1978 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 27 

BIOASSAY OF 

14,2,2-TETRACHLOROETHANE 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 79-34-5 

NCI-CG-TR-27 

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

Public Health Service 

National Institutes of Health 
BIDASSAY OF
 

1,1,2,2-TETRACHLOROETHANE
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20014
 

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

Public Health Service
 

National Institutes of Health
 

DHEW Publication No. (NIH) 78-827
 

REPORT ON THE BIOASSAY OF 1,1,2,2-TETRACHLOROETHANE

 

FOR POSSIBLE CARCINOGEN1CITY 

CARCINOGENESIS PROGRAM, DIVISION OF CANCER CAUSE AND PREVENTION
 

NATIONAL CANCER INSTITUTE, NATIONAL INSTITUTES OF HEALTH
 

CONTRIBUTORS: This report presents the results of the bioassay of
 

1,1,2,2-tetrachloroethane conducted for the Carcinogen Bioassay and
 

Program Resources Branch, Carcinogenesis Program, Division of Cancer
 

Cause and Prevention, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland. This bioassay was conducted
 

by Hazleton Laboratories America, Inc., Vienna, Virginia, initially
 

under direct contract to the NCI and currently under a subcontract
 

to Tracor Jitco, Inc., prime contractor for the NCI Carcinogenesis
 

Bioassay Program.
 

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

principal investigators for the contract were Dr. M. B. Powers (3),
 

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

(3,5); the technical supervisor of animal treatment and observation
 

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

Histopathology was performed by Dr. R. H. Habermann (3) and reviewed by Dr. R. W. Voelker (3) at the Hazleton Laboratories America,
 

Inc., and the diagnoses included in this report represent the interpretation of these pathologists. Pathologists from NCI (1) and
 

Tracor Jitco (6) have reviewed selected slides and concur with the
 

overall histopathologic evaluation of the study.
 

Compilation of individual animal survival, pathology, and
 

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

the statistical analysis was performed by Dr. J. R. Joiner (6) and
 

Mr. W. W. Belew (8), using methods selected for the Bioassay Program
 

by Dr. J. J. Gart (9).
 

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

Corporation (8) under the direction of the NCI. Those responsible
 

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

Thomas (8), the task leader, Dr. M. R. Kornreich (8), and the senior
 

biologist, Ms. P. Walker (8). The final report was reviewed by
 

members of the participating organizations.
 

Ill
 
The following scientists at the National Cancer Institute were
 

responsible for evaluating the bioassay experiment, interpreting the
 

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

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

R. A. Griesemer (1), Dr. R. A. Squire (1), and Dr. J. M. Ward (l).
 

1.	 Carcinogenesis Program, Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health,
 

Bethesda, Maryland.
 

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

American Health Foundation, Hammon House Road, Valhalla,
 

New York.
 

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

Vienna, Virginia.
 

4.	 No wit w h the Center for Regulatory Services, 2347 Paddock Lane,
 

Reston, Virginia.
 

5.	 No wit w h Rhodia, Inc., 23 Belmont Drive, Somerset, New Jersey.
 

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

Maryland.
 

7.	 EG&G Mason Research Institute, 1530 Ea'fft Jefferson Street,
 

Rockville, Maryland.
 

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

Boulevard, McLean, Virginia.
 

9.	 Mathematical Statistics and Applied Mathematics Section, Field
 

Studies and Statistics Branch, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

IV
 
SUMMARY
 

A bioassay for possible carcinogenicity of technical-grade
 

1,1,2,2-tetrachloroethane was conducted using Osborne-Mendel rats and
 

B6C3F1 mice. At initiation of the study the rats were approximately
 

7 weeks old, and the mice were approximately 5 weeks old. 1,1,2,2­

Tetrachloroethane in corn oil was administered by gavage, at either
 

of two dosages, to two groups of 50 male and 50 female animals of
 

each species, 5 days a week. Treatment was over a period of 78 weeks,
 

followed by observation periods of 32 weeks for the rats and 12 weeks
 

for the mice. The high and low time-weighted average dosages were,
 

respectively, 108 and 62 mg/kg/day for male rats, 76 and 43 mg/kg/day
 

for female rats, and 282 and 142 mg/kg/day for the mice of both
 

sexes.
 

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

vehicle controls. These animals were intubated with corn oil at the
 

same rate as the high dose animals. Twenty animals of each sex were
 

placed on test as untreated controls for each species. These animals
 

were not intubated.
 

Among mice, hepatocellular carcinomas were observed in 2/16
 

(13 percent) male untreated controls, 1/18 (6 percent) male vehicle
 

controls, 13/50 (26 percent) low dose males, 44/49 (90 percent) high
 

dose males, 0/18 female untreated controls, 0/20 female vehicle
 

controls, 30/48 (63 percent) low dose females, and 43/47 (91 percent)
 

of the high dose females. 1his incidence of hepatocellular carcinoma
 

indicated a highly significant (P < 0.001) positive dose-related
 

trend in mice of both sexes.
 

No statistically significant incidence of neoplastic lesions was
 

observed in male or female rats. However, two hepatocellular carcinomas and one neoplastic nodule, which are rare tumors in the male
 

Osborne-Mendel rat, were observed in the high dose males.
 

Under the conditions of this study, orally administered 1,1,2,2­

tetrachloroethane is a liver carcinogen in B6C3F1 mice of both sexes.
 

The results do not provide conclusive evidence for the carcinogenicity
 

of 1,1,2,2-tetrachloroethane in Osborne-Mendel rats.
 

V 

TABLE OF CONTENTS
 

Page
 

I. INTRODUCTION	 l
 

II. MATERIALS AND METHODS	 3
 

o
 A. Chemicals
 

B. Dosage Preparation	 ^
 

C. Animals
 

D. Animal Maintenance
 

E. Gastric Intubation
 

F. Selection of Initial Dose Levels
 

G. Experimental Design
 

H. Clinical and Histopathologic Examinations
 

I. Data Recording and Statistical Analyses
 

III. CHRONIC TESTING RESULTS: RATS	 17
 

A. Body Weights and Clinical Observations
 

B. Survival	 ^
 

C. Pathology	 21
 

D. Statistical Analyses of Results
 

IV.	 CHRONIC TESTING RESULTS: MICE 31
 

J

01
 

A. Body Weights and Clinical Observations


B. Survival	 ^
 

C. Pathology	 ^
 

D. Statistical Analyses of Results
 

V. DISCUSSION	 43
 

VI. BIBLIOGRAPHY	 44
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN A~1
 

RATS TREATED WITH 1,1,2,2-TETRACHLOROETHANE
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN B-1
 

MICE TREATED WITH 1,1,2,2-TETRACHLOROETHANE
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC C~1
 

LESIONS IN RATS TREATED WITH 1,1,2,2­

TETRACHLOROETHANE
 

vn
 
 D-l 

TABLE OF CONTENTS (Concluded)
 

Page
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC


LESIONS IN MICE TREATED WITH 1,1,2,2­

TETRACHLOROETHANE
 

viii
 
LIST OF ILLUSTRATIONS
 

Page
 

Figure Number 

1 GROWTH CURVES FOR 1,1,2,2-TETRACHLOROETHANE 

CHRONIC STUDY RATS 18 

2 SURVIVAL COMPARISONS OF 1,1,2,2-TETRACHLOROETHANE 

CHRONIC STUDY RATS 20 

3 GROWTH CURVES FOR 1,1,2,2-TETRACHLOROETHANE 

CHRONIC STUDY MICE 32 

4 SURVIVAL COMPARISONS OF 1,1,2,2-TETRACHLOROETHANE 

CHRONIC STUDY MICE 34 

LIST OF TABLES 

Table Number Page 

1 DESIGN SUMMARY FOR OSBORNE-MENDEL RATS~ 

1,1,2,2-TETRACHLOROETHANE GAVAGE EXPERIMENT 8 

2 DESIGN SUMMARY FOR B6C3F1 MICE—1,1,2,2­

TETRACHLOROETHANE GAVAGE EXPERIMENT 9 

3 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

1,1,2,2-TETRACHLOROETHANE 23 

4 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH 1,1,2,2-TETRACHLOROETHANE 26 

5 COMPARISON OF SELECTED TUMOR RATES IN MALE 

OSBORNE-MENDEL RATS BETWEEN MATCHED VEHICLE 

CONTROLS AND HISTORICAL VEHICLE CONTROLS 29 

6 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

1,1,2,2-TETRACHLOROETHANE 37 

7 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED WITH 

1,1,2,2-TETRACHLOROETHANE 39 

IX
 
LIST OF TABLES (Concluded) 

Table Number Page 

Al SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE 

RATS TREATED WITH 1,1,2,2-TETRACHLOROETHANE A-3 

A2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE RATS TREATED WITH 1,1,2,2­

TETRACHLOROETHANE A-7 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH 1,1,2,2­

TETRACHLOROETHANE B-3 

B2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH 1,1,2,2­

TETRACHLOROETHANE B-6 

Cl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH 

1,1,2,2-TETRACHLOROETHANE C-3 

C2 SUMMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH 

1,1,2,2-TETRACHLOROETHANE C-7 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH 

1,1,2,2-TETRACHLOROETHANE D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH 

1,1,2,2-TETRACHLOROETHANE D-6 

x
 
I. INTRODUCTION
 

1,1,2,2-Tetrachloroethane (NCI No. C03554), an aliphatic chlorinated hydrocarbon, is one of a group of halogenated solvents selected
 

for bioassay by the National Cancer Institute. Solvents were selected
 

on the basis of large-scale production, extensive use, and lack of
 

adequate chronic toxicity data.
 

The Chemical Abstracts Service (CAS) Ninth Collective Index
 

(1977) name for this compound is 1,1,2,2-tetrachloroethane. It is
 

also called acetylene tetrachloride or sym-tetrachloroethane.
 

1,1,2,2-Tetrachloroethane was the first chlorinated hydrocarbon
 

solvent to be manufactured on a large scale. Originally, it was used
 

primarily as an intermediate in the manufacture of di- , tri- , and
 

tetra- chloroethylene. It was also used as an industrial solvent for
 

cellulose acetate, fats, waxes, greases, rubber, and sulfur (Hardie,
 

1964). In recent years, however, 1,1,2,2-tetrachloroethane has been
 

largely replaced by less toxic solvents. Only one domestic manufacturer is currently producing 1,1,2,2-tetrachloroethane, and most of
 

it is used at the same location as an intermediate in the manufacture
 

of trichloroethylene and tetrachloroethylene (National Institute for
 

Occupational Safety and Health, 1976). Currently, minor uses of
 

1,1,2,2-tetrachloroethane include use as a carrier or reaction solvent in the manufacturing processes for other chemicals and use as
 

*
 

The CAS registry number is 79-34-5
 

1 
an analytical reagent in polymer characterization tests (National
 

Institute for Occupational Safety and Health, 1976).
 

Based on production data for the synthesis products of 1,1,2,2­

tetrachloroethane, it appears that annual production of this compound
 

is at least 40 million pounds (Stanford Research Institute, 1975).
 

The National Institute for Occupational Safety and Health (1976)
 

estimates that approximately 5000 workers in the United States are
 

potentially exposed to 1,1,2,2-tetrachloroethane annually. The major
 

concerns in occupational exposure are the potential of 1,1,2,2-tetrachloroethane for causing liver damage as well as gastrointestinal and
 

'f ,*
 

neurologic disturbances (National Institute for Occupational Safety
 

and Health, 1976).
 

2 
II. MATERIALS AND METHODS
 

A. Chemicals
 

1,1,2,2-Tetrachloroethane was purchased from Aldrich Chemical
 

Company, Milwaukee, Wisconsin. Analysis was performed by Hazleton
 

Laboratories America, Inc., Vienna, Virginia. Gas-liquid chromatography (GLC) showed eight peaks with the major peak comprising over
 

90 percent of the total area. Infrared (IR) analysis was consistent
 

with the structure of the compound. GLC and IR analyses were repeated 15 and 25 months after the initial analyses. The results were
 

virtually identical with those recorded previously and suggested
 

little or no decomposition over this period.
 

Throughout this report the term 1,1,2,2-tetrachloroethane is
 

used to represent this material.
 

B. Dosage Preparation
 

/3\
 

Fresh solutions of 1,1,2,2-tetrachloroethane in Duke's corn oil
 

(S. F. Sauer Company) were prepared weekly, sealed, and stored in
 

dark bottles at 34°F. The concentration of 1,1,2,2-tetrachloroethane
 

in corn oil (on a weight/volume basis) was 5 percent for the rat
 

chronic bioassay and ranged from 1 to 4 percent for the mouse chronic
 

bioassay.
 

C. Animals
 

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

3 
comparative study of the tumorigenic responsiveness to carbon tetrachloride of five different strains of rats (Reuber and Glover, 1970).
 

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

for carcinogenesis bioassays and has proved satisfactory in this
 

capacity.
 

Rats and mice of both sexes were obtained through contracts
 

with the Division of Cancer Treatment, National Cancer Institute.
 

The Osborne-Mendel rats were procured from the Battelle Memorial
 

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

Charles River Breeding Laboratories, Inc.', Wilmington, Massachusetts.
 

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

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

treatment and control groups.
 

D. Animal Maintenance
 

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


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

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

conditioning system provided filtered air at the rate of 12 complete
 

changes of room air per hour. Fluorescent lighting was provided on a
 

12-hour-daily cycle. The rats were individually housed in suspended
 

galvanized-steel wire-mesh cages with perforated floors. The mice
 

were housed by sex in groups of ten in solid-bottom polypropylene
 

cages equipped with filter tops. Sanitized cages with fresh bedding
 

(Sanichips

(R)

 , Shurfire) were provided once each week for mice. Rats
 

4 
received sanitized cages with no bedding with the same frequency.
 

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

first 10 weeks and once a month thereafter, while fresh heat-


sterilized glass water bottles were provided three times a week.
 

