National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 64 

1978 

BIOASSAY OF 

1-NITRONAPHTHALENE 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 86-57-7 

NCI-CG-TR-64 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

1-ΝITRONAPHTHALENE
 

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) 78-1314
 

REPORT ON THE BIOASSAY OF 1-NITRONAPHTHALENE
 

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
 

1-nitronaphthalene conducted for the Carcinogenesis Testing Program,
 

Division of Cancer Cause and Prevention, National Cancer Institute
 

(NCI), National Institutes of Health, Bethesda, Maryland. This is
 

one of a series of experiments designed to determine whether selected
 

environmental chemicals have the capacity to produce cancer in animals. Negative results, in which the test animals do not have a
 

greater incidence of cancer than control animals, do not necessarily
 

mean 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 1-nitronaphthalene 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. Η. 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).
 

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, and
 

the diagnoses included in this report represent the interpretation of
 

these pathologists. Histopathology findings and reports were reviewed
 

by Dr. R. L. Schueler (4).
 

Compilation of individual animal survival, pathology, and summary
 

tables was performed by EG&G Mason Research Institute (5); the statistical analysis was performed by Mr. W. W. Belew (6), and Dr. A. Chu (5)
 

using methods selected for the Bioassay Program by Dr. J. J. Gart (7).
 

This report was prepared at METREK, a Division of The MITRE Corporation (6) under the direction of the NCI. Those responsible for
 

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

(6), the task leader, Dr. M. R. Kornreich (6), the senior biologist,
 

Ms. P. Walker (6), the chemist, Dr. N. Zimmerman (6), and the technical editor, Ms. P. A. Miller (6). The final report was reviewed by
 

members of the participating organizations.
 

The statistical analysis was reviewed by members of the Mathematical Statistics and Applied Mathematics Section of the NCI: Dr.
 

J. J. Gart (7), Mr. J. Nam (7), Dr. H. M. Pettigrew (7), and Dr. R.
 

E. Tarone (7).
 

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 (1), Dr. D. G. Goodman (1), Dr. R.
 

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

Squire (1,8), and Dr. J. Μ. Ward (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.	 Tracor Jitco, Inc., 1776 East Jefferson Street, Rockville,
 

Maryland.
 

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

Rockville, Maryland.
 

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

Boulevard, McLean, Virginia. .
 

7.	 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.
 

8.	 Now with the Division of Comparative Medicine, Johns Hopkins
 

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

IV
 
SUMMARY
 

A bioassay of technical-grade l-nitronaphthalene for possible
 

carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice·
 

1-Nitronaphthalene 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
 

in the chronic study were, respectively, 0.18 and 0.06 percent for
 

rats and 0.12 and 0.06 percent for mice. After a 78-week period of
 

chemical administration, the rats were observed for an additional
 

period of up to 31 weeks and the mice for an additional period of up
 

to 20 weeks. For rats 50 animals of each sex were placed on test as
 

controls for the low dose groups and 25 of each sex for the high dose
 

groups. For mice 50 animals of each sex were placed on test as controls for each dosed group.
 

In both species adequate numbers of animals in all groups survived sufficiently long for the development of late-appearing tumors;
 

however, no compound-related increase in the incidence of neoplasms,
 

nonneoplastic lesions, or other toxic effects was evident.
 

Under the conditions of this bioassay 1-nitronaphthalene was not
 

demonstrated to be carcinogenic in Fischer 344 rats or B6C3F1 mice.
 

TABLE OF CONTENTS
 

Page
 

I. INTRODUCTION 1
 

II. MATERIALS AND METHODS 3
 

A. Chemicals 3
 

B. Dietary Preparation 3
 

C. Animals 4
 

D· Animal Maintenance 4
 

E. Selection of Initial Concentrations 8
 

F. Experimental Design 9
 

G. Clinical and Histopathologic Examinations 12
 

H. Data Recording and Statistical Analyses 14
 

III. CHRONIC TESTING RESULTS: RATS 19
 

A. Body Weights and Clinical Observations 19
 

B· Survival 19
 

C. Pathology 22
 

D· Statistical Analyses of Results 22
 

IV. CHRONIC TESTING RESULTS: MICE 32
 

A· Body Weights and Clinical Observations
 

B. Survival ^2
 

C. Pathology ^Z
 

D· Statistical Analyses of Results
 

V. DISCUSSION ^
 

VI. BIBLIOGRAPHY 4 5
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH 1-NITRONAPHTHALENE A-l
 

APPENDIX Β SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH 1-NITRONAPHTHALENE B-l
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH 1-NITRONAPHTHALENE C-l
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH 1-NITRONAPHTHALENE D-l
 

vii
 
LIST OF ILLUSTRATIONS 

Figure Number Page 

1 GROWTH CURVES FOR 1-NITRONAPHTHALENE CHRONIC 

STUDY RATS 20 

2 SURVIVAL COMPARISONS OF 1-NITRONAPHTHALENE 

CHRONIC STUDY RATS 21 

3 GROWTH CURVES FOR 1-NITRONAPHTHALENE CHRONIC 

STUDY MICE 33 

4 SURVIVAL COMPARISONS OF 1-NITRONAPHTHALENE 

CHRONIC STUDY MICE 34 

LIST OF TABLES 

Table Number Page 

1 DESIGN SUMMARY FOR FISCHER 344 RATS—1-NITRONAPHTHALENE FEEDING EXPERIMENT 10 

2 DESIGN SUMMARY FOR B6C3F1 MICE—1-NITRONAPHTHALENE FEEDING EXPERIMENT 11 

3 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

1-NITRONAPHTHALENE 23 

4 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH 1-NITRONAPHTHALENE 26 

5 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

1-NITRONAPHTHALENE 36 

6 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH 1-NITRONAPHTHALENE 39 

Al SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH 1-NITRONAPHTHALENE A-3 

Vlll 
LIST OF TABLES (Concluded) 

Table Number Page 

A2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN

FEMALE RATS TREATED WITH 1-NITRONAPHTHALENE 

 A-8 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN

MALE MICE TREATED WITH 1-NITRONAPHTHALENE 

 B-3 

B2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN

FEMALE MICE TREATED WITH 1-NITRONAPHTHALENE 

 B-7 

CI SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC

LESIONS IN MALE RATS TREATED WITH 1-NITRONAPHTHALENE 

 C-3 

C2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC

LESIONS IN FEMALE RATS TREATED WITH 1-NITRONAPHTHALENE 

 C-ll 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC

LESIONS IN MALE MICE TREATED WITH 1-NITRONAPHTHALENE 

 D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC

LESIONS IN FEMALE MICE TREATED WITH 1-NITRONAPHTHALENE 

 D-10 

ix
 

I. INTRODUCTION
 

1-Nitronaphthalene (NCI No· CO1956), a monosubstituted naphthalene derivative with a variety of commercial uses, was selected for
 

bioassay by the National Cancer Institute because of its structural
 

analogy to the suspected carcinogen 1-naphthy1amine (International
 

Agency for Research on Cancer [IARC], 1974), and its similarity to
 

both the tumorigenic agent 2-nitronaphthylene (Conzelman et al·,
 

1970) and the human bladder carcinogen 2-naphthy1amine (IARC, 1974).
 

The Chemical Abstracts Service (CAS) Ninth Collective Index
 

(1977) name for this compound is 1-nitro-naphthalene· It is also
 

known as alpha-nitronaphthalene or simply as nitronaphthalene.
 

Most of the 1-nitronaphthalene produced appears to be used as
 

an intermediate for the preparation of 1-naphthy1amine, which is used
 

in the manufacture of numerous dyes and intermediates, and in the
 

production of rodenticides (Treibl, 1967). 1-Nitronaphthalene is
 

also sulfonated to produce l-nitronaphthalene-5-sulfonic acid, a dye
 

intermediate (Hawley, 1971). 1,5- and 1,8-Dinitronaphthalenes,
 

produced by further nitration of 1-nitronaphthalene, have had limited
 

use in the dye industry (Treibl, 1967).
 

1-Nitronaphthalene is also used as a deblooming agent for petroleum and oils (in concentrations of 2-3 parts/1000 parts oil) (Treibl,
 

1967), and as a modifier to decrease the burning rate of explosives
 

(Bureau of Explosives, 1977).
 

*The CAS registry number is 86-57-7.
 
Specific production statistics for 1-nitronaphthalene are not
 

available; however, one U.S. company reported production or sales in
 

excess of 1000 lbs or $1000 in value in 1975 (U.S. International
 

Trade Commission, 1977).
 

A risk of exposure to 1-nitronaphthalene exists for all workers
 

involved in the manufacture and handling of the compound and the production of its derivatives. Workers who produce or handle petroleum,
 

oils, or explosives which contain 1-nitronaphthalene may also be exposed to the compound. The general population may experience exposure
 

as a result of industrial discharge of 1-nitronaphthalene into rivers
 

and streams. 1-Nitronaphthalene has been detected in the Rhine River
 

(Gusten et al·, 1974), and an unspecified isomer of nitronaphthalene
 

has been detected in the Waal River in the Netherlands (Meijers, 1973;
 

as cited in Urso, 1977).
 

1-Nitronaphthalene is a moderate local irritant (Sax, 1975) and
 

its vapors are poisonous and lacrimatory (Treibl, 1967).
 
II. MATERIALS AND METHODS
 

A· Chemicals
 

1-Nitronaphthalene was purchased from Aldrich Chemical Company,
 

Madison, Wisconsin, and chemical analysis was performed by Mason Research Institute, Worcester, Massachusetts. Although the narrow
 

range of the experimentally observed melting point (50° to 53°C)
 

suggested a compound of fairly high purity, the deviation from the
 

literature value of 61.5°C indicated the presence of impurities.
 

Thin-layer chromatography, visualized with ultraviolet light, revealed a single major spot with an R of 0.67 and one other spot of
 

uncharacterized identity. The observed χ of 335 nm was close to
 J


 max
 

the reported value of 330 nm. The extraneous peak at 220 nm indicated the presence of a significant impurity or impurities.
 

Throughout this report the term 1-nitronaphthalene is used to
 

represent this material.
 

B· Dietary Preparation
 

The basal laboratory diet for both treated and control animals
 

consisted of Wayne Lab-Blox (Allied Mills, Inc., Chicago, Illinois).
 

1-Nitronaphthalene was administered to the treated animals as a component of the diet.
 

The chemical was removed from its container and proper amounts
 

were ground to a powder in a Quaker City crystal mill, sifted and
 

weighed out under an exhaust hood. The compound was hand blended in
 

an aluminum bowl with an aliquot of the ground feed. Once visual
 
homogeneity was attained, the mixture was placed in a 6 kg capacity
 

Patterson-Kelley standard model twin-shell stainless steel V-blender
 

along with the remainder of the feed to be prepared· After 20 minutes of blending, the mixtures were placed in double plastic bags,
 

and stored in the dark at 4°C. The mixture was prepared once weekly·
 

C. Animals
 

Two animals 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
 

Institute. All rats and mice were supplied by Charles River Breeding
 

Laboratories, Inc., Wilmington, Massachusetts except for the high dose
 

control rats, which were supplied by Laboratory Supply Company, Inc.,
 

Indianapolis, Indiana. Treated and control animals for both species
 

were received in separate shipments.
 

Upon arrival, a sample of animals was 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 species and
 

sex.
 

D. Animal Maintenance
 

All animals were housed by species in rooms having a temperature
 

range of 23° to 34°,C and a range in relative humidity of 5 to 90
 

percent. Incoming air was filtered through Tri-Dek 15/40 denier
 
Dacron(R)

 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 11 months of study, high dose treated and control rats
 

were housed in wire-mesh cages (Fenco Cage Products, Boston, Massachusetts) suspended over newpapers. Low dose treated and control rats
 

were held in wire-mesh cages for the first 13 months of study. Newspapers under cages were replaced daily and cages and racks washed
 

weekly. For the remainder of the study, all rats were held in suspended polycarbonate cages (Lab Products, Inc., Garfield, New Jersey)
 

equipped with disposable nonwoven fiber filter sheets. Clean cages
 

and bedding were provided twice weekly. SAN-I-CELR)

 corncob bedding
 

(Paxton Processing Company, Paxton, Illinois) was used in polycarbonate cages for low dose treated and control rats for the duration
 

of the study and for high dose treated and control rats until the
 

last 2 months of the study. Hardwood chip bedding (Aspen bedding,
 

American Excelsior Company, Baltimore, Maryland) was used for high
 

dose treated and control rats for the final 2 months of study.
 

Stainless steel cage racks (Fenco Cage Products) were cleaned once
 

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

Mice were housed by sex in polycarbonate cages fitted with perforated stainless steel lids or wire bar lids (both from Lab Products,
 

Inc.). Nonwoven fiber filter bonnets were used over cage lids. Mice
 
were initially housed ten per cage. High dose treated and control
 

mice and low dose treated and control mice were housed five per cage
 

after 13, 14, 18, and 18 months on test, respectively. Clean cages,
 

lids, and bedding were provided three times per week when cage populations were ten, and twice per week when cage populations were
 

reduced to five.
 

Hardwood chip bedding (Ab-sorb-dri , Wilner Wood Products Company, Norway, Maine) was used for the first 2 months for high dose
 

treated mice, for the first 4 months for high dose control mice, and
 

for the first 8 months for low dose treated and low dose control
 

(R)
 

mice. Corncob bedding (SAN-I-CEL ) was used for the next 12 months.
 

A second type of corncob bedding (Bed-o-Cobs , The Andersons Cob
 

Division, Maumee, Ohio) was then used for the remainder of 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, water was supplied as needed between changes.
 

During quarantine low dose treated and control rats and mice
 

received pelleted Wayne Lab-Blox · Other groups received Wayne Lab-


Blox meal during quarantine. During the period of chemical administration, treated and control animals received treated or untreated
 

Wayne Lab-Blox meal as appropriate. The food, replenished daily,
 

(R)
 

was supplied in Alpine aluminum feed cups (Curtin Matheson Scientific, Inc., Woburn, Massachusetts) for the first 14 months of study
 
for high dose treated and control rats and for the entire study for
 

all other rat and mouse groups· All groups received feed, whether
 

treated or untreated, ad libitum· High dose treated and control rats
 

were fed from stainless steel gangstyle hoppers (Scientific Cages,
 

Inc., Bryan, Texas) after the first 14 months of study. During the
 

untreated observation period, rats were fed pellets on the cage floor
 

and mice were fed pellets from the food hopper incorporated into the
 

wire bar cage lids.
 

All treated and control rats were housed in a room with other
 

-k
 

rats receiving diets treated with 5-nitro-o-toluidine (99-55-8);
 

hydrazobenzene (530-50-7); 2-aminoanthraquinone (117-79-3); 3-amino9-ethylcarbazole hydrochloride; 6-nitrobenzimidazole (94-52-0); 2,4­

diaminoanisole sulfate (615-05-4); and APC (8003-03-0).
 

High dose mice were in a room with other mice receiving diets
 

treated with 2,5-toluenediamine sulfate (6369-59-1); 5-nitro-o-toluidine (99-55-8); hydrazobenzene (530-50-7); 6-nitrobenzimidazole (94­

52-0); 3-amino-9-ethylcarbazole hydrochloride; 5-nitro-o-anisidine
 

(99-59-2); and 2,4-diaminoanisole sulfate (615-05-4). High dose
 

control mice were in a room in which other mice were receiving diets
 

treated with 2-methyl-l-nitroanthraquinone (129-15-7); acetylaminofluorene (53-96-3); p-cresidine (120-71-8); 4-chloro-m-phenylenediamine (5131-60-2); and fenaminosulf (140-56-7). Low dose treated and
 

control male mice were in a room in which other mice were receiving
 

*
 

CAS registry numbers are given in parentheses.
 
diets treated with amitrole (61-82-5); N,N-dimethyl-p-nitrosoaniline
 

(138-89-6); 2,5-toluenediamine sulfate (6369-59-1); 2,4-dinitrotoluene
 

(121-14-2); 2-aminoanthraquinone (117-79-3); 3-amino-4-ethoxyacetanilide (17026-81-2); 3-amino-9-ethylcarbazole hydrochloride; 1-amino2-methylanthraquinone (82-28-0); 5-nitro-o-anisidine (99-59-2);
 

4-nitroanthranilic acid (619-17-0); 5-nitroacenaphthene (602-87-9);
 

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

(615-05-4); and APC (8003-03-0). Low dose treated and control female
 

mice were in a room with other mice receiving diets treated with
 

diarylanilide yellow (6358-85-6).
 

E.	 Selection of Initial Concentrations
 

In order to establish the maximum tolerated concentrations of
 

1-nitronaphthalene 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. 1-Nitronaphthalene was incorporated into the basal laboratory diet and supplied
 

ad libitum to three of the four groups of each species in concentrations of 0.05, 0.10, and 0.15 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. Individual body weights
 

were recorded weekly throughout the study. Daily food consumption
 

8
 
per cage was monitored during the test. At the end of the observation period, all survivors were sacrificed and necropsied·
 

The highest concentration causing no deaths, no compound-related
 

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

19 percent relative to controls during the 6-week subchronic test was
 

to be selected as the high concentration utilized for the rat and
 

mouse chronic bioassays.
 

A single death occurred among the female rat group receiving
 

a dietary concentration of 0.05 percent. This death and all gross
 

abnormalities observed were attributed to the development of chronic
 

murine pneumonia. The initial high concentration selected for administration to rats and mice in the chronic bioassay was 0.06 percent.
 

However, when the chronic bioassay was begun, concentrations of 0.05
 

and 0.06 percent were utilized for rats and mice, respectively.
 

F. Experimental Design
 

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

treated and untreated observation periods, and time-weighted average
 

concentrations) are summarized in Tables 1 and 2.
 

