1978 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 109 

BIOASSAY OF 

4-NITROANTHRANILIC ACID 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 619-17-0 

NCI-CG-TR-109 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

4-NITROANTHRANILIC ACID
 

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) 78-1364 

REPORT ON THE BIOASSAY OF 4-NITROANTHRANILIC ACID
 

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
 

4-nitroanthranilic acid conducted for the Carcinogenesis Testing Program, Division of Cancer Cause and Prevention, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland. This
 

is one of a series of experiments designed to determine whether selected chemicals have the capacity to produce cancer in animals. Negative results, in which the test animals do not have a significantly
 

greater incidence of cancer than control animals, do not necessarily
 

mean the test chemical is not a carcinogen because 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 a potential risk to man. The
 

actual determination of the risk to man from animal carcinogens requires a wider analysis.
 

CONTRIBUTORS: This bioassay of 4-nitroanthranilic acid was conducted
 

by Mason Research Institute, Worcester, Massachusetts, initially under
 

direct contract to the NCI and currently under a subcontract to Tracor
 

Jitco, Inc., prime contractor for the NCI Carcinogenesis Testing Program.
 

The experimental design was determined by the NCI Project Officers, Dr. J. H. Weisburger (1,2) and Dr. E. K. Weisburger (1). The
 

principal investigators for the contract were Dr. E. Smith (3) and
 

Dr. A. Handler (3). Animal treatment and observation were supervised
 

by Mr. G. Wade (3) and Ms. E. Zepp (3). Chemical analysis was performed by Midwest Research Institute (4) and the analytical results
 

were reviewed by Dr. N. Zimmerman (5).
 

Histopathologic examinations were performed by Dr. R. W. Fleischman (3), Dr. D. W. Hayden (3), Dr. A. S. Krishna Murthy (3), Dr. A.
 

Russfield (3), and Dr. Yoon (3) at the Mason Research Institute, the
 

pathology narratives were written by Dr. A. Russfield (3), and the
 

diagnoses included in this report represent the interpretation of
 

these pathologists. Histopathology findings and reports were reviewed
 

by Dr. R. L. Schueler (6).
 

Compilation of individual animal survival, pathology, and summary tables was performed by EG&G Mason Research Institute (7); the
 

statistical analysis was performed by Mr. W. W. Belew (5), using
 

iii
 
methods selected for the Carcinogenesis Testing Program by Dr. J. J.
 

Gart (8).
 

This report was prepared at METREK, a Division of The MITRE Corporation (5) under the direction of the NCI. Those responsible for
 

this report at METREK are the project coordinator, Dr. L. W. Thomas
 

(5), task leader Dr. M. R. Kornreich (5), senior biologist Ms. P.
 

Walker (5), biochemist Dr. B. Fuller (5), and technical editor Ms.
 

P. A. Miller (5). The final report was reviewed by members of the
 

participating organizations.
 

The following other scientists at the National Cancer Institute
 

were responsible for evaluating the bioassay experiment, interpreting
 

the results, and reporting the findings: Dr. K. C. Chu (1), Dr. C.
 

Cueto, Jr. (1), Dr. J. F. Douglas (l), Dr. D. G. Goodman (1), Dr. R.
 

A. Griesemer (1), Dr. H. A. Milman (1), Dr. T. W. Orme (1), Dr. R. A.
 

Squire (1,9), Dr. J. M. Ward (1), and Dr. C. E. Whitmire (1).
 

1.	 Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

2.	 Now with the Naylor Dana Institute for Disease Prevention, American Health Foundation, Hammon House Road, Valhalla, New York.
 

3.	 Mason Research Institute, 57 Union Street, Worcester, Massachusetts.
 

4.	 Midwest Research Institute, 425 Volker Boulevard, Kansas City,
 

Missouri.
 

5.	 The MITRE Corporation, METREK Division, 1820 Dolley Madison
 

Boulevard, McLean, Virginia.
 

6.	 Tracer Jitco, Inc., 1776 East Jefferson Street, Rockville,
 

Maryland.
 

7.	 EG&G Mason Research Institute, 1530 East Jefferson Street,
 

Rockville, Maryland.
 

8.	 Mathematical Statistics and Applied Mathematics Section, Biometry
 

Branch, Field Studies and Statistics Program, Division of Cancer
 

Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
 

IV
 
9.	 Now with the Division of Comparative Medicine, Johns Hopkins
 

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

SUMMARY
 

A bioassay of 4-nitroanthranilic acid for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 4-Nitroanthranilic acid was administered in the feed, at either of two
 

concentrations, to groups of 50 male and 50 female animals of each
 

species. The high and low time-weighted average concentrations used
 

for the chronic study were, respectively, 1.5 and 0.46 percent for
 

rats and 1.0 and 0.46 percent for mice. After a 78-week period of
 

chemical administration, the rats were observed for an additional
 

period of up to 32 weeks and the mice for an additional period of up
 

to 17 weeks. For rats 50 animals of each sex were placed on test as
 

low dose controls and 25 animals of each sex were placed on test as
 

high dose controls. For mice 50 animals of each sex were placed on
 

test as controls for each dosed group.
 

No statistically significant increases in tumor incidence were
 

observed among rats or mice receiving diets containing 4-nitroanthranilic acid.
 

Under the conditions of this bioassay evidence was not provided
 

for the carcinogenicity of 4-nitroanthranilic acid in Fischer 344
 

rats or B6C3F1 mice.
 

VII
 

TABLE OF CONTENTS
 

Page
 

I. INTRODUCTION 1
 

II. MATERIALS AND METHODS 2
 

A. Chemicals 2
 

B. Dietary Preparation 4
 

C. Animals 4
 

D. Animal Maintenance 5
 

E. Selection of Initial Concentrations 9
 

F. Experimental Design 10
 

G. Clinical and Histopathologic Examinations 13
 

H. Data Recording and Statistical Analyses 15
 

III. CHRONIC TESTING RESULTS: RATS 20
 

A. Body Weights and Clinical Observations 20
 

B. Survival 20
 

C. Pathology 23
 

D. Statistical Analyses of Results 24
 

IV. CHRONIC TESTING RESULTS: MICE 34
 

A. Body Weights and Clinical Observations 34
 

B. Survival 34
 

C. Pathology 37
 

D. Statistical Analyses of Results 37
 

V. DISCUSSION 46
 

VI. BIBLIOGRAPHY 48
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH 4-NITROANTHRANILIC ACID A-l
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH 4-NITROANTHRANILIC ACID B-l
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH 4-NITROANTHRANILIC ACID C-l
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH 4-NITROANTHRANILIC ACID D-l
 

IX
 
LIST OF ILLUSTRATIONS 

Figure Number Page 

1 CHEMICAL STRUCTURE OF 4-NITROANTHRANILIC 

ACID 

GROWTH CURVES FOR 4-NITROANTHRANILIC

CHRONIC STUDY RATS 

 ACID 

21 

SURVIVAL COMPARISONS OF

ACID CHRONIC STUDY RATS 

 4-NITROANTHRANILIC 

22 

GROWTH CURVES FOR 4-NITROANTHRANILIC

CHRONIC STUDY MICE 

 ACID 

35 

SURVIVAL COMPARISONS OF 4-NITROANTHRANILIC 

ACID CHRONIC STUDY MICE 36 

LIST OF TABLES 

Table Number Page 

DESIGN SUMMARY FOR FISCHER 344 RATS— 

4-NITROANTHRANILIC ACID FEEDING EXPERIMENT 11 

DESIGN SUMMARY FOR B6C3F1 MICE—4-NITROANTHRANILIC ACID FEEDING EXPERIMENT 12 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

4-NITROANTHRANILIC ACID 25 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH 4-NITROANTHRANILIC ACID 29 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

4-NITROANTHRANILIC ACID 38 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH 4-NITROANTHRANILIC ACID 41 
LIST OF TABLES (Concluded)
 

Table Number 

Al SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH 4-NITROANTHRANILIC 

ACID A-3 

A2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE RATS TREATED WITH 4-NITROANTHRANILIC 

ACID A-8 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH 4-NITROANTHRANILIC 

ACID B-3 

B2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH 4-NITROANTHRANILIC 

ACID B-7 

Cl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH 4-NITROANTHRANILIC ACID C-3 

C2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH 

4-NITROANTHRANILIC ACID C-12 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH 4-NITROANTHRANILIC ACID D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH 

4-NITROANTHRANILIC ACID D-8 

I. INTRODUCTION
 

4-Nitroanthranilic acid (NCI No. C01945), a nitrobenzene derivative formerly used as a dye intermediate, was selected for bioassay
 

by the National Cancer Institute along with other dye intermediates
 

in an attempt to identify those chemicals which may be responsible
 

for the increased incidence of bladder cancer observed among workers
 

in the dye manufacturing industry (Wynder et al., 1963; Anthony and
 

Thomas, 1970). Aromatic nitro and amino compounds are thought to
 

contribute to the increased cancer risk in this industry (Wynder et
 

al., 1963).
 

The Chemical Abstracts Service (CAS) Ninth Collective Index
 

*
 

(1977) name for this compound is 2-amino-4-nitro-benzoic acid.
 

4-Nitroanthranilic acid does not appear to be in current use
 

commercially in the United States for any application and has not
 

been produced in this country in commercial quantities (greater than
 

1000 pounds or $1000 in value annually) since 1968 (Urso, 1977).
 

Although exposure to 4-nitroanthranilic acid is presently restricted to those engaged in laboratory research, workers at dye manufacturing facilities may have experienced significant contact with
 

the chemical in the past. Little is known concerning the toxicity of
 

4-nitroanthranilic acid in humans.
 

*
 

The CAS registry number is 619-17-0.
 
II. MATERIALS AND METHODS
 

A. Chemicals
 

4-Nitroanthranilic acid (Figure 1) was purchased from J. T. Baker
 

Chemical Company, Phillipsburg, New Jersey. Chemical analysis was
 

performed by Midwest Research Institute, Kansas City, Missouri. The
 

experimentally determined melting point (264° to 267°C) suggested a
 

compound of high purity due to its narrow range and proximity to the
 

value (264°C) reported in the literature (Rupe and Kerstend, 1926).
 

Analysis by thin-layer chromatography utilized two solvent systems
 

(chloroform: 1,4-dioxane:acetic acid and butanol:diethylamine.-water).
 

Each plate was visualized by ultraviolet light and by furfural. The
 

presence of three impurities of lower motility than the major compound
 

was indicated by these analyses. Elemental analysis was consistent
 

with C H N 0 , the molecular formula for 4-nitroanthranilic acid.
 

Titration of the carboxyl group with sodium hydroxide gave a result
 

that was 98 percent of the theoretical. This cannot be construed as
 

a purity minimum, since possible contaminating compounds might also
 

contain a carboxyl group. High pressure liquid chromatography showed
 

the presence of two peaks. Nuclear magnetic resonance and infrared
 

analyses were consistent with the structure of the compound. The
 

results suggested a compound of high purity with the presence of some
 

minor impurities.
 

Throughout this report the term 4-nitroanthranilic acid is used
 

to represent this material.
 
COOH 

NO' 

FIGURE 1 

CHEMICAL STRUCTURE OF 4-NITROANTHRANILIC ACID 
B. Dietary Preparation
 

The basal laboratory diet for both treated and control animals
 

®
 

was Wayne Lab-Blox (Allied Mills, Inc., Chicago, Illinois). 4-Nitroanthranilic acid was administered to the treated animals as a component of the diet. The chemical was ground into a powder and mixed
 

with an aliquot of ground feed. Once visual homogeneity was attained,
 

the mixture was placed into a 6 kg capacity Patterson-Kelley twin-


shell stainless steel V-blender with the remainder of the meal. After
 

20 minutes of blending, the mixtures were placed in double plastic
 

bags and stored in the dark at 4°C. The mixtures were used for only
 

one week.
 

C. Animals
 

Two animal species, rats and mice, were used in the carcinogenicity bioassay. Fischer 344 rats and B6C3F1 mice were obtained through
 

contracts of the Division of Cancer Treatment, National Cancer Insti­

* *
 

tute. High dose treated and high dose control rats and low dose
 

treated, high dose treated, and high dose control mice were supplied
 

by Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts. Low dose treated and low dose control rats and low dose control mice were supplied by ARS/Sprague-Dawley, Madison, Wisconsin.
 

All treated rat and mouse groups were received in separate shipments
 

from their respective controls.
 

*
 

As defined on pages 9 and 12,
 
Upon arrival, a sample of animals were sacrificed and examined
 

for parasites and other signs of disease. The remaining animals were
 

quarantined by species for 2 weeks prior to initiation of the test.
 

Animals were assigned to groups and distributed among cages so that
 

the average body weight per cage was approximately equal for a given
 

sex and species.
 

D. Animal Maintenance
 

All	 animals were housed by species in rooms having a temperature
 

®
 

range of 23° to 34°C. Incoming air was filtered through Tri-Dek
 

(R)
 15/40 denier Dacron filters (Tri-Dim Filter Corp., Hawthorne, New
 

Jersey) providing six changes of room air per hour. Fluorescent
 

lighting was provided on a 12-hour-daily cycle.
 

Rats were housed five per cage by sex. During quarantine and for
 

the first 13 months of study, low dose treated rats and their controls
 

were housed in galvanized- or stainless-steel wire-mesh cages suspended above newspapers. High dose treated rats and their controls
 

were housed in galvanized wire-mesh cages during quarantine and for
 

the first 11 months of study. Newspapers under cages were replaced
 

daily and cages and racks washed weekly. For the remainder of the
 

study, rats were housed in suspended polycarbonate cages equipped with
 

disposable nonwoven fiber filter sheets. Clean bedding and cages were
 

provided twice weekly. Low dose treated rats and their controls were
 

®
 provided with Ab-sorb-dri hardwood chip bedding (Wilner Wood Products
 
Company, Norway, Maine) for 9 months after being placed in polycarbon­

®
 ate cages. Corncob bedding (SAN-I-CEL , Paxton Processing Company,
 

Paxton, Illinois) was used for these animals and for high dose treated
 

rats and their controls for the next 12 months. For the remainder of
 

CR)
 the study, Bed-o-Cobs (The Andersons Cob Division, Maumee, Ohio) was
 

provided in rat cages. Stainless steel cage racks were cleaned once
 

every 2 weeks, and disposable filters were replaced at that time.
 

Mice were housed by sex in polycarbonate cages. During quarantine and periods of chemical administration, cages were fitted with
 

perforated stainless steel lids. During the observation period,
 

stainless steel wire bar lids were used. Both types of lids were
 

from Lab Products, Inc., Garfield, New Jersey. All mice were housed
 

ten per cage for the first part of the study. High dose treated and
 

control mice and low dose treated and control mice were reduced to
 

five per cage after 13, 14, 19 and 19 months, respectively. Cages,
 

lids, filters, and bedding were provided three times per week when
 

cage populations were ten and twice per week when cage populations
 

were five. Ab-sorb-dri bedding was used for 2 months (high dose
 

treated mice), 4 months (high dose control mice) or 9 months (low
 

®
 dose treated and control mice). Subsequently, SAN-I-CEL was used
 

®
 for 12 months, then Bed-o-Cobs was used for the remainder of the
 

study. Reusable filter bonnets and pipe racks were sanitized every 2
 

weeks throughout the study.
 
Water was available ad libitum for both species from 250 ml
 

water bottles equipped with rubber stoppers and stainless steel
 

sipper tubes. Bottles were replaced twice weekly and, for rats only,
 

refilled as needed between changes.
 

Wayne Lab-Blox

@


 was supplied ad libitum throughout the entire
 

(R)
 test. Pelleted Wayne Lab-Blox was supplied during the quarantine
 

®


and final observation periods. Alpine aluminum feed cups (Curtin
 

Matheson Scientific, Inc., Woburn, Massachusetts) containing stainless steel baffles were used to distribute powdered feed to all mice
 

and to low dose treated and control rats during the entire period of
 

compound administration and to high dose treated and control rats for
 

the first 13 months. High dose treated and control rats were fed
 

from stainless steel gangstyle feed hoppers (Scientific Cages, Inc.,
 

Bryan, Texas) during the last 5 months of the study. Food hoppers
 

were changed on the same schedule as were cages. Food was replenished
 

daily in Alpine feed cups. During the final observation period,
 

mice were fed pellets from a wire bar hopper incorporated into the
 

cage lid, and rats were fed pellets on the cage floor.
 

Low dose treated rats and their controls were housed in a room
 

*
 with other rats receiving diets containing acetylaminofluorene (53­

93-3); dulcin (150-69-6) and L-arginine glutamate (4320-30-3); sodium
 

nitrite (7632-00-0); L-arginine glutamate (4320-30-3); N-butylurea
 

*
 CAS registry numbers are given in parentheses,
 
(592-31-4); N,N-dimethyl-p-nitrosoaniline (138-89-6); 2,5-toluenediamine sulfate (6369-59-1); 2,4-dinitrotoluene (121-14-2); 1,5-naphthalenediamine (2243-62-1); N-(l-naphthyl)ethylenediamine dihydrochloride
 

(1465-25-4); 2-chloro-p-phenylenediamine sulfate (61702-44-1); aniline
 

hydrochloride (142-04-1); and p-anisidine hydrochloride (20265-97-8).
 

High dose control rats were housed with other rats receiving diets
 

containing 5-nitro-o-toluidine (99-55-8); hydrazobenzene (530-50-7);
 

2-aminoanthraquinone (117-79-3); 3-amino-9-ethylcarbazole hydrochloride; 6-nitrobenzimidazole (94-52-0); 1-nitronaphthalene (86-57-7);
 

2,4-diaminoanisole sulfate (615-05-4); and APC (8003-03-0). High dose
 

treated rats were housed with other rats receiving diets containing
 

3-amino-4-ethoxyacetanilide (17026-81-2); l-amino-2-methylanthraquinone (82-28-0); 5-nitro-o-anisidine (99-59-2); and 5-nitroacenaphthene
 

(602-87-9).
 

High dose, low dose, and high dose control mice were housed in
 

a room with other mice, receiving diets containing 2,5-toluenediamine
 

sulfate (6369-59-1); 2-aminoanthraquinone (117-79-3); N,N-dimethy1-pnitrosoaniline (138-89-6); 3-amino-4-ethoxyacetanilide (17026-81-2);
 

3-amino-9-ethylcarbazole hydrochloride; l-amino-2-methylanthraquinone
 

(82-28-0); 5-nitro-o-anisidine (99-59-2); 2,4-dinitrotoluene (121­

14-2); 1-nitronaphthalene (86-57-7); 5-nitroacenaphthene (602-87-9);
 

3-nitro-p-acetophenetide (1777-84-0); and 2,4-diaminoanisole sulfate
 

(615-05-4). Low dose control mice were housed in a room with other
 
mice receiving diets containing 2-methyl-l-nitroanthraquinone (129­

15-7); p-cresidine (120-71-8); fenaminosulf (140-56-7); 4-chloro-mphenylenediamine (5131-60-2); and cinnamyl anthranilate (87-29-6).
 

E. Selection of Initial Concentrations
 

In order to establish the maximum tolerated concentrations of
 

4-nitroanthranilic acid for administration to treated animals in the
 

chronic studies, subchronic toxicity tests were conducted with both
 

rats and mice. Animals of each species were distributed among four
 

groups, each consisting of five males and five females. 4-Nitroanthranilic acid was incorporated into the basal laboratory diet and
 

supplied ad libitum to three of the four rat groups and three of the
 

four mouse groups in concentrations of 0.45, 0.90, and 1.35 percent.
 

The fourth group of each species served as a control group, receiving
 

only the basal laboratory diet. The dosed dietary preparations were
 

administered for a period of 4 weeks, followed by a 2-week observation
 

period during which all animals were fed the untreated basal diet.
 

The highest concentration causing no deaths, no compound-related
 

gross abnormalities, and no mean body weight depression in excess of
 

20 percent relative to controls was selected as the high concentration utilized for the rat and mouse chronic bioassays.
 

Four of the five female rats treated with 0.90 percent 4-nitroanthranilic acid died. No other deaths were recorded for any treated
 

rat group. Mean weight depression was approximately 20 percent for
 

males receiving a chemical concentration of 1.35 percent, and 2
 
percent for females receiving the same concentration. The high concentration selected for use in the rat chronic bioassay was 1.50 percent for both males and females.
 

The only deaths recorded among treated mice were three males
 

receiving 1.35 percent 4-nitroanthranilic acid. Mean weight depression was approximately 6 and 14 percent for males treated with concentrations of 0.90 and 1.35 percent, respectively, and 19 and 4 percent
 

for females receiving the same respective concentrations. The high
 

concentration selected for use in the mouse chronic bioassay was 1.00
 

percent for both males and females.
 

