1979 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 149 

BIOASSAY OF 

N,N'-DIETHYLTHIOUREA 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 105-55-5 

NCI-CG-TR-149 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

N,N'-DIETHYLTHIOUREA
 

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) 79-1705
 

REPORT ON THE BIOASSAY OF N.N'-DIETHYLTHIOUREA
 

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
 

N,N'-diethylthiourea 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 N,N'-diethylthiourea was conducted by
 

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

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

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. F. 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 Dr. N. J. Wosu
 

(4) at Litton Bionetics, Inc., the pathology narratives were written
 

by Dr. N. J. Wosu (4), and the diagnoses included in this report
 

represent the interpretation of this pathologist. Histopathology
 

findings and reports were reviewed by Dr. R. L. Schueler (8).
 

ill
 
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. Helfand (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 result's, and reporting the findings: Dr. K. C. Chu (1), 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 (1), Dr. H. A. Milman (1), Dr.
 

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

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

1.	 Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

2.	 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.
 

iv
 
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, B.C.
 

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

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

v
 

SUMMARY
 

A bioassay for the possible carcinogenicity of N,N'-diethylthiourea was conducted using Fischer 344 rats and B6C3F1 mice. N,N'-


Diethylthiourea was administered in the feed, at either of two concentrations, to groups of 50 males and 50 females of each species.
 

Twenty animals of each sex and species, except for 19 male mice, were
 

placed on test as controls. The high and low dietary concentrations
 

of N,N'-diethylthiourea were, respectively, 250 and 125 ppm for rats
 

and 500 and 250 ppm for mice. The compound was administered in the
 

diet for 103 weeks, followed by an observation period of 1 week for
 

all dosed groups.
 

There were no significant positive associations between the
 

dosages of N,N'-diethylthiourea administered and mortality in rats
 

or mice of either sex. Adequate numbers of animals in all groups
 

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

Compound-related mean body weight depression was apparent among dosed
 

male and female mice when compared to their respective controls, indicating that the concentrations of N,N'-diethylthiourea administered
 

to mice may have approximated the maximum tolerated dosages.
 

There were statistically significant elevated incidences of
 

follicular-cell carcinomas of the thyroid in high dose male rats. In
 

addition, there were statistically significant elevated incidences of
 

a combination of thyroid follicular-cell carcinomas and follicularcell adenomas in high dose male and female rats. '
 

Under the conditions of this bioassay, N,N'-diethylthiourea was
 

carcinogenic to Fischer 344 rats, causing follicular-cell carcinomas
 

of the thyroid in males and follicular-cell neoplasms of the thyroid
 

in females. There was no evidence for the carcinogenicity of the
 

compound in B6C3F1 mice.
 

vii
 

TABLE OF CONTENTS
 

Page
 

I. INTRODUCTION 1
 

II. MATERIALS AND METHODS 3
 

A. Chemicals 3
 

B. Dietary Preparation 4
 

C. Animals 5
 

D. Animal Maintenance 6
 

E. Selection of Initial Concentrations 7
 

F. Experimental Design 9
 

G. Clinical and Histopathologic Examinations 12
 

H. Data Recording and Statistical Analyses 13
 

III. CHRONIC TESTING RESULTS: RATS 18
 

A. Body Weights and Clinical Observations 18
 

B. Survival 18
 

C. Pathology 18
 

D. Statistical Analyses of Results 23
 

IV. CHRONIC TESTING RESULTS: MICE 32
 

A. Body Weights and Clinical Observations 32
 

B. Survival 32
 

C. Pathology 36
 

D. Statistical Analyses of Results 36
 

V. DISCUSSION 41
 

VI. BIBLIOGRAPHY 43
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH N,N'-DIETHYLTHIOUREA A-l
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH N,N'-DIETHYLTHIOUREA B-l
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH N,N'-DIETHYLTHIOUREA C-l
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH N,N'-DIETHYLTHIOUREA D-l
 

IX
 
LIST OF ILLUSTRATIONS 

Figure Number Page 

1 CHEMICAL STRUCTURE OF N,N'-DIETHYLTHIOUREA 2 

2 GROWTH CURVES FOR N.N1-DIETHYLTHIOUREA CHRONIC 

STUDY RATS 19 

SURVIVAL COMPARISONS OF N,N'-DIETHYLTHIOUREA 

CHRONIC STUDY RATS 20 

GROWTH CURVES FOR N,N'-DIETHYLTHIOUREA CHRONIC 

STUDY MICE 33 

SURVIVAL PROBABILITY COMPARISONS OF N,N'­

DIETHYLTHIOUREA CHRONIC STUDY MICE 34 

PERCENT SURVIVAL OF N,N'-DIETHYLTHIOUREA CHRONIC STUDY MICE 35 

LIST OF TABLES 

Table Number Page 

DESIGN SUMMARY FOR FISCHER 344 RATS— 

N,N'-DIETHYLTHIOUREA FEEDING EXPERIMENT 10 

DESIGN SUMMARY FOR B6C3F1 MICE—N,N'-DIETHYLTHIOUREA FEEDING EXPERIMENT H 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

N,N'-DIETHYLTHIOUREA 24 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH N,N'-DIETHYLTHIOUREA 28 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

N,N'-DIETHYLTHIOUREA 37 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH N,N'-DIETHYLTHIOUREA 39 
LIST OF TABLES (Concluded) 

Table Number 

Al SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH N.N'-DIETHYLTHIOUREA A-3 

A2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE RATS TREATED WITH N,N'-DIETHYLTHIOUREA A-7 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH N,N'-DIETHYLTHIOUREA B-3 

B2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH N,N'-DIETHYLTHIOUREA B-6 

Cl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH N,N'­

DIETHYLTHIOUREA C-3 

C2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH N,N'­

DIETHYLTHIOUREA C-8 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH N.N1 -

DIETHYLTHIOUREA D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH N.N1 

-

DIETHYLTHIOUREA D-6 

XI
 

I. INTRODUCTION
 

N,N'-Diethylthiourea (Figure 1) (NCI No. C03816), a corrosion
 

inhibitor and accelerator in elastomer manufacture, was selected for
 

bioassay by the National Cancer Institute because of the structural
 

similarity of this compound to ethylene thiourea, a tumorigen in hybrid mice (C57BL/6 x C3H/Anf and C57BL/6 x AKR) (Innes et al., 1969).
 

The Chemical Abstracts Service (CAS) Ninth Collective Index
 

*
 

(1977) name for this compound is N,N'-diethylthiourea. It is also
 

called 1,3-diethyl-2-thiourea, and 1,3-diethylthiourea.
 

N,N1-Diethylthiourea is used as a corrosion inhibitor in solutions of hydrochloric acid or sulfuric acid for the pickling of
 

iron or steel, and for reducing the corrosion of ferrous metals and
 

aluminum alloys in brine (Hawley, 1971; Rose and Rose, 1966).
 

N,N'-Diethylthiourea is also used as a vulcanization accelerator in
 

the manufacture of elastomers (Hawley, 1971).
 

Specific production data for N,N'-diethylthiourea are not
 

available; however, this compound is produced annually in quantities
 

greater than 1000 pounds or $1000 in value by two U.S. companies
 

(Stanford Research Institute, 1977).
 

The potential for exposure to N,N'-diethylthiourea is greatest
 

for workers involved in the production of this compound and the formulation and use of corrosion inhibitive solutions containing N,N'­

diethylthiourea, and those in the elastomer manufacturing industry.
 

*The CAS registry number is 105-55-5.
 
CH3CH2—NH—C—NH—CH2CH3 

FIGURE 1 

CHEMICAL STRUCTURE OF N, N'-DIETHYLTHIOUREA 
II. MATERIALS AND METHODS
 

A. Chemicals
 

*
 Practical-grade N,N"-diethylthiourea was purchased from Pfaltz
 

and Bauer Chemical Company, Stamford, Connecticut. Chemical analysis
 

was performed by Midwest Research Institute, Kansas City, Missouri.
 

The experimentally determined range in melting point, 74° to 76°C,
 

was close to that reported in the literature (77°C [Beilstein's Handbuch der Organischen Chemie, 1973]). Thin-layer chromatography (TLC)
 

was performed utilizing two solvent systems (i.e., ethyl acetate and
 

acetonerchloroform) and visualized by ultraviolet light, dichromate
 

and heat. The plate developed with ethyl acetate revealed the presence of two spots, one of which was an impurity, remaining at the
 

origin. Development with the second solvent system resulted in detection of no impurities. Elemental analysis was within the acceptable
 

limits (5 percent) of experimental variation expected for C^Ei2^2^'
 

the molecular formula for N,N'-diethylthiourea. Titration of the
 

thiourea function provided results greater than 99 percent of theoretical. High pressure liquid chromatography indicated the presence
 

of two impurities. The results of infrared (IR) and nuclear magnetic
 

resonance (NMR) analyses were consistent with those reported in the
 

literature (Sadtler Standard Spectra). Ultraviolet/visible (UV/VIS)
 

analysis revealed X at 252 nm with a molar extinction coefficient
 

max
 

*
 

Similar to technical-grade (i.e., may contain minor impurities).
 
(O of 13.8 x 10 . The reported literature \ was at 250 ran and «
 max
 3
 

was 15.8 x 10 (Gosaier and Rao, 1967).
 

A second batch of the compound was purchased nine months later
 

from the same supplier. The experimentally determined range in melting point for this batch was 76° to 78°C. Elemental analysis was, as
 

previously, within acceptable limits (5 percent) of experimental variation. TLC, performed as for the first batch, indicated no impurities.
 

Titration of the thiourea function again provided results greater than
 

99 percent of theoretical. High speed liquid chromotography showed
 

the presence of one impurity (0.1 percent of the total) of high
 

motility. IR and NMR analyses were consistent with those reported in
 

the literature (Sadtler Standard Spectra). UV/VIS analysis revealed
 

3 3
 \ at 215 and 240 nm withe of 11 x 10 and 14 x 10 , respectively,
 max
 

Throughout this report the term N,N'-diethylthiourea is used to
 

represent these batches of this practical-grade chemical.
 

B. Dietary Preparation
 

The basal laboratory diet for both dosed and control animals
 

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

N,N"-Diethylthiourea 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 250 and 500 ppm of N,N'-diethylthiourea were analyzed spectrophotometrically. The mean result
 

immediately after preparation was 73.6 percent of theoretical (ranging
 

from 62.8 to 83.2 percent) including correction for the analytical
 

method of recovery used.
 

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 the Frederick Cancer Research Center,
 

Frederick, Maryland. 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 were
 

housed 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 piece of stainless steel mesh 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 was checked daily
 

for diluting accuracy. Water bottles were changed and washed twice
 

weekly, and sipper tubes were washed at weekly intervals. During the
 

period of chemical administration, dosed and control animals received
 

treated or untreated Wayne Lab-Blox meal as appropriate. The feed
 
was supplied in hanging stainless steel 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
 

receiving diets containing 4-nitro-o-phenylenediamine (99-56-9); and
 

l-phenyl-3-methyl-5-pyrazolone (89-25-8); and other rats intubated
 

with 3-(chloromethyl)pyridine hydrochloride (3099-31-8).
 

All dosed and control mice were housed in a room with mice receiving diets containing EDTA trisodium salt (150-38-9); 3,3'-dimethoxybenzidine-4,41

-diisocyanate (91-93-0); triphenyltin hydroxide
 

(76-87-9); diaminozide (1596-84-5); carbromal (75-65-6); p-quinone
 

dioxime (105-11-3); 4-amino-2-nitrophenol (119-34-6); other mice
 

intubated with lithocholic acid (434-13-9); and other mice receiving
 

I.P. injections of methiodol sodium (126-31-8).
 

E. Selection of Initial Concentrations
 

In order to establish the maximum tolerated concentrations
 

of N,N'-diethylthiourea for administration to dosed animals in the
 

chronic studies, subchronic toxicity tests were conducted with both
 

rats and mice. Rats were distributed among five groups, each consisting of five males and five females. N,N'-Diethylthiourea was
 

incorporated into the basal laboratory diet and supplied ad libitum
 

to four of the five rat groups in concentrations of 147, 215, 316 and
 

*
 

CAS registry numbers are given in parentheses.
 
464 ppm. The remaining rat group served as a control group, receiving
 

only the basal laboratory diet.
 

