1979 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

NO. 121 

BIOASSAY OF 

DIMETHYL TEREPHTHALATE 

FOR POSSIBLE CARCINOGEN ICITY 

CAS No. 120-61-6 

NCI-CG-TR-121 

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

DIMETHYL TEREPHTHALATE
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20205
 

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
 

Public Health Service
 

National Institutes of Health
 

NIH Publication No. 79-1376
 

BIOASSAY OF
 

DIMETHYL TEREPHTHALATE
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

FOREWORD! This report presents the results of the bioassay of
 

dimethyl terephthalate conducted for the Carcinogenesis Testing
 

Program, Division of Cancer Cause and Prevention, National Cancer
 

Institute (NCI), National Institutes of Health, Bethesda, Maryland.
 

This is one of a series of experiments designed to determine whether
 

selected chemicals have the capacity to produce cancer in animals.
 

A negative result, in which the test animals do not have a greater
 

incidence of cancer than control animals, does not necessarily mean
 

that the test chemical is not a carcinogen, inasmuch as the experiments are conducted under a limited set of circumstances. A positive
 

result demonstrates that the test chemical is carcinogenic for
 

animals under the conditions of the test and indicates that exposure
 

to the chemical is a potential risk to man. The actual determination
 

of the risk to man from chemicals found to be carcinogenic in animals
 

requires a wider analysis.
 

CONTRIBUTORS: This bioassay of dimethyl terephthalate was conducted
 

by Hazleton Laboratories America, Inc. (D, Vienna, Virginia,
 

initially under direct contract to NCI (2) and currently under a
 

subcontract to Tracor Jitco, Inc. (3), Rockville, Maryland, prime
 

contractor for the NCI Carcinogenesis Testing Program.
 

The principal investigators for the dimethyl terephthalate study
 

were Drs. M. B. Powers (1) and R. W. Voelker (1). Drs. Powers, C.
 

Cueto, Jr. (2), and 0. G. Fitzhugh (3,4) were responsible for the
 

selection of the doses administered during the chronic study. Ms. K.
 

J. Petrovics (1) was responsible for data management and Mr. G.
 

Najarian (1) for animal care. Histopathologic examinations were
 

performed by Drs. D. A. Banas and R. H. Habermann (1) and reviewed
 

by Dr. Voelker, and the diagnoses included in this report represent
 

their interpretation.
 

Animal pathology tables and survival tables were compiled at EG&G
 

Mason Research Institute (5). The statistical analyses were
 

performed by Dr. J. R. Joiner (3) and Ms. P. L. Yong (3), using
 

iii
 
methods selected for the bioassay program by Dr. J. J. Gart (6).
 

Chemicals used in this bioassay were analyzed at Midwest Research
 

Institute under the direction of Dr. E. Murrill (7), and feed
 

mixtures containing the test chemical were analyzed at Hazleton
 

Laboratories by Dr. C. L. Guy ton and Mr. E. Missaghi. The results
 

of these analyses were reviewed by Dr. C. W. Jameson (3).
 

This report was prepared at Tracor Jitco in collaboration with
 

Hazleton Laboratories and NCI. Those responsible for the report at
 

Tracor Jitco were Dr. C. R. Angel, Acting Director of the Bioassay
 

Program; Dr. S. S. Olin, Deputy Director for Science; Dr. J. F.
 

Robens, toxicologist; Dr. R. L. Schueler, pathologist; Dr. G. L.
 

Miller, Ms. L. A. Owen, and Mr. W. D. Reichardt, bioscience writers;
 

and Dr. E. W. Gunberg, technical editor, assisted by Ms. Y. E.
 

Presley.
 

The following scientists at NCI were responsible for evaluating the
 

bioassay experiment, interpreting the results, and reporting the
 

findings: Dr. Kenneth C. Chu, Dr. Cipriano Cueto, Jr., Dr. J.
 

Fielding Douglas, Dr. Richard A. Griesemer, Dr. Thomas E. Hamm, Dr.
 

William V. Hartwell, Dr. Morton H. Levitt, Dr. Harry A. Milman, Dr.
 

Thomas W. Orme, Dr. A. R. Patel, Dr. Sherman F. Stinson, Dr. Jerrold
 

M. Ward, and Dr. Carrie E. Whitmire.
 

(1) Hazleton Laboratories America, Inc., 9200 Leesburg Turnpike,
 

Vienna, Virginia.
 

(2) Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

(3) Tracor Jitco, Inc., 1776 East Jefferson Street, Rockville,
 

Maryland.
 

(4) 4208 Dresden Street, Kensington, Maryland.
 

(5) EG&G Mason Research Institute, 1530 East Jefferson Street,
 

Rockville, Maryland.
 

(6) Mathematical Statistics and Applied Mathematics Section, Biometry
 

Branch, Field Studies and Statistics, Division of Cancer Cause
 

and Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

(7) Midwest Research Institute, 425 Volker Boulevard, Kansas City,
 

Missouri.
 

IV
 
SUMMARY
 

A bioassay of dimethyl terephthalate for possible carcinogenicity was
 

conducted by administering the test chemical in feed to F344 rats and
 

B6C3F1 mice.
 

Groups of 50 rats of each sex and 50 mice of each sex were administered dimethyl terephthalate at one of two doses, either 2,500 or 5,000
 

ppm, for 103 weeks, then observed for 2 additional weeks. Matched
 

controls consisted of 50 untreated rats of each sex and 50 untreated
 

mice of each sex. All surviving rats were killed at 105 or 106 weeks
 

and all surviving mice at 104 or 105 weeks.
 

Administration of dimethyl terephthalate had no appreciable effect on
 

the mean body weights of the rats and mice of either sex. No clinical
 

signs related to administration of the test chemical were noted in the
 

rats. Survivals of the rats and the mice at the end of the bioassay
 

were not affected by the test chemical. Both species may have been
 

able to tolerate higher doses.
 

In rats and mice of each sex, no tumors occurred at incidences that
 

clearly were related to administration of the test chemical.
 

Although it is recognized that both rats and mice may not have
 

received a dose of the test chemical sufficiently high to provide
 

maximum test sensitivity, it is concluded that under the conditions
 

of this bioassay, dimethyl terephthalate was not carcinogenic for
 

F344 rats or B6C3F1 mice.
 

v
 

TABLE OF CONTENTS
 

I. Introduc ti on 1
 

II. Materials and Methods 5
 

A. Chemical 5
 

8. Dietary Preparation 7
 

C. Animals 8
 

D. Animal Maintenance 8
 

E. Subchronic Studies 11
 

F. Chronic Studies 13
 

G. Clinical and Pathologic Examinations 13
 

H. Data Recording and Statistical Analyses 16
 

III. Results - Rats 23
 

A. Body Weights and Clinical Signs (Rats) 23
 

B. Survival (Rats) 25
 

C. Pathology (Rats) 27
 

D. Statistical Analyses of Results (Rats) 28
 

IV. Results - Mice 31
 

A. Body Weights and Clinical Signs (Mice) 31
 

B. Survival (Mice) 33
 

C. Pathology (Mice) 35
 

D. Statistical Analyses of Results (Mice) 37
 

V. Discussion 41
 

VI. Bibliography 43
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in
 

Rats Administered Dimethyl Terephthalate in
 

the Diet 45
 

Table Al Summary of the Incidence of Neoplasms in
 

Male Rats Administered Dimethyl
 

Terephthalate in the Diet 47
 

vii
 
Table A2 Summary of the Incidence of Neoplasms in 

Female Rats Administered Dimethyl 

Terephthalate in the Diet 51 

Appendix B Summary of the Incidence of Neoplasms in 

Mice Administered Dimethyl 

Terephthalate in the Diet 55 

Table Bl Summary of the Incidence of Neoplasms in 

Male Mice Administered Dimethyl 

Terephthalate in the Diet 57 

Table B2 Summary of the Incidence of Neoplasms in 

Female Mice Administered Dimethyl 

Terephthalate in the Diet 62 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Administered Dimethyl 

Terephthalate in the Diet 67 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Administered Dimethyl 

Terephthalate in the Diet 69 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Administered Dimethyl 

Terephthalate in the Diet 74 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Administered Dimethyl 

Terephthalate in the Diet 79 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Administered Dimethyl 

Terephthalate in the Diet 81 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Administered Dimethyl 

Terephthalate in the Diet 86 

Appendix E Analyses of the Incidence of Primary 

Tumors in Rats Administered Dimethyl 

Terephthalate in the Diet 91 

viii
 
Table El Analyses of the Incidence of Primary Tumors 

in Male Rats Administered Dimethyl 

Terephthalate in the Diet 93 

Table E2 Analyses of the Incidence of Primary Tumors 

in Female Rats Administered Dimethyl 

Terephthalate in the Diet 100 

Appendix F Analyses of the Incidence of Primary Tumors 

in Mice Administered Dimethyl 

Terephthalate in the Diet 105 

Table Fl Analyses of the Incidence of Primary Tumors 

in Male Mice Administered Dimethyl 

Terephthalate in the Diet 107 

Table F2 Analyses of the Incidence of Primary Tumors 

in Female Mice Administered Dimethyl 

Terephthalate in the Diet 112 

Appendix G Analysis of Dosed Diets for Concentrations of 

Dimethyl Terephthalate 115 

TABLES 

Table 1 Dimethyl Terephthalate Chronic Feeding 

Studies in Rats 14 

Table 2 Dimethyl Terephthalate Chronic Feeding 

Studies in Mice 15 

FIGURES 

Figure 1 Growth Curves for Rats Administered Dimethyl 

Terephthalate in the Diet 24 

Figure 2 Survival Curves for Rats Administered 

Dimethyl Terephthalate in the Diet 26 

Figure 3 Growth Curves for Mice Administered Dimethyl 

Terephthalate in the Diet 32 

Figure 4 Survival Curves for Mice Administered 

Dimethyl Terephthalate in the Diet 34 

ix
 

I. INTRODUCTION
 

Dimethyl terephthalate (CAS 120- OCH,
 

61-6; NCI C50055) is one of the
 

basic monomers used in the
 

synthesis of polyester fibers 

(Dux, 1974; Goodman, 1965). The =o 

original process for the 

OCH, 

synthesis of synthetic fibers
 

Dimethyl terephthalate
 involved the alcoholysis of
 

dimethyl terephthalate with ethylene glycol to form a linear
 

polymer, polyethylene terephthalate (PET). This was then spun
 

into a fiber given the trade name Terylene® by Imperial
 

Chemical Industries, Ltd., in England. A comparable fiber,
 

Dacron®, produced by Dupont in the United States, was obtained
 

by reacting terephthalic acid with ethylene glycol (Moncrief£,
 

1970). Other PET fibers include Fortrel®, similar in
 

composition to Dacron®, and Kodel®, a polymer of dimethyl
 

terephthalate and 1,4-cyclohexanedimethanol (Moncrieff, 1970).
 

Today, terephthalic acid competes with dimethyl terephthalate as
 

a starting material for these fibers, although the volume of
 

production of the latter remains sizeable. In the United States,
 
production of dimethyl terephthalate, which was initiated in
 

1953, reached 145 million pounds per year in 1960 and 2.8 billion
 

pounds per year in 1976 (Blackford, 1977).
 

More than 85% of dimethyl terephthalate is consumed in the
 

manufacture of PET fibers for apparel, home furnishings, tire
 

cord, ropes, sailcloth, and polyester fiberfill. In industry,
 

these fibers are used as conveyer belts, in industrial laundries,
 

for electrical fabrics, and for fire hose (Moncrieff, 1970). The
 

second largest use of dimethyl terephthalate, which accounts for
 

only 8% of the market, is in the manufacture of polyester film,
 

used as photographic film, x-ray film, graphic arts film, and
 

microfilm; computer, audio and video magnetic tape; and
 

packaging. PET barrier resins are used for the manufacture of
 

nonbreakable bottles for soft drinks (Blackford, 1977).
 

Dimethyl terephthalate polymerized with 1,4-butanediol yields a
 

polybutylene terephthalate (PBT) resin. PBT resins are
 

thermoplastic resins used in automobile ignition systems and in
 

nonautomotive electrical and electronic connectors, switches,
 

housings, machine gears, and injection-molded parts (Blackford,
 

1977). Finally, small quantities of dimethyl terephthalate are
 

used directly as herbicide intermediates and in adhesives,
 

printing inks, coatings, and paints (Towle et al., 1965).
 
The oral LDc0 for dimethyl terephthalate has been reported as
 

in excess of 6,500 mg/kg when the chemical was administered to
 

male Long-Evans rats (Krasavage et al., 1973) and as greater than
 

3,200 mg/kg when the chemical was administered to rats of
 

unspecified strain (Eastman Chemical Products, 1976). The oral
 

LDcfl in mice of unspecified strain also has been reported as
 

greater than 3,200 mg/kg (Eastman Chemical Products, 1976). The
 

chemical, administered in the diet to rats of unspecified strain
 

at 50,000 ppm for 28 days, caused weight loss and high mortality
 

(Fassett and Irish, 1963). The chemical caused a reduction in
 

average body weight when administered in the diet to male
 

Long-Evans rats at a dose of 10,000 ppm for 96 days, while doses
 

of 5,000 and 2,500 ppm were without effect (Krasavage et al.,
 

1973).
 

This monomer was selected for the Carcinogenesis Testing Program
 

because of its large volume of production in the United States,
 

and the resulting extensive human exposure of workers in the
 

chemical industry.
 

3 

II. MATERIALS AND METHODS
 

A. Chemical
 

Three lots of technical-grade dimethyl terephthalate,
 

manufactured by Eastman Chemical Products, Inc., Kingsport,
 

Tennessee, were obtained for use in these studies. Qualitative
 

analyses of Lot No. B3A, used in the 90-day rat and mouse
 

subchronic studies, were performed at Midwest Research
 

Institute. The melting point was 142 C, which was consistent
 

with the value of 141 C given in the literature (Smith, 1921).
 

Thin-layer chromatography indicated a slight impurity at the
 

origin. A single homogeneous peak was obtained by vapor-phase
 

chromatography. Elemental analyses were correct for
 

C

10H10^4' t*ie molecular formula of dimethyl terephthalate.
 

The infrared, ultraviolet, visible, and nuclear magnetic
 

resonance spectra were consistent with the spectra for dimethyl
 

terephthalate in Sadtler Standard Spectra (Sadtler Research
 

Laboratories, Philadelphia, Pa.). Similar results were obtained
 

for Lot No. C4B, a white microcrystalline powder used in the
 

90-day rat subchronic studies and during weeks 0 to 52 of the rat
 

chronic studies and weeks 0 to 53 of the mouse chronic studies.
 
The third lot of dimethyl terephthalate (Lot No. EC 2/27/76) was
 

obtained in briquette form and was used during weeks 53 to 103 of
 

the rat chronic studies and weeks 54 to 103 of the mouse chronic
 

studies. Prior to use in the toxicity studies, this lot was
 

ground to a powder and analyzed for identity and purity by
 

Midwest Research Institute. The powdered material was found by
 

thin-layer chromatography to be homogeneous. The melting point
 

was 141 to 142 C, and results of elemental analyses agreed with
 

theoretical values. One system of vapor-phase chromatography
 

indicated a single, homogeneous peak, while a second system
 

indicated a trace impurity of less than 0.01%. The infrared,
 

ultraviolet, and nuclear magnetic resonance spectra were
 

consistent with spectra given in Sadtler Standard Spectra.
 

The effects of heat on the stability of dimethyl terephthalate
 

alone and the stability of a dimethyl terephthalate mix of 1:9
 

with animal meal were measured at Midwest Research Institute,
 

using vapor-phase chromatography. The results of the heat
 

stability analysis indicated that dimethyl terephthalate is
 

stable under conditions of storage for at least 2 weeks at
 

temperatures up to 60 C, and for the dosed feed mixtures
 

theoretically containing 9.7% dimethyl terephthalate and stored
 

at temperatures up to 45°C for 2 weeks, 10.1 _+ 0.3% was
 

recovered.
 
During the bioassay, the bulk chemical was stored at room
 

temperature.
 

