1979 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 136 

BIOASSAY OF 

ALDICARB 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 116-06-3 

NCI-CG-TR-136 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

ALDICARB
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20205
 

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

Public Health Service
 

National Institutes of Health
 

NIH Publication No. 79-1391
 

BIOASSAY OF
 

ALDICARB
 

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
 

aldicarb conducted for the Carcinogenesis Testing Program,
 

Division of Cancer Cause and Prevention, National Cancer
 

Institute (NCI), National Institutes of Health, Bethesda,
 

Maryland. This is one of a series of experiments designed to
 

determine whether selected environmental chemicals have the
 

capacity to produce cancer in animals. 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 test and indicates that
 

exposure to the chemical is a potential risk to man. The actual
 

determination of the risk to man from chemicals found to be
 

carcinogenic in animals requires a wider analysis.
 

CONTRIBUTORS; This bioassay of aldicarb was conducted by Gulf
 

South Research Institute (GSRl), New Iberia, Louisiana, initially
 

under direct contract to NCI and currently under a subcontract to
 

Tracor Jitco, Inc., Rockville, Maryland, prime contractor for the
 

NCI Carcinogenesis Testing Program.
 

The experimental design for this bioassay is based on guidelines
 

for carcinogen bioassays in small animals that have been
 

established by NCI (1). The doses for the chronic studies were
 

selected by Drs. E. E. Storrs (2) and 0. G. Fitzhugh (3,4). The
 

principal investigator was Mr. R. J. Wheeler (2). Histologic
 

examination of animal tissues was performed by Drs. E. Bernal (2)
 

and R. A. Ball (2), and the diagnoses included in this report
 

represent the interpretation of these pathologists.
 

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

Mason Research Institute (5). Statistical analyses were performed by Dr. J. R. Joiner (3) and Ms. P. L. Yong (3), using
 

methods selected for the bioassay program by Dr. J. J. Gart (6).
 

Chemicals used in this bioassay were analyzed at Midwest Research
 

Institute under the direction of Dr. E. Murrill (7). Chemicals
 

and dosed food mixtures used in this bioassay were analyzed at
 

GSRI under the direction of Mr. Wheeler. Analyses of the feed
 

mixtures were performed by Mr. M. Billedeau (2) and Mr. J. S.
 

Perrin (2). The results of the analyses were reviewed by Dr. C.
 

W. Jameson (3).
 

This report was prepared at Tracer Jitco (3) 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, Mr.
 

W. D. Reichardt, and Ms. L. A. Owen, Ms. M. S. King, 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. Harry A. Miltnan, Dr. Thomas W.
 

Orme, Dr. A. R. Patel, Dr. Sherman F. Stinson, Dr. Jerrold M.
 

Ward, and Dr. Carrie E. Whitmire.
 

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

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

(2) Gulf South Research Institute, Atchafalaya Basin
 

Laboratories, P. 0. Box 1177, New Iberia, Louisiana.
 

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

Maryland.
 

(4) 4208 Dresden Street, Kensington, Maryland.
 

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

Rockville, Maryland.
 

(6) Mathematical Statistics and Applied Mathematics Section,
 

Biometry Branch, Field Studies and Statistics, Division of
 

iv
 
Cancer Cause and Prevention, National Cancer Institute,
 

National Institutes of Health, Bethesda, Maryland.
 

(7) Midwest Research Institute, 425 Volker Boulevard, Kansas City,
 

Missouri.
 

SUMMARY
 

A bioassay of aldicarb for possible carcinogenicity was conducted 

by administering the test chemical in feed to F344 rats and 

B6C3F1 mice. 

Groups of 50 rats and 50 mice of each sex were administered
 

aldicarb at one of two doses, either 2 or 6 ppm, for 103 weeks
 

and were then observed for an additional 0 to 2 weeks. Matched
 

controls consisted of 25 untreated rats and 25 untreated mice of
 

each sex. All surviving animals were killed at weeks 103 to 105.
 

Mean body weights of the dosed male and female rats were essentially the same as those of the corresponding controls. Mean
 

body weights of the dosed male and female mice also were essentially the same as those of corresponding controls. Hyperactivity
 

was noted in the dosed groups of mice. Survival was not affected
 

significantly in dosed groups of either the rats or the mice and
 

was 72% or greater in all dosed or control groups at week 90.
 

Sufficient numbers of animals were at risk for the development of
 

late-appearing tumors.
 

No tumors occurred in either the rats or mice at incidences that
 

could clearly be related to administration of the test chemical.
 

In both rats and mice, however, there was no indication either
 

through weight depression or early mortality that maximum
 

tolerated dose levels were used. Therefore, the studies may not
 

have been conducted using maximum sensitivity for the assessment
 

of the possible carcinogenicity of aldicarb.
 

It is concluded that under the conditions of this bioassay,
 

technical-grade aldicarb was not carcinogenic for F344 rats or
 

B6C3F1 mice of either sex.
 

vii
 

TABLE OF CONTENTS
 

Page
 

I. Introduction 1
 

II. Materials and Methods 5
 

A. Chemical 5
 

B. Dietary Preparation 6
 

C. Animals 7
 

D. Animal Maintenance 7
 

E. Subchronic Studies 9
 

F. Chronic Studies 12
 

G. Clinical and Pathologic Examinations... 15
 

H. Data Recording and Statistical Analyses 16
 

III. Resul ts - Rats 23
 

A. Body Weights and Clinical Signs (Rats) 23
 

B. Survival (Rats) 23
 

C. Pathology (Rats) 26
 

D. Statistical Analyses of Results (Rats) 27
 

IV. Results - Mice 41
 

A. Body Weights and Clinical Signs (Mice) 41
 

B. Survival (Mice) 41
 

C. Pathology (Mice) 44
 

D. Statistical Analyses of Results (Mice) 45
 

V. Discussion 55
 

VI. Bibliography. 57
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in
 

Rats Administered Aldicarb in the Diet 61
 

Table Al Summary of the Incidence of Neoplasms in
 

Male Rats Administered Aldicarb in the Diet 63
 

Table A2 Summary of the Incidence of Neoplasms in
 

Female Rats Administered Aldicarb in the Diet... 67
 

Appendix B Analyses of the Incidence of Primary Tumors
 

in Mice Administered Aldicarb in the Diet 71
 

ix
 
Table Bl Summary of the Incidence of Neoplasms in 

Male Mice Administered Aldicarb in the Diet.... 73 

Table B2 Summary of the Incidence of Neoplasms in 

Female Mice Administered Aldicarb in the Diet.. 76 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Administered Aldicarb 

in the Diet.... 81 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Administered Aldicarb 

in the Diet 83 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Administered Aldicarb 

in the Diet.... 88 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Administered Aldicarb 

in the Diet 93 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Administered Aldicarb 

in the Diet 95 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Administered Aldicarb 

in the Diet .' 98 

Appendix E Analysis of Formulated Diets for 

Concentrations of Aldicarb. 101 

TABLES 

Table 1 Aldicarb Subchronic Feeding Studies 

in Rats 10 

Table 2 Aldicarb Subchronic Feeding Studies 

in Mice 11 

Table 3 Aldicarb Chronic Feeding Studies in Rats 13 

Table 4 Aldicarb Chronic Feeding Studies in Mice 14 

x
 
Table 5 Analyses of the Incidence of Primary Tumors 

in Male Rats Administered Aldicarb 

in the Diet

Page 

 30 

Table 6 Analyses of the Incidence of Primary Tumors 

in Female Rats Administered Aldicarb 

in the Diet 35 

Table 7 Analyses of the Incidence of Primary Tumors 

in Male Mice Administered Aldicarb 

in the Diet 47 

Table 8 Analyses of the Incidence of Primary Tumors 

in Female Mice Administered Aldicarb 

in the Diet 51 

FIGURES 

Figure 1 Growth Curves for Rats Administered Aldicarb 

in the Diet 24 

Figure 2 Survival Curves for Rats Administered Aldicarb 

in the Diet 25 

Figure 3 Growth Curves for Mice Administered Aldicarb 

in the Diet 42 

Figure 4 Survival Curves for Mice Administered Aldicarb 

in the Diet 43 

xi
 

I. INTRODUCTION
 

CH,H
 

3 I
 I


CH3
 

Aldicarb
 

The carbamate pesticide aldicarb (CAS 116-06-3; NCI C08640), which
 

is 2-methyl-2-(methylthio)propionaldehyde O-(methylcarbamoyl)­

oxime, is used for the control of insects, nematodes, and mites
 

(Kuhr and Borough, 1976). It is now registered for use on
 

cotton, sugar beets, sugar cane, potatoes, peanuts, and a variety
 

of field- and nursery-grown ornamental plants (Environmental
 

Protection Agency, 1975). The commercial product contains from 5
 

to 15% of the active ingredient adsorbed to organic granules. As
 

a systemic pesticide, it is applied below the soil surface for
 

absorption by plant roots (Environmental Protection Agency, 1975;
 

Kuhr and Dorough, 1976). Aldicarb ranked fourth among the
 

carbamate insecticides in terms of the volume expended for
 

agricultural purposes in 1974, which was 1.6 million pounds
 

(Ayers and Johnson, 1976).
 
Aldicarb has a half-life of 9 to 12 days in soil under laboratory
 

conditions, being rapidly converted to aldicarb sulfoxide. This
 

sulfoxide derivative is the major metabolite and is more
 

persistent than aldicarb. In one experiment, as much as 50% of
 

35
 radioactivity applied as S aldicarb was recovered in the
 

sulfoxide in sand in the laboratory after 12 weeks (Coppedge et
 

al., 1967). Under field conditions, however, aldicarb was
 

completely metabolized within 1 week, and the sulfoxide was lost
 

after about 4 weeks (Bull, 1968). This pattern has been
 

confirmed in another study of the fate of aldicarb, where the
 

half-life of aldicarb and all toxic metabolites was reported to
 

be greater than 8 weeks in the laboratory, and less than 1 week
 

in the field (Bull et al., 1970). Carbon dioxide is the final
 

product of degradation (Richey et al., 1977).
 