Mice were distributed among six groups, each consisting of five
 

males and five females. N,N'-Diethylthiourea was incorporated into
 

the basal laboratory diet and supplied ad libitum to five of the six
 

mouse groups in concentrations of 680, 1000, 1470, 2160 and 3150 ppm.
 

The sixth mouse group 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 basal laboratory diet. Individual body weights
 

and food consumption data were recorded twice weekly throughout the
 

study. Upon termination of the study all survivors were sacrificed
 

and necropsied.
 

At the end of the subchronic test, mean body weight gain among
 

male rats dosed with 316 ppm was 3 percent greater than the mean body
 

weight gain of their controls, while female rats receiving the same
 

concentration had a mean body weight gain 11 percent less than that
 

of their controls. Mean body weight gain among male rats dosed with
 

215 ppm was 10 percent less than the mean body weight gain of their
 

controls, while female rats receiving the same concentration had a
 

mean body weight gain 1 percent less than that of their controls.
 

One female rat receiving a concentration of 316 ppm died while
 
another had an arched back and rough coat. The high concentration
 

selected for administration to dosed rats in the chronic bioassay was
 

250 ppm.
 

At the end of the subchronic test, mean body weight gain among
 

male mice dosed with 680 ppm was 10 percent less than the mean body
 

weight gain of their controls, while female mice receiving the same
 

concentration had a mean body weight gain 8 percent less than that
 

of their controls. The high concentration selected for administration to dosed mice in the chronic bioassay was 500 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 were approximately 6 weeks old at the time the test was
 

initiated and were placed on test simultaneously. The dietary concentrations of N,N'-diethylthiourea utilized were 250 and 125 ppm.
 

Throughout this report those rats 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
 

were supplied with feed containing N,N*-diethylthiourea for 103 weeks
 

followed by a 1-week observation period.
 

All mice were approximately 6 weeks old at the time the test
 

was initiated and were placed on test simultaneously. The dietary
 
TABLE 1
 

DESIGN SUMMARY FOR FISCHER 344 RATS
 

N,N'-DIETHYLTHIOUREA FEEDING EXPERIMENT
 

INITIAL 

GROUP 

SIZE 

N,N' -DIETHYLTHIOUREA 

CONCENTRATION3 

OBSERVATION PERIOD 

TREATED UNTREATED 

(WEEKS) (WEEKS) 

MALE 

CONTROL 20 0 0 104 

LOW DOSE 50 125 

0 

103 

1 

HIGH DOSE 50 250 

0 

103 

1 

FEMALE 

CONTROL 20 0 0 104 

LOW DOSE 50 125 

0 

103 

1 

HIGH DOSE 50 250 

0 

103 

1 

Concentrations given in parts per million. 

10
 
TABLE 2
 

DESIGN SUMMARY FOR B6C3F1 MICE
 

N,N'-DIETHYLTHIOUREA FEEDING EXPERIMENT
 

INITIAL 

GROUP 

SIZE 

N,N' -DIETHYLTHIOUREA 

CONCENTRATION3 

OBSERVATION PERIOD 

TREATED UNTREATED 

(WEEKS) (WEEKS) 

MALE 

CONTROL 19 0 0 104 

LOW DOSE 50 250 

0 

103 

1 

HIGH DOSE 50 500 

0 

103 

1 

FEMALE 

CONTROL 20 0 0 104 

LOW DOSE 50 250 

0 

103 

1 

HIGH DOSE 50 500 

0 

103 

1 

Concentrations given in parts per million. 

11
 
concentrations of N,N'-diethylthiourea utilized were 500 and 250 ppm.
 

Throughout this report those mice 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
 

mice were supplied with feed containing N,N'-diethylthiourea for 103
 

weeks followed by a 1-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
 

of rats were recorded once monthly throughout the bioassay. Body
 

weights of mice were recorded once a week for the first 5 weeks and
 

at monthly intervals thereafter.
 

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.
 

12
 
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, e&ophagus, 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 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,
 

13
 
1969). Data tables were generated for verification of data transcription and for statistical review.
 

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

that bear on the possibility of carcinogenicity are discussed in the
 

statistical narrative sections.
 

Probabilities of survival were estimated by the product-limit
 

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

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

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

missing; animals dying from natural causes were not statistically
 

censored. Statistical analyses for a possible dose-related effect
 

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

equality 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
 

14
 
tumors), or when lesions could have appeared at multiple sites (e.g.,
 

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

The purpose of the statistical analyses of tumor incidence is to
 

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

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

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

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

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

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

significance level of 0.05 may be made. The Bonferroni inequality
 

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

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

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

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

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

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

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

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

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.
 

15
 
A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation of
 

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

tumor was observed were excluded by basing the statistical tests on
 

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

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

tumor was found, comparisons were based exclusively on animals that
 

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

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

Cochran-Armitage tests, etc.) were followed.
 

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

incidence of tumors. Curves of the proportions surviving without an
 

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

during which animals died naturally or were sacrificed was entered
 

as the time point of tumor observation. Cox1s 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
 

16
 
the exact interval on the odds ratio (Gart, 1971). The relative risk
 

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

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

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

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

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

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

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

larger proportion in the treated group than in the control.
 

The lower and upper limits of the confidence interval of the
 

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

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

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

would be within the interval calculated from the experiment. When
 

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

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

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

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

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

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
 

No evidence of mean body weight depression was associated with
 

compound administration in either male or female rats (Figure 2).
 

No abnormal clinical signs were recorded.
 

i

f
 

B.	 Survival
 

The estimated probabilities of survival for male and female rats
 

in the control and N,N'-diethylthiourea-dosed groups are shown in
 

Figure 3. The Tarone test for association between increased dosage
 

and mortality was not significant for either males or females.
 

There were adequate numbers of male rats at risk from late-


developing tumors as 82 percent (41/50) of the high dose, 82 percent
 

(41/50) of the low dose, and 80 percent (16/20) of the controls survived on test until the termination of the study.
 

For females 84 percent (42/50) of the high dose, 88 percent
 

(44/50) of the low dose, and 90 percent (18/20) of the controls
 

survived on test until the termination of the study. Thus, there
 

were adequate numbers of female rats 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).
 

18
 
MEAN BODY WEIGHT (GRAMS) MEAN BODY WEIGHT 

O O

S O O 

I I I I 

H 8­

m 

O 

m 

en 

5 

m 

m 

7; 
cD

c2

1

~n CO 

c 5 33 

< 5- ^ < m

^ •£ 33 

o H 

co 0 

3 CO 

> o 

33 

CO 

O 

CO 

O 

z i" 

Z m 

6 31 § m C5 _j 

X 33 CO 01 •< m H O 

r- co -^ 

1 % 

0 % C. r 

33

5

 — 

 a- o 

X 

33 

O 

0 g_ 

\

i o 

PROBABILITY OF SURVIVAL PROBABILITY OF SUR

O

 *-* O O ­

 fo -t^ O} CO C 

1

 1 1 1 1 1 D 

> 

H 

co 

O 

sr 

I

j

• 

I 

r

f

 i-5 

33 i ! I f? H o —

 CO <" 

m

§ 8 S ' J 

S "" 

1 1 1 1 1 I 1 1 1 0 

c3 O O O o 

c3 ro Ibi oi oo D 
A relatively high incidence of thyroid tumors was observed and
 

appeared to be related to the dietary administration of N,N'-diethylthiourea. The summary of thyroid tumor incidence is as follow:
 

Contro

Males

Low High

l Dose Dose

 Females 

 Low

 Control Dose

 High 

Dose 

Thyroid 

Number of Animals with Tissues 

Examined Histopathologically (18) (45) (48) (18) (46) (46) 

C-Cell Adenoma 0 0 2 O i l 

C-Cell Carcinoma 1 0 1 0 0 1 

Follicular-Cell Adenoma

(All Types) 

0 0 6 0 4 9 

Follicular-Cell Carcinoma

(All types) 

0 1 1 1 0 1 8 

Nearly all of these neoplasms were recognized and described during gross examination. Microscopically they were of follicular-cell
 

as well as C-cell origin and included benign-appearing as well as
 

malignant types. C-cell adenomas were discrete, well-delineated and
 

generally consisted of a solid arrangement of monomorphous well-


differentiated cells. The malignant C-cell neoplasms were more pleomorphic and showed a less organized cellular arrangement, but remained
 

well-differentiated and had moderate to low mitotic activity. Although
 

generally less well-delineated than the adenomas, there was no extra
 

glandular invasion or metastasis. The follicular adenomas were generally nodular, well-differentiated and in many cases cystic. They were
 

21
 
mostly papillary in arrangement. The malignant follicular-cell neoplasms were generally large and showed variable histologic appearance
 

even within the same neoplasm. Follicular, solid and papillary
 

patterns, as well as combinations of these were recognized. Most of
 

these were markedly cystic as well. The degree of differentiation
 

was variable. Many of these destroyed adjacent parenchyma by invasion as well as by comparison. Three of these tumors invaded local
 

tissue, the most frequent sites being the trachea and lungs. None
 

was observed to metastasize to distant sites. Occasionally the same
 

animal had more than one type of thyroid tumor (e.g., C-cell and
 

follicular-cell types within the same lobe or benign and malignant
 

tumors within contralateral lobes). Such neoplasms were listed
 

individually. Thus, the number of neoplasms may be found to exceed
 

the number of animals bearing them.
 

There were a few neoplasms found in other organs. These were
 

similar in type, incidence, and distribution in dosed and control
 

groups and were, therefore, not considered to be associated with
 

compound administration.
 

Thyroid hyperplasia (cystic and follicular-cell) was commonly
 

recognized and appeared to be related to dietary administration and
 

dosage of the compound. Other nonneoplastic lesions were of the
 

frequency and severity expected in aged Fischer 344 rats.
 

It was concluded from this pathologic examination that
 

under the conditions of this bioassay N,N'-diethylthiourea was
 

22
 
carcinogenic in Fischer 344 rats, inducing thyroid neoplasms and
 

hyperplasia.
 

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 N,N'-diethylthiourea-dosed groups and where such tumors were observed in at least
 

5 percent of the group.
 

For male rats, the incidence of follicular-cell carcinomas of
 

the thyroid was significant (P = 0.001) using the Cochran-Armitage
 

test when comparing the dosed groups to the control. The Cochran-


Armitage test was supported by a significant (P = 0.021) Fisher exact
 

test comparing the high dose group to the control. Furthermore, the
 

combined incidences of follicular-cell carcinomas or follicular-cell
 

adenomas of the thyroid in male rats resulted in a significant (P <
 

0.001) Cochran-Armitage test and a significant (P = 0.004) high dose
 

Fisher exact test.
 

For female rats, the Cochran-Armitage test indicated a significant (P < 0.001) positive association between dose and the combined
 

incidence of follicular-cell carcinomas or follicular-cell adenomas
 

of the thyroid. This result was supported by a significant (P =
 

0.001) high dose Fisher exact test comparison.
 

23
 
TABLE 3
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE RATS TREATED WITH N.N'-DIETHYLTHIOUREA*
 

TOPOGRAPHY : MORPHOLOGY
 

Subcutaneous Tissue: Fibrosarcoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Skin and Subcutaneous Tissue: Fibrosarcoma or Neurof ibrosarcoma"
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Leukemia or
 

Malignant Lymphoma^1
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

LOW 

CONTROL DOSE 

0/20(0.00) 3/50(0.06) 

N.S. N.S. 

Infinite 

0.250 

Infinite 

87 

0/20(0.00) 3/50(0.06) 

N.S. N.S. 

Infinite 

0.250 

Infinite 

87 

2/20(0.10) 8/50(0.16) 

N.S. N.S. 

1.600 

0.364 

14.699 

99 89 

HIGH
 

DOSE
 

1/50(0.02)
 

N.S.
 

Infinite
 

0.022
 

Infinite
 

104
 

2/50(0.04)
 

N.S.
 

Infinite
 

0.123
 

Infinite
 

104
 

2/50(0.04)
 

N.S.
 

0.400
 

0.032
 

5.277
 

88 
TOPOGRAPHY : MORPHOLOGY
 

Pituitary: Chromophobe Adenoma or
 

Chromophobe Carcinoma"3
 

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
 

Thyroid: Follicular-Cell Carcinoma
 

P Values
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 3 (CONTINUED)
 

CONTROL
 

0/17(0.00)
 

N.S.
 

1/18(0.06)
 

N.S.
 

104
 

0/18(0.00)
 

P = 0.001
 

LOW
 

DOSE
 

6/46(0.13)
 

N.S.
 

