1978 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 73 

BIOASSAY OF 

ALLYL CHLORIDE 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 107-05-1 

NCI-CG-TR-73 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

ALLYL CHLORIDE
 

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
 

DREW Publication No. (NIH) 78-1323
 

REPORT ON THE BIOASSAY OF ALLYL CHLORIDE
 

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 allyl
 

chloride conducted for the Carcinogenesis Testing Program, Division
 

of Cancer Cause and Prevention, National Cancer Institute (NCI),
 

National Institutes of Health, Bethesda, Maryland. This is one of a
 

series of experiments designed to determine whether selected chemicals
 

have the capacity to produce cancer in animals. Negative results, in
 

which the test animals do not have a significantly greater incidence
 

of cancer than control animals, do not necessarily mean the test chemical is not a carcinogen because the experiments are conducted under
 

a limited set of circumstances. Positive results demonstrate that the
 

test chemical is carcinogenic for animals under the conditions of the
 

test and indicate a potential risk to man. The actual determination
 

of the risk to man from animal carcinogens requires a wider analysis.
 

CONTRIBUTORS: This bioassay of allyl chloride was conducted by
 

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

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

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

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

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

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

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

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

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

Histopathologic examinations were performed by Dr. R. H. Habermann (3) and reviewed by Dr. R. W. Voelker (3) at the Hazleton Laboratories America, Inc., and the diagnoses included in this report
 

represent the interpretation of these pathologists. Histopathology
 

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

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

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

R. Joiner (7), using methods selected for the Carcinogenesis Testing
 

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

iii
 
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), task leader Dr. M. R. Kornreich (6), senior biologist Ms. P.
 

Walker (6), biochemist Dr. B. Fuller (6), and technical editor Ms.
 

P. A. Miller (6). The final report was reviewed by members of the
 

participating organizations.
 

The following other scientists at the National Cancer Institute
 

were responsible for evaluating the bioassay experiment, interpreting
 

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

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

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

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

1.	 Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

2.	 Now with the Naylor Dana Institute for Disease Prevention, American Health Foundation, Mammon House Road, Valhalla, New York.
 

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

Vienna, Virginia.
 

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

Reston, Virginia.
 

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

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

Boulevard, McLean, Virginia.
 

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

Maryland.
 

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

Rockville, Maryland.
 

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.
 

iv
 
SUMMARY
 

A bioassay for possible carcinogenicity of technical-grade allyl
 

chloride (3-chloropropene) was conducted using Osborne-Mendel rats
 

and B6C3F1 mice. At initiation of the study the rats were approximately 6 weeks old and the mice approximately 5 weeks old. Allyl
 

chloride in corn oil was administered by gavage to two groups of each
 

species for 5 days a week for 78 weeks, followed by observation periods of 30 to 33 weeks for the rats and 14 weeks for the mice. The
 

time-weighted average dosages were, respectively, 77 and 57 mg/kg/day
 

for high and low dose male rats; 73 and 55 mg/kg/day for high and low
 

dose female rats; 199 and 172 mg/kg/day for high and low dose male
 

mice; and 258 and 129 mg/kg/day for high and low dose female mice.
 

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

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

same time that dosed animals were gavaged with allyl chloride in corn
 

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

controls for each species. These animals were not intubated.
 

Survival of high dose male mice and high dose rats of both sexes
 

was extremely poor. Fifty percent of the high dose male mice were
 

dead by week 27; the 10 members of this group that survived past week
 

48 were sacrificed in week 56. Among the high dose rats, 50 percent
 

of the males had died by week 14 and 50 percent of the females had
 

died by week 38. Because of early mortality in these groups, the number of animals surviving long enough to be at risk from late-developing
 

tumors was not adequate for meaningful statistical analysis.
 

In this bioassay, squamous-cell carcinomas of the forestomach in
 

male and female mice and squamous-cell papillomas of the forestomach
 

in female mice occurred in incidences that were higher than in historical controls. No other neoplasms occurred in statistically significant
 

increased incidences in dosed rats or mice.
 

Under the conditions of this bioassay no convincing evidence was
 

presented for the carcinogenicity of allyl chloride in Osborne-Mendel
 

rats of either sex. The results are suggestive that allyl chloride is
 

carcinogenic in male and female B6C3F1 mice since the compound, when
 

administered by gavage, caused a low incidence of neoplastic and
 

nonneoplastic lesions of the forestomach.
 

TABLE OF CONTENTS
 

Page
 

I. INTRODUCTION 1
 

II. MATERIALS AND METHODS 3
 

A. Chemicals 3
 

B. Dosage Preparation 5
 

C. Animals 5
 

D. Animal Maintenance 6
 

E. Gastric Intubation 7
 

F. Selection of Initial Dose Levels 7
 

G. Experimental Design 8
 

H. Clinical and Histopathologic Examinations 13
 

I. Data Recording and Statistical Analyses 14
 

III. CHRONIC TESTING RESULTS: RATS 19
 

A. Body Weights and Clinical Observations 19
 

B. Survival 21
 

C. Pathology 23
 

D. Statistical Analyses of Results 24
 

IV. CHRONIC TESTING RESULTS: MICE 36
 

A. Body Weights and Clinical Observations 36
 

B. Survival 36
 

C. Pathology 39
 

D. Statistical Analyses of Results 42
 

V. DISCUSSION 48
 

VI. BIBLIOGRAPHY 51
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH ALLYL CHLORIDE A-l
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH ALLYL CHLORIDE B-l
 

APPENDIX C SUMMARY OF'THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH ALLYL CHLORIDE C-l
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH ALLYL CHLORIDE D-l
 

VII
 
Figure Number
 

1
 

2
 

Table Number
 

LIST OF ILLUSTRATIONS 

Page 

CHEMICAL STRUCTURE OF ALLYL CHLORIDE 4 

GROWTH CURVES FOR ALLYL CHLORIDE CHRONIC 

STUDY RATS 20 

SURVIVAL COMPARISONS OF ALLYL CHLORIDE 

CHRONIC STUDY RATS 22 

GROWTH CURVES FOR ALLYL CHLORIDE CHRONIC 

STUDY MICE 37 

SURVIVAL COMPARISONS OF ALLYL CHLORIDE 

CHRONIC STUDY MICE 38 

LIST OF TABLES 

Page 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS—­

ALLYL CHLORIDE GAVAGE EXPERIMENT 

DESIGN SUMMARY FOR B6C3F1 MICE—ALLYL 

CHLORIDE GAVAGE EXPERIMENT 10 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

ALLYL CHLORIDE AND SURVIVING AT LEAST 52 

WEEKS 25 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH ALLYL CHLORIDE AND SURVIVING AT LEAST 

52 WEEKS 29 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

ALLYL CHLORIDE AND SURVIVING AT LEAST 

52 WEEKS 43 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH ALLYL CHLORIDE 45 

Vlll 
LIST OF TABLES (Concluded) 

Table Number Page 

Al SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH ALLYL CHLORIDE A-3 

A2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH ALLYL CHLORIDE A-7 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH ALLYL CHLORIDE B-3 

B2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH ALLYL CHLORIDE B-6 

Cl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH ALLYL 

CHLORIDE C-3 

C2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH ALLYL 

CHLORIDE C-8 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH ALLYL 

CHLORIDE D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH ALLYL 

CHLORIDE D-7 

IX
 

I. INTRODUCTION
 

Allyl chloride (NCI No. C04615) is one of a group of halogenated
 

chemical intermediates selected for carcinogenesis bioassay by the
 

National Cancer Institute. Chemicals were selected on the basis of
 

large-scale production, extensive use, and lack of adequate chronic
 

toxicity data.
 

The Chemical Abstracts Service (CAS) Ninth Collective Index
 

*
 

(1977) name for this compound is 3-chloro-l-propene. It is also
 

called 3-chloropropene or chloropropylene.
 

Allyl chloride is one of the most commercially important allyl
 

compounds. Commercial-scale production of allyl chloride began in
 

1945 and increased to 295 million pounds annually in 1972 (Stanford
 

Research Institute, 1975). It is an extremely useful chemical intermediate since it can react both as an organic halide and as an olefin
 

(Pilorz, 1964). Most derivatives of allyl chloride do not reach an
 

end-use market themselves, but are part of further syntheses. Important "first generation" derivatives of allyl chloride include glycerol,
 

epichlorohydrin, and allyl alcohol (Pilorz, 1964). Other derivatives
 

include medicinals, such as barbiturates, diuretics (Pilorz, 1964),
 

and herbicides (Kuwahara et al., 1973).
 

The National Institute for Occupational Safety and Health (1976)
 

estimates that approximately 5000 workers in the United States are
 

*
 

The CAS registry number is 107-05-1
 
potentially exposed to allyl chloride annually. Human exposure to
 

allyl chloride occurs principally by vapor inhalation in the working
 

areas of industrial plants employing this compound for syntheses.
 

Liver damage was reported in employees of the plastics industry after
 

exposure to air concentrations varying from 1 to 113 ppm of allyl
 

chloride for 16 months (Hausler and Lenich, 1968). Vapor exposure
 

also produces eye and lung damage (Pilorz, 1964). Allyl chloride can
 

be absorbed rapidly through the skin (Pilorz, 1964). Observations of
 

industrial exposure indicate that liquid allyl chloride is a skin
 

irritant which can cause dermatitis, damage to underlying tissues of
 

the skin, chemical burns, and deep-seated pain (National Institute
 

for Occupational Safety and Health, 1976).
 
II. MATERIALS AND METHODS
 

A. Chemicals
 

One batch of technical-grade allyl chloride (Figure 1) was purchased by Hazleton Laboratories America, Inc., Vienna, Virginia,
 

from Aldrich Chemical Company, Inc. The purity of the compound was
 

initially determined by gas-liquid chromatography (GLC) total-area
 

analysis and by infrared spectroscopy. Six peaks were revealed; the
 

fourth peak accounted for 98 percent of the total area and was
 

presumed to be allyl chloride. One minor peak accounted for about
 

1.4 percent of the total area and the other four peaks totaled less
 

than 1 percent of the area. This indication of purity in the range
 

of 98 percent was consistent with the purity noted by the supplier.
 

The infrared spectrum of the allyl chloride was consistent with that
 

expected from the structure of the compound.
 

Second and third purity determinations were conducted approximately 19 and 26 months, respectively, after the original analysis
 

in order to establish the stability of allyl chloride after storage.
 

The second and third purity determinations, using GLC, showed the
 

major peak to be approximately 98 and 99 percent, respectively, of
 

the total area. The infrared spectra obtained in both of these
 

analyses were consistent with the pattern shown in the first analysis.
 

Therefore it was assumed that this batch of allyl chloride remained
 

stable during the storage period of approximately 2 years.
 
H 

= c - c - cc 

A 

FIGURE 1 

CHEMICAL STRUCTURE OF ALLYL CHLORIDE 
Throughout this report the term allyl chloride is used to represent this technical-grade material.
 

B. Dosage Preparation
 

®
 Fresh solutions of allyl chloride in Duke's corn oil (S. F.
 

Sauer Company, Richmond, Virginia) were prepared weekly, sealed, and
 

stored in dark bottles at 1°C. The concentration of allyl chloride
 

in corn oil varied from 5.5 to 7.0 percent for the rat chronic
 

bioassay and from 2.0 to 5.0 percent for the mouse chronic bioassay.
 

These allyl chloride solutions were considered generally stable for
 

10 days under the indicated storage conditions.
 

C. Animals
 

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

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

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

carcinogenesis bioassays and has proved satisfactory in this capacity.
 

Rats and mice of both sexes were obtained through contracts with
 

the Division of Cancer Treatment, National Cancer Institute. The
 

Osborne-Mendel rats were procured from the Battelle Memorial Institute, Columbus, Ohio, and the B6C3F1 mice from the Charles River
 

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

animals were quarantined for at least 10 days, observed for visible
 
signs of disease or parasites, and assigned to the various treated
 

and control groups.
 

D. Animal Maintenance
 

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


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

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

conditioning system provided filtered air at a rate of 12 complete
 

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

12-hour-daily cycle.
 

The rats were individually housed in suspended galvanized-steel
 

wire-mesh cages with perforated floors. The mice were housed by sex
 

in groups of 10 in solid-bottom polypropylene cages equipped with
 

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

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

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

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

week for the first 10 weeks and once a month thereafter. Fresh heat-


sterilized glass water bottles and sipper tubes were provided three
 

®
 times a week. Food (Wayne Lab-Blox meal, Allied Mills, Inc.,
 

Chicago, Illinois) and water were available ad libitum.
 

The rats dosed with allyl chloride and the untreated and vehicle
 

*
 

control rats were housed in the same room with rats intubated with
 

chloroform (67-66-3); carbon tetrachloride (56-23-5); 1,1,2,2-tetrachloroethane (79-34-5); and 1,2-dibromoethane (106-93-4).
 

CAS registry numbers are given in parentheses.
 
The mice dosed with allyl chloride and the untreated and vehicle
 

control mice were housed in the same room as mice intubated with
 

1,1,2,2-tetrachloroethane (7934-5); chloroform (67-66-3); 3-sulfolene
 

(77-79-2); chloropicrin (76-06-2); trichlorofluoromethane (75-69-4);
 

dlbromochloropropane (96-12-8); iodoform (75-47-8); methylchloroform
 

(71-55-6); 1,2-dibromoethane (106-93-4); 1,2-dichloroethane (107-06­

2): 1,1-dichloroethane (75-34-3); trichloroethylene (79-01-6); carbon
 

tetrachloride (56-23-5); 1,1,2-trichloroethane (79-00-5); hexachloroethane (67-72-1) carbon disulfide (75-15-0); and tetrachloroethylene
 

(127-18-4).
 

E. Gastric Intubation
 

Intubation was performed for five consecutive days per week on
 

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

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

weights for each group were recorded at weekly intervals for the
 

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

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

gavaged with allyl chloride solutions under a hood to minimize extraneous exposure of other animals and laboratory personnel to the chemical.
 

F. Selection of Initial Dose Levels
 

In order to estimate the maximum tolerated dosages of allyl
 

chloride 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. Intubation was performed
 

5 days per week for 6 weeks, followed by a 2-week observation period
 

to detect any delayed toxicity. Allyl chloride, dissolved in corn
 

oil, was introduced by gavage to five of the six rat groups at dosages of 56, 100, 178, 316, and 562 mg/kg/day and to five of the six
 

mouse groups at dosages of 178, 316, 562, 1000, and 1780 mg/kg/day.
 

The sixth group of each species served as a vehicle control group,
 

receiving only corn oil.
 

Based on observations during the subchronic toxicity tests, the
 

initial high dosage selected for the chronic bioassay was 110 mg/kg/
 

day for rats of both sexes.
 

At a level of 562 mg/kg/day or less only one mouse died during
 

the 8-week study (a female treated with 562 mg/kg/day). No retardation in body weight gain was observed in either sex at 562 mg/kg/day
 

or less. The initial high dosages selected for the mouse chronic
 

bioassay were 400 mg/kg/day for males and 300 mg/kg/day for females.
 

G. Experimental Design
 

The experimental design parameters for this 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.
 

