1979 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

NO. 155 

BIOASSAY OF 

2, 4, 6-TRICHLOROPHENOL 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 88-06-2 

NCI-CG-TR-155 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

2,4,6-TRICHLOROPHENOL
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20014
 

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

Public Health Service
 

National Institutes of Health
 

DHEW Publications No. (NIH) 79-1711
 
11

 
BIOASSAY OF
 

2,4,6-TRICHLOROPHENOL
 

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
 

2,4,6-trichloropheno1 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. A negative result, in which the test animals
 

do not have a greater incidence of cancer than control animals,
 

does not necessarily mean that the test chemical is not a
 

carcinogen, inasmuch as the experiments are conducted under a
 

limited set of circumstances. A positive result demonstrates that
 

the test chemical is carcinogenic for animals under the conditions
 

of the tests and indicates that exposure to the chemical is a
 

potential risk to man. The actual determination of the risk to
 

man from chemicals that are carcinogenic in animals requires a
 

wider analysis.
 

CONTRIBUTORS; This bioassay of 2,4,6-trLchloropheno1 was
 

conducted by the NCI Frederick Cancer Research Center (FCRC) (1),
 

Frederick, Maryland, operated for NCI (2) by Litton Bionetics, Inc.
 

The manager of the bioassay at FCRC was Dr. B. Ulland, the
 

toxicologist was Dr. E. Gordon, and Drs. R. Cardy and D. Creasia
 

compiled the data. Ms. S. Toms was responsible for management of
 

data, Mr. D. Cameron for management of histopathology, Mr. L.
 

Callahan for management of the computer branch, and Mr. R. Cypher
 

for management of the facilities. Mr. A. Butler performed the
 

computer services. Necropsies were performed by Drs. B. Ulland,
 

R. Schueler, R. Ball, and R. Cardy. The lesions of the rats and
 

mice were reviewed by Drs. J. L. Stookey and J. M. Ward (2), and
 

the diagnoses included in this report represent their interpretations.
 

ill
 
Animal pathology tables and survival tables were compiled at EG&G
 

Mason Research Institute (3). Statistical analyses were performed
 

by Dr. J. R. Joiner (4), and Ms. P. L. Yong <"4), using methods
 

selected for the bioassay program by Dr. J. J. Gart (5). The
 

chemicals used in this bioassay were analyzed at FCRC Cancer
 

Research Center by Dr. W. Zielinsky. The chemical analyses and
 

narrative were reviewed and approved by Dr. Lijinsky O).
 

This report was prepared at Tracer Jitco (5) under the direction
 

of NCI. Those responsible for the report at Tracor Jitco were Dr.
 

C. R. Angel, Acting Director of the Bioassay Program; Dr. S. S.
 

Olin, Deputy Director for Science; Dr. J. F. Robens, toxicologist;
 

Dr. R. L. Schueler, pathologist; Dr. G. L. Miller, Ms. L. A. Owen,
 

Ms. M. S. King, and Mr. W. D. Reichardt, bioscience writers; and
 

Dr. E. W. Gunberg, technical editor, assisted by Ms. Y. E. Presley.
 

The following scientists at NCI were responsible for evaluating
 

the bioassay experiment, interpreting the results, and reporting
 

the findings: Dr. Kenneth C. Chu, Dr. Cipriano Cueto, Jr., Dr. J.
 

Fielding Douglas, Dr. Richard A. Griesemer, Dr. Thomas E. Hamm,
 

Dr. William V. Hartwell, Dr. Morton H. Levitt, Dr. Harry A. 

Milman, Dr. Thomas W. Orme, Dr. A. R. Patel, Dr. Sherman F. 

Stinson, Dr. Jerrold M. Ward, and Dr. Carrie E. Whitmire. 

(1)	 Frederick Cancer Research Center, P.O. Box B, Frederick,
 

Maryland.
 

(2)	 Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

(3)	 EG&G Mason Research Institute, 1530 East Jefferson Street,
 

Rockville, Maryland.
 

(4)	 Tracor Jitco, Inc., 1776 East Jefferson Street, Rockville,
 

Maryland.
 

(5)	 Mathematical Statistics and Applied Mathematics Section,
 

Biometry Branch, Field Studies and Statistics, Division of
 

Cancer Cause and Prevention, National Cancer Institute,
 

National Institutes of Health, Bethesda, Maryland.
 

iv
 
SUMMARY

 

A bioassay of 2,4,6-trichlorophenol for possible carcinogenicity 

was conducted by administering the test chemical in feed to F344 

rats and B6C3F1 mice. 

Groups of 50 rats of each sex were administered 2,4,6-trichlorophenol at one of two doses, either 5,000 or 10,000 ppm, for 106 

or 107 weeks. Matched controls consisted of 20 untreated rats of 

each sex. All surviving rats were killed at the end of 

administration of the test chemical. 

Groups of 50 male mice were administered 2,4,6-trichlorophenol at 

one of two doses, either 5,000 or 10,000 ppm for 105 weeks. 

Groups of 50 female mice were administered the test chemical at 

one of two doses, initially either 10,000 or 20,000 ppm, for 38 

weeks. Because of excessively lowered body weights in the dosed 

groups of the females, the doses for the females were then 

reduced to 2,500 and 5,000 ppm, respectively, and administration 

at the lowered doses was continued for 67 weeks. The 

time-weighted average doses for the female mice were either 5,214 

or 10,428 ppm. Matched controls consisted of 20 untreated mice 

of each sex. All surviving mice were killed at the end of 

administration of the test chemical. 

Mean body weights of dosed rats and mice of each sex were lower 

than those of corresponding controls and were dose related 

throughout the bioassay. Survivals to the end of the experiment 

were 68% or greater in all groups of rats and 80% or greater in 

all groups of mice. 

In the male rats, lymphomas or leukemias occurred at incidences 

that were dose related (P = 0.006) and in direct comparisons were 

significantly higher in the low-dose (P = 0.019) and high-dose 

(P = 0.004) groups than in the corresponding control group 

(controls 4/20, low-dose 25/50, high-dose 29/50). Leukocytosis 

and monocytosis of the peripheral blood and hyperplasia of the 

bone marrow also occurred in some dosed male rats not having 

lymphoma or leukemia. 

In the female rats, monocytic leukemia did not occur at 

incidences that were significant. However, as in the male rats, 

leukocytosis and monocytosis of the peripheral blood and 
hyperplasia of the bone marrow occurred in the dosed female rats 

but not in the controls (blood leukocytosis and monocytosis: 

controls 0/20, low-dose 6/50, high-dose 3/50; bone marrow 

hyperplasia: controls 0/20, low-dose 16/50, high-dose 2/50). 

In both the male and female mice, hepatocellular carcinomas or 

adenomas occurred at incidences that were dose related (P less 

than 0.001), and in direct comparisons were significantly higher 

in the low- and high-dose male groups and the high-dose female 

group (P less than or equal to 0.001) than in the corresponding 

control groups (males: controls 4/20, low-dose 32/49, high-dose 

39/47; females: controls 1/20, low-dose 12/50, high-dose 24/48). 

It is concluded that under the conditions of this bioassay, 2,4,6­

trichlorophenol was carcinogenic in male F344 rats, inducing 

lymphomas or leukemias. The test chemical was also carcinogenic 

in both sexes of B6C3F1 mice, inducing hepatocellular carcinomas 

or adenomas. 

vi 
TABLE OF CONTENTS
 

I. Introduction 1
 

II. Materials and Methods 3
 

A. Chemical 3
 

B. Dietary Preparation 3
 

C. Animals 4
 

D. Animal Maintenance 5
 

E. Subchronic Studies 7
 

F. Chronic Studies 10
 

G. Clinical and Pathologic Examinations 10
 

H. Data Recording and Statistical Analyses 14
 

III. Results - Rats 21
 

A. Body Weights and Clinical Signs (Rats) 21
 

B. Survival (Rats) 21
 

C. Pathology (Rats) 24
 

D. Statistical Analyses of Results (Rats) 26
 

IV. Results - Mice 29
 

A. Body Weights and Clinical Signs (Mice) 29
 

B. Survival (Mice) 29
 

C. Pathology (Mice) 32
 

D. Statistical Analyses of Results (Mice) 34
 

V. Discussion 37
 

VI. Bibliography 39
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in
 

Rats Administered 2,4,6-Trichlorophenol
 

in the Diet 41
 

Table Al Summary of the Incidence of Neoplasms in
 

Male Rats Administered 2,4,6-Trichlorophenol
 

in the Diet 43
 

vii
 
Table A2 Summary of the Incidence of Neoplasms in 

Female Rats Administered 2,4,6-Trichlorophenol 

in the Diet 48 

Appendix B Summary of the Incidence of Neoplasms in 

Mice Administered 2,4,6-Trichlorophenol 

in the Diet 53 

Table Bl Summary of the Incidence of Neoplasms in 

Male Mice Administered 2,4,6-Trichlorophenol 

in the Diet 55 

Table B2 Summary of the Incidence of Neoplasms in 

Female Mice Administered 2,4,6-Trichlorophenol 

in the Diet 59 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Administered 

2,4,6-Trichlorophenol in the Diet 63 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Administered 

2,4,6-Trichlorophenol in the Diet 65 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Administered 

2,4,6-Trichlorophenol in the Diet 72 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Administered 

2,4,6-Trichlorophenol in the Diet 79 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Administered 

2,4,6-Trichlorophenol in the Diet 81 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Administered 

2,4,6-Trichlorophenol in the Diet 86 

Appendix E Analyses of the Incidence of Primary Tumors 

in Rats Administered 2,4,6-Trichlorophenol 

in the Diet 91 

Table El Analyses of the Incidence of Primary

in Male Rats Administered 

2,4,6-Trichlorophenol in the Diet

 Tumors 

 93 

viii
 
Table E2 Analyses of the Incidence of Primary Tumors 

in Female Rats Administered 

2,4,6-Trichlorophenol in the Diet 100 

Appendix F Analyses of the Incidence of Primary Tumors 

in Mice Administered 2,4,6-Trichlorophenol 

in the Diet 105 

Table Fl Analyses of the Incidence of Primary Tumors 

in Male Mice Administered 2,4,6-Trichlorophenol 

in the Diet 107 

Table F2 Analyses of the Incidence of Primary Tumors 

in Female Mice Administered 

2,4,6-Trichlorophenol in the Diet Ill 

TABLES 

Table 1 2,4,6-Trichlorophenol Subchronic Feeding 

Studies in Rats and Mice 8 

Table 2 2,4,6-Trichlorophenol

Studies in Rats

 Chronic Feeding 

 11 

Table 3 2,4,6-Trichlorophenol Chronic Feeding 

Studies in Mice 12 

FIGURES 

Figure 1 Growth Curves for Rats Administered 

2,4,6-Trichlorophenol in the Diet 22 

Figure 2 Survival Curves for Rats Administered 

2,4,6-Trichlorophenol in the Diet 23 

Figure 3 Growth Curves for Mice Administered 

2,4,6-Trichlorophenol in the Diet 30 

Figure 4 Survival Curves for Mice Administered 

2,4,6-Trichlorophenol in the Diet 31 

ix
 
X

 
I. INTRODUCTION
 

2,4,6-Trichloropheno1 (CAS 88-06-2; 

NCI 002904) is a germicidal agent 

that has been used to preserve wood 

and glue as well as to protect 

textiles against mildew (Stanford 

Research Institute, 1976). Produc- Cl 

tion of this chemical (for sale as 

2, 4, 6-Trichlorophenol 

an end product) was discontinued in 

1975 by Dow Chemical Company (1978), 

the only manufacturer of 2,4,6-trichlorophenol in the United
 

States, because of the high cost of removing toxic dioxin
 

impurities. However, a small quantity (2,204 pounds) was
 

imported for domestic use in 1976 (United States International
 

Trade Commission, 1977).
 

The chemical has been reported to be produced when water
 

containing phenol (Eisenhauer, 1964; Smith et al., 1975) or
 

certain aromatic acids (Larson and Rockwell, 1977) is treated
 

with hypochlorite, suggesting the possibility of human exposure
 

to 2,4,6-trichlorophenol in treated industrial waste water. The
 
chemical is also an end product of lindane metabolism in mammals
 

(Tanaka et al., 1977).
 

The oral LD of 2,4,6-trichlorophenol has been reported as 820
 

mg/kg body weight in rats of unspecified strain (NIOSH, 1976).
 

2,4,6-Trichlorophenol was tested by Innes et al. (1969) in a
 

large-scale screen of industrial compounds for carcinogenic
 

activity. The results of this preliminary bioassay in mice
 

suggested a possible association of the incidence of tumors with
 

administration of the test chemical; therefore, 2,4,6-trichlorophenol was selected for further testing in the Carcinogenesis
 

Testing Program.
 
II. MATERIALS AND METHODS
 

A. Chemical
 

2,4,6-Trichlorophenol (Omal , Dowicide 2S) was obtained from 

the Dow Chemical Company as a light, pinkish-orange solid. Its 

melting point was 65 and its boiling point was 251 to 252 C; 

corresponding values given in the literature (Windholz, 1976) 

were 69 and 246 C, respectively. Elemental analysis showed 

average values of 36.2% carbon and 1.5% hydrogen (theoretical: 

36.5% C and 1.5% H). Its infrared spectrum was consistent with 

the chemical structure, and identical to that of a standard. 

Mass spectral analysis showed a molecular ion as the base peak at 

m/e 197. Its purity was determined by gas-liquid chromatography 

to be 96 to 97%, with up to 17 minor contaminants. The chlorinated dibenzo-p-dioxin content of the 2,4,6-trichlorophenol was 

not determined. 

B. Dietary Preparation
 

Test diets containing 2,4,6-trichlorophenol were prepared by 

mixing the appropriate amount of the chemical with autoclaved 
Wayne® Sterilizable Lab Meal containing 4% fat (Allied Mills, 

Inc., Chicago, 111). The weighed chemical was first mixed with 

an equal amount of the lab meal using a mortar and pestle. The 

mixing was continued with second and third additions of feed, and 

final mixing was performed with the remaining quantity of feed 

for a minimum of 15 minutes in a Patterson-Kelly twin-shell 

blender with an intensifier bar. The material was then stored in 

sealed 3-kg plastic bags at 7 C until used. 

C. Animals 

Male and female F344 (Fischer) rats and B6C3F1 mice were obtained 

as 4-week-old weanlings, all within 3 days of the same age, from 

the NCI Frederick Cancer Research Center (Frederick, Md.). The 

animals were housed within the test facility for 2 weeks and then 

were assigned four rats of the same sex to a cage and five mice 

of the same sex to a cage. For use in the chronic study, the 

male rats weighed 90 to 105 g, averaging at least 100 g; for 

female rats, 80 to 95 g, averaging at least 90 g; for male mice, 

18 to 22 g, averaging at least 19.5 g; and for female mice, 17 to 

21 g, averaging at least 18.5 g. Individual animals were 

identified by ear punch. 
D. Animal Maintenance
 

The animals were housed in polycarbonate cages (Lab Products
 

Inc., Garfield, N.J.), 19 x 10-1/2 x 8 inches for the rats and
 

11-1/2 x 7-1/2 x 5 inches for the mice. The cages were
 

suspended from aluminum racks (Scientific Cages, Inc., Bryan,
 

Tex.) and were covered by nonwoven polyester-fiber 12-mil-thick
 

filter paper (Hoeltge, Inc., Cincinnati, Ohio). The bedding used
 

®
 

was hardwood chips (Absorb-dri , Northeastern Products, Inc.,
 

Warrenburg, N.Y.). The feed was presterilized Wayne
 

Sterilizable Lab Meal containing 4% fat, provided ad_ libitum in
 

suspended stainless steel hoppers and replenished as required, at
 

least three times per week. Water, acidified to pH 2.5, was
 

supplied ad libitum from glass bottles with sipper tubes
 

suspended through the tops of the cages.
 