Infinite
 

0.624
 

Infinite
 

87
 

4/50(0.08)
 

N.S.
 

1.440
 

0.159
 

69.469
 

104
 

1/45(0.02)
 

N.S.
 

Infinite
 

0.022
 

Infinite
 

104
 

HIGH
 

DOSE
 

6/48(0.13)
 

N.S.
 

Infinite
 

0.598
 

Infinite
 

101
 

3/50(0.06)
 

N.S.
 

1.080
 

0.096
 

55.565
 

104
 

11/48(0.23)
 

P = 0.021
 

Infinite
 

1.309
 

Infinite
 

91 
TOPOGRAPHY : MORPHOLOGY
 

Thyroid: Follicular-Cell Carcinoma or
 

Follicular-Cell Adenoma^3
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-Cell Adenoma or C-Cell
 

Carcinoma^
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Testis: Interstitial-Cell Tumor
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 3 (CONTINUED)
 

CONTROL
 

0/18(0.00)
 

P < 0.001
 

1/18(0.06)
 

N.S.
 

104
 

14/20(0.70)
 

N.S.
 

94
 

LOW
 

DOSE
 

1/45(0.02)
 

N.S.
 

Infinite
 

0.022
 

Infinite
 

104
 

0/45(0.00)
 

N.S.
 

0.000
 

0.000
 

7.461
 

37/49(0.76)
 

N.S.
 

1.079
 

0.793
 

1.629
 

88
 

HIGH
 

DOSE
 

15/48(0.31)
 

P = 0.004
 

Infinite
 

1.857
 

Infinite
 

91
 

3/48(0.06)
 

N.S.
 

1.125
 

0.100
 

57.811
 

104
 

36/50(0.72)
 

N.S.
 

1.029
 

0.753
 

1.579
 

88
 
TABLE 3 (CONCLUDED) 

o
 

Treated groups received doses of 125 or 250 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.
 

NJ
 
TABLE 4
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE RATS TREATED WITH N,N'-DIETHYLTHIOUREA^
 

TOPOGRAPHY : MORPHOLOGY
 

Hematopoietic System: Leukemia or
 

Malignant Lymphoma•t 

0
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

oo
 

Pituitary: Chromophobe Adenoma or
 

Chromophobe Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-Cell Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

CONTROL
 

3/20(0.15)
 

N.S.
 

104
 

5/18(0.28)
 

N.S.
 

87
 

0/18(0.00)
 

P = 0.006
 

LOW
 

DOSE
 

7/50(0.14)
 

N.S.
 

0.933
 

0.245
 

5.215
 

89
 

18/47(0.38)
 

N.S.
 

1.379
 

0.607
 

4.166
 

95
 

1/46(0.02)
 

N.S.
 

Infinite
 

0.022
 

Infinite
 

104
 

HIGH
 

DOSE
 

4/49(0.08)
 

N.S.
 

0.544
 

0.104
 

3.477
 

83
 

22/45(0.49)
 

N.S.
 

1.760
 

0.806
 

5.126
 

64
 

8/46(0.17)
 

N.S.
 

Infinite
 

0.939
 

Infinite
 

100
 
TOPOGRAPHY : MORPHOLOGY
 

Thyroid: Follicular-Cell Carcinoma or
 

Follicular-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
 

Uterus: Endometrial Stromal Polyp
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 4 (CONTINUED) 

CONTROL
 

0/18(0.00)
 

P < 0.001
 

0/20(0.00)
 

N.S.
 

4/19(0.21)
 

N.S.
 

86
 

LOW
 

DOSE
 

4/46(0.09)
 

N.S.
 

Infinite
 

0.380
 

Infinite
 

104
 

6/50(0.12)
 

N.S.
 

Infinite
 

0.667
 

Infinite
 

101
 

6/49(0.12)
 

N.S.
 

0.582
 

0.161
 

2.569
 

104
 

HIGH
 

DOSE
 

17/46(0.37)
 

P = 0.001
 

Infinite
 

2.227
 

Infinite
 

80
 

6/49(0.12)
 

N.S.
 

Infinite
 

0.680
 

Infinite
 

84
 

4/48(0.08)
 

N.S.
 

0.396
 

0.085
 

1.955
 

76 
TABLE 4 (CONCLUDED) 

o 

Treated groups received doses of 125 or 250 ppm in feed. 

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

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. 

CO 

o 
There were no other significant positive associations between
 

administration of the compound and an increased incidence of tumors
 

at any site in either male or female rats.
 

Based upon these statistical results, the administration of
 

N,N'-diethylthiourea was associated with the increased incidence of
 

follicular-cell carcinomas of the thyroid in male and follicular-cell
 

neoplasms of the thyroid in female Fischer 344 rats.
 

31
 
IV. CHRONIC TESTING RESULTS: MICE
 

A.	 Body Weights and Clinical Observations
 

Dose-related mean body weight depression was apparent in both
 

male	 and female mice after week 30 (Figure 4).
 

No abnormal clinical signs were recorded.
 

B. Survival
 

The estimated probabilities of survival for male and female mice
 

in the control and N,N'-diethylthiourea-dosed groups are shown in
 

Figure 5. The Tarone test for association between dosage and mortality was not significant for either male or female mice.
 

The actual percentage of male and female mice surviving on test
 

in the dosed and control groups are shown in Figure 6. There were
 

adequate numbers of male mice at risk from late-developing tumors.
 

Despite 2 low dose and 4 control males missing by week 18, 94 percent
 

(47/50) of the high dose, 94 percent (47/50) of the low dose and
 

79 percent (15/19) of the controls survived on test for at least 80
 

weeks.
 

Eight females from the high dose group, 2 from the low dose
 

group and 1 control were missing by week 22. There were, however,
 

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

as 60 percent (30/50) of the high dose, 66 percent (33/50) of the low
 

dose and 70 percent (14/20) of the controls survived on test until
 

the termination of the study.
 

32
 
50- -50 

40­ -40 

< 

DC 

-30 

I 

(J 

>20 -

O 

CD 

CONTROL 

— 20 

ID­ LOW DOSE — 10 

MALE MICE HIGH DOSE 

I 

15 

T 

30 

I 

45 

I 

60 

I 

75 

TIME ON TEST (WEEKS) 

T 

90 

I 

105 120 

50­ -50 

40­ -40 

< 

DC 

I 

O 

LU 

g 

>­ 20­ D 

O 

CQ 

TOCONTROL 

LOW DOSE 

-30 

-20 

-10 

FEMALE MICE HIGH DOSE 

I 

15 30 45 

I 

60 

I 

75 

TIME ON TEST (WEEKS) 

90 

I 

105 120 

FIGURE 4 

GROWTH CURVES FOR N,N'-DIETHYLTHIOUREA CHRONIC STUDY MICE 
PROBABILITY OF SURVIVAL PROBABILITY OF SUR

o o o 

o a> 00 

I I 

s 

30 

•o 

30 

g O O 

m 00 

I 8­

•o 

i 

v> 

O -n 

Z 30 . m 

-

m 

^ 

en 

I 

O 

30 

m 

O 

30 

O 

O 

w 

2 

O 

I \ 

o o 
PERCENT SURVIVAL PERCENT SURVIVAL 

o p o o P p k> bo o io * 01 

I j I i I I I 

-O 

m 

30 

O 

o 

z o

I H 

o 

O 

-n 

Z 

6 ^ $­ m m 

O 

Lj3

|

>

: 

30 m m m > 

O 

3D 

O 

O 

1 

r f 

o 

m 

o s­ 0

 

m 

0 
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).
 

In both sexes, the neoplasms observed were similar in type and
 

distribution in dosed and control mice, and were well within the
 

incidence expected to occur spontaneously in aged B6C3F1 mice. The
 

severity and incidence of nonneoplastic lesions were also not unusual.
 

Based on the results of this pathologic examination, N,N"-diethylthiourea 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 N,N*-diethylthiourea-dosed groups and where such tumors were observed in at least
 

5 percent of the group.
 

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

indicated a positive association between the administration of N,N'­

diethylthiourea and an increased tumor incidence. Thus, under the
 

conditions of this bioassay, there was no statistical evidence that
 

N,N'-diethylthiourea was a carcinogen in B6C3F1 mice.
 

36
 
TABLE 5
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE MICE TREATED WITH N,N'-DIETHYLTHIOUREA£
 

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 Lymphoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Circulatory System: Hemangioma or
 Hemangiosarcema"
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

CONTROL
 

2/13(0.15)
 

N.S.
 

99
 

3/15(0.20)
 

N.S.
 

93
 

1/15(0.07)
 

N.S.
 

104
 

LOW
 

DOSE
 

4/46(0.09)
 

N.S.
 

0.565
 

0.096
 

5.886
 

104
 

11/48(0.23)
 

N.S.
 

1.146
 

0.369
 

5.853
 

90
 

1/48(0.02)
 

N.S.
 

0.313
 

0.004
 

24.060
 

104
 

HIGH
 

DOSE
 

6/46(0.13)
 

N.S.
 

0.848
 

0.183
 

8.071
 

99
 

12/49(0.24)
 

N.S.
 

1.224
 

0.404
 

6.185
 

76
 

3/49(0.06)
 

N.S.
 

0.918
 

0.083
 

47.229
 

99
 
TABLE 5 (CONCLUDED) 

LOW HIGH
 

TOPOGRAPHY : MORPHOLOGY CONTROL DOSE DOSE
 

Liver: Hepatocellular Carcinoma 2/14(0.14) 5/48(0.10) 2/49(0.04)
 

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

Relative Risk (Control) _— 0.729 0.286
 

Lower Limit 0.141 0.023
 

Upper Limit 7.229 3.739
 

Weeks to First Observed Tumor 104 71 104
 

Liver: Hepatocellular Carcinoma or
 

Hepatocellular Adenoma^ 5/14(0.36) 7/48(0.15) 3/49(0.06)
 

LO P Values0 P = 0.006(N) N.S. P = O.OIO(N)
 00
 

Relative Risk (Control) 0.408 0.171
 

Lower Limit 0.143 0.033
 

Upper Limit 1.439 0.788
 

Weeks to First Observed Tumor 93 71 104
 

Treated groups received doses of 250 or 500 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.
 
TABLE 6
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE MICE TREATED WITH N,N'-DIETHYLTHIOUREA2
 

TOPOGRAPHY: MORPHOLOGY CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Hematopoietic System:

Malignant Lymphoma^5 

 Leukemia or 

8/19(0.42) 15/48(0.31) 9/41(0.22) 

P Values N.S. N.S. N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.742 

0.374 

1.732 

0.521 

0.224 

1.336 

Weeks to First Observed Tumor 93 78 92 

Uterus: Endometrial Stromal Polyp 

P Values0 

0/17(0.00) 

N.S. 

3/45(0.07) 

N.S. 

2/38(0.05) 

N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Infinite 

0.239 

Infinite 

Infinite 

0.139 

Infinite 

Weeks to First Observed Tumor 62 104 

Treated groups received doses of 250 or 500 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.
 
In male mice a possible negative association between dose and
 

the combined incidence of hepatocellular carcinomas or hepatocellular
 

adenomas was noted.
 

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
 

N,N'-diethylthiourea that could not be established under the conditions of this test.
 

40
 
V. DISCUSSION
 

There were no significant positive associations between the dosages of N,N'-diethylthiourea administered and mortality in rats or
 

mice of either sex. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors.
 

Compound-related mean body weight depression was apparent among
 

dosed male and female mice when compared to their respective controls,
 

indicating that the concentrations of N,N'-diethylthiourea administered to mice may have approximated the maximum tolerated dosages.
 

Neoplasms and hyperplasia of the thyroid were observed with
 

greater frequency among dosed rats than among controls. When the
 

incidences of follicular-cell carcinomas of the thyroid in male rats
 

(i.e., 0/18, 1/45 [2 percent], and 11/48 [23 percent] in the control,
 

low dose, and high dose, respectively) were analyzed, there was a
 

statistically significant positive association between dosage and
 

increased incidence. This finding was supported by the high dose
 

to control Fisher exact comparison. In both sexes of rats, statistical analysis of the incidences of a combination of follicular-cell
 

carcinomas and follicular-cell adenomas of the thyroid resulted in
 

significant positive Cochran-Armitage tests. For males and females,
 

the high dose to control Fisher exact comparisons were also significant.
 

