1978 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 147 

BIOASSAY OF 

MEXACARBATE 

FOR POSSIBLE CARCINOGENICITY 

CAS No.315-18-4 

NCI-CG-TR-147 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

MEXACARBATE
 

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) 78-1703 

REPORT ON THE BIOASSAY OF MEXACARBATE
 

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
 

mexacarbate 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 mexacarbate was conducted by Hazleton
 

Laboratories America, Inc., Vienna, Virginia, 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. M. B. Powers (3),
 

Dr. R. W. Voelker (3), Dr. W. A. Olson (3,4) and Dr. W. M. Weatherholtz (3). Chemical analysis was performed by Dr. C. L. Guyton
 

(3,5) and the analytical results were reviewed by Dr. N. Zimmerman
 

(6); the technical supervisor of animal treatment and observation
 

was Ms. K. J. Petrovics (3).
 

Histopathologic examinations were performed by Dr. W. A. Kelly
 

and Dr. L. M. Nelson (consultants for Hazleton Laboratories) and reviewed by Dr. R. W. Voelker (3) at the Hazleton Laboratories America,
 

Inc., and the diagnoses included in this report represent the interpretation of these pathologists. Histopathology findings and reports
 

were reviewed by Dr. R. L. Schueler (7).
 

Compilation of individual animal survival, pathology, and summary tables was performed by EG&G Mason Research Institute (8); the
 

statistical analysis was performed by Mr. W. W. Belew (6,9) and Mr.
 

iii
 
R. M. Helfand (6), using methods selected for the Carcinogenesis
 

Testing Program by Dr. J. J. Gart (10).
 

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

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

(6), task leader Dr. M. R. Kornreich (6,11), senior biologist Ms. P.
 

Walker (6), biochemist Dr. B. Fuller (6), and the technical editor
 

Ms. P. A. Miller (6). The final report was reviewed by members of
 

the	 participating organizations.
 

The following other scientists at the National Cancer Institute
 

were responsible for evaluating the bioassay experiment, interpreting
 

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

Cueto, Jr. (1), Dr. J. F. Douglas (1), Dr. D. G. Goodman (1,11), Dr.
 

R. A. Griesemer (1), Dr. M. H. Levitt (1), Dr. H. A. Milman (1), Dr.
 

T. W. Orme (1), Dr. R. A. Squire (1,12), Dr. S. F. Stinson (1), 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.	 No wit w h the Naylor Dana Institute for Disease Prevention, American Health Foundation, Hammon House Road, Valhalla, New York.
 

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

Vienna, Virginia.
 

4.	 Now with the Center for Regulatory Services, 2347 Paddock Lane,
 

Reston, Virginia.
 

5.	 Now with Rhodia, Inc., 23 Belmont Drive, Somerset, New Jersey.
 

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

Boulevard, McLean, Virginia.
 

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

Maryland.
 

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

Rockville, Maryland.
 

9.	 No wit w h the Solar Energy Research Institute, Cole Boulevard,
 

Golden, Colorado.
 

IV
 
10.	 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.
 

11.	 Now with Clement Associates, Inc., 1010 Wisconsin Avenue, N.W.,
 

Washington, D.C.
 

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

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

SUMMARY
 

A bioassay of technical-grade mexacarbate for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice.
 

Mexacarbate was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. The time-weighted average high and low dietary concentrations
 

of mexacarbate were 418 and 209 ppm for male rats, 678 and 339 ppm
 

for female rats, 654 and 327 ppm for male mice and 135 and 68 ppm
 

for female mice. After a 78-week period of chemical administration,
 

observation of rats continued for an additional 33 to 34 weeks and
 

observation of mice continued for 14 to 15 additional weeks. For
 

each species, 20 animals of each sex were placed on test as controls.
 

All groups except the male control mice survived sufficiently
 

long to be at risk from late-appearing tumors. Because of poor survival of the male control mice, a pooled control group was used for
 

statistical analysis of tumor incidence in male mice.
 

The possibility that female mice in this study did not receive
 

maximum tolerated dosages of mexacarbate should be considered. Administration of mexacarbate had no significant effect on survival or
 

body weights of female mice.
 

No neoplasms occurred in statistically significant increased
 

incidences when dosed rats were compared to controls.
 

Among male mice surviving at least 56 weeks, significant associations with dietary concentration were indicated by the Cochran-


Armitage test for hepatocellular carcinomas, for subcutaneous
 

fibrosarcomas and for fibromas of the skin. In none of these cases,
 

however, were these results supported by significant Fisher exact
 

tests.
 

Under the conditions of this bioassay, sufficient evidence was
 

not obtained for the carcinogenicity of mexacarbate for Osborne-Mendel
 

rats or B6C3F1 mice.
 

VII
 

TABLE OF CONTENTS
 

Page
 

1. INTRODUCTION 1
 

II. MATERIALS AND METHODS 4
 

A. Chemicals 4
 

B. Dietary Preparation 4
 

C. Animals 5
 

D. Animal Maintenance 5
 

E. Selection of Initial Concentrations 7
 

F. Experimental Design 8
 

G. Clinical and Histopathologic Examinations 12
 

H. Data Recording and Statistical Analyses 13
 

III. CHRONIC TESTING RESULTS: RATS 18
 

A. Body Weights and Clinical Observations 18
 

B. Survival 20
 

C. Pathology 20
 

D. Statistical Analyses of Results 22
 

IV. CHRONIC TESTING RESULTS: MICE 30
 

A. Body Weights and Clinical Observations 30
 

B. Survival 30
 

C. Pathology 33
 

D. Statistical Analyses of Results 34
 

V. DISCUSSION 45
 

VI. BIBLIOGRAPHY 47
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH MEXACARBATE A-l
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH MEXACARBATE B-l
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH MEXACARBATE C-l
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH MEXACARBATE D-l
 

IX
 
Figure Number
 

1
 

2
 

Table Number
 

Al
 

LIST OF ILLUSTRATIONS 

Page 

CHEMICAL STRUCTURE OF MEXACARBATE 2 

GROWTH CURVES FOR MEXACARBATE CHRONIC STUDY 

RATS 19 

SURVIVAL COMPARISONS OF MEXACARBATE CHRONIC 

STUDY RATS 21 

GROWTH CURVES FOR MEXACARBATE CHRONIC STUDY 

MICE 31 

SURVIVAL COMPARISONS OF MEXACARBATE CHRONIC 

STUDY MICE 32 

LIST OF TABLES 

Page 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS— 

MEXACARBATE FEEDING EXPERIMENT 

DESIGN SUMMARY FOR B6C3F1 MICE—MEXACARBATE 

FEEDING EXPERIMENT 10 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

MEXACARBATE 23 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED WITH 

MEXACARBATE 26 

TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF 

PRIMARY TUMORS AT SPECIFIC SITES IN MALE MICE 

TREATED WITH MEXACARBATE 35 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED WITH 

MEXACARBATE 40 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

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

Table Number Page 

A2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE RATS TREATED WITH MEXACARBATE A-6 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH MEXACARBATE B-3 

B2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH MEXACARBATE B-6 

Cl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH 

MEXACARBATE C-3 

C2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH 

MEXACARBATE C-8 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH 

MEXACARBATE D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH 

MEXACARBATE D-7 

XI
 

I. INTRODUCTION
 

Mexacarbate (Figure 1) (NCI No. C00544) is one of a group of
 

agricultural pesticides that scientists at the National Cancer Institute noted, in the late 1960s, had not been adequately tested for
 

carcinogenicity. In 1969, the Report of the Secretary's Commission
 

on Pesticides and their Relationship to Environmental Health (U.S.
 

Department of Health, Education, and Welfare, 1969) recommended
 

first-priority testing for mexacarbate. This recommendation was
 

partially based upon the inconclusive results of a study by Bionetics
 

Research Laboratories (1968) in which an elevated incidence of tumors
 

was observed in mexacarbate-treated mice.
 

The Chemical Abstracts Service (CAS) Ninth Collective Index
 

(1977) name for this compound is 4-(dimethylamino)-3,5-dimethylphenyl
 

•Jy
 

methylcarbamate. It is also called 4-dimethylamino-3,5-xylyl methylcarbamate. Mexacarbate is a phenylcarbamate insecticide (Matsumura,
 

1975).
 

Production of mexacarbate has been suspended since 1974 by Dow
 

Chemical Company, the sole producer, as a result of high production
 

costs and an inadequate market (Gray, 1977). Prior to that, high
 

toxicity to animals resulted in the recommendation that mexacarbate
 

not be used by homeowners (Virginia Polytechnic Institute, 1968).
 

Mexacarbate has been used as an insecticide and as a molluscicide for
 

*
 

The CAS registry number is 315-18-4.
 
C—NH—CH3 

CH3 CH3 

FIGURE 1 

CHEMICAL STRUCTURE OF MEXACARBATE 
the control of pests on lawns, turf, and flowers (U.S. Environmental
 

Protection Agency, 1974).
 
II. MATERIALS AND METHODS
 

A.	 Chemicals
 

®
 Technical-grade mexacarbate (Zectran ) was purchased from Dow
 

Chemical Company, Midland, Michigan. Chemical analysis was performed by Hazleton Laboratories America, Inc., Vienna, Virginia.
 

The experimentally determined melting point (61° to 78°C) had a 17°
 

spread and differed from the literature value of 85°C (Windholz,
 

1976); this suggested the presence of impurities. Gas-liquid chromatography (GLC), which indicated the presence of five minor peaks,
 

confirmed the presence of impurities.
 

The same material, retested a year later, had a melting point
 

range of 60° to 85°C. GLC using the same methodology as the first
 

year, showed the presence of three peaks of major prominence and
 

twelve minor peaks; the three major peaks accounted for approximately
 

78, 12, and 8 percent of the total area. The 78 percent peak was
 

assumed to be mexacarbate.
 

Throughout this report the term mexacarbate is used to represent
 

this technical-grade material.
 

B. Dietary Preparation
 

The basal laboratory diet for both dosed and control animals con­

®
 sisted of Wayne Lab-Blox meal (Allied Mills, Inc., Chicago, Illinois)
 

®
 plus 2 percent Duke's corn oil (S. F. Sauer Company, Richmond,
 

!
 

Virginia) by weight. Fresh mixtures of	 mexacarbate in corn oil were
 
prepared each week and stored in the dark. These mixtures of mexacarbate in corn oil were incorporated into the appropriate amount of laboratory diet in a twin-shell blender fitted with an accelerator bar.
 

C. Animals
 

Two animal species, rats and mice, were used in the carcinogenicity bioassay. The Osborne-Mendel rat was selected on the basis of a
 

comparative study of the tumorigenic responsiveness to carbon tetrachloride of five different strains of rats (Reuber and Glover, 1970).
 

The B6C3F1 mouse was selected because it has been used by the NCI for
 

carcinogenesis bioassays and has proved satisfactory in this capacity.
 

Rats and mice of both sexes were obtained through contracts with
 

the Division of Cancer Treatment, National Cancer Institute. The
 

Osborne-Mendel rats were procured from Battelle Memorial Institute,
 

Columbus, Ohio, and the B6C3F1 mice were obtained from the Charles
 

River Breeding Laboratories, Inc., Wilmington, Massachusetts. Upon
 

receipt, animals were quarantined for at least 10 days, observed for
 

visible signs of disease or parasites, and assigned to the various
 

dosed and control groups.
 

D. Animal Maintenance
 

All animals were housed by species in temperature- and humidity-


controlled rooms. The temperature range was 20° to 24°C, and the
 

relative humidity was maintained between 45 and 55 percent. The air
 

conditioning system in the laboratory provided filtered air at a
 

rate of 12 to 15 complete changes of room air per hour. Fluorescent
 
lighting was provided on a 12-hour-daily cycle. The rats were individually housed in suspended galvanized-steel wire-mesh cages with
 

perforated floors. Mice were housed by sex in groups of ten in
 

solid-bottom polypropylene cages equipped with filter tops. Sani­

®
 tized cages with fresh bedding (Sanichips , Pinewood Sawdust Company,
 

Moonachie, New Jersey) were provided once each week for mice. Rats
 

received sanitized cages with no bedding with the same frequency.
 

Food hoppers were changed and heat-sterilized once a week for the
 

first 10 weeks and once a month thereafter. Fresh heat-sterilized
 

glass water bottles and sipper tubes were provided three times a
 

week. Food and water were available ad libitum.
 

Dosed rats and their controls were housed in the same room with
 

other rats receiving diets containing dioxathion (78-34-2); dicofol
 

(115-32-2); nitrofen (1836-75-5); endosulfan (115-29-7); and trifluralin (1582-09-8).
 

All mice, including controls, were housed in the same room as
 

other mice receiving diets containing chlorobenzilate (510-15-6);
 

dioxathion (78-34-2); DDT (50-29-3); methoxychlor (72-43-5); DDE
 

(72-55-9); TDK (72-54-8); dicofol (115-32-2); pentachloronitrobenzene
 

(82-68-8); clonitralid (1420-04-8); nitrofen (1836-75-5); endosulfan
 

(115-29-7); trifluralin (1582-0908); amitrole (61-82-5); acetylaminofluorene (53-96-3); safrole (94-59-7); and sulfallate (95-06-7).
 