Food (Wayne Lab-Blox®, Allied Mills, Inc.) and water were available
 

ad libitum.
 

The 1,1,2,2-tetrachloro.ethane-dosed and both vehicle and untreated control rats were housed in the same room with rats treated
 

*
 

with allyl chloride (107-05-1), 1,2-dibromoethane (106-93-4), carbon
 

tetrachloride (56-23-5), and chloroform (67-66-3). All mice utilized
 t
 

in the 1,1,2,2-tetrachloroethane bioassay, including controls, were
 

housed in the same room as mice treated with allyl chloride (107-05-1),
 

chloroform (67-66-3), chloropicrin (76-06-2), dibromochloropropane
 

(96-12-8), 1,2-dibromoethane (106-93-4), 1,2-dichloroethane (107-06-2),
 

1,1-dichloroethane (75-34-3), trichloroethylene (79-01-6), 3-sulfolene
 

(77-79-2), iodoform (75-47-8), methylchloroform (71-55-6), 1,1,2­

trichloroethane (79-00-5), tetrachloroethylene (127-18-4), hexachloroethane (67-72-1), carbon disulfide (75-15-0), trichlorofluoromethane
 

(75-69-4), and carbon tetrachloride (56-23-5).
 

E. Gastric Intubation
 

Intubation was performed for five consecutive days per week
 

on a mg/kg of body weight basis, utilizing the most recently observed
 

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

*
 

CAS registry numbers are given in parentheses.
 

5 
body weights for each group were recorded at weekly intervals for the
 

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

one sex within a treatment group received the same dose. Animals
 

were gavaged with 1,1,2,2-tetrachloroethane solutions under a hood to
 

minimize extraneous exposure of other animals and laboratory personnel
 

to the chemical.
 

F. Selection of Initial Dose Levels
 

Subchronic toxicity tests were conducted with both rats and mice
 

in order to estimate the maximum tolerated dosages of 1,1,2,2-tetrachloroethane for administration to treated animals in the chronic
 

studies. Animals of each species were distributed among six groups,
 

each consisting of five males and five females. Intubation was
 

performed 5 days per week for 6 weeks, followed by a 2-week observation period to detect any delayed toxicity. 1,1,2,2-Tetrachloroethane dissolved in corn oil was introduced by gavage to five of the
 

six rat groups at dosages of 56, 100, 178, 316, and 562 mg/kg/day and
 

five of the six mouse groups at dosages of 32, 56, 100, 178, and 316
 

mg/kg/day. The sixth group of each species served as a vehicle
 

control group receiving only corn oil.
 

In rats, a dose-related retardation in body weight gain was
 

observed. At 56, 100, and 178 mg/kg/day retardation was 3, 9, and
 

38 percent in the males and 9, 24 and 41 percent in the females,
 

respectively. One male rat died at 100 mg/kg/day and all five female
 

rats died at 316 mg/kg/day, but no deaths of female rats occurred at
 

6 
lower dosage levels. The initial high dose selected for the chronic
 

study was 100 mg/kg/day for both male and female rats.
 

In mice, no retardation of body weight gain and no deaths were
 

observed in any of the test groups. The initial high dose selected
 

for the chronic bioassay was 200 mg/kg/day for both male and female
 

mice.
 

G. Experimental Design
 

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

untreated observation periods, and the time-weighted average dosages)
 

are summarized in Tables 1 and 2.
 

The low dose, high dose, and vehicle control rats were approximately 7 weeks old at initiation of the experiment. The untreated
 

controls were 5 months younger than the treated rats and placed on
 

study 5 months after the treated rats. The high and low dosages
 

initially utilized for rats of both sexes were 100 and 50 mg/kg/day,
 

respectively. In week 15 the dosages were raised to 65 mg/kg/day for
 

low dose males, and to 130 mg/kg/day for high dose males, In week 26
 

the dosages were decreased to 40 mg/kg/day for the low dose females
 

and to 80 mg/kg/day for the high dose females. Beginning in week 33
 

intubation ceased for all high dose rats for 1 week, followed by 4
 

weeks of dose administration. This pattern of cyclic administration
 

was maintained for the remainder of the treatment period. Low dose
 

rats were not affected by this change. The vehicle control rats
 

7 
MALE
 

UNTREATED CONTROL
 

VEHICLE CONTROL
 

LOW DOSE
 

HIGH DOSE
 

FEMALE
 

UNTREATED CONTROL
 

VEHICLE CONTROL
 

LOW DOSE
 

HIGH DOSE
 

a
 

TABLE 1
 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS
 

1,1,2,2-TETRACHLOROETHANE GAVAGE EXPERIMENT
 

INITIAL 1,1,2, 2-TETRA­ OBSERVATION PERIOD TIME -WEIGHTED 

NUMBER OF CHLOROETHANE TREATED UNTREATED AVERAGE 

ANIMALS DOSAGE3 (WEEKS) (WEEKS) DOSAGE 

20 0 109 0 

20 0 78 32 0 

50 50 14 62 

65 64 

0 32 

50 100 14 108 

130 18 

130C 36 9 

0 32 

20 0 109 0 

20 0 78 32 0 

50 50 25 43 

40 53 

0 32 

50 100 25 76 

80 7 

80C 36 9 

0 32 

Dosages, given in mg/kg body weight, were administered by gavage five consecutive
 

days per week.
 

b . , E(dosage X number of weeks received)
 lime-weighted average dosage = —7 r-2

 :—: -r
 2(weeks receiving treatment)
 

Thase dosages were cyclically administered with a pattern of 1 dose-free week
 

followed by 4 weeks (5 days per week) of treatment at the level indicated.
 

8 
TABLE 2
 

DESIGN SUMMARY FOR B6C3F1 MICE
 

1,1,2,2-TETRACHLOROETHANE GAVAGE EXPERIMENT
 

INITIAL 1,1,2,2-TETRA- OBSERVATION PERIOD TIME-WEIGHTEI
 

MALE
 

UNTREATED CONTROL
 

VEHICLE CONTROL
 

LOW DOSE
 

HIGH DOSE
 

FEMALE
 

UNTREATED CONTROL
 

VEHICLE CONTROL
 

LOW DOSE
 

HIGH DOSE
 

NUMBER OF
 

ANIMALS
 

20
 

20
 

50
 

50
 

20
 

20
 

50
 

50
 

CHLOROETHANE
 

DOSAGE3
 

0
 

0
 

100
 

150
 

200
 

150
 

0
 

200
 

300
 

400
 

300
 

0
 

—
 

0
 

100
 

150
 

200
 

150
 

0
 

200
 

300
 

400
 

300
 

0
 

TREATED UNTREATED AVERAGE
 

(WEEKS) (WEEKS) DOSAGE
 

90 0
 

78 13 0
 

18 142
 

3
 

5
 

52
 

12
 

18 284
 

3
 

5
 

52
 

12
 

-- 90
 —
 

78 13 0
 

18 142
 

3
 

5
 

52
 

12
 

18 284
 

3
 

5
 

52
 

12
 

Dosages, given in rag/kg body weight, were administered by gavage five consecutive
 

days per week.
 

bm. . . , , rS(dosage X number of weeks received)
 Time-weighte 0 B d averag e
 e dosage = -=-7 , :—: rr
 2(weeks receiving treatment)
 

9 
received corn oil with the same frequency and in amounts equal to
 

that received by the respective female and male high dose groups.
 

The vehicle control, low dose, and high dose mice were approximately 5 weeks old on the day the first dose was administered.
 

Untreated control mice, born 1 week later than treated mice, were
 

placed on test 1 week after treatment had begun. Male mice received
 

the same dosages as female mice throughout the experiment. Initial
 

dosages for high and low dose mice were 200 and 100 mg/kg/day,
 

respectively. In week 19, dosages were raised to 300 and 150 mg/kg/
 

day, respectively. Three weeks later the dosages were raised again,
 

to 400 and 200 mg/kg/day, respectively. In week 27 the dosages were
 

lowered to 300 mg/kg/day for high dose mice, and to 150 mg/kg/day for
 

low dose mice. Vehicle control mice received corn oil by gavage in
 

amounts and frequencies corresponding to the high dose mice.
 

Vehicle and untreated control animals of both species were
 

maintained and observed in the same manner as dosed animals.
 

H. Clinical and Histopathologic Examinations
 

Animals were weighed immediately prior to initiation of the
 

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

for mortality. Body weights, food consumption, and data concerning
 

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

and location of tissue masses were recorded at weekly intervals for
 

the first 10 weeks and at monthly intervals thereafter. The presence
 

10
 
of tissue masses was determined by observation and palpation of each
 

animal.
 

A necropsy was performed on each animal regardless of whether it
 

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

bioassay. The animals were euthanized by exsanguination under sodium
 

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

of major tissues, organs, or gross lesions taken from sacrificed animals and, whenever possible, from animals found dead.
 

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

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

and bile duct, pancreas, esophagus, stomach, small intestine, large
 

intestine, kidney, urinary bladder, pituitary, adrenal, thyroid,
 

parathyroid, pancreatic islets, testis, prostate, brain, uterus,
 

mammary gland, and ovary.
 

Tissues for which slides were prepared were preserved in 10 percent buffered formalin, embedded in paraffin, sectioned, and stained
 

with hematoxylin and eosin prior to microscopic examination. An
 

occasional section was subjected to special staining techniques for
 

more definitive diagnosis.
 

A few tissues were not examined for some animals, particularly
 

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

11
 
preclude histopathologic interpretation. Thus, the number of animals
 

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

animals that were placed on experiment in each group.
 

I. Data Recording and Statistical Analyses
 

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

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

recommended by the International Union Against Cancer (Berenblum,
 

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

These data were analyzed using the statistical techniques
 

described in this section. Those analyses of the experimental results
 

that bear on the possibility of carcinogenicity are discussed in the
 

statistical narrative sections.
 

Probabilities of survival were estimated by the product-limit
 

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

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

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

missing; animals dying from natural causes were not statistically
 

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

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

12
 
equality and used Tarone's (1975) extensions of Cox's methods for
 

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

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

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

The incidence of neoplastic or nonneoplastic lesions has been
 

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

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

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

histologically. However, when macroscopic examination was required
 

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

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

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

The purpose of the statistical analyses of tumor incidence is to
 

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

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

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

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

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

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

significance level of 0.05 may be made. The Bonferroni inequality
 

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

13
 
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.
 

Under the assumption of a linear trend, this test determined if the
 

slope, of the dose-response curve is different from zero at the one-


tailed 0.05 level of significance. Unless otherwise noted, the direction of the significant trend was a positive dose relationship.
 

This method also provides a two-tailed test of departure from linear
 

trend.
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation of
 

tumors. In this analysis, deaths that occurred before the first tumor was observed were excluded by basing the statistical tests on
 

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

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

tumor was found, comparisons were based exclusively on animals that
 

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

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

Cochran-Armitage tests, etc.) were followed.
 

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

incidence of tumors. Curves of the proportions surviving without an
 

14 4
observed tumor were computed as in Saffiotti et al. (1972). The week
 

during which animals died naturally or were sacrificed was entered as
 

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

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

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

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

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

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


tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

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

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

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

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

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

c
 

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

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

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

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

larger proportion in the treated group than in the control.
 

The lower and upper limits of the confidence interval of the
 

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

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

15
 
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.
 

16
 
III. CHRONIC TESTING RESULTS: RATS
 

A. Body Weights and Clinical Observations
 

A dose-related retardation in body weight gain for both male
 

and female rats was observed throughout most of the treatment period
 

(Figure 1). Body weight curves for dosed and control rats tended to
 

converges however, during the post-treatment observation period.
 

Clinical signs, including mortality, were observed in the
 

treated female rats early in the study. Deaths occurred in the high
 

dose females as early as week 1, and by week 5 about 20 percent of
 

the animals in this group had died from apparent compound toxicity.
 

A few low and high dose females developed a hunched appearance at the
 

onset of treatment (week 1) with the incidence gradually increasing
 

in all treated groups as the study progressed.
 

Other signs observed were squinted or reddened eyes (often with
 

a reddish discharge or brown crust) and occasional abdominal urine
 

stains. These signs were observed with greater frequency in the
 

treated groups than in the controls for the duration of compound
 

administration (week 1 through week 78) and were noted at comparable
 

rates in treated and control rats during the last 6 months of the
 

study.
 

Respiratory signs, characterized by labored respiration,
 

wheezing, and/or nasal discharge, were observed at a low or moderate
 

incidence in all groups during the first year, and increased as the
 

animals aged. As the study approached termination, these signs were
 

17 7
FIGURE 1

 

GROWTH CURVES FOR 1,1,2,2-TETRACHLOROETHANE CHRONIC STUDY RATS 

18 
apparent in a comparatively greater number of treated animals than
 

controls.
 

Clinical signs commonly associated with aging were observed with
 

comparable frequency in treated and control animals during the second
 

year of the study. These signs included sores on the body and/or
 

extremities, discoloration of the fur, localized alopecia, bloated
 

appearance, and palpable nodules, tissue masses, or swollen areas.
 

B. Survival
 

The estimated probabilities of survival for male and female rats
 

in the control and 1,1,2,2-tetrachloroethane-treated groups are shown
 

in Figure 2.
 

For male rats the Tarone test for association between increased
 

dosage and elevated mortality was not statistically significant.
 

Survival was relatively good with at least 50 percent of the male
 

rats in the high dose, low dose, and vehicle control groups surviving
 

until termination of the study. Although five animals were sacrificed
 

in week 60, 50 percent of the untreated control group survived at
 

least 90 weeks.
 

For female rats the Tarone test indicated a significant (P =
 

0.005) association between increased dosage and elevated mortality.
 

