National Cancer Institute 

CARCINOGENESIS 

Technical Report Series

No. 3 

January, 1977 

BIOASSAY OF 

1, 1, 1-TRICHLOROETHANE 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 71-55-6 

NCI-CG-TR-3 

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

Public Health Service 

National Institutes of Health 
BIOASSAY OF 1,1,1-TRICHLOROETHANE 


FOR POSSIBLE CARCINOGENICITY 


Carcinogen Bioassay and Program Resources Branch 


Carcinogenesis Program 


Division of Cancer Cause and Prevention 


National Cancer Institute 


Bethesda, Maryland 


November 1976 


DHEW Publication No. (NIH) 77-803 


BIOASSAY OF 1,1,1-TRICHLOROETHANE 

FOR POSSIBLE CARCINOCENICITY 


Carcinogenesis Program, Division of Cancer Cause and Prevention 


National Cancer Institute 


November 1976 


CONTRIBUTORS: This report presents the results of the carcinogenesis bio-assay 


conducted under the direction of the Carcinogen Bioassay and Program Resources 


Branch, Carcinogenesis Program, Division of Cancer Cause and Prevention, 


National Cancer Institute (NCI), Bethesda, Maryland. This research was 


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


under direct contract to the NCI and currently under a subcontract to Tracor
 

Jitco, Inc., prime contractor for the NCI Carcinogenesis Bioassay Program. 


The results of this study were reviewed and this report was prepared at Tracor 


Jitco. Those responsible for the report are the toxicologists, Drs. W. E. 


MacDonald2

, and Jane F. Robens2; the technical editor, Dr. E. W. Gunberg2; and 


the technical writer, Ms. B. G. J. Ross2

. 


The experimental design, including doses, was determined by the NCI Project 


'4
 Officers, Drs. J. H. Weisburgerl

 and E. K. Weisburger1'. The principal 


investigators for the contract were Drs. M. B. Powers3

, R. W. Voelker3, W. 


'5 '6
 A. Olson3 , and W. N. Weatherholtz3 . Chemical analysis was performed 


iii 

'7
 by Dr. C. L. Guyton3

; the technical supervisor of animal treatment and 


observation was Ms. K. J. Petrovics3

. 


The pathologic examinations were done by the Hazleton Laboratories America,
 

Inc.3

, and the Experimental Pathology Laboratories8. The histopathologic 


evaluation was conducted by Dr. D. A. Willigan9 and reviewed by Dr. C. N.
 

Barron2

. 


Compilation of individual animal survival, pathology, and summary tables was
 

performed by EG&G Mason Research Institute10; the statistical analysis was
 

performed by Dr. J. R. Joiner2

, using methods selected for the Bioassay
 

Program by Dr. J. J. Gart11. This report was reviewed by members of the 


participating organizations1,2,3

. 


1

Carcinogenesis Program, Division of Cancer Cause and Prevention, National
 

Cancer Institute, National Institutes of Health, Bethesda, Maryland. 


2

Tracor Jitco, Inc., 1776 E. Jefferson Street, Rockville, Maryland. 


3

Hazleton Laboratories America Inc., 9200 Leesburg Turnpike, Vienna, Virginia. 


4

Now with the Naylor Dana Institute for Disease Prevention, American Health 


Foundation, Hammond House Road, Valhalla, New York. 


5

Now with the Center for Regulatory Services, 2347 Paddock Lane, Reston, 


Virginia. 


6

Now with the Department of Food Science and Nutrition, Commonwealth of 


Massachusetts, University of Massachusetts, Amherst, Massachusetts. 


iv 

7

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


8

Experimental Pathology Laboratories, 17 Pine Street, Herndon, Virginia. 


9

Donald A. Willigan, Inc., 730 Park Avenue, Bound Brook, New Jersey. 


1OEG&G Mason Research Institute, 1530 East Jefferson St., Rockville, Maryland. 


11Field Studies and Statistics, Division of Cancer Cause and Prevention, 


National Cancer Institute, National Institute of Health, Bethesda, Maryland. 


v 


SUMMARY
 

The carcinogenesis bioassay of technical grade 1,1,1-Trichloroethane was
 

conducted using Osborne-Mendel rats and B6C3F1 mice. 1,1,1-Trichloroethane was 


administered orally by gavage in corn oil to 50 animals of each sex and
 

species at two dose levels 5 days per week for 78 weeks. 


Rats: The experiment was originally started using doses of 3,000 and 1,500
 

mg/kg of body weight. After a few weeks the study was terminated, and the
 

animals discarded because of marked signs of intoxication. The experiment was 


restarted with rats 7 weeks of age that were put on doses of 1,500 and 750
 

mg/kg. There was a moderate depression of body weight in the first year of the 


study. During the second year a yellow discoloration of the fur of the lower 


abdomen and increased eye and nasal discharge and dyspnea were noted. Both 


males and females given the test chemical exhibited early mortality when 


compared with the untreated controls, and the statistical test for dose-


related trend was significant (P < 0.04). All surviving animals were killed at 


117 weeks of age. 


Mice: Male and female weanlings were started on test at 5 weeks of age and
 

killed at 96 weeks of age. Initially, the doses for male and female mice were
 

4,000 and 2,000 mg/kg body weight. During the 10th week of the study, doses
 

were increased to 5,000 and 2,500 mg/kg, since the animals apparently could 


tolerate a higher dose. Doses were again increased at week 20 to 6,000 and 


3,000 mg/kg and maintained at these levels to the end of the study. Time-


weighted average doses for the high- and low-dose mice were, respectively, 


5,615 and 2,807 mg/kg. There was a moderate depression of body weight
 

throughout the study in both sexes of mice, and the survival 


vii 

was significantly decreased. In the female mice, there was a positive dose-


related trend (P = 0.002) in the proportions surviving. 


A variety of neoplasms were represented in both l,1,1-trichloroethane treated
 

and matched-control rats and mice. However, each type of neoplasm has been 


encountered previously as a lesion in untreated rats or mice. The neoplasms 


observed are not believed attributable to 1,1,1-Trichloroethane exposure,
 

since no relationship was established between the dosage groups, the species, 


sex, type of neoplasm, or the site of occurrence. Even if such a relationship
 

were inferred, it would be inappropriate to make an assessment of 


carcinogenicity of l,1,1-trichloroethane on the basis of this test, because of 


the abbreviated life spans of both the rats and the mice. 


viii 

TABLE OF CONTENTS
 

Page
 

1.0 Introduction ................................................... 1 


2.0 Materials and Methods .......................................... 2 


Chemicals ................................................. 2 


Dosage Preparation ........................................ 2 


Animals ................................................... 2 


Animal Maintenance ........................................ 3 


Subchronic Toxicity Tests ................................. 4 


Design of Chronic Studies ................................. 5 


Clinical and Pathologic Examinations ...................... 9 


Data Recording and Statistical Analyses ................... 10 


3.0 Results ........................................................ 12 


A. Rats 


Body Weights and Clinical Signs .......................... 12 


Survival ................................................. 14 


Pathology ................................................ 16 


Statistical Analysis of Results .......................... 18 


B. Mice 


Body Weights and Clinical Signs ........................... 20 


Survival .................................................. 20 


Pathology ................................................. 24 


Statistical Analysis of Results ........................... 25 


4.0 Discussion ....................................................... 28 


5.0 Bibliography ..................................................... 30 


APPENDICES
 

Appendix A Summary of the Incidence of Tumors in Rats
 

Exposed to 1,1,1-Trichloroethane .......................... 32 


Appendix B Summary of the Incidence of Tumors in Mice
 

Exposed to 1,1,1-Trichloroethane .......................... 35 


Appendix C Summary of the Incidence of Nontumor Pathology .............
 

 in Rats Exposed to 1,1,1-Trichloroethane ................... 38 


Appendix D Summary of the Incidence of Nontumor Pathology .............


 in Mice Exposed to 1,1,1-Trichloroethane ................... 53 


ix
 
FIGURES


 Page
 

Figure 1 Growth Curves for Rats - 1,1,1-Trichloroethane ........... 14 


Figure 2 Survival Curves for Rats - 1,1,1-Trichloroethane ......... 16 


Figure 3 Growth Curves for Mice - 1,1,1-Trichloroethane ........... 22 


Figure 4 Survival Curves for Mice - 1,1,1-Trichloroethane ....... . 23 


TABLES
 

Table 1 Design of 1,1,1-Trichloroethane Chronic 


 Study: Rats . .......... . . ............................... 6 


Table 2 Design of 1,1,1-Trichioreothane Chronic 


 Study: Mice ......................................... . . .. 7 


Table 3 Comparison of Survival of Control Groups, 


1,1, 1-Trichloroetnane-Treated, and Carbon 


Tetrachloride-Treated (Positive Control) Rats ..... 17 


Table 4 Comparison of the Incidence of Liver Tumor in 


Control Groups, 1,1, 1-Trichloroethane-Treated, 


 and Carbon Tetrachloride-Treated (Positive Control) ........ 19 


Table 5 Statistical Analyses of the Incidence of rumors 


at Specific Sites in Matched Controls and 


1, 1, 1-Trichloroethane-Treated Rats ....... . .... . . . . 20 


Table 6 Comparison of Survival of Control Groups, 


1,1, 1-Trichloroethane-Treated, and Carbon 


Tetrachloride-Treated (Positive Control) Mice . ............ 24 


Table 7 Comparison of the Incidence of hepatocellular 


Carcinoma in Control Groups, 1, 1, 1-Trichloroethane-Treated, 


 and Carbon Tetrachloride-Treated (Positive Control) Mice ... 26 


Table 8 Statistical Analyses of the Incidence of Tumors at 


Specific Sites in Matched Controls and 


1, 1, 1-Trichloroethane-Treated Mice ....... .... .. 27 


x
 
INTRODUCTION
 

1,1,1-Trichloroethane (commonly called methylchloroform) is one of a group of
 

halogenated hydrocarbons selected for testing in the Carcinogenesis Bioassay 


Program. The rationale for its selection includes its structural relationship
 

to carbon tetrachloride, its wide use in industry, its extensive exposure of
 

humans, and the incomplete knowledge of its carcinogenic potential. In 1959 


Browning reported that 1,1,1-trichloroethane was replacing the more toxic 


industrial solvents: trichloroethylene, tetrachloroethylene, and carbon 


tetrachloride. Furthermore a growing market has developed for 1,1,1­

Trichloroethane after reports suggested the carcinogenicity of carbon
 

tetrachloride (Reuber and Glover, 1970; Della Porta et al., 1961;
 

Eschenbrenner and Miller, 1946) and of trichloroethylene (National Cancer
 

Institute, 1976). In the years 1970 through 1973, domestic sales grew from 327 


to 566 million pounds (Chemical Economics Handbook, 1975). The Environmental
 

Protection Agency permits 1,1,1-Trichloroethane to be used as a solvent or 


cosolvent in pesticide formulations for the postharvest fumigation of citrus
 

fruits (U.S. Environmental Protection Agency, 1972). The United States 


Occupational Standard requires that no worker be exposed to a concentration in 


excess of 350 ppm by volume, or 1,900 mg/m3 determined as a time-weighted
 

average exposure over an 8-hour workday (U.S. Dept. of Labor, 1974). 