The high dose, low dose, and control rats were all approximately
 

6 weeks old at the time they were placed on test. The initial high
 

and low concentrations of 1-nitronaphthalene in diets were 0.05 and
 

0.03 percent, respectively. The low dose rat group (0.03 percent)
 

was sacrificed after 5 months and no histopathologic examinations
 
TABLE 1
 

DESIGN SUMMARY FOR FISCHER 344 RATS
 

1-NITRONAPHTHALENE FEEDING EXPERIMENT
 

1-NITROINITIAL NAPHTHALENE OBSERVATION PERIOD TIME-WEIGHTED 

GROUP CONCENTRATION TREATED UNTREATED AVERAGE 

SIZE (PERCENT) (WEEKS) (WEEKS) CONCENTRATIONa 

MALE 

LOW DOSE 

CONTROL 50 0 0 107 0 

HIGH DOSE 

CONTROL 25 0 0 109 0 

LOW DOSE 50 0.05 12 0.06 

0.06 66 

0 29 

HIGH DOSE 50 0.18 78 0.18 

0 31 

FEMALE 

LOW DOSE 

CONTROL 50 0 0 108 0 

HIGH DOSE 

CONTROL 25 0 0 109 0 

LOW DOSE 50 0.05 12 0.06 

0.06 66 

29 

HIGH DOSE 50 0.18 78 0.18 

0 31 

a Σ(concentration X weeks received)
 Time-weighted average concentration =
 Σ(weeks receiving chemical)
 

10
 
TABLE 2
 

DESIGN SUMMARY FOR B6C3F1 MICE
 

1-NITRONAPHTHALENE FEEDING EXPERIMENT
 

MALE 

INITIAL 

GROUP 

SIZE 

1-NITRONAPHTHALENE 

CONCENTRATION 

(PERCENT) 

OBSERVATION PERIOD 

TREATED 

(WEEKS) 

UNTREATED 

(WEEKS) 

LOW DOSE CONTROL 50 0 0 96 

HIGH DOSE CONTROL 50 0 0 98 

LOW DOSE 50 0.06 

0 

78 

18 

HIGH DOSE 50 0.12 

0 

78 

20 

FEMALE 

LOW DOSE CONTROL 50 0 0 97 

HIGH DOSE CONTROL 50 0 0 98 

LOW DOSE 50 0.06 

0 

78 

19 

HIGH DOSE 50 0.12 

0 

78 

20 

11
 
were performed because the dose was considered, on the basis of
 

weight depression, to be too low. At that time, a new high dose rat
 

group, receiving a dietary concentration of 0·18 percent, was started·
 

The initial high dose treated and high dose control groups which had
 

been on test for 3 months became the low dose treated and low dose
 

control groups· At this time, the dosage for the new low dose group
 

was increased from 0.05 to 0.06 percent. Treated rats were supplied
 

with dosed feed for a total of 78 weeks followed by a 29- to 31-week
 

observation period.
 

The high dose, low dose, and control mice were all approximately
 

6 weeks old at the time they were placed on test. The initial high
 

and low concentrations of 1-nitronaphthalene in diets administered to
 

males and females were 0.06 and 0.03 percent, respectively. The low
 

dose mice (0.03 percent) were sacrificed after 5 months and no histopathologic examinations were performed because the dose was considered, on the basis of weight depression, to be too low. At that time,
 

a new high dose mouse group, receiving a dietary concentration of 0.12
 

percent was started. The initial high dose group became the low dose
 

group. Treated mice were supplied with dosed feed for a total of 78
 

weeks followed by an 18- to 20-week observation period.
 

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. Body weights were recorded twice weekly for the first
 

12
 
12 weeks of the study and at monthly intervals thereafter· 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· The presence
 

of tissue masses and lesions was determined by monthly observation
 

and palpation of each animal.
 

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, or gross lesions taken from sacrificed animals and, whenever
 

possible, from animals found dead.
 

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 and bile
 

duct (mice), pancreas, esophagus, stomach, small intestine, large
 

intestine, kidney, urinary bladder, pituitary, adrenal, thyroid,
 

parathyroid, testis, prostate, brain, ear, uterus, mammary gland, and
 

ovary.
 

Tissues for which slides were prepared were preserved in 10 percent buffered formalin, embedded in paraffin, sectioned, and stained
 

with hematoxylin and eosin prior to microscopic examination. An
 

13
 
occasional section was subjected to special staining techniques for
 

more definitive diagnosis·
 

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 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
 

14
 
in the form of graphs· Animals were statistically censored as of the
 

time that they died of other than natural causes or were found to be
 

missing; animals dying from natural causes were not statistically
 

censored. Statistical analyses for a possible dose-related effect on
 

survival used the method of Cox (1972) for testing two groups for
 

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

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
 

15
 
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
 

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

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

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
 

during which animals died naturally or were sacrificed was entered as
 

the time point of tumor observation. Cox's methods of comparing
 

16
 
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 ρ / where ρ is the true binomial probability of the
 

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

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

c
 

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
 

would be within the interval calculated from the experiment· When
 

the lower limit of the confidence interval is greater than one, it
 

17
 
can be inferred that a statistically significant result (a P < 0.025
 

one-tailed test when the control incidence is not zero, Ρ < 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.
 

18
 
III. CHRONIC TESTING RESULTS: RATS
 

A· Body Weights and Clinical Observations
 

Mean body weight depression was observed in male and female high
 

dose rats. The difference from controls was more apparent in females
 

than males (Figure 1). Large palpable masses were observed in two
 

low dose females. One low dose male had a growth on the posterior
 

ventral surface, a crusted cutaneous lesion developed on the dorsolateral surface of a low dose control male, and one high dose female
 

exhibited rectal bleeding. No other clinical abnormalities were
 

reported.
 

B. Survival
 

The estimated probabilities of survival for male and female rats
 

in the control and 1-nitronaphthalene-treated groups are shown in
 

Figure 2.
 

For male rats the Cox test for positive association between
 

increased dosage and accelerated mortality was not significant. Five
 

animals were terminated from each of the groups in week 78. Additionally, 10 rats were terminated from the low dose control group in week
 

29. In the low dose group, 5 rats were reported moribund in week 41;
 

no common cause of death could be ascertained. Thirty-six out of 50
 

of the high dose, 29/50 of the low dose, 13/25 of the high dose control, and 27/50 of the low dose control male rats survived until termination of the experiment. The survival of male rats was, therefore,
 

adequate to permit meaningful statistical analyses.
 

19
 
TIME ON TEST (WEEKS)

 

FIGURE 1 

GROWTH CURVES FOR 1-NITRONAPHTHALENE CHRONIC STUDY RATS 

20 
45 60 75 

TIME ON TEST (WEEKS) 

FIGURE 2 

SURVIVAL COMPARISONS OF 1-NITRONAPHTHALENE CHRONIC STUDY RATS 

2I 
For female rats the Cox test was also not significant· As with
 

the males, 5 animals from each of the groups were sacrificed in week
 

78 and 10 additional rats from the low dose control were sacrificed
 

in week 29. Survival of female rats was adequate for meaningful statistical analyses with 38/50 of the high dose, 37/50 of the low dose,
 

15/25 of the high dose, and 29/50 of the control group surviving at
 

week 100 of the study.
 

C. Pathology
 

Histopathologic findings on neoplasms in rats are summarized in
 

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

summarized in Appendix C (Tables CI and C2).
 

A variety of neoplasms were observed in rats fed 1-nitronaphthalene. These neoplasms were similar in number and type to neoplasms
 

observed in control animals and the occurrence of the neoplasms was
 

not considered to be compound-related.
 

Inflammatory and degenerative lesions which commonly occur in
 

aging Fischer 344 rats were seen and they were not considered to be
 

compound-related.
 

Based upon this histopathologic examination it is the conclusion
 

that there was no carcinogenic effect attributable to feeding Fischer
 

344 rats 1-nitronaphthalene.
 

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
 

22
 
ANALYSES OF THE

SPECIFIC SITES IN MALE

TOPOGRAPHY: MORPHOLOGY 

Lung: Alveolar/Bronchiolar Adenoma or 

Alveolar/Bronchiolar Carcinoma^ 

 Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor ro
 

Hematopoietic System: Leukemia or 

Malignant Lymphoma 

 Values0 

Relative Risk (Control) d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 

Pituitary: Adenoma NOS, Basophil Adenoma 

or Chromophobe Adenoma 

 Values0 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 

TABLE 3 

 INCIDENCE OF PRIMARY TUMORS AT 

 RATS TREATED WITH 1-NITRONAPHTHALENE* 

LOW DOSE HIGH DOSE LOW 

CONTROL CONTROL DOSE 

0/46(0.00) 3/25(0.12) 1/48(0.02) 

N.S. 

Infinite 

0.051 

Infinite 

78	 103 

2/46(0.04) 4/25(0.16) 3/48(0.06) 

N.S. 

1.438 

0.173 

16.575 

79 85 104 

12/41(0.29) 3/21(0.14)	 2/45(0.04) 

 = 0.002(Ν) 

0.152 

0.018 

0.628 

101 78 92 

HIGH
 

DOSE
 

3/49(0.06)
 

N.S. 

0.510 

0.074 

3.594 

93 

1/50(0.02) 

 = 0.040( 

0.125 

0.003 

1.189 

109 

3/43(0.07) 

N.S. 

0.488 

0.073 

3.406 

107 
TOPOGRAPHY: MORPHOLOGY 

Adrenal : Pheochromocytoma o r , 

Pheochromocytoma, Malignan t 

 Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Thyroid: Adenocarcinoma NOS or 

Follicular-Cell Carcinomab 

 Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Thyroid: C-Cell Adenoma or C-Cell 

Carcinoma 

 Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

TABLE 3 (Continued)
 

LOW DOSE 

CONTROL 

6/43(0.14) 

107 

2/45(0.04) 

— 

107 

1/45(0.02) 

_—— 

107 

HIGH DOSE
 

CONTROL
 

4/25(0.16) 

68 

0/23(0.00) 

_—« . 

0/23(0.00) 

LOW
 

DOSE
 

1/48(0.02) 

 = 0.040(N) 

0.149 

0.003 

1.162
 

107
 

1/43(0.02) 

N.S. 

0.523 

0.009 

9.671
 

107
 

3/43(0.07) 

N.S. 

3.140 

0.264 

160.819 

92 

HIGH
 

DOSE
 

3/48(0.06) 

N.S. 

0.391 

0.063 

2.153 

109 

3/45(0.07) 

N.S. 

Infinite 

0.317 

Infinite 

0/45(0.00) 

N.S. 

109 
TABLE 3 (Concluded)
 

LOW DOSE HIGH DOSE LOW HIGH 

TOPOGRAPHY: MORPHOLOGY CONTROL CONTROL DOSE DOSE 

Pancreatic Islets: Islet-Cell Adenoma 2/42(0.05) 2/25(0.08) 1/48(0.02) 1/47(0.02) 

 Values0 N.S. N.S. 

Relative Risk (Control) 0.438 0.266 

Lower Limit 0.008 0.005 

Upper Limit 8.110 4.902 

Weeks to First Observed Tumor 107 109 107 109 

Testis: Interstitial-Cell Tumor 33/45(0.73) 19/24(0.79) 41/48(0.85) 46/49(0.94) 

 Values0 N.S. N.S. 

Relative Risk (Control) 1.165 1.186 

Lower Limit 0.924 0.963 

Upper Limit 1.426 1.411 

Weeks to First Observed Tumor 78 78 78 78 

Treated groups received time-weighted average concentrations of 0.06 or 0.18 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 Ρ < 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 4
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE RATS TREATED WITH l-NITRONAPHTHALENE*
 

TOPOGRAPHY: MORPHOLOGY 

Hematopoietic System: Leukemia 

 Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Hematopoietic System: Leukemia or 

Malij*nant Lymphoma^ 

 Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Liver: Neoplastic Nodule or 

Hepatocellular Carcinoma*5 

 Values 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

LOW DOSE HIGH DOSE LOW HIGH 

CONTROL CONTROL DOSE DOSE 

2/49(0.04) 2/23(0.09) 3/48(0.06) 1/50(0.02) 

N.S. N.S. 

___ 1.531 0.230 

0.183 0.004 

17.665 4.242 

101 106 73 86 

4/49(0.08) 2/23(0.09) 3/48(0.06) 2/50(0.04) 

N.S. N.S. 

0.766 0.460 

0.118 0.036 

4.285 6.082 

101 106 73 86 

2/49(0.04) 2/23(0.09) 0/47(0.00) 2/49(0.04) 

N.S. N.S· 

0.000 0.469 

0.000 0.037 

3.519 6,202 

97 106 107 
____ 

___ 

TOPOGRAPHY: MORPHOLOGY 

Pituitary: Carcinoma NOS or
 

Adenocarcinoma NOSb
 

 Values 0 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 

Pituitary: Adenoma NOS or Chromophobe 

Adenoma 

ho 

 Values 0 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 

Adrenal: Pheochromocytoma or 

Pheochromocytoma, Malignant 

 Values 0 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 

TABLE 4 (Continued ) 

LOW DOSE 

CONTROL 

2/43(0.05) 

107 

18/43(0.42) 

76
 

2/46(0.04)
 

108 

HIGH DOSE
 

CONTROL
 

0/21(0.00) 

8/21(0.38) 

— 

78 

3/23(0.13) 

109 

LOW 

DOSE 

1/43(0.02) 

N.S. 

0.500 

0.009 

9.239 

84 

9/43(0.21) 

 = 0.031(N) 

0.500 

0.226 

1.030 

84 

1/47(0.02) 

N.S. 

0.489 

0.008 

9.071 

78 

HIGH
 

DOSE
 

1/41(0.02) 

N.S. 

Infinite 

0.028 

Infinite 

107 

11/41(0.27) 

N.S. 

0.704 

0.318 

1.740 

98 

2/47(0.04) 

N.S. 

0.326 

0.029 

2.683 

109 
TOPOGRAPHY: MORPHOLOGY 

Thyroid : C-Cell Adenoma o r C-Cell 

Carcinoma* 3 

 Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Mammary: Adenoma NOS or 

Adenocarcinoma NOSb 

 Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Mammary: Fibroadenoma 

 Values0 

Relative Risk (Control) d 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

TABLE 4 (Continued)
 

LOW DOSE 

CONTROL 

1/47(0.02) 

107 

1/49(0.02) 

1 01 

4/49(0.08) 

101 

HIGH DOSE
 

CONTROL
 

3/21(0.14) 

109 

2/23(0.09) 

98 

4/23(0.17) 

—— 

109 

LOW
 

DOSE
 

1/45(0.02) 

N.S. 

1.044 

0.014 

80.198 

107 

4/48(0.08) 

N.S. 

4.083 

0.424 

196.654 

95 

8/48(0.17) 

N.S. 

2.042 

0.589 

8.695 

95 

HIGH
 

DOSE
 

1/42(0.02) 

N.S. 

0.167 

0.003 

1.951 

109 

0/50(0.00) 

N.S. 

0.000 

0.000 

1.549 

6/50(0.12) 

N.S. 

0.690 

0.186 

3.075 

98 
TABLE 4 (Concluded)
 

LOW DOSE HIGH DOSE LOW HIGH 

TOPOGRAPHY: MORPHOLOGY CONTROL CONTROL DOSE DOSE 

Uterus: Endometrial Stromal Polyp 10/48(0,21) 6/23(0.26) 9/46(0.20) 10/49(0.20) 

 Values0 N.S. N.S. 

Relative Risk (Control)d 0.939 0.782 

Lower Limit 0.372 0.302 

Upper Limit 2.330 2.352 

Weeks to First Observed Tumor 78 87 84 91 

Treated groups received time-weighted average concentrations of 0.06 or 0.18 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 Ρ < 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.
 
every type of malignant tumor in either sex where at least two such
 

tumors were observed in at least one of the control or 1-nitronapthalene-dosed groups and where such tumors were observed in at least 5
 

percent of the group.
 

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

indicated a significant positive association between the administration of 1-nitronaphthalene and tumor incidence· Additional time-


adjusted analyses also indicated no significant positive associations.
 

Thus, at the dose levels used in this experiment there was no convincing evidence that 1-nitronaphthalene was a carcinogen in Fischer 344
 

rats.
 

When low dose female rats having pituitary adenomas were grouped
 

with those having pituitary chromophobe adenomas and the resulting
 

incidence of females with tumors was compared to the controls, the
 

Fisher exact tests showed a negative association. This trend was not
 

significant, however, under the Bonferroni criterion.
 

Similarly, in male rats the combined incidences of pituitary
 

adenomas, chromophobe adenomas, or basophil adenomas was significantly
 

(P = 0.002) higher in the low dose control than in the low dose group.
 

However, the incidence in the low dose control of 12/41 (29 percent)
 

appeared unexpectedly high when compared to the historical control
 

incidence of 21/594 (3 percent) in male Fischer 344 rats observed at
 

Mason Research Institute during the NCI Bioassay Program.
 

30
 
The Fisher exact comparison of the incidence of adrenal pheochromocytomas in the low dose treated male rats with the low dose control
 

male rats gave a value of Ρ = 0·040· This value was not significant
 

under the Bonferroni criterion. Similarly, the value of Ρ = 0·040
 

for the Fisher exact test comparing the incidences of leukemia or
 

malignant lymphomas in the high dose males with that in the high dose
 

control males 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 3 and 4, 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 a significantly
 

increased rate of tumor incidence induced in rats by 1-nitronaphthalene that could not be established under the conditions of this
 

test.
 

31
 
IV. CHRONIC TESTING RESULTS: MICE
 

A· Body Weights and Clinical Observations
 

Mean body weight depression was apparent in both male and female
 

treated mice (Figure 3) . No clinical abnormalities were observed in
 

treated or control males or females.
 

B. Survival
 

The estimated probabilities of survival for male and female mice
 

in the control and 1-nitronaphthalene-treated groups are shown in
 

Figure 4.
 

For male mice the Cox test for positive association between
 

increased dosage and accelerated mortality was not significant. Five
 

animals were sacrificed from the high dose group and from each of the
 

control groups in week 78. Adequate numbers of male mice were available for meaningful statistical analyses of the incidence of late-


developing tumors, with 42/50 of the high dose, 45/50 of the low dose,
 

37/50 of the high dose control, and 42/50 of the low dose control surviving to the termination of the study.
 

For female mice the Cox test for a positive dose-related trend
 

in mortality was also not significant. As with the males, 5 animals
 

were terminated in week 78 from the high dose and each control group.
 

Survival was relatively good with 35/50 of the high dose, 44/50 of
 

the low dose, 35/50 of the high dose control, and 37/50 of the low
 

dose control surviving until termination of the study. The survival
 

of female mice was adequate for meaningful statistical analyses.
 

32
 
TIME ON TEST (WEEKS)

 

FIGURE 3 

GROWTH CURVES FOR 1-NITRONAPHTHALENE CHRONIC STUDY MICE 

33 
TIME ON TEST (WEEKS) 

FIGURE 4 

SURVIVAL COMPARISONS OF 1-NITRONAPHTHALENE CHRONIC STUDY MICE 

34 
C. Pathology
 

Histopathologic findings on neoplasms in mice are summarized in
 

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

summarized in Appendix D (Tables Dl and D2).
 

