at weaning and at 74 days of age, mating behavior,
reproductive performance as measured In Task 2 (beginning at 74 days of
age), sperm assessment and selected organ weights. F, male and female
pups born to dams fed 2.5X dlethy] phthalate had significantly lower body
weights than controls at weaning and at 74 days of age. The dlethyl
phthalate-exposed F. had significantly fewer live pups per litter than did
controls. Males had significantly reduced sperm concentrations and signifi-
cantly Increased prostate weights In comparison with controls. Both males
and females exposed to dlethyl phthalate had significantly Increased liver
weights; females also had significantly Increased pituitary weights. In
contrast, there were no significant, adverse compound-related effects on
fertility, reproduction or organ weights In F, mice exposed to 5%
d1-n-octyl phthalate.
The fertility of Sherman rats was not affected by dietary exposure to
d1{2-ethylhexyl) phthalate (up to 0.4%). Significantly Increased relative
kidney and liver weights, however, were observed In F, males and females
(Carpenter et a!., 1953) (Section 5.5.1.).
0783p 5-19 08/26/86
-------
The testlcular effects of phthallc acid esters have been studied exten-
sively In rats. Orally administered d1(2-ethylhexyl) phthalate, d1-n-butyl
phthalate, n-butyl benzyl phthalate, dl-n-pentyl phthalate, d1-1sobutyl
phthalate, and dl-n-hexyl phthalate cause testlcular atrophy characterized
In general by reduced testlcular weight, hlstologlcal evidence of degenera-
tion, reduced testlcular zinc concentration and either an Increase or
decrease 1n testlcular testosterone concentration (Gray et al., 1977, 1982;
Gangolll, 1982; Olshl and Hlraga, 1980a, 1983; Gray and Butteruorth, 1980;
Mangham et al., 1981; Olshl, 1985; Agarwal et al.. 1985; Cater et al., 1976,
1977; NTP, 1982b; Kluwe et al., 1982b; Foster et al., 1980). These studies
are summarized In Table 5-6. Cater et al. (1977) demonstrated that
co-administration of zinc could counteract the degenerative effects of
dl-n-butyl phthalate, while Olshl and Hlraga (1983). demonstrated that
co-administration of zinc had no effect on d1(2-ethylhexyl) phthalate-
promoted atrophy. Furthermore, Gray and Butterworth (1980) demonstrated
that when rats were removed from d1 (2-ethylhexyl) phthalate exposure,
testlcular weight and morphology were restored within 12-20 weeks of expo-
sure; Olshl (1985) observed only slight recovery after 45 days. Equlmolar
concentrations (compare with effective phthallc add esters) of dimethyl
phthalate, dlethyl phthalate, dlpropyl phthalate, d1-n-heptyl phthalate and
d1-n-octyl phthalate did not cause testlcular atrophy In rats when adminis-
tered orally for 4-10 days (Gray and Butterworth, 1980; Foster et al., 1980).
Sjoberg et al. (1985) Investigated the kinetics of orally administered
DEHP In 25-, 40- and 60-day-old male Sprague-Dawley rats 1n an attempt to
elucidate the greater testlcular sensitivity to this compound In young
animals. For the toxldty study, groups of 7-8 rats/group from each of the
three age designations were treated by gavage with either 1 g OEHP/kg 1n
0783p 5-20 08/26/86
-------
TABLf 5-6
Orally Administered Phthalate Esters Causing Testlcular Atrophy In Rats
CO
CO
•o
Compound
Vehicle
Effective Dose(s)
Duration
Reference
DEHP
en
i
ro
BBP
DBP
O
00
CD
OPeP
DIBP
DHP
diet
diet
diet
diet
diet
diet
corn oil
corn oil
corn oil
none; gavage
none; gavage
diet
corn oil
corn oil
corn oil
corn oil
Corn oil
corn oil
corn oil
diet
corn oil
corn oil
1.0. 2.OX (7SO. 1500 mg/kg/day)
12,000 pp« (674 mg/kg/day)
1.0. 2.OX
2X
2X (1200 •g/kg/day)
1.5 or 3X
2800 mg/tcg/day
2800 mg/kg/day
2500 mg/kg/day
2000 mg/kg/day
2000 Mg/kg/day
2.5 or 5.OX
2000 mg/kg/day
equlmolar to 2800 mg DEHP/kg
2000 mg/kg
500. 1000. 2000 mg/kg/day
2200 mg/kg/day
2100 mg/kg/day
equlmolar to 2800 rag DEHP/kg/day
2X
equlmolar to 2800 mg DEHP/kg/day
2400 rog/kg/day
90 days
104 weeks
17 weeks
7 days
10 days
90 days
10 days
9 days
21 days
10 days
14 days
14 days
4-9 days
10 days
9 days
6 days
4 days
4 days
10 days
7 days
10 days
4 days
Gangolll. 1982*
NTP. 1982b; Kluwe et al.. 1982b
Gray et al.. 1977*
Olshl and Hlraga. 1980<)
Gray and Butterworth. 1980
Shaffer et al.. 194S
Gray and Butterworth. 1980
Gray et al.. 1982
Mangham et al.. 1981
Olshl and Hlraga. 1983
Olshl. 1985
Agarwal et al., 1985
Cater et al.. 1976
Gray and Butterworth. 1980
Gray et al.. 1982
Cater et al.. 1977
Gray et al.. 1982
foster et al.. 1980
Gray and Butterworth. 1980
Otshl and Hlraga, 1980a
Gray and Butterworth, 1980
foster el al.. 1980
*These are probably the same study
-------
corn oil or with corn oil alone dally for 14 days. Body weights and the
following organ weights were recorded: liver, testes, ventral prostate
seminal vesicles. In addition, testes were fixed, sectioned and evaluated
using light microscopy.
For the kinetic study, groups of 9-10 rats from each of the three age
designations were utilized. DEHP at a dose of 1 g/kg was administered as a
single gavage dose. Blood samples were drawn from a Jugular cannula at 1,
3, 5, 7, 9, 12, 15, 24 and 30 hours postdoslng (0.25 ml/sample). DEHP and
MEHP analysis was conducted on hexane extracts by gas chromatography.
For the excretion studies, two groups of six rats each were utilized.
One group consisted of 25-day-old animals and the other of 60-day-old
animals. Each animal received 1 g 14C-DEHP/kg 1n corn oil by gavage.
Urine was collected each day for 3 days. Excretion was quantified by
scintillation counting. In addition, allquots of urine were extracted,
evaporated, dissolved 1n dlethyl ether and streaked on thin layer plates of
silica gel. Standards of DEHP and MEHP were utilized. Radioactive zones
were located utilizing a radio scanner.
For the Jjrc vitro metabolism evaluations, four groups of six rats each
were utilized. Groups consisted of two groups of 25-day -old animals, one
pretreated with phenobarbHal and the other not pretreated. The same
procedure was followed with the 60-day-old animals. DEHP was given by
gavage 1n corn oil at a dose of 1 g/kg/day for 14 days. PhenobarbHal was
given by 1.p. Injection of three dally doses of 100 mg/kg. Liver mlcrosomal
preparations were utilized to evaluate the rate of conversion of MEHP to Us
hydroxylated product, mono-(2-ethyl-5-hydroxyhexylJphthalate.
Protein binding of MEHP to blood plasma from 25-, 40- and 60-day-old
rats was also evaluated. This was accomplished using 14C-MEHP and an
equilibrium dialysis technique.
0783p 5-22 08/29/86
-------
The 25-day-old rats were the only age group exhibiting significantly
reduced testlcular weights. Liver weights were Increased In all treated
groups In the toxlclty study. The testes of the 25-day-old animals showed
severely affected seminiferous tubules. The cell type most affected was the
primary spermatocyte. Some spermatogonlal Involvement was also seen. No
abnormalities were seen In animals from the other age groups.
No age-related differences were seen 1n maximum MEHP plasma concentra-
tion or MEHP plasma elimination half-lives. The mean area under the MEHP
plasma concentration curve was significantly greater In 25-day-old rats than
In 40- or 60-day-old rats. Cumulative excretion of 14C-DEHP was 44 and
26% of the administered dose for 25- and 60-day-old rats, respectively.
Significant differences were not seen In conversion of MEHP to mono-
(2-ethyl-5-hydroxyhexyl)phthalate using liver mlcrosomes from 25- and
60-day-old rats. Significant differences among the age groups In binding of
MEHP to plasma proteins were not seen.
The authors concluded that their data suggested that the Increased
susceptibility of young rats to the testlcular effects of DEHP may In part
be explained by greater absorption of DEHP from the gastrointestinal tract
of the young animals based on he larger amount of excreted radioactivity and
the Increased area under the plasma MEHP concentration time curve In the
young animals. The possibility of differential tissue sensitivity was also
suggested.
Species differences In phthallc acid ester-promoted testlcular atrophy
have also been observed. Gray et al. (1982) failed to observe testlcular
atrophy In hamsters gavaged with dl-n-butyl, d1(2-ethylhexyl) and d1-n-
pentyl phthalates at equlmolar doses equivalent to those that caused atrophy
0783p 5-23 08/26/86
-------
In rats. In the same study, mice gavaged with equlmolar doses of dl-n-
butyl, d1(2-ethylhexyl) and dl-n-pentyl phthalates had only slight focal
atrophy (Gray et al., 1982). B6C3F1 mice fed 6000 ppm (1325 mg/kg/day)
d1(2-ethylhexyl) phthalate In the diet for 103 weeks had a slight but sig-
nificantly higher Incidence of seminiferous tubule atrophy than did controls
(NTP, 1982b; Kluwe et al., 1982b).
5.5. CHRONIC AND SUBCHRONIC TOXICITY
Chronic or subchronlc oral studies have been conducted with d1(2-ethyl-
hexyl), dl-n-butyl, dimethyl, dllsononyl, n-butyl benzyl and d1-n-octyl
phthalates. The Hver, kidney and testes appear to be the organs affected
most by phthallc add esters.
5.5.1. D1-2(ethylhexyl) Phthalates. Oral studies with d1(2-ethylhexyl)
phthalate have been conducted on rats (Carpenter et al., 1953; Harris et
al., 1955; Nlkonorow et al., 1973; Gray et al., 1977; Popp et al., 1985;
Gannlng et al., 1985; Nagasaki et al., 1974; Maslenko, 1968; NTP, 1982b;
Kluwe et al., 1982b; Shaffer et al., 1945), mice (NTP, 1982a; Gannlng et
al., 1985; Nagasaki et al., 1974; Ota et al., 1974), ferrets (Lake et al.,
1976, 1977a), guinea pigs (Carpenter et al., 1953), and dogs (Carpenter et
al., 1953, Harris et al., 1955). These studies are summarized 1n Table 5-7.
The studies that show adverse effects at the lowest levels of exposure are
those of Carpenter et al. (1953), Gray et al. (1977) and Nagasaki et al.
(1974).
Carpenter et al. (1953) fed d1(2-ethylhexyl) phthalate to rats, guinea
pigs and dogs. Groups of Sherman rats (32/sex/group) were fed 0, 0.04, 0.13
or 0.4X d1(2-ethylhexyl) phthalate In the diet (0, 20, 60 or 200 mg/kg/day
doses provided by the Investigators) for 2 years, and were allowed to breed
within the first year. After 1 year, groups of eight males and eight
0783p 5-24 08/26/86
-------
TABLE 5-7
Oral Toxlclty Summary for 01(2-ethylhexy1) Phthalate
co
CO
•o
Species/Strain Number and Sex
Dose. Vehicle and
Duration of Treatment
Endpolnts Monitored
Effects
Reference
Rat/Sherman
Rat/F344
en
I
ro
en
Rat/NR
Rat/Wlstar
Rat/Ulstar
0 Rat/Wlstar
oo
co
2 generations:
P| = 32H and
32F/group
(reduced to 8M
and BF/group
after 1 year);
F! . 3?H and
32F/group
SOH and SOf/
group
NR/NR
43H and 43F/
group
ION and 10F/
group
20H and 20F
?OM and 20F/
group
Pi: 0. 0.04. 0.13 or 0.4X
diet (0. 20. 60. or 200
mg/kg/day) for 2 years;
(Fj) 0. 0.4X diet (0. 190
mg/kg/day) for 1 year
0. 6000. 12.000 ppm diet
(0. 322. 674 mg/kg/day for
•ales; 0. 394. 774 mg/kg/
day for females) for 105
weeks
0. 0.375. 0.75. 1.5 or 3X
(0. 0.2. 0.4. 0.9. 1.9 g/
rat) for 90 days
0. 0.1. 0.5X diet for up
to 24 months (Interim
Mils at 3. 6. 12 months)
0.34 or 3.40 g/kg/day for
3 months (gavage: vehicle*
olive oil)
0 g/kg/day for 3 months
(olive oil)
0. 0.35X diet for 12
months
body weight, mortality, food
consumption, hematology, ferti-
lity, liver and kidney weights,
hlstopathology (major organs)
body weight, mortality, food
consumption, clinical signs
of toxlclty. gross and micro-
scopic pathology
growth, mortality, hematology.
pathology (extent not reported)
mortality, body weight, food
consumption, organ weights.
hlstopathology
behavior; body weight; hemato-
logy; serum proteins; gross
and microscopic examination of
kidneys, liver and spleen
behavior; body weight; food
consumption; hematology; serum
proteins; gross and microscopic
examination of liver, kidneys
and spleen
Carpenter
et a!.. 1953
(0.4X): significantly increased
relative liver and kidney weights
In P| males (1 year only) and Fj
males and females; no hlstopatho-
loglcal changes
Moderate reductions In body weight NIP. I962b;
In low- and high-dose males and In Kluwe et a)..
high-dose females: slight reductions 198?b
In food consumption (all treated
rats); Increased Incidence of hyper-
trophy of cells In the anterior
pituitary (males only; 1/46. 0/43
and 2P/49 for 0. low- and high-dose
rats, respectively); seminiferous
tubule degeneration (1/49. 2/44.
43/48 for 0, low- and high-dose
rats, respectively
(0.75-3X) slight decrease In growth Shaffer
(1.5. 3X) tubular atrophy and et al., 1945
degeneration In testes
Reduced body weight and food con- Harris et al.,
sumption In rats fed 0.5X DfHP; 1955
significant Increases In absolute
and relative liver and kidney
weights In rats fed 5X DEHP (3 and
6 months; but not at 12 or 24 months)
Increased mortality In high-dose Nlkonorow
group (75X); statistically slgnlfl et al.. 1973
cant Increase In relative liver
weight In low dose group (changes
In high dose group NR)
Increased mortality (30X vs. 10X. Nlkonorow
controls); significantly decreased et al., 1973
body weight; significantly Increased
relative liver weight; no hlsto-
loylcal changes
-------
TABLE 5-7 (cont.)
o
—J
CD
Species/Strain Number and Sex
Dose. Vehicle and
Duration of Treatment
Endpolnts Monitored
Effects
Reference
Rat/Sprague-
Dawley
derived-CD
15M and 15F/
group
Rat/CF-344/
Cr/BR
Rat/NR
Rat/NR
Rat/NR
Mouse/B6C3fl
1 Of/group
NR/male
NR/NR
NR/NR
SON and 50F/
group
Mouse/NR
Mouse
NR/NR
NR/NR
0. 0.2. 1.0 or 2.OX diet
(0. 150. 750. 1500 mg/kg/
day) for 17 weeks
1.2X diet for 3 or 6
months
0.02. 0.2. 2% diet for
-2 years
500. 1000 ppn diet for 48
weeks
0.5 mg/kg/day (vehicle not
reported) for 6 months
0. 3000. 6000 ppm diet
(0. 672. 13?5 mg/kg/day.
males; 0. 799. 1821 mg/kg/
day, females) for 103 weeks
body weight, food consumption,
clinical signs of toxlctty.
serum biochemistry, hematology.
urlnalysls. gross and micro-
scopic pathology (major organs)
preneoplastl'c foci In liver
Induction of hepatic and
Mitochondria! peroxlsomes
NR
NR
body weight. Mortality, food
consumption, clinical signs of
toxlclty. gross and microscopic
pathology
o
oo
500. 1000 ppm diet for 48 NR
weeks
0.5. 5 g/kg/day diet for NR
1-3 months
Reduced body weight gain and food
consumption (1. 2X); significantly
reduced packed cell volume (1. 2X);
significantly reduced hemoglobin
concentrations (1, 2X; males only);
significantly Increased relative and
absolute liver weight (0.?. 1. ?X);
dose-related Increase In Incidence of
testlcular damage (significant at 1.
2X) and castration cells In pituitary;
significantly reduced relative and
absolute lestes weight (1. 2%)
None
Dose-related Induction of palmltoyl
CO-A dehydrogenase. carnttlne acetyl-
transferase; Induction of cytochrome
P-4SO {significant at ?X only)
Interstitial nephritis (more severe
at 1000 ppm than at 500 ppm);
Increased SGPT; decreased blood
glucose (500. 1000 ppm)
None; recommend 2.5 mg/t HjO based
on odor and taste
Moderately decreased body weight
gain In low- and high-dose females;
no effects on food consumption;
Increased Incidence of seminiferous
tubule degeneration (1/49. 2/48.
7/49 for 0. low and high dose,
respectIvely)
No changes In SGPT or blood glucose
Degenerative changes In kidneys and
liver
Gray et al..
1977;
Gangolll, 1982
Popp et al..
1985
Canning
et al.. 1985
Nagasaki
et al.. 1974
Maslenko, 1968
NIP. 198?b;
Kluwe et al..
1982b
Nagasaki
et al.. 1974
Ota et al.,
1974
CO
cr*
-------
TABLE 5-/ (cont.)
Species/Strain Number and Sex
o
—I
CO
Dose. Vehicle and
Duration of Treatment
Endpolnts Monitored
Effects
Reference
Ferret/aTblno
Ferret/albino
(1150-1850 g)
Guinea pigs/
hybrid, NOS
Dog/Cocker
Spaniel;
Ulre-Halred
Terrier
Dog/mongrel
Dog/NR
o
oo
00
6-7/group
(sex NR)
6-7 males/
group
24M and 23F
23K and 23F
24H and 22F
4/group.
'randomly
separated by
breed and sex*
1 (sex NR)
1 (sex NR)
no concurrent
control
If; no con-
current control
0. IX diet for T4 months
0, IX (average - 1200 mg/
kg/day) diet for 14 months
0.13X diet for 1 year
(64 mg/kg/day)
0.04X diet for 1 year
(19 mg/kg/day)
OX diet for 1 year
gelatin capsules; 0.03
ml/kg 5 times/week for 19
doses, then 0.06 mi/kg/day
for 240 doses TWA .54.7
mg/kg/day; controls given
gelatin capsules only
0.06 mi/kg/day for 77
doses then 0.09 roi/kg/day
for 169 doses (gavage with
gelatin capsules) TWA --
79.3 mg/kg/day
5 g/kg/day (gavage) for
14 weeks
0.1 g/kg diet for 14 weeks
biochemistry and ultrastructure
of the liver
enzyme activities. DMA content.
and protein In liver homogenate
and mlcrosomal fractions; llpld
peroxldatlon In mlcrosomal
fractions; microscopic (light
and EH) examination of liver
tissue; liver hlstochemlslry;
microscopic examination of
major tissues; body weight
body weight, mortality, food
consumption, hematology. liver
and kidney weights, hlstopatho-
logy (major organs)
body weight, liver and kidney
weight, sulfobromophthaleln
test, plasma prothrombln time,
plasma cholInesterase, gross and
microscopic pathology (major
organs)
same as above
body weight, hematology. gross
and microscopic pathology
(major organs)
body weight, hematology. gross
and microscopic pathology
Marked enlargement of liver; slgnlf-
Icantly decreased activities of
succenate dehydrogenase. aniline
4 -hydroxylase. and mlcrosomal
glucose 6-phosphatase; deci eased
AP activity In centr I lobular region;
Increased AP In mtdzonal region;
Increased smooth endoplasmlc retlc-
ulura and numbers of lysosomes and
autophaglc vacuoles
Significantly reduced body weight;
significantly Increased absolute
liver weight; morphological and
biochemical changes In liver;
testlcular damage
Significantly Increased relative
liver weight In females fed both
doses; no other effects
None
Fatty vdcuolatlon and congestion In
liver; cloudy swelling and conges-
tion In kidney
chronic cholecystitis; some hemosl-
derosls of spleen
None
lake et al..