1
 
2.0 MATERIALS AND METHODS
 

Chemicals
 

Two batches of technical grade 1,1,1-trichloroethane were purchased from 


Aldrich Chemical Company, Inc., Milwaukee, Wisconsin. The purity was checked
 

by Hazleton Laboratories America, Inc., Vienna, Virginia, using gas-liquid 


chromatography (glc) and infrared spectrophotometry. Analyses by glc showed
 

that both batches contained approximately 95% 1,1,1-trichloroethane and 3% pdioxane, an inhibitor routinely added to commercial preparations of 1,1,1­

trichloroethane. The remaining 2% of the glc peak area contained several minor 


impurities, two of which may have been 1,1-dichloroethane and 1,1­

dichloroethylene. Throughout this report, the term 1,1,1-trichloroethane is
 

used to represent the technical grade material. 


Dosage Preparation
 

Fresh solutions of 1,1,1-trichloroethane in corn oil in amounts sufficient to 


dose all animals were prepared weekly, sealed, and refrigerated to reduce 


volatilization. The concentration of 1,1,1-trichloroethane in corn oil was 75% 


for rats and 40-60% for mice. Duke's corn oil was purchased from a 


distributor, C. F. Sauer Co., Richmond, Virginia. Dosing was conducted under a 


hood to minimize extraneous exposure of other animals and laboratory
 

personnel. 


Animals
 

The Osborne-Mendel rat was selected because of the experience gained by the 


Food and Drug Administration, where this strain has been used for many 


2 

years as a general-purpose test animal. In addition, it was known to be
 

sensitive to the carcinogenic effects of carbon tetrachloride administered by
 

subcutaneous injection (Reuber and Glover, 1970). The B6C3F1 hybrid mouse was 


selected because it has been extensively used by NCI for carcinogenesis 


bioassays. 


Rats and mice of both sexes, obtained through contracts of the Division of
 

Cancer Treatment, National Cancer Institute, were used in these tests. The 


Osborne-Mendel rats, and the B6C3F1 hybrid mice were obtained from the Charles 


River Breeding Laboratories, Inc., Wilmington, Massachusetts. Upon receipt,
 

animals were quarantined for at least 10 days, determined to be free from 


observable disease or parasites, and assigned to the various experimental and 


control groups. 


Animal Maintenance
 

All animals were housed in temperature- and humidity-controlled rooms. 


Incoming air was filtered through 2-inch-thick disposable fiberglass filters 


at a rate of 12 changes of room air per hour. Lighting was provided on a 12­

hour-per-day cycle. Rats were individually housed in suspended steel, wire-


mesh cages, and mice were in polypropylene cages equipped with filter tops. 


Ten mice were housed in each cage. Clean cages with bedding (Sanichips®,
 

manufactured by Shurfire) were provided twice each week for mice; rats were
 

given clean wire cages weekly. 


Food hoppers were changed and heat-sterilized once a week for the first 10 


weeks and once a month thereafter. Heat-sterilized glass water bottles were 


provided twice a week for rats and three times a week for mice. Food 


3 

(Wayne® Laboratory Blox Meal) and water were consumed ad libiturn Racks were
 

repositioned in the room on a weekly basis. 


Housed in the same room with the rats given 1,1,1-trichloroethane, were rats
 

treated with trichloronitronmethane, and trichlorofluoromethane; the matched
 

controls for 1,1,1-trichloroethane and trichlorofluoromethane; and the vehicle 


controls for trichloronitromethane. 


The 1,1,1-trichloroethane-treated mice were maintained in the same room as
 

mice receiving 1,1,2,2-tetrachloroethane, trichloromethane, 3-chloro-1­

propene, trichloronitromethane, 1,2-dibromo-3-chloropropane, 1,2­

dibromoethane, 1,2-dichloroethane, 1,1-dichloroethane, trichloroethene, 2,5­

dihydrothiophene 1,1-dioxide, triiodomethane, 1,1,2-trichloroethane,
 

tetrachloroethene, hexachloroethane, carbon disulfide, trichlorofluoromethane, 


and tetrachloromethane (carbon tetrachloride). The control mice to these 17 


chemicals were also housed in the same room as the 1,1,1-trichloroethanetreated mice. 


Subchronic Toxicitity Tests
 

Subchronic toxicity studies were conducted to establish the maximum tolerated
 

doses (MTD) of 1,1,1-trichloroethane for administration to the rats and mice 


in the chronic study. On the basis of results from the range-finding study, 


doses of 1,000, 1,780, 3,160, 5,620, and 10,000 mg/kg were administered in
 

corn oil by gavage to five animals of each sex and species. Animals were dosed 


5 days a week for 6 weeks, followed by 2 weeks of observation. 


At 3,160 mg/kg none of the rats died and there was no reduction of weight 


4 

gain, while at 5,620 mg/kg, two female rats died and weight gain in the 


surviving females was reduced. At 10,000 mg/kg, two male rats died and weight 


gain in the survivors was reduced. The high dose for rats in the chronic study 


was therefore set at 3,000 mg/kg; the low dose was half that amount, or 1,500 


mg/kg. No gross pathology was observed in rats at necropsy in the subchronic 


tests. 


At 5,620 mg/kg none of the mice died and none had reduced weight gain, whereas 


at 10,000 mg/kg only one male and one female survived. The high dose for mice
 

in the chronic study was therefore set at 4,000 mg/kg and the low dose at
 

2,000 mg/kg. No gross pathology was observed in mice at necropsy in the
 

subchronic tests. 


Design of Chronic Studies
 

Tables 1 and 2 show the numbers of rats and mice of each sex used in the
 

study, including those used as matched controls. Also shown is the dosage,
 

duration of treatment, observation period, and the time-weighted average dose
 

for each category of test animal. 


The rats were started on the study at 7 weeks of age. Those on the low dose
 

were treated for 78 weeks, 5 days per week, with 750 mg/kg, while rats on the 


high dose received 1,500 mg/kg for the same period of time. Both groups were 


observed to 110 weeks, when the surviving animals were killed. (The high dose 


for rats had been set originally at 3,000 mg/kg; this dosage proved to be too
 

toxic, however, and the study was terminated, the animals discarded, and the
 

study restarted as indicated above (see table 1). 


5 



The mice were started at 5 weeks of age and were treated 5 days per week, 


for a total of 78 weeks at varying dosages. Since the test chemical did not 


cause toxic signs, both the high and low dosages were raised twice during 


the treatment period. Surviving animals were observed for 12 weeks 


following the treatment and then killed in the 90th week of the study. 


Animals which received a known carcinogen, carbon tetrachloride, served as the 


positive control for this study and for the entire series of halogenated
 

chemicals tested. The purpose of this control was to verify the sensitivity of 


the test animals to carcinogenicity by halogenated hydrocarbons and to serve 


as a check on procedures and techniques. The animals used were of the same 


strain and source as those dosed with 1,1,1trichloroethane. The positive
 

control rats were housed separately from the 1,1,1-trichloroethane-dosed rats, 


but were in the same room as the 1,1,1-trichloroethane-dosed mice. The design
 

of the carbon tetrachloride study (positive control) was essentially the same 


as that of 1,1,1-tri chloroethane. The high dose for male rats was 74 mg/kg
 

and the high dose for females 160 mg/kg. The high dose for both male and
 

female mice was 2,500 mg/kg. Groups of males and females of both species were
 

also administered low doses which were one-half the high doses. Untreated 


animals of the same strain, source, and age were used as matched controls to 


the carbon tetrachloride-treated (positive control) rats and mice. 


Untreated animals of the same strain and source were used as untreated matched 


controls to the 1,1,1-trichloroethane-treated rats and mice; there were 20
 

animals of each sex of each species. They were started at the same time as the 


1,1,1-trichloroethane-treated rats and mice and were housed in the same room 


as the treated animals. They received identical animal care, 


8 

except that neither the test substance nor the corn oil was administered.
 

There were no vehicle control animals used. 


Clinical and Pathologic Examinations
 

All animals were inspected twice daily. Body weights and food consumption were 


recorded weekly for the first 10 weeks and monthly thereafter. A necropsy was 


performed on each animal regardless of whether it died, was killed early, or
 

survived to termination. All animals were injected with sodium pentobarbital
 

intraperitoneally (0.3 to 0.5 ml for rats and 0.05 to 0.1. ml for mice) until
 

they were completely anesthetized. The animals were then exsanguinated and 


immediately necropsied. The following tissues were taken from killed animals
 

and, where practical, from those found dead: brain, pituitary, adrenal,
 

thyroid, parathyroid, trachea, esophagus, thymus, salivary gland, lymph nodes 


(mesenteric and cervical), heart, nasal passages, lung, spleen, liver, kidney, 


stomach, small intestine, large intestine, pancreas, urinary bladder, prostate 


or uterus, seminal vesicles and testis with epididymis or ovary, skin with 


mammary gland, muscle, nerve, bone, bone marrow, and tissue masses. 