A major factor in attaining this level of significance was the death
 

of 10 of the high dose rats in the first 5 weeks of the study: 8 with
 

pneumonia and 2 with no reported lesions. Despite these early losses,
 

50 percent of the high dose|Tgroup survived more than 92 weeks and 40
 

19
 
FIGURE 2

 

SURVIVAL COMPARISONS OF 1,1,2,2-TETRACHLOROETHANE CHRONIC STUDY RATS 

20 
percent survived until the end of the study. In the low dose and
 

vehicle control groups 58 and 70 percent, respectively, survived
 

until the end of the study. In the untreated control group, 65
 

percent survived until the end of the study despite the sacrifice of
 

five animals in week 60. There is no evidence that the early deaths
 

were tumor-related.
 

C. Pathology
 

Histopathologic findings on neoplasms in rats are tabulated in
 

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

are tabulated in Appendix C (Tables Cl and C2).
 

Isolated occurrences of several unusual tumors were observed in
 

rats. Hepatocellular carcinomas, rare tumors in the Osborne-Mendel
 

rat, were observed in 2/49 high dose males. Another high dose male
 

(1/49) had a neoplastic liver nodule. One papilloma of the stomach
 

(1/49) and one squamous-cell carcinoma of the stomach (1/49) were
 

observed, each in yet other high dose males. In females only one of
 

these tumor types occurred, a hepatocellular carcinoma (1/20) in an
 

untreated control.
 

A variety of other neoplasms were observed among both control
 

and chemically treated rats. Each of these other types of tumors
 

have been encountered previously as a spontaneous lesion in the
 

Osborne-Mendel rat. No apparent difference in the frequency of these
 

neoplasms between the control groups and dosed groups was noted in
 

this test. The inflammatory, degenerative, and proliferative lesions
 

!T
 

21
 
seen in the control and dosed animals were similar in number and kind
 

to those lesions occurring naturally in aged rats.
 

This pathologic examination provided no convincing evidence for
 

the carcinogenicity of 1,1,2,2-tetrachloroethane in Osborne-Mendel
 

rats.
 

D. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

rats are summarized in Tables 3 and 4. The analysis for every type
 

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

1,1,2,2-tetrachloroethane-dosed groups of either sex is included.
 

Data from the untreated control groups were not used in the
 

following statistical comparisons because the untreated rats were
 

started on test 5 months after the treated rats and because the
 

survival rate of male untreated rats was low.
 

Neither the Cochran-Armitage tests nor the Fisher exact tests
 

indicated any statistically significant increase in the proportion
 

of tumors found in dosed groups over that found in vehicle control
 

groups for any tumor type for either sex.
 

Because the observed incidence was higher in the vehicle control
 

than in the dosed groups for certain tumors, the incidence of these
 

tumors in the vehicle control groups was compared to the corresponding
 

spontaneous tumor rates compiled to date for the historical vehicle
 

controls in the NCI Bioassay Program. In female rats, the incidence
 

of fibroadenoma of the mammary gland in the controls from this
 

r
 

22
 
TABLE 3
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT g
 

SPECIFIC SITES IN MALE RATS TREATED WITH 1,1,2,2-TETRACHLOROETHANE
 

HIGH
 

DOSE
 

2/49(0.04)
 

N.S.
 

0.816
 

0.046
 

47.195
 

111
 

3/49(0.06)
 

N.S.
 

Infinite
 

0.255
 

Infinite
 

68
 

5/48(0.10)
 

P = 0.038(N)
 

0.292
 

0.084
 

1.124
 

98
 

TOPOGRAPHY: MORPHOLOGY
 

Subcutaneous Tissue: Fibroma"
 

P Values0
 

Relative Risk (Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Neoplastic Nodule or
 

Hepatocellular Carcinoma*3
 

P Values0
 

Relative Risk (Vehicle Control)4
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Chromophobe Adenoma^
 

P Values0
 

Relative Risk (Vehicle Control)4
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VEHICLE LOW
 

CONTROL DOSE
 

1/20(0.05) 2/50(0.04)
 

N.S. N.S.
 

0.800
 

0.045
 

46.273
 

110 97
 

0/20(0.00) 0/50(0.00)
 

N.S. N.S.
 

5/14(0.35) 5/48(0.10)
 

P = 0.036(N) P = 0.038(N)
 

0.292
 

0.084
 

1.124
 

90 73
 
TOPOGRAPHY: MORPHOLOGY
 

Thyroid: Follicular-Cell
 

Carcinoma^
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pancreatic Islets: Islet-Cell
 

Adenoma*5
 

P Values0
 

Relative Risk (Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Adenocarcinoma
 

P Values0
 

Relative Risk (Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 3
 

(CONTINUED)
 

VEHICLE
 

CONTROL
 

3/20(0.15)
 

N.S.
 

P = 0.015
 

83
 

2/20(0.10)
 

N.S_._
 

110
 

2/20(0.10)
 

P = 0.045(N)
 

110
 

LOW
 

DOSE
 

0/49(0.00)
 

P - 0.022(N)
 

0.000
 

0.000
 

0.673
 

2/49(0.04)
 

N.S.
 

0.408
 

0.032
 

5.381
 

110
 

2/50(0.04)
 

N.S.
 

0.400
 

0.032
 

5.277
 

39
 

HIGH
 

DOSE
 

2/49(0.04)
 

N.S.
 

0.272
 

0.025
 

2.233
 

111
 

2/49(0.04)
 

N.S.
 

0.408
 

0.032
 

5.381
 

111
 

0/49(0.00)
 

N.S.
 

0.000
 

0.000
 

1.372
 
___ 

TABLE 3
 

(CONCLUDED)
 

TOPOGRAPHY: MORPHOLOGY
 

Mammary Gland: Fibroadenoma
 

P Values0
 

Relative Risk (Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

All Sites: Hemangiosarcoma
 

P Values0
 

Relative Risk (Vehicle Control)A
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VEHICLE
 

CONTROL
 

1/20(0.05)
 

N.S.
 

110
 

0/20(0.00)
 

N.S.
 

LOW
 

DOSE
 

1/50(0.02)
 

N.S.
 

0.400
 

0.005
 

30.802
 

110
 

2/50(0.04)
 

N.S.
 

Infinite
 

0.123
 

Infinite
 

108
 

HIGH
 

DOSE
 

0/49(0.00)
 

N.S.
 

0.000
 

0.000
 

7.624
 

3/49(0.06)
 

N.S.
 

Infinite
 

0.255
 

Infinite
 

110
 

a

Dosed groups received time-weighted average doses of 62 and 108 mg/kg by gavage.
 

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

C

Beneath the incidence of each of the controls is the probability level for the Cochran-Armitage
 

test for dose-related trend in proportions when it is below 0.05, otherwise N.S. - not significant. Departure from linear trend is noted when it is below 0.05 for any comparison. Beneath
 

the dose group incidence is the probability level for the Fisher exact (conditional) test for
 

the comparison of that dose group with the vehicle control group when it is below 0.05, otherwise N.S.- not significant.
 (N) Less incidence in the dose group(s) than in a control group results in a negative indication.
 

Relative Risk of the treated group versus the control group is shown along with the lower and
 

upper limit of the 95% confidence interval for that relative risk.
 
TABLE 4
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE RATS TREATED WITH 1,1,2,2-TETRACHLOROETHANES
 

TOPOGRAPHY: MORPHOLOGY
 

Subcutaneous Tissue: Fibroma
 

P Values0
 

d
 Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Chromophobe
 

Adenoma^
 

P Values0
 

Relative Risk (Vehicle Control)*1
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-Cell
 

Carcinoma"
 

P Values0
 

d
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VEHICLE
 

CONTROL
 

1/20(0.05)
 

N.S.
 

Ill
 

3/20(0.15)
 

N.S.
 

101
 

0/20(0.00)
 

N.S.
 

LOW
 

DOSE
 

2/50(0.04)
 

N.S.
 

0.800
 

0.045
 

46.273
 

74
 

11/49(0.22)
 

N.S.
 

1.497
 

0.460
 

7.741
 

81
 

1/49(0.02)
 

N.S.
 

Infinite
 

0.024
 

Infinite
 

111
 

HIGH
 

DOSE
 

1/50(0.02)
 

N.S.
 

0.400
 

0.005
 

30.802
 

111
 

6/48(0.13)
 

N.S.
 

0.833
 

0.204
 

4.799
 

90
 

1/50(0.02)
 

N.S.
 

Infinite
 

0.023
 

Infinite
 

108
 
TOPOGRAPHY: MORPHOLOGY
 

Pancreatic Islet: Islet-Cell
 

Adenoma"
 

P Values0
 

Relative Risk (Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Adenocarcinoma
 

c
 

P Values
 

Relative Risk (Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Fibroadenoma
 

P Values0
 

Relative Risk (Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 4
 

(CONTINUED)
 

VEHICLE
 

CONTROL
 

0/20(0.00)
 

N.S.
 

—r
 

0/20(0.00)
 

N.S.
 

9/20(0.45)
 

P = 0.047(N)
 

96
 

LOW
 

DOSE
 

1/50(0.02)
 

N.S.
 

Infinite
 

0.023
 

Infinite
 

111
 

1/50(0.02)
 

N.S.
 

Infinite
 

0.023
 

Infinite
 

111
 

13/50(0.26)
 

N.S.
 

0.578
 

0.287
 

1.316
 

101
 

HIGH
 

DOSE
 

0/50(0.00)
 

N.S.
 

2/50(0.04)
 

N.S.
 

Infinite
 

0.123
 

Infinite
 

67
 

11/50(0.22)
 

N.S.
 

0.489
 

0.230
 

1.152
 

67
 
___ 

TABLE 4
 

(CONCLUDED)
 

TOPOGRAPHY: MORPHOLOGY 

VEHICLE 

CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Uterus: Endometrial Stromal 

Polypb 

P Values0 

0/20(0.00) 

N.S. 

8/50(0.16) 

N.S. 

4/48(0.08) 

N.S. 

Departure from Linear Trend 

Relative Risk (Vehicle Control)d 

Lower Limit 

Upper Limit 

P = 0.044 

Infinite 

0.952 

Infinite 

Infinite 

0.402 

Infinite 

Weeks to First Observed Tumor 74 74 

All Sites: Hemangiosarcoma" 0/20(0.00) 1/50(0.02) 0/50(0.00)
 

P Values0 N.S.
 

Relative Risk (Vehicle Control)d Infinite
 

Lower Limit o 0.023
 

Upper Limit Infinite
 

Weeks to First Observed Tumor 111
 

a

Dosed groups received time-weighted average doses of 43 and 76 mg/kg by gavage.
 

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

Beneath the incidence of each of the controls is the probability level for the Cochran-Armitage
 

test for dose-related trend in proportions when it is below 0.05, otherwise N.S.- not signif­ icant. Departure from linear trend is noted when it is below 0.05 for any comparison. Beneath
 

the dose group incidence is the probability level for the Fisher exact (conditional) test for
 

the comparison of that dose group with the vehicle control group when it is below 0.05, otherwise N.S. - not significant.
 (N) Less incidence in the dose group(s) than in a control group results in a negative indication.
 

Relative Risk of the treated group versus the control group is shown along with the lower and upper
 

limit of the 95% confidence interval for that relative risk.
 
bioassay (9/20 or 45 percent) was significantly higher (P < 0.05)
 

than that of the historical controls (39/200 or 20 percent). In male
 

rats, several tumor rates of the controls from this bioassay were
 

significantly higher (P < 0.05) than those of the historical controls
 

(Table 5). Because of this phenomenon, several tumors had the appearance of occurring more frequently in control than in dosed animals.
 

TABLE 5
 

COMPARISON OF SELECTED TUMOR RATES IN MALE OSBORNE-MENDEL
 

RATS BETWEEN MATCHED VEHICLE CONTROLS AND HISTORICAL VEHICLE CONTROLS
 

HISTORICAL MATCHED 

VEHICLE ^ VEHICLE^ 

TOPOGRAPHY : MORPHOLOGY CONTROLS CONTROLS 

Pituitary: Chromophobe adenoma 15/200 (7.50) 5/15 (33)
 

Thyroid: Follicular-cell carcinoma 5/200 (2.50) 3/20 (15)
 

Pancreatic Islets: Islet-cell adenoma 5/200 (2.50) 2/19 (11)
 

Number of tumor-bearing animals/number of animals examined (percent),
 

To provide additional insight, 95 percent confidence intervals
 

on the relative risk have been estimated and entered in the tables
 

based upon the observed tumor incidence rates. In many of the intervals shown in Tables 3 and 4, the value one is included; this indicates the absence of statistically significant results. It should
 

also be noted that many of the confidence intervals have an upper
 

limit greater than one, indicating the theoretical possibility of a
 

29
 
significantly increased rate of tumor incidence induced in rats by
 

1,1,2,2-tetrachloroethane that could not be established under the
 

conditions of this test.
 

30
 
IV. CHRONIC TESTING RESULTS: MICE
 

A. Body Weights and Clinical Observations
 

No appreciable difference in body weight gain patterns was
 

observed among female mouse groups (Figure 3). In males, a slight
 

dose-related trend was observed in the vehicle control, low dose, and
 

high dose groups beginning in week 40 and continuing for the duration
 

of the 78-week treatment period.
 

During the first year of the study, treated mice displayed
 

patterns of behavior and physical appearance that were generally comparable to the control mice. Body sores in the males and generalized
 

or localized alopecia (more prevalent in the females) were the predominant signs observed beginning in week 14. These signs persisted
 

throughout the study. Other clinical signs often observed in group-


housed laboratory mice were observed at a comparable rate among
 

treated and control groups. These signs included a hunched appearance, penile, vulvar, or anal irritation with occasional anal prolapse, rough or stained fur, squinted or reddened eyes, and palpable
 

nodules.
 

Beginning in week 60, pronounced abdominal distension was
 

observed in a few high dose mice. Thereafter, it was noted in an
 

increasing number of high dose females. From cessation of treatment
 

(week 78) until termination of the study, about 95 percent of the
 

high dose females and a few mice in the remaining groups had distended
 

31
 
FIGURES

 

GROWTH CURVES FOR 1,1,2,2-TETRACHLOROETHANE CHRONIC STUDY MICE 

32 
abdomens. Necropsy of these mice revealed liver tumors that were
 

subsequently diagnosed as hepatocellular carcinomas.
 