F. Experimental Design
 

The experimental design parameters for the chronic study (species, sex, group size, actual concentrations administered, duration
 

of treated and untreated observation periods and the time-weighted
 

average average concentrations) are summarized in Tables 1 and 2.
 

Low dose and high dose rats were each started on test 2 weeks
 

after their respective control groups. All rats were approximately 6
 

weeks old at the time they were placed on test. Rats received initial
 

dietary concentrations of 1.50 and 0.45 percent. Throughout this report those rats receiving the former concentration are referred to as
 

the high dose groups, while those initially receiving the latter concentration are referred to as the low dose groups. The low concentration was increased to 0.46 percent in week 17 in order to facilitate
 

dosage formulation. Dosed rats received 4-nitroanthranilic acid in
 

10
 
TABLE 1
 

DESIGN SUMMARY FOR FISCHER 344 RATS
 

4-NITROANTHRANILIC ACID FEEDING EXPERIMENT
 

INITIAL 4-NITROANTHRANILIC OBSERVATION PERIOD TIME-WEIGHTED
 

GROUP ACID TREATED UNTREATED AVERAGE
 

SIZE CONCENTRATION3

 (WEEKS) (WEEKS) CONCENTRATION3'
 

MALE
 

LOW DOSE
 

CONTROL 50 0 0 107 0
 

HIGH DOSE
 

CONTROL 25 0 0 109 0
 

LOW DOSE 50	 0.45 16 0.46
 

0.46 62
 

0 28
 

HIGH DOSE 50	 1.50 78 1.50
 

0 32
 

FEMALE
 

LOW DOSE
 

CONTROL 50 0 0 107 0
 

HIGH DOSE
 

CONTROL 25 0 0 109 0
 

LOW DOSE 50	 0.45 16 0.46
 

0.46 62
 

0 28
 

HIGH DOSE 50	 1.50 78 1.50
 

0 32
 

a
 Concentrations given in percentages of feed.
 

S (concentration X weeks received)
 Ti me>— MPT crh fpH aven-flof * r nnr pnf ra fi nn = .
 

£(weeks receiving chemical)
 

11
 
TABLE 2
 

DESIGN SUMMARY FOR B6C3F1 MICE
 

4-NITROANTHRANILIC ACID FEEDING EXPERIMENT
 

INITIAL 4-NITROANTHRANILIC OBSERVATION PERIOD 

GROUP ACID TREATED UNTREATED 

SIZE CONCENTRATION3 (WEEKS) (WEEKS) 

MALE 

LOW DOSE CONTROL 50 0 0 93 

HIGH DOSE CONTROL 50 0 0 98 

LOW DOSE 50 0.46 78 

0 16 

HIGH DOSE 50 1.00 78 

0 17 

FEMALE 

LOW DOSE CONTROL 50 0 0 94 

HIGH DOSE CONTROL 50 0 0 98 

LOW DOSE 50 0.46 78 

0 18 

HIGH DOSE 50 1.00 78 

0 18 

Concentrations in percentages of feed. 

12
 
the feed for 78 weeks. High and low dose control animals received
 

untreated feed during the same period. Rats were observed for an
 

additional 28 to 32 weeks after the period of chemical administration.
 

Low dose mice were placed on test 2 weeks after their controls.
 

High dose mice were placed on test 8 weeks after their controls. All
 

mice were approximately 6 weeks old when they were placed on test.
 

Mice received concentrations of 1.00 and 0.46 percent of the chemical
 

in their feed. Throughout this report those mice receiving the former
 

concentration are referred to as the high dose groups, while those
 

receiving the latter concentration are referred to as the low dose
 

groups. Dosed mice received 4-nitroanthranilic acid in the feed for
 

78 weeks. High and low dose control animals received untreated feed.
 

Mice were observed for an additional 16 to 18 weeks after the period
 

of chemical administration.
 

G. Clinical and Histopathologic Examinations
 

Animals were weighed immediately prior to initiation of the experiment. From the first day, all animals were inspected twice daily
 

for mortality. Food consumption, for two cages from each group, was
 

monitored for seven consecutive days once a month for the first nine
 

months of the bioassay and for three consecutive days each month
 

thereafter. Body weights were recorded twice weekly for the first 12
 

weeks of the study and at monthly intervals thereafter. The presence
 

of tissue masses and lesions was determined by monthly observation
 

and palpation of each animal.
 

13
 
A necropsy was performed on each animal regardless of whether it
 

died, was killed when moribund, or was sacrificed at the end of the
 

bioassay. The animals were euthanized by carbon dioxide inhalation,
 

and were immediately necropsied. The histopathologic examination
 

consisted of gross and microscopic examination of major tissues,
 

organs, and gross lesions taken from sacrificed animals and, whenever
 

possible, from animals found dead.
 

Tissues were preserved in 10 percent buffered formalin, embedded
 

in paraffin, sectioned, and stained with hematoxylin and eosin prior
 

to microscopic examination. An occasional section was subjected to
 

special staining techniques for more definitive diagnosis.
 

Slides were prepared from the following tissues: skin, subcutaneous tissue, lungs and bronchi, trachea, bone marrow, spleen, lymph
 

nodes, thymus, heart, salivary gland, liver, gallbladder (mice), pancreas, esophagus, stomach, small intestine, large intestine, kidney,
 

urinary bladder, pituitary, adrenal, thyroid, parathyroid, testis,
 

prostate, brain, ear, Zymbal's gland, uterus, mammary gland, and
 

ovary.
 

A few tissues were not examined for some animals, particularly
 

for those that died early. Also, some animals were missing, cannibalized, or judged to be in such an advanced state of autolysis as
 

to preclude histopathologic interpretation. Thus, the number of animals for which particular organs, tissues, or lesions were examined
 

14
 
microscopically varies and does not necessarily represent the number
 

of animals that were placed on experiment in each group.
 

H. Data Recording and Statistical Analyses
 

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

(Linhart et al., 1974). The data elements include descriptive information on the chemicals, animals, experimental design, clinical observations, survival, body weight, and 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) when testing two groups for
 

equality and used Tarone's (1975) extensions of Cox's methods when
 

15
 
testing a dose-related trend. One-tailed P-values have been reported
 

for all tests except the departure from linearity test, which is only
 

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

The incidence of neoplastic or nonneoplastic lesions has been
 

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

specific anatomic site (numerator) to the number of animals in which
 

that site was 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, pp. 48-52) was used to compare the tumor incidence of a control
 

group to that of a group of treated animals at each dose level. When
 

results for a number of treated 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, pp. 6-10) requires that the P-value for any comparison
 

be less than or equal to 0.05/k. In cases where this correction was
 

16
 
used, it is discussed in the narrative section. It is not, however,
 

presented in the tables, where the Fisher exact P-values are shown.
 

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

continuity correction (Armitage, 1971, pp. 362-365), was also used
 

when appropriate. Under the assumption of a linear trend, this test
 

determined 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 was 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). The week
 

17
 
during which animals died naturally or were 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 to its control was calculated from
 

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

is defined as p /p where p is the true binomial probability of the
 

incidence of a specific type of tumor in a treated group of animals
 

and p is the true probability of the spontaneous incidence of the
 

same type of tumor in a control group. The hypothesis of equality
 

between the true proportion of a specific tumor in a treated 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 treated group than in the control.
 

The lower and upper limits of the confidence interval of the
 

relative risk have been included in the tables of statistical analyses. The interpretation of the limits is that in approximately 95
 

percent of a large number of identical experiments, the true ratio
 

of the risk in a treated group of animals to that in a control group
 

18
 
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 (a 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.
 

19
 
III. CHRONIC TESTING RESULTS: RATS
 

A. Body Weights and Clinical Observations
 

Compound-related mean body weight depression was apparent among
 

high dose rats of both sexes but not among low dose rats (Figure 2)..
 

White discoloration of the lens was observed in the eyes of one
 

high dose male and six high dose females. Shortly after this observation was made only one of the seven afflicted animals was alive (a
 

high dose female). Palpable subcutaneous masses were found in four
 

low dose females, one low dose control female, one low dose male, and
 

one high dose male. One low dose male and one high dose female had
 

lesions on or near the tail and one low dose male developed a firm
 

nodule on the tail. Clinical observations peculiar to the control
 

groups were ulcerative inguinal lesions in one low dose control
 

female and one low dose control male.
 

B. Survival
 

The estimated probabilities of survival for male and female rats
 

in the control and 4-nitroanthranilic acid-dosed groups are shown in
 

Figure 3. For both male and female rats the Cox test indicated a
 

significant difference in survival between the high dose and the high
 

dose control.
 

Five males from each group were sacrificed in week 77 or 78.
 

Survival was good in all groups until about week 80, after which the
 

high dose group showed increased mortality. In week 90, 56 percent
 

(28/50) of the high dose, 74 percent (37/50) of the low dose, 64
 

20
 
750­ •750 

600­ -600 

05 

I- 450­ -450 X 

g 

g 300 H -300 

QQ 

LOW DOSE CONTROL 

HIGH DOSE CONTROL 

150­ -150 

LOW DOSE 

MALE RATS HIGH DOSE 

T~ ~r ~r ~\ 

15 30 45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

750 750 

LOW DOSE CONTROL 

_,_,—,­ HIGH DOSE CONTROL 

\-600 

-300 

-150 

120 

TIME ON TEST (WEEKS) 

FIGURE 2 

GROWTH CURVES FOR 4-NITROANTHRANILIC ACID CHRONIC STUDY RATS 

21 
- -

1 0­

T| ^ ; ^'^\.,, — 1 0 

_J 

< 

> 

> 

IT 

13

co 

08-

 06­

* T* • ^fcii^.-..., *i } ^••j i "i \ L • L* ^-" 

1 ^r^^TM"^* 

1 k 

\ '­

— 08 

-

-06 

U_ 

O 

I-

-

1

CD 

CO 

O 

CC 

D. 

 04­

02-

—— LOW DOSE CONTROL

_ ,,^.^^., HIGH DOSE CONTROL

\ 

1 

"L L 

 L_ 

-

-04 

-

-02 

LOW DOSE 

_ — — — HIGH DOSE MALE RATS 

00- I I I I I I I I I I I I I 0 0 

0 15 30 45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

1 0- — 1 0 -y-l T- — -L 

"• -L i==^ 1 ^ L ­

08­ "

l

""L, liis — 08 

< - N....,Viq_ _ 

TLL 

^06 — 06 ­

co *•

 J!.. 

O J - \ 

H 

_l 04- K. — 04 

DQ i CQ _ ^^^^— LOW DOSE CONTROL • O 

DC 

Q. ._,_,_, HIGH DOSS CONTROL "' 

02- — 02 I 

LOW DOSE L 

HIGHDOSE FEMALE RATS ^ 

0 0 0 0 i I i I i I i I i I i I i I i 

0 15 30 45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

FIGURE 3 

SURVIVAL COMPARISONS OF 4-NITROANTHRANILIC ACID CHRONIC STUDY RATS 

22 
percent (16/25) of the high dose control and 78 percent (39/50) of
 

the low dose control rats were still alive on test. Thus, there
 

were adequate numbers of male rats at risk from late-developing
 

tumors.
 

Five females from each group were sacrificed in week 77 or 78.
 

In week 90, 84 percent (42/50) of the high dose, 64 percent (32/50)
 

of the low dose, 64 percent (16/25) of the high dose control and 78
 

percent (39/50) of the low dose control rats were still alive on test.
 

Thus, there were adequate numbers of female rats at risk from late-


developing tumors.
 

C. Pathology
 

Histopathologic findings on neoplasms in rats are tabulated in
 

Appendix A (Tables Al and A2); findings on nonneoplastic lesions are
 

tabulated in Appendix C (Tables Cl and C2).
 

The sites at which tumors were most often found were the pituitary gland in both sexes, the testes in males, and the uterus and
 

mammary gland in females. The incidences of interstitial-cell
 

tumors of the testes and of leukemia appeared to be reduced in high
 

dose male rats by 4-nitroanthranilic acid feeding, possibly due
 

to shortened lifespans.
 

There was a marginally increased number of neoplasms of the skin
 

and subcutaneous tissue in low dose males, but this effect was not
 

dose-related. The few transitional-cell tumors that were found all
 

23
 
occurred in treated rats (papillomas of the kidney/pelvis and bladder
 

in two high dose males and a papilloma of the bladder in one high dose
 

female). An oligodendroglioma was an unusual tumor found in the brain
 

of one low dose female.
 

Rats of all groups exhibited the usual spectrum of nonneoplastic
 

inflammatory and degenerative lesions. In addition, high dose rats
 

showed extensive metastatic calcification in various tissues and
 

parathyroid hyperplasia. These animals also had severe renal disease.
 

The results of this histopathologic evaluation provided no evidence for the carcinogenicity of 4-nitroanthranilic acid when administered in the diet to Fischer 344 rats under the conditions of this
 

experiment.
 

D. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

rats are summarized in Tables 3 and 4. The analysis is included for
 

every type of malignant tumor in either sex where at least two such
 

tumors were observed in at least one of the control or 4-nitroanthranilic acid-dosed groups and where such tumors were observed in at
 

least 5 percent of the group. The Cochran-Armitage test was not
 

used in these analyses since the low dose group and its control were
 

started at a different time from the high dose group and its control.
 

None of the statistical tests for any site in rats of either sex
 

indicated a significant positive association between the administration of 4-nitroanthranilic acid and tumor incidence. Thus, at the
 

24
 
TABLE 3 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT 

SPECIFIC SITES IN MALE RATS TREATED WITH 4-NITROANTHRANILIC ACID£

 

TOPOGRAPHY : MORPHOLOGY 

LOW DOSE

CONTROL

 HIGH DOSE 

 CONTROL 

LOW 

DOSE 

Skin: Squamous-Cell Carcinoma

Basal-Cell Carcinoma 

 or 

1/46(0.02) 0/25(0.00) 3/46(0.07) 

P Values0 N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

3.000 

0.252 

153.954 

Weeks to First Observed Tumor 107 74 

i-o Subcutaneous

P Values0 

 Tissue: Lipoma 0/46(0.00) 0/25(0.00) 3/46(0.07) 

N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Infinite 

0.602 

Infinite 

Weeks to First Observed Tumor 96 

Lung: Alveolar/Bronchiolar

P Values0 

 Carcinoma 0/45(0.00) 1/25(0.04) 3/44(0.07) 

N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Infinite 

0.616 

Infinite 

Weeks to First Observed Tumor 109 97 

HIGH 

DOSE 

0/48(0.00) 

N.S . 

0/48(0.00) 

N.S. 

2/47(0.04) 

N.S. 

1.064 

0.059 

61.436 

77 
TOPOGRAPHY : MORPHOLOGY 

Lung: Alveolar /Bronchiolar Adenoma or i 

Carcinoma 

P Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Hematopoietic System: Leukemia or 

Malignant Lymphomai

0 

P Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Pituitary: Adenoma NOS , Chromophobe 

Adenoma, or Basophil Adenomab 

P Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

TABLE 3 (Continued) 

LOW DOSE 

CONTROL 

1/45(0.02) 

105 

4/46(0.09) 

99 

9/44(0.20) 

105 

HIGH DOSE 

CONTROL 

3/25(0.12) 

78 

4/25(0.16) 

85 

3/21(0.14) 

78 

LOW 

DOSE 

4/44(0.09) 

N.S. 

4.091 

0.426 

196.572 

96 

4/46(0.09) 

N.S. 

1.000 

0.198 

5.058 

73 

4/38(0.11) 

N.S. 

0.515 

0.125 

1.678 

105 

HIGH 

DOSE 

2/47(0.04) 

N.S. 

0.355 

0.032 

2.923 

77 

0/48(0.00) 

P = 0.012(N) 

0.000 

0.000 

0.557. 

1/33(0.03) 

N.S . 

0.212 

0.004 

2.457 

79 
TABLE 3 (Continued) 

TOPOGRAPHY : MORPHOLOGY 

LOW DOSE 

CONTROL 

HIGH DOSE

CONTROL

 LOW 

 DOSE 

Adrenal: Pheochromocytoma NOS or 

Malignant Pheochromocytoma'3 

P Values0 

6/45(0.13) •4/25(0.16) 3/43(0.07) 

N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.523 

0.089 

2.281 

Weeks to First Observed Tumor 97 68 84 

N3 

Thyroid j : C-Cell Adenoma or i 

Carcinoma0 

P Values 

 C-Cell 

3/42(0.07) 0/23(0.00) 2/41(0.05) 

N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.683 

0.060 

5.651 

Weeks to First Observed Tumor 106 105 

Testis: Interstitial-Cell

P Values0 

 Tumor 44/45(0.98) 19/24(0.79) 37/43(0.86) 

N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.880 

0.838 

1.018 

Weeks to First Observed Tumor 77 78 74 

HIGH 

DOSE 

5/47(0.11) 

N.S. 

0.665 

0.160 

3.106 

79 

3/40(0.08) 

N.S. 

Infinite 

0.357 

Infinite 

98 

1/45(0.02) 

P < O.OOl(N) 

0.028 

0.001 

0.151 

110 
TABLE 3 (Concluded)
 

created groups received time-weighted average doses of 0.46 or 1.5 percent in feed.
 

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

The probability level for the Fisher exact test for the comparison of a treated group with its
 

control group is given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. A negative designation (N) indicates a lower incidence
 

in the treated group than in the control group.
 

The 95% confidence interval of the relative risk of the treated group to the control group.
 

NJ
 

00
 
TABLE 4

 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT 

SPECIFIC SITES IN FEMALE

TOPOGRAPHY : MORPHOLOGY 

Hematopoiet ic System: Leukemia or 

Malignant Lymphoma" 

P Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

to 

VO Liver: Neoplastic Nodule or 

Hepatocellular Carcinoma" 

P Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Pituitary: Adenoma NOS or Chromophobe 

Adenoma" 

P Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

 RATS TREATED WITH 4-NITROANTHRANILIC ACID£ 

LOW DOSE HIGH DOSE LOW HIGH 

CONTROL CONTROL DOSE DOSE 

3/48(0.06) 2/23(0.09) 2/46(0.04) 1/46(0.02) 

N.S. N.S. 

0.696 0.250 

0.060 0.004 

5.792 4.600 

105 106 106 99 

1/47(0.02) 2/23(0.09) 0/45(0.00) 2/43(0.05) 

N.S. N.S. 

0.000 0.535 

0.000 0.042 

19.447 7.038 

107 106 77 

19/46(0.41) 8/21(0.38) 19/44(0.43) 9/31(0.29) 

N.S. N.S. 

1.045 0.762 

0.613 0.322 

1.779 1.919 

Weeks to First Observed Tumor 72 78 74 73 
___ 

___ 

___ 

___ 

___ 

_ __ 

TABLE 4 (Continued) 

TOPOGRAPHY: MORPHOLOGY
 

Adrenal: Pheochromocytoma NOS or
 

Malignant Pheochromocytoma^3
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-Cell Adenoma or C-Cell
 

Carcinoma"
 

u> 

o P Values0 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Fibroadenoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

LOW DOSE
 

CONTROL
 

2/47(0.04)
 

__-.
 

105
 

2/45(0.04)
 

105
 

9/48(0.19)
 

93
 

HIGH DOSE
 

CONTROL
 

3/23(0.13)
 

„
 

109
 

3/21(0.14)
 

109
 

4/23(0.17)
 

109
 

LOW
 

DOSE
 

0/44(0.00)
 

N.S.
 

0.000
 

0.000
 

3.599
 

3/41(0.07)
 

N.S.
 

1.646
 

0.199
 

18.875
 

78
 

8/46(0.17)
 

N.S.
 

0.928
 

0.341
 

2.469
 

89
 

HIGH
 

DOSE
 

7/45(0.16)
 

N.S.
 

1.193
 

0.308
 

6.659
 

84
 

3/38(0.08)
 

N.S.
 

0.553
 

0.083
 

3.833
 

73
 

3/46(0.07)
 

N.S.
 

0.375
 

0.061
 

2.059
 

77
 
TABLE 4 (Concluded) 

TOPOGRAPHY : MORPHOLOGY 

LOW DOSE 

CONTROL 

HIGH DOSE 

CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Uterus: Endometrial Stromal Polyp 15/46(0.33) 6/23(0.26) 10/43(0.23) 3/38(0.08) 

P Values N.S. N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.713 

0.322 

1.502 

0.303 

0.055 

1.280 

Weeks to First Observed Tumor 78 87 78 97 

Treated groups received time-weighted average doses of 0.46 or 1.5 percent in feed. 

