National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 55 

1978 

BIOASSAY OF 

1,2-DICHLOROETHANE 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 107-06-2 

NCI-CG-TR-55 

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

Public Health Service 

National Institutes of Health 
BIDASSAY OF
 

1,2-DICHLOROETHANE
 

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) 78-1361
 
REPORT ON THE BIOASSAY OF 1,2-DICHLOROETHANE
 

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
 

1,2-dichloroethane 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 in
 

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

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 1,2-dichloroethane was conducted by
 

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

under direct contract to the NCI and currently under a subcontract
 

to Tracer 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
 

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

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 (l), 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.	 No wit w h the Naylor Dana Institute for Disease Prevention, American Health Foundation, Hammon House Road, Valhalla, New York.
 

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

Vienna, Virginia.
 

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

Reston, Virginia.
 

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

6.	 Th MITR e E Corporation, METREK Division, 1820 Dolley Madison
 

Boulevard, McLean, Virginia.
 

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

Maryland.
 

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

Rockville, Maryland.
 

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 1,2-dichloroethane for possible
 

carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1
 

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

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

each species. The 78-week period of chemical administration was
 

followed by an observation period of 32 weeks for the low dose rats
 

of both sexes. The last high dose male rat died after 23 weeks of
 

observation and the last high dose female rat died after 15 weeks of
 

observation. All treated groups of mice were observed for an additional 12 or 13 weeks following chemical administration.
 

Initial dosage levels for the chronic bioassay were selected on
 

the basis of a preliminary subchronic toxicity test. Subsequent
 

dosage adjustments were made during the course of the chronic bioassay. The time-weighted average high and low doses of 1,2-dichloroethane in the chronic study were 95 and 47 mg/kg/day, respectively,
 

for rats of both sexes. The high and low time-weighted average doses
 

for the male mice were 195 and 97 mg/kg/day, respectively, and 299
 

and 149 mg/kg/day, respectively, for the 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 times that dosed animals were gavaged with the 1,2-dichloroethane
 

mixtures. Twenty animals of each sex were placed on test as untreated
 

controls for each species. These animals were not intubated.
 

A statistically significant positive association between dosage
 

and the incidence of squamous-cell carcinomas of the forestomach and
 

hemangiosarcomas of the circulatory system occurred in the male rats,
 

but not in the females. There was also a significantly increased incidence of adenocarcinomas of the mammary gland in female rats.
 

The incidences of mammary adenocarcinomas in female mice were
 

statistically significant. There was a statistically significant
 

positive association between chemical administration and the combined
 

incidences of endometrial stromal polyps and endometrial stromal sarcomas in female mice. The incidence of alveolar/bronchiolar adenomas
 

in both" male and female mice was also statistically significant.
 

Under the conditions of this study, 1,2-dichloroethane was carcinogenic to Osborne-Mendel rats, causing squamous-cell carcinomas of
 

the forestomach, hemangiosarcomas, and subcutaneous fibromas in male
 

vil
 
rats and causing mammary adenocarcinomas in female rats. This
 

compound was also found to be carcinogenic to B6C3F1 mice, causing
 

mammary adenocarcinomas and endometrial tumors in female mice, and
 

causing alveolar/bronchiolar adenomas in mice of both sexes.
 

vlil
 
TABLE OF CONTENTS
 

Page
 

I. INTRODUCTION 1
 

II. MATERIALS AND METHODS 5
 

A. Chemicals 5
 

B. Dosage Preparation 5
 

C. Animals 5
 

D. Animal Maintenance 6
 

E. Gastric Intubation 7
 

F. Selection of Initial Dose Levels 8
 

G. Experimental Design 9
 

H. Clinical and Histopathologic Examinations 13
 

I. Data Recording and Statistical Analyses 15
 

III. CHRONIC TESTING RESULTS: RATS 20
 

A. Body Weights and Clinical Observations 20
 

B. Survival 22
 

C. Pathology 24
 

D. Statistical Analyses of Results 27
 

IV. CHRONIC TESTING RESULTS: MICE 39
 

A. Body Weights and Clinical Observations 39
 

B. Survival 41
 

C. Pathology 42
 

D. Statistical Analyses of Results 45
 

V. DISCUSSION 58
 

VI. BIBLIOGRAPHY 61
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH 1,2-DICHLOROETHANE A-l
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH 1,2-DICHLOROETHANE B-l
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH 1,2-DICHLOROETHANE C-l
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH 1,2-DICHLOROETHANE D-l
 

ix
 
LIST OF ILLUSTRATIONS 

Figure Number Page 

1 GROWTH CURVES FOR 1,2-DICHLOROETHANE 

CHRONIC STUDY RATS 21 

2 SURVIVAL COMPARISONS OF 1,2-DICHLOROETHANE 

CHRONIC STUDY RATS 23 

3 GROWTH CURVES FOR 1,2-DICHLOROETHANE 

CHRONIC STUDY MICE 40 

4 SURVIVAL COMPARISONS OF 1,2-DICHLOROETHANE 

CHRONIC STUDY MICE 42 

LIST OF TABLES 

Table Number Page 

1 DESIGN SUMMARY FOR OSBORNE-MENDEL RATS— 

1,2-DICHLOROETHANE GAVAGE EXPERIMENT 10 

2 DESIGN SUMMARY FOR B6C3F1 MICE—I,2­

DICHLOROETHANE GAVAGE EXPERIMENT 11 

3 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

1,2-DICHLOROETHANE 28 

4 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH 1,2-DICHLOROETHANE 31 

5 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

1,2-DICHLOROETHANE 46 

6 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH 1,2-DICHLOROETHANE 49 

x 
LIST OF TABLES (Concluded) 

Table Number Page 

Al SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

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

A2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE RATS TREATED WITH 1,2-DICHLOROETHANE A-7 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

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

B2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH 1,2-DICHLOROETHANE B-6 

Cl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH 1,2­

DICHLOROETHANE C-3 

C2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH 

1,2-DICHLOROETHANE C-8 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH 1,2­

DICHLOROETHANE D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH 1,2­

DICHLOROETHANE D-7 

xi
 
I. INTRODUCTION
 

1,2-Dichloroethane (NCI No. C00511), a chlorinated aliphatic
 

hydrocarbon, is one of several halogenated solvents selected for
 

bioassay by the National Cancer Institute.
 

The Chemical Abstracts Service (CAS) Ninth Collective Index
 

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

known as ethylene chloride; ethylene dichloride; and alpha beta
 

dichloroethane.
 

Although the major use of 1,2-dichloroethane is as an intermediate in the synthesis of vinyl chloride (approximately 80 percent of
 

U.S. 1,2-dichloroethane production in 1974 [Chemical Economics Newsletter, 1975]), the compound also finds application as a constituent
 

in lead-containing antiknock preparations, as an ingredient in
 

fumigant-insecticide formulations and, to a more limited extent, as
 

a component of metal degreasing mixtures (U.S. Department of Health,
 

Education, and Welfare, 1976). 1,2-Dichloroethane is additionally
 

employed as an intermediate in the synthesis of the chlorinated
 

solvents 1,1,1-trichloroethane, trichloroethylene, and perchlorethylene (Chemical Economics Newsletter, 1975) and as a constituent of
 

rubber cements and acrylic-type adhesive formulations (U.S. Department
 

of Health, Education, and Welfare, 1976).
 

*
 

The CAS registry number is 107-06-2.
 

1 
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 of
 

the Division of Cancer Treatment, National Cancer Institute. Both
 

the Osborne-Mendel rats 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
 

dosed and control groups.
 

D. Animal Maintenance
 

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


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

relative humidity was maintained between 45 and 55 percent. The
 

air conditioning system in the laboratory provided filtered air at a
 

rate of 12 to 15 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 10 in solid-bottom polypropylene cages equipped with
 

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. Fresh
 

6 
heat-sterilized glass water bottles were provided three times a week.
 

(B)
 Food (Wayne Lab-Blox , Allied Mills, Inc., Chicago, Illinois) and
 

water were available ad libitum.
 

The rats treated with 1,2-dichloroethane and the vehicle control
 

*
 

rats were housed in the same room as other rats intubated with 1,1­

dichloroethane (75-34-3), dibromochloropropane (96-12-8), trichloroethylene (79-01-6), and carbon disulfide (75-15-0). Untreated control
 

rats were housed in a different room along with other rats intubated
 

with 1,1,2-trichloroethane (79-00-5), and tetrachloroethylene (127­

18-4).
 

All mice used in the 1,2-dichloroethane study were housed in the
 

same room as other mice intubated with 1,1,2,2-tetrachloroethane
 

(79-34-5), chloroform (67-66-3), allyl chloride (107-05-1), chloropicrin (76-06-2), dibromochloropropane (96-12-8), 1,2-dibromoethane
 

(106-93-4), 1,1-dichloroethane (75-34-3), trichloroethylene (79-01-6),
 

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

1,1,2-trichloroethane (79-00-5), tetrachloroethylene (127-18-4),
 

hexachloroethane (67-72-1), carbon disulfide (75-15-0), trichlorofluoromethane (75-69-4), and carbon tetrachloride (56-23-5).
 

E. Gastric Intubation
 

Intubation was performed for five consecutive days per week on
 

a mg/kg 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
 

CAS registry numbers are given in parentheses.
 

7
 
first 10 weeks and at monthly intervals thereafter. All animals of
 

one sex within a treated group received the same dose. Animals were
 

gavaged with the test solution 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 establish the maximum tolerated dosages of 1,2­

dichloroethane 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. 1,2-Dichloroethane
 

mixed with corn oil was introduced by gavage to five of the six rat
 

groups at dosages of 40, 63, 100, 159, and 251 mg/kg/day and to five
 

of the six mouse groups at dosages of 159, 251, 398, 631 and 1000
 

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

group, receiving only the corn oil by gavage. Intubation was performed 5 consecutive days per week for 6 weeks, followed by a 2-week
 

observation period to detect any delayed toxicity.
 

A dosage inducing no mortality and resulting in a depression in
 

mean group body weight of approximately 20 percent relative to controls was selected as the initial high dose. When weight gain criteria were not applicable, mortality data alone were utilized.
 

At 159 mg/kg/day, all the rats survived for the entire 8 weeks.
 

However, at 251 mg/kg/day three male rats and one female rat died
 

before the end of the experiment. Mean body weight depression was
 

8
 
not significant in males, except in those receiving 251 mg/kg/day.
 

At this level mean body weight depression Was 50 percent. In females,
 

mean body weight depression progressed from 10 percent at 40 mg/kg/day
 

to 17 percent at 100 mg/kg/day and 32 percent at 159 mg/kg/day. The
 

initial high dose selected for both male and female rats was 100 mg/
 

kg/day.
 

All male mice receiving doses of 159 mg/kg/day survived to the
 

end of the experiment and all females dosed with 251 mg/kg/day or
 

less survived to the end of the experiment. No males survived to
 

termination of the experiment when treated with 398 mg/kg/day, and no
 

females survived when treated with 631 mg/kg/day. Body weights for
 

the treated mice, when compared to the body weights of the control
 

mice, were greater or approximately the same for all groups except
 

the female mice receiving 398 mg/kg/day. This group experienced
 

drastic weight loss. The initial high doses selected for use in the
 

chronic study were 150 and 250 mg/kg/day for male and female mice,
 

respectively.
 

G. Experimental Design
 

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

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

are summarized in Tables 1 and 2.
 

The treated and vehicle control rats were all approximately 9
 

weeks old at the time the experiment began. The untreated controls,
 

9
 
TABLE 1
 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS
 

1,2-DICHLOROETHANE GAVAGE EXPERIMENT
 

MALE
 

UNTREATED CONTROL
 

VEHICLE CONTROL
 

LOW DOSE
 

HIGH DOSEd
 

FEMALE
 

UNTREATED CONTROL
 

VEHICLE CONTROL
 

LOW DOSE
 

HIGH DOSEd
 

p
 

TIME-WEIGHTED 

INITIAL 1,2-DICHLORO­ OBSERVATION PERIOD AVERAGE DOSAGE 

NUMBER OF E THANE TREATED UNTREATED OVER A 78-WEEK 

ANIMALS DOSAGE3 (WEEKS) (WEEKS) PERIODb 

__ 

20 —_ 106 

20 0 78 32 0 

50 50 7 47 

75 10 

50 18 

50C 34 9 

0 32 

50 100 7 95 

150 10 

100 18 

100C 34 9 

0 23 

__ 

20 106 __. 

20 0 78 32 0 

50 50 7 47 

75 10 

50 18 

50C 34 9 

0 32 

50 100 7 95 

150 10 

100 18 

iooc 34 9 

0 15 

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

days per week.
 

bm. .. . , 2(dosage X weeks received)
 Time-weighted average dosage = s—zn :
 78 weeks
 Q
 

These dosages were cyclically administered with a pattern of 1 dosage-free week
 

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

All animals in this group died before the bioassay was terminated.
 

10
 
TABLE 2
 

DESIGN SUMMARY FOR B6|c3Fl MICE
 

1,2-DICHLOROETHANE GAVAGE EXPERIMENT
 

INITIAL 1,2-DICHLORO­ OBSERVATION PERIOD 

NUMBER OF E THANE TREATED UNTREATED TIME-WEIGHTED 

ANIMALS DOSAGE3 (WEEKS) (WEEKS) AVERAGE DOSAGE 

MALE
 

UNTREATED CONTROL 20	 H—
 90
 —
 —
 

VEHICLE CONTROL 20	 0 ?8 12 0
 

LOW DOSE 50 75 8 97
 

100 70
 

0 12
 

HIGH DOSE 50 150 8 195
 

200 70
 

0 13
 

FEMALE
 

UNTREATED CONTROL 20	 91
 —	 —
 —
 

VEHICLE CONTROL 20 0 78 90 0
 

LOW DOSE 50	 125 8 149
 

200 B
 

150 67
 

0	 13
 

HIGH DOSE 50	 250 8 299
 

400 3
 

300 67
 

0	 13
 Q
 

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

days per week.
 

b .	 2(dosage X weeks received)
 Time-weighted average dosage = -r—; —* :—q • : r-,
 2;(weeks receiving chemical;
 

11
 
which did not have the same median birth date as the other three
 

groups, were included in the test from 9 weeks after the first doses
 

were administered until 14 weeks after the final observations were
 

made on the treated groups. The initial doses utilized for the first
 

7 weeks of the experiment for rats of both sexes were 100 and 50 mg/
 

kg/day. Throughout this report those rat groups receiving initial
 

dosages of 100 mg/kg/day are referred to as the high dose groups and
 

those receiving initial dosages of 50 mg/kg/day are referred to as
 

the low dose groups. The high and low doses were increased to 150
 

and 75 mg/kg/day, respectively, for the next 10 weeks and then
 

decreased again, to 100 and 50 mg/kg/day for the last 61 weeks of
 

chemical administration. In week 36, intubation ceased for all
 

treated animals for 1 week, followed by 4 weeks of dose administration. This cyclic pattern of dosage administration continued for the
 

remainder of the dosing period. The last high dose male rat died
 

during week 23 of the observation period following chemical administration and the last high dose female rat died during week 15 of the
 

observation period. Low dose and vehicle control rats were observed
 

for 32 weeks after dose administration.
 

The vehicle control and treated mice were all approximately 5
 

weeks old on the day the first dose was administered. The untreated
 

control mice had a median birth date approximately 2 weeks later than
 

the treated mice and were started on test 2 weeks after the other
 

groups and were observed a corresponding 2 weeks longer at the end
 

12
 
of the bioassay. Throughout this report those male mice receiving
 

initial dosages of 150 mg/kg/day and those female mice receiving
 

initial dosages of 250 mg/kg/day are referred to as the high dose
 

groups and those male mice receiving initial dosages of 75 mg/kg/day
 

and those female mice receiving initial dosages of 125 mg/kg/day are
 

referred to as the low dose groups. High and low dose male mice
 

received 150 and 75 mg/kg/day, respectively, of 1,2-dichloroethane
 

for the first 8 weeks of the study, and 200 and 100 mg/kg/day
 

thereafter. High and low dose females, respectively, received 250
 

and 125 mg/kg/day for the first 8 weeks, 400 and 200 mg/kg/day for
 

the next 3 weeks, and 300 and 150 mg/kg/day for the final 67 weeks of
 

dosage administration. Observation continued for 13 weeks after the
 

dosing period.
 