Tissues were preserved in 10% buffered formalin, embedded in paraffin,
 

sectioned, stained with hematoxylin and eosin, and examined microscopically. 


In evaluating suspected treatment-related effects in rats, the matched-control 


group was compared to the test group. Complete data on all tumors are 


presented for the matched controls and for the 1, 1, 1-trichloroethane-treated 


groups in Appendixes A and B. For positive (carbon tetrachloride) controls, 


only the data relating to survival and specific lesions of concern are 


presented. 


9
 
The intent was to evaluate all organs, tissues, and gross lesions for every 


animal as specified in the pathology protocol for the Bioassay Program. 


However, a few tissues (especially small organs) were lost during the necropsy 


and the histologic preparation process; therefore, the denominator used for a 


particular organ, tissue, or lesion in Appendixes A and B may not necessarily
 

equal the number of animals placed on experiment in each group. 


Data Recording and Statistical Analyses
 

Pertinent data for this experiment have been recorded in an automatic data 


processing system, the Carcinogenesis Bioassay Data System (Linhart at al., 


1974). The data elements include descriptive information on the chemicals,
 

animals, experimental design, clinical observations, survival, animal weight,
 

and individual pathologic results as recommended by the International Union
 

Against Cancer (UICC) (Berenbium, 1969). Data tables were generated for
 

statistical review and verification of data transcription. 


Survival probabilities were estimated by the product limit procedure of Kaplan 


and Meier (1958) and presented in this report in the form of graphs. Deaths
 

due to accident are not included; all other deaths are recorded in the system. 


Statistical tests of differences in survival between groups are compared using 


the method of Cox (1972) for two groups and an extension of this method by
 

Throne (1975) for more than two groups. 


The number of animals with tumors was analyzed as a percentage of the number
 

of tissues examined. For some sites, such as liver or lung, the animal is
 

counted in the denominator of the tables showing such tumors at that site only 


if the site had a histologic examination. For tumors that 


10 

appeared at several sites, a count is entered in the denominator for any 


animal that had at least one such site histologically examined for that tumor. 


Statistical analysis of tumor incidence was made using the Fisher exact test
 

(Cox 1970) to compare the controls to each dose level. In addition, the 


Armitage and Cochran test for linear trend in proportions with continuity 


correction (Armitage, 1971) was used. This test, assuming a linear trend, 


determines if the slope of the dose-response curve is different from zero (P < 


0.05). The method also calculates the probability level of a departure from
 

linear trend. 


A conservative adjustment, the Bonferroni inequality (Miller, 1966) was used
 

for simultaneous comparisons of several treatments with a control. For the 


comparison of k doses with a control, this correction requires a significance
 

level less than or equal to 0.05/k for the overall comparison to be
 

significant at the 0.05 level. This adjustment was not made in the tables
 

where the Fisher exact test results are shown but is discussed in the analysis 


when appropriate. 


11 

 

3.0 RESULTS 


A. RATS
 

Body Weights and Clinical Signs (Rats)
 

Average weight gains of male rats appeared to be treatment related during the
 

first year of the study. However, there was little difference among groups of
 

female rats until the second year, when deaths made any comparison 


questionable (see figure 1). 


During the first year of the study, the appearance and behavior of the treated 


rats were generally comparable to those of the matched controls, except that
 

by week 10 urine stains were evident on a few animals in the treated groups.
 

As the study progressed, increasing numbers of treated females, and, to a
 

lesser extent, treated male rats, showed urine staining of the abdominal fur.
 

Respiratory involvement characterized by wheezing, rapid or labored breathing, 


a nasal discharge that was sometimes bloody in appearance, and/or a hunched
 

appearance were noted at a low or moderate incidence among rats in all groups, 


including matched controls, during the latter part of the first year. The 


number of treated animals showing respiratory signs increased somewhat over
 

that of the matched controls as the study progressed. Toward the end of the
 

experiment all surviving rats showed wheezing and a hunched appearance. Signs 


of aging commonly observed in laboratory rats were noted during the second
 

year in comparable numbers of control and treated rats. These signs included
 

rough fur, sores on the body and/or extremities, alopecia or desquamation of
 

the tail, squinted eyes, and bloody discharge or crust around the eyes. The 


latter sign was noted more often in treated animals than in the matched 


controls. 


12 


Survival (Rats)
 

The survival of both sexes of dosed rats was less than that of the matched-


control groups. In male rats 6/20 (30%) of the controls, 32/50 (64%) of the
 

low-dose group, and 36/50 (722) of the high-dose group died within a year of
 

the start of the study. The Throne statistical test of survival showed a dose-


related positive trend (P < 0.001) in the proportions of deaths over the 


period of the experiment. 


In female rats 1/20 (5%) of the matched controls, 24/50 (48%) of the low-dose
 

group, and 21/50 (42%) of the high-dose group died in the first year. As in
 

male rats, the statistical test for positive dose-related trend was
 

significant (P 'z 0.04). Figure 2 shows the estimated probability of survival
 

of rats. 


In both sexes, the early mortality in the 11,1-trichloroethane-treated rats 


may have affected the incidence of late-appearing tumors; this is especially 


true in the males, since none survived to the scheduled termination of the 


study. 


Fewer rats receiving 1,1,1-trichloroethane survived at both 78 and 110 weeks 


than did the positive control rats receiving the known carcinogen, carbon 


tetrachloride (see table 3). 


14 


 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3. Comparison of Survival of Control Groups, 


1, 1, 1-Trichloroethane-Treated, and Carbon Tetrachloride-


Treated (Positive Control) Rats 


Group 1,1,1-Trichloroethane Carbon Tetrachloride


 Initial Number Number Initial Number Number 


No. of Alive at Alive at No. of Alive at Alive at


 Animals 78 Weeks 110 Weeksa Animals 78 Weeks 110 Weeksa
 

Male
 

Control 20 7 0 20 20 12 

Low Dose 50 1 0 50 34 15 

High Dose 50 4 0 50 35 8 

FEMALE 

Control 20 14 3 20 18 14 

Low Dose 50 9 2 50 38 20 

High Dose 50 12 1 50 21 14 a

Time in study at last weighing. 


Pathology (Rats)
 

A variety of neoplasms was represented among both 1,1,1-trichloroethanetreated and matched-control animals (see Appendix A). These included
 

hemangiosarcoma (subcutaneous tissue in the abdomen), papillary
 

cystadenocarcinoma (mammary gland and subcutaneous tissue in the groin),
 

lipoma (heart), hemangioma (mesenteric artery, spleen), leiomyoma (artery
 

in thymus region), adrenal cortical adenoma, and pheochromocytoina. Some
 

thyroid neoplasms occurred sporadically: follicular-cell adenoma and
 

carcinoma and papillary cystadenoma. One hepatic-cell adenoma was observed.
 

Mammary gland neoplasms included the following types: fibroadenoma,
 

adenocarcinoma, and papillary cystadenocarcinoma. Other neoplasms were
 

identified as follows: transitional-cell carcinoma (urinary bladder), 


16
 
chromophobe adenoma, endometrial stromal polyp, malignant glioma (brains) and 


osteosarcorna (mesentery: inetastatic). 


Of the malignant neoplasms, the following occurred only in test rats: 


papillary cystadenocarcinoma in the subcutis of 1/50 high-dose females;
 

urinary bladder transitional-cell carcinoma in 1/50 high-dose males; brain 


malignant glioma in 1/48 low-dose males, and mesenteric metastatic 


osteosarcoma in 1/50 high-dose females. Follicular carcinoma was observed in
 

1/20 matched-control females and 1/49 high-dose females. All other malignant
 

neoplasms occurred in the matched-control animals. 


Each of the types of neoplasm represented had been encountered previously as a 


spontaneous lesion in the rat and no relationship in type or incidence to
 

chemical treatment was apparent. 


A variety of nonneoplastic lesions was represented among both the matched-


control and 1,1,1-trichloroethane-treated animals (see Appendix C). Such
 

lesions have been encountered previously as spontaneous occurrences in aging
 

laboratory rats. 


Of the spontaneous lesions, chronic murine pneumonia was prevalent and was the 


most probable cause for the high incidence of natural deaths. It was
 

characterized by a variety of inflammatory changes including abscesses,
 

pleuritis, and bronchiectasis. 


The only proliferative hepatocellular lesion (adenoma) in rats treated with 


1,1,1-trichloroethane was in a high-dose female. None occurred in the 


17 

 

 

 

matched-control goups; however, several neoplastic nodules and hepatocellular carcinomas occurred in the positive-control rats treated with carbon 


tetrachloride (see table 4). 


Table 4. Comparison of the Incidence of Liver Tumors in Control 


Groups, 1, 1, 1-Trichloroethane-Treated, and Carbon 


Tetrachloride-Treated (Positive Control) Rats 


 Hepatocellular Carcinoma Neoplastic Nodules
 

Group CCl 3CH3 Cl4 CCl3CH3 CC14 


MALES
 

Control 0/20 0/20 0/20 0/20 


Low Dose 0/49 2/50 0/49 2/50 


High Dose 0/50 2/50 0/50 1/50 


FEMALES
 

Control 0/20 0/20 0/20 0/20 


Low Dose 0/50 4/49 0/50 2/49 


High Dose 0/50 1/49 1/50a

 3/49 
 a

Hepatocellular adenoma. 


Statistical Analyses of Results (Rats)
 

There were no tumors at any site that appeared in sufficient numbers to 


indicate a statistically significant dose relationship. Table 5 shows the
 

incidence of those tumors that had a proportion of greater than 5% in any dose 


group in either sex. The proportion of the rats with tumors was higher in the
 

untreated group of both sexes than in the dose groups. There is no statistical 


evidence of carcinogenicity of the chemical in these results; however, the 


significant difference in survival of the dosed groups compared to the 


controls and the low survival rate of all groups should be considered in 


evaluation of the data. 