19/7a
take et al.,
1976
Carpenter
et al., 1953
Carpenter
et al.. 1953
Carpenter
et al.. 1953
Harris et a).
1955
Harris et al.
1955
NR = Not reported; NOS = not otherwise specified
-------
females were continued on test for 1 year more. Groups of 32 male and 32
female progeny were chosen from the control and high-dose groups and placed
on the appropriate control or high-dose diet for 1 year. Hybrid guinea pigs
(~22-24/sex/group') were fed either 0, 0.04 or 0.13X d! (2-ethylhexyl) phtha-
late In the diet (0, 19 or 64 mgAg/day) for 1 year. Groups of four dogs
(wire-haired terrier and cocker spaniel, "randomly separated by breed and
sex") were kept as controls or fed gelatin capsules equivalent to a TWA of
54.7 mg/kg/day for a total of 259 dally doses (0.03 ma/kg 5 times/week for
a total of 19 doses, then 0.06 ml/kg/day for 240 doses). One mongrel dog
(sex not specified) was given gelatin capsules equivalent to a TWA of 79.3
mg/kg/day for a total of 246 dally doses (0.06 ml/kg for 77 doses, then
0.09 mi/kg for 169 doses). Body weight, mortality, food consumption,
fertility, hematology, liver weights, kidney weights and hlstopathology
{major organs) were monitored for the parental rats. All endpolnts but
fertility were assayed for the F rats, guinea pigs and dogs. In addi-
tion, measurements of plasma prothrombln time and plasma chollnesterase, and
the sulfobromophthalln test for liver function, were performed for dogs.
Parental male rats and F. males and females fed 0.4X d1(2-ethylhexyl)
phthalate (200 mg/kg/day) had significantly Increased liver and kidney
weights, but no hlstopathologlcal changes. No other compound-related
effects were observed In rats. Significantly Increased relative liver
weight without accompanying hlstologlcal change was observed In female
guinea pigs fed 0.04 or 0.13X d1(2-ethylhexyl) phthalate (19 or 64 mg/kg/
day, respectively). Fatty vacuolatlon and congestion In the liver, and
cloudy swelling and congestion In the kidneys were observed 1n the dog given
a TWA dose equivalent to 79.3 mg d!(2-ethylhexyl) phthalate/kg/day. No
other effects were observed 1n dogs.
0783p 5-28 08/26/86
-------
Gray et al. (1977) fed either 0, 0.2, 1.0 or 2.0% dl(2-ethylhexyl)
phthalate to groups of "15 male and 15 female Sprague-Dawley derived CO rats
for 17 weeks. Dietary concentrations were equivalent to 0, 150, 750 and
1500 mg/kg/day as reported In a subsequent review (Gangolll, 1982). Body
weight, food consumption, clinical signs of toxldty, serum biochemistry,
urlnalysls and hematology were monitored (Gray et al., 1977). Gross and
microscopic pathology were performed on all animals at the end of the study.
Effects were observed at all levels of exposure to d1(2-ethylhexyl)
phthalate. Significantly Increased absolute and relative liver weights were
observed In all dl(2-ethylhexyl) phthalate-exposed groups. Food consumption
and growth were reduced In rats fed either 1 or 2% d1(2-ethylhexyl)
phthalate. In . comparison with controls, significantly reduced testkular
weights, significantly Increased testlcular damage (dose-related) and a
significant decrease In hemoglobin concentration were observed In male rats
fed either 1 or 2% d1{2-ethylhexyl} phthalate. Both males and females fed
either 1 or 2% dl(2-ethylhexyl) phthalate had a significantly reduced packed
cell volume In comparison with controls. Nagasaki et al. (1974) reported
that Interstitial nephritis. Increased SGPT and decreased blood glucose were
observed In rats fed either 500 or 1000 ppm d\(2-ethylhexyl) phthalate In
the diet for 48 weeks. The dietary levels are equivalent to 25 or 50
mg/kg/day, respectively, assuming that a rat consumes a dally amount of food
equal to 5% of Its body weight. No other details were available.
5.5.2. Dlethyl Phthalate. Toxldty studies of dlethyl phthalate are
summarized In Table 5-8. U.S. EPA (1980a) summarized a study by Food
Research Laboratories (1955) 1n which groups of 30 rats (strain and sex not
reported) were fed dlethyl phthalate at concentrations of 0.5, 2.5 or 5.0%
for 104 weeks. The dietary levels are equivalent to 250, 1250 or 2500
mg/kg/day, assuming a dally food consumption equal to 5% of the body weight.
0783p 5-29 08/26/86
-------
TABLE 5-8
Oral Toxlclty Summary for Dlethyl Phthalate
co
CO
•o
Species/ Number and
Strain Sex
Rat/NR 30/group
(sex NR)
Dose.
Vehicle and
Duration of
Treatment
0.5, 2.5 or
554 diet for
104 weeks
Endpolnts Monitored Effects
NR Small but significant
reduction In body
weight gain for rats
fed 5X DEP; food con-
sumption was not affected
Reference
Food Research
Laboratories ,
1955
Rat/CD
CO
o
o
CD
15 H and
15F/group
0, 0.2, 1.0
or 5% diet
for 16 weeks
body weight, food
consumption, water
Intake, hematology.
urInalysls, serum
biochemistries,
gross and mUro-
scoplc pathology
Significantly reduced
body weight (males and
females, 5X; females,
IX)
Brown et al.,
1978
Oog/NR
3
1
1
3
(sex
(sex
(sex
( sex
NR)
NR)
NR)
NR)
0.5X diet NR
for 1 year
1.5X diet
for 1 year
2. OX diet
for 1 year
2.5X diet
for 1 year
None Food Research
Laborator
1955
ies,
NR = Not reported
CD
-------
The only effect observed was a small but significant reduction In growth
rate among rats fed 5% dlethyl phthalate. Food consumption was not affect-
ed. U.S. EPA (1980a) did not report which endpolnts were monitored 1n the
study.
Food Research Laboratories (1955) also fed dlethyl phthalate to dogs at
concentrations of 0.5% (three dogs), 1.5% (one dog), 2.0% (one dog) and 2.5%
(three dogs) for 1 year. Food consumption varied throughout the study;
average doses as provided 1n the study were 114, 343, 500 and 629 mg/kg/day.
No effects were observed at any level of exposure. Again, the endpolnts
which were monitored 1n the study were not reported.
Brown et al. (1978) fed groups of 15 male and 15 female CD rats either
0, 0.2, 1.0 or 5.0% dl(2-ethylhexyl) phthalate (0, 150, 770 or 3160
mg/kg/day, males; 0, 150, 750 or 3710 mg/kg/day, females) 1n the diet for 16
weeks. Variables that were monitored 1n the study Include body weight, food
consumption, water Intake, hematology, urlnalysls, serum biochemistries, and
gross and microscopic pathology. Terminal body weights of male and female
rats fed 5% dlethyl phthalate and female rats fed 1% dlethyl phthalate were
reduced significantly In comparison with controls. Paired feeding studies
Indicated that these reductions were not due to decreased food consumption.
In comparison with controls, statistically significant decreases 1n absolute
organ weights (brain, heart, spleen, kidneys) and Increases In relative
organ weights (brain, liver, stomach, small Intestine, full calcium, testes,
kidneys) were observed 1n males and females fed 5.0% dlethyl phthalate for
16 weeks. These changes were attributed to the compound-related effect on
growth rate since dose-related changes 1n gross or microscopic pathology
were observed. No other effects were observed.
0783p 5-31 08/26/86
-------
5.5.3. 01-n-butyl Phthalate. The oral toxldty of d1-n-butyl phthalate
has been tested 1n rats (Smith, 1953; Nlkonorow et al., 1973; Maslenko,
1968; Lefaux, 1968; Plekacz, 1971; LeBreton, n.d.; Bornmann et al., 1956)
and mice (Ota et al., 1974). These studies are summarized In Table 5-9.
The only Investigators who reported effects are Smith (1953), Ota et al.
(1974) and Nlkonorow et al. (1973).
Smith (1953) fed either 0, 0.01, 0.05, 0.25, or 1.25% d1-n-butyl
phthalate 1n the diet to groups of 10 male Sprague-Dawley rats for 1 year.
Equivalent doses using a factor of 5% are 0, 5, 25, 125 or 625 mg/kg/day.
Endpolnts monitored Include body weight, food consumption, hematology and
gross and microscopic pathology. The only effect observed was 50% mortality
during the first week of the study among rats fed 1.25% d1-n-butyl phthalate.
Increased relative liver weight 1n the absence of hlstopathologlcal
liver lesions were observed In rats treated with 120 or 1200 mg/kg/day for 3
months (Nlkonorow et al., 1973), Degenerative changes 1n the kidneys and
liver were reported to occur 1n mice fed 500 or 5000 mg d1-n-butyl phtha-
late/kg/day In the diet for 1-3 months (Ota et al., 1974). No other details
were given.
5.5.4. Dimethyl Phthalate. Lehman (1955) fed groups of rats (number, sex
and strain not reported) dimethyl phthalate at levels of 2, 4 or 8% 1n the
diet (1000, 2000 or 4000 mg/kg/day using a food factory of 0.05) for 2 years
(Table 5-10). U.S. EPA (1980a) Incorrectly attributed this study to Oralze
et al. (1948). No effects were observed among rats fed 2% dimethyl
phthalate. A minor effect on growth was observed at 8%, while "nephritic
Involvement" (U.S. EPA, 1980a) was observed at 4 and 8%.
0783p 5-32 10/09/87
-------
TA. . 5-9
Oral loxtclty Sumnary for Dl-n-butyl Phlhaldte
CD
CO
•o
Species/
Strain
Rat/Sprague-
Oawley
Number and
Sex
10 M/group
Dose, Vehicle and
Duration of Treatment
0. 0.01. 0.05. 0.?5
or 1.25X diet for 1
year
Endpolnts fkmltored
body weight, food consumption.
heoatology. gross and micro-
scopic pathology (Major organs)
Effects
50% mortality In first week In
1 . ?SX group
Reference
Smith. 1953
Rat/Wlstar
Rat/Ulstar
Rat/Wlstar
tn
i
CO
CO
Rat/NR
10 M and 0. 0.1? or 1.20 g/kg/
10 f/group day for 3 Months
?0 H and 0 or 0.125X diet for
20 F/group 1 year
40 H and 0 or 1250 ppn for
40 F/group 7-12 Months (30 rats/
group killed after 7
Months; the renalntng
rats were killed after
12 Months)
NR/NR 0, 100. 300 ppn diet
for 21 Months
body weight, behavior, hemato-
logy. serum proteins, gross and
Microscopic exaMlnatton of liver,
kidney and spleen
body weight, behavior, hemato-
logy, serun proteins, gross and
Microscopic examination of liver,
kidney and spleen
body weight; kidney, liver and
spleen weights; SCOT and SGP1
activities
NR
Increased relative liver weight
(0.12 and 1.20 g/kg/day); no
changes In pathology of liver
or other tissues
No compound-related hematologl-
cal or hlstologlcal changes;
4/40 and 6/40 controls and
treated rats died, respectively
None
None
Nlkonorow
et al., 1973
Nlkonorow
et al., 1973
Plekac*.
1971
LeBreton.
n.d.
Rat/NR
Rat/NR
Rat/NR
NR/NR
NR/NR
NR/NR
CO
Mouse/NR
NR/NR
500 ppn diet for 15 NR
months; 500 or 1000
mg/kg (2 times/week)
by gavage (vehicle NR)
for 1 year
2.5 mg/kg/day for 6 NR
months (vehicle NR)
100 mg/kg/day for 21 NR
months or 5 genera-
tions; 300 mg/kg/day
for 21 months or 3
generations; 500 mg/
kg/day for 15 months
or 3 generations
0.5. 5 g/kg/day diet NR
for 1-3 months
None
None
'No carcinogenic or poisonous
effects'
Degenerative changes In kidney
and liver
Bornmann
et al.. 1956
Maslenko.
1968
Lefaux. 1968
Ota et al.,
1974
NR = Not reported
-------
TABU 5-10
Oral Toxlclty Summary for Miscellaneous Phthalate Esters
CD
CO
•o
Ester
Dimethyl
phthalate
Species/
Strain
rat/NR
Number and
Sex
NR/NR
Dose. Vehicle and Endpotnts Honltored
Duration of Treatment
2. 4 or 8% diet for 2 NR
years
Effects
•Minor' effect on growth at
4 and 8%; 'some Indication of
nephritic Involvement* at 8%
Reference
Lehman,
1955*
Dllsononyl
phthalate
rat/NR
dog/NR
I
CO
n-Butyl
benzyl
phthalate
rat/NR
rat/F344
o
CO
n-Butyl
benzyl
phthalate
mouse/
B6C3F1
dog/NR
h and F
(numbers NR)
4 N and F
(not clear
whether 4
dogs/group or
4 dogs total;
appears to be
4 dogs total)
NR. NR
50 H. 50 F/
group
50 H. 50 F/
group
NR/NR
0. 50. 150. 500 ing/leg/
day for 13 weeks
(vehicle NR)
0. 0.125. 0.500% for
13 weeks; 2% for 8
weeks then Increased
to 4% for remaining 5
weeks (TWA . 2.8%)
0. 0.25. O.S. 1.0. 1.5
or 2.OX diet for 90 days
0. 6000 or 12.000 ppm
diet for 103 weeks
(females) or 28 weeks
(males)
0. 3000 or 6000 ppn
diet for 103 weeks
0. 1. 2 or 5% diet In
capsule form for 90
days
NR
NR
growth, heutology.
urlnalysls. gross and
Microscopic pathology
body weight, food con-
sumption, mortality.
clinical signs of toxlc-
Ity. gross and micro-
scopic pathology
body weight, mortality.
clinical signs of tox-
Iclty. gross and micro-
scopic pathology
weight gain, mortality.
food consumption, hema-
tology. urlnalysls.
liver and kidney function
(50. 150 mg/kg/day) no effects Livingston,
(500 mg/kg/day) slight reduc- 1971
tlon In growth rate. Increased
liver weight (NOS)
(0.125X) no effect; (O.SX) Livingston.
questionable Increased liver 1971
weight (NOS); (2.8X) decreased
body weight; Increased liver
weight, hlstologlcal changes
In liver, gall bladder, spleen
and kidney
0.25-0.5%; no effects; (1.50%) Honsanto.
slightly reduced growth rate; 1972
(2.OX) slightly reduced growth
rate; Increased liver weight
(1-2.OX) but no hlstopatho-
loglcal changes were observed
Increased mortality associated NIP. 1982a
with 'unexplained Internal
heroorrhaglng' In treated male
rats only; slightly reduced
body weight In treated females
accompanied by reduction In
food consumption
Reduced body weight In treated NTP. 1982a
males and females; no data on
food consumption
Initial reduction In body Monsanto,
weight due to refusal to eat 1972
(5X group only)
co
-------
TABLE 5-10 (conl.)
00
CO
•o
Ester
Species/
Strain
Number and
Sex
Dose. Vehicle and
Duration of Treatment
Endpolnts Monitored
Effects
Reference
Ot-n-octyl
phthalate
rat/
Ulstar
mouse/
40 H and
40 f/group
pairs of 20
M and f/group
0 or 3SOO pp* diet for
7-12 months (30 rats
killed after 7 months;
remainder killed after
12 months)
1.25. 2.5 or 5X In
diet for 2 generations
body weight; kidney,
liver and spleen weights;
S&OT and SGP1 activities
number of 1Itters/patr.
X pups born alive, live
pup weight, weight at
weaning, mating behavior.
reproductive performance.
sperm counts
Elevated relative liver weight
(females at 7 and 12 months);
elevated relative kidney weight
(females at 12 months); signi-
ficantly elevated SCOT and SGPT
(males and females at 12 months)
None
Plekdc;,
19/1
Gulall et
al., 1985
tn
i
tn
•U.S. EPA (1980b) Incorrectly attributed these data to OraWe et al. (1948)
NR * Mot reported; NOS ~ not otherwise specified
O
vD
co
-------
5.5.5. D11sononyl Phthalate. Livingston (1971) exposed rats and dogs
orally (method not specified) to dllsononyl phthalate for 13 weeks (see
Table 5-10). Male and female rats (strain, numbers not reported) were given
0, 50, 150 or 500 mg/kg/day. No effects were observed among low- and
middle-dose rats. Increased liver weight and a slight reduction In growth
rate were observed among high-dose rats. Dogs were given 0, 0.125 or 0.5%
dimethyl phthalate for 13 weeks, or 2% for 8 weeks followed by 4% for 5
weeks (TWA 2.8%). Dogs given a TWA concentration of 2.8% dimethyl phthalate
had decreased body weights, Increased liver weights, and hlstologlcal
changes in the liver, gall bladder, spleen and kidneys. Assuming a dog
consumes a dally amount of food equal to 2.5% of Us body weight (Durkln,
1985), the TWA concentration Is equivalent to 700 mg/kg/day. No effects
were observed among low-dose dogs (31.25 mg/kg/day), but middle-dose (125
mg/kg/day) dogs had Increased liver weights.
5.5.6. n-Butyl Benzyl Phthalate. NTP (1982a) fed n-butyl benzyl
phthalate to female F344 rats at concentrations of 0, 6000 or 12,000 ppm and
B6C3F1 mice of both sexes at concentrations of 0, 3000 or 6000 ppm (see
Section 5.1. for doses) for 103 weeks. The only noncardnogenlc effects
observed In female rats and male and female mice were reductions In growth
rate (see Table 5-10). Growth rate reduction In female rats was accompanied
by reduced food consumption. Data on food consumption were not reported for
mice. Male F344 rats were also fed 0, 6000 or 12,000 ppm n-butyl benzyl
phthalate, but the study was terminated after 28 weeks because of high
mortality among treated rats. Mortality was attributed to unexplained
hemorrhaglng.
0783p 5-36 08/26/86
-------
Krauskopf (1973) reported 90-day feeding studies on rats and dogs
(strains, sex, numbers not reported) conducted by Monsanto (1972). Rats
were fed 0, 0.25, 0.5, 1.0, 1.5 or 2% (0, 125, 250, 500, 750 or 1000 mg/kg/
day, assuming a food Factor of 0.05) n-butyl benzyl phthalate, while dogs
were fed 0, 1, 2 or 5% (0, 250, 500 or 1250 mg/kg/day, assuming a food
factor of 0.025) n-butyl benzyl phthalate. No adverse effects were observed
among dogs fed n-butyl benzyl phthalate at any level, or among rats fed 0.25
or 0.5% n-butyl benzyl phthalate. Increased liver weights without accom-
panying hlstopathologlcal changes were observed among rats fed 1-2% n-butyl
benzyl phthalate. Slightly reduced growth rate was observed at the two
highest doses. In a draft report. NTP (1985) conducted a toxldty and
mating trial study In F344 rats concomltantly. The toxldty portion of this
report was conducted to determine the no toxic effect level and to evaluate
the dose response of BBP. Rats were administered concentrations of either
0, 0.03, 0.09, 0.28, 0.83 or 2.50% BBP 1n the diet for 26 weeks. There were
15 male animals 1n each dose group, starting at 6 weeks of age. Throughout
the study, body weight gain was significantly depressed at the 2.5% BBP
level when compared with the controls. There were no deaths attributed to
BBP toxIcHy. All the rats given 2.5% BBP had small testes upon gross
necropsy at the 26-week termination. Five of 11 had soft testes and only
1/11 had a small prostate and seminal vesicle. In the 0.03, 0.09, 0.28 and
0.83% BBP dose groups there were no grossly observable effects on male
reproductive organs. The kidneys of six animals 1n the 2.5% group contained
focal cortical areas of 1nfarct-l1ke atrophy. In addition, testlcular
lesions were also observed at the 2.5% dose level. Lesions were
characterized by atrophy of seminiferous tubules and aspermla. The other
treatment groups showed no evidence of abnormal morphology 1n any other
organs.
