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National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 105
 

BIOASSAY OF 

m-CRESIDINE 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 102-50-1 

NCI-CG-TR-105 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

m-CRESIDINE
 

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) 78-1355
 

REPORT ON THE BIOASSAY OF m-CRESIDINE
 

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
 

m-cresidine conducted for the Carcinogenesis Testing Program, Division of Cancer Cause and Prevention, National Cancer Institute (NCI),
 

National Institutes of Health, Bethesda, Maryland. This is one of a
 

series of experiments designed to determine whether selected chemicals
 

have the capacity to produce cancer in animals. Negative results, in
 

which the test animals do not have a significantly greater incidence
 

of cancer than control animals, do not necessarily mean the test chemical is not a carcinogen because the experiments are conducted under
 

a limited set of circumstances. Positive results demonstrate that the
 

test chemical is carcinogenic for animals under the conditions of the
 

test and indicate a potential risk to man. The actual determination
 

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

CONTRIBUTORS: This bioassay of m-cresidine was conducted by Mason
 

Research Institute, Worcester, Massachusetts, initially under direct
 

contract to the NCI and currently under a subcontract to Tracor Jitco,
 

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

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

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

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

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

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

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

Russfield (3), Dr. D. S. Wyand (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 (6).
 

Compilation of individual animal survival, pathology, and summary
 

tables was performed by EG&G Mason Research Institute (7); the statistical analysis was performed by Mr. W. W. Belew (5) and Dr. J. R.
 

Joiner (6) using methods selected for the Bioassay Program by Dr. J.
 

J. Gart (8).
 

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

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

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

Ms. P. Walker (5) and the technical editor, Ms. P. A. Miller (5).
 

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 (8), Mr. J. Nam (8), Dr. H. M. Pettigrew (8), and Dr. R.
 

E. Tarone (8).
 

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

1.	 Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

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

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

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

Missouri.
 

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

Boulevard, McLean, Virginia.
 

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

Maryland.
 

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

Rockville, Maryland.
 

8.	 Mathematical Statistics and Applied Mathematics Section, Biometry
 

Branch, Field Studies and Statistics Program, Division of Cancer
 

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

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

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

SUMMARY
 

A bioassay of technical-grade m-cresidine for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice.
 

m-Cresidine in corn oil was administered by gavage five days a week
 

at either of two dosages, to groups of 50 male and 49 or 50 female
 

animals of each species. The dosages used in the chronic bioassay
 

for low and high dose rats were 0.08 and 0.16 gm/kg/day, respectively.
 

The time-weighted average dosages used for low and high dose mice
 

were 0.06 and 0.11 gm/kg/day, respectively. After a 77-week dosing
 

period observation of rats continued for an additional 32 to 33 weeks.
 

After a 53-week dosing period, observation of mice continued for an
 

additional observation period of up to 41 weeks. For each species,
 

50 animals of each sex were placed on test as untreated controls
 

and 25 animals of each sex were placed on test as vehicle controls.
 

The urinary bladder and the kidney were the target organs of
 

m-cresidine toxicity in male and female rats. Papillary transitional-


cell carcinomas of the urinary bladder occurred in 0/45 low dose males,
 

5/44 (11 percent) high dose males, 1/46 (2 percent) low dose females,
 

and 2/44 (5 percent) high dose females but did not occur in any untreated control or vehicle control rats. Although the incidences in
 

each dosed rat group were not statistically significant when compared
 

to vehicle controls, comparison with historical controls indicates
 

that these bladder carcinomas are rare and are, therefore, considered
 

to be compound-related in both sexes.
 

Among mice, dose-related nonneoplastic lesions were observed
 

at higher incidences for males than females in the kidneys, spleen
 

and thymus. Dose-related toxic effects were also observed in the
 

testes of male mice. No neoplasms occurred in male mice at statistically significant incidences.
 

Under the conditions of this bioassay, m-cresidine was carcinogenic to Fischer 344 rats, causing papillary transitional-cell carcinomas of the urinary bladder in both sexes. No convincing evidence
 

was provided for carcinogenicity in female B6C3F1 mice. Poor survival
 

of male B6C3F1 mice receiving m-cresidine precluded evaluation of the
 

possible carcinogenicity of the compound in these animals.
 

vn
 

TABLE OF CONTENTS
 

I. INTRODUCTION 1
 

II. MATERIALS AND METHODS 2
 

A. Chemicals 2
 

B. Dosage Preparation 3
 

C. Animals 3
 

D. Animal Maintenance 3
 

E. Gastric Intubation 6
 

F. Selection of Initial Dose Levels 7
 

G. Experimental Design 8
 

H. Clinical and Histopathologic Examinations 11
 

I. Data Recording and Statistical Analyses 12
 

III. CHRONIC TESTING RESULTS: RATS 18
 

A. Body Weights and Clinical Observations 18
 

B. Survival 18
 

C. Pathology 21
 

D. Statistical Analyses of Results 25
 

IV. CHRONIC TESTING RESULTS: MICE 35
 

A. Body Weights and Clinical Observations 35
 

B. Survival 35
 

C. Pathology 38
 

D. Statistical Analyses of Results 40
 

V. DISCUSSION 47
 

VI. BIBLIOGRAPHY 50
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH m-CRESIDINE A-l
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH m-CRESIDINE B-l
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH m-CRESIDINE C-l
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH m-CRESIDINE D-l
 

ix
 
LIST OF ILLUSTRATIONS 

Figure Number Page 

1 GROWTH CURVES FOR m-CRESIDINE CHRONIC STUDY 

RATS 19 

SURVIVAL COMPARISONS OF m-CRESIDINE CHRONIC 

STUDY RATS 20 

GROWTH CURVES FOR m-CRESIDINE CHRONIC STUDY 

MICE 36 

SURVIVAL COMPARISONS OF m-CRESIDINE CHRONIC 

CHRONIC STUDY MICE 37 

LIST OF TABLES 

Table Number Page 

DESIGN SUMMARY FOR FISCHER 344 RATS—m-CRESIDINE GAVAGE EXPERIMENT 

DESIGN SUMMARY FOR B6C3F1 MICE—m-CRESIDINE 

GAVAGE EXPERIMENT 10 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

m-CRESIDINE 26 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH m-CRESIDINE 31 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

m-CRESIDINE SURVIVING AT LEAST 52 WEEKS 41 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH m-CRESIDINE 43 

Al SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH m-CRESIDINE A-3 
LIST OF TABLES (Concluded) 

Table Number Page 

A2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE RATS TREATED WITH m-CRESIDINE A-7 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH m-CRESIDINE B-3 

B2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH m-CRESIDINE B-6 

Cl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH m-CRESIDINE C-3 

C2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH 

m-CRESIDINE C-10 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH m-CRESIDINE D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH 

m-CRESIDINE D-7 

xi
 

I. INTRODUCTION
 

m-Cresidine (NCI No. C02993), an aromatic amine and dyestuff intermediate, was selected for bioassay by the National Cancer Institute
 

because of the high incidence of bladder cancer associated with exposure to aromatic amines and several other classes of chemicals among
 

workers in the dye manufacturing industry (Wynder et al., 1963).
 

The Chemical Abstracts Service (CAS) Ninth Collective Index
 

•&
 

(1977) name for this compound is 4-methoxy-2-methylbenzenamine. It
 

is also called 4-methoxy-2-methylaniline and 2-methyl-p-anisidine.
 

m-Cresidine is used as an intermediate for the synthesis of
 

C.I. (Colour Index) Azoic Diazo Coupling Component 24 (C.I. 37540)
 

(Society of Dyers and Colourists, 1956).
 

Specific production figures for m-cresidine are not available;
 

however, this compound does not appear to be produced commercially
 

in the United States in quantities greater than 1000 pounds or $1000
 

in value annually (Stanford Research Institute, 1977).
 

*
 

The CAS registry number is 102-50-1.
 
II. MATERIALS AND METHODS
 

A. Chemicals
 

Technical-grade m-cresidine (2-methyl-p-anisidine) was purchased
 

by the NCI for Mason Research Institute from Carroll Products, Wood
 

River Junction, Rhode Island and chemical analysis was performed by
 

Midwest Research Institute, Kansas City, Missouri. Thin-layer chromatography (TLC) was performed utilizing two solvent systems (chloroform
 

and benzene:ethyl acetate), and each plate was visualized with ultraviolet light and furfural. TLC results indicated the presence of one
 

impurity. Differences between results of the experimental elemental
 

analysis and those expected on a theoretical basis suggested impurities. Titration of the amino group gave a result which was 98 percent of the theoretical. This does not necessarily mean that the test
 

chemical was 98 percent pure in-cresidine as similar amino compounds
 

may have been present as contaminants. Vapor-phase chromatography
 

indicated the presence of three impurities, one of higher motility
 

and two of lower motility than the major compound. Infrared analysis
 

was consistent with that reported in the literature (Sadtler Standard
 

Spectra, a). Nuclear magnetic resonance analysis was consistent with
 

the structure of the compound (Sadtler Standard Spectra, b). Ultraviolet analyses showed two \ at 233 and 296 nm with respective
 

max
 

molar extinction coefficients of 8300 and 2600, Values reported in
 

the literature (Sadtler Standard Spectra, c) are >, = 255.5 and 296
 max
 

with respective e values of 8031 and 2740. These values suggest that
 

the purity of the compound was approximately 96 percent.
 

2
 
Throughout this report the term m-cresidine is used to represent
 

this technical-grade material.
 

B. Dosage Preparation
 

Fresh solutions of m-cresidine in shelf-grade Mazola corn oil
 

(Best Foods, Inc., Englewood Cliffs, New Jersey) were prepared weekly,
 

sealed, and stored in dark vials at 4°C. The solutions were prepared
 

on a weight basis.
 

C. Animals
 

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

contracts with the Division of Cancer Treatment, National Cancer Institute. Animals of both species were supplied by Charles River Breeding
 

Laboratories, Wilmington, Massachusetts. Treated and control animals
 

for both species were received in separate shipments.
 

Upon arrival, a sample of animals was sacrificed and examined for
 

parasites and other visible signs of disease. The remaining animals
 

were quarantined for 2 weeks prior to initiation of test. Animals
 

were assigned to groups and distributed among cages so that average
 

body weight per cage was approximately equal for a given sex and
 

species.
 

D. Animal Maintenance
 

All	 animals were housed by species in rooms having a temperature
 

®
 

range of 23° to 34°C. Incoming air was filtered through Tri-Dek
 
15/40 denier Dacron®filters (Tri-Dim Filter Corp., Hawthorne, New
 

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

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

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

for the first 16 months of study, rats were housed in galvanized-


steel wire-mesh cages (Fenco Cage Products, Boston, Massachusetts)
 

suspended over newspapers. Newspapers under cages were replaced
 

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

study, all rats were housed 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-CEL corncob bedding (Paxton Processing Company,
 

Paxton, Illinois) was used during the first 6 months that rats were
 

housed in polycarbonate cages. Aspen hardwood chip bedding (American
 

Excelsior Company, Baltimore, Maryland) was used for the remainder of
 

the 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 (Lab Products, Inc.). Nonwoven fiber
 

filter bonnets were used over cage lids. All female mice and treated
 

male mice were housed ten per cage for the first 12 months and five
 

per cage thereafter, while male control mice were housed ten per cage
 

for the first 13 months and five per cage thereafter. Clean cages,
 
lids, and bedding were provided three times per week when cage populations were ten and twice per week when cage populations were five.
 

Ab-sorb-dri ®

 hardwood chip bedding (Wilner Wood Products Company,
 

Norway, Maine) was used for the treated and control mice for the
 

<S)
 first 3 and 4 months of the study, respectively. SAN-I-CEL was then
 

used for the next 12 months, after which a second corncob bedding
 

®
 (Bed-o-Cobs , The Andersons Cob Division, Maumee, Ohio) was used for
 

8 months. Aspen bedding was then used until the end of the study.
 

Reusable filter bonnets and pipe racks were sanitized every 2 weeks
 

throughout the study.
 

Water was available ad libitum 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 and the period of compound administration, all
 

®
 animals were supplied with Wayne Lab-Blox meal (Allied Mills, Inc.,
 

®
 Chicago, Illinois) ad libitum. Rats and mice were fed from Alpine
 

aluminum feed' cups (Curtin Matheson Scientific, Inc., Woburn, Massachusetts) for the first 13 and 16 months of study, respectively. For
 

the remainder of the study, rats and mice were fed from stainless
 

steel gangstyle food hoppers (Scientific Cages, Inc., Bryan, Texas).
 

During the observation period after compound administration, rats were
 

fed Wayne Lab-Blox pellets on the cage floor. Mice were fed pellets
 

from wire bar lids which replaced the perforated cage lids during this
 
period. Food hoppers of all types were changed on the same schedule
 

®
 

as were cages. Food was replenished daily in Alpine feed cups.
 

Rats dosed with m-cresidine were housed in the same room with
 

their vehicle controls, and with other rats receiving diets containing 2,5-dithiobiurea (142-46-1); fenaminosulf (140-56-7); and cupferron (135-20-6).
 

Mice dosed with m-cresidine were housed in a room where other
 

mice were receiving diets containing 1,5-naphthalenediamine (2243­

62-1); N-(l-naphthyl)ethylenediamine dihydrochloride (1465-25-4);
 

and IH-benzotriazole (95-14-7). Control mice were in a room with
 

other mice receiving diets containing 2,5-dithiobiurea (142-46-1);
 

cupferron (135-20-6); 4-chloro-o-phenylenediamine (95-83-0); o-anisidine hydrochloride (134-29-0); fenaminosulf (140-56-7); and p-anisidine hydrochloride (20265-97-8).
 

E. Gastric Intubation
 

Intubation was performed for five consecutive days per week on
 

a gm/kg body weight basis utilizing the most recently observed group
 

mean body weight as a guide for determining the dose. Mean body
 

weights for each group were recorded at weekly intervals for the
 

first 10 weeks and at monthly intervals thereafter. All animals of
 

one sex within a treated group received the same dose. Animals were
 

gavaged with test solutions under a hood to minimize extraneous exposure of other animals and laboratory personnel to the chemical.
 

*
 

CAS registry numbers are given in parentheses.
 
F

*
 Selection of Initial Dose Levels
 

In order to establish the maximum tolerated concentrations of
 

m-cresidine 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 six groups,
 

each consisting of five males and five females. m-Cresidine, dissolved in corn oil, was introduced by gavage to five of the six rat
 

groups at dosages of 0.02, 0.04, 0.08, 0.15, and 0.3 gm/kg/day and
 

five of six mouse groups at dosages of 0.04, 0.08, 0.15, 0.3, and 0.6
 

gm/kg/day. The sixth group of each species served as a control group,
 

receiving only the corn oil. Intubation was performed 5 days per
 

week for a period of 7 weeks, followed by a 1-week observation period
 

during which all animals were fed the untreated basal diet.
 

The highest dosage causing no deaths, no compound-related gross
 

abnormalities, and no mean body weight depression in excess of 15
 

percent relative to controls was selected as the high concentration
 

utilized for the rat and mouse chronic bioassays.
 

The only death reported among treated rats was one female receiving 0.15 gm/kg/day. Mean body weight depression was 26.5, 4.5, and
 

3.6 percent, respectively, in males treated with 0.3, 0.15, and 0.08
 

gm/kg/day. In females mean body weight depression, which occurred
 

only in the group receiving 0.3 gm/kg/day, was 6.5 percent. The initial high dose selected for the chronic bioassay in rats was 0.16 gm/
 

kg/day for both males and females.
 

7
 
Deaths occurred in male mice treated with m-cresidine at a dosage of 0.3 gm/kg/day or more and in female mice treated with 0.08
 

gm/kg/day or more. Mean body weight depression was 8.4 percent in
 

males treated with 0.3 gm/kg/day, the only group of males experiencing mean body weight depression, and 18.4, 11.1, and 13.4 percent in
 

females treated with 0.6, 0.3, and 0.15 gm/kg/day, respectively. The
 

initial high dose selected for the chronic bioassay in mice was 0.16
 

gm/kg/day for both males and females.
 

G. Experimental Design
 

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

treated and untreated observation periods, and the time-weighted
 

average dosages) are summarized in Tables 1 and 2.
 

The treated and vehicle control rats were approximately 6 weeks
 

old when the first dose was administered and at that time untreated
 

control rats were approximately 10 weeks old. The dosages of mcresidine administered to rats were 0.16 and 0.08 gm/kg/day; throughout this report, the rats receiving the former dosage are referred to
 

as the high dose rat groups and the rats receiving the latter dosage
 

are referred to as the low dose rat groups. These levels were maintained throughout the 77 weeks of compound administration. An observation period of up to 33 weeks followed.
 