The contaminated bedding was disposed of through an enclosed
 

vacuum line that led to a holding tank from which the bedding was
 

fed periodically into an incinerator. The cages were sanitized
 

twice per week and the feed hoppers twice per month at 82 to
 

88 C in a tunnel-type cagewasher (Industrial Washing Machine
 

Corp., Mataway, N. J.) using the detergents, Clout (Pharmacal
 

Research Laboratories, Greenwich, Conn.) or Oxford D'Chlor
 

(Oxford Chemicals, Atlanta, Ga.). The bottles were sanitized at
 
82 to 88 C in a tunnel-type bottle washer (Consolidated
 

Equipment Supply Co., Mercersburg, Pa.) three times per week,
 

using a Calgen Commercial Division detergent (St. Louis, Mo.).
 

The racks for the cages were sanitized at or above 82 C in a
 

rack washer (Consolidated Equipment Supply Co.) once per month,
 

using the Calgen Commercial Division detergent, and the filter
 

paper was changed at the same time.
 

The animal rooms were maintained at 22 to 24 C and 45 to 55%
 

relative humidity. Incoming air was passed through a filter of
 

65% efficiency and a bag filter of 95% efficiency at the intake
 

and expelled without recirculation through a "Z"-type roughing
 

filter of 30% efficiency and a bag system of 90 to 95% efficiency
 

at the exhaust (American Air Filters, Louisville, Ky.; Mine
 

Safety Appliances, Pittsburgh, Pa.). Room air was changed 15
 

times per hour. The air pressure was maintained negative to a
 

clean hallway and positive to a return hallway. Fluorescent
 

lighting was provided on a 12-hour-per-day automatic cycle.
 

Rats administered 2,4,6-trichlorophenol and their corresponding
 

controls were housed in the same room as rats on feeding studies
 

of the following chemicals:
 
(CAS 999-81-5) (2-chloroethyl)trimethylammonium chloride (CCC)
 

(CAS 51-03-6) piperonyl butoxide
 

Mice administered 2,4,6-trichlorophenol and their corresponding
 

controls were housed in the same room as mice on feeding studies
 

of the following chemicals:
 

(CAS 103-33-3) azobenzene
 

(CAS 128-66-5) C.I. vat yellow 4
 

(CAS 20941-65-5) ethyl tellurac
 

(CAS 298-00-0) methyl parathion 

(CAS 72-56-0) p,p'-ethyl-DDD 

(CAS 85-44-9) phthalic anhydride 

(CAS 51-03-6) piperonyl butoxide 

E. Subchronic Studies
 

Subchronic feeding studies were conducted to estimate the maximum
 

tolerated doses (MTD's) of 2,4,6-trichlorophenol, on the basis of
 

which two concentrations (referred to in this report as "low" and
 

"high" doses) were selected for administration in the chronic
 

studies. Groups of rats or mice consisting of five males or five
 

females were fed diets ad libitum which contained 10,000 to
 

46,000 ppm 2,4,6-trichlorophenol for rats and 6,800 to 31,500 for
 

mice for a period of 7 weeks, followed by 1 week of additional
 

observation. Each animal was weighed twice per week. Table 1
 

shows the doses fed, the survival in each dosed group at the end
 

of the study, and the mean body weights of dosed groups
 
Table 1. 2,4,6-Trichlorophenol Subchronic Feeding Studies
 

in Rats and Mice
 

Dose
 

(ppm)
 

RATS
 

0
 

10,000
 

14,700
 

21,500
 

31,500
 

46,000
 

MICE
 

0
 

6,800
 

10,000
 

14,700
 

21,500
 

31,500
 

Male
 

Survival (a)
 

5/5
 

5/5
 

5/5
 

4/5
 

4/5
 

3/5
 

5/5
 

5/5
 

5/5
 

5/5
 

5/5
 

3/5
 

Female
 

Mean Weight
 

at Week 7
 

as % of
 

Control
 

100
 

96
 

89
 

73
 

47
 

39
 

100
 

99
 

99
 

83
 

79
 

57
 

Survival (a)
 

5/5
 

5/5
 

5/5
 

5/5
 

4/5
 

2/5
 

4/5
 

5/5
 

5/5
 

5/5
 

5/5
 

3/5
 

Mean Weight
 

at Week 7
 

as % of
 

Control
 

100
 

92
 

84
 

73
 

67
 

42
 

100
 

110
 

110
 

101
 

93
 

68
 

(a) Number surviving/number in group.
 
of animals at week 7, expressed as percentages of mean body
 

weights of corresponding control groups.
 

At the end of the subchronic studies, all animals were killed
 

using CO- and necropsied. The lowest dose at which histopathologic findings were observed in the rats was 46,000 ppm; at
 

this dose moderate to marked increase in splenic hematopoiesis
 

was seen in male and female rats and midzonal vacuolation of
 

hepatocytes was seen in two males. In male and female mice dosed
 

at 21,500 ppm, all tissues were essentially normal.
 

Ten percent depression in body weight was a major criterion for
 

the estimation of MTD's. The doses that were required to produce
 

this response were determined by the following procedure: first,
 

least squares regressions of mean body weights versus days on
 

study were used to estimate mean body weights of each of the
 

dosed groups at day 49. Next, probits of the percent weights of
 

each of the dosed groups at day 49 relative to weights of
 

corresponding control groups were plotted against logarithms of
 

the doses, and least squares regressions fitted to the data were
 

used to estimate the doses required to induce 10% depression in
 

weight. No histopathologic lesions were observed at the doses
 

selected.
 
The low and high doses for chronic studies were set at 5,000 and
 

10,000 ppm for male and female rats; 5,000 and 10,000 ppm for
 

male mice; and 10,000 and 20,000 ppm for female mice.
 

F. Chronic Studies
 

The test groups, doses administered, and durations of the chronic
 

feeding studies are shown in tables 2 and 3. Because of
 

excessive depression in body weight gain in the dosed groups of
 

female mice, doses administered to the females were reduced after
 

week 38 as indicated.
 

G. Clinical and Pathologic Examinations
 

All animals were checked twice daily. Observations for sick,
 

tumor-bearing, and moribund animals were recorded daily.
 

Clinical examination and palpation for masses were performed each
 

month, and the animals were weighed at least once per month.
 

Moribund animals and animals that survived to the termination of
 

the bioassay were killed using CO. and necropsied.
 

The pathologic evaluation consisted of gross and microscopic
 

10
 
Table 2. 2,4,6-Trichloropheno1 Chronic Feeding Studies
 

in Rats 

2,4,6-TriSex and Initial chlorophenol Time on 

Test No. of in Diet (b) Study 

Group Animals (a) (ppm) (weeks) 

Male 

Matched-Control 20 0 107 

Low-Dose 50 5,000 106 

High -Dose 50 10,000 106 

Female
 

Matched -Control 20 0 107
 

Low-Dose 50 5,000 106-107
 

High -Dose 50 10,000 106
 

(a) All animals were 6 weeks of age when placed on study.
 

(b) Test and control diets were provided ad libitum 7 days per
 

week.
 

11
 
Table 3. 2,4,6-Trichlorophenol Chronic Feeding Studies
 

in Mice
 

2, 4, 6-Tri-


Sex and Initial chlorophenol Time on Time-Weighted
 

Test No. of in Diet (b) Study Average Dose (c)
 

Group Animals (a) (ppm) (weeks) (ppm)
 

Male
 

Matched-Control 20 0 105
 

Low-Dose 50 5,000 105
 

High -Dose 50 10,000 105
 

Female
 

Matched-Control 20 0 105
 

Low-Dose 50 10,000 38
 

2,500 67 5,214
 

High -Dose 50 20,000 38
 

5,000 67 10,428
 

(a) All animals were 6 weeks of age when placed on study.
 

(b) Test and control diets were provided ad 1ibiturn 7 days per week.
 

(c) Time-weighted average dose = Z(dose in ppm x no. of weeks at that dose)
 

Z(no. of weeks receiving each dose)
 

12
 
examination of major tissues, major organs, and all gross
 

lesions. The tissues were preserved in neutral buffered 10%
 

formalin, embedded in paraffin, sectioned, and stained with
 

hematoxylin and eosin. The following tissues were examined
 

microscopically: skin, lungs and bronchi, trachea, bone marrow
 

(femur), spleen, lymph nodes (mesenteric and submandibular),
 

thymus, heart, salivary glands (parotid, sublingual, and
 

submaxillary), liver, pancreas, esophagus, stomach (glandular and
 

nonglandular), small and large intestines, kidney, urinary
 

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

prostate, mammary gland, uterus, ovary, brain (cerebrum and
 

cerebellum), and all tissue masses. Peripheral blood smears also
 

were made for all animals, whenever possible.
 

Necropsies were performed on all animals found dead unless
 

precluded in whole or in part by autolysis or cannibalization.
 

Thus, the number of animals from which particular organs or
 

tissues were examined microscopically varies and does not
 

necessarily represent the number of animals that were placed on
 

study in each group.
 

13
 
H. Data Recording and Statistical Analyses
 

Pertinent data on this experiment have been recorded in an
 

automatic data processing system, the Carcinogenesis Bioassay
 

Data System (Linhart et al., 1974). The data elements include
 

descriptive information on the chemicals, animals, experimental
 

design, clinical observations, survival, body weight, and
 

individual pathologic results, as recommended by the
 

International Union Against Cancer (Berenblum, 1969). Data
 

tables were generated for verification of data transcription and
 

for statistical review.
 

These data were analyzed using the appropriate 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
 

14
 
a possible dose-related effect on survival used the method of Cox
 

(1972) for testing two groups for equality and Tarone's (1975)
 

extensions of Cox methods for testing for 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 is examined (denominator). In most instances,
 

the denominators included only those animals for which that site
 

was examined histologically. However, when macroscopic
 

examination was required to detect lesions prior to histologic
 

sampling (e.g., skin or mammary tumors), or when lesions could
 

have appeared at multiple sites (e.g., lymphomas), the
 

denominators consist of the numbers of animals necropsied.
 

The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a
 

significantly higher proportion of tumors than did the control
 

animals. As a part of these analyses, the one-tailed Fisher
 

exact test (Cox, 1970) was used to compare the tumor incidence of
 

a control group with that of a group of dosed animals at each
 

15
 
dose level. When results for a number of dosed 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) 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), was also used. Under the
 

assumption of a linear trend, this test determines 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 is a positive dose
 

relationship. This method also provides a two-tailed test of
 

departure from linear trend.
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation
 

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

first tumor was observed were excluded by basing the statistical
 

tests on animals that survived at least 52 weeks, unless a tumor
 

was found at the anatomic site of interest before week 52. When
 

16
 
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 an animal died naturally or was sacrificed
 

was entered as the time point of tumor observation. Cox's
 

methods of comparing these curves were used for two groups;
 

Tarone's extension to testing for linear trend was used for three
 

groups. The statistical tests for the incidence of tumors which
 

used life-table methods were one-tailed and, unless otherwise
 

noted, in the direction of a positive dose relationship.
 

Significant departures from linearity (P less than 0.05,
 

two-ta'iled test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared with its control was calculated
 

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

relative risk is defined as p /p where p is the true
 

17
 
binomial probability of the incidence of a specific type of tumor
 

in a dosed 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 dosed 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
 

dosed 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% of a large number of identical experiments, the
 

true ratio of the risk in a dosed 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 (P less than 0.025 one-tailed test when the
 

control incidence is not zero, P less than 0.050 when the control
 

incidence is zero) has occurred. When the lower limit is less
 

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

lower limit indicates the absence of a significant result while
 

the upper limit indicates that there is a theoretical possibility
 

18
 
of the induction of tumors by the test chemical, which could not
 

be detected under the conditions of this test.
 

19
 
20

 
III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

Mean body weights of both dosed male and dosed female rats were
 

lower than those of corresponding controls and were dose related
 

throughout the bioassay (figure 1). Other clinical signs were
 

common to both the dosed and the control groups. Fluctuation in
 

the growth curves may be due to mortality; as the size of a group
 

diminishes, the mean body weights may be subject to variation.
 

B. Survival (Rats)
 

Estimates of the probabilities of survival for male and female
 

rats administered 2,4,6-trichlorophenol in the diet at the doses
 

of this bioassay, together with those for the matched controls,
 

are shown by Kaplan and Meier curves in figure 2. The result of
 

the Tarone test indicates no statistically significant
 

dose-related trend in mortality in either sex.
 

In male rats, 34/50 (68%) of the high-dose group, 35/50 (70%) of
 

21
 
0 ° 0 

O oogooo 

A A A A 

0 ° 

A A A 

a a 

D a a 

00 

D 

0 D 

O 

I

o 

UJ 

 300­

P o 

Do°

 A 

jgAA* 

o 

o 

m 

8 

100)1 

D

O

A

MALE RATS 

 MATCHED CONTROL 

 LOW DOSE 

 HIGH DOSE 

40 50 60 70 

TIME ON STUDY (WEEKS) 

100 110 

C3 

UJ 

g 

O 

O 

m 

D

D D

 D

 D 

D D D

 O O

 t 

O 

FEMALE RATS 

D

O

A

 MATCHED CONTROL 

 LOW DOSE 

 HIGH DOSE 

20 30 40 50 60 70 80 90 100

TIME ON STUDY (WEEKS) 

Figure 1. Growth Curves for Rats Administered 2,4,6-Trichlorophenol in the Diet 

 110 

22 
PROBABILITY OF SURVIVAL PROBABILITY OF SURVIVAL 

(5 

ro 

f 

I 

CJ 

o 

30 

to 

U> 

S. 5 

3. 

n 

O 

3 

I" 

e 

CD 

O 

S 
the low-dose group, and 18/20 (90%) of the control group lived to
 

the end of the bioassay. In females, 39/50 (78%) of the
 

high-dose group, 39/50 (78%) of the low-dose group, and 14/20
 

(70%) of the control group lived to the end of the bioassay.
 

Sufficient numbers of rats of each sex were at risk for the
 

development of late-appearing tumors.
 

C. Pathology (Rats)
 

Histopathologic findings on neoplasms in rats are summarized in
 

Appendix A, tables Al and A2; findings on nonneoplastic lesions
 

are summarized in Appendix C, tables Cl and C2.
 

Three types of neoplasms occurred in appreciable numbers in the
 

dosed rats, and only one of these, neoplasms of the hematopoietic
 

system, appears to be compound related. The other two neoplasms
 

which occurred at a high incidence were interstitial-cell tumors
 

of the testes in male rats and pituitary chromophobe adenomas in
 

both sexes of rats. Both of the latter neoplasms occurred with
 

equal frequency in dosed and control groups of animals, and the
 

type, distribution, and incidence of these neoplasms is similar
 

to that found in aged F344 rats.
 

24
 
Leukemias and hematopoietic disorders have been reported in the
 

F344 strain of rats (Davey and Moloney, 1970); however, their
 

incidence in the dosed groups, the occurrence of hyperplasia in
 

the bone marrow and leukocytosis in blood smears of both males
 

and females, together with the virtual absence of any of these
 

lesions in control males or females, indicates that the effects
 

were compound related. The incidences of these neoplasms are
 

summarized as follows:
 

MALES FEMALES
 

Low High Low High
 

Control Dose Dose Control Dose Dose
 

Number of
 

Animals
 

Necropsied 20 50 50 20 50 50
 

Ma lignant 

Lymphoma 1(5%) 2(4%) 0(0%) 0(0%) 0(0%) 2(4%) 

Leukemia 3(15%) 23(46%) 29(58%) 3(15%) 11(22%) 11(22%) 

Bone Marrow 

Hyperplasia 0(0%) 26(52%) 15(30%) 0(0%) 16(32%) 2(4%) 

Leukocytosis 0(0%) 13(26%) 11(22%) 0(0%) 6(12%) 3(6%) 

The leukemias were characterized by the presence of large numbers 

of circulating monocytes in the blood. The cell types varied 

from mature, well-differentiated monocytes to a variety of 

immature developing and blast forms. In addition to their 

presence in circulating blood, similar monocytic cells were 

usually observed in the liver, spleen, lymph tissues, and bone 

25 
marrow and occasionally in lung, adrenals, and other organs. An 

aleukemic form was also observed where neoplastic cells were not 

found in circulating blood but were seen in the spleen and liver 

and occasionally in bone marrow and other organs. In addition to 

those rats diagnosed as having monocytic leukemia, a large number 

of additional dosed rats manifested hyperplastic bone marrows 

and/or a leukocytosis, seen on peripheral blood smears. 