*
 

CAS registry numbers are given in parentheses,
 
E. Selection of Initial Concentrations
 

In order to establish the maximum tolerated concentrations of
 

mexacarbate for addition to the diets of dosed 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. Mexacarbate was
 

premixed with a small amount of corn oil. This mixture was then
 

incorporated into the laboratory diet and fed ad libitum to five of
 

the six rat groups and five of the six mouse groups in concentrations
 

of 100, 178, 316, 562, and 1000 ppm. The sixth group of each species
 

served as a control group, receiving only the basal diet of corn oil
 

and laboratory chow. The dosed dietary preparations were administered for a period of 6 weeks, followed by a 2-week observation period during which all animals were fed the basal diet.
 

A concentration inducing no mortality and resulting in a depression in mean group body weight of approximately 20 percent relative
 

to controls was selected as the initial high concentration for the
 

chronic study.
 

In rats, depressions in mean body weight at 316, 562, and 1000
 

ppm were 4, 35, and 35 percent, respectively, in the males and 12,
 

14 and 24 percent, in the females. No deaths occurred at any level.
 

The high doses selected for administration to rats in the chronic
 

study were 375 and 600 ppm for males and females, respectively.
 
In male mice, depressions in mean body weight at 316 and 562 ppm
 

were 20 and 15 percent, respectively. In the female mice, depressions in mean body weight at 100, 178, and 316 ppm were 13, 45, and
 

35 percent, respectively. No deaths occurred among male or female
 

mice at any level. The high concentrations selected for administration to mice in the chronic study were 450 and 74 ppm for males and
 

females, respectively.
 

F. Experimental Design
 

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

treated and untreated observation periods, and the time-weighted
 

average concentrations) are summarized in Tables 1 and 2.
 

All rats shared the same median date of birth and were approximately 6 weeks old when the bioassay began. The concentrations of
 

mexacarbate initially utilized for male rats were 375 and 188 ppm.
 

Throughout this report those males initially receiving the former
 

concentration are referred to as the high dose group and those initially receiving the latter concentration are referred to as the
 

low dose group. In week 18 of the study, the high and low concentrations administered to the male rats were increased to 430 and
 

215 ppm, respectively, as the animals appeared to be tolerating the
 

initial concentrations administered. For female rats, the initial
 

dietary concentrations administered were 600 and 300 ppm. Throughout
 

this report those female rats initially receiving the former concentration are referred to as the high dose group and those initially
 

8
 
TABLE 1
 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS 

MEXACARBATE FEEDING EXPERIMENT 

INITIAL 

GROUP 

SIZE 

MEXACARBATE 

CONCENTRATION3

OBSERVATION PERIOD

TREATED UNTREATED

 (WEEKS) (WEEKS)

 TIME-WEIGHTED 

 AVERAGE 

CONCENTRATION13 

MALE 

CONTROL 20 0 110 0 

LOW DOSE 50 188 

215 

0 

17

61 

33 

 209 

HIGH DOSE 50 375 

430 

0 

17

61 

33 

 418 

FEMALE 

CONTROL 20 0 110 0 

LOW DOSE 50 300 

350 

0 

17

61 

33 

 339 

HIGH DOSE 50 600 

700 

0 

17

61 

34 

 678 

a
 

Concentrations given in parts per million.
 

b 2 (concentration X weeks received)
 

Tnn<=>— WPI oh t-pd avprapf > rnnrpn trflt" i <
 
TABLE 2
 

DESIGN SUMMARY FOR B6C3F1 MICE
 

MEXACARBATE FEEDING EXPERIMENT
 

INITIAL OBSERVATION PERIOD TIME-WEIGHTED 

GROUP MEXACARBATE TREATED UNTREATED AVERAGE 

SIZE CONCENTRATION3

 (WEEKS) (WEEKS) CONCENTRATION*3 

MALE
 

CONTROL 20 0	 91 0
 

LOW DOSE 50	 225 6 327
 

275 14
 

350 58
 

0
 14
 

HIGH DOSE 50	 450 6 654
 

550 14
 

700 58
 

0	 15
 

FEMALE
 

CONTROL 20 0	 91 0
 

LOW DOSE 50	 37 6 68
 

50 14
 

75 58
 

0	 14
 

HIGH DOSE 50 74 6 135
 

100 14
 

150 58
 

0	 14
 

a
 

Concentrations given in parts per million.
 

b	 ^(concentration X weeks received
 

Timr=— w<=> 1 oh fpH avprapf > rnnr fnt-rat i <in = : : : : :
 (weeks receiving chemical)
 

10
 
receiving the latter concentration are referred to as the low dose
 

group. During week 18, the high and low concentrations administered
 

to female rats were increased to 700 and 350 ppm, respectively, and
 

these concentrations were maintained until termination of chemical
 

administration (week 78). Final observations of all rats were made
 

32 weeks after chemical administration was discontinued.
 

All mice shared the same median date of birth and were approximately 6 weeks old on the first day of the bioassay. The initial
 

concentrations administered to the male mice were 450 and 225 ppm.
 

Throughout this report those male mice initially receiving the former
 

concentration are referred to as the high dose group and those initially receiving the latter concentration are referred to as the low
 

dose group. Initial concentrations administered to the female mice
 

were 74 and 37 ppm. Throughout this report those female mice initially receiving the former concentration are referred to as the high
 

dose group and those initially receiving the latter concentration are
 

referred to as the low dose group. During week 7, the high and low
 

concentrations were increased to 550 and 275 ppm for the males, and
 

to 100 and 50 ppm for the females. In week 21 the high and low concentrations were again increased, to 700 and 350 ppm for the male
 

mice, and to 150 and 75 ppm for the females. The concentration
 

increases were made in response to apparent toleration of the chemical by the animals. The levels administered during week 21 were
 

maintained throughout the remainder of the dosing period. Final
 

11
 
observations of mice were made 12 weeks after chemical administration
 

was discontinued.
 

G. Clinical and Histopathologic Examinations
 

Animals were weighed immediately prior to initiation of the
 

experiment. Body weights, food consumption, and data concerning
 

appearance, behavior, signs of toxic effects, and incidence, size,
 

and location of tissue masses were recorded at weekly intervals for
 

the first 10 weeks and at monthly intervals thereafter. From the
 

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

presence of tissue masses was determined by 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 exsanguination under sodium
 

pentobarbital anesthesia, and were immediately necropsied. The histopathologic examination consisted of gross and microscopic examination
 

of major tissues, organs, and gross lesions taken from sacrificed
 

animals and, whenever possible, from animals found dead.
 

Tissues were preserved in 10 percent buffered formalin, embedded
 

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

to microscopic examination. An occasional section was subjected to
 

special staining techniques for more definitive diagnosis.
 

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

12
 
nodes, thymus, heart, salivary gland, liver, gallbladder (mice), pancreas, esophagus, stomach, small intestine, large intestine, kidney,
 

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

prostate, brain, uterus, mammary gland, and ovary.
 

A few tissues were not examined for some animals, particularly
 

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

preclude histopathologic interpretation. Thus, the number of animals
 

for which particular organs, tissues, or lesions were examined microscopically varies and does not necessarily represent the number of
 

animals that were placed on experiment in each group.
 

H. Data Recording and Statistical Analyses
 

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

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

as recommended by the International Union Against Cancer (Berenblum,
 

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

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

that bear on the possibility of carcinogenicity are discussed in the
 

statistical narrative sections.
 

13
 
Probabilities of survival were estimated by the product-limit
 

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

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

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

missing; animals dying from natural causes were not statistically
 

censored. Statistical analyses for a possible dose-related effect
 

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

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

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.
 

14
 
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
 

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
 

15
 
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
 

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
 

t c t
 

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
 

c
 

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

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

16
 
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,
 

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
 

A slight dose-related mean body weight depression was observed
 

in male and female rats throughout most of the dosing period (Figure 2), but was not clearly apparent during the observation period
 

following chemical administration. In female rats dose-related mean
 

body weight depression was extremely slight and body weight curves
 

for the three female groups tended to converge as the study progressed. 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 signs were observed during the first 20 weeks of the
 

study except for occasional hunched appearance, reddened or squinted
 

eyes, and abdominal urine stains in a few dosed rats. From week 22
 

to cessation of compound administration (week 78) a hunched appearance was observed in an increasing number of dosed rats. During the
 

same period, abdominal urine stains were observed in approximately 30
 

to 80 percent of the high dose females and in 10 to 40 percent of the
 

low dose females. Abdominal urine stains were observed at comparable
 

rates in the controls (males and females) and the dosed male rats.
 

Respiratory signs characterized by labored respiration, wheezing, and/
 

or nasal discharge were present at a low incidence in all groups.
 

Other signs often associated with aging in laboratory rats were observed at similar frequencies in the control and dosed animals during
 

18
 
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FIGURE 2 

GROWTH CURVES FOR MEXACARBATE CHRONIC STUDY RATS 

19 
the second year. These included sores on the body and/or extremities,
 

localized alopecia, rough or stained fur, reddish discharge around
 

body orifices, tissue masses, and palpable nodules.
 

B. Survival
 

The estimated probabilities of survival for male and female rats
 

in the control and mexacarbate-dosed groups are shown in Figure 3.
 

The Tarone tests for association between dosage and mortality were
 

not significant for either male or female rats.
 

Among the male rats 64 percent (32/50) of the high dose and
 

48 percent (24/50) of the low dose groups survived on test over 105
 

weeks. Fifty percent (10/20) of the control rats survived on test
 

over 98 weeks. Among the female rats 68 percent (34/50) of the high
 

dose, 68 percent (34/50) of the low dose, and 65 percent (13/20)
 

of the control group survived on test at least 110 weeks. Thus,
 

adequate numbers of rats were at risk from late-developing tumors.
 

C. Pathology
 

Histopathologic findings on neoplasms in rats are tabulated in
 

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

tabulated in Appendix C (Tables Cl and C2).
 

Malignant lymphoma, histiocytic type, occurred in 2/49 (4 percent) low dose males, 2/48 (4 percent) high dose males, 6/50 (12
 

percent) low dose females, and 1/50 (2 percent) high dose females.
 

No histiocytic malignant lymphomas were observed in male or female
 

20
 
PROBABILIT

Y OF SURVIVAL PROBABILITY OF SURVIV

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control rats. Leukemia, granulocytic type, occurred in one low dose
 

male, one low dose female, and one high dose female. Leukemia was
 

not observed in high dose males or in control rats of either sex.
 

However, since granulocytic leukemia and multiple malignant lymphoma
 

can occur spontaneously in the Osborne-Mendel rat at incidences
 

similar to those observed in this study these neoplasms were not considered to be related to compound administration.
 

Other neoplasms occurred in rats in this study with essentially
 

comparable frequency in the control and dosed animals. Inflammatory,
 

degenerative, and proliferative lesions as seen in the control and
 

dosed animals were similar in number and type to lesions that occur
 

naturally in aged Osborne-Mendel rats. The nonneoplastic lesions
 

that occurred most frequently were chronic murine pneumonia and
 

chronic inflammation of the kidneys.
 

This pathologic examination provided no evidence for the carcinogenicity of mexacarbate in Osborne-Mendel rats under the conditions of this bioassay.
 

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 for every type
 

of tumor that was observed in more than 5 percent of any of the
 

mexacarbate-dosed groups of either sex is included.
 

For females the Cochran-Armitage test indicated a significant
 

(P = 0.031) negative association between dosage and the incidence
 

22
 
TABLE 3 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT 

SPECIFIC SITES IN MALE RATS TREATED WITH MEXACARBATE* 

TOPOGRAPHY: MORPHOLOGY CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Subcutaneous Tissue: Fibroma 

P Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

1/20(0.05) 

N.S. ___ 

2/49(0.04) 

N.S. 

0.816 

0.046 

47.195 

1/48(0.02) 

N.S. 

0.417 

0.006 

32.057 

Weeks to First Observed Tumor 55 110 111 

K3 

OJ Subcutaneous Tissue:

P Values0 

 Fibrosarcoma 2/20(0.10) 

P = 0.037(N) 

1/49(0.02) 

N.S. 

0/48(0.00) 

N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.204 

0.004 

3.754 

0.000 

0.000 

1.400 

Weeks to First Observed Tumor 85 109 

Hematopoietic System:

Malignant Lymphoma'3 

P Values0 

 Leukemia or 

0/20(0.00) 

N.S. 

3/49(0.06) 

N.S. 

2/48(0.04) 

N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Infinite 

0.256 

Infinite 

79 

Infinite 

0.128 

Infinite 

106 
__ _ 

___ 

TOPOGRAPHY: MORPHOLOGY
 

Pituitary: Chromophobe Adenoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pancreatic Islets: Islet-Cell Adenoma
 

P ValuesC
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Salivary Gland: Mixed Tumor, Benign
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 3 (CONTINUED) 

CONTROL
 

3/20(0.15)
 

N.S.
 

96
 

0/20(0.00)
 

N.S.
 

0/14(0.00)
 

N.S.
 

LOW
 

DOSE
 

11/49(0.22)
 

N.S.
 

1.497
 

0.460
 

7.741
 

104
 

0/49(0.00)
 

N.S.
 

2/40(0.05)
 

N.S.
 

Infinite
 

0.153
 

Infinite
 

90
 

HIGH
 

DOSE
 

7/47(0.15)
 

N.S.
 

0.993
 

0.261
 

5.533
 

90
 

3/47(0.06)
 

N.S.
 

Infinite
 

0.267
 

Infinite
 

0/40(0.00)
 

N.S.
 