All mice were approximately 6 weeks old when the first dose was
 

administered. The initial dosages of m-cresidine administered to
 
TABLE 1
 

DESIGN SUMMARY FOR FISCHER 344 RATS
 

in-CRESIDINE GAVAGE EXPERIMENT
 

INITIAL OBSERVATION PERIOD 

GROUP m-CRESIDINE TREATED UNTREATED 

SIZE DOSAGE3 (WEEKS) (WEEKS) 

MALE 

UNTREATED CONTROL 50 0 0 110 

VEHICLE CONTROL 25 0 0 110 

LOW DOSE 50 0.08 77 

0 32 

HIGH DOSE 50 0.16 77 

0 33 

FEMALE 

UNTREATED CONTROL 50 0 0 110 

VEHICLE CONTROL 25 0 0 110 

LOW DOSE 49 0.08 77 

0 32 

HIGH DOSE 50 0.16 77 

0 33 

Dosages, given in gm/kg body weight, were administered by gavage 5
 

consecutive days per week.
 
TABLE 2
 

DESIGN SUMMARY FOR B6C3F1 MICE
 

tn-CRESIDINE GAVAGE EXPERIMENT
 

INITIAL OBSERVATION PERIOD TIME-WEIGHTED 

GROUP m-CRESIDINE TREATED UNTREATED AVERAGE 

SIZE DOSAGE3 (WEEKS) (WEEKS) DOSAGEb 

MALE
 

UNTREATED CONTROL 50 0 0 98 0
 

VEHICLE CONTROL 25 0 0 95 0
 

LOW DOSE 50 0.08 32 O.Ob
 

0.02 21
 

0 40
 

HIGH DOSE 50 0,16 32 0.11
 

0.04 21
 

0 25
 

FEMALE
 

UNTREATED CONTROL 50 0 0 98 0
 

VEHICLE CONTROL 25 0 0 95 0
 

LOW DOSE 50 0.08 32 0.06
 

0.02 21
 

0 41
 

HIGH DOSE 50 0.16 32 0.11
 

0.04 21
 

0 41
 

a
 

Dosages, given in gm/kg body weight, were administered by gavage 5 consecutive days per week.
 

b . , S (dosage X weeks received)
 

receiving chemical)
 

1C)
 
mice were 0.16 and 0.08 gm/kg/day; throughout this report, the mice
 

initially receiving the former dosage are referred to as the high
 

dose mouse groups and the mice initially receiving the latter dosage
 

are referred to as the low dose mouse groups. After 32 weeks the
 

doses were reduced to 0.04 and 0.02 gm/kg/day for the high and low
 

dose mice, respectively. These doses were maintained for the remainder of the period of dose administration, which was only 21
 

weeks. The early cessation of chemical administration (i.e., after
 

week 53) was in response to excessive mortality among treated mice.
 

An observation period of up to 41 weeks followed.
 

H. Clinical and Histopathologic Examinations
 

Animals were weighed immediately prior to initiation of the
 

experiment. Body weights were recorded twice weekly for the first
 

12 weeks of the study and at monthly intervals thereafter. From the
 

first day, all animals were inspected twice daily for mortality.
 

Food consumption, for two cages from each group, was monitored for
 

seven consecutive days once a month for the first nine months of the
 

bioassay and for three consecutive days each month thereafter. 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
 

11
 
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 (mice), pancreas, esophagus, stomach, small intestine, large intestine, kidney,
 

urinary bladder, pituitary, adrenal, thyroid, parathyroid, brain,
 

test is, prostate, 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
 

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.
 

I. Data Recording and Statistical Analyses
 

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

12
 
(Linhart et al., 1974). The data elements include descriptive information on the chemicals, animals, experimental design, clinical observations, survival, body weight, and individual pathologic results,
 

as recommended by the International Union Against Cancer (Berenblum,
 

1969). Data tables were generated for verification of data transcription and for statistical review.
 

These data were analyzed using the statistical techniques described in this section. Those analyses of the experimental results
 

that bear on the possibility of carcinogenicity are discussed in the
 

statistical narrative sections.
 

Probabilities of survival were estimated by the product-limit
 

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

in the form of graphs. Animals were statistically censored as of the
 

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

missing; animals dying from natural causes were not statistically
 

censored. Statistical analyses for a possible dose-related effect
 

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

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

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

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

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

The incidence of neoplastic or nonneoplastic lesions has been
 

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

specific anatomic site (numerator) to the number of animals in which
 
that site was examined (denominator). In most instances, the denominators included only those animals for which that site was examined
 

histologically. However, when macroscopic examination was required
 

to detect lesions prior to histologic sampling (e.g., skin or mammary
 

tumors), or when lesions could have appeared at multiple sites (e.g.,
 

lymphomas), the denominators consist of the numbers of animals necropsied.
 

The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a significantly higher proportion of tumors than did the control animals.
 

As a part of these analyses, the one-tailed Fisher exact test (Cox,
 

1970, pp. 48-52) was used to compare the tumor incidence of a control
 

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

results for a number of treated groups, k, are compared simultaneously
 

with those for a control group, a correction to ensure an overall
 

significance level of 0.05 may be made. The Bonferroni inequality
 

(Miller, 1966, pp. 6-10) requires that the P-value for any comparison
 

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

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

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

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

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

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

determined if the slope of the dose-response curve is different from
 

14
 
zero at the one-tailed 0.05 level of significance. Unless otherwise
 

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

from linear trend.
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation of
 

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

tumor was observed were excluded by basing the statistical tests on
 

animals that survived at least 52 weeks, unless a tumor was found at
 

the anatomic site of interest before week 52. When such an early
 

tumor was found, comparisons were based exclusively on animals that
 

survived at least as long as the animal in which the first tumor was
 

found. Once this reduced set of data was obtained, the standard procedures for analyses of the incidence of tumors (Fisher exact tests,
 

Cochran-Armitage tests, etc.) were followed.
 

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

incidence of tumors. Curves of the proportions surviving without an
 

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

during which animals died naturally or were sacrificed was entered as
 

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

these curves were used for two groups; Tarone's extension to testing
 

for linear trend was used for three groups. The statistical tests for
 

the incidence of tumors which used life-table methods were one-tailed
 

and, unless otherwise noted, in the direction of a positive dose
 

15
 
relationship. Significant departures from linearity (P < 0,05, two-


tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared to its control was calculated from
 

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

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

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

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

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

between the true proportion of a specific tumor in a treated group
 

and the proportion in a control group corresponds to a relative risk
 

of unity. Values in excess of unity represent the condition of a
 

larger proportion in the treated group than in the control.
 

The lower and upper limits of the confidence interval of the
 

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

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

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

would be within the interval calculated from the experiment. When
 

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

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

one-tailed test when the control incidence is not zero, P < 0.050
 

when the control incidence is zero) has occurred. When the lower
 

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

16
 
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.
 

17
 
III. CHRONIC TESTING RESULTS: RATS
 

A. Body Weights and Clinical Observations
 

Mean body weight of the high dose males was initially lower than
 

that of the other male rats; however, this effect was only apparent
 

until week 48. No appreciable differences in mean body weights were
 

evident among female rats (Figure 1). Fluctuations in the growth
 

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

the mean body weight may be subject to wide variations.
 

Cutaneous/subcutaneous lesions were observed on the dorsal surface in one untreated control male, in the vaginal area in one low
 

dose female, on the nose in one high dose male, on the tail in one
 

high dose female, and behind the right foreleg in one vehicle control
 

male. White discoloration of the eyes was apparent in two low dose
 

females and one high dose male.
 

B.	 Survival
 

The estimated probabilities of survival for male and female rats
 

in the control and m-cresidine-dosed groups are shown in Figure 2.
 

For male rats the Tarone test for positive association between
 

dosage and mortality was significant when dosed groups were compared
 

to the vehicle control. Five male rats were sacrificed from the
 

untreated control group in week 79 and five from the high dose group
 

in week 78. With 48 percent (24/50) of the high dose, 62 percent
 

(31/50) of the low dose, 68 percent (17/25) of the vehicle control,
 

and 64 percent (32/50) of the untreated control animals surviving on
 

18
 
-600 

750 750 

750­

CO 

600­

X 

(D 

LU 

450­

§300-

CD 

150­

FEMALE RATS 

-|-1 

15 30 

-450 

-300 

60 

r 

75 

TIME ON TEST (WEEKS) 

90 

UNTREATED CONTROL 

VEHICLE CONTROL 

LOW DOSE 

HIGH DOSE 

-150 

105 120 

-750 

- 600 

-450 

-I 1 1 1— 

45 60 

TIME ON TEST (WEEKS) 

90 

UNTREATED CONTROL 

VEHICLE CONTROL 

LOW DOSE 

HIGH DOSE 

T" 

-300 

— 150 

105 120 

FIGURE 1 

GROWTH CURVES FOR m-CRESIDINE CHRONIC STUDY RATS 

19 
PROBABILIT

Y OF SURVIVAL O ;­ 03 O I i I 

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1 33 

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PROBABILITY O
test until the end of the study, adequate numbers of male rats were
 

at risk from late-developing tumors.
 

For female rats the Cox test showed a significantly greater mortality in the high dose group than in the vehicle control group.
 

Five females were sacrificed from the untreated control group in week
 

79 and five from the high dose group in week 78. With 44 percent
 

(22/50) of the high dose, 57 percent (28/49) of the low dose, 52 percent (13/25) of the vehicle control, and 72 percent (36/50) of the
 

untreated control animals alive on test until the end of the study,
 

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

tumors.
 

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 Cl and C2).
 

Compound- and dose-related neoplastic, hyperplastic, and degenerative lesions were limited to the urinary system. Papillary
 

transitional-cell carcinomas of the urinary bladder occurred in 5/44
 

(11 percent) high dose males; 1/46 (2 percent) low dose females; and
 

2/44 (5 percent) high dose females. No animals in the low dose male,
 

untreated control, or vehicle control groups developed bladder cancers.
 

All of these tumors were papillary carcinomas which had a cauliflower-


like pattern and grew into the lumen of the bladder. Microscopically,
 

the	 transitional cells formed sheets which were supported by a fine
 

21
 
fibrovascular stroma. The epithelial cells were slightly pleomorphic
 

with oval, round, or irregularly shaped vesicular nuclei and frequently single prominent nucleoli. Occasional mitotic figures and
 

invasion of the papillary stroma were noted. No invasion of the
 

bladder wall or metastases were seen. Occasional polymorphonuclear
 

leucocytes were present within cystic spaces in the tumor. In some
 

tumors, there were numerous mast cells in the stroma. Occasional
 

large vascular spaces containing blood or a pink proteinaceous material were noted in the stroma.
 

An additional compound- and dose-related lesion noted was epithelial hyperplasia of the renal pelvis. This change occurred in 26/45
 

(58 percent) high dose males and 29/45 (64 percent) high dose females,
 

Normally, the renal papilla is covered by transitional epithelium 1
 

to 6 cells thick. Microscopically, the epithelial hyperplasia was
 

characterized by irregularity of the surface of the renal pelvis and
 

papilla and extensive epithelial proliferation, up to about 50 cells
 

thick, with infolding of the papillary surface. Frequently, large
 

hemocysts formed immediately beneath the epithelium. In addition,
 

foci of mineralization and a fine fibrovascular stroma became incorporated into the epithelium.
 

Additional compound- and dose-related nephrotoxic lesions affected the renal papilla. Varying degrees and combinations of acute
 

papillitis, hemorrhage, necrosis, and mineralization occurred which
 

22
 
were distinctly different lesions from those associated with nephropathy in aged Fischer 344 rats. Varying degrees of architectural
 

disarray of the renal papilla were observed. Collecting tubules were
 

dilated and contained large amounts of granular and homogenous, pink,
 

hyaline cast material. Occasionally, the casts showed basophilic
 

stippling or a more uniform basophilia indicating mineralization.
 

Polymorphonuclear leucocytes sometimes occurred in the lumen of collecting tubules. Scattered mononuclear cells and a few polymorphonuclear leucocytes occurred in the interstitium of the papilla.
 

Slight to severe degrees of mineralization appeared to start at the
 

basement membrane of collecting tubules and encroached upon necrotic
 

tubular epithelial cells. Interstitial fibrosis was seen in these
 

areas.
 

Spontaneous renal disease (recorded as nephrosis, nephropathy,
 

or chronic glomerulonephritis) commonly observed in aged Fischer 344
 

rats occurred at a high but approximately equal incidence in all
 

groups of both sexes; however, the severity of the lesions was much
 

greater in animals treated with m-cresidine, suggesting that the
 

compound enhanced a naturally occurring pathologic process in the
 

Fischer 344 rat. Lesions were observed in the glomeruli, tubules,
 

basement membranes, and the interstitium of the affected kidneys.
 

The morphologic features observed were variable. The glomeruli
 

varied from normal to shrunken, vacuolated, hyalinized, and sclerotic. Focal glomerular adhesions, thickening of capillary loops and
 

23
 
increases in mesangial density were noted. Occasionally, Bowman's
 

space was enlarged, and hyalinization of the basement membrane of
 

Bowman's capsule occurred.
 

Varying degrees of tubular lesions were noted. Tubular degeneration and regeneration occurred. Focal tubules were dilated, lined
 

by a flattened epithelium, and surrounded by a hyalinized basement
 

membrane. Basement membrane hyalinization sometimes progressed to
 

the point where the tubules were lost and only "ghost-like" basement
 

membranes remained. In severely affected kidneys, focal areas of
 

tubular destruction and loss were replaced by interstitial fibrosis.
 

Varying degrees of tubular dilatation and accumulation of pink proteinaceous material within were noted. In severely affected animals
 

treated with m-cresidine, "end-stage" renal disease occurred, with
 

numerous dilated tubules filled with pink proteinaceous material.
 

Occasional cysts were noted in the parenchyma.
 

A single tubular adenocarcinoma of the kidney occurred in the
 

outer cortex of a high dose male. The center of the neoplasm was
 

cystic and contained a light pink granular material. In some areas
 

neoplastic epithelial cells formed tubular structures. There were
 

moderate numbers of mitotic figures, and the mass was supported by
 

a fine fibrovascular stroma.
 

The remaining neoplastic, proliferative, degenerative, and
 

inflammatory lesions observed in control and treated rats were
 

24
 
considered to be unrelated to compound administration and within the
 

normal incidence limits in Fischer 344 rats.
 

This histopathologic examination provided evidence for carcinogenicity of m-cresidine to Fischer 344 rats. The compound induced
 

transitional-cell carcinomas of the bladder. In addition, m-cresidine
 

was nephrotoxic, inducing epithelial hyperplasia of the renal pelvis
 

and renal papillae lesions; and an increased severity of spontaneous
 

renal disease.
 

D. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

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

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

tumors were observed in at least one of the control or m-cresidine­ *
 

dosed groups and where such tumors were observed in at least 5 percent of the group.
 

For males the Cochran-Armitage test indicated a significant
 

(P = 0.014) positive association between dose and the incidence of
 

transitional-cell carcinomas of the urinary bladder. The Fisher
 

exact tests, however, were not significant. In historical data collected by this laboratory for the NCI Carcinogenesis Testing Program
 

none of the 250 male and 1/249 female untreated Fischer 344 rats had
 

a tumor of the urinary bladder. Making the assumption of a binominal
 

distribution with a probability of 1/251 of spontaneous incidence
 

(the most conservative estimate), the probability of observing 5 or
 

25
 
___ 

___ 

___ 

TABLE 3
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE RATS TREATED WITH m-CRESIDINE£
 

HIGH
 

DOSE
 

4/45(0.09)
 

N.S.
 

0.741
 

0.138
 

4.745
 

0/45(0.00)
 

N.S.
 

2/44(0.05)
 

N.S.
 

Infinite
 

0.172
 

Infinite
 

TOPOGRAPHY : MORPHOLOGY
 

Skin and Subcutaneous Tissue: Fibroma
 

P Values0
 

Relative Risk (Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

KJ
 

ON Skin and Subcutaneous Tissue:
 

Fibrosarcomab
 

P Values
 

Departure from Linear Trend
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Lung: Alveolar/Bronchiolar Carcinoma
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VEHICLE
 

CONTROL
 

3/25(0.12)
 

N.S.
 

96
 

0/25(0.00)
 

N.S.
 

P = 0.035
 

0/25(0.00)
 

N.S.
 

LOW
 

DOSE
 

7/47(0.15)
 

N.S.
 

1.241
 

0.318
 

6.961
 

80
 

3/47(0.06)
 

N.S.
 

Infinite
 

0.328
 

Infinite
 

76
 

3/47(0.06)
 

N.S.
 

Infinite
 

0.328
 

Infinite
 

109
 

94 

109 
_ _ _ 

___ 

TOPOGRAPHY: MORPHOLOGY
 

Hematopoietic System: Leukemia or
 

Malignant Lymphomab
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma or
 

Neoplastic Nodule**
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Urinary Bladder: Transitional-Cell
 

Carcinoma*5
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 3 (CONTINUED) 

VEHICLE
 

CONTROL
 

0/25(0.00)
 

N.S.
 

0/25(0.00)
 

N.S.
 