A chronic bioassay was initiated using dosages of 110 and 55 mg/
 

kg/day for rats. Due to lack of toxicity, dosage levels were raised
 

8
 
TABLE 1
 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS
 

ALLYL CHLORIDE GAVAGE EXPERIMENT
 

INITIAL

GROUP SIZE

MALE 

UNTREATED 

CONTROL 20 

VEHICLE 

CONTROL 20 

LOW DOSE 50 

HIGH DOSE 50 

FEMALE 

UNTREATED 

CONTROL 20 

VEHICLE 

CONTROL 20 

LOW DOSE 50 

HIGH DOSE 50 

ALLYL


 CHLORIDE


 DOSAGE3


0


0


70


55


0


140


110


55


0


0


0


55


0


110


55


0


 OBSERVATION PERIOD

 TREATED UNTREATED

 (WEEKS) (WEEKS)

 TIME-WEIGHTED 

 AVERAGE 

DOSAGEb 

0 110 0 

 78 32 0 

 10

 68 

 32 

 57 

 10

 16 

 52 

 30 

 77 

0 110 0 

 78 33 0 

 78

 32 

 55 

 26

 52 

 32 

 73 

a
 

Dosages, given in mg/kg body weight, were administered by gavage 5
 

consecutive days per week.
 

, 2 (dosage X weeks received)
 
TABLE 2
 

DESIGN SUMMARY FOR B6C3F1 MICE
 

ALLYL CHLORIDE GAVAGE EXPERIMENT
 

TIME-WEIGHTED 

ALLYL OBSERVATION PERIOD AVERAGE DOSAGE 

INITIAL CHLORIDE TREATED UNTREATED OVER A 78-WEEK 

GROUP SIZE DOSAGE3 (WEEKS) (WEEKS) PERIODb 

MALE 

UNTREATED 

CONTROL 20 0 0 90 0 

VEHICLE 

CONTROL 20 0 78 13 0 

LOW DOSE 50 200 15 172 

250 1 

200 9 

200° 42 11 

0 13 

d 

HIGH DOSE 50 400 15 199 

500 1 

400 9 

400° 3 1 

200° 21 6 

FEMALE 

UNTREATED 

CONTROL 20 90 

VEHICLE 

CONTROL 20 0 78 13 

LOW DOSE 50 150 25 129 

150° 42 11 

0 14 

HIGH DOSE 50 300 25 258 

50 300° 42 11 

0 14 

Dosages, given in rag/kg body weight, were administered by gavage 5
 

consecutive days per week.
 

2(dosage X weeks received)
 Time-weighted average dosage =
 78 weeks
 

"These dosages were cyclically administered with a pattern of 1 dose-


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

Terminated in week 56.
 

10
 
twice. Effective week 6, the dosages were raised to 140 and 70 mg/
 

kg/day for both sexes and in week 12, the dosage levels for male rats
 

were raised again, this time to 180 and 90 mg/kg/day. Because of excessive mortality after week 12, this bioassay was terminated during
 

week 31 and the animals were discarded. Based on observations during
 

this bioassay, a new bioassay of allyl chloride was initiated at the
 

following levels: 140 and 70 mg/kg/day for male rats and 110 and 55
 

mg/kg/day for female rats.
 

At initiation of this study the treated and untreated control
 

rats were approximately 6 weeks old. The vehicle control rats were
 

approximately 7 weeks old when they were started on test; however,
 

they were placed on test approximately 3 months before the untreated
 

controls and the dosed groups.
 

Gavage was performed five consecutive days per week. The initial
 

dosages utilized for male rats were 140 and 70 mg/kg/day. Throughout
 

this report the male rats initially receiving the former dosage are
 

referred to as the high dose group and those initially receiving the
 

latter dosage are referred to as the low dose group. In week 11 the
 

high and low dosages were reduced to 110 and 55 mg/kg/day, respectively. After 16 weeks the dosage administered to the high dose
 

males was decreased to 55 mg/kg/day, the same dosage received by the
 

low dose group. This dosage was maintained for the remainder of the
 

compound administration period. Initially, the female rats received
 

dosages of 110 and 55 mg/kg/day. Throughout this report the female
 

11
 
rats initially receiving the former dosage are referred to as the
 

high dose group and those initially receiving the latter dosage are
 

referred to as the low dose group. In week 27, because of toxic
 

effects, the dosage level for high dose females was lowered to 55 mg/
 

kg/day. The vehicle control rats received corn oil in volumes equal
 

to those administered to the high dose groups. Untreated control
 

rats received no intubations. After the 78-week dosing period, rats
 

were observed for 30 to 33 weeks.
 

At the initiation of the study the vehicle control and treated
 

mice were approximately 5 weeks old. The untreated control mice had
 

a median birth date approximately 2 weeks later than the other mice,
 

and were placed on test a corresponding 2 weeks later.
 

Throughout this report the male mice receiving initial dosages
 

of 400 mg/kg/day are referred to as the high dose and those receiving
 

initial dosages of 200 mg/kg/day are referred to as the low dose.
 

The female mice intubated with 300 and 150 mg/kg/day are referred to,
 

respectively, as the high and low dose groups.
 

The dosages utilized for high dose male mice were 400 mg/kg/day
 

for the first 15 weeks, 500 mg/kg/day the next week, 400 mg/kg/day
 

from week 17 through week 29, and 200 mg/kg/day from week 30 until
 

week 56 when all surviving animals in this group were sacrificed.
 

The dosage utilized for low dose males was 200 mg/kg/day except
 

during week 16, when they received 250 mg/kg/day. The dosages
 

used for high and low dose female mice were 300 and 150 mg/kg/day,
 

12
 
respectively, throughout the 78 weeks of the experiment. In order to
 

decrease total intake of allyl chloride, in week 26 intubation ceased
 

for all mice for 1 week and was followed by 4 weeks of intubation at
 

the previous dose levels. This pattern of cyclic administration continued for the remainder of the dosing period.
 

After the 78-week dosing period the surviving groups were observed for up to 14 weeks.
 

H. Clinical and Histopathologic Examinations
 

Animals were weighed immediately prior to initiation of the
 

experiment. 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. From the
 

first day, all animals were inspected daily for mortality. The
 

presence of tissue masses was determined by observation and palpation
 

of each animal.
 

A necropsy was performed on each animal regardless of whether it
 

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

bioassay. The animals were euthanized by exsanguination under sodium
 

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

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

13
 
Tissues 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.
 

Slides were prepared from the following tissues: subcutaneous
 

tissue, lungs and bronchi, trachea, bone marrow, spleen, lymph nodes,
 

thymus, heart, salivary gland, liver, gallbladder (mice), pancreas,
 

esophagus, stomach, small intestine, large intestine, kidney, urinary
 

bladder, pituitary, adrenal, thyroid, parathyroid, testis, prostate,
 

brain, uterus, mammary gland, and ovary.
 

A few tissues were not examined for some animals, particularly
 

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

preclude histopathologic interpretation. Thus, the number of animals
 

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

animals that were 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,
 

14
 
1969). Data tables were generated for verification of data transcription and for statistical review.
 

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

that bear on the possibility of carcinogenicity are discussed in the
 

statistical narrative sections.
 

Probabilities of survival were estimated by the product-limit
 

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

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

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

missing; animals dying from natural causes were not statistically
 

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

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

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

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

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

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

The incidence of neoplastic or nonneoplastic lesions has been
 

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

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

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

histologically. However, when macroscopic examination was required
 

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

15
 
tumors), or when lesions could have appeared at multiple sites (e.g.,
 

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

The purpose of the statistical analyses of tumor incidence is to
 

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

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

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

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

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

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

significance level of 0.05 may be made. The Bonferroni inequality
 

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

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

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

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

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

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

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

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

zero at the one-tailed 0.05 level of significance. Unless otherwise
 

noted, the direction of the significant trend was a positive dose relationship. This method also provides a two-tailed test of departure
 

from linear trend.
 

16
 
A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation of
 

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

tumor was observed were excluded by basing the statistical tests on
 

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

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

tumor was found, comparisons were based exclusively on animals that
 

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

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

Cochran-Armitage tests, etc.) were followed.
 

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

incidence of tumors. Curves of the proportions surviving without an
 

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

during which animals died naturally or were sacrificed was entered as
 

the time point of tumor observation. Cox1s methods of comparing
 

these curves were used for two groups; 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
 

17
 
the exact interval on the odds ratio (Gart, 1971). The relative risk
 

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

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

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

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

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

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

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

larger proportion in the treated group than in the control.
 

The lower and upper limits of the confidence interval of the
 

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

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

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

would be within the interval calculated from the experiment. When
 

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

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

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

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

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

the lower limit indicates the absence of a significant result while
 

the upper limit indicates that there is a theoretical possibility
 

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

detected under the conditions of this test.
 

18
 
III. CHRONIC TESTING RESULTS: RATS
 

A. Body Weights and Clinical Observations
 

All groups of rats gained weight consistently during the first
 

46 weeks of the experiment (Figure 2). Between week 46 and week 50,
 

the mean body weight of high dose male rats decreased from 557 grams
 

to 528 grams. The high dose male rats continued to lose weight so
 

that at the end of the dosing period the mean body weight of animals
 

in this group had dropped to 487 grams. Low dose male rats experienced no appreciable mean body weight depression relative to controls.
 

Throughout the bioassay, male and female rats treated with allyl
 

chloride experienced consistent mean body weight depression relative
 

to controls. Fluctuations in the growth curve may be due to mortality;
 

as the size of the group diminishes, the mean body weight may be subject to wide variations.
 

Hunched appearance and abdominal urine stains were the predominant clinical signs observed during the study. Abdominal urine
 

stains were noted in an increasing number of treated rats as the
 

experiment progressed. By week 42 approximately 40 percent of the
 

high dose males and high and low dose females had this condition.
 

Abdominal urine stains were infrequently noted in the controls until
 

the last 6 months of the study when the observation was noted in
 

approximately 30 percent of the control rats.
 

A few rats showed hunched posture during the first few weeks of
 

the study, but their appearance and behavior were otherwise normal.
 

19
 
750 750 

600­

CO 

450 

X 

Hi 

9 300­

UNTREATED CONTROL 

VEHICLE CONTROL 150

 

LOW DOSE 

HIGH DOSE 

75 90 105 

TIME ON TEST (WEEKS) 

750­

600­

I- 450 — 

LU 

5 

g 

CQ 

UNTREATED CONTROL 

VEHICLE CONTROL 

LOW DOSE 

HIGH DOSE 

150­

FEMALE RATS 

~r ~r ~T 

15 30 45 60 90 105 

TIME ON TEST (WEEKS) 

FIGURE 2 

GROWTH CURVES FOR ALLYL CHLORIDE CHRONIC STUDY RATS 

20 

- 600 

450 

-300 

— 150 

120 

-750 

-600 

-450 

— 300 

- 150 

120 
By week 10 more rats, particularly the females, exhibited a hunched
 

appearance. By week 26, 30 percent of the treated males and 50 percent of the treated females had a hunched appearance. As the study
 

progressed more animals in all groups including the controls showed
 

hunched appearance and at the end of the study (in week 110), most
 

or all survivors had a hunched appearance.
 

Respiratory signs, characterized by labored respiration,
 

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

incidence in all groups including controls during the latter part of
 

the first year, increasing gradually as the rats aged. Other signs
 

commonly associated with aging in the laboratory rat were observed at
 

a comparable rate in control and treated animals during the second
 

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

the body and/or extremities, reddish discharge or crust around the
 

body orifices, and palpable subcutaneous masses or nodules.
 

B.	 Survival
 

The estimated probabilities of survival for male and female rats
 

in the control and allyl chloride-dosed groups are shown in Figure 3.
 

For both male and female rats the Tarone test indicated a significant association (P < 0.001) between increased dosage and accelerated
 

mortality. For both sexes the departure from linearity was significant (P < 0.001), primarily because of the extremely poor survival
 

among the high dose groups.
 

21
 
PROBABILITY OF SURVIVAL

 PROBABILITY OF SURVIVA

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Fifty percent (25/50) of the low dose males survived until week
 

77 and 50 percent (25/50) of the low dose females survived until week
 

99. As a result, adequate numbers of low dose rats were at risk
 

from late-developing tumors.
 

For the high dose groups, however, 50 percent (25/50) of the
 

males had died by week 14 and 50 percent (25/50) of the females had
 

died by week 38. Only 34 percent (17/50) of the high dose males
 

survived one year; none survived until the end of the study. Only
 

12 percent (6/50) of the high dose females survived until the end of
 

the study. These unusually early deaths were not associated with
 

observed tumors. The small numbers of high dose males and females
 

that survived long enough to be at risk from late-developing tumors
 

precluded meaningful analysis of the incidence of these types of
 

tumors for these groups.
 

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).
 

A variety of neoplasms were observed among both treated and control rats. Each of the types of tumors observed had been encountered
 

historically as a spontaneous lesion in the Osborne-Mendel rat. No
 

difference in the frequency of neoplasms or nonneoplastic lesions were
 

noted in this test between the control and treated animals.
 

23
 
Results of this histopathologic examination present no evidence
 

that allyl chloride is carcinogenic in Osborne-Mendel rats of either
 

sex.
 

D. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

rats are summarized in Tables 3 and 4. Due to the high early mortality in both male and female high dose rats, many rats may have died
 

before they were at risk from late-developing tumors. To partially
 

compensate for this, these analyses were performed based solely upon
 

those rats that survived at least 52 weeks or, if the tumor of interest was observed earlier than 52 weeks, at least until the first tumor
 

of that type was observed. The analysis for every type of tumor that
 

was observed in more than 5 percent of any of the allyl chloride-dosed
 

groups of either sex is included.
 

For all analyses neither the Cochran-Armitage tests nor the
 

Fisher exact tests indicated any statistically significant increase
 

in the proportion of tumors found in dosed rats over that found in
 

control rats for any tumor type for either sex. These results, therefore, provided no conclusive evidence of the carcinogencity of allyl
 

chloride. In the high dose groups of both sexes these results must
 

be considered statistically inconclusive due to elevated mortality.
 

In the low dose groups, however, adequate numbers of rats were at
 

risk for meaningful statistical analyses.
 

24
 
TABLE 3 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT 

SPECIFIC SITES IN MALE RATS TREATED WITH ALLYL CHLORIDE3 AND SURVIVING AT LEAST 52 WEEKS 

UNTREATED VEHICLE LOW HIGH 

TOPOGRAPHY: MORPHOLOGY CONTROL CONTROL DOSE DOSE 

Subcutaneous Tissue: Fibroma 0/20(0.00) 0/19(0.00) 3/45(0.07) 0/17(0.00) 

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

Relative Risk (Untreated Control) Infinite 

Lower Limit 0.283 

Upper Limit Infinite 

Relative RLsk (Vehicle Control) Infinite 

l-o Lower Limit 0.272 

Ln 

Upper Limit Infinite 

Weeks to First Observed Tumor 77 

Subcutaneous Tissue: Fibrosarcoma 1/20(0.05) 0/19(0.00) 1/45(0.02) 0/17(0.00) 

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

Relative Risk (Untreated Control) 0.444 0.000 

Lower Limit 0.006 0.000 

Upper Limit 34.903 21.164 

Relative Risk (Vehicle Control) Infinite 

Lower Limit 0.024 

Upper Limit Infinite 

Weeks to First Observed Tumor 54 105 
TOPOGRAPHY: MORPHOLOGY 

Pituitary: Chromophobe Adenoma 

P Values0 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Thyroid: Follicular-Cell Carcinoma 

P Values0 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

TABLE 3 (Continued) 

UNTREATED 

CONTROL 

2/20(0.10) 

N.S. 