A variety of neoplasms were observed in the treated mice. These
 

neoplasms appeared to be randomly and spontaneously distributed and
 

were judged to be unrelated to the administration of 1-nitronaphthalene·
 

Nonneoplastic lesions which commonly occur in aging B6C3F1 mice
 

were seen. These lesions were not considered to be compound-related.
 

On the basis of the histopathologic examinations, the conclusion
 

is that 1-nitronaphthalene was not carcinogenic to B6C3F1 mice.
 

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
 

tumors were observed in at least one of the control or 1-nitronaphthalene-dosed groups and where such tumors were observed in at least
 

5 percent of the group.
 

When considered separately, the Fisher exact comparisons for the
 

incidences of alveolar/bronchiolar adenomas or alveolar/bronchiolar
 

carcinomas in treated female mice were not significant. When animals
 

with either of these tumors were pooled and the resulting combined
 

incidences analyzed, the value of Ρ = 0.031 obtained for the Fisher
 

35
 
TABLE 5
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE MICE TREATED WITH 1 -NITRONAPHTHALENE*
 

LOW DOSE HIGH DOSE LOW HIGH 

TOPOGRAPHY: MORPHOLOGY CONTROL CONTROL DOSE DOSE 

Lung: Alveolar/Bronchiolar Carcinoma 6/48(0.13) 4/45(0.09) 0/47(0.00) 1/49(0.02) 

 Values 0 

 = 0.014(N) = 0.049( 

Relative Risk (Control) 0.000 0.230 

Lower Limit 0.000 0.005 

Upper Limit 0.637 2.209 

Weeks to First Observed Tumor 96 97 98 

Lung: Alveolar/Bronchiolar Adenoma or 

Alveolar/Bronchiolar Carcinoma^ 6/48(0.13) 11/45(0.24) 8/47(0.17) 9/49(0.18) 

 Values 0 N.S. N.S. 

Relative Risk (Control) 1.362 0.751 

Lower Limit 0.450 0.305 

Upper Limit 4.403 1.806 

Weeks to First Observed Tumor 96 78 96 78 

Hematopoietic System: Malignant Lymphoma 4/48(0.08) 2/45(0.04) 4/49(0.08) 2/49(0.04) 

 Values N.S. N.S. 

Relative Risk (Control) 1.837 0.918 

Lower Limit 0.278 0.069 

Upper Limit 19.547 12.222 

Weeks to First Observed Tumor 96 97 75 78 
TABLE 5 (Continued)
 

LOW DOSE
 

TOPOGRAPHY: MORPHOLOGY CONTROL
 

Hematopoietic System: Malignant Lymphoma
 

or Leukemia 4/48(0.08)
 

 Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 96
 

Circulatory System: Hemangiosarcoma or
 

Hemangioma^ 2/48(0.04)
 

 Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 96
 

Liver: Hepatocellular Carcinoma 7/48(0.15)
 

 Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 78
 

HIGH DOSE
 

CONTROL
 

2/45(0.06)
 

97
 

0/45(0.00)
 

10/45(0.22)
 

93
 

LOW
 

DOSE
 

4/49(0.08)
 

N.S.
 

1.837
 

0.278
 

19.547
 

75
 

0/49(0.00)
 

N.S.
 

0.000
 

0.000
 

3.309
 

8/49(0.16)
 

N.S.
 

1.119
 

0.386
 

3.346
 

96
 

HIGH
 

DOSE
 

3/49(0.06)
 

N.S.
 

1.378
 

0.166
 

15.892
 

78
 

1/49(0.02)
 

N.S.
 

Infinite
 

0.049
 

Infinite
 

98
 

8/49(0.16)
 

N.S.
 

0.735
 

0.277
 

1.882
 

98
 
TABLE 5 (Concluded)
 

Treated groups received time-weighted average concentrations of 0.06 or 0.12 percent in feed.
 

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

C

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 Ρ < 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.
 

oo
 
TABLE 6
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES INFEMALE MICE TREATED WITH l-NITRONAPHTHALENE*
 

TOPOGRAPHY:MORPHOLOGY 

Lung: Alveolar/Bronchiolar Adenoma ­

or Alveolar/Bronchiolar Carcinoma 

 Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to Firs t Observed Tumor 

Hematopoietic System: Malignant Lymphoma 

 Values0 

Relative Risk (Control) d 

Lower Limit 

Upper Limit 

Weeks to Firs t Observed Tumor 

Hematopoietic System: Malignant Lymphoma 

or Leukemia^ 

 Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

LOW DOSE HIGH DOSE LOW 

CONTROLL CONTROLL DOSEE 

4/46(0.09) 1/45(0.02) 4/44(0.09) 

N.S. 

1.046 

0.207 

5.276 

96 98 96 

5/48(0.10) 11/46(0.24) 4/46(0.09) 

N.S. 

0.364 

0.091 

1.126 

96 95 93 

5/48(0.10) 12/46(0.26) 4/46(0.09) 

N.S. 

0.835 

0.176 

3.634 

96 95 93 

HIGH
 

DOSEE 

7/46(0.15) 

 = 0.031 

6.848 

0.935 

301.000 

97 

7/49(0.14) 

N.S. 

0.597 

0.215 

1.538 

60 

7/49(0.14) 

N.S. 

0.548 

0.201 

1.371 

60 

39
 
TABLE 6 (Continued ) 

TOPOGRAPHY: MORPHOLOGY 

LOW DOSE 

CONTROL 

HIGH DOSE 

CONTROL 

LOW 

DOSE 

Liver: Hepatocellular

 Values0 

 Carcinoma 1/47(0.02) 4/45(0.09) 0/46(0.00) 

N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.000 

0.000 

19.040 

Weeks to Firs t Observed Tumor 96 78 

^

Stomach: Squamous-Cell Papilloma

Squamous-Cell Carcinoma^ 

 Values0 

 or 

1/44(0.02) 3/42(0.07) 0/46(0.00) 

N.S. 

° Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.000 

0.000 

17.820 

Weeks to First Observed Tumor 96 98 

Pituitary:

 Values0 

 Adenoma NOS 2/42(0.05) 6/37(0.16) 0/37(0.00) 

N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.000 

0.000 

3.803 

Weeks to First Observed Tumor 97 98 

HIGH 

DOSE 

1/48(0.02) 

N.S. 

0.234 

0.005 

2.254 

98 

1/48(0.02) 

N.S. 

0.292 

0.006 

3.474 

98 

2/44(0.05) 

N.S. 

0.280 

0.029 

1.461 

91 
TABLE 6 (Concluded)
 

Treated groups received time-weighted average concentrations of 0.06 or 0.12 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 Ρ < 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.
 
exact comparison of the high dose to the high dose control was not
 

significant under the Bonferroni criterion.
 

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

indicated a significant positive association between the administration of 1-nitronaphthalene and tumor incidence. Thus, at the dose
 

levels used in this experiment there was no conclusive evidence that
 

1-nitronaphthalene was a carcinogen in B6C3F1 mice.
 

In male mice, the Fisher exact test indicated a negative association (P = 0.049) when the incidence of alveolar/bronchiolar carcinoma
 

in the high dose mice was compared to that in the high dose controls.
 

This result, however, was not significant using the Bonferroni criterion. The Fisher exact test comparing the incidences of this same
 

tumor in low dose mice also showed a negative association (P = 0.014)·
 

When the incidences of alveolar/bronchiolar adenomas were combined
 

with those of alveolar/bronchiolar carcinomas no significant results
 

were observed.
 

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 a significantly
 

42
 
increased rate of tumor incidence induced in mice by 1-nitronaphthalene that could not be established under the conditions of this
 

test.
 

43
 
V. DISCUSSION
 

Under the conditions of this bioassay, adequate numbers of
 

1-nitronaphthalene-treated rats and mice survived sufficiently long
 

for the development of late-appearing tumors. However, exposure to
 

the compound did not result in a positive association between dietary
 

concentration and the incidence of any tumor in either species· In
 

rats and mice, no compound-related increase in the incidence of neoplasms, nonneoplastic lesions, or other toxic effects was evident.
 

In both species and sexes there was at least slight compound-related
 

mean body weight depression.
 

Under the conditions of this bioassay 1-nitronaphthalene was not
 

demonstrated to be carcinogenic in Fischer 344 rats or B6C3F1 mice.
 

44
 
VI. BIBLIOGRAPHY
 

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.
 

Bureau of Explosives, Washington, D.C. Personal communication, June
 

14, 1977.
 

Chemical Abstracts Service. The Chemical Abstracts Service (CAS)
 

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

Chemical Society, Washington, D.C., 1977.
 

Conzelman, G.M. Jr., J.E. Moulton, and L.E. Flanders, III, "Tumors in
 

the Urinary Bladder of a Monkey: Induction with 1-Nitronaphthalene." GANN 61:79-80, 1970.
 

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.
 

Gusten, H., K.-H. Schweer, and L. Stieflitz, "Identification of Non-


Biodegradable Organic Pollutants in Riverwater." Arhiv ζa
 

Higijenu Rada i Toksikologiju 25:207-212, 1974.
 

Hawley, G.G·, editor, The Condensed Chemical Dictionary, 8th edition.
 

Van Nostrand Reinhold Company, New York, 1971.
 

International Agency for Research on Cancer, IARC Monographs on the
 

Evaluation of Carcinogenic Risk of Chemicals to Man: Some
 

Aromatic Amines, Hydrazine and Related Substances, N-Nitroso
 

Compounds, and Miscellaneous Alkylating Agents, Volume 4.
 

Lyon, France, 1974.
 

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

Observations." Journal of the American Statistical Association
 

53:457-481, 1958.
 

45
 
Linhart, M.S., J.A. Cooper, R.L. Martin, N.P. Page, and J.A. Peters,
 

"Carcinogenesis Bioassay Data System.f!

 Computers and Biomedical
 

Research 7:230-248, 1974.
 

Meijers, A.P., H O 6:244, 1973 as cited in Urso, 1977.
 2
 

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

Co., New York, 1966.
 

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.
 

Sax, N.I·, "General Chemicals." Dangerous Properties of Industrial
 

Materials, 4th edition. N.I. Sax, editor. Van Nostrand
 

Reinhold Company, New York, 1975.
 

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

£2_:679-682, 1975.
 

Treibl, H.G., "Naphthalene Derivatives." Kirk-Othmer Encyclopedia
 

of Chemical Technology, 2nd edition, Vol. 13. Interscience,
 

New York, 1967.
 

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

Industries Center, Stanford Research Institute, Menlo Park,
 

California. Personal communication, June 22, 1977.
 

U.S. International Trade Commission, Synthetic Organic Chemicals,
 

United States Production and Sales, 1975. USITC Publication
 

804, U.S. Government Printing Office, Washington, D.C., 1977.
 

46
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH 1-NITRONAPHTHALENE
 

TABLE A1 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN I MALE RATS ι TREATED WITH 1!-NITRONAPHTHALENE 

LOW DOSE CONTROL (UNTR) 01-0037 

HIGH DOSE CONTROL (UNTR) 01-0084 LOW DOSE 01-0036 HIGH DOSE 01-0106 

ANIMALS INITIALLY IN STUDY 

ANIMALS NECROPSIED 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 

50 

46 

** 46 

25 

25 

25 

50 

49 

48 

50 

50 

49 

INTEGUMENTARY SYSTEM 

•SKIN 

SQUAMOUS CELL PAPILLOMA BASAL-CELL CARCINOMA 

SEBACEOUS ADENOCARCINOMA 

HEMANGIOSARCOMA 

(46) (25) (49) 

1 [2%) 

1 (296) 

1 (2%) 

(50) 

1 (2%) 

*SUBCUT TISSUE 

FIBROMA 

(46) (25) (49) 

2 (4%) 

(50) 

1 (2%) 

RESPIRATORY SYSTEM 

•TRACHEA 

SQUAMOUS CELL CARCINOMA 

ADENOCARCINOMA, NOS, METASTATIC 

(45) 

1 (2%) 

(11) (47) 

1 (2%) 

(48) 

tLUNG 

ADENOCARCINOMA, NOS, METASTATIC 

ALVEOLAR/BRONCHIOLAR ADENOMA 

ALVEOLAR/BRONCHIOLAR CARCINOMA 

PHEOCHROMOCYTOMA, METASTATIC 

OSTEOSARCOMA, METASTATIC 

(46) 

1 (2%) 

(25) 

2 (8%) 

1 (4%) 

1 (4%) 

(48) 

1 (2%) 

1 (2%) 

(49) 

2 (4%) 

1 (256) 

HEMATOPOIETIC SYSTEM 

•MULTIPLE ORGANS 

UNDIFFERENTIATED LEUKEMIA 

MYELOMONOCYTIC LEUKEMIA 

LYMPHOCYTIC LEUKEMIA 

MONOCYTIC LEUKEMIA 

(46) 

1 (2%) 

1 (2%) 

(25) 

2 (8%) 

2 (8%) 

(49) 

2 (4%) 

(50) 

1 (256) 

#BONE MARROW 

OSTEOSARCOMA­ METASTATIC 

(44) (25) (48) 

1 (2%) 

(47) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED

• NUMBER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

A-3
 
TABLE Al (CONTINUED)
 

LOW DOSE HIGH DOSE
 CONTROL (UNTR) CONTROL (UNTR)
 01-0037 01-0084
 

•SPLEEN	 (46) (25)
 

HEMANGIOMA
 

OSTEOSARCOMA, METASTATIC
 

MYELOMONOCYTIC LEUKEMIA
 

#LYMPH NODE (38) (24)
 

ADENOCARCINOMA, NOS, METASTATIC 1 (3%)
 

•MANDIBULAR	 L. NODE (38) (24)
 

GLIOMA,METASTATIC
 

iMEDIASTINAL L.NODE (38) (24)
 

ALVEOLAR/BRONCHIOLAR CAf METASTA
 

CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVE SYSTEM
 

#SAIIVARY GLAND (38) (24)
 

LYMPHANGIOSARCOMA
 

#LIVER (46) (25)
 

NEOPLASTIC NODULE
 

HEPATOCELLULAR CARCINOMA
 

PHEOCHROMOCYTOMA, INVASIVE
 

«STOMACH (45) (24)
 

SQUAMOUS CELL PAPILLOMA 1 (4%)
 

BASAL-CELL CARCINOMA 1 (4%)
 

URINARY SYSTEM
 

#URINARY BLADDER (42) (23)
 

TRANSITIONAL-CFLL PAPILLOMA
 TRANSITIONAL-CELL CARCINOMA
 

ENEOCRINE SYSTEM
 

•PITUITARY	 (41) (21)
 

CARCINOMA.NOS
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OP ANIMALS NECROPSIED
 

A-4
 

LOW DOSE
 01-0036
 

(48)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

(41)
 

(41)
 

(41)
 

(48)
 

1 (2%)
 

(48)
 

2 (4%)
 

(48)
 

(47)
 

1 (2%)
 

(45)
 

2 (4%)
 

HIGH DOSE
 01-0106
 

(48)
 

(47)
 

(47)
 

1 (2%)
 

(47)
 

1 (2X)
 

(47)
 

(49)
 

2 (4%)
 

1 (2%)
 

(47)
 

(48)
 

1 (2%)
 

(43)
 
TABLE Al (CONTINUED) 

LOW DOSE HIGH DOSE CONTROL(UNTR) 01-0037 CONTROL (UNTR) 01-0084 LOW DOSE 01-0036 HIGH DOSE 01-0106 

ADENOMA, NOS 

CHROMOPHOBE ADENOMi 2 (5X) 10 (24%) 1 (5%) 2 (4%) 3 (7%) 

BASOPHIL ADENOMA 2 (10%) 

«ADRENAL (43) (25) (48) (48) 

ADENOCARCINOMA, NOS, METASTATIC 1 (2%) 

PHEOCHEOMOCYTOMA 6 (14%) 2 (8%) 1 (2%) 1 (2%) PHEOCHROMOCYTOMA, MALIGNANT 2 (8%) 2 (4%) 

OSTEOSARCOMA, METASTATIC 1 (2%) 

#THYROID (45) (23) (43) (45) 

ADENOMA, NOS 1 (2%) 

iDENOCARCINOMA, NOS 2 (4%) 

FOLLICULAR-CELL CARCINOMA 1 (2%) 3 (7%) 

C-CELL ADENOMA 1 (2%) 2 (5%) 

C-CELL CARCINOMA 1 (2%) 

•PARATHYROID (32) (15) (22) (29) 

ADENOMA, NOS 1 (3%) 

#PANCREATIC ISLETS (42) (25) (48) (47) 

ISLET-CELL ADENOMA 2 (5%) 2 (8%) 1 (2%) 1 (2%) 

REPRODUCTIVE SYSTEM 

•MAMMARY GLAND (46) (25) (49) (50) 

FIBROADENOMA 1 (4%) 1 (2%) 

•PREPUTIAL GLAND (46) (25) (49) (50) 

CARCINOMA,NOS 1 (4%) 

ADENOMA, NOS 1 (4%) 

#PROSTATE (45) (23) (47) (49) 

PARAGANGLIOMA, NOS 1 (2%) 

•TESTIS (45) (24) (48) (49) 

INTERSTITIAL-CELL TUMOR 33 (73%) 19 (79%) 41 (85%) 46 (94%) 

NERVOUS SYSTEM 

«BRAIN (44) (25) (48) (49) 

GLIOMA, NOS 1 (2%) 

ASTROCYTOMA . _ 1 12%l 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

• NUMBER OF ANIMALS NECROPSIED 

A-5 
LOW DOSE
 CONTROL(UNTR)
 01-0037
 

(46)
 

(46)
 

(46)
 

(46)
 

(46)
 

50
 

6
 

2
 

15
 

27
 

HIGH DOSE
 CONTROL (UNTR)
 01-0084
 

(25)
 

1 (4%)
 

(25)
 

(25)
 

(25)
 

1 (4%)
 

(25)
 

1 (4X)
 

25
 

3
 

4
 

5
 

13
 

LOW DOSE
 01-0036
 

(49)
 

(49)
 

1 (2%)
 

(49)
 

2 (4%)
 

(49)
 

(49)
 