0/25(0.00)
 

P = 0.014
 

LOW
 

DOSE
 

4/47(0.09)
 

N.S.
 

Infinite
 

0.506
 

Infinite
 

77
 

4/47(0.09)
 

N.S.
 

Infinite
 

0.506
 

Infinite
 

99
 

0/45(0.00)
 

N.S.
 

HIGH
 

DOSE
 

1/45(0.02)
 

N.S.
 

Infinite
 

0.030
 

Infinite
 

108
 

1/45(0.02)
 

N.S.
 

Infinite
 

0.030
 

Infinite
 

109
 

5/44(0.11)
 

N.S.
 

Infinite
 

0.737
 

Infinite
 

104
 
___ 

TABLE 3 (CONTINUED) 

VEHICLE
 

TOPOGRAPHY : MORPHOLOGY CONTROL
 

Pituitary: Adenoma NOS or Chromophobe
 

Adenoma*3 2/22(0.09)
 

P Values0 N.S.
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 110
 

Adrenal: Pheochromocytoma 6/25(0.24)
 

P Values0 P = 0.013(N)
 10

 d
 00

 Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 105
 

Thyroid: Follicular-Cell Carcinoma 0/23(0.00)
 

P Values N.S.
 

Relative Risk (Vehicle Control) —_
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

LOW
 

DOSE
 

6/45(0.13)
 

N.S.
 

1.467
 

0.294
 

14.114
 

70
 

6/47(0.13)
 

N.S.
 

0.532
 

0.162
 

1.807
 

106
 

1/44(0.02)
 

N.S.
 

Infinite
 

0.029
 

Infinite
 

95
 

HIGH
 

DOSE
 

3/37(0.08)
 

N.S.
 

0.892
 

0.112
 

10.101
 

78
 

2/45(0.04)
 

P = 0.021(N)
 

0.185
 

0.020
 

0.953
 

108
 

2/39(0.05)
 

N.S.
 

Infinite
 

0.180
 

Infinite
 

109
 
TABLE 3 (CONTINUED)
 

VEHICLE
 

TOPOGRAPHY: MORPHOLOGY CONTROL
 

Pancreatic Islets: Islet-Cell Adenoma or
 

Islet-Cell Carcinomab 1/24(0.04)
 

P Values0 N.S.
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 98
 

Body Cavities: Mesothelioma NOS or
 

Mesothelioma, Malignant^ 2/25(0.08)
 

10
 

'•£> P Values0 N.S.
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 110
 

Testis: Interstitial-Cell Tumor 19/25(0.76)
 

P Values0 N.S.
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 98
 

LOW
 

DOSE
 

3/45(0.07)
 

N.S.
 

1.600
 

0.139
 

82.076
 

109
 

0/47(0.00)
 

N.S.
 

0.000
 

0.000
 

1.789
 

35/45(0.78)
 

N.S.
 

1.023
 

0.788
 

1.414
 

95
 

HIGH
 

DOSE
 

2/41(0.05)
 

N.S.
 

1.171
 

0.065
 

67.374
 

78
 

3/45(0.07)
 

N.S.
 

0.833
 

0.104
 

9.528
 

104
 

35/44(0.80)
 

N.S.
 

1.047
 

0.806
 

1.432
 

74
 
TABLE 3 (CONCLUDED)
 

Treated groups received time-weighted average doses of 0.08 or 0.16 mg/kg body weight by gavage,
 

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

£
 

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors in
 

the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N) indicates a lower incidence in the treated group(s) than in the control group.
 

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

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 

CO
 

o
 
__ _ 

___ 

TABLE 4
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE RATS TREATED WITH m-CRESIDINE£
 

TOPOGRAPHY : MORPHOLOGY
 

Lung: Alveolar /Bronchiolar Adenoma or
 

Alveolar/Bronchiolar Carcinoma*5
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Adenoma NOS or Chromophobe
 

Adenoma"
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-Cell Adenoma or C-Cell
 

Carcinoma"
 

? Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VEHICLE
 

CONTROL
 

1/24(0.04)
 

N.S.
 

104
 

7/23(0.30)
 

N.S.
 

92
 

1/23(0.04)
 

N.S.
 

110
 

LOW
 

DOSE
 

3/49(0.06)
 

N.S.
 

1.469
 

0.127
 

75.534
 

109
 

17/42(0.40)
 

N.S.
 

1.330
 

0.634
 

3.267
 

88
 

4/45(0.09)
 

N.S.
 

2.044
 

0.221
 

98.348
 

109
 

HIGH
 

DOSE
 

2/45(0.04)
 

N.S.
 

1.067
 

0.059
 

61.532
 

110
 

8/36(0.22)
 

N.S.
 

0.730
 

0.274
 

2.069
 

62
 

2/41(0.05)
 

N.S.
 

1.122
 

0.063
 

64.580
 

110
 
___ 

___ 

___ 

TABLE

TOPOGRAPHY: MORPHOLOGY
 

Mammary Gland: Fibroadenoma
 

P Values
 

Departure from Linear Trend 

£
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Adenoma NOS or Adenocarcinoma NOS15
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Uterus: Endometrial Stromal Polyp
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

4 (CONTINUED) 

VEHICLE
 

CONTROL
 

3/24(0.13)
 

N.S.
 

P = 0.001
 

110
 

2/24(0.08)
 

N.S.
 

74
 

4/24(0.17)
 

P = 0.012(N)
 

100
 

LOW
 

DOSE
 

21/49(0.43)
 

P = 0.008
 

3.429
 

1.182
 

16.446
 

88
 

4/49(0.08)
 

N.S.
 

0.980
 

0.154
 

10.354
 

66
 

8/47(0.17)
 

N.S.
 

1.021
 

0.312
 

4.266
 

109
 

HIGH
 

DOSE
 

8/46(0.17)
 

N.S.
 

1.391
 

0.377
 

7.593
 

100
 

1/46(0.02)
 

N.S.
 

0.261
 

0.005
 

4.802
 

110
 

0/44(0.00)
 

P - 0.013(N)
 

0.000
 

0.000
 

0.582
 
TABLE 4 (CONCLUDED) 

*a
 

Treated groups received time-weighted average doses of 0.08 or 0.16 mg/kg body weight by gavage.
 

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

c
The probability level for the Cochran-Armitage test is given beneath the incidence of tumors in
 

the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N) indicates a lower incidence in the treated group(s) than in the control group.
 

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

^The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 
more animals with such tumors out of 44 males (as in the high dose
 

group) was P < 0.0001, a significant result. Similar analyses for
 

urinary bladder tumors did not give statistically significant numbers
 

in the females.
 

For females the Fisher exact test indicated a significantly
 

(P = 0.008) higher incidence of mammary fibroadenomas in the low dose
 

group than in the control group. The high dose comparison and the
 

Cochran-Armitage test, however, were not significant.
 

The possibility of a negative association between dose and incidence was noted for adrenal pheochromocytomas in males and for endometrial stromal polyps in females.
 

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 tumor induction in rats by
 

m-cresidine that could not be established under the conditions of
 

this test.
 

34
 
IV. CHRONIC TESTING RESULTS: MICE
 

A. Body Weights and Clinical Observations
 

Growth curves for mice of both sexes were erratic (Figure 3).
 

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

of the group diminishes, the mean body weight may be subject to wide
 

variations.
 

No clinical abnormalities were observed among mice of any group.
 

B.	 Survival
 

The estimated probabilities of survival for male and female mice
 

in the control and m-cresidine-dosed groups are shown in Figure 4.
 

For male mice the Tarone test for positive association between
 

dosage and mortality was significant (P < 0.001) when comparing the
 

dosed groups to the vehicle control. The departure from linear trend
 

was also significant (P < 0.001) due to accelerated mortality in the
 

high dose group. Five animals were sacrificed from the untreated
 

control group in week 80. Due to evidence of toxicity observed in
 

weeks 26 through 28 in both treated groups, the dosages were lowered
 

in week 33. Survival was very poor in the high dose treated group
 

with a median survival of 26 weeks; the single surviving animal died
 

at week 78. Survival was slightly better in the low dose treated
 

group with a median survival of 52 weeks; 15 animals were still alive
 

on test at the termination of the study. In both dosed groups sufficient numbers of male mice did not survive long enough to be at risk
 

from late-developing tumors.
 

35
 
UNTREATED CONTROL 

VEHICLE CONTROL 

LOW DOSE 

HIGH DOSE 

-i 1 r 

45 60 75 105 120 

TIME ON TEST (WEEKS) 

50- -50 

40 — -40 

</3 

< 

<r 

£• 30— -30 

IX 

LU 

> 20 — -20 

Q 

O 

m 

UNTREATED CONTROL < 

LU 

10— VEHICLE CONTROL -10 

LOW DOSE 

FEMALE MICE 

HIGH DOSE 

~ I ' I ~ 

15 30 45 60 90 105 120 

TIME ON TEST (WEEKS) 

FIGURES 

GROWTH CURVES FOR m-CRESIDINE CHRONIC STUDY MICE 

36 
PROBABILIT

Y OF SURVIVAL PROBABILITY OF 

c3 O P 

3

i: t

o * 

i ll i

-

I 

oi ~ 

s 

C 33 

1 • 

w _ 

4

8

r

-

r1 

*. 

r

Z 

Ol 

1 ,.I* 

r 

o 

-

r

1

 ...j-

C) 

33 33 

Ol 

mm *

g

m m

­ J*"

1

 

o --J 33 01 

i

j O 

i 

O­

O 

-, 

CO 

o < 

S 

o 

1 

o 

S 

1-

3 1 1 1 1 

<3 O O 

c3 to i» 
For female mice the Cox test showed a significantly higher mortality in the high dose group than in the vehicle control group.
 

Five animals were sacrificed from the untreated control group in week
 

80. Due to evidence of toxicity observed in weeks 26 through 28 in
 

the high dose treated groups, the dosages were lowered in week 33.
 

With 60 percent (30/50) of the high dose, 86 percent (43/50) low dose,
 

84 percent (21/25) vehicle control, and 80 percent (40/50) untreated
 

control animals alive on test until the termination of the study,
 

adequate numbers of female mice were at risk from late-developing
 

tumors.
 

C. Pathology
 

Histopathologic findings on neoplasms in mice are summarized in
 

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

summarized in Appendix D (Tables Dl and D2).
 

The incidence and type of neoplasms observed among control and
 

treated mice were similar to those often occurring in B6C3F1 mice.
 

Except for liver neoplasms in high dose females, there was no evidence of compound-related neoplasia. The lack of tumor development
 

in high dose males and the lowered incidence of tumors in low dose
 

males are attributed to early mortality caused by a nephrotoxic
 

effect of the chemical.
 

Hepatocellular neoplasms (adenomas or carcinomas) were observed
 

in 0/23 vehicle control, 1/50 (2 percent) low dose, and 5/45 (11
 

percent) high dose female mice. Since the number of liver neoplasms
 

38
 
was not great and the natural incidence is variable, their distribution in female mice in this study might be due to chance.
 

Hepatocellular carcinoma was generally characterized by a mass
 

composed of hepatocytes that produced compression of the adjacent
 

parenchyma and lacked portal areas. Hepatocytes were basophilic,
 

either small or large cell type, had vacuolated or granular cytoplasm,
 

and had normal-sized or enlarged nuclei. Mitotic activity was minimal
 

to moderate. Other changes included a trabecular growth pattern, one-


cell thick or multiple-cell thick liver plates, and acinar formations
 

which were often associated with moderate degrees of anaplasia. Occasional areas of necrosis were noted.
 

Hepatocellular carcinoma also occurred in male mice; however,
 

there was no relationship to chemical administration, perhaps because
 

of the shortened life spans of the treated male mice.
 

Nephrotoxic changes occurred in treated mice and were dose- and
 

sex-related; being more pronounced in males. Principal renal lesions
 

involved the tubules and renal papillae; glomeruli were usually spared.
 

Tubular changes appeared as well-demarcated areas of degeneration and
 

atrophy in the cortex. Degenerative cytoplasmic changes included vacuolation, reduction in volume and loss of acidophilia, with subsequent
 

reduction in tubular diameters. Nuclei were often swollen and pale.
 

Loss of tubular mass resulted in condensation of interstitial stroma
 

and capsular depression overlying the affected areas. Necrosis of
 

39
 
the renal papilla was frequently associated with the tubular lesions,
 

especially in the treated male mice.
 

Additional dose-related lesions included atrophy of the thymus,
 

spleen, and occasionally lymph nodes, and multinucleate (spermatidic)
 

giant cells in the testes. Hepatocellular cytoplasmic vacuolation
 

was common in chemically treated males.
 

This histopathologic examination did not provide evidence for the
 

carcinogenecity of m-cresidine in B6C3F1 mice. However, m-cresidine
 

was nephrotoxic in 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 primary tumor in either sex where at least two such
 

tumors were observed in at least one of the control or m-cresidinedosed groups and where such tumors were observed in at least 5 percent of the group. Due to the accelerated mortality in the treated
 

males, the analyses of the males were based exclusively upon those
 

mice surviving at least 52 weeks or, if the tumor of interest was
 

observed earlier, surviving at least until the earliest tumor of
 

interest was oberved.
 

For female mice when the incidences of hepatocellular adenomas
 

and hepatocellular carcinomas were combined, the Cochran-Armitage
 

test indicated a significant (P = 0.027) positive association between dose and incidence. The Fisher exact tests, however, were not
 

40
 
TABLE 5
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE MICE TREATED WITH m-CRESIDINE
 

SURVIVING AT LEAST 52 WEEKS3*6
 

TOPOGRAPHY : MORPHOLOGY
 

Lung: Alveolar/Bronchiolar Carcinoma
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Lung: Alveolar/Bronchiolar Adenoma or
 

Alveolar/Bronchiolar Carcinoma^*» e
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Leukemia or
 

Malignant Lymphoma
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VEHICLE LOW 

CONTROL DOSE 

4/24(0.17) 1/23(0.04) 

N.S. N.S. 

0.261 

0.006 

2.380 

70 93 

4/24(0.17) 4/38(0.11) 

N.S. N.S. 

0.632 

0.131 

3.113 

70 28 

2/24(0.08) 1/24(0.04) 

N.S. N.S. 

0.500 

0.001 

8.943 

83 80 

HIGH
 

DOSE
 

0/2(0.00)
 

N.S.
 

0.000
 

0.000
 

6.649
 

0/17(0.00)
 

N.S.
 

0.000
 

0.000
 

1.437
 

0/2(0.00)
 

N.S.
 

0.000
 

0.000
 

20.146
 
TABLE 5 (CONCLUDED)
 

TOPOGRAPHY : MORPHOLOGY 

VEHICLE 

CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Liver: Hepatocellular Carcinoma 

P Values0 

5/24(0.21) 

N.S. 

3/22(0.14) 

N.S. 

0/2(0.00) 

N.S. 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

0.655 

0.114 

2.941 

0.000 

0.000 

4.925 

Weeks to First Observed Tumor 95 93 

Treated groups received time-weighted average doses of 0.06 or 0.11 mg/kg body weight by gavage.
 

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

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors in
 

the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N) indicates a lower incidence in the treated group(s) than in the control group.
 

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

For sites where the first tumor of interest was observed earlier than 52 weeks, the analyses
 

were based upon all animals that survived until or past the date that the first tumor was observed.
 
TABLE 6
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

a
 SPECIFIC SITES IN FEMALE MICE TREATED WITH m-CRESIDINE


TOPOGRAPHY : MORPHOLOGY
 

Lung: Alveolar/Bronchiolar Adenoma or
 

Alveolar/Bronchiolar Carcinoma"
 

c
 

P Values
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Malignant
 

Lymphoma
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma
 

P Values
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VEHICLE
 

CONTROL
 

0/23(0.00)
 

N.S.
 

_—
 

1/24(0.04)
 

N.S.
 

«..._
 

94
 

0/23(0.00)
 

N.S.
 

LOW
 

DOSE
 

2/49(0.04)
 

N.S.
 

Infinite
 

0.143
 

Infinite
 

93
 

4/50(0.08)
 

N.S.
 

1.920
 

0.207
 

92.583
 

79
 

1/50(0.02)
 

N.S.
 

Infinite
 

0.025
 

Infinite
 

94
 

HIGH
 

DOSE
 

3/44(0.07)
 

N.S.
 

Infinite
 

0.324
 

Infinite
 

94
 

1/46(0.02)
 

N.S.
 

0.522
 

0.007
 

40.096
 

94
 

4/45(0.09)
 

N.S.
 

Infinite
 

0.489
 

Infinite
 

94 
TOPOGRAPHY rMORPHOLOGY
 

Liver: Hepatocellular Adenoma or
 

Hepatocellular Carcinoma
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Adenoma NOS
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Ovary: Cystadenoma NOS
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 6 (CONTINUED)
 

VEHICLE
 

CONTROL
 

0/23(0.00)
 

P = 0.027
 

0/17(0.00)
 

N.S.
 

0/20(0.00)
 

N.S.
 