The untreated controls received no 1,2-dichloroethane or corn
 

oil, while the vehicle controls were intubated with pure corn oil.
 

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.
 

13
 
A necropsy was performed on each animal regardless of whether it
 

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

bioassay. The animals were euthanized by exsanguination under sodium
 

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

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

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

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

duct (mice), pancreas, esophagus, stomach, small intestine, large intestine, kidney, urinary bladder, pituitary, adrenal, thyroid, parathyroid, testis, prostate, brain, tunica vaginalis, uterus, mammary
 

gland, and ovary.
 

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
 

14
 
microscopically varies and does not necessarily represent the number
 

of animals that were placed on experiment in each group.
 

I. Data Recording and Statistical Analyses
 

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

(Linhart et al., 1974). The data elements include descriptive information on the chemicals, animals, experimental design, clinical
 

observations, survival, body weight, and individual pathologic results,
 

as recommended by the International Union Against Cancer (Berenblum,
 

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

These data were analyzed using the statistical techniques
 

described in this section. Those analyses of the experimental results
 

that bear on the possibility of carcinogenicity are discussed in the
 

statistical narrative sections.
 

Probabilities of survival were estimated by the product-limit
 

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

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

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

missing; animals dying from natural causes were not statistically
 

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

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

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

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

15
 
for all tests except the departure from linearity test, which is only
 

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

The incidence of neoplastic or nonneoplastic lesions has been
 

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

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

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

histologically. However, when macroscopic examination was required
 

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

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

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

The purpose of the statistical analyses of tumor incidence is to
 

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

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

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

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

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

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

significance level of 0.05 may be made. The Bonferroni inequality
 

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

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

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

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

16
 
The Cochran-Armitage test for linear trend in proportions, with
 

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

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

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


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

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

trend.
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation of
 

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

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

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

tumor was found, comparisons were based exclusively on animals that
 

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

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

Cochran-Armitage tests, etc.) were followed.
 

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

incidence of tumors. Curves of the proportions surviving without an
 

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

during which animals died naturally or were sacrificed was entered as
 

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

17
 
these curves were used for two groups; Tarone's extension to testing
 

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

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

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

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


tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

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

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

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

t c t
 

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

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

c
 

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

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

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

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

larger proportion in the treated group than in the control.
 

The lower and upper limits of the confidence interval of the
 

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

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

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

would be within the interval calculated from the experiment. When
 

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

18
 
can be inferred that a statistically significant result (a P < 0.025
 

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

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

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

the lower limit indicates the absence of a significant result while
 

the upper limit indicates that there is a theoretical possibility
 

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

detected under the conditions of this test.
 

19
 
III. CHRONIC TESTING RESULTS: RATS
 

A. Body Weights and Clinical Observations
 

No distinct dose-related mean body weight depression was apparent
 

in either male or female rats relative to vehicle controls (Figure 1).
 

The untreated controls, however, did weigh more than other groups
 

after the first 6 months of the study. Fluctuations in the growth
 

curves may be due to mortality; as the size of the group diminishes,
 

the mean body weight may be subject to wide variations.
 

The effect of the compound on survival was evident as early as
 

week 2, gradually increasing as the study progressed. The difference
 

in survival between low and high dose rats of both sexes became substantial after the first year (54 weeks). During the last 26 weeks
 

of the study, the decreased survival for the controls was probably
 

due to chronic respiratory and renal involvement.
 

Beginning with week 6 of the study, several rats in both treated
 

groups started to show a hunched appearance and transient labored
 

respiration. One or two control rats also began to exhibit these
 

signs but, as the study progressed, the incidence was considerably
 

greater in the treated groups than in the controls. Other signs such
 

as abdominal urine stains, cloudy or squinted eyes, or eyes with a
 

reddish crust were also observed with greater frequency in the
 

treated groups than in the controls through the first year. Thereafter, all signs were observed at comparable rates in treated and
 

20
 
FIGURE 1

 

GROWTH CURVES FOR 1,2-DICHLOROETHANE CHRONIC STUDY RATS 

21 
control rats. Respiratory signs, characterized by labored respiration, wheezing, and/or nasal discharge were observed at a low to
 

moderate incidence in all groups during the early part of the second
 

year, but were the predominant observations in all survivors at termination of the study.
 

Signs associated with aging in the group-housed laboratory rat
 

were noted with comparable frequency in treated and control rats
 

during the second year of the study. Such signs included sores on
 

the tail and other parts of the body, localized alopecia, discolored
 

or stained fur, bloated appearance, and/or swollen areas. The incidence of palpable nodules and/or tissue masses was slightly greater
 

in the treated than in the control animals. Isolated signs observed
 

intermittently in a few animals included circling or head tilt, and
 

abnormal gait. A low dose female was observed to have a broken leg
 

and subsequently died.
 

B. Survival
 

The estimated probabilities of survival for male and female rats
 

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

Figure 2.
 

For male rats the Tarone test showed a significant (P < 0.001)
 

association between increased dosage and elevated mortality. However,
 

there was a significant (P = 0.002) departure from linear trend, partially due to the sharp increase in mortality in the high dose males
 

22
 
FIGURE 2

 

SURVIVAL COMPARISONS OF 1,2-DICHLOROETHANE CHRONIC STUDY RATS 

23 
and partially because the vehicle controls had a greater mortality
 

than the low dose males during the early portion of the study.
 

For the high dose male rats survival was low, as 50 percent
 

(25/50) were dead by week 55 and 84 percent (42/50) were dead by week
 

75. Survival was higher in the other groups, as 52 percent (26/50)
 

of the rats lived at least 82 weeks in the low dose group and 50 percent (10/20) lived at least 72 weeks in the vehicle control group.
 

Despite the sacrifice of five animals in week 57, 50 percent (10/20)
 

of the untreated control group survived at least 87 weeks.
 

For female rats the Tarone test again showed a significant
 

(P < 0.001) do,se-mortality association. The departure from linear
 

trend was significant (P = 0.018), primarily because of the elevated
 

mortality in the high dose group—where 50 percent (25/50) of the
 

rats were dead by week 57 and 80 percent (40/50) were dead by week
 

75. Fifty percent (25/50) of the rats survived at least 85 weeks in
 

the low dose group and at least 88 weeks in the vehicle control
 

group. Despite the sacrifice of five females in week 57, 65 percent
 

(13/20) of the untreated control group survived until the end of the
 

study.
 

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).
 

Squamous-cell carcinomas of the forestomach occurred in 3/50
 

(6 percent) low dose males, 9/50 (18 percent) high dose males, and
 

24
 
1/49 (2 percent) low dose females. None of these tumors occurred in
 

controls. These lesions were characterized microscopically by acanthosis and hyperkeratosis in the superficial areas. The basal
 

epithelial layer contained papillary cords and nests of anaplastic
 

squamous epithelium supported by dense bands of fibrous connective
 

tissue. The carcinoma extended through the muscularis mucosa, submucosa, muscular layers, and serosa and metastasized (transcoelomic) to
 

adjacent tissues in one high dose male.
 

Hemangiosarcomas occurred in the spleen of 6/49 (12 percent) low
 

dose males, 2/49 (4 percent) high dose males, 2/50 (4 percent) low
 

dose females, and 1/50 (2 percent) high dose females. Hemangiosarcomas were diagnosed at a variety of other body sites including: the
 

liver in 1/50 (2 percent) low dose males and 1/50 (2 percent) high
 

dose females; the adrenal in 1/49 (2 percent) high dose males; the
 

pancreas in 1/50 (2 percent) low dose males, 1/48 (2 percent) high
 

dose males and 1/50 (2 percent) high dose females; the stomach in
 

2/50 (4 percent) low dose males; the large intestine in 1/48 (2 percent) low dose females; the subcutaneous tissue in 2/50 (4 percent)
 

low dose females and 1/50 (2 percent) high dose females; and the
 

abdominal cavity in 1/50 (2 percent) low dose and 1/50 (2 percent)
 

high dose males. No hemangiosarcomas were found in male or female
 

controls.
 

Microscopically, the hemangiosarcomas consisted of capillaries
 

and cavernous vascular spaces lined with hyperchromatic, plump anaplastic endothelial cells. There was piling up of these cells around
 

25
 
the vascular spaces. These cells invaded and replaced the normal
 

architecture of the spleen and other tissues involved.
 

Adenocarcinomas were observed in the mammary gland of 1/20
 

(5 percent) untreated control males, 1/20 (5 percent) vehicle control
 

males, 2/50 (4 percent) low dose males, 2/20 (10 percent) untreated
 

control females, 1/50 (2 percent) low dose females, and 18/50 (36
 

percent) high dose females. Microscopically, mammary adenocarcinomas
 

were characterized by irregular acini lined by anaplastic epithelium
 

and supported by a dense fibrous stroma. Acini were frequently lined
 

by multiple layers of epithelium, and papillary infoldings or projections were present. Larger hyperchromatic cells were present and
 

mitoses were frequent in the anaplastic adenocarcinomas. Fibroadenomas of the mammary gland occurred in 2/20 (10 percent) untreated control females, 14/50 (28 percent) low dose females, 8/50 (16 percent)
 

high dose females, and 1/20 (5 percent) untreated control males.
 

Subcutaneous fibromas were observed in 5/50 (10 percent) low
 

dose males, 6/50 (12 percent) high dose males, 1/20 (5 percent)
 

vehicle control females, 1/50 (2 percent) low dose females, and 2/50
 

(4 percent) high dose females.
 

Other unusual tumors observed include: renal tubular-cell adenocarcinomas in 1/50 (2 percent) high dose males and 1/50 (2 percent)
 

high dose females; tubular-cell adenomas in 1/50 (2 percent) high
 

dose males and 2/50 (4 percent) high dose females; a leiomyosarcoma
 

of the stomach in 1/50 (2 percent) high dose males; and an adenocarcinoma of the small intestine in 1/50 (2 percent) high dose males.
 

26
 
Other neoplasms that occurred in this study were similar in type
 

and frequency to these occurring naturally in aged Osborne-Mendel
 

rats.
 

Both acanthosis and hyperkeratosis of the forestomach occurred
 

in 1/20 (5 percent) vehicle control males, 2/50 (4 percent) low dose
 

males, 1/50 (2 percent) high dose males, 1/20 (5 percent) untreated
 

control females, 1/20 (5 percent) vehicle control females, 6/50 (12
 

percent) low dose females, and 7/50 (14 percent) high dose females.
 

Acanthosis alone occurred in 1/50 (2 percent) low dose males and
 

hyperkeratosis alone occurred in 1/50 (2 percent) high dose males.
 

Other inflammatory, degenerative, and proliferative lesions were
 

similar in the control and treated animals and consistent with lesions
 

occurring naturally in aged rats.
 

An increased incidence of the following neoplasms, observed
 

during the histopathologic examinations, provided evidence for the
 

carcinogenicity of 1,2-dichloroethane in Osborne-Mendel rats:
 

squamous-cell carcinomas of the forestomach, hemangiosarcomas of the
 

spleen and other body sites, renal tubular-cell adenomas, and renal
 

tubular-cell adenocarcinomas in rats of both sexes, adenocarcinomas
 

of the mammary gland in female rats, and subcutaneous fibromas in
 

male rats.
 

D. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

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

27
 
TABLE 3 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT 

SPECIFIC SITES IN MALE RATS TREATED WITH 1,2-DICHLOROETHANE* 

TOPOGRAPHY: MORPHOLOGY 

POOLED 

VEHICLE 

CONTROL 

MATCHED 

VEHICLE 

CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Subcutaneous Tissue: Fibroma 

P Values0 

Relative Risk (Pooled Vehicle Control) 

Lower Limit 

Upper Limit 

0/60(0.00) 

P = 0.010 

0/20(0.00) 

N.S. ___ 

5/50(0.10) 

P = 0.017* 

Infinite 

1.508 

Infinite 

6/50(0.12) 

P = 0.007* 

Infinite 

1.912 

Infinite 

Relative Risk (Matched Vehicle Control) 

Lower Limit 

Upper Limit 

Infinite 

0.525 

Infinite 

Infinite 

0.667 

Infinite 

Weeks to First Observed Tumor 75 68 

Tunica Vaginalis:

P Values0 

 Mesothelioma NOS 0/60(0.00) 

N.S. 

0/20(0.00) 

N.S. 

3/50(0.06) 

N.S. 

0/50(0.00) 

N.S. 

Departure from Linear Trend P = 0.010 P = 0.047 

Relative Risk (Pooled Vehicle Control) 

Lower Limit 

Upper Limit 

Relative Risk (Matched Vehicle Control) 

Lower Limit 

Upper Limit 

. 

___ ___ 

Infinite 

0.718 

Infinite 

Infinite 

0.250 

Infinite 

Weeks to First Observed Tumor 69 
TABLE 3 (Continued) 

POOLED MATCHED 

VEHICLE VEHICLE LOW HIGH 

TOPOGRAPHY : MORPHOLOGY CONTROL CONTROL DOSE DOSE 

Stomach: Squamous-Cell Carcinoma 0/60(0.00) 0/20(0.00) 3/50(0.06) 9/50(0.18) 

P Values0 P = 0.001 P = 0.010 N.S. P = 0.001* 

P = 0.039** 

Relative Risk (Pooled Vehicle Control) Infinite Infinite 

Lower Limit 0.718 3.139 

Upper Limit Infinite Infinite 

Relative Risk (Matched Vehicle Control) ___ Infinite Infinite 

Lower Limit 0.250 1.096 

Upper Limit Infinite Infinite 

Weeks to First Observed Tumor 77 51 

Circulatory System: Hemangio sarcoma 1/60(0.02) 0/20(0.00) 9/50(0.18) 7/50(0.14) 

P Values0 P = 0.021 N.S. P ­ 0.003* P = 0.016* 

P = 0.039** 

Relative Risk (Pooled Vehicle Control)

d ___ 10.800 8.400 

Lower Limit 1.578 1.134 

Upper Limit 462.176 370.010 

Relative Risk (Matched Vehicle Control)

d Infinite Infinite 

Lower Limit 1.096 0.809 

Upper Limit Infinite Infinite 

Weeks to First Observed Tumor 70 73 61 
TABLE 3 (Concluded) 

TOPOGRAPHY : MORPHOLOGY 

POOLED 

VEHICLE 

CONTROL 

MATCHED 

VEHICLE 

CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Pituitary: Chromophobe Adenoma 3/60(Oi05) 2/20(0.10) 1/50(0.02) 4/49(0.08) 

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

Relative Risk (Pooled Vehicle Control) 

Lower Limit 

Upper Limit 

0.400 

0.008 

4.786 

1.633 

0.289 

10.646 

Relative Risk (Matched Vehicle

Lower Limit 

Upper Limit 

 Control) 0.200 

0.004 

3.682 

0.816 

0.131 

8.603 

Weeks to First Observed Tumor 84 108 95 37 

Treated groups received time-weighted average doses of 47 or 95 mg/kg by gavage.
 

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

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

the 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
 

pooled vehicle control group (*) or the matched 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.
 
___ 

TABLE 4
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

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

TOPOGRAPHY : MORPHOLOGY 

Pituitary: Chromophobe Adenoma 

P Values 

Relative Risk (Pooled Vehicle Control) 

Lower Limit 

Upper Limit 

Relative Risk (Matched Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Thyroid: Follicular-Cell Adenoma 

P Values0 

Departure from Linear Trend 

Relative Risk (Pooled Vehicle Control) 

Lower Limit 

Upper Limit 

Relative Risk (Matched Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

POOLED 

VEHICLE 

CONTROL 

13/59(0.22) 

N.S. 

68 

0/58(0.00) 

N.S. 

P = 0.011 

MATCHED 

VEHICLE 

CONTROL 

7/20(0.35) 

P = 0.017(N) 

90 

0/20(0.00) 

N.S. 

P = 0.047 

LOW 

DOSE 

7/50(0.14) 

N.S. 

0.635 

0.232 

1.569 

0.400 

0.144 

1.187 

53 

3/50(0.06) 

N.S. 