__—.
 

77 
TABLE 3 (CONCLUDED)
 

TOPOGRAPHY : MORPHOLOGY CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Thyroid: Follicular-Cell Adenoma or 

Follicular-Cell Carcinomab 1/20(0.05) 2/48(0.04) 1/47(0.02) 

P Values0 N.S. N.S. N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.833 

0.047 

48.155 

0.426 

0.006 

32.720 

Weeks to First Observed Tumor 110 104 111 

Treated groups received time-weighted average doses of 209 or 418 ppm in feed.
 

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

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.
 
___ 

TABLE 4
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE RATS TREATED WITH MEXACARBATE*
 

TOPOGRAPHY: MORPHOLOGY
 

Hematopoietic System: Malignant
 

Lymphoma*3
 

P Values0
 

Departure From Linear Trend
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Leukemia or
 

Malignant Lymphoma"
 

P Values0
 

Departure From Linear Trend
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Chromophobe Adenoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

CONTROL
 

0/20(0.00)
 

N.S.
 

P = 0.016
 

0/20(0.00)
 

N.S.
 

P = 0.019
 

9/20(0.45)
 

P = 0.031(N)
 

79
 

LOW
 

DOSE
 

6/50(0.12)
 

N.S.
 

Infinite
 

0.666
 

Infinite
 

102
 

7/50(0.14)
 

N.S.
 

Infinite
 

0.809
 

Infinite
 

79
 

14/49(0.29)
 

N.S.
 

0.635
 

0.324
 

1.427
 

79
 

HIGH
 

DOSE
 

1/50(0.02)
 

N.S.
 

Infinite
 

0.022
 

Infinite
 

88
 

2/50(0.04)
 

N.S.
 

Infinite
 

0.123
 

Infinite
 

88
 

10/49(0.20)
 

P = 0.040(N)
 

0.454
 

0.208
 

1.092
 

87
 
___ 

TOPOGRAPHY :MORPHOLOGY
 

Mammary Gland: Adenoma NOS
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Adenocarcinoma NOS
 

P Values0
 

Departure From Linear Trend
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Fibroadenoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 4 (CONTINUED) 

CONTROL
 

0/20(0.00)
 

N.S.
 

0/20(0.00)
 

N.S.
 

P = 0.047
 

5/20(0.25)
 

N.S.
 

109
 

LOW
 

DOSE
 

2/50(0.04)
 

N.S.
 

Infinite
 

0.123
 

Infinite
 

111
 

3/50(0.06)
 

N.S.
 

Infinite
 

0.250
 

Infinite
 

39
 

12/50(0.24)
 

N.S.
 

0.960
 

0.377
 

3.140
 

68
 

HIGH
 

DOSE
 

3/50(0.06)
 

N.S.
 

Infinite
 

0.250
 

Infinite
 

0/50(0.00)
 

N.S.
 

12/50(0.24)
 

N.S.
 

0.960
 

0.377
 

3.140
 

84 

93 
___ 

___ 

TABLE 4 (CONCLUDED)
 

LOW HIGH
 

TOPOGRAPHY: MORPHOLOGY CONTROL DOSE DOSE
 

Mammary Gland: Adenoma NOS, Adeno­ carcinoma NOS or Fibroadenoma^ 5/20(0.25) 17/50(0.34) 15/50(0.30)
 

P Values0 N.S. N.S. N.S.
 

Relative Risk (Control) 1.360 1.200
 

Lower Limit 0.580 0.499
 

Upper Limit 4.184 3.784
 

Weeks to First Observed Tumor 109 39 84
 

Uterus: Endometrial Stromal Polyp 1/20(0.05) 0/49(0.00) 1/50(0.02)
 

ro
 P Values0 

oo
 N.S. N.S. N.S.
 

Relative Risk (Control) 0.000 0.400
 

Lower Limit 0.000 0.005
 

Upper Limit 7.624 30.802
 

Weeks to First Observed Tumor 110 112
 

Treated groups received time-weighted average doses of 339 or 678 ppm in feed.
 

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


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.
 
of pituitary chromophobe adenomas. The Fisher exact tests, however,
 

were not significant under the Bonferroni criterion. Similarly,
 

for males the Cochran-Armitage test indicated a significant negative
 

association between dosage and the incidence of fibrosarcomas of the
 

subcutaneous tissue. The Fisher exact tests, however, were not significant.
 

Based upon these statistical results, there was no evidence of
 

the carcinogenicity of mexacarbate in rats.
 

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 3 and 4, 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 rats by
 

mexacarbate that could not be established under the conditions of
 

this test.
 

29
 
IV.	 CHRONIC TESTING RESULTS: MICE
 

A.	 Body Weights and Clinical Observations
 

No readily apparent dose-related trend in mean body weight
 

patterns was observed in male or female mice (Figure 4). All three
 

groups of male mice maintained similar group mean body weights
 

throughout the bioassay.
 

There was no evidence that the administration of mexacarbate at
 

the levels used in this study produced any effect upon the physical
 

appearance or behavior of the dosed mice. Signs commonly observed
 

in laboratory mice were observed at a comparable rate for all groups
 

during the first year, increasing gradually as the animals aged.
 

These common signs included a hunched appearance, sores and/or desquamation on the tail and other parts of the body, localized alopecia,
 

stains on the fur,a bloated appearance, and penile, vulvar, and/or
 

anal irritation. Palpable nodules, tissue masses, and/or swollen
 

areas on the body were observed with a slightly greater frequency
 

in the dosed mice, particularly among the males.
 

B.	 Survival
 

The estimated probabilities of survival for male and female mice
 

in the control and mexacarbate-dosed groups are shown in Figure 5.
 

For both male and female mice the Tarone test did not indicate a significant positive association between dosage and mortality.
 

In male mice, 66 percent (33/50) of the high dose group and 68
 

percent (34/50) of the low dose group, but only 10 percent (2/20) of
 

30
 
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31 
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the control group, survived on test until the end of the study. Of
 

the 18 control mice that did not survive, 12 had chronic inflammation
 

of the kidney and also had amyloidosis at one or more sites; 5 were
 

autolyzed or missing. The early deaths in the controls were not
 

tumor-related since no tumors were observed in this group. Because
 

of the poor survival of these controls, it was necessary to use a
 

pooled control group for statistical analysis of tumor incidence.
 

In female mice, 90 percent (45/50) of the high dose group, 84
 

percent (42/50) of the low dose group, and 85 percent (17/20) of
 

the control group survived on test until the termination of the
 

study. Thus, adequate numbers of female mice were at risk from late-


developing tumors.
 

C. Pathology
 

Histopathologic findings on neoplasms in mice are tabulated in
 

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

tabulated in Appendix D (Tables Dl and D2).
 

Fibrosarcomas of the subcutaneous tissues occurred in 6/46 (13
 

percent) low dose males and 7/47 (15 percent) high dose males. Cutaneous fibromas occurred in 1/46 (2 percent) low dose males and 6/47
 

(13 percent) high dose males. Fibromas and fibrosarcomas of the skin
 

and subcutaneous tissue are not uncommonly observed in the B6C3F1 mouse
 

and in the absence of suitable matched control mice, these lesions
 

were not considered to be related to the administration of mexacarbate.
 

33
 
Hepatocellular carcinomas occurred in 0/15 control males, 4/46
 

(9 percent) low dose males, 15/47 (32 percent) high dose males, 1/20
 

(5 percent) control females, 1/48 (2 percent) low dose females and
 

2/48 (4 percent) high dose females. Hepatocellular adenomas occurred
 

in 2/46 (4 percent) low dose males, and 1/48 (2 percent) high dose females .
 

Malignant lymphoma was observed in 8/46 (17 percent) low dose and
 

3/47 (6 percent) high dose male mice, and leukemia occurred in 2/46
 

(4 percent) low dose and 2/47 (4 percent) high dose male mice. These
 

neoplasms were not observed in matched control animals. Other neoplasms
 

that occurred in mice in this study showed no appreciable difference in
 

frequency between control and dosed animals.
 

Other inflammatory, degenerative, and proliferative lesions seen
 

in the dosed and control animals were lesions that occur naturally in
 

aged B6C3F1 mice.
 

This pathologic examination provided suggestive evidence for the
 

association of hepatocellular carcinomas with administration of mexacarbate in male B6C3F1 mice.
 

D. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

mice are summarized in Tables 5 and 6. The analysis of every type
 

of tumor that was observed in more than 5 percent of any of the
 

mexacarbate-dosed groups of either sex is included.
 

34
 
TABLE 5
 

TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE MICE TREATED WITH MEXACARBATEa»f
 

TOPOGRAPHY : MORPHOLOGY
 

Skin: Fibroma
 

P Values0
 

Relative Risk (Pooled Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Subcutaneous Tissue: Fibrosarcoma
 

P Values0
 

Relative Risk (Pooled Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

POOLED MATCHED LOW 

CONTROL CONTROL DOSE 

0/26(0.00) 0/10(0.00) 1/43(0.02) 

P = 0.014 P = 0.037 N.S. 

— —_ Infinite 

0.033 

Infinite ___ 

Infinite 

0.013 

Infinite 

91 

0/26(0.00) 0/10(0.00) 6/43(0.14) 

P = 0.049 N.S. N.S. 

_—_ Infinite 

0.993 

Infinite 

Infinite 

0.416 

Infinite 

76 

HIGH
 

DOSE
 

6/45(0.13)
 

N.S.
 

Infinite
 

0.949
 

Infinite
 

Infinite
 

0.397
 

Infinite
 

92
 

7/45(0.16)
 

P = 0.034*
 

Infinite
 

1.151
 

Infinite
 

Infinite
 

0.482
 

Infinite
 

85
 
___ 

___ 

TOPOGRAPHY: MORPHOLOGY
 

Liver: Hepatocellular Carcinoma
 

P Values0
 

Relative Risk (Pooled Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma or
 

Hepatocellular Adenoma'3
 

P Values0
 

Relative Risk (Pooled Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)
 

Lower Limit
 

Upper Liniit
 

Weeks to First Observed Tumor
 

TABLE 5 (CONTINUED)
 

POOLED MATCHED
 

CONTROL CONTROL
 

4/26(0.15) 0/10(0.00)
 

P = 0.022 P = 0.002
 

84
 

4/26(0.15) 0/10(0.00)
 

P = 0.032 P = 0.005
 

——
 

84
 

LOW
 

DOSE
 

4/43(0.09)
 

N.S.
 

0.605
 

0.124
 

3.008
 

Infinite
 

0.240
 

Infinite
 

91
 

6/43(0.14)
 

N.S.
 

0.907
 

0.241
 

4.029
 

Infinite
 

0.416
 

Infinite
 

91
 

HIGH
 

DOSE
 

15/45(0.33)
 

P = 0.029**
 

2.167
 

0.794
 

8.144
 

Infinite
 

1.171
 

Infinite
 

63
 

15/45(0.33)
 

P = 0.029**
 

2.167
 

0.794
 

8.144
 

Infinite
 

1.171
 

Infinite
 

63
 
_ __ 

T&BLE 5 (CONTINUED) 

TOPOGRAPHY : MORPHOLOGY
 

Hematopoietic System: Malignant
 

Lymphomab
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Pooled Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)C
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Leukemia or
 

Malignant Lyinphoma°
 

P Values0
 

g


Departure from Linear Trend
 

Relative Risk (Pooled Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

POOLED
 

CONTROL
 

1/26(0.04)
 

N.S.
 

P = 0.026
 

90
 

1/26(0.04)
 

N.S.
 

P = 0.021
 

90
 

MATCHED
 

CONTROL
 

0/10(0.00)
 

N.S.
 

P = O.C37
 

0/10(0.00)
 

N.S.
 

P = 0.034
 

_—
 

LOW
 

DOSE
 

8/43(0.19)
 

N.S.
 

4.837
 

0.714
 

208.686
 

Infinite
 

0.594
 

Infinite
 

76
 

10/43(0.23)
 

P = 0.030*
 

6.047
 

0.951
 

254.726
 

Infinite
 

0.774
 

Infinite
 

76
 

HIGH
 

DOSE
 

3/45(0.07)
 

N.S.
 

1.733
 

0.150
 

88.917
 

infinite
 

0.149
 

Infinite
 

57
 

5/45(0.11)
 

N.S.
 

2.889
 

0.352
 

133.354
 

Infinite
 

C.313
 

Infinite
 

57
 
___ 

00 

TOPOGRAPHY: MORPHOLOGY
 

Lung: Alveolar/Bronchiolar Adenoma
 

P Values0
 

Relative Risk (Pooled Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Adrenal: Pheochromocytoma
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Pooled Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 5 (CONTINUED) 

POOLED MATCHED
 

CONTROL CONTROL
 

1/30(0.03) 0/13(0.00)
 

N.S. N.S.
 

———
 

50
 

0/26(0.00) 0/10(0.00)
 

N.S. N.S.
 

P = 0.027
 

LOW
 

DOSE
 

3/43(0.07)
 

N.S.
 

2.093
 

0.179
 

107.238
 

Infinite
 

0.196
 

Infinite
 

91
 

3/43(0.07)
 

N.S.
 

Infinite
 

0.373
 

Infinite
 

Infinite
 

0.155
 

Infinite
 

91
 

HIGH
 

DOSE
 

4/45(0.09)
 

N.S.
 

2.667
 

0.283
 

128.260
 

Infinite
 

0.289
 

Infinite
 

0/44(0.00)
 

N.S.
 

85 
TABLE 5 (CONCLUDED)
 

Treated groups received time-weighted average doses of 327 or 654 ppm in feed.
 

