1978 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 139 

BIOASSAY OF 

TRIPHENYLTIN HYDROXIDE 

FOR POSSIBLE CARCINOGENIC!! Y 

CAS No. 76-87-9 

NCI-CG-TR-139 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

TRIPHENYLTIN HYDROXIDE
 

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) 78-1394
 

REPORT ON THE BIOASSAY OF TRIPHENYLTIN HYDROXIDE
 

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 triphenyltin hydroxide conducted for the Carcinogenesis Testing Program,
 

Division of Cancer Cause and Prevention, National Cancer Institute
 

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

one of a series of experiments designed to determine whether selected
 

chemicals have the capacity to produce cancer in animals. Negative
 

results, in which the test animals do not have a significantly
 

greater incidence of cancer than control animals, do not necessarily
 

mean the test chemical is not a carcinogen because the experiments
 

are conducted under a limited set of circumstances. Positive results
 

demonstrate that the test chemical is carcinogenic for animals under
 

the conditions of the test and indicate a potential risk to man.
 

The actual determination of the risk to man from animal carcinogens
 

requires a wider analysis.
 

CONTRIBUTORS: This bioassay of triphenyltin hydroxide was conducted
 

by Litton Bionetics, Inc., Bethesda, Maryland, initially under direct
 

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

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

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

Weisburger (1,3). The principal investigators for the contract were
 

Dr. S. M. Garner (4,5) and Dr. B. M. Ulland (4,5). Mr. S. Johnson
 

(4) was the coprincipal investigator for the contract. Animal treatment and observation were supervised by Mr. R. Cypher (4), Mr. D. S.
 

Howard (4) and Mr. H. D. Thornett (4); Mr. H. Paulin (4) analyzed
 

dosed feed mixtures. Ms. J. Blalock (4) was responsible for data
 

collection and assembly. Chemical analysis was performed by Midwest
 

Research Institute (6) and the analytical results were reviewed by
 

Dr. N. Zimmerman (7).
 

Histopathologic examinations were performed by Drs. B. Cockrell
 

(4), F. M. Garner (4), E. Gorgacz (4), P. Hildebrandt (4), R. Montali
 

(4), C. Montgomery (4), H. Seibold (4), and N. Wosu (4) and reviewed
 

by Dr. A. DePaoli (4) at Litton Bionetics, Inc.; the pathology narratives were written by Dr. A. DePaoli (4), and the diagnoses included
 

in this report represent the interpretation of these pathologists.
 

Histopathology findings and reports were reviewed by Dr. R. L.
 

Schueler (8).
 

iii
 
Compilation of individual animal survival, pathology, and summary tables was performed by EG&G Mason Research Institute (9); the
 

statistical analysis was performed by Mr. W. W. Belew (7,10) and Mr.
 

R. M. He Ifand (7), using methods selected for the Carcinogenesis
 

Testing Program by Dr. J. J. Gart (11).
 

This report was prepared at METREK, a Division of The MITRE Corporation (7) under the direction of the NCI. Those responsible for
 

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

(7), task leader Ms. P. Walker (7), senior biologist Mr. M. Morse
 

(7), biochemist Mr. S. C. Drill (7), and technical editor Ms. P. A.
 

Miller (7). 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 (l), Dr. C.
 

Cueto, Jr. (1), Dr. J. F. Douglas (1), Dr. D. G. Goodman (1,12), Dr.
 

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

T. W. Orme (l), Dr. R. A. Squire (1,13), Dr. S. F. Stinson (l), Dr.
 

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

1.	 Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

2.	 Now with the U.S. Environmental Protection Agency, 401 M Street
 

S.W., Washington, D.C.
 

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

4.	 Litton Bionetics, Inc., 5516 Nicholson Lane, Kensington, Maryland.
 

5.	 Now with Hazleton Laboratories America, Inc., 9200 Leesburg
 

Turnpike, Vienna, Virginia.
 

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

Missouri.
 

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

Boulevard, McLean, Virginia.
 

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

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

Rockville, Maryland.
 

10.	 Now with the Solar Energy Research Institute, Cole Boulevard,
 

Golden, Colorado.
 

11.	 Mathematical Statistics and Applied Mathematics Section, Biometry
 

Branch, Field Studies and Statistics Program, Division of Cancer
 

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

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

Washington, D.C.
 

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

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

SUMMARY
 

A bioassay of triphenyltin hydroxide for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. Triphenyltin hydroxide was administered in the feed, at either of two
 

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

species. The high and low concentrations of triphenyltin hydroxide
 

were, respectively, 75 and 37.5 ppm for rats and mice. After a
 

78-week period of compound administration, there was an additional
 

observation period of 26 weeks for both species. Twenty animals
 

of each sex and species were placed on test as controls.
 

For male mice, there was a significant positive association
 

between dosage and mortality. In both species, however, adequate
 

numbers of animals survived sufficiently long to be at risk from
 

late-developing tumors. Except for a slight depression of mean body
 

weight gain in male rats and female mice, compound-related mean body
 

weight depression was not observed in either species. In female rats
 

no significant accelerated mortality, retardation of growth, or other
 

signs of toxicity were associated with the dietary administration of
 

triphenyltin hydroxide. Therefore it is possible that the compound
 

was not administered at the maximum tolerated concentrations.
 

No tumors occurred at a significantly higher incidence in dosed
 

rats or mice than in their controls.
 

Under the conditions of this bioassay, there was no evidence for
 

the carcinogenicity of triphenyltin hydroxide to Fischer 344 rats or
 

to B6C3F1 mice.
 

VII
 

TABLE OF CONTENTS
 

Page
 

I. INTRODUCTION 1
 

II. MATERIALS AND METHODS 4
 

A. Chemicals 4
 

B. Dietary Preparation 4
 

C. Animals 5
 

D. Animal Maintenance 6
 

E. Selection of Initial Concentrations 8
 

F. Experimental Design 9
 

G. Clinical and Histopathologic Examinations 9
 

H. Data Recording and Statistical Analyses 10
 

III. CHRONIC TESTING RESULTS: RATS 18
 

A. Body Weights and Clinical Observations 18
 

B. Survival 18
 

C. Pathology 18
 

D. Statistical Analyses of Results 21
 

IV. CHRONIC TESTING RESULTS: MICE 28
 

A. Body Weights and Clinical Observations 28
 

B. Survival 28
 

C. Pathology 32
 

D. Statistical Analyses of Results 32
 

V. DISCUSSION 37
 

VI. BIBLIOGRAPHY 38
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH TRIPHENYLTIN HYDROXIDE A-l
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH TRIPHENYLTIN HYDROXIDE B-l
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH TRIPHENYLTIN
 

HYDROXIDE C-l
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH TRIPHENYLTIN
 

HYDROXIDE D-l
 

IX
 
LIST OF ILLUSTRATIONS 

Figure Number Page 

1 CHEMICAL STRUCTURE OF TRIPHENYLTIN HYDROXIDE 

GROWTH CURVES FOR TRIPHENYLTIN HYDROXIDE 

CHRONIC STUDY RATS 19 

SURVIVAL COMPARISONS OF TRIPHENYLTIN HYDROXIDE CHRONIC STUDY RATS 20 

GROWTH CURVES FOR TRIPHENYLTIN HYDROXIDE 

CHRONIC STUDY MICE 29 

SURVIVAL COMPARISONS OF TRIPHENYLTIN HYDROXIDE CHRONIC STUDY MICE 30 

PERCENT SURVIVAL OF TRIPHENYLTIN HYDROXIDE 

CHRONIC STUDY MICE 31 

LIST OF TABLES 

Table Number Page 

DESIGN SUMMARY FOR FISCHER 344 RATS—TRIPHENYLTIN HYDROXIDE FEEDING EXPERIMENT 10 

DESIGN SUMMARY FOR B6C3F1 MICE—TRIPHENYLTIN HYDROXIDE FEEDING EXPERIMENT 11 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

TRIPHENYLTIN HYDROXIDE 22 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH TRIPHENYLTIN HYDROXIDE 25 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

TRIPHENYLTIN HYDROXIDE 33 
LIST OF TABLES (Concluded) 

Table Number 

6 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH TRIPHENYLTIN HYDROXIDE 35 

Al SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH TRIPHENYLTIN HYDROXIDE A-3 

A2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE RATS TREATED WITH TRIPHENYLTIN HYDROXIDE A-7 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH TRIPHENYLTIN HYDROXIDE B-3 

B2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH TRIPHENYLTIN HYDROXIDE B-6 

Cl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH TRIPHENYLTIN HYDROXIDE C-3 

C2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH TRIPHENYLTIN HYDROXIDE C-8 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH TRIPHENYLTIN HYDROXIDE D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH TRIPHENYLTIN HYDROXIDE D-7 

XI
 

I. INTRODUCTION
 

Triphenyltin hydroxide (Figure 1) (NCI No. C00260), an organometalic compound used as a fungicide and antifeeding compound for
 

insect control, was selected for bioassay by the National Cancer
 

Institute because of its use on edible crops and a lack of adequate
 

chronic toxicity data.
 

The Chemical Abstracts Service (CAS) Ninth Collective Index
 

*
 (1977) name for this compound is hydroxytriphenylstannane. It is
 

also called hydroxytriphenyltin, fentin hydroxide, TPTH, TPTOH, and
 

ENT 2009.
 

Triphenyltin hydroxide, a nonsystemic fungicide, is effective
 

against many of the fungi which are susceptible to the action of copper fungicides (Martin and Worthing, 1977). Triphenyltin hydroxide
 

is used to control early and late blight on potatoes; leaf spot on
 

sugar beets and peanuts; scab and several diseases on pecans (Farm
 

Chemicals Handbook, 1976); blast diseases of rice; coffee berry
 

disease (Martin and Worthing, 1977); and most of the other important
 

fungus diseases (Spencer, 1973).
 

Triphenyltin hydroxide can also be used as an antifeeding compound for the control of surface feeding insects (Farm Chemicals
 

Handbook, 1976).
 

*
 

The CAS registry number is 76-87-9.
 
FIGURE 1

 

CHEMICAL STRUCTURE OF TRIPHENYLTIN HYDROXIDE 
Specific production data for triphenyltin hydroxide are not available; however, this compound is produced in commercial quantities (in
 

excess of 1000 pounds or $1000 in value annually) (Stanford Research
 

Institute, 1977).
 

The potential for exposure to triphenyltin hydroxide is greatest
 

for agricultural workers, but some exposure may also occur in pesticide production facilities. Residents of agricultural communities
 

may be exposed to airborne residues following spraying operations.
 

Exposure may also occur via ingestion of residues in food crops.
 

Triphenyltin hydroxide was not lethal to germ cells in a dominant
 

lethal study of ICR/Ha Swiss mice following intraperitoneal injections
 

of 1.3 mg/kg to 7 males (8 to 10 weeks old) and 8.5 mg/kg to 9 males,
 

and administration of 11 mg/kg by gavage on 5 successive days to 10
 

males (Epstein et al., 1972).
 
II. MATERIALS AND METHODS 

A. Chemicals
 

Triphenyltin hydroxide was purchased from Pfaltz and Bauer Chemical Company. Analysis was performed by Midwest Research Institute.
 

The melting point (121° to 123°) was similar to that reported in the
 

literature (119° to 121°C [Suzuki et al., 1968]). Thin-layer chromatographic plates visualized with ultraviolet light and dithizone
 

showed one spot when an ethyl ether:benzene:acetic acid solvent
 

system was used and two spots when an n-butanol:acetic acid solvent
 

system was used. Elemental analysis was close to the theoretical.
 