0783p 5-37 08/31/87
-------
H1stopatholog1cal changes were also seen at the 2.5% BBP level after 10
weeks of exposure In the maUng trial portion of this study. After hlsto-
pathologlcal examination, testlcular lesions were characterized by atrophy
of seminiferous tubules and a near total absence of mature sperm production.
When 10/30 females successfully mated with the 2.5% treatment level males,
none were pregnant at necropsy. The Investigators concluded that the data
suggest a depression In male reproductive organ weights by either a direct
or Indirect toxic effect after 2.5% BBP administration. BBP at 0.83% In the
diet did not result In any treatment-related effects as evaluated by the
authors. The Investigators concluded from the results of both studies that
a threshold for toxlclty would be between 0.83 and 2.5% BBP.
In contrast to the author's conclusions, some alterations 1n animals fed
0.83% BBP were noted which may have been compound related 1n that they
occurred In the 2.5% group also, but not In lower exposure groups. Liver-
to-body weight ratios were significantly Increased In both the 0.83 and 2.5%
diet groups, while llver-to-braln weight ratio was Increased In the 0.83%
group alone. Absolute liver weight was also Increased In the 0.83% group.
Hematologlcal evaluations showed small but significant elevations In mean
corpuscular hemoglobin 1n the 0.83% group at 60, 90, 120 and 150 days, but
not at 30 or 180 days, while mean corpuscular hemoglobin concentration was
Increased at 60 and 120 days. Interestingly, no alterations In these
parameters was seen 1n the lower dose groups. The 2.5% group showed a
consistent pattern of Increased retlculocytes, decreased red blood cells,
Increased mean corpuscular volume, Increased mean corpuscular hemoglobin and
hemoglobin concentration 1n addition to reduced cellularlty of the bone
marrow.
0783p 5-38 08/31/87
-------
5.5.7. 01-n-octyl Phthalate. A Polish abstract (Plekacz, 1971) reports
that groups of 40 male and female rats (strain not reported) were fed either
0 or 3500 ppm (0 or 175 mg/kg/day, using a food factor of 0.05) d1-n-octyl
phthalate In the diet for 7-12 months. Elevated relative liver weight was
observed among d1-n-octyl phthalate-treated females at 7 and 12 months.
SGOT and SGPT were significantly Increased 1n both males and females at 12
months. Increased kidney weight was reported among females at 12 months.
Effects on spleen weight or body weight were not observed. Hlstopathologl-
cal examination was apparently not performed.
5.5.8. Human Studies. The health status of 147 workers who handled
phthalate plastldzers was evaluated by Mllkov et al. (1973). Workers were
exposed to a mixture of compounds Including d1-n-butyl phthalate, OAP-789,
d1-n-octyl phthalate, dllsooctyl phthalate, n-butyl benzyl phthalate,
seladnates, adlplnates, vinyl chloride, carbon monoxide amd mixed ethers.
Phthalate exposure was estimated to be 1-40 mg/m3. Effects attributed to
phthalate exposure Included polyneurUls (frequency and Intensity Increased
with duration of employment), decline 1n vestlbular and olfactory excitabil-
ity and reductions In thrombocytes, leukocytes, hemoglobin and "blood color
Index."
GIHoll et al. (1978) performed clinical neurological electromyographlc
and electroneurologlc tests on 38 workers In the phthalate plastldzer
Industry. Of the 38 workers, 23 had been exposed only to phthalate esters
(not otherwise specified) for an average of 4.5 years; the remainder had
been exposed only to alcohols or only to phthallc anhydride. Ambient
concentrations of phthalate esters were
-------
motor types. The frequency and severity Increased wHh length of exposure;
no cases were found 1n workers exposed for <2 years.
Aldyreva et al. (1974) reported an Increase In the Incidence of mis-
carriages and menstrual disorders among women exposed to phthalate esters In
the synthetic leather Industry. Details concerning the exposed and control
populations were not given. Thless et al. (1978) examined morbidity among
101 workers employed In the production of d1(2-ethylhexyl) phthalate for an
average of 12 years (range=4 months to 35 years). Exposure ranged from
0.0006-0.01 ppm (0.01-0.16 mg/m3). There was no evidence of a higher
Incidence of miscarriages or deformities of offspring among female workers
or the wives of male workers. No other compound-related effects were
observed, though dl(2-ethylhexyl) phthalate was found 1n the blood and urine
of both exposed and control groups.
5.6. OTHER RELEVANT INFORMATION
Acute oral toxlcltles for phthalate esters are summarized 1n Table 5-11.
5.7. SUMMARY
D1(2-ethylhexyl) and n-butyl benzyl phthalates have been tested for
carcinogenic potential In feeding studies with F344 rats and B6C3F1 mice.
D1(2-ethy1hexyl) phthalate was found to cause Increased Incidences of liver
neoplasms 1n both rats and mice (NTP, 1982b; Kluwe et al., 1982b). n-Butyl
benzyl phthalate caused an Increase 1n myelomonocytlc leukemia In female
F344 rats (NTP, 1982a). Because of high background Incidence of myelomono-
cytlc leukemia 1n F344 rats and because dose-related and significant
decreases 1n malignant lymphoma, all lymphoma, and leukemia or lymphoma were
observed 1n male B6C3F1 mice (NTP, 1982a), there 1s only limited evidence to
conclude that n-butyl benzyl phthalate 1s carcinogenic.
0783p 5-40 08/31/87
-------
TABLE 5-11
Acute Oral Toxlclty of Phthalate Esters
Phthalate Ester
D1(2-ethylhexy1)
Dimethyl
Dlethyl
Dlbutyl
n-Butyl benzyl
D1-n-octyl
Dlhexyl
Dlnonyl
Oldecyl
Species
rat
rabbit
guinea pig
mouse
rat
mouse
rabbit
guinea pig
rat
rabbit
rat
mouse
mouse (H)
mouse (M)
rat (MiF)
mouse (M)
mouse (F)
rat
rat
rat
rat
LD50
26 g/kg
33.9 g/kg
26.3 g/kg
33.5 g/kg
6.9 ma/kg
7.2 mi/kg
4.4 mi/kg
2.4 mi/kg
8.2 ml/kg
1.0 g/kg
23.0 g/kg
12.5 g/kg
14.95 g/kg
-8 g/kg
>20 ml/kg
9 g/kg
14.8-17.0
9.77 g/kg
2.33 g/kg
6.16 g/kg
4.17 g/kg
>13 g/kg
29.6 g/kg
>2 g/kg
>64 g/kg
Reference
Krauskopf, 1973
Shaffer et al., 1945
Krauskopf, 1973
Krauskopf, 1973
Dralze et al., 1948
Dralze et al. , 1948
Dralze et al., 1948
Dralze et al., 1948
Krauskopf, 1973
Sandermeyer and Klrwln, 1981
Radeva and Dlnoeva, 1966;
Gesler, 1973
Homrowskl and Nlkonorow, 1959;
Nlkonorow et al., 1973
Komarova, 1979
Smith, 1953
Lehman, 1955
Komarova, 1979
Oraorl, 1976;
Yamada et al., 1975
Mlyahara et al., 1973;
Omorl, 1976
NTP, 1982a
NTP, 1982a
NTP, 1982a
Sandermeyer and Klrwln, 1981
Sandermeyer and Klrwln, 1981
Sandermeyer and Klrwln, 1981
Sandermeyer and Klrwln, 1981
0783p
5-41
08/31/87
-------
The mutagenklty and genotoxklty of phthalk acid esters have been
reviewed by Thomas and Thomas (1984) and Hopkins (1983). D1-2(ethylhexyl}
phthalate and metabolites have yielded mostly negative results In Ames tests
with S. typhlmurlum, and mixed results with j_n vitro and hi vivo tests of
genotoxklty. Dlethyl phthalate, dimethyl phthalate, and d1-n-butyl phtha-
late were found to be mutagenk 1n in vitro mkroblal assays with S. typhl-
murlum (Kozumbo et al., 1982; Rubin et al., 1979; Seed, 1982).
Oral studies have shown that d1(2-ethylhexyl) phthalate, dl-n-butyl
phthalate, and dl-n-heptyl phthalate can produce adverse effects upon the
developing fetus when mice and rats are exposed during gestation (Wolkowskl-
Tyl, 1984a,b; Bell et al., 1979; Bell, 1980; Shlota and M1ma, 1985; Shkta
and N1sh1mura, 1982; Shlota et al., 1980; Nakamura et al., 1979; Yag1 et
al., 1978, 1980; Tomlta et al., 1982b; Onda et al., 1974). Whether the
observed effects (reduced fetal weight, fetal mortality, gross external and
skeletal malformations) represent a primary effect of the compound )n
question or whether they occur as a result of maternal toxklty has yet to
be demonstrated unequivocally. Studies conducted by NTP (Wolkowsk1-Tyl et
al., 1984a,b) Indicate that mice are more sensitive than rats.
NTP has recently conducted reproduction and fertility assessments on
CD-I mke for dlethyl phthalate (Reel et al., 1984) and d1-n-octyl phthalate
(Gulatl et al., 1985). Dietary d1-n-octyl phthalate had no effects on
reproduction and fertility among parental or F, mke. Dietary dlethyl
phthalate had no effects on reproduction and fertility 1n parental mke, but
dlethyl phthalate-exposed F, mke had fewer pups/litter than did controls,
as well as Increased liver weights (males and females), Increased prostate
weights, Increased pituitary weights (females only) and decreased sperm
concentrations. Booth et al. (1983) and Plasterer et al. (1985) reported
that dimethyl phthalate had no effects on reproduction 1n CD-I mke.
0783p 5-42 08/31/87
-------
Dimethyl phthalate was administered by gavage on days 7-15 of gestation.
The fertility of Sherman rats was not affected by dietary administration of
dl(2-ethylhexyl) phthalate (up to 0.4%) for 1-2 years (Carpenter et al.,
1953).
Orally administered d1(2-ethylhexyl), d1-n-butyl, n-butyl benzyl,
dl-n-pentyl, d11sobutyl and d1-n-heptyl phthalates have been shown to cause
testlcular atrophy In rats to mice (Gray et al., 1977, 1982; Shaffer et al.,
1945; Gangolll, 1982; 01shl and Hlraga, 1980a, 1983; Gray and Butterworth,
1980; Mangham et al., 1981; Olshl, 1985; Agarwal et al., 1985; Foster et
al., 1980). 01-n-octyl, dimethyl, dlethyl, dlpropyl and d1-n-heptyl phtha-
lates did not cause testlcular atrophy In rats (Gray and Butterworth, 1980;
Foster et al., 1980). Species differences In phthallc add ester-promoted
testlcular atrophy have been observed. Gray et al. (1982) failed to observe
testlcular atrophy in hamsters gavaged with dl-n-butyl, d1(2-ethylhexyl) and
d1-n-pentyl phthalates at doses equlmolar to those that caused atrophy In
rats. In the same study, mice gavaged with equlmolar doses of d1-n-butyl,
d1(2-ethylhexyl) and dl-n-pentyl phthalates had only slight focal atrophy.
Chronic or subchronlc oral studies have been conducted with d1(2-ethyl-
hexyl), d1-n-butyl, dimethyl, dllsononyl, n-butyl benzyl and dl-n-octyl
phthalates (Carpenter et al., 1953; Harris et al., 1955; Nlkonorow et al.,
1973; Gray et al., 1977; Gangolll, 1982; NTP, 1982a,b; Kluwe et al., 1982b;
Shaffer et al., 1945; Popp et al., 1985; Canning et al., 1985; Nagasaki et
al., 1974; Ota et al., 1974; Lake et al., 1976, 1977a; Maslenko, 1968; Food
Research Laboratories, 1955; Brown et al., 1978; Smith, 1953; Lefaux, 1968;
Plekacz, 1971; LeBreton, n.d.; Bornmann et al., 1956; Lehman, 1955;
Livingston, 1971; Monsanto, 1972). Liver, kidneys and testes appear to be
target organs. Occupational exposure to phthalate esters has been asso-
ciated wlh polyneuropathy (Mllkov et al., 1973; G1l1ol1 et al., 1978).
0783p 5-43 08/31/87
-------
Acute oral LD5Qs have been reported for d1(2-ethylhexyl), dimethyl,
d1-n-butyl, dlethyl, n-butyl benzyl, d1-n-octyl, dlhexyl, dlnonyl and
dldecyl phthalates. These values are summarized 1n Table 5-11.
0783p 5-44 08/31/87
-------
6. AQUATIC TOXICITY
Many aquatic toxIcHy tests wHh phthalate esters have used concentra-
tions greater than the aqueous solubility of these compounds. In these
cases, H 1s necessary to determine 1f toxic effects occur at concentrations
that are environmentally plausible. Some Investigators have used carriers
or solvents to dispense or emulsify phthalate esters In water, and thus may
have Influenced toxlclty by Increasing phthalate availability. Furthermore,
the carriers or solvents may have toxic effects of their own (Sugatt and
Foote. 1981 ).
Another concern In Interpreting the results of aquatic toxlclty tests Is
that some phthalate esters (such as n-butyl benzyl and d1-n-butyl phtha-
lates) are rapidly blodegraded 1n natural waters (t <2 days); such
exposure conditions could change significantly during a 96-hour static
bloassay. Of 32 acute toxlclty studies with phthalate esters reviewed by
Sugatt and Foote (1981), 28 were static exposures, and all results were
based on nominal rather than measured concentrations. This Illustrates the
need for caution 1n applying these results to environmental situations.
6.1. ACUTE
Data concerning the acute toxlclty of phthalate esters to aquatic verte-
brates and Invertebrates are presented 1n Tables 6-1 and 6-2, respectively.
The ranges of acute LC,Q or EC,- values 1n the various phthalate esters
are presented In Table 6-3. Four of the esters had LC5Q values for only
one species. The other esters had a fairly wide range of values. Ten of
the esters had LC_n or EC,n values <10 mg/i. In at least one species.
Six of the esters were acutely toxic at concentrations of <1.0 mg/n..
0784p 6-1 06/06/86
-------
TABLE 6-1
Acute Toxlclty of Phthallc Acid Esters to Aquatic Vertebrates
o
GO
T3
CT
1
ro
O
LT>
^
en
>^
CD
Species Chemical
Fathead minnow BBP
Plmephales promelas
DBP
OOP
DUP
S-7903
Golden orfe DAP
Leuclscus Idus melanotus
DEP
Goldfish BBP
Carasslus auratus
DBP
DEHP
OOP
Rainbow trout BBP
Salmo qalrdnerl
OBP
DEHP
Toxic
Concentration
<»g/i)
2.1
2.25
2.32
5.3
1.0-1.8
1.30
2.02
10
>}QQO
1000
0.4
61
200
1-12
NR
200b
3.3
1.2-1.8
2.6
6.47
>100
540
note
(«g/t)
FRESHWATER
1.0
<1.06
NR
2.2
0.56
NR
NR
3.2
NR
NR
0.3
11
100
0.5
200
NR
<0.36
>0.5. <2.0
NR
NR
NR
230
Effect Measured
SPECIES
96-hour LCso hardwater
14-day LCcg. flowthrough exposure
96-hour LCso. flowthrough exposure
96-hour LCso softwater
reduced egg hatchablllty and larval
survival
96-hour LCso
LCso. newly hatched larvae
reduced egg hatchablllty
96-hour LCso
0-10* mortality. 96-hour
48-hour LCso
48-hour LCso. 1ab '
heart rate depression
dose-related depression of heart rate
heart rate depression
LCso. embryo-larval stages
96-hour LCso
96-hour LCso
96-hour LCso
96-hour LCso
96-hour LCso
96-hour LCso
Reference
Gledhtll et al.. 1980
Gledhlll et al.. 1980
Gledhtll et al.. 1980
Gledhlll et al., 1980
McCarthy et al.. 1985
Mayer and Sanders. 1973
McCarthy and Uhttmore. 1985
McCarthy et al.. 1985
ABC. 1979a
ABC. 1979b
Juhnke and Luedemann, 1978
Juhnke and Luedemann. 1978
Pfuderer and Francis. 1975
Pfuderer and Francis. 1975
Pfuderer and Francis. 1975
Blrge et al.. 1979
Gledhlll et al. . 1980
Hrudey et al.. 1976
Johnson and Flnley. 1980
Mayer and Sanders. 1973
Johnson and Flnley. 1980
Hrudey et al. . 1976
-------
TABLE
(cont.)
o
-J
00
•£
Species
Rainbow trout
Sal mo galrdnerl
Toxic
Chemical Concentration NOEC
(mg/l) (mg/l)
FRESHWATER
OOP NR 1000
139.1 >71.87. <148
Effect Measured
SPECIES (cont.)
48-hour survival
.2 22-day LCjg at water hardness of
Reference
Sllvo. 1974
Blrge et al.. 1978
139.5
149.2
1S4.0
SO mg/l CaC03. embryos exposed
from fertilization through hatching.
flowthrough
>55.3. <7K87 26-day LC50 at water hardness of
50 mq/l CaC03. embryos exposed
front fertilization through 4 days after
hatching, flowthrough
>0.5. <48.9 26-day LC^g at water hardness of
200 mg/i CaCOj, embryos exposed
from fetlUzatlon through 4 days after
hatching, flowthrough
>0.5, <48.9 22-day LCtn. at water hardness of
200 mg/t caCOj, embryos exposed
From fetlllzatton through hatching.
flowthrough
Coho salmon
Oncorhynchus klsutch
Channel catfish
Ictalurus punctatus
o
tn
~»^
tn
\
03
OUP
S-790a
DEHP
OBP
OEHP
DINP
OOP
>1000
>1000
>100
2.91
>100
0.42
0.87
0.69
1.21
NR 96-hour Uso
1000 96-hour LCSO
NR 96-hour IC^n,
NR 96-hour LC$o
NR 96-hour LC50
>0.01. <0.10 7-day LCjQ of embryos exposed from
fertilization through 4 days after
hatching
>0.1. <1.0 3-day LCjp of embryos exposed from
fertilization to hatching
>0.01, <0.1 7-day LC^p, of embryos exposed from
fertilization through 4 days after
hatching
>0.01, <0.1 3-day LCjQ of embryos exposed from
fertilization to hatching
Blrge et al.. 1978
Blrge et al.
Blrge et al.
1978
1978
ABC. 1979c
ABC. 1979d
Johnson and Flnley, 1980
Mayer and Sanders. 1973
Johnson and Flnley. 1980
Blrge et al.. 1978
Blrge et al.. 1978
Blrge et al.. 1978
Blrge et al.. 1978
-------
TABLE 6-1 (cont.)
o Toxic
2J Species Chemical Concentration
4^ (mg/t)
•o
Blueglll sunflsh BBP 1.7
Lepomls macrochlrus 43.3
DBP 0.73
1.22
DEHP >100
>770
DEP 98.2
110
DMP 49.5
Redear sunflsh DINP 4.67
Lepomls mlcrolophus
cr
i
* 71.9
OOP 6.18
77.2
Largemouth bass OOP 32.9
NOEC Effect Measured
FRESHWATER SPECIES (cont.)
0.36 96 -hour 1C 50
22 96 -hour LC50
NR 96-hour LC^g
NR 96-hour LCso
NR 96 -hour LCSO
770 96-hour LC$o
<6.8 96-hour LC^o
NR 96 -hour LCio
<13 96-hour LC<,0
>0.1-<1.0 7- to 8-day LCcg of embryos exposed
froa fertilization through 4 days after
hatching
>0.1-<1.0 3- to 4-day LCjQ of embryos exposed
from fertilization to hatching
>0.1-<1.0 7- to 8-day LCtn of embryos exposed
from fertilization through 4 days after
hatching
>0.1-<1.0 3- to 4-day LCjQ of embryos exposed
fro* fertilization to hatching
>0.3. <35.5 7- to 8-day LCtQ of embryos from
Reference
Gledhlll et al.. 1980
U.S. EPA. 1978c
Mayer and Sanders.