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


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

the corresponding 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
 

pooled control group (*) or the matched control group (**) is given beneath the incidence of tu­ mors in that 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 inci­ dence 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.
 Q
 

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

group when P < 0.05.
 f
 

These analyses were based solely upon animals surviving at least 56 weeks, except for sites
 

where the first tumor of interest was observed earlier than 56 weeks in any group of this
 

sex and species, where 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
 

SPECIFIC SITES IN FEMALE MICE TREATED WITH MEXACARBATE1
 

TOPOGRAPHY : MORPHOLOGY
 

Lung: Alveolar /Bronchiolar Adenoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Cbserved Tumor
 

Hematopoietic System: Malignant Lymphoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Leukemia or
 

Malignant Lymphoma^5
 

P Values0
 

Relative Risk (Control).
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

CONTROL
 

1/20(0,05)
 

N.S.
 

—_
 

87
 

4/20(0.20)
 

N.S.
 

91
 

5/20(0.25)
 

N.S.
 

—_
 

87
 

LOW
 

DOSE
 

2/48(0.04)
 

N.S.
 

0.833
 

0.047
 

48.155
 

92
 

9/48(0.19)
 

N.S.
 

0.938
 

0.307
 

3.804
 

75
 

10/48(0.21)
 

N.S.
 

0.833
 

0.308
 

2.794
 

75
 

HIGH
 

DOSE
 

1/48(0.02)
 

N.S.
 

0.417
 

0.006
 

32.057
 

92
 

5/48(0.10)
 

N.S.
 

0.521
 

0.128
 

2.415
 

58
 

6/48(0.13)
 

N.S.
 

0.500
 

0.149
 

1.878
 

58
 
TABLE 6 (CONCLUDED) 

Q
 

Treated groups received time-weighted average doses of 68 or 135 ppm in feed.
 

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.
 
Due to the poor survival of the mexacarbate control the analyses
 

for the males are based solely on those mice surviving at least 56
 

weeks. Also due to the poor survival of the mexacarbate control,
 

two groups of controls were used for analyses of the male mouse data:
 

the control group for the mexacarbate bioassay (designated in this
 

section as the "matched" control) and a pooled control group that
 

combined the untreated matched controls from the studies of chlorobenzilate and mexacarbate. These control males were of the same
 

strain, were tested concurrently by the same laboratory in the same
 

room for at least a year, and were examined by the same pathologists.
 

For male mice the Cochran-Armitage test indicated a significant
 

positive association between dosage and the incidence of hepatocellular carcinomas when the dosed groups were compared to either the
 

matched control (P = 0.002) or the pooled control (P = 0.022). The
 

Fisher exact test comparing high dose to pooled control had a probability level of P = 0.029, a marginal result which was not significant under the Bonferroni criterion. In historical control data
 

collected by this laboratory for the NCI Carcinogenesis Testing Program, 74/482 (15 percent) of the untreated B6C3F1 male mice had this
 

tumor, compared to the 15/45 (33 percent) in the high dose group.
 

It should also be noted that one of the 16 untreated control groups
 

in the historical data had an incidence of hepatocellular carcinomas
 

that was higher (35 percent) than that found in the high dose group
 

of this bioassay.
 

42
 
In male mice the Cochran-Armitage test for a positive association between dosage and the incidence of fibroma of the skin was
 

significant using both the matched control (P = 0.037) and the pooled
 

control (P = 0.014). The Fisher exact tests, however, were not significant.
 

For fibrosarcoma of the subcutaneous tissue in males, the Cochran-


Armitage test was significant (P = 0.049) when the dosed groups were
 

compared to the pooled control group. The Fisher exact test comparing
 

the pooled control group to the high dose group had a probability
 

level of P = 0.034, a marginal result which was not significant under
 

the Bonferroni criterion. In historical control data collected by
 

this laboratory, 23/432 (5 percent) of the untreated male B6C3F1 mice
 

had this tumor, compared to the incidences in this study of 0/26, 0/10,
 

6/43 (14 percent), and 7/45 (16 percent) observed in the pooled control,
 

matched control, low dose, and high dose groups, respectively.
 

For both male and female mice there were no other tumors at any
 

site for which, under the Bonferroni criterion, the statistical tests
 

showed a significant association between the administration of mexacarbate and an elevated incidence of tumors.
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

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

observed tumor incidence rates. In many of the intervals shown
 

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

43
 
absence of statistically significant results. It should also be
 

noted that many of the confidence intervals have an upper limit
 

greater than one, indicating the theoretical possibility of tumor
 

induction in mice by mexacarbate that could not be established
 

under the conditions of this test.
 

44
 
V. DISCUSSION
 

In both species, adequate numbers of mexacarbate-dosed animals
 

survived long enough to be at risk from late-developing tumors.
 

Because of poor survival of the male control mice, a pooled control
 

group was used for the statistical analyses of tumor incidences among
 

male mice. While mean body weight depression, relative to controls,
 

was observed in dosed rats, dietary administration of mexacarbate had
 

no significant effect on survival, mean body weight, or clinical manifestations of abnormalities in male or female mice. This may indicate that the concentrations of mexacarbate administered to mice did
 

not approximate the maximum tolerated concentrations.
 

No neoplasms occurred in statistically significant increased incidences when dosed rats were compared to controls.
 

Application of the Cochran-Armitage test to the incidence of
 

hepatocellular carcinoma among male mice surviving at least 56 weeks
 

indicated a significant positive association between the dietary
 

concentration of mexacarbate and tumor incidence. Significant
 

associations between dietary concentration and tumor incidence in
 

male mice surviving at least 56 weeks were also indicated for fibromas of the skin and for subcutaneous fibrosarcomas. These results
 

were not, however, supported by results of Fisher exact tests using
 

the Bonferroni correction for any tumor in male mice. In addition,
 

in historical control data collected by this laboratory for the NCI
 

Carcinogenesis Testing Program, 74/482 (15 percent) of the untreated
 

45
 
male B6C3F1 mice had hepatocellular carcinomas, and 1 of the 16 untreated control groups included in this historical data had an incidence that was higher (35 percent) than the incidence observed among
 

high dose male mice in this bioassay (34 percent).
 

Mexacarbate has been previously bioassayed for carcinogenicity
 

(Bionetics Research Laboratories, 1968). Mexacarbate was administered to groups of 18 (C57BL/6 x C3H/Anf) Fl mice of each sex and 18
 

(C57BL/6 x AKR) Fl mice of each sex. Mice were gavaged daily with
 

4.64 mg/kg body weight mexacarbate from 7 days to 4 weeks of age and
 

then fed 11 mg mexacarbate per kg of diet until the mice were 78
 

weeks of age. An increased incidence of lung adenomas was observed
 

in (C57BL/6 x C3H/Anf) Fl mice of both sexes (i.e., 4/14 [29 percent]
 

males and 3/17 [18 percent] females). Increased incidences of "hepatomas" were observed in male mice of both strains (i.e., 5/14 [36 percent] C57BL/6 x C3H/Anf Fl and 2/17 [12 percent] C57BL/6 x AKR Fl),
 

but no "hepatomas" were observed among female mice. The International
 

Agency for Research on Cancer (1976) did not consider these data sufficient to allow an evaluation of the carcinogenicity of mexacarbate
 

to be made.
 

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

was no convincing evidence that dietary administration of mexacarbate
 

was carcinogenic to Osborne-Mendel rats or B6C3F1 mice.
 

46
 
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.
 

Bionetics Research Laboratories, Evaluation of Carcinogenic, Teratogenic, and Mutagenic Activities of Selected Pesticides and
 

Industrial Chemicals. Vol. I: Carcinogenic Study. U.S. Department of Health, Education, and Welfare, National Cancer Institute,
 

Bethesda, Maryland, 1968.
 

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.
 

Gray, H., Dow Chemical Company, U.S.A., Midland, Michigan. Personal
 

communication, March 24, 1977.
 

International Agency for Research on Cancer, IARC Monographs on the
 

Evaluation of Carcinogenic Risk. Vol. 12: Some Carbamates,
 

Thiocarbamates and Carbazides. United Nations World Health
 

Organization, Geneva, Switzerland, 1976.
 

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

Observations." Journal of the American Statistical Association
 

53.: 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.
 

Matsumura, F., Toxicology of Insecticides. Plenum Press, New York,
 

1975.
 

47
 
Miller, R.G., Simultaneous Statistical Inference. McGraw-Hill Book
 

Co., New York, 1966.
 

Reuber, M.D. and E.L. Glover, "Cirrhosis and Carcinoma of the Liver
 

in Male Rats Given Subcutaneous Carbon Tetrachloride." Journal
 

of the National Cancer Institute 44:419-423, 1970.
 

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.
 

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

^2_:679-682, 1975.
 

U.S.	 Department of Health, Education, and Welfare, Report of the
 

Secretary's Commission on Pesticides and their Relationship to
 

Environmental Health. Parts I and II. E. M. Mrak. NTIS No.
 

PB-251-630, 1969.
 

U.S.	 Environmental Protection Agency EP , A Compendium of Registered
 

Pesticides. U.S. Government Printing Office, Washington, D.C.,
 

1974.
 

Virginia Polytechnic Institute, Pesticide Information Manual. Miscellaneous Publication No. 8, Virginia Cooperative Extension
 

Service, Blacksburg, Virginia, 1968.
 

Windholtz, M., editor, The Merck Index: An Encyclopedia of Chemicals
 

and Drugs, 9th edition. Merck and Company, Inc., Rahway, New
 

Jersey, 1976.
 

48
 
Review of the Bioassay of Mexacarbate* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

June 29, 1978
 

The Clearinghouse on Environmental Carcinogens was
 

established in May, 1976, in compliance with DREW 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
 

carcJnogens 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 carcinogenesls or related fields and,
 

collectively, provide expertise in chemistry, biochemistry,
 

biostatisties, toxicology, pathology, and epidemiology.
 

Representatives of various Governmental agencies participate
 

as ad hoc members. The Data Evaluation/Risk Assessment
 

Subgroup of the Clearinghouse Is charged with the responsi­ bility of providing a peer review of reports prepared on
 

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

on the bioassay of Mexacarbate for carcinogenicity.
 

Although the report concluded that Mexacarbate was not
 

carcinogenic under the conditions of test, the reviewer
 

noted that the incidence of hepatocellular carcinomas in the
 

high dose treated male mice was statistically significant if
 

compared to matched controls. However, the Incidence was
 

not statistically significant when compared with historical
 

controls. The reviewer questioned the use of the historical
 

control data since they may sometimes provide fallacious
 

comparisons for commonly occurring tumor types, especially
 

for those that may be influenced by dietary contaminants.
 

After some discussion regarding alternative motions, the
 

reviewer moved that the report on the bioassay of Mexacarbate
 

be accepted as written. The motion was approved without
 

obj ection.
 

C1 e a rin gho us e Membe rs_ present :
 

Arnold L. Brown (Chairman), Mayo Clinic
 

Paul Nettesheim, National Institute of Environmental
 

Health Sciences
 

Verne Ray, Pfizer Medical Research Laboratory
 

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

Louisa Strong, University of Texas Health Sciences Center
 

Subsequent to this review, changes may have been made
 

in the bioassay report either as a result of the review
 

or other reasons. Thus, certain comments and criticisms
 

reflected in the review may no longer be appropriate.
 

49
 

l U . '•• . GOVER N MI- NT P R I N ~ I N r 0 Fc i T E : 1978-260-899/3183
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH MEXACARBATE
 

TABLE A1

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH MEXACARBATE 

c:ONTEOL (VEH ) 

01-M070 

LOB DOSE 01-M071 HIGH DOSE 

01-M072 

ANIMALS INITIAILY IN STBDI 20 50 50 

ANIMAL S MISSING 1 

ANIMALS NECROPSIED 20 «9 18 

AKIMAL S EXAMINE D HISTOPAIHOLOGICALLY ** 20 U9 18 

INTEGUMENTAR Y SYSTEM 

*SUBCUT TISSUE (20) (49) (48)
 

FIBROMA 1 (5X) 2 («X) 1 (2X)
 

FIBROSARCOMA 2 (10X) 1 (2X)
 

LIPOMA 1 (2X)
 

HEMANGIOSAECOMA 1 (2X)
 

FESPIBATORY SYSTEM 

*NASAL TURBINAT E (20) (49) (48) 

OSTEOSARCOMA 1 (2X) 

ILUNG (20) (49) (48)
 FIBPOSARCOMA, METASTATIC 1 <2X)
 HEMANGIOSABCOMA, METASTATIC 1 (2X)
 

HEMATOPOIETIC SYSTEM
 

*MDLTIPLE ORGANS (20) *9) (48)
 

NALIG.LYMPHOMA, HISTIOCYTIC TYPE 2 (4X) 2 (4X)
 

GRANOLOCYTIC LEUKEMIA 1 <2X)
 

tSPLEEN (20) 

HEMASGIOMA (2X> 1 (2X) 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM
 

ISALIVARY GLAND (14) («0)
 

____ MIXE.p._TUHOR.i._BEN!Gg
 

* NUMBER OP ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZEU ANIMALS 

A-3
 
TABLE Al (CONTINUED) 

CONTROL (VEH) LOH DOSE HIGH DOSE 

01-M070 01-H071 01-M072 

ISTOMACH (20) (47) SQUAMOUS CELL PAPILLOHA 1 (2X) 

URINARY SYSTEM
 

tKIDNEY (20) (47) 

TUBULAR-CELL ADENOMA 1 (2X) 

HAHAHTOMA + 1 (2*) 

ENDOCRINE SYSTEM 

tPITUITARY (20) (47) 

CHROMOPHOBE ADENOMA 3 (15*) 11 (22X) 7 (15*) 

fADRENAL (20) (49) (47) 

PHEOCHROHOCYTOBA 1 (2X) 

•THYROID	 (20) (48) (47) FOLLICULAR-CELL ADENOMA 1 (2X) 1 (2X) FOLLICULAP-CELL CARCINOMA 1 (2X) 

iPANCHEATIC ISLETS	 (20) (49) (47) ISLET-CELL ADENOMA

 3 (6X) 

REPRODUCTIVE SYSTEM 

NONE 

NERVOU S SYSTEM 

IBRAIN (20) (49) (47) 

ASTSOCYTOMA 1 (2*) 

OLIGODENDROGLIOMA 2 (U«) 

SPECIAL SENSE ORGANS 

NON E 

MUSCIILOSKELETAI SYSTEM 

NONE. 