1
 

50
 

5
 

10
 

5
 

1
 

29
 

HIGH DOSE
 01-0106
 

(50)
 

1 <2X)
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

50
 

4
 

5
 

5
 

36
 

SPECIAL SENSE ORGANS
 

*EAR CANAL
 

SQUAMOUS CELL CARCINOMA
 

MUSCULOSKELETAL SYSTEM
 

•LUMBAR	 VERTEBRA
 

OSTEOSARCOMA
 

BOEY CAVITIES
 

•BODY CAVITIES
 

MESOTHELIOMA, NOS
 

•MEDIASTINUM
 

ALVEOLAR/BRONCHIOIAB CA, METASTA
 

•PLEURA
 

ALVEOLAR/BRONCHIOLAR CA, METASTA
 

ALL OTHER SYSTEMS
 

SITE UNKNOWN
 

CARCINOMA,NOS
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY
 NATURAL DEATHS
 MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL MISSING
 

a>	 INCLUDES AUTOLYZED ANIMALS
 

TABLE Al (CONTINUED)
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

• NUMEER OF ANIMALS NECROPSIED
 

A-6
 
TABLE Al (CONCLUDED)
 

LOW DOSE HIGH DOSE
 CONTROL(UNTR) CONTROL (UNTR) LOW DOSE HIGH DOSE
 01-0037 01-0084 01-0036 01-0106
 

TUMOP SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 34 22 43 47
 TOTAL PRIMARY TUMORS 61 41 71 69
 

TOTAL ANIMALS WITH BENIGN TUMORS 33 20 41 46
 TOTAL BENIGN TUMORS 55 31 51 57
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 5 9 15 8
 TOTAL MALIGNANT TUMORS 5 10 18 9
 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1 2 1 3
 TOTAL SECONDARY TUMORS 4 3 4 3
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 1 2 3
 

TOTAL UNCERTAIN TUMORS 1 2 3
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

# SECONDARY TUMORS: METASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT OBGAN
 

A-7
 
TABLE A2
 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH 1-NITRONAPHTHALENE
 

LOW DOSE CONTROL (UNTR) 02-0037 

HIGH DOSE CONTROL (UNTR) 02-0084 LOW DOSE 02-0036 HIGH DOSE 02-0106 

ANIMALS INITIALLY IN STUDY 

ANIMALS NECBOPSIED 

ANIMALS EXAMINED HISTOPATHOLOGICALLY** 

50 

49 

49 

25 

23 

23 

50 

48 

47 

50 

50 

50 

INTEGUMENTARY SYSTEM 

• SKIN 

SQUAMOUS CELL CARCINOMA 

BASAL-CELL TUMOR 

TRICHOEPITHELIOMA· 

SEBACEOUS ADENOCARCINOMA 

LIPOMA 

(49) (23) 

1 (4%) 

(48) 

1 (2%) 

1 (2X) 

(50) 

1 (2%) 

1 (2%) 

*SUBCUT TISSUE 

SQUAMOUS CELL CARCINOMA 

FIBBOMA LEIOMYOSARCOMA 

(49) (23) (48) 

1 (2%) 

1 (2%) 

(50) 

1 (2%) 

1 (2%) 

RESPIBATORY SYSTEM 

#LUNG 

CARCINOMA, NOS, METASTATIC 

ADENOCARCINOMA, NOS, METASTATIC 

HEPATOCELLULAR CARCINOMA, METAST 

AIVEOLAR/BRONCHIOLAR ADENOMA 

FOLLICULAR-CELL CARCINOMA, METAS 

SARCOMA, NOS 

(49) 

1 (2%) 

1 (2%) 

1 (2%) 

(23) 

1 (4%) 

(47) 

2 (4%) 

(50) 

1 (2%) 

1 (2%) 

1 (2%) 

1 (2%) 

1 (2%) 

HEMATOPOIETIC SYSTEM 

•MULTIPLE ORGANS 

MALIGNANT LYMPHOMA, NOS 

MALIG.LYMPHOMA, LYMPHOCYTIC TYPE UNDIFFERENTIATED LEUKEMIA 

MYELOMONOCYTIC LEUKEMIA 

MONOCYTIC LEUKEMIA 

(49) 

2 (4%) 

2 (4%) 

(23) 

2 (9X) 

(48) 

3 (6%) 

(50) 

1 (2%) 

1 (2%) 

tSPLENIC CAPSULE 

ADENOCARCINOMA, NOS, METASTATIC 

(49) (2 3) (46) (49) 

1 (2%) 

# NUMBER OF ANIMALS WITH TISSU E EXAMINED

• NUMBER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

A-8
 
TABLE A2 (CONTINUED) 

LOW DOSE CONTROL (UNTR) 02-0037 

HIGH DOSE CONTROL (UNTR) 02-0084 LOW DOSE 02-0036 HIGH DOSE 02-0106 

•MEDIASTINAL L.NODE 

ADENOCARCINOMA, NOS, METASTATIC 

«MESENTERIC L. NODE 

CARCINOMA, NOS, METASTATIC 

#RENAL LYMPH NODE 

ADENOCARCINOMA, NOS, METASTATIC 

(41) 

(41) 

(41) 

1 (2%) 

(21) 

(21) 

(21) 

(41) 

(41) 

(41) 

(48) 

1 (2%) 

(48) 

1 (2*) 

(48) 

CIFCUIATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

#LIVER 

CARCINOMA, NOS, METASTATIC 

ADENOCARCINOMA, NOS, METASTATIC 

NEOPLASTIC NODULE 

HEPATOCELLULAR CARCINOMA 

•HEPATIC CAPSULE 

ADENOCARCINOMA, NOS, METASTATIC 

•PANCREAS 

CARCINOMA, NOSr METASTATIC 

•ESOPHAGUS 

SQUAMOUS CELL PAPILLOMA 

(49) 

1 (2%) 

2 (4%) 

(49) 

(46) 

(48) 

(23) 

2 (9%) 

(23) 

(22) 

(2 2) 

(47) 

(47) 

(43) 

(47) 

(49) 

1 (2%) 

2 (4%) 

(49) 

1 (2%) 

(48) 

1 (2%) 

(46) 

1 (2%) 

URINABY SYSTEM 

•KIDNEY TUBOLAR-CELL ADENOCARCINOMA 

•KIDNEY/CAPSULE 

CARCINOMA, NOS, METASTATIC 

•URINARY BLADDER 

TRANSITIONAL-CELL PAPILLOMA 

(49) 

(49) 

(41) 

(23) 

(23) 

(22) 

• NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMEER OF ANIMALS NECROPSIED 

(47) 

(47) 

(44) 

1 12%) 

(49) 

1 (2%) 

(49) 

1 (2X) 

(47) 

A-9 
TABLE A2 (CONTINUED)
 

LOW DOSE CONTROL(UNTR) 02-0037 

HIGH DOSE CONTROL (UNTR) 02-0084 LOW DOSE 02-0036 HIGH JOSE 02-0106 

ENDOCRINE SYSTEM 

tPITUITARY 

CARCINOMA,NOS 

ADENOMA, NOS ADENOCARCINOMA, NOS 

CHROMOPHOBE ADENOMA 

(43) 

3 

2 

15 

(7%) 

(5%) 

(35%) 

(21) 

1 

7 

(5%) 

(33%) 

(43) 

1 

9 

(2%) 

(21%) 

(41) 

1 (2%) 

11 (27%) 

«ADRENAL 

CORTICAL ADENOMA 

PHEOCHROMOCYTOMA PHEOCHROMOCYTOMA, MALIGNANT 

(46) 

2 (4%) 

(23) 

2 

1 (9%) (4%) 

(47) 

1 

1 

(2%) 

(2%) 

(47) 

1 (2%: 

2 (4%) 

#THYROID 

ADENOMA, NOS 

ADENOCARCINOMA, NOS 

FOLLICULAR-CELL CARCINOMA 

C-CELL ADENOMA 

C-CELL CARCINOMA 

(47) 

1 

2 

1 

(2%) 

(14%) 

(2%) 

(21) 

2 

1 (10%) 

(5%) 

(45) 

1 (2%) 

(42) 

1 (2%) 

1 (2%) 

tTHYBOID FOLLICLE 

PAPILLARY CYSTADENOCARCINOMA,NOS 

(47) (21) 

1 (5%) 

(45) (42) 

REPRODUCTIVE SYSTEM 

•MAMMARY GLAND 

ADENOMA, NOS 

ADENOCARCINOMA, NOS 

PAPILLARY CYSTADENOCARCINOMA,NOS 

INFILTRATING DUCT CARCINOMA 

FIBROADENOMA 

(49) 

1 

1 

1 

4 

(2%) 

(2%) 

(2%) 

(8%) 

(23) 

2 

1 

4 

(9%) 

(4%) 

(17%) 

(48) 

4 

8 

(8%) 

(17%) 

(50) 

6 (12%) 

•PREPUTIAL GLAND 

SQUAMOUS CELL CARCINOMA 

(49) (23) (48) (50) 

1 (2%) 

#UTERUS 

ADENOCARCINOMA, NOS 

ENDOMETRIAL STROMAL POLYP 

(48) 

4 

10 

(8%) 

(21%) 

(23) 

6 (26%) 

(46) 

1 

9 

(2%) 

(20%) 

(49) 

10 (20%) 

#UT£RUS/ENDOMETRIUM 

UNDIFFERENTIATED CARCINOMA 

(48) (23) (46) (49) 

1 (2%) 

#OVARY 

CARCINOMA, NOS 

(47) (22) (45) (49) 

1 (2%) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED

* NUMEER OF ANIMALS NECROPSIED 

 MICROSCOPICALLY 

Α-IO 
TABLE A2 (CONTINUED)
 

LOW DOSE CONTROL (UNTR 02-0037 ) HIGH DOSE CONTROL (UNTR) 02-0084 

ADENOCARCINOMA, NOS 

GRANULOSA-CELL TUMOR 

NERVOUS SYSTEM
 

#BRAIN (49) (23)
 

ASTROCYTOMA
 

SPECIAL SENSE ORGANS
 

•EAR CANAL	 (49) (23)
 

FIBROMA 1 (2%)
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

•BODY CAVITIES	 (49) (23)
 

MESOTHELIOMA, MALIGNANT 1 (2%)
 

•MEDIASTINUM	 (49) (23)
 

SARCOMA, NOS
 

ALL OTHER SYSTEMS
 

NONE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 50 25
 NATURAL DEATHS	 5 3
 

MORIBUND SACRIFICE	 7 5
 SCHEDULED SACRIFICE	 15 5
 ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 23 12
 

ANIMAL MISSING
 

@ INCLUDES AUTOLYZED ANIMALS
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

• NUMBER OF ANIMALS NECROPSIED
 

Α-II
 

LOW DOSE
 02-0036
 

1 (2%)
 

(47)
 

(48)
 

(48)
 

(48)
 

50
 

7
 

4
 

5
 

34
 

HIGH DOSE
 02-0106
 

1 <2X)
 

1 {2%)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

(5C)
 

1 (2%)
 

50
 

9
 

7
 

5
 

29
 
TABLE A2 (CONCLUDED)
 

LOW DOSE HIGH DOSE
 CONTROL(UNTR) CONTROL (UNTR) LOW DOSE HIGH DOSE
 02-0037 02-0084 02-0036 02-0106
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 32 19 32 34
 TOTAL PRIMARY TUMORS 56 34 46 52
 

TOTAL ANIMALS WITH BENIGN TUMORS 27 18 27 26
 TOTAL BENIGN TUMORS 39 23 37 36
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 15 8 8 12
 TOTAL MALIGNANT TUMORS 17 9 8 13
 

TOTAL ANIMALS WITH SECONDARY TUMORS* 2 3
 TOTAL SECONDARY TUMORS 4 10
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 2 1 3
 

TOTAL UNCERTAIN TUMORS 2 1 3
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

• PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

A-I2
 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH 1-NITRONAPHTHALENE
 

TABLE B1
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH 1-NITRONAPHTHALENE
 

ANIMALS INITIALLY IN STUDY
 

ANIMALS MISSING
 

ANIMALS NECROPSIED
 

HIGH DOSE LOW DOSE
 CONTROL(UNTR) CONTROL (DNTR)
 05-0077 05-0037
 

50 50
 

46 48
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY* * 45 48
 

INTIGUMENTARY SYSTEM
 

*SKIN
 

SQUAMOUS CELL CARCINOMA
 

RESPIBATOBY SYSTEM
 

#LUNG
 

HEPATOCELLULAR CARCINOMA, METAST
 ALVEOLAR/BRONCHIOLAR ADENOMA
 

AIVEOLAR/BRONCHIOLAR CARCINOMA
 

HEMATOPOIETIC SYSTEM
 

•MULTIPLE ORGANS
 

MALIGNANT LYMPHOMA, NOS
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE
 

LEUKEMIA,NOS
 

#SPLEEN
 

HEMANGIOMA
 MALIG.LYMPHOMA, HISTIOCYTIC TYPE
 

•MANDIBULAR	 L. NODE
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE
 

#MESENTERIC L. NODE
 

MALIGNANT LYMPHOMA, NOS
 

#RENAL LYMPH NODE
 

KALIGNANT LYMPHOMA, NOS
 

#LIVER
 

MALIG.LYMPHOMA* HISTIOCYTIC TYPE
 

(46)
 

(45)
 

1 (2%)
 7 (16%)
 4 (9%)
 

(46)
 

(45)
 

1 (2%)
 

(35)
 

1 (3%)
 

(35)
 

(35)
 

(45)
 

(48)
 

(48)
 

6 (13%)
 

(48)
 

2 (4%)
 

2 (4%)
 

(47)
 

1 (2%)
 

(44)
 

(44)
 

(44)
 

(48)
 

# NUMEER OF ANIMALS WITH TISSU E EXAMINED MICROSCOPICALLY 

* NUilEER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-3
 

LOtf DOSE
 05-0036
 

50
 

49
 

49
 

(49)
 

1 (2%)
 

(47)
 

2 (4%)
 8 (17%)
 

(49)
 

1 (2%)
 

(47)
 

(37)
 

(37)
 

1 (3%)
 

(37)
 

(49)
 

1 [2%)
 

HIGH DOSE
 05-0105
 

50
 

1
 

49
 

49
 

(49)
 

(49)
 

8 (16%)
 

1 (2%)
 

(49)
 

1 (2%)
 

(47)
 

(47)
 

(47)
 

1 (2%)
 

(47)
 

1 (2%)
 

(49)
 
TABLE B11 (CONTINUED)
 

-
 HIGH DOSE LOW DOSE
 CONTROL(UNTR) CONTROL (UNTR)
 05-0077 05-0037
 

#FEYERS PATCH (43) (48)
 

MALIGNANT LYMPHOMA, NOS
 

CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVE SYSTEM
 

#IIVER (45) (4 8)
 

HEPATOCELLULAR CARCINOMA 10 (22%) 7 (15%)
 HEMANGIOMA 1 (2%)
 

HEMANGIOSARCOMA
 

«PANCREAS (4 8)
 

SEMINOMA/DYSGERMINOMA, METASTATI
 

#STOMACH (42) (47)
 

SQUAMOUS CELL PAPILLOMA 1 (2%)
 

SQUAMOUS CELL CARCINOMA 1 (2%)
 

#SMALL INTESTINE (43) (48)
 

SEMINOMA/DYSGERMINOMA, METASTATI
 

URINARY SYSTEM
 

NONE
 

ENDOCRINE SYSTEM
 

#THYROID (40) (4 7)
 

FOLLICULAR-CELL ADENOMA 1 (2%)
 

REPROEOCTIVE SYSTEM
 

•TESTIS	 (45) (47)
 

INTERSTITIAL-CELL TUMOR
 

SEMINOMA/DYSGERMINOMA
 

NERVOUS SYSTEM
 

NONE
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

B-4
 

LOW DOSE
 05-0036
 

(47)
 

1 (2X)
 

(49)
 

8 (16%)
 

(45)
 

(48)
 

(47)
 

(38)
 

(48)
 

1 (2%)
 

HIGH DOSE
 05-0105
 

(48)
 

(49)
 

8 (16%)
 

1 (2%)
 

(46)
 

1 (2%)
 

(48)
 

(48)
 

1 (2%)
 

(43)
 

(47)
 

1 (2%)
 
TABLE B1 (CONTINUED)
 

HIGH DOSE LOW DOSE
 CONTROL(UNTR) CONTROL (UNTR)
 05-0077 05-0037
 

SPECIAL SENSE ORGANS
 

*EAfi CANAL ("6) (48)
 

SQUAMOUS CELL CARCINOMA 1 (2%)
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BOEY CAVITIES
 

*EERITCNEUM (46) (48)
 

SEMINOMA/DYSGERMINOMA, METASTATI
 

ALL OTHEH SYSTEMS
 

NONE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 50 50
 NATURAL DEATHS 7 3
 

MORIBUND SACRIFICE 1
 SCHEDULED SACRIFICE 5 5
 

ACCIDENTALLY KILLED
 TERMINAL SACRIFICE 37 42
 

ANIMAL MISSING
 

9 INCLUDES AUTOLYZED ANIMALS
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMEER OF ANIMALS NECROPSIED
 

B-5
 

LOW DOSE
 05-0036
 

(49)
 

(49)
 

50
 

4
 

1
 

45
 

HIGH DOSE
 05-0105
 

(49)
 

(49)
 

1 i2%)
 

50
 

2
 

5
 

42
 

1
 
TABLE B1 (CONCLUDED)
 

HIGH DOSE LOW DOSE
 CONTROL(UNTR) CONTROL (UNTR) LOM DOSE HIGH DOSE
 05-0077 05-0037 05-0036 05-0105
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 21 17 19 21
 TOTAL PRIMARY TUMORS 25 21 22 22
 

TOTAL ANIMALS WITH BENIGN TUMORS 8 2 9 8
 TOTAL BENIGN TUMORS 8 3 9 8
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 15 15 13 1U
 TOTAL MALIGNANT TUMORS 17 18 13 14
 

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

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGH OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ FBIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

# SECONDARY TUMORS: METASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 
TABLE B2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH 1-NITRONAPHTHALENE 

