TECHNICAL REPORT DATA
(fteae rt*d IntOvctions on tht reverte btfort complttinf)
1. REPORT NO.
tPA/600/8-88/053
2.
3. RECIPIENT'S ACCESSION NO.
PB88-178934
4. TITLE AND SUBTITLE
Health Effects Assessment for
hsters
6. REPORT DATE
Selected Phthalic Acid
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
«. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD£ or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFlERS/OPEN ENDED TERMS C. COSATI Field/GfOUp
8. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS {Thu Report)
Unclassified
21. NO. Of PAGES
2O. SECURITY CLASS (Thiipage)
Unclassified
22. PRICE
EPA f»tm 2220-1 (R«». 4-77) PMKVIOUS KOITION is OMOLKTC
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EPA/600/8-88/053
October. 1987
HEALTH EFFECTS ASSESSMENT
FOR SELECTED PHTHALIC ACID ESTERS
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has been reviewed 1n accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with selected
phthallc add esters. All estimates of acceptable Intakes and carcinogenic
potency presented In this document should be considered as preliminary and
reflect limited resources allocated to this project. Pertinent toxlcologlc
and environmental data were located through on-line literature searches of
the TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The basic
literature searched supporting this document Is current up to May, 1986.
Secondary sources of Information have also been relied upon In the prepara-
tion of this report and represent large-scale health assessment efforts that
entail extensive peer and Agency review. The following Office of Health and
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Hater Quality Criteria for Phthalate
Esters. Prepared by the Office of Health and Environmental Assess-
ment, Environmental Criteria and Assessment Office, Cincinnati, OH
for the Office of Water Regulations and Standards, Washington, DC.
EPA 440/5-80-067. NTIS PB81-117780.
U.S. EPA. 1980b. Hazard Profile for Phthalate Esters. Prepared
by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of
Solid Waste, Washington, DC.
U.S. EPA. 1980c. Hazard Profile for Butyl Benzyl Phthalate.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Solid Waste, Washington, DC.
U.S. EPA. 1980d. Hazard Profile for D1-n-butyl Phthalate.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Solid Waste, Washington, DC.
U.S. EPA. 1980e. Hazard Profile for Dlethyl Phthalate. Prepared
' by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of
Solid Waste, Washington, DC.
U.S. EPA. 1980f. Hazard Profile for D1-n-0ctyl Phthalate.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Solid Waste, Washington, DC.
U.S. EPA. 1980g. Hazard Profile for B1s(2-ethylhexyl) Phthalate.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Solid Waste, Washington, DC.
111
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U.S. EPA. 1983a. Reportable Quantity Document for 1,2-Benzene-
dlcarboxyllc acid, dlbutyl ester (Dlbutyl phthalate). Prepared by
the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of
Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1983b. Reportable Quantity Document for 1,2-Benzene-
dlcarboxyllc add, dlethyl ester (Dlethyl phthalate). Prepared by
the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of
Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1985a. Drinking Water Criteria Document for Phthallc
Add Esters. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Drinking Water, Washington, DC. Draft.
The Intent In these assessments 1s to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfDs (formerly AIS) or subchronlc reference dose, 1s
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants In ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$j) and oral (RfD$g)
exposures.
The RfD (formerly AIC) Is similar In concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the llfespan [see U.S. EPA (1980h) for a discussion of this concept]. The
RfD 1s route-specific and estimates acceptable exposure for either oral
(RfOg) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes Is Insignificant.
1v
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Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained In U.S.
EPA (1984).
For compounds for which there Is sufficient evidence of cardnogenldty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980c). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-j*s have been computed, 1f appro-
priate, based on oral and Inhalation data 1f available.
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
Carc1nogen1c1ty data sufficient for derivation of a q-|* were located
only for b1s(2-ethylhexyl) phthalate, which was associated with Increased
Incidence of liver tumors 1n rats and mice of both sexes fed diets
containing the compound (NTP, 1982a). An Interim q-j* of 8.36xlO~3
(mg/kg/day)'1 for oral exposure was derived. This compound 1s classified
as a B2 carcinogen.
and Rf°0 values and CSs were calculated for several phthalate
esters based on their oral toxlclty. For dlethyl phthalate an RfDso and
RfDg of 525 and 52.5 mg/day were based on a 16-week study In rats (Brown
et a!., 1978). A CS of 8 was based on reduced reproductive capacity In a
2-generat1on study using mice (Reel et al., 1984).
An RfD$o of 88 rog/day and an RfDo of 8.8 mg/day for d1-n-butyl
phthalate were based on a 52-week dietary study using rats (Smith, 1953;
U.S. EPA, 1980a). A CS of 12.8 was based on developmental toxlclty using
mice (Shlota and N1sh1mura, 1982; Shlota et al., 1980).
A CS of 7 was calculated based on chronic nephritis 1n a 2-year study
using rats (Lehman, 1955). Data were considered Inadequate for RfD
development.
Limited evidence of cardnogenlcHy 1n rats was obtained for butyl
benzyl phthalate. Female rats fed the material In the diet experienced a
statistically significant Increased Incidence of leukemia and lymphomas
(NTP, 1982b). A similar response, however, was not observed In male rats
and a dose-related decrease In similar cancers was noted 1n male mice In the
same experiment. Data were considered Inadequate for quantitative risk
estimate, but adequate for assignment of a Group C we1ght-of-ev1dence
classification, possible human carcinogen. The text of the document
describes possible development of RfDso an(^ Rf^Q values for noncarclno-
genlc endpolnts.
For d1-n-octyl phthalate, data were Inadequate for RfD development; a CS
of 6 was based on mild liver effects 1n a 7- to 12-month dietary experiment
using rats (Plekacz, 1971).
v1
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher OeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
vll
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TABLE OF CONTENTS
Page
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND .EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation ,
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . . ,
3.3.1. Oral ,
3.3.2. Inhalation ,
CARCINOGENICITY ,
4.1. HUMAN DATA
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDs)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDci)
. . , 1
. , 4
. . . 4
. . . 6
. . . 7
, , , 7
. . . 7
. . . 12
. . . 12
. . . 12
. . . 14
. . . 15
. . . 15
, , , 19
, . . 21
, . . 21
, . , 21
. . . 21
. . . 27
, . . 27
. . . 27
. , 29
. . . 31
. . 31
, . . 31
, . . 41
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LIST OF TABLES
No. Title Page
1-1 Physical and Chemical Properties and Half-Lives for
Selected Phthalates 2
4-1 Hematopoletlc Neoplasms 1n F344/N Rats and B6C3F1 Mice
Fed Butyl Benzyl Phthalate 1n the Diet for 103 Weeks 23
4-2 Liver Neoplasms In F344/N Rats and B6C3F1 Mice Fed
B1s(2-ethylhexyl) Phthalate 1n the Diet for 103 Weeks .... 25
5-1 ADIs for Phthalate Esters 30
6-1 Summary Table for B1s(2-ethylhexyl) Phthalate 32
6-2 Summary Table for Dlethyl Phthalate 33
6-3 Summary Table for D1-n-butyl Phthalate 34
6-4 Summary Table for Dimethyl Phthalate 35
6-5 Summary Table for Butyl Benzyl Phthalate 36
6-6 Summary Table for D1-n-octyl Phthalate. ... 37
6-7 Cancer Data Sheet for Derivation of q-|* 48
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I-'
TABLE OF CONTENTS (cont.)
Page
6.2. REFERENCE DOSE (RfD) 41
6.2.1. Oral (RfD0) 41
6.2.2. Inhalation (RfDj) 47
6.3. CARCINOGENIC POTENCY (q-|*) 47
6.3.1. Oral 47
6.3.2. Inhalation 49
7. REFERENCES 50
1x
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LIST OF ABBREVIATIONS
BCF B1oconcentrat1on factor
bw Body weight
CAS Chemical Abstract Service
CS Composite score
DMSO Dimethyl sulfoxlde
PEL Frank-effect level
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
HTO Maximum tolerated dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
RfD Reference dose
RfOi Inhalation reference dose
RfD0 Oral reference dose
RfD§ Subchronlc reference dose
RfDsi Subchronlc Inhalation reference dose
RfD$o Subchronlc oral reference dose
RQ Reportable quantity
RVd Dose-rating value
RVe Effect-rating value
SGOT Serum glutamlc oxaloacetlc transamlnase
SGPT Serum glutamlc pyruvlc transamlnase
x1
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected physical and chemical properties and available half-life data
for dimethyl, dlethyl, d1-n-butyl, d1-n-octyl, b1s-(2-ethylhexyl) and butyl
benzyl phthalate are presented In Table 1-1. These chemicals can be classi-
fied as benzenedlcarboxyllc acid dlesters (U.S. EPA, 1980b-g).
