SEPA
EPA/690/R-20/007F | September 2020 | FINAL
United States
Environmental Protection
Agency
Provisional Peer-Reviewed Toxicity Values for
p-Phthalic Acid
(Terephthalic Acid)
(CASRN 100-21-0)
supERFUND
U.S. EPA Office of Research and Development
Center for Public Health and Environmental Assessment
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A ¦""¦"Mfc United States
environmental Protection
LbI M * Agency
EPA/690/R-20/007F
September 2020
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
p-Phthalic Acid
(Terephthalic Acid)
(CASRN 100-21-0)
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
ii
/;-Phthalic acid
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AUTHOR, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Daniel D. Petersen, MS, PhD, DABT, ATS, ERT, MRSB
Center for Public Health and Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
CONTRIBUTOR
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
PRIMARY INTERNAL REVIEWERS
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
Laura Carlson, PhD
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
This document was externally peer reviewed under contract to:
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA
Office of Research and Development (ORD) CPHEA website at
https://www.epa.gov/pprtv/forms/contact-us-about-pprtvs.
in
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 2
QUESTIONS REGARDING PPRTVs 2
INTRODUCTION 3
METHODS 6
Literature Search 6
Screening Process 6
LITERATURE SEARCH AND SCREENING RESULTS 7
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 9
HUMAN STUDIES 17
Oral Exposures 17
Inhalation Exposures 17
ANIMAL STUDIES 18
Oral Exposures 18
Inhalation Exposures 35
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 37
Genotoxicity Studies 37
Supporting Toxicity Studies 41
Absorption, Distribution, Metabolism, and Excretion Studies 50
Mode-of-Action/Mechanistic Studies 51
DERIVATION 01 PROVISIONAL VALUES 52
DERIVATION OF PROVISIONAL ORAL REFERENCE DOSES 52
Derivation of a Subchronic Provisional Reference Dose 52
Derivation of a Chronic Provisional Reference Dose 54
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 56
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 57
MODE-OF -ACTION DISCISSION 59
DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES 60
APPENDIX A. LITERATURE SEARCH STRATEGY 62
APPENDIX B. DETAILED PECO CRITERIA 64
APPENDIX C. SCREENING PROVISIONAL VALUES 65
APPENDIX D. DATA TABLES 68
APPENDIX E. BENCHMARK DOSE MODELING RESULTS 106
APPENDIX F. REFERENCES 125
iv
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
IVF
in vitro fertilization
ACGIH
American Conference of Governmental
LC50
median lethal concentration
Industrial Hygienists
LD50
median lethal dose
AIC
Akaike's information criterion
LOAEL
lowest-observed-adverse-effect level
ALD
approximate lethal dosage
MN
micronuclei
ALT
alanine aminotransferase
MNPCE
micronucleated polychromatic
AR
androgen receptor
erythrocyte
AST
aspartate aminotransferase
MOA
mode of action
atm
atmosphere
MTD
maximum tolerated dose
ATSDR
Agency for Toxic Substances and
NAG
7V-acetyl-P-D-glucosaminidase
Disease Registry
NCI
National Cancer Institute
BMC
benchmark concentration
NO A F.I.
no-observed-adverse-effect level
BMCL
benchmark concentration lower
NTP
National Toxicology Program
confidence limit
NZW
New Zealand White (rabbit breed)
BMD
benchmark dose
OCT
ornithine carbamoyl transferase
BMDL
benchmark dose lower confidence limit
ORD
Office of Research and Development
BMDS
Benchmark Dose Software
PBPK
physiologically based pharmacokinetic
BMR
benchmark response
PCNA
proliferating cell nuclear antigen
BUN
blood urea nitrogen
PND
postnatal day
BW
body weight
POD
point of departure
CA
chromosomal aberration
PODadj
duration-adjusted POD
CAS
Chemical Abstracts Service
QSAR
quantitative structure-activity
CASRN
Chemical Abstracts Service registry
relationship
number
RBC
red blood cell
CBI
covalent binding index
RDS
replicative DNA synthesis
CHO
Chinese hamster ovary (cell line cells)
RfC
inhalation reference concentration
CL
confidence limit
RfD
oral reference dose
CNS
central nervous system
RGDR
regional gas dose ratio
CPHEA
Center for Public Health and
RNA
ribonucleic acid
Environmental Assessment
SAR
structure activity relationship
CPN
chronic progressive nephropathy
SCE
sister chromatid exchange
CYP450
cytochrome P450
SD
standard deviation
DAF
dosimetric adjustment factor
SDH
sorbitol dehydrogenase
DEN
diethylnitrosamine
SE
standard error
DMSO
dimethylsulfoxide
SGOT
serum glutamic oxaloacetic
DNA
deoxyribonucleic acid
transaminase, also known as AST
EPA
Environmental Protection Agency
SGPT
serum glutamic pyruvic transaminase,
ER
estrogen receptor
also known as ALT
FDA
Food and Drug Administration
SSD
systemic scleroderma
FEVi
forced expiratory volume of 1 second
TCA
trichloroacetic acid
GD
gestation day
TCE
trichloroethylene
GDH
glutamate dehydrogenase
TWA
time-weighted average
GGT
y-glutamyl transferase
UF
uncertainty factor
GSH
glutathione
UFa
interspecies uncertainty factor
GST
glutathione-S-transferase
UFC
composite uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFd
database uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFh
intraspecies uncertainty factor
HEC
human equivalent concentration
UFl
LOAEL-to-NOAEL uncertainty factor
HED
human equivalent dose
UFS
subchronic-to-chronic uncertainty factor
i.p.
intraperitoneal
U.S.
United States of America
IRIS
Integrated Risk Information System
WBC
white blood cell
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV document.
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DRAFT PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
P-PHTHALIC ACID (TPA) (CASRN 100-21-0)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
Currently available PPRTV assessments can be accessed on the U.S. Environmental
Protection Agency's (EPA's) PPRTV website at https://www.epa.gov/pprtv. PPRTV
assessments are eligible to be updated on a 5-year cycle and revised as appropriate to incorporate
new data or methodologies that might impact the toxicity values or affect the characterization of
the chemical's potential for causing adverse human-health effects. Questions regarding
nomination of chemicals for update can be sent to the appropriate U.S. EPA Superfund and
Technology Liaison (https://www.epa.gov/research/fact-sheets-regional-science).
QUALITY ASSURANCE
This work was conducted under the U.S. EPA Quality Assurance (QA) program to ensure
data are of known and acceptable quality to support their intended use. Surveillance of the work
by the assessment managers and programmatic scientific leads ensured adherence to QA
processes and criteria, as well as quick and effective resolution of any problems. The QA
manager, assessment managers, and programmatic scientific leads have determined under the
QA program that this work meets all U.S. EPA quality requirements. This PPRTV was written
with guidance from the CPHEA Program Quality Assurance Project Plan (PQAPP), the QAPP
titled Program Quality Assurance Project Plan (PQAPP) for the Provisional Peer-Reviewed
Toxicity Values (PPRTVs) and Related Assessments/Documents (L-CPAD-0032718-QP), and the
PPRTV development contractor QAPP titled Quality Assurance Project Plan—Preparation of
Provisional Toxicity Value (PTV) Documents (L-CPAD-0031971-QP). As part of the QA
system, a quality product review is done prior to management clearance. A Technical Systems
Audit may be performed at the discretion of the QA staff.
All PPRTV assessments receive internal peer review by at least two Center for Public
Health and Environmental Assessment (CPHEA) scientists and an independent external peer
review by at least three scientific experts. The reviews focus on whether all studies have been
correctly selected, interpreted, and adequately described for the purposes of deriving a
provisional reference value. The reviews also cover quantitative and qualitative aspects of the
provisional value development and address whether uncertainties associated with the assessment
have been adequately characterized.
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DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. EPA programs or external parties who may choose to use PPRTVs are
advised that Superfund resources will not generally be used to respond to challenges, if any, of
PPRTVs used in a context outside of the Superfund program.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVS
Questions regarding the content of this PPRTV assessment should be directed to the
U.S. EPA Office of Research and Development (ORD) CPHEA website at
https://www.epa.gov/pprtv/forms/contact-us-about-pprtvs.
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INTRODUCTION
/;-Phthalic acid, CASRN 100-21-0, also commonly known as terephthalic acid (TPA), is
an aromatic acid with a structure consisting of a benzene ring substituted with two carboxylic
acid groups at the 1 and 4 (para) positions. TPA is used for polyester fibers, films, and
polyethylene terephthalate solid state resins and engineering resin production and manufacture
(OHCD. 2001). TPA is listed on the U.S. EPA's Toxic Substances Control Act (TSCA) public
inventory (U.S. HP A. 2018b) and registered with Europe's Registration, Evaluation,
Authorisation and Restriction of Chemicals (REACH) program (ECHA. 2018).
TPA is made from /^-xylene through a liquid-phase air oxidation process, in which
manganese and cobalt acetate are used as catalysts and sodium bromide is used as a promoter.
Purification of crude TPA is performed using hot water under pressure and selective catalytic
hydrogenation of contaminants (OHCD. 2001).
The empirical formula for TPA is C8H6O4 (see Figure 1). A table of physicochemical
properties for TPA is provided below (see Table 1). TPA is a white solid, with moderate water
solubility. In the air, TPA will exist in the particulate phase based on a vapor pressure of
9.2 x 10~6 mm Hg. TPA will be degraded in the atmosphere by a reaction with photochemically
produced hydroxyl radicals with a half-life of 8.6 days, calculated from an estimated reaction
rate constant of 3.32 x io~12 cm3/molecule-second at 25°C. Because of TPA's low vapor
pressure, negligible volatilization from dry soil surfaces is expected. Low volatilization from
water or moist soil surfaces is expected based on an estimated Henry's law constant of
1.63 x 10 9 atm-m3/mole. The estimated Koc for TPA indicates potential for mobility in soil and
negligible potential to adsorb to suspended solids and sediment in aquatic environments. TPA
does not contain functional groups that are likely to hydrolyze under environmental conditions;
therefore, hydrolysis is not expected to be an important fate process.
Hw
OH
O
Figure 1. TPA (CASRN 100-21-0) Structure
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Table 1. Physicochemical Properties of TPA (CASRN 100-21-0)
Property (unit)
Value3
Physical state
Needles, white crystals, or powder
Boiling point (°C)
341 (predicted average)
Melting point (°C)
368 (experimental average)
Density (g/cm3 at 25 °C)
1.47 (predicated average)
Vapor pressure (mm Hg at 25°C)
9.2 x 10 6 (experimental average)
pH (unitless)
3.88b
pKa (unitless)
3.54 and 4.46b
Solubility in water (mg/L at 25°C)
9.03 x 10 s (experimental average)
Octanol-water partition constant (log Kow)
2.00 (experimental average)
Henry's law constant (atm-m3/mol at 20°C)
1.63 x 10 9 (predicted average)
Soil adsorption coefficient Koc (L/kg)
24.5 (predicted average)
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
3.32 x 10 12 (predicted average)
Atmospheric half-life (d)
8.6°
Relative vapor density (air = 1)
NV
Molecular weight (g/mol)
166.13
Flash point (open cup in °C)
205 (predicted average)
aUnless otherwise noted, data were extracted from the U.S. EPA CompTox Chemicals Dashboard (terephthalic
acid; CASRN 100-21-0; https://comptox.epa.gov/dashboard/DTXSID6026080. Accessed August 5, 2020).
bECHA (2018). At saturation in water; pH varies with concentration.
°U.S. EPA (2012b) (with user-entered inputs for water solubility = 17 mg/L. vapor pressure = 6 ¦: 1011 mm Hg,
and log Kow = 2; SMILES: C1=CC(=CC=C1C(=0)0)C(=0)0.
NV = not available; SMILES = simplified molecular input line entry system; TPA = terephthalic acid.
A summary of available toxicity values for TPA from U.S. EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for TPA (CASRN 100-21-0)
Source
(parameter)3'b
Value
(applicability)
Notes
Reference0
Noncancer
IRIS
NV
NA
U.S. EPA (2018c)
HEAST (RfD)
1 mg/kg-d
Based on bladder hyperplasia in a chronic oral
study in rats
U.S. EPA (2011a)
HEAST (sRfD)
1 mg/kg-d
Based on bladder hyperplasia in a chronic oral
study in rats
U.S. EPA (2011a)
DWSHA
NV
NA
U.S. EPA (2018a)
ATSDR
NV
NA
ATSDR (2019)
IPCS
NV
NA
IPCS (2018)
CalEPA
NV
NA
CalEPA (2016a):
CalEPA (2016b):
CalEPA (2018)
OSHA
NV
NA
OSHA (2018); OSHA
(2018); OSHA (2020)
NIOSH
NV
NA
NIOSH (2016)
ACGIH (TLV-TWA)
10 mg/m3
Based on analogy to the TLV for particulates
(insoluble) not otherwise specified
ACGIH (2018)
DFG (MAK)
5 mg/m3
Based on absence of effects in an unpublished
28-d rat inhalation study
MAK-Commission
(2015)
Cancer
IRIS
NV
NA
U.S. EPA (2018c)
HEAST
NV
NA
U.S. EPA (2011a)
DWSHA
NV
NA
U.S. EPA (2018a)
NTP
NV
NA
NTP (2016)
IARC
NV
NA
IARC (2018)
CalEPA
NV
NA
CalEPA (2016b):
CalEPA (2017);
CalEPA (2018)
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Table 2. Summary of Available Toxicity Values for TPA (CASRN 100-21-0)
Source
(parameter)3'b
Value
(applicability)
Notes
Reference0
ACGIH
NV
NA
ACGIH (2018)
HEEP (WOE)
Group C: Possibly
carcinogenic to
humans
Based on limited animal evidence for bladder
tumors
U.S. EPA (1986)
"Sources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; CalEPA = California Environmental Protection Agency; DFG = German
Research Foundation; DWSHA = Drinking Water Standards and Health Advisories; HEAST = Health Effects
Assessment Summary Tables; HEEP = Health and Environmental Effects Profile; IARC = International Agency for
Research on Cancer; IPCS = International Programme on Chemical Safety; IRIS = Integrated Risk Information
System; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program;
OSHA = Occupational Safety and Health Administration.
Parameters: MAK = maximum allowable concentration; RfD = reference dose; sRfD = reference concentration for
subchronic oral exposure; TLV = threshold limit value; TWA = time-weighted average; WOE = weight of
evidence.
°Reference date is the publication date for the database and not the date the source was accessed.
NA = not applicable; NY = not available; TPA = terephthalic acid.
METHODS
Literature Search
Four online scientific databases (PubMed, Web of Science [WOS], TOXLINE, and Toxic
Substances Control Act Test Submissions [TSCATS] via TOXLINE) were searched by
U.S. EPA's Health and Environmental Research Online (HERO) staff and stored in the HERO
database.1 The literature search focused on chemical name and synonyms (identified as
"valid/validated" or "good" via the CompTox2 Chemicals Dashboard and ChemSpider3) with no
limitations on publication type, evidence stream (i.e., human, animal, in vitro, in silico), or health
outcomes. Full details of the search strategy for each database are presented in Appendix A.
The initial database searches were conducted in February 2018 and updated in July 2018,
May 2019 and March 2020. Further details are given below, and a schematic of the literature
search and disposition is shown as Figure 2.
Screening Process
Two screeners independently conducted a title and abstract screen of the search results
using DistillerSR4 to identify study records that met the Population, Exposure, Comparator, and
Outcome (PECO) eligibility criteria (see Appendix B for a more detailed summary):
1 U.S. EPA's HERO database provides access to the scientific literature behind U.S. EPA science assessments. The
database includes more than 2,500,000 scientific references and data from the peer-reviewed literature used by
U.S. EPA to develop its regulations.
2CompTox Chemicals Dashboard: https://comptox.epa.gov/dashboard/DTXSID6026080.
'ChemSpider: http://www.chemspider.com/Chemical-Structure.7208.html.
'DistillerSR is a web-based systematic review software used to screen studies available at
https://www.evidencepartners.com/products/distillersr-svstematic-review-software.
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• Population: Humans, laboratory mammals, and other animal models of
established relevance to human health (e.g., Xenopus embryos); mammalian
organs, tissues, and cell lines; and bacterial and eukaryote models of genetic
toxicity.
• Exposure: In vivo (all routes), ex vivo, and in vitro exposure to the chemical
of interest, including mixtures to which the chemical of interest may
contribute significantly to exposure or observed effects.
• Comparator: Any comparison (across dose, duration, or route) or no
comparison (e.g., case reports without controls).
• Outcome: Any endpoint suggestive of a toxic effect on any bodily system, or
mechanistic change associated with such effects. Any endpoint relating to
disposition of the chemical within the body.
Records that were not excluded based on title and abstract screening advanced to full-text
review using the same PECO eligibility criteria. Studies that have not undergone peer review
were included if the information could be made public and sufficient details of study methods
and findings were included in the report. Full-text copies of potentially relevant records
identified from title and abstract screening were retrieved, stored in the HERO database, and
independently assessed by two screeners using DistillerSR to confirm eligibility. At both
title/abstract and full-text review levels, screening conflicts were resolved by discussion between
the primary screeners with consultation by a third reviewer to resolve any remaining
disagreements. During title/abstract or full-text level screening, studies that were not directly
relevant to the PECO criteria, but could provide supplemental information, were categorized (or
"tagged") relative to the type of supplemental information they provided (e.g., review,
commentary, or letter with no original data; conference abstract; toxicokinetics and mechanistic
information aside from in vitro genotoxicity studies; studies on routes of exposure other than oral
and inhalation; acute exposure studies only; etc.). Conflict resolution was not required during
the screening process to identify supplemental information (i.e., tagging by a single screener was
sufficient to identify the study as potential supplemental information).
LITERATURE SEARCH AND SCREENING RESULTS
The database searches yielded 420 unique records that were captured in DistillerSR. Of
the 420 studies identified, 93 were included following title and abstract screening. These
93 were reviewed at the full-text level, and 54 were considered relevant to the PECO eligibility
criteria (see Figure 2). This included 42 in vivo animal studies, 2 human studies, and 10 in vitro
genotoxicity studies. The detailed search approach, including the query strings and PECO
criteria, are provided in Appendix A and Appendix B, respectively.
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PubMed
(n - 326)
Literature Searches (March 2020)
wos
(n = 5)
ToxNet
(n =123)
Other Sources
(n=2)
~
TITLE AND ABSTRACT SCREENING
Title and Abstract Screening
(420 records after duplicate removal)
~
Excluded (n = 327)
Not relevant to PECO (n = 327)
FULL-TEXT SCREENING
Full-Text Screening
Excluded (n = 22)
Not relevant to PECO (n = 22}
t
Studies Considered Further (/?
= 54)
* Human health effect studies (n-
2)
* Animal health effect studies (n =
42)
* Genotoxicity studies (n = 10)
Tagged as Supplemental/Other (n = 17)
* Other routes of exposure besides oral and
inhalation (n = 5), acute toxicity studies
(n = 0), mechanistic studies (in vitro or in
vivo; n = 1), ADME/PBPK studies (n - 5), and
review articles (n= 6)
Figure 2. Literature Search and Screening Flow Diagram for TPA (CASRJN 100-21-0)
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REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide overviews of the relevant noncancer and cancer databases,
respectively, for TPA and include all potentially relevant repeated short-term, subchronic, and
chronic studies, as well as reproductive and developmental toxicity studies. Principal studies are
identified in bold. The phrase "statistical significance" and the term "significant," used
throughout the document, indicates ap-value of < 0.05 unless otherwise specified.
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Table 3A. Summary of Potentially Relevant Noncancer Data for TPA (CASRN 100-21-0)
Category"
Number of Male/Female,
Strain, Species, Study Type,
Reported Doses, Study
Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
Subchronic to
chronic
141 workers (47% male)
occupationally exposed to TPA.
Average duration of
employment 6.2 yr.
Three cumulative
exposure
categories:
not-detected,
~50 mg/m3, and
~80 mg/m3 (low,
medium, and high,
respectively)
Slight increase in SACE activity in the
exposed workers (12, 17, and 15%
increase over controls).
NDr
NDr
Dai et al. (2005b)
PR
Animal
1. Oral (mg/kg-d)
Short term
30 M/30 F, weanling F344, rat,
diet, 14 d
Reported doses: 0, 0.5, 1.5, 3, 4,
or 5% TPA in the diet
M: 0, 658, 1,904,
3,740, 4,860, 5,710
F: 0, 599, 1,836,
3,760, 4,770, 5,520
Reduced body weight and increased
incidence of bladder calculi and
associated gross and histopathological
lesions in both males and females.
Urinary pH and electrolyte
concentrations were altered at lower
doses.
3,760
4,770
Chinetal. (1981):
Heck (1981)
PR
Short term
10 M, weanling F344, rat, diet,
14 d
Reported doses: 0 or 4% TPA in
the diet
0, 4,900
Reduced body weight and increased
incidence of bladder calculi. Alterations
in urinary pH and electrolyte
concentrations were also observed.
NDr
4,900
Wolkowski-Tvl
and Chin (1983)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for TPA (CASRN 100-21-0)
Category"
Number of Male/Female,
Strain, Species, Study Type,
Reported Doses, Study
Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Subchronic
12-52 M/12-23 F, S-D, rat,
diet, 90 d
Reported doses: 0, 0.04, 0.2, 1,
or 5% TPA in the diet
M: 0, 36.0, 179,
906, 4,550
F: 0, 40.0, 197, 997,
4,970
Increased incidences of bladder calculi
and hyperplasia in males. Urinary
acidosis in both sexes. Sediment in the
urine and changes in urinary electrolytes
were observed in males and females at
lower doses.
906
4,550
Dai et al. (2006a):
Dai et al. (2005c)
PR
Subchronic
6 M/6 F, weanling, albino rat
(strain NS), diet, 90 d
Reported doses: 0, 1, 3.2, or
10% TPA in the diet
M: 0, 859, 2,754,
10,500
F: 0, 992, 3,170,
11,200
Four of six males died. Other observed
effects were hematuria, depressed body
weights, and renal injury (2/12)
associated with the presence of calculi in
the urinary tract (all severe in males, less
so in females).
2,754
10,500
(PEL)
Duoont Giem Co
NPR
(1955)
Subchronic
30 M/30 F, Wistar, rat, diet,
90 d
Reported doses: 0, 0.03, 0.154,
0.5, 2, or 5% TPA in the diet
M: 0, 15.3, 79.09,
266, 1,020, 2,650
F: 0, 19.3, 114.5,
313, 1,280, 3,100
Low incidences of bladder and urethra
calculi, chronic cystitis, chronic
urethritis, and transitional cell
hyperplasia of the bladder and urethra in
males and females.
3,100
NDr
Ledoux and Reel
(1982): Ball etal.
(2012)
NPR
Subchronic
30 M/30 F, CD, rat, diet, 90 d
Reported doses: 0, 0.03, 0.154,
0.5, 2, or 5% TPA in the diet
M: 0, 14.6, 76.15,
247, 976, 2,590
F: 0, 17.6, 86.57,
286, 1,260, 2,840
Reduced body weight in females. Low
incidences of urinary bladder calculi,
chronic cystitis, and chronic urethritis
and transitional cell hyperplasia in the
bladder and urethra.
1,260
2,840
Ledoux and Reel
(1982): Ball etal.
(2012)
NPR
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Table 3A. Summary of Potentially Relevant Noncancer Data for TPA (CASRN 100-21-0)
Category"
Number of Male/Female,
Strain, Species, Study Type,
Reported Doses, Study
Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Subchronic to
chronic
30 M, Wistar, rat, diet, 22 wk
Prior to TPA feeding, treated
animals received i.p. injections
of vehicle (5% citrate buffer)
2 times/wk for 4 wk; control
animals did not receive vehicle
injections
Reported doses: 0, 1, or 5%
TPA in the diet
0, 829, 4,280
Reduced body weight, increased absolute
and relative bladder weights, and
increased bladder hyperplasia. Sediment
in urine and changes in urinary pH and
electrolyte levels were seen in both dose
groups.
829
4,280
Cui et al. (2006a)
PR
Chronic
20-38 M, Wistar, rat, diet,
48 wk
Reported doses: 0 or 5% TPA in
the diet
0, 3,680
Increased incidences of bladder calculi
and hyperplasias at 12, 24, and 48 wk.
Elevated absolute and relative bladder
weights and reduced body weights were
also reported, although the data were not
shown.
NDr
3,680
Cui et al. (2007);
Cui et al. (2006b):
Shi et al. (2006)
PR
Chronic
50 M/50 F, Wistar, rat, diet,
24 mo
Reported doses: 0, 1, 2, or 5%
TPA in the diet
M: 0, 736, 1,470,
3,680
F: 0, 842, 1,680,
4,210
Body weight reduced by >10% in males
and females. At higher doses in both
sexes, increased incidences of high blood
urea levels, nephropathy, and urinary
tract calculi were observed.
736
1,470
Gross (1977)
NPR
Chronic
126 M/126 F, F344, rat, diet,
24 mo
Doses reported as ADDs by
study authors
M: 0, 19.5, 138.2,
995.4
F: 0, 19.2, 136.6,
989.8
Bladder hyperplasia in females.
995.4
NDr
Grubbs (1979):
Preache (1983):
ICI Americas Inc
NPR
(1992)
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Table 3A. Summary of Potentially Relevant Noncancer Data for TPA (CASRN 100-21-0)
Category"
Number of Male/Female,
Strain, Species, Study Type,
Reported Doses, Study
Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Reproductive/
Developmental
10 breeding pairs/group, Wistar,
rat, diet, 90 d prior to mating
through postweaning and
PNDs 21-51 for weanlings
Reported doses: 0, 0.03, 0.154,
0.5, 2, or 5% TPA in the diet
M: 0, 15.3,79.09,
266, 1,020, 2,650
F: 0, 19.3, 114.5,
313, 1,280, 3,100
Significantly decreased pup body weight.
Significantly increased renal and bladder
calculi in pups upon necropsy
(PNDs 21-51).
313
1,280
Ledoux and Reel
(1982)
NPR
Reproductive/
Developmental
9-10 breeding pairs/group,
CD, rat, diet, 90 d prior to
mating through postweaning
and PNDs 21-51 for
weanlings
Reported doses: 0,0.03,0.154,
0.5,2, or 5% TPA in the diet.
M: 0,14.6, 76.15,
247, 976,2,590
F: 0,17.6,86.57,
286,1,260, 2,840
Significantly decreased pup body
weight; decreased proportion of pups
surviving to PND 21. Significantly
increased renal and bladder calculi in
pups at necropsy (PNDs 21-51).
NDr
17.6
Ledoux and Reel
(1982)
NPR,
PS
Reproductive
10 M, S-D, rat, diet, 90 d
Reported doses: 0, 0.2, 1, or 5%
TPA in the diet
0, 172, 861,4,310
Significant reductions in sperm head
counts and in several other sperm
motility parameters. Ultrastructural
changes in cells from several stages of
spermatogenesis. Some sperm motility
parameters were affected at lower doses.
861
4,310
Cui et al. (2004)
PR
Reproductive
5 M, S-D, rat, gavage (dissolved
in corn oil), daily for 4 wk
0, 10, 100, 1,000
Significant reduction in sperm
progressive motility.
100
1,000
Kwack and Lee
(2015)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for TPA (CASRN 100-21-0)
Category"
Number of Male/Female,
Strain, Species, Study Type,
Reported Doses, Study
Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
2. Inhalation (mg/m3)
Developmental
22-25 F, S-D, rat, whole-body
aerosol inhalation, 6 hr/d on
GDs 6-15
Reported exposures: 0, 0.90,
4.73, or 10.40 mg/m3
0, 0.59, 2.96, 6.240
Maternal: No effects.
Fetal: No effects.
Maternal:
6.240
Fetal:
6.240
NDr
NDr
Chemical
Manufacturers
Association (2000)
NPR
'Duration categories are defined as follows: Acute = exposure for <24 hours; short term = repeated exposure for 24 hours to <30 days; long term (subchronic) = repeated
exposure for >30 days <10% lifespan for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure
for >10% lifespan for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 2002).
bDosimetry: Doses are presented as ADDs (mg/kg-day) for oral noncancer effects and as HECs (mg/m3) for inhalation noncancer effects.
°Notes: NPR = not peer reviewed; PR = peer reviewed; PS = principal study.
ADD = adjusted daily dose; F = female(s); FEL = frank effect level; GD = gestation day; HEC = human equivalent concentration; i.p. = intraperitoneal;
LOAEL = lowest-observed-adverse-effect level; M = male(s); ND = no data; NDr = not determined; NOAEL = no-observed-adverse-effect level; NS = not specified;
PND = postnatal day; SACE = serum angiotensin-converting enzyme; S-D = Sprague-Dawley; TPA = terephthalic acid.
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Table 3B. Summary of Potentially Relevant Cancer Data for TPA (CASRN 100-21-0)
Category
Number of Male/Female, Strain,
Species, Study Type, Reported
Doses, Study Duration
Dosimetry3
Critical Effects
Reference
(comments)
Notesb
Human
1. Oral (mg/kg-d)
ND
1. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
Carcinogenicity
20-38 M, Wistar, rat, diet, 48 wk
Reported doses: 0 or 5% TPA in the
diet
0, 1,090
Increased transitional cell carcinoma and
papilloma in bladder in treated group.
Cui et al. (2006b)
PR
Carcinogenicity
50 M/50 F, Wistar, rat, diet, 24 mo
Reported doses: 0, 1, 2, or 5% TPA
in the diet
M: 0, 210, 419, 1,050
F: 0,215,429, 1,070
Increased bladder and ureter tumors
(primarily transitional cell tumors or
squamous cell carcinomas) in high-dose
males and females.
Gross (1977)
NPR
Carcinogenicity
126 M/126 F, F344, rat, diet, 24 mo
Reported doses: M: 0, 19.5, 138.2,
995.4 mg/kg-d; F: 0, 19.2, 136.6,
989.8 mg/kg-d
M: 0, 5.41, 38.49, 274.2
F: 0,4.98,35.41,255.8
Increased transitional cell adenomas in
bladder in high-dose females.
ICI Americas Inc (1992);
Preache (1983)
NPR
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Table 3B. Summary of Potentially Relevant Cancer Data for TPA (CASRN 100-21-0)
Category
Number of Male/Female, Strain,
Species, Study Type, Reported
Doses, Study Duration
Dosimetry3
Critical Effects
Reference
(comments)
Notesb
2. Inhalation (mg/m3)
ND
'Dosimetry: Oral exposures are expressed as HEDs (mg/kg-day); HEDs are calculated using DAFs. as recommended by U.S. EPA (2011b): HED = ADD
(mg/kg-day) x DAF. The DAF is calculated as follows: DAF = (BWa ^ BWh)1'4, where DAF = dosimetric adjustment factor, BWa = animal body weight, and
BWh = human body weight, using study (if available) or reference body-weight values for B\V„ and the reference value of 70 kg for BWh.
bNotes: NPR = not peer reviewed; PR = peer reviewed.
ADD = adjusted daily dose; BW = body weight; DAF = dosimetric adjustment factor; F = female(s); HED = human equivalent dose; M = male(s); ND = no data;
TPA = terephthalic acid.
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HUMAN STUDIES
Oral Exposures
No oral studies have been identified.
Inhalation Exposures
Dai et al (2005b)
In a cohort study, Dai et al. (2005b) investigated the potential health effects of inhaled
TPA in an industrial setting. Some of the data in this study appear to be identical to data
presented in a study available only in Chinese (Li ct al.. 1999). One hundred forty-one workers
(47% males) occupationally exposed to TPA dust and 77 unexposed workers (48% males) were
recruited from two Chinese fiber factories. Workers had an average age of 30.3 years and an
average duration of employment of 6.2 years. TPA concentrations were monitored in air for all
exposed workers and in 10% of the unexposed workers using personal dust samplers, apparently
each for a single 8-hour day. Cumulative exposure levels of TPA for each worker were
calculated based on job history duration and mean concentration of TPA exposure, based on the
location for each job. Blood and urine samples were collected in the morning prior to the 8-hour
monitoring period, and an additional urine sample was collected after the shift. Blood samples
were subject to hematological analysis (hemoglobin [Hb] and red blood cell [RBC], white blood
cell [WBC], lymphocyte, and platelet counts) and serum chemistry (alanine aminotransferase
[ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], y-glutamyl transferase
[GGT], lactate dehydrogenase [LDH], albumin, and electrolytes). Urine was analyzed for TPA
concentration by high-performance liquid chromatography (HPLC). The urine was also
analyzed for ALP, GGT, LDH, ai- and P2-microglobulins, pH, and Ca2+, Na+, and K+
electrolytes. All workers underwent pulmonary function tests (inspiratory vital capacity [VC],
forced vital capacity [FVC], forced expiratory volume in the first second [FEVi], FEVi/FVC,
peak expiratory volume [PEV], and maximal expiratory flow rate at 75% [MEF75], 50%
[MEF50], and 25% [MEF25] of VC were measured) and had chest radiographs. Statistical
analysis included two-way analyses of variance (ANOVAs) for comparison of means with a
X2 test. Comparisons were made between unexposed and tertiles of cumulative TPA exposure
(based on measured concentrations of TPA in air or urinary TPA levels). Nonparametric tests
were used when variables were not normally distributed.
Monitoring results indicated that geometric mean air levels of TPA were 8.03 mg/m3
(range 0.15-138.32 mg/m3) in Plant I and 2.19 mg/m3 (range 0.30-14.21 mg/m3) in Plant II.
After calculation of cumulative exposures, exposed workers were grouped into three cumulative
exposure categories: not-detected (detection limit not reported), -50 mg/m3, and -80 mg/m3
(low, medium, and high, respectively). Similar categories were formed based on urine TPA
concentrations: not detected, -1 mmol/mol creatine, and -5 mmol/mol creatine (low, medium,
and high, respectively). The results of pulmonary function tests were similar in exposed and
unexposed workers. The only difference was a slight increase in serum angiotensin-converting
enzyme (SACE) activity in the exposed workers (12, 17, and 15% increase over the unexposed
workers in low-, medium-, and high-cumulative-exposure groups, respectively) that was
significant in the medium- and high-cumulative-exposure groups but did not increase with
exposure level. No evidence of lung disease was detected by radiography. No differences were
found between unexposed workers and exposed workers for any of the hematological indices.
Significant increases in serum AST {21%) and LDH (11%) occurred in the
medium-cumulative-exposure group, but the changes were within reference values and were not
seen in the high-exposure group (see Table D-l). There was also a slight significant decrease in
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serum albumin (-3%) in the high-exposure group. In urine, the only changes were slight
increases in the concentrations of sodium and calcium in the exposed workers (see Table D-l).
Serum TPA levels were comparable to those measured in the urine.
ANIMAL STUDIES
Oral Exposures
Short-Term Studies
Chin et al (1981); Heck (1981)
In a published, peer-reviewed study. Chin et al. (1981) investigated the induction of
bladder calculi by TPA (reported to be "high-purity") in commercially obtained weanling Fischer
344 (F344) rats. Additional data on urine electrolyte concentrations were reported by Heck
(1981). Twenty-eight-day-old weanling F344 rats (30 males and 30 females/group) were fed
diets containing 0, 0.5, 1.5, 3, 4, or 5% TPA for 14 consecutive days. Chin et al. (1981) reported
the average daily doses of rats exposed to 3, 4, and 5% TPA in feed to be 3,740, 4,860, and
5,710 mg/kg-day, respectively, for males, and 3,760, 4,770, and 5,520 mg/kg-day, respectively,
for females. Average daily doses for the 0.5 and 1.5% TPA levels in food were not provided but
were calculated for this review to be 658 and 1,904 mg/kg-day for males and 599 and
1,836 mg/kg-day for females.5 The study did not indicate whether validation or quantification of
TPA in the food was done nor describe the frequency of dietary preparation. Individual body
weights, food, and water intake per cage were monitored every other day throughout the study.
Urine collected just prior to sacrifice was analyzed for pH, and for concentrations of
calculus-forming materials (e.g., calcium, phosphate) and TPA. The entire urinary system,
including the urethra, bladder, ureters, and kidneys, was visually analyzed for calculi. The
composition of the calculi collected from four samples, each containing 14-18 calculi from the
bladders of TPA-exposed rats, was analyzed. Urinary tract tissues from 10 control male rats and
10 male rats on the 4% TPA diet were collected for histologic examination (hematoxylin and
eosin staining). Statistical analysis was performed by the study authors and comparison of
means was done using either one-way ANOVA with a Dunnett's test or a
Student-Newman-Keuls test, when appropriate.
Animals in the high-dose treatment groups developed diarrhea, which the study authors
attributed to incomplete absorption of TPA. Male and female body weights in each exposure
group were plotted graphically during three different time periods: Exposure Days 0-2, 6-8, and
12-14. The mean values were extracted for this review using GrabIT! Software.6 Compared
with controls, significant (>10%) decreases in body weights occurred at Days 6-8 and 12-14 in
both males and females exposed to 4 (males only) and 5% dietary TPA (see Table D-2). Food
intake was significantly reduced during the first 2 days of exposure in highest-dose males and in
females from the two highest dose groups but was similar to controls at the later time periods.