Infinite 

0.695 

Infinite 

Infinite 

0.250 

Infinite 

84 

HIGH 

DOSE 

5/49(0.10) 

P = 0.020**(N) 

0.463 

0.138 

1.275 

0.292 

0.087 

0.953 

50 

0/50(0.00) 

N.S. 
TABLE 4 (Continued) 

TOPOGRAPHY : MORPHOLOGY
 

Mammary Gland: Adenocarcinoma NOS
 

P Values0
 

e
 

Departure from Linear Trend
 

Relative Risk (Pooled Vehicle Control)
 

Lower Limit.
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Fibroadenoma
 

P Values0
 

Departure from Linear Trerid
 

Relative Risk (Pooled Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

POOLED
 

VEHICLE
 

CONTROL
 

1/59(0.02)
 

P < 0.001
 

P = 0.003
 

102
 

5/59(0.08)
 

N.S.
 

P = 0.014
 

97
 

MATCHED
 

VEHICLE
 

CONTROL
 

0/20(0.00)
 

P < 0.001
 

P = 0.021
 

0/20(0.00)
 

N.S.
 

P = 0.008
 

_—
 

LOW
 

DOSE
 

1/50(0.02)
 

N.S.
 

1.180
 

0.015
 

90.792
 

Infinite
 

0.022
 

Infinite
 

74
 

14/50(0.28)
 

P = 0.007*
 

P = 0.005**
 

3.304
 

1.218
 

10.874
 

Infinite
 

1.819
 

Infinite
 

77
 

HIGH
 

DOSE
 

18/50(0.36)
 

P < 0.001*
 

P = 0.002**
 

21.240
 

3.573
 

857.928
 

Infinite
 

2.400
 

Infinite
 

20
 

8/50(0.16)
 

N.S.
 

1.888
 

0.582
 

6.874
 

Infinite
 

0.952
 

Infinite
 

54
 
TABLE 4 (Continued) 

POOLED MATCHED 

VEHICLE VEHICLE LOW HIGH 

TOPOGRAPHY : MORPHOLOGY CONTROL CONTROL DOSE DOSE 

Mammary Gland: Adenocarcinoma NOS or 

Fibroadenomab 6/59(0.10) 0/20(0.00) 15/50(0.30) 24/50(0.48) 

P Values0 P < 0.001 P < 0.001 P = 0.009* P < 0.001* 

P = 0.003** P < 0.001** ___ 

Relative Risk (Pooled Vehicle Control)d _— 2.950 4.720 

Lower Limit 1.178 2.082 

Upper Limit 8.538 12.691 ___ ___ 

Relative Risk (Matched Vehicle Control) Infinite Infinite 

Lower Limit 1.965 3.279 

Upper Limit Infinite Infinite 

Weeks to First Observed Tumor 97 74 20 

Circulatory System: Hemangiosarcoma 0/59(0.00) 0/20(0.00) 4/50(0.08) 4/50(0.08) 

P Values0 P = 0.042 N.S. P = 0.041* P = 0.041* ___ ___ Relative Risk (Pooled Vehicle Control) Infinite Infinite 

Lower Limit 1.089 1.089 

Upper Limit Infinite Infinite ___ ___ Relative Risk (Matched Vehicle Control) Infinite Infinite 

Lower Limit 0.386 0.386 

Upper Limit Infinite Infinite 

Weeks to First Observed Tumor 93 65 
TABLE 4 (Concluded) 

o
 

Treated groups received time-weighted average doses of 47 or 95 mg/kg by gavage.
 

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

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

the 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
 

pooled vehicle control group (*) or the matched 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.
 

e
 

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

group when P < 0.05.
 
every type of malignant tumor in either sex where at least two such
 

tumors were observed in at least one of the control or 1,2-dichloroethane-dosed groups and where such tumors were observed in at least
 

5 percent of that group.
 

Two types of control groups were used for statistical analyses:
 

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

vehicle control group) and a pooled vehicle control group which combined the vehicle controls from the studies of 1,2-dichloroethane,
 

1,1,2-trichloroethane, and trichloroethylene. The pooled control rats
 

were of the same strain, were housed in the same room, were tested
 

concurrently for at least one year, and were diagnosed by the same
 

pathologists. The untreated control group was not used for analyses
 

of tumor incidence because the test conditions of the vehicle controls
 

more closely resembled those of the treated groups.
 

For male rats the Cochran-Armitage test indicated a significant
 

(P = 0.010) positive association between dosage and the incidence of
 

fibromas of the subcutaneous tissue when the dosed groups were compared to the pooled control group. The Fisher exact test confirmed
 

this result in comparing both low dose (P = 0.017) and high dose
 

(P = 0.007) rats to the pooled control. In historical data compiled
 

by Hazleton Laboratories for the NCI Bioassay Program, 2/200 (1 percent) of the vehicle control male Osborne-Mendel rats had this tumor.
 

Based upon these results the administration of 1,2-dichloroethane to
 

male Osborne-Mendel rats under the conditions of this experiment was
 

35
 
associated with an increased incidence of fibromas of the subcutaneous
 

tissue.
 

For male rats the Cochran-Armitage test also indicated a significant positive association between dosage and the incidence of squamouscell carcinomas of the stomach whether comparing to the pooled vehicle
 

control (P < 0.001) or the matched vehicle control (P = 0.010). The
 

Fisher exact test confirmed these results by a significant (P = 0.001)
 

comparison of the high dose to the pooled vehicle control group; the
 

comparison of high dose to matched vehicle control was not significant
 

under the Bonferroni criterion. This tumor was not observed in any of
 

the 200 historical vehicle control male Osborne-Mendel rats. Based
 

upon these results the administration of 1,2-dichloroethane to male
 

rats was associated with an increased incidence of squamous-cell
 

carcinomas of the stomach under the conditions of this experiment.
 

For the male rats the Cochran-Armitage test indicated a significant (P = 0.021) positive association between dosage and the incidence
 

of hemangiosarcomas when comparing dosed groups to the pooled vehicle
 

control group. In comparisons of both the high dose and low dose
 

groups to the pooled control group, the Fisher exact test confirmed
 

these results (P = 0.016 and P = 0.003, respectively); for the comparison of low dose to matched vehicle control the results were not
 

significant under the Bonferroni criterion. In the historical
 

controls 3/200 (1.5 percent) of the vehicle control males had a
 

hemangiosarcoma. Based upon these results the administration of
 

36
 
1,2-dichloroethane to male Osborne-Mendel rats was associated with an
 

increased incidence of hemangiosarcomas under the conditions of this
 

experiment.
 

In female rats, adenocarcinomas of the mammary gland were
 

observed at necropsy as early as week 20 in the high dose group. The
 

Cochran-Armitage test detected a significant (P < 0.001) positive
 

association between dosage and the incidence of mammary adenocarcinomas in comparing dosed groups to either control. For both comparisons
 

the departure from linear trend was significant due to the elevated
 

incidence in the high dose group. The Fisher exact tests were significant in comparing the high dose group to either the matched vehicle control (P < 0.001) or the pooled vehicle control (P = 0.002)
 

group. Historically, this tumor was observed in 4/200 (2 percent)
 

of the vehicle control females.
 

Fibroadenomas of the mammary gland were also noted, especially
 

in the low dose female rats. The Fisher exact test was significant
 

in comparing the low dose group to either the matched vehicle control
 

(P = 0.005) group or the pooled vehicle control (P = 0.007) group.
 

The incidence in the high dose group, however, was not significantly
 

different, from that of the control groups. Historically this tumor
 

was observed in 39/200 (20 percent) of the vehicle controls, but in
 

this bioassay it occurred in 5/59 (8 percent) of the pooled vehicle
 

control females and in none of the 20 matched vehicle control females.
 

When female rats with either an adenocarcinoma or a fibroadenoma
 

were considered, test results were uniformly significant: The
 

37
 
Cochran-Armitage test was significant (P < 0.001) compared to either
 

control group. The Fisher exact test was significant (P < 0.001) in
 

comparing either dosed group to either of the control groups.
 

Based upon these results the administration of 1,2-dichloroethane
 

to female Osborne-Mendel rats was associated with an increased incidence of mammary adenocarcinomas under the conditions of this test.
 

For female rats the Cochran-Armitage test indicated a significant (P = 0.042) positive association between dosage and the incidence
 

of hemangiosarcomas when comparing treated groups to the pooled
 

vehicle control group. In comparisons of both the high dose and low
 

dose groups to the pooled control group, however, the Fisher exact
 

test provided P = 0.041, a result that is not significant under the
 

Bonferroni criterion.
 

The possibility of a negative association between chemical
 

administration and the incidence of pituitary chromophobe adenomas
 

was noted for the female rats. It may be, however, that this result
 

reflected the poor survival in dosed females.
 

In summary, there were statistically significant incidences of
 

fibromas of the subcutaneous tissue, of squamous-cell carcinomas of
 

the stomach, and of hemangiosarcomas in male rats and statistically
 

significant incidences of mammary adenocarcinomas in female rats.
 

38
 
IV.	 CHRONIC TESTING RESULTS: MICE
 

A.	 Body Weights and Clinical Observations
 

No distinct, dose-related mean body weight depression was observed in male mice or low dose female mice (Figure 3). Mean body
 

weight depression for high dose female mice was apparent as early as
 

week 15. Fluctuations in the growth curves may be due to mortality;
 

as the size of the group diminishes, the mean body weight may be
 

subject to wide variations.
 

Throughout the study the appearance and behavior in the treated
 

mice was generally comparable with that in the control mice, although
 

decreased survival of treated mice was evident during the second year.
 

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

alopecia were the predominant signs observed in all groups as early
 

as week 6. These signs were particularly apparent in the males and
 

persisted in all groups throughout the study. Other clinical signs,
 

often associated with aging and group-housed laboratory mice, observed at a comparable frequency in all groups during the second year
 

included a hunched appearance, anal, penile, or vulvar irritation
 

(occasionally with prolapse), rough or stained fur, reddish or brown
 

crust around eyes, and abdominal distension or bloating. Palpable
 

nodules and/or tissue masses and swelling around the abdominal
 

midline were observed with slightly greater frequency in the treated
 

groups than in the controls.
 

39
 
FIGURE 3

 

GROWTH CURVES FOR 1,2-DICHLOROETHANE CHRONIC STUDY MICE 

w 
B.	 Survival
 

The estimated probabilities of survival for male and female mice
 

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

Figure 4.
 

For male mice there was no statistically significant association
 

between dosage and mortality. In the high dose group 50 percent (25/
 

50) of the mice survived at least 84 weeks and 42 percent (21/50)
 

survived until the end of the study. In the vehicle control group 55
 

percent (11/20) survived until the end of the study. In the other
 

two groups, however, survival was low: 52 percent (26/50) of the low
 

dose and 55 percent (11/20) of the untreated control groups survived
 

less than 74 weeks.
 

For female mice the Tarone test showed a significant (P < 0.001)
 

positive association between increased dosage and elevated mortality.
 

The departure from linear trend was significant (P < 0.001) because
 

of the severe mortality in the high dose group, where 72 percent
 

(36/50) of the animals died between weeks 60 and 80; these deaths may
 

have been tumor-related as 25/36 (69 percent) had one or more tumors.
 

Survival was high in the other groups as 68 percent (34/50) of the
 

low dose, 80 percent (16/20) of the vehicle control, and 80 percent
 

(16/20) of the untreated control groups survived until the end of the
 

study.
 

41
 
FIGURE 4

 

SURVIVAL COMPARISONS OF 1,2-DICHLOROETHANE CHRONIC STUDY MICE 

42 
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).
 

Hepatocellular carcinomas occurred in 2/17 (12 percent) untreated
 

control males, 1/19 (5 percent) vehicle control males, 6/47 (13
 

percent) low dose males, 12/48 (25 percent) high dose males, 0/19
 

untreated control females, 1/20 (5 percent) vehicle control females,
 

0/50 low dose females, and 1/47 (2 percent) high dose females.
 

Microscopically, the hepatocellular carcinomas varied greatly in
 

appearance. Some lesions contained well-differentiated hepatocytes
 

with a relatively uniform arrangement of the cords, whereas others
 

consisted of anaplastic cells with mitotic figures, 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 hepatic cells and occasionally pseudoacinar formation. Some of the tumors were characterized by discrete
 

areas of highly anaplastic cells. The hepatic neoplasms occurring in
 

the control mice were not different in morphology from those noted
 

in the treated mice.
 

Squamous-cell carcinomas of the forestomach occurred in 1/19
 

(5 percent) vehicle control males, 1/46 (2 percent) low dose males,
 

2/46 (4 percent) high dose males, 1/20 (5 percent) vehicle control
 

females, 2/50 (4 percent) low dose females, and 5/48 (10 percent)
 

43
 
high dose females. The microscopic appearance of the squamous-cell
 

carcinomas of the stomach in the mice was comparable to that described for the rats.
 

Uterine adenocarcinomas occurred in 3/49 (6 percent) low dose
 

and 4/47 (9 percent) high dose female mice but in no controls.
 

Microscopically, thickening of the endometrium and invasion of the
 

anaplastic, hyperchromatic glandular epithelial cells into the myometrium were observed. The anaplastic cells formed irregular acini,
 

cords, and sheets of cells supported by strands of fibrous connective
 

tissue. Squamous metaplasia and mitotic figures were also seen.
 

Endometrial stromal sarcomas of the uterus occurred in 2/49
 

(4 percent) low dose and 3/47 (6 percent) high dose females but in
 

no controls. Microscopically, the endometrial stromal sarcomas
 

consisted of spindled to ovoid cells, some of which were anaplastic
 

with hyperchromatic nuclei and scanty cytoplasm and invaded nearby
 

tissue and organs. Endometrial stromal polyps were found in 3/49 (6
 

percent) low dose females and 2/47 (4 percent) high dose females but
 

in no controls.
 

Mammary gland adenocarcinomas were present in 9/50 (18 percent)
 

low dose females and 7/48 (15 percent) high dose females.
 

Hemangiosarcomas occurred in the spleen of 1/48 (2 percent) high
 

dose males and 1/50 (2 percent) low dose females and in the mesenteric
 

lymph node of 1/47 (2 percent) high dose males.
 

44
 
Alveolar/bronchiolar adenomas were present in none of the
 

untreated or vehicle control males, 1/47 (2 percent) low dose males,
 

15/48 (31 percent) high dose males, 1/19 (5 percent) untreated control females, 1/20 (5 percent) vehicle control females, 7/50 (14
 

percent) low dose females, and 15/48 (31 percent) high dose females.
 

An alveolar/bronchiolar carcinoma occurred only in 1/48 (2 percent)
 

high dose females.
 

Other neoplasms that occurred were not considered unusual for
 

aged B6C3F1 mice.
 

The inflammatory, degenerative, and proliferative lesions
 

observed were similar in the control and treated animals.
 

An increased incidence of the following neoplasms, observed
 

during the histopathologic examinations, provided evidence for the
 

carcinogenicity of 1,2-dichloroethane in B6C3F1 mice: mammary adenocarcinomas, uterine adenocarcinomas, endometrial stromal neoplasms of
 

the uterus, and squamous-cell carcinomas of the forestomach in
 

females; and alveolar/bronchiolar adenomas in males and females.
 

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 1,2­

dichloroethane-dosed groups of either sex is included.
 

Two types of control groups were used for statistical analyses:
 

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

45
 
TABLE 5
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

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

TOPOGRAPHY: MORPHOLOGY
 

Subcutaneous Tissue: Fibrosarcoma
 

P Values0
 

Relative Risk (Pooled Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Lung: Alveolar/Bronchiolar Adenoma
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Pooled Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

POOLED
 

VEHICLE
 

CONTROL
 

1/59(0.02)
 

N.S.
 

90
 

0/59(0.00)
 

P < 0.001
 

P = 0.011
 

MATCHED 

VEHICLE LOW HIGH 

CONTROL DOSE DOSE 

0/19(0.00) 0/47(0.00) 4/48(0.08) 

P = 0.041 N.S. N.S. 