In air, gaseous phthallc add esters are predicted to react with
hydroxyl radicals. The actual atmospheric half-life because of adsorption
onto airborne partlculate matter may be longer than the estimated half-life
given In Table 1-1. Removal of phthalate esters from the atmosphere by wet
and dry deposition has been observed (Kawamura and Kaplan, 19&3; Altas and
G1am, 1981; Karasek et al., 1978; Weschler, 1984).
In water, the phthalate esters apparently blodegrade, volatilize, adsorb
to sediments and bloconcentrate depending upon the size and complexity of
the ester chains, environmental conditions and presence of fulvlc adds
(Callahan et al., 1979). Studies Indicate that phthallc acid esters undergo
rapid primary degradation and mineralization (half-lives range from days to
weeks) by bacteria commonly found In the environment (Saeger and Tucker,
1973a,b; Gledhlll et al., 1980). The rates of degradation have been shown
to decrease with Increasing size and complexity of the phthalate chain.
Monitoring data and sediment-water partitioning coefficients Indicate that
adsorption to suspended solids and sediments 1s also likely to occur for all
the phthalates (Sullivan et al., 1982; Mabey et al., 1981), although
complexatlon with fulvlc acid can cause solubH1zat1on (Khan, 1980; Ogner
and Schnltzer, 1970; Matsuda and Schnltzer, 1971).
0066h -1- 10/21/86
-------
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Phthallc add ester half-lives In soil were estimated from blodegrada-
tlon data from a garden soil study (Shanker et al., 1985). Removal by
mechanisms other than blodegradatlon, however, may also be significant from
lower molecular weight phthalates. For example, dimethyl and dlethyl phtha-
late are predicted to be highly mobile 1n soil and also have the potential
to volatilize from dry soil surfaces. Overall, short-chain phthalates
blodegrade at a faster rate than longer chain phthalates and anaerobic
degradation 1s slower than aerobic degradation (Shanker et al., 1985).
0066h -3- 08/05/86
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Absorption factors per se for the phthalate esters could not be located
In the available literature. In general, excretion profiles Indicate that
alky! phthallc add esters and/or their degradation products are probably
well absorbed from the gastrointestinal tract.
When b1s(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 1n the feces (Williams and Blanch-
field, 1974). When b1s(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 In the urine, while 24-57% was excreted as
metabolites 1n the feces within 1-4 days (Williams and Blanchfleld, 1974;
Daniel and Bratt, 1974). When treated by gavage with 100 mg/kg l4C-b1s-
(2-ethylhexyl) phthalate In corn oil, rats, mice and cynomologus monkeys
excreted -30-40% of the radioactive dose In the urine within 24 hours and
-50% of the radioactive dose 1n the feces within 24 hours (rats and mice) or
48 hours (monkeys) (A.D. Little, Inc., 1984). Blood levels of radioactivity
were higher In monkeys than 1n rats or mice. In humans, 10-15% of a single
oral dose of b1s(2-ethylhexyl) phthalate was excreted In the urine as
metabolites within 24 hours of administration (Schmld and Schlatter, 1985).
Absorption of b1s(2-ethylhexyl) phthalate and/or Us degradation products
may be greater than urinary levels of metabolites would Indicate, since
substantial biliary excretion has been observed In rats, dogs and miniature
pigs (Daniel and Bratt, 1974; Ikeda et al., 1980).
Gastrointestinal absorption of d1-n-butyl phthalate can be Inferred from
observations that >90% of a single dose of d1-n-butyl phthalate administered
0066h -4- 10/21/86
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to rats by gavage (60, 270 or 2310 mg/kg, vehicles = corn oil, DMSO) was
excreted as metabolites 1n the urine within 2 days; the remainder was
excreted In the feces (Tanaka et a!., 1978; Williams and Blanchfleld, 1975).
Apparent hydrolytlc activity toward b1s(2-ethylhexyl) phthalate 1n
pancreatic homogenates led Albro and Thomas (1973) to hypothesize that very
little. If any. Intact phthalate dlester Is absorbed from the gastrointes-
tinal tract. Further studies have shown that phthalate esters [b1s(2-ethyl-
hexyl] phthalate, dimethyl phthalate, d1-n-butyl phthalate, dl-n-octyl
phthalate) are readily hydrolyzed 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 1n the
Intestinal contents of rats, ferrets and baboons (Rowland, 1974; Rowland et
al., 1977; Lake et al,, 1977a).
Recent gavage studies on rats demonstrated that b1s(2-ethylhexyl)
phthalate was hydrolyzed to monoethylhexyl phthalate, which was subsequently
absorbed (Telrlynck and Belpalre, 1985; 01sh1 and Hlraga, 1982). Telrlynck
and Belpalre (1985) reported that plasma concentrations of 8.8+0.7 vg/mi
b1s(2-ethylhexyl) phthalate and 63.2>8.7 yg/ml monoethylhexyl phthalate
were reached within 3 hours after a single oral dose of b1s(2-ethylhexyl)
phthalate (2.8 g/kg 1n corn oil). Pollack et al. (1985) found that 80% of a
single oral (gavage In corn oil) dose of b1s(2-ethylhexyl) phthalate was
hydrolyzed to Its monoester derivative (monoethylhexyl phthalate) and subse-
quently absorbed; 1354 of the dose was absorbed as b1s(2-ethylhexyl) phtha-
late. The ratio of the area under the curves for monoethylhexyl phthalate
to d1(2-ethylhexyl) phthalate was -7. Repetitive oral dosing did not affect
the extent of absorption.
0066h -5- 10/21/86
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2.2. INHALATION
Pertinent quantitative data regarding the absorption of phthalate esters
by Inhalation could not be located In the available literature.. Pegg (1982)
exposed adult male Sprague-Oawley rats to l4C-b1s(2-ethylhexyl) phthalate
aerosol at 100 mg/m3 for 6 hours In a heads-only exposure chamber. Radio-
activity equivalent to 3.83 ymol of parent compound was recovered from
urine, feces, skin and carcass, 72 hours after exposure. In another phase
of the experiment, radioactivity equivalent to 3.94 ymol of parent com-
pound was recovered from urine, feces, skin and carcass 72 hours after oral
administration of 25 ytnol/kg parent compound. On the basis of these
results and the blood levels of radioactivity measured at several Intervals
following exposure, the Investigators concluded that absorption 1s rapid and
extensive, following Inhalation exposure. Noting the clearance of radio-
activity from lung tissue following exposure, the Investigators concluded
that absorption from the lung 1s rapid and virtually complete.
0066h -6- 10/21/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
Chronic or subchronlc oral studies have been conducted with b1s(2-ethyl-
hexyl), d1-n-butyl, dlethyl, butyl benzyl and dl-n-octyl phthalates. The
liver, kidney and testes appear to be the organs affected most by phthallc
acid esters. Only those studies having a direct bearing on risk assessment
are reported In this document.
3.1. SUBCHRONIC
3.1.1. Oral.
3.1.1.1. BIS(2-ETHYLHEXYL) PHTHALATE -- Subchronlc oral studies have
been conducted with b1s(2-ethylhexyl) phthalate on rats (Shaffer et a!.,
1945; Harris et al., 1955; Nlkonorow et al.. 1973; Gray et al., 1977;
GangolU, 1982; Popp et al.. 1985; Nagasaki et al., 1974; Maslenko, 1968),
mice (Nagasaki et al., 1974; Ota et al., 1974), ferrets (Lake et al., 1976,
1977b), guinea pigs (Carpenter et al., 1953) and dogs (Carpenter et al.,
1953; Harris et al., 1955). The studies In which adverse effects were
observed at the lowest levels of exposure are those of Gray et al. (1977)
and Nagasaki et al. (1974) using rats.
Gray et al. (1977) fed 0, 0.2, 1.0 or 2.0% b1s(2-ethylhexyl) phthalate
In the diet 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 (GangolU, 1982). Body weight, food consumption, clini-
cal signs of toxldty, serum biochemistry, urlnalysls and hematology were
monitored (Gray et al., 1977). Gross and microscopic pathological examina-
tions were performed on all rats at the end of the study. Effects were
observed at all levels of exposure. Significantly Increased absolute and
relative liver weights were observed 1n all exposed groups. Food consump-
0066h -7- 10/28/87
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tlon and growth were reduced In rats fed 1 or 2% b1s(2-ethy'lhexyl) phtha-
late. Compared with controls, significantly reduced testlcular weights,
significantly Increased testlcular damage (dose-related) and a significant
decrease In hemoglobin concentration were observed 1n male rats fed the 1 or
2% concentration. Both males and females fed either 1 or 2% b1s(2-ethyl-
hexyl) phthalate had a significantly reduced packed cell volume compared
with controls.