Buccafusco et al . .
Johnson and F Inley,
U.S. EPA. 1978c
U.S. EPA, 1978c
Buccafusco et al . .
U.S. EPA. 1978c
Blrge et al.. 1978
Blrge et al.. 1978
Blrge et al.. 1978
Blrge et al.. 1978
Blrge et al.. 1978
1973
1981
1980
1981
Hlcropterus salmoldes
fertilization through 4 days after
hatching, hardwater
42.1
63.9
66.1
>0.3. <46.3
>0.3. <46.3
>0.3, <35.5
7- to 8-day LCso of embryos from
fertilization through 4 days after
hatching, softwaler
3- to 4-day LCjn of embryos from
fertilization to hatching, softwater
3- to 4-day LCsg of embryos from
fertilization to hatching, hard water
Blrge et al.. 1978
Blrge et al.. 1978
Blrge et al.. 1978
CD
cr>
-------
TABLE 6-1 (cont.)
Toxic
2 Species Chemical Concentration NOEC Effect Measured
00 (mg/l) (ntg/l)
FRESHWATER SPECIES (cont.)
Perch OOP NR Maturation 3- to 4-day survival
Perca fluvlatllls
Roach OOP NR saturation 3- to 4-day survival
Rutllus rutllus
Leopard frog DINP 3.63 >0.1. <1.0 7- to 8-day \.C$$ of embryos exposed
Rana plplens fro* fertilization through 4 days
after hatching
4.94 >0.1. <1.0 3- to 4-day LCcn of embryos exposed
fro* fertilization to hatching
OOP 4.44 >0.1. <1.0 7- to 8-day LC50 of embryos exposed
from fertilization through 4 days
after hatching
<^ 5.52 >0.1. <1.0 3- to 4-day LCcg of embryos exposed
^ fro* fertilization to hatching
Fowler's toad DINP 2.95 >0.1, <1.0 7- to 8-day LC50 of embryos exposed
Bufo fowler 1 from fertilization through 4 days
after hatching
23.51 >0.1. <1.0 3- to 4-day LCjn of embryos exposed
fro* fertilization to hatching
OOP 3.88 >0.1, <1.0 7- to 8-day LCcn of embryos exposed
Reference
Nehrlng, 1966
Nehrlng. 1966
Blrge et al. ,
Blrge et al.,
Blrge et al . .
Blrge et al. ,
Blrge et al. ,
Blrge et al . ,
Blrge et al . ,
1978
1978
1978
1978
1978
1978
1978
44.14
>0.1. <1.0
from fertilization through 4 days
after hatching
3- to 4-day LC$n, of embryos exposed
from fertilization to hatching
Blrge et al.. 1978
O
en
Bleak
Alburnus alburnus
DMP
100-115
SALTWATER SPECIES
NR
96-hour LCjQ. brackish water
(7 ppth salinity)
Linden et al., 1979
en
•»v
CD
-------
TABLE 6-1 (cont.)
o
— 1
oo
•o
cr<
i
o»
Species
Sheepshead minnow
Cvpr Inodon varlegatus
Hullett
Huqll cephalus
Shiner perch
Cymatogaster aqqregata
English sole
Parophrys vetulus
Toxic
Chemical Concentration
(»»q/i)
BBP 3.0
378
440
DEHP >550
>770
DEP 29.6
DNP S8.0
S-711b NR
OEP 26
BBP 0.08
0.24
0.51
BBP 0.1
0.30-0.45
O.SS-0.66
NOEC
(nxj/l)
SALTWATER
1.0
355
360
550
7/0
22.2
?1.5
1000
10-15
NR
NR
NR
NR
NR
NR
Effect Heasured
SPECIES (cont.)
96-hour ICjn
96 -hour LC^g
96-hour LC-50
96-hour LC5Q
96-hour LC$0
96-hour LC^o
96-hour Lf-so
no Mortality
86-hour LCjQ
effect on coloration
effect on schooling behavior
96-hour LCt,Q
sublethal effects on equilibrium and
activity
lethal threshold
96-hour LCjQ
Reference
Gledhlll et al.. 19BO
U.S. EPA. 1978C
Heltmuller et al.. 1981
Heltrouller et al., 1981
U.S. EPA. 1978c
U.S. EPA. 197Bc
U.S. EPA. 1978c
EG&G Bionomics. 1980
Shlmada et al.. 1983
Oiretlch et al.. 1983
Ozretlch et al.. 1983
Ozrettch et al.. 1983
Randall et al.. 1983
Randall et al.. 1983
Randall et al.. 1983
aS-790 . dl(heptyl. nonyl) phthalate (Monsanto. 1983a)
bS-711 - dlfheptyl. nonyl. undecyl) phthalate (Nonsanto. 1983b)
03
er>
-------
TABU 6-2
Acute Toxlclty of Phthallc Acid Esters to Aquatic Invertebrates
--J
tn
\
CD
Species
Protozoa
Uronema par due* 1
tntoslphon sulcatum
Tetrahymena pyrlformls
Cladoceran
Daphnla magna
Cladoceran
Daphnla magna
Toxic
Chemical Concentration NOEC Effect Measured
(rog/l) (mg/l)
DAP
DEP
DAP
DEP
DBP
DIBP
BBP
BBP and
DEHP (1:1
w/w mixture)
DAP
DBP
22
48
13
19
0.05
0.05
1.0
1.6-2.2
3.7
2.43
1.91
92
0.97
22
1.8
5.2
FRESHWATER SPECIES
<22 20-hour toxic threshold (5X Inhibition
of cell multiplication)
<48 20-hour toxic threshold |5X Inhibition
of cell multiplication)
<13 72-hour toxic threshold (5X Inhibition
of cell multiplication)
<19 72-hour toxic threshold (5X Inhibition
of cell multiplication)
NR complete growth Inhibition
NR complete growth Inhibition
NH 48-hour ECjQ. no solvent carrier
0.62 48-hour EC^Q. various solvent carriers
<1.0, <2.5 48-hour ECjQ. lake water
<2.5 48-hour LCi,0. river water containing
natural humlc acid
<1.0 48-hour LC5Q. lake water with 250 ppffl
fulvlc acid added
<3b 48-hour LC«,o
<0.15 48-hour LC$O. duplicate tests
NR 24-hour £CS0. Immobilization
0.56 decreased fecundity
NR 48-hour LCSO
Reference
Brlngmann and Kuhn, 1980a
Brlngnwnn and Kuhn, 19BOa
Brlngmann and Kuhn. 1980b
Brlngmann and Kuhn. 1980b
Yoshlzawa et a). . 1977
Yoshlzawa et al., 197;
Barer a and Adams, 1983
Barera and Adams, 1983
Gledhlll et al.. 1980;
landvatter. n.d.
landvatter, n.d.
landvatter, n.d.
UBlanc, 1980
landvatter, n.d.;
Monsanto, 1983d
Brlngmann and Kuehn,
1982
McCarthy et al.. 1985
McCarthy and Whltmore.
1985
-------
TABLE 6-2 (cont.)
Toxic
Species Chemical Concentration NOEC
(mg/l) (mg/t)
o
~j
CO
Effect Measured
Reference
•£ FRESHWATER SPECIES (cont.)
Cladoceran DEHP 1.59 <1.0
Daphnta magna
2.0 NR
2.30 <1.0
48-hour
<96 hour
48-hour
48-hour
LCso.
-old
LC50
LC50.
lake
water.
daphnlds
Landvatter, n
.d.
Monsanto. 1983d
lake
water.
daphnlds
Landvatter. n
.d.
<72 hours old
3.85 <1 .0
48-hour
LCSO.
of unspecified
5.29 <1.0
8.90 <1.0
11 1.1
13.9 <1.0
48-hour
<6 days
48-hour
48 hours
48-hour
48-hour
LC50.
old
LC$0.
old
LCso.
LCSO.
lake
age
lake
lake
water.
water.
water.
daphnlds <24
lake
daphnlds
daphtds
daphnlds
hours old
water with 250 ppm
Landvatter. n
Landvatter. n
Landvatter. n
LeBlanc. 1980
Landvatter. n
.d.
.d.
.d.
.d.
i
oo
OEP
41
NR
fulvlc acid added, daphnlds of unspeci-
fied age
24-hour ECso. Immobilization
Cladoceran
Daphnla magna
0 Midge larvae
tn Chlronomus plumosus
\ — —
tn
^
CO
52
DMP 33
DOP 1.0
DUP 15
16
S-711* >10
S-790 0
DBP 0
4
5
DEHP >'
.12
.76
.0
.46
18
10
0.32
10
<3.2
10
<2.5
<0.056
NR
NR
NR
NR
48-hour LCso
48-hour LCso
decreased fecundity
48-hour LCso
48-hour LCso
48-hour ECso. Inmobl 1 Izat Ion
48-hour LCso
48-hour
48-hour
48-hour
48-hour
48-hour
LCso
£C50
LCso
LCSO
ECSO
. 3rd-4th Instar
larvae
. 2nd Instar larvae
. 3rd-4th Instar
and 48-hour ICy
larvae
)
Brlngmann and Kuehn,
1982
LeBlanc. 1980
LeBlanc. 1980
McCarthy et al.. 1985
McCarthy and Whltmore. 1985
ABC. 1979e
Monsanto. 1983c
Landvatter, n.d.
ABC. I979f
Streufert. 1977
Streufert. 1977
Streufert, 1977
Streufert. 1977
-------
TABLE 6-2 (cont.)
o
-J
CD
I
10
Species
Chemical
Toxic
Concentration
(i*g/t)
NOEC
Effect Measured
Reference
FRESHWATER SPECIES (cont.)
Midge larvae
Paratanytarsus parthero-
genetlca
Blackfly larvae
Slroullum sp.
Scud
Ganroarus pseudollnmaeus
Scud
Gammarus pulex
Crayfish
Orconcctes nals
Nematode
Panaqrellus redlvlvus
Mysld shrimp
Mysldopsls bahla
Grass shrimp
Palaemonetes puqlo
S-711*
DMP
DBP
DEHP
DEHP
DBP
OBP
BBP
DfP
OMP
S-711*
DBP
DEHP
DMP
>10
0.7-1.0
2.10
>32
NR
>10.00
NR
0.028
0.9
9.63
7.59
73.7
NR
10 ppm
NR
100 ppm
NR
NR
NR
NR
0.4
NR
0.28
O.OOP8
SALTWATER
0.4
3.S5
3.94
47.8
1000
1 ppm
1 ppm
10 ppm
48-hour LC5Q
9-24X Mortality. 24-hour
96-hour LCjg
96-hour LC$o
no Mortality
96-hour LCjo
96-hour survival rate
96-hour change In distribution of
larval stages during development
relative to control distribution
SPECIES
96-hour LC$g
96-hour LC5Q
96-hour I €50
96-hour LC5Q
non-toxic
larval mortality during 6-day exposure
larval mortality during 6-day exposure
larval mortality during 6-day exposure
Monsanto, 1983e
Gjullln et al.. 1949
Mayer and Sanders, 1973;
Sanders et al., 1973
Sanders et al. , 1973
Shell Oil Co.. 198?
Mayer and Sanders, 1973;
Sanders et al.. 1973
Samolloff et al. . 1980
Samolloff et al.. 1980
Gledhlll et al.. 1980
U.S. EPA. 1978c
U.S. EPA. 1978c
U.S. EPA. 1978c
EG&G Btoneralcs, n.d.
Laughlln et al., 1977
Laughlln et al. , 1977
Laughlln et al., 1977
oo
-------
TABLE 6-2 (cent.)
o
•-J
oo
4^
•o
1
0
o
in
CD
Species
Brine shrimp
Arteala sallna
Copepod
Nltocra splnlpes
Copepod
Nltocra splnlpes
Mud crab
Rhl thropanopeus harrlsM
•S-711 = d1(heptyl. nonyl.
NR = Not reported
Toxic
Chemical Concentration
(«g/O
DBP
OOP
DEP
OEHP
DHP
DMP
DBP
DEHP
DEP
DIBP
DMP
DNP
DBP
DMP
undecyl)
S.6
8.0
8.2
10.3
10 ppn
saturation
NR
61.5
SO ppn
saturation
SO
NR
NR
1.7
>300
74
3.0
62
>300
NR
NR
phthalate (Monsanto.
NOEC
(flKj/1)
SALTWATER
NR
NR
NR
NR
NR
NR
123
1?.2
10 ppn
NR
NR
SO ppn
120
NR
NR
NR
NR
NR
NR
1 .0 ppn
1 .0 ppra
1983b)
Effect Measured
SPECIES (cont.)
24-hour LC<,o. Larvae
24 -hour LCjg
24-hour survival of larvae
24-hour hatching success of eggs
72-hour hatching success of eggs
24-hour LC50. larvae
24-hour survival of larvae
24-hour hatching success of eggs
72-hour hatching success of eggs
24-hour LC$o. larvae
slight reduction In hatching success.
40-hour
72-hour hatching success of eggs
24-hour survival of larvae
96-hour LCso
96-hour LCjo
96-hour LC«,g
96-hour LC5Q
96-hour LCso
96-hour LCi,o
survival, development time and
abnormalities of larvae
survival, development time and
abnormalities of larvae
Reference
Hudson et al.. 1978
Hudson et al., 1981
Sugawara. 1974b
Sugawara. 1974b
Sugawara. 1974a
Price et al.. 1974
Sugawara. 1974b
Sugawara. 1974b
Sugawara. 1974a
Price et al.. 1974
Sugawara. 1974a
Sugawara. 1974a
Sugawara. 1974b
Linden et al.. 1979
Linden et al.. 1979
Bengtsson and larkpea. 1983
Linden et al., 1979
Linden et al.. 1979
Linden et al.. 1979
Laughlln et al.. 1977
Laughlln et al.. 1977
-------
TABLE 6-3
0
—J
co
Phthalate
Ester
DMP
DEP
DAP
DPP
o> DBP
- DIBP
BBP
OOP
DEHP
DNP
DINP
DDP
DUP
Range of Acute LC5Q and EC5Q Values for Phthalate Esters
Solubility3
Limit
(mg/i)
1744-5000
210-1000
100
56
6.2
0.71-2.9
3
0.285-1.3
NR
NR
0.33
NR
Range
Algae
26.1-185 (3)b
3-90.3 (3)
NR
0.9-65 (1)
0.0034-0.6 (1)
NR
0.11-1.0 (5)C
NR
31.000 (1)
NR
NR
NR
<360->1000 (1)
of Acute LC5Q or
Invertebrates
7-73.4 (4)
7.6-74 (3)
22 (1)
NR
1.7->10.0 (4)
3.0 (1)
0.9-92 (2)
1.0->10 (2)
1.6->300 (4)
>300 (1)
NR
>saturat1on (1)
15-16 (1)
EC5Q Values (mg/i or
Fish
49.5-115 (3)
29.6-110.0 (3)
0.4 (1)
NR
0.73-6.47 (4)
NR
0.51 440.0 (4)
0.69-200.0 (7)d
540->770 (5)
NR
0.42-71.85 (4)d
NR
>1000 (2)
ppm)
All Organisms
7-185 (10)
3-110.0 (9)
0.4-22.0 (2)
0.9-6.5 (1)
0.0034->10 (9)
3.0 (1)
0.11 -440 (11)C
0.69-200.0 (9)d
1.6-31,000 (10)
>300 (1 )
0.42-71.85 (4)d
>saturat1on (1)
15->1000 (4)
Source: Sugatt and Foote, 1981
o Number In parentheses Is the number of species tested.
^ C0ne species of algae had a clearly exceptional LC,0 of 1000 mg/i.
oo Includes two amphibian species
NR = Not reported
-------
Data concerning chronic toxlcity of phthallc add esters to aquatic
vertebrates are presented In Table 6-4. D1(2-ethylhexyl) phthalate was the
ester for which there was the most data. Toxic effects were reported at
concentrations as low as 0.0037 mg/8. In brook trout, Salvellnus fontlnal Is
(Mayer et a!., 1977). In embryo-larval tests with fathead minnows, Plme-
phales promelas. the order of decreasing toxldty for four esters was d1{2-
ethylhexyl) phthalate, n-butyl benzyl phthalate, d1-n-butyl phthalate and
dl-n-octyl phthalate. 01(2-ethylhexyl) phthalate caused decreased collagen
content of the backbones of fry exposed to concentrations of 0.011-0.100
mg/i for 127 days (Mayer et al., 1977). n-butyl benzyl phthalate caused
reduced growth at 0.360 mg/i (Gledhlll et al., 1980), while d1-n-butyl
phthalate and d1-n-octyl phthalate affected survival and/or egg hatchabUHy
at 1.0 and 10.0 mg/l, respectively (McCarthy and WhHmore, 1985).
Data concerning chronic toxIcHy of phthalates to aquatic Invertebrates
are presented In Table 6-5. Once again, d1(2-ethylhexyl) phthalate appeared
to be more toxic than the other esters, having Inhibited reproduction of
Daphnla magna at concentrations as low as 0.003 mg/i (Mayer and Sanders,
1973). N-butyl benzyl phthalate, d1-n-octyl phthalate and d1-n-butyl
phthalate were about equal In toxldty to Daphnla magna, adversely affecting
reproduction at 0.76, 1.0 and 1.8 mg/l, respectively (GledhUl et al.,
1980; McCarthy and Whltmore, 1985).
0784p 6-12 05/15/86
-------
TABLE 6-4
Chronic Toxlclty of Phthallc Acid Esters to Aquatic Vertebrates
— J
oo
T5
1
CO
o
tn
tn
CO
Toxic
Species Chemical Concentration NOEL Effect Measured
(mg/l) (mg/l)
FRESHWATER SPECIES
Rainbow trout DEHP 0.014-0.054 0.005 Decreased collagen content of backbone. 90-day
Sal mo qalrdnerl exposure, eggs and fry
0.054 0.005-0.014 Mortality of sac fry. decreased protein content
exposure was 12-day eggs and 90-day post-hatch
NR 0.1 No effect on growth or survival of adults, 60-day
exposure
Brook trout DEHP 0.0037-0.052 NR Decreased collagen content of backbone. 150-day
Salve! Inus fontlnalls exposure, adults
Fathead minnow DEHP 0.011-0.100 NR Decreased collagen content of backbone, no effects
Plmephales proroelas growth, 127-day exposure, fry
NR 0.062 No effects on growth or survival, 56-day exposure,
embryo-larval stages
BBP 0.36 0.14 Reduced growth, normal hatching and survival
0.22 NR Embryo-larval stages, exposure for 30-day post-
hatch mean chronic value
DBP 1.0 0.56 Effects on survival, hatching rate 20-day embryo-
larval test
OOP 10 3.2 65X decreased hatchabl 1 1 ty. no effect survival
S-711 NR 0.001-0.265 34-Day embryo-larval test, no effects on egg
hatchabll tty, fry survival, growth 30-day exposure
Frog DEHP 2.0 NR Retarded development, reduced pigmentation, 8- to
Xenopus laevls 30-week exposure, tadpoles
Reference
Mayer et al . .
197?
Mehrle and
Mayer. 1976
McCarthy and
Mhltmore. 1985
Mayer et al . .
197?
Mayer et al. .
1977
Mehrle and
Mayer. 1976
Gledhlll et al..
1980
U.S. EPA. 1980a;
Pickering. 1983
McCarthy and
WhHmore. 1985
McCarthy and
WhHmore. 1985
Monsanto. 1983f
Dumper t and
Zlet/. 1984
-------
TABLE 6-5
Chronic Toxlctty of Phthallc Acid Esters to Aquatic Invertebrates
o
— 1
CO
"° Species Chemical
Cladoceran DEHP
Oaphnla magna
DEHP
DBP
DOP
BBP
D1DP
-------
6.3. PLANTS
Data concerning effects of phthallc acid esters on aquatic plants and
bacteria are presented In Table 6-6. There are four species for which
sufficient data are available to compare t.he toxldty of different esters.