Titration of the basic group with hydrochloric acid was 97 to 98 percent of the theoretical. Infrared analysis was not inconsistent with
 

the structure of the compound. Ultraviolet analysis showed X at
 

max
 

246, 252, 258, 262, 264 and 268 nm with respective molar extinction
 

coefficients of 552, 759, 954, 782, 794, and 527. Second and third
 

batches were purchased from the same supplier 10 and 14 months later,
 

respectively. Analyses suggested the compounds to be of similar
 

purity.
 

Throughout this report, the term triphenyltin hydroxide is used
 

to represent this material.
 

B. Dietary Preparation
 

The basal laboratory diet for both dosed and control animals 

(3) consisted of Wayne Lab-Blox (Allied Mills, Inc., Chicago, Illinois). 
Triphenyltin hydroxide was administered to the dosed animals as a
 

component of the diet.
 

The chemical was removed from its container and a proper amount
 

was blended with an aliquot of the ground feed using a mortar and
 

pestle. Once visual homogeneity was attained, the mixture was placed
 

in a 6 kg capacity Patterson-Kelley standard model twin-shell stainless steel V-blender along with the remainder of the feed to be prepared. After 20 minutes of blending, the mixtures were placed in
 

double plastic bags and stored in the dark at 4°C. The mixture was
 

prepared once weekly.
 

Dosed feed preparations containing 37.5 and 75.0 ppm of triphenyltin hydroxide were analyzed spectrophotometrically. The mean result immediately after preparation was 88.1 percent of theoretical
 

(ranging from 81.3 to 98.8 percent), including correction for the
 

analytical method of recovery used. After 7 days at ambient room
 

temperature, the mean result was 57.9 percent of theoretical (ranging
 

from 54.3 to 62..0 percent) including correction for analytical method
 

of recovery used. Data were not corrected for any loss which may have
 

been due to instability of the chemical.
 

C. Animals
 

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

through contracts of the Division of Cancer Treatment, National
 

Cancer Institute. All rats were supplied by A. R. Schmidt, Madison,
 
Wisconsin. All mice were supplied by Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts.
 

Rats and mice were approximately 4 weeks old when received.
 

Upon receipt, animals were examined for visible signs of disease or
 

parasites. Obviously ill or runted animals were culled. The remaining animals were quarantined for 2 weeks prior to initiation of test.
 

Animals which did not manifest clinical signs of disease were placed
 

on test at this time. Animals were assigned to groups and distributed
 

among cages so that the average body weight per cage was approximately
 

equal for a given species and sex.
 

D. Animal Maintenance
 

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


controlled rooms. The temperature range was 22° to 26°C and the relative humidity was maintained between 45 and 55 percent. Incoming
 

air was filtered through HEPA filters (Flanders Filters, McLean,
 

Virginia) at a rate of 12 to 15 complete changes of room air per
 

hour. Fluorescent lighting was provided 8 hours per day (9:00 a.m.
 

to 5:00 p.m.).
 

All rats were housed four per cage by sex and all mice five per
 

cage by sex. Throughout the study dosed and control animals of both
 

species were housed in polycarbonate cages (Lab Products, Inc., Garfield, New Jersey) suspended from aluminum racks. Racks were fitted
 

with a continuous stainless steel mesh lid over which a sheet of
 

filter paper was firmly secured. Filter paper was changed at 2-week
 
intervals, when the racks were sanitized. Clean cages and bedding
 

®
 

were provided twice weekly. Ab-sorb-dri hardwood chip bedding
 

(Wilner Wood Products Company, Norway, Maine) was used in polycarbonate cages for the entire bioassay.
 

Acidulated water (pH 2.5) was supplied to animals in water bottles filled by an automated metering device that v/as checked daily
 

for diluting accuracy. Water bottles were changed twice weekly and
 

sipper tubes were washed at weekly interval?. During the period of
 

chemical administration, dosed and control animals received treated
 

(R)
 

or untreated Wayne Lab-Bio:; meal as appropriate. The feed was supplied in hanging stainless steei hoppers which were refilled three
 

times per week and sanitized weekly. Food and water were available
 

ad libitum for both species.
 

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

~tf
 

receiving diets containing diaminozide (1596-84-5) and carbromal
 

(77-65-6); and other rats intubated with p-nitrostyrene (102-96-5).
 

All dosed and control mice were housed in a room with mice receiving diets containing EDTA trisodium salt (150-38-9); diaminozide
 

(1596-84-5); 3,3'-dimethoxybenzidine-4,4'-diisocyanate (91-93-0);
 

p-quinone dioxime (105-11-3); 4~amino-2-nitrophenol (119-34-6);
 

carbromal (75-65-6); N,N'~diethylthiourea (105-55-5); other mice
 

intubated with lithocholic acid (434~13~9J; and mice receiving I.P.
 

injections of methiodal sodium (434-13-9).
 

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

In order to establish the maximum tolerated concentrations of
 

triphenyltin hydroxide for administration to dosed animals in the
 

chronic studies, subchronic toxicity tests were conducted with both
 

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

groups, each consisting of five males and five females. Triphenyltin
 

hydroxide was incorporated into the basal laboratory diet of five of
 

the six groups of both species in concentrations of 100, 146, 213,
 

315 and 464 ppm. The sixth group of each species served as a control
 

group, receiving only the basal laboratory diet.
 

The dosed dietary preparations were administered for a period
 

of 7 weeks, followed by a 1-week observation period during which all
 

animals were fed the untreated basal diet. Individual body weights
 

and food consumption data were recorded twice weekly throughout the
 

study. Upon termination of the observation period, all survivors
 

were sacrificed and necropsied.
 

All rats died at a dietary concentration of 464 ppm. At the end
 

of the subchronic test, mean body weight gain among male rats receiving a dietary concentration of 100 ppm was 25 percent less than the
 

mean body weight gain of their controls, while female rats receiving
 

the same concentration displayed a mean body weight gain of 10 percent less than their controls.
 

All mice died at a dietary concentration of 464 ppm. At the end
 

of the subchronic test, mean body weight gain among both male and
 
female mice receiving a dietary concentration of 100 ppm was 6 percent less than the mean body weight gain of their respective control
 

groups.
 

The high concentration selected for administration to dosed
 

groups of both species in the chronic bioassay was 75 ppm.
 

F. Experimental Design
 

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

treated and untreated observation periods) are summarized in Tables
 

1 and 2.
 

All rats and mice were approximately 6 weeks old at the time
 

the test was initiated. All groups of the same species were placed
 

on test simultaneously. The dietary concentrations of triphenyltin
 

hydroxide utilized were 75 and 37.5 ppm. Throughout this report
 

those animal groups receiving the former concentration are referred
 

to as the high dose groups and those receiving the latter concentration are referred to as the low dose groups. Dosed rats and mice
 

were supplied with feed containing triphenyltin hydroxide for 78
 

weeks followed by a 26-week observation period.
 

G. Clinical and Histopathologic Examinations
 

Animals were weighed immediately prior to initiation of the
 

experiment. From the first day, all animals were inspected twice
 

daily for mortality. Food consumption data were collected at monthly
 

intervals from 20 percent of the animals in each group. Body weights
 
TABLE 1
 

DESIGN SUMMARY FOR FISCHER 344 RATS
 

TRIPHENYLTIN HYDROXIDE FEEDING EXPERIMENT
 

INITIAL TRIPHENYLTIN 

GROUP HYDROXIDE 

SIZE CONCENTRATION3 

MALE
 

CONTROL 20 0
 

LOW DOSE 50 37.5
 

0
 

HIGH DOSE 50 75
 

0
 

FEMALE
 

CONTROL 20 0
 

LOW DOSE 50 37.5
 

0
 

HIGH DOSE 50 75
 

0
 

Concentrations given in parts per million.
 

OBSERVATION PERIOD
 

TREATED UNTREATED
 

(WEEKS) (WEEKS)
 

0 104
 

78
 

26
 

78
 

26
 

0 104
 

78
 

26
 

78
 

26
 

10
 
TABLE 2
 

DESIGN SUMMARY FOR B6C3F1 MICE
 

TRIPHENYLTIN HYDROXIDE FEEDING EXPERIMENT
 

INITIAL TRIPHENYLTIN 

GROUP HYDROXIDE 

SIZE CONCENTRATION3 

MALE
 

CONTROL 20 0
 

LOW DOSE 50 37.5
 

0
 

HIGH DOSE 50 75
 

0
 

FEMALE
 

CONTROL 20 0
 

LOW DOSE 50 37.5
 

0
 

HIGH DOSE 50 75
 

0
 

Concentrations given in parts per million.
 

OBSERVATION PERIOD
 

TREATED UNTREATED
 

(WEEKS) (WEEKS)
 

0 104
 

78
 

26
 

78
 

26
 

0 104
 

78
 

26
 

78
 

26
 

11
 
were recorded once a week for the first 6 weeks, every 2 weeks for
 

the next 10 weeks, and at monthly intervals for the remainder of the
 

bioassay.
 

All moribund animals or animals that developed large, palpable
 

masses that jeopardized their health were sacrificed. A necropsy
 

was performed on each animal regardless of whether it died, was sacrificed when moribund, or was sacrificed at the end of the bioassay.
 

The animals were euthanized by carbon dioxide asphyxiation, and were
 

immediately necropsied. The histopathologic examination consisted
 

of gross and microscopic examination of all major tissues, organs,
 

and gross lesions taken from sacrificed animals and, whenever possible, from animals found dead.
 

Tissues were preserved in a 10 percent neutral buffered formalin
 

solution, embedded in paraffin, sectioned, and stained with hematoxylin and eosin prior to microscopic examination.
 

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

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

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

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

A few tissues were not examined for some animals, particularly
 

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

12
 
to preclude histopathologic interpretation. Thus, the number of animals for which particular organs, tissues, or lesions were examined
 

microscopically varies and does not necessarily represent the number
 

of animals that were recorded in each group at the time that the test
 

was initiated.
 

H. Data Recording and Statistical Analyses
 

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

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

as recommended by the International Union Against Cancer (Berenblum,
 

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

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

that bear on the possibility of carcinogenicity are discussed in the
 

statistical narrative sections.
 

Probabilities of survival were estimated by the product-limit
 

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

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

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

missing; animals dying from natural causes were not statistically
 

13
 
censored. Statistical analyses for a possible dose-related effect
 

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

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

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

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

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

The incidence of neoplastic or nonneoplastic lesions has been
 

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

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

that site was examined (denominator). In most instances, the denominators included only those animals for which that site was examined
 

histologically. However, when macroscopic examination was required
 

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

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

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

The purpose of the statistical analyses of tumor incidence is to
 

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

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
 

14
 
significance level of 0.05 may be made. The Bonferroni inequality
 

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

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

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

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

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

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

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

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

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

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

from linear trend.
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation of
 

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

tumor was observed were excluded by basing the statistical tests on
 

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

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

tumor was found, comparisons were based exclusively on animals that
 

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

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

Cochran-Armitage tests, etc.) were followed.
 

15
 
When appropriate, life-table methods were used to analyze the
 

incidence of tumors. Curves of the proportions surviving without an
 

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

during which animals died naturally or were sacrificed was entered as
 

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

these curves were used for two groups; Tarone1s extension to testing
 

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

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

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

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


tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

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

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

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

t c t
 

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

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

c
 

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

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

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

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

larger proportion in the treated group than in the control.
 

The lower and upper limits of the confidence interval of the relative risk have been included in the tables of statistical analyses.
 

16
 
The interpretation of the limits is that in approximately 95 percent
 

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

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

be within the interval calculated from the experiment. When the
 

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

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

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

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

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

the lower limit indicates the absence of a significant result while
 

the upper limit indicates that there is a theoretical possibility
 

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

detected under the conditions of this test.
 

17
 
III. CHRONIC TESTING RESULTS: RATS
 

A. Body Weights and Clinical Observations
 

A very slight dose-related mean body weight depression was evident in male rats after week 40, while no distinct mean body weight
 

depression was associated with compound administration in females
 

(Figure 2).
 