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

£• 

The probability level for the Fisher exact test for the comparison of a treated group with its
 

control group is given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. A negative designation (N) indicates a lower incidence
 

in the treated group than in the control group.
 

The 95% confidence interval of the relative risk of the treated group to the control group.
 
dose levels used in this experiment there was no convincing evidence
 

that 4-nitroanthranilic acid was a carcinogen in Fischer 344 rats.
 

For male rats, the Fisher exact test comparing the incidence of
 

interstitial-cell tumors of the testis in the high dose treated group
 

with that in the high dose control yielded a negative result (P <
 

0.001). The historical data on this tumor in untreated male Fischer
 

344 rats collected by Mason Research Institute for the NCI Carcinogenesis Testing Program was 251/334 (75 percent), which compared
 

favorably with the incidence levels in the two controls and the low
 

dose treated group. However, the observed incidence of interstitial-


cell tumors of the testis in the high dose group was far below this.
 

Some—but not all—of this effect may be attributable to the elevated
 

mortality in the high dose group.
 

In male rats a possibly negative association between dose and
 

incidence was indicated for the comparison of the incidence of leukemia or malignant lymphoma in the high dose treated group with the
 

incidence in the high dose control. This effect, however, is probably attributable to the elevated mortality in the high dose group.
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

risk have been estimated and entered in the tables based upon the
 

observed tumor incidence rates. In many of the intervals shown in
 

Tables 3 and 4, the value one is included; this indicates the absence
 

of statistically significant results. It should also be noted that
 

32
 
many of the confidence intervals have an upper limit greater than one,
 

indicating the theoretical possibility of tumor induction in rats by
 

4-nitroanthranilic acid that could not be established under the conditions of this test.
 

33
 
IV. CHRONIC TESTING RESULTS: MICE
 

A. Body Weights and Clinical Observations
 

Mean body weight depression became apparent in all treated groups
 

of mice after approximately 5 months of compound administration
 

(Figure 4).
 

No clinical abnormalities were observed in treated or untreated
 

mice of either sex.
 

B. Survival
 

The estimated probabilities of survival for male and- female mice
 

in the control and 4-nitroanthranilic acid-dosed groups are shown in
 

Figure 5. For both male and female mice the Cox tests indicated no
 

significant positive associations between increased dosage and accelerated mortality.
 

Five males were sacrificed from the high dose and high dose control groups in week 78, and from the low dose control group in week
 

80. Survival was good with 90 percent (45/50) of the high dose, 98
 

percent (49/50) of the low dose, 74 percent (37/50) of the high dose
 

control and 82 percent (41/50) of the low dose control surviving on
 

test until the termination of the experiment. Thus, there were
 

adequate numbers of male mice at risk from late-developing tumors.
 

Five females from the high dose and high dose control groups
 

were sacrificed in week 78 and five from the low dose control group
 

in week 80. There were adequate numbers of female mice at risk from
 

34
 
r-40 

TIME ON TEST (WEEKS) 

^ 

/>~* •"!>* / 

V 

I l^ \ 45 60 75 

TIME ON TEST (WEEKS) 

FIGURE 4 

^30 

T^ 

90 

LOW DOSE CONTROL 

HIGH DOSE CONTROL 

LOW DOSE 

HIGH DOSE 

^20 

^10 

I I 

105 120 

-50 

-40 

-30 

I 

90 

-20 

LOW DOSE CONTROL 

HIGH DOSE CONTROL 

LOW DOSE 

HIGH DOSE 

—10 

I 

105 120 

GROWTH CURVES FOR 4-NITROANTHRANILIC ACID CHRONIC STUDY MICE 

35 
PROPORTION SURVIVING PROPORTION SURVIVIN

_^ O 0 O 0 

D O O O O 

O ro ** O3 00 3 to *» CT> 

0 — 1 1 1 1 1 1 1 1 1 O 

1 1 1 1 1 I 

1 | 

• s 1 ' 

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30 

5

 , ! j < 5- 1 > 1 < 01 

X. f X (~ 1 5 K i C 

i— 5 i 5§ 5 | o i I 

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>

S S 8 g ,^ § I i I m m

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S 

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% d fc­

* S d fiZ m s 

m 3 0 . 0

 

§2 ^ r ^ H

10 > O m <

S

J 

 : m Ov Z C eg g_ H 30 -1 ° ?q g- m •""* J • < 30 01 S \ :- s S •

I

> m

'

r c

m

n 

z 2 M m 

_ xs 1 7\ r- £2

 

^j

2 S- ai > 

O 

a 

o 

CD 

1 «- o~ 

o 

M r 

1

-i Tl 

m D <; 2 > > s S- g~ i— m m

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o -

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O m m 

o i | i | i | i | i 1

10 — 

1 o i i i i 

C5 O O p o 

1 

C3 0 

C C o o 

3 M •^ O5 
late-developing tumors as 72 percent (36/50) of the high dose, 74
 

percent (37/50) of the low dose, 70 percent (35/50) of the high dose
 

controls, and 78 percent (39/50) of the low dose controls survived
 

on test until the termination of the study.
 

C.	 Pathology
 

Histopathologic findings on neoplasms in mice are tabulated in
 

Appendix B (Tables Bl and B2); findings on nonneoplastic lesions are
 

tabulated in Appendix D (Tables Dl and D2).
 

No increases in tumor incidence were considered to be related
 

to the feeding of 4-nitroanthranilic acid. The tumors most frequently observed in all groups involved the lung, the liver, and the
 

hematopoietic system. Two rare tumors were observed: a testicular
 

seminoma in one low dose control male and a hemangiosarcoma of the
 

urinary bladder in one high dose female. No nonneoplastic toxic
 

lesions could be attributed to compound administration, although the
 

usual spectrum of degenerative and inflammatory lesions was observed
 

in all groups.
 

This histopathologic evaluation provided no evidence that
 

4-nitroanthranilic acid was carcinogenic to B6C3F1 mice under the
 

conditions of this study.
 

D.	 Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

mice are summarized in Tables 5 and 6. The analysis is included for
 

every type of malignant tumor in either sex where at least two such
 

37
 
00 

TABLE 5
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE MICE TREATED WITH 4-NITROANTHRANILIC ACID£
 

TOPOGRAPHY : MORPHOLOGY
 

Lung: Alveolar/Bronchiolar Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Lung: Alveolar/Bronchiolar Adenoma or
 

Alveolar/Bronchiolar Carcinoma"
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Malignant
 

Lymphomab
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

CONTROL
 

4/45(0.09)
 

N.S.
 

97
 

11/45(0.24)
 

N.S.
 

78
 

2/46(0.04)
 

N.S.
 

97
 

LOW
 

DOSE
 

3/50(0.06)
 

N.S.
 

0.675
 

0.104
 

3.779
 

94
 

10/50(0.20)
 

N.S.
 

0.818
 

0.346
 

1.919
 

94
 

3/50(0.06)
 

N.S.
 

1.380
 

0.166
 

15.934
 

94
 

HIGH
 

DOSE
 

1/50(0.02)
 

N.S.
 

0.225
 

0.005
 

2.167
 

95
 

4/50(0.08)
 

P = 0.027(N)
 

0.327
 

0.082
 

1.017
 

95
 

3/50(0.06)
 

N.S.
 

1.380
 

0.166
 

15.934
 

78
 
TOPOGRAPHY : MORPHOLOGY
 

Circulatory System: Hemangioma or
 

Hemangiosarcoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma
 

P Values
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Adenoma or
 

Hepatocellular Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 5 (Continued) 

CONTROL
 

0/45(0.00)
 

P = 0.035
 

10/45(0.22)
 

N.S.
 

93
 

10/45(0.22)
 

N.S.
 

93
 

LOW
 

DOSE
 

0/50(0.00)
 

N.S.
 

10/50(0.20)
 

N.S.
 

0.900
 

0.372
 

2.186
 

94
 

16/50(0.32)
 

N.S.
 

1.440
 

0.690
 

3.174
 

94
 

HIGH
 

DOSE
 

3/50(0.06)
 

N.S.
 

Infinite
 

0.543
 

Infinite
 

78
 

9/50(0.18)
 

N.S.
 

0.810
 

0.321
 

2.018
 

95
 

9/50(0.18)
 

N.S.
 

0.810
 

0.321
 

2.018
 

95
 
TABLE 5 (Concludsd)
 

o
 

Treated groups received doses of 0.46 or 1.0 percent in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 Q
 

The probability level for the Fisher exact test for the comparison of a treated group with the
 

control group is given beneath the incidence of tumors in the treated group with P < 0.05; otherwise, not significant (N.S.) is indicated. A negative designation (N) indicates a lower incidence
 

in the treated group than in the control group.
 

The 95% confidence interval of the relative risk of the treated group to the control group.
 
TABLE 6
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE MICE TREATED WITH 4-NITROANTHRANILIC ACID*
 

TOPOGRAPHY :MORPHOLOGY
 

Lung: Alveolar/Bronchiolar Adenoma or
 

Alveolar/Bronchiolar Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Malignant Lymphoma
 

or Leukemia"
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Circulatory System: Hemangioma or
 

Hemang i o s ar c oma"
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

LOW 

CONTROL DOSE 

1/45(0.02) 5/41(0.12) 

N.S. N.S. 

5.488 

0.651 

252.552 

98 94 

12/46(0.26) 5/42(0.12) 

N.S. N.S. 

0.456 

0.137 

1.261 

94 94 

0/46(0.00) 1/42(0.02) 

N.S. N.S. ___ 

Infinite 

0.059 

Infinite 

94 

HIGH
 

DOSE
 

1/48(0.02)
 

N.S.
 

0.938
 

0.012
 

72.085
 

78
 

8/49(0.16)
 

N.S.
 

0.626
 

0.245
 

1.509
 

76
 

3/49(0.06)
 

N.S.
 

Infinite
 

0.566
 

Infinite
 

76
 
___ 

TOPOGRAPHY: MORPHOLOGY
 

Liver: Hepatocellular Carcinoma
 

P Values
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Adenoma or
 

Hepatocellular Carcinoma*3
 

JN P Values0
 

S3 j
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Stomach: Squamous-Cell Papilloma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 6 (Continued) 

CONTROL
 

4/45(0.09)
 

N.S.
 

78
 

*
 

4/45(0.09)
 

N.S.
 

78
 

3/42(0.07)
 

N.S.
 

—_
 

98
 

LOW
 

DOSE
 

0/41(0.00)
 

N.S.
 

0.000
 

0.000
 

1.176
 

1/41(0.02)
 

N.S.
 

0.274
 

0.006
 

2.623
 

94
 

3/40(0.08)
 

N.S.
 

1.050
 

0.149
 

7.404
 

94
 

HIGH
 

DOSE
 

1/47(0.02)
 

N.S.
 

0.239
 

0.005
 

2.300
 

95
 

1/47(0.02)
 

N.S.
 

0.239
 

0.005
 

2.300
 

95
 

0/47(0.00)
 

N.S.
 

0.000
 

0.000
 

1.482
 
TABLE 6 (Concluded)
 

TOPOGRAPHY: MORPHOLOGY CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Pituitary: Adenoma NOS, Chromophobe 

Adenoma, or Basophil Adenoma 

P Values0 

6/37(0.16) 

P = O.OIO(N) 

4/36(0.11) 

N.S. 

0/40(0.00) 

P = O.OIO(N) 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.685 

0.154 

2.638 

0.000 

0.000 

0.573 

Weeks to First Observed Tumor 98 94 

a

Treated groups received doses of 0.46 or 1.0 percent in feed. 

Number of tumor-bearing animals/number of animals examined at site (proportion) .
 £
 

The probability level for the Fisher exact test for the comparison of a treated group with the
 

control group is given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. A negative designation (N) indicates a lower incidence
 

in the treated group than in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 
tumors were observed in at least one of the control or 4-nitroanthranilic acid-dosed groups and where such tumors were observed in at
 

least 5 percent of the group. Since the low dose control mice came
 

from a different supplier, the high dose control mice were used as
 

the control for both dosed groups.
 

For males the Cochran-Armitage test indicated a significant (P =
 

0.035) positive association between dose and the combined incidence
 

of hemangiosarcomas or hemangiomas. The Fisher exact tests, however,
 

were not significant.
 

No other statistical tests for any site in mice of either sex
 

indicated a significant positive association between the administration of 4-nitroanthranilic acid and tumor incidence under the Bonferroni criterion. Thus, at the dose levels used in this experiment
 

there was no convincing evidence that 4-nitroanthranilic acid was a
 

carcinogen in B6C3F1 mice.
 

In female mice the Fisher exact test comparing the combined incidence of pituitary adenomas NOS, chromophobe adenomas, or basophil
 

adenomas in the high dose treated group to that in the high dose control group indicated a significant (P = 0.010) negative association.
 

The Cochran-Armitage test was also significant (P = 0.010). The historical incidence of this type of tumor in B6C3F1 untreated female
 

mice raised at Mason Research Institute for the NCI Carcinogenesis
 

Testing Program was 22/350 (6 percent), compared to the 6/37 (16
 

44
 
percent) observed in the control group and the 0/40 observed in the
 

high dose group.
 

In male mice the Fisher exact test comparing the combined incidence of alveolar/bronchiolar adenomas or alveolar/bronchiolar carcinomas in the high dose treated group to that in the high dose control
 

group yielded a significant negative association (P = 0.027). This
 

result, however, was not significant under the Bonferroni criterion.
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

risk have been estimated and entered in the tables based upon the
 

observed tumor incidence rates. In many of the intervals shown in
 

Tables 5 and 6, the value one is included; this indicates the absence
 

of statistically significant results. It should also be noted that
 

many of the confidence intervals have an upper limit greater than one,
 

indicating the theoretical possibility of tumor induction in mice by
 

4-nitroanthranilic acid that could not be established under the conditions of this test.
 

45
 
V. DISCUSSION
 

In both species, adequate numbers of animals in all groups survived long enough to be at risk from late-developing tumors. Depression of mean group body weight, relative to controls, was observed
 

for high dose rat groups and all dosed mouse groups. This observed
 

growth retardation indicates that concentrations of 4-nitroanthranilic
 

acid fed to these animals approximated maximum tolerated dosages.
 

In rats none of the statistical tests applied indicated a significant positive association between the dietary administration of
 

4-nitroanthranilic acid and tumor incidence. Isolated occurrences
 

of rare transitional-cell papillomas of the kidney/pelvis, and
 

bladder and a single oligodendroglioma of the brain were noted in
 

treated rats. These neoplasms were not considered evidence of
 

carcinogenicity of 4-nitroanthranilic acid.
 

For some sites, tumor incidences in the high dose rat groups
 

were lower than in corresponding control groups. The most likely
 

cause of these reduced tumor incidences in high dose groups is the
 

elevated mortality observed among high dose groups during the observation period following compound administration. Of the 50 high
 

dose rats of each sex placed on test, only 6 males and 2 females died
 

natural deaths during the dosing period, but 30 males and 41 females
 

died during the untreated observation period. The high dose rats in
 

this study received triple the dosage administered to the low dose
 

rats.
 

46
 
In mice, none of the statistical tests indicated significantly
 

increased tumor incidences associated with 4-nitroanthranilic acid
 

administration.
 

Under the conditions of this bioassay, evidence was not provided
 

for the carcinogenicity of 4-nitroanthranilic acid in Fischer 344
 

rats or B6C3F1 mice.
 

47
 
VI. BIBLIOGRAPHY
 

Anthony, H.M., and G.M. Thomas, "Tumors of the Urinary Bladder: An
 

Analysis of the Occupations of 1,030 Patients in Leeds, England."
 

Journal of the National Cancer Institute 45:879-895, 1970.
 

Armitage, P., Statistical Methods in Medical Research, Chapter 14.
 

J. Wiley & Sons, New York, 1971.
 

Berenblum, I., editor, Carcinogenicity Testing. International Union
 

Against Cancer, Technical Report Series, Vol. 2. International
 

Union Against Cancer, Geneva, 1969.
 

Chemical Abstracts Service. The Chemical Abstracts Service (CAS)
 

Ninth Collective Index, Volumes 76-85, 1972-1976. American
 

Chemical Society, Washington, B.C., 1977.
 

Cox, D.R., Analysis of Binary Data, Chapters 4 and 5. Methuen and
 

Co., Ltd., London, 1970.
 

Cox, D.R., "Regression Models and Life-Tables." Journal of the Royal
 

Statistical Society, Series "B" 34:187-220, 1972.
 

Gart, J.J., "The Comparison of Proportions: A Review of Significance
 

Tests, Confidence Limits, and Adjustments for Stratification."
 

International Statistical Institute Review 39:148-169, 1971.
 

Kaplan, E.L., and P. Meier, "Nonparametric Estimation from Incomplete
 

Observations." Journal of the American Statistical Association
 

21:457-481, 1958.
 

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

"Carcinogenesis Bioassay Data System." Computers and Biomedical
 

Research 7:230-248, 1974.
 

Miller, R.G., Simultaneous Statistical Inference. McGraw-Hill Book
 

Co., New York, 1966.
 

Rupe, H. and L. Kersten, "5- and 4-Nitroisatin." Helvetica Chimica
 

Acta 9:578, 1926.
 

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

Kaufman, "Respiratory Tract Carcinogenesis in Hamsters Induced
 

by Different Numbers of Administration of Benzo (a) Pyrene and
 

Ferric Oxide." Cancer Research 32:1073-1079, 1972.
 

48
 
Tarone, R.E., "Tests for Trend in Life-Table Analysis." Biometrika
 

62:679-682, 1975.
 

Urso, S., Research Analyst, Chemical-Environmental Program, Chemical
 

Industries Center, Stanford Research Institute, Menlo Park,
 

California. Personal communication, 1977.
 

Wynder, E.L., J. Onderdonk, and N. Mantel, "An Epidemiological Investigation of Cancer of the Bladder." Cancer Ib:1388-1407, 1963.
 

49
 

Review of the Bioassay of 4-Nitroanthranilic Aci-d*
 

for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

June 29, 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 responsi­ bility of providing a peer review of reports prepared on
 

NCI-sponsored bioassays of chemicals studied for carcinogenic­ ity. It is in this context that the below critique is given
 

on the bioassay of 4-Nitroanthranilic Acid for carcinogenicity.
 

The reviewer agreed with the conclusion that the compound
 

was not carcinogenic in rats or mice, under the conditions of
 

test. He considered both the experimental design and the
 

animal survival rate to be adequate. He noted a negative
 

trend in several tumor types among treated animals. The
 

reviewer moved that the report on the bioassay of 4-Nitro­ anthranilic Acid be accepted as written. The motion was
 

approved without objection.
 

Clearinghouse Members present:
 

Arnold L. Brown (Chairman), Mayo Clinic
 

Paul Nettesheim, National Institute of Environmental
 

Health Sciences
 

Verne Ray, Pfizer Medical Research Laboratory
 

Verald K. Rowe, Dow Chemical U.S.A.
 Michael B. Shimkin, University of California at San Diego
 

Louise Strong, University of Texas Health Sciences Center
 

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.
 