B. Survival
 

The estimated probabilities of survival for male and female mice
 

in the control and 1,1,2,2-tetrachloroethane-treated groups are shown
 

in Figure 4.
 

For male mice the Tarone test for association between increased
 

dosage and elevated mortality was significant (P < 0.001). The
 

departure from linear trend was also significant (P < 0.001). Both
 

results are principally due tp the death of 33 high dose mice in
 

weeks 69 and 70, leaving only one high dose mouse that survived for
 

the remainder of the study. Subsequent histopathologic examination
 

of these animals revealed acute toxic tubular nephrosis as the
 

apparent cause of death. In addition, hepatocellular carcinomas were
 

evident in most of these mice. At least 50 percent of the animals in
 

the low dose, vehicle control, and untreated control groups survived
 

until the end of the experiment.
 

For female mice the Tarone test for association between increased
 

dosage and elevated mortality was significant (P < 0.001). The
 

departure from linear trend was also significant (P = 0.003) due to
 

the relatively severe mortality in the high dose group. However,
 

50 percent of the high dose group survived more than 82 weeks and
 

34 percent survived more than 90 weeks. For the low dose, vehicle
 

33
 
FIGURE 4

 

SURVIVAL COMPARISONS OF 1,1,2,2-TETRACHLOROETHANE CHRONIC STUDY MICE 

34 
control, and untreated control groups 74, 75, and 85 percent, respectively, survived until week 92, the end of the study.
 

C. Pathology
 

Histopathologic findings on neoplasms in mice are tabulated in
 

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

tabulated in Appendix D (Tables Dl and D2).
 

During weeks 69 and 70, 33 high dose male mice died. Hepatocellular carcinomas were present in all but 1 of these 33 male mice.
 

These mice apparently died suddenly, as evidenced by the presence of
 

a large amount of food in the stomach of several of the mice. Sections of stomach and intestine failed to indicate compound-related
 

alterations in the high dose male mice.
 

Hepatocellular carcinomas occurred in 2/16 untreated control
 

males, 1/18 vehicle control males, 13/50 low dose males, 44/49 high
 

dose males, 30/48 low dose females, 43/47 high dose females, and in
 

no female control animals. The earliest hepatocellular carcinoma was
 

diagnosed in a high dose male mouse dying in week 52, while in the
 

low dose males hepatocellular carcinoma was not diagnosed until week
 

84. The three high dose male mice that died prior to week 52 had no
 

liver tumors. Therefore, a dose-response relationship was noted in
 

both the incidence of liver tumors and in the time of tumor detection
 

in the male mice. There was metastasis to the lung in one low dose
 

male mouse.
 

35
 
Microscopically, the hepatocellular carcinomas varied greatly in
 

appearance. Some were composed of well-differentiated hepatic cells
 

that had a relatively uniform arrangement of cords, whereas others
 

were composed of anaplastic cells with large hyperchromatic nuclei,
 

often with eosinophilic inclusion bodies and with vacuolated pale
 

cytoplasm. The arrangement of the neoplastic liver cells in the
 

more anaplastic carcinomas varied from short stubby cords to nests
 

of hepatic cells and occasionally pseudo-acinar formation. Mitotic
 

figures were often present. Some of the tumors were characterized by
 

discrete highly anaplastic areas within otherwise well-differentiated
 

tumors. The hepatic neoplasms occurring in the 1,1,2,2-tetrachloroethane-treated mice did not differ morphologically from the spectrum
 

of hepatocellular carcinomas occasionally noted in control mice.
 

This pathologic evaluation provides evidence for the hepatocarcinogenicity of 1,1,2,2-tetrachloroethane in B6C3F1 mice.
 

D.	 Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

mice are summarized in Tables 6 and 7. The analysis for every type
 

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

1,1,2,2-tetrachloroethane-dosed groups of either sex is included.
 

Two control groups were used for statistical analyses: the
 

vehicle control group (designated in this section as the "matched"
 

vehicle control group) and a pooled vehicle control group, combining
 

the vehicle controls from the studies of 1,1,2,2-tetrachloroethane
 

36
 
TABLE 6
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE MICE TREATED WITH 1,1,2,2-TETRACHLOROETHANE2
 

TOPOGRAPHY: MORPHOLOGY
 

Lung : Alveolar/Bronchiolar
 

Adenoma
 

P Values0
 

Relative Risk (Matched
 

Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled ,
 

Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular
 

Carcinoma
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Matched ,
 

Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled
 

Vehicle Control)*1
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 72
 

MATCHED
 

VEHICLE
 

CONTROL
 

1/18(0.06)
 

N.S.
 

92
 

1/18(0.05)
 

P <0.001
 

P = 0.022
 

POOLEDVEHICLE
 

CONTROL
 

1/36(0.03)
 

N.S.
 

3/36(0.08)
 

P< 0.001
 

P = 0.007
 

LOW
 

DOSE
 

2/39(0.05)
 

N.S.
 

0.923
 

0.052
 

53.075
 

1.846
 

0.101
 

1 "5.075
 

92
 

13/50(0.26)
 

P = 0,033**
 

4.680
 

0.805
 

193.753
 

3.120
 

0.944
 

16.026
 

84
 

HIGH
 

DOSE
 

2/47(0.04)
 

N.S.
 

0.766
 

0.043
 

44.252
 

1.532
 

0.083
 

88.440
 

69
 

44/49(0.90)
 

P <0.001*
 

P< 0.001**
 

16.163
 

3.420
 

525.786
 

10.776
 

4.225
 

37.023
 

52
 
(

TABLE 6 

CONCLUDED) 

TOPOGRAPHY: MORPHOLOGY 

MATCHED 

VEHICLE 

CONTROL 

POOLED 

VEHICLE 

CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

All Sites:

P Values0 

 Lymphomab 0/18(0.00) 

N.S. 

0/36(0.00) 

N.S. 

4/50(0.08) 

N.S. 

3/49(0.06) 

N.S. 

Relative Risk (Matched , 

Vehicle Control) 

Lower Limit 

Upper Limit 

Infinite 

0.350 

Infinite 

Infinite 

0.231 

Infinite 

Relative Risk (Pooled 

Vehicle Control) 

Lower Limit 

Upper Limit 

Infinite 

0.674 

Infinite 

Infinite 

0.446 

Infinite 

Weeks to First Observed Tumor 82 52 

H)osed groups received time-weighted average doses of 142 and 284 mg/kg by gavage.
 

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

Beneath the incidence of each of the controls is the probability level for the Cochran-Armitage
 

test for dose-related trend in proportions when it is below 0.05, otherwise N.S.- not signif­ icant. Departure from linear trend is noted when it is below 0.05 for any comparison. Beneath
 

the dose group incidence is the probability level for the Fisher exact (conditional) test for
 

the comparison of that dose group with the vehicle control group (*) and the pooled control
 

group (**) when either is below 0.05, otherwise N.S. - not significant.
 (N) Less incidence, in the dose group(s) than in a control group results in a negative indication.
 

Relative Risk of the treated group versus the control group is shown along with the lower and
 

upper limit of the 95% confidence interval for that relative risk.
 
TABLE 7
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE MICE TREATED WITH 1,1,2,2-TETRACHLOROETHANE3
 

MATCHED
 

VEHICLE
 

TOPOGRAPHY: MORPHOLOGY CONTROL
 

Lung: Alveolar /Bronchiolar
 

Adenoma or Carcinoma 0/20(0,00)
 

P Values N.S.
 

Relative Risk (Matched ,
 

Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled
 

Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular
 

Carcinoma 0/20(0.00)
 

P Values0 P < 0.001
 

Relative Risk (Matched ,
 

Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled ,
 

Vehicle Control)
 -—­ Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

POOLED
 

VEHICLE
 

CONTROL
 

1/40(0.03)
 

N.S.
 

1/40(0.03)
 

P < 0.001
 

LOW
 

DOSE
 

1/46(0.02)
 

N.S.
 

Infinite
 

0.026
 

Infinite
 

0.870
 

0.011
 

66.805
 

30/48(0.63)
 

P < 0.001*
 

P < 0.001**
 

Infinite
 

4.354
 

Infinite
 

25.000
 

4.591
 

964.569
 

58
 

HIGH
 

DOSE
 

1/44(0.02)
 

N.S.
 

Infinite
 

0.027
 

Infinite
 

0.909
 

0.012
 

69.770
 

76
 

43/47(0.91)
 

P < 0.001*
 

P < 0.001**
 

Infinite
 

6.805
 

Infinite
 

36.596
 

7.490
 

1119.509
 

53
 
TABLE 7
 

(CONCLUDED)
 

TOPOGRAPHY: MORPHOLOGY 

MATCHED 

VEHICLE 

CONTROL 

POOLED 

VEHICLE 

CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

All Sites:

P Values0 

 Lymphoma 0/20(0.00) 

N.S. 

2/40(0.05) 

N.S. 

7/48(0.15) 

N.S. 

3/47(0.06) 

N.S. 

Departure from Linear Trend P = 0.040 

Relative Risk (Matched 

Vehicle Contr

Lower Limit 

Upper Limit 

ol)d Infinite 

0.843 

Infinite 

Infinite 

0.266 

Infinite 

Relative Risk (Pooled

Vehicle Contr

Lower Limit 

Upper Limit 

d 

ol) 2.917 

0.595 

27.579 

1.277 

0.154 

14.694 

Weeks to First Observed Tumor 80 76 

Dosed groups received time-weighted average doses of 142 and 284 mg/kg by gavage.
 

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

Beneath the incidence of each of the controls is the probability level for the Cochran-Armitage
 

test for dose-related trend in proportions when it is below 0.05, otherwise N.S. - not significant. Departure from linear trend is noted when it is below 0.05 for any comparison. Beneath
 

the dose group incidence is the probability level for the Fisher exact (conditional) test for
 

the comparison of that dose group with the vehicle control group (*) and the pooled control
 

group (**) when either is below 0.05, otherwise N.S. - not significant.
 

(N) Less incidence in the dose grbup(s) than in a control group results in a negative indication.
 

"Relative risk of the treated group versus the control group is shown along with the lower and
 

upper limit of the 95% confidence interval for that relative risk.
 
and chloropicrin. The control mice used for the pool were of the
 

same strain, were housed in the same room, were placed on test at
 

approximately the same time, and were diagnosed by the same pathologists.
 

For male mice, the Cochran-Armitage tests for a positive association between increased dosage and elevated incidence of hepatocellular carcinoma were highly significant (P < 0.001) using either the
 

matched vehicle or pooled vehicle controls. A significant departure
 

from linear trend was noted (P = 0.022 using the matched controls, P =
 

0.007 using the pooled controls) due to the extremely sharp increase
 

in tumor incidence among the dosed groups. The Fisher exact tests
 

confirmed the significantly (P < 0.001) higher incidence of this
 

tumor in the high dose group compared to either the matched vehicle
 

or pooled vehicle controls, as well as for the low dose group compared
 

to the pooled vehicle control (P = 0.033). The spontaneous tumor rate
 

for hepatocellular carcinoma, as observed in the historical vehicle
 

controls at Hazleton Laboratories for male B6C3F1 mice compiled by
 

the NCI Bioassay Program, was 74/612 (12 percent) compared to the
 

rates of 13/50 (26 percent) in the low dose and 44/49 (90 percent) in
 

the high dose 1,1,2,2-tetrachloroethane-treated males. Finally, the
 

lower limit of the 95 percent confidence interval on the relative
 

risk was greater than the value one for the comparison of either of
 

the dosed groups to either of the control groups. These statistical
 

tests indicate that the occurrence of hepatocellular carcinoma in
 

41
 
male mice was associated with oral administration of 1,1,2,2-tetrachloroethane at the dose levels used in this experiment.
 

Similarly, the incidence of hepatocellular carcinoma was significant in female mice. The Cochran-Armitage tests for positive
 

dose-related trend in proportions were found to be significant (P <
 

0.001) when compared to either the matched vehicle controls or
 

the pooled vehicle controls. The results of the Fisher exact tests
 

confirmed this positive finding: both high and low dose animals
 

demonstrated significant (P < 0.001) increases in hepatocellular
 

carcinoma compared to either the matched vehicle controls or the
 

pooled vehicle controls. The spontaneous tumor rate for hepatocellular carcinoma, observed in the historical vehicle controls at
 

Hazleton Laboratories for female B6C3F1 mice, was 8/560 (1 percent)
 

compared to rates of 30/48 (63 percent) in the low dose and 43/47 (91
 

percent) in the high dose 1,1,2,2-tetrachloroethane-treated females.
 

Finally, the entire range of the 95 percent confidence interval on
 

the relative risk is greater than the value one for the comparison of
 

either of the dosed groups to either of the control groups. These
 

statistical tests indicate that the occurrence of hepatocellular
 

carcinomas in female B6C3F1 mice was associated with the oral administration of 1,1,2,2-tetrachloroethane at the dose levels used in this
 

experiment.
 

42
 
V. DISCUSSION
 

Under the conditions of this study, administration of 1,1,2,2-­

tetrachloroethane was associated with a significant increase in the
 

incidence of hepatocellular carcinomas in mice of both sexes.
 

Although a variety of neoplasms were observed in the treated rats,
 

none of these was found to be statistically significant.
 

Statistical tests indicated a strong association between oral
 

administration of 1,1,2,2-tetrachloroethane and occurrence of hepatocellular carcinomas in both male and female mice. Incidences of
 

hepatocellular carcinoma exhibited a highly significant (P < 0.001)
 

positive dose-related trend in mice of both sexes.
 