Aldicarb is highly toxic to rodents by both oral and dermal
 

routes, the acute oral LD,-0 being in the range of 0.8 mg/kg in
 

male Sherman rats, 0.65 mg/kg in female Sherman rats (Gaines,
 

1969), and 1 mg/kg in female rats of an unspecified strain
 

(Weiden et al., 1965), whereas the dermal LD,-,, is 3 and 2.5
 

mg/kg in male and female Sherman rats, respectively (Gaines,
 

1969). The acute oral LD,-n of aldicarb for male Swiss white
 

mice has been reported as 0.3 to 0.5 mg/kg (Black et al., 1973).
 

Thirteen-week feeding studies indicated that a dose of 0.5 mg/kg
 
body weight/day in the diet increased significantly the mortality
 

in CFE rats (Weil and Carpenter, 1969), although 2-year feeding
 

studies indicated that a dose of 0.3 mg/kg body weight/day
 

administered to Greenacres Laboratory Controlled Flora rats
 

caused no adverse effects (Weil, 1975).
 

The mode of action of aldicarb is cholinesterase inhibition
 

(Ryan, 1971; Koelle, 1975). Aldicarb -,ulf oxide, the major
 

metabolite, has 76 times greater anticholinesterase activity than
 

the parent compound and is believed to be the active form of the
 

pesticide, since it is considerably more persistent in plants
 

(Metcalf et al., 1966). Neither aldicarb nor aldicarb sulfoxide
 

was toxic for Greenacres Laboratory Controlled Flora rats in
 

2-year feeding studies at a dose of 0.3 mg/kg/day; however,
 

aldicarb sulfoxide caused some deaths in the females at a dose of
 

0.6 mg/kg/day (Weil, 1975). In mosquitoes, the sulfoxide was
 

less toxic than the parent compound (Metcalf et al., 1966).
 

Aldicarb was one of many pesticides that were selected for study
 

by the Careinogenesis Bioassay Program.
 

II. MATERIALS AND METHODS
 

A. Chemical
 

Aldicarb was obtained in a single batch (Lot No. RDS-643-D) as
 

the technical-grade material from Union Carbide Corporation, New
 

York, New York. The identity and purity of this batch was
 

confirmed in analysis at Gulf South Research Institute. The
 

melting point was 96 to 98°C (Windholz, 1976: 99 to 100°C).
 

Thin-layer and gas-liquid chromatography indicated no impurities
 

and conformed to the manufacturer's specification of 99 % for
 

the technical-grade material. Elemental analyses (C, H, N, S)
 

were correct for C H..N-0 S, the molecular formula of
 

aldicarb. Nuclear magnetic resonance and infrared spectra agreed
 

with those reported in the literature (Sadtler Standard Spectra,
 

Sadtler Laboratories, Philadelphia, Pa.; Kieth et al., 1970).
 

Upon completion of the bioassay this lot of aldicarb was
 

reanalyzed by Midwest Research Institute. Analysis by gas-liquid
 

and high-pressure liquid chromatography and infrared spectrometry
 

indicated that this material had not changed under storage
 

conditions for approximately 4 years.
 
B. Dietary Preparation
 

All diets were formulated using Wayne Lab Blox Meal (Allied
 

Mills, Inc. Chicago, 111.) to which was added the required amount
 

of aldicarb for each dietary concentration. The test compound
 

was first dissolved in a small amount of acetone (Mallinckrodt
 

Inc., St. Louis, Mo.) which was then added to the feed. Corn oil
 

(LouAna®, Opelousas Refinery Co., Opelousas, La.) was also
 

added to the feed, primarily as a dust suppressant, and the diets
 

were mixed mechanically for not less than 25 minutes to assure
 

homogeneity and to allow for evaporation of the acetone. Final
 

diets, including those for the control groups of animals,
 

contained corn oil equal to 2% of the final weight of feed.
 

Formulated diets were stored at ambient room temperature until
 

used, but not longer than 1 week*
 

The stability of aldicarb in feed was tested at Midwest Research
 

Institute by determining the concentration of the compound in
 

formulated diets at intervals over a 7-day period. Diets
 

containing 39 and 7 ppm aldicarb showed no significant change in
 

aldicarb concentration on standing at ambient temperature for
 

this period-


As a quality control check on the accuracy of preparation of the
 
diets, the concentration of aldicarb was measured in randomly
 

selected batches of formulated diets at 8-week intervals during
 

the chronic study. Results are summarized in Appendix E. At
 

each dietary concentration, the mean of the analytical
 

concentrations for the checked samples was within 11% of the
 

theoretical concentration, -md the coefficient of variation was
 

never more than 0.20.
 

C. Animals
 

F344 (Fischer) rats and B6C3F1 hybrid mice of each sex were
 

obtained from the NCI Frederick Cancer Research Center
 

(Frederick, Md.). The rats were 8 weeks of age and the mice 6
 

weeks of age when placed on study.
 

D. Animal Maintenance
 

The rats were housed individually in hanging galvanized steel
 

mesh cages (Hoeltge, Cincinnati, Ohio), and the mice were housed
 

five per cage in polypropylene cages (Lab Products, Inc.,
 

Garfield, N.J.). The mouse cages were covered with polyester
 

filter bonnets (Lab Products, Inc.), and the filter bonnets were
 
sanitized once per week. The cages for the rats were sanitized
 

every 2 weeks, and those for the mice were sanitized twice per
 

week. Cages and racks were washed in an industrial washer
 

(Industrial Washing Machine Corp., Matawan, N.J.) at 82°C with
 

. ®
 Acclaim detergent (Economics Laboratory, Inc., St. Paul,
 

Minn.) and then rinsed. Absorbent Kimpak cage liners
 

(Kimberly Clark Corp., Neenah, Wis-) were placed under the rat
 

cages and were changed twice per week. Absorb-dri hardwood
 

chip bedding (Lab Products, Inc.) was used in the mouse cages and
 

was changed twice per week. Feed jars, water bottles, sipper
 

tubes, and stoppers were sanitized twice per week. The filter
 

bonnets, feed jars, water bottles, sipper tubes, and stoppers
 

were washed in a Vulcan Autosan washer (Louisville, Ky.) at
 

82 C, using Acclaim detergent, and then rinsed.
 

Cage racks for each species were rotated to a new position in the
 

room once per week; at the same time, each cage was moved to a
 

different row within the same column of a rack. Rats and mice
 

were housed in separate rooms. Control and dosed rats were
 

housed on the same rack, whereas cages for control and dosed mice
 

were placed in separate racks in the same room. Aldicarb was the
 

only compound on test in each room.
 

The animal rooms were maintained at 22 to 24 C, and the relative
 
humidity was 40 to 70%. The air was filtered through permanent
 

air maze filters (Air Maze Incom International, Cleveland, Ohio)
 

and was changed 10 to 12 times per hour. Fluorescent lighting
 

provided illumination 10 hours per day. Food and tap water were
 

provided ad libitum. Fresh feed was provided twice per week, and
 

any feed remaining from the previous day was discarded.
 

E. Subchronic Studies
 

Subchronic feeding studies were conducted to estimate the maximum
 

tolerated doses (MTD's) of aldicarb 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 10 rats and 10 mice of each sex were administered diets
 

containing aldicarb at one of several doses for 13 weeks, and
 

groups of 10 control animals of each species and sex were
 

administered basal diet only. The animals were weighed once per
 

week. Tables 1 and 2 show the doses given, the survivals of
 

animals in each dosed group at the end of the study, and the mean
 

body weights of the dosed groups of animals at week 13, expressed
 

as percentages of mean body weights of corresponding controls.
 

At the end of the 13 weeks, all surviving animals were killed and
 
Table 1. Aldicarb Subchronic Feeding Studies in Rats
 

Male Female
 

Mean Weight Mean Weight
 

at Week 13 at Week 13
 

Dose as % of as % of
 

(ppm) Survival (a) Control Survival(a) Control
 

0 (b, c) 10/10 100 10/10 100
 

5 10/10 100 10/10 101
 

10 10/10 100 10/10 105
 

20 10/10 95 10/10 97
 

40 10/10 84 9/10 90
 

80 (b) 10/10 68 10/10 81
 

160 0/10 0/10
 

320 0/10 0/10
 

(a) Number surviving/number in group.
 

(b) Microscopic examination was performed on tissues of 10 male
 

and 10 female controls and on 8 male and 8 female animals
 

dosed at 80 ppm.
 

(c) One female control had mild centrilobular fatty degeneration
 

and another had mild periportal parenchymatous degeneration
 

of the liver.
 

10
 
Table 2. Aldicarb Subchronic Feeding Studies in Mice
 

Male Female
 

Mean Weight Mean Weight
 

at Week 13 at Week 13
 

Dose as % of as % of
 

(ppm) Survival (a) Control Survival (a) Control
 

0 (b) 10/10 100 10/10 (c) 100
 

0.5 10/10 94 10/10 97
 

1 10/10 91 10/10 94
 

2.5 10/10 91 10/10 94
 

5 10/10 88 10/10 94
 

10 10/10 91 10/10 94
 

20 (b) 10/10 93 10/10 96
 

40 (b) 10/10 95 9/10 (d) 96
 

(a) Number surviving/number in group.
 

(b) Microscopic examination was performed on 10 male and 10
 

female controls, on 10 males and 8 females dosed at 20 ppm,
 

and on 8 males and 10 females dosed at 40 ppm.
 

(c) All control female mice showed diffuse parenchymatous
 

degeneration of the liver, which was confirmed by a second
 

set of microscopic sections. Sections showed a diffuse
 

involvement of hepatocytes throughout the lobule. The cells
 

were somewhat swollen in appearance and contained coarsely
 

granular eosinophilic material.
 

One female control had benign teratoma of the ovary.
 

(d) The left ovary of one female dosed at 40 ppm had a large,
 

encapsulated mass with a lobular surface, and dark-brown
 

diffusely scattered foci on the cut surface. It was
 

diagnosed as a benign teratoma. Another female dosed at 40
 

ppm showed mild diffuse fatty degeneration of the liver.
 

11
 
necropsied. Gross and histopathologic findings are given as
 

footnotes in tables 1 and 2.
 