HIGH DOSE CONTROL (UNTR) 06-0077 

LOW DOSE CONTROL (UNTB) 06-0037 LOW DOSE 06-0036 HIGH !)OSE 06-0105 

ANIMALS INITIALLY IN STUDY 

ANIMALS NECROPSIED 

50 

46 

ANIMALS EXAMINED HISTOPATHOLOGICALLY** 46 

50 

48 

47 

50 

46 

46 

50 

49 

48 

INTEGUMENTARY SYSTEM 

•SKIN 

FIBBOSAECOMA 

(46) 

2 (4%) 

(4 8) (46) (49) 

•SUBCUT TISSUE 

FIBEOSABCOMA 

LEIOMYOSARCOMA 

(46) (4 8) 

1 (2%) 

(46) (49) 

1 (2%) 

RESPIRAT0RY SYSTEM 

#LUNG 

ALVEOLAR/BRONCHIOLAE ADENOMA 

ALVEOLAB/BRONCHIOLiE CARCINOMA 

(45) 

1 (2%) 

(46) 

3 (7%) 1 (2%) 

(44) 

3 (7%) 

1 (2%) 

(46) 

5 M1%) 2 (4%) 

HEMATOPOIETIC SYSTEM 

•MULTIPLE OEGANS 

MALIGNANT LYMPHOMA, NOS 

MALIG.LYMPHOMA, UNDIFFEB-TYPE 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 

LYMPHOCYTIC LEUKEMIA 

(46) 

3 (7%) 

1 (2%) 6 (13%) 

1 (2%) 

(48) 

1 (2X) 

2 (4X) 

(46) 

3 (7%) 

1 (2X) 

(49) 

6 ;12X) 

#SPLEEN 

HEMANGIOSARCOMA 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 

(43) (4 6) 

1 (2%) 

1 [2%) 

(46) (48) 

1 :2X) 

#PEYERS PATCH 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 

(43) 

1 (2%) 

(44) (46) (48) 

•KIDNEY 

MALIGNANT LYMPHOMA, NOS 

(43) (46) (46) (48) 

1 (2%) 

«THYMUS 

MALIGNANT LYMPHOMA. NOS 

(27) (31) 

1 (3%) 

(25) (38) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED

• NUflEER OF ANIMALS NECBOPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

B-7
 
TABLE B2 (CONTINUED) 

HIGH DOSE LOW DOSE
 CONTROL(UNTR) CONTROL (UNTR)
 06-0077 06-0037
 

CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVE SYSTEM
 

«LIVER (45) (47)
 

HEPATOCELLULAR CARCINOMA 4 (9%) 1 (2%)
 

ilBBOSASCOMA 1 [2%)
 

tSTOMACH (42) (44)
 

SQUAMOUS CELL PAPILLOMA 3 (7%) 1 (2%)
 

SQUAMOUS CELL CARCINOMA
 

#COLON (41) (40)
 LEIOMYOSARCOMA 1 (3%)
 

URINARY SYSTEM
 

NONE
 

ENDOCRINE SYSTEM
 

«PITUITARY (37) (4 2)
 

CARCINOMA,NOS 1 (2%)
 ADENOMA, NOS 6 (16%) 2 (5%)
 

«ADRENAL (43) (45)
 

CORTICAL ADENOMA 1 (2%)
 PHEOCHROMCCYTOMA 1 (2%)
 

«THYROID (30) (43)
 

FOLLICULAR-CELL ADENOMA
 

«PANCREATIC ISLETS (41) (4 4)
 

ISLET-CELL ADENOMA 1 (2%)
 

REPRODUCTIVE SYSTEM
 

«MAMMARY GLAND (46) (48)
 

ADENOCARCINOMA- NOS 1 (2%)
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

B-8 

LOW DOSE
 06-0036
 

(*»6)
 

(46)
 

(42)
 

(37)
 

(45)
 

(31)
 

1 (3%)
 

(43)
 

(46)
 

1 (2%)
 

HIGH DOSE
 06-0105
 

(48)
 

1 (2%)
 

(48)
 

1 (2%)
 

(47)
 

(44)
 

2 (5%)
 

(46)
 

(43)
 

(47)
 

(49)
 
TABLE B2 (CONTINUED) 

HIGH DOSE LOW DOSE
 CONTROL (UNTR) CONTROL (UNTR)
 06-0077 06-0037
 

#UTEBUS (43) (45)
 

LEIOMYOSARCOMA 1 (2%)
 ENDOMETRIAL STROMAL POLYP 3 (7%)
 

HEMANGIOMA
 

#OVARY (41) (4 5)
 

LUTEOMA 1 (2%)
 TUBULAR ADENOMA 1 (2%)
 

NEBVOUS SYSTEM
 

NONE
 

SPECIAL SENSE OBGANS
 

*HARDERIAN GLAND (46) (**8)
 

CARCINOMA,NOS
 

PAPILLARY ADENOMA
 

PAPILLABY CYSTADENOMA, NOS
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BCDY CAVITIES
 

•ABDOMINAL	 CAVITY (46) (48)
 

LEIOMYOSARCOMA
 

All OTHEB SYSTEMS
 

NONE
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

• NUMBER OF ANIMALS NECROPSIED
 

B-9
 

LOW DOSE
 06-0036
 

(44)
 

1 (256)
 

(45)
 

(46)
 

(46)
 

1 (2%)
 

HIGH DOSE
 06-0105
 

(48)
 

(47)
 

(49)
 

1 (2%)
 

1 (2X)
 

1 (2%)
 

(49)
 
TABLE B2 (CONCLUDED)
 

HIGH DOSE LOW DOSE
 CONTROL (UNTR) CONTROL (UNTR) LOW DOSE HIGH DOSE
 06-0077 06-0037 06-0036 06-0105
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 50 50 50 50
 NATURAL DEATHS 8 6 5 5
 

MORIBUND SACRIFICE 2 2 1 5
 

SCHEDULED SACRIFICE 5 5 5
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 35 37 44 35
 

ANIMAL MISSING
 

9 INCLUDES AUTOLYZED ANIMALS
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 22 20 12 20
 

TOTAL PRIMARY TUMORS 32 24 12 23
 

TOTAL ANIMALS WITH BENIGN TUMORS 12 11 5 7
 

TOTAL BENIGN TUMORS 13 11 5 9
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 18 11 7 14
 

TOTAL MALIGNANT TUMORS 19 13 7 14
 

TOTAL ANIMALS WITH SECONDARY TUMORSt
 TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS WITH TUMORS UNC2RTAIN­ EENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ ERIMARY OR METASTATIC
 TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

Β-IO
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH 1-NITRONAPHTHALENE
 

TABLE CI

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS 

IN MALE RATS TREATED WITH 1-NITRONAPHTHALENE 

ANIMALS INITIALLY	 IN STUDY
 

ANIMALS NECROPSIED
 ANIMALS EXAMINED HISTOPATHOLOGICALLY**
 

INTEGUMENTARY SYSTEM
 

• SKIN
 

EPIDERMAL INCLUSION CYST
 

NECROSIS, NOS
 

•SUBCUT TISSUE
 

ABSCESS, NOS
 

RESPIRATORY SYSTEM
 

•LARYNX
 

INFLAMMATION ACUTE AND CHRONIC
 

INFLAMMATION, CHRONIC
 

#TRACHEA
 

INFLAMMATION, NOS
 

INFLAMMATION, ACUTE/CHRONIC
 

INFLAMMATION, CHRONIC
 

•TRACHEAL SUBMUCOSA
 

HYPERPLASIA, NOS
 

#LUNG/ERONCHUS
 

BRONCHIECTASIS
 

INFLAMMATION, FOCAL
 

ABSCESS, NOS
 

INFLAMMATION, ACUTE/CHRONIC
 INFLAMMATION, CHRONIC
 

PERIVASCULAR CUFFING
 

tBPONCHIAL MUCOUS GLA
 

ABSCESS, NOS
 

NECROSIS. NOS
 

LOW DOSE
 CONTROL (UNTR)
 01-0037
 

50
 

46
 

46
 

(46)
 

(46)
 

(46)
 

(45)
 

9 (20%)
 

10 (22%)
 

(45)
 

(46)
 

8 (17%)
 

(46)
 

1 (2%)
 

1 f2%)
 

HIGH DOSE
 CONTROL (UNTR)
 01-0084
 

25
 

25
 

25
 

(25)
 

1 (4%)
 

(25)
 

(25)
 

1 (4%)
 

7 (28%)
 

(11)
 

1 (9%)
 

(11)
 

(2 5)
 

2 (8%)
 

1 (4%)
 

(25)
 

# NUMEER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

C-3 

LOS DOSE HIGH DOSE
 01-0036 01-0106
 

50 50
 

49 50
 

48 49
 

(49)	 (50)
 

1 (2%)
 

(49)	 (50)
 

1 (2%) 1 (2%)
 

(49) (50)
 

(47) ("8)
 

32	 (68%)
 

1 (2%) 43 (90%)
 

(47)	 (48)
 

1 (2%)
 

(48)	 (49)
 

8 (16%)
 

1 (2%)
 

1 (2%)
 

2 (4%)
 

(48) (49)
 
TABLE CI (CONTINUED)
 

LOW DOSE CONTROL (UNTR) 01-0037 

HIGH DOSE CONTROL (UNTR) 01-0084 LOM DOSE 01-0036 HIGH DOSE 01-0106 

HYPERPLASIA, ADENOMATOUS 1 (2%) 

«LUNG/BRONCHIOLE 

INFLAMMATION, NOS 

INFLAMMATION, FOCAL 

(46) 

1 

1 

(2%) 

(2%) 

(25) (48) (49) 

«LUNG 

ATELECTASIS 

CONGESTION, NOS 

EDEMA, NOS 

INFLAMMATION, NOS INFLAMMATION, FOCAL 

INFLAMMATION, INTERSTITIAL 

INFLAMMATION, SUPPURATIVE 

BRONCHOPNEUMONIA, ACUTE 

ABSCESS, NOS 

PNEUMONIA, CHRONIC MURINE 

INFLAMMATION, CHRONIC 

GRANULOMA, NOS 

PERIVASCULITIS 

HYPERPLASIA, ALVEOLAR EPITHELIUM 

(46) 

1 

1 

1 

1 

3 

1 

1 

1 

1 

5 

(2%) 

(2%) 

(2%) 

(2%) 

(7%) 

(2%) 

(2%) 

(2%) 

(2%) 

(11%) 

(25) 

2 (8%) 

1 (4%) 1 (4%) 

11 (44%) 

1 (4%) 

(48) 

1 (2%) 

1 (2%) 

(49) 

1 (2%) 

9 (18%) 

«LUNG/ALVEOLI 

HEMORRHAGE 

(46) (25) (48) 

2 (4%) 

(49) 

HEMATOPOIETIC SYSTEM 

«BONE MARROW 

HYPERPLASIA, HEMATOPOIETIC 

HYPOPLASIA, HEMATOPOIETIC 

(44) (25) 

2 (8%) 

(48) 

2 (4%) 

(47) 

«SPLEEN 

THROMBOSIS, NOS 

CONGESTION, NOS 

FIBROSIS 

INFARCT, HEALED 

HEMOSIDEROSIS RETICULOCYTOSIS 

HYPERPLASIA, HEMATOPOIETIC 

HYPERPLASIA, ERYTHROID 

HYPERPLASIA, RETICULUM CELL HYPERPLASIA, LYMPHOID HEMATOPOIESIS 

(46) 

1 

1 

1 

1 

12 

8 

(2%) 

(2%) 

(2%) 

(2%) 

(26%) 

(17%) 

(25) 

1 (4%) 

1 (4%) 

1 (4%) 

(48) 

2 (4%) 

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

(48) 

•LYMPH NODE (38) 

1 I3XL 

(24) (41) (47) 

• NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

C-4
 
TABLE CI (CONTINUED) 

HIGH DOSE
 CONTROL (UNTR) CONTROL (UNTR)
 

01-0037 01-0084
 

HYPERPLASIA, NOS 1 (3%)
 

PLASMACYTOSIS 1 (4%)
 

HYPERPLASIA, RETICULUM CELL 3 (8%)
 

•MANDIBULAR L.	 NODE (38) (24)
 

HYPERPLASIA, PLASMA CELL
 

•MEDIASTINAL	 L-NODE (38) (24)
 

PLASMACYTOSIS 1 (3%)
 

HYPERPLASIA, PLASMA CELL
 

•MESENTERIC	 L. NODU (38) (24)
 

HEMATOPOIESIS
 

•RENAL LYMPH	 NODS (38) (24)
 

HYPERPLASIA, NOS
 

CIRCULATORY SYSTEM 

•LYMPHATIC VESSELS 

INFLAMMATION, NOS 

(46) 

1 (2%) 

(2 5) 

•HEART 

PERIARTERITIS 

(46) (25) 

1 (4%) 

•HEART/ATRIUM 

INFLAMMATION PROLIFERATIVE 

(46) (25) 

•MYOCARDIUM 

INFLAMMATION, NOS 

INFLAMMATION, INTERSTITIAL 

INFLAMMATION, ACUTE/CHRONIC 

INFLAMMATION, CHROUIC FOCAL 

FIBROSIS 

FIBROSIS, FOCAL 

FIBROSIS, DIFFUSE 

DEGENERATION, NOS 

(46) 

1

22

3

7

 (2%) 

 (48%) 

 (7%) 

 (15%) 

(25) 

1

10

 (4%) 

 (40%) 

*AORTA 

INFLAMMATION, CHRONIC

MEDIAL CALCIFICATION 

CALCIFICATION, FOCAL 

 FOCAL 

(46) 

1 [2%) 

(25) 

1 (4%) 

•PULMONARY ARTERY 

HYPERTROPHY. NOS 

(46) 

1 12%) 

(25) 

• NUMEER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMEER OF ANIMALS NECROPSIED
 

LOW DOSE
 

01-0036
 

(41)
 

(41)
 

(41)
 

1 (2%)
 

(41)
 

(49)
 

(48)
 

(48)
 

1 (2%)
 

(48)
 

1 (2%)
 

1 (2%)
 

2 (4%)
 

11 (23%)
 

(49)
 

(49)
 

HIGH DOSE
 

01-0106
 

(47)
 

1 (2%)
 

(47)
 

1 (2%)
 

(47)
 

(47)
 

1 (2%)
 

(50)
 

(49)
 

(49)
 

(49)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

C-5
 
TABLE CI (CONTINUED)
 

LOW DOSE CONTROL(UNTR) 01-0037 HIGH DOSE CONTROL (UNTR) 01-0084 LOW DOSE 01-0036 HIGH DOSE 01-0106 

•TESTICULAR ARTERY 

CALCIFICATION, NOS 

(46) (25) (49) 

1 (2%) 

(50) 

DIGESTIVE SYSTEM 

#LIVER 

CONGESTION, NOS 

CONGESTION, CHRONIC PASSIVE HEMORRHAGE INFLAMMATION, FOCAL GRANULOMATOU 

CHOLANGIOFIBROSIS 

DEGENERATION, HYALINE 

NECROSIS, FOCAL 

NECROSIS, COAGULATIVE 

METAMORPHOSIS FATTY 

HYPERPLASIA, NODULAR 

HYPERPLASIA, NOS 

HYPERPLASIA, FOCAL 

ANGIECTASIS 

(46) 

3 (7%) 

1 (2%) 1 (2%) 

23 (50%) 

(25) 

1 (4%) 

1 (4%) 

1 (4%) 

4 (16%) 

(48) 

1 (2%) 

1 (2%) 

1 (2%) 

1 (2%) 

1 (2%) 3 (6%) 

1 (2%) 9 (19%) 

1 (2%) 

(49) 

1 (2%) 

•LIVER/CENTRILOBULAR 

NECROSIS, NOS 

(46) (25) (48) (49) 

1 (2%) 

#LIVER/PERIIPORTAL 

FIBROSIS 

(46) 

1 (2%) 

(25) (48) (49) 

*BILE DUCT 

INFLAMMATION, NOS 

INFLAMMATION, ACUTE/CHRONIC 

HYPERPLASIA, NOS 

HYPERPLASIA, FOCAL 

(46) 

6 (13%) 

32 (70%) 

1 (2%) 

(25) 

6 (24%) 

(49) 

1 (2%) 

3 (6%) 

(50) 

«PANCREAS 

INFLAMMATION, NOS 

INFLAMMATION, INTERSTITIAL 

INFLAMMATION, ACUTE/CHRONIC 

HYPERPLASIA, INTRADUCTAL 

(42) 

10 (24%) 

1 (2%) 

(2 5) 

1 (4%) 

(48) 

14 (29%) 

(47) 

1 (2%) 

tPANCEEATIC DUCT 

HYPERPLASIA, NOS 

(42) (2 5) 

1 (4%) 

(48) (47) 

#PANCR£ATIC ACINUS 

ATROPHY- NOS 

(42) 

4 10%) 

(25) (48) (47) 

# NUMEEfi OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

• NUMBER OF ANIMALS NECROPSIED 

C-6
 
TABLE CI (CONTINUED)
 

LOW DOSE HIGH DOSE
 CONTROL(UNTR) CONTROL (UNTR)
 01-0037 01-0084
 

#STOMACH (45) (24)
 

EPIDERMAL INCLUSION CYST 1 (2%) 1 (4%)
 

ULCEP, NCS 2 (4%)
 

PERIARTERITIS
 HYPERPLASIA, NOS 6 (13%)
 

HYPEFKEEATOSIS 1 {2%)
 ACANTHOSIS 1 (2%)
 

tPEYERS PATCH (<*3) (24)
 

HYPERPLASIA, NOS 7 (16%) 2 (8%)
 

#ILEUM (43) (24)
 

HYPERPLASIA, LYMPHOID
 

•COLON	 (43) (24)
 

NEMATODIASIS 3 (7%)
 

URINARY SYSTEM
 

#KIDNEY (46) (24)
 

CONGESTION, NOS
 

GLOMERULONEPHRITIS, NOS 33 (72%) 5 (21%)
 

INFLAMMATION, INTERSTITIAL 1 (2%)
 

GLOMERULONEPHRITIS, SUBACUTE
 

NEPHROPATHY 1 (4%)
 

NEPHROSIS, NOS 16 (67%)
 

GLOMERULOSCLEROSIS, NOS
 

#URINARY BLADDER (42) (23)
 

CALCULUS, NOS 3 (13%)
 INFLAMMATION, NOS 1 (2%)
 HYPERPLASIA, EPITHELIAL 3 (7%)
 

ENCOCRINE SYSTEM
 

#PITUITARY (41) (21)
 HYPERPLASIA, NOS 3 (7%)
 

