1979 

National Cancer Institute 

CARCiNOGENESIS 

Technical Report Series 

No. 138 

BIOASSAY OF 

SULFISOXAZOLE 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 127-69-5 

NCI-CG-TR-138 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

SULFISOXAZOLE
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20014
 

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

Public Health Service
 

National Institutes of Health
 

DREW Publication No. (NIH) 79-1393
 
ii

 
BIOASSAY OF
 

SULFISOXAZOLE
 

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 bioasay of
 

sulfisoxazole 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. Negative results, in which the test animals
 

do not have a greater incidence of cancer than control animals,
 

do not necessarily mean that the test chemical is not a
 

carcinogen, inasmuch as the experiments are conducted under a
 

limited set of circumstances. Positive results demonstrate that
 

the test chemical is carcinogenic for animals under the
 

conditions of the test and indicate 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 sulfisoxazole was conducted by
 

Hazleton Laboratories America, Inc., Vienna, Virginia, initially
 

under direct contract to NCI and currently under a subcontract to
 

Tracer Jitco, Inc., Rockville, Maryland, prime contractor for the
 

NCI Carcinogenesis Testing Program.
 

The NCI project officers who were responsible for selecting the
 

protocols used in this bioassay were Drs. N. P. Page (1,2) and C.
 

Cueto (1). The principal investigators were Drs. M. B. Powers
 

(3) and R. W. Voelker (3). Ms. K. J. Petrovics (3) was
 

responsible for data management, and Mr. G. Najarian (3) for
 

animal care. Histopathologic examinations were performed by Drs.
 

B. W. Ulland (3) and D. A. Banas (3) 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 (4). Statistical analyses were
 

ill
 
performed by Dr. J. R. Joiner (5) and Ms. P. L. Yong (5), using
 

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 t4st chemical were analyzed at Hazleton
 

Laboratories by Dr. C. L. Guyton (3) and Mr. E. Missaghi (3).
 

The results of these analyses were reviewed by Dr. C. W. Jameson
 

(5).
 

This report was prepared at Tracer Jitco (5) in collaboration
 

with Hazleton Laboratories and NCI. Those responsible for the
 

report at Tracor Jitco were Dr. L. A. Campbell, 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, Mr. W. D. Reichardt, and Ms. L. A. Waitz,
 

bioscience writers; and Dr. E. W. Gunberg, technical editor,
 

assisted by Ms. Y. E. Presley and Ms. P. J. Graboske.
 

The following scientists at NCI (1) 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. Harm, Dr. William V. Hartwell, Dr. Morton H. Levitt,
 

Dr. Harry A. Milman, Dr. Thomas W. Orme, Dr. Sherman F. Stinson,
 

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

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

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

(2) Now with Office of Toxic Substances - TS 788, the
 

Environmental Protection Agency, 401 M Street,
 

S.W., Washington, D.C.
 

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

Vienna, Virginia.
 

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

Rockville, Maryland.
 

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

Maryland.
 

iv
 
(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.
 
vi

 
SUMMARY
 

A bioassay of sulfisoxazole for possible carcinogenicity was
 

conducted by administering the chemical by gavage to Fischer 344
 

rats and B6C3F1 mice.
 

Groups of 50 rats of each sex and 50 mice of each sex were
 

administered sulfisoxazole suspended in aqueous 0.5%
 

carboxymethyl cellulose 7 days per week at one of two doses,
 

either 100 or 400 mg/kg body weight for the rats and either 500
 

or 2,000 mg/kg for the mice. Vehicle controls consisted of
 

groups of 50 rats of each sex and 50 mice of each sex that were
 

administered only the aqueous 0.5% carboxymethyl cellulose.
 

Untreated controls consisted of groups of 50 rats of each sex and
 

50 mice of each sex. The dosed groups of the rats and mice were
 

administered the chemical by gavage for 103 weeks, then observed
 

for 1 to 3 additional weeks; the vehicle-control groups were
 

similarly administered 0.5% carboxymethyl cellulose alone. All
 

surviving rats and mice were killed at weeks 104 to 106.
 

Mean body weights of high-dose male rats and female mice were
 

slightly lower than those of corresponding vehicle controls
 

during the last 40 to 50 weeks of the bioassay; mean body weights
 

of dosed female rats and male mice were unaffected. Survival
 

rates were unaffected by the test chemical, and adequate numbers
 

of animals were at risk for the development of late-appear ing
 

tumors.
 

No tumors occurred in the dosed groups of rats or mice of either
 

sex at incidences that were significantly higher than those of
 

the vehicle-control groups.
 

It is concluded that under the conditions of this bioassay,
 

sulfisoxazole was not carcinogenic for either Fischer 344 rats or
 

B6C3F1 mice.
 

vii
 
viii

 
TABLE OF CONTENTS
 

I. Introduction 1
 

II. Materials and Methods 5
 

A. Chemical 5
 

B. Dosage Preparation 6
 

C. Animals 7
 

D. Animal Maintenance 7
 

E. Subchronic Studies 10
 

F. Chronic Studies 12
 

G. Clinical and Pathologic Examinations 12
 

H. Data Recording and Statistical Analyses 16
 

III. Results - Rats 23
 

A. Body Weights and Clinical Signs (Rats) 23
 

B. Survival (Rats) 23
 

C. Pathology (Rats) 26
 

D. Statistical Analyses of Results (Rats) 27
 

IV. Results - Mice 29
 

A. Body Weights and Clinical Signs (Mice) 29
 

B. Survival (Mice) 29
 

C. Pathology (Mice) 33
 

D. Statistical Analyses of Results (Mice) 34
 

V. Discussion 37
 

VI. Bibliography 41
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in Rats
 

Administered Sulfisoxazole by Gavage 45
 

Table Al Summary of the Incidence of Neoplasms in Male
 

Rats Administered Sulfisoxazole by Gavage .... 47
 

Table A2 Summary of the Incidence of Neoplasms in Female
 

Rats Administered Sulfisoxazole by Gavage .... 52
 

ix
 
Appendix B Summary of the Incidence of Neoplasms in Mice 

Administered Sulfisoxazole by Gavage 57 

Table Bl Summary of the Incidence of Neoplasms in Male 

Mice Administered Sulfisoxazole by Gavage .... 59 

Table B2 Summary of the Incidence of Neoplasms in Female 

Mice Administered Sulfisoxazole by Gavage .... 63 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Administered Sulfisoxazole 

by Gavage 67 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Administered Sulfisoxazole 

by Gavage 69 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Administered 

Sulfisoxazole by Gavage 75 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Administered Sulfisoxazole 

by Gavage 81 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Administered 

Sulfisoxazole by Gavage 83 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Administered 

Sulfisoxazole by Gavage 88 

Appendix E Analyses of the Incidence of Primary Tumors in 

Rats Administered Sulfisoxazole by Gavage .... 93 

Table El Analyses of the Incidence of Primary Tumors in 

Male Rats Administered Sulfisoxazole 

by Gavage 95 

Table E2 Analyses of the Incidence of Primary Tumors in 

Female Rats Administered Sulfisoxazole 

by Gavage 100 
Appendix F Analyses of the Incidence of Primary Tumors in 

Mice Administered Sulfisoxazole by Gavage .... 105 

Table Fl Analyses of the Incidence of Primary Tumors in 

Male Mice Administered Sulfisoxazole 

by Gavage 107 

Table F2 Analyses of the Incidence of Primary Tumors in 

Female Mice Administered Sulfisoxazole 

by Gavage 112 

TABLES 

Table 1 Sulfisoxazole Subchronic Oral Gavage Studies 

in Rats and Mice 11 

Table 2 Chronic Gavage Studies with Sulfisoxazole in 

Rats 13 

Table 3 Chronic Gavage Studies with Sulfisoxazole in 

Mice 14 

FIGURES 

Figure 1 Growth Curves for Rats Administered 

Sulfisoxazole by Gavage 24 

Figure 2 Survival Curves for Rats Administered 

Sulfisoxazole by Gavage 25 

Figure 3 Growth Curves for Mice Administered 

Sulfisoxazole by Gavage 30 

Figure 4 Survival Curves for Mice Administered 

Sulfisoxazole by Gavage 31 

xi
 
xii

 
I. INTRODUCTION
 

N 

CH3 CH3 

Sulfisoxazole 

Sulfisoxazole (CAS 127-69-5; NCI C50022) is an antimicrobial drug 

that is a derivative of sulfanilamide; the chemical name is N ­

(3,4-dimethyl-5-isoxazolyl)sulfanilamide (Koralkovas and Burckhalter, 1976). The sulfanilamide part of the molecule is a 

structural analog and an effective antimetabolite of p-aminobenzoic-acid (PABA), one of the components of folic acid. The incorporation of sulfanilamides into folic acid precursors inhibits 

the synthesis of folic acid in susceptible microorganisms and 

hence, by indirectly inhibiting the formylation of S'-phosphoribosyl-4-carboxamide-5-aminoimidazole, prevents the biosynthesis 

of purine (Lehninger, 1975). Susceptible microorganisms are those 

that must synthesize their own folic acid; thus, bacteria that do 
not require folic acid or that can utilize preformed folic acid
 

are not affected (Weinstein, 1975). While some toxic effects may
 

be produced by sulfanilamides in mammals, these are not due to
 

folic acid deficiency, since mammalian cells do not synthesize
 

folic acid and depend on the diet as a source of this material.
 

Sulfisoxazole was patented in 1947 (Stecher, 1968) and was first
 

used clinically in 1949 (Hay ton et al., 1976). It is a
 

broad-spectrum antibacterial agent, effective against both
 

gram-positive and gram-negative organisms (Weinstein, 1975). The
 

foremost clinical use of this drug is in the treatment of urinary
 

tract infections such as cystitis, pyelitis, and pyelonephritis
 

(Stanford Research Institute, 1973). Other uses include the
 

treatment of trachoma, inclusion conjunctivitis, nocardiosis,
 

chancroid, certain types of meningococcal meningitis, and otitis
 

media as well as adjunctive therapy for malaria (American Medical
 

Association, 1971). The normal adult dose is 1 gram, given
 

orally every 4 to 6 hours. The parenteral dose is 100 mg/kg/day,
 

given in divided doses (Weinstein, 1975).
 

Sulfisoxazole is available in 500 mg tablets; as acetyl
 

sulfisoxazole in a pediatric suspension; as the diolamine salt
 

for injection; as the diolamine salt in a 4% solution and 4%
 

ointment for eye, ear, and nose applications; and as a 10%
 
vaginal cream. Sulfisoxazole is also marketed in combination
 

with phenazopyridine, the latter providing pain relief from
 

urinary tract infections (Physician's Desk Reference, 1977;
 

Kastrup and Schwach, 1977; Weinstein, 1975).
 

Although the use of sulfonamide drugs has declined in the past
 

few years due to the emergence of drug-resistant strains of
 

bacteria and the development of newer antimicrobial drugs with
 

fewer side effects (American Medical Association, 1971;
 

Weinstein, 1975), these compounds are still widely prescribed on
 

a chronic basis for the treatment of recurrent urinary tract
 

infections and certain other infectious diseases (American
 

Medical Association, 1971). For 1977, approximately 990,000 new
 

prescriptions for Sulfisoxazole tablets, suspensions, or syrups
 

from a single manufacturer were written (National Disease and
 

Therapeutic Index, 1977). Sulfisoxazole was selected for study
 

in the Carcinogenenesis Testing Program because of its extensive
 

clinical use in humans.
 

II. MATERIALS AND METHODS
 

A. Chemical
 

Sulfisoxazole was obtained as the USP-grade chemical in two
 

different lots from Hoffmann-LaRoche, Inc., Nutley, New Jersey.
 

Lot No. 414034 was used for the subchronic study and Lot No.
 

466094 for the chronic study. USP specifications require 99 to
 

101% purity on a dry basis with a melting range of 194 to 199°C
 

(USP, 1975).
 

The identity and purity of both lots of Sulfisoxazole were
 

confirmed in analysis at Midwest Research Institute. The melting
 

range for Lot No. 414034 was 196 to 199°C and for Lot No.
 

466094, 194 to 199°C, with decomposition. Titration of the
 

suIfamide acid group with tetrabutyl ammonium hydroxide indicated
 

a purity of 98.0 + 0.3% for Lot No. 414034 and 99.3 + 0.6% for
 

Lot No. 466094. High-pressure liquid chromatography showed one
 

homogeneous peak for both lots. Elemental analyses (C, H, N, S)
 

for both lots were correct for CjjHigN-O-S, the molecular
 

formula of Sulfisoxazole. Nuclear magnetic resonance and
 

infrared spectra were consistent with spectra for Sulfisoxazole
 

given in the literature (Sadtler Standard Spectra, Sadtler
 
Research Laboratories, Philadelphia, Pennsylvania; Turczan and
 

Medwick, 1972).
 

The bulk chemical was stored at room temperature.
 

B. Dosage Preparation
 

Sulfisoxazole was suspended in an aqueous 0.5% carboxymethyl
 

cellulose (Sigma, St. Louis, Mo.) solution for administration
 

during these studies. Suspensions were prepared at desired
 

concentrations once per week and stored at 4 C for up to 1
 

week. To ensure the uniformity of the suspension, it was stirred
 

continuously during the dosing time using a magnetic stirring bar.
 

Due to problems encountered in the analytical method that was
 

used and to the 1- to 5-month lag period between preparation and
 

analysis, analyses of the suspensions varied considerably (i.e.,
 

greater than + 10%) from the concentrations established for use
 

in the bioassay during the first year of the study. A
 

modification in the analytical procedures and prompt performance
 

of the analyses resulted in an improvement in the recoveries
 

obtained from subsequent samples, which were shown to be within a
 

+ 10% tolerance limit.
 
C. Animals
 

Fischer 344 rats and B6C3F1 mice were obtained through a National
 

Cancer Institute contract from the Frederick Cancer Research
 

Center Animal Farm, Frederick, Maryland, through contracts with
 

the Division of Cancer Treatment, NCI. They were received at the
 

test lab at 4 weeks of age, and housed within the test
 

facilities. Animals determined to be free from observable
 

disease were assigned to the various dosed and control groups
 

based on initial individual body weights so that a homogeneous
 

distribution of mean weights and weight ranges was obtained
 

between groups. Rats were approximately 5 weeks of age and mice
 

were approximately 7 weeks of age when placed on study.
 

D. Animal Maintenance
 

All animals were housed in rooms maintained at a temperature of 

20 to 24°C and a relative humidity of 45 to 55%. Incoming air 

was filtered through 2-inch-thick disposable fiberglass filters 

at a rate that allowed 12 changes of room air per hour. 

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

The rats and mice were housed in polycarbonate cages covered with 
stainless steel cage lids and nonwoven fiber filter bonnets
 

(Filtek, Appleton, Wis.). The rats were initially housed five
 

per cage; at week 52, however, the males were divided into groups
 

of two or three per cage. The mice were housed five per cage
 

throughout the study.
 

All cages were furnished with heat-treated hardwood chip bedding
 

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

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

were provided ad_ libitum. Feed hoppers and water bottles were
 

refilled twice per week.
 

Cages and water bottles 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; a cage and
 

rack washer was used for the feed hoppers, cages, and racks. The
 

detergent used was Super Soilax®. When racks were washed, 

clean racks containing cages of animals were randomly 

repositioned in the rooms. 

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

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

Rats administered sulfisoxazole by gavage were maintained in the
 
same room as rats being administered the following chemicals:
 

Feed Studies
 

(CAS 119-53-9) benzoin 

(CAS 120-61-6) dimethyl terephthalate 

(CAS 89-78-1) dl-menthol 

(CAS 13463-67-7) titanium dioxide
 

Gavage Studies
 

(CAS 108-60-1) bischloroisopropyl ether
 

(CAS 7488-56-4) selenium disulfide
 

Drinking Water Studies
 

(CAS 108-95-2) phenol
 

At week 48, the rats fed titanium dioxide, dl-menthol, or benzoin
 

were moved to a separate room for the remainder of the bioassay.
 

Mice administered sulfisoxazole by gavage were maintained in the
 

same room as mice being administered the following chemicals:
 

Feed Studies
 

(CAS 119-53-9) benzoin
 

(CAS 120-61-6) dimethyl terephthalate
 

(CAS 89-78-1) dl-menthol
 

(CAS 13463-67-7) titanium dioxide
 

Gavage Studies
 

(CAS 108-60-1) bischloroisopropyl ether 

(CAS 7488-56-4) selenium disulfide 

Drinking Water Studies
 

(CAS 108-95-2) phenol
 
E. Subchronic Studies
 

Subchronic oral gavage studies were conducted to estimate the
 

maximum tolerated doses (MTD's) of sulfisoxazole, on the basis of
 

which two concentrations (hereinafter referred to as "low" and
 

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

studies. Groups of ten males and ten females of each species
 

were administered sulfisoxazole by gastric intubation 7 days per
 

week. Ten animals of each sex and species received only the 0.5%
 

aqueous carboxymethyl cellulose solution. Animals were observed
 

daily for deaths and weighed once per week. Table 1 shows the
 

number of animals in each dosed group that survived during the
 

course of administration and the week on study when the last
 

death occurred. The table also shows the mean body weights of
 

the dosed animals at week 13, expressed as percentages of mean
 

body weights of controls.
 

