OFFICIAL NTP 

FILE COPY 

National Cancer Institute 

CARCINOGENESIS DO NOT REMOVE FROM THIS OFFICE 

Technical Report Series 

No. 101 

1978 

BIOASSAY OF 

FORMULATED FENAMINOSULF 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 140-56-7 

NCI-CG-TR-101 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 


FORMULATED FENAMINOSULF
 


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) 78-1351
 


REPORT ON THE BIOASSAY OF FORMULATED FENAMINOSULF
 


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 for­


mulated fenaminosulf 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 re­


quires a wider analysis.
 


CONTRIBUTORS: This bioassay of formulated fenaminosulf was conducted
 


by Mason Research Institute, Worcester, Massachusetts, initially under
 


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


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


gram.
 


The experimental design was determined by the NCI Project Offi­


cers, Dr. J. H. Weisburger (1,2) and Dr. E. K. Weisburger (1). The
 


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


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


by Mr. G. Wade (3) and Ms. E. Zepp (3). Chemical analysis was per­


formed by Midwest Research Institute (4) and the analytical results
 


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



Histopathologic examinations were performed by Dr. A. S. Krishna
 


Murthy (3) and Dr. D. S. Wyand (3) at the Mason Research Institute,
 


and the diagnoses included in this report represent the interpreta­


tion of these pathologists. Histopathology findings and reports were
 


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



Compilation of individual animal survival, pathology, and sum­


mary tables was performed by EG&G Mason Research Institute (7); the
 


statistical analysis was performed by Mr. W. W. Belew (5) and Dr. J.
 


R. Joiner (6) using methods selected for the Carcinogenesis Testing
 


Program by Dr. J. J. Gart (8).



iii
 

This report was prepared at METREK, a Division of The MITRE Cor­


poration (5) under the direction of the NCI. Those responsible for
 


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


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


Walker (5), biochemist Mr. S. C. Drill (5), and technical editor Ms.
 


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


participating organizations.
 


The following other scientists at the National Cancer Institute
 


were responsible for evaluating the bioassay experiment, interpreting
 


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


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


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


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



1.	 Carcinogenesis Testing Program, Division of Cancer Cause and
 


Prevention, National Cancer Institute, National Institutes of
 


Health, Bethesda, Maryland.
 


2.	 No wit w h the Naylor Dana Institute for Disease Prevention, Ameri­


can Health Foundation, Hammon House Road, Valhalla, New York.
 


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


setts.
 


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


Missouri.
 


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


Boulevard, McLean, Virginia.
 


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


Maryland.
 


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


Rockville, Maryland.
 


8.	 Mathematical Statistics and Applied Mathematics Section, Biometry
 


Branch, Field Studies and Statistics Program, Division of Cancer
 


Cause and Prevention, National Cancer Institute, National Insti­


tutes of Health, Bethesda, Maryland.
 


9.	 No wit w h the Division of Comparative Medicine, Johns Hopkins
 


University, School of Medicine, Traylor Building, Baltimore,
 


Maryland.
 


IV
 

SUMMARY
 


A bioassay of formulated fenaminosulf for possible carcinogen­


icity was conducted using Fischer 344 rats and B6C3F1 mice. Fenami­


nosulf 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 fenami­


nosulf were, respectively, 0.10 and 0.05 percent for rats, 0.19 and
 


0.10 percent for male mice, and 0.10 and 0.05 percent for female
 


mice. After a 78-week period of compound administration, observation
 


of the rats continued for up to an additional 31 weeks and observa­


tion of the mice continued for up to an additional 19 weeks.
 


Fifty male mice and 50 rats of each sex were placed on test as
 


controls and fed only the basal diet. For female mice, 50 animals
 


served as controls for the high dose group and 50 as controls for the
 


low dose group.
 


For female rats there was no significant association between
 


fenaminosulf dosage and mortality and, if the 21 male rats that died
 


in the first two weeks of the bioassay were excluded from considera­


tion, the same was true for male rats.. For both male and female mice
 


there was a significant positive association between dosage and mor­


tality. In all groups of both species, however, adequate numbers of
 


animals survived sufficiently long to be at risk from late-developing
 


tumors.
 


No convincing, statistically significant positive associations
 


were demonstrated between chemical administration and the incidence
 


of neoplasms in either sex of either species. An increased inci­


dence of necrosis and mineralization of the tubular cells of the
 


renal papilla occurred in treated rats and mice. These nonneoplas­


tic lesions were not present in control animals of either species.
 


Under the conditions of this bioassay, dietary administration
 


of formulated fenaminosulf was not carcinogenic in either Fischer
 


344 rats or B6C3F1 mice.
 


TABLE OF CONTENTS
 


Page
 


I. INTRODUCTION 1



II. MATERIALS AND METHODS 3



A. Chemicals 3



B. Dietary Preparation 3



C. Animals 4



D. Animal Maintenance 4



E. Selection of Initial Concentrations 8



F. Experimental Design 9



G. Clinical and Histopathologic Examinations 13
 


H. Data Recording and Statistical Analyses 15
 


III. CHRONIC TESTING RESULTS: RATS 20
 

A. Body Weights and Clinical Observations 20
 


B. Survival 20
 

C. Pathology 23
 

D. Statistical Analyses of Results 25
 

IV. CHRONIC TESTING RESULTS: MICE 33
 

A. Body Weights and Clinical Observations 33
 


B. Survival 33
 

C. Pathology 36
 

D. Statistical Analyses of Results 37
 

V. DISCUSSION 44
 

VI. BIBLIOGRAPHY 47
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 


RATS TREATED WITH FENAMINOSULF A-l
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 


MICE TREATED WITH FENAMINOSULF B-l
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 


LESIONS IN RATS TREATED WITH FENAMINOSULF C-l
 


APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 


LESIONS IN MICE TREATED WITH FENAMINOSULF D-l
 


VII
 

LIST OF ILLUSTRATIONS
 


Figure Number
 


1



Table Number
 


Al
 


Page 

GROWTH CURVES FOR FENAMINOSULF CHRONIC STUDY 

RATS 21 

SURVIVAL COMPARISONS OF FENAMINOSULF CHRONIC 

STUDY RATS 22 

GROWTH CURVES FOR FENAMINOSULF CHRONIC STUDY 

MICE 34 

SURVIVAL COMPARISONS OF FENAMINOSULF CHRONIC 

STUDY MICE 35 

LIST OF TABLES 

Page 

DESIGN SUMMARY FOR FISCHER 344 RATS—FENAMINOSULF FEEDING EXPERIMENT 10 

DESIGN SUMMARY FOR B6C3F1 MICE—FENAMINOSULF 

FEEDING EXPERIMENT 11 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

FENAMINOSULF SURVIVING AT LEAST 52 WEEKS 26 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH FENAMINOSULF 29 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

FENAMINOSULF SURVIVING AT LEAST 52 WEEKS 38 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH FENAMINOSULF SURVIVING AT LEAST 52 

WEEKS 40 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH FENAMINOSULF A-3 

Vlll
 

LIST OF TABLES (Concluded) 

Table Number 

A2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE RATS TREATED WITH FENAMINOSULF A-7 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH FENAMINOSULF B-3 

B2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH FENAMINOSULF B-6 

Cl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH FENAMINOSULF C-3 

C2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH FENAMINOSULF C-7 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH FENAMINOSULF D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH FENAMINOSULF D-7 

ix
 


I. INTRODUCTION
 


Fenaminosulf (NCI No. C03010), an aromatic diazo compound used
 


exclusively as a fungicide, was selected for bioassay by the National
 


Cancer Institute because of conflicting reports concerning its ability
 


to induce hepatomas in rats (Herrmann and DuBois, 1949; Miller et al.,
 


1957). The structural similarity of fenaminosulf to the carcinogenic
 


aminoazo dyes, such as dlmethylaminoazobenzene (Terayama, 1967) was an
 


additional factor in its selection for testing.
 


The Chemical Abstracts Service (CAS) Ninth Collective Index
 


(1977) name for this compound is sodium 4-(dimethylamino)phenol diaze­


*

 nesulfonate. It is also known as p-dimethylaminobenzenediazo sodium
 


(8)
 
 sulfonate; sodium 4-dimethylaminobenzenediazosulfonate; DAS; Dexon ;



diazoben; and Bayer 22555.
 


Fenaminosulf is registered by the U.S. Environmental Protection
 


Agency as a seed-treatment fungicide for beans, beets, corn, cotton,
 


cucumbers, peas, sorghum, spinach, and sugar beets; and as the active
 


ingredient in commercial fungicides for use on avocados, ornamentals,
 


sugarcane, lawns, and turf (Carter et al., 1973; as cited in Interna­


tional Agency for Research on Cancer, 1975).
 


Specific production figures for fenaminosulf are not available;
 


however, the inclusion of this compound in the 1977 Directory of Chem­


ical Producers, U.S.A. (Stanford Research Institute, 1977) implies an
 


*



The CAS registry number is 140-56-7,
 

annual commercial production in excess of 1000 pounds or $1000 in
 


value.
 


The potential for exposure to fenaminosulf is greatest for agri­


cultural workers, although workers in fenaminosulf production facil­


ities may also be exposed. The general population may be exposed via
 


dermal contact to fenaminosulf on packaged seeds, in lawn and garden
 


fungicides, and to residues in soils and turf. Ingestion is unlikely
 


since fenaminosulf is apparently not sprayed directly on food crops.
 


Persistence may not be a major problem because fenaminosulf is labile
 


in the environment (Farm Chemicals Handbook, 1976).
 

II. MATERIALS AND METHODS 

A. Chemicals
 


A fenaminosulf formulation manufactured by Chemagro Corporation
 


(Kansas City, Missouri) under the trade name Dexon was purchased by
 


the NCI for Mason Research Institute. Chemical analysis was performed
 


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


of this formulation was estimated by the manufacturer to contain 35
 


percent fenaminosulf, 41 percent Kaolin clay, 12 percent synthetic
 


silica, 5 percent sodium naphthalene sulfonate, and 6 percent sodium
 


ligno-sulfate.
 


The results of elemental analysis .were consistent with those
 


which would be expected from this formulation. Direct current polar­


ography indicated that the formulation was 30 to 35 percent pure fen­


aminosulf.
 


Throughout this report the term fenaminosulf is used to represent
 


this mixture.
 


B.	 Dietary Preparation
 


The basal laboratory diet for both treated and control animals
 


(5)
 
 consisted of Wayne Lab-Blox (Allied Mills, Inc., Chicago, Illinois).
 


Fenaminosulf was administered to the treated animals as a component
 


of the diet. The chemical was hand-mixed with an aliquot of the
 


ground feed until visual uniformity was attained. This premix was
 


then placed into a 6 kg capacity Patterson-Kelley twin-shell stain­


less steel V-blender along with the remainder of the feed and blended
 

for 20 minutes. Prepared diets were placed in double plastic bags
 


and stored in the dark at 4°C. Mixtures were prepared weekly and
 


stored for not longer than 2 weeks.
 


C.	 Animals
 


Two animal species, rats and mice, were used in the carcino­


genicity bioassay. Fischer 344 rats and B6C3F1 mice were obtained
 


through contracts of the Division of Cancer Treatment, National Can­


cer Institute. The animals were received in several separate ship­


ments from Charles River Breeding Laboratories, Inc., Wilmington,
 


Massachusetts. All male mice to be assigned to treated groups and



the female mice to be assigned to the high dose group were received
 


approximately 5 weeks before the mice to be used as controls for
 


these groups. Low dose female mice were received 3 months after the
 


first shipment and the controls for this group were received 1 week
 


later. Rats to be utilized for the high dose and control groups were
 


received 12 weeks before the low dose rats.
 


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


other signs of disease. The remaining animals were quarantined by
 


species for 2 weeks prior to initiation of the test. Animals were
 


assigned to groups and distributed among cages so that the average
 


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


cies .



D.	 Animal Maintenance
 


All animals were housed by species in rooms having a temperature
 


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


4


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


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


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


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


the first 16 months of study, high dose and control rats were housed
 


in galvanized-steel wire-mesh cages suspended above newspapers. Low
 


dose rats were housed in galvanized wire-mesh cages during quarantine
 


and for the first 14 months of study. Newspapers under cages were re­


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


the study, rats were housed in suspended polycarbonate cages equipped
 


with disposable nonwoven fiber filter sheets. Clean bedding and cages
 


®


were provided twice weekly. Corncob bedding (SAN-I-CEL , Paxton Pro­


cessing Company, Paxton, Illinois) was used for the first 7 months
 


that high dose and control rats were housed in polycarbonate cages and
 


for the first 6 months that low dose rats were housed in polycarbonate
 


cages. For the remainder of the study Aspen hardwood chip bedding
 


(American Excelsior Company, Baltimore, Maryland) was provided in rat
 


cages. Stainless steel cage racks were cleaned once every two weeks,
 


and disposable filters were replaced at that time.
 


Mice were housed by sex in polycarbonate shoe box type cages
 


fitted with perforated stainless steel lids (Lab Products, Inc.,
 


Garfield, New Jersey) and nonwoven fiber filter bonnets. All mice
 


were housed ten per cage for the first part of the study. Low dose
 

treated and control females, treated males and high dose females, and
 


control males and high dose control females were reduced to five per
 


cage after 11, 14, and 13 months, respectively. Cages, lids, filters,
 


and bedding were provided three times per week when the number of mice
 


per cage was ten and twice per week when cage populations were five.
 


.®
 Ab-sorb-dn hardwood chip bedding (Wilner Wood Products Company,
 


Norway, Maine) was used for 2 months (control males and high dose
 


control females) and 3 months (treated males and high dose females).
 


(R)
 
 Subsequently, SAN-I-CEL was used for the next 12 months for these
 


groups and for the first 12 months for low dose treated and control
 


(R)
 
 females. A second corncob bedding (Bed-o-Cobs , The Andersons Cob
 


Division, Maumee, Ohio) was used for the next 8 months. Aspen
 


bedding was then provided for the remainder of the study. Reusable
 


filter bonnets and pipe racks were sanitized every 2 weeks throughout
 


the study.
 


Water was available ad libitum for both species from 250 ml wa­


ter bottles equipped with rubber stoppers and stainless steel sipper
 


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


filled as needed between changes.
 