No neoplasms were observed in dosed rats at an incidence significantly higher than that observed in controls. In bioassays using
 

the same strain of rats following a similar protocol and conducted
 

by the same laboratory, only a low incidence (about 5 percent) of
 

hepatocellular carcinoma was observed in rats receiving carbon tetrachloride (considered a positive control) (National Cancer Institute,
 

1976). It appears, therefore, that the Osborne-Mendel rat may have a
 

low degree of sensitivity to induction of hepatocellular carcinoma by
 

oral administration of chlorinated organic compounds.
 

Under the conditions of this study, orally administered 1,1,2,2­

tetrachloroethane is a liver carcinogen in B6C3F1 mice. The results
 

of this study do not, however, provide evidence for carcinogenicity
 

of 1,1,2,2-tetrachloroethane in Osborne-Mendel rats.
 

43
 
VI. BIBLIOGRAPHY
 

Armitage, P., Statistical Methods in Medical Research. Chapter 14.
 J. Wiley & Sons, New York, 1971.
 

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

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

Union Against Cancer, Geneva, 1969.
 

Chemical Abstracts Service, The Chemical Abstracts Service (CAS)
 

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

Chemical Society, Washington, D.C., 1977.
 

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

Co., Ltd., London, 1970.
 

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

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

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

Tests, Confidence Limits, and Adjustments for Stratification."
 

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

Hardie, D.W.F., "Chlorocarbons and Chlorohydrocarbons." Kirk-Othmer
 

Encyclopedia of Chemical Technology, 2nd edition, Volume 5.
 Interscience, New York, 1964.
 

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.
 

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

Co., New York, 1966.
 

National Cancer Institute, Carcinogenesis Bioassay of Trichloroethylene, CAS No. 79-01-6. U.S. Department of Health, Education
 

and Welfare, DHEW Publication No. (NIH) 76-802, National Cancer
 

Institute, Bethesda, Maryland, Technical Report Series No. 2,
 

February 1976.
 

National Institute for Occupational Safety and Health, Criteria
 

for a Recommended Standard—Occupational Exposure to 1,1,2,2­

Tetrachloroethane. U.S. Government Printing Office, DHEW,
 

Washington, D.C., (NIOSH) Publication No. 77-121, 1976.
 

44
 
Reuber, M.D., and E.L. Glover, "Cirrhosis and Carcinoma of the Liver
 

in Male Rats Given Subcutaneous Carbon Tetrachloride." Journal
 

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

Saffiotti, U., R. Montesano, A. R. Sellakumar, F. Cefis, and D.G.
 Kaufman, "Respiratory Tract Carcinogenesis in Hamsters Induced
 

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

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

Stanford Research Institute, Chemical Economics Handbook. Menlo Park,
 

California, 1975.
 

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

62:679-682, 1975.
 

45
 

APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH 1,1,2,2-TETRACHLOROETHANE
 

TABLE Al

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH 1.1,2,2-TETRACHLOROETHANE 

CONTROL (ONTE) 

01-031H 

CONTROL (VEH) 

01-011M 

LOU DOSE 

01-012M 

HIGH DOSE 

01-013H 

ANIMALS INITIALLY IN STDDY 

ANIMALS NECHOPSIED ANIHALS EXAMINED HISTOPATHOLOGICA LLY** 

20 

20 

20 

20 

20 

20 

50 

50 

50 

50 

U9 

49 

INTEGUMENTARY SYSTEM 

•SKIN 

SQUASOUS CELL CABCINOMA (20) (20) 

1 <5X) 

(50) (»9) 

• SDBCUT TISSUE 

ADEHOCARCINQMA, NOS 

ADENOCARCINOMA, NOS, METASTATIC FIBROMA 

FIBROSARCOMA 

LIPOMA 

(20) 

(5X) 

(20) 

1 <5X) 

(50) 

1 (2%) 

2 («*) 

1 (2*) 

(19) 

1 (2X) 

2 («X) 

1 <2X) 

EESPIRAT08Y SYSTEM 

NONE 

HEMATOPOIETIC SYSTEM 

*MDLTIPLE ORGANS 

MALIG.LYBPHOMA, HISTIOCYTIC TYPE 

LYBPHOCYTIC LEOKEMIA 

(20) 

1 (5X) 

(20) (50) (U9) 

1 (2X) 

tSPLEEH 

HENANGIOSARCOHA 

MALIG.LYMPHOMA. HISTIOCYTIC TYPE 

(20) (19) (50) 

1 (2%) 

1 <2X) 

(»9) 

3 (6X) 

fLIVER 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE (20) (20) (50) 

1 (2X) 

(19) 

CIPCOLATOHY SYSTEH 

BOSS 

t NOHBER OF ANIMAL S WITH TISSUE EXAMINE D

* DUMBER OF ANIHAL S NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

A-3 
TABLE A1 (CONTINUED)
 

DIGESTIVE SYSTEM
 

tSALIVAFY GLAND
 

CARCINOMA, NOS
 

ILIVEB
 NEOPLASTIC NODDLE
 

HEPATOCELLDLAR CARCINOMA
 

#PANCBEAS
 

HEMANGIOSARCOMA
 

* STOMACH
 

PAPILLOMA, NOS
 

SQUAMOUS CELL CARCINOMA
 

tSMALL INTESTINE
 

FIBBOSAFCOBA
 

ORINABY SYSTEM
 

*KIONEY
 

TOBOLAB-CELL ADENOHA
 

MIXED TOMOB, MALIGNANT
 

HAMABTOMA
 

ENDOCRINE SYSTEM
 

tPITBITABY
 

CHBOMOPHOBE ADENOMA
 

tADRENAL
 

CORTICAL CARCINOMA
 

tTHYHOID
 

FOLLICHLAR-CELL CABCINOMA
 

tPARATHYBOID
 

ADENOHA, NOS
 

tPANCBEATIC ISLETS
 

ISLET-CELL ADENOMA
 

CONTROL (ONTR)
 

01-031M
 

(14)
 

1 <7X)
 

(20)
 

(20)
 

(20)
 

(20)
 

1 (5X)
 

(20)
 

(20)
 

2 (10X)
 

(20)
 

2 (10X)
 

(19)
 

1 (5%)
 

(3)
 

(20)
 

CONTBOL (VEH)
 

01-011M
 

(11)
 

(20)
 

(20)
 

(20)
 

(20)
 

(20)
 

1 (5X)
 

(It)


5 (36%)
 

(20)
 

(20)
 

3 (15X)
 

(20)
 

(20)
 

2_J10X1
 

LOU DOSE
 

01-012M
 

<U1)
 

(50)
 

(49)
 

1 <2X)
 

(50)
 

(17)
 

(50)
 

1 (2X)
 

(48)


5 (10X)
 

(50)
 

("9)
 

(50)


1 (2X)
 

(19)
 

2_J1J1
 

HIGH DOSE
 

01-013M
 

(28)
 

(t9)
 

1 (2X)
 

2 (tX)
 

(19)
 

(US)
 

1 <2X)
 

1 <2X)
 

(49)
 

(49)
 

1 (2X)
 

(48)
 

5 (10X)
 

(49)
 

(49)
 

2 (4X)
 

(49)
 

(«9)
 

2_14X>
 

* NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

A-4
 
TABLE Al (CONTINUED)
 

REPBODUCTIVE SYSTEM
 

*HA»HARY GLAND
 

ADENOCARCINOMA, NOS
 

FIBROADENOMA
 

#TESTIS
 

MESOTHELIOBA, NOS
 

NERVOUS SYSTEH
 

NONE
 

SPECIAL SENSE ORGANS
 

NONE
 

HUSCDLOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

•ABDOMINAL CAVITY
 

LIPOHA
 

ALL OTHER SYSTEMS
 

NONE
 

ANIHAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY
 

NATURAL DEATHS
 

HOBIBDND SACRIFICE
 SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL MISSING
 

» IKlfiBJ.3-4ST.o.I,S.SSP._.AflIB.415
 

CONTROL (UNTR)
 

01-031M
 

(20)
 

1 (5%)
 

1 <5X)
 

(20) '
 

(20)
 

20
 

11
 

5
 

U
 

CONTROL (VEH)
 

01-011S
 

(20)
 

2 (10X)
 

1 (5X)
 

(20)
 

(20)
 

20
 

9
 

1
 

10
 

Loa DOSE
 

01-012M
 

(50)
 

2 (UX)
 

1 <2X)
 

(50)
 

(50)
 

50
 

23
 

1
 

26
 

HIGH DOSE
 

01-013H
 

(49)
 

(U8)
 

1 (2X)
 

(49)
 

2 <UX)
 

50
 

25
 

25
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

A-5
 
TABLE Al (CONCLUDED)
 

CONTROL (UN TR) CONTROL (VEH) LOW DOSE HIGH DOSE
 

01-031K 01-011M 01-012M 01-013M
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 6 11 17 20
 

TOTAL PRIMARY TUMORS 11 16 19 26
 

TOTAL ANIMALS WITH BENIGN TUMORS 2 9 11 13
 

TOTAL BENIGN TOMOHS 3 10 12 14
 

TOTAL ANIMALS KITH MALIGNANT TDMORS 6 6 7 9
 

TOTAL MALIGNANT TUMORS 8 6 7 10
 

TOTAL ANIMALS WITH SECONDARY TIIBORS* 1
 

TOTAL SECONDARY TUHOBS 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT 2
 

TOTAL UNCERTAIN TUMORS 2
 

TOTAL ANIMALS WITH TUMORS UNCERTAINPRIMARY OH METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PBIHARY TOHOSS: ALL TOHORS EXCEPT SECONDARY TUHORS
 

t SECONDARY TUMORS: METASTATIC TUMORS OR TOHORS INVASIVE INTO AN ADJACENT ORGAN
 

A-6
 
TABLE A2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH 1,1,2,2-TETRACHLOROETHANE 

CONTROL (ONTR) CONTROL (VEH)
 

01-031F 01-011F
 

ANIMALS INITIALLY IN STUDY 20 20
 

ANIMALS NECROPSIED 20 20
 

ANIMALS EXAMINED HISTOPATHO LOGICALLY *'* 20 20
 

INTEGUMENTARY SYSTEM
 

*SUBCOT TISSUE (20) (20)
 FIBROMA 1 (5X)
 LIPOMA
 

RESPIRATORY SYSTEM
 

*LUNG (20) (20)
 RHABDOMYOSARCOMA, METASTATIC
 

HEMATOPOIETIC SYSTEM
 

•MULTIPLE ORGANS (20) (20)
 MALIG.LYMPHOMA, LYMPHOCYTIC TYPE
 

MALIG.LYNPHOMA, HISTIOCYTIC TYPE
 

*SUBCOT TISSUE/BACK (20) (20)
 MALIG.LYMPHOMA, HISTIOCYTIC TYPE
 

*SPLEEN (20) (20)
 MALIG.LYMPHOMA, LYMPHOCYTIC TYPE
 

CIRCULATORY SYSTEM
 

*HEART (20) (20)
 RHABDOMYOSARCOMA
 

MIXED TUMOR, METASTATIC 1 (5X)
 

DIGESTIVE SYSTEM
 

iLIVER (20) (20)
 -. HEPATOC.ELLULAR CARCINOMA _ _. 1 J5XI
 

t NUMBE R OF ANIMAL S HITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

LOW DOSE
 

01-OUP
 

50
 

50
 

50
 

(50)
 

2 (4%)
 

(50)
 

1 (2X)
 

(50)
 

1 (2%)
 

1 (2%)
 

(50)
 

(U9)
 

(50)


1 <2X)
 

(50)
 

HIGH DOSE
 

01-015F
 

50
 

50
 

50
 

(50)


1 (2X)
 

1 (2X)
 

(50)
 

(50)
 

(50)
 

1 <2X>
 

(48)
 

1 (2X)
 

(50)
 

(50)
 

A-7 
TABLE A2 (CONTINUED) 

DRIHABX SYSTEM 

•KIDNEY 

MIXED TUMOR, MALIGNANT 

HAMARTOMA 

ENDOCRINE SYSTEM 

•PITUITARY 

CHROMOPHOBE ADENOMA 

•ADRENAL 

COBTICAL CARCINOMA 

PHEOCH80MOCYTOMA 

tTHYBOID 

FOLLICOLAH-CELL CARCINOMA 

C-CELL ADENOMA 

C-CELL CARCINOMA 

tPANCREATIC ISLETS 

ISLET-CELL ADENOMA 

REPRODUCTIVE SYSTEM 

•MAMMARY GLAND 

ADENOMA, SOS 

ADENOCARCINOMA, NOS 

FIBROMA 

FIBROADENOMA 

tUTEROS 

ADENOCARCINOMA, NOS 

EHDOMETRIAL STROBAL

HEMANGIOM A 

HEHANGIOSARCONA 

fOTABY 

CYSTADENOCABCIHOBA,

GRANOLOSA-CELL TUMOR 

NERVOOS SYSTEM 

NSfiE _ _ 

 POLYP 

 NOS 

t NUMBER OF ANIMALS WITH TISSUE

* NUMBER OF ANIMALS NECROPSIED 

CONTROL (ONTR) 

01-031F 

(20) 

1 <5X) 

2 (10X) 

(19) 

6 <32X) 

(20) 

(20) 

2 (10*) 

2 (10X) 

(20) 

1 <5X) 

(20) 

2 (10X) 

2 (10X) 

(20) 

1 (5X) 

(20) 

1 <5X) 

CONTROL (VEH) 

01-011F 

(20) 

1 (5X) 

(20) 

3 (15X) 

(20) 

(20) 

(20) 

(20) 

1 (5X) 

9 (H5%) 

(20) 

(20) 

 EXAMINED MICROSCOPICALLY 

LOW DOSE 

01-01KF 

(50) 

1 (2X) 

(U9) 

11 (22*) 

(U9 ) 

1 (2X) 

(t9) 

1 (2X) 

(50) 

1 (2X) 

(50) 

1 (2%) 

1 (2%) 

13 (26X) 

(50) 

2 <HX) 

8 (16X) 

1 (2X) 

(50) 

1 <2X) 

HIGH DOSE 

01-015F 

(50) 