0'. 000 4.917 

0.000 0.507 

23.389 236.738 

Infinite 

0.383 

Infinite 

65 

0/19(0.00) 1/47(0.02) 15/48(0.31) 

P < 0.001 N.S. P < 0.001* 

P = 0.003** 

P = 0.046 

Infinite Infinite 

0.067 5.766 

Infinite Infinite 

Infinite Infinite 

0.022 1.952 

Infinite Infinite 

83 81 
TABLE 5 (Continued) 

POOLED 

TOPOGRAPHY: MORPHOLOGY 

VEHICLE 

CONTROL 

Hematopoietic System:

Lymphoma" 

 Malignant 

4/59(0.07) 

P Values0 N.S. 

Relative Risk (Pooled Vehicle Control) 

Lower Limit 

Upper Limit 

Relative Risk (Matched Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 66 

Liver: Hepatocellular Carcinoma 4/59(0.07) 

P Values0 P = 0.006 

Relative Risk (Pooled Vehicle Control) 

Lower Limit 

Upper Limit 

Relative Risk (Matched Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 72 

MATCHED 

VEHICLE 

CONTROL 

2/19(0.10) 

N.S. 

90 

1/19(0.05) 

P = 0.025 

90 

LOW 

DOSE 

8/47(0.17) 

N.S. 

2.511 

0.718 

10.711 

1.617 

0.370 

14.802 

64 

6/47(0.13) 

N.S. 

1.883 

0.474 

8.556 

2.426 

0.331 

108.995 

72 

HIGH 

DOSE 

5/48(0.10) 

N.S. 

1.536 

0.349 

7.324 

0.990 

0.184 

9.880 

61 

12/48(0.25) 

P = 0.009* 

3.688 

1.204 

14.672 

4.750 

0.800 

197.680 

58 
TABLE 5 (Concluded) 

TOPOGRAPHY : MORPHOLOGY 

POOLED 

VEHICLE 

CONTROL 

MATCHED 

VEHICLE 

CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Stomach: Squamous-Cell Carcinoma 

P Values0 

1/59(0.02) 

N.S . 

1/19(0.05) 

N.S. 

1/46(0.02) 

N.S. 

2/46(0.04) 

N.S. 

Relative Risk (Pooled Vehicle

Lower Limit 

Upper Limit 

 Control) 1.283 

0.017 

98.529 

2.565 

0.137 

147.995 

Relative Risk (Matched Vehicle

Lower Limit 

Upper Limit 

 Control) 0.413 

0.006 

31. 749 

0.826 

0.047 

47.694 

Weeks to First Observed Tumor 82 90 77 

Treated groups received time-weighted average doses of 97 or 195 mg/kg by gavage.
 

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

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
 

pooled vehicle control group (*) or the matched 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.
 

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 1,2-DICHLOROETHANE' 

TOPOGRAPHY: MORPHOLOGY
 

Lung: Alveolar /Bronchidlar Adenoma
 

P Values0
 

Relative Risk (Pooled Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Malignant
 

Lymphoma'3
 

P Values
 

Departure from Linear Trend
 

Relative Risk (Pooled Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

POOLED
 

VEHICLE
 

CONTROL
 

2/60(0.03)
 

P < 0.001
 

90
 

8/60(0.13)
 

N.S.
 

P = 0.048
 

—_
 

56
 

MATCHED
 

VEHICLE
 

CONTROL
 

1/20(0.05)
 

P = 0.005
 

90
 

4/20(0.20)
 

P = 0.024(N)
 

——
 

56
 

LOW
 

DOSE
 

7/50(0.14)
 

P = 0.046*
 

4.200
 

0.844
 

39.891
 

2.800
 

0.403
 

123.408
 

91
 

10/50(0.20)
 

N.S.
 

1.500
 

0.577
 

4.029
 

1.000
 

0.339
 

3.981
 

70
 

HIGH
 

DOSE
 

15/48(0.31)
 

P < 0.001*
 

P = 0.016**
 

9.375
 

2.336
 

80.509
 

6.250
 

1.093
 

255.479
 

62
 

2/48(0.04)
 

N.S.
 

0.313
 

0.033
 

1.473
 

0.208
 

0.021
 

1.349
 

68
 
TABLE 6 (Continued) 

TOPOGRAPHY : MORPHOLOGY
 

Stomach: Squamous-Cell Carcinoma
 

P Values0
 

Relative Risk (Pooled Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Adenocarcinoma NOS
 

P Values0
 

Departure from Linear Trend6
 

Relative Risk (Pooled Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VEHICLE
 

CONTROL
 

1/60(0.02)
 

P = 0.035
 

90
 

0/60(0.00)
 

P = 0.007
 

P = 0.037
 _
 

VEHICLE
 

CONTROL
 

1/20(0.05)
 

N.S.
 

90
 

0/20(0.00)
 

N.S.
 

LOW
 

DOSE
 

2/50(0.04)
 

N.S.
 

2.400
 

0.129
 

138.746
 

0.800
 

0.045
 

46.273
 

82
 

9/50(0.18)
 

P = 0.001*
 

P = 0.039**
 

Infinite
 

3.139
 

Infinite
 

Infinite
 

1.096
 

Infinite
 

88
 

HIGH
 

DOSE
 

5/48(0.10)
 

N.S.
 

6.250
 

0.732
 

288.916
 

2.083
 

0.259
 

96.358
 

36
 

7/48(0.15)
 

P = 0.003*
 

Infinite
 

2.416
 

Infinite
 

Infinite
 

0.843
 

Infinite
 

63
 

POOLED
 MATCHED
 
TABLE 6 (Continued)
 

POOLED 

VEHICLE 

TOPOGRAPHY : MORPHOLOGY CONTROL 

Endometrium/Uterus : Adenocarcinoma NOS 1/60(0.02) 

P Values0 N.S. 

Relative Risk (Pooled Vehicle Control) 

Lower Limit 

Upper Limit 

Relative Risk (Matched Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 90 

Uterus: Endome trial Stromal Polyp 0/60(0.00) 

P Values0 N.S. 

Relative Risk (Pooled Vehicle Control) 

Lower Limit 

Upper Limit 

Relative Risk (Matched Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

MATCHED 

VEHICLE 

CONTROL 

0/20(0.00) 

N.S. 

0/20(0.00) 

N.S. 

LOW 

DOSE 

3/49(0.06) 

N.S. 

3.673 

0.305 

188.787 

Infinite 

0.255 

Infinite 

91 

3/49(0.06) 

N.S. 

Infinite 

0.733 

Infinite 

Infinite 

0.255 

Infinite 

91 

HIGH 

DOSE 

4/47(0.09) 

N.S. 

5.106 

0.527 

245.743 

Infinite 

0.410 

Infinite 

57 

2/47(0.04) 

N.S. 

Infinite 

0..376 

Infinite 

Infinite 

0.130 

Infinite 

63 
___ 

___ 

___ 

TABLE 6 (Continued) 

POOLED 

VEHICLE 

TOPOGRAPHY: MORPHOLOGY CONTROL 

Uterus: Endometrial Stromal Sarcoma 0/60(0.00) 

P Values0 N.S. 

_ Relative Risk (Pooled Vehicle Control) 

Lower Limit 

Upper Limit 

Relative Risk (Matched Vehicle Control)

d 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor —— 

Uterus: Endometrial Stromal Polyp or 

Endometrial Stromal Sarcoma"3 0/60(0.00) 

P Values0 P - 0.017 

Relative Risk (Pooled Vehicle Control) 

Lower Limit 

Upper Limit 

Relative Risk (Matched Vehicle Control) —_ 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

MATCHED 

VEHICLE 

CONTROL 

0/20(0.00) 

N.S. 

—— 

0/20(0.00) 

N.S. 

_— 

LOW 

DOSE 

2/49(0.04) 

N.S. 

Infinite 

0..360 

Infinite 

Infinite 

0.125 

Infinite 

81 

5/49(0.10) 

P = 0.016* 

Infinite 

1.538 

Infinite 

Infinite 

0.536 

Infinite 

81 

HIGH 

DOSE 

3/47(0.06) 

N.S. 

Infinite 

0.765 

Infinite 

Infinite 

0.266 

Infinite 

71 

5/47(0.11) 

P = 0.014* 

Infinite 

1.603 

Infinite 

Infinite 

0.559 

Infinite 

63 
TABLE 6 (Concluded)
 

Treated groups received time-weighted average doses of 149 or 299 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
 

pooled vehicle control group (*) or the matched 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.
 
vehicle control group) and a pooled vehicle control group, combining
 

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

trichloroethane, and trichloroethylene. The pooled control mice
 

were of the same strain, were housed in the same room, were tested
 

concurrently for at least one year, and were diagnosed by the same
 

pathologists. The untreated control group was not used for the
 

analyses of tumor incidence because the test conditions of the vehicle control more nearly approximated those of the dosed mice.
 

A significant number of hepatocellular carcinomas were observed
 

in male mice. The Cochran-Armitage test indicated a positive dose-


response association when comparing to either the matched (P = 0.025)
 

or the pooled (P = 0.006) controls. The Fisher exact test supported
 

this finding with a significant (P = 0.009) comparison of the high dose
 

to the pooled control group. In historical vehicle control data collected by Hazleton Laboratories for the NCI Bioassay Program, 19/180
 

(11 percent) of the B6C3F1 male mice had a hepatocellular carcinoma
 

and 20/180 (11 percent) had either a hepatocellular carcinoma, a hepatocellular adenoma, or a neoplastic nodule. Based upon these results
 

the administration of 1,2-dichloroethane at the dose levels of this
 

study was associated with the increased incidence of hepatocellular
 

carcinomas in male B6C3F1 mice.
 

A large number of alveolar/bronchiolar adenomas were found in
 

both male and female high dose mice. For both sexes the Cochran-


Armitage test showed a significant (P < 0.005) positive dose-response
 

54
 
association when the dosed groups were compared to either control
 

group. For males the departure from linear trend was significant,
 

primarily because of the elevated incidence in the high dose group.
 

For both males and females the Fisher exact test indicated that the
 

high dose group had a significantly (P _<_ 0.016) higher incidence rate
 

than either of the controls. For female mice the Fisher exact test
 

comparing the low dose group to the pooled control group was not significant under the Bonferroni criterion. In the historical vehicle
 

controls, 6/180 (3 percent) of the male and 5/180 (3 percent) of the
 

female B6C3F1 mice had this tumor. Based upon these results the
 

administration of 1,2-dichloroethane was associated with the increased
 

incidence of alveolar/bronchiolar adenomas in both male and female
 

mice under the conditions of this study.
 

In female mice the Cochran-Armitage test also indicated a significant (P = 0.007) positive association between dosage and the
 

incidence of adenocarcinomas of the mammary gland when compared to
 

the pooled control. The departure from linear trend was significant
 

(P = 0.037), partially because the incidence was higher in the low
 

dose than in the high dose group. The Fisher exact test confirmed
 

these results with significant (P _£ 0.003) comparisons of both high
 

dose and low dose groups to the pooled vehicle control group. The
 

comparison of low dose to matched vehicle control was not significant
 

under the Bonferroni criterion. In the historical vehicle controls,
 

none of the 180 females had this tumor.
 

55
 
To investigate endometrial tumors in females the proportion of
 

mice with either an endometrial stromal polyp or an endometrial
 

stromal sarcoma was considered. The Cochran-Armitage test indicated
 

a significant (P = 0.017) positive association between dosage and
 

the combined incidence. The Fisher exact tests confirmed these results in comparing either the high dose (P = 0.014) or the low dose
 

(P = 0.016) groups to the pooled vehicle control group. In the
 

historical controls none of the 180 mice had this tumor.
 

Based upon these results the administration of 1,2-dichloroethane
 

was associated with an increased incidence of mammary adenocarcinomas
 

and of endometrial tumors in female B6C3F1 mice under the conditions
 

of this experiment.
 

For male mice the Cochran-Armitage test indicated a significant
 

positive association between dosage and the incidence of fibrosarcomas
 

of the subcutaneous tissue when comparing to the matched control (P =
 

0.041). The Fisher exact tests, however, were not significant.
 

For female mice the Cochran-Armitage test indicated a significant
 

(P = 0.035) positive association between dosage and the incidence of
 

squamous-cell carcinomas of the forestomach when comparing the dosed
 

groups to the pooled vehicle control. The Fisher exact tests, however, were not significant. Additionally, a time-adjusted analysis,
 

based upon those female mice which survived at least 36 weeks (the
 

time of the first observed squamous-cell carcinoma), indicated similar
 

findings. In the historical vehicle controls maintained by this
 

56
 
laboratory for the NCI Bioassay Program, only 1/180 female B6C3F1
 

mice had these neoplasms. Under the assumption, of a binominal distribution with a spontaneous incidence rate of 1/180, the probability of
 

observing 5 or more tumors out of 48 mice (as in the high dose group)
 

was P < 0.00001, a significant result. The probability of observing
 

1 or more tumors out of 20 mice (as in the matched vehicle control)
 

was P = 0.105, which was not a significant result.
 

For female mice the Cochran-Armitage test indicated a significant
 

negative association between dosage and the incidence of malignant
 

lymphomas. The Fisher exact tests, however, were not significant.
 

In summary, there were statistically significant incidences of
 

hepatocellular carcinomas and of alveolar/bronchiolar adenomas in male
 

mice and significant incidences of alveolar/bronchiolar adenomas, of
 

mammary adenocarcinomas, of endometrial stromal polyps, and of squamouscell carcinomas in female mice.
 

57
 
V. DISCUSSION
 

Under the conditions of this bioassay there was a statistically
 

significant association between increased dosage and elevated mortality in both male and female rats and in female mice. During the
 

second year of the study mortality rates in the male mice were higher
 

for low dose and untreated control than for high dose mice. Despite
 

this accelerated mortality, positive associations were established
 

between 1,2-dichloroethane administration and the incidences of
 

several neoplasms.
 

In rats squamous-cell carcinomas of the forestomach occurred in
 

3/50 (6 percent) low dose males, 9/50 (18 percent) high dose males,
 

and 1/49 (2 percent) low dose females, but in no high dose females or
 

male or female controls. Statistical analyses of these incidences
 

revealed a significant positive association between dosage and tumor
 

incidence in males but not in females.
 

Hemangiosarcomas occurred at a variety of body sites in all
 

groups of treated rats. Statistical tests indicated a significant
 

positive association between dosage and the incidence of hemangiosarcomas in male rats but not in females.
 

Adenocarcinomas of the mammary gland were observed in 0/20 vehicle
 

control, 1/50 (2 percent) low dose, and 18/50 (36 percent) high dose
 

female rats. These incidences provided significant positive associations between dosage and incidence. In addition, these malignant
 

tumors were observed in female mice and the reported incidences (9/50
 

58
 
[18 percent] low dose, 7/48 [15 percent] high dose, none in controls)
 

were also statistically significant.
 

In mice hepatocellular carcinomas occurred at incidences (i.e.,
 

2/17 [12 percent] untreated control males, 1/19 [5 percent] vehicle
 

control males, 6/47 [13 percent] low dose males, 12/48 [25 percent]
 

high dose males, 1/20 [5 percent] vehicle control females, and 1/47
 

[2 percent] high dose females) that indicated a statistically significant positive dose-related association in males but not in females.
 

Due to high incidence variability of hepatocellular neoplasms in historical control male mice, this statistical result is not considered
 

to be convincing evidence that these tumors are attributable to
 

administration of the chemical.
 

The increased incidence of endometrial stromal polyps in dosed
 

female mice was not statistically significant. The same was true for
 

endometrial stromal sarcomas in female mice. However, when the
 

incidences of female mice having either of these endometrial tumors
 

were evaluated, a significant positive association between chemical
 

administration and tumor incidence was demonstrated.
 

Alveolar/bronchiolar adenomas in mice were observed in no control males, 1/47 (2 percent) low dose males, 15/48 (31 percent) high
 

dose males, 1/19 (5 percent) untreated control females, 1/20 (5 percent) vehicle control females, 7/50 (14 percent) low dose females,
 

and 15/48 (31 percent) high dose females. The statistical association between chemical administration and the development of alveolar/
 

bronchiolar adenomas was significantly positive for both sexes.
 