HYPERPLASIA, FOCAL
 

HYPERPLASIA, CHfiOMOPHOBE-CELL 2 (5%)
 

tPITUITAPY/BASOPHIL (41) (21)
 NODULE 1_15%L
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

• NUMBER OF ANIMALS NECROPSIED
 

C-7
 

LOW DOSE
 01-0036
 

(48)
 

1 (2%)
 

(48)
 

(48)
 

2 (4%)
 

(47)
 

3 (6%)
 

(48)
 

1 (2%)
 

1 (2%)
 2 (4%)
 

35 (73%)
 

1 (2%)
 

(47)
 

(45)
 

3 (7%)
 

(45)
 

HIGH OOSE
 01-0106
 

(47)
 

(48)
 

(48)
 

(46)
 

(48)
 

45	 (94%)
 

(48)
 

(43)
 

(43)
 
TABLE C1 (CONTINUED)
 

LOW DOSE CONTROL (UNTR) 01-0037 

HIGH DOSE CONTROL (DNTR) 01-0084 LOH DOSE 01-0036 HIGH DOSE 01-0106 

#ADRENAL COETEX 

METAMORPHOSIS FATTY HYPERTROPHY, FOCAL 

HYPERPLASIA, NODULPF 

HYPERPLASIA, NOS 

HYPERPLASIA, FOCAL 

(43) 

1 (2%) 

1 (2%) 

(2 5) 

1 (4%) 

(48) 

3 (6%) 

1 (2%) 

4 (8%) 

(48) 

#ZONA FASCICOLATA 

CONGESTION, NOS 

(43) (25) (48) (48) 

1 (2%) 

#ADfiENAL MEDULLA 

NECROSIS, NOS 

CALCIFICATION, NOS HYPERPLASIA, NODULAR 

HYPERPLASIA, NOS 

HYPERPLASIA, FOCAL 

(43) 

1 (2%) 

1 (2%) 1 (2%) 

6 (14%) 

(25) (48) 

1 (2%) 

3 (6%) 

(48) 

#TBYSOID 

LYMPHOCYTIC INFLAMMATORY INFILTR 

HYPERPLASIA, ADENOKATOUS 

HYPERPLASIA, C-CELL 

(45) 

1 (2%) 

1 (2%) 

(23) (43) 

1 (2%) 

(45) 

#PANCREATIC ISLETS 

CONGESTION, NOS 

HYPERPLASIA, NOS 

(42) 

2 (5%) 

(2 5) (48) 

1 (2%) 

(47) 

REFROEUCTIVE SYSTEM 

•MAMMARY GLAND 

GALACTOCELE 

HYPERPLASIA, NOS LACTATION 

(46) 

5 (11%) 

(25) 

3 (12%) 

7 (28%) 

(49) 

1 (2%) 1 (2%) 

(50) 

•PREPUTIAL GLAND 

ABSCESS, NOS HYPERPLASIA, NOS 

(46) 

1 {2%) 

1 (2%) 

(25) (49) (50) 

•PROSTATE 

INFLAMMATION, NOS 

INFLAMMA1ION, FOCAL 

INFLAMMATION, ACUTE INFLAMMATION, ACUTE FOCAL 

INFLAMMATION, ACUTE/CHRONIC 

(45) 

21 (47%) 

3 (7%) 

(23) 

1 (4%) 

(47) 

2 (4X) 6 (13%) 

5 (11%) 

(49) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

• NUMEER OF ANIMALS NECROPSIED 

C-8
 
TABLE CI (CONTINUED)
 

LOW DOSE CONTROL(UNTR) 01-0037 

HIGH DOSE CONTROL (DNTR) 01-0084 LOW DOSE 01-0036 HIGH DOSE 01-0106 

ATROPHY, NOS 

HYPERPLASIA, EFIThFLIAL 

HYPERPLASIA, FOCAL 

HYPERPLASIA, PAPILLARY METAPLASIA, SQUAMOUS 

5 (11%) 

2 (4%) 

5 (11%) 

4 (17%) 

1 (2%) 

*SEMINAL VESICLE 

ATROPHY, NOS (46) (25) 

1 (4%) 

(49) (50) 

iTESTIS 

HEMORRHAGE 

DEGENERATION, NOS 

CALCIFICATION, FOCAL 

ATROPHY, NOS 

ASPERMATOGENESIS 

HYPERPLASIA, INTERSTITIAL CELL 

(45) 

2 (4%) 

1 (2%) 19 (42%) 

(24) 

4 (17%) 

12 (50%) 

2 (8%) 

(^8) 

1 (2%) 

36 (75%) 

3 (6%) 

(49) 

6 (12%) 

fTESIIS/TUEULE 

DEGENERATION, NOS 

(45) 

6 (13%) 

(24) (48) (49) 

1 (2%) 

•EPIDIDYMIS 

STEATITIS 

(46) (25) (49) (50) 

1 (2%) 

NERVOUS SYSTEM 

#ERAIN 

HEMORRHAGE 

CALCIFICATION, FOCAL 

(44) (25) 

2 (8%) 

1 (4%) 

(48) 

1 (2%) 

(49) 

SPECIAL SiNSE ORGANS 

•EYE/COPNEA 

INFLAMMATION, ACUTT FOCAL 

(46) (25) (49) 

1 (2%) 

(50) 

*£YI/RETINA 

DEGENERATION, NOS 

(46) (25) (49) 

1 (2%) 

(50) 

•EYE/CRYSTALLINE LENS 

CATARACT 

(46) (25) (49) 

1 (2%) 

(50) 

fiOSCUIOSKELETAL SYSTEM 

*SKEIETAL MUSCLE 

CALCIFICATION. FOCAL 

(46) (25) 

1 (4%) 

(49) (50) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

• NUMBER OF ANIKALS NECROPSIED 

C-9
 
*CARTILAGE,NOS
 

CYST, NOS
 

BOEY CAVITIES 

NONE 

ALL OTHER SYSTEMS 

NONE 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPORTED 

JUTO/NECROPSY/HISTO PERF 

ΑϋΤΟ/NECROPSY/NO HISTO 

AUTOLYSIS/NO NECROPSY 

TABLE CI (CONCLUDED)
 

LOW DOSE CONTROL(UNTR) 

01-0037 

(46)
 

1 (2%)
 

1 

4 

HIGH DOSE 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-IO
 

CONTROL (UNTR) 

01-0084 

(25) 

LOW DOSE HIGH DOSE 

01-0036 01-0106 

(49) (50) 

2 1 

1 1 

1 
TABLE C2
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS
 

TREATED WITH 1-NITRONAPHTHALENE
 

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

02-0037 02-0084 02-0036 02-0106
 

ANIMALS INITIALLY IN STUDY 50 25 50 50
 

ANIMALS NECEOPSIED 49 23 48 50
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY** 49 23 47 50
 

INTEGUMENTARY SYSTEM
 

NONE
 

EESPIRATOEY SYSTEM
 

•LARYNX	 (49) (2 3) (48) (50)
 

INFLAMMATION ACUTE AND CHRONIC 1 (4%)
 INFLAMMATION, CHRONIC 3 (13%)
 

#TRACHEA (48) (5) (47) (46)
 

INFLAMMATION, NOS 9 (19%)
 

INFLAMMATION, ACUTE/CHRONIC 25 (53%)
 

INFLAMMATION, CHRONIC 10 (2U) 1 (2%) 22 (48%)
 

HYPERPLASIA, EPITHELIAL 1 (2%)
 

FCLYP, INFLAMMATORY 1 (2%) 2 (4%)
 

#LDNG/ERONCHDS (49) (2 3) (47) (50)
 

BRONCHIECTASIS 1 (2%) 1 (2%)
 

INFLAMMATION, NOS 1 (2%)
 

INFLAMMATION, CHRONIC 9 (18%)
 

#LUNG/ERONCHIOLE (49) (23) (47) (50)
 

INFLAMMATION, NOS 1 (2%)
 

tLUNG (49) (23) (47) (50)
 

HEMORRHAGE 2 (4%)
 

INFLAMMATION, NOS 1 (2%)
 

INFLAMMATION, FOCAL 7 (14%) 1 (2%)
 

INFLAMMATION, INTERSTITIAL 2 (4%) 3 (13%)
 

BRONCHOPNEUMONIA NECROTIZING 1 (2%)
 

PNEUMONIA, CHRONIC MURINE 8 (35%) 1 (2%)
 

GRANULOMA, FOREIGN BODY 1 (4%)
 PERIVASCULITIS	 6 ί^2%)
 

# NUMBER OF ANIMALS WITH TISSU E EXAMINED MICROSCOPICALLY 

• NUMBER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

C-ll
 
TABLE C2 (CONTINUED)
 

LOW DOSE CONTROL(UNTR) 02-0037 HIGH DOSE CONTROL(ONTR) 02-0084 

CALCIFICATION, POCAL 

HYPERPLASIA, EPITHELIAL 1 (4%) 

1 (4%) 

•LONG/ALVEOLI 

HEMORRHAGE (49) (23) 

HEMATOPOIETIC SYSTEM
 

#BONE MARROW (48) (22)
 

HYPERPLASIA, HEMATOPOIETIC 1 (5%)
 

#SPLEEN (49) (2 3)
 

HEMATOMA, NOS 1 (4%)
 

HEMOSIDEROSIS 2 (9%)
 

HYPERPLASIA, NOS 1 (2%)
 HYPERPLASIA, HEMATOPOIETIC 3 (6%) 3 (13%)
 HYPERPLASIA, ERYTHROID 17 (35%) 4 (17%)
 HYPERPLASIA, PLASMA CELL 1 (2%)
 HYPERPLASIA, RETICULUM CELL 11 (22%)
 

HEMATOPOIESIS 3 (13%)
 

EBYTHROPOIESIS
 

#LYMPH NODE (41) (21)
 INFLAMMATION, NOS 3 (7%)
 

HYPERPLASIA, NOS 2 (5%)
 PLASMACYTOSIS 3 (7%)
 

HYPERPLASIA, PLASMA CELL 1 (2%)
 

•MANDIBULAR	 L. NODE (41) (21)
 

HYPERPLASIA, PLASMA CELL
 

•MEDIASTINAL	 L.NODE (41) (21)
 

HEMORRHAGE
 

CIBCUIATORY SYSTEM
 

•HEART	 (49) (23)
 

NECROSIS, FOCAL
 

•APEX	 OF HEART (49) (23)
 

SCAR
 

•MYOCARDIUM	 (49) (23)
 

INFLAMMATION. NOS 1 (2%)
 

• NUMBER OF ANIMALS WITH TISSUE EXAMINED MICSOSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-12
 

LOW DOSE
 02-0036
 

(47)
 

(46)
 

(46)
 

(41)
 

(41)
 

(41)
 

1 (2%)
 

(47)
 

1 (2%)
 

(47)
 

(47)
 

HIGH DOSE
 02-0106
 

(50)
 

1 (2%)
 

(48)
 

(49)
 

1 (2%)
 

2 (4%)
 

(48)
 

(48)
 

1 (2%)
 

(48)
 

(49)
 

(49)
 

1 (2%)
 

(49)
 
TABLE C2 (CONTINUED)
 

LOW DOSE HIGH DOSE CONTROL(UNTR) 02-0037 CONTROL (UNTR) 02-0084 

INFLAMMATION, INTERSTITIAL 24 (49%) 1 (4%) 

INFLAMMATION, ACUTE/CHRONIC FIBROSIS 5 (10%) 

FIBROSIS, FOCAL 

FIBROSIS, DIFFUSE 

DEGENERATION, NOS 4 (17%) 

•CORONARY ASTERY (49) (23) 

INFLAMMATION, ACUTE 

•PCRTAL VEIN (49) (23) 

THROMBUS, MURAL 1 (2%) 

DIGESTIVE SYSTEM
 

#PAROTID GLAND (44) (22)
 

INFLAMMATION, CHRONIC
 

tLIVER (49) (23)
 

CONGESTION, CHRONIC PASSIVE 1 (4%)
 

FIBROSIS 1 (2%)
 

CHOLANGICFIBROSIS 1 (4%)
 

PERIVASCULITIS 1 (2%)
 NECROSIS, FOCAL 4 (8%)
 

NECROSIS, COAGULATIVE 2 (4%)
 NECROSIS, HEMORRHAGIC
 METAMORPHOSIS FATTY 1 (2%) 2 (9%)
 

BASOPHILIC CYTO CHANGE 4 (17%)
 HYPERPLASIA, NODULAR 1 (2%)
 

HYPEBPLASIA, FOCAL 22 (45%) 3 (13%)
 

ANGIECTASIS 1 (2%)
 

#LIVER/CENTRILOBULAR (49) (23)
 

CONGESTION, PASSIVE
 

NECROSIS, NOS
 

*BILE DUCT (49) (23)
 

INFLAMMATION, NOS 5 (10%)
 

HYPERPLASIA, NOS 27 (55%) 2 (9%)
 

HYPERPLASIA, FOCAL
 

#PANCREAS (46) (22)
 

INFLAMMATION, NOS 7 (15%)
 

INFLAMMATIONX ACUTE/CHRONIC
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMEER OF ANIMALS NECROPSIED
 

C-I3
 

LOW DOSE
 02-0036
 

2 (4%)
 

4 (9%)
 

7 (15%)
 

(48)
 

1 (2%)
 

(48)
 

(46)
 

(47)
 

1 (2%)
 

1 (2%)
 3 (6%)
 

1 (2%)
 

24 (51%)
 

(47)
 

(48)
 

7 (15%)
 

6 (13%)
 

(43)
 

2_12I%1
 

HIGH DOSE
 02-0106
 

(50)
 

(50)
 

(43)
 

1 (2%)
 

(49)
 

2 (4%)
 

1 {?%)
 

1 (2%)
 

(49)
 

1 (2%)
 

1 (?%)
 

(50)
 

(48)
 
TABLE C2 (CONTINUED)
 

LOW DOSE HIGH DOSE
 CONTROL(UNTR) CONTROL (UNTR)
 02-0037 02-0084
 

#PANCREATIC DUCT (46) (22)
 

HYPERPLASIA, NOS 1 (2%)
 

«PANCREiTIC ACINUS (46) (22)
 

ATROPHY, NOS 2 (4%)
 

•STOMACH	 (48) (2 3)
 

INFLAMMATION, NOS 2 (4%)
 

INFLAMMATION, FOCAL 2 (4%)
 HYPERPLASIA, EPITHELIAL 1 (2%)
 

tGASTRIC MUCOSA (48) (23)
 

NECROSIS, FOCAL
 

HYPERPLASIA, NOS 1 (2%)
 

#PEYEfiS PATCH (47) (23)
 

HYPERPLASIA, NOS 6 (13%) 4 (17%)
 

«ILEUM (47) (23)
 

HYPERPLASIA, LYMPHOID
 

•COLON	 (43) (22)
 

NEMATODIASIS 3 (7%)
 

PARASITISM 2 (9%)
 

OBINfiBY SYSTEM
 

«KIDNEY (49) (23)
 

HYDRONEPHROSIS 1 (2%)
 

GLOMEfiULCNEPHRITIS, NOS 33 (67%) 4 (17%)
 

INFLAMMATION, INTERSTITIAL 1 (2%)
 GLOMERULONEPHRITIS, MEMBRANOUS 1 (2%)
 

PYELONEPHRITIS, ACUTE 1 (4%)
 

GLOMERULONEPHRITIS, SUBACUTE
 

INFLAMMATION, CHRONIC 1 (2%)
 PYELONEPHRITIS, CHFONIC 1 (4%)
 NEPHROSIS, NOS 10 (43%)
 

NECROSIS, FOCAL
 

CALCIFICATION, FOCAL 1 (4%)
 

iKIDNEY/TUBULE (49) (23)
 

NECROSIS, NOS 1 (4%)
 

«URINARY BLADDER (41) (22)
 

INFLAMMATION. NOS 1 (2%)
 

# NUMEER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUPEER OF ANIMALS NECROPSIED
 

C-I4
 

LOH DOSE
 02-0036
 

(43)
 

(43)
 

(44)
 

(44)
 

1 (2%)
 

(44)
 

(44)
 

1 (2%)
 

(44)
 

4 (9%)
 

(47)
 

30	 (64%)
 

1 (2%)
 

(47)
 

(44)
 

HIGH DOSE
 02-0106
 

(48)
 

(48)
 

(47)
 

(47)
 

(47)
 

(47)
 

(47)
 

(49)
 

1 (2%)
 

32	 (65%)
 

(49)
 

(47)
 
TABLE C2 (CONTINUED)
 

LOW DOSE HIGH DOSE CONTROL(UNTR) CONTROL (UNTR) 02-0037 02-0084 

HYPERPLASIA, EPITHELIAL 

ENDOCRINE SYSTEM
 

•PITUITARY	 (43) (21)
 

HEMORRHAGIC CYST 1 (5%)
 

HYPERPLASIA, NOS 2 (556)
 HYPERPLASIA, FOCAL 1 (5%)
 HYPERPLASIA, CRROMOPHOBE-CELL 1 (2%)
 

tADRENAL COHTEX (46) (23)
 

NODULE 1 (2%)
 

METAMORPHOSIS FATTY
 

HYPEFPLASIA, NODULAR
 

HYPERPLASIA, NOS 7 (15%)
 

HYPERPLASIA, FOCAL
 

«ADRENAL 1EDULLA (46) (23)
 

HYPERPLASIA, NOS 4 (9%)
 

HYPERPLASIA, FOCAL
 

tTHYROID (47) (21)
 HYPERPLASIA, C-CELL 3 (14%)
 

HYPERPLASIA, FOLLICOLAR-CELL 1 (2%)
 

•PANCREATIC ISLETS	 (46) (2 2)
 

HYPERPLASIA, NOS 1 (2%)
 

REEBCEOCTIVE SYSTEM
 

•MAMMARY GLAND	 (49) (23)
 

DILATATION/DUCTS
 

GALACTOCELE 5 (10%) 1 (4%)
 

HYPERPLASIA, NOS 17 (35%) 1 (4%)
 

HYPERPLASIA, PAPILLARY 1 (2%)
 LACTATION 9 (39%)
 

•MAMMARY DUCT	 (49) (2 3)
 HYPERPLASIA, NOS
 

•UTERUS	 (48) (2 3)
 

HYDROMETRA 3 (6%)
 INFLAMMATION- SUPPURATIVE 1 i2%>
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