®
 Wayne Lab-Blox was supplied ad libitum throughout the entire
 


test. Pelleted Wayne Lab-Blox was supplied to treated and control
 


male mice and high dose treated and control female mice during the
 


final observation period. During the quarantine and dosing periods,
 


(R)
 


all animals received Wayne Lab-Blox® meal. Alpine aluminum feed
 

cups (Curtin Matheson Scientific, Inc., Woburn, Massachusetts)
 


containing stainless steel baffles were used to distribute powdered
 


feed until the last 5 months of the study for rats, all control male
 


mice, and high dose control female mice. This same apparatus was
 


used until the last 4 months of the study for treated male mice and
 


high dose female mice, and until the last 7 months of the study for
 


low dose treated and control female mice. After these periods stain­


less steel gangstyle food hoppers (Scientific Cages, Inc., Bryan,
 


Texas) were utilized.
 


During the final observation period, treated and control male
 


mice and high dose female mice were fed pellets from a wire bar hop­


per incorporated into the cage lid, low dose treated and control fe­


males were fed meal from gangstyle hoppers, and rats were fed pellets
 


on the cage floor. Food hoppers were changed on the same schedule as
 


®

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


Treated and control rats were housed with rats being intubated
 


with m-cresidine (102-50-1); and with other rats receiving diets
 


containing 2,5-dithiobiurea (142-46-1) and cupferron (135-20-6).
 


All treated male mice, high dose treated female mice, and low
 


dose control female mice were housed with other mice receiving diets
 


containing 2-methyl-l-nitroanthraquinone (129-15-7); acetylamino­


fluorene (53-96-3); p-cresidine (120-71-8); and 4-chloro-m-phenylene­


diamine (5131-60-2). Low dose treated female mice, high dose control
 


*



CAS registry numbers are given in parentheses.
 

male mice, low dose control male mice, and high dose control female
 


mice were housed with other mice receiving diets containing cupferron
 


(135-20-6); 2,5-dithiobiurea (142-46-1); 4-chloro-o-phenylenediamine
 


(95-83-0); o-anisidine hydrochloride (134-29-0); and p-anisidine
 


hydrochloride (20265-97-8).
 


E. Selection of Initial Concentrations
 


In order to establish the maximum tolerated concentrations of
 


fenaminosulf for administration to treated animals in the chronic
 


studies, Subchronic toxicity tests were conducted with both rats and
 


mice. Animals of each species were distributed among five groups,
 


each consisting of five males and five females. Fenaminosulf was
 


incorporated into the basal laboratory diet and supplied ad libitum
 


to four of the five rat groups and four of the five mouse groups in
 


concentrations of 0.008, 0.015, 0.030, and 0.060 percent. The fifth
 


group of each species served as a control group, receiving only the
 


basal laboratory diet. The dosed dietary preparations were admin­


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


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


The highest concentration causing no deaths, no compound-related
 


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


30 percent relative to controls was selected as the high concentration
 


utilized for the rat and mouse chronic bioassays.
 


No deaths or gross abnormalities were observed in male or female
 


rats treated with fenaminosulf. Mean body weight depression was
 

approximately 28 and 8 percent, respectively, in male and female rats
 


receiving a dietary concentration of 0.060 percent. The initial high
 


dose selected for use in the rat chronic bioassay was 0.10 percent
 


for both sexes.
 


One of the five male and one of the five female mice receiving
 


dietary concentrations of 0.060 percent fenaminosulf died. No mean
 


body weight depression was observed among male mice. There was,
 


however, slight spleen enlargement in all males treated with 0.060
 


percent. Mean body weight depression was approximately 14 percent
 


in female mice treated with 0.060 percent. The initial high doses
 


selected for use in the mouse chronic bioassay were 0.20 and 0.10
 


percent for males and females, respectively.
 


F. Experimental Design
 


The experimental design parameters for the chronic study (spe­


cies, sex, group size, actual concentrations administered, duration
 


of treated and untreated observation periods, and the time-weighted
 


average concentrations) are summarized in Tables 1 and 2.
 


The rat groups receiving an initial concentration of 0.20 per­


cent had a lower time-weighted average dose at the end of the study,
 


than the rat groups receiving an initial concentration of 0.10 per­


cent, and thus will be referred to as the low dose groups throughout
 


this report, while the latter groups will be referred to as the high
 


dose groups. At the time of inclusion in the study, high dose and
 


control male and female rats were approximately 6 weeks old. Low
 

TABLE 1



DESIGN SUMMARY FOR FISCHER 344 RATS
 


FENAMINOSULF FEEDING EXPERIMENT
 


INITIAL OBSERVATION PERIOD
 


GROUP FENAMINOSULF TREATED UNTREATED
 


SIZE CONCENTRATION a (WEEKS) (WEEKS)
 


MALE
 


CONTROL 50 0 0 110
 


LOW DOSEC 50 0.20 1



0.05 77
 


0 27
 


HIGH DOSE° 50 0.10 1



0.05 6



0.10 71
 


0 31
 


FEMALE
 


CONTROL 50 0 0 110
 


LOW DOSEC 50 0.20 1



0.05 77
 


0 27
 


HIGH DOSE° 50 0.10 1



0.05 6



0.10 71
 


0 31
 


a~
Concentrations given in percentages in feed.
 


b 2 (concentration X



TIME-WEIGHTED
 


AVERAGE
 


CONCENTRATION
 


0



0.05
 


0.10
 


0



0.05
 


0.10
 


weeks received)
 


Group designations were determined by time-weighted average concentrations,
 


10
 

TABLE 2



DESIGN SUMMARY FOR B6C3F1 MICE
 


FENAMINOSULF FEEDING EXPERIMENT
 


INITIAL OBSERVATION PERIOD TIME -WEIGHTED 

GROUP FENAMINOSULF TREATED UNTREATED AVERAGE 

SIZE CONCENTRATION3 (WEEKS) (WEEKS) CONCENTRATION 

MALE
 


CONTROL 50 0 0 97 0



LOW DOSE 50 0.10 1 0.10
 

0.05 6



0.10 71
 


0 17
 


HIGH DOSE 50 0.20 1 0.19
 

0.10 6



0.20 71
 


0 17
 


FEMALE
 


LOW DOSE CONTROL 50 0 0 97 0



HIGH DOSE CONTROL 50 0 0 98 0



LOW DOSEC 50 0.20 1 0.05
 

0.05 77
 


0 19
 


HIGH DOSE° 49 0.10 1 0.10
 

0.05 6



0.10 71
 


0 17
 


a-, .. .
 Concentrations given in percentages in feed,
 


^(concentration X weeks received)
 


2) (weeks receiving chemical)
 


Group designations were determined by time-weighted average concentrations,
 


11
 


c 
dose male and female rats were also approximately 6 weeks old; how­


ever, they were started on test 12 weeks later than the other groups.
 


The high and low concentrations utilized for both sexes for the first
 


week were 0.20 and 0.10 percent. The dietary concentrations of fena­


minosulf for all treated rats were reduced to 0.05 percent in week 2



and in week 8 the concentration administered to the high dose male
 


and female rats was increased to 0.10 percent. These concentrations
 


were maintained for the remainder of the fenaminosulf administration
 


period. Subsequent to chemical exposure was an untreated observation
 


period of up to 31 weeks.
 


As the female mouse group receiving an initial concentration of
 


0.20 percent had the lower time-weighted average dose at the end of
 


the bioassay, this female mouse group will be referred as the low
 


dose group throughout this report; the female mouse group receiving
 


an initial concentration of 0.10 percent, on the other hand, will be
 


referred to as the high dose group. For males the initial concentra­


tions utilized were 0.20 and 0.10 percent and the males receiving the
 


former concentration will be referred to as the high dose group while
 


those receiving the latter will be referred to as the low dose group.
 


At the time of inclusion in the study all mice were approximately 6



to 7 weeks old. High and low dose males and high dose females were
 


approximately 5 weeks older than their controls. The low dose fe­


males were 12 weeks younger than the other treated mice and the low
 


dose control females were 1 week younger than the low dose treated
 


12
 

females. The high and low dose male mice received initial dietary
 


concentrations of 0.20 and 0.10 percent, respectively. After 1 week
 


the concentrations were decreased to 0.10 and 0.05 percent for high
 


and low dose male mice, respectively. Six weeks later concentrations
 


were increased to original levels and these were maintained for the
 


remainder of the fenaminosulf administration period. Subsequently,
 


the male mice were observed for an untreated period of up to 17 weeks.
 


The high and low dose females received initial dietary concentrations
 


of 0.10 and 0.20 percent, respectively. After 1 week the concentra­


tion administered to both groups was decreased to 0.05 percent. Six
 


weeks later the concentration administered to the high dose groups
 


was increased to 0.10 percent. These concentrations were maintained
 


for the remainder of the fenaminosulf administration period. An
 


untreated observation period of up to 19 weeks followed.
 


G. Clinical and Histopathologic Examinations
 


Animals were weighed immediately prior to initiation of the
 


experiment. Body weights were recorded twice weekly for the first
 


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


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


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


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


bioassay and for three consecutive days each month thereafter. The
 


presence of tissue masses and lesions was determined by monthly
 


observation and palpation of each animal.
 


13
 

A necropsy was performed on each animal regardless of whether it
 


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


bioassay. The animals were euthanized by carbon dioxide inhalation,
 


and were immediately necropsied. The histopathologic examination con­


sisted 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, subcuta­


neous tissue, lungs and bronchi, trachea, bone marrow, spleen, lymph
 


nodes, thymus, heart, salivary gland, liver, gallbladder (mice), pan­


creas, 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, canni­


balized, or judged to be in such an advanced state of autolysis as
 


to preclude histopathologic interpretation. Thus, the number of ani­


mals 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.
 


14
 

H.	 Data Recording and Statistical Analyses
 


Pertinent data on this experiment have been recorded in an auto­


matic data processing system, the Carcinogenesis Bioassay Data System
 


(Linhart et al., 1974). The data elements include descriptive infor­


mation on the chemicals, animals, experimental design, clinical ob­


servations, 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 transcrip­


tion	 and for statistical review.
 


These data were analyzed using the statistical techniques de­


scribed in this section. Those analyses of the experimental results
 


that bear on the possibility of carcinogenicity are discussed in the
 


statistical narrative sections.
 


Probabilities of survival were estimated by the product-limit
 


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


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


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


missing; animals dying from natural causes were not statistically
 


censored. Statistical analyses for a possible dose-related effect
 


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


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


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.
 


15
 

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 denomi­


nators 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 necrop­


sied.
 


The purpose of the statistical analyses of tumor incidence is to
 


determine whether animals receiving the test chemical developed a sig­


nificantly higher proportion of tumors than did the control animals.
 


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


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


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


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


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


significance level of 0.05 may be made. The Bonferroni inequality
 


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


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


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


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


16
 

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 re­


lationship. This method also provides a two-tailed test of departure
 


from linear trend.
 


A time-adjusted analysis was applied when numerous early deaths
 


resulted from causes that were not associated with the formation of
 


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


tumor was observed were excluded by basing the statistical tests on
 


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


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


tumor was found, comparisons were based exclusively on animals that
 


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


found. Once this reduced set of data was obtained, the standard pro­


cedures 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
 


17
 

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


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


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


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


relationship. Significant departures from linearity (P < 0.05, two-
 

tailed test) were also noted.
 


The approximate 95 percent confidence interval for the relative
 


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


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


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


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


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


c



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


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


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


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


larger proportion in the treated group than in the control.
 


The lower and upper limits of the confidence interval of the
 


relative risk have been included in the tables of statistical analy­


ses. 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
 


18
 

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


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


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


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


the lower limit indicates the absence of a significant result while
 


the upper limit indicates that there is a theoretical possibility
 


of the induction of tumors by the test chemical which could not be
 


detected under the conditions of this test.
 


19
 

III. CHRONIC TESTING RESULTS: RATS
 


A. Body Weights and Clinical Observations
 


No distinct mean body weight depression was associated with com­


pound administration in either males or females (Figure 1). Although
 


the low dose male groups experienced high early mortality, the mean
 


body weight for this group was consistently higher than that for the
 


other male groups.
 


Two high dose females developed subcutaneous masses, one high
 


dose female had a cutaneous growth, and one control male developed a



crusted cutaneous lesion. One high dose female and one low dose male
 


exhibited discoloration of the eye and there was brown exudate from
 


the eyes of one low dose female.
 


B.	 Survival
 


The estimated probabilities of survival for male and female rats
 


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


Twenty-one of the original high dose male rats died in weeks 1



or 2 from toxic effects—at which point the dosage was lowered and
 


the original high dose group was renamed as the low dose group.
 


These 21 animals were excluded for test purposes; the Tarone test did
 


not indicate a positive association between dosage and mortality.
 


Five animals were sacrificed from the high dose treated group
 


and five from the control group in week 78. Adequate numbers of
 


males were at risk from late-developing tumors as 78 percent (39/50)
 


20
 

750­ -750 

CONTROL 

MALE RATS 

LOW DOSE 

600 — -600 

HIGH DOSE 

I- 450­

X 

o 

LU 

g 

§300­

CO 

150­

-450 

-300 

- 150 

I \ 

15 30 45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

750 750 

— 600 

^450 

-300 

-150 

15 120 

TIME ON TEST (WEEKS) 

FIGURE 1 

GROWTH CURVES FOR FENAMINOSULF CHRONIC STUDY RATS 

21 
PROBABILITY OF SURVIVAL 

PROBABILITY OF SURVI

o 

p o 

b bo •fe b> 

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high dose, 58 percent (29/50) low dose, and 64 percent (32/50) control
 


rats survived on test until the termination of the study.
 


For female rats, the Tarone test for association between dosage
 


and mortality was not significant. Five animals were sacrificed
 


from the high dose and five from the control group in week 78. With
 


78 percent (39/50) high dose, 82 percent (41/50) low dose and 72 per­


cent (36/50) control rats alive on test until the end of the study,
 


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


C. Pathology
 


Histopathologic findings on neoplasms in rats are summarized in
 


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


summarized in Appendix C (Tables Cl and C2).
 