All rats died at doses of 160 or 320 ppm, and mean weights
 

decreased at doses of 40 or 80 ppm. The data for the mice showed
 

no effects clearly related to administration of aldicarb at any
 

of the doses tested.
 

In a 13-week feeding study reported previously (Weil and
 

Carpenter, 1969), mortality increased in male and female CFE rats
 

administered aldicarb at 0.5 mg/kg body weight/day (considered by
 

the laboratory to be about 10 ppm), but was not significantly
 

increased in the rats administered 0.1 mg/kg body weight/day.
 

Doses for the chronic studies of aldicaru in both rats and mice
 

were set at 2 and 6 ppm.
 

F. Chronic Studies
 

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

feeding studies are shown in tables 3 and 4.
 

12
 
Table 3. Aldicarb Chronic Feeding Studies in Rats
 

Sex and Initial Aldicarb Time on Study
 

Test No. of Doses (b) Dosed Observed
 

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

Male
 

Matched-Control 25 0 105
 

Low-Dose 50 2 103 2
 

High-Dose 50 6 103 2
 

Female
 

Matched-Control 25 0 105
 

Low-Dose 50 2 103 2
 

High-Dose 50 6 103 2
 

(a) Rats were 8 weeks of age when placed on study.
 

(b) Test and control diets were provided ad libitum.
 

13
 
Table 4. Aldicarb Chronic Feeding Studies in Mice
 

Sex and Initial Aldicarb Time on Study
 

Test No. of Doses (b) Dosed Observed
 

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

Male
 

Matched-Control 25 0 103-104
 

Female
 

Matched-Control 25 0 103-104
 

Low-Dose 50 2 103 0-1
 

High -Dose 50 6 103 0-1
 

Low-Dose 50 2 103 0-1
 

High-Dose 50 6 103 0-1
 

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

(b) Test and control diets were provided ad libitum.
 

14
 
G. Clinical and Pathologic Examinations
 

All animals were observed twice daily. Clinical examination for
 

signs of toxicity and palpation for masses were performed each
 

month, and the animals were weighed every 2 weeks. Moribund
 

animals and animals that survived to the end of the bioassay were
 

killed using pentobarbitol and necropsied.
 

The pathologic evaluation consisted of gross and microscopic 

• 

examination of major tissues, major organs, and all gross 

lesions. The following tissues were examined microscopically:
 

skin, lungs and bronchi, trachea, bone and bone marrow, spleen,
 

lymph nodes, heart, salivary gland, liver, gallbladder (mice),
 

pancreas, stomach, small intestine, large intestine, kidney,
 

urinary bladder, pituitary, adrenal, thyroid, parathyroid,
 

mammary gland, prostate or uterus, testis or ovary, and brain.
 

Occasionally, additional tissues were also examined
 

microscopically. The tissues were preserved in neutral buffered
 

10% formalin, embedded in paraffin, sectioned, and stained with
 

hematoxylin and eosin. Special staining techniques were utilized
 

when indicated for more definitive diagnosis. Blood smears of
 

all animals were routinely prepared.
 

Necropsies were also performed on all animals found dead, unless
 

15
 
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.
 

H. Data Recording and Statistical Analyses
 

Pertinent data on this experiment have been recorded 'in an
 

automatic data processing system, the Careinogenesis 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.
 

16
 
Probabilities of survival were estimated by the product-limit
 

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

report in the form of graphs. Animals were statistically
 

censored as of the time that they died of other than natural
 

causes or were found to be missing; animals dying from natural
 

causes were not statistically censored. Statistical analyses for
 

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

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

extensions of Cox's 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.
 

17
 
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
 

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.
 

18
 
A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation
 

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

first tumor was observed were excluded by basing the statistical
 

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

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

such an early tumor was found, comparisons were based exclusively
 

on animals that survived at least as long as the animal in which
 

the first tumor was found. Once this reduced set of data was
 

obtained, the standard procedures for analyses of the incidence
 

of tumors (Fisher exact tests, Cochran-Armitage tests, etc.) were
 

followed.
 

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

incidence of tumors. Curves of the proportions surviving without
 

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

The week during which 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.
 

19
 
Significant departures from linearity (P less than 0.05,
 

two-tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared to its control was calculated
 

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

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

binomial probability of the incidence of a specific type of tumor
 

in a 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
 

20
 
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 greater than unity, the lower 

limit indicates the absence of a significant result while the 

upper limit indicates that there is a theoretical possibility of 

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

detected under the conditions of this test. 

21 

III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

Mean body weights of the dosed male and female rats were
 

essentially the same as those of the corresponding controls
 

(figure 1). Tachypnea occurred in dosed groups but not in
 

control groups.
 

B. Survival (Rats)
 

Estimates of the probabilities of survival for male and female
 

rats administered aldicarb in the diet at the doses of this
 

bioassay, together with those for the matched controls, are shown
 

by the Kaplan and Meier curves in figure 2. In each sex, the
 

result of the Tarone test for positive dose-related trend in
 

mortality is not significant. In male rats, an indicated
 

departure from linear trend (P = 0.013) is observed because the
 

low-dose male rats survived longer than either the high-dose or
 

the control rats.
 

In male rats, 39/50 (78%) of the high-dose group, 44/50 (88%) of
 

23
 
Z 300­

(9 

a 

o 

03 

MALE RATS 

D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

10 20 40 60 60

 100 110 

TIME ON STUDY (WEEKS) 

500­

}Ay

iaf Z 

O 

Ul 

a 

2 200­

6° 

A* 5 150­ O

§ FEMALE RATS 

100|| D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

TIME ON STUDY (WEEKS) 

Figure 1. Growth Curves for Rats Administered Aldicarb in the Diet 

24 
f

PROBABILITY OF SURVIVAL PROBABILITY OF 

1 1; ' i 

_ * 

E

; iS 5 8; t3 J> i5 !? ii 13 ; 5 i5 i; 

* £ 3! o- —r oe 1;

o­ r*** o­ > 0 Ci I­ > 0 C

 

m 1

 E S r i

i » - I. s- s1

i-

­

III 8 ^ S m ^TM w m O ni 1. 

cs g a I' 0 > > J m

H

1 «- 5 8- cn ^ oi- o

0 H H

i«- ! 

i S°' ^ 

0 o 0 

z

« S- n. 2 

3 5 cV c

o a ° 

Si' i 8- « S­ 

s 

70

 

WEEKS) 

i S, > 2° 

IP 

8 m - 

3-

° 

nJ 

5' >5 

8­ i •• c JnftSRq> -• >fs^ 

a 

* §- 8- 

t ...>

8°'^Q Ir% 
the low-dose group, and 18/25 (72%) of the control group were
 

still alive at week 90 on study. In females, 46/50 (92%) of the
 

high-dose group, 44/50 (88%) of the low-dose group, and 24/25
 

(96%) of the control group were still alive at week 90 on study.
 

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

development of 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.
 

A variety of neoplasms occurred in both dosed and control
 

animals. The majority were thought not to be compound related.
 

In the males, neoplastic nodules occurred in the livers of 1/24
 

(4%) controls, 1/47 (2%) low-dose animals, and 5/48 (10%)
 

high-dose animals. One hepatocellular carcinoma was observed in
 

the low-dose male group. No hepatic neoplasms were observed in
 

the females. Focal cellular change was found in the livers of
 

2/24 (8%) of the control males, 4/47 (9%) of the low-dose males,
 

26
 
and 6/48 (13%) of the high-dose males. In the females, the
 

incidences of this lesion were 4/25 (16%) in control, 4/48 (8%)
 

in low-dose, and 5/50 (10%) in high-dose groups.
 

Pancreatic islet-cell adenomas occurred in dosed groups of males
 

(low-dose 5/49 (10%); high-dose 6/48 (13%)) and females (low-dose
 

2/49 (4%); high-dose 2/50 (4%)), but in none of the male or
 

female controls.
 

This histopathologic examination provided no conclusive evidence
 

for the carcinogenicity of aldicarb in P344 rats under the
 

conditions of this bioassay. However, the occurrences of hepatic
 

neoplasms in the dosed male rats and pancreatic islet-cell
 

adenomas in both dosed males and both females were regarded as
 

compound related.
 

D. Statistical Analyses of Results (Rats)
 

Tables 5 and 6 contain the statistical analyses of the incidences
 

of those primary tumors that occurred in at least two animals in
 

one group and with an incidence of at least 5% in one or more
 

than one group.
 

27
 
In male rats, the result of the Cochran-Armitage test for
 

positive dose-related trend in the incidence of interstitial-cell
 

tumor of the testis is significant (P = 0.010), and the Fisher
 

exact test shows that the high-dose incidence is significantly (P
 

= 0.014) higher than that in the control group. However, the
 

incidence of this tumor in F344 control male rats of this
 

laboratory is 220/275 (80%) compared with 18/24 (75%) in the
 

control groups, 43/49 (88%) in the low-dose group, and 46/48
 

(96%) in the high-dose group of this study.
 

In females, the result of the Cochran-Armitage test for the
 

incidence of animals with either adenoma or carcinoma of the
 

pituitary is significant (P = 0.048), but the results of the
 

Fisher exact tests are not significant. The historical records
 

of this laboratory show an incidence of 114/273 (42%), compared
 

with 14/25 (56%) in the control group, 33/48 (69%) in the
 

low-dose group, and 37/48 (77%) in the high-dose group of this
 

s tudy.
 

The results of the statistical test on the incidence of
 

islet-cell adenomas of the pancreas in male rats are not
 

significant. The incidence of these tumors in male F344
 

historical-control rats at this laboratory is 23/275 (8.4.%),
 

compared with 0/24 in the control group, 5/49 (10%) in the
 

28
 
low-dose group and 6/48 (13%) in the high-dose group of this
 

study. The incidence of these tumors in the control group of
 

male rats in this study is lower than would be expected from the
 

historical information.
 

Significant results in the negative direction are observed in the
 

incidence of pituitary tumors in male rats and in the incidence
 

of leukemia in female rats.
 