* NUMBE R OF ANIMAL S HITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

+ THIS IS CONSIDERED TO BE A BENIGN FORM OF THE MALIGNANT MIXED TUMOR OF THE KIDNEY AND CONSISTS OF PROLIFERATIVE LIPOCYTES, TUBULAR STRUCTURES, FIBROBLASTS, AND VASCULAR SPACES IN

 

VARYING PROPORTIONS. 

A-4
 
TABLE Al (CONCLUDED) 

CONTROL (VEH) LOW DOSE HIG H DOSE 

01-M070 01-8071 01-B072 

EODT CAVITIES 

NONE 

A LL OTHER SYSTEMS. 

NONE 

ANIMA L DISPOSITION SUMMAR Y 

ANIMALS INITIALLY IN STUDY 20 50 50 

NATURA L DEATHS 1M 31 19 MORIBUN D SACRIFICE 2 SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 30 ANIMA L MISSING 1 

8 INCLUDES AOTOLYZED ANIMAL S 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TDMORS* 6 21 16
 

TOTAL PRIMARY TUMORS 7 28 19
 

TOTAL ANIMALS WITH BENIGN TUMORS 1 15 13
 

TOTAL BENIGN TUMORS 5 19 16
 

TOTAL ANIMALS WITH MALIGNAN 2 T TDMORS 8 3
 

TOTAL MALIGNANT TUMORS 2 9 3
 

TOTAL ANIMALS WITH SECONDARY TUKORS# 2
 

TOTAL SECONDARY TUMORS 2
 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TDNORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAINPRIMARY OR SETASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

t SECONDARY TDMORS: METASTATIC TUHORS OR TUMORS INVASIVE INTO UN ADJACENT ORGAN
 

A-5
 
TABLE A2 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH MEXACARBATE 

CONTROL (VEH) LOW DOSB HIGH DOSE 

01-F070 01-F073 01 -F 07 K 

ANIMAL S INITIALLY IN STUDY 20 50 50 

ANIMALS NBCROPSIED 20 50 50 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY ** 20 50 50 

INTEGUMENTAR Y SYSTEM 

*SUBCUT TISSUE (20) (50) (50)
 

FIBROMA 1 (5*)
 

FIBPOSARCOMA, HETAST4TIC 1 (2%)
 

LIPOMA 1 (2*)
 

RESPIRATORY SYSTEM
 

1LDNG (20) (50) (50)

 ADENOCARCINOMA, NOS, METASTATIC 2

 HEPATOCELLULAR CARCINOMA, METAST 1 (2X)

 CORTICAL CARCINOMA, METASTATIC 1 (2X)

 FIBPOSARCOMA, METASTATIC 1 (2X)

 

HENATOPOIETIC SYSTEM 

*MOLTIPLE ORGANS (20) (50) (50)
 

MALIG.LYMPHOMA , HISTIOCYTIC TYPE 6 (12X) 1 (2X)
 

GRANULOCYTIC LEOKEMIA 1 (2«) 1 (2X)
 

ISPLEEN (20) (50) (50)
 

HEMANGIOMA 1 (2%)
 

CIRCULATORY SYSTEM
 

NONE
 

LIGESIIVE SYSTE1
 

ILIVER (20) (50) (50)

 

HEPATOCELLOLAR CARCINOMA <2X)

 

£IBROSAECOBAi_METASIATIC_
 

t NUMBER OF ANIMALS 1IITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED **EXOLUDES PARTIALLY AU10LY2ED ANIMALS 

A-6 
HIGH DOSE 

01-F074 

(50) 

2 («X) 

(50) 

2 (»X> 

(«9) 

10 (20X) 

(50) 

(50) 

2 (4X) 

(50) 

2 (IX) 

(50) 

3 (6X) 

12 (2UX) 

(50) 

1 <2X) 

(50) 

1 (2X) 

iPANCREAS 

GBANULOSA-CELL

PIBBOSARCOHA,

tSTOHACH 

FIBBOSABCOMA . 

UBINAHY SYSTEM 

NOHE 

HNDOCRINE SYSTEM 

tPITUITARY 

ADENOMA, NOS 

CHROBOPHOBE ADENOHA 

(ADRENA L 

CORTICAL CARCINOMA 

NEUFOPIBROBA 

•THYROID 

FOLLICULAR-CELL ADENOMA 

C-CELL ADBNOHA 

*PANCFEATIC ISLETS 

ISLET-CELL ADENOMA 

SEPBODUCTITE SYSTEM 

*MANMAB 7 GLAN D 

ADENOMA. NOS 

ADENOCARCINOMA, NOS 

FIBBOADBNOHA 

tUTEBUS 

ADENOCABCINOMA, NOS 

ENDOMETBIAL STROMAL POLYP 

fOVAR Y 

GRANOLOSA-CELL TUMOR 

GB4NUL,OSA-CSL.L._C.A.B.C.IN.a.flJ 

* NUMBER OF ANIMALS KITH TISSUE

* NUMBER OF ANIMALS NECROPSIED 

TABLE A2 (CONTINUED) 

CONTBOL (VEH) 

01-P070 

(20) 

 CARCINOMA, HETAST 

 HETASTATIC 

(20) 

(20) 

9 (H5X) 

(20) 

(20) 

1 (5%) 

(20) 

(20) 

5 (25X) 

(20) 

1 (5X) 

(20) 

 EXAMINED MICROSCOPICALLY 

A-7 

LOR DOSE 

01-F073 

(50) 

1 (2«) 

(50) 

(19) 

1 (2*) 

11 (29%) 

(50) 

1 (2*) 

1 (2*) 

(U9) 

1 (2«) 

(50) 

(50) 

2 (ItX) 

3 (6*) 

12 (24%) 

(«9> 

1 <2X) 

(19) 

.-1...J2S1 
TABLE A2 (CONTINUED) 

COltTSOL (VBH) LOU DOSE HIGH DOSE 

01-P070 01-P07J 01-F07U 

HEBVOU 5 SJSTEB 

HfcSAI S (20) (50) (50) 

HESIHG10BA 1 (5*) 

SPLCIAL SEHS8 ORUANS 

SO SB 

SUSCULOSKELETAL SYSTEH 

NON E 

BODlf CAVITIES 

*-ES8»TEP» (,-0) (50) (50) 

GHAHU105A-CBLL CAnCIHOKA, flETAST 1 (2%) 

"laSOSiPCO^A, II2TA STATIC 1 (2*) 

AL', OT1ER Sf 

TOSS 

ASL^A L DISfOSITIOS 

JSiriAHi is sxui^if 20 50 50 

NAtUSAi, UiiTlti* 15 16 

BORIfaUN D S*CRIFICE 1 1 

SCHEDULED ^ACSIPICK 

ACC1DESTALLT KlLLliD 

TESBINA L SACRIHC2 33 

ANIHA L 3ISSIHG 

INCLUDES A'JTOLKZbO ANHAIS _ _ 

NUK3JR OF AMIHAL S HI M TISSUE EXAMIS8D HICEOSCOPICALLY 

NUMBE R OP ASiBALS. SECftOPi'IED 

A-8 
TABLE A2 (CONCLUDED) 

COHTKOI (VBH) LOB DOSE HIGH DOSE 

01-F070 01-F073 01-F074 

T01OH BUSBAR* 

TOTAL A1HALS KIT H PPIMAF J TU10RS* ^^ 33 28 

TO1AL rRIHAR? TUKOXS 1i) 46 36 

TOTAL AHiBAL b H1TH BW1GH 1'UMOSS 11 29 21 

TO'JAL SENIbN IHBOSs 17 33 30 

T'JTAL ANI1ALS »IIH MALIfaNAN T TUMORS 1 11 5 

TOTAL fIALI&NA» r TUBOES 1 13 5 

TOTAL AUlBALi Wli H SiCOSDARJ TUMORS* 4 3 

TOC&L SECONDARJ TUROPS 5 7 

TOTAL ANIMAL S KITH TUflORE UUCBRTAIH­ SEUISS OP BALIGBAN T 1 

TOTAL UNCiRTAI N TUHORS 1 

TOTAL ANIMAL S WITH TUBORS USCE8TA1N­ PBIMARY 08 MKHSTATIt:

 

TOTAL USCEHtAIH TUTORS 

» OBIRARI TUBOKS: ALL IUSOFS EXCEPT SECO»DARY TOBOPS 

t bSCOHDAR/ TUftORS : BE1 ASTATIC TDMORS OR TUBORS INVASIVE INTO AN ADJACEDT ORGA N 

A-9 

APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH MEXACARBATE
 

TABLE Bl

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH MEXACARBATE 

COHTROL (VEH) LOU DOSE HIGH DOSE 

02-0077 02-R078 02-H079 

ANIMAL S INITIALLY IN STUDY 20 50 50 

ANIMAL S KlbSINt, 1 1 1 

AN1F1LS NKCROPSIED 15 16 47 

ANTHALS EXAMINED HrSTGPATHULOGICALLT** 15 46 1)7 

INTEGUMENTARY iYST?"!
 

*SKIS (15) (<»6) (47) 

ADHEXA L ADeSOH l 1 (2*) 

P1MOH» 1 (2X) 6 (13*) 

•SUBCUT TIbSUt, (15) (46) (47) 

FI5ROSi8COCA 6 (13*) 7 (15%) 

REbflPAIOR Y SYSTEM 

• LUNG (15) (46) (46) 

HEPATOCELLULAR CAPC1NOMA , MSTAST 2 (4*) 

AL»EOLAR/BPONC!!IOLAB ABENO«.A 3 (7%) 4 (9*) 

FI^ROSAPCOIA, METASrAHC 1 (2*) 

4ECATOPOIETIC FYSTiJH 

*bRAIN (14) (46) (47) 

rALIG.liHPHOBA , BIbTIOCYTIC TYPE 2 (»*) 

*"!OLTIPLE ORGANS (15) (46) (47) 

.1ALIG .LJ1PH01A, HISTIOCYTIC TYPE 5 (11*) 

GRJNULOCYTIC Ll.UKEflf 2 (4*) 2 (4*) 

*CERV1CAL L1"!?H NCI0E (13) (45) (45) 

PlbROSCRCOCA, FETASTAT1C 1 (2*) 

«ALlG.LY»P:iOi1A, HIbTlOCYTIC TYPE 1 (2*) 

»,1ESENTER1C L. SOUE (13) (45) (45) 

HECANGIOH A 1 (2*) 

1AHG.L!(BPi!OflA, H1STIOCYTIC TYPE 1 (2*) 1 (2X) 

• AXILLAR Y LY1PH NCD E (13) (45) (45) 

riBROSARCOjlA,,. fETAbTATIC 1 (2*1 

* SD1BER OP ANIMALS HIM TISSUE BXAHISED HICROSCOPICALLT 

* SUIbBR 0? AKIBAL S JtiiCfcOPSIED 

**fcXCLUDES PARTIALLY AJTOLYZ8.1) ANIMALS 

B-3 
TABLES! (CONTINUED) 

COHT9OL(VEH) LOU DOSE HIGH DOSE 

02-9077 02-H078 02-H079 

tSBALL IHThSTlNE (11) (13) (13) 

MALIG.LYMPHOlli, H1STIOCYTIC TYPE 1 (2%) 

CIRCULATOR Y SYSTEK 

NONE 

Dlt-ESTIVE FYET"1 

ILHEH (15) (16) («7) 

HEPATOCELLULAR ADEHOH A 2 (H) 

HEPATOLELLULA8 CARl-iNOli 1 (9*) 15 (32%) 

HEa*NG7OSABCO(!» 1 (2%) 

tlAlfai INT2ST1NE (13) (15) (46) 

FI^ROSlRCO^i 1 (2X) 

DB1NAPJ SYiTEtl 

*MDN<? Y (15) (16) (17) 

"I'jSObARCCHA, "ErAorATlC 1 (2*) 

ENlOCRIN E SYSTB8 

*ADPE>«AL (15) (16) (16) 

PIEOCHKOBOCYronA 3 (7%) 

StPRODUCTIVE SYSTEM 

tons 

SEBVOU S SYSTEM 

SOUL 

SPKIA L SE13S OPGAK S 

(15) (16) (17) 

1 I25L 

» 1U19tR OP AtlMAL S WI1H TISSOE SXABINED MICROSCOPICALLY 

» «iUfBt!P 0» 4H1MAL5 NELtOPSlED 

B-4 
TABLEBl (CONCLUDED) 