After 13 weeks of administration of the test chemical, the
 

animals were observed for 1 additional week and then killed and
 

necropsied. The footnotes to table 1 indicate the number of
 

animals having clinical signs and the degree of the finding.
 

Based on these data, the doses selected for the chronic studies
 

10
 
Table 1. Sulfisoxazole Subchronic Oral Gavage Studies
 

in Rats and Mice
 

Male Female
 

Week on Week on
 

Study Mean Weight Study Mean Weight
 

Dose when Last at week 13 when Last at Week 13
 

(mg/kg/ Surviv- Animal as % of Surviv- Animal as % of
 

day) al(a) Died Control al(a) Died Control
 

RATS
 

100 5/5 103 5/5 100
 

215 5/5 102 5/5 100
 

464 5/5 97 5/5 99
 

l,000(b) 5/5 94 5/5 102
 

2,160(c) 1/5 13 91 5/5 98
 

MICE(d)
 

100 5/5 104 5/5 104
 

215 5/5 104 5/5 104
 

464 5/5 108 5/5 100
 

1,000 5/5 104 5/5 100
 

2,160 3/5 3 104 5/5 104
 

(a) Numbers surviving/number in group.
 

(b) Two males had slight interstitial nephritis.
 

(c) Two males had severe interstitial nephritis; eight males and four
 

females had tubular nephrosis.
 

(d) No dose-related histopathologic findings were reported for the mice.
 

11
 
were 100 and 400 rag/kg for the rats and 500 and 2,000 mg/kg for
 

the mice.
 

F. Chronic Studies
 

The test groups, doses administered, and durations of the chronic
 

feeding studies are shown in tables 2 and 3.
 

G. Clinical and Pathologic Examinations
 

All animals were observed twice per day for deaths. Clinical
 

signs and the presence of palpable masses were recorded every
 

week. Mean body weights were recorded every 2 weeks for the
 

first 12 weeks and monthly thereafter.
 

Animals that were moribund and those that survived to the
 

termination of the study were killed by exsanguination under
 

sodium pentobarbital anesthesia (Diabutal®, Diamond
 

Laboratories, Inc., Des Moines, Iowa). The Diabutal ,
 

containing 60 mg/ml sodium pentobarbital, was injected
 

intraperitoneally at a volume of 0.3 to 0.5 ml for the rats and
 

0.03 to 0.05 ml for the mice.
 

12
 
Table 2. Chronic Gavage Studies with
 

Sulfisoxazole in Rats
 

Sex and Initial Sulf isoxazole Time on Study 

Test No. of Dose (b) Dosed Observed 

Group Animals(a) (mg/kg) (weeks) (weeks) 

Male 

Untreated-Contro 1 50 0 106-107 

Vehicle-Control (c) 50 0 103 3 

Low-Dose 50 100 103 3 

High-Dose 50 400 103 2 

Female
 

Untreated-Contro 1 50 0 106-107
 

Vehicle-Control(c) 50 0 103 3
 

Low-Dose 50 100 103 3
 

High-Dose 50 400 103 3
 

(a) Rats were approximately 5 weeks of age when placed on study.
 

(b) Dosed rats were administered a suspension of sulfisoxazole in
 

0.5% aqueous carboxymethyl cellulose by gavage 7 days per
 

week. A volume of 1 ml/kg body weight was administered,
 

based on the group mean weight and adjusted at weighing
 

periods.
 

(c) Vehicle controls received a volume of the 0.5% carboxymethyl
 

cellulose solution equal to the highest volumetric dose of
 

test solution given.
 

13
 
Table 3. Chronic Gavage Studies with
 

Sulfisoxazole in Mice
 

Sex and 

Test 

Group 

Initial 

No. of 

Animals(a) 

Sulf isoxazole 

Dose (b) 

(mg/kg) 

Time 

Dosed 

(weeks) 

on Study 

Observed 

(weeks) 

Male 

Untreated-Contro 1 50 0 104 

Vehicle-Control(c) 50 0 103 1 

Low-Dose 50 500 103 1 

High-Dose 50 2,000 103 1-2 

Female
 

Untreated-Contro 1 50 0 104
 

Vehic le-Control(c )50 0 103 1
 

Low-Dose 50 500 103 2
 

High-Dose 50 2,000 103 2
 

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

(b) Dosed mice were administered a suspension of sulfisoxazole in
 

0.5% aqueous carboxymethyl cellulose by gavage 7 days per
 

week. A volume of 10 ml/kg body weight was administered,
 

based on the group mean weight and adjusted at weighing
 

periods.
 

(c) Vehicle controls received a volume of the 0.5% carboxymethyl
 

cellulose solution equal to the highest volumetric dose of
 

test solution given. Vehicle-control groups were started
 

approximately 1 week before other groups.
 

14
 
The pathologic evaluation consisted of gross and microscopic
 

examination of major tissues, major organs, and all gross lesions
 

from killed animals and from animals found dead. The different
 

tissues were preserved in 10% buffered formalin, embedded in
 

paraffin, sectioned, and stained with hematoxylin and eosin. The
 

following tissues were examined microscopically: skin, lungs and
 

bronchi, trachea, bone and bone marrow, spleen, lymph nodes,
 

heart, salivary gland, liver, gallbladder (mice), pancreas,
 

stomach, small intestine, large intestine, kidney, urinary
 

bladder, pituitary, adrenal, thyroid, parathyroid, mammary gland,
 

prostate or uterus, testis or ovary, and brain. Occasionally,
 

additional tissues were also examined microscopically. Special
 

staining techniques were utilized when indicated for more
 

definitive diagnosis.
 

A few tissues from some animals were not examined, particularly
 

from those animals that may have died early, been missing, or
 

been in advanced states of cannibalization or autolysis. 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.
 

15
 
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 

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
 

16
 
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.
 

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
 

17
 
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
 

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
 

18
 
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.
 

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 Pt/p where p is the true
 

19
 
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
 

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
 

20
 
the Induction of tumors by the test chemical, which could not be
 

detected under the conditions of this test.
 

21
 
22

 
III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

Mean body weights of the dosed male rats were slightly lower than
 

those of corresponding vehicle controls during the last 40 weeks
 

of the bioassay (figure 1); mean body weights of the females were
 

unaffected. Other clinical signs occurred at comparable frequencies in dosed and control groups and included hunched or thin
 

appearance, body sores, alopecia, urine stains, respiratory
 

involvements, and various lesions of the eyes. The eye lesions
 

were noted in all groups at increasing frequency from week 10 to
 

termination of the study.
 

B. Survival (Rats)
 

The Kaplan and Meier curves estimating the probabilities of 

survival for male and female rats administered sulfisoxazole by 

gavage at the doses of this bioassay, together with those of the 

vehicle controls, are shown in figure 2. Two control groups, a 

vehicle-control and an untreated-control, were used in this 

study. However, in the statistical analysis, only the 

23 
8 s o 

fi S fi A § 

D 

O 

(9 a ui 

3 

o 

o m 

z 

UI 

5 

MALE RATS 

A D VEHICLE CONTROL 

100H 

O LOW DOSE 

A HIGH DOSE 

40 80 60 70 

TIME ON STUDY (WEEKS) 

I 300­

< 

2 

FEMALE RATS 

D VEHICLE CONTROL 

O LOW DOSE 

A HIGH DOSE 

70 

TIME ON STUDY (WEEKS) 

Figure 1. Growth Curves for Rats Administered Sulfisoxazole by Gavage 

24 
PROBABILITY OF SURVIVAL PROBABILITY OF SURVIVA

p p a p o o o p p 

§ g S g 

> O D > o

 

< 5 

I I i 1

P ? m n> 8 S 

5 

s' g 15 S <» 

o 

S H 

QJ m 

|

S 

» s 

i 6 

v> £ 2 a. 

o— 
vehicle-control group is used, because the test conditions of the 

vehicle-control group more closely resemble those of the dosed 

groups. The result of the Tarone test for dose-related trend in 

mortality is not significant in either sex. 

In male rats, 36/50 (72%) of the high-dose group, 32/50 (64%) of 

the low-dose group, and 38/50 (76%) of the vehicle-control group 

lived to the end of the bioassay. In females, 40/50 (80%) of the 

high-dose group, 43/50 (86%) of the low-dose group, and 35/50 

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

bioassay. 

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 neoplastic and nonneoplastic lesions were observed
 

in this study. These were of a type, incidence, and distribution
 

26
 
commonly observed in aged Fischer 344 rats and are therefore
 

considered spontaneous and not related to compound administration.
 

Based on the pathologic examination, sulfisoxazole was neither
 

carcinogenic nor toxic to Fischer 344 rats under the conditions
 

of this bioassay.
 

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. Two control groups, a 

vehicle-control and an untreated-control, were used in this 

study. However, in the statistical analysis, only the 

vehicle-control group is used, because the test conditions of the 

vehicle-control group more closely resemble those of the dosed 

groups. 

In male rats, the result of the Cochran-Armitage test for 

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

Fisher exact test comparing the incidence of tumors in the 

27 
vehicle-control group with that in each dosed group are not 

significant. 

In female rats, the results of the Cochran-Armitage test for the 

incidence of raonocytic leukemia and the combined incidence of 

malignant lymphocytic lymphoma and monocytic leukemia of the 

hematopoietic system are significant (P = 0.016 and P = 0.033, 

respectively), but those of the Fisher exact test are not. There 

is no other incidence of tumors in female rats with significant 

statistical test results. 

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

in the tables, the value of one is included; this indicates the 

absence of significant positive results. It should also be noted 

that each of the intervals has an upper limit greater than one, 

indicating the theoretical possibility of the induction of tumors 

by sulfisoxazole, which could not be detected under the 

conditions of this test. 

28 
IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

Mean body weights of the high-dose female mice were slightly
 

lower than those of corresponding vehicle controls during the
 

last 50 weeks of the bioassay (figure 3); mean body weights of
 

the males were unaffected. Other clinical signs occurred at
 

comparable rates for dosed and control groups and included 

hunched or thin appearance, body sores, alopecia, genital 

irritation and swelling, and distended abdomen. 

B. Survival (Mice)
 

The Kaplan and Meier curves estimating the probabilities of 

survival for male and female mice administered sulfisoxazole by 

gavage at the doses of this bioassay, together with those of the 

vehicle controls, are shown in figure 4. Two control groups, a 

vehicle-control and an untreated-control, were used in this 

study. However, in the statistical analysis, only the 

vehicle-control group is used, because the test conditions of the 

vehicle-control group more closely resemble those of the dosed 

29 
o o g O

a

 A

 a 

D n n 8

A

 ° CD° 

A 

X 30­

(9 

u! 

S no Q 

O 

<a 

Z 

111 

5 

MALE MICE 

D VEHICLE CONTROL 

O LOW DOSE 

A HIGH DOSE 

40 60 60 70 100 

TIME ON STUDY (WEEKS) 

n a B rfi OO Qu

 QO 

u 

a a 

a 

o a 

iu 

S "\r & 

,A 

g o 8 

FEMALE MICE 

Q VEHICLE CONTROL 

O LOW DOSE 

A HIGH DOSE 

10 20 30 40 50 70 80 90 100 110 

TIME ON STUDY (WEEKS) 

Figure 3. Growth Curves for Mice Administered Sulfisoxazole by Gavage 

30 
1.00 

0.90 

45 60 75 

TIME ON STUDY (WEEKS) 

::::>A^_ 6--­

< 

k 

> 

0) 

u. 

o ABILITY IB

 

O 

C 

FEMALE MIC E 

0.20­ D VEHICLE CONTROL 

O LOW DOSE 

0.10­ A HIGH DOSE 

000­

TIME ON STUDY (WEEKS) 

Figure 4. Survival Curves for Mice Administered Sulfisoxazole by Gavage 

31 
groups. In each sex of mice, the vehicle-control group was
 

started on study 1 week earlier than the dosed groups; however,
 

the Tar one test for dose-related trend in mortality is applied as
 

if the three groups were started on study at the same time. The
 

Cox test is also used to compare the survival of the
 

vehicle-control group with that of each dosed group. The result
 

of the Tarone test is not significant in either sex. The results
 

of the Cox test comparing the survival of the vehicle-control
 

group with that of each dosed group are also not significant in
 

either sex.
 

In male mice, 34/50 (68%) of the high-dose group, 36/50 (72%) of
 

the low-dose group, and 30/50 (60%) of the vehicle-control group
 

lived to the end of the bioassay. In females, 42/50 (84%) of the
 

high-dose group, 40/50 (80%) of the low-dose group, and 43/50
 

(86%) of the vehicle-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.
 

32
 
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.
 

There was a high incidence of primary liver tumors in dosed male
 

mice. It was also high in both untreated- and vehicle-control
 

males. This finding is considered to be unrelated to compound
 

administration.
 

A moderate number of hematopoietic neoplasms and a low incidence
 

of other neoplasms were observed in both control and dosed groups
 

of mice. These neoplasms were of the usual number and type
 

observed in B6C3F1 mice of this age.
 

Other degenerative, proliferative, and inflammatory lesions
 

observed were also of the usual number and kind observed in aged
 

B6C3F1 mice, and their incidences in control and dosed groups of
 

mice were comparable.
 

Based on the pathologic examination, sulfisoxazole at the dosage
 

used was neither carcinogenic nor toxic to B6C3F1 mice under the
 

conditions of this bioassay.
 

33
 
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 in one group and at an incidence of at least 5% 

in one or more than one group. Two control groups, a 

vehicle-control and an untreated-control, were used in this 

study. However, in the statistical analysis, only the 

vehicle-control group is used, because the test conditions of the 

vehicle-control group more closely resemble those of the dosed 

groups. In each sex of mice, the vehicle-control group was 

started on study 1 week earlier than the dosed groups; however, 

the Cochran-Armitage test for dose-related trend in the incidence 

of tumors is applied as if the three groups were started on study 

at the same time. 

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

positive dose-related trend in the incidence of tumors and the 

results of the Fisher exact test are not significant. In female 

mice, the Fisher exact test comparing the incidence of 

hepatocellular carcinomas in the low-dose and vehicle-control 

groups indicates a P value of 0.030, which is above the 0.025 

level for significance when the Bonferroni inequality criterion 

is used for multiple comparison. The incidence of this tumor in 

34 
the high-dose females is not significant, nor is the result of 

the Cochran-Armitage test for the females. The result of the 

Cochran-Armitage test on the incidence of female mice with either 

alveolar/bronchiolar adenoma or carcinoma is significant (P = 

0.006). The Fisher exact comparison of incidences in the 

high-dose and control groups indicates a P value of 0.030, which 

is above the 0.025 level required for significance when the 

Bonferroni inequality criterion is used for multiple comparison. 

Significant results in the negative direction are observed in the 

incidence of lung tumors in male mice and in the incidence of 

adenocarcinomas of the nummary gland in female mice. 

In most of the 95% confidence intervals for 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 adenocarc inomas of the mammary gland in 

high-dose female mice) has an upper limit greater than one, 

indicating the theoretical possibility of the induction of tumors 

by sulfisoxazole, which could not be detected under the 

conditions of this test. 

35 
36

 
V. DISCUSSION
 

Mean body weights of the high-dose male rats and female mice were 

slightly lower than those of the corresponding vehicle controls 

during the last 40 to 60 weeks of the bioassay; mean body weights 

of the dosed female rats and male mice were unaffected. No other 

clinical signs were observed that could be related to 

administration of the test compound. Survival rates of both rats 

and mice were unaffected by the test chemical. All dosed groups 

of rats and mice could probably have tolerated higher doses. 

Adequate numbers of rats and mice in dosed and control groups 

were at risk for the development of late-appearing tumors. 

In the male rats and male mice, no tumors occurred in the dosed 

groups at incidences that were significantly higher than those of 

the vehicle-control groups. 

In the female rats, monocytic leukemia occurred at incidences 

that were dose related (P = 0.016), as did combined monocytic 

leukemia and lymphocytic lymphoma (P = 0.033); however, in direct 

comparisons, the incidence of these tumors in the individual 

dosed groups were not significantly higher than those for the 

vehicle-control groups, and, in addition, there were four animals 

37 
with monocytic leukemia among the untreated controls. Thus, the 

occurrence of these tumors in the dosed groups of female rats 

cannot be clearly related to administration of the test chemical. 

In the female mice, alveolar/bronchiolar adenomas or carcinomas 

occurred at incidences that were dose related (P = 0.006), and, 

in a direct comparison, the incidence of the tumors in the 

high-dose group was higher (P = 0.030) than that for the 

vehicle-control group. Similarly, hepatocellular carcinomas 

occurred in the low-dose group at an incidence that was higher 

(P = 0.030) than that for the vehicle-control group. However, 

these P values for direct comparisons of dosed groups with 

control groups are above the level of P *= 0.025 required for 

significance when the Bonferroni inequality criterion is used for 

multiple comparison. Thus, the occurrence of alveolar/bronchiolar adenomas or carcinomas in the high-dose group and 

of hepatocellular carcinomas in the low-dose group cannot be 

clearly related to administration of the test material. 