59
 
Under the conditions of this study, 1,2-dichloroethane is carcinogenic to Osborne-Mendel rats, causing squamous-cell carcinomas of
 

the stomach, hemangiosarcomas and subcutaneous fibromas in male rats
 

and causing mammary adenocarcinomas in female rats. This compound
 

was also found to be carcinogenic to B6C3F1 mice, causing mammary
 

adenocarcinomas and endometrial tumors in female mice, and alveolar/
 

bronchiolar adenomas in mice of both sexes.
 

60
 
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.
 

Chemical Economics Newsletter, "Ethylene Bichloride Report Abstract."
 

Chemical Information Services, Stanford Research Institute.
 

Menlo Park, California. November-Becember 1975.
 

Cox, B.R., Analysis of Binary Bata, Chapters 4 and 5. Methuen and
 

Co., Ltd., London, 1970.
 

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

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

Ehrenberg, L., S. Osterman-Golkar and B. Singh, "On the Reaction
 

Kinetics and Mutagenic Activity of Methylating and -halogenoethylating Gasoline Additives." Radiation Botany 15:185-194,
 

1974.
 

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

Tests, Confidence Limits, and Adjustments for Stratification."
 

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

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

Observations." Journal of the American Statistical Association
 

_53_:457-481, 1958"!
 

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

"Carcinogenesis Bioassay Bata System." Computers and Biomedical
 

Research 7:230-248, 1974.
 

McCann, J., V. Simmon, B. Streitwieser and B.N. Ames, "Mutagenicity
 

of Chloroacetaldehyde, a Possible Metabolic Product of 1,2­

Bichloroethane (Ethylene Bichloride), Chloroethanol (Ethylene
 

Chlorohydrin), Vinyl Chloride, and Cyclophosphamide." Proceedings of the National Academy of Sciences, U.S.A. 72:3190-3193,
 

1975.
 

61
 
Miller, R.G., Simultaneous Statistical Inference. McGraw-Hill Book
 

Co., New York, 1966.
 

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.
 

Sykes, J.F., and A.K. Klein, "Chloro-organic Residues in Milk of Cows
 

Orally Administered Ethylene Bichloride." Journal of the
 

Association of Official Agricultural Chemists 40:203-209, 1957.
 

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

62_: 679-682, 1975.
 

U.S.	 Department of Health, Education, and Welfare, Criteria for a
 

Recomended Standard...Occupational Exposure to Ethylene Dichloride. Public Health Service, Center for Disease Control,
 

National Institute for Occupational Safety and Health. DHEW
 

Publication No. (NIOSH) 76-139, 1976.
 

U.S.	 Department of Health, Education, and Welfare, National Occupational Hazard Survey, Volume III. Public Health Service, Center
 

for Disease Control, National Institute for Occupational Safety
 

and Health. DHEW Publication No. (NIOSH) 78-114, 1977.
 

U.S.	 International Trade Commission, Synthetic Organic Chemicals.
 

United States Production and Sales, 1974. USITC Publication 776,
 

Washington, D.C., 1976.
 

62
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH 1,2-DICHLOROETHANE
 
TABLE Al

 

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

CONTRO L (UNT8 ) CONTRO L (VEH) L OW DOSE HIG H DOS E 

01-031M 01-071M 01-072M 01-073M 

ANIMAL S INITIALL Y I N STUDY 20

 20 50 50

 

ANIMAL S NECROPSI3D 20

 20

 50 50

 

ANIMAL S EXAMINE D HI STOPAPHOLOGICAL L Y** 20 20

 50

 50 

INTEGUMENTAR Y SYSTEM 

*SUEi;UT TISSU E (20 ) (20) (50) (50) 

FIBROMA 5 (10%) 6 O2X) FIBEOSARCOM A

 1 (5%) 1 (2X ) 

RESPIEATOR Y SYSTEM 

NON E 

HEMATOPOIETIC SYSTEM 

*MUiriPLE ORGAN S (20 ) (20) (50) (50) LYMPHOCYTI C LEUKEMI A

 1 (5X)

 

ISPLEE N (20 ) (20) (t9) (19) S.JUAMOUS CELI CARCIN3MA , METASTA 1 (2X) LEIOMYOSARCOMA , METASTATI C 1 (2% ) HEHANGIOSAECOM A 6 (12*) 2 (1%) HEMANGIOSARCOMA , METASTATI C 1 (2X ) 

ITHYUUS (13) (12) (10) (24) SJUAMOU S CELL CARCINOM A

 1 (3% ) 

CIRCULATOR Y SYSTE M 

NON E 

DIGESTIV E SYSTE M 

#SALIVA8 Y GLAN D (1» ) (10) (32) (9) 

CAHCINOMA.NOS __ .. l.USL 

# NUMBE R DP ANIMAL S KIT H TISSU E EXAMINE D MICROSCOPICALL Y 

* NUMBE R OF ANIMAL S NECROPSIE D 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

A-3 
TABLE Al (CONTINUED) 

CONTRO L (UNTR ) CONTRO L (VEH ) L C W DOSE HIG H DOSE 

01-031 M 01-071M 01-072M 01-073 M 

• LIV E P. (20 ) (20 ) (50) (50) 

5J.UAMJU S CELL CARCINOMA , HETAST A 1 (2% ) 

NEOPLASTT C NODUL E 1 (2« ) 

HEPATOOELLULA R CARCINOM A 1 (2X ) 

HEMAN3IOSAECOM A 1 (2% ) 

•PANCREA S (20) (20) (50) (18) 

SJ.IJAMOU S CEL L CARCINOMA , METAST A 1 (2% ) 

LEIOMYOSARCO H A, META5TATI C 1 (2% ) 

HEMANGIOSARCOM A 1 (2% ) 1 (2% ) 

•STOMAC H (20 ) (20 ) (50) (50 ) 

SjUAMOII S CEL L CARCINOM A 3 (6X ) 9 (18% ) 

LEIOMY1SARCO M A 1 (2% ) 

HEMANGIOSAPCON A 2 (14%) 

•SMAL L INTESTIN F (20 ) (20 ) (50) (50) 

ADENOCARCINCSA , NO S 1 (2X ) 

PIBROSARCO m 1 (5%) 

UPINAR Y SYSTF M 

•KIDNE Y (20 ) (20 ) (50) (50) 

TOBOLAR-CFL L ADENOH A 1 (2% ) 

TUBULAR-CEL L ADENO C A3 CI NO N A 1 (2% ) 

LIPOB A 1 (2« ) 

MIXE D TUMOR , MALIGNAN T 1 (2% ) 

HAMARTOM A + 1 (2%) 2 (14%) 

ENDOCBIN E SYSTE M 

tPITUITAR Y (20 ) (20 ) (50) (K9 ) 

CHBOMOPHOB E ADENOM A 2 (10% ) 2 (10% ) 1 (2% ) U (8% ) 

•ADRENA L (20 ) (20 ) (50 ) («9) CORTICA L ADENOM A 1 (2X ) 

CORTICA L CARCINOM A 2 (10% ) 

HEMANjIOSAKCOMA , METASTATI C 1 (2« ) 

•THYROI D (19 ) (20 ) (50) (50) 

FOLLICQLAR-CEL L ADENOM A 2 (t% ) 1 (2% ) 

FOLLICULAR-CEL L CARCINOM A 1 (5%) 

•PANCREATI C ISLETS (20 ) (20 ) (50) (18) 

_I3LET-CEL L ADENOM A 1-J55I 1 J2%1 _ . 

» NUMBE R OF ANIMAL S WIT H TISSU E EXAMINE D MICROSCOPICALL Y 

* NUMBE R O F ANIMAL S NECROPSIE D 

+ 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. 

A-4 
TABLE Al (CONTINUED) 

CONTRO L (UNTB ) 

01-031M 

CONTRO L (VEH ) 

01-071M 

L C W DOSE 

01-072H 

HIGH DOSE 

01-073 M 

HFPRODUCTIV E SYSTE M 

*MANHAR Y GLAN D 

ADENOCARCINOMA ,

FIBROADENOM A 

 NO S 

(20 ) 

1

1

 (5X) 

 (5%) 

(20 ) 

1 (5X) 

(50) 

2 (i»X ) 

(50) 

NERVOU S SYSTE M 

NON E 

SPECIA L SENS E ORGAN S 

NON E 

BOSCULOSKELrTA L

NON E 

 SYSTE M 

BODY CAVITIE S 

*ABDOMINA L CAVIT Y 

HEMANGIOSARCOM A 

*TUNIC A VAGINALI S 

MESOTHELIOHA, NOS 

(20 ) 

(20 ) 

(20 ) 

(20) 

(50) 

1

(50) 

3

 (2%) 

 (6%) 

(50) 

1

(50) 

 (2% ) 

A L L OTHE R SYSTEM S 

*MULriPL E ORGAN S 

ADENOCAPCINCMA ,

HEMANGIOSARCON A 

 NOS , NETASTATi : 

(20 ) (20 ) (50) ("50) 

1

3

 (2% ) 

 (6% ) 

ANIMA L DISPOSITIO N SUMMAR Y 

ANIMAL S INITIALL Y I N STUD Y 

NATURA L DEATH S 

MORIBUN D SACRIFICE 

SCHEDULE D SACRIFICE 

ACCIDENTALL Y KILLE D 

TERMINA L SACRIFICE 

ANIMA L HISSIN G 

20 

11 

5 

it 

20 

16 

it 

50 

US 

1 

1 

50 

50 

a INCLUDES AUJ.OLYZE D ANIMAL S 

# NUMBE R OF ANIMAL S WITH TISSUE

* NUMBE R O F ANIMAL S NECRDPSIE D 

 EXAMINE D MICROSCOPICALLY 

A-5 
TABLE Al (CONCLUDED) 

:ONTHOL(UNTR ) 

01-031M 

CONTRO L (VEH ) 

01-071M 

L OW DOSE 

01-072 M 

HIG H DOSE 

01-073M 

TUMOP. SUMMAR Y 

TOTA L ANIMAL S WIT H PRIMAR Y TUMORS * 

T3TAL PPIHAR Y TUMOS S 

5 

11 

U 

a 20 

31 

20 

39 

TOTA L ANIMAL S WIT H BENIG N TUMOR S 

T3TA L BFNIG N TUMOR S 

2 

3 

3 

3 

7 

10 

10 

17 

TOTAL ANIMAL S WIT H MALIGNAN T

TOTA L MALIGNAN T TUMOR S 

 TUMOE S 6 

8 

1 

1 

15 

18 

16 

21 

TOTAL ANIMAL S WIT H SECONDAR Y

TOTAL SECONDAR Y TUMOR S 

 TUMORS * 1 

1 

4 

7 

TOTAL ANIMAL S WITH TUMDR S UNCERTAIN ­

BENIG N O R MALIGNAN T 

TOTAL UNCERTAI N TUMOR S 

3 

3 

1 

1 

TOTA L ANIMAL S WIT H TUMOR S UNCERTAIN ­

PRIMAR Y O R MFTASTATIC 

TOTA L UNCERTAI N TUMOR S 

* PRIMAR Y TUMORS: ALL TUMORS EXCEPT SECONDARY TUBORS
 

# SECONDARY TUMORS: METASTATIC TUMORS 3R TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

A-6
 
TABLE A2

 

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

CONTROL(UNTH) 

01-031F 

CONTROL (VEH) 

01-071P 

LOW DOSE 

01-07tF 

HIGH DOSE 

01-075F 

ANIMALS

ANIMALS

ANIMALS

 INITIALLY IN STUDY
 20 

 NECROPSIED
 20 

 EXAMINED HISTOPATHOLOSIC ALLY**
 20 

20 

20 

20 

50 

50 

50 

50 

50 

50 

INTEGUMENTARY SYSTEM
 

*SUBCtJT TISSU2
 

FIBROMA
 

FIBROSARCOMA
 

HSMANSIOSARCOMA
 

HEMANGIOPERICYTOMA. DOS
 

(20) (20) 

1 (5*) 

(50) 

1

2

 (2*)<-

 (»%) 

(50) 

2 (1%) 

2 (4%) 

1 (2X) 

1 <2X) 

RESPIRATORY SYSTEM
 

fLUNG
 

ADENOCARCINOMA, NOS, METASTATIC
 

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

2 (KB) 

HEMATOPOIETIC SYSTEM
 

fSPLEEN
 

HEMANGIOSARCOBA
 

(20) (20) (50) 

2 («) 

(50) 

1 (2X) 

CI8COLATORY SYSTEM
 

tHEART
 

MIXED TUMOR, METASTATIC
 

(20) 

1 (5*) 

(20) (50) (50) 

DIGESTIVE SYSTEM
 

• SALIVARY GLAN D
 

SQUAMOUS CELL CARCINOMA
 (15) (15) (30) 

1 (3%) 

(7) 

tLIVES
 

HEPAIOCELLaLAR CARCINOMA
 

HEMANGIOSARCOMA
 

(20) 

1 (5%) 

(20) (50) 

2 («X) 

(50) 

1 (2S) 

tPANCREAS
 

HEMANGIOSARCOMA
 

(20) (19) (50) 

._

(50) - 1 12*1 _. 

I NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OE ANIMALS NECROPSIED
 

<- MULTIPLE OCCURRENCE OF MORPHOLOGY IN THE SAME ORGAN TISSUES IS COUNTED ONCE ONLY
 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS
 

A-7
 
TABLE A2 (CONTINUED) 

CONTRO L (UNTR ) 

01-031F 

CONTRO L (VEH ) 

01-071P 

LC« DOSE 

01-07UF 

HIG H DOSE 

01-075F 

• STOMAC H 

SguAMOU S CELL CARCINOM A 

(20 ) (20 ) (49) 

1 (2% ) 

(50) 

*LARGE INTESTINE 

HEMANGIOSAECOH A 

(19) (20) (U8) 

1 (2% ) 

(50) 

URINAR Y SYSTE M 

*KIDNF Y 

TUBULAR-CEL L ADENOM A 

TUBULAR-CEL L ADENOCA S CINO N A 

MIXE D TUMOR , MALIGNAN T 

HAFARTOM A + 

(20 ) 

1 (5%) 

2 (10% ) 

(20) (50) (50) 

2 (4% ) 

1 (2% ) 

1 (2% ) 

ENDOCRIN E SYSTF M 

•PITUITAR Y 

CHROBOPHOB E ADENOM A 

(19 ) 

6 (32%) 

(20 ) 

7 (35%) 

(50) 

7 (1UJS ) 

(19)

5 (10% )

•ADRENA L 

CORTICA L CARCINOM A 

(20 ) (20 ) (50) 

1 (2% ) 

(50) 

1 (2% ) 

#THYHOI D 

FOLLICULAH-CELL ADENOM A 

C-CEL L ADENOM A 

C-C5LL CARCINOM A 

(20 ) 

2 (10%) 

2 (10% ) 

(20 ) (50) 

3 (6%) 

(50) 

•PANCREATI C ISLETS 

ISLET-CEI L ADENOM A 

(20 ) 

1 (5%) 

(19) (50) (50) 

REPRODUCTIV E SYSTE M 

*MAMMAR Y 3LAN D 

ADENOCARCINOMA ,

"IBROADE N ~>B A 

 SOS 

(23 ) 

2 (10%) 

2 (10%) 

(20 ) (50) 

1 (2%) 

1U (28%) 

(50) 

18 (36%) 

8 (16% ) 

• UTERU S 

ENDOMETRIA L STROMA L POLY P 

HEBANGIOM A 

(20 ) 

1 (5%) 

(20 ) (U8 ) 

2 (14%) 

(U9 ) 

1 (2% ) 

tOVAH Y 

CYSTADENOCARCINOMAj . NO S 

(20 ) 

1_15$L 

(20 ) (47)

 (U7 ) 

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

* NUBBF 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. 