CONTBOL(VEH) LOU DOSE HIGH DOSE 

02-1077 02-B078 02-H079 

NOSE 

BODY CAVITlhS 

•JONS 

All OTHER SYSTcSS 

NONE 

ANJ.MA L DISPOSITION bUMMAR i 

ANI1ALS 1NITIALL I IN STUM 20 50 50

 

NATURA L DEATHS 17 14 17 

MORIBUN D SACRIFICE 1

 

SCHEDUIED bACR LPlCfi 

ACCIDENTALLY K [LL2D 

T2PMIHAL SACRIFICE 2 34 32

 

ANIMA L 1ISSIN6 1 1 1 

S INCLUDES AUTOLYZ ..D ANIMAL S 

TU10R bUHMfR Y 

TOTAL ANICAL " Mlf H PKIMAR I TOMOBS* 24 28 

TOTAL MI1ARY CUBORS 30 41 

TOTAL ANIMAL S DI-B BhNIG1^ TUBORS 9 11 

TOTAL HENTuS TIIHOBS 9 13 

TOTAL ASIMAL i HI 'H "!ALIG1ANT TUMORS 18 2<* 

aOTBL liLIGNAK T THROBS ^ 28 

TOTAL ANIMAL S WI TH SECONDAR Y TUBORSt 1 3 

TO1AL SECOSDAR I TU10RS 2 4 

10TIL ANIKAL ^ Hl'lH TUPIORb UHCEBTA1N­

"FNIbN OP MALIGNHN I 

TOTAL UNCbNTAI U TOBORS 

TOTAL AN1CAL3 DI'tH TUBOPS OUCEETAISPRIMAR Y OR RtTAS'fATIC

 

TOTAL U1CERTAI * TlMORS 

* PRIMAR Y IL'BOKS: 11LL TD10SS EXCEPT SECONDARY TOHORS 

• SECOSDAR* TD1ORS : METASTATIC TOBORS OB "PlISOBS INVASIV E INTO &N ADJACENT OHGiN 

B-5 
TABLE B2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH MEXACARBATE 

CO»TROL(VEH) LOW DOSE HIGH DOSE 

02-F077 02-F080 02-POB1 

ANIMAL S INITIALL Y IN STUD Y 20 50 50 ANIMAL b NECPOPilED 2 0 48 48 

ANIMAL S EXWINB D H1STOPATHOLOG1CALLY ** 20 48 48 

INTEGUMENTAR Y SYSTEM 

NONE 

RESPIRAIOPJ SirSTSI 

• LUN G (20) (48) (48) 

».LVEOL4S/B. l'ONCdIOLftP AUENOSA 1 (5%) 2 (4%) 1 (2*) 

HE"!ATOPO1ETIC SYSTtM 

» MULTIPLE OSGANS (20) (48) (4b) MALI^.L^IP-OMA , HIbllOOSTIC TYPE J (15*) i) (17%) 2 (4X) 

LY'PHOCYTIC LLOKEniA 1 (2*) 1 (2%) SPANOLuCYlIC Li-UXESI A 1 (5*) 

»bPLEf < (20) (48) (47)

 HEfAM G LOSARCOM A 1 (2%)

 

1 KESEi(TERIC L. NODE (19) (47) (47) MA1IG.LYKPHOMA , HISTIOCYTIC TYPE 1 <2X) 1 (2S) 

»5HAL L ISTESTIN E (20) (48) (48) .lALIG.LY.IPaOSA, H1ST1OC1TJC TYPE 1 (2%) 

«ThtBU S (19) (47) (46) MALIU.LflPHOIA , LY1PHOCYT1C TYPE 1 (bt) 

MALIG.LYMPUOSA , HI S1IOCJTIC TYPE 1 (2%) 

Cli-CnLATOS/ SYSTEB 

* NUIBtR OS AH1MALS lillH TISSU E EXABINh D MICROSCOPICALLY 

* XUHE^ B O" ANiBALS N5CPOPS1ED 

**EXCLUD£S PARTIALLY AUTOLYZED ANIMALS 

B-6 
TABLE B2 (CONTINUED) 

CONTROL (VSH) LOU DOSE HIGH DOSE 

02-F077 02-P080 02-F081 

bYSTtM 

»LIVE P (20) (48) (48) 

HE°ATOuElLULA H ADENOH A 1 (2*) 

HEPATOCELLULAR CJHClNO'iA 1 (5*) 1 (2X) 2 (H%) 

• SMALL INTBETIN S (20) ("«8) (48) 

ADt.NOl«A , SuS 1 (2X) 

UR1.SA8Y S«:,TE1 

NOH2 

ENiX)CPlSE jfSTCI 

tPIT'IlTABf (14) (29) (35) 

ChTOROOHOni; AI)SSO."A 1 (3*) 

RE^SODGCTI »E S»ST£« 

*VAGIN A (20) (48) (48) 

SP'JAMODS CtLL C^CISOBA ' 1 (2*) 

tlU'SBJS (20) (48) (48) 

LNDOBbTRIA l STRO«A L POLYP 1 (2X) 

*oyi»p)t (20) (48) (47) 

AB.SOli , Hl.i> 1 (2X) 

NLRVOU b SYSItP l 

k'ONr. 

SO>CIM SE'SE uR«A«S 

VOSE 

".U bCULOSKELETA L 

NO\'L 

* MI'HK O« ANIMALS rfllK TISSUE EXAMINU ) MICROSCOPICALLY 

* NUM3K R O F ANirAL S SECPOPSIE D 

B-7 
TABLE B2 (CONCLUDED) 

CONTROL (VEH) LOVI DOSE HIGH DOSE 

02-P077 02-P080 02-P081 

BObf CfVITlE S 

SONS 

ALL OTHEF SYSIFMS 

TONE 

ANIHA L DISPOSITION SUS1AB! 

ANI1AL S INITIALL Y IN STCUY 20 50 50

 

NAT'JEA L LiElTH* 

MOhlbUW SACRIHCL 

SCrtEDULE O SACRIPICF 

ACCIDENTALL Y SILLE D 

TERMINA L SACBIPICE 17

 

A11SAL alSblNG 

ol INCLUDES AUlulltZLD ASIBJ>LS 

TU1OR sUBIAF Y 

TOTAL ANIMAL S Kll d PPlMAf i TUHOHS* 5> 16 13 

TOTAL tBISSPJ rUIORS 7 1o 13 

TOTAL ANIKAL b WIT H Bc.NIG8 TUI»OPS 1 3 5 

TO1AL FE.H1GN TUHOBb 1 3 5 

iOTAL A1IHAL S WITH 1HLIGNAN T TUROES 5 13 8 

TOTAL SALIt.NAS'1 TU1OBS 0 13 8 

TOTAL ANI1AL S WITH SlCONDARJ TU1ORS* 

T01AL bECONDAII ? 1UKOBS 

1OTAL 4SMALS WITH TUHOKS USCEHTA1SiMIGN Ofi 1AL1GN4NT

 

TOTAL UUCS1-TAI K TUQUE S 

TOTAL ANIMAL S WI1H IU.1OHS U1CEP.TAINPRI«AS!( uR lETAStATIC

 

TOTAL ilNCE'FTAIS TU1OPS 

* I-RIMAR* IU80PS: ULL 10HOSS EXCEPT SECOSDARJ TUHORS 

» aECONDAB f i'OHORS: rlEl'ASTATIC TUSORS OR TUSORS INVASIVE INTO AN ADJACENT OBGAN 

B-8 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH MEXACARBATE
 

TABLE Cl 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH MEXACARBATE 

CONTROL (VEH ) LOU DOSE HIGH DOSE 

01-M070 01-M071 01-M072 

ANIMAL S INITIALL Y IN STUDY 20 50 50 ANIMAL S MISSING 1 ANIMAL S NECEOPSIED 20 49 118 ANIMAL S EXAMINE D HISTOPATHOLOGICALL Y ** 20 19 48 

INTEGUMENTARY SYSTEM
 

*SKIN (20) (19) (48)
 

EPIDERMAL INCLUSION CYST 1 (5X) 1 (2*)
 

INFLAMMATION, NOS 1 (2*)
 

RESPIRATORY SYSTEM
 

fTRACHEA (20) (49) (18)
 INFLAMMATION, NOS 1 (5*) 6 (12*) 2 (1*)
 INFLAMMATION, ACUTE 1 (2X)
 

#IUNG (20) («°) (48)
 

INFLAMMATION, NOS 1 (2*)
 INFLAMMATION, ACUTE 1 (5*) 5 (10*) 7 (15*)
 ABSCESS, NOS 9 (18*) 2 (4*)
 PNEUMONIA, CHRONIC MURINE 9 (45*) 11 (29*) 25 (52*)
 CALCIFICATION, NOS 1 (5*) 1 (2*) 3 (6*)
 CALCIFICATION, FOCAL 1 (5*)
 

HEMATOPOIETIC SYSTEM
 

#SPLEEN (20) (49) (47)
 

HEMORRHAGE 1 (2*)
 

ABSCESS, NOS 1 (2*)
 

HYPERPLASIA, NOS 1 (2*) 1 (2*)
 

HEMATOPOIESIS 6 (30*) 7 (14*) 6 (13*)
 

tLYMPH NODE (20) (49) (45)
 

INFLAMMATION, NOS 7 (14*) 4 (9*)
 

ANGIECTASIS 1 (2*)
 

iCERVICAL LYMPH NODE (20) (49) (45)
 

I NUMBE R OP ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

**EXCLUD£S PARTIALLY AUXOLYZED ANIMALS 

C-3
 
TABLE Cl (CONTINUED) 

CONTROL (TEH) LOW DOSE HIG H DOSE 

01-M070 01-M071 01-H072 

tTHYMUS (11) (10) (12)
 

HEMORRHAG E 1 (3%)
 

CIRCULATORY SYSTEM
 

tHEART (20) (49) (18)
 PERIARTERITIS 2 (10%)
 

ARTERIOSCLEROSIS, NOS 3 (6X)
 

CALCIFICATION, NOS 5 (25%) 2 (4%) 3 (6%)
 

tBYOCARDIBM (20) (49) (48)
 

FIBROSIS 1 (2X)
 

DEGENERATICN, NOS 12 (60%) 6 (12X) 16 (33%)
 

*AORTA (20) (19) (48)
 

PEEIARTERITIS 1 (2X) 1 (2%)
 

ARTERIOSCLEROSIS, NOS 6 (SOX) 5 (10X) 1 (8%)
 

MEDIAL CALCIFICATION 1 (5X> 1 (2%)
 

DIGESTIVE SYSTIB
 

tLIVER (20) (49) (48) 

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

THROMBOSIS, NOS 1 (2X) 

ABSCESS, NOS 1 (2X) 

DEGENERATICN, NOS 1 (5%) 7 (14%) 5 (10%) 

METAMORPHOSIS FATTY 9 (45X) 9 (18X) 5 (10%) 

ANGIECTASIS 2 (4X) 1 (2%) 

tLIVER/CENTRILOBOLAR (20) (49) (48) 

NECROSIS, SOS 3 (6*) 

CYTOPLASMIC VACOOLIZATION 1 (2%) 

*BILE DDCT (20) (49) (48) 

HYPERPLASIA , NOS 2 (10X) 5 (10%) 8 (17%) 

tPANCPEAS (20) (19) (47) 

PERIARTERITI S 3 (15X) 7 (14%) 6 (13%) 

ABTERIOSCLEROSIS, NOS 1 (5X) 2 («%) 

ATSOPHY, NOS 1 (2%) 

*PANCREATIC DOCT (20) (49) (47)

 

HYPERPLASIAi_NOS__ 

* NDBBER OF ANIMALS SITH TISSDE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECBOPSIED
 

C-4 
' T ABLE Cl (CONTINUED) 

CONTROL (TEH) LOU DOSE HIGH DOSE 

01-H070 01-H071 01-H072 

•ESOPHAGUS (20) (46) (48) 

DILATATION, NOS 2 (4X) 

iSTOMACH (20) (49) (47) INFLAMMATION, NOS 

ULCER FOCAL 

1 (5X) 

3 (15X) 

1 <2X) 

3 (6*) CALCIFICATION, NOS 6 (30*) 7 (14X) 8 (17X) HYPEHKERATOSIS 

ACANTHOSIS 1

1

 (2*) 

 (2X) 

*SMALL INTESTINE (20) (49) (47) INFLAMMATION, NOS 3 <6X) 2 (4X) PERIARTESITIS 1 <2X) 

•DUODENUM (20) (49) (47) CALCIFICATION, NOS 2 (10X) 

•LARGE INTESTINE 

PARASITISM 

(20) (49) 

2 (4*) 

(47) 

8 (17X) 

•COLON (20) (49) (47) INFLAMMATION, NOS 5 (10X) 1 (2X) 

•CECUM (20) (49) (47) 

INFLAMMATION, NOS <2X) 

URINARY SYSTEM 

• KIDNEY (20) (49) (47) CALCULUS, NOS 1 <5X) 1 (2*) 5 (11X) CYST, NOS 1 <2X) ABSCESS, NOS 2 (4*) INFLAMMATION CHRONIC 19 (95X) 35 (71*) 37 (79X) NEPHROPATHY, TOXIC 

CALCIFICATION, NOS 5 (25X) 

2 (4X) 

2 (4X) 

1 (2X) 

5 (11X) 

•KIDNEY/PELVIS 

INFLAMMATION, NOS 

(20) 

1 (5X) 

(49) 

3 <6X) 

(47) 

3 <6X) 

•URINARY BLADDER 

CALCULUS, NOS 

INFLAMMATION. NOS. 