A variety of nonneoplastic lesions and disorders were encountered 

with regularity in both control and dosed animals. Such lesions 

were considered to be common in aged F344 rats, and the 

incidences of these lesions were considered to be within normal 

limits for this age and strain of rat. 

Based on the histopathologic examination, 2,4,6-trichlorophenol 

was carcinogenic for male F344 rats, inducing tumors of the 

hematopoietic system under the conditions of this bioassay. 

D. Statistical Analyses of Results (Rats)
 

Tables El and E2 in Appendix E contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

26
 
least two animals of one group and at an incidence of at least 5% 

in one or more than one group. 

In male rats, the result of the Cochran-Armitage test for 

positive dose-related trend is significant (P = 0.003) in the 

incidence of monocytic leukemia. The results of the Fisher exact 

test comparing the incidence of the tumors in each dosed group 

with that in the control group are significant (P = 0.013 in the 

low-dose group and P = 0.002 in the high-dose group). The 

statistical conclusion is that the incidence of this tumor in 

male rats is associated with the administration of 2,4,6-trichlorophenol. When the incidence of either lymphoma or leukemia 

in male rats is analyzed, the results of the statistical tests 

are significant, and the main contributor to this significance is 

the incidence of monocytic leukemia. The historical incidence to 

date of monocytic leukemia in male control rats at this 

laboratory is 11/255 (4%), compared with the following incidences 

in this study: controls 3/20 (15%); low-dose group, 23/50 (46%); 

and high-dose group, 28/50 (56%). 

The results of the statistical tests on the incidence of 

hematopoietic tumors in female rats are not significant. The 

current historical records at this laboratory show that the 

incidence of some form of lymphoma or leukemia in female control 

27 
rats is 42/420 (10%), compared with the following incidences in 

this study: controls 3/20 (15%); low-dose group 11/50 (22%); 

high-dose group 13/50 (26%). 

Significant results in the negative direction are observed in the 

incidences of pituitary and mammary tumors in male and female 

rats and of tumors of the integumentary system and the thyroid in 

female rats. 

28 
IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

Mean body weights of dosed mice of each sex were lower than those
 

of corresponding controls and were dose related throughout the
 

bioassay (figure 3). Fluctation in the growth curves may be due
 

to mortality; as the size of a group diminishes, the mean body
 

weight may be subject to variation. Other clinical signs were
 

common to both the dosed and control groups.
 

B. Survival (Mice)
 

Estimates of the probabilities of survival for male and female
 

mice administered 2,4,6-trichlorophenol in the diet at the doses
 

of this bioassay, together with those for the matched controls,
 

are shown by Kaplan and Meier curves in figure 4. The result of
 

the Tarone test indicates no statistically significant
 

dose-related trend in mortality in either sex.
 

In male mice, 45/50 (90%) of the high-dose group, 44/50 (88%) of
 

the low-dose group, and 16/20 (80%) of the control group lived to
 

29
 
D 0 ^DD nD0 00 ­ U 

DDDD D

 O O

0Q0

 ° O 

 00 

a

Du

 o

 0 o O 0 

A 

.0 B8. A AAA 

, A AA AA AAA 

AA O 

A

. 

A

 A 

A A 

o 

A 

MALE MICE 

D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

40 50 60 70 100 110 

TIME ON STUDY (WEEKS) 

D ° D 

a DD 

DQDD Doses lowered for 

n 

D DD 0« -oo -

DDDD O OO A X 0

 A A . AA 2 A A A UJ 

AAA a n o 

a 

o 

m ° °D

 o ° ^ 

D D QO O° ° A A 

dftfi0 A A A 

A 

FEMALE MICE r D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

TIME ON STUDY (WEEKS) 

Figure 3. Growth Curves for Mice Administered 2,4,6-Trichlorophenol in the Diet 

30 
PROBABILITY OF SURVIVAL PROBABILITY OF SURVIVAL 

-> O D 

. MA 

tj,

m

O O 3. z

c

3

S

w Z

' o 2 D =. -c 

0J 

:?J 

CD

e_

5*

if

o

CD" 
the end of the study. In females, 40/50 (80%) of the high-dose
 

group, 44/50 (88%) of the low-dose group, and 17/20 (85%) of the
 

control group lived to the end of the study.
 

Sufficient numbers of mice of each sex were at risk for the
 

development of late-appearing tumors.
 

C. Pathology (Mice)
 

Histopathologic findings on neoplasms in mice are summarized in
 

Appendix B, tables Bl and B2; findings on nonneoplastic lesions
 

are summarized in Appendix D, tables Dl and D2.
 

Several types of neoplasms occurred frequently in dosed mice;
 

these included hepatocellular and pulmonary neoplasms,
 

hemangiosarcomas of various organs, and malignant lymphomas.
 

With the exception of the hepatocellular neoplasms, however, most
 

neoplasms occurred in equal numbers in control and dosed mice,
 

and the type, distribution, and incidence of these neoplasms is
 

similar to that found in aged B6C3F1 mice.
 

The incidence of hepatocellular neoplasms and hyperplasias was
 

high in all dosed groups of mice, but it was especially high in
 

32
 
the two dosed groups of male mice, where most of the livers were
 

affected. The incidences of these lesions are summarized in the
 

following table:
 

MALES FEMALES 

Low High Low High 

Control Dose Dose Control Dose Dose 

Number of Animals
 

with Tissues
 

Examined
 

Microscopically 20 49 47 20 50 48
 

Hepatocellular
 

Adenoma 3(0%) 22(45%) 32(68%) 1(5%) 12(24%) 17(35%)
 

Hepatocellular
 

Carcinoma 1(5%) 10(20%) 7(15%) 0(0%) 0(0%) 7(14%)
 

Hyperplasia 2(10%) 12(24%) 6(13%) 1(5%) 1(2%) 6(13%)
 

In addition to these neoplasms, hepatocellular damage, ranging
 

from individual liver cell abnormalities, through focal areas of
 

cellular alteration, to focal and nodular areas of hyperplasia
 

was commonly present in the livers of dosed mice.
 

A variety of nonneoplastic lesions were encountered with regularity in both control and dosed animals. Such lesions are commonly
 

seen in aged B6C3F1 mice, and occurred with no appreciable
 

differences in frequency between control and dosed mice.
 

Based on the histopathologic examination, 2,4,6-trichlorophenol
 

33
 
was carcinogenic for B6C3F1 mice, inducing hepatocellular
 

carcinomas and adenomas in both males and females.
 

D. Statistical Analyses of Results (Mice)
 

Tables Fl and F2 in Appendix F contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

least two animals of one group and at an incidence of at least 5%
 

in one or more than one group.
 

The result of the Cochran-Armitage test for positive dose-related
 

trend in the incidence of male mice with hepatocellular
 

carcinomas or adenomas is significant (P less than 0.001). The
 

results of the Fisher exact test comparing the incidence of the
 

tumors in the control group with that for each dosed group are
 

significant (P less than or equal to 0.001). The
 

historical-control male B6C3F1 mice of this laboratory have an
 

incidence of liver tumors of 99/323 (30%), compared with 32/49
 

(65%) in the low-dose group and 39/47 (83%) in the high-dose
 

group of this study. In females, the result of the Cochran-


Armitage test on the incidence of hepatocellular carcinoma is
 

significant (P = 0.005), but the results of the Fisher exact test
 

are not significant. When the incidence of female mice with
 

34
 
hepatocellular carcinoma or adenoma is analyzed, the results of
 

the Cochran-Armitage test and that of the Fisher exact test
 

comparing the incidence in the high-dose group with that in the
 

control group are significant (P less than 0.001). The
 

historical-control female mice of this laboratory have an
 

incidence of liver tumors of 14/324 (4.3%), compared with 12/50
 

(24%) in the low-dose group and 24/48 (50%) in the high-dose
 

group of this study. The statistical conclusion is that the
 

occurrence of liver tumors in male and female mice is associated
 

with the administration of 2,4,6-trichlorophenol.
 

35
 
36

 
V. DISCUSSION

 

Mean body weights of the dosed rats and mice of each sex were 

lower than those of corresponding controls and were dose related 

throughout the bioassay. No other clinical signs could be 

related to administration of the test chemical. Survival of the 

dosed rats and mice was 68% or greater in all groups of rats and 

80% or greater in all groups of mice. 

In the male rats, lymphomas or leukemias occurred at incidences 

that were dose related (P = 0.006), and in direct comparisons 

were significantly higher in the low-dose (P = 0.019) and 

high-dose (P = 0.004) groups than in the corresponding control 

group (controls 4/20, low-dose 25/50, high-dose 29/50). 

Leukocytosis and monocytosis of the peripheral blood and 

hyperplasia of the bone marrow also occurred in some dosed male 

rats not having lymphoma or leukemia. 

In the female rats, monocytic leukemia did not occur at 

incidences that were significant. Leukocytosis and monocytosis 

of the peripheral blood and hyperplasia of the bone marrow 

occurred in the dosed female rats, but not in the controls (blood 

leukocytosis and monocytosis: controls 0/20, low-dose 6/50, 

37 
high-dose 3/50; bone marrow hyperplasia: controls 0/20, low-dose 

16/50, high-dose 2/50). 

In both the male and female mice, hepatocellular carcinomas or 

adenomas occurred at incidences that were dose related (P less 

than 0.001), and in direct comparisons were significantly higher 

in the low- and high-dose male groups and the high-dose female 

groups (P less than or equal to 0.001) than in the corresponding 

control groups (males: controls 4/20, low-dose 32/49, high-dose 

39/47; females: controls 1/20, low-dose 12/50, high-dose 24/48). 

In previous tests for tumorigenicity (National Technical 

Information Service, 1968; Innes et al. , 1969), it was reported 

that when 2,4,6-trichlorophenol was administered at 100 mg/kg 

body weight by stomach tube for 3 weeks, then in the diet at 260 

ppm for 18 months, to hybrid mice (C57BL/6 x C3H/Anf and C57BL/6 

x AKR), elevated incidences of reticulum-cell sarcoma (P = 0.05) 

and of hepatoma (P = 0.05) were observed. 

It is concluded that under the conditions of this bioassay, 

2,4,6-trichlorophenol was carcinogenic in male F344 rats, 

inducing lymphomas or leukemias. The test chemical was also 

carcinogenic in both sexes of B6C3F1 mice, inducing hepatocellular carcinomas or adenomas. 

38 
VI. BIBLIOGRAPHY
 

Armitage, P., Statistical Methods in Medical Research, John Wiley
 

& Sons, Inc., New York, 1971, pp. 362-365.
 

Berenblum, I., ed., Carcinogenicity Testing; A Report o_f the
 

Panel on Carcinogenicity of the Cancer Research Commission of the
 

UICC, Vol. 2._ International Union Against Cancer, Geneva, 1969.
 

Cox, D. R., Regression models and life tables. J. R. Statist.
 

Soc. B 34;187-220, 1972.
 

Cox, D. R., Analysis of Binary Data, Methuen & Co., Ltd., London,
 

1970, pp. 48-52.
 

Dow Chemicals, Personal Communication. 26 May 1978.
 

Gart, J. J., The comparison of proportions: a review of
 

significance tests, confidence limits and adjustments for
 

stratification. Rev. Int. Stat. Inst. 39:148-169, 1971.
 

Eisenhauer, H. R., Oxidation of phenolic water. 3_. WPCF
 

36(9):1116-1128, 1964.
 

Innes, J. R. M., Ulland, B. M., Valeric, M. G., Petrucelli, L.,
 

Fishbein, L., Hart, E. R., Pallotta, A. J., Bates, R. R., Falk,
 

H. L., Gart, J. J., Klein, M., Mitchell, I. and Peters, J.,
 

Bioassay of pesticides and industrial chemicals for
 

tumorigenicity in mice: a preliminary note. J._ Nat. Cancer Inst.
 

42:1101-1114, 1969.
 

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

incomplete observations. J_^ Am. Statist. Assoc. 53:457-481, 1958.
 

Larson, R. A. and Rockwell, A. L., Gas chromatographic
 

identification of some chlorinated aromatic acids, chlorophenols,
 

and their aromatic acid precursors. J. Chromatogr.
 

139_(1): 186-190, 1977.
 

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

Peters, J. A., Carcinogenesis bioassay data system. Comp. and
 

Biomed. Res. 7:230-248, 1974.
 

Miller, R. G., Jr., Simultaneous Statistical Inference,
 

McGraw-Hill Book Co., New York, 1966, pp. 6-10.
 

39
 
National Institute for Occupational Safety and Health, Suspected
 

Carcinogens, 2nd edition, Christensen, H.E., ed., National
 

Institute for Occupational Safety and Health, Cincinnati, Ohio,
 

1976, p. 176.
 

National Technical Information Service, Evaluation of
 

Carcinogenic, Teratogenic, and Mutagenic Activities o_f_ Selected
 

Pesticide and Industrial Chemicals, Vol. I., Carcinogenic Study,
 

U. S. Department of Commerce, Springfield, Va., 1968, p. 64.
 

Saffiotti, U., Monesano, R., Sellakumar, R. A., Cefis, F., and
 

Kaufman, D. G., Respiratory tract carcinogenesis in hamsters
 

induced by different numbers of administrations of benzo (a)
 

pyrene and ferric oxide. Cancer Res. 32;1073-1081, 1972.
 

Smith, J. G., Lee, S. F., and Netzer, A., Chlorination in dilute
 

aqueous systems; 2,4,6-trichlorophenol. Environ. Letters
 

10(l):47-52, 1975.
 

Stanford Research Institute, Stage 1^ Chemical Dossier, Stanford
 

Research Institute, Menlo Park, April 1976.
 

Tanaka, K., Kurihara, N., and Nakajima, M., Pathway of
 

chlorophenol formation in oxidative biodegradation of BHC.
 

Agric. Biol. Chem. 41(4) -.723-725, 1977.
 

Tarone, R. E., Tests for trend in life table analysis.
 

Biometrika 62(3) ;679-682, 1975.
 

United States International Trade Commission, Imports of
 

Benzenoid Chemicals and Products - 1976, USITC Publication 828,
 

United States International Trade Commission, Washington, D.C.,
 

1977, p. 103.
 

Windholz, M., ed., Merck Index, Merck & Co., Inc., Rahway, N.J.,
 

1976.
 