Water intake was significantly increased in a dose-related manner in the three highest dose
groups in both males and females on Days 6-8 and 12-14.
5Reported dietary intakes (% TPA in food) were converted to adjusted daily doses (ADDs) using the following
equation: ADD = [% TPA in food x 10,000 (mg TP A/kg food) x food intake (kg food/day)] ^ average body weight
(BW; kg) and data for body weight and food intake provided in the study (graphically reported body-weight and
food-intake data were extracted using GrabIT! software).
' GrabIT! software is a free software product (© 1999-2020) from shemes.com—all rights reserved. Grablt!,
Shemes. and each of their logos are trademarks of shemes.com.
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The incidence of calculi increased in a dose-related manner (see Table D-3). In the two
highest dose groups, calculi were significantly increased occurring in 57 and 93% of males and
in 20 and 73% of females, respectively. No calculi were observed in controls, and only the
occasional calculus was found in the lower dose groups. The calculus mass increased with dose
and was greater in males than in females given the same dose. Calculi were made up primarily
of TP A, but also included significant amounts of calcium and phosphate. Grossly observable
lesions in the urinary tract occurred primarily in animals with calculi. These included an
irregularly thickened bladder wall in all affected rats, hydronephrosis in some rats, and frequent
hematuria in high-dose (exactly which dose[s] not reported) rats.
Urinary acidosis was observed in both sexes fed diets containing 0.5, 3, and 4% TPA
(urinalysis of the 1.5 and 5% TPA groups was not reported) (see Table D-4). Hypercalcemia
was also observed in all exposed groups examined, and the increases were significant (p < 0.01)
over controls in the 3- and 4%-TPA groups. Further analysis of a subset of the tested rats by
Heck (1981) showed significant increases in urinary ammonium concentrations in all treated
groups and generally significant decreases in urinary sodium, potassium, and sulfate in the 3- and
4%-TPA groups (see Table D-5).
Chin et al. (1981) provided representative images of some histological lesions in urinary
tract tissues from controls and animals fed 4% TPA diets. The authors described urinary
bladder, ureters, and kidney tissues from control rats as normal, except for a few small foci of
mineralization in the tubules of the outer medulla. Six out of the 10 treatment animals in the
4%-TPA group had macroscopic calculi, and histological lesions were primarily observed in
these animals. Bladder lesions consisted of diffusely hyperplastic transitional epithelium with
varying degrees of severity. Ulceration of the hyperplastic epithelium and neutrophil infiltration
of the lamina propria were described as frequent. Ureters in the treated group were normal
except for one animal that showed a dilated ureter with a thinned epithelial layer. This animal
also exhibited severe hydronephrosis in one kidney and minimal hydronephrosis in the other.
According to the study authors, most of the animals in the 4%-TPA group contained more
mineralized foci in the kidneys than did the controls.
The NOAEL of 3,760 mg/kg-day and the LOAEL of 4,770 mg/kg-day are identified for
this study based on increased incidence of bladder calculi and associated gross and
histopathological lesions in weanling female F344 rats fed TPA in their diets for 14 days.
Significant changes in urine pH and electrolyte levels were observed at lower doses and may be
suggestive of mechanisms leading to calculi formation.
Wolkowski-Tyl and Chin (1983)
TPA at 4% in the diet was used as positive control for calculus formation in a follow-up
study conducted by Wolkowski-Tyl and Chin (1983) using a protocol similar to that of the Chin
et al. (1981) study. Weaned 28-day-old F344/CrlBr inbred albino rat pups (10 males/group)
were administered TPA powder at a concentration of 0 or 4% (4,900 mg/kg-day)7 in the diet for
14 consecutive days. The control and TPA treatment groups were also given a daily gavage of
0.5% carboxymethyl cellulose in tap water, which was used as a vehicle for additional treatment
7The reported dietary intake (% TPA in food) was converted to an ADD using the following equation:
ADD = [% TPA in food x 10,000 (mg TP A/kg food) x food intake (kg food/day)] ^ time-weighted average (TWA)
B W (kg) and data for food intake and body weight reported in the study (graphically reported body-weight data
were extracted using GrabIT! software).
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groups not reported here (additional treatment groups included sodium bicarbonate,
chlorothiazide, allopurinol, and Neutra-Phos). The study did not indicate whether validation or
quantification of TP A in food was done; diets were prepared fresh weekly. Individual body
weights, and food and water intake per cage were recorded every other day beginning on
Postnatal Day (PND) 28. On PND 42, the animals were sacrificed, and blood and urine samples
were collected for determination of hematocrit and for measurements of calcium and magnesium
ions. Urine pH and TPA concentrations were also recorded. The complete urinary system was
examined macroscopically for the presence of calculi. Calculi from the urethra, bladder, ureters,
and kidney were counted, dried, weighed, and stored for further analysis not described in this
report. Statistical analysis performed by the study authors included Student's Mest with /-test for
equality of variance and x2- Only data for negative control and TPA-treated rats receiving
vehicle gavages are described below.
Diarrhea and crystalline encrustation at the urogenital orifice and papilla were observed
in animals treated with TPA (the number of animals affected was not reported). Compared with
controls, statistically significant depressions in mean body weights ranging from 8 to 17% (data
extracted from graphical images using GrabIT! Software)6 were observed in treated rats
throughout the study (see Table D-6). The study authors indicated body-weight reductions of
20% in TPA-exposed rats at termination. Total food intake in treated animals was significantly
decreased (15% decrease) and water intake was significantly increased (see Table D-7).
Compared with control rats, urine from treated rats was hyperacidic. Significant increases in
urinary calcium (-160% increase) and magnesium (—150% increase) (data displayed
graphically), and serum calcium (6% increase) and magnesium (27% increase) were also
observed. Hematocrit levels remained comparable to controls (see Table D-8). Calculi,
primarily found in the bladder lumen, were significantly increased (5/10) in rats fed 4,900 mg
TPA/kg-day; none were observed in controls (see Table D-9).
The only dose tested, 4,900 mg/kg-day, is a LOAEL in this study for significantly
increased incidence of calculi in the bladder and decreased body weights. Significant changes in
urine pH and levels of electrolytes were also observed. A NOAEL could not be determined.
Subchronic Studies
Daietal. (2005c); Dai et al. (2006a)
In two published, peer-reviewed reports, Dai et al. (2005c) and Dai et al. (2006a)
evaluated the effects of TPA (>99.99% purity) exposure on Sprague-Dawley (S-D; Shanghai
Animal Center) rats in a subchronic feeding study. Male and female S-D rats
(12-23 females/group and 12-52 males/group) were fed diets containing 0, 0.04, 0.2, 1, or 5%
TPA for 90 days. Adjusted daily doses (ADDs) were estimated in this report to be 0, 36.0, 179,
906, and 4,550 mg/kg-day for males and 0, 40.0, 197, 997, and 4,970 mg/kg-day for females.8
Details of dietary preparation or whether validation of dietary concentrations was done were not
reported. It is unknown whether animals were monitored for clinical signs or mortality. Initial
and final body weights were measured. No information on feed or water intake was included in
the report. Blood and urine were collected from rats prior to sacrifice (Day 90) for analysis.
8Reported dietary intakes (% TPA in food) were converted to ADDs using the following equation: ADD = [% TPA
in food x 10,000 (mg TP A/kg food) x food intake (kg food/day)] ^ BW (kg). Average body weights were
calculated from initial and final body weights provided in the study report. Food intake was calculated from body
weight using the allometric equation (food consumption in kg/day = 0.056 x [body weight in kg0 6611]) from U.S.
EPA (1988).
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Urine volume was recorded, and urine was analyzed for calcium, magnesium, zinc, potassium,
sodium concentrations, pH, and presence of TP A sediment. Alpha 2u-globulin (a2u-g), a major
urinary protein secreted by the liver in male rats, was measured in both urine and serum;
however, precipitates were not analyzed to determine whether a2u-g was a component of the
crystals. The brain, heart, liver, kidney, spleen, lung, and bladder were weighed. Bladders were
inspected for calculi and micro calculi, and collected tissues were fixed for histopathological
analysis, PCNA immunohistological (bladder) analysis, and for measurements of superoxide
dismutase (SOD), malondialdehyde (MDA), and total antioxidative capability (T-AOC).
Student's Wests were used to test for significant differences between treated and control groups.
TPA exposure had no significant dose-related effects on body weight or body-weight
gain. Sporadic changes not related to treatment occurred in some serum endpoints (total protein,
albumin, and triglycerides; data not shown). Urine pH decreased in males and females at the
highest dose and in females at the lowest dose and second highest dose (see Table D-10).
Significant changes in urinary electrolytes were observed primarily in the two highest dose
groups. Statistically significant organ weight changes appeared to be random and not related to
exposure (see Table D-l 1). At necropsy, one male exhibited an enlarged bladder. A white
urinary sediment appeared in all male treatment groups and in the highest three female treatment
groups (see Table D-12). Bladder calculi were statistically significant in males in the highest
dose group (21/52) but not in females at any dose. Incidences of simple (9/52) and atypical
(5/52) bladder hyperplasias occurred in highest-dose males but were not statistically significant;
no hyperplasia was observed in any other dose group in males. One highest-dose female bladder
had simple hyperplasia. The majority of hyperplasias were PCNA positive (86.7%) and
generally coincided with the presence of sediment and calculi; three cases of hyperplasia,
however, had no calculi. See the "Mode-of-Action/Mechanistic Studies" section for additional
discussion of relevant mechanistic results from these studies. However, in brief, because a2u-g
crystals are male-specific, and crystals were found in females, the a2u-g mechanism is less
likely. Furthermore, because a2u-g was not demonstrated to be a component of the crystals,
there is insufficient evidence to consider an a2u-g-related mechanism of action.
A NOAEL of 906 mg/kg-day and a LOAEL of 4,550 mg/kg-day are identified for
increased incidences of bladder calculi and hyperplasia in male S-D rats exposed to TPA in the
diet for 90 days. Urinary acidosis was also observed in both males and females at the highest
dose tested. Sediment in urine and alterations in urine electrolytes were observed at lower doses
in both sexes.
Dupont Chem Co (1955)
In a 90-day feeding study performed by Haskell Laboratory (Dupont Chem Co. 1955).
the potential effects of TPA exposure were investigated in weanling albino rats. Few study
details were available in the unpublished, non-peer-reviewed summary. Commercially obtained
albino rats (6 males and 6 females/treatment group; were fed diets containing 0, 1.0, 3.2, or 10%
TPA). TPA concentrations in the diets were converted to ADDs of 0, 859, 2,754, and
10,500 mg/kg-day for males and 0, 992, 3,170, and 11,200 mg/kg-day for females.9 The animals
9Reported dietary intakes (% TPA in food) were converted to ADDs using the following equation: ADD = [% TPA
in food x 10,000 (mg TP A/kg food) x food intake (kg food/day)] ^ BW (kg). TWA body weights were calculated
from body-weight data provided in the study report. Food intake was calculated from body weight using the
allometric <
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were observed for clinical signs (paleness, cyanosis, weakness, condition of body fur, frequency
of urine, and diarrhea). Body weights were measured three times weekly through the fourth
week of treatment, and twice weekly thereafter. Food consumption was recorded daily and
presented as weekly averages; rough estimations of water consumption were made periodically.
Urine samples were collected from four rats in the 10%-TPA group to estimate the amount of
TPA recovered. Hematological analysis was done prior to dosing, once during treatment, and at
sacrifice. Necropsies were performed at sacrifice, and the animals were examined for gross
pathology; blood was also collected for measuring blood urea nitrogen (BUN) and plasma
calcium and phosphorus. Major organs were weighed and examined for micropathology.
Urinary calculi collected from the bladder and kidney were counted and analyzed for content.
The available summary did not describe any statistical analyses performed by the study authors.
Four out of six male rats fed 10,500 mg TPA/kg-day died; the deaths were attributed to
concretions of TPA in the urinary tract. By Treatment Day 11, five out of the six high-dose
males had exhibited hematuria (blood in the urine), with the last male developing hematuria
2 weeks later. No females died. The study authors described the females as being affected by
hematuria much less frequently, and with less severity, than males. They attributed blood in the
urine as a direct result of damage to the urinary tract from the formation of calculi composed
principally of calcium phosphate. Other clinical signs that the study authors noted included
drying and cracking of the skin and mild to severe diarrhea (incidences were not reported). No
clinical symptoms were described in the 1.0 and 3.2% treatment groups.
Compared with controls, body-weight gains and body weights were severely depressed at
30, 60, and 90 days in high-dose males (45-51% decreased body weight) and females (33—36%
decreased body weight) (statistical analyses were not provided) (see Table D-13). The study
authors indicated that significant reductions in food consumption were observed in high-dose
males and females and that water intake was approximately twice that of controls. No changes
outside of the normal range were observed in BUN or plasma calcium or phosphorus
concentrations in any treatment group. The available summary indicated a slight tendency
toward anemia in all TPA treatment groups at the end of the study and possible moderate
hyperphosphatemia in the high-dose rats (the data for these effects were not available).
Organ-weight measurements were not reported. At necropsy, calculi and related injury to the
urinary tract was observed in 2/12 and 11/11 rats in the 2,754- and 10,500-mg/kg-day dose
groups, respectively. Renal injury was consistently severe in the males of the high-dose group
(less so in females) and attributed to the presence of calculi. Females were apparently able to
eliminate the calculi more easily than males. Pathology of the urinary tract in the affected
mid-dose animals was considered mild. No pathology was observed in low-dose rats.
A frank effect level (FEL) of 10,500 mg/kg-day is determined based on the death of
4/6 males and accompanying clinical signs (hematuria), reduced body weights, and severe renal
injury associated with the presence of calculi in the urinary tract. The next lower dose of
2,754 mg/kg-day appears to be a NOAEL, although mild renal injury was observed in 2/12
animals at this dose. Confidence is reduced because of limited details available in the report.
Ledoux and Reel (1982); Ball et al. (2012)
In an unpublished, non-peer-reviewed study, Chemical Industry Institute of Toxicology
(CUT) initiated a 90-day TPA feeding study with a follow-on, one-generation reproductive
range-finding study in two rat strains (Ledoux and Reel 1982). Commercially obtained Wistar
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and CD rats (30 males and 30 females/strain/dose) were fed TPA in the diet at target dietary
exposure levels of 0, 0.03, 0.125, 0.5, 2.0, and 5% for 90 days (diets prepared by Zeigler
Brothers, Gardners, PA). The study authors indicated that weekly analysis of feed samples
identified a consistently higher than expected TPA concentration in the 0.125%-group feed, with
an average, instead, of 0.154% TPA (the other samples were consistent with the target dietary
concentrations). Based on the time-weighted average (TWA) body weights and the mean total
TPA levels consumed/rat cited in the study, dietary exposure levels are determined to be
equivalent to 0, 15.3, 79.09, 266, 1,020, and 2,650 mg/kg-day in Wistar males, 0, 19.3, 114.5,
313, 1,280, and 3,100 mg/kg-day in Wistar females, 0, 14.6, 76.15, 247, 976, and
2,590 mg/kg-day in CD males, and 0, 17.6, 86.57, 286, 1,260, and 2,840 mg/kg-day in CD
females.10 Observations for clinical signs, morbidity, and mortality were conducted twice daily.
Physical examinations and measurements of food consumption and body weight were performed
weekly. Sacrifices were done on five rats/strain/dose group on Study Days 30 and 60, and on
10 rats/strain/group on Study Day 90. Ten breeding pairs were maintained for the
one-generation reproductive study; these animals were continued on their respective diets from
mating through postweaning periods. Weaned offspring were fed the same diet as their parents
up to PND 51. Additional details and results of the reproductive portion of the study are
described later in the "Reproductive and Developmental Studies" section.
The study report indicates that for animals in the subchronic study group, urine was
collected prior to sacrifice for measurements of pH, specific gravity, electrolyte concentrations,
and levels of TPA. At each sacrifice, the animals were necropsied; the kidneys were weighed,
and the kidneys, lower urinary tract structures, and any tissues with gross abnormalities were
fixed for histological examination. The study authors performed statistical analysis using
ANOVA and Dunnett's test, with each cage of rats as the experimental unit and the average
effects per cage as dependent variables.
One male and one female high-dose Wistar rat died on Study Days 34 and 60,
respectively. Three highest-dose CD females died on Study Days 59, 75, and 90. No deaths in
the other groups were observed. During the first 4 weeks of the study, the number of animals
showing clinical signs, including diarrhea, weight loss, or urogenital discharge was greater in
highest-dose male (37 vs. 3% in controls) and female (43 vs. 10% in controls) Wistar rats, and in
female (57 vs. 20% in controls) CD rats, compared with their respective controls. However,
there were no significant clinical differences between groups by the end of the study.
Statistically significant reductions in mean body weights were observed primarily in
highest-dose animals of both strains and sexes (see Table D-14). Except for CD female rats at
13 weeks (with 15% decreased body weight, compared with controls), the magnitudes of change
were small (<10% of controls). Significant decreases in total average body weight gains
appeared to be dose related with the greatest decreases in CD females (see Table D-15).
Decreased total weight gains in Wistar rats were significant only in the highest-dose group at
13 weeks. Reduced body weights were generally attributed to reductions in food consumption
(see Table D-16).
10Reported dietary intakes (% TPA in food) were converted to ADDs in mg/kg-day using the following equation:
ADD =[% TPA in food x 10,000 (mg TP A/kg food)] ^ BW (kg), based on TWA body weights and TPA
consumption reported in the study.
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Presentation of results in the available study report was incomplete. For example, kidney
weight data were not provided. Furthermore, general results of histological examinations were
discussed in text, but no histopathology incidence tables were provided. Observations included
distention and enlargement of the urinary bladder, calculi, and distention of the caecum and
colon in male and female rats of both strains given 5% dietary TPA. Calculi were observed in
1/5 male Wistar rats at 2,650 mg/kg-day at the 30-day sacrifice, and in 3/10 Wistar males, 1/10
Wistar females, and 1/10 CD females, all from the highest-dose groups, at the 90-day sacrifice.
Other noted histological changes included frequent chronic inflammation in the urinary bladder
submucosa and the renal cortex, medulla, and pelvis, that appeared more often in treated animals.
In the bladder, inflammation was apparently associated with minimal to moderate hyperplasia of
the transitional epithelium and was greatest in rats given 5% TPA in their diets. The study
authors noted that these lesions were more frequently observed in females, and that lesions of the
bladder and urethra were more common in Wistar versus CD rats. However, the study authors
indicated that the low incidences (less than half the animals) of lesions overall prevent drawing
any definitive conclusions of a potential relation to treatment. Some of the incidence data from
this study were summarized in a secondary assessment (Ball et al.. 2012) and are presented in
Table D-17.
For Wistar rats, a NOAEL of 3,100 mg/kg-day is identified in female rats. A LOAEL
cannot be established due to lack of statistically significant effects of bladder and urethra calculi,
chronic cystitis, chronic urethritis, and transitional cell hyperplasia of the bladder and urethra in
males and females, as reported by Ball et al. (2012). Although there were statistically significant
decreases in body weight, a LOAEL was not identified for this effect because the changes were
not considered biologically significant (i.e., changes were <10%).
In CD rats, a NOAEL of 1,260 mg/kg-day and a LOAEL of 2,840 mg/kg-day are
identified for decreased body weight (>10%) in female rats treated with TPA in the diet for
90 days. As indicated by Ball et al. (2012), other findings at this dose were low incidences of
urinary bladder calculi, chronic cystitis, chronic urethritis, and transitional cell hyperplasia in the
bladder and urethra.
Chronic/Carcinogenicity Studies
Cut et al. (2006a)
In a published, peer-reviewed study, Cui et al. (2006a) reported the effects of repeated
exposure to dietary TPA (99.9% purity) in Wistar rats, with a focus on understanding the
development of urinary bladder carcinogenesis. Male Wistar rats (30 males/group) were treated
in the following manner: Group 1: control (rats maintained on basal diets); Group 2: animals
received intraperitoneal (i.p.) injections of vehicle (5% citrate buffer) twice/week for 4 weeks,
followed by 22 weeks exposure to 1% dietary TPA; and Group 3: i.p. vehicle twice/week (as
above), followed by 22 weeks of exposure to 5% dietary TPA. Control animals (Group 4,
20 males) did not receive vehicle injections. Average daily doses corresponding to 1 and 5%
dietary TPA were determined to be 829 and 4,280 mg/kg-day as calculated for this review.11
Additional groups of rats (Groups 5-7, 15 per group) were pretreated with
"Reported dietary intakes (% TPA in food) were converted to ADDs using the following equation:
ADD = [% TPA x 10,000 (mg TP A/kg food) x food intake (kg food/day)] ^ B W (kg). In the absence of TWA or
starting body-weight data in the rat study, the reference body weight of 0.217 kg for male Wistar rats in a
subchronic study from U.S. EPA (1988) was used. Food intake data reported in the study were used.
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A-rn ethyl-A-nitrosourea (MNU in citrate buffer) by injection for 4 weeks prior to TP A exposure
in order to initiate urinary bladder carcinogenesis.
The study did not indicate whether animals were observed for clinical signs or morbidity.
Body weights and food consumption were measured weekly for the first 20 weeks, then once
every 2 weeks, and at termination. Freshly voided urine was collected from eight rats/group at
Study Week 12 for analysis of electrolytes (calcium, sodium, chloride, and potassium) pH, and
urinary TPA concentration. Necropsies were performed at sacrifice (26 weeks). Absolute and
relative bladder weights were measured. Organs including brain, heart, liver, spleen, lung,
kidneys, and bladder were fixed for histopathological analysis. Urinary tracts were observed for
calculus formation. Sections from all animals were processed for proliferating cell nuclear
antigen (PCNA) immunohistochemical analysis to detect clonal cell proliferation. Differences
between means were analyzed by the study authors using ANOVA with least significance
difference tests. Fisher's exact or x2 tests were used to assess differences in incidences of
lesions.
No mortalities in the TPA treatment groups were reported. Significant decreases in mean
final body weights were observed in both dose groups (8 and 12% decreased, relative to controls
at 829 and 4,280 mg/kg-day, respectively). Absolute and relative bladder weights were
significantly increased by 60 and 82%, respectively, at the high dose (see Table D-18). Results
from urinalysis are shown in Table D-19. Significant dose-related decreases in urinary pH,
sodium, potassium, and chloride, and increases in calcium and phosphorus were observed in both
treatment groups. Urinary volume was significantly increased by 76% over controls at the high
dose and increasing amounts of urine precipitate were observed in a dose-related manner.
Macroscopically, 4/15 rats fed 4,280 mg/kg-day had numerous calculi versus none in controls.
Moderate precipitates (incidence not reported), but no calculi, were observed at the low dose, but
these incidences were not statistically significantly increased. Simple hyperplastic lesions in the
bladder occurred in 2/15 low-dose and 5/15 high-dose animals and were statistically significant
at the high dose. Animals receiving 4,280 mg TPA/kg-day in their diets also had incidences of
papillary or nodule bladder hyperplasia (4/15 vs. 0/15 in controls) that were not significantly
elevated. Hyperplastic lesions in high dose animals had increased PCNA indices compared with
bladder tissues collected from control rats. No treatment related papillomas or transitional cell
carcinomas were observed (see Table D-20).
A NOAEL of 829 mg/kg-day and a LOAEL of 4,280 mg/kg-day are determined for
significantly decreased body weights (>10% change from controls), increased relative and
absolute bladder weights, and increased incidences of simple hyperplasia in the bladder. Near
significant incidences of calculi and papillary or nodule hyperplasia in the bladder were also
reported. Significant changes in urinary pH and electrolyte levels, as well as sediment in the
urine, were observed in both dose groups.
No evidence of carcinogenic effects in the bladder was noted in this study in any
treatment group. The lack of concordance between urine precipitates, bladder calculi, and
hyperplastic lesions of the bladder makes the cause and effect relationships unclear as there are
animals with precipitates but no calculi, and animals with hyperplasia but no calculi. It is thus
unclear whether calculi are a key event in the progression of downstream effects.
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Cui et al. (2006b); Cui et al. (2007); Shi et al (2006)
Three peer-reviewed publications by the same group reported separate, mechanistically
focused results from a single study in rats (Cui et al.. 2007; Cui et al.. 2006b; Shi et al.. 2006).
Male Wistar rats (20/control group, 38/treatment group) were fed diets containing 0 or 5% TPA
(>99.9% purity) for 48 weeks. A 5% dietary intake of TPA is determined to be equivalent to an
ADD of 3,680 mg/kg-day.12 Additional treatment groups included diets with 5% TPA plus 4%
NaHCCte, or 4% NaHCCte alone. Interim sacrifices (four controls and eight treated) were
performed at Weeks 12 and 24. Body weights were measured once per week for the first
13 weeks, and then biweekly thereafter. The study report did not indicate whether measurements
of food and water consumption or observations for clinical signs were included in the study
design. At each sacrifice, complete necropsies were performed. Urinary bladders were excised,
weighed, and fixed for histopathology. PCNA immunohistochemical analysis was done on all
lesions to detect clonal cell proliferation. At 48 weeks, tumor incidence was recorded; the
largest tumors were removed for various molecular assessments to investigate the potential
mechanisms of cancer development (Cui et al.. 2007; Shi et al.. 2006). See the
"Mode-of-Action/Mechanistic Studies" section. The study authors performed statistical analysis
using one-way ANOVA, followed by least significant difference tests.
Two animals in the treatment group died from urethral obstruction. Hematuria was found
in "some" treated rats after 2 weeks of exposure (incidences were not provided). Mean body
weights of treated rats were described as "consistently lower than controls." Mean absolute and
relative urinary bladder weights of rats fed TPA were significantly increased as reported by the
study authors (data not provided). Bladder calculi and papillary or nodular hyperplasias were
significantly increased in treated rats at the 12-, 24-, and 48-week time points, respectively,
compared with none in the controls (see Table D-21).
Statistically significant incidences of bladder papillomas were observed at 24 (8/8) and
48 (18/20) weeks, and a significant incidence of transitional cell carcinomas in the bladder
(16/20) occurred in TPA-treated rats at the end of the study, indicating that TPA acts as a bladder
carcinogen in rats following oral exposure. At all time points, bladder lesions had significantly
higher PCNA labeling indices than corresponding control tissues and labeling increased from
papillary or nodular hyperplasia to papilloma to transitional cell carcinomas.
For non-neoplastic endpoints, the single exposure level of 3,680 mg/kg-day is identified
as a LOAEL based on increased incidences of bladder calculi and hyperplasias at 12, 24, and
48 weeks. Because 3,680 mg/kg-day is the only dose tested, a NOAEL cannot be identified.
Elevated absolute and relative bladder weights and reduced body weights were also reported,
although the data were not shown.
Gross (1977)
An unpublished, non-peer-reviewed study performed at Hebrew University-Hadassah
Medical School for EI DuPont de Nemours and Company reported the effects of chronic feeding
of TPA (97.3% purity) in rats (Gross. 1977). Groups of Wag/Rij (Wistar) rats (50 males and
12The reported dietary intake of 5% TPA in food was converted to an ADD by applying the following equation:
ADD = [% TPA x 10,000 (mg TP A/kg food) x food intake (kg food/day)] ^ BW (kg). In the absence of
body-weight or food-intake values in the study report, reference values from U.S. EPA (1988) for body weight
(0.462 kg) and food intake (0.034 kg/day) for male Wistar rats in a chronic study were used.
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50 females/dose group) were fed chow containing 0, 1,2, or 5% TPA for 24 months. These diets
are equivalent to ADDs of 0, 736, 1,470, and 3,680 mg/kg-day in males and 0, 842, 1,680, and
4,210 mg/kg-day in females, based on reference body-weight and food-consumption values for
male and female Wistar rats in a chronic study (U.S. EPA. 1988).13 Limited description of
methods was provided in the available report. The animals were observed daily. Body weights
were recorded weekly for the first 3 months, and then biweekly thereafter until Study Week 40.
All animals found moribund or dead throughout the study were subject to necropsy and
histopathological examination except for those with advanced autolysis. At sacrifice, blood was
collected for hematology and limited serum chemistry (blood urea) analysis. The liver, kidney,
heart, spleen, submaxillary, and adrenal glands were weighed. Histological examination was
done on these and other tissues (pituitary, thyroid, bladder, bone marrow, stomach, small
intestine, pancreas, and others). Limited statistical analysis of some data was performed by the
study authors, although complete description of the statistical methods used was not provided.
Graphically depicted cumulative mortality curves for male and female rats in the
low- and mid-dose groups did not differ appreciably from those of the controls; some of the
animals in each group died, with an upward trend beginning at -19 months. As indicated by the
study authors, the predominant cause of death in all groups (except high dose TPA), including
controls, was tumors of the pituitary. In the high-dose TPA treatment group, a significant
number of animals died throughout the experiment beginning in the second month; at 24 months,
the percent survival of high-dose males and females was 32 and 30%, respectively, compared
with 66 and 74% survival in controls (see Table D-22). The study authors indicated that the
formation of calculi in the urinary tract was the main cause of death in the high-dose animals.
No data on food or water consumption were provided. Growth curves were generated and
presented in an appendix that was not available for independent review. At the end of the
experiment, final body weights of males fed 1,470 and 3,680 mg/kg-day were significantly
decreased, relative to controls, by 10 and 22%, respectively. Female body weights were
significantly reduced by 20% in the 4,210-mg/kg-day group (see Table D-23). No significant
changes in any of the hematological endpoints measured (hemoglobin, and RBC and WBC
counts) were observed. Compared with controls, the percent of animals with increased blood
urea levels of >40 mg % (40 mg/dL) was significantly (p < 0.05) elevated in high-dose animals
(females: 26 vs. 5% in controls; males: 23 vs. 17% in controls; data not shown).
Changes in organ weights were generally consistent with the observed reduction in body
weight, with absolute organ weights decreasing and relative organ weights increasing, most
notably in mid- and high-dose males and high-dose females (see Table D-24). An exception was
the adrenal gland, which showed increases in both absolute and relative weights in high-dose
males and females, but not significantly so in females. Statistically significant decreases in both
absolute and relative liver, kidney, and heart weight in low- and mid-dose females in the absence
of significant body-weight changes in these groups are of uncertain toxicological significance
because the relative weights were not decreased in the high-dose group and no similar changes
were seen in males.
13Reported dietary intakes (% TPA in food) were converted to ADDs using the following equation:
ADD = [% TPA x 10,000 (mg TP A/kg food) x food intake (kg food/day)] ^ BW (kg). In the absence of sufficiently
reported body weight and food consumption data in the study, reference values recommended by U.S. EPA (1988)
for body weight (0.462 kg M/0.297 kg F) and food intake (0.034 kg/day M/0.025 kg/day F) for male and female
Wistar rats in a chronic study were used.
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Urinary tract calculi were observed almost exclusively in high-dose animals of both
sexes. Ninety-three percent of high-dose females and 89% of high-dose males had calculi,
compared with single incidences or none in the other treatment groups or controls; incidence of
calculi was significantly increased in both sexes at the highest dose (see Table D-25). Calculi
were found both filling and distending the urinary bladder and were also present in the pelvis of
the kidney. The incidences were 0%, 0%, 0% and 89% in males and 0%, 2%, 0% and 93% in
females. Analysis of kidneys from high-dose animals indicated a significant increase in
incidences of nephropathy, ranging from focal areas of destruction to overall loss of kidney
structure with infiltration of inflammatory cells and papillary necrosis. Other pathological
changes, described by the study authors as being nearly exclusive to high-dose animals, included
hyperplasia of the pelvis, ureteral, and/or bladder epithelium; infiltration of transitional cells; and
epithelial squamous metaplasia.
Tumor incidences in various tissues for this study are provided in Table D-26.
Treatment-related tumors were present in the bladder and ureter in 1/43, 1/48, and 21/37 males
and in 0/48, 2/47, and 21/34 females in the low-, medium-, and high-dose groups, respectively.
The bladder and ureter tumors were significantly increased in both sexes at the highest dose. No
bladder or ureter tumors were observed in the controls (0/45 males and 0/46 females). The
discussion within the available text of the Gross (1977) report indicates that these lesions were
primarily transitional cell tumors or squamous cell carcinomas. The study authors reported that
spontaneous tumors (where incidence in controls exceeded incidence in treatment groups)
occurred primarily in the pituitary and thyroid in both sexes and in mammary glands in females;
incidences of tumors in the adrenal medulla at the same level (2/46 in females) as the low dose
were also noted. There was an unexplainable decrease in several spontaneous tumors primarily
in the high-dose animals.
For non-neoplastic endpoints, a LOAEL of 1,470 and a NOAEL of 736 mg/kg-day are
determined for this study based on a 10% decrease in body weight, which is considered to be
biologically significant, in male Wag/Rij Wistar rats exposed to dietary TPA for 24 months. At
higher doses in both sexes, increased incidences of high blood urea levels, nephropathy, and
urinary tract calculi were observed.
Grubbs (1979): Preache (1983)
The Industry Institute of Toxicology (ITT) conducted a 24-month bioassay in rats to
evaluate the toxicologic and carcinogenic potential of TPA (Preache. 1983; Grubbs. 1979). A
portion of the pathological samples were later reanalyzed by Experimental Pathology
Laboratories, Inc. (EPL), along with additional samples that had been stored for future analysis
(ICI Americas Inc. 1992). The results from both unpublished, non-peer-reviewed reports
(original and reanalyzed/revised) are discussed here. F344 rats (126/sex/dose) were fed target
dietary levels of TPA (Amoco Chemicals Corp., "purified grade") equaling 0, 20, 142, and
1,000 mg/kg-day for 24 months. ADDs for the first 12 months of the study, based on recorded
body weights and food consumption rates, were reported by the study authors to be 0, 19.5,
138.2, and 995.4 mg/kg-day in males and 0, 19.2, 136.6, and 989.8 mg/kg-day in females. For
the purposes of this review, the reported doses at 12 months are adopted as the doses for the full
duration of the study. The animals were observed twice daily for general physical appearance,
morbidity, and mortality. Food consumption and body weights were measured approximately
weekly for the first 13 weeks, biweekly for an additional 12 weeks, and monthly thereafter.
Hematology, clinical chemistry, and urinalysis were performed on 5 animals/sex/group sacrificed
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at 6 and 12 months, on 20 animals/group at 18 months, and on the remaining surviving animals
at 24 months. Each animal was evaluated for neurological function and subjected to
ophthalmologic examinations of both eyes prior to sacrifice, whereupon necropsies were
performed. At each sacrifice, including any animals sacrificed due to a moribund state, brain,
heart, liver, kidneys, lungs, testes, and ovaries, were weighed; these and >30 other tissues were
preserved for histopathology. Histopathological examination was originally performed on
control and high-dose animals, and only low- and mid-dose groups that died or had evidence of
gross masses. Later, EPL re-evaluated the urinary bladders from a portion of these samples
(234 males and 210 females from either control or high-dose groups), along with urinary
bladders and eyes from an additional 214 male and 203 female rats exposed to low- and
mid-dose levels that were sacrificed at 6, 12, 18, or 24 months. The original study authors
conducted statistical analysis of the data using ANOVA and Tukey's procedure to determine the
differences between control and treated groups. All comparisons were limited to within-sex
analysis.
Experimental issues were reported that could affect the interpretation of the study results.
First, there was a possibility that animals were exposed to continuous light during an undefined
period of the study; the study authors thought this may have contributed to the high incidence of
cataracts observed in both test and control animals of both sexes. An alternative explanation is
that animals could have been exposed to an ocular virus. There was also an uncharacteristically
high incidence of uterine adenocarcinomas in females from all groups that could not be
explained; the authors suspected that this could also be related to continuous lighting and its
effects on hormones. Second, animals were exposed to excess levels of vitamins, resulting from
lack of autoclaving of the animal diets; the effect of this exposure is unknown. The study
authors noted that interpretation of animal body-weight data was confounded by significant
differences in initial (Day 0) body weights between rats designated for treatment groups versus
those marked for controls, with significantly lower starting weights in the treated rats. Control
and treated rats were also not weighed on the same day. Finally, the study authors indicated that
the concentrations of TPA in the diet were not as carefully controlled as desired, and
considerable deviations from the intended dose were observed during the first 24 weeks of the
study. Analytical analysis of TPA recovered from feed was done on Weeks 1, 5, 9, 12, 13, 18,
and 24, but not at later time points. The results indicated that the low-dose concentrations varied
from the target level mean by 16.7% over the first 24 weeks. On Week 24, a deviation of +71%
was observed. The study authors indicated that when this data point was dropped, the mean
deviation fell to within 9% of target. Mean variations in the mid- and high-dose concentrations
equaled 9.1 and 7.7%, respectively. It is unknown what potential deviations occurred throughout
the duration of the study. Therefore, because of this uncertainty, confidence in the dosing
provided by the study authors is low. In summary, because of experimental errors, confidence in
this study is too low to be considered as a principal study.