B. Dietary Preparation
 

The diet for each dosed group was prepared by mixing the amount
 

of chemical required to achieve the desired dietary concentration
 

with a small amount of the basal diet, Wayne® Lab-Blox Meal
 

(Allied Mills, Inc., Chicago, 111.), in a Waring blender. This
 

premix was then combined with the remaining amount of basal diet
 

required. Corn oil (Duke's® Corn Oil, C. F. Sauer Co.,
 

Richmond, Va.) equal to 2% of the final weight of feed was then
 

added, primarily as a dust suppressant. This mixture was
 

thoroughly mixed in a Patterson-Kelly twin-shell blender fitted
 

with an intensifier bar. Control animals were administered basal
 

diet containing 2% corn oil. Fresh diets were prepared once per
 

week and stored at room temperature until used.
 

As a quality control check on the accuracy of the diet
 

preparation and the homogeneity of the mixtures, the dimethyl
 

terephthalate concentration was determined for randomly selected
 

batches of formulated diet during the chronic studies. Results
 

are summarized in Appendix G. At each dietary concentration, the
 
mean of the analytical concentrations for the checked samples was
 

within 4.3% of the theoretical concentration, with a coefficient
 

of variation of 5.7%.
 

C. Animals
 

F344 rats (Fischer) and B6C3F1 mice were obtained from the NCI
 

Frederick Cancer Research Center, Frederick, Maryland, through
 

contracts with the Division of Cancer Treatment, National Cancer
 

Institute. Animals were quarantined for 14 days, determined to
 

be free from observable disease or parasites, and assigned to
 

dosed or control groups on the basis of initial individual body
 

weights, so that a homogeneous distribution of mean weights and
 

weight ranges was obtained between groups. At the beginning of
 

the chronic studies, the rats were approximately 7 weeks old and
 

the mice were approximately 8 weeks old.
 

D. Animal Maintenance
 

All animals were housed in rooms maintained at 20 to 24 C and
 

45 to 55% relative humidity. Incoming air was filtered through
 

2-inch-thick disposable fiberglass filters at a rate that allowed
 

8
 
12 changes of room air per hour. Air was not recirculated.
 

Fluorescent lighting was provided on a 12-hour-per-day cycle.
 

The rats and mice were initially housed five per cage in
 

polycarbonate cages covered with stainless steel cage lids and
 

non-woven fiber filter bonnets (Filtek, Appleton, Wis.). After
 

56 weeks, the male rats were divided two or three per cage to
 

termination of the bioassay.
 

All cages were furnished with heat-treated hardwood chip bedding
 

(Sani-chips , Shurfire Products Corporation, Beltsville, Md.);
 

the bedding was changed twice each week. Diets and well water
 

were provided ad libitum.
 

Cages, water bottles, and sipper tubes were sanitized at 81 C
 

twice per week, feed hoppers once per week, and cage racks once
 

per month. An industrial dishwasher was used for the water
 

bottles and sipper tubes; a cage and rack washer was used for the
 

feed hoppers, cages, and racks. The detergent used in these
 

washers was Acclaim (Economics Laboratory, St. Paul, Minn.).
 

When racks were washed, clean racks containing cages of animals
 

were randomly repositioned in the room.
 

The rats and mice were housed in separate rooms. Control animals
 

were housed in the same room as the respective dosed animals.
 

9
 
Prior to week 52 on study, the rats on the dimethyl terephthalate
 

study were housed in the same room as rats on studies of the
 

following chemicals:
 

Feed Studies
 

(CAS 119-53-9) benzoin
 

(CAS 13463-67-7) titanium dioxide
 

(CAS 89-78-1) dl-menthol
 

Gavage Studies
 

(CAS 7488-56-4) selenium disulfide
 

(CAS 127-69-5) sulfisoxazole
 

(CAS 108-60-1) bis(2-chloro-l-methylethyl) ether
 

Drinking Water Studies
 

(CAS 108-95-2) phenol
 

After week 52, the rats on the dimethyl terephthalate study were
 

housed in the same room as rats on studies of selenium disulfide,
 

sulfisoxazole, and phenol.
 

Mice on the dimethyl terephthalate study were housed in the same
 

room as mice on studies of the following chemicals:
 

Feed Studies
 

(CAS 119-53-9) benzoin
 

(CAS 13463-67-7) titanium dioxide
 

(CAS 89-78-1) dl-menthol
 

10
 
Gavage Studies
 

(CAS 7488-56-4) selenium disulfide
 

(CAS 127-69-5) sulfisoxazole
 

(CAS 108-60-1) bis(2-chloro-l-methylethyl) ether
 

Drinking Water Studies
 

(CAS 108-95-2) phenol
 

E. Subchronic Studies
 

Subchronic feeding studies were conducted to establish the
 

maximum tolerated doses of dimethyl terephthalate, on the basis
 

of which two concentrations (referred to in this report as "low"
 

and "high" doses) were selected for administration in the chronic
 

studies. On the basis of the results of a 14-day range-finding
 

study, doses of 1,750, 2,500, 5,000, 10,000 and 20,000 ppm were
 

selected for administration in the Subchronic studies. At each
 

dose, 10 males and 10 females of each species were provided the
 

test diets 7 days per week for 13 weeks, and control groups
 

consisting of 10 males and 10 females of each species were fed
 

basal diet containing 2% corn oil.
 

No compound-related effects were noted in the physical
 

appearance, behavior, or food consumption of the rats or mice.
 

All rats survived until the end of the study. Body weight gains
 

11
 
in males and females were unaffected by the test compound at
 

doses of 1,750 to 5,000 ppm. At the end of the study, the body
 

weight gain of males fed 10,000 ppm was 90% of the controls, and
 

of those males fed 20,000 ppm was 83% of the controls. Mean body
 

weight gain at the end of the study for females fed 10,000 ppm
 

was 83% of the controls, and of those females fed 20,000 ppm was
 

71% of the controls.
 

Deaths in mice occurred in one male at 2,500 ppm, one male at
 

5,000 ppm, one male at 20,000 ppm, and two females at 20,000
 

ppm. There was no distinct effect of the test chemical on body
 

weight gain in the mice at any dose.
 

No gross alterations related to the test chemical were noted in
 

the dosed rats or mice at necropsy. Microscopically diffuse
 

hepatic cell swelling in the livers was observed in rats and mice
 

from all dosed groups. This finding was considered to be
 

compound related but not dose related.
 

The low and high doses for the chronic studies were set at 2,500
 

and 5,000 ppm, respectively, for both the rats and the mice.
 

12
 
F. Chronic Studies
 

The designs of the chronic feeding studies in the rats and the
 

mice are shown in tables 1 and 2.
 

G. Clinical and Pathologic Examinations
 

All animals were observed twice daily. Clinical signs and the
 

presence of palpable masses were recorded every week. Mean body
 

weights and food consumption were recorded every 2 weeks for the
 

first 12 weeks and every month thereafter. Moribund animals and
 

animals that survived to the end of the study were killed by
 

exsanguination under sodium pentobarbital anesthesia
 

(Diabutal®, Diamond Laboratories, Inc., Des Moines, Iowa) and
 

necropsied.
 

The pathologic evaluation consisted of gross and microscopic
 

examination of major tissues, major organs, and all gross
 

lesions. The tissues were preserved in 10% buffered formalin,
 

embedded in paraffin, sectioned, and stained with hematoxylin and
 

eosin. The following tissues were examined microscopically:
 

brain (frontal cortex and basal ganglia, parietal cortex and
 

thalamus, and cerebellum and pons), pituitary, spinal cord (if
 

13
 
Table 1. Dimethyl Terephthalate Chronic Feeding Studies
 

in Rats
 

Dimethyl 

Initial Terephthalate Time on Study 

Sex and No. of in Diet(b) Dosed Observed 

Test Group of Animals (a) (ppm) (weeks) (weeks) 

MALE 

Mat ched-Contro 1 50 0 105-106 

Low-Dose 50 2,500 103 2 

High -Dose 50 5,000 103 2 

FEMALE
 

Matched-Control 50 0 106
 

Low-Dose 50 2,500 103 2
 

High -Dose 50 5,000 103 2
 

(a) Rats were approximately 7 weeks of age when placed on study.
 

(b) The test chemical was administered in a diet containing 2% corn oil.
 

The control animals received only 2% corn oil in the diet. Diets
 

were provided ad libitum.
 

14
 
Table 2. Dimethyl Terephthalate Chronic Feeding Studies
 

in Mice
 

Sex and
 

Test Group
 

MALE
 

Matched-Control
 

Low-Dose
 

High -Dose
 

FEMALE
 

Matched-Control
 

Low-Dose
 

High -Dose
 

Initial
 

No. of
 

of Animals (a)
 

50
 

50
 

50
 

50
 

50
 

50
 

Dimethyl
 

Terephthalate
 

in Diet (b)
 

(ppm)
 

0
 

2,500
 

5,000
 

0
 

2,500
 

5,000
 

Time on Study
 

Dosed Observed
 

(weeks) (weeks)
 

104-105
 

103 2
 

103 2
 

105
 

103 2
 

103 2
 

(a) Mice were approximately 8 weeks of age when placed on study.
 

(b) The test chemical was administered in a diet containing 2% corn oil.
 

The control animals received only 2% corn oil in the diet. Diets
 

were provided ad libitum.
 

15
 
neurologic signs were present), eyes (if grossly abnormal),
 

esophagus, trachea, salivary gland, mandibular lymph node,
 

thyroid, parathyroid, heart, thymus, lungs and mainstern bronchi,
 

liver, gallbladder (mice), pancreas, spleen, kidney, adrenal,
 

stomach, small intestine, colon, urinary bladder, prostate or
 

uterus, testes or ovaries, sternebrae, femur or vertebrae
 

including marrow, mammary gland, tissue masses, and any unusual
 

lesions.
 

Necropsies were also performed on all animals found dead, unless
 

precluded in whole or in part by autolysis or cannibalization.
 

Thus, the number of animals from which particular organs or
 

tissues were examined microscopically varies, and does not
 

necessarily represent the number of animals that were placed on
 

study in each group.
 

H. Data Recording and Statistical Analyses
 

Pertinent data on this experiment have been recorded in an automatic data processing system, the Carcinogenesis Bioassay Data
 

System (Linhart et al., 1974). The data elements include
 

descriptive information on the chemicals, animals, experimental
 

design, clinical observations, survival, body weight, and
 

16
 
individual pathologic results, as recommended by the
 

International Union Against Cancer (Berenblum, 1969). Data
 

tables were generated for verification of data transcription and
 

for statistical review.
 

These data were analyzed using the appropriate statistical
 

techniques described in this section. Those analyses of the
 

experimental results that bear on the possibility of
 

carcinogenicity are discussed in the statistical narrative
 

sections.
 

Probabilities of survival were estimated by the product-limit
 

procedure of Kaplan and Meier (1958) and are presented in this
 

report in the form of graphs. Animals were statistically
 

censored as of the time that they died of other than natural
 

causes or were found to be missing; animals dying from natural
 

causes were not statistically censored. Statistical analyses for
 

a possible dose-related effect on survival used the method of Cox
 

(1972) for testing two groups for equality and Tarone's (1975)
 

extensions of Cox's methods for testing for a dose-related
 

trend. One-tailed P values have been reported for all tests
 

except the departure from linearity test, which is only reported
 

when its two-tailed P value is less than 0.05.
 

17
 
The incidence of neoplastic or nonneoplastic lesions has been
 

given as the ratio of the number of animals bearing such lesions
 

at a specific anatomic site (numerator) to the number of animals
 

in which that site is examined (denominator). In most instances,
 

the denominators included only those animals for which that site
 

was examined histologically. However, when macroscopic examination was required to detect lesions prior to histologic sampling
 

(e.g., skin or mammary tumors), or when lesions could have
 

appeared at multiple sites (e.g., lymphomas), the denominators
 

consist of the numbers of animals necropsied.
 

The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a
 

significantly higher proportion of tumors than did the control
 

animals. As a part of these analyses, the one-tailed Fisher
 

exact test (Cox, 1970) was used to compare the tumor incidence of
 

a control group with that of a group of dosed animals at each
 

dose level. When results for a number of dosed groups (k) are
 

compared simultaneously with those for a control group, a
 

correction to ensure an overall significance level of 0.05 may be
 

made. The Bonferroni inequality (Miller, 1966) requires that the
 

P value for any comparison be less than or equal to 0.05/k. In
 

cases where this correction was used, it is discussed in the
 

18
 
narrative section. It is not, however, presented in the tables,
 

where the Fisher exact P values are shown.
 

The Cochran-Armitage test for linear trend in proportions, with
 

continuity correction (Armitage, 1971), was also used. Under the
 

assumption of a linear trend, this test determines if the slope
 

of the dose-response curve is different from zero at the
 

one-tailed 0.05 level of significance. Unless otherwise noted,
 

the direction of the significant trend is a positive dose
 

relationship. This method also provides a two-tailed test of
 

departure from linear trend.
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation
 

of tumors. In this analysis, deaths that occurred before the
 

first tumor was observed were excluded by basing the statistical
 

tests on animals that survived at least 52 weeks, unless a tumor
 

was found at the anatomic site of interest before week 52. When
 

such an early tumor was found, comparisons were based exclusively
 

on animals that survived at least as long as the animal in which
 

the first tumor was found. Once this reduced set of data was
 

obtained, the standard procedures for analyses of the incidence
 

of tumors (Fisher exact tests, Cochran-Armitage tests, etc.) were
 

followed.
 

19
 
When appropriate, life-table methods were used to analyze the
 

incidence of tumors. Curves of the proportions surviving without
 

an observed tumor were computed as in Saffiotti et al. (1972).
 

The week during which an animal died naturally or was sacrificed
 

was entered as the time point of tumor observation. Cox's
 

methods of comparing these curves were used for two groups;
 

Tarone's extension to testing for linear trend was used for three
 

groups. The statistical tests for the incidence of tumors which
 

used life-table methods were one-tailed and, unless otherwise
 

noted, in the direction of a positive dose relationship.
 

Significant departures from linearity (P less than 0.05, two-


tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared to its control was calculated
 

from the exact interval on the odds ratio (Gart, 1971). The
 

relative risk is defined as p /p where p is the true
 

t c u
 

binomial probability of the incidence of a specific type of tumor
 

in a dosed group of animals and p is the true probability of
 

the spontaneous incidence of the same type of tumor in a control
 

group. The hypothesis of equality between the true proportion of
 

a specific tumor in a dosed group and the proportion in a control
 

group corresponds to a relative risk of unity. Values in excess
 

20
 
of unity represent the condition of a larger proportion in the
 

dosed group than in the control.
 

The lower and upper limits of the confidence interval of the
 

relative risk have been included in the tables of statistical
 

analyses. The interpretation of the limits is that in
 

approximately 95% of a large number of identical experiments, the
 

true ratio of the risk in a dosed group of animals to that in a
 

control group would be within the interval calculated from the
 

experiment. When the lower limit of the confidence interval is
 

greater than one, it can be inferred that a statistically
 

significant result (P less than 0.025 one-tailed test when the
 

control incidence is not zero, P less than 0.050 when the control
 

incidence is zero) has occurred. When the lower limit is less
 

than unity, but the upper limit is greater than unity, the lower
 

limit indicates the absence of a significant result while the
 

upper limit indicates that there is a theoretical possibility of
 

the induction of tumors by the test chemical, which could not be
 

detected under the conditions of this test.
 

21
 

III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

Administration of dimethyl terephthalate had no appreciable
 

effect on the mean body weights of either the male or the female
 

rats (figure 1). No clinical signs related to administration of
 

the test chemical were observed.
 

Clinical signs involving the eyes were noted in both control and
 

dosed animals throughout the course of the bioassay. The eyes
 

were frequently pale, squinted, and lacrimating; the eyeballs
 

were exophthalmic, and the corneas sometimes cloudy or opaque.
 