18
 

The first tumors observed in the male rats were hemangioma in the spleen at 72 


weeks in a matched-control animal, cortical adenoma of the adrenal at 28 weeks 


in a low-dose animal, and lipoma in the heart at 50 weeks in a high-dose
 

animal. In female rats, the first tumor seen was fibroadenoma in the mammary 


tissue at 58 weeks in a matched-control animal, endometrial stromal polyp of
 

the uterus at 64 weeks in a low-dose animal, and papillary cystadenocarcinoma
 

in the mammary tissue at 56 weeks in a high-dose animal. 


B. MICE
 

Body Weight and Clinical Signs (Mice)
 

Treated animals of both sexes gained less weight than did the matched controls 


(see figure 3). The reduction in weight gain appears directly related to the
 

treatment. 


Throughout the test, the appearance and behavior of the treated and matched-


control mice were generally similar. Clinical signs commonly observed in
 

group-housed mice and usually associated with aging were observed at a similar 


rate among matched-control and treated animals during the study. These signs 


included: alopecia (generalized or localized), sores on the back and other 


body parts, anal and/or penile irritation, hunched appearance, rough hair 


coat, and occasional abdominal distension. 


Survival (Mice)
 

Figure 4 shows the estimated probability of survival of mice. In male mice, 


the Tarone test showed no significant difference between the proportions of 


the groups surviving (p 0.55). In male mice, 10/20 (50%) of the matched-


control group, 21/50 (42%) of the low-dose group, and 25/50 


20 


22 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

(50%) of the high-dose group died within a year of the start of the 


experiment 


In female mice, 1/20 (5%) of the matched-control group, 9/50 (18%) of the
 

low-dose group, and 20/50 (40%) of the high-dose group died within the
 

first year of the study. The Tarone test for positive dose-related trend 


in the proportions surviving had a significance level of P = 0.002. 


Table 6 shows that while few mice receiving carbon tetrachloride survived
 

until the planned termination of the test, from 25 to 40% of those treated 


with 1,1,1-trichloroethane reached the planned termination date. The high
 

early mortality in mice receiving 1,1,1-trichloroethane may have lowered
 

the incidence of late-appearing tumors.
 

Table 6. Comparison of Survival of Control Groups, 


1,1, 1-Trichloroethane-Treated, and Carbon Tetrachloride-


Treated (Positive Control) Mice 


Group 1,1,1-Trichloroethane Carbon Tetrachloride 

Initial Number Number Initial Number Number 

No. of Alive Alive No. of Alive at Alive at 

Animals at 78 at 90 Animals 78 Weeks 90 Weeks 

Weeks Weeks 

MALE 

Control 20 6 2 20 13 7 

Low Dose 50 21 15 50 11 0 

High Dose 50 14 11 50 2 1 

FEMALE 

Control 20 12 11 20 18 17 

Low Dose 50 28 23 50 10 0 

High Dose 50 14 13 50 3 1 

23
 
Pathology (Mice)
 

A variety of neoplasms was represented among both the 1,1,1-trichloro-ethanetreated and matched-control mice (see Appendix B). These included fibrosarcoma 


and sarcoma of the subcutis, alveolar /bronchiolar adenoma, hepatic-cell 


adenoma and carcinoma, cystadenocarcinoma of the ovary, and adrenal cortical
 

adenoma. Malignant lymphoma, occurred in a number of organs either at primary
 

(lymph node, spleen) or metastatic (liver, pancreas, spleen, brain, kidney,
 

ovary) sites. 


Fibrosarcoma and sarcoma of the subcutis were observed in 1/47 low-dose 


females and 1/50 high-dose females, respectively. Hepatocellular carcinoma
 

occurred in 1149 high-dose males. Cyatadenocarcinoma of the ovary occurred in 


1/43 high-dose females. Malignant lymphoma of the spleen appeared in 1/15 


matched-control males, 2/44 high-dose males (with liver metastases), and 1/48
 

low-dose females. The few other cases of malignant lymphoma occurred in 


matched-control animals. 


Each of the types of neoplasm represented had been encountered previously as a 


spontaneous lesion in the mouse and no relationship in type or incidence to 


chemical treatment was apparent. 


A variety of nonneoplastic lesions was represented among both the matched-


control and chemical-treated animals (see Appendix D). Such lesions have been 


encountered previously as spontaneous occurrences in aging laboratory mice. Of 


the spontaneous lesions, chronic murine pneumonia was the most significant
 

pathologically. It occurred in all groups of matched-control and test animals 


and was the probable cause for the high incidence of early death. 


24 

 

 

 

The nearly 100% incidence of hepatocellular carcinoma in the positive-


control groups receiving carbon tetrachloride stands in marked contrast to 


the very low incidence among the 1,1,1-trichloroethane-treated mice and the 


matched-controls (see table 7). 


Table 7. Comparison of the Incidence of Hepatocellular Carcinoma 


in Control Groups, 1,1,1-Trichloroethane-Treated, and Carbon 


Tetrachloride-Treated (Positive Control) Mice 


Group 1,1,1-Trichloroethane Carbon Tetrachloride 


MALE
 

Control 2/19 2/19 


Low Dose 0/47 49/49 


High Dose 1/49 47/48 


FEMALE
 

Control 1/20 1/20 


Low Dose 0/48 40/40 


High Dose 0/50 43/45 


Statistical Analyses of Results (Mice)
 

Table 8 shows the proportions of primary tumors of the liver and malignant
 

lymphoma that accounted for most of the tumors observed in mice. In the
 

dosed groups the proportion of animals observed to have tumors was not
 

statistically significant; the matched-control groups had a higher
 

proportion of animals with tumors than any of the dosed groups. There were
 

no vehicle controls with an environment and period of test comparable to 


that of the dosed groups, but, due to the low incidence of tumors in the
 

dosed groups, the use of such vehicle-control groups could not show a 


25
 

dose-related association. The early deaths that occurred in the high-dose mice 


should be considered when inferences are made on the incidences of tumors
 

observed in the groups. 


The first lesions observed in the male mice were alveolar/bronchiolar tumor of 


the lung and malignant lymphoma in a matched-control animal at 80 weeks,
 

hemangiosarcoma in the low-dose animal group at 89 weeks, and hepatocellular 


adenoma of the liver at 50 weeks in a high-dose mouse. In the females, 


malignant lymphoma was observed at 80 weeks in the matched group, fibrosarcoma 


in the subcutaneous tissue at 54 weeks in the low-dose group, and
 

cystadenocarcinoma of the mammary at 26 weeks in the high-dose group. 


The low incidence of tumors of any type precluded interpretation of age-


adjusted statistical analyses. 


27 

4.0 DISCUSSION
 

The studies were not completely adequate tests of carcinogenicity because of 


the short survival time of the dosed animals. 


In rats, treatment with 1,1,1-trichloroethane failed to elicit a statistically 


significant increase in either the total number of neoplasms or in any
 

specific type of neoplasm. However, there was compound-related and dose-


related early mortality among the rats treated with 1, 1, 1-trichloroethane, 


and insufficient numbers survived to have demonstrated a significant incidence 


of late-developing tumors. The observation of a small number of hepatocellular 


carcinomas and neoplastic nodules in the carbon tetrachloride-treated positive 


control rats but not in the matched controls, suggests that Osborne-Mendel 


rats may respond positively to a potent chlorinated hydrocarbon hepatic
 

carcinogen, but this requires confirmation. 


In the mice, as in the rats, there were no tumors that could be related to
 

treatment. Survival of mice treated with 1,1,1-trichloroethane was longer than 


that of the rats. Only 3% of the rats survived to termination of the
 

experiment, compared with 31% of the mice. However, no carcinogenic response 


was demonstrated. 


Had the data indicated a positive carcinogenic effect for l,1,1­

trichloroethane, the presence of the inhibitor p-dioxane, or other possibly
 

carcinogenic impurities, would have raised some questions regarding the 


results. However, in the present study it is evident that such carcinogenic 


components (Argus et al.,1965 and 1973; Hoch-Ligeti et al., 1970) of technical 


grade 1,1,1-trichloroethane, if present, were in such low concentrations that
 

their influence was not revealed. 


28 

These studies cannot be regarded as appropriate tests for the carcinogenicity 


of l,1,1-trichloroethane in the test animals because of the abbreviated life 


spans of both the rats and mice. In addition, no previous studies adequate to 


evaluate carcinogenicity have been reported in the literature. 


29 

5.0 BIBLIOGRAPHY
 

Argus, M. F., Arcos, J.C., and Hoch-Ligeti, C. 1965. Studies on the 


carcinocenic activity of protein-denaturing agents: Hepatocarcinogenicity
 

of dioxane. J. Natl. Cancer Inst 35:949-958. 


Argus, M. F., Sohal, R. S., Bryant, G. H., Hoch-Ligeti, C., and Arcos, J. C.
 

1973. Dose-response and ultrastructural alterations in dioxane
 

carcinogenesis. Europ. J. Cancer 9:237-243. 


Armitage, P. 1971. Statistical Methods in Medical Research, p. 135. John Wiley 


and Sons, New York. 


Berenblum, I., ed. 1969. Carcinogenicity Testing. UICC Technical Report
 

Series, Vol. 2. International Union Against Cancer, Geneva. 


Browning, E. 1959. Toxic solvents: A review. Brit. J. Indust Med. 16:23-39. 


Chemical Economics Handbook. 1975. Chemical Information Services, Stanford
 

Research Institute, Menlo Park, California. 


Cox, D. R. 1970. Analysis of Binary Data pp. 61-65. Methuen, London. 


Cox, D. R. 1972. Regression models and life tables. .3. Statist Soc. B 


34:187-220. 


Della Porta, C., Terracini, B., and Shubik, P. 1961. Induction with carbon 


tetrachloride of liver cell carcinomas in hamsters. J. Natl. Cancer Inst. 
 26:855-863. 