6- and 12-Month Interim Sacrifices:
At 6 months, 5 animals/group were examined, and there were no gross lesions in any of
the control or treated rats. There were also no treatment-related histopathologic tissue
alterations. A variety of spontaneous lesions were observed in all groups, but the study authors
reported that the lesions were not due to the treatment regimen. At 52 weeks (12 months),
mortalities and/or sacrifices due to morbidity were as follows: controls (five females), low dose
(three females, one male), mid dose (nine females, one male), and high dose (five females).
Several females that died (in all groups) were found to have ovarian abscesses containing
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Escherichia coli. During the first 12 months, no overt treatment-related clinical signs were
observed. At 6 months, ophthalmological examinations indicated that 3/5 high-dose males had
cataracts, and a high incidence of cataracts was again observed in TPA-treated males at
12 months (incidence not available), and to a lesser degree in treated females. Neurological
evaluations were found to be within normal limits for all animals sacrificed at 6 and 12 months.
There were significant decreases in mean body weights of both male and female rats of all
groups compared with controls throughout the first 12 months of treatment (see Tables D-27 and
D-28). However, these decreases may have been influenced by differences in initial body
weights between groups and an unexplained period of weight loss in the control females. At
times, the body-weight decreases exceeded 10% in females of all groups. Food consumption
was also significantly varied throughout the study in all treated male and female groups relative
to controls (see Tables D-29 and D-30). Six-month terminal sacrifice weights were significantly
reduced in low- and high-dose females, with decreases of 14, 6, and 13% compared with controls
at 19.2, 136.6, and 989.8 mg/kg-day, respectively (see Table D-31). Female terminal body
weights at 12 months and final body weights in males at 6 and 12 months were not statistically
different from controls. Furthermore, body weight in females was biologically significantly
(>10%) reduced at 6 months, but not at 12 months.
Absolute and relative organ weights were measured from only five animals per group at
both the 6- and 12-month time points. Absolute and relative heart weights in high-dose males
were significantly decreased at 6 months by 10 and 17%, respectively, relative to controls, but
not at 12 months (see Table D-31). In females, absolute and relative liver weights were
significantly increased (23 and 30%) in the mid-dose group at 6 months and relative liver weight
was also increased (23%) in the high-dose group at that time. Relative liver weight was also
significantly increased at 12 months in high-dose females, although the magnitude of change was
<10%. Finally, absolute, but not relative, ovary weight was significantly increased in high-dose
females at 12 months. No significant changes in kidney weights were observed in males or
females. Urinalysis (pH, specific gravity, and urine output), hematology (RBC, Hb, hematocrit,
and WBC), and clinical chemistry (glucose, BUN, ALT, and ALP) measurements were also done
on a small number of animals (n = 5) and showed no clear dose-related effects.
There were no consistent gross pathology findings in any treatment group at 6 or
12 months. Several spontaneous histological lesions were observed in both the control and
high-dose rats, but the incidences were not significant and not considered by the study authors to
be treatment related, although the number of animals evaluated was low. Lesions relating to the
bladder are shown in Table D-32. Histological analysis of other tissues was not performed in the
low- and mid-dose groups.
18- and 24-Month Findings:
Available data for the 18- and 24-month sacrifices are limited to summary descriptions
written by the study authors that could not be independently evaluated. By 24 months, several
mortalities or sacrifices due to morbidity were described. Between 18 and 24 months, 75 males
and 105 females died, and an additional 36 males and 33 females were sacrificed (dose groups
were not specified). The numbers of surviving animals were comparable across groups in males,
and although there were more female survivors in the control group, no dose-related effect on
survival was observed. In females, the study authors indicated that uterine adenocarcinomas
were the primary cause of death in 8/24, 17/43, 23/34, and 21/37 animals that died in the control,
low-, mid-, and high-dose groups, respectively. The most prominent clinical signs among all
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groups were ocular effects. At 18 months, all animals (including controls) had cataracts,
although differences in severity were observed. The cataracts in males treated with TPA were
considered "mature," whereas only 50% of the control males had this cataract designation.
Although the severity appeared to be slightly less in female rats, the incidences were higher in
treated animals than in controls. At 24 months, cloudy or opaque eyes occurred in >95% of all
males (including controls) and in 91% of female controls and 96-100%) of those treated with
TPA. The frequency of matter-crusted eyes was slightly higher in mid- and high-dose females
(15-20%)) than those in the control and low-dose groups (<6%>). Other ocular effects noted
included dark brown hemorrhagic staining around eyelids, the presence of corneal crystals,
vascular evidence of anemia, iris-corneal adhesions, and one instance of eyelid tumor (further
details and data for these effects were not available). No treatment-related neurological effects
were observed.
The decreases in body weights observed during the first 12 months of treatment were not
biologically significant and were only maintained in high-dose males and females, and a
concomitant increase in water intake was reported. At 24 months, high-dose females were
described as having more moderate to heavy sediment in their urine compared with controls.
Reduced urine pH was noted in treated male animals as well as those lacking triple phosphates
(crystals) in the urine. At the 18- and 24-month necropsies, 2/27 and 11/86 high-dose females,
respectively, showed evidence of urinary bladder calculi (data not reported). No
exposure-related clinical chemistry or hematological changes were noted. Kidney weights of
high-dose males were reduced at 18 months. At 24 months, heart and kidney weights were
reduced in mid- and high-dose females, but the authors did not indicate whether these were
absolute or relative organ weights. Other sporadic organ-weight changes were described, which
the study authors attributed to changes in body weight, rather than to organ-specific toxicity.
Gross necropsy indicated that sand-like particles, or calculi, occurred in 16/126 high-dose
females over the course of the study.
The initial histopathological evaluation showed a nonsignificant increase in the incidence
of bladder hyperplasia in high-dose females at 18 months (5/27 vs. 0/22 in controls) and
24 months (14/79 vs. 8/83 in controls) (see Table D-32). The incidence of bladder hyperplasia in
high-dose males did not differ from controls at either time point. At 24 months, females also
exhibited significantly increased incidence of squamous metaplasia (9/79 vs. 0/83 controls).
Squamous metaplasias were always seen adjacent to a tumor.
A follow-up reanalysis was done on a portion of bladder, uterus, and eye tissues from
control and high-dose animals from sacrifices at 6, 12, 18, and 24 months, as well as samples
from low- and mid-dose animals. The available report ("ICI Americas Inc. 1992) did not include
revised incidence tables. Data from the pathologist summary text are included in Table D-32
where possible but reporting of data in the text was incomplete. In the bladder, noted findings
were hyperplasia in 1 mid-dose female and 4 high-dose females (and no males) at 18 months and
in 9 low-, 3 mid-, and 0 high-dose males and 7 low-, 2 mid-, and 24 high-dose females at
24 months. Discrepancies in the numbers of animals and some of the findings between the
reanalysis and the original report were not specifically addressed. In the reanalysis several
lesions were recategorized from transitional cell adenomas to hyperplasias. Ocular changes,
including retinal degeneration and cataracts, were observed in low- and mid-dose male and
female rats at 18 months, and in all animals at 24 months. Incidences of other non-neoplastic
lesions in the spleen, kidney, adrenal glands, pituitary, testes, and ovaries were within the
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expected range for F344 rats. The study authors reported that at 18 months, uterine
abnormalities occurred more frequently in treated females, and uterine masses occurred only in
treated groups. There were no treatment-related microscopic changes in animals from any
treatment group sacrificed at 6 or 12 months.
The original study reported transitional cell adenomas in the bladder's of 15/79 high-dose
females and 1/83 controls at 24 months, which was identified as a statistically significant
difference by Fisher's exact test performed for the purposes of this PPRTV assessment. In the
reanalysis, as noted above, several lesions were recategorized from transitional cell adenomas to
hyperplasias. This occurred primarily in high-dose females. Bladder tumors reported in the
reanalysis (all at 24 months) were transitional cell adenomas in 10 high-dose females and
1 control female, transitional cell carcinoma in 1 high-dose female, and transitional cell
papillomas in 2 low-dose females. Based on the data reported for the reanalysis, the incidence of
bladder adenomas was significantly increased in high-dose females by a Fisher's exact test
performed for the purposes of this PPRTV assessment.
Nine of the 15 animals (females) with transitional cell adenomas and both animals with
transitional cell carcinoma (as reported in the original study) had calculi in the bladder at
24 months. Uterine adenocarcinomas occurred in 30/81 and 32/75 low- and mid-dose females
combined over all sacrifice periods. The study authors reported that these aggressive metastatic
uterine adenomas or adenocarcinomas appeared be treatment related (statistical significance not
reported). Forty percent of high-dose females (vs. none in controls) at 18 months exhibited
uterine neoplasias. However, the study authors also noted that similar tumors were observed in
control animals from a different study that were housed in the same room as the TP A control
animals. By 24 months, uterine masses did in fact appear in all groups, occurring in 17%
controls, and in 22, 24, and 25% of females in low-, mid-, and high-treatment groups,
respectively. The study authors indicated that the high incidence of uterine tumors could
potentially be due to light-induced increases in estrogen, although there is little evidence to
support this.
For non-neoplastic findings, a LOAEL cannot be determined because significant effects
were not consistently observed throughout the 24-month study. Therefore, the highest dose of
995.4 mg/kg-day is identified as the NOAEL. As discussed previously, confidence in this study
is low because of experimental deficiencies (i.e., exposure to continuous light during an
undefined period of the study, exposure to excess levels of vitamins, the concentrations of TP A
in the diet were not as carefully controlled as desired).
Reproductive and Developmental Studies
Ledoux and Reel (1982)
Exposure details for this unpublished, non-peer-reviewed 90-day feeding study and
following one-generation reproductive range-finding study was described above under
"Subchronic Studies." In brief, Wistar and CD rats (9-10 breeding pairs/group) that had already
been on TPA exposure diets for -90 days were continued on their diets through mating,
gestation, and lactation until scheduled sacrifice. Calculated doses (equivalent to 0, 0.03, 0.154,
0.5, 2, and 5% TPA in feed) were 0, 15.3, 79.09, 266, 1,020, and 2,650 mg/kg-day (males) and 0,
19.3, 114.5, 313, 1,280, and 3,100 mg/kg-day (females) in Wistar rats, and 0, 14.6, 76.15, 247,
976, and 2,590 mg/kg-day (males) and 0, 17.6, 86.57, 286, 1,260, and 2,840 mg/kg-day
(females) in CD rats (calculation details were described in the 90-day summary). At weaning,
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litter sizes were reduced to 2 males and 2 females/litter from 5 litters (equaling
20 pups/strain/group) for continued exposure to the same diet as their parents for 30 days (until
PND 51). Reproductive and developmental endpoints, including fertility index, litter size, sex,
viability, and survivability were recorded. All animals were observed twice daily for clinical
signs and mortality. Offspring body weights were recorded on PND 1 and at weaning (PND 21).
Gross necropsies were performed on all offspring and on parental animals. The animals were
examined for lesions in the thoracic and abdominal viscera, with a focus on renal and urinary
systems. The study authors performed statistical analysis using ANOVA and Dunnett's test,
using the litter as the experimental unit and average effects per litter as dependent variables.
Five treated Wistar dams, one treated CD dam, and two treated CD parental males died
between TPA Exposure Days 116 and 148. The deaths were not attributed to treatment by the
study authors, although they primarily occurred at the 2 and 5% dietary TPA levels. Four of the
animals died due to hair in the intestinal tract; in one case, a dam died during labor. Clinical
signs in parental control and treated animals during Experimental Days 91-147 primarily
included weight loss (quantitative body-weight-gain data were not provided), which the study
authors indicated was evenly distributed across groups, without correlation with TPA exposure
level. The study authors reported that reproductive performance was not significantly affected
by TPA exposure. There were no significant changes in the fertility index or litter size between
respective controls and treated Wistar or CD rats (data not shown).
Seventeen Wistar and 23 CD pups (approximately 5% of the total number of pups) across
all treatment groups were born dead. Of the pups found dead, the study authors reported that a
total of 76% of Wistar and 96% of CD stillborn pups were clustered in the two highest dietary
concentrations of TPA. There was no significant effect on the number of pups per litter alive on
PND 0, 1, or 21. However, the proportions of CD rat male and female pups surviving to PND 21
were significantly decreased in the high-dose group (see Table D-33). Nonsignificant decreases
were seen in Wistar rats. From birth to weaning, there were no notable treatment-related clinical
signs in Fi offspring of either strain. On PND 1, body weights of Wistar high-dose male, female,
and combined sexes were significantly reduced by 17—19% from controls (see Table D-34). In
CD rats, pup weight was biologically significantly (>5%) reduced in males and females at
>1,260 mg/kg-day and in combined sexes at the highest dose on PND 1. On PND 21, pup
weights of Wistar male, female, and combined sexes were biologically significantly (>5%)
reduced at >1,280 mg/kg-day. In CD rat pups, body weights of male, female, and combined
sexes were biologically significantly (>5%) reduced at all doses at PND 21.
Postweaning, a number of unscheduled deaths occurred from PNDs 24 to 36 in high-dose
weanlings of both strains. The presence of calculi in the bladder was associated with 10/19 and
12/18 deaths in high-dose weanling Wistar and CD rats, respectively. Gross necropsy of Fi
offspring between PNDs 21 and 51 indicated no notable findings in the bladder of animals fed
0.03, 0.154, 0.5, or 2% TPA in their diets. At the highest dose, the primary findings were
significantly increased incidences of renal calculi and thickened bladder walls, occurring in
8/18 male and 16/31 female Wistar weanlings and in 5/9 male and 9/13 female CD weanlings
(see Table D-35). Other gross observations reported by the study authors in high-dose animals
included enlarged caecum and bladders, kidney dilation, and spots on the kidney.
This study identifies a LOAEL of 1,280 mg/kg-day and a NOAEL of 313 mg/kg-day in
Wistar rats for biologically significant (>5%) decreases in pup body weights on PND 21. There
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were also significant increases in renal and bladder calculi in pups upon necropsy (PNDs 21-51)
at higher doses. In CD rats, a LOAEL of 17.6 mg/kg-day (the lowest dose) is identified for
biologically significant (>5%) reduced pup body weights at PND 21. Because 17.6 mg/kg-day is
the lowest dose tested, a NOAEL cannot be identified for CD rats.
Cui et at. (2004)
In a published, peer-reviewed study, Cui et al. (2004) investigated the effects of TP A
(>99.99% purity) on testicular function in rats. Commercially obtained male S-D rats
(10 males/group) were fed daily diets containing 0, 0.2, 1, or 5% TPA for 90 days. Doses were
determined for this review to be equivalent to 0, 172, 861, and 4,310 mg TPA/kg-day based on
reference body-weight and food-consumption values for male S-D rats in a subchronic study.14
Recordings of clinical signs or water consumption were not included in the study methods. Feed
consumption (data not shown) and body-weight gain were monitored. At sacrifice (Day 91),
blood was collected for serum testosterone measurements and testes were removed and weighed.
Left testes were used for sperm head counts and biochemical assays; the right testes from six
males were preserved for histopathological analysis. Three testes from the control and high-dose
males were used for electron microscopic observation. Sperm from the cauda epididymides were
measured for multiple motility parameters using Computer-Assisted Sperm Analysis (CASA).
The study authors applied Duncan's test to evaluate the data for statistical significance.
TPA treatment up to 4,310 mg/kg-day did not cause any significant changes in food
consumption (data not shown), body-weight gains, or absolute or relative testis weights,
compared with controls (see Table D-36). Significant reductions in sperm head counts and daily
sperm gain production (19% decrease from controls) were reported at the high dose. TPA
treatment significantly affected several sperm motility parameters in a dose-related manner
(see Table D-37). Straight line velocity (VSL) (27-39% decrease) and percent straightness
(STR) (18-24%) decrease) were significantly reduced from control values in all treatment groups.
Linearity (LIN), and beat cross frequency (BCF) also decreased with increasing exposure to TPA
and were significant starting at 861 (LIN only) and 4,310 mg/kg-day, respectively. No obvious
histological changes were observed. Electron microscopic evaluation identified aberrations in
cells from several stages of spermatogenesis (data displayed in images only). Observations
included abnormal distribution of heterochromatin in spermatogonia, spermatocytes, and Sertoli
cells; indistinction of the nuclear membrane in spermatogonia, spermatocytes, spermatozoa, and
Sertoli cells; vacuolization and/or loss of mitochondrial cristae in spermatogonia, spermatocytes,
and Sertoli cells; and liposome hyperplasia in spermatogonia. No changes were observed in
Leydig cells. Testicular enzymes were largely unaffected, except for sorbitol dehydrogenase
(SDH), which was significantly reduced by 16%, compared with controls. Serum testosterone
was also unchanged with TPA treatment. The study did not evaluate fertility or reproductive
performance.
Given the absence of histological findings, and lack of fertility assessment, in male
Wistar rats, a NOAEL of 861 mg/kg-day and a LOAEL of 4,310 mg/kg-day with low confidence
are determined for significant reductions in sperm head counts, several sperm motility
14Reported dietary intakes (% TPA in food) were converted to ADDs using the following equation: ADD = [% TPA
in food x 10,000 (mg TP A/kg food) x food intake (kg/day)] ^ average BW (kg). Body-weight and food-intake
values were not reported, so reference values from U.S. EPA (1988) of 0.267 kg (BW) and 0.023 kg/day (food
intake) for male S-D rats in a subchronic study were used.
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parameters, daily sperm gain production, and abnormal changes in sperm cell structure
throughout spermatogenesis observed by electron microscopy following exposure to TPA in the
diet for 90 days. Collectively, these changes indicate the potential for TPA to affect male
reproductive performance. Although significant reductions in some sperm motility parameters
were observed at lower doses (i.e., 172 and 861 mg/kg-day), the biological significance of these
findings is uncertain because fertility does not appear to be affected in other studies. Electron
microscopy was only performed on controls and high-dose samples, and therefore, it cannot be
determined whether any structural changes occurred at lower dose levels.
Kwack and Lee (2015)
The effects of TPA exposure on male reproductive organs were further investigated by
Kwack and Lee (2015). S-D rats (five males/group, 6 weeks old at the start of the study) were
treated by daily gavage with TPA doses of 0, 10, 100, or 1,000 mg/kg-day for 4 weeks. Similar
treatments were done using other phthalic acid isomers. In vitro studies on mouse testis Sertoli
cells, human testis cancer cells, and human fetal liver cells were also performed. No clinical
observations, body weights, or measurements of food and water consumption were recorded. At
4 weeks, the testes, cauda epididymides, and spermaducts were dissected from rats under
anesthesia. Absolute and relative testis and epididymis weights were recorded, and CASA was
used to evaluate semen parameters in the controls and the rats treated with 1,000 mg/kg-day.
The percentage of mobile, static, progressive, and rapid sperm were determined for all treatment
groups. The study authors analyzed the data by one-way ANOVA and Tukey's post-hoc
comparisons.
The authors reported no significant changes in relative or absolute testis or epididymis
weights (data not shown), or total sperm counts in rats treated with 1,000 mg/kg-day TPA,
compared with controls (see Table D-38). Sperm progressive motility (a measure of forward
progression) was significantly reduced by 26% at the high dose, compared with controls. A
general decline in other sperm motility parameters measured using CASA (amplitude of lateral
head displacement, beat cross frequency, linearity, straightness, velocity average path, velocity
curved line, and velocity straight line) were observed, but decreases were determined not to be
statistically significant.
Based on decreased sperm motility, this study identifies LOAEL and NOAEL values of
1,000 and 100 mg/kg-day, respectively, in rats treated with TPA by gavage for 4 weeks.
Inhalation Exposures
No primary reports of short-term, subchronic, or chronic inhalation studies of TPA in
animals have been located.
Reproductive and Developmental Studies
Chemical Manufacturers Association (2000)
In an unpublished, non-peer-reviewed study, Chemical Manufacturers Association (2000)
investigated the teratological effects of inhaled TPA in female rats. Gravid S-D rats
(22-25/group) were exposed to a purified TPA particulate aerosol by whole-body inhalation for
6 hours/day, 7 days/week on Gestation Days (GDs) 6-15; analyzed TWA concentrations
reported by the study authors were 0, 0.90, 4.73, and 10.40 mg/m3. The mass median
aerodynamic diameters (MMAD) were 4.16, 4.87, and 5.39 for the low-, medium-, and
high-exposure concentrations, respectively, with associated respirable fractions of 91.1, 89.4, and
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85.0%. Geometric standard deviations (GSD; og) were not reported. Control rats were exposed
to filtered air only. The rats were observed twice daily on weekdays, and once daily on
weekends, and for 3 hours after exposures for signs of toxicity. Body weights were recorded on
GDs 0, 5, 6, 11, 16, and 20 (study termination). Dams were sacrificed on GD 20 and subjected
to gross necropsies. Any lesions or abnormalities were noted, and uterine horns, fetuses, and
ovaries were removed and weighed. Gross observations of fetuses were recorded, and one-half
of each litter was randomly selected for either a skeletal or wet visceral examination. All
anomalies were recorded and given a severity score based on historical control data. For
statistical analysis, the study authors used a multilevel linear model to analyze log-transformed
pup body weights using the pup as a nested factor within the dam. Log-transformed dam body
weights were analyzed by multivariate ANOVA. Other statistical methods included ANOVA
with Dunnett's test and a log-linear model for analysis of fetal anomalies.
No maternal deaths occurred during the study. Except for slightly higher, yet
nonsignificant, incidences of scaly tail in TPA-exposed groups, clinical signs were sporadic in
nature and not related to exposure. Dam body weights, body-weight gain, uterine weights, and
corrected body weights (body weights minus uterine weights) were comparable to controls. No
notable gross necropsy findings in dams were reported. There were no signs of maternal toxicity
at the exposure concentrations tested.
TPA had no effect on litter viability; numbers of live and dead fetuses, total and live
implants, and resorptions; or fetal sex ratio. Fetal body weights in all treatment groups,
measured by sex, or combined, were comparable to controls. There were no significant gross
external findings that the study authors considered treatment related. One fetus in the
4.73-mg/m3 group, and one in the 10.40-mg/m3 group, had short and/or filamentous tails. A
second fetus in the 10.40-mg/m3 group had agnathia (absence of a portion or the entirety of one
or both jaws). Visceral anomalies (variations and malformations) were also not considered by
the study authors to be treatment related and differences were not statistically significant.
Visceral variations were observed primarily in the kidneys of all treatment groups, including the
controls, with hydroureter and hydronephrosis being the most common defects. One fetus in the
10.40-mg/m3 group also had fused kidneys with mispositioned ureters and ovaries.
Several anomalies were observed in the ribs, including ribs that were wavy, bulbous, and
incompletely ossified, and reduced 13th and rudimentary 14th ribs. The study authors classified
most of these anomalies as normal variations based on occurrences in in-house historical controls
(one rib anomaly, the appearance of gnarled ribs in a fetus in the 4.73-mg/m3 group, was
considered a malformation). When combined, a statistically significant increase in total rib
anomalies was observed in the mid-dose group, compared with controls (see Table D-39). This,
however, was primarily due to a high incidence of bulbous ribs in a single litter (eight fetuses in
one litter) in this group. Incidence of rib anomalies was not significantly increased in the
high-dose group. Statistical analysis between controls and treated groups indicated no
significant differences in the incidences of any individual skeletal anomalies. Three other
skeletal malformations (in areas other than the ribs) were noted, including a misaligned sacral
vertebrae, which was consistent with a filamentous tail, in a fetus in the 4.73-mg/m3 group; a
malformed skull in a 10.40-mg/m3 group fetus; and a reduced jaw in one control animal. The
study authors concluded that the skeletal rib anomalies, although statistically significant at the
mid-exposure level, were not an indicator of TPA teratogenicity, citing these as common
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anomalies based on in-house historical values, a lack of dose-response, and absence of other
signs of embryotoxicity.
In this study, the high-exposure concentration of 10.40 mg/m3 is a NOAEL for both
maternal and fetal effects in female S-D rats exposed by inhalation to TPA particulates for
6 hours/day, 7 days/week on GDs 6-15. LOAEL values are not identified. The TWA
concentrations of 0, 0.90, 4.73, and 10.40 mg/m3 in this study correspond to human equivalent
concentrations for extrarespiratory effects (HECers) of 0.59, 2.96, and 6.240 mg/m3,
respectively.15
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Table 4A provides an overview of genotoxicity studies of TPA and Table 4B provides an
overview of other supporting studies on TPA.
Genotoxicity Studies
The genotoxicity of TPA has been evaluated in a limited number of in vitro and in vivo
studies (see Table 4A for more details). The genotoxicity tests for TPA were negative. No
mutagenicity was detected in Salmonella typhimurium with and without metabolic activation
(Lee and Lee, 2007; Lerda, 1996; Brooks et at., 1989; Zeiger et at., 1985; Zeiger et at., 1982;
Florin et al.. 1980). TPA did not induce clastogenic effects in vitro or in vivo; no chromosomal
aberrations (CAs) were observed in Chinese hamster ovary (CHO) cells [Ishidate et al. (1988) as
reported in Ball et al. (2012); Lee and Lee (2007)1. and there were no increases in micronuclei
(MN) in binucleate human lymphocytes (Lerda. 1996) or in bone marrow from ICR mice
administered up to 2,100 mg/kg TPA by i.p. injection [Bioreliance (2001) as reported in OECD
(2001); Lee and Lee (2007)1. The urinary bladder is a primary target of TPA-induced toxicity.
No deoxyribonucleic acid (DNA) damage was detected by comet assays on cells isolated from
the bladders of rats exposed to doses as high as 2,000 mg/kg (Kvova et al .. 2018). Finally, there
was no evidence of TPA-induced unscheduled DNA synthesis (UDS) in HeLa cells (Lerda.
1996). and no induction of umu gene expression, a bacterial operon induced by DNA damage,
was observed when incubated with TPA-treated rat liver microsomes and a S. typhimurium
NM2009 bacterial suspension (Dai et al.. 2006b).
15HECs were calculated per U.S. EPA (1994) methodology for particulates as follows: 6-hour TWA exposure
concentration (mg/m3) x 6-hour daily exposure period/24 hour x the regional deposited dose ratio (RDDR) for
extrarespiratory effects (2.6, 2.5, or 2.4 for the low-, medium-, or high-exposure groups, respectively). RDDR
values were calculated by U.S. EPA software using MMAD and body-weight data from the study and assumed
values for sigma g (which was not reported in the study) ranging from low (monodisperse) to high (polydisperse). It
was found that choice of sigma g had little influence on the RDDR calculation.
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Table 4A. Summary of TP A (CASRN 100-21-0) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation"
Comments
References
Genotoxicity studies in prokaryotic organisms
Mutation
Salmonella typhimurium TA98,
TA100, TA1535, TA1538
0-400 ng/plate;
5 doses
Ames assay. No evidence of
mutagenicity in any of the strains tested,
with or without S9 activation.
Brooks et al.
(1989)
Mutation
S. typhimurium TA98, TA100,
TA1535, TA1537
3 (imol/plate
Preincubation assay. No evidence of
mutagenicity or cytotoxicity with or
without S9 activation in any of the
strains tested.
Florin et al.
(1980)
Mutation
S. typhimurium TA98, TA100,
TA102, TA1535, TA1537
0, 20, 100, 500, 2,500,
or 12,500 nM
Ames assay. No evidence of cytotoxicity
or mutagenicity in any of the strains
tested, with or without S9 activation.
Lee and Lee
(2007)
Mutation
S. typhimurium TA98, TA100,
TA1535, TA1537, TA1538
0, 0.5, 5, 50, 500,
5,000 ng/plate
Ames assay. No evidence of
mutagenicity in any of the strains tested,
with or without S9 activation.
Lerda (1996)
Mutation
S. typhimurium TA98, TA100,
TA1535, TA1537
0, 100, 133, 1,000,
3,333,
100,000 ng/plate
Preincubation assay. No evidence of
mutagenicity in any of the strains tested,
with or without S9 activation.
Zeieer et al.
(1982); Zeieer et
al. (1985)
DNA damage
(induction of umu
gene expression)
S. typhimurium NM2009
Isolated S-D rat liver microsomes
containing TPA and an
NADPH-generating system were
incubated with the NM2009
bacterial suspension, and umu gene
expression was measured as the
specific galactosidase activity per
unit per protein
0.025, 0.05,
0.1 ^mol/L
No dose-related induction of umu gene
expression was detected with or without
phenobarbital, or
3-methylcholanthrene-induced or diet
control rat liver microsomes.
Dai et al. (2006b)
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Table 4A. Summary of TP A (CASRN 100-21-0) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation"
Comments
References
Genotoxicity studies in mammalian cells—in vitro
CA
CHO cells
0, 20, 100, 500, 2,500,
12,500 nM
No increase in CA with or without S9
activation. There was no evidence of
cytotoxicity.
Lee and Lee
(2007)
CA
CHL cells
Up to 2,000 ng/mL or
12 mM
No increase in CAs without activation
using a 48-hr treatment with no recovery.
Ishidate et al.
(1988) as
reDorted in Ball et
al. (2012)
MN
Binucleate human lymphocytes
0, 0.5, 5, 50,
500 iig/mL
—
ND
No increase in MN/1,000 binucleated
cells.
Lerda (1996)
UDS
HeLa heteroploidy human cells
0, 0.5, 5, 50,
500 |ig/mL
—
—
No DNA repair was observed with or
without activation with hydroxyurea.
Lerda (1996)
Genotoxicity studies—mammalian species in vivo
MN (bone
marrow)
Male ICR mice were administered
TPA by single i.p. injection; mice
were sacrificed 24 hr after dosing;
bone marrow was evaluated for
MN
0, 20, 100, 500, 2,500,
12,500 ^mol/kg (~0,
3.3, 17, 83, 400,
2,100 mg/kg)
NA
The percent of MNPCEs was 0.28% in
control and 0.54% average in treated
groups. Effects occurred without a dose-
response relationship and results were
considered negative.
Lee and Lee
(2007)
MN (bone
marrow)
Male and female ICR mice
(5/sex/group) were administered
TPA by a single i.p. injection;
animals were sacrificed at 24 or
48 hr after dosing; bone marrow
was evaluated for MN
0, 200, 400,
800 mg/kg
NA
1 high-dose male died and was replaced.
No dose-related increases in MN,
compared with controls, at 24 hr. At
48 hr, control and high-dose groups had
2 and 8 MN per 20,000 PCEs,
respectively. The results were
considered negative by the researchers.
No differences between males and
females were observed.
Bioreliance
(2001) as
reported in
OECD (2001)
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Table 4A. Summary of TPA (CASRN 100-21-0) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation"
Comments
References
DNA damage
(comet assay)
Male Wistar or S-D rats were
administered TPA by gavage at 3
and 24 hr before sacrifice; cells
from the urinary bladder were
isolated for a comet assay
0, 500, 1,000,
2,000 mg/kg
NA
No significant increases in the average
tail length were observed.
Kvova et al.
(2018)
a- = negative.
CA = chromosomal aberration; CHL = Chinese hamster lung; CHO = Chinese hamster ovary; DNA = deoxyribonucleic acid; i.p. = intraperitoneal; MN = micronuclei;
MNPCE = micronucleated polychromatic erythrocyte; NA = not applicable; NADPH = reduced form of nicotinamide adenine dinucleotide phosphate; ND = no data;
PCE = polychromatic erythrocyte; S-D = Sprague-Dawley; TPA = terephthalic acid; UDS = unscheduled DNA synthesis.
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Supporting Toxicity Studies
A number of supporting acute, short-term, subchronic, chronic, and
reproductive/developmental studies are summarized in Table 4B. These include inadequately
reported studies (primarily from secondary sources), studies that evaluated only one endpoint,
studies published in a foreign language with limited English translations, and studies conducted
via routes of exposure other than oral or inhalation (e.g., injection). These studies support that
the bladder is a target of TPA toxicity. Studies that evaluated only a single endpoint were not
considered as principal studies for the derivation of provisional reference values given the
availability of comprehensive studies that evaluated multiple endpoints for p-phthalic acid.
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Table 4B. Other TPA (CASRN 100-21-0) Studies
Test3
Materials and Methodsb'c
Results
Conclusions
References
Supporting evidence—noncancer effects in animals following oral exposure
Acute
Male and female S-D rats (5/sex) received a
single oral dose of 5,000 mg/kg TPA in water by
gavage and were observed for 14 d. Endpoints
evaluated included clinical signs, body weights,
and gross necropsy.
No deaths were noted. Within 48 hr of
dosing, all animals exhibited diarrhea.
Redness around the nose occurred in 3/5
males and 2/5 females. Increased mean body
weights were reported (data not shown).
Rat LD5o: >5,000 mg/kg.
Amoco Corporation
(1990) as cited in
OECD (2001)
Acute
Rat (no other details provided).
ND
RatLDso: >15,300 mg/kg.
Amoco Corporation
(1975) as cited in
OECD (2001)
Acute
10-20 F Wistar rats were given TPA via gavage
to determine the LD5o.
ND
Rat LD5o = 1,960 mg/kg.
Cauiolle et al.
(1991) as cited in
OECD (2001)
Acute
Rat; acute lethality study.
ND
Rat LD5o = 18,800 mg/kg.
NIOSH (1985) as
cited in U.S. EPA
(1986)
Acute
30 F Swiss albino mice were administered by
gavage suspensions of 10 and 20% TPA in 0.5%
sodium carboxymethylcellulose solution to
determine the LD5o.
Animals that died did so within 48 hr of
treatment. Surviving animals had no
abnormal behavior except lethargy.
Mouse LD50:
>5,000 mg/kg.
Hoshi et al. (1968)
Acute
Swiss mouse; acute lethality study.
ND
Mouse LD5o: 1,470 mg/kg.
BG Chemie (1990)
as cited in MAK-
Commission (2012)
Acute
Male S-D rats were administered 2 doses (at
21-hr intervals) of 0 or 2,000 mg/kg TPA via
gavage. 2 animals were sacrificed at 3, 6, and
9 hr after the final dose (controls sacrificed at
6 hr only). Endpoints evaluated included
mortality, clinical signs, body weight, and
scanning electron microscopy analysis of bladder
tissues.
Micro crystals were observed in the bladder 6
and 9 hr after dosing (4/6 animals). Raised
ridges (1/6) and pleated surfaces was visible
in the bladder epithelium 9 hr after dosing.
TPA induced formation of
microcrystals and changes
to the bladder epithelium
within 6-9 hr of acute
gavage exposure to
2,000 mg/kg.
Kvova and Terada
(2018)
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Table 4B. Other TPA (CASRN 100-21-0) Studies
Test3
Materials and Methodsb'c
Results
Conclusions
References
Subchronic
Male and female Wistar rats (number/group NS)
were administered 0 or 5% TPA in the diet for
1 wk, followed by 3% dietary TPA through
Exposure D 90 [-1,400 and 1,700 mg/kg-d for
males and females, respectively, as reported in
Ball et al. (2012)1.
Increased incidence of bladder calculi in
11/18 males and 3/19 females. Moderate to
mild transitional cell hyperplasia in
13/18 males and 3/19 females.
TPA was reported to
induce calculi and
hyperplasia in the bladder
by subchronic dietary
exposure. Primary study
report not available.
Amoco Corporation
(1972) as cited in
OECD (2001): Ball
etal. (2012)
Subchronic
S-D rats (17-18 M orF/group) received 0, 50,
500, or 5,000 mg/kg-d TPA in the diet for 90 d.
Incidences in the bladder at 0, 50, 500, and
5,000 mg/kg-d, respectively:
Simple hyperplasia: 1/18, 10/17, 5/18, 7/17;
Atypical hyperplasia: 0/18, 0/17, 10/18, 5/17;
Calculi: 0/18, 0/17, 2/18, 10/17;
Transitional cancer: 0/18, 0/17, 0/18, 4/17.
TPA was reported to
induce calculi, hyperplasia
and cancer in the bladder
by subchronic dietary
exposure. Primary study
report not available.
Qi et al. (2002)
foreign language
study as cited in
MAK-Commission
(2012)
Chronic
Albino rats (30/sex/group; strain NS) were fed 0,
0.05, 0.16, 0.50, 1.5, or 5% TPA in the diet for
15 wk. Treatments correspond to approximately
0, 37.9, 122, 393, 1,220, and 3,837 mg/kg-d in
males and 0, 46, 147, 447, 1,456, and
4,523 mg/kg-d in females.
Significant increases in bladder calculi
(9/17 males), chronic inflammation, and
proliferative hyperplasia. Males were more
affected than females.
TPA was reported to
induce calculi,
inflammation, and
hyperplasia in the bladder
by subchronic dietary
exposure. Primary study
report not available.
Reliability was decreased
because of the age of the
studv. according to OECD
(2001).