In each of the 95% confidence intervals for relative risk, except
 

that for the incidence of testis tumors in the high-dose males,
 

the value of one is included; this indicates the absence of
 

significant positive results. It should also be noted that each
 

of the intervals has an upper limit greater than one, indicating
 

the theoretical possibility of tumor induction by aldicarb, which
 

could not be detected under the conditions of this bioassay.
 

29
 
Table 5. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Aldicarb in the Diet (a)
 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

High 

Dose 

Lung: Alveolar/Bronchiolar Adenoma (b) 1/22 (5) 2/49 (4) 3/48 (6) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.898 

0.050 

51.910 

1.375 

0.120 

70.655 

Weeks to First Observed Tumor 105 91 98 

oo 

o 

Hematopoietic System: Leukemia (b) 2/24 (8) 5/49 (10) 8/48 (17) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.224 

0.222 

12.283 

2.000 

0.446 

18.398 

Weeks to First Observed Tumor 100 100 97 
Table 5. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Aldicarb in the Diet (a)
 

1 «-oni-imied) -

Topography: Morphology

 Matched 

 Control 

Low 

Dose 

High 

Dose 

Liver: Neoplastic Nodule or 

Hepatocellular Carcinoma (b) i/M \*> 1/47 (2) 5/48 (10) 

P Values

/ ,\ (c,d) KN S'

b

' N.S. N.S. 

Relative Risk 

Lower

Upper

 Limit 

 Limit 

0.511 

0.007 

39.263 

2.500 

0.306 

115.634 

Weeks to First Observed Tumor 105 105 103 

Pituitary: Adenoma or Carcinoma, 8/2°

 (40) 10/43 (23) 6/43 (14) NOS (b)

N.S. P = 0.026 (N) P °'021 (N) P Values (c.d) =

0.581 0.349 

Relative Risk (f) 0.256 0.121 

Lower Limit __ — • » - 1.466 1.004 

96 68
 96
 

Weeks to First Observed Tumor
 
__ 

Table 5. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Aldicarb in the Diet (a)
 

(continued)
 

Matched Low
 

Topography ; Morphology Control Dose
 

Thyroid: C-cell Carcinoma (b) 0/22 (0) 0/48 (0)
 

P Values (c,d) N.S.
 —
 

Relative Risk (f)
 

Lower Limit
 —
 Upper Limit
 —
 

Weeks to First Observed Tumor
 —
 

NO Thyroid: C-cell Carcinoma
 

or Adenoma (b) 2/22 (9) 3/48 (6)
 

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

Relative Risk (f) 0.688
 

Lower Limit 0.086
 

Upper Limit 7.863
 

Weeks to First Observed Tumor 105 105
 

High
 

Dose
 

2/39 (5)
 

N.S.
 

Infinite
 

0.172
 

Infinite
 

64
 

2/39 (5)
 

N.S.
 

0.564
 

0.044
 

7.391
 

64
 
Table 5. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Aldicarb in the Diet (a)
 

(continued)
 

Topography: Morphology


Pancreatic Islets: Islet-cell
 

Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Testis: Interstitial-cell Tumor (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Low 

 Control Dose 

 0/24 (0) 5/49 (10) 

 N.S. N.S. 

Infinite 

0.636 

Infinite 

103 

 18/24 (75) 43/49 (88) 

P = 0.010 N.S. 

1.170 

0.915 

1.527 

89 75 

High
 

Dose
 

6/48 (13)
 

N.S.
 

Infinite
 

0.824
 

Infinite
 

96
 

46/48 (96)
 

P = 0.014
 

1.278
 

1.020
 

1.466
 

66
 
Table 5. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Aldicarb in the Diet (a)
 

(continued)
 

(a) Dosed groups received 2 or 6 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 6. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Aldicarb in the Diet (a)
 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

High 

Dose 

Hematopoietic System: Leukemia (b) 4/25 (16) 6/50 (12) 1/50 (2) 

P Values (c,d) P = 0.017 (N) N.S. P = 0.040 (N) 

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.750 

0.200 

3.353 

0.125 

0.003 

1.189 

Weeks to First Observed Tumor 90 55 105 

Pituitary: Carcinoma, NOS (b) 1/25 (4) 0/48 (0) 3/48 (6)
 

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

Relative Risk (f) 0.000 1.563
 

Lower Limit 0.000 0.135
 

Upper Limit 9.720 80.296
 

Weeks to First Observed Tumor 91 — 105
 
Table 6. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Aldicarb in the Diet (a)
 

(continued)
 

Matched Low High 

Topography; Morphology Control Dose Dose 

Pituitary: Adenoma or Carcinoma, 

NOS (b) 14/25 (56) 33/48 (69) 37/48 (77) 

P Values (c,d) P = 0.048 N.S. N.S. 

Relative Risk (f) 1.228 1.376 

Lower Limit 0.825 0.944 

Upper Limit 1.959 2.103 

Weeks to First Observed Tumor 90 86 78 

Thyroid: C-cell Adenoma (b) 1/24 (4) 2/44 (5) 3/47 (6)
 

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

Relative Risk ( f) 1.091 1.532
 

Lower Limit 0.061 0.133
 

Upper Limit 62.902 78.688
 

Weeks to First Observed Tumor 105 105 92
 
Table 6. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Aldicarb in the Diet (a)
 

(continued)
 

Topography; Morphology


Mammary Gland or Mammary Duct:
 

Carcinoma, NOS, or Adeno carcinoma,
 

NOS (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Fibroadenoma
 

or Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Low 

 Control Dose 

 0/25 (0) 2/50 (4) 

 N.S. N.S. 

Infinite 

0.151 

Infinite 

91 

 4/25 (16) 8/50 (16) 

 N.S. N.S. 

1.000 

0.303 

4.197 

91 82 

High
 

Dose
 

3/50 (6)
 

N.S.
 

Infinite
 

0.309
 

Infinite
 

5/50 (10)
 

N.S.
 

0.625
 

0.150
 

2.928
 

102
 

92 
Table 6. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Aldicarb in the Diet (a)
 

(continued)
 

Matched Low High
 

Topoj>raj>hy: Morphology Control Dose Dose
 

Uterus: Endometrial Stromal Polyp (b) 9/24 (38) 9/47 (19) 15/49 (31)
 

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

Relative Risk (f) 0.511 0.816
 

Lower Limit 0.215 0.406
 

Upper Limit 1.276 1.838
 

Weeks to First Observed Tumor 79 72 91
 

u> Adipose Tissue: Lipoma (b) 0/25 (0) 3/50 (6) 1/50 (2)
 

oo
 

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

Relative Risk (f) Infinite Infinite
 

Lower Limit 0.309 0.027
 

Upper Limit Infinite Infinite
 

Weeks to First Observed Tumor 96 105
 
Table 6. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Aldicarb in the Diet (a)
 

(continued)
 

(a) Dosed groups received 2 or 6 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.
 

w	 (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.
 

IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

Mean body weights of the dosed male and female mice were essentially the same as those of corresponding controls (figure 3).
 

Hyperactivity was reported for the dosed groups of mice.
 

B. Survival (Mice)
 

Estimates of the probabilities of survival for male and female
 

mice administered aldicarb in the diet at the doses of this
 

bioassay, together with those for the matched controls, are shown
 

by the Kaplan and Meier curves in figure 4. In each sex, the
 

result of the Tarone test for dose-related trend in mortality is
 

not significant.
 

In male mice, 45/50 (90%) of the high-dose group, 48/50 (96%) of
 

the low-dose group, and 21/25 (84%) of the matched-control group
 

were still alive at week 90 on study. In females, 44/50 (88%) of
 

the high-dose group, 45/50 (90%) of the low-dose group, and 19/25
 

41
 
a a

-oao

o

0 aaaoa a D 0?A' aaooaooo DA anaAD noooa 

 oo AAO o a oao no 

AO .a 

u 

>

O 

O 

a 

i 

2 

MALE MICE 

D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

40 50 60 70 80 90 100 110 

TIME ON STUDY (WEEKS) 

aa aa aaai 

ago a oaa oo 

ggagSogoA^oo^00* 

(9 AOQC 

I"

a

o

a 20 

2 

s

 15 

( 

FEMALE MICE 

D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

40 BO 60 70 

TIME ON STUDY (WEEKS) 

Figure 3. Growth Curves for Mice Administered Aldicarb in the Diet 

42 
PROBABILITY OF SURVIVAL PROBABILITY O

8 § 8 § is 

3­ > o a 

I r S 

i

 § » S­ H o x m i S 3 

o S " "0 

0 g- H m a 

Oi­

8 

> 

a. u> 

5' 

> 2 

S S- 

8- 

co 

a 

S 

-

5 

* 

^ 
(76%) of the matched-control group were still alive at week 90 on
 

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.
 

A variety of benign and malignant tumors occurred at different
 

anatomic sites in dosed and control mice. In general, these
 

tumors are not unusual and occur in B6C3F1 mice independent of
 

administration of any test chemical. The majority of neoplasms
 

occurred at approximately the same incidence in dosed and control
 

groups. However, the incidence of benign and malignant tumors of
 

the liver (hepatocellular adenomas and hepatocellular carcinomas)
 

in males, but not in females, was somewhat greater in the low-


and high-dose groups that in the control group, as shown in the
 

following table:
 

44
 
Male Female 

Low High Low High 

Control Dose Dose Control Dose Dose 

Number of Animals
 

with Tissues
 

Examined
 

Microscopically 24 49 49 25 49
 48
 

Hepatocellular
 

Carcinoma 4(17%) 10(20%) 13(27%) 3(12%) 0(0%) 4(8%)
 

Hepatocellular
 

Adenoma 1(4%) 4(8%) 5(10%) 0(0%) 0(0%) 0(0%)
 

Animals Bearing
 

Liver Tumors 5(21%) 14(29%) 18(37%) 3(12%) 0(0%) 4(8%)
 

Based on the histopathologic examination, the evidence was not
 

sufficient to indicate a carcinogenic effect of aldicarb in
 

B6C3F1 mice under the conditions of this bioassay.
 

