National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 53 

1978 

BIOASSAY OF 

2-AMINO-5-NITROTHIAZOLE 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 121-66-4 

NCI-CG-TR-53 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

2-AMINO-5-NITROTHIAZOLE
 

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
 

DHEW Publication No. (NIH) 78-1359
 

BIOASSAY OF
 

2-AMINO-5-NITROTHIAZOLE
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

FOREWORD; This report presents the results of the bioassay of
 

2-amino-5-nitrothiazole 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 environmental 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 animal carcinogens requires
 

a wider analysis.
 

CONTRIBUTORS; This bioassay of 2-amino-5-nitrothiazole was
 

conducted by The Dow Chemical Company, Indianapolis, Indiana,
 

initially under direct contract to NCI and currently under a
 

subcontract to Tracer Jitco, Inc., prime contractor for the NCI
 

Carcinogenesis Testing Program.
 

The experimental design and doses were determined by Dr. E. K.
 

Weisburger^. Dr. C. G. Gerbig^ supervised the preparation of the
 

diets and was responsible for animal care. Histopathologic
 

examinations were performed by Dr. J. L. Emerson^ »•% the
 

principal investigator, and the diagnoses included in this report
 

represent his interpretation. Dr. Emerson also prepared a
 

preliminary draft of sections of this report.
 

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

Mason Research Institute^. The statistical analyses were performed by Dr. J. R. Joiner-*, using methods selected for the
 

bioassay program by Dr. J. J. Gart". Chemicals used in this
 

bioassay were analyzed under the direction of Dr. E. Murrill^,
 

and the analytical results were reviewed by Dr. S. S. Olin^. The
 

structural formula was supplied by NCI-'-.
 

This report was prepared at Tracor Jitco-> under the direction of
 

NCI. Those responsible for the report at Tracor Jitco were
 

Dr. Marshall Steinberg, Director of the Bioassay Program; Dr. L.
 

A. Campbell, Deputy Director for Science; Drs. J. F. Robens and
 

C. H. Williams, toxicologists; Dr. R. L. Schueler, pathologist;
 

Dr. G. L. Miller, Ms. L. A. Waitz, and Mr. W. D. Reichardt,
 

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

assisted by Ms. Y. E. Presley.
 

The statistical analysis was reviewed by members of the
 

Mathematical Statistics and Applied Mathematics Section of NCI":
 

Dr. John J. Gart, Mr. Jun-mo Nam, Dr. Hugh M. Pettigrew, and Dr.
 

Robert E. Tarone.
 

The following other scientists at NCI^ were responsible for
 

evaluating the bioassay experiment, interpreting the results, and
 

reporting the findings: Dr. Kenneth C. Chu, Dr. Cipriano Cueto,
 

Jr., Dr. J. Fielding Douglas, Dr. Dawn G. Goodman, Dr. Richard A.
 

Griesemer, Dr. Harry A. Milman, Dr. Thomas W. Orme, Dr. Robert A.
 

Squire°, and Dr. Jerrold M. Ward.
 

1-Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

Dow Chemical Company, P.O. Box 68511, Indianapolis,
 

Indiana.
 

%ow with Abbott Laboratories, D-469 AP9, North Chicago,
 

Illinois.
 

iv
 
^EG&G Mason Research Institute, 1530 East Jefferson Street,
 

Rockville, Maryland.
 

5

Tracor Jitco, Inc., 1776 East Jefferson Street, Rockville,
 

Maryland.
 

^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.
 

^Midwest Research Institute, 425 Volker Boulevard, Kansas City,
 

Missouri.
 

%ow with the Division of Comparative Medicine, Johns Hopkins
 

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

V 

SUMMARY
 

A bioassay of 2-amino-5-nitrothiazole for possible carcinogenicity was conducted by administering the test chemical in feed
 

to Fischer 344 rats and B6C3F1 mice.
 

Groups of 50 rats and 50 mice of each sex were fed 2-amino-5­

nitrothiazole at one of the following doses, either 300 or 600
 

ppm for rats, and either 50 or 100 ppm for mice. The rats were
 

dosed for 110 weeks, followed by 1 week of observation; the mice
 

were dosed for 104 weeks. Matched controls consisted of 50
 

untreated rats and 50 untreated mice of each sex. All surviving
 

rats were killed at week 111, all surviving mice at week 104.
 

The mean body weights of the groups of rats and mice fed
 

2-amino-5-nitrothiazole in the diet were slightly lower than
 

those of the controls throughout most of the period of administration. No other clinical signs related to administration of the
 

chemical were noted. There was a dose-related trend in mortality
 

only in the male rats; however, sufficient numbers of rats were
 

at risk in all groups for development of late-appearing tumors.
 

In male rats, there was a significant dose-related trend (P =
 

0.044) in the incidences of malignant lymphomas, lymphocytic
 

leukemias, or undifferentiated leukemias, although the results of
 

direct comparisons of incidences in each of the dosed groups with
 

those in the controls were not significant. There was also a
 

significant dose-related trend in the incidence of granulocytic
 

leukemia in the male rats (P = 0.014) and a significantly
 

increased incidence of this tumor (P = 0.023) in the high-dose
 

group (matched controls 2/50, low-dose 4/50, high-dose 9/49).
 

When the incidences of all neoplasms of the hematopoietic system
 

(lymphomas and all leukemias) were combined, greater significance
 

was attained for both the dose-related trend (P = 0.001) and the
 

direct comparison (P = 0.002) of the incidence of the high-dose
 

group with that in the matched controls (controls 13/50, low-dose
 

19/50, high-dose 28/49). The reliability of the incidence of
 

hematopoietic tumors in the male controls was supported by that
 

for male controls observed in a similar bioassay of another test
 

vii
 
chemical at the same laboratory (13/50). The incidences of the
 

combined hematopoietic tumors in the dosed female rats were not
 

significant when compared with the incidence in the matched
 

controls.
 

In female rats, there was a significant dose-related trend in the
 

incidence of chromophobe adenomas of the pituitary (P = 0.016)
 

and a. higher incidence (P = 0.021) in the high-dose group than in
 

the matched controls (controls 19/45, low-dose 29/47, high-dose
 

29/44). The incidence of this lesion in dosed male rats was much
 

lower than that in dosed females, and the dose-related trend (P =
 

0.048) was only marginally significant (controls 3/46, low-dose
 

3/45, high-dose 8/43). The incidences of chromophobe adenomas of
 

the pituitary which were observed in control groups of rats used
 

in a similar bioassay of another test chemical at the same
 

laboratory were 13/49 (27%) for the males and 26/50 (52%) for the
 

females. Because of the variability in incidences of the tumor
 

among different control groups, the occurrence of chromophobe
 

adenomas of the pituitary in the dosed female rats cannot be
 

clearly associated with the administration of 2-amino-5-nitrothiazole.
 

Also in female rats, there was a higher incidence of endometrial
 

stromal polyps of the uterus in the low-dose group (P = 0.023)
 

than in the matched controls (controls 2/50, low-dose 9/49, high-


dose 3/50). Since, however, only three high-dose animals had
 

this tumor, the occurrence of uterine tumors in the low-dose
 

group cannot be clearly associated with administration of the
 

test chemical.
 

In the mice, no neoplasms were observed at a statistically
 

significant incidence in the dosed groups when compared with the
 

controls.
 

It is concluded that under the conditions of this bioassay, the
 

occurrence of tumors of the hematopoietic system, i.e., lymphoma
 

and granulocytic leukemia, in dosed male Fischer 344 rats was
 

associated with administration of 2-amino-5-nitrothiazole.
 

2-Amino-5-nitrothiazole was not carcinogenic in female Fischer
 

344 rats or in male or female B6C3F1 mice.
 

viii
 
TABLE OF CONTENTS
 

Page
 

I. Introduction	 1
 

II. Materials and Methods	 3
 

A. Chemical	 3
 

6. Dietary Preparation	 4
 

C. Animals	 4
 

D. Animal Maintenance	 5
 

E. Subchronic Studies	 7
 

F. Designs of Chronic Studies	 8
 

G. Clinical and Pathologic Examinations	 8
 

H. Data Recording and Statistical Analyses	 11
 

III. Results -Rats	 17
 

A. Body Weights and Clinical Signs (Rats)	 17
 

B. Survival (Rats)	 17
 

C. Pathology (Rats)	 20
 

D. Statistical Analyses of Results (Rats)	 23
 

IV. Results - Mice	 27
 

A. Body Weights and Clinical	 Signs (Mice) 27
 

B. Survival (Mice)	 27
 

C. Pathology (Mice)	 30
 

D. Statistical Analyses of Results (Mice)	 32
 

V. Discussion	 35
 

VI.	 Bibliography 39
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in
 

Table Al Summary of the Incidence of Neoplasms in
 

Rats Fed 2-Amino-5-Nitrothiazole in the Diet 41
 

Male Rats Fed 2-Amino-5-Nitrothiazole in the Diet.. 43
 

Table A2 Summary of the Incidence of Neoplasms in Female
 

Rats Fed 2-Amino-5-Nitrothiazole in the Diet 47
 

ix
 
Page 

Appendix B Summary of the Incidence of Neoplasms in 

Mice Fed 2-Amino-5-Nitrothiazole in the Diet 51 

Table Bl Summary of the Incidence of Neoplasms in 

Male Mice Fed 2-Amino-5-Nitrothiazole in the Diet.. 53 

Table B2 Summary of the Incidence of Neoplasms in Female 

Mice Fed 2-Amino-5-Nitrothiazole in the Diet 57 

Appendix C Summary of the Incidence of Nonneoplastic Lesions 

in Rats Fed 2-Amino-5-Nitrothiazole in the Diet.... 61 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Fed 2-Amino-5-Nitrothiazole 

in the Diet 63 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Fed 2-Amino-5-Nitrothiazole 

in the Diet 71 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Fed 2-Amino-5-Nitrothiazole 

in the Diet 79 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Fed 2-Amino-5-Nitrothiazole 

in the Diet 81 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Fed 2-Amino-5-Nitrothiazole 

in the Diet 88 

Appendix E Analyses of the Incidence of Primary Tumors 

in Rats Fed 2-Amino-5-Nitrothiazole in the Diet.... 95 

Table El Analyses of the Incidence of Primary Tumors in Male 

Rats Fed 2-Amino-5-Nitrothiazole in the Diet 97 

Table E2 Analyses of the Incidence of Primary Tumors in Female 

Rats Fed 2-Amino-5-Nitrothiazole in the Diet 105 

Appendix F Analyses of the Incidence of Primary Tumors 

in Mice Fed 2-Amino-5-Nitrothiazole in the Diet.... Ill 

Table Fl Analyses of the Incidence of Primary Tumors in Male 

Mice Fed 2-Amino-5-Nitrothiazole in the Diet 113 

X 
Page 

Table F2 Analyses of the Incidence of Primary Tumors in Female 

Mice Fed 2-Amino-5-Nitrothiazole in the Diet 119 

TABLES 

Table 1 Design of 2-Amino-5-Nitrothiazole Chronic 

Feeding Studies in Rats 9 

Table 2 Design of 2-Amino-5-Nitrothiazole Chronic 

Feeding Studies in Mice 10 

FIGURES 

Figure 1 Growth Curves for Rats Fed 2-Amino-5-Nitrothiazole 

in the Diet 18 

Figure 2 Survival Curves for Rats Fed 2-Amino-5-Nitrothiazole 

in the Diet 19 

Figure 3 Growth Curves for Mice Fed 2-Amino-5-Nitrothiazole 

in the Diet 28 

Figure 4 Survival Curves for Mice Fed 2-Amino-5-Nitrothiazole 

in the Diet 29 

XI
 

I. INTRODUCTION
 

2-Amino-5-nitrothiazole (CAS 121-66-4; NCI C03065) is an
 

antiprotozoal drug for animals which is now used in the form of
 

the acetyl derivative to control histomoniasis (blackhead) in
 

turkeys. The use of acetyl-2-amino-5-nitrothiazole in animal
 

feed and the allowable residues in food products from treated
 

animals (0.1 ppm) are regulated by the Food and Drug Administration (FDA, 1976). Nitrothiazole compounds are structurally
 

related to the nitrofurans, and derivatives of both compounds
 

have chemotherapeutic uses. The , nitrothiazoles have shown
 

schistosomicidal, anthelinintic, and amoebicidal activity (Rollo,
 

1975), whereas the nitrofurans are primarily antibacterial agents
 

(Morris et al., 1969; Fingl, 1975). Some nitrofurans
 

(4-substituted 2-hydrazinothiazoles) have shown carcinogenic
 

activity in rats, causing primarily mammary gland tumors (Cohen
 

et al., 1975).
 

2-Amino-5-nitrothiazole was selected for testing for carcinogenicity in the bioassay program because of its structural relationship to the carcinogenic nitrofurans.
 

1 

II. MATERIALS AND METHODS
 

A. Chemical
 

2-AMINO-5-NITROTHIAZOLE 

2-Amino-5-nitrothiazole was obtained from Eastman Kodak Co.,
 

Rochester, New York, in a single batch (Lot No. 672-1) which was
 

used during all phases of the studies. This batch was 99.0 i
 

0.5% pure as determined by polarographic analysis.
 

Elemental analysis (C, H, N, S) agreed with theoretical values
 

for C3H3N302S, the molecular formula for 2-amino-5-nitrothiazole.
 

High-pressure liquid chromatography (uv detector) showed one
 

impurity which accounted for 0.9% of the total peak area.
 

Nuclear magnetic resonance and infrared spectra were consistent
 

with reference spectra for the structure of 2—amino-5—
 

nitrothiazole.
 

3 
Analyses performed after completion of the bioassay showed no
 

detectable change in the purity of the test chemical.
 

B. Dietary Preparation
 

Diets containing 2-amino-5-nitrothiazole were prepared by
 

blending a 10% premix with sufficient finely ground Wayne® Lab
 

Blox animal meal (Allied Mills, Inc., Chicago, 111.) for 20
 

minutes in a 20-kg Patterson-Kelly Twin Shell Blender to obtain
 

the appropriate concentration. Dietary preparations were stored
 

in plastic-lined fiber drums at approximately 4°C for no longer
 

than 14-17 days.
 

The stability of 2-amino-5-nitrothiazole in feed over a 14-day
 

interval at 4°C was confirmed by analysis at Midwest Research
 

Institute using the standard method of the Association of
 

Official Analytical Chemists (Horwitz, 1970) for the assay of
 

2-amino-5-nitrothiazole in feed. The concentrations of 2-amino5-nitrothiazole in selected batches of prepared diets were
 

checked during the chronic study, using the same analytical
 

method.
 

C. Animals
 

Rats and mice of each sex, obtained through contracts of the
 

Division of Cancer Treatment, National Cancer Institute, were
 

4 
used in these bioassays. The rats were of the Fischer 344 strain
 

obtained from A. R. Schmidt/Sprague-Dawley, Madison, Wisconsin,
 

and the mice were B6C3F1 hybrids obtained from Charles River
 

Breeding Laboratories, Inc., Wilmington, Massachusetts. On
 

arrival at the laboratory, all animals were quarantined (rats for
 

7 days, mice for 14 days) and were then assigned to control or
 

dosed groups. Rats were earmarked and mice were toe-clipped to
 

allow individual identification.
 

D. Animal Maintenance
 

All animals were housed in temperature- and humidity-controlled
 

rooms. The temperature was maintained at 21-26°C, and the
 

relative humidity was maintained at 45-55%. The room air was
 

changed 15 times per hour. Illumination was provided by
 

fluorescent light for 14 hours per day. Food and deionized
 

chlorinated well water were supplied ad libitum.
 

Rats in the chronic study were housed individually, first in
 

suspended cages made of stainless-steel wire mesh (Ford Fence
 

Co., Indianapolis, Ind.), and at week 45 in suspended filtered
 

polycarbonate cages (Maryland Plastics, Federalsburg, Md.)
 

equipped with an automatic watering system and lined with autoclaved Absorb-Dri® bedding (Lab Products, Inc., Garfield, N. J.).
 

The cages were changed, washed, and sanitized at 82°C twice per
 

5 
week. The feeders were changed, washed, and sterilized once per
 

week, and the cage filters were changed every 2 weeks.
 

Mice were housed five per cage in filtered prebedded cages made
 

of disposable polypropylene (Lab Products, Inc., Garfield, N.J.).
 

The cages were changed twice per week and the used cages were
 

incinerated. Feeders, water bottles, and cage lids were also
 

changed twice per week, and cage filters were changed once per
 

•
 

week. Feeders and sipper tubes were washed and sterilized prior
 

to use. Water bottles and cage lids were sanitized at 82°C.
 

Rats and mice were housed in separate rooms. The animal racks
 

were rotated once per week, but the cages were kept in fixed
 

positions on the racks. The rats fed 2-amino-5-nitrothiazole
 

were housed in the same room as rats fed the positive control,
 

N-2-fluorenylacetamide (CAS 53-96-3) and rats that received
 

3-nitropropionic acid (CAS 504-88-1) by gavage. The mice fed
 

2-amino-5-nitrothiazole were housed in the same room as mice fed
 

N,N'-dicyclohexylthiourea (CAS 1212-29-9), proflavine
 

hydrochloride (CAS 952-23-8), 1,3-dichloro-5,5-dimethylhydantoin
 

(CAS 118-52-5), or N-2-fluorenylacetamide, and mice receiving
 

3-nitropropionic acid by gavage. Untreated controls were housed
 

in the same room with respective dosed animals.
 

6 
E. Subchronic Studies
 

Subchronic feeding studies were conducted to estimate the maximum
 

tolerated doses of 2-amino-5-nitrothiazole, on the basis of which
 

low and high concentrations (hereinafter referred to as "low
 

doses" and "high doses") were determined for administration in
 

the chronic studies. In the Subchronic studies, 2-amino-5­

nitrothiazole was added to the animal feed in concentrations
 

ranging from 375 to 4,000 ppm for rats and from 30 to 500 ppm for
 

mice. The chemical was provided in feed to dosed groups of five
 

male and five female animals of each species for 6 weeks, and the
 

animals were given basal diets for the last 2 weeks of the study.
 

In male rats, mean body weight gain was 92% of that of the
 

matched controls at 750 ppm, 75% at 1,500 ppm, 53% at 3,000 ppm,
 

and 43% at 4,000 ppm. In females, mean body weight gain was 93%
 

of that of the matched controls at 750 ppm, 81% at 1,500 ppm, 53%
 

at 3,000 ppm, and 43% at 4,000 ppm. No deaths occurred among
 

rats, and the only gross pathologic changes were slightly
 

enlarged thyroids in rats tested at the two highest doses. The
 

low and high doses for the chronic studies using rats were set at
 

300 and 600 ppm.
 

No effects on growth were observed in male mice. One male at 140
 

ppm died. In female mice, mean body weight gain was unaffected
 

7 
at 30 ppm. Mean body weight gain was 82% of that of the controls
 

at 60 ppm, 96% at 140 ppm, 61% at 260 ppm, and 57% at 500 ppm.
 

Hydronephrosis was found in a total of seven mice of both sexes
 

among all groups, and pyelonephritis in one mouse. The low and
 

high doses for the chronic studies using mice were set at 50 and
 

100 ppm.
 

F. Designs of Chronic Studies
 

The designs of the chronic studies are shown in tables 1 and 2.
 

G. Clinical and Pathologic Examinations
 

All animals were observed twice daily for signs of toxicity and
 

weighed every 14 days during the first 3 months and every 28 days
 

thereafter. Clinical observations were recorded once per week.
 