A-8 

 OF PROLIFERATIVE 
CONTRO L (UNTR ) 

01-031F 

CONTRO L (VEH ) 

01-071F 

L C W DOSE 

01-074F 

HIG H DOSE 

01-075F 

GHANULOSA-CEL L TDMO H 1 (5X) 1 (2% ) 

KEBVOU S SYSTE M 

NON E 

SPECIA L SENS E ORGAN S 

NON E 

MUSCULOSKELETA L SYSTE M 

NON E 

BODY CAVITIE S 

NON E 

A L L OTHE R SYSTEM S 

NON E 

ANIMA L DISPOSITIO N SUMMAR Y 

ANIMAL S INITIALL Y I N STUD Y 

NATURA L DEATH S 

MORIBUN D SACRIFICE 

SCHEDULE D SACRIFIC E 

ACCIDENTALL Y KILLE D 

TERMINA L SACRIFICE 

ANIMA L MISSIN G 

20 

2 

5 

13 

2 o

12 

fi

50 

«5 

U

1 

SO 

U7 

3 

i> INCLUDE S AUTOLYZED_ANI«AL S 

* NUMBE R O F ANIMAL S WIT H TISSU E

* NUMBE R O F ANIMAL S NECROPSIE D 

TABLE A2 (CONTINUED) 

 EXAMINE D MICPOSCOPIC A LIY 

A-9 
TABLE A2 (CONCLUDED) 

CONTRO L (UNTR ) 

01-031F 

CONTRO L (VEH ) 

01-071F 

L CW DOSE 

01-071F 

HIGH DOSE 

01-075F 

TUMO R SUMMAR Y 

TOTA L ANIMAL S WIT H PRIMAR Y

TOTA L PRIMAR Y TUMOR S 

 TUMORS * 11 

21 

7 

9 

21 

39 

33 

17 

TOTA L ANIMAL S WIT H BENIG N

TOTA L BPNIG N TUMOR S 

 TUMOR S 12 

I D 

7 

f) 

20 

28 

18 

19 

TOTA L ANIMAL S WIT H MALIGNAN T

TOTA L MALIGNAN T TUMOR S TUMOR S 6 

7 

8 

11 

25 

26 

TOTA L ANIMAL S WIT H SECONDAR Y

TOTAL SECONDAR Y TUMOR S 

 TUMORS * 1 

1 

2 

2 

TOTAL ANIMAL S WIT H TUMDR S

BENIG N O R MALIGNAN T 

TOTAL UNCERTAI N TUMOR S 

 UNCERTAIN ­ 1 

1 

2 

2 

TOTA L ANIMAL S WIT H TUMOB S

PRIBAR Y O R MTTASTATI C 

TOTAL UNCERTAI N TUMORS 

 UNCF8TAIN ­

* PRIMAR Y TUMORS: ALL TUMORS EXCEPT SECONDARY TUMOPS
 

* SECONDARY TUMOPS: METASTATIC TUMORS OR TUMORS INVASIV E INTO AN ADJACENT ORGAN
 

A-IO
 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH 1,2-DICHLOROETHANE
 
TABLE Bl

 

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

CONTROL (UNTE) 

02-M081 

CONTRO L (VEH ) 

02-M071 

L OW DOSE 

02-M072 

HIG H DOSE 

02-M073 

ANIMALS INITIALLY IN STUDY 20 20 

ANIMAL S NECROPSIE D 18 19 

ANIMALS EXAMINE D HI STOPATHOLOGICALL Y ** 17 19 

50 

U7 

«6 

50 

18 

1(7 

INTEGUMENTAR Y SYSTEM 

*SKIN 

SJUAMOUS CELL

FIBEOSARCOM A 

 CARCINOM A 

(18 ) 

1 (6X) 

(19) (17) 

1 (2*) 

(18) 

*SUBCOr TISSU E 

FIBROSARCOM A 

(18) (19) (17) (18) 

l| (8% ) 

RESPIRATOR Y SYSTEM 

*LUNG 

HEPATOCELLULA R CARCINOMA , METAST 

ALVEOLAR/BRONCHIOLAR ADENOM A 

(17) (19) («7) 

1

1

 (2%) 

 (2«) 

(18)

1 

15 

(2%) 

(31%) 

HEMATOPOIETIC SYSTEM 

*MULIIPLE ORGAN S 

MALIG.LYMPHOMA ,

MALIG.LYMPHOHA ,

 LYBPHOCYTIC

 HISTIOCYTIC

 TYPE 

 TYPE 

(18) (19) 

1 (5«) 

(17) 

1 (•)%) 

(18) 

H (8X) 

(SPLEEN 

HEMANGIOSARCOM A 

(17 ) (18) (17) (18) 

1 (2% ) 

#MESENTERI C L. NODE 

HEMANGIOSARCOH A 

MALIG.LYMPHOMA , HISTIOCYTIC TYPE 

(17) (19) (16) 

2 (1*) 

(17) 

1 

1 

(2%) 

(2%) 

tRENA L LYMP H NODE 

SQUAMOU S CELL CARCINOMA , METASTA 

(") (19) 

1 (5%) 

(16) (17) 

tKIDNEY 

MALIG.LYMPHOMA , LYMPHOCYTIC TYPE 

MALIG.LYMPHOMA , HISTIOCYTIC TYPE 

(17) (18) 

1 (6X) 

(17) 

2

(18) 

 (IS1 

CIRCULATOR Y SYSTEM 

H2HE 

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

* NUMBE R OF ANIMAL S NECROPSIE D 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-3 
TABLE Bl (CONTINUED) 

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

02-MQ81 02-M071 02-M072 02-M073 

DIGESTIV E SYSTE M 

ILIVER 

HEPATOCELLULAR CARCINOMA 

(17) 

2 (12*) 

(19) 

1 (5*) 

(t7) 

6 (13X) 

(U8) 

12 (25X) 

• STOMACH 

SaUAMOU S CELL CARCINOM A 

(17) (19) 

1 (5*) 

(U6) 

1 (2*) 

(U6) 

2 (UX ) 

URINAR Y SYSTEM 

NONE 

ENDOCRINE SYSTEM 

NONE 

REPRODUCTIV E SYSTEM 

NONE 

NERVOU S SYSTEM 

NONE 

SPECIAL SENSE ORGAN S 

NONE 

MUSCULOSKELETA L SYSTEM 

NONE 

BODY CAVITIES 

NON E 

ALL OTHER SYSTEMS 

. NON.E 

* NUMBER OF M1IMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECR3PSIED 

B-4 
TABLE Bl (CONCLUDED)
 

CONTROL (UNTF ) 

02-M081 

CONTROL (VEH) 

02-M071 

L CW DOSE 

02-M072 

HIGH DOS

02-M073

ANIMA L DISPOSITION SUMMAR Y 

ANIMALS INITIALLY IN STUDY 20 

NATURA L DEATHS 12 

MORIBUN D SACRIFICE 1

 

SCHEDULE D SACRIFICE 

ACCIDENTALL Y KILLE D 

TERMINA L SACRIFICE 7 

ANIMAL MISSING 

20 

9 

11 

50 

39 

11 

50 

29 

21 

8 INCLUDES AUTOLYZE D ANIMAL S 

TUMOR SUMMAR Y 

TOTAL ANIMAL S WITH PRIMAR Y

TOTA L PRIMAR Y TUMORS 

 TUMORS* 2 

3 

U 

!( 

15 

17 

28 

H O 

TOTAL ANIMAL S WITH BENIG N

TOTAL BENIGK TUMORS 

 TUMOR S 1 

1 

15 

15 

TOTAL ANIMAL S WITH MALIGNAN T

TOTAL MALIGNAN T TUMOR S 

 TDMORS 2 

3 

It 

H 

15 

16 

22 

25 

TOTAL ANIMAL S WITH SECONDARY TUMORS* 

TOTAL SECONDAR Y TUMOR S 

1 

1 

1 

1 

1 

1 

TOTAL ANIMAL S WITH TUM3R S UNCERTAIN ­

BENIG N O R MALIGNAN T 

TOTAL UNCERTAI N TUMOR S 

TOTA L ANIMAL S WIT H TUMOR S ONCERTAIK ­

PRIMAR Y O R METASTATi: 

TOTA L UNCERTAI N TUMOR S 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SEIONDARY TUMORS
 

E 

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

B-5 
TABLE B2

 

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

CONTHOL(UNTR ) CONTROL (VEH ) L O U DOSE HIGH DOSE 

02-E081 02-F071 02­F07U 02­P075 

ANIMAL S INITIALL Y I N STUD Y 20 20 50 50 

ANIMAL S NECROPSIE D 19 20 50 48 

ANIMAL S EXAMINE D HI STOPATHOLOGICAL L Y ** 19 20 50 U8 

INTEGUMENTAR Y SYSTEM 

*SUBCUT TISSU E (19 ) (20) (50) ("8) 

SQUAMOU S CELL CARCINOM A 1 <2X) 1 (2%) 

ADEMOMA , NO S 1 (2% ) 

OSTEOSABCOM A 1 (2% ) 

RESPIRATORY SYSTEM 

*LUN G (19 ) (20 ) (50) (1*8) 

ADENOCARCINOMA , NOS , METASTATI C 3 (6%) 1 <2X ) 

ALVEOLAR/ERONCHIOLA R ADENOM A 1 (5%) 1 (5%) 7 (1U% ) 15 (31%) 

ALVEOLAR/EHONCHIOLA R CARCINOM A 1 (2%) 

05TEOSARCOMA , METASTATI C 1 (2*) 

HEMATOPOISTIC SYSTE M 

•MULTIPL E ORGAN S (19 ) (20) (50) ("8) 

MALIG.LYMPHOMA , LYMPHOCYTI C TYP E 2 (11% ) 2 (10%) 

MALIG.LYMPHO M A , HISTIOCYTI C TYP E 1 (5%) 2 (10X) 8 (16% ) 1 (2% ) 

*SPLEE N (19) (20) (50) (16) 

SJUAMOU S CELL CARCINOMA , METAST A 1 (2*) 

ADENOCABCINOMA , NOS, METASTATI C 1 (2% ) 

ENOOMETBIA L STROMA L SARCOMA , ME T 1 (2X ) 

HEMANGIOSARCOM A 1 (2%) 

MALIS . LYMPHOMA , HISTIOCYTIC TYP E 1 (2% ) 1 (2% ) 

tMESENTERI C L. NODE (19 ) (20 ) (50) (39) 

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

tRENA L LYMP H NOD E (19 ) (20) (50) (39) 

MALIG.LYMPHOMA , HISTIOCYTIC TYPE 1 (2*) 

CIRCULATOR Y SYSTE M 

NON E _ _ _ _ 

# NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R O F ANIMAL S NECHOPSIE D 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-6
 
TABLE B2 (CONTINUED) 

---z~-~-----I-: 

CONTRO L (UNTR ) CONTRO L (VEH ) L CD DOSE HIGH DOSE 

02-F081 02-F071 02-F074 02-F075 

DIGESTIV E SYSTE M 

iLIVER (19) (20 ) (50)

 (47) 

HEPATOCELLULA R CARCINOM A 1 (5*) 1 (2*) 

tPANCREA S (19) (20) (50)

 (149) 

SQUAMOU S CELL CARCINOMA , METAST A 1

 (2%) 

ADENOCARCINOMA , NOS, METASTATIC 1 (2X ) 

ENDOMETPIA L STROMAL SARCOMA , ME T 1 <2X ) 

tESOPHAGU S (19) (20) (50)

 (46)

 

SeBAHOn S CELL CARCINOMA , METAST A 1 (2X)

 

#STOMACH (19) (20 ) (50) (4B) 

SQOAMOU S CELL CARCINOM A 1 (5%) 2 («*) 5 (10% ) 

tSMAL L INTESTIN E (19) (20) (50) (46 )

 

SQUABOUS CELL CARCINOMA , METASTA 2 (1%) 

•LARG E INTESTIN E (19 ) (19) (50)

 (147) 

S2UAMOU S CELL CARCINOMA , METAST A 2

 (U« ) 

ENDOMETRIA L ST80MAL SARCOMA , MET 2 (4X ) 

tCOLON (19) (19) (50)

 (U7 )

 

ADENOCARCINCMA , NO S 1 <2X )

 

URINABI T SYSTE M 

(KIDNE Y (19 ) (20) (50)

 (47) 

TUBULAR-CEL L ADENOCARCINOM A 1 (2*) 

ENDOMETEIAL STROMAL SARCOMA, MET 1 (2*) 

#URINAR Y BLADDER (19) (19) (19)

 (45) 

ENDOMETRIA L STROMA L SARCOMA , ME T 1 (2X ) 

ENDOCRIN E SYSTE M 

*ADRENA L (19 ) (20) (50)

 (47 ) 

ENDOMETRIA I STKOMA L SARCOMA , ME T 1 (2*) 

REPRODUCTIV E SYSTEM 

*MAMMAR Y GLAN D (19 ) (20) (50)

 (48) 

ADENOCARCINOMA i NOS ._ 9 J[1S*1. _ _ __7

 11 s XL 

t NUMBE R O F ANIMAL S KIT H TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBE R OF ANIMAL S NECROPSIE D 

B-7 
TABLE B2 (CONTINUED) 

CONTROL (UNTR ) CONTROL (VEH ) L CD DOSE HIGH DOSE 

02-F081 02-F071 02-F07U 02-F075 

*VAGINA (19) (20) (50) C»8) ADENOCARCINOMA , NOS , METASTATIC 1 (2«) 

tUTEBU S (19) (20) (19) (147) 

ADENOCARCINOflA . NO S 3 (6*) U (9*) 

ENDOMBTRIA L STRONAL POLY P 3 (6«) 2 (US) 

EKDOMETHI M STROMA L SARCOH A 2 («*) 3 (6«) 

*OVA8 Y (19 ) (20) (U9) (It 6) 

ADENOCARCINOMA , NOS, METASTATIC 1 (2*) GRASULOSA-CEL L TUHO R 1 (2*) 1 (2%) ENDOMETRI M STRONAL SARCOMA , MET 1 (2% ) 

NERVOU S SYSTE M 

NON E 

SPECIAL SENSE ORGAN S 

*HAPDERIA N GLA8 D (19 ) (20 ) (50) (148) ADESOMA, NOS 1 (2%)

 

MUSCHLOSKELETA L SYSTEM 

NONE 

BODY CAVITIE S 

NONE 

A L L OTHE R SYSTEM S 

_ U2HE __ 

* NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* N01BER OF ANIMAL S NECROPSIE D 

B-8 
TABLE B2 (CONCLUDED)
 

CONTROL (UNTR ) 

02-F081 

CONTROL (VEH ) 

02-F071 

L CW DOSE 02-F07U HIG H DOSE 

02-F07 5 

ANIMA L DISPOSITION SUMMAR Y 

ANIMAL S INITIAL!,! IN STUDY 20 

NATURA L DEATH S 3 

MORIBUN D SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALL Y KILLE D 1

 

TERMINAL SACRIFICE 16 

ANIMA L MISSIN G 

20 

t 

16 

50 

15 

1 

31 

50 

«9 

1 

8 INCLUDES AUTOLYZE D ANIMAL S 

TUMOR SUMMAR Y 

TOTAL ANIMAL S WIT H PRIMAR Y TUMORS * 

TOTAL PRIMAR Y TUMORS 

it 

(I 6 

7 

33 

43 29

 

U 3 

TOTAL ANIMAL S WIT H BENIG N TUMOR S 

TOTA L BENIG N TONORS 

1 

1 1 1 

12 

12 16

 

17 

TOTAL ANIMAL S WIT H MALIGNAN T TUMOR S 

TOTA L MALIGNAN T TUMORS 

3 

3 

5 

6 

26 

30 

21 

25 

TOTAL ANIMAL S WIT H SECONDAR Y TUMORS * 

TOTAL SECONDARY TUMORS 

6 

13 

6 

13 

TOTAL ANIMAL S WITH TUMOR S UNCERTAIN ­ BENIG N O R MALIGNAN T 

TOTAL UNCERTAI N TUMOR S 

1 

1 

1 

1 

TOTA L ANIMAL S WITH TUMOR S UNCERTAIN ­

PRIMAR Y OR METASTATIC

 

TOTA L UNCERTAI N TUMOR S 

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

B-9
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH 1,2-DICHLOROETHANE
 
TABLE Cl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

TREATED WITH 1,2-DICHLOROETHANE 

CONTRO L (DNTR) 

01-031M 

CONTRO L (VEH ) 