90 

1/19(0.05) 

N.S. 

90 

VEHICLE 

CONTROL 

0/16(0.00) 

N.S. 

2/19(0.10) 

N.S. 

104 

LOW 

DOSE 

1/45(0.02) 

N.S. 

0.222 

0.004 

4.167 

Infinite 

0.020 

Infinite 

110 

5/44(0.11) 

N.S. 

2.159 

0.277 

101.862 

1.080 

0.205 

10.982 

76 

HIGH 

DOSE 

0/17(0.00) 

N.S. 

0.000 

0.000 

3.778 

1/17(0.06) 

N.S. 

1.118 

0.015 

82.445 

0.559 

0.010 

9.702 

88 
TOPOGRAPHY: MORPHOLOGY 

Thyroid: Follicular-Cell Adenoma or 

Follicular-Cell Carcinomab 

P Values0 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Thyroid: C-Cell Adenoma 

P Values0 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor
 

TABLE 3 (Continued)
 

UNTREATED 

CONTROL 

1/19(0.05) 

N.S. 

90 

0/19(0.00) 

N.S. 

VEHICLE 

CONTROL 

3/19(0.16) 

N.S. 

103 

1/19(0.05) 

N.S . 

110
 

LOW 

DOSE 

6/44(0.14) 

N.S. 

2.651 

0.361 

118.816 

0.884 

0.218 

5.055 

65 

0/44(0.00) 

N.S. 

0.000 

0.000 

7.800 

HIGH 

DOSE 

1/17(0.06) 

N.S. 

1.118 

0.015 

82.445 

0.373 

0.008 

4.101 

0/17(0.00) 

N.S. 

0.000 

0.000 

19.052 

88 
TABLE 3 (Concluded) 

o 

Treated groups received time-weighted average doses of 57 and 77 rag/kg by gavage. 

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

 

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

in the corresponding control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability level for the Fisher exact test for the comparison of a treated group 

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

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

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

00

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

SPECIFIC SITES IN FEMALE RATS

TOPOGRAPHY: MORPHOLOGY 

Subcutaneous Tissue: Fibroma 

P Values0 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

TABLE 4 

 OF THE INCIDENCE OF

 TREATED WITH ALLYL

UNTREATED 

CONTROL 

0/20(0.00) 

N.S. 

Subcutaneous Tissue: Fibrosarcoma 0/20(0.00) 

P Values0 N.S. 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

 PRIMARY TUMORS AT 

CHLORIDEa AND SURVIVING AT LEAST

VEHICLE 

CONTROL 

0/18(0.00) 

N.S. 

0/18(0.00) 

N.S. 

LOW 

DOSE 

1/42(0.02) 

N.S. 

Infinite 

0.027 

Infinite 

Infinite 

0.024 

Infinite 

78 

2/42(0.05) 

N.S . 

Infinite 

0.149 

Infinite 

Infinite 

0.136 

Infinite 

92 

 52 WEEKS 

HIGH 

DOSE 

2/19(0.011) 

N.S. 

Infinite 

0.326 

Infinite 

Infinite 

0.295 

Infinite 

101 

1/19(0.05) 

N.S. 

Infinite 

0.058 

Infinite 

Infinite 

0.052 

Infinite 

95 
TABLE 4 (Continued) 

TOPOGRAPHY: MORPHOLOGY 

UNTREATED

CONTROL

 VEHICLE 

 CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Pituitary:

P Values0 

 Chromophobe Adenoma 6/19(0.32)

P = 0.027(N)

 6/18(0.33) 

P = 0.021(N) 

6/42(0.14) 

N.S. 

1/19(0.05) 

P = 0.045*(N) 

P = 0.037**(N) 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

0.452 

0.145 

1.502 

0.167 

0.004 

1.189 

u> 

o 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 110 108 

0.429 

0.139 

1.418 

89 

0.158 

0.004 

1.124 

103 

Thyroid:

P Values0 

 Follicular-Cell Carcinoma 0/20(0.00)

N.S .

 0/17(0.00) 

 N.S. 

1/42(0.02) 

N.S. 

1/19(0.05) 

N.S. 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Infinite 

0.026 

Infinite 

Infinite 

0.058 

Infinite 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Infinite 

0.023 

Infinite 

Infinite 

0.050 

Infinite 

Weeks to First Observed Tumor 92 110 
TOPOGRAPHY: MORPHOLOGY 

Thyroid: Follicular-Cell Adenoma or 

Follicular-Cell Carcinoma^ Q 

P Values 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Thyroid: C-Cell Carcinoma 

P Values0 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

TABLE 4 (Continued) 

UNTREATED 

CONTROL 

0/20(0.00) 

N.S. 

2/20(0.10) 

N.S. 

110 

VEHICLE 

CONTROL 

1/17(0.05) 

N.S. 

110 

0/17(0.00) 

N.S. 

LOW 

DOSE 

1/42(0.02) 

N.S. 

Infinite 

0.026 

Infinite 

0.405 

0.006 

31.046 

92 

1/42(0.02) 

N.S . 

0.238 

0.004 

4.359 

Infinite 

0.023 

Infinite 

103 

HIGH 

DOSE 

1/19(0.05) 

N.S. 

Infinite 

0.058 

Infinite 

0.895 

0.012 

66.483 

110 

0/19(0.00) 

N.S. 

0.000 

0.000 

3.408 
TOPOGRAPHY: MORPHOLOGY
 

Thyroid: C-Cell Adenoma or C-Cel.T
 

Carcinoma*3
 

P Values0
 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

u> 

N5 Weeks to First Observed Tumor 

Mammary Gland : Adenocarcinoma NOS
 

P Values0
 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 4 (Continued) 

UNTREATED VEHICLE
 

CONTROL CONTROL
 

4/20(0.20) 0/17(0.00)
 

P = 0.007(N) N.S.
 

61
 

2/20(0.10) 0/18(0.00)
 

N.S. N.S.
 

110
 

LOW
 

DOSE
 

1/42(0.02)
 

P = 0.034*(N)
 

0.119
 

0.003
 

1.117
 

Infinite
 

0.023
 

Infinite
 

103
 

0/42(0.00)
 

N.S.
 

0.000
 

0.000
 

1.595
 

HIGH
 

DOSE
 

0/19(0.00)
 

N.S.
 

0.000
 

0.000
 

1.077
 

1/19(0.05)
 

N.S.
 

0.526
 

0.009
 

9.234
 

Infinite
 

0.052
 

Infinite
 

83 
TOPOGRAPHY : MORPHOLOGY 

Mammary Gland: Fibroadenoma Q 

P Values 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

LO Weeks to First Observed Tumor U> 

Uterus: Endome trial Stromal Polyp 

c P Values 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor
 

TABLE 4 (Continued) 

UNTREATED 

CONTROL 

2/20(0.10) 

N.S. 

61 

0/20(0.00) 

N.S. 

VEHICLE 

CONTROL 

7/18(0.39) 

N.S. 

109 

0/18(0.00) 

N.S. 

LOW 

DOSE 

13/42(0.31) 

N.S. 

3.095 

0.809 

26.440 

0.796 

0.373 

2.018 

82 

3/42(0.07) 

N.S. 

Infinite 

0.297 

Infinite 

Infinite 

0.269 

Infinite 

110
 

HIGH 

DOSE 

4/19(0.21) 

N.S. 

2.105 

0.344 

20.839 

0.541 

0.142 

1.750 

0/19(0.00) 

N.S . 

83 
TABLE 4 (Concluded)
 

Treated groups received time-weighted average doses of 55 or 73 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
 

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

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

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

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

For sites where the first tumor of interest was observed earlier than 52 weeks, the analyses
 

were based upon all animals that survived until or past the date that the first tumor was observed.
 
The possibility of negative associations between administration
 

of the chemical and the incidence of pituitary chromophobe adenomas
 

and thyroid C-cell neoplasms was observed in female rats. Mortality,
 

however, was greater in the high dose group as only 6/50 (12 percent)
 

high dose females survived until the end of the study compared to
 

15/50 (30 percent) vehicle control and 13/20 (65 percent) untreated
 

control rats.
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

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

observed tumor incidence rates. In all of the intervals shown in
 

Tables 3 and 4 the value one is included; this indicates the absence
 

of statistically significant results. It should also be noted that
 

all of the confidence intervals have an upper limit greater than one,
 

indicating the theoretical possibility of tumor induction in rats by
 

allyl chloride that could not be established under the conditions of
 

this test.
 

35
 
IV. CHRONIC TESTING RESULTS: MICE
 

A.	 Body Weights and Clinical Observations
 

No significant depression in mean body weight was observed for
 

allyl chloride-treated male mice (Figure 4). Among female mice a
 

slight but consistent mean body weight depression was observed after
 

week 10 for the high dose group and after week 20 for the low dose
 

group.
 

Throughout the study, signs often observed in group-housed laboratory mice were noted at a comparable rate among control and treated
 

mice. These signs included: sores on the body (more prevalent in
 

males because of fighting), penile, anal, or vulvar irritation, anal
 

prolapse, reddened or squinted eyes, hunched posture, soft feces,
 

palpable nodules, and alopecia. The incidence of these signs generally increased in all groups during the last 6 months of the study.
 

The only symptoms likely to be attributable to allyl chloride
 

toxicity were observed in the 10 high dose male mice surviving beyond
 

week 48. An apparent loss of equilibrium was observed in 8 of the
 

10, and abdominal distension was observed in all 10 of these animals.
 

These signs were not noted in any of the other groups.
 

B.	 Survival
 

The estimated probabilities of survival for male and female mice
 

in the control and allyl chloride-dosed groups are shown in Figure 5.
 

In male mice the Tarone test for a positive dose-related trend
 

in mortality was significant (P < 0.001). There was a significant
 

36
 
50 

— 40 

-30 

-20 

UNTREATED CONTROL 

VEHICLE CONTROL 

LOW DOSE — 10 

HIGH DOSE 

MALE MICE 

\ ] \ ' I ' \ I 

45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

-50 

— 40 

— 30 

-20 

UNTREATED CONTROL 

VEHICLE CONTROL 

LOW DOSE —10 

HIGH DOSE 

FEMALE MICE 

90 105 120 

TIME ON TEST (WEEKS) 

FIGURE 4 

GROWTH CURVES FOR ALLYL CHLORIDE CHRONIC STUDY MICE 
PROBABILITY OF SURVIVAL PROBABILITY OF SURVIV

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O
 

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 m co
 O
 

JC
 

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 o
 o
 
departure from linear trend (P < 0.001), primarily because of the
 

extremely poor survival among the high dose group. Forty-eight
 

percent (24/50) of the high dose group were dead by week 27; the 10
 

members of this group that survived past week 48 were sacrificed in
 

week 56. At the same time, 10 of the 20 vehicle control mice were
 

sacrificed. There was no indication of an association between the
 

early deaths of high dose male mice and observed tumors. There
 

were not adequate numbers of high dose male mice at risk from late-


developing tumors. Survival of low dose male mice, however, was
 

adequate for meaningful statistical analysis, with 50 percent (25/50)
 

living at least 86 weeks.
 

In female mice the Tarone test also indicated a positive dose-


related trend in mortality (P = 0.022). However, with 68 percent
 

(34/50) of the high dose group and 80 percent (40/50) of the low dose
 

group surviving to the end of the experiment, adequate numbers of female mice were at risk from late-developing tumors.
 

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).
 

Increased incidences of stomach lesions, both neoplastic and
 

nonneoplastic, were observed in treated male and female mice, as
 

shown in the following table:
 

39
 
Untreated 

Control 

Vehicle 

Control 

Low

Dose

 High 

 Dose 

Males 

Number of Animals Necropsied (18) (20) (46) (50) 

Squamous-Cel1 Carcinoma
 

Squamous-Cell Papilloma
 

Leiomyosarcoma
 

Acanthosis
 

Hyperkeratosis
 

Females
 

Number of Animals Necropsied
 

0 0 2 0

0

0

0

0 

0

0

0

0 

0

1 

9

9 

0

0 

19 

19 

(20) (19) (48) (45)
 

Squamous-Cell Carcinoma
 

Squamous-Cell Papilloma
 

Leiomyosarcoma
 

Acanthosis
 

Hyperkeratosis
 

0

3

0 

2

1 

0 

0

0

0

0

0 

0 

0

0

0

0 

17 25 

17 25 

Squamous-cel1 carcinomas of the forestomach were observed in
 

four treated mice. Metastases of this lesion occurred in the two low
 

dose males, but not in the two low dose females. These tumors were
 

not observed in the control animals and are infrequently observed in
 

B6C3F1 mice. Microscopically, early squamous-cell carcinoma of the
 

stomach showed acanthosis of the squamous epithelium. The surface
 

was covered with squames of irregular needle-like structures of
 

keratin that projected into the lumen. At the base of the epithelial
 

layer there were papillary cords and nests of anaplastic squamous
 

epithelial cells, supported with dense bands of fibrous connective
 

tissue invading and replacing the lamina propria and muscularis
 

40
 
mucosa. In well-differentiated lesions, nests of basophilic cells
 

with intercellular spines surrounding central areas of keratin
 

(epithelial pearls) were seen. The more undifferentiated squamous
 

cells had large nuclei of varying shapes, contained coarse, irregular
 

chromatin, and had one or more nucleoli. Mitotic figures were frequently seen. In advanced lesions the cords and nests of anaplastic
 

squamous epithelial cells invaded the muscular layers and serosa, and
 

extended to the glandular portion of the stomach and other organs.
 

The tumor masses in the abdominal cavity consisted of squames of
 

keratin enclosed in nests of anaplastic squamous epithelial cells,
 

fibrinous mats, and necrotic tissues infiltrated with inflammatory
 

cells. Squamous-cel1 papillomas of the stomach were present in one
 

low dose female and three high dose females but not in any controls.
 

Leiomyosarcoma of the stomach was present in a single treated male
 

mouse. Acanthosis and hyperkeratosis of the forestomach occurred
 

with increased incidence in the treated mice of both sexes.
 

Hepatocellular carcinomas occurred in increased numbers in the
 

low dose male group (8/46 [17 percent] versus 2/20 [10 percent] in
 

the vehicle controls; and 1/49 [2 percent] in the high dose males)
 

but was not in excess of the incidence occasionally seen in control
 

groups. Other proliferative, inflammatory, and degenerative lesions
 

were seen in the control and treated animals without apparent relationship to the administration of the chemical.
 

41
 
Oral administration of allyl chloride was associated with
 

squamous-cell carcinomas in the stomachs of two male and two female
 

treated mice and papillomas in the stomachs of four females, and with
 

proliferative lesions in the forestomach of male and female mice at
 

both dose levels.
 

D. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

mice are summarized in Tables 5 and 6. Due to the high early mortality in high dose male mice, many may have died before they were at
 

risk from late-developing tumors. To partially compensate for this,
 

the analyses for males were performed based solely upon those male
 

mice that survived at least 52 weeks or, in the event that the tumor
 

of interest was observed earlier than 52 weeks, upon those males which
 

survived at least until that tumor was detected. For both males and
 

females the analysis for every type of tumor that was observed in
 

more than 5 percent of any of the allyl chloride-dosed groups of
 

either sex is included.
 

Neither the Cochran-Armitage tests nor the Fisher exact tests
 

indicated any statistically significant increase in the proportion of
 

tumors found in dosed mice over that found in control mice for any
 

tumor type for either sex. For male mice the incidence of tumors at
 

most sites was greater in the low dose than in the high dose group;
 

probably due to the longer survival of the low dose mice.
 