• HUMEEB OF ANIMALS NECROPSIED
 

C-I5
 

LOW DOSE
 02-0036
 

1 (2%)
 

(43)
 

1 (2%)
 

1 (2%)
 

(47)
 

5 (11%)
 3 (6%)
 2 (4%)
 

4 (9%)
 

(47)
 

1 (2%)
 

(45)
 

(43)
 

(48)
 

1 (2%)
 7 (15%)
 14 (29%)
 

(48)
 

1 (2%)
 

(46)
 

3 (7%)
 

HIGH DOSE
 02-0106
 

1 (2%)
 

(41)
 

(47)
 

(47)
 

(42)
 

3 (7%)
 

(48)
 

(50)
 

(50)
 

(49)
 
TABLE C2 (CONTINUED) 

LOW DO! CONTR 3E 

OL (UNTR) 02-0037 

HIGH DOSE CONTROL (UNTR) 02-0084 LOW DOSE 02-0036 HIGH DOSE 02-0Π6 

PYOMETRA 

ABSCESS, NOS 

HYPERPLASIA, 

HYPERPLASIA, 

ADENOMATOUS 

STROMAL 

2 

5 

(4%) 

(10%) 

3 (13%) 

1 

1 

1 

(2%) 

(2%) 

(2%) 

•CERVIX UTERI 

INFLAMMATION 

INFLAMMATION 

FIBROSIS 

,

,

 SUPPURATIVE 

 ACUTE FOCAL 

(48) (23) (46) 

1 

1 

(2%) 

(2%) 

(49) 

1 (2%) 

#UTEBUS/ENDOMETRIUM 

HEMORRHAGE 

INFLAMMATION 

INFLAMMATION 

INFLAMMATION 

INFLAMMATION 

INFLAMMATION 

ABSCESS, NOS 

INFLAMMATION 

INFLAMMATION 

HYPERPLASIA, 

HYPERPLASIA, 

HYPERPLASIA, 

HYPERPLASIA, 

, NOS 

, FOCAL 

, SUPPURATIVE 

, ACUTE 

, ACUTE NECROTIZING 

, ACUTE/CHRONIC 

, CHRONIC 

NOS 

EPITHELIAL 

CYSTIC 

ADENOMATOUS 

(48) 

14 

1 

2 

1 

2 

1 

(29%) 

(2%) 

(4%) 

(2%) 

(4%) 

(2%) 

(23) 

1 (4%) 

1 (4%) 

1 (4%) 

1 (4%) 

(46) 

1 

1 

15 

1 

2 

1 

3 

11 

(2%) 

(2%) 

(33%) 

(2%) 

(4%) 

(2%) 

(7%) 

(24%) 

(49) 

7 (14%) 

1 (2%) 

1 (2%) 

2 (4%) 

#OVABY/OVIDUCT 

EETENTION FLUID 

INFLAMMATION 

INFLAMMATION 

ABSCESS, NOS 

INFLAMMATION 

, NOS 

, ACUTE 

, ACUTE/CHRONIC 

(48) 

1 (2%) 

(23) 

1 (4%) 

1 (4%) 

(46) 

1 

5 

1 

1 

(2%) 

(11%) 

(2%) 

(2%) 

(49) 

iOVARY 

CYST, NOS 

INFLAMMATION 

INFLAMMATION 

ABSCESS, NOS 

INFLAMMATION 

, SUPPURATIVE 

, ACUTE NECROTIZING 

, FOCAL GRANULOMATOU 

FIBROSIS, FOCAL 

HYPERPLASIA, INTERSTITIAL CELL 

(47) 

4 

1 

1 

(9%) 

(2%) 

(2%) 

(22) 

3 (14%) 

(45) 

4 

1 

1 

1 

(9%) 

(2%) 

(2%) 

(2%) 

(49) 

6 (12%) 

2 (4%) 

NERVOUS SYSTEM 

#ERAIN 

HYDROCEPHALUS,. NOS 

(49) (23) 

1 14X1. (47) (50) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED

* NUMBER OF ANIMALS NECROPSIED 

 MICROSCOPICALLY 

C-I6 
TABLE C2 (CONCLUDED)
 

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

02-0037 02-0084
 

HEMORRHAGE 1 (4%)
 CALCIFICATION, FOCAL 1 (4%)
 

•CEREBELLUM	 (49) (23)
 

INFARCT HEMORRHAGIC
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

•SKULL	 (49) (23)
 

OSTEOPETROSIS
 

•STERNUM	 (49) (23)
 

OSTEOPETROSIS
 

ΒΟΕ CAVITIES
 

•ABDOMINAL	 CAVITY (49) (23)
 

STEATITIS
 

•PLEURA	 (49) (23)
 

INFLAMMATION, ACUTE/CHRONIC
 

ALL OTHER SYSTEMS
 

OMENTUM
 

NECROSIS, FOCAL
 

SPECIAL MORPHOLOGY SUMMARY
 

AUTO/NECROPSY/HISTO PERF
 

AUTO/NECROPSY/NO HISTO
 

AUTOLYSIS/NO NECROPSY 1 2
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

• NUMEER OF ANIMALS NECROPSIED
 

C-I7
 

LOW DOSE
 

02-0036
 

(47)
 

1 (2%)
 

(48)
 

1 (2%)
 

(48)
 

1 (2%)
 

(48)
 

(48)
 

1 (2%)
 

2
 

1
 

2
 

HIGH DOSE
 

02-0106
 

(50)
 

(50)
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

2 

APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH 1-NITRONAPHTHALENE
 

TABLE Dl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

TREATED WITH 1-NITRONAPHTHALENE 

HIGH DOSE CONTROL (UNTR) 05-0077 

LOW DOSE CONTROL (ONTR) 05-0037 LOH DOSE 05-0036 HIGH DOSE 05-0105 

ANIMALS INITIALLY IN STUDY 

ANIHAIS MISSING 

ANIMALS NECEOPSIED 

50 

46 ANIMALS EXAMINED HISTOPATHOLOGICALLY ** 45 

50 

48 

48 

50 

49 

49 

50 

1 

49 

49 

INTiGUMENTARY SYSTEM 

• SKIU 

FIBROSIS ALOPECIA 

HYPERKERATOSIS 

ACANTHOSIS 

(46) (4 8) 

1 (2%) 

1 (2%) 

(49) 

1 (2%) 

1 (2%) 

(49) 

•SUBCUT TISSUE 

AESCESS, NOS 

NECROSIS, NOS 

(46) (48) 

1 (2%) 

(49) 

1 (2*) 

(49) 

RESFIBATORY SYSTEM 

tLONG/ERONCHUS 

INFLAMMATION, NOS INFLAMMATION, FOCAL 

(45) (48) 

1 (2X) 

1 (2%) 

(47) (49) 

«LUNG 

INFLAMMATION, NOS 

INFLAMMATION, INTERSTITIAL 

ARTERIOSCLEROSIS, NOS 

HYPERPLASIA, EPITHELIAL 

(45) 

1 (2%) 

(48) 

1 (2%) 14 (29%) 

2 (4%) 

(47) (49) 

#L0NG/ALVEOLI 

INFLAMMATION, FOCAL 

FIBROSIS, FOCAL 

(45) (48) 

2 (4%) 

1 (2%) 

(47) (49) 

HIMATCFOIETIC SYSTEM 

#EONE MARROW 

HYPERPLASIA, HEMATOPOIETIC 

(45) (47) (45) 

1 (2%) 

(46) 

1 (2X) 

#SPLEEN 

CONGESTION. NOS 

(45) (47) (47) 

1 12%) 

(47) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED

* NUMEER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

D-3 
TABLE Dl (CONTINUED)
 

HIGH DOSE LOW DOSE
 CONTROL(UNTR) CONTROL (UNTR)
 05-0077 05-0037
 

INFLAMMATION, NOS 1 (2X)
 FIBROSIS 1 (2%)
 

HYPERPLASIA, NOS 2 (4%)
 

HYPERPLASIA, HEMATOPOIETIC 2 (4%)
 

HYPERPLASIA, ERYTHROID 2 (4%)
 

HYPERPLASIA, RETICULUM CELL 3 (7%)
 

HYPERPLASIA, LYMPHOID 2 (4%)
 

HEMATOPOIESIS 1 [2%)
 ERYTHROPOIESIS
 

«LYMPH NODE (35) (44)
 

HEMORRHAGIC CYST 1 (2%)
 INFLAMMATION, NOS 13 (30%)
 

DEGENERATION, CYSTIC 1 (2%)
 HYPERPLASIA, NOS 2 (5%)
 

HYPERPLASIA, HEMATOPOIETIC 1 (2X)
 HYPERPLASIA, LYMPHOID 2 (5«)
 

MYELOID METAPLASIA 2 (5%)
 

«PAROTID LYMPH NODE (35)
 m)
 HYPERPLASIA, LYMPHOID
 

«MEDIASTINAL L.NODE (35) (44)
 

NECROSIS, NOS 1 (2%)
 

«PANCREATIC L-NODE (35) (4 4)
 

INFLAMMATION, NOS 1 (2%)
 HYPERPLASIA, NOS
 

«LUMBAR LYMPH NODE (35) (4 4)
 

HYPERPLASIA, PLASMA CELL
 

«MESENTERIC L- NCDE (35) (44)
 

HEMORRHAGE 1 (2%)
 INFLAMMATION, NOS 9 (20%)
 

HYPERPLASIA, NOS
 

HYPERPLASIA, LYMPHOID
 

«THYMUS (19) (34)
 

NECROSIS, NOS 1 (3X)
 

CIRCULATORY SYSTEM
 

«HEART/VENTRICLE (44) (48)
 

MELANIN 2 (4%)
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMEER OF ANIMALS NECROPSIED
 

D-4
 

LOW DOSE
 05-0036
 

2 (4%)
 

(37)
 

(37)
 

(37)
 

(37)
 

(37)
 

(37)
 

1 (3%)
 

1 (3%)
 

(32)
 

(48)
 

HIGH DOSE
 05-0105
 

1 (2%)
 1 (2%)
 

(47)
 

(47)
 

1 i2%)
 

(**7)
 

(47)
 

1 (2X)
 

(47)
 

1 (2X)
 

(47)
 

2 (4X)
 

(34)
 

C»9)
 
TABLE Dl (CONTINUED)
 

HIGH DOSE LOW DOSE
 

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

05-0077 05-0037 05-0036 05-0105
 

•MYOCARDIUM 

INFLAMMATION, INTERSTITIAL 

FIBROSIS 

(44) (48) 

2 (4%) 

5 (10%) 

(48) (49) 

•ELOCD VESSEL 

INFLAMMATION, NOS 

(46) (48) 

2 (4%) 

(49) (49) 

•PULMONARY ARTERY 

MINERALIZATION 

(46) (48) 

2 (4%) 

(49) (49) 

DIGESTIVE SYSTEM 

•SALIVARY GLAND 

INFLAMMATION, NOS 

PERIVASCULAR CUFFING 

(43) (47) 

2 (4%) 

1 (2%) 

(46) (48) 

•LIVER 

INFLAMMATION, FOCAL 

DEGENERATION, NOS 

NECROSIS, NOS 

NECROSIS, FOCAL 

METAMORPHOSIS FATTY 

BASOPHILIC CYTO CHANGE 

MEGALOCYTOSIS 

HYPERPLASIA, NODULAfi 

HYPERPLASTIC NODULE 

HYPERPLASIA, FOCAL 

ANGIECTASIS 

MYELOID METAPLASIA 

(45) 

2 (4%) 

1 (2%) 

3 (7%) 

(4 8) 

13 (27%) 

3 (6%) 

2 (4%) 

1 (2%) 

1 (2%) 

1 (2%) 

(49) 

1 (2%) 

2 (4%) 

(49) 

1 (2%) 

1 (2%) 

2 (4%) 

#LIVER/PERIPORTAL 

INFLAMMATION, NOS 

(45) 

1 (2%) 

(48) (49) (49) 

#LIVER/HEPATOCYTES 

EEGENERATION, NOS 

(45) (48) 

1 (2%) 

(49) (49) 

«GALLBLADDER 

INFLAMMATION, FOCAL 

(46) (48) 

1 (2%) 

(49) (49) 

*BILE DUCT 

INFLAMMATION, NOS 

(46) 

1 (2%) 

(48) (49) (49) 

«PANCREAS 

CYSTIC DUCTS 

(44) (48) (45) (46) 

1 (2%) 

# NUMBER OF ANIMALS

* NUMEER OF ANIMALS

 WITH TISSUE EXAMINED

 NECROPSIED 

 MICROSCOPICALLY 

D-5
 
TABLE Dl (CONTINUED)
 

HIGH DOSE CONTROL (UNTR) 05-0077 

LOW DOSE CONTROL (UNTR) 05-0037 

INFLAMMATION, NOS 

INFLAMMATION, FOCAL 

DEGENERATION, CYSTIC 

METAMORPHOSIS FATTY 

7 

1 

1 

1 

(15%) 

(2%) 

(2%) 

(2%) 

•PANCREATIC DUCT 

HYPERPLASIA, NOS 

(44) (48) 

1 (2%) 

#PANCREATIC ACINUS 

ATROPHY, NOS HYPEBTROPHY, FOCAL HYPERPLASIA, FOCAL 

(44) (48) 

1 

1 {2%) 

(2%) 

•STOMACH INFLAMMATION, NOS 

ULCER, NOS 

INFLAMMATION, FOCAL INFLAMMATION, INTERSTITIAL 

INFLAMMATION, ACUTE 

INFLAMMATION, CHRONIC 

HYPERPLASIA, NOS 

HYPERPLASIA, FOCAL HYPERKERATOSIS 

ACANTHOSIS 

(42) 

1 (2%) 

(47) 

13 

1 

1 

1 

1 

1 

3 

3 

(28%) 

(2%) 

(2%) 

(2%) 

(2%) 

(2%) 

(6%) 

(6%) 

•GASTRIC MUCOSA 

HYPERPLASIA, FOCAL 

(42) (47) 

1 (2%) 

#PEYERS PATCH 

HYPERPLASIA, NOS 

(43) (48) 

2 (4%) 

#ILEUM 

HEMORRHAGE 

INFLAMMATION, NOS 

(43) (48) 

1 

2 (2%) 

(4%) 

#COLON 

PARASITISM 

(38) (4 5) 

1 (2%) 

URINABY SYSTEM
 

#KIDNEY (45) (47)
 

CALCULUS, NOS 20 (44%)
 

HYDRONEPHROSIS
 

GLOMERULONEPHRITIS. NOS 6 (13%)
 

# NUHEER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

D-6
 

LOW DOSE 05-0036 HIGH DOSE 05-0105 

(45) 

(45) 

(46) 

(46) 

1 (2%) 

(48) (48) 

1

1

1

 (2%) 

 (2%) 

 (2%) 

(48) 

(47) 

(47) 

(48) 

(48) 

(48) 

(47) (47) 

(48) 

1 (2%) 

(49) 
TABLE Dl (CONTINUED)
 

INFLAMMATION, NOS
 

INFLAMMATION, INTERSTITIAL
 

INFLAMMATION, CHRONIC
 

PERIVASCULITIS
 ARTERIOSCLEROSIS, NOS
 

NEPHROSIS, NOS
 

GLOMERULOSCLEROSIS, NOS
 

HYPERPLASIA, TUBULAR CELL
 

#KIDNEY/TUBULE
 

DEGENERATION, NOS
 NECROSIS, FOCAL .
 

METAMORPHOSIS FATTY
 

#URINARY BLADDER
 

INFLAMMATION, NOS
 INFLAMMATION, CHRONIC SUPPORATIV
 

HYPERPLASIA, EPITHELIAL
 

ENEOCRINE SYSTEM
 

•PITUITARY
 

HYPERPLASIA, NOS
 HYPERPLASIA, FOCAL
 

#ADRENAL CORTEX
 

NODULE
 

HYPERTROPHY, FOCAL
 HYPERPLASIA, NOS
 

#ADRENAL MEDULLA
 DEGENERATION, NOS
 

tTHYROID
 LYMPHOCYTIC INFLAMMATORY INFILTR
 

HYPERPLASIA, FOCAL
 

HYPERPLASIA, PAPILLARY
 

HYPERPLASIA, C-CELL
 

HYPERPLASIA, FOLLICULAR-CELL
 

«PANCREATIC ISLETS
 

HYPERPLASIA, NOS
 

REPRODUCTIVE SYSTEM
 

•-PREPUTIAL GLAND
 DILATATION/DUCTS
 

HIGH DOSE
 CONTROL (UNTR)
 05-0077
 

5 (11%)
 

1 (2%)
 

2 (4%)
 

1 (2%)
 

1 (2%)
 

2 (4%)
 

(45)
 

1 (2%)
 

9 (20%)
 

(44)
 

(36)
 

(43)
 

(43)
 

(40)
 

(44)
 

(46)
 

LOW DOSE
 CONTROL (U NTS)
 05-0037
 

1 (2%)
 23 (49%)
 

(47)
 

1 (2%)
 

(4 8)
 

4 (8%)
 

9 (19%)
 

(4 2)
 

3 (7%)
 3 (7%)
 

(45)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

(4 5)
 

1 (2%)
 

(47)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

(48)
 

2 (4%)
 

(48)
 

LOW DOSE
 05-0036
 

(48)
 

(48)
 

1 (2%)
 

(34)
 

(46)
 

(46)
 

(38)
 

1 (3%)
 

1 (3%)
 

(45)
 

(49)
 

HIGH DOSE
 05-0105
 

1 (2%)
 

(49)
 

(48)
 

(40)
 

(45)
 

(45)
 

(43)
 

(46)
 

(49)
 

1 12%)
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

• NUMBER OF ANIMALS NECROPSIED
 

D-7
 
TABLE Dl (CONTINUED)
 

— -	 ­ HIGH DOSE LOW DOSE
 CONTROL (UNTR) CONTROL (UNTR)
 05-0077 05-0037
 

AESCESS, NOS	 2 (4X)
 

tPROSTATE (44) (<*8)
 

INFLAMMATION, SUPPURATIVE
 

INFLAMMATION, CHRONIC SUPPURATIV
 

#TESIIS/TUBULE (45) (47)
 

IEGENERATION, NOS 2 (4%) 4 (9%)
 

*SCRCTUM (46) (48)
 