For the freshwater alga, Selenastrum caprlcornutum. n-butyl benzyl phthalate
was 2-3 orders of magnitude more toxic than dimethyl and dlethyl phthalates
(U.S. EPA, 1978c). Dlallyl phthalate was -20 times more toxic than dlethyl
phthalate, which was -50 times more toxic than n-butyl benzyl phthalate to
the blue-green alga, Hlcrocystls aeruqlnosa (BMngmann and Kuehn. 1978;
Gledhlll et al., 1980). Among saltwater algae, the order of decreasing
toxldty of phthalates to the dlnof lagellate, Gymnod1n1um breve, was
d1-n-butyl, dlphenyl, dlethyl, dimethyl and d1(2-ethylhexyl) phthalates
(Wilson et al., 1978). The range of toxic concentrations 1n this species
was -107 (Table 6-7). In the green alga, Skeletonema costatum. n-butyl
benzyl phthalate was -100 times more toxic than dimethyl and dlethyl phtha-
lates (U.S. EPA, 1978c). The difficulty Tn making generalizations about the
relative toxldty of phthalates 1s Illustrated by the fact that n-butyl
benzyl phthalate was the most toxic of three esters to Selenastrum and
Skeletonema. but was the least toxic of three esters to Hlcrocystls.
6.4. RESIDUES
Pharmacoklnetlc Information for phthalates and aquatic organisms 1s
summarized In Table 6-7. Data from model ecosystem studies concerning
phthalate ester residues are presented 1n Table 6-8. Monitoring data for
phthalate residues 1n various fish species are presented 1n Table 6-9.
0784p 6-15 06/06/86
-------
TABLE 6-6
Acute Toxtctty of Phthalate Esters to Aquatic Plants and Bacteria
o
CD
T3
Species Chemical
Toxic
Concentration
(mg/l)
NOEC
(mq/1)
Effect Neasured
Reference
FRESHWATER SPECIES
BACTERIA
Nixed bacteria D8P
OEHP
Nixed microorganisms
Pseudoroonas put Ida DAP
DEP
&• Pseudomonas aeruglnosa ONP
PLANTS
Selenastrum BBP
capr Icornutum
DMP
Selenastrum DEP
capr Icornu turn
DUP
S-790
S-711
NR
NR
NR
NR
NR
1500 ppm
0.11
0.13
0.4
42.7
39.8
90.3
85.6
>1000
>1000
>1000
1000
1000
100
100
400
1000 ppm
<0.07
NR
0.1
NR
<22.2
NR
<360
<360
NR
growth Inhibition of cultures Isolated from
pond hydrosoll
growth Inhibition of cultures Isolated from
pond hydrosoll
growth Inhibition and physiological activity
In flow-through hydrosoll microcosm
16-hour toxic threshold (3X Inhibition of cell
Multiplication)
16-hour toxic threshold (3X Inhibition of cell
multiplication)
temporary and slight growth Inhibition
96-hour ECjg. chlorophyll a
96-hour ECjQ, cell number
96-hour LC«,o. cell number
96-hour EC<,Q. chlorophyll a
96-hour ECso. ce'l number
96-hour EC5Q. chlorophyll a
96-hour EC^Q. cell number
96-hour EC^Q. chlorophyll a and cell number
96-hour EC^g. chlorophyll a and cell number
96-hour ECjg. chlorophyll a and cell number
Johnson. 1975
Johnson. 1975
Nut? and Jones. 1977
Brlngmann and Kuehn,
1980b
Brlngmann and Kuehn.
1980b
Perez et al. . 1976
U.S. EPA. 1978c
U.S. EPA. 1978c
Gledhlll et al.. 1980
U.S. EPA. 1978c
U.S. EPA. 1978c
U.S. EPA. 19/8c
U.S. EPA. 1978C
EG&G Bionomics. I979a
EG&G Bionomics, 1979b
EG&G Bionomics, 1978
o
o
er
00
-------
TABLE 6-6 (cont.)
06/06/86
Species
Hlcrocystls aeruqlnosa
Navlcula pelllculosa
Scenedesmus
quadrlcauda
Gvmnodlnlum breve
Skeletonema costatum
Chemical
DAP
DEP
BBP
S-711
BBP
S-711
DAP
DEP
DBP
DPP
DEP
DHP
DEHP
BBP
DHP
Toxic
Concentration
(ntg/t)
0.65
15
1000
>1000
0.6 (0.2-2)
>1000
2.9
10
0.0034-0.2 ppm
0.02-0.6 ppm
0.9-2.4 ppm
1 .3-6.5 ppm
3-6.1 ppm
33 ppm
54-96 ppm
125-185 ppm
31.000 ppm
NR
0.17 (0.08-0.36)
0.19 (0.09-0.38)
0.6 (0.3-2.0)
26.1 (15.9-39.3)
29.8 (22.2-40.8)
NOEC
(reg/l)
FRESHWATER
<0.65
<15
560
NR
0.3
NR
<2.9
<10
NR
NR
NR
NR
NR
NR
NR
NR
NR
100.000 ppra
<0.03
NR
0.1
<11.9
NR
Effect Measured
SPECIES (cont.)
8-day toxic threshold (3% Inhibition of cell
multiplication)
8-day toxic threshold (3X Inhibition of cell
multiplication)
96-hour l-C^o- cell number
96-hour ECjQ. chlorophyll a and cell number
96-hour EC$o. c«'l number
96-hour EC«,o. chlorophyll a and cell number
B-day toxic threshold (3X Inhibition of cell
multiplication)
6-day toxic threshold (3% Inhibition of cell
mult Ipl (cat ton)
96-hour EC5Q. growth rate, duplicate tests
96-hour LC<,0. cell population, duplicate tests
96-hour ECi,0. growth rate, duplicate tests
96-hour LC^Q, cell population, duplicate tests
96-hour fCt,o. growth rate, duplicate tests
96-hour tCijQ. cell population
96-hour EC^Q. growth rate, duplicate tests
96-hour LCi,Q. cell population, duplicate tests
96-hour ECi,o. growth rate
96-hour LC<,O. cell population
96-hour ICjo. chlorophyll a
96-hour fC^Q. cell number
96-hour LCt,Q. cell number
96-hour EC<,o. chlorophyll a
96-hour ECi,0. cell number
Reference
Brlnqmann and Kuehn,
1978
Brlngmann and Kuehn,
1978
Gledhlll et al.. 19BO
EG&G Bionomics. 1978
Gledhlll et al. . 1980
EG&G Bionomics. 19/8
Brlngmann and Kuehn,
1980b
Brlmjmann and Kuehn,
1980b
Wilson et al.. 19/8
Wl Ison et al. , 19/8
Wilson et al., 19/8
Wilson et al.. 19/8
Wilson et a)., 19/8
Wl Ison et a 1 . . 19/8
Wilson et al. . 19/8
Wilson et al. , 19/8
Wilson et al. , 1978
Wl Ison et a 1 . . 19/8
U.S. EPA. 19/8c
U.S. tPA. 19)0c
Gledhlll et al.. 1900
U.S. EPA. 19/8c
U.S. EPA, 19/8c
-------
TABLE b-b (cont.)
O
-~j
oo
->
•o
Toxtc
Species Chemical Concentration
(i»9/t)
Skeletonema costatun DIP 65.6 (22. 3-193)
BS.O (Sb. 9-124)
D8P SOX ss
SOX ss
NR
NR
S-711 >1000
Dunallella tertlolecta BBP 1.0(0.2-5)
S-711 >1000
NOEC
(iog/i)
FRESHWATER
<39.4
NR
20X ss
20% ss
50* ss
NR
NR
0.3
NR
Effect Measured
SPECIES (cont.)
96-hour EC^rj. chlorophyll a
96-hour fC<,0. cell number
96-hour growth rate, 14 ppth salinity
96-hour growth rate. 22 ppth salinity
96-hour growth rate. 27 ppth salinity
96-hour growth rate. 36 ppt salinity
96-hour £C$o. chlorophyll a and cell number
96-hour LC^g. cell number
96-hour EC <,rj. chlorophyll a and cell number
Reference
U.S. EPA. 19/Bc
U.S. EPA. 1978c
Medlln, 1980
Medlln. 1900
Nedlln. 1980
Medlln. 1980
EG&G Bionomics.
Gledhtll et al.
EG&G Bionomics.
1978
. 1980
1978
cr>
i
00
NR « Not reported
o
cr
-------
TABLE 6.7
Data from Uptake and Elimination Studies with Phthallc Acid Esters In Aquatic Biota
o
•—J
00
4*
T3
O
O
\
CO
Species
Chemical
Water
Concentration
(rag/l)
Tissue
Tissue
Concentration
(pq/9)
BCF
Ourat Ion
(days)
Depuration
Half-time
(days)
Reference
FRESHWATER SPECIES
FISH
Fathead minnow
Plmephales prpmelas
Rainbow trout
Sal mo qalrdnerl
Mosqultof Ish
Gambusla afflnls
BlueglTl
Lepomls macrochlrus
INVERTEBRATES
Water flea
Oaphnla magna
Damsel fly
DEHP
DEHP
DEHP
BBP
OEHP
DEP
DMP
DBP
DEHP
DIDP
DBP
0.001-0.062
0.0019
NR
0.07
0.5
0.1
10.0
0.00973
0.0057
0.00582
0.00942
O.OOB74
0.00008
0.0001
0.0001
0.00008
0.0054
0.0003
0.1
10.0
0.0003
NR
NR
0.0001
whole body
whole body
whole body
muscle
blood
bile
liver
btle
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
NR
NR
NR
0.0?1
0.142
51.4
0.86
NR
?6.5
469
NR
0.64
NR
NR
NR
NR
0.4
0.6
NR
2.8
NR
18.26
1551
NR
NR
NR
NR
886-155
458
42-113
NR
NR
NR
NR
247
NR
NR
663
112
114
117
57
5000
NR
6000
400
518
420
NR
NR
5000
209
116
?700
56
14
36
1
1
1
1
1
2
2
21
35
42
?1
21
14
7
10
14
1
7
2
2
7
21
21
7
12.2
NR
NR
NR
NR
NR
NR
NR
NR
NR
>1. <2
NR
3
>1. <2
>1. <2
NR
3
3
NR
NR
NR
NR
NR
NR
NR
NR
NR
Mayer. 1976;
Mehrle and Mayer . 1976
Mayer and Sanders. 1973
Mehrle and Mayer. 1976
Melancon et al . . 1977
Nelancon et al. . 1977
Melancon et al. , 1977
Melancon et al., 1977
Statham et al.. 1976
Metcalf et al.. 1973
Metcalf et al.. 1973
Barrows et al . . 1980
Macek et al.. 1979
Barrows et al . , 1980
Barrows et al. . 1980
Barrows et al.. 1980
Sanders et al. . 1973
Sanders et a). , 1973
U.S. EPA. 1972
Mayer and Sanders. 1973
Macek el al.. 1979
Mayer and Sanders. 1973
Metcalf et al., 1973
Mi-tcalf et al. . 1973
Sanders et al. , 1973
Brown and Thompson. 19B2a
Brown and Thompson. 1982a
Sanders et aJ., 1973
Ischnura vertical);
-------
TABLE 6-7 (cont.)
o
-J
CD
•o
0>
1
o
0
v^
o
CO
cr«
Species
Sowbug
Asellus brevlcaudus
Midge
Chlronomus plumosus
Mayfly
Hexagenla blllneata
Scud
Gamroarus pseudollmnaeus
Mosquito larvae
Culex sp.
Mosquito pupae
Culex sp.
Snail
Physa sp.
Glass shrimp
Palaeroonetes kakladensls
PLANTS
Alga
Selenastrum caprlcornutum
Plant
Elodea sp.
Chemical
DEHP
DBP
DEHP
DBP
DEHP
DBP
DEHP
DEHP
DEHP
OEHP
OBP
DBP
OEHP
Water
Concentration
(mg/l)
0.0019
0.062
0.00018
0.00018
0.000?
0.0003
0.0003
0.00008
0.0001
0.0001
0.0001
0.0001
0.0001
0.063
0.0001
0.0001
0.0001
0.1
10.0
0.1
10.0
0.1
10.0
0.00008
NR
0.1
10.0
Tissue
Tissue Concentration
(wg/g)
FRESHWATER
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
whole body
SPECIES (cont.
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
5.4
16.37
3657
2.03
4346
85.7
487
NR
NR
23.24
290
BCF
70
250
720
6600
29?
350
3100
430
1900
575
2300
6700
1400
260
3600
13.400
NR
NR
NR
NR
NR
NR
NR
5000
22.700
NR
NR
Duration
(days)
21
21
7
7
2
7
7
7
7
7
7
NR
14
21
14
14
3
2
2
2
2
2
2
3
NR
2
?
Depuration
Half-time
(days)
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
<4
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
Reference
Sanders et al.. 1973
Sanders et al. . 1973
Mayer and Sanders. 1973
Sanders et al.. 1973
Streufert et al.. 1980
Mayer <\nd Sanders. 1973
Sanders et al.. 1973
Mayer and Sanders. 1973
Sanders el al.. 1973
Mayer and Sanders, 1973
Sanders et al. . 1973
Sanders et al.. 1973
Mayer and Sanders, 1973
Sanders et al.. 1973
Mayer and Sanders. 1973
Sanders et al.. 1973
Sanders et al.. 1973
Metcalf et al.. 1973
Metcalf et al.. 1973
Metcalf et al.. 1973
Metcalf et al.. 1973
Metcalf et al., 1973
Metcalf et al.. 1973
Sanders et al. . 1973
Casserly et al.. 1983
Metcalf el al. . 1973
Motcalf el al.. 1973
-------
TABL[ 6-7 (cont.)
o
— 1
co
T3
i
Species
FISH
Sheepshead minnow
Cypr Inodon varlegatus
Hullet
Hug 11 cephalus
INVERTEBRATES
Brine shrimp
Artemla sallna
Hussel
Mvtllus edum
Water Tissue
Chemical Concentration Tissue Concentration BCF
-------
o
—4
CD
TABLE 6-6
Data from Model Ecosystem Studies Concerning Phthalate Residues
i
IV)
Species
Alga
Water flea (Daphnla sp.)
Mosquito (Culex plplens)
Snail (Physa sp. )
Fish (Ganbusla afflnls)
Alga
Water flea (Oaphnla sp.)
Mosquito (Culex plplensl
Snail (Physa sp.)
Fish (Gambusla afflnls)
Alga IQedogoMua sp.)
Snail (Physa sp.)
Mosquito (Culex sp.)
Fish (Gambusla afflnls)
Plant (Menthu aquatlca)
Plant (Chara chara)
Planarian (Dendrocoelun lacteum)
Leech (Helobdella sp.)
Snail (Planorbls corneus)
Scud (Gammarus pulex)
Midge (Chlronorous sp.) and
Ollgochaete (Tublfex sp.)
Caddlsfly (Llmnephllus sp.)
Alderfly (Slalls sp.)
River lamprey (Lampetra planer 11
Minnow (Phoxlnus phoxlnus)
Stickleback (Pungltlus punqltlus)
Chemical
DOP
DOP
DOP
DOP
DOP
DOP
DOP
DOP
OOP
DOP
DEHP
DEHP
DEHP
DEHP
DEHP
DEHP
DEHP
DEHP
OEHP
DEHP
DEHP
OEHP
DEHP
DEHP
DEHP
DEHP
Water
Concentration
0.000064
0.000064
0.000064
O.OOOOf 4
O.OOOUH
0.00345
0.00345
0.00345
0.00345
0.00345
0.0078
0.0078
0.0078
0.0078
0.001013
0.001013
0.001013
0.001013
0.001013
0.001013
0.001013
0.001013
0.001013
0.001013
0.001013
0.001013
Tissue
Concentration
(v-g/9)
1.8
0.16
0.59
0.65
0.59
2.28
32.5
18.3
1.51
0.004
19.1
20.3
36.6
0.20b
18.53
18.50
4.15
2.00
17.70
25.19
1.23
19.46
2.30
10.70
0.18
0.31
BCF
28.500
2.600
9.400
13.600
9.400
660
9.426
5.300
438
1.16
NR
NR
NR
NR
18.292
18.263
4.097
1.974
17.473
24.456
1.214
19.210
2.271
10.563
178
306
Duration
(days)
33
33
33
33
33
3
3
3
3
3
33
33
33
33
27
27
27
27
27
27
27
27
27
27
27
27
Reference
Sanborn et al. , 1975
Sanborn et al. . 1975
Sanborn et al. . 1975
Sanborn et al. . 1975
Sanborn et al. . 1975
Sanborn et al.. 1975
Sanborn et al. , 1975
Sanborn et al. . 1975
Sanborn et al.. 1975
Sanborn et al. . 1975
Metcalf et al.. 1973
Metcalf et al.. 1973
Metcalf et al.. 1973
Metcalf et al. , 1973
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Soedergren. 1982
Socdergrcn. 1982
o
en
CO
-------
TABLE 6-9
Monitoring Data For Phthallc Acid Esters In Aquatic Organisms
o
co
•o
1
ro
CO
O
cn
CD
cr>
Species
Lake trout
Salvellnus namavcush
Whlteflsh
Coregonus
Fish (general)
Herring fillets
Clupea harengus
Mackerel fillets
Scomber scombrls
Cod liver
Gadus morhua
Plaice fillets
Hlppoglossoldes platessoldes
Redflsh fillets
Sebastes marlnus
Chemical
DBP
DEP
DEHP
DBP
DEP
DEHP
DBP
DEHP
DEHP
OHP
DEHP
DHP
DEHP
DHP
DEHP
DHP
DEHP
OHP
Tissue
Concentration
(ng/q)
FRESHWATER
0-3.2
0-2.0
0-1.3
0.04-0.07
1.3-2.2
0.4-0.7
0-0.5
0-3.2
SALTWATER
4.71
17
6.5
27.2
5.19
<0.01
<0.01
<0.01
<0.01
<0.01
Location
SPECIES
Lake Superior
Lake Superior
Lake Superior
Lake Superior
Lake Superior
Lake Superior
North America
North America
SPECIES
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - GulF of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Atlantic Ocean - Gulf of St. Lawrence
Reference
Swain. 1978
Swain. 1978
Swain. 1978
Swain. 1978
Swain. 1978
Swain. 1978
Johnson et al.
Johnson et al.
Muslal el al..
Muslal et al. .
Muslal et al . .
Mus la 1 et a 1 . .
Muslal et al..
Muslal et al. .
Muslal et al . .
Muslal et al..
Muslal et al . ,
Muslal et al..
. 1977
. 1977
1981
1981
1981
1981
1981
1981
1981
1981
1981
1981
-------
The Information 1n these three tables Indicates that phthalates 1n
general are not strongly bloaccumulated by fishes, even though phthalates
are fairly I1poph1l1c. This 1s because fishes are able to metabolize and
eliminate phthalates, especially d1(2-ethylhexyl) phthalate, rather quickly
(Soedergren, 1982). In both fish and Invertebrates, d1(2-ethylhexyl) phtha-
late was degraded to the monoester (monoethylhexyl phthalate) and then to
free phthallc add, phthallc anhydride and a variety of conjugates (Mehrle
and Mayer, 1976; Sodergren, 1982). In studies with several benthlc Inverte-
brate species exposed to radlolabeled d1(2-ethylhexyl) phthalate, Sodergren
(1982) concluded that the capacity to metabolize and eliminate d1(2-ethyl-
hexyl) phthalate was the primary determinant of accumulation. Those species
that accumulated radioactivity to the greatest extent were those that had
almost all of the radioactivity still 1n the form of d1(2-ethylhexyl) phtha-
late, while lower total amounts of radioactivity were found 1n species that
had metabolized the compound to other forms.
In a 35-day study with bluegllls, Lepomls macrochlrus. and radlolabeled
d1(2-ethylhexyl) phthalate (Macek et al., 1979), food and water did not
accumulate radioactivity to a greater extent than fish exposed to d1(2-
ethylhexyl) phthalate In water alone. Steady-state whole-body concentra-
tions In bluegllls exposed to d1(2-ethylhexyl) phthalate only In the diet
were -1/3 of those 1n fish exposed to d1(2-ethylhexyl) phthalate In water.