No abnormal clinical signs were recorded.
 

B. Survival
 

The estimated probabilities of survival for male and female rats
 

in the control and triphenyltin hydroxide-dosed groups are shown in
 

Figure 3. The Tarone test for association between increased dosage
 

and elevated mortality was not significant for either males or females .
 

For both sexes, there were adequate numbers of rats at risk from
 

late-developing tumors. Eighty-four percent (42/50) of the high dose
 

males, 76 percent (38/50) of the low dose males, and 75 percent (15/
 

20) of the control males survived on test until the conclusion of the
 

study. Ninety percent (45/50) of the high dose females, 80 percent
 

(40/50) of the low dose females, and 90 percent (18/20) of the control females survived on test until the end of the study.
 

C. Pathology
 

Histopathologic findings on neoplasms in rats are summarized in
 

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

summarized in Appendix C (Tables Cl and C2).
 

18
 
MEAN BODY WEIGHT (GRAMS) MEAN BODY WEIGHT (G

s 

3D

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m 

O 

3D 

O 

O 

O 

< 

3D 
PROBABILITY OF SURVIVAL PROBABILITY OF SURVIV

c3 O ° O O eD 0 O O 

c3 N) -^ Ol 00 C3 cD N) •^ Ol 

i 1 1 1 1 1 [ 1 1 1 1 1 1 1 1 1 

o— o — 

S CO -n _ m > 

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r~ 30 

> tp ~ m i? ~~ > r~ 3D ^3 >

8 en - 

^ 

> 

30 w C*J 

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8 

z _ CO 

O

•n 

33 =J £- d £­ =5 ^ m s 

m m -n o 0 Z 7* ^ 

x

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5 s s 

< m m if

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U1 

6 i \ 

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m

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C3 10 .b 0) 00 C3 cD 10 ^ en 
A variety of neoplasms occurred both in the control and dosed
 

groups while other neoplasms occurred only, or with a greater frequency, in dosed rats as compared with controls. These lesions,
 

however, are not uncommon in this strain of rats.
 

The incidences of inflammatory, degenerative, and proliferative
 

lesions were similar in dosed and control animals, and were consistent
 

with spontaneous lesions found in aged Fischer 344 rats (Appendix C).
 

The results of this pathologic examination indicate that triphenyltin hydroxide was not carcinogenic in Fischer 344 rats under
 

conditions of this bioassay.
 

D.	 Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

rats are summarized in Tables 3 and 4. The analysis 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 triphenyltin
 

hydroxide-dosed groups and where such tumors were observed in at
 

least	 5 percent of the group.
 

None of the statistical tests for any site of either male or
 

female rats indicated a significant positive association between
 

chemical administration and tumor incidence. Based upon these statistical results there was no evidence that triphenyltin hydroxide
 

was carcinogenic in Fischer 344 rats under the conditions of this
 

test.
 

21
 
___ 

TABLE 3
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE RATS TREATED WITH TRIPHENYLTIN HYDROXIDE*
 

HIGH
 

DOSE
 

0/50(0.00)
 

N.S.
 

9/46(0.20)
 

N.S.
 

1.957
 

0.463
 

17.603
 

4/49(0.08)
 

N.S.
 

0.816
 

0.131
 

8.603
 

TOPOGRAPHY : MORPHOLOGY
 

Hematopoietic System: Leukemia or Malignant Lymphoma"
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

tsj
 Weeks to First Observed Tumor
 

Pituitary: Chromophobe Adenoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Adrenal: Pheochromocytoma or Pheochromo­ cytoma, Malignant^
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

CONTROL
 

0/20(0.00)
 

N.S.
 

P = 0.005
 

2/20(0.10)
 

N.S.
 

104
 

2/20(0.10)
 

N.S.
 

104
 

LOW
 

DOSE
 

6/50(0.12)
 

N.S.
 

Infinite
 

0.667
 

Infinite
 

94
 

5/48(0.10)
 

N.S.
 

1.042
 

0.192
 

10.410
 

94
 

2/50(0.04)
 

N.S.
 

0.400
 

0.032
 

5.277
 

104
 

86 

104 
TABLE 3 (CONTINUED) 

TOPOGRAPHY: MORPHOLOGY CONTROL 

Thyroid: C-Cell Adenoma or C-Cell 

Carcinoma^ 2/18(0.11) 

P Values0 P = 0.041(N) ___ Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 104 

Pancreatic Islets: Islet-Cell Adenoma or 

Islet-Cell Carcinomab 2/19(0.11) 

P Values0 N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 89 

Testis: Interstitial-Cell Tumor 17/19(0.89) 

P Values0 N.S. 

Relative Risk (Control)0 _— 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 89 

LOW
 

DOSE
 

2/41(0.05)
 

N.S.
 

0.439
 

0.035
 

5.743
 

100
 

3/48(0.06)
 

N.S.
 

G.594
 

0.076
 

6.774
 

100
 

46/50(0.92)
 

N.S.
 

1.028
 

0.898
 

1.275
 

63
 

HIGH
 

DOSE
 

0/44(0.00)
 

N.S.
 

0.000
 

0.000
 

1.370
 

3/49(0.06)
 

N.S.
 

0.582
 

0.074
 

6.640
 

96
 

49/50(0.98)
 

N.S.
 

1.095
 

0.961
 

1.185
 

76
 
TABLE 3 (CONCLUDED)
 

Treated groups received doses of 37.5 or 75 ppm in feed.
 

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

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

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

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

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

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

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 TRIPHENYLTIN HYDROXIDE5
 

TOPOGRAPHY : MORPHOLOGY
 

Subcutaneous Tissue: Basal-Cell Tumor
 

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: Chromophobe Adenoma
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

CONTROL
 

2/20(0.10)
 

P = 0.035(N)
 

104
 

4/20(0.20)
 

N.S.
 

93
 

7/17(0.41)
 

N.S.
 

P = 0.036
 

LOW
 

DOSE
 

1/50(0.02)
 

N.S.
 

0.200
 

0.004
 

3.681
 

67
 

2/50(0.04)
 

N.S.
 

0.200
 

0.020
 

1.297
 

73
 

32/47(0.68)
 

N.S.
 

1.653
 

0.936
 

3.547
 

HIGH
 

DOSE
 

0/50(0.00)
 

N.S.
 

0.000
 

0.000
 

1.845
 

3/50(0.06)
 

N.S.
 

0.300
 

0.049
 

1.642
 

84
 

26/49(0.53)
 

N.S.
 

1.289
 

0.705
 

2.231
 

Weeks to First Observed Tumor 104 72
 84
 
TABLE 4 (CONCLUDED)
 

TOPOGRAPHY : MORPHOLOGY CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Mammary Gland:

P Values0 

 Fibroadenoma 1/20(0.05) 

N.S. 

8/50(0.16) 

N.S. 

4/50(0.08) 

N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

3.200 

0.432 

138.771 

1.600 

0.175 

77.168 

Weeks to First Observed Tumor 104 98 104 

a

Treated groups received doses of 37.5 or 75 ppm in feed.
 

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

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

the control group when P < 3.05; otherwise, not significant (N.S.) is indicated. The probability
 

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

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

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

e

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

group when P < 0.05.
 
In male rats the Cochran-Armitage test indicated a significant
 

negative association between dose and the combined incidence of
 

C-cell adenomas and C-cell carcinomas of the thyroid. The Fisher
 

exact tests, however, were not significant.
 

In female rats the Cochran-Armitage test indicated a significant
 

negative association between dose and the incidence of basal-cell
 

tumors of the subcutaneous tissue. The Fisher exact tests, however,
 

were not significant.
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

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

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

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

of statistically significant results. It should also be noted that
 

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

indicating the theoretical possibility of tumor induction in rats by
 

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

27
 
IV. CHRONIC TESTING RESULTS: MICE
 

A. Body Weights and Clinical Observations
 

No consistent dose-related mean body weight depression was noted
 

in either male or female mice (Figure 4). In female mice, however,
 

mean body weight was lower in dosed animals than in controls beginning
 

in week 45.
 

No abnormal clinical signs were recorded.
 

B. Survival
 

The estimated probabilities of survival for male and female mice
 

in the control and triphenyltin hydroxide-dosed groups are shown in
 

Figure 5. For male mice the Tarone test for association between increased dosage and elevated mortality was significant (P = 0.017);
 

but for females it was not significant.
 

The percentages of male and female mice surviving on test are
 

shown in Figure 6. For males, despite 4 missing high dose males and
 

6 missing low dose males, there were adequate numbers at risk from
 

late-developing tumors. Sixty-six percent (33/50) of the high dose,
 

74 percent (37/50) of the low dose, and 95 percent (19/20) of the
 

control mice survived on test until the termination of the study.
 

For females, despite 2 missing high dose, 8 missing low dose,
 

and 2 missing control group mice, there were adequate numbers at risk
 

from late-developing tumors. Seventy-six percent (38/50) of the high
 

dose, 72 percent (36/50) of the low dose, and 65 percent (13/20) of
 

the control mice survived on test until the end of the study.
 

28
 
-50 

-40 

— 30 

-20 

CONTROL 

10- -10 

LOW DOSE 

MALE MICE HIGH DOSE 

I I I 1 I [ I

 

15 30 45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

120 

TIME ON TEST (WEEKS) 

FIGURE 4 

GROWTH CURVES FOR TRIPHENYLTIN HYDROXIDE CHRONIC STUDY MICE 

29 
c3 0 0 0 O c3 0 0 0 

c3 NJ •f^ Ol 00 c^ cD fO •t* Oi 

c/j 1 | 1 1 1 1 1 1 1

 I 1 1 1 1 1 1 

c <=-

o — 

•33 

^

^

m > <

 i— >

m > r~ r~ S •o

 m 

2 (J1

 ~ O

5 *-r m 00

O •^ 

1£

m 

­

< to CO 

0 ~~ 0 °~

 

0 

2

5

­

^37 

H -^ 8 _ H£

~J 01 0 1 ­

^ 

^ OT m

 m 

o *3 i -

z 

3C5 H H 

Vj>l — C m m 0

 3* 3§-

r 3 8­

Z<» g S

 < m

 m

 

r" m m

 

H * 4 A 

C/3 z <2 w. -xj _

 -j

I H Ul

r 

3D 1 1

O

• |

X 

m io_ i i—«ii o — 1 

0 1

CO 5

0 ° l j< 

I

3D Jv/ 1 

O !i

 FH ! 

Z 1 pi ! 

0 I r i i- § i ni

 3 

o o i H °J I i H in — H

 

C D g 3 73

° 0 O

 0 g O w 8 8 r

 

m

O 

r •< _

m m -

o 

m -•

 _» NJ — 1 1 j 1 | 1 | 1 i ^ ro o — 1 I | I | 

0 i

 

1 

_. 

o o o c o o 

3 0 3 0 

3 ro -Cfc O5 CO o c3 M -C* C5 
1 0­ — 1 0 

!L_. 

08 -08 

> 06- -06 

tr 

CO 

04 ­ -04 

CC 

LLJ Q_ 

C ONTROL 

02- - 02 

LOW DOSE 

HIGH DOSE MALE MICE 

0 0 - i _l_ \ ' I ' T r -0 0 

15 30 45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

— 1 0 

08 08 

06 — — 06 

CC 

C/3 

-04 

o 

CC 

LLJ 

Q_ 

CONTROL 

02- - 02 

LOW DOSE 

FEMALE MICE HIGH DOSE 

00- | n > 1 1 r ~~T T-

-0 0 

15 30 45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

FIGURE 6 

PERCENT SURVIVAL OF TRIPHENYLTIN HYDROXIDE CHRONIC STUDY MICE 

31 
C.	 Pathology
 

Histopathologic findings on neoplasms in mice are summarized in
 

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

summarized in Appendix D (Tables Dl and D2).
 