40
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS ADMINISTERED 2,4,6-TRICHLOROPHENOL IN THE DIET
 

41
 
42

 
TABLE A1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

ADMINISTERED 2,4,6-TRICHLOROPHENOL IN THE DIET 

ANIMALS INITIALLY IN STUDY
 

ANIMALS NECROPSIED
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY
 

INTEGUMENTARY SYSTEM
 

XSKIN
 

SQUAMOUS CELL CARCINOMA
 

TRICHOEPITHELIOMA
 

XSUBCUT TISSUE
 

SQUAMOUS CELL CARCINOMA, INVASIV
 

TRICHOEPITHELIOMA
 

FIBROMA
 

FIBROSARCOMA
 

RHABDOMYOSARCOMA
 

FIBROADENOMA
 

RESPIRATORY SYSTEM
 

ttLUNG
 

ALVEOLAR/BRONCHIOLAR ADENOMA
 

ALVEOLAR/BRONCHIOLAR CARCINOMA
 

HEMATOPOIETIC SYSTEM
 

^MULTIPLE ORGANS
 

MALIGNANT LYMPHOMA, NOS
 

LEUKEMIA, NOS
 

MONOCYTIC LEUKEMIA
 

XHEMATOPOIETIC SYSTEM
 

MALIGNANT LYMPHOMA, NOS
 

MONOCYTIC LEUKEMIA
 

*RENAL LYMPH NODE
 

SARCOMA, NOS
 

MATCHED
 

CONTROL
 

20
 

20
 

20
 

(20)
 

1 (5%)
 

2 (10%)
 

(20)
 

1 (5%)
 

1 <5X)
 

(18)
 

2 (1U)
 

(20)
 

1 (5%)
 

3 (15X)
 

(20)
 

(20)
 

LOW DOSE
 

50
 

50
 

50
 

(50)
 

1 (2%)
 

1 (2%)
 

(50)
 

3 (6X)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)


1 (2%)
 

23 (46%)
 

(50)


1 (2X)
 

(50)


1 (2%)
 

HIGH DOSE
 

50
 

50
 

50
 

(50)
 

1 (2%)
 

2 (4%)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

1 (2%)
 

(50)
 

1 (2X)
 

26 (52%)
 

(50)
 

2 (450
 

(50)
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

X NUMBER OF ANIMALS NECROPSIED
 

43
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

SJEJUNUM (20) (49)

 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE
 

CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVE SYSTEM
 

XUPPER LIP (20) (50)
 

SQUAMOUS CELL PAPILLOMA 1 (25O
 

8SALIVARY GLAND (20) (50)
 

ADENOMA, NOS 1 (5X)
 

FIBROADENOCARCINOMA 1 (5%)
 

SLIVER (20) (49)
 

HEPATOCELLULAR ADENOMA 1 (53O
 

NEOPLASTIC NODULE 1 (2X)
 

#STOMACH (20) (50)
 

SQUAMOUS CELL PAPILLOMA
 

ftJEJUNUM (20) (49)
 

MUCINOUS ADENOCARCINOMA 1 (5%)
 

fCOLONIC SUBMUCOSA (20) (50)


LIPOMA 1 (2%)
 

URINARY SYSTEM
 

ttURINARY BLADDER (20) (46)
 

PAPILLOMA, NOS
 

TRANSITIONAL-CELL PAPILLOMA 1 (2X)
 

ENDOCRINE SYSTEM
 

^PITUITARY (20) (49)


ADENOMA, NOS 1 (2%)
 

CHROMOPHOBE ADENOMA 10 (50%) 7 (14%)
 

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

HIGH DOSE 

(49)


1 (2%)
 

(50)
 

(50)
 

(50)
 

(49)


2 (4%)
 

(49)
 

(48)
 

(49)


1 (2X)
 

(50)


1 (2JO
 

4 (85O
 

44
 
ACIDOPHIL CARCINOMA
 

ftADRENAL
 

CORTICAL ADENOMA
 

PHEOCHROMOCYTOMA
 

PHEOCHROMOCYTOMA, MALIGNANT
 

•THYROID
 

ADENOMA, NOS
 

ADENOCARCINOMA, NOS
 

C-CELL ADENOMA
 

C-CELL CARCINOMA
 

*PARATHYROID
 

ADENOMA, NOS
 

ADENOCARCINOMA, NOS
 

8PANCREATIC ISLETS
 

ISLET-CELL ADENOMA
 

REPRODUCTIVE SYSTEM
 

KMAMMARY GLAND
 

ADENOMA, NOS
 

FIBROMA
 

LIPOMA
 

#TESTIS
 

INTERSTITIAL-CELL TUMOR
 

INTERSTITIAL-CELL TUMOR, MALIGNA
 

NERVOUS SYSTEM
 

ftBRAIN
 

ASTROCYTOMA
 

SPECIAL SENSE ORGANS
 

*ZYMBAL'S GLAND
 

CARCINOMA, NOS
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED
 

CONTROL
 

(20)
 

3 (15%)
 

(20)
 

1 (5%)
 

2 (10%)
 

(17)
 

(20)
 

(20)
 

2 (10%)
 

(20)
 

18 (90%)
 

(20)
 

(20)
 

1 (5%)
 

LOW DOSE
 

(50)
 

1 (2%)
 

1 (2%)
 

(49)
 

1 (2%)
 

1 (2%)
 

(39)
 

1 (3%)
 

1 (3%)
 

(50)
 

(50)
 

1 (2%)
 

1 (2%)
 

(50)
 

40 (80%)
 

(50)
 

1 (2%)
 

(50)
 

HIGH DOSE
 

1


(49)


1


4


2


(49)
 

1


2


4


1


(43)
 

(50)
 

1


(50)
 

(50)


37


1


(50)
 

(50)
 

 (2%)
 

 (2%)
 

 (8%)
 

 (4%)
 

 (2%)
 

 (4%)
 

 (8%)
 

 (2%)
 

 (2%)
 

 (74%)
 

 (2%)
 

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

45
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

BODY CAVITIES
 

*PLEURA (20) (50) (50)
 

ALVEOLAR/BRONCHIOLAR CA, METASTA 1 (2%)
 

XTUNICA VAGINALIS (20) (50) (50)
 

MESOTHELIOMA, NOS 1 (5%) 2 (4X) 1 (2%)
 

ALL OTHER SYSTEMS
 

^MULTIPLE ORGANS (20) (50) (50)
 

MUCINOUS ADENOCARCINOMA, METASTA 1 (55O
 

MESOTHELIOMA, NOS 1 (55O 1 (25O
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 20 50 50
 

NATURAL DEATHS 2 9 H
 

MORIBUND SACRIFICE 6 2
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 18 35
 

ANIMAL MISSING
 

a INCLUDES AUTOLYZED ANIMALS
 

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

46
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 20 49 49
 

TOTAL PRIMARY TUMORS 53 99 100
 

TOTAL ANIMALS WITH BENIGN TUMORS 19 43 43
 

TOTAL BENIGN TUMORS 40 61 60
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 9 29 33
 

TOTAL MALIGNANT TUMORS 1 1 34 39
 

TOTAL ANIMALS WITH SECONDARY TUMORS* 2 1
 

TOTAL SECONDARY TUMORS 2 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 2 4 1
 

TOTAL UNCERTAIN TUMORS 2 4 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

47
 
TABLE A2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

ADMINISTERED 2,4,6-TRICHLOROPHENOL IN THE DIET 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 20 50 50
 

ANIMALS NECROPSIED 20 50 50
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 20 50 50
 

INTEGUMENTARY SYSTEM
 

XSKIN (20) (50) (50)
 

SQUAMOUS CELL PAPILLOMA 1 (2X)
 

TRICHOEPITHELIOMA 1 (5X)
 

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

FIBROSARCOMA 1 (55O 1 (25O
 

LIPOMA 1 (2X)
 

FIBROADENOMA 2 (105O 1 (25O
 

RESPIRATORY SYSTEM
 

*NASAL MUCOSA (20) (50) (50)
 

ADENOCARCINOMA, NOS 1 (2%) 1 (25{)
 

SLUNG (18) (50) (50)
 

ALVEOLAR/BRONCHIOLAR ADENOMA 1 (25O
 

ALVEOLAR/BRONCHIOLAR CARCINOMA 1 (2X)
 

HEMATOPOIETIC SYSTEM
 

8CEREBRUM (20) (50) (49)
 

MALIGNANT RETICULOSIS 1 (2X)
 

^MULTIPLE ORGANS (20) (50) (50)


LEUKEMIA,NOS 1 (2X)
 

MONOCYTIC LEUKEMIA 3 (15*) 11 (22X) 10 (20%)
 

*HEMATOPOIETIC SYSTEM (20) (50) (50)
 

MALIGNANT LYMPHOMA, NOS 2
 

CIRCULATORY SYSTEM
 

NONE
 

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

48
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

DIGESTIVE SYSTEM
 

SSMALL INTESTINE (20) (4S) (48)
 

CYSTADENOCARCINOMA, NOS 1 (2%)
 

MUCINOUS ADENOCARCINOMA 1 (2%)
 

*RECTUM (20) (50) (50)
 

ADENOCA IN ADENOMATOUS POLYP 1 (5%)
 

URINARY SYSTEM
 

NONE
 

ENDOCRINE SYSTEM
 

#PITUITARY (20) (49) (49)
 

CARCINOMA, NOS 1 (2%)
 

ADENOMA, NOS 3 (15%) 3 (6%)
 

CHROMOPHOBE ADENOMA 4 (20%) 10 (20%) 8 (16%)
 

CHROMOPHOBE CARCINOMA 1 (2%)
 

SADRENAL (20) (50) (49)
 

CORTICAL ADENOMA 1 (5%)
 

PHEOCHROMOCYTOMA 1 (5%)
 

ttTHYROID (20) (49) (50)
 

ADENOCARCINOMA, NOS 1 (2%) 1 (2%)
 

FOLLICULAR-CELL ADENOMA 1 (2%)
 

FOLLICULAR-CELL CARCINOMA 1 (2%)
 

C-CELL ADENOMA 3 (15%) 1 (2%) 1 (2%)
 

REPRODUCTIVE SYSTEM
 

XMAMMARY GLAND (20) (50) (50)
 

ADENOCARCINOMA, NOS 1 (5%)
 

PAPILLARY CYSTADENOMA, NOS 1 (2%)
 

FIBROADENOMA 2 (10%)
 

XVAGINA (20) (50) (50)
 

SQUAMOUS CELL CARCINOMA 1 (5%)
 

ttUTERUS (20) (50) (49)
 

ENDOMETRIAL STROMAL POLYP 1 (5%) 3 (6%) 2 (4%)
 

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

49
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

SOVARY (20) (50) (49)
 

LIPOMA 1 (25O
 

NERVOUS SYSTEM
 

SBRAIN (20) (50) (49)
 

CARCINOMA, NOS, METASTATIC 1 (2%)
 

ASTROCYTOMA 2 (4X)
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

*RIB (20) (50) (50)
 

OSTEOSARCOMA 1 (2X)
 

BODY CAVITIES
 

NONE
 

ALL OTHER SYSTEMS
 

NONE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 20 50 50
 

NATURAL DEATHS 2 10 6
 

MORIBUND SACRIFICE 4 1 5
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 14 39 39
 

ANIMAL MISSING
 

3 INCLUDES AUTOLYZED ANIMALS
 

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

50
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 16 32 27
 

TOTAL PRIMARY TUMORS 25 40 34
 

TOTAL ANIMALS WITH BENIGN TUMORS 13 18 13
 

TOTAL BENIGN TUMORS 18 22 13
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 6 17 20
 

TOTAL MALIGNANT TUMORS 7 18 21
 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1
 

TOTAL SECONDARY TUMORS 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

H PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

51
 
52

 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE ADMINISTERED 2,4,6-TRICHLOROPHENOL IN THE DIET
 

53
 
54

 
TABLE B1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

ADMINISTERED 2,4,6 TRICHLOROPHENOL IN THE DIET 

ANIMALS INITIALLY IN STUDY
 

ANIMALS MISSING
 

ANIMALS NECROPSIED
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY
 

INTEGUMENTARY SYSTEM
 

*SUBCUT TISSUE
 

FIBROSARCOMA
 

RESPIRATORY SYSTEM
 

SLUNG
 

BILE DUCT CARCINOMA, METASTATIC
 

HEPATOCELLULAR CARCINOMA, METAST
 

ALVEOLAR/BRONCHIOLAR ADENOMA
 

ALVEOLAR/BRONCHIOLAR CARCINOMA
 

HEMATOPOIETIC SYSTEM
 

^MULTIPLE ORGANS
 

MALIGNANT LYMPHOMA, NOS
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE
 

*SUBCUT TISSUE
 

MAST-CELL TUMOR
 

8LYMPH NODE
 

MALIG.LYMPHOMA, LYMPHOCYTIC TYPE
 

#LIVER
 

KUPFFER-CELL SARCOMA
 

CIRCULATORY SYSTEM
 

^MULTIPLE ORGANS
 

HEMANGIOMA
 

MATCHED
 

CONTROL
 

20
 

20
 

20
 

(20)


1 (5X)
 

(20)
 

1 (5X)
 

2 (10%)
 

(20)


2 (102)
 

(20)
 

(19)
 

(20)
 

(20)


1 (55O
 

LOW DOSE
 

50
 

1
 

49
 

49
 

(49)
 

1 (2X)
 

(48)
 

1 (2%)
 

7 (15X)
 

6 (13X)
 

(49)
 

1 (25i)
 

1 (2X)
 

(49)
 

1 (25O
 

(46)
 

1 (2X)
 

(49)
 

(49)
 

HIGH
 

50
 

49
 

49
 

(49)
 

(47)


1
 

1
 

6
 

1
 

(49)
 

1
 

(49)
 

(47)
 

(47)


1
 

(49)
 

DOSE
 

(2%)
 

(2%)
 

(13X)
 

(2%)
 

(2%)
 

(2X)
 

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

55
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

HEMANGIOSARCOMA	 1 (250 

8SPLEEN (20) (49) (47) 

HEMANGIOSARCOMA 3 (650 4 (9%) 

SHEART (20 ) (49) (47) 

HEMANGIOMA 1 (2%) 

•SALIVARY	 GLAND (20 ) (48) (47)

 

HEMANGIOSARCOMA 1 (25O

 

ftLIVER (20) (49) (47) 

HEMANGIOSARCOMA 1 (5>O 1 (25O 2 (4%) 

DIGESTIVE SYSTEM 

SLIVER (20) (49) (47)
 

BILE DUCT CARCINOMA 1 (25O
 

HEPATOCELLULAR ADENOMA 3 (155O 22 (455O 32 (685O
 

HEPATOCELLULAR CARCINOMA 1 (55O 10 (205O 7 (15%)
 

SARCOMA, NOS 1 (25O
 

URINARY SYSTEM
 

NONE
 

ENDOCRINE SYSTEM
 

8THYROID (20) (47) (46)
 

ADENOCARCINOMA, NOS 1 (2%)
 

REPRODUCTIVE SYSTEM
 

NON E
 

NERVOUS SYSTEM
 

NON E
 

SPECIAL SENSE ORGANS
 

*EYE/LACRIMAl GLAN D (20) (49) (49)
 

ADENOCARCINOMA. NOS 1 (25Q

 

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

56
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

MUSCULOSKELETAL SYSTEM 

XVERTEBRAL COLUMN

OSTEOSARCOMA (20) 

1 (55O 

(49) (49) 

BODY CAVITIES 

*MESENTERY 

LIPOMA 

(20) 

1 (5%) 

(49) (49) 

ALL OTHER SYSTEMS 

NONE 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY

NATURAL DEATHS

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE

ANIMAL MISSING 

 20 

4 

 16 

50 

4 

1 

44 

1 

50 

5 

45 

a INCLUDES AUTOLYZED ANIMALS 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

X NUMBER OF ANIMALS NECROPSIED 

57
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 14 42 42
 

TOTAL PRIMARY TUMORS 14 59 56
 

TOTAL ANIMALS WITH BENIGN TUMORS 6 26 34
 

TOTAL BENIGN TUMORS 6 29 39
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 8 26 13
 

TOTAL MALIGNANT TUMORS 8 29 17
 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1 2
 

TOTAL SECONDARY TUMORS 1 2
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 1
 

TOTAL UNCERTAIN TUMORS 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

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

58
 
TABLE B2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

ADMINISTERED 2,4,6-TRICHLOROPHENOL IN THE DIET

 

MATCHED 

CONTROL LOW DOSE 

ANIMALS INITIALLY IN STUDY 

ANIMALS MISSING 

ANIMALS NECROPSIED 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 

20 

20 

20 

50 

50 

50 

INTEGUMENTARY SYSTEM
 

XSUBCUT TISSUE (20) (50)
 

FIBROSARCOMA 1 (5X)
 

RESPIRATORY SYSTEM
 

8LUNG (20) (50)


ALVEOLAR/BRONCHIOLAR ADENOMA 1 (550 4 (85O
 

ALVEOLAR/BRONCHIOLAR CARCINOMA
 

SARCOMA, NOS, METASTATIC
 

HEMATOPOIETIC SYSTEM
 

^MULTIPLE ORGANS (20) (50)
 

MALIGNANT LYMPHOMA, NOS 5 (10X)
 

MALIG.LYMPHOMA, UNDIFFER-TYPE 1 (25O
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 4 (8X)
 

GRANULOCYTIC SARCOMA 1 (2X)
 

XABDOMINAL CAVITY (20) (50)


MALIGNANT LYMPHOMA, NOS 1 (2X)
 

XHEMATOPOIETIC SYSTEM (20) (50)
 