These results suggest that d1(2-ethylhexyl) phthalate uptake from water Is
more Important than d1(2-ethylhexyl) phthalate uptake from food.
6.5. SUMMARY
It 1s difficult to draw conclusions about the relative toxldty of
phthallc acid esters to aquatic biota because of the large variability 1n
toxkHy of each ester to different species. It Is also difficult to pick
0784p 6-24 05/15/86
-------
out those species most sensitive to phthalates; however. Table 6-10 contains
the most and least sensitive species and toxic concentrations reported for
each ester. All of the esters listed In Table 6-10 caused toxic effects at
<3.2 mg/i. The lowest concentration reported to cause toxic effects was
0.003 mg/8. dl{2-ethylhexyl) phthalate, which caused decreased production
of offspring by Daphnla magna (Mayer and Sanders, 1973).
Although there were large differences In species sensitivity among major
taxonomlc groups, none of these groups except bacteria were especially more
or less sensitive than other groups. Bacteria were clearly less sensitive
than other organisms to d1-n-butyl, dlallyl, dlethyl and dimethyl phthalates
(Sugatt and Foote, 1981). The available Information concerning freshwater
and saltwater species Indicated no difference 1n phthalate ester toxldty
between freshwater and saltwater environments.
Many Investigators have reported toxic effects of phthalates at concen-
trations greater than their aqueous solubility; however, the data Indicate
that all of the phthalates except dlhexyl, dlnonyl, d1-n-decyl and dllso-
decyl phthlates were toxic to at least one species at concentrations near or
below their solubility (Sugatt and Foote, 1981).
Information concerning residues of phthallc acid esters In aquatic biota
suggests that accumulation Is determined primarily by the degree to which
species can metabolize and eliminate them (Soedergren, 1982). Fish gener-
ally have a well-developed mechanism 1n this regard and therefore do not
accumulate phthalates to a great extent.
0784p 6-25 06/06/86
-------
TABLE 6-10
Range of Species Sensitivity for Algae. Invertebrates and Vertebrates to Phthalate Esters
-J
00
•o
Compound3
BBP
DAP
DBP
DEHP
DEP
01BP
i
ro
°* DINP
DHP
OOP
DUP
aComparlsons
parlsons for
No. of
Species
Compared
15
6
IB
16
16
2
4C
13
12
4
Host Sensitive Species
Least Sensitive Species
Toxic Nontoxlc Toxic Nontoxlc
Species Concentration Concentration Species Concentration Concentration
algae 0.03 NR
(S. costatum)
Ide (L. jjus) 0.4 0.3
neraatode 0.028 0.0028
(P. redlvlvus)
water flea 0.003 NR
algae (G. breve) 3.0 NR
protozoa O.OS NR
(T. pyrlformls)
catfish 1.0 0.10
(i. punctatus)
water flea 1.7 NR
(D. magna)
catfish 0.1 0.01
(I_. punctatus)
water flea IS <3.2
(D. magna)
for DHP. DPP. DNP and OOP could not be made because comparable
DIDP could not be made because no toxic affects occurred at any
° bBacterla were even less
^^
^x
jjj clncludes two
^^
oo
amphibian
sensitive to these phthalate esters.
species.
algae 1.000 S60
(H. aeruglnosa)
protozoab 22 <22
(U. parductl)
algae (S. costatunp NR SOX saturated
solution
algae (G. breve) 31.000 NR
brine shrlmpb NR 123
1.000 NR
(P. promelas)
rainbow trout >1.000 NR
(S. qalrdnerl)
results were available for only 1 species for each ester. Corn-
concentration tested.
-------
7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
RfDs have been derived for d1(2-ethylhexyl) phthalate, dimethyl phtha-
late, dlethyl phthalate, d1-n-butyl phthalate, ethylphthalyl ethylglycoate,
and butylphthalyl butylglycoate (U.S. EPA, 1980b). These are summarized In
Table 7-1. A cancer-based water qualHy criterion for d1 (2-ethylhexyl)
phthalate was derived (U.S. EPA, 1980b). A drinking water document for this
class of compounds 1s currently In preparation.
7.2. AQUATIC
U.S. EPA (1980b) did not derive an ambient water quality criterion for
the protection of aquatic life for phthalates, but did, however, note that
acute and chronic toxldty to freshwater aquatic life occurred at concentra-
tions as low as 0.940 arid 0.003 mg/1, respectively. For saltwater biota,
U.S. EPA (1980a) noted that acute toxldty occurred at concentrations as low
as 2.944 mg/l, and that toxklty to one algal species occurred at 0.0034
mg/l. More recent data (see Chapter 6) gave no Indication of toxic
effects occurring at concentrations <0.003 mg/l 1n either freshwater or
saltwater.
Earlier U.S. EPA (1972, 1976) documents recommended criteria for phtha-
lates for the protection of aquatic life. U.S. EPA (1972) recommended a
level of 0.003 mg/l to protect fish and their food supply. This was based
on the 0.003 mg/l concentration reported to Inhibit growth of Daphnla
maqna (Mayer and Sanders, 1973) and contained a safety factor of 10. U.S.
EPA (1976) recommended a criteria of 0.003 mg/l for freshwater aquatic
life, recognizing that this concentration caused adverse effects In Daphnla.
This level was considered acceptable because other species appeared to be
much more resistant.
0785p 7-1 09/02/86
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o
~J
CD
TABLE 7-1
Existing ADIs/RfOs for Phthallc Acid Esters from U.S. EPA, 1980ba
Ester
Dlethyl
Dlbutyl
r!o Butylphthalyl
Ethylphthalyl
Dimethyl
butylglycoate
ethylglycoate
ADI
(mg/kg/day)
13
1.3
10
2.5
10
Dose
(mg/kg/day)
NOEL
NOAEL
NOEL
NOEL
NOEL
= 1250
= 125
= 1000
= 250
= 1000
Species
rat
rat
rat
rat
rat
Reference
Food Research Lab. , 1955
Smith, 1953
Solver et al. , 1950;
Hazelton Labs. , 1950
Hodge et al.. 1953
Lehman, 1955b
aThese values are all currently under review and a drinking water document Is currently under development.
blncorrectly attributed to Dralze et al. (1948) In U.S. EPA (1980b)
o
\
o
>•»
CD
-------
8. RISK ASSESSMENT
Risk assessment for phthalate esters must be performed on a compound-by-
compound basis, since not all phthallc acid esters produce the same effects.
For example, dl (2-ethylhexyl) phthalate causes testlcular atrophy, but when
administered In equlmolar doses, d1-n-octyl phthalate does not (Gray and
Butterworth, 1980; Foster et al., 1980); both compounds are 8-carbon
dlesters.
The following section contains assessments for dl(2-ethylhexyl),
dlethyl, d1-n-butyl, dimethyl, dl-n-octyl, n-butyl benzyl and dllsononyl
phthalate. There were either Insufficient or no available published data on
chronic toxlclty with which to assess the other phthalate esters covered by
this document.
8.1. DI(2-ETHYLHEXYL) PHTHALATE
In lifetime feeding studies conducted by NTP (1982b), d1(2-ethylhexyl)
phthalate was shown to cause statistically significant Increased Incidences
of hepatocellular carcinoma and hepatocellular carcinoma or neoplastk
nodules In F344 rats dietary concentrations >6000 ppm and hepatocellular
carcinoma and hepatocellular carcinoma or adenoma In B6C3F1 mice at dietary
levels >3000 ppm. Based on these results, IARC (1982b) concluded that there
1s sufficient evidence that d1(2-ethylhexyl) phthalate 1s carcinogenic for
rats and mice. The U.S. EPA came to an equivalent conclusion. Using the
EPA classification system for we1ght-of-ev1dence OEHP 1s a Group B2 carcino-
gen, meaning there 1s sufficient animal evidence and thus probably carcino-
genic 1n humans. Other effects observed at low levels of exposure In oral
teratogenlcHy and chronic studies Include the following: Increased
relative liver weight In female guinea pigs (19 mg/kg/day) (Carpenter et
0786p 8-1 08/26/86
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al., 1953); liver and kidney congestion In a dog (79.9 mg/kg/day) (Carpenter
et al., 1953); teratogenlc effects 1n the absence of maternal toxldty In
CD-I mice (91 mg/kg/day on days 0-18 gestation) (Wolkowskl-Tyl et. al.,
1984b); and Interstitial nephritis, Increased SGOT, and Increased blood
glucose In rats 500 ppm) (Nagasaki et al., 1974). Testlcular effects were
also observed In a number of studies on rats, but these effects occurred at
higher levels of exposure (Gray et al., 1977, 1982; Gangolll, 1982; NTP,
1982b; Kluwe et al., 1982b; Olshl and Hlraga, 1980a, 1983; Gray and Butter-
worth, 1980; Hangham et al., 1981; 01sh1, 1985). Doses <19 mg/kg/day have
not been tested.
Using data from NTP (1982b), q *s were derived for combined hepato-
cellular carcinoma and neoplastlc nodules 1n rats, and combined hepatocellu-
lar carcinoma and adenoma In mice (Tables 8-1 to 8-4), As seen from Tables
8-1 to 8-4, the experimental doses were multiplied by le/Le In order to
expand the dose over the entire experimental period. Because the weights of
the rats and mice In the different treatment groups varied, each dose was
transformed to the corresponding human dose before the calculation of q *
by multiplying the animal dose by the cube root of the ratio of the animal
body weight to the reference human (70 kg) body weight. From these doses,
human q * values were calculated directly using the computerized multi-
stage model developed by Howe and Crump (1982); no further adjustments were
necessary. The highest value, an adjusted human q * of 8.36xlO"3
{mg/kg/day)"1 (Interim value as discussed later) was obtained from data on
male mice. This value differs slightly from the value estimated by U.S. EPA
(1980b). The 1980 value was calculated before the availability of NTP
(1982) that provided estimates of doses and utilized default food
consumption values. The concentrations 1n drinking water corresponding to
risk levels of 10"5, 10'6 and 10~7 are 4.19x10'2, 4.19xlO~3 and
0786p 8-2 08/31/86
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TABLE 8-1
Cancer Data Sheet for Derivation of q-|*
Compound: d1(2-ethylhexyl) phthalate
Reference: NTP, 1982b
Species, strain, sex: rat, F344/N, male
Body weight: 0.4 kg (control); 0.36 kg (low dose); 0.32 kg (high dose]
Length of exposure (le) (weeks) = 103
Length of experiment (Le) (weeks) = 105 (0, low dose); 104 (high dose)
Llfespan of animal (L) (weeks) = 105 (0, low dose); 104 (high dose)
Tumor site and type: hepatocellular carcinoma or neoplastlc nodules
Route, vehicle: oral, diet
Experimental Doses
or Exposures
(mg/kg/day)a
0
322
674
Transformed Dose
(mg/kg/day)b
0
54.52
110.79
Incidence
No. Responding/No.
3/50
6/49
12/49
Examined
aThe dietary concentrations were 0, 6000 or 12,000 ppm; the doses 1n
mg/kg/day were provided by NTP (1982b).
bDose x le/Le x (WA/70)1/3 x (Le/L)3
WA = rat body weight
transformed dose where L=Le;
Unadjusted q-]* from study = not calculated (see text)
Human q-|* = 2.95xlO"3 (mg/kg/day)'1
0786p
8-3
05/15/86
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TABLE 8-2
Cancer Data Sheet for Derivation of q-|*
Compound: d1(2-ethylhexyl) phthalate
Reference: NTP, 1982b
Species, strain, sex: rat, F344/N, female
Body weight: 0.27 kg (control); 0.26 (low dose); 0.23 kg (high dose)
Length of exposure (le) = 103 weeks
Length of experiment (Le) = 105 weeks
Llfespan of animal (L) = 105 weeks
Tumor site and type: hepatocellular carcinoma or neoplastlc nodules
Route, vehicle: oral, diet
Experimental Doses
or Exposures
(mg/kg/day)a
0
394
774
Transformed Dose
(mg/kg/day)b
0
59.93
112.88
Incidence
No. Responding/No.
0/50
6/49
13/50
Examined
aThe rats were given 6000 or 12,000 ppm 1n the diet; the doses In mg/kg/day
were provided by NTP (1982b).
bDose x le/Le x (WA/70)1/3 x (Le/L)3 = transformed dose where L=Le;
WA = rat body weight
Unadjusted q-j* from study = not calculated (see text)
Human q-|* = 3.52xlO"3 (mg/kg/day)'1
0786p 8-4 05/15/86
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TABLE 8-3
Cancer Data Sheet for Derivation of q-|*
Compound: dl(2-ethylhexyl) phthalate
Reference: NTP, 1982b
Species, strain, sex: mouse, B6C3F1, male
Body weight: 0.04 kg (measured)
Length of exposure (le) = 103 weeks
Length of experiment (Le) = 105 weeks (0, low dose); 104 weeks (high dose)
Llfespan of animal (L) = 105 weeks (0, low dose); 104 weeks (high dose)
Tumor site and type: hepatocellular carcinoma or adenoma
Route, vehicle: oral, diet
Experimental Doses
or Exposures
(mg/kg/day)a
0
672
1325
Transformed Dose
(mg/kg/day)b
0
54.70
108.89
Incidence
No. Responding/No.
14/50
25/48
29/50
Examined
aThe mice were given 3000 or 6000 ppm 1n the diet; the doses In mg/kg/day
were provided by NTP (1982b).
bDose x le/Le x (WA/70)1/3 x (Le/L)3 = transformed dose where L=Le;
HA = mouse body weight
Unadjusted q-|* from study = not calculated (see text)
Human q-j* = 8.36xlO~3 (mg/kg/day)'1
0786p 8-5 05/15/86
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TABLE 8-4
Cancer Data Sheet for Derivation of q-|*
Compound: d1(2-ethylhexyl) phthalate
Reference: NTP, 1982b
Species, strain, sex: mouse, B6C3F1, female
Body weight: 0.039 kg (control); 0.034 (low dose); 0.030 (high dose)
Length of exposure (le) = 103 weeks
Length of experiment (Le) = 105 weeks
Llfespan of animal (L) = 105 weeks
Tumor site and type: hepatocellular carcinoma or adenoma
Route, vehicle: oral, diet
Experimental Doses
or Exposures
(mg/kg/day)a
0
799
1821
Transformed Dose
(mg/kg/day)b
0
61.61
134.68
Incidence
No. Responding/No.
1/50
12/50
18/50
Examl ned
aThe mice were given 3000 or 6000 ppm 1n the diet; the doses In mg/kg/day
were provided by NTP (1982b).
bDose x le/Le x (WA/70)1/3 x (Le/L)3 = transformed dose where L=Le;
HA = mouse body weight
Unadjusted q-|* from study = not calculated (see text)
Human q-|* = 4.73xlO~3 (mg/kg/day)'1
0786p 8-6 05/15/86
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4.19x10 * mg/i, assuming a 70 kg human consumes 2 I/day. Turnbull and
RodMcks (1985) have cautioned that using rodent data to estimate d1(-
2-ethylhexyl) phthalate-promoted carcinogenic risk to humans may ov-
erestimate the actual risk. This caution was based on several factors
Including differences between rodents and primates In the metabolism of
d1(2-ethylhexyl) phthalate, a nonlinear relationship between the ad-
ministered dose of dl (2-ethylhexyl) phthalate and the dose of the hypot-
hesized "proximate carcinogenic species" In rodents, the fact that the hypo-
thesized "proximate carcinogenic species" 1s produced to a greater extent In
rodents than In primates and differences In target site sensitivities bet-
ween humans and rodents for liver tumors In general. These factors have not
been evaluated as yet by EPA to see 1f an alternate risk assessment approach
Is warranted. Until such an analysis Is conducted the q * should be con-
sidered to be an Interim value.
8,2. DIETHYL PHTHALATE
U.S. EPA (1980b) derived an RfD of 13 mg/kg/day for (Methyl phthalate.
This value was based on a chronic oral rat NOEL of 1250 mg/kg/day (2.5%
diet) defined by Food Research Laboratories (1955) and an uncertainty factor
of 100. Higher doses (5% diet) caused a reduction 1n body weight. A rep-
roduction study by Reel et al. (1984) demonstrated that F, but not
parental mice exposed to 2.5% dlethyl phthalate In the diet had fewer
pups/litter, Increased liver weights (males and females), Increased prostate
weights, decreased sperm concentration and Increased pituitary weight
(females only) 1n comparison with controls. Assuming that mice consume 13/4
of their weight In food/day, 2.5% Is equivalent to 3250 mg/kg/day, a value
well above the NOEL used to derive the RfD. Dlethyl phthalate did not cause
testlcular atrophy 1n rats (Gray and Butterworth, 1980; Foster et al., 1980).
0786p 8-7 08/31/86
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Although In general H Is preferable to utilize chronic data over sub-
chronic data for RfD development, deficiencies 1n reporting of the Food
Research study reduce confidence In the data. Therefore, based upon a
revaluation of the two studies, the subchronlc study of Brown et al. (1978)
1s chosen as the basis of the RfD. This study defined a NOAEL of 750
mg/kg/day with decreased body weight and Increased liver weight seen at the
next highest exposure level. Applying an uncertainty factor of 1000 (10 for
subchronlc to chronic, 10 for Interspecles variability and 10 for 1n-
terlndlvldual variability) results In an RfD of 0.75 mg/kg/day, or 52.5
mg/day for a 70 kg human.
8.3. DI-n-BUTYL PHTHALATE
U.S. EPA (1980b) derived an RfD of 1.3 mg/kg/day based on a 52-week oral
rat NOAEL of 125 mg/kg/day (Smith, 1953) and an uncertainty factor of 100.
A higher dose (1.25% diet or 625 mg/kg/day) caused 50% mortality within 1
week of the Initial exposure (Smith, 1953).. A re-evaluation of this study
suggests that the duration was not truly chronic and suffered from def-
iciencies of limited numbers of animals of a single sex. These factors
suggest the application of an additional uncertainty factor of 10. The
resulting RfD estimate 1s 0.12 mg/kg/day (8.6 mg/day for a 70 kg human).
Onda et al. (1974) observed the formation of renal cysts 1n the FI and
Fp generations of 3CL and ICR mice exposed orally to either 10 or 100
mg/kg/day for three generations. These doses are below the NOAEL used by
U.S. EPA (1980a) to derive the RfD for d1-n-butyl phthalate. Since no
details of the Onda et al. (1974) study were reported, 1t was not con-
sidered In risk assessment.
When d1-n-butyl phthalate (0.12 or 0.6 g/kg/day) was administered to
rats by gavage during gestation, an Increased number of resorptlons and
0786p 8-8 10/09/87
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reduced fetal body weight were observed at the 0.6 g/kg dose (Nlkonorow et
al., 1973). No gross skeletal effects were observed. Maternal toxldty was
not reported, but significantly reduced placental weights were observed at
both doses. Since there were no effects on reproductive or fetal endpolnts
1n rats exposed to 0.12 g/kg/day, the reduced placental weight probably
represents a NOAEL. The LOAEL for this study (0.6 g/kg/day) Is well above
the NOAEL used to derive the RfD.
Shlota et al. (1980) and Shlota and Nlshlmura (1982) observed maternal
toxldty, fetotoxlclty and gross external malformations 1n ICR mice fed 1%
dl-n-butyl phthalate In the diet (2100 mg/kg/day, as provided by the In-
vestigators) on days 0-18 of gestation. Significantly reduced numbers of
ossified coccygla were observed at all levels of treatment (80, 180, 370 or
660 mg/kg/day), but there were no significant differences between controls
and treated mice In Incidences of skeletal malformations, lumbar rib
variations or delayed sternal ossification. Doses <660 mg/kg/day would
therefore represent NOAELs for this study and 2100 mg/kg/day represents an
PEL. 01-n-butyl phthalate has been shown to cause testlcular atrophy 1n
rats, but only at doses greater than the NOAEL (125 mg/kg/day) used to
derWe the RfD (Cater et al., 1976, 1977; Gray et al., 1982; Gray and
Butterworth, 1980). The RfD of 0.1 mg/kg/day 1s therefore recommended for
Ingestlon of d1-n-butyl phthalate.