A variety of neoplasms was observed with approximately equal fre­


quency in the treated and control rats. The most frequently observed
 


neoplasms in the male rats were interstitial-cell adenomas of the tes­


tis. In the female rats, the most commonly observed neoplasms were
 


adenomas of the pituitary gland, fibroadenomas of the mammary gland,
 


and endometrial stromal polyps of the uterus. A high spontaneous
 


incidence of these tumors is characteristic of aged Fischer 344 rats.
 


A neoplasm which was observed in the treated female rats was endome­


trial stromal sarcoma. This neoplasm was seen in 3/48 (6 percent)
 


low dose females and 1/47 (2 percent) high dose females but in none
 


of the control females.
 


23
 

There were instances in this study, as noted in the summary
 


tables, where neoplasms occurred only in treated animals, or with
 


increased frequency when compared to the control animals. The nature
 


and incidence of these lesions were similar to those known to occur
 


spontaneously in aged Fischer 344 rats.
 


A high incidence of necrosis and mineralization of the tubules of
 


the renal papilla was present in the treated rats. These lesions were
 


not observed in control rats. Mineralization of tubules was present
 


in 21/41 (51 percent) low dose and 32/48 (67 percent) high dose male
 


rats and 34/48 (71 percent) low dose and 12/49 (24 percent) high dose
 


female rats. The severity of the papillary necrosis and mineraliza­


tion was quite variable and was superimposed on chronic renal disease
 


(nephrosis, nephropathy) commonly seen in aged Fischer 344 rats.
 


Several other nonneoplastic lesions commonly seen in aged Fischer 344
 


rats were observed with approximately equal frequency in the treated
 


and control animals.
 


Under the conditions of this study, the administration of fena­


minosulf did not appear to induce neoplastic lesions in Fischer 344
 


rats. Although endometrial stromal sarcomas were present only in
 


treated female rats, the low incidence observed in this study does
 


not provide conclusive evidence that these neoplasms were induced by
 


the compound. The concentrations of the compound administered did
 


have a toxic effect on the kidney, producing tubular necrosis and
 


mineralization of the renal papilla.
 


24
 

D. Statistical Analyses of Results
 


The results of the statistical analyses of tumor incidence in
 


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


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


tumors were observed in at least one of the control or fenaminosulf­


dosed groups and where such tumors were observed in at least 5 percent
 


of the group. Because of high early mortality noted in rats of both
 


sexes, the analyses for males were based on those rats surviving at
 


least 52 weeks.
 


In male rats the Fisher exact test indicated a significantly
 


(P = 0.021) higher incidence of interstitial-cell tumors of the
 


testis in the low dose treated group than in the control. The high
 


dose comparison and the Cochran-Armitage test, however, were not
 


significant.
 


For both male and female rats the possibility of a negative
 


association between chemical administration and the incidence of
 


leukemia or of malignant lymphomas was observed. For females,
 


however, none of the Fisher exact tests were significant under the
 


Bonferroni criterion.
 


No other statistical tests for any site indicated a significant
 


association between compound administration and incidence. Based
 


upon these results there was no convincing statistical evidence of
 


the carcinogenicity of fenaminosulf in rats.
 


25
 

TABLE 3



ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 


SPECIFIC SITES IN MALE RATS TREATED WITH FENAMINOSULF
 


SURVIVING AT LEAST 52 WEEKSa



TOPOGRAPHY: MORPHOLOGY
 


Skin and Subcutaneous Tissue: Fibroma
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


Hematopoietic System: Leukemia or
 


Malignant Lymphoma
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


Pituitary: Adenoma NOS, Chromophobe
 


Adenoma, or Acidophil Adenoma"
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


CONTROL
 


2/50(0.04)



N.S.
 


86
 


10/50(0.20)



P = 0.002(N)
 


78
 


7/45(0.16)



N.S.
 


LOW
 


DOSE
 


2/29(0.07)



N.S.
 


1.724
 


0.130
 


22.468
 


105
 


1/29(0.03)



P = 0.037(N)
 


0.172
 


0.004
 


1.109
 


105
 


7/26(0.27)



N.S.
 


1.731
 


0.577
 


5.029
 


HIGH
 


DOSE
 


3/49(0.06)



N.S.
 


1.531
 


0.183
 


17.671
 


108
 


1/49(0.02)



P - 0.004(N)
 


0.102
 


0.002
 


0.675
 


108
 


9/42(0.21)



N.S.
 


1.378
 


0.502
 


3.955
 


Weeks to First Observed Tumor 78 105
 
 78
 

TOPOGRAPHY : MORPHOLOGY
 


Adrenal: Pheochromocytoma
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


Thyroid: C-Cell Carcinoma
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


Thyroid: C-Cell Carcinoma or C-Cell
 


Adenoma^
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


TABLE 3 (CONTINUED) 

CONTROL
 


3/50(0.06)



N.S.
 


78
 


2/37(0.05)



N.S.
 


109
 


3/37(0.08)



N.S.
 


109
 


LOW
 


DOSE
 


6/29(0.21)



N.S.
 


3.448
 


0.796
 


19.588
 


105
 


1/26(0.04)



N.S.
 


0.712
 


0.012
 


12.845
 


105
 


5/26(0.19)



N.S.
 


2.372
 


0.505
 


13.893
 


105
 


HIGH
 


DOSE
 


3/47(0.06)



N.S.
 


1.064
 


0.149
 


7.571
 


103
 


2/44(0.05)



N.S.
 


0.841
 


0.064
 


11.135
 


108
 


3/44(0.07)



N.S.
 


0.841
 


0.120
 


5.944
 


108
 

TABLE 3 (CONCLUDED) 

LOW HIGH 

TOPOGRAPHY: MORPHOLOGY CONTROL DOSE DOSE 

Pancreatic Islets: Islet-Cell Carcinoma 

or Islet-Cell Adenoma"3 1/47(0.22) 3/29(0.10) 2/47(0.04) 

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

Relative Risk (Control) 4.862 2.000 

Lower Limit 0.411 0.108 

Upper Limit 245.698 115.483 

Weeks to First Observed Tumor 110 105 108 

Testis: Interstitial-Cell Tumor 42/50(0.84) 29/29(1.00) 40/47(0.85) 


00 P Values0 N.S. P = 0.021 N.S. 


Departure from Linear Trend P = 0.025 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

• 1.190 

1.007 

1.190 

1.013 

0.842 

1.208 

Weeks to First Observed Tumor 78 105 100 

Treated groups received time-weighted average doses of 3.05 or 0.10 percent in feed.
 


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


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


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


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


given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not signifi­


cant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designa­


tion (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.
 


e

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


group when P < 0.05.
 

___ 

TABLE 4



ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 


SPECIFIC SITES IN FEMALE RATS TREATED WITH FENAMINOSULF*
 


TOPOGRAPHY: MORPHOLOGY
 


Hematopoietic System: Leukemia or
 


Malignant Lymphoma
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


to
 


VO
 


Pituitary: Adenoma NOS, Chromophobe
 


Adenoma, or Acidophil Adenoma"
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


Adrenal: Pheochromocytoma
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


CONTROL
 


7/49(0.14)



P - O.OIO(N)
 


96
 


17/39(0.44)



N.S.
 


78
 


3/49(0.06)



N.S.
 


110
 


LOW
 


DOSE
 


1/48(0.02)



P = 0.032(N)
 


0.146
 


0.003
 


1.072
 


91
 


18/40(0.45)



N.S.
 


1.032
 


0.598
 


1.791
 


84
 


2/46(0.04)



N.S.
 


0.710
 


0.062
 


5.914
 


63
 


HIGH
 


DOSE
 


1/50(0.02)



P = 0.028(N)
 


0.140
 


0.003
 


1.030
 


109
 


17/41(0.41)



N.S.
 


0.951
 


0.542
 


1.678
 


101
 


2/46(0.04)



N.S.
 


0.710
 


0.062
 


5.914
 


70
 

___ 

TOPOGRAPHY: MORPHOLOGY
 


Thyroid: C-Cell Carcinoma
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


Thyroid: C-Cell Carcinoma or C-Cell
 


Adenoma"
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


Mammary Gland: Fibroadenoma
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


TABLE 4 (CONTINUED) 

CONTROL
 


2/45(0.04)



N.S.
 


110
 


2/45(0.04)



N.S.
 


110
 


12/49(0.24)



N.S.
 


103
 


LOW
 


DOSE
 


2/46(0.04)



N.S.
 


0.978
 


0.074
 


12.993
 


105
 


2/46(0.04)



N.S.
 


0.978
 


0.074
 


12.993
 


105
 


8/48(0.17)



N.S.
 


0.681
 


0.265
 


1.642
 


105
 


HIGH
 


DOSE
 


3/49(0.06)



N.S.
 


1.378
 


0.166
 


15.892
 


109
 


7/49(0.14)



N.S.
 


3.214
 


0.654
 


30.445
 


91
 


8/50(0.16)



N.S.
 


0.653
 


0.254
 


1.581
 


70 
TABLE 4 (CONCLUDED)
 

LOW HIGH 

TOPOGRAPHY: MORPHOLOGY CONTROL DOSE DOSE 

Uterus: Endometrial Stromal Polyp 5/46(0.11) 7/48(0.15) 4/47(0.09) 


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


Relative Risk (Control) 

Lower Limit 

Upper Limit 

1.342 

0.396 

4.998 

0.783 

0.165 

3.409 

Weeks to First Observed Tumor 110 105 109 

Uterus: Endometrial Stromal Sarcoma 0/46(0.00) 3/48(0.06) 1/47(0.02) 


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


Relative Risk (Control) _— Infinite Infinite 


Lower Limit 0.578 0.053 


Upper Limit Infinite Infinite 


Weeks to First Observed Tumor 91 91 


a

Treated groups received time-weighted average doses of 0.05 or 0.10 percent in feed.
 


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


C

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


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


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


given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not signifi­


cant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designa­


tion (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.
 

To provide additional insight into the possible carcinogenicity
 


of this compound, 95 percent confidence intervals on the relative
 


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


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


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


of statistically significant results. It should also be noted that
 


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


indicating the theoretical possibility of tumor induction in rats by
 


fenaminosulf that could not be established under the conditions of
 


this test.
 


32
 

IV. CHRONIC TESTING RESULTS: MICE
 


A. Body Weights and Clinical Observations
 


There was no significant mean body weight depression in treated
 


male mice when compared to controls until approximately week 32, at
 


which time the mean body weight of the treated male mice was consis­


tently lower than that of control mice (Figure 3). Slight mean body
 


weight depression was noted when low dose female mice were compared
 


to their controls. Fluctuations in the growth curve may be due to
 


mortality; as the size of the group diminishes, the mean body weight
 


may be subject to wide variations.
 


No clinical abnormalities were observed in treated or control
 


mice of either sex.
 


B.	 Survival
 


The estimated probabilities of survival for male and female mice
 


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


Nineteen of the 50 high dose male mice died in weeks 1 or 2
 


from toxic reactions. After excluding these mice, the Tarone test
 


still indicated a significant positive association between dose and
 


mortality. Twelve high dose male mice died in weeks 42 and 43, nine
 


of which were autolyzed. With only 13 of the high dose male mice
 


surviving on test beyond week 52, five of which were sacrificed in
 


week 78, inadequate numbers of high dose male mice were at risk from
 


late-developing tumors. Five control male mice were sacrificed in
 


week 79. Survival was adequate in the low dose and control groups
 


33
 

50- -50 

40 — -40 

C/3 

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O 

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s 

>20 -20 ­

o 

CO 

CONTROL 

10— -10 

LOW DOSE 

HIGH DOSE MALE MICE 

I I I 

15 30 45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

50 

HIGH DOSE CONTROL 

-'—'—'- LOW DOSE CONTROL 

LOW DOSE 

_ HIGH DOSE 

T 

60 75 105 120 

TIME ON TEST (WEEKS) 

FIGURES 

GROWTH CURVES FOR FENAMINOSULF CHRONIC STUDY MICE 

34 
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with 78 percent (39/50) of the low dose and 84 percent (42/50) of the
 


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For female mice the Cox tests also showed significant positive
 


differences between each of the dosed groups and its respective con­


trol; for the low dose those females that died in weeks 1 and 2 were
 


excluded for this Cox test. The departure from linear trend was also
 


significant, primarily because survival was poorer in the low dose
 


group than in the high dose group. Five females from the high dose
 


treated group, five from the low dose control, and five from the high
 


dose control group were sacrificed in week 79. Adequate numbers of
 


female mice were at risk from late-developing tumors with 64 percent
 


(32/50) of the high dose, 72 percent (36/50) of the low dose control,
 


and 80 percent (40/50) of the high dose control mice alive on test
 


until the end of the study. In the low dose group, 18/21 of those
 


mice surviving at least 52 weeks were alive on test until the end
 


of the study. Since no tumors were observed in females that died
 


before week 78, there was no evidence that early mortality was tumor-
 

related.
 


C. Pathology
 


Histopathologic findings on neoplasms in mice are summarized in
 


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


summarized in Appendix D (Tables Dl and D2).
 


A variety of neoplasms occurred with approximately equal fre­


quency in the treated and control mice. Occasionally, as shown in
 


36
 

the summary tables, neoplasms occurred only in the treated mice or
 


with an increased frequency when compared with the control animals.
 


The nature and incidence of these neoplasms were similar to sponta­


neously occurring neoplasms in B6C3F1 mice. An unusual tumor was a
 


teratoma of the ovary in 1/37 (3 percent) of the high dose mice.
 


The treated mice had a variety of nonneoplastic lesions. The
 


incidence and severity of the lesions were approximately equal in
 


the treated and control groups, with the exception of 13/16 low dose
 


female mice that died in weeks 32 and 33 having either kidney nephro­


pathy, kidney tubule mineralization, or both.
 


The results of this microscopic examination indicate that the
 


administration of fenaminosulf was not carcinogenic to B6C3F1 mice.
 