(18) 

6 (13X) 

<U9 ) 

1 (2X) 

(50) 

1 (2X) 

1 (2X) 

(50) 

(50) 

1 <2X) 

2 («X) 

1 (2X) 

11 (22X) 

(48) 

« (8X) 

(«8) 

1 <2X) 

A-8 
SPECIAL SENSE ORGANS
 

MODE
 

MUSCDLOSKELETAL SYSTEM
 

MODE
 

BODY CAVITIES
 

HONE
 

ALL OTHER STSTEHS
 

NONE
 

ANIMAL DISPOSITION SDMMARY
 

ANIMALS INITIALLY 19 STUDY
 NATURAL DEATHS
 

MORIBUND SACRIFICE
 

SCHEDULED SACBIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL MISSING
 

9 INCL.ODES iBTQLY.ZED.AHIMA.lS
 

t NUMBER OF ANIHALS WITH TISSUE « NUMBER OF ANIMALS NECROPSIED 

TABLE A2 (CONTINUED) 

CONTROL (ONTH) CONTROL (VEH) LOW DOSE HIGH DOSE
 

01-031F 01-011F 01-014F 01-015F
 

20 20 50 50
 

2 6 20 30
 

1
 

5
 

13 1t 29 30
 

— ——
 EXAMINED MICROSCOPICALLY 

A-9 
TABLE A2 (CONCLUDED)
 

CONTROL (DNTH) CONTROL (VEH)
 

01-031F 01-011F
 

TUHOR SUMMARY
 

TOTAL ANIMALS KITH PRIMARY TOHORS* 11 12
 

TOTAL PRIHARY TDHORS 21 15
 

TOTAL ANIMALS KITH BENIGN TDHOBS 12 11
 

TOTAL BENIGN TUMORS 1<» 14
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 6 1
 

TOTAL MALIGNANT TUMORS 7 1
 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1
 

TOTAL SECONDARY TUMORS 1
 

TOTAL ANIMALS WITH TUHORS UNCERTAINBENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUHORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAINPRIMARY OR HETASTATIC
 

TOTAL UNCERTAIN TDHORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TOHORS
 

* SECONDARY TUHORS: HETASTATIC TUHORS OR TUMORS INVA SIVE INTO AN ADJ
 

LOW DOSE
 

01-014F
 

28
 

48
 

24
 

38
 

7
 

9
 

1
 

1
 

1
 

1
 

ACENT ORGAN
 

HIGH DOSE
 

01-015F
 

23
 

33
 

21
 

27
 

5
 

5
 

1
 

1
 

A-IO
 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH 1,1,2,2-TETRACHLOROETHANE
 

TABLE Bl

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH 1,1,2,2-TETRACHLOROETHANE 

CONTROL (UNTR) 

02-M021 

CONTROL (VEH) 

02-M011 

LOH DOSE 

02-M012 

HIGH DOSE 

02-H013 

ANIMALS INITIALLY IN STODY 

ANIMALS MISSING 

ANIMALS NECROPSIED 

ANIMALS EXAMINED HISTOPATHOLOGICALLY ** 

20 

19 

19 

20 

1 

18 

18 

50 

19 

18 

50 

K9 

49 

INTEGUMENTARY SYSTEM 

*SKIN 

SQUAMOUS CELL CARCINOMA 

FIBROSARCOMA 

(19) 

1 (5X) 

1 (5X) 

(18) (49) <t9) 

•SUBCUT TISSUE 

FIBROMA 

FIBROSARCOMA 

(19) (18) (49) 

1 <2X) 

2 (4X) 

(49) 

RESPIRATORY SYSTEM 

tLUNG 

HEPATOCELLULAR CARCINOMA, METAST ALVEOLAR/BRONCHIOLAR ADENOMA 

(19) 

2 (11X) 

(18) 

1 (6%) 

(39) 

1 <3X) 

2 (5X) 

(47) 

2 (4X) 

HEMATOPOIETIC SYSTEM 

•MULTIPLE ORGANS 

MALIG.LYHPHOHA, LYMPHOCYTIC TYPE 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 

(19) 

1 (5X) 

2 (11X) 

(18) <«9) 

1 (2X) 

2 (i»») 

(49) 

1 (2X) 

*SHBCUT TISSUE 

MALIG.LYMPHOMA. HISTIOCYTIC TYPE 

(19) (18) (19) (49) 

1 <2X) 

OLIVER 

HALIG.LYMPHOMA, HISTIOCYTIC TYPE (19) (18) (50) 

1 (2X) 

(49) 

1 (2X) 

CIRCULATORY SYSTEM 

BONE 

» NUHBEB OF ANIHALS HITH TISSUE EXAMINED

* NUMBE R OF ANIMAL S NECEOPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 HICHOSCOPICALL1T 

B-3
 
TABLE Bl (CONTINUED)
 

DI6ESTITE SYSTEM 

*LIVBR 

HEPiTOCELLUIAR CARCINOMA 

HEBANGIOBA 

HEBAHGIOSABCOHA 

DBIHAHI SISTBM 

tKIDNET 

ADBROCARCIHOHA, SOS 

TOBOLiR-CELL ADENOMA 

TUBULAR-CELL ADEMOCARCINOHA 

FIBROSARCOMA 

ENDOCRINE SrsTEH 

*THYROID 

FOLLICDLAR-CELL ADENOHA 

REPRODUCTIVE SISTEH 

HONE 

KEHVOOS SYSTEM 

NOHE 

SPECIAL SENSE OR6ANS 

NONE 

HOSCOLOSKELETAL STSTEH 

MORE 

BODY CAVITIES 

-SQS3 

1 ^~ "• "* ""* ~" "-•—~— —••——•——•—.— •— .»TM_ «•__. 

CONTROL (UNTR) 

02-H021 

(19) 

2 (11X) 

1 <5X) 

(19) 

1 (5X) 

1 <5X) 

(16) 

CONTROL (VEH) 

02-H011 

(18) 

1 (6X) 

1 (6X) 

(18) 

1 (6X) 

(17) 

L OW DOSE 

02-H012 

(50) 

13 (26X) 

(39) 

1 (3X) 

(38) 

HIGH DOSE 

02-B013 

(»9) 

44 (90X) 

(47) 

(47) 

1 (2X) 

* NDHBE8 OF ANIHALS KITH TISSOE EXAMINED MICROSCOPICALLY
 

« ND8BER OF ANIHALS NECROPSIED
 

B-4
 
TABLE Bl (CONCLUDED)
 

HIGH DOSE
 

02-8013
 

50
 

47
 

2
 

1
 

45
 

50
 

3
 

3
 

i»5
 

47
 

CONTROL (UNTR)
 

02-H021
 

ALL OTHER SYSTEMS
 

NONE
 

AHIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IV STUDY 

NATURAL DEATHS 

BORIBDND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

ANIMAL HISSING 

20 

8 

12 

a INCLUDES AUTOLYZED ANIMALS 

TUMOR SUMMARY
 

TOTAL ANIMALS HITH PRIMARY TUMORS* 9
 TOTAL PRIMARY TUMORS 12
 

TOTAL ANIMALS WITH BENIGN TUMORS 2
 

TOTAL BEKIGN TDMORS 2
 

TOTAL ANIMALS KITH MALIGNANT TUMORS 9
 TOTAL MALIGNAHT TUMORS 10
 

TOTAL ANIMALS WITH SECONDARY TUMORS*
 TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT
 TOTAL UNCERTAIN TOMOHS
 

TOTAL ANIMALS WITH TUMORS UNCERTAINPRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUHORS: ALL TDHOSS EXCEPT SECONDARY TUHORS
 

CONTROL (VEH) LOU DOSE
 

02-B011 02-B012
 

20 50
 

10 23
 

9 27
 1
 

4 17
 U 23
 

3 3
 

3 3
 

1 17
 1 20
 

1
 

1
 

* SECONDARY TUMORS: METASTATIC TDBORS OR TOHOES INVASIVE INTO AN ADJACENT ORGAH
 

B-5
 
TABLE B2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH 1,1,2,2-TETRACHLOROETHANE 

_
 

ANIMALS INITIALLY IN STUDY
 

ANIMALS HISSING
 

ANIHALS NECROPSIED
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY**
 

INTEGUMENTARY SYSTEH
 

HOME
 

RESPIRATORY SYSTEH
 

ilUNG
 

At.VEOI.AR/BRONCHIOLAR ADENOMA
 

ALVBOLAR/BRONCHIOLAB CARCINOMA
 

HBMATOPOIETIC SYSTEM
 

•MULTIPLE ORGAHS
 

MALIG.LYMPHONA, LIMPHOCYTIC TYPE
 

HALIG.LYMPHOBA. HISTIOCYTIC TYPE
 

iSPLEEN
 

HEHANGIOSARCOMA
 

HALIG.LYMPHOMA, HISTIOCYTIC TYPE
 

tMESENTERIC L. NODE
 

ADENOCARCINOHA, NOS, HETASTATIC
 

MALIG.LYMPHOMA, LYHPHOCYTIC TYPE
 

CIRCULATORY SYSTEH
 

NONE
 

DIGESTIVE SYSTEH
 

*LIVER
 

HEPATOCELLULAR CARCINOMA
 

URINARY SYSTEH
 

_ B2HE _ _
 

CONTROL (ONTR)
 

02-P021
 

20
 

1
 

19
 

19
 

(19)
 

1 <5X)
 

(19)
 

(19)
 

(19)
 

(19)
 

CONTROL (VEH)
 

02-P011
 

20
 

20
 

20
 

(20)
 

(20)
 

(19)
 

(20)
 

1 (5X)
 

(20)
 

LOW DOSE
 

02-F014
 

50
 

1
 

48
 

48
 

(i»6)
 

1 (2X)
 

(<»8)
 

2 (4X)
 

3 (6*)
 

(46)
 

1 <2X)
 

1 (2X)
 

(46)
 

1 (2X)
 

(48)
 

30 (63*)
 

HIGH DOSE
 

02-F015
 

50
 

1
 

47
 

47
 

(44)
 

1 <2X)
 

(«7)
 

1 (2X)
 

2 (4X)
 

(46)
 

1 (2X)
 

(46)
 

(47)
 

43 (91%)
 

f NOHBER OF ANIMALS WITH TISSUE EXAMINE D MICROSCOPICALLY 

» NUMBER OF ANIHALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-6 
TABLE B2 (CONTINUED) 

CONTROL (UNTR) CONTROL (VEH) LOB DOSE HIGH DOSE
 

02-F021 02-F011 02-FOH 02-F015
 

ENDOCRINE SYSTEH
 

fPITUITARY (19) (15)
 

CHROMOPHOBE CARCINOMA 1 (5X)
 

REPRODUCTIVE SYSTEM
 

•MAHMABY GLAND (19) (20)
 ADENOCARCINOHA, NOS
 

IUTE8US (18) (20)
 ADENOCARCINOMA, NOS 1 <5X)
 ENDOMETRIAL STROMAL POLYP
 

ENDOMETRIAL STROMAL SARCOMA 1 <5X)
 

tOVARY (18) (20)
 

CYSTADENOMA, NOS
 

ENDOMETRIAL STROMAL SARCOMA, MET 1 (5%)
 TERATOMA, NOS 1 <5X>
 

NERVODS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

NONE
 

HOSCOLOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*PERITONEUM (19) (20)
 ENDOMETRIAL STRONAL SARCOMA , MET 1 (5X)
 

ALL OTHER SYSTEMS
 

SQS.S
 

I NUMBER OF ANIMALS WITH TISSDE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

(«6) (»6)
 

(t8) (147)
 

1 (2X)
 

(«6) (U6)
 

1 (2X) 1 (2X)
 

C»6) («6)
 

1 (2*)
 

(t8) («7)
 

B-7 
TABLE B2 (CONCLUDED)
 

ANIHAL DISPOSITION SOHHARY
 

ANIMALS INITIALLY IN STODI


NATORAL DEATHS


RORIBOMD SACRIFICE
 

SCHEDULED SACRIFICE
 ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE


ANIMAL HISSING


9 INCLDDES AOTOLYZED ANIHALS
 

TOHOR SOHHART
 

TOTAL ANIHALS BITH FRIHABT TDHORS*


TOTAL PRIHARY TUHORS


TOTAL ANIMALS WITH BENIGN TUMORS
 TOTAL BENIGN TDHORS


TOTAL ANIRALS BITH MALIGNANT TOHORS


TOTAL MALIGNANT TDRORS


TOTAL ANIHALS WITH SECONDARY TOHOHSt
 

TOTAL SECONDARY TDHORS
 

TOTAL ANIMALS BITH TUMORS UNCERTAINBENIGN OR MALIGNANT
 

TOTAL DNCERTAIN TOHORS
 

TOTAL ANIHALS HITH TOHOHS UNCERTAIN­ PBIHART OH HETASTATIC
 

TOTAL DHCERTAIN TIIBORS
 

CONTROL (ONTR)
 

02-P021
 

 20
 

2
 

 17
 

1
 

2
 

2
 

1
 

1
 

1
 

1
 

CONTROL (VEH)
 

02-F011
 

20
 

5
 

15
 

2
 

3
 

1
 

2
 

1
 

3
 

1
 

1
 

LOU DOSE HIGH DOSE
 02-F014 02-F015
 

50 50
 

1 1 36
 

1
 

1
 

37 12
 

1 1
 

33 43
 

42 49
 

2 2
 

2 2
 

33 43
 

40 47
 

* PRIHARI TOHORS: ALL TDHORS EXCEPT SECONDARY TUMORS
 1 SECONDARY TOHORS: HETASTATIC TOHORS OR TDMORS INVASIVE INTO AN ADJACENT ORGAN
 

B-8
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH 1,1,2,2-TETRACHLOROETHANE
 