Amoco Corporation
(1970) as cited in
OECD (2001)
Chronic
F344 rats (4 F/group) were fed diets containing 0,
0.5, 2, or 5% TPA in the diet (~0, 565, 2,260, and
5,650 mg/kg-d) for 6 mo.
A decrease in urinary pH and significant
changes in urinary electrolytes were observed
in all dose groups. Two high-dose females
developed calculi in the bladder; the
incidence was not significant.
TPA was reported to
produce low incidence of
calculi in the bladder by
6-mo dietary exposure.
Primary study report not
available.
Heck (1979)
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Table 4B. Other TPA (CASRN 100-21-0) Studies
Test3
Materials and Methodsb'c
Results
Conclusions
References
Supporting evidence—reproduction and development effects in animals following oral exposure
Gestational/
lactational/feeding
exposure of pups
Gravid F344 rats (5-7/group) were administered
0, 0.5, or 5% TPA in the diet (~0, 560, or
4,700 mg/kg-d) from GD 7 through parturition
and weaning. A separate group of 4 dams
received 5% (-4,700 mg/kg-d) TPA from PND 1
through weaning. Pups were sacrificed starting
on PND 5 and continuing every 5 d until
PND 45.
No calculi were seen in pups of any group
during lactation (i.e., up to PND 20). From
PND 25-45, when pups were self-feeding, a
high incidence of calculi was found in pups of
both 5% TPA groups (similar incidence in
both). No calculi occurred in pups from the
control or low-dose groups. No calculi were
found in dams.
Appearance of calculi
coincided with onset of
self-feeding. Weanling
rats were susceptible to
calculus formation only
when TPA is ingested at
high concentrations in the
diet. Transport of TPA to
the fetus by the placenta or
through the milk is
insufficient to induce
calculi. Incidence of
bladder calculi was the
only endpoint evaluated.
Wolkowski-Tvl et
al. (1982)
Gestational/
lactational/feeding
exposure of pups
Pregnant F344 rats (7 controls and 5 treated)
were administered 0 or 5% TPA
(-4,700 mg/kg-d) in the diet beginning on GD 7
for up to 54 d. 1 dam/group was sacrificed on
GDs 18 and 20; the remaining dams were
allowed to litter and were sacrificed on PND 35.
Increased pup mortality compared with
controls (14% mortality by PND 2). Pups
exposed in utero and through lactation to
PND 35 had high incidences of calculi in
urinary tract tissues. Pup weight was also
reduced.
TPA was reported to
induce calculi in pup,
increase pup mortality, and
decrease pup weight.
Primary study report not
available.
Heck (1979)
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Table 4B. Other TPA (CASRN 100-21-0) Studies
Test3
Materials and Methodsb'c
Results
Conclusions
References
Multigeneration
reproduction study
Alpk: APfSD (Wistar derived) breeding pairs
(26 M and 26 F/group) were fed diets containing
0, 1,000, 5,000, or 20,000 ppm TPA from 10 wk
prior to mating through weaning Fi litters.
Exposure and breeding were repeated to generate
the F2 generation. Treatments were equivalent to
0, 92.2, 461, and 1,840 mg/kg-d for males, and 0,
103, 513, and 2,050 mg/kg-d for females.
Decreased F0 and Fi parental body weights at
high dose; decreased absolute and relative
kidney weights in males and increased
relative male and female liver weights in both
generations. Bladder changes in high-dose
males and females were greater in Fi than in
F0. No effects on any reproductive endpoints
including sperm number, motility, or
morphology. Developmental effects include
decreased anogenital distance in high-dose Fi
and F2 females and delayed preputial
separation in mid- and high-dose males.
These were considered to be related to
decreased pup body weights.
TPA was reported to affect
pup body weights and
developmental milestones.
Primary study report not
available.
Milbum (2003)
1-generation
reproduction study
Male and female C3H/He mice (numbers NS)
were fed a control diet or a diet containing 0.5%
TPA from weaning, through mating, to death.
No treatment effects on the estrous cycle,
growth during premating and between mating
and parturition, litter size, average body
weight of pups at birth or on PNDs 12 and 20,
or on pup growth and rearing rates were
observed (data were not shown).
TPA was reported not to
affect reproduction in
mice. The study was
available only as an
abstract. Primary study
report not available.
Naeasawa and
Fuiimoto (1973)
Supporting evidence—noncancer effects in humans following inhalation exposure
Occupational
Industrial hygiene study in workers of a chemical
fiber factory (further details not available).
Endpoints evaluated: liver and kidney function.
Regression analysis indicated that liver and
renal injury (based on serum and urine
analysis) correlated with exposure to TPA
after adjustment for multiple confounding
factors.
TPA was reported to affect
serum biomarkers for liver
and kidney injury in
exposed workers. This is a
foreign language study
with an English abstract.
Primary study report not
available in English.
Yaoetal. (2002)
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Table 4B. Other TPA (CASRN 100-21-0) Studies
Test3
Materials and Methodsb'c
Results
Conclusions
References
Supporting evidence—noncancer effects in animals following inhalation exposure
Acute
Male and female S-D rats (5/sex) were exposed
to 2.02 mg/L TPA as a particulate for 2 hr, and
were observed for 14 d. Endpoints evaluated
included mortality, clinical signs, body weights,
and gross necropsy.
No deaths occurred. Clinical signs included
diarrhea, redness around the nose, and
discolored fur. Increased mean body weights
were described (data not shown). 1 male had
dark lungs; enlarged mandibular lymph nodes
occurred in 1 male and 1 female.
Rat LC50: >2.02 mg/L
(>2,020 mg/m3).
Amoco Corporation
(1987) as cited in
MAK-Commission
(2012)
Acute
Male F344 rats (12/group) were exposed nose
only to 0, 55.0, 109.0, or 235.0 mg/m3 for
30 min. Sacrifices were done 24 hr and 14 d
postexposure. Rats were evaluated for clinical
signs and signs of pulmonary toxicity.
No treatment-related effects were observed.
TPA was reported not to
have produced any effects
in this acute inhalation
study.
Thomson et al.
(1988)
Acute
Male rats (10/group; strain NS) were exposed
nose only to target TPA concentrations of 30,
100, or 1,000 mg/m3 for 4 hr.
No treatment-related abnormalities were
observed.
TPA was reported not to
have produced any effects
in this acute inhalation
study. Primary study
report not available.
ICI Internal Report
CTL/R/909 (1987)
as cited in OECD
(2001)
Short term
Male rats (number and strain NS) were exposed
to 21.5 mg/m3 TPA by inhalation for 6 hr/d,
5 d/wk, for 4 wk (continuous concentration
~3.8 mg/m3).
No deaths were recorded, and no signs of
toxicity or gross pathological changes were
noted. Histopathology was not conducted.
TPA was reported not to
have produced any effects
in this short-term
inhalation study. Primary
study report not available.
Amoco Corporation
(1973) as cited in
OECD (200 T)
Short term
Male and female rats (number and strain NS)
were exposed by inhalation to 0, 0.52, 1.2, or
3.3 mg/m3 TPA for 6 hr/d for 4 wk (continuous
concentration of -0.13, 0.3, or 0.83 mg/m3).
No exposure-related deaths, clinical
chemistry, hematology, body, or organ weight
changes were observed. Tracheal epithelial
lining degeneration occurred in 19/20 high-
exposure rats, compared with 1/20 controls.
Incidences of trachea epithelial lining
degeneration occurred in 5, 30, 65, and 95%
of animals at 0, 0.52, 1.3, and 3.3 mg/m3,
respectively.
TPA was reported to
produce degeneration of
the tracheal epithelial
lining in this short-term
inhalation study. Primary
study report not available.
Amoco Corporation
(1973) and Jernigan
et al. (1988) as cited
in OECD (2001)
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Table 4B. Other TPA (CASRN 100-21-0) Studies
Test3
Materials and Methodsb'c
Results
Conclusions
References
Short term
Male and female S-D rats (10/sex/group) were
exposed to TPA aerosol concentrations of 0, 1,3,
or 10 mg/m3 nose only for 28 d.
No clinical signs or effects on body weight,
food or water intake, eyes, locomotor activity,
grip strength, righting reflex, body
temperature, hematology, serum chemistry,
urinalysis, organ weights, or gross or
histological pathology, including the lung,
larynx, trachea, and nasal tissues.
TPA was reported not to
have produced any effects
in this apparently
comprehensive short-term
inhalation study. Primary
study report not available.
Plastics Europe
(2008) as cited in
MAK-Commission
(2015)
Chronic
Male S-D rats and Hartley guinea pigs were
exposed by inhalation to TPA dusts (10 mg/m3,
"respirable" dust concentration 5 mg/m3) for
6 hr/d, 5 d/wk for 6 mo.
No effects on body weight, organ (lung, liver,
kidney, or spleen) weights, clinical chemistry,
or urinalysis. No gross or histological
changes outside of normal limits were
described.
TPA was reported not to
have produced any effects
in this 6-mo inhalation
study. Primary study
report not available.
Lewis et al. (1982)
as cited in OECD
(200Ft: Heck and
Tvl (1985)
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Table 4B. Other TPA (CASRN 100-21-0) Studies
Test3
Materials and Methodsb'c
Results
Conclusions
References
Supporting evidence—noncancer effects in animals following other exposure routes
Acute (i.p)
Male and female rat; acute lethality study.
ND
Rat LD5o = 1,210 mg/kg
(F) and 2,250 mg/kg (M).
BG Chemie (1990)
as cited in MAK-
Commission (2012)
Acute (i.p)
Mouse; acute lethality study.
ND
Mouse
LD50 = 880-1,900 mg/kg.
BG Chemie (1990)
as cited in MAK-
Commission (2012)
One-generation
reproduction study
(i-P-)
Female CF1 mice were dosed via i.p. injection
with 0, 20, 50, or 100 mg/kg-d TPA for a total of
6 wk (3 wk prior to mating and 3 wk during
mating). Endpoints evaluated included percent
pregnancy, number of live births, deaths, and
birth weights. Pup weights, percent survival, and
sex were measured 3 wk after birth. Histological
analysis of kidney, liver, and spleen was done in
dams.
No effects on fertility, reproduction, or pup
growth were observed. Pup survival
(number/litter) was reduced at 50 mg/kg-d
(5.59 vs. 9.20 in controls), but not at the
higher dose.
TPA was reported not to
have affected reproduction
or pup growth.
Halletal. (1993)
"Acute = exposure for <24 hours; short term = repeated exposure for >24 hours <30 days; subchronic = repeated exposure for >30 days <10% lifespan (>30 days up to
approximately 90 days in typically used laboratory animal species); chronic = repeated exposure for >10% lifespan for humans (more than approximately 90 days to
2 years in typically used laboratory animal species) (U.S. EPA. 2002).
bWhen doses in mg/kg-day were not provided, reported dietary intakes (% TPA in food) were converted to ADDs (mg/kg-day) using the following equation:
ADD = | TP A (mg/kg food) x food intake (kg food/day )| ^ BW (kg) using appropriate reference body-weight and food-intake values (U.S. EPA. 1988).
°When applicable, reported exposure concentrations were converted to continuous concentrations using the following equation: exposure concentration
(mg/m3) x hours/day x days/week.
ADD = adjusted daily dose; BW = body weight; F = female(s); GD = gestation day; i.p. = intraperitoneal; LC50 = median lethal concentration; LD5o = median lethal
dose; M = males(s); ND = no data; NS = not specified; PND = postnatal day; S-D = Sprague-Dawley; TPA = terephthalic acid.
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Acute oral lethality studies with TPA reported median lethal dose (LD50) values ranging
from 1,960-18,800 mg/kg in rats [Cajolle et al. (1991) and Amoco Corporation (1975, 1990) as
cited in OECD (2001); NIOSH (1985) as cited in U.S. EPA (1986)1. and from
l,470->5,000 mg/kg in mice [BG Chemie (1990) as cited in MAK-Commission (2012); Hoshi et
al. (1968)1. Deaths typically occurred within 48 hours of exposure. A single inhalation lethality
study in rats reported in a median lethal concentration (LCso) of >2,020 mg/m3 [Amoco
Corporation as cited in MAK-Commission (2012); OECD (2001)1. Additional acute inhalation
studies reported no effects. Reported LDso values by i.p. injection were 1,210 and 2,250 mg/kg
in rats and between 880 and 1,900 mg/kg in mice.
Several supporting animal studies evaluated bladder effects after oral exposure. A
two-dose acute exposure by gavage showed the formation of microcrystals in the bladder starting
as early as 6 hours after dosing (Kvova and Terada. 2018). Calculi in the bladder were observed
in weanling F344 rats fed 5% TPA, but not 0.5% TPA, in the diet from weaning to PND 45
(Wolkowski-Tvl et al.. 1982). and after 90 days of 5% TPA exposure ( -3,680-4,210 mg/kg-day)
in feed, incidences of hyperplasia, in conjunction with calculi, were reported in male and female
Wistar rats, with males appearing to be more sensitive [Amoco Corporation (1972) as cited in
Ball et al. (2012); OECD (2001)1. Similar findings were reported in a foreign language study
[Qi et al. (2002) as summarized in MAK-Commission (2012)1 in a 90-day feeding study in S-D
rats. Calculi and atypical hyperplasia in the bladder occurred at 500 mg/kg-day; simple
hyperplasia did occur at a lower dose (50 mg/kg-day), but in the absence of visible calculi. At
the highest dose (5,000 mg/kg-day), 4/17 animals were reported to have transitional epithelial
cancer [Qi et al. (2002) as cited in MAK-Commission (2012)1. Highlighting the fact that
females may be less sensitive to TPA-induced bladder effects. Heck (1979) found only two
individuals with bladder calculi in female F344 rats administered 5% TPA (-5,650 mg/kg-day)
for 6 months in the diet, and [Amoco Corporation (1970) as cited in OECD (2001)1 also noted
that males rats were more affected than females in a 15-week feeding study.
A few supporting studies evaluated the potential effects of TPA on reproduction and
development. Evidence indicates that TPA administered either orally, or by i.p. injection, does
not affect female reproductive endpoints in mice (Hall et al.. 1993; Nagasawa and Fujimoto.
1973) or rats (Milburn. 2003; Heck. 1979). However, Milburn. (2003) and Heck (1979) did
report TPA-decreased pup weights, supporting the findings from Ledoux and Reel (1982). An
abstract by Nagasawa and Fujimoto (1973) indicates that 0.5% dietary TPA from weaning to
16 months-of-age caused no changes to the pattern of estrous cycle, growth during the virginial
stage, or the interval between mating and parturition, and no changes in litter size, the average
weight of pups at birth and PNDs 12 and 20, or in pup growth and rearing rates, compared with
controls. Six weeks of i.p. injections of up to 100 mg/kg-day also had no impact on fertility,
reproduction, or pup growth; limited details suggest pup survival may have been reduced (Hall et
al.. 1993). Both Heck (1979) and Wolkowski-Tvl et al. (1982) looked at calculi formation in rats
exposed during different developmental stages. Both studies indicate that exposure in utero, or
in utero through lactation, does not lead to calculi formation in offspring. Bladder calculi were
only observed once pups began self-feeding.
A number of inhalation studies, all with extremely limited details, were summarized in
OECD (2001). One study indicated incidence of degeneration of the tracheal epithelial lining in
rats exposed to 3.3 mg/m3, 6 hours/day, for 4 weeks [Amoco Corporation (1973) and Jernigan et
al. (1988) as cited in OECD (2001)1. The remaining studies reported no exposure-related effects
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[Amoco Corporation (1973), Lewis et al. (1982), and ICI Internal Report CTL/R/909 (1989) all
as cited in OECD (2001)1. A seemingly comprehensive study of rats exposed to TP A aerosols at
up to 10 mg/m3 for 28 days found no lesions in the trachea or other respiratory tissues and no
systemic effects, but only a brief summary was located [Plastics Europe (2008) as cited in MAK-
Commission (2015)1.
Absorption, Distribution, Metabolism, and Excretion Studies
Based on excretion in urine and feces, it is estimated that -97% of TP A administered
orally is rapidly absorbed by the gastrointestinal (GI) tract (Hoshi and Kuretani. 1967).
Following oral exposure via gavage in rats, approximately 64% of administered TPA remained
in the stomach, small intestine, caecum, and to a lesser degree, in the large intestine 2 hours after
exposure. TPA was no longer detectable by 24 hours after exposure (Hoshi and Kuretani. 1967).
A single dermal 5-hour application in rats resulted in negligible absorption; repeated dermal
dosing resulted in recovery of—13% of the administered dose, indicating that some absorption
through the skin did occur (Moffitt et al.. 1975). Similarly, a longer ocular exposure (24 hours)
in rabbits yielded a 37% recovery, indicating some absorption through ocular tissues (Moffitt et
al.. 1975).
Distribution is rapid following oral exposure, with a blood distribution half-life of
2.43-3.4 hours in rats and 27 hours in rabbits [Hoshi et al. (1966) as cited in Ball et al. (2012)1.
Estimated half-lives are notably shorter after intravenous (i.v.) dosing; the computer-estimated
value for terminal TPA half-life was 1.2 hours in rats following an i.v. injection, suggesting that
GI absorption has some rate-limited effect (Wolkowski-Tvl et al.. 1982). Plasma clearance was
approximately equal to glomerular filtration rate, with the highest concentrations of TPA in urine
occurring within hours of exposure (Wolkowski-Tvl et al .. 1982). TPA is transported through
the placenta in pregnant rats and distributed into fetal tissues; radioactivity was tracked through
the placenta, to the fetus, and then to amniotic fluid. Similar to dams, radioactivity in fetuses
was highest in the bladder, with a half-life in the fetal bladder of approximately 3 hours.
However, TPA concentrations in fetal tissues were approximately two orders of magnitude lower
than in dams, indicating that in utero exposure levels are likely to be low (Wolkowski-Tvl et al..
1982). Some distribution has also been noted in other tissues, primarily the liver and kidney in
rats either fed diets containing 0.5% TPA or given a single oral dose, but the TPA is rapidly
excreted and does not accumulate (Hoshi and Kuretani. 1968).
Studies on TPA metabolism found only the parent TPA compound present in the urine in
rats dosed either orally or via i.v. injections, indicating that TPA is not metabolized (Wolkowski-
Tvl et al.. 1982; Heck, 1979; Hoshi and Kuretani. 1967). Another study in chickens where TPA
was infused into the renal portal also failed to identify any TPA metabolites (Trcmaine and
Ouebbemann. 1985).
Rapid elimination of unchanged TPA given orally, or by i.v. injection, has been described
above. In rats gavaged with 85 mg/kg radioactive TPA, 93.8 and 3.3% of the dose was excreted
in urine and feces, respectively (Hoshi and Kuretani. 1967). Similar recovery levels were
described by Moffitt et al. (1975). In both studies, near 100% elimination was evident within
48 hours of dosing.
No information on absorption, distribution, metabolism, or excretion (ADME) following
inhalation of TPA has been identified.
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Mode-of-Action/Mechanistic Studies
Bladder calculi associated with TPA exposure were hypothesized to be the primary cause
of urinary tract irritation, lesions, and regenerative cell proliferation that could eventually lead to
tumors in the bladder (Cohen et al.. 2002; Heck and Tvi. 1985). Several researchers have
focused their attention on the physical characteristics of bladder calculi in TPA exposed rodents,
and the mechanisms of TPA-induced calculi formation (Cui et al.. 2006a; Dai et al.. 2005a; Dai
et al. 2005c; Heck and Tvi 1985; Chin et al. 1981; Heck. 1981; Heck. 1979). Heck (1979) and
Chin et al. (1981) studied the composition of TPA-induced bladder calculi, identifying calcium
terephthalate (Ca-TPA) as the principal component, particularly in weanling rats. Heck (1981)
studied the equilibria and concentrations of components required for calculus formation, as well
as the solubility properties of Ca-TPA. Results from this study indicate that a urinary
concentration of approximately 100 mM TPA is required to induce calculi formation, but that
other kinetic factors influence the speed of calculus formation once saturation is reached.
Extrapolating to humans. Heck (1979) estimated that an 8-mM concentration of TPA would be
required to saturate a human urine sample, which the study author calculated to require an
exposure of 2.4 g of TP A/day. Hypercalciuria and aciduria were also determined to be
necessary, but not sufficient, for TPA-induced calculi (Wolkowski-Tvl and Chin. 1983).
Other studies focused on downstream mechanisms occurring once calculi were formed
that could potentially lead to tumor formation. Hyperplastic bladder lesions in TPA-treated rats
had positive indices for PCNA (Cui et al.. 2006b); the lesions also showed increases in positive
indices for cyclin D1 and CDk4. Importantly, none of the transitional cell carcinoma (TCC)
tumors that formed had detectable mutations in the K-ras and H-ras genes, providing support
that TPA exposure may lead to changes in components of the anti-oncogenic Rb pathway (Cui et
al.. 2006b). The same study authors also performed proteomics on normal bladder tissues and
TPA-induced TCCs to identify potential proteins that may be involved in TPA-induced
tumorigenesis (Cui et al.. 2007). They found an elevation in prostaglandin E2 (PGE2), which is
known to be involved in carcinogenesis, in TPA-TCC- tissues (Shi et al.. 2006).
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DERIVATION OF PROVISIONAL VALUES
DERIVATION OF PROVISIONAL ORAL REFERENCE DOSES
Derivation of a Subchronic Provisional Reference Dose
The database of potentially relevant studies for deriving an oral subchronic reference
value for TPA includes several oral feeding studies in rats (Dai ct al.. 2006a; Dai et al.. 2005c;
Cui et al.. 2004; Ledoux and Reel 1982; Dupont Chem Co. 1955). Collectively, these studies
identify the urinary tract, and in particular the bladder, as a target of TPA toxicity, as indicated
most notably by increased incidences of bladder calculi and associated urinary tract
histopathology. Decreased body weight was also reported in several studies, both in adults and
in pups exposed in utero and via lactation. There is limited evidence for an effect on sperm
count, motility, and ultrastructure in two studies (Kwack and Lee. 2015; Cui et al.. 2004).
Single- or multiple-generation reproduction studies (Milburn. 2003; Hall et al.. 1993; Ledoux
and Reel. 1982) however, did not report a change in fertility following TPA treatment. The
interpretation of the observed changes is unclear, because of the small number of studies that
reported TPA-induced sperm effects and the lack of consistency across studies. The sperm
motility endpoint is not considered further as the critical effect.
The most sensitive, potential POD for bladder effects is a NOAEL (ADD) of
906 mg/kg-day for increased incidence of bladder calculi in male rats fDai ct al. (2005c);
see Table D-12], The NOAEL (ADD) of 197 mg/kg-day for increased incidence of white
sediment in the urine in female rats (Dai ct al.. 2005c) is lower than the NOAEL for bladder
calculi in male rats from the same study, but the biological relevance of the sediment effect is
unclear. As discussed previously, there is an inconsistent cause-effect relationship between
precipitates, calculi and hyperplastic lesions.
For effects on body weight, the most sensitive, potential PODs were in Wistar and CD rat
pups in the developmental portion of the Ledoux and Reel (1982) study (see Table D-34). In
Wistar rats, a NOAEL (ADD) of 313 mg/kg-day is identified for biologically significant (>5%),
decreased pup weight on PND 21. In CD rats, a LOAEL (ADD) of 17.6 mg/kg-day is identified
for biologically significant (>5%), decreased pup weight on PND 21.
To provide a common basis for comparing potential points of departure (PODs) and
critical effects for deriving a subchronic p-RfD for TPA, data sets representing the most sensitive
endpoints (i.e., bladder effects and pup weight effects) were selected for benchmark dose (BMD)
analysis. All available continuous or dichotomous-variable models in the Benchmark Dose
Software (BMDS, Version 2.7) were fit to the data sets for the most sensitive endpoints.
Appendix E contains details of the modeling results for these data sets. The HED, in mg/kg-day,
was used as the dose metric. The standard reporting benchmark response (BMR) of 10% extra
risk for bladder incidence data was used. The BMR for decreased fetal body weight used was
5% RD change from control means, which is considered a biologically significant response for
developmental aged animals. The incidence data for bladder calculi from Dai ct al. (2005c) were
not amenable to modeling because the lesions were seen only at the highest dose
(see Table D-12). For decreased pup weight in Wistar and CD rats (Ledoux and Reel. 1982). one
or more available BMD models provided adequate fit to the data. Candidate PODs are presented
in Table 5.
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In U.S. EPA's Recommended Use of Body Weight314 as the Default Method in Derivation
of the Oral Reference Dose (U.S. EPA. 201 lb), the Agency endorses a hierarchy of approaches
to derive human equivalent oral exposures from data from laboratory animal species, with the
preferred approach being physiologically based toxicokinetic modeling. Other approaches may
include using some chemical-specific information without a complete physiologically based
toxicokinetic model. In lieu of chemical-specific models or data to inform the derivation of
human equivalent oral exposures, U.S. EPA endorses body-weight scaling to the 3/4 power
(i.e., BW3/4) to extrapolate toxicologically equivalent doses of orally administered agents from
all laboratory animals to humans for deriving an oral reference dose (RfD) under certain
exposure conditions. More specifically, the use of BW3'4 scaling for deriving an RfD is
recommended when the observed effects are associated with the parent compound or a stable
metabolite, but not for portal-of-entry effects. A validated human physiologically based
toxicokinetic model for TPA is not available for use in extrapolating doses from animals to
humans. Furthermore, the most sensitive endpoints being considered are not portal-of-entry
effects and TPA does not readily metabolize. Therefore, scaling by BW3/4 is relevant for
deriving HEDs for the considered effects.
Following U.S. EPA (2011b) guidance, the doses administered resulting in the most
sensitive endpoints are converted to an HED through application of a dosimetric adjustment
factor (DAF) derived as follows:
DAF = (BWa1/4 - BWh1/4)
where
DAF = dosimetric adjustment factor
BWa = animal body weight
BWh = human body weight
Study-specific body weight is used to calculate the DAF for each dose group (U.S. EPA.
201 lb). Calculated HEDs are presented in Table D-12 for male rats exposed subchronically to
TPA (Dai et at.. 2005c) and Table D-34 for female rats exposed to TPA during pregnancy
(Ledoux and Reel, 1982).
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Table 5. Candidate PODs in Rats Administered TPA for the Derivation of the
Subchronic p-RfD
Endpoint
POD (HED) (mg/kg-d)
Dai et al. (2005c)
Increased bladder calculi in males
220 (NO A F.I'
Ledoux and Reel (1982)
Decreased pup weight in combined sexes in Wistar rats at PND 21
59.9 (BMDLos)
Decreased pup weight in male Wistar rats at PND 21
58.8 (BMDLos)
Decreased pup weight in female Wistar rats at PND 21
61.8 (BMDLos)
Decreased pup weight in combined sexes in CD rats at PND 21
55.5 (BMDLos)
Decreased pup weight in male CD rats at PND 21
54.6 (BMDLos)
Decreased pup weight in female CD rats at PND 21
54.4 (BMDLos)
aModeling results are described in more detail in Appendix E.
bData were not amenable to BMD modeling.
BMD = maximum likelihood estimate of the dose associated with the selected BMR; BMDL = 95% lower
confidence limit on the BMD (subscripts denote BMR: i.e., 5 = dose associated with 5% relative deviation);
BMR = benchmark response; HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level;
NDr = not determined; NOAEL = no-observed-adverse-effect level; PND = postnatal day; POD = point of
departure; p-RfD = provisional reference dose; TPA = terephthalic acid.
Among all the sensitive endpoints evaluated, the lowest POD (HED) following oral
exposure to TPA is for decreased pup weight in female CD rats (I.edoux and Reel. 1982). The
BMDLos (HED) of 54.4 mg/kg-day for decreased pup weight is expected to be protective of all
developmental effects during a susceptible life stage, as well as any systemic effects
(e.g., bladder calculi observed following subchronic TPA exposure). The choice of decreased
pup weight as the critical effect is supported by observations of TPA-induced pup weight effects
in other studies [i.e., Milburn (2003); Heck (1979)1 and in two rat strains (i.e., Wistar and CD
rats) from the Ledoux and Reel (1982) study. In summary, the Ledoux and Reel (1982) study is
selected as the principal study because it identified the most sensitive POD and was adequate in
its experimental design and protocol. However, because the study is not peer reviewed, a
screening-level subchronic p-RfD is derived for TPA in Appendix C, in lieu of a subchronic
p-RfD.
Derivation of a Chronic Provisional Reference Dose
Chronic oral studies on TPA are limited to a group of papers published on a 48-week
study in rats that are primarily mechanistic in nature and a 22-week study in rats (Cui et al..
2006a). There were also two, unpublished, non-peer-reviewed 2-year studies in rats (Preache.
1983; Grubbs. 1979; Gross. 1977). In addition to the aforementioned chronic studies, the
developmental/reproductive study from Ledoux and Reel (1982) is also considered relevant to
the derivation of the chronic p-RfD.
The 48-week study (Cui et al.. 2007; Cui et al.. 2006b; Shi et al.. 2006) evaluated a single
exposure dose and reported on limited endpoints. Given the availability of more comprehensive
studies that evaluated multiple effects at various doses, the 48-week study (Cui et al.. 2007; Cui
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et al.. 2006b; Shi ct al.. 2006) was not considered for deriving the chronic p-RfD. In addition,
the 2-year study (Preache. 1983; (jrubbs. 1979) in rats conducted by the ITT was not considered
further because of experimental issues described above (e.g., dosing uncertainty). The remaining
two studies in the chronic TPA database (Cui ct al.. 2006a; Gross. 1977) were considered
adequate for deriving a chronic p-RfD. A NOAEL (ADD) and LOAEL (ADD) of 829 and
4,280 mg/kg-day, respectively, were identified for increased bladder hyperplasia, increased
bladder weight, and decreased body weight in male Wistar rats exposed to TPA in the diet for
22 weeks (Cui ct al.. 2006a). In the 2-year feeding study by Gross (1977). urinary tract effects
(calculi, nephropathy, increased blood urea levels) were seen only at the high dose in both sexes
(3,680-4,210 mg/kg-day) of Wistar rats; the most sensitive effect was decreased body weight in
male rats, which defines a LOAEL and a NOAEL of 1,470 (ADD) and 736 mg/kg-day (ADD),
respectively. In the developmental portion of the Ledoux and Reel (1982) study (see
Table D-34) as discussed above, a NOAEL (ADD) of 313 mg/kg-day is identified for
biologically significantly (>5%) decreased pup weight on PND 21 in Wistar rats. In CD rats, a
LOAEL (ADD) of 17.6 mg/kg-day is identified for biologically significantly (>5%) decreased
pup weight on PND 21.
Following U.S. EPA (2011b) guidance, the doses administered resulting in the most
sensitive endpoints are converted to an HED through application of a DAF derived as follows:
DAF = (BWa1/4 - BWh1/4)
where
DAF = dosimetric adjustment factor
BWa = animal body weight
BWh = human body weight
Calculated HEDs are presented in Tables D-18 and D-23 for male rats exposed
chronically to TPA (Cui et al.. 2006a; Gross. 1977) and Table D-34 for female rats exposed to
TPA during pregnancy (Ledoux and Reel. 1982).
To provide a common basis for comparing potential points of departure (PODs) and
critical effects for deriving a chronic p-RfD for TPA, data sets representing the most sensitive
endpoints were selected for benchmark dose (BMD) analysis. Data for simple hyperplasia from
Cui et al. (2006a) were suitable for modeling, which was performed using the available
dichotomous models in U.S. EPA's Benchmark Dose Software (BMDS; Version 2.7). HEDs
were used as the dose metric. The standard reporting benchmark response (BMR) of 10% extra
risk for incidence data was used. Other sensitive endpoints in the Cui et al. (2006a) study
(i.e., reduced body weight and increased absolute and relative bladder weights) could not be
modeled because the type of variance data shown in the study report was not identified. For
decreased body weight observed in the 2-year feeding study in male and female Wistar rats
(Gross. 1977). a benchmark response (BMR) of 10% relative deviation (RD) was used because a
10%) change in body weight for adult animals is generally considered to be biologically
significant. The BMR for decreased fetal body weight used was 5% RD change from control
means, which is considered a biologically significant response in developmentally aged animals.
For decreased pup weight in Wistar and CD rats (Ledoux and Reel. 1982) and decreased body
weight in adult Wistar rats (Gross. 1977), one or more available BMD models provided adequate
fit to the data as described above. Candidate PODs are presented in Table 6.
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Table 6. Candidate PODs in Rats Administered TPA for the Derivation of the Chronic
p-RfDa
Endpoint
POD (HED) (mg/kg-d)
C'ui et al. (2006a)
Increased bladder hyperplasia in males
95.0 (BMDLio)
Decreased body weight in males
196 (NOAEL)b
Increased absolute bladder weight in males
196 (NOAEL)b
Increased relative bladder weight in males
196 (NOAEL)b
Gross (1977)
Decreased body weight in males
373 (BMDLio)
Ledoux and Reel (1982)
Decreased pup weight in combined sexes in Wistar rats at PND 21
59.9 (BMDLos)
Decreased pup weight in male Wistar rats at PND 21
58.8 (BMDLos)
Decreased pup weight in female Wistar rats at PND 21
61.8 (BMDLos)
Decreased pup weight in combined sexes in CD rats at PND 21
55.5 (BMDLos)
Decreased pup weight in male CD rats at PND 21
54.6 (BMDLos)
Decreased pup weight in female CD rats at PND 21
54.4 (BMDLos)
"Modeling results are described in more detail in Appendix E.
bData could not be BMD modeled because the type of variance data shown in the study report was not identified.
BMD = maximum likelihood estimate of the dose associated with the selected BMR; BMDL = 95% lower
confidence limit on the BMD (subscripts denote BMR: i.e., 5 = dose associated with 5% relative deviation);
BMR = benchmark response; HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level;
NDr = not determined; NOAEL = no-observed-adverse-effect level; PND = postnatal day; POD = point of
departure; p-RfD = provisional reference dose; TPA = terephthalic acid.
When the BMD results in Table 6 are compared, the lowest POD (HED) is for decreased
pup weight in female CD rats (Ledoux and Reel. 1982). The BMDLos (HED) of 54.4 mg/kg-day
for decreased pup weight in female CD rats is expected to be protective of all developmental
effects during a susceptible life stage, as well as any potential systemic effects observed
following chronic TPA exposure. However, because the Ledoux and Reel (1982) study is not
peer reviewed, a screening-level chronic p-RfD is derived for TPA in Appendix C, in lieu of a
chronic p-RfD.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
The database of inhalation studies on TPA is inadequate for deriving a provisional
reference concentration (p-RfC). Available inhalation studies on TPA are limited to an
unpublished, non-peer-reviewed developmental toxicity study in rats, which reported no
maternal or fetal effects at the exposure levels tested (Chemical Manufacturers Association,
2000). There are a number of other inhalation studies but they were not available for
independent review and are only briefly cited in various secondary sources (MAK-Commission.
2015; Ball et al.. 2012; MAK-Commission. 2012; OECD. 2001). These studies also only tested
a single exposure (MAK-Commission. 2012). and thus can only be considered as supporting.
Most of these studies report no effects (see Table 4B). The short duration of exposure in the
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Chemical Manufacturers Association (2000) study (i.e., 9 days) makes extrapolation to
subchronic or chronic durations highly uncertain, particularly because no effects were seen at the
high dose, even though the exposures are in a sensitive life stage. It is unclear whether the
selection of the highest concentration from the Chemical Manufacturers Association (2000)
study to derive p-RfCs would be protective of toxicity following long-term exposure to TPA.
Given this uncertainty, derivation of p-RfCs or screening p-RfCs is precluded.
Table 7 summarizes the subchronic and chronic values derived for TPA.
Table 7. Summary of Noncancer Reference Values for TPA (CASRN 100-21-0)
Toxicity Type
(units)
Species/
Sex
Critical
Effect
p-Reference
Value
POD
Method
POD
(HED/HEC)
UFc
Principal
Study
Screening subchronic
p-RfD (mg/kg-d)
CD Rat/F
Decreased
pup weight
5 x KT1
BMDLos
54.4
100
Ledoux and
Reel (1982)
Screening chronic
p-RfD (mg/kg-d)
CD Rat/F
Decreased
pup weight
5 x KT1
BMDL05
54.4
100
Ledoux and
Reel (1982)
Subchronic p-RfC
(mg/m3)
NDr
Chronic p-RfC (mg/m3)
NDr
BMDL = 95% lower confidence limit on the benchmark dose (subscripts denote benchmark response:
i.e., 10 = dose associated with 10% extra risk); F = female(s); HEC = human equivalent concentration;
HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level; NDr = not determined;
POD = point of departure p-RfC = provisional reference concentration; p-RfD = provisional reference dose;
UFC = composite uncertainty factor; TPA = terephthalic acid.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Following U.S. EPA (2005) Guidelines for Carcinogen Risk Assessment, the database for
TPA provides "Suggestive Evidence of Carcinogenic Potential" by oral exposure (see Table 8).