D. Statistical Analyses of Results
 


The results of the statistical analyses of tumor incidence in
 


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


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


tumors were observed in at least one of the control or fenaminosulf­


dosed groups and where such tumors were observed in at least 5 per­


cent of the group. Because of high early mortality noted in mice
 


of both sexes, these analyses were based on those mice surviving at
 


least 52 weeks. No Cochran-Armitage tests were used in the analyses
 


of the female mice because the high dose group and its control were
 


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


37
 

___ 

___ 

TABLE 5



ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 


SPECIFIC SITES IN MALE MICE TREATED WITH FENAMINOSULF
 


SURVIVING AT LEAST 52 WEEKS3



HIGH
 


DOSE
 


0/13(0.00)



N.S.
 


0.000
 


0.000
 


5.581
 


1/13(0.08)



N.S.
 


0.516
 


0.012
 


3.391
 


0/13(0.00)



N.S.
 


0.000
 


0.000
 


66.474
 


TOPOGRAPHY: MORPHOLOGY
 


Lung: Alveolar/Bronchiolar Carcinoma
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


oo
 


Lung: Alveolar/Bronchiolar Carcinoma or
 


Alveolar/Bronchiolar Adenoma^
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


Hematopoietic System: Leukemia or
 


Malignant Lymphoma"
 


P Values0



e



Departure from Linear Trend
 


Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


CONTROL
 


3/47(0.06)



N.S.
 


97
 


7/47(0.15)



N.S.
 


97
 


1/49(0.02)



N.S.
 


P = 0.009
 


97
 


LOW
 


DOSE
 


3/42(0.07)



N.S.
 


1.119
 


0.158
 


7.921
 


90
 


7/42(0.17)



N.S.
 


1.119
 


0.365
 


3.421
 


90
 


7/43(0.16)



P = 0.019
 


7.977
 


1.088
 


349.807
 


87
 


95 
TABLE 5 (CONCLUDED) 

LOW HIGH 

TOPOGRAPHY: MORPHOLOGY CONTROL DOSE DOSE 

Liver: Hepatocellular Carcinoma 15/49(0.31) 7/43(0.16) 2/13(0.15) 


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


Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.532 

0.202 

1.243 

0.503 

0.060 

1.752 

Weeks to First Observed Tumor 94 88 95 

Liver: Hepatocellular Carcinoma or 

Hepatocellular Adenoma^ 15/49(0.31) 9/43(0.21) 2/13(0.15) 

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

CO 

vo Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.684 

0.294 

1.485 

0.503 

0.060 

1.752 

Weeks to First Observed Tumor 94 88 95 

ireated groups received time-weighted doses of 0.10 or 0.19 percent 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 signifi­


cant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designa­


tion (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.
 


e

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


group when P < 0.05.
 

TABLE 6



ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 


SPECIFIC SITES IN FEMALE MICE TREATED WITH FENAMINOSULF
 


SURVIVING AT LEAST 52 WEEKS3



LOW DOSE HIGH DOSE LOW HIGH 


TOPOGRAPHY: MORPHOLOGY CONTROL CONTROL DOSE DOSE 


Lung: Alveolar/Bronchiolar Carcinoma 3/45(0.07) 3/50(0.06) 0/20(0.00) 1/39(0.03) 

P Values0 N.S. N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

___ 

0.000 

0.000 

3.598 

0.427 

0.008 

5.060 

Weeks to First Observed Tumor 97 79 93 

Lung: Alveolar/Bronchiolar Carcinoma 

or Alveolar/Bronchiolar Adenoma^ 

P Values0 

4/45(0.09) ___ 4/50(0.08) 3/20(0.15) 

N.S. 

4/39(0.10) 

N.S. 

Relative Risk (Control) 

Lower Limit 

1.687 

0.265 

1.282 

0.253 

Upper Limit 8.837 6.438 

Weeks to First Observed Tumor 97 79 93 93 

Hematopoietic System:

Malignant Lymphoma'3 

P Values0 

 Leukemia or 

6/46(0.13) 

^^^ 

6/50(0.12) ___ 3/20(0.15) 

N.S. 

5/39(0.13) 

N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

_.__ 1.150 

0.200 

4.701 

1.068 

0.277 

3.872 

Weeks to First Observed Tumor 68 98 93 91 
___ 

TABLE 6 (CONTINUED) 

TOPOGRAPHY : MORPHOLOGY
 


t



Liver: Hepatocellular Carcinoma
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


Liver: Hepatocellular Carcinoma or
 


Hepatocellular Adenoma^5



P Values0



j



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


Pituitary: Adenoma NOS
 


P Values0



Relative Risk (Control)
 


Lower Limit
 


Upper Limit
 


Weeks to First Observed Tumor
 


LOW DOSE
 


CONTROL
 


0/45(0.00)



__—



__._
 


0/45(0.00)



1/32(0.03)



80
 


HIGH DOSE
 


CONTROL
 


2/49(0.04)



98
 


2/49(0.04)



98
 


0/42(0.00)

 ___ •



__—



LOW
 


DOSE
 


2/19(0.11)



N.S.
 


Infinite
 


0.706
 


Infinite
 


97
 


4/19(0.21)



P = 0.006
 


Infinite
 


2.228
 


Infinite
 


93
 


3/16(0.19)



N.S.
 


6.000
 


0.523
 


291.426
 


97
 


HIGH
 


DOSE
 


3/37(0.08)



N.S.
 


1.986
 


0.239
 


22.690
 


78
 


3/37(0.08)



N.S.
 


1.986
 


0.239
 


22.690
 


78
 


3/32(0.09)



N.S.
 


Infinite
 


0.796
 


Infinite
 


95
 

TABLE 6 (CONCLUDED)
 


Treated groups received time-weighted average doses of 0.05 or 0.10 percent in feed.
 


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


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


control group is given beneath the incidence of tumors in the treated group when P < 0.05;
 


otherwise, not significant (N.S.) is indicated. A negative designation (N) indicates a lower
 


incidence in the treated group than in the control group.
 


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


.p­
 N3
 

In male mice the incidence of leukemia or malignant lymphoma was
 


increased in the low dose treated group. The Fisher exact test showed
 


a significantly (P = 0.019) greater incidence in the low dose than in
 


the control group. However, in historical data compiled by this labo­


ratory for the NCI Carcinogenesis Testing Program 29/275 (11 percent)
 


of the untreated male B6C3F1 mice had a malignant lymphoma or leukemia,
 


compared to the 7/43 (16 percent) observed in the low dose group.
 


In female mice the combined incidence of hepatocellular adenomas
 


or hepatocellular carcinomas was increased in the treated groups com­


pared to their respective controls. The results of the Fisher exact
 


test comparing the low dose treated group to its control was signifi­


cant (P = 0.006). This was not supported, however, by significant
 


high dose Fisher exact test results.
 


To provide additional insight into the possible carcinogenicity
 


of this compound, 95 percent confidence intervals on the relative
 


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


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


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


of statistically significant results. It should also be noted that
 


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


indicating the theoretical possibility of tumor induction in mice by
 


fenaminosulf that could not be established under the conditions of
 


this test.
 


43
 

V. DISCUSSION
 


It is recognized that the results reported in this study are not
 


for pure or technical-grade fenaminosulf, but for the commercially
 


available formulated product containing fenaminosulf.
 


There was no significant association for female rats between
 


fenaminosulf dosage and mortality; this was also true for male rats
 


if the 21 males that died in the first two weeks of the bioassay are
 


excluded from consideration. For both male and female mice there was
 


a significant positive association between dosage and mortality. In
 


all groups of both species, except for high dose male and low dose
 


female mice, adequate numbers of animals survived sufficiently long
 


to be at risk from late-developing tumors.
 


No convincing statistical evidence was provided for a significant
 


positive association between compound administration and the incidence
 


of any tumor in male or female rats. Endometrial stromal sarcomas
 


were observed only in treated female rats (i.e., 3/48 [6 percent] low
 


dose and 1/47 [2 percent] high dose). These incidences did not, how­


ever, prove to be statistically significant when compared to controls.
 


There were increased incidences of necrosis and mineralization
 


of the renal papillary tubules in treated rats and mice when compared
 


to controls. The severity of these lesions was variable and they
 


were observed in addition to the chronic renal disease often seen in
 


aging rodents.
 


44
 

When those female mice having either hepatocellular carcinomas
 


or hepatocellular adenomas were combined and the resulting tumor
 


incidences statistically analyzed, the low dose group had an inci­


dence significantly higher than that of the low dose control group.
 


This finding was not, however, supported by similar results for the
 


high dose females. In addition, the historical incidence for this
 


combination of tumors in control female mice at Mason Research
 


Institute during the NCI Carcinogenesis Testing Program was 19/275
 


(7 percent), in contrast to the 0/46 observed in the low dose controls
 


during this chronic study. The importance of the significant Fisher
 


exact comparison for hepatocellular neoplasms in low dose female
 


mice, therefore, appears questionable and is considered as insuffi­


cient evidence of carcinogenicity.
 


When those male mice having leukemia or malignant lymphoma were
 


combined and the resulting tumor incidences statistically analyzed,
 


the Fisher exact test indicated a significantly greater incidence of
 


these neoplasms in the low dose group when compared with controls.
 


However, the incidence of these neoplasms in the historical control
 


untreated male B6C3F1 mice compiled by this laboratory for the Carci­


nogenesis Testing Program is 29/275 (11 percent) as compared to 7/43
 


(16 percent) observed in the low dose male mice in this bioassay, not
 


a convincing difference.
 


No unusual tumors were observed among mice of either sex and
 


no convincing statistical evidence was provided for a significant
 


45
 

positive association between compound administration and the incidence
 


of any tumor in either sex.
 


Contradictory carcinogenicity data have been obtained in two
 


other studies with fenaminosulf. An unspecified number of Sprague-
 

Dawley rats fed fenaminosulf at a concentration of 1000 mg/kg of diet
 


developed "hepatomas resembling those produced by dimethylaminoazoben­


zene" after 12 months (Herrmann and DuBois, 1949); however, no liver
 


tumors were found in 2 groups of 20 Holtzmann rats 15 months after
 


administration of a diet containing 1.35 or 4.0 millimoles of fenami­


nosulf per kg of feed (339.12 or 1004.8 mg/kg) (Miller et al., 1957).
 


Under the conditions of this bioassay, dietary administration of
 


formulated fenaminosulf was not carcinogenic in either Fischer 344
 


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.
 


Carter, L.J., J.G. Mitchell, and D.J. Wilson, EPA Compendium of Regis­


tered Pesticides, Volume II: Fungicides and Nematacides. Tech­


nical Service Division, Office of Pesticides Programs, U.S.
 


Environmental Protection Agency, Washington, D.C., 1973.
 


Chemical Abstracts Service. The Chemical Abstracts Service (CAS)
 


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


Chemical Society, Washington, D.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.
 


Farm Chemicals Handbook. Mesiter Publishing Company, Willoughby,
 


Ohio, 1976.
 


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.
 


Herrmann, R.G. and K.P. DuBois, "Studies on the Toxicity and Pharma­


cological Action of p-Dimethylaminobenzenediaso Sodium Sulfonate
 


(DAS)." Journal of Pharmacology and Experimental Therapeutics
 


_95j262-271, 1949.
 


International Agency for Research on Cancer. IARC Monographs on the
 


Evaluation of Carcinogenic Risk of Chemicals to Man, Volume 8.
 


IARC, Lyon, France, 1975.
 


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.
 


47
 

Miller, J.A., E.G. Miller, and G.C. Finger, "Further Studies on the
 


Carcinogenicity of Dyes Related to 4-Dimethylaminoazobenzene.
 


The Requirement for an Unsubstituted 2-Position." Cancer Re­


search 17:387-398, 1957.
 


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


Co., New York, 1966.
 


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


Kaufman, "Respiratory Tract Carcinogenesis in Hamsters Induced
 


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


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


Stanford Research Institute, 1977 Directory of Chemical Producers,
 


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


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


jj^:679-682, 1975.
 


Terayama, H., "Aminoazo Carcinogenesis—Methods and Biochemical Prob­


lems." Methods in Cancer Research 1:399-449, 1967.
 


48
 

Review of the Bioassay of Formulated Fenaminosulf*
 


for Carcinogenicity
 


by the Data Evaluation/Risk Assessment Subgroup
 


of the Clearinghouse on Environmental Carcinogens
 


April 26, 1978
 


The Clearinghouse on Environmental Carcinogens was
 


established in May, 1976, in compliance with DHEW Committee
 


Regulations and the Provisions of the Federal Advisory
 


Committee Act. The purpose of the Clearinghouse is to
 


advise the Director of the National Cancer Institute (NCI)
 


on its bioassay program to identify and to evaluate chemical
 


carcinogens in the environment to which humans may be
 


exposed. The members of the Clearinghouse have been drawn
 


from academla, industry, organized labor, public interest
 


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


research organizations. Members have been selected on the
 


basis of their experience in carcinogenesis or related
 


fields and, collectively, provide expertise in chemistry,
 
 biochemistry, biostatistics, toxicology, pathology, and
 


epidemiology. Representatives of various Governmental
 


agencies participate as ad hoc members. The Data Evaluation/
 


Risk Assessment Subgroup of the Clearinghouse is charged
 


with the responsibility of providing a peer review of
 


reports prepared on NCI-sponsored bioassays of chemicals
 


studied for carcinogenicity. It is in this context that the
 


below critique is given on the bioassay of Formulated
 


Fenaminosulf for carcinogenicity.
 


The primary reviewer said that the compound was not
 


carcinogenic in rats or mice under the conditions of test.
 
 He noted that only 35% of the tested compound was estimated
 


to be Fenaminosulf, the remainder being clay, silica,
 
 sodium naphthalene sulfonate, and sodium ligno-sulfate.
 
 Despite certain experimental shortcomings, he said that the
 


study was adequate to conclude that Formulated Fenaminosulf
 


was not carcinogenic under the conditions of test.
 


Although the secondary reviewer agreed that the study
 


was "essentially negative," he pointed out the elevated
 


incidence of hepatocellular carcinomas in low dose treated
 


female mice and hematopoietic system tumors in low dose
 


treated male mice. The meaningfulness of these increases
 


was obscured by excessive early mortality due to toxicity.
 
 If Formulated Fenaminosulf is still a major environmental
 


hazard, he suggested that it be retested, at least in mice.
 


49
 

A motion was made that the report on the bioassay of
 


Formulated Fenaminosulf be accepted as written. The motion
 


was seconded and approved unanimously.
 