Animals that were moribund at the time of the daily examinations
 

were killed and necropsied; however, some moribund animals were
 

isolated from their cage—mates for a few days prior to being
 

killed.
 

The pathologic evaluation consisted of gross and microscopic
 

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

from killed animals and animals found dead. The following
 

tissues were microscopically examined: skin, lungs and bronchi,
 

trachea, bone marrow, spleen, lymph nodes, thymus, heart,
 

8 
Table 1. Design of 2-Amino-5-Nitrothiazole Chronic Feeding
 

Studies in Rats
 

2-Amino-5­

Sex and 

Test 

Initial 

No. of 

Nitrothiazole 

in Dietb 

Time 

Dosed 

on Study

c 

Observed 

Group Animals3 (ppm) (weeks) (weeks ) 

Male 

Matched-Control 50 0 111 

Low-Dose 50 300 110 1 

High-Dose 50 600 110 1 

Female 

Matched-Control 50 0 111 

Low-Dose 50 300 110 1 

High-Dose 50 600 110 1 

a

All animals were 50 days of age when placed on study.
 

^Diets containing 2-amino-5-nitrothiazole were administered 7 days
 

per week.
 

C

A11 animals were started on study on the same day.
 

9 
Table 2. Design of 2-Amino-5-Nitrothiazole Chronic Feeding
 

Studies in Mice
 

Sex and 

Test 

Group 

Initial 

No. of 

Animals3 

2-Amino-5­

Nitrothiazole 

in Dietb 

(ppm) 

Time 

Dosed 

(weeks) 

on Study0 

Observed 

(weeks) 

Male 

Matched-Control 

Low-Dose 

High-Dose 

50 

50 

50 

0 

50 

100 

104 

104 

104 

Female 

Matched-Control 

Low-Dose 

High-Dose 

50 

50 

50 

0 

50 

100 

104 

104 

104 

a

All animals were 53 days of age when placed on study.
 

^Diets containing 2-amino-5-nitrothiazole were administered 7 days
 

per week.
 

C

A11 animals were started on study on the same day.
 

10
 
salivary gland, liver, gallbladder (mice), pancreas, esophagus,
 

stomach, small intestine, large intestine, colon, kidney, urinary
 

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

testis or ovary, prostate or uterus, brain, and eyes. Peripheral
 

blood smears were prepared from each animal whenever possible.
 

Occasionally, additional tissues were also examined microscopically. The different tissues were preserved in 10% buffered
 

formalin, embedded in paraffin, sectioned, and stained with
 

hematoxylin and eosin. 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 died early. Also, some animals were
 

cannibalized or judged to be in such an advanced state of
 

autolysis as to preclude histopathologic evaluation. Thus, the
 

number of animals from which particular organs or tissues were
 

examined microscopically varies, and does not necessarily
 

represent the number of animals that were placed on study in each
 

group.
 

H. Data Recording and Statistical Analyses
 

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

System (Linhart et al., 1974). The data elements include descrip11
 
tive 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 statistical techniques
 

described in this section. Those analyses of the experimental
 

results that bear on the possibility of carcinogenicity are
 

discussed in the statistical narrative sections.
 

Probabilities of survival were estimated by the product-limit
 

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

report in the form of graphs. Animals were statistically
 

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

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

causes were not statistically censored. Statistical analyses for
 

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

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

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

One-tailed P values have been reported for all tests except the
 

departure from linearity test, which is only reported when its
 

two-tailed P value is less than 0.05.
 

The incidence of neoplastic or nonneoplastic lesions has been
 

12
 
given as the ratio of the number of animals bearing such lesions
 

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

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

the denominators included only those animals for which that site
 

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

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

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

consist of the numbers of animals necropsied.
 

The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a
 

significantly higher proportion of tumors than did the control
 

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

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

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

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

compared simultaneously with those for a control group, a correction to ensure an overall significance level of 0.05 may be made.
 

The Bonferroni inequality (Miller, 1966) requires that the P
 

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

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

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

where the Fisher exact P values are shown.
 

13
 
The Cochran-Armitage test for linear trend in proportions, with
 

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

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

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


tailed 0.05 level of significance. Unless otherwise noted, the
 

direction of the significant trend is a positive dose relationship. This method also provides a two-tailed test of departure
 

from linear trend.
 •
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation
 

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

first tumor was observed were excluded by basing the statistical
 

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

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

such an early tumor was found, comparisons were based exclusively
 

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

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

obtained, the standard procedures for analyses of the incidence
 

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

followed.
 

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).
 

14
 
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 < 0.05, two-tailed test) were
 

also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared with its control was calculated
 

from the exact interval on the odds ratio (Gart, 1971). The relative risk is defined as Pt/Pc where pt is the true binomial
 

probability of the incidence of a specific type of tumor in a
 

dosed group of animals and pc 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
 

15
 
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 < 0.025 one-tailed test when the control
 

incidence is not zero, P < 0.050 when the control incidence is
 

zero) has occurred. When the lower limit is less than unity, but
 

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

the absence of a significant result while the upper limit indicates that there is a theoretical possibility of the induction of
 

tumors by the test chemical, which could not be detected under
 

the conditions of this test.
 

16
 
III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

Mean body weights of rats of each sex were slightly less than
 

weights of the controls in a dose-related manner (figure 1).
 

Fluctuations in the growth curve may be due to mortality; as the
 

size of a group diminishes, the mean body weight may be subject
 

to variation.
 

Early during the second year of the study, approximately 75% of
 

the rats developed acute swellings of the cervical salivary
 

glands. The clinical appearance was consistent with that of
 

sialodacryoadenitis. Control animals as well as dosed animals
 

developed this condition, which lasted for approximately 2 weeks.
 

The animals ate less feed, developed rough coats, and in some
 

cases, lost weight. Unilateral cataracts were observed at the
 

end of the first year and through the second year in both control
 

and dosed animals.
 

B. Survival (Rats)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female rats fed 2-amino-5-nitrothiazole in
 

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

the matched controls, are shown in figure 2.
 

17
 
Figure 1. Growth Curves for Rats Fed 2-Araino-S-Nitrothiazole in the Diet 

18 
Figure 2. Survival Curves for Rats Fed 2-Amino-5-Nitrothiazole in the Diet 

19 
In male rats, there was a dose-related positive trend (P - 0.042)
 

in mortality; however, 27/50 (54%) of the high-dose males lived
 

at least 2 years. There was no dose-related trend in mortality
 

in the female rats, and over 65% of all the female rats (35/50
 

[70%] high-dose, 33/50 [66%] low-dose, 33/50 [66%] matched
 

controls) lived to the end of the study. 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 neoplasms were observed in both the control and
 

dosed groups, each of which has been previously encountered as a
 

spontaneous lesion in the rat. Some types of neoplasms occurred
 

only in rats of dosed groups, or with a greater frequency in
 

dosed groups when compared with controls; the converse was also
 

true.
 

The incidences of undifferentiated and lymphocytic types of
 

malignant lymphoma, leukemia, and granulocytic leukemia of the
 

spleen or multiple organs increased in the dosed male groups.
 

This trend was not as evident in the females. The incidences of
 

lymphoma and leukemia were as follows:
 

20
 
Matched
 

Males Control
 

Number of animals with tiss lue
 

examined microscopically 50
 

Malignant Lymphoma,
 

Undifferentiated 5* (10%)
 

Malignant Lymphoma,
 

Lymphocytic 4 (8%)
 

Malignant Lymphoma,
 

Histiocytic 0
 

Malignant Lymphoma, NOS,
 

(not otherwise specified) 0
 

Lymphocytic
 

Leukemia 4 (8%)
 

Granulocytic
 

Leukemia 2 (4%)
 

Total number of animals wit :h
 

Lymphoma or Leukemia 13 (26%)
 

Females
 

Number of animals with tiss me
 

examined microscopically 50
 

Malignant Lymphoma,
 

Undifferentiated 4 (8%)
 

Malignant Lymphoma,
 

Lymphocytic 1 (2%)
 

Lymphocytic
 

Leukemia 1 (2%)
 

Granulocytic
 

Leukemia 2 (4%)
 

Total number of animals wit :h
 

Lymphoma or Leukemia 7 (14%)
 

Low
 

Dose
 

50
 

8 (16%)
 

4 (8%)
 

1 (2%)
 

1 (2%)
 

4 (8%)
 

4 (8%)
 

19 (38%)
 

50
 

10 (20%)
 

1 (2%)
 

1 (2%)
 

2 (4%)
 

14 (28%)
 

High
 

Dose
 

49
 

10 (20%)
 

8 (16%)
 

0
 

0
 

6 (12%)
 

9 (18%)
 

28 (57%)
 

50
 

7 (14%)
 

1 (2%)
 

2 (4%)
 

1 (2%)
 

10 (20%)
 

*Includes three animals with Undifferentiated leukemia.
 

21
 
The undifferentiated malignant lymphoma was considered to be the
 

same as that described by Moloney et al. (1970). Many of the
 

high-dose animals died or were killed in moribund condition
 

because of the leukemia.
 

The nonneoplastic lesions consisted of degenerative,
 

proliferative, and inflammatory changes that are commonly
 

observed in aging rats (Sass et al., 1975). These conditions
 

•
 

occurred in a random fashion and did not appear to be related to
 

administration of the test chemical.
 

Focal myocarditis ranging from acute to chronic occurred in 8/48
 

(17%) control males, 22/49 (45%) low-dose males, 21/48 (43%)
 

high-dose males; 3/48 (6%) control females, 11/47 (23%) low-dose
 

females, and 16/49 (33%) high-dose females. Although the incidence was greater in dosed groups than in controls, it was not
 

considered to be related to administration of the test chemical,
 

since it is a common finding in aged rats.
 

The incidence of endometrial stromal polyps of the uterus was
 

higher in the low-dose females than in the control and high-dose
 

females (controls 2/50 [4%], low-dose 9/49 [18%], high-dose 3/50
 

[6%]). However, this benign proliferative lesion was not associated with an increased incidence of malignant tumors in the
 

uterus.
 

22
 
Suppurative inflammation of the preputial glands of male and
 

female rats was observed in all groups. A low incidence of
 

adenoma of the preputial gland was present in all groups.
 

The increased incidence of pituitary angiectasis in dosed female
 

rats was associated with an increased incidence of chromophobe
 

adenoma of the pituitary gland.
 

There was a dose-related increase in the incidence of hematopoietic neoplasms in male rats. The incidence of the undifferentiated type of malignant lymphoma was lower than that
 

previously reported for this strain (Turusov, 1973), but the
 

onset was earlier.
 

In the judgment of the pathologist, 2-amino-5-nitrothiazole
 

administered to Fischer 344 rats was carcinogenic for males, but
 

not the females, under the conditions of this study.
 

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 in one group and with an incidence of at least
 

5% in one or more than one group.
 

In male rats, the results of the Cochran-Armitage test for positive dose-related trend in the combined incidence of malignant
 

23
 
lymphoma, lymphocytic leukemia, or undifferentiated leukemia are
 

significant (P = 0.044), but the results of the Fisher exact test
 

are not. The results of the Cochran-Armitage test for the
 

incidence of granulocytic leukemia are significant (P = 0.014),
 

and the results of the Fisher exact test show that the incidence
 

in the high-dose group is significantly higher (P = 0.023) than
 

that in the controls. In the analyses of the incidence of any
 

type of leukemia or lymphoma, the results of the Cochran-Armitage
 

test are significant (P = 0.001), and the results of the Fisher
 

exact test show a higher incidence of these tumors in the
 

high-dose group (P = 0.002) than in the matched controls. The
 

statistical conclusion is that the occurrence of neoplasms of the
 

hematopoietic system in male rats is associated with 2-amino-5­

nitrothiazole at the doses used in this study. There were two
 

groups of controls at this laboratory. The group matched with
 

2-amino-5-nitrothiazole had an incidence of 13/50 (26%)
 

hematopoietic tumors and the other group had 14/50 (28%).
 

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

positive dose-related trend in proportions for chromophobe
 

adenoma of the pituitary are significant (P = 0.016), and the
 

results of the Fisher exact test show significantly greater
 

incidences of this tumor in the high-dose group (P = 0.021) than
 

in the matched controls. The results of the Fisher exact
 

24
 
comparison of the incidences in the low-dose and control animals
 

show a P value of 0.048, which is above the 0.025 level required
 

when multiple comparison is considered. The high incidence seen
 

in the matched controls (19/45, 42%) indicates a high spontaneous
 

rate of this type of tumor in these animals. The incidence of
 

this tumor in the second female control group at this laboratory
 

was 26/50 (52%). In male rats, the results of the Cochran-


Armitage test for the incidence of this tumor indicates a
 

probability level of 0.048, but the results of the Fisher exact
 

test are not significant.
 

In the analyses of endometrial stromal polyp of the uterus in
 

female rats, although the results of the Cochran-Armitage test
 

for positive dose-related trend in incidences are not significant
 

at the 0.05 level, there is a significant departure from linear
 

trend (P = 0.009), due to the greater incidence of this tumor in
 

the low-dose group (9/49) than in the high-dose group (3/50).
 

The results of the Fisher exact test show a significantly higher
 

incidence of this tumor in the low-dose group than in the matched
 

controls (P = 0.023), but the incidence in the high-dose group is
 

not significant.
 

In male rats, the incidences of alveolar/bronchiolar adenoma of
 

the lung and interstitial-cell tumor of the testis were higher in
 

the control group than in the dosed groups. This may have
 

25
 
occurred because the dosed animals did not live as long as the
 

control animals.
 

26
 
IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

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

those of the corresponding controls in a dose-related manner
 

throughout the study. Toward the end of the study mean body
 

weights of the female mice at both doses were lower than those of
 

the corresponding controls (figure 3). Fluctuations in a growth
 

curve may be due to mortality; as the size of a group diminishes,
 

the mean body weight may be subject to variation.
 

During the first year of the study, the dosed mice were generally
 

comparable to the controls in appearance and behavior. Focal
 

alopecia, focal dermatitis, and small palpable nodules in the
 

perineal area associated with fighting were observed in
 

increasing numbers of male mice, beginning at week 34.
 

B. Survival (Mice)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female mice fed 2-amino-5-nitrothiazole in
 

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

the matched controls, are shown in figure 4.
 

In male mice, the results of the Tarone test for dose-related
 

trend in mortality are not significant; at least 66% of the
 

27
 
Figure 3. Growth Curves for Mice Fed 2-Amino-5-Nitrothiazole in the Diet 

28 
Figure 4. Survival Curves for Mice Fed 2-Amino-S-Nitrothiazole in the Diet 

29 
animals (33/50 [66%] high-dose, 37/50 [74%] low-dose, 38/50 [76%]
 

matched controls) lived to the end of the study. In the male
 

high-dose group, two animals were reported missing. There is no
 

positive dose-related trend in mortality in the female mice, and
 

at least 70% of every female group (41/50 [82%] high-dose, 38/50
 

[76%] low-dose, 35/50 [70%] matched controls) lived to the end of
 

the study. Sufficient numbers of mice of each sex were at risk
 

for development of late-appearing tumors.
 

•
 

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.
 

A variety of neoplasms were observed in both the control and
 

dosed groups, each of which has been encountered previously as a
 

spontaneous lesion in the mouse.
 

The incidences of hepatocellular carcinoma, adenoma, and
 

hyperplasia were as follows:
 

30
 
Matched Low High
 

Males Control Dose Dose
 

Number of animals with tissi Lie
 

examined microscopically 49 50 48
 

Hepatocellular
 

Carcinoma 16 (33%) 11 (22%) 11 (23%)
 

Hepatocellular 

Adenoma 4 (8%) 6 (12%) 4 (8%) 

Hyperplasia, Nodular or 

Hyperplastic Nodule 1 (2%) 1 (2%) 1 (2%) 

Females
 

Number of animals with tissi ue
 

examined microscopically 49 50 50
 

Hepatocellular
 

Carcinoma 1 (2%) 2 (4%) 4 (8%)
 

Hepatocellular
 

Adenoma 1 (2%) 4 (8%) 1 (2%)
 

Hyperplasia, Nodular 0 (0%) 1 (2%) 0 (0%)
 

The incidence of proliferative hepatocellular lesions was greater
 

in males than in females, but there was no indication that these
 

lesions were related to administration of the test chemical.
 

Other lesions that occurred among dosed and control groups were
 

also considered to be spontaneous. Some types of neoplasms
 

occurred only in mice of dosed groups, or with a greater
 

frequency in dosed groups when compared with controls; the
 

converse was also true.
 

31
 
Several chronic inflammatory, degenerative, and proliferative
 

conditions were observed in all groups. These conditions occurred in a random fashion and were considered to be of common
 

occurrence, spontaneous, and not related to administration of the
 

test chemical.
 

Based on the histologic examination, there was no evidence for
 

the carcinogenicity of 2-amino-5-nitrothiazole in B6C3F1 mice
 

under the conditions of this bioassay.
 

D. Statistical Analyses of Results (Mice)
 

Tables Fl and F2 in Appendix F contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

least two animals of one group and with an incidence of at least
 

5% in one or more than one group.
 

The results of the Cochran-Armitage test for positive dose­ »
 

related trend in the incidence of alveolar/bronchiolar adenoma of
 

the lung in female mice (P = 0.048) and the incidence of combined
 

alveolar/bronchiolar adenoma and carcinoma of the lung in female
 

mice (P = 0.034) are significant. However, the results of the
 

Fisher exact test are not significant for these tumors.
 

In female mice, the incidences of hematopoietic tumors in the
 

dosed groups are lower than that in the control group. These
 

32
 
significant trends in the negative direction cannot be explained
 

by low survival in the dosed groups, since the survivals of the
 

dosed and control groups of female mice are comparable.
 

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 2-amino-5-nitrothiazole, which could not be detected under the
 

conditions of this test.
 

33
 

V. DISCUSSION
 

The mean body weights of the groups of rats and mice administered
 

2-amino-5-nitrothiazole in this bioassay were slightly lower than
 

those of the controls throughout most of the period of
 

administration. No clinical signs related to administration of
 

the test chemical were noted. There was a dose-related trend in
 

mortality only in the male rats; however, sufficient numbers of
 

rats and mice were at risk in all groups for development of
 

late-appearing tumors.
 

In male rats, there was a significant dose-related trend (P =
 

0.044) in the incidences of malignant lymphomas, lymphocytic
 

leukemias, or undifferentiated leukemias, although the results of
 

direct comparisons of incidences in each of the dosed groups with
 

those in the controls were not significant. There was also a
 

significant dose-related trend in the incidence of granulocytic
 

leukemia in the male rats (P = 0.014) and a significantly
 

increased incidence of this tumor (P = 0.023) in the high-dose
 

group (matched controls 2/50, low-dose 4/50, high-dose 9/49).
 

When the incidences of all neoplasms of the hematopoietic system
 

(lymphomas and all leukemias) were combined, greater significance
 

was attained for both the dose-related trend (P = 0.001) and the
 

direct comparison (P = 0.002) of the incidence in the high-dose
 

group with that in the matched controls (controls 13/50, low-dose
 

35
 
19/50, high-dose 28/49). The reliability of the incidence of
 

hematopoietic tumors in the male controls was supported by that
 

for male controls observed in a similar bioassay of another test
 

chemical at the same laboratory (13/50). The incidences of the
 

combined hematopoietic tumors in the dosed female rats were not
 

significant when compared with the incidence in the matched
 

controls.
 