There are no pertinent human data, but several studies in laboratory animals have evaluated TPA
for carcinogenicity. Male Wistar rats treated by TPA in the diet at 3,680 mg/kg-day for
48 weeks had significantly elevated incidence (16/20) of transitional cell carcinomas in the
bladder, versus 0/12 in controls; no other doses were tested in this study (Cui ct al.. 2006b). A
study of male and female Wistar rats exposed to TPA in the diet for 2 years found significant
increases in bladder and ureter tumors (primarily transitional cell tumors or squamous cell
carcinomas) in the high-dose group fed 3,680-4,210 mg/kg-day with incidences of 57% (21/37)
in males and 62% (21/34) in females, in comparison to 0% incidence in controls
(n = 45-46/group) and 0-4% incidence in lower dose groups (n = 43-48) fed
736-1,680 mg/kg-day (Gross. 1977). A second 2-year study (ICI Americas Inc. 1992; Preache.
1983) conducted in male and female F344 rats, was performed at lower doses. In this study,
incidence of transitional cell bladder tumors (primarily adenomas) in high-dose females fed
(10/73) 989.8 mg/kg-day was significantly increased versus controls. Although the available
data for TPA are consistent with one of the examples provided in the U.S. EPA's Cancer
Guidelines (U.S. EPA. 2005) for the descriptor "Likely to Be Carcinogenic to Humans" (which
states that supporting data for this descriptor include "an agent that has tested positive in animal
experiments in more than one species, sex, strain, site, or exposure route, with or without
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evidence of carcinogenicity in humans"), tumors were only significant at the highest doses tested
and the only tumor site observed was the urinary tract. As stated in the Cancer Guidelines (U.S.
EPA. 2005). one of the examples for a chemical to be considered to have "Suggestive Evidence
of Carcinogenic Potential" is "a statistically significant increase at one dose only, but no
significant response at the other doses and no overall trend." The Cancer Guidelines (U.S. EPA.
2005) further state that the descriptor "Suggestive Evidence of Carcinogenic Potential" is
appropriate when "the weight of evidence is suggestive of carcinogenicity, a concern for
potential carcinogenic effects is raised, but the data are not judged sufficient for a stronger
conclusion." The mechanistic data for urinary bladder tumors also provide support for the
descriptor "Suggestive Evidence of Carcinogenic Potential" for TP A. Mode-of-action (MO A)
information indicates that the induction of urinary bladder tumors in rats by dietary TPA
exposure is a high-dose phenomenon that might be related to the formation of urinary bladder
calculi. The relevance of calculi-associated bladder tumors to humans has come into question
given the following considerations: (1) rodents may be more prone to calculi formation or to
prolonged presence of calculi due to their horizontal anatomy (although humans spend a
significant fraction of the day horizontal while sleeping) and the ureter of humans is at the
bottom of the bladder (when standing), leading to passage of calculi, while in the rodent, the
ureter is on the side, leading to retention of calculi (2) calculi formation in rodents appears to be
a high-dose phenomenon, based on the necessity to have enough calculus-forming constituents
for precipitation to occur; it is unclear whether such a dose could be reached in humans (Cohen
et al.. 2002; Heck. 1981). Thus, based on the Cancer Guidelines (U.S. EPA. 2005) and the
carcinogenicity data from available animal studies and mechanistic studies, the WOE descriptor
of "Suggestive Evidence of Carcinogenic Potential" is appropriate for TPA for the oral route of
exposure.
There is "Inadequate Information to Assess the Carcinogenic Potential" of TPA by
inhalation exposure. No suitable human or animal data are available by this route (see Table 8).
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Table 8. Cancer WOE Descriptors for TPA (CASRN 100-21-0)
Possible WOE
Descriptor
Designation
Route of Entry
(oral, inhalation, or both)
Comments
"Carcinogenic to
Humans "
NS
NA
The available data do not support this
descriptor.
"Likely to Be
Carcinogenic to
Humans "
NS
NA
The available data do not support this
descriptor.
"Suggestive Evidence of
Carcinogenic Potential"
Selected
Oral
The available studies, described above,
suggest that TPA at high doses in the diet
can induce bladder tumors in rats.
However, the relevance of these data to
humans at environmental exposure levels
is uncertain because humans would
unlikely be exposed at these levels.
Mechanistic data informing the formation
of bladder tumors following TPA exposure
that would lead to a plausible mode of
action is unclear.
"Inadequate
Information to Assess
Carcinogenic Potential"
Selected
Inhalation
This descriptor is selected due to the lack
of any information on the carcinogenicity
of TPA by inhalation exposure.
"Not Likely to Be
Carcinogenic to
Humans "
NS
NA
The available data do not support this
descriptor.
NA = not applicable; NS = not selected; TPA = terephthalic acid; WOE = weight of evidence.
MODE-OF-ACTION DISCUSSION
The Guidelines for Carcinogenic Risk Assessment (U.S. EPA. 2005) define MO A ".. .as a
sequence of key events and processes, starting with interaction of an agent with a cell,
proceeding through operational and anatomical changes, and resulting in cancer formation."
Examples of possible modes of carcinogenic action for any given chemical include
"mutagenicity, mitogenesis, programmed cell death, cytotoxicity with reparative cell
proliferation, and immune suppression."
Evidence from genotoxicity tests (see Table 4A) were mostly negative. It has been
proposed that TPA-associated tumor formation in the bladder may be a secondary response to the
formation of calcium-TPA calculi following TPA exposure (Heck and Tvl. 1985). leading to
cytotoxicity and reparative cell proliferation. One hypothesis is that urolith-caused irritation to
the bladder epithelium contributes to hyperplastic proliferative lesions that could then progress to
papillomas, squamous cell metaplasias, and eventually tumors (Gross, 1977). In several TPA
studies, calculi in the bladder were nearly always present in animals that also exhibited lesions
(Cui ct al.. 2006b; Cui ct al.. 2006a; Dai et al.. 2005c; Preache. 1983; Ledoux and Reel 1982;
Gross. 1977). Several reviews have discussed the potential relationship between urinary tract
calculi, cell proliferation, and carcinogenesis (Cohen. 2002; Cohen et al.. 2002; Cohen et al..
2000; Cohen. 1998. 1995a. b). Several chemicals are capable of causing urinary calculi when
administered at high doses that also induce bladder tumors (Cohen ct al.. 2002). Similarly, there
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appears to be a relatively high dose threshold for TPA-induced calculi (see Table 3 A). Finally,
some hyperplastic lesions are found in bladders that do not have calculi; thus, it is possible that
calculi are correlated with hyperplasia and not causal (Cui et al.. 2006a).
A second hypothesis of TPA-induced bladder tumors that may be independent of calculi
formation has also been proposed. Dai et al. (2005c) proposed that TPA may interact with
a2u-g, a protein secreted by the male rat liver to form white sediment in the bladder that could
also give rise to bladder cell proliferation and possibly cancer. While this mechanism is usually
only found in male rats exposed to certain hydrocarbons, it could be a partial explanation,
leading to higher incidence in males than females (although the incidence rate in males and
females is similar in other studies). Another related hypothesis is that the TPA/a2u-g crystals
may create a "concentrated reservoir" of the chemical, and that the effects would be seen in
animals that do not form crystals, but at higher doses due to the lack of the "reservoir." Thus, the
crystals themselves might not be the toxic entity, but rather a concentrated form of the chemical.
This mechanism does not account for the increase in tumors found in females, which do not form
a2u-g. In S-D rats, Dai et al. (2005c) demonstrated an increase in a2u-g in serum and urine in a
TPA dose-dependent manner, along with the appearance of white sediment (precipitates);
however, the presence of a2u-g was not demonstrated in the crystals. There were, however,
instances of hyperplasia without calculi. Other researchers also reported the appearance of
sediment in the urine (Cui et al.. 2006a; Preache. 1983). Additional evidence, however, to
support this hypothesis, including staining of the proposed crystals to show the presence of
a2u-g, and a male-only pattern of expression, would be required to discount the relevance of this
partial mechanism to humans, who do not form a2u-g. As mentioned previously, the evidence
suggests the calculi are composed of Ca-TPA, not a2u-g, thus this potential mechanism for the
formation of calculi is unclear.
In any case, the MOA is unclear. Some hyperplastic lesions are found in bladders that do
not have calculi; thus, it is possible that calculi are correlated with hyperplasia and not causal Cui
et al. (2006a). It is also unclear which, if any, of the hyperplastic lesions are preneoplastic, or
whether the eventual neoplastic lesions arise from some other subset of cells. These hyperplastic
lesions have thus not been shown to be preneoplastic, and the relationships between the various
cell types is unclear. Finally, although there is no evidence that TPA is genotoxic, the data that
would characterize a nongenotoxic MOA are inconsistent. There is insufficient/inconsistent data
to support a nongenotoxic MOA because there are occurrences of hyperplasia without calculi
suggesting that calculi may not be a key event in the progression. Thus, important
considerations in the Bradford-Hill rationale (consistency, temporality) are not met.
DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES
The WOE of the available data for TPA constitutes only "Suggestive Evidence of
Carcinogenic Potential, " with tumors at only one site and in one species. This descriptor is
based on rat data from three studies (two unpublished) showing TPA induction of bladder
tumors. The tumors were increased at high doses (the single highest doses in each study), and
mechanistic data are unclear whether the carcinogenic potential of TPA is associated with a key
event (calculus formation) that itself only occurs at high doses. It is unclear whether calculus
formation is a key event in the progression because hyperplastic lesions are found in animals
without calculi [e.g., Cui et al. (2006a)"I. Considering the inconsistent data supporting this
hypothesized relationship, discussed above, and the appropriateness of using bladder tumor
incidence data obtained in rats fed high doses of TPA to derive quantitative estimates of cancer
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risk for humans, who are expected to experience much lower exposure levels, is questionable.
For chemicals with "Suggestive Evidence of Carcinogenic Potential, " cancer risk estimates may
or may not be derived, depending on strengths and weaknesses of the particular database. In
light of the uncertainties discussed here, provisional cancer risk estimates were not derived for
TPA (see Table 9). If the bladder calculi MOA is operating and responsible for the TPA-induced
bladder tumors, the POD [BMDLos of 54.4 mg/kg-day for decreased pup weight in female rats;
Ledoux and Reel (1982)1 used for the derivation of the subchronic and chronic p-RfDs is lower
than that of the bladder hyperplasia POD [BMDLio of 95.0 mg/kg-day in male rats; Cui et al.
(2006a)1 indicating that the p-RfDs derived are protective of cancer.
Table 9. Summary of Cancer Risk Estimates for TPA (CASRN 100-21-0)
Toxicity Type (units)
Species/Sex
Tumor Type(s)
Cancer Risk Estimate
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3) 1
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor;
TPA = terephthalic acid.
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APPENDIX A. LITERATURE SEARCH STRATEGY
Non-date-limited literature searches were conducted in February 2018 and updated in
July 2019, May 2019, and March 2020 for studies relevant to the derivation of provisional
toxicity values for terephthalic acid (TPA; CASRN 100-21-0). Synonyms included in the search
included terephthalic acid and para-dicarboxylic acid. Searches were conducted using
U.S. EPA's Health and Environmental Research Online (HERO) database of scientific literature.
HERO searches the following databases: PubMed, TOXLINE (including the Toxic Substances
Control Act Test Submissions [TSCATS] database), and Web of Science (WOS). In addition,
the following databases were searched outside of HERO: U.S. EPA Chemical Data Access Tool
(CDAT), U.S. EPA ChemView, Defense Technical Information Center (DTIC), European
Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), European Chemicals
Agency (ECHA), U.S. EPA Health Effects Assessment Summary Tables (HEAST), International
Programme on Chemical Safety (IPCS) INCHEM, U.S. EPA Integrated Risk Information
System (IRIS), Japan Existing Chemical Data Base (JECDB), National Toxicology Program
(NTP), and Organisation for Economic Co-operation and Development (OECD), including
eChemPortal. The following additional sources were checked for regulatory values: American
Conference of Governmental Industrial Hygienists (ACGIH), Agency for Toxic Substances and
Disease Registry (ATSDR), California Environmental Protection Agency (CalEPA), U.S. EPA
Office of Water (OW), International Agency for Research on Cancer (IARC), Occupational
Safety and Health Administration (OSHA), and World Health Organization (WHO).
LITERATURE SEARCH STRINGS
PubMed
("P-PHTHALIC ACID"[TW] OR "100-21-0"[EC/RN NUMBER] AND ("2019/05/01"[PDAT] :
"3 000" [PD AT]))"
WOS
((TS="P-PHTHALIC ACID" AND ((WC=("TOXICOLOGY" OR "ENDOCRINOLOGY &
METABOLISM" OR "GASTROENTEROLOGY & HEPATOLOGY" OR
"GASTROENTEROLOGY & HEPATOLOGY" OR "HEMATOLOGY" OR
"NEUROSCIENCES" OR "OBSTETRICS & GYNECOLOGY" OR "PHARMACOLOGY &
PHARMACY" OR "PHYSIOLOGY" OR "RESPIRATORY SYSTEM" OR "UROLOGY &
NEPHROLOGY" OR "ANATOMY & MORPHOLOGY" OR "ANDROLOGY" OR
"PATHOLOGY" OR "OTORHINOLARYNGOLOGY" OR "OPHTHALMOLOGY" OR
"PEDIATRICS" OR "ONCOLOGY" OR "REPRODUCTIVE BIOLOGY" OR
"DEVELOPMENTAL BIOLOGY" OR "BIOLOGY" OR "DERMATOLOGY" OR
"ALLERGY" OR "PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH") OR
SU=("ANATOMY & MORPHOLOGY" OR "CARDIOVASCULAR SYSTEM &
CARDIOLOGY" OR "DEVELOPMENTAL BIOLOGY" OR "ENDOCRINOLOGY &
METABOLISM" OR "GASTROENTEROLOGY & HEPATOLOGY" OR "HEMATOLOGY"
OR "IMMUNOLOGY" OR "NEUROSCIENCES & NEUROLOGY" OR "OBSTETRICS &
GYNECOLOGY" OR "ONCOLOGY" OR "OPHTHALMOLOGY" OR "PATHOLOGY" OR
"PEDIATRICS" OR "PHARMACOLOGY & PHARMACY" OR "PHYSIOLOGY" OR
"PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH" OR "RESPIRATORY
SYSTEM" OR "TOXICOLOGY" OR "UROLOGY & NEPHROLOGY" OR
"REPRODUCTIVE BIOLOGY" OR "DERMATOLOGY" OR "ALLERGY")) OR (TS="RAT"
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OR TS="RATS" OR TS="MOUSE" OR TS="MURINE" OR TS="MICE" OR TS="GUINEA"
OR TS="MURIDAE" OR TS=RABBIT* OR TS=LAGOMORPH* OR TS=HAMSTER* OR
TS=FERRET* OR TS=GERBIL* OR TS=RODENT* OR TS="DOG" OR TS="DOGS" OR
TS=BEAGLE* OR TS="CANINE" OR TS="CATS" OR TS="FELINE" OR TS="PIG" OR
TS="PIGS" OR TS="SWINE" OR TS="PORCINE" OR TS=MONKEY* OR TS=MACAQUE*
OR TS=BABOON* OR T S=MARMO SET * OR TS="CHILD" OR T S=" CHILDREN" OR
TS=ADOLESCEN* OR TS=INFANT* OR TS="WORKER" OR TS="WORKERS" OR
TS="HUMAN" OR TS=PATIENT* OR TS=MOTHER OR TS=FETAL OR TS=FETUS OR
TS=CITIZENS OR TS=MILK OR TS=FORMULA OR TS=EPIDEMIO* OR
TS=POPULATION* OR TS=EXPOSURE* OR TS=QUESTIONNAIRE OR SO=EPIDEMIO*)
OR TI=TOXIC*)) AND (PY=2019-2020))OS
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APPENDIX B. DETAILED PECO CRITERIA
Table B-l. Population, Exposure, Comparator, and Outcome (PECO) Criteria
PECO Element
Evidence
Population
Humans, laboratory mammals, and other animal models of established relevance to human
health (e.g,,Xenopus embryos); mammalian organs, tissues, and cell lines; and bacterial and
eukaryote models of genetic toxicity.
Exposure
In vivo (all routes), ex vivo, and in vitro exposure to the chemical of interest, including
mixtures to which the chemical of interest may contribute significantly to exposure or
observed effects.
Comparator
Any comparison (across dose, duration, or route) or no comparison (e.g., case reports without
controls).
Outcome
Any endpoint suggestive of a toxic effect on any bodily system, or mechanistic change
associated with such effects. Any endpoint relating to disposition of the chemical within the
body.
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APPENDIX C. SCREENING PROVISIONAL VALUES
For reasons discussed in the main Provisional Peer Reviewed Toxicity Value (PPRTV)
document, it is inappropriate to derive provisional toxicity values for terephthalic acid (TPA)
because the principle study is not peer reviewed. However, information is available for this
chemical, which although insufficient to support deriving a provisional toxicity value under
current guidelines, may be of use to risk assessors. In such cases, the Center for Public Health
and Environmental Assessment (CPHEA) summarizes available information in an appendix and
develops a "screening value." Appendices receive the same level of internal and external
scientific peer review as the provisional reference values to ensure their appropriateness within
the limitations detailed in the document. Users of screening toxicity values in an appendix to a
PPRTV assessment should understand that there could be more uncertainty associated with the
derivation of an appendix screening toxicity value than for a value presented in the body of the
assessment. Questions or concerns about the appropriate use of screening values should be
directed to the CPHEA.
DERIVATION OF SCREENING PROVISIONAL ORAL REFERENCE DOSES
As discussed in the main body of the report, the reproductive/developmental study by
Ledoux and Reel (1982) was chosen as the principle study and the corresponding 5% benchmark
dose lower confidence limit (BMDLos) human equivalent dose (HED) of 54.4 mg/kg-day for
decreased pup weight in female CD rats was identified as the most sensitive point of departure
(POD) for deriving screening-level provisional reference dose (p-RfD) values. The choice of
decreased pup weight as the critical effect is supported by observations of TPA-induced pup
weight effects in other studies [i.e., Milburn (2003); Heck (1979)1 and in two rat strains
(i.e., Wistar and CD rats) from the Ledoux and Reel (1982) study.
Derivation of Screening Subchronic Provisional Reference Dose
The screening subchronic p-RfD is derived by applying a composite uncertainty factor
(UFc) (see Table C-l) of 100 (reflecting an interspecies uncertainty factor [UFa] of 3, an
intraspecies uncertainty factor [UFh] of 10, and a database uncertainty factor [UFd] of 3) to the
selected POD of 54.4 mg/kg-day.
Screening Subchronic p-RfD = POD (HED) UFc
= 54.4 mg/kg-day -M00
= 5 x 10"1 mg/kg-day
Table C-l summarizes the uncertainty factors for the screening subchronic p-RfD for
TPA.
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Table C-l. Uncertainty Factors for the Screening Subchronic p-RfD for
TPA (CASRN 100-21-0)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rats and humans following TPA exposure. The toxicokinetic
uncertainty has been accounted for by calculating an HED through application of a DAF as outlined in
the U.S. EPA's Recommended Use of Body Weight3"'4 as the Default Method in Derivation of the Oral
Reference Dose (U.S. EPA, 1988).
UFd
3
A UFd of 3 (10°5) is applied to account for deficiencies in the database. Numerous repeated-dose oral
studies of TPA are available, and findings are consistent across studies, although a number of studies
are unpublished and/or poorly reported and some others included only a single dose level. Although
both key chronic studies are unpublished and not peer reviewed, they both included adequate numbers
of male and female rats and multiple dose groups; investigated a range of endpoints, including the
target urinary tract; identified dose-response relationships; and provided useable documentation.
Single- and multiple-generation reproductive studies are available, but of reduced utility due to poor
reoortine or non-oeer-reviewed status (Milbum. 2003; Hall et al.. 1993; Ledoux and Reel. 1982).
None of these studies has reported any effect on fertility, although studies of testicular and sperm
effects (Kwack and Lee. 2015; Cui et al.. 2004) have found some SDerm chanses of uncertain
toxicological significance. Effects on pup body weights and developmental milestones have been
reported in the developmental/reproductive studies, as has some evidence for an effect on pup
survival. No oral teratogenicity studies were located.
UFh
10
A UFh of 10 is applied to account for human variability in susceptibility, in the absence of information
to assess toxicokinetic and toxicodynamic variability of TPA in humans.
UFl
1
A UFl of 1 is applied because the POD is a BMDL05.
UFS
1
A UFS of 1 is applied because developmental toxicity was used as the critical effect. The
developmental period is recognized as a susceptible life stage when exposure during a time window of
development is more relevant to the induction of developmental effects than lifetime exposure (U.S.
EPA. 1991).
UFC
100
Composite UF = UFA x UFD x UFH x UFL x UFS.
BMD = maximum likelihood estimate of the dose associated with the selected BMR; BMDL = 95% lower
confidence limit on the BMD (subscripts denote BMR: i.e., 5 = dose associated with 5% relative deviation);
BMR = benchmark response; DAF = dosimetric adjustment factor; HED = human equivalent dose;
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfD = provisional reference dose; TPA = terephthalic acid; UF = uncertainty factor;
UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic
uncertainty factor.
Derivation of Screening Chronic Provisional Reference Dose
The screening chronic p-RfD is derived using the same POD (BMDLos [HED] of
54.4 mg/kg-day for decreased pup weight in female CD rats from the Ledoux and Reel (1982)
study as the screening subchronic p-RfD and applying a UFc of 100 (reflecting a UFa of 3, a
UFh] of 10, and a UFd of 3).
Screening Chronic p-RfD = POD (HED) UFc
= 54.4 mg/kg-day -M00
= 5 x 10"1 mg/kg-day
Table C-2 summarizes the uncertainty factors for the screening chronic p-RfD for TPA.
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Table C-2. Uncertainty Factors for the Screening Chronic p-RfD for
TPA (CASRN 100-21-0)
UF
Value
Justification
UFa
3
A UFa of 3 (100 5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rats and humans following TPA exposure. The toxicokinetic
uncertainty has been accounted for by calculating an HED through application of a DAF as outlined in
the U.S. EPA's Recommended Use of Body Weight3"'4 as the Default Method in Derivation of the Oral
Reference Dose (U.S. EPA, 1988).
UFd
3
A UFd of 3 (10°5) is applied to account for deficiencies in the database. Numerous repeated-dose oral
studies of TPA are available, and findings are consistent across studies, although a number of studies
are unpublished and/or poorly reported and some others included only a single dose level. Although
both key chronic studies are unpublished and not peer reviewed, they both included adequate numbers
of male and female rats and multiple dose groups; investigated a range of endpoints, including the
target urinary tract; identified dose-response relationships; and provided useable documentation.
Single- and multiple-generation reproductive studies are available, but of limited utility due to poor
reDortinu or nonoral exposure (Milbum. 2003: Hall et al.. 1993; Ledoux and Reel. 1982s). None of
these studies has reported any effect on fertility, although studies of testicular and sperm effects
(Kwack and Lee. 2015; Cui et al.. 2004) have found some SDerm chanees of uncertain toxicolosical
significance. Effects on pup body weights and developmental milestones have been reported in the
developmental/reproductive studies, as has some evidence for an effect on pup survival. No oral
teratogenicity studies were located.
UFh
10
A UFh of 10 is applied to account for human variability in susceptibility, in the absence of information
to assess toxicokinetic and toxicodynamic variability of TPA in humans.
UFl
1
A UFl of 1 is applied because the POD is a BMDL05.
UFS
1
A UFS of 1 is applied because developmental toxicity was used as the critical effect. The
developmental period is recognized as a susceptible life stage when exposure during a time window of
development is more relevant to the induction of developmental effects than lifetime exposure (U.S.
EPA. 1991).
UFC
100
Composite UF = UFA x UFD x UFH x UFL x UFS.
BMD = maximum likelihood estimate of the dose associated with the selected BMR; BMDL = 95% lower
confidence limit on the BMD (subscripts denote BMR: i.e., 5 = dose associated with 5% relative deviation);
BMR = benchmark response; DAF = dosimetric adjustment factor; HED = human equivalent dose;
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfD = provisional reference dose; TPA = terephthalic acid; UF = uncertainty factor;
UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies variability uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor;
UFS = subchronic-to-chronic uncertainty factor.
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APPENDIX D. DATA TABLES
Table D-l. Serum Chemistry and Urine Endpoints in Chinese Fiber Factory Workers
Exposed to Ambient TPA Dusta
Cumulative Exposure Group (mg/m3)
Control
Not Detected
-50
-80
Serum Endpoint
r-
II
3,
(n = 52)
(n = 59)
IT
II
©
ALB (g/L)
48.81+ 2.78bc
48.99 ± 2.44 (0%)
48.58 ± 2.68 (0%)
47.39 + 2.74* (-3%)
ALT (U/L)
13.96 ± 15.07
11.85 ±8.63 (-15%)
15.4 ± 22.6 (+10%)
13.67+ 9.39 (-2%)
AST (U/L)
14.16 ±5.37
15.4 ± 4.85 (+9%)
17.96 ± 12.45* (+27%)
16.57 + 5.79 (+17%)
GGT (U/L)
15.05 ± 10.81
12.94 ± 10.74 (-14%)
14.1 ±8.17 (-6%)
12.77 + 5.45 (-15%)
ALP (U/L)
72.31 ±24.11
78.6 ± 28.5 (+9%)
75.93 ±26.01 (+5%)
68.57+ 19.19 (-5%)
LDH (U/L)
280.25 ±73.38
286 ±56.14 (+2%)
309.78 + 63.45* (+11%)
279.73 + 49.45 (0%)
Control
Not Detected
-50
-80
Urine Endpoint
(*=71)
(n = 46)
(n = 57)
(n = 24)
pH
5.71 ±0.4
5.74 ±0.6
5.71 + 0.84
5.63 + 0.91
K+ (mmol/mol Cr)
4.5 ±2.18
5.02 ±2.13 (+12%)
4.24 ± 1.20 (-6%)
4.54+ 1.72 (+1%)
Na+ (mmol/mol Cr)
19.84 ± 10.3
23.53 ±11.12 (+19%)
24.42 ± 8.75* (+23%)
25.22+ 11.33* (+27%)
Ca2+ (mmol/mol Cr)
0.19 ± 0.1
0.3 ±0.19* (+58%)
0.33 +0.14* (+74%)
0.3+ 0.11* (+58%)
"Dai et al. (2005b): Li etal. (1999).
bData are mean ± SD.
°Value in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
* Significantly different from control (p < 0.05), as reported by the study authors.
ALB = albumin; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;
Cr = creatinine; GGT = y-glutamyl transferase; LDH = lactate dehydrogenase; SD = standard deviation;
TPA = terephthalic acid.
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Table D-2. Body Weights of F344 Weanlings Rats Exposed to TPA (CASRN 100-21-0)
for 14 Days3
Exposure Days
Male: ADD (HED) in mg/kg-db
0
658 (121)
1,904 (354.4)
3,740 (690)
4,860 (877)
5,710 (993)
0-2
57.30, d
57.7 (+0.6%)
61.1* (+7%)
59.6 (+4%)
56.2 (-2%)
53.9 (-6%)
6-8
80.6
80.2 (-0.5%)
83.2 (+3%)
80.0 (-0.8%)
72.8* (-10%)
61.2* (-24%)
12-14
104.8
101.9 (-3%)
107.8 (+3%)
103.4 (-1%)
93.4* (-11%)
77.2* (-26%)
Exposure Days
Female: ADD (HED) in mg/kg-d
0
599 (108)
1,836 (330.4)
3,760 (669)
4,770 (842)
5,520 (954)
0-2
51.8
56.0* (+8%)
54.6* (+5%)
52.9 (+2%)
54.1 (+4%)
51.8 (+0.02%)
6-8
70.6
73.9 (+5%)
73.4* (+4%)
69.8 (-1%)
66.0* (-7%)
59.5* (-16%)
12-14
87.9
92.5* (+5%)
92.4* (+5%)
87.2 (-1%)
84.0* (-4%)
76.2* (-13%)
aChin et al. (1981).
bDoses correspond to 0, 0.5, 1.5, 3, 4, and 5% TPA in the diet.
Data are mean values (g) based on graphically reported body-weight data extracted using GrabIT! software;
variance values were not extracted.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
* Significantly different from control (p < 0.05), as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose; TPA = terephthalic acid.
Table D-3. Incidence and Mass of Calculi in the Bladders of F344 Weanlings Rats Exposed
to TPA (CASRN 100-21-0) for 14 Days3
Effect
Males: ADD (HED) in mg/kg-db
0
658 (121)
1,904 (354.4)
3,740 (690)
4,860 (877)
5,710 (993)
Incidence of
calculi0
0/30
0/30
0/30
3/30 (+10%)
17/30* (+57%)
28/30** (+93%)
Mean massd
NA
NA
NA
9.4 + 2.4
10.1+ 1.4
38.8 + 7.1
Effect
Females: ADD (HED) in mg/kg-d
0
599 (108)
1,836 (330.4)
3,760 (669)
4,770 (842)
5,520 (954)
Incidence of
calculi
0/30
0/30
1/30 (+3%)
1/30 (+3%)
6/30* (+20%)
22/30** (+73%)
Mean mass
NA
NA
NDr
2.1
4.3 + 1.9
20.3 + 7.1
aChin et al. (1981).
bDoses correspond to 0, 0.5, 1.5, 3, 4, and 5% TPA in the diet.
°Values denote number of animals showing changes + total number of animals examined (% incidence).
dValues are mean ± SE.
* Significantly different from control (p < 0.05), by two-tailed Fisher's exact test, as conducted for this review.
**Significantly different from control (p < 0.01), by two-tailed Fisher's exact test, as conducted for this review.
ADD = adjusted daily dose; HED = human equivalent dose; NA = not applicable; NDr = not determined;
SE = standard error; TPA = terephthalic acid.
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Table D-4. Urinary Endpoints of F344 Weanlings Rats Exposed to TPA (CASRN 100-21-0) in the Diet for 14 Days3
Endpoint
Male: ADD (HED) in mg/kg-db
0
658 (121)
1,904 (354.4)
3,740 (690)
4,860 (877)
5,710 (993)
pH
6.30 ± 0.10c,d
5.88 ±0.05**
ND
5.77 ±0.03**
5.73 ±0.02**
ND
Ca2+ (mM)
5.5 ±0.6
11.1 ± 1.1
(+102%)
ND
22.5 ±2.2**
(+309%)
22.2 ± 1.9**
(+304%)
ND
PO ,3 (mM)
96 ± 13
68 ±8
(-29%)
ND
88 ± 11
(-8%)
113 ± 11
(+18%)
ND
TPA (mM)
NA
46 ±3
ND
68 ±7
81 ± 6
ND
Endpoint
Female: ADD (HED) in mg/kg-d
0
599 (108)
1,836 (330.4)
3,760 (669)
4,770 (842)
5,520 (954)
pH
6.22 ±0.08
5.8 ±0.04**
ND
5.73 ±0.03**
5.74 ±0.03**
ND
Ca2+ (mM)
4.9 ±0.7
11 ± 1.5
(+124%)
ND
23.8 ± 1.3**
(+386%)
23.5 ±2.7**
(+380%)
ND
PO ,3 (mM)
99 ± 19
59 ±5*
(-40%)
ND
109 ±11
(+10%)
128 ±11
(+29%)
ND
TPA (mM)
NA
37 ±4
ND
81 ± 2
101 ±9
ND
aChin et al. (198D.
bDoses correspond to 0, 0.5, 1.5, 3, 4, and 5% TPA in the diet.
Data are mean ± SEM; n = 10-28.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control (p < 0.05) by Dunnett's test, as reported by the study authors.
**Significantly different from control (p < 0.01), by Dunnett's test, as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose; ND = no data; SEM = standard error of the mean; TPA = terephthalic acid.
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Table D-5. Urinary Electrolyte and TPA (CASRN 100-21-0) Concentrations in Weanling F344 Rats Exposed to TPA in the
Diet for 14 Days"
Male/Female: ADD (HED) in mg/kg-db
Endpoint
Sex
0/0 (0/0)
658/599 (121/108)
3,740/3,760 (690/669)
4,860/4,770 (877/842)
Number of animals
n
18M, 10F
9 M, 14 F
17 M, 10 F
19M, 13F
pH
M
6.35 ± 0.11c,d
5.79 ±0.04**
5.75 ±0.03**
5.74 ±0.02**
F
6.19 ± 0.12
5.73 ±0.03**
5.65 ±0.03**
5.78 ±0.04**
Na+ (mM)
M
149 ± 16
192 ± 28 (+29%)
103 ±8* (-31%)
77 ± 6** (-48%)
F
120 ±9
155 ± 22 (+29%)
130 ± 18 (+8%)
61 ± 7* (-49%)
NH/(mM)
M
109 ± 23
324 ±41** (+197%)
308 ± 28** (+183%)
422 ± 26** (+287%)
F
111 ±21
347 ±42** (+213%)
372 ± 14** (+235%)
458 ±24** (+313%)
K+(mM)
M
256 ± 34
223 ± 24 (-13%)
116 ± 15** (-55%)
126 ±9** (-51%)
F
312 ±53
168 ± 17** (-46%)
139 ± 9** (-55%)
138 ± 14** (-56%)
Ca2+ (mM)
M
5.6 ±0.7
11.7 ± 1.3 (+109%)
22.5 ± 2.2** (+302%)
22.4 ± 2** (+300%)
F
4.9 ±0.7
11 ±1.5 (+124%)
25 ± 1.2** (+410%)
22.4 ± 3.1** (+357%)
Mg2+ (mM)
M
37.6 ±4.7
34.4 ± 2.4 (-9%)
29.7 ±3.7 (-21%)
34.3 ± 2.9 (-9%)
F
44.1 ±5.8
28.5 ± 2* (-35%)
36.1 ±2.4 (-18%)
37 ± 4.2 (-16%)
CI (mM)
M
162 ± 13
194 ± 23 (+20%)
144 ± 15 (-11%)
135 ± 12 (-17%)
F
169 ± 18
200 ± 20 (+18%)
183 ± 6 (+8%)
142 ± 12 (-16%)
PO ,3 (mM)
M
92 ± 13
71 ± 11 (-23%)
88 ± 11 (-4%)
113 ± 11 (+23%)
F
107 ± 19
59 ± 5* (-45%)
108 ± 6 (+1%)
121 ± 12 (+13%)
71
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September 2020
Table D-5. Urinary Electrolyte and TPA (CASRN 100-21-0) Concentrations in Weanling F344 Rats Exposed to TPA in the
Diet for 14 Days"
Male/Female: ADD (HED) in mg/kg-db
Endpoint
Sex
0/0 (0/0)
658/599 (121/108)
3,740/3,760 (690/669)
4,860/4,770 (877/842)
Number of animals
n
18M, 10F
9 M, 14 F
17 M, 10 F
19M, 13F
SO ,2 (mM)
M
32.1 ±3.4
34.2 ± 1.8 (+7%)
16.3 ± 1.8** (-49%)
21.6 ± 1.7** (-33%)
F
34.2 ±3.7
41.9 ±3.9 (+23%)
24.1 ±2.2* (-30%)
24 ± 1.9* (-30%)
"Heck (1981).
bData are mean ± SEM.
Doses correspond to 0, 0.5, 3, and 4% TPA in the diet.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control mean] x 100.
* Significantly different from control (p < 0.05) by Dunnett's test, as reported by the study authors.
**Significantly different from control (p < 0.01) by Dunnett's test, as reported by the study authors.
ADD = adjusted daily dose; F = female(s); HED = human equivalent dose; M = male(s); SEM = standard error of the mean; TPA = terephthalic acid.
72
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September 2020
Table D-6. Body Weights of Male F344 Rat Pups Exposed to TPA (CASRN 100-21-0) in
the Diet for 14 Days"
Exposure Day
ADD (HED) in mg/kg-db
0
4,900 (874)
0
50.870, d
49.55 (-3%)
2
60.47
55.86* (-8%)
4
68.53
61.72* (-10%)
6
78.78
69.57* (-12%)
8
84.87
71.93* (-15%)
10
93.37
80.43* (-14%)
12
102.31
87.39* (-15%)
14
108.84
90.85* (-17%)
aWolkowski-Tvl and Chin (1983).
bDoses correspond 0 and 4% TPA in the diet.
Data are mean values based on graphically reported body-weight data extracted using GrabIT! software; accurate
variance values could not be extracted due to overlapping data points.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
*The study authors indicated in the text that significant depressions in body weight were observed beginning on
Day 2 of the study.
ADD = adjusted daily dose; HED = human equivalent dose; TPA = terephthalic acid.