51
 

U.S. GOVERNMEN T PRINTIN G OFFICE . 1978-260-899/3180
 

APPENDIX A 

SUMMARY OF THE INCIDENCE OF NEOPLASMS 

IN RATS TREATED WITH 4-NITROANTHRANILIC ACID 

TABLE A1

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

TREATED WITH 4-NITROANTHRANILIC ACID 

—•­- • ' ­— LOW DOSE CONTROL (USTR) 

01-0030 

HIGH DOSE CONTROL (UNTR ) 

01-008U 

LOif DOSE 

01-0034 

-———­— 

HIGH DOSE 

01-0104 

ANIMAL S INITIALL Y I N STUD Y 50 25 50 50 

ANIMAL S MISSIN G 2 

ANIMAL S NECROPSIE D 46 25 46 48 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY* * 45 25 44 48 

INTEGUMENTARY SYSTEM
 

*SKIN (46) (25) (46) (48) 

SQUAMOUS CELL PAPILLOMA 2 <4X) 

3QUAMOUS CELL CARCINOMA 1 (2%) 1 <2*) 

BASAL-CELL CARCINOMA 2 (4X) 

TPICHO-3PITHELIOMA 1 (2X> 

*SUBCUT TISSUF (46) (25 ) (46) (48) 

FIBROMA 

LIPOMA 3 (1%) 

HEMANGIOKA 1 (2«) 

RESPIRATORY SYSTEM
 

tTRACHEA (45) (ID (42) (8)
 

SQUAMO'JS CELL CARCINOMA 1 (21)
 

*LUNG (45) (25) (44) (47)
 

ALVEOLAR/BRONCHIOLAR ADENOMA 1 (2%) 2 (8*) 1 (2%)
 

ALVEOLAR/BFONCHIOLAR CARCINOMA 1 (4K) 3 (7%) 2 <4X)
 

PHEOCH80MOCYTOMA, METASTATIC 1 (4%)
 

"IBROSAPCOKA, MFTASTATIC 1 (2X)
 

HEMATOPOIETIC SYSTEM
 

*MaLTIPLi; ORGANS (46) (25) (46) (48) 

MALIGNANT LYMPHOKA, NOS 1 (2%) 

UNDIFF3RENTIATED LEUKEMIA 2 (8S) 

WYELCM1NOCYTIC LEUKEMIA 1 (2*1 4 (•)%) 

LYflPHOCYTIC LEUKEMIA 2 (4X) 2 (B%) 

•BONE MARRO W (45) (25) (42) 

« NUMBE R O F ANIMAL S WIT H TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R O F ANIMAL ? NSCROPSIE D 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

A-3
 
TABLE Al (CONTINUED) 

LOW DOSE CONTROL (UNTS ) 

01-0030 

HIGH DOSE CONTRO L (UNTR) 

01-008U 

L OW DOSE 

01-003K 

HIGH DOSE 

01-0101 

•CERVICA L LYMP H NODE 

ALVEGLAVBRONCHIOLA R CA , METAST A 

«(!EDIASTIN* L L.NOD E 

ALVEOLAR/BPONCHIOLA R CA , ME1ASTA 

C-CEIL CAPCINOMA , BETASTATIC 

(11) 

(11) 

(21) 

(2U ) 

(38) 

(38) 

(29) 

1 (3X) 

(29) 

1 (3X) 

1 (3S) 

CIRC'J'.HTOE Y

NON " 

 SYSTE M 

DI~,3STIV E SYSTE M 

•SALIVAR Y GLAN D 

CARCINOMA , NOS 

• LIVER 

NECPLASTI C NODUL E 

HTPATOCFLLULA R CARCINOM A 

•STPIACH 

SQUAMO'J S CFLL PAPILLOMA 

BASAL-CEL L CARCINOM A 

(13) 

(1*5) 

(15) 

(21) 

(25) 

(21) 

1

1

 (t%) 

 (4%) 

(10) 

1 (3*) 

(11) 

1 (2X) 

(13) 

(10) 

(16)

1

(16) 

1

 (2%) 

 (2X) 

UBINAR Y SYSTE M 

*KinN5Y/P3LVI S 

TRANSITIONAL-CEL L PAPILLOMA 

•URINAR Y 3LADDEP 

TRANSITIONAL-CEL L PAPILLOM A 

(15) 

(11) 

(21) 

(23) 

(11) 

(13) 

(17) 

1

(13) 

1

 (2%) 

 (2%) 

"NDOCRIN E SYSTE M 

• PIT'JITAR Y 

AD3NOMA , NOS 

CHEOMOPHOE E ADENOM A 

BASOPHIL ADENOM A 

•ADRENA L 

CO RTIC \L_ADENOa A ____ _ 

(11)

9 (20*) 

(15) 

. -_,1-_2«U 

(21 )

1

2

(25) 

» NUMBE R 0" ANIMAL S WITH TISSUE EXAMINED MICROSCOPICAltY 

* N'JMBEK n? ANIMALS NECROPSIED 

 (5t) 

 (10%) 

(38) 

2 (5X) 

2 (5*) 

(13) 

(33) 

1

(47) 

 (3%) 

A-4 
TABLE A1 (CONTINUED) 

LOW DOSE CONTROL (UNTE) HIGH DOSE CON IROL (UNTR)

01-0030 01-0034

PHECCHROttOCYTOMA 6 (13*) 2 (8«)

PHECCHROKOCYTOKA, MALIGNAN T 2 (8«) GANGLIONFUROM A 

•THYROID (42) (23)

C-CELL ADENOM A 2 (5%)

C-CELL CARCINOMP 1 (2iS) 

#PANCREATIC ISLETS (45) (25)

ISLET-CELL ADENOM A 1 (2JS) 2 (8X)

REPRODUCTIVE SYSTEM
 

*MAHHAF Y JLAND (46) (25)


FI3POSARCOMA
 

FIBPOADENOFA 1 (4%)
 

*P»FPUTIAL GLAND (46) (25)


CARCINOMA, NOS 1 (4X)
 

AD3NCPH, NOS 1 (2X) 1 (4*)
 

SEBACEOUS ADENOM A
 SEBAC^US UDENOCARCINOMA
 

*T~STIS (45) (24)


INIEBSTITIAL-CFLL TUMOR 44 (98%) 19 (79X)


NERVOU S SYSTEM
 

NONE
 

*r AO CANAL (46) (25)


SQiHMOUE CELL CARCINOM A 1 (4*)
 

*ZfCBAL'S GLAND (46) (25)


SEBfCHOHS ADENOCARCINOMA
 

MUSCUL05KELETAL SYSTEM
 

1

:1; OF ANIMAL S JITH TISSUE EXAMINED IICROSCOPICALLY
 

CR 0° ANI1ALS NECROPSIED
 

A-5
 

 LOW DOSE
 

 01-0034
 

3 (7%)
 

1 (2»)
 

 (41)
 

2 (5)1)
 

 (43)
 

2 (5%)
 

 (46)
 

1 (2%)
 

 (46)
 

 (43)
 

 37 (86%)
 

 (46)
 

 (46)
 

HIGH DOSE
 

01-0104
 

4 (9%)
 

1 (2%)
 

(40)
 

2 (5%)
 1 (3%)
 

(43)
 

(48)
 

(48)
 

1 (2X)
 

1 (2%)
 

1 (2X)
 

(45)
 

1 (2X)
 

(48)
 

(48)
 

1 (2S)
 
TABLE Al (CONTINUED) 

LOW DOSE HIGH DOSE — ——— CONTROL(UNTR ) CONTRO L (UNIR) L OU DOSE HIGH DOSE 

01-0030 01-0084 01-0034 01-010U 

BOOf C4VITTF S 

•BOD Y CAVITIE S (46) (25) (46) (48) 

IHSOTriSLICMA , NO S 3 (7% ) 2 (41)

 

*«"DIASTI SU I " (46 ) (25) (46) (48) 

MVEOHR/BTDNCrilOLA E CA , ME1AST A 1 (4*)

 

*PL"i!RA (46) (25) (46) (48)

 ALVEOHR/BPONCHIOLA R CA , METAST A 1 (4% )

 

A L L OTHE R SYSTFP S 

NOM " 

ANIPA L DISPOSITIO N SUMMAR Y 

ANI1M S IMITIALL Y TXJ STUD Y 50 25 50 50

 

"lA-U^A L Drp"Ho) 7 3 7 22

 

MORIBU'J D SACRIFICE 6 4 6 14

 SCrlEC'JL" D SACRIFIC3 15 5 5 5

 

aCCID^'JTALL Y KILLE D T E^MIN\ L SACPIFIC" 22 13 30 9

 

ANIMA L MISSIN G 2

 

* N'JIP^P 0? ANI1ALS fclTH TISSUE EXAMINE D MICROSCOPICALLY 

« NB1B" H OF ANIMAL S NECROPSI^I D 

A-6 
TABLE Al (CONCLUDED)
 

. LOW DOSE HIGH DOSE CONTROL (UNTR ) CONTROL (UNTR ) L OW COSE HIGH DOSE 

01-0030 01-0084 01-0034 01-0104 

TUflO" SUMMAR Y 

TOTA L ANIMAL S WIT H PRIMAR Y TUMORS * 1*14 22 43 16

 

TOTAL PRIMAR Y TUMORS 75 4 1 71 22 

TOTA L ANIMAL S WIT H BENIG N TUMCE S 44 20 40 9 

"•OTAL BENIG N TUMOR S 65 31 56 13 

TOTA L ANIMAL S WIT H MULIGNAN T TUMOR S 7 9 12 7

 

TOTA L 1ALIGNAN T TUMOR S 7 10 13 8

 

TOTAL ANIMALS WITH SECONDARY TUMORS* 2 1
 TOTAL SECONDARY TUMORS 3 1
 

TOTAL ANIMAL S WITH TUMORS UNC'JRTAIN3ENIGN OH MALIGNAN T 3 2
 TOTAL UNCTPTAIN TUMORS 3 2
 

TOTAL ANIMAL S WITH TUMORS UNCERTAINPRIMAR Y IS METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

* SFCONDARY THMOPS: MCTASTMIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

A-7
 
TABLE A2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

TREATED WITH 4-NITROANTHRANILIC ACID 

_ ,—. . — _ , ._ 

LOW DOSE HIGH DOSE CONTRO L (UNTR ) CONTRO L (USTR ) L O U DOSE HIGH DOSE 

02-0030 02-0084 02-0034 02-0104 

ANIMAL S INITIALL Y I N STUD Y 50 25 50 50 

ANIMAL S NFCROPSIT 48 23 46 46 

ANIMAL S EXAMINE D H I ST O PATHOLOGICALLY* * 47 23 45 45 

INTEGUMENTAR Y SYST5 * 

*SK!N («8) (23) (46) <4b )

 

ADENTMA , NO S 1 (2)1)
 

SrBACEOU= AD^NOCARCINOMA 1 (4%)
 

FI 3 R C '1A 1 (2«)
 

'I3BCSARCOMA 1 (2S)
 

FIBPOADCNCMA 1 (2*)
 

*SJBCUT TISSU^ (18) (23) (46) (46)

 

FIBEOFA 2 (4%)
 

SYST: M 

*LUN G (17) (23 ) (45) (43)

 

SCUAMOII S CELL CAFCINOIA 1 (2% ) 1 (2%)

 

ALVOLAE/BFONChlOLA S ADENOM A 1 (4X ) 1 (2% )

 ALifECLAVHONCHIOLA B CARCINOM A 1 (2%)

 

''laPOSAPCOPI A 1 (2% ) LEICMYOSAPCOK A 1 (2%)

 LEIOMYOS J PCOMA , M^TASTATI C 1 (2*)

 

HEKATOPOlrTIC SYSTEM
 

•MULTIPL" OPGAI.S (48) (23 ) (46 ) (46) 

MALIGNAN T LYBPH01A, NOS 1 (2*) 

MALIG.LYCPF01A, LYMPHOCYTIC TYPE 1 (2%) 

'JN'DIFFr^ENTIATrD LEUKEMIA 2 (9*) MY5LCMONOCYTIC LEUKFBIA 1 (21,) 1 (2%) 

<BON T " MARR01 * (47 ) (22 ) (43 ) (42)

 

1 (2%) 

• SPLEE N (47 ) (23 ) (45 ) (43) 

H^MANSISEA 

* NJ1BE ? O F ANIMAL S WIT H TISSUE EXAMINE D MICROSCOPICALL Y 

* Ml»Br ° OF ANIMAL S NECROPSIE D 

**EX~LUDEb PARTIALLY AUTOLYZEU ANIMALb 

A-8 
TABLE A2 (CONTINUED) 

LOW DOSE CONTRO L (ONTR )

02-0030

 HIGH DOSE CONTROL (UNTR )

 02-0034

 LOW COSE

 02-0034

 HIGH DOSE 

 02-0104 

MYELCMONOCYTIC LEUKEMIA

KTfUCHEA L LYMP H NOD E

"IBEOSftRCCMA , METASTATIC

 1 (2*) 

 (42) (21 ) (39)

 1 (3*) 

 (28) 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

tLIVEP

NFOFLASTIC NODDLE

HEPATOCSLLULAR CARCINOMA

tSTOMACH

SQUAMOUS CFLL PAPILLOMA

BASAL-CELL CARCINOMA

 (47)

 1 (2%)

 (46)

 (23)

 2 (9*)

 (23)

 (45)

 (414)

 (43) 

1 (2X) 

1 (2X) 

 (43) 

2 (5J) 

1 (2%) 

UHINASY SYSTER 

• URISAPY SLAIDSR

TRANSITIONAL-CELL PAPILLOMA

 (46) (22) (41) (37) 

1 (3%) 

ENDOCRINE SYSTZM 

•PITUITUPY

CARCINOMA,NOS

ADFNOMA , NOS

CHEOMOPHOEE ADENOMA 

 (46) 

1 (2*) 

 19 (41%) 

(21) 

1

7

 (5%) 

 (33*) 

(44) 

11 (25*) 

8 (18*) 

(31) 

1 (3*) 

8 (26*) 

tADRENAL (47) 

SQUAMOUS CFLL CARCINOMA, ME1ASTA 

CORTICAL ADENOM A 1 (2%} 

PKEOCHROMOCYTOMA 2 (41) 

PHEOCHROMOCYTOCA, MALIGNANT 

• THYPOIE (45) 

C-CF.LL ADFNOMA 2 (4%) 

C-C'LL CARCINOMA 

tTHYROI D FOLLICLE (45) 

PAi!iLA.HY_CXS_TADENOC.A£C.iJjl03A.iJ(OS 

(23) 

2 (9X) 

1 (4%) 

(21) 

2 (10*) 

1 (5%) 

121) 

1-1521. 

* NUMBER OF ANIMALS WITH TISSUE SXAMINED MICROSCOPICALLY 

* NU1BFS OF ANIMALS NECROPSIED 

(4U) 

1 (2*) 

(41) 

2 (5*) 

1 <2X) 

(41) 

(45) 

6 (13*) 

1 (2*) 

(38) 

2 (5*) 

1 (3*) 

(38) 

A-9 
TABLE A2 (CONTINUED) 

—	 __-._.-——.
 LOW DOSE HIGH DOSE
 CONTROL (UNTH) CONTROL (UNTR)
 

02-OD30 02-0084
 

•PANCPHATIC	 ISLETS (46) (22)
 ISLET-CELL ADKNOMA 2 (4%)
 

REPRODUCTIVE SYSTEM
 

*MAM«AR Y GLAND (48) (23)
 ADENCCARCINOMA, NOS 2 (9%)
 PAPILLARY CYSTADENOMA, NOS 2 (4%)
 

INFILTRATING DUCT CARCINOMA 1 (4X)
 FIERCADEfiOMA 9 (19%) 4 (17%)
 

"CLITOSAL GLAND (48) (23)
 CARCINOMA, NOS
 

SQUAMOUS CELL CARCINOMA
 

ADENCMA , NOS
 

"VAGINA (48) (23)
 FIBEOSAPCCMA 1 (2%)
 LYMPHANGIOSARCOMA 1 (2%)
 

CUTERUS (46) (23)
 ADENOCA8CINOMA, NOS
 

LEICMYOSA&COMA
 

FNDOMFTRIAI STHOMAL POLYP 15 (33%) 6 (26%)
 

•UTERUS/ "NDOMETRIUM (46) (23)
 CARCINOMA, NOS 1 (2X)
 

NERVOUS SYSTEM
 

tBRAIN (47) (23)
 OLIGCDENDROGLIOHA
 

SPECIAL SENSE CP3ANS
 

*r AR CANAL (48) (23)
 FIBROSARCCMA 1 (2*)
 

MUSC'UOSKFLIITAL SYSTEM
 

*	 NUMBE R 0" ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

*	 NUMBER OF ANIMALS NECROPSIED
 

A-10
 

LOW COSE HIGH DOSE
 

02-0034 02-0104
 

(44)	 (39)
 

1 (2%)
 

(46)	 (46)
 

1 (2%)
 

8 (17%) 3 (7%)
 

(46)	 (46)
 

1 (2%)
 

1 (2%)
 

2 (4%)
 

(46) (46)
 

(43)	 (38)
 

2 (5%)
 

1 (2%)
 

10	 (23%) 3 (8%)
 

(43) (38)
 

(43)	 (42)
 

1 (2%)
 

(46) (46)
 
BODY CAVITIES
 

*POPY CAVITIES
 

MFSOTHELIOMA, NOS
 

ALL OTHER SYSTEMS
 

NON?
 

ANIMA L DISPOSITION SUMMAR Y
 

ANIMAL S INITIALLY IN STUDY
 

NATURAL DEATHS
 

MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMA L MISSING
 

3 INCLUDES AUTOLYZED ANIMALS
 

TUMCR SUCMARY
 

TOTAL ANIMALS WITH PRIMARY TURORS*


''OTAL PRIMARY TUTORS


TOTAL ANI'ALS WITH BENIGN IUMCRS


TOTAL BENIGN TUMORS


TABLE A2 (CONCLUDED) 

LOW DOSE CONTROL(UNTR ) 

02-0030 

HCONTR°0S

LE(UNTR) 

02-0084 

LOW DOSE 02-0034 HIGH DOSE 

02-0104 

(48) (23) (46) (46) 

1 (2%) 

50 25 50 50 6 3 1 1 31 8 5 10 12 

15 5 5 5 

21 12 24 

 38 19 35 22 

 66 34 59 34 

 36 18 33 19 

 54 23 46 27 

TOTHL ANIMAL S WITH MALIGNAN T TUMORS

TOTAL MALIGNANT TUTORS

 9 

 12

8 

9

1 2 

 13 

TOTAL ANI1ALS WITri SECONDARY TUMOBS* T

0"AL SECONDARY TUMOFS

 3 

3 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT

TO^AL UNCERTAIN TUMORS

 2 

2 

TOTAL ANIMALS WITH TUMOPS UNCERTAINPSIMAEY OR METASTATIC 

TOTAL UNCERTAIN TUMORS 

* PRIMAR Y TUMOFS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

A-ll 

APPENDIX B 

SUMMARY OF THE INCIDENCE OF NEOPLASMS 

IN MICE TREATED WITH 4-NITROANTHRANILIC ACID 

TABLE Bl

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

TREATED WITH 4-NITROANTHRANILIC ACID

 

LOW DOSE
 CONTHOL (UNTR)
 

05-1030
 

ANIMAL S INITIALLY IN STUDY 50
 

ANIMALS NECROPSIED 46
 

ANIMALS EXA1INFD HI 3TOPHTHOLOGICA LLY** 46
 

INTETJMENTHRY SYSTFP!
 

NONE
 

8SSPIFATCKY SYSTEM
 

*LUNG


HEPATOCSLLULAR CARCINOHA, METAST


ALVECHS/BEONCHIOLAH ADENOMA


ALVECLAR/BRONCHIOLAR CARCINOMA


HEMATOFOirilC SYSTEM
 

*MUL"'IFLE ORGANS


MALIGNUN T LYMPKOMA , NOS


MALIG.LY.1PHOMA, HISTIOCYTIC TYP3


HALIGNUNT LYHPHOMA , MIXED TYPE
 

*SU3CIIT "ISSU1:


PLA5»A-CELL TUKOE
 

4BONT MARRO W


HEMANGIQK A
 

CSPL'ES


HEMASTIOM A
 

H"MA1I5IOSA5C01A
 

lAIIu.LYIPHOMS, HISTIOC^TIC TYPE
 

*!HNriE'JLA" I. NODE


"ALIG.LYMPFO>iA, HISTIOCYTIC TYPE
 

• SKALL IN^'-STINE


MAJ.IGtLIMPHOIS.j. HISTIO£Y,TIC TYPE
 

 (46)
 

1(2%)
 

5 (11%)
 

2 (4«)
 

 (46)
 

1 (2i)
 

1 (2«)
 

 (46)
 

 (4o)
 

 (46)
 

 (34)
 

 (46)
 

I

cWT%o¥(UNTR)


05-0077


50


46


45


(45)


1 (2%)


7 (16%)


4 (9%)


(46)


(46)


(45)


(45)


1 <2X)
 

(35)


1 (3«)
 

(43)


— •__


 LOU DOSE
 

 05-0034
 

 50
 

 50
 

 50
 

 (50)
 

1 (2%)
 

8 (16%)
 

3 (6%)
 

 (50)
 

2 (4%)
 

1 (2%)
 

 (50)
 

1 (2%)
 

 (50)
 

 (50)
 

 (45)
 

 (50)
 

««... __.
 