The oral U&CQ of sulfisoxazole has been reported as 10,000 

rag/kg for white rats and albino mice (Schnitzer et al., 1946). 

When the rats were administered sulfisoxazole in the diet for 26 

weeks at daily doses beginning at 2,190 rag/kg and ending at 1,350 

mg/kg, they showed no inhibition of growth and no macroscopic or 

38 
microscopic change that could be attributed to the chemical. A
 

number of sulfonamides have been reported to induce hyperplasia
 

of the thyroid gland in rats of unspecified strain (Astwood et
 

al., 1943; Mackenzie and Mackenzie, 1943); this effect was
 

believed to be mediated by pituitary thyrotropin (Swarm et al.,
 

1973). When Charles River CD rats were administered sulfamethoxazole, the hyperplasia progressed to adenoma formation and
 

metastases to the lung (Swarm et al., 1973). No evidence of
 

effects on the thyroid is found in reports on sulfisoxazole,
 

including the 26-week chronic study by Schnitzer et al. (1946)
 

and the present 103-week study.
 

It is concluded that under the conditions of this bioassay,
 

sulfisoxazole was not carcinogenic for either Fischer 344 rats or
 

B6C3F1 mice.
 

39
 
40

 
VI. BIBLIOGRAPHY
 

American Medical Association, Sulfonamides. In: AMA Drug
 

Evaluations, PSG Publishing Co., Inc., Littleton, Mass., 1971,
 

pp. 769-785 and 966.
 

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

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

Astwood, E. B., Sullivan, J., Bissell, A., and Tyslowitz, R.,
 

Action of certain sulfonamides and thiourea upon the function of
 

the thyroid gland of the rat. Endocrinology 32;210-225, 1943.
 

Berenblum, I., ed., Carcinogenicity Testing, A Report o_f the
 

Panel on Carcinogenicity of the Cancer Research Commission p_f the
 

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

Cox, D. R., Regression models and life tables. J^ R_^ Statist.
 Soc. B 34:187-220, 1972.
 

Cox, D. R., Analysis of Binary Data, Methuen & Co., Ltd., London,
 1970, pp. 48-52.
 

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

significance tests, confidence limits and adjustments for
 

stratification. Rev. Int. Statist. Inst. 39(2) ;148-169, 1971.
 

Hayton, W. L., Ong, J. T. H., Runkel, R. A., and Welling, P. G.,
 

Sulfisoxazole. J^ Am. Pharm. Assoc. 16(11);617-620, 1976.
 

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

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

1958.
 

Kastrup, E. K. and Schwach, G. H., Sulfonamides. In: Facts and
 

Comparisons, Facts and Comparisons, Inc., St. Louis, Missouri,
 

1977, p. 364. 

Korolkovas, A. and Burckhalter, J. H., Sulfonamides. In: 

Essentials £f Medicinal Chemistry, Wiley-Interscience 

Publication, New York, 1976, pp. 464-479. 

Lehninger, A. L., The biosynthesis of nucleotides. In: 

Biochemistry, Worth Publishers, Inc., New York, 1975, pp. 730-732
 

and 739.
 

41
 
Linhart, M. S., Cooper, J. A., Martin, R. L., Page, N. P., and
 

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

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

Mackenzie, J. B. and Mackenzie, C. G., The effect pf "Sulfa" 

drugs on the thyroid gland in rats and mice. Federation 

Proceedings 1^:122-123, 1942. 

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

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

National Disease and Therapeutic Index, IMS America, Ltd.,
 

Ambler, Pa., April, 1977, pp. 105-106.
 

Physician's Desk Reference, Medical Economics Co., Oradell, N.
 

J., 1977.
 

Sadtler Standard Spectra, Sadtler Research Laboratories,
 

Philadelphia, Pa., IR No. R663.
 

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.
 

Schnitzer, R. J., Foster, R. H. K., Ercoli, N., Soo-Hoo, G.,
 

Mangieri, C. N., and Roe, M. D., Pharmacologicol and chemotherapeutic properties of 3,4 -dimethyl-5-sulfanilamido-isoxazole.
 

£r Pharmacol. Exp. Ther. 88: 47-57, 1946.
 

Stanford Research Institute, Sulfisoxazole. Chemical Dossier,
 

Stanford Research Institiute, Menlo Park, Calif., 1973.
 

Stecher, P. G., ed., The Merck Index. An Encyclopedia of
 

Chemicals and Drugs, Merck & Co., Inc., Rahway, N. J., 1968, p.
 

1002.
 

Swarm, R. L., Roberts, G. K. S., Levy, A. C., and Hines, L. R.,
 

Observations on the thyroid gland in rats following the
 

administration of sulfamethoxazole and trimethoprim. Toxicol.
 

Appl. Pharmacol. 24:351-363, 1973.
 

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

Biometrika 62(3);679-682, 1975.
 

Turczan, J. and Medwick, T., Identification of sulfonamides by
 

NMR spectroscopy. J^ Pharm. Sci. £1:434-443, 1972.
 

42
 
United States Pharmacopeial Convention, Sulfisoxazole. In: The
 

United States Pharmacopeia XIX, United States Pharmacopeial
 

Convention, Inc., Rockville, Md., 1975, pp. 480-482.
 

Weinstein, L., Antimicrobial agents. In: The Pharmacological
 

Basis of Therapeutics, Goodman, L. S. and Oilman, A., eds.,
 

Macmillan Publishing Co., Inc., New York, 1975, pp. 1113-1124.
 

43
 
44

 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS ADMINISTERED SULFISOXAZOLE BY GAVAGE
 

45
 
46

 
TABLE A1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

ADMINISTERED SULFISOXAZOLE BY GAVAGE 

—— • T^.^— 

UNTREATED 

CONTROL 

VEHICLE 

CONTROL LOW DOSE HIGH DOSE 

ANIBAL S INITIALL Y IN STUDY

SNIKtLS NECROFSIED

SNIBALS EXAMINE D HISTOPATHOLOGICALLY

 50 

 19 

 19 

50

50

50

 50 

 50 

 50 

50 

50 

50 

INTEGUMENTAR Y SYSTEM 

*SK.IN

PAPILLOMA , NOS

SQUAMOU S CELL PAPILLOMA 

SuOAHOO S CELL CAECINOBA

BASAL-CE1L CARCINOM A 

 (49]f 

1 (2*) 

1 (2X) 

(50)

1

2

 (2%)

 («%) 

 (50) 

1 (2X) 

(50) 

1 (2X) 

1 (2X) 

1 (2X) 

*SUBCUT TISSUE

FIBPOMA

FIBBOSAPCCBf

HEMANGIOSBFCOM A 

OS7EOSAHCC1-A 

NEGEOFIBFCBA 

 (19) 

1 (2K ) 

2 (IX) 

(50)

1

2

 (2*)

 (UX)

 (50) 

6 (12X) 

1 (2X) 

1 (2X) 

2 (IX) 

(50) 

2

2

 (»X) 

 OX) 

EESPIBATOPY SYSTEB 

#TPACHE A

FOLLICULAR-CELL CABCINOMS, BETAS 

 (18) (50) (50) 

1 (2X) (19) 

*LUNG

ALVEOLAE/EPCNCHIOLAF ADENOMA

ALVEOLAE/EPONCHIOIA ? CAFCINCMA

IJJTERSTITIfL-CELl TtlKOR, METtSTB

PHEOCHSOMOCYTOHA, METASTATIC 

FIBSOSAFCCCA, BETASTfTIC 

CSTEOSAPCCMA , METASTATIC 

 (48) 

2 (IX) 

1 (2X) 

1 (2*) 

(50)

1 (2X) 

 (50) 

1 (2X) 

1 (2X) 

1 (2X) 

(50) 

1 (2X) 

1 (2X) 

B5MATOPOIETIC SYSTEM 

*BULTIPLE OFGANS

MALIG.LYMEHCMA , UNDIFFEP-TYPE 

MALIG.LYBPHOBA^ LYMPHOCYTIC TYPE

 (19) 

1 (2X) 

(50)

1 (2X) 

 (50) 

1 12%) 

(50) 

« NUMBEE OF ANIHALS WITH TISSOE EXAMINED BICEOSCOPICHLLY 

* NOBBEE OF ASIMALS NECEOPSIED 

47
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

UNTR

CON

EATED 

TROL 

VEHICLE 

CONTROL 

OSDIFFERENHATED LEUKEMIA 

BYEIOMOHOCYTIC LEOKBBIA 

HOHOCTTIC 1BOKEHIA 

1

6 (12%) 

 (2X) 

1 (2%) 

8 (16t) 

•SHBCDT TISSUI/GHOIH 

BALIS. LYHPHOMA . HISTIOCYTIC TYPE 

(«9) (50) 

ISPLfiEN 

FIBROSARCCHA, HETASTATIC 

HBSOTHELICKA, HETASTATIC 

AHGIOSARCCMA 

MALIG. LYMPHCMA. HISTIOCYTIC TYPE 

(18) 

1 (2*) 

(50) * 

tBPONCHIAL IYBPH

FIBROSARCCFA,

 NODE 

 METASTATIC 

(U7) 

1 (2%) 

(50) 

tMESENTEBIC I . NODE 

FIBPOSARCCHA, METASTATIC 

(17) 

1 (2X) 

(50) 

* LIVED 

MONOCYTIC 1EUKEMIA 

(18) (50) 

1 (2%) 

CIRCULATORY SYSTEM 

tHEART (18) (50) 

ADENOCARCINOHA , NOS, METASTATIC 

ALVEOLAR/ERONCHIOLAB CA, BETASTA 

FIBROSABCCBA, BETASTATIC 

DIGESTIVE SYSTIM 

tLIV£P (18) (50) 

NEOPLASTIC NODOLE 1 (2%) 

HEPATOCEUUIAP Cf?CINOM A 2 (U% ) 

iPANCBEAS (18) (50) 

FIBBnsAECCr.A, BETASTATIC 1 (2X) 

><E£OTHE1ICRA, BETiSTATIC 

tESOPHAGOS (18) (17) 

FOLlICOH?-CEtI CIIBCIBOI1A, PIETAS 

tSMALL INTESTINE (U8) (50)
 

I NUMBER OF ANIMALS WITH TISSUE EXAMINED BICPOSCOPICA1LY
 

* NUMBEK OF ANIMALS NECROFSIED
 

LOW DOSE 

6 (12%) 

(50) 

(50) 

1 (2%) 

(18) 

(18) 

(50) 

(50) 

1 (2%) 

1 (2%) 

(50) 

2 (1«) 

2 (1%) 

(19) 

1 (2%) 

(16) 

1 (2%) 

(18)
 

HIGH DOSE 

8 (16%) 

(50) 

1 (2%) 

(50) 

1 (2%) 

1 (2%) 

(50) 

(50) 

(50) 

(50) 

1 (2X) 

(50) 

2 (IX) 

(50) 

(17) 

(50)
 

48
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

———­—— ­ ... 

UNTREATED VEHICLE 

CONTROL CONTROL 

tDOODENUM ("8) (50) f BUCINOOS ADEKOCARCINOBA 1 (2*)

tILEOB (48) (50) 

ADENOBATOOS POLYP, NCS 

OBINAR Y SYSTEM 

tKIDNEY (48) (50) 

MIXED TOHOE, BENIGN 

ENDOCRINE SYSTEM 

•PITUITARY (47) (49) 

CABCINOHA.NOS 1 (2%) 

CHBOBOPHCEE ADENOBA 1 (2%) 4 (8«) 

IADP.ENAL (48) (50) 

COBTICAL ADENCM A 1 (2«) 

PHEOCHBOMOCYTOMA 5 (10*) 3 (6S) 

PHEOCHBOMOCYT01A, MALIGNANT 2 (4%) 

MESOTHELICBA, HETASTATIC 

OSTEOSAPCCBA, METASTATIC 

tADEiKAL BEDOILA (48) (50) 

GANGLICNED5CBA 1 (2%) 

tTHYRCID (48) (49) 

FOLLICULAB-CELL ADEHOBA 1 (2*) 

FOLLICDLAF-CELL CABCINOHA 

C-CELL CABCINCBA 2 (4*) 1 (2%) 

«PAPATHYSOIE (37) (37) 

ADENOMA, NCS 

•PANCREATIC ISLETS (48) (50) 

ISLET-CEII ADENCMA 3 (6X) 2 (4%) 

REPRODUCTIVE SYSTEM
 

*H»!1I!ARY GLBNI («9) (50)


* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICPOSCOPICAILY
 

* NUBBE? OF ANIMALS NECRCPSIED
 

LOW DOSE 

(48) 

(48) 

(50) 

1 (2*) 

(44) 

4 (9») 

(50) 

10 (20%) 

1 (2%) 

1 (2%) 

(50) 

(44) 

1 (2*) 

1 (2X) 

1 (2*) 

(34) 

1 (3X) 

(19) 

1 (2*) 

(50)


HIGH DOSE 

(50) 

(50) 

1 (2*) 

(50) 

(50) 

5 (10*) 

(50) 

1 (2%) 9 (18K) 

1 (2*) 

(50) 

(48) 

2 (4*) 

(40) 

(50) 

 (50)
 

49
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

UNTREATED VEHICLE

 

CONTROL CONTROL

*PEEPUTIAL GIANC 

CAFCINOHA.NO S 

(19) 

3 (6%) 

(50)

2 (U<)

• SQUAMOU S CELL CARCINOM A 1 (2%) 

ADENOMA , DCS 

*TESTIS (it It) (48)

INTERSTITIAL-CELL "OKOR 39 (89%) U5 (9IIX)

INTERSTITIAL-CELl TIJHOH, PI ALIGN A 1 (2%) 

MBSOTHELICNA , HALIGNSN T 

M£SOTHELICKA, METASTATIC 

*EPIDIDYBIS (U9 ) (50)

NESOTHELICP.A, METASTATIC 

KEPVOU S SYSTEM 

TONE 

SPECIAL SENSI CEGA1S 

*ZTHBAL'S GLAlil (U9) (50) 

CAPCINOM»,1IOS 

BOSCI'LOSKELETAI SYSTEfl 

•BONE/OPPER IXTBIWITY (19) (50) 

OSTEOSARCCMA 

BODY CAVITIES 

* MEDIASTINUM (l»9) (50) 

ALVEOLAR/ERONCHIOLAB CA, HET&STA 

FIBROSARCCKA 

*HESENTEPY (50) 

FIEROSARCCHA 1 (2%) 

M£SOTHELIOHA. MALIGNANT 

"TUNICA VAGINALIS (50) 

HeSOTHELICgA._»QS 

* NUHBEP. OF ANIMALS WITH TISSUE EXAHINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

50 

 LOW DOSE 

( = C) 

 i| (8%) 

1 (2*) 

 (19) « 3 (88%) 

1 (2%) 

1 (2%) 

 (50) 

1 (2%) 

(50)

1 (2%) 

(50)
 

1 (2%)
 

(50)

1 (2%) 

1 (2%) 

(50) 

1 (2%) 

(50) 

HIGH DOSE 

(50) 

3 (6%) 

2 (»%) 

(«9) 

U6 (9tt%) 

(50) 

 (50) 

(50)
 

 (50) 

(50) 

(50) 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

ALL OTHER SYSTIHS 

*HOLIIPLB ORGANS

HBSOTHELICMA, DOS 

DIAPHRAGM 

FIBROSARCCEA, METASTATIC 

ANIMAL DISPOSITION SUMMAR Y 

ANIHALS INITIALLY IN STUDY

NATURAL DEATHS

MORIBUND SACRIFICE

SCREDULID SACRIFICE 

ACCIDBNTALIY KIHED 

TERMINAL SACRIFICE

ANIMAL HISSING 

9 INCLUDES AOTCLYZED ANIMALS 

TUMOR SUMMARY 

TOTAL ANIMAL S WITH PRIMARY

TOTAL PRIRARY TOMOPS

 TUHORS*

TOTAL ANIMAL S BITH BENIGN TUMORS

TOTAL BENIGN TUMORS

TOTAL ANIHAI S BITH MALIGNA*1" TUMO'S

TOTAL HA1IGNANT TOMOSS

TOTAL ANIMALS WITH SECONDARY TUMORS*

TOTAL SECONDARY TUMOES

TOTAL ANIMALS HITH TUMORS UNCERTAINBENIGN OR MALIGNAN T

TOTAL UNCERTAIN TUMOKS

TOTAL ANIHAIS WITH TUMORS UNCERTAINPRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

UNTREATED VEHICLE 

CONTROL CONTROL LOW DOSE 

 (l»9) (50) (50) 

2 (»X) 

1 

 50 50 50 19 11 16 1 2 

 31 38 32 

 U3 «8 <17 

 80 81 100 

 U2 47 K5 55 59 73 

 20 21 20 2« 21 23 

2 c 

5 1U 

1 1 It 

1 1 U 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

I SECONDARY TUMORS: METASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

51
 

HI6H DOSE 

(50) 