Table D-7. Food and Water Intake of Male F344 Rat Pups Exposed to
TPA (CASRN 100-21-0) in the Diet for 14 Days3
Endpoint
ADD (HED) in mg/kg-db
0
4,900 (874)
Water (mL/cage-d)
5.86 ± 0.190, d
7.80 ± 0.34* (+33%)
Food (g/cage-d)
51.46 ± 1.59
43.50 ± 1.85* (-15%)
"Wolkowski-Tvl and Chin (1983).
bDoses correspond 0 and 4% TPA in the diet.
Data are mean ± SEM; n = 10.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
* Significantly different from control (p < 0.05), by Student's /-test with /-test, as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose; SEM = standard error of the mean; TPA = terephthalic
acid.
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September 2020
Table D-8. Serum and Urinary Endpoints in Male F344 Rat Pups Exposed to
TPA (CASRN 100-21-0) in the Diet for 14 Days3
Endpoint'd
ADD (HED) in mg/kg-db
0
4,900 (874)
Urinary endpoint
pH
7.00 ±0.15
5.74 ±0.04*
Blood/serum endpoint
Calcium
Magnesium
Hematocrit
3.12 ±0.02
0.73 ±0.02
42.1 ±0.5
3.31 ±0.02* (+6%)
0.93 ±0.03* (+27%)
41.0 ±0.5 (-3%)
aWolkowski-Tvl and Chin (1983).
bDoses correspond 0 and 4% TPA in the diet.
Data are mean ± SEM; n = 10.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
* Significantly different from control (p < 0.05), by Student's /-test with /-test, as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose; SEM = standard error of the mean; TPA = terephthalic
acid.
Table D-9. Incidence of Calculi in Male F344 Rat Pups Exposed to
TPA (CASRN 100-21-0) in the Diet for 14 Days3
Endpoint0
ADD (HED) in mg/kg-db
0
4,900 (874)
Incidence of calculi
0/10 (0%)
5/10* (50%)
"Wolkowski-Tvl and Chin (1983).
bDoses correspond 0 and 4% TPA in the diet.
°Values denote number of animals showing changes + total number of animals examined (% incidence).
* Significantly different from control (p < 0.05), by two-tailed Fisher's exact test, as conducted for this review.
ADD = adjusted daily dose; HED = human equivalent dose; TPA = terephthalic acid.
74
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September 2020
Table D-10. Urinary Endpoints in Male and Female S-D Rats Exposed to
TPA (CASRN 100-21-0) in the Diet for 90 Days3
Endpoint
Male: ADD (HED) in (mg/kg-d)b
0
36.0 (8.77)
179 (43.8)
906 (220)
4,550 (1,100)
Number examined («)
n = 12
n = 12
n = 10
n = 12
n = 9
Ca2+
(g/mol Cr)
0.39 ± 0.31c-d
0.45 ±0.48
(+15%)
0.52 ±0.36
(+33%)
8.23 ±7.6**
(+2,010%)
124.56 ± 15.72*
*
(+31,839%)
Mg2+
(g/mol Cr)
16.2 ±7.62
30.37 ± 11.06
(+88%)
41.65 ± 11.61**
(+157%)
43.38 ±21.2**
(+168%)
119.65 + 55.69*
*
(+639%)
Zn2+
(g/mol Cr)
0.1±0.11
0.16 ±0.07
(+60%)
0.1 ±0.06
(0%)
0.18 ± 0.12
(+80%)
0.74 + 0.72**
(+640%)
K+
(g/mmol Cr)
0.11 ±0.04
0.4 ±0.05
(+264%)
0.29 ±0.13
(+164%)
0.4 ±0.28**
(+264%)
0.31 + 0.26
(+182%)
Na+
(g/mmol Cr)
0.26 ±0.16
0.48 ±0.14
(+85%)
0.34 ±0.18
(-31%)
0.39 ±0.32
(+50%)
0.91 + 1.28*
(+250%)
pH (n = 11)
6.53 ±0.47
6.05 ±0.25
6.39 ±0.45
5.92 ±0.38
5.66 + 0.18**
Endpoint
Female: ADD (HED) in (mg/kg-d)
0
40.0 (9.03)
197 (44.9)
997 (225)
4,970 (1,130)
Number examined («)
n = 12
n = 12
n = 10
n = 12
n = 9
Ca2+
(g/mol Cr)
8.61 ±6.46
9.69 ±6.15
(+13%)
9.93 ±3.98
(+15%)
25.92 ±23.22
(+201%)
44.12 ±25.78**
(+412%)
Mg2+
(g/mol Cr)
25.64 ± 16.66
44.45 ± 14.48
(+73%)
47.26 ± 15.02
(+84%)
49.94 ± 15.68
(+95%)
86.85 + 68.57**
(+239%)
Zn2+
(g/mol Cr)
0.05 ±0.02
0.08 ±0.06
(+60%)
0.11 ±0.07
(+120%)
0.18 ±0.26
(+260%)
0.22 + 0.17*
(+340%)
K+
(g/mmol Cr)
0.26 ±0.14
0.27 ±0.14
(+4%)
0.21 ±0.07
(-19%)
0.58 ±0.3**
(+123%)
0.33 + 0.28
(+27%)
Na+
(g/mmol Cr)
0.50 ±0.25
0.5 ±0.22
(0%)
0.23 ±0.11
(-54%)
0.6 ±0.4
(+20%)
0.75 + 0.14**
(+50%)
pH(«= 11)
6.56 ±0.06
6.2 ±0.56**
6.27 ±0.54
6.08 ±0.77*
5.77 + 0.22**
aDai et al. (2005c): Dai et at (2006a).
bDoses correspond to 0, 0.04, 0.2, 1, and 5% TPA in the diet.
Data are mean ± variance (specified by the study authors as ".v"),
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
* Significantly different from control (p < 0.05) by Student's t-test, as reported by the study authors.
**Significantly different from control (p < 0.01) by Student's t-test, as reported by the study authors.
ADD = adjusted daily dose; Cr = creatinine; HED = human equivalent dose; S-D = Sprague-Dawley;
TPA = terephthalic acid.
75
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September 2020
Table D-ll. Relative Organ Weights of Male and Female S-D Rats Exposed to
TPA (CASRN 100-21-0) in the Diet for 90 Days3
Endpoint
(g/100 g BW)
Male: ADD (HED) in mg/kg-db
0
36.0 (8.77)
179 (43.8)
906 (220)
4,550 (1,100)
Number
examined (n)
n = 12
n = 12
n = 11
n = 12
n =52
Liver
2.998 +0.43 lcd
3.27 ±0.193
(+9%)
3.218 ± 0.118
(+7%)
3.383 ±0.363*
(+13%)
2.94 + 0.295
(-2%)
Spleen
0.185 ±0.031
0.169 ±0.029
(-9%)
0.173 ±0.017
("7%)
0.178 + 0.021
(-4%)
0.167 + 0.03
(-10%)
Kidney
0.719 ±0.13
0.776 ± 0.044
(+8%)
0.748 ± 0.077
(+4%)
0.781 + 0.034 (+9%)
0.778 + 0.115
(+8%)
Adrenal gland
0.014 ±0.003
0.012 ±0.004
(-14%)
0.017 ±0.005
(+21%)
0.015 + 0.004 (+7%)
0.014 + 0.003
(0%)
Brain
0.507 ± 0.047
0.463 ± 0.079
(-9%)
0.433 ±0.078*
(-15%)
0.487 + 0.099
(-4%)
0.474 + 0.113
("7%)
Endpoint
(g/100 g BW)
Female: ADD (HED) in mg/kg-d
0
40.0 (9.03)
197 (44.9)
997 (225)
4,970 (1,130)
Number
examined(n)
n = 12
n = 12
n = 12
n = 12
n =23
Liver
3.16 ±0.295
3.329 ±0.427
(+5%)
3.128±0.354
(-1%)
3.295 + 0.376
(+4%)
3.125 + 0.359
(-1%)
Spleen
0.205 ± 0.026
0.202 ±0.036
(-2%)
0.193 ±0.027
(-6%)
0.235 + 0.023**
(+15%)
0.208 + 0.05
(+2%)
Kidney
0.776 ± 0.065
0.751 ±0.135
(-3%)
0.728 ±0.139
(-6%)
0.848 + 0.037**
(+9%)
0.78 + 0.073
(+1%)
Adrenal gland
0.031 ±0.009
0.04 ±0.035
(+29%)
0.027 ± 0.005
(-13%)
0.03 + 0.006
(-3%)
0.03 +0.005
(-3%)
"Dai et al. (2005c): Dai et at (2006a).
bDoses correspond to 0, 0.04, 0.2, 1, and 5% TPA in the diet.
Data are mean ± variance (specified by the study authors as 'V),
dValue in parenthesis is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
* Significantly different from control (p < 0.05) by Student's t-test, as reported by the study authors.
**Significantly different from control (p < 0.01) by Student's t-test, as reported by the study authors.
ADD = adjusted daily dose; BW = body weight; HED = human equivalent dose; S-D = Sprague-Dawley;
TPA = terephthalic acid.
76
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September 2020
Table D-12. Incidence of Calculi, Sediment, and Non-neoplastic Lesions in Bladders of
Male and Female S-D Rats Exposed to TPA (CASRN 100-21-0) in the Diet for 90 Days3
Endpoint
Male: ADD (HED) in (mg/kg-d)b
0
36.0 (8.77)
179 (43.8)
906 (220)
4,550 (1,100)
Bladder calculi
Amount0
0/12 (0%)d
0/12 (0%)
0/11 (0%)
0/12 (0%)
21/52* (40%)
Urine white
sediment
+
0/12 (0%)
5/12* (42%)
5/11* (46%)
6/12* (50%)
13/52 (25%)
Urine white
sediment
++
0/12 (0%)
0/12 (0%)
0/11 (0%)
4/12* (33%)
9/52 (17%)
Urine white
sediment
+++
0/12 (0%)
0/12 (0%)
0/11 (0%)
2/12 (17%)
8/52 (15%)
Bladder
hyperplasia
Simple
0/12 (0%)
0/12 (0%)
0/11 (0%)
0/12 (0%)
9/52 (17%)
Bladder
hyperplasia
Atypical
0/12 (0%)
0/12 (0%)
0/11 (0%)
0/12 (0%)
5/52 (10%)
Endpoint
Female: ADD (HED) in (mg/kg-d)
0
40.0 (9.03)
197 (44.9)
997 (225)
4,970 (1,130)
Bladder calculi
Amount
0/12 (0%)
0/12 (0%)
0/12 (0%)
0/12 (0%)
1/23 (4%)
Urine white
sediment
+
0/12 (0%)
0/12 (0%)
2/12 (17%)
4/12* (33%)
8/23* (35%)
Urine white
sediment
++
0/12 (0%)
0/12 (0%)
0/12 (0%)
1/12 (8%)
4/23 (17%)
Urine white
sediment
+++
0/12 (0%)
0/12 (0%)
0/12 (0%)
0/12 (0%)
3/23 (13%)
Bladder
hyperplasia
Simple
0/12 (0%)
0/12 (0%)
0/12 (0%)
0/12 (0%)
1/23 (4%)
Bladder
hyperplasia
Atypical
0/12 (0%)
0/12 (0%)
0/12 (0%)
0/12 (0%)
0/23 (0%)
"Dai et al. (2005c): Dai et at (2006a).
bDoses correspond to 0, 0.04, 0.2, 1, and 5% TPA in the diet.
°+ = minor, ++ = moderate, +++ = large.
dValues denote number of animals showing changes/total number of animals examined (% incidence).
* Significantly different from control (p < 0.05), by two-tailed Fisher's exact test, as conducted for this review.
ADD = adjusted daily dose; HED = human equivalent dose; S-D = Sprague-Dawley; TPA = terephthalic acid.
77
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September 2020
Table D-13. Body-Weight Data for Male and Female Albino Weanling Rats Exposed to
TPA (CASRN 100-21-0) in the Diet for 90 Days3
Endpoint'd
Male: ADD (HED) in (mg/kg-d)b
0
859 (217)
2,754 (693.5)
10,500 (2,290)
Body weight (g)°
Initial body weight
104.3ef
105
105
105
30 d
252.3
242 (-4%)
251 (-1%)
138.4 (-45%)
60 d
351.3
346 (-2%)
343 (-2%)
172 (-51%)
90 d
421.3
415 (-1%)
396 (-6%)
226 (-46%)
Body-weight gain (%)
30 d
142
130 (-8%)
139 (-2%)
32 (-79%)
60 d
237
230 (-3%)
227 (-4%)
64 (-73%)
90 d
304
295 (-3%)
277 (-9%)
115 (-62%)
Endpoint
Female: ADD (HED) in (mg/kg-d)
0
992 (225)
3,170 (719.2)
11,200 (2,320)
Body weight (g)e
Initial body weight
94.3
94
94
94
30 d
177
178 (+0.6%)
180 (+2%)
118 (-33%)
60 d
216.3
210 (-3%)
212 (-2%)
142 (-34%)
90 d
240.3
239 (-0.5%)
235 (-2%)
154 (-36%)
Body-weight gain (%)
30 d
88
89 (+1%)
91 (+2%)
26 (-71%)
60 d
129
123 (-5%)
126 (+2%)
51 (-60%)
90 d
155
154 (-1%)
150 (-3%)
64 (-59%)
"Dupont Chem Co (1955).
bDoses correspond to 0, 1, 3.2, and 10% TPA in the diet.
°Body weights at 30, 60, and 90 days were calculated from body-weight-gain data provided in the study.
Statistical analysis was not performed by the study authors.
"Data are mean values; variance values were not reported; n = 6/sex/group.
fValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
ADD = adjusted daily dose; HED = human equivalent dose; TPA = terephthalic acid.
78
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September 2020
Table D-14. Adjusted Mean Body Weights of Male and Female Wistar and CD Rats
Exposed to TPA (CASRN 100-21-0) in the Diet for 90 Days3
Male: ADD (HED) in (mg/kg-d)b
15.3
79.09
266
1,020
2,650
Wistar
0
(4.44)
(22.81)
(76.0)
(293)
(750)
4 wk
401.80, d
396.9 (-1%)
402 (0%)
399.9 (0%)
393.2 (-2%)
374.1** (-7%)
8 wk
401.4
410.5 (+2%)
400.9 (0%)
393.3 (-2%)
386.4 (-4%)
369.8** (-8%)
13 wk
471.6
468 (-1%)
483 (+2%)
464.1 (-2%)
448.9 (-5%)
431.6** (-8%)
14.6
76.15
247
976
2,590
CD
0
(4.23)
(21.99)
(71.5)
(282)
(741)
4 wk
396.2
387.8 (-2%)
390.6 (-1%)
384.6* (-3%)
385.5* (-3%)
375.5** (-5%)
8 wk
429.8
415.1 (-3%)
428.7 (0%)
415 (-3%)
418 (-3%)
418 (-3%)
13 wk
485.8
447.9 (-8%)*
458.7 (-6%)
458.6 (-6%)
450.2* (-7%)
440.5** (-9%)
Female: ADD (HED) in (mg/kg-d)
19.3
114.5
313
1,280
3,100
Wistar
0
(4.84)
(27.89)
(78.7)
(321)
(773)
4 wk
377.8
375.8 (-1%)
376 (0%)
373.7 (-1%)
371.4** (-2%)
360.6** (-5%)
8 wk
395.7
398.6 (+1%)
400.6 (+1%)
397.1 (0%)
390.8 (-1%)
379.2** (-4%)
13 wk
404.7
391.1 (-3%)
404.7 (0%)
400.8 (-1%)
394.6 (-2%)
383.9** (-5%)
17.6
86.57
286
1,260
2,840
CD
0
(4.65)
(22.83)
(75.0)
(321)
(732)
4 wk
379.9
376.8 (-1%)
380.5 (0%)
369.9 (-3%)
366.9** (-3%)
351.5** (-7%)
8 wk
401.4
410.5 (+2%)
400.9 (0%)
393.3 (-2%)
386.4 (-4%)
369.8** (-8%)
13 wk
426.8
427.1 (0%)
411.4 (-4%)
409.6 (-4%)
390.6** (-8%)
362** (-15%)
"Ledoux and Reel (1982).
bDoses correspond to 0, 0.03, 0.154, 0.5, 2, and 5% TPA in the diet.
Data are adjusted means (g) extracted from graphically reported data using GrabIT! software; variance values were
not reported; n = ~30/sex/treatment group.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) control
mean] x 100.
* Significantly different from control (p < 0.05), based on Dunnett's two-tailed /-test, as reported by the study
authors.
**Significantly different from control (p < 0.01), based on Dunnett's two-tailed t-test, as reported by the study
authors.
ADD = adjusted daily dose; HED = human equivalent dose; TPA = terephthalic acid.
79
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September 2020
Table D-15. Adjusted Mean Body-Weight Gains of Male and Female Wistar and CD Rats
Exposed to TPA (CASRN 100-21-0) in the Diet for 90 Days3
Male: ADD (HED) in (mg/kg-d)b
15.3
79.09
266
1,020
2,650
Wistar
0
(4.44)
(22.81)
(76.0)
(293)
(750)
Body-weight
130° d
125
137
130
108
75**
gain (g)
(-4%)
(+5%)
(0%)
(-17%)
(-43%)
14.6
76.15
247
976
2,590
CD
0
(4.23)
(21.99)
(71.5)
(282)
(741)
Body-weight
131
106*
117
101**
99**
82**
gain (g)
(-19%)
(-11%)
(-23%)
(-24%)
(-37%)
Female: ADD (HED) in (mg/kg-d)
19.3
114.5
313
1,280
3,100
Wistar
0
(4.84)
(27.89)
(78.7)
(321)
(773)
Body-weight
73
70
71
69
63
44**
gain (g)
(-4%)
(-2%)
(-6%)
(-14%)
(-40%)
17.6
86.57
286
1,260
2,840
CD
0
(4.65)
(22.83)
(75.0)
(321)
(732)
Body-weight
92
87
81
64**
54**
19**
gain (g)
(-5%)
(-12%)
(-30%)
(-41%)
(-79%)
"Ledoux and Reel (1982).
bDoses correspond to 0, 0.03, 0.154, 0.5, 2, and 5% TPA in the diet.
Data are adjusted means (g) extracted from graphically reported data using GrabIT! software; variance values were
not reported, n = ~30/sex/treatment group.
dValue in parenthesis is percent change relative to control = [(treatment mean - control mean) control
mean] x 100.
* Significantly different from control (p < 0.05), based on Dunnett's two-tailed /-test, as reported by the study
authors.
**Significantly different from control (p < 0.01), based on Dunnett's two-tailed t-test, as reported by the study
authors.
ADD = adjusted daily dose; HED = human equivalent dose; TPA = terephthalic acid.
80
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FINAL
September 2020
Table D-16. Adjusted Mean Cumulative Food Consumption of Male and Female Wistar
and CD Rats Exposed to TPA (CASRN 100-21-0) in the Diet for 90 Days3
Male: ADD (HED) in (mg/kg-d)b
Wistar
0
15.3
(4.44)
79.09
(22.81)
266
(76.0)
1,020
(293)
2,650
(750)
4 wk
625.60, d
615.2 (-2%)
620.3 (-1%)
634.7 (+1%)
599.9 (-4%)
563.5** (-10%)
8 wk
1,277.5
1,254.7
(-2%)
1,260.2
(-1%)
1,285.8 (+1%)
1,228.2 (-4%)
1,188.3* (-7%)
13 wk
2,095.8
2,051.1
(-2%)
2,074.6
(-1%)
2,107.5 (+1%)
2,008 (-4%)
1,992.5 (-5%)
CD
0
14.6
(4.23)
76.15
(21.99)
247
(71.5)
976
(282)
2,590
(741)
4 wk
593.9
581.5 (-2%)
573 (-4%)
582.5 (-2%)
565.4 (-5%)
561 (-6%)
8 wk
1,223.6
1,170.9
(-4%)
1,186.5
(-3%)
1,175.2 (-4%)
1,154.2 (-6%)
1,183.9 (-3%)
13 wk
2,036.3
1,920.1
(-6%)
1,953.6
(-4%)
1,944.8 (-4%)
1,914.9 (-6%)
1,991.1 (-2%)
Female: ADD (HED) in (mg/kg-d)
Wistar
0
19.3
(4.84)
114.5
(27.89)
313
(78.7)
1,280
(321)
3,100
(773)
4 wk
602.4
606.5 (+1%)
601.2 (0%)
593.5 (-1%)
587.1 (-3%)
529.3** (-12%)
8 wk
1,206.3
1,212.9
(+1%)
1,207.4 (0%)
1,175.3 (-3%)
1,183.9 (-2%)
1,111.5** (-8%)
13 wk
1,970.5
1,945.7
(-1%)
1,962.7 (0%)
1,909.2 (-3%)
1,926.8 (-2%)
1,834.5** (-7%)
CD
0
17.6
(4.65)
86.57
(22.83)
286
(75.0)
1,260
(321)
2,840
(732)
4 wk
605.5
585.3 (-3%)
583 (-4%)
583.2 (-4%)
567.5** (-6%)
508.1** (-16%)
8 wk
1,196.5
1,178.1
(-2%)
1,170.2
(-2%)
1,162.5 (-3%)
1,149.2 (-4%)
1,077.6**
(-10%)
13 wk
1,962.5
1,917.8
(-2%)
1,889.6
(-4%)
1,878.3 (-4%)
1,860.2*
(-5%)
1,746.8**
(-11%)
aLedoux and Reel (1982).
bDoses correspond to 0, 0.03, 0.154, 0.5, 2, and 5% TPA in the diet.
Data are adjusted means (g) extracted from graphically reported data using GrabIT! software; variance values were
not reported; n = ~30/sex/treatment group.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) control
mean] x 100.
* Significantly different from control (p < 0.05), based on Dunnett's two-tailed /-test, as reported by the study
authors.
**Significantly different from control (p < 0.01), based on Dunnett's two-tailed t-test, as reported by the study
authors.
ADD = adjusted daily dose; HED = human equivalent dose; TPA = terephthalic acid.
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Table D-17. Incidence of Urinary Tract Effects in Male and Female Wistar and CD Rats
Exposed to TPA (CASRN 100-21-0) in the Diet for 90 Days3
Observation0
ADD (HED) in (mg/kg-d)b
Wistar
CD
2,650 M, 3,100 F
(750, 773)
2,590 M, 2,840 F
(741, 732)
Urinary bladder calculi
4/9 M, 1/9 F
1/7 F
Chronic cystitis
3/10 M, 4/10 F
1/9 M, 4/10 F (1/10 F control)
Transitional cell hyperplasia (bladder)
3/10 M, 5/10 F
1/9 M, 4/10 F (1/10 F control)
Urethra calculi
2/7 M
ND
Chronic urethritis
2/7 M, 4/10 F
4/9 F
Transitional cell hyperplasia (urethra)
2/7 M, 5/10 F
4/9 F (1/10 F control)
'Data as reported in Ball et al. (2012) regarding Ledoux and Reel (1982): the only data provided on controls are
shown.
bDoses correspond to 5% TPA in the diet.
°Values denote number of animals showing changes total number of animals examined.
ADD = adjusted daily dose; F = female(s); HED = human equivalent dose; M = male(s); ND = no data;
TPA = terephthalic acid.
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September 2020
Table D-18. Body and Bladder Weights in Male Wistar Rats Treated with
TPA (CASRN 100-21-0) in the Diet for 22 Weeks3
Endpoint
ADD (HED) in (mg/kg-d)b
0
829 (196)
4,280 (1,010)
Body weight (g)
424.6 ± 36.33c-d
389.13 ± 37.35* (-8%)
375.4 ± 28.36** (-12%)
Absolute bladder weight (g)
0.094 ±0.035
0.1 ±0.045 (+6%)
0.15 ±0.075** (+60%)
Relative bladder weight (% BW)
0.022 ± 0.006
0.025 ± 0.009 (+14%)
0.04 ± 0.02** (+82%)
aCui et al. (2006a).
bDoses correspond to 0, 1, and 5% TPA in the diet.
Data are mean ± variance (type of variance not specified by the study authors); n = 30 (controls),
n = 15 (treatment groups).
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
* Significantly different from control (p < 0.05), based on ANOVA and least significance difference tests, as
reported by the study authors.
**Significantly different from control (p < 0.01), based on ANOVA and least significance difference tests, as
reported by the study authors.
ADD = adjusted daily dose; ANOVA = analysis of variance; BW = body weight; HED = human equivalent dose;
TPA = terephthalic acid.
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September 2020
Table D-19. Urinary Endpoints in Male Wistar Rats Treated with TPA (CASRN 100-21-0)
in the Diet for 22 Weeks3
Urinary Endpoint
ADD (HED) in (mg/kg-d)b
0
829 (196)
4,280 (1,010)
pH
6.43 ± 0.25c,d
5.98 ±0.38*
5.43 ±0.21**
Volume (mL)
5.83 ± 1.06
7.89 ± 0.85 (+35%)
10.24 ± 1.57** (+76%)
Sodium (mM)
119.26 ± 18.77
104.55 ±3.27* (-12%)
88.79 ±5.71** (-26%)
Potassium (mM)
286.2 ±55.94
225.83 ±36.63* (-21%)
79.78 ± 26.55** (-72%)
Calcium (mM)
4.2 ± 1.54
9.81 ±2.17** (+134%)
14.83 ±3.96** (+253%)
Chloride (mM)
151.35 ±30.85
122.91 ± 16.01** (-19%)
90.41 ± 17.04** (-40%)
Phosphorus (mM)
29.63 ± 1.43
33.25 ±1.12** (+12%)
31.77 ±2.2** (+7%)
Urine precipitate
± or -e
++
+++
aCui et al. (2006a).
bDoses correspond to 0, 1, and 5% TPA in the diet.
Data are mean ± variance (type of variance not specified by the study authors); n = 30 (controls),
n = 15 (treatment groups).
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
e- = no change; ± = trace; + = slight; ++ = moderate; +++ = marked.
* Significantly different from control (p < 0.05), based on ANOVA and least significance difference tests, as
reported by the study authors.
**Significantly different from control (p < 0.01), based on ANOVA and least significance difference tests, as
reported by the study authors.
ADD = adjusted daily dose; ANOVA = analysis of variance; HED = human equivalent dose; TPA = terephthalic
acid.
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September 2020
Table D-20. Incidences of Calculi and Histopathological Findings in the Urinary Bladders
of Male Wistar Rats Treated with TPA (CASRN 100-21-0) in the Diet for 22 Weeks3
Endpoint
ADD (HED) in (mg/kg-d)b
0
829 (196)
4,280 (1,010)
Calculi
0/15°
0/15 (0%)
4/15 (27%)
Simple hyperplasia
0/15+
2/15 (13%)
5/15* (33%)
PN hyperplasia
0/15
0/15 (0%)
4/15 (27%)
Papilloma
0/15
0/15 (0%)
0/15 (0%)
Transitional cell carcinoma
0/15
0/15 (0%)
0/15 (0%)
aCui et al. (2006a).
bDoses correspond to 0, 1, and 5% TPA in the diet.
°Values denote number of animals showing changes total number of animals examined (% incidence).
* Significantly different from control (p < 0.05), by two-tailed Fisher's exact test, as conducted for this review.
{Significant test for trend (p < 0.05), by x2 test, as conducted for this review.
ADD = adjusted daily dose; HED = human equivalent dose; PN = papillary or nodule hyperplasia;
TPA = terephthalic acid.
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September 2020
Table D-21. Calculi and Histopathological Changes in the Urinary Bladder of Male Wistar
Rats Exposed to TPA (CASRN 100-21-0) in the Diet for up to 48 Weeks"
Dose: ADD (HED) in (mg/kg-d)b
Treatment
Endpoint
0
3,680 (1,090)
12 wk
Calculi
0/4 (0%)c
7/8* (88%)
PN hyperplasia
0/4 (0%)
7/8* (88%)
24 wk
Calculi
0/4 (0%)
8/8** (100%)
PN hyperplasia
0/4 (0%)
8/8** (100%)
Papilloma
0/4 (0%)
8/8** (100%)
48 wk
Calculi
0/12 (0%)
20/20** (100%)
PN hyperplasia
0/12 (0%)
20/20** (100%)
Papilloma
0/12 (0%)
18/20** (90%)
Transitional cell carcinoma
0/12 (0%)
16/20** (80%)
aCui et al. (2006b).
bDoses correspond to 0 and 5% TPA in the diet.
°Values denote number of animals showing changes total number of animals examined (% incidence).
* Significantly different from control (p < 0.05), by two-tailed Fisher's exact test, as conducted for this review.
**Significantly different from control (p < 0.01), by two-tailed Fisher's exact test, as conducted for this review.
ADD = adjusted daily dose; HED = human equivalent dose; PN = papillary or nodule hyperplasia;
TPA = terephthalic acid.
Table D-22. Survival of Male and Female Wistar Rats Fed TPA (CASRN 100-21-0) in the
Diet for 24 Months3
Endpoint
Male: ADD (HED) in (mg/kg-d)b
0
736 (210)
1,470 (419)
3,680 (1,050)
Survival at 24 mo
33/50 (66%)°
26/50 (52%)
37/50 (74%)
16/50** (32%)
Endpoint
Female: ADD (HED) in (mg/kg-d)
0
842 (215)
1,680 (429)
4,210 (1,070)
Survival at 24 mo
37/50 (74%)
38/50 (76%)
42/50 (84%)
15/50*** (30%)
"Gross (1977).
bDoses correspond to 0, 1, 2, and 5% TPA in the diet.
°Values denote number of animals showing changes total number of animals examined (% incidence).
**Statistically different from control (p < 0.01), by Fisher's exact test performed for this review.
***Statistically different from control (p < 0.0001), by Fisher's exact test performed for this review.
ADD = adjusted daily doses; HED = human equivalent dose; TPA = terephthalic acid.
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September 2020
Table D-23. Mean Body Weights of Male and Female Wistar Rats Fed TPA
(CASRN 100-21-0) in the Diet for 24 Months3
Endpoint
Male: ADD (HED) in (mg/kg-d)b
0
736 (210)
1,470 (419)
3,680 (1,050)
Number of animals («)
n = 34
n = 32
n = 40
n = 17
Final body weight (g)
331.1 ±9.1c-d
330.6 ± 9.3 (0%)
298.7 ± 6.9** (-10%)
257.8 ± 7.8** (-22%)
Endpoint
Female: ADD (HED) in (mg/kg-d)
0
842 (215)
1,680 (429)
4,210 (1,070)
Number of animals («)
n = 40
n = 38
n =42
n = 20
Final body weight (g)
190.2 ±5.6
188.6 ± 4 (-1%)
181.3 ±3.9 (-5%)
151.8 ±3.3** (-20%)
aGross (1977).
bDoses correspond to 0, 1, 2, and 5% TPA in the diet.
Data are mean ± SE.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
**Significantly different from control (p < 0.01), as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose; SE = standard error; TPA = terephthalic acid.
Table D-24. Absolute and Relative Organ Weights of Male and Female Wistar Rats Fed
TPA (CASRN 100-21-0) in the Diet for 24 Months3
Endpoint
Male: ADD (HED) in (mg/kg-d)b
0
736 (210)
1,470 (419)
3,680 (1,050)
Number of animals («)
n = 34
n = 32
a
ll
o
n = 17
Absolute Organ Weights (mg)
Liver
9,938 ±407c d
9,708 ± 447 (-2%)
8,733 ± 329* (-12%)
8,201 ±486*** (-18%)
Kidney
1,239 ±31
1,143 ±29 (-8%)
1,078 ±23*** (-13%)
1,205 ± 57 (-3%)
Heart
904 ± 17
937 ± 23 (+4%)
877 ± 17*** (-3%)
839 ± 38*** (-7%)
Spleen
538 ±20
516 ± 25 (-4%)
455 ±23*** (-15%)
433 ± 40* (-20%)
Submaxillary gland
277 ±9
218 ±8 (-21%)
209 ± 7 (-25%)
188 ± 8*** (-32%)
Adrenal
23 ±0.9
22 ± 0.8 (-4%)
24 ± 0.9 (+4%)
31 ±3** (+35%)
Testis
1,860 ± 34
1,906 ± 58 (+3%)
1,772 ± 46 (-5%)
1,712 ±61* (-8%)
Relative Organ Weights (mg/100 g BW)
Liver
2,981 ±74
2,906 ± 74 (-3%)
2,923 ± 94 (-2%)
3,150 ± 121 (+6%)
Kidney
381 ± 12
351 ± 9 (-8%)
368 ± 12 (-3%)
472 ± 24***(+24%)
Heart
296 ±7
287 ± 7 (-3%)
293 ± 7 (-1%)
326 ± 10** (+10%)
Spleen
163 ±5
154 ± 5 (-6%)
151 ± 7 (-7%)
165 ± 13 (+1%)
Submaxillary gland
69 ±2.6
66 ± 1.9 (-4%)
70 ± 1.7 (+1%)
73 ± 25 (+6%)
Adrenal
7.3 ±0.47
7 ± 0.37 (-4%)
8.2 ± 0.39 (+12%)
12.1 ± 1.2*** (+66%)
Testis
571 ± 17
585 ± 19 (+3%)
601 ± 18 (+5%)
646 ± 35 (+13%)
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September 2020
Table D-24. Absolute and Relative Organ Weights of Male and Female Wistar Rats Fed
TPA (CASRN 100-21-0) in the Diet for 24 Months3
Endpoint
Female: ADD (HED) in (mg/kg-d)
0
842 (215)
1,680 (429)
4,210 (1,070)
Number of animals («)
a
ll
o
n = 38
n = 42
n = 20
Absolute Organ Weight (mg)
Liver
7,950 ±350
6,950 ±200**
(-13%)
6,650 ± 190***
(-16%)
6,430 ±210*** (-19%)
Kidney
961 ±35
776 ± 14***(-19%)
748 ± 13*** (-22%)
877 ± 85 (-9%)
Heart
704 ± 19
659 ± 14 (-6%)
616 ± 10*** (-13%)
588 ± 12***(-17%)
Spleen
389 ±21
407 ±31 (+5%)
341 ± 10 (-12%)
375 ± 44 (-4%)
Submaxillary gland
182 ±5
179 ± 4 (-2%)
178 ± 3 (-2%)
153 ± 5 (-16%)
Adrenal
22 ± 1
20 ± 0.7 (-9%)
20 ± 0.6 (-9%)
24 ± 0.7 (+9%)
Relative Organ Weights (mg/100 g BW)
Endpoint
0
842 (215)
1,680 (429)
4,210 (1,070)
Liver
4,173 ± 146
3,965 ± 92*** (-5%)
3,673 ± 79*** (-12%)
4,245 ± 128 (+2%)
Kidney
518 ±24
418± 11***(-19%)
419 ± 10*** (-19%)
587 ± 63 (+13%)
Heart
377 ± 10
353 ± 7* (-6%)
343 ± 5*** (-9%)
390 ± 10 (+3%)
Spleen
206 ± 12
213 ± 13 (+3%)
189 ± 4 (-8%)
248 ± 29 (+20%)
Submaxillary gland
98 ±3.4
96 ± 2.5 (-2%)
100 ±2.1 (+2%)
100 ±3.4 (+2%)
Adrenal
12 ±0.7
11 ±0.4 (-8%)
11 ±0.4 (-8%)
16 ± 0.6* (+33%)
"Gross (1977).
bDoses correspond to 0, 1, 2, and 5% TPA in the diet.
Data are mean ± SE.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
* Significantly different from control (p < 0.05), as reported by the study authors.
**Significantly different from control (p < 0.02), as reported by the study authors.
***Significantly different from control (p < 0.01), as reported by the study authors.
ADD = adjusted daily dose; BW = body weight; HED = human equivalent dose; SE = standard error;
TPA = terephthalic acid.
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September 2020
Table D-25. Incidence of Urinary Tract Calculi and Nephropathy in Wistar Rats Fed
TPA (CASRN 100-21-0) in the Diet for 24 Months3
Endpoint
Male: ADD (HED) in (mg/kg-d)b
0
736 (210)
1,470 (419)
3,680 (1,050)
Calculi
0/45 (0%)c
0/48 (0%)
0/50 (0%)
42/47** (89%)
Nephropathy
0/45 (0%)
1/43 (2%)
0/48 (0%)
32/37** (87%)
Endpoint
Female: ADD (HED) in (mg/kg-d)
0
842 (215)
1,680 (429)
4,210 (1,070)
Calculi
0/46 (0%)
1/48 (2%)
0/50 (0%)
39/42** (93%)
Nephropathy
0/46 (0%)
0/48 (0%)
1/47 (2%)
27/34** (80%)
aGross (1977).
bDoses correspond to 0, 1, 2, and 5% TPA in the diet.
°Values denote number of animals showing changes total number of animals examined (% incidence).
**Statistically different from control (p < 0.01), by Fisher's exact test (two-tailed), performed for this review.
ADD = adjusted daily dose; HED = human equivalent dose; TPA = terephthalic acid.