MALIGNANT LYMPHOMA, NOS 1 (5X)
 

tSPLEEN (20) (50)
 

MALIGNANT LYMPHOMA, NOS 1 (2X)
 

ftMANDIBULAR L. NODE (20) (47)
 

MALIGNANT LYMPHOMA, NOS 1 (55i)
 

(JKIDNEY (20) (50)
 

MALIGNANT LYMPHOMA, NOS
 

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

HIGH DOSE
 

50
 

2
 

48
 

48
 

(48)
 

(48)
 

1 (2X)
 

2 (4X)
 

1 (2%)
 

(48)
 

4 (8X)
 

(48)
 

(48)


2 (4X)
 

(48)
 

(48)
 

(48)


1 (25O
 

59
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE
 

CIRCULATORY SYSTEM
 

XSUBCUT TISSUE (20) (50)


HEMANGIOMA 1 (2%)
 

HEMANGIOSARCOMA
 

SBONE MARROW (20) (50)
 

HEMANGIOSARCOMA
 

*SPLEEN (20) (50)


HEMANGIOMA 1 (2%)
 

HEMANGIOSARCOMA 2 (4%)
 

#HEART (20) (48)
 

HEMANGIOSARCOMA
 

«LIVER (20) (50)
 

HEMANGIOSARCOMA 1 (5%)
 

#OVARY (20) (50)
 

HEMANGIOSARCOMA
 

DIGESTIVE SYSTEM 

SLIVER 

HEPATOCELLULAR ADENOMA 

HEPATOCELLULAR CARCINOMA 

(20) 

1 (5%) 

(50)

12 (24%) 

SARCOMA, NOS 

SARCOMA, NOS, UNC PRIM OR META 

URINARY SYSTEM 

NONE 

ENDOCRINE SYSTEM
 

^PITUITARY (20) (49)
 

ADENOMA, NOS
 

CHROMOPHOBE ADENOMA 1 (2%)
 

ttADRENAL (20) (48)


CORTICAL ADENOMA 1 (5%) 1 (2%)
 

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

HIGH DOSE
 

(48)
 

1 (2%)
 

(48)
 

1 (2%)
 

(48)
 

1 (2%)
 

(48)


1 (2%)
 

(48)
 

(48)


1 (2%)
 

(48)


17 (35%)
 

7 (15%)
 

1 (2%)
 

1 (2%)
 

(46)
 

1 (2%)
 

(46)
 

60
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

PHEOCHROMOCYTOMA 1 (2X)
 

REPRODUCTIV E SYSTEM
 

#OVARY (20) C50) (48)
 

ADENOCARCINOMA , NOS 1 (2%)
 

GRANULOSA-CEL L TUMOR 1 (2X)
 

TUBULA R ADENOM A 1 (25{)
 

NERVOU S SYSTEM
 

NON E
 

SPECIAL SENSE ORGANS
 

*EYE/LACRIMAL GLAND (20) (50) (48)
 CARCINOMA,NOS 1 (2%)
 ADENOMA, NOS 1 (55O
 

ADENOCARCINOMA, NOS 1 (2X)
 

MUSCULOSKELETAL SYSTEM
 

XVERTEBRAL COLUMN (20) (50) (48)
 RHABDOMYOSARCOMA, INVASIVE 1 (55O
 

KRIB (20) (50) (48)
 

RHABDOMYOSARCOMA 1 (5%)
 

BODY CAVITIES
 

NONE
 

A LL OTHER SYSTEMS
 

NON E
 

# NUMBER OF ANIMAL S WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

61
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY


NATURAL DEATH3


MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE


ANIMAL MISSING
 

3 INCLUDES AUTOLYZED ANIMALS
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS*


TOTAL PRIMARY TUMORS


TOTAL ANIMALS WITH BENIGN TUMORS


TOTAL BENIGN TUMORS


TOTAL ANIMALS WITH MALIGNANT TUMORS


TOTAL MALIGNANT TUMORS


TOTAL ANIMALS WITH SECONDARY TUMORS*


TOTAL SECONDARY TUMORS


TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

MATCHED
 

CONTROL LOW DOSE
 

 20 50
 

3 6
 

 17 44
 

6 30
 

9 39
 

3 19
 

4 22
 

4 15
 

5 17
 

1
 

1
 

HIGH DOSE
 

50
 

8
 

40
 

2
 

33
 

44
 

19
 

19
 

19
 

23
 

1
 

1
 

1
 

1
 

1
 

1
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

62
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN RATS ADMINISTERED 2,4,6-TRICHLOROPHENOL IN THE DIET
 

63
 
64

 
TABLE C1.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

ADMINISTERED 2,4,6-TRiCHLOROPHENOL IN THE DIET 

ANIMALS INITIALLY IN STUDY
 

ANIMALS NECROPSIED
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY
 

INTEGUMENTARY SYSTEM
 

XSUBCUT TISSUE
 

ABSCESS, NOS
 

RESPIRATORY SYSTEM
 

ftLUNG
 

EDEMA, NOS
 

BRONCHOPNEUMONIA SUPPURATIVE
 

GRANULOMA, NOS
 

HEMATOPOIETIC SYSTEM
 

KBLOOD
 

LEUKOCYTOSIS, NOS
 

LEUKOCYTOSIS, NEUTROPHILIC
 

MONOCYTOSIS
 

ANEMIA, NOS
 

XHEMATOPOIETIC SYSTEM
 

HYPERPLASIA, LYMPHOID
 

ttBONE MARROW
 

HYPERPLASIA, DIFFUSE
 

HYPERPLASIA, HEMATOPOIETIC
 

ftSPLEEN
 

CONGESTION, NOS
 

INFARCT, NOS
 

INFARCT, FOCAL
 

HEMOSIDEROSIS
 

#SINUSOID OF LYMPH NO
 

CONGESTION, NOS
 

MATCHED
 

CONTROL
 

20
 

20
 

20
 

(20)
 

(18)
 

1 (6%)
 

(20)
 

(20)
 

(20)
 

(20)
 

2 (105O
 

(20)
 

LOW DOSE
 

50
 

50
 

50
 

(50)
 

1 (250
 

(50)


1 (25O
 

(50)
 

6 (125O
 

7 (145O
 

4 (85O
 

1 (25O
 

(50)
 

(49)


26 (535O
 

(49)
 

(50)
 

HIGH DOSE
 

50
 

50
 

50
 

(50)
 

(50)
 

1 (2X)
 

(50)
 

2 (4X)
 

9 (1850
 

2 (4X)
 

(50)


1 (25O
 

(50)


14 (28%)
 

1 (250
 

(50)


1 (2%)
 

1 (25O
 

1 (25O
 

(50)


1 (25O
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

X NUMBER OF ANIMALS NECROPSIED
 

65
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE
 

1 (25O
 

(50)
 

(50)
 

(50)
 

(50)
 

2 (45O
 

(36)
 

(50)
 

1 (25O
 

(50)
 

(50)
 

37 (745O
 

2 (45O
 

1 (2%)
 

(50)


1 CZ5O
 

(50)
 

(50)


1 (25O
 

HEMOSIDEROSIS
 

#MANDIBULAR L. NODE
 

HYPERPLASIA, RETICULUM CELL
 

#CERVICAL LYMPH NODE
 

STEATITIS
 

HYPERPLASIA, LYMPHOID
 

ftRENAL LYMPH NODE
 

EDEMA, NOS
 

HEMORRHAGE
 

HEMOSIDEROSIS
 

8HEPATIC SINUSOID
 

LEUKOCYTOSIS, NOS
 

STHYMUS
 

ATROPHY, NOS
 

CIRCULATORY SYSTEM
 

SHEART
 

FIBROSIS, DIFFUSE
 

SHEART/ATRIUM
 

THROMBOSIS, NOS
 

ttMYOCARDIUM
 

INFLAMMATION, FOCAL
 

INFLAMMATION, CHRONIC
 

INFLAMMATION, CHRONIC FOCAL
 

FIBROSIS
 

FIBROSIS, DIFFUSE
 

DEGENERATION, NOS
 

NECROSIS, FOCAL
 

8ENDOCARDIUM
 

THROMBOSIS, NOS
 

XARTERY
 

THROMBOSIS, NOS
 

INFLAMMATION, NOS
 

XMESENTERIC ARTERY
 

MINERALIZATION
 

S NUMBER OF ANIMALS WITH TISSUE

x NUMBER OF ANIMALS NECROPSIED 

MATCHED
 

CONTROL
 

(20)
 

(20)


1 (5X)
 

1 (55O
 

(20)


1 (55O
 

1 (55O
 

1 (55O
 

(20)
 

(15)
 

(20)
 

(20)
 

(20)
 

1 (550
 

14 (7050
 

2 (10%)
 

13 (6550
 

(20)
 

(20)


1 (550
 

1 (55O
 

(20)
 

LOW DOSE
 

(50)


1 (2X)
 

(50)
 

(50)
 

(49)


2 (4%)
 

(38)
 

1 (3%)
 

(50)
 

(50)


1 (2%)
 

(50)
 

33 (6650
 

2 (4%)
 

1 (2%)
 

1 (25O
 

(50)
 

(50)
 

(50)
 

 EXAMINED MICROSCOPICALLY 

66 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE
 

SLIVER (20) (49)
 

THROMBOSIS, NOS
 

PERIARTERITIS 1 (5X)
 

SPANCREAS (20) (50)


PERIARTERITIS 1 (2X)
 

XMESENTERY (20) (50)
 

PERIARTERITIS
 

SPROSTATE (17) (48)


PERIARTERITIS 1 (2%)
 

DIGESTIVE SYSTEM
 

iSALIVARY GLAND (20) (50)


INFLAMMATION, CHRONIC 1 (25O
 

INFLAMMATION, CHRONIC FOCAL 1 (2%)
 

ATROPHY, NOS 1 (5%)
 

SLIVER (20) (49)
 

CYST, NOS
 

INFLAMMATION, SUPPURATIVE
 

INFLAMMATION, CHRONIC DIFFUSE 1 (2%)
 

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

NECROSIS, FOCAL 1 (25O
 

METAMORPHOSIS FATTY 3 (65O
 

LIPOIDOSIS 1 (5X) 4 (82)
 

BASOPHILIC CYTO CHANGE
 

HYPERPLASIA, NODULAR 1 (2X)
 

ANGIECTASIS
 

#LIVER/CENTRILOBULAR (20) (49)
 

DEGENERATION, NOS
 

NECROSIS, NOS
 

METAMORPHOSIS FATTY 1 (25O
 

HYPERTROPHY, NOS
 

(JLIVER/HEPATOCYTES (20) (49)
 

NECROSIS, NOS 1 (5X)
 

SBILE DUCT (20) (49)


HYPERPLASIA, NOS 5 (25%) 8 (16X)
 

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

HIGH DOSE
 

(50)


2 (4X)
 

(50)


3 (6X)
 

(50)


1 (25O
 

(47)
 

(50)
 

(50)


1 (25O
 

1 (2X)
 

2 (43O
 

4 (8X)
 

4 (8X)
 

1 (25O
 

1 (2X)
 

1 (25O
 

(50)
 

1 (2X)
 

1 (2%)
 

3 (650
 

1 (25O
 

(50)
 

(50)


7 (145£)
 

67
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

*PANCREAS
 

INFLAMMATION, CHRONIC
 

INFLAMMATION, CHRONIC FOCAL
 

#PANCREATIC DUCT
 

HYPERPLASIA, FOCAL
 

8PANCREATIC ACINUS
 

ATROPHY, NOS
 

ATROPHY, FOCAL
 

tSTOMACH
 

ULCER, NOS
 

INFLAMMATION, CHRONIC FOCAL
 

ttGASTRIC MUCOSA
 

ULCER, NOS
 

#GASTRIC SUBMUCOSA
 

INFLAMMATION, GRANULOMATOUS
 

8DUODENUM
 

INFLAMMATION, CHRONIC
 

INFLAMMATION, CHRONIC DIFFUSE
 

ttCOLON
 

PARASITISM
 

URINARY SYSTEM
 

*KIDNEY
 

CAST, NOS
 

INFLAMMATION, INTERSTITIAL
 

INFLAMMATION, CHRONIC
 

INFLAMMATION, CHRONIC FOCAL
 

SCLEROSIS
 

NEPHROPATHY
 

#KIDNEY/GLOMERULUS
 

DEGENERATION, NOS
 

ttKIDNEY/TUBULE


CAST, NOS
 

MATCHED
 

CONTROL
 

(20)
 

1 (5X)
 

1 (55O
 

(20)
 

(20)
 

3 (155O
 

(20)
 

1 (5%)
 

(20)
 

(20)
 

(20)
 

(20)
 

(20)
 

17 (85X)
 

1 (5X)
 

10	 (5050
 

4 (20%)
 

(20)
 

1 (5X)
 

(20)
 

2 (105J)
 

LOW DOSE
 

(50)
 

(50)
 

(50)
 

3 (65O
 

(50)


1 (2X)
 

(50)
 

(50)


1 (2X)
 

(49)
 

(50)


1 (25{)
 

(50)
 

36 (72X)
 

40 (80X)
 

(50)
 

(50)
 

HIGH DOSE
 

(50)


1 (2X)
 

1 (25O
 

(50)
 

1 (2X)
 

(50)
 

1 (2X)
 

9 (18X)
 

(49)


1 (2X)
 

1 (2%)
 

(49)
 

1 (2*)
 

(49)
 

(49)
 

1 (25O
 

1 (2%)
 

(48)
 

(50)
 

2 (4SO
 

16 (32%)
 

22 (445O
 

1 (2%)
 

4 (85O
 

41 (82>{)
 

(50)
 

(50)
 

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

68
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

DEGENERATION, NOS
 

PIGMENTATION, NOS
 

ftURINARY BLADDER
 

CALCULUS, NOS
 

ENDOCRINE SYSTEM
 

*PITUITARY
 

CYST, NOS
 

HYPERPLASIA, FOCAL
 

ANGIECTASIS
 

1ADRENAL
 

NECROSIS, NOS
 

SADRENAL CORTEX
 

HEMORRHAGE
 

HYPERPLASIA, FOCAL
 

#ADRENAL MEDULLA
 

HYPERPLASIA, NOS
 

#THYROID
 

COLLOID CYST
 

^PARATHYROID
 

HYPERPLASIA, NOS
 

HYPERPLASIA, DIFFUSE
 

REPRODUCTIVE SYSTEM
 

XMAMMARY GLAND
 

GALACTOCELE
 

HYPERPLASIA, DIFFUSE
 

LACTATION
 

#PROSTATE
 

INFLAMMATION, INTERSTITIAL
 

INFLAMMATION, SUPPURATIVE
 

INFLAMMATION, CHRONIC
 

INFLAMMATION, CHRONIC SUPPURATIV
 

HYPERPLASIA, EPITHELIAL
 

MATCHED
 

CONTROL LOW DOSE
 

(20) (46)


1	 (25O
 

(20) (49)


1 (25O
 

1 (25O
 

(20) (50)


1	 (25O
 

(20) (50)
 

1 (550
 

1	 (2%)
 

(20) (50)
 

1 (5%)
 

(20) (49)


1	 (25O
 

(17) (39)
 

(20)	 (50)
 

2 (10%)
 

1	 (550
 

(17) (48)


1 (2*)
 

1 (25O
 

1 (65O 2 (4%)
 

1 (25O
 

2 (12%)
 

HIGH DOSE
 

1 (25O
 

1	 (2X)
 

(49)
 

(50)


1 (2JO
 

1	 (25O
 

(49)
 

(49)
 

(49)
 

(49)


1 (25O
 

(43)
 

1 (25O
 

1 (25O
 

(50)


1 (25O
 

1 (25O
 

(47)
 

1 (250
 

1 (2X)
 

1 (25O
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 x NUMBER OF ANIMALS NECROPSIED
 

69
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

#PROSTATIC GLAND (17) (48) (47)
 

INFLAMMATION, SUPPURATIVE 1 (2%)
 

INFLAMMATION, ACUTE FOCAL 1 (2%)
 

INFLAMMATION, ACUTE/CHRONIC 1 (2%)
 

