1978 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 74 

BIOASSAY OF 

1,1,2-TRICHLOROETHANE 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 79-00-5 

NCI-CG-TR-74 

BIDASSAY OF
 

1,1,2-TRICHLOROETHANE
 

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) 78-1324
 

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

FOR POSSIBLE CARCINOGENICITY
 

CARCINOGENESIS TESTING PROGRAM
 

DIVISION OF CANCER CAUSE AND PREVENTION
 

NATIONAL CANCER INSTITUTE, NATIONAL INSTITUTES OF HEALTH
 

FOREWORD: This report presents the results of the bioassay of 1,1,2­

trichloroethane conducted for the Carcinogenesis Testing Program,
 

Division of Cancer Cause and Prevention, National Cancer Institute
 

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

one of a series of experiments designed to determine whether selected environmental chemicals have the capacity to produce cancer
 

animals. Negative results, in which the test animals do not have a
 

in greater incidence of cancer than control animals, do not necessarily mean the test chemical is not a carcinogen because the experiments are conducted under a limited set of circumstances. Positive
 

results demonstrate that the test chemical is carcinogenic for animals under the conditions of the test and indicate a potential risk
 

to man. The actual determination of the risk to man from animal
 

carcinogens requires a wider analysis.
 

CONTRIBUTORS: This bioassay of 1,1,2-trichloroethane was conducted
 

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

under direct contract to the NCI and currently under a subcontract
 

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

Testing Program.
 

The experimental design was determined by the NCI Project Officers, Dr. J. H. Weisburger (1.2) and Dr. E. K. Weisburger (1). The
 

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

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

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

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

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

Histopathologic examinations were performed by Dr. 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. Histopathology
 

findings and reports were reviewed by Dr. R. L. Schueler (7).
 

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

statistical analysis was performed by Mr. W. W. Belew (6) and Dr. J.
 

iii
 
R. Joiner (7), 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 (6) under the direction of the NCI. Those responsible for
 

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

(6), the task leader, Dr. M. R. Kornreich (6), the senior biologist,
 

Ms. P. Walker (6), and the technical editor, Ms. P. A. Miller (6).
 

The final report was reviewed by members of the participating organizations .
 

The statistical analysis was reviewed by members of the Mathematical Statistics and Applied Mathematics Section of the NCI: Dr.
 

J. J. Gart (9), Mr. J. Nam (9), Dr. H. M. Pettigrew (9), and Dr. R.
 

E. Tarone (9).
 

The following other scientists at the National Cancer Institute
 

were responsible for evaluating the bioassay experiment, interpreting
 

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

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

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

Squire (1,10), and Dr. J. M. Ward (1).
 

1.	 Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

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

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

Boulevard, McLean, Virginia.
 

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

Maryland.
 

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

Rockville, Maryland.
 

iv
 
9.	 Mathematical Statistics and Applied Mathematics Section, Biometry
 

Branch, Field Studies and Statistics Program, Division of Cancer
 

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

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

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

v
 

SUMMARY
 

A bioassay of technical-grade 1,1,2-trichloroethane for possible
 

carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1
 

mice. 1,1,2-Trichloroethane in corn oil was administered by gavage,
 

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

of each species, 5 days a week for a period of 78 weeks, followed by
 

an observation period of up to 35 weeks for rats and up to 13 weeks
 

for mice.
 

The high and low time-weighted average dosages of 1,1,2-trichloroethane were, respectively, 92 and 46 mg/kg/day for male and female
 

rats, and 390 and 195 mg/kg/day for the male and female mice.
 

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

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

same rate as the high dose group of the same sex. Twenty animals of
 

each sex were placed on test as untreated controls for each species.
 

These animals were not intubated.
 

No neoplasms were observed at statistically significant incidences in male or female rats.
 

In both male and female mice, administration of 1,1,2-trichloroethane was associated with a significantly increased incidence of
 

hepatocellular carcinomas. Hepatocellular carcinomas were observed
 

in 2/17 (12 percent) untreated control males, 2/20 (10 percent)
 

vehicle control males, 18/49 (37 percent) low dose males, and 37/49
 

(76 percent) high dose males. Hepatocellular carcinomas were also
 

observed in 2/20 (10 percent) untreated control females, 0/20 vehicle
 

control females, 16/48 (33 percent) low dose females, and 40/45 (89
 

percent) high dose females. Both the Fisher exact test comparing
 

tumor incidences of dosed to control groups and the Cochran-Armitage
 

test for positive dose-related trend indicated a highly significant
 

(P < 0.001) association between hepatocellular carcinomas in all
 

mouse groups and the administration of 1,1,2-trichloroethane.
 

A positive dose-related association between administration of
 

1,1,2-trichloroethane and the incidence of pheochromocytoma of the
 

adrenal gland was indicated by the Cochran-Armitage test for mice of
 

both sexes. Fisher exact tests confirmed these results for high dose
 

female mice but not for other mouse groups. There were no other neoplasms for which statistical tests indicated a positive association
 

between dosage and tumor incidence in mice.
 

The results of this study do not provide convincing evidence for
 

the carcinogenicity of 1,1,2-trichloroethane in Osborne-Mendel rats.
 

vii
 
Under the conditions of this bioassay 1,1 ,2-trichloroethane is carcinogenic in B6C3F1 mice, causing hepatocellular carcinomas and adrenal
 

pheochromocytomas.
 

viii
 
TABLE OF CONTENTS
 

Page
 

I. INTRODUCTION 1
 

II. MATERIALS AND METHODS 3
 

A. Chemicals 3
 

B. Dosage Preparation 3
 

C. Animals 4
 

D. Animal Maintenance 4
 

E. Gastric Intubation 6
 

F. Selection of Initial Dose Levels 6
 

G. Experimental Design 7
 

H. Clinical and Histopathologic Examinations 11
 

I. Data Recording and Statistical Analyses 12
 

III. CHRONIC TESTING RESULTS: RATS 17
 

A. Body Weights and Clinical Observations 17
 

B. Survival 19
 

C. Pathology 21
 

D. Statistical Analyses of Results 22
 

IV. CHRONIC TESTING RESULTS: MICE 28
 

A. Body Weights and Clinical Observations 28
 

B. Survival 30
 

C. Pathology 30
 

D. Statistical Analyses of Results 33
 

V. DISCUSSION 43
 

VI. BIBLIOGRAPHY 45
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH 1,1,2-TRICHLOROETHANE A-l
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH 1,1,2-TRICHLOROETHANE B-l
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH 1,1,2­

TRICHLOROETHANE C-l
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH 1,1,2­

TRICHLOROETHANE D-l
 

ix
 
LIST OF ILLUSTRATIONS 

Figure Number Page 

1 GROWTH CURVES FOR 1,1,2-TRICHLOROETHANE 

CHRONIC STUDY RATS 18 

SURVIVAL COMPARISONS OF 1,1,2-TRICHLOROETHANE CHRONIC STUDY RATS 20 

GROWTH CURVES FOR 1,1,2-TRICHLOROETHANE 

CHRONIC STUDY MICE 29 

SURVIVAL COMPARISONS OF 1,1,2-TRICHLOROETHANE CHRONIC STUDY MICE 31 

LIST OF TABLES 

Table Number Page 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS— 

1,1,2-TRICHLOROETHANE GAVAGE EXPERIMENT 

DESIGN SUMMARY FOR B6C3F1 MICE—1,1,2­

TRICHLOROETHANE GAVAGE EXPERIMENT 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

1,1, 2-TRICHLOROETHANE 23 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH 1,1,2-TRICHLOROETHANE 24 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

1,1 ,2-TRICHLOROETHANE 34 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH 1,1,2-TRICHLOROETHANE 37 
LIST OF TABLES (Concluded) 

Table Number Page 

Al SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH 1,1,2-TRICHLOROETHANE A-3 

A2 SUMMARY OF THE INCIDENCE

FEMALE RATS TREATED WITH

ETHANE

 OF NEOPLASMS IN 

 1,1,2-TRICHLORO­

 A-7 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH 1,1,2-TRICHLOROETHANE B-3 

B2 SUMMARY OF THE INCIDENCE

FEMALE MICE TREATED WITH

ETHANE

 OF NEOPLASMS IN 

 1,1,2-TRICHLORO­

 B-7 

Cl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH 1,1,2­

TRICHLOROETHANE C-3 

C2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH 1,1,2­

TRICHLOROETHANE C-7 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH 1,1,2­

TRICHLOROETHANE D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH 1,1,2­

TRICHLOROETHANE D-7 

XI 

I. INTRODUCTION
 

1,1,2-Trichloroethane (NCI No. C04579), 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-trichloroethane. It is also
 

called vinyl trichloride or beta-trichloroethane.
 

Production data for 1,1,2-trichloroethane are considered proprietary by the U.S. Federal Trade Commission, since there are only two
 

manufacturers of the chemical. (If three or more companies produce
 

a chemical, production must be reported to the federal government.)
 

However, 90 million pounds of vinylidene chloride were manufactured
 

by dehydrohalogenation of 1,1,2-trichloroethane in 1974 (Stanford
 

Research Institute, 1975), implying a minimum production of approximately 124 million pounds of 1,1,2-trichloroethane in that year.
 

Most 1,1,2-trichloroethane is used as a chemical intermediate in the
 

production of vinylidene chloride (Stanford Research Institute,
 

1975). Other applications include use in adhesives, in the production of teflon tubing, in lacquer, and in coating formulations
 

(Folkerson, 1977), and as a solvent for fats, oil, waxes, and other
 

products (Hawley, 1971).
 

*The CAS registry number is 79-00-5.
 
Exposure of human populations to 1,1, 2-trichloroethane occurs
 

primarily through inhalation of vapors released during its manufacture and subsequent use as a chemical intermediate. Since the
 

chemical is readily absorbed through the skin (Hawley, 1971), dermal
 

contact following accidental spills or carbon handling represents an
 

additional route of exposure.
 
II. MATERIALS AND METHODS
 

A. Chemicals
 

One batch of technical-grade 1,1,2-trichloroethane was purchased
 

by Hazleton Laboratories America, Inc., Vienna, Virginia, from Aldrich
 

Chemical Company. The purity of the compound was initially determined by Hazleton using gas-liquid chromatography (GLC) and infrared
 

spectrophotometry. The GLC total-area analysis revealed seven peaks;
 

the major peak accounted for 99.2 percent of the total area. The infrared spectrum of the 1,1,2-trichloroethane was consistent with that
 

expected from the structure of the compound.
 

Purity determinations were repeated by Hazleton Laboratories
 

seven and thirteen months, respectively, after the initial analysis
 

to assess the stability of the 1,1,2-trichloroethane after storage.
 

The chromatograph from the second GLC analysis showed a peak accounting
 

for 90.8 percent of the total area. In the third analysis the major
 

peak accounted for 95.4 percent of the total area. The infrared spectra were consistent with the first analysis. These results indicate
 

stability of the test compound.
 

Throughout this report the term 1,1,2-trichloroethane is used to
 

represent this technical-grade material.
 

B. Dosage Preparation
 

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

(S. F. Sauer Company, Richmond, Virginia) were prepared weekly,
 

sealed and stored in dark bottles at 1°C. The concentration of
 
1,1,2-trichloroethane in corn oil administered to rats ranged from
 

3.5 to 5.0 percent. The concentration administered to mice ranged
 

from 3.0 to 4.0 percent.
 

C. Animals
 

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

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

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

carcinogenesis bioassays and has proved satisfactory in this capacity.
 

Rats and mice of both sexes were obtained through contracts with
 

the Division of Cancer Treatment, National Cancer Institute. The
 

Osborne-Mendel rats were procured from 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
 

treated and control groups.
 

D. Animal Maintenance
 

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


controlled rooms. The temperature range was 20° to 25°C and the
 

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

conditioning system in the laboratory provided filtered air at a rate
 
of 12 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, while mice were housed by sex
 

in groups of ten in solid-bottom polypropylene cages equipped with
 

(R)
 filter tops. Sanitized cages with fresh bedding (Sanichips , Pinewood
 

Sawdust Company, Moonachie, New Jersey) were provided once each week
 

for mice. Rats received sanitized cages with no bedding with the
 

same frequency. Food hoppers were changed and heat-sterilized once a
 

week for the first 10 weeks and once a month thereafter, while fresh
 

heat-sterilized glass water bottles were provided three times a week.
 

(R)
 Food (Wayne Lab-Blox meal, Allied Mills, Inc., Chicago, Illinois)
 

and water were available ad libitum.
 

The rats dosed with 1,1,2-trichloroethane and their untreated
 

*
 controls were housed in the same room with rats intubated with
 

tetrachloroethylene (127-18-4). Vehicle control rats for the 1,1,2­

trichloroethane study were housed in the same room as rats intubated
 

with dibromochloropropane (96-12-8), 1,2-dichloroethane (107-06-2),
 

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

disulfide (75-15-0).
 

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

mice intubated with 1,1,2,2-tetrachloroethane (79-34-5), chloroform
 

(67-66-3), dibromochloropropane (96-12-8), chloropicrin (76-06-2),
 

*
 

CAS registry numbers are given in parentheses.
 
1,2-dichloroethane (107-06-2), 1,1-dichloroethane (75-34-3), allyl
 

chloride (107-05-1), trichloroethylene (79-01-6), 3-sulfolene (77-79­

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

(106-93-4), 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 body weight basis utilizing the most recently observed group
 

mean body weight as a guide for determining the dose. Mean 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 treated group received the same dose at each administration. Gavage of treated animals was performed under a hood to
 

minimize extraneous exposure of other animals and laboratory personnel to the chemical.
 