Nagasaki et al. (1974) reported that Interstitial nephritis. Increased
SGPT and decreased blood glucose were observed 1n rats fed either 500 or
1000 ppm b1s(2-ethylhexyl) phthalate 1n the diet for 48 weeks. The dietary
levels were equivalent to 25 or 50 mg/kg/day, respectively, assuming that a
rat consumes a dally amount of food equal to 5% of Us body weight (U.S.
EPA, 1980h). No other details were available.
3.1.1.2. DIETHYL PHTHALATE -- In a Food Research Labs. (1955) study,
dlethyl phthalate was fed 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 reported by the
Investigator were 114, 343, 500 and 629 mg/kg/day. No effects were observed
at any level of exposure, but the endpolnts monitored were not reported.
Brown et al. (1978) fed groups of 15 male and 15 female CD rats 0, 0.2,
1.0 or 5.0% dlethyl phthalate (0, 150, 770 or 3160 mg/kg/day, males; 0, 150,
750 or 3710 mg/kg/day, females) In the diet for 16 weeks. Variables
monitored 1n the study Included 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 signifi-
cantly compared with controls. Paired feeding studies Indicated that these
0066h -8- 10/28/87
-------
reductions were not due to decreased food consumption. Compared with
controls, statistically significant decreases 1n absolute organ weights
(brain, heart, spleen, kidneys) and Increases 1n relative organ weights
(brain, liver, stomach, small Intestine, full calcium, testes, kidneys) were
observed In 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 In gross or microscopic pathology were not
observed. No other effects were observed.
3.1.1.3. OI-n-BUTYL PHTHALATE -- The subchronlc oral toxldty of
d1-n-butyl phthalate has been tested 1n rats (Smith, 1953; Nlkonorow et a!.,
1973; Plekacz, 1971; Bornmann et al., 1956; Maslenko, 1968) and mice (Ota et
al., 1974), but the only studies that reported effects were Smith (1953),
Nlkonorow et al. (1973) and Ota et al. (1974).
Smith (1953) fed 0, 0.01, 0.05, 0.25 or 1.25X d1-n-butyl phthalate In
the diet to groups of 10 male Sprague-Dawley rats for 1 year. Equivalent
doses using a food factor of 5X are 0, 5, 25, 125 or 625 mg/kg/day. The
only effect observed was 50% mortality during the first week of the study In
the high-dose group.
Increased relative liver weight In the absence of hlstopathologlcal
liver lesions was observed In rats treated with 120 or 1200 mg/kg/day for 3
months (Nlkonorow et al., 1973). Degenerative changes 1n the kidneys and
Hver occurred 1n mice fed 500 or 5000 mg d1-n-butyl phthalate/kg bw/day In
the diet for 1-3 months (Ota et al., 1974). No other details were given.
3.1.1.4. DIMETHYL PHTHALATE -- Pertinent data regarding the sub-
chronic oral toxldty of dimethyl phthalate could not be located 1n the
available literature.
0066h -9- 10/28/87
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3.1.1.5. BUTYL BENZYL PHTHALATE --There are very few oral long-term
BBP studies. In a draft report, NTP (1985) conducted a toxlclty and mating
trial study 1n F344 rats concomltantly. The toxlclty 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
toxlclty. 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.
H1stopatholog1cal changes were also seen at the 2.5% BBP level after 10
weeks of exposure 1n the mating 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 1n male reproductive organ weights by either a direct
or Indirect toxic effect after 2.5% BBP administration. BBP at 0.83% 1n the
diet did not result In any treatment-related effects as evaluated by the
0066h -10- 10/28/87
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authors. The Investigators concluded from the results of both studies that
a threshold for toxldty 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 1n lower exposure groups. Liver-
to-body weight ratios were significantly Increased 1n both the 0.83 and 2.554
diet groups, while I1ver-to-bra1n weight ratio was Increased In the 0.83%
group alone. Absolute liver weight was also Increased 1n 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 In addition to reduced cellularUy of the bone
marrow.
Krauskopf (1973) reported 90-day feeding studies on rats and dogs
(strains, sex, numbers not reported) conducted by Monsanto (1972). Rats
were fed diets containing 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) butyl benzyl phtha-
late, while dogs were fed diets containing 0, 1, 2 or 5% (0, 250, 500 or
1250 mg/kg/day, assuming a food factor of 0.025). No adverse effects were
observed among dogs fed butyl benzyl phthalate at any level, or among rats
fed 0.25 or 0.5% butyl benzyl phthalate. Increased liver weights without
accompanying hlstopathologlcal changes were observed among rats fed 1-2%
butyl benzyl phthalate. Slightly reduced growth rate was observed at the
two highest doses.
0066h -11- 10/28/87
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3.1.1.6. DI-n-OCTYL PHTHALATE An abstract of a Polish study
(Plekacz, 1971) reported that groups of 40 male and female rats (strain not
reported) were fed diets containing 0 or 3500 ppm (0 or 175 mg/kg/day, using
a food factor of 0.05) d1-n-octyl phthalate 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. H1stopatholog1cal examination was apparently not performed.
3.1.2. Inhalation. Pertinent data regarding the subchronlc toxldty of
Inhalation of phthalate esters could not be located In the available
literature.
3.2. CHRONIC
3.2.1. Oral.
3.2.1.1. BIS{2-ETHYLHEXYL) PHTHALATE -- Chronic oral toxldty studies
with b1s(2-ethylhexyl) phthalate have been conducted on rats (Carpenter et
a!., 1953; NTP, 1982a; Kluwe et al., 1982a; Canning et a!., 1985) and mice
(NTP, 1982a; Kluwe et al., 1982a).
The study In which adverse effects were observed at the lowest levels of
exposure Is that of Carpenter et al. (1953). Groups of Sherman rats
(32/sex/group) were fed 0, 0.04, 0.13 or 0.4% b1s(2-ethylhexyl) phthalate In
the diet (equivalent doses of 0, 20, 60 or 200 mg/kg/day 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 females were continued on test
for 1 more year. 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. Parental male rats and F. males and females
0066h -12- 10/28/87
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fed 0.4% b1s(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.
3.2.1.2. OIETHYL PHTHALATE U.S. EPA (1980a) summarized a study by
Food Research Labs. (1955) 1n which groups of 30 rats (strain and sex not
reported) were fed diets containing 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 (U.S. EPA, 1980h). The only effect observed was a small but
significant reduction In growth rate among rats fed 5% dlethyl phthalate.
Food consumption was not affected. U.S. EPA (1980a) did not report
endpolnts monitored 1n the study.
3.2.1.3. DI-n-BUTYL PHTHALATE -- In chronic oral toxlclty studies of
d1-n-butyl phthalate, unspecified numbers of rats were fed dietary concen-
trations of 0, 100 or 300 ppm for 21 months (Lefaux, 1968). No effects were
observed.
3.2.1.4. 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 factor of 0.05)
for 2 years. U.S. EPA (1980a) Incorrectly attributed this study to Dralze
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" at 8% was observed (U.S. EPA, 1980a).
3.2.1.5. BUTYL BENZYL PHTHALATE -- NTP (1982b) fed butyl benzyl
phthalate In the diet to female F344 rats at concentrations of 0, 6000 or
12,000 ppm and to B6C3F1 mice of both sexes at concentrations of 0, 3000 or
6000 ppm for 103 weeks. The only noncardnogenlc effects observed In female
0066h -13- 10/28/87
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rats and male and female mice were reductions In growth rate In all treated
groups. Growth rate reduction 1n female rats was accompanied by reduced
food consumption. Food consumption data 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.
3.2.1.6. DI-n-OCTYL PHTHALATE -- Pertinent data regarding chronic
oral toxlclty of d1-n-octyl phthalate could not be located 1n the available
literature.
3.2.2. Inhalation. The health status of 147 workers who handled
phthalate plastlclzers was evaluated by MUkov et al. (1973). Workers were
exposed to a mixture of compounds Including d1-n-butyl phthalate, DAP-789,
d1-n-octyl phthalate, d11sooctyl phthalate, butyl benzyl phthalate, selad-
nates, adlplnates, vinyl chloride, carbon monoxide and mixed ethers.
Phthalate exposure was estimated to be 1-40 mg/m3. Effects attributed to
phthalate exposure Included polyneurltls (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."
G1l1ol1 et al. (1978) performed clinical neurological electromyographlc
and electroneurologlc tests on 38 workers In the phthalate plastlclzer
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
-------
The frequency and severity Increased with length of exposure; no cases were
found In workers exposed for <2 years.
Thless et al. (1978) examined morbidity among 101 workers employed In
the production of b1s(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 mis-
carriages or deformities of offspring among female workers or the wives of
male workers. No other compound-related effects were observed, though
b1s(2-ethylhexyl) phthalate was found In the blood and urine of both exposed
and control groups.