41
 
For mice, none of the statistical tests for any site revealed
 

a significant positive association between administration of the
 

compound and increased tumor incidence.
 

Under the conditions of this bioassay, N,N'-diethylthiourea was
 

carcinogenic to Fischer 344 rats, causing follicular-cell carcinomas
 

of the thyroid in males and follicular-cell neoplasms of the thyroid
 

in females. There was no evidence for the carcinogenicity of the
 

compound in B6C3F1 mice.
 

42
 
VI. BIBLIOGRAPHY
 

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

J. Wiley & Sons, New York, 1971.
 

Beilstein's Handbuch der Organischen Chemie, 4th edition. Springer
 

Verlag, Berlin, p. 118, 1973.
 

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

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

Union Against Cancer, Geneva, 1969.
 

Chemical Abstracts Service, The Chemical Abstracts Service (CAS)
 

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

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

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

Co., Ltd., London, 1970.
 

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

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

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

Tests, Confidence Limits, and Adjustments for Stratification."
 

International Statistical Institute Review 39:148-169, 1971.
 

Gosaier, R.K. and C.N.R. Rao, "Electronic Absorption Spectra of Thiourea Derivatives." Can. J. Chem. 45(16):1897, 1967.
 

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

Van Nostrand Reinhold Company, New York, 1971.
 

Innes, J.R.M., B.M. Ulland, M.G. Valerio, L. Petrucelli, L. Fishbein,
 

E.R. Hart, A.J. Pallotta, R.R. Bates, H.L. Falk, J.J. Gart, M.
 

Klein, I. Mitchell, and J. Peters, "Bioassay of Pesticides and
 

Industrial Chemicals for Tumorigenicity in Mice: A Preliminary
 

Note." Journal of the National Cancer Institute 42(6):1101-1114,
 

1969.
 

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.
 

43
 
Miller, R.G., Simultaneous Statistical Inference. McGraw-Hill Book
 

Co., New York, 1966.
 

Rose, A. and E. Rose, editors, The Condensed Chemical Dictionary, 7th
 

edition. Van Nostrand Reinhold Company, New York, 1966.
 

Sadtler Standard Spectra. Sadtler Research Laboratories, Philadelphia, Pennsylvania, NMR No. 190, IR No. 11236.
 

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
 

62:679-682, 1975.
 

44
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH N,N'-DIETHYLTHIOUREA
 

TABLE Al

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH N.N'-DIETHYLTHIOUREA 

ANIMAL S INITIALLY IN STUDY

ANIMAL S NECROPSIED

ANIMAL S EXAMINE D HISTOPAT HOLOGICA LLY**

INTEGUMENTAR Y SYSTEM 

*SKIN

NEUROFIBROSARCOM A 

• SUBCUT TISSUE

FIBROSARCOM A

RESPIRATOR Y SYSTEM 

t^RACHE A

FOL1ICULAR-CELL CARCINOMA . INVA S 

*LUN G

ALVEOLAR/BRONCHIOLA P ADENOM A 

ALVEOLAR/BRONCHIOLA R CARCINOM A

"OLLICULAR-CELL CARCINOMA ,

OSTEOSARCOMA , METASTATIC

HEMATOPOIETIC SYSTEM 

*MULTIPLE ORGAN S

LEUKEMIA , NOS

UNDIFFERENTIATE D LEUKEMI A

LYMPHOCYTI C LEUKEMI A

GRANULOCYTI C LEUKEMI A

MONOCYTI C LEUKEMI A

*MESENTEPIC L. NOD E

OSTEOSARCOM A

CIRCULATOR Y SYSTE M 

FOLLTCtlLAP-CEL L CARCINOMA .

 INVA S 

 INVA S 

CONTROL (UNTR )

11-1365

 20

 20

 20

 (20 )

 (20)

 (19)

 (20)

 (20 )

 1 (5%) 

1 (5!!)

 (17 )

 LOW DOSE 

 11-1363 

 50 

 50 

 50 

 (50) 

 (50) 

3 (6X ) 

 (144) 

 ("48) 

1 (2% ) 

1 (2X) 

 (50) 

4 (8X) 

1 (2X ) 

2 (<4X ) 

1 (2X ) 

 (149) 

1 (2% ) 

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

* NUMBE R OF ANIMAL S NECROPSIE D 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

A-3 

HIGH DDSE 

11-1 1361 

50 

50 

50 

(50)

1 (2X ) 

(50) 

1 (2J) 

(16)

1 (2X ) 

(49)

1 (2*) 

1 (2*) 

2 (1*) 

(50) 

1 (2X) 1 (2*) 

,iu, 

(19)

1 J2XI 
DIGESTIV E SYSTE M 

• SMAL L INTESTTN F 

NEOP1ASM, NOS 

ADENOCARCINOMA , NO S 

• SMAL L !NTESTT N 4 L SES

 

OSTEOSAPCOM A 

URINAR Y SYSTE M 

• KIDNE Y 

LIPOSARCOM A 

OSTEO SARCOM A 

EMDOC3IN E SYSTEM 

• PITUITAF Y 

CHROKOPHOB E ADENOM A 

CH80MOPHOBE CARCINOM A 

• ADRENA L 

PHEOCHROMOCYTOM A 

H EM ANGIOM A 

OSTEOSARCOM A 

• THYROI D 

FOLLICULAR-CEL L ADENOM A 

FOLLICULAR-CEL L CARCINOM A 

C-CEIL ADENOM A 

C-CELL CARCINOM A 

• PARATHYROI D 

ADENOMA , NO S 

• PANCFEATI C ISLETS 

TSLF^-CELL ADENOM A ISLET-CELL CARCINOM A 

REPRODUCTIV E SYSTE M 

• PREPMTIA L GLAN D 

CARCINOMA^NO S 

* MJMBF R O F ANIMAL S WITH TISSUE

* NUMBE R O F ANIMAL S NECROPSIE D 

TABLE Al (CONTINUED) 

CONTRO L (UNTR) L C H ECSE 

11-1365 11-1363 

(19) (49) 

1 (2X) 

(19) (49) 

1 (2X) 

(20) (50) 

1 <2X ) 

1 (2X) 

(17) (46) 

6 (13X) 

(18 ) (50) 

1 (6%) 4 (8X) 1 <6X ) 

1 (2X) 

(18) (45) 

1 (2X ) 

1 (6X ) 

(13) (29) 

1 (3X ) 

(19) (49) 

2 (4% ) 

1 (5%} 

(20 ) (50 ) 

 EXAMINE D MICROSCOPICALL Y 

HIGH DOSE 

11-1361 

(48) 

1 <2X ) 

(48) 

(50) 

(48) 

5 (10X) 

1 (2X) 

(50) 

3 <6X) 

(48) 

6 (13X) 

11 (23X) 

2 (4*) 

1 (2X ) 

(21) 

(48) 

(50) 

1 (2X1 

A-4 
TABLE A1 (CONTINUED) 

CONTROL(UNTR ) LCW DCSE HIGH D3 SE 

11-1365 11-1363 11-1361 

ADENOMA , NOS 1 (2i) 

• TEST IS (20) (1491 (5°) 

INTERSTITIAL-CEL L TUMO R 14 (70*) 37 (76X) 3b (72*) 

NERVOU S SYSTE M 

»BRAI N (19) (49) (U9 ) 

OSTEOSARCOMA , METASTATI C 1 (2X ) 

GLIOMA , NOS 1 (2X ) 

EPENDYMOH A 1 (5*) 

SPECIAL SENSE ORGAN S 

• EXTERNA L EAR (20) (50) (50) 

SQUAHOU S CELI PAPILLOM S 1 (2*) 

MUSCULOSKELETA L SYSTEM 

*BU?CLE OF THORA X (20 ) (50) (50) 

FOILICULAP-CELL CARCINOMA , INVA S 1 (2*) 

BODY CAVITIES 

*"UNICA VAGINALI S (20) (50) (50) 

MESOTHELIOMA, NOS 1 (2X) 

A LL OTHER SYSTEMS 

*«DLTIPLE ORGAN S (20 ) (50 ) (50) 

MESOTHELIOMA , MALIGNAN T 1 (2X) 

ANIMA L EISPOSTTION SBMMAR Y 

ANIMAL S INITIALLY IN STUDY 20 50 50 

NATURA L DEATHS 3 6 6 

MORIBUN D SACRIFICE 1 3 3 

SCHEDULED SACRIFICE 

ACCIDENTALL Y KILLE D 

TERMINA L SACRIFICE 16 41 41

 

ANIMA L MISSING 

8 INCLUDES AUTQLYZE D ANIMAL S 

I NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

A-5 
TABLE A 1 (CONCLUDED)
 

CONTROL(UNTR ) L CH CCSE HIGH DOSE 

11-1365 11-1363 11-1361 

TUMO R SUMMAR Y 

m O"AL ANIMAL S WIT H PRIMAR Y TUMORS * 15 18 47

 

"OTAI PRIMAR Y TUMOR S 21 7C 77

 

TOTAL ANIMAL S WIT H ESNIG N TUMOR S 1 5 4 2 43 

TOTA L BENIG N TUMOR S 1b 50 55

 

TO"-AL ANIMAL S WIT H MALIGNAN T TUMOE S 4 16 19

 

TOTAL MALIGNAN T TUMOR S 5 19 21 

TO^AL ANIMAL S WITH SECONDARY TUMOHSt 1 3
 

TOTAL SECONDARY TUMORS 2 5
 

TOTAL A1INALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 1 1
 

TOTAL UNCERTAIN TUMOPS 1 1
 

TOTAL ANIMALS WITH TUMOSS UNCERTAIN­ PRIMARY OR ME1ASTATIC
 

"-OTAL UNCERTAIN TUMORS
 

* PRTMAPY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

# SECONDARY TUMOPS: ME1ASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT OEGAH
 

A-6
 
TABLE A2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH N,N'-DIETHYLTHIOUREA 

CONTROL (UKTR) 

11-1366 

ANIMALS INITIALL Y IN STUDY 20 

A MI HALS HISSING 

ANIMALS NECROPSIED 20 

ANIMALS EXAMINED HISTOPATHOLOGICALLY** 20 

INTEGUMENTAR Y SYSTEM 

NONE 

RESPIRATORY SYSTE1 

*LUNG (20)

 

ALVEOLAR/BRONCHI OLAF ADENOMA 

ALVEOLAR/BRONCHIOLAR CARCINOM A 

HEMATOPOIETIC SYSTEM 

•MULTIPLE ORGANS
 

LEUKEMIA.NOS
 

GRANULOCYTIC LEUKEMIA
 

MONOCYTIC LEUKEMIA
 

• SPLEEN
 

HEMANGIOSARCONA
 

• LIVES 

GRANU10CY"IC LEUKSfllA 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

• PAROTID GLAN D ____ CISTADENQMAA .NQS 

I NUMBER OF ANIMALS KITH TISSUE

* NUMBE R OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

(20) 

1 <5X) 

1 (5*) 

1 (5X) 

(20) 

(20) 

(19) 

 EXAMINED MICROSCOPICALLY 

10R EOS I HIGH DOSE 

11-136U 11-1362 

50 50 

1 

50 (49 

50 49

 

(49) 

1 (2X) 1 (2%) 

1 (2*) 

(50) (49) 

4 (8*) 3 (6%) 

1 (2X) 1 (2X) 

1 <2X) 

(49) (48) 

<2X> 

(49) (49)

 

1 (2%) 

(49) (46) 

A-7 
IIIVE R

 

HEHANGIOH A 

[TRINAP Y SYSTE M 

NON E 

ENDOCRINE SYSTEM 

• PITUITAR Y 

CHBOMOPHOB E ADEN01 A 

CHROMOPHOB E CARCINOM A 

• ADRENA L 

ADENOMA , NO S 

CORTICA L ADENOM A 

PHEOCHPOMOCYTOM A 

••"HYROID 

"OLLTCULAR-CEL L ADENOM A 

"TLLICULAR-CELL CARCINOMA 

C-CEL L ADENOM A 

C-CEL1 CAPCINOM A 

REPRODUCTIV E SYSTE M 

'MAMMAR Y GLAN D 

ADENOCARCINOMA , NO S

 

PAPUIAR Y ADENOCARCINOM A 

CYSTftDENOMA , NO S 

FIBRO ADENO M A 

»UT"R'JS 

A DENOCARCTNOMA , NOS 

FNDOMETKIA L ^"OMA L POLYP 

• UTERUS / IN DO MET PHI" 

JDhNOCARCINOMA , NO S 

NEFVOtJ S SYSTF M 

• BPPT N 

NEOPLASM , NO*" , M ETA S TATIC 

* NUrBE P O F ANIMAL S VI^H TISSUE

« NUMBE R OF ANIMAL S NECPOPSIED 

TABLE A2 (CONTINUED) 

CONTROL (UNTF) LOW ECS!