—__
 

LOW
 

DOSE
 

1/50(0.02)
 

N.S.
 

Infinite
 

0.025
 

Infinite
 

94
 

2/34(0.06)
 

N.S.
 

Infinite
 

0.155
 

Infinite
 

93
 

0/39(0.00)
 

N.S.
 

HIGH
 

DOSE
 

5/45(0.11)
 

N.S.
 

Infinite
 

0.666
 

Infinite
 

94
 

0/31(0.00)
 

N.S.
 

2/41(0.05)
 

N.S.
 

Infinite
 

0.150
 

Infinite
 

53
 
TABLE 6 (CONCLUDED)
 

3.
 

Treated groups received time-weighted average doses of 0.06 or 0.11 mg/kg body weight by gavage.
 

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

£

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors in
 

the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N) indicates a lower incidence in the treated group(s) than in the control group.
 

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

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 
significant. No other statistically significant results were observed
 

for either male or female mice.
 

Based upon these results there was no statistical evidence that
 

m-cresidine was a carcinogen in mice.
 

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 all 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 all of the
 

confidence intervals have an upper limit greater than one, indicating
 

the theoretical possibility of tumor induction in mice by m-cresidine
 

that could not be established under the conditions of this test.
 

46
 
V. DISCUSSION
 

A high rate of dose-related mortality was observed among male
 

mice. In all other groups in this bioassay, adequate numbers of animals survived long enough to be at risk from late-developing tumors.
 

Among rats dose-related lesions were limited to the urinary system. Papillary transitional-cell carcinomas of the urinary bladder
 

occurred in 5/44 (11 percent) high dose males, 1/46 (2 percent) low
 

dose females, and 2/44 (5 percent) high dose females. No bladder
 

tumors were observed among rats in the low dose male group, untreated
 

control groups or vehicle control groups. The Cochran-Armitage test
 

indicated a significant positive relationship between dose and the
 

incidence of papillary transitional-cell carcinomas of the urinary
 

bladder for male rats but not for females. According to the Fisher
 

exact test results, no group of dosed rats had this tumor at an incidence significantly higher than the corresponding vehicle control
 

group. When a binomial distribution and a spontaneous incidence for
 

this neoplasm of 1/251 were assumed, the observation of 5 or more
 

animals with such neoplasms out of a group of 44, as in the high dose
 

male rats, was a significant event. The incidence observed in female
 

rats did not provide a similar, statistically significant result; however, these tumors occur rarely in control female rats (1/249 in the
 

historical controls) and the incidence observed in dosed female rats
 

in this bioassay is considered to be biologically important evidence
 

for the carcinogenicity of m-cresidine in these rats.
 

47
 
A single tubular-cell adenocarcinoma of the kidney occurred in
 

one high dose male rat. Epithelial hyperplasia of the renal pelvis
 

was observed in 26/45 (58 percent) high dose male rats and 29/45 (64
 

percent) of the high dose female rats, but not in low dose or control
 

rat groups. Mineralization of the renal papilla was observed in 7/47
 

(15 percent) low dose males, 27/45 (60 percent) high dose males, 3/49
 

(6 percent) low dose females, and in 34/45 (76 percent) high dose
 

females, but in no untreated or vehicle control rats. Renal lesions
 

(nephrosis, nephropathy or glomerulonephritis) commonly occurring in
 

aged Fischer 344 rats occurred at a similar incidence in dosed and
 

control rats, but the severity of the lesions was much greater in
 

animals dosed with m-cresidine, suggesting that the compound enhanced
 

a naturally occurring pathologic process.
 

Among female mice, there was a significant positive association
 

between the incidence of hepatocellular neoplasms (adenomas and/or
 

carcinomas) and dosage; however the incidence was not significantly
 

greater in either the low dose or the high dose group than in the
 

vehicle control group.
 

Dose-related toxic effects observed at higher incidences in male
 

mice than female mice include nephrotoxicity (necrosis of renal papilla and nephrosis) and atrophy of the spleen and thymus. The presence of multinucleate (spermatidic) giant cells in the testes were
 

also dose-related in male mice. Since the same dosages were administered to both sexes, the high incidences of these toxic effects and
 

48
 
associated accelerated mortality among male mice indicates that male
 

mice were more sensitive than females to m-cresidine toxicity.
 

Under the conditions of this bioassay, m-cresidine was carcinogenic to Fischer 344 rats, causing papillary transitional-cell carcinomas of the urinary bladder in both sexes. No convincing evidence
 

was provided for carcinogenicity in female B6C3F1 mice. Poor survival
 

of male B6C3F1 mice receiving m-cresidine precluded evaluation of the
 

possible carcinogenicity of this compound in these animals.
 

49
 
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.
 

Chemical Abstracts Service, The Chemical Abstracts Service (CAS)
 

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

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

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

Co., Ltd., London, 1970.
 

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

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

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

Tests, Confidence Limits, and Adjustments for Stratification."
 

International Statistical Institute_Review 39:148-169, 1971.
 

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

Observations." Journal of the American Statistical Association
 

5,3:457-481, 1958.
 

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

Peters, "Carcinogenesis Bioassay Data System." Computers
 

and Biomedical Research 7:230-248, 1974.
 

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

Co., New York, 1966.
 

Sadtler Standard Spectra, a. Sadtler Research Laboratories, Philadelphia, Pennsylvania. IR No. 18724.
 

Sadtler Standard Spectra, b. Sadtler Research Laboratories, Philadelphia, Pennsylvania. NMR No. 6105M.
 

Sadtler Standard Spectra, c. Sadtler Research Laboratories, Philadelphia, Pennsylvania. UV 6909.
 

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.
 

50
 
Society of Dyers and Colourists. Colour Index, 2nd edition, Volume 3.
 

Yorkshire, England, 1956.
 

Stanford Research Institute, 1977 Directory of Chemical Producers,
 

U.S.A. Menlo Park, California, 1977.
 

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

6:2:679-682, 1975.
 

Wynder, E.L., J. Onderdonk, and N. Mantel, "An Epidemiological Investigation of Cancer of the Bladder." Cancer 16:1388-1407, 1963.
 

51
 

Review of the Bioassay of m-Cresidine* for Carcinogenlcity
 

by the Data Evaluation/Risk Assessment Subgroup of the
 

Clearinghouse on Environmental Carcinogens
 

March 6, 1978
 

The Clearinghouse on Environmental Carcinogens was
 

established in May, 1976, in compliance with DHEW Committee
 

Regulations and the Provisions of the Federal Advisory
 

Committee Act. The purpose of the Clearinghouse is to
 

advise the Director of the National Cancer Institute (NCI)
 

on its bioassay program to identify and to evaluate chemical
 

carcinogens in the environment to which humans may be
 

exposed. The members of the Clearinghouse have been drawn
 

from academia, industry, organized labor, public interest
 

groups, State health officials, and quasi-public health and
 

research organizations. Members have been selected on the
 

basis of their experience in carcinogenesis or related fields
 

and, collectively, provide expertise in chemistry, biochemistry,
 biostatistics, toxicology, pathology, and epidemiology.
 Representatives of various Governmental agencies participate
 

as ad hoc members. The Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse is charged with the responsibility of
 

providing a peer review of reports prepared on NCI-sponsored
 

bioassays of chemicals studied for carcinogenicity. It is in
 

this context that the below critique is given on the bioassay
 

of m-Cresidine for carcinogenicity.
 

The primary reviewer noted that the compound may be
 

of little commercial importance since the quantities
 

produced in the United States were reported to be less
 

than 1,000 pounds or $1,000 in value. He said that m-Cresidine
 

induced papillary transitional-cell carcinomas of the urinary
 

bladder in both sexes of treated rats. It also appeared to
 

cause a dose-related increase in liver tumors in female rats,
 although it may not be statistically significant when compared
 

to historical controls. The high mortality among the treated
 

male mice precluded an assessment of carcinogenicity in this
 

group. The primary reviewer briefly described the experimental
 

design under which m-Cresidine was tested. Despite the studies'
 

shortcomings, he said that they did not invalidate the con­ clusion on the carcinogenicity of m-Cresidine. He suggested
 

that the conclusion, with respect to the treated female mice,
 be reworded to note the dose-related increase in liver tumors
 

with an appropriate qualification indicating that it may not
 

be statistically significant.
 

53
 
The secondary reviewer agreed with the conclusion
 

given in the report. He noted that a mineralization was
 

observed in the urinary bladder of some treated rats. He
 

questioned whether the material may have been involved in
 

the induction of the bladder cancers. A Program pathologist
 

said that the material was likely calcification in the
 

tissue.
 

It was moved that the report on the bioassay of
 

m-Cresidine be accepted. The motion was seconded and
 

approved unanimously.
 

Members present were:
 

Gerald N. Wogan (Chairman), Massachusetts Institute of
 

Technology
 

Arnold Brown, Mayo Clinic
 

Lawrence Garfinkel, American Cancer Society
 

E. Cuyler Hammond, American Cancer Society
 

Joseph Highland, Environmental Defense Fund
 

Henry Pitot, University of Wisconsin Medical Center
 

George Roush, Jr., Monsanto Company
 

Sheldon Samuels, Industrial Union Department, AFL-CIO
 

Michael Shimkin, University of California at San Diego
 

John Weisburger, American Health Foundation
 

Sidney Wolfe, Health Research Group
 

Subsequent to this review, changes may have been made
 

in the bioassay report either as a result of the review
 

or other reasons. Thus, certain comments and criticisms
 

reflected in the review may no longer be appropriate.
 

fiU.S. GOVERNMENT PRINTING OFFICE: 1978 260-899/3168 1-3 54 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH m-CRESIDINE
 

TABLE Al

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH m-CRESIDINE 

CONTROL (UNTR)

01-0160

 CONTROL (VEH)

 01-0175

 LOU DOSE 

 01-0165 

HIG H DOSE 

01-0170 

ANIMAL S

ANIMAL S

ANIMALS

 INITIALLY IN STUD Y 

 HECHOPSIED 

 EXAMINED HISTOPATHOLOGICALLY ** 

50 

50 

50 

25 

25 

25 

50 

17 

117 

50 

45 

145 

INTEGUMENTAR Y SYSTE M 

*SKIN 

SQUAMOU S CELL PAPILLOMA 

SQUAMOUS CELL CARCINOMA 

BASAL-CELL CARCINOM A 

FIEROM A 

FIEROSARCOMA 

(50) 

1 

1 

(2X) 

(2*) 

(25) 

1 (4X) 

(47) 

1 

1 

1 

2 

(2X) 

(2X) 

(2X) 

(IX) 

(45) 

1 (2X) 

4 (9X) 

*SUBCUT TISSUE 

SABCOMA, NOS 

FIEROM A 

FIEROSAECOB A 

LIEOMA 

(50) 

1 

1 

1 

(2X) 

(2X) 

(2X) 

(25) 

3 

1 

(12X) 

(«*) 

(47) 

5 

3 (11*) (6X) 

(45) 

RESPISA10RY SYSTEM 

ILUN G 

HEFATOCELLULAR CARCINOMA , METAS T 

ALVEOLAR/BEO»CHIOLAE ADENOHA 

ALVEOLAR/BRONCHIOLA R CARCINOM A 

(19)

1 <2X ) 

 (25) (17) 

1 (2X) 

3 (6X) 

(Kit) 

1 (2X) 

2 (5X) 

HEMATOEOIETIC SYSTEM 

*MULTIPLE OBGAN S 

MALIGNAN T LZMEHOMA . NO S 

LEUKEMIA.NO S 

MYELOMONOCYTIC LEUKEMI A 

(50) 

1 (25!) 

9 (18X) 

(25) (47) 

1 (2X) 

1 (2X) 

(45) 

MYELCMONOCYTIC LEUKEMI A 

(50) (25) (47)

2 (4X) 

(43) 

CIBCULATCRY SYSTEM 

•HEART 

_ NOS,, _HETASTATICT 

(18) (25) (47) (44) 

f NUHBE8 OF ANIMALS KITH TISSUE EXAMINED

* NUMBI R OF ANIMAL S NECROPSIE D 

**EXCLUDES PARTIAI.tY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

A-3 
DIGESTIVE SYSTEM 

tLIVER 

NEOPLASTIC NODULE 

HEPATOCELLOLAR CARC1NOHA 

tSBALI INTESTINE 

LEICHYOSABCOMA 

tJEJUlUJB 

ADINCCABCINOMA , NOS 

tILEUfi 

LEICMYOSABCOMA 

U8INARY SYSTEM 

tKIDNE Y 

TOBUIAR-CELL ADENOCAECINOMA 

tUEINAE Y BLADDLP. 

TBANSITIOHAL-CELL CARCINOM A 

ENDOCRIN E SYSTEM 

tPITUITARY 

ADfNCBA , NOS 

CHBOMOPHOBE ADENOM A 

• ALRENA I 

PHIOCHROMOCYTOMA 

IIHYRCIC 

FOILICDLAfi-CELL CAfiCINOH A 

C-CEIL ADENOM A 

C-CELL CAECINOMA 

tPAKCBZATIC ISLETS 

ISLET-CELL ADENOM A

 

ISLET-CELL CABCINOM A 

SEPEODtlClIVE SYSTEM 

*MAHMAB Y GLAND 

FIEECADENOM A 

* NUMBEE OP ANIMALS HITH TISSUE

* NOMBE B OF ANIBALS KECEOPSIED 

TABLE A1 (CONTINUED) 

CCNTR01 (DNTB) 01-0160 

CONTROL (VEH) 

01-0175 LOW DOSE 

01-0165 

HIG H DOSE 

01-0170 

(149) (25) (47) 

2 <4X) 

2 (4%) 

(45) 

1 (2X) 

(49) (25) (45) (43) 

1 («) 

(49) (25) (45) (13) 

1 (2X) 

(49) (25) 

1 (4X) 

(45) (43) 

(50) (25) (47) (45) 

1 <2X ) 

(50) (25) (45) (44) 

5 {11«) 

(45) 

5

2

 (11*) 

 ("»«) 

(22) 

2 (9X) 

(45) 

2

4

 <4X ) 

 (9X) 

<37) 

3 <8») 

(50) 

3 (6*) 

(25) 

6 (24X) 

(47) 

6 <13S) 

(45) 

2 (4X) 

(37) 

1 (3%) 

1 (3*) 

2 (5X) 

(23) 

1 («) 

(44) 

1 (2X) 

1 (2X) 

1 (2X) 

(39) 

2 <5X) 

1 (3X) 

(47) 

1 <2X) 

(24) 

1 (4X) 

(45) 

2 (4X) 

1 (2X) 

(41) 

2 (5X) 

(50) (25) (47) (45) 

1 (2%) 

 EXAMINED HICBOSCOPICALLY 

A-4 
*PEEPUTIAL GLAND

 

CAECINOMA, NOS 

SEBACEOUS ADENOM A 

tTESTIS 

INTEESTITIAL-CELL TUMOE 

NERVOU S SYSTEM 

tBEAI N 

GLIOIIA. NOS 

*CEBEBBAL COETEX 

GLICtA, NOS 

SPECIAL SENSE ORGANS 

*EAH 

SQUAMOU S CELL CARCINOMA 

MUSCUL O SKELETAL SYSTEM 

*BOJIE 

FIBECSARCOMA, INVASIV E 

BODY CAVITIES 

•BODY CAVITIES 

MESCTHELIOBA, NOS 

BESOTHELIOMA, MALIGNANT 

*PERITCNEUM 

SQUAMOU S CELL CARCINOMA , INVASI V 

ALL OTHER SYSTEMS 

NON E 

I NUMBE R Of ANIMAL S KITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBIB OF ASIMALS NECBOESIED 

TABLE Al (CONTINUED) 

CONTROL (UNTfi) CONTROL(VEH ) 

01-0160 01-0175 

(50) (25) 

(50) (25) 

12 (81%) 19 (76%) 

(50) (21) 

(50) (21) 

1 (2«) 

(50) (25) 

(50) (25) 

(50) (25) 

1 (1») 

(50) (25) 

L OW DOSE

01-0165

(17)

1 (2%) 

(15)

35 (78%)

(15)

1 (2%) 

(15)

(17)

1 (2%) 

(17)

1 (2%) 

(17)

(17)

1 (2%) 

 HIG H DOSE 

 01-0170 

 (15) 

 (11) 

 35 (80X) 

 (12) 

 (12) 

 (H5 ) 

 (15) 

 (15) 

2 (IS) 

 (15) 

A-5 
TABLE Al (CONCLUDED) 