Dark red crusted material was observed around the eyes. During
 

the first year of the study, other clinical signs were noted
 

infrequently and included a hunched and/or thin appearance,
 

sores, soft feces, and a head tilt. The appearance and behavior
 

of the rats during the second half of the study were characterized by signs of aging. Animals were frequently observed to be
 

hunched and/or thin, to have sores on the body or extremities,
 

and to have stains on the abdominal fur. Other signs noted less
 

frequently were soft feces, a head tilt, abdominal distention,
 

wheezing, dyspnea, decreased activity, a red discharge from the
 

23
 
n g 

a a 

K 

I 100 

Q 

O 

m 

2

< 

UJ 

 200 

{1 100­ D

O

A

MALE RATS 

 MATCHED CONTROL 

 LOW DOSE 

 HIGH DOSE 

0 10 20 30 40 50 60 70 

TIME ON STUDY (WEEKS) 

100 110 

O 

IX 

O 

LU 

5 

Q 

O 

CO 

z 

< 

UJ 

S 

FEMALE RATS 

100- D MATCHED CONTROL II O LOW DOSE 

A HIGH DOSE 

—I 1 1 20 30 60 70 80 90 100 110 

TIME ON STUDY (WEEKS) 

Figure 1. Growth Curves for Rats Administered Dimethyl Terephthalate in the Diet 

24 
nose, rough hair coats, paralysis, and swellings or discharges
 

involving the urogenital area. Tissue masses, nodules, and
 

wart-like lesions were noted more frequently in male than in
 

female rats, and the incidence of these findings in dosed animals
 

was lower than, or comparable to, incidences in control animals.
 

B. Survival (Rats)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female rats administered dimethyl
 

terephthalate in the diet at the doses of this bioassay, together
 

with those of the matched controls, are shown in figure 2. The
 

result of the Tarone test for positive dose-related trend in
 

mortality is not significant in either sex.
 

In male rats, 41/50 (82%) of the high-dose group, 38/50 (76%) of
 

the low-dose group, and 35/50 (70%) of the matched-control group
 

lived to the end of the bioassay. In females, 38/50 (76%) of the
 

high-dose group, 34/50 (68%) of the low-dose group, and 42/50
 

(84%) of the matched-control group lived to the end of the
 

bioassay.
 

25
 
" ti­ 1f—Z 

-^A­

~fe 

~-*\ 

-,-A 

TWr^ 

(O 

C

£

 <!•=/, 

CD 

O 

DC 

020­

010­

nnn090­

< 

CC 060­

co 

o 050­

K 

TM 040­

m 

O 

IT 

020­

010­

000­

OABILIT

Y

O

§

MALE RATS 

D MATCHED CONTROL 

O LOW DOSE 

L\ HIGH DOSE 

20 30 40 50 60 70 

TIME ON STUDY (WEEKS) 

" a b-~ro— c?n 

I 

\ 

FEMA -E RATS 

D MATCHED CONTROL 

O LOW DOSE 

L\ HIGH DOSE 

90 100 110 

O— 

^x

-^w­ i

•<• r Wvn. 

O-i £ IS>~ 

fc— 3­ O 2v m 

°0 A

( ^'"m 

6. 6 

1 

20 30 40 50 60 70 80 90 100 110 

TIME ON STUDY (WEEKS) 

Figure 2. Survival Curves for Rats Administered Dimethyl Terephthalate in the Diet 

26 
Sufficient numbers of rats of each sex were at risk for the
 

development of late-appearing tumors.
 

C. Pathology (Rats)
 

Histopathologic findings on neoplasms in rats are summarized in
 

Appendix A, tables Al and A2; findings on nonneoplastic lesions
 

are summarized in Appendix C, tables Cl and C2.
 

A variety of tumors were observed in both control and dosed
 

rats. Each of the tumor types observed has been encountered
 

previously in aging F344 rats. These tumors occurred with no
 

appreciable difference in frequency between control and dosed
 

rats.
 

Degenerative, proliferative, and inflammatory lesions that
 

occurred were similar in number and kind to those lesions
 

commonly found in aged F344 rats.
 

Based on this histopathologic examination, there was no evidence
 

for the carcinogenicity of dimethyl terephthalate for F344 rats
 

under the conditions of this bioassay.
 

27
 
D. Statistical Analyses of Results (Rats)
 

Tables El and E2 in Appendix E contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

least two animals of one group and at an incidence of at least 5%
 

in one or more than one group.
 

The results of the Cochran-Armitage test for positive
 

dose-related trend in incidences of tumors and those of the
 

Fisher exact test comparing the incidences in the dosed groups
 

with those in the control group in the positive direction are not
 

significant in either sex. For several tumors, the incidences in
 

the control groups exceed those in the dosed groups.
 

In each of the 95% confidence intervals of relative risk, shown
 

in the tables, the value of one or less than one is included;
 

this indicates the absence of significant positive results. It
 

should also be noted that each of the intervals (except that for
 

the incidence of fibroma of the integumentary system in male
 

rats, that for the incidence of pheoch romocy toma of the adrenal
 

in high-dose males, and that for the incidence of fibroadenoma of
 

the mammary gland in high-dose females) has an upper limit
 

greater than one, indicating the theoretical possibility of the
 

28
 
induction of tumors by dimethyl terephthalate, which could not be
 

detected under the conditions of this test.
 

29
 

IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

Administration of dimethyl terephthalate had no effect on the
 

mean body weights of either the male or the female mice (figure
 

3).
 

Throughout the study, alopecia, usually involving the head, was
 

observed more frequently in the dosed female mice than in the
 

control female mice. Signs of fighting, such as sores, alopecia,
 

and swollen, red, protruding, or enlarged testes, penis, or anus
 

were observed more frequently in dosed male mice than in control
 

male mice. Otherwise, the control and dosed groups of mice were
 

comparable in appearance and behavior. The clinical signs, which
 

increased in incidence as the mice aged, included thinness; a
 

hunched appearance; abdominal distention; urine stains; decreased
 

activity; swollen, lacrimating, opaque, cloudy, small, or protruding eyes; swelling of the neck, lower midline, inguinal region,
 

or anus; rough hair coats; and tissue masses. The appearance of
 

palpable nodules, tissue masses, and wart-like lesions did not
 

appear to be related to the administration of the chemical.
 

31
 
o 

II 30­

O 

8 

n

H a o 

n

8 

n A g 2 § 8s

 8 8 D 

Q n 

o 

Q 

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m 

01 

S 

MALE MICE 

D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

—I— 

20 

—I— 

40 50 60 

TIME ON STUDY (WEEKS) 

90 100 110 

8 52 

I- 8 n a X 

2 n S 8 A UJ n 8 a a S 

0 

o 8 m 

i in 

FEMALE MICE 

O MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

10 20 30 40 50 60 70 90 100 110 

TIME ON STUDY (WEEKS) 

Figure 3. Growth Curves for Mice Administered Dimethyl Terephthalate in the Diet 

32 
These findings were noted more frequently in male than in female
 

mice, and increased in frequency with age.
 

B. Survival (Mice)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female mice administered dimethyl
 

terephthalate in the diet at the doses of this bioassay, together
 

with those of the matched controls, are shown in figure 4. The
 

result of the Tarone test for positive dose-related trend in
 

mortality is not significant in either sex.
 

In male mice, 39/50 (78%) of the high-dose group, 41/50 (82%) of
 

the low-dose group, and 32/50 (64%) of the matched-control group
 

lived to the end of the bioassay. In females, 34/50 (64%) of the
 

high-dose group, 42/50 (84%) of the low-dose group, and 35/50
 

(70%) of the matched-control group lived to the end of the
 

bioassay.
 

Sufficient numbers of mice of each sex were at risk for the
 

development of late-appearing tumors.
 

33
 
PROBABILITY OF SURVIVAL PROBABILITY OF SUR

O O O O O O O O 

fe g S 3 g § S g 

UJ 
C. Pathology (Mice)
 

Histopathologic findings on neoplasms in mice are summarized in
 

Appendix B, tables Bl and B2; findings on nonneoplastic lesions
 

are summarized in Appendix D, tables Dl and D2.
 

An increased incidence of primary lung tumors was observed in
 

male B6C3F1 mice fed dimethyl terephthalate. Alveolar/bronchiolar
 

adenomas or carcinomas were observed in 1/49 control males, 8/49
 

low-dose males, and 13/49 high-dose males. Alveolar/bronchiolar
 

carcinomas were observed in 1/49 control males, 1/49 low-dose
 

males, and 6/49 high-dose males. Alveolar/bronchiolar adenomas
 

were usually small solitary lesions located in the subpleural
 

area or immediately adjacent to a bronchiole. The cells involved
 

were cuboidal to tall columnar and tended to be situated
 

perpendicularly to the basement membrane in a single layer.
 

These cells were arranged in complex papillary projections
 

forming discrete nodules and compressing adjacent alveolar
 

walls. Mitoses were rare.
 

Alveolar/bronchiolar carcinomas, however, were less discrete
 

lesions and tended to be larger, occasionally multiple, or
 

consisting of a confluence of two or more nodules. The
 

individual cells tended to be less rigidly arranged along
 

35
 
basement membranes and were often piling up into multiple layers
 

or arranged in solid sheets of cells without a papillary
 

pattern. The cells often showed increased basophilia and a
 

moderate mitotic index. Evidence of invasion into adjacent
 

bronchioles, vessels, or surrounding lung parenchyma was
 

frequently present.
 

In high-dose females, 27/49 mice developed malignant lymphoma, as
 

compared with 16/48 control females. However, the occurrence of
 

lymphomas in aged female B6C3F1 is quite variable and it appears
 

unlikely that this increased incidence is related to compound
 

administration, particularly as none of the low-dose females
 

developed this neoplasm.
 

Other neoplasms observed were of the usual number and type
 

observed in mice of this age and strain. Other degenerative,
 

proliferative, and inflammatory lesions observed were also of the
 

usual number and kind observed in aged B6C3F1 mice and were
 

comparable in incidence between control and dosed mice.
 

Based on this histopathologic examination, a dose-related
 

increase in primary tumors of the lung in male B6C3F1 mice may
 

have been associated with long-term dietary administration of
 

dimethyl terephthalate under the conditions of this bioassay.
 

36
 
D. Statistical Analyses of Results (Mice)
 

Tables Fl and F2 in Appendix F contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

least two animals of one group and at an incidence of at least 5%
 

in one or more than one group.
 

In male mice, the result of the Cochran-Artnitage test for
 

positive dose-related trend in the incidence of alveolar/
 

bronchiolar carcinomas is significant (P = 0.023), but the
 

results of the Fisher exact test are not significant. The result
 

of the Cochran-Armitage test Cor the combined incidence of
 

alveolar/bronchiolar adenomas or carcinomas is significant (P =
 

0.001), and the Fisher exact test shows that the incidences in
 

the low- and high-dose groups are significantly higher than that
 

in the control group (P = 0.015 and P less than 0.001,
 

respectively). Other male control groups concurrently occupying
 

the same room as the mice in this study had incidences of
 

alveolar/ bronchiolar adenomas and carcinomas of 5/49 (10%), 6/46
 

(13%), and 9/49 (18%), as compared with 1/49 (2%) in the dimethyl
 

terephthalate matched controls.
 

From these results one may infer that the incidences of these
 

tumors in the dimethyl terephthalate control group were
 

37
 
inordinately low. The highest incidence in the concurrent
 

control groups exceeds that observed in the low dose animals in
 

this study (8/49, 16%). Three of the 21 lesions among all of the
 

controls were observed at 84, 95, and 96 weeks respectively, and
 

the other 18 were seen later at 104 weeks.
 

If the incidence of 5/49 in one of the concurrent control groups
 

is substituted for that of the matched controls in the present
 

study, the Fisher exact test comparing this control group with
 

the high dose (13/49, 27%) results in a probability level of P =
 

0.033. Using 6/46 as the incidence of the control group, the
 

result is P = 0.082, and using 9/49 as the control incidence the
 

result is P = 0.234. None of these results are statistically
 

significant.
 

The variability evidenced by these control groups prevents an
 

outright conclusion that the 13/49 (27%) incidence of lung tumors
 

observed in the high dose male group in this study is associated
 

with the administration of the chemical.
 

The result of the Cochran-Armitage test for dose-related trend in
 

the incidence of lymphomas in female mice indicates a departure
 

from linear trend (P less than 0.001) because the incidence of
 

the tumor in the control group is greater than that in the
 

38
 
low-dose group. The Fisher exact comparison of the incidence of
 

lymphomas in the high-dose group with that in the control group
 

shows a P value of 0.025, which is at the 0.025 level required
 

for significance when the Bonferroni inequality criterion is used
 

for multiple comparison; however, the incidence in the low-dose
 

group is significantly lower (P = 0.005) than that in the control
 

group. Furthermore, in another concurrent control group at this
 

laboratory (a 104-week study), the incidence of lymphoma and
 

leukemia in female mice was 20/49 (40%).
 

A significant trend in the negative direction is observed in the
 

incidence of hepatocellular carcinomas in female mice, in which
 

the incidence in the control group exceeds the incidences in the
 

dosed groups.
 

39
 

V. DISCUSSION
 

Administration of dimethyl terephthalate had no appreciable
 

effect on the mean body weights or survivals of the rats and mice
 

of either sex. Except for higher incidences of alopecia among
 

dosed female mice and injuries due to fighting among dosed male
 

mice, clinical signs in the rats and mice were associated with
 

aging and were common to both dosed and control groups. Both
 

species may have been able to tolerate higher doses. Dosed and
 

control rats and mice of each sex survived long enough for the
 

development of late-appearing tumors.
 

In the male and female rats, no tumors occurred in dosed groups
 

at incidences that were significantly higher than those for
 

corresponding control groups.
 

In the male mice, alveolar/bronchiolar adenomas or carcinomas
 

occurred at incidences that were dose related, and in direct
 

comparisons the incidences were significantly higher in the dosed
 

groups than that in the matched-control group. The incidences of
 

alveolar/bronchiolar adenomas or carcinomas and their variability
 

in three other concurrent control groups of B6C3F1 mice did not
 

permit the conclusion that the incidence of these tumors observed
 

41
 
in dosed male mice in this study was associated with the
 

administration of the test chemical.
 

In the female mice, lymphomas occurred at incidences that were
 

dose related; however, there was a departure from linear trend
 

because the incidence in the control group was higher than that
 

in the low-dose group. In direct comparisons, the incidence of
 

the tumors in the high-dose group was higher than that in the
 

control group. However, the P value for the high-dose group is
 

just at the level required by the Bonferroni criterion (P =
 

0.025) when multiple comparisons are made, and a concurrent
 

female control group held for a comparable length of time at the
 

laboratory had an incidence of lymphoma and leukemia of 20/49
 

(40%). Thus, the occurrence of lymphomas in the dosed female
 

B6C3F1 mice cannot clearly be related to the administration of
 

the test chemical.
 

Although it is recognized that both rats and mice may not have
 

received a dose of the test chemical sufficiently high to provide
 

maximum test sensitivity, it is concluded that under the
 

conditions of this bioassay, dimethyl terephthalate was not
 

carcinogenic for F344 rats or B6C3F1 mice.
 

42
 
VI. BIBLIOGRAPHY
 

Armitage, P., Statistical Methods in Medical Research, John Wiley
 

& Sons, Inc., New York, 1971, pp. 362-365.
 

Berenblum, I., ed., Carcinogenic ity Testing; A Report of the
 

Panel on Carcinogenicity of the Cancer Research Commission <of_
 

UICC, Vol. 2_, International Union Against Cancer, Geneva, 1969.
 

Blackford, J. L., Dimethyl terephthalate and terephthalic acid.
 

In: Chemical Economics Handbook, Stanford Research Institute,
 

Menlo Park, Calif., 1977, pp. 695.4021C-695 .4023H.
 

Cox, D. R., Regression models and life tables. J^ R_^ Statist.
 

_^ B 34(2): 187-220, 1972.
 

Cox, D. R., Analysis of Binary Data, Methuen & Co., Ltd., London,
 

1970, pp. 48::5T;
 

Dux, J. P., Polyester fibers. In: Chemical and Process
 

Technology Encyclopedia, Considine, D. M., ed., McGraw-Hill Book
 

Co., New York, 1974, pp. 896-900.
 

Eastman Chemical Products, Inc., Dimethyl terephthalate ,
 

Publication No. GN-309A, Eastman Chemical Products, Inc.,
 

Kingsport, Tenn., 1972, pp. 1-3.
 