Eschenbrenner, A. B. and Miller, E. 1946. Liver necrosis and the induction of 


carbon tetrachloride hepatomas in strain A mice. J. Natl. Cancer Inst. 
 6:325-341. 


Hoch-Ligeti, C., Argus, H. F., and Arcos, J. C. 1970. Induction of carcinomas
 

in the nasal cavity of rats by dioxane. Brit. J. Cancer 24:164-167. 


Kaplan, E. L. and Meier, P. 1958. Nonparametric estimation from incomplete 


observations. J. Amer. Statist. Assn. 53:457-481. 


Klassen, C. D. and Plaa, G. L. 1969. Comparison of the biochemical alterations 


elicited in livers from rats treated with carbon tetrachloride,
 

chloroform, 1,1,2-trichloroethane, and 1,1, 1-trichloroethane. Biochem. 


Pharmacol. 18:2019-2027. 


Linhart, M. S., Cooper, J. A., Martin, R. L., Page, N. P., and Peters, .3. A. 


1974. Carcinogenesls bioassay data system. J. Comp. Biomed. Res. 
 7:230-248. 


Miller, R. C., Jr. 1966. Simultaneous Statistical Inference McGraw-Hill, New
 

York. 


30 

National Cancer Institute. 1976. Carcinogenesis Bioassay of Trichloroethylene
 

NCI-CG-TR-2. Carcinogenesis Program, Division of Cancer Cause and
 

Prevention, National Institutes of Health, Bethesda, Maryland. USDHEW 


Pub. No. (NIH) /76-802. 


Reuber, M. D. and Glover, E. L. 1970. Cirrhosis and carcinoma of the liver in
 

male rats given subcutaneous carbon tetrachloride. J. Natl. Cancer Inst. 
 44:419-423. 


Sontag, J. M., Page, N. P., and Saffiotti, U. 1976. Guidelines for Carcinogen
 

Bioassay in Small Rodents, NCI-CG-TR-1. Carcinogenesis Program, Division
 

of Cancer Cause and Prevention, National Institutes of Health, Bethesda, 


Maryland. USDHEW Pub. No. (NIH) 76-801. 


Squire, R. A. and Levitt, H. H. 1975. Report of a workshop on classification 


of specific hepatocellular lesions in rats. Cancer Res. 35:3214-3233. 


Tarone, R. E. 1975. Tests for trend in life table analysis. Biometrika 62:679­

b82. 


U.S. 	Department of Health, Education, and Welfare, Food and Drug
 

Administration. 1973a. Trichloroethane: Aerosol Drug Products for Human 


Use. Federal Register 38 (No. 156): 21935-21936, 21 CFR Part 130,
 

August 14, 1973. 


U.S. Department 	of Health, Education, and Welfare, Food and Drug
 

Administration, 1973b. Human drugs containing trichloroethane: Notice to
 

drug manufacturers, Packers, and Distributors. Federal Register 38 (No.
 

156): 21950-21951, 21 CFR Part 130, August 14, 1973. 


U.S. Department of Labor, Occupational Health and Environmental Control. 1972.
 

Air contaminants. Federal Register 37 (No. 202): 22139-22144, 29 CFR Part 


1910, October 18, 1972. 


U.S. Dept. 	of Labor, Occupational Safety and Health Standards, Federal
 

Register, Vol. 39, No. 125- Thursday, June 27, 1974, page 23542. 


U.S. Environmental Protection Agency. 1972. Tolerances and exemptions from 


tolerances for pesticide chemicals in or on raw agricultural commodities.
 

Code of Federal Regulations 40 CFR Sec. 180.1012. 


U. S. Environmental Protection Agency, 1975. Preliminary Study of Selected
 

Potential Environmental Contaminants - Optical Brighteners, Methyl
 

Chloroform, Trichloroethylene, Tetrachloroethylene, Ion Exchange Resins. 


31 


APPENDIX A. 


SUMMARY OF THE INCIDENCE OF TUMORS IN RATS 


TREATED WITH 


1,1,1-TRICHLOROETHANE 


33 






APPENDIX B. 


SUMMARY OF THE INCIDENCE OF TUMORS IN MICE 


TREATED WITH 


1,1,1-TRICHLOROETHANE 


39
 





APPENDIX C 


SUMMARY OF THE INCIDENCE OF NONTUMOR PATHOLOGY 


IN RATS EXPOSED TO 


1 ,1 ,1-TRICHLOROETHANE 


45
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 TABLE C1 


SUMMARY OF THE INCIDENCE OF NONTUMOR PATHOLOGY 


IN MALE RATS TREATED WITH l,l,1-TRICHLOROETHANE 


CONTROL LOW DOSE HIGH DOSE 


ANIMALS INITIALLY IN STUDY 20 50 50 


ANIMALS NECROPSIED 20(100%) 49(100%) 50(100%) 


ANIMALS EXAMINED HISTOPATHOLOGICALLY 20 49 50 


ANIMALS WITH NON-TUMOR PATHOLOGY 20(100%) 48 (98%) 50(100%) 


INTEGUMENTARY SYSTEM * 2 (10%) 


SKIN 2 


EDEMA 2 


SUBCUT TISSUE 2 


EDEMA 2 


RESPIRATORY SYSTEM 20 (100%) 48 (98%) 50 (100%) 


TRACHEA 10 23 23 


INFLAMMATION 1 


ULCER 5 1 


INFLAMMATION SUPPURATIVE 1 2 


INFLAMMATION ACUTE 2 6 7 


ULCER ACUTE 7 11 


INFLAMMATION ACUTE SUPPURATIVE 1 


INFLAMMATION SUBACUTE 8 4 1 


TRACHEAL SUBMUCOSA 4 2 


HEMORRHAGE 4 2 


LUNG/BRONCHUS 10 15 24 


BRONCHIECTASIS 10 10 6 


ULCER 1 


INFLAMMATION ACUTE 1 7 


ULCER ACUTE 6 


INFLAMMATION ACUTE SUPPURATIVE 2 5 


INFLAMMATION CHRONIC 1 


INFLAMMATION CHRONIC SUPPURATIVE 1 


LUNG/BRONCHIOLE 14 6 


INFLAMMATION ACUTE SUPPURATIVE 2 1 


INFLAMMATION SUBACUTE 3 1 


INFLAMMATION CHRONIC 9 


INFLAMMATION CHRONIC SUPPURATIVE 3 


FIBROSIS 1 


47
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

TABLE Cl MALE RATS: NONTUMOR PATHOLOGY 


(CONT.) 


CONTROL LOW DOSE HIGH DOSE 


LUNG 20 28 29 

BROICHIECTASIS 1 

CONGESTION 8 6 

EDEMA 2 1 

INFLAMMATION FOCAL 1 

BRONCOPNEUMONIA ACUTE 1 6 

INFLAMMATION ACUTE 2 5 

INFLAMMATIONA CUTE SUPPURATIVE 9 7 8 

BRONCOPNEUMONIA ACUTE SUPPURATIVE 2 

ABSCESS 

PNEUMONIA CHRONIC MURINE 

INFLAMMATION CHRONIC 5 

INFLAMMATION FOCAL CHRONIC 4 

INFLAMMATION CHRONIC SUPPURATIVE 7 11 2

 BRONCOPNEUMONIA CHRONIC SUPPURATIVE 1 2

 ABSCESS CHRONIC 1 1

 INFLAMMATION GRANULOMATOUS 1

 FIBROSIS DIFFUSE 1 

LUNG/ALVEOLI 1 19 25 

COLLAPSE 1 2 

EDEMA 17 25 

CIRCULATORY SYSTEM 2 (10%) 5 (10%) 7 (14%) 

ATRIUM 

THROMBOSIS 

1 

1 

MYOCARDIUM 

INFLAMMATION CHRONIC 

FIBROSIS 

DEGENERATION 

1 

1 

PERICARDIUM 

INFLAMMATION 

EPICARDIUM 

INFLAMMATION 

INFLAMMATION ACUTE 

INFLAMMATION ACUTE 

INFLAMMATION SUBACUTE

INFLAMMATION CHRONIC 

LIPO-GRANULOMA 

NECROSIS FAT 

1 

1 

4 

1 

1 

1 

1 

6 

4 

2 

1 

1 

AORTA 

MEDIAL CALCIFICATION 

48 

 

 

 

 

 

 

 

 

 

 

 

 

 

TABLE C1 MALE RATS: NONTUMOR PATHOLOGY (CONT.) 


CONTROL LOW DOSE HIGH DOSE 


CORONARY ARTERY 


MEDIAL CALCIFICATION 


MESENTERIC ARTERY 


MEDIAL CALCIFICATION 


PORTAL VEIN 1 


THROMBOSIS 1 


DIGESTIVE SYSTEM 17 (85%) 8 (16%) 7 (14%) 

SALIVARY GLAND 

INFLAMMATION ACUTE 

1 

1 

LIVER 

CONGESTION 

ABSCESS CHRONIC 

PELIOSIS HEPATIS 

NECROSIS FOCAL 

INFARCT 

METAMORPHOSIS FATTY 

HYPERTROPHY 

13 

11 

1 

1 

1 

4 

1 

1 

2 

3 

3 

LIVER/CENTRILOBULAR 

CONGESTION 

1 

1 

LIVER/PERIPORTAL 

FIBROSIS 

1 

1 

LIVER/KUFFER CELL 

HYPERTROPHY 

1 

1 

BILE DUCT 

HYPERPLASIA 

1 

1 

PANCREAS 

INFLAMMATION CHRONIC 

PERIARTERITIS 

3 

2 

1 

ESOPHAGUS 

DISTENTION 

FOREIGN-BODY GRANULOMA 

2 

1 

1 

STOMACH 

HEMORRHAGE 

2 

1 

49 

TABLE C1 MALE RATS: NONTUMOR PATHOLOGY (CONT.) 


 

STOMACH (CONT.) 