F. Selection of Initial Dose Levels
 

In order to estimate the maximum tolerated doses of 1,1,2­

trichloroethane for administration to treated animals in the chronic
 

studies, subchronic toxicity tests were conducted with both rats and
 

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

each consisting of five males and five females. A solution of 1,1,2­

trichloroethane in corn oil was administered by gavage to five of the
 

six rat groups at dosages of 32, 56, 100, 178, and 316 mg/kg/day and
 
five of the six mouse groups at dosages of 56, 100, 178, 316, and 562
 

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

receiving only the corn oil. Intubation was performed 5 days per
 

week for 6 weeks, followed by a 2-week observation period to detect
 

any delayed toxicity.
 

In week 1 of the study, one male rat died at a dosage of 56 mg/
 

kg/day and one female rat died at 100 mg/kg/day. At 56 and 100 mg/
 

kg/day the mean body weight gain, expressed as a percentage of the
 

weight gained by the control animals was, respectively, 96 and 97
 

percent for males, and 84 and 94 percent for females. The initial
 

high dose selected for both male and female rats in the chronic study
 

was 70 mg/kg/day.
 

One male mouse died at 316 mg/kg/day and one female died at 178
 

mg/kg/day. At 178 and 316 mg/kg/day the mean body weight gain,
 

expressed as a percentage of the weight gained by the control animals
 

was, respectively, 101 and 99 percent for males, and 96 and 94 percent for females. The initial high dose selected for both male and
 

female mice in the chronic study was 300 mg/kg/day.
 

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.
 
TABLE 1
 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS
 

1,1,2-TRICHLOROETHANE GAVAGE EXPERIMENT
 

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

NUMBER OF CHLOROE THANE TREATED UNTREATED AVERAGE 

ANIMALS DOSAGE3 (WEEKS) (WEEKS) DOSAGEb 

MALE 

UNTREATED 

CONTROL 20 0 0 111 0 

VEHICLE
 

CONTROL 20 0 78 33 0
 

LOW DOSE 50 35 20 46
 

50 58
 

0 34
 

HIGH DOSE 50 70 20 92
 

100 58
 

0 34
 

FEMALE
 

UNTREATED
 

CONTROL 20 0 0 111 0
 

VEHICLE
 

CONTROL 20 0 78 33 0
 

LOW DOSE 50 35 20 46
 

50 58
 

0 34
 

HIGH DOSE 50 70 20 92
 

100 58
 

0 35
 

Dosage, given in mg/kg body weight , was administered by gavage five
 

consecutive days per week.
 

(dosage X weeks received)
 Time-weighted average dosage = ——­ 2-t
 (weeks receiving chemical)
 
MALE
 

UNTREATED
 

CONTROL
 

VEHICLE
 

CONTROL
 

LOW DOSE
 

HIGH DOSE
 

FEMALE
 

UNTREATED
 

CONTROL
 

VEHICLE
 

CONTROL
 

LOW DOSE
 

HIGH DOSE
 

ft
 

TABLE 2
 

DESIGN SUMMARY FOR B6C3F1 MICE
 

1,1,2-TRICHLOROETHANE GAVAGE EXPERIMENT
 

INITIAL

NUMBER OF

ANIMALS

 1,1,2-TRI­

 CHLOROE THANE 

DOSAGE3 

20 0 

20 0 

50 150 

200 

0 

50 300 

400 

0 

20 0 

20 0 

50 150 

200 

0 

50 300 

400 

0 

Dosage, given in mg/kg body weight
 

consecut ive days per week.
 2
 

Time— wfii fhted average dosape ­

 OBSERVATION PERIOD TIME-WEIGHTED 

TREATED UNTREATED AVERAGE 

(WEEKS) (WEEKS) DOSAGEb 

0 91 0
 

78 12 0
 

8 195
 

70
 

12
 

8 390
 

70
 

13
 

0 91 0
 

78 12 0
 

8 195
 

70
 

13
 

8 390
 

70
 

13
 

, was administered by gavage five
 

(dosage X weeks received)
 

receiving chemical)
 
1,1,2-Trichloroethane-treated and untreated control rats had a
 

median age of approximately 6 weeks at the start of the study. The
 

vehicle control rats were approximately 8 weeks old on their first
 

day of intubation, which began 4 weeks earlier for the vehicle controls than for the other rat groups. For the first 20 weeks of the
 

experiment, the dosages used for rats were 70 and 35 mg/kg/day of
 

1,1,2-trichloroethane. Throughout this report the rats initially
 

receiving the former dosage are referred to as the high dose groups
 

and those receiving the latter are referred to as the low dose groups.
 

As the animals appeared to be tolerating the chemical in week 20 of
 

the study, the doses were increased in week 21 to 100 and 50 mg/kg/day
 

for the high and low dose animals, respectively, and these doses were
 

maintained for the remainder of the 78-week dosing period. After the
 

dosing period, observation of the rats continued for up to 35 additional weeks.
 

The vehicle control and treated mice were approximately 5 weeks
 

old on the day intubation began. Untreated control mice had a median
 

birth date 2 weeks later than the other mouse groups and their observation period lasted a corresponding 2 weeks longer than that of
 

treated mice. The initial dosages of 1,1,2-trichloroethane utilized
 

for the mice were 300 and 150 mg/kg/day. Throughout this report the
 

mice initially receiving the former dosage are referred to as the
 

high dose groups and those receiving the latter are referred to as
 

the low dose groups. High and low doses were increased to 400 and
 

10
 
200 mg/kg/day, respectively, in week 9 because of apparent tolerance
 

to the chemical. These levels were maintained for the remainder of
 

the 78-week dosing period. After the dosing period, observation of
 

the mice continued for up to 13 additional weeks.
 

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 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, bone marrow, spleen,
 

lymph nodes, thymus, heart, salivary gland, liver, gallbladder and
 

bile duct (mice), pancreas, esophagus, stomach, small intestine, large
 

11
 
intestine, kidney, urinary bladder, pituitary, adrenal, thyroid, parathyroid, testis, prostate, nerves, brain, tunica vaginalis, 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
 

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.
 

12
 
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
 

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.
 

13
 
The purpose of the statistical analyses of tumor incidence is to
 

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

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

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

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

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

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

significance level of 0.05 may be made. The Bonferroni inequality
 

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

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

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

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

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

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

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
 

14
 
tumor was observed were excluded by basing the statistical tests on
 

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

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

tumor was found, comparisons were based exclusively on animals that
 

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

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

Cochran-Armitage tests, etc.) were followed.
 

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

incidence of tumors. Curves of the proportions surviving without an
 

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

during which animals died naturally or were sacrificed was entered as
 

the time point of tumor observation. Cox1s methods of comparing
 

these curves were used for two groups; 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
 

15
 
and p is the true probability of the spontaneous incidence of the
 

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

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

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

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

larger proportion in the treated group than in the control.
 

The lower and upper limits of the confidence interval of the
 

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

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

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

would be within the interval calculated from the experiment. When
 

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

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

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

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

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

the lower limit indicates the absence of a significant result while
 

the upper limit indicates that there is a theoretical possibility
 

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

detected under the conditions of this test.
 

16
 
III. CHRONIC TESTING RESULTS: RATS
 

A. Body Weights and Clinical Observations
 

There were no appreciable differences between the weight gain
 

patterns in the treated and untreated control rats (Figure 1). Fluctuations in the growth curve may be due to mortality; as the size of
 

the group diminishes, the mean body weight may be subject to wide
 

variations.
 

During the first 6 months of the study the appearance and
 

behavior of the treated rats and the untreated controls were generally comparable. Occasional hunched appearance and eye discharges,
 

observed in all groups as early as week 3, were noted in a few more
 

treated than control rats.
 

As the study progressed, an increasing number of treated rats
 

showed clinical signs which included a hunched appearance, rough
 

fur, urine stains on the abdominal area, dyspnea, and squinted eyes,
 

sometimes with reddish exudate. The incidence and frequency of these
 

signs were similar in low and high dose groups, except that the high
 

dose females showed an elevated incidence of abdominal urine staining
 

from week 26 until intubation ceased in week 78.
 

Signs of respiratory difficulty characterized by wheezing, dyspnea, and nasal exudate (sometimes bloody in appearance) were noted in
 

treated and control groups at a low or moderate incidence during the
 

latter part of the first year, and this incidence increased as the
 

17
 
750 •750 

- 600 

-450 

-300 

UNTREATED CONTROL 

VEHICLE CONTROL — 150 

LOW DOSE 

HIGH DOSE 

~T 

60 75 90 105 120 

TIME ON TEST (WEEKS) 

750- •750 

600 — i— 600 

450- — 450 

g 300 — — 300 

CO 

UNTREATED CONTROL 

VEHICLE CONTROL 150-' — 150 

LOW DOSE 

HIGH DOSE FEMALE RATS 

15 30 45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

FIGURE 1 

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

18 
animals aged. As the study approached termination more treated animals than controls exhibited respiratory difficulty.
 

Other signs often associated with aging in laboratory rats were
 

observed at a comparable rate in controls and treated rats during the
 

second year of the study. These signs included alopecia, sores on
 

the body and/or extremities, stains on the fur, reddish exudate
 

around the eyes, and intermittent soft feces. Palpable subcutaneous
 

masses and swelling were observed at a comparable rate in treated rats
 

and untreated controls during the last 8 to 10 months of the study.
 

B. Survival
 

The estimated probabilities of survival for male and female rats
 

in the control and 1,1,2-trichloroethane-dosed groups are shown in
 

Figure 2.
 

For rats of both sexes the Tarone test for positive association
 

between increased dosage and accelerated mortality was not significant. For both sexes the high dose groups showed poorer survival
 

than the low dose or the untreated control groups until around week
 

90. The vehicle control groups had unexpectedly poor survival with
 

only 5 percent (1/20) of the males and 20 percent (4/20) of the females surviving until termination of the study.
 

Among the male rats, at least 50 percent of the high dose, low
 

dose, and untreated control groups survived more than 96 weeks. Among
 

the female rats 50 percent of the high dose, low dose, and untreated
 

19
 
PROBABILITY OF SURVIVA

PROBABILITY OF SURVIVAL 
control groups survived more than 105 weeks. Thus adequate numbers
 

of rats were at risk from late-developing tumors.
 

C. Pathology
 

Histopathologic findings on neoplasms in rats are tabulated in
 

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

tabulated in Appendix C (Tables Cl and C2).
 

Adrenal cortical carcinomas occurred in 1/50 (2 percent) high
 

dose males, 2/50 (4 percent) low dose females and 1/50 (2 percent)
 

high dose females. Lesions of this type were not present in any
 

untreated or vehicle control rats. Microscopically, the adrenal
 

cortical carcinomas had nests and sheets of large anaplastic cells,
 

with nuclear atypia, large nucleoli, and some multinucleated cells.
 

The cells were acidophilic, supported by dense bands of fibrous
 

connective tissue. Mitotic figures and metastases were often seen.
 

This neoplasm metastasized to the lung, liver, and spleen in one high
 

dose female. A cortical-cell adenoma occurred in one low dose female
 

The histologic structure of the adrenal adenoma closely simulated the
 

normal adrenal cortex. The tumor cells were enlarged and vacuolated
 

and surrounded by a fibrous capsule.
 

Transitional-cell carcinoma of the kidney occurred in 1/50
 

(2 percent) low dose males. Renal tubular adenoiras were presen'


1/50 (2 percent) low dose and 1/50 (2 percent) high -'osc males.
 

Hemangiosarcomas of the spleen occurred in 3/4-9 (6 percr nt) low io^,
 

males, in the pancreas in 1/49 (2 percent) low dose nales, and as j
 

21
 

 i 
tissue mass in the abdomen in 1/50 (2 percent) low dose males.
 

Hemangiosarcoma occurred as a subcutaneous tissue mass in one high
 

dose male and one low dose female. Some of the above hemangiosarcomas metastasized to nearby organs.
 

Other neoplasms observed in treated and control animals in this
 

study were observed at incidences known to occur spontaneoulsy in
 

Osborne-Mendel rats. The nonneoplastic lesions that occurred most
 

frequently were chronic murine pneumonia and chronic nephritis.
 

Other inflammatory, degenerative, and proliferative lesions seen in
 

the control and treated animals were similar in number and kind to
 

those lesions often found in aged rats.
 

This study did not provide histopathologic evidence for the
 

carcinogenicity of 1,1,2-trichloroethane 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. In these analyses no statistical comparisons of the dosed groups to the vehicle control groups
 

were made because of the atypically poor survival noted in both male
 

and female vehicle control groups. The analysis for every type of
 

tumor that was observed in more than 5 percent of any of the 1,1,2­

trichloroethane-dosed groups of either sex is included.
 

Only those comparisons between the dosed groups and the untreated
 

control groups are presented here since the survival was poor for the
 

vehicle control groups and since the vehicle control groups were
 

22
 
TABLE 3
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

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

TOPOGRAPHY : MORPHOLOGY
 

Pituitary: Chromophobe Adenoma
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Malignant
 

Lymphoma'3
 

P Values
 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

UNTREATED
 

CONTROL
 

0/19(0.00)
 

N.S.
 

P = 0.033
 

1/20(0.05)
 

N.S.
 

80
 

LOW
 

DOSE
 

5/47(0.11)
 

N.S.
 

Infinite
 

0.533
 

Infinite
 

98
 

1/50(0.02)
 

N.S.
 

0.400
 

0.005
 

30.802
 

42
 

HIGH
 

DOSE
 

1/46(0.02)
 

N.S.
 

Infinite
 

0.023
 

Infinite
 

112
 

3/50(0.06)
 

N.S.
 

1.200
 

0.106
 

61.724
 

94
 

Treated groups received time-weighted average doses of 46 or 92 mg/kg by gavage.
 

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

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

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

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

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

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

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

group when P < 0.05.
 