Fassett, D. W. and Irish, D. D., eds., Esters. In: Industrial
 

Hygiene and Toxicology, Vol. II, Interscience Publishers, New
 

York, 1963, p. 1911.
 

Gart, J. J., The comparison of proportions: A review of
 

significance tests, confidence limits and adjustments for
 

stratification. Rev. Int. Stat. Inst. 39(2) : 148-169, 1971.
 

Goodman, I., Polyesters. In: Kirk-Othmer Encyclopedia o_f
 

Chemical Technology, Vol. 16, Interscience Publishing Co., Inc.,
 

New York, 1965, pp. 159 and 189.
 

Kaplan, E. L. and Meier, P., Nonparametric estimation from
 

incomplete observations. J. Am. Statist. Assoc. 53:457-481, 1958.
 

43
 
Krasavage, W. J., Yanno, F. J., and Terhaar, C. J., Dimethyl
 

terephthalate (DMT): acute toxicity, subacute feeding and
 

inhalation studies in male rats. Amer. Indust. Hygiene Assoc.
 

J^:455-462, October, 1973.
 

Linhart, M. S., Cooper, J. A., Martin, R. L., Page, N. P., and
 

Peters, J. A., Carcinogenesis bioassay data system. Comp. and
 

Biomed. Res. 7;230-248, 1974.
 

Miller, R. G., Jr., Simultaneous Statistical Inference,
 

McGraw-Hill Book Co., New York, 1966, pp. 6-10.
 

Moncrieff, R. W., Polyesters. In: Man-Made Fibres, Wiley
 

Interscience Division, John Wiley & Sons, Inc., New York, 1970,
 

pp. 400-439.
 

Saffiotti, U., Montesano, R., Sellakumar, A. R., Cefis, F., and
 

Kaufman, D. G., Respiratory tract carcinogenesis in hamsters
 

induced by different numbers of administrations of benzo (a)
 

pyrene and ferric oxide. Cancer Res. 32:1073-1081, 1972.
 

Smith, M. E., Friedel and Crafts' reaction. The 

carbomethoxybenzoyl chlorides with aromatic hydrocarbons and 

aluminum chloride. In: Journal of the American Chemical 

Society, Vol. 43, Lamb, A. B., ed., Eschenbach Printing Co.,
 

Easton, Pa., 1921, pp. 1920-1924.
 

Tarone, R. E., Tests for trend in life table analysis.
 

Biometrika 62:679-682, 1975.
 

Towle, P. H., Baldwin, R. H., and Meyer, D. H., Phthalic acid.
 

In: Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 15,
 

Interscience Publishing Co., Inc., New York, 1965, pp. 462-487.
 

44
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET
 

45
 

TABLE A1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET

 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STJDY 50 50 50
 

ANIMALS NECEOPSIED 50 49 49
 

ANIMALS EXAMINED HISTO? ATHOLOGICALLY 50 49 49
 

INTEGUMENTAR Y SYSTEM 

*SKIN (50) (49) (49) 

SQUAMOU S CELL PAPILLOM A 3 (6X)

SO.JAMGUS CELL CABCIHOM A \ (2%) 2 (4S) 1 (2%) 

TRICHGEPlTriELIOrtA 1 (2%) 

SEBACEOUS ADENOM A 1 (2%) 

KERATOACANTHOM A 5 (10% ) 3 (6%) 2 (4X) 

FIBPOMA 1 (2%) 

FIBROSAHCOM A 1 (2% ) 

HEMANGIOPERICYTOMA , NO S 1 (2%) 

*SUBCUT TISSUE (50) (49) (49) 

FIBROMA 8 (16% ) 1 (2X) 

FIBROSABCOMA 1 (2%) 1 (2X) 

MESOThELIOMA , METASTATI C 1 (2% ) 

HEMANGIOSA3COM A 1 (2%) 

HESPIBATORY SYSTE M 

SLUNG (50) (49) (49) 

ALVEOLAR/BRONCHIOLAR AOEHCMA 1 (2%) 2 (4X) 

ALVEOLAR/3RONCHIOLAK CARCINOMA 1 (2%) 2 (4%) 

FIBROSARCOMA, METASTATIC 1 (2% ) 

HEMANGIOSAHCOMA, METASTATIC 1 (2%) 

HEHATOFOIETI C SYSTE M 

*MULTIPLE ORGAN S (50) (49) (49) 

KALIG. LYMPHOMA , L Y MPHO C YTIC TYP E 1 (2% ) 1 (2%) 1 (2%) 

MALIG.LYMPHOMA , HISTIOCYTIC TYPE 1 (2% ) 1 (2%) 

MONOCYTI C LEUKEMI A 1 0 (20%) 13 (27X) 5 (10%) 

#S?LEEN (50) (48) (49)

 

KALIG.LYMPriOMA A _HiSTIOCYTIC_TYP E ____ _ 

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

47
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

»THYilU S (18) (44) (25)

 

ALVEOLAR/BRCNCHIGLA R CA , METAST A 1 (2% )

 

CIRCULATOR Y SYSTE M 

fHEAB T (50) (49) (49)

 

HLVEOLAii/bRONCHIOLA R CA , HETAST A 1 (2%) 

FIBiOSARCOMA , '1ETA3TATIC 1 (2%)

 

DIGESTIVE SYSTE M 

SSALIVAB Y GLAN D (U9 ) (49) (48) 

FI3ROSARCOMA 1 (2%) 1 (2X) 

*LIVEE (50) (49) (49) 

NEOPLASTiC NODUL E 2 (H%) 1 (2%) 

HEPAIOCELLULA R CARCINOM A 2 (4% ) 

•SMALL INTESTINE (i.9) (49) (49)

 

AD£NOCAKC1NOMA , NO S 1 (2%)

 

URINAB Y SYSTitf 

#KIDNJ Y (50) (49) (49)

 

MIXE D TUK05 , MALIGNAN T 1 (2%)

 

ENDOCEINr , SYSTE M 

#PITUITABY (43) (49) (48) 

CARCINOMA , NOS 1 (2%) 

CHRCMOPHO£ E ADENOM A 2 (US) 6 (128) 4 (8X) 

fAJBENA L (50) (49) (49) 

CORTICAL ADENOM A 1 (2%) 

PHEOCHROKOCYTOMA 11 (22%) 6 (12%) 2 (4X) 

tTHYROI D (50) (48) (48) 

FOLLICULAR-CELL ADENOM A 1 (2%) 

FOLLICULAR-CEL L CASCINOM A 1 (2%) 

C-CELL ADENOM A 3 J6S1 1 12X1 2 J4X1 

* NUMBE R OF ANIMAL S WIT H TISSUE EXAMINE D MICHOSCOPICALL Y 

* NJHBEfl OF ANIMAL S NECROPSIE D 

48 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

C-CELL CARCINOM A 1 (2%) 3 (655) 

tPANCEEATJC ISLETS 

ISLET-CELL ADENOMA 

(50) 

5 (10%) 

(49) 

1 (2X) 

(49) 

1 (2%) 

ISLET-CELL CARCINOMA 1 (2%) 1 (2*) 1 (2%) 

REPRODUCTIVE SYSTEM 

*MAMMAR Y GLAND (50) (49) (49) 

FIBROADENOM A 1 (2X) 

*PREPUTIAL GLAND (50) (49) (49) 

CARCINOMA,NO S 6 (12X) 6 (12%) 3 (6X) 

ADENOMA, NOS 1 (2%) 

IT3STIS (49) (49) (49) 

INTERSTITIAL-CELL TUMOR 44 (9035) 45 (9~S) 46 (94%) 

NEEVOU S SYSTEM 

tBRAIN (5J) (49) (49) 

ASTBOCYTOHA 1 (256) 1 (2%) 

SPECIAL SENSE ORGAN S 

*ZYMbAL'S GLAND (50) (49) (49)
 

CARCINOMA, NOS 2 (4«) 2 (4%)
 

MUSCULOSKiLiTAL SYSTEM
 

*RIB (50) (49) (49) 

FIBBOSARCOMA, .IhTrtSTATIC 1 (2%) 

BODY CAVITIES 

*PSRITCNtAL CAVIT/ (50) (49) (49) 

MESOTHELIOKA, dALIJNAN T 1 (2%) 

A LL OTHER SYSTEMS 

*MULTIPLE OR3AN S (50 ) (49) (49) 

___ ME3QTHELIPMAJ._NOS 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

49 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

HZMANGIOSAFCOM A 

DIAPKBAG H 

FIBROSARCOMA, MiTAalATIC
 

ANIMAL DISPOSITION SUMMAR Y
 

ANIMALS INITIALLY IN STUDY
 

NATURAL DEATHS
 

MORIBUND SACRIFICE
 

SCHEI/ULED SACRIFICE 

ACCIDENTALL Y KILLED 

TERMINA L SACRIFICE 

ANIMA L MISSIN G 

INCLUDE S AUTOLYZi D ANIMAL S 

IM06 SUMMAR Y
 

TOTAL ANIMALS WITH PRIMARY TUMORS*
 

TOTAL PRIMARY TUMORS
 

TOTAL ANIMALS WITH BENIGN TUMORS
 

TOTAL BENIGN TUMORS
 

TOTAL ANIMALS fcllH MALIGNANT TUMORS
 

TOTAL MALIGNANT TUMORS
 

TOTAL ANIMALS WITH SECONDARY TUMORS*


TOTAL SECONDARY TUMORS


TOTAL ANIMALS WITH TUMORS UNCEKTAINBENIGN OE MALIGNANT


TOTAL UNCERTAIN TUMORS


TOTAL ANIMALS WITH TUMORS UNCEBTAINPRIMARY OR "12TASTATIC
 

TOTAL UNCSRTAIN TUHOSS
 

CONTROL LOW DOSE HIGH DOSE 

1 (2%} 

50 50 50 

12 12 7 

3 2 

35 38 

48 49 49 

117 99 83 

46 46 48 

82 67 62 

23 21 18 

32 31 20 

1 2 1 

1 6 1 

3 1 1 

3 1 1 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUBOBS
 

# SECONDARY TUMORS: METASTATIC TUMORS OE TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

50
 
TABLE A2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET

 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 50 50 50
 

ANIMALS NECROP3IED 50 49 50
 

ANIMALS EXAMINED HISTOPATHOLOGICALI.Y 50 49 50
 

INTEGUMENTARY SYSTEM
 

*SKIN (50) (49) (50)
 

KERATOACANTHOMA 1 (2%)
 

*SUBCUT TISSUE (50) (49) (50)
 

FIBROMA 2 (4%)
 

BESPIHAT08Y SYSTiM
 

*NOSE (50) (49) (50)
 

SQUAMOUS CELL CARCINOMA 1 (2%)
 

*LUNG (50) (49) (50)
 

ALVEOLAK/BRONCHIOLAH ADENOMA 3 ((>%)
 

ACINAR-CELL CARCINOMA , METASTATI 1 (2%) 

ENDOMETKIAL STROMAL SARCOMA, MET 1 (2«) 

HEMATOPOIETIC SYSTEM 

*MULTIPLE ORGAN S (50) (49) (50) 

MALIG.LYMPHOMA , LYMPHOCYTIC TYPE 1 (2%) 

MONOCYTIC LEUKEMI A 7 (14%) 7 (14%) 3 (6%) 

#MANDIBULA E L. NODE (50) (49) (50)
 

HEMANGIOSARCOMA , INVASIV E 1 (2%)

 

tCEHVICAL LYMP H NODI, (50) (50) 

SQUAMOUS CELL CARCINOMA, METASTA 1 (2%) 

ACINAR-CELL CARCINOMA , d^TASTATI 1 (2%) 

JtMaSENTEfclC L. NODE (50) (49) (50)
 

AC!SA!z£iLL_CARCINOMAx_METAS2AT! 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

51
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

#THYMU S (22 ) (43) (29) 

ACINAR-CELL CARCINOMA , METASTATI 1 (35S) 

CIRCULATOR Y SYSTEM 

NON E 

DIGESTIVE SYST3M 

*TONGU E (50) (49) (50) 

SQUAMOU S CELL PAPILLOM A 1 (2%) 

SSALIVAR Y GLAN D (50) (47) (50)

 

HEMANGIOSARCOMA 1 (2X)

 

#LIV£R (50) (49) (50) 

HEPATOCELLULA 3 CARCINOM A 1 (2%) 1 (2%)

 

#PANCRZA S (49) (49) (50) 

ACINAR-CELL CARCINOM A 1 (2%) 

ftSTOMACH (50 ) (48) (49) 

ENDOMETRIA L STROMA L SARCOMA, MET 1 (2%) 

#COLON (50) (49) (50)

 

HEMANGIOSARCOM A 1 (2%)

 

URINAR Y SYSTEM 

#URINAR Y BLADDER (48) (46) (45) 

ACINAR-CEL L CARCINOMA , MLTASTATI 1 (2% ) 

ENJOMETRIA L STKOMAL SARCOMA , MET 1 (2%) 

ENDOCRINE SYSTEM 

(fPITUITAR Y (46) (46) (48) 

CHEOMOPHOBE ADENOM A 2 1 (46%) 16 (35%) 19 (40X) 

tADRENA L (49 ) (49) (49) 

COBTICAL CARCINOMA 1 _^2%X 

f NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

52
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE 

PHEOCHHOMOCYTOM A 1 (2%) 

tTHYROI D (50) (<*9) 

FOLLICULAR-CELL ADENOM A 

FOLLICULAR-CELL CARCINOM A 

C-CELL ADENOM A 1 (2%) 1 (2%) 

C-CELL CARCINOM A 2 (4% ) 

#PANCR£AIIC ISLETS (49) (49) 

ISLET-CiiLL ADENOM A 

ISLET- CELL CARCINOM A 1 (2%) 

UNPRODUCTIV E SYSTEM 

*MAMMAR Y GLAN D (50) (49) 

ADENOMA , NOS 1 (2%) 

ADENOCARCINOMA , NO S 2 (4%) 

FIBROADENOM A 17 (34S) 12 (24S) 

*PSEPUTIAL GLAN D 

CARCINOMA , SOS 

(50)

1 (2%) 

(49) 

1 (2%) 

ADENOCAfiCINOMA , NOS 1 (2%) 

#UTEBU S (48) (48) 

ACINAR-CE1L CARCINOMA , METASTATI 

ENDOMETRIA L

ENDOMETHIA L

 STROMA L

 STROMA L

 POLY P 

 SARCOM A 

10 

1 

(21% ) 

(2%) 

10 

1 

(21%) 

(2%) 

#OVAH Y (48 ) (48) 

ACINAR-CELL CARCINOMA , METASTAT I 

NEEVOU S SYSTEM 

tBRAI N (49) (49) 

GLIOMA , NOS 1 (2%) 

ASTROCYTOM A 1 (2% ) 

SPECIAL SENSE ORGAN S 

*£YE/CORN£lA (50) (49) 

SQUAMOU S CELL CARCINOM A 

MUSCULOSKELETA L SYSTEM 

NON E 

# NUMBER OF ANIMALS "w'lTli TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH 

(50) 

1 

1 

3 

(50) 

1 

(50) 

7 

(50) 

1 

(t9) 

1 

6 

2 

(48) 

1 

(50) 

(50)

1 

DOSE 

(2%) 

(2X) 

(6%) 

(2%) 

(14%) 

(2%) 

(2X) 

(12%) 

(4«) 

(295) 

(2%) 

53
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

BODY CAVITIE S 

*HiSENTl.RY (50) (49) (50) 

ACINAR-CELL CARCINOMA , HETASTATI 1 (2%) 

LNDOMETRIA L STHOMA L SARCOMA , BET 1 (255) 

A LL OTHER SYSTEM S 

NON E 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 50 50 50
 

NATURAL DEATHS 16 12
 

MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 38
 

ANIMAL MISSING
 

a) INCLUDES AUTOLYZED ANIMALS
 

TUMOfi SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 33 38 29
 

TOTAL PRIMARY TUMORS 71 56 49
 

TOTAL ANIMALS WITH BENIGN TUMORS 36 30 23
 

TOTAL BENIGN TUMORS 56 40 35
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 13 15 13
 