50 

12 

1 

1 

36 

49 

93 

<»7 

71 

18 

20 

2 

2 

2 

2 
TABLE A2. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

ADMINISTERED SULFISOXAZOLE BY GAVAGE

 

• ­ • ~-l 

UNTREATED 

CONTROL VEHICLE 

CONTROL LOW DOSE HI6H DOSE 

ANIMALS

ANIMALS

ANIMALS

 INITIULY IN STUDY 

 NECROPSIED 

 EXAMINE D HISTOPATHOIOGICAUT 

50 

50 

50 

50 

50 

50 

50 

50 

= 0 

50 

50 

50 

INTEGUMENTARY SYSTEM 

•SKIM 

PAPILLOHA, HOS 

•SUBCOT TISSUE 

FI BROOK 

FIBROSARCCHA 

(50) 

(50) 

1 (2%) 

(50) 

(50) 

(50) 

2 {<»*) 

(50) 

(50) 

(50) 

1 (2*) 

uESPIHATOHY SYSTEM 

HOME 

HEHiTOPOIETIC SYSTEM 

*mJLHPLE ORGANS

MAIIG.LYHPBCBA, LYMPHOCYTIC

LEUKEMIA, 8CS 

GBANOtOCYTIC LEUKEMIA 

HONOCYTIC LEOKEHIA

 TYPE 

 (50) 

4 (8«) 

(50) 

1 (2%) 

1 (2%) 

1 (2%) 

3 (6%) 

(50) 

3 (6%) 

(50) 

9 (18X) 

CIRCULATORY SYSTEM 

HONE 

DIGESTIVE SYSTEM 

tLI»£E 

HKPATOCEI LOLAS CARCINOMA 

(50) (50) 

1 (2X) 

(50) (50) 

SYSTER 

t NUBBEB

* NUMBER

 OF

 OF

 ANIMAL S

 ANIMAL S

 WITH TISSDE EXAMINED

 NECROPSIED 

 MICROSCOPICALLY 

52 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

UNTREATED VEHICLE 

CONTROL CONTROL 

INDOCRINE SYSTIM 

tPITUITARY (»7) («9)

ADENOMA, NCS 2 («)

 

CHRONOPHCEI ADENOMA 17 (36*) 18 (37%)

 

IAD9ENAL (50) («9)

CORTICAL ADENOMA 1 (2*) 1 (2«)

 

PHBOCHROHCCYTOHA 1 (2«)

 

tTHYRCID («9) (U7)

 

C-CELL ADIROHA 1 (2%)

 

C-CELL CARCINOM A 1 (2«)

 

tPARATHTROID (33) (32)

ADENOMA, NCS 1 (3%)

 

•PANCREATIC ISLETS (50) (50)

 

ISLET-CELL ADENOMA 1 (2*)

 

REPRODUCTIVE SYSTEM 

•SAMHAPY GLAN I (50) (50)

 

ADENOMA, NCS 1 (2») 1 (2«)

 

ADENOCARCINORA, NOS 1 (2*) 

PAPILLARY CYSTADENOHA, NOS 2 (««) 

FIBPOADEHCMA 6 (12U) 12 (2tt«) 

*PREPOTIAL GLAND (50) (50) 

CAPCINCMA,KOS 1 <2«) 3 (6«) 

ADENOMA, NCS 2 («X) 

IUTEFOS (50) («9) 

CARCINOMA, NOS 1 (2*) 

PAPILLARY CYSTADENOKA, NOS 

ENDOHETRIA1 STROHAL EOLYP 6 (12») 5 (10*) 

BNDOHBTRIAL STROHAL SARCOMA 1 (2%) 

NERVOUS SYSTEM 

•CEREBROM (50) (50) . .ASTR.OCY.TCH.A. , ,, ,

 . 

* NOHBER OF ANIMALS 8ITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS MECROFSIED
 

LOW DOSE 

(50) 

1 (2«) 19

 (38X) 

(50) 

2 («%) 

(50) 

(38) 

(50) 

1 (2*) 

(50) 

1 (2») 

16 (32*) 

(50) 

(«9) 

1 (2*) 6 (12«) 

(50) 

1 ltf\ 

HI8HDOSE 

(-40) 

1 (2*) 

17 (3««) 

(50) 

<«9) 

2 («*) 

(13) 

(«9) 

(50) 

15 (30*) 

(50) 

1 (2») 

1 (21) 

(•18) 

8 (17*) 

(50) 

53
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED)

 

UNTREATED VEHICLE 

CONTROL CONTROL LOW DOSE HIBHDOSE 

SPECIAL SENSE C5GANS 

• EYS/CONJUNCTIVA (50) (50) (50) (50) 

SytJAIIOOS CEIL CARCINOMA 1 (2V) 

MOSCULOSKELEfAL SYSTEM 

HONE 

EOLY CAVITIES 

HONE 

ALI OTHER SYSTEMS 

NONE 

ANIMA L DISPOSITION SUMMAR Y 

ASIMALS INITIALLY IN STODY 50 50 50 50 

NATURAL DIATH9 11 15 « 8 

nOBIBONi; SACPIFICE 3 2 

SCHEDULED SACBIFICE 

ACCIDEHTAtlY RULE D 

TERMINAL SACEIFICE 39 35 «3 «0 

ANIHAI. HISSING 

9 INCLDDES AyTOLYZED_ASHIAI.S 

* NUHBEP OF ANIMAL S BITH TISSUE EXAHINED HICFOSCOPICALLY 

* 10MBEE OF ANIMALS NECBCPSIED 

54 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

UNTREATED VEHICLE 

CONTROL CONTROL LOW DOSE HIGH DOSE 

TUMOB SUMMAR Y 

TOTAL ANIMAL S WITH PBIHARY TUMORS* 30 38 37 35 

TOT»L PRIMAR Y TUHOBS 42 56 5« 55 

TOTAL ANIMAL S WITH BENIGN TUMORS 27 32 36 32 

TOTAL BENIGN TUMORS 3» us U8 H2 

TOTAL ANIMALS WITH MALIGNANT TOBORS 8 11 6 11 

TOTAL MALIGNAN T TDMOPS 8 11 6 13 

TOTAL ANIMAL S WITH SECONDARY TOMORSt 

TOTAL SECCNDAPY TUMOFS 

TOTAL ANIMAL S WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 

TOTAL ONCEFTAIN TDMOFS 

TO"AL ANIMAL S WITH TUMORS tTNCEPTAIN-

PRIdAP.Y OP HETASTATIC 

TOTAL nNCEBTAIN THMOPS 

* PRIMAR Y TUMCBS: ALL TUMORS EXCEPT SECONDARY TUMOPS * SECONDARY TOMOPS: METASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACINT ORGAN 

55 
56

 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE ADMINISTERED SULFISOXAZOLE BY GAVAGE
 

57
 
58

 
TABLE B1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

ADMINISTERED SULFISOXAZOLE BY GAVAGE 

UNTREATED 

CONTROL 

VEHICLE 

CONTROL LOW DOSE HI6H DOSE 

ANIMALS INITIAILY IN STUDY

ANIMALS HISSING

ANIMALS NECROISIED

ARIBAL5 EXAMINED HISTOPATHOLOGICAILI

 50 

1 

 !»9 

 !»9 

50 

50 

50 

50 

50 

50 

50 

1*9 

U9 

IHTIGUHENTARY SISTER 

»SKIH 

BASAL-CELL

FIBROMA 

 TOHOP 

(*9)

1 (2*) 

(50) (50) 

1 (2%) 

(«9) 

*SOBCDT TISSOE 

FIBROMA 

PIBSOSARCCHA 

FIBROUS HISTIOCYTOMA 

(49) 

6 (12%) 

(50) 

"» (8*) 

1 (2%) 

(50) 

2

5

 («%) 

 (10%) 

(U9) 

3 (6%) 

FKSPIBATOEY SYSTEM 

tLUNG 

HBPATOCEILDLAR CARCINOMA. METAST 

ALVBOLAB/ERONCHIOLAR ADENOMA 

ALVEOLAB/BROKCHIOLAR CARCINOMA 

CORTICAL CARCINOMA, BETASTATIC 

SEBACEOUS ADENOCABCIHOHA, BETAST 

FIB80SABCCMA, HETASTATIC 

(49) 

2 (U%) 

8 (16%) 

1 (2%) 

1 (2%) 

(50) 

2 <U%) 

3 (6%) 

1 (2%) 

1 (2%) 

1 (2%) 

1 (2%) 

(50) 

3 (6%) 

3 (6%) 

2 ("»%) 

(U9) 

1 (2X) 

HEMATOPOIETIC SYSTEM 

•MULTIPLE ORGANS

MALIG.LYJ1IHOBA, LYBPHOCYTIC TYPE

HiLIG.LYHEHOMA, HISTIOCYTIC TYPE

BALIGNANT IYBPHOMA, MIXED TYPE

GHANOLOCYTIC LEUKEMI A 

 (19) 

1 (2%) 

U (8%) 

1 (2%) 

(50) 

1

2

1

 (2%) 

 («%) 

 (2%) 

(50) 

5 (10%) 

3 (6% ) 

3

1

 (6%) 

 (2%) 

tSPLEEM

HBBANGICBA 

HJSHANGIOSABCOMA 

 (U9) (50) 

2 (U% ) 

(50) 

1 (2% ) 

(U9) 

1 (2%) 

1 t2%) 

I NDMBER OP ANIMALS WITH TISSUE EXAMINED

* NOMBEB OF ANIMALS NECROPSIED 

 MICPOSCOPICALLY 

59 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

UNTREATED VEHICLE 

CONTROL CONTROL

• CDOOEMOR (09) (09)

MALIG.LYHPHOHA, HISTIOCYTIC TYPE 1 (2%) 

•THYHDS (19) (22)

LIPOSARCCKA 1 (5%) 

CIRCULATORY SYSTEM 

MOMS 

DIGESTIVE SYSTEM 

•LIVSR (09) (50)

HZPATOCELLOLAP ADENOMA 3 (6%) 

HEPATOCBIIOLAB CARCIMOMA 17 (35%) 15 (30%)

HEHAMGIOSASCOHA 2 (0%)

•81 Li DIICT (09) (50)

CiPCIMOSIFCOMA 1 (2%) 

• PANCREAS (49) (50)

CORTICAL CASCIMOMI, KETASTATIC 1 (2%) 

• STOMACH (09) (09)

CARCINOMA, MOS 1 (2%) 

SQUAMOOS CELL PAPILLOMA 1 (2%) 

ADENOMATOOS POLYP, NOS 

•SHALL IMTESTIMZ (09) (09)

HEHAHGIOSAFCOMA, METASTATIC 1 (2%) 

•JEJUNDM (09) (09)

CARCIHOHK.MOS 1 (2%) 

OPIMAHY SYSTEM 

•URINARY BUEIBH (09) (50)

TBAMSITICNA1-CELL PAPILLOMA 1 (2%) 

EIOOCSIME SYSTEM
 

•ADPSNAL	 (U9)
 

COPTIC^L AtBMOM A
 

t BOMBER OF ANIMALS ilTH TISSUE EXAMINED MICROSCOPICALLY
 » ROHBEP OF ANIMALS MECRCPSIED
 

 LOW DOSE 

 (50) 

 (22) 

 (50) 

 13 (26%) 

1 (2%) 

 (50) 

 (09) 

 (09) 

 (50) 

 (50) 

 (50) 

HIGH DOSE 

(09) 

(8) 

(09) 

1 (2%) 20 (01%) 

2 (0%) 

(09) 

(08) 

(09) 

1 (2%) 

1 (2%) 

(09) 

(09) 

(09) 

(09)
 

60
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

UNTREATED

CONTROL

 VEHICLE 

 CONTROL LOW DOSE HI6HDOSE 

CORTICAL CARCINOM A

PKEOCHROMCCYTOHA

tTHYEOID

FOLLICOLAP-CELL ADENOM A

 (47)

 1 (2*) 

2 («%)

 (47)

 5 (10*) 

 (48) (US) 

1 (2*) 

REPRODUCTIVE SYSTEM 

•PROSTATE

HttMANGIOSfBCOHA. METASTATIC

 (49) (50)

 1 (2%) 

 (50) (19) 

ITESTIS

INTERSTITIAL-CELL TDHOR

 (U9) (50) («7) («8) 

1 (2%) 

MESVOUS SYSTEM 

NONE 

SPICI1L SENSE CROONS 

*EYELID

S.-BACEOUS AOENOCARCINOHA

 (M9) (50)

 1 (2X) 

 (50) (»9) 

•HUPDEHIAN GLAND

CARCINCRA.NOS

 (49) (50)

 1 (2«) 

 (SO) (19) 

BUSCnLOSKELETAI SYSTEM 

NONE 

EOEY CAVITIES 

RONE 

ALL OTHEP SYSTEMS 

* MULTIPLE ORGANS 

CARCINOSAFCOHA,

HZHANSIOSAECOBA 

t NOMBER OF ANIMALS

* ROHBER OF ANIMALS

 METASTATIC 

 ilTH TISSUE

 NBCHOFSIED 

(49) (50) 

1 (2%) 

_ 1-I2SL 

 EXAMINED MICROSCOPICALLY 

(50) 

61 
TABLE 61. MALE MICE: NEOPLASMS (CONTINUED) 

UNTREATED VEHICLE 

CONTROL CONTROL 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 50 50
 NATURAL DEATHS 12 18
 HORIBUND SACRIFICE 1
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED 1 1
 

TERMINAL SACRIFICE 36 30
 

ANIMAL HISSING 1
 

3 INCLUDES AUTCLYZID ANIMALS
 

TUHOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 32 29

 

TOTAL PRIMARY TUMORS 45 43

 

TOTAL ANIMAL S WITH BENIGN TOHORS 12 

TOTAL BENIGN TUMORS 13 

TOTAL ANIMAL S WITH MALIGNAN T TUMORS 26 25 

TOTAL MALIGNANT TUMOPS 32 35

 

TOTAL ANIMAL S WITH SECONDAR 3 Y TUMORS* 7 

TOTAL SECONDAR Y TUMORS 3 9 

TOTAL ANIMALS WITH TUMORS UNCERTAINEENIGN OR MALIGNAN T

 

TOTAL UNCERTAIN TUMORS 

TOTAL ANIMA1 S WITH TUMORS UNCERTAINPRIMARY OR METASTATIC

 

TOTAL UNCERTAI N TUMORS 

* PRIMAR Y TUMCRS : ALL TUMORS EXCEPT SECONDAFY TUMORS 

» SECONDARY TDHOPS: METASTATIC TUMORS OR TUMORS INVASIVE INTO All

LOW DOSE 

50
 

14
 

36
 

31 

41 

9 

12 

25 

29 

3 

3 

 ADJACEN T ORGAN 

HI6H DOSE 

50
 

11
 

2
 

34
 

28 

36 

25 

32 

62 
TABLE B2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

ADMINISTERED SULFISOXAZOLE BY GAVAGE 

UNTREATED VEHICLE 

CONTROL CONTROL LOW DOSE HIGH DOSE 

ANIBALS INITIAILY IN STUDY 50 50 50 50 

ARIBALS BISSING 1 

ANIBALS NECROFSIED 50 49 50 50 

ANIBALS EXABIHED HISTOPATHOLOGICALLY 50 U9 50 50 

INTEGUHENTARY SYSTEM 

»SUBCOT TISSDE (50) (49) (50) (50) 

FIBSOSARCCBA 1 (2*) 

HEBANGIGBA 1 (2*) 1 (2*) 

RESPIRATORY SYSTEB 

• LUNG (50) (49) (50) (50) 

ADENOCARCINOBA. NOS, BETASTATIC 1 (2*) 

ALVEOLAR/ERONCHIOLAR ADENOBA 2 (U*) 1 (2*) 3 (6*) 

ALVKOLAB/BFONCHIOLAR CAPCINOBA 2 (»*) 

HIMATOPOIETIC SYSTEB 

*BOITIPLE ORGANS (50) (49) (50) (50)

BALIG.LYBPHOBA, LYBPHOCYTIC TYPE 3 (6*) 6 (12*) 7 (14*) 10 (20*) 

BALIG.LYBPHOMA. HISTIOCYTIC TYPE . 10 (20*) 7 (14*) 6 (16*) 10 (20*) 

MALIGNAN T LYBPHOHA, MIXED TYPE 3 (6*) 3 (6*) 1 (2*) 

GRANOLOCYTIC LEOKEHIA 1 (2*) 1 (2*) 

t SPLEEN (50) (49) (50) (50)

 

HBBANGIOSAPCOMA 1 (2*)

 

IRESENTERIC I. NODE (48) (48) (50) (50)

 

MALIGNANT 1YMPBOHJ, BIXED TYPE 1 (2X) 

CIRCULATORY SYSTEB
 

NONE
 

t NHBBER OF ASIBALS WITH TISSUE EXABINED MICROSCOPICALLY
 * NUKBEH OF ANIMALS NECRCPSIFD
 

63 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

— — ,.— -„._-—«__-, «. -_ ! -——-„_ .. ­ ­. 