11-136 6 11-136 4

(20 ) (49)

(18) (47) 

5 (28%} 17 (36X) 

1 (2X ) 

(20) (49) 

1 (2X) 

1 (5%) 1 (2X) 

(18 ) (46) 

4 (9X) 

1 <2X) 

1 (2X ) 

(20 ) (50) 

1 (2X) 

1 (5%) 

6 (12X) 

(19) (49) 

1 (5X ) It (21% ) 6 (12*) 

(19 ) (49) 

1 (2X) 

(20 ) (49 ) 

 EXAMINE D MICROSCOPICALL Y 

 HIGH DOSE 

 11-1362 

 (49) 

1 <2X ) 

(45) 

20 (44X ) 

2 (4X) 

(48) 

1 (2X) 

2 (4X) 

(46) 

9 (20X) 

8 (17X) 

1 (2*) 

1 (2%) 

(49) 

1 (2X) 

1 (2X) 

6 (12X ) 

(48) 

4 (8X) 

(48) 

1 (2*) 

(48) 

1 (2X1 

A-g 
TABLE A2 (CONTINUED) 

CHRONOPHOBE CAPCINOBA, INVASIVE

CONTROL(UNTR )

11-136b

 LCW DOSE

 11-136U

 HIGH DOSn 

 11-1362 

1 (2*) 

SPECTA L

NON E 

 SENS E ORGAN S 

MUSCULOSKELETA L

NON E 

 SYSTE M 

BOD Y CAVITIE S 

*MESENTE6 Y

LTPOB A

 (20 ) (50) (U9 ) 

1 (2X) 

A LL OTHER

NON E 

 SYSTEMS 

ANIMA L DISPOSITION SUrMAEY 

ANIMAL S INITIALL Y IN STUD Y

NATURA L DEATH S

MORIBUN D SACRIFICE

SCHEDULE D SACRIFICE 

ACCIDENTALLY KILLED 

TEPMINA L SACRIFICE

ANIMA L MISSING

S_ISCLUDES_AUTgLYZED_ANIMALS 

t NUMBE R OF ANIMAL S WITH TISSUE

* NUMBE R OF ANIMAL S NECROPSIED 

 20 50

 2 5

 1

 18 ft

 EXAMINE D MICROSCOPICALLY 

 50 

U 

U 

 U 1 

1 

A-9 
TABLE A2 (CONCLUDED) 

CONTROL (UNTR ) LO U DCSE HIGH DOSE 

I1-13b6 11-1364 11-1362 

TM\]*0*> SUMMAR Y 

"OTAL ANIMAL S WIT H PRIMAP Y TUMOPS * 13 33 41

 

TOTA L PRTMAP Y "•HMOHS 15 66

 

"OTAL A»'IMAT S WIT H BENIG N -"UN01S 10 28 31

 TOTJIL 3ENI G N TUMOP S 10 38 47

 

TO"AL ANIMAL S KIT MALIGNAN T TUMOR S 11 17

 NAM T "UMOP S ^ 5 11 19

 

TOTAL ANIMAL S WIT H SECONDAR Y HUMORS* 

"•OTAL SECONDAP Y ^'JIO^S 

TO^AL ANIMAL S WIT H TUrOIS UNCERTAIN ­

DENIG N O B 1ALIGNAN T 

TOTA L UNCERTftj o "UMORS 

TO"AL AN I" AT s WIT H TUMOR S UNCE1TAIN ­ FPIMAB Y O R METASTATT C

 

TOTA L UNCE^TJT N TUMOR S 

* PRIMAR Y TUMORS : AI L "(IMnoS EXCEPT SECONDAFY TUHOHS 

t SECONDAR Y T'lMOPS : METASTATIC TIIHORS OR TUMORS INVASIV E INTO AM ADJACENT OBGAN 

A-10 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH N,N'-DIETHYLTHIOUREA
 

TABLE Bl

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH N,N'-DIETHYLTHIOUREA 

CONTROL (UNTR ) LOW DOSE HIGH D3SE 

22-2365 22-2363 22-2361 

ANIMALS INITIALLY IN STUDY 820 50 50 ANIMAL S MISSING 1 2 

ANIMAL S NECROPSIED 15 18 19 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY ** 15 18 49 

INTEGUMENTAR Y SYSTEM 

*SHBCUT TISSUE (15) (18) (19) 

FIBROSARCOMA 1 (2X) 

RESPIRATOR Y SYSTE M 

ILUNS (13) (16) (16)
 NEOPLASM, NOS, METASTATIC 1 (2%)
 

ALVEOIAR/BRONCHIOL&R ADENOMA 2 (15*) 1 (9%) 5 (11%)
 ALVEOLAP/BRONCHIOLAR CARCINOMA 1 (2X)
 SARCOMA, NOS, METASTATIC 1 (2X)
 

HEMATOPOIETIC SYSTEM 

*MDLTIPLE ORGAN S (15) (18) (19) MALIGNAN T LYMPHOMA , NO S 1 (2X) 1 (8X) P4LIG. LYMPHOMA , LYMPHOCYTIC TYPE 1 (2X) MALIG . LYMPHOMA , HISTIOCYTIC TYP E 2 (13%) 2 (IX) 6 (12X) IEUKEMTA.NO S 1 (7X ) 2 (IX) 1 <2X ) GRANULOCYTI C LEUKEMI A 1 <2X ) 

fSPLEE N (11) (18) (13) SARCOMA , NOS 1 (2X) HEMA«JGIO* A 1 (2X ) H E M ANGIOSARCOM A 1 (7*) 1 (2*) 1 (2*) MAIIG.LYNPHONA , HISTIOCY^IC TYPE 2 (IX) 1 (2X ) 

tLYMPH NODE (11) (15) (12) MALIG . LYMPHOKA , UNDI PPER-TY PE 1 (2X ) 

tLIVER (11) (18) (19) MALIG . LYMPHOMA , LYMPHOCYTIC TYPE 1 (2X) 

CIRCULATOR Y SYSTEM 

NONE 

* NUMBE R O F ANIMAL S WIT H TISSU E EXAMINE D MICROSCOPICALL Y 

* NUMBE R O F ANIMAL S NECROPSIE D 

9 20 ANIMAL S INITIALL Y IN STUDY BUT ONE ANIMA L WAS FOUN D TO BE FEMALE IN A MAL E GROU P 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-3 
TABLE Bl (CONTINUED) 

CONTROL! ON TR)

22-2365 LOB DOSE 22-2363

 HIGH DOSE 

 22-2361 

DIGESTIVE SYSTEM 

tLIVER (14) (18) («9) 

HEPATOCELLULA R ADENOM A 3 (21*) 2 (IX) 1 (2*) 

HEPATOCELLIILA R CARCINOM A 2 (1<4*) 5 (1 OX) 2 (HI ) 

SARCOMA , NOS 1 (2*) 

HEMANGIOM A 1 (2X) 

HEMANGIOSARCOM A 1 (7X) 1 (2X) 

URINARY SYSTEM 

NONE 

ENDOCRIN E SYSTE M 

IADPENA L (10) (U2 ) (35) 

PHEOCHROMOCYTON A 1 (3X) 

• THYROI D (7) (30) (31) 

POI.LICOLAP-CELL ADENOM A 1 (1UX ) 

REPPODCC7IVE SYSTE M 

• TE^TIS

TNTERSTITIAL-CELL T UMO S

 (15) («7) (Hit) 

1 (2X) 

NERVOUS SYSTEM 

NONE 

SPECTAL SENSE ORGANS 

NONE 

HUSCI1LOSKELETAL SYSTEM 

NONZ 

BODY CAVITIE S 

NON E 

t NUfBE R OF ANIMALS WITH TISSUE EXAMINE D MICROSCOPICALLY 

* KI'HBE t OF ANT.1ALS NECfOPSIE D 

B-4 
TABLEBl (CONCLUDED) 

CONTROL(nNTR) L C W DCSE HIG H DOSE 

22-2365 22-2363 22-2361 

A LL (VHEP SYSTEMS 

HONE 

ANIMAL DISPOSITION SUMMAR Y
 

ANTMALS INITIALLY IN STUDY 50 50

 

NATURAL DEATHS 10

 

MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 40 

ANIMAL MISSING 2

 

AMIMAL DELETED (WRONG SEX)
 

9 INCLUDES AOTOLYZEB ANIMALS
 

TUMO R SUMMAR Y 

TOTAL ANIMAL S HITH PRIMAR Y TUMORS * 8 20 23 

TOTAL PRIMAR Y TUMORS 13 21 29 

TOTAL ANIMAL S HITH 5 BENIGN TUMORS 6 8 

TOTAL BENIGN TUMORS 6 6 10 

TOTAL ANIMAL S HITH MALIGNAN T TUHCRS 5 16 18 

TOTAL MALIGNAN T TUMOR S 7 18 19 

TO^AL ANIMAL S HITH SECONDARY TUMORS* 1 1 

TOTAL SECONDARY TUMORS 1 1 

TOTAL ANIMAL S HITH TUMORS UNCERTAIN ­

BENIGN OR MALIGNAN T 

TOTAL UNCERTAI N TUMORS 

TOTAL ANIMAL S WITH TUMORS UNCERTAINPRIMAR Y OR METASTATIC

 

TOTAL UNCERTAI N TUMORS 

* PRIMAR Y TUMORS: ALL TUMORS EXCEPT SECONDARY TOMORS 

* SECONDARY TUMORS : METASTATIC TUHORS OR TUMORS INVASIVE INTO AN ADJACENT ORGA N 

B-5 
TABLE B2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH N,N'-DIETHYLTHIOUREA 

1:ONTROL (UNTP) L OU EOSI HIGH DOSE 

22-2366 22-2364 22-2362 

ANIMAL S INITIALL Y I N STUDY 20 50 50 

ANIMAL S PISSIN G 1 2 8 

ANIMAL S NECROPSTE E 19 48 U1 

ANIMAL ? EXAMINE D HISTOPAT H ^LOGICALLY* * V) 47 U1 

INTEGUMENTAR Y SYSTE M 

»?UBCU T T ISSU E (19 ) (48) (41 ) 

1YXOP A 1 (2*) 

H EM ANGIOSARCOM A 1 (2X) 

RESPIRATOR Y SYSTEM 

*NOSE (19) (U8 ) (11)

 "IBROSA8COM A 1 (2%)

 

« LOU'S (18) (45) (U1 ) 

SQUAMOU S CELL CARCINOMA , METAST A 1 (2X) HEPATOCELLULA P CARCINOMA , METAST 1 (2%) 

ALVEOLAR/B"ONCHIOLA R ADENOM A 1 (6*) 1 (2X) 

HEMA^OPOISTT C SYSTEM 

*MULTIPLE ORGAN S (19) (US ) (11) 

MALIGNAN T LYMPHOMA , NOS 1 (5X) 3 (6X) 3 (7%) 

MALIG.LYMPH01A , LYMPHOCYTI C TYP E 1 (5X) 2 (4X) 1 (2X) 

MALIG.LYMPHOMA , HISTIOCYTIC TYP E 3 (16X) 7 (15*) 2 (5X) 

TEUKEKIA.NO S 1 (5*) 1 (2%) 1 (2X) 

PLASMACYTI C LEUKEMI A 1 (2X ) 

ERYTHROCYTIC LEUKEMI A 1 (2X) 

ISPLEE N (18 ) ((16) (40 ) 

MALTG.LYMPHOMA , LYMPHOCYTIC TYPE 2 (5X) 

*MESENTERIC L. NOD E (17) (46) (40) 

MALIG.LYPIPHOHA , LYMPHOCYTIC TYPE 1 (6*) 

• KIDNEY (18) (46) (40) 

MALIG.LYMPHOMA . HISTIOCYTIC_TTPE J_J6?1 

* NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-6 
TABLE B2 (CONTINUED) 

CONTROL (UNTR)

22-2366 LCH ECSE 22-2361

 HIGH DOSE 

 22-2362 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

*IIP (19) (U8) (11) 