In female rats, there was a significant dose-related trend in the
 

incidence of chromophobe adenomas of the pituitary (P = 0.016)
 

and a higher incidence (P = 0.021) in the high-dose group than in
 

the matched controls (controls 19/45, low-dose 29/47, high-dose
 

29/44). The incidence of this lesion in dosed male rats was much
 

lower than that in dosed females, and the dose-related trend (P =
 

0.048) was only marginally significant (controls 3/46, low-dose
 

3/45, high-dose 8/43). The incidences of chromophobe adenomas of
 

the pituitary which were observed in control groups of rats used
 

in a similar bioassay of another test chemical at the same
 

laboratory were 13/49 (27%) for. the males and 26/50 (52%) for the
 

females. Because of this variability in incidences of the tumor
 

among different control groups, the occurrence of chromophobe
 

adenomas of the pituitary in the dosed female rats cannot be
 

clearly associated with the administration of 2-amino-5-nitrothiazole.
 

36
 
Also in female rats, there was a higher incidence of endometrial
 

stromal polyps of the uterus in the low-dose group (P = 0.023)
 

than in the matched controls (controls 2/50, low-dose 9/49,
 

high-dose 3/50). Since, however, only three high-dose animals
 

had this tumor, the occurrence of uterine tumors in the low-dose
 

group cannot be clearly associated with administration of the
 

test chemical.
 

In previous work, Cohen et al. (1975) administered 2-amino-5­

nitrothiazole in the diet to Sprague-Dawley rats at 1,000 ppm for
 

46 weeks. Tumors of the mammary gland, kidney, pelvis, and lungs
 

resulted, but the incidences were low. No increased incidences
 

of tumors in these specific organs were observed in the present
 

bioassay.
 

In the mice, no neoplasms were observed at a statistically
 

significant incidence in the dosed groups when compared with the
 

controls.
 

It is concluded that under the conditions of this bioassay, the
 

occurrence of tumors of the hematopoietic system, i.e., lymphoma
 

and granulocytic leukemia, in dosed male Fischer 344 rats was
 

associated with administration of 2-amino-5-nitrothiozole.
 

2-Amino-5-nitrothiazole was not carcinogenic in female Fischer
 

344 rats or in male or female B6C3F1 mice.
 

37
 

VI. BIBLIOGRAPHY
 

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

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

Berenblum, I., ed., Carcinogenicity Testing; A Report of the
 

Panel on Carcinogenicity of the Cancer Research Commission
 

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

1969.
 

Cohen, S. M., Erturk, E., Von Esch, A. M., Crovetti, A. J. , and
 

Bryan, G. T., Carcinogenicity of 5-nitrofurans and related
 

compounds with amino-heterocyclic substitutes. J. Na 11.
 

Cancer Inst. 54(4);841-850. 1975.
 

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

Soc. B 34(2);187-220. 1972.
 

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

1970, pp. 48-52.
 

Fingl, E. , Laxatives and cathartics. In: The Pharmacological
 

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

Macmillan Publishing Co., Inc., New York, 1975, pp. 976-986.
 

Food and Drug Administration, Code of Federal Regulations, 21.
 

Food and Drugs (special edition of the Federal Register),
 

Office of the Federal Register, Washington, D.C., 1976,
 

section 556.20.
 

Cart, 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.
 

Horwitz, W., ed., Official Methods of Analysis of the Association
 

of Official Analytical Chemists, llth ed., Association of
 

Official Analytical Chemists, Washington, D.C., 1970,
 

p. 729.
 

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

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

1958.
 

39
 
Linhart, M. S., Cooper, J. A., Martin, R. L., Page, N. P., and
 

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

and Biomed. Res. ]_: 230-248, 1974.
 

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


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

Moloney, W. C., Boschetti, A. E., and King, V. P., Spontaneous
 

leukemia in Fischer rats. Cancer Res. 30;41-43, 1970.
 

Morris, J. E., Price, J. M., Lalich, J. J., and Stein, R. J., The
 

carcinogenic activity of some 5-nitrofuran derivatives in
 

the rat. Cancer Res. 29;2145-2156, 1969.
 

Rollo, I. M., Drugs used in the chemotherapy of helminthrasis.
 

In: The Pharmacological Basis of Therapeutics, Goodman, L.
 

S. and Gilman, A., eds., Macraillan Publishing Co., Inc., New
 

York, 1975, pp. 1018-1044.
 

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.
 

Sass, B., Rabstein, L. S., Madison, R., Nims, R. M., Peters, R.
 

L., and Kelloff, G. J., Incidence of spontaneous neoplasms
 

in F344 rats throughout the natural life-span. _J_. Natl.
 

Cancer Inst. 54(6);1449-1453, 1975.
 

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

Biometrika 62(3):679-682. 1975.
 

Turusov, V. S., ed., Pathology of Tumors in Laboratory Animals,
 

Vol. 1, Tumors of the Rat, International Agency for Research
 

on Cancer, Geneva, 1973.
 

40
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS FED 2-AMINO-5-NITROTHIAZOLE IN THE DIET
 

41
 

TABLE A1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

FED2-AMINO-5-NITROTHIAZOLE IN THE DIET 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 50 50 50
 

ANIMALS NECROPSIED 50 50 49
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 50 50 49
 

INTEGUMENTARY SYSTEM
 

*SKIN (50) (50) (49)
 

SQUAMOOS CELL PAPILLOMA 1 (2%) 1 (2%)
 

TRICHOEPITHELIOHA 1 (2%)
 

SEBACEOUS ADENOMA 1 (2%)
 

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

FIBROMA 1 (2%) 1 (2*)
 

FIBROSARCOMA 1 (2%) 1 (2«) 1 (2X)
 

LIPOKA 1 (2%)
 

RESPIRATORY SYSTEM
 

#LU!1G (50) (50) (43)
 

PLVECLAR/BRONCHIOLAR ADENOMA 3 (6«)
 

C-CEIL CARCINOMA, MBTA3TATIC 1 (2X)
 

HEMATOFOIFTIC SYSTEM 

*MUITIPLF ORGANS (5*) (50) (49) 

MALIG.LYMPHOHA, UNDIFF ER-T YPE 

MALIG.LYRPHOMA, LYRPHOCYTTC TYPF 

1 (2%) 

a (8%) 

7 (14%) 

U (3%) 

9 (18%) 

8 (16%) 

UNDIFFERSNTIATED LEUKFMTA 2 (U%) 

LYMPHOCYTIC LEUKEMIA 4 (8%) U (8%) 6 (12%) 

GPANULOCYTIC LEUKEKIA 2 (UK) 4 (8%) 9 (18%) 

tSPLHFN <"9) (47) (49) 

KALIG. LYMPHOMA, UNDIFF^B-TYPE 1(2%) 1 (2%) 1 (2%) 

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

UNOIFFKRENTIATED lEUKEfllf. 1 (2X) 

*LYI«PH NODE («1) (U1) (42) 

FQLLICUL AR-CELL .CARCINOKAt ,HFTAS ., .__.—— 1.12*1... HI- u -J. >-— <r *­• 

* NUKBF? OF ANIMALS WITH TISSUE EXAMINED UICPOSCOPICALLY
 

* NUK^ER OF ANIMALS NECROPSIEP
 

43
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

tTHYMU S 

MALIGNAN T LYKPHOMA , NO S 

CIFCUIATCP Y SYSTE M 

•HFAHT 

ANITSCHKOW-CE1L

DIGFSTIVF SYSTEM 

' *FALATE 

 SARCOM A 

SQUAMOU S CELL CARCINOM A 

"TONGUE 

SQUAMOU S CELL CARCINOM A 

•LIVER 

NEOPLASTIC NODUL E 

HEPATOCELLULA R CARCINOM A 

URINAR Y SYSTE M 

NONS 

^ — 

ENCCCfilN E SYSTEM 

#EITUITAR Y 

CHROMOEHOBE ADENOM A 

• ADRENA L 

CORTICAL ADENOM A 

CORTICAL CARCINOM A 

PHEOCHROMOCYTOMA 

PHEOCHROMOCYTOMA, MALIGNAN T 

•THYROID 

FOLLICULAR-CELL ADENOM A 

FOLLICULAR-CELL CARCINOMA 

C-CELL ADENOM A 

C-CELL CARCINOMA 

• PARATHYROI D 

f NUMBER OF ANIMAL S WITH TISSUE

* NUMBER OF ANIMAL S NECROPSIED 

CONTROL 

(37) 

((*8) 

1 (2%) 

(50) 

1 (2%) 

(50) 

(U9 ) 

(1*6) 

3 (7%) 

(1*9) 

1 (2«) 

1* (8*) 

1 (2X) 

C»6) 

1 (2X) 

3 (7%) 

1 (2%) 

(37) 

LOW DOSE 

<»1 ) 

1 (2S) 

(49) 

(50) 

(50) 

1 (2%) 

(1*9) 

1 (2%) 

OS) 

3 (7X) 

(<»7) 

1 (2*) 

1* (9X) 

(<*8) 

3 (6X) 

7 (15X) 

(31) 

 EXAMINE D MICROSCOPICALLY 

HIGH DOSE 

(31) 

(1*8) 

(U9 ) 

(<*9) 

(U9 ) 

1 (2X) 

(1*3) 

8 (19%) 

("8) 

1 (2X) 

((*6) 

1 <2X) 

3 (7X) 

U -(9%) 

1 (2X) 

(3D 

44 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DO iSE 

tPANCPEATIC ISLETS (U9 ) <U4 ) (45) 

ISLET-CELL ADENOH A a (8«) 4 (9*) 3 (7%) 

REPRODUCTIV E SYSTEM 

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

ADFNOMA , NOS 1 (2X) 

FIBROM A 1 (2%) 

FIBROADENOM A 1 (2%) 1 (2%) 4 (BX) 

*PRFPUTIA L GLAN D (50) (50) (49) 

CARCINOMA , NOS 1 (2%) 

ADFNOMA , NO S 2 (UX ) 1 (2% ) 1 (2X) 

#TFSTIS (50) (50) (49) 

INTFBSTITIAL-CBLL TOMOR U8 (96%) 48 (96%) 41 (84%) 

*SCP.CTOM (50) (50) (49)

 

FIBROSARCOMA 1 (2*)

 

NFFVCU S SYSTE M 

#MIC3RAI N (50) (50) (49 )

 

ASTROCYTOM A 1 (2% ) 

SPECIA L SENSE ORGAN S 

*EAP CANA L (50) (50) (49) 

SQUAKOU S CELL CARCINOM A 1 (2X) 

MUSCULOSKELETA L SYSTEM 

*SKULL (50) (50) (49)

 

OSTEOMA 1 (2*) 

90CY CAVITIE S 

*AEDOMINAL CAVITY (50) (50) (49)

 

MESOTHELIOMA , MALIGNAN T - 1 (2%)

 

*PEFITONFU M (50) (50) (49 ) 

..._._« ESOTH1L JQMA.i.,,.NOS__ , , ... ...» ,.,,.„,.,J_-l^,L,_ .._.-.-..._ -..«. ....._-..»_., .*•»..*,.,*«. .— -.— ^ ,:„—— 

# NUKBtR OF ANIMALS WITH ?IS?UE FXAMINET) MICROSCOPICALLY
 *. NUKPF.R OF ANIMALS NECROPSIEP
 

45
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

1CONTROL LOW DOSE HIGH DOSE
 

*TUNICA VAGINALIS (50) (51) (U9)
 

KESOTHELIOBA, NOS 1 (2*)
 

MSSOTHELIOMA, MALIGNANT 1 (2%)
 

ALL OTHER SYSTEMS
 

*HU1TIPLE ORGANS (50) (50) («9)
 

FIBROUS HISTIOCYTOMA, MALIGNANT 1 (2%)
 

MESOTHF.LIOMA, MALIGNANT 1 (2%)
 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 

NATURAL DEATHS 

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

ANIMAL MISSING 

50 

15 

5 

30 

50 

16 

8 

26 

! 

50 

15 

1U 

21 

3 INCLUDES AUTOLYZED ANIMALS 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 1*9 18 46
 

TOTAI PRIMARY TUMOES 99 105 107
 

TOTAL ANIMALS WITH BENIGN TUMORS 48 48 42
 

TOTAL BENIGN TUMORS 72 73 66
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 23 26 31
 

TOTAL MALIGNANT TUMORS 26 30 41
 

TOTAL ANIMALS WITH SECONDARY TOMORS# 1 1
 

TOTAL SECONDARY TUMORS 1 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 1 1
 

TOTAL UNCERTAIN TOHORS 1 2
 

TOTAL ANIMALS WITH TUHORS UNCERTAIN­ ERIBARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUBORS: ALL TOHORS EXCEPT SECONDARY TOHORS
 

# SECONDARY TOHORS: HETASTATIC TOHORS OR TOHORS INVASIVE INTO AN ADJACENT ORGAN
 

46
 
TABLE A2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

FED 2-AMINO-5-NITROTHIAZOLE IN THE DIET 

HIGH DOSE
 

50
 

50
 

50
 

(50)
 

(50)
 

-1 (2%)
 

1 (2%)
 

(50)
 

1 (2%)
 

1 (2X)
 

1 (2%)
 

(50)
 

6 (12X)
 

1 (2%)
 

2 (<»*)
 

1 (2X)
 

(50)
 

1 (2«)
 

(3<0
 

ANIHALS INITIALLY IN STUDY
 

ANIMALS NECROPSiED
 

ANIHALS EXAMINED HISTOPATHOLOGICALLY
 

IHTEGUHENTARY SYSTEH
 

*SKIN
 

SEBACEOUS ADENOHA
 

*SUBCUT TISSUE
 

SQUABOUS CELL CARCINOMA
 

SEBACEOUS ADENOHA
 

SEBACEOUS ADENOCARCINOMA
 

FIBROMA
 

RESPIRATORY SYSTEH
 

*LUNG
 

SQUAMOUS CELL CARCINOHA, METASTA
 

ALVEOLAR/BRONCHIOLAR ADENOMA
 

ALVEOLAR/BRONCHIOLAR CARCINOHA
 

C-CELL CARCINOHA, HETASTATIC
 

PHEOCHROMOCYTOHA, HETASTATIC
 

LIPOSARCOHA, HETASTATIC
 

HEHATOPOIETIC SYSTEH
 

*MULTIPLE ORGANS
 

MALIG.LYMPHOHA, UNDIFFER-TYPE
 

MALIG.LYMPHOHA, LYHPHOCYTIC TYPE
 

LYHPHOCYTIC LEUKEMIA
 

GRANULOCYTIC LEUKEMIA
 

tSPLEEN
 

PHEOCHROMOCYTOMA, HETASTATIC
 

HALIG.LYMPHOHA, UNDIFFER-TYPE
 

GRANULOCYTIC LEUKEHIA
 

•LYMPH NODE
 

„„ C^liL,CAR£iNQ«i*-flIIiST4TIC_.
 

CONTROL
 

50
 

50
 

50
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

H (8%)
 

1 (2%)
 

1 (2*)
 

2 (US)
 

(50)
 

(«U)


2,15ii__.
 

LOW DOSE
 

50
 

50
 

50
 

(50)
 

(50)
 

1 (2X)
 

1 (2%)
 

(50)
 

1 (2«)
 

1 (2X)
 

(50)
 

10	 (20%)
 

1 (2%)
 

1 (2%)
 

1 (2X)
 

(50)
 

1 (2%)
 

I (2%)
 

(39)
 

t NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIHALS NECROPSIED
 

47
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVE SYSTEH
 

NONE
 

URINARY SYSTEM
 

NONE
 

ENCOCBINE SYSTEM
 

tPITOITARY
 

CARCINOMA, NOS
 

CHROMOPHOBE ADENOMA
 

#ADRENAL
 

PHEOCHROMOCYTOHA
 

PHEOCHROMOCYTOMA, MALIGNANT
 

fTHYROID
 

FOLLICULAR-CELL ADENOMA
 

FOLLICULAR-CELL CABCINOBA
 

C-CELL ADENOMA
 

C-CELL CARCINOMA
 

fPARATHYROID
 

ADENOMA, NOS
 

fPANCREATIC ISLETS
 

ISLET-CELL ADENOMA
 

REPRODUCTIVE SYSTEH
 

*HAMMARY GLAND
 

ADENOMA, NOS
 

ADENOCARCINOMA, NOS
 

PAPILLARY ADENOCARCINOMA
 

FlgR^ADENOfl^
 

CONTROL
 

(45)
 

19 (42*)
 

(49)
 

3 (6«)
 

(50)
 

1 (2X)
 

3 (6X)
 

2 (1%)
 

(37)
 

(49)
 

1 (2«)
 

(50)
 

1 (2X)
 

-_.J2-J2ail_.
 

LOW DOSE
 

(47)
 

1 (2«)
 

29 (62X)
 

(49)
 

1 12%)
 

(47)
 

4 (9X)
 

3 (6«)
 

(34)
 

1 <3X)
 

(50)
 

2 (4«)
 

(50)
 

3 (6X)
 

,_12_I22XL—
 

HIGH DOSE
 

(44)
 

29 (66%)
 

(50)
 

(48)
 

1 (2%)
 

3 (6X)
 

5 (10X)
 

(30)
 

1 (3%)
 

(48)
 

1(2%)
 

(50)
 

1(2%)
 

1 (2%)
 

2 (4%)
 

J4.J2S51
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED HICROSCOPICALLY
 

* NUMBER OF ANIMALS NEC80PSIED
 

48
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

*PREPUTIAL GLAN D (50) (50) (50) 

CARCINOMA , NOS 1 (2%) 

ADENOHA , NOS 2 (H%) 2 (i»«) 2 (<»*) 

tUTERUS (50) C*9) (50) 

LEIOMYOM A 1 (2*) 1 (2*) 

ENDONETRIAL STROMAL POLYP 2 (!»*) 9 (19%) 3 (6%) 

#OVAR Y (50) 0*9) (48)

 

GRANULOSA-CEL L TUMO R 1 (235)

 

SERTOLI-CELL TUMO R 1 (2% )

 

NEBVOOS SYSTEM 

tBRAIN/MENINGES (49) 0*9) 0*9) 

SQUAMOU S CELL CARCINOMA , METAST A 1 (2% ) 

f ERAI N (49) 0*9) (49) 

CARCINOMA , NOS, METASTATIC 1 (2%) 

SPECIAL SENSE ORGANS 

*EYE (50) (50) (50)

 

SARCOMA , NOS 1 (2%)

 

PIUSCULOSKELETA L SYSTEM 

NON E 

BOCY CAVITIE S 

NON E 

AIL OTHER SYSTEMS 

LUMBOSACRA L REGION 

^TMLIPOSAHCQH _. ,__„,„._ .. ,_-. __!„„__ _.