TABLE 4
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE RATS TREATED WITH 1,1,2-TRICHLOROETHANE*
 

TOPOGRAPHY :MORPHOLOGY
 

Subcutaneous Tissue: Fibroma
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Chromophobe Adenoma
 

P Values0
 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Kidney: Hamartoma*
 

P Values0
 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

UNTREATED
 

CONTROL
 

2/20(0.10)
 

N.S.
 

P = 0.047
 

Ill
 

2/20(0.10)
 

N.S.
 

Ill
 

0/20(0.00)
 

N.S.
 

LOW
 

DOSE
 

0/50(0.00)
 

N.S.
 

0.000
 

0.000
 

1.345
 

9/48(0.19)
 

N.S.
 

1.875
 

0.444
 

16.902
 

55
 

4/50(0.08)
 

N.S.
 

Infinite
 

0.386
 

Infinite
 

112
 

HIGH
 

DOSE
 

1/50(0.02)
 

N.S.
 

0.200
 

0.004
 

3.682
 

106
 

5/48(0.10)
 

N.S.
 

1.042
 

0.192
 

10.410
 

112
 

1/50(0.02)
 

N.S.
 

Infinite
 

0.022
 

Infinite
 

112
 

*This is considered to be a benign form of the malignant mixed tumor of the kidney and consists
 

of proliferative lipocytes, tubular structures, fibroblasts, and vascular spaces in varying
 

proportions.
 
TOPOGRAPHY : MORPHOLOGY
 

Thyroid: Follicular-Cell Adenoma or
 

Follicular-Cell Carcinomab
 

P Values0
 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Adenocarcinoma NOS
 

P Values0
 

ro 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

b
 

Mammary Gland: Fibroadenoma
 

P Values0
 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 4 (Continued) 

UNTREATED
 

CONTROL
 

0/20(0.00)
 

N.S.
 

1/20(0.05)
 

N.S.
 

110
 

6/20(0.30)
 

N.S.
 

82
 

LOW
 

DOSE
 

3/50(0.06)
 

N.S.
 

Infinite
 

0.250
 

Infinite
 

105
 

0/50(0.00)
 

N.S.
 

0.000
 

0.000
 

7.475
 

16/50(0.32)
 

N.S.
 

1.067
 

0.482
 

2.931
 

70
 

HIGH
 

DOSE
 

1/50(0.02)
 

N.S.
 

Infinite
 

0.022
 

Infinite
 

113
 

4/50(0.08)
 

N.S.
 

1.600
 

0.175
 

77.169
 

51
 

9/50(0.18)
 

N.S.
 

0.600
 

0.229
 

1.828
 

87
 
TABLE 4 (Concluded)
 

UNTREATED LOW HIGH
 

TOPOGRAPHY : MORPHOLOGY CONTROL DOSE DOSE
 

Mammary Gland:, Ad eno carcinoma NOS or
 

Fibroadenoma 7/20(0.35) 16/50(0.32) 13/50(0.26)
 

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

Relative Risk (Untreated Control) 0.914 0.743
 

Lower Limit 0.439 0.338
 

Upper Limit 2.288 1.928
 

Weeks to First Observed Tumor 82 70 51
 

Uterus: Endometrial Stromal Polyp 0/20(0.00) 5/50(0.10) 0/50(0.00)
 

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

Departure From Linear Trend P = 0.010
 

Relative Risk (Untreated Control) Infinite
 

Lower Limit 0.525
 ro
 

Upper Limit Infinite
 

Weeks to First Observed Tumor 90
 

treated groups received time-weighted average doses of 46 or 92 mg/kg by gavage.
 

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

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

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

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

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

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

S

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

group when P < 0.05.
 
maintained in another room. Additionally, the vehicle controls were
 

put on test at the age of 8 weeks (compared to 6 weeks for the other
 

groups) and at a time 4 weeks before the other groups were started.
 

No statistically significant differences were found when comparing
 

the specific tumor incidences in the untreated control group to those
 

in the vehicle control group or to the corresponding spontaneous
 

tumor rates observed in the historical vehicle control record for
 

Osborne-Mendel rats compiled by this laboratory for the NCI Bioassay
 

Program.
 

For both male and female rats neither the Cochran-Armitage tests
 

nor the Fisher exact tests were significant for any type of tumor.
 

On the basis of these results there was no statistical evidence
 

for the carcinogenicity of 1,1,2-trichloroethane in rats at the dose
 

levels used in this experiment.
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative ris
 

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

tumor incidence rates. In all of the intervals shown in Tables 3 and
 

4, the value one is included; this indicates the absence of statistically significant results. It should also be noted that all of the
 

confidence intervals have an upper limit greater than one, indicating
 

the theoretical possibility of a significantly increased rate of
 

tumor incidence induced in rats by 1,1,2-trichloroethane that could
 

not be established under the conditions of this test.
 

27
 
IV. CHRONIC TESTING RESULTS: MICE
 

A. Body Weights and Clinical Observations
 

There was no appreciable difference between body weight gain in
 

the treated and untreated mice (Figure 3).
 

During the first year of the experiment the appearance and
 

behavior of treated mice was generally similar to that of controls.
 

Sores on the body and/or extremities, and generalized or localized
 

alopecia were observed throughout this study, particularly in male
 

mice. Other clinical signs frequently associated with group-housed
 

or aging laboratory mice were observed at comparable rates among
 

control and treated mice. These signs included a hunched appearance,
 

anal prolapse, penile or vulvar redness, rough or stained fur,
 

palpable nodules, and reddish discharge or crust around the eyes.
 

After 46 weeks of compound administration, abdominal distension
 

was evident in a few high dose males and females and thereafter was
 

observed in gradually increasing numbers in these groups. By week
 

74, approximately 70 percent of the high dose animals had distended
 

abdomens which persisted until they either died, were sacrificed in
 

extremis, or were sacrificed at termination of the bioassay. Abdominal distension was also seen in two untreated control females, six
 

low dose females, and one low dose male. Subsequent necropsy of
 

these mice indicated that liver tumors were the cause of this abdominal distension.
 

28
 
-50 

40 — -40 

— 30 

I 

(3 

20 — -20 

Q 

O 

CQ UNTREATED CONTROL 

VEHICLE CONTROL 

10 — — 10 

LOW DOSE 

HIGH DOSE 

MALE MICE 

r^ \ 1 

15 30 45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

50­

40 — — 40 

-30 

U 

Q 

20 — — 20 

O 

CD UNTREATED CONTROL 

VEHICLE CONTROL 

10— -10 

LOW DOSE 

HIGH DOSE 

FEMALE MICE 

T ~T~ ~l ' I i T "T" 1 

15 30 45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

FIGURES 

GROWTH CURVE FOR 1,1,2-TRICHLOROETHANE CHRONIC STUDY MICE 

29 
Bo Survival
 

The estimated probabilities of survival for male and female mice
 

in the control and 1,1,2-trichloroethane-dosed groups are shown in
 

Figure 4.
 

In male mice the Tarone test for association between increased
 

dosage and accelerated mortality was not significant. At least 50
 

percent of the male mice in each group were alive after week 86.
 

Thus adequate numbers of male mice were at risk from late-developing
 

tumors.
 

In female mice the Tarone test indicated a significant (P <
 

0.001) association between increased dosage and accelerated mortality.
 

Although the low dose group exhibited the greatest mortality, largely
 

due to the early deaths of 8 mice in week 36 and 11 mice in week 55,
 

the departure from linear trend was not considered significant (P =
 

0.058). There was no indication that these low dose mice died from
 

any common cause. The early deaths in the low dose females were not
 

associated with tumors: in 23 of the 24 deaths prior to week 58 (not
 

counting the 1 animal that was missing) no tumor at any site was observed. Fifty percent of the mice were still alive after 81, 58, 89,
 

and 90 weeks for the high dose, low dose, vehicle control, and untreated control groups, respectively.
 

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).
 

30
 
PROBABILITY OF SURVIVAL PROBABILITY OF SURVIVA

o 

_L 

CO 

3D 

< 

O 

O 

-o

> g­ 33 

8 

CO 

£§ c/) 0) r m 

- -1 o O *. 33 

O 

m 

H 

O 

3) 

o 

o 

CO 

c 

o 

3 

o 
Hepatocellular carcinomas were observed in 2/17 (12 percent)
 

untreated control males, 2/20 (10 percent) vehicle control males,
 

18/49 (37 percent) low dose males, and 37/49 (76 percent) high dose
 

males. Hepatocellular carcinomas were also seen in 2/20 (10 percent)
 

untreated control female, 0/20 vehicle control female, 16/48 (33 percent) low dose female, and 40/45 (89 percent) high dose female mice.
 

Microscopically, the hepatocellular carcinomas varied greatly
 

in appearance. Some lesions contained well-differentiated hepatic
 

cells that had a relatively uniform arrangement of the cords, and
 

others had very anaplastic liver cells with large hyperchromatic
 

nuclei, often with inclusion bodies and with vacuolated, pale cytoplasm. Arrangement of the neoplastic liver cells varied from short
 

stubby cords to nests of cells and occasionally acinar formation.
 

Mitotic figures were often present. Some of the tumors were characterized by discrete areas of highly anaplastic cells. Metastasis to
 

the lung occurred in one low dose male, one high dose male, and two
 

high dose female mice. The hepatic neoplasms that occurred in the
 

control mice were not different in appearance from those noted in the
 

chemically treated mice.
 

Adrenal pheochromocytomas were present in 8/48 (17 percent) high
 

dose males and in 12/43 (28 percent) high dose females but not in any
 

other mouse groups. The neoplastic cells occurred in nests of large
 

irregular or polyhedral cells with central nuclei and abundant
 

cytoplasm, and were surrounded by a thin vascular connective tissue
 

32
 
stroma. An adrenal cortical carcinoma occurred in one high dose male
 

with metastasis to the lung, cervical lymph nodes, pancreas, prostate,
 

and epididymis.
 

Squamous-cel1 carcinomas of the forestomach occurred in one low
 

dose and one high dose male and one high dose female. A squamouscell papilloma occurred in one low dose male.
 

Other neoplasms occurred in mice with no appreciable difference
 

in frequency between control and treated animals. A relatively low
 

incidence of degenerative and inflammatory lesions occurred in the
 

treated and control mice.
 

The increased incidence of hepatocellular carcinomas and adrenal
 

pheochromocytomas in male and female mice provided histopathologic
 

evidence for the carcinogenicity of 1,1,2-trichloroethane in B6C3F1
 

mice.
 

D. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

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

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

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

Two control groups were used in the standard statistical analyses, the untreated control group and the vehicle control group. The
 

incidence of specific tumors in these control groups was compared to
 

the corresponding spontaneous tumor rates for the historical controls
 

33
 
TABLE 5
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE MICE TREATED WITH 1,1,2-TRICHLOROETHANE£
 

TOPOGRAPHY: MORPHOLOGY


Lung: Alveolar/Bronchiolar
 

Adenoma or Alveolar/Bronchiolar Carcinomab


c
 

P Values


Relative Risk (Untreated ,
 

Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Vehicle ,
 

Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Liver: Hepatocellular
 

Carcinomab


P Values0


Relative Risk (Untreatedd
 

Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Vehicle ,
 

Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


UNTREATED
 

 CONTROL
 

 2/18(0.11)
 

 N.S.
 

 84
 

 2/17(0.12)
 

 P < 0.001
 

 91
 

VEHICLE LOW 

CONTROL DOSE 

0/20(0.00) 3/49(0.06) 

N.S. N.S. 

0.551 

0.071 

6.284 

Infinite 

0.255 

Infinite 

90 

2/20(0.10) 18/49(0.37) 

P < 0.001 P = 0.047* 

P = 0.022** 

3.122 

0.885 

25.955 

3.673 

1.020 

30.643 

90 55 

HIGH
 

DOSE
 

1/50(0.02)
 

N.S.
 

0.180
 

0.003
 

3.307
 

Infinite
 

0.012
 

Infinite
 

91
 

37/49(0.76)
 

P < 0.001*
 

P < 0.001**
 

6.418
 

2.025
 

47.713
 

7.551
 

2.337
 

56.311
 

19
 
TOPOGRAPHY : MORPHOLOGY

UNTREATED 

 CONTROL 

Adrenal: Pheochromocytoma 0/18(0.00) 

P Values0 P = 0.003 

Relative Risk (Untreated 

Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle 

Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Hematopoietic System: Malignant Lymphomab

 1/18(0.06) 

P Values0

e 

Departure from Linear Trend P

 N.S, 

= 0.046 

Relative Risk (Untreated 

Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle , 

Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 91 

TABLE 5 (Continued)
 

VEHICLE


CONTROL


0/20(0.00)


P = 0.003


2/20(0.10)


N.S.


 LOW
 

 DOSE
 

 0/49(0.00)
 

 N.S.
 

 7/49(0.14)
 

 N.S.
 

2.571
 

0.374
 

113.260
 

1.429
 

0.309
 

13.396
 

 76
 

HIGH
 

DOSE
 

8/48(0.17)
 

N.S.
 

Infinite
 

0.900
 

Infinite
 

Infinite
 

0.992
 

Infinite
 

76
 

1/50(0.02)
 

N.S.
 

0.360
 

0.005
 

27.724
 

0.200
 

0.004
 

3.681
 

66
 90
 
TABLE 5 (Concluded)
 

Treated groups received time-weighted average doses of 195 or 390 mg/kg by gavage.
 

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

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

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

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

untreated control group (*) or the vehicle control group (**) is given beneath the incidence of
 

tumors in that treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. For
 

both Cochran-Armitage and Fisher exact tests a negative designation (N) indicates a lower incidence in the treated group(s) than in the control group.
 