SQUAMOUS CELL CARCINOMA 1 (2X) 

FIBROSARCOMA 1 (2%) 

• LIVER (19) (16) (1C) 

HEPATOCELLULA P ADENOM A 2 (5X) 

HEPATOCELLOLAR CARCINOM A 1 (2X ) 

URINAR Y SYSTEM 

NONE 

ENDOCRINE SYSTEM 

tPITUITAR Y (9) (20 ) (23) 

CHROMOPHOB E CAPCINOM A 1 (5X) 

BASOPHIL ADENOM A 1 (5X) 

ITHYROI D (12) (31) (25) 

FOUICtJLAR-CELL ADENOM A 1 (8*) 

REPRODUCTIV E SYSTE M 

"MAMMAR Y GLAN D (19) (U8 ) (11) 

CARCINOMA,NO S 1 (5%) 

*UTERUS (17) (15) (38) 

LEIOMYOSARCOMA 1 (2*) 

ENDOMETRIAL STROMAL POLYP 3 (7%) 2 (5*) 

IOVARY (16 ) (13) (35) 

PAPILLARY CYSTADENOMA. NOS 1 (6*) 

GRANULOSA-CELL TUMOR 1 (3*) 

NERVOU S SYSTE M 

NON E 

* NUMBE R O F ANIMAL S WITH TISSU E EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIE D 
TABLE B2 (CONTINUED) 

CONTROL (ONTR ) LCW DCSE HIGH 00 SE 

22-2366 22-2364 22-2362 

SPECIA L SENSE ORGAN S 

NONE 

MIJSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

*ABDOMINA L HALL (19) (U8) (41) 

FIBHOSARCOM A 1 (2%) 

A LL OTHER SYSTEMS 

NONE 

ANIMA L DISPOSITION SUMMAR Y 

ANIMAL S INITIALLY IN STUDY 20 50 50 

NATURA L DEATHS U 12 6 

MORIBUN D SACRIFICE 1 3 6 

SCHEDULED SACRIFICE 

ACCIDENTALL Y KILLE D 

TERMINA L SACRIFICE 11 33 30 

ANIMA L MISSING 1 2 8 

l_IfiCLUDES_AUTQLYZED_ANI«&.LS_­

t NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

B-8 
TABLb B2 (CONCLUDtD)
 

CONTRO L (UMTS ) L OW DOSE HIG H DOSE 

22-2366 22-236U 22-2362 

TUMO R SUBBAR Y 

TOTAL ANIMAL S WIT H PBTBAS Y TUMORS ' 1 1 23 15 

TOTAL PRIBAR Y TU10BS 12 28 15 

TOTAL ANIMAL S WIT H BENIG N TUMOR S 3 6 14

 

TOTAL BENTG N TUMOB S 3 6 U

 

TOTA L ANIBAL S WIT H MALIGNAN T TUMOR S 9 19 10 TOTAL BALTGNAN T TUMOOS 9 22 10

 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1 1
 

TOTAL SECONDARY TUMORS . 1 1
 

TOTAL ANIBALS WITH TdBORS UNCEFTAINBENTGN OR MALIGNANT 1
 

TOTAL UNCERTAIN TUMORS 1
 

TOTAL ANIBALS WITH TUMORS UNCERTAINPRIMARY OR BITASTATIC
 

"OTAL UNCERTAIN TUBORS
 

* PRIMARY TUTORS: AIL TUHORS EXCEPT SECONDARY TUMORS
 

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

B-9
 

APPENDIX C
 

•-SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH N,N'-DIETHYLTHIOUREA
 

TABLE Cl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

TREATED WITH N, N'-DIETHYLTHIOUREA 

CONTROL (UNTE) LOU COS! HIGH DOSE 

11-1365 11-1363 11-1361 

ANIMAL S INITIALL Y IN STUD Y 2 0 50 50 

ANIMAL S NECROPSIE E 2 0 50 50 

ANIMAL S EXAMINE D HIS^OPATHOLOGICALLY* * 2 0 50 50 

SYSTEM 

POKE 

"ESPIRATOH Y SYSTE M 

«TRACHEA (19) (44) (46)
 

TNFLAMNATION, CHRONIC SUPPURATIV 1 (5%)
 

*L1IKT (20) (W8) (49)
 MINERALIZATION 1 (2%)
 ATELECTASIS 5 (10%) 3 (6%)
 CONGESTION, DOS 2 (10%) 8 (17%) 5 (10J)
 HEMORRHAGE 3 (15%) 7 (15%) 2 (4%)
 BROVCHOPNEUHONIA. ACUTE 1 (2%)
 PNEUMONIA, CHRONIC NURINE 4 (20%) 7 (15%) 10 (20%)
 GRANULOMA, FOREIGN BODY 1 (2%)
 PERIVASCULAR CUFFING 1 (2%)
 HYPERPLASIA, ADENOMATOUS 1 (5%) 2 (<•*)
 

HRHATOPOIETIC SYSTEM 

ISPLEEN (19) (50) (48) 

HEHOSIEEROSIS 2 (4%) 

HEMATOPOIESIS 1 (5%) 1 (2*) 

MYEIOPOIESIS 1 (5%) 

tMANDIBULAB L. NODS (17) (49) (44) 

HYPERPLASIA, LYMPHOID 1 (2%) 

IMESENTEPIC L. NODI (17) (49) (44)

 

INFLAMMATION, CHRONIC 1 (2%)

 

DEPLETION
 

* NUMBE R OF ANIMAL S UITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIHALS NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

C-3 
HYPERPLASIA, LYMPHOID 

CIRCULATOR Y SYSTEM 

•HEART 

THROMBUS , MURA L 

• MYOCARDIU M 

INFLAMMATION. ACU^E/CHRONIC 

INFLAMMATION , CHRONIC 

INFLAMMATION , CHRONIC FOCAL 

FIBPOSIS 

FIBROSIS, FOCAL 

*CORONAEY ARTER Y 

INFLAMMATION , CHRONIC 

DIGESTIVE SYSTEM 

tLIVEF 

CONGESTION, NOS 

INFLAMMATION , FOCAL 

INFLAMMATION , CHRONIC FOCAL 

CHOLANGIOFIBROSIS 

DEGENERATION , NOS 

DEGENERATION , GRANULA R 

DEGENEBATION, HYDROPIC 

NECROSIS, NOS 

METAMORPHOSI S FATTY 

CYTOPLASMIC VACUOLIZATION 

CLEAR-CELL CHANG E 

ANGIECTASI S 

*EILE DUCT 

HYPERPLASIA , NO S 

• PANCREA S 

ATROPHY . NOS 

ATROPHY, "OCAL 

• PANCREATIC ACINU S 

ATROPHY , NO S 

• SMALL INTESTINE 

INFLAMMATION . NOS 

• NUMBE R OP ANIMAL S WITH TISSUE

* NUMBER OF ANIMALS NECROPSIED 

TABLE Cl (CONTINUED) 

CONTROL fUNTR ) L OU DOSE 

11-1365 11-1363 

1 (6X) 1 (2X) 

(19) («7) 

1 (2X) 

(19) (U7 ) 

6 (32X) 8 (17%) 

14 (21% ) 12 (26%) 

1 (2%) 

(20) (50) 

1 (2X) 

(20) (50) 

1 (2X) 

1 (5X) 

1 <2X ) 

1 (2X) 

1 (2X) 

1 (2% ) 

1 (5S) 3 (6X) 

1 (2X) 

(20) (50) 

6 (30X) 7 (1UX) 

(19) (U9 ) 

1 (5%) 

1 (5X) 1 (2X) 

(19) (U9 ) 

2 (11*) 1 (2X ) 

(19) (49) 

1 J5X1 

 EXAMINE D MICROSCOPICALL Y 

HIG H 

11-1 

1 

(«9) 

(U9 ) 

1 

1 

7 

1 1 

(50) 

(50) 

2 

1 

1 

2 

1 

1 

(50) 

2U 

(US ) 

(U8 ) 

(US ) 

DOSE 

,361 

<2X) 

(2X) 

(2X) 

(14X) 

U2X ) 

(»«) 

(2X) 

(2X) 

C»X) 

<2X ) 

(2*) 

(48X) 

C-4 
TABLE Cl (CONTINUED)
 

CONTROL (ONTB) LCH ECSE 

11-1365 11-1363 

IPEYERS PATCH (19) ,«, HYPERPLASIA , LYMPHOI D 1 (5X) 

•COLON (20) (48) 

"ARASITISM 7 (15X) 

URINAR Y SYSTEM 

• KIDNE Y (20) (50) 

HYDRONEPHROSI S 

CONGESTION, ACUTE 1 (5X) 

INFLAMMATION , NOS 1 (2X) 

INFLAMMATION , CHRONIC 2 (1 OX) 8 (16X) 

NEPHPOPATHY 

NEPHPOPATHY , TOXIC 4 (2 OX) 9 (18X) 

HYPERPLASIA , TUBULA R CELL 

• KIDNEY/CORTEX (20) (50) 

CYST, NOS 1 (2X) 

• UEIHAP Y BLADDER (18) (41)

 

CALCULUS , NOS 1 (6X) 

ENDOCRINE SYSTEM 

• PITUITAR Y (17) (46) 

CONGESTION, NOS 2 (4X) 

HEMORPHAGI C CYST 

• ADRENA L (18) (50) 

CONGESTION, NOS 

HEnOPSHJGIC CYST 1 (2%) 

CYTOPLASMIC VACUOLIZATIO N 

•ADRENA L CORTEX (18) (50) 

METAMORPHOSI S FATTY 1 <2X ) 

• THYROI D (18) (45) 

FOLLICULA R CYST, NOS 1 (2X ) 

A"ROPhY , NOS 

HYPEPPLASIA, C-CELL 2 (4X) 

HYPEPPLASIA , FOLLICULAR-CEL L 

* NUMBER OF ANIMALS WI"H TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMAL^ NECPOPSIED
 

HIGH D3SE 

11-1361 

(48) 

1 <2X) 

(49) 

12 (24X) 

(50) 

1 (2X) 

15 (JOX) 

1 (2X) 

3 (6X) 

1 (2X) 

(50) 

(.0) 

(48) 

1 (2X) 

(50) 

2 (4X) 

(50) 

(48) 

4 (8X) 

1 (2X) 

1 <2X) 

C-5
 
»TMHYROID FOLLICLE


ATROPHY, NOS


HYPERPLASIA, CYSTIC


PEPRODUCTTVE SYSTEM
 

tPROSTATE .

INFLAMMATION , GRANULOMATOIJ S

HYPERPLASIA , NOS

tTESTIS

ATROPHY , NOS

NEPVOII S SYSTE M 

*BRAI N

HEMATOMA , NOS

SPECIAL SENSE ORGANS
 

NONE
 

BUSCtJLOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*ABDOBINAL CAVITY


INFLAMMATION, MO S


ALL OTHER SYSTEMS
 

*MULTIPLE ORGANS


LEUKOCYTOSIS, NOS

ADIPOSE TISSUE 

INFLAMMATIONI ._GRiNDLgMATpUSJ

* NDKBER OF ANIMAL S WIT H TISSUE

* NUMBER OF ANIMAL S NECEOPSIED 

TABLECl (CONTINUED) 

CONTROL(UNTR ) LCH CCSI HIGH DOSE 

11-1365 11-1363 11-1361 

 (18) (45)

6 (13JS)

1 (2%)

 (US) 

6 (13*) 

5 (1 OX) 

 (17 ) (44 ) (50) 

1 (2*) 

1 (2X ) 

 (20) (49) (50) 

2 (10% ) 7 (14X) 

 (19) (49) (49) 

1 (2%) 

 (20) (50) (50) 

1 (5S) 

 (20) (50) (50) 

1 (2X) 

1 

 EXAMINE D MICROSCOPICALLY 

C-6 
TABLE Cl (CONCLUDED) 