01-071M 

L OW DOSE 

01-072B 

HIGH DOSE 

01-073M 

ANIMAL S

ANIMAL S

ANIMAL S

 INITIALL Y I N STUDY 

 NECBOPSIE D 

 EXAMINE D HI STOPATHOLOGICAL L 1 ** 

20 

20 

20 

20 

20 

20 

50 

50 

50 

50 

50 

50 

INTEGUMENTAR Y SYSTEM 

*SKIN 

INFLAMMATION , NO S 

(20) 

1 (5%) 

(20 ) (50) (50) 

1 (2X ) 

*SUB;UT TISSU E ABSCESS, NOS (20 ) (20) 

2 (10%) 

(50) 

1 (2*) 

(50) 

1 (2X ) 

RESPIRATOR Y SYSTE M 

•TRACHE A 

INFLAMMATION , NO S 

(15) (20) (50) 

1 (2*) 

(50) 

*LUNG/BRONCHU S 

ABSCESS , NOS 

(20 ) (20) (50) 

1 (2% ) 

(50) 

tLUN G 

PNEUMONIA , CHRONI C MJRIN E 

CALCIU M DEPOSIT 

(20 ) 

16 (SOX ) 

1 (5X) 

(20) 

15 (75X) 

(50) 

U7 (9HX ) 

(50) 

30 (60X) 

HEMATOPOIETIC SYSTEM 

*BONE MARRO W 

METAMORPHOSI S FATT Y 

(3) (20 ) (US) 

1 (2X ) 

(«8) 

3 (6X ) 

iSPLEEN 

HEMORRHAG E 

HEMATOPOIESI S 

(20) 

1 <5X ) 

(20) 

1 (5%) 

(19) 

5 (10X ) 

(49) 

1 (2X ) 

2 (HX ) 

KCERVICA L LYMP H NOD E 

INFLAMMATION , NO S 

(19) 

1 (5%) 

(16) (50) 

1 <2X ) 

(ltd) 

tTRACHEA L LYMP H

ANGIECTASI S 

 NODE (19) (16) (50) 

1 J2X) («t) 

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

* NUMBE R O F ANIMAL S NECROPSIE D 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

C-3 
TABLECl (CONTINUED) 

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

01-031M 01-071M 01-072M 01-073M 

IMESENTERIC L. NODE (19) (16)

 (50) (KU ) 

ANGIECTASI S 1 (2X) 

KTHYMU S (13) (12)

 (10) <2« ) 

ANGIECTASI S 1 (»*) 

CIRCULATOR Y SYSTEM 

#HEAH T (20 ) (20)

 (50) (50) 

THROMBUS , ORGANIZE D 4 (8X) 

CALCIU B DEPOSIT 1 (5X)

 1 (2«) 

•MYOCARDIUM (20) (20)

 (50) (50) 

INFLAMMATION , NOS 2 (10%) 

FIBROSIS 1 (2X) 

DEGENERATION , NOS 1 (5X)

 3 (6X) 2 (»*) 

#ENDOCARDIDH (20) (20) (50) (50) 

HYPERPLASIA . NOS 1 (5X)

 

*AORT A (20) (20) (50) (50) 

HEDIA L CALCIFICATI3N 2 (10»)

 1 (2X) 1 (2X ) 

*MESENTERIC ARTER Y (20 ) (20)

 (50) (50) 

MEDIA L CALCIFICATI3N 1 (5X)

 

DIGESTIVE SYSTE M 

*LIVER (20) (20) (50) (50) 

CYST, NOS 1 <2X ) 

THROHBUS, ORGANIZED 1 (2X) 

INFLAMMATION , NOS 1 .(5*1 1 (2X) 1 (2X) 

PERIARTERITI S 1 (2X) 

METAMORPHOSI S FATTY 2 (10X) 2 (10X) 6 (12*) 

ANGIECTASI S 3 (15X) 2 (»*) 4 (8X) 

*BILE DUCT (20) (20) (50) (50) 

HIPERPLASIA, NOS 1 (20%) 1 (5%)

 1 (2*) 1 <2X ) 

•PANCREA S (23) (20)

 (50) (18) 

PERIARTERITI S 1 (20% ) 1 (5*)

 1 <2X ) 

•ESOPHAGUS (15) (20) (50) (50)

 

- _IfiCl.MfliTIQlU fiOS 1 I2S1 , 

# NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECR3PSIED
 

C-4
 
CONTRO L (DNTR ) CONTRO L (VEH)i LOW DOSE HIG H DOSE 

01-031M 01-071M 01-072M 01-073M 

• STOMAC H (23 ) (20 ) (50) (50) 

INFLAMMATION , NOS 1 (2% ) 

ULCER, FOCAL 3 (6%) 3 (6%) 

CALCIU M DEPOSIT 2 (10% ) 1 (5%) 1 (2% ) 1 (2% ) 

HYPERKERATOSI S 1 (5%) 2 (4%) 2 (U% ) 

ACANTHOSI S 1 (5%) 3 (6%) 1 (2% ) 

•COLON (19 ) (20) (50) (47) 

NEMATODIASI S 1 (5%)

 

URINAR Y SYSTE M 

*KIDNF Y (20 ) (20) (50) (50) 

HYDRONEPHROSI S 1 (2% ) 

CYST, NO S 1 (2% ) 

PYELONEPHRITIS , NO S 1 (5%) 3 (6«) 2 (4% ) 

INFLAMMATION , CHRONI C 15 (75%) 6 (30%) 29 (58%) 8 (16% ) 

CALCIUM DEPOSIT 1 (5%) 1 (2% ) 

*URINAR Y BLADDE R (19 ) (18) (49) (49 ) 

INFLAMMATION , NO S 1 (5% )

 1 (2% ) 2 (4% ) 

HYPE8PLASIA, EPITHELIAL 1 (2%) 

ENDOCRIN E SYSTE M 

•PITUITAR Y (20 ) (20) (50) («9 ) 

ANGIECTASI S 1 (5%) 

•ADRENA L (20 ) (20 ) (50) (19) 

ANGIECTASI S 2 (4% ) 2 (4% ) 

•ADRENA L CORTEX (20 ) (20) (50) (49) 

DEGENERATION , NOS 2 (4% ) 2 (4% ) 

ANGIECTASI S 1 (5%) 

•THYROI D (19) (20) (50) (50) 

ULIIMOBRANCHIA L CYST 2 (11% ) CYST, NO S 1 (2*) 1 (2% ) 

HYPERPLASIA , C-CELL 1 (5% ) 

HYPERPLASIA , FOLLICU L AR -CELL 1 (5%) 1 (2% ) 

•PARATHYROI D ( 3 ) (20) (50) (50) 

HYPERPLASIA , SOS 2 (67%) 2 I<J*1 1 12*1 . 

» NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

TABLECl (CONTINUED)
 

• C-5
 
TABLE Cl (CONTINUED) 

CONTROL (UNTR) 

01-031K 

CONTROL (VEH) 

01-071M 

L C W DOSE 

01-072M 

HIG H DOSE 

01-073M 

REPRODUCTIV E SYSTEM 

•PROSTAT E 

INFLAMMATION , NO S 

CALCIU M DEPOSIT 

*SEMINA L VESICLE 

INFLAMMATION , NOS 

#TESriS GBANOLOMA , SPERMATIC 

ATROPHY , NO S 

*EPIDIDYMI S 

NECROSIS , FAT 

ATROPHY , NO S 

(20 ) 

5

(20 ) 

1

(20) 

1

11

(20) 

1

3

 (25%) 

 (5*) 

 (5*) 

 (55*) 

 (5X) 

 (15*) 

(13) 

(20) 

(20) 

7

(20) 

1

 (35*) 

 (5*) 

(15) 

2 (4*) 

1 (2*) 

(50) 

(50) 

28 (56*) 

(50) 

(28) 

3 

(50) 

1 

(50) 

13 

(50) 

(11*) 

(2*) 

(26*) 

NERVOU S SYSTE M 

(tBRAIN/MENINGES 

INFLAMMATION , NO S 

(20) (20) (50) 

2 (4*) 

(50) 

SPECIAL SENSE ORGAN S 

*EYE/LACRIMA L GLAN D 

INFLAMMATION , NO S 

(20) 

1 (5*) 

(20) (50) (50) 

MUSCULOSKELETAL

NON E 

 SYSTEM 

BODY CAVITIE S 

*PERITONEUM 

HEMORRHAG E 

INFLAMMATION , NO S 

*PLEUR A 

INFLAMMATION , NO S 

*PERICARDIU M 

!!IFLAMMiUO,N,._NOS 

(20) 

1 (5*) 

(20 ) 

(20) 

J__U2S1 

(20) 

(20) 

(20) 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECEOPSIED 

(50) 

(50) 

1 (2*) 

(50) 

1_12*L_ .. 

(53)

1 

(50) 

(50) 

1 

(2*) 

I2SL-. 

C-6 
TABLECl (CONCLUDED) 

CONTROL (UNTR ) CONTRO L (VEH) L OW DOSE HIG H DOSE 

01-031B 01-071M 01-072M 01-073K 

*HESENT?:RY 

PERIARTERITI S 

(20 ) 

a (20*) (20) 

1 (5X) 

(50) 

1 <2X ) 

(50) 

A LL OTHER SYSTEM S 

NONE 

SPECIA L MORPHOLOGY SUMMAR Y 

NO LESIO N REPORTED 2 7 

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

* NUHBO OF ANIMAL S NECROPSIE D 

JC-7
 
TABLE C2 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

TREATED WITH 1,2-DICHLOROETHANE 

CONTRO L (UNTR) CONTRO L (VEH ) L OW DOSE HIGH DOSE 

01-031F 01-071F 01-07UF 01-075F 

ANIMAL S INITIALL Y I N STUDY 20 20 50 50

 

ANIMAL S NECSOPSIED 20 20 50 50

 

ANIMAL S EXAMINE D HI STOPAIHOLOGICALLY ** 20 20 50 50

 

INTEGUMENTAR Y SYSTEM 

«SKI N (20 ) (20) (50) (50) 

INFLAMMATION , NO S 1 <2X) HYPEHKERATOSI S 1 (2X ) ACANTHOSI S 1 (2% ) 

RESPIRATOR Y SYSTEM 

tLUN G (20 ) (20) (50) (50) PNEUMONIA . CHRONIC MORIN E 13 (90% ) 19 (95*) «« (88J) 35 (70S) 

HEMATOPOIETIC SYSTEM 

IBONE MARRO W (1) (20) (U9) (50) 

METAMORPHOSI S FATTY 4 (8X) 

ISPLEEN (20) (20) (50) (50) HEMORRHAG E 3 (6X ) HEMATOPOIESIS 1 (5*) 16 (32X) 

#CERVICA L LYMP H NODE (20 ) (19) (19) (45) 

INFLAMMATION . NOS 1 <5X ) 2 (1*) 1 <2X ) 

CIRCULATOR Y SYSTEM 

*H£ART (20). (20 ) (50) (50) 

THROMBUS , ORGANIZE D a (8% ) 

fMYOCARDIU M (20) (20 ) (50) (50) 

INFLAMMATION , NOS 3 (6X) 2 (UX ) 

FIBROSIS 1 (5%) 

*A08T A (20) (20) (50) (50) 

_ THROMBUS.. fiBSiJIIZED___ 1-12*1 . 

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

* NOMBE P OF ANIMAL S NECROPSIE D 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 
TABLE C2 (CONTINUED) 

CONTROL (UNTR) 

01-031F 

CONTROL (VEH) 

01-071F 

L CH DOSE 

01-Q74F 

HIGH DOSE 01-075F 

BEDIM CALCIFICATION 1 (5X) 1 (2«) 

DIGESTIV E SYSTE M 

tSALIVAR Y GLAN D 

INFLAMMATION , NOS 

(15) (15) (30) (7) 

1 (1U% ) 

FIBROSI S 1 (1UX ) 

ATROPHY, NOS 1 (1i»X) 

ftLIVE R 

INFLAMMATION , NOS 

(20) (20) 

1 (5X) 

(50) (50) 

6 (12X) 

ABSCKSS, NOS 1 (2X) 

METAMORPHOSI S

ANGIECTASI S 

 FATTY 1 (5%) 1

1

 (2*) 

 (2X ) 1 (2X) 

tLIVER/CENTRILOBULAR 

DEGENERATION , NOS 

(20) (20) (50) 

1 (2*) 

(50) 

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

*BILE DUCT 

HYPERPLASIA , NO S 

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

1 (2X) 

#PANCREA S 

INPLAHHATIOH, NOS 

(20) (19) (50) 

1 (2%) 

(50) 

PERIARTERITI S 1 (2*) 

IESOPHAGUS (15) (20) (50) (50) 

IMPLAMNATION , NO S 1 (2*) 

#STOMAC H 

INFLAMMATION ,

ULCER, FOCAL 

 NOS 

(20 ) 

1 (5%) 

(20) (19) 

2

5

 (HX ) 

 (10%) 

(50) 

1 (2% ) 

3 (6%) 

HYPERKERATOSI S 

ACANTHOSI S 

PARAKERATOSI S 

1 (5%) 

1 (5S) 

1

1

 (5X) 

 (5*) 

6

8

2

 (12% ) 

 (16% ) 

 (IX) 

7

7

 (1U% ) 

 (1UX ) 

*GASTRIC SUBNUCOSA (20) (20) <U9) (50) 

ULCFR, NOS 1 (2X ) 

URINAR Y SYSTEM 

tKIDNF Y 

PYELONEPHRITIS , NOS 

INFLAMHATIONj. CHRONIC 

(20 ) 

2_I!*521 

(20) 

3.115*1. 

(50) 

2 (U% ) 

1t_i28Sl 

(50) 

_6_J12SI. 

# NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

•C-9 
TABLE C2 (CONTINUED) 

CONTROL (UNTR) 

01-031F 

CONTROL (VEH) 

01-071F 

LC» DOSE 01-07i*F HIGH DOSE 

01-075F 

CALCIU M DEPOSIT 1 (5X) 

ENDOCRIN E SYSTEM 

tADRENA L 

ANGIECTASI S 

tADHENA L CORTEX 

DEGENERATION , NOS 

ANGIECTASI S 

#THT80ID 

HYPERPLASIA , C-CELL 

•PARATHYROI D 

HYPERPLASIA, NOS 

(20 ) 

(20) 

3 <15X ) 

(20) 

1 (20%) 

( 1 )

1 (100*) 

(20) 

2 (10X) 

(20) 

2 (10X) 

(20) 

(20 ) 

(50) 

10 (20X) 

(50) 

4 (8X) 

(50) 

(50) 

(50) 

5

(50) 

"4

(50) 

(50) 

 <10X) 

 (8X) 

REPRODUCTIV E SYSTEM 

*VAGIN A 

INFLAMMATION , NO S 

tUTERUS 

HYDROMETR A 

INFLAMMATION , NO S 

ABSCESS, NCS 

IUTEE US/EN DOMETRIU M 

INPLAMHATICN , NOS 

HYPERPLASIA , CYSTIC 

tOVAR Y 

CYST, NOS 

INFLAMMATION , NO S 

(20) 

(20) 

t (20%) 

(20) 

1 (5%) 

1 <5X) 

(20) 

(20) 

(20) 

1 (5X) 

(20) 

(20) 

1 (5X) 

(50) 

3 (6X) 

(»8) 

1 (2X) 

7 <15X) 

1 (2X ) 

(i»8) 

(17) 

1 (2X ) 

(50) 

2 (IX) 

<U9) 

1 <2X ) 

3 (6%) 

(149) 

(17) 

2 (UX ) 

NERVOU S SYSTE M 

*BRAIN/MENINGI S 

INFLAMMATION , NOS 

(20 ) (20) 

1 (5*) 

(50) 

1 (2X) 

(50) 

SPECIAL SENSE ORGAN S 

HQfiE. 