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

6

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

group when P < 0.05.
 
TABLE 6
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE MICE TREATED WITH 1,1,2-TRICHLOROETHANE*
 

TOPOGRAPHY rMORPHOLOGY


Lung: Alveolar/Bronchiolar
 

Adenoma or Alveolar/Bronchiolar Carcinomab


P Values0


Relative Risk (Untreated ,
 

Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Vehicle ,
 

Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Liver: Hepatocellular
 

Carcinomab


P Values0


Relative Risk (Untreated ,
 

Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Vehicle ,
 

Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


UNTREATED
 

 CONTROL
 

 1/20(0.05)
 

 N.S.
 

 91
 

 2/20(0.10)
 

 P < 0.001
 

 91
 

VEHICLE LOW HIGH 

CONTROL DOSE DOSE 

0/20(0.00) 3/48(0.06) 2/39(0.05) 

N.S. N.S. N.S. 

1.250 1.026 

0.110 0.058 

6A.251 58.952 

Infinite Infinite 

0.260 0.157 

Infinite Infinite 

55 79 

0/20(0.00) 16/48(0.33) 40/45(0.89) 

P < 0.001 P = 0.041* P < 0.001* 

P = 0.002** P < 0.001** 

3.333 8.889 

0.907 2.898 

28.087 54.670 

Infinite Infinite 

2.200 6.515 

Infinite Infinite 

64 49 
TABLE 6 (Continued) 

TOPOGRAPHY : MORPHOLOGY

UNTREATED 

 CONTROL 

VEHICLE 

CONTROL 

Adrenal: Pheochromocytoma

P Values0

 0/20(0.00) 

 P< 0.001 

0/20(0.00) 

P< 0.001 

Departure from Linear Trend P = 0.021 P = 0.021 

Relative Risk (Untreated 

Control) 

Lower Limit 

Upper Limit 

w 

00 

Relative Risk (Vehicle 

Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Hematopoietic System: Malignant Lymphomab

P Values0

 0/20(0.00) 

 N.S. 

4/20(0.20) 

P ­ 0.043(N) 

Relative Risk (Untreated , 

Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle 

Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 69 

LOW
 

DOSE
 

0/48(0.00)
 

N.S.
 

4/48(0.08)
 

N.S.
 

Infinite
 

0.402
 

Infinite
 

0.417
 

0.088
 

2.063
 

91
 

HIGH
 

DOSE
 

12/43(0.28)
 

P = 0.006*
 

P = 0.006**
 

Infinite
 

1.782
 

Infinite
 

Infinite
 

1.782
 

Infinite
 

85
 

2/46(0.04)
 

N.S.
 

Infinite
 

0.133
 

Infinite
 

0.217
 

0.022
 

1.406
 

70
 
TABLE 6 (Concluded)
 

o
 

Treated groups received time-weighted average doses of 195 or 390 mg/kg by gavage.
 

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

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

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

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

untreated control group (*) or the vehicle control group (**) is given beneath the incidence of
 

tumors in that treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. For
 

both Cochran-Armitage and Fisher exact tests a negative designation (N) indicates a lower incidence in the treated group(s) than in the control group.
 

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

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

group when P < 0.05.
 
for this laboratory compiled to date on B6C3F1 mice for the NCI Bioassay Program; no significant differences were observed.
 

In dosed male mice, hepatocellular carcinomas were found in
 

large numbers and were detected as early as week 19. The Cochran-


Armitage tests for positive dose-related trend were highly significant (P < 0.001) using either the untreated controls or the vehicle
 

controls. Additionally, the Fisher exact test comparing tumor incidences of the dosed to the control groups confirmed these positive
 

findings: vehicle control-high dose (P < 0.001); untreated control-


high dose (P < 0.001); and vehicle control-low dose (P = 0.022).
 

The comparison between the low dose and the untreated control was P =
 

0.047, a marginal result which was not significant when the Bonferroni
 

criterion was applied. These statistical results indicate that the
 

occurrence of hepatocellular carcinomas in male mice was associated
 

with the administration of 1,1,2-trichloroethane at the dose levels
 

of this experiment.
 

The incidence of hepatocellular carcinomas was also highly
 

significant in female mice. The Cochran-Armitage tests for positive
 

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

0.001) compared to either the untreated control or the vehicle control. The results of the Fisher exact tests confirmed these positive
 

findings: high dose animals demonstrated significant (P < 0.001)
 

tumor increases when compared to either the untreated or the vehicle
 

controls. The low dose group was significantly different from the
 

40
 
vehicle control (P = 0.002); the comparison of low dose to untreated
 

control had a probability level of P = 0.041, a marginal result which
 

was not significant under the Bonferroni criterion. These statistical
 

tests indicate that the occurrence of hepatocellular carcinomas in
 

female mice was associated with the administration of 1,1,2-trichloroethane at the dose levels of this experiment.
 

For high dose groups, both male and female mice exhibited an unusually high incidence of pheochromocytomas of the adrenal gland. In
 

the males the Cochran-Armitage tests indicated a significant (P =
 

0.003) positive association between dose and tumor incidence compared
 

to both the untreated and vehicle control groups. Fisher exact tests,
 

however, were not significant. For female mice not only did the
 

Cochran-Armitage tests prove significant (P < 0.001), but the Fisher
 

exact tests confirmed these results for comparisons between the high
 

dose group and both the untreated (P = 0.006) and the vehicle (P =
 

0.006) control groups. In historical data collected by this laboratory for the NCI Bioassay Program on B6C3F1 mice used as vehicle controls, 0/180 males and 0/180 females had pheochromocytomas. Assuming
 

a binomial distribution and a spontaneous tumor rate of 1/181, both
 

the probability of observing 8 pheochromocytomas out of 48 males and
 

the probability of observing 12 pheochromocytomas out of 43 females
 

are less than 0.00001. Based upon these results the administration
 

of 1,],2-trichloroethane was associated with an increased incidence
 

of pheochromocytomas in male and female mice.
 

41
 
There were no other tumors for which statistical tests indicated
 

a positive association between dosage and tumor incidence. The possibility of a negative association between dosage and the incidence of
 

malignant lymphoma was noted for female mice.
 

42
 
V. DISCUSSION
 

There were no significant associations between administration of
 

1,1,2-trichloroethane and mortality in rats of either sex or in male
 

mice. Although there was a significant association between increased
 

dosage and accelerated mortality among female mice, adequate numbers
 

of animals in all groups survived sufficiently long to be at risk
 

from late-developing tumors.
 

The possibility that the rats in this bioassay did not receive
 

dosages approximating the maximum tolerated dosage must be considered
 

because compound administration had no significant effect upon survival or body weight gain in either sex. The premature deaths observed in rats receiving the second and third lowest dosages in the
 

preliminary study may have caused difficulty in selecting the appropriate dosages for the chronic study.
 

Adrenal cortical carcinoma, transitional-cell carcinoma of the
 

kidney, renal tubular adenoma, and hemangiosarcomas of the spleen,
 

pancreas, abdomen, and subcutaneous tissue were some of the neoplastic lesions observed in treated but not control rats. In all these
 

cases, however, no statistically significant difference could be
 

found between the dosed groups and the untreated control groups.
 

In treated mice of both sexes, the incidence of hepatocellular
 

carcinomas was highly significant (P < 0.001) when compared to the
 

respective untreated or vehicle control groups, as well as to combined
 

controls (of 1,1,2-trichloroethane and those of four other studies).
 

43
 
Hep atocellular carcinomas metastasized to the lung in one low dose
 

male, one high dose male, and two high dose female mice. Administration of 1,1,2-trichloroethane also apparently shortened the latency
 

period for development of hepatocellular carcinomas. The first and
 

second hepatocellular carcinomas observed in each group of treated
 

mice were, respectively, in weeks 55 and 74 in low dose males, in
 

weeks IP and 47 in high dose males, in weeks 64 and 75 in low dose
 

females, and both in week 49 in high dose females. No hepatocellular
 

carcinomas were observed in male or female control mice before week
 

90. Pheochromocytomas were observed in the high dose mouse groups of
 

both sexes (8/48 or 17 percent in the male and 12/43 or 28 percent in
 

thf iemale mice) but not in the low dose or in either control group.
 

The historical incidences of this tumor in male and female B6C3F1
 

vehicle controls used at this laboratory for the NCI Bioassay Program
 

art' 0/180 and 0/180. respectively. Assuming a binomial distribution
 

and a spontaneous tumor rate of 1/181 for both sexes, the probability
 

of observing this tumor in the incidences that were revealed by this
 

bioassav is less than 0.00001 for both sexes.
 

The results of this study do not provide convincing evidence for
 

the careinogenicity of 1,1,2-trichloroethane in Osborne-Mendel rats.
 

Under the conditions of this bioassay the compound is carcinogenic in
 

hb03FI mice of both sexes, causing hepatocellular carcinomas and
 

adrenal pheochromocytomas.
 

44
 
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, B.C., 1977.
 

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

Co., Ltd., London, 1970.
 

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

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

Folkerson, J., Dow Chemical, Midland, Michigan. Personal communication, February 7, 1977.
 

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

Tests, Confidence Limits, and Adjustments for Stratification."
 

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

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

Van Nostrand Reinhold Company, New York, 1971.
 

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." Carcinogenesis Technical Report Series No. 2, NCICG-TR-2, DREW Publication No. (NIH) 76-802, 1976.
 

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.
 

46
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH 1,1,2-TRICHLOROETHANE
 

TABLE A1

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH 1,1,2-TRICHLOROETHANE 

LOU DOSE 

01-132M 

50 

50 

50 

(50) 

2 (4%) 

(50)
 

1 (2)4)
 

(50)
 

(49)
 

3 (6X)
 

(47)
 

(50)
 

1 (2X)
 

(50) 

HIGH DOSE 

01-1 33M 

50 

50 

50 

(50) 

1 (2%) 

1 (2X ) 

1 (2%) 

(50)
 

2 (14%)
 

(50)
 

1 (2%)
 

(50)
 

(16)
 

(50)
 

(50) 

crONTROL (UNTR) 

ANIMAL S INITIALL Y I N STUDY 

ANIMAL S NECROPSIED 

ANIMAL S EXAMINE D HISTOPATHOLOSICA LLY « 

INTEGUMENTAR Y SYSTEM 

*SUBCOT TISSUE 

FIBROM A 

FIBROSARCOM A 

HEMANGIOSARCOM A 

RESPIRATOR Y SYSTE M 

NON 2 

HEMATOPOIETIC SYSTEM
 

*MULTIPLE ORGANS
 

MALIG.LYMPHOMA, LYMPHOCYTIC TYPE
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE
 

»SUBCUT TISSUE
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE
 

JSPLEEN
 

HEMANGIOSARCOMA
 

tCERVICAL LYMPH NODE
 

MALI3. LYMPHOMA, HISTIOCYTIC TYPE
 

CIRCULATORY SYSTEM
 

fENDOCAHDIUM
 

SARCOMA, NOS
 

DIGESTIV E SYSTE M 

ftLIVE H 

HEPATOCELLULAB_CARCINOMA 

01-131S 

20 

20 

20 

(20) 

(20)
 

1 (5X)
 

(20)
 

(20)
 

(20)
 

(20)
 

(20) 

CONTROL (VEH) 

01-081M 

20 

20 

20 

(20 ) 

(20)
 

(20)
 

(20)
 

(20)
 

1 (5%)
 

(20)
 

(20) 

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

* NUMBE R OF ANIMAL S NECROPSIE D 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

A-3 
TABLE Al (CONTINUED) 

CONTROL (UNTR) CONTROL (VEH) LOW DOSE HIGH DOSE
 

01-131M 01-081M 01-132M 01-133M
 

tPANCHEAS (20) (20) (K 9) (50)
 

HEMANGIOSAHCOMA 1 (2%)
 

URINARY SYSTEM
 

*K1DNEY (20) (20) (50) (50)
 

TRANSITIONAL-CELL CARCINOMA 1 (2%)
 

TUBULAR-CELL ADENOMA 1 (2X) 1 (2%)
 LIPOSARCOMA 1 (5%)
 

MIXED TUMOR, MALIGNANT 1 (2%)
 

HEMANGIOSARCOMA, METASTATIC 1 (24)
 

UAHARTOHA + 1 <5X) 1 (5X) 1 (2%)
 

tHIGHI KIDNEY (20) (20) (50) (50)
 

MIXED TUMOR, MALIGNANT 1 (5«)
 

ENDOCRINE SYSTEM
 

*PITUITARY (19) (20) (U7) (U6)
 

CHROMOPHOBE ADENOMA 1 (5%) 5 (11%) 1 (2%)
 

•ADRENAL	 (20) (20) (50) (50)
 

CORTICAL CARCINOMA 1 (2X)
 

MIXED TUMOR, METASTATIC 1 (5*)
 

tTHYROID (20) (19) (48) (50)
 

FOLLICULAR-CELL ADENOMA 1 (2X)
 

FOLLICULAR-CELL CARCINOMA 1 (54) 1 (5%)
 

C-CELL CAPCINOMA 1 (2)4)
 

JPANCHEATIC ISLETS (20) (20) (U9) (50)
 

ISLET-CELL ADENOMA 1 (2*)
 

REPRODUCTIVE SYSTEM
 

'MAMMARY GLAND (20) (20) (50) (50)
 

ADENOCARCINOMA, SOS 1 (5X) 1 (2%) 1 (2%)
 FIBROADENOMA 1 (2*)
 

tTEsris (20) (19) (U 7) (i»8)
 

INTERSTITIAL-CELL TUMOR
 -_ 1 15«i _
 

t NUMBE R O F ANIMAL S WIT H TISSUE EXAMINE D MICHOSCQPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

+ THIS IS CONSIDERED TO BE A BENIGN FORM OF THE MALIGNANT MIXED TUMOR OF THE KIDNEY AND CONSISTS OF PROLIFF.RATIVE 

LIPOCYTF.S, TUBULAR STRUCTURES, FIBROBLASTS, AND VASCULAR SPACES IN VARYING PROPORTIONS. 