TOTAL MALIGNANT TUMORS 15 16 14
 

TOTAL ANIHALS WITH SECONDARY TUMORS* 1 4
 

TOTAL SECONDARY TUMORS 1 13
 

TOTAL ANIMALS HITH TUMORS UNCERTAINBENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCEBTAINPRIMABY OR METASTATIC
 

TOTAL UNCERTAIN TUMOES
 

* PBIHABY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

# SECONDARY TUMORS: BETASTATIC TUHORS OB TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

54
 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET
 

55
 

TABLE B1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET

 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 50 50
 

ANIMALS MISSING 1
 

ANIMALS NECROPSIES 50 U9
 

ANIMALS EXAMINED HISTOPATHOLOGIC ALL Y 49 49
 

INTSGUMENTAH Y SYSTE M 

*SKIN 

FIBROMA 

FIBHOSAHCOMA 

(50) 

2 (4%) 

(49) 

2 (4«) 

1 (2X) 

*SUBCUT TISSUE 

FIBROMA 

FIBROSAECOMA 

FIBROUS HISTIOCYTOMA 

(50) 

1

11

1

 (2%) 

 (22%) 

 (2%) 

(49) 

3 (6%) 

7 (14%) 

RESPIRATOR Y SYSTEM 

*L'JNG (49) (49)
 

HEPATOCELLULAR CARCINOMA, METAST 1 (2%)
 

ALVEOLAR/BHONChlOLAR ADENOMA 1 (2%) 7 (14%)
 

ALViOLAE/BrfONCdlOLAE CA&CINOMA 1 (2%) 1 (2%)
 

ACINAR-CELL CARCINOMA, METASTATI 1 (2%)
 

FIBBOSARCOMA, METASTATIC 6 (12%) 1 (2«)
 

RHABDOMYOSARCOMA, METASTATIC
 

HEMANGIOSA3COMA, METASTATIC 1 (2«)
 

HtMATOPOItTIC 3YST£M
 

*MULTIPL£ ORGAN S (50) (49) 

MALIG. LYMPHOMA , U N DIFF2R-TYPE 1 (2%) 

MALIG.LYMPriOMA , LYMPHOCYTI C TYPE 1 (2%) 1 (2%) 

KALIG.LYMt-HOMA , HISTIOCYTIC TYP n 3 (6%) 

MALIGNAN T LYMPHOMA , MIXE D TYPE 

GRANULOCYTI C LEUKEMI A 1 (2%) 

*BON E KAERO K (49) (49) 

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALd NECROPSIED
 

50
 

1
 

49
 

49
 

(49)
 

1 (2%)
 

1 (2%)
 

(49)
 

2 (4*)
 

8 (16$)
 

(49)
 

1 (2%)
 

a (16*)
 

6 (12%)
 

2 (4%)
 

1 (2%)
 

(49) 

3 (6*) 

1 (2%) 

(49) 

57
 
TABLE 81. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIG H DOSE 

tSPLEcN (49 ) (49) (49)

 

ALINAB-CL.LL CARCINOMA , METASTAT I 1 (2%)

 

HE.IANGIOSAfiCOMA 1 (2%) 1 (27.)

 

#LYMP H NODE (49 ) (49) C*9)

 

ALINAR-CELL CAHLINOSA , METASIATI 1 (2%) 

MALIGNAN T LYMPHOMA , MIX^-L TYPE 1 (2%) 

#CERVICA L LYMP n NODE, (49 ) (49) (49) 

RHABDOMYOSAHCOMA , MEIASTA1IC 1 (2X ) 

tBRONCHIA L LYMP H NOD E (49 ) (49) (49) 

FIBSOSARLOMA , METASTATIC 1 (2«J 

tMriSENTERIC L. NOD E (49 ) (49) (49) 

MtflANGIOK A 2 (4»)

 

fAXILLAE Y LYMP H NOD£ (49 ) (49) (49) 

FI3BOSARC03A, MEIASTATIC 1 (2%) 

JflriYMU S (27 ) (16) (26) 

FIBROSARCCm, METASTATIC. 1 (4%) 1 (6%) 1 (4%) 

CIRCULAIOB Y SYSTEM 

#H£AE T (48) (49) (49) 

FIBRGSARC03A , 1E1A5JATIC 1 (2%) 1 (2%) 

RHABDOMY03AHCOM A 1 (2%) 

Hr,MANGIOSAECO«A , 1ETASTATIC 1 (2%) 

DIGESriVr, SYSTE M 

tLIVER (49) (49) (49)

Hr.PATOCELLJLA E ADENOM A 2 (4%) 2 (4%) 

HEPATOCELLJLAfi CARCINOM A 17 (35%) 13 (27% ) 15 (31%) 

AC1NAP.-CELL CARCINOMA , METAbTATI 1 (2%) 

FIBEOSARCOliA , METASTATIC 1 (2«) 1 (2%)

 

ShABi/OMYOSAHCOMA , METASTATI C 1 (2%)

 

HEMANGIOM A 1 (2%) 

HEMANGIOSAECOM A 1 (2X) 3 (6«) 

*PANCHEAS (49 ) (49) (49)

 

ACINAB-CELL CARCINOM A 1 12*1

 

# NUMBER OF ASIKALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

58
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

#STOHACH (49 ) (49) (49) 

SQUAMOUS CELL PAPILLOMA 1 (2%)

 

ACINAR-CELL CARCINOMA , METASTATI 1 (2%) 

U&INAR Y SYSTEM 

tKIDNEY (49 ) (49) (49) 

ACINAE-CELL CARCINOMA, METASTATI 1 (2%) 

FIBBOSARCOHA, MfiTASIATIC 1 (2% ) 

ENDOCRINE SYSTEM 

tADRENA L (48) (47) (48) 

CORTICAL ADENOM A 1 (2%) 1 (2% ) 

ACINAR-CELL CAflCINOMA , METASTATI 1 (2«) 

PHECCHROMGCYTOM A 1 (2%) 

*THYROID (48) (47) (47) 

FOLLICULAB-CELL ADENOM A 1 (2X) 1 (2% ) 

#PANCREATI C ISLETS (49) (49) (49) 

ISLET-CELL ADENOM A 1 (2%) 1 (2%) 

REPRODUCTIV E SYSTEM 

tPSOSIAIE (47 ) (48) (49) 

ACINAH-i-ELL CARCINOMA , METASTAT I 1 (2X) 

tlEMANGIOK A 1 (2%) 

NERVOU S SYSTEM 

NON E 

SPECIAL SENSE ORGAN S 

*£YE/LACR1MAL GLAN D (50) (49) (49)-

ADiNOliA, NOS 1 (2%)

 

*hAEDaRIA N GLAN D (50) (49) (49) 

ADi.NOBAt NOS 1 J.2%1 2 J4%1 

# NUMbi.fi OF ANIMAL S WIT H USSdh EXAMINE D MICROSCOPICALLY 

* NJhBE R OF ANIMAL S NECROPSIE D 

59 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

flUSCULOSKELETA L bYSTE M 

NON E 

BODY CAVITIES 

NONE 

ALL OTHEB

NON E 

 SYST^IS 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY

NATURAL DEATHS

MORIBUND 3ACBIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE

ANIMAL MISSING

1_INCLJJDES_ A UTOLYZED_ ANIMALS 

 50

 18

 32

 50

 8

 41

 1

 50 

 10 

 39 

1 

# NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY * NUMBER OF ANIMALS NECROPSIED 

60
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 36 33 34
 

TOTAL PRIMARY TUMORS 52 46 51
 

TOTAL ANISALS WITH BENIGN TUMORS 13 15 14
 

TOTAL BENIGN TUMORS 13 19 16
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 30 25 27
 

TOTAL MALIGNANT TUMORS 39 21 35
 

TOTAL ANIMALS WITH SECONDARY TUMORS! 8 2 4
 

TOTAL SECONDARY iUMORS 19 4 12
 

TOTAL ANIMALS KITH TUMORS UNCERTAINBENIGN OH MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCEETAINPRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TJMORS EXCEPT SECONDARY TUMORS
 

* SECONDARY TUMORS: rtETASTAlIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

61
 
TABLE B2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET

 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALL Y IN SlUu Y 50 50 50 

ANIflAlS NECfiCPSIED 48 50 49 

ANIMAL S EXAMINE D HISTOPATHOLOGICALL Y 48 5 0 49 

INTiGUfliNTAE Y SYSTE M 

*SKIN (48) (50) (49)
 

iQUAMOUS CELL PAPILLOMA 1 (2%)
 

*SJBCUI TISSUE (48) (50) (49)
 

FIB&CSARCOMA 1 (2%) 1 (2%)
 

HuMANGIOSARCOMA 1 (2%)
 

RESPIRATORY SYSTEM
 

(48 ) (50) (49) 

ADjiNOCAHCINOHA , NOS , HETASTATIC 2 (4% ) 1 (2%) 

ALVEOLAR/EtiONCHIOLAR ADENOM A 4 (8fc) 4 (8%) 

ALVEOLAR/BSONCrilOLA H CAECINOK A 1 (2%) 

OSIEOSAECOKA , MxiTASTATI C 1 (2%) 

HEMATOPOIETIC SYSTE M 

*KULTIPLi. ORGAN S (48) (50) (49) 

MALIGNAN T LYMPH03A , NO S 1 (2%) 1 (2X) 

MALIG.LYMPiiOMA , UN DIFFilx-TY Pi 1 (2%) 

MALIG.LYBPH0.1A, L Yi-lPHOC YTIC TYPE 9 (19X) 4 (8%) 9 (18%) 

KALIG . LYMr-HOMA , HIST^OCYTIC TYPi 6 (13%) 15 (31%) 

SSPLESN (43) (50) (49) 

AD^NOCAfiClNOMA, NOS, BETASTAXIC 1 (255) 

HEMANGIOSAHCOBA 1 (2%) 

*CERVICAL LYMP H NODE (48) (48) (48) 

ADLNOCAaCINOflA , NO; META51ATIC 1 (2%) 

#KESENTERIC L. NOD E (43) (48) (48) 

4 NUMBER OF ANIMALS kITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBiE OF ANIHALo NECROPSIED
 

62 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE 

tLIVER ('48) (50) 

MALIG.LYMPHOBA , HISTIOCYTIC TYP E 1 (i%) 

*STOMACH (48 ) (49) 

BAST-CELL TUMO R 1 (255) 

CiRCULATOBY SYSTEM 

tHEART (48) (49) 

ADENOCARCINOMA , NOS , METASTATIC 

DIG2SXIVE SYSTEM 

iLIVER 

HEPATOCELLULAf i

HEMANGIOSARCOKA 

CARCIN O M A 

(48 ) 

5 (10f« ) 

(50) 

1

1

 (2% ) 

(2%) 

SSTOMAC H 

SQUABOU S CELL PAPILLO

ADLNOCAHCINOMA , NOS,

M A 

 METASTATIC 

(48 ) (49) 

1 (2% ) 

#SBALL INTESTIN E 

ADENOCABCINOMA , NOS , MEIASTATIC 

(US ) (50) 

U8INAR Y SYSTEM 

#KIDNtY (48) (50) 

TUiOi.AR-C5LL ADLHOCARC1NO M A 1 (2% ) 

ENDOCRIN E SYSTE M 

#PI1UITAH Y (46 ) (44) 

CHKOMOPHO^i . ADENOM A 3 (7%) 1 (2% ) 

*A3RENA L (48 ) (50) 

PHiOCnfiOMOCYTOM A 1 (2«) 2 (4%) 

tltlYROI D (47 ) (50) 

FOLLICULAR-CEL L ADuNOK A 1 (2%) 1 (2%) 

tPANCRtATIC ISLETS (43) (50) 

ISLET-CELL ADENOM A 1 12%) _ 

* NUMBER OF ANIMALS WITH TIoSU., EXAMINED MICROSCOPICALLY
 

* NJMEER OF ANIMALS KECPOPSIED
 

HIGH DOSE 

(49) 

(49) 

', "8) 

1 (2% ) 

(49 ) 

(49) 

1 (2% ) 

1 (2%) 

(49 ) 

1 (2% ) 

(49) 

(49) 

1 (2% ) 

(49) 

(47) 

(49) 

63
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

flEPaODJCTIV h SYSTEM 

*KAHHARY GLANJ (48) (50) (49)
 

ADs-NOMA, NOS 1 (2%)
 

ADENOCARCINOMA, NOS 2 (4») 2 (4X) 2 (4X)
 

*UrERUS (47) (50) (49)
 

ADENOCAHCiNOMA, NOS 1 (2%)
 

ENDOMETKIAL STROHAL POLYP 2 (4%)
 

hEMANGIOSARCOMA 1 (2%) 1 (2%)
 

*OVABY (47) (50) (48)
 

PAPILLARY CYSTAD£NOMA, NOS 3 (6%)
 

NEtVOUS SYSTh.l
 

#B3AIN (48) (50) (49)
 

ASTROCYTOMA 1 (2%)
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

NONE
 

ALL OTHER SYSTEMS
 

* NUMBER Of ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

64 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL -DISPOSITION SUMMAR Y 

ANIKAL S INITIALL Y I N STUD Y 50 50 50 

NATUEA L DEATHS 14 16 

MORIBUN D oACHIFICS 1

 

SCHEDULE D 3ACHI?ICiJ 

ACCIDENTALL Y KILLEJ 

TERMINA L SACRI?ICE 35 42 

ANIMA L MISSIN G 

S> INCLUDE S AUTOLYZjS D ANIMAL o 

TUMOE SUMMAR Y
 

TOTAL ANIhALS VII A ?BI3AtY TUBGK5* 28 20 32
 

TOTAL PRIMARY TUMORS 37 26 37
 

TOTAL ANIMALi HITK B2NIGS TUKCRS 11 11 4
 

TOTAL BENIGN TUMORS 1 1 13 4
 

IJTAL AMflALa i.ITH MALIGNANT TUMORS 24 11 31
 

IOTAL MALIGNANT I'JSORS 26 12 33
 

TOTAL ANIKALS KITH SECONDARY IUKORS* 3 2
 

TOIAL ii,CO:.'DAEY IJ30FS 3 6 

TUTAI ANIMAL S HIT!1 TJHOfc o UNCi-fiTAIN -

BiiNiGN OR KALIJNAK I 1 

TOTA L UNCERTAI N TiJMOR S 1 

TOTAI AM1ALS WIT. . I'JflORS bNC£RTAIK -

PRIMAti Y O B HjrASTAlI C 

TOTA L USCjJBTAI K TUMOR S 

* PHIMAf Y TUTORS : A LI TUKOK o tXC£P T SECONDAR Y TUMOR S 

» SECONDAR Y TJ'-IOiiS: .1i.I A3 T ATI C 1UMOR3 OF TUMORS INVASIV E INTO AN ADJACENT ORGA N 

65 

APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN RATS ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET
 

67
 

TABLE C1.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET 

ANIMAL S INITIALL Y I N STUD Y 

ANII1AL3 SfiCROPSIii) 

ANIMAL S EXAMINE D HI STO PA1 r.OLOiil.. ALL Y 

INT£GUMEN7AI: Y 8Y3IE H 

*SKIK 

tPIDi-PMA L INCLUSIO N CYS T 

*5U3C'J1 IlSSUr. 

Ni-CFOSIS , FA T 

RESPItATOB Y JYSrt,"! 

*TEACiiEA 

PNEUMONIA , CHRONI C KUPIKr , 

»LJN G 

iDiMA, NUS 

li-'r'LAaMATION , SUPPUri ATIV 3 

PNEUMONIA , CHRONI C HJRIH H 

HYt>?E?LASIA , ALViOLA K tPITHLLIU B 

SL'JNG/ALVEOLI 

EPI'i HiLI ALIZATIC N 

HaMATOPCIETl C 5YSTJ M 

*EON E MARRO W 

PiHIAS IERITIS 

riYPCPLASIA , HEBMOPCIiTIC 

tSPLEE N 

ANSI2CTAS1 5 

HEMATOPOI^JI S 

tMESrlHTEBIC L. NODj, 

LYBPHANGIEC7ASI S 

CONTROL 

50 

50 

50 

(50 ) 

(50) 

3 (6%) 

(50 ) 

(5J) 

1 (2%) 

9 (18%) 

(50) 

1 (2%) 

(50) 

1 (2X) 

(50 ) 

1 (27.) 