HIGH DOSE
 

05-0103
 

50
 

50
 

50
 

(50)
 

3 (6%)
 

1 (2%)
 

(50)
 

1 <2S)
 

(50)
 

(50)
 

1 (2*)
 

(49)
 

1 (2*)
 

1 (2*)
 

(50)
 

(50)
 

5 (441
 

* SOHBE R OF ASIiULS WIT H 1153113 EXA1INE D MICROSCOPICALL Y 

* NUPIBE ? O F ANIMAL S NECROPSIE D 

**LXCLUM.S PARTIALLY AUlOLY^tU ANIMALb 

B-3 
TABLE Bl (CONTINUED) 

LOW DOSE CONTROL (UNTR)

05-OD3 0

 HIGH DOSE CONTROL (UNTR)

 05-0077

 LOW COSE 

 95-0034 

HIGH DOSE 

05-0103 

CIPCULATf Y

NON " 

 SYSTE M 

DIGTSTIV F SYSTE.1 

*LIV' P

H"PATOCELLUU P ADENOM A 

rf'PATlCri.L'JLAK CARCINOM A

«ST01ACd

SJUAIOU S CEL1 PAPI'LOh A 

 (16) 

 1 2 (2-)*) 

 (15) 

(i*5)

10

(42 )

1

 (22% )

 (2%)

 (50) 

6

 10

 (50 ) 

2

 (12% ) 

(20%) 

 (1/5) 

(50) 

9

(50) 

 (18% ) 

OFINAPY SY3TT" 

ENDCCPIN E SYSTE M 

•PITUITAR Y 

ADENCMH , NO S 

KADRFNA L 

PH^CCrnOMOCYTO M 

(tADP'NAL/CHPSOL' ) 

ADENOMA , NOS 

fHYROI D 

ADENCCARCINOMA , NO S 

(39)

1

(11)

(IK )

(41)

2

 (3X ) 

 (5<S ) 

 (36 ) 

 (43) 

 (43 ) 

 (10) 

(44 )

(50 )

1 (2% ) 

(50)

1 (2%) 

!t")

 (39 ) 

 (50) 

 (50) 

 C*5) 

REPRODUCTIV E SYSTE M 

*PR"PUTIA L GLAN D 

CA^CINOKA.NO S 

»""STIS 

S"MINOKA/DYSGE=MIMOM A 

(46 )

(46 )

1 (2%1 

 (16) 

 (45 ) 

(50 )

1

(50)

 (2%) 

 (50) 

 (50) 

NERVOU S SYSTF M 

* N'UIEFR 0" ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBE R OF ANIMALS NECROPSIED 

B-4 
TABLE Bl (CONTINUED) 

LOW DOSE HIGH DOSE
 CONTROL (UNTR ) CONTROL (UNTR ) LOW COSE HIG H DOSE 

05-0030 05-0077 05-0031* 05-010 3 

S:; opjAss 

*riARDEPIA H GLAti P (1»6) (U6 ) (50) (50) D A?ILLAR Y CYbTADENOKA , NO S 1 (2J) 1 (2% )

 

*t-Ht, CANA L (U6) (U6) (50) (50)
 

SJUAIQnS CELL CAICINOIA 1 (2%)
 

Ma^CULnbKELI" rAL SYS"1"! 

fON F 

BODY CAVITPS 

HONE
 

ALL lThE- jYSTFMS
 

^o^"
 

ANIMAL DISPOSITION SUGARY
 

ANIIfLS INITIALLY IN STUDY 50 50 50 50
 

NATURA L DEATH* 1 7
 

lO^tlPIj'ND SACRIFIC E 1 1 

SCHECULED SrtCKIFICE 5 5 5
 

ACCIDENTALLY KILLED 3
 

Tr=MI K l A L SACBIFIC ^ «1 37 49 «5 

ANICA L M 

* HU M PEE 0 " AM1AL C fcI TH nSSUE ^XAIIND D HIC ROSCOPICALL Y « NJ"3=: F OF ANIMAL S N3CPOPSIE D 

3-5 
TABLE Bl (CONCLUDED) 

LOW DOSE HIGH DOSE CONTRO L (UNTE ) CONTRO L (UNTR ) LOW DOSE HIGH DOSE 

05-0030 05-0077 05-003U 05-0103 

TUMOR SUMARY
 

TOTAL ANIMALS WITH PRIMARY TUMOPS* 19 21 30 15
 

TOTAL PRIMARY TUMORS 26 25 37 19
 

TOTAL ANIMALS HUH BENIGN TUMORS 17
 

TOTAL BSNIGN TUMORS 19
 

TOTAL ANIMALS WITH MAIIGSANT TUMORS 16 15 16 12
 TOTAI MALIGNANT TUMORS 19 17 17
 

TOTAL ANIMALS KITH SECONDARY TUMORS* 1 1 1
 

TOTAL SECONDARY TUMORS 1 1 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT 1
 

TOTAL UNCERTAIN TUMORS 1
 

TOTAL ANIMALS KITH TUMORS UNCERTAIN-


PalBAFY OP. MTTAS^ATIC
 

TOTAL OSC^/TAIF TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

» SECCND»PY TUMORS: METASTHTIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

B-6
 
TABLE B2 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

TREATED WITH 4-NITROANTHRANILIC ACID 

LOW DOSE HIGH DOSE CONTRO L (UNTR ) CONTRO L (UNIR ) L OW COSE HIGH DOSE 

06-0030 06-0077 06-0031 06-0103 

ANIMAL S INITIALL Y I N STUD Y 5 0 50 50 50 

ANIMAL S MISSIN G 3 

ANIMAL S NECFOPSIE D 1 7 16 42 19 

MII1ALS T-XMINE D "IISTOPATHOLOGICALLY* * 17 16 11 48 

INTZG'JM^NTAR Y SYST'P 

*SKIS (47 ) (16) (12) (19)

SQUAMOU S CFLL F1PILLOM A 1 (2X ) 

"IBBCSHSCOB A 2 (1%) 

*SU3CUI TISSU E (17) (16) (42 ) (19)

H'llA.NGIOSAFCOil A 1 (2*) 

RESPIRATOR Y SYSTF M 

tL'JNT (46) (15) (11) (18) 

CARCINOMA , NOS, METASTATI C 1 (2%) 

ALVF1LA8/BFOSCHIOLA R ADENOS A 1 (21) 5 (12*) 1 (2X) 

ALVECUVBBONCHIOLA R CARCINOM A 1 (2X) 

HEMATOFCIITIC SYSTF M 

*KHLTIPt ; ORGAN S (17) (46) (12) (49) 

MALIGNAN T LYMPHOMA , NOS 2 (41) 3 (7S) 

J1ALIG.LY'"PHOMA , UNDIFF£R-TYE S 1 (2X) 

MALIG . LYMPHOMA , LY.1PHOCYTIC TYP E 1 (2*) 

MAIIG.LY1PHO"A , HISTIOCYTIC TYPE 2 (IX ) 6 (13% ) 5 (10X) 

MALIGtHN T LY1PHOMH , MIXE D TYPE 3 (7X) 1 (2H) 

LYMPHOCYTI C LEHKEII A 1 (2%) 

• SPLE3 N (15) (13) (39) (18) H-MANGIOSAFCOM A i (21) 1 (3X)

 

*nESESTEni C L. NOD " (27) (11) (38) (12) 

1ALIGNAN T LYMPHOKA , MIXE D TYP E 1 <3X ) 

tLIVF R (16) (15) (41) (17) 

* SU133>? O F ANIMAL S JIT H TISSU E EXAMINE D MICROSCOPICALL Y 

* NU13" ? OF ANIMAL S NECROPSIE D 

**EXCLUDES PARTIALLY AUTOLY2&U ANIMALS 

B-7 
TABLE B2 (CONTINUED) 

LOW DOSE HIGH DOSE •—— —— CONTRO L (imR) CONTROL (UNTH ) L O U DOSE HIGH DOSE 

06-0030 06-0077 06-0034 06-0103 

*PEY-;RS PATCH (45) (43) (40) (45) 

"IALIG.LYMPHOMA , HISTIOCYTIC TYPE 1 (2% ) 

((KIDNE Y (45) (43) (41 ) (47) 

MALIG.LYKPHOMA , HISTIOCYnC TYP E 1 (2*) 

•THYHU S (21) (27 ) (37 ) (37) It.LIG. LYMPHOMA , LYMPHOCYTIC TYPE 1 (3%) 

CIRCULATOR Y SYSTE1 

DIGESTIV E SYSTE M 

*LIV2 S

C\RCII:MA , NOS , M-:TASTATIC (46 ) 1 (2% ) (45) (41 ) (47) 

HEPATOCELLULA R 'iDTHOM A 1 (2J) 

HtPATOJELLULA R CARCINOM A

HEMAN"IOSARCOM A 

4 (9% ) 4 (9i) 

1 (2*) 

1 (2S) 

• STOKAC H (45 ) (42 ) (40 ) (47) SC'OAMO'J S J"LL PAPILLOM A 3 (7%) 3 (8*) ^DE N OCA PC I NONA , NOS 1 12%) 

URISArt Y SYSTP1 

• UPIKAH Y 3HrrFB (42 ) (41) (39) (43) 

HEMANGIOSABCOM A 1 (23) 

EN50CFIN " SYSTE M 

«?ITUITA? Y

^D~NOm , SOS

 (37 ) 

3 (8X ) 

(37) 

b (16% ) 

(36) 

3 (8%) 

(40) 

CFROMOPHOB E ADStiOM A 1 (3X ) 

BASOPHI L ADENOM A 1 (3X) 

*ADPF!)A L

C03TIC\L ADENOM A 

 (44 ) (43 ) 

1 (2%) 

(i»0 ) 

2 (5X) 

(47) 

» Tri v o 1 I D

PAPILLAR Y CYSTiDENOHA ^ JJ2^ 

 (44 ) (30) (37) 

J LiSJ „ .

(42) 

1 (2*1 ... 

# N"J1B3H n' AMRAL J KIT H TISSU E EXAMINE D MICROSCOPICALL Y 

* K'JBB^ e O F ANIMAL S NECROPSI^ D 

B-8 
• PANCREATI C

 ISLET S 

ISLET-CrL L ADENOM A 

REPRODUCTIV E SYSTE M 

• MAMMAR Y GLAN T 

ADENCCARCINOBA , NO S 

?IBSnAD3HOB A 

• UTERU S 

ENDOMF'BIA L STJOMA L TOLY P 

#OTESUS/E'«DOMETSIU, 1 

CARCINOMA , MOS 

*OVA?,Y/CVIDUC T 

PAPILHR Y ADENOM A 

INTrAD'ICTA L PAPILLOM A 

*OVA D Y 

LUTEOM \ 

TU9IJLA? . ADZN0.1 A 

HEMANtUOI A 

NERVOU S SYSTEM 

SPECIA L SEISE ORGAN S 

*EA R CUNA L 

SJUABOO S CELL CARCINOM A 

PIUSCULOSKELET^ L SYSTE M 

NOM E 

BODY CAVITIES 

*ABDCMINA L CAVIT Y 

» NUMBE R Of ANIMAL S WIT H TISSU2

* NUMBE R 0 ? ANIMAL S NECROPSIE D 

TABLE B2 (CONTINUED) 

LOW DOSE HIGH DOSE CONTRO L (UNTR ) CON TROL (UNT3 )

06-0030 06-0077

(39 ) (41)

1 (2X ) 

(1*7) (46 )

1 (2%) 

1 (21 ) 

(43 ) (43)

1 (21)

(43) (43 )

1 (2« ) 

(43 ) (43 )

1 (2».) 

1 (2*) 

(44 ) (41 )

1 (2« ) 

(47) (46 )

(47 ) (46)

 EXAMINE D MICROSCOPICALL Y 

B-9 

 LOW DOSE HIGH DOSE 

 06-0031* 06-0103 

 (41) (43) 

 (42 ) (49) 

 (40) (46) 

1 (3*) 2 (4«) 

 (40 ) (46) 

 (!*0) (46) 

 (J9 ) (44) 

1 (3%} 1 (2% ) 

1 (2% ) 

 (42 ) (49) 

1 (2%) 

 (42 ) (49) 
TABLE B2 (CONCLUDED) 

LOW DOSE HIGH DOSE CONTRO L (UUTE ) CONTRO L (UHTR ) LO B EOS'! HIGH DOSE 

06-5030 06-0077 Oh-003 U 06-0 103 

A LL OTHES SYSTEi-.S 

MOM " 

ANIMA L riSECSITlO N S'J*!MAK Y 

ANI1AL 3 INITIALL Y I N STOnY 50 50 50 50 

MAT'J^A L DEATH S 5 8 10 9

 

10^13'JMD SACRIFIC E 1 2

 

SC-^D'JLEr SACRIFIC E 5 5 5

 

ACCIDENTALL Y KILLE D 

TFSMIN'A L SACEIFIC E 39 3 D 37 36

 

ASI1AL MI?SIN~ , 3 

it INCLUDF s A'TTOLYIE D ANIMAL S 

TIJiiO B SUMMAR Y 

WTBL 8NTXAL S WIT H PSIMABY TUKOPS * 17 22 18 18 

TOTA L PPIflAP Y "UMOP S 21 32 25 20 

TD'A L ANIMAL S '.ITU BrnlG N TU1C3S 7 1/ 12 7 

TOTA L BENIG N TUMOR S 8 13 18 7 

"i"1 A I. f)I1«LS WIT H 1AII-3NAN T TUflOSS 1 1 13 7 12 

TOTA L 1»LTRNA,' T T'JIOES 13 19 -* 13 

TO"H L ANI1A1 ? VIT A STCONDAR Y TUMORS * 1 

"1TAL ;rCOt,DAF Y T'JUOR S 2 

TJTia SNTIAL 1 : WIT H TUMOR S UNCERTHIN ­

3"NI^ N O R MALIJKAV T 

TOTA L 'JNCrRTUT * T'JMOR S 

TOTA L AMIMAL S WIT H TUMOR S UNCERIAIN ­

PRT«AF Y O B METASTATI C 

TOT A L JSC^PTAI N T'JMOR S 

* PPIMAP Y TUMOFS : ALL TUMOR S EXCEPT SECONDAR Y TIJHORS 

* S^CONOAR Y Tl'MORS : METASTATI C TUMOR S O R TUMOR S INVASIV E INT O A N ADJACEN T ORGA N 

B-10 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH 4-NITROANTHRANILIC ACID
 

TABLE Cl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

TREATED WITH 4-NITROANTHRANILIC ACID 

~—• LOW DOSE HIGH DOSE CONTRO L (UNTR ) CONTRO L (UNTR ) L OU DOSE HIG H DOSE 

01-0030 01-0084 31-0034 01-0104 

ANIMAI S INI-HLL Y I N STUD Y ^0 25 50 50 

ANIMAL S MISSIN G 2 

ANIMAL S NECROPSIF D 4 6 25 46 48 

ANIMAL S IXH1INF D H I STO PATHOLOGICALLY* * 45 25 1*4 M R 

IN"E'5 IJM' rN ' T 'AR Y SYST^ r 

*S<I N (46 ) (25 ) (46 ) (48) 

5 BSC^ S ^ , NO S 2 (4X ) 

prgctn^Tc ; 1 (2% ) 2 (4% ) 

N ' T - 1CRGS T S , NO S 1 (4J) 

*S'J"Ci!T TIESU F (46 ) (25 ) (46 ) (48) 

TN*H""UTTC»I, PY03RANULOMATCU S 1 (2%) 

TLCIr 1 (2%) 

FI3STJS DYSPLASI A 1 (2S ) 

n

ES = Tf (\TORf SYSTEM 

'LARYN X (46 ) (25) (46 ) (48) 

TNFLAHMATIC N ACi>' T ' 2 AN D CHRONI C 1 (4« ) TNFLAf M »TION, CMRONI C 7 (28X) 5 (10%) 

»T^CH- A (45 ) (11 ) (42 ) (8)

 

IN"LA(1HTICN , NO S 1 (9X )

 LYMPHO;YTI C IMFHB»ATO D Y INFILTR 2 (41)

 INFLAM1STICN , ACUTE/CHHOM C 2 4 (53S) 30 (7U) 

M t:TMAPIASIA , Sj'JAMOU S 1 (2%) 

*LJNJ/SanMCHU S (45) (25) (44) (1*7) 

aRONCHI'CTHbl S 2 (8*) 1 (2*) 

INFLAMMATION , FOCA L 1 (4S) 

INFLAMMATION , ACUT E 1 (2%) 

LYMPrtQI D 

(45) (25 ) (44) (47) 

BF3NCHIOLT CTHSIS 1 (2*) IY1FHOCYTIC INFLAM1ATORY INFILT1 5 (11%) 

* N'Mprc j 0' ASIt.AL S WIT H TISSUE EXAMINE D MICROSCOPICALL Y 

* NJ1BE1 ' OF A'lIIAL S NECROPSIE D 

**tXCLUDEb PARTIALLY AUl'OLYZED ANIMALS 

C-3
 
TABLE Cl (CONTINUED) 

LOW DOSE
 CONTROL (UNTR)
 mw(o«TR,
 01-0030 01-0081
 

HYFEBPLASIA, LYMPHOID 6 (13X)
 

• LUNG (15 ) (25)
 

EMPHYS1FA, NOS 1 (2%)
 ATM3L3CTASIS 1 (2'.)
 EDHMA, NOS
 

BF1NCHOPNEUKONIA, SOS
 

INFLAMMATION, FOCAL
 

INFLAMMATION, INTERSTITIAL t* (9%) 2 (8%)
 

BPONCHOPNEUKONIA, ACUTE 1 (1«)
 ABSCESS, NOS 2 (IS) 1 (IX)
 

PNEUMONIA, CHRONIC MURINE 11 (11%)
 

OEANULOMA , NOS 1 (IX)
 

Pf-HIVASCULITIS 5 <iix >
 ISFARCT, FOCAL
 

CALCIFICATION, FOCAL
 

HYP7BPLASIA, ADENOMATOUS 1 (2%)
 

HYPERPLASIA, ALVEOLAR EPITHELIUM 1 (2%)
 

METAPLASIA, SQUAMOUS
 

HEKATOPOIETIC SYSTEM
 

«B01E HARRO W 125)
 

HEMOR3HAG E 1 (2X)
 

FIBROSIS, FOCAL
 

KARYORRHEXIS 1 (2X)
 HYPERPLASIA, HEMATOPOIETIC H (9X) 2 (3%)
 

EEYTHROPOIFSIS 1 (2*)
 MY'LCPOIESIS
 

•SPLEEN	 (K 5) (25)
 CONGESTION, NJS 1 (2X)
 

P"3IARTERITIS
 

HEMOSIDEROSIS 1 C»X)
 HYPERPLASIA, HEM ATOPOinlC 1 (24) 1 (UX)
 HYPEEPLASIA, ERYTHROID 1 (K%)
 

HYPERPLASIA, LYMPHOID 1 (2X)
 HEMATOPOITSIS 1 (2X)
 

MYELCPOIFSIS 1 (2X)
 

•SPLENIC CAPSULE (25)
 

HEMOEEHATE 1 (2*)
 

fLYMPH NODE (11) (21*)
 

£14.
 