CONTROL (UNTE) CONTROL (VEH) LOW DOSE HIGH DOSE 

01-0160 01-0175 01-0165 01-0170 

ANIMA L DISPOSITION SUMMAR Y 

ANIMAL S INITIALLY I N STUD Y 

NATURA L DEATHS 

MORIBUN D SACRIFICE 

SCHHIULED SACRIFICE 

ACCIDENTALLY KILLED 

•TERMINAL SACRIFICE 

ANIMA L MISSING 

50 

32 

25 

1 

17 

50 

10 

7 

2 

31 

50 

11 

7 

5 

24 

3 INCLUDES AUTOLYZE D ANIMAL S 

£UtMAR Y 

TOTAL ANIMALS WIT H PRIMAR Y

TOIAL PRIMAR Y TUMORS 

 TUMORS* U9 

76 

21 

38 41 

81 

36 

65 

IOTA! ANIMALS WITH BENIG N

TOTAL BENIG N TUMORS 

 TUMORS 46 

56 

23 

33 

39 

60 

36 

47 

TOTAL ANIMALS HITH MALIGNAN T

TOTAI MALIGNAN T TOMORS 

 TUMORS 17 

20 

15 

19 

14 

16 

TOTAL ANIMALS HU H SECONDARY

TOTAI SECONDARY TUMORS 

 lOMORSt 

10TAL ANIMAL S HITH TUMORS

BINIG N O R MALIGNAN T 

TOTA I UNCERTAI N TUMORS 

 ONCERTAIN ­

TOTAL ANIMALS WITH TUMORS

tEIMAB Y OR METASTATIC 

TOTAI UNCERTAI N TUMORS 

 UNCERTAINPRIMAR Y TUMORS : ALL TUMORS EXCEPT SECONDARY TUMORS 

SECONEAR Y TUH08S: ME1ASTA1IC IOMORS OR TUMORS INVASIVE INTO All ADJACENT ORGA N 

A-6 
TABLE A2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH m-CRESIDINE 

CONTROL (UNTR) CONTROL (VEH) LOB DOSE HIG H DOSE 

02-0160 02-0175 02-0165 02-0170 

ANIMAL S INITIALLY IN STUDY 50 25 349 50 ANIHALS HISSING 1 ANIMAL S KECBOPSIED 49 24 49 46 ANIHALS EXAMINED HISTOPATHOLOGICALLY** 49 24 49 45 

INTEGUMENTARY SYSTEM 

*SKIN (119) (24) (49) (46) 

SQUABOUS CELL PAPILLOMA 1 (2%) 

SQUANOUS CELL CARCINOMA 1 <2X) 

FIBROMA <2X) 

*SUBCUT TISSUE (49) (24) (49) (46) 

FIEBOHA 2 (4X) 

LIPOMA 1 (2X) 

RESPIRATORY SYSTEM
 

• LUNG (49) (24) (49) (45) 

ADENOCAECINOMA, NOS, METASTATIC 1 (2X) 

ALVEOLAR/BRONCHIOLAB ADENOM A 3 (6X) 

ALVEOLAR/BRONCHIOLAR CARCINOMA 1 <4X) 2 (UX) 

OSTEOSARCOMA, METASTATIC 1 <2X) 

HEMATOPOIETIC SYSTEM 

•MULTIPLE ORGANS (49) (24) (49) (46) 

LEUKEMIA, NOS 1 (2X) 

MYELOMONOCYTIC LEUKEMIA 6 (12X) 

4BONE BARROW (US) (24) (47) (44) MALIG.LYMPHOMA, HISTIOCYTIC TYPE 1 (2X) 

CIECULATCRY SYSTEM 

* HEART (48) (24) (48) (45) 

FIBRCSARCOMA 1.12X1 

t NUMBER OF ANIMALS ilTH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

dNOTE: 50 ANIMALS WERE INITIALLY IN STUDY BUT ONE WAS FOUND TO BE A MAL E IN A FEMALE GRCUP AMD 

MAS DELETED. 

A-7 
DIGESIIVE SYSTEM 

tLIVER 

HEEATOCELLULAfi CARCINOMA 

URINAB J SYSTEM 

*UEtINABY BLADDER 

TRANSITIONAL-CELL CARCINOM A 

ENDOCRIN E SYSTEM 

fPITOITARY 

ADOCMA, NOS 

CHHOMOPHOBE ADENOM A 

*AER£HAI 

CORTICAL ADENOMA 

PHEOCHROMOCYTOMA 

tTHYRCID 

FOIIICULAS-CELL ADENOM A 

FOLLICULAR-CELL CARCINOMA 

C-CELL ADENOM A 

C-CELI CARCINOM A 

*PANCBIATIC ISLETS 

ISIP.T-CELL CABCINOMA 

BEPBODOCTIVE SYSTEM 

*MAMBAR Y GLAND 

ADENOMA, NOS 

ADENOCARCINOMA, NOS 

PAPILLARY ADENOCARCINOM A 

FIE ROM A 

FIERO ADENOM A 

*CIITCEAL GLAND 

CARCINOMA, flOS __ ._ 

t NUMBER OF ANIMALS HITH TISSUE

* NUMBE R OF ANIMALS NECROPSIED 

TABLE A2 (CONTINUED) 

CONTROL (ONTR) CONTROL (VEH) 

02-0160 02-0175 

(K8) (21) 

1 (2%) 

(«9) <2t) 

(39) (23) 

15 (38X) 

2 (5X) 7 (30») 

(K9) (2U) 

3 (6X) 

(45) (23) 

2 (UX) 1 (HX ) 

(48) (23) 

(19) (24) 

1 (UX) 

1 (4X) 

1 (4X) 

12 (2UX) 3 (13X) 

(M9) (24) 

 EXAMINED MICROSCOPICALLY 

LOU DOSE 02-0165 

09) 

1 (2X) 

<46) 

1 (2X) 

(42) 

15 (36X) 

2 (5X) 

(47) 

2 («X) 

(45) 

1 (2X) 

3 (7X) 

1 (2X) 

(46) 

(49) 

3 (6X) 

1 (2X) 

1 (2X) 

21 (43X) 

(49) 

_..1_J?X1 ., 

HIG H DOSE 

02-0170 

(44) 

1 <2X) 

(44) 

2 (5X) 

(36) 

8 (22X) 

(45) 

1 (2X) 

(41) 

1 (2%) 

1 (2X) 

2 (5X) 

(42) 

1 (2X) 

(46) 

1 (2X) 

8 (17X) 

(46) 

A-8 
TABLE A2 (CONTINUED) 

CONTROL (ONTB) CONTROL (VEH) LOW DOSE HIG H DOSE 

02-0160 02-0175 02-0165 02-0170 

ADENOMA, NOS 1 (2%) 1 (2%) 

tUIEBUS (1)6) (24) (1)7) (44) 

CABCINOHA. NOS, INVASIVE 1 (2X) 

ENDOHETFIAL STBOHAL POLYP 5 (11X) 4 (17X) 8 (17%) 

•CEBVIX DTEBI (46) (24) (47) (44) 

FIBBCHA 1 (2X) 

*UTEBUS/INDOMETBIUM (46) (24) (47) (44) 

ADENCCABCINOHA, NOS 1 (2X) 

NEBVOOS SISTER 

tBEAIH (49) (24) (47) (43) 

GLIOM. NOS 1 (2X) 

ASlfiOCYTOMA 1 (2X) 

OLIGODENDBOGLIOHA 1 (2X) 

SPECIAL SENSE ORGAN S 

*ZYMBAL' S GLAND (49) (24) (49) (46) 

CEEUBINOUS CABCINOHA 1 (2X) 

HUSCOLOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NONE 

ALL OTHIB SYSTEMS 

10HEE IEG 

OSIICSAHCOHA . 

• NUMB IB OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMB IF CF ANIMALS NECfiOPSIED 

A-9 
TABLE A2 (CONCLUDED) 

CONTROL (OUT8) CONTROL (VEH) LOW DOSE HIG H DOSE 

02-0160 02-0175 02-0165 02-0170 

AJilHAL DISPOSITION SUMMAR Y 

ANIMALS INITIALLY IN STUDY 50 25 50 50

 

NATURA L DEATHS 2 11 17 

MORIBUN D SACRIFICE 6 9 6

 

SCHEEU1ED SACRIFICE 5

 

ACCIDENTALLY KILLED 1

 

TERMINAL SACBIFICE 36 13 28 22 

ANIBA L HISSING 1 

ANIHA I DELETED (WRONG SEX) 

a INCLUDES AUTOLYZED ANIMALS 

TUMO R SUBMAR Y 

TOTAL ANIMALS WITH PRIMARY TBHORS* 31 12 38 19 

TOTAL PRIMARY TUMORS 52 19 75 29 

TOTAI ANIMAL S WIT H BENIG N TUMORS 27 10 34 16 

TOTAI EENIGN TUM08S 40 16 61 22 

TOTAL ANIMALS WITH MALIGNAN T TUMORS 10 1U

 

TOTAI MALIGNANT TUMORS 12 14

 

TOTAL ANIMALS WIT H SECONDARY TUMORS * 2 

TOTAI SECONDARY TUMORS 2 

TOTAL ANIMALS WITH TUMORS UNCERTAIN ­

BENIG N O R MALIGNAN T 

TOTAI UNCERTAIN TUMOES 

TOTAL ANIMALS WITH TUMOBS UNCERTAIN ­ ESIMAE Y OR METASTATIC

 

TOTAI UNCERTAI N TUMOR S 

* fSIMAR Y TUMORS : ALL TUMORS EXCEPT SECONDARY TUMORS 

• SECONtARY TUMORS: METASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN 

A-IO 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH m-CRESIDINE
 

TABLE Bl

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH m-CRESIDINE 

CONTROL (DNTB)

05-0160 COB TROL (VEH) 05-0175 LOU DOSE 05-0165

 HIG H DOSE 

 05-0170 

ANIMAL S

ANIMAL S

ANIMALS

ANIMALS

 INITIALLY IN STUD Y

 MISSING

 KECROPSIED

 EXAMINED HISTOEATHOLOGICALLY**

 50

 50

 49

 25

 24

 24

 50

 46

 45

 50 

1 

 41 

 36 

1N1EGUMENTAR Y SYSTEM 

NON E 

RESPIRATOR Y SYSTEM 

*IUNG

HEPATOCELLULAR CARCINOMA, METAST

ALVEOLAB/BRONCHIOLAB ADENOM A

ALVEOLAE/BHONCHIOLAB CARCINOMA

 (47)

 2 (4X) 

4 (9X)

 3 (6X)

 (24)

 4 (17S)

 (44)

 3 (7X) 

1 (2X) 

 (36) 

HEMATOPOIETIC SYSTEM 

*MULTIPIE ORGANS

MALIGNAN T LYMPHOMA . NOS

MALIG.LYMPHOMA , LYMPHOCYTIC TYP E

GBANULOCYTIC LEUKEMI A

 (50)

 1 (2X) 

 (24)

 1 (4S)

 1 (4X) 

 (46)

 1 (2X) 

 (41) 

tSPLEEN

HERANGIOSAKCOM A

HAMAFTOMA

 (49)

 1 (2%)

 (24) (41)

 1 (2X) 

1 (2X) 

 (32) 

tMESENTJEIC L. NODE

SARCOMA, NOS

 (40) (20) (31)

 1 (3X) 

 (26) 

CIECULATCHY SYSTEM 

NON E 

DIGESTIVE SYSTEM 

tLIVEB

HEPATQCILLULAR, CABCINOMA

 (49)

 1! 

 (24) (44) (36) 

* NUHBIB OF ANIMALS WITH TISSUE EXAMINED

* NUMBER OF ANIMALS NECfiOPSIED 

**EXCiUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

B-3 
TABLE Bl (CONTINUED) 

CONTROL(UNTH ) CCNTROL(VEH ) LOU DOSE HIGH DOSE 

05-0160 05-0175 05-0165 05-0170 

tSTOMACB (<(9) (24) (39) (35) 

ADEKCMATOU S POLYP, DOS 1 (2*) 

UBINAR Y SYSTEM 

NON E 

ENEOCRKil SYSTEM 

*THYRCIE (42) (22) (34) (28) 

FOtllCULAR-CELL CARCINOM A 1 ( 3%) 

REPBODUCTIVE SYSTEM 

tTESTIS (49) (24) (41) (35) 

INTERSTITIAL-CELL TUMOR 1 (2X) 

NEKVOO S SYSTEM 

NONE 

SPHCIAI SENSE ORGAN S 

NON E 

MUSCULOSKELE1AL SYSTEM 

NON E 

BODY CAVITIES 

NONE 

ALL OTHIF SYSTEMS 

NONE 

t NUMBE R OF ANIMALS KITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

B-4 
TABLE B l(CONCLUDED) 

CONTROL (DNT6) CONTROL (VEH) LOB DOSE HIG H DOSE 

05-0160 05-0175 05-0165 05-0170 

ANIMA L DISPOSITION SUMMAR Y 

ANIMAL S INITIALLY IN STUDY 50 25 50 50 

NATURAL DEATHS 3 3 27 32 

MORIEUN D SACRIFICE 8 16 

SCHEDULED SACRIFICE 5 

ACCIDENTALLY KILLED 1 

TERMINAL SACRIFICE 42 22 15 

AHISAL MISSING 1 

d INCLUDES AUTOLYZED ANIMALS 

lUfiCS SUMMAR Y 

TOTAL ANIMALS HITH PRIMARY TUBOSS* 20 9 10 

TOTAL PRIMAR Y TUMORS 26 11 12 

TOTAL ANIMALS HITH BENIGN TUMORS 6 a 

TOTAL BENIGN TUMORS 6 4 

IOTAL ANIMALS KITH MALIGNANT TUMORS 18 9 7 

TOTAI MALIGNANT TUMORS 20 11 8 

TOTA1 ANIMALS HITH SECONDARY 1UHORS* 2 

TOTAI SECONDARY TUMORS 2 

IOTAL ANIMALS HITH TUMORS UNCERTAIN ­ BENIG N OR MALIGNAN T

 

TOTAI UNCERTAIN TUMORS 

TOTAL ANIMALS HITH TUMORS UNCIRTAIN ­ EEIMAR* OR METASTATIC

 

TOTAI UNCERTAIN TUMORS 

* PRIMAR Y TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS t SECONEARY TUMORS: ME1ASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN 

B-5 
TABLE B2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH m-CRESIDINE 

c:ONTBOL(UNTE) CONTROL (VEH)

06-0160 06-0175

ANIMAL £ INITIALLY IN STUDY 50 25

ANIMAL S KISSING 

ANIMALS KECROPSIED 50 24

ANIMALS EXAMINED HISTOfATHOLOGICALLY** 50 24

IN1EGUMEHTARY SYSTEM 

*SKIN (50) (24)

HEBANGIOMA 

*SUBCUT TISSUE (50) (24)

FIEBOSARCOMA 1 (2*) 1 (4X) HEHANGIOSA8COMA 1 <2X) NEORILEMOMA, MALIGNAN T 

ttESPIRAWBY SYSTEM 

fLUNG (50) (23) HEFATOCELLULAR CARCINOMA, METAST 1 (2X) ALVEOLAB/BRONCHIOLAB ADENOMA 1 (2X) ALVEOLAR/BEONCHIOLAB CARCINOMA 3 (6X) 

HEMATOEOIETIC SYSTEM 

*MULTIEIE ORGANS (50) (24) MALIGNANT LYMPHOMA , DOS 3 (6X) MALIG.LYMPHOMA , LYMPHOCYTIC TYPE 

• SPLEEN (49) (23) HEMANGIOH A 

HEMANGIOSABCOMA 1 (2X) MALIG.LYMPHOMA , HISTIOCYTIC TYPE 1 (2*) 

*MANDIBULAB L. NODE («0) (18) MALIGNAN T LYMPHOMA, NOS 1 (3X) 

ttlESENTIBIC L. NODE (»0) (18)

PAU<;iJtXH?tt9HA.£ t-YWfU2Sni£ TifE 1 JfiSJ,

« NUMBE R OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 LON DOSE HIG H DOSE 

 06-0165 06-0170 

 50 50 

2 

 50 46 

 50 46 

 (50) (46) 

1 (2X) 

 (50) (46) 

1 (2X) 

 (49) (44) 

1 (2X) 1 <2X) 

1 (2X) 2 (5X) 

 (50) (46) 

1 (2X) 

3 <6X) 1 (2X) 

 (49) (43) 

1 <2X) 

 (41) (40) 

 (41) (40) 

^ . . _ 

B-6 
• PEYERS PATCH

MALIGNANT LYMPH OMA, NOS

CIBCDLATCRY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

*LIVEE


HEFATOCELLULAB ADENOMA


HEEAIOCELLULAE CARCINOMA


ANGIOSABCOHA


OBIHASY SYSTEM
 

NCNE
 

ENDOCBINE SYSTER
 

tPITUITABY


ADINCMA. NOS


tTHYBOIE

FOLLICOLAB-CELL ADENORA

BEPRODDCTITE SYSTEM 

• MAMMAR Y GLAND

PAPILLARY ADENOCARCIMOBA

• UTEROS

HEMANGIOMA

iOVABI


CYSTADENOMA. NOS


NERVOUS SYSTEM
 

NONE
 

t NUMBER OF ANIMALS WITH TISSUE

* NUM B IB Of ANIMALS NECBOPSIEC 

TABLE 82 (CONTINUED) 