D. Statistical Analyses of Results (Mice)
 

Tables 7 and 8 contain the statistical analyses of the incidences
 

of those primary tumors that occurred in at least two animals in
 

one group and with an incidence of at least 5% in one or more
 

than one group.
 

In male mice, the result of the Cochr an-Armit age test for
 

positive dose-related trend in the incidence of animals with
 

either fibresarcoma or sarcoma of the subcutaneous tissue in the
 

45
 
integumentary system is significant (P = 0.043), but the results
 

of the Fisher exact test are not significant. In females, the
 

results of the Cochran-Armitage test and Fisher exact test are
 

not significant in the positive direction.
 

In each of the 95% confidence intervals for the relative risk,
 

shown in the tables, the value of one or less than one is 

included; this indicates the absence of significant positive 

results. It should also be noted that each of the intervals 

(except that for the incidence of hepatocellular carcinoma in
 

low-dose female mice) has an upper limit greater than one,
 

indicating the theoretical possibility of the induction of tumors
 

by aldicarb, which could not be detected under the conditions of
 

this test.
 

46
 
Table 7. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Aldicarb in the Diet (a)
 

Topography: Morphology


Integumentary System: Fibrosarcoma
 

or Sarcoma, NOS, of the Subcutaneous
 

Tissue (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Lung: Alveolar /Bronchiolar Adenoma
 

or Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Low 

 Control Dose 

 0/24 (0) 1/50 (2) 

P = 0.043 N.S. 

Infinite 

0.026 

Infinite 

104 

 1/24 (4) 6/49 (12) 

 N.S. N.S. 

2.939 

0.392 

132.164 

104 103 

High
 

Dose
 

4/49 (8)
 

N.S.
 

Infinite
 

0.467
 

Infinite
 

94
 

5/48 (10)
 

N.S.
 

2.500
 

0.306
 

115.634
 

104
 
Table 7. Analyses of the Incidence of Primary Tumors in Male Mice 

Administered Aldicarb

(continued) 

Matched
 

Topography: Morphology Control
 

Hematopoietic System: Lymphoma
 

or Leukemia (a) 1/24 (4)
 

P Values (c,d) N.S.
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 95
 

oo 

All Sites: Hem angiosar coma or 

Angiosarcoma (b) 0/24 (0) 

P Values (c,d) N.S.
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 

 in the Diet (a) 

Low
 

Dose
 

3/50 (6)
 

N.S.
 

1.440
 

0.125
 

74.077
 

60
 

3/50 (6)
 

N.S.
 

Infinite
 

0.297
 

Infinite
 

97 

High
 

Dose
 

2/49 (4)
 

N.S.
 

0.980
 

0.054
 

56.627
 

104
 

3/49 (6)
 

N.S.
 

Infinite
 

0.303
 

Infinite
 

61 
Table 7. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Aldicarb in the Diet (a)
 

(continued)
 

Topography : Morphology


Liver: Hepatocellular Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Liver: Hepatocellular Adenoma or
 

Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 4/24 (17)
 

 N.S.
 

 64
 

 5/24 (21)
 

 N.S.
 

64
 

Low
 

Dose
 

10/49 (20)
 

N.S.
 

1.224
 

0.405
 

4.919
 

79
 

14/49 (29)
 

N.S.
 

1.371
 

0.544
 

4.389
 

79
 

High
 

Dose
 

13/49 (27)
 

N.S.
 

1.592
 

0.567
 

6.133
 

85
 

18/49 (37)
 

N.S.
 

1.763
 

0.740
 

5.436
 

85
 
Table 7. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Aldicarb in the Diet (a)
 

(continued)
 

(a) Dosed groups received 2 or 6 ppm.
 

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

(c) Number of tumor-bearing 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 8. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Aldicarb in the Diet (a)
 

Topography ; Morphology
 

Lung: Alveolar/Bronchiolar Adenoma
 

or Carcinoma (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Lymphoma or
 

Leukemia (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Low 

Control Dose 

1/25 (4) 4/50 (8) 

N.S. N.S. 

2.000 

0.215 

96.452 

103 98 

6/25 (24) 8/50 (16) 

N.S. N.S. 

0.667 

0.233 

2.114 

67 23 

High
 

Dose
 

1/50 (2)
 

N.S.
 

0.500
 

0.007
 

38.493
 

104
 

10/50 (20)
 

N.S.
 

0.833
 

0.318
 

2.519
 

71
 
Table 8. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Aldicarb in the Diet (a)
 

(continued)
 

Topography: Morphology


Liver: Hepatocellular Carcinoma (b)


P Values (c,d)


Departure from Linear Trend (e)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


N>
 

Pituitary: Adenoma, NOS (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 3/25 (12)
 

 N.S.
 

P = 0.021
 

 104
 

 2/21 (10)
 

 N.S.
 

94
 

Low
 

Dose
 

0/49 (0)
 

P = 0.035 (N)
 

0.000
 

0.000
 

0.843
 

—
 

3/40 (8)
 

N.S.
 

0.788
 

0.099
 

8.941
 

104
 

High
 

Dose
 

4/48 (8)
 

N.S.
 

0.694
 

0.129
 

4.461
 

98
 

2/43 (5)
 

N.S.
 

0.488
 

0.038
 

6.417
 

104
 
Table 8. Analyses of the Incidence of Primary Tumors in Female Mice 

Administered Aldicarb in the Diet (a) 

(continued) 

(a) Dosed groups received 2 or 6 ppm. 

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

(c) Number of tumor-bearing tumors in the control group is the probability level for the CochranArmitage 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. 

V. DISCUSSION
 

Mean body weights of the dosed male and female rats were essentially
 

the same as those of the corresponding controls. Mean body weights
 

of the dosed male and female mice also were essentially the same as
 

those of corresponding controls. Tachypnea was reported for the
 

dosed groups of rats and hyperactivity for the dosed groups of
 

mice. Survival was not affected significantly in dosed groups of
 

either the rats or the mice and was 72% or greater in all dosed or
 

control groups at week 90. These findings suggest that a maximum
 

tolerated dose level may not have been used. Therefore, the studies
 

may not have been conducted using maximum sensitivity for the
 

assessment of the possible carcinogenicity of aldicarb.
 

In female rats, adenomas or carcinomas of the pituitary occurred at
 

incidences that were dose related (P = 0.048), and in male mice,
 

fibrosarcomas or sarcomas of the subcutaneous tissue occurred at
 

incidences that were dose related (P = 0.043); however, in direct
 

comparisons the incidences of neither tumor were significantly
 

higher in the individual dosed groups than in the corresponding
 

control groups (pituitary tumors: controls 14/25 (56%), low-dose
 

33/48 (69%), high-dose 37/48 (77%); subcutaneous tissue tumors:
 

55
 
controls 0/24, low-dose 1/50 (2%), high-dose 4/49 (8%)). The
 

incidence of pituitary tumors in historical-control female F344 rats
 

at this laboratory also was high, 114/273 (42%). Thus, the
 

occurrence of tumors of the pituitary in the female rats and tumors
 

of the subcutaneous tissue in the male mice cannot clearly be
 

related to administration of the test chemical. No tumors occurred
 

at significant incidences by any test in either the male rats or the
 

female mice.
 

In a previous 2-year feeding study using rats of unspecified strain
 

that were administered diets containing aldicarb at doses equivalent
 

to 0.005, 0.025, 0.05, or 0.1 mg/kg/day, the incidences of tumors in
 

test animals were not significantly greater than those in control
 

groups (Weil and Carpenter, 1965); body weight gain and mortality
 

also were unaffected. No adverse effects were noted when aldicarb
 

was fed at 0.3 mg/kg/day to Greenacres Laboratory Controlled Flora
 

rats for 2 years (Weil, 1975). Aldicarb was not carcinogenic when
 

administered to male C3H/HeJ mice by painting a concentration of
 

0.125% on the skin twice per week for a maximum period of 28 months
 

(Weil and Carpenter, 1966).
 

It is concluded that under the conditions of this bioassay,
 

technical-grade aldicarb was not carcinogenic for F344 rats or
 

B6C3F1 mice of either sex.
 

56
 
VI. BIBLIOGRAPHY
 

Armitage, P., Statistical Methods iin Medical Research, John
 

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

Ayers , J. H. and Johnson, 0. H., Insecticides. In: Chemical
 

Economics Handbook, Stanford Research Institute, Menlo Park,
 

Calif., 1976, sec. 573.3007 E-F.
 

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

Report Series, Vol. 2^. International Union Against Cancer,
 

Geneva, 1969.
 

Black, A. L., Chiu, Y., Fahmy, M. A. H., and Fukuto, F. R.,
 

Selective toxicity of N-sulfenylated derivatives of insecticidal
 

methylcarbamate esters. J. Agr. Fd Chem. ^(5):747-751, 1973.
 

Bull, D. L., Metabolism of UC-21149 (2-methyl-2-methylthio)
 

propionaldehyde O-(methylcarbamoyl)oxime) in cotton plants and
 

soil in the field. J. Econ. Entomol. £1(6):1598-1600, 1968.
 

Bull, D. L., Stokes, R. A., Coppedge, J. R., and Ridgway, R. L.,
 

Further studies of the fate of aldicarb in soil. J. Econ.
 

Entomol. £3(4):1283-1289, 1970. ~
 

Coppedge, J. R., Lindquist, D. A., Bull, D. L., and Dorough, H.
 

W., Fate of 2-methyl-2-(methylthio) propionaldehyde 0-(methylcarbamoyl)oxime (Temik) in cotton plants and soil. J. Agr. Fd
 

Chem. 1.5(5): 902-910, 1967. ~ ~ 

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

Soc. B 34:187-220, 1972. 

Cox, D. R., Analysis £f_ Binary Data, Methuen and Co., Ltd., 

London, 1970, pp. 48-52.
 

Environmental Protection Agency, Initial Scientific and
 

Minieconomic Review Aldicarb, U. S. Environmental Protection
 

Agency, Office of Pesticide Programs, Criteria and Evaluation
 

Division, Washington, D. C., 1975, pp. 24-25.
 

Gaines, T. B., Acute toxicity of pesticides. Toxicol. Appl.
 