A-4 
TABU- Al (CONTINUED) 

CONTROL(UNTH) CONTROL (VEH)


01-131M 01-081M


NERVOUS SYSTEM
 

#BRAIN (20) (20)


ASTROCYTOMA 1 (5X)
 

#MEDULLA OBLONGATA (20) (20)


ASTROCYTOMA


SPECIAL SENSE ORGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

•VERTEBRAL	 COLUMN (20) (20)


OSTEOSARCOMA


BODY CAVITIES
 

•ABDOMINAL CAVITY (20) (20)


HEMANGIOSARCOMA


• TUNICA VAGINALIS (20) (20)


MEbOTHELIOHA, NOS


ALL OTHER SYSTEMS
 

NONE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 20 20


NATURA L DEATH* 11 19


MORIBUND SACRIFICE


SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 6 1


ANIMAL MISSING
 

i_INCLUDES_AUTOLYZED_ANIMALS
 

i	 NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

*	 NUMBER OF ANIMALS NECHOPSIBD
 

A-5
 

 LOW DOSE HIGH DOSE
 

 01-132M 01-133M
 

 (50) (49)
 

 (50)	 (49)
 

1 (2X)
 

 (50)	 (50)
 

1 (2%)
 

 (50)	 (50)
 

1 (2X)
 

 (50)	 (50)
 

1 (2X) 2 (IX)
 

 50 50
 

 39 35
 

1
 

 11 14
 
TABLE Al (CONCLUDED)
 

CONTROL (UNTR) CONTROL (VEH) LOW DOSE HISH DOSE 

01-131M 01-081M 01-132M 01-133M 

TUMO R SUMMAR Y 

TOTAL ANIMAL S WIT H PRIMAR Y TUMORS * It 6 21 1 1 

TOTAL PRIMARY TUMORS 4 9 26 14 

TOTAL ANIMAL S WIT H BENIG N TUMOR S 1 3 1 1 a

 TOTAL BENIG N TUMOBS 1 3 13

 " 

TOTAL ANIMAL S WITH MALIGNAN T TU1IORS 3 5 12 8 

TOTAL MALIGNAN T TUMOR S 3 6 12 8 

TOTAL ANIMALS WITH SECONDARY TUMOHS* 1 1
 

TOTAL SECONDARY TUMORS 1 1
 

TOTAL ANIMALS WITH TUMORS UNCEBTAINBENIGN OR MALIGNANT 1
 

TOTAL UNCERTAIN TUMORS 1
 

TOTAL ANIHALS WITH TUMORS UNCERTAINPRIMARY OH METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

A-6
 
TABLE A2

 

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

c:ONTROL (UNTR) CONTROL (VEH ) LOW DOSE HIGH DOSE
 

01-131F 01-081F 01-134F 01-135F
 

ANIMALS INITIALLY IN STUDY 20 20 50 50
 

ANIMALS NECROPSIED 20 19 50 50
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY ** 20 19 50 50
 

INTEGUMENTARY SYSTEM
 

*SUBCUT TISSUE (20) (19) (50) (50)
 

FIBROMA 2 (10X) 1 (2X)
 

FIBROSARCOMA 1 (2X)
 

HEMANGIOSARCOMA 1 (2X)
 

RESPIRATORY SYSTEM
 

*LUNG (20) (19) (50) (50)
 

ADENOCARCINOMA, NOS, METASTATIC 1 (2X)
 

CORTICAL CARCINOMA. METASTATIC 1 (2X)
 

FIBROUS HISTIOCYTOMA, MALIGNANT 1 (2X)
 

HBMATOPOIETIC SYSTEM
 

*MULTIPLE ORGANS (20) (19) (50) (50)
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 1 (5X) 1 (2X)
 

tSPLEEN (20) (19) (49) (50)
 

CORTICAL CARCINOMA. METASTATIC 1 (2X)
 

MALIG.LYMPHOMA. HISTIOCYTIC TYPE 1 (2X)
 

ILYMPH NODE (20) (19) (U7) (45)
 

FIBROUS HISTIOCYTOMA, MALIGNANT 1 (2X)
 

ICERVICAL LYMPH NODE (20) (19) (47) (45)
 

SQUASOUS CELL CARCINOMA 1 (2%)
 

*MESENTEBIC L. NODE (20) (19) (47) (45)
 

FIBROSARCOMA 1 (2X)
 

#THYMUS (19) (15) (41) (35)
 

SQUAMOUS CELL CARCINOMA 1 J2X^
 

t NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

A-7 
TABLE A2 (CONTINUED) 

CONTROL (UNTH) CONTROL (VEH) LOB DOSE
 

01-131F 01-081F 01-134F
 

CIRCULATOBY SYSTEM
 

tENDOCARDIUM (20) (19) (50)
 SARCOMA, NOS 1 (5X)
 

DIGESTIVE SYSTEM
 

ILIVER (20) (19) (50)
 

NEOPLASTIC NODULE 1 (5X) 1 (2X)
 CORTICAL CARCINOMA, METASTATIC
 

ISflALL INTESTINE (20) (19) (50)
 

FIBROSARCOMA 1 (2X)
 

»LABGE INTESTINE (20) (19) (50)
 FIBROSAHCOMA
 

URINARY SYSTEM
 

*KIDNEY (20) (19) (50)
 HAMABTOMA+ 4 (8X)
 

ENDOCRINE SYSTEM
 

• PITUITARY (20) (19) (48)
 

CHHOMOPHOBE ADENOMA 2 (10X) 2 (11X) 9 (19X)
 

»ADHENAL (20) (19) (50)
 CORTICAL ADENOMA 1 (2X)
 CORTICAL CARCINOMA 2 (tX)
 LIPOSARCOMA 1 (5%)
 

tTHYHOID (20) 118) (50)
 FOLLICULAH-CELL ADENOMA 2 (4X)
 FOLLICULAR-CELL CARCINOMA 1 (2X)
 

#PANCHEATIC ISLETS (20) (19) (47)
 ISLET -CELL ADENOMA 1 _(23t)_
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

+ THIS IS CONSIDERED TO BE A BENIGN FORM OF THE MALIGNANT MIXED TUMOR OF THE KIDNEY AND CONSISTS

LIPOCYTES, TUBULAR STRUCTURES, FIBROBLASTS, AND VASCULAR SPACES IN VARYING PROPORTIONS. 

HIGH DOSE
 

01-135F
 

(50)
 

(50)
 

1 (2X)
 

1 (2X)
 

(46)
 

(50)
 

1 (2%)
 

(50)
 

1 (2X)
 

(48)
 

5 (10X)
 

(50)
 

1 (2X)
 

(50)
 

1 (2X)
 

(48)
 

 OF PROLIFERATIVE 

A-8 
TABLE A2 (CONTINUED) 

CONTBOL(UNTR) CONTROL (VEH) LOW DOSE HIGH DOSE 

01-131F 01-081F 01-134F 01-135F 

REPRODUCTIVE SYSTEM 

*MAMMAHY GLAND (20) (19) (50) (50) 

ADENOMA, NOS 2 (I»X) 

ADENOCARCINOMA, NOS 1 (5X) 1 (8X) 

FIBROADENOMA 6 (30%} 2 (11X) 16 (32X) 9 (18X) 

tUTERUS (20) (19) (50) (50) 

ENDOMETRIAL STROMAL POLYP 5 (10X) 

NERVOUS SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

NONE 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NONE 

A LL OTHER SYSTEMS 

NONE 

ANIMA L DISPOSITION SUMMAR Y 

ANIMAL S INITIALLY IN STUDY 20 20 50 50 

NATURA L DEATHS 12 15 17 29 

MORIBUN D SACRIFICE 1 1 

SCHEDULED SACRIFICE 

ACCIDENTALL Y KILLED 

TERMINA L SACRIFICE 8 4 32 21 

ANIMA L MISSIN G 

t_IICLUDES_AUTOLYZED_ANIMAL S 

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

* NUMBE R OF ANIMAL S NECBOPSIED 

A-9 
TABLE A2 (CONCLUDED)
 

CONTROL (UNTR) CONTROL (VEH) LOW DOSE HIGH DOSE 01-131F 01-081F 01-134F 01-135F 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 11 4 3U 22
 

TOTAL PRIMARY TUMORS 15 4 50 28
 

TOTAL ANIMALS WITH BENIGN TUMORS 9 U 29 15
 

TOTAL BENIGN TUMORS 10 4 40 17
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 3 6 9
 

TOTAL MALIGNANT TUMORS 1 9 10
 

TOTAL ANIMALS WITH SECONDARY TUMORSI
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 1 1
 

TOTAL UNCERTAIN TUMOBS 1 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

i SECONDARY TUMORS: METASTATIC TUMORS OH TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

A-IO
 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH 1,1,2-TRICHLOROETHANE
 

TABLE Bl

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE. TREATED WITH 1.1,2-TRICHLOROETHANE 

CONTROL (UNT8) CONTROL (VEH) 

02-M141 02-M131 

ANIMALS INITIALLY IN STUDY

ANIMALS NECROPSIED

ANIMAL S EXAMINED HI STOPATHOLOGICALL Y **

 20

 18

 18

 20 

 20 

 20 

INTEGUMENTARY SYSTEM
 

*SUBCUT TISSUE (18) (20)
 

FIB803ARCOMA
 

RESPIRATORY SYSTEM
 

*LUNG (18) (20)
 

HEPATOCELLULAB CARCINOMA, METAST
 

ALVEOLAH/BRONCHIOLAR ADENOMA 2 (11Ji)
 

ALVEOLAH/BRONCHIOLAR CARCINOMA
 

CORTICAL CARCINOMA, METASTATIC
 

HEMATOPOIETIC SYSTEM
 

'MULTIPLE ORGANS (18) (20)
 

MALIG. LYMPHOMA, LYMPHOCYTIC TYPE
 

MALIJ. LYMPHOMA, HISTIOCYTIC TYPE 1 (&X) 1 (5%)
 

• SPLEEN (18) (20)
 

MALIJ. LYMPHOMA, HISTIOCYTIC TYPE
 

tCERVICAL LYMPH NODE (18) (20)
 

CORTICAL CARCINOMA, METASTATIC
 

IMESENTERIC L. NODE (18) (20)
 

MALIG. LYMPHOMA, LYMPHOCYTIC TYPE
 

tLIVSB (17) (20)
 

HALIG. LYMPHOMA, HISTIOCYTIC TYPE 1 (5X)
 

CIRCULATORY SYSTEM
 

NONE
 

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

* NUMBE R OF ANIMAL S NECHOPSIE D 

**rXCl,TOES PARTIALLY AUTOLYZED ANIMALS 

LOB DOSE
 

02-M132
 

50
 

49
 

49
 

(49)
 

2 (4i)
 

(49)
 

1 (2X>
 

2 (4)1)
 

1 (2*1
 

(49)
 

1 (2%)
 

4 (8S)
 

(49)
 

1 (2%)
 

(48)
 

(48)
 

1 (2%)
 

(49)
 

HIGH DOSE
 

02-M133
 

50
 

50
 

50
 

(50)
 

(50)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

(50)
 

1
 (2X)
 

(49)
 

(49)
 

1 (2%)
 

(49)
 

(49)
 

B-3 
TABLE Bl (CONTINUED) 

CONTROL (UtiTR) 

02-M141 

CONTROL (VEH) 

02-M131 

LOW DOSE 

02-H132 

HIGH DOSE 

02-M1J3 

DIGESTIVE SYSTEM 

*LIVER 

HEPATOCELLULAR CARCINOMA 

CORTICAL CABCINOMA, .METASTATIC 

•PANCREAS 

COBTICAL CARCINOMA, METASTATIC 

•STOMACH 

SQUAMOUS CELL PAPILLOMA 

SQUAMOUS CELL CARCINOMA 

•SMALL INTESTINE 

ADENOCAHCINOHA, NOS 

(17) 

2

(18) 

(18) 

(18) 

 (12%) 

(20) 

2

(20) 

(20) 

(20) 

 (10%) 

(49) 

18 (37%) 

(19) 

(49) 

1 (2%) 

1 (2%) 

(49) 

(49) 

37

1

(48) 

1

(50) 

1

(50) 

1

 (76%) 

 (2*) 

 (2%) 

 (2%) 

 (2%) 

URINAR Y SYSTEM 

•KIDNEY 

HEPATOCELLULAR CARCINOMA, METAST 

TUBULAR-PELL ADENOMA 

(18) 

1 (6%) 

(20) (49) 

1 (24) 

(50) 

ENDOCRINE SYSTEM 

•PITUITARY 

CHROMOPHOBE ADENOMA 

•ADR3NAL 

CORTICAL CARCINOMA 

PHEOCHROMOCYTUMA 

•THYROID 

FOLLILULAR-CELL ADENOMA 

FOLLICOLAR-CEL1 CARCINOMA 

(18) 

(18) 

(18) 

(19) 

(20) 

(20) 

1 (5%) 

(49) 

2

(49) 

(49) 

1

 (4%) 

 (2%) 

(Kb) 

(48) 

1 (2%) 

8 (17X) 

(Kb) 

REPRODUCTIVE SYSTEM 

•PROSTATE 

CORTICAL CARCINOMA, METASTATIC 

*EPIDIDYMIS 

CORTICAL CARCINOMA,. METASTATIC 

(18) 

(18) 

(19) 

(20) 

» NUMBE R O F ANI1AL S WIT H TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBER OF ANIMAL S NECBOPSIED 

(48) 

(49) 

(46) 

1 (2*) 

(50) 

1 12%)_ . 