Table D-26. Tumor Incidences in Wistar Rats Fed TPA (CASRN 100-21-0) in the Diet for
24 Months3
Tumor location
Male: ADD (HED) in (mg/kg-d)b
0
736 (210)
1,470 (419)
3,680 (1,050)
Pituitary
36/45 (80%)°
37/43 (86%)
43/48 (90%)
21/37 (57%)
Thyroid
19/45 (42%)
14/43 (33%)
17/48 (35%)
7/37 (19%)
Adrenal medulla
0/45 (0%)
1/43 (2%)
1/48 (2%)
1/37 (3%)
Bladder and ureter
0/45 (0%)
1/43 (2%)
1/48 (2%)
21/37** (57%)
Tumor location
Female: ADD (HED) in (mg/kg-d)
0
842 (215)
1,680 (429)
4,210 (1,070)
Pituitary
33/46 (72%)
36/48 (75%)
37/47 (79%)
14/34 (41%)
Thyroid
19/46 (41%)
14/48 (29%)
18/47 (38%)
7/34 (21%)
Mammary gland
11/46 (24%)
8/48 (17%)
8/47 (17%)
1/34 (3%)
Adrenal medulla
2/46 (4%)
2/48 (4%)
0/47 (0%)
0/34 (0%)
Bladder and ureter
0/46 (0%)
0/48 (0%)
2/47 (4%)
21/34** (62%)
aGross (1977).
bDoses correspond to 0, 1, 2, and 5% TPA in the diet.
°Values denote number of animals showing changes total number of animals examined (% incidence).
**Statistically different from control (p < 0.01), by Fisher's exact test performed for this review.
ADD = adjusted daily dose; HED = human equivalent dose; TPA = terephthalic acid.
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September 2020
Table D-27. Mean Body Weights of Male F344 Rats Fed TPA (CASRN 100-21-0) in the
Diet for 52 Weeks3
Study week
ADD (HED) in (mg/kg-d)b
0
19.5 (5.30)
138.2 (37.54)
995.4 (268.2)
0
205 ± llc-d
195 ± 14* (-5%)
195 ±11* (-5%)
196 ± 12* (-4%)
1
235 ± 11
223 ±11 (-5%)
222 ± 13 (-6%)
221 ± 11 (-6%)
2
255 ± 14
245 ±11 (-4%)
242 ± 13 (-5%)
241 ± 11 (-5%)
3
269 ± 12
262 ± 11* (-3%)
260 ± 12* (-3%)
253 ±11* (-6%)
4
283 ± 13
274 ± 10 (-3%)
279 ±11 (-1%)
268 ±11 (-5%)
5
297 ± 13
288 ± 12 (-3%)
286 ± 36 (-4%)
280 ± 12 (-6%)
6
308 ± 16
298 ± 13 (-3%)
299 ± 14 (-3%)
291 ± 15 (-6%)
7
317 ± 16
306 ± 13* (-3%)
305 ± 14* (-4%)
296 ± 18* (-7%)
8
325 ± 15
313 ± 14 (-4%)
316 ± 14 (-3%)
307 ± 14 (-6%)
9
340 ± 16
321 ± 15 (-6%)
322 ± 15 (-5%)
313 ± 30 (-8%)
10
343 ± 17
337 ± 15 (-2%)
339 ± 15 (-1%)
325 ± 16 (-5%)
11
362 ± 20
338 ± 15* (-7%)
343 ± 15* (-5%)
332 ± 15* (-8%)
12
362 ± 17
342 ± 15 (-6%)
345 ± 16 (-5%)
333 ± 15 (-8%)
13
359 ±21
351 ± 16 (-2%)
349 ± 15 (-3%)
336 ± 14 (-6%)
15
375 ±21
360 ± 19* (-4%)
361 ± 15* (-4%)
348 ± 17* (-7%)
17
374 ± 20
362 ± 16 (-3%)
361 ± 16 (-3%)
350 ± 16 (-6%)
19
390 ± 20
378 ± 17* (-3%)
380 ± 19* (-3%)
365 ± 16* (-6%)
21
401 ±21
383 ± 18 (-4%)
383 ± 17 (-4%)
376 ± 17 (-6%)
23
426 ± 33
393 ± 19* (-8%)
397 ± 17* (-7%)
385 ± 17* (-10%)
25
415 ±28
439 ± 24 (+6%)
400 ± 18 (-4%)
398 ± 19 (-4%)
30
414 ± 21
411 ±21 (-1%)
410 ±21 (-1%)
397 ± 17* (-4%)
34
422 ± 24
411 ±24* (-3%)
419 ±20 (-1%)
399 ± 18* (-5%)
39
432 ± 22
418 ±25* (-3%)
425 ± 20* (-2%)
409 ± 20* (-5%)
43
440 ± 23
429 ± 20* (-3%)
434 ± 20 (-1%)
419 ±20* (-5%)
47
447 ± 22
432 ± 20* (-3%)
440 ± 21 (-2%)
425 ± 20* (-5%)
52
456 ± 23
442 ±21* (-3%)
449 ± 22* (-2%)
428 ± 20* (-6%)
aGrubbs (1979).
bADD (mg/kg-day) were reported by the study authors.
Data are mean ± SD (g).
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) control
mean] x 100.
* Significantly different from control (p < 0.05), as reported by the study authors; statistics were only performed at
monthly intervals.
ADD = adjusted daily dose; HED = human equivalent dose; SD = standard deviation; TPA = terephthalic acid.
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September 2020
Table D-28. Mean Body Weights of Female F344 Rats Fed TPA (CASRN 100-21-0) in the
Diet for 52 Weeks3
Study week
ADD (HED) in (mg/kg-d)b
0
19.2 (4.40)
136.6 (31.18)
989.8 (223.8)
0
137 ± 60, d
130 ± 6* (-5%)
130 ± 13* (-5%)
131 ± 5* (-4%)
1
146 ±6
136 ± 6 (-7%)
135 ± 6 (-8%)
137 ± 6 (-6%)
2
155 ±6
143 ± 7 (-8%)
145 ± 6 (-6%)
140 ± 7 (-10%)
3
163 ±7
150 ± 8* (-8%)
149 ± 6* (-9%)
147 ± 7* (-10%)
4
169 ±7
155 ± 7 (-8%)
163 ± 11 (-4%)
164 ± 7 (-3%)
5
173 ±7
160 ± 7 (-8%)
159 ± 7 (-8%)
157 ± 6 (-9%)
6
178 ±7
163 ± 7 (-8%)
163 ± 7 (-8%)
160 ± 7 (-10%)
7
183 ± 10
165 ± 8* (-10%)
164 ± 7* (-10%)
161 ± 6* (-12%)
8
184 ±8
168 ± 8 (-9%)
167 ± 8 (-9%)
164 ±7 (-11%)
9
193 ±8
170 ± 8 (-12%)
169 ± 16 (-12%)
164 ± 7 (-15%)
10
192 ±7
185 ± 11 (-4%)
172 ± 8 (-10%)
170 ± 9 (-11%)
11
204 ± 12
176 ± 9* (-14%)
174 ± 8* (-15%)
172 ± 7* (-16%)
12
207 ±8
179 ± 9 (-14%)
176 ± 9 (-15%)
171 ± 7 (-17%)
13
202 ± 14
179 ±9 (-11%)
176 ± 9 (-13%)
171 ± 7 (-15%)
15
208 ± 11
185 ±14* (-11%)
184 ± 9* (-12%)
180 ± 8* (-13%)
17
203 ±8
186 ± 9 (-8%)
184 ± 9 (-9%)
172 ± 8 (-15%)
19
214 ±9
190 ± 10* (-11%)
188 ± 9* (-12%)
184 ± 8* (-14%)
21
217 ± 12
196 ± 9 (-10%)
189 ± 9 (-13%)
184 ± 9 (-15%)
23
238 ± 27
196 ± 10* (-18%)
194 ± 20* (-18%)
192 ± 11* (-19%)
25
230 ± 11
203 ± 11 (-12%)
197 ± 10 (-14%)
192 ± 9 (-17%)
30
212 ± 14
204 ± 12* (-4%)
201 ± 11* (-5%)
196 ± 10* (-8%)
34
210± 11
210 ± 12* (0%)
199 ± 13* (-5%)
190 ± 10* (-10%)
39
217 ± 11
208 ± 12* (-4%)
204 ± 12* (-6%)
197 ± 12* (-9%)
43
220 ± 12
211 ± 12* (-4%)
207 ± 13* (-6%)
199 ± 12* (-10%)
47
223 ± 13
213 ± 13* (-4%)
208 ± 12* (-7%)
200 ± 11* (-10%)
52
227 ± 13
223 ± 18* (-2%)
217 ± 15* (-4%)
207 ± 18* (-9%)
aGrubbs (1979).
bADD (mg/kg-day) were reported by the study authors.
Data are mean ± SD (g).
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) control
mean] x 100.
* Significantly different from control (p < 0.05), as reported by the study authors; statistics were only performed at
monthly intervals.
ADD = adjusted daily dose; HED = human equivalent dose; SD = standard deviation; TPA = terephthalic acid.
91
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FINAL
September 2020
Table D-29. Food Consumption of Male F344 Rats Fed TPA (CASRN 100-21-0) in the Diet
for 52 Weeks"
Study weeks
ADD (HED) in (mg/kg-d)b
0
19.5 (5.30)
138.2 (37.54)
995.4 (268.2)
0-1
17.2 ± 0.80, d
15.3 ±0.8** (-11%)
15.8 + 0.9** (-8%)
15.8 + 0.9** (-8%)
1-2
17.7 ±0.5
16.4 ± 0.6** (-7%)
15.7 + 0.9** (-11%)
15.8 + 0.8** (-11%)
2-3
17.1 ±0.5
16.7 ± 0.8 (-2%)
15.9+ 1.1** (-7%)
15.5 + 0.7** (-9%)
3-4
17.7 ±0.7
16.0 ± 0.6** (-10%)
16.0 + 0.5** (-10%)
15.8 + 0.8** (-11%)
4-5
17.0 ± 1.5
16.1 ±0.6** (-5%)
16.4 + 0.6** (-4%)
16.0 + 0.6** (-6%)
5-6
16.7 ±0.8
16.4 ± 1.0 (-2%)
15.7 + 1.4** (-6%)
15.8+1.2** (-5%)
6-7
16.6 ±0.6
15.9 ± 0.7** (-4%)
15.7 + 0.9** (-5%)
15.9 + 0.6** (-4%)
7-8
16.4 ±0.7
15.5 ± 0.8** (-5%)
15.4 + 1.0** (-6%)
15.5 + 0.8** (-5%)
8-9
16.4 ±0.5
15.5 ± 1.1** (-5%)
15.9 + 0.9** (-3%)
15.4 + 0.7** (-6%)
9-10
16.3 ± 1.3
15.2 ± 1.0** (-7%)
15.9 + 1.3 (-2%)
15.5 + 0.7** (-5%)
10-11
15.1 ± 1.5
15.6 ± 0.8 (+3%)
15.5 + 1.7 (+3%)
15.3 + 0.7 (+1%)
11-12
15.6 ± 1.2
14.9 ± 0.6** (-4%)
15.4 + 0.7 (-1%)
15.1 + 0.6 (-3%)
12-13
15.8 ±0.7
15.1 ±0.8** (-4%)
15.1 + 0.6** (-4%)
15.1+ 0.7** (-4%)
14-15
16.4 ±0.8
16.4 ± 1.6 (0%)
15.3 + 1.5** (-7%)
15.5+1.1 (-5%)
16-17
16.3 ± 1.1
16.5 ± 1.9 (+1%)
16.3 + 0.7 (0%)
15.8 + 0.8 (-3%)
18-19
16.4 ± 1.4
14.6 ±0.9** (-11%)
14.5 + 0.6** (-12%)
14.6 + 0.6** (-11%)
20-21
16.3 ± 1.1
15.0 ± 0.7** (-8%)
15.3 + 0.9** (-6%)
15.4+1.2** (-6%)
22-23
15.1 ± 1.9
16.2 ± 0.8* (+7%)
15.5 + 0.6 (+3%)
15.4 + 0.6 (+2%)
25-26
15.0 ± 1.4
18.1 ± 1.1* (+21%)
16.3 + 0.8* (+9%)
16.8+1.3* (+12%)
29-30
15.1 ± 1.0
17.5 ± 1.3* (+16%)
15.4+1.1 (+2%)
15.4+1.1 (+2%)
34-35
14.9 ±0.7
14.6 ± 1.2 (-2%)
14.9 + 0.8 (0%)
15.0+1.0 (+1%)
38-39
15.8 ± 1.7
17.5 ± 1.3* (+11%)
16.2+ 1.1 (+3%)
15.7+1.2 (-1%)
42-43
15.1 ± 1.1
15.5±1.2 (+3%)
16.3 + 1.0* (+8%)
15.6+1.0 (+3%)
46-47
18.3 ± 1.0
17.4 + 0.9** (-5%)
17.5 + 0.9** (-4%)
17.3 + 1.0** (-5%)
51-52
16.7 ± 1.2
17.5 + 1.2* (+5%)
17.4+1.3* (+4%)
17.2+1.2 (+3%)
aGrubbs (1979).
bADD (mg/kg-day) were reported by the study authors.
Data are mean ± SD (g/animal-day).
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
* Statistically significantly higher from control (p < 0.05), as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose; SD = standard deviation; TPA = terephthalic acid.
92
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FINAL
September 2020
Table D-30. Food Consumption of Female F344 Rats Fed TPA (CASRN 100-21-0) in the
Diet for 52 Weeks3
Study weeks
ADD (HED) in (mg/kg-d)b
0
19.2 (4.40)
136.6 (31.18)
989.8 (223.8)
0-1
10.8 ± 0.8°'d
9.6 ±0.5** (-11%)
9.2 ± 0.5** (-15%)
9.2 ± 0.5** (-15%)
1-2
11.7 ± 0.5
9.9 ± 0.7** (-15%)
9.8 ± 0.5** (-16%)
9.9 ± 0.5** (-15%)
2-3
11.8 ± 0.6
10.3 ± 0.6** (-13%)
10.1 ±0.5** (-14%)
9.7 ± 0.7** (-18%)
3-4
11.8 ± 0.8
10.1 ±0.9** (-14%)
9.8 ± 0.7** (-17%)
9.7 ± 0.6** (-18%)
4-5
11.5 ± 0.6
9.8 ± 1.0** (-15%)
10.5 ± 0.5** (-9%)
10.7 ± 0.7** (-7%)
5-6
11.1 ± 0.5
10.2 ± 0.7** (-8%)
9.8 ± 0.5** (-12%)
9.9 ±0.7** (-11%)
6-7
10.9 ±0.4
9.9 ± 0.9** (-9%)
9.8 ± 1.5** (-10%)
9.8 ± 0.5** (-10%)
7-8
10.4 ±0.5
9.5 ± 1.0** (-9%)
9.3 ±0.5** (-11%)
9.2 ± 0.7* (-12%)
8-9
10.4 ±0.5
9.6 ± 1.0** (-8%)
9.4 ± 1.1** (-10%)
9.6 ± 1.1** (-8%)
9-10
10.8 ±0.4
9.3 ± 1.0** (-14%)
9.6 ± 1.0** (-11%)
9.8 ± 1.3** (-9%)
10-11
9.5 ±0.5
10.6 ± 0.9* (+12%)
9.2 ± 0.5 (-3%)
9.5 ± 0.6 (0%)
11-12
10.1 ±0.7
8.7 ± 0.6** (-14%)
8.8 ± 0.5** (-13%)
9.0 ±0.6** (-11%)
12-13
10.6 ±0.7
9.5 ± 0.5** (-10%)
9.3 ± 0.5** (-12%)
9.2 ± 0.6** (-13%)
14-15
10.5 ±0.5
10.3 ± 1.6 (-2%)
10.9 ±3.5 (+4%)
9.5 ± 1.3 (-10%)
16-17
10.1 ±0.9
10.0 ± 0.6 (-1%)
9.6 ± 0.6** (-5%)
9.3 ± 0.8** (-8%)
18-19
10.7 ± 1.0
9.5 ±0.6** (-11%)
9.5 ±0.5** (-11%)
9.1 ±0.6** (-15%)
20-21
10.4 ±0.6
9.5 ±1.1** (-9%)
9.3 ±0.8** (-11%)
9.5 ± 1.4** (-9%)
22-23
9.4 ± 1.1
9.7 ± 1.0 (+3%)
9.2 ± 0.6 (-2%)
8.6 ± 1.0** (-9%)
25-26
8.5 ±0.9
10.5 ± 0.7* (+24%)
9.8 ± 1.4* (+15%)
9.7 ± 0.8* (+14%)
29-30
8.7 ±0.8
12.1 ±0.8* (+39%)
11.9 ± 1.3* (+37%)
11.7 ±0.8* (+34%)
34-35
9.0 ±0.8
8.8 ± 0.5 (-2%)
8.8 ± 0.5 (-2%)
8.9 ± 0.7 (-1%)
38-39
9.4 ±0.5
10.9 ± 0.9 (+16%)
10.5 ± 0.9 (+12%)
10.8 ± 0.9 (+15%)
42-43
8.9 ±0.8
9.4 ± 0.8* (+6%)
10.3 ± 1.0* (+16%)
9.4 ± 0.8* (+6%)
46-47
11.7 ±1.1
10.6 ± 0.7** (-9%)
11.3 ±0.7 (-3%)
11.2 ±0.7 (-4%)
51-52
10.6 ±0.8
11.7 ±0.9* (+10%)
11.6 ± 1.0* (+9%)
11.3 ± 1.1* (+7%)
aGrubbs (1979).
bADD (mg/kg-day) were reported by the study authors.
Data are mean ± SD (g/animal-day).
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
* Statistically significantly higher from control (p < 0.05), as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose; SD = standard deviation; TPA = terephthalic acid.
93
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FINAL
September 2020
Table D-31. Terminal Body Weights and Absolute and Relative Organ Weights of Male
and Female F344 Rats Sacrificed at 6 and 12 Months Following Exposure to
TPA (CASRN 100-21-0) in the Diet3
Endpoint
Male: ADD (HED) in (mg/kg-d)b
0
19.5 (5.30)
138.2 (37.54)
995.4 (268.2)
Terminal body weight
6 mo
12 mo
358 ± 20°'4 e
433 ± 16
375 ± 19 (+5%)
422 ± 22 (-3%)
384 ±11 (+7%)
416 ± 19 (-4%)
374 ± 10 (+4%)
412 ± 14 (-5%)
Absolute heart
6 mo
12 mo
1.02 ±0.07
1.43 ±0.07
1.01 ±0.06 (-1%)
1.27 ±0.1 (-11%)
1.02 ± 0.05 (0%)
1.43 ±0.15(0%)
0.92 ± 0.05* (-10%)
1.23 ±0.09 (-14%)
Relative heart
6 mo
12 mo
0.29 ±0.02
0.33 ±0.02
0.27 ± 0.02 (-7%)
0.3 ± 0.02 (-9%)
0.27 ± 0.01 (-7%)
0.35 ± 0.03 (+6%)
0.24 ± 0.02* (-17%)
0.3 ± 0.02 (-9%)
Absolute kidney
6 mo
12 mo
2.24 ±0.2
2.92 ±0.14
2.4 ±0.16 (+7%)
2.81 ±0.12 (-4%)
2.58 ± 0.32 (+15%)
2.77 ± 0.07 (-5%)
2.37 ± 0.5 (+6%)
2.64 ± 0.36 (-10%)
Relative kidney
6 mo
12 mo
0.63 ± 0.05
0.68 ±0.03
0.64 ± 0.06 (+2%)
0.67 ± 0.02 (-1%)
0.67 ± 0.09 (+6%)
0.66 ± 0.02 (-3%)
0.64 ±0.14 (+2%)
0.64 ± 0.09 (-6%)
Absolute liver
6 mo
12 mo
8.33 ± 1.12
10.84 ±0.76
9.14 ±0.23 (+10%)
11.9 ±0.86 (+3%)
9.65 ± 0.55 (+16%)
10.59 ± 0.54 (-2%)
9.7 ± 0.26 (+16%)
11.13 ±0.79 (+3%)
Relative liver
6 mo
12 mo
2.47 ±0.33
2.52 ±0.13
2.44 ±0.11 (-1%)
2.65 ± 0.09 (+5%)
2.48 ±0.12(0%)
2.54 ± 0.06 (+1%)
2.59 ± 0.05 (+5%)
2.7 ±0.13 (+7%)
94
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FINAL
September 2020
Table D-31. Terminal Body Weights and Absolute and Relative Organ Weights of Male
and Female F344 Rats Sacrificed at 6 and 12 Months Following Exposure to
TPA (CASRN 100-21-0) in the Diet3
Endpoint
Female: ADD (HED) in (mg/kg-d)
0
19.2 (4.40)
136.6 (31.18)
989.8 (223.8)
Terminal body weight
6 mo
12 mo
206 ± 15
216 ± 14
177 ± 12* (-14%)
220 ± 15 (+2%)
193 ± 6 (-6%)
216 ± 15 (0%)
180 ± 5* (-13%)
203 ± 14 (-6%)
Absolute heart
6 mo
12 mo
0.65 ± 0.05
0.86 ± 10
0.6 ± 0.04 (-8%)
0.76 ± 0.04 (-12%)
0.65 ± 0.02 (0%)
0.77 ± 0.02 (-10%)
0.58 ±0.09 (-11%)
0.81 ± 0.04 (-6%)
Relative heart
6 mo
12 mo
0.32 ±0.02
0.4 ±0.03
0.34 ± 0.03 (+6%)
0.34 ± 0.02* (-15%)
0.34 ± 0.02 (+6%)
0.36 ± 0.02 (-10%)
0.32 ± 0.04 (0%)
0.4 ± 0.04 (0%)
Absolute kidney
6 mo
12 mo
1.44 ±0.44
1.66 ±0.07
1.36 ±0.09 (-6%)
1.62 ±0.12 (-2%)
1.4 ±0.09 (-3%)
1.61 ±0.12 (-3%)
1.31 ±0.12 (-9%)
1.57 ±0.08 (-5%)
Relative kidney
6 mo
12 mo
0.7 ±0.06
0.77 ±0.03
0.77 ± 0.07 (+10%)
0.74 ± 0.03 (-4%)
0.72 ± 0.03 (+3%)
0.75 ± 0.04 (-3%)
0.73 ± 0.05 (+4%)
0.78 ± 0.03 (+1%)
Absolute liver
6 mo
12 mo
4.53 ±0.57
5.85 ±0.47
4.46 ± 0.36 (-2%)
5.69 ± 0.42 (-3%)
5.55 ±0.16* (+23%)
5.66 ±0.51 (-3%)
4.89 ± 0.33 (+8%)
5.79 ± 0.36 (-1%)
Relative liver
6 mo
12 mo
2.21 ±0.27
2.7 ±0.08
2.52 ± 0.2 (+14%)
2.59 ±0.1 (-4%)
2.87 ±0.12* (+30%)
2.62 ±0.16 (-3%)
2.72 ±0.13* (+23%)
2.86 ±0.14* (+6%)
Absolute ovaries
6 mo
12 mo
NA
0.51 ±0.07
NA
0.46 ± 0.04 (-10%)
NA
0.49 ± 0.03 (-4%)
NA
0.66 ±0.13* (+29%)
Relative ovaries
6 mo
12 mo
NA
0.24 ± 0.04
NA
0.21 ±0.02 (-13%)
NA
0.23 ± 0.02 (-4%)
NA
0.33 ± 0.08 (+38%)
aGrubbs (1979).
bADD (mg/kg-day) were reported by the study authors.
Data for absolute organ weight measurements are mean ± SD (g) for five animals/group.
dData for relative organ weight measurements are mean ± SD (g/100 g BW) for five animals/group.
"Value in parentheses is percent change relative to control = [(treatment mean - control mean) + control
mean] x 100.
* Statistically significantly higher from control (p < 0.05), as reported by the study authors.
ADD = adjusted daily dose; BW = body weight; HED = human equivalent dose; NA = not applicable;
SD = standard deviation; TPA = terephthalic acid.
95
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FINAL
September 2020
Table D-32. Incidences of Bladder Lesions in Male and Female F344 Rats Exposed to
TPA (CASRN 100-21-0) in the Diet for up to 24 Months3
Male: ADD (HED) in (mg/kg-d)b
Endpoint
0
19.5 (5.41)
138.2 (38.49)
995.4 (274.2)
Number of bladders examined
12 mo
5
0
1
7
18 mo
27
20
14
27
24 mo
87
0
0
82
18 mo, revised0
26
11
15
26
24 mo, revised
85
84
85
80
Hyperplasia
12 mo
0/5 (0%)d
NA
0/1 (0%)
2/7 (29%)
18 mo
0/27 (0%)
1/20 (5%)
0/14 (0%)
QUI (0%)
24 mo
2/87 (2%)
NA
NA
2/82 (2%)
18 mo, revised
ND
0/11 (0%)
0/15 (0%)
0/26 (0%)
24 mo, revised
ND
9/84 (11%)
3/85 (4%)
0/80 (0%)
Transitional cell papilloma
12 mo
0/5 (0%)
ND
0/1 (0%)
1/7 (14%)
18 mo
0/27 (0%)
0/20 (0%)
0/14 (0%)
0/27 (0%)
24 mo
0/87 (0%)
NA
NA
0/82 (0%)
18 mo, revised
ND
0/11 (0%)
0/15 (0%)
0/26 (0%)
24 mo, revised
ND
0/84 (0%)
0/85 (0%)
0/80 (0%)
Female: ADD (HED) in (mg/kg-d)
Endpoint
0
19.2 (4.98)
136.6 (35.41)
989.8 (255.8)
Number of bladders examined
12 mo
9
3
7
7
18 mo
22
16
12
27
24 mo
83
0
0
79
18 mo, revised
21
12
16
23
24 mo, revised
71
81
75
73
Hyperplasia
12 mo
0/9 (0%)
0/3 (0%)
0/7 (0%)
0/7 (0%)
18 mo
0/22 (0%)
1/16 (6%)
0/12 (0%)
5/27 (19%)
24 mo
8/83 (10%)
NA
NA
14/79 (18%)
18 mo, revised
ND
0/12 (0%)
1/16 (6%)
4/23 (17%)
24 mo, revised
ND
7/81 (9%)
2/75 (3%)
24/73 (33%)
Squamous metaplasia
12 mo
0/9 (0%)
0/3 (0%)
0/7 (0%)
0/7 (0%)
18 mo
0/22 (0%)
0/16 (0%)
0/12 (0%)
2/27 (0%)
24 mo
0/83 (0%)
NA
NA
9/79** (11%)
Transitional cell papilloma
12 mo
0/9 (0%)
0/3 (0%)
0/7 (0%)
0/7 (0%)
18 mo
0/22 (0%)
0/16 (0%)
0/12 (0%)
0/27 (0%)
24 mo
1/83 (1%)
NA
NA
0/79 (0%)
18 mo, revised
ND
0/12 (0%)
0/16 (0%)
0/23 (0%)
24 mo, revised
ND
2/81 (2%)
0/75 (0%)
0/73 (0%)
96
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FINAL
September 2020
Table D-32. Incidences of Bladder Lesions in Male and Female F344 Rats Exposed to
TPA (CASRN 100-21-0) in the Diet for up to 24 Months3
Females: ADD (HED) in (mg/kg-d)
Endpoint
0
19.2 (4.98)
136.6 (35.41)
989.8 (255.8)
Transitional cell adenoma
12 mo
18 mo
24 mo
24 mo, revised
0/9 (0%)
0/22 (0%)
1/83 (1%)
1/71 (1%)
0/3 (0%)
0/16 (0%)
NA
0/81 (0%)
0/7 (0%)
0/12 (0%)
NA
0/75 (0%)
0/7 (0%)
2/27 (7%)
15/79** (19%)
10/73** (14%)
Transitional cell carcinoma
12 mo
18 mo
24 mo
24 mo, revised
0/9 (0%)
0/22 (0%)
0/83 (0%)
ND
0/3 (0%)
0/16 (0%)
NA
0/81 (0%)
0/7 (0%)
0/12 (0%)
NA
0/75 (0%)
0/7 (0%)
QUI (0%)
2/79 (3%)
1/73 (1%)
aICI Americas Inc (1992): Preache (1983): Grubbs (1979).
bMeasured daily doses of TPA (mg/kg-day) during the first 12 months on treatment diets, as reported by the study
authors.
" Data in italics indicate the new and/or reanalysis of histological data performed by ICI Americas Inc (1992).
dValues denote number of animals showing changes total number of animals examined (% incidence).
* Statistically different from control (p < 0.05), by Fisher's exact test (two-tailed) performed for this review.
**Statistically different from control (p < 0.01), by Fisher's exact test (two tailed) performed for this review.
ADD = adjusted daily dose; HED = human equivalent dose; NA = not applicable; ND = no data;
TPA = terephthalic acid.
97
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FINAL
September 2020
Table D-33. Survival of Offspring of Wistar and CD of Rats Exposed to TPA (CASRN 100-21-0) in the Diet for 90 Days Prior
to Mating, and through Mating, Gestation, and Lactation3
Proportion of Females Surviving
Proportion of Males Surviving
Strain
ADD (HED) in
(mg/kg-d)b
Number
of Litters
Day 1
Day 21
Day 1
Day 21
Wistar
0
8
1 ±0
0.93 ±0.05
1±0
0.9 ±0.06
19.3 (4.84)
9
0.97 ± 0.02 (-3%)0, d
0.85 ±0.11 (-9%)
1 ± 0 (0%)
0.88 ±0.11 (-2%)
114.5 (27.89)
10
0.98 ± 0.01 (-2%)
0.95 ± 0.02 (+2%)
0.96 ± 0.04 (-4%)
0.96 ± 0.04 (+7%)
313 (78.7)
10
0.88 ±0.1 (-12%)
0.85 ±0.1 (-9%)
0.88 ±0.1 (-12%)
0.88 ±0.1 (-2%)
1,280 (321)
10
0.9 ±0.1 (-10%)
0.8 ±0.14 (-14%)
0.87 ±0.1 (-13%)
0.76 ±0.13 (-16%)
3,100 (773)
7
0.95 ± 0.04 (-5%)
0.8 ±0.14 (-14%)
0.95 ± 0.05 (-5%)
0.74 ±0.14 (-18%)
CD
0
5
1 ±0
0.97 ±0.02
0.97 ±0.02
0.98 ±0.02
17.6 (4.65)
7
1 ± 0 (0%)
1 ± 0 (+3%)
0.98 ± 0.02 (+1%)
0.95 ± 0.04 (-3%)
86.57 (22.83)
4
1 ± 0 (0%)
1 ± 0 (+3%)
1 ± 0 (+3%)
0.96 ± 0.04 (-2%)
286 (75.0)
6
1 ± 0 (0%)
0.97 ± 0.02 (0%)
1 ± 0 (+3%)
1 ± 0 (+2%)
1,260 (321)
5
0.9 ± 0.07 (-10%)
0.7 ±0.18 (-28%)
0.93 ± 0.04 (-4%)
0.73 ±0.19 (-26%)
2,840 (732)
4
0.96 ± 0.04 (-4%)
0.39 ±0.21* (-60%)
1 ± 0 (+3%)
0.49 ±0.21* (-50%)
"Ledoux and Reel (1982).
bDoses equivalent to 0, 0.03, 0.154, 0.5, 2, and 5% TPA in the diets of dams.
Data are mean ± SE.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) control mean] x 100.
* Statistically significantly higher from control (p < 0.05), as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose; SE = standard error; TPA = terephthalic acid.
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Table D-34. Body Weights of Offspring of Wistar and CD Rats Exposed to TPA (CASRN 100-21-0) in the Diet for 90 Days
Prior to Mating, and through Mating, Gestation, and Lactation3
Mean BW
Wistar Rat: ADD (HED) in (mg/kg-d)b
(g)
0
19.3 (4.84)
114.5 (27.89)
313 (78.7)
1,280 (321)
3,100 (773)
Number of
litters
8
8
10
9
8
6
Combined
Day 1
6.6 ± 0.21°'d
6.9 ± 0.27 (+5%)
7.1 ±0.39 (+8%)
6.8 ± 0.24 (+3%)
6.4 ± 0.20 (-3%)
5.4 ± 0.22* (-18%)
Day 21
48.6 ± 1.86
52.8 ± 2.84 (+9%)
53.1 ±3 (+9%)
48.2±1.84 (-1%)
41.3 ±2.28 (-15%)
31.6 ± 3.75** (-35%)
Male
Day 1
6.7 ±0.23
7.1 ± 0.28 (+6%)
7.3 ± 0.4 (+9%)
7.0 ± 0.24 (+4%)
6.6 ±0.21 (-1%)
5.4 ±0.18* (-19%)
Day 21
50.1 ± 1.82
54.3 ± 3.03 (+8%)
54.7 ±3.23 (+9%)
49.6 ± 2.02 (-1%)
42.7 ± 2.22 (-15%)
32.0 ± 3.63* (-36%)
Female
Day 1
6.4 ±0.19
6.7 ± 0.27 (+5%)
7.0 ± 0.38 (+9%)
6.5 ± 0.26 (+2%)
6.2 ±0.18 (-3%)
5.3 ± 0.24* (-17%)
Day 21
46.2 ± 2.00
51.6 ±2.8 (+12%)
51.7 ±2.86 (+12%)
46.3 ± 1.68 (0%)
39.8 ± 2.25 (-14%)
31.5 ± 3.83* (-32%)
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Table D-34. Body Weights of Offspring of Wistar and CD Rats Exposed to TPA (CASRN 100-21-0) in the Diet for 90 Days
Prior to Mating, and through Mating, Gestation, and Lactation3
Mean BW
CD Rat: ADD (HED) in (mg/kg-d)
(g)
0
17.6 (4.65)
86.57 (22.83)
286 (75.0)
1,260 (321)
2,840 (732)
Number of
litters
5
7
4
6
4
3
Combined
Day 1
7.7 ±0.64
7.2 ± 0.26 (-6%)
8 ± 0.56 (+4%)
7.6 ± 0.23 (-1%)
7.4 ±0.17 (-4%)
7 ± 0.66 (-9%)
Day 21
58.1 ±5.23
50.7 ± 2.93 (-13%)
55.1 ±8.49 (-5%)
52.2 ± 2.44 (-10%)
45.4 ±3.18 (-22%)
25.2 ± 3.69** (-57%)
Male
Day 1
8.0 ±0.78
7.3 ± 0.26 (-9%)
8.1 ±0.55 (+1%)
8.2 ± 0.30 (+2%)
7.6 ±0.21 (-5%)
7.2 ± 0.70 (-10%)
Day 21
59.8 ±5.87
51.0 ±3.10 (-15%)
56.1 ±9.26 (-6%)
54.9 ± 3.40 (-8%)
46.3 ±3.12 (-23%)
25.9 ±3.71* (-57%)
Female
Day 1
7.5 ±0.52
7.1 ± 0.26 (-5%)
7.8 ± 0.62 (4%)
7.2 ± 0.20 (-4%)
7.1 ±0.16 (-5%)
6.8 ± 0.62 (-9%)
Day 21
57.5 ±4.73
50.2 ± 2.84 (-13%)
54.1 ±8.22 (-6%)
51.2 ±2.44 (-11%)
44.4 ±3.01 (-23%)
23.9 ±3.76* (-58%)
"Ledoux and Reel (1982).
bDoses equivalent to 0, 0.03, 0.154, 0.5, 2, and 5% TPA in the diets of dams.
Data are mean ± SE.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) control mean] x 100.
* Statistically significantly higher from control (p < 0.05), as reported by the study authors.
** Statistically significantly higher from control (p < 0.01), as reported by the study authors.
ADD = adjusted daily dose; BW = body weight; HED = human equivalent dose; SE = standard error; TPA = terephthalic acid.
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Table D-35. Incidence of Renal and Bladder Calculi in Fi Rats Exposed to
TPA (CASRN 100-21-0) from Gestation through Weaning and in the Diet for up to
30 Days3
Strain
ADD (HED)
(mg/kg-d)b
Male
Female
Wistar
0
0/31 (0%)c-d
0/21 (0%)
19.3 (4.84)
0/26 (0%)
0/31 (0%)
114.5 (27.89)
0/31 (0%)
0/33 (0%)
313 (78.7)
0/34 (0%)
0/33 (0%)
1,280 (321)
0/34 (0%)
1/32 (3%)
3,100 (773)
8/18* (44%)
16/31* (51%)
CD
0
0/17 (0%)
0/20 (0%)
17.6 (4.65)
0/21(0%)
0/24 (0%)
86.57 (22.83)
0/13 (0%)
0/12 (0%)
286 (75.0)
0/21 (0%)
0/22 (0%)
1,260 (321)
1/17 (6%)
1/16 (6%)
2,840 (732)
5/9* (56%)
9/13* (70%)
"Ledoux and Reel (1982).
bDoses equivalent to 0, 0.03, 0.154, 0.5, 2, and 5% TPA in the diets of dams.
°Values denote number of animals showing changes total number of animals examined (% incidence),
incidence includes all weanling rats necropsied between Days 21-51.