 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

49
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY
 

NATOHAL DEATHS
 

MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL MISSING
 

S INCLUDES AUTOLYZED ANIMALS
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS*
 

TOTAL PRIMARY TUMOBS
 

TOTAL ANIMALS HITH BENIGN TUMORS
 

TOTAL BENIGN TUMORS
 

TOTAL ANIMALS WITH MALIGNANT TUMORS
 

TOTAL MALIGNANT TUMORS
 

TOTAL ANIMALS HITH SECONDARY TUMORS*
 

TOTAL SECONDARY TOHORS
 

TOTAL ANIMALS WITH TOHORS UNCERTAIN­ BENIGN OR MA>LIGNANT
 

TOTAL UNCERTAIN TDMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

CONTROL LOW DOSE HIGH DOSE 

50 50 50 

4 7 8 

13 10 7 

33 33 35 

<*0 1*4 44 

59 86 78 

35 40 38 

45 62 56 

11 21 19 

14 23 22 

3 2 1 

3 4 2 

1 

1 

* PRIMARY TUMORS: ALL TUHORS EXCEPT SECONDARY TDBORS
 

f SECONDARY TUHORS: HETASTATIC TUMORS OR TOHOBS INVASIVE INTO AH ADJACENT ORGAN
 

50
 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE FED 2-AMINO-5-NITROTHIAZOLE IN THE DIET
 

51
 

TABLE B1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

FED 2-AMINO-5-NITROTHIAZOLE IN THE DIET 

CONTROL LOW DOSE
 

ANIMALS INITIALLY IN STUDY 50 50
 

ANIHALS MISSING
 

ANIMALS NECPOPSIED 49 50
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 49 50
 

INTEGUMENTARY SYSTEM
 

*SKIN (49) (50)
 

ADENOCAPCINOMA, -NOS, METASTATIC 1 (2%)
 

SEBACEOUS ADENOMA 2 («X)
 

*SUBCUT TISSUE (49) (50)
 

ADENOCARCINOMA, NOS, METASTATIC 1 (2*)
 

FIBROMA 1 (2%)
 

FIBROSARCOMA 2 (4%) 2 (4%)
 

RFSPIRATORY SYSTEM
 

tLUNG (1*9) (49)
 

ADENOCARCINOMA, NOS, MF.TASTATIC 1 (2%)
 

HEPATOCELLOLAR CARCINOMA, MFTAST 3 (6%) 2 (US)
 

ALVEOLAR/BRONCHIOLAR ADENOMA 10 (2CX) 10 (20%)
 

ALVEOLAR/BRONCHIOLAR CARCINOMA i* (8X) 2 (4%)
 

CORTICAL CARCINOMA, METASTATIC 1 (2%) 1 (2«)
 

FIBKCSARCOMA, METASTATIC 1 (2%)
 

H'MATOFOIETIC SYSTEM
 

*MUITIPLE ORGANS (t»9) (50)
 

MALIG.LYMPHONA, LYMFHOCYTTC TYPE i* (8%) 5 (10*)
 

MALIG.LYMPHOMA, HISTIOCY^IC TYP? 1 (2%)
 

G3ANULOCYTIC LEUKEMIA
 

MONOCYTIC LEOKEMIA
 

GRANULOCYTIC SARCOMA 1 (2*)
 

tSPLEEN (1*6) (<*3)
 

H^MANGIOMA
 

HEMANGIOSASCOMA i* (9%) 3 (6%)
 

_,,JAIjIGtLJMfiQNJ4_HimQCJIIC...TYPE, .,..l,i2«L.^
 

* NUMBER OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBE R OF ANIMAL S NECROPSI^E 

HIGH DOSE
 

50
 

2
 

48
 

48
 

(U8)
 

(48)
 

3 (6%)
 

(48)
 

11 (23%)
 

1 (2%)
 

1 (2%)
 

(48)
 

2 (4%)
 

3 (6%)
 

2 (4%)
 

(46)
 

1 (2%)
 

1 (2%)
 

53 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE
 

#KZSENTERIC L. NODS (i»0) (33)
 

KALIG. LYMPHOMA, LYMPHOCYTIC TYPF 1 (3%) 1 (3*)
 

*LIV"F (U9) (50)
 

GRANULOCYTIC LEUKEMIA 1 12%)
 

#SMALL INTESTINE (47) (44)
 

MALIG. LYMPHOMA, LYMPHOCYTIC TYPF 1 (2X)
 

CIRCULATORY SYSTEM
 

NOME
 

DIGESTIVE SYSTEM
 

*LIVER (49) (50)
 

R3PATOCEILULAR ADENOMA « (8*) 6 (12*)
 

H5PATOCELLULAR CARCINOMA 16 (33%) 11 (22X)
 

CORTICAL CARCINOMA, METASTATIC 1 (2%) 1 (2*)
 

HEMANGIOMA 1 (2%)
 

HEMANGIOSARCOMA 2 (<**) 1 (2*)
 

ANGIOSARCOMA 1 (2%)
 

#PANCREAS (48) (46)
 

CORTICAL CARCINOMA, METASTATIC 1 (2X)
 

DPINARY SYSTEM
 

#KIDNEY (48) (47)
 

ADENOCARCINOMA, NOS 1 <2X)
 

ENDQCSIHF STSTEM
 

#ADRENAL (46) (49)
 

CORTICAL CARCINOMA 1 (2%) 1 (2*)
 

PHEOCHBOMOCYTOMA 1 (2*)
 

tTHYROID (43) (39)
 

FOLLIC0LAR-CELL ADENOMA 1 (3X)
 

fPANCREATIC ISLETS (48) (46)
 

ISL,ET-CJL,L A21£2fii _, _,
 __1.I2I1_.
 

# NUMBER OF ANIMALS WITH TISSUE EXABINED MICROSCOPICALLY
 

* BOMBER OF ANIHALS NECROPSIED
 

HIGH DOSE
 

(29)
 

(43)
 

(45)
 

(48)
 

4 (8X)
 

11 (23*)
 

3 (6%)
 

2 (4«)
 

(45)
 

(48)
 

(46)
 

(40)
 

(45)
 

i_J2.Sl__
 

54
 
CONTROL LOW DOSE HIGH DOSE
 

REPRODUCTIVE SYSTEM
 

#TBSTIS (<*7) (1*8) (46)
 

INTEBSTITIAL-CELL TUBOR 1 (2%)
 

NFBVCUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

*HARDERIAN GLAND (49) (50) (18)
 

PAPILLARY ADENOMA 1 (2%)
 

PAPILLARY CYSTADENOBA, NOS 1 (2X)
 

MUSCOLOSKELETAL SYSTEB
 

NONE
 

BOCY CAVITIES
 

*ABDONINAL CAVITY («»9) (50) (48)
 

CORTICAL CARCINOMA, BETASTATIC 1 (2%)
 

ALL CTHEE SYSTEBS
 

NONE
 

ANIBAL DISPOSITION SOBBARY
 

ANIBALS INITIALLY IN STUDY 50 50 50
 

NATURAL DEATHS 10 12 13
 

BOEIBUHD SACRIFICE 2 1 2
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERBIKAL SACRIFICE - 38 37 33
 

ANIBAL HISSING 2
 

1 jNcyjpjig ftSjoLjzgp.MIWis
 

* NUMBER OF ANIMALS «ITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

55
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS*
 

TOTAL PRIMARY TUMORS
 

TOTAL ANIMALS WITH BENIGN TUMORS
 

TOTAL BENIGN TUMORS
 

TOTAL ANIMALS WITH MALIGNANT TUMORS
 

TOTAL MALIGNANT TUHORS
 

TOTAL ANIMALS WITH SECONDARY TDMORS*
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS WITH TUBORS UNCERTAIN­ BENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ PEIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

CONTROL LOW DOSE HIGH DOSE 

39 32 34 

54 53 45 

15 18 15 

17 23 17 

31 25 2t 

37 30 28 

a 5 1 

6 9 1 

* PRIMARY TUHORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

# SECONDARY TUMORS: METASTATIC TDMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

56
 
TABLE B2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

FED 2-AMINO-5-NITROTHIAZOLE IN THE DIET 

CONTROL LOW DOSE
 

ANIMALS INITIALLY IN STUDY 50 50
 

ANIMALS NECROPSIED 50 50
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 50 50
 

INTEGUMENTARY SYSTEM
 

*SOBCOT TISSUE (50) (50)
 

FIBEOSARCOMA 1 (2X)
 

RESPIRATORY SYSTEM
 

#LUNG (47) (48)
 

ADENOCARCINOMA, NOS, METASTATIC
 

ALVEOLAE/BRONCHIOLAR ADENOMA 2 (4%) 2 (4%)
 

ALVEOLAR/BRONCHIOLAR CARCINOMA 2 (4%)
 

HEMATOEOIETIC SYSTEM
 

*NULTIPLE ORGANS (50) (50)
 

MALIG.LYMPHOMA, LYMPHOCYTIC TYPE 11 (22*) 3 (6X)
 

MALIG.LYMPHOBA, HISTIOCYTIC TYPE 6 (12%) 2 (4X)
 

DNDIFFERENTIATED LEUKEMIA 1 (2%)
 

LYHPHOCYTIC LEUKEMIA 2 (14%)
 

' GRANULOCYTIC LEUKEMIA 1 (2%)
 

tSPLEEN (HI) (49)
 

HEMANGIOSARCOMA 3 (6%)
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 2 (4%)
 

tLYMPH NODE (38) (39)
 

ALVEOLAR/BBONCHIOLAR CA, METASTA 1 (3S)
 

tMESENTERIC L. NODE (38) (39)
 

WALIG.LYMPHOMA, LYMPHOCYTIC TYPE 1 (3%)
 

HALIG.LYMPHOMA, HISTIOCYTIC TYPE 1 (3S)
 

#LUNG (47) (48)
 

_ JiiU&«J£BEBQA&*-U£EBQ£XXI£_m£ l«ttil__.
 

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

HIGH DOSE
 

50
 

50
 

50
 

(50)
 

2 (4%)
 

(49)
 

1 (2%)
 

7 (14%)
 

1 (2%)
 

(50)
 

6 (12%)
 

1 (2%)
 

1 (2%)
 

(49)
 

4 (8%)
 

(35)
 

(35)
 

1 (3%)
 

(49)
 

57
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

•••^•IMMB«H«*IIMBaa «V
 

CONTROL LOW DOSE
 

•SMALL INTESTINE (48) (47)
 

MALIG.LYHPHOBA, LYHPHOCYTIC TYPE 1 (2X)
 

MALIG.LYMPHOBA, HISTIOCYTIC TYPE
 

•KIDNEY	 (49) (50)
 

MALIG.LYBPHOMA, LYHPHOCYTIC TYPE
 

•THYMUS	 (38) (43)
 

MALIGNANT LYHPHOHA, NOS 1 (2%)
 

GRANULOCYTIC SARCOMA
 

CIBCDIATORY SYSTEH
 

•
 

IHEART (49) (50)
 

ALVEOLAE/BHONCHIOLAR CA, BETASTA 1 (2«)
 

DIGESTIVE SYSTEH
 

tLIVER (49) (50)
 

HEPATOCELLULAR ADENOMA 1 (2%) 4 (8%)
 

HEPATOCELLULAR CARCINOMA 1 (2%) 2 (4X)
 

HEMANGIOMA 1 (2X)
 

HEHANGIOSARCOMA 1 <2X) 1 <2X)
 

•DUODENOM	 (48) (t7)
 

ADENOMATOOS POLYP, NOS
 

URINARY SYSTEB
 

NONE
 

ENDOCRINE SYSTEM
 

•PITUITARY	 0*3) (42)


CHROHOPHOBE ADENOMA	 2 (5U) 6 (14X)
 

•THYROID	 (HO) (44) .
 FOLLICULAR-CELL ADENOMA
 

REPRODUCTIVE SYSTEM
 

*HAHHARY GLAND (50) (50)
 

JDEggCARCINOHA, IDS
 

I SOMBER OF AHIHALS KITH TISSUE EXAMINED MICROSCOPICALLY
 * NOHBER OF AMIHALS NECROPSIED
 

HIGH DOSE
 

(50)
 

1 (2X)
 

(50)
 

1 (2X)
 

(41)
 

1 (2%)
 

(50)
 

(50)
 

1 (2X)
 

t (8X)
 

1 (2X)
 

(50)
 

1 (2X)
 

(43)
 

6 .(14X)
 

(43)
 

2 (5X)
 

(50)
 

_1_J2XL._
 

58 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

HIGH DOSE
 

1 (2X)
 

(50)
 

1 (2X)
 

(«6)
 

(50)
 

1 (2%)
 

(50)
 

FIBROADENOBA
 

ICTERUS
 

SAECOHA, NOS
 

LEIOBYOSARCOBA
 

ENDOBETRIAL STROHAL POLYP
 

HEHANGIOHA
 

tOVARY
 

LOTFOBA
 

GRANULOSA-CELL TUBOR
 

TERATOSA, BENIGN
 

HERVCOS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

*EYE/LACRIBAL GLAND
 

PAPILLARY CYSTADENOBA, NOS
 

H.USCUIOSKELETAL SYSTEB
 

^SKELETAL HOSCLE
 

HEMANGIOSARCOHA
 

BOEY CAVITIES
 

NONE
 

ALL OTHER SYSTEMS
 

- MS5- _ . _
 

CONTROL
 

(i»7)
 

2 (<m>
 

(39)
 

1 (3X)
 

(50)
 

(50)
 

LOW DOSE
 

(1*9)
 

1 (2X)
 

1 (2X)
 

1 (2X)
 

.C»7)
 

1 (2X)
 

1 (2X)
 

(50)
 

(50)
 

1 (2X)
 

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

59
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

HIGH DOSE
 

50
 

6
 

3
 

41
 

28
 

45
 

16
 

19
 

21
 

26
 

1
 

1
 

 AH ADJACENT ORGAN 

ANIMAL DISPOSITION SUMMARY
 

ANIHAtS INITIALLY IN STODY
 

NATURAL DEATHS
 

HORIBOND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL MISSING
 

9 INCLUDES AOTOLYZED ANIMALS
 

TUMOR SUMMARY
 

TOTAL ANIMALS HITH PRIMARY TUMORS*
 

TOTAL PRIMARY TUMORS
 

TOTAL ANIMALS HITH BENIGN TUMORS
 

TOTAL BENIGN TUMORS
 

TOTAL ANIMALS HITH MALIGNANT TUMORS
 

TOTAL MALIGNANT TDHORS
 

TOTAL ANIMALS HITH SECONDARY TUMORS*
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS HITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS HITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TOHORS: ALL TtJMORS EXCEPT SECONDABI TOHORS 

ff SECONDARY TOHORS: HETASTATIC TUMORS OR TUMORS IIVASIVE III TO

CONTROL LOW DOSE 

50 50 

14 9 

1 3 

35 38 

26 31 

31 40 

3 16 

5 17 

23 19 

25 23 

1 

2 

1 

1 

60
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN RATS FED 2-AMINO-5-NITROTUIAZOLE IN THE DIET
 

61
 

TABLE C1. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE 

RATS FED 2-AMINO-5-NITROTHIAZOLE IN THE DIET 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 50 50 50
 

ANIMALS NECBOPSIED 50 50 49
 

ANIMALS EXAMINED HI STOPATHOLOGICALLY 50 50 49
 

INTEGUMENTARY SYSTEM
 

*SKIN (50) (50) (49)
 

CYST, NOS 1 (2%)
 

HYPERKERATOSIS 2 (4«)
 

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

ULCEE, NOS 1 (2%)
 

RESPIRATORY SYSTEM
 

*NASAL CAVITY 

INFLAMMATION, SUPPURATIVE 

INFLAMMATION, CHRONIC 

(50) 

1 (2%) 

(50) (49) 

2 (UX) 

#TRACHEA 

INFLAMMATION, NOS 

INFLAMMATION, SUPPURATIVE 

INFLAMMATION, CHRONIC 

HYPEPPLASIA, LYMPHOID 

(49) 

17

1

3

 (35%) 

(2%) 

 (6%) 

(47) 

14

1

1

 (30*) 

(2%) 

 (2X) 

(49) 

9 (18X) 

1 (2%) 

1 (2*) 

#L.UNG/BEONCHUS 

BRONCHIECTASIS 

INFLAMMATION, FOCAL 

INFLAMMATION, SUPPORATIVE 

HYPERPLASIA, NOS 

HYPERPLASIA, LYMPHOID 

(50) 

4

8

 (8%) 

 (16%) 

(50) 

i*

1

1

19

 (8*) 

 (2%) 

(2%) 

 (38%) 

(48) 

1 (2%) 

1 (2*) 

20 (42%) 

tLONG 

ATFLFCTASIS 

CONGESTION, NOS 

HEMOFRHAG3 

BRONCHOPNEUaONIA, NOS 

INFLAMMATION, NOS 

..__-IKi.AMiII2lU_EQ£Al_„„—..—._. 

(50) 

1

2

 (2%) 

 (4X) 

(50) 

2

1

1

 (US) 

 (2%) 

(2%) 

(48) 

1 (2%) 

„ l_I2%i__ 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

63
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

INFLAMMATION, INTERSTITIAL 

INFLAMMATION, SOPPURATIV? 1 (2X) 

ERONCHOPNEOMONIA SOPPDRATIVE 1 (2X) 

BRONCHOPNEUNONIA ACUTE SUPPURATI 1 (2X) 

PNEUMONIA, CHRONIC MUFINE 12 (24X) 5 (10X) 

FIBROSIS 

NECROSIS, FOCAL 

1

1

 (2X) 

 (2X) 

PIGMENTATION, NOS 1 (2%) 

HSMOSIDEROSIS 1 (2X) 

ALVEOLAR MACROPHAGES 5 (10X) 2 (UX) 

HYPERPLASIA, ADENOKATOUS 1 (2X) 

HYPERPLASIA, ALVEOLAR EPITHELIUM 

tLUNG/ALVEOLI (50) (50) 

CONGESTION, NOS 

EDEMA, NOS 

1

1

 (2«) 

 (2%) 1 (2X) 

HEMORRHAGE 1 (2%) 

HENATOPOIETIC SYSTEM
 

fBONE HARROW (U9) (49)
 

HYPOPLASIA, NOS 1 (2X)
 

HYPERPLASIA, NOS H <8X) 1 (2X)
 

HYPERPLASIA, HEMATOPOIETIC « (8*) 8 (16X)
 

HYPERPLASIA, ERYTHROID 1 (2X)
 

HYPERPLASIA, GRANULOCYTIC 3 (6X)
 

F.RYTHROPOIESIS 1 (2X)
 

#SPLEEN («9) (47)
 

RUPTURE 1 <2X)
 

CONGESTION, NOS 1 (2X) 2 (<»X)
 

FIBROSIS 1 (2X)
 

NECROSIS, FOCAL 1 (2X)
 

HEHOSIDEROSIS 23 (H7%) 31 (66X)
 

ATROPHY, NOS 1 <2X)
 

LEUKEBOID REACTION 1 (2X)
 

HYPERPLASIA, RETICULUH CELL
 

HEMATOPOIESIS 25 (51X) 31 (66%)
 

ERYTHROPOIESIS 2 C*X)
 

GRANULOPOIESIS 1 (2X) 1 <2X)
 

*LYHPH NODE (U1) (41)
 

HEHOSIDEROSIS 1 (2X)
 

#MESENTEFIC L. NODE (<»1) (41)
 

HY.PJJiPlAJIA.i £25 „­

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

1 (2X)
 

1 (2X)
 2 (a*)
 

1 (2X)
 

2 (<»X)
 

1 (2X)
 

(48)
 

(48)
 

11 (23X)
 

7 (15X)
 

(49)
 

1 (2X)
 

2 (t«)
 

18 (37X)
 

2 (4X)
 

18 (37X)
 

2 (4X)
 

5 (10X)
 

(42)
 

(42)


l_i2H_
 

64
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

tTHYNUS (37) 0*1) (31)
 

LYMPHANGIECTASIS 1 (2%)
 