ULCER 

INFLAMMATION FOCAL 


CALCIUM DEPOSITION 


GASTRIC MUCOSA 

HEMORRHAGE 

SMALL INTESTINE 

HEMORRHAGE 

LARGE INTESTINE 

INFLAMMATION ACUTE HEMORRHAGIC 

COLONIC SUBMUCOSA 

HEMORRHAGE 

 

URINARY SYSTEM 

 KIDNEY 

MINERALIZATION 

HYDRONEPHROSIS 

CONGESTION 

HEMORRHAGE 

PYELONEPHRITIS 


ABSCESS 

INFLAMMATION CHRONIC 

INFLAMMATION CHRONIC CYSTIC 

INFARCT HEALED 

KIDNEY/CORTEX 

HEMORRHAGE 

ABSCESS 

FIBROSIS DIFFUSE 

RENAL TUBULE 

DILATATION 

CAST 

URINARY BLADDER 

HEMORRHAGE 

CONTROL 

1 


1 


1 


1 


1 


16 (80%) 

10 

4 

5 

1 


1 

1 


8 

8 

8 

2 

1 


LOW DOSE 

2 

2 

18 (37%) 

13 

1 


3 

3 

1 


6 

4 


1 


3 


1 

1 

1 

1 


HIGH DOSE
 

2 


2 


1 


1 


22 (44%)


20 


1 


7 


1 


11 


2 


5 


5 


5 


50
 
 

TABLE C1 MALE RATS: NONTUMOR PATHOLOGY (CONT.) 


CONTROL LOW DOSE HIGH DOSE 


URINARY BLADDER (CONT.) 


ULCER ACUTE 1 


ULCER CHRONIC 1 


ENDOCRINE SYSTEM


 PITUITARY 


CYST 


ADRENAL 


CYST 


CONGESTION 


HEMORRHAGE 


HEMATOCYST 


ANGIECTASIS 


METAPLASIA OSSEOUS 


ADRENAL CORTEX 


HEMORRHAGE 


DEGENERATION 


LIPOIDOSIS 


ADRENAL MEDULLA 


CYST 


HYPERPLASIA 


THYROID 


CYST 


PARATHYROID 


HYPERPLASIA 


PANCREATIC ISLETS 


HYPERPLASIA 


4 (20%) 


2 


1 


1 


3 


1 


2 


1 


1 


10 (20%) 


3 


3 


2 


1 


1 


5 


5 


1 


1 


1 


1 


8 (16%) 


3 


3 


1 


1 


1 


3 


3 


1 


1 


2 


2 


1 


1 


HEMATOPOIETIC SYSTEM 13 (65%) 27 (55%) 19 (38%) 


BONE MARROW 2 3 


HYPERPLASIA HEMATOPOIETIC 2 3 


51
 
 

 

 

 

 

TABLE C1 MALE RATS: NONTUMOR PATHOLOGY (CONT.) 


CONTROL LOW DOSE HIGH DOSE 


SPLEEN 12 19 16 

CONGESTION 3 


INFLAMMATION ACUTE 1 


HEMOSIDEROSIS 10 11 9 


ATROPHY 1 


LYMPHOID DEPLETION 1 


MYELOID METAPLASIA 1 6 7 


HEMATOPOIESIS 


LYMPH NODE 6 14 10 


LYMPHANGIECTASIS 1 2 


CONGESTION 3 6 2 


EDEMA 1 


HEMORRHAGE 1 


INFLAMMATION 1 


 INFLAMMATION ACUTE 3 


INFLAMMATION ACUTE HEMORRHAGIC 2 


INFLAMMATION SUBACUTE 1 


HYPERPLASIA RETICULAR-CELL 3 5 


LYMPHOID HYPERPLASIA 1 


THYMUS 3 


CONGESTION 1 


HEMORRHAGE 2 


REPRODUCTIVE SYSTEM 7 (35%) 14 (29%) 12 (24%) 


 MAMMARY GLAND 1 


CYST 1 


PROSTATE 3 8 9 


EDEMA 1 


INFLAMMATION 


INFLAMMATION ACUTE 1 3 3 


INFL&MMATIOI ACUTE SUPPURATIVE 1 


INFLAMMATION SUBACUTE 1 


INFLAMMATION CHRONIC 3 2 


INFLAMMATION CHRONIC SUPPURATIVE 1 2 


FIBROSIS DIFFUSE 2 


ATROPHY 1 1 


SEMINAL VESICLE 1 1 


INFLAMMATION ACUTE 1 1 


TESTIS 6 8 4 


ATROPHY 2 2 2 


ATROPHY FOCAL 2 


ASPERRMATOGENESIS 4 4 2 


52 

 

 

 

 

 

 

 

 

 

-------------------------------------------------------------------- 

-------------------------------------------------------------------- 

 

 

------------------------------------------------------------------- 

 

 

 

 

 

 

 

TABLE C1 MALE RATS: NONTUMOR PATHOLOGY (CONT.) 


CONTROL LOW DOSE HIGH DOSE 


EPIDIDYMIS 1 


NECROSIS FAT 


ATROPHY 1 


NERVOUS SYSTEM 1 (5%) 1 (2%) 

BRAIN/MENINGES 

INFLAMMATION ACUTE 

INFLAMMATION GRANULOMATOUS 

1 

1 

1 

1 

BRAIN 

ABSCESS 

1 

1 

MUSCULOSKELETAL SYSTEM 


NONE 


SPECIAL SENSE ORGANS 


NONE 


ALL OTHER SYSTEMS

 ABDOMEN 

LIPO-GRANULOMA 

NECROSIS FAT 

1(2%) 2 (4%) 

1 

1 

1 

PLEURA 

INFLAMMATION ACUTE 

INFLAMMATION SUBACUTE 

1 

1 

1 

1 

1 

NO LESION REPORTED 


AUTOLYSIS/NO NECROPSY PERFORMED 
 1 


ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 

NATURAL DEATH* 

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY EXILED 

TERMINAL SACRIFICE 

20 

20 

50 

50 

50 

49 

1 

* INCLUDES AUTOLYZED ANIMALS 

* SYSTEM PERCENTAGES ARE BASED ON NUMBER OF ANIMALS NECROPSIED. 


53
 
TABLE C2 


SUMMARY OF THE INCIDENCE OF NONTUMOR PATHOLOGY 


IN FEMALE RATS TREATED WITH 1,1,1-TRICHLOROETHANE 


CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 20 50 50 

ANIMALS NECROPSIED 20(100%) 50(100%) 50(100%) 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 20 50 50 

ANIMALS WITH NON-TUMOR PATHOLOGY 20(100%) 49 (98%) 50(100%) 

INTEGUMENTARY SYSTEM 


NONE 


RESPIRATORY SYSTEM * 20 (100%) 47 (94%) 49 (98%) 

TRACHEA 9 14 17 

ULCER 1 

INFLAMMATION SUPPURATIVE 2 

INFLAMMATION ACUTE 3 9 4 

ULCER ACUTE 1 3 7 

INFLAMMATION SUBACUTE 5 2 3 

LUNG/BRONCHUS 15 15 14 

BROICHIECTASIS 15 7 8 

INFLAMMATION ACUTE 1 3 

ULCER ACUTE 2 

INFLAMMATION ACUTE SUPPURATIVE 3 1 

INFLAMMATION CHRONIC 2 

ULCER CHRONIC 1 

INFLAMMATION CHRONIC SOPPURATIVE 2 2 

LYMPHOID HYPERPLASIA 1 

LUNG/BRONCHIOLE 3 2 3 

INFLAMMATION CHRONIC 2 

INFLAMMATION CHRONIC SUPPURATIVE 1 3 

FIBROSIS 1 1 

LUNG 19 36 37 

CONGESTION 7 21 

EDEMA 3 4 

HEMORRHAGE 1 

BRONCHOPNEUMONIA 1 

INFLAMMATION 1 

BRONCHOPNEUMONIA ACUTE 6 5 

INFLAMMATION ACUTE 2 

INFLAMMATION ACUTE SUPPURATIVE 2 9 5 

BRONCHOPNEUMONIA ACUTE SUPPURATI 4 2 

54
 
 

 

 

 

 

 

 

 

 

 

 

 

 

TABLE C2 FEMALE RATS: NONTUMOR PATHOLOGY (CONT.) 


CONTROL LOW DOSE HIGH DOSE 

LUNG 

PNEUMONIA CHRONIC MURINE 

INFLAMMATION CHRONIC 

BRONCHOPNEUMONIA CHRONIC 

INFLAMMATION FOCAL CHRONIC 

INFLAMMATION CHRONIC SUPPURATIVE 

BRONCHOPNEUMONIA CHRONIC SUPPURA 

ABSCESS CHRONIC 

FIBROSIS DIFFUSE 

2 

12 

1 

3 

1 

1 

5 

4 

3 

2 

7 

8 

1 

LUNG/ALVEOLI 

COLLAPSE 

EDEMA 

3 

3 

10 

1 

9 

18 

2 

16 

CIRCULATORY SYSTEM 

HEART 

2 (10%) 

1 

17 (34%) 20 (40%) 

1 

ABSCESS CHRONIC 

FIBROSIS DIFFUSE 1 

1 

MYOCARDIUM 

INFLAMMATION SUBACUTE 

1 

1 

PERICARDIUM 

INFLAMMATION 

EPICARDIUM 

INFLAMMATION 

INFLAMMATION ACUTE 

INFLAMMATION ACUTE FIBRINOUS 

INFLAMMATION SUBACUTE 

INFLAMMATION CHRONIC 

INFLAMMATION CHRONIC 

SUPPURATIVE 

FIBROSIS 

1 

1 

17 

1 

2 

1 

4 

8 

1 

18 

1 

7 

3 

1 

6 

DIGESTIVE SYSTEM 12 (60%) 9 (18%) 16 (32%)

 SALIVARY GLAND 

CYST 

ABSCESS CHRONIC 

1 

1 

LIVER 

CONGESTION 

NECROSIS 

METAMORPHOSIS FATTY 

ATROPHY 

ANGIECTASIS 

6 

5 

1 

1 

2 

1 

1 

4 

3 

1 

HEPATIC CAPSULE 

FIBROSIS 

1 

1 

55
 
 

 

 

 

 

 

 

TABLE C2 FEMALE RATS: NONTUMOR PATHOLOGY (CONT.) 