B-4 
TABLE Bl (CONTINUED) 

CONTRO L (UNTB ) CONTBOL ( VEH) LOW DOSS HIGH DOSE 

02-M141 02-N13 1 02-M132 02-M13 3 

NERVOU S SYSTE M 

#Ct)8EBRUI 1 (18) (19 ) (49) (49 ) 

EPENDYMOB A 1 (5X) 

SPECIA L SENS E ORGAN S 

*HABDERIA N GLAN D (18) (20) (49) (50) 

ADENOMA , NOS 1 (2X ) 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NONE 

A LL OTHER SYSTEM S 

NON E 

ANIMA L DISPOSITIO N SUMMAR Y 

ANIMAL S INITIALL Y IN STUD Y 20 20 50 50 

NATURA L DEATH S 9 10 23 30 

MORIBUN D SACRIFICE 2 1 

SCHEDULE D SACRIFICE 

ACCIDENTALL Y KILLE D 1 

TERMINA L SACRIFICE 11 10 24 19 

ANIMA L MISSIN G 

*_INCLUDES_AUTOLYZED_ANIMAL S 

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

* NUMBE R O F ANIMAL S NECROPSIE D 

B-5 
TABLE Bl (CONCLUDED) 

CONTHOL(UNTH) CONTROL (VEH) LOW DOSE HIGH DOSE 

02-M141 02-M131 02-M132 02-M1J3 

TUHOR SUMMAR Y 

TOTAL ANIMALS WITH PRIMARY TUMORS* U 6 28 38 

TOTAL PRIMARY TUMORS 5 6 36 b1 

TOTAL ANIMALS WITH BENIGN TUMORS 2 1 6 9 

TOTAL BENIGN TUMORS 2 1 6 9 

TOTAL ANIMALS WITH MALIGNANT TUMORS 3 5 27 38 

TOTAL MALIGNANT TUMORS 3 5 30 1*2 

TOTAL ANIMALS WITH SECONDARY TUMORS* TOTAL SECONDARY TUMORS 1

 i 1 i 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 

TOTAL UNCERTAIN ""UMORS 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIL 

^OTAL UNCERTAIN TUMORS 

* PRIMARY TUMORS. ALL TUMORS EXCEPT bELONDARY TUMORS 

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

B-6
 
TABLE B2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TRtAThD WITH 1,1 2-TRlfHLOROhTHANL 

CONTRO L (UNTH ) CONTRO L (VEH ) LO W DOSE HIG H DOSE 

02-F141 02-F131 02-F13 4 02-F13 5 

ANIMAL S INITIALL Y IN STUD Y 20 20 50 50 

ANIMAL S MISSIN G 1 

ANIMAL S NECHOPSIE D 20 20 48 46 

ANIMAL S EXAMINE D HISTOPATHOLOGICALL Y ** 19 20 _ 48 45 

INTEGUMENTAR Y SYSTEM 

*SKIN (20) (20) (48) (46) 

SQUAMOU S CELL CARCINOM A 1 (55!) 

RESPIRATOR Y SYSTE M 

#LUN G (20 ) (20 ) (48 ) (39 ) 

HEPATOCELLULA R CARCINOMA , METAS T 2 (5%) 

ALVEOLAR/BRONCHIOLA R ADENOM A 1 (5%) 3 (6«) 1 (3% ) 

ALVEOLAR/BRONCHIOLA B CARCINOM A 1 (3%) 

SARCOMA , NOS, METASTATIC 1 (3X) 

HSMATOPOIETI C SYSTEM 

'MULTIPL E ORGAN S (20) (20) (48 ) (46) 

MALIG.LYMPHOMA , LYMPHOCYTI C TYP E 1 (5X ) 3 (6X) 

MALIG.LYMPHOMA . HISTIOCYTIC TYP E 2 (10X ) 1 (2X) 1 (2% ) 

#CEHVICA L LYMP H NODE (20) (20 ) (48) (45 ) 

SARCOMA , NOS, METASTATIC 1 (2% ) 

#LUMBA R LYMP H NOD E (20) (20) (48) (45)

 

MALIG.LYMPHOMA , LYMPHOCYTIC TYPE 1 (5%) 

KKIDNE Y (20 ) (20 ) (48) (45) 

MALIGNAN T LYMPHOHA , NO S 1 (2%) 

CIRCULATOR Y SYSTE M 

tENDOCARDIU M (20) (20 ) (48) (38) SARCOMA ^ NOS 1 (3 %) 

* NUMBE R O F ANIMAL S HITH TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBE R OF ANIMAL S NECROPSIE D 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-7 
TABLF B2 (CONTINUED) 

DIGESTIV E SYSTE M 

• LIVER 

HEPATOCELLULA B CARCINOM A 

*BILE DUCT 

BILE DUCT CARCINOM A 

• STOMAC H 

SQUAMOU S CELL CARCINOM A 

• SMAL L INTESTIN E 

ADENOCARCINOMA , NO S 

URINAH Y SYSTE M 

• KIDNE Y 

SARCOMA , NOS, METASTATIC 

ENDOCaiN E SYSTE M 

• ADRENA L 

PHEOCHROMOCYTOM A 

• THYROI D 

FOLLICULAR-CEL L ADENOM A 

REPHODOCTIV E SYSTE M 

• OVAR Y 

GRANULOSA-CEL L TUMO R 

NERVOU S SYSTE M 

*CRANIA L NERV E 

NEUROFIBROM A 

SPECIA L SENS E ORGAN S 

NON E 

MUSCULOSKELETAL SYSTEM 

NON E 

* NUMBE R OF ANIMAL S WITH TISSUE

* NUMBE R OF ANIMAL S NECROPSIE D 

LONTROL(UNTR ) C0» THOL ( VEri)

02-F1U1 02-F131

(20) (20)

2 (10)4 )

(20 ) (20 )

(20 ) (20)

(20) (20 )

(20) (20)

(20) (20 )

(70) (20)

(20) (20 )

1 (5% ) 

(20) (20 )

 EXAMINE D MICROSCOPICALLY 

 LOW DOSn 

 02-F134 

 (H8 ) 

 16 (334} 

 ("48) 

 (48) 

 (48) 

 (48) 

 (48) 

 (t8) 

 (46) 

 (H8 ) 

1 (2%) 

HIGH DOSE 

02-F135 

(15) 

40 (89%) 

(46) 

1 (2%) 

(^5) 

1 (2% ) 

(44 ) 

1 (2%) 

(45) 

1 (2%) 

(43 ) 

12 (28%) 

(35) 

1 (3%) 

(38) 

(46 ) 

2 (U%) 
TABLF B2 (CONCLUDED) 

CONTROL(UNTS ) CONTROL (VEH ) LOW DOSE HIGH DOSE 

02-F1U1 02-F131 02-F134 02-F1J5 

BODY CAVITIES
 

NONE
 

A L L OTHER SYSTEM S 

NONE 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 20 20 50 50
 

NATURAL DEATH8 28 33
 

MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 1 1 18 21 15
 ANIMA L MISSING 1
 

3 INCLUDES AUTOLYZED ANIMALS
 

TUMOR SUMMAR Y
 

TOTAL ANIMAL S WITH PRIMARY TUMORS' 1 5 20
 

TOTAL PRIMARY TUMORS U 5 24 63
 

TOTAL ANIMALS WITH BENIGN TUMORS 1 <J 16
 

TOTAL BENIGN TUMORS 1 U 16
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 3 4 18 40
 

TOTAL MALIGNANT TUMORS 3 U 20 47
 

TOTAL ANIMALS WITH SECONDARY TUMORS*
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OB MALIGNANT 1
 TOTAL UNCERTAIN TUMORS 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAINPRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

B-9
 

APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

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

TABLE Cl

 

SUMMARY OF THE INCIDENCE OP NONNEOP1ASTIC LI SIGNS IN MALI RATS 

TREATED WITH 1,1 2-TRICHLOROETHANF 

CONTROL(UNTa) CONTROL (VEH) LOU DOSE HIGH DOSE
 

01-131M 01-081M 01-132M 01-133M
 

ANIMALS INITIALLY IN STUDY 20 20 50 50
 

ANIMALS NECROPSIED 20 20 50 50
 

ANIMAL S EXAMINED HI bTOPATHOLOGICALLY ** 20 20 50 50
 

INTEGUMENTARY SYSTEM
 

*SKIN (20) (20) (50) (50)
 EPIDERMAL INCLUSION CYST 1 (5%) 1 (2%)
 INFLAMMATION, NOb 1 (2X)
 ABSCESS, NOS 1 (2%)
 

HYPERKERATOSIS 1 (2%)
 

ACANTHOSIS 1 (2%)
 

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

ABSCESS, NOS 1 (5X)
 

RESPIRATORY SYSTEH
 

tTRACHEA (20) (20) (48) (50)
 

INFLAMMATION, NOS 1 (5X)
 

KLUNG (20) (20) (50) (50)
 

PNEUMONIA, CHRONIC MURINE 14 (70*) 19 (95S) 45 (90%) 34 (68*)
 

HEMATOPOIETIC SYSTEM
 

(tSPLEEN (20) (20) (49) (50)
 HEMATOPOIESIS 1 (5%) 1 (5%) 1 (2*) 2 (US)
 

ICEHVICAL LYMPH NODE (20) (20) (47) (46)
 

INFLAMMATION, NOS 1 (2X)
 

*TRACHEAL LYMPH NODE (20) (20) (47) (46)
 

ANGIECTASIS 1 (5X)
 

*THYMUS (16) (16) (37) (27)
 

INFLAMMATION,. NOS 1 i4M.
 

* NUMBE R OF ANIMAL S HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBE R OF ANIMAL S NECEOPSIE D 

•**FXCLUDES PARTIALLY All TOLLED ANIMALS 

C-3 
TABLtCl (CONTINUED) 

CIRCULATOR Y SYSTE M 

*HEART 

THROMBOSIS , NOS 

CALCIU M DEPOSIT 

#MYOCARDIU M 

FIDROSI S 

DEGENERATION , NO b 

tENDOCARDIU M 

HYPERPLASIA, NOS 

*AORTA 

INFLAMMATION , NO S 

MEDIA L CALCIFICATIO N 

DIGESTIV E SYSTEM 

#LIVER 

INFLAMMATION , NO S 

PELIOSIS HEPATI S 

METAMORPHOSI S FATT Y 

FOCAL CELLULA R CHANG E

 

ANUIECTASI S 

ILIViR/CENTRILOBULA R 

DEGENERATION , NO S 

*BILE DUCT 

HYPERPLASIA, NOS 

• PANCREA S 

PERIARTERITI S 

tSTOMACH 

ULCER , FOCAL 

CALCIU M DEPOSIT 

URINAR Y SYSTE M 

IKIDNE Y 

HYDRONEPHBOSI S 

THROMBUS , ORGANIZE D 

PYELONEPHRITIS , NO S 

INFLAMMATION , CHRONIC 

CALCIU M DEPOSIT

 

i NUMBE R OF ANIMAL S KITH TISSUE

* NUMBER OF ANIMAL S NECROPSIED 

CONTROL(UNTR ) CONTROL (VEH ) 

01-131M 01-081H 

(20) (20 ) 

(20) (20 ) 

3 (15%) 

(20) (20) 

1 (5%) 

(20) (20 ) 

2 (10% ) 

2 (10%) 

(20) (20) 

2 (10%) 

1 (5%) 

1 (5%) 

1 (5%) 

(20) (20) 

1 (5*) 

(20 ) (20) 

2 (10%) 1 (5%) 

(20) (20) 

1 (5%) 1 (5X ) 

(20) (20 ) 

2 (10%) 

(20) (20) 

it (20% ) 

13 (65% ) 12 (60%) 

1 I5%L 

 EXAMINE D MICROSCOPICALL Y 

C-4 

L OU DOSE 

01-132M 

(bO ) 

(50) 

2 (4% ) 

(50) 

(50) 

2 (4% ) 

(50) 

2 (4% ) 

1 (2%) 

2 (4% ) 

(50) 

1 (2% ) 

(50) 

3 (6%) 

(U9 ) 

(50) 

1 (2%) 

2 (4% ) 

(50) 

1 (2% ) 

3 (6%) 

22 (44%) 

2 J4%1 

dIG H DOSE 

01-133M 

(50) 

1 (2% ) 

1 (2% ) 

(50) 

3 (6%) 

1 (2% ) 

(50) 

4 (8%) 

(50) 

(50) 

U (8X) 

6 (12% ) 

1 (2%) 

(50 ) 

(50) 

5 (10%) 

(50) 

(50) 

(50) 

3 (6%) 

1 (2%) 

15 (30%) 
ULEFT KIDNEY
 

INFLAMMATION, CHRONIC
 

tUKINABY BLADDER
 

INFLAMMATION, NOS
 

FNDOC3INE SYSTEM
 

IPITUITARY
 

ANGIECTASIS
 

tADRENAL COBTEX
 

ANGIECTASIS
 

iTHYHOID
 

FOLLICULAB CYST, NOS
 

•PARATHYROID
 

HYPERPLASIA, NOS
 

REPRODUCTIVE SYSTEM
 

*PENIS
 

KPIDERMAL INCLUSION CYST
 

ABSCESS, NOS
 

&PROSTATE
 

INFLAMMATION, NOS
 

*SEMINAL VESICLE
 

INFLAMMATION, NOS
 

(tTESTIS
 

CALCIUM DEPOSIT
 

CALCIFICATION, NOS
 

ATROPHY, NOS
 

*EPIDIDYMIS
 

NECHOSIS, FAT
 

NEBVOOS SYSTEM
 

NONE
 

# NUMBE R O F ANIMAL S WITH TISSUE

* NUMBE R O F ANIHAL S NECROPSIE D 

05 

TABLE C 1 (CONTINUED) 