TABLE Cl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

TREATED WITH 1,1,2,2-TETRACHLOROETHANE 

ANIMALS INITIALLY IN STUDY
 ANIMALS NECROPSIED
 ANIMALS EXAMINED HISTOPATHOLOGICALLY**
 

INTEGUMENTARY SYSTEM
 

•SKIN
 

INFLAMMATION, NOS
 

ULCER, NOS
 

HYPERKERATOSIS
 

ACANTHOSIS
 

•SOBCOT TISSUE
 ABSCESS, NOS
 

RESPIRATORY SYSTEM
 

tTRACHEA
 INFLAMMATION, NOS
 

tLUHG
 

PNEUMONIA, CHRONIC MUHINE
 CiLCIDM DEPOSIT
 

HEHATOPOIETIC SYSTEM
 

tSPLEEN
 INFLAMMATION, NOS
 

HEHATOPOIESIS
 

tCESVICAL LYMPH NODE
 INFLAMMATION, NOS
 

•HESENTERIC L. NODE
 INFLAMMATION, NOS
 

CIRCULATORY SYSTEM
 

* HE ART
 

CitCiafl-EBESSII __


CONTROL (ONTR)
 

01-031M
 

20
 

20
 

20
 

(20)
 

1 <5X)
 

(20)
 

(15)
 

(20)
 

16	 (SOX)
 

1 (5X)
 

(20)
 

1 <5X)
 

(19)
 

1 (5X)
 

(19)
 

(20)
 

 J_i5il


CONTROL (VEH)
 

01-011H
 

20
 

20
 

20
 

(20)
 

1 (5X)
 

1 (5X)
 

(20)
 

1 (5X)
 

(19)
 

1 (5X)
 

(20)
 

11	 (55X)
 

1 (5X)
 

(19)
 

(19)
 

(19)
 

(20)
 

 1_I5SJ


* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

C-3 

LOB DOSE HIGH DOSE
 01-012M 01-013M
 

50 50
 

50 49
 

50 49
 

(50)	 (49)
 

1 <2X)
 

1 (2X)
 

(50)	 (49)
 

1 (2X)
 

(50)	 (49)
 

1 (2X) 1 <2X)
 

(50)	 C»9)
 

25 (SOX) 32 (65X)
 

(50)	 (49)
 

1 (2X)
 

2 (4X)
 

(47) (47)
 

(47)	 (47)
 

1 (2X)
 

(50)	 (49)
 

 i-iiSL __
 
TABLECl (CONTINUED)
 

tfitOCABDIOM
 

INFLAMMATION, NOS
 PIBBOSIS
 

DEGENERATION, NOS
 

•ENDOCARDIUM
 

HYPERPLASIA, NOS
 

*AOBTA
 

MEDIAL CALCIFICATION
 

*MESE»TEBIC ABTEBY
 

MEDIAL CALCIFICATION
 

DIGESTIVE SYSTEM
 

*LIVEB
 

INFLAMHATION, NOS
 PELIOSIS HEPATIS
 

METAMORPHOSIS FATTY
 

FOCAL CELLULAR CHANGE
 

ANGIECTASIS
 

*BILE DUCT
 

FIBBOSIS
 

HYPESPLASIA, NOS
 

•PANCREAS
 

INFLAMMATION, NOS
 

PERIARTERITIS
 

•STOMACH
 

CALCIDM DEPOSIT
 

HYPERKERATOSIS
 ACANTHOSIS
 

fCOLON
 

NEMATODIASIS
 

_E4Bi5IIJSM
 

CONTROL (ONTR)
 

01-031H
 

(20)
 

2 (10X)
 

1 <5X)
 

(20)
 

1 (5X)
 

(20)
 

2 (10X)
 

(20)
 

1 (5X)
 

(20)
 

1 <5X)
 

2 (10X)
 

3 (15X)
 

(20)
 

u (20*)
 

(20)
 

a (20%)
 

(20)
 

2 (10X)
 

(19)
 

1 (5X>
 

CONTROL (VEH)
 

01-011H
 

(20)
 

1 (5X)
 

(20)
 

(20)
 

3 (15X)
 

(20)
 

(20)
 

(20)
 

1 (5X)
 

(20)
 

3 (15X)
 

(20)
 

2 (10X)
 

1 (5X)
 

1 (5X)
 

(20)
 

LOH DOSE
 01-012H
 

(50)
 

1 (2X)
 

(50)
 

(50)
 

5 (10X)
 

(50)
 

2 (»X)
 

(50)
 

1 (2X)
 

2 (tX)
 

2 (OX)
 

(50)
 

1 (2X)
 

(a 9)
 

6 (12X)
 

(50)
 

1 (8X)
 

1 <2X)
 

1 (2X)
 

(»9)
 

i.iZSl
 

HIGH DOSE
 

01-013B
 

(49)
 

1 (2X)
 

(*9)
 

(«9)
 

(K9)
 

(«9)
 

1 (2*)
 

9 (18X)
 

1 <2»)
 

(U9)
 

1 (2*)
 

1 (2X)
 

(19)
 

1 <2X)
 

2 (4«)
 

C»8)
 

1 <2X)
 

2 («X)
 

2 («X)
 

(H9)
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

» NUMBER OF ANIMALS NECROPSIED
 

O4
 
TABLE Cl (CONTINUED) 

CONTROL (UNTR) CONTROL (VEH)
 

01-031M 01-011M
 

URINARY SYSTEM
 

•KIDNEY	 (20) (20)
 

CYST, NOS 1 <5X)
 

PYELONEPHRITIS, KOS 1 (5%)
 

INFLAMMATION, CHBONIC 15 (75%) 1» (70X)
 

CALCIUM DEPOSIT 1 <5X)
 

*URINARY BLADDER (19) (20)
 

INFLAMMATION. NOS 1 (5X) 1 (5X)
 

ENDOCRINE SYSTEM
 

•PITUITARY	 (20) (11)
 

CYST, NOS
 

ANGIECTASIS 1 (5X) 1 (7X)
 

tADRENAL CORTEX (20) (20)
 

DEGENERATION, NOS 1 (5X)
 

ANGIECTASIS 1 (5X)
 

tTHYROID (19) (20)
 

OLTIMOBRANCHIAL CYST 2 (11%)
 

FOLLICULAR CYST, NOS
 

HYPERPLASIA, C-CELL 1 <5X) 2 (10X)
 

HYPERPLASIA, FOLLICULAR-CELL 1 <5X)
 

•PARATHYROID	 (3) (20)
 

HYPERPLASIA, NOS 2 (67X) 1 (5X)
 

REPRODUCTIVE SYSTEM
 

tPROSTATE (20) (18)
 

INFLAMMATION, NOS 5 (25X) 2 (11X)
 

*SEMINAL VESICLE (20) (20)
 

INFLAMMATION, NOS 1 (5X) 2 (10X)
 

ITESTIS (20) (20)
 

GRANOLOHA, SPERMATIC 1 (5%)
 

CALCIUM DEPOSIT 1 (5X)
 

ATROPHY, NOS 11 (55X) 8 (10X)
 

*EPIDIDYMIS (20) (20)
 

NECROSIS, FAT 1 (5X)
 _ -illSEfll,. NOS 3(15X1.
 

# NUMBER OF ANIMALS KITH TISSUE EXAMINE D MICROSCOPICALLY * NUMBER OF ANIMALS NECROPSIED 

LOU DOSE
 01-012M
 

(50)
 

26 (52X)
 

2 (IX)
 

(19)
 

(i»8)
 

1 <2X)
 

(50)
 

1 (2X)
 

(K 9)
 

2 (IX)
 

1 <2X)
 

(50)
 

1 (2X)
 

C*0)
 

1 (3X)
 

(50)
 

(50)
 

20 (10X)
 

(50)
 

1 (2X>
 

HIGH DOSE
 01-0138
 

(19)
 

1 (2X)
 

1 (2X)
 

19 (39X)
 

(U7)
 

1 (2X)
 

(l»8)
 

(i»9)
 

3 (6X)
 

(19)
 

1 (2X)
 

(19)
 

(33)
 

(19)
 

(18)
 

17 (35X)
 

(19)
 

C-5 
TABLE Cl (CONCLUDED)
 

CONTROL (ONTR) CONTROL (VEH)
 

01-031M 01-011M
 

NERVOUS SISTER
 

HONE
 

SPECIAL SENSE ORGANS
 

•EYE/LACHIHAL GLAND (20) (20)
 INFLAMMATION, NOS 1 <5X)
 

HDSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

•ABDOMINAL CATITY (20) (20)
 NECROSIS, FAT
 

•PERITONEUM	 (20) (20)
 INFLAMMATION, NOS 1 (5%)
 

•PERICARDIUM	 (20) (20)
 INFLAMMATION, NOS 2 (10X)
 

•MESENTERY	 (20) (20)
 PEHI»HTBBITIS 4 (20X) 3 (15X)
 

ALL OTHER SYSTEMS
 

NONE
 

SPECIAL MORPHOLOGY SOMMARY
 

NO LESION REPORTED 1
 

AOTOLYSIS/NO NECROPSY
 

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

LOB DOSE
 

01-012M
 

(50)
 

(50)
 

(50)
 

1 (2X)
 

(50)
 

(50)
 

4 (8X)
 

8
 

HIGH DOSE
 01-013M
 

(49)
 

(U9)
 

1 (2X)
 

(49)
 

(l»9)
 

(<»9)
 

2 (4X)
 

8
 

1
 

C-6
 
TABLE C2

 

SUMMARY OF THE INCIDENCEOF NONNEOPLASTIC LESIONS IN FEMALE RATS 

TREATED WITH 1,1,2,2-TETRACHLOROETHANE 

CONTROL (OHTR) CONTROL (VEH) LOB DOSE HIGH DOSE
 

01-031F 01-011F 01-01HF 01-015F
 

ANIMALS INITIALLY IH STUDY 20 20 50 50
 

ANIHALS NECROPSIED 20 20 50 50
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY ** 20 20 50 50
 

INTEGUMENTARY SYSTEM
 

•SDBCUT TISSUE (20) (20) (50) (50)
 ABSCESS. NOS 1 (2%)
 

RESPIRATORY SYSTEM
 

tTRACHEA (15) (20) (50) (50)
 INFLAMMATION, NOS 2 (10%)
 

tLDNG (20) (20) (50) 150)
 PNEUMONIA, CHRONIC MURIME 18 (90%) 8 <UO%) 31 (68%) 3« (76%)
 HYPERPLASIA. ADENOMATOUS 1 (2%)
 

HEMATOPOIETIC SYSTEM
 

tSPLEEN (20) (20) (49) (»8)
 HEMATOPOIESIS 2 (10%) 3 (6*) 2 (»%)
 

•CERVICAL LYMPH NODE (20) (18) (50) (50)
 INFLAMMATION, NOS 1 (2%)
 ANGIECTASIS 1 (2%) 1 (2*)
 

IHESENTEBIC L. NODE (20) (18) (50) (50)
 

PE8IARTERITIS 1 (6%)
 

tTHYMUS (15) (19) (U5) (38)
 ABSCESS, NOS 1 (2%)
 

CIRCULATORY SYSTEM
 

*MYOCARDIUM (20) (20) (50) (50)
 INFLAMMATION, NOS 1 (5%)
 - EIBEQSI§_	 JLiSSL
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

C-7 
TABLE C2 (CONTINUED) 

CONTROL (UNTR) CONTROL (VEH)
 

01-031F 01-011F
 

tENDOCARDIOM (20) (20)
 HYPERPLASIA, NOS 2 (10X)
 

*AORTA (20) (20)
 MEDIAL CALCIFICATION 1 (5X)
 

DIGESTIVE SYSTEM
 

tLIVER (20) (20)
 CYST, NOS 1 (5X)
 INFLAMMATION, NOS
 

METAMORPHOSIS FATTY 1 (5%)
 FOCAL CELLULAR CHANGE
 

ANGIECTASIS 1 (5X)
 

tLIVER/CENTRILOBULAR (20) (20)
 NECROSIS, NOS 1 (5X)
 

•BILE DUCT (20) (20)
 HYPERPLASIA, NOS 1 (5X)
 

tSTOMACH (20) (20)
 INFLAMMATION, NOS 1 <5X)
 ULCER, FOCAL
 

HIPBRKERATOSIS 1 (5X)
 ACANTHOSIS 1 (5X)
 

URINARY SYSTEM
 

tKIDNEY (20) (20)
 CYST, NOS
 INFLAMMATION, CHRONIC 9 (15%) 2 (10X)
 CALCIUM DEPOSIT 1 (5X) 1 (5X)
 

ENDOCRINE SYSTEM
 

tADRENAL CORTEX (20) (20)
 DEGENERATION, NOS 3 (15X)
 ANGIECTASIS 3 (15X) 4 (20%)
 

tTHYROID (20) (20)
 FOLLICULAR CYST, NOS 1 (5%)
 HYPERPLASIA, C-CELL 1 (20X)
 

HY.E.EBP.i45.JAx._JQlilc.UL4,g=gELi_ . 1 I5S1
 

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

LOU DOSE
 01-014F
 

(50)
 

(50)
 

(50)
 

1 (2X)
 

1 (2X)
 

1 <2X)
 

(50)
 

(50)
 

1 (2*)
 

(19)
 

1 (2X)
 

(50)
 

1 (2X)
 

12 (24X)
 

(49)
 

5 (10X)
 

(49)
 

1 <2X)
 

HIGH DOSE
 01-015F
 

(50)
 

(50)
 

(50)
 

1 (2X)
 

4 (8X)
 

1 (2X)
 

1 <2X)
 

(50)
 

(50)
 

1 (2X)
 

(49)
 

(50)
 

2 (<•«)
 

(49)
 

(50)
 

1 12%)
 