Chronic Inhalation studies on phthalate esters In experimental animals
could not be located 1n the available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. A number of oral studies have shown that exposure to
b1s(2-ethylhexyl) or d1-n-butyl phthalate during gestation can have adverse
effects upon the developing fetus. 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 toxldty has not been determined.
B1s(2-ethylhexyl) phthalate-lnduced fetotoxlc and teratogenlc effects
have been reported 1n rats and mice (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.,
1982; Onda et al., 1974; Nlkonorow et al., 1973). Studies conducted by NTP
(Wolkowsk1-Tyl et al., 1984a,b) Indicate that mice are more sensitive to
b1s(2-ethylhexyl) phthalate than rats. The studies that show effects at the
lowest level of exposure and 1n the absence of maternal toxldty report a
0066h -15- 10/28/87
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significantly Increased Incidence of malformed fetuses/litter In CD-I mice
whose dams were fed 91 mg/kg/day throughout gestation (Wolkowsk1-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 (Tomlta
et al., 1982); and the formation of renal cysts 1n the FI and F? genera-
tions of mice exposed orally (not otherwise specified) to 10 or 100 mg/kg/
day for 3 generations (Onda et al., 1974) (no other details were provided).
The decreased fetal body weights observed by Tomlta et al. (1982) were not
observed In ICR or CD-I mice treated at somewhat higher (0.05% diet or -65
mg/kg/day) or lower (44 mg/kg/day) doses throughout gestation (Wolkowsk1-Tyl
et al., 1984b; Shlota et al., 1980; Shlota and Nlshlmura, 1982). The study
conducted by Wolkowsk1-Tyl et al. (1984b) provided a NOEL of 44 mg/kg/day
and a LOAEL of 91 mg/kg/day for b1s(2-ethylhexyl) phthalate-promoted terato-
genlc effects.
Plasterer et al. (1985) reported that dimethyl phthalate had no effects
on reproduction 1n CD-I mice. Groups of 50 female mice were gavaged with 0
or the HTD (3500 mg/kg/day) of dimethyl phthalate 1n 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, 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 Shlota and Nlshlmura (1982) reported terato-
genlc effects and resorptlons In mice caused by dl-n-butyl phthalate, but
only at a dietary concentration (IX) that also produced a significant
depression of maternal weight gain. Dietary levels tested were 0, 0.05,
0.1, 0.2, 0.4 and l.n%, corresponding to Intakes of 0, 80, 180, 370, 660 and
2100 mg/kg/day. No serious effects on the fetuses or dams were observed 1n
0066h -16- 10/28/87
-------
mice fed <0.4X d1-n-butyl phthalate throughout gestation. Coccygeal ossifi-
cation was retarded In all treated groups. In a 3-generat1on study, Onda et
al. (1974) observed renal cyst formation In the F, and F_ generations of
mice exposed orally (not otherwise specified) to 10 or 100 mg dl-n-butyl
phthalate/kg/day, but no other details were given. An Increased number of
resorptlons and significantly reduced fetal body weights were observed In
rats gavaged with 600 mg d1-n-butyl phthalate/kg/day throughout gestation
(Nlkonorow et al., 1973); reduced placenta! weights were observed In mice
gavaged with 120 or 600 mg d1-n-butyl phthalate/kg/day. This study,
however, did not randomly select test animals and the animals were not
examined for gross or visceral malformations.
A recent study Indicated 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 b1s(2-ethylhexyl) phthalate/kg throughout lactation.
NTP recently conducted reproduction and fertility assessments on CD-I
mice for dlethyl phthalate (Reel et al., 1984) and d1-n-octyl phthalate
(Gulatl et al., 1985) by using the "fertility assessment by continuous
breeding" protocol, which consists of four tasks: 1) a range-finding study
to determine MTD; 2) a continuous breeding study entailing exposure during 7
days before mating, 98 days of cohabitation and 21 days of segregation; 3) a
cross-over breeding study to determine the affected sex; and 4) a reproduc-
tive performance assessment of control and high-dose Utters from Task 2.
Task 3 Is performed only If adverse effects are detected 1n Task 2. If no
adverse effects are detected 1n Task 2, then Task 4 Is performed.
0066h -17- 10/28/87
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Based on the range-finding studies, dietary concentrations of 0, 0.25,
1.25 and 2.5X dlethyl phthalate and 0, 1.25, 2.5 and 5X d1-n-octyl phthalate
were chosen for Task 2. No adverse compound-related effects (number of
pairs able to produce at least one Utter, number of Utters/pair, propor-
tion of pups born alive, sex of pups born alive, live pup weight) were
observed for either dlethyl phthalate or d1-n-octyl phthalate; therefore,
Task 4 was performed for both compounds. Endpolnts monitored for Task 4
Included body weight at weaning and at 74 days of age, mating behavior,
reproductive performance as measured 1n 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 dlethyl phthalate had significantly lower body
weights than controls at weaning and at 74 days of age. The dlethyl
phthalate-exposed F, mice had significantly fewer live pups per Utter
than did controls. Hales had significantly reduced sperm concentrations and
significantly Increased prostate weights 1n 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
b1s(2-ethylhexyl) phthalate (up to 0.4%). Significantly Increased relative
kidney and liver weights, however, were observed 1n F. males and females
(Carpenter et al., 1953).
The testlcular effects of phthallc add esters have been studied exten-
sively In rats. Orally administered b1s(2-ethylhexyl) ph halate, dl-n-butyl
phthalate and butyl benzyl phthalate cause testlcular atrophy characterized
0066h -18- 10/28/87
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in general by reduced testlcular weight, hlstologlcal evidence of degenera-
tion, reduced testlcular zinc concentration and either an Increase or
decrease In testlcular testosterone concentration {Gray et al., 1977, 1982;
Gangolll, 1982; Olshl and Hlraga, 1980, 1983; Gray and Butterworth, 1980;
Mangham et al., 1981; Olshl, 1985; Agarwal et al., 1985; Cater et al., 1976,
1977; NTP, 1982a; Kluwe et al., 1982a). Cater et al. (1977) demonstrated
that co-administration of zinc could counteract the degenerative effects of
d1-n-butyl phthalate, while 01sh1 and Hlraga (1983) demonstrated that
co-administration of zinc had no effect on b1s(2-ethylhexyl) phthalate-
promoted atrophy. Furthermore, Gray and Butterworth (1980) demonstrated
that when exposure to b1s(2-ethylhexyl) phthalate was discontinued In rats,
testlcular weight and morphology were restored within 12-20 weeks; 01sh1
(1985) observed only slight recovery after 45 days. Equlmolar concentra-
tions of dimethyl phthalate, dlethyl phthalate and dl-n-octyl phthalate did
not cause testlcular atrophy 1n rats when administered orally for 4-10 days
(Gray and Butterworth, 1980; Foster et al., 1980).
Species differences In phthaHc acid ester-promoted testlcular atrophy
have also been observed. Gray et al. (1982) failed to observe testlcular
atrophy 1n hamsters gavaged with d1-n-butyl and b1s(2-ethylhexyl) phthalates
at equlmolar doses equivalent to those that caused atrophy In rats. In the
same study, mice gavaged with equlmolar doses of d1-n-butyl and b1s(2-ethyl-
hexyl) phthalates had only slight focal atrophy. B6C3F1 mice fed 6000 ppm
(1325 mg/kg/day) b1s(2-ethylhexyl) phthalate 1n the diet for 103 weeks had a
slight but significantly higher Incidence of seminiferous tubule atrophy
than controls (NTP, 1982a; Kluwe et al., 1982a).
3.3.2. Inhalation. Data pertaining to the teratogenlc or reproductive
effects In laboratory animals of Inhaled phthalates could not be located 1n
the available literature.
0066h -19- 10/28/87
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Aldyreva et al. (1974} reported an Increase 1n the Incidence of mis-
carriages and menstrual disorders among women exposed to phtha'late esters 1n
the synthetic leather Industry. Details concerning the exposed and control
populations were not given.
0066h -20- 10/28/87
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4. CARCINOGENICITY
4.1. HUNAN DATA
Data regarding the carclnogenlclty of phthalate esters In humans could
not be located 1n the available literature.
4.2. BIOASSAYS
4.2.1. Oral. B1s(2-ethylhexyl) and butyl benzyl phthalates have been
tested for oncogenlclty 1n NTP-dlrected feeding studies on rats and mice
(NTP, 1982a,b). HUbourn and Montesano (1982) reviewed other oral studies
on b1s{2-ethylhexyl) phthalate (Carpenter et al., 1953; Harris et al., 1955)
conducted before the NTP bloassays and concluded that they were Insufficient
to assess the carcinogenic potential of phthalate esters because of design
and reporting limitations; U.S. EPA (1985) concurred with this evaluation.