I NUMBER OF ANIMALS WITH TISSUE 2XAHISED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-4
 

LOW DOSE HIGH DOSE
 

01-0031 01-0101
 

1 (2X)
 

(11) (17)
 

1 (2X)
 

1 (2%)
 

1 <2X)
 

1 (2*)
 

1 (24)
 

13	 (28X)
 

1 (2*)
 2 (IX)
 

1 <2X)
 

(1*2) (U5)
 

1 (2%)
 

(i*U) (1*7)
 

1 (28)
 

(It) (17)
 

(38) (29)
 
TABLE Cl (CONTINUED) 

HIGH DOSE CONTROL (UNTR) CONTROL (UNTE) LOW DOSE HIGH DOSE 

01-0030 01-0084 01-003U 01-0101 

*S'JBMANDI3ULAF L.NOBE (<*1) (2t) (38) (29) 

HYFEBPLASIA, NOS 1 (3*) 

*MANDIBULAR L. NODE 

HYPERPLASIA, NOS {HD (2U) (38) (29) 

1 (3X) 

•LUMBAR LYMPH NODE (1*1) <2U) (38) (29) 

INFLAMMATION ACUTE AND CHRONIC 1 <3X) 

•MESENTFRIC L. NODE 

HYPEFPLASIA, NOS (41) (2H) (38) (29) 

1 (3X) 

(tTHYMUS (35) (22) (27) (33) 

HYPESPLASIA, EPITHELIAL 1 (3*) 

CIRCULATORY SYSTFM 

*HIARI 

THROMBUS, MURAL 

(1*5) (25) <(*U) (47) 

2 (4X) 

P"RIAPTERITIS 1 (<**) 2 (5*) PrHIVA3CULITIS 2 («) 

CALCIFICATION, FOCAL 10 (21X) 

•MYOCARDIUM (45) (25) (1*4) (47) 

INFLAMMATION, FOCAL 1 (2*) 

INFLAMMATION, INTERSTITIAL 5 (11*) INFLAMMATION, ACUTE/CHRONIC 3 (7*) 5 (11X) FIBROSIS 1 (2%) 2 (5X) 

FIBROSIS, FOCAL 1 (i*%) 6 (1UX) 

FI3ROSIS, DIFFUSE K (9X) 

DEGENERATION, NOS 13 (29*) 10 (UOX) 15 (32JS) 

•ENDOCARDIUM (U5) (25) (i*i*) (47) 

CALCIFICATION, SOS 3 (6*) 

•AORTA (46) (25) (i*6) (48) 

MEDIAL CALCIFICATION 7 (15X) 

CALCIFICATION, N05 5 (10*) 

CALCIFICATION, FOCAL 1 (I**) 

•CORONARY ARTERY (1*6) (25) (46) (48) 

MEDIAL CALCIFICATION 1 (2X> 

CiI,£IFICAlIONA NOS .__..• __«l_nlTr. , 2 (4X) 

* NUMEEP 0" ANIMAL S KITH TISSUE EXAMINED MICROSCOPICALLY 

* NU»1B?H Of ANIMAL S NLCROPSIED 

C-5 
TABLE Cl (CONTINUED) 

LOW DOSE

CONTRO L (UNTR )

 HIGH DOSE 

 CONTROL (UNTH ) L OW DOSE HIGH DOSE 

01-0030 01-0084 01-0034 01-9104 

*I1ESENTEPT C HFTEP Y 

TH"C1BTSIS , NO S 

1"DIAL CALCIFICATIO N 

CALCIFICA T ION , NOS 

(46 ) (25 ) (46 ) (18) 

3 (6% ) 

2 (4% ) 

4 (8X) 

DIGESTIV E SYSTE M 

•ALVEOLU S DENTALI S 

INFLAMMATION . ACUT ­

(46 ) (25) (16) (48) 

1 (2%) 

•PAPO'ir JLAN D 

INFLAMMATION , INTERSTITIA L 

(43 )

1 (2S) 

 (24 ) (10) (40 ) 

*S JB1AXIL1AR Y GLAN D 

HYPERPLJSIf , FOCA L 

(43)

1 (2S) ' (21) (10) (10) 

•LIVE R 

CONGESTION , NO S 

(15)

1 (2%) 

 (25 ) (44 ) (16) 

CONGESTION , CHFONI C PASSIV E 1 (4% ) 

INFLAMMATION , ACUT E FOCA L 2 (IS) 

CHOLAN",IOFIPROSI S 

PERIART-RITI S 

1 (4% ) 

1 (2« ) 

DEGENERATION , NO S 2 <4« ) 

DEGENERATION ,

DEGENERATION ,

 HYALIN E 

 FOSINOPHILI C 

1 (2i) 

5 (11% ) 

NTCPOSIS , FOCAI 

"1ETA10RPHOSI S FATT Y 

1

3

 (2? )

 (7? )

 1

 4

 (4*) 

 (16X) 

2 (5%) 

6 (14%) 2 (4% ) 

"YPEFPLASIA , HYPEPPLASIA ,

-1VPERPLASIP ,

 NODULA R 

 NO S 

 FOCA L 

1

8

 (2« ) 

 (131S) 

1 (2X ) 

28 (64%) 

KLIVER/CE'ITPILOBULA P 

DEGENERATION , .OS 

INFARCT , NO S 

(15) (25) (44 ) 

3 (7%) 

(16) 

1 (2% ) 

METAMCFPHOSI S FATT Y 1 (2J) 

•tLIVER/IEPITOCYTE S (45) (25) (44 ) (40 ) 

riYPE'PHSIf, FOCA L 6 (13<) 

*BIL ­ DUG" 1 

IN^LABMATION ,

INFLAMMATION ,

 N'OS 

 ACUTE/CHRONI C 

(46 )

5 (1H) 

 (25 ) (46 ) 

1 (2%) 

(48) 

_ HYPFRPL.ASIAx-HQS _ __, 1 1 I2.4SL 6 J24£l 28 (61%) ..________ „_,_„._ 

N'T." BE R 0" ANICfL S MI^ H TISSU E EXAMINE D MICROSCOPICALL Y 

Ii[]«B"i= O F ANIfAL S NECPOPSIE D 

C-6 
HYPERPLASIA , FOCAL
 

•PANCREAS
 

HEMOKH-HGIC CYST
 

INFLAMMATION, NOS
 

INFLAMMATION, INTERSTITIAL
 

INFLAMMATION, NEC80TIZIUG
 

INFLAMMATION , ACUTE/CHRONIC
 

PERIARTE3ITIS
 

ATROPHY , FOCAL
 

•PANCREATIC	 DUCT
 

HYP'RPLASIA, NOS
 

•PANCREATIC	 ACINUS
 

ATROPHY , NOS
 

ATROPHY, FOCAL
 

•ESOPHAGUS
 

INFLAMMATION , ACUT? TOCAL
 

•STOMACH
 

EPIDERMAL INCLUSION CYSI
 

PEHIAPT-RITIS
 

CALCIFICATION, NOS
 

CALCIFICATION, FOCAL
 

HYPERK"BAT OSIS
 

«GAST R IC MUCOSA
 

CALCIFICATION, 105
 

•PEY^RS PATCH
 

HYPERPLASIA, NOS
 

HYPERPLASIA , LYMPHOID
 

•JEJUNUM
 

HEMORRHAG E
 

TNFARC', NOS
 

lILEUf
 

PERIUPTSRITIS
 

HYP"RPLASIA, LYI'PHOID
 

•COLON
 

PAfiiSITISfl
 

# NUBB" R 0 " ANIM»L S WIT H TISSUE 

* NU1B" H OF !IN T MAL S (J2CROPSIE D 

TABLE Cl (CONTINUED) 

LOW DOSE
 CONTROL (UNTR) ci>{ft:R8LE

(UNTR)
 

01-0031 01-0084
 

(45) (25) 

1 (2^5) 1 (4%) 

1 (2S) 

2 (4%) 

(45)	 (25)
 

1 (4*)
 

(45) (25)
 

13	 (29X)
 

2 (4*)
 

(44)	 (25)
 

1 (2*)
 

(45)	 (24)
 

1 (4%)
 

1	 (2?)
 

(45) (24)
 

(45) (24)
 

2 <8S)
 

1 (2?)
 

(45) (24)
 

(45) (24)
 

(44)
 (24)
 

EXAMINE D MICROSCOPICALL Y 

C-7 

LOW DOSE
 

01-0034
 

7	 (15X)
 

(43)
 

6 (14K)
 

1 (2%)
 

(43)
 

(43)
 

2 (5S)
 

(43)
 

(43)
 

(43)
 

(43)
 

1 (2*)
 

(43)
 

(43)
 

1 (2%)
 

(38)
 

5 J1321.
 

HIGH DOSE
 

01-0104
 

(43)
 

1 (2%)
 

1 (2%)
 

5 (12%)
 

(43)
 

(43)
 

(36)
 

(46)
 

1 (2X)
 

3 (11)
 13 (39S)
 

(46)
 

1 (2%)
 

(45)
 

(45)
 

1 (21)
 

1 (2*)
 

(45)
 

1 (2S)
 

1 (2X)
 

(38)


i.JlJ]
 
TABLE Cl (CONTINUED) 

LOW DOSE CONTROL (UNTR) HIGH DOSE COSTEOL (UNTR) LOU DOSE HIGH DOSE 

01-0030 01-0084 01-0034 01-0104 

URINAR Y SYSTEM 

tKIDNEY (15) (24) (44) (17) 

CCNG'STIOI, NOS 1 (2S) 

GLOMT3JLONEPHHITIS, NOS 34 (76%) 5 (21%) 31 (70%) 

GLOMEPULONEPHHITIS, FOCAL 3 (7%) 

INFLAMATION, INTERSTITIAL 5 (11%) 2 (5«) 

P"^IAn7FRITI3 

Nt?HPOD ATHY 1 (4%) 

1 (2%) 

NE^HHOSIS, NOS 16 (67%) 11 (87%) 

CALCIFICATION, FOCAL 19 (40%) 

*KIDNEY/1EDULLA (15) (24) (44) (17) 

MULTTPL^ CYSTS 1 (2%) 

*KIDNEY/3LOMERULUS 

INFLAMMATION , MEMBRANOU S (15) 

9 (20%) 

(24) (41) (17) 

t'JFINUPY 3LADPER (14) (23) (43) (13) CALCULUS, NOS 3 (13S) 

INFLAMMATICN , ACUTE/CHRONIC 1 (2X) 

INCLUSION, CYTOPLASMIC 1 (2%) 

"NIQCSINT SYSTEM 

•PITUITARY 

CONGESTION, NOS (41) 

1 (2^) 

(21) (38) (33) 

HYPE5FHSIA, NODULA R 1 (3%) 

HYPERPLASIA, FOCAL 6 (14%) 3 (8%) 

HYpropLASIf, CHROMOPHOBJ-CELL 1 (3%) 1 (3%) 

*PI"-1IT*RY/BASOPHIL (44) (21) (38) (33) 

NODUL" 1 (5%) 

*AD"NAl 

FYPE3P1ASIA, NODULAR (45) (25) (43) 

3 (7%) 

(17) 

*ADaF'JAL J^RT^X 

NODU11: 

(45) 

1 (2J) 

(25) (43) (47) 

1 (2%) 

HYPERTROPHY, FOCAL 1 (4%) 

HYPEBPHSIA, NODULAR 1 (2%) 

HYPJRPLASIA, FOCAL 7 (16%) 3 (7») 

*AOFENA L 1EDULLA (45) (25) (43) (17) 

(2*1 

NtJJ1ETM R 0" 1NINAL S HITri TISSUE EXH1INE D MICROSCOPICALLY 

NIJ1PES O F ANIMAL S NECROPSIE D 

C-8 
TABLEC1 (CONTINUED) 

LOW DOSE CONTROL(UNTR ) HIGH DOSE CONTRO L (UNT8 ) L O W — — DOSE HIGH DOSE 

01-0030 01-0081 01-0031 01-0101 

HYPEF^LASIA , FOCA L 1 <9« ) 1 (2% ) 

K-HVP1I E 

t!LTIMO3SANChIA L CYS T 

MYP"E D LASIA , "OCAL 

4YPERPLASI A , C-C^LL 

(12) 

2 

1 

(5% ) 

(2% ) 

(23 ) (11) 

1 (2% ) 

(10) 

1 

2 

(3%) 

(5% ) 

*PA tU T H Y !Uir > 

HYPERPLASIP , HOS 

(32 ) (15 ) (26) (29) 

8 (28% ) 

tPANCHLATI C ISL C TS 

HYEEBPLASIA , KOS 

'YPEFPLASIA , FOCA L 

(15)

2 (IX ) 

(25 ) (13) 

1 

2 

(2% ) 

(5%) 

(13) 

BEP'i'lCUCTIV 1 ' SYSTE M 

*CHC«Aa Y GLAN D (146) (25) (46 ) (18) 

TALAC^OCiL " 1 (2% ) 

"YPtR=LASIA ,

LACTATIO N 

 HU N 3 (71) 3

7

 (12%) 

 (28% ) 1 (2% ) 

*DR^DniIA L GLAN D (46 ) (25) (46 ) (18) 

PE3CES- , HO C 2 (1«) 

tp^nSTSl " 

IS"LArTMA"I0 1 . , NC S 

INFLA11ATION , FCCA L 

INFLA"1A T IO'J, ACUT E 

:N'LM"1AT TON, PL'JT11 FOCAL 

TNFLAI"1A T IOK , PCUT"/CHRONI C 

D" J 

T r N rI :!H"ION , NO S 

A^riOP'IY , [vPS 

HYr'E 0 PLASIA , EPIT'^LIAL 

(15) 

1 

10 

4 

13 

2 

(2% ) 

(22% ) 

(97.) 

(29% ) 

(••I) 

(23 ) 

1 (1%) 

4 (17% ) 

(43 ) 

1 

6 

4 

3 

1 

(2% ) 

(11S) 

(9») 

(7% ) 

(2% ) 

(16) 

3 

1 

(7%) 

(2% ) 

PjaPB'LJSIA.

HYPERPLASIA ,

 PAtlLLA^ Y 

 AD^NOKWOU S 

2 

1 (1«)

(2S ) 

•SEMINA L V^SICL V 

flOlhi . NC S 

F1PE= D I. ASIf , e>AlILLA» Y 

(146) 

26 

1 

(57% ) 

(2« ) 

(25) 

1 (14%) 

(46) (148)

1 (2% ) 

*COA'5JLA'"ttl6 GLAN D 

UTROFhv , NC S 

(16) 

3 (7% ) 

(25) (16) (18) 

tIESTI S (15) (21) (43 ) (15) 

i51%l 

* N'J*3i;R

* NUI B : T

 11"

 0? 

 ANIMAL S «IT F UE r XAMINE D (II CPOSCOPICALLY 

C-9 
TABLE Cl (CONTINUED) 

—__ 

LOW DOSE HIGH DOSE CONTROL (UNTR) CONTROL (UNTR) L OW COSE HIGH DOSE 

11-OD30 01-0081* 01-003<t 01-0101* 

D^SENERATICN , NO S 37 (86X) 1 (2X) 

CALCIFICATION ,

AT.ROPHY , SOS 

 FOCA L 

1 (2*) 

l»

12

 (17X) 

 (50%) 

1 (2%) 

39 (87%) 

HYPOSPSRBATOG^N'SI S 5 (11*) 

HY'EPPLASIA , INTERSTITIA L CZL L 2 (S%) 8 (19*) 

ST3STIS/TJB-JL E 

D^GEN^ATION , NO S 

(U5 ) 

in (22%) 

(2K ) (t»3) (US) 

*FPIDICY1I S (16) (25) (i»6) (1*8) 

IM'LAHIATION , ACUTE/CHRONI C 1 (2%) 

N^PVOU S SYSTE M 

*E3AI N (U5 ) (25 ) (U3 ) (1*6) 

iriOBH<AG r 2 (9% ) 

CALCIFICATION , FOCA L 1 (U% ) 

*ChPr5RA L CGRT~ X (t5) (25) (1*3) (16) 

H r MC^"HAJ E 1 (2%) MALACI A 1 12%) 

»C""3ELL IB (U5 ) (25 ) (13) (1*6) 

IN'AKC : hEKOPPFAGI C 1 (2*) 

SPECIAL SFNSE ORGAN S 

* EY^ (K6 ) (25) (46 ) (1*8) 

SY^ECHIA ,

CATAPAC TM 

 POSTEFIO R 1 (27.) 

1 <2« ) 1 (2%) 

1 (2% ) 

*EYE/RE T I'J A (16) (25 ) (U6 ) <t8 ) 

OSTENTATION, NOS 1 (2%) 3 (6%) 

* rAP (146) (25 ) (U6 ) 0»8) 

I^TAELASIA , SQUAMOU S 1 (2*) 

MUSC'JLOSKFL"!'! SYSTE1 

*SKt'L;HL (U6 ) (25) (46 ) (U8) 

____ C A L.C.JfIC. A1IQ SU_FO 

* N'JMB'R 0° ANIMAL S WITH TISSUE EXAIIN^D MICROSCOPICALLY 

* NU1B33 OF ANIMAL S NECROPSIED 

C-10 
TABLE Cl (CONCLUDED) 

LOW DOSE HIGH DOSE
 CONTRO L (UHTR ) CONTRO L (UNTR ) LO S DOSE HIGH DOSE 

01-0030 01-0081 01-003U 01-0101 

BODY CAVITIES
 

*M3SENTERY (16) (25) (16) (U8)
 

PERIARTSRI7IS 3 (6%)
 

ALL OTHEP SYSTEMS
 

ADIPOSE IISSU2
 

NECROSIS, NOS 2
 

INFLAMMATION, ACUTE/CHRONIC 1
 

NFCFOSI?, FOCAL 2
 

SPECIAL PORFHOLOGY SUMMARY
 

ANIMA L MIESING/NO NECROPSY 2
 

"UTO/NECROPSY/KISTO PEPF 1
 

«,UTO/S!CROPSY/NO HISTO 1 2
 

AUTOIYSIS/NO NECROPSY 1 2 2
 

# MU1B"E 0? ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUHB'R 0" ANIMALS NECROPSIED
 

C-ll
 
TABLE C2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

TREATED WITH 4-NITROANTHRANILIC ACID 

— LOW DOSE HIGH DOSE ———-—— CONTROL (UNTR ) CONTROL (UNTR ) L O U EOSF. HIGH DOSE 

02-0030 02-0084 02-0034 02-0104 

ANIMAL S INITIALL Y I N STUD Y 5fl 25 50 50 

ANIMAL S NSCP.OPSIID 48 23 H6 46 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY * 1,7 23 45 45 r*

INTF5UMFNTARY
 

*SKI N (43) (23) (46) (46)
 

"IBPOSIS 1 (2%)
 

RESPIRATORY SYSTEM
 

'LARYNX (48) (23) (46) (46)
 INFLAMMATION ACUTE AND CHRONIC 1 (4X)
 

INFLAMMATION, CHRONIC 3 (13%)
 

KTRACHF A (47) (5) (45) (5)
 LYMPHCCY^IC INFLAMMATORY INFILTR 4 (9*)
 

INFLAMMATION, ACUTVCHRONIC 18 (38%) 24 (53«)
 

INFLAMMATION, CHRONIC 2 (4X)
 

POLYP, INFLAMMATORY 1 (2X)
 

ILUNG/ERONCHUS (47) (23) (45) (43)
 

BRONCHIECTASIS 2 (4*) 3 (7X)
 INFLAMMATION, NOS 1 (2*)
 INFLAMMATION, ACUTE FOCAL 1 (2X)
 INFLAMMATION , CHRONIC 1 (2X)
 PIBROSIS 1 (2*)
 

KLUNG/EFONCHIOL E (47) (23) (45) (43)
 IN"LAP.MATICN , NOS 4 (9>!)

 

LYMPHOCYTI C INFLAMMATOR Y INFILTR 7 (151) 

INFLAMMATION , ACUTVCHRONIC 5 (1 1JS) 

HYiERPLASIA , LYMPHOI D 2 (4?) 

*LON G (47 ) (23) (45) (13)
 rlDEMA , NO S 2 (4X)
 

TNFLAMMATION, FOCAL 4 (9*)
 

« NUMBF P 0" ANIMAL S KIT H TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBE R O F ANIMAL S N^CROPSIE D 

**EXCLUDES PARTIALLY AUTOLY^ED ANIMALS 

C-12
 

3 
TABLE C2 (CONTINUED) 

.—— LOW DOSE HIGH DOSE -—• — 

CONTRO L (UNTR) 

02-0030 

CONTRO L (UNTR ) 

02-0081 

L OW DOSE 

02-0031 HIGH DOSE 02-010K 

PNEUMONIA , CHSOHIC MURIN E 8 (35%) 20 (47X) 

GRANULTMA , NO S 1 (2%) 

INFLAMMATION , FOCA L GRANULOflATO O 1 (2X) 3RANULOMA , FORFIG N BODY 1 (IX) 

"I3RCSIS, DIFFUS E 

OFRIVASCULITI S INFAPCT , FOCA L 

15 (32*) 

1 (2X) 

1 (2%) 

1 (2X) 

CALCIFICATION , FOCA L 1 (KX ) 20 (K7%) 

HYPEBPLASIA , EPITHELIA L 1 (IX) 

HYPE3PLASIA , ALVEOLA E EPITHELIU M 1 (2%) 

*L<JNG/AIV;OLI (23) (US ) (43) 

SPITHELIALIZATION 1 (2X) 

lC SYSTEM
 

*BONF MAFPOW (K7) (22) (13) (12) 

HYPCELASIA, NOS 1 

OSTEOSCLEROSIS 16 (38X) 

1V3LCFI3EOSIS 1 (2X) 6 (11%) 

HYPERPHSIA , HErATOEOIETI C 1 (21) 2 <5X) 

#SPLEE N (17) (23) (15) (K3) 

CONGTSTION, NOS 1 (2%) 

HEUATOIH, NOS 1 (KX) INFLAMMATION, ACUT" 1 (2X)
 CALCIFICATION, NOS 6 (11X)
 

2 (9X) 2 (IX) 

HYPERPLASIA , HEMATOFOIETIC 3 (13%) 3 (7X) 

HYPFPPL\SIA , EPYTHROI D U (17X) 3 (7X) HFMATOPOIESI S 2 (US) 3 (137.) 