CONTROL (UNTR) CONTROL (VEH)
 

0 1 - 1 3 1M 01-081B
 

(20)	 (20)
 

1 (5X)
 

(17) (20)
 

(19) (20) 

1 (5%) 

(20) (20) 

1 (5*) 

(20) (19) 

1 (5X) 

(20) (20) 

4 (20%) 

(20) (20)
 

(17)	 (17)
 

2 (12X)
 

(20) (20)
 

(20)	 (19)
 

5 (25X) 7 (37X)
 

(20) (20)
 

 EXAMINE D MICROSCOPICALL Y 

LOW DOSE
 

01-132M
 

(50)
 

(48)
 

1 (2%)
 

(47)
 

(50)
 

3 (6)4)
 

(48)
 

(50)
 

1 (2)4)
 

(50)
 

1 (2i4)
 

1 (2%)
 

(40)
 

4 (10X)
 

(50)
 

2 (4/1)
 

(47)
 

1 (2X)
 

14 (30S)
 

(50)
 

HIGH DOSE
 

01-133H
 

(50)
 

(47)
 

1 (2%)
 

(46)
 

(50)
 

3 (6%)
 

(50)
 

(50)
 

1 (2X)
 

(50)
 

(30)
 

2 (7%)
 

(50)
 

2 (4S)
 

(48)
 

2 (4%)
 

7	 (15X)
 

(50)
 

1 (2%)
 
TABLE Cl (CONCLUDED)
 

CONTBOL(UNTR )

01-131M

 CONTRO L (VE H 

 01-081M 

) LOW DOSE

01-132M HIGH DOSE  01-133M 

SPECIA L SENSE ORGAN S 

*EYE 

SYNECHIA , ANTERIO R 

CATARAC T 

*EYE/CORNE A 

VASCULARIZATIO N 

*EYE/RETIN A 

ATROPHY, NOS 

(20)

1 (5X) 

(20 )

1 (5X) 

(20)

 (20) 

 (20) 

 (20) 

(50)

(50)

(50)

 (50) 

1 (2%) 

 (50) 

 (50) 

1 12%) 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

*PERITONEUM 

INFLAMMATION, NOS 

(20) (20) (50) 

1 (2%) 

(50) 

'PERICARDIUM 

FIBROSIS 

(20) (20) (50) 

1 (2*) 

(50) 

*MESENTERY 

PERIARTEHITIS 

NECROSIS, FAT 

(20) 

1 (5*) 

(20) 

1

1

 (5X) 

 (5%) 

(50) 

1 (2%) 

(50) 

2 (H%) 

ALL OTHER SYSTEMS 

NONE 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPORTED 

f NUMBER

* NUMBER

 OF ANIMALS

 OF ANIMALS

 WITH TISSUE EXAMINED MICROSCOPICALLY 

 NECROPSIED 

C-6
 
TABLE C2

 

SUMMARY Oh THL INCIDLNCF OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

TREATED WITH 1 1,2-TRICHLOROETHANE 

CONTROL (UNTR) 

01-131F 

CONTROL (VEH) 

01-081F 

LOU DOSE 

01-13<tF 

ANIMALS INITIALLY IN STUDY 

ANIMALS NECROPSIED 

ANIMALS EXAMINED HI STOPATHOLOGICALL Y 

20 

20 

** 20 

20 

19 

19 

50 

50 

50 

INTEGUMENTARY SYSTEM
 

*SUBCUT TISSUE (20) (19) (50)
 

ABSCESS, NOS 1 (5%)
 

RESPIRATORY SYSTEM
 

•TRACHEA	 (20) (19) (50)
 

INFLAMMATION, NOS 1 (2X)
 

*LUNG (20) (19) (50)
 

PNEUMONIA, CHRONIC MURIN E 17 (85X) 17 (89X) 43 (86X)
 

HEKATOPOIFTIC SYSTEM
 

tSPLEEN (20) (19) (U 9}
 

ANGIECTASIS
 

HEMATOPOIESIS 1 (5S) 1 <5X) 5 (10*)
 

tSPLENIC CAPSULE (20) (19) (49)
 

INFLAMMATION, NOS 1 (5%}
 

tCERVICAL LYMPH NODE (20) (19) (U 7)
 

INFLAMMATION, NOS 1 (2X)
 

HYPERPLASIA, NOS
 

*MESENTERIC L. NODE (20) (19) (47)
 

INFLAMMATION, NOS 1 (5*)
 

ANGIECTASIS
 

CIRCULATORY SYSTEM
 

*HEART	 (20) (19) (50)
 

•^HROMBUS^ ORGANIZED 1 15X1.	 1 J2X1
 

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

* NUMBE R OF ANIMAL S NECROPSIE D 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

HIGH DOSE
 

01-135F
 

50
 

50
 

50
 

(50)
 

(50)
 

(50)
 

32 (64X)
 

(50)
 

1 (2X)
 

4 (8%)
 

(50)
 

(45)
 

1 (2*)
 

1 (2X)
 

(45)
 

1 (251)
 

1 (2X)
 

(50)
 

1 ±2%L
 

C-7 
TABLE C2 (CONTINUED) 

CONTRO L (UNTR ) CONTRO L (VLH ) 

01-131F 01-081F 

MYOCARDIU M (20) (19 ) 

INFLAMMATION , NO S 

FIBROSIS 

tENDOCASDIU M (20) (19) 

HYPEBPLASIA , NO S 

*AOETA (20) (19)

 

MEDIA L CALCIFICATIO N 1 (5%)

 

DIGESTIV E SYSTE M 

ILIVER (20) (19) 

INFLAMMATION , NOS 

PELIOSIS HEPATIS 

METAMORPHOSI S FATTY 1 (5*)

 

FOCAL CELLULA R CHANG E 

*BILE DUCT (20) (19 ) 

HYPERPLASIA , NO S 

IPANCREA S (20) (19)

 

INFLAMMATION , NOS 1 (5% )

 

PERIABTERITI S 1 (5%)

 

ATROPHY , NOS 

•ESOPHAGUS (19 ) (19) 

INFLAMMATION , NO S 

tSTOMACH (20) (19)

 

ULCER , FOCAL 1 <5X ) 

CALCIUM DEPOSIT 1 (5%) 

HYPEBKERATOSI S 

UBINA8 Y SYSTE M 

#KIDNE Y (20) (19) 

MINERALIZATIO N 1 (5%) 

HYDRONEPHBOSI S 

PYELONEPHRITIS , NOS 

INFLAMMATION , CHRONIC 8 (U0% ) 2 (IDS ) 

CALCIUM DEPOSIT 1 (5%) 

IKIDNEY/CAPSUL E (20) (19 )

 

INFLAMMATION , NO S 1 i5«)

 

i NUMBE R OF ANIMAL S KITH TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBE R OF ANIMALS NECROPSIED 

L0» DOSE 

01-134F 

(50) 

1 (2*) 

(50) 

1 (2*) 

(50) 

(50) 

2 (4X ) 

1 (2JS) 

2 (•*») 

2 (4X ) 

(50) 

6 (12X) 

(i(7 ) 

1 (2X ) 

(50) 

1 (2%) 

( U 9) 

1 (2%) 

1 (2% ) 

(50) 

1 (2X) 

14 (28*) 

(50) 

HIGri DOSE 

01-135F 

(50) 

1 (2% ) 

2 (4%) 

(50) 

1 (2%) 

(50) 

(50) 

1 (2%) 

1 (2%) 

(50) 

6 (12X ) 

(48) 

1 (2%) 

(50) 

1 (2%) 

(49 ) 

1 (2% ) 

(50) 

2 (4X ) 

2 (4% ) 

(50) 

C-8 
TABLt C2 (CONTINUhD) 

CONTRO L (UNTR ) CONTRO L (VEri) 

01-1J1F 01-081F 

ENDOCRIN E SYSTE M 

• PITUITAR Y (20) (19) 

ANGIECTASI S 1 (5*)

 

IADRENA L CORTE X (20) (19 ) 

ANGIECTASI S 4 (20% ) 3 (16% ) 

tTHYRUI D (20) (18 )

 

INFLAMMATION , NO S 

REPRODUCTIV E SYSTE M 

»VAGIN A (20) (19 ) 

INFLAMMATION , NO S 

POLY P 

tUTERU S (20 ) (19 ) 

HYDROMETR A 

(tCEPVI X UTER I (20 ) (19)

 

POLYP , INFLAMMATOR Y 

tliTERUS/ENDOMETRIU M (20 ) (19 )

 

INFLAMMATION , NO S 1 (5%)

 

HYPEHPLASIA , CYSTIC 

*OVAH / (20) (19)

 

CYST, NOS 1 (5X) 

INFLAMMATION , NO S 1 (5% )

 

NERVOU S SYSTE M 

NON E 

SPECIA L SENS E ORGAN S 

NON E 

MUSCULOSKELETA L SYSTE M 

NON E 

# NUMBE R O F ANIMAL S HIT H TISSUE EXAMINh D MICROSCOPICALL Y 

* NUMBE R O F ANIMAL S NECEOPSIE D 

L O B DOSE 

01-134F 

(48) 

1 (2% ) 

(50) 

4 (8%) 

(50) 

1 (2J4) 

(50) 

1 (2% ) 

1 (2X ) 

(50) 

7 (14S) 

(50) 

1 (2% ) 

(50) 

2 (4%) 

1 (2%) 

(50) 

2 (4% ) 

rfIGH 

01-1 

(48 ) 

(50) 

5 

(50) 

(50) 

(50) 

4 

(50) 

(50) 

1 

(50) 

2 

DOSE 

35F 

(10%) 

(8%) 

(2X) 

(4% ) 

C-9 
TABLE C2 (CONCLUDED)
 

CONTROL (UNIR) CONTROL (VEH ) L OW DOSE HIGH DOSE 

01-131F 01-081F 01-13UF 01-135F 

BODY CAVITIES
 

*ABDOMINAL CAVITY (20) (19) (50) (50)
 

NECROSIS, FAT 1 <5X) 1 (2*)
 

'PERITONEUM (20) (19) (50) (50)
 

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

•PERICARDIUM	 (20) (19) (50) (50)
 

INFLAMMATION. DOS 1 (2X)
 

*MESENTE8Y (20) (19) (50) (50)
 

PERIARTERITIS 2 (10X)
 

ALL OTHER SYSTEMS
 

NONE
 

SPECIAL MORPHOLOGY SUMMAKY
 

NO	 LESION REPORTED
 

AUTOLYSIS/NO NECROPSY
 

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-IO
 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

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

TABLE Dl

 

SUMMARY OF THL INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICETREATED WITH 1,1,2-TRICHLOROETHANE

 

CONTROL (UNTR) CONTROL (VEH)
 

02 -Ml 11 02-M131
 

ANIMALS INITIALLY IN STUDY 20 20
 

ANIMALS NECROPSIED 18 20
 

ANIMAL S EXAMINED HI STOPATHO LOGICALLY** 18 20
 

INTEGUMENTARY SYSTEM
 

*SKIN (18) (20)
 

INFLAMMATION, NOS 1 (6%)
 

ABSCESS, NOS
 

•SUBCUT	 TISSUE (18) (20)
 

EPIDERMAL INCLUSION CYST 2 (10X)
 

ABSCESS, NOS 2 (10X)
 

RESPIRATORY SYSTEM
 

*LUNG (18) (20)
 

PNEUMONIA, CHRONIC MURINE 5 (28X)
 

HYPERPLASIA, ADENOMATOUS
 

LEUKEMOID REACTION 1 (5X)
 

HEMATOPOIETIC SYSTEM
 

*BONE MARRO W (18) (19)
 

LEUKEMOID REACTION 1 (5)6)
 

tSPLEEN (18) (20)
 

AMYLOIDOSIS 3 (15X)
 

HEMATOPOIESIS
 

*LYMPH NODE (18) (20)
 

ANGIECTASIS
 

((CERVICAL LYMPH NODE (18) (20)
 

INFLAMMATION, NOS 1 (6X)
 

»HESi;NTEBIC L. NODE (18) (20)
 

INFLAMMATION, NOS 9 (50X) 1 (5X)
 

ANGIECTASIS 2 J1 Dt)_ 2 J10XI _
 

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

* NUMBE R O F ANIMAL S NECROPSIE D 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

LOW DOSE
 

02-M132
 

50
 

19
 

19
 

(19)
 

2 (IX)
 

(19)
 

1 <2X)
 

(19)
 

1 (2X)
 

(43)
 

(19)
 

6 (12X)
 

(18)
 

(18)
 

(18)
 

2 (4X)
 

3 16X)_
 

HIGH DOSE
 

02- Ml 33
 

50
 

50
 

50
 

(50)
 

(50)
 

(50)
 

1 (2X)
 

(18)
 

(19)
 

2 (4%)
 

(19)
 

1 (2%)
 

(19)
 

(19)
 

1 (2%)
 