8.4. DIMETHYL PHTHALATE
U.S. EPA (1980b) derived an RfD of 10 mg/kg/day for dimethyl phthalate
based on a chronic rat NOEL of 1000 mg/kg/day and an uncertainty factor of
100. Higher doses caused chronic nephritis and decreased growth rate
(Lehman, 1955). There are no other chronic oral studies for dimethyl
phthalate. No adverse effects upon reproduction, growth or survival of
0786p 8-9 10/09/87
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offspring were observed In mice gavaged with dimethyl phthalate (3500 mg/kg)
on days 7-15 of gestation (Booth et a!., 1983; Plasterer et al., 1985). The
pups were not examined for malformations. Furthermore, testlcular effects
were not observed In rats gavaged with dimethyl phthalate at doses equlmolar
to those at which d1(2-ethylhexyl) phthalate caused testlcular atrophy In
rats (Gray and Butterworth, 1980; Foster et al., 1980). A Devaluation of
the Lehman (1959) study suggests that the data as reported, are Inadequate
for RfD development.
8.5. OI-n-OCTYL PHTHALATE
The only available chronic study on d1-n-octyl phthalate was reported In
an abstract by Plekacz (1971), In which Wlstar rats were given either 0 or
3500 ppm dl-n-octyl phthalate In the diet for 7-12 months. Assuming that a
rat consumes 5% of Us weight In food/day, 3500 ppm Is equivalent to a dose
of 175 mg/kg/day. Females had elevated kidney and liver weights, and both
males and females had Increased SGOT and SGPT. D1-n-octyl phthalate did not
cause testlcular atrophy In rats when given orally at a dose equlmolar to
that at which dl(2-ethylhexyl} phthalate caused testlcular atrophy In rats
(Gray and Butterworth, 1980; Foster et al., 1980). Furthermore, adverse
effects on reproduction and fertility were not observed In 2 generations of
CD-I mice fed 1.25, 2.5 or 5X (12,500-50,000 ppm) d1-n-octyl phthalate In
the diet (Gulat! et al.. 1985).
The data base for d1-n-octyl phthalate Is limited and does not define a
NOAEL, but the LOAEL of 3500 ppm (175 mg/kg/day) could be used to derive a
provisional RfO. However, because of lack of details of data reporting, an
RfD Is not derived at this time.
0786p 8-10 08/31/86
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8.6. n-BUTYL BENZYL PHTHALATE
n-Butyl benzyl phthalate has been tested for oncogenlclty In feeding
studies on F344 rats and B6C3F1 mice conducted by NTP (1982a).
Statistically significant Increases In the Incidences of mononuclear cell
leukemia and leukemia or lymphoma were observed In female rats. Because of
the normally high background Incidence of myelomonocytlc leukemia In F344
rats, and because dose-related and significant decreases In malignant
lymphoma, all lymphoma, and leukemia or lymphoma were observed In male mice
In the same study, there Is Insufficient evidence to conclude that n-butyl
benzyl phthalate Is carcinogenic. IARC (1982a) concluded that the NTP
(1982a) studies are Insufficient to assess the carcinogenic potential of
9
n-butyl benzyl phthalate. The equivalent EPA we1ght-of-ev1dence
classification for this compound Is Group C meaning that there Is limited
animal data and that the compound Is considered a possible human
carcinogen. It Is therefore not appropriate to derive a q * for n-butyl
benzyl phthalate until further testing Is performed.
Increased mortality caused by unexplained hemorrhaglng was observed In
male F344 rats fed 6000 or 12,000 ppm (300 or 600 mg/kg/day, us'lng a food
factor of 0.05) n-butyl benzyl phthalate (NTP, 1982a). The study was
terminated after 28 weeks. In 90-day feeding studies on rats conducted by
Monsanto (1972), rats were fed 0, 0.25, 0.5, 1.0, 1.5 or 2% (0, 125, 250,
500, 750 or 1000 mg/kg/day) n-butyl benzyl phthalate, and dogs were fed 0,
1, 2 or 5X (0, 250, 500 or 1250 mg/kg/day) n-butyl benzyl phthalate. No
adverse effects were observed among dogs fed n-butyl benzyl phthalate at any
level, or among rats fed 125 or 250 mg/kg/day n-butyl benzyl phthalate.
Increased liver weights without accompanying hlstopathologkal changes were
observed among rats fed 500-1000 mg/kg/day n-butyl benzyl phthalate.
0786p 8-11 09/01/87
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Dietary concentrations of 2.5 or 5% have been shown to cause testlcular
atrophy 1n a 14-day study on rats (Agarwal et al., 1985).
In the NTP (1985) study, rats were fed dietary levels of 0, 0.03, 0.09,
0.28 and 0.83% butyl benzyl phthalate. Using data presented 1n the report,
these dietary levels correspond to ~0r 17, 51, 159 and 470 mg/kg/day. At
2.5%, weight gain was significantly depressed and testlcular and kidney
lesions were apparent. In addition, I1ver-to-body weight ratios were
Increased and hematologlcal evaluations suggested a pattern of Increased
erythrocyte turnover. At 0.83%, the only effects noted were Increased
absolute liver weight, Increased I1ver-to-body weight and I1ver-to-braln
weight ratios and Increases In mean corpuscular hemoglobin.
Using the NOEL of 159 mg/kg/day (0.28%) and applying an uncertainty
factor of 1000, an RfD of 11.1 mg/day could be developed; however, this
value would not be protective for potential carcinogenic effects of this
compound.
8.7. DIISONONYL PHTHALATE
The database for d11sononyl phthalate Is restricted to unpublished
studies conducted by Livingston (1971) and reported 1n Krauskopf (1973).
Dogs were dosed orally (method not specified) to 0, 0.125, 0.5% or a TWA of
2.8% (0, 31.25, 125 or 700 mg/kg/day using a food factor of 0.025)
d11sononyl phthalate for 13 weeks, with apparently only one dog/level of
treatment. Rats were exposed orally to 0, 50, 150 or 500 mg/kg/day for 13
weeks. A slight reduction In growth rate and Increased liver weight
(absolute or relative not specified) were observed In high-dose rats. No
effects were reported for rats treated with 50 or 150 mg/kg/day dllsononyl
phthalate. The dog treated with a TWA of 2.8% (700 mg/kg/day) dllsononyl
0786p 8-12 10/09/87
-------
phthalate had decreased body weight, Increased liver weight and histologlcal
changes In the liver, gall bladder and spleen. The dog given 0.5% (125
mg/kg/day} dllsononyl phthalate had Increased liver weight; no effects were
observed at 0.125% (31.25 mg/kg/day). This report 1s considered Inadequate
for RfD development.
8.8. SUMMARY
An Interim q * of 8.36xlO"3 (mg/kg/day)"1 was derived for d1(2-
ethylhexyl) phthalate based on the Incidence of hepatocellular carcinoma or
adenoma In male mice In the NTP (1982b) study. The concentrations In water
associated with risk levels of 10"5, 10"6 and 10"7 are 4.19xlO~2,
4.19xlO"3 and 4.19xlO~4 mg/s., assuming that a 70 kg human consumes 2
l/day.
An RfD of 0.75 mg/kg/day (52.5 mg/day) for dlethyl phthalate, was
derived based on a chronic oral rat NOEL of 750 mg/kg/day 1n the study by
Brown et al. (1978} and using an uncertainty factor of 1000. An RfD of
0.125 mg/kg/day (8.8 mg/day) for d1-n-butyl phthalate was derived. The
value Is lower by a factor of 10 than that derived by U.S. EPA (1980b) based
on a 52-week oral rat 'NOAEL of 125 mg/kg/ day In the study by Smith (1953).
The difference Is In the uncertainty factor with 1000. The U.S. EPA (1980b)
derived an RfD of 10 mg/kg/day (700 mg/day) for dimethyl phthalate based on
a chronic rat NOAEL of 1000 mg/kg/day 1n the study by Lehman (1955) using an
uncertainty factor of 100. A revaluation suggested that this report
provides an Inadequate basis for RfD development.
The only data available for d1-n-octyl phthalate based on a subchronlc
rat LOAEL of 175 mg/kg/day In the study by Plekacz (1971) were considered
Inadequate for risk assessment. An RfD of 0.16 mg/kg/day (11.1 mg/day) was
derived for n-butyl benzyl phthalate based on a subchronlc rat NOEL of 159
0786p 8-13 10/09/87
-------
mg/kg/day In the NTP (1985) study. An uncertainty factor of 1000 was_used.
It should be noted that butyl benzyl phthalate has been classified as an EPA
Group C carcinogen. The proposed RfD would not necessarily be protective
for potential carcinogenic effects. An RfO was not developed for dllsononyl
phthalate because of limited data.
0786p 8-14 08/31/86
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9. REPORTABLE QUANTITIES
9.1. REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC TOXICITY
Oral studies have shown that d1(2-ethylhexyl), d1-n-butyl and d1-n-
heptyl phthalates can produce adverse effects upon the developing fetus when
mice and rats are exposed during gestation (Wolkowsk1-Tyl, 1984a,b; Bell et
al., 1979; Bell, 1980; Shlota and Mima, 1985; Shlota and Nlshlmura, 1982;
Shlota et al., 1980; Nakamura et al., 1979; Yag1 et al., 1978, 1980; Tomlta
et al., 1982b; Onda et al., 1974). These studies are summarized In Tables
5-4 and 5-5. Whether the observed effects (reduced fetal weight, fetal
mortality, gross external and skeletal malformations) represent a primary
effect of the compound 1n question or whether they occur as a result of
maternal toxlclty has yet to be demonstrated unequivocally. Studies
conducted by NTP (Holkowskl-Tyl et al., 1984a,b) Indicate that mice are more
sensitive than rats.
Chronic or subchronlc oral studies have been conducted with d1(2-ethyl-
hexyl), d1-n-butyl, dimethyl, d11sononyl, n-butyl benzyl and dl-n-octyl
phthalates (Carpenter et al., 1953; Harris et al., 1956; Nlkonorow et al.,
1973; Gray et al., 1977; Gangolll, 1982; NTP, 1982a,b; Kluwe et al., 1982b;
Shaffer et al., 1945; Popp et al., 1985; Canning et al., 1985; Nagasaki et
al., 1974; Ota et al., 1974; Lake et al., 1976, 1977a; Haslenko, 1968; Food
Research Laboratories, 1955; Brown et al., 1978; Smith, 1953; Lefaux, 1968;
Plekacz, 1971; LeBreton, n.d.; Bornmann et al., 1956; Lehman, 1955; Living-
ston, 1971; Monsanto, 1972). Liver, kidneys and testes appear to be target
organs. Relevant Inhalation studies could not be located 1n the published
literature as dted 1n the Appendix.
9.1.1. D1(2-ethylhexyl) Phthalate. Relevant chronic and subchronlc data
for d1(2-ethylhexyl) phthalate are summarized 1n Table 5-7. The most severe
0787p 9-1 06/06/86
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effects occurring at the lowest dose were the teratogenlc effects In the
offspring of mouse dams treated by gavage wHh 91, 191 or 292 mg/kg/day on
days 0-18 of gestation 1n the Wolkowsk1-Tyl et al. (1984b) study (see Table
5-4). These effects (external and visceral malformations and skeletal
defects) occurred 1n the absence of signs of maternal toxlclty at 91
mg/kg/day, warranting an RV of 10. The dose of 91 mg/kg/day (measured by
Investigators) was multiplied by the cube root of the ratio of mouse weight
(0.029 kg; measured) to the reference human weight (70 kg) and by the human
weight (70 kg) to obtain a human MED of 475 mg/day, which corresponds to an
RV of 1.5. Multiplying the RVg by the RVd yields a CS of 15, corre-
sponding to an RQ of 1000. Equivalent or less severe effects occurred at
higher doses; therefore, calculation of a CS for these effects 1s not neces-
sary. The only doses lower than 91 mg/kg/day at which effects occurred were
19 and 64 mg/kg/day, at which guinea pigs treated for 1 year had Increased
relative liver weights. The RV& 1s 4. Multiplying the dose of 19 mg/kg/
day by the cube root of the ratio of the reference guinea pig weight of 0.83
kg (Durkln, 1985) to the reference human body weight (70 kg) and by 70 kg
results 1n an MED of 304 mg/day, which corresponds to an RV of 1.8. The
CS 1s 7.2, which corresponds to an RQ of 1000.
9.1.2. Dlethyl Phthalate. Toxldty data for dlethyl phthalate are summa-
rized In Table 5-8. The most severe effect 1s the reduced sperm concentra-
tion and reduced numbers of pups/Utter 1n F, mice exposed to 2.5% dlethyl
phthalate In the diet (Reel et al., 1984). Assuming that a mouse consumes
13X of Us weight 1n food/day, 2.5X 1s equivalent to a dose of 3250 mg/kg/
day. Multiplying 3250 mg/kg/day by the cube root of the ratio of the refer-
ence mouse weight (0.03 kg) to human weight (70 kg), and by the human weight
(70 kg) yields a human MED of 17,152 mg/day, which corresponds to an RV.
0787p 9-2 06/06/86
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of 1. An RV of 8 1s assigned on the basis of reduced reproductive
capacity. Multiplying the RVg by the RVd yields a CS of 8, which corre-
sponds to an RQ of 1000. U.S. EPA (1983b) derived an RQ of 5000 based on
the 2-year study by Food Research Laboratories (1955), In which rats had
significantly reduced body weight gain (RV =4) at a dietary level of 5%
(2500 mg/kg/day; MED=29,925 mg/day; RVd=l). The CS 1s 4. The reproduc-
tion study of Reel et al. (1984) was not available during the preparation of
the previous RQ document by U.S. EPA (1983b).
9.1.3. D1-n-Butyl Phthalate. Toxldty data are summarized In Table 5-9
and teratogenldty data are summarized In Table 5-5. The most severe
effects were the fetotoxldty, teratogenldty and maternal toxldty In ICR
mice exposed orally to 2100 mg d1-n-butyl phthalate/kg/day (Shlota and
Nlshlmura, 1982; Shlota et al., 1980). These effects warrant an RV of 9.
Multiplying 2100 mg/kg/day by the product of the cube root of the ratio of
mouse weight (0.03 kg; measured) to human weight (70 kg), and by the human
weight (70 kg) yields a human MED of 11,083 mg/day, which corresponds to an
RVrf of 1. Multiplying the RVg by the RV yields a CS of 9, corre-
sponding to an RQ of 1000.
Onda et al. (1974) apparently observed renal cysts 1n the F, and F_
generatlons of rats treated orally with 10 or 100 mg d1-n-butyl phthalate/
kg/day for three generations. Since no details were provided, this study
could not be considered 1n the derivation of an RQ.
Smith (1953) observed 50% mortality (5/10) within 1 week of dally
exposure to 1.25X (625 mg/kg/day)
-------
exhibit pathologic or hematologlc effects after 1 year of treatment (U.S.
EPA, 1983a). Furthermore, using these data to derive a CS would not result
1n an RQ >1000 .
Shlota et al. (1980) and Shlota and Nlshlmura (1982) fed d1-n-butyl
phthalate to ICR mice on days 0-18 of gestation. In addition to the
maternal toxldty, fetotoxldty and gross external malformations observed at
2100 mg/kg/day, there were significantly reduced numbers of ossified
coccygla at all levels of treatment (80, 180, 370 or 660 mg/kg/day), but
there were no significant differences between controls and treated mice 1n
Incidences of skeletal .malformations, lumbar Mb variations or delayed
sternal ossification. In a previous RQ determination, U.S. EPA (1983a) used
delayed ossification at 80 mg/kg/day as the basis for the RQ of 1000. An
MED of 420 mg/day, an RV, of 1.6 and an RV of 8 were calculated yield-
Ing a CS of 12.8 and an RQ of 1000. Nlkonorow et al. (1973) treated rats
wHh 600 mg/kg/day on days 0-21 of gestation and found reduced fetal body
weight and Increased numbers of resorptlons (RV =8). Multiplying 600
mg/kg/day by the cube root of the rat weight (0.165 kg with study) to the
human weight (70 kg) and by 70 kg results 1n an MED of 5590 mg/day, which
corresponds to an RV. of 1. The CS of 8 corresponds to an RQ of 1000.
In subchronlc studies, Nlkonorow et al. (1973) found Increased liver
weight without hlstologlcal evidence of liver damage (RV =4) 1n rats
treated with >120 mg/kg/day for 3 months; however, no treatment-related
effects were observed 1n rats given 0.125% 1n the diet (62.5 mg/kg/day) for
1 year. Therefore, H 1s not necessary to divide the subchronlc dose by an
uncertainty factor of 10, because the resulting dose would be well below
62.5 mg/kg/day. Multiplying 120 mg/kg/day by the cube root of the reference
0787p 9-4 06/06/86
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rat weight (0.35 kg) to 70 kg, and by 70 kg, results In an MED of 1436
mg/day, corresponding to an RV of 1. The CS of 4 would correspond to an
RQ of 5000.
Ota et al. (1974) observed marked degenerative changes In the liver and
kidneys of mice given 500 or 5000 mg/kg/day for 3 months. This Information
was taken from an abstract, which provided little detail; therefore, this
study was not considered for RQ derivation.
9.1.4. Dimethyl Phthalate. ToxUUy data are summarized In Table 5-10.
Lehman (1955) observed chronic nephritis (RV =7) 1n rats fed 8% dimethyl
phthalate and decreased body weight (RV =4) 1n rats fed 4% dimethyl phtha-
late for 2 years. Assuming that a rat consumes 5% of Its weight In food per
day, 8X Is equivalent to a dose of 4000 mg/kg/day and 4X 1s equivalent to
2000 mg/kg/day. Multiplying 2000 and 4000 mg/kg/day by the product of the
cube root of the ratio of rat weight (0.35 kg; assumed) to human weight (70
kg; assumed), and human weight (70 kg) yields human HEDs of 23,940 and
47,879 mg/day, respectively. Both MEDs correspond to RV s of 1. Multi-
plying the RV by the RV s of 4 and 7 yields CSs of 4 and 7, respec-
tively, corresponding to RQs of 5000 and 1000, respectively.
9.1.5. D1-n-0ctyl Phthalate. Only two chronic toxldty studies were
available for the assessment of d1-n-octyl phthalate (see Table 5-10); the
2-generat1on reproduction and fertility assessment conducted by Gulat! et
al. (1985) on CD-I mice, and the 12-month toxldty study by Plekacz (1971)
conducted on Wlstar rats. No effects were observed by Gulatl et al. (1985).
A CS of 6 can be derived from Plekacz (1971) on the basis of elevated liver
and kidney weights (female rats) and Increased SGOT and SGPT (male and
female) 1n rats fed 3500 ppm d1-n-octyl phthalate. Assuming that a rat
consumes 5X of Us body weight 1n food per day, 3500 ppm 1s equivalent to a
0787p 9-5 06/06/86
-------
dose of 175 mg/kg/day. Multiplying 175 mg/kg/day by the cube root of the
ratio of rat weight (0.35 kg; assumed) to human weight (70 kg; assumed) and
human weight yields a human MED of 2095 mg/day. The MED 1s assigned an
RV. of 1. The RV of 6 Is assigned on the basis of the above effects.
Multiplying the RV by the RV yields a CS of 6. The RQ for dl-n-octyl
phthalate Is therefore 1000.