2 (4X) 

(50) 

LOW DOSE HIGH DOSE 

50 50 

49 49 

49 49 

(49) (49) 

2 (4S) 

(49) (49) 

1 (2*) 

(49) (48) 

1 (2%) 

(49) (49) 

1 (2*) 

13 (27%) 15 (3U) 

1 (2% ) 

(49) (49) 

(49) (49) 

1 (255) 

(48) (49) 

(48) (49) 

1 J2%J. 

* NUBBLE OF ANIMALS '.JlIH TISSUE EXAMINED MICROSCOPICALLY
 * NJHBER OF ANIMALS NECSOPSItD
 

69
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

CIRCULATORY bYSTE/i 

#HEAR T (50 ) {« 9) (49 ) 

FiaROSIo 34 (78%) 25 (5H) 45 (92%) 

Pi. SI ART E FITI 3 1 (2%) 

fHiART/AIRIUK (50) (49) (49)

 

IHKCMbCilJ, »'0o 1 (2%) 

*MYOCAFD1U K (50) (49) (49) 

INFLAM1AIION , NOS 1 (2%) 

FIBPOSIS 1 (2%) 14 (29X) 

DEGENERATION' , 303 43 (86*) 39 (80X) 45 (92S) 

*AOt(ri A (50) (49) (49)

 

IJ.FLAHMATION , NO S 1 (2%)

 

DIGESTIVE SYSTEM 

tSALlVAE Y GLAN D (49 ) (49) (48) 

CYST, NGS 1 (2%) 1 (2%) 

INFLAMMATION , CHRONI C 1 (2%) 

NECROSIS, FAT 1 (2%) 

f LIVER 

HERNIA, NOS 

INFLAMMATION, NOS 

PELIOSIS HEPATIS 

METASORPH03IS FATTY 

FOCAL CELLULAR CHAN'Jb 

ANGIECTASIS 

(50) 

1 (2%) 

1 (255) 

(49) 

2 (455) 

1 (2%) 

1 (255) 

1 (255) 

1 (2%) 

1 (2%) 

(49) 

1 (2%) 

*BILE DUCT 

HYPERPLASIA, NOS 

(50) 

1 (2%) 

(49) 

1 (2*) 

(49) 

*PANCEEAS 

THROMBOSIS, NOS 

PERIARTERITIS 

ATROPHY, NOS 

(50) (49) (49) 

1 (2%) 

3 (6X) 

1 (2%) 

tSTOMACH 

INFLAMMATION, NOS 

ULCEB^ NOS 

(50) (49) 

1 (2%) 

(49) 

1 J2X1 

# NUMBER

* NUMBE R

 OF ANIMALS

 OP ANIMAL S

 WIT H TISSUE EXAMINE D

 NECROPSIiD 

 MICROSCOPICALLY 

70 
TABLE C1.MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE 

ULCER, FOCAL 1 (2\)

 

HYPERKSRATOSIS 

ACANTHOSIS 

•COLON (49) (49) 

NEMATODIA5IS 3 (6%) 4 (8%) 

HYPERPLASIA , LYMPHOI D 1 (2%) 

URINAR Y SYSTEM 

*KI2NK Y (50) (49) 

PYELONEPHRITIS , NO5 1 (2%) 

INFLAMMATION , CHRONI C 38 (76%) 38 (78%) 

tUSINAR Y BLADDER (43) (46) 

hYPERPLASIA , EPITHELIAL 1 (2%) 

ENDOCRINE SYST2.1 

tPITUITAR Y (48 ) (49)

 

HYPERPLASIA , CHROKOPHOBE-CSL L 1 (2%) 

#AORENA L (50 ) (49)

 

i/EGENERAIION , LIPOID 1 (2%)

 

AN^IECTASiS 

#AD8£NA L MiDULL A (50 ) (49 )

 

HYPEHPLASIA , NO S 2 (4% )

 

tTHYROI D (50) (48) 

KYPEPPLASIA , C-CELL 1 (2?.) 

REPRODUCTIV E JYSISS 

*MAMMAfe Y ^LAN J (50) (49)

 

LACTATIO N 1 (2% )

 

8PROSTATE (44) (48) 

INFLAMMATION , SUPPJRATIV E 2 (5%) 1 (2%) 

*TESTIS (49 ) (49) 

» NUMBr. 8 Or1 ANIKAL S WII H TISSUE EXAMINE D MICROSCOPICALL Y 

* NUKBEi i OF ANIMAL S NECROPS1E D 

HIGH DOSE 

1 (2«) 

1 (2%) 

(49) 

4 (8%) 

(49) 

27 (55%) 

(47) 

(48) 

(49) 

1 (2% ) 

(49 ) 

1 (2% ) 

(48) 

1 (2%) 

(49 ) 

(47) 

(49) 

71 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

HYP,OSPERMATOGENESIS


*EPIDIDYMIS


NECBOSIS, FAT


NEEVOUS SYSTEM
 

*BRAIN/MENINGE3


ANGIECTASIS


tBRAIN
 HYDROCEPHALUS, INTERNAL


SPECIAL SENSE ORGANS
 

*iY£


INFLAMMATION, NOS


SYNECHIA, ANTEBIOK


SYNECHIA, POSTERIOR


CATARACT


*EYK/CORNEA


SCLEROSIS


VASCULARIZATION


MUSCULOSKEL2TAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*ABDOMINAL CAVITY


NECROSIS , FAT

*PiiRITONi,AL CAVIT Y

NECROSIS, FAT

*MES£NTER Y

LYMPKANGI^CTASI S

INFLAMMATION, CHRONIC

CONTROL LOW DOSE HIGH DOSE 

1 (2%) 

 (50) (49) (49) 

2 (4%) 1 (2%) 1(2%) 

 (50) (49) (49) 

1(2%) 

 (50) (49) (49) 1 (2X) 

 (50) (49) (49) 

1 (2%) 

1 (2») 

3 (6%) 

4 (B%) 3 (6%) 

 (50) (49) (49) 

1 (2«) 

1(2%) 

 (50) (49) (49) 

1 (2%) 1 (2% ) 

 (50 ) (49) (49) 

1 (2%) 

 (50 ) (49) (49) 

1 (2%) 

1 (2%) 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUdBLR OF ANIMALS NECROPSIES
 

72 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

NiCROSIS, PAT 4 (8%) 4 (8%) 6 (12%) 

ALL OTHhR SYSTEMS 

NON E 

SPECIAL MORPHOLOGY SUMHABY 

AUTOLYSIS/NO NECROPSY

> NUKBEfi OF ANIMALS «iIIH TISSUL EXAMINED HICROSCOPICA LIY * NOMctH OF ANIMALS N£CROPSIED 

1 1 

73
 
TABLE C2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 50 50 50
 

ANIMALS NECROPSIED 50 49 50
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 50 49 50
 

INTEGUMENTARY SYSTEM
 

*SKIN (50) (49) (50)
 

HYPERKERATOSIS 1 (2%)
 

ACANIH05IS 1 (2%)
 

*SUBCUT TISSUE (50) (49) (50)
 

ABSCESS, NOS 1 (2%)
 

NECROSIS, FAT 2 (4X) 2 (4X)
 

BESPIBATOBY SYSTEM
 

#LUNG/BBONCHUS (50) (49) (50)
 

HYPERPLASIA, LYMPHOID 1 (2%)
 

#LUNG (50) (49) (50)
 

CONGESTION, NOS 1 (2%)
 

PNEUMONIA, CHRONIC MURINE 20 (40%) 11 (22%) 8 (16%)
 

HYPERPLASIA, ALVEOLAE EPITHELIUM 1 (2X)
 

HEMATOPOIETIC SYSTEM
 

#SPLEEN (49) (49) (49) 

PHAGOCYTIC CELL 1 (2%) 

HEMATOPOIESIS 1 (2%) 

tCBRVICAL LYMP H NODE (50) (49) (50) 

INFLAHHAIION, NOS 1 (255) 

CIECULATOHY SYSTEM 

tHEART (50) (49) (50)

 

MINERALIZATION 1_J2%1 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECHOPSIED
 

74
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE 

1 (2%) 

19 (38») 

(50) 

(50) 

19 (38%) 

(50) 

2 (4%) 

2 (4«) 

1 (2%) 

1 (2«) 

(50) 

(49) 

1 (2%) 

(50) 

8 (16X) 

(50) 

(50) 

1 (2%) 

1 (2%) 

1 (2%) 

9 (18S5) 

(45) 

1 i2*l 

THROMBUS , ORGANIZE D 

F1BROSIS 

#LEFT AURICULA R APPE N 

THROMBUS , ORGANIZE D 

#MYOCARDIU M 

FIBROSIS 

DEGENERATION , NOS 

DIGESTIVE SYSTEM 

•LIVER 

HERNIA , NOS 

INFLAMMATION , NO S 

NECROSIS, CENTRA L 

METAMORPHOSI S FATTY 

CYIOPLASMIC VACUOLIZATIO N 

FOCAL CELLULA R CHANG E 

hjiPATOCYTOMEGALY 

ANGIECTASIS 

#BILi, DUCT 

HYPEfiPLASIA, NOS 

tSTOMACH 

ULCER, NOS 

#COLON 

NiMATODIAi>I S 

*RECTUM 

NEMATODIASIS 

URINAR Y SYST£M 

*KIDNE Y 

CALCULU S , NOS 

HYDBONEPHSOSI S 

MULTIPLE CYSTS 

INFLAMMATION ,

#UEINAE Y BLADDER 

 CHRONI C 

HYPEHPLASIA ^ EPITHELIA L 

CONTROL LOW DOSE 

16 (32%) 30 (6 IS) 

(50) (49) 

1 (2%) 

(50) (49) 

9 (18%) 

25 (50%) 30 (61%) 

(50) (49) 

3 (6%) 

1 (2%) 

2 (4%) 

1 (2%) 

1 (235) 

4 (8%) 4 (8%) 

1 (2%) 

(50) (49) 

1 (2%) 

(50) (48) 

(50) (49) 

1 (2% ) 5 (10X) 

(50) (49) 

1 (2«) 

(49 ) (49) 

3 (6«) 5 (10«) 

(48) (46) 

#	 NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

*	 NUMBER OF ANIMALS NECROPSIED
 

75
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

jiNDOCBINE SYSTEM 

• PITUITARY (46 ) (46) (48) 

CYST, NOS 2 (458) 1 (258) 3 (658) 

MULTIPLE CYSTS 1 (2«) 

ANGIECTASI S 1 (2X ) 1 (2«) 1 (2%) 

f ADRENA L (49) (49) (49) 

CYST, NOS 1 (2%) 

ANGIECTASIS 1 (258)

 

ffTHYROID (50) (49) (50) 

CYSTIC FOLLICLES 1 (2X) 

riYPERPLASIA, C-C2LL 2 (438) 1 <2X) 

REPRODUCTIV E SYSTE M 

*KAHMAfi Y GLAN D (50) (49) (50) 

3ALACTOCELE 5 (10% ) 2 (4%) 8 (1658) 

INFLAMMATION , NO S 1 (258) 

LACTATIO N 7 (14% ) 1 (2«) 9 (18%) 

*VAGIN A (50 ) (49) (50)

 

PROLAPSE 1 (2%)

 

#UT£RU S (48 ) (48) (49) 

KYDfiOMETR A 3 (658) 2 (458) 2 (458) 

INFLAMMATION , NO S 1 (258) 

NECROSIS, FAT 2 (4X) 

#UTE8US/LND CULT RIO M (48) (48) (49)

 

HYPhRPLASIA , CYSTIC 1 (254)

 

#OVAR Y (48) (48) (48) 

CYST, NOS 1 (255) 3 (6*) 

NECROSIS , r'AT 1 (258) 

NiRVOU S SYSTEM 

NON E 

SPLCIAL Sr.NSE ORGAN S 

*EYE (50) (49) (50) 

SYNECHIA , ANTERIO R 1 J25S1 1 J2581 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

76
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

SYhj&ChlA, .

CATARAC T

 POSTERIO R 1

 1

 (2% )

 (2%)

 1

 1

 (2%)

 (2%)

 2

 4

 (4%) 

 (8%) 

*EY£/CORNEA

HYPfi&PLASIA , E?ITHLLIA L

VASCULA R NATIO N

 (50)

 1

 2 

 (2%) 

 (49) (50) 

*£Y£/CONJJM_TIVA

INFLAMMATION , NOi

 (50)

 1 (2%) 

 (49) (50) 

hUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

*AbDOMIKAL CAVITY

NECROSIS, FAT

 (50)

 4 (8%)

 (49) (50) 

7 (14%) 

*PEBI10NEAL CAVITY

NECPOSIS, FAT

*HiSENTER Y

NECROSIS , FAT

 (50)

 (50 )

 1 (2%)

 (49)

 (49)

 2 (4X )

 (50) 

1 (2X) 

 (50) 

1 (2X) 

A LL OIHtft SYSTEM S 

AJJ.POi.i TISSUE 

NECROSIS, FAT 1 

SPECIAL MORPHOLOGY SJMMAR Y 

NO LESION RaPORTtD 1 1

AUIOLYSIS/NO NECROPSY 1 

* NJBbER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY * NUMBER OF ANIMALS N2CPOPSIED 

3 

77
 

APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN MICE ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET
 

79
 

TABLE D1. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUD Y 50 50 50 

ANIMALS MISSING 1 1 

ANIMALS SECEOPSIED 50 49 49 

ANIMALS EXAMINE D HISTOP ATHOLOGIC ALL Y 49 49 49 

INTEGUMENTAR Y SYSTEM 

*SKIN (50) (49) (49) 

SEBACEOUS CYST 1 (2% ) 

ULCER, NOS 1 (2%) 

INFLAMMATION , CHRONIC 

METAPLASIA, OSSEOUS 

1 (2%) 2 (4%) 4

2

 (8%) 

 (4%) 

*SUBCUT TISSUE 

SEBACEOUS CYST 

(50) (49) 

2 (4S) 

(49) 

EDEMA , NOS 

INFLAMMATION ,

ABSCESS, NOS 

INFLAMMATION ,

 SUPPURATIVi , 

 ChHOHIC 

1 

1 

1 

(2%) 

(2%) 

(2%) 

3 (6%) 

1 (2%) 

NECROSIS, FAT 1 (2%) 

RESPIRATORY SYSTEM 

fLUN G (49 ) (49) (49) 

CONGESTION , NOS 1 (2%) 1 (2») 2 (U%) 

HEMORRHAG E 1 (2% ) 

INFLAMMATION, SUPP'JRATIVE 1 (2%) 1 (2%) 

PNEUMONIA , CH20N1C HUBIN E 5 (10% ) 6 (12*) 10 (20%) 

HYPERPLASIA , ADENOMATOU S 1 (2%) 

riYPERPLASIA , ALVEOLA R EPITtiELIU M 1 (2% ) 

HEhATOPOIETIC SYSTE M 

#BONE MARRO W (49 ) (49) (49) 

HYPERPLASIA , HEMATOP01LIIC 2 (4% ) 

t!Yt>ERPLA3IA, GRANULOCYTIC 1 (2%) 

#SPLE2 N (49 ) (49) (49) 

CONGESTION^ NOS 1 i

2

%l_ 

# NUMBER OF ANIMALS hITH TISSUE EXAMINED MICROSCOPICALLY
 

* NJMoLR OF ANIMALS NECROPSIED
 

81
 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

ATROPHY , NOS 1 (2%) 

LEUKEMOI D REACTIO N 1 (2%) 

HYPhHPLASIA , LYMPHOI D 6 (12%) 5 (10% ) 4 (856) 

h£HATOPOI2SIS 10 (20%) 4 (8%) 8 (16%) 

•HSSLNTiRIC L. NOD L (49 ) (49) (49) 

LYMPHANG1LCTASI S 1 (2%) 

CONGESTION, NOS 9 (18% ) 7 (14% ) 3 (6%) 

dEMGBRHAG E 1 (2%) 