The observed neoplasms occurred with approximately equal frequency in dosed and control mice or occurred in insignificant numbers. These lesions are not uncommon in this strain of mice.
 

In addition, a number of degenerative, proliferative, and inflammatory changes were encountered in dosed and control mice. As
 

with the neoplastic lesions, these changes are not uncommon in this
 

strain of mice.
 

The results of this pathologic examination indicate that triphenyltin hydroxide was not carcinogenic in B6C3F1 mice under the conditions of this bioassay.
 

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 triphenyltin
 

hydroxide-dosed groups and where such tumors were observed in at
 

least	 5 percent of the group.
 

None of the statistical tests for any site of either male or
 

female mice indicated a significant positive association between
 

chemical administration and tumor incidence. Based upon these
 

32
 
TABLE 5
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE MICE TREATED WITH TRIPHENYLTIN HYDROXIDE2
 

TOPOGRAPHY: MORPHOLOGY
 

Lung: Alveolar/Bronchiolar Adenoma or
 

Alveolar /Bronchiolar Carcinoma^
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Leukemia or Malignant Lymphomak
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma or
 

Hepatocellular Adenoma'3
 

P Values
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

CONTROL
 

3/20(0.15)
 

N.S.
 

104
 

2/20(0.10)
 

N.S.
 

103
 

5/19(0.26)
 

N.S.
 

LOW
 

DOSE
 

5/44(0.11)
 

N.S.
 

0.758
 

0.168
 

4.536
 

102
 

5/44(0.11)
 

N.S.
 

1.136
 

0.210
 

11.319
 

98
 

6/44(0.14)
 

N.S.
 

0.518
 

0.156
 

1.932
 

HIGH
 

DOSE
 

6/45(0.13)
 

N.S.
 

0.889
 

0.218
 

5.104
 

104
 

10/46(0.22)
 

N.S.
 

2.174
 

0.531
 

19.281
 

76
 

10/44(0.23)
 

N.S.
 

0.864
 

0.324
 

2.871
 

Weeks to First Observed Tumor 104 75 76
 
TABLE 5 (CONCLUDED)
 

3.
 

Treated groups received doses of 37.5 or 75 ppm In feed.
 

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

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

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

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

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

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

TABLE 6
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE MICE TREATED WITH TRIPHENYLTIN HYDROXIDE2
 

LOW HIGH
 

TOPOGRAPHY : MORPHOLOGY CONTROL DOSE DOSE
 

Hematopoietic System: Leukemia or Malignant Lymphomab 6/18(0.33) 9/42(0.21) 14/48(0.29)
 

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

Relative Risk (Control) 0.643 0.875
 

Lower Limit 0.252 0.392
 

Upper Limit 1.924 2.429
 

Weeks to First Observed Tumor 88 79 83
 

to
 

Ln Liver: Hepatocellular Adenoma or Hepatocellular Carcinoma^ 1/18(0.06) 2/42(0.05) 4/48(0.08)
 

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

Relative Risk (Control) 0.857 1.500
 

Lower Limit 0.049 0.166
 

Upper Limit 49.369 72.294
 

Weeks to First Observed Tumor 104 104 97
 

Treated groups received doses of 37.5 or 75 ppm in feed.
 

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

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

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

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

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

The 95% confidence interval on the relative risk of the treated group to the control group.
 
statistical results there was no evidence that triphenyltin hydroxide
 

was a carcinogen in B6C3F1 mice under the conditions of this test.
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

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

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

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

of statistically significant results. It should also be noted that
 

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

indicating the theoretical possibility of tumor induction in mice by
 

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

36
 
V. DISCUSSION
 

In male mice there was a significant dose-related decrease in
 

survival; however, in both species adequate numbers of animals in all
 

groups survived sufficiently long to be at risk fruii, late-developing
 

tumors. Male rats and female mice had a slight depression of mean
 

body weight gain relative to controls. In rats and female mice no
 

significant accelerated mortality, retardation in growth, or other
 

signs of toxicity were associated with the dietary administration of
 

triphenyltin hydroxide. Therefore it is possible that the compound
 

was not administered to these animals at the maximum tolerated concentration.
 

No tumors occurred in rats or mice at a significantly higher
 

incidence in dosed groups than in corresponding control groups.
 

Under the conditions of this bioassay, there was no evidence for
 

the carcinogenicity of triphenyltin hydroxide to Fischer 344 rats or
 

to B6C3F1 mice.
 

37
 
VI. BIBLIOGRAPHY
 

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

J. Wiley & Sons, New York, 1971.
 

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

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

Union Against Cancer, Geneva, 1969.
 

Chemical Abstracts Service, The Chemical Abstracts Service (CAS)
 

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

Chemical Society, Washington, 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.
 

Epstein, S.S., E. Arnold, J. Andrea, W. Bass, and Y. Bishop, "Detection of Chemical Mutagens by the Dominant Lethal Assay in the
 

Mouse." Toxicology and Applied Pharmacology 23:288-325, 1972.
 

Farm Chemicals Handbook, Meister 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.
 

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

Observations." Journal of the American Statistical Association
 

5_3_:457-481, 1958.
 

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

"Carcinogenesis Bioassay Data System." Computers and Biomedical
 

Research 7:230-248, 1974.
 

Martin, H. and C.R. Worthing, editors. Pesticide Manual, fifth edition. British Crop Protection Council, 1977.
 

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.
 

38
 
Spencer, E.Y., Guide to the Chemicals Used in Crop Protection. Publication 1093, Information Canada, Ottawa, 1973.
 

Stanford Research Institute, 1977 Directory of Chemical Producers,
 

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

Suzuki, R., H. Shoyama, and K. Tabuko, "Organotin Compounds." Japan
 

Patent 68 29,371, December 1968.
 

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

62:679-682, 1975.
 

39
 

Review of the Bioassay of Triphenyltin Hydroxide*
 

for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

June 29, 1978
 

The Clearinghouse on Environmental Carcinogens was
 

established in May, 1976, in compliance with DREW Committee
 

Regulations and the Provisions of the Federal Advisory
 

Committee Act. The purpose of the Clearinghouse is to
 

advise the Director of the National Cancer Institute (NCI)
 

on its bioassay program to identify and to evaluate chemical
 

carcinogens in the environment to which humans may be exposed.
 

The members of the Clearinghouse have been drawn from
 

academia, industry, organized labor, public interest groups,
 

State health officials, and quasi-public health and research
 

organizations. Members have been selected on the basis of
 

their experience In carcinogenesis or related fields and,
 collectively, provide expertise In chemistry, biochemistry,
 

biostatistics, toxicology, pathology, and epidemiology.
 

Representatives of various Governmental agencies participate
 

as ad hoc members. The Data Evaluation/Risk Assessment
 

Subgroup of the Clearinghouse is charged with the responsibility of providing a peer review of reports prepared on
 

NCI-sponsored bioassays of chemicals studied for carcinogenic-


Ity. It is in this context that the below critique is given
 

on the bioassay of Triphenyltin Hydroxide for carcinogenicity.
 

The reviewer agreed with the conclusion in the report
 

that Triphenyltin Hydroxide was not carcinogenic in rats or
 

mice, under the conditions of test. Although the control
 

groups were smaller than the optimal size, he thought the
 

study was adequate enough on which to base the conclusion.
 The reviewer moved that the report on the bioassay of Triphenyltin Hydroxide be accepted as written. The motion was
 

approved without objection.
 

Clearinghouse Members present:
 

Arnold L. Brown (Chairman), Mayo Clinic
 

Paul Nettesheim, National Institute of Environmental
 

Health Sciences
 

Verne Ray, Pfizer Medical Research Laboratory
 

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

Louise Strong, University of Texas Health Sciences Center
 

Subsequent to this review, changes may have been made
 

in the bioassay report either as a result of the review
 

or other reasons. Thus, certain comments and criticisms
 

reflected in the review may no longer be appropriate.
 

41
 

JJ.L.S . G0\ERNMEN T PR.N T N G OFF'C E '978-26 0 899/ 3 8 3 

APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH TRIPHENYLTIN HYDROXIDE
 

TABLE Al

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH TRIPHENYLTIN HYDROXIDE 

CONTROL (UNTR) LOW DOSE HIGH DOSE
 

1 1-1335 11-1333 11-1331
 

8NIMALS INITIALLY IN STUDY 20 50 50
 

ANIMALS NECROfSIED 20 50 50
 

ANIMALS EXAMINED HISTO PATHOLOGICALLY** 20 50 50
 

INTEGUMENTAR Y SYSTEM 

•SDBCUT TISSUE (20) (50) (50) 

BASAL-CELL TUHOR 2 {«*) 

SEBACEOUS ADENOM A 1 (2X) 

FIBROMA 2 (UX) 

CARCINOSAiCOSA 1 15%) 

NEUROFIBROMA 1 <5X) 

NEUROFIBROSASCOMA 1 <2X) 

RESPIRATORY SYSTEM 

*LUNG (20) (19)
 

ALVEOLAR/dRONCHIOLAR ADENOMA 1 (5X) 1 (2X) (UX)
 C-CELL CAKCINOMA, METASTATIC 1 (2X)
 NEUROPIBROSARCOMA, METASTATIC (2X)
 

HEMATOPOIETIC SYSTEM
 

*MULTIPLE ORGANS (20) (50) (50)

 

MALIGNANT LYMPHOMA, NOS 3 (6X) 

LEUKEMIA.NOS 3 (6X)

 

CIRCULATOR Y SYSTE M 

NONE 

DIGESTIVE SYS1EM 

ILIVER (19) (50) (50)

 

HEPAIOCELl.UL&R_ADENOM A 

t NUMBE R OF ANIMAL S KITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

A-3 
TABLE Al (CONTINUED)
 

CONTROL (UNTR) LOW DOSE HIGH DOSE
 

11-1335 11-1333 11-1331
 

•PANCREAS	 (19) (taj (49)
 ADENOMA, NOS 1 (5X)
 

*SMALL INiESilNE (20) (U9) (50)
 SARCOMA, SOS 1 (2*)
 

URINARY SYSTEM
 

NONE
 

ENDOCRINE SYSTEM
 

IPITU1TARY (20) (US) (46)
 CHHOMOPHOdE ADENOMA 2 (10X) 5 (10*) 9 (20*)
 

•ADRENAL	 (20) (50) (K9)
 

PHEOCHROMOCYTOMA 2 (10%) 2 («*) 3 (6*)
 

PHEOCHROMOCYTOMA, MALIGNANT 1 (2*)
 

tTHYHOIO (18) (41) («"»)
 FOLLICULAK-CELL ADENOMA 1 (6X)
 

C-CELL ADiNOMA 1 (6») 1 (2*)
 C-CELL CAaCINOMA 1 (6*) 1 (2X)
 

• PANCREATIC J.SLETS (19) (1*8) (49)
 

ISLET-CELL ADENOMA 2 imj 2 (<**) 3 (6*)
 

ISLET-CELi. CARCINOMA 1 (2X)
 

REPRODUCTIVE oYSTEM
 

*MAMMAR Y iSLAND (20) (50) (50)
 

FIBROADENOMA 1 (2X)
 

*TESTIS (19) (50) (50)
 

INTERSTITIAL-CELL TUMOR 17 (89*) 1*6 (92*) 49 (98*)
 

NERVOUS SYSTEM
 

*BBAIN (20) (18) (47)
 

GLIOMA, NUS 1 (2*)
 

SPECIAL SENSE ORGANS
 

NONE
 

» NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBE R OF AHIMALS NECROPSIED
 

A-4
 
TABLE A1 (CONTINUED) 

SUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*ABDOMINAL CAVITY


MESOTHELIUMA, NOS


*PERITONEOM


MESOTHELIUMA, NOS


*TUNICA VAGINALIS


MESOTHELIOMA, NOS


ALL OTHER SYSTEMS
 

NONE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY


NATURAL DEATHS


MORIBUND SACRIFICE


SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE


ANIMAL MISSINu
 

a	 INCLUDES AUt'OLYZED ANIMALS
 

t NUMBE R OF ANIMALS WITH TISSUE

* NUMBE R OF ANIMAL S NECROPSIED 

CONTROL(UNTR)


11-1335


 (20)


 (20)


 (20)


 20


 2


 3
 

 15


 LOW DOSE HIGH DOSE
 

 11-1333 11-1331
 

 (50)	 (50)
 

1 (2JS)
 

 (50)	 (50)
 

1 (2%)
 

 (50)	 (50)
 

2 (4X)
 

 50 50
 

6
 

6 8
 

 38 12
 

 EXAMINE D MICROSCOPICALLY 

A-5 
TABLE Al (CONCLUDED) 

CONTROL (UNTR) L OW DOSE HIGH DOSE 

11-1335 11-1333 11-133 1 

TUMO R SUMMAR Y 

TOTAL ANIMAL S WIT H PRIMAR Y TUMORS * 18 49 50 

TOTAL PHIHAR Y TUMOR S 30 76 71 

TOTAL ANIMALS ilTH BFNIGN TDMORS 17 HI 50
 

TOTAL BENIGN TUMORS 28 64 67
 

TOTAL ANIMAL S WIT H MALIGNAN 2 T TUMORS 8 3 

TOTAL MALIGNAN T TUMOR S 2 9 3 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1 1 

TOTAL SECONDAR Y TUMORS 1 1 

TOTAL ANIMAL S WITH TUMOR S UNCERTAIN ­

BENIGN OR MALIGNANT 3 1 

TOTAL UNCERTAI N TUMORS 3 1 

TOTAL ANIMAL S HITH TUSORS UNCERTAIN ­

PRIMAR Y O R HETASTATIC

 

TOTAL UNCERTAI N TUMORS 

* PRIMAR Y TUMORS : ALL TUMOR S EXCEPT SECONDAR Y TUMOR S 

• SECONDAR Y TJMORS : METASTATIC TUMORS 08 TUMORS INVASIVE INTO AN ADJACENT ORGAH 

A-6 
TABLE A2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

TREATED WITH TRIPHENYLTIN HYDROXIDE 

CONTROL (UNIR) LOW DOSE HIGH DOSE 

11-1336 11-1334 11-1332 

ANIMAL S INITIALLY IN STUD Y 20 50 50 

ANIMALS NEC80PSIED 20 50 50 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY* * 20 50 50 

INTEGUMENTAR Y SYSTEM 

*SKIN (20) (50) (50) 

BASAL-CELi. CARCINOM A 1 (2%) 

*SUBCU T TISSUE (20) (50) (50) 

BASAL-CELL TUMO R 2 (10J5) 1 (2*) 

FIBROADENOM A 1 (2X) 

RESPIRATORY SYSTEM 

ILUN G (20) (50) (50) 

BASAL-CELi. CARCINOMA , METASTATIC 1 (2%) 

ALVEOLAR/BROBCHIOLA R ADENOM A 2 (IX) 1 (2%) 

ALVEOLAE/BRONCHIOLAB CARCINOMA 1 (5)t) 

HEMATOPOIETIC SYSTEM 

*MULTIPL2 ORGANS (20) (50) (50) 

MALIGNAN T LYMPHOMA . NOS 2 (10)1) 2 (4%) 1 (2%) 

LEUKEMIA,NO S 2 (10X) 1 (2%) 

tMESENTERIC j,. NOD E (20) (1*4) (50) 

MALIGNAN T LYMPHOMA , NOS 1 (2X) 

CIRCULATOR Y SYSTEM 

(HEART (20) (49) (50) 

SARCOMA , NOS 1 (21} 

DIGESTIVE SYSi'EM 

tLIVEfi (19) (50) (50) 

NEQPLASTIC NODULE , 

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECSOPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

A-7 
TABLE A2 (CONTINUED)
 

CONTROL (UHtH) LOW DOSE HIGH DOSE
 

11-1336 11-1334 11-1332
 

URINARY SYSTEM
 

NONE
 

ENDOCRINE SYSiEM
 

(tPITUITAEY (17) (47) (49)
 CHEOMOPHOBE ADENOMA 7 (41X) 32 (68X) 26 (53X)
 

•ADRENAL	 (20) (48) (50)
 CORTICAL 4DENOMA 1 (5*)
 PHEOCHROMJCYTOMA 1 (2X)
 

tldYHOID	 (17) (47) (42)
 FOLLICULAh-CELL ADENOMA 1 (2%)
 

C-CELL ADENOMA 1 (2X)
 

C-CELL CArtCINOMA 1 (6X)
 

SEPEODUCTIVE bYSXEM
 

*MAMMAR Y GLAND (20) (50) (50)
 ADENOMA, NOS 1 (2X)
 FIBROADENOMA 1 (5*) 8 (16X) 4 (8X)
 

»»AMMARY DUCi (20) (50) (50)
 

CYSTADENOMA, NOS 1 (2X)
 

IUTERUS (18) (47) (48)
 ENDOMETEIAL STROMAL POLYP 1 (6*) 1 (2*) 1 (2X)
 

NERVOOb SYSTEM
 

*BHAIN (18) (47) (49)
 

GLIOMA, NOS 1 (2»)
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCOLOSKSLETAL SYSTEM
 

NONE
 

* NUMBER OF AUIMALS HUH TISSUE EXAfllNED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

A-8
 
TABLE A2 (CONCLUDED)
 

CONTROL(UNTB) LOU DOSE HISS DOSE
 

11-1336 11-1334 11-1332
 

BODY CAVITIES
 

MOKE
 

ALL OTHEB SYSTEMS
 

OMENTUM
 

LIPOSARCOMA
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INIIIALLY IN STUDY 20 50 50
 

NATURAL DEATHS
 

MORIBUND SACRIFICE 5
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERHINAL SACRIFICE 18 145
 

ANIMAL MLSSINS
 

3 INCLUDES AUTOLYZED ANIMALS
 

TUMOR SUMMAR Y
 

TOTAL ANIMAi.3 WITH PSIMAHY TUMORS* 12 39 31
 

TOTAL PRIMARY TUMORS 18 53 39
 

TOTAL ANIMALS WITH BENIGN TUMORS 9 36 29
 

TOTAL BENIGN TUMORS 12 U7 35
 

TOTAL ANIMAi.3 WITH MALIGNANT TUMORS 6 5 U
 

TOTAL MALIGNANT TUMORS 6 5 t
 

TOTAL ANIMALS WITH SECONDARY TUMORSt 1
 

TOTAL SECONDARY TUMORS


TOTAL ANIMALS WITH TUMORS HNCERIAINBENIGN OR MiLIGNANT 1
 

TOTAL UNCERTAIN TUMORS 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAINPBIHAHY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

A-9
 

 1 

APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH TRIPHENYLTIN HYDROXIDE
 

TABLE Bl

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH TRIPHENYLTIN HYDROXIDE 

_-" ' -'— •-

CONTROL(UNTR) 

22-2335 

LOW DOSE 

22-2333 

HIGH DOSE 

22-2331 

ANIMALS INITIALLY IN STUCK 

ANIMALS MISSIliG 

ANIMALS NECBOPSIED 

ANIMALS EXAMINED HISTO PATHOLOGICALLY** 

20 

20 

20 

50 

6 

in 

44 

50 

4 

46 

15 

INTEGUMENTARY SYSTEM
 

NONE
 

RESPIRATORY SYSTEM
 

fLUNG (20) ' (44) (45)
 

HEPATOCELLULAR CARCINOMA, METAST 4 (9%)
 

ALVEOLAR/dRONCHIOLAR ADENOMA 2 (10X) 4 (9X) 6 (13*)
 

ALVEOLAR/BRONChlOLAR CARCINOMA 1 (5X) 1 (2%)
 

HEMATOPOIETIC SYSTEM
 

*MULTIPLE ORGANS (20) (44) (46)
 

MALIGNANT LYMPHOMA, NOS 3 (7X) 6 (13%)
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 2 (4X)
 

MALIGNANT LYMPHOMA, MIXED TYPE 1 (2X)
 

LEUKEMIA,!<OS 1 (2%)
 

tLYMPH NODE (20) (38) (37)
 

MALIGNANT LYMPHOMA, NOS 1 (5X)
 

tMESENTERIC L. NODE (20) (38) (37)
 

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

•LIVER	 (19) (44) (44)
 

GRANULOCY1IC SARCOMA 1 (2%)
 

ISMALL INTfSIINE (19) (44) (44)
 

MALIG.LYMPHOMA, UNDIFPER-TYPE 1 (2X)
 

CIRCULATORY SYSTEM
 

NONE
 

* NUMBE R OF ANIMAL S KITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-3 
TABLE Bl (CONTINUED) 

CONTROL(UNTR) LOU DOSE HIGH DOSE 

22-2335 22-2333 22-2331 

DIGESTIVE SYSiEB 

ULIVER (19) (4<t) (U4) 

BILE DUCT CARCINOBA 1 (2X) 

HEPATOCELi-nLAH ADENOMA 2 (11%) 5 (11%) 3 (7%) 

HEPATOCELLULAR CARCINOBi 3 (16*) 1 (2X) 7 (16X) 

*COLON (18) (11) (43) 

SAHCOBA, MOS 1 (2X) 

URINABY SYSTEM 

NONE 

JSDOCRINE SYSIEB 

tADRENAL (16) (36) (37) 

SARCOMA, DOS 1 (3X) 

#THYHOID (15) (33) (38) 

FOLLICULAK-CELL ADEHOMA 1 (3X) 

BEPHODHCTIVE SYSTEB 

tTESTIS (20) (U3) (U5) 

INTERSTITIAL-CELL TUH08 1 (2X) 

NEBVOU S SYSTEM 

NON E 

SPECIAL SENSE ORGAN S 

NON E 

HUSCULOSKELETAL SYSTEM 

NON E 

I NUMBE R OF ANIMAL S KITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBE R OF ANIMALS HECROPSIED 

B-4 
TABLE Bl (CONCLUDED)
 

CONTROL (UNTR) LOU DOSE HIGH DOSE
 

22-2335 22-2333 22-2331
 

BODY CAVITIES
 

•MESENTERY	 (20) (4U) (46)
 CARCINOMA,NOS 1 (5)1)
 

ALL OTHER SYSTEMS
 

NONE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 20 50 50
 

NATURAL DEATHS 1 4 9
 MORIBUND SACRIFICE 3 4
 SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 19 37 33
 ANIMAL HISSING 6 4
 

3 INCLUDES AUi'OLYZED ANIMALS
 

TUMOR SUMMARY
 

TOTAL ANIMAl-S BITH PRIMARY TUMORS* 10 19 22
 

TOTAL PRIMARY TUMORS 11 19 29
 

TOTAL ANIMALS WITH BENIGN TUMOBS 4 10 8
 

TOTAL BENiGN TUMORS 4 10 10
 

TOTAL ANIMAi.3 WITH MALIGNANT TUMORS 7 9 17
 

TOTAL MALIGNANT TUMORS 7 9 19
 

TOTAL ANIHALS WITH SECONDARY TUMORS* 4
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMA-S WITH TUMORS UNCERTAINBENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS KITH TUMORS UNCEBTAINPEIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