CONTROL (0NIB) CONTROL (VEH)

06-0160 06-0175

 (19) (24)

 1 (2X) 

 (49)	 (23)


 2 (4X)


 (42)	 (17)


 (41) (17)

 (50) (24)

 (49) (22)

 1 (5X) 

 (48)	 (20)


 EXAMINED MICROSCOPICALLY 

 LOB DOSE HIGH DOSE 

 06-0165 06-0170 

 (47) (42) 

 (50)	 (45)
 

1 (2X)
 

1	 (2X) 4 (9X)
 

1 (2X)
 

 (34)	 (31)
 

2 (6X)
 

 (36) (32) 

1 (3X) 

 (50) (46) 

1 (2X) 

 (46) (42) 

 (39)	 (41)
 

2 (5%)
 

B-7 
TABLE B2 (CONTINUED) 

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

06-0160 06-0175 06-0165 06-0170 

SPECIAL SENSE ORGANS 

*EYE/IACRIMAL GLAN D (50) (24) (50) (46) 

PAPIILAR Y ADENOHA 1 (2)1) 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NONE 

A LL OTHEB SYSTEMS 

NONE 

ANIMAL tISEOSITION SOMMAEY 

ANIMAL S INITIALLY IN STUDY 50 25 50 50 

M A IDEAL DEATHS 3 4 6 9 

MOEIBUN D SACRIFICE 2 1 9 

SCHEDULED SACRIFICE 5 

ACCIDENTALLY KILLED 

TESHINAL SACRIFICE 40 21 43 30 

ANIIiA L HISSING 2 

* NUHBE R OF ANIMALS WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUHBE R OF ANIMALS NECROPSIED 

B-8 
TABLE B2 (CONCLUDED) 

CONTBOL(UNTR ) CONTROL (VEH) LOW DOSE HIGH DOSE 

06-0160 06-0175 06-0165 06-0170 

IUMO H SUHMABY 

TOTAL ANIMALS WIT H PRIMAR Y TUMORS* 1 2 3 10 15 TOTAI EEINAR Y TDMOE S 15 3 11 16 

TOTAI ANIMAL S WIT H BENIG N TUMCE S 1 1 <1 7 TOTAL BENIGN TUMOES 1 1 4 7 

TCTA1 ANIMAL S WITH MALIGNAN T TUMOR S 11 2 7 9 

TOTAI MALIGNAN T TUMORS 1<» 2 7 9 

10TAL ANIMALS WIT H SECONDAR Y TUMORS* 1 

TOTAI SECONDARY TUBORS 1 

TOTAL ANIKALS WIT H TOMORS DNCERTAINBENIG N OR MALIGNAN T

 

TOTAI ONCEETAIN TDMOE S 

TOTAI ANIMALS WIT H TUMOHS DNCERTAINPEIMAE J OE METASTATIC

 

TOTAI UNCERTAI N TUMORS 

* PhlHAE Y TUHOES: ALL TDMORS EXCEPT SECONDARY TUMORS 

* SECONDARY TUMORS : METASTATIC TUMORS OE TUMOHS INVASIV E INTO AN ADJACENT OBGA N 

B-9 

APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH m-CRESIDINE
 

TABLEC1

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

TREATED WITH m-CRESIDINE 

ANIMAL S INITIALLY IS STUDY 

ANIMALS BECBOPSIED 

ANIMALS EXAMINE D HI STOEAIHOLOGICALLY ** 

INTEGUMZNTAE Y SYSTEM 

*SKIN 

INFLAMMATION , NOS 

ULCEE, FOCAL 

INFLAMMATION, SUPPURATIVE 

HYPEBPLASIA, BASAL CELL 

BESPIHATORY SYSTEM 

*LAEYN X 

NEC SCSI S, NOS 

*LUNG 

CONGESTION, NOS 

CONGESTION, CHEONIC

EDEMA, NOS 

HEMORRHAGE 

INFLAMMATION , FOCAL 

 PASSIVE 

INFLAMMATION , INTERSTITIAL 

BEONCHOPNEUMONIA , ACUTE 

INFLAMMATION , FOCAL GRANULOBATO U 

FIBEOSIS, DIFFUSE 

PEEIVASCULITIS 

HYPEBPLASIA, NOS 

HYPERPLASIA, ALVEOLAR EPITHELIU M 

f LUNG/A IVEOLI 

HEMCBBHAGE 

HEMATOEOIETIC SYSTEM 

*SPLEEN 

FIBBCSIS 

* NUMBE R OF ANIMAL S WITH TISSUE

*. NUMBER OF AWIMALS NECEOPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

CONTROL (ONTB)

01-0160

50

50

50

(50)

1 <2X) 

(50)

(<49)

1 (2*) 

K (8X) 

1 (2X) 

1 (2X) 

1 (2X) 

(19)

1 (2X) 

(50)

1 12%1 

 CONTROL (VEH) 

 01-0175 

 25 

 25 

 25 

 (25) 

 (25) 

 (25) 

<4 (16X) 

2 (8%) 

 (25) 

 (25) 

 EXAMINE D MICROSCOPICALLY 

LOH DOSE

01-0165

50

«7

i)7

(«7)

1 (2X> 1 (2X) 

1 (2X)

(47)

<U7)

1 (2X)

1 (2%) 

2 (tX) 

1 (2*) 

1 <2X) 

1 (2X) 

1 (2X) 

6 (13X) 

(«7)

(«7)

 HIGH DOSE 

 01-0170 

 50 t5

 

 145 

 (K5) 

1 (2X) 

 (U5) 

1 (2X) 

 (KU ) 

 (t (9X) 

2 <5X) 

 («<i) 

 (143) 

C-3 
TABLE Cl (CONTINUED)
 

CONTR

01-0

OL (U NTH) CCNTEOL(VEH) 

160 01-0175 

FIEBOSIS, FOCAL 

INBABCT, FOCAL 

HEMOSIDEROSIS 

HYPEEPLASIA, HEMATO

HYPEHPLASIA, RETICUL

POIETIC 

U M CELL 

2 (UX) 

tSPLENIC FOLLICLES 

ATROPHY , NOS 

(50) (25) 

*MANCIBULA B L. NODE 

HYPEBPLASIA , PL A SB A CELL 

(49)

1 (2X) 

 (23) 

tCERVICAL LYMP." NODE 

PIGMENTATION , NOS 

(49) (23) 

tPANCBEATIC L.NODE 

HZMCBRHAG E 

FIEROSIS 

HYPERPLASIA, HEMATOPOIETIC 

(49) (23) 

tLUMBA R LYMPH NODE 

LYMPHANGIECTASIS 

(49) (23) 

tMESENTERIC L. NOD E 

ATRCPHY, NOS 

HYPEBPLASIA, PLASMA CELL 

(49)

1 (2X) 

 (23) 

* &NA L IYHPH NODE 

HEMORRHAGE 

HYPEEPLASIA, HEMATOPOIETIC 

(49) (23) 

tTHYMU S 

CYST, NOS 

HEMORRHAGE 

ATROPHY, NOS 

(24) (20) 

1 (5X) 

CIBCULAIORY SYSTEM 

tHEARl (48) (25) 

PERIABTERITIS 1 (4X) 

tHIARl/VENTBICLE (48) (25) 

HYPERPLASIAi FOCAL 

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

LOW DOSE 

01-0165 

1 (2X) 

1 <2X) 

1 (2X) 

(47) 

(45) 

(45) 

1 <2X) 

(45) 

1 (2*) 

1 (2X) 

1 (2X) 

(45) 

1 (2X) 

(45) 

(45) 

1 (2X) 

(40) 

2 (5X) 

1 (3X) 

(47) 

1 (2X) 

(47) 

1 12X) 

HIGH DOSE 

C1-0170 

1 (2X) 

1 (2X) 

(43)

2 <5X) 

(40) 

(40) 

(40) 

(40) 

(40) 

1 (3X) 

(40) 

1 <3X) 

(29) 

1 (3X) 

2 (7X) 

(44) 

(44) 

C-4
 
IHYOCABDIDH
 

INFLAMMATION, NOS
 

INFLAMMATION, INTERSTITIAL
 

FIEBOSIS
 

DEGENEBATION, NOS
 

NECEOSIS, FOCAL
 

*AOBTA
 

INFLAMMATION, CHBONIC
 

*Pl)LMONAEY ABTEBY
 

MINERALIZATION
 

*SUBCCSTAL AETEBY
 

PEEIVASCULITIS
 

DIGESTIVE SYSTEM 

tSALIVAE Y GLAND 

HYEJEPLASIA , INTBADDCTAL 

tLIVEE 

CONGESTION, NOS 

INFLAMMATION, CHBONIC FOCAL 

NECBOSIS, FOCAL 

HE1AHOBPHOSIS FATTY 

BASOPHILIC CYTO CHANGE 

EOEINOPHILIC CYTO CHANGE 

CLEAB-CELL CHANGE 

HYSEEPLASIA, FOCAL 

*LIVEE/CENTEILOBaLAE 

CONGESTION, PASSIVE 

MEIAKOBPHOSIS FATTY 

*EILE DUCT 

HYPEBPLASIA, NOS
 

*PANCBEAS
 

INFLAMMATION , NOS 

INFLAMMATION, FOCAL 

CHEONIC 

* NUMBEB OF ANIMALS KITH TISSDE

* NUMBE B OF ANIMAL S NECEOPSIED 

TABLE Cl (CONTINUED) 

CCNTBOL(UNTB) CONTBOL(VEH ) 

01-0160 01-0175 

(25) 

1 (2X)
 

2 (4X)
 

1 (2X)
 

(50)	 (25) 

(50)	 (25)
 

11 (44X)
 

(50)	 (25)
 

(50) (23) 

1 (2X) 

(49) (25) 

1 (2X) 

3 (6X) 

5 (20X) 

1 (2X) 

(49) (25) 

1 (2X) 

(50) (25) 

2 (4X) 

(47) (24) 

2 (4X) 

1 (4X) 

 EXAMINED MICBOSCOPICALL Y 

LOU DOSE 

01-0165 

(47)
 

1 (2X)
 

(47) 

(47)
 

18 (38X)
 

(47)
 

(47) 

1 (2X) 7 (15X) 

4 (9X) 

(47) 

(47) 

(<»5) 

1 (2X) 

EIG H DOSE 01-0170 

(44) 

1 (2X>
 1 (2X)
 

1 (2X)
 

[45)
 

1 (2X)
 

(45)
 

11 (24X)
 

(45)
 

1 <2X)
 

(42) 

(45) 

1 (2X) 

1 (2X) 

6 (13X) 

2 (4X) 

5 (11X) 

2 (4X) 

(15) 

1 (2X) 

(45) 

(41) 

1 (2X) 

1 (2X1 

C-5 
TABLECl (CONTINUED) 

CONTROL (UNTH ) 

01-0160 

CONTROL (VEH) 

01-0175 

LOW DOSE 

01-0165 

EIG H DOSE 

01-0170 

INFLAMMATION,

PEBIARTEBITIS 

 CHRONIC FOCA L 1 (2X) 

2 (4X) 

1 (2X) 

« ESOPHAGUS 

NECROSIS, NOS 

(48) (19) (42) (40) 

1 (3X) 

*PEBIESOPHAGEAL II SSU 

INFLAMMATION , NOS 

INFLAMMATION , ACUTE

NECROSIS, NOS 

 FOCAL 

(48) (19) 

1 (2X) 

1 (2X) 

1 (2X) 

(40) 

tSTOMACH 

INFLAMMATION , NOS 

HYPERKERATOSIS 

AC AN T HO SIS 

(U9) 

1 (2X) 

1 (2X) 

(25) (44) (41) 

1 <2X ) 

1 (2X) 

1 (2X) 

tPEYERS PATCH 

HYPERPLASIA, NOS 

(49) 

1 <2X) 

(25) (45) (43) 

ICOLON 

HINEBALIZATION 

NEMATODIASIS 

PABASITISM 

(48) (25) 

2 (8X) 

(45) 

3 (7X) 

1 (2X) 

(40) 

1 <3X ) 

3 (8X) 

URINAR Y SYSTEM 

tKIDNE Y 

HYIBCNEPHEOSIS 

CONGESTION, NOS 

GLOMERULONEPHRITIS, NOS 

INFLAMMATION , NOS

INPLAMHATION, INTERSTITIAL

GLOBERDLONEPHRITIS, CHRONIC

FIEFOSIS, DIFFUSE

PEEIABTERITIS

NEfHEOPATH Y

NEPHROSIS, NOS

NECROSIS, (1EDDLLARY

CALCIFICATION, NOS

HYFEFPLASIA, TUBULAR CELL

(50) 

1 (2X) 

4 (8X) 

 35 (70X)

(25) 

1 (4X) 

 16 (64X)

(47) 

1 (2X) 

1 (2X) 

 41 (87X)

 1 (2X)

(45) 

 32 (71X) 

1 (2X) 

1 (2X) 

6 (13X) 

2 (4X) 

3 (7X) 

1 (2X) 

1 (2X) 

tKIDNIY/HEDULLA

MINIBALIZAIION

 (50) (25) (47)

 1.J2X1 

 (45) 

» NUMBE R

* NUMBE R

 OF ANIMALS

 OF ANIMALS

 MITH TISSUE

 NECROPSIED 

 EXAMINE D MICROSCOPICALLY 

C-6 
#BENA l PAPILLA

 

MINERALIZATIO N 

HEMOBBHAGE 

NECROSIS, FOCAL 

*KIDNEY/PELVIS 

HYPIBPLASIA, EPITHELIAL 

XUBINAE Y BLADDER 

INFIABMATION , ACUTE NECBOTIZING 

ENDOCRIN E SYSTEM 

• PITUITARY 

CYST, NOS 

CONGESTION, NOS 

HEMORRHAG E 

HYPEEPLASIA, FOCAL 

HYPEBPLASIA, CHROHOPHOBE-CEIL 

«ADRENA I 

HEMORRHAG E 

METAMORPHOSIS FATTY 

*ADRENA l COBTEX 

NOEUL E 

IAEHENA I MEDULLA 

HYPERPLASIA, NOE 

HYFEPPLASIA, FOCAL 

tTHYROIC 

CYST, NOS 

CYSTIC FOLLICLES 

HYPEEPLASIA, C-CELL 

METAPLASIA, SQUAMOU S 

tPARATBYROID 

HYPEBPLASIA , NOS 

((PANCREATIC ISLETS 

HYPEEPLASIA , NOS 

HEPRODUCTITE SYSTEM 

*MAMMAR Y GLAN D 

GAIACTOCELE .. 

# NUMBE R OF ANIMAL S WITH TISSUE

* NUMBE R OP ANIMALS NEC8OPSIED 

TABLE Cl (CONTINUED) 

COHTBOL(UMTB) 

01-0160 

(50) 

(50) 

(50) 

(U5) 

1 <2X) 

(50) 

(50) 

(50) 

(37) 

1 (3X) 

2 (5*) 

(20) 

(K7) 

(50) 

CONTBOL(VEH ) 

01-0175 

(25) 

(25) 

(25) 

(22) 

1 (5X) 

1 <5X) 

(25) 

(25) 

(25) 

1 (»*) 

(23) 

6 (26%) 

1 (M) 

(12) 

(2«) 

(25) 

 EXAMINE D MICBOSCOPICALL Y 

LOU DOSE 

01-0165 

(17) 

7 (15X) 

(U7) 

(«5) 

1 (2*) 

(45) 

1 (2«) 

2 (4*) 

(i»7) 

1 (2X) 

1 (2«) 

(17) 

1 <2X) 

(17) 

1 <2X ) 

(11)

1 (2X) 

1 (2X) 

H (9X) 

(20) 

(15) 

(17) 

1 (2S) 

HIG H DOSE 

01-0170 

(15) 

27 (60X) 

1 (2X) 

1 <2X ) 

(15) 

26 (58X) 

(««) 

(37) 

1 (3X) 

1 (3X) 

6 (16X) 

(15) 

(15) 

(15) 

1 (2X) 

1 <2X ) 

(39) 

1 (3X) 

(18) 

1 <6X) 

(11)

1 (2X) 

(IE) 

C-7 
TABLE Cl (CONTINUED) 

CONTROL (UNTR) CONTROL (VEH)

01-0160 01-0175

#PROSTATE (48) (24)

MINERALIZATIO N 

HEMORRHAG E 

INFLAMMATION . NOS 3 (6X) 

INFLAMMATION , FOCAL 1 (4S) 

INFLAMMATION , ACUTE 

INFLAMMATION , ACUTE FOCAL 5 (21X)

INFLAMMATIO N ACUTE AND CHRONIC 

METAPLASIA , SQUAMOUS 

*SEMINAl VESICLE (50) (25)

HEMORRHAG E 

INFLAMMATION , ACUTE FOCAL 

ATBOPHY, NOS 

HYEEEELASIA , PAPILLAR Y 

tTESTIS (50) (25)

PERIARTEKITIS 

PERIVASCULITIS 1 (2%) 

CALCIFICATION, NOS 3 (6X) 

CALCIFICATION, FOCAL 1 (2X) 

ATROPHY , NOS 1 1 (22X) 

ATROPHY, FOCAL 

HYEEEPLASIA , INTERSTITIAL CELL 4 (8%) 1 (4X)

»IESTIS/TUBULE (50) (25)

MINERALIZATIO N 

DEGENERATION , NOS 

NERVOU S SYSTEM 

IBRAI N (50) (24)

 

INFARCT, FOCAL 

SPECIAL SENSE ORGANS 

NONE 

BUSCULCSKELETA L SYSTEM 

*SKELE1AL MUSCLE (50) (25) 

MINERALIZATIO N 

* NDHBE R OF ANIMALS KITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

 LOW DOSE 

 01-0165 

 (44) 

1 (2X) 

1 (2X) 

1 (2X) 

2 (5X) 

5 (11X) 

1 (2%) 

1 (2X) 

 (47) 

1 (2X) 

1 (2X) 

1 (2X) 

 (45) 

2 (4X) 

 (45) 

(45) 

1 (2X) 

(47) 

HIGH DOSE 01-0170 

(43) 

1 (2X ) 

7 (16X) 

(45) 

1 (2X) 

(44) 

1 (2X) 

1 <2X ) 

(44) 

1 (2X) 

2 (5X) 

(42) 

(45) 

C-8 
TABLE CI (CONCLUDED) 

CONTBCL(UNTB)

01-0160

 CONTEOL(VEH)

 01-0175

 LOU DOSE 01-0165 HIGH DOSE 01-0170 

BODY CAVITIES 

*M£BIASTINUM 

INFLAMMATION, ACUTE 

*P1EURA 

FIEROSIS, DIFFUSE 

(50) 

(50) 

1 (2X) 

(25)

1 («) 

(25)

 (H7) 

 (17) 

(15) 

(45) 

ALL OTHER SYSTEMS 

NEC K 

INFLAMMATION , FOCAL 

•MULTIPLE ORGANS 

BINEBALIZATION 

(50) (25) (K7) (15) 

1 (2%) 

ADIPOSE TISSUE 

INBIAMMATION , CHRONIC 

CHENTU1! 