INFLAMMATION , NO S 1 (2%) 1 (2X) 

riYPERPLASIA, LYMPriOID 8 (16%) 7 (14%) 10 (20%) 

CIRCULATOR Y SYSTEM 

JtHEART (43) (49) (49) 

THROMBOSIS , NOS 1 (2%) 

PERIAHTiRlTI S 1 (2%) 1 (2%) 1 (2%) 

tMYOCARDIU M (48) (49) (49)

 

INFLAMHATION , SUPPURATIV E 1 (2%)

 

INFLAMMATION , CHRONI C 1 (2%)

 

DIGESTIVE SYSTEM 

tLIViR (49 ) (49) (49) 

CYST, NOS 1 (2%) 

THROMBOSIS, NOS 1 (2%) 1 (2%) 

INFLAMMATION , NO S 1 (2%) 

NECROSIS, NOS 2 (4%) 3 (6%) 1 (2X) 

NECROSIS, FOCAL 1 (2%) 3 (6X) 

NECROSIS, COAGULATIVJ S 1 (2%) 

INFARCT, NOS 2 (4%) 4 (8%) 1 (2X) 

HYPiRPLASIA , FOCAL 2 (4%) 

HEHATOPOIESI S 1 (2%) 

*GALL£L ADDER (50) (49) (49)

 

INFLAMMATION , CHHONIC 1 (2%)

 

tPANCREA S (49) (49) (49)

 

FIBEOSIS 1 (2%)

 

PEEIARTERITIS 2 (4%)

 

tSTOMACH (49) (49) (49)

 

ULCER, FOCAL 1 J2%)_

 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICEOSCOPICALLY
 

* NUMBER OF ANIMALS NECBOPSIED
 

82
 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

#P£Y£BS PATCH 

HYPEBPLASIA , LYMPHOI D 

#DUODtNUB 

INFAECT, NOS 

tCOLON 

NEMATODIASI S 

URINAR i SYSTEM 

*KIDNE Y 

HYDBONEPHBOSI S 

HEMORRHAG E 

PYELONEPHRITIS , NO S 

PYELONEPHRITIS , ACUTi 

INFLAMMATION , CHRONIC 

• URINAR Y BLADDiR 

INFLAMMATION, CHRONIC 

HYPERPLASIA , EPITHELIA L 

ENDOCRIN E SYSTEM 

»AJH~NA L CORTE X 

CYST, NOS 

• ADRENA L MEDULL A 

HYPfcEPLASI<\ , NO S 

• THYROI D 

hYPERPLASIA , FOLLIC J LAR-CEL L 

RtPaODUCTIV E SYSTE M 

*PiUPUTIAL 3LAU D 

St3ACEOU5 CYST 

tPHOSTAT L 

INFLAMMATION , SUPPJKATIV E 

*bS«INAL VESICL E 

DISTEHTION 

* NUi'JBiR OF ANIMAL S tflTh TISSUE

* NJKBER OF ANIMALS NECROPSIED 

CONTROL LOW DOSE HIGH DOSE 

(49 ) (49) (49) 

1 (2%) 

(49) (49) (49) 

1 (255) 

(49) (48) (49) 

1 (2%) 5 (10%) 

(49 ) (49) (49) 

1 (2«) 1 (2% ) 

1 (2%) 

1 (2X) 

1 (2%) 

2 (4%) 4 (8f») 1 1 (22%) 

(43) (49) (49) 

2 (<i%) 

1 (2%) 1 (2%) 

(43) (47) (48) 

2 (4%) 

(48 ) (47) (48) 

2 (4%) 2 (H%) 1 (2% ) 

(48) (47) (47) 

2 (4%) 

(50) (49) (49) 

1 (2% ) 

(47) (48) (49) 

1 (2%) 

(50) (49) (49) 

2 J4XL 1 I2%1 

 EXAMINE D MICROSCOPICALL Y 

83 
TABLE D1. MALE MICE: NONNEQPLASTIC LESIONI (CONTINUED)

 

CONTROL LOW DOSE HIGH DOSE

 

(»SJ
 

1 (2%)
 

1 (2%)
 

3 (7%)
 

1 (2%)
 

(49)
 

1 (2%)
 

1 (2%)
 

<*9>
 

(«9)
 

(«)


1 (2«)
 

1
 

#TESTIS
 

GRANULOMA, SPEaMA-IIC
 

FIBHOSIS
 

CALCIFICATION, NOS
 

AIEOPHY, NOS
 

HYPOSPERMATOGENESIS
 

•EPIDIDYMIS
 

INFLAMMATION, NOS
 

3P.ANULOMA, SPcRMAIIC
 

NERVOUS SYSTEM
 

NONE
 

SPECIAL SENSE OKGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

*VERTEBRAL COLUMN
 

OSTEOPHYTE
 

BODY CAVITISS
 

* PERITONEUM
 

INFLAMMA1ION, NOS
 

*MESENIERY
 

THROMBOSIS, SOS
 

PERIARTERITIS
 

NECROSIS, fAT
 

ALL OTHER SYSTEMS
 

ADIPOSE TISSUE
 

INFLAMMATION. CHRONIC
 

(18)
 

1 (6%)
 

1 (6%)
 

1 (6%)
 

(50)
 

1 (2%)
 

1 (2X)
 

(50)
 

1 (2%)
 

(50J
 

(50)
 

1 (2%)
 

1 (2%)
 

(49)
 

1 (2%)
 

1 (2%)
 

(49)
 

(49)
 

(49)
 

# NUHBEB OF ANI3ALS HITH TISSUE SXAHINED MlCBOSCOPICALLY
 

* NUHBEH OF ANIMALS NECROPSIED
 

84
 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

SPECIAL MORPHOLOGY SUMMABY 

NO LESION R£POHTED

ANIMAL MISSING/NO NECROPSY

AUTO/NECROPSY/NO HISTO

 2

 1 

5

 1

 1 

1 

> NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY * NUMBER OF ANIMALS NECROPSIED 

85
 
TABLE 02. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALL Y IN STUD Y 50 50 50 

ANIMAL S t^CROPSIED 43 50 49 

ANIMAL S EXAMINE D rflSIGPAThOLOGICALLY 48 50 49 

IN1-JGUKEKIA H Y SYSTE M 

NONj i 

BESPIEATCH Y SYSTEM 

#LJN G (48 ) (50) (49 ) 

CONGESTION , NOS 1 (2%) 2 (4% ) 2 (4%) 

HEMORRHAG E 1 (2%) 

PNEUMONIA , ASPIRATIO N 1 (2%) 

INFLAMMATION , SJPPURATIV E 1 (2%) 

PNEUMONIA , CHRONI C MURIN G 4 (8%) 7 (14% ) 5 (10%) 

riEMATOPOIETIC SYSTEM 

IBON E MARRO W 

riYPEBPLASIA, HEMAIOPOIiTIC 

HYPERPLASIA , GRANULOCY1IC 

(43) 

2 (4%) 

(50) (49) 

1 (2«) 

•SPLEEN 

CONGESTION , NOS 

ATROPHY , NOS 

HYPERPLASIA , LYMPHOI D 

HEMATOP01ESIS 

(43) 

1

1

5

 (2%) 

 (2%) 

 (10%) 

(50) 

8

4

 (16%) 

 (8%) 

(<*9) 

1

2

 (2%) 

 (4%) 

#HESENT£hIC L. NODis 

INFLAMMATION, CHROSIC 

LYMPHOIO 

(43) 

1

1 

 (2%) 

(48) 

4 (8%) 

(48) 

2 (4%) 

CIECULATOPY SYSTEM
 

#H£ART (48 ) (49) (48) 

INFLAMMATION. CHRONIC 

* NUMBLR OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NJMBER OF ANIMALS NECROPSIED
 

86 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

#MYOCABDIU M (48) (49) (48)

 

INFLAMMATION , NOS 1 (2%)

 

DIGESTIVE SYSTEM 

iLIVER (43) (50) (49)

 

CONGESTION, NOS 2 (4%) 1 (295) 

NECROSIS, NOS 2 (4X) 

NECFOSIS, FOCAL 1 (2%)

 

INFARCT, NOS 1 (2«)

 

FOCAL CELLULAR CHANG E 1 (2%)

 

tBILE DUCT (48) (50) (49) 

FIBfiOSIS 1 (2%) 

tPANCEEAS (48) (50) (49) 

MINERALIZATIO N 1 (2%) 

HEMOBHHAGIC CYST 1 (2%) 

tPANCREATIC ACINUS (48) (50) (49) 

ATROPHY , NOS 1 (2%) 

#STOMAC H (48) (49) (49) 

ULCER, FOCAL 1 (2%)

 

MASTOCYTOSIS 1 (2%)

 

*P£YERS PATC H (48) (50) (49) 

.".YPEHPLASIA, LYMPHOID 3 (655) 

tCOLON (48) (50) (49) 

NEMATODIASI S 2 (455) 1 (2%) 

UKINAR Y SYSTJLM 

tKIDNE Y (48) (50) (49) 

HYDRONEPHROSI S 1 (2%) 1 (235) 

INFLAMMATION , CHRONIC 2 (4%) 3 (6%) 

INFARCT, NOS 2 (455) 2 (4%) 

#URINAR Y BLADDr-R (46) (49) (46) 

HEMORRHAG E 1 (2%) 

INFLAMMATION , CHRONIC __ 1_J2S1 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIKALS HECROPSItD
 

87
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

ENLOCRINi SYSTEM 

#ADEr.NA L MEDULL A (48) (50) (49)

 

HYPESPLASIA , NOS 1 (2%)

 

fcTHYROID (47) (50) (47)

 

CYSTIC FOLLICLES 1 (2%) 2 (456)

 

HYPEEPLASIA , FOLLICUL AR-CELL 1 (236) 1 (2%)

 

REPRODUCTIV E JYSTEM 

*MAMMAK Y GLAN D (<*8) (50) (49) 

LACTATIO N 2 (455) 2 (456) 3 (6%) 

tUTERU S (47) (50) (49) 

HYDEOMETR A 1 (256) 

THROMBOSIS , NOS 1 (2%) 

HEMORRHAG E 1 (256) 

INFLAMMATION , CHRONIC 1 (2«) 

#UTERUS/ENDOMETRIU M (47) (50) (49) 

INFLAMMATION , SUPPURATIV E 1 (256) 

HYPESPLASIA, CYSTIC 39 (83X) 39 (78%) 33 (6756) 

SOVAR Y (47) (50) (48) 

FOLLICULA R CYST, NO S 5 (1156) 6 (12%) 5 (1056) 

PAROVARIA H CYST 2 (4%) 4 (8%) 2 (4%) 

HEMORSHAGI C CYST 5 (1156) 

NERVOU S SYSTEM 

tBRAIN/MENINGZ S (48) (50) (49)
 

INFLAMMATION , NO S 

SPECIAL SfiNSE ORGAN S 

*EYE (48) (50) (49)
 

INFLAMHATION X _NOS _ 

« NUflBEB OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

88 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

ABSCESS, HOS 1 (2%) 

CATABACT 1 (2% ) 

MUSCULCSKiLETAL SYSTEM 

*SKiiL£TAL MUSCL E (48) (50) (49) 

CALCIFICATION, DYSIROPHIC 1 (2%) 

BODY CAVITIES 

*P£RITONEUM (43) (50) (49) 

INFLAMMATION, SUPPURAT1VE 1 (2%) 

*M£SENTERY (43) (50) (49 ) 

PERIARTERITx S 1 (2«) 

ALL CTHEB SYSTEM S 

NON E 

SPECIAL MORPHOLOGY SUMMAR Y 

NO LiSIGN REPORTE D 1 1 

AUTOLYSIS/NO NECROPSY 2 1 

* NUMBER OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBtS OF ANIMAL S NECROPSIiD 

89 

APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS IN
 

RATS ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET
 

91
 

__ 

Table El. Analyses of the Incidence of Primary Tumors in Male Rats 

Administered Dimethyl Terephthalate in the Diet (a) 

Topography ; Morphology


Integumentary System: Squamous-cell
 

Papilloma of the Skin (b)


P Values (c,d)


Departure from Linear Trend (e)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

u> 

Integumentary System:
 

Keratoacanthoma of the Skin (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Matched
 

 Control
 

 0/50 (0)
 

 N.S.
 

P = 0.013
 

 5/50 (10)
 

 N.S.
 

Low
 

Dose
 

3/49 (6)
 

N.S.
 

Infinite
 

0.614
 

Infinite
 

105
 

3/49 (6)
 

N.S.
 

0.612
 

0.100
 

2.967
 

High
 

Dose
 

0/49 (0)
 

—
 

—
 

—
 

—
 

2/49 (4)
 

N.S.
 

0.408
 

0.040
 

2.358
 

Weeks to First Observed Tumor 83 105 105 
Table El. Analyses of the Incidence of Primary

Administered Dimethyl Terephthalate in

(continued) 

Matched
 

Topography: Morphology Control
 

Integumentary System: Skin tumors (b,g) 7/50 (14)
 

P Values (c,d) N.S.
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 83
 

Integumentary System: Fibroma (b) 8/50 (16) 

P Values (c,d) P = 0.005 (N) 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 92 

 Tumors in Male Rats 

 the Diet (a) 

Low
 

Dose
 

8/49 (16)
 

N.S.
 

1.166
 

0.401
 

3.489
 

103
 

1/49 (2)
 

P = 0.017 (N)
 

0.128
 

0.003
 

0.898
 

105 

High
 

Dose
 

4/49 (8)
 

N.S.
 

0.583
 

0.133
 

2.139
 

105
 

1/49 (2)
 

P = 0.017 (N)
 

0.128
 

0.003
 

0.898
 

105 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats 

Administered Dimethyl Terephthalate in the Diet (a) 

(continued) 

Matched Low High 

Topography: Morphology Control Dose Dose 

Hematopoietic System: Lymphoma or 

Leukemia (b) 13/50 (26) 14/49 (29) 7/49 (14) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 1.099 0.549 

Lower Limit 0.536 0.203 

Upper Limit 2.266 1.348 

Weeks to First Observed Tumor 20 64 48 

Liver: Neoplastic Nodule or 

Hepatocellular Carcinoma (b) 4/50 (8) 0/49 (0) 1/49 (2) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 0.000 0.255 

Lower Limit 0.000 0.005 

Upper Limit 1.100 2.459 

Weeks to First Observed Tumor 106 99 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats

 

Administered Dimethyl Terephthalate in the Diet (a) 

(continued) 

Topography: Morphology


Pituitary: Chromophobe Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Adrenal: Pheochromocytoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 

Matched
 

 Control
 

 2/48 (4)
 

 N.S.
 

 105
 

 11/50 (22)
 

P = 0.006 (N)
 

76 

Low
 

Dose
 

6/49 (12)
 

N.S.
 

2.939
 

0.558
 

28.625
 

105
 

6/49 (12)
 

N.S.
 

0.557
 

0.183
 

1.505
 

87 

High
 

Dose
 

4/48 (8)
 

N.S.
 

2.000
 

0.302
 

21.281
 

91
 

2/49 (4)
 

P = 0.008 (N)
 

0.186
 

0.021
 

0.793
 

105 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Dimethyl Terephthalate in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

Thyroid: C-cell Carcinoma or
 

Adenoma (b) 3/50 (6) 2/48 (4)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 0.694
 

Lower Limit 0.060
 

Upper Limit 5.794
 

Weeks to First Observed Tumor 105 105
 

VO
 

Pancreatic Islets: Islet-cell
 

Carcinoma or Adenoma (b) 6/50 (12) 2/49 (4)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 0.340
 

Lower Limit 0.035
 

Upper Limit 1.793
 

Weeks to First Observed Tumor 86 105
 

High
 

Dose
 

4/48 (8)
 

N.S.
 

1.389
 

0.248
 

9.031
 

105
 

2/49 (4)
 

N.S.
 