UNTREATED VEHICLE 

CONTROL CONTROL LOW DOSE 

DIGESTIVE SYSTIM 

•LITEE (50) (49) (50) 

HSPATOCEllDLAP ADENOMA 1 (2*) 

HEPATOCELLOLAR CARCINOMA 2 (4%) 5 (10*) 

•PANCREAS (50) (49) (50) 

CARCINOMA , NOS, HETASTATIC 1 (2%) 

•STOMACH (50) (49) (49) 

CARCINOMA, NOS 1 (2%) 

UBINAH Y SYSTEM 

NON£ 

INEOCfilNE SYSTEM 

tPITUITAPY (45) (42) (44) 

CHPOHOPHOEI ADENOM A 1 (2X) 2 (5X) 1 (2*) 

•ADPENAL (50) (48) (49) 

PHEOCHROMCCYTCHA 1 (2%) 1 (2%) 

•THYROID (49) (48) (48) 

FOLLICULAR-CEIL ADENOMA 1 (2*) 1 <2X) 

REPRODUCTIVE SYSTEM 

•MAMMARY GLANE (50) (49) (50) 

ADENOMA, NCS 

ADENOCABCIKCMA, NOS 1 (2X) 5 (10X) 1 (2X) 

FIBHOADENCKA 1 (2X) 

•UTERUS (50) (49) (50) 

FIBROSAPCCKA 

BSDOMBTRIAI STRCMAL FOLYP 1 (2X) 1 (2*) 2 (4X) 

H£HANGIOMA 1 (2X) 1 (2%) 

BE MA NG IDSA SCO MA 1 (2*) 1 (2%) 

•OVARY (50) (49) (50) 

S£PTOLI-CJIL_ TJMOF 1 X2S.L. 

* NUMBER OF «.NIHALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE 

(50) 

2 (4%) 

(50) 

(50) 

(31) 

1 (3X) 

(50) 

(46) 

2 (4X) 

(50) 

1 (2X) 

(50) 

1 (2X) 

1 (2X) 

(50) 

64
 
TABLE 62. FEMALE MICE: NEOPLASMS (CONTINUED) 

UNTREATED VEHICLE 

CONTROL CONTROL LOW DOSE HIGH DOSE 

tMESOVARIUM (50) (U9) (50) (50) 

CARCINOMA, NOS, METASTATIC 1 (2%) 

NERVOUS SYSTEM 

NONE 

SPECIAL SENS! CEGANS 

*HARDERIAN G1AND (50) («9) (50) (50) 

ADENOMA, NCS 2 (U») 2 (US) 

HUSCULOSKELETSI SYSTEM 

NONE 

EOEY CAVITIES 

NONE 

All OTHER SYSTEMS 

'MULTIPLE ORGANS (50) («9) (50) (50) 

FIBROSARCCKA 1 (2*) 

JNIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 50 50 50 50 

NATURA L DIATH3 

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALIY KILLED 1 

TERMINAL SACRIFICE 10 tt2 

AtllHAL MISSING 

8 INCLUDES AaTCLYZED ANIMALS 

t NUMBER OF ANIMALS WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

65 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

UNTREATED

CONTROL

 VEHICLE 

 CONTROL LOW DOSE HIGH DOSE 

THROB SUMMAR Y 

TOTAL ANIMALS WITH PRIMARY TUMORS*

TOTAL PRIMAR Y TUMORS

 26

 30

 2«

 31

 29

 35

 31 

 35 

TOTAL ANIMAL S WITH BENIGN TUMORS

TOTAL EEHIGH TUMORS

 7

 8

 7

 8

 10

 11

 7 

7 

TOTAL ANIMALS KITH MALIGNANT TOMORS

TOTAL HAIIGNANT TUMORS

 22

 22

 20

 23

 22

 21

 26 

 28 

TOTAL ANIMALS WITH SECONDARY TOHOPS*

TOTAL SECONDARY TUMORS

 1

 2

 1 

1 

TOTAL ANIMAL S WITH TUMORS

BENXGN OR HAIIGNANT 

TOTAL UNCERTAIN TUMOES 

 UKCEPTAINTOTAL ANIMAL S WITH TUMORS

PRIMARY OH RETASTATIC 

TOTAL UNCEmiN TOMORS 

 UNCERTAIN­

* PRIMARY TOflCBS: ALL TUMORS EXCEPT SECONDARY TUMOPS 

* SECONDARY TUMORS: METASTATIC TUMORS OR TUMOPS INVASIVE INTO AN ADJACENT ORGA N 

66 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN RATS ADMINISTERED SULFISOXAZOLE BY GAVAGE
 

67
 
68

 
TABLE C1. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

ADMINISTERED SULFISOXAZOLE BY GAVAGE 

UNTREATED 

CONTROL 

VEHICLE 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIAILT IN STUDY 

JHIKALS NECP.OESIED 

AHIHALS IXAHIHID HIS V JPATHOLOGICALIY 

50 

U9 

49 

50 

50 

50 

50 

50 

50 

50 

50 

50 

IHTEGUHEHIAPY SYSTEM 

• SKIN 

EPIDERMAL INCLU ' OH CYST 

RYPERKERATCSIS 

ACAHTHOSIS 

C»9> 

1 (2X) 

1 (2*) 

1 <2«) 

(50) 

3 (6*) 

1 (2%) 

(50) 

1 (2%) 

(50) 

1 (2%) 

*SDBCOT TISSUE 

STEATITIS 

INFLAMMATION , C - ONIC 

l"*9) 

1 (2%) 

(SO) 

1 (2%) 

(50) (50) 

FBSPIRATORY SYSTEM 

tLl'HG 

MINERALIZATION 

HfcHORRHAGE 

INFLAMMATION, S

INFLAHHATICN, A

PNEUnOHIA, CHFO

 P0RATIVE 

 TE 

C HOPIN E 

(«8) 

5 (10X) 

1 (2%) 

39 (81*) 

(50) 

1 (2X) 

2 («%) 

U6 (92%) 

(50) 

6 (12%) 

1 (2%) «3 (86%) 

(50) 

5 (10%) 

t« (88%) 

HEBATOPOIETIC SYSTEM 

•SPLEEN 

ECTOPIA 

FIBPOSIS 

FIBPOSIS, FOCAL 

AHYLOIDOSIS 

HEHOSIDE5CSIS 

HJiHATOPOIISIS 

(48) 

1 (2%) 

1 <2X) 

5 (10») 

(50) 

1 (2*) 

1 (2*) 

3 {6») 

(50) 

2 (»*) 

1 (2%) 

1 (2%) 

(50) 

2 <«%) 

ISPLEHIC CAPSULE 

FIBPOSIS, FOCAL 

(K8) (50) (50) 

1 (2%) 

(50) 

tLYHPH NODE 

A,THQP_aXi "53 

("7) 

. .1_1281_.._. _ 

(50) ««B) <50) 

» NOMBER OF ANIMALS WITH TISSOE EXAHIHED MICROSCOPICALLY 

* SOBBE5 OF AKINALS HECROPSIED 

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

UNTREATED VEHICLE
 

CONTROL CONTROL
 

•CERVICAL LYiPH RODE	 (47) (50)
 AHYLOIDOSIS 1 (2X)
 

•BRONCHIA! IYMPH RODE	 (47) (50)
 HEMORRHAGE 1 (2X)
 ATROPHY, NCS 1 (2X)
 

IHESBRTERIC I. NODE (47) (50)
 

LYNPHARGIECTASIS 1 (2X)
 AHYLOIDOSIS 1 (2*)
 ATROPHY, NCS 1 (2X)
 

CIRCULATORY SYSTEM
 

•HEART/ATRIDN	 (48) (50)
 

THROMBOSIS, ROS 8 (17X) 2 (4X)
 

•HYOCARDIOB	 (48) (50)
 

INFLAHHATICN, CHRORIC 6 (13X) 13 (26X)
 

FIBHOSIS 23 (48X) 27 (54X)
 

FIBROSIS, fOCAL 2 (4X)
 DBGBNERATICN, ROS 11 (23X) 6 (12X)
 

•AORTA	 (49) (50)
 THROMBOSIS, ROS
 

INFLAMMATION, CHRONIC 1 (2X)
 

DIGESTIVE SYSTEM
 

•SALIVARY GLAND (48) (49)
 

IMFLAMRATIOR, ACOTE
 

IVFLAMHATICR, CHRORIC
 

•LIVER	 (48) (50)
 

FIBROSIS 1 (2X)
 CIRRHOSIS, POSTAL 3 (6X)
 HEPATITIS, TOXIC 2 (»X) 2 <«X)
 

PBLIOSIS HEPATIS
 NECROSIS, ROS 2 (4X) 2 (4X)
 

HBTARORPHOSIS FATTY 1 (2X) 2 (4X)
 

HEMOSIDERCSIS
 

FOCA1 CEL1DLAR CHARGE 25 (52X1 28 156X1
 

t SOMBER OF ASIHALS VITH TISSUE EXAMINED MICROSCOPICALLY
 

* NOMBEP OF AHIRALS NECSOPSIED
 

LOW DOSE
 

(48)
 

(48)
 

1 (2X)
 

(48)
 

1 (2X)
 

1 (2X)
 

(50)
 

4 (8X)
 

(50)
 

1 (2X)
 

34	 (68X)
 

1 (2X)
 

2 («X)
 

(50)
 

1 (2X)
 

(49)
 

1 (2X)
 

1 (2X)
 

(50)
 

1 (2X)
 

1 (2X)
 

1 (2X)
 

1 (2X)
 

1 (2X)
 20 <40X>
 

HIGH DOSE
 

(50)
 

(50)
 

1 (2X)
 

(50)
 

1 (2X)
 

(50)
 

1 (2X)
 

(50)
 

2 (IX)
 32 (64X)
 

9	 (18X)
 

(50)
 

1 (2X)
 

(50)
 

(50)
 

2 {»«)
 

1 (2X)
 

18 (36X)
 

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

LOW DOSE 

UNTREATED VEHICLE 

CONTROL CONTROL 

HEBJITOEOIESIS 1 (2*) 

tPOPIAL TRACT (48) (50)

 

FIBROSIS 1 (2%)

 

tLIVEP/CENTF IIOBU1AR (48) (50)

 

NECROSIS, VOS 5 (10X) 1 (2X>

 

*LIVER/PERIFCFTAL (48) (50)

 

FIBROSIS 1 (2%)

 

tSILE DUCT 118) (50)

 

INFLAfMATICI , NOS 1 (2%)

 

INFLAKMATICH, CHRONIC " (8X)

 

FIBROSIS 3 (6*) 7 (14*)

 

HYPERPLASIA, NOS 33 (69*) 31 (62X)

 

*PfNCPEAS (48) (50)

 

INFLABBATICN , CHRONIC 4 (8X) 3 (6*)

 

PBRIARTEPITIS 3 (6*) 1 (2X)

 

ATFOPHY , NCS 6 (13*) 6 (12X)

 

•STOMACH (48) (48)

 

HEf!0"FHAGE 1 (2X)

 

ULCER, NOS 

INFLAMBATICN, CHRONIC 2 (4X)

 

NECROSIS, NOS 1 (2%) 2 {<»*)

 

NECROSIS, FOCAL 2 (t%)

 

ACANTHOSIS 

*1APGE INTESTINE C»8) (50)

 

PAEASITISfl 8 (17*) 7 (14X)

 

I»FASCT, NCS 

OBINABY SYSTF.B 

•KIDNEY (48) (50)

 

IKFLABBATICN, CHRONIC 42 (88*) 45 (90X)

 

CALCIFICATION, DOS 1 (2*) 

PIGHENTATIC», DOS 

HEMOSIDEFCSIS 2 (IX)

 

*KIDHEI/TOB01E C*8) (50) 

PJtGHfNTiTICN. KOS 1 12SL_ . 

I NOBBER OF fNIHAlS WITH TISSUE EXAMINED HICRCSCOPICAILY
 

* NOBBE3 OF ANIBAtS NECPCPSIED
 

HIGH DOSE 

(50) 

(50) 

2 (4X) 

(50) 

(50) 

10 (20X) 

36 (72X) 

(50) 

3 (6X) 

13 (26X) 

(U8) 

1 (2X) 

1 (2X) 

1 (2X) 

(U9) 

7 (14X) 

(50) 

45 (90%) 

(50) 

(50) 

(50) 

3

(50) 

(50) 

2

6

32

(49) 

2

11

(49) 

1

1

1

1

(49) 

12

1

(50) 

44

2

(50) 

 (6X) 

 (4*) 

 (12X) 

 (64*) 

 O«) 

 (22X) 

 (2X) 

 (2X) 

 (2X) 

 (2X) 

 (24*) 

 (2X) 

 (88X) 

 (tX) 

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

 

UNTREATED VEHICLE 

CONTROL CONTROL 

ENDOCRINE SYSTIH 

•PITUITARY (*7) («9J

 

CYST. NOS 

HYPEEPLASIA, FOCAL 2 («*} 1 (2*) 

•ADRENAL («8) (50)

 

THROMBOSIS, NOS 1 (2%)

 

HBRORRHAGB 

NECROSIS, NOS 

HECPOSIS, FOCAL 1 (2*) 

BBTABOBPHOSIS PUTTY It (8«) 

J

»ADEENAL COBTIX (U8) (50) 

THEOHBOSIS, HOS 1 (2*) 

DEGENERATION, HOS 1 (8*) 

HYFERPLASIA. NOS 

HYPEBPLASIA, FOCAL 

tADBENAL MEDULLA («8) (50) 

RYPEBPLASIA, NOS 5 (10») 6 (12X) 

•THYBOID («8) (l»9) 

FOLLICULAP CYST, BOS 

HYPERPLASIA, C-CELL l» (8*) 1 (2«) 

•PANCREATIC ISLETS (18) (50)

 

RYPEBPLASIA, NOS 2 (»*) 1 (2%)

 

REPRODUCTIVE SYSTEM 

*BABHAPY GLAN T <t9> 050) 

CYST, HOS 1 (2«)

 

CYSTIC DUCTS 5 (10X) 

INPLABBATICN. CHPONIC 1 (2*) 

HYPBRPLASIA, CYSTIC 

•PEEPUTIAL GLAND (U9) (50) 

IHPLABSATICN. NOS 1 (2*)

 

INFLABBA^ICH, CHRONIC 

HYPEHPLASIf, HCS 

•PROSTATE («6) (49) 

IBFtAHHATICH. ACOTE 2 <1J> _„„ . , ,. _ 

t NHBBER OF ANIMALS HITH TISSUE EXAMINED MICBOSCOPICA1LI
 

* NUMBER OF SHIBALS NECHOPSIED
 

72
 

LOW DOSE 

(««) 

3 (7«) 

(50) 

1 (2«) 

2 (««) 

(50) 

(50) 

9 (18*) 

(OK) 

1 (2*) 

2 (5*) 

(«9) 

(50) 

(50) 

2 («%) 

1 (2%) 

(50) 

1j (22X) 

HIGH DOSE 

(50J 

1 (2X) 

1 (2%) 

(50) 

1 (2») 

1 (2%) 

(50) 

1 (2%) 

1 (2«) 

1 (2*) 

(50) 

9 (18%) 

(«8) 

2 («*) 

(50) 

1 (2*) 

(50) 

1 (2*) 

2 (»*) 

1 (2*) 

(50) 

1 (2*) 

(50) 

7 n»«) 
TABLE C1.MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

UNTREATED 

CONTROL 

VEHICLE 

CONTROL 

INFLABBATICN, CHSOKIC 

NECSOSIS, »OE 

7 (15*) 17 (35X) 

2 (UX) 

fTESHS 

HEMORRHAGE 

ABSCESS, NCS 

INFLABBATICN, CHROMIC 

PEFIARTERITIS 

DiGENERATICN, NOS 

HYPERPLASIA, INTERSTITIAL CEIL 

(UI4) 

1 (2X) 

2 (5X) 

11 (25*) 

10 (23X) 

(18) 

1 (2X) 

3 (6X) 

13 (27X) 

*EPIDIDYMIS 

STE.VTITIS 

ISFLAHBATICN, ACOTE 

INFLAMMATION, CHRONIC 

NECROSIS, KOS 

NECROSIS, FAT 

(U9) 

1

1

 (2%) 

 (2X) 

(50) 

1 (2X) 

1 <2X) 

*SCROTIIB 

NECROSIS, FAT 

(U9) (50) 

1 (2X) 

fERVOUS SYSTEM
 

ICEREBELLDH (U8) (50)
 

HEMORRHAGE
 

SPECIAL SENSE ORGANS
 

*EYE (U9) (50)
 

HEBORFHAGE 3 (6X)
 

SYNECHIA, ANTERIOR 1 (2X)
 

SYNECHIA, POSTERIOR 1 (2X) 2 (!»*)
 

CiTARACT 1 (2X) 2 («*)
 

PHTHISIS 3ULBI 1 (2X)
 

•EYE/FETINA	 (K9) (50)
 

INFLAMMATION, CHRONIC 1 (2X)
 

DEGENERATION, NOS 1 (2*) 1) (8X)
 

MUSCULOSKELETAI SYSTEM 

NON£ 

*	 NUBBER OF ANIBALS HITH TISSOE EXAHINED BICROSCOPICALLY
 

*	 NUBBE? OF ANIBALS NECROPSIED
 

• "~ "*~~~* **-•
 

LOW DOSE HIGH DOSE
 

« (8*) 3	 (6X)
 

(19)	 (19)
 

1 (2X)
 

11 (22X)
 

18 (37X) 19 (39X)
 

(50)	 (50)
 

2 («X)
 

1 (2X)
 

1 1 2*)
 

1	 (2X) 1 (2X)
 

(50) (50)
 

(49)	 (50)
 

1 (2X)
 

(50) (50)
 

4	 (8X)
 

1	 (2X)
 

(50)	 (50)
 

1 (8X)
 

73 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)

 

UNTREATED 

CONTROL 

VEHICLE 

CONTROL LOW DOSE HIGH DOSE 

BODY CAVITIES 

• MEDIASTINUM 

HEMORRHAGE 

(19) 

1 (2%) 

(50) (5C) (50) 

• ABDOMINAL CAVITY 

STEATITIS 

NBCROSIS, FAT 

(49) (50)

7 (1U%) 

 (50) (50) 

1 12%) 

•MESENTERY 

STEATITIS 

INFLAMMATICN .