* Statistically different from control (p < 0.05), by Fisher's exact test (two-tailed) performed for this review.
ADD = adjusted daily dose; HED = human equivalent dose; TPA = terephthalic acid.
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Table D-36. Body-Weight Gain and Testicular Endpoints in Male S-D Rats Treated with
TPA (CASRN 100-21-0) in the Diet for 90 Days3
Endpoint
ADD (HED) in (mg/kg-d)b
0
172 (42.7)
861 (214)
4,310 (1,070)
Body-weight gain (g)
240.98 ±34.8c d
240.84 ±34.45
(0%)
229.7 ±33.07
(-5%)
211.44 ±35.3
(-12%)
Absolute testis (g)
3.2 ±0.27
3.13 ±0.21
(-2%)
3.22 ±0.19
(+1%)
3.12 ±0.35
(-3%)
Relative testis
(% of BW)
0.88 ±0.121
0.89 ±0.105
(+1%)
0.88 ±0.076
(0%)
0.93 ±0.097
(+6%)
Sperm head count
(106/g)
113.32 ± 10.31
112.84 ± 11.69
(0%)
106.94 ± 13.11
(-6%)
91.43 ± 13.42**
(-19%)
Daily sperm gain
production (106/g-d)
18.58 ± 1.69
18.5 ±2.15
(0%)
17.53 ± 1.92
(-6%)
14.99 ±2.2**
(-19%)
"Cui et at (2004).
bDoses equivalent to 0, 0.2, 1, and 5% TPA in the diet.
Data are mean ± SD; n = 10.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) control
mean] x 100.
**Significantly different from control (p < 0.01), as reported by the study authors.
ADD = adjusted daily dose; BW = body weight; HED = human equivalent dose; SD = standard deviation;
S-D = Sprague-Dawley; TPA = terephthalic acid.
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Table D-37. Sperm Motility Parameters in Male S-D Rats Treated with
TPA (CASRN 100-21-0) in the Diet for 90 Days3
Parameter
ADD (HED) in (mg/kg-d)b
0
172 (42.7)
861 (214)
4,310 (1,070)
Number of animals («)
n = 6
n = 5
n = 6
n = 6
VCL (nM/s)
398.97 ± 35.67c-d
369.48 ±20.26
("7%)
378.68 ±28.93
(-5%)
365.28 ± 15.22
(-8%)
VAP (nM/s)
117.75 ± 11.85
112.9 ± 11.05
(-4%)
114.63 ± 10.23
(-3%)
103.77 ± 12.13
(-12%)
VSL (nM/s)
87.58 ±22.19
63.92 ± 12.94*
(-27%)
62.92 ± 15.34*
(-28%)
53.17 ± 18.72**
(-39%)
BCF (Hz)
7.58 ± 1.4
5.9 ± 1.47
(-22%)
5.82 ± 1.51
(-23%)
4.9 ± 1.49**
(-35%)
ALH (|im)
50.53 ±7.87
46.3 ±5.58
(-8%)
46.63 ± 9.02
(-8%)
50.23 ± 10.11
(-1%)
LIN (%)
21.85 ±5.23
16.5 ±3.01
(-25%)
15.62 ±3.26*
(-29%)
14.1 ±5.32*
(-36%)
STR (%)
75.38 ± 11.65
61.86 ±2.38*
(-18%)
60.05 ±7.96*
(-20%)
57.17 ± 11.59**
(-24%)
aCui et al. (2004).
bDoses equivalent to 0, 0.2, 1, and 5% TPA in the diet.
Data are mean ± SD.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) control
mean] x 100.
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
**Statistically significantly different from control (p < 0.01), as reported by the study authors.
ADD = adjusted daily dose; ALH = amplitude of lateral head displacement; BCF = beat cross frequency;
HED = human equivalent dose; LIN = linearity; SD = standard deviation; S-D = Sprague Dawley;
STR = straightness; TPA = terephthalic acid; VAP = average path velocity; VCL = curvilinear velocity;
VSL = straight line velocity.
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Table D-38. Sperm Parameters in Male Rats Exposed to TPA (CASRN 100-21-0) by Daily
Gavage for 4 Weeks3
ADD (HED) in (mg/kg-d)b
Parameter
0
1,000 (249)
Sperm count (millions/mL)
7.66 ± 2.530, d
7.72 ± 1.94 (+1%)
Sperm motility
VAP (|im/s)
96.8 ±7.35
73.5 ± 4.3 (-24%)
VSL (|im/s)
87.9 ± 17.7
66.6 ± 1.02 (-24%)
VCL (|im/s )
215 ±22.8
175.8 ±31.6 (-18%)
ALH (|im)
26.7 ± 2
23.8 ± 1 (-11%)
BCF (Hz)
35.2 ±3.7
32.6 ± 2.9 (-7%)
STR (%)
90.8 ±2.6
90.6 ± 1.2 (-0.2%)
LIN (%)
40.9 ±2.5
37.9 ± 2 (-7%)
ADD (HED) in (mg/kg-d)
Parameter
0
10 (2.5)
100 (24.9)
1,000 (249)
Progressive motility (%)
54.18®
54.03 (0%)
55.52 (+2%)
39.87* (-26%)
Sperm mobility (%)
89.73
94.51 (+5%)
91.86 (+2%)
84.96 (-5%)
"Kwack and Lee (2015).
bReported doses (mg/kg-day).
Data are mean ± SD, n = 5 rats/group.
dValue in parentheses is percent change relative to control = [(treatment mean - control mean) control
mean] x 100.
eMeans were extracted from graphical images using GrabIT! software.
* Significantly different from control (p < 0.05) by ANOVA and Tuckey's post hoc comparisons, as reported by the
study authors.
ADD = adjusted daily dose; ALH = amplitude of lateral head displacement; ANOVA = analysis of variance;
BCF = beat cross frequency; HED = human equivalent dose; LIN = linearity; SD = standard deviation;
STR = straightness; TPA = terephthalic acid; VAP = velocity average path; VCL = velocity curved line;
VSL = velocity straight line.
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Table D-39. Skeletal Anomalies in Fetuses of S-D Rats Exposed to TPA (CASRN 100-21-0)
Aerosols on GDs 6-15a
Analytical Concentration (HECer) (mg/m3)b
Effect
0
0.90 (0.59)
4.73 (2.96)
10.40 (6.240)
Number examined
151/23°
162/24
147/22
171/25
Ribs
Wavy
2/2
0/0
4/4d
5/4
Bulbous
4/3
0/0
1 l/4e
9/4
Reduced 13 th
1/1
2/2
3/2
8/5
Rudimentary 14th
2/2
1/1
5/5
2/2
Incomplete ossification
2/2
0/0
7/2
4/3
All rib anomalies
7/5
3/3
19/8*
19/11
% Affected
4.6/22
1.9/13
13/36*
11/44
Summary of Skeletal Evaluation Scores
Scoref
0
144/18
159/21
128/14
152/14
1
1/1
2/2
3/2
7/5
2
3/3
0/0
3/2
4/2
3
2/2
1/1
9/7
6/5
4
1/1
0/0
4/1
2/1
5
0/0
0/0
1/18
0/0
aChemical Manufacturers Association (2000).
bCorrected (i.e., respirable-sized particles) TWA concentrations for dams exposed 6 hours/day, 7 days/week on
GDs 6-15; calculated extrarespiratory HECs appear in parentheses.
°Fetus/litter.
dOne fetus had ribs that appeared gnarled; this was considered by the study authors to be a malformation.
eEight fetuses from a single litter had bulbous ribs.
f0 = no visible abnormality; 1 = variation within normal limits; 2 = slight variation; 3 = moderate variation;
4 = severe variation; 5 = malformation.
8Pup exhibited both a variation and a malformation.
* Significantly different from controls (p < 0.05), as reported by the study authors.
ER = extrarespiratory; GD = gestation day; HEC = human equivalent concentration; S-D = Sprague-Dawley;
TPA = terephthalic acid; TWA = time-weighted average.
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APPENDIX E. BENCHMARK DOSE MODELING RESULTS
MODELING PROCEDURE
Dichotomous Noncancer Data
The benchmark dose (BMD) modeling of dichotomous data is conducted with
U.S. EPA's Benchmark Dose Software (BMDS; Version 2.7 was used for this document). For
these data, the Gamma, Logistic, Log-Logistic, Log-Probit, Multistage, Probit, and Weibull
dichotomous models available within the software are fit using a benchmark response (BMR) of
10% extra risk. Alternative BMRs may also be used where appropriate, as outlined in the
Benchmark Dose Technical Guidance (U.S. EPA. 2012a). In general, the BMR should be near
the low end of the observable range of increased risk in the study. BMRs that are too low can
result in widely disparate benchmark dose lower confidence limit (BMDL) estimates from
different models (high model dependence). Adequacy of model fitting is judged by three
criteria: (1) goodness-of-fit/>-value (p < 0.1), (2) visual inspection of the dose-response curve,
and (3) scaled residual at the data point (except the control) closest to the predefined BMR
(absolute value < 2.0). Among all models providing adequate fit, the BMDL from the model
with the lowest Akaike's information criterion (AIC) is selected as a potential point of departure
(POD), if the BMDLs are sufficiently close (less than approximately threefold); if the BMDLs
are not sufficiently close (greater than approximately threefold), model-dependence is indicated,
and the model with the lowest reliable BMDL is selected.
Continuous Data
BMD modeling of continuous data is conducted with U.S. EPA's BMDS (Version 2.7).
All continuous models available within the software (Exponential, Hill, Linear, Polynomial, and
Power models) are fit using a standard reporting BMR of 1 standard deviation (SD) relative risk.
Alternate BMRs may also be used (e.g., BMR = 10% RD for body weight based on a
biologically significant weight loss of 10%), as outlined in the Benchmark Dose Technical
Guidance (U.S. EPA. 2012a). In general, the BMR should be near the low end of the observable
range of increased risk in the study. BMRs that are too low can result in widely disparate BMDL
estimates from different models (high model dependence). An adequate fit is judged based on
the x2 goodness-of-fit p-walue (p > 0.1), magnitude of the scaled residuals in the vicinity of the
BMR (absolute value < 2.0), and visual inspection of the model fit. In addition to these three
criteria forjudging adequacy of model fit, a determination is made as to whether the variance
across dose groups is homogeneous. If a homogeneous variance model is deemed appropriate
based on the statistical test provided by BMDS (i.e., Test 2), the final BMD results are estimated
from a homogeneous variance model. If the test for homogeneity of variance is rejected
{p-walue < 0.1), the model is run again while modeling the variance as a power function of the
mean to account for this nonhomogeneous variance. If this nonhomogeneous variance model
does not adequately fit the data (i.e., Test 3; p-w alue < 0.1), the data set is considered unsuitable
for BMD modeling. Among all models providing adequate fit, the lowest BMDL is selected if
the BMDL estimates from different models vary more than approximately threefold (indicating
model dependence); otherwise, the BMDL from the model with the lowest AIC is selected as a
potential POD from which to derive the reference value.
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Decreased Pup Weight in Male and Female Wistar Rats Following TPA Exposure via Diet
for 90 Days Prior to Mating through Postweaning (Ledoux and Reel, 1982)
The procedure outlined above for continuous data was applied to the data for decreased
pup weight in male and female Wistar rats following TPA exposure via diet for 90 days prior to
mating through postweaning |"Ledoux and Reel (1982); see Table D-34], The BMD modeling
results are presented in Table E-l and Figure E-l. The constant variance model provided
adequate fit to the variance data, and adequate fit to the means was provided by all available
models. The BMDLs for the models providing adequate fit are sufficiently close (i.e., differ by
-Valucb
Means
/>-Valucb
Scaled Residual at
Dose Nearest BMD
AIC
BMDos
(HED)
(mg/kg-d)
BMDLos
(HED)
(mg/kg-d)
Constant variance
Exponential (model 2)c- *
0.3833
0.5483
-0.355
249.0319
78.7234
59.944
Exponential (model 3)°
0.3833
0.3829
-0.3573
251.0318
79.0636
59.9441
Exponential (model 4)°
0.3833
0.3902
-0.308
250.9843
71.6596
35.4053
Exponential (model 5)°
0.3833
0.2466
-0.5254
252.7752
96.5983
36.3945
Hillc
0.3833
0.2498
-0.52
252.749182
95.4929
32.1315
Linear"1
0.3833
0.4895
-0.425
249.399362
96.5738
78.1725
Polynomial (2-degree)d
0.3833
0.4895
-0.425
249.399362
96.5738
78.1725
Polynomial (3-degree)d
0.3833
0.4895
-0.425
249.399362
96.5738
78.1725
Power0
0.3833
0.4895
-0.425
249.399362
96.5738
78.1725
aLedoux and Reel (1982).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Tower restricted to be >1.
Coefficients restricted to be negative.
* Selected model.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the dose associated with the
selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., 5 = dose
associated with 5% relative deviation); BMR = benchmark response; HED = human equivalent dose;
TPA = terephthalic acid.
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Exponential 2 Model, with BMR of 0.05 Rel. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
Exponential 2
60
55
50
45
40
35
30
25
20
BMDL
3fJ\D
100
0
200
300
400
500
600
700
800
dose
07:26 08/11 2020
Figure E-l. Fit of Exponential 2 Model to Data for Decreased Pup Weight in Male and
Female Wistar Rats Following TPA Exposure via Diet for 90 Days Prior to Mating through
Postweaning (Ledoux and Reel, 1982)
Decreased Pup Weight in Male Wistar Rats Following TPA Exposure via Diet for 90 Days
Prior to Mating through Postweaning (Ledoux and Reel, 1982)
The procedure outlined above for continuous data was applied to the data for decreased
pup weight in male Wistar rats following TPA exposure via diet for 90 days prior to mating
through postweaning |"Ledoux and Reel (1982); see Table D-34], The BMD modeling results are
presented in Table E-2 and Figure E-2. The constant variance model provided adequate fit to the
variance data, and adequate fit to the means was provided by all available models. The BMDLs
for the models providing adequate fit are sufficiently close (i.e., differ by
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Table E-2. Decreased Pup Weight in Male Wistar Rats Following TPA Exposure via Diet
for 90 Days Prior to Mating through Postweaning3
Model
Variance
/>-Valucb
Means
/>-Valucb
Scaled Residual at
Dose Nearest BMD
AIC
BMDos
(HED)
(mg/kg-d)
BMD Los
(HED)
(mg/kg-d)
Constant variance
Exponential (model 2)c *
0.3103
0.5737
-0.3637
252.5633
77.0854
58.8168
Exponential (model 3)°
0.3103
0.4082
-0.4013
254.5518
82.7344
58.8488
Exponential (model 4)°
0.3103
0.4074
-0.3464
254.5567
74.4376
36.785
Exponential (model 5)°
0.3103
0.2556
-0.5415
256.3851
97.8234
37.6158
Hillc
0.3103
0.2582
-0.539
256.36507
97.1229
33.4038
Lineal
0.3103
0.5295
-0.439
252.828823
94.7266
76.9098
Polynomial (2-degree)d
0.3103
0.5295
-0.439
252.828823
94.7266
76.9098
Polynomial (3-degree)d
0.3103
0.5295
-0.439
252.828823
94.7266
76.9098
Power0
0.3103
0.5295
-0.439
252.828823
94.7266
76.9098
aLedoux and Reel (1982).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Tower restricted to be >1.
Coefficients restricted to be negative.
* Selected model.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the dose associated with the
selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., 5 = dose
associated with 5% relative deviation); BMR = benchmark response; HED = human equivalent dose;
TPA = terephthalic acid.
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Exponential 2 Model, with BMR of 0.05 Rel. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
65
Exponential 2
60
55
50
45
40
35
30
25
BMDL
20
0
200
300
400
500
600
700
800
dose
19:13 08/10 2020
Figure E-2. Fit of Exponential 2 Model to Data for Decreased Pup Weight in Male Wistar
Rats Following TPA Exposure via Diet for 90 Days Prior to Mating through Postweaning
(Ledoux and Reel, 1982)
Decreased Pup Weight in Female Wistar Rats Following TPA Exposure via Diet for
90 Days Prior to Mating through Postweaning (Ledoux and Reel, 1982)
The procedure outlined above for continuous data was applied to the data for decreased
pup weight in female Wistar rats following TPA exposure via diet for 90 days prior to mating
through postweaning |"Ledoux and Reel (1982); see Table D-34], The BMD modeling results are
presented in Table E-3 and Figure E-3. The constant variance model provided adequate fit to the
variance data, and adequate fit to the means was provided by all available models. The BMDLs
for the models providing adequate fit are sufficiently close (i.e., differ by
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September 2020
Table E-3. Decreased Pup Weight in Female Wistar Rats Following TPA Exposure via
Diet for 90 Days Prior to Mating through Postweaning"
Model
Variance
/>-Valucb
Means
/>-Valucb
Scaled Residual at
Dose Nearest BMD
AIC
BMDos
(HED)
(mg/kg-d)
BMDLos
(HED)
(mg/kg-d)
Constant variance
Exponential (model 2)c *
0.4121
0.3238
-0.4693
248.8078
82.4489
61.7604
Exponential (model 3 )c *
0.4121
0.3238
-0.4693
248.8078
82.4489
61.7604
Exponential (model 4)°
0.4121
0.2137
-0.3761
250.6302
67.9907
32.2851
Exponential (model 5)°
0.4121
0.1209
-0.6034
252.3714
93.3897
33.4975
Hillc
0.4121
0.1235
-0.59
252.328388
91.3872
29.2144
Lineal
0.4121
0.2749
-0.527
249.269353
100.62
80.2109
Polynomial (2-degree)d
0.4121
0.2749
-0.527
249.269353
100.62
80.2109
Polynomial (3-degree)d
0.4121
0.2749
-0.527
249.269353
100.62
80.2109
Power0
0.4121
0.2749
-0.527
249.269353
100.62
80.2109
aLedoux and Reel (1982).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Tower restricted to be >1.
Coefficients restricted to be negative.
* Selected model.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the dose associated with the
selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., 5 = dose
associated with 5% relative deviation); BMR = benchmark response; HED = human equivalent dose;
TPA = terephthalic acid.
Ill
/;-Phthalic acid
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September 2020
Exponential 2 Model, with BMR of 0.05 Rel. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
Exponential 2
60
55
<> <>
50
45
40
35
30
25
20
BMDL
100
200
300
400
dose
500
600
700
800
07:42 08/11 2020
Figure E-3. Fit of Exponential 2 Model to Data for Decreased Pup Weight in Female
Wistar Rats Following TPA Exposure via Diet for 90 Days Prior to Mating through
Postweaning (Ledoux and Reel, 1982)
Decreased Pup Weight in Male and Female CD Rats Following TPA Exposure via Diet for
90 Days Prior to Mating through Postweaning (Ledoux and Reel, 1982)
The procedure outlined above for continuous data was applied to the data for decreased
pup weight in male and female CD rats following TPA exposure via diet for 90 days prior to
mating through postweaning |"Ledoux and Reel (1982); see Table D-34], The BMD modeling
results are presented in Table E-4 and Figure E-4. The constant variance model provided
adequate fit to the variance data, and adequate fit to the means was provided by all available
models. The BMDLs for the models providing adequate fit are sufficiently close (i.e., differ by
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September 2020
Table E-4. Decreased Pup Weight in Male and Female CD Rats Following TPA Exposure
via Diet for 90 Days Prior to Mating through Postweaning3
Model
Variance
/>-Valucb
Means
/>-Valucb
Scaled Residual at
Dose Nearest BMD
AIC
BMDos
(HED)
(mg/kg-d)
BMDLos
(HED)
(mg/kg-d)
Constant variance
Exponential (model 2)°
0.1342
0.4796
0.1715
163.4117
57.6879
39.8961
Exponential (model 3)°
0.1342
0.5261
-0.2503
164.1524
158.293
43.8932
Exponential (model 4)°
0.1342
0.4796
0.1715
163.4117
57.6879
33.2875
Exponential (model 5)°
0.1342
0.328
-0.2503
166.1524
158.293
43.8932
Hillc
0.1342
0.3335
-0.187
166.118876
140.366
55.2759
Linear4 *
0.1342
0.6122
0.0536
162.605554
71.7181
55.4981
Polynomial (2-degree)d
0.1342
0.5414
-0.106
164.075162
121.581
56.8571
Polynomial (3-degree)d
0.1342
0.544
-0.0474
164.062316
107.468
56.8926
Power0
0.1342
0.5333
-0.181
164.11615
138.854
56.7445
aLedoux and Reel (1982).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Tower restricted to be >1.
Coefficients restricted to be negative.
* Selected model.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the dose associated with the
selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., 5 = dose
associated with 5% relative deviation); BMR = benchmark response; HED = human equivalent dose;
TPA = terephthalic acid.
113
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Linear Model, with BMR of 0.05 Rel. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
Linear
80
70
60
50
40
30
20
10
BMDL
BMQ
0
100
200
300
400
500
600
700
dose
08:12 08/11 2020
Figure E-4. Fit of Linear Model to Data for Decreased Pup Weight in Male and Female CD
Rats Following TPA Exposure via Diet for 90 Days Prior to Mating through Postweaning
(Ledoux and Reel, 1982)
Decreased Pup Weight in Male CD Rats Following TPA Exposure via Diet for 90 Days
Prior to Mating through Postweaning (Ledoux and Reel, 1982)
The procedure outlined above for continuous data was applied to the data for decreased
pup weight in male CD rats following TPA exposure via diet for 90 days prior to mating through
postweaning |"Ledoux and Reel (1982); see Table D-34], The BMD modeling results are
presented in Table E-5 and Figure E-5. The constant variance model provided adequate fit to the
variance data, and adequate fit to the means was provided by all available models. The BMDLs
for the models providing adequate fit are sufficiently close (i.e., differ by
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September 2020
Table E-5. Decreased Pup Weight in Male CD Rats Following TPA Exposure via Diet for
90 Days Prior to Mating through Postweaning3
Model
Variance
/>-Valucb
Means
/>-Valucb
Scaled Residual at
Dose Nearest BMD
AIC
BMDos
(HED)
(mg/kg-d)
BMDLos
(HED)
(mg/kg-d)
Constant variance
Exponential (model 2)°
0.1482
0.4347
0.4889
169.9029
58.381
39.1203
Exponential (model 3)°
0.1482
0.4865
0.1016
170.5483
164.124
43.782
Exponential (model 4)°
0.1482
0.4347
0.4889
169.9029
58.381
32.3256
Exponential (model 5)°
0.1482
0.2954
0.1016
172.5482
164.133
43.7778
Hillc
0.1482
0.2981
4.99 x 10 5
172.529938
213.31
38.8895
Linear4 *
0.1482
0.5488
0.386
169.163521
72.113
54.6046
Polynomial (2-degree)d
0.1482
0.4785
0.223
170.591947
133.189
56.1618
Polynomial (3-degree)d
0.1482
0.4785
0.223
170.591947
133.189
56.1618
Power0
0.1482
0.4825
0.158
170.570045
148.96
56.2269
aLedoux and Reel (1982).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Tower restricted to be >1.
Coefficients restricted to be negative.
* Selected model.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the dose associated with the
selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., 5 = dose
associated with 5% relative deviation); BMR = benchmark response; HED = human equivalent dose;
TPA = terephthalic acid.
115
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Linear Model, with BMR of 0.05 Rel. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
Linear
90
80
70
60
50
40
30
20
10
BMDL
0
200
300
400
500
600
700
dose
19:21 08/10 2020
Figure E-5. Fit of Linear Model to Data for Decreased Pup Weight in Male CD Rats
Following TPA Exposure via Diet for 90 Days Prior to Mating through Postweaning
(Ledoux and Reel, 1982)
Decreased Pup Weight in Female CD Rats Following TPA Exposure via Diet for 90 Days
Prior to Mating through Postweaning (Ledoux and Reel, 1982)
The procedure outlined above for continuous data was applied to the data for decreased
pup weight in female CD rats following TPA exposure via diet for 90 days prior to mating
through postweaning |"Ledoux and Reel (1982); see Table D-34], The BMD modeling results are
presented in Table E-6 and Figure E-6. The constant variance model provided adequate fit to the
variance data, and adequate fit to the means was provided by all available models. The BMDLs
for the models providing adequate fit are sufficiently close (i.e., differ by
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September 2020
Table E-6. Decreased Pup Weight in Female CD Rats Following TPA Exposure via Diet
for 90 Days Prior to Mating through Postweaning3
Model
Variance
/>-Valucb
Means
/>-Valucb
Scaled Residual at
Dose Nearest BMD
AIC
BMDos
(HED)
(mg/kg-d)
BMDLos
(HED)
(mg/kg-d)
Constant variance
Exponential (model 2)°
0.1644
0.4495
0.1273
161.0159
55.0169
38.6817
Exponential (model 3)°
0.1644
0.4974
-0.3253
161.7049
151.545
42.5884
Exponential (model 4)°
0.1644
0.4495
0.1273
161.0159
55.0169
32.9356
Exponential (model 5)°
0.1644
0.3043
-0.3253
163.7049
151.545
42.5884
Hillc
0.1644
0.3136
-0.245
163.644549
130.142
54.9865
Linear4 *
0.1644
0.5963
-0.00487
160.099523
69.214
54.3605
Polynomial (2-degree)d
0.1644
0.5217
-0.164
161.577874
112.804
55.6005
Polynomial (3-degree)d
0.1644
0.5267
-0.107
161.551855
100.791
55.6673
Power0
0.1644
0.5091
-0.243
161.643124
129.641
55.4353
aLedoux and Reel (1982).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Tower restricted to be >1.
Coefficients restricted to be negative.
* Selected model.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the dose associated with the
selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., 5 = dose
associated with 5% relative deviation); BMR = benchmark response; HED = human equivalent dose;
TPA = terephthalic acid.
117
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Linear Model, with BMR of 0.05 Rel. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
Linear
80
70
60
50
40
30
20
10
BMDL
3MD.
0
100
200
300
400
500
600
700
dose
09:21 08/11 2020
Figure E-6. Fit of Linear Model to Data for Decreased Pup Weight in Female CD Rats
Following TPA Exposure via Diet for 90 Days Prior to Mating through Postweaning
(Ledoux and Reel, 1982)
BMD Output for Figure E-6:
Polynomial Model. (Version: 2.21; Date: 03/14/2017)
Input Data File: C:/Users/JKaiser/Desktop/BMDS240/Data/lin_pupwt_f_CD_LR_Lin-
ConstantVariance-BMR05.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/lin_pupwt_f_CD_LR_Lin-ConstantVariance-BMR05.pit
Tue Aug 11 15:02:40 2020
BMDS Model Run
The form of the response function is:
Y[dose] = beta_0 + beta_l*dose + beta_2*dose/s2 + ...
Dependent variable = Mean
Independent variable = Dose
rho is set to 0
Signs of the polynomial coefficients are not restricted
A constant variance model is fit
Total number of dose groups = 6
Total number of records with missing values = 0
118
/;-Phthalic acid
-------
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
alpha = 85.6196
rho = 0 Specified
beta_0 = 54.6853
beta 1 = -0.0405127
FINAL
September 2020
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -rho
have been estimated at a boundary point, or have been specified by
the user,
alpha
beta_0
beta 1
and do not appear in the correlation matrix )
alpha
1
-1.2e-007
7. 5e-008
beta_0
-1. 2e-007
1
-0.53
beta_l
7.5e-008
-0.53
1
Interval
Variable
Limit
alpha
113.183
beta_0
57.8477
beta_l
0.025234
Estimate
74 .7222
54.1511
-0.0391186
Parameter Estimates
Std. Err.
19.623
1.88608
0.00708413
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
36.2618
50. 4545
-0.0530032
Table of Data and Estimated Values of Interest
Dose
Obs Mean
Est Mean Obs Std Dev Est Std Dev Scaled Res.
0
4. 65
22.83
75
321
732
57.5
50.2
54.1
51.2
44.4
23.9
54.2
54
53.3
51.2
41.6
25 .5
10.6
7.51
16.4
5.98
6.02
6.51
64
64
64
64
64
64
0.866
-1.15
0.195
-0.00487
0. 649
-0.324
Model Descriptions for likelihoods calculated
Model A1: Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma^2
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Model A2 : Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma(i)^2
Model A3: Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma^2
Model A3 uses any fixed variance parameters that
were specified by the user
Model R: Yi = Mu + e(i)
Var{e(i)} = Sigma^2
Likelihoods of Interest
Model
A1
A2
A3
fitted
R
Log(likelihood)
-75.662630
-71.734959
-75.662630
-77.049762
-87.468813
# Param's
7
12
7
3
2
AIC
165.325260
167.469918
165.325260
160.099523
178.937627
Explanation of Tests
Test 1:
Test
Test
Test
Do responses and/or variances differ among Dose levels?
(A2 vs. R)
Are Variances Homogeneous? (A1 vs A2)
Are variances adeguately modeled? (A2 vs. A3)
Does the Model for the Mean Fit? (A3 vs. fitted)
(Note: When rho=0 the results of Test 3 and Test 2 will be the same.)
Tests of Interest
Test
-2*log(Likelihood Ratio) Test df
p-value
Test
Test
Test
Test
31.4677
7. 85534
7. 85534
2.77426
10
5
5
4
0.0004909
0.1644
0.1644
0.5963
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose levels
It seems appropriate to model the data
The p-value for Test 2 is greater than .1. A homogeneous variance
model appears to be appropriate here
The p-value for Test 3 is greater than .1. The modeled variance appears
to be appropriate here
The p-value for Test 4 is greater than .1. The model chosen seems
to adeguately describe the data
Benchmark Dose Computation
Specified effect = 0.05
Risk Type = Relative deviation
Confidence level = 0.95
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BMD = 69.214
BMDL = 54.3605
BMDU = 96.8278
Increased Incidence of Simple Bladder Hyperplasia in Male Wistar Rats Exposed to TPA
in the Diet for 22 Weeks CCiii et at, 2006a)
Incidences of simple hyperplasia in the bladder of male Wistar rats exposed to
terephthalic acid (TPA) in the diet for 22 weeks were fit to all dichotomous models in the BMDS
(Version 2.7) using the procedure described above for dichotomous data. All models provided
an adequate fit to the data (see Table E-7). The BMDLs for the models were not sufficiently
close (differed by greater than approximately threefold), so the model with the lowest BMDL
was selected (LogLogistic). This is also the best fitting model, with the lowest AIC. Figure E-7
shows the fit of the LogLogistic model to the data. Based on HEDs, the 10% benchmark dose
(BMDio) and 10% benchmark dose lower confidence limit (BMDLio) for increased incidence of
simple bladder hyperplasia in male Wistar rats were 194 and 95.0 mg/kg-day, respectively.
Table E-7. BMD Modeling Results for Simple Hyperplasia in the Urinary Bladders of
Male Wistar Rats Treated with TPA (CASRN 100-21-0) in the Diet for 22 Weeks"
Model
DF
x2
X2
Goodness-of-Fit
/j-Valueb
Scaled Residual
at Dose Nearest
BMD
AIC
BMDio
(HED)
(mg/kg-d)
BMDLio
(HED)
(mg/kg-d)
Gamma0
2
0.52
0.77
0.65
33.34
228.34
129.34
Logistic
1
1.55
0.21
0.88
37.00
515.89
342.36
LogLogistic4 *
2
0.24
0.88
0.42
33.11
194.44
95.03
LogProbitd
1
2.01
0.16
1.11
37.27
423.05
210.75
Multistage (1-degree)6
2
0.52
0.77
0.65
33.34
228.34
129.34
Multistage (2-degree)6
2
0.52
0.77
0.65
33.34
228.34
129.34
Probit
1
1.49
0.22
0.88
36.89
478.82
316.18
Weibull0
2
0.52
0.77
0.65
33.34
228.34
129.34
aCui et al. (2006a).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Tower restricted to >1.
dSlope restricted to >1.
"Betas restricted to >0.
* Selected model. All models provided adequate fit to the data. BMDLs for models providing adequate fit were not
sufficiently close (differed by >threefold), so the model with the lowest BMDL (LogLogistic) was selected.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the exposure concentration
associated with the selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote
benchmark response: i.e., 10 = dose associated with 10% extra risk); BMR = benchmark response; DF = degree(s)
of freedom; HED = human equivalent dose; TPA = terephthalic acid.
121
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Log-Logistic Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.6
0.5
0.4
~u
o
o
<
§ 0.3
o
ro
£
0.2
0.1
0
0 200 400 600 800 1000
dose
00:58 08/24 2018
Figure E-7. Fit of LogLogistic Model to the Data for Increased Incidence of Simple
Hyperplasia in the Urinary Bladders of Male Wistar Rats Exposed to
TPA (CASRN 100-21-0) in the Diet for 22 Weeks (Cui et al.. 2006a)
Decreased Body Weight in Male Wistar Rats Exposed to TPA in the Diet for 24 Months
(Gross. 1977)
The procedure outlined above for continuous data was applied to the data for decreased
terminal body weight of male Wistar rats exposed to dietary TPA for 24 months (Gross. 1977).
The constant variance model did not provide an adequate fit to the variance data, but the
nonconstant variance model did. With the nonconstant variance model, all of the tested models
except the Hill model provided adequate fit to the means (see Table E-8). The Hill model failed
because there were insufficient degrees of freedom available in the data set. BMDLs for the
models providing adequate fit were sufficiently close (differed by less than approximately
threefold), so the model with the lowest AIC was selected (Linear model; 2- and 3-degree
Polynomial models converged on the Linear model). Figure E-8 shows the fit of the Linear
model to the data. Based on HEDs, the BMDio and BMDLio for decreased body weight in male
rats were 448 and 373 mg/kg-day, respectively.
Log-Logistic
BMDL
122
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Table E-8. BMD Modeling Results for Decreased Body Weight in Male Wistar Rats
Exposed to TPA (CASRN 100-21-0) in the Diet for 24 Months3
Model
Variance
/>-Valucb
Means
/>-Valucb
Scaled Residual at
Dose Nearest BMD
AIC
BMD io
(HED)
(mg/kg-d)
BMDLio
(HED)
(mg/kg-d)
Nonconstant variance
Exponential (model 2)°
0.99
0.25
-0.584
1,073.5
411.80
331.51
Exponential (model 3)°
0.99
0.12
-0.842
1,075.2
469.27
335.14
Exponential (model 4)°
0.99
0.25
-0.584
1,073.5
411.80
264.04
Hill0 d
0.99
NA
-0.041
1,074.7
422.74
317.26
Linear6' *
0.99
0.26
-0.765
1,073.4
448.78
372.76
Polynomial (2-degree)6
0.99
0.26
-0.765
1,073.4
448.78
372.76
Polynomial (3-degree)6
0.99
0.26
-0.765
1,073.4
448.78
372.76
Power0
0.99
0.10
-0.878
1,075.4
475.76
373.39
aGross (1977).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Tower restricted to be >1.
dThe degrees of freedom were less than or equal to 0, and the x2 test for fit was not valid.
"Coefficients restricted to be negative.
* Selected model. The constant variance model did not provide an adequate fit to the variance data, but the
nonconstant variance model did. With the nonconstant variance model applied, all models except the Hill model
provided adequate fit to the means. BMDLs for models providing adequate fit were sufficiently close (did not
differ by more than approximately threefold), so the model with the lowest AIC was selected (Linear model). The
2- and 3-degree Polynomial models converged on the Linear model.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the dose associated with the
selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., 10 = dose
associated with 10% relative deviation); BMR = benchmark response; HED = human equivalent dose; NA = test
for fit is not valid; TPA = terephthalic acid.
123
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Linear Model, with BMR of 0.1 Rel. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
360
Linear
340
320
8- 300
280
260
240
BMDL
BMD
0
200
400
600
800
1000
dose
15:30 08/24 2018
Figure E-8. Fit of Linear Model to Data for Body Weight in Male Wistar Rats Exposed to
TPA (CASRN 100-21-0) in the Diet for 24 Months (Gross. 1977)
124
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APPENDIX F. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2018). Terephthalic
acid (100-21-0). 2018 TLVs and BEIs. Based on the documentation of the threshold limit
values for chemical substances and physical agents and biological exposure indices
[TLV/BEI], Cincinnati, OH.
AT SDR (Agency for Toxic Substances and Disease Registry). (2019). Toxic substances portal:
Toxicological profiles. Atlanta, GA. http://www.atsdr.cdc.gov/toxprofiles/index.asp
Ball. GL; Md.ellan. CJ; Bhat VS. (2012). Toxicological review and oral risk assessment of
terephthalic acid (TPA) and its esters: A category approach. Crit Rev Toxicol 42: 28-67.
http://dx.doi.org/10.3109/104Q8444.2011.623149
Brooks. AL; Sciler. FA; Hanson. RL; Henderson. RF. (1989). In vitro genotoxicity of dyes
present in colored smoke munitions. 13: 304-313.
http://dx.doi.org/10.1002/em.28501304Q5
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