B-5
 

4 
TABLE B2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED 

WITH TRIPHENYLTIN HYDROXIDE 

CONTROL (UNTR) LOW DOSE HIGH DOSE 

22-2336 22-2334 22-2332 

ANIMALS INITIALLY IN STUD Y 20 50 50 

ANIMALS HISSING 2 8 2 

ANIMALS NECROPSIED 18 42 U8 

ANIMALS EXAMINE D HISTOPATHOLOGICALLY** 18 1)2 K8 

INTEGOMENTARY SYSTEM
 

NONE
 

RESPIRATORY SYSTEM
 

ILUNi (18) (HO) (46)
 

ALVEOLAR/oBONCHIOLAR ADENOMA 1 (3X) 2 (4X)
 

HEMATOPOIETIC SYSTEM
 

*MHLIIPLE OBGANS (18) (42) (48)
 

MALIGNANT LYMPHOMA, NOS 2 (11%) 3 (7X) 7 (15X)
 

MALIG.LYUt-HOMA, HISTIOCYTIC TYPE 1 (6X) 3 (7X) 2 (4X)
 

PLASMA-CELL TUMOR 1 (2X)
 

LEUKEMIA,NOS 2 (11X) 1 (2%)
 

*MEDIASTINUM (18) (42) (48)
 

MALIGNANT LYKPHOMA. NOS 1 (2%)
 

• BONE MARROW (10) (35) (29)
 

HEMANGIOSARCOMA 1 (3X)
 

*SPLEEN (18) (39) (45)
 

HEMANGIOSARCOBA 1 (3X)
 

MALIGNANT LYMPHOMA, NOS 1 (2X)
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 1 (3X) 1 (2%)
 

IMESENTEHIC L . NODE (15) (40) (38)
 

SABCOBA, UOS 1 (3X)
 

MALIGNANT LYMPHOMA. NOS 1 (3X)
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 1 (3X)
 

MALIGNANT LYMPH0.1A. MIXED_TYgE 1 17*)
 

t NUMBER OF SNIMALS HITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-6 
TABLE B2 (CONTINUED) 

CONTROL(OMIB)

22-2336

 LOU DOSE

 22-2334

 HIGH DOSE 

 22-2332 

*LIVER

MALIGNAN T LYMPHOMA , NOS

tTHYMU S

MALIG.LYMPHOMA , HISTIOCYTIC TYPE

 (18)

 (1)

 1 (100X) 

 (12)

 (1)

 (48) 

1 (2X) 

 (6) 

;iRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

tLIVEE

HEPATOCELLULAB ADENOMA

HEPATOCELLULAH CARCINOMA

S4RCOMA, NOS

 (18)

 1 (61)

 (42)

 2 (5X)

 1 (2X) 

 (48) 

3 (6X) 

1 (2%) 

URINARY SYSTEM 

NONE 

ENDOCRINE SYSTEM 

NONE 

REPRODUCTIVE SYSTEM 

IUTEEU S

ENDOMETRIA L STROMA L

tOVARY

ADENOCARCINOBA, NOS

 POLYP

 (18)

 (17)

 1 (6*) 

 (40)

 1 (3X) 

 (33)

 (45) 

 (37) 

NEKVOUS SYSTEM 

*BRAIN

OLIGODENDKOGLIOMA

 (18)

 1 (6X) 

 (40) (45) 

SPECIAL SENSE ORGANS 

NONE _ . 

* NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF AMIMALS NSC80PSIED 

B-7 
HUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*MESENTEHY
 

HEMANGIOMA
 

ALL OTHER SYSl'EMS
 

HONE
 

JNIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY
 

NATURAL DEATHS
 

H08IBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL MISSING
 

i INCLUDES AUIOLYZED ANIMALS
 

TABLE B2 (CONTINUED) 

CONTROL (ONTR)
 

22-2336
 

(18)
 

1 (6%)
 

20
 

13
 

2
 

LOW DOSE HIGH DOSE 

22-2334 22-2332 

(12) (US) 

50 50 

36 38 

2 

I NUMBER OF ANIMALS SITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

B-8
 
TABLE B2 (CONCLUDED) 

CONTROL (UHTR) LOW DOSE HIGH DOSE 

22-2336 22-2334 22-2332 

TUMO R SUMMAR Y 

TOTAL ANINAl.5 MITH PRIMARY TDHO8S» 10 15 18 

TOTAL PRIMAR Y TUMORS 11 17 21 

TOTAL ANIMAL S HITH 2 BENIG N TUMOBS 4 5 

TOTAL EENiGN TUHORS 2 4 5 

TOTAL ANIMAL S WITH MALIGNAN T TUHORS 8 11 14 

TOTAL MALIGNAN T TUMORS 9 13 15 

TOTAL ANIMAL S HUH SECONDARY TUMORS* 

1OTAL SECONDAR Y TUMOBS 

TOTAL ANIMAL S MITH TUMORS UNCERTAINBENIG N OR MALIGNAN T 1

 

TOTAL UNCuBTAIN TOMOES 1 

TOTAL ANIMALS KITH TUMORS UNCERTAINPRIHAR Y OR SETASTATIC

 

TOTAL UNCERTAI N TUMORS 

* PEIMAB Y TUMORS : ALL TUMORS EXCEPT SECONDAR Y TUMORS 

I SECONDAR Y TUMORS : METASIATIC TUMORS OB TUMORS INVASIV E INTO AN ADJACENT ORGAK 

B-9 

APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH TRIPHENYLTIN HYDROXIDE
 

TABLE Cl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

TREATED WITH TRIPHENYLTIN HYDROXIDE 

CONTBOL(ONTB) LOU DOSE HIGH DOSE
 

11-1335 11-1333 11-1 331
 

ANIHALS INITIALLY IN STUDY 20 50 50
 ANIMALS NECROPSIED 20 50 50
 

ANIMALS EXAMINED HISTO PATHOLOGICALLY** 20 50 50
 

INTEGUMENTARY SYSTEM
 

• SKIN (20) (50) (50)
 

EPIDEBMAL INCLUSION CYSI 1 (2X)
 

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

HEMATOMA, NOS 1 (5*)
 

INFLAMMATION ACUTE AND CHHONIC 1 (2*)
 

REbPIBATORY SYSTEM
 

ITEACHEA (20) (18) C»8)
 

INFLAMMATION, NOS 2 (10X)
 

*LUNG/BRONCHUS (20) (U9) (49)
 

HYPERPLAS1A, EPITHELIAL 1 (2X)
 

*LUNG (20) (49) (K9)
 

HEHOERHAGu 1 (2X)
 

PNEUMONIA, ASPIRATION 1 (2X)
 

PNEUMONIA, CHRONIC MURINE 9 (45X) 21 (U3X) 16 (33»)
 

INPLAMMATJ-ON. FOCAL GRANULOMATOU 1 (5«)
 

PERIVASCUi-ITIS 1 (2X)
 

HYPERPLASiA, ADENOMATOUS 2 (10*) 1 (2X) 4 (8*)
 

HEMATOPOIETIC SYSIEM
 

*BONE MARROH (18) C»5) (47)
 

HYPEBPLASJ.A, HEBATOPOIETIC 2 (UX) 1 12%)
 

tSPLEEN (19) (50) (50)
 

CONGESTION, NOS 1 (2X)
 

HEMOSIDEROSIS. . . . . 6 (32%) 9 (18X) 10 120%)
 

I NUMBS R OF AiilMALS WIT H TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMALS NECBOPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

C-3 
TABLE Cl (CONTINUED) 

CONTROL (UNTB) LOW DOSE HIGH DOSE 

11-1335 11-1333 11-133 1 

LEUKEHOI D REACTION 2 (4X) 

HYPERPLASj.4, LYMPHOID 1 (2X) 

HEMATOPOIliSIS 5 (26X) 5 (10X) 10 (20X) 

•CERVICAL LYMPH NODE	 (20) (45) (49)
 

CYST, NOS	 1 <2X)
 

EDEMA, NOa	 2 (4X)
 

*MESENTERIC L. NODE (20) (45) (49)
 

EDEMA, NOS 2 (10X) 2 (4X) 1 (2%)
 

HYPERPLASIA, 8ETICULUM CELL 1 (2X)
 

tRENAL LYMPH NODE (20) (45) (49)
 

EDEHA, NOS 1 (2X)
 

CIRCULATORY SYSTEM
 

• rfEART (20) (49) (49) 

ENDOCARDIlIS, VERRUCOU S 1 (2X) 

PEEIVA5CU1.ITIS 1 <2X) 

• MYOCARDIU M (20) (49) (49) 

INFLAMMATION , FOCAL 1 (5X) 

FIBR03IS 1 (5X) 2 (4X) 5 (10X) 

FIBKOSIS, FOCAL 1 (2X) 1 (2X) 

DEGENERATION , NOS 7 (35X) 20 (41X) 15 (31X) 

DEGENERATION, GRANULAR 1 (2X) 1 (2X) 

DEGENERATION , HYALIN E 4 (20%) 6 (12X) 9 (18*) 

*AOETA (20) (50) (50) 

PERIARIER1TI 5 1 (2X) 

DIGESTIVE SYSIEM
 

ISALIVASY GLiND (19) (47)
 

INFLA.IHATiON, CHRONXC
 

ATROPHY, FOCAL
 

ILIVER (19) (50)
 

CYST, NOS <2X)
 IdROMBOSIS, NOS
 

CONGESTION, NOS	 1 (2X)
 DEGENERAIION, NOS
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-4
 
TABLECl (CONTINUED) 

CONTROL(UHTH ) L OW DOSE HIGH DOSE 

11-1335 11-1333 11-1331 

NECROSIS, FOCAL 1 (2X) METAMORPHOSIS FATTY 1 (5*) 1 (2X) 

BASOPHILIC CYTO CHANG E 4 [21 X) 6 (12X) 8 (16X) HYPEBPLAS1A, FOCAL 2 (11X) 8 (16X) 7 (14X) LEUKEHOI D REACTION 3 (6X) 

iLIVEB/CENTEiLOBOLAH (19) (50) (50) DEGENERATION , NOS 1 (2X) NECROSIS, NOS 1 (2X) 

*BILE 3UCT (20) (50) (50) 

HEMOHRHAGj. 1 (2X) 

HYPERPLASIA , NOS 5 (25X) 16 (32X) 11 (22%) 

• PANCREA S (19) (48) (49) INFLAMMATION , NO S 1 (2X) 

FIBBOSIS 1 (2X) 

PERIAHTERj-TIS 2 (4X) 

PEHIVASCULITIS 1 (2%) ATROPHY , FOCAL 1 (5X) 2 (4X) 2 (4X) 

tPANCREATIC ACINUS (19) (48) (49 ) 

ATEOPHY , UOS 2 (4X) 

•STOMACH (20) (49) (49) ULCER, NOb 1 (2%) 

GRANULATION , TISSUE 1 (2%) 

HYPERPLASJ.A, EPITHELIAL 1 (2%) 

*LARGE INTESilNE (20) (48) (49 ) 

NEMATODIAalS 6 (30%) 16 (33X) 17 (35X) 

URINAR Y SYSTEd 

• KIDNE Y (20) (50) (50) CYST, NOS 1 (2X) INFLAMMATION , CHRONIC 17 (85X) 42 (84X) 43 (86X) 

HEMOSIDEROS1S 1 (2X) 

*KIDNEY/TBBUL E (20) (50) (50) BASOPHILIC CYTO CHANG E 1 (5X) <2X) 1 (2*) 

ENDOCRINE SYSIEM
 

•ADRENAL	 (20) (50) (49)
 

SIIOM. NOS
 

• NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-5
 
TABLE Cl (CONTINUED) 

HEBOSIDEEOSIS 

*ADRENA L CORTEX 

HYPERPLAS1A, DOS 

*ADSENAL MEDULL A 

HYPERPLASiA , NOS 

•THYROID 

HYPERPLASIA , C-CELL 

tPANCREATIC J.SLETS

HYPEfiPLASiA, NOS

CONTROL (UHT8)

11-1335

1 (5%) 

(20) 

(20) 

(18) 

1 (6*) 

 (19 )

 LOU DOSE 

 11-1333 

(50) 

1 (2*) 

(50) 

<2X) 

(11) 

 (18)

HIGH DOSE 

11-1331 

(49) 

(19) 

(41) 

2 (5X) 

 (49) 

1 (2X) 

REPRODUCTIVE SYSTEM 

*SEMINAL VESICLE

INFLAMMATION, NOS

tTESTIS

GRANULOMA, SPERMATIC

DEGENERATION, NOS

ATROPHY, NOS

 (20)

 (19)

 1 (5X)

 (50)

 (50)

 1 (2%) 

3 (6X)

 (50) 

1 (2X) 

 (50) 

1 (2%) 

1 (2X) 

NERVOUS SYSTEM 

»BRAIN

HEMOBRHAGiC CYST

GLIOSIS

ATROPHY, NOS

 (20) (48)

 1 (2X) 

1 (2X) 

 (47) 

1 (2X) 

SP3CIAL SENSE ORGANS 

NONE 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

*MESENTEHY (20) (50)

INFLAMMATION. MOS .