PERIARTERITIS 

NECROSIS, FAT 

 CHRONIC 

(M9) 

1 (2*) 

(50) (50) 

1 (2*) 

2 (K%) 

(50) 

2

1

 («*) 

 (2X) 

ALL OTHER SYSTEMS 

NONE 

SPECIAL (IOPPHCIOGY SUMBAFY 

NO LESION BEPORTED 

AUTO/NECPCPSY/HISTO PESF 

ADTOLYSIE/KO NECROPSY 

» NUHBER OF ANIMALS HITH TISSOE EXAMINED KICROSCOPICALLY 

* NUMBER OF BNIMALS NECROPSIED 

74 
TABLE C2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

ADMINISTERED SULFISOXAZOLE BY GAVAGE 

UNTREATED VEHICLE 

CONTROL CONTROL LOW DOSE 

ANIMAL S INITIALL Y IN STIJEY 50 50 50 

ANIMAL S NECROPSIED 50 50 50 

ANIMALS EXAMINED HISTOPATHOLOGICSLLY 50 50 50 

INTEGUMENTAR Y SYSTEM 

*SKI(i (50) (50) (50)

 

EPIDERMA L INCLUSION CYST 1 (2%) 

INFLAMMATION , CHBONIC 1 (2%)

 

*SOBCOT TISSUE (50) (50) (50)

 

NECROSIS. FAT 

RESPIRATORY SYSTE M 

tTEACHEA (50) ("9) (50)

 

CALCIFICATION, NOS 1 (2%)

 

tLUNG (50) {»9) <5C) 

HEMORRHAG E 12 (2U«) 8 (16%) 7 (14%) 

PNEUMONIA , ASPIPATION 1 (2X) 

ABSCESS, NCS 1 (2%) 

PNEUMONIA , CHRONIC HUPINE U6 (92%) 44 (90%) 50 (100%) 

HYPEBPLASIA, ALVEOLA? EPITHELIUM 

HEMATOPOIETIC SYSTEM 

*BON£ HARROW (50) (50) (50)

 

HYPOPLASIA, NOS 1 (2%) 

tSPLEEH (50) (50) (50) 

ECTOPIA 1 (2%) CONGESTICR, NOS 1 (2%) 

HEMORRHAG E 1 (2%) 

HfiMOSIDEEOSIS 9 (18%) 13 (26%) 10 (20%) 

ATROPHY, NCS 1 (2%) 

HEMATOFOIEEIS _ ,. ._ 9 (18Si _ _ 3 (6%) _. 

I NUMBER OP ANIMALS HITH TISSDE EXAMINED MICROSCOPICALLY
 

* NDHBEB OF ANIHALS NECROPSIED
 

HIGH DOSE 

50 

50 

50 

(50) 

(50) 

1 (2%) 

(50) 

(50) 

3 (6%) 

47 (94%) 

2 (4%) 

(50) 

(49) 

4 (8%) 

1 (2%) 

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

IHESENTERIC t. NODE
 

HEHOR1HAGI
 

HECPOSIS, NOS
 

*THYSUS
 

HEMORRHAGE
 

CIRCOLATOBI SYSTEM
 

tHEABT
 

PERIARTBFITIS
 

*HEAET/ATRIOI1
 

THROMBOSIS, NOS
 

•MYOCARDIUM
 

INFLAMMATION, CHRONIC
 

FIBROSIS
 

DEGENERATION, NOS
 

CALCIFICATION, NOS
 

DIGESTIVE SYSTIM
 

t LIVER
 

HEMORRHAGE
 

HEPATITIS, TOXIC
 

NECROSIS, KOS
 

NECROSIS, FOCAL
 

INFAPCT, NCS
 

MBTAMORFHOSIS FATTY
 

FOCAL CELLGLAR CHANGE
 

HENATOPOIEEIS
 

ILIVEF/CENTPIIOBULAR
 

NSCROSIS, NOS
 

*BILE DOCT
 

BILE STA?IS
 INFLAMMATICN, CHRONIC
 

FIB30SIS
 

HYPERPLASIA, NOS
 

*PANCEEAS
 

INFLAMMATION. CHRONIC
 

* NOMBER OF ANIflSLS WITH TISSUE

* W'MBES OF ANIMAL S NECPOPSIED 

UNTREATED VEHICLE
 

CONTROL CONTROL
 

(U9) (50)
 

1 (2*)
 

1 (2%)
 

(37)	 (10)
 2 (5%)
 

(50)	 (19)
 

1 (2X)
 

(50)	 («9)
 

2 (a*)
 

(50)	 (t9)
 13 (26%) 3 (6X)
 

20 (UOX) 5 (10%)
 

3	 (6*) 5 (10X)
 

1 (2*)
 

(50)	 (50)
 

2 (««)
 

1 (2X) 1 (2*)
 1 <2t) 3 (6%)
 

1 <2X)
 

2 («*) U (8%)
 

38 (76X) 29 (58%)
 

1 (2%)
 

(50)	 (50)
 

2 («X)
 

(50)	 (50)
 

2 («*)
 

6 (12X) 5 (10%)
 

17 (31%) 7 d«%)
 

(50)	 (50)
 

1 12»i_ _
 

 EXAMINE D MICROSCOPICALLY 

76 

LOW DOSE
 

(50)
 

(2«)
 

(50)
 

(50)
 

(50)
 

9 (18%)
 

2 (<*%)
 

1 (2%)
 

(50)
 

1 (2%)
 

1 (2%)
 

10 (80%)
 

(50)
 

(50)
 

1 (2%)
 

7 (11%)
 

(50)
 

HIGH DOSE
 

(50)
 

(17)
 

1 (6«)
 

(50)
 

(50)
 

(50)
 

10	 (20%)
 

6 (12%)
 

8 (16%)
 

(50)
 

1 (2%)
 

1 (2%)
 5 (10%)
 

39 (78%)
 

(50)
 

1 (2%)
 

(50)
 

3 (6%)
 

10 (20%)
 

(«9)
 

1 (2*1
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

PESIARTEFniS
 

ATROPHY, NCS
 

ATROPHY, FCCAL
 

IPANCREATIC IOCT
 HYPERPLASIA, FOCAL
 

ISTOHACH
 CYST, NOS
 HEMORRHAGE
 DICER, NOS
 

ULCER, FOCAL
 INFLAMMATION, CHRONIC
 NECROSIS, DOS
 

CALCIFICATION, NOS
 

ACANTHOSIS
 

IGASTRIC SUBMOCOSA
 

IDEHA, DOS
 

tLARGE INTESTINE
 

PARASITISM
 

1 COLON
 

PARASITISM
 

UBINABY SYSTEK
 

(KIDNEY
 INFLAMMATION, CHRONIC
 

METAMORPHOSIS FATTY
 

PI6MENTATICN, NOS
 

IKIDSEY/TUBDII
 

PIGMENTATION, NOS
 

ENDOCRINE SYSTEM
 

«PITDITAHY
 CYST, NOS
 

HEMORRHAGE
 HEMATOHA, DOS
 PIGMENTATION, NOS _
 

UNTREATED
 CONTROL
 

5 (10%)
 

1 (2X)
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

7 (1U%)
 

(50)
 

(50)
 

38 (76X)
 

1 (2t)
 

(50)
 

(U7)
 

1 (2*)
 

2 (»*)
 

VEHICLE
 CONTROL
 

2 (4X)
 

(50)
 

(50)
 

1 (2*)
 

1 (2%)
 

1 (2X)
 

1 (2*)
 

(50)
 

(50)
 

7 (1U%)
 

(50)
 

(50)
 

20 («OX)
 

(50)
 

(49)
 

2 C»%)
 

3 (6%)
 

LOW DOSE
 

1 (2%)
 

3 (6*)
 

(50)
 

(50)
 

1 (2X)
 

3 (6»)
 

(50)
 

(50)
 

5 (10%)
 

(50)
 

(50)
 

22	 (UU%)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

5 (10%)
 

2 (U%)
 

HIGH DOSE
 

7 (1«X)
 

(K9)
 

1 (2%)
 

(t9>
 

1 (2*)
 

1 (2%)
 

(U9)
 

1 (2%)
 

(«9)
 

(H9)
 

8 (16%)
 

(50)
 

29 (58%)
 

(50)
 

1 (2%)
 

(50)
 

3 (6%)
 

2 («%)
 

1 (2%)
 

i NUMBER OF ANIMALS UITH TISSUE EXAMINED MICPOSCOPICALLY
 

* NUMBE? OF ASIMALS NECROPSIED
 

77
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

-1 _,. ... 11 __ IT -_r 

UNTREATED VEHICLE 

CONTROL CONTROL 

HYPERPLASIA .

HYPBBPLASIA,

ANGIECTASIS 

 NOS 

 FOCAL 

1

a

 (2*) (9%) 

1 (2*) 

5 (10%) 

1 (2X) 

IAD5ENAL (50) C*9) 

THROMBOSIS, NOS 1 (2X) 

HEMORRHAG E 1 (2%) 

ANGIECTASIS 1 (2%) 

IADSBNAL COPTIX (50) (U9) 

THROMBOSIS, NOS 

DEGENERATION, NOS « <8X) « (8X) 

ANGIECTASIS 2 (<t%) 

fADRENAL HEC01LA (50) (U9) 

HYPERP1ASIA, NOS •3 (6«) 

tTHYFOID («9) (t7) 

INFLAMMATION, CHSONIC 

FIBROSIS 

HYPERPLASIA, C-CELL 

1 (2%) 

1 (2*) 

3 (6X) 2 («X) 

tPANCPEATIC ISLETS (50) (50) 

HYPERPLASIA , NOS 

REPRODUCTIVE SYSTEM 

• MAMMAR Y GLAH I (50) (50) 

GALACTOCELF 2 (»X) 1 <2X) 

CYST, NOS 9 (18%) 2 («X) 

CYSTIC DUCTS 7 (1»X) 22 (tttX) 

INFLAMMATION , ACOTB 1 (2X) 

INFLAMMATION , CHRONIC 1 (2%) 

HYPERPLASIA , NOS 

HYPEPPLAEIi, CYSTIC 

*PSEPOTIAL GIAND (50) (50) 

NECROSIS, NOS 1 (21) 

*DTEHUS (50) (l»9) 

HYDROMETR A 1 <2X) 1 (2X) 

HEMORRHAGE 

PYOHETBA 

*OTEBOS/ENDC BETE IDM (50) (i»9) _ INFLAMHiTICN, VESICULAR 3 MOSL 

I NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBEP OF ANIMALS NECSOPSIED
 

LOW DOSE 

3 (6X) 

1 (8X) 

(50) 

1 (2X) 

(50) 

2 («X) 

5 (10X) 

(50) 

3 (6X) 

(50) 

3 (6X) 

(50) 

1 (2X) 

(50) 

22 (K«X) 

1 (2X). 

2 (UX) 

(50) 

(«9)

1 <2X) 

C»9) 

HIGH DOSE 

1 (2X) 

3 (6X) 

(50) 

1 (2X) 

(50) 

5 (10X) 

(50) 

(H9) 

8 (16X) 

l«9) 

(50) 

3 (6X) 

1 <2X) 

24 (USX) 

(50) 

(«8) 

1 (2X) 

1 (2X) 

(«8) 

„,.„, < 

78
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

— — • —— —— ——
 UNTREATED VEHICLE
 

CONTROL CONTROL LOW DOSE
 

*OVARY/PAROVARIAN (50) (19) (19)
 NECROSIS, FAT 1 (2*)
 

tOVA&Y (50) (U9) (19)
 

CYST. NOS 1 (2*) 1 (2X) 3 (6%)
 

PAROVARIAN CYST 1 (2*)
 

HEMORRHAGE 1 (2*)
 

NERVOUS SYSTEM
 

i BRAIN (SO) (50) (50)
 

HYDROCEPEA1US, NOS 1 (2%)
 

tCEHEBELLUM (50) (50) (50)
 

HEMORRHAGE 1 (2«)
 

SPECIAL SENSE ORGANS
 

*EYE (50) (50) (50)
 

SYNBCHIA, ANTERIOR 1 (2%) 1 (2%)
 

SYNECHIA, POSTERIOR 1 (2%)
 CATARACT 1 <2X) 1 (2*)
 

PHTHISIS BDLBI
 

*EYE/CORNEA (50) (50) (50)
 

INFLAMMATION, CHRONIC 1 (2%)
 

•EYE/IRIS	 (50) (50) (50)
 

INFLAMMATION, CHRONIC 1 (2%)
 

•EYE/FETINA	 (50) (50) (50)
 

INFLAMMATION, CHRONIC 1 (2%)
 

DEGENERATION, NOS 1 (2%) 1 (2%) U (8%)
 

HOSCULOSKELETA1 SYSTEM
 

NONE
 

EOtY CAVITIES
 

*ABDOMINAL CAVITY (50) (50) (50)
 

ST.EATITIS ...... 1 (2%>
 

t NUMBER OF ASIMALS WITH TISSOE EXAMINED MICROSCOPICALIY
 

* BOMBER OF ANIMALS NECSOPSIID
 

HI6H DOSE
 

(18,
 

(<»S)
 

(50)
 

(50)
 

(50)
 

1 (2*)
 

(50)
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%i
 

79
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

UNTREATED 

CONTROL 

VEHICLE 

CONTROL LOW DOSE HI8H DOSE 

NECROSIS,

•HESHHTBRY 

NECROSIS,

 FAT 

 TAT 

1

(50) 

1

 (2*) 

 (2X) 

3

(50) 

 (6*) 2 (»«) 

(SO) 

1 (2*) 

2

(50) 

 {«*) 

ALL OTHER SYSTEMS 

HONE 

SPECIAL BOBPHC10GI SOBHAPY 

AUTO/NECBCESY/HISTO PERF 

f NUHBER OF AHIHALS WITH TISSUE

* NPMBER OF AHIHAIS NECRCPSIED 

 EXXHINED MICPOSCOPIC*ILT 

80 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN MICE ADMINISTERED SULFISOXAZOLE BY GAVAGE
 

81
 
82

 
TABLE D1. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

ADMINISTERED SULFISOXAZOLE BY GAVAGE

 

•" LJ*~ -ir-_-i_J--_ i—' IIP..' — 

UNTREATED 

CONTROL 

VEHICLE 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INIT1AILY IN STUDY 

1NIBALS HISSING 

ANIMALS NECP.CPSIED 

ANIMALS EXAHINBD HISTOPATHOLOGICALLY 

50 

1 

149 

49 

50 

50 

50 

50 

50 

50 

50 

49 

l»9 

INTEGUMENTARY SYSTEM 

•SKIS 

INFLAMMATION, CHRONIC 

INFLAMMATION. GP.ANULCMATOUS 

FIBBOSIS 

ACANTHOSIS 

METAPLASIA, OSSEOOS 

(49) 

2 («*} 

1 (2%) 

1 (2%) 

1 (2*) 

(50) (50) 

1 (2*) 

(<»9) 

*SOBCUT TISSUE 

ABSCESS, NCS 

NECPOSIS, FfT 

(49) (50) 

1 (2%) 

1 (2*) 

(50) C»9) 

RESPIRATORY SYSTEM 

*LUNG 

THROMBOSIS, NOS 

EMBOLHS, SIPTIC 

CONGESTION, NOS 

EDEMA, NOS HSMOBBHAGE 

INFLAMMATICN, FOCAL 

PNEUMONIA, CHBONIC MORINE 

LEUKOCYTOSIS, NO? 