The NTP (1982a,b) studies, though not flawless, provided the only reasonable
tests of oncogenlclty.
Butyl benzyl phthalate at 0, 6000 or 12,000 ppm 1n the diet 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,
1982b). Control mice and female control rats were killed after 106 weeks of
testing; treated male rats and male controls were killed after 29 weeks; and
male and female mice and female rats exposed to butyl benzyl phthalate were
killed after 104-106 weeks. Endpolnts monitored Included body weight, food
consumption, mortality, clinical signs of toxlclty, and gross and micro-
scopic pathology. When treated animals were compared with controls, a
number of compound-related effects were observed. Increased mortality
associated with 'unexplained Internal hemorrhaglng" was observed In 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.
0066h -21- 08/24/87
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Survival curves were comparable for treated and control mice and female
rats. Reduced body weights were observed In 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 food consumption data were not reported for mice and male
rats. A statistically significant Increase (p=0.011, Fisher Exact test) 1n
mononuclear cell leukemia was observed 1n high-dose female rats (Table 4-1)
and was frequently accompanied by splenomegaly and hepatomegaly. A statis-
tically significant Increase 1n 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 4-1).
NTP (1982b) concluded that butyl benzyl phthalate was "probably carcino-
genic for female F344/N rats." In a separate report, Kluwe et al. (19825),
however, concluded that since the background Incidence of myelomonocytlc
leukemia Is normally high 1n F344/N rats (8-15X and 9-24% In females and
males, respectively), results presented In NTP (1982b) provide only
equivocal evidence of butyl benzyl phthalate-lnduced cancer In female rats.
Furthermore, the fact that significant and dose-related decreases In Inci-
dences of malignant lymphoma, all lymphoma, and lymphoma or leukemia were
observed In male mice contributes to the uncertainty that butyl benzyl
phthalate may cause leukemia 1n humans. IARC (1982a) concluded that the NTP
0066h -22- 08/24/87
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(1982b) studies were Insufficient to assess the carcinogenic potential of
butyl benzyl phthalate.
B1s(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 B6C3F1 mice at levels of 0, 3000 or 6000 ppm 1n the diet for 103
weeks (NTP, 1982a; Kluwe et al., 1982a). 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, mortality and clinical signs of
toxicH'y were monitored. Animals surviving 103 weeks on the test were main-
tained 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 In
b1s(2-ethylhexyl) phthalate-treated female mice, but was not accompanied by
a reduction 1n food consumption. Body weight was reduced moderately In low-
and high-dose male rats 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 4-2). A signifi-
cantly greater Incidence (Fisher Exact test) of hepatocellular carcinoma or
neoplastlc nodules was observed 1n high-dose male rats, middle- and hlgh-
0066h -24- 10/09/87
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-------
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 4-2). Significantly decreased Incidences of Interstitial
cell tumors of the testes, pituitary carcinoma or adenoma and thyroid C-cell
carcinoma or adenoma were also observed In high-dose male rats.
NTP (1982a), Kluwe et al. (1982a), U.S. EPA (1985) and IARC (1982b)
concluded that these results provide sufficient evidence of b1s(2-ethyl-
hexyl) phthalate-lnduced cardnogenlclty In rats and mice. This conclusion,
however, 1s disputed. Northrup et al. (1982) claim that the NTP (1982a)
results are equivocal since the HTD 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 1n humans because b1s(2-ethylhexyl) phthalate Is
metabolized differently In rats than In humans. In response, Kluwe et al.
(1983) noted that the HTO technically was not exceeded since there were no
compound-related effects on survival, the Incidence of liver tumors was
Increased In b1s(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 In rodents. More
recently, Turnbull and RodMcks (1985) concluded that using NTP (1982a) data
to estimate b1s(2-ethylhexyl) phthalate-lnduced carcinogenic risk to humans
will probably overestimate actual risk. This conclusion was based on the
differences between rodents and primates In the metabolism of b1s(2-ethyl-
hexyl) phthalate, a nonlinear relationship between the administered dose of
b1s(2-ethylhexyl) phthalate to the dose of the "proximate carcinogenic
species" 1n rodents, the fact that the "proximate carcinogenic species,"
which Is hypothesized to Induce cancer, Is produced to a greater extent In
0066h -26- 08/24/87
-------
rodents than In primates and that there are differences In target-site
sensitivity between humans and rodents for liver tumors In general.
Results of NTP (1982a,b) bloassays Indicate that b1s{2-ethylhexyl)
phthalate Is carcinogenic for B6C3F1 mice and F344 rats of both sexes, but
are Insufficient to assess the carcinogenic potential of butyl benzyl
phthalate. The relevance of these studies to the carcinogenic potential of
pthalate esters In humans Is questionable. Adequate cancer bloassays have
not been conducted for other pthalate esters.
4.2.2. Inhalation. Animal bloassays regarding the cardnogen1c1ty of
Inhaled phthalate esters could not be located In the available literature.
4.3. OTHER RELEVANT DATA
The mutagenldty and genotoxldty of phthallc add esters have been
reviewed by Thomas and Thomas (1984) and Hopkins (1983). B1s(2-ethylhexyl)
phthalate and Us metabolites have yielded mostly negative results 1n Ames
tests with S. typhlmurlum. and mixed results with _l£ vitro and In vivo tests
of genotoxldty. Dlethyl phthalate, dimethyl phthalate and dl-n-butyl
phthalate were found to be mutagenlc In \n_ vitro mlcroblal assays with S.
typhlmurlum (Kozumbo et al., 1982; Rubin et al., 1979; Seed, 1982).
4.4. WEIGHT OF EVIDENCE
In lifetime feeding studies conducted by NTP (1982a), b1s(2-ethylhexyl)
phthalate was shown to cause Increased Incidences of liver neoplasms In
F344/N rats (hepatocellular carcinoma, hepatocellular carcinoma or neoplas-
tlc nodules) and In B6C3F1 mice (hepatocellular carcinoma, hepatocellular
carcinoma or adenoma). Based on these results, IARC (1982b) concluded that
there 1s sufficient evidence that b1s(2-ethylhexyl) phthalate 1s carcino-
genic for rats and mice. No human studies were available for evaluation.
0066h -27- 08/24/87
-------
Using the IARC ranking scheme, b1s{2-ethylhexyl) phthalate can be classified
as a Group 26 compound. Using the EPA scheme, this compound can be classi-
fied as a B2 chemical meaning there Is sufficient animal evidence and thus
1s probably carcinogenic In humans (U.S. EPA, 1986b).
Butyl benzyl phthalate has also been tested for oncogenlclty 1n feeding
studies on F344/N rats and B6C3F1 mice (NTP, 1982a,b) (see Table 4-1).
Based on the observation of Increased Incidences of mononuclear cell
leukemia and leukemia or lymphoma In female rats, NTP (1982b) concluded that
butyl benzyl phthalate was "probably carcinogenic for female F344/N rats."
In a separate report, however, Kluwe et al. (1982b) concluded that since the
background Incidence of myelomonocytlc leukemia Is normally high 1n F344/N
rats, results presented 1n NTP (1982b) provide only equivocal evidence of
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, 1982b)
adds to the uncertainty that butyl benzyl phthalate may cause cancer 1n
humans. IARC (1982a) concluded that the NTP (1982b) studies are Insuffi-
cient to assess the carcinogenic potential of butyl benzyl phthalate.
A recent review of the available data by the Carcinogen Assessment Group
has concluded that based upon EPA criteria butyl benzyl phthalate 1s appro-
priately classified as a Group C, possible human carcinogen.
Other phthalate esters have not been tested for oncogenlclty. There-
fore, these compounds are best classified as IARC Group 3 and EPA Group D
meaning that there Is Inadequate data to assess the carcinogenic potential.
0066h -28- 10/28/87
-------
5. REGULATORY STANDARDS AND CRITERIA
ADIs have been derived for b1s(2-ethylhexyl) phthalate, dimethyl phtha-
late, dlethyl phthalate and d1-n-butyl phthalate. These are summarized In
Table 5-1.
U.S. EPA (1980a) calculated ambient water quality criteria for several
of the phthalates, based on contributions from drinking water and consump-
tion of 6.5 g of fish/day. Based on an ADI of 700 mg/day (10 mg/kg/day)
from the 2-year rat study by Lehman (1955), a water quality criterion of 313
mg/l was calculated for dimethyl phthalate. For dlethyl phthalate, a
criterion of 350 mg/l was calculated, based on the ADI of 875 mg/day (13
mg/kg/day) from the rat study by Food Research Labs (1955). A water quality
criterion of 34 mg/l for d1-n-butyl phthalate was based on the ADI of 8.8
mg/day Incorrectly reported as 88 mg/day In U.S. EPA (1980a); the ADI was
based on a NOAEL of 125 mg/kg/day from the 52-week study In rats by Smith
(1953).