 CONTROL LOW DOSE HIGH DOSE 

LIVER/CENTRILOBULAR 1 2 


NECROSIS 1 


ATROPHY 2


 LIVER/PERIPORTAL 1 2


 FIBROSIS 1 2


 BILE DUCT 3 2 3 


INFLAMMATION CHRONIC 1


 HYPERPLASIA 2 2 3 


PANCREAS 1 1


 INFLAMMATION CHRONIC 1


 PERIARTERITIS 1


 PANCREATIC ACINUS 1


 ATROPHY 1


 ESOPHAGUS 2


 GRANULOMA 1


 FIBROSIS 1


 STOMACH 2 2 1 


INFLAMMATION HEMORRHAGIC 1


 INFLAMMATION ACUTE 1 


ULCER ACUTE 1


 INFLAMMATION SUBACUTE 1


 INFLAMMATION CHRONIC 1 


GASTRIC MUCOSA 2 2 


EDEMA 1


 HEMORRHAGE 2 1 


SMALL INTESTINE 1


 ULCER CHRONIC 1


 LARGE INTESTINE 1


 EDEMA 1


 COLON 1


 INFLAMMATION ACUTE 1
 

56
 
 

 

 

 

 

 

TABLE C2 FEMALE RATS: NONTUMOR PATHOLOGY (CONT) 


CONTROL LOW DOSE HIGH DOSE
 

URINARY SYSTEM 15 (75%) 23 (46%) 15 (30%) 

KIDNEY 

MINERALIZATION 

HYDRONEPHROSIS 

CONGESTION 

HEMORRHAGE 

PYELONEPHRITIS 

ABSCESS 

INFLAMMATION CHRONIC

 CALCIUM DEPOSITION 

12 

2

 1 

7 

4 

21 

5 

14 

1 

2 

13 

2 

2 

7 

1 

1 

KIDNEY/CORTEX 

FIBROSIS 

1 

1 

RENAL TUBULE 

DILATATION 

CAST 

4 

4 

4 

3 

3 

3 

2 

2 

2 

ENDOCRINE SYSTEM 

PITUITARY 

CYST 

12 (60%) 

2 

2 

19 (38%) 

4 

4 

21 (42%)

 6 

6 

ADRENAL 

CONGESTION 

EDEMA 

HEMORRHAGE 

HERATOCYST 

ANGIECTASIS 

9 

7 

3 

16 

14 

1 

2 

1 

15 

13 

3 

8 

ADRENAL CORTEX 

CYST 

DEGENERATION 

LIPOIDOSIS 

HYPERTROPHY 

ANGIECTASIS 

3 

3 

8 

1 

8 

10 

10 

1 

ADRENAL MEDULLA 

HYPERRPLASIA 

1 

1 

2 

2 

THYROID 

DILATATION 

FOLLICULAR CYST 

HYPERPLASIA C-CELL 

PARATHYROID 

CONGESTION 

2 

1 

1 

1 

1 

57

 

 

 

TABLE C2 FEMALE RATS: NONTUMOR PATHOLOGY (CONT.) 


CONTROL LOW DOSE HIGH DOSE
 

PANCREATIC ISLETS 1


 HYPERPLASIA 1 


HEMATOPOIETIC SYSTEM 18 (90%) 34 (68%) 34 (68%) 

BONE MARROW 1 4 

CONGESTION 1 

HEMORRHAGE 1 

HYPERPLASIA HEMATOPOIETIC 1 3 

SPLEEN 17 26 29 

CONGESTION 1 4 1 

INFLAMMATION ACUTE 2 1 

HEMOSIDEROSIS 10 9 9 

HYPERPLASIA RETICULUM-CELL 1 

MYELOID METAPLASIA 10 11 19 

LYMPH NODE 6 18 16 

LYMPHANGIECTASIS 3 2 

CONGESTION 3 5 3 

HEMORRHAGE 2 2 

INFLAMMATION 1 

INFLAMMATION ACUTE 3 1 

INFLAMMATION SUBACUTE 3 

INFLAMMATION CHRONIC 1 

GRANULOMA 1 

HEMOSIDEROSIS 2 

PLASMACYTOSIS 1 1 

HYPERPLASIA RETICULUM-CELL 2 1 5 

LYMPHOID HYPERPLASIA 6 4 

MYELOID METAPLASIA 1 

REPRODUCTIVE SYSTEM 4 (20%) 8 (16%) 5 (10%) 

VAGINA 

INFLAMMATORY POLYP 

UTERUS 

HYDROMETRA 

3 

2 

4 

2 

58

 

 

 

 

 

 

 

 

 

 

 

TABLE C2 FEMALE RATS: NONTUMOR PATHOLOGY (CONT.)
 

UTERUS(CONT.) 

HEMORRHAGE 

1 

CONTROL LOW DOSE HIGH DOSE 

INFLAMMATION ACUTE SUPPURATIVE 

 INFLAMMATION CHRONIC SUPPURATIVE 

1 

1 

UTERUS/ENDOMETRIUM 

CYST 

INFLAMMATION ACUTE 

INFLAMMATION ACUTE CYSTIC 

HYPERPLASIA 

4 

3 

1 

6 

1 

3 

1 

1 

4 

2 

1 

1 

OVARY 

CYST 

NERVOUS SYSTEM 2 (10%) 2 (14%) 1 (2%) 

CHOROID PLEXUS 

ANGIECTASIS 

1 

1 

BRAIN 

ABSCESS 

GLIOS1S 

ATROPHY 

1 

1 

1 

1 

1 

1 

 MEDULLA OBLONGATA 

ABSCESS 

1 

1 

MUSCULOSKELETAL SYSTEM 1 (2%) 

SKELETAL MUSCLE 1 

INFLAMMATION ACUTE 1 

SPECIAL SENSE ORGANS 


NONE 


59

 

 

 

 

 

 

 

 

 

TABLE C2 FEMALE RATS: NONTUMOR PATHOLOGY (CONT.) 


CONTROL LOW DOSE HIGH DOSE 


ALL OTHER SYSTEMS 1 (5%) 4 (8%) 9 (18%) 

ABDOMEN 

LIPO-GRANULOMA 

NECROSIS FAT 

1 

1 

1 

MEDIASTINUM 

INFLAMMATION ACUTE SUPPURATIVE 

ABSCESS CHRONIC 

FIBROSIS 

4 

1 

2 

1 

PLEURA 

INFLAMMATION 

INFLAMMATION ACUTE SUPPURATIVE 

INFLAMMATION SUBACUTE 

INFLAMMATION CHRONIC 

1 

1 

3 

1 

2 

7 

1 

6 

NO LESION REPORTED 1 


ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 

NATURAL DEATHS 

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

20 

16 

1 

3 

50 

48 

2 

50 

47 

2 

1 

* INCLUDES AUTOLYZED ANIMALS 

*SYSTEM PERCENTAGES ARE BASED ON NUMBER OF ANIMALS NECROPSIED. 


60 

APPENDIX D 


SUMMARY OF THE INCIDENCE OF NONTUMOR PATHOLOGY 


IN MICE EXPOSED TO 


1,1,1-TRICHLOROETHANE 


61 


 

 

TABLE Dl 


SUMMARY OF THE INCIDENCE OF NONTUMOR PATHOLOGY 


IN MALE MICE TREATED WITH 1,1,1-TRICHLOROETHANE 


CONTROL LOW DOSE HIGH DOSE 


ANIMALS INITIALLY IN STUDY 20 50 50 

ANIMALS MISSING 1 

ANIMALS NECROPSIED 15(100%) 47(100%) 50(100%) 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 15 47 49 

ANIMALS WITH NON-TUMOR PATHOLOGY 14 (93%) 45 (96%) 49 (98%) 

INTEGUMENTARY SYSTEM * 2 (13%) 12 (26%) 15 (30%) 

SKIN 

EDEMA 

ULCER 

INFLAMMATION ACUTE 

ABSCESS CHRONIC 

ACANTHOSIS 

PARAKERATOSIS 

1 

1 

12 

1 

11 

2 

15 

1 

1 

14 

SUBCUT TISSUE 

EDEMA 

ABSCESS 

1 

1 

RESPIRATORY SYSTEM 10 (67%) 40 (85%) 46 (92%) 

TRACHEA 2 

INFLAMMATION 2 

LUNG 10 40 46 

CONGESTION 9 18 31 

EDEMA 11 18 

HEMORRHAGE 1 

BRONCHOPNEUMONIA 1 3 

INFLAMMATION 1 9 9 

BRONCHOPNEUMONIA ACUTE 4 1 

ABSCESS 1 1 

PNEUMONIA CHRONIC MURINE 

BRONCHOPNEUMONIA CHRONIC 3 

CIRCULATORY SYSTEM 1 (7%) 

AORTA 1 

INFLAMMATION ACUTE 1 

63 

 

 

TABLE D1 MALE MICE: NONTUMOR PATHOLOGY (CONT.) 