9.1.6. n-Butyl Benzyl Phthalate. The toxlclty data for n-butyl benzyl
phthalate are summarized on Table 5-10. In a chronic dietary study, there
was a dose-related and significant early mortality from unexplained hemor-
rhaglng 1n male F-344 rats fed 6000 or 12,000 ppm n-butyl benzyl phthalate
In the diet for 28 weeks (NTP, 1982a). In a subchronlc study by Monsanto
(1972), the only effect \n rats treated for 90 days was Increased liver
weight at >10,000 ppm. Since the discrepancy cannot be resolved, a CS for
the mortality 1s calculated. Assuming that a rat consumes 554 of Us body
weight In food per day, 6000 ppm 1s equivalent to 300 mg/kg/day. Multiply-
ing 300 mg/kg/day by the cube root of the ratio of rat weight (0.375 kg In
the study) to human weight (70 kg) and by the human weight (70 kg) yields a
human dose of 3674 mg/day. Because the mortality occurred during 15-28
weeks, the dose should be divided by an uncertainty factor of 10. The
resultant MED of 367 mg/day corresponds to an RV. of 1.7. Multiplying the
RV by the RV of 10 for mortality results In a CS of 17, which corre-
sponds to an RQ of 1000.
9.1.7. D11sononyl Phthalate. The only studies available for the assess-
ment of dllsononyl phthalate are unpublished studies on dogs and rats
conducted by Livingston (1971) and reported by Krauskopf (1973) (see Table
5-6). The RQ Is based on slightly reduced growth rate and Increased liver
weight In rats treated with 500 mg dllsononyl phthalate/kg/day for 13 weeks.
0787p 9-6 06/06/86
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Dividing 500 mg/kg/day by 10 and multiplying by the cube root of the ratio
of reference rat weight (0.35 kg) to the reference human weight (70 kg) and
human weight (70 kg) yields a human MED of 598 mg/day. The MED Is corre-
sponds to an RV of 1.3. An RV of 4 Is assigned on the basis of the
above effects. Multiplying the RV by the RV yields a CS of 5.2. The
dog(s) given a TWA concentration of 2.8% had hlstologlcaal changes In liver,
gall bladder, spleen and kidney. Assuming that a dog consumes a dally
amount of food equal to 2.5% of Us body weight, the 2.8% concentration 1s
equivalent to 700 mg/kg/day. Dividing by an uncertainty factor of 10 and
multiplying by the cube root of the reference dog weight of 12.7 kg (Ourkln,
1985) to the human weight, and by 70 kg, results In an MED of 2774 mg/day.
The RVrf Is 1, the RVg Is 6 and the CS 1s 6, which corresponds to an RQ
of 1000.
9.1.8. D1-n-Heptyl Phthalate. The only available study of dl-n-heptyl
phthalate 1s the teratogenlcHy study by Nakashlma et al. (1977), reported
as an abstract (see Table 5-5). It 1s not appropriate to calculate a CS for
this study, because, In the absence of other toxlclty data, 1t Is not known
1f fetotoxldty and teratogenlclty are the most sensitive endpolnts for this
chemical. Furthermore, the data were not clearly presented.
9.1.9. Summary. CSs were calculated for d1(2-ethylhexyl) phthalate,
dlethyl phthalate, d1-n-butyl phthalate, dimethyl phthalate, d1-n-octyl
phthalate, n-butyl benzyl phthalate and dllsononyl phthalate (Table 9-1).
In each case, the data that resulted 1n the highest CS are recommended as
the bases for the RQs (Tables 9-2 to 9-8). The RQ for each of the phthalate
esters listed above 1s 1000. Data were not sufficient for deriving an RQ
for the other phthalate esters discussed 1n this document.
0787p 9-7 06/06/86
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lABlf 9-1
Summary of RQs Derived for Phthallc Acid Esters
0
—J
GO
-0
o
i
co
o
o»
•*>,
o
0>
^^
00
cr
Compound Species
(bw/kg)
Olethylhexyl phthalate guinea pig
mouse
Dlethyl phthalate rat
mouse
Dlbutyl phthalate rat
rat
mouse
mouse
Dimethyl phthalate rat
rat
Dloctyl phthalate rat
n-Butyl benzyl male rat
phthalate
Dltsononyl phthalate rat
dog
Animal Dose
(mg/kg/day)
19
91
?500
3250
600
1?0
2100
80
4000
2000
175
300
500
700
Chronic
Human MED
(rag/day)
305
475
29.925
17.152
5.590
1.436
11.083
420
47.879
23.940
2.095
367'
598*
2.774'
RVd
1.8
1.5
1.0
1.0
1.0
1.0
1.0
1.6
1.0
1.0
1.0
1.7
1.0
1.0
Effect
Increased relative
liver weight
leratogenlctty without
maternal toxlclty
Reduced body weight
Decreased sperm concen-
tration; reduced number
of pups/Utter In F )
Increased fetal resorp-
tlons; decreased fetal
body weight
Increased liver weight
Fetotoxlclty; terato-
genlclty; maternal
toxlclty
Eetotoxlclty
Chronic nephritis
Decreased body weight
E levated liver and
kidney weights (f ):
Increased SCOT and
SGPT (male and female)
Mortality due to unex-
plained hemorrhagtng
Slightly reduced growth
rate; Increased liver
weight
Hlstologlc changes In
1 Iver , gallbladder ,
spleen and kidney
RVe CS RQ Reference
4 7.2 1000 Carpenter
et al.. 1953
10 15 1000 Molkowskl-lyl
et al.. I984b
4 4 5000 Food Research
Lab.. 1955
8 8 1000 Reel et al. .
1984
8 8 1000 Nlkonorow
et al.. 1973
4 4 5000 Nlkonorow
et al.. 1973
9 9 1000 Shlota and
Nlshlmura.
1982; Shlota
et al.. 1980
8 12.8 1000 Shlota
et al.. 1980
7 7 1000 Lehman. 1955
4 4 SOOO Lehman. 1955
6 6 1000 Plekacz. 1971
10 17 1000 NTP. 1982a
4 4 5000 Livingston.
197)
6 6 1000 Livingston,
19M
"The e was divided by 10 to approximate chronic exposure
-------
TABLE 9-2
D1(2-ethylhexyl) Phthalate
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 305 mg/day
Effect: teratogenk!ty without maternal toxldty
Reference: Wolkowskl-Tyl et al., 1984b
RVd: 1.5
RVe: 10
Composite Score: 15
RQ: 1000
'Equivalent human dose
0787p 9-9 05/15/86
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TABLE 9-3
Olethyl Phthalate
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 17,152 rug/day
Effect: reduced number of pups/Utter; decreased sperm
concentrations
Reference: Reel et a!., 1984
RVd: 1
RVe: 8
Composite Score: 8
RQ: 1000
*Equ1valent human dose
0787p 9-10 05/15/86
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TABLE 9-4
D1-n-butyl Phthalate
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 420 mg/day
Effect: fetotoxUHy
Reference: Shlota et al., 1980
RVd: 1.6
RVe: 8
Composite Score: 12.8
RQ: 1000
*Equ1valent human dose
0787p 9-11 06/06/86
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TABU 9-5
Dimethyl Phthalate
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 47,879 mg/day
Effect: chronic nephritis
Reference: Lehman, 1955
RVd: 1
RVe: 7
Composite Score: 7
RQ: 1000
'Equivalent human dose
0787p 9-12 05/15/86
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TABLE 9-6
D1-n-octyl Phthalate
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 2095 mg/day
Effect: elevated liver and kidney weights; Increased SGOT and
SGPT
Reference: Plekacz, 1971
RVd: 1
RVe: 6
Composite Score: 6
RQ: 1000
'Equivalent human dose
0787p 9-13 05/15/86
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TABLE 9-7
n-Butyl Benzyl Phthalate
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 367 mg/day
Effect: mortality
Reference: NTP. 1982a
RVd: 1.7
RVe: 10
Composite Score: 17
RQ: 1000
*Equ1valent human dose
0787p 9-14 05/15/86
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TABLE 9-8
Dllsononyl Phthalate
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 2774
Effect: hlstologlc changes 1n liver, gall bladder, spleen and
kidney
Reference: Livingston, 1971
RVd: 1
RVe: 6
Composite Score: 6
RQ: 1000
*Equ1valent human dose
0787p 9-15 05/15/86
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9.2. WEIGHT OF EVIDENCE AND POTENCY FACTOR (F=1/ED1Q) FOR CARCINOGENICITY
9.2.1. D1(2-Ethylhexyl) Phthalate. In lifetime feeding studies conducted
by NIP (1982b), dl(2-ethylhexyl} phthalate was shown to cause Increased
Incidences of liver neoplasms In F344/N rats (hepatocellular carcinoma,
hepatocellular carcinoma or neoplastlc nodules) and 1n B6C3F1 mice (hepato-
cellular carcinoma, hepatocellular carcinoma or adenoma). This study was
discussed In detail In Section 5.1. and Is summarized 1n Table 5-3. Based
on these results, IARC (1982b) concluded that there 1s sufficient evidence
that d1 (2-ethylhexyl) phthalate Is carcinogenic for rats and mice. No human
studies were available for evaluation. IARC has ranked d1(2-ethylhexyl)
phthalate as a group 28 compound. Using the EPA scheme, this compound can
be classified as a 82 chemical (U.S. EPA, 1986b).
Since d1{2-ethylhexyl) phthalate Is probably carcinogenic for humans, H
1s appropriate to derive a potency factor. As discussed 1n Chapter 8, the
highest q^, a value of 8.36xlO~3 (mg/kg/day)'1 (Interim value), was
calculated from the data on Increased Incidence of hepatocellular carcinoma
or adenoma In male mice; therefore, the same data are used In the
calculation of F. The doses used In the multistage model were adjusted
before the calculation of the q * as follows:
dose x le/L£ x (WA/70)1/3 x UE/L)3
where le = length of treatment study
U = length of study
W. = animal body weight
L = Hfespan of the animal; In this case L=L..
0?87p 9-16 08/28/87
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In order to obtain a human 1/ED,Q(F), adjustments for body weight and
less-than-Hfetlme exposure are normally applied to the unadjusted animal
l/EQ,n obtained from the computerized multistage model. However, since
body weight varied 1n some of the dose groups In the NTP (1982b) study,
these adjustments were applied to the doses before the calculation of
l/ED,n. The resulting l/ED,n 1s thus adjusted (human) F values (Table
9-9). Because the F factor of 5.14xlO~2 (mg/kg/day)"1 Is <1, d1(2-
ethylhexyl) phthalate Is placed In Potency Group 4. An EPA Group B2
chemical In Potency Group 4 has a low hazard ranking under CERCLA. The
potency value 1s considered Interim because there Is evidence suggesting
that metabolites may be responsible for the effects. EPA has not yet
evaluated the possibility of utilizing metabolized dose as a means of
accomplishing the Interspedes conversion for the quantitative estimate.
Until EPA evaluates the cancer data In the context of potential differences
1n metabolized dose the q,* should be viewed as an Interim estimate.
Some dispute exists, however, concerning whether rodent studies on
d1(2-ethylhexyl) phthalate can be used to quantify potential effects In
humans (Northrup et al., 1982; Kluwe et al., 1983; Turnbull and Rodrlcks,
1985). These doubts are based primarily on differences In the way
d!(2-ethylhexyl) phthalate Is metabolized In rodents and humans, and
hypotheses that the proximate carcinogenic species Is produced to a greater
extent In rodents than 1n humans (Turnbull and Rodrlcks, 1985) (see Section
5.1.). Turnbull and Rodrlcks (1985) suggest that human potency factors for
d1(2-ethylhexyl) phthalate that are based on rodent data probably over-
estimate the carcinogenic risk of d1(2-ethylhexyl) phthalate for humans.
0787p 9-17 08/28/87
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TABLE 9-9
Derivation of Potency Factor (F)
Agent: D1(2-ethylhexyl) Phthalate
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or
physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/
exposure (ml/kg):
Transformed doses*
(mg/kg/day):
Tumor Incidence:
Unadjusted 1/ED10:
1/ED10 (F factor):
NTP. 1982b
Oral
Mouse
B6C3F1
Male
Diet
0.04 kg
103 weeks
105 weeks (low dose); 104 weeks (high dose)
105 weeks (low dose); 104 weeks (high dose)
Liver
Hepatocellular carcinoma or adenoma
0
0
3000
672
6000 ppm
1325 mg/kg/day (measured)
0 54.7 108.89
14/50 25/48 29/50
Not calculated (see text)
5.14xlO~2 (mg/kg/day)"1
*For all data from NTP (1982b), doses were transformed prior to calculation
of 1/EO-)Q due to differences between treatment groups 1n body weight:
dose x le/Le x (0.04/70)1/3 x (Le/L)3 = transformed dose, where Le/L = 1
0787p
9-18
05/15/86
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9.2.2. n-Butyl Benzyl Phthalate. n-Butyl benzyl phthalate has also been
tested for oncogenldty In feeding studies on F344/N rats and B6C3F1 mice
conducted by NTP (1982a). These data are discussed In Section 5.1. and are
summarized In Table 5-2. Based on the observation of increased Incidences
of mononuclear cell leukemia and leukemia or lymphoma In female rats, NTP
(1982a) concluded that n-butyl benzyl phthalate was "probably carcinogenic
for female F344/N rats." In a separate report, however, Kluwe et al.
(1982a) concluded that since the background Incidence of myelomonocytIc
leukemia Is normally high In F344/N rats, results presented In NTP (1982a)
provide only equivocal evidence of n-butyl benzyl phthalate-lnduced cancer
In female rats. Furthermore, the fact that dose-related and significant
decreases In malignant lymphoma, all lymphoma and leukemia or lymphoma were
observed In male mice (NTP, 1982a) adds to the uncertainty that n-butyl
benzyl phthalate may cause cancer 1n humans. IARC (1982a) concluded that
the NTP (1982a) studies are Insufficient to assess the carcinogenic
potential of n-butyl benzyl phthalate.
Based on the normally high background Incidence of leukemia In F344/N
rats, on the compound-related decreases In leukemia and lymphomas In male
B6C3F1 mice, and on Interspecles differences In the metabolism of phtha-
lates, the NTP (1982a) study provides only limited evidence of n-butyl
benzyl phthalate-lnduced carclnogenlclty. Therefore, n-butyl benzyl
phthalate Is best classified as an EPA Group C chemical, albeit with no
potency factor derived.
9.2.3. Other Phthalate Esters. Other phthalate esters have not been
tested for oncogenldty. These compounds are best classified In EPA Group D.
0787p 9-19 08/28/87
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10. REFERENCES
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of DUP to fathead minnows (Plmephales promelas). Prepared for Monsanto
Chemical Co., St. Louis, MO. TSCA 8d Submission Doc. No. 878210835, F1che
No. OTS 0206236, OTS, Washington, DC.
ABC (Analytical B1o Chemistry Laboratories, Inc.). 1979b. Acute toxldty
of S-790 to fathead minnows (Plmephales promelas). Prepared for Monsanto
Chemical Co., St. Louis, MO. TSCA 8d Submission Doc. No. 878211027, Flche
No. OTS 0206236, OTS, Washington, DC.
ABC (Analytical Bio Chemistry Laboratories, Inc.). 1979c. Acute toxldty
of DUP to rainbow trout (Salmo galrdnerl). Prepared for Monsanto Chemical
Co., St. Louis, MO. TSCA 8d Submission Doc. No. 878210836, Flche No. OTS
0206236, OTS, Washington, DC.
ABC (Analytical Bio Chemistry Laboratories, Inc.). 1979d. Acute toxldty
of S-790 to rainbow trout (Salmo qalrdnerl). Prepared for Monsanto Chemical
Co., St. Louis, MO. TSCA 8d Submission Doc. No. 878211026, Flche No. OTS
0206236, OTS, Washington, DC.
ABC (Analytical Bio Chemistry Laboratories, Inc.). 1979e. Acute toxldty
of DUP to Daphnla maqna. Submitted to Monsanto Chemical Co., St. Louis, MO.
TSCA 8d Submission Doc. No. 878210834, Flche No. OTS 0206236. OTS, Wash-
ington, DC.
0788p 10-1 05/15/86
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ABC (Analytical Bio Chemistry Laboratories, Inc.). 1979f. Acute toxklty
of S-790 to Daphnla magna. Prepared for Monsanto Chemical Co., St. Louis,
MO. TSCA 8d Submission Doc. No. 878211028, Flche No. OTS 0206236, OTS,
Washington, DC.
Abe, S. and M. Sasaki. 1977. Chromosome aberrations and sister chromatld
exchanges In Chinese hamster cells exposed to various chemicals. J. Natl.
Cancer Inst. 58: 1635-1641.
Agarwal, O.K., R.R. Marenpot, J.C. Lamb, IV and W.M. Kluwe. 1985a. NEED
TITLE OF ARTICLE. Toxicology. 35(3): 189-206.
Agarwal, O.K., W.H. Lawrence and J. Autlan. 1985b. Antlfertlllty and
mutagenlc effects In mice from parenteral administration of d1-2-ethylhexyl
phthalate (DEHP). J. Toxlcol. Environ. Health. 16: 71-84.
Aklyama, T., M. Koga, R. Shlnohara, A. Kldo and S. Eton. 1980. Detection
and Identification of trace organic substances 1n the aquatic environment.
3. UOEH. (Japan.) 2: 285-300.
Albro. P.W. and 8. Moore. 1974. Identification of the metabolites of
simple phthalate dlesters 1n rat urine. J. Chromatogr. 94: 209-218.
(CUed In Kluwe, 1982)
Albro, P.W. and R.O. Thomas. 1973. Enzymlc hydrolysis of d1 (2-ethylhexyl)
phthalate by Upases. Blochem. Blophys. Acta. 306(3): 380-390.
0788p 10-2 08/26/86
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pollutant organlcs off Southern California. In: Hater Chlorlnatlon.
Environ. Impact Health Eff. 4(2): 871-874.
Zelger, E., S. Haworth, W. Speck and K. Mortelmans. 1982. Phthalate ester
testing In the national toxicology program's environmental mutagenesls test
development program. Environ. Health Perspect. 45: 99-101.
ZHko, V. 1973. Determination of phthalates In biological samples. Int.
J. Environ. Anal. Chem. 2: 241-252.
Zoeteman, B.C.J., E. Degreef and F.J.J. Brlnkman. 1981. Persistence of
organic contaminants In ground water, lessons from soil pollution Incidents
In the Netherlands. Scl. Total Environ. 21: 187-202.
0788p 10-56 08/31/87
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Zuercher, F. and W. Glger. 1976. Volatile organic trace components In the
Glatt River. Vom Wasser. 47: 37-55.
0788p 10-57 08/31/87
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APPENDIX
LITERATURE SEARCHED
This profile 1s based on data Identified by computerized literature
searches of the following:
CASR online (U.S. EPA Chemical Activities Status Report)
CAS online STN International
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted In October, 1985. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 6 and 7), and the
following secondary sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1980. Documentation of the Threshold Limit Values, 4th ed. (In-
cludes Supplemental Documentation, 1981, 1982, 1983). Cincinnati,
OH. 486 p.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1985. TLVs: Threshold Limit Values for Chemical Substances and
Physical Agents In the Workroom Environment wUh Intended Changes
for 1985-1986. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John WHey and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 28. John Wiley and
Sons, NY. p. 2879-3816.
0789p A-l 05/15/86
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Clayton, G.O. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
Grayson, M. and D. Eckroth, Ed. 1978-1983. K1rk-0thmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyons, France.
ITII (International Technical Information Institute). 1982. Toxic
and Hazardous Industrial Chemicals Safety Manual for Handling and
Disposal with Toxlclty and Hazard Data. ITII, Tokyo, Japan. 700 p.
NTP (National Toxicology Program). 1984. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, N.I. 1979. Dangerous Properties of Industrial Materials, 5th
ed. Van Nostrand Relnhold Co.. NY.
SRI (Stanford Research Institute). 1984. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1985. Status Report on Rebuttable Presumption Against
Registration (RPAR) or Special Review Process. Registration Stan-
dards and the Data Call 1n Programs. Office of Pesticide Programs,
Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1983. Synthetic
Organic Chemicals. U.S. Production and Sales, 1982, USITC Publ.
1422, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
0789p A-2 05/15/86
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In addition, approximately 30 compendia of aquatic toxldty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Sele'cted Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and H.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, 0. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0789p A-3 05/15/86
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