INFLAMMATION, CHRONIC SUPPURATIV
 

NEEVCUS SYSTEM
 

#CEREERAL CORTEX (45) (48)
 MINERALIZATION 3 (6%)
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BCEY CAVITIES
 

•ABDChINAL CAVITY	 (46) (4 8)
 STEATITIS 1 (2%)
 

All CTHER SYSTEMS
 

NONE
 

SPECIAL KCEEHCLOGY SUMMARY
 

NO LESION REPORTED 8
 

ANIMAL MISSING/NO NECROPSY
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

• NUMEER CF ANIMALS NECROPSIED
 

D-8
 

LOW DOSE
 05-0036
 

(47)
 

1 (2%)
 

(48)
 

(49)
 

1 (2X)
 

(48)
 

(49)
 

22
 

HIGH DOSE
 05-0105
 

(47)
 

1 (2%)
 

(47)
 

(49)
 

(48)
 

(49)
 

20
 

1
 
TABLE Dl (CONCLUDED)
 

HIGH DOSE LOW DOSE

 

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

 

05-0077 05-0037 05-0036 05-0105 

AUTC/NECROPSY/HISTO PERF 1

 

AUTO/NECROPSY/NO HISTO 1 

AUTOLYSIS/NO NECROPSY 4 2 1 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

• NUMBER OF ANIMALS NECROPSIED
 

D-9
 
TABLE D2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

TREATED WITH 1-NITRONAPHTHALENE 

ANIMALS INITIALLY IN STUDY
 

ANIMAIS NECROPSIED
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY
 

INTEGUMENTARY SYSTEM
 

•SKIN
 

INFLAMMATION ACUTE AND CHRONIC
 FIBROSIS
 

FIBROSIS, FOCAL
 

•SOBCUT TISSUE
 

MINERALIZATION
 

INFLAMMATION ACUTE AND CHRONIC
 

FIBROSIS
 

RESFIFATORY SYSTEM
 

#LUNG/ERONCHUS
 

INFLAMMATION, FOCAL
 

#LUNG
 

INFLAMMATION, INTERSTITIAL
 

PERIARTERITIS
 

HYPERPLASIA, EPITHELIAL
 

HEMATOPOIETIC SYSTEM
 

#BONE MARROW *
 

MYELOFIBROSIS
 

•SPLEEN
 

HYPERPLASIA, HEMATOPOIETIC
 

HYPERPLASIA, ERYTHROID
 

HYPERPLASIA, RETICULUM CELL
 

HYPERPLASIA, LYMPHOID
 HEMATOPOIESIS
 

HIGH DOSE
 CONTROL (UNTR)
 06-0077
 

50
 

46
 

** 46
 

(46)
 

1 (2%)
 

1 (2%)
 

(46)
 

("5)
 

(45)
 

2 (4%)
 

1 (2%)
 

(44)
 

(43)
 

2 (5%)
 

4 (9%)
 

1 i2%)
 

LOW DOSE
 

CONTROL (ONTR)
 06-0037
 

50
 

48
 

47
 

(48)
 

(48)
 

1 (2%)
 

1 (2%)
 

(46)
 

1 (2%)
 

(46)
 

10 (22%)
 

3 (7%)
 

(4 5)
 

1 (2%)
 

(46)
 

16 (35%)
 

6 (13%)
 

10 (22%)
 

1 i2%)
 

LOW DOSE
 06-0036
 

50
 

46
 

46
 

(46)
 

(46)
 

(44)
 

(44)
 

(43)
 

(46)
 

2 (4%)
 

2 (4%)
 

HIGH DOSE
 06-0105
 

50
 

49
 

48
 

(49)
 

1 (2%)
 

(49)
 

1 (2%)
 

(46)
 

(46)
 

(47)
 

(48)
 

# NUMEER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMEER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

D-IO 
TABLE D2 (CONTINUED)
 

HIGH DOSE LOW DOSE CONTROL (UNTR) 06-0077 CONTROL (UNTR) 06-0037 

EEYTHROPOIESIS 

MYELOPOIESIS 1 (2%) 

•SPLENIC CAPSOLE (43) (46) 

ABSCESS, NOS 

#LYMPH NODE (41) (39) 

CYST, NOS 1 (3X) INFLAMMATION, NOS 15 (38%) 

HYPERPLASIA, NOS 1 (3%) 

RETICULOCYTOSIS 1 (3%) 

HYPERPLASIA, HEMATOPOIETIC 2 (5%) 

MYELOID METAPLASIA 1 (3K) 

#LUMBAE LYMPH NODE (41) (3 9) 

HYPERPLASIA, PLASMA CELL 

HYPERPLASIA, LYMPHOID 

#THYMOS 

ECTOPIA 

(27) (3D 

CIBCOIATORY SYSTEM
 

tHEABT/VENISICLE (45) (46)
 

MELANIN 4 (9%)
 

•MYOCARDIUM	 (45) (46)
 

INFLAMMATION, CHBONIC FOCAL
 

CALCIFICATION, FOCAL 1 (2%)
 

•CORONARY	 ARTERY (46) (48)
 

INFLAMMATION, ACUTE
 

•PULMONARY	 ARTERY (46) (4 8)
 

HYPERPLASIA, NOS 1 (2%)
 

DIGESTIVE SYSTEM
 

#SA1IVARY GLAND (43) (4 5)
 

INFLAMMATION, NOS 2 (4%)
 

PERIVASCULAR CUFFING 4 (9%)
 

#LIVER (45) (47)
 

INFLAMMATION- NOS 1 12%)
 

# NUMEER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMEEH OF ANIMALS NECROPSIED
 

D-ll
 

LOW DOSE
 06-0036
 

2 (4%)
 

(46)
 

1 (2%)
 

(30)
 

(30)
 

(25)
 

1 (4%)
 

(43)
 

(43)
 

(46)
 

(46)
 

(42)
 

(46)
 

HIGH DOSE
 06-0105
 

2 (436)
 

(48)
 

(36)
 

(36)
 

2 (6%)
 

1 (3%)
 

(38)
 

(47)
 

(47)
 

1 (2%)
 

(49)
 

1 (2%)
 

(49)
 

(48)
 

(48)
 
TABLE D2 (CONTINUED) 

HIGH DOSE 

CONTROL(UNTR) 

06-0077 

LOW DOSE 

CONTROL (UNTR) 

06-0037 

LOW DOSE 

06-0036 

HIGH DOSE 

06-0105 

INFLAMMATION, FOCAL 

INFLAMMATION, GRANULOMATOUS 

INFLAMMATION, FOCAL GRANULOMATOU 

NECROSIS, FOCAL 

CYTOPLASMIC CHANGE, NOS 

MEGALOCYTOSIS 

HYPERPLASTIC NODULE 

HYPERPLASIA, FOCAL 

HYPERPLASIA, DIFFUSE 

ANGIECTASIS 

HEMATOPOIESIS 

1 

1 

1 

(2%) 

(2%) 

(2%) 

22 

1 

1 

3 

(47%) 

(2%) 

12%) 

(6X) 

1 

1 

1 

1 

(2%) 

(2%) 

(2%) 

(2%) 

1

2

1

1

 (2%) 

 (4%) 

 (2%) 

 (2%) 

•LIVER/PERIPORTAL 

INFLAMMATION, NOS 

(45) 

1 (2%) 

(47) (46) (48) 

•GALLBLADDER 

INFLAMMATION, NOS 

(46) (48) 

3 (6%) 

(46) (49) 

•BILE DUCT 

INFLAMMATION,

INFLAMMATION,

 NOS 

 CHRONIC 

(46) 

1 (2%) 

(48) 

1 (2%) 

(46) (49) 

1 (2%) 

#PANCREAS 

INFLAMMATION, NOS 

INFLAMMATION, CHRONIC

PERIARTERITIS 

METAMORPHOSIS FATTY 

ATROPHY, FOCAL 

 FOCAL 

(41) (44) 

5 

1 

(11%) 

(2%) 

(43) 

2 

1 (5%) 

(2%) 

(47) 

1 (2%) 

•PANCREATIC DUCT 

LYMPHOCYTIC INFLAMMATORY INFILTR 

(41) (44) 

1 (2%) 

(43) (47) 

#PANCREATIC

ATROPHY,

 ACINUS 

 NOS 

(41) (44) (43) 

1 (2%) 

(47) 

#STOMACH 

INFLAMMATION, NOS 

ULCER, NOS 

INFLAMMATION, FOCAL 

ULCER, FCCAL 

INFLAMMATION, ACUTE FOCAL 

INFLAMMATION, CHRONIC 

INFLAMMATION, CHRONIC FOCAL 

INFLAMMATION, CHRONIC DIFFUSE 

HYPERPLASIA. NOS 

(42) (44) 

7 

1 

1 

1 

(16%) 

(2%) 

(2%) 

(2%) 

(46) 

1 

1 

2 

1 

1 

(2%) 

(2%) 

(4%) 

(2%) 

(2%) 

(48) 

1 (2%) 

# NUMEER

• NUMEER

 OF ANIMALS

 OF ANIMALS

 WITH TISSUE EXAMINED

 NECROPSIED 

 MICROSCOPICALLY 

D-I2 
TABLE D2 (CONTINUED)
 

HYPERPLASIA, EPITHELIAL
 

HYPERPLASIA, ADENOMATOUS
 

HYPERKERATOSIS
 

ACANTHOSIS
 

•GASTRIC MUCOSA
 ULCER, ACUTE
 

HYPERPLASIA, FOCAL
 

•PEYERS PATCH
 

HYPERPLASIA, NOS
 

ORINARY SYSTIM
 

•KIENEY
 

GLOMERULONEPHRITIS, NOS
 

INFLAMMATION, INTERSTITIAL
 GLOMERULONEPHRITIS, CHRONIC
 

PERIVASCULITIS
 

GLOMERULCSCLEPOSIS, NOS
 

•KIENEY/CORTEX
 

SCAR
 

•KIDNEY/GLOMERULUS
 

AMYLOIDOSIS
 

•KIINEY/PELVIS
 

INFLAMMATION, ACUTE/CHRONIC
 

•UEINARY	 BLADDER
 

INFLAMMATION, NOS
 

HYPERPLASIA, EPITHELIAL
 

ENECCEINF. SYSTEM
 

•PITUITARY
 

HYPERPLASIA, FOCAL
 

•ADRENAL CORTEX
 

NODDLE
 

•THYROID
 

FOLLICULAR CYST* NOS
 

• NUMBER OF ANIMALS HITH TISSUE EXAMINED


• NUMEER OF ANIMALS NECROPSIED
 

HIGH DOSE LOW DOSE
 CONTROL(UNTR) CONTROL (UNTR)
 06-0077 06-0037
 

1 (2*)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

(^2) (44)
 

1	 (2%)
 

(43)	 (44)
 

1 (2%)
 

(43) (46)
 

14 (30%)
 

3 (7%) 16 (35%)
 

4 (9%)
 

(43) (46)
 

(43)	 (46)
 

1 (2%)
 

(43)	 (46)
 

1 (2%)
 

(41) (46)
 

4 (9%)
 

10 (22%)
 

(37)	 (42)
 

6 (14%)
 

(43)	 (4 5)
 

3 (7%)
 

(30) (43)
 

1 12X1 _ .
 

 MICROSCOPICALLY
 

D-13
 

LOW DOSE
 06-0036
 

(46)
 

(46)
 

1 (2%)
 

(46)
 

1 (2%)
 

(46)
 

(46)
 

(46)
 

(46)
 

(37)
 

(45)
 

(31)
 

HIGH DOSE
 06-0105
 

(48)
 

1 (2%)
 

(48)
 

1 (2%)
 

(48)
 

1 (2%)
 

(48)
 

1 (2%)
 

(48)
 

(48)
 

(47)
 

(44)
 

(46)
 

(43)
 
TABLE D2 (CONTINUED)
 

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

06-0077 06-0037 

INFLAMMATION , NOS 1 (2%) 

REPRODUCTIVE SYSTIM
 

•MAMMARY GLAND	 (46) (4 8)
 

GALACTOCELE 1 (2%)
 HYPERPLASIA, NOS 4 (8%)
 

•UTERUS	 (43) (4 5)
 

FYBROMETRA 4 (9%) 1 (2%)
 

INFLAMMATION , SUPPURATIVE
 

INFLAMMATION , ACUTE
 

ABSCESS, NOS 3 (7%)
 FIBROSIS 1 (2%)
 

#UTERUS/ENDCMETRIUM (43) (45)
 

CYST, NOS 2 (5%)
 

INFLAMMATION , NOS 10 (22%)
 

INFLAMMATION , SUPPURATIVE 4 (9%)
 

HYPERPLASIA, NOS 1 (2%) 4 (9%)
 

HYPERPLASIA, CYSTIC 35 (81%) 18 (40%)
 

HYPERPLASIA, ADENOMATOUS 1 (2%)
 

#CVARY/OVIDUCT (43) (45)
 

INFLAMMATION , NOS 5 (11%)
 

#CVARY (41) (4 5)
 

CYST, NOS 1 (2%) 3 (7%)
 

FEMOFRHAGIC CYST
 

INFLAMMATION , NOS 4 (9%)
 

LYMPHOCYTIC INFLAMMATORY INFILTR 1 (2%)
 

INFLAMMATION , SUPPURATIVE 10 (22%)
 

ABSCESS, NOS 4 (9%)
 

INFLAMMATION ACUTE AND CHRONIC
 

INFLAMMATION , CHRONIC
 

FIBROSIS
 

LEGENERATION , CYSTIC 1 (2%)
 CALCIFICATION, NOS
 

NERVCUS SYSTEM
 

#ERAIN/MENINGES (43) (44)
 

PERIARTERITIS
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

LOW DOSE
 

06-0036
 

(46)
 

(44)
 

1 (2%)
 

1 (2%)
 

(44)
 

11	 (25%)
 

29	 (66%)
 

(44)
 

(45)
 

4 (9%)
 

1 (2%)
 

6 (13%)
 

1 (2%)
 

3 (7%)
 

(44)
 

HIGH DOSE
 

06-01C5
 

(49)
 

(48)
 

2
 

1
 

(48)
 

1
 

6
 

33
 

(48)
 

(47)
 

4
 

1
 

2
 

1
 

1
 

(46)
 

1
 

(4%)
 

(2%)
 

(2%)
 

(13%)
 

(69%)
 

(9%)
 

(2%)
 

(4%)
 

(2%)
 

(2%)
 

(2%)
 

D-14
 
TABLE D2 (CONCLUDED)
 

HIGH DOSE LOW DOSE
 CONTROL (UNTP) CONTROL (UNTR)
 06-0077 06-0037
 

NECBOSIS, FIBRINOID
 

SPECIAL SENSE OBGANS
 

NONE
 

MUSCUICSKELETAL SYSTEM
 

• EONE (46) (48)
 

RESORPTION 3 (6%)
 

•VEBTEEPA	 (46) (48)
 

OSTE0SCLEB0SIS 1 (2%)
 

•SKELETAL	 MUSCLE (46) (4 8)
 

ABSCESS, NOS
 

EOEY CAVITIES
 

NONE
 

All CTHEB SYSTEMS
 

OMENTUM
 

NECBOSIS, FAi 1
 

SPECIAL MORPHOLOGY SUMMARY
 

NO LESION REPOPTED 1 1
 

AUTO/NECROPSY/HISTO PERF 2 2
 

AUTO/NECROPSY/NO HISTO 1
 

AUTOLYSIS/NO NECROPSY 4 2
 

# NUMEER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

D-15
 

LOW DOSE
 06-0036
 

(46)
 

(46)
 

(46)
 

1 (2%)
 

2
 

4
 

HIGH DOSE
 06-0105
 

1 {2%)
 

(49)
 

(49)
 

(49)
 

6
 

1
 

1
 

Review of the Bioassay of 1-Nitronaphthalene* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup of the
 

Clearinghouse on Environmental Carcinogens
 

January 18, 1978
 

The Clearinghouse on Environmental Carcinogens was
 

established in May, 1976 under the authority of the National
 

Cancer Act of 1971 (P.L. 92-218). The purpose of the Clear­ inghouse is to advise on the National Cancer Institute's
 

bioassay program to identify and evaluate chemical carcino­ gens 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 organic chemistry, bio­ statistics, biochemistry, toxicology, pathology, and epide­ miology. Representatives of various Governmental agencies
 

participate as ad hoc members. The Data Evaluation/Risk
 

Assessment Subgroup of the Clearinghouse is charged with
 

the responsibility of providing a peer review of NCI bioassay
 

reports on chemicals studied for carcinogenicity. In this
 

context, below is the edited excerpt from the minutes of
 

the Subgroup's meeting at which 1-Nitronaphthalene was
 

reviewed.
 

After a brief description of the conditions of test,
 

the primary reviewer said that the study appeared to be
 

adequate for evaluative purposes. He agreed with the
 

staff's conclusion that 1-Nitronaphthalene was not carcinogenic in treated rats or mice, under the conditions of test.
 

The secondary reviewer also agreed with the staff's
 

conclusion that 1-Nitronaphthalene was not carcinogenic
 

in either test species. He pointed out the chronic
 

inflammation of the trachea found in the treated animals.
 He also noted that the major impurity in the 1-Nitronaphthalene
 

was not identified. The secondary reviewer recommended that
 

dietary concentrations be given in mg/kg body wt./day rather
 

than in parts/million. In conclusion, he commented on the
 

undesirable practice of housing more than one study in the
 

same room at the same time.
 

It was moved that the report be accepted as written.
 The motion was seconded and approved unanimously.
 

47
 
Members Present Were:
 

Arnold Brown (Acting Chairman), Mayo Clinic
 

Lawrence Garfinkel, American Cancer Society
 

Joseph Highland, Environmental Defense Fund
 

Charles Kensler, Arthur D. Little Company
 

Verald K. Rowe, Dow Chemical, U.S.A.
 

Sheldon Samuels, Industrial Union Department, AFL-CIO
 

Louise Strong, University of Texas Health Sciences Center
 

Sidney Wolfe, Health Research Group
 

*	 Subsequent to this review, changes may have been made
 

in the bioassay report either as a result of the
 

review or other reasons. Thus, certain comments and
 

criticisms reflected in the review may no longer be
 

appropriate.
 

«U.S. GOVERNMENT PRINTING OFFICE: 1978—26Ο-899/3Ο57 

48
 

DHEW Publication (NIH) No. 78-1314