42
 
TABLE 5
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE MICE TREATED WITH ALLYL CHLORIDE3 AND SURVIVING AT LEAST 52 WEEKS
 

UNTREATED VEHICLE LOW HIGH 

TOPOGRAPHY: MORPHOLOGY CONTROL CONTROL DOSE DOSE 

Lung: Alveolar/Bronchlolar Adenoma 0/12(0.00) 3/17(0.18) 6/35(0.17) 0/10(0.00) 

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

Relative Risk (Untreated Control) Infinite 

Lower Limit 0.600 

Upper Limit Infinite 

Relative Risk (Vehicle Control) 0.971 0.000 

Lower Limit 0.245 0.000 

Upper Limit 5.468 2.523 

Weeks to First Observed Tumor 56 79 

Liver: Hepatocellular Carcinoma 1/12(0.08) 2/17(0.12) 8/36(0.22) 1/10(0.10) 

c 

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

Relative Risk (Untreated Control) 2.667 1.200 

Lower Limit 0.433 0.017 

Upper Limit 114.336 84.143 

Relative Risk (Vehicle Control) 1.889 0.850 

Lower Limit 0.442 0.015 

Upper Limit 17.011 13.725 

Weeks to First Observed Tumor 90 56 90 56 
TABLE 5 (Concluded) 

TOPOGRAPHY: MORPHOLOGY 

UNTREATED 

CONTROL 

VEHICLE 

CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Stomach: Squamous-Cell Carcinoma 0/12(0.00) 0/17(0.00) 2/36(0.06) 0/10(0.00) 

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

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Infinite 

0.107 

Infinite 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Infinite 

0.146 

Infinite 

Weeks to First Observed Tumor 76 

Treated groups received time-weighted average doses of 172 and 199 mg/kg by gavage. 

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

c 

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

in the corresponding control group when P < 0.005; otherwise, not significant (N.S.) is indicated. The probability level for the Fisher exact test for the comparison of a treated group 

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

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

indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N) 

indicates a lower incidence in the treated group(s) than in the control group. 

The 95% confidence interval on the relative risk of the treated group to the control group. 
TABLE 6
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE MICE TREATED WITH ALLYL CHLORIDE'
 

TOPOGRAPHY : MORPHOLOGY 

Lung: Alveolar /Bronchiolar Adenoma 

P Values0 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit Ul
 

Weeks to First Observed Tumor 

Hematopoietic System: 

Malignant Lymph oma 

P Values0 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

UNTREATED 

CONTROL 

1/20(0.05) 

N.S . 

90 

3/20(0.15) 

N.S. 

87 

VEHICLE 

CONTROL 

1/19(0.05) 

N.S. 

91 

1/19(0.05) 

N.S. 

91 

LOW 

DOSE 

5/48(0.10) 

N.S. 

2.083 

0.260 

96.358 

1.979 

0.247 

91.529 

91 

6/48(0.13) 

N.S. 

0.833 

0.205 

4.799 

2.375 

0.325 

106.788 

39 

HIGH 

DOSE 

4/45(0.09) 

N.S. 

1.778 

0.194 

85.520 

1.689 

0.187 

81.255 

92 

8/45(0.18) 

N.S. 

1.185 

0.330 

6.425 

3.378 

0.511 

145.991 

81 
TABLE 6 (Concluded) 

UNTREATED VEHICLE LOW HIGH
 

TOPOGRAPHY : MORPHOLOGY CONTROL CONTROL DOSE DOSE
 

Stomach: Squamous-Cell Papilloma or
 

Squamous-Cell Carcinoma^ 0/20(0.00) 0/19(0.00) 3/47(0.06) 3/45(0.07)
 

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

Relative Risk (Untreated Control) Infinite Infinite
 

Lower Limit 0.266 0.279
 

Upper Limit Infinite Infinite
 

Relative Risk (Vehicle Control) Infinite Infinite
 

Lower Limit 0.254 0.265
 

Upper Limit Infinite Infinite
 

Weeks to First Observed Tumor 91 92
 ON
 

Treated groups received time-weighted average doses of 129 and 258 mg/kg by gavage.
 

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

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

in the corresponding control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability level for the Fisher exact test for the comparison of a treated
 

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

the incidence of tumors in that treated group when P < 0.05; otherwise, not significant (N.S.)
 

is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N)
 

indicates a lower incidence in the treated group(s) than in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 
Rare stomach tumors--squamous-cell papillomas and squamous-cell
 

carcinomas--were observed in 2/46 (4 percent) low dose males, 3/47
 

(6 percent) low dose females, and 3/45 (7 percent) high dose females.
 

In historical vehicle control data tabulated by this laboratory for
 

the NCI Carcinogenesis Testing Program, 1/180 male and 1/180 female
 

B6C3F1 mice had either a squamous-cell papilloma or a squamous-cell
 

carcinoma of the stomach. Assuming a binomial distribution with a
 

probability of 1/180 of a spontaneous tumor, the probability of
 

observing 2 or more tumors out of 46 males was P < 0.029. For a
 

spontaneous tumor rate of 1/180, the probabilities of 3 such tumors
 

occurring by chance in a sample of either 47 or 45 females is very
 

small (P < 0.003).
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

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

observed tumor incidence rates. In all of the intervals shown in
 

Tables 5 and 6, the value one is included; this indicates the absence
 

of statistically significant results. It should also be noted that
 

all of the confidence intervals have an upper limit greater than one,
 

indicating the theoretical possibility of tumor induction in mice by
 

allyl chloride that could not be established under the conditions of
 

this test.
 

47
 
V. DISCUSSION
 

Because of excessive early mortality of high dose male rats,
 

high dose female rats, and high dose male mice (50 percent of each
 

group died by week 14, week 38, and week 27, respectively) the majority of animals in these groups did not survive long enough to be at
 

risk from late-developing tumors. Any conclusions derived from this
 

bioassay are, then, based on observations of the remaining groups.
 

Although a compound-related reduction in mortality was also observed among low dose rats, 50 percent of the low dose males survived
 

until week 77 and 50 percent of the low dose females survived until
 

week 99. This survival was considered adequate for meaningful statistical analysis of tumor incidence. Survival of low dose male mice
 

(50 percent living at least 86 weeks) was also considered adequate for
 

statistical analysis. Female mice, with 68 percent of the high dose
 

group and 80 percent of the low dose group surviving until the end of
 

the experiment, were the only species and sex for which animals in
 

all groups could be considered to have lived long enough to be at risk
 

from late-developing tumors.
 

Among the groups in which an adequate number of mice had survived
 

long enough to be at risk from late-appearing tumors, proliferative
 

nonneoplastic stomach lesions (i.e., acanthosis and hyperkeratosis)
 

were observed in 20 percent of the low dose males, 39 percent of the
 

high dose males, 36 percent of the low dose females, and 56 percent
 

48
 
of the high dose females, but in none of the control mice. In addition, squamous-cell carcinomas of the forestomach were detected in
 

2/46 low dose males and 2/47 low dose females. Metastases of this
 

lesion occurred in the two low dose males. Squamous-cell papillomas
 

of the forestomach were observed in 1/47 low dose females and 3/45
 

high dose females. These neoplasms were not observed in any other
 

treated or control mice. The historical data for vehicle control
 

B6C3F1 mice at this laboratory for the NCI Carcinogenesis Testing
 

Program indicate that 1/180 males and 1/180 females had either a
 

squamous-cell papilloma or a squamous-cell carcinoma of the forestomach. The occurrence of these neoplasms at the incidences observed in
 

this bioassay was statistically and significantly higher than in the
 

historical incidences. The proliferative nonneoplastic stomach
 

lesions, squamous-cell papillomas and squamous-cell carcinomas, may
 

all represent progressive stages in a neoplastic process. When the
 

probable pathogenesis of this tumor is coupled with the known chemical reactivity of the compound and the statistical evidence for the
 

rare occurrence of this tumor, the results are strongly suggestive
 

of the carcinogenic action of allyl chloride in mice.
 

There were no other neoplasms in rats or mice for which statistical significance could be attributed to differences in incidence
 

between control and treated groups.
 

Under the conditions of this bioassay no convincing evidence was
 

presented for the carcinogenicity of allyl chloride in Osborne-Mendel
 

49
 
rats of either sex. The results are strongly suggestive that allyl
 

chloride is carcinogenic in male and female B6C3F1 mice since the
 

compound, when administered by gavage, is associated with neoplastic
 

and nonneoplastic lesions of the forestomach.
 

50
 
VI. BIBLIOGRAPHY
 

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

J. Wiley & Sons, New York, 1971.
 

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

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

Union Against Cancer, Geneva, 1969.
 

Chemical Abstracts Service, The Chemical Abstracts Service (CAS)
 

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

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

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

Co., Ltd., London, 1970.
 

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

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

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

Tests, Confidence Limits, and Adjustments for Stratification."
 

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

Hausler, M. and R. Lenich, "Effect of Chronic Exposure to Allyl
 

Chloride." Archiv fuer Toxikologie 23:209-214, 1968.
 

International Technical Information Institute, Toxic and Hazardous
 

Industrial Chemicals Safety Manual. ITII, Tokyo, Japan, 1975.
 

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

Observations." Journal of the American Statistical Association
 

_53_:457-481, 1958~
 

Kuwahara, M., M. Mutsukado, K. Ono, T. Kawamura, and Y. Uno, Agricultural and Gardening Herbicides Containing Phosphonamides. Japan,
 

1973.
 

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

"Carcinogenesis Bioassay Data System." Computers and Biomedical
 

Research 7:230-248, 1974.
 

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

Co., New York, 1966.
 

51
 
National Institute for Occupational Safety and Health, Criteria for a
 

Recommended Standard....Occupational Exposure to Allyl Chloride.
 

U.S. Department of Health, Education, and Welfare, Public Health
 

Service, Center for Disease Control. HEW Publication No. (NIOSH)
 

76-204, September 1976.
 

Pilorz, B.H., "Chlorocarbons and Chlorohydrocarbons," Kirk-Othmer
 

Encyclopedia of Chemical Technology. 2nd edition. Vol. 5.
 

Interscience, New York, 1964.
 

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

in Male Rats Given Subcutaneous Carbon Tetrachloride." Journal
 

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

Saffiotti, U., R. Montesano, A.R. Sellakumar, F. Cefis, and D.G.
 

Kaufman, "Respiratory Tract Carcinogenesis in Hamsters Induced
 

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

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

Stanford Research Institute, "Research Program on Hazard Priority
 

Ranking of Manufactured Chemicals." Phase II, Final Report.
 

Chemicals:61-79. Menlo Park, California, 1975.
 

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

62:679-682, 1975.
 

52
 
Review of the Bioassay of Allyl Chloride* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

June 29, 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,
 

biostatistics , toxicology, pathology, and epidemiology.
 

Representatives of various Governmental agencies participate
 

as ad hoc members, The Data Evaluation/Risk Assessment
 

Subgroup of the Clearinghouse is charged with the responsibility of providing a peer review of reports prepared on
 

NCI-sponsored bioassays of chemicals studied for carcinogenicity. It Is in this context that the below critique is given
 

on the bioassay of Allyl Chloride for carcinogenicity.
 

The reviewer said that the study should be considered
 

Inadequate for drawing any conclusion about the compound's
 

carcinogenicity. After a brief description of the experimental design, the reviewer said that the poor survival in
 

the high dose treatment groups precluded an evaluation of
 

the carcinogenicity of Allyl Chloride. A Program staff
 

member said that the compound would be considered by the
 

Chemical Selection Working Group to determine if it should
 

be retested. The reviewer moved that the bioassay of Allyl
 

Chloride was inadequate for drawing any conclusion on its
 

carcinogenicity. The motion was approved without objection.
 

_M embers pr e_s e rvt t
 

Arnold L. Brown (Chairman), Mayo Clinic
 

Paul Nettesheim, National Institute of Environmental
 

Health Sciences
 

Verne Ray, Pfizer Medical Research Laboratory
 

Verald K'. Rowe , Dow Chemical U.S.A.
 Michael B. Shimkin , University of California at San Diego
 

Louise Strong, University of Texas Health Sciences Center
 

Subsequent to this review, changes may have been made
 

in the bioassay report either as a result of the review
 

or other reasons. Thus, certain comments and criticisms
 

reflected In the review may no longer be appropriate.
 

53
 

APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH ALLYL CHLORIDE
 

TABLE A1

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH ALLYL CHLORIDE 

CONTROL (UNT8) 

01-0318 

CONTFOL(VEH) 

01-021H 

LOI DOSE 

01-032B 

HIGH DOSE 

01-0330 

AXIHALS INITIALLY IS STUDY 20 

ANIBALS HISSING 

ANIMALS NECROPSIED 20 

AHiMALS EXAMINED HISTOPATHOLOG1CALLY** 20 

20 

1 

19 

19 

50 

50 

50 50 50 

INTEGUMENTARY SYSTEB
 

»SUBCUT TISSUE (20) (19) (50) (50)
 

FIBROMA 3 (6X)
 

F1BBOSARCOHA 1 (5*)
 

FIBEOUS HISTIOCYTOBA 1 (51)
 FIBROUS HISIIOCYTOHA, HALIGHANI
 

L1POHA 1 (2X>
 HEHANGIOSAECOHA 1 (2*) 1 (2*)
 

KESPIUATOHY SYSTEH
 

HONE
 

HEBATOPO1KTIC SYSTEM
 

*BULTIPLE ORGANS (20) (19) (50) (50)
 

LYMPHOCYT1C LEUKEMIA 1 (5%)
 

•SPLEEN	 (20) (17) (50) (50)
 

HSBASG10SAHCOBA 1 (2*>
 

fMESUaTBHIC L. KODE (19) (17) (50) (49)
 

BEBANGIOMA 1 (2»)
 

CISCULATOKY SYSTEH
 

NUKE
 

DIGESTIVE SYSTEM
 

*3AL1VAHY GLAND (11) (17) (41) (18) 

lASl'IHOaA.IIOS 

t KUHbEH OF ANIBALS WITH TISSUE BXAHINED MICROSCOPICALLY 

* SUBBEh OF AHISALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 
I 

TABLE Al (CONTINUED) 

COHTSCL (ONTR) CONTROL (VBH) LOU DOSE HIGH DOSE
 

01-0318 01-021B 01-032H 01-033H
 

(PiKCBEAS (20) (16) (50) (50)
 OSl'EOSABCOBA, BETAS>TAT1C 1 (2«)
 

HbTOBACH (20) (19) (50) (50)
 OSIEUSAKCOHA, SETASTAT1C 1 <2»>
 

tSBALL 1STEST1BE (20) (19) C»9) (50)
 HBKOSA6COHA 1 (5*)
 

UKlNAIiJ SISTEB
 

•KID8BJ	 (20) (19) (50) (50)
 HAHAP.TOBA+ 1 (2*)
 

ENDOCHI1IE STSTEB 

•PITUITARY 

CbBOBOPHOBE ADE8OBA 

(20) 

2 (10%) 

(16) (50)

1 (2*) 

 (50) 

*AI)RE!tAL 

CuHTiCAL CAkCIHOBA 

PbEOCHROBOCYTOBA 

bEHANGIOSASCOHA 

(20) 

2 (10*) 

(19) 

1 (5») 

1 (5») 