*UIKBA R LYMP H NOD E (K2) (21) (39) (28) 

LYMPHANGIECTASI S 1 (3X) 

*BESENTEf<I C L . NOD E (U2) (21) (39) (28) 

H"BORRHAG E 1 (3*1 

*THYMUS (36) (20) (31) (35)
 

ATROPHY, SOS 3 (9X)
 

CIRCULATORY SYSTEM
 

(47)	 (23) (45) (43)
 

3(7% )
 

# NUMBER OF ANIMAL S WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMAL S N3CROPSIED
 

C-13
 
TABLE C2 (CONTINUED) 

— ~— _—­— —.—_ ——.— ­. wTMTM—m __. 

cbNTR^MUNTR) ^NT^flUNTB) LOW COSE HIGH DOSE 

02-0030 02-0084 02-0034 02-0104 

PESIART^RITIS 2 (M) 

PERIVASCULITIS 1 (2X) 

CALCIFICATION, FOCAL 24 (56X) 

HYPERTROPHY, NOS 1 (2«) 

(•MYOCARDIUM (47) (23) (45) (43) 

INFLAMMATION, FOCAL 1 (2X) 

INFLAMMATION, INTERSTITIAL 1 (4X) 

INFLAMMATION, ACUTE/CHRONIC 2 (4*) 6 (13X) 

INFLAMMATION, CHRONIC FOCAL 2 (4X) 

FIBROSIS, FOCAL 1 (2X) 

FIBROSIS, DIFFUSE 1 (2X) 

DEGENERATION, NOS 2 («*) 4 (17*) 27 (63X) 

CALCIFICATION, FOCAL 1 (2*) 

•ENDOCARDIUM (47) (23) (45) (43) 

INFLAMMATION, ACUTE/CHRONIC 3 (6%) 

• AORTA (48) (23) (46) (46) 

MEDIAL CALCIFICATION 22 (48X) 

CALCIFICATION, NOS 1 (2%) 

•CORONARY ARTERY (48) (23) (46) (46) 

CALCIFICATION, NOS 18 (39X) 

•PULMONARY ARTERY 

CALCIFICATION, NOS 

(48) (23) (46) (46) 

1 <2X) 

CALCIFICATION, FOCAL 1 (2X) 

•MESENTERIC ARTERY (48). (23) (46) (46) 

MEDIAL CALCIFICATION 1 (2X) 

CALCIFICATION, NOS 4 (9X) 

DIGESTIVE SYSTEM 

tSALIVARY GLAND (46) (22) (43) (38) 

CALCIFICATION, NOS 5 (13%) 

CALCIFICATION, FOCAL 1 (3X) 

*LIVR (47) (23) (45) (43) 

CONGESTION, CHRONIC PASSIVE 1 <4X) 7 (16X) 

HFMORRHAGS 1 (2X) 

INFLAMMATION, FOCAL 1 (2X) 

INFLAMMATION. ACUTE EQC.AL. ,JJUri -(2S1 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

• NUMBER OF ANIMALS SECROPSIED 

C-14 
TABLE C2 (CONTINUED) 

._.._._.._____ 

LOW DOSE CONTROL (UNTR) 

02-0030 CONTROL (UNTR) 02-008U LOW DOSE 02-0031 

HIGH DOSE 

02-0104 

SCLEROSIS 

CHOLANGIOFIBFOSIS 

P5RIVASCULITIS 

NECROSIS, FOCAL 

NECROSIS, COAGULATIVE 

METAMORPHOSIS FATTY 

3ASOPHILIC CYTO CHANGE 

HYPERTROPHY, NOS 

HYPERPLASIA, NOS 

HYPESPLASIA, FOCAL 

HYPERPLASIA, DIFFUSE 

1 (2%) 

1 (2%) 

1 (2%) 

1 (2%) 

4 (9%) 

1 (2X) 

1 (2*) 

21 (05%) 

1 (2X) 

1 (IX) 

2 (9X) U (17%) 

3 (13X) 

1 <2X) 

1 (9%) 

1 (2%) 

26 (58%) 

5 (12%) 

2 (5%) 

*LIVFR/CSNTRILOBULAR 

NECROSIS, NOS 

METAMORPHOSIS FATTY 

(47) (23) (45) 

2 (<•*) 

1 (2%) 

(13) 

tLIVER/HFPATOCYIES 

HYPFBPLASIA, FOCAL 

(47) 

2 («*) 

(23) (it5) (13) 

*BILE DUCT 

INFLAMMATION, ACUTE/CHRONIC 

INFLAMMATION WITH FIBROSIS 

HYPERPLASIA, NOS 

HYPEHPLASIA, FOCAL 

(K8) 

1 (2%) 

1 (2%) 

4 (8%) 

(23) 

2 (9%) 

(46) 

2 (4%) 

2 (4%) 

(16) 

tPANCFEAS 

INFLAMMATION, INTERSTITIAL 

INFLAMMATION, ACUTE/CHRONIC 

CALCIFICATION, NOS 

ATROPHY, NOS 

ATROPHY, FOCAL 

(16) 

2 (it*) 

1 (2«) 

(22) (4U) 

7 (16%) 

1 (2%) 

(39) 

3 (8%) 

tPANCREATIC ACINUS 

DEGENERATION, GRANULA R 

ATROPHY, NOS 

ATROEHY, FOCAL 

(U6) 

1 (231) K (9%) 

1 (2J) 

(22) (44) 

1 (2%) 

5 (11%) 

(39) 

•STOMACH 

•JLCEF, NOS 

INFLAMMATION, ACUTE 

REACTION, "OPEIGN BODY 

CALCIFICATION, FOCAL 

(46) (23) (14) (13) 

3 (7X) 

1 <2X) 

1 (2%) 

22 (51%) 

IGASTRIC MUCOSA (46) (23) (41) (13) 

6(11%) 

t NU1BES OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBE R OF ANIMALS NECROPSISD 

C-15 
TABLE C2 (CONTINUED) 

__^ 

—— , ,_ 

LOW DOSE HIGH DOSE CONTRO L ('INTR) CONTRO L (UNTB ) L O U DOSE HIGH DOSE 

02-0030 02-0084 02-0034 02-0104 

tSKJAL L INTESTIN E (47 ) (23) (42 ) (39)

 

GRANULONA , NO S 1 ( 3 %)

 

HYPE8PLASIA , LYMPHOI D 1 (2% ) 1 (3%)

 

tPEYER S PATC H (47) (23 ) (42 ) (39) 

*COLCN (46) (22) (41) (32)
 

ULCER, FOCAL 1 (255)
 

NEMATODIASIS 1 (3%)
 

PARASITISM	 2 (9?) 7 (17X)
 

CALCIFICATION, FOCAL	 1 (30
 

URINAR Y SYSTEM
 

fKIDNEY (47) (23) (45) (45)
 

FOREIGN BODY, NOS 1 (2%)
 

GLOMERULON^PHRITIS, NOS 32 (68%) 4 (17%) 12 (27%)
 

GLOMESULONFPHRITIS, FOCAL 1 (2%)
 

INFLAMMATION, INTERSTITIAL 2 (435) 3 (7%)
 

PYELONEPHRITIS, ACUT' 1 (4%)
 

PNEUMONIA, CHRONIC MURINE 1 (2%)
 

1LOMF.FULONFPHRITIS, CHRONIC 1 (21)
 

PYELONEPHRITIS, CHRONIC 1 (4%)
 

NEPHROSIS, NOS 10 (43X) 40 (89%)
 

CALCIFICATION, FOCAL 1 (4%) 26 (58X)
 

•KIDNEY/CORTEX	 (47) (23) (45) (45)
 

CYST, NOS 1 (21)
 

HKI3NFY/GLOMERULUS (47) (23) (45) (45)
 

INFLAMMATION, MEMBRANOUS 7 (15%)
 

ttKIDNEY/TUBULE (47) (23) (45) (45)
 

NFCRCSIS, NOS 1 (4»)
 

HKIDNiY/PFLVIS (47) (23) (45) (45)
 

INFLAMMATION.. ACU.T,S./C.HRQN1;C. J (22J
 

* NU1BSR OF ANIMAL S UITH TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBE E O F ANIMAL S NECROPSIE D 

C-16 
TABLE C2 (CONTINUED) 

LOW DOSE HIGH DOSE CONTROL (UNTR ) CONTROL (UNTR) 

02-0030 02-0081 

FNDOCRINE SYSTEM
 

(PITUITARY (16) (21)
 MINERALIZATION
 

CYST, NOS
 

HEHORRHAGIC CYST 1 (5X)
 NECROSIS, FOCAL 1 (2X)
 

HYPERTROPHY, FOCAL 1 (2%)
 

HYPERPLASIA, NOS
 

HYPERPLASIA, FOCAL 6 (13*) 1 (5%)
 

IADRFNAL (17) (23)
 METAMORPHOSIS FATTY 1 (2*)
 

HYPERPHSIA, NODULAR
 

HYPERPLASIA, FOCAL 1(2%)
 HEMATOPOIESIS
 

#ADRENAL CORTEX (17) (23)
 

HEMORRHAGE 2 (IX)
 

10DULE 4 (9X)
 

DEGENERATION, NOS 2 (IX)
 

NECROSIS, FOCAL 1 (2X)
 

METAMORPHOSIS FATTY 1 (2X)
 

PIGMENTATION, NOS 1 (2X)
 

HYPERPLASIA, NODULAR 1 (2X)
 HYPERPLASIA, FOCAL 9 (19X)
 

*ADPENAL MEDULLA (17) (23)
 HYPEPPLASIA, NODULAR 1 <2X)
 HYPERPLASIA, NOS
 

HYPERPLASIA, FOCAL 2 (IX)
 

*THYROID (45) (21)
 ULTIMOBRANCHIAL CYST
 

HYPERPLASIA, FOCAL
 

HYPERPLASIA, C-CELL 3 (11X)
 

tPARATHYROID (28) (9)
 HYPEEPLASIA, NOS
 

REPRODUCTIVE SYSTEM
 

*HArMAR Y GIAN D (18) (23)
 

P-IliI&!IQlUflBCI5 

HBHBFH OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

NUMBER OF ASIKALS NECROPSIED
 

017
 

L OW DOSE 

02-0031 

(11)
 

1 (2X)
 

1 <2X)
 

1 (2X)
 

(4U)
 

5 (11X)
 

1 (2%)
 

1 (2X)
 

1 (2X)
 

(11)
 

2 (5%)
 

(11)
 

(11)
 

2 (5X)
 

(28)
 

(16)
 

1 (9X)
 

HIGH DOSE 

02-0104 

(31)
 

(15)
 

(15)
 

(15)
 

3 <7X)
 

(3B)
 

2 (5X>
 

3 (8X)
 

(31)
 

21 (68X)
 
TABLE C2 (CONTINUED) 

LOW DOSE HIGH DOSE CONTROL (UNTR) CONTROL (UNT8) LOH DOSE HIGH DOS'! 

02-0030 02-0084 02-0034 02-0104 

GALAC't'OCELE 6 (13%) 1 (4%) 4 (9%) 1 (2%) 

INFLAMMATION, ACUTE 1 (2%) 

CALCIFICATION , FOCAL 1 (2%) 

HYPEPPLASIA, NOS 1 (2%) 1 (4%) 13 (28%) 

HYPSEPLASIA, 

LACTATION 

CYSTIC 1 (2ft) 9 (39%) 16 (35%) 

*MAFMAP Y DUCT (48) (23) (46) (46) 

FIBROSIS 1 (2%) 

*CLTTCRAL GLAND (48) (23) (46) (46) 

ABSCESS, NOS 1 (2*) 1 (2%) 

*VAGINA (48) (23) (46) (46) 

FOLYE 1 (2%) 1 (2%) 

»UT"RUS 

HYDROM=;TRA 

(46) 

2 (4%) 

(23) (43) 

6 (14%) 

(38) 

PYOMET3A 3 (13%) 4 (11%) 

tUTERUS/FNDOMETRIUM (46) (23) (43) (38) 

INFLAMMATION, NOS 1 (4%) 

INFLAMMATION, ACUTE 6 (13%) 18 (42%) 

INFLAMMATION, 

INFLAMMATION, 

ACUTE NECROTIZIN3 

ACUTE VESICULAR 

1 

1 

(2%) 

(2%) 

INFLAMMATION ACUTE AND CHSONIC 2 (5%) 

INFLAMMATION, ACUTE/CHRONIC 1 (2%) 

INFLAMMATION, CHRONIC 1 (4%) 

ATROPHY, NOS 1 (3%) 

HYPERTROPHY, 

HYPERPLASIA, 

NOS 

NOS 1

1

 (2%) 

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

HYPFRPLASIP , CYSTIC 7 (15%) 1 (4%) 6 (14%) 

HUTFRtlS/MYOMFTRIUK ABSCESS, NOS 

(46) (23) (-13) (38) 

1 (3%) 

•OVAPY/OVIDUCT (46) (23) (43) (38) 

RI-TFNTION FL'JID 1 (2*) 

INFLAMMATION , SUPPURATIVE 1 (2% ) 

INFLAMMATION, ACUTE 1 (2%) 1 (4%) 1 (3%) 

ABSCESS, NOS 1 (4%) 1 (3% ) 

INFLAMMATION, ACUT5/CHRONIC 1 (2%) 

tOVUH Y (47) (22) (43 ) (36 ) 

CYSTJ._NOS 

* NUMBE R O F ANIMAL S WIT H TISSUE EXAMINE D MICROSCOPICALL Y 

* NII1BE F O F ANIMAL S NECROPSIE D 

C-18 
TABLE C2 (CONTINUED) 

LOW DOSE 

CONTROL(UNTR ) HIGH CONTROL DOSE 

 (UNTH )

02-0030 02-0094

INFLAMMATION, ACUTE 

"ESCISS, NOS 

HYPIRPLASIA, NOS 

NERVOUS SYSTEM
 

• BRAIN/fiF , HINGE S (47) (23 ) 

INFLAMMATION, ACUTE
 

*PSAIN (47) (23) 

HYERCCEPHALUS, NOS 1 (4%) 

HFMOFBHAG F 1 <UX ) 

INFLAMMATION, SUPPURATIVE 

GLIOSIS 

MALACI A 

CALCIFICATION, FOCAL 1 (4«) 

SPECIAL SENSE 03GA>S
 

* EY F (48) (23)
 CATARACT 1 (2%)
 

(48) (23)
 

INFLAMMATION, NOS
 

"EYE/RETINA (48) (23)
 DEGENERATION, NOS 1 (2X)
 

*MIDELE EAR (48) (23)
 

INFLAMMATION, SUPPURATIVE
 

MUSCULOSKELEIAL SYSTEM
 

*3UP.SA (48 ) (23) INFLAMMATION, ACUTE/CHRONIC 

BODY CAVITIES
 

*MESENT"RY (48 ) (23) CALCIFICATION, NOS 

ALL OTHER SYSTEMS
 

__NONZ
 

» NUMBE R OF ANIMAL S WITH TISSUE 3XAHINED MICROSCOPICALLY
 

* NU1SF" OF ANIKALS HECROPSIF.D
 

C-19
 

 LOB COSE 

 02-0034 

(43)
 

(43)
 

1 <2X)
 

1 (2X)
 

1 <2X)
 

(46)
 

(46)
 

(46)
 

(46)
 

1 (2X)
 

(46) 

(46) 

HISH DOSE 

02-0104 

2 (6%)
 

1 OX)
 

(42)
 

2 (5%)
 

(42)
 

(46)
 

(46)
 

1 (2%)
 

(46)
 

(46)
 

(46) 

(46)
 

1 (2%)
 
TABLE C2 (CONCLUDED) 

LOW DOSE HIGH DOSE 

CONTROL (tJNTR) CONTROL (UNTR) LOW DOSE HIGH DOSE
 

02-0030 02-0081* 02-003U 02-0104
 

SPECIAL MORPHOLOGY SUMMAR Y
 

AUTO/NECBOPSY/NO HISTO 1 1 1
 

AUTOLYSIS/NO NECROPSY 2 2 1 4
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMAL S NECROPSIED
 

C-20
 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH 4-NITROANTHRANILIC ACID
 

TABLE Dl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

TREATED WITH 4-NITROANTHRANILIC ACID 

LOW DOSE HIGH DOSE CONTROL(UNTR ) COHTROL (UNTR) L0» DOSE HIGH DOSE 

05-0030 05-0077 05-0034 05-0103 

ANIMAL S INITIALL Y I N STUD Y 50 50 50 50 

ANIMAL S NECPOPSIE D 46 46 50 50 

ANIMAL S EXAMINE D HISTO PATHOLOGICALL Y ** 46 45 50 50 

INTEGUMENTAR Y SYSTE M 

*SKI M (46 ) (46) (50) (50) 

ULCER , NO S 1 (2%) 

INFLAMMATION , GBANULONATOU S 1 (2*) 

GRANTILTMA , PYOGFNI C 1 (2%) 

HYPERPLASIA , NO S 1 (2%) 

BESPIRATOR Y SYSTE M 

»LUNG/BROSCHU S (46) (45) (50) (50)

 

INFLAMMATION , "OCAL 1 (2X )

 

*LUNG/ERONCHIOL F (46 ) (45) (50) (50) 

METAPLASIA , N0 £ 1 (2*) 

tl'JNG (46) (45) (50) (50) 

EMPHYSEMA , NO S 1 (2*) 

HFMORPMAT : 1 (2% ) 

INFLAMMATION , INTERSTITIA L 7 (15«) 

ABSCESS , NCS 1 (2*) 

PNEUMONIA , CHRONI C HURIN E 4 (8X) 6 (12%) 

ARTERIOSCLEROSIS , NO S 1 (2*) 

tLUNfi/ALVSOL I (46 ) (45) (50) (50)

 

INFLAMMATION , NO S 1 (21)

 

HEMATOFOIETI C SlSl^t 

• SPLEE N (46 ) (45) (50) (49) 

CONGESTION , NO S 2 (^55)

 

FIBRCSI S 1 (2«)

 

» NUMBE R O F ANIMAL S WIT H TISSUE EXA1IN3 D MICHOSCOPICALtY 

* NUMBE R CF ANIMAL S NFCROPSIE D 

**hXCLUD£S PARTIALLY AUTOLYZED ANIMALS 

D-3 
TABLE Dl (CONTINUED) 

LOW DOSE HIGH DOSE CONTROL (UNTE) CONTROL (UNTR)

05-0030 05-0077

HYP^BELASIA , RLTICULU M CELL 3 (7%) 

HYPF.RPLASIA , LYMPHOI D 

HFMAIOPOIFSIS 1 (2X) 1 (2K)

CLYhFI l NOD E 

HFMCESHAG S 

HYF'BPMSIA , NC:; 

(34 ) 

1 (31) 

1 (3S ) 

(35)

• MANHEULA P L. 

HYPFBPLASIA , 

NOD E 

RFTICIILU M CELL (34 ) 

1 (3X ) 

(35)

*M::S"NTE D IC L. NOD F (34 ) (35)

TH^OKBISIS , 

HEMOKEHAG r N G S 1

1

 (3-? ) 

 (3i5) 

CIRCULATOR Y SYSTE M 

fillDOCARDIU M (11) 

INFLAMMATIO N PROLIFERATT VE 1 (2%) 

DIGESTIVE SYSTEM
 

•SALIVARY	 GLAND (37) (13)
 

CALC'JLUS, NOS
 

INFLAMMATION , CilSONIC
 

?"3IVASCULAB CUFFING 5 (14*)
 

tLIVR (46) (45)
 

INFLAMMATION, FOCAL 2 (4*)
 

INFIAC1ATION, NFCROTIZING 1 (2J)
 

INFLAMMATION, CHRONIC FOCAL
 

DEGENERATION, "03 1 (2*)
 NTCROSIS, FOCAI 2 (4%)
 

srcHosis, hmnrpHAsic 1 (24)
 

METHMORPHOSIS FATTY 8 (17S) 3 (7%)
 

HYPEPPLASIA, NOS 1 (2?)
 

HYPERPLHSIA, FOCAL 1 (2*)
 

HEMATOPOIESIS
 

•LIVEF/frSIFOFTAL	 (46) (15)
 

INFLAMMATION , NOS 1 (2%)
 

*3ILE DUCT	 (46) (46)
 

* NUMBE R Or ANIMAL S WITH TISSUE EXAMINSD MICROSCOPICALLY
 

* NUMBE R OF ANIMAL S NECROPSIED
 

D-4 

 L0« DOSE

 05-0034

 HIGH DOSS 

 05-0103 

1 <2X ) 

 (45)

 1

 (50) 

 (2*) 

 (45 )

 (45)

 (50) 

 (50) 

(50 ) (50) 

(19)

1 (2%) 

1 (2%) 

 (50) 

(50) (50) 

1 (2%) 

1 (2%) 

1 (2%) 

(50) (50) 

(50) (50) 
TABLE Dl (CONTINUED) 

LOW DOSE CONTRO L (UNTB )

05-0030

 HIGH DOSE COHT SOL (UNTR )

 05-1077

T_VMBP 0 CYTI< ­ IN"LAi1KATOB Y INFILT n 1 (2M 

apA'iCR'A .