Members present were:
 


Michael Shimkin (Acting Chairman), University of California
 


at San Diego
 


Joseph Highland, Environmental Defense Fund
 


George Roush, Jr., Monsanto Company
 


Louise Strong, University of Texas Health Sciences Center
 


John Weisburger, American Health Foundation
 


(David Clayson, Eppley Institute for Cancer Research,
 
 submitted a written review)
 


*	 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.
 


i^U.S. GOVERNMEN T PRINTIN G OFFICE ; 1978-260-899/3205
 


50
 

APPENDIX A



SUMMARY OF THE INCIDENCE OF NEOPLASMS
 


IN RATS TREATED WITH FENAMINOSULF
 


TABLE A1 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH FEN AMINOSULF 

c:OSTROL (UNTR)LOU DOSE HIGH DOSE
 


01-0160 01-R151 01-0140
 


ANIMALS INITIALLY IN STUDY 5050 50
 


ANIMALS NECROPSIED 50 43 1)9
 


ANIMALS EXAMINED HISTOPATHOLOGICALLY ** 50 41 48
 


INTEGUMENTARY SYSTEM
 


*SKIN (50)(43) (49)
 


FIBEOMA 1 (2%)



*IBROSARCCMA 1 (2%)
 


*SOBCOT TISSUE (50)(43) (49)
 


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


FIBROMA 1(2X) 2 (5%) 3 (6%)

 FIBHOSARCOMA 1 (2<S)
 


LEIOHYOSARCOHA 1 (2«)
 


FIBROADENCMA 1 (2%)
 


RESPIRATORY SYSTEM 

»LUNG 

ALVEOLAR/BPONCHIOLJR CARCINOMA 

C-CELL CARCINOMA, METASTATIC 

(49) 

1 (2%) 

 (41) 

1 (2*) 

(48) 

1 (2%) 

HEMATOPOIETIC SYSTEM
 


*MULTIPLE ORGANS (50)(43) (49)
 


LEUKEMIA, NOS 1(2X)
 


MYELOMONOCYTIC LEUKEMIA 9 (18%)
 


•SPLEEN	 	 (50) (41) (48)
 


MYELOMONOCYTIC LEUKEMIA 1 (2!5) 1 (2«)
 


#THYMUS (24) (23) (34)
 


C-CELL CARCINOMA, METASTATIC 1 <4X)
 


CIRCULATORY SYSTEM
 


tHEAHT (48) (40) (48) 

____SARCQMAi_NOSi_gETASTATIC 

* NUMBER O F ANIMAL S WIT H TISSUEEXAMINE D MICROSCOPICALL Y 

* NUMBER OF ANIMAL S NECROPSIE D 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

A-3 
TABLE A1 (CONTINUED)
 


CONTROL (UNTH) LOW DOSE HIGH DOSE
 


01-0160 01-R150 01-0 140
 


DIGESTIVE SYSTEM
 


•LIVER	 	 (49) (41) (48)
 


NEOPLASTIC NODULE 1 (2X)
 


•JEJUNUM	 	 (49) (36) (47)
 


SARCOMA, NOS 1 (3X)
 


URINARY SYSTEM
 


NONE
 


ENDOCKINE SYSTEM
 


•PITUITARY	 	 (45) (30) (42)
 


ADENOMA, NOS 5 (11X) t (13X) 5 (12X)
 


CHROHOPHOBE ADENOMA 2 (4%) 3 (10X) 2 (5X)
 


ACIDOPHIL ADENOMA 2 (5X)
 


•ADRENAL	 	 (50) (41) (47)
 


CORTICAL ADENOMA 1 (2X) 1 <2X)
 


PHEOCHROMOCYTOHA 3 <6X) 6 (15X) 3 (6X)
 


•THYROID	 	 (37) (31) (44)
 


FOLLICULAR-CELL CARCINOMA 1 (3X) 1 (2X)
 


C-CELL ADENOMA 1 (3X) U (13X) 1 (2X)
 


C-CELL CARCINOMA 2 <5X) 1 (3X) 2 (5X)
 


•PARATHYROID	 	 (20) (17) (24)
 


ADENOMA, NOS 1 (6X)
 


•PANCREATIC	 ISLETS (47) (40) (47)
 


ISLET-CELL ADENOMA 1 (2X) 2 (5X) 2 (IX)
 


ISLET-CELL CARCINOMA 1 (3X)
 


REPRODUCTIVE SYSTEM
 


*PREP'!TIAL GLAND (50) (43) (49)
 


CARCINOMA, NOS 2 (»X)
 


•TESTIS	 	 (50) (41) (47)
 


INTERSTITIAL-CELL TUMOH <J2 _[8«Xl_ 29 _[71X)_ 10 J85X).



» NUMBER OF ANIMAL S WITH TISSUE EXAMINED MICROSCOPICALLY
 


* NUMBER OF ANIMALS NECROPSIED
 


A-4
 

NERVOUS SYSTEM
 


ICEREBRAL CORTEX
 

GLIOMA, NOS


SPECIAL SENSE ORGANS
 


*ZYNBAL'S GLAND
 

SEBACEOUS ADENOCARCINOMA
 

MDSCULOSKELETAL SYSTEM
 


NONE
 


BODY CAVITIES
 


*BOD!( CAVITIES
 

MESOTHELIOMA, NOS


ALL OTHER SYSTEMS
 


NONE
 


ANIHAL DISPOSITION SUMMARY
 


ANIMALS INITIALLY IN STUDY
 

NATURAL DEATHS
 

MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 


TERMINAL SACRIFICE
 

ANIMAL MISSING
 


I_rMCLODES_AUTQLIZED_AfiIH»LS
 


TABLE A1 (CONTINUED)
 


CONTROL(UNTR)
 

01-0160


 (50)


 1 (2X)
 


(50)


 (50)


 50


 5


 8


 5


 32


 LOW DOSE HIGH DOSE 

 01-R150 01-011(0 

 (39) (47) 

 (U3)(«9) 

1 (2%) 

 (1*3)(U9) 

1 (2%) 

 50 50 

 21 3 

3 

5 

 29 39 

I NUMBER OP ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 


* NUMBER OF ANIMALS NECROPSIED
 


A-5
 

TABLE Al (CONCLUDED)
 


TUMOR SUMMARY
 


TOTAL ANIMALS WITH PRIMARY TUMORS*
 TOTAL PRIMARY TUMORS


TOTAL ANIMALS WITH BENIGN TUMORS
 TOTAL BENIGN TUMORS


TOTAL ANIMALS WITH MALIGNANT TUMORS


TOTAL MALIGNANT TUMORS


TOTAL ANIMALS WITH SECONDARY TUMORSf


TOTAL SECONDARY TUMORS


TOTAL ANIMALS WITH TUMORS UNCERTAIN­
 BENIGN OP MALIGNANT
 TOTAL UNCERTAIN TUMORS


TOTAL ANIMALS WITH TUMORS UNCERTAIN­


PEIMARY OR METASTATIC
 


TOTAL UNCERTAIN TUMORS
 


CONTROL(UNTR) 


01-0160 


 49
 76


 16
 56


 17


 20


 1


 1


LOW DOSE HIGH DOSE
 

01-B150 01-01UO
 

 29 «2
 60 66
 

 29 11
 52 60
 

6 6


6 6


1


2


1


2


* PRIMARY TU.10BS: ALL TUMORS EXCEPT SECONDARY TUHORS
 


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


A-6
 

TABLE A2

 

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

ANIMAL S INITIALL Y IN STUDY 

ANIMAL S HISSING 

ANIMALS NECBOPSIED 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY* * 

INTEGUMENTAR Y SYSTEM 

*SUBCUT TISSUE 

FIBROHA 

RESPIRATOR Y SYSTEM 

• LUNG
 

SQUAMOUS CELL CARCINOMA
 

ALVEOLAR/BRONCHIOLAS ADENOMA
 

HEMATOPOIETIC SYSTEM
 


*(1ULTIPLE ORGANS
 

MALIGNANT 1YMPHOMA, NOS
 

LEUKEMIA,NOS
 

MYELOMONOCYTIC LEUKEMIA
 

tSPLEFN
 

MYELOHONOCYTIC LEUKEMIA
 

CIRCULATORY SYSTEM
 


NONE
 


DIGESTIVE SYSTEM
 


*LIVER
 

HEPATOCELLULAR CARCINOMA
 

*COLON
 

ADENOMATOUS POLYP, NOS
 

URINARY SYSTEM
 


NONE.
 


CONTROL(UNTR) LOW DOSE HIG H DOSE 

02-0160 02-R150 02-011(0 

 50 50 50 

1 

 19 US 50 

 49 U8 50 

 («9) (US) (50) 

2 (14%) 1 (2%) 

 (19) (US) (1(9) 

1 (2%) 

1 (2%) 

 (K9) (US) (50) 

1 (2X) 

1 (2%) 

6 (12*) 

 (K7) (US) (H9) 

1 (2%) 

 (KB) (US) (50) 

1 (2%) 1 (2«) 

 (U9) (U5) (U2) 

1 (2Jt) 

* NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIE D 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

A-7 
ENDOCRINE SYSTE M 

*PITUITARY 

NEOPLASM , NOS 

ADENOMA , NOS 

CHROMOPHOBI ADENOM A 

ACIDOPHI L ADENOH A 

• ADRENA L 

CORTICAL CARCINOM A 

PHEOCHROHOCYTOM A 

#THYROID 

C-CELL ADENOH A 

C-CELL CARCINOMA 

REPRODUCTIV E SYSTE M 

*MAMMAR Y GLAN D 

ADENOCA8CINOMA , NOS 

PAPILLAR Y ADENOCA8CINOM A 

FIBBOADENCM A 

*CLITORAL GLAN D 

ADENOMA , NO S 

tUTERUS 

NEOPLASM , NOS 

ENDOMETRIA L STROMA L POLYP 

ENDOMETRIA L STROMAL SARCOM A 

OOVAR Y 

GRANULOSA-CEL L TUMOR 

NERVOU S SYSTE M 

*B8AIN 

ASTROCYTOM A 

SPECIAL SENS E ORGAN S 

•ZYMBAL'S GLAND
 


____ CERUnlNOUS_C&RCINOMA
 


TABLE A2 (CONTINUED) 

CONTROL (DNTR) 

02-0160 

(39) 

15 (38X) 

2 (5%) 

(19) 

3 (6X) 

(15) 

2 (1%) 

(19) 

12 (21X) 

(19) 

1 (2X) 

(16) 

5 (11X) 

(17) 

(19) 

1 <2X ) 

(49) 

LOW DOSE HIGH DOSE 02-R150 02-0140 

(10) 

(11) 

1 <2X ) 

16 (UOX) 16 (39X) 

2 (5%) 

1 (2X) 

(16) (46) 

1 (2X) 

2 (IX) 2 (IX) 

(16) (49) 

4 (8X) 

2 (IX) 3 (6X) 

(18) 

(50) 

1 (2X) 

1 (2X) 

8 (17X) 8 (16X) 

(18) (50) 

1 (2X) 

(18) («7) 

1 (2X) 

7 (15X) 4 (9X) 

3 (6X) 1 (2X) 

(18) 

(19) 

1 (2X) 

(18) (50) 

1 <2X ) 

(18) (50)
 


*	 NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 


*	 NUMBER OF ANIMALS SECBOPSIED
 


A-8
 

TABLE A2 (CONCLUDED)
 


CONTROL(DNTR) L0¥ DOSE HIGH DOSE 

02-0160 02-E150 02-0140 

HDSCDLOSKELETAL SYSTEM
 


NONE
 


BODY CAVITIES
 


NONE
 


ALL OTHER SYSTEMS
 


NONE
 


ANIMAL DISPOSITION SUMHARY
 


ANIMALS INITIALLY IN STUDY 50 50 50
 
 NATURAL DEATHS 2 6 3

 MORIBUND SACRIFICE 6 3 3

 SCHEDULED SACRIFICE 5 5

 ACCIDENTALLY KILLED
 
 TERMINAL SACRIFICE 36 41 39
 
 ANIMAL MISSING 1



9 INCLUDES AUTOLYZED ANIMALS
 


TUBOR SUMMARY
 


TOTAL ANIMALS WITH PRIMARY TUMORS* 31 33 30
 
 TOTAL PRIMARY TUMORS 52 47 47
 


TOTAL ANIMALS WITH BENIGN TUMORS 27 30 25
 
 TOTAL BENIGN TUMORS 10 38 36
 


TOTAL ANIMALS WITH MALIGNANT TUMORS 10 8 8

 TOTAL MALIGNANT TDNOBS 12 8 9



TOTAL ANIMALS WITH SECONDARY TUMORS*
 


TOTAL SECONDARY TUMORS
 


TOTAL ANIMALS WITH TUMORS UNCERTAIN­
 BENIGN OR MALIGNANT 1 2

 TOTAL UNCERTAIN TUMORS 1 2



TOTAL ANIMALS WITH TOMORS UNCERTAIN­
 PRIMARY OR BBTASTATIC
 
 TOTAL UNCERTAIN TUMORS
 


* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 
 * SECONDARY TUHORS: METASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 


A-9
 


APPENDIX B



SUMMARY OF THE INCIDENCE OF NEOPLASMS
 


IN MICE TREATED WITH FENAMINOSULF
 


TABLE Bl

 

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

CONTROL (UNTR) LOW DOSE HIGH DOSE
 


05-0160 05-0140 05-0150
 


ANIMALS INITIA1LY IN STUDY 50 50 50
 
 ANIHALS MISSING 1



ANIMALS NECROPSIED 50 44 22
 
 ANIMALS EXAMINED HISTOPATHOLOGICALLY** 49 44 22
 


INTEGUMENTARY SYSTEM
 


NONE
 


RESPIRATORY SYSTEM



*LUNG (47) (43) (22)
 
 HEPATOCELLULAR CARCINOMA, METAST 2 (4X)
 


ALVEOLAR/BRONCHIOLAR ADENOMA 4 (9X) 4 (9X) 1 (5X)
 
 ALVEOLAR/BRONCHIOLAR CARCINOMA 3 (6X) 3 (7X)
 