(«9)

1 (2*) 

 (50) 

•THYROID 

JOLLICULAR-CELL ADESOBA 

FOLLICULAR-CELL CARC1NOBA 

C-CtLL AUEKOSA 

(19) 

1 (5X) 

(19) 

1 (5*) 

2 (11*J 1 (5*) 

(19)

1 <2*) 

5 (10%)

 (49) 

1 (2%) 

• J-ANCKEAT1C ISLETS 

ISLET-CELL ADENOBA 

(20) (16) 

1 <6*> 

(50)

1 (21) 

 (50) 

HEPHODUCIIVE SISTEB
 

•BaBBAHlf GLAND (20) (19) (50) (50)
 ADKaOCAECIHUtlA, HUS 1 (5*) 1 (5*)
 FIBROADENOHA 1 <5»>
 

SEKVOUS SYSTEB
 

NONE
 

SPECIAL SENSE ORGANS
 

NONE
 

* NUBbEB OF ANIBALS H1TB TISSUE EXAMINE D BICROSCOPICALLI 

* HOBBEtt OP AHIHALS NECROPS1ED +

 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) 

COHTEOL (UHTR) 

01-0318 

CONTROL(VBH) 

01-021H 

10K DOSE 

01-0328 

HIGH DOSB 

01-033B 

MOSCULOSKELETAL SJSTEH 

•SKELETAL BUSCLE FIBROUS H1ST1OCITOBA, BAL1GNANT 

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

bOUY CAVITIES 

•BEbENTERY OSTKOSARCOBA, HETASTAT1C 

(20) (19) 

1 (2*) 

(50) 

ALL OTHER SYSTEHS 

NONE 

ANISAL DISPOSITION SUHBARY 

AN1BALS INITIALLY III STUDY

NATURAL DEATH*

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE ACCIDENTALLY KILLED 

TE8KIHAL SACRIFICE AS1BAL BISS1NG

 20

 11

 5 

4

 20 

 12 

7 

1 

50

42

1 

7 

 50 

 50 

a INCLUDES AUTOLY2ED AN1BALS 

» SJRbER OF ANIBALS U1TH TISSUE tXABISED SICEOSCOPICALLY * SUHBES OF ANIBALS NECKOPSIED 

A-5
 
TABLE Al (CONCLUDED)
 

COHTBOL (OHTR) t CONTROL (VEH) LOU DOSE HIGH DOS1
 

01-031H 01-021B 01-032H 01-033B
 

TUHOB SUBBABY
 

TOTAL ASIBALS KITH PHIBABI TUBOKS* 6 9 14 4
 

TOTAL PRIBABY TUBOBS 11 12 . 17 4
 

TOTAL ANIBALS WITH BENIGN TDBORS 2 5 8 1
 

TOTAL BENIGN TUBORS 3 5 8 1
 

TOTAL ANIBALS WITH HAL1GIANT TUMORS b 4 9 3
 TOTAL SALIGHANT TUHOHS 8 7 9 3
 

TOTAL ANIMALS KITH SECOHDARI TDBORS* 1
 TOTAL SECONDARY TUBOHS 3
 

TOTAL AN1HALS WITH TOBOBS UMCERTA1N­ BEMIGH OR BAL1GMAST
 

TOTAL UNCERTAIN TUBORS
 

TOTAL ANIBALS WITB TUBOBS USCEBTA1NPhlMAHK OB BETASTATIC
 

TOTAL UNCERTAIN TUROSS
 

* PRIHAB* TUHORS: ALL TDBOBS EXCEPT SECOHDARI TDBORS
 

t SECONDARY TUMORS: BETASTATIC TUSOBS OB TOBORS INVASIVE INTO AN ADJACBHT OHGAS
 

A-6
 
TABLEA2 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH ALLYL CHLORIDE 

AttlBALS INITIALLY IN STUDY


ANISALb NECROPSIED


ASltlALS EXABINEO HIdTOPATHOLOGICALLY


INTEGUaiHTARY SYSTEM
 

*SK1»


SEbACEOUS ADESOUA
 

*SUBCUT TISSOE


SO.UAMOUS CELL CARC1»OBA. B31ASTA
 

FIbROBA
 

FIBROSASCOSA
 

HEBASGIOSARCOBA
 

RESPIRATORY SYSTEB
 

• LUNG


SQUABOUS CELL CARCINOMA, BE1ASTA
 

ADEHOCARCIilOBA, NOS, BET ASTATIC
 

ri&BOSARCOaA
 

HSMATOPOIETIC SYSTEM
 

•MULTIPLE ORGANS


HAL1G.LYBPHUBA, HIST1OCYTIC TYPE
 

tSPLBEH


HfiflANGIOSAHCOBA
 

*LIMPH HODJ5


ADENUCASCINOBA, NOS, BETASTAT1C
 

#THYMUS


syuAflaus CELL CARCISOBA
 ADEKOCARCISOMA, NOS, BETASTAT1C
 

CiKCOLATORY SYSTEB
 

tHEART


HIXEB TUBOR, BETASTATIC


* XUBBER OF AalBALS KITH TISSUE

» SUBSER OF ANIBALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

CONTROL (ONTR)
 

01-031F
 

 20
 

 20
 

 ** 20
 

 (20)
 

 (20)
 

 (20)
 

 UO)
 

 (20)
 

 (20)
 

 C^^)
 

 (20)
 

1 (5*1
 

CONTROL (VEH)
 

01-021F
 

20
 

20
 

20
 

(20)
 

(20)
 

(20)
 

(20j
 

(20)
 

(20)
 

(19)
 

(20)
 

 EXAHIiJED SICROSCOP1CALLY 

LOW DOSE
 

01-03UF
 

50
 

50
 

50
 

(50)
 

(50)
 

1 (2»)
 

1 (2*)
 

2 (tX)
 

2 (t*i
 

(50)
 

1 (2*)
 

1 (2»)
 

(50)
 

1 (2*)
 

(50)
 

1 (2»)
 

(50)
 

(39)
 

1 (3ft)
 

(50)
 

HIGH DOSE
 

01-035F
 

50
 

50
 

50
 

(50)
 

1 (2*)
 

(50)
 

2 (I*)
 

1 (2%)
 

(50)
 

1 (2*)
 

(50)
 

(49)
 

1 (2»)
 

(49)
 

1 (2X)
 

(37)
 

1 (3X)
 

(50)
 

A-7 
TABLE A2 (CONTINUED) 

CONTROL (UNTR) CONTROL (VEH) LOW DOSE men DOSS 

01-031P 01-021P 01-034F 01-035? 

UIiiESTlVE SY5TES 

*LIVEB (20) (20) (50) (50)

 KEOPLA3TIC NODULE 2 (10X)

 hEPATOCELLOLAR CAKC1NOSA 1 (5*)

 

tv ANCRhA b (20) (20) (50) (50) L1POBA 1 (2*) 

•ESGPdAGUS (15) (11) (50) (50) f^UABOU S CELL CAKCINOBA, BBTASTA 1 (2»>

 

UiilNABl SlaTiM 

HKlIJNi.! (20) (20) (50) (50) TUBULAK-CELL ADENOBA 1 (2») 1 (2*> fllXED TUBOR, HALIGHAN T 1 (5*) 1 (2*) 1 (2*) HAflAHTOBA + t (10*) 

EKOOCHIJ..E SJSTEB 

•PITUITARY (19) (20) (50) (50) CHKOHOPHOBE ADENOMA 6 (32») 6 (30*) 6 (12*) 1 (2*) 

*ADJiESAL (20) (20) (50) (50)

 COHTICAL ADENOBA 1 (5»)

 1-HJSOCHHOHOCYTOMA 1 (5*)

 

tTtiyhUID (20) (19) (50) (»8) FULLICULAH-CELI. ADEKOBA 1 (5*) POLUCULAfi-CBLL CABC1NORA 1 <2*> 1 (2*) C-CELL ADEMOaA 2 (10*) L-CBLL CAHCINOBA 2 (10*) 1 (2*) 

IPiNCSfiATIC ISLETS (^0) (20) (50) (50)

 ISLE'f-CELL ADEMOBA 1 (M) 1 (5*)

 ISLET-CELL CARCIHOSA 1 (5*)

 

SEPfiODUCrlVE SISTE8 

•BABBABI GLAND (20) (20) (50) (50) 

AljEHOCARCINOHlj NOS 2 (10*) 1 (2» 

» NUBBER OP ANIdALS VilTH TISSOB BXAHIHBD BICHOSCOPICALLl 

* NUMBER OP AN1BALS NBCHOPSIBD 

+ 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. 

•Mi 
TABLE A2 (CONTINUED) 

CONTROL(UKTR)

01-031F

 CO8TROL(V2H)

 01-021F

 LOW DOSE

 01-034F

 HIGH DOSE 

 01-035F 

FifcfcOSAHCOHA

FIBKOADESOHA 2 (10%)

 1 (5*) 

7 (35*) 13 (26*) 4 (8») 

tOTEKOS

SO.UAHOUS CELL CASCISOBi

tHDosaraiAL STROBAL POLIP HEBANGIO8A

 (20)

 1 (5%) 

 (20)

 1 (5») 

 (50)

 3 (6X) 

 (49) 

*OVAH1

C2SIAD£HOCA8ClNO(tA, KOS

 (20)

 1 (5%)

 (20) (SO) (<I9) 

1 (2%) 

NBBVOUS SJSPBH 

HOME 

SPECIAL SENSE OSGASS 

NONE 

MUSCULOSKELETAL SISPES 

NONE 

BOOK CA»ItISS 

NONE 

ALL OIHfiS SfSTESS 

OlAPttHAGB 

SQUAMOOS CELL CAHCIKOBA, HEIASTA

AOEHOCASCISOMA, NOS, hETAS'l'ATiC

 1 

1 

ANIHAL OISPOSITION SUMBAE» 

AN18ALS INITIALLY IS STUD* 

NAPU&AL DEATH* 

HUHlbUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLI KILLED 

T8PS1NAL SAC8IP1CE 

ABISAL MISSING 

20 

2 

5 

13 

20 

15 

50 

31 

19 

50 

42 

2 

a__INCLUUEb AUrOLIZEp AHIMALS 

I BJSbtk OB AHIHALS WITH TISSUE EXABISED MICHOSCOPICALL1 

* HUMBtH UP iMIMALS NECiOPSIED 

A-9
 
TABLE A2 (CONCLUDED) 

CONTROL (UNTR) CONTROL (TEH) LOW DOSE HIGH DOS! 

01-031P 01-021F 01-034F 01-035P 

TOBOK SUBHABY
 

TOTAL ANIBALS WITH PBIBARY TUHORS* 14 12 26. 11
 

TOTAL PRIBAKY TUMORS 21 22 3b 18
 

TOTAL ANIMALS WITH BENIGN TUMORS 12 12 21 8
 

TOTAL BENIGN TUBORS 14 17 24 12
 

TOTAL ANIMALS H1TH BALIGNAN 6 T TUBORS 2 9 

TOTAL BALIGNANT TUMORS 7 3 11 

TOTAL ANIMALS KITH SECONDARY TUHORS* 1 1
 

TOTAL SECONDARY TUHORS 1 4
 

TOTAL ANIMALS B1TH TUHOBS UNCERTAINBENIGN OR BALIGNANT 2
 

TOTAL UNCERTAIN TUHORS 2
 

TOTAL ASIMALS WITH TUHORS ONCEBTA1NPHIHAHY OR BETA STATIC
 

TOTAL UNCERTAIN TUMORS
 

* PS1HABU TUMORS: ALL TUBORS EXCEPT SECONDARY TUHOBS
 

t SECONDARY TUMORS: METASTAtlC TUHORS O8 TUBORS INVASIVE INTO AN ADJACENT ORGAN
 

A-IO
 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH ALLYL CHLORIDE
 

TABLE Bl

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH ALLYL CHLORIDE 

CGUTBOL (UUTKI CONTROL (VEH)

02-B041 02-H031

 LOU DOSE

 02-8032

 UIHiH DOSE 

 02-H033 

ANIMALS INITIALLY IS S1UDY 20

ANIMALS NKCfiOPSlED 18

AiUSALb EXAMINED HISTOPATBOLOGICALLY** 1b

 20

 20

 20

 50

 46

 45

 50 

 50 

 49 

IHTEGUHSNTABY SYSTBK
 

*SUBCUT TISSOB (18) (20) (46) (50)
 

FIBROflA 1 (2*)
 

HSSPiSATOK* SYSTSB
 

*LO!IG (15) (20) (45) (49)
 

SgUAItOUS CELL CABCIHOBA, BiTASTA 1 (2*)
 

ALVKOLAK/BROHCHIOLAB ADENOMA 3 (15*) 6 (13*)
 

HSBATOPO1ETIC SYSTEH
 

*BaLTIl>Lii 0»GA»S (18) (20) (46) (50) 

flALIG.LYBPHOBA, LYBPHOCJTIC TYPE 1 (5») 1 (2X) 2 (4») 

HALH..LYBPHOBA, HIS1IOCYT1C TYPE 1 (2») 

LYStHOCYTlC LBUKBBIA 2 (4») 

UlLbfiStEBIC L. NODE (15) (19) (39) (28) 

aALIG.LYBPHOBA, LYBPHOCYTIC TYPE 1 (3*) 

CiaCOLAIOHY SYSTBB
 

NONE
 

UIGE3T1VE SYSTEB
 

tLIVEB (15) (20) (46) (49) 

SgUABOUS CELL CABCIMOBA, HETASTA 1 (2*> HEPATOCELLULAB CAKCIHOBA 1 (7*) 2 (10*) 8 (17*) 1 (2*) 

LilOBYOSARCOBA, 1 (2*) HEBANGIOBA 1 (2*1 

* SUSBEk OP AHIBALS NITB TISSUE EXABIHED BICBOSCOPICALLY 

* NJfljEK OF AKIflALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-3I
 
TABLE Bl (CONTINUED) 

COK18OL (UNTS)

02-B041

 CONTROL(VEH)

 02-H031

 LOU DOSE

 02-B032

 SIGH DOSE 

 02-H033 

• PA.NCKEAS

SyUAKOUS CELL CABCiSOBA, HETASTA

ibrOHACB

SQUASOU5 CELL CABCIHOBA

LhlOflYOSASCOMA

 (lit)

 (15)

 (20)

 (20)

 (1»5)

 1 (2J) 

 («6)

 2 (t») 

1 (2») 

 (43) 

 (U9) 

UEXSAH *

NONJ b 

 SYSTEM 

ENDoCHl«£ SfSl'BH 

NONE 

KilPKODUCTIVE SISTEM 

»Sfll)lDfl1IS

bUUABOUS CELL CASCIHOBA, SETASIA

 (18) (20) (46)

 1 (2*) 

 (50) 

NHS»OOS SYSTEB 

JONE 

SPECIAL SESSE OHGANS 

NUNK 

BUSCULOSKELEPAL SYSTEB 

NONE 

bOUi CAVITIES 

NONE 

ALL Oi'HEH SYSTEHS 

HONK 

» MUMBEH OP ANIBALS HITH TISSUE EXABIBED BICHOSCOPICALLY 

* SUSBEK OF ANIMALS HKCBOPSIED 

8-41
 
TABLE Bl (CONCLUDED)
 

CONTROL (UN1R) COHTBOL(VEH) LOU DOSE HIGH DOSE
 02-H041 02-B031 02-B032 02-B033
 

ANIMAL DISPOSITION SUMBABY
 

ANIHALS INITIALLY IN STUDY 20 20 50 50
 NATURAL DEATH4 12 4 27 40
 MORIBUND SACRIFICE 1
 SCHEDULED SACBIPICE 10
 ACCIDENTALLY KILLED 1
 

TiikMlNAL SACRIFICE 6 21 10
 ANIMAL MISSING
 

J) INCLUDES AUTOLYZED AMIHALS
 

TtMlOR SUB.1AR1T 

10TAL ASIaALS WITH PSIBAfil TU80RS* 1 5 19
 TOTAL PR1SAKY TDMORS 1 6 24
 

TOTAL AiJlMALS KITH 3ENIGH TUBORS 3 8
 TOTAL BE8IGN TUMOKS 3 8
 

TOTAL ANIMALS KITH SALIGNAHT TOMOES 1 3 12
 

TOTAL MALIGNANT TOHOES 1 3 16
 

TOTAL ANIMALS KITH SECONDARY TOHORS» 2
 

TOTAL SECONDARY TOHORS 5
 

TOTAL ANIMALS HITS 1DBORS UNCtHTAIN3tHluS OR HALJGNANT
 

TOTAL UNCERTAIN TUHOBS
 

TOTAL ANIMALS WITH THB08S UNCERTAINPRIMARY OR .IfiTASTATIC
 TOTAL UNCERTAIN TUBOBS
 

* PklflAfil TUHOES: ALL TUMORS EXCEPT SECONDARY TUMORS
 

* biiCOKBAHJ TUBOKS: BiiTASTATIC TUBORS OB TUBOHS INVASIVE INTO AS ADJACENT ORGAH
 

B-5
 
TABLE B2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH ALLYL CHLORIDE 

CONTBOL (ONTR)

02-P041

 CONTROL (VEH)

 02-F031

 LOU DOSE

 02-F03*

 BI6H DOS! 