HEMOSIDER05IS 2 (5%) 1 (3%)
 

ANGIECTASIS 1 (2%)
 

CIRCULATORY SYSTEM
 

tHEART (48) (49) (48)
 

FIBROSIS, FOCAL 1 (2X)
 

f HEART/ATRIUM (U8) (49) (48)
 

THROMBOSIS, NOS 1 (2%)
 

#MYOCARDIUM (US) (49) (48)
 

INFLAMMATION, FOCAL 2 (U%) 2 (4X)
 

INFLAMMATION, INTERSTITIAL 1 (2%) 2 (4%)
 

ABSCESS, NOS 1 (2%)
 

INFLAMMATION, CHRONIC FOCAL 1 (2%)
 

FIBROSIS 4 (8%) 1 (2*)
 

FIBROSIS, FOCAL 1 (2%) 16 (33%) 18 (38%)
 

SCAR 1 (2»)
 

DEGENERATION, NOS 6 (13%) 1(2%)
 

NECROSIS, FOCAL 1 (2%)
 

#ENDOCARDIUM (48) (49) (48)
 

INFLAMMATION, FOCAL 2 (4%)
 

*PULMONARY ARTERY (50) (50) (49)
 

MEDIAL CALCIFICATION 1 (2%)
 

CALCIFICATION, FOCAL 2 (4%)
 

IHEPATIC SINUSOID (49) (49) (49)
 

CONGESTION, NOS 1 (2%)
 

DIGESTIVE SYSTEM
 

#LIVER (49) (49) (49)
 

CONGESTION, NOS 1 (2%)
 

HEMORRHAGE 1 (2%)
 

CIRRHOSIS, NOS 1 (2%)
 

DEGENERATION, CYSTIC 1 (2%)
 

NECROSIS, NOS 1 (2%)
 

NECROSIS, FOCAL ___.1.I2J|L__..„,.__ ._1_12%L_
 

# NUMBER OF ANIMALS HITH TISSUE E5WMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

65
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

HETAHORPHOSIS PATTY 

PIGHENTATION, NOS 

1 (2X) 7 (1UX) 

1 (2X) 

FOCAL CELLULAR CHANGS 2 (4X) 

PHAGOCYTIC CELL 

ANGIECTASIS 

1 (2%) 

HYPERPLASIA, HEHATOPOIETIC 

HYPERPLASIA, RETICULUH CELL 

HYPERPLASIA, LYBPHOID 1 (2X) 

HEMATOPOIESIS 

ERYTHROPOIESIS 

4 (8%) 

1 (2X) 

#LIVER/CENTRILOBULAR («9) (49) 

HETAHORPHOSIS FATTY 2 (4X) 2 <4X) 

PIGHENTATION, NOS 1 (2%) 

ILIVER/HEPATOCYTES (49) (49) 

DEGENERATION, NOS 

*BILE DUCT (50) (50) 

LYHPHOCYTIC INFLAHHATORY INFILTR 1 (2X) 

HYPERPLASIA, NOS 

HYPERPLASIA, FOCAL 

1

18

 (2X) 

 (36X) 

2

26

 (4X) 

 (52X) 

•PANCREAS (49) (44) 

EDEHA, NOS 1 <2X) 

PERIARTERITIS 1 (2X) 

fPANCREATIC DUCT (49) (44) 

HYPERPLASIA, FOCAL 2 (4X) 5 (11X) 

tSTOHACH (it 9) (50) 

ULCER, NOS 

OLCER, FOCAL 

1

1

 (2X) 

 (2X) 3 (6X) 

INFLAHHATION, SUPPURATIVE 

EROSION 1 (2X) 1 (2X) 

fGASTRIC HUCOSA («9) (50) 

EROSION 1 <2X) 

tCARDIAC STOHACH («9) (50) 

ULCER, FOCAL 

tPEYEBS PATCH (49) (49) 

HYPERPLASIA, LYMPHOID 5 (10X) 4 (8X) 

•ILEUH (49) (49) 

HUCOCE1E _„ _ . J-I2X1 

I NUMBER OF ANIBALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

8 (16X)
 

2 (<*X)
 

3 (6X)
 

1 (2X)
 

1 (2X)
 

(49)
 

3 (6X)
 

(49)
 

1 (2X)
 

(49)
 

2 (4X)
 

28


C»5)
 

(45)
 

3


(47)
 

1


1


(47)
 

(47)
 

2


(«3)
 

4


(43)
 

 (57X)
 

 (7X)
 

 <2X)
 

 (2X)
 

 (4X)
 

 (9X)
 

66 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

fCOLON (32) (33)
 

NENATODIASIS 3 (9X) 3 (9X)
 

RINARY SYSTEM­

#KIDNEY (50) (1*9)
 

CAST, NOS 1 (2X)
 

CONGESTION, NOS 1 (2X)
 

INFLAMMATION, INTERSTITIAL 1 (2%) 8 (16X)
 

ABSCESS, NOS 1 (2%)
 

INFLAMMATION, CHRONIC 8 (16X) 6 (12X)
 

INFLAMMATION, CHRONIC FOCAL 26 (52%) 16 (33X)
 

INFLAMMATION, CHRONIC DIFFUSE 1 (2*) 2 (UX)
 

GLOHERULOSCLEROSIS, NOS 1 (2X)
 

PIGMENTATION, NOS
 

tKIDNEY/CORTEX (50) (U9)
 

INFARCT, FOCAL 1 (2X)
 

PIGMENTATION, NOS 5 (10X)
 

tKIDNEY/TUBOLE (50) . (<»9)
 

CAST, NOS 1 (2%)
 

DEGENERATION, HYALINE 1 (2X)
 

PIGMENTATION, NOS 3 (6X) 1 (2X)
 

tCONVOLHTED TUBULES (50) (49)
 

PIGMENTATION, NOS 2 (4X)
 

CYTOPLASMIC VACUOLIZATION 1 (2X)
 

#0. BLADDER/SOBMOCOSA (H7) (42)
 ' HEMORRHAGE 1 (2X)
 

NCOCRINE SYSTEM 

#PITUITARY (46) (45) 

CYST, NOS 

MULTIPLE CYSTS 

1 (2X) 1 (2X) 

1 (2X) 

CONGESTION, NOS 1 (2X) 

HEMORRHAGE 1 (2%) 

HSMOPRHAGIC CYST 

HYPERPLASIA, NOS 1 (2X) 

_ HYPERPLASIA, FOCAL  MGIECTASI s, , __„„ ._„_„ 2_Jfi81 _2.iJ*SL_, 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIHALS NECROPSIED
 

HIGH DOSE
 

(31)
 

1 (3X)
 

(49)
 

2 (4X)
 

5 (10X)
 

18 (37X)
 

2 (4X)
 

2 (4S)
 

(49)
 

1 (2X)
 

2 (4X)
 

(49)
 

2 (4X)
 

2 (4«)
 

(49)
 

2 (4X)
 

(43)
 

(43)
 

1 (2X)
 

1 (2X)
 

D__»_i_i2xi._
 

67
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE
 

(48)
 

(48)
 

(48)
 

2 (4%)
 

(46)
 

4 (9%)
 

1 (2%)
 

29 (63X)
 

2 (4X)
 

(49)
 

1 (2X)
 

(49)
 

1 (2X)
 

(49)
 

1 (2X)
 

(«2)
 

1 (2X)
 

(49)
 

3'1 (63X)
 

4 (8X)
 

5 (10X)
 

4 (8X)
 

__«_______—_
 («9) _
 

tADRENAL
 

ANGIECTASIS
 

tADBBNAL CORTEX
 

HYPZRPLASIA, NODULAR
 

•ADRENAL MEDULLA
 

HYPERPLASIA, NODULAR
 

HYPERPLASIA, NOS
 

HYPERPLASIA, FOCAL
 

•THYROID
 

CYSTIC FOLLICLES
 

LYNPHOCYTIC INFLAHMATORY INFILTR
 

NECROSIS, NOS
 

HYPERPLASIA, C-CELL
 

HYPERPLASIA, POLLICULAR-CELL
 

REPRODUCTIVE SYSTEH
 

*MAHHARY GLAND
 

GALACTOCELE
 

*FENIS
 

PROLAPSE
 

*PREPUTIAL GLAND
 

ULCER, NOS
 

INFLAMMATION, SUPPURATIVE
 

INFLAMMATION, CHRONIC
 

•PROSTATE
 

INFLAMMATION, DIFFUSE
 

INFLAMMATION, SUPPURATIVE
 

iTESTIS
 

NECROSIS, NOS
 

CALCIFICATION, DYSTROPHIC
 

ATROPHY, NOS
 

ATROPHY, FOCAL
 

ASPERMATOGENESIS
 

HYPERPLASIA, INTERSTITIAL CELL
 

ITESTIS/TUBOLE
 

?A,LCJ?I5AJIQBA MQS
 

CONTROL
 

(49)
 

1 <2X)
 

(«»9)
 

1 (2%)
 

(<»9)
 

2 (4X)
 

1 (2X)
 

C»6)
 

23 (50%)
 

(50)
 

(50)
 

(50)
 

2 (a*)
 

2 («X)
 

<U4)
 

2 (5%)
 

(50)
 

32 (6U%)
 

7 (1UX)
 

t (8X)
 

1 <2X)
 

(50)
 

1.1211
 

LOW DOSE
 

(U7)
 

1 (2X)
 

(47)
 

(47)
 

1 (2X)
 

4 (9)1)
 

(48)
 

1 (2X)
 

1 (2*)
 

29 (60%)
 

(50)
 

(50)
 

(50)
 

1 (2X)
 

1 (2X)
 

(»2)
 

(50)
 

1 (2X)
 

1 (2X>
 

19 (38X)
 

19	 (38%)
 

2 (*%)
 

(50)
 .______.___—«
 

t NUMBER OF ANIMALS WITH TISSUE EXARINED MICROSCOPICALLY
 * RUBBER OF ANIMALS NECROPSIED
 

68
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

CALCIFICATION, FOCAL 2 (4*)
 

*EPIDIDYMIS (50) (50)
 

INFLAMMATION, SUPPURATIVE
 

NERVOUS SYSTEM
 

*NEURON (50) (50)
 

CYTOPLASMIC VACUOLIZATION
 

IBRAIN/HENINGES (50) (50)
 

THROMBOSIS, NOS 1 <2X)
 

IBRAIN (50) (50)
 

HEMORRHAGE
 

GLIOSIS
 

DEGENERATION, NOS
 

tBRAIN STEM (50) (50)
 

HEMORRHAGE
 

NECROSIS, NOS 1 (2X)
 

tHIDBRAIN (50) (50)
 

NECROSIS, NOS 1 (2X)
 

MALACIA 1 (2X)
 

*SPINAL CORD (50) (50)
 

NECROSIS, NOS
 

NECROSIS, FOCAL
 

* SCIATIC NERVE (50) (50)
 

DEGENERATION, MYELIN
 

SPECIAL SENSE ORGANS
 

*EYE (50) (50)
 

DEGENERATION, NOS 1 (2X)
 

CATARACT 13 (26X) 5 (10%)
 

*EYE/CORNEA (50) (50)
 

INFLAMMATION, INTERSTITIAL 1 (2X)
 

*LE»S CAPSULE (50) (50)
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

2 (4%)
 

(49)
 

1 (2X)
 

(49)
 

1 (2X)
 

(49)
 

(49)
 

1 (2%)
 

1 (2X)
 

1 (2X)
 

(49)
 

1 (2%)
 

(49)
 

(49)
 

1 (2X)
 

1 (2%)
 

(49)
 

1 (2%)
 

(49)
 

7 (1U%)
 

(49)
 

(49)
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE
 

(49)
 

1 (2*)
 

(49)
 

(U9)
 

(U9)
 

(49)
 

(49)
 

1
 

CALCIFICATION, NOS
 

HOSCOLOSKEIETAL SYSTEH
 

*SKELETAL HOSCLE
 

ATROPHY, HOS
 

BODY CAVITIES
 

*ABDOHINAL CAVITY
 

NECROSIS, FAT
 

*PERITONEUM
 

EFFUSION, NOS
 

*PERITONEAL CAVITY
 

RETENTION FLUID
 

*PLEURA
 

HYDROTHORAX
 

*MESENTERY
 

STEATITIS
 

NECROSIS, FAT
 

ALL OTHEP SYSTEHS
 

ADIPOSE TISSUE
 

INFLAMMATION, FOCAL
 

SPECIAL KORPHOLOGY SUHBARY
 

AOTOLYSIS/NO NECROPSY
 

CONTROL
 

1 (2X)
 

(50)
 

(50)
 

1 (2X)
 

(50)
 

(50)
 

(50)
 

1 (2*)
 

(50)
 

2 (<»*)
 

1
 

LOW DOSE
 

(50)
 

.(50)
 

(50)
 

1 (2%)
 

(50)
 

1 (2«)
 

(50)
 

(50)
 

1 (2X)
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

70
 
TABLE C2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE 

RATS FED 2-AMINO-S-NITROTHIAZOLE IN THE DIET 

ANIMALS INITIALLY IN STUDY
 

ANIMALS NECROPSIED
 

ANIMALS EXAMINED HI STOPATHOLOGICALLY
 

INTEGOBENTARY SYSTEM
 

*SKIN
 

NECROSIS, FOCAL
 

RESPIRATORY SYSTEM
 

#TEACHEA
 

INFLAMMATION, NOS
 

INFLAMMATION, CHRONIC SUPPdRATIV
 

NECROSIS, NOS
 

METAPLASIA, SQUAMOUS
 

HYPERPLASIA, LYMPHOID
 

#LUNG/ERONCHUS
 

BRONCHIECTASIS
 

INFLAMMATION, NOS
 

HYPERPLASIA, FOCAL
 

HYPERPLASIA, LYMPHOID
 

#1,0 NG
 

BRONCHOPNEUMONIA, NOS
 

INFLAMMATION, NOS
 

INFLAMMATION, INTERSTITIAL
 

PNEUMONIA, CHRONIC MURINS
 

INFLAMMATION, CHRONIC SUPPURATIV
 

PFRIVASCULAR CUFFING
 

HEMOSIDEROSIS
 

ALVEOLAR NACROPHAGES
 

HYPEFPLASIA, LYMPHOID
 

#LUNG/ALVEOLI
 

CONGESTION, NOS
 

.._._I2EM* .825 , — ,- - ...
 

CONTROL


50
 

50
 

50
 

(50)
 

1 (2%)
 

(1*9)
 

17 (35*)
 

1 (2%)
 

(50)
 

2 (1%)
 

1 (2%)
 

27 (5US)
 

(50)
 

1 (2%)
 

5 (105)
 

2 (14%)
 

2 (U%)
 

1 (2*)
 

(50)
 

1 (2%)
 

 LOW DOSE
 

50
 

50
 

50
 

(50)
 

(50)
 

26	 (52%)
 

1 (2*)
 

2 (HI)
 

(50)
 

2 (4%)
 

25 (50%)
 

(51)
 

3 (6%)
 

1 (21)
 

2 («*)
 

1 (2*)
 

(50)
 

1 (2%)
 

..__ l_.i«L—
 

# NUMBER OF ANIMALS WITH TISSU2 FXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

71
 

HIGH DOSE
 

50
 

50
 

50
 

(50)
 

C*9)
 

U (29%)
 

2 (14%)
 

1 (2%)
 

1 (2%)
 

(50)
 

2 (14%)
 

1 (2%)
 

31 (62%)
 

(50)
 

1 (2%)
 

2 (H%)
 

1 (2%)
 

2 (U%)
 

(50)
 

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

CON! •ROL LOW DOS ;E
 

HEMATOPOIETIC SYSTEM
 

*BLOOD (50) (50)
 

ANEHIA, NOS 1 (2%)
 

#BONE HARROW (50) (U9)
 

HYPERPLASIA, NOS 1 (2%) 1 (2%)
 

MYELOFIBROSIS 1 (2%)
 

HEHATOPOISTIC TISSUE DISORDER 1 (2X)
 

HYPERPLASIA, HEM ATOPOIETIC 3 (6%) 7 (14%)
 

HYPERPLASIA, GRANULOCYTIC 2 (14%)
 

#SPLEFN (50) (50)
 

CONGESTION, NOS 1 (2%)
 

NECROSIS, COAGULATIVE
 

HEMOSIDEROSIS 3U (68* ) 34 (68%)
 

ATROPHY, NOS 1 (2«)
 

LEOKEMOID REACTION 1 (2%)
 

HYPERPLASIA, RETICULUM CELL 1 . (2%) 1 (2X)
 

HEMATOPOIESIS 1*0 (80%) 39 (78%)
 

ERYTHROPOIESIS 2 (H%)
 

GRANULOPOIESIS
 

#LYMPH NODE (UH) (39)
 

HEMOSIDEROSIS 1 (2%)
 

#MANDIBOLAR L, NODE (4U) (39)
 

LYMPHANGIECTASIS
 

tCERVICAL LYHPH NODE («4) (39)
 

CONGESTION, NOS 1 (2%)
 

HEMOSIDEROSIS 1 (2%)
 

#THYMUS (39) (37)
 

PEBIARTERITIS
 

HEMOSIDEROSIS 1 (3%) 1 (3%)
 

CIRCULATORY SYSTEM 

#HEART 

PERIARTERITIS 

(U8) (47) 

1 (2X) 

#HEART/ATRIUM (48) (47) _ THROJIBOSIS^NPS. ______ 1 (2%) 

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

72
 

HIGH DC ISE
 

(50)
 

(50)
 

5
 

(50)
 

1
 

39
 

1
 

35
 

1
 

1
 

(34)
 

(34)
 

1
 

(34)
 

(36)
 

1
 

4
 

(49)
 

'1
 

(49)
 

(1C*)
 

(2%)
 

(78*)
 

(2%)
 

(70%)
 

(2%)
 

(2%)
 

(3«)
 

(3%)
 

(11%)
 

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

CONTROL LOW DOSE HIGH DOSE 

tBYOCARDIUM (48) (47) (49)
 

INFLAMMATION, FOCAL 1 (2%)
 

INFLAMMATION, INTERSTITIAL 6 (13%) 5 (10%)
 

FIBROSIS 1 (2%)
 

FIBROSIS, FOCAL 2 (4%) 5 (11%) 12 (24%)
 

*PULMONARY ARTERY (50) (50) (50)
 

CALCIFICATION, FOCAL 1 (2%)
 

DIGESTIVE SYSTEM
 

*TONGUE (50) (50) (50)
 

HYPERPLASIA, EPITHELIAL 1 (2%)
 

HYPERKERATOSIS 1 (2%)
 

#LIVER (49) (49) (49)
 

INFLAMMATION, NOS 1 (2%)
 

FIBROSIS 1 (2%)
 

NODULE 1 (2%)
 

ADHESION, NOS 1 (2%)
 

NECROSIS, FOCAL 1 (2%)
 

NECROSIS, COAGULATIVE 1 (2%)
 

METAMORPHOSIS FATTY 9 (18%) 9 (18%) 4 (8%)
 

PIGMENTATION, NOS 1 (21)
 

FOCAL CELLULAR CHANGE 1 (2%)
 

ANGIECTASIS 3 (6%) 1 (2%) 4 (8%)
 

HYPERPLASIA, RETICULUM CELL 1 (2%)
 

HYPERPLASIA, LYMPHOID 1 (2%)
 

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

ERYTHROPOIESIS 1 (2%)
 

tLIVEP/CFNTRILOEULAR (49) (43) (49)
 