» NUMBER OF ANIMALS KITH TISSUE EXAMINED MICBOSCOPICALLI 

* NUMBER OF ANIMALS NECROPSIE0 

 (50) 

 i_-L2Ji_ 

C-6 
TABLE Cl (CONCLUDED) 

CONTROL(UNTR) LO» DOSS HIGH DOSE 

11-1335 11-1333 11-1331 

ALL OTHER SYSTEMS 

ADIPOSE TISSDE 

NECROSIS, FAT 

SPECIAL MORPHOLOGY SOHHARY 

HO LESION REPORTED 

* NUMBE R OF ANIMALS UITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF AMXHALS NECROPSIED 

C-7 
TABLE C2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

TREATED WITH TRIPHENYLTIN HYDROXIDE 

CONTROL (UHTH) LOR DOSE HIGH DOSE
 

11-1336 11-1334 11-1332
 

ANIMALS INITIALLY IS STUDY 20 50 50
 ANIMALS NEC80PSIED 20 SO 50
 ANIMALS EXAMINED HISTO PATHOLOGICALLY ** 20 50 50
 

INTEGUMENTARY SYSTEM
 

NONE
 

RESPIBATOHY SYSTEM
 

tTBACHEA (16) (49) (18)
 

INFLAMMATION. NOS 1 (6X) 1 (2X)
 

• LUNG (20) (50) (50)
 PNEUMONIA, CHRONIC MUEINE 9 (45X) 21 (1)8%) 18 (36X)
 

INFLAMMATION, FOCAL GRANULOHATOU 1 (2%)
 

BASOPHILIk. CYTO CHANGE 1 (2X)
 FOAM-CELL 2 (4X) 2 (UX)
 

HYPEHPLASiA, ADENOMATOUS 1 (2X) 4 (8X)
 

HEMATOPOIETIC SYSTEM
 

•SPLEEN	 (17) C»6) (50) 

HEMOSIDEHOSIS 3 (18X) 12 (26X) 12 (24X) 

LEUKEBOID REACTION 1 (2X) 3 (6X) 

HEMATOPOIiiSIS 3 (18X) 13 (28X) 8 (16%) 

tCEBVICAL LYHPH NODE (20) (44) (50)

 

EBEMA, NOS 1 (2X)

 

#MiSENTERIC L. NODE (20) (44) (50) 

EDEMA, NOS 2 (5X) 1 12*) 

HYPEHPLASIA, BETICULUM CELL 1 (2X) 1 (2X) 

CIRCULATORY SYSTEM 

#MYOCARDIU M (20) (19) (50) 

INFLAMflAI10NJ_CH8QNIC 1_L2*J 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

** EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

C-K L. o 
TABLE C2 (CONTINUED) 

CONTROL (UNTR) LOW DOSE 

11-1336 11-1334 

FIBBOSIS 2 (10*) DEGENERATION, NOS 5 (25*) 19 (39X) 

DEGENERATION, HYALINE 3 (15X) 5 (10*) 

* AORTA (20) (50) 

INFLAHHAT.LON, NECBOIIZING 1 (2%) 

DIGESTIVE SYSTEM
 

•SALIVARY GLAND (20) (46)
 

INFLAMMATION, CHRONIC 1 (2X)
 

• LIVER (19) (50)
 DEGENERATION, NOS 2 (4»)
 

NECROSIS, FOCAL 1 (5»)
 METAMORPHOSIS FATTY 1 (5%)
 BASOPHILIC CYTO CHANGE 4 (21X) 15 (30X)
 

FOCAL CELi-ULAR CHANGE
 

HYPEBPLASIA, NOS 4 (8X)
 HYPEHPLASJ.A. FOCAL 8 (U2S) 13 (26%)
 

LEUKEMOID REACTION 1 (2X)
 

HEMATOPOItlSIS
 

*LIVER/CENTBILOBULAR (19) (50)
 

NECROSIS, NOS 2 (4X)
 

•LIVER/PERIPURIAL	 (19) (50)
 FIBHOSIS 1 (2X)
 

*BILE DUCT (20) (50)
 

HYPERPLASJ.A, NOS 6 (30*) 20 (40X)
 

fPANCBEAS (18) (49)
 FIBROSIS
 

ATROPHY, NOS 1 (6X)
 ATROPHY, FOCAL 1 (6X) 4 (8X)
 

tPANCREATIC ACINUS (18) (49)
 

ATEOPHY, NOS 1 <6X)
 

ISTOHACH (19) (49)
 

CYST, NOS 1 (2X)
 

ILARG E INTESriNE (20) (47) 

SEMATOD 

* NDHBER OF A&IMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUHBER OF ANIMALS NECROPSIED
 

C-9
 

HIGH DOSE
 

11-1332
 

1 (2X)
 15 (30%)
 

6 (12X)
 

(50)
 

1 (2X)
 

(49)
 

(50)
 

13 (26*)
 

1 (2X)
 

1 (2*)
 

21 (42X)
 

3 (6*)
 

1 (2X)
 

(50)
 

(50)
 

(50)
 

17 (34*)
 

(50)
 

(50)
 

1 (2*)
 

(50)
 

(49)
 
PARASITISM
 

URINARY SYSTEM
 

•KIDNEY
 

CYST, NOS
 

INFLAMMATION, CHRONIC
 

•KIDNEY/CORTtX
 

CYST, NOS
 

tKIDNEJ/PELVlS
 

INFLAMMATION, CHRONIC
 

ENDOCRINE SYSIEM
 

•PITUITARY
 

CYST, NOS
 

HEMORRHAGE
 

HEMORRHAGIC CYST
 

•ADRENAL
 

CYST, NOS
 

LIPOIDOSIb
 

ANGIECTASlS
 

•ADRENAL	 MEDULLA
 

HYPERPLASiA, NOS
 

•THYROID
 

INFLAMMATION. NEC80TIZING
 

HYPERPLASlA, C-CELL
 

• PANCREATIC iSLETS
 

HYPE8PLASJ.A, NOS
 

REPRODUCTIVE jYSTEH
 

*MAMMAR Y GLAMD
 

DILATATIOd/DUCTS
 

RETENTION FLUID
 

CYSTIC DUCTS
 

•	 NUMB3R OF ANIMALS HITH TISSUE EXAKINED MICROSCOPICALLY
 

*	 NUMBER OF ANIMALS NECBOPSIED
 

TABLE C2 (CONTINUED)
 

CONTROL (UNTR) LOW DOSE
 

11-1336 11-1334
 

1 (2X)
 

(20) (50)
 

1 (2X)
 

15 (75X) 1)3 (86%)
 

(20)	 (50)
 

1 (2X)
 

(20)	 (50)
 

1 (2*)
 

(17) (U7)
 

3 (6X)
 

1 12%)
 

1 (2X)
 

(20)	 (48)
 

1 (5%)
 

1 (2X)
 

(20)	 (48)
 

1 (2X)
 

(17)	 (47)
 

1 (6X)
 

1 (6X) 3 (6X)
 

(18)	 (49)
 

1 (2X)
 

(20)	 (50)
 

2 (4X)
 

1 (2X)
 

1 ISX) 3 J.6%1
 

C-10
 

HIGH DOSE
 

11-1332
 

(50)
 

36 (72X)
 

(50)
 

(50)
 

(49)
 

3 (6X)
 

(50)
 

1 (2X)
 

(50)
 

1 <2X>
 

(42)
 

1 (2X)
 

(50)
 

(50)
 

2 (4X)
 

1 <2X)
 
TABLE C2 (CONTINUED) 

CONTROL (DNTB) LOW DOSE HIGH DOSE 

11-1336 11-1331* 11-1 332 

tUTERtfS (18) (47) (48) CYST. NOS 2 (4X) 1 (2X) HEMORRHAGE 1 (2X) 

ICEBVIX UTERI (18) (1*7) (48)

 CYST, NOS 1 (6X)

 

tUTERUS/ENDOlIETRIUM (18) It 7) (48) 

hYPEBPLASlA, NOS 3 (17X) 2 (4X) 2 (IX) HYPEBPLAS.LA, CYSTIC 1 (6*) 2 (UX) 

#OVAH Y (17) (47) (45) 

CYST, NOS 2 (4X) FOLLICULAB CYST, NOS 1 (6X) 3 (6X) 

NERVOU S SYSTEM 

IBRAI N O8) (47) (49 ) HYDBOCEPHALUS, NOS 1 (6X) 1 (2X) ATROPHY, NOS 1 (6X) 6 (13X) 

*CE8EBELLUM (18) (47) (49) 

HEMORRHAG E 1 (6X)

 

SPECIAL SENSE ORGAN S 

NONE 

MUSCOLOSKELETA L SYSTEM 

NONE 

BODY CAVITIES 

*PELVIS (20) (50) (50)

 

SIEATITIS 1 (5X) 

*MESENTEfiY (20) (50) (50)

 

HEMAI011A. OBSANIZED . I_15XJ.

 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-ll
 
TABLE C2 (CONCLUDtD)
 

CONTROL (UNIE) LOU DOSE HIGH DOSE
 

11-1336 11-133U 11-1332
 

ALL OTHER SY Si'tMS 

ADIPOSE TISSUE
 

STEATITIS
 

SPECIAL MOBPHOLOGY SUMMARY
 

NO LESION REPORTED
 

» NUBBEB OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-12
 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH TRIPHENYLTIN HYDROXIDE
 

TABLE Dl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

TREATED WITH TRIPHENYLTIN HYDROXIDE 

CONTROL (UNTH) 

22-2335 

LOW DOSE 

22-2333 

HIGH DOSE 

22-2331 

ANIMALS INITIALLY IN STUDY 

ANIMALS HISSING 

ANIMALS NECROfSIED 

JNIMALS EXAMINED HISTOPATHOLOGICALLY** 

20 

20 

20 

50 

6 

44 

44 

50 

4 

46 

45 

INTEGUMENTARY SYSTEM 

NONE 

RESPIRATORY SYSTEM 

ILUNQ

EDEMA, NOS

PNEUMONIA, CHRONIC MUBINE

PERIVASCULAR CUFFING

 (20)

 1 (5X) 

 (414)

 2 (5X)

 (45) 

1 (2%) 

3 (7X) 

HEMATOPOIETIC SYSTEM 

tSPLEEN

HYPEBPLASiA, RETICULUB CELL

HYPERPLASJ.A, LYMPHOID

 (19) (41)

 1 (2X) 

 (41) 

1 (2X) 

ILYMPH NODE

INFLAMMATION, NECROTIZING

HYPERPLASiA, NOS

HYPERPLASiA, RETICULUM CELL

 (20) (38)

 1 (3X) 

1 (3X) 

1 (3H)

 (37) 

1 (3X) 

IMESENTERIC L. NODE

INFLAMMATION. CHEONIC

 (20) (38) (37) 

1 (3%) 

CIRCULATORY SYSTEM 

• HEAR T

MINERALI2ATION

 (18) (40) (U1 ) 

1 (2X) 

*MYOCARDIU M

FIBROSIS. FOCAL

 (18) (40)

 .