CONTROL (UNTR ) LCH DCSE HIG H DOSE 

11-1365 11-1363 11-1361 

SPECTAl MORPHOLOGY SUMMAR Y 

NO LESIO N REPOPTE D 

» NUMBE R O F ANIMAL S WIT H TISSUE EXAMINE D MIC80SCOPICALLY 

* NUMBE R OF ANIMAL S NECEOPSIED 

C-7 
TABLE C2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

TREATED WITH N,N'-DIETHYLTHIOUREA 

ANIMAL S INITIALL Y IN STUDY 

ANIMALS MISSING 

ANIMAL S NECROPSIED 

ANIMAL S EXAMINE D HISTOPATHOLOGICA LLY ** 

INTEGUMENTAR Y SYSTEM 

• SKIN 

DERHAI INCLUSION CYST 

RESPIRATOF Y SYSTEM 

f"PACHEA 

INFLAMMATION , NOS INFLAMMATION , SUPPURATIV E 

INFLAMMATION , CHRONIC SUPPORATI V 

*LUNG 

ATELECTASIS 

THROMBOSIS, NOS 

CONGESTION, NOS 

EDEMA , NOS 

HEMORRHAG E 

BRONCHOPNEUMONIA , NOS 

INFLAMMATION , INTERSTITIAL 

PNEUMONIA , CHPONIC MUP.INE 

B^ONCHOPNEUMONIA , CHRONIC 

PYPEBPLASIA , ADENOMATOU S 

HEMATOPOIETIC SYSTE M 

*EPT.EEN 

PIGMENTATION , NOS 

HEMOSIDE"OSTS 

HENATOPOIESIS 

*ME?ENTERIC L. NOD E 

HYPERPLASIA , DIFFUSE 

CONTROL (UNTR) 

11-1366 

20 

20 

20 

(20) 

(19) 

3 (16X) 

(20) 

3 (15%) 

5 (25%) 

2 (10X ) 

6 (30*) 

1 (5%) 

(20) 

2 (10*) 

3 (15%) 

(18) 

LOW DOSI 

1 1 - 1 36 4 

50 

50 

50 

(50) 

(45) 

1 (2%) 

1 (2X) 

1 (2X) 

(49) 

4 (8X) 

1 <2X ) 

6 (12X) 

1 (2X) 

3 (6X) 

7 (14*) 

1 (2X ) 

(49) 

5 (10*) 

4 (8*) 

(50) 

I NUMBE P OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBE R OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

HIGH DOSE 

11-1362 

50 

1 

49 

49 

(49) 

1 (2X) 

(46) 

1 (2X ) 

(49) 

2 (4X) 

1 (2*) 

1 (2X ) 

1 (2X) 

1 <2X ) 

13 (27X) 

1 <2X ) 

2 <4X ) 

(48) 

1 (2X ) 

4 (8X) 

2 (4X) 

(47) 

1 [2*1 
TABLE C2 (CONTINUED) 

PYPERPLASIA , RETICULU H CELL 

CIRCULATORY SYSTEM 

*MYOCARDIU N 

INFLAMMATION , ACUTE/CHRONIC 

INFLAMMATION , CHROMIC FOCAL 

TBPOSIS 

SCLEPOSIS 

FIBROSIS, FOCAL 

"AOTA 

INFLAMMATION , CHRONIC FOCAL 

DIGESTIVE SYSTE M 

*SAIIVAP Y GLAN D 

A"ROPHY , FOCAL 

#LIVE P INFLAMMATION , ACUTE FOCAL 

G»ANULONA , NOS 

DEGENERATION , NOS 

NECROSIS, FOCAL 

METAMORPHOSI S FATTY 

BASnPHILIC CYTO CHANG E 

HYOEPPLASIA , FOCAL 

I YMPHOCYTOSIS 

HEMATOPOIESI S 

ILIVER/CENTRILOBULA P 

NECROSIS, NOS 

*BIT,E EUCT 

HYPEPPLASIA , NOS 

tPANCREA S 

TNFLAMMATION . ACUTE/CHRONIC 

FIBROSIS, DIFFUSE 

ATROPHY , FOCAL 

IPANCRZATI C ACINU S 

CYTOPLASMI C V ACUOLIZATI ON 

t NUMBE R OF ANIMAL S UI^H TISSUE

* NUMBE R OF ANIMAL S NECPOPSIED 

HIGH DDSE 

11-1362 

2 (»X) 

(48) 

5 (10X) 

8 (17X) 

1 <2X) 

(49) 

(46) 

(49) 

1 <2X) 

1 (2X) 

1 (2X) 

1 <2X ) 

1 (2X) 

12 (24X) 

1 (2%) 

(49) 

(49) 

9 (18% ) 

(48) 

1 (2X) 

1 (2 X) 

2 (4X) 

(48) 

CONTBOL(OHTR) 

11-1366 

(18) 

3 (17X) 

(20) 

(19) 

(20) 

1 (5X) 

3 (15*) 

(20) 

(20) 

1 (5%) 

(20) 

(20) 

 EXAMINE D MICROSCOPICALL Y 

LCD DOSE 

11-1364 

(46) 

1 <2X) 

7 (15X) 

3 (7X) 

' <2X ) 

(50) 

1 (2X) 

(19) 

1 <2X ) 

(49) 

1 (2X) 

4 (8%) 

2 (4X) 

1 (2X) 

(49) 

2 (4X) 

(50) 

4 (8X) 

(47) 

1 (2X) 

(47) 

1 (2X) 

C-9 
•PEYEPS	 PATCH
 

HYPERPLASIA,


tlLEUH
 

HYPEPPLASIA,


•COLON
 

PARASITISM
 

HYPERPLASIA,


URINAR Y SYSTEtl 

• KIDNE Y 

INFLAMMATION,

INFLAMMATION ,

INFLAMMATION ,

NEPHROPATHY ,

 LYMPHOID
 

 LYPPHOID
 

 LYMPHOID
 

 CHRONIC 

 CHPONIC FOCAL 

 GP ANULOPIATOU S 

 TOXIC 

NEPHROSIS , CHOLEMIC 

TNFARCT , NOS 

EKDOCHIN E SYSTEB 

tPITUITAP Y 

CYST. NOS 

HEMOPPHAGIC CYST 

HYPERPLASIA , CHFOMOPHOBE-CELL 

*ADPENAL 

HEMORRHAGIC CYST
 

LIPOIDOSIS
 

CYTOPLASHIC VACOOIIZATION
 

ANGIECTASIS
 

• ADRENA L CORTEX 

METAMORPHOSIS FATTY 

•THYROID 

FOLLICIJLAP CYST, SOS 

INFLAMMATION , ACDTE FOCAL 

ATROPHY , NOS 

HYPERPLASIA , CYSTIC 

__ HYPERPLASIA. C-CELL 

TABLE C2 (CONTINUED) 

CONTROL (U NT R) 

11-1366 

(19)
 

(19)
 

(19) 

5 (26*) 

(20) 

5 (25*) 

(18) 

3 (17X) 

1 (6X) 

(20) 

1 (5X) 

1 (5X) 

(20) 

(18) 

1 (6*) 

L CK ECSE 

11-1364 

(49)
 

(49)
 

(19) 

It <8X) 

(50) 

5 (10X) 

4 (8X) 

1 (2X) 

(47)
 

1 <2X)
 

1 <2X)
 

1 (2X)
 

(49)
 

2 (4X)
 

4 (8X)
 

2 (4*)
 

(49)
 

1 (2X)
 

(46)
 

3 (7X)
 

HIGH DOSE 

11-1362 

(48)
 

1 (2X)
 

(48)
 

1 <2X)
 

(47)
 

5 (11X)
 

1 (2X)
 

(49) 

17 (35X) 

1 (2X ) 

1 (2X ) 

3 (6X) 

1 (2X) 

(45)
 

1 (2X)
 

(48)
 

2 (4X)
 

(48)
 

(46)
 

1 <2X)
 

1 (2*)
 

1 <2X)
 

6 113X)
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECPOPSIED
 

C-10 
TABLE C2 (CONTINUED) 

CONTROL (UNTR ) L OU DCSE 

11-1366 11-136U 

HYOOI D FOLLICLE (18) (46 ) 

ATROPHY , NO S 3 (7X) 

HYPERPLASIA , CYSTIC 1 (2X) 

HYPEPPLASIA , &DENOHATOU S 

REPRODUCTIV E SYSTE M 

*MAr»!AR Y GLAN D (20) (50) 

DILATATION/DUCT S 1 (2X) 

CYSTIC DUCTS 2 (4X) 

HYPESPLASIA , NO S 1 (2X) 

*NAMP1ARY DUCT (20) (50) DILATATION , NO S 1 <2X) 

• UTERU S (19) (U9) 

DILATATION , HOS 

HEKOHPHAS E 2 («X) 

HEMAT0.1A, NOS 1 (5*) 

INFLAMMATION , NOS 1 (5%) 

NECROSIS, NOS 1 (5X) 

POLYPOI D HYPEPPLASI A 1 (5X) 

HrERUS/INDOMITRIU M (19) 

INFLAMMATION , NOS 2 (1 IX) 2 («X) T NFLAMATION . FOCAL 

INFLAMMATION , SUPPHPATIV E 3 (1611) 

INFLAMMATION , CHRONIC SUPPDRATI V 2 (11X) 

"IBROSIS, DIFFUSE 1 (2X) 

HYPEPPLASIA, NOS 1 (5X) 

HYPERPLASIA, CYSTIC 2 (11%)
 

KUTEPUS/MYOMETRTUM (19)
 ABSCESS, NOS 1 (5X)
 

IOVARY (19) (09)
 

CYST, NOS 1 (2X)
 

NEPVOUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

NONE
 

t NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBEP OF ANIMALS NECEOPSIED
 

HIGH DOSE 

11-1362 

(16) 11 (21X) 

<t (9*) 

1 (2X) 

(19)
 

(18)
 

1 (2X)
 

1 (2X)
 

(18)
 

1 (2X)
 

1 (2X)
 

2 (IX)
 

(<t 8)
 

1 <2X)
 

(17)
 

C-ll
 
TABLE C2 (CONCLUDED) 

CONTROL (UNTR) LOM BCSE HIGH DOSE 

U-1366 11-1364 11-1362 

BUSCDLOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NONE 

ALL OTHEB SYSTEMS 

NONE 

SPECIAL MORPHOLOG Y SUMMAR Y 

N O LESION REPORTED 2 9 2 

ANIHA L MISSING/NO NECROPSY 1 

» NUMBER OF ANIMAL S WIT H TISSUE EXAMINE D MICROSCOPICALLY 

* NOHBE P OF ANIMAL S NECROPSIED 

C-12 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH N,N'-DIETHYLTHIOUREA
 

TABLE Dl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

TREATED WITH N,N'-DIETHYLTHIOUREA

 

CONTROL (UNTR) LOW DOS! HIGH DOSE 

22-2365 22-2363 22-2361 

ANIMAL S INITIALL Y IN STUDY 820 50 50 

ANIMAL S MISSING It 2 

ANIMAL S NECROPSIED 15 48 49 

ANIMAL S EXAMINE D HISTOPATHOLOSICALLY* * 15 <48 49 

INTEGUMENTARY SYSTEM
 

*SKIN (15) (48) (49) 

INFLAMMATION , GR ANtJLOM ATOUS <2X)

 

RESPIRATOR Y SYSTEM 

*LUN G (13) (46) (46)
 

ATELECTASIS 1 (2X)
 

EDEMA, NOS 1 (2%) 

PNEUMONIA, ASPIRATION <2X ) 

PNEUMONIA. CHRONIC MUSINE 

TNPIAMNATION, GRANULOIATOUS	 1 (2X) 

HEMATOPOIETIC SYSTEM
 

tSPLEEN (14) (48) (43)

 

HEMORRHAG E 1 (2X>

 

HYPEPPLASIA , LYMPHOI D 1 (7%) 2 (4X) 1 (2») 

IMANDIBULA R L. NOD E (14) (45) (42) HYPERPLASIA , NOS 1 (2%)

 

IMES2NTERIC L. NOE Z (14) (45) (42) CONGESTION, CHRONI C 1 (2X)

 

HEMOFSHASIC CYST 1 (2X)

 

INFLAMMATION , HEMORRHAGIC 1 (2X) 

INFLAMMATION , GP ANULOMATOU S 1 (7%) 2 (4%) 2 (5*) 

HYPERPLASIA , DIFFUSE 1 (2X) 

HYPE'PLASIA , PLASM A CELL 1 (2X)

 

HYPEPPLASIA , IYMPHOI D 1 (7X) 2 (4%) 1 (2X)

 

CIPCDLATOI'Y SYSTEM 

NONE 

« NUMBE R 0" ANIMAI S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIE D 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

« 20 ANIMAL S INITIALL Y T N STUDY BUT ONE ANIMA L WAS FOUN D TO BI FEMAL E IN A MALE GROUP 

0-3 
TABLE Dl (CONTINUED) 