NECROSIS, FOCAL 1 (27=)
 

METAMORPHOSIS FA.TTY 2 (4%) 2 (<4%)
 

*LIVER/PFRIPORTAL (49) (49) (49)
 

METAMORPHOSIS FATTY 1 (2%) 2 (4%)
 

CLIVER/HEPATOCYTFS (49) (49) (49)
 

NECROSIS, FOCAL 1 (2X)
 

*BILE DOCT (50) (50) (50)
 

INFLAMMATION, FOCAL 3 (6%)
 

# NUMBER OF *NIMALS WITH TISSU2 EXUMINED MICROSCOPICALLY
 * NUMBFP OF ANIMALS NECROPSIED
 

73
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

HYPERPLASIA, FOCAL	 15 (30%) 16 (32X) 19 (38X)
 

•PANCREAS	 («9) (50) (48)
 

LYMPHOCYTIC INFLAMMATORY INFILTR 1 (2X)
 

ADHESION, NOS 1 (2X)
 

#PANCfiEATIC DOCT (49) (50) (48)
 

HYPERPLASIA, FOCAL 5 (10X) 9 (18X) 7 (15X)
 

#STOMACH (50) (50) (50)
 

ULCEE, NOS 1 (2%)
 

ULCER, FOCAL 1 (2X)
 

FROSION 1 (2X)
 

NECROSIS, FOCAL 1 (2X)
 

#CARDIAC STOMACH (50) (50) (50)
 

ULCER, NOS 1 (2X)
 

ULCER, FOCAL 1 (2*)
 

#PEYERS PATCH (H9) (i»8) (48)
 

HYPEEPLASIA, LYHPHOID 4 (8X) 10 (21X) 3 (6X)
 

f COLON (35) (40) (28)
 

NEMATODIASIS 5 (14X) 6 (15X) 4 (14X)
 

URINAEY SYSTEM
 

#KIDNEY (49) (50) (50)
 

INFLAMMATION, INTEESTITIAL 1 (2X) 1 (2X) 1 (2X)
 

INFLAMMATION, CHRONIC 2 (H%) 1 (2X)
 

INFLAMMATION, CHRONIC FOCAL 12 (2UX) 5 (10X) 3 (6X)
 

NEPHROSIS, NOS 1 (2X)
 

CALCIFICATION, FOCAL 1 (2X)
 

PIGMENTATION, NOS 2 (H%) 2 (4X)
 

#KIDNEY/CORTEX («9) (50) (50)
 

CYST, NOS 1 (2X) 1 (2X)
 

PIGMENTATION, NOS 17 (35X) 28 (56X) 36 (72X)
 

HYPERPLASIA, LYMPHOID 1 (2X)
 

tKIDNEY/TUBOLE (49) (50) (50)
 

CAST, NOS 1 (2*)
 

PIGMENTATION, NOS 2 («*) 5 (10X)
 

•CONVOLUTED TUBOLES	 (49) (50) (50)
 

- £A3I*Jfifi-	 . .1.1211
 

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

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

HYALINE MEMBRANE
 

METAMORPHOSIS FATTY
 

PIGMENTATION, NOS
 

#KIDNEY/PELVIS
 

CALCIFICATION, FOCAL
 

tURINARY BLADDER
 

CALCULUS, NOS
 

INFLAMMATION, CHRONIC
 

HYPERPLASIA, EPITHELIAL
 

ENCCC5INE SYSTEM
 

tPITOITARY
 

CYST, NOS
 

HEMORRHAGE
 

HEMORRHAGIC CYST
 

HEMOSIDEROSIS
 

HYPERPLASIA, NOS
 

HYPERPLASIA, FOCAL
 

ANGIECTASIS
 

#ADRENAL
 

DEGENERATION, NOS
 

ANGIECTASIS
 

#ADRENAL CORTEX
 

HEMORRHAGE
 

NECROSIS, FOCAL
 

*'ADF,ENAL MEDULLA
 

CYST, NOS
 

HYPERPLASIA, FOCAL
 

tTHYROID
 

CYSTIC FOLLICLES
 

LYMPHOCYTIC INFLAMMATORY INFILTR
 

HYPERPLASIA, C-CELL
 

HYPERPLASIA, FOLLICULAR-CFLL
 

REEFCDUCTIVE SYSTEM
 

*MAM«ARY GLAND
 

SAJiiCTOCIiLJ^ _, . -_,-„ .


CONTROL
 

1 <2X)
 

(49)
 

1 (2X)
 

(35)
 

1 (3X)
 

1 (3X)
 

1 (3X)
 

(45)
 

1 (2X)
 

2 <4X)
 

2 (4X)
 

1 (2X)
 

3 (7X)
 

1 (2X)
 

3 (7X)
 

(49)
 

1 (2X)
 

3 (6X)
 

(49)
 

1 (2X)
 

(49)
 

(50)
 

1 <2X)
 

39 (78X)
 

(50)
 

 5.J1SS1,
 

LOW DOSE
 

1 (2X)
 

3 <6X)
 

(50)
 

(43)
 

(47)
 

1 (2*)
 

2 (4%)
 

2 (US)
 

2 (US)
 

22 (47X)
 

(49)
 

10 (20X)
 

(49)
 

1 (2X)
 

1 (2S)
 

(49)
 

1 (2S)
 

(47)
 

33 (70*)
 

2 (4S)
 

(50)
 

5_iiSil.
 

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

75
 

HIGH DOSE
 

2 (4X)
 

(50)
 

1 (2X)
 

(44)
 

(44)
 

2 (5«)
 

2 (5*)
 

23 (52X)
 

(50)
 

1fi (36S)
 

(50)
 

(50)
 

1 (2%)
 

(1*8)
 

4 (8X)
 

1 (2%)
 

36 (75%)
 

2 (4X)
 

(50)
 

,_„_-_,4_ J12SL.
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

HYPERPLASIA, NOS 1 <2X)
 

METAPLASIA, SQOAMOOS
 

ADENOSIS 1 (2X) 1 (2X)
 

*PREPOTIAL GLAND (50) (50)
 

INFLAMMATION, SUPPORATIVE 7 (14X) 2 (4*)
 

ABSCESS, NOS
 

HYPERPLASIA, NOS 1 (2X)
 

*VAGINA (50) (50)
 

INFLAMMATION, SUPPORATIVE 1 (2X)
 

#OTFROS (50) (49)
 

HYDROHETRA 1 (2X)
 

LYMPHOCYTIC INFLAMMATORY INFIL/TR 1 (2X)
 

INFLAMMATION, SOPPORATIVE 1 (2X)
 

NECROSIS, NOS 1 (2X)
 

PIGMENTATION, NOS 1 (2X)
 

#OTEROS/ENDOMETRIOM (50) (49)
 

CYST, NOS 1 (2X) 1 (2X)
 

HEMORRHAGE 1 <2X)
 

INFLAMMATION, FOCAL 1 (2X)
 

ULCER, FOCAL 1 (2X)
 

LYMPHOCYTIC INFLAMMATORY INFILTR 1 (2X)
 

INFLAMMATION, SOPPORATIVE 8 (16%) 6 (12X)
 

INFLAMMATION, VESICOLAR 1 (2X)
 

HYPERPLASIA, NOS
 

HYPERPLASIA, FOCAL 1 (2X)
 

HYPERPLASIA, CYSTIC 2 (4X) 1 (2X)
 

#OVARY/OVIDOCT (50) (49)
 

INFLAMMATION, NOS
 

INFLAMMATION, FOCAL
 

INFLAMMATION, SOPPORATIVE 5 (10X) 7 (14X)
 

*OVARY (50) (49)
 

CYST, NOS 9 (18X) 7 (14X)
 

FOLLICOLAR CYST, NOS 2 (4X)
 

INFLAMMATION, SOPPORATIVE 1 (2X)
 

NEEVOOS SYSTEM
 

* BRAIN (49) (•9)
 

* NUMBER OF ANIMALS HITH TISSOE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

1 (2X)
 

(50)
 

1 (2X)
 

1 (2X)
 

1 (2X)
 

(50)
 

(50)
 

(50)
 

4 (8X)
 

3 (6X)
 

1 (2X)
 

1 (2X)
 

(50)
 

5 (10X)
 

1 (2X)
 

1 (2X)
 

(48)
 

11 (23X)
 

(49)
 

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

CONTROL LOW DOSE
 

NECROSIS, FOCAL
 

HALACIA 1 (2%)
 

tCEREBELLUB (U9) C*9)
 

NECROSIS, FOCAL
 

*SPINAL CORD (50) (50)
 

HEMORRHAGE 1 (2*)
 

SPECIAL SENSE ORGANS
 

*EYE (50) (50)
 

CATARACT 11 (22%) 16 (32%)
 

*EYE/CORNEA (50) (50)
 

IHFLABBATION, INTERSTITIAL
 

BUSCULOSKELETAL SYSTEB
 

*SKELETAL MUSCLE (50) (50)
 

ATROPHY, NOS 1 (2%)
 

BOEY CAVITIES
 

*HESENTERY (50) (50)
 

FIBROSIS
 

NECROSIS, FOCAL
 

NECROSIS, FAT
 

CALCIFICATION, FOCAL
 

ALL OTHER SYSTEHS
 

DIAPHRAGM
 

HERNIA, NOS 1 2
 

ADIPOSE TISSUE
 

INFLAHHATIOH, HOS
 

OBBNTUB
 

NECROSIS, FAT 1
 

SPECIAL MORPHOLOGY SUHBARY
 

NONE
 

t HUHBER OP AHIBALS WITH TISSDB EXAHINED HICROSCOPICALLT
 * NOHBEB OF AHIHALS HECROPSIED
 

HIGH DOSE
 

1 (2%)
 

(49)
 

1 (2%)
 

(50)
 

(51)
 

21 (42*)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

1 (2*)
 

1 (2*)
 

1 (2%)
 

1 (2«)
 

2
 

4
 

77
 

APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN MICE FED 2-AMINO-5-NITROTHIAZOLE IN THE DIET
 

79
 

TABLE D1.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

FED 2-AMINO-5-NITROTHIAZOLE IN THE DIET 

CONTROL LOW DOSE HIGH DOSE
 

50 50
 

ANIMAIS MISSING 2
 

ANIMALS NECROPSIED 49 50 48
 

ANIMALS FXAMINSD HISTOPATHOLOGICALLY 49 50 48
 

ANIMALS INITIALLY IN STUDY 50
 

INTEGUMENTARY SYSTEM
 

*SKIN (49) (50) (48)
 

CYST, NOS 1 (2*)
 

ULCER, NOS 1 (2%)
 

ULCER, FOCAL 1 (2%)
 

INFLAMMATION, SUPPURATIVE 2 (UX)
 

INFLAMMATION, VESICULAR 1 (2%)
 

INFLAMMATION, CHRONIC 1 (2X)
 

NECROSIS, NOS 1 (2S)
 

HYPFRPLASIA, NOS 1 (2%)
 

RESPIRATORY SYSTEM
 

#LUNG/BRONCHUS (49) (49) (48)
 

METAPLASIA, SQUAHOUS 1 (2*)
 

HYPEPPLASIA, LYMPHOID 11 (22%) 4 (8*)
 

tLUNG (49) (49) (48)
 

CONGESTION, NOS 1 <2X) 1 (29.)
 

EDEMA, NOS 1 (2%)
 

HEMORRHAGE 1 (2*)
 

INFLAMMATION, SUPPURATIVE 1 (2%)
 

ALVEOLAR MACROPHAGES 1 (2*) 1 (2*)
 

HYPERPLASIA, ADENOMATOUS 1 (2%) 1 (2%)
 

HYPEPPLASIA, LYMPHOID 1 (2*)
 

HEMATOPOIETIC SYSTEM
 

*BLOOD (49) (50) (48)
 

ANEMIA, NOS 1 (2X)
 

#BONE MARRO W (46) (44) (48)
 

„ ,HYPSRPMSIAi,,HEMA10P,OIETIC , „,..„.
—,2_iaiL_._


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

81
 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

HYPEPPLASIA, GRANULOCYTIC 2 (4X) 2 (5X)
 

#SPLEFN (46) (48) (46)
 

HEMOERHAGE 1 (2X)
 

AMYLOIDOSIS 1 (2X)
 

HEMOSIDEROSIS 1 (2X)
 

ANGIFCTASIS 1 (2X)
 

LEOKEMOID REACTION 1 <2X) 1 (2X)
 

LYMPHOCYTOSIS 1 (2X)
 

HYPERPLASIA, HEMATOPOIETIC 1 (2X)
 

HYPERPLASIA, RETICOLUM CELL 1 (2X)
 

HYPERPLASIA, LYMPHOID 2 (4X) 5 (10X)
 

HEMATOPOIESIS 24 (52X) 28 (58X) 28 (61X)
 

ERYTHROPOIESIS 2 (4%)
 

GRANDLOPOIESIS 1 (2X)
 

#LYMPH NODE (40) (33) (29)
 

INFLAMMATION, NOS 1 (3X)
 

HYPEEPLASIA, LYMPHOID 1 <3X)
 

HEMATOPOIESIS 1 (3X)
 

fMANDIBOLAE L. NODE (40) (33) (29)
 

HYPERPLASIA, LYMPHOID 2 (6X)
 

#MEDIASTINAL L. NODE (40) (33) (29)
 

HYPERPLASIA, LYMPHOID 1 (3X)
 

fMESENTERIC L. NODE (40) (33) (29)
 

THROMBOSIS, NOS 1 (3X)
 

CONGESTION, NOS 3 (8*) 2 (6X) 1 (3%)
 

tTRYNUS (35) (20) (31)
 

HYPEEPLASIA, LYMPHOID "^
 1 (3%)
 

CIRCULATORY SYSTEM
 

tMYOCARDIUM (49) (49) (48)
 

INFLAMMATION, INTERSTITIAL 1 (2%)
 

ICAPDIAC VALVE (49) (49) (48)
 

MELANIN 1 <2X)
 

*PULMONARY ABTSRY (49) (50) (48)
 

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

82
 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

DIGESTIVE SYSTEM 

•SALIVARY GLAND 

FIB POSTS 

(<*3) (47) 

1 (2%) 

#LIVEB 

CYST, NOS 

CONGESTION, NOS 

HEMORRHAGE 

LYBPHOCYTIC INFLAMMATORY INFILTR 

INFLAHHATION, SUPPURATIVE 

FIBROSIS, FOCAL 

DEGENERATION, HYALINE 

NECROSIS, FOCAL 

AMYLOIDOSIS 

(49) 

1 (2%) 

1 (2%) 

(50) 

1 (2%) 

1 (2%) 

1 (2X) 

METAMORPHOSIS FATTY 

PIGMENTATION, NOS 

FOCAL CELLULAR CHANGE 

4 (8X) 1 (2%) 

1 (2%) 

HYPEPPLASIA, NODULAR 

HYPERPLASTIC NODULE 

ANGIECTASIS 

LEUKEBOID REACTION 

HYPERPLASIA, HEMATOPOIETIC 

HYPERPLASIA, RETICOLUM CELL 

HYPERPLASIA, LYMPHOID 

HEMATOPOIBSIS 

1

1

1

1

1

 (2%) 

 (2*) 

 (2*) 

 (2%) 

 (2%) 

1 (211) 

1 (2%) 

1 (2*) 

tHEPATIC CAPSULE 

HEMATOMA, NOS 

(U9) 

1 (2«) 

(50) 

#LIVER/CENTRILOBULAR 

METAMORPHOSIS FATTY 

(149) 

1 (2%) 

(50) 

t LI VEB/PE HI PORTAL 

LYMPHOCYTIC INFLAHMATORY INFILTR 

HYPERPLASIA, LYHPHOID 

(49) 

1 (2%) 

(50) 

1 (2X) 

#LIVER/HEPATOCYTES 

DEGENERATION, NOS 

NECROSIS, NOS 

NECROSIS, COAGOLATIVE 

(49) (50) 

1 (2%) 

1 (2X) 

*BILE DUCT 

CYST, NOS 

.„ IN£LAMMATIONA_NOS ________ 

(49) (50) 

l-U&L 

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

HIGH DOSE
 

(1*4)
 

(48)
 

1 (2*)
 

1 (2X)
 

1 (2%)
 

1 (2%)
 

3 (6%)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

2 (*%)
 

(48)
 

(48)
 

1 (2%)
 

(48)
 

(48)
 

1 (2X)
 

(48)
 

2 (4X)
 

••^.^.•.•••^^^.^.••klM^*
 

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

HIGH DOSE
 

1 (2X)
 

2 <4X)
 

1 (2X)
 

1 (2X)
 

(45)
 

1 (2X)
 

1 (2X)
 

(45)
 

1 (2X)
 

(45)
 

1 (2X)
 

1 (2X)
 

(45)
 

4 (9X)
 

(35)
 

1 (3X)
 

2 (6X)
 

(48)
 

1 (2X)
 

1 (2X)
 

1 (2X)
 

INFLAMMATION, FOCAL
 

LYMPHOCYTIC INFLAMMATORY INFILTR
 

INFLAMMATION, SUPPURATIVE
 

HYPERPLASIA, NOS
 

HYPERPLASIA, FOCAL
 

HYPERPLASIA, RETICULUM CELL
 

#PANCREAS
 

CYSTIC DUCTS
 

FDEMA, NOS
 

INFLAMMATION, CHRONIC FOCAL
 

FIBROSIS
 

NECROSIS, NOS
 

*PANCREATIC DUCT
 

CYST, NOS
 

HYPERPLASIA, FOCAL
 

#SMALL INTESTINE
 

INFLAMMATION, NOS
 

NECROSIS, NOS
 

tPEYERS PATCH
 

HYPERPLASIA, NOS
 

HYPERPLASIA, LYMPHOID
 

tCOLON
 

INFLAMMATION, NOS
 

NEMATODIASIS
 

URINARY SYSTEM
 

tKIDNEY
 

PYELONEPHRITIS, NOS
 

LYMPHOCYTIC INFLAMMATORY INFILTR
 

INFLAMMATION, INTERSTITIAL
 

INFLAMMATION, SUPPURATIVF
 

INFLAMMATION, CHRONIC
 

INFLAMMATION, CHRONIC DIFFUSE
 

FIBROSIS
 

PERIARTERITIS
 

INFARCT, NOS
 

AMYLOIDOSIS
 

CYTOFLASMIC VACUOLIZ ATION
 HVPPRP n i cft nriirtO-LA T A ^ITl NOHT1 * nu u UL,£ T BP
 n
 

CONTROL
 

1 (2X)
 

4 (8X)
 

(48)
 

1 (2»)
 

1 (2X)
 

1 (2X)
 

(48)
 

1 (2X)
 

(HI)
 

(47)
 

1 (2X)
 

2 (4X)
 

(22)
 

4 (18X)
 

(48)
 

2 (4X)
 

1 (2X)
 

1 (2%)
 

1 (2X)
 

.
 