U.S. EPA (1982) derived a human q^ for b1s(2-ethylhexyl) phthalate of
1.41xlO~2 (mg/kg/day)'1 based on the Incidence of hepatocellular
adenomas and carcinomas In male mice 1n the NTP (1980) draft of the chronic
cancer study. Water quality criteria of 17.5, 1.75 and 0.175 yg/l were
calculated based on consumption of water and fish that may result 1n
estimated Increased cancer risk levels of 10~5, 10~6 and 10~7, respec-
tively.
0066h -29- 08/26/87
-------
TABLE 5-1
ADIs for Phthalate Esters
Ester
b1s(2-Ethylhexyl)
Dlethyl
AOI
(mg/kg/day)
0.02
13
Dose
(mg/kg/day)
LOAEL = 19
NOEL = 1250
Species
guinea
pig
rat
Reference
Carpenter
et al., 1953
Food Research
Dl-n-butyl
Dimethyl
0.1
10
NOAEL = 125 rat
NOEL = 1000 rat
Labs, 1955;
U.S. EPA,
1980a
Smith, 1953;
U.S. EPA,
1980a
Lehman, 1955*;
U.S. EPA,
1980a
*Incorrectly attributed to Dralze et al. (1948) 1n U.S. EPA (1980a)
0066h
-30-
10/28/87
-------
6. RISK ASSESSMENT
Risk assessment for phthalate esters should be performed on a compound-
by-compound basis, since not all the esters produce the same effects. For
example, b1s(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.
Quantitative criteria for phthalate esters are summarized In Tables 6-1
through 6-6.
6.1. SUBCHRONIC REFERENCE DOSE (RfD.)
*)
6.1.1. Oral (RfDSQ).
6.1.1.1. BIS(2-ETHYLHEXYL) PHTHALATE -- It 1s Inappropriate to derive
an RfOcn for b1s(2-ethylhexyl) phthalate because It has been shown to
oU
cause Hver tumors 1n F344 rats and B6C3F1 mice (NTP, 1982a).
6.1.1.2. DIETHYL PHTHALATE -- Brown et al. (1978) conducted the only
subchronlc study on dlethyl phthalate that yielded adverse effects. Groups
of 15 male and 15 female CD rats were fed diets containing 0, 0.2, 1.0 or 5%
dlethyl phthalate {0, 150, 770 or 3160 mg/kg/day, males; 0, 150, 750 or 3710
mg/kg/day, females) for 16 weeks. Terminal body weights of male and female
rats fed 5% dlethyl phthalate were reduced significantly 1n comparison with
controls. Although slight but significant changes were seen In females at
the IX level, the use of multiple T tests for the comparisons (without
correction) and the small magnitude of the changes suggests that the 1%
feeding level (750 mg/kg/day) represents a NOAEL 1n this study and could be
used 1n the derivation of an RfD... In a 2-year study on rats (Food
Research Labs, 1955) significant reduction In body weight was observed In
0066h -31- 08/26/87
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0066h
-36-
08/26/87
-------
TABLE 6-6
Summary Table for D1-n-octyl Phthalatea>b
Oral
Species
Experimental
Exposure/Dose
Effect
RfD or CS
RfD$o rat 3500 ppm diet
for 7-12 months
(175 mg/kg/day)
RfDo rat 3500 ppm diet
for 7-12 months
(175 mg/kg/day)
Maximum CS rat 3500 ppm diet
for 7-12 months
(175 mg/kg/day)
(RVd=l)
Increased SGPT
and SGOT; In-
creased liver and
kidney weights
Increased SGPT
and SGOT; In-
creased liver and
kidney weights
Increased SGPT
and SGOT; In-
creased liver
and kidney
we1ghts(RVe=6)
NO
NO
aSource: Plekacz, 1971
bOnly oral data were available.
NO = Not determined
0066h
-37-
08/26/87
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rats fed 5X dlethyl phthalate but not In rats fed <2.5X. Deficiencies In
the reporting of the Food Research Study, however, reduce confidence 1n the
use of these data. Therefore, the NOAEL of 750 mg/kg/day Is chosen as the
basis for the RfOso- Applying an uncertainty factor of 10 for Inter-
species extrapolation and 10 for 1nter1nd1v1dual variability results In an
RfD_Q of 8 mg/kg/day or 525 mg/day.
6.1.1.3. DI-n-BUTYL PHTHALATE U.S. EPA (1980a) derived an ADI of
0.1 mg/kg/day based on a 52-week oral rat NOAEL of 125 mg/kg/day (Smith,
1953) and an uncertainty factor of 1000. A higher dose (1.25X 1n the diet
or 625 mg/kg/day) caused 50% mortality within 1 week of the Initial exposure
(Smith, 1953).
Onda et al. (1974) observed the formation of renal cysts In the F, and
Fp generations of mice exposed orally to either 10 or 100 mg/kg/day for 3
generations. These doses are below the NOAEL used by U.S. EPA (1980a) to
derive the ADI for d1-n-butyl phthalate. Since no details of the Onda et
al. (1974) study were reported, 1t was not considered 1n risk assessment.
When 0.12 or 0.6 mg/kg/day (120 or 600 mg/kg) d1-n-butyl phthalate was
administered to rats by gavage during gestation, an Increased number of
resorptlons and reduced fetal body weight were observed at the 600 mg/kg
dose (Nlkonorow et al., 1973). No gross skeletal effects were observed.
Maternal toxlclty was not reported, but significantly reduced placental
weights were observed at both doses. Since there were no effects on repro-
ductive or fetal endpolnts In rats exposed to 120 mg/kg/day, the reduced
placental weight probably represents a NOAEL. The LOAEL for this study (600
mg/kg/day) 1s well above the NOAEL (125 mg/kg/day) used to derive the ADI.
0066h -38- 10/28/87
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Shlota et al. (1980) and Shlota and N1sh1mura (1982) observed maternal
toxlclty, fetotoxIcHy and gross external malformations In mice fed 1%
d1-n-butyl phthalate 1n the diet (2100 mg/kg/day, as provided by the
Investigators) 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 Mb varia-
tions or delayed sternal ossification. Doses <660 mg/kg/day would therefore
represent NOAELs for this study and 2100 mg/kg/day represents a PEL.
D1-n-butyl phthalate has been shown to cause testlcular atrophy 1n rats, but
only at doses greater than the NOAEL (123 mg/kg/day) used to derive the ADI
(Cater et al., 1976, 1977; Gray et al., 1982; Gray and Butterworth, 1980).
The RfD-g for dl-n-butyl phthalate can therefore be based on the rat NOAEL
of 123 mg/kg/day defined by Smith (1953). Dividing 125 mg/kg/day by an
uncertainty factor of 100 (10 for differences In sensitivity among humans;
10 for Interspedes extrapolation) yields an RfD-0 of 1.25 mg/kg/day or 88
mg/day for a 70 kg human.
6.1.1.4. DIMETHYL PHTHALATE -- Studies pertaining to the subchronlc
toxlclty of dimethyl phthalate could not be located In the available
literature.
6.1.1.5. BUTYL BENZYL PHTHALATE -- Butyl benzyl phthalate has been
tested for oncogenlclty 1n feeding studies on F344 rats and 86C3F1 mice
(NTP, 1982b). Statistically significant Increases In the Incidences of
mononuclear cell leukemia and leukemia or lymphoma were observed In female
rats. However, because of the naturally high background Incidence of myelo-
monocytlc leukemia In F344 rats, and because dose-related and significant
decreases 1n malignant lymphoma, all lymphoma and leukemia or lymphoma were
0066h -39- 10/09/87
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observed In male mice 1n the same study, there Is limited evidence to con-
clude that butyl benzyl phthalate 1s carcinogenic. IARC (1982a) concluded
that the NTP (1982b) studies are Insufficient to assess the carcinogenic
potential of butyl benzyl phthalate. It 1s not appropriate to derive a
q * for butyl benzyl phthalate until further testing 1s performed. Butyl
benzyl phthalate has been classified as a Group C, possible human carcino-
gen, using the EPA welght-of-evidence criteria.