(49) 

2 (4%) 

1 (2*) 

1 (2*) 

2 (4«) 

1 <2») 

(50) 

1 (2*) 

5 (10%) 

2 (4*) 

1 (2%) 

2 (4») 

(50) 

1 (2%) 

2 (4») 

4 (8%) 

1 (2*) 

(49) 

1 (2%) 

4 (8«) 

5 (10%) 

HEHATOPOIETIC SYSTEM 

IBONE MARROW 

HYPERPLASIA, GRANOLOCYTIC 

HYPEHPLASIA, MEGAKABYOCYTIC 

MYELOID METAPLASIA 

(49) 

1 (2%) 

(50) 

2 (4«) 

("9) 

3 (6%) 

(49) 

tSPLEEN 

A1F.OPHY€ NCS 

(49) 

. 

(50) 

1...X2SL-..,- ,. 

(50) 

.. • , 

(49) 

2_X*L&I_ 

t NUMBER

* HDH6EB

 OF

 OF

 AKIHALS

 ANIMALS

 WITH TISSDE

 NEC30PSIED 

 EXAMINE D MICROSCOPICALLY 

83 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

UNTP IEATED VEH IICLE CON ITROL CON TROL LOW 01 ISE HIGH IDOSE 

LSUKEMCID FEACTION 

HYPERPLASIA , LYMPHOI D 

HEMATOPOIESIS 

8 

3 

(16X) 

(6X) 

1 

1 

2 

(2X)

(2X) 

(«*) 

1 

7 

(2X) 

(10X) 

2 

3 

<«*)

(6X) 

*CE"VICAL LYMP H NODE 

INFLAMMATION , NOS 

(09) (50) 

1 (2X) 

(50) (09) 

*MESENTBPIC L. NODE 

LYMPHANGIECTASIS 

CCNGBSTICN, NOS 

INFLAMMATION , NOS 

INFLAMMATION , ACUTE 

HYPERPLASIA , RETICOLUM

HYPE8PLASIA, LYMPHOID 

HfiMATOPOIESIS 

 CELL 

(09) 

1 

3 

3 

1 

1 

13 

1 

(2X) 

(fiX) 

(«X) 

(2X) 

(2X)

(27X) 

(2X) 

(50) 

11 

5 

(22X) 

(10X) 

(50) 

2 

2 

1 

5 

1 

(OX) 

(OX) 

(2X) 

(10X) 

(2X) 

(09) 

2 

3 

1 

(0*) 

(6X) 

(2X) 

CISCOiATORY SYSTEM 

•HEART (89) (50) (50) 

MINERALIZATION <2X ) 

DILATATION, NOS 1 (2%) 1 (2X) 

PiRIARTERITIS 1 (2X) 

METAPLASIA, C5SEODS 1 (2%) 

tAOPICUHR APPENDAG E (09) (50) (50) 

THROMBOSIS, NCS 1 (2%) 

•MYOCARDIUM (50) (50) (09) 

INFLAMMATION, FOCAL 1 (2X) 

DEGENERATION, NOS 1 (2X) 

•AORTA (09) (50) (50) 

INFLAMMATION, NOS 1 (2X) 

DIGESTIVE SYSTEM 

tLIVEE (tt9) (50) (50) (09) 

CYST, NOS 

"HHOHBOSIS, NOS 

1 (2*) 

2 (OX) 1 (2X) 

ABSCESS, NCS 1 (2X) 

NECROSIS, KOS 

INPARCT, NCS 

3

3

 (6X) 

 (6») 

1 (2%) 1

0

 (2X) <8X) 

AHYLOIDOSIS 

* NUMBER OF AMMALS HITH TISSUE EXAMINED MICROSCOPICALLY * NUMBER OF ANIMAL S NECRCPSIED 

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

UNTREATED VEHICLE
 CONTROL CONTROL
 

KETANOBPHOSIS FATTY
 

FOCAL CELIUIAR CHANGE	 1 (2%)
 

AMGIBCTASIS
 

•LITER/CENTRIIOBOLAR	 (09) (50)
 

NECROSIS, NOS 1 (2%)
 

•LITER/PERIPCBTAI	 (09) (50)
 

FI BROS IS 1 (2%)
 

• BILE DUCT (09) (50)
 

CYST, NOS


HYPEPPIASIA, NOS 1 (2»)
 

• ESOPHAGUS (09) (50)
 

RUPTURE 1 (2%)
 

INFLAMMATION, SUPPURATIVE
 

•STOMACH	 (09) (09)
 

OLCES, FCCAL 3 (6%) 2 (0%)
 

HYPERKERATOSIS
 

AC1NTHOSIS
 

•PEYERS PATCH (09) (09)
 

HYPERP1ASIA, LYHPHOID 1 (2%)
 

• LARGE INTESTINE (09) (50)
 

INFLANNATICN. ACUTE
 

NEMATODIASIS 1 (2<) 2 (0%)
 

DRINABY SYSTEM
 

• KIDNEY (09) (50)
 

HYDRONEPBROSIS
 

THROMBOSIS, BOS 1 (2%)
 

CONGESTION, ROS 1 (2X)
 

INFLAMMATICN, CHRONIC 6 (12%) 9 (18%)
 

ISFLAKHATICN. CHRONIC DIFFUSE 1 (2%)
 

MKTAPLASIA, OSSEOUS
 

•URINARY	 BLADDER (09) (50)
 

INFLAMMATION, CHRONIC 2 (0%)
 

HYPEFPLASIA. EPITHELIAL
 

* NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICA1LY
 

* NUMBE? OF ANIMALS NECRCESIED
 

85
 

LOW DOSE
 

1 (2%)
 

2 (0%)
 

(50)
 

(•50)
 

(50)
 

(09)
 

1 (2%)
 

(50)
 

(50)
 

3 (6%)
 

(50)
 

10 (28%)
 

(50)
 

., .,_
 

HIBHDOSE
 

(09)
 

1 (2%)
 

(09)
 

(09)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

(09)
 

1 (21)
 

2 (0»)
 

2 («)
 

(09)
 

(07)
 

1 (2%)
 

1 (2%)
 

(09)
 

2 (0%)
 

10 (29%)
 

1 (2%)
 

(09)
 

1 12»
 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

UNTREATED VEHICLE 

CONTROL CONTROL 

INDOCilNE SYSTEM 

•PITUITARY («0) (33)
 

CYST, HOS 2

 

IADPENAL 

CONGESTION, NOS 

IADRBHAL MEDULLA (48) (49) 

HYPERPLASIA, NOS 2 (4«) 

tTHYROID (47) (47) 

HYPEHPLASIA, C-CELL 1 (2»)

 

REPRODUCTIVE SYSTEM 

•PREPUTIAL GIAN D (49) (50)

 

DISTBNTICN 

tPROSTATE (49) (50) 

INFLAHHA^ICN, SUPPORATIVE 1 (2*) 

INFLAMMATION, ACUTE 

•SEMINAL VESICLE (49) (50) 

DISTENTICS 

ATROPHY, NCS 1 (2*) 

tTESTIS (49) (50) 

ATROPHY, KCS 2 (4%) 

HYPOSPERHATOGENESIS 

•EPIDIDYMIS (19) (50) 

SBANULOMA, SPEBNATIC 

MEHVOUS SYSTEM 

NONE 

SPECIAL SENSE CRGA8S 

*IYE (49) (50) ABSCESS. CHBONIC 1 (2X1 

t NUHBER OF ANIMALS RITH TISSUE EXAMINED MICROSCOPICALLY
 

* NDMBEP OF ANIMALS HECROPSIED
 

86 

LOW DOSE
 

(46)
 

(49) 

(48) 

(50) 

(50) 

1 <2X) 

(SO) 

1 (2X) 

(47) 

4 (9«) 

(50) 

2 (4%) 

(50) 

HIGH DOSE
 

(39)
 

(49) 

0»8) 

(49) 

1 (2X) 

(49) 

(49) 

2 («*) 

(48) 

1 (2X) 

(49) 

1 (2%) 

(49) 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

UNTREATED

CONTROL

 VEHICLE 

 CONTROL LOW DOSE HIGH DOSE 

HOSCULOSKELETAL SYSTEM 

NONE 

EODY CAVITIES 

•HEDIASTINUM

INFLAMMATION , CHBONIC

 (49) (50) (50) (19) 

2 (4%) 

•ABDOMINAL CAVITY

NECROSIS, FAT

 (49) (50) (50) (49) 

1 (2*) 

•PERITONEUM

INFLAMHATICN, NOS

 (49) (50) (50) (49) 

1 (2%) 

*PLEUBA

INFLAMMATION, INFLAMHATICN, SOPPURATIVE

 CHFONIC SOPPURATIV

 (49) (50)

 1 (2%) 

 (50) (49) 

1 (2») 

•PERICARDIUM

INFLAMMATION . CHBONIC

 (49) (50) (50) (49) 

1 

ALL OTHEF SYSTIMS 

•MULTIPLE ORGANS

EMBOIUS, SIPTIC

LEUKOCYTCSIS, NOS

LEDKEMOID PBACTION

 (U9)

 1 (2X) 

1 (2%) 

 (50) (50)

 1 (2%) 

 (49) 

SPECIAL MOFPHCLOGY SDMMABY 

N O LESION BEPOBTED

ANIMA L HISSING/NO NECROPSY

AUTOLYSIS/NO NECROPSY

 1 

5 7 8 7 

1 

I NUMBER

* NUMBER

 OF

 OF

 ANIMAL S

 ANIMALS

 HITH TISSUE EXAMINE D

 NECROPSIED 

 MICROSCOPICALLY 

87 
TABLE D2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONSIN FEMALE MICE 

ADMINISTERED SULFISOXAZOLE BY GAVAGE

 

UNTREATED 

CONTROL 

VEHICLE 

CONTROL LOW DOSE HIGH DOSE 

IKIHALS INITIAILY IN STOEY 

INIMALS HISSING 

JNIHALS HECPCFSIED 

MIHALS EXAMINE D HISTOPATHO LOGICALLY 

50 

50 

50 

50 

1 

U9 

49 

50 

50 

50 

50 

50 

50 

WEGUMENTASY SYSTEM 

NONE 

RESPIRATORY SYSTEM 

*LUNG 

CONGESTION, NOS 

HEMORRHAGE 

PiiEOMONI*, CHPONIC MURINE 

PIGMENTATION. NOS 

ALVEOLAR KACROPHAGES 

LEUKOCYTGSIS, NOS 

(50) 

1 (2%) 

3 (6X) 

1 (2») 

(119) 

1 (2X) 0 (8X) 

a (8%) 1 <2X) 

1 (2X) 

(50) 

1 (2*) 

1 (2%) 

(50) 

2 (»%) 

2 («%) 

HEMATOPOIETIC SYSTEM 

•BONE HARROW 

riB?0!IS OSTEODYSTROPHY 

HYPEPPLASIA, GRANOLOCYTIC 

(50) 

1 (2*) 

(«9) (50) 

1 (2«) 

(50) 

ISPLiEN 

HYPERPLASIA. LYMPHOID 

HSMATOPCIESIS 

(50) 

3

1

 (6%) 

(2X) 

(U9) 

7 (1ttX) 

(50) 

5 (10X) 

3 (6%) 

(50) 

1 (2») 2 («») 

ICERVICAL LYMFH NODE 

HYPERPL1SIA, LYMPHOID 

(<»8) (It8) 

1 (2X) 

(50) (50) 

tMESENTEPIC L. NODE 

INFLAMMATION, NOS 

HYPERPLASIA, LYMPHOID 

(U8) 

H (8X) 

(«8) 

1 (2X) 

5 (10%) 

(50) 

5 (10X) 

(50) 

« (8») 

IREN1L LYMPH NODE 

HYPEKPIASIA, IYMPHOID 

(18) 

,

(«8) 

-, . „ .. „ _ 

(50) 

1 I2X) 

(50) 

* NUMBER

* NUNBE5

 OF

 OF

 ANIMAL S

 ANIMAL S

 WITH TISSUE

 NECROPSIED 

EXAMINED MICROSCOPICALLY 

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

fTHYMUS
 

HYPEHPLASIJ, LYHPHOID
 

CIPCHLATORY SYSTEM
 

» HEART
 

PBRIARTERITIS
 

DIGESTIVE SYSTEM
 

•LIViR
 

CONGESTION, NOS
 

H£HORP.HAGE
 

NECROSIS, NOS
 

tBILE DOCT
 

CYST, NOS
 

•PANCREAS
 

CYSTIC DtlCTS
 

iPANCREATIC ACINUS
 

ATBOPHY, NOS
 

tSTOMACH
 INFLAMMATION, FOCAL
 

OJ.CER, FCCAL
 

INFLAHHATICN, CHPONIC
 

IGASTHIC HOCCSA
 

RYPEEPLASIA, FOCAL
 

IGASTHIC SOBHDCOSA
 

1DENA. NOS
 

ILARGE INTESTINE
 

NSHATODIASIS
 

08INASY SYSTEE
 

IKIDNET
 

CYST. NOS
 

UNTREATED
 

CONTROL
 

(29)
 

(50)
 

1 (2«)
 

(50)
 

1 (2%)
 

1 (2*)
 

1 (2%)
 

(50)
 

(50)
 

3 (6*)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

(50)
 

C»9)
 

1 (2%)
 

(50)
 

1 12%)
 

VEHICLE
 

CONTROL
 

(29)
 

1 (3X)
 

(U9)
 

(49)
 

(U9)
 

(19)
 

3 (6%)
 

(U9)
 

1 (2X)
 

(U9)
 

2 (1%)
 

1 (2%)
 

(U9)
 

(U9)
 

(U9)
 

(19)
 

LOW DOSE
 

(21)
 

(50)
 

(50)
 

1 (2X)
 

(50)
 

1 (2«)
 

(50)
 

« (8X)
 

(50)
 

(19)
 

1 (2»)
 

(19)
 

1 (2«)
 

(«9)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

HIGH DOSE
 

(20)
 

(50)
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

1 (2X)
 

(50)
 

(50)
 

(50)
 

1 (2X)
 

(50)
 

* NUMBER OF ANIHALS KITH TISSUE EXAMINED MICBOSCOPICALLY
 

» HDHBER OF ANIMALS NECPCPSIED
 

89
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

UNTREATED VEHICLE 

CONTROL CONTROL

PYELONEPHRITIS, NOS 

INFLAHHATICN, CHPONIC 5 (10*) 

PtfRIARTEBITIS 

GLOHHSULOfCLBBOSIS. AMYLOIDOSIS  ROS 

1 (2*) 

1 (2X) 

1 (2«) 

METAPLASIA. OSSEOUS 

tKIDMEY/TUBOLE (50) (49)

PIGHBNTATICN, NOS 

tORINARY ELIEDER (49) (48)

AHYLOIDOSIS 1 (2*) 

ERDOCEIHE SYSTEN 

•ADRENAL CORTIX (50) (48)

DEGENERATION, ROS 

HYPERTROPHY, NOS
 

tTHYBOID (49) 

CYSTIC F011ICLBS 1 (2*) 

INFLAMMATION, CHRONIC 1 (2*) 

HYPBRPLASIA. FOLLICULAR-CBLL 1 (2X) 

{••PRODUCTIVE SYSTEM 

•MAMMARY	 GLAMI (50)
 METAPLASIA, SQOAHOUS 1 (2X)
 

IDTBRUS (50) (49)
 

HYDROMETRA 1 (2%)
 THROMBOSIS, ROS
 

ANGIECTASIS 1 (2*)
 

IUTB1US/BNDC HETBI0n (50) (49)
 

INFLAMMATION, SUPPOBATIVE
 

HYPBRPLASIA, CYSTIC 41 (82*) 45 (921)
 

tOTARY (50) (49)
 

CYSTIC FOIIICLBS
 POLLICDLAP CYST, ROS 4 (8*)
 

PAROTARIAN CYST 7 (14X) 9 (18X)
 

HSHORHHAGIC CYST
 

I ROHBBR OF AHIHALS WITH TISSOE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECRCPSIED
 

90
 

 LOW DOSE 

1 (2*) 

3 (6*) 

 (50) 

1 (2X) 

 (49) 

 (49) 

(48)
 

(50)
 

(50) 

1 (2X) 

(50) 

42 (84X) 

(50) 

4 (8X) 

5 (10X) 

1 IU*1 

HI6H DOSE 

1 (2() 

1 (2») 

(50) 

(50) 

(50) 

1 (2*) 

(46)
 

(50)
 

(50) 

1 (2*) 

(50) 

44 (88X) 

(50) 

8 (16*) 

11 (22*) 1 (2«) 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

—­. > ' 

UNTREATED

CONTROL

 VEHICLE 

 CONTROL LOW DOSE HIGH DOSE 

INFLAHHATICN, NOS 

f RIGHT OTABT 

PAROTARIAN CYST 

THROMBOSIS, NOS 

ILEFI OTARI 

THRONBOS, ORGANIZED 

HKMOPHHAGIC CYST 

1 (2%) 

(50)

1 (2%) 

(50)

1 (2*) 

 («9) 

 (U9) 

(50) 

1 (2V) 

(50) 

1 (2%) 

(50) 

(50) 

NIRVOUS SYSTEH 

tBFAIN 

COMPRESSION 

HSHATOfOIBSIS 

(50) (U8) (50) 

1 (2%) 

1 (2*) 

(50) 

SPECIAL SENSE ORGANS 

•EYE 

INFLAHHATICN, NOS 

PHTHISIS EtlLBI 

(50) (K9) 

1 (2%) 

1 (2») 

(50) (50) 

MQSCQLOSKBLETAI SYSTEM 

• SKELETAL MOSCLE

PARASITISM

 (50)

 1 (2%) 

 (19) (50) (50) 

BODY CAVITIES 

• PERITONEUM

INFLAMMATION, NOS

 (50)

 2 («*) 

 (49) (50) (50) 

ALL OTHER SYSTEMS 

NONE 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION FEEOBTED ] 2 1— 

* NOHBEB OF A1IHALS ilTH TISSOE EXAMINED HICPOSCOPICALtY 

* ROBBER OF ANIMALS NECRCPSIED 

91
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

UNTREATED VEHICLE
 CONTROL CONTROL LOW DOSE HIGH DOSE
 

AHIBAL HISSING/NO NECROPSY
 

* NOHBBH OF ANIMALS ilTH TISSDE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECPOPSIED
 

92
 
APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN RATS ADMINISTERED SULFISOXAZOLE BY GAVAGE
 

93
 
94

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

Administered Sulfisoxazole by Gavage (a)
 

Vehicle Low
 

Topography; Morphology Control Dose
 

Integumentary System: Fibroma
 

of the Subcutaneous Tissue (b) 1/50 (2) 6/50 (12)
 

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

Departure from Linear Trend (e) P = 0.026
 

Relative Risk (f) 6.000
 

vo Lower Limit 0.768
 

Upper Limit 269.891
 

Weeks to First Observed Tumor 106 96
 

Hematopoietic System:
 

Monocytic Leukemia (b) 9/50 (18) 6/50 (12)
 

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

Relative Risk (f) 0.667
 

Lower Limit 0.211
 

Upper Limit 1.935
 

Weeks to First Observed Tumor 96 101
 

High
 

Dose
 

2/50 (4)
 

N.S.
 