 02-J035 

AHIBALS INITIALLY IS STUDY 20

AfllHALS NECROPSIED 20

ASIBALS EXABISED HISTOPATHOLOGICALLY ** 20

 20

 19

 19

 50

 48

 48

 50 

 45 

 44 

INTEGUBESTARY SYSTEH 

*SUbCUT TISSUE

FIBttOSAHCOBA

LSIUBYOSARCOBA

 (20)

 1 (5») 

 (19) (48)

 1 (2») 

 (45) 

RiSSPIRATOBY SYSTEB 

*LUSG

ADBNOCARCINOBA, SOS, BBTASTATiC

ALVEOLAH/BKOSCH1OLAR ADEBOBA

OSTBOSARCOHA, aETASl'ATIC

 (20)

 1 (5«)

 (19)

 1 (5»)

 (48)

 1 (2%) 

5 (10*)

 1 (2») 

 (45) 

4 (9*) 

HEflATOPOLBTIC SYSTEB 

*3lJl.rii>J.E ORGANS 

HALIG.LYMPMOBA 

MALiG.LYSPHOftA 

, 

, 

LYJ1PHOCYTIC 

HISTIOCYT1C 

TYPE 

TYPE 

BALlGSAwr LYBPHOJ1A, HIXED TYPE 

(20) 

1 

2 

(5%) 

(10*) 

(19) 

1 (5t) 

(48) 

1 (2*) 

4 |8») 

(45) 

6 

t 

(13*) 

(2%) 

HoPLEEN 

LJS10BYOSARCOBA i BETASliTXC 

(20) 

1 (b*) 

(19) (48) (45) 

• Mi-^ENTliRIC L. SODS 

LilOSYOSARCOMA 

BAL1G.LYHPHOMA 

»SflHLL 1HTESTI8E 

MALlG.LIMi'HOHA 

i 

• 

i 

SETASTATIC 

HISTIOt_YTlC 

HISTIOCYT1C 

TYPE 

TYPE 

(20) 

1 

(20) 

(5*) 

(19) 

(19) 

(45) 

1

(47) 

 (21) 

(42) 

(44) 

1 «i%) 

SYSTEM 

10NE 

» NUMbK R OF AJlBALS HUH TISSUE EXABIS2D

* SUBBJR OP AMIBALS StCSOPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 HICBOSCOPICALLK 

B-6
 
TABLE B2 (CONTINUED) 

CONTROL (OliTB)

02-F041

 CONTROL (VEH)

 02-F031

 LOW DOSE

 02-S034

 BIGH DOSE 

 02-F035 

UlbtbliVB SYSTEM 

»L1VER

HhPAl'OLELLULAH CAflCIMOHA

PlaROSARCOHA, METASTATIC

itSTOMALH

SUUA.1UUS CELL PAPILLOBA

i^OAMOOS CELL CARCINOMA

 (20)

 1 (5X)

 (^0)

 (19)

 (19)

 (48)

 1 (2*)

 1 (2») 

 (47)

 1 (2»)

 2 (4») 

 (45) 

1 (2J) 

 (<|5) 

3 (7») 

UM».AFI SYSTEM 

NOK t 

SYSTEM 

CHHOBOPHOBE AUEKOflA

(17)

 1 (6%) 

 (18) (43) (41) 

• ADRENAL

CORl'iCAL CAEC1HOBA

 (20) (19) (47) (45) 

1 (2») 

h£,PhODUCTIVE SYSTEM 

'SAHHA8I GLAND

AUENOCABCIMOMA, NOS

fUVAtl Y

CYaTADENOBA, HOS

tiEMlNGIOSARCOHJV

 (20)

 (20)

 (19)

 (19)

 1 (5*) 

 (48)

 1 (2») 

 (48)

 1 (2*) 

 (45) 

 (43) 

SJSBVUDb bYi-TEB 

bPELIAL SENSE OHGANS 

GLAUD 

AH£MOHA. UPS 

(20) (19) 

1 (5*1 

(48) 

T 

(4 a) 

» HUBBUB OP ANIMALS KITH TISSUE EXABIgED MICROSCOPICALLY 

* 1U.1Bi,R OF AS1BALS NBCROPSIED 

B-?
 
TABLE B2 (CONTINUED) 

CONTROL (UNTR)

02-F041

 CONTROL(VEB)

 02-F031

 LOU DOSE

 02-F034

 BIG8 DOSB 

 02-F035 

BUbCULOSKSLEl'AL SYSTEB 

OSTKOSABCOBA 

(20) (19) C»8) 

1 (2*) 

(45) 

BUDJ CAVITIES 

NOSE 

ALL OTHER SJSTEflS 

NONt, 

,I8AL DISPOSITION SUMHARY 

ANiBALS ISMIALLY IN STUDY

MATUHAL OKATH0

HOfilBUMD SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED

TEKBINAL SACRIFICE

ANIMAL HISSING 

 20

 3

 1 

 16

 20 

2 

 18 

50

9

1 

40

 50 

 15 

1 

 34 

INCLUDES AUTOLYiED ANISALS 

» NUMBJSS OF ANIMALS KITH TISSUE EXABINED MICROSCOPICALLY 

* NUBtBH OF AN1HALS NECROPSIED 

!

B-8
 
TABLE B2 (CONCLUDED)
 

COMTHOL(UMTR) COMT80L (»EU) LOW DOSE HIGH DOSE
 

02-^041 02-?031 02-F034 02-F035
 

TUnOK bUBBAR*
 

TOTAL ifllBALS WITH PRIBARi TUHOBS* 7 4 18 15
 

TOTAL PRIMARY TUBORS 7 II 20 17
 

TOTAL ANIBALS WITH BENIliH TUBOES 2 3 7 7
 

TOTAL BENIGN TOBOBS 2 3 7 7
 

TOTAL AHIBALS rflTH BALIGBAHT TOBOHS S 1 11 9
 TOTAL MALIGNANT TUBOHS 5 1 13 10
 

TOTAL ANIBALS WITH SECOHDAHI TUHORS* 1 2
 

TOTAL SECONDAH* TOBOHS 2 3
 

TOTAL ANMALS WITH TUBOES UNCERTA1NbEulGa OR aALlGHAKT
 

TOfAL UNCERTAIN TUHORS
 

TOTAL ANIBALS KITH TUMORS UHCERTAINPKIHARX OB MLTASTATIC
 

TOTAL UNCERTAIN TUBORS
 

* PHi.lARS TUBOKS: ALL TUBOHS 2XCEPT SECO»DARJ TUBOBS
 

* SKCOSlJARl TUMORS: BETAbTATIC TUBORS OH TU3O8S ISVASI?E INTO AS ADJACEBT ORGA»
 

B-9
 

APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH ALLYL CHLORIDE
 

TABLE Cl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATFD WITH ALLYL THLORDE 

CONTROL (UMTS) 

01-031H 

CONTROL (VBH> 

01-021B 

LOU DOSE 

01-032H 

B1«H BOS1 

01-0341 

ANIMALS INITIALLY III STDDY 

A8IHALS MISSING 

AHIMALS NBCROPS1BD 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 

20 

20 ** 20 

20 

1 

19 

19 

50 

50 

50 

50 

50 

SO 

IsTEGUSBHTARY SYSTEB 

»SKIN 

EPIDB8SAL INCLUSIOH CIST 

IMFLAHHATIO8, DOS 

INFLAMMATION, SOPPURAT1VE 

(20) 

1 <&*> 

(19) 

1 (5*) 

(50) 

,-_-—,_­ _-__.,__­_ 

(50) 

1 (2*) 

1 (2») 

HliSi-lKATORY SYSTEM 

*HASAL CAVITY 

INFLAMMATION, 80S 

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

1 (2%) 

•THACdEA 

INFLAMMATION DOS 

INFLAMMATION, SUPPUBATIVE 

(15) (19)

3 (16*) 

3 (16%) 

(50) (50) 

tLiISG/BROHCtilOLE 

INFLABMATION, SUPPDBATITE 

(20) (19) 

2 (11*) 

(50) (50) 

tLUNb 

fauaflOIJlA, CHEOHIC HURIHE 

CALCIUM DEPOSIT 

ALVEOLAR MACROPHAGES 

(20) 

16 (80%) 

1 (5») 

(19)

13 (68*) 

1 (S») 

(50) 

43 (B6S) 

(50> 

45 (90*) 

2 (4») 

rtiHArOPOISTIC SYSTEM 

IBUNh MARROH 

HETAIlORPiiOSlS PATTY 

(3) (19) (50) (50) 

1 (2*) 

»SPLLE« 

HKBATOPOIEbIS 

(20) 

1 (5X) 

(17) 

1 (6*> 

(50) 

1 (2*) 

(50) 

• l-EKVlCAi. LJBPH NODE 

INFLAMMATION, SOS (19) 

1 (5*1 

(17) (50) 

1 (2*) 

(49) 

* NUMBE R OF ANIMALS UITH TISSUE EXAMINED

* «artB£B OF ANIMAL S NECROfSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

C-3 
»TliYHUS 

ASG1ECTASIS 

CIRCULATOR* SYSTEB
 

•HEART
 

FIBROSIS 

CALCIUil DEPOSIT 

KMYOCAKDIOH
 

IAFLAMMAT1OB, NOS
 

INFLAMMATION, INTERSTITIAL
 

FIBKOS1S
 

DBGfiNERATIOl., SOS
 

CALCIBH DEPOSIT
 

CALCIFICATION, NOS
 

4ENDOCARUIUB
 

HJFEHPLASIA, NOS
 

*AOK1A
 

BJSD1AL CALCIFICATION
 

CALCIFICATION, BOS
 

*CORONAHY ARTERY
 

MEDIAL CALCIFICATION
 

CALCIFICATION, NOS
 

»PULBONAKJ ARTERY
 

CALCIFICATION, FOCAL
 

•8ESBSTER1C ABTEHT
 

PLB1ABTERITIS
 

MEDIAL CALCIFICATION
 

*PRObTATIC ARTERY
 

MEDIAL CALCIFICATION
 

DIGESTIVE SYSTEM
 

*LIVER
 

THROMBUS, ORGANIZED
 

INFLAMMATION. NOS
 

» NUBtJER OF ANIMALS H1TH TJ.SSOE

» SOMBER OF ANIHALS SECROPSIED 

TABLECl (CONTINUED) 

CONTROL (UNTR) CONTROL (VEtt)
 

01-031M 01-021H
 

(13) (2) 

(19) 

1 (5%)
 

(20)	 (19)
 

2 (10*) 3 (16*)
 

2 (11*)
 

13 (68*)
 

1 (5*1 

(20) (19) 

(20) (19)
 

2	 (10*)
 

3 (16*)
 

(20) (19)
 

1 (5»)
 

(20)	 (19)
 

1 (5*)
 

(20) (19)
 

2 (11*)
 

1 (5«>
 

(20) (19)
 

(20) (19)
 

1 (5M
 

 EXAMINED MICROSCOPICALLY 

LOK DOSE
 

01-032H
 

(10)
 

1 (3*J
 

(50)
 

1 (2*>
 

7 (14*)
 

(50)
 

5 (10*)
 

1 (2*>
 

(50)
 

(50)
 

8 (16*)
 

(50)
 

1 (2*)
 

(50)
 

(50)
 

5 (10*)
 

(50)
 

(50)
 

1 (2*)
 

1 (2*1
 

HIGH DOSE
 

01-033B
 

(26) 

(50)
 

2 («)
 

(50)
 

1 (2*)
 

1 (2*)
 

(50) 

(50)
 

4 (8*)
 

(50>
 

1 (2*)
 

(50)
 

(50)
 

1 (8*)
 

(50)
 

1 (2»)
 

(U9)
 

1 (2*1
 

e-4
 
TABLE Cl (CONTINUED) 

?I6HOSIS
 

CIRKSOSIS, SOS
 

1-ELlObIS HEP&TIS
 

NKCROS1S, UOS
 

METAMORPHOSIS FATTY
 

CYTOPLASIIIC VACDOLIZATION
 

HSPArOCfTOMEGALY
 

ANGiSCTASIS
 

•L1VKB/CKNTBILOBULJ8
 

itCHUSlS, dOS
 

*BlLi DUCT
 

INFLAMMATION, NOS
 

FlbKOSIS
 

riYPfcBPLASIA, SOS
 

•PANCREAS
 

FIBKOblS, FOCAL
 

PEhlARTERlTIS
 

»3TGSACH
 

ULCER, FOCAL
 

CALCIUB DEPOSIT
 

rllPEKKEKATOSlS
 

ACAaTHOSIS
 

•GASTK1C	 HUCOSA
 

CALCIFICATION, NOS
 

*COLON
 

SSBAIODIASIS
 

UhlaAHY SYSTEB
 

*KIi)SEY
 

BYDHONBPHfiOSIS
 

CYST, SOS
 

PYELOJ1EPHH1TIS, NOS
 

ABSCESS, BOS
 

INFLAMMATION, CHROMIC
 

CALCIUM DEPOSIT
 

tKIDSEY/HEDULLA
 

_. CALC1IICST10S. 80S
 

CONTROL (UHTR)
 

OT-031H
 

2 (10*)
 

3 (15*)
 

(20)
 

(20)
 

U (20*)
 

(20)
 

4 (20*)
 

(20)
 

2 (10*)
 

(20)
 

(19)
 

1 (5*)
 

(20)
 

1 (5*)
 

15 (75*)
 

1 (5*)
 

(20)
 

COSTBOL(VEH)
 