8TESTIS (20) (50) (50)
 

INFARCT, NOS 1 (2%)
 

HYPERPLASIA, INTERSTITIAL CELL 2 (4?O
 

KEPIDIDYMIS (20) (50) (50)
 

GRANULOMA, SPERMATIC 2 (45O 1 (2%)
 

^SPERMATIC CORD (20) (50) (50)
 

ABSCESS, NOS 1 (5%)
 

GRANULOMA, NOS 1 (5%)
 

NERVOUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

*EYE (20) (50) (50)
 

CATARACT 16 (80X)' 21 (42'/.) 15 (30X)
 

XEYE/CORNEA (20) (50) (50)
 

INFLAMMATION, SUPPURATIVE 1 (5%)
 

XEYE/RETINA (20) (50) (50)
 

DEGENERATION, NOS 16 (80%) 17 (34?O 12 (24X)
 

MUSCULOSKELETAL SYSTEM
 

*BONE (20) (50) (50)
 

FIBROUS OSTEODYSTROPHY 1 (2*)
 

*MUSCLE HIP/THIGH (20) (50) (50)
 

INFLAMMATION, CHRONIC FOCAL 1 (2X) 1
 

BODY CAVITIES
 

^PERITONEUM (20) (50) (50)
 

INFLAMMATION, CHRONIC 1 (2X)
 

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

70
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

INFLAMMATION, CHRONIC FOCAL 1 (2X)
 

ALL OTHER SYSTEMS
 

NONE
 

SPECIAL MORPHOLOGY SUMMARY
 

NO LESION REPORTED 1
 

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

71
 
TABLE C2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

ADMINSTERED 2,4,6-TRICHLOROPHENOL IN THE DIET 

ANIMALS INITIALLY IN STUDY


ANIMALS NECROPSIED


ANIMALS EXAMINED HISTOPATHOLOGICALLY


INTEGUMENTARY SYSTEM
 

XSUBCUT TISSUE


ABSCESS, NOS
 

RESPIRATORY SYSTEM
 

tfLUNG/BRONCHIOLE


LYMPHOCYTIC INFLAMMATORY INFILTR
 

SLUNG


CONGESTION, NOS
 

HEMORRHAGE
 

INFLAMMATION, ACUTE SUPPURATIVE


GRANULOMA, NOS
 

INFLAMMATION, FOCAL GRANULOMATOU
 

HYPERPLASIA, ADENOMATOUS


HEMATOPOIETIC SYSTEM
 

*BLOOD


LEUKOCYTOSIS, NOS
 

LEUKOCYTOSIS, NEUTROPHILIC
 

MONOCYTOSIS
 

«BONE MARROW


HYPERPLASIA, DIFFUSE
 

KSPLEEN


INFARCT HEMORRHAGIC


HEMOSIDEROSIS


HEMATOPOIESIS
 

GRANULOPOIESIS
 

MATCHED
 

CONTROL
 

 20
 

 20
 

 20
 

 (20)
 

 (18)
 

 (18)
 

1 (6%)
 

1 (6%)
 

 (20)
 

 (20)
 

 (20)
 

1 (5%)
 

 12 (60%)
 

LOW DOSE
 

50
 

50
 

50
 

(50)
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

3 (6%)
 

2 (4%)
 

2 (4%)
 

(50)
 

16 (32%)
 

(50)
 

14 (28%)
 

1 C25O
 

1 (2%)
 

HIGH DOSE
 

50
 

50
 

50
 

(50)


1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

1 (25£)
 

1 (2X)
 

(50)
 

3 (6%)
 

(50)
 

2 (4X)
 

(50)
 

13 (26%)
 

1 (2%)
 

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

72
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

ttSPLENIC FOLLICLES
 

ATROPHY, NOS
 

«SPLEHIC RED PULP
 

HYPERPLA5IA, NOS
 

#LYMPH NODE
 

HEMOSIDEROSIS
 

HYPERPLASIA, DIFFUSE
 

ttMEDIASTINAL L.NODE
 

EDEMA, NOS
 

HEMORRHAGE
 

HEMOSIDEROSIS
 

SMESENTERIC L. NODE
 

HISTIOCYTOSIS
 

LYMPHOCYTOSIS
 

SHEPATIC SINUSOID
 

LEUKOCYTOSIS, NOS
 

CIRCULATORY SYSTEM
 

#MANDIBULAR L. NODE
 

LYMPHANGIECTASIS
 

8HEART
 

PERIARTERITIS
 

#HEART/ATRIUM
 

THROMBOSIS, NOS
 

#MYOCARDIUM
 

INFLAMMATION, CHRONIC
 

FIBROSIS
 

DEGENERATION, NOS
 

8CARDIAC VALVE
 

INFLAMMATION, CHRONIC FOCAL
 

SPANCREAS
 

PERIARTERITIS
 

MATCHED
 

CONTROL
 

(20)
 

(20)
 

(20)
 

8 (40X)
 

(20)
 

(20)
 

(20)
 

(20)
 

(20)
 

(20)
 

(20)


H (70X)
 

(20)
 

(20)
 

LOW DOSE
 

(50)
 

(50)
 

(50)
 

(50)
 

(50)


1 C2X)
 

1 (2X)
 

(50)
 

1 (2X)
 

(50)
 

(50)
 

(50)
 

1 (2%)
 

(50)


34 (68*)
 

2 (4X)
 

(50)
 

(50)


1 (2%)
 

HIGH DOSE
 

(50)


1 (2X)
 

(50)


1 (2X)
 

(50)


1 (2X)
 

1 (25O
 

(50)


1 (23O
 

1 (2X)
 

1 (2X)
 

(50)
 

(50)
 

(50)
 

1 (2*)
 

(50)


1 (2%)
 

(50)
 

(50)


40 (80X)
 

1 (2X)
 

2 (4X)
 

(50)


1 (2X)
 

(44)


1 (255)
 

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

73
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

KMESENTERY 

PERIARTERITIS 

(20) (50)

1 (2%) 

DIGESTIVE SYSTEM 

USALIVARY GLAND 

INFLAMMATION, CHRONIC 

INFLAMMATION, CHRONIC FOCAL 

ATROPHY, NOS 

(19) (50) 

1

1

 (2%) 

 (2%) 

#LIVER 

INFLAMMATION, FOCAL 

INFLAMMATION, CHRONIC 

GRANULOMA, NOS 

(20) (50)

1

4

 (2%) 

 (8%) 

NECROSIS, NOS 

METAMORPHOSIS FATTY 

LIPOIDOSIS 

1 15%-) 

3

2

 (6%) 

 (4%) 

BASOPHILIC CYTO CHANGE 

FOCAL CELLULAR CHANGE 

HYPERPLASIA, NODULAR 

HYPERPLASIA, FOCAL 

2 (10%) 

1 (5%) 1

3

1

 (250 

 (6%) 

 (2%) 

SLIVER/CENTRILOBULAR 

INFLAMMATION, NECROTIZING 

LIPOIDOSIS 

(20) (50)

1 (25O 

1 (2%) 

ttLIVER/PERIPORTAL

INFLAMMATION, CHRONIC FOCAL 

(20) (50) 

#LIVER/HEPATOCYTES 

METAMORPHOSIS FATTY 

(20) 

1 (5X) 

(50) 

8BILE DUCT 

INFLAMMATION, CHRONIC 

(20) (50) 

HYPERPLASIA, NOS 1 (5%) 

«PANCREAS 

INFLAMMATION, CHRONIC 

(20) (50) 

INFLAMMATION, CHRONIC FOCAL 

SPANCREATIC ACINUS 

FIBROSIS, FOCAL 

(20) (50) 

ATROPHY, FOCAL 2 (10%) 6 (125O 

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

HIGH DOSE
 

(50)
 

(48)
 

3 (6X)
 

1 (2X)
 

(50)
 

1 (2X)
 

1 (2%)
 

13 (26%)
 

3 (6%)
 

1 (2%)
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

1 (2%)
 

3 (6%)
 

(44)


1 (2%)
 

2 (5%)
 

(44)


1 (2%)
 

7 (16%)
 

74
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE
 

8ESOPHAGUS 

INFLAMMATION, NECROTIZING 

(20) (50) 

1 (2%) 

USTOMACH 

ULCER, NOS 

INFLAMMATION, NECROTIZING 

(20) (50) 

1 (2%) 

#SMALL INTESTINE 

ULCER, PERFORATED 

ADHESION, NOS 

(20) (48)

2 (4%) 

1 (2%) 

8DUODENAL SEROSA 

INFLAMMATION, CHRONIC 

(20) (48) 

SCOLON 

PARASITISM 

(20) (49) 

2 (4%) 

URINARY SYSTEM 

#KIDNEY 

HYDRONEPHROSIS 

(20) (50) 

INFLAMMATION, INTERSTITIAL 

INFLAMMATION, CHRONIC 

INFLAMMATION, CHRONIC FOCAL 

SCLEROSIS 

NEPHROPATHY 

GLOMERULOSCLEROSIS, NOS 

8 (40%) 

1 (5%) 

1 (5%) 

8 (40%) 

27

2

17

 (54%) 

 (4%) 

 (34%) 

#KIDNEY/GLOMERULUS 

NEPHROPATHY 

(20) 

1 (5%) 

(50) 

SURINARY BLADDER 

INFLAMMATION, CHRONIC FOCAL 

(19) (48) 

1 (2%) 

ENDOCRINE SYSTEM 

^PITUITARY 

CYST, NOS 

MULTIPLE CYSTS 

(20)

2 (10%) 

(49)

3 (6%) 

HADRENAL 

LYMPHOCYTIC INFLAMMATORY INFILTR 

(20) 

1 (5%) 

(50) 

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

HIGH DOSE
 

(48)
 

(49)
 

1 (2%)
 

(48)
 

(48)


2 (4%)
 

(47)
 

(50)
 

1 (2%)
 

13 (26%)
 

26 (52%)
 

21 (42%)
 

1 (2X)
 

(50)
 

(48)
 

(49)
 

1 (2%)
 

2 (4%)
 

(49)
 

75
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

ftADRENAL CORTEX (20) (50) (49)


METAMORPHOSIS FATTY 1 (2%) 1 (25O
 

HYPERPLASIA, NODULAR 1 (2?O
 

HYPERPLASIA, FOCAL 1 (2%)
 

STHYROID (20) (49) (50)
 

COLLOID CYST 1 (2X)
 

INFLAMMATION, CHRONIC FOCAL 1 (2X)
 

REPRODUCTIVE SYSTEM
 

XMAMMARY GLAND (20) (50) (50)
 

DILATATION, NOS 1 (2%)
 

DILATATION/DUCTS 1 (5%) 2 (45O 1 (2X)
 

GALACTOCELE 1 (2>O 1 (2%)
 

CYST, NOS 1 (25O
 

HEMATOMA, NOS 1 (25O
 

FIBROSIS 1 (2%)
 

HYPERPLASIA, EPITHELIAL 2 C10X)
 

HYPERPLASIA, FOCAL 1 (2%)
 

XMAMMARY DUCT (20) (50) (50)
 

HYPERPLASIA, FOCAL 1 (2X)
 

XVAGINA (20) (50) (50)
 

PROLAPSE 1 (2X)
 

EPIDERMAL INCLUSION CYST 1 (5X)
 

SUTERUS (20) (50) (49)
 

GRANULATION, TISSUE 1 (2X)
 

HEMOSIDEROSIS 1 (250
 

ftCERVIX UTERI (20) (50) (49)
 

PROLAPSE 1 (2%)
 

#UTERUS/ENDOMETRIUM (20) (50) (49)
 

NECROSIS, FOCAL 1 (2%)
 

INFARCT, NOS 1 (2%)
 

ftOVARY (20) (50) (49)
 

FOLLICULAR CYST, NOS 1 (2X)
 

NERVOUS SYSTEM
 

ftCEREBRAL VENTRICLE (20) (50) (49)
 

DILATATION, NOS 1 (5X)
 

ft NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 x NUMBER OF ANIMALS NECROPSIED
 

76
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

SPECIAL SENSE ORGANS
 

*EYE (20) C50) (50)
 

CATARAC T 4 (20X) 8 (165O 3 (6%)
 

*EYE/CORNEA (20) (50) (50)
 

INFLAMMATION, NOS 1 (5X)
 

*EYE/RETINA (20) (50) (50)
 

DEGENERATION, NOS 4 (20X) 7 (1<m 3 (6X)
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

^PERITONEUM (20) (50) (50)
 

INFLAMMATION, FOCAL 1 (25O
 

INFLAMMATION, CHRONIC 1 (2%)
 

^MESENTERY (20) (50) (50)
 

STEATITIS 2 (4X)
 

NECROSIS, FOCAL 1 (2X)
 

ALL OTHER SYSTEMS
 

NONE
 

SPECIAL MORPHOLOGY SUMMARY
 

NONE
 

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

77
 
78

 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN MICE ADMINISTERED 2,4,6-TRICHLOROPHENOL IN THE DIET
 

79
 
oo 

o 
TABLE D1.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

ADMINISTERED 2,4,6-TRICHLOROPHENOL IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 20 50 50 

ANIMALS MISSING 1 

ANIMALS NECROPSIED 20 49 49 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 20 49 49 

INTEGUMENTARY SYSTEM
 

XSKIN (20) (49) (49)
 

CYST, NOS 1 (5X)
 

XSUBCUT TISSUE (20) (49) (49)
 

INFLAMMATION, NOS 1 (23O
 

RESPIRATORY SYSTEM
 

SLUNG (20) (48) (47)
 

INFLAMMATION, CHRONIC FOCAL 1 (5X)
 

GRANULOMA, NOS 1 (2X)
 

HEMATOPOIETIC SYSTEM
 

XBLOOD (20) (49) (49)
 

LEUKOCYTOSIS, NEUTROPHILIC
 

ffBONE MARROW 

HYPOPLASIA, NOS 

HYPERPLASIA, NOS 

HYPERPLASIA, HEMATOPOIETIC 

(20) 

1 (55O 

(47)

1

1

 (2X) 

 (2%) 

(47) 

«SPLEEN 

HYPERPLASIA, HEMATOPOIESIS  LYMPHOID 

(20) 

3 

1 (15%)

(5X.) 