2.000
 

0.108
 

115.621
 

85
 

8/50 (16)
 

N.S.
 

0.889
 

0.325
 

2.382
 

91
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Sulfisoxazole by Gavage (a)
 

(continued)
 

Topography ; Morphology
 

Hemato pole tic System: All
 

Lymphoma or Leukemia (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VO
 

Liver: Hepatocellular Carcinoma
 

or Neoplastic Nodule (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Vehicle
 

Control
 

11/50 (20)
 

N.S.
 

96
 

1/50 (2)
 

N.S.
 

106
 

Low
 

Dose
 

7/50 (14)
 

N.S.
 

0.636
 

0.228
 

1.645
 

101
 

4/50 (8)
 

N.S.
 

4.000
 

0.415
 

192.805
 

106
 

High
 

Dose
 

10/50 (20)
 

N.S.
 

0.909
 

0.381
 

2.140
 

88
 

2/50 (4)
 

N.S.
 

2.000
 

0.108
 

115.621
 

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

Administered Sulfisoxazole by Gavage (a) 

(continued) 

Topography: Morphology

Vehicle 

 Control 

Low 

Dose 

High 

Dose 

Pituitary : Chromophobe 

Adenoma (b) 4/49 (8) 4/44 (9) 5/50 (10) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.114 

0.220 

5.626 

1.225 

0.280 

5.833 

Weeks to First Observed Tumor 86 99 75 

vo 

Adrenal: Pheochromocy toma or 

Malignant Pheochromocy toma (b) 5/50 (10) 10/50 (20) 10/50 (20) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

2.000 

0.675 

6.944 

2.000 

0.675 

6.944 

Weeks to First Observed Tumor 91 97 89 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Sulfisoxazole by Gavage (a)
 

(continued)
 

Vehicle Low
 

Topography ; Morphology Control Dose
 

Preputial Gland: Carcinoma, NOS (b) 2/50 (4) 4/50 (8)
 

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

Relative Risk (f) * ^.000
 

Lower Limit 0.301
 

Upper Limit 21.316
 

Weeks to First Observed Tumor 106 103
 

VO Testis: Interstitial-cell
 00
 

Tumor (b) 45/48 (94) 43/49 (88)
 

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

Relative Risk (f) 0.936
 

Lower Limit 0.843
 

Upper Limit 1.082
 

Weeks to First Observed Tumor 87 85
 

High
 

Dose
 

3/50 (6)
 

N.S.
 

1.500
 

0.180
 

17.329
 

105
 

46/49 (94)
 

N.S.
 

1.001
 

0.907
 

1.106
 

66
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Sulfisoxazole by Gavage (a)
 

(continued)
 

(a) Dosed groups received 100 or 400 rag/kg. 

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

(c) Beneath the incidence of tumors in the vehicle-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 vehicle-control group when P 

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

(d) A negative trend (N) indicates a lower incidence in a dosed group than in the vehicle-control 

group. 

vo (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 

vehicle-control group. 
Table E2.


Topography: Morphology


Hematopoietic System:
 

Monocytic Leukemia (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

o
 

o
 Weeks to First Observed Tumor


Hematopoietic System: Malignant
 

Lymphocytic Lymphoma or Monocytic
 

Leukemia (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

 Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Sulfisoxazole by Gavage (a)
 

High
 

Dose
 

9/50 (18)
 

N.S.
 

3.000
 

0.803
 

16.338
 

91
 

9/50 (18)
 

N.S.
 

2.250
 

0.676
 

9.394
 

91
 

Vehicle
 

 Control
 

 3/50 (6)
 

P = 0.016
 

 98
 

 4/50 (8)
 

P = 0.033
 

98
 

Low
 

Dose
 

3/50 (6)
 

N.S.
 

1.000
 

0.140
 

7.133
 

106
 

3/50 (6)
 

N.S.
 

0.750
 

0.115
 

4.206
 

106
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Sulfisoxazole by Gavage (a)
 

(continued)
 

Topography! Morphology
 

Hematopoietic System: All
 

Lymphoma or Leukemia (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
 

Veh ic le


Control


6/50 (12)


N.S.


98


18/49 (37)


N.S.


75
 

 Low High 

 Dose Dose 

 3/50 (6) 9/50 (18) 

 N.S. N.S. 

0.500 1.500 

0.085 0.517 

2.200 4.749 

 106 91 

 19/50 (38) 17/50 (34) 

 N.S. N.S. 

1.034 0.926 

0.590 0.513 

1.821 1.667 

77 77 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Sulfisoxazole by Gavage (a)
 

(continued)
 

Vehicle Low High
 

Topography: Morphology Control Dose Dose
 

Mammary Gland: Fibroadenoma (b) 12/50 (24) 16/50 (33) 15/50 (30)
 

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

Relative Risk (f) 1.333 1.250
 

Lower Limit 0.663 0.611
 

Upper Limit 2.754 2.615
 

Weeks to First Observed Tumor 88 99 103
 

o Preputial Gland: Carcinoma, NOS (b) 3/50 (6) 0/50 (0) 1/50 (2)
 10
 

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

Relative Risk (f) 0.000 0.333
 

Lower Limit 0.000 0.006
 

Upper Limit 1.663 3.983
 

Weeks to First Observed Tumor 94
 106 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Sulfisoxazole by Gavage (a)
 

(continued)
 

Vehicle Low
 

Topjography^ Morphology Control Dose
 

Preputial Gland: Carcinoma or
 

Adenoma, NOS (b) 3/50 (6) 0/50 (0)
 

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

Relative Risk (f) 0.000
 

Lower Limit 0.000
 

Upper Limit 1.663
 

o
 Weeks to First Observed Tumor 94
 CO —
 

Uterus: Endometrial Stromal
 

Polyp (b) 5/49 (10) 6/49 (12)
 

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

Relative Risk (f) 1.200
 

Lower Limit 0.327
 

Upper Limit 4.654
 

Weeks to First Observed Tumor 106 106
 

High
 

Dose
 

2/50 (4)
 

N.S.
 

0.667
 

0.058
 

5.570
 

106
 

8/48 (17)
 

N.S.
 

1.633
 

0.509
 

5.913
 

95
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Sulfisoxazole by Gavage (a)
 

(continued)
 

(a) Dosed groups received 100 or 400 mg/kg. 

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

(c) Beneath the incidence of tumors in the vehicle-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 vehicle-control group when P 

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

(d) A negative trend (N) indicates a lower incidence in a dosed group than in the vehicle-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 

vehicle-control group. 
APPENDIX F
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN MICE ADMINISTERED SULFISOXAZOLE BY GAVAGE
 

105
 
106

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

Administered Sulfisoxazole by Gavage (a)
 

Topography; Morphology
 

Integumentary System:
 

Fibro sarcoma of the
 

Subcutaneous Tissue (b)
 

P	 Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Lung: Alveolar/Bronchiolar
 

Adenoma or Carcinoma (b)
 

P	 Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Vehicle


Control


4/50 (8)


N.S.


100


4/50 (8)


P = 0.029 (N)


73
 

 Low	 High
 

 Dose	 Dose
 

 5/50 (10) 3/49 (6)
 

 N.S.	 N.S.
 

1.250	 0.765
 

0.286	 0.118
 

5.954	 4.288
 

 80 92
 

 5/50 (10) 0/49 (0)
 

 N.S.	 N.S.
 

1.250	 0.000
 

0.286	 0.000
 

5.954	 1.100
 

104
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice 

Administered Sulfisoxazole by Gavage (a) 

(continued) 

Topography: Morphology

Vehicle 

 Control 

Low 

Dose 

High 

Dose 

Hematopoietic System: All Lymphoma (b) 3/50 (6) 8/50 (16) 5/49 (10) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

2.667 

0.685 

14.816 

1.701 

0.351 

10.426 

o 

oo 

Weeks to First Observed Tumor 90 77 104 

Hematopoietic System: All 

Lymphoma or Leukemia (b) 4/50 (8) 8/50 (16) 5/49 (10) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

2.000 

0.576 

8.539 

1.276 

0.292 

6.070 

Weeks to First Observed Tumor 89 77 104 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Sulfisoxazole by Gavage (a)
 

(continued)
 

Topography: Morphology


All Sites: Hemangios arcoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

o Weeks to First Observed Tumor
 NO
 

All Sites: Hemangios arcoma or
 

Hemangioma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Vehicle
 

 Control
 

 5/50 (10)
 

 N.S.
 

 63
 

 5/50 (10)
 

 N.S.
 

63
 

Low
 

Dose
 

1/50 (2)
 

N.S.
 

0.200
 

0.004
 

1.699
 

100
 

2/50 (4)
 

N.S.
 

0.400
 

0.040
 

2.313
 

100
 

High
 

Dose
 

3/49 (6)
 

N.S.
 

0.612
 

0.100
 

2.967
 

63
 

3/49 (6)
 

N.S.
 

0.612
 

0.100
 

2.967
 

63
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Sulfisoxazole by Gavage (a)
 

(continued)
 

Topography ; Morphology
 

Liver: Hepatocellular
 

Carcinoma (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma
 

or Adenoma (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Vehicle Low High 

Control Dose Dose 

15/50 (30) 13/50 (26) 20/49 (41) 

N.S. N.S. N.S. 

0.867 1.361 

0.426 0.755 

1.741 2.493 

100 93 71 

15/50 (30) 13/50 (26) 21/49 (43) 

N.S. N.S. N.S. 

0.867 1.429 

0.426 0.802 

1.741 2.592 

100 93 71 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Sulfisoxazole by Gavage (a)
 

(continued)
 

Topography; Morphology 

Vehicle 

Control 

Low 

Dose 

High 

Dose 

Adrenal: Pheochromocytoma 2/49 (4) 5/49 (10) 0/49 (0) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

2.500 

0.433 

25.265 

0.000 

0.000 

3.379 

Weeks to First Observed Tumor 104 93 — 

(a) Dosed groups received 500 or 2,000 mg/kg. 

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

(c) Beneath the incidence of tumors in the vehicle-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 vehicle-control group when P 

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

(d) A negative trend (N) indicates a lower incidence in a dosed group than in the vehicle-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 

vehicle-control group. 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Sulfisoxazole by Gavage (a)
 

Vehicle Low High
 

Topography; Morphology Control Dose Dose
 

Lung: Alveolar /Bronchiolar
 

Adenoma or Carcinoma (b) 0/49 (0) 1/50 (2) 5/50 (10)
 

P Values (c,d) P = 0.006 N.S. P = 0.030
 

Relative Risk (f) Infinite Infinite
 

Lower Limit 0.053 1.237
 

Upper Limit Infinite Infinite
 

Weeks to First Observed Tumor 105 96
 

Hematopoietic System:

Lymphoma (b) 

 All 

16/49 (33) 16/50 (32) 20/50 (40) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.980 

0.521 

1.847 

1.225 

0.690 

2.205 

Weeks to First Observed Tumor 77 73 71 
F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Sulfisoxazole by Gavage (a)
 

(continued)
 

Topography: Morphology


Hematopoietic System: All
 

Lymphoma or Leukemia (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Liver: Hepatocellular
 

Carcinoma (b)


P Values (c,d)


Departure from Linear Trend (e)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Vehicle
 

 Control
 

 17/49 (35)
 

 N.S.
 

 77
 

 0/49 (0)
 

 N.S.
 

P = 0.019
 

Low
 

Dose
 

16/50 (32)
 

N.S.
 

0.922
 

0.496
 

1.709
 

73
 

5/50 (10)
 

P = 0.030
 

Infinite
 

1.237
 

Infinite
 

103
 

High
 

Dose
 

20/50 (40)
 

N.S.
 

1.153
 

0.658
 

2.040
 

71
 

2/50 (4)
 

N.S.
 

Infinite
 

0.290
 

Infinite
 

105
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Sulfisoxazole by Gavage (a)
 

(continued)
 

Topography: Morphology


Pituitary: Chromophobe Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Mammary Gland: Adenocarc inoma,
 

NOS (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Vehicle
 

 Control
 

 2/42 (5)
 

 N.S.
 

 104
 

 5/49 (10)
 

P = 0.018 (N)
 

104
 

Low
 

Dose
 

1/44 (2)
 

N.S.
 

0.477
 

0.008
 

8.824
 

105
 

1/50 (2)
 

N.S.
 

0.196
 

0.004
 

1.665
 

105
 

High
 

Dose
 

1/31 (3)
 

N.S.
 

0.677
 

0.012
 

12.354
 

105
 

0/50 (0)
 

P = 0.027 (N)
 

0.000
 

0.000
 

0.777
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice 

Administered Sulfisoxazole by Gavage (a) 

(continued) 

Vehicle Low High
 

Topography; Morphology Control Dose Dose
 

All Sites: Hetnangioma or
 

Hemangiosarcoma (b) 2/49 (4) 4/50 (8) 1/50 (2)
 

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

Relative Risk (f) 1.960 0.490
 

Lower Limit 0.296 0.008
 

Upper Limit 20.886 9.103
 

Weeks to First Observed Tumor 104	 105 105
 

(a) Dosed groups received 500 or 2,000 mg/kg. 

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

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

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

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 vehicle-control group 

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

(d) A negative trend (N) indicates a lower incidence in a dosed group than in the vehicle-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 

vehicle-control group. 
116

 
Review of the Bioassay of Sulfisoxazole* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup of the
 

Clearinghouse on Environmental Carcinogens
 

August 31, 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
 

(NCI) on its bioassay program to identify and to 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, State health officials, and
 

quasi-public health and research organizations. 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
 

Sulfisoxazole for carcinogenicity.
 

The primary reviewer noted that Sulfisoxazole is a widely used
 

antibiotic for urinary tract infections. She agreed with the conclusion
 

in the report that Sulfisoxazole was not carcinogenic, under the conditions
 

of test. She briefly described the experimental design and noted the
 

absence of any unusual highlights in the conduct or results of the
 

study. The primary reviewer remarked on the lack of toxicity displayed
 

in treated rats and mice, suggesting that maximum tolerated doses may
 

not have been achieved.
 

The secondary reviewer agreed with the conclusion in the report
 

that Sulfisoxazole was not carcinogenic, under the conditions of test.
 

Although the study was adequately conducted, he noted the four-fold
 

difference in dose levels, in both treated rats and mice. He commented
 

on the increased incidence of lung tumors in treated female mice, which
 

appeared to be dose-related, and the negative association for these
 

tumors among treated male rats. The secondary reviewer concluded that
 

the study was a valid test for the carcinogenicity of Sulfisoxazole and
 

that the compound would not appear to pose a risk to humans.
 

A motion was approved unanimously that the report on the bioassay
 

of Sulfisoxazole be accepted as written.
 

117
 
Members present were;
 

Arnold Brown (Chairman), University of Wisconsin Medical School
 

Joseph Highland, Environmental Defense Fund
 

Michael Shimkin, University of California at San Diego
 

Louise Strong, University of Texas Health Sciences Center
 

(Kenneth Wilcox, Michigan State Health Department, submitted a written review)
 

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.
 

•6U.S. GOVERNMENT PRINTING OFFICE: 1978 381 217 326 5 

118 

HEW Publication No. (NIH) 79-1303