* NUMBER OF ANIMALS WITH TISSOE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

C-IO 
CONTROL (UNTR) 

01-031F 

CONTRO L (VEH ) 

01-071F 

L CW DOSE 

01-07UF 

HIGH DOSE 

01-075F 

MUSCUI.OSKELETA L SYSTE M 

NON E 

BODY CAVITIE S 

*PLEUR A 

INFLAMMATION , NO S 

(20 ) (20 ) (50) 

1 (2X) 

(50) 

1 (2% ) 

*PERICARDIU M 

INFLAMMATION , NO S 

(20 ) (20) (50) 

6 (12)1) 

(50) 

3 (6X) 

*ME SENTER Y 

PERIA8TERITI S 

(20 ) (20) (50) 

1 (2«) 

(50) 

ALL OTHER SYSTEMS 

NON E 

SPECIAL MORPHOLOGY SUMMAR Y 

NJ LESIO N REPORTE D 1 1 5 

« NUHBE B O F ANIMAL S WIT H TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBE R OF ANIMAL S NECBOPSIE D 

TABLE C2 (CONCLUDED) 

C-ll
 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH 1,2-DICHLOROETHANE
 
TABLE Dl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

TREATED WITH 1,2-DICHLOROETHANE

 

CONTRO L (UNTR ) CONTRO L (VEH ) L CW DOSE HIGH DOSE 

02-M08 1 02-M071 02-M07 2 02-M07 3 

ANIMAL S INITIALLY I N STUD Y 20 20 50 50 

ANIMAL S NECBOPSIE D 18 19 47 48 

ANIMAL S EXAMINE D HISTOPA IHOLOGICA LLY ** 17 19 46 47 

INTEGUMENTAR Y SYSTEM 

*SKIN (18) (19) (17) (48) 

EPIDERMA L INCLUSION :YST 2 (4% ) 

INFLAMMATION , NOS 1 (6%) 1 (555) 

ACARIASI S 1 (2% ) 

ACANTHOSI S 1 (2% ) 

*SOBCUT TISSUE (18) (19) (17) (48)

 

ABSCESS, NOS 1 (6%) 1 (5*) 1* (9X )

 

SESPIEATOR Y SYSTE M 

tTRACHE A (17 ) (19) (17) (48 )

 

INFLAMMATION , NO S 3 (6% )

 

ULUN G (17) (19) (17) (48 ) 

PNEUMONIA , CHRONI C MURIN E 5 (11% ) 11 (23% ) 

HFMATOPOIETIC SYSTE M 

•SPLEE N (17 ) (18) (47) (48 ) 

AMYLOIDOSIS 4 (24%) 7 (39%) 23 (49%) 11 (23 %) 

HEMATOPOIESI S 1 (6%) 3 (6% ) 

#MESENTERI C L. NODE (17) (19 ) (16) (47 ) 

INFLAMMATION , NO S 2 (11*) 1 (2% ) ANGIECTASI S 2 (11*) 2 (4% ) 

CIRCULATOR Y SYSTEM 

tHEAH T (17) (19) (46) (48) 

THROMBUS . ORGANIZE D 1 J5*L 2 S±%1 _ 1_12%1_ 

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

* NUMBE R OF ANIMAL S NECROPSIE D 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

D-3 
TABLEDl (CONTINUED) 

CONTROL (ONTR) 

02-H081 

CONTROL (VEH ) 

02-M071 

L OW DOSE 

02 ­M 07 2 

HIGH DOSE 

02-M073 

CALCIU M DEPOSIT 1 <2X ) 2 (i*X) 

*MYOCARDIU M 

INFLAMMATION , NO S 

(17 ) (19) 

1 (5*1 

(16) 

1 (2X ) 

(U8 ) 

tENDOCARDID M 

INFLAMMATION , NOS 

(17) (19) 

1 (5*) 

<«6) 

2 (<**) 

(1*8) 

DIGESTIV E SYSTE M 

tLIVER 

AMYLOIDOSI S 

HYPERPLASIA , NODULA R 

tPANCREA S 

INFLAMMATION , NO S 

tSTOMAC H 

CALCIU M riEPOSIT 

HYPERKESATOSI S 

ACANTHOSI S 

tLARG ? INTESTIN E 

NEMATODIASI S 

(17) 

(17) 

(17 ) 

(17) 

(19) 

3 (16*) 

(18) 

1 <6«) 

(19) 

1 (5X) 

1 (5*) 

(19) 

(i*7) 

5 (11*) 

(U7) 

(U6 ) 

K (9*) 

3 (7X) 

(U7 ) 

U (9X) 

(1*8) 

1 (2X ) 

1 (2*) 

(48) 

(U6 ) 

1 (2X ) 

5 (11*) 

1 (9*) 

(1*8) 

1* (8X) 

tCOLON 

NEMATODIASI S 

(17) (19) 

3 (16*) 

(147) (US) 

URINAR Y SYSTEM 

•KIDNE Y 

CYST, NOS 

PYELONEPHRITIS , NO S 

INFLAMMATION , CHRONI C 

AHYLOIDOSI S 

CALCIU M DEPOSIT 

JURINAR Y BLADDER 

CALCULUS , NOS 

INFLAMMATION , NO S 

CALCIU M DEPOSIT 

(17) 

3 (18X) 

5 (29*) 

it (2«*> 

(17 ) 

(18) 

1

12

6

(19) 

 (6*) 

 (67*) 

 (33*) 

(«7) 

2 (UX ) 

2 (1**) 

21 (51*) 

20 (U3*) 

1 (2*) 

(1*7) 

(«8) 

16 (33X) 

9 (19X) 

1 (2*) 

(1*8) 

1 (2*) 

2 (UX ) 

2 («X ) 

HNDOCRIN F SYSTE M 

_HOHE 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

• D-4 
TABLED! (CONTINUED) 

CONTROL (HNTR ) 

02-M08 1 

CONTRO L (VEH ) 

02-M07 1 

L OW DOSE 

02-M07 2 

HIG H DOSE 

02-M07 3 

REPRODUCTIVE SYSTEH 

*PENIS 

EPIDERMA L INCLUSION CYST 

tPROSTATE 

INFLAMMATION , NOS 

*SEMINA L VESICLE 

INFLAMMATION , NO S 

fTESTIS 

CALCIU M DEPOSIT 

ATROPHY , NOS 

*EPIDIDYMI S 

GBANULOMA . SPERMATIC 

(18) 

(17) 

(18 ) 

(17) 

(18) 

(19 ) 

1 (5X ) 

(19) 

1 (5*) 

(19) 

(19) 

(19) 

(1*7) 

(46) 

(U7 ) 

1 (2% ) 

(U7 ) 

1 (2% ) 

3 (6% ) 

(47) 

(48) 

(1*5) 

1 (2X ) 

(48 ) 

(48 ) 

2 (4« ) 

4 (8%) 

(48) 

2 (4% ) 

NERVOU S SYSTEM 

iBHAIN/MENINGE S 

INFLAMMATION , NOS 

(17 ) (19) 

1 (5%) 

(18) 

1 (2%) 

(48) 

SPECIAL

NONE 

 SENSE ORGAN S 

MUSCULOSKELETA L

NON E 

 SYSTEM 

BODY CAVITIE S 

*PERICARDIU M 

INFLAMMATION , NO S 

(18 ) (19 ) (47) (48) 

1 (2%) 

ALL OTHER SYSTEMS 

N.QUE 

» NUMBER DP ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

D-5 
TABLE Dl (CONCLUDED)
 

CONTROL (DNTR) 

02-M081 

CONTROL (VEH) 

02-tl071 LCW DOSE 

02-H072 

HIGH DOSE 02-H073 

SPECIAL MORPHOLOGY SUMMAR Y 

NO LESION REPORTED 6 1 3 7 

AUTO/NECROPSY/NO HISIO 1 1 1 

AUTOLYSIS/NO NECROPSY 2 1 3 2 

0-6
 
TABLE D2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

TREATED WITH 1,2-DICHLOROETHANE 

CONTRO L (UNTR ) CONTROL (VEH ) L OW DOSE HIGH DOSE 

02-F081 02-F071 C2-F071 02-F075 

ANIMAL S INITIALL Y IN STUD Y 20 20 50 50 

ANIMAL S NECROFSIE D 19 20 50 48 

ANIMAL S EXAMINE D HISTOPATHOLOGIC A LLY ** 19 20 50 148 

INTEGUMENTAR Y SYSTEM 

*SKIN (19 ) (20) (50) («3) 

EPIDERMA L INCLUSIO N CYST 1 (2% ) 2 (<tX ) 

INFLAMMATION , NOS 3 (6% ) ACABIASI S 1 (2% ) 1 (2% ) 

HYPERKERATOSI S 1 (2X ) ACANTHOSI S 1 (2% ) 

EESPIBATOR Y SYSTEM 

ITBACHE A (19) (20) («8) (<t5 ) INFLAMMATION , NO S 1 (2%) 

#LUN G (19) (20) (50) (149} 

THROMBOS , ORGANIZE D 1 (2%) 

PNEUMONIA , CHRONIC MURIN E 1 (2*) 6 (13*) CALCIU M DEPOSI T 1 (2% ) 

HEMATOPOIETIC SYSTE M 

• SPLEE N (19 ) (20) (50) (U6 )

 AMYLOIDOSIS 2 («*)

 HEMATOPOIESI S 1 (5X) 5 (10*)

 

•CERVICA L LYMP H NODE (19) (20) (50) (39) INFLAMMATION , NO S 1 (2% )

 

iMESENTERIC L. NODE (19 ) (20) (50) (39) INFLAMMATION , NO S 1 (2% )

 

CIRCULATOR Y SYSTE M 

NON E 

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

* NUMBE R OF ANIMAL S NECROPSIE D 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

D-7 
TABLE D2 (CONTINUED) 

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

02-F081 02-F071 02-F074 02-F075 

DIGESTIV E SYSTE M 

•SALIVAR Y GLAN D (19 ) (19) (50) (37) 

CYST. NOS 1 (2%) 

•LIVER (19) (20 ) (50) (47) 

THROMBUS , ORGANIZE D 1 (2%) INFLAMBATION ,

AMYLOIDOSI S 

 NO S 1 <2X ) 

1 (2% ) ANGIECTASI S 1 (2% ) 

•PANCREA S 

INFLAMMATION , NOS 

(19) 

1 (5%) 

(20) (50) (48) 

•STOMACH (19) (20) (50) (48) 

CALCIU M DEPOSIT 1 (2% ) 

HtfPERKERATOSI S 1 (5*) 2 (4$) ACANTHOSI S 1 (5%) 1 (2%) 

•LARG E INTESTINE (19) (19) (50) (47) 

NEMATODIASI S 5 (10*) 

»COLON (19) (19) (50) (47) 

NEBATODIASI S 1 (5*) 

URINAR Y SYSTEM 

•KIDNE Y (19) (20) (50) (47) 

HYDRONEPHROSI S 1 (2X ) 

PYELONEPHRITIS , NO S 2 (1*%) AMYLOIDOSI S 1 (2% ) 

•URINAR Y BLADDER (19) (19) (49) (45) 

INFLAMMATION , NOS 1 (5*) CALCIU M DEPOSIT 1 (2%) 

ENDOCRIN E SYSTE M 

NON E 

REPRODUCTIV E SYSTEM 

•UTERU S (19 ) (20) (49) (47) 

HYDROMETR A 2-.P6S1. a_J22Si 5.110X1 - - 1-UX.1_ 

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

* NUMBE R OF ANIMAL S NECROPSIE D 

•D-8 
CONTROL (UNTR) 

02-F081 

CONTROL (VEH ) 

02-F071 

LCH DOSE 

02-F07I* 

HIGH DOSE 

02-F075 

INFLAMMATION , NO S 10 (20X) 9 (19*) 

fUTERUS/ENDOMETRIU M 

INFLAMMATION , NOS 

HYPERPLASIA , NO S 

HI PERPLASIA, CYSTIC 

(19) 

2

7

 (11*) 

 (37%) 

(20) 

2 (10*) 

11 (55X) 

(19) 

1 (2*) 

17 (35X) 

(117) 

»OVAR Y 

CYST, NOS 

INFLAMMATION, NOS 

(19)

10

2

 (53*) 

 (11*) 

(20) 

10 (50*) 

3 (15*) 

(19) 

17 (35*) 

10 (20X) 

(«6) 

5

1

 (11*) 

 (2*) 

NERVOU S SYSTE M 

tBRAIN/MENINGE S 

INFLAMMATION , NOS 

(19 ) (20) (50) («6) 

1 (2*) 

SPECIAL SENSE ORGAN S 

NONE 

MUSCULOSKELETA L SYSTEM 

NON E 

BODY CAVITIE S 

•PERITONEUM 

INFLAMMATION , NO S 

(19) (20) (50) 

1 (2*) 

(U8) 

ALL OTHER SYSTEMS 

NON E 

SPECIAL MORPHOLOG Y SUMMAR Y 

NO LESION REPORTED 

ACCIDENTA L DEATH 

AUTOLYSIS/N O NECROPS Y 

3

1 

1 3 10 

2 

* NUHBE P OF ANIMAL S WIT H TISSUE

* NUMBE R OF ANIMAL S NECROPSIE D 

 EXAMINE D MICROSCOPICALL Y 

TABLE D2 (CONCLUDED) 

D-9
 
Review of the Bioassay of 1,2-Dichloroethane*for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup of the
 

Clearinghouse on Environmental Carcinogens
 

March 6, 1978
 

The Clearinghouse on Environmental Carcinogens was
 

established in May, 1976, in compliance with DHEW Committee
 

Regulations and the Provisions of the Federal Advisory
 

Committee Act. The purpose of the Clearinghouse is to
 

advise the Director of the National Cancer Institute (NCI)
 

on its bioassay program to identify and to evaluate chemical
 

carcinogens in the environment to which humans may be
 

exposed. The members of the Clearinghouse have been drawn
 

from academia, industry, organized labor, public interest
 

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

research organizations. Members have been selected on the
 

basis of their experience in carcinogenesis or related fields
 

and, collectively, provide expertise in chemistry, biochemistry,
 biostatistlcs, toxicology, pathology, and epidemiology.
 Representatives of various Governmental agencies participate
 

as ad hoc members. The Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse is charged with the responsibility of
 

providing a peer review of reports prepared on NCI-sponsored
 

bioassays of chemicals studied for carcinogenicity. It is in
 

this context that the below critique is given on the bioassay
 

of 1,2-Dichloroethane for carcinogenicity.
 

The primary reviewer said that the chemical induced
 

squamous-cell carcinomas of the forestomach, hemangio­ sarcomas, and subcutaneous fibromas in male rats; mammary
 

adenocarcinomas in female rats; mammary adenocarcinomas
 

and endometrial tumors in female mice; and alveolar/
 

bronchiolar adenomas in mice of both sexes. Although
 

there were shortcomings in the experimental design and
 

conduct of the study, he said they were not significant
 

enough to invalidate the findings. Given the carcinogenicity
 

of 1,2-Dichloroethane in both sexes of rats and mice, he
 

concluded that the chemical poses a potential carcinogenic
 

risk to humans.
 

The secondary reviewer pointed out that 1,2-Dichloro­ ethane was one of the few chlorinated hydrocarbons which
 

induced mammary cancer in both mice and rats. He suggested
 

that the corn oil vehicle, in which 1,2-Dichloroethane
 

was administered, may have localized in the mammary gland
 

resulting in a concentration of the chemical at that site.
 

63
 
A carcinogenic response was elicited in the mammary gland,
 as opposed to other fatty tissues, due to its sensitivity
 

and epithelial component.
 

A motion was made that the report on the bioassay of
 

1,2-Dichloroethane be accepted as written. It was seconded
 

and approved unanimously.
 

Members present were:
 

Gerald N. Wogan (.Chairman), Massachusetts Institute of
 

Technology
 

Arnold Brown, Mayo Clinic
 

Lawrence Garfinkel, American Cancer Society
 

E. Cuyler Hammond, American Cancer Society
 

Joseph Highland, Environmental Defense Fund
 

Henry Pitot, University of Wisconsin Medical Center
 

George Roush, Jr., Monsanto Company
 

Sheldon Samuels, Industrial Union Department, AFL-CIO
 

Michael Shimkin, University of California at San Diego
 

John Weisburger, American Health Foundation
 

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 ana'
 

criticisms reflected in the review may no longer be
 

appropriate.
 

•{I U . S . GOVERNMEN T PRINTIN G OFFICE : 1978-260-899/3153
 

64
 
DHEW Publication No. (NIH) 78-1361