LOW DOSE
 

1 (2X)
 

3 (6X)
 

1 (2X)
 

(46)
 

(46)
 

1 (2X)
 

(44)
 

(«4)
 

2 (5X)
 

(36)
 

5 (14X)
 

(47)
 

1 (2X)
 

1 (2*)
 

1 (2X)
 

1 (2*)
 

1 (2X)
 

1 mi
 

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

84 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

HYPERPLASIA, LYHPHOID	 1 (21) 1 (2X)
 

•KIDNEY/CORTEX	 (48) (47) (18)
 

FIBROSIS, FOCAL 1 (2X)
 

INFARCT, NOS 1 (2X)
 

•KIDNEY/TUBULE	 (48) (47) (48)
 

DEGENERATION, HYALINE 1 (2X) 1 (2X)
 

tURINARY BLADDER (47) (49) (44)
 

CALCULUS, NOS 1 (2X)
 

INFLAMMATION, CHRONIC 1 (2X)
 

INFLAMMATION, CHRONIC FOCAL 1 (2X)
 

PERIARTERITIS 1 (2X)
 

HYPERPLASIA, EPITHELIAL 1 (2X)
 

ENDOCRINE SYSTEM
 

•PITUITARY	 (31) (45) (36)
 

CYST, NOS 2 (6X)
 

tADRENAL/CAPSULE (46) (49) (46)
 

HYPERPLASIA, NOS 1 (2X)
 

HYPERPLASIA, FOCAL 28 (61X) 35 (71X) 34 (741)
 

•ADRENAL CORTEX (46) (49) (46)
 

HYPERPLASIA, NOS 2 (4X)
 

•ADRENAL MEDULLA (46) (49) (46)
 

HYPERPLASIA, NOS 1 (21)
 

•THYROID	 (43) (39) (40)
 

CYSTIC FOLLICLES 1 (21)
 

HYPERPLASIA, FOLLICULAR-CELL 2 <5X) 2 (SX)
 

•PANCREATIC	 ISLETS (48) C«6) (45)
 

HYPERPLASIA, NOS 2 (4X)
 

REPRODUCTIVE SYSTEM
 

*PREPUTIAL GLAND (49) (50) (48)
 

DILATATION, NOS 1 (2X)
 

CYST, NOS 4 (81)
 

2 Jill
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

85
 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

#PROSTATE (39) (33)
 

INFLAMMATION, SUPFURATIVE 1 (3X)
 

*SEMINAL VESICLE (49) (50)
 

INFLAMMATION, SUPPURATIVF
 

INFLAMMATION, CHRONIC SDPPURATIV
 

#TESTIS (47) (48)
 

ATROPHY, NOS 1 (2«)
 

ATROPHY, FOCAL 1 (2X)
 

ASPERMATOGENESIS 1 (2%) 1 (2%)
 

*EPIDIDYMIS (49) (50)
 

LYMPHOCYTIC INFLAMBATORY INFILTR 3 (6%)
 

INFLAMMATION, SOPPOBATIVE 1 (2X)
 

CALCIFICATION, FOCAL 1 (2%)
 

NFEVOaS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

*EYF (49) (50)
 

PUS
 

INFLAMMATION, SDPPORATIVE
 

DEGENERATION, NOS 1 (2«)
 

CATARACT 2 (4X)
 

PHTHISIS BOLBI
 

* EYE/COP NBA (<I9) (50)
 

INFLAMMATION, INTERSTITIAL
 

MOSCULOSKELETAL SYSTEM
 

*SKELETAL HOSCLE (49) (50)
 

DEGENERATION, NOS
 

BODY CAVITIES
 

*ABDOHINAL CAVITY (49) (50)
 

HEMORRHAGE
 »» ^«M.M.:.^1»_—.«««>=W«.
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIHALS NECEOPSIED
 

86
 

HIGH DOSE
 

(35)
 

1 (3«)
 

(48)
 

1 (2%)
 

1 (2X)
 

(46)
 

3 (7%)
 

1 (2X)
 

(48)
 

1 (2X)
 

1 (2«)
 

(48)
 

1 (2X)
 

1 (2S)
 

1 (2X)
 

(48)
 

1 (2X)
 

(48)
 

1 <2X)
 

(KB)
 

1 1ZXI-­
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE
 

1	 (2%)
 

(48)
 

1 (2%)
 

(48)
 

1 (2X)
 

(1*8)
 

2
 

FIBEOSIS
 

NECROSIS, FAT
 

*PEP.ITONEOB
 

HENOPERITONEUH
 

INFLAMMATION, HOS
 

NECROSIS, FOCAL
 

*PLEOEA
 

HYDROTHORAX
 

*MESENTERY
 

NECROSIS, FAT
 

AL1 CTHER SYSTEMS
 

ADIPOSE TISSUE
 

INFLAMMATION, NOS
 

FIBROSIS
 

SPECIAL MORPHOLOGY SUMMARY
 

NO LESION REPORTED
 

ANIMAL MISSING/NO NECROPSY
 

ADTOLYSIS/NO NECROPSY
 

CONTROL LOW DOSE
 

1 (2%)
 

1 (2%)
 

(49)	 (50)
 

1 (2»)
 

1 (2%)
 

(49) (50)
 

(49)	 (50)
 

2 (4%)
 

2
 

1
 

1
 

1
 

# NDMEFP OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

87
 
TABLE 02. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE 

MICE FED2-AMINO-5-NITROTHIAZOLE IN THE DIET 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 50 50 50
 ANIMALS NECROPSIED 50 50 50
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 50 50 50
 

INTEGUMENTARY SYSTEM
 

*SKIN (50) (50) (50)
 

ULCER, NOS 1 (2%)
 

HYPERKERATOSIS 1 (2X)
 

*SUBCOT TISSUE (50) (50) (50)
 

FDEMA, NOS 1 (2*)
 

INFLAMMATION, FOCAL GRANULOMATOU 1 (2%)
 

RESPIRATORY SYSTEM 

*NASAL CAVITY 

HYPEPPLASIA, NOS 

(50) (50) 

1 (21) 

(50) 

#LUNG/BBONCHUS 

HYPERPLASIA, LYMPHOID 

(47) 

18 (38%) 

(48) 

1 (2%) 

(49) 

3 (6%) 

#LUNG 

INFLAMMATION, FOCAL 

ALVEOLAR MACROPHAGES 

HYPEPPLASIA, LYMPHOID 

(47) 

1

1

 (2%) 

 (2%) 

(48) (49) 

3 (6%) 

#LUNG/ALVEOLI 

CONGESTION, NOS 

(47) (48) (49) 

1 (2%) 

HFMATOPOIF.TIC SYSTEM
 

#BCNE MARROW (46) (49) (50)
 

HYPFRPLASIA, HSMATOPOI FTIC 3 (7«) 2 (4%) 1 (2%)
 

HYPERPLASIA, GRANULOCYTIC 1 (2%)
 

#SPLEEN (47) (49) (49)
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

88
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

HEBOSIDEROSIS 2 (4*)
 

ANGIECTASIS 2 (4X)
 

LEUKEMOID REACTION 1 (2X)
 

HYPERPLASIA, LYBPHOID 6 (13X) 5 (10X) 13 (27X)
 

HEMATOPOIESIS 19 (UOS) 35 (71X) 23 (47%)
 

MYELOPOIESIS 1 (2X)
 

tLYBPH NODE (38) (39) (35)
 

HYPFEPLASIA, LYBPHOID 1 (3X)
 

tMESBNTERIC L. NODE (38) (39) (35)
 

INFLABBATION, GRANULOBATOUS 1 (3X)
 

tTHYMUS (38) (43) (41)
 

HYPEEPLASIA, LYBPHOID 1 (3X) 1 (2X)
 

CIRCULATORY SYSTEB
 

tHEART/ATRIUB (49) (50) (50)
 

MELANIN 1 (2X)
 

*MYOCARDIUB (49) (50) (50)
 

INFLAMMATION, INTERSTITIAL 1 (2X)
 

tCARDIAC VALVE (49) (50) (50)
 

BELANIN 1 (2X)
 

*UTERINE ARTERY (50) (50) (50)
 

THEOBBOSIS, NOS 1 (2X)
 

tHEPATIC SINUSOID (49) (50) (50)
 

CONGESTION, NOS 1 (2X)
 

DIGESTIVE SYSTEB
 

tLIVEE (49) (50) (50)
 

THEOBBOSIS, NOS 1 (2X)
 

PELIOSIS HEPATIS 1 (2X) 1 (2X)
 

DEGENERATION, HYALINE 1 (2X)
 

NECROSIS, FOCAL 1 (2X) 1 (2X)
 

BETABORPHOSIS FATTY 2 (4X) 4 (8X)
 

HEBOSIDEROSIS 1 (2X)
 

CYTOPLASBIC VACUOLIZATION 1 (2X)
 

t NUBBER OF ANIBALS WITH TISSUE EXAHINED BICROSCOPICALLY
 * NUBBEE OF ANIMALS NECROPSIED
 

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

 

HIGH DOSE
 

1 (2X)
 

2 (4X)
 

1 (2X)
 

(50)
 

(50)
 

1 (2X)
 

2 (4X)
 

(50)
 

1 (2«)
 

1 (2%)
 

(49)
 

(49)
 

1 (2X)
 

(50)
 

5' (10*)
 

(50)
 

1 (2%)
 

(46)
 

2 (UX)
 

(50)
 

3 (6X)
 

(50)
 

HYPERPLASIA, NODULAR
 

ANGIECTASIS
 

HYPERPLASIA, RETICOLUM CELL
 

HYPERPLASIA, LYHPHOID
 

HEMATOPOIESIS
 

*LIVER/CENTRILOBULAR
 

NECROSIS, FOCAL
 

#LIVER/HEPATOCYTES
 

NECROSIS, NOS
 

NECROSIS, FOCAL
 

*BILE DUCT
 

CYST, NOS
 

HYPEEPLASIA, NOS
 

#PANCREAS
 

HEMATOPOIESIS
 

tPANCREATIC DUCT
 

DISTFNTION
 

CYST, NOS
 

HYPEPPLASIA, NOS
 

fPEYERS PATCH
 

HYPERPLASIA, LYMPHOID
 

#DUODENUH
 

INFLAMMATION, NOS
 

•COLON
 

NEMATODIASIS
 

URINARY SYSTEM
 

#KIDNFY
 

GLOMEROLONEPHRITIS, NOS
 

LYMPHOCYTIC INFLAMMATORY INFILTR
 

INFLAMMATION, CHRONIC FOCAL
 

HYPERPLASIA, LYMPHOID
 

tKIDNEY/CORTEX
 

SCAR
 

CONTROL
 

1 (2X)
 

2 (4X)
 

3 (6X)
 

(49)
 

(49)
 

1 (2X)
 

(50)
 

(44)
 

(44)
 

(48)
 

(48)
 

(36)
 

(49)
 

1 (2X)
 

1 (2%)
 

10 (201)
 

(49)
 

1 (2%)
 

LOW DOSE
 

1 (2X)
 

1 (2X)
 

1 (2%)
 

3 (6X)
 

(50)
 

1 (2X)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

1 (2»)
 

(50)
 

1 (2%)
 

2 (4X)
 

1 (2*)
 

(47)
 

3 (6*)
 

(47)
 

(40)
 

1 (3*)
 

(50)
 

1 (2*)
 

1 (2X)
 

(50)
 

t NUMBER OF ANIMALS WITH TISSUE EXAHINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

90
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

#KIBNEY/TUBULE (<»9) (50)
 

DEGENERATION, HYALINE
 

•CONVOLUTED TUBULES (<*9) (50)
 

PIGHENTATION, NOS 1 (2%)
 

#URINARY BLADDER (30) (44)
 

PERIABTERITIS 1 (2«)
 

ENDOCRINE SYSTEH 

tPITUITARY 

HYPERPLASIA, NOS 

HYPERPLASIA, FOCAL 

ANGIECTASIS 

(43) (42) 

1 (2%) 

1 (2%) 

1 (2%) 

#ADRENAL 

INFLAHHATION, NOS 

(48) (49) 

1 (2%) 

•ADRENAL/CAPSULE 

HYPERPLASIA, FOCAL 

(i»8) 

43 (90%) 

(49) 

45 (92%) 

fADRENAL CORTEX 

HEMORRHAGE 

CYTOLOGIC DEGENERATION 

(48) (49) 

tTHYROID 

CYSTIC FOLLICLES 

HYPERPLASIA, FOLLICOLAR-CELL 

<<»0) 

1 (3%) 

6 (15*) 

(U4) 

7 (16%) 

#PARATHYROID 

CYST, NOS 

MELANIN 

(16) (18) 

REPRODUCTIVE SYSTEH
 

*HAHNARY GLAND (50) (50>
 

HETAPLASJA, SQOABOOS
 

tOTEROS (47) (49)
 

HYDROHETRA
 

HEHORRHAGE
 

EBBI45TIBIXI5 ._. l-12iLt NORBER OF ANIMALS WITH TISSUE EXAHINED BICROSCOPICALLY
 * NUMBER OF ANIHALS NECROPSIED
 

HIGH DOSE
 

(50)
 

1 (2%)
 

(8)
 

1


1


(50)
 

'1


(50)
 

1


__.._„_ 1._


(50)
 

(40)
 

(43)
 

1


2


(50)
 

(50)
 

45


(50)
 

1


 (2%)
 

 (5%)
 

 (90%)
 

 (2%)
 

2 (4%)
 

0»3)
 

8 (19%)
 

 (13%)
 

 (13%)
 

 (2%)
 

 (2%)
 

 (2% _____
 ) _


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

HIGH DOSE
 

(50)
 

2 (4X)
 

37 (7UX)
 

(50)
 

(50)
 

1 (2X)
 

1 (2X)
 

(46)
 

7 (15X)
 

4 (9X)
 

(»6)
 

(50)


1 (2%)
 

(50)
 

(50)
 

1 (2X)
 

(50)
 

l.J2iL_,
 

tUTEPUS/ENDOMETRIUM
 

CYST, NOS
 

INFLAMMATION, SUPPURATIVE
 

HYPERPLASIA, NOS
 

HYPERPLASIA, CYSTIC
 

fOVARY/OVIDOCT
 

LYMPHOCYTIC INFLAMMATORY INFILTR
 

INFLAMMATION, SOPPDRATIVE
 

NECROSIS, NOS
 

#OVARY/PAROVARIAN
 

FIBROSIS
 

NECROSIS, FAT
 

*OVARY
 

CYST, NOS
 

FOLLICOLAR CYST, NOS
 

MULTIPLE CYSTS
 

PAROVARIAN CYST
 

HEMORRHAGE
 

HEMATOHA, NOS
 

HBHORRHAGIC CYST
 

LYMPHOCYTIC INFLAHHATORY IHFILTR
 

INFLAMMATION, SUPPURATIVE
 

INFLAMMATION, CHRONIC
 

NECROSIS, FAT
 

tOVARY/FOLLICLE
 

HEMORRHAGE
 

NERVOUS SYSTEM
 

fBRAIN/MENINGES
 

PBRIVASCULAR COFFING
 

•CEREBRUM
 

ATROPHY, HOS
 

fBRAIN
 

PSRIVASCULAR CUFFING
 

SPECIAL SENSE ORGANS
 

*EYE
 

ClTAgA^^J „ ,.^
 

CONTROL
 

(l»7)
 

3 (6X)
 

1 (2U)
 

19 (OCX)
 

(«7)
 

1 <2X)
 

3 (6X)
 

1 (2X)
 

<«7)
 

(39)


4 (1CX)
 

1 <3X)
 

1 (3X)
 

1 (3%)
 

(39)
 

(«7)
 

(47)
 

(«7)
 

(50)
 

LOW DOSE
 

0»9)


2 («X)
 

27 (55X)
 

(49)
 

(49)
 

(47)
 

10 (21X)
 

3 (6X)
 

2 (4X)
 

1 (2*)
 

1 (2X)
 

1 (2X)
 

1 (2X)
 

1 (2X)
 

(47)
 

1 (2X)
 

(49)
 

(49)
 

1 (2X)
 

(49)
 

(50)
 

I NUMBER OF ANIMALS KITH TISSUE EJCABIMBD HICROSCOPICALLY 

* NOMBER OF ANIMALS NECROPSIED 

92 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED)

 

HIGH DOSE
 

(50)
 

(50)
 

(50)
 

(50)
 

1 (2%)
 

1 (2*)
 

1 (2X)
 

2 (<»X)
 

(50)
 

MUSCDLOSKELETAL	 SYSTEM
 

*SKELETAL MUSCLE
 

H3MORRHAGB
 

INFLAMMATION, NOS
 

DEGENERATION, NOS
 

BODY CAVITIES
 

*P£PITONEUM
 

CYST, NOS
 

HEMORRHAGE
 

*PLEURA
 

HYDBOTHORAX
 

•MESENTERY
 

STEATITIS
 

FIBROSIS
 

NECROSIS, FOCAL
 

HBCROSIS, FAT
 

AIL OTHER SYSTEMS
 

•MULTIPLE ORGANS
 

CONGESTION, NOS
 

HYPERPLASIA, LYBPHOID
 

ADIPOSE TISSUE
 

INFLAMMATION, FOCAL
 

NECROSIS, FAT
 

SPFCIAL MORPHOLOGY SUMBARY
 

AUTO/NECROPSY/HISTO PERF
 

CONTROL LOW DOSE
 

(50)	 (50)
 

1 (2X)
 

1 (2%)
 

1 (2X)
 

(50)	 (50)
 

1	 (2*)
 

1 (2%)
 

(50)	 (50)
 

1 (2X) 1 (2*)
 

(50)	 (50)
 

(50)	 (50)
 

1 (2X)
 

1 (2%)
 

1
 

1
 

1
 

t	 NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS HECROPSIED
 

93
 

APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN RATS FED 2-AMINO-5-NITROTHIAZOLE IN THE DIET
 

95
 

__ 

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

Fed 2-Araino-5-Nitrothiazole in the Diet3
 

Topography: Morphology
 

Lung: Alveolar /Bronchiolar
 

Adenoma "
 

P Values0 »d
 

Relative Risk (Matched Control) f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Malignant
 

Lymphoraa, Lyrnphocytic Leukemia,
 

or Undiff erentiated Leukemia*3
 

P Values0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

3/50 (6)
 

P = 0.039 (U)
 

102
 

11/50 (22)
 

P = 0.044
 

96
 

Low	 High
 

Dose	 Dose
 

0/50 (0)	 0/48 (0)
 

N.S.	 N.S.
 

0.000	 0.000
 

0.000	 0.000
 

1.663	 1.730
 

_*
 

15/50 (30) 19/49 (39)
 

N.S.	 N.S.
 

1.364	 1.763
 

0.653	 0.897
 

2.943	 3.629
 

85 64
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed 2-Amino-5-Nitrothiazole in the Diet3
 

(continued)
 

Matched Low High
 

Topography: Morphology Control Dose Dose
 

Hematopoietic System: Granulocytic
 

Leukemia" 2/50 (4) 4/50 (8) 9/49 (18)
 

P Valuesc»d P = 0.014 N.S. P = 0.023
 

Relative Risk (Matched Control)f 2.000 4.592
 

Lower Limit 0.301 1.015
 

Upper Limit 21.316 41.883
 

Weeks to First Observed Tumor 90 68 97
 

Hematopoietic System: All Lymphoma
 

or Leukemia'5 13/50 (26) 19/50 (38) 28/49 (57)
 

P Values0>d P - 0.001 N.S. P = 0.002
 

Relative Risk (Matched Control)f 1.462 2.198
 

Lower Limit 0.773 1.269
 

Upper Limit 2.839 3.929
 

Weeks to First Observed Tumor 90 68 64
 
Table El. Analyses of the Incidence of Primary Tumors in Hale Rats
 

Fed 2-Araino-5-Nitrothiazole in the Diet3
 

(continued)
 

Topography; Morphology
 

Pituitary: Chromophobe Adenoma''
 

P Valuesc»d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First observed Tumor
 

Adrenal: Pheochromocytoma'*
 

P Values0 «d
 

Relative Risk (Matched Control)*
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

3/46 (7)
 

P = 0.048
 

111
 

4/49 (8)
 

N.S.
 