CONTROL LOW DOSE HIGH DOSE 


DIGESTIVE SYSTEM 8 (53%) 13 (28%) 5 (10%)

 LIVER 

HEMATOMA 

LYMPHOOCYTIC INFLAM INFILTRATE 

AMYLOIDOSIS 

HYPERPLASIA 

ANGIECTASIS 

8 

7 

1 

9 

1 

4 

4 

5 

2 

1 

2 

LIVER/CENTRILOBULAR 

NECROSIS FOCAL 

1 

1 

LIVER/KUPFFER CELL 

HYPERPLASIA 

1 

1 

PANCREAS 

PERIARTERITIS 

1 

1 

SMALL INTESTINE 

LYMPHOID HYPERPLASIA 

1 

1 

COLON 

HEMATODIASIS 

URINARY SYSTEM 13 (87%) 7 (15%) 7 (14%)

 KIDNEY 

HYDRONEPHROSIS 

LYMPHOCYTIC INFLAM INFILTRATE 

INFLAMMATION ACUTE SUPPURATIVE 

INFLAMMATION CHRONIC 

INFLAMMATION CHRONIC CYSTIC 

FIBROSIS DIFFUSE 

AMYLOIDOSIS 

12 

2 

2 

4 

2 

3 

5 

4 

1 

1 

7 

6 

1 

KIDNEY/CORTEX 

LYMPHOCYTIC INFLAM INFILTRATE 

2 

2 

RENAL TUBULE 

CYTOPLISMIC VACUOLIZATION 

2 

2 

URINARY BLADDER 

INFLAMMATION 

64
 
 

 

 

 

 

 

 

 

 

 

TABLE Dl MALE MICE: NONTUMOR PATHOLOGY (CONT.) 


CONTROL LOW DOSE HIGH DOSE 


ENDOCRINE SYSTEM 3 (20%) 

ADRENAL 3 

AMYLOIDOSIS 3 

HEMATOPOIETIC SYSTEM 10 (67%) 15 (32%) 14 (28%) 

 BONE MARROW 

HYPERPLASIA HEMATOPOIETIC 

1 

1 

1 

1 

SPLEEN 

AMYLOIDOSIS 

HYPERPLASIA HEMATOPOIETIC 

LYMPHOID HYPERPLASIA 

MYELOID METAPLAS1A 

8 

7 

1 

9 

4 

1 

3 

2 

7 

3 

4 

LYMPH NODE 

CONGESTION 

HEMORRHAGE 

INFLAMMATION ACUTE 

LYMPHOID DEPLETION 

HYPERPLASIA RETICULAM-CELL 

LYMPHOID HYPERPLASIA 

3 

2 

1 

1 

9 

3 

1 

1 

5 

1 

9 

4 

5 

CERVICAL LYMPH NODE 

ANGIECTASIS 

SUPERIOR DEEP CERVIC 

ANGIECTASIS 

REPRODUCTIVE SYSTEM 1 (7%) 1 (2%) 

PROSTATE 

INFLAMMATION ACUTE 

1 

1 

 SEMINAL VESICLE 

DILATATION 

1 

1 

EPIDIDYMIS 

SPERMATOGENIC GRANULOMA 

65
 
 

 

 

 

 

TABLE Dl MALE MICE: NONTUMOR PATHOLOGY (CONT.) 


CONTROL LOW DOSE HIGH DOSE 


NERVOUS SYSTEM 1 (7%) 


BRAIN/MENINGES 1 


INFLAMMATION ACUTE 1 


MUSCULOSKELETAL SYSTEM 


NONE 


SPECIAL SENSE ORGANS 


NONE 


ALL OTHER SYSTEMS 


NONE 


NO LESION REPORTED 1 2 1 

AUTOLYSIS/NECROPSY PERF/NO HISTO 

AUTOLYSIS/NO NECROPSY PERFORMED 4 3 

ANIMAL DISPOSITION SUMMARY

 ANIMALS INITIALLY IN STUDY 

NATURAL DEATH 

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

MISSING 

20 

17 

2 

1 

50 

35 

15 

50 

37

2

11

* INCLUDES AUTOLYZED ANIMALS 

* SYSTEM PERCENTAGES ARE BASED ON NUMBER OF ANIMALS NECROPSIED. 


66
 
 

 

 

 

 

 

 

 TABLE D2 


SUMMARY OF THE INCIDENCE OF NONTUMOR PATHOLOGY 


IN FEMALE MICE TREATED WITH 1,1,1-TRICHLOROETHANE 


CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 20 50 50 

ANIMALS NECROPSIED 18(100%) 48(100%) 50(100%) 

ANIMALS EXAMINED HISTOPATOLOGICALLY 18 48 50 

ANIMALS WITH NON-TUMOR PATHOLOGY 18.(100%) 48(100%) 50(100%) 

RESPIRATORY SYSTEM * 14 (78%) 42 (88%) 43 (86%) 

TRACHEA 

INFLAMMATION ACUTE 

1 

1 

LUNG/BRONCHUS 

INFLAMMATORY POLYP 

1 

1 

LUNG 14 

CONGESTION 9 

EDEMA 1 

HEMORRHAGE 

INFLAMMATION 4 

INFLAMMATION ACUTE SUPPURATIVE 

 BRONCHOPNEUMONIA ACUTE SUPPURATIVE 

PNEUMONIA CHRONIC MURINE 

BRONCHOPNEUMONIA CHRONIC 1 

42 

16 

6 

6 

24 

6 

1 

43 

29 

13 

2 

17 

3 

2 

CIRCULATORY SYSTEM 1 (2%) 

MYOCARDIUM 1 

INFLAMMATION ACUTE 1 

DIGESTIVE SYSTEM 4 (22%) 14 (29%) 8 (16%) 

SALIVARY GLAND 1 

LYMPHOCYTIC INFLAM INFILTRATE 1 

67
 
 

 

 

 

 

 

 

TABLE D2 FEMALE MICE: NONTUMOR PATHOLOGY (CONT.) 


CONTROL LOW DOSE HIGH DOSE 


LIVER 

LYMPHOCYTIC INFLAM INFILTRATE 

INFLAMMATION SUBACUTE 

NECROSIS 

NECROSIS FOCAL 

AMYLOIDOSIS 

HYPERPLASIA 

ANGIECTASIS 

LYMPHOID HYPERPLASIA 

MYELOID METAPLASIA 

3 

2 

1 

13 

1 

7 

2 

1 

1 

1 

8 

6 

1 

1 

LIVER/CENTRILOBULAR 

NECROSIS 

1 

1 

PANCREATIC DUCT 

DILATATION 

STOMACH 

ULCER ACUTE 

1 

1 

SMALL INTESTINE 

LYMPHOID HYPERPLASIA 

1 

1 

COLON 

HEMATODIASIS 

URINARY SYSTEM 6 (33%) 9 (19%) 2 (4%) 

KIDNEY 

HYDRONEPHROSIS 

PYELONEPHRITIS 

LYMPHOCYTIC INFLAM INFILTRATE 

INFLAMMATION ACUTE SUPPURATIVE

 INFLAMMATION CHRONIC 

INFLAMMATION CHRONIC CYSTIC 

ATROPHY 

5 

1 

4 

1 

9 

4 

1 

2 

3 

2 

2 

2 

URINARY BLADDER 

LYMPHOCYTIC INFLAM INFILTRATE 

1 

1 

68
 
 

 

 

 

TABLE D2 FEMALE MICE: NONTUMOR PATHOLOGY (CONT.) 


CONTROL LOW DOSE HIGH DOSE 


ENDOCRINE SYSTEM 1 (6%) 6 (13%) 1 (2%) 

ADRENAL 5 1 

CONGESTION 

AMYLOIDOSIS 

1 

4 

1 

ADRENAL CORTEX 

HYPERPLASIA 

1 

1 

1 

1 

HEMATOPOIETIC SYSTEM 8 (44%) 26 (54%) 11 (22%) 

BONE MARROW 

HEMORRHAGE 

HYPERPLASIA HEMATOPOIETIC 

3 

1 

2 

4 

4 

SPLEEN 

CONGESTION 

INFLAMMATION ACUTE 

AMYLOIDOSIS 

ATROPHY 

HYPERPLASIA FOLLICULAR-CELL 

HYPERPLASIA HEMATOPOIETIC 

LYMPHOID HYPERPLASIA 

MYELOID METAPLASIA 

6 

1 

5 

24 

1 

3 

7 

1 

4 

14 

11 

1 

1 

1 

1 

4 

6 

LYMPH NODE 

HEMORRHAGE 

INFLAMMATION ACUTE 

INFLAMMATION ACUTE SUPPURATIVE 

INFLAMMATION CHRONIC 

PLASMA CELL INFILTRATE 

HYPERPLASIA RETICULUM-CELL 

LYMPHOID HYPERPLASIA 

3 

1 

2 

8 

1 

1 

1 

1 

1 

3 

1 

1 

REPRODUCTIVE SYSTEM 15 (83%) 27 (56%) 23 (6%) 

VAGINA 

INFLAMMATION CHRONIC 

1 

1 

UTERUS 

HYDROMETRA 

INFLAMMATION 

INFLAMMATION ACUTE SUPPURATIVE 

1 

1 

2 

2 

3 

3 

UTERUS/ENDOMETRIUM 

CYST 

15 26 19 

7 

69
 
 

 

 

 

 

TABLE D2 FEMALE MICE: NONTUMOR PATHOLOGY (CONT.) 


CONTROL LOW DOSE HIGH DOSE 


UTERUS/ENDOMETRIUM (CONT.) 

HYPERPLASIA 

HYPERPLASIA CYSTIC 15 

1 

25 12 

FALLOPIAN TUBE 

DILATATION 

1 

1 

OVARY 

CYST 

FOLLICULAR CYST 

HEMORRHAGE 

ATROPHY 

ANGIECTASIS 

5 

2 

1 

2 

4 

2 

2 

1 

2 

1 

1 

NERVOUS SYSTEM 


NONE 


MUSCULOSKELETAL SYSTEM 


NONE 


SPECIAL SENSE ORGANS 


NONE 


ALL OTHER SYSTEMS 2 (4%) 

PLEURA 2 

INFLAMMATION ACUTE 2 

NO LESION REPORTED 


AUTOLYSIS/NO NECROPSY PERFORMED 2 2 


ANIMAL DISPOSITION SUMMARY 

ANIMALS LEFT IN STUDY 

NATURAL DEATH* 

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

20 

9 

11 

50 

27 

1 

22 

50 

36 

1 

13 

* INCLUDES AUTOLYZED ANIMALS 

• SYSTEM PERCENTAGES ARE BASED ON NUMBER OF ANIMALS NECROPSIED. 

70