HEMATOPOIETIC SYSTEM
 


*MULIIPLE ORGANS (50) (44) (22)
 
 MALIGNANT IYMPHOMA, NOS 1 (2X) 1 (2X)
 
 MALIG.LYMPHOMA, HISTIOCYTIC TYPE 1 (2X)
 


ISPLEEN (49) (43) (20)
 
 HEMANGIOMA
 


HEMANGIOSARCOMA 1 (2X) 1 (2X)
 
 MALIGNANT LYMPHOMA, NOS 1 (2X)
 


tLYBPH NODE (40) (10) (14)
 
 MALIGNANT LYMPHOMA, NOS 1 <3X)
 


#MESENTERIC L. NODE (40) (40)
 
 (11)
 
 MALIGNANT LYMPHOMA, NOS
 


MALIG.LYMPHOMA, HISTIOCYTIC TYPE 1 (3X)
 


"LIVER (49) (44) (22)
 
 MALIG.LYMPHOMA, HISTIOCYTIC TYPE
 


*PEYERS PATCH (49) (-42) (19)
 
 _ HALIG..LYMPHOMAi_HISTIOCYTIC TYPE__ _



f NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECHOPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-3 
TABLE Bl (CONTINUED)
 


CONTROL (UNTR) LOU DOSE HIGH DOSE
 


05-0160 05-01UO 05-0150
 


JTHYHUS (30) (21) (7)
 
 MALIGNANT LYMPHOMA, NOS 1 (IX)
 


CIRCULATORY SYSTEM
 


NONE
 


DIGESTIVE SYSTEM
 


*LIVE8 («9) (It) (22)
 
 HEPATOCELLULAR ADENOMA 2 (5*)
 


HEPATOCELLULAR CARCINOMA 15 (31X) 7 (16%) 2 (9%)
 


tSTOMACH («9) («1) (19)
 


ADENOMATOUS POLYP, NOS 1 (2X)
 


URINARY SYSTEM
 


NONE
 


ENDOCRINE SYSTEM
 


ITHYHOID (<*2) (39) (14)
 


FOLLICULAR-CELL ADENOMA
 


FOLLICDLAR-CELL CARCINOMA
 


REPRODUCTIVE SYSTEM
 


«TESTIS (U9) («i|) (22)
 


INTERSTITIAL-CELL TUMOR 1 (2X)
 
 EMBRYONAL CARCINOMA
 


NERVOUS SYSTEM
 


NONE
 


SPECIAL SENSE ORGANS
 


*HARDERIAN GLAND (50) (UK) (22)
 


£ISTJDENCMAX_NOS
 


# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 


» NUMBER OF ANIMALS NECROPSIED
 


B-4
 

TABLE Bl (CONCLUDED)
 


CONTROL (UNTR) 


05-0160 


HUSCULOSKELETAL SYSTEM
 


NONE
 


BODY CAVITIES
 


NONE
 


ALL OTHER SYSTEMS
 


NONE
 


ANIMAL DISPOSITION SUMMARY
 


ANIMALS INITIALLY IN STUDY 50 


NATURAL DEATHS 3 


MORIBUND SACRIFICE 
 SCHEDULED SACRIFICE 5 
 ACCIDENTALLY KILLED
 
 TERMINAL SACRIFICE 42 
 ANIMAL MISSING 


9 INCLUDES AUTOLYZED ANIMALS
 


TUMOR SUMMAR Y
 


TOTAL ANIMALS WITH PRIMARY TUMORS* 20 


TOTAL PRIMARY TUMORS 26 


TOTAL ANIMALS WITH BESIGN TUMORS 6 
 TOTAL BENIGN TUMORS 6 


TOTAL ANIMALS WITH MALIGNANT TUMORS 18 
 TOTAL MALIGNANT TUMORS 20 


TOTAL ANIMALS WITH SECONDARY TUMOHSt 2

 TOTAL SECONDARY THMOPS 2



TOTAL ANIMALS WITH TUMORS UNCERTAIN­


BENIGN OR MALIGNANT
 


TOTAL UNCERTAIN TUMORS
 


TOTAL ANIMALS WITH TUMORS UNCERTAIN­


PRIMARY OR METASTATIC
 


TOTAL UNCERTAIN TUMORS
 


LOU DOSE HIGH DOSE 

05-0110 05-0150 

50 50
 


9 36
 


1 1



5



39 8



1



20 3



24 3



6 1



6 1



15 2



18 2



* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 


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


B-5
 

TABLE B2

 

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

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


06-0160 06-0220 06-R151 06-01KO
 


ANIMALS INITIALLY 111 STUDY 50 50 50 350
 


ANIMALS MISSING 2 2 1



ANIMALS NECROPSIED 50 47 13 12
 


ANIMALS EXAMINED HISTOPATHOLOGICALLY ** 50 141 38 39
 


INTEGUMENTARY SYSTEM
 


*SKIN (50) (1»7) (13) (12)
 


KERATOACANTHOMA 1 (2X)
 


*SUBCUT TISSUE (50) (17) (13) (12)
 


FIBROSARCCMA 1 (2«)
 


HEMANGIOSARCOMA 1 (2*)
 


RESPIRATORY SYSTEM
 


*LONG (50) (16) (39) (39)
 


HEPATOCELLDLAR CARCINOMA, METAST 1 (2%)
 


ALVEOLAR/BRONCHIOLSR ADENOMA 1 (2%) 1 (2X) 3 (8*) 3 (8%)
 


ALVEOLAR/BRONCHIOLA8 CARCINOMA 3 (6*) 3 (1%) 1 (3X)
 


HEMATOPOIETIC SYSTEM
 


*MULTIPLE ORGANS (50) (17) (13) (12)
 


MALIGNANT LYMPHOMA, NOS 3 (6X) 1 (2X) 2 (5X) 2 (5X)
 


MALIG.LYNPHOMA, HISTIOCYTIC TYPE 3 (6X)
 


IBONE HARROW (19) (39) (35) (32)
 


HEBANGIOSARCOMA 1 (3X)
 


*SPL£EN (19) (15) (38) (38) 

HEMANGIOSARCOM A 1 (2*) 1 (3%) 

BALIG. LYMPHOMA. HISTIOCYTIC TYPE 1 (2%) 2 (IX) 1 (3X) 

*MANDIBULAE L. NODE (10) (38) (29) (35) 

MALIGNAN T LYMPHOMA , NOS 1 (3%) 

tMESENTERIC L. NODE (10) (38) (29) (35) 

MALIG N ANT_LYMPHOMA t _NO S 1_IIS) 

* NUMBE R OF ANIMAL S HITH TISSDE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED **EXCLUDES

 PARTIALLY AUTOLYZED ANIMALS 

a 50 ANIMALS WERE INITIALLY IN THE STUDY BUT ONE ANIMA L WAS FOUND TO BE A MALE IN A FEMALE GROUP. 

B-6 
TABLE B2 (CONTINUED) 

HIGH DOSE CONTROL (UNTR) 

06-0160

 LOW DOSE CONTROL(UNTH)

 06-0220

 LOW DOSE

 06-R151

 HIGH DOSE 

 06-0140 

fPEYERS PATCH 

MALIGNANT LYMPHOMA, NOS 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE

 (49)

 1 (2%)

 (44) . (34)

 1 (3S) 

 (37) 

1 (3X) 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

»LIVER 

HEPATOCELLULAR ADENOMA 

HEPATOCELLULAR CARCINOMA

 (49)

 2 (4X)

 (>46) (36)

 2 (6X) 

2 (6%)

 (37) 

3 (8X) 

URINARY SYSTEM 

NONE 

ENDOCRINE SYSTEM 

• PITUITARY 

ADENOMA, NOS 

• ADRENAL/CAPSULE 

ADENOMA, NOS 

• THYROID 

FOLLICULAR-CELL ADENOMA

 (U2)

 (47)

 (41)

 (33)

 1 (3X)

 (40)

 1 (3%) 

 (29)

 1 (3!5) 

 (25)

 3 (12X)

 (37)

 (27)

 (32) 

3 (9%) 

 (39) 

 (31) 

REPRODUCTIVE SYSTEM 

*MAP1MAR Y GLAN D 

ADENOCARCINOMA , NOS 

• OVA4Y 

PAPILLARY ADENOMA 

PAPILLARY CYSTADENOMA, NOS 

TERATOMA, BENIGN

 (50)

 (48)

 (47 )

 (40)

 1 (3X) 

 (43)

 1 (2% ) 

 (32)

 1 (3%) 

 (42) 

 (37) 

1 (3X) 

NERVOUS SYSTEM 

NONE 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

B-7 
TABLE B2 (CONTINUED) 

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

06-0160 06-0220 06-R151 06-0140 

SPECIAL SENS E ORGAN S 

*HARDERIA N GLAN D (50) (47) (43) (42) 

CYSTADENOMA , NOS 1 (2%) 

MUSCtJLOSKELETA L SYSTEM 

NON E 

BODY CAVITIES 

NONE 

A LL OIHEH SYSTEMS 

NON E 

ANIMAL DISPOSITION SUMMAR Y 

ASIflALS INITIALL Y IN STUDY 50 50 50 50

 

NATURA L DEATHS 3 4 23 10

 

MORIBUN D SACRIFICE 2 3 7 1

SCHEDULE D SACRIFICE 5 5 5

ACCIDENTALL Y KILLED 

TERMINA L SACRIFICE 40 36 18 32 

ANIMA L MISSING 2 2 1

ANIMA L DELFTED (WRON G SEX) 1

* NUMBER OF ANIMAL S WIT H TISSUE EXAMINE D MICROSCOPICALLY 

» NUMBF R OF ANIMAL S NECROPSIE D 

B-8 
TABLE B2 (CONCLUDED) 

HIGH DOSE LOU DOSE 

CONTROL (UNTR) CONTROL(UNT8 ) LOW DOSE HIGH DOSE 

06-0160 06-0220 06-R151 06-01HO 

TUMO R SUMMAR Y 

TOTAL ANIMAL S WITH PRIMAB Y TUMORS* 12 1U 10 16
 


TOTA L PRIMAR Y TUMORS 15 15 15 19
 


TOTAL ANIMALS WITH BENIGN TUMORS
 


TOTAL BENIGN TUMOHS
 


TOTAL ANIMAIS WITH MALIGNANT TUMORS 1 1 10
 


TOTAL MALIGNANT TUMORS 11* 1 1
 


TOTAL ANIMALS WITH SECONDARY TUMORS* 1



TOTAL SECONDARY TUMORS 1



TOTAL ANIMAL S KITH TUMORS UNCERTAIN­


BENIGN OR MAIIGNANT
 


TOTAL UNCERTAIN TUMORS
 


TOTAL ANIMAIS WITH TUMORS UNCERTAIN­


PRIMARY OR METASTATIC
 


TOTAL UNCERTAIN TUMORS
 


* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 


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


B-9
 


APPENDIX C



SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 


IN RATS TREATED WITH FENAMINOSULF
 


ANIMALS INITIALLY IN STODY
 


ANIMALS NECROPSIED
 


ANIMALS EXAMINED HISTOPATHO LOGICALLY**
 


INTEGUMENTARY SYSTEM
 


*SKIN
 


EPIDERMAL INCLUSION CYST
 


INFLAMMATION, SUPPUHATIVE
 


RESPIRATORY SYSTEM
 


ILONG
 


CONGESTION, CHRONIC PASSIVE
 


INFLAMMATION, INTERSTITIAL
 


FIBROSIS, DIFFUSE
 


HYPERPLASIA, NOS
 


HYPERPLASIA, EPITHELIAL
 


HYPERPLASIA, ALVEOLAR EPITHELIUM
 


iLUNG/ALVEOLI
 


HEMOBRHAGE
 


HEMATOPOIETIC SYSTEM
 


tSPLEEN
 


FIBROSIS
 


HEMOSIDEROSIS
 


HEMATOPOIESIS
 


tLYMPH NODE
 


INFLAMMATION, NOS
 


*MANDIBULAR L. NODE
 


HYPERPLASIA, PLASMA CELL
 


tMESENTERIC L. NODE
 


HYPERPLASIA.,. PLASMA CELL
 


TABLE Cl 

I:ONTROL (UNTR)
 

01-0160
 

50
 

50
 

50
 

(50)
 

1 (2%)
 


(49)
 

1 (2«)
 
 U (8%)
 

1 (2X)
 
 1 (2%)
 


1 <2*>
 


(19)
 

1 (2X)
 


(50)
 

1 (2%)
 


2 (4X)
 


(49)
 

(49)
 

1 (2%)
 


(49)
 

1 12%) .