(49) 

2 (45O 

1 (2%) 

(47) 

2 (4JO 

SLYMPH NODE 

CONGESTION, NOS 

HEMOSIDEROSIS 

HYPERPLASIA, NOS 

PLASMACYTOSIS 

(19) 

1 

1 

(5%)

(5%) 

(46) (47)

1 (25O 

3 (6X) 

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

81
 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

HYPERPLASIA, LYMPHOID
 

ttMESENTERIC L. NODE
 

CONGESTION, N05
 

HEMORRHAGE
 

HYPERPLASIA, LYMPHOID
 

SLUNG/ALVEOLI
 

HISTIOCYTOSIS
 

KLIVER
 

HEMATOPOIESIS
 

ftPEYERS PATCH
 

HYPERPLASIA, LYMPHOID
 

CIRCULATORY SYSTEM
 

SHEART
 

PERIVASCULITIS
 

ftHEART/ATRIUM
 

THROMBOSIS, NOS
 

MYOCARDIUM
 

INFLAMMATION, CHRONIC FOCAL
 

INFLAMMATION, PYOGRANULOMATOUS
 

XCORONARY ARTERY
 

INFLAMMATION, CHRONIC
 

INFLAMMATION, CHRONIC FOCAL
 

XMESENTERIC ARTERY
 

INFLAMMATION, CHRONIC
 

XRENAL ARTERY
 

INFLAMMATION, CHRONIC
 

XEPIDIDYMIS
 

PERIARTERITIS
 

#THYROID
 

PERIARTERITIS
 

PERIVASCULITIS
 

MATCHED
 

CONTROL
 

( 19)
 

3 (16%)
 

(20)
 

(20)
 

1 (55O
 

(20)
 

(20)
 

(20)
 

(20)
 

(20)
 

(20)
 

(20)
 

(20)
 

(20)
 

LOW DOSE
 

(46)
 

1 (2%)
 

4 (9%)
 

(48)


1 (25O
 

(49)
 

1 (250
 

(46)


1 (2%)
 

(49)


1 (250
 

(49)


1 (2%)
 

(49)


1 (2%)
 

(49)
 

1 (2%)
 

1 (25O
 

(49)
 

(49)


1 (25O
 

(49)
 

(47)
 

1 (25O
 

HIGH DOSE
 

1 (25O
 

(47)
 

4 (950
 

1 (25£)
 

3 (65C)
 

(47)
 

(47)
 

(43)
 

1 (25O
 

(47)
 

(47)
 

(47)


1 (25O
 

1 (25O
 

(49)


1 (2%)
 

(49)


1 (2%)
 

(49)


1 (2%)
 

(49)


1 (2%)
 

(46)
 

1 (254)
 

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

82
 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

DIGESTIVE SYSTEM
 

•SALIVARY GLAND (20) (48) (47)


INFLAMMATION, CHRONIC 7 (35X) 10 (21JO 14 (30X)
 

INFLAMMATION, CHRONIC FOCAL 2 (45O
 

•LIVER	 (20) (49) (47)
 

INFLAMMATION, NECROTIZING 2 (4%)
 

INFLAMMATION, CHRONIC 1 (55O
 

INFLAMMATION, CHRONIC FOCAL 1 (5X)
 

NECROSIS, NOS 2 (10X) 1 (25O
 

INFARCT, NOS 1 (5%)
 

INFARCT, FOCAL 1 (5X) 1 (2X)
 

LIPOIDOSIS 1 (55O 1 (2X)
 

HYPERPLASIA, NODULAR 1 (550 3 (65O
 

HYPERPLASIA, FOCAL 1 (53O
 

ANGIECTASIS
 

•LIVER/CENTRILOBULAR	 (20) (49) (47)
 

NECROSIS, NOS 1 (550
 

•LIVER/HEPATOCYTES	 (20) (49) (47)
 

DEGENERATION, NOS 1 (255)
 

HYPERTROPHY, FOCAL 1 (2X)
 

HYPERPLASIA, NODULAR 1 (25O 1
 

HYPERPLASIA, NOS 10 (20K) 2 (4X)
 

HYPERPLASIA, FOCAL 1 (22)
 

*BILE DUCT (20) (49) (47)
 

INFLAMMATION, NOS 1 (2%)
 

INFLAMMATION, CHRONIC 3 (6%)
 

INFLAMMATION, CHRONIC FOCAL 2 (4%)
 

INFLAMMATION CHRONIC CYSTIC 1 (2%)
 

NECROSIS, NOS 1 (2%)
 

HYPERPLASIA, NOS 1 (2%)
 

((PANCREAS (20) (48) (47)
 

HEMORRHAGE 1 (55O
 

STEATITIS 1 (55O
 

•STOMACH	 (20) (47) (46)
 

INFLAMMATION, SUPPURATIVE 1 (2X)
 

•SMALL	 INTESTINE (20) (46) (43)


DIVERTICULUM 1 (2X)
 

» NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

X NUMBER OF ANIMALS NECROPSIED
 

83
 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE
 

((COLON (19) (47)
 

PARASITISM 1 (5%)
 

URINARY SYSTEM
 

SKIDNEY (20) (49)
 

INFLAMMATION, INTERSTITIAL 1 (2X)
 

INFLAMMATION, CHRONIC 9 (45X) 4 (8X)
 

PYELONEPHRITIS, CHRONIC
 

HYPERPLASIA, TUBULAR CELL 1 (55O
 

#KIDNEY/PELVIS	 (20) (49.'
 

INFLAMMATION, CHRONIC FOCAL
 

ffURINARY BLADDER (18) (48)


CALCULUS, NOS 1 (25O
 

INFLAMMATION, CHRONIC FOCAL
 

ENDOCRINE SYSTEM
 

*ADRENAL CORTEX (20) (49)
 

HYPERPLASIA, NODULAR 1 (55O
 

«THYROID (20) (47)
 

ULTIMOBRANCHIAL CYST
 

INFLAMMATION, FOCAL GRANULOMATOU
 

REPRODUCTIVE SYSTEM
 

*PREPUTIAL GLAND	 (20) (49)
 

ABSCESS, CHRONIC	 1 (2%)
 

SPROSTATE (20) (48)
 

INFLAMMATION, CHRONIC FOCAL 1 (2X)
 

*TESTIS (19) (49)


INFLAMMATION, FOCAL GRANULOMATOU 1 (2%)
 

XEPIDIDYMIS (20) (49)
 

DILATATION, NOS 1 (5%)
 

STEATITIS 1 (5X)
 

8 NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 x NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

(46)
 

(47)
 

10	 (2U)
 

2 (450
 

(47)


1 (23O
 

(45)
 

1 (25O
 

(45)
 

(46)
 

1 (2X)
 

1 (25S)
 

(49)
 

(42)
 

(46)
 

(49)
 

84
 
TABLE 01. MALE MICE: NONNEOPLASTIC

INFLAMMATION, CHRONIC FOCAL


GRANULOMA, SPERMATIC


NECROSIS, FAT


NERVOUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

*ISCHIOCAVERNOSUS MUS
 PARASITISM


BODY CAVITIES
 

XMESENTERY


GRANULATION, TISSUE


ALL OTHER SYSTEMS
 

HEAD
 

HEMATOMA, ORGANIZED


SPECIAL MORPHOLOGY SUMMARY
 

NO LESION REPORTED


ANIMAL MISSING/NO NECROPSY


AUTOLYSIS/NO NECROPSY


 LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

1 (2SO
 

1 (2%)
 

1 (55O
 

 (20) (49) (49)
 1 (55O
 

 (20) (49) (49)
 1 (2%)
 

1
 

2 2
 

1
 

1
 

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

85
 
TABLE 02.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

ADMINISTERED 2,4,6-TRICHLOROPHENOL IN THE DIET 

MATCHED 

CONTROL LOW DOSE 

ANIMALS INITIALLY IN STUDY 20 50 

ANIMALS MISSING 

ANIMALS NECROPSIED 20 50 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 20 50 

INTEGUMENTARY SYSTEM
 

NONE
 

RESPIRATORY SYSTEM
 

*LUNG/BRONCHIOLE (20) (50)
 

LYMPHOCYTIC INFLAMMATORY INFILTR
 

ttLUNG (20) (50)
 

LYMPHOCYTIC INFLAMMATORY INFILTR 1 (2%)
 

HYPERPLASIA, ALVEOLAR EPITHELIUM 1 (250
 

HEMATOPOIETIC SYSTEM
 

ttBONE MARROW (20) (50)
 

HYPERPLASIA, HEMATOPOIETIC
 

#SPLEEN (20) (50)
 

INFLAMMATION, GRANULOMATOUS
 

HEMOSIDEROSIS 3 (155O 2 (4%)
 

HYPERPLASIA, RETICULUM CELL
 

HYPERPLASIA, LYMPHOID 1 (2X)
 

HEMATOPOIESIS 1 (2X)
 

KSPLENIC FOLLICLES (20) (50)
 

NECROSIS, NOS 1 (2X)
 

ttLYMPH NODE (20) (47)
 

HYPERPLASIA, RETICULUM CELL 1 (5X)
 

HYPERPLASIA, LYMPHOID 1 (23O
 

ftMANDIBULAR L. NODE (20) (47)
 

HYPERPLASIA, LYMPHOID 1 (25O
 

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

HIGH DOSE 

50
 

2
 

48
 

48
 

(48)
 

1 (2X)
 

(48)
 

(48)
 

(48)
 

4 (8X)
 

1 (2X)
 

(48)
 

(48)
 

(48)
 

1 (25O
 

86
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC

ttABDOMINAL LYMPH NODE
 

INFLAMMATION, GRANULOMATOUS
 

ttMESENTERIC L. NODE
 

CONGESTION, NOS
 

EOSINOPHILIC INFILTRATE
 

HYPERPLASIA, RETICULUM CELL
 

HYPERPLASIA, LYMPHOID
 

SLIVER
 

HEMATOPOIESIS
 

#PEYERS PATCH
 

HYPERPLASIA, RETICULUM CELL
 

HYPERPLASIA, LYMPHOID
 

CIRCULATORY SYSTEM
 

^MULTIPLE ORGANS
 

PERIARTERITIS
 

KLUNG
 

PERIVASCULITIS
 

KMYOCARDIUM
 

INFLAMMATION, CHRONIC FOCAL
 

SOVARY
 

THROMBOSIS, NOS
 

DIGESTIVE SYSTEM
 

SSALIVARY GLAND
 

INFLAMMATION, NOS
 

INFLAMMATION, CHRONIC
 

INFLAMMATION, CHRONIC FOCAL
 

ttLIVER
 

INFLAMMATION, NECROTIZING
 

INFLAMMATION, ACUTE/CHRONIC
 

INFLAMMATION, CHRONIC
 

INFLAMMATION, CHRONIC NECROTIZIN
 

 LESIONS (CONTINUED) 

MATCHED
 

CONTROL
 

(20)
 

(20)
 

(20)
 

1 (5%)
 

(19)
 

(20)
 

(20)
 

(20)
 

(20)
 

(20)
 

1 (5%)
 

10	 (SOX)
 

2 (10%)
 

(20)
 

6 (30%)
 

LOW DOSE
 

(47)
 

(47)
 

1 (2%)
 

2 (4%)
 

(50)
 

(50)
 

2 (4%)
 

(50)
 

1 (2%)
 

(50)
 

(48)
 

1 (2%)
 

(50)
 

(46)
 

15 (33%)
 

(50)
 

1 (2%)
 

6 (12%)
 

HIGH DOSE
 

(48)


1


(48)


2


1


2


1


(48)
 

(48)


2


1


(48)
 

(48)


1


(48)
 

(48)


1


(47)
 

18


(48)


1


16


1


 (2%)
 

 (4%)
 

 (2%)
 

 (4%)
 

 (2%)
 

 (4%)
 

 (2%)
 

 (2%)
 

 (2%)
 

 (38%)
 

 (2%)
 

 (33%)
 

 (2%)
 

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

87
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

NECROSIS, NOS
 

NECROSIS, FOCAL
 

INFARCT, FOCAL
 

LIPOIDOSIS
 

HYPERTROPHY, NOS
 

HYPERPLASIA, NODULAR
 

HYPERPLASIA, FOCAL
 

HIVER/HEPATOCYTES
 

HYPERPLASIA, NOS
 

HYPERPLASIA, FOCAL
 

#BILE DUCT
 

DILATATION, NOS
 

INFLAMMATION, CHRONIC
 

HYPERPLASIA, FOCAL
 

ttPANCREAS
 

CYSTIC DUCTS
 

INFLAMMATION, CHRONIC
 

INFLAMMATION, CHRONIC FOCAL
 

UPANCREATIC DUCT
 

DILATATION, NOS
 

CYST, NOS
 

SSTOMACH
 

INFLAMMATION, SUPPURATIVE
 

ttCOLON
 

PARASITISM
 

URINARY SYSTEM
 

#KIDNEY
 

INFLAMMATION, CHRONIC
 

PYELONEPHRITIS, CHRONIC
 

INFARCT, NOS
 

#KIDNEY/ CORTEX
 

INFARCT, FOCAL
 

*KIDNEY/PELVIS
 

INFLAMMATION, FOCAL
 

MATCHED
 

CONTROL
 

1 (5%)
 

(20)
 

(30)
 

(19)
 

(19)


1 (55O
 

(20)
 

(20)
 

(20)


6 (30%)
 

4 (2050
 

(20)
 

(20)


1 (55O
 

LOW DOSE
 

1 (25O
 

1 (2*)
 

(50)
 

1 (2%)
 

(50)
 

(48)
 

1 (250
 

1 (25O
 

(48)
 

1 (25O
 

(50)


1 (25O
 

(48)


3 (6%)
 

(50)


4 (8%)
 

5 (10X)
 

(50)


1 (25O
 

(50)
 

HIGH DOSE
 

1 (25O
 

1 (2%)
 

2 (4%)
 

1 (25O
 

1 (2%)
 

(48)


3 (6%)
 

2 (4%)
 

(48)


1 (2X)
 

2 (450
 

1 (250
 

(48)
 

1 (250
 

(48)
 

(47)
 

(47)
 

(48)


6 (1350
 

3 (65O
 

1 (25O
 

(48)
 

(48)
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 x NUMBER OF ANIMALS NECROPSIED
 

88
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

INFLAMMATION, CHRONIC
 

INFLAMMATION, CHRONIC FOCAL
 

8URINARY BLADDER
 

INFLAMMATION, CHRONIC
 

INFLAMMATION, CHRONIC FOCAL
 

INFLAMMATION, CHRONIC DIFFUSE
 

ENDOCRINE SYSTEM
 

#ADRENAL CORTEX
 

HYPERPLASIA, NODULAR
 

STHYROID
 

HYPERPLASIA, FOLLICULAR-CELL
 

REPRODUCTIVE SYSTEM
 

ttUTERUS
 

HYDROMETRA
 

SUTERUS/ENDOMETRIUM


CYST, NOS
 

MULTIPLE CYSTS
 

HYPERPLASIA, DIFFUSE
 

HYPERPLASIA, PAPILLARY
 

HYPERPLASIA, CYSTIC
 

#UTERUS/MYOMETRIUM
 

INFLAMMATION, CHRONIC FOCAL
 

SOVARY
 

FOLLICULAR CYST, NOS
 

NERVOUS SYSTEM
 

ttBRAIN/MENINGES
 

INFLAMMATION, CHRONIC
 

SPECIAL SENSE ORGANS
 

NONE
 

MATCHED
 

CONTROL
 

1 (5%)
 

(20)
 

1 (5%)
 

2 (10%)
 

(20)
 

1 (5%)
 

(20)
 

(20)
 

(20)
 

1 (5%)
 

2 (10%)
 

1 (5%)
 

(20)
 

(20)
 

(20)


1 (5%)
 

LOW DOSE
 

1 (2%)
 

(47)


9 (19%)
 

1 (2%)
 

(48)
 

(48)


1 (2%)
 

(50)


1 (2%)
 

(50)


1 (2%)
 

1 (2%)
 

3 (6%)
 

1 (2%)
 

5 (10%)
 

(50)
 

1 (2%)
 

(50)


1 (2%)
 

(50)
 

HIGH DOSE
 

2 (4%)
 

2 (4%)
 

(46)


6 (13%)
 

1 (2%)
 

(46)
 

(45)
 

(48)
 

(48)
 

1 (2%)
 

(48)
 

(48)
 

1 (2%)
 

(48)
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 x NUMBER OF ANIMALS NECROPSIED
 

89
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

MUSCULOSKELETAL SYSTEM
 

^SKELETAL MUSCLE (20) (50) (48)
 

PARASITISM 1 (2K)
 

BODY CAVITIES
 

^PERITONEUM (20) (50) (48)
 

INFLAMMATION, GRANULOMATOUS 1 (2X)
 

*PLEURA (20) (50) (48)
 

INFLAMMATION, CHRONIC 1 (2X)
 

XMESENTERY (20) (50) (48)
 

CYST, NOS 1 (5X)
 

ALL OTHER SYSTEMS
 

NONE
 

SPECIAL MORPHOLOGY SUMMARY
 

NO LESION REPORTED 2
 

ANIMAL MISSING/NO NECROPSY 2
 

AUTO/NECROPSY/HISTO PERF 1
 

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

90
 
APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN RATS ADMINISTERED 2,4,6-TRICHLOROPHENOL IN THE DIET
 

91
 
92

 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered 2,4,6-Trichlorophenol in the Diet (a)
 

Topography: Morphology


Integumentary System:
 

Trichoepithelioma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


U)
 

Lung: Alveolar/Bronchiolar
 

Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 2/20 (10)
 

 N.S.
 

 107
 

 2/18 (11)
 

 N.S.
 

107
 

Low
 

Dose
 

4/50 (8)
 

N.S.
 

0.800
 

0.128
 

8.436
 

106
 

1/50 (2)
 

N.S.
 

0.180
 

0.003
 

3.307
 

86
 

High
 

Dose
 

2/50 (4)
 

N.S.
 