Pharmacol. 14:515-534, 1969.
 

57
 
Gart, J. J., The comparison of proportions: a review of
 

significance tests, confidence limits and adjustments for
 

stratifiation. Rev. Int^ Statist. Inst. 39(2) ;148-169, 1971.
 

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

incomplete observation. J. Amer. Statist. Assn. 53:457-481, 1958.
 

Koelle, G. B., Anticholinesterase agents. In: The
 

Pharmacological Basis £f_ Therapeutics, Goodman, L. S. and Gilman,
 

A., eds., Macmillan Publishing Co., Inc., New York, 1975, pp.
 

445-447.
 

Kuhr, R. J. and Dorough, H. W., Carbamate Insecticides;
 

Chemistry, Biochemistry, and Toxicology, CRC Press, Inc.,
 

Cleveland, Ohio, 1976, pp. "2^6, 103-112, 187-190, 211-213, and
 

219-220.
 

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

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

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

Metcalf, R. L., Fukuto, T. R., Collins, C., Borck, K., Burk, J.,
 

Reynolds, H. T., and Osman, M. F., Metabolism of 2-methyl-2­

(methylthio)-propronaldehyde 0-(methylcarbamoyl)-oxime in plant
 

and insect. J. Agr. Fd Chem. 14:579-584, 1966.
 

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

McGraw-Hill, New York, 1966.
 

Richey, F. A., Jr., Bartley, W. J., and Sheets, K. P., Laboratory
 

studies on the degradation of (the pesticide) aldicarb in soils.
 

J. Agr. Fd Chem. 25_(1) :47-51, 1977.
 

Ryan, A. J., The metabolism of pesticidal carbamates. CRC
 

Critical Reviews in Toxicology l(l);33-54, 1971.
 

Sadtler #A4419. Cited in: Keith, L. H. and Alford, A. L.,
 

J.O.A.C. 5.3:162, 1970.
 

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

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

induced by different numbers of administration of benzo(a) pyrene
 

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

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

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

58
 
Weiden, M. H. J., Moorefield, H. H., and Payne, L. K., 0­

(methylcarbamoyl)oximes: a new class of carbamate
 

insectide-araricides. .J. Econ. Entomol. 5J3:154-155, 1965.
 

Weil, C., Mellon Institute Report No. 35-72, Section C, EPA
 

Pesticide Petition No. 3F1414, Cited in: Initial Scientific and
 

Minieconomic Review £f Aldicarb, EPA-540/1-75-013, U. S.
 

Environmental Protection Agency, Office of Pesticide Program,
 

Criteria and Evaluation Division, Washington, D.C., 1975
 

Weil, C., and Carpenter, C., Mellon Institute Report No. 28-123,
 

EPA Pesticide Petition No. 9F0798, 1965. Cited in: Initial
 

Scientific and Minieconomic Review of_ Aldicarb, EPA 540/1-75-013,
 

U. S. Environmental Protection Agency, Office of Pesticide
 

Programs, Criteria and Evaluation Division, Washington, D. C.,
 

1975.
 

•
 

Weil, C., and Carpenter, C., Mellon Institute Report No. 29-5,
 

EPA Pesticide Petition No. 9F0798, 1966. Cited in: Initial
 

Scientific and Minieconomic Review of_ Aldicarb, EPA 540/1-75-013,
 

U. S. Environmental Protection Agency, Office of Pesticide
 

Programs, Criteria and Evaluation Division, Washington, D. C.,
 

1975.
 

Weil, C. and Carpenter, C., Mellon Institute Report No. 26-47,
 

Section C, EPA Pesticide Petition No. 9F0798, 1969. Cited in:
 

Initial Scientific and Minieconomic Review £f_ Aldicarb, EPA
 

540/1-75-013, U. S. Environmental Protection Agency, Office of
 

Pesticide Programs, Criteria and Evaluation Division, Washington,
 

D. C., 1975.
 

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

1976.
 

59
 

APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS ADMINISTERED ALDICARB IN THE DIET
 

61
 

TABLE A1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

ADMINISTERED ALDICARB IN THE DIET

 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALLY IN STDDY 25 50 50 

ANIHALS NECPOPSIED 24 49 48 

ANIMALS EXAMINED HISTOPAIHOLOGICAILY 24 49 48 

INTEGUMENTAR Y SYSTEM 

*SKIN (24) (49) (48) 

SQOAMOOS CELL CARCINOM A 1 (4S) 

FIBROMA 1 (2X) 

*SUBCUT TISSUE (24) (49) (48) 

FIBROSARCOttA 1 (4S) 1 (28) 

RESPIRATORY SYSTEM 

*LUNG (22) (49) (48) 

ALVEOLAF/BHONCHIOLAP ADENOM A 1 (5S) 2 (4X) 3 (6%) 

C-CELL CARCINOMA , METASTATIC 1 (2») 

FIBROSARCOMA, METASTATIC 1 (235) 

HEMATOPOIETIC SYSTEM 

*MULTIPLE ORGANS (24) (49) (48) 

LEUKEMIA,NO S 1 (4%) 2 (4X) 

ONDIFFEEENTIAIED LEDKEMI A 1 (4X) 3 (6X) 8 (17%) 

ISPLEEN (23) (49) (48) 

HEMANGIOSAECOMA 1 (4X) 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

#LIVER (24) (47) (48)
 

NEOELASTIC NODUL E 1 (4X1
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUBBEE OF ANIMALS NECROPSIED
 

63
 
TABLE A1.MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

HEEATOCELLULAR CARCINOMA 1 (2X) 

IDUODENOM 

SARCOMA , NOS 

(24) (46) 

URINAR Y SYSTEM 

•KIDNEY (24) (49) 

TUBULAR-CELL ADENOMA 

* KIDNEY/PEL VIS (24) (49) 

TRANSITIONAL-CELL CARCINOMA 

tURINAFY BLADDER (23) (44) 

CARCINOMA, NOS 1 (4X) 

ENDOCRINE SYSTEM 

JPITOITAHY (20) (43) 

CARCINOMA, NOS 

ADENOMA, NOS 8 (40X) 10 (23X) 

tADRENAL (23) (48)

PHEOCHEOMOCYTOMA 2 (4%) 

tADRENAL MEDULLA (23) (48) 

NEOROBLASXOMA 

ITHYROID (22) (48) 

PAPILLARY ADENOM A 

C-CELL ADENOMA 2 (9X) 3 (6X) 

C-CELL CARCINOMA 

tPANCREATIC ISLETS (24) (49) 

ISLET-CELL ADENOHA 5 (1CX) 

EEPKODUCTIVE SYSTEM 

*MAMMAB Y GLAN D (24) (49) 

FIBROMA 1 (2X) 

FIERO ADENOMA 1 ,(4X) 1 (2%) 

*TESTIS (24) (49) 

INTERSTITIAL-CELL TUMOR 18 (?5%1 „„ 43 (88X) 

f NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE 

(47)

1 (2X) 

(48) 

1 (2X) 

(48) 

1 (2*) 

(42) 

(43) 

1 (2X) 5 (12X) 

(47)

1 (2X ) 

(47) 

1 (2») 

(39) 

1 (3*) 

2 (5X) 

(48)

6 (13S) 

(48) 

1 (2%) 

(48) _ ^^^.(96^1 

64
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

*EPIDIDYMIS

LIPOMA

 (24) (49) (48) 

1 (2%) 

NERVOU S SYSTEM 

NONF 

SPECIAL SENSE ORGAN S 

*EAR CANAL

SQUAMOUS CELL CARCINOMA

 (24) (49) (48) 

2 (4X) 

MUSCULOSKELEIAL SYSTEM 

*SKELE1AL MUSCLE

LIFCMA

*MUSCLE HIP/THIGH

FIBROUS HISTIOCYTOBA, MALIGNANT

 (24)

 1 (4X)

 (24)

 (49)

 (49)

 1 (2X) 

 (48) 

1 (2%) 

 (48) 

BODY CAVITIES 

*PERITONEU« MESCTHELIOMA, NOS (24)

 1 (4X)

 (49)

 1 (2X) 

 (48) 

ALL OTHER SYSTEMS 

*MULTIPLE ORGANS

FIBEOSAFCOMA

 (24) (49) (48) 

2 (4X) 

ANIMA L DISPOSITION SUMMAR Y 

ANIMAL S INITIALLY IN STUDY 

NATURA L DEAIH3 

MORIBUN D SACRIFICE 

**SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINA L SACRIFICE 

ANIMA L MISSING 

25 

4 

11 

2 

8 

50 

7 

9 

2 

32 

50 

2 

23 

2 

1 

22 

8_INCLUDES AUrOLYZED^ANIHALS 

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

** 

Animals are in fact early terminal sacrifices, but appear 

as scheduled sacrifices due to system interpretation. 