01-021B
 

3 (16*>
 

7 (37*)
 

7 (37*)
 

(1U)
 

(19)
 

8 (U2*>
 

5 (26*)
 

11 (58*)
 

(16)
 

3 (19*)
 

(19)
 

(19)
 

2 (11*)
 

(19)
 

(19)
 

1 <5»)
 19 (100*)
 

(19)
 

2 (11»»
 

LOU DOSE
 

01-032B
 

1 (2*)
 

t (8»)
 

2 («*)
 

1 (2*)
 12 (2t%)
 

8	 (1b*)
 

(50)
 

(50)
 

(50)
 

8	 (16*)
 

(50)
 

1 (2*)
 

6 (12*)
 

1 <2»)
 

1 (2*)
 

(50)
 

(»9)
 

(50)
 

2 t<t»)
 

1 (2»)
 3 (6»)
 

42 (84*)
 

7 (14*)
 

(50)
 

BIGB DOSE
 

01-033H
 

8 (16X)
 

1	 (8*)
 

t	 (8*)
 

(49)
 

1 (W
 

(50)
 

(50)
 

2 (4*)
 

(50)
 

2 (4*)
 

4 (8»)
 

(50)
 

;so)
 

(50)
 

1 (2*)
 4 (8»)
 

14	 (26%)
 

5 (10*)
 

(50)
 

» NOHbER OF ANIMALS WITH TISSUE B1AHI8ED MICROSCOPICALLY
 

* DUMBER OP ANIMALS HECROPSIED
 

C-5
 
TAJBLEC1 (CONTINUED) 

fXIDSliY/PELYlS
 

HYPEBPLASIA, EPITHELIAL
 

tUEINAKI BLADD4H
 

IKPLAHMATIOii, SOS
 

ISFLAHflATlON, SUPPUSAT1VE
 

HYPEBPLASIA, EPITHELIAL
 

ENUOChlHE SYSTEB
 

fPITUlTARJ
 

A.tGiECTASIS
 

•ADRESAL COKTEX
 

DEGENERATION, SOS
 

CYTOHEGALY
 

AHUIECPASIS
 

tl-HYROID
 

ULTIaJBRAJClilAL CYST
 

FOLL1CULAB CYST, UOS
 

H1PERPLASIA, C-CELL
 

HYPKBPLAS1A, FOLLICULAF-CELL
 

*PAHATHYHOID
 

HYPERPLASIA, BOS
 

hiPKODUCTlVE SYSTEM
 

•PROSTATE
 

i.<ri.AnaATj;o«, »os
 INFLAddATlOII, SUPPUKAT1VE
 

MYPERPLASIA, EPITHELIAL
 

METAPLASIA, SOUAHOUS
 

•SEMINAL	 VESICLE
 

INPLABHATIU1I, HOS
 

*i'ESTIS
 

GHANULOBA, SPEfiMATIC
 

PEHIARTER1T1S
 

LALCIUB DEPOSIT
 

ATEOPHY, NOS
 

» NUMJE R OF AHIBAL S WITH TISSUE

* SUBBBk OP AdISALS iEChOPSIED 

COHTROI. (UBTS)
 

01-031(1
 

COSTBOL(VEH)
 

01-021H
 

(19)
 

2 (11%)
 

(18)
 

1 <6»)
 

1 <6»)
 

(16)
 

(19)
 

1 (5*)
 

(19)
 

1 (5*)
 

4 (21*)
 

1 (5%)
 

(18)
 

4 (22*)
 

(18)
 

8 (44*)
 

1 (&*)
 

4 (22*)
 

(19)
 

(18)
 

2 (11*)
 

8 J<*4*^
 

 JSXAB1UED MICROSCOPICALLY 

(20)
 

(19)
 

1


(20)
 

1


(20)
 

1


(19)
 

2


 (5*)
 

 (5»)
 

 (5*)
 

 (11X)
 

1 (5*)
 

1 (5*)
 

(3)
 

2 (6?*)
 

(20)
 

5 (25*)
 

UO)
 

1 (5»)
 

(20)
 

1 (5*)
 

11	 IbSX)
 

LOU DOSE
 

01-032H
 

(50)
 

(49)
 

3 (6*>
 

(50)
 

(49)
 

1 (2*)
 

3 (6»>
 

(49)
 

4 (8*)
 

(23)
 

5 (22*)
 

(43)
 

4 (9*)
 

(50)
 

2 (4*)
 

(49)
 

20	 (41*)
 

HIGH DOSE
 

01-0338
 

(50)
 

(49)
 

U (8*)
 

(50)
 

(50)
 

(49)
 

1 (2*)
 

(26)
 

3 (12*)
 

(33)
 

5 (15*)
 

(50)
 

3 (6*)
 

(49)
 

1 12%)
 

9 (18*1
 

C-6 
*SPIUID)(.1iS
 

NECROSIS, PAP
 

ATROPHY, NOS
 

HYPiSRPLASIA, iPITHELlAl.
 

NERVOUS SYSTEM
 

SPECIAL SENSE ORGANS
 

*EYE/LACR1B1L GLAND
 

ISPLAMMATIO!*, &OS
 

MUbCULObKELETAL SYSTEB
 

*BO1»£
 

OSPEOPOBOS1S
 

BODY cAVITIfii
 

•PJiKITORlUH
 ISPLAIMAflON, NOS
 

*PEhIcA8DIU1
 

INFLAMMATION, NOS
 

•ItbENTBBY
 PEBIAHTEB1T1S
 NiChOSlS, PAT
 

ALl, OTHER SYS1EHS
 

NONb
 

SPECIAL SUBHARS
 

NO LESION REPORTED
 ANIHAL HISSING/MO HECtpPSY
 *

 MUlB^ h OP AalSALS KITH TISSUE

* NO(!B£K OF ANIMAL S NECBOtblED 

(TXBLE Cl (CONCLUDED)
 

CONTROL (UNT8 ) CONTROL (VBH)

01-03114 01-021H

(20) (19)
 

1 (5*)
 

3 (1b%)
 

1 (5)1)
 

(20)	 (19)
 

1 (5*1
 

(20)	 (19)
 

1 (5»)
 

(20)	 (19)
 

1 (5*)
 

(20)	 (19)
 

2 (10*)
 

(20)	 (19)
 U (20%)
 

 EXAHlJiED HICROSCOPICALLX 

 LOU DOSE HIGH DOSE 

 01-032B 01-0338 

(50) (50)
 

(50) (50)
 

(50) (50)
 

(50) (50)
 

(50)	 (50)
 

1 (2»> 2 (4»)
 

(50)	 (50)
 

5 (10*> 1 (2X)
 

1 (2»)
 

C-7 
TABLE C2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH ALLYL CHLORIDE 

CUNT30L (ONTH) CONTROL (VEH) 

01-031F 01-021P 

ANIBALi. INITIALLY IB STUDY 20 20 

ANIMAL S HECROPSISD 20 20 

ASIBALS EX4SI82D HISTOPATHOLOGICALLY ** 20 20 

INTSGUBlllTAitl SYSTEM 

*SUBCUT TISSUE (20) (20) 

Ai>Si_SSS, NOS 

KiSPIKATOKY SYSTEB 

OMAcmSA (15) (20) 

INFLAMMATION, NOS 5 (25*) 

laFLABflATION, SUPPUBAT1VB 1 (5*) 

afcTAPLASlA, SOUABOUS 1 (5*) 

• LUNli/bBONCHIOLE (20) (20) 

IS/LABBATION, SUPPORATIVE 4 (20*) 

H.UNG (20) (20) 

FOREIGN bODY, sos 1 (5*) coiMsasi'iuN, sos 1 (5*) 

M2HOBJidAGlS 2 (10*) 

PSiUBONIA, CHR08IC HUfilHE 18 (90*) 13 (65*) 

ALVEOLA R BACGOPHAGES f> (30*) 

HIPBfiPLASIA, ALVEOLAR EPITHELIUE 1 (5*) 

riKBAPOtOlETIC SYSTES 

• SPLElill (20) (20) 

HrfnOKKHAGE 1 (5*) 

HbEOSlS, FOCAL 1 (5*) 

Hi'MATOPOIESIS 4 (20*) 

KCEHViCAL LXHP H NODE (20) (20) 

UFLABBAIIOM, SOS 

AUGliiCI'ASIS 

KJ^EEPLASIA, LYBPUOII) 2 (10*1 

• NUBBE8 OP AMISALS WiTH TISSUE EXAHIaED BICROSCuPICALLY
 

* SUauEK OF ANIHALS SECSOtSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

LOW DOSE 

01-034F 

50 

50 

50 

(50) 

(50)

1 (2*) 

(50) 

(50) 

44 (88*) 

(50) 

6 (12%) 

(50) 

3 (6%) 

HIGH DOSE 

01-035F 

50 

50 

50 

(50) 

1 (2*) 

(50) 

(50) 

(50) 

43 (86*) 

(49) 

1 (^*) 

(49) 

1 (^*) 

1 (2*) 

C-8 
(H'CYDUS

 

AMaicCTASIS 

CIRCJi-ATOP* SJSTEM 

»(iYOCAKDlUR 

liifLAMMATIOH , SUPPUKAT1VE 

J-ISKOSIS 

(.^OCARDIUH

i..fLAMflATIOa, HOS 

•AORTA 

MEIJIAL CALCIFICATION 

•liSiNTKRlC Afii-ERK 

PERj-AhlEHITIS 

OlGj^SfLV E SYSTEM 

•LiViK 

INFLAMMATION , SOS 

tflBROSIS 

PKLiOSIb HEi'A'XIS 

UlXkUhlS, SoS 

StrABORPHOSIS PAfTY 

CJ10PLASMIC VACUOLIZATiON 

loCAL CELLULAR CHANG E 

MEPAToCKTOtlEGALS 

A^ISC-IASIS 

«LiVLR/CJ.STRJ;LOBULAK 

UKbEi*ERA!l IONr NOS 

NLCSObIS, NOS 

*BJ.Lh. UUCT 

IHPLAHHAT10N, SOS 

FlbROblS 

H»P£,hPLASlA, SOS 

*1'ASCREAS 

flbROSIS 

PLRI»KrEHiTIS 

» DUMBER OP AM.1ALS WITH TISSUE

* HU.lBSh OP HNIBALS NECROVSIED 

TABLE C2 (CONTINUED) 

CONTROL (USTH) CONTROL (VEH) 

01-031P 01-021P 

(15) (19) 

(20) (20) 

1 (5%) 

1 (•*%} 1 (5%) 

UO) (20) 

(20) (20) 

1 (b*) 

(20) (20) 

3 (15%) 

(/O) (20) 

1 (5*) 

6 (30%) 

6 (30%) 

2 (10%) 

(20) (20) 

1 (b*) 

(20) (20) 

6 (10%) 

3 (15%) 

1U (70%) 

(20) (20) 

1 (5») 

1 <5*> 

 EXABI8SD BICfiOSCOPICALLY 

LOU DOSE 

01-034P 

(39) 

(50) 

(50)

1 (2%) 

(50) 

(50) 

(50) 

3 (64) 

2 (4%) 

4 (84) 

2 (44) 

(50) 

1 (2%) 

(50) 

(50) 

H1UH DOSE 

01-035P 

(37) 

1 (3%) 

(50) 

1 (24) 

(50) 

(50) 

(50) 

(50) 

1 (2%) 

1 (2%) 

1 (2%) 

1 (2%) 

1 (2%) 

2 (4%) 

(50) 

1 (^%) 

(50) 

(50) 
•PANCREATIC

 ACINUS 

HYPEKPLASIA, FOCAL 

fESOPHAGUS 

GhAHULOHA, FOKBIGS BODY 

tSl'OBACH 

liPLAMBATIOH, HOS 

ULCEH, FOCAL 

HYPtBKERATOSIS 

ACANTHOS1S 

URIHAK Y SYSTEB 

nKioitsr HIDRONEPHROSIS

 

PYELONEPHRITIS, HOS 

ISFLABBAT10N, CHBOHIC 

CALCIUH DEPOSIT 

• UlijSEY/PELVIS 

HfPBRPLASIA, EPITHELIAL 

tUHlflAHY BLADDER 

ISPLABNAIION, SOS 

sjbocfUBB sisiaa 

•PITUiTARI 

ANG1SCTASIS 

«ai>R£MAL COKTEX 

DfitiENERAl'IOS, SOS 

CYTOBEGALY 

ANGIECTASIS 

tADtitNAL NEQULLA 

HJPERPLASIA, FOCAi. 

UriYHOlD 

ULTI3UBRA.1CHIAL CYST 

liYPEiiPLASIA, C-CELL 

*PAfiA'rHKHOIU 

riJPfiRPLASIAj HOS 

i SUSbEB UP AN1BALS WITH 1'ISSOE

» aUBBi.H i>f ANIMALS HECROPSIED 

TABLE C2 (CONTINUED) 

CONTROL (UNTR) CONTROL (VEH) 

01-031F 01-02 IF 

(20) (20) 

1 (51) 

(1i) (11) 

1 (7») 

(20) (20) 

1 (5*) 

1 (5*) 

1 (5%) 

(20) (20) 

y (ts*) 14 (70X) 

1 (5») 

(20) (20) 

4 (20X) 

(19) (20) 

(19) (20) 

(20) (20) 

if (20*) 

3 t15») 

(20) (20) 

1 (5*) 

<^0) (19) 

2 (11%) "4 (20%) ^ (37*) 

(1) (16) 

1 (100*) 3 (19*) 

 EXAH1NED BICROSCOPICALLY 

LOH DOSE 

01-03UF 

(50) 

(50) 

(50) 

1 (21) 

(50) 

2 («*> 16 (32*) 

1 (2*> 

(50) 

(50) 

(50) 

1 (2*) 

(50) 

1 (2*) 

10 (20*) 

(50) 

(50) 

(8) 

HIGH DOSE 

01-035F 

(50) 

(50> 

(50) 

(50) 

1 (2*) 

2 (4*) 

1 (2») 

1 (2*) 

(SO) 

(48) 

2 (4*) 

(50) 

1 (2») 

(50) 

1 (2*) 

2 (4*) 

(50) 

(48) 

(6) 

c-io 
ktPKODUCTIYE	 SYSTEM
 

*VAGINA
 

INFLAMMATION, NOS
 

»U'IBRUS
 

hYDHOMETHA
 

»UTE8US/ENDOllliTKIU»
 

CXbT, NOS
 

INFLAMMATION, NOS
 

IHPLihMATIOH, SUPPUHATIVE
 

HYPKfvPLAbIA, CYSTIC
 

*OVABY
 

CIST, NOb
 

NBKVOUb blSTEM
 

SOSfc
 

bPECiAL i-ENSi ORGANS
 

*hYE/COKNEA
 

mFLAflflATIOM, NOS
 

MUS<-ULOSKfcL£a/>.L SYSTfiS
 

*bKELElaL MUbCLE
 

bhANULOMA, NOS
 

BuDY LAVI'lIES
 

».1El/lAbTINUB
 

GfiANULOMA, POHEIGK BODY
 

•H.EUHA
 

FlbBOSlS, FOCAL
 

*PahiCAhDIU8
 

iNFLitlMATIOIij SOb
 

» NUMbE R OF ANIBALS KITH TISSUE

* ^UnbE^ OF ANIMALS NjsCkOVSltD 

TABLE C7 CONTINUED) 

CONTROL (UNTS) COHTROL (VEH)
 

01-031F 01-021F
 

(20) (20)
 

(20)	 (20)
 H (20*)
 

(20)	 (20)
 

1 (5%)
 

1 (5X)
 

2 (10*)
 

1 (5X) 1 (5*)
 

(20)	 (20)
 

..*.&%}
 

(20) (20)
 

(20)	 (20)
 

2 (10X)
 

(20)	 (20)
 

1 (5»)
 

(20)	 (20)
 

1 (5*)
 

(20) (20)
 

 JjXABISEU 8ICROSCOPICALL 

LOH DOSE HIGH DOSE
 

01-03HF 01-035F
 

(50) (50)
 . 1 (81) 3 (6*)
 

(50)	 (19)
 » (8») 4 (8X)
 

(50)	 (49)
 

3 (6%) 1 (2*)
 

1 (2X) 1 (2*)
 

(50) (U9)
 

(50)	 (50)
 

1 (2»)
 

(50) (50)
 

(50) (50)
 

(50) (50)
 

(50)	 (50)
 

3 (6X) 2 (4X>
 

C-ll 
TABLE C2 (CONCLUDED)
 

CONTHOL (DNTR)

01-031P

 CONTROL (VEH) 

 01-021F 

MSTAPLASIA, OSSEOUS 

»£PlLABDiCla

1NPLA1.1AT10C, SUPPUBfli?!.