 LOW DOSE HIGH DOSE 

 01-R150 01-0140 

 50 50 

 M3 49 

 41 48 

 (43) (49) 

1 (2X) 1 (2%) 

 (41) (48) 

2 (5%) 1 (2«) 

2 (5%) 1 (2X) 

 (41) (48) 

 (41) (48) 

2 (4X) 

1 (2*) 

 (34) (47) 

1 (2X) 

 (34) (47) 

 (34) (47) 

 __ 

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

* NUMBE R OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

C-3 
CIRCULATORY SYSTEM
 


*MYOCARDIUM
 


INFLAMMATION, INTERSTITIAL
 


FIBROSIS
 


DEGENERATION, NOS
 


DIGESTIVE SYSTEM
 


tSALIVARY GLAND
 


HYPERTROPHY, FOCAL
 


HYPERPLASIA, INTRADUCTAL
 


OLIVER
 


INFLAMMATION, CHRONIC FOCAL
 


NECROSIS, FOCAL
 


METAMORPHOSIS FATTY
 


HYPERPLASIA, FOCAL
 


#LIVER/CENTRILOBULAH
 


CONGESTION, PASSIVE
 


*BILE DUCT
 


HYPERPLASIA, NOS
 


*PANCREAS
 


INFLAMMATION, NOS
 


INFLAMMATION, CHROHIC FOCAL
 


tPANCREATIC ACINUS
 


STROPHY, NOS
 


ISTOMACH
 


HYPERKERATCSIS
 


ACANTHOSIS
 


*PEYERS PATCH
 


HYPEBPLASIA, NOS
 


•JEJUNUM
 


METAPLASIA, OSSEOUS
 


*COLON
 


PARASITISM
 


TABLE Cl (CONTINUED) 

CONTROL (UNTR) LOW DOSE HIGH DOSE 

01-0160 01-8150 01-0140 

(48) (40) (48) 

1 (2«) 

2 (4%) 

1 (2*) 

(50) (38) (46) 

1 <3X) 

1 (2%) 

(49) (41) (48) 

1 (296) 

3 (6%) 1 (2%) 

1 (2%) 2 (4X) 

1 (2%) 4 (10X) 5 (10X) 

(49) (41) (48) 

1 (2%) 

(50) (43) (49) 

2 (4%) 2 (4X) 

(47) (40) (47) 

2 (4%) 2 (4X) 

1 (2%) 

(47) (40) (47) 

1 <2X) 

(49) (40) (46) 

1 (2%) 

1 (2%) 1 (3X) 

(49) 

1 (2%) 

(36) (47) 

2 <4») 

(49) (36) (47) 

1 (3X) 

(48) (30) (43) 

. 2.J5X1 

# NUMBER OF ANIMALS WITH TISSUE EXAHINED MICROSCOPICALLY
 


* NUMBER OF ANIMALS NECRCPSIED
 


04
 

TABLECl (CONTINUED)
 


CONTROL (UNTR) LOW DOSE
 


01-0160 01-R150
 


URINARY SYSTEM
 


tKIDNEY (50) (1*1)
 


HYDRONEPHROSIS
 


CONGESTION, NOS 1 (2X)
 


6LOMEHOLONEPHRITIS, NOS U (8X)
 


NEPHROPATHY 39 (95X)
 


DEGENERATION. CYSTIC 1 (2*)
 


NEPHROSIS, NOS 35 (70X)
 


HYPERPLASIA, EPITHELIAL 1 (2X)
 


*KIDNEY/TUBULE (50) (11)
 
 MINERALIZATION 21 (51)8)
 


ENDOCRINE SYSTEM
 


*PITUITARY (H5) (30)
 


CYST, NOS 1 (3X)
 


CONGESTION, NOS 1 (2X)
 
 HYPERPIASIA, NOS 1 (3%)
 


*ADHENAL MEDULLA (50) (11)
 
 HYPERPLASIA, NOS 2 (5X)
 


HYPERPLASIA, FOCAL 2 (55!)
 


*THYHOID (37) (31)
 


CYSTIC FOLLICLES 1 (3*)
 


FOLLICULAR CYST, NOS
 


HYPERPLASIA, PAPILLARY
 


HYPERPLASIA, C-CELL 2 (5*)
 


•PARATHYROID	 	 (20) (17)
 
 HYPERPLASIA, NOS
 


REPRODUCTIVE SYSTEM
 


*MAMMARY GLAND (50) (13)
 


HYPERPLASIA, NOS
 


tPROSTATE (48) (26)
 


INFLAMMATION, NOS 3 (6X)
 


ABSCESS, NOS
 


HYPERPLASIA. FOCAL. __ __ . _ 1 J4S1
 


t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 


* NUMBER OF ANIMALS NECHOPSIED
 


C-5
 


HIGH DOSE
 


01-011(0
 


(48)
 


1 (2%)



5 (10*)
 


42 (88X)
 


(48)
 


32 (67X)
 


(42)
 


2 (5X)
 


(47)
 


1 (2%)
 


5 (11S)
 


(44)
 


1 (2*)
 


1 (2X)
 


1 (2X)
 


(24)
 


1 (4X)
 


(49)
 


2 (IX)
 


(39)
 


1 <3X)
 

TABLE Cl (CONCLUDED)
 


CONTROL (UNTE)
 LOW DOSE HIGH DOSE 


01-0160
 01-R150 01-0140 


ItTESTIS
 (SO)
 (U1) (17) 


PERIVASCIUITIS
 1 (2%)
 


CALCIFICATION, NOS
 3 (6«)
 


CALCIFICATION, FOCAL
 1 (2%)
 


ATROPHY, NOS
 11 (22%)
 4 (10%) 9 (19X) 


HYPERPLASIA, INTERSTITIAL CELL
 4 (8%)
 5 (11*) 


tTESTIS/TUBULE
 (SO) •
 (41) (U7) 


HINERALIZATION
 3 (7X) 


NERVOUS SYSTEM
 


NONE
 


SPECIAL SENS" ORGANS
 


*EYE/RETINA
 (SO)
 (43) (49) 


DEGENERATION, NOS
 1 (2%) 


MUSCDLOSKELETAL SYSTEM
 


NONE
 


BODY CAVITIE S 

*PLEUR A

(SO ) (43) (49) 

FIBROSIS, DIFFUS E 1 (2% ) 

A L L OTHER SYSTEM S 

OMENTtl M 

NECROSIS, FAT
 1 1 


SPECIAL MORPHOLOGY SUMMAR Y
 


NO LESION REPORTED
 1 


AUTO/NECROPSY/NO HISTO
 2 1 


AUTOLYSIS/NO NECROPSY
 7 1 


» NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 


* NUMBER OP ANIMALS NSCHOPSIED
 


C-6
 

TABLE_C2
 
 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH FENAMINOSULF
 


CONTROL(UNTB) LOW DOSE HIGH DOSE
 


02-0160 02-R150 02-01<10
 


ANIMALS INITIALLY IN STUDY 50 50 50
 


ANIMALS MISSING 1



ANIMALS NECEOPSIED U1 K8 50
 


ANIMALS EXAMINED HISTOPATHOLOGICALLY** 19 48 50
 


INTEGUMENTARY SYSTEM
 


NONE
 


RESPIRATORY SYSTEM
 


ILUNG (U9) (18) («9)
 


CONGESTION, ACUTE PASSIVE 1 (2*)
 


INFLAMMATION, INTERSTITIAL 3 (6X)
 


PNEUMONIA, CHEONIC MURINE 1 (2S)
 


HEMATOPOIETIC SYSTEM
 


*SPLEEN (U7) C*8) (1*9)
 


HEHOSIDEROSIS 3 (6%) 5 (10*) 6 (12*)
 


HYPEHPLASIA, HEMATOPOIETIC 2 (US)
 


HYPEEPLASIA, EEYTHHOID 2 (KX)
 


HEMATOPOIESIS 8 (17X) 6 (12X)
 


CIRCULATORY SYSTEM
 


IMYOCARDIUM (M8) (1*8) (SO)
 


INFLAMMATION, INTERSTITIAL 1 (2%)



FIBROSIS 1 (2%)
 


FIBROSIS, FOCAL 1 (2*)
 


DIGESTIVE SYSTEM
 


fLIVEE («8) (1(8) (50)
 


INFLAMMATION, ACUTE/CHRONIC 1 (2%)



INFLAMMATION, CHEONIC FOCAL 1 (2X)
 


» NUMBE R OF ANIMAL S WIT H TISSUE EXAMINE D MICEOSCOPICA LLY 

* NUMBE R OF ANIMAL S NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

C-7
 

TABLE C2 (CONTINUED) 

CONTROL (ONTR) LOH DOSE
 HIGH DOSE
 

02-0160 02-R150
 02-0140
 

NECROSIS, COAGULATIVE 1 (2X)
 METAMORPHOSIS FATTY BASOPHILIC CYTO CHANGE 

1

2

 (2X) 

 (»%) 

3

9

 (6X)
 

 (19X)
 

2

17

 (1%)
 

 (34%)
 

HYPERPLASIA, FOCAL 

ANGIECTASIS
 1 (2%) 1 (8X)
 10 (20%)


2 (4X)
 HEKATOPOIESIS
 1 <2X)
 

*BILE DUCT	 HYPERPLASIA, NOS (119) 

2 (4%)
 

(18)
 (50)
 

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

tPANCREAS INFLAMMATION, NOS
 (l»8) (16)
 (47)
 

1 (2«)
 

•STOMACH	 (19) (15)
 (47)
 INFLAMMATION, NOS 1 (2*)
 

ACANTHOSIS 1 (2X)
 1 (2X)
 

*GASTRIC SUBMUCOSA (19) (15)
 (17)
 EDEMA, NOS 1 (2%)
 

tPEYEES PATCH HYPERPLASIA, NOS (19) 

2 (4«)
 

(16)
 (48)
 

3 (6X)
 

#COLON (19) (15)
 (42)
 PARASITISM 1 (2X)
 1 <2X)
 

URINABY SYSTEM 

tKIDNEY (18) (18) (49)
 HYDPONEPHROSIS 1 (2X) CYST, NOS 

GLOMEPULONIPHRITIS, NOS * (8%) 

1 (2X)
 

3 (6X)
 NEPHROPATHY UU (92X) 35 (71X)
 NEPHROSIS, NOS 29 (60%) 

tKIDNEY/CORTEX METAMORPHOSIS FATTY (18) 

1 (2%) 

(1«) (49)
 

tKIDNEY/TUBULE 

MINERALIZATION (18) (18) 31 (71X) 

(49)
 

12 (24X)
 

ENDOCRINE SYSTEM
 

*ADSENAL MEDULLA (19) (16)
 (46)
 HYPERPLASIA, FOCAL 1 19S) _ .
 1 12X1 _ _.


# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-8
 
*THYBOID
 


HYPEEPLASIA, C-CFLL
 


*PARATHYROID
 


HYPERPLASIA, NOS
 


tPANCREATIC ISLETS
 


HYPERPLASIA, NOS
 


REPRODUCTIVE SYSTEM
 


*MABMARY GLAND
 


DILATATION/DUCTS
 


GALACTOCELE
 


HYPERPLASIA, NOS
 


*MAMMARY DUCT
 


HYPEHPLASIA, CYSTIC
 


*UTERUS
 


HYDROtlETRA
 


HEMATOMA, NOS
 


ABSCESS, NOS
 


POLYP, INFLAMMATORY
 


•OVARY
 


INFLAMMATION, CHRONIC
 


NERVOUS SYSTEM
 


NONE
 


SPECIAL SENSF ORGANS
 


*LENS CAPSULE
 


CALCIFICATION, NOS
 


MUSCULOSKELETAL	 SYSTEM
 


NONE
 


BODY CAVITIES
 


NONE
 


TABLE C2 (CONTINUED)
 


CONTROL (UNTR)
 

02-0160
 

(45)
 

2 (4%)
 

(27)
 

(48)
 

(49)
 

1 (2%)



(49)
 

1 (2%)



(46)
 

1 (2%)
 


1 (2*)
 


1 (2%)
 


(47)
 

1 (2%)
 


(49)
 

1 (2«)
 


 LOW DOSE HIGH DOSE
 


 02-R150 02-0140
 


 (U6) (49)
 


2 (4*) 3 (6%)
 


 (21)	 	 (35)
 


1 (5S)
 


 (46)	 	 (47)
 


1 (2%) 1 (2%)
 


 (48) (50)
 


3 (6X)	 	 5 (10%)
 


1 (2%)



 (48) (50)
 


 (48) (47)
 


1 (2«)
 


 (48) (49)
 


 (48)	 	 (50)
 


# NUHBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 


* NUMBER OF ANIMALS NECROPSIED
 


C-9
 

TABLE C2 (CONCLUDED) 

CONTROL (UNTR ) LOW DOSE HIGH DOSE 

02-0160 02-8150 02-0110 

A LL OTHER SYSTEMS 

OMENTU M 

NECROSIS, NOS
 


CRANIOBUCCAL POOCH
 


CYST, NOS
 


SPECIAL MORPHOLOGY SUMMAR Y
 


NO LESION REPORTED 2 1



ANIMAL HISSING/NO NECROPSY 1

 AUTOLYSIS/NO NECROPSY 2



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


C-IO
 

APPENDIX D



SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 


IN MICE TREATED WITH FENAMINOSULF
 


JABLE Dl
 


CONTROL (DKTR) LOU DOSE HIGH DOSE
 


05-0160 05-01110 05-0150
 


ANIMALS INITIALLY IS STUDY 50 50 50
 


ANIMALS MISSING 1



ANIMALS NECEOPSIED 50 44 22
 


ANIMALS EXAMINED HISTOPATHOLOGICALLY ** 49 44 22
 


INTEGUMENTARY SYSTEM
 


*SCIBCUT TISSUE (50) (44) (22)
 


HEMATOMA, NOS 1 (2X)
 


INFLAMMATION, ACUTE FOCAL 1 (2%)
 


ABSCESS, NOS 1 (2X)
 


RESPIRATORY SYSTEM
 


ILDNG/BRONCHUS (17) (1)3) (22)
 


INFLAMHATION, NOS 1 (2%)
 


*LUNG (47) (43) (22)
 


INFLAMMATION, INTERSTITIAL
 


HEMATOPOIETIC SYSTEM
 


tSPLEEN (49) (43) (20)
 


HYPEHPLASIA, HEMATOPOISTIC 1 (2%)
 


HEMATOPOIESIS
 


EHYTHSOPOIESIS 2 (4%)
 


iMESENTESIC L. NODE (40) (40) (14)
 


INFLAMMATION, NOS 2 (5%)
 


HEMATOPOIESIS
 


#RENAL LYMPH NODE (40) (40) (14)
 


HYPERPLASIA, NOS 2 (5%)
 


CIRCULATORY SYSTEM
 


NONE
 


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

* NUMBF.R OP ANIMAL S NECHOPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

D-3 
TABLE Dl (CONTINUED) 

CONTROL (UNTR ) L O W DOSE HIGH DOSE 

05-0160 05-01UO 05-0150 

DIGESTIV E SYSTE M 

(1*9) (i*H) (22)
 


ABSCESS, NOS
 


NECROSIS, FOCAL
 


NECROSIS, COAGULATIVE
 


METAMORPHOSIS FATTY 1 (2X)
 


HYPERPLASTIC NODULE 1 (2*)
 


HYP2BPLASIA, FOCAL 1 (551)
 


ANGIECTASIS 1 (2%)
 


HEMATOPOIESIS
 


tLIVER/KUPFFER CELL (1*9) (22)
 


HYPEHPLASIA, NOS 1 (2%)
 


*GALLBLADDER (50) (UK) (22)
 


INFLAMMATION, NOS 2 (5%)
 


IPANCBEAS (K6) (1*2) (18)
 