NECROSIS, FAT 

PIGMENTATION, NOS 

SPECIAL KOBPHOLOGY SUMMAR Y 

AUTCIYSIS/NO NECROPSY 

* NUI1BH F CF ANIMAL S WITH TISSUE EXAMINE D

* NUHBI B OF ANIMALS NEC80PSIED 

 MICROSCOPICALLY 

C-9 
TABLE C2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

TREATED WITH m-CRESIDINE 

CONTROL (UNTE) 

02-0160 

CONTEOL (VEH) 

02-0175 

LOW

02­

 DOSE 

0165 

HIG H 02-0 DOSE 170 

ANIMAL S INITIALLY IN STUD Y 50 25 8U9 50 

ANIMAL S HISSING 1 

ANIMAL S KICROPSIED 49 24 «9 46 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY** 49 24 49 45 

INTEGUMENTAR Y SYSTEM 

*SKIN (19) (21) (49) (46)
 

EPIDEBHAL INCLUSION CYST 1 (2X)
 

ATEOFHY, NOS 1 (2X)
 

RESPIBA10RY SYSTEM
 

*LUN6/EEONCHUS (49) (24) (49) (45)
 

INFLAMMATION, NOS 1 (21)
 

*LUNG (49) (24) (49) (45)
 

CONGESTION, NOS 1 (IX)
 

CONGESTION. ACUTE PASSIVE 1 (2*)
 

EDEMA, NOS 2 (4%)
 

HEMORRHAGE 2 (4X)
 

INFLAMMATION, FOCAL 1 (4S) 1 (2%)
 

INFLAMMATION, INTERSTITIAL 1 (2X)
 

INFLAMMATION, CHHONIC 1 (2X)
 

PEBIARTEBITIS 1 (IS)
 

CY10MEGALY 1 (2*)
 

HYtEFPLASIA, ALVEOLAE EPITHFLIOM 2 (8«)
 

HEMATOPOIETIC SYSTEM
 

tBONE MAREOW (45) (24) (47) (44)
 

HYPEEPLAS1A, HEMATOEOIEIIC 1 (2X)
 

*SPLEEN (47) (24) (48) (45)
 

HEMCSIDEEOSIS 3 (6X)
 

HYPEEPLASIA, HEMATOFOIETIC 1 (4X)
 

t NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY * NUMBE E OF ANIMAL S NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

SINOTE: 50 ANIMALS WEEE INITIALL Y IN STUDY BUT ONE MAS FODND TO BE A MAL E IN A FEMAL E GRCBP AND HA S 

DELETED. 

c-io 
TABLE C2 (CONTINUED) 

COHTEOL(OSTH) 

02-0160 

CONTROL (VEH) 

02-0175 

LOW DOSE 

02-0165 

HIGH DOSE 

02-0170 

tSPLENIC FOLLICLES 

ATROPHY, NOS 

(47) (24) (48) 

1 (2X) 

(45) 

tMEDIASTINAL L.NODE 

HEMORRHAG E 

(44) (24) 

1 (2X) 

(39) 

1BESEHTERIC L. NODE 

HEMORRHAG E 

(24) (46) 

1 (2X) 

(39) 

*THYMUS 

CYST, NOS 

HEMORRHAGE 

(30) (18) 

<6X) 

(38) 

<3X> 

(29) 

CIRCULATORY SYSTEM 

(HEART 

NECRCSIS, FOCAL 

(148) (24) (48) (45) 

1 (2X) 

*MYOCAEtIU« 

FIBRCSIS 

DEGENERATION, NOS 

(U8) 

1 (2X) 

(24) (48) (45) 

1 (2X) 

*ARTERY 

NECROSIS, FOCAL 

(49) (46) 

1 (2X) 

*PULMONARY ASTERY 

MINERALIZATION 

(K9) (2U) 

5 (21X) 

(49) 

6 (12X) 

(46) 

(2X) 

DIGESTIVE SYSTEM 

tLIVER

INFLABBATION, ACUTE 

INFLAMMATION, ACUTE/CHRONIC

INFLAMMATION , CHRONIC FOCAL

NECROSIS, NOS 

NECROSIS, FOCAL

METAMORPHOSIS FATTY

BASOPHILIC CYTO CHANGE

EOSINOPHILIC CYTO CHANGE 

CLEAR-CELL CHANGE 

HYtEtFLASIA. FOCAL 

 (48) 

1 (2X) 

1 (2X) 

1 (2X) 

1 (2JS) 

2 (4X) 

(24) 

2

17

 (8X) (71X) 

(49) 

1 (2X) 

1 (2X) 8 (16X) 

21 (43X) 

4 (8X) 

(44) 

1 (2X) 

1 <2X) 

3 (7X) 2 (5X) 

1 (2X) 

1 (2X) 1 (2X) 

* NUMBE R

* HUHBIR

 OF ANIMALS

 OF ANIMALS

 KITH TISSUE

 NECROPSIED 

 EXAMINED MICROSCOPICALLY 

c-n 
ANGIECIASIS 

HEHATOFOIESIS 

* LIVER/ HEPATOCYTES 

NUCLEA R ALTERATION 

*BILE DUCT 

HYFERPLASIA, SOS 

HYPEEPLASIA, FOCAL 

*PANCREAS 

INFLAMMATION , CHRONIC 

INFLAMMATION, CHRONIC FOCAL 

PEBIARTERITIS 

NECBOSIS, FOCAL 

#PANCHEATIC ACINUS 

ATROPHY , FOCAL 

»ESOPHAGUS 

DILATATION, NOS 

EPIDERMAL INCLUSION CYST 

NECBOSIS, NOS 

ISTOHACB 

INFLAMMATION , NOS 

NECROSIS, FOCAL 

tGASTRIC SUBMUCOSA 

EDIKA , NOS 

#PEYEBS PATCH 

HYPIHPLASIA, NOS 

tlLEUB 

ULCER, FOCAL 

tCOLON 

NEHATODIASIS 

PARASITISM 

URINAR Y SYSTEM 

IKIDNE Y 

MINERALIZATION 

* NOHBE R OF ANIMALS KITH TISSUE

* NUMBE R OF ANIMALS NECROPSIED 

TABLE C2 (CONTINUED) 

CONTROL (UNTR) CONTROL (VEH) 

02-0160 02-0175 

1 (1*) 

(48) (21)

1 <4X ) 

(19) (24) 

2 (UX ) 

1 <2X) 

(48) (23) 

(t8) (23) 

(19) (18) 

1 <6X) 

(49) (23) 

1 (2*) 

(49) (23) 

1 <2X) 

(49) (24) 

2 (4X) 

(19) (21) 

(19) (24) 

1 (2X) 3 (13X) 

(48) (24) 

 EXAMINED MICROSCOPICALLY 

LOB DOSE 

02-0165 

(49) 

(49) 

(46) 

(16) 

(41) 

(45) 

(15) 

(46) 

(46) 

1 (2X) 

(46) 

2 (IX) 

3 (7X) 

(19) 

5 J10X1 

HIG H DOSE 

02-0170 

2 <5X) 

(44) 

(46) 

(42) 

1 (2X) 

1 (2X) 

1 (2X) 

1 (2X) 

(42) 

1 (2X) 

(37) 

1 (3X) 

1 (3X) 

(45) 

1 (2X) 

(45) 

(45) 

(45) 

(44) 

2 (5X) 

(45) 

1 ^2SL ^ 

C-12 
TABLE C2 (CONTINUED) 

CCNTBOL(UNTB) 

02-0160 

CONTBOL(VEH )

02-0175

 LO U DOSE 

 02-0165 

HIG H DOSE 

02-0170 

CYE1, NOS 

GLOMERULONEPHRITIS,

GLOMERULONEPHRITIS .

NEEHBOEATHY 

NEPHBOSIS, NOS

NECROSIS, FOCAL 

POSTMORTEM CHANG E 

NECROSIS, MEDULLARY 

 NOS

 CHRONIC 

1 (8X) 

 29 (60X) 

17 (71X)

1 (2X) 

 37 (76X) 

1 (2X) 

26 (58X) 

11 (21X) 

1 (2X) 

K (9X) 

tKIDNEY/COETEX

METABORPHOSIS FATTY

 (18) 

1 (2X) 

(21) (19) (1*5) 

*KIDNEY/BEDULL A

CALCIFICATION, NOS 

 (18) (21) (19) (15) 

1 (2X> 

*BENAL EAPILLA

HINEBALIZATION 

INFLAMMATION , ACUTE

NECROSIS, NOS 

 FOCAL 

 (18) (21) (19) 

3 (6%) 

(15) 

31 (76X) 

1 (2X) 

2 (IX) 

*KIBNEY/EELVIS

MINIRALIZATION 

HYPEEPLASIA, EPITHELIAL 

 (18) (21) (19) 

1 (8X) 

(15) 

29 (6<t X) 

&NDOCBINE SYSTEM 

*PITUI1AEY

CYST, NOS 

HYPEBPLASIA, FOCAL 

HYPEBPLASLA, CHBOMOPHOBE-CE1L 

 (39) (23) (12) 

1 (2X) 

1 (2X) 

1 (2X) 

(36) 

tADRENA I

ANGIECTASIS 

 (19) (21) (17) 

1 (2X) 

(15) 

*ADRENAI CORTEX

HYFIRPLASIA, NODULAB 

 (19) (21) (17) (15) 

1 (2X) 

tAEBENA L MEDULLA

HYPEBPLASIA, NOS 

 (19) (21) (17) 

1 <2X) 

(15) 

ITHYBOIE

CYST, NOS 

COLLOID CYST 

 (15) (23) (1*5) 

1 (2X) 

(11) 

1 (2X) 

* NUHBE B OF ANIMALS KITH TISSUE

* NUHBE B OF ANIMALS NECROPSIED 

 EXAMINE D MICROSCOPICALLY 

C-13 
TABLE C2 (CONTINUED) 

CONTROL (DNTfi) CONIBOL(VEH) 

02-0160 02-0175 

HYEEBPLASIA, PAPILLAEY 

HYEEEPLASIA, C-CELL 2 (4X) 2 (9X) 

BEPBODOC1I7E SYSTEM 

*MAHMAB Y GLAND (19) (24) 

DIIATATION/DUCTS 1 <2X) 

GALACTOCELE 3 (13X) 

HYPEBPLASIA, NOS 

HYPEBPLASIA, FOCAL 1 (4X) 

*MAMHAR Y DDCI (49) (24) 

HYPEBPLASIA, CYSTIC 1 (2X) 

•MABMABY LOBULE (49) (24) 

RYPEBPLASIA, NOS 1 («) 

*CiITOBAL GLAND (49) (24) 

INFLAMMATION, FOCAL GHA NOLCHATOD 1 (4X) 

tUlEBDS (U6) (24) 

HYIBOHETBA 1 (2X) 

HEMATOMA, NOS 1 12%) 

PO1YP, INFLAMMATOB Y 1 (2«) 

tUTEBUS/ENDOHETBIOM (46) (24) 

HYPEBPLASIA, CYSTIC 

iOVABY (47) (24) 

INFLAMMATION , CHRONIC 1 <2X ) 

NERVOUS SYSTEH 

*BBAI N (49) (24) 

HEMORRHAG E 

SPECIAL SENSE ORGAN S 

»EY E (49) (24) 

INFLAMMATION, CHBONIC 

CATAf|iCT 

* NUMBEB OF ANIMALS MITH TISSUE EXAMINE D MICBOSCOPICALLY 

* NUBBEfi OF ANIMALS NECBOPSIED 

LOW DOSE 

02-0165 

(49) 

15 (31X) 

1 <2X) 

(49) 

C»9) 

4 (8X) 

(49) 

(47) 

2 (4X) 

(47) 

3 (6X) 

(45) 

(47) 

1 (2X) 

(49) 

HIG H DOSE 

02-0170 

1 (2X) 

(<»6) 

3 (7X) 

(46) 

(46) 

(46) 

(44) 

2 (5X) 

(44) 

1 (2X) 

(45) 

(43) 

(46) 

1 (2%) 

1 (2X) 

C-I4 
TABLE C2 (CONTINUED) 

CCNTBCL(UNTB) CONTEOL(VEH) LOU DOSE HIGH DOSE 

02-0160 02-0175 02-0165 02-0170 

*EYE/CCBNE A (49) (21) (49) (46) 

INFLAMMATIO N PEOLIFEEATIVE 1 (2X) 

*L£NS CAPSULE (49) (24) (49) (46) 

CALCIFICATION, DOS 1 (2%) 

MUSCULOSKELEIA L SYSTE M 

NON E 

BOD Y CAVITIES 

*MEDIASTI1IDH (49) (24) (49) (46) 

EDEHA , NOS 1 (2%) 

PEEIABTEBITIS 2 (IX) 

*»ESENTEBY (49) (24) (49) (46) 

PEBIABTEBIIIS 1 (2X ) 

A LL OTHER SYSTEMS 

*MULTIPLE ORGAN S (49) (24) (49) (45) 

NECECSIS, FOCAL 1 (251) 

ADIPOSE TISSUE 

INFLAMMATION , CHBONIC 

OMENTU M 

INELAMBATION , NO S 

NECECSIS, NOS 

NECBOSIS, FAT 

SPECIA L BOEPHOLOGY SUMMAE Y 

NO IESION EEP08TED 

ANIMA L MISSING/NO NECEOPS Y 

AD1C/NECBQPSY/HISTO PEEF 

AUIC/NECBOPSY/NO HISIO 

* NUMBI E OF ANIMALS KITH TISSUE EXAMINED MICBOSCOPICALL Y 

* (lUMBE E OF ANIMAL S NECEOPSIED 

C-!5 
TABLE C2 (CONCLUDED) 

CONTROL (ONT8)

02-0160

 CONTEOL(VEH)

 02-0175

 I.OKDOSE

 02-0165

 RIGHDOS E 

 02-0170 

AU10LYSIS/NO NECKOPSY 1 « 

NUHBE E OF ANIMAL S HUH TISSOE EXAMINE D HICROSCOPICALL Y 

NOKBZ E OF ANIMAL S NECEOPSIED 

C-I6 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH m-CRESIDINE
 

TABLE Dl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

TREATED WITH m-CRESIDINE 

c:ONTBOL (UNTK) CONTROL (VEH) LOi DOSE 

05-0160 05-0175 05-0165 

ANIMALS INITIALLY IN STUDY 50 25 50 

ANIMAL S KISSING 

ANIHALS NECHOPSIED 50 24 46 ANIMALS EXAMINED HISTOPATHOLOGICALLY** 49 24 45 

INTEGUMENTAR Y SYSTEM 

*SUBCG1 TISSUE (50) (24) (46) HEMATOMA, NOS 1 (2X) INFLAHMATION, ACUTE FOCAL 1 (2X) ABSCESS, NOS 1 (2X) 