0.400
 

0.032
 

5.277
 

106
 

1/50 (2)
 

N.S.
 

0.180
 

0.003
 

3.307
 

106
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered 2,4,6-Trichlorophenol in the Diet (a)
 

(continued)
 

Topography: Morphology


Lung: Alveolar /Bronchiolar
 

Carcinoma or Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Hematopoietic System: Monocytic
 

Leukemia (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 

Matched Low High 

 Control Dose Dose 

 2/18 (11) 1/50 (2) 2/50 (4) 

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

0.180 0.360 

0.003 0.029 

3.307 4.740 

 107 86 106 

 3/20 (15) 23/50 (46) 28/50 (56) 

P = 0.003 P = 0.013 P = 0.002 

3.067 3.733 

1.095 1.373 

14.502 17.192 

107 64 69 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered 2,4,6-Trichlorophenol in the Diet (a)
 

(continued)
 

Topography: Morphology


Hematopoietic System:
 

Lymphoma or Leukemia (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


VO
 

Ln
 

Pituitary: Chromophobe Adenoma (b)


P Values (c,d)


Departure from Linear Trend (e)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Matched
 

 Control
 

 4/20 (20)
 

P = 0.006
 

 107
 

 10/20 (50)
 

P less than 0.001 (N)
 

P = 0.044
 

Low
 

Dose
 

25/50 (50)
 

P = 0.019
 

2.500
 

1.036
 

8.761
 

64
 

7/49 (14)
 

P = 0.003 (N)
 

0.286
 

0.117
 

0.718
 

High
 

Dose
 

29/50 (58)
 

P = 0.004
 

2.900
 

1.230
 

9.922
 

69
 

4/50 (8)
 

P less than 0.001 (N)
 

0.160
 

0.045
 

0.486
 

Weeks to First Observed Tumor 107 106 106
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats 

Administered 2,4,6-Trichlorophenol in the Diet (a) 

(continued) 

Matched Low High 

Topography: Morphology Control Dose Dose 

Adrenal: Pheochromocytoma (b) 3/20 (15) 2/50 (4) 6/49 (12) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 0.267 0.816 

Lower Limit 0.024 0.199 

Upper Limit 2.190 4.706 

Weeks to First Observed Tumor 107 84 79 

Thyroid: C-cell 

Carcinoma or Adenoma (b) 2/20 (10) 2/49 (4) 5/49 (10) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 0.408 1.020 

Lower Limit 0.032 0.188 

Upper Limit 5.381 10.204 

Weeks to First Observed Tumor 107 96 98 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered 2,4,6-Trichlorophenol in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

Thyroid: Adenoma, NOS, or
 

Adenocarcinoma, NOS (b) 1/20 (5) 0/49 (0)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 0.000
 

Lower Limit 0.000
 

Upper Limit 7.624
 

Weeks to First Observed Tumor 107
 —
 

Parathyroid: Adenoma, NOS, or
 VO
 

Adenocarcinoma, NOS (b) 0/17 (0) 2/39 (5)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) Infinite
 

Lower Limit 0.135
 

Upper Limit Infinite
 

Weeks to First Observed Tumor 106
 

High
 

Dose
 

3/49 (6)
 

N.S.
 

1.224
 

0.108
 

62.958
 

0/43 (0)
 

—
 

—
 

—
 

—
 

79 
00 

Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered 2,4,6-Trichlorophenol in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

Mammary Gland: Adenoma, NOS (b) 2/20 (10) 0/50 (0)
 

P Values (c,d) P = 0.024 (N) N.S.
 

Departure from Linear Trend (e) P = 0.042
 

Relative Risk (f) 0.000
 

Lower Limit 0.000
 

Upper Limit 1.345
 

Weeks to First Observed Tumor 107
 —
 

Testis: Interstitial-cell Tumor (b) 18/20 (90) 40/50 (80)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 0.889
 

Lower Limit 0.775
 

Upper Limit 1.190
 

Weeks to First Observed Tumor 103 84
 

High
 

Dose
 

0/50 (0)
 

N.S.
 

0.000
 

0.000
 

1.345
 

—
 

38/50 (76)
 

N.S.
 

0.844
 

0.735
 

1.147
 

98 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered 2,4,6-Trichlorophenol in the Diet (a)
 

(continued)
 

(a) Dosed groups received 5,000 or 10,000 ppm.
 

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

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated. Beneath
 

the incidence of tumors in a dosed group is the probability level for the Fisher exact test for
 

the comparison of that dosed group with the matched-control group when P is less than 0.05;
 

otherwise, not significant (N.S.) is indicated.
 

(d) A negative trend (N) indicates a lower incidence in a dosed group than in a control group.
 

(e) The probability level for departure from linear trend is given when P is less than 0.05 for any
 

comparison.
 VD
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control group.
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered 2,4,6-Trichorophenol in the Diet (a)
 

Matched Low
 

Topography: Morphology Control Dose
 

Integumentary System: Fibroadenoma
 

of the Subcutaneous Tissue (b) 2/20 (10) 1/50 (2)
 

P Values (c,d) P = 0.035 (N) N.S.
 

Relative Risk ( f ) 0.200
 

Lower Limit 0.004
 

Upper Limit 3.681
 

Weeks to First Observed Tumor 92 92
 

o
 

o
 

Hematopoietic System: Monocytic
 

Leukemia (b) 3/20 (15) 11/50 (22)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 1.467
 

Lower Limit 0.450
 

Upper Limit 7.595
 

Weeks to First Observed Tumor 103 69
 

High
 

Dose
 

0/50 (0)
 

N.S.
 

0.000
 

0.000
 

1.345
 

—
 

10/50 (20)
 

N.S.
 

1.333
 

0.398
 

7.002
 

104
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered 2,4,6-Trichorophenol in the Diet (a)
 

(continued)
 

Topography: Morphology


Hematopoietic System: Lymphoma or
 

Leukemia (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Pituitary: Carcinoma, NOS,
 

or Adenoma, NOS (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Matched
 

 Control
 

 3/20 (15)
 

 N.S.
 

 103
 

 3/20 (15)
 

P = 0.042 (N)
 

 92


Low
 

Dose
 

11/50 (22)
 

N.S.
 

1.467
 

0.450
 

7.594
 

69
 

3/49 (6)
 

N.S.
 

0.408
 

0.061
 

2.857
 

 92


High
 

Dose
 

13/50 (26)
 

N.S.
 

1.733
 

0.556
 

8.773
 

1/49 (2)
 

N.S.
 

0.136
 

0.003
 

1.599
 

 106
 

55 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered 2,4,6-Trichorophenol in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

Pituitary: Chromophobe
 

Carcinoma or Adenoma (b) 4/20 (20) 11/49 (22)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 1.122
 

Lower Limit 0.392
 

Upper Limit 4.404
 

Weeks to First Observed Tumor 107 107
 

o
 

N3
 

Thyroid: C-cell Adenoma (b) 3/20 (15) 1/49 (2)
 

P Values (c,d) P = 0.041 (N) N.S.
 

Relative Risk (f) 0.136
 

Lower Limit 0.003
 

Upper Limit 1.599
 

Weeks to First Observed Tumor 107 106
 

High
 

Dose
 

8/49 (16)
 

N.S.
 

0.816
 

0.255
 

3.392
 

106
 

1/50 (2)
 

N.S.
 

0.133
 

0.003
 

1.568
 

106
 
Table E2. Analyses of

Administered

 the Incidence of Primary Tumors in Female

 2,4,6-Trichorophenol in the Diet (a) 

 Rats 

(continued) 

Topography: Morphology 

Matched

Control

 Low 

 Dose 

High 

Dose 

Mammary Gland: Fibroadenoma (b) 2/20 (10) 0/50 (0) 0/50 (0) 

P Values (c,d) P = 0.024 (N) N.S. N.S. 

Departure from Linear Trend (e) P = 0.042 

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.000 

0.000 

1.345 

0.000 

0.000 

1.345 

o 

to 

Weeks to First Observed Tumor 92 — 

Uterus: Endometrial Stromal 

Polyp (b) 1/20 (5) 3/50 (6) 2/49 (4) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.200 

0.106 

61 . 724 

0.816 

0.046 

47.195 

Weeks to First Observed Tumor 100 106 87 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats 

Administered 2,4,6-Trichorophenol in the Diet (a) 

(continued) 

(a) Dosed groups received 5,000 or 10,000 ppm.
 

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

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated. Beneath
 

the incidence of tumors in a dosed group is the probability level for the Fisher exact test for
 

the comparison of that dosed group with the matched-control group when P is less than 0.05;
 

otherwise, not significant (N.S.) is indicated.
 

(d) A negative trend (N) indicates a lower incidence in a dosed group than in a control group.
 

(e) The probability level for departure from linear trend is given when P is less than 0.05 for any
 

comparison.
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control group.
 
APPENDIX F
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN MICE ADMINISTERED 2,4,6-TRICHLOROPHENOL IN THE DIET
 

105
 
106

 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered 2,4,6-Trichlorophenol in the Diet (a)
 

Topography: Morphology


Lung: Alveolar /Bronchiolar
 

Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Lung: Alveolar/Bronchiolar
 

Carcinoma or Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 2/20 (10)
 

 N.S.
 

 105
 

 3/20 (15)
 

 N.S.
 

105
 

Low
 

Dose
 

6/48 (13)
 

N.S.
 

1.250
 

0.253
 

12.039
 

93
 

13/48 (27)
 

N.S.
 

1.806
 

0.579
 

9.115
 

93
 

High
 

Dose
 

1/47 (2)
 

N.S.
 

0.213
 

0.004
 

3.909
 

105
 

7/47 (15)
 

N.S.
 

0.993
 

0.261
 

5.532
 

95 
Table Fl. Analyses of

Administered

(continued) 

Topography: Morphology


Hematopoietic System: Malignant
 

Lymphoma (b)


P Values (c,d)


Relative Risk ( f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


o 

00 All Sites: Hemangios arcoma (b)

P Values (c,d)

Relative Risk (f) 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

 the Incidence of Primary Tumors in Male

 2,4,6-Trichlorophenol in the Diet (a) 

 Mice 

Matched 

 Control 

Low 

Dose 

High 

Dose 

 2/20 (10) 3/49 (6) 1/49 (2) 

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

0.612 

0.078 

6.996 

0.204 

0.004 

3.754 

 105 105 105 

 1/20 (5) 5/49 (10) 4/49 (8) 

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

2.041 

0.254 

94.440 

1.633 

0.179 

78.704 

105 102 91 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered 2,4,6-Trichloropheno1 in the Diet (a)
 

(continued)
 

Topography: Morphology


All Sites: Hemangiosarcoma or
 

Hemangioma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Liver: Hepatocellular Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 2/20 (10)
 

 N.S.
 

 105
 

 1/20 (5)
 

 N.S.
 

97
 

Low
 

Dose
 

5/49 (10)
 

N.S.
 

1.020
 

0.188
 

10.204
 

102
 

10/49 (20)
 

N.S.
 

4.082
 

0.655
 

172.772
 

102
 

High
 

Dose
 

5/49 (10)
 

N.S.
 

1.020
 

0.188
 

10.204
 

91
 

7/47 (15)
 

N.S.
 

2.979
 

0.429
 

131.059
 

105
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice

 

Administered 2,4,6-Trichlorophenol in the Diet (a) 

(continued) 

Matched Low High 

Topography; Morphology Control Dose Dose 

Liver: Hepatocellular Carcinoma 

or Adenoma (b) 4/20 (20) 32/49 (65) 39/47 

P Values (c,d) P less than 0.001 P = 0.001 P less 

Relative Risk (f) 3.265 4.149
 

Lower Limit 1.408 1.878
 

Upper Limit 10.877 12.093
 

Weeks to First Observed Tumor 97 102 95
 

(a) Dosed groups received 5,000 or 10,000 ppm.
 

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

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated. Beneath
 

the incidence of tumors in a dosed group is the probability level for the Fisher exact test for
 

the comparison of that dosed group with the matched-control group when P is less than 0.05;
 

otherwise, not significant (N.S.) is indicated.
 

(d) A negative trend (N) indicates a lower incidence in a dosed group than in a control group.
 

(e) The probability level for departure from linear trend is given when P is less than 0.05 for any
 

comparison.
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control group.
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice

 

Administered 2,4,6-Trichlorophenol in the Diet (a) 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

High 

Dose 

Lung: Alveolar /Bronchiolar 

Carcinoma or Adenoma (b) 1/20 (5) 4/50 (8) 3/48 (6) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.600 

0.175 

77.169 

1.250 

0.110 

64.251 

Weeks to First Observed Tumor 105 105 105 

Hematopoietic System:

Lymphoma (b)

 Malignant 

 2/20 (10) 12/50 (24) 7/48 (15) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

2.400 

0.614 

20.902 

1.458 

0.316 

13.664 

Weeks to First Observed Tumor 91 82 35 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice 

Administered 2,4,6-Trichlorophenol in the Diet (a) 

(continued) 

Matched Low High 

Topography: Morphology Control Dose Dose 

All Sites: Hemangios arcoma 

or Hemangioma (b) 1/20 (5) 4/50 (8) 5/50 (10) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 1.600 2.000 

Lower Limit 0.175 0.249 

Upper Limit 77.169 92.596 

Weeks to First Observed Tumor 105 86 105 

Liver: Hepatocellular Carcinoma 

or Adenoma (b) 1/20 (5) 12/50 (24) 24/48 (50) 

P Values (c,d) P less than 0.001 N.S. P less than 0.001 

Relative Risk (f) 4.800 10.000 

Lower Limit 0.803 1.872 

Upper Liit 200.025 394.581 

Weeks to First Observed Tumor 105 105 105 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered 2,4,6-Trichlorophenol in the Diet (a)
 

(continued)
 

Topography: Morphology 

Matched 

Control 

Low 

Dose 

High 

Dose 

Liver: Hepatocellular Carcinoma 

or Adenoma (b) 1/20 (5) 12/50 (24) 24/48 (50) 

P Values (c,d) P less than 0.001 N.S. P less than 0.001 

Relative Risk (f) 

Lower Limit 

Upper Li it 

4.800 

0.803 

200.025 

10.000 

1.872 

394.581 

Weeks to First Observed Tumor 105 105 105 

(a) Dosed groups received time-weighted average doses of 5,214 or 10,428 ppm.
 

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

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated. Beneath
 

the incidence of tumors in a dosed group is the probability level for the Fisher exact test for
 

the comparison of that dosed group with the matched-control group when P is less than 0.05;
 

otherwise, not significant (N.S.) is indicated.
 

(d) A negative trend (N) indicates a lower incidence in a dosed group than in a control group.
 

(e) The probability level for departure from linear trend is given when P is less than 0.05 for any
 

comparison.
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control group.
 
114

 
Review of the Bioassay of 2,4,6-Trichlorophenol* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

December 13, 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 on the Institute's bioassay program to identify and 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, and State health officials.
 

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 2,4,6-Trichlorophenol.
 

The reviewer for the report on the bioassay of 2,4,6-Trichlorophenol agreed with the conclusion that the compound was carcinogenic
 

in both rats and mice. After a brief description of the experimental
 

design, he said that animal survival was adequate. He moved that the
 

report on the bioassay of 2,4,6-Trichlorophenol be accepted as written.
 

The motion was seconded and approved without objection.
 

Clearinghouse Members Present;
 

Arnold L. Brown (Chairman), University of Wisconsin Medical School
 

Joseph Highland, Environmental Defense Fund
 

William Lijinsky, Frederick Cancer Research Center
 

Henry Pitot, University of Wisconsin Medical Center
 

Verne A. Ray, Pfizer Medical Research Laboratory
 

Verald K. Rowe, Dow Chemical USA
 

Michael Shimkin, University of California at San Diego
 

Louise Strong, University of Texas Health Sciences Center
 

Kenneth Wilcox, Michigan State Health Department
 

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.
 

115
 

<TU.S. GOVERNMEN T PRINTIN G OFFICE : 1979-281-217/301 6 
DHEW Publication No. (NIH) 79-1711