 (41) 

1 12K1 

i NUMBE R OF ANIMALS SITH TISSUE EXAMINE D

* NUMBER OF ANIMALS NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

D-3 
TABLE Dl (CONTINUED)
 

COHTBOL(UNTB) LOW DOSE
 

22-2335 22-2333
 

DIGESTIVE SYSTEM 

•SALIVARY GLAND 

PSEIVASCULAE CUFFING 

(18) (36) 

1 (3X) 

tLIVBB 

INFLAMMATION. NECROTIZII1G 

INFLAMMATION, ACUTB/CHBONIC 

PEHIVASCUi-AB CUFFING 

NECROSIS, NOS 

NECROSIS, FOCAL 

NECROSIS, HEMOBBHAGIC 

INFAHCT, NOS 

HYPEBPLASJ.A, NOS 

HEMATOPOItSIS 

(19) 

1

1

 (5*) 

 (5X) 

(14) 

2 (5X) 

1 (2X) 

1 (2X) 

ILIVEB/PERIPORTAL 

INFLAMMATJ-ON, NOS 

(19) Itt) 

1 (2X) 

*BiLE DUCT 

DILATATION, NOS 

LYMPHOCYTiC INFLANMATOB Y INFILTR 

(20) 

1 (5%) 

C4t) 

*PEYnRS PATCH 

HYPERPLASJ.A, NOS 

(19) (14) 

1 (2X) 

• LARGE INTESTINE 

PAHASITISil 

(18) 

3 (17*) 

(41) 

5 (12X) 

•COLON 

PABASITISM 

(18) (41) 

UBINARY SYSTEd
 

•KIDNEY	 (19) (t4)
 

LYBPHOCYT^C INFLAMMATORY INFILTE
 

PERIVASCULAR CUFFING 3 (16*) 2 (5X)
 

•URINARY	 BLADDER (19) (38)
 

tERIVASCULAR CUFFING
 

METAPLASIA, SQUAMOUS 1 (3K)
 

ENDOCBINE SYSTEM
 

•PANCREATIC ISLETS (19) (41)
 

HYPEKPLAS.LA. NOS
 

• NUMBER OF AMIHALS KITH TISSUE EXAMINED MICBOSCOPICALLY
 

* NUMBER OF ANIMALS NECBOPSIED
 

D-4
 

HIGH DOSE
 

22-2331
 

(34)
 

(44)
 

1 (2X)
 

1 (2X)
 

1 (2X)
 

1 (2X)
 

2 (5X)
 

(44)
 

(46)
 

1 (2X)
 

(44)
 

(13)
 

12 (28X)
 

(13)
 

3 (7X)
 

(41)
 

1 (2X)
 

1 (2X)
 

(33)
 

1 (3X)
 

(41)
 

1 (2X1
 
TABLE Dl (CONTINUED) 

CONTROL(OMTR)

22-2335

 LOW DOSE

 22-2333

 HIGH DOSE 

 22-2331 

REPRODUCTIVE SYSTEM 

• PROSTATE

INFLAMMATION, NOS

tTESTIS

ATROPHY, NOS

 (20)

 (20)

 1 (5X) 

 (38)

 1 (3X) 

 (43)

 (40) 

 (45) 

NERVOUS SYSTEM 

IBRAIN

SPONGIOSIj

COBPOHA AHYLACEA

CALCIFICATION. FOCAL

 (19)

 3 (16X)

 (44)

 1 (2X) 

9 (20*)

 (13) 

 14 (33*) 

1 (2*) 

SPECIAL SENSE ORGANS 

NONE ' 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

•MESENTERY

STEATITIS

NECROSIS, FAT

 (20)

 1 (5X) 

1 (5X) 

 (44) (46) 

ALL OTHEB SYSTEMS 

NONE 

SPECIAL MOHPHOLOSY SUMMARY 

NO LESION REPORTED 

ANIMAL HISSING/NO NECROPSY 

13 

f NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECBOPSIED 

D-5 
TABLE Dl (CONCLUDED)
 

CONTROL(ONTR) LOW DOSE HIGH DOSE
 

22-2335 22-2333 22-2331
 

AUTO/NECROESY/NO HISIQ
 

NUMBER OF ANIHALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

NUMBER OF ANIMALS NECBOPSIED
 

D-6
 
TABLE D2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

TREATED WITH TRIPHENYLTIN HYDROXIDE 

CONTROL (UNTB) LOU DOSE HIGH DOSS
 

22-2336 22-2334 22-2332
 

ANIMALS INITIALLY IN STUDY 20 50 50
 

ANIMALS HISSING 2 8 2
 

ANIMALS NECROPSIED 18 12 48
 

4&IMALS EXAHINED HISTOPATHOLCK UCALLY** 18 42 na
 

INTEGUMENTARY SYSTEM
 

*SKIN (18) (1*2) (18)
 

ABSCESS, NOS 1 (2%)
 

HESPIRATOBY SYSTEM
 

*LUNG (18) (tO) (1*6)
 ATELECTAS1S 1 (3*)
 

CONGESTION, NOS 1 (6X) 1 (3X)
 

EDEMA, NOS 1 (6%)
 

HEMORRHAGE 1 (3XJ 1 (2X)
 INFLAMMATION. INTERSTITIAL 1 (6X) 3 (8X) 1 (2%)
 PNEUMONIA. CHRONIC BURINE 3 (17X) 2 (5X) 1* (9X)
 

PERIVASCUi-AR CUFFING 1 (6*) 3 (8X) 3 (7*)
 

HEMATOPOIETIC SYSTEM
 

ISPLEEN (18) (39) (1(5)
 

PERIVASCULAR CUFFINS 1 (2X)
 

HYPERPLASIA, NOS 1 (3%) 1 (2%)
 

HYPE8PLAS1A. RETICULUM CELL 1 (3X)
 

HYPERPLASIA, LYMPHOID 1 (3%) 2 (H%)
 

ILYMPH NODE (15) (1*0) (38)
 

HYPERPLASIA, NOS 1 (3X)
 

tMESENTERIC L. NODE (15) (1*0) (38)
 

HYPERPLASIA , NOS 2 (5X) 1 (3«) 

HYE>EHPLASj.A , LYBPHOIB 1 (3S) 1 (3X) 

CIRCULATORY SYSTEM
 

*PULMONARY ASTERY (18) (U2) (18)
 

HYPERTROPHY. NOS 1
 

» NUMBE R OF ANIMALS KITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECBOPSIED **EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

D-7 
TABLE D2 (CONTINUED) 

CONTROL(OMIH) LOU DOSE HIGH DOSE 

22-2336 22-2331 22-2332 

DIGESTIVE SYSTEM 

*SALIVARY GLAND (16) (40) (39)
 INFLAMMATION, SUPPURATIVE 1 (3X)
 PERIVASCU1.AR CUFFING 1 (3X) 1 (3X)
 

*LIVER (18) (42) (48)
 INFLAMMATION, FOCAL 1 (2X)
 

LYMPHOCYT1C INFLAMMATORY INFILTR 2 (5X) 2 (4X)
 

PERIVASCUi-AR CUFFING 2 (5X) 7 (15X)
 

NECROSIS, FOCAL 1 (6X) 3 (7X)
 HYPERPLASIA, NODDLAB 1 (2X)
 HYPEHPLAS^A, NOS 1 (2X)
 ANGILCTASlb 1 (2X) 1 (2X)
 

•PEYERS PATCH (17) (41) (45)
 HYPEBPLAS^A, NOS 1 (2X)
 

• LARGE INTESilNE (17) (42) (47)
 

NEMATODIASIS 2 (5X)
 PARASITISM 1 (2X) 12 (26X)
 

*COLON (17) (42) (47)
 

PARASITISM 3 (6X)
 

URINAR Y SYSTEM 

tKIDNEY (18) (42) (48)
 

INFLAMMATION, FOCAL 1 (2X)
 

LYBPHOCYT1C IHFLAMBAIORY INFILTR 1 (6X) 1 (2X) 2 (UX)
 

PERIVASCU^AR CUFFING 1 (6X) H (10X) 7 (15X)
 

INDOCEINE SYSiEM
 

*IHYBOID (10) (33) (37)
 

HYPERPLASIA, CYSTIC 1 (10X)
 

tTHYROID FOLLICLE (10) (33) (37)
 

DILATATION, NOS 1 (3X)
 

REPRODUCTIVE oYSTEM
 

tUTERUS (18) (40) (45)
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

« NUMBE R Of ANIMAL S NECROPSIE D 

D-8
 
TABLE D2 (CONTINUED) 

CONTROL(UMTB ) LOH DOSE HIGH DOSE 

22-2336 22-2334 22-2332 

HEMOH8HAGJ.C CYST 1 (6X) 

ICERVIX DTEBi (18) (40) (45) 

INFLAMMATION. SUPPURATIVE 1 (6X) 

lUIERUS/ENDOMETRIl' B (18) (40) (45 ) 

CYST, NOS 6 (33X) 9 (23X) 6 (13X) 

INFLAMMATION , NO:; 1 (6X) 2 (5%) 

INFLAHBATJ.ON, ACUT E 1 (3*) 

HyPEPPLAS_A , SOS 2 (5X) 

HYPEItPLASIA , CYSTIC 3 (17*) 3 (8X) 9 (201) 

• OVAR Y (17) (33) (37) 

CYST, NO.S I (12%) 3 (9*) 3 (8«) 

FOLLlCULA n CYST, NO S 3 (IBS ) 1 (3X) 

PAROVABIAf i CYS1 3 (18X) 1 (3X) 1 (3X) 

HEKORRHiGi C CYST 1 (3X) 

NERVOU S JYSTiln 

*BHAIN (18) (40) (45)
 

SPONGIOS1S 1 (2X)
 

HEHORHHAGfi 1 (6X)
 

PEHIVASCDLA R CUFFIN G 1 (3X) 1 (2X) 

COBPOB A AflYtACE A 7 (39X) 2 (5X) 5 (11X) 

SPECIAL SENSE ORGANS
 

*BYE/LACRIMA1, GLAND (18) (42) (48)
 

HYPERPLASiA, NOS 1 (2X)
 

MU5CDLOSKEIETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*PERITONEU M (18) (42) (48 ) 

INFLAMMATi-GN , G[< AN ULOMATOU S 1 (2X) 

»MESENT£RY (18) (42) (48)
 

NECROSIS. FAT 1 (6X1 l_ilJ_J
 

I NUMBER OF AalMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF AMIBAIS HECEOPSIED
 

D-9
 
ALL OTHER 5YSIEMS
 

*MULTIPLE ORGANS
 

PEHIVASCULAR CUFFING
 

SPECIAL MORPHuLOGY SUMMAR Y
 

NO LESION REPORTED
 

ANIMAL MI-jSINS/NO NECROPSY
 

AUTO/NECKuPSY/HISTO PERF
 

TABLE D2 (CONCLUDED)
 

CONTROL (ONIR) LOW DOSE HIGH DOSE
 

22-2336 22-2334 22-2332
 

(IB) (it 2) (ItB)
 

1


2


* NUMBER OF Ai»IMALS HUH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF AMlMALS NECROPSIED
 

D-10
 

3 C7X)
 

6 2
 

8 2
 

1
 

DHEW Publication No. (NIH) 78-1394