0.340
 

0.035
 

1.793
 

105
 
(continued) 

Topography:

Table El. Analyses of the Incidence of Primary Tumors in Male Rats 

Administered Dimethyl Terephthalate in the Diet (a) 

Matched 

 Morphology Control 

Low 

Dose 

High 

Dose 

Preputial Gland: Carcinoma, NOS (b) 6/50 (12) 6/49 (12) 3/49 (6) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.020 

0.293 

3.556 

0.510 

0.087 

2.243 

Weeks to First Observed Tumor 83 87 91 

ro

Preputial Gland: Carcinoma, NOS, 

 or Adenoma, NOS (b) 7/50 (14) 6/49 (12) 3/49 (6) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.875 

0.261 

2.820 

0.437 

0.077 

1.793 

Weeks to First Observed Tumor 83 87 91 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Dimethyl Terephthalate in the Diet (a)
 

(continued)
 

Topography: Morphology 

Matched 

Control 

Low 

Dose 

High 

Dose 

Testis: Interstitial-cell Tumor (b) 44/49 (90) 45/49 (92) 46/49 (94) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.023 

0.894 

1.155 

1.045 

0.917 

1.158 

Weeks to First Observed Tumor 74 87 48 

(a) Dosed groups received 2,500 or 5,000 ppm.
 

(b) Number of tumor-bearing animals/number of animals examined at site (percent).
 

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated.
 

Beneath the incidence of tumors in a dosed group is the probability level for the Fisher exact
 

test for the comparison of that dosed group with the matched-control group when P is less than
 

0.05; otherwise, not significant (N.S.) is indicated.
 

(d) A negative (N) indicates a lower incidence in a dosed group than in a control group.
 

(e) The probability level for departure from linear trend is given when P is less than 0.05 for
 

any comparison.
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control group.
 

(g) These tumors include squamous-cell papilloma, squamous-cell carcinoma, trichoepithelioma,
 

sebaceous adenoma, keratoacanthoma and hemangiopericytoma, NOS.
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Dimethyl Terephthalate in the Diet (a)
 

Matched Low High
 

Topography: Morphology Control Dose Dose
 

Lung: Alveolar/Bronchiolar Adenoma (b) 3/50 (6) 0/49 (0) 0/50 (0)
 

P Values (c,d) P = 0.038 (N) N.S. N.S.
 

Relative Risk (f) 0.000 0.000
 

Lower Limit 0.000 0.000
 

Upper Limit 1.696 1.663
 

Weeks to First Observed Tumor 106
 — —
 

Hematopoietic System: Lymphoma or
 

Leukemia (b) 8/50 (16) 7/49 (14) 3/50 (6)
 

P Values (c,d) N.S. N.S. N.S.
 

Relative Risk (f) 0.893 0.375
 

Lower Limit 0.298 0.067
 

Upper Limit 2.598 1.460
 

Weeks to First Observed Tumor 87 61 102
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Dimethyl Terephthalate in the Diet (a)
 

(continued) 

Topography: Morphology 

Matched 

Control 

Low 

Dose 

High 

Dose 

Pituitary: Chromophobe Adenoma (b) 21/46 (46) 16/46 (35) 19/48 (40) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.762 

0.434 

1.322 

0.867 

0.517 

1.455 

Weeks to First Observed Tumor 87 92 85 

Thyroid: C-cell Carcinoma (b) 0/50 (0) 2/49 (4) 3/50 (6)
 

P Values (c,d) N.S. N.S. N.S.
 

Relative Risk (f) Infinite Infinite
 

Lower Limit 0.302 0.601
 

Upper Limit Infinite Infinite
 

Weeks to First Observed Tumor 105 104
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Dimethyl Terephthalate in the Diet (a)
 

(continued) 

Topography: Morphology 

Matched 

Control 

Low 

Dose 

Thyroid: C-cell Carcinoma 

or Adenoma (b) 1/50 (2) 3/49 (6) 

P Values (c,d) N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

3.061 

0.256 

157.341 

Weeks to First Observed Tumor 106 105 

(—> 

° Mammary Gland: Fibroadenoma (b) 17/50 (34) 12/49 (24) 

P Values (c,d) P = 0.01.3 (N) N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.720 

0.353 

1.423 

Weeks to First Observed Tumor 106 97 

High
 

Dose
 

3/50 (6)
 

N.S.
 

3.000
 

0.251
 

154.270
 

104
 

7/50 (14)
 

P = 0.017 (N)
 

0.412
 

0.159
 

0.944
 

85
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats 

Administered Dimethyl Terephthalate in the Diet (a) 

(continued) 

Matched Low
 

Topography: Morphology Control Dose
 

Uterus: Endometrial Stromal Polyp (b) 10/48 (21) 10/48 (21)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 1.000
 

Lower Limit 0.412
 

Upper Limit 2.427
 

Weeks to First Observed Tumor 95 105
 

£J Uterus: Endometrial Stromal Polyp
 

<-*> or Sarcoma (b) 11/48 (23) 11/48 (23)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 1.000
 

Lower Limit 0.436
 

Upper Limit 2.293
 

Weeks to First Observed Tumor 95 102 

High
 

Dose
 

6/49 (12)
 

N.S.
 

0.588
 

0.190
 

1.638
 

105
 

8/49 (16)
 

N.S.
 

0.712
 

0.273
 

1.769
 

78 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Dimethyl Terephthalate in the Diet (a)
 

(continued)
 

(a) Dosed groups received 2,500 or 5,000 ppm.
 

(b) Number of tumor-bearing animaIs/number of animals examined at site (percent).
 

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated. Beneath
 

the incidence of tumors in a dosed group is the probability level for the Fisher exact test for
 

the comparison of that dosed group with the matched-control group when P is less than 0.05;
 

otherwise, not significant (N.S.) is indicated.
 

(d) A negative (N) indicates a lower incidence in a dosed group than in a control group.
 

(e) The probability level for departure from linear trend is given when P is less than 0.05 for
 

any comparison.
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control
 

group.
 
APPENDIX F
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS IN
 

MICE ADMINISTERED DIMETHYL TEREPHTHALATE IN THE DIET
 

105
 

Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Dimethyl Terephthalate in the Diet (a)
 

Matched Low
 

Topography: Morphology Control Dose
 

Integumentary System: Fibroma (b) 3/50 (6) 5/49 (10)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 1.701
 

Lower Limit 0.351
 

Upper Limit 10.426
 

Weeks to First Observed Tumor 86	 102
 

o	 Integumentary System: Fibrosarcoma (b) 11/50 (22) 8/49 (16)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 0.742
 

Lower Limit 0.283
 

Upper Limit 1.846
 

Weeks to First Observed Tumor 86 85
 

High
 

Dose
 

3/49 (6)
 

N.S.
 

1.020
 

0.143
 

7.273
 

105
 

9/49 (18)
 

N.S.
 

0.835
 

0.336
 

2.014
 

81
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice 

Administered Dimethyl Terephthalate in the Diet (a) 

(continued) 

Matched Low 

Topography: Morphology Control Dose 

Lung: Alveolar/Bronchiolar Carcinoma (b) 1/49 (2) 1/49 (2)
 

P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


M
 

0

 Lung: Alveolar/Bronchiolar
 

Carcinoma or Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

P = 0.023
 

 104
 

 1/49 (2)
 

P = 0.001
 

104
 

N.S.
 

1.000
 

0.013
 

76.918
 

105
 

8/49 (16)
 

P = 0.015
 

8.000
 

1.137
 

346.538
 

84
 

High
 

Dose
 

6/49 (12)
 

N.S.
 

6.000
 

0.769
 

269.767
 

105
 

13/49 (27)
 

P less
 

than 0.001
 

13.000
 

2.085
 

537.589
 

105
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Dimethyl Terephthalate in the Diet (a)
 

(continued)
 

Topography: Morphology


Hematopoietic System: Lymphoma or
 

Leukemia (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


All Sites: Hemangios arcoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 7/50 (14)
 

 N.S.
 

 77
 

 2/49 (4)
 

 N.S.
 

102
 

Low
 

Dose
 

1/49 (2)
 

P = 0.032 (N)
 

0.146
 

0.003
 

1.073
 

105
 

4/49 (8)
 

N.S.
 

2.000
 

0.302
 

21.298
 

81
 

High
 

Dose
 

4/49 (8)
 

N.S.
 

0.583
 

0.133
 

2.139
 

0/49 (0)
 

N.S.
 

0.000
 

0.000
 

3.379
 

102 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Dimethyl Terephthalate in the Diet (a)
 

(continued)
 

Topography: Morphology


All Sites: Hemangios arcotna
 

or Hemangioma (b)


P Values (c,d)


Departure from Linear Trend (e)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Liver: Hepatocellular Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 3/49 (6)
 

 N.S.
 

P = 0.028 (N)
 

 102
 

 17/49 (35)
 

 N.S.
 

93
 

Low
 

Dose
 

6/49 (12)
 

N.S.
 

2.000
 

0.455
 

11.748
 

81
 

13/49 (27)
 

N.S.
 

0.765
 

0.386
 

1.481
 

102
 

High
 

Dose
 

0/49 (0)
 

N.S.
 

0.000
 

0.000
 

1.662
 

—
 

15/49 (31)
 

N.S.
 

0.882
 

0.466
 

1.655
 

61
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Dimethyl Terephthalate in the Diet (a)
 

(continued)
 

Topography: Morphology 

Matched 

Control 

Low 

Dose 

High 

Dose 

Liver: Hepatocellular 

Carcinoma or Adenoma (b) 19/49 (39) 13/49 (27) 16/49 (33) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.684 

0.353 

1.288 

0.842 

0.464 

1.512 

Weeks to First Observed Tumor 93 102 61 

(a) Dosed groups received 2,500 or 5,000 ppm.
 

(b) Number of tumor-bearing animals/number of animals examined at site (percent).
 

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated.
 

Beneath the incidence of tumors in a dosed group is the probability level for the Fisher exact
 

test for the comparison of that dosed group with the matched-control group when P is less than
 

0.05; otherwise, not significant (N.S.) is indicated.
 

(d) A negative (N) indicates a lower incidence in a dosed group than in a control group.
 

(e) The probability level for departure from linear trend is given when P is less than 0.05 for
 

any comparison.
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control group.
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Dimethyl Terephthalate in the Diet (a)
 

Topography; Morphology
 

Lung: Alveolar/Bronchiolar Carcinoma
 

or Adenoma (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

M
 

10

 Hematopoietic System: Lymphoma (b)
 

P Values (c,d)
 

Departure from Linear Trend (e)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

4/48 (8)
 

N.S.
 

105
 

16/48 (33)
 

P = 0.014
 

P less than 0.001
 

87
 

Low
 

Dose
 

5/50 (10)
 

N.S.
 

1.200
 

0.275
 

5.712
 

105
 

5/50 (10)
 

P = 0.005 (N)
 

0.300
 

0.094
 

0.780
 

87
 

High
 

Dose
 

0/49 (0)
 

N.S.
 

0.000
 

0.000
 

1.056
 

—
 

27/49 (53)
 

P = 0.025
 

1.653
 

1.000
 

2.782
 

75 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Dimethyl Terephthalate in the Diet (a)
 

(continued)
 

Topography: Morphology


Liver: Hepatoce llular Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Pituitary: Chromophobe Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 5/48 (10)
 

P = 0.010 (N)
 

 98
 

 3/46 (7)
 

 N.S.
 

105
 

Low
 

Dose
 

1/50 (2)
 

N.S.
 

0.192
 

0.004
 

1.630
 

105
 

1/44 (2)
 

N.S.
 

0.348
 

0.007
 

4.142
 

105
 

High
 

Dose
 

0/49 (0)
 

P = 0.027 (N)
 

0.000
 

0.000
 

0.776
 

—
 

1/49 (2)
 

N.S.
 

0.313
 

0.006
 

3.733
 

89
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Dimethyl Terephthalate in the Diet (a)
 

(continued)
 

Matched Low High 

Topography: Morphology Control Dose Dose 

Ovary: Papillary Cystadenoma, NOS (b) 0/47 (0) 3/50 (6) 0/48 (0) 

P Values (c,d) N.S. N.S. — 

Departure from Linear Trend (e) P = 0.016 (N) 

Relative Risk (f) Infinite — Lower Limit 0.566 

Upper Limit Infinite — 

— 

Weeks to First Observed Tumor — 105 — 

(a) Dosed groups received 2,500 or 5,000 ppm.
 

(b) Number of tumor-bearing animals/number of animals examined at site (percent).
 

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated.
 

Beneath the incidence of tumors in a dosed group is the probability level for the Fisher exact
 

test for the comparison of that dosed group with the matched-control group when P is less than
 

0.05; otherwise, not significant (N.S.) is indicated.
 

(d) A negative (N) indicates a lower incidence in a dosed group than in a control group.
 

(e) The probability level for departure from linear trend is given when P is less than 0.05 for
 

any comparison.
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control group.
 
APPENDIX G
 

ANALYSIS OF DOSED DIETS FOR
 

CONCENTRATIONS OF DIMETHYL TEREPHTHALATE
 

115
 

APPENDIX G
 

Analysis of Dosed Diets for
 

Concentrations of Dimethyl Terephthalate
 

Duplicate 4-g samples of dosed diets were agitated with 10 ml of
 

benzene and aliquots of the supernatant were analyzed by gas
 

chromatography using a flame ionization detector. Spiked samples
 

and a feed blank were worked up simultaneously with the dosed
 

feed samples. All assays of dosed feed samples were corrected
 

for recovery losses. These analyses were performed at Hazleton,
 

and the results are tabulated below.
 

Theoretical Sample Coefficient of 

Concentrations No. of Analytical Variation Range 

(ppm) Samples Mean (ppm) (%) (ppm) 

2,500 7 2391 5.38 2120-2513 

5,000 6 4912 5.72 4482-5297 

117 

Review of the Bioassay of Dimethyl Terephthalate* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

December 13, 1978
 

The Clearinghouse on Environmental Carcinogens was established
 

in May, 1976, in compliance with DHEW Committee Regulations and the
 

Provisions of the Federal Advisory Committee Act. The purpose of
 

the Clearinghouse is to advise the Director of the National Cancer
 

Institute on the Institute's bioassay program to identify and evaluate
 

chemical carcinogens in the environment to which humans may be exposed.
 

The members of the Clearinghouse have been drawn from academia, industry,
 

organized labor, public interest groups, and State health officials.
 

Members have been selected on the basis of their experience in carcinogenesis or related fields and, collectively, provide expertise in
 

chemistry, biochemistry, biostatistics, toxicology, pathology, and
 

epidemiology. Representatives of various Governmental agencies participate as ad hoc members. The Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse is charged with the responsibility of providing
 

a peer review of reports prepared on NCI-sponsored bioassays of chemicals
 

studied for carcinogenicity. It is in this context that the below critique is given on the bioassay of Dimethyl Terephthalate.
 

The primary reviewer for the report on the bioassay of Dimethyl
 

Terephthalate said that the compound was not carcinogenic in either
 

sex of treated rats or in treated female mice. In treated male mice,
 

Dimethyl Terephthalate induced a statistically significant incidence
 

of lung tumors. After a brief description of the experimental
 

design, the reviewer said that the dose levels tested and survival
 

were adequate. Based on the results of the study, he concluded that
 

Dimethyl Terephthalate could be considered to pose "some carcinogenic
 

risk" to human beings.
 

The secondary reviewer also agreed'with the conclusions presented
 

in the report. One Subgroup member questioned the significance of the
 

lung tumors, since an elevated incidence was observed in only one sex.
 

It was moved that the report on the bioassay of Dimethyl
 

Terephthalate be accepted as written. The motion was seconded and
 

approved without objection.
 

Clearinghouse Members Present:
 

Arnold L. Brown (Chairman), University of Wisconsin Medical School
 

Joseph Highland, Environmental Defense Fund
 

William Lijinsky, Frederick Cancer Research Center
 

119
 
Henry Pitot, University of Wisconsin Medical Center
 

Verne A. Ray, Pfizer Medical Research Laboratory
 

Verald K. Rowe, Dow Chemical USA
 

Michael Shimkin, University of California at San Diego
 

Louise Strong, University of Texas Health Sciences Center
 

Kenneth Wilcox, Michigan State Health Department
 

Subsequent to this review, changes may have been made in the
 

bioassay report either as a result of the review or other reasons.
 

Thus, certain comments and criticisms reflected in the review may
 

no longer be appropriate.
 

120
 

NIH Publication No. 79-1376