CONTROL (ONTR) LOU DOSE HIG H DOSE 

22-2365 22-2J63 22-2361 

DIGESTIVE SYSTEM 

tUVEP (<48) («9) 

CYST, NOS 

HSMOPRHAGIC CYST 

INFLAMMATION , NOS 

DEGENERATION , GRANtlLA R 

DEGENERATION, HYDROPIC
 

1 

1

1

1

1 

(2%) 

(2X ) 

(2%) 

(2X ) (2*) 

(2%) 

TNFARCT, NOS AMYLOIDOSI S i (7X) 1 (2X ) 

METAMORPHOSI S FATTY 2 (IX ) 

NUCLEA R ENLARGEMEN T 1 (2X > 

HYPERPLASIA , NOS 1 (2X ) 

HYPEPPLASIA , DIFFUSE 1 (2S) 

HYPEPPLASIA , PETICULU1 CELL 1 (2X ) 

ILIVER/HEPATOCYTES (11) (18) (19) 

BASOPHILIC CYTO CHANG E 1 (2X ) 

HYPERPLASIA , DIFFUSE 2 (IX) 

IEUODENU M (15) (16) (17) 

AMYLOIEOSI S 1 (2%) 

IILEUM (15) (16) (17) 

FIBROSIS 1 (2X ) 

ICOLON (15) (17) (16) 

NEMATODIASI S 1 (27X) 3 (6X) 

URINARY SYSTEM 

«KIDNEY (11) (U8) (47) 

HYDRONEPHROSI S 1 (2X) 1 (2X) 

PYELONEPHRITIS , CHRONIC 1 (2X) 

FIBROSIS, FOCAL 1 (2X) 

ENDOCRINE SYSTEM 

NONE 

REPRODUCTIVE SYSTEM 

NONE 

* NUMBER OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

D-4 
TABLE Dl (CONCLUDED) 

CONTRO L (UNTS )

22-2365

 LC U DOSE

 22-2363

 HIG H DOSE 

 22-2361 

NEPVO'lS SYSTE M 

*BPAT N

CYT9PLASMT C VACtlOLTZATIO N

 (15) (U7 ) (46) 

1 (2*) 

SPECTAL 'ENSE ORGANS 

NONE 

HUSCHLOSKLLETAL SYSTEM 

*lA"YNfiEA L MUSCL E

OAPASITIS M

 (15 ) (18)

 1 (2X) 

 (1*9) 

BOD Y CAVITIE S 

NON E 

ALL OTHER SYSTEMS 

* MULTIPLE ORGANS

AMYLOIDOSIS

 (15)

1 (7)5) 

 (18) (49) 

SOECTAL MORPHOLOGY SUMMARY 

NO LESION REPOFTED 3 15

ANIMAL MISSING/NO NECROPSY 4 2 

AUTO/NECPOPSY/HISTO PERF 1

AUTOLYSIS/NO NECROPSY

» NUMBER OF ANIMAL S WITH TISSUE EXAMINED MICROSCOPICALLY * NUMBER OF ANIMALS NECPOPSIED 

 15 

1 

1 

D-5
 
TABLE D2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

TREATED WITH N,N'-DIETHYLTHIOUREA 

CONTROL (UNTR)

22-2366

 LOU EOS I

 22-2364

 HIGH DOSE 

 22-2362 

ANIMAL S INITIALL Y IN STUDY

ANIMAL S HISSING

ANIBALS NECEOPSIED

ANIBALS EXAHINE D HISTOPATHOLOGICALLY

 20

 1

 19

 19

 50

 2

 48

 47

 50 

8 

 1*1 

 41 

INTEGUMENTAR Y SYSTE M 

NONE 

RESPIBATOP Y SYSTEM 

ILUN G

A^ELECTASIS

CONGESTION, NOS

PNEUMONIA , CHRONIC MURIN E

TIFLAMMATION , CHRONIC

INFLAMMATION , GEANOLOMATOU S

 (18)

 2 (1 1X)

 (45)

2 (4*) 1 (2X)

2 (4X)

1 (2*) 

2 (4X ) 

 (41) 

2 (5*) 2 (5*) 

2 (5*) 

HEMATOPOIETIC SYSTEM 

IBONE MABPO W

HYPERPLASIA. GRANULOCYTIC

 (19) (44) (39) 

2 (5X) 

ISPLEEN

CONGESTION, CHPONIC

INFARCT, NOS

HYPERPLASIA , NOS

HYPERPLASIA, RETICULUM

HYPERPLASIA , LYMPHOI D

HEMATOPOIESI S

 CELL

 (18)

 1 (6X)

 1 (6*)

 1 (6X)

 (46)

 1 (2X) 

1 (2*) 

1 (2») 

2 (4%)

 1 (2X ) 

 (40) 

1 (3%) 

3 (8X) 

fSPLENTC FOLLICLES

HYPEPPLASIA , PETICULUM CELL

 (18) (46)

 1 (2%) 

 (40) 

*MANDIBOLA H L. NODE

HYPEPPLASIA , RETICULU1

HYPEFPLASIA , LYMPHOI D

 CELL

 (17)

 1 (6%) 

 (46 )

 3 (7X) 

 (40) 

*MESENTERIC L. NODE

CONGE STIONi_CH£ONIC

 (17) (46) (40) 

J_JJJl_ 

» NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D

* NUMBE H OF ANIMAL S NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALL Y 

D-6 
INFLAMMATION, CHRONIC


INFLAMMATION, GRANOLONATOUS


PIGMENTATION, NOS


HYPERPLASIA, EETICULUM CELL


HYPERPLASIA, LYMPHOID


CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVE SYSTEM
 

tLIVER


INFLAMMATION, DIFFUSE


INFLAMMATION, SUPPUEATIVE


FIBEOSIS, FOCAL


DEGENEPATION, GRANULAR


DEGENERATION, HYDROPIC


METAMORPHOSIS FATTY


HYPEPPLASIA, DIFFUSE


tLIVER/PERIPORTAI


INFLAMMATION , GRANULOMATO U S

"IBPOSIS

*LIVEP/HEPATOCYT ES

HYPERPLASIA , NOS

• PANCREAS

ATROPHY , NOS

*EMAL L INTESTIN E

HYPERPLASIA , LYMPHOI D

tPEYESS PATCH

HYPERPLASIA , RETICULU M CELL

• COLON

N EM A1* 0 CIA SIS

PARASITIS M

URINAP Y SYSTE M 

* NIJ13ER OF ANIMAL S W I^H TISSUE

» NUMBE R 0 " ANIMAL S NECEOPSIE D 

TABLE D2 (CONTINUED) 

CONTROL (UHTR)

22-2366 LCH DCSE 22-2361

 HIGH DOSE 

 22-2362 

1 (3X) 

1 (2X) 1 (3X) 

1 (3X) 

2 (12X) 1 (3X) 

1 (2X) 2 (5X) 

 (19) (46) (40) 

1 (2X) 

1 (3X) 

1 (3X) 

1 (5X) 

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

2 (4X) 1 (3X) 

1 (3X) 

 (19) (46) (40) 

1 (3X) 

1 (5X) 

 (19) (46) (40) 

2 (4X) 

 (18) (44) (40) 

1 (6X) 

 (17 ) (43) (J9) 

1 (2X) 

 (17) (43) (39) 

1 (6X) 

 (18 ) (42) (39) 

1 (2X) 1 (3X) 

1 (2X) 

(40) 

 EXAMINE D MICROSCOPICALL Y 

D-7 
TABLE D2 (CONTINUED)
 

HIG H DOSE 

22-23D2 

2 (5%) 

(28) 

(23) 

1 <K% ) 

(25) 

1 (K% ) 

2 (8%) 

(10) 

(38) 

1 (3%) 

(38) 

8 (2 IX ) 

(38) 

1 (3% ) 

(38) 

(35) 

1 (11% ) 

PERIVASCULA R CUPPIN G 

IUFIMAR Y BLADDE P

LYBPHOCYTIC INFLABBATOR Y IVPILT P 

ENDOCRIN E SYSTEM 

• PITUIT.APY

HEPIOPRHAGIC CYS T 

HYPEEPLASIA , CHROMOPHOBE-CEL L

 

CYST, NOS 

POLLTCULA R CYST, NOE 

DEGENERATION , NOS 

HYPESPLASIA , FOCA L 

• PANCREATI C ISLETS

HYPERTROPHY , NO S 

REPRODUCTIV E SYSTE1 

fUTERU S

HYDRONETP A

FIBROSIS, DIFFUSE 

HYPERPLASIA , STROMA L 

tUTERUS/ENDOMETPIU M

CYST, NOS

HYPEFPLASIA , CYSTIC

(HJTERUS/HYOMETRIU N

ABSCESS, NOS 

AHYLOIDOSI S 

• OVARY/OVIDUCT

CYST, NOS

tOVAH Y

CYST, NOS

PAROVARIA N CYST 

ABSCESS. NOS 

CONTRCL(UNTR ) 

22-236b 

 (15) 

 (9) 

 (18 ) 

 (17) 

1 (6% ) 

 (17) 

1 (6X) 

2 (12K ) 

 (17 ) 

 (17) 

, 1 (6%) 

 (16 ) 

3 (19%) 

L O U DOSE 

22-236U 

(31) 

(20) 

1 (5%) 

1 (3%) 

1 (3%) 

(KK ) 

1 (2% ) 

(K5 ) 

6 (13%) 

(15) 

5 (11*1 

(45) 

1 (2*) 

(15, 

(KJ) 

5 (12%) 

1 (2*) 

» NUMBER OF ANIMALS WITH TISSDE EXAHINED MICROSCOPICALLY
 

* NOBBER 01 ANIMALS NECFOPSIED
 

0-8
 
TABLh D2 (CONCLUDED) 

CONTRO L (UNTR ) LO W DOSE HIGH DOSE 

22-2366 22-2J64 22-2362 

NERVOU S SYSTE1 

• BRAI N (19) (UU) (38) 

COROOP A AMYLACE A 1 <5X ) 

SPECTA L SENS E ORGAN S 

NON E 

MUSCULOSKELETA L SYSTE M 

NON E 

BODY CAVITIES 

•MESENTERY	 (19) (18) (t 1)
 

STEATITIS 1 (2%)
 

ALL nTHEP SYSTEMS
 

NONE
 

SPECIAL HOPPHOLOGY SUMMARY
 

NO LESION REPORTED 1 5 5
 

ANIMAL MISSING/NO NECROPSY 1 2 8
 

A'JTO/NECROPSY/HISTO PERP 1 1 1
 AIITO/NECROPSY/NO HISTO 1
 

AUTOLYSIS/NO NECROPSY 1
 

# NUMBER OF ANIMALS WI"-H TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECEOPSIED
 

D-9
 

Review of the Bioassay of N,N'-Diethylthiourea* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup of the
 

Clearinghouse on Environmental Carcinogens
 

August 31, 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 carcinogenicity. It
 

is in this context that the below critique is given on the bioassay of
 

N,N'-Diethylthiourea for carcinogenicity.
 

The primary reviewer agreed with the conclusion in the report that
 

N,N'-Diethylthiourea was carcinogenic in both sexes of treated rats.
 

After a brief description of the experimental design, she noted as
 

shortcomings of the study: 1) the small number of matched controls; 2)
 

the fact that other chemicals were under test in the same room in which
 

this study was conducted; and 3) the treated animals may not have received
 

a maximum tolerated dose, since a noticeable weight effect was not
 

observed. Despite the shortcomings, she said that the study was still
 

valid, although she questioned if the thyroid effect was sufficient
 

evidence to regard N,N'-Diethylthiourea to be a carcinogen. The primary
 

reviewer felt no statement could be made concerning the human risk posed
 

by N,N'-Diethylthiourea.
 

A Program staff pathologist commented that C-cell tumors are the
 

most common type of thyroid neoplasms in Fischer rats, occurring about
 

three or four times more frequently than follicular-cell tumors.
 

A motion was approved unanimously that the report on the bioassay
 

of N,N'-Diethylthiourea be accepted as written.
 

45
 
Members present were:
 

Arnold Brown (Chairman), University of Wisconsin Medical School
 

Joseph Highland, Environmental Defense Fund
 

Michael 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.
 

46
 4U S GOVERNMENT PRINTING OFFICE 1978— 2B1-217/326J 

DHEW Publication No. (NIH) 79-1705