(20) 

_5_i25.*i.

(49) 

1 (2X) 

2_.U4SL_ 

(45) 

t NUMBER OF ANIHAL S MITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

C-5 
TABLECl (CONTINUED) 

CONTPOL(VEH) 

01-B070 

L0« DOSE 

01-M071 HIGH DOSE 

01-11 072 

HBOCRINF SYSTE M 

IPITUITAP Y 

CIST, N03 

riYPEBPLASIA, NOS 

H1PERPLA3IA , CHPOHOPHOBE-CEL L 

*ADRENA L 

CALCIFICATION , NOS 

HYTERPLASIA , NO S 

IADRENA L COPTFX 

DEGENERATION , NO S 

tTil.YROT1) 

CYSTIC FOLLICLES 

HYPEHPLASIA , FOLLICULAR-CEL L 

trSHATHYSOI 1 ) 

HXPERP I ASIA , NO S 

»PfiNC D ESTIv . ISLETS 

HYPE?P ! ASIA , NO S 

(20) 

1 (5X) 

1 (5%) 

(20) 

1 (5%) 

(20) 

8 (tO«) 

(20) 

4 (20X ) 

1 (5X) 

(20 ) 

t (20*) 

(20 ) 

(»9) 

1 (2%) 

1 (2*) 

(K9 ) 

1 (2S) 

(19) 

10 (20*) 

(18) 

7 (15*) 

1 (2*) 

(U9 ) 

1 (2*) 

(U9) 

2 {»*) 

(H7 ) 

t (9*) 

2 (UX) 

1 (2X) 

(17) 

1 12%) 

3 (6%) 

(17) 

11 (30X) 

(17) 

6 (13X) 

5 (11X ) 

(17) 

1 (9X) 

(17) 

1 (2X) 

REPRODUCTIV E SYSTE M 

•PROSTATE 

INFLAtlBATICSI , NOS 

ATROPHY , NO S 

HYPEBTFOPHY , NO S 

*SE(1INAL VESICL F 

AT BO PHY , NOS 

HYPEFT"CPHY , NOS 

*TF.STIS 

PEPIARTEPITI S 

ARTERIOSCLEROSIS , NO S 

CALCIFICATION, NOS 

ATROPHY , NO S 

*EPIDIDY1IS 

NECROSIS, FAT 

* NUMbE ? O F ANIMAL S KITH TISSDE

* NUP1BE F OF BUIHAL S NBCHOPSIED 

(20) 

3 (15X) 

(20) 

(20) 

1 <5X ) 

1 (5X) 

1 (5X) 

9 (15*) 

(20) 

(»5) 

10 (22X) 

1 (2*) 

(19) 

1 (2X) 

(U8 ) 

3 (6*) 

17 (35X) 

(H9) 

_ _ 1 J2SI

 EXAMINE D HICBOSCOPICALLY 

­

(11)

6 (11X) 

2 <5X) 

1 (2X) 

(18) 

1 (8X) 

1 (2X) 

(16) 

7 (15X) 

11 (30X) 

(18) 

C-6 
TABLE Cl1

 (CONCLUDED) 

CONTROL (TEH) LOW DOSE HIGH DOSE 

01-N070 01-M071 01-H072 

NERVOU S SYSTE M 

*BRAIN/MENINGES (20) (t9) (17) 

INFLAMMATION , DOS 2 (10%) 1 (2%) 

SPECIAL SENSE ORGAN S 

*EYE (20) («9) (U8)
 

INFLAMMATION, SOS 1 (2%)
 

CATARACT 1 (2%) 1 (2*)
 

fWSCOLOSKELETAL SYSTEM
 

*BONE (20) (1*9) (US)
 

FIBROBS OSTEODYSTROPHY 5 (25%) 3 (6%) 6 (13%)
 

*SKELETAL MOSCLE (20) (t9) («8)
 

INFLAMMATION, NOS 1 (2*)
 

BODY CAVITIES
 

*PLEUSA (20) (<49) (US)
 

INFLAMMATION, NOS 2 (!»*)
 

*PEPICAEDIUM (20) (U9) (US)
 

INFLAMMATION, NOS 1 (5X) 4 (8*)
 

*MESENTERY (20) (49) («8)
 

PERIARTERITIS 1 (5*) 3 (6X) 5 (10%)
 

ARTERIOSCLEROSIS, NOS 14 (20X) 1 (2%) 5 (10%)
 

ALL OTHER SYSTEMS
 

NONE
 

SPECIAL MORPHOLOGY SUMMARY
 

ANIMAL MISSING/NO NECROPSY PERF 1
 

AUTOLYSIS/NO NECROPSY PERFORMED 1 1
 

* NUHBER OF ANIMALS HITH TISSDE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECHOPSIED
 

C-7
 
TABLE C2 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH MEXACARBATE 

c:ONTROL (VEH) L0» DOSE HIGH DOSE
 

01-F070 01-F073 01-F07U
 

ANIMALS INITIALLY IN STUDY 20 50 50
 

ANIHALS NECPOPSIED 20 50 50
 ANIMALS EXAMINED HISTOPATHOLOGICALLY** 20 50 50
 

INTEGUMENTARY SYSTEM
 

*SKIN (20) (50) (50)
 INFLAMMATICN, NOS 1 (2%) 3 (6%)
 

PESPIRATORY SYSTEM
 

fTRACHEA (20) (50) (13)
 

INFLAMMATICN, NOS 1 (5%) 2 (U%) « (9%)
 

*LUNG (20) (50) (50)
 INFLAMMATION, ACUTE 2 (10%) 3 (6%) 6 (12%)
 

ABSCESS, NOS 1 (5%) 2 (1%) 6 (12%)
 

PNEUMONIA, CHRONIC HUHINE 11 (55%) 31 (62%) 19 (38%)
 

CALCIFICATION, NOS 2 (10%) 1 (2%)
 

HEMATOPOIETIC SYSTEM 

tSPLEEN (20) (50) (50) ABSCESS, NOS 1 (2%) HEMATOPOIESIS 1 (5%) It (28%) 9 (18%) 

ILYMPH NODE 

INFLAMMATICN, NOS 

(20) (50) 

5 (10%) 

(50)

4 (8%) 

tCERVICAL LYMPH NODE (20) (50) (50) INFLAMMATICN, HOS 1 (5%) 

fMESENTERIC L. NODE 

INFLAMMATICN, NOS 

<2J3> (50) 

2 (t%) 

(5.Q) 

tTHYMOS 

...CYST., NOS _ _ _ _ . (17) (42) (46) 

2 _(tX) . __ 

t NOBBE D OF ANIMALS IITH TISSUE EXAMINE D MICPOSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

**EXCLUDhS PARTIALLY AUTOLYZhD ANIMALS 
TABLE C2 (CONTINUED)
 

CONTROL (VEH) LOU DOSE HIGH DOSE 

01-F070 01-F073 01-F07II 

CIRCULATOR Y SYSTEM 

tHEART (20) (50) (50) 

THROMBOSIS , NOS 1 (2X) 

ARTERIOSCLEFOSIS, NOS 1 (2X) 2 (IX) 

*MYOCARDIU M (20) (50) (50) 

DEGENERATION , NOS 3 (6*) 1 (2X) 

*ENDOCARDIU M (20) (50) (50)

 

INFLAMMATION , NOS 1 (2*)

 

*AORTA (20) (50) (50) 

ARTERIOSCLEROSIS, NOS 2 (10X) 2 (4X) 2 (tX) 

DIGESTIVE SYSTEM 

*LIVER (20) (50) (50) 

CYST, NOS 1 (5X) t <8X) 

DEGENERATION , NOS 2 (10*) 3 (6*) 2 (IX) 

NECROSIS, FOCAL 2 (10*) 1 (2X) 

METAMORPHOSI S FATTY 3 (15X) 3 (6X) 6 (12X) 

HYPERPLASIA , NOS 1 (5X) 1 (2X) 1 (2X) 

HYPERPLASIA , FOCAL 1 (5*) 

tLIVEP/CENTPILOBULAF (20) (50) (50) 

NECROSIS, NOS 2 (4X) 3 (6X) 

*BILE DOCT (20) (50) (50) 

HYPERPLASIA , NOS 7 (35X) 8 (16*) t <8X) 

IPANCREAS (20) (50) (50) 

PERIA8TESITIS 2 (10X) 1 (2X) 

ARTERIOSCLEROSIS, NOS 2 <«X ) 

ATROPHY , NOS 1 (2X) 2 (tX) 

•ESOPHAGUS (20) (50) (50) 

DILATATION , NOS 1 (5*) 1 (2X) 

ISTOHACH (20) (50) (50) 

INFLAMMATICN , NOS 1 (5X) 

ULCER, NOS 2 (tX) 2 (tX) 

ULCES FOCAL 3 (6X) 1 (2X> NECROSIS, FAT 1 (2X) 

_ CALCIFICATION,. NOS . 2 JJ2S1 1_J2SL . 2 (<»X) 

I NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-9
 
TABLE C2 (CONTINUED) 

CONTROL (TEH) LOW DOSE
 HIGH DOSE
 

01-F070 01-F073
 01-F07*
 

IDUODENUM
 (20)	 (50)
 (19)
 

INFLAMMATION, SOS
 2 (10X)
 1 (2X)
 

tLARGE INTESTINE
 (20)	 (50)
 (U9)
 PARASITISM
 1 (5*) 2 (1*)
 5 (10X)
 

«COLON
 (20) (50)
 (49)
 INFLAMMATION, NOS
 3 (6X)
 

URINARY SYSTEM
 

tKIDNEY
 (20)	 (50)
 (50)
 CALCULUS, NOS
 3 (15X) 11 (22X)
 15 (30X)
 PYELONEPHRITIS, NOS
 1 (2X)
 INFLAMMATION CHBONIC
 12 (60X) 16 (32X)
 14 (28X)
 NEPHROPATHY, TOXIC
 5 (10X)
 1 <2X)
 CALCIFICATION, NOS
 3 (15X) 2 <«X)
 2 (IX)
 

tKIDNEY/PELVIS
 (20)	 (50)
 (50)
 INFLAMMATION, NOS
 1 <5X) 2 (1%)
 1 (2X)
 

tOHINASY BLADDER
 (20)	 (50)
 (50)
 INFLAMMATION, NOS
 1 (5*) 5 <10X)
 2 (4X)
 

ENDOCRINE SYSTEM
 

*PITUITAFY
 (20)	 (i»9)
 (49)
 CYST, NOS
 2 (10X) 3 (6X)
 1 (2X)
 NECROSIS, FOCAL
 1 <2X)
 HYPEBPLASIA, NOS
 5 (10X)
 5 (10X)
 HYPBRPLASIA, FOCAL
 1 (2X)
 

1ADRENAL CORTEX
 (20)	 (50)
 (50)
 DEGENERATION, NOS
 7 (35X) 20 (40X)
 20 (40X)
 

f THYROID
 (20)	 (i»9)
 (50)
 CYSTIC FOLLICLES
 1 (2X)
 5 (10X)
 

IPARATHYFOID
 (20)	 (50)
 (50)
 HYPEFPLASIA, NOS
 1 <5X)
 1 <2X)
 

IPANCFEATIC ISLETS
 (20)	 (50)
 (50)
 

HYPERPlASJAj. NOS
 5-J«*L _.
 

t NDMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

C-10 
TABLE C2 (CONTINUED) 

CONTROL (VEH) L OW DOSE HIG H DOSE 

01-F070 01-F073 01-F074 

REPRODUCTIV E SYSTEM 

*MAMMAR Y GLAN D (20) (50) (50) 

INFLAMMATION , NO S 1 (2%) 

*VAGIN A (20) (50) (50) 

INFLAMMATION , NO S 2 (10*) 5 (10%) 6 (12%) 

* UTERUS (20) (U9) (50) 

HYDROMEIRA 5 (10S) 8 (16*) 

HEHATOMETRA 

INFLAMMATION, NOS 2 (10*) 

1 (7%) 

2 ('»?) 

tUTEHUS/ENDOMETFIUM 

HYPEBPLASIA, CYSTIC 

(20) 

3 (15*) 

(49) 

3 (6*) 

(50) 

1 (2%) 

tOVARY (20) (19) (50) 

CYST, NOS 3 (6*) 

INFLAMMATION, NOS 1 (2%) 1 (25!) 