65
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

TUMCE SUMMAR Y 

TOTAL ANIMAL S KITH PRIMAP.Y TUMORS* 

TOTAL PRIMAR Y TOMOPS 

22 

39 

147 

75 

47 

91 

TOTAL ANIMALS WITH BENIGN

TOTAL BENIGN TUMORS 

 TUMORS 20 

31 

U7 

67 

46 

67 

TOTAL ANIMALS WITH MALIGNAN T

TOTAL MALIGNAN T TUMORS 

 TUMOPS 6 

6 

7 

7 

16 

19 

TOTAL ANIMALS HITH SECONDARY

TOTAL SECONDARY TUMORS 

 TUMORSt 2 

2 

TOTAL ANIMALS HITH TUMORS

BENIGN OR MALIGNANT 

TOTAL UNCERTAIN TUMORS 

 UNCERTAIN2 

2 

1 

1 

5 

5 

TOTAL ANIMALS WITH TUMOES UNCERTAINEBIMARY OR METASTATIC 

TOTAL UNCERTAIN TUMORS 

* PRIMARY TUMOES: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

66
 
TABLE A2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

ADMINISTERED ALDICARB IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIHALS INITIALLY IN STUDY 25 50 50 

ANIMALS NECROPSIED 25 50 50 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 25 50 50 

INTEGUMENTAR Y SYSTEM 

NONE 

RESPIRATORY SYSTEM 

NONE 

HEHATOPOIETIC SYSTEM 

*MULTIPLE ORGANS (25) (50) (50) 

LEUK!BIA,NOS 1 (4S) 1 (2X) 

UNDIFFERENTIAIED LEUKEMIA 3 (12%) 5 (10X) 1 (2X) 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

fHEFATIC CAPSULE (25) (49) (50) 

LIPCMA 1 (4*) 

URINAR Y SYSTEM 

#KIDNE Y (24) (49) (50) 

TUBULAR-CELL ADENOCARCINOM A 1 (4X) 

ENDOCRIN E SYSTEM 

*PITUI1ABY (25) (48) (48)
 

CARCINOMA,NOS 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECEOPSIED
 

67
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

* TM— "-1" ~~ • " ' • 1 « • ' ­ ­ ­ — ' 

MATCHED 

CONTROL LOW DOSE 

ADEKCMA , NO S 13 (52*) 33 (69*) 

IADRENA I 

CORTICAL ADENOM A 

PHEOCHROMOCYTOMA 

(24)

1 (4X) 

(47) 

1 (2*) 

#THYRCID 

C-CILL ADENOM A 

(24) 

1 (455) 

(44) 

2 (5*) 

#PANCRIATIC ISLETS 

ISLET-CELL ADENOH A 

(24) (49)

2 (4*) 

REPRODUCTIVE SYSTEM 

*MAMMAR Y GLAND (25) (50) 

CARCINOMA, NOS 2 (UX ) 

ADENOMA, NOS 1 (2X) 

ADENOCARCINOMA , NOS 

FIEROADENOM A 4 (16X) 7 (14X) 

* MA MM A BY DOCT (25) (50) 

CARCINOMA , NOS 

*CLITOFAL GLAND (25) (50)

CARCINOMA , NOS 1 (2«) 

tUTERUS (24) (47) 

ADEKCMA , NOS 1 (41) 

SARCOMA, NOS 1 (2X) 

LEIOMYOSARCOMA 2 (4X) 

ENDOMETEIAL STROMAL POLYP 9 (38%) 9 (19X) 

NERVOUS SYSTEM 

*ERAIN (25) (49) 

CARCINOMA, NOS, INVASIVE 1 (4X) 

SPECIAL SENSE ORGAN S 

NONE 

MOSCULCSKELETAL SYSTEM
 

_NONE
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECPOPSIED
 

HIGH DOSE 

34 (71%) 

(46) 

1 (2X) 

(47) 

3 (6X) 

(50) 

2 (4X) 

(50) 

2 (4X> 

5 (10X) 

(50) 

1 (2%) 

(50) 

(49) 

1 (2X) 

15 (31X) 

(50) 

68
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

BODY CAVITIES
 

* MEDIASTINUM (25) (50) (50)
 

ADNEXAL CARCINOMA 1 (2X)
 

*ABDOMINAL CAVITY (25) (50) (50)
 

LIPCHA 1 (2X)
 

ALL OTHER SYSTEMS
 

ADIPOSE TISSUE
 

LIFCMA
 

ANIMAL DISPOSITION SOHBAHY
 

ANIMALS INITIALLY IN STUDY 25 50 50
 

NATURAL DEATHS 1 2 U
 

MORIBUND SACRIFICE 6 20 10
 

**SCHEDULED SACRIFICE 2 2 2
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 16 26 34
 

ANIMAL MISSING
 

t» INCLUDES AUTOLYZED ANIMALS
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

**
 

Animals are in fact early terminal sacrifices, but appear
 

as scheduled sacrifices due to system interpretation.
 

69
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

TUflOR SUMMAR Y 

TOTAL ANIMALS WITH PRIMAR Y TUHORS* 21 45 46 

TOTAL PRIMARY TOHOES 36 71 70 

TOTAL ANIMALS WITH BENIGN TUMORS 19 40 44 

TOTAL BENIGN TUMORS 30 58 62 

TOTAL ANIMALS HITH MALIGNAN T TUMORS 6 13 7 

TOTAL MALIGNANT TUMORS 6 13 8 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1 

TOTAL SECONDARY TUMORS 1 

TOTAL ANIMALS HITH TUMORS UNCERTAIN ­

BENIG N OR MALIGNAN T 

TOTAL UNCERTAIN TUMORS 

TOTAL ANIMALS WIT H TUHORS UNCERTAIN ­

ERIMARY OR HETASTATIC 

TOTAL UNCERTAIN TUMORS 

* PRIMAR Y TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS 

f SECONDARY TUMORS: MEIASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN 

70 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE ADMINISTERED ALDICARB IN THE DIET
 

71
 

TABLE B1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

ADMINISTERED ALDICARB IN THE DIET 

MATCHED 

CONTROL LOW DOSE 

ANIMALS INITIALLY IN STUDY 25 50 

ANIHALS NECROPSIED 24 50 

ANIMAL S EXAMINE D HISTOPATHOLOG1CALLY 24 50 

INTEGUMENTAR Y SYSTEM 

*SUBCUT TISSUE (24) (50) 

SARCOMA , NOS 

FIEROSARCOHA 1 (2%) 

FIBKOUS HISTIOCYTOBA. MALIGNAN T 1 (4X) 

RESPIRATORY SYSTEM 

#LUN G (24) (49) 

HEPATOCFLLULAR CARCINOMA , METAST 1 (2») 

ALVEOLAR/BRONCHIOL*.R ADENOMA 1 (4%) 6 (12X) 

ALVEOLAF/BRONCHIOLA R CARCINCM A 

HEMATOPOIETIC SYSTEM 

*MULTIPLE ORGANS (24) (50) 

MALIGNAN T LYMPHOMA , NO S 

LEDKEMIA,NO S 1 (4%) 1 (2«) 

LYMPHOCYTIC LEUKEMI A 1 (2%) 

tSPLEEN (24) (49) 

HEMANGIOSARCOM A 

tLYMP H NODE (23) (5C) 

MALIGNAN T LYMPHOMA , NO S 1 (2X) 

tSMALL INTESTINE (20) (45) 

MAIIGNAN T LYMPHOMA , NO S 

CIRCULA10PY SYSTEM
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBEF OF ANIMALS NECROPSIED
 

HIGH DOSE 

50 

49 

49 

(49) 

1 (2X) 

3 (6X) 

(48) 

3 (6%) 

2 (4») 

(49) 

1 (2X) 

(49) 

2 (4S) 

(47) 

(48) 

1 (2%) 

73
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

DIGESTIVE SYSTEM 

#LIVER

HEPATOCELLULAR ADENOM A

HEPATOCELLULAR CARCINOMA

HEMANGIOSARCOMA

ANGIOSARCOHA

 (24)

 1 (4X)

 4 (17%)

 (49)

 4 (8X)

 10 (20X)

 2 (4X)

 1 (2%) 

 (49) 

5 (10X) 

 13 (27X) 

1 (2%) 

URINAR Y SYSTEM 

NON E 

ENDOCRINE SYSTEM 

tADRENA I

PHECCHROMOCYTOMA

#THYROI D

FOLLICULAR-CELL ADENOM A

 (2U)

 (19)

 (49)

 1 (2X) 

 (U7)

 1 (2X) 

 (49) 

 (45) 

REPRODUCTIVE SYSTEM 

NONE 

NERVCU E SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

*HARDERIA N GLAN D

ADESCMA , NOS

PAPILLAF Y ADENOM A

 (24) (50) (49) 

1

 1

 (2%) 

 (2X) 

BUSCULOSKELETAL SYSTEM 

NON E 

BODY CAVITIES 

__NONE 

t NUMBER OF ANIMALS WITH TISSDE EXAMINED MICROSCOPICALLY 

* NUMBEF OF ANIMALS NECROPSIED 

74
 
TABLE B1.MALE MICE: NEOPLASMS (CONTINUED) 

ALL CTHEP SYSTEMS
 

NONE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY


NATCFAL DEATHS


MOEIBUND SACRIFICE


SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED


TEEKINAL SACRIFICE


ANIHAI HISSING
 

5) INCLUDES AUTOLYZED ANIMALS
 

TUMCE SUKMARY
 

TOTAL ANIMALS HITH PRIMARY TUMORS*


TOTAL PRIMARY TUMORS


TOTAL ANIMALS WITH BENIGN TUMORS


TOTAL BENIGN TUMORS


TOTAL ANIMALS HITH MALIGNANT TUMORS


TOTAL MALIGNANT TUMORS


TOTAL ANIMALS HITH SECONDARY TUMORS*


TOTAL SECONDARY TUMORS


TOTAL ANIMALS WITH TUMORS UNCHRTAINBENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS HITH TUMORS UNCERTAINPEIMAFY OP METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

MATCHED
 

CONTROL
 

 25
 

2
 

4
 

2
 

 17
 

8
 

8
 

2
 

2
 

6
 

6
 

LOW DOSE HIGH DOSE
 

50 50 

3 3 

6 6 

41 41 

27 30 

29 34 

11 10 

12 10 

16 22 

17 24 

1 

1 

* PRIMARY TUHORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

t SECONDARY TUMORS: ME1ASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

75
 
TABLE B2. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

ADMINISTERED ALDICARB IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 25 50 50 

ANIMAL S NECKOPSIED 25 50 50 

ANIMAL S EXAMINED HISTOPATHOLOGICALLY 25 50 50 

INTEGUMENTAR Y SYSTEM 

*SUBCUI TISSUE (25) (50) (50) 

SARCOMA, NOS 1 (2X) 

FIEROSARCOMA 1 (2X) 

RESPIRATORY SYSTEM 

*LUNG (25) (50) (50)
 

ALVECLAR/BRONCHIOLAR ADENOMA 1 (4X) 2 (4X) 1 (2X)
 

ALVIOLAR/BRONCHIOLAR CARCINOMA 2 (4X)
 

OSTEOSARCOMA. METASTATIC 1 (2X)
 

HEMATOPOIETIC SYSTEM 

*MULTIPLE ORGANS (25) (50) (50) 