CYST , 10S

'^LA-M^CN , »OLA L

I\FH M 'A T ION , I\"PS"ITIAL

:r"Hf"«A 1 '

TC N , ALlJT FJCA L

:"~LA"«A'~*OF , Cl'RJNI C FOC

HiPTRnLA^IA , TCAL

A L 

 (14)

 2 (54 ) 

1 (2'.) 

2 (5'.) 

 (i|it)

KPAN'CR f »TIC

A^ROfHV ,

 ^CT [ J=

 FrcA L

 (1414)

 1 (21) 

 (UU )

*STO»I1C' l

V";=TA3L r FO'"I1 4 30D^ T 'lFLAt"1AriOM, i>0 5

T I-FLA^^A^'CM , ACUT E

I'l^LA'IATION , 5HANULC^ATOU S 

q/prpoi^^^' i "FI"r'

h

i

T 'L''"AL

HYPT^p i n-^tA, FOfA L

HY?rp?LAS T A , AfNunATOU S

 (45 )

 2 («°S) 

1 (2'.) 

2 (U^ l 

2 (t? ) 

 (Hi )

 1 (21) 

» s UL L INTSTN:: •lYP^KiLASIA , LY","HOID (to ) (t3 )

• IL^Mr t h

l TRPL A 5I» , L •' iPHOI D 

(Hi) (1)3)

«CT^3' i (t1 ) (38 )

•H3ASITT3 1 

UPI>J A 'Y SY5T1"' 

*KID - :Y (ttb ) (U5 )

CAL C JL IS, \OS 20 (4tS) 

(jLCt1 rl''LOM? 1 iFIr^IS , NO S 2 (4^ ) 

J_C1- R JLCN~ t h"ITM:3 . FOCA L 1 (21) 

IN'HrlATIOh , TN^SRSTITIA L 7 (1555) 5 (11X ) 

INFLAIIl'IC1 !, c IRONI C 1 (2*) 

"Y"LC( CPH^ITjs, C1I°ONI C

I">FLA V 1A'"ICN , C-'IOMC FOCA L 

P-R1VAJCULITI3 2 (It*)
 

NE?"POPAThY


* MtJC3" R Of ANI1AL S S.ITH TISSJ ^ 'XAMIN^ D II IROSCOPICALL Y 

* NU1B- T O F ANIMAL S 'JECROPSIE D 

D-5 

LOtl COSE 

 05-0034 

 (50) 

1 (29!) 

1 (2%) 

 (50 ) 

 (50) 

 (50) 

1 (2%) 

 (50 ) 

 (49 ) 

 (50 ) 

1 (2%) 

HIG H BOS" 

05-0103 

(48) 

1 (2*) 

(t8) 

(50) 

1 (2?) 

1 (2% ) 

1 (2% ) 

(50) 

1 (2J) 

(50) 

1 (2% ) 

<t7 ) 

3 (6*) 

(50) 

1 (2%) 

1 (21) 

1 (21)
 
TABLE Dl (CONTINUED) 

— •• •—­ LOW DOSE HIGH DOSE
 CONTROL (UNTR) CONTROL (UNTH) LOW DOSE HIGH DOSE
 

'55-0030 05-0077 05-0034 05-0103
 

NEPHEOSIS, NOS 1 (2%)
 

"KYLOIDOSIS 2 (UX)
 HYPF.HPLASIA, TUBULAR CELL 2 (4%)
 

1"TAPHS!A, OSSEOUS 1 (2%)
 

#KIDNEY/TU3ULF (46) (45) (50) (50)
 

DEJENEPATION, NOS 1 (2X)
 METAMORPHOSIS FATTY 9 (20X)
 AT YFIA, NOS 1 (2*)
 

*KIDNEY/PELVIS (46) (45) (50) (50)
 

INFLAMMATION, ACUTE/CHRONIC 3 (7)5)
 

((URINARY BLADDER (46) (44) (50) (50)
 

HYPERPLASIA, EPITHELIAL 2
 <«*>
 

"URETHRA (46) (46) (50) (50)
 

CALCULUS, NOS 1 (2%)
 

ENDOCRINE SYSTEH
 

•PITUITARY	 (39) (36) (44) (39)
 

HYPEFPLASIA, "OCAL 1 <3X)
 

* ADR^NAl (44) (43) (50) (50)
 

ACCESSORY STRUCTURE 1 (2%)
 

N-CROSIS, FOCAL	 1 <2J)
 

•ADRTNAI/CAPSUL:	 (44) (43) (50) (50)
 

HYPEBPLASIA, NOS	 29 (5816) 29 (58X)
 

*AD"NAL COKTEX («4) (43) (50) (50)
 

PYPEPPLASIA, NOS 2 (5*)
 

HYPERPLASIA, FOCAL 14 (32%)
 

*PAP*THYniD (17) (18) (25) (19)
 

CYST, NOS 1 (6?)
 

REPRODUCTIVE SYSTEK 

•PROSTATE (46) (44) (49) (50) 

HYPERPLASIA, EPITHELIAL 1 (2%) 

*TESTIS/TUBULE 

DEGENERATION.. NOS 

(46) 

3 J7

'L 

(45) 

2 i4^J. _ 

(50) (50) 

u ..__.- • • r-

# NUMBER OF ANI1ALS WITH TISSUE EXAMINED MIC80SCOPICALLY 

0° ANIMALS NECROPSIED 

D-6
 
TABLE Dl (CONCLUDED) 

LOW DOSE HIGH DOSE CONTRO L (ONTR ) CONTRO L (UNTR ) LO W COSE HIG H DOSE 

05-0030 05-0077 05-0034 05-0103 

NERVOU S SYSTEM 

tBRAIN (46) (U5) (50) (50)
 

CALCIFICATION, FOCAL 9 (1(3%) 7 (14»,)
 

SPECIAL SENSE ORGANS
 

NON"
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

"ABDOMINAL CAVITY (46) (46) (50) (50)
 

STEATITIS 1 (2%)
 

NECROSIS, "AT 1 (21)
 

ALL 0""HEB SYSTEMS
 

ADIPOSE TISSUE
 

NECROSIS, FAT 1
 

SPECIAL COSFHOLtm SUM1ARY
 

NO LEGION R"POETD 2 8 U 10
 

ACCIEINTAL DEATH 3
 

AUTO/UECHOPSY/NO HIST3 1
 

AUTOLYSI3/NO NECROPSY 1 U
 

* NU1BEP Op ANIMAL S ^II-i TISSUI EXAMINED MICROSCOPICALLY
 

* NUMBFR OF ANIMALS IrECROPSIED
 

D-7
 
TABLE D2

 

SUMMARY OF THE INCIDENCE OP NONNEOPLASTIC LESIONS IN FEMALE MICE 

TREATED WITH 4-NITROANTHRANILIC ACID 

LOW DOSE HIGH DOSE CONTRO L (UNTR ) CONTRO L (UN T R) LOH DOSE HIGH DOSE 

06-0030 06-0077 06-003U 06-0103 

ANIMAL S INITIALL Y IN STUDY 50 50 50 50 

ANIMAL S MISSIN G 3 

ANIMAL S NTCROPSIE D U 7 4 6 142 149 

ANIMAL S IXUMINF D HI SIJ P ATHOLOGICAL L Y ** 47 146 141 148 

TNTE3UMENT1R Y SYSTE M 

*SKIN (147) (46) (142) (49) 

INFLAMMATION , ACUT E 1 (2X ) 

"I9ROSI S 1 (25) 

FIBHOSIS , FOCU L 1 (25) 

SESPIPATQP Y SYSTf i 

*LARYN X (47 ) (46) (42 ) (149)

 

INFLAMMATION , CHRONI C 1 (2% ) 

»LUN" . (46 ) (45 ) (41 ) (146) 

INFLAMMATION , INTERSTITIA L 2 (4? ) 2 (4i5) 

FN3UM31IA , CHROMI C MQRIN E 6 ( 1 5fc) 2 (14*) 

PEHIAPPERITI S 1 (21,) 1 (2S) 

«LUNG/ALV-:OL I («o ) («5 ) (41 ) (H8 )

 

EMPHYSEMA , NO S 1 (21 ) 

HEMATOPCIETI C SYSTE M 

*r?0!,'E MAFR3 K (45 ) (44 ) (40 ) (148) 

HYPCFL\SIA , NO S 1 (2? ) 

MYELOFIBF.OSI S 1 (21 ) 

HY?T??LASIA , HEiUTOFOIETI C 3 (8X) 

'5PLEE N (45) (43) (?° ) (US) 

^rtYLOIOOSI S 1 (2*) 

LY.1PHOCYTOSI S 2 (4? ) 

HYPLRPLASIA , R'TIC'ILU M CEL L 2 (5%) 

HYPLEFHS1A, LYf'PHOI D 3 (7?) 4 (9%) 1 (3%) 

l_^6il_ 

* NOISES OF UNIMUL S WITH TISSUE EXAMINE D MICROSCOPICALLY
 

* NUM3E R OF ANIMAL ? NECROPSIE D 

**EXCLUDfcS PARTIALLY AUTOLYiED ANIMALS 

D-8 
TABLE D2 (CONTINUED) 

LOW DOSE CONTRO L (UHTR ) 

06-0030 

HIGH DOSE CONTROL (UNTH ) 

06-0077 

—

L O U DOSE

06-0034

 • • 

 HIGH DOSE 

 06-0103 

»AB3C!"INA L LYS1PH NOD ^ 

INFLAMMATIO N ACUT E AN D

HYPERPLASTA , NO S 

»PANCREATI C L.t'ODF 

HYPFRPLASIA , NO S 

HYPFRPLASIA , PETICULU M

 CHRONI C 

 CELL 

(27 ) 

(27 ) 

1 (4S ) 

(11) 

(11) 

(38)

2

(38)

1

 <5X) 

 (3X) 

 (42)

1

 (42) 

 (2*) 

CIRC'JUTOPY SYSTEM 

*Wt 

p'TiA'TraiTis 

ttHEATJT/ATRTU M 

CALCIFICATION , FOCAL 

*MY^CAPDI'I» , 

CALCIFICATION , FOCA L 

•PULIONUS Y IPTP Y 

4YPFPPLASIA , NOS 

(16) 

(16) 

1 (2%) 

(16) 

(47 ) 

(15) 

(15) 

(15) 

1

(46 ) 

1

 (2% ) 

 (2%) 

(11)

(11)

(41)

(12)

 (48) 

1

 (48) 

 (48) 

 (49) 

 (2*) 

DT3JSTIV F SYSTE M 

ItfALTVAR f GLAN D 

INFLAMMATION , CHRONIC 

PF.'UVASCUH R CUFFIN G 

*LIVE R 

INFLAMMATION , FOCAL 

1FCHOSIS, FOCA L 

NECROSIS, COASULATIV E 

rYTOPLASHI C CHANGE , NO S 

HYPERPLASIA , NODULA R 

HY?ER?L^SIA , DIFFUS E 

ANGIECTASI S 

*LIVE^/CSN~RIIOBULA R 

N"CROSIS , NO j 

*LIVH/P"aiPORTA L 

INXLAMIATION^.NO S 

(29 ) 

1 (3*) 

(46) 

1 (21) 

1 (2S) 

2 (4/6 ) 

1 (21) 

(46) 

(16) 

(13) 

(15) 

1 (2X ) 

1 (2%) 

1 (2%) 

(15) 

(15) 

1 (2X) 

* NU1B33 0" ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY 

* NU1BEE OF ANIMAL S NECROPSIED 

(10)

1 (3X) 

(41)

(11)

(41 )

 (16) 

 (47 ) 

 (17)

1

 (47) 

 (2S) 

D-9 
TABLE D2 (CONTINUED) 

LOW DOSE HIGH DOSE CONTRO L (UNTR ) CONTRO L (UNTH ) L O W DOSE HIGH DOSE 

06-0030 06-0077 06-003U 06-0103 

^P^RPLA^IA , LYMPHOI D 1 (2X ) 

*BIL" DUC T 

TN^LAMIATIOS , NOS INFLAIKATIC h , CHRONI C 

(17) (1b) 

1 (2%) 

(12) 

1 (2% ) 

(19) 

1 (2*) 

JPANCS3A 3 

DILATA^TON/DUCI S m"LA"1ATI01, CHtiONI C FOCA L 

JTRTPhf , FOCA L 

(39 ) («1 ) (11) 

2 (5% ) 

1 (2%) 

(13) 

1

1

 (24) 

 (2*) 

*PANC=)'ATI C DUC T 

LY1t>HO;YTIC INFLAMMATOR Y INFILT R 

(39)

1 (3i) 

 (U1 ) (11) (13) 

• STOl-lACH 

INFLA^1^ m ICN' f NO S 

(15)

3 (7«) 

 (12) (10) (17) 

'JLC2=i , NO S 

IN'mMATIP h , IC'JTF 

1 (3% ) 1

1

 (2*) 

 (2« ) INFLAMMATIO N ACU" AN' D CHRONI C 1 (3«) 

'PFY^P S ?\T,I 

HY=ES?LASIA , NO S 

(15)

1 (2% ) 

 (it3 ) (10) (15) 

*EUOr"TJ1 p

:"3?i\ (15)

1 (2% ) 

 (143) (10) (15) 

tCOLO N 

PERIAR T ~fiITl s 

(13) (11) (38) (12) 

1 (2% ) PARASITIS M 1 (2%) 

URINAR Y SYSTE M 

KKID'JE Y 

^L J1rH JLON^PHEIT I S, NOS 

G L O lE^'^ONTPHRITIS , FOCA L 

I'.'FL'iin'-ioN, I K :TLPSTITIA L 

(15)

2 (1^) 

1 (2% ) 

9 (20% )

 (43 ) 

3 (1%) 

(11) (17) 

rL3SE= r ILOKrPHPITIS , CHRONI C 1 (2*) 

P"SIVASCULITI 3 

NT'PrtROPATH Y 

AIYLOIDOSI 5 ; 

CALCIFICATION , FOCA L 

it (9%) 

1 (2% ) 

3 (6*) 

1 (2% ) 

•KIDNEY/GLCMIPULU S (15) (U3 ) (11) (17) 

» VG13SR 0' ANIMAL S hlT H TISSU E "XAMIN2 D MICROSCOPICALL Y 

* N'JIBE'} u" ANI"AL 3 NSCPOPSIF D 

D-10 
TABLE D2 (CONTINUED) 

LOW DOSE CONTRO L (UNTR ) 

06-0030 

HIGH DOSE CONTRO L (UMTR ) 

06-0077 

. 

L O W DOSE 

06-0034 

HIGH DOSS 

06-0103 

*KIDNEY/F5LVI S 

TNPLAM1ATICN , ACUTE/CHRONI C 

*JPIMAP Y 3LADDE = 

IMl'LAB*,A m ION , CtiPONI C 

P"=IVAECULITI S 

(45) 

1 (2% ) 

(142) 

(43) 

1 (2% ) 

(41 ) 

( «D 

(39 ) 

1 (3% ) 

1 (3X) 

(47) 

(43) 

"NDO^RIN I SYSTFf ] 

»PITUITAB / 

H/praPLASI A , FOCAL 

#AD°-'JA L 

A1YLOIKOSI 5 

KAIP-NHL/rAFSUL " 

HYP-PPLASIJ , NO1 , 

tADR^'IA L CO^T- X 

NODUL f 

HYP^FHSIA , NO-5 

t-HYRDI D 

HIP'RPLASIA , FOLLICULAP- C ^LL 

(37) 

(1414) 

(144) 

(44 ) 

1 (2% ) 

2 (54 ) 

(U 14) 

(37 ) 

(43 ) 

(143) 

(43 ) 

(30) 

(36 ) 

(40 ) 

(40 ) 

38 (95X) 

(40 ) 

1 (3*) 

(37 ) 

1 (3% ) 

(140) 

1 (3%) 

(47) 

1 (2% ) 

(47 ) 

41 (87% ) 

(147) 

(142) 

H:PRODJC"IV : sYSTn " 

*«AfBA c Y 1LAN D 

LAC'A" ! J N 

• U^ERJ S 

HYD^OI^TR A 

DY01-T7 A 

^rpopHY , NO S 

•1E T A"LASIA , SJUAMOU S 

«rjT"BUS/ENDl»irTPIU M 

CYST , 'jns T

 \F L A w M ATION , KU S 

IN'tAIIA^ION , A^UTM 2 

I»"HMilHTIO> i A C ITS AN D CHRONI C 

(47 ) 

(43 ) 

4 (9',) 

1 (24 ) 

(43 ) 

1 (2* ) 

(146) 

(43 ) 

4 (9% ) 

(43 ) 

2 (5%) 

(142) 

1 (2% ) 

(40 ) 

5 (13%) 

8 (20%) 

1 (3«) 

(40 ) 

1 (3% ) 

(149) 

(46 ) 

9 (20%) 

6 (13%) 

1 (2% ) 

(Mb ) 

3 (7%) 

o? «,I»I»IALS WITH TISSUE FXAIINED IICRJSCOPICALLY * >,'J1BE= 0" ANIfAL5 ; NECROPSIED 

D-ll 
TABLE D2 (CONTINUED) 

HYPEBPLASIA, NCS 

HYPERPLASIP, CYSTIC 

METAPLASIA, SQUABOOS 

•OVARY/OVIDUCT 

ABSCFSS, NOS 

CYST, NOS

THROMBOSIS, NOS INFLAMMATION ACUT^ AND CHRONIC

INFLAMMATION, CHRONIC

AMYLOIDOSIS

LOW DOSE

CONTRO L (UNTB )

06-3030

33 (77*) 

(43) 

(44)

 5 (11*)

 HIGH DOSE 

 CONTEOL (UNTH ) 

 06-0077 

1 (2*) 

35 (81*) 

(13) 

 (41)

 1 (2*)

L OU DOSE 

06-0034 

1 (3*) 

17 (43*) 

1 (3*) 

(40) 

10 (25*) 

 (39)

 9 (23*)

 1 (3*)

HIG H DOSE 

06-010 3 

7 (15*) 

(4t>) 

6 (13*) 

 (44) 

7 (16*) 

i (2%) 1 (2*) 

1 (2%) 

1 (2*) 

NPRVOtTS SYSTEM 

"(BRAIN

CALCIFICATION, FOCAL

 (45) (43) (39)

 5 (13*)

 (46) 

1 (2*) 

SPECIAL SENSF ORGAN S 

NONF 

BUSCULOSKELETAL SYSTEM 

•VERTEBRA

OSTEOPOROSIS

 (47) (46)

 1 (2*) 

 (42) (49) 

BODY CAVITIES 

•ABDOMINAL CAVITY

NECROSIS, FAT

*PERITCN"U1

INFH»MATION WITH FIBBOSIS

•PLEURA

HYPERPLASIA, LYHPHOID

 (47)

 (47)

 (47)

 1 (2*) 

 (46)

 (46)

 (46)

 (42)

 (42)

 1 (2*) 

 (42)

 (49) 

1 (2*) 

 (49) 

 (49) 

A L L OTHE R SYSTifl S 

* NUIiru OF ANIMAL S WITH TISSU" EXAMINED MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECHOPSIED 

D-12 
TABLE D2 (CONCI UDED) 

LOW DOSE HIGH DOSF CONT R ji (ON1R ) CONTRO L (UNTR | LOrf DOSE HIGH DOSE

 

16-0031 06-0077 06-003U 06-0103 

SPFCIAL PORPHOLO-5 Y SU1MAR Y 

NO LESION EEPOPTED 1 1 1 1
 

ANIPA L 1I5SING/NO NECROPSf 3
 

AUTO/NjCROPSY/HISTO PEhF 1 2 1 3
 

AUTO/N^CEOPSY/NO HIS70 1 1
 AUTOLYSIS/NC NECROPSV 3 4 5 1
 

* NU1BE B 0 " ANIMAL S WIT H TISSU " EXAMINE D 1ICR )SCOPICALL Y 

* SUBB^ R O F ANIMAL S N'CROPSIE C 

D-13 


DHEW Publication No. (NIH) 78-1364