I>E5VOUS SYSTEM 

tBPAIN/MENINGIS (20) (50) (50) 

INFLAMMATION, NOS 1 (2%) 

SPECIAL SENSE CPGANS 

*EYE (20) (50) (50) 

CATAPACT 1 (2«) 

MUSCULOSKELETA L SYSTEM 

*BONE ' (20 ) (50) (50) 

FIBPOO S OSTEODYSTROPH Y 3 (15%) 1 (2*) 2 (1%) 

BCDY CAVITIES 

*ABDOMINA L CAVIT Y (20 ) (50) (50) 

NECROSIS , FAT 1 (2%) 

*PLEUBA (20) (50) (50) 

INFLAMMATICJU-NQS 1_ 

I NUMBE R OF ANIMAL S KITH TISSUE EXAMINE D MICROSCOPICALLY 

* NOMBE? OF ANIMAL S NECPOPSIED 

C-ll 
TABLE C2 (CONCLUDED) 

CONTROL (VEH) LOW DOSE HIGH DOSE 

01-F070 01-P073 01-F07U 

*PERICARDI(JH (20) (50) (50)
 

INFLAMMATION . NOS 1 (2%)
 

*MESENTERY (20) (50) (50) PERIARTERI1IS 1 <2X) 

ARTERIOSCLEROSIS, NOS 2 (10*) 1 (2%) 1 (2%) 

ALL OTHER SYSTEMS
 

NONE
 

SPECIAL MORPHOLOGY SUMMARY
 

NONE
 

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-I2
 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH MEXACARBATE
 

TABLE Dl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE TREATED WITH MEXACARBATE 

CONTROL (VEH ) LOW DOSE HIG H DOSE 

02-M077 02-M078 C2-H079 

ANIMALS INITIALLY IN STUDY 20 50 50 

ASIMALS MISSIHG 1 1 1

 

ANIMAL S NECROPSIED 15 06 17 

ANIMAL S EXAMINE D HISTOPATHOtOGICALLY ** 15 16 «7

 

INTEGUMENTAR Y SYSTEM 

*SKIN
 (15)
 (16) (17)
 

CYST, NOS
 1 (7X)
 

INFLAMMATION, NOS
 2 (13X)
 5 (11X) 5 (11X)
 

*SUBCUT TISSUE
 (15)
 (16)	 (17)
 

INFLAMMATION, ACUTE MEMBRANOUS
 1 <2X)
 

ABSCESS, NOS
 1 <9X) 11 (23X)
 

RESPIRATORY SYSTEM
 

*LONG
 (15) (16)	 (16)
 

INFLAMMATION, ACUTE
 3 (7X) 3 <7X)
 

PNEUMONIA, CHRONIC MURINE
 2 (IX)
 

HYPEPPLASIA, NOS
 2 (IX) 3 (7X)
 

HEHATOPOIETIC SYSTEM
 

tSPLEEN
 (15)
 (17)
 

ACCESSORY SPLEEN
 1 <2X)
 

AMYLOIDOSIS
 9 (60X)
 7 (15X) 6 (13X)
 

METAMORPHOSIS FATTY
 1 (2X)
 

CALCIUM DEPOSIT
 1 (7X)
 

HEMATOPOIESIS
 3	 (7X) <9X) 

ICERVICAL LYMPH NODE
 (13)
 (15)	 (15) INFLAMMATION, NOS
 1 <8X)
 2 («X) <2X) 

•LUMBAR	 LYMPH NODE
 (13)
 (15)	 (15)

 INFLAMMATION, NOS
 1 (2X>
 

tMESENTEPIC L. NODE
 (13)
 (15) (15)
 

INFLAMMATION, NOS
 2 (15X)
 13	 (29X) 6 (13X)
 

ANGIECTASIS
 1-J2X1.__
 

* NUMBER OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE S OF ANIMALS NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

D-3
 
TABLE Dl (CONTINUED)
 

CONTROL (VEH) LOW DOSE HIG H DOSE 

02-N077 02-M078 02-S079 

CIRCULATOR Y SYSTE M 

*HEAHT 

CALCIUM DEPOSIT 

(15) 

3 (20X) 

(U6) (47) 

•MYOCARDIU M 

DEGENERATION , 80S 

(15) (46)

 

2 (4%) 

(47) 

•ENDOCARDIU M 

INFLAMMATION , NOS 

(15) 

1 (7X) 

C*6) (47) 

DIGESTIVE SYSTE M 

I1IVER 

INFLAMMATION , NOS 

DEGENERATION , NOS 

INFARCT , SOS 

(15) (46)

 

1 (2*) 

2 {««) 

<t7) 

1 (2X) 

2 (4«) AMYLOIDOSI S 

CALCIU M DEPOSIT 

9 (60X) 

1 (7%) 

4 (9X) 2 (4X) 

HYPERPLASIA , NODOLA R 5 (11%)

 8 (17X) 

*HEPATIC CAPSUL F (15) (»6)

 INFARCT , NCS 1 (2%)

 

(47) 

1 (2X) 

tPANCRFA S (15) (46) AMYLOIDOSI S

 

ATHOPHY , NOS 

(47) 

1 (2X) 

1 (2X) 

tESOPHAGU S (15) (42) INFLAMMATION , NOS 1 (2*)

 

(46) 

((STOMAC H (15) (46)

CALCIU M DEPOSIT 1 <7X ) 1 (2*) 

(47) 

2 (4X) 

*LARGE INTESTINE (13) (45) PARASITIS M 1 (8X) 1 (2*)

 

(46) 

3 (7X) 

*PECTUM (15) (46) - PROLAPSE _

 , 7 J15.S1 _. (47) 4 (9X1 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

D-4
 
TABLE Dl (CONTINUED) 

CONTROL (VEH) LOW DOSE HIG H DOSE 

02-M077 02-M078 02 -M 07 9 

URINAR Y SYSTEM 

tKIDNE Y (15) <<»6 ) (47) 

HYDRONEPHROSI S 2 (t*) 

THROMBOSIS, NOS 1 (2%) 

PYELONEPHRITIS , NO S 1 (7*) 3 (7*) 1 (2*) 

ABSCESS, NOS 1 (7%) 1 (2*) 

INFLAMMATIO N CHRONIC 12 (80*) 16 (35*) 19 (140%) 

AMYLOIDOSI S 9 (60%) 7 (15%) 8 (17*) 

CALCIU M DEPOSIT 1 (2*) 

tURINAR Y BLADDER (11) (16) (46) INFLAMMATION , NO S

 3 (21*) 4 (9X) 2 (H% ) 

ENDOCRIN E SYSTE M 

(PITUITAR Y (5) (28) (27) CYST, NOS

 2 (7%) 

tADRENA L (15) (46) (1*6) 

AMYLOIDOSIS 1 (7*) 1 (2*) 1 (2*) 

HYPERTROPHY , NOS 1 (2*) 

ITHYROI D (11 ) (43) (1*5) 

AMYLOIDOSIS 3 (27*) 3 (7*) 1* (9*) 

HYPERPLASIA , NOS 1 (2%) 

REPRODUCTIV E SYSTEM 

*PENIS (15)

 (1*6) (1*7) 

INFLAMMATION , NOS 1 (2*) 

•PROSTATE (15)

 (K6 ) (1*6) 

INFLAMMATION , NOS 2 (13*) 3 (7*) 1 (2*) 

*SEMISAL VESICLE (15)

 (i*6) (1*7) 

INFLAMMATION , NOS 1 (7*) 2 (4*) 1 (2*) HYPERTROPHY , NOS

 1 (7*) 2 (it*) 2 (4*) 

ITESTIS (15) (1*6) (47) 

CALCIU M DEPOSIT 1 (7*) ATROPHY , NOS

 1 (7*) U (9*) 3 (6X) 

*SCROTUM (15)

 (1*6) (47) 

CYST, NOS . __ 1 J2*L _ 

t NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE " OF ANIMAL S NECPOPSIED 

D-5 
T\BLE Dl (CONCLUDED) 

CONTROL (VEH)

02-H077

 LOW DOSE

 02-H078

 HIG H DOSE 

 02-M079 

NERVOU S SYSTE M 

NON E 

SPECIAL SENSE ORGANS
 

*HARDEBIAN GLAND
 (15) (<)6)

HYPEPPLASIA, NOS
 1 (2*)
 

 (47)
 

MOSCULOSKELETAI SYSTEM
 

NONE
 

BODY CAVITIES
 

NONE
 

ALL OTHW SYSTEMS
 

NONE
 

SPECIAL BORPHOIOGY SUMMARY
 

NO LESION SEPOPTED
 1
 1

ANIMAL MISSING/NO NECROPSY PERF
 1
 1

AUTOLYSIS/NO NECROPSY PERFORMED
 U
 3

 5
 

 1
 

 2
 

t NUMBE" OF ANIMALS WITH TISSOE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECPOPSIED
 

D-6
 
TABLE D2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE TREATED WITH MEXACARBATE 

CONTROL (VEH ) LOU DOSE HIG H DOSE 

02-F077 02-F080 02 -t 081 

ANIMAL S INITIALL Y IN STUDY 20 50 50 

ANIMAL S NECEOPSIED 2 0 48 18

 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY ** 20 18 18

 

INTEGUHENT1PY SYSTEM 

NONE 

RESPIRATOR Y SYSTEM 

*TSACHEA (20) C<5) 

INFLAMMATION , NOS 2 (IX) 

*LUNG
 (20)
 (48)	 (18)
 INFLAMMATION, ACUTE
 3 (6X)
 

PNEUMONIA, CHRONIC MDRINE
 2 (10X)
 2 (4X) 2 (<»*)
 HYPERPLASIA, NOS
 1	 <2X)
 

HEMATOPOIETIC SYSTEM
 

tSPLEEN
 (20)
 (18) (47)
 NECROSIS, NOS
 1 (5X)
 AMYLOIDOSIS
 1 (5X)
 2 (UX)
 

HYPERPLASIA, LYMPHOID
 2 (4X)
 HEMATOPOIESIS
 3 (15X)
 5 (10X) 8 (17X)
 

tCERVICAL LYMPH NODE
 (19)
 (47)	 (47)
 

INFLAMMATION, NOS
 3 <6X) 2 <4X)
 

*MESENTERIC L. NODE
 (19)
 (47)	 (47)
 INFLAMMATION, NOS
 4 (9X) 2 (4X)
 

tSENAL LYMPH NODE
 (19)
 (17)	 (47)
 

INFLAMMATION, NOS
 4 (9X) 1 <2X)
 

CIRCULATOR Y SYSTE M 

IHEAET (19 ) (18) 

PERIAHTESITIS 

I NUMBE R OF ANIMAL S UITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMALS NECSOPSIED 

**EXCLUDKS PARTIALLY AUTOLYZED ANIMALS 

D-7 
TABLE D2 (CONTINUED)
 

CONTROL(VEH ) LOW DOSE HIG H DOSE 

02-F077 02-F080 02-F081 

EIGESTIV E SYSTE M 

tLIVER (20) (K8 ) («8) 

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

INFLAMMATION , NO S 1 (5%) 

DEGENERATION , NOS 1 (2«) 1 (2X) 

NECROSIS, FOCAL 1 (5%) 2 (4X) 

AMYLOIDOSIS 2 (««) 

METAMORPHOSI S FATTY 1 (2%) 

HYPEBPLASIA , NODULA R 1 (2X) « (8%) 

ANGIECTASI S 1 (2X) 

HEMATOPOIESI S 3 (6%) 

tPANCREA S (19) (i»7) (17) 

CYST, NOS 1 (2*) 

INFLAMMATION , NOS 1 <5X) 

ABSCESS, NOS 1 (2«) 

ATROPHY , NOS 1 (2*) 

•LARG E INTESTINE (20) (18) (18)

 

PARASITIS M 1 <5X) 

URINAR Y SYSTEM 

tKIDNE Y (20) (i*8) (18) 

INFLAMMATIO N CHRONIC 3 (6*) 2 (IX) 

PERIARTEPI1IS 1 (2*> NEPHFOPATHY, TOXIC 1 (2«) 

PIGMENTATION , NOS 1 (5X) 

4UPINAR Y BLADDER (19) (18) (16) 

INFLAMMATION , NOS 1 (2%) 

ENDOCRIN E SYSTE M 

*PITUITA?Y (11) (29) (35) 

CYST, NOS 1 (7X) 

HYPERPLASIA , NOS 1 (3*) 2 (6X) 

tADRENA L (20) (17) (15) 

CYST, NOS 1 (2*)

 

PERIARTESITIS 1 (2*)

 

tTHYROID (18) (45) (15) 

INFLAMMATION , NOS 1 J2X) 

* NDMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NEC80PSIED
 

D-8
 
TABLE D2 (CONCLUDED) 

CONTROL (VEH ) L OW DOSE HIG H DOSE 

02-F077 02-F080 02-F081 

REPRODUCTIV E SYSTEM 

tUTERUS (20) (48) (48) HYDROMETRA 5 (10%) 

INFLAMMATION, 80S 11 (55%) 29 (60%) 22 (46%) 

tUTEROS/ENDOHETRIUM (20) (48) (48)
 

CYST, DOS 1 (2%)
 

INFLAMMATION, DOS 1 (2%)
 HYPEBPLASIA, DOS 1 (5%)
 HYPERPLASIA. CYSTIC 13 (65%) 39 (81*) 44 (92%)
 

tOVAEY (20) (48) (47)
 

CYST, NOS 4 (20%) 12 (25%) 18 (38%)
 

INFLAMMATION, NOS 8 (40%) 21 (44%) 15 (32%)
 

NERVOUS SYSTEM
 

*BRAIN (20) (47) (48)
 

CYST, NOS 1 (5%)
 

SPECIAL SENSE ORGANS
 

*HARDEEIAN GLAND (20) (48) (48)
 

HYPERPLASIA, NOS 1 (5%)
 

MUSCULOSKELETAI SYSTEM
 

NONE
 

BODY CAVITIES
 

*PLEOBA (20) (48) (48)
 

INFLAMMATION, NOS 2 (4%)
 

ALL OTHEE SYSTEMS
 

NONE
 

SPECIAL BORPHOIOGY SOHMAFY
 

NO LESION REPORTED 1
 

AUTOLYSIS/NO NECROPSY PERFORMED 2 2
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBEP OF ANIMALS NECROPSIED
 

D-9
 





DHEW Publication No. (NIH) 78-1703