Increased mortality that was due to unexplained hemorrhaglng was
observed 1n male F344 rats fed 6000 or 12,000 ppm butyl benzyl phthalate
(300 or 600 mg/kg/day, using a food factor of 0.05) {NTP, 1982b). 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 2X (0, 125, 250,
500, 750 or 1000 mg/kg/day) butyl benzyl phthalate and dogs were fed 0, 1, 2
or 5% (0, 250, 500 or 1250 mg/kg/day) butyl benzyl phthalate. No adverse
effects were observed among dogs fed butyl benzyl phthalate at any level, or
among rats fed 125 or 250 mg/kg/day butyl benzyl phthalate. Dietary concen-
trations of 2.5 or 5% have been shown to cause testlcular atrophy In 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, 0.83X and 2.5X butyl benzyl phthalate. Using data presented In the
report, these dietary levels correspond to ~0, 17, 51, 159, 470 and 2875
mg/kg/day. At 2.5X, 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 Hver-
to-bra1n weight ratios and Increases 1n mean corpuscular hemoglobin.
0066h -40- 10/09/87
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Using the NOEL (0.28%) of 159 mg/kg/day and applying an uncertainty
factor of 100, an RfDSQ of 111 nig/day could be developed; however, this
value would not be protective for potential carcinogenic effects of this
compound.
6.1.1.6. DI-n-OCTYL PHTHALATE The only available toxldty study on
d1-n-octyl phthalate was reported 1n an abstract by Plekacz (1971), In which
Wlstar rats were given either 0 or 3500 ppm d1-n-octyl phthalate In the diet
for 7-12 months. Assuming that a rat consumes the equivalent of 5% of Us
weight In food/day, 3500 ppm corresponds 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. In rats, d1-n-octyl phthalate did not cause
testlcular atrophy when given orally at a dose equlmolar to that at which
b1s(2-ethylhexyl) phthalate caused testlcular atrophy (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 5% (12,500-50,000 ppm) dl-n-octyl phthalate In the diet (Gulatl et al.,
1985). Inadequate data are presented In the abstract to support RfDSQ
estimation.
6.1.2. Inhalation (RfDSI). Subchronlc or chronic Inhalation studies on
phthalate esters could not be located 1n the available literature. There-
fore, It 1s not possible to derive RfDSI values.
6.2. REFERENCE DOSE (RfO)
6.2.1. Oral (RfOQ).
6.2.1.1. BIS(2-ETHYLHEXYL) PHTHALATE -- Since b1s(2-ethylhexyl)
phthalate was found to cause liver tumors In F344 rats and B6C3F1 mice {NTP,
1982a), It Is Inappropriate to derive an RfO. or a CS for chronic toxldty.
0066h -41- 08/26/87
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6.2.1.2. OIETHYL PHTHALATE Only two chronic studies were available
for use In the derivation of an RfDQ and a CS for dlethyl phthalate.
U.S. EPA (1980a) derived an ADI of 13 mg/kg/day for dlethyl phthalate
based on a chronic oral rat NOEL of 1250 mg/kg/day (2.5% diet) {Food
Research Labs, 1955) and an uncertainty factor of 100. Higher doses (5%
diet) caused a reduction In body weight. A 2-generat1on reproduction study
by Reel et al. (1984) demonstrated that F, but not parental mice exposed
to 2.5X 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) In comparison
with controls. Assuming that mice consume food equivalent to 13% of their
body weight/day, 2.5X 1s equivalent to 3250 mg/kg/day, a.value well above
the NOEL (1250 mg/kg/day) used to derive the ADI. Dlethyl phthalate did not
cause testlcular atrophy In rats (Gray and Butterworth, 1980; Foster et al.,
1980).
Although In general H 1s preferable to utilize chronic data over
subchronlc data for RfD development, deficiencies 1n reporting of the Food
Research study reduce confidence 1n the data. Therefore, the subchronlc
study of Brown et al. (1978) 1s chosen as the basis of the RfDQ. 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 Inter-
species variability and 10 for 1nter1nd1v1dual variability) results In an
RfDQ of 0.75 mg/kg/day, or 52.5 mg/day for a 70 kg human.
The highest CS carv be derived from the study of Reel et al. (1984) on
the basis of the adverse reproductive effects "bserved among mice exposed to
2.5X dlethyl phthalate 1n the diet. Assuming that a mouse consumes food
0066h -42- 08/26/87
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equivalent to 13% of Us body weight/day, 2.5X Is equivalent to a dose of
3250 mg/kg/day. Multiplying 3250 mg/kg/day by the cube root of the ratio of
the reference mouse weight (0.03 kg) to reference 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 of 1. An RV of 8 1s assigned on the basis of
reduced reproductive capacity. Multiplying the RV by the RV yields a
CS of 8. U.S. EPA (1983b) derived an RQ of 5000 based on the 2-year study
by Food Research Labs (1955), In which rats had significantly reduced body
weight gain (RVg=4) at a dietary level of 5% (2500 mg/kg/day; MED=29,925;
RV.=1). The resulting CS 1s 4. The reproduction study by Reel et al.
(1984) was not available during the preparation of the previous RQ document
(U.S. EPA, 1983b).
6.2.1.3. DI-n-BUTYL PHTHALATE -- No effects were observed In chronic
studies on the toxldty of d1-n-butyl phthalate In rats (LeFaux, 1968).
Because these chronic studies failed to define a threshold for toxldty, an
RfDQ for d1-n-butyl phthalate can be based on the subchronlc study by
Smith (1953) using rats. A higher dose (1.25X diet or 625 mg/kg/day) caused
50% mortality within 1 week of administration (Smith, 1953). An RfD of 0.12
mg/kg/day can be derived by dividing the NOAEL of 125 mg/kg/day by an
uncertainty factor of 1000 (10 for Interspedes extrapolation; 10 for using
a subchronlc study to estimate chronic toxldty; 10 for differences 1n
sensitivity among humans). This RfD, equivalent to 8.6 mg/day for a 70 kg
human, Is adopted as the RfOQ for d1-n-butyl phthalate. However, It 1s
noted that the study has a number of deficiencies.
There are a number of studies from which CSs for d1-n-butyl phthalate
can be derived. The most severe effects were the fetotoxldty,
teratogenldty and maternal toxldty 1n mice exposed orally to 2100 mg
0066h -43- 10/28/87
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d1-n-butyl phthalate/kg/day (Shlota and Nlshlmura, 1982; Shlota et al.t
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 reference human weight (70 kg), and by the human weight (70 kg)
yields a human MED of 11,083 mg/day, which corresponds to an RV. of 1.
Multiplying the RVg by the RVd yields a CS of 9.
Shlota et al. (1980) and Shlota and Nlshlmura (1982) also observed
significantly reduced numbers of ossified coccyges at all levels of treat-
ment (80, 180, 370, 660 or 2100 mg/kg/day), but there were no significant
differences between controls and treated mice 1n Incidences of skeletal
malformations, lumbar rib 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. The corresponding MED for this
dose level Is 420 mg/day; the RV. 1s 1.6. An RV of 8 1s appropriate
for fetotoxldty resulting In a CS of 12.8.
6.2.1.4. DIMETHYL PHTHALATE -- U.S. EPA (1980a) derived an ADI 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 offspring were observed 1n mice gavagecl with dimethyl
phthalate (3500 mg/kg) on days 7-15 of gestation (Booth et al., 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 b1s(2-ethylhexyl)
phthalate caused testlcular atrophy 1n rats (Gray and Butterworth, 1980;
Foster et al., 1980). A revaluation of the Lehman (1955) study suggests
0066h -44- 10/28/87
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that the data, as presented In this paper, Is Inadequate for development of
an RfD_.
Lehman (1955) observed chronic nephritis (RVe=7) In rats fed 8%
dimethyl phthalate and decreased body weight (RVg=4) In rats fed 4%
dimethyl phthalate for 2 years. Assuming that a rat consumes 5X of Its
weight In food per day, 8% Is equivalent to a dose of 4000 mg/kg/day and 4%
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 by human weight (70 kg) yields human MEDs
of 23,940 and 47,879 mg/day, respectively. Both MEOs correspond to RV.s
of 1. Multiplying the RVrf by the RV s of 4 and 7 yields CSs of 4 and 7,
respectively.
6.2.1.5. BUTYL BENZYL PHTHALATE -- The only chronic studies on butyl
benzyl phthalate are the oncogenlclty studies by NTP (1982b) on F344 rats
and B6C3F1 mice. Female rats received 0, 6000 or 12,000 ppm and mice of
both sexes received 0, 3000 or 6000 ppm for 103 weeks. Male rats also
received 0, 6000 or 12,000 ppm but the study was terminated after 28 weeks
because of high, dose-related mortality among treated rats. Mortality was
attributed to unexplained hemorrhaglng. The only other noncarclnogenlc
effect was reduction In growth rate among all treated mice and treated
female rats, although the reduction In growth among female rats was accom-
panied by reduced food consumption. Data on food consumption were not
reported for mice. Since these data do not provide a clear NOAEL or LOAEL,
this experiment 1s not suitable for risk assessment and It 1s best to derive
the RfDg from the subchronlc data used to derive the RfDSQ. An RfDQ
of 11.1 mg/day could be proposed based upon the NOEL of 159 mg/kg/day
(0.28%) from the NTP (1985) study by applying an additional uncertainty
factor of 10 to the RfnSQ, which Is described In Section 6.1.1.5.