SESFIRA10RY SYSTEM 

NON E 

HEMATOPCIETIC SYSTEM 

•BONE HARROW 

HYPF.HPLASIA, HEMATOEOIETIC 

(49) (21) (41) 

1 (2X) 

tSPLEEN 

ATROPHY, NOS 

HEMATOPOIESIS 

ERYTHROPOIESIS 

(49) 

2 (4X) 

(24)

1 (4X) 

 (41) 

14 (34*) 

tUANDIBULAR L. NODE (40) (20) (31) ATRCPHY. NOS 

tHESENTERIC L. NODE 

HEMORRHAGE 

(40) (20)

10 (SOX)

 (31) 

2 (6X) ATBOFHY, NOS 

tRENAL IYMPH NODE 

HYPERPLASIA, NOS 

(40) 

2 <5X) 

(20) (31) 

tTHYMUS 

._ ATROPHY. NOS 

(30) (16) _ __ , ._ (24) 

 16_ (67X) . _ 

* NUMBE R OF ANIMALS * NUMBER OF ANIMAL S KITH TISSUE EXAMINED

 NECBOPSIED 

 MICROSCOPICALLY 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

filGH DOSE 

05-0170 

50 

1 

41 

36 

(41) 

(33) 

(32) 

18 (56X) 

(26) 

1 (4X) 

(26) 

1 <4X) 

2 (8X) 

(26) 

(19) 

15_179X1 

D-3 
TABLEDl (CONTINUED) 

CIRCULATORY SYSTEM 

#HEAKT 

THROMBOSIS. NOS 

INFLAMMATION . CHRONIC 

DIGESTIVE SYSTEM 

*SALIVARY GLAND 

LYMFHOCYTIC TNFLAMHATOR Y INFILTR 

tllVEB 

HECECSIS, FOCAL 

METAMORPHOSIS FATTY 

CY10PLASMIC VACUOLIZATION BASOPHILIC CYTO CHANGE

 

AHGIECTASIS 

*IIVER/KUPFFER CEIL HYPERPLASIA, NOS

 

tLIVER/HEPATOCYTES 

CYTCELASMIC VACUOLIZATIO N 

tPANCEEA S 

CYSTIC DOC IS 

PESIVASCULITIS NECROSIS, FAT

 

ATROPHY, FATTY 

tSTOMACH 

ULCIR, NOS 

INFLAMMATION , ACUTE FOCAL 

CALCIFICATION, FOCAL 

HYPERPLASIA, FOCAL 

tPEYERS PATCH 

INFLAMMATION , ACUTE 

HYPERPLASIA, LYMPHOID 

#COLON 

PARASITISM 

URINAR Y SYSTEM 

*KIDNI Y 

HYIJeONEPHRfiSIS 

CONTROL (ONTR) 

05-0160 

(49) 

(K7) 

(49) 

1 (2X) 

1 (2X) 

(49) 

1 (2X) 

(49) 

(46) 

1 (2X) 

1 (2») 

1 (2%) 

(49) 

(49) 

1 (2X) 

1 (2X) 

(48) 

(49) 

2_J4J1_ 

CONTRO L (VEH) 

05-0175 

(24) 

1 (4X) 

(23) 

17 (74X) 

(24) 

1 (4X) 

2 (8X) 

(24) 

(24) 

(22) 

2 (9X) 

(24) 

1 (4%) 

(24) 

(20) 

2 (10X) 

(24) 

LOW DOSE 

05-0165 

(44) 

1 (2X) 

(43) 

4 <9X) 

(44) 

1 <2X) 

(44) 

(44) 

10 (23X) 

(37) 

(39) 

1 (3X) 

(37) 

(32) 

3 (9X) 

(43) 

HIG H DOSE 

05-0170 

(36) 

(34) 

(36) 

1 (3X) 

3 (8X) 

(36) 

(36) 

11 (31X) 

(32) 

(35) 

3 (9X) 

2 <6X) 

1 (3X) 

(35) 

(30) 

3 (10X) 

(36) 

t NUMBI R OF ANIMALS HITH TISSOE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMALS NEC80PSIED 

D-4 
TABLE Dl (CONTINUED) 

CONTBOL(ONTB)

05-0160

 CONTRO L (VEH)

 05-0175

EYBICNEPHRITIS,

INFLAMMATION, C

HEPHBOSIS, NOS 

 HOE 

HRONIC 1 <2X) 

1 (4X)

tRENAL PAPILLA 

NECROSIS, NOS 

(49) (24)

iNDOCRIN! SYSTEM 

tTHYROI D (42) (22)

HYPERPLASIA, FOCAL 1 (2S) 

HYPERPLASIA, FOLLICULAR-CELL 1 (5X) 

•PARATHYROID (20) (14)

HYIIRPLASIA, NOS 

tfANCBIATIC ISLETS (46) (22)

HYPIBPLASIA, NOS 3 (14X) 

REPRODUCTIVE SYSTEM 

• PEEPCTIAL GLAN D (50) (24)

DILA1ATION, NOS 1 (2X)

tTESTIS (49) (24)

DEGENERATION , NOS 

CALCIFICATION, FOCAL 

MUL1INUCLEATE GIANT-CELL 

ATBOPHY, NOS 

ATROPHY, FOCAL 5 (21X) 

HYPERPLASIA, INTERSTITIAL CEIL 

iTEST IS/TUBULE (49) (24)

NECBCSIS, FOCAL 1 <2X) 

NERVOUS SYSTEM 

NONE 

SPiCIAL SENSE ORGAN S 

NONE 

(1USCULOSKELETAL SYSTEM 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECBOPSIED 

D-5 

 LOW DOSE 

 05-0165 

2 <5X) 

 28 (65X) 

 (43) 

13 (30X) 

 (34) 

 (20) 

 (37) 

 (46) 

1 (2X) 

 (41) 

1 <2X ) 

1 (2X) 

10 (24%) 

3 (7X) 

1 (2X) 

 (41) 

HIGH DOSE 

C5-0170 

32 (89X) 

(36) 

20 (56X) 

(28) 

(14) 

(32) 

(41) 

(35) 

3 (9X) 

22 (63X) 

2 (6%) 

(35) 
TABLE Dl (CONCLUDED) 

CONTEOL (UNTR) CCNTEOL(VEH ) LOW DOSE HIGH DOSE 

05-0160 05-0175 05-0165 05-0170 

BODY CAVITIES 

*ABDOMINAL CAVITY (50) (2U) 

ADHESION, NOS 1 (2%) 

*M!SENT!RY (50) (24) 

STEA1ITIS 1 (2X) 

ABSCESS, NOS 1 (2X) 

ALL OTHER SYSTEMS 

ADIPOSE 1ISSDE 

STEA1IIIS 1 

NECECSIS, FA1 2 

SPECIAL MORPHOLOGY SUMMAR Y 

SO LESION 6EPORTED 17 2 2 

ANIMA L MISSING/NO NECSOPSY 1 

ACCIDENTAL DEAT H 1 

AUtO/NECROPSY/HISTO PESF 1 1 

AOTC/NECBOPSY/NO HISTO 1 1 5 

AUTCLYSIS/NO NECROPSY 1 <t 7 

* NUMB IE OF ANIMALS HUH TISSUE EXAMINED MICROSCOPICALLY 

* NOMBE B Of ANIMALS NECBOPSIED 

0-6 
TABLE D2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

TREATED WITH m-CRESIDINE 

CONTROL (UNT8) CONTEOL(VEH)

06-0160 06-0175

ANIMALS INITIALLY IN STDDY 50 25

ANIMAL S BISSING 

ANIMAL S HECROPSIED 50 24

ANIMALS EXAMINED HI STOPATHOLOGICALLY** 50 24

INTEGUMBNTAH Y SYSTE M 

NONE 

RESPIRATORY SYSTEM
 

NONE
 

HEMATOPOIETIC SYSTEM 

tBONE HARRO H (19) 122) 

MYELCFIBROSIS 11 (50)5) 

*SPLE£S (U9) (23) 

ATRCFHY, NOS 

HYPERPLASIA, LYMPHOI D 1 (2X) 

HEMATOPOIESIS 1 («X) 

ERY1HBOPOIESIS 1 (2X) 

iMANDIBULA R L. NODE («0) (18) 

HYPJRPLASIA , NOS 

HYPERPLASIA , PLASM A CELL 1 (3X) 

iMEDIASTINA L L.NOD E (40) (18) 

HYPERPLASIA . NOS 1 (3X) 

*LUKBA R LYHPH NODE (40) (18) 

H1TPEBELASIA, NOS 1 (3X) 

•MESENTBEIC L. NODE (40) (18) 

HEMORRHAG E 5 (28%) 

ATROPHY . NOS 

* NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D HICROSCOPICALLY 

* NHMBI R OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

D-7 

 LOU DOSE 

 06-0165 

 50 

 50 

 50 

(49) 

17 (35%) 

(49) 

1 (2X> 

(41) 

1 (2X) 

(41) 

(41) 

(41) 

1 <2X ) 

HIGH DOSE 

06-0170 

£0 

2 

46 

46 

(44) 

19 (43X) 

(43) 

4 (9X) 

(40) 

(40) 

(40) 

(40) 

2 (5%) 

1-1321. 
TABLE D2 (CONTINUED) 

CONTROL (UNTR) 

06-0160 

CONTROL (VEH) 

06-0175 

LOW DOSE 

06-0165 

HIG H DOSE 

06-0170 

iKiNA L LYMPH NODE 

HYPIRPLASIA, NOS 

HYPEBPLASIA, PLASM A CELL 

(40) 

1 (3X) 

1 (3X) 

(18) (41) (40) 

tTHYMUS 

ATBCEHY, NOS 

(31) (15) (33) (29) 

7 (2«X) 

CIRCULATCRY SYSTEM 

tMYOCAREIU M 

INFLAMMATION , ACUTE DIFFUSE 

(50) 

1 (2X) 

(23) (49) (44) 

DIGESTIVE SYSTEM 

• SALIVAB Y GLAN D 

LYBPHOCYTIC INFLAMMATORY

ATBOPHY, NOS 

 INFILTR 

(48) (23) 

8 (35%) 

1 (4X1 

(49) 

20 (41X) 

(45) 

18 (<(OX) 

«LIVEB 

NECROSIS, NOS 

NECROSIS, FOCAL 

INFARCT , NOS 

HEMATOPOIESIS 

(49) 

1

1

1

 (2X) 

 (2X) 

 <2X ) 

(23) 

1 (IX) 

(50) 

1 (2X) 

1 (2X) 

(45) 

1 (2X) 

1 (2X) 

•BILE DUCT 

INFLAMMATION , CHRONIC FOCAL 

(50) 

2 (4X) 

(21) (50) (46) 

tPANCBEA S 

DILATATION/DUCTS 

NECROSIS, FAT 

METAMORPHOSIS FATT Y 

ATBOPHY, FATTY 

(47) (23) 

1 (IS) 

(43) 

2 (5X) 

1 (2X) 

(40) 

tSTOMACB 

INFLAMMATION ,

INFLAMMATION,

 ACUTE FOCAL 

 CHRONIC 

(49) 

1 <2X) 

1 (2%) 

(23) (47) (43) 

tttlERS PATCH 

HYEIBPLASIA , LYMPHCI D 

(49) 

<2X) 

(2U) (47) (42) 

tCOLON 

JE.BATODIASIS 

(50) (23) (37) 

* NUMBE R

* NUMBE R

 OF ANIMAL S KITH TISSUE

 OF ANIMAL S NECROPSIED 

 EXAMINE E MICROSCOPICALLY 

D-8 
TABLE D2 (CONTINUED) 

CONTROL (OUTB) 

06-0160 

CONTROL (VEH) 

06-0175 

L O U DOSE 

06-0165 

HIGH DOSE 

06-0170 

PARASITISM t (11*) 

UBINAB S SYSTEM 

tKIDNE Y

LYBIHOCYTIC INFLAMBATOB Y INFILTB

INFLAMMATION , CHRONIC

INFLAMMATION, CHRONIC FOCAL

NEPHROSIS, NO S 

GLOMERULOSCLEROSIS. NOS 

PIGMENTATION, NOS 

CYTOPLASMIC VACUOLIZATION 

 (49) 

1 (2X) 

2 (4)1) 

1 (2%) 

1 (2X) 

(23) 

1 (4X) 

(149) 

1 (2%)

1 (2X) 

(46) 

 17 (37*) 

1 <2X) 

tHENA l EAPILLA 

NECROSIS, NOS 

,49, (23) (49) (46) 

6 (13X) 

#UBINAR I BLADDER 

INFLAMMATION , CHRONI C FCCAL 

(50) 

1 (2X) 

(20) (49) (41) 

tU.BLAEEER/SUBMUCOS A 

INFLAMMATION . CHRONIC 

INFLAMMATION , CHRONIC

PERIVASCULITI S 

 FOCAL 

(50) 

1 (2X) 

16 (32%) 

1 (2%) 

(20) (49) (41) 

* U. BLADCEE/MUSCULAEI S 

CALCIU M DEPOSIT 

(50) 

1 (2X> 

(20) (49) (41) 

ENDOCRIN E SYSTEM 

ITKYRCIt 

HYEIRPLASIA ,

HYPEEPLASIA,

 C-CELL 

 FOLLICULAR-CELL 

(41) 

2

1

 (5X) 

 (2X) 

(17) (36)

1 (3%) 

 (32) 

JEANCBEATIC ISLET5 

HYEE8PLASIA , NOS 

(47) (23) (43)

1 (2%) 

 (40) 

REPRODUCTIV E SYSTEM 

*UTE80S 

HYCROMETB A 

INFLAMMATION , SUPPURATIV E 

(19) 

5 (10X, (22) 

1 (5X) 

1 15XJ. 

(46)

1 (2%)

 (42) 

2 (5%) 

* NUMBE R

* tlUMBB R

 OF

 OF

 ANIMALS

 ANIMAL S

 WITH TISSUE

 NECROPSIED 

 EXAMINED MICROSCOPICALLY 

D-9 
TABLE D2 (CONTINUED) 

CONTROL (OUTE) 

06-0160 

CONTROL (VEH ) 

06-0175 

LOU DOSE 

06-0165 

HIG H DOSE 

06-0170 

PYOHETBA 

INFLAMMATION , GRANOLOHATOUS 

INFLAMMATION , P YOGB AN OLOM ATOUS 

NECROSIS, FAT

CALCIFICATION, NOS

 1 (2%) 

1 (2X) 

2 (9X) 

1 (5X) 

1 (2*) 

1 (2X) 

*UTERUS/ENDOMETRIU M

INFLAMMATION , SOFPUBATIV E

HYFEBPLASIA , NOS 

HYPERPLASIA, CYSTIC

 (1(9) 

2 (tX) 

32 (65S) 

(22) 

10 (t5X)

("6) 

1

19

 (2X) (41X) 20 (18S) 

tOVAR Y

CYST, NOS

FOILICOLAR CYST, NOS PAROVARIA N CYST

THROMBOSIS, NOS

HEMOBFHAGIC CYST

INFLAMMATION, SOPPUBATIVE

INFLAMMATION , CHRONIC

INFLAMMATION , GRANULOMATOU S

 (t8)

 6 (13X) 

1 (2%) 

1 (2X)

 (20)

 1 (5X)

 1 (5X)

 (39)

 2

 1

 2

 (SS)

 (3X) 

(5X) 

(K1 ) 

1 (2X) 3 (7X) 

1 (2X) 

1 (2%) 

NERVOU S SYSTEM 

t-CN E 

SPECIAL SENSE ORGANS 

NONE 

MUSCULCSKELETAL SYSTEM 

NON E 

BODY CAVITIES 

NON E 

ALL OTHER SYSTEMS 

*MULTIPLE ORGANS

ABJilCJDOSIS

 (50)

 J_JJ31 

(2"4) (50) (<46) 

* J.UBBHR

* NUMBIR

 OF ANIMALS

 OF ANIMAL S

 KIT H TISSUE

 NECEOPSIED 

EXAMINE D MICROSCOPICALLY 

D-IO 
TABLE D2 (CONCLUDED) 

CONTROL (OHTB)

06-0160

 CONTBOL ( VEH)

 06-0175

 LOB DOSE

 06-0165

 HIGH DOSE 

 06-0170 

OHENTUH 

PEBIVASCULITIS 

SPECIAL fOEPHOLOGY SUMMAEY 

N O LESION BEPOETED 2 3 9 1 

ANIMA L HISSING/NO NECROPSY 2 

AOTC/NECBOPSY/HIST 2 O PERF 1 2 1 

AUTCIYSIS/NO NECROPSY 1 2 

* KUHBI B OB ANIMALS HUH 1ISSUI EXAMINE D MICROSCOPICALLY 

* NUHBI B 07 ANIMALS NECBOPSIED 

D-ll 

DHEW Publication No. (NIH) 78-1355