MALIGNANT LYHPHOMA , NOS 3 (12X) 2 (4X) 3 (6X) 

MALIG.LYHPHOMA, LYMPHOCYTIC TYPE 1 (4X) 1 (2X) 

LEUKEMIA,NOS 2 (4X) 1 (2X) 

LYMPBOCYTIC LEUKEMIA 2 (4X) 2 (4X) 

GRANULOCYTIC LEUKEMIA 2 (8X) 1 (2X) 1 (2X) 

• SPLEEN (24) (49) (50) 

HEMANGIOMA 1 (4X) 

HEMANGIOSARCOM A 1 (2X) 

•LYMPH NODE (20) (47) (48) 

MALIG.LYMPHOMA, LYMPHOCYTIC TYPE 1 (2X) 1 (2X) 

*EUODENUM (20) (45) (40)
 

MALIGNANT LYMPUOMA, NOS 1 (3X)
 

CIBCDLATORY SYSTEM
 

NONE	 ,
 

* NUMBER OP ANIMALS ilTH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBEF Of ANIMALS NECROPSIED
 

76
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

DIGESTIVE SYSTEM 

tSALIVARY GLAN D

FIBBOSABCOMA

 (24) (50) (48) 

1 (2%) 

ILIVEK

HEPATOCELLULAE CARCINOMA

OSTECSAPCOMA, METASTATIC

 (25)

 3 (12%)

 (49) (48) 

4 (8X) 

1 (2%) 

URINARY SYSTEM 

NONE 

ENDOCRINE SYSTEM 

iPITUITAEY

ADENOMA, NOS

CHROMOPHOBE CARCINOMA

 (21)

 2 (10%)

 (40)

 3 (8X)

 (43) 

2 (5X) 

1 (2%) 

HEPEODUCTIVE SYSTEM 

*MAMMA?Y GtAND

CARCINOMA,NOS

ADENOMA, NOS

ADENOCARCINOMA, NOS

 (25)

 1 (4X)

 (50)

 2 (4X)

 (50) 

1 (2X) 

2 (««) 

1 (2X) 

•DTEEOS

SARCOMA, NOS

FIBROMA

ENDOMETRIAL STROMAL POLYP

 (25)

 1 (4%)

 1 (4*)

 (50)

 1 (2X)

 1 (2%) 

1 (2X) 

 (49) 

1 (2%) 

NERVOUS SYSTEM 

NCNE 

SPECIAL SENSE ORGANS 

*HARDEFIAN GLAND 

AEENOMA. NOS 

(25) (50) 

t NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY * NUMBEE OB ANIMALS NECEOPSIED 

(50) 

(2%) 

77
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

MUSCULOSKELETAL SYSTEH 

*SKOLL (25) (50) (50) 

OSTEOSARCOMA 1 (2*) 

*PELVIC BONES (25) (50) (50) 

OSTEOSARCOMA 1 (2X) 

BODY CAVITIES 

NCNE 

ALL OTHEB SYSTEMS 

*MULTIELE ORGANS (25) (50) (50) 

SARCOMA, NOS 1 (W) 

FIEPODS HISTIOCYTOMA, MALIGNANT 1 (2X) 

ANIMAL EISFOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 25 50 50 

NATURAL DEATHS 3 3 

MOFIBUND SACRIFICE 5 12 11 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLEE 1 

TERMINAL SACRIFICE 16 38 36 

ANIKAL MISSING 

a INCLUDES AUIOLY2ED ANIMALS. 

* NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

78
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

TUMO E SUMMAR Y 

TOTAL ANIMALS WITH PRIMAR Y

TOTAL PRIMARY TUMOES 

 TUMORS * 15 

17 

21 

23 

22 

28 

TOTAL ANIMALS WITH BENIG N TUMCRS 

TOTAL BENIGN TUMOR S 

6 

6 

9 

9 

5 

6 

TOTAL ANIMAL S WITH MALIGNAN T

TOTAL MALIGNAN T TUMORS 

 TUMORS 11 

11 

14 

11 

20 

22 

TOTAL ANIMALS WITH SECONDARY TUMORS*

TOTAL SECONDARY TUMORS

 1 

2 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT 

TOTAL UNCERTAIN TUMORS 

TOTAL ANIMALS WITH TUMORS UNCERTAINEFIMAFY OR METASTATIC 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMOBS: ALL TUMORS EXCEPT SECONDARY TUHORS
 

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

79
 

APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPIASTIC LESIONS
 

IN RATS ADMINISTERED ALDICARB IN THE DIET
 

81
 

TABLE C1.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

ADMINISTERED ALDICARB IN THE DIET 

ANIMALS INITIALLY IN STUDY
 

ANIMALS NECEOPSIED
 

ANIMALS EXAMINED HI STOPATHOLOGICALLY
 

INTEGUMENTARY SYSTEM
 

*SKIN
 

CYST, NOS
 

RESPIRATORY SYSTEM
 

#LUNG
 

INFLAMMATION, CHRONIC
 

HYPEF.PLASIA, ADENOMATOUS
 

HEMATOPOIETIC SYSTEM
 

tBONE MARROW
 

FIBROUS DYSPLASIA
 

SSFLEEN
 

CONGESTION, NOS
 

FIBROSIS, FOCAL
 

INFARCT, NOS
 

INFAPCT, HEALED
 

LIPOIDOSIS
 

HYPERPLASIA, LYMPHOID
 

HEBATOPOIESIS
 

fLYHPH NODE
 

HYPERPLASIA, NOS
 

•MANDIEDLAK L. NODE
 

CYST, NOS
 

tMESENTERIC L. NODE
 

HYPEPPLASIA. NOS
 

MATCHED
 

CONTROL LOW DOSE
 

25 50
 

24 1*9
 

24 09
 

(24)	 (49)
 

2 (4X)
 

(22)	 (49)
 

1 (2X)
 

(23)	 (49)
 

(23)	 (49)
 

1 (2X)
 

1 (2X)
 

2	 (9X)
 

1 (2X)
 

1 (2X)
 

1 (2%)
 

1 (2%)
 

(20)	 (45)
 

(20)	 (45)
 

(20)	 (45)
 

HIGH DOSE
 

50
 

48
 

48
 

(48)
 

(48)
 

1 (2X)
 

(47)
 

1 (2X)
 

(48)
 

2 (4X)
 

2 (4X)
 

2 (H%)
 

(44)
 

1 (2X)
 

(44)
 

1 (2X)
 

(44)
 

1 (2X1
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

83
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

#BENAL LYMPH NODE (20) (45) 

CYS1, NOS 1 (2X) 

CIHCOLA10HY SYSTEM 

THRCHBOSIS, NOS 1 (2%)
 

*PANCPEATIC ARTERY, (24) (49) (48)
 

THROHBOSIS, NOS 1 12%)
 

DIGESTIVE SYSTEM
 

•SALIVARY GLAND (22) (46) (48)
 

INFLAMMATION, NOS 2 (9%) 1 (2X) 1 (2%)
 

HYPEEPLASIA, NOS 2 (9X) 1 (2X)
 

#L1VER (24) (47) (48)
 

CONGESTION, NOS 1 (4X)
 

INFLAMMATION, NOS 1 (2%)
 

METAMORPHOSIS FATTY 2 (8X)
 

FOCAL CELLULAR CHANGE 2 (8*) 4 (9%) 6 (13*)
 

CYTOLOGIC DEGENERATION 1 (2X)
 

HEMATOPOIESIS 1 (2X) 4 (8X)
 

tLIVER/CENTRILOBULAB (24) (47) (48)
 

METAMORPHOSIS FATTY 1 (2X)
 

#BILE COCT (24) (47) (48)
 

HYPEPPLASIA, NOS 5 (2155) 9 (19X) 17 (35%)
 

tFANC BIAS (24) (49) (48)
 

PERIARTERITIS .,^1 <2X1 1 12%)
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECBOPSIED
 

84
 
TABLE C1.MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

PERIVASCULITIS 2 (4%)
 

ATROPHY, NOS 1 (2*) 1 (2%)
 

ATROPHY, FOCAL 4 (17%) 5 (10%) 4 (8%)
 

#STOHACH (24) (45) (46)
 

ULCEE, ACUTE 1 (2%)
 

INFLAMMATION, CHRONIC 2 (8%) 2 (4%)
 

HYPERPLASIA. NOS 1 (i»%) 1 (2%)
 

HYPERPLASIA, EPITHELIAL 1 (4%)
 

HYPEEPLASIA, FOCAL 1 (2%)
 

*DUODENUH (24) (46) (47)
 

INFLAMMATION, CHRONIC 1 (2%)
 

URINARY SYSTEH
 

#KIDNEY (24) (49) (48)
 

INFLAMMATION, CHRONIC 15 (63%) 37 (76%) 38 (79%)
 

f KIDNEY/MEDULLA (24) (49) (48)
 

HYPEFPLASIA, EPITHELIAL 1 (2%)
 

#KIENEY/FELVIS (24) (49) (48)
 

HYPIBPLASIA, EPITHELIAL 2 (4X)
 

ENDOCRINE SYSTEM
 

•PITUITARY	 (20) (43) (43)
 

HEMCBFHAGE 1 (2%)
 

HEMORRHAGIC CYST 1 (5X) 2 (5%)
 

HYPERPLASIA, NOS 1 (5X)
 

ANGIECTASIS 1 (2%)
 

tADRENAl (23) (48) (47)
 

ANGIECTASIS 1 (2%)
 

tACRENAL CORTEX (23) (48) (47)
 

HEMOFFHAGE 1 (2%)
 

LIPCIDOSIS 2 (4%) 1 (2%)
 

ANGIECTASIS 1 (2%)
 

METAPLASIA, OSSEOUS 1 (4X)
 

tADRENAL MFDULLA (23) (48) (47)
 

HYPERPLASIA^ NOS „ 2 ,j(9X_l
 r i -- . , .„, . ...
 

# NUMBEE OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUHBEE OF ANIHALS NECROPSIED
 

85
 
TABLE C1.MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

#TdYROID (22) (48) (39) 

HYFIEPLASIA, C-CELL 1 (5X) 6