 (20) (20) 

2 (10%) 

»Ri.StSlLRY

PLKiABTERlTIS 

oELKOSIS, FAT 

 (20) (20) 

ALL OTHER SYSTEHS
 

BOSPHOLOGS SUMMARY
 

HO LESION REPORTED
 

c SUMbiR OF ANIMAL S V.ITH TISSUE EXAMINED MICROSCOPICALLY 

( OF ANIMALS iMECROPSIJtD 

LOB DOS£ HIQH DOSE
 

01-03UF 01-03bF
 

1 (2*1
 

(50) (50)
 

(50)	 (50)
 1 (2*)
 

1 (2*)
 

C-12 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH ALLYL CHLORIDE
 

TABLE Dl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE TREATED WITH ALLYL CHLORIDE 

COUTROL(USTK) COSTROL(VEH) 

02-8041 02-H031 

AJ.I8ALS INITIALLY In STUDI 20 20 

ANIWAL S NKCROPSIfib 1b 20 

ANIBAL S SXAMINEi; HliTOPA'I HULOblCALLY ** 15 20 

laTSGUItajARY SYSTEM 

*i.UN (18) (20) IStLAllMATION, NOS 2 (10*) 

*SL)bCUl TISSUE (18) (20) ABSCESS, SOS 1 (6») 1 (5*) 

hLii'IP.irOiiY SYSTEM 

»LUN u (15) (20) t-NbtHoNlA, CHkONI c IUJRIMfS 

diPERPLASIA, ALVEOLAR BPlfHELIUB 

H^dA'lot-uILlIC SYSl'Efl 

4SfLEEH (15) (20) ASJLUIUOSIS 7 (47*) 2 (10*) HKBAIOPOlESIS 3 (15*) 

KBi-h NODE (19) 

itiFLAntlATIOS, NOS 

*CERV1CAL LiSPri HODE (15) (19) 

.LNfLAKMATION, SOS 1 (5%) 

*Ci.Sli!lTEliH, L. NODE (15) (19)
 

1 (7*) 7 (37*)
 

ASGIECTASIS
 

CIRCULATOR* SYSTEH
 

(20) 

» NUMbi.fi OF ANISAJ.S dlXH TISSUE EXAMINED aiCROSCOPICALLI 

* suaUEH OF ANJ.HALS Sl;ciioPSlEi> 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

LOU DOSE 

02-8032 

50 

46 

1(5 

(46) 

2 (4*) 

(46) 

3 (7*) 

(45) 

4 (9*) 

1 (2*) 

(46) 

6 (13*) 

1 (2i) 

(39) 

<3*> 

(39) 

(39)
 

10 (26t)
 

1 (3*)
 

(46)
 

1 (2M
 

HIGH DOSE 

02-B033 

50 

50 

49 

(50) 

1 (2*) 

(50) 

1 (2*) 

(49) 

3 (6*) , 

(48) 

3 (6*) 

4 (3») 

(28)
 

(28)
 

(28)
 

(49) 

D-3 
*MYOCf.HDIUH
 

DEGENERATION, NOS
 

UIt=ESTl»E SYSTEM
 

*LI»KK
 

THROMBUS, ORGANIZED
 

AMYLOIDOSIS
 

METAMORPHOSIS FATTY
 

*PANCEEAS
 

cYbT, SOS
 

INFLAMMATION, SOS
 

•STOMACH
 

ULCKR, NOS
 

CALC10S DEPOSIT
 

HIPEPKERATOSIS
 

ACANTHOSIS
 

•COLON
 

NBSAT00IASIS
 

UKINABY SYSTEM
 

•KIDNEY
 

HYDhONtPUHOblS
 

CJST, HOS
 

PJELONiPHRITIi, JlOS
 

1SFLA3HATION, CHHONIC
 

AflYLOiDOSIS
 

• UfclNAR X	 bLADDER
 

CALCULJS, NOS
 

INFLAMMATION, NOS
 

HitEHPLASIA, EPITHELIAL
 

ENDOCRINE SI&TEB
 

«ralKOI0
 

fOLLICJLAR CYbT, NOS
 

jSR OF ANIMALS KITS TISSUE

OF ANIMALS SBCROtblED 

TABLE Dl (CONTINUED) 

CONTROL (JSTK) CONTROL (VEH)
 

02-H041 02-B031
 

(15) (20)
 

(15) (20)
 

(14) (20)
 

1 (7*)
 

(15) (20)
 

(13) (20)
 

(15) (20)
 

1 (5*)
 2 (10*)
 

12 (80*) 2 (10*)
 

7 (47*) 2 (10*)
 

(15) (19)
 

2 (11*)
 

(10)	 (20)
 

1 (10*) 1 (5*)
 

 EXAMINED MICEOSCOPICALLJ 

LOU DOSE
 

02-B032
 

(46)
 

1 (2«)
 

(46)
 

1 (2S>
 

1 (2*)
 

1 (2*)
 

(45)
 

1 (2*>
 

(46)
 

1 (2*)
 

9 (20*)
 

9 (20*)
 

(44)
 

1 (2*)
 

(46)
 

1 (2*)
 

5 (11*)
 

10 (22*)
 

5 (11*)
 

(44)
 

1 (2*)
 

(38)
 

H1GB DOSE
 

02-8033
 

(49)
 

(49)
 

2 (4*)
 

(13)
 

(49)
 

1 (2»)
 

19 (39X)
 

19 (39*)
 

(46)
 

(49)
 

5 (1C*)
 

3 (6*)
 

^ (4*)
 

(47)
 

1 (•**)
 1 (2*)
 

1 (2*)
 

(37)
 

D-4 
FABLE Dl (CONTINUED) 

CONTROL (USTS)

02-BOm

 CONTROL (VEH ) 

 02-8031 

LOV DOSE 

02-H032 

HIGH DOSB 

02-9033 

KEPROUUCTIVB SJSTEM 

KPKObl'ATS 

1MFLAMMAT1OM, «OS 

*bfiMlNAL VESICLE 

N, NOS 

• I'tbTlS 

ATEOPHI, SOb 

*EPlL>-Lt>YMlb

J.KFLAHHATIOM, NOS

GKANULOBA , bPhRBATIC

(IB) 

(1b)

1 ("'*) 

 (18)

(12) 

 (20) 

 (20)

(10) 

1 (3*) 

(U6) 

1 (2%) 

(16) 

 (16)

 1 (2»)

(50) 

1 (2») 

 (50) 

1 (2*) 

1 (2%) 

SPECIAL SENSE OiiGiSb 

• JAHDjiSIAi GLAND

ISPLAHBATIUN, Hob

KYPEhPLAbIA , NOS

 (IB) t20) (16)

 1 (2») 

1 (2») 

 (50) 

lUbLULUi-KELJerAL SYSTEM 

Euji oAVITIfcS 

NoHli 

ALL Oi'rtEB 

bPtl_IAL BOnPHOLOGY 

..O ^.^blOj hgPOBfED

I SUi'.fltH OP 4S1BALS rtlTH

* JU.lbil< of A.iltlALS 

 TISSUE EXAHINED

 3 

 BICKOSCOi'ICALLK 

D-5 
TABLED! (CONCLUDED) 

CONTROL (OUTR)

02-BOal

 CONTROL (VEH) 

 02-M031 

LOH DOSE 

02-0032 

HIGH DOSE 

02-B033 

AllrO/HLCKOPSY/HISTO t'SKf 1 

AUi'U/JlKCSOPiY/NO H1STO 3 1 1 

AUTOLYSIS/NO SBCROPbJ 2 4 

SUBt>£8 0? ANIMALS HITM TISSUE EXAH1NED BICBOSCOPICALLY 

OP Ai.lMALS KECROPSIED 

D-d 
TABLE D2

 

SUMMARY OF THE INCIDENCE OF NONNEOPtASTIC LESIONS IN FEMALE MICE TREATED WITH ALLYL CHLORIDE 

CGalfiOL (JSTH) 

02-P041 

CONTROL (V EH) 

02-F031 

LOU DOSE 

02-F034 

HIGH DOSE 

02-F035 

ANIMALS INITIALLY In STUDY

ANIMALS NECSOPSIED ANa.!ULb EXAMINED HISTOPATHOLOUICALLY **

 20 

 20 20 

20 

19 

19 

50 

48 

48 

50 

45 

44 

INTEiiUSENTARY SYST3H 

»SK1» 

I8FLAMNAIION, U8ANULOBATOUS 

(20) (19) (48) 

1 (2%) 

(45> 

*SUBCUT TISSUE 

ABSCESS, NOS 

(20) (19) (48) (45) 

1 (2*) 

ShSPIBATOKY SYSIED 

• LUNG 

PUJSUnOlUA, CBROHIC MURIflE 

(20) 

1 (5*) 

(19) 

1 (5*) 

(48) 

3 (6t) 

(45) 

5 ("*) 

HiiMATOPOIETIC SYSTEM 

»SPL2EN 

H^SATOPOIESIS 

(20) (19) (48) 

1 (2*) 

C»5) 

3 (7* 

»LfrtPH NODE 

I.«Pl.AS.1ArlOM, SOS 

(20) 

1 (5*) 

(19) (45) 

1 (2») 

(42) 

*aKONCHIAL LYMPH 

IHFLAMSATIOJl, 

NODE 

DOS 

(20) (19) (45) (42) 

1 (2») 

»Mt'SSNTEfiIC L. NODE 

INFLAHHAIIOli, 

ANGIECTASIS 

NOS 

(20) (19) 

1 (5») 

1 (5*) 

0»5> 

1 (2») 

(42) 

1 (2%) 

CIRCULATORY SYSTEM 

»«!iI>OCAHDIUB 

aifPERPLASIA. HOS 

(20) (19) (45)

1 12%} 

* NUMBEf c OF aNIHALS WITH TISSUE BXABISED

* JUHBER OP AMIBALS MECHOPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 HICSOSCOPICALU 

1D-7 
TABLE D2 (CONTINUED)
 

comaoi.(UNTfi] I CONTROL (VEH) 

02-F041 02-F031 

DlGhSTi»B 3Z3TEH 

*LIVEtt (20) (19) 

LBUKEMOID REACTION 1 (5*)

 

*BILE UUCT (20) (19)

 

DiLAfATIOS, NOS 1 (5*) 

HYPSMPLASIA, NOS 1 (5»)

 

(PANCREAS (20) (19)

 

CYST, NOS 1 <5»)

 

CI3TIC DUCTS 

luPLAMMATlOM, MOS 1 (5»)

 

AlttOPHI, SOS 

*STOSACH (20) (19)

 

JLCER, NOS 

HYPJSBKERATOSIS 

ACANTHOSIS 

•SMALL 1NTESTIME (20) (19) 

HYPSHPLASIA, LMPH01D 

»Pi.»£SS PATCH (20) (19)

 

UIPEHPLASIA, LYMPHOID 

UiilNAH! 

NOHii 

tKUOCKlSE SY3T2B
 

»THlfi<OlD (16) (16)
 

POLLICOLAR CIST, SOS 1 (b») 

MKPI.RPLASIA, FOLLICULAH-CEI.L 1 (o*) 

HtPKOUUCTiVE SYSTEM 

*»At.INA (20) (19) 

UPLAHBAIiOJI, MOS 

(20) (19) 

t NUBojiK OF ANIBALS WITH TISSUE BXAH1NSD H1CSOSCOPICALLK
 

* -lUOBjiK UP AHIBALS HECKOPS1ED
 

LOH DOSE 

02-F034 

(48) 

(48) 

(46) 

2 (4%) 

2 (4») 

(47) 

1 (2*) 

17 (36») 

17 (36%) 

(47) 

2 (4») 

(47) 

1 (2») 

(43)
 

(48)
 

HIGH DOSE 

02-FOJ5 

(45) 

(45) 

(45) 

1 (2%) 

2 (4%) 

1 {2X> 

(45) 

1 (2*) 

25 (561) 

25 (56*) 

(44) 

2 (5») 

(44) 

(41)
 

(45) 

(43) 

t>-8 
TABLE D2 (CONCLUDED) 

COHTHOL(OMTB) 

02-F041 

COSTEOL (»EH) 

02-F031 

LOR DOSE 

02-F034 

HIGH DOSI 

02-F035 

IHFLABBATIOH, SOS 

HJTKRUS/ENDOSETRIUB 

IHFLABMATION. MOS HYPERtLASIA, CYSTIC 

»OVAKY/OVIDOCT 

IBKLABBATIOH, 80S 

»iJVAH Y

CIST, HOS

INPLABMATIOB. NOS

C20) 

3 

6 (30X) 

(20) 

 (20)

 12 (60*)

 5 (25*)

(19) 

2 (11*) 

9 (U7%) 

(19) 

 (19)

 1 (21*)

 4 (21*)

(48) 

19 (to*) 

(48) 

1 (2») 

 (48)

 11 (23*)

(43) 

5 

13 (30*) 

(K3) 

2 (S») 

 (43) 

 11 (26*) 

3 (7») 

SKliVUUS SYSTEB 

SOSE 

bPSCIAl. bfiNSe ORGANS 

»rtAR3ihIAN GLAND

INrLAftftATION, 80S

HYPERPLAS1A, HOS

 (20) (19) (48)

 1 (2*) 

2 (4*)

 (45) 

4 (9*) 

(IUSCI1LOSKELSTAL SYSTEB 

MOili; 

bUDK CAVITIBS 

*PKhlTOaiSJ«

IMfi-ABMATION, SOS

 (20) (19)

 1 (5*)

 (48) (45) 

1 (2*) 

ALL OTHKR SYSTEMS 

"MULTIPLE ORGANS

i-EUKJSBOID REACTIOH

 (20) (19) (48)

 1 (2*) 

 (45) 

SORPHOLOGY SU.1BARY 

NO LESION REPORTED 

AUTO/NUCHOPSY/HO HISTO 

LYSIS/NO JIECSQgSY 

* SUKbBh OF ANIBALS WITH TISSUE EXABISEU BICHOSCOPICALLY 

OP AN1BALS MECROPSIED 

D-9
 


DHEW Publication No. (NIH) 78-1323