C-8 
# PARATHYROID
 

HYPERPLASIA, NOS
 

REPRODUCTIVE SYSTEM
 

•MAMMARY	 GLAND
 

GALACTOCELE
 

•VAGINA
 

INFLAMMATION, NOS
 

ttJTEROS
 

HYDROHETRA
 

*UTERUS/ENDOMETRIUM
 

INFLAMMATION, NOS
 

HYPERPLASIA, CYSTIC
 

tOVAHY
 

CYST, NOS
 

NERVOUS SYSTEM
 

tBRAIN/MENINGES
 

INFLAMMATION, NOS
 

tCEREBRUM
 

HYDROCEPHALUS, NOS
 

tBRAIN
 

INFLAMMATION, SUPPURATIVE
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCOLOSKELETAL SYSTEM
 

CONTROL (UNTR) CONTROL (VEH)
 

01-031F 01-011F
 

(D (20)
 

1 (100X)
 

(20) (20)
 

(20) (20)
 

(20)	 (20)
 « (20%)
 

(20)	 (20)
 

1 (5X)
 

1 (5X)
 

(20)	 (20)


3 (15X)
 

(20) (20)
 

(20) (20)
 

(20) (20)
 

TABLE C2 (CONTINUED)
 

LOU DOSE
 

01-011IF
 

(50)
 

(50)
 

(50)
 

1 (2X)
 

(50)


1 (2X)
 

(50)


1 (2*)
 

(50)
 

(50)


1 (2X)
 

(50)
 

(50)


1 (2X)
 

HIGH DOSE
 01-015F
 

(50)
 

(50)
 

1 (2X>
 

(50)
 

C»8)
 

» (8X)
 

(U8)
 

1 <2X)
 

(18)
 

(50)
 

(50)
 

1 (2X)
 

(50)
 

*	 NDMBER OF ANIMALS WITH TISSDE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-9
 
TABLE C2 (CONCLUDED)
 

LOV DOSE
 

01-OHF
 

(50)
 

(50)
 

1 (2*)
 

5
 

HIGH DOSE
 

01-015F
 

(50)
 

(50)
 

<t
 

BODY CAVITIES
 

*PLEURA
 

INFLAMMATION, NOS
 

*PE8ICA8DIOB
 

INFLAHMATION, NOS
 

ALL OTHER SYSTEMS
 

DOME
 

SPECIAL MORPHOLOGY SOHHASY
 

HO LESION REPORTED
 

CONTROL (OHTR)
 

01-031F
 

(20)
 

(20)
 

CONTROL (VEH)
 

01-011F
 

(20)
 

1 <5X)
 

(20)
 

1 (5*)
 

1
 

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 * NDMBER OF ANIMALS NECROPSIED
 

C-IO
 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH 1,1,2,2-TETRACHLOROETHANE
 

TABLE Dl 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

TREATED WITH 1,1,2,2-TETRACHLOROETHANE 

CONTROL (ONTR) 

02-H021 

CONTROL (VEH) 

02-M011 

LOB DOSE 

02-S012 

HIGH DOSE 

02-M013 

ANIMALS INITIALLY IN STUDY 

ANIMALS HISSING 

ANIMALS NECROPSIED 

ANIHALS EXAMINED HISTOPATHO LOGICALLY *' 

20 

19 

' 19 

20 

1 

18 

18 

50 

U9 

48 

50 

49 

H9 

INTEGUMENTARY SYSTEM 

*SKIS 

EPIDERMAL INCLUSION CYST 

INFLAMMATION. DOS 

(19) (18) 

1

1

 (6*) 

 (6%) 

(l»9) <»9) 

*SUBCUT TISSUE 

ABSCESS, NOS 

(19) 

1 (5%) 

(18) (i»9) 

1 (2X) 

(»9) 

1 (2%) 

RESPIRATORY SYSTEM 

*LDNG 

PNEUMONIA, CHRONIC MOHINE 

(19) (18) 

2 (11%) 

(39) (H7) 

1 (2%) 

HEMATOPOIETIC SYSTEM t 

ISPLEEN 

AMYLOID, NOS 

AMYLOIDOSIS 

(")

2 (12*) 

(18) 

1 (6%) 

(39) 

5 (13%) 

(47) 

tLYNPH NODE 

ANGIECTASIS 

(19) 

1 (5%) 

(18) (39) (47) 

tHESENTERIC L. NODE 

INFLAMMATION, NOS 

(19) (18) 

4 (22%) 

(39) 

2 (5%) 

(47) 

CIRCULATORY SYSTEM 

*HEART 

_£4tCIUM DEPOSIT. . 

(19) (18) (39) 

.

(47) 

1-12.SL.. 

# NUMBE R OF ANIMAL S KITH TISSUE EXAMINE D

* NUMBE R OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

D-3 
TABLEDI (CONTINUED) 

" 

CONTROL (ONTR) 

02-B021 

CONTROL (VEH) 

02-H011 

L0> DOSE 02-M012 

HIGH DOSE 

02-M013 

DIGESTIVE SYSTEM 

OLIVER THBOHBUS, ORGANIZED AMYLOID, NOS 

HYPBRPLASIA, MODULAR 

(19) 

1 (5X) 

(18) 

1

1

 (6X) 

 (6X) 

(50) («9) 

tLARGE INTESTINE NEMATODIASIS 

(19) 

2 (11«) 

(18) (39) (i»7) 

tCOLON 

PARASITISM (19) (18) (39) (17) 

1 12%) 

ORIHABY SYSTEM 

tKIDNSr 

HYDRONEPHROSIS 

PYBLONEPHBITIS. NOS 

INFLAMMATION, CHROMIC 

NEPHROPATHY AMYLOID, NOS 

AMYLOIDOSIS 

CALCIDII DEPOSIT 

(19) 

7 (37X) 

6 (32X) 

(18) 

1 (6X) 

5 (28X) » (22X) 

4 (22%) 

(39) 

3 (8X) 

13 (33X) 

3 (8X) 5 (13X) 

(U7) 

3 (6X) 

10 (21X) 

1 <2X) 

ENDOCRINE SYSTEM 

tADRENAL CORTEX AN6IECTASIS 

(19) (18) (39) (47) 

1 (2X) 

BEPRODBCTIVE SYSTEM 

tPBOSTATE INFLAMMATION, NOS (18) (18) (39) (17) 

1 (2X) 

•SEMINAL VESICLE INFLAMMATION. NOS (19) (18) 

1 <6X) 

(«9) (<19) 

tTESTIS 

CALCIUM DEPOSIT ATROPHY, NOS 

(19) 

1 <5X> 

(18) (39) 

1 (3X) 

3 (8X) 

(17) 

1 (2%) 

*EPIDIDYMIS _ -Gfi4N5!10HAx_SESfiflATI£ (19) (18) (t9) 

. J.J2SL 

(19) 

* NOMBEB OP ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY * NUMBER OF ANIMALS NECROPSIED 

D-4
 
TABLE Dl (CONCLUDED) 

CONTROL (DHTR) 

02-8021 

CONTROL (VEH) 

02-H011 

LOH DOSE 

02-M012 

HIGH DOSE 

02-M013 

NERVOUS SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

NONE 

HOSCOLOSKBLETAL SYSTEM 

NONE 

BODY CAVITIES 

•MEDIASTINUM 

CYST, NOS 

(19) 

1 (5%) 

(18) (t9) (19) 

ALL OTHEE SYSTEMS 

NONE 

SPECIAL MORPHOLOGY SUMMAR Y 

NO LESION REPORTED 

ANIMA L MISSING/NO NECROPSY 

NECROPSY PERF/NO HISTO PERFORMED 

MJTO/NECBOPSY/HISTO PEEP 

AUTOLYSIS/NO NECROPSY 

5 

1 

2 

1 

1 

18 

1 

1 

1 

4 

1 

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECBOPSIEO 

D-5
 
TABLE D2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

TREATED WITH 1.1.2,2-TETRACHLOROETHANE 

CONTROL (ONTR) CONTROL (VEH) LOB DOSE HI6H DOSE
 

02-F021 02-F011 02-FOU 02-F015
 

ANIMALS INITIALLY IN STUDY 20 20 50 50
 ANIMALS MISSING 1 1 1
 ANIHALS NBCROPSIED 19 20 U8 47
 AHIBALS EXABINBD HISTOPATHOLOGICALLY 19 20 48 47
 

INTEGDBZNTARY SYSTEM
 

NONE
 

RESPIRATORY SYSTEM
 

ILUNG (19) (20) (16) (44)
 

BRONCHOPNEDMONIA, ACOTB 2 (11X)
 PNEUMONIA, CHRONIC BDRINE 1 <5X) 6 (13X) e (18%)
 

HEBATOPOIETIC SYSTEM
 

tSPLEEN (19) (19) (»6) (46)
 INFLABBATION. NOS 1 (2X)
 HBHATOPOIESIS 2 (11X) 1 12%}
 

tLYBPR NODE (19) (20) («6) (46)
 HYPERPLASIA, LYBPROID 1 (5X)
 

tBESENTERIC L. NODE (19) (20) (46) (46)
 INFLABBATION, NOS 1 <5X)
 ANGIECTASIS 1 (2X)
 

CIRCOLATORY SYSTEB
 

# HEART	 (19) (20) («6) (44)
 THROMBUS, ORGANIZED	 2 (5X)
 

tHYOCABDIOM (19) (20) (46) (44)
 FIBROSIS 1 (5X) 1 (2X)
 

•ENDOCARDIUM	 (19) (20) (46) (44)
 

BJCEME1ASIJU_B25 1-J2SL
 

t NUMBER OF ANIMALS BITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS HECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

0-6 
TABLE D2 (CONTINUED) 

CONTROL (UNTH) 

02-F021 CONTROL (VEH) 02-F011 

LOR DOSE 

02-F01U 

HIGH DOSE 

02-F015 

*COROHARY ARTERY INFLAMMATION, CHRONIC (19) 

1 (5X) 

(20) (»8) (U7) 

DIGESTIVE SYSTEM 

tSALIVARY GLAND 

CYST, NOS 

INFLAMMATION, NOS 

(19) (19) («0) 

1 <3X) 

(39) 

1 (3X) 

tLIVEB 

THKOHBDS, ORGANIZED 

PELIOSIS HEPATIS 

HYPE8PLASIA, NODULAR 

(19) (20) C»8) 

1 (2X) 

1 (2X) 

i» (8X) 

(U7) 

» (9X) 

1 (2X) 

*BILE DOCT 

HYPERPLASIA, NOS 

(19) (20) 

1 (5X) 

(»8) (»7) 

*PANCREAS 

CYST, NOS 

THBONBDS, ORGANIZED 

INFLAMMATION, NOS 

PERIARTERITIS 

(19) (20) 

1 (5X) 

(«6) 

2 (IX) 

<«6) 

2 (UX) 

1 (2X) 

1 (2X) 

*STOMACH 

INFLAMMATION, NOS HYPERKEBATOSIS 

(19) (20) 

1 (5X) 

2 (10%) 

C»6) C»6) 

•LARGE INTESTINE 

NEHATODIASIS 

(19) (20) 

1 (5X) 

(«6) (46) 

URINARY SYSTEM 

•KIDNEY 

HYDRONEPHBOSIS 

INFLAMMATION, CHBONIC 

(19) (20) (*6) (U6) 

16 (35X) 

5 (11X) 

ENDOCBINE SYSTEM 

iADBENAL CORTEX 

ANGIECTASIS 

(18) (20) (U6) («6) 

1 (2X) 

REPRODOCTIVE SYSTEM 

tOTEROS 

- -HYfiSQflEIHi _ 

(18) (20) (U6) 

_ -2 J2SL

(»6) 

- a_I2Sl 

i NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

« NUMBER OF ANIMALS NECROPSIED 

Df7 
TABLE D2 (CONTINUED) 

#UTEROS/ENDOMETRIUM
 

INFLAMMATION, NOS
 

INFLAMMATION, ACUTE
 

HYPERPLASIA, CYSTIC
 

•OVARY/OVIDOCT
 

INFLAMMATION, NOS
 

*OVABY
 

CYST, DOS
 

FOLLICULAR CYST, NOS
 

INFLAMMATION, SOS
 

IKFLAMMATION, SDPPDRATIVE
 

NERVOUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGAHS
 

*HARDEHIAN GLAHD
 

HYPERTROPHY, NOS
 

HaSCOLOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*PESICABDIDH
 INFLAMMATION, NOS
 

*HESENTERY
 

PERIASTERITIS
 

ALL OTHER SYSTEMS
 

SQ&S
 

COHTBOL (UNTS)
 

02-F021
 

(18)
 

1 (6X)
 

15 (83X)
 

(18)
 

(18)
 

4 (22%)
 

3 (17X)
 

(19)
 

(19)
 

(19)
 

CONTROL (VEH)
 

02-F011
 

(20)
 

6 (30%)
 

9 (45X)
 

(20)
 

(20)
 

5 (25%)
 

2 (10X)
 

(20)
 

(20)
 

(20)
 

LOW DOSE
 

02-F01U
 

(46)
 

7 (15X)
 

9 (20%)
 

<«6)
 

1 (2X)
 

(i»6)
 

5 (11X)
 

7 (15X)
 

(«8)
 

(148)
 

(48)
 

HIGH DOSE
 

02-F015
 

(46)
 

3 (7X)
 

(46)
 

(46)
 

4 (9X)
 

(47)
 

1 (2X)
 

(47)
 

1 <2X)
 

(47)
 

1 <2X)
 

* KDHBES OF ANIMALS WITH TISSUE EXAHINED HICROSCOPICALLY
 * NDBBES OF ANIMALS HECROPSIED
 

D-8
 
TABLE D2 (CONCLUDED) 

CONTROL (UNTB) 

02-P021 

CONTROL (VEH) 

02-F011 

LOW DOSE 

02-F01U 

HIGH DOSE 

02-F015 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPORTED ANIMAL (IISSIKG/NO NECROPSY 

AOTOLYSIS/NO NECROPSY 

1 

1 

1 8 

1 

1 1 

2 

*U.S. GOVERNMENT PRINTING OFFICE: 1978-260-899:3201 

D-9 

DHEW Publication No. (NIH) 78-827