0066h -45- 10/28/87
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However, this estimate would not be protective for potential carcinogenic
effects of butyl benzyl phthalate.
The highest CS for butyl benzyl phthalate 1s based on early dose-related
mortality among male F344 rats fed 6000 or 12,000 ppm for 28 weeks (NTP,
1982b). In the subchronlc study by Monsanto (1972), the only effect In rats
treated for 90 days was Increased liver weight at concentrations >10,000
ppm; the only effect In dogs was decreased Initial growth at 50,000 ppm
because of their refusal to eat. There were no other studies available that
could be considered In the derivation of a CS for butyl benzyl phthalate.
Since there 1s no explanation why compound-related early mortality was
observed among male rats In the NTP (1982b) study but not In the Monsanto
(1972) study, a CS Is derived on the basis of mortality among male rats fed
6000 ppm for 28 days. Assuming that a rat consumes food equivalent to 5% of
Us body weight/day, 6000 ppm Is equivalent to 300 mg/kg/day. Multiplying
300 mg/kg/day by the cube root of the ratio of rat weight (0.375 kg 1n the
study) to human weight (70 kg) and by the human weight (70 kg) yields an
equivalent 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
RVd by the RVg of 10 for mortality results 1n a CS of 17.
6.2.1.6. DI-n-OCTYL PHTHALATE -- Chronic studies on the toxlclty of
dl-n-octyl phthalate could not be located In the available literature. One
abstract of a subchronlc study (described In Section 6.1.1.6.) was located.
However, Inadequate data were presented to allow RfOQ development.
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 dl-n-octyl phthalate. Assuming that a rat con-
0066h -46- 10/28/87
-------
sumes food equivalent to 5X of Us body weight/day, 3500 ppm 1s equivalent
to a 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 1s assigned on the basis of the above effects.
d e
Multiplying the RVrf by the RVg yields a CS of 6.
6.2.2. Inhalation. Data pertaining to the toxldty of Inhaled phthalate
esters could not be located In the available literature.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. Evidence of oncogenk potential sufficient for computation
of carcinogenic potency has been generated only for b1s(2-ethylhexyl)
phthalate (NTP, 1982a).
Using data from NTP (1982a), q *s can be derived for combined hepato-
cellular carcinoma and neoplastlc nodules In rats, and combined hepatocellu-
lar carcinoma and adenoma 1n mice using the computerized multistage model
developed by Howe and Crump (1982). The highest value, an adjusted human
Interim q * of 8.36xlO~3 (mg/kg/day)'1 was obtained from data on male
mice (Table 6-7). Turnbull and RodMcks (1985) have cautioned that using
rodent data to estimate b1s(2-ethylhexyl) phthalate-promoted carcinogenic
risk to humans may overestimate the actual risk. This caution was based on
several factors Including differences between rodents and primates 1n the
metabolism of b1s(2-ethylhexyl) phthalate, a nonlinear relationship between
the administered dose of b1s(2-ethylhexyl) phthalate and the dose of the
hypothesized "proximate carcinogenic species" 1n rodents, the fact that the
hypothesized proximate carcinogenic species Is produced to a greater extent
In rodents than In primates, and differences In target site sensitivities
between humans and rodents for liver tumors In general. These factors have
not yet been evaluated by the EPA. As a result, the proposed Interim q *
0066h -47- 10/28/87
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TABLE 6-7
Cancer Data Sheet for Derivation of q-|*
Compound: b1s(2-ethylhexy1) phthalate
Reference: NTP, 1982a
Species, strain/sex: mouse, B6C3F1, male
Body weight: 0.04 kg (measured)
Length of exposure (1e) = 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 Transformed Dose& Incidence
or Exposures3 (mg/kg/day) No. Responding/No. Examined
(mg/kg/day)
0 0 14/50
672 54.70 25/48
1325 108.89 29/50
aThe mice were given 3000 or 6000 ppm 1n the diet; the doses 1n 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 = mouse body weight
Unadjusted q-j* from study = not calculated (see text)
Human q-j* « 8.36x10~3 (mg/kg/day)'1
0066h -48- 08/26/87
-------
value may be revised at a later date. D1(2-ethy1hexyl)phthalate Is a Group
B2 carcinogen using the U.S. EPA welght-of-evidence approach, meaning that
there are sufficient animal data and the compound Is considered a probable
human carcinogen.
NTP (1982b) conducted cancer bloassays of butyl benzl phthalate 1n both
F344/N rats and B6C3F1 mice. No treatment related Increases In Incidence of
either neoplastlc or non-neoplastlc lesions were noted In either sex of mice.
In rats, Increased mortality due to "unexplained Internal hemorrhage"
was observed In treated males beginning at the 14th treatment week. This
portion of the study was terminated after 28 weeks. Female rats showed
Increased Incidence of mononuclear cell leukemia and leukemia or lymphoma at
the high dose (1200 ppm). Since the background Incidence of leukemia 1s
normally high 1n F344/N rats, and because decreases In Incidence of
malignant lymphoma, all lymphoma or leukemia were seen In male mice this was
considered to be equivocal evidence of carclnogenldty. Butyl benzyl
phthalate 1s considered a Group C, possible human carcinogen using the U.S.
EPA we1ght-of-ev1dence classification system. Data were considered
Inadequate for quantitative risk assessment.
6.3.2. Inhalation. The oncogenldty of Inhaled phthalate esters has not
been tested.
0066h -49- 10/28/87
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7. REFERENCES
A.D. Little, Inc. 1984. DEHP Metabolism Studies. Protocol II. Species
difference 1n the metabolism of a single oral dose of DEHP. OTS 4(e)
submission. Microfiche No. 0508494.
Agarwal, O.K., R.R. Haronpot, J.C. Lamb, IV and W.M. Kluwe. 1985. Adverse
effects of butyl benzyl phthalate on the reproductive and hematopoletlc
systems of male rats. Toxicology. 35(3): 189-206.
Albro, P.W. and R.O. Thomas. 1973. Enzymlc hydrolysis of d1(2-ethylhexyl)
phthalate by Upases. Blochem. Blophys. Acta. 306(3): 380-390.
Aldyreva, M.V., A.S. Izyumova and L.A. T1moflevskaya. 1974. Occupational
hygiene and effect of phthalate plastldzers on workers In the synthetic
leather Industry. Gig. Tr. Sostoyanle Spetslf1chesk1kh Funkts. Rab.
Neftekhlm. Khlm. Prom-st1. p. 154-159.
Atlas, E. and C.S. Glam. 1981. Global transport of organic pollutants:
Ambient concentrations In the remote marine atmosphere. Science. 211:
163-165.
Bell, F.P. 1980. Effect of d1-2-ethylhexyl phthalate 1n the female rat:
Inhibition of hepatic and adrenal sterologenesls In vitro. Bull. Environ.
Contam. Toxlcol. 24(1): 54-58.
0066h -50- 10/28/87
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Bell, P.P., M. Makovske, D. Schneider and C.S. Patt. 1979. Inhibition of
sterologenesls In brain and liver of fetal and suckling rats from dams fed
by dl-2-ethylhexyl phthalate plastldzer. L1p1ds. 14(4): 372-377.
Booth, G.M., W.S. Bradshaw and M.H. Carter. 1983. Screening of priority
chemicals for potential reproductive hazard. Prepared for NIOSH, Cincin-
nati, OH. PB 213 017. p. 104.
Bornmann, G., et al. 1956. Behavior of the organism as Influenced by
various plastldzers. Z. Lebens-Unters. Folsch. 103: 413-424.
Brown, D., K.R. Butterworth, I.F. Gaunt, P. Grasso and S.D. Gangolll. 1978.
Short-term oral toxldty study of dlethyl phthalate In the rat. Food
Cosmet. Toxlcol. 16: 415-478.
Callahan, M.A., H.W. Sllmak, N.W. Gabel, et al. 1979. Fate of 129 Priority
Pollutants. Vol. II. Office of Water Planning and Standards. U.S. EPA,
Washington, DC. (December), p. (94)1-28.
Carpenter, G.P., C.S. Well and H.F. Smyth, Jr. 1953. Chronic oral toxldty
of d1(2-ethylhexyl) phthalate for rats, guinea pigs and dogs. J. Ind. Hyg.
Occup. Med. p. 219-226.
Carter, J.E., D.B. Ball and R.V. Petersen. 1974. The \n_ vitro hydrolysis
of d1-(2-ethylhexyl) phthalate by rat tissues. Drug Metab. DIsposH. 2(4):
341-344.
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