1 18%)_
 

D-3 
CIRCULATORY SYSTEM
 

tHEAHT
 

CALCIUM DEPOSIT
 

IMYOCAHDIUM
 

DEGENERATION, NOS
 

*MESSNTERIC ARTERY
 

PEHIARTERITIS
 

DIGESTIVE SYSTEM
 

(LIVER
 

THROMBUS, ORGANIZED
 

INFLAMMATION, NOS
 

AMYLOIDOSIS
 

FOCAL CELLULAR CHANGE
 

HYPEBPLASIA, NODULAR
 

ANGIECTASIS
 

•PANCREAS
 

THBOMBUS, ORGANIZED
 

INFLAMMATION, NOS
 

CALCIUM DEPOSIT
 

tSTOMACH
 

THROMBUS, ORGANIZED
 

HYPERKEHATOSIS
 

ACANTHOS1S
 

ICOLON
 

NEMATODIASIS
 

URINAR Y SYSTEM
 

tKIDNEY
 

HYDRONEPHROSIS
 

PYELONEPHRITIS, NOS
 

INFLAMMATION, CHRONIC
 

AMYLOIDOSIS
 

CALCIUM DEPOSIT
 

ATROPHY,. NOS
 

TABLE Dl (CONTINUED)
 

CONTROL (UNTR)


02-M141


(18)


(18)


(18)


(17)


(18)


(18)


(18)


1 (6X)
 

(18)


3 (17X)
 1 <6X)


1 ^656)_
 

 CONTROL (VEH)
 

 02-M131
 

 (20)
 

2 (10X)
 

 (20)
 

1 (5X)
 

 (20)
 

 (20)
 

2 (10X)
 

1 (5X)
 

 (20)
 

 (20)
 

 (20)
 

 (20)
 

1 (5*)
 6 (30%)
 

4 (20X)
 

1 (5X)
 

LOU DOSE
 

02-M132
 

(49)
 

5 (10X)
 

(49)
 

(49)
 

(49)
 

1 (2%)
 

1 (2X)
 

1 (2X)
 

1 (2X)
 

(49)
 

1 (2X)
 

(49)
 

1 (2X)
 

1 (2%)
 

(49)
 

(49)
 

1 (2X)
 

16 (33X)
 

2 (UX)
 

1 <2X)
 

HIGH DOSE
 

02-M133
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

1 (2X)
 

(49)
 

3 (6X)
 

1 (2X)
 

(48)
 

2 <UX)
 

1 (2X)
 

2 (4S)
 

(50)
 

1 (2X)
 

(49)
 

(50)
 

2 (i»X)
 

1 (2*)
 

# NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECHOPSIED
 

D-4
 
TABLE Dl (CONTINUED) 

CONTROL(UNTR ) CONTROL(VEH )

02-H141 02-M131

ftURINAR Y BLADDE R (18) (19)

INFLAMMATION , NOS

ENDOCRINE SYSTEM
 

tADRENAL CORTEX (18) (20)


ANGIECTASIS


tADHENAL MEDULLA (18) (20)


DEGENERATION, NOS


REPRODUCTIVE SYSTEM
 

tTESTIS (17) (19)


GBANULOMA , SPERMATIC 1 (5%)


CALCIUM DEPOSIT 1 (5%)
 

ATHOPHY, NOS 1 ((,%) 3 (16*)


*EPIDIDYBIS (18) (20)


GBANULOMA, SPERMATIC 1 (5)S)


NERVOUS SYSTEM
 

#BRAIN/MENINGES (18) (19)


INFLAMMATION , NOS

SPECIAL SENSE ORGANS
 

*EYE (18) (20)


CATARACT


ATROPHY, NOS


*HARDERIAN GLAND (18) (20)


INFLAMMATION. NOS


MUSCULOSKELETAL SYS1EM
 

NONE
 

BODY CAVITIES
 

NONE
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

D-5
 

 LOW DOSE HIG H DOSE 

 02-M132 02-B133 

 (U9 ) (46 ) 

1 (2%) 

 (49) (48) 

2 (4%) 

 (49) (48) 

1 (2%) 

 (49) (48) 

1 (2%) 

3 (6X) 2 (4%) 

 (49) (50) 

1 (2*) 

 (49) (49) 

1 (2%) 

 (49) (50) 

1 (2X) 

1 (2%) 

 (49) (50) 

1 (2*) 
TABLE Dl (CONCLUDED) 

CONTROL (UNIB)

02-B11H

 CONTROL (VEH)

 02-M131

 LOW DOSE

 02-M132

 HIGH DOSE 

 02-M133 

A LL OTHER

NON E 

 SYSTEMS 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPORTED 1

AUTOLYSIS/KO NECROPSY 2

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

6 7 

1 

D-6
 
TABLE D2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

TREATED WITH 1,1,2-TRlCHLOROETHANE 

CONTROL (UNTR)

02-F141

 CONTROL (VEH)

 02-F131

 LOW DOSE 

 02-F134 

HIGH DOSE 

02-F135 

ANIMALS INITIALLY IN STUDY

ANIMALS MISSING

ANIMALS NECROPSIED

ANIMALS EXAMINED HISTOPATHOLOGICALL Y **

 20

 20

 19

 20

 20

 20

 50 

1 

 48 

 1*8 

50 

46 

45 

INTEGUMENTARY SYSTEM 

*SUBCUT TISSUE

ABSCESS, NOS

 (20) (20)

 1 (5X) 

 (1*8) (46) 

2 <4X) 

RESPIRATORY SYSTEM 

ITRACHEA

INFLAMMATION, NOS 

 (20) (19) (18) (37) 

1 (3%) 

*LUNG

PNEUMONIA, CHBONIC MURINE

 (20)

 7 (35X) 

 (20) (48) (39) 

4 (10S) 

HEMATOPOIETIC SYSTEM 

ISPLEEN

INFLAMMATION, NOS

ANGIECTASIS

hEMATOPOIESIS

 (20)

 1 (5X) 

 (20)

 1 (5%) 

 (48) 

1 (2%) 

(45) 

3 (7X) 

tLYMPH NODE

INFLAMMATION, NOS 

 (20) (20) (48) (45) 

1 (2%) 

#MESENTERIC L. NODE

INFLAMMATION, NOS

ANGIECTASIS

 (20)

 6 (30%)

 2 (10X)

 (20)

 3 (15X) 

 (48) 

1 (2X) 

(45) 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

• SALIVARY GLAND

CYST, NOS 

INFLAMMATION, NOS 

 (20) (19) (48) (35) 

1 (3%) 

1 13 X) 

# NUMBE R O F ANIMAL S KIT H TISSU E EXAMINE D

* NUMBE R OF ANiMAL S NECROPSIE D 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALL Y 

D-7 
TABLE D2 (CONTINUED) 

CONTROL (UNTH) CONTROL (VEH)
 

02-F141 02-F131
 

tLIVER 

THROMBUS, ORGANIZED 

INFLAMMATION, NOS 

PELIOSIS HEPATIS 

HYPERPLASTIC NODULE 

(20) 

1 (5%) 

(20) 

1 (5%) 

•PANCREAS 

INFLAMMATION, NOS 

(20) 

1 (5X> 

(20) 

•STOMACH 

ULCER, FOCAL 

HYPERKEHATOSIS 

ACANTHOSIS 

(20) 

1 

1 (5%) 

(5X) 

(20) 

1 (5%) 

tSMALL INTESTINE 

THROMBUS, ORGANIZED 

(20) (20) 

•COLON 

NEMATODIASIS 

(20) 

4 (20%) 

(20) 

URINABY SYSTEM
 

iKIDNEY (20) (20)
 

HYDRONEPHROSIS 1 (5%)
 

ENDOCRINE SYSTEM
 

•ADRENAL	 CORTEX (20) (20)
 

DEGENERATION, NOS
 

tTHYROID (20) (20)
 

FOLLICULAR CYST, NOS 1 (5%) 2 (10%)
 

REPRODUCTIVE SYSTFM
 

•UTERUS	 (20) (20)
 

HYDROMSTRA it (20*) 4 (20%)
 

CYST, NOS
 

•UTE8US/ENDOKETHIUM	 (20) (20)
 

CYST, NOS
 

INFLAMMATION. NOS 1 (5*)
 

HYPERPLASIAt CYSTIC 3 _115*L 11 155*)_
 

# NUMBE R O P ANIMAL S KITH TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBER OF ANIMAL S NECROPSIED 

LOW DOSE
 

02-F134
 

C.8J
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

(47)
 

(48)
 

1 (2*)
 

(48)
 

(U8)
 

(U8)
 

(48)
 

1 (2%)
 

(48)
 

(46)
 

6 (13X)
 

1 (2X)
 

(46)
 

1 (2*)
 

1 (2*)
 

1 1	 _i24X)_
 

HIGH DOSE
 

02-P135
 

(45)
 

3 (7%)
 

(42)
 

(45)
 

1 (2%)
 

1 (2%)
 

(44)
 

1 (2%)
 

(44)
 

(45)
 

3 (7%)
 

(43)
 

(35)
 

1 (3%)
 

(37)
 

(37)
 

D-8 
TABLE D2 (CONTINUED) 

CONTEOL(UNTR ) CONTROL (VEH ) LO K DOSE HIGH DOSE 

02-F1H1 02-F131 02-F13U 02-F135 

• OVAR Y (20) (20) («6) (38) 

CYST, NOS 11 (55X) 6 (30%) a (9X) 3 (8X) 

THROMBUS, ORGANIZED 1 (3X) 

INFLAMMATION, NOS 1 (5X) 

• LEFT OVARY (20) (20) (1(6) (38) 

CYST, NOS 1 (2») 

NEKVOU3 SYSTEM 

NONE 

SPECIA L SENS E ORGAN S 

»EYE (20) (20) («8) (16) 

PHTHISIS BULBI 1 (2X) 

*EYE/LACRIMA L GLAN D (20) (20) (US ) (1*6) 

INFLAMMATION , NOS 1 (5%) 

*HARDE8IAN GLAND (20) (20) (US) (Kb) 

HYPEBPLASIA, NOS 1 (2%) 

HYPERPLASIA, CYSTIC 1 (2%) 

MUSCULOSKELETA L SYSTE M 

NON E 

BODY CAVITIES 

(•PERITONEU M (20) (20) (48) (U6 ) 

INFLAMMATION , NOS 1 (5X) 

A L L OTHE R SYSTEM S 

NON E 

* NUMBE R O F ANIMAL S WIT H TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECPOPSIE D 

D-9 
TABLE D2 (CONCLUDED)
 

CONTROL(UNTR) CONTROL(VEH) LOU DOSE HIGH DOSE
 

02-F1U1 02-F131 02-F13U 02-F135
 

SPECIAL MORPHOLOGY SUMMAR Y
 

NO LESION REPORTED
 1 20 3
 

ANIMA L MISSING/NO NECROPSY
 1
 

NECROPSY PERF/NO HISTO PERFORMED
 1
 

AUTO/NECROPSY/NO HISTO 1
 

AUTOLYSIS/NO NECROPSY
 1 4
 

* NOMB2R OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

D-IO
 
Review of the Bioassay of 1,1,2-Trichloroethane* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup of the
 

Clearinghouse on Environmental Carcinogens
 

January 18, 1978
 

The Clearinghouse on Environmental Carcinogens was
 

established in May, 1976 under the authority of the National
 

Cancer Act of 1971 (P.L. 92-218). The purpose of the Clear­ inghouse is to advise on the National Cancer Institute's
 

bioassay program to identify and evaluate chemical carcino­ gens in the environment to which humans may be exposed. The
 

members of the Clearinghouse have been drawn from academia,
 industry, organized labor, public interest groups, State
 

health officials, and quasi-public health and research
 

organizations. Members have been selected on the basis of
 

their experience in carcinogenesis or related fields and,
 collectively, provide expertise in organic chemistry, bio­ statistics, biochemistry, toxicology, pathology, and epide­ miology. Representatives of various Governmental agencies
 

participate as ad hoc members. The Data Evaluation/Risk
 

Assessment Subgroup of the Clearinghouse is charged with
 

the responsibility of providing a peer review of NCI bioassay
 

reports on chemicals studied for carcinogenicity. In this
 

context, below is the edited excerpt from the minutes of
 

the Subgroup's meeting at which 1,1,2-Trichloroethane was
 

reviewed.
 

The primary reviewer said that he agreed with the
 

staff's conclusion that the evidence was not convincing
 

that 1,1,2-Trichloroethane was carcinogenic in the treated
 

rats, under the conditions of test. In the mice, however,
 it induced hepatocellular carcinomas and adrenal pheo­ chromocytomas. He added that the malignant nature of the
 

hepatocellular carcinomas was evident based on their cellular
 

characteristics and lung metastases. He felt that the maximum
 

tolerated dose probably was not reached in the treated rats.
 Based on the results from the mouse portion of the study,
 the primary reviewer concluded that 1,1,2-Trichloroethane
 

may pose a carcinogenic risk to humans.
 

The secondary reviewer was critical of the study in
 

that a number of other compounds, some of which are carcino­ genic, were tested at the same time and in the same room
 

as 1,1,2-Trichloroethane. However, he agreed that the results
 

in the treated mice were sufficiently significant to conclude
 

that the carcinogenic effect was induced by 1,1,2-Trichloroethane
 

47
 
It was moved that the report be accepted as written
 

and that 1,1,2-Trichloroethane be considered as posing a
 

potential carcinogenic risk to humans. The motion was
 

seconded and approved by all the Subgroup members except
 

Dr. Rowe, who abstained.
 

Members Present Were:
 

Arnold Brown (Acting Chairman), Mayo Clinic
 

Lawrence Garfinkel, American Cancer Society
 

Joseph Highland, Environmental Defense Fund
 

Charles Kensler, Arthur D. Little Company
 

Verald K. Rowe, Dow Chemical, U.S.A.
 

Sheldon Samuels, Industrial Union Department, AFL-CIO
 

Louise Strong, University of Texas Health Sciences Center
 

Sidney Wolfe, Health Research Group
 

Subsequent to this review, changes may have been made
 

in the bioassay report either as a result of the
 

review or other reasons. Thus, certain comments and
 

criticisms reflected in the review may no longer be
 

appropriate.
 

48
 

DHEW Publication No. (NIH) 78-1324