88
 

Low High 

Dose Dose 

3/45 (7) 8/43 (19) 

N.S. N.S. 

1.022 2.853 

0.143 0.738 

7.254 15.707 

105 77 

4/47 (9) 1/48 (2) 

N.S. N.S. 

1.043 0.255 

0.207 0.005 

5.284 2.457 

85 111 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed 2-Araino-5-Nitrothiazole in the Diet3
 

(continued)
 

Topography: Morphology
 

Thyroid: Follicular-cell
 

Carcinoma**
 

p Values6 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-cell Adenoma
 

or Carcinoma'*
 

P Values0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Low 

Control Dose 

1/46 (2) 3/48 (6) 

N.S. N.S. 

2.875 

0.241 

147.682 

Ill 101 

1/46 (2) 3/48 (6) 

N.S. N.S. 

2.875 

0.241 

147.682 

Ill 101 

High
 

Dose
 

3/46 (7)
 

N.S.
 

3.000
 

0.252
 

153.954
 

106
 

4/46 (9)
 

N.S.
 

4.000
 

0.414
 

192.454
 

106
 
Table El. Analyses of the Incidence of Primary Tumors in Hale Rats

 

Fed 2-Amino-5-Mtrothiazole in the Meta

 

(continued) 

Topography: Morphology
 

Thyroid: C-cell Adenoma*1
 

F Values0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-cell Adenoma or
 

Carcinoma*5
 

F Values0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tuaior
 

Matched
 

Control
 

3/46 (7)
 

N.S.
 

Ill
 

4/46 (9)
 

N.S.
 

Ill
 

Low
 

Dose
 

7/48 (15)
 

N.S.
 

2.236
 

0.54y
 

12.700
 

109
 

7/4CJ (15)
 

N.S.
 

1.677
 

0.459
 

7.336
 

109
 

High
 

Dose
 

4/46 (9)
 

* N.S.
 

1.333
 

0.238
 

8.645
 

85
 

5/46 (11)
 

N.S.
 

1.250
 

0.286
 

5.923
 

85
 
Table El. Analyses of the Incidence of Primary Tumors in

Fed 2-Amino-5-Nitrothiazole in the Diet3 

(continued) 

Topography: Morphology
 

Pancreatic Islets: Islet-cell
 

Adenoma"
 

P Valuesc»d
 

Relative Risk. (Hatched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Fibroadenooa'3
 

P Valuesc»d
 

Relative Risk (Matched Control) f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hatched
 

Control
 

4/49 (8)
 

N.S.
 

88
 

1/50 (2)
 

N.S.
 

Ill
 

Low
 

Dose
 

4/44 (9)
 

N.S.
 

1.114
 

0.220
 

5.626
 

111
 

1/50 (2)
 

N.S.
 

1.000
 

0.013
 

76.970
 

111
 

 Male Rats 

High
 

Dose
 

3/45 (7)
 

N.S.
 

0.817
 

0.126
 

4.558
 

107
 

4/49 (8)
 

N.S.
 

4.082
 

0.422
 

196.666
 

102
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed 2-Araino-5-Nitrothiazole in the Diet3
 

(continued)
 

Topography: Morphology
 

Testis: Interstitial-cell
 

Tumor''
 

P Valuesc»d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

All Sites: Mesothelioraab
 

P Valuesc»d
 

Relative Risk (Hatched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Low High 

Control Dose Dose 

48/50 (96) 48/50 (96) 41/49 (84) 

P ­ 0.020 (H) N.S. P ­ 0.043 (N) 

1.000 0.872 

0.931 0.806 

1.074 1.016 

84 68 85 

2/50 (4) 3/50 (6) 0/49 (0) 

M.S. N.S. N.S. 

1.500 0.000 

0.180 0.000 

17.329 3.448 

105 92 —— 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed 2-Amino-5-Nitrothiazole in the Dieta
 

(continued)
 

a

Dosed groups received 300 or 600 ppm.
 

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

G

Beneath the incidence of tumors in the matched-control group is the probability level for the
 

Cochran-Armitage test when P < 0.05; otherwise, not significant (N.S.) is indicated. Beneath the
 

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

comparison of that dosed group with the matched-control group when P < 0.05; otherwise, not
 

significant (N.S.) is indicated.
 

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

group.
 

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

^The 95% confidence interval of the relative risk between each dosed group and the matched-


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

Fed 2-Amino-5-Nitrothiazole in the Diet3
 

Topography: Morphology
 

Hematopotetic System: Malignant
 

Lymphoma or Lymphocytic Leukemia"5
 

P Values0 »d
 

Relative Risk (Matched Control)^
 

Lo.wer Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: All Lymphoma
 

or Leukemia*5
 

P Values0 >d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

5/50 (10)
 

N.S.
 

98
 

7/50 (14)
 

N.S.
 

98
 

Low High 

Dose Dose 

12/50 (24) 9/50 (18) 

N.S. N.S. 

2.400 1.800 

0.857 0.586 

8.071 6.377 

47 69 

14/50 (28) 10/50 (20) 

N.S. N.S. 

2.000 1.429 

0.832 0.535 

5.348 4.071 

47 69 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed 2-Amino-5-Nitrothiazole in the Diet3
 

(continued)
 

Topography; Morphology
 

Pituitary: Chromophobe Adenoma'3
 

P Values0 >d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Adrenal: Pheochromocytomab
 

P Valuesc»d
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Low High 

Control Dose Dose 

19/45 (42) 29/47 (62) 29/44 (66) 

P ­ 0.016 P ­ 0.048 P » 0.021 

1.461 1.561 

0.944 1.015 

2.273 2.380 

90 94 70 

3/49 (6) *0/49 (0) 0/50 (0) 

P ­ 0.036 (N) N.S. N.S. 

0.000 0.000 

0.000 0.000 

1.662 1.629 

__ 

107 —— 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats

 

Fed 2-Amno-5-Nitrothiazole in the Diet3

 

(continued) 

Topography: Morphology
 

Thyroid: C-cell Carcinoraab
 

P Values0 >d
 

Relative Risk Olatched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-cell Adenoma or
 

Carcinoma"
 

V Value sc»d
 

Relative Risk (Hatched Control)E
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

2/50 (4)
 

N.S.
 

Ill
 

5/50 (10)
 

N.S.
 

Ill
 

Low High 

Dose Oose 

3/47 (6) 5/48 (10) 

N.S. N.S. 

1.596 2.604 

0.191 0.451 

18.399 26.304 

99 111 

5/47 (11) 8/48 (17) 

N.S. N.S. 

1.064 1.667 

0.261 0.52U 

4.329 6.036 

99 106 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed 2-Amino-5-Nitrothiazole in the Diet3
 

(continued)
 

Topography; Morphology
 

Mammary Gland: Adenocarcinoma, NOSb
 

P Values0 »d
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Fibroadenoraa*3
 

P Values0 »d
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

1/50 (2)
 

N.S.
 

98
 

12/50 (24)
 

N.S.
 

94
 

Low
 

Dose
 

3/50 (6)
 

N.S.
 

3.000
 

0.250
 

154.270
 

111
 

12/50 (24)
 

N.S.
 

1.000
 

0.458
 

2.192
 

90
 

High
 

Dose
 

1/50 (2)
 

N.S.
 

1.000
 

0.013
 

76.970
 

111
 

14/50 (28)
 

N.S.
 

1.167
 

0.558
 

2.477
 

107
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed 2-Amino-5-Nitrothiazole in the Dieta
 

(continued) 

Matched Low High 

Topography ; Morphology Control Dose Dose 

Uterus: Endometrial Stromal 

Polypb 2/50 (4) 9/49 (18) 3/50 (6) 

P Values0 » d N.S. P = 0.023 N.S. 

Departure from Linear Trend6 P = 0.009 

Relative Risk (Matched Control)f 4.592 1.500 

Lower Limit 1.018 0.181 

Upper Limit 41.883 17.329 

Weeks to First Observed Tumor 111 63 111 

a

Dosed groups received 300 or 600 ppm.
 

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

c

Beneath the incidence of tumors in the matched-control group is the probability level for the
 

Cochran-Armitage test when P < 0.05, otherwise, not significant (N.S.) is indicated. Beneath the
 

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

the comparison of that dosed group with the matched-control group when P < 0.05; otherwise, not
 

significant (N.S.) is indicated.
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed 2-Amino-5-Nitrothiazole in the Diet3
 

(continued)
 

°A negative trend (N) indicates a lower incidence in a dosed group than in the matched-control group.
 

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

^The 95% confidence interval of the relative risk between each dosed group and the matched-control
 

group.
 
APPENDIX F
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN MICE FED 2-AMINO-5-NITROTHIAZOLE IN THE DIET
 

111
 

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

Fed 2-Amino-5-Mitrothiazole in the Diet3 

Matched Low High
 

Topography: Morphology Control Dose Dose
 

Subcutaneous Tissue: Fibrosarcoma'-' 2/49 (4) 2/50 (4) 3/4b (6)
 

P Valuesc»a iN . S . U.S. N.S.
 

Relative Risk (Matched Control )f 0.960 1.531
 

Lower Limit 0.074 0.183
 

Upper Limit 13.058 17.665
 

Weeks to First Observed Tumor 77 99 79
 

Lung: Alveolar/Bronchiolar Adenoma'5 10/49 (20) 10/49 (20) 11/48 (23)
 

P Valuesc»d N.S. N.S. N.S.
 

Relative Risk (Matched Control)^ 1.000 1.123
 

Lower Limit 0.412 0.479
 

Upper Limit 2.430 2.666
 

Weeks to First Observed Tumor 81 b2 64
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male ILLce 

Fed 2-Amino-5-Nitrothiazole in

(continued) 

Topography: Morphology
 

Lung: Alveolar/Bronchiolar
 

Carcinoma^
 

P Values0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Lung: Alveolar/Bronchiolar Adenoma
 

or Carcinoma'1
 

t> Valuesc»d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hatched
 

Control
 

4/49 (8)
 

N.S.
 

100
 

14/49 (29)
 

N.S.
 

81
 

 the Dieta 

Low High 

Dose Dose 

2/49 (4) 1/48 (2) 

N.S. N.S. 

0.500 0.255 

0.047 0.005 

3.315 2.457 

100 80 

12/49 (24) 12/48 (25) 

N.S. N.S. 

0.857 0.875 

0.406 0.414 

1.784 1.820 

82 64 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Fed 2-Amino-5-Nitrothiazole in the Diet3
 

(continued)
 

Topography: Morphology
 

Hematopoietic System:
 

Granulocytic Leukemia"
 

P Valuesc»d
 

Relative Risk (Matched Control) ^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Lymphoiaa^
 

P Values0 «d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

1/49 (2)
 

N.S.
 

88
 

6/49 (12)
 

N.S.
 

87
 

Low High 

Dose Dose 

0/50 (0) 3/48 (6) 

N.S. N.S. 

0.000 3,063 

0.000 0.257 

18.285 157.336 

• 

104 

8/50 (16) 2/48 (4) 

N.S. N.S. 

1.307 0.340 

0.430 0.035 

4.243 1.791 

81 100 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Fed 2-Araino-5-Nitrothiazole in the Dieta
 

(continued)
 

Topography: Morphology
 

Hematopoietlc System: All Neoplasms*5
 

V Values0 »d
 

Relative Risk (Hatched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

All Sites: Hemangiosarcoraa'3
 

P Valuesc»d
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

8/49 (16)
 

N.S.
 

87
 

5/49 (10)
 

N.S.
 

81
 

Low High 

Dose Dose 

8/50 (16) 7/48 (15) 

N.S. N.S. 

0.980 0.893 

0.349 0.299 

2.757 2.594 

81 78 

4/50 (8) 3/48 (6) 

N.S. N.S. 

0.784 0.613 

0.1&5 0.101 

3.426 2.963 

92 82 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Fed 2-Amino-5-Nitrothiazole in the Diet3
 

(continued)
 

Topography; Morphology
 

Liver: HepatocellularCarcinoma^5
 

P Values0»d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Adenoma
 

or Carcinoma^
 

P Values0>d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

16/49 (33)
 

N.S.
 

94
 

20/49 (41)
 

N.S.
 

94
 

Low High 

Dose Dose 

11/50 (22) 11/48 (23) 

N.S. N.S. 

0.674 0.702 

0.317 0.330 

1.381 1.437 

99 70 

16/50 (32) 15/48 (31) 

N.S. N.S. 

0.784 0.766 

0.436 0.418 

1.392 1.376 

99 70 

a

Dosed groups received 50 or 100 ppm.
 

^Number of tumor-bearing animals/number of animals examined at site (percent),
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Fed 2-Amino-5-Nitrothiazole in the Dieta
 

(continued)
 

c

Beneath the incidence of tumors in the matched-control group is the probability level for the
 

Cochran-Armitage test when P < 0.05, otherwise, not significant (N.S.) is indicated. Beneath the
 

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

the comparison of that dosed group with the matched-control group when P < 0.05; otherwise, not
 

significant (N.S.) is indicated.
 

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

group.
 

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

^The 95% confidence interval of the relative risk between each dosed group and the matched-control
 

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

Fed 2-Araino-5-Nitrothiazole in the Dieta
 

Topography: Morphology
 

Lung: Alveolar /Bronchiolar Adenoma'3
 

P Values0>d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Lung: Alveolar /Bronchiolar Adenoma
 

or Carcinoma**
 

P Values0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

2/47 (4)
 

P = 0.048
 

100
 

2/47 (4)
 

P = 0.034
 

100
 

Low High 

Dose Dose 

2/48 (4) 7/49 (14) 

N.S. N.S. 

0.979 3.357 

0.074 0.682 

13.027 31.811 

100 101 

4/48 (8) 8/49 (16) 

N.S. N.S. 

1.958 3.837 

0.296 0.820 

20.832 35.590 

96 101 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice 

Fed 2-Atnino-5-Nitrothiazole in the Diet3 

(continued) 

Topography: Morphology
 

Hematopoietic System: Malignant
 

Lyinphoraa, Undiff erentiated Leukemia,
 

or Lymphocytic Leukemia"
 

P Values0 »d
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: All Neoplasms'3
 

P Valuesc«d
 

Relative Risk (Matched Control) ^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Low High 

Control Dose Uose 

20/50 (40) 12/50 (24) 11/50 (22) 

P = 0.030(N) N.S. P = 0.041(N) 

0.600 0.550 

0.303 0.269 

1.141 1.069 

75 94 76 

21/50 (42) 12/50 (24) 12/50 (24) 

P = 0. 032(N) P = 0.0440O P = 0.044(N) 

0.571 0.571 

0.291 0.291 

1.074 1.074 

75 94 76 
Table F2. Analyses of the Incidence of Primary Tumors In Female Mice
 

Fed 2-Aoiino-5-Nitrothiazole in the Oieta
 

(continued
 

Topography: Morphology
 

All Sites: '-lemangiosarcoma^
 

P Valuesc»d
 

Relative Risk (Matched Control)*
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma"
 

P Valuesc>d
 

Relative Risk (Hatched Control)*
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tunor
 

Matched Low 

Control Dose 

1/50 (2) 4/50 (8) 

H.S. N.S. 

4.000 

0.412 

192.807 

100 72 

1/49 (2) 2/50 (4) 

N.S. N.S. 

1.960 

0.105 

113.312 

100 91 

High
 

Pose
 

4/50 (8)
 

N.S.
 

4.000
 

0.412
 

192.807
 

65
 

4/50 (8)
 

N.S.
 

3.920
 

0.405
 

138.989
 

101
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Fed 2-Amino-5-Nitrothiazole in the Diet3
 

(continued)
 

Topography: Morphology
 

Liver: Hepatocellular Adenoma
 

or Carcinoma"
 

P Valuesc»d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Chromophobe Adenoma'5
 

P Values0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

a

Dosed groups received 50 or 100 ppm.
 

Matched Low High 

Control Dose Oose 

2/49 (4) 6/50 (12) 5/50 (10) 

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

2.940 2.450 

0.555 0.424 

28.662 24.778 

100 91 101 

2/43 (5) 6/42 (14) 6/43 (14) 

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

3.071 3.000 

0.589 0.574 

29.705 29.042 

100 98 72 

^Number of tumor-bearing animals/number of animals examined at site (percent).
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Fed 2-Amino-5-Nitrothiazole in the Diet3
 

(continued)
 

c

Beneath the incidence of tumors in the matched-control group is the probability level for the
 

Cochran-Armitage test when P < 0.05, otherwise, not significant (N.S.) is indicated. Beneath the
 

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

the comparison of that dosed group with the matched-control group when P < 0.05; otherwise, not
 

significant (N.S.) is indicated.
 

^A negative trend (N) indicates a lower incidence in a dosed group than in the matched-control group.
 

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

^The 95% confidence interval of the relative risk between each dosed group and the matched-control
 

group.
 

Review of the Bioassay of 2-Amino-5-Nitrothiazole
 

for Carcinogenicity by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

March 6, 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 2-Amino-5-Nitrothiazole for carcinogenicity.
 

The primary reviewer for the report on the bioassay
 

of 2-Amino-5-Nitrothiazole agreed with the conclusion that
 

the compound was associated with granulocytic leukemia in
 

treated male rats. It was not carcinogenic in female rats or
 

either sex of mice, under the conditions of test. After
 

a brief description of the experimental design and conditions
 

of test, he noted the negative dose-related trend with respect
 

to hematopoetic tumors in treated female mice. He pointed
 

out increases in a number of tumors observed in treated
 

animals, although none were clearly associated with the
 

administration of 2-Amino-5-Nitrothiazole.
 

The secondary reviewer observed that granulocytic
 

leukemia was not sex linked. Therefore, it was unusual
 

to find it in one sex and not the other. He suggested
 

that the observed incidence might be within a normal
 

statistical variation. Another Subgroup member said
 

that leukemia might be expected to occur with greater
 

frequency among females as a result of a hormonal influence.
 

125
 
It was noted by a Subgroup member that the "real-life
 

significance may be quite minimal" with respect to the
 

carcinogenicity of 2-Amino-5-Nitrothiazole.
 

A motion was made that the report be accepted as written,
 The motion was seconded and approved unanimously. A second
 

motion was passed unanimously that the record show that the
 

results were unusual with respect to the induction of
 

granulocytic leukemias in only one sex of treated rats.
 

Members present were:
 

Gerald N. Wogan (Chairman), Massachusetts Institute of
 

Technology
 

Arnold Brown, Mayo Clinic
 

Lawrence Garfinkel, American Cancer Society
 

E. Cuyler Hammond, American Cancer Society
 

Joseph Highland, Environmental Defense Fund
 

Henry Pitot, University of Wisconsin Medical Center
 

George Roush, Jr., Monsanto Company
 

Sheldon Samuels, Industrial Union Department, AFL-CIO
 

Michael Shimkin, University of California at San Diego
 

John Weisburger, American Health Foundation
 

Sidney Wolfe, Health Research Group
 

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.
 

126
 

«O.S. GOVERNMENT PRINTING OFFICE.-1978 260-899/3106 1-3 

DHEW Publication No. (NIH) 78-1359