CYSTIC DUCTS 1 (2%)
 


INFLAMMATION, NOS 1 (6X)
 


PliBIVASCTHITIS 1 (2%)
 


DEGENERATION, CYSTIC 1 (6X)
 
 NECROSIS, FAT 1 (2%)
 


(•PANCREATIC ACINUS (U6) (K2) (18)
 


DEGENERATION, NOS 1 (2%)



ATEOPHY, NOS
 


HYPERTROPHY, NOS
 
 HYPERTROPHY, FOCAL
 


#STOMACH (K9) (19)
 


INFLAMMATION, NOS
 


ACANTHOSIS
 


*PEY£RS PATCH (H9) (19)
 


INFLAMMATION, ACUTE 1 (2%)
 


HYPERPLASIA, LYMPHOID 1 (2%)
 


*COLON (1*8) (1*0) (18)
 


PARASITISM 1 (3%)
 


URINARY SYSTEM
 


tKIDNEY (1*9) (UU) (21)
 
 ____ HYDRONEPHEOSIS
 


i NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 
 * NUMBER 3F ANIMALS NECBOPSIED
 


D-4
 

TABLE Dl (CONTINUED) 

HIGH DOSE 

05-0160 05-01UO 05-0150 

CONTROL (DNTR) LOW DOSE 

INFLAMMATION , NOS 2 (10%)
 


INFLAMMATION , SUPPURATIV E 1 (2%)
 


INFLAMMATION , CHRONIC 1 (2%)



NEPHBOPATH Y 3 (14*)
 


#KIDNEY/TUBUL E (49) (44) (21) 

MINERALIZATIO N 1 (5X) 

ENDOCRINE SYSTEM
 


*ADRENAL (47) (38) (21)
 


NECROSIS, NOS
 


CALCIFICATION, NOS
 


ITHYROID (42) (39) (14)
 


INFLAMMATION, NOS 1 (3X)
 


INFLAMMATION, FOCAL 1 (3%)
 
 HYPEBPLASIA, FOCAL 1 (2%)
 


*PANCREATIC ISLETS (46) (42) (18)
 


INFLAMMATION, NOS
 


HYPEBPLASIA, ADENOHATOUS
 


BEPRODUCTIVE SYSTEM
 


*PREPUTIAL GLAND (50) (44) (22)
 


DILATATION, NOS 1 (2%)
 


INFLAMMATION, NOS 1 (2%)
 


*TESIIS (49) (44) (22)
 


MINERALIZATION 1 (5S)
 


DEGENERATION, NOS 1 (2%)
 
 ATROPHY, NOS
 


tTESTIS/TUBULE (49) (44) (22)



MINERALIZATION
 


NECROSIS, FOCAL 1 (2%)
 


NERVOUS SYSTEM
 


NONE
 


SPECIAL SENSE ORGANS
 


NONE
 


* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 


* NUMBER OF ANIMALS NECROPSIED
 


D-5
 

TABLE Dl (CONCLUDED) 

CONTROL (UNTR ) LOW DOSE HIGH DOSE 

05-0160 05-01KO 05-0150 

MUSCULOSKELETAL SYSTEM
 


NONE
 


BODY CSVITIES
 


*ABDOMINAL CAVITY (50) («U) (22)
 


ADHESION, NOS 1 (2*)
 


*MESENTERY (50) (It) (22)
 


STEATITIS 1 (2%)
 


ABSCESS, NOS 1 (2%)



ALL OTHER SYSTEMS
 


ADIPOSE TISSUE
 


STEATITIS 1



NECROSIS, FAT 2



SPECIAL MORPHOLOGY SUMMAR Y
 


NO LESION REPORTED 17 18 9



ANIMA L MISSING/NO NECROPSY 1



NO NECROPSY PERFORMED 19
 

AUTO/NECROPSY/HISTO PEBF 1 2



AOTO/NECROESY/NO HISTO 1



AU70LYSIVNO NECROPSY 5 9



* NUMBER OF ANIMAL S WITH TISSUE EXAMINED MICROSCOPICALLY
 


* NUMBER OP ANIMALS NECSOPSIFD
 


D-6
 

TABLE D2

 

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

HIGH DOSE CONTROL(UNTR) 

06-0160 

LOW DOSE CONTROL(UNTR ) 

06-0220 

L OW 

06­

 DOSE 

R151 

HIG H 

06-0

 DOSE 

1 UO 

ANIMALS INITIAllY IN STUDY 50 

ANIMALS MISSING 

ANIMALS NECROPSIED 50 

ANIMALS EXAMINED HISTOPATHOLOGICALLY** 50 

50 

2 

U7 

U7 

50 

2 

143 

3B 

350 

1 

12 

39 

INTEGUMENTARY SYSTEM
 


*SUBCUT TISSUE (50) (U7 ) (U3) (U2 ) 

MINERALIZATION 1 (2%) 

INFLAMMATION, NOS 1 (2%) 

NECROSIS, NOS 1 (2%) 

RESPIRATORY SYSTEM
 


ILUNG (50) (U6) (39) (39)
 


INFLAMMATION, INTERSTITIAL 1 (3X)
 


HEMATOPOIETIC SYSTEM
 


ISPLEEN (U9 ) (U5 ) (38) (38 ) 

HYPERPLASIA, LYMPHOID 1 (2%) HEMATOPOIESIS 1 (2%) 7 (18%) 5 (13%) 

ERYTHROPOIHSIS 1 (2%) 

*MANDIBULAR L. NODE (UO) (38) (29) (35)
 


HYPERPLASIA, PLASMA CELL 1 (3%)
 


tMEDIASTINAL L.NODE (38) (29) (35)
 


HYPERPLASIA, NOS 1 (3%)
 


*LUMBAR LYMPH NODE (UO) (38) (29) (35)
 


HYPERPLASIA, NOS 1 (3%)
 


fMESENTERIC L. NODE (UO) (38) (29) (35)
 


INFLAMMATION, NOS 1 (3%)
 


HEMATOPOIESIS 1 (3%)
 


»RENAL LYMPH NODE (UO) (38) (29) (35)
 


HYPERPLASIA^. NOS
 


* NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBER OF ANIMAL S NECROPSIED "EXCLUDES

 PARTIALLY AUTOLYZED ANIMALS 

5) 50 ANIMAL S WER E INITIALL Y IN THS STUD Y BUT ONE ANIMA L WAS FOUN D TO BE A MAL E IN A FEMAL E GROUP . 

D-7
 

HYPERPLASIA, PLASMA CELL
 


CIRCULATORY SYSTEM
 


(•CARDIOVASCULAR SYSTE
 
 PERIVASCHLITIS
 


tMYOCARDIUM
 
 INFLAMMATION, ACUTE DIFFUSE
 


DIGESTIVE SYSTEM
 


#LIVER
 


NECROSIS, NOS
 


NECROSIS, FOCAL
 
 INFARCT, NOS
 


METAMORPHOSIS FATTY
 


HYPERPLASIA, FOCAL
 


HEMATOPOIESIS
 


*BILE DUCT
 
 INFLAMMATION, CHRONIC FOCAL
 


(•PANCREAS
 
 DILATATION/DUCTS
 


•PANCREATIC ACINUS
 
 HYPERTROPHY, FOCAL
 


'STOMACH
 


INFLAMMATION, ACUTE FOCAL
 


INFLAMMATION, CHRONIC
 


tPEYERS PATCH
 


HYPERPLASIA, LYMPHOID
 


*COLON
 
 NEM.ATODIASIS
 


URINAEY SYSTEM
 


ttKIDNFY
 


GLOMERULONEPHRITISt NOS
 


*	 NUMBER OF ANIMAL S WITH TISSUE
 

*	 NUMBER OF ANIMAL S NECEOPSIED
 


TABLE D2 (CONTINUED)
 


HIGH DOSE LOW DOSE
 
 CONTROL (UNTB) CONTROL (UNTH)
 

06-0160 06-0220
 

1 <3X)
 


(50) (17)
 

(50)	 	 (15)
 

1 (2X)
 


(19)	 	 (16)
 

1 (2X)
 


1 (2X)
 


1 (2«)
 


1 (2%}



(50)	 	 (17)
 

2 (IX)
 


(17) (45)
 

(17) (15)
 

(19)	 	 (16)
 

1 (2X)
 


1 (2%)
 


(19)	 	 (44)
 

1 (2X)
 


(50)	 	 (42)
 

1 (2)8)
 


(19)	 	 (46)
 

1 12X1.


 EXAMINED MICROSCOPICALLY
 


D-8
 


 LOW DOSE
 


 06-R151
 


 (M3)
 


1 (2%)



 (39)
 


 (36)
 


1	 (3X)
 


2 ((,%)



1	 (3%)
 


 (43)
 


 (31)
 


 (31)
 


1 (3%)
 


 (31)
 


 (34)
 


 (27)
 


 (39)
 


2 15%).



HIGH DOSE
 
 06-0110
 


(42)
 


(39)
 


(37)
 


1 (3X)
 


1 (3X)
 


(12)
 


(38)
 


1 (3*)
 


(38)
 


(36)
 


(37)
 


(35)
 


(39)
 


1 13X1
 

TABLE D2 (CONTINUED) 

HIGH DOSE CONTROL (UNTR) 

06-0160 

LOW DOSE 

CONTROL(UNTR) 

06-0220 

LOW DOSE 

06-8151

 HIGH DOSE 

 06-0140 

LYMPHOCYTIC INFLAMMATORY INFILTR 

INFLAMMATION, CHRONIC 

INFLAMMATION, CHRONIC FOCAL 

NEPHROPATHY 

GLOMERULOSCLEROSIS, NOS 

1 (2%) 

2 {«*) 

1 (2%) 

1 (2%) 

15 (38?) 

1 (3*) 

*KIDNEY/TUBt!LE 

MINERALIZATION 

(49) (46) (39) 

8 (21%) 

 (39) 

tUEINARY BLADDEE 

INFLAMMATION, NOS 

INFLAMMATION, CHRONIC FOCAL 

HYPEHPLASIA, EPITHELIAL 

(50) 

1 (2%) 

(45) (36) (36) 

1 (3%) 

2 (6%) 

tU.BLADDER/SUEMUCOSA 

INFLAMMATION, CHRONIC 

INFLAMMATION, CHRONIC FOCAL 

PEHIVASCOLITIS 

(50) 

1 (2%) 

16 (32%) 

1 (2*) 

(45) (36) (36) 

fD. BLADDER/MUSCULAR IS 

CALCIUM DEPOSIT 

(50) 

1 (2*) 

(45) (36) (36) 

ENDOCRINE SYSTEM 

*ADR£NAL/CAPSULE 

HYPERPLASIA, NOS 

(K7) (40) (37) 

4 (11%)

 (39) 

2 (5«) 

tTHYEOID 

FOLLICDLAR CYST, NOS 

NECROSIS, FOCAL 

HYPERPLASIA, C-CELt 

HYPERPLASIA, FOLLICULAR-CELL 

(41) 

2 

1

 (5%) 

 (2%) 

(29) (27) 

1 (4%) 

 (31) 

1 (3X) 

REPRODUCTIVE SYSTEM 

'MAMMARY GLAND 

HYPERPLASIA, NOS 

METAPLASIA, SQUAMOUS 

(50) (47) 

1 (2*) 

(43) 

1 (21) 

 (42) 

•UTERUS 

HYDROMETRA 

PYOMETRA 

ABSCESS, NCS 

NECROSIS, FAT _ _ _ 

(49) 

5 (105!) 

._ 1 illl ­ . 

(45) (36) (37) 

1 (3%) 

2 <5X) 

1 (3%) 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

D-9 
TABLE D2 (CONTINUED) 

HIGH DOSELOW DOSE CONTROL(UNTB )

06-0160 

 CONTROL(UNTR )

 06-0220 

CALCIFICATION, NOS 1 (2%) 

MiTAPLASIA, SQUAMOUS 

*DTEBUS/ENDCMETRIU? I (09) (45) INFLAMMATION, SUPPURATIVE 2 (K%) HYPERPLASIA, NOS 

HYPERPLASIA, CYSTIC 32 (65%) 

tOVAEY/OVIDUCT (U9) INFLAMMATION, NOS 

DEGENERATION, NOS 1 (2%) 

• OVASY(48) (40)

CYST, NOS 6 (13%) 

INFLABMATICN, NOS 

INFLAMMATION, SUPPURATIVE 1 (2%)

ABSCESS, NOS 

INFLACHATION, CHRONIC 1 (2%)

DEGENERATION, NOS 

NERVOUS SYSTEM 


NONE 


SPECIAL SENSE ORGANS 


NONE 


MUSCIILOSKELFTAI SYSTEM 


NONE 


BODY CAVITIES 


'PERITONEUM(50) (47)


INFLAMMATION, NOS


ALL OTHER SYSTEMS 


•MULTIPLE	 ORGANS (50) (47)
 

A&YLOIDOSIS 1_J281 


» NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 


* NU1BEH OF ANIMALS NECROPSIED 


D-IO 


 LOH DOSE 

 06-R151 

2 (6%) 


(36) 


9 (25%) 


4 (11%) 


(36) 


(32)


 3 (9%) 


5 (16%)


 2 (6%) 


(43)


 (43)


HIGH DOSE 

06-0140 

(37) 


1 (3%) 


3 (8%) 


(37) 


1 (3%) 


 (37) 


1	 (3%) 


1 (3X) 


1 (3%) 


 (42) 


1 (2%) 


 (42) 

TABLE D2 (CONCLUDED)
 


HIGH DOSE LOW DOSE 

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

06-0160 06-0220 06-R151 06-0140 

OMENTU M 

PEHIVASCULITI S 1

SPECIAL MORPHOLOGY SUMMAR Y
 


NO LESION REPORTED 2 30 2 11
 


ANIMAL MISSING/NO NECROPSY 2 2 1



NiCROPSY PERF/NO HISTO PERFORMED 2



AUTO/NECROPSY/HISTO PERF 2 1



AUTO/NECRCFSY/NO HISTO 3 3



AUTOLY5IS/NO NECROPSY 1 5 6



* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 


* NUMBER OF ANIMALS NECROPSIED
 


D-ll
 


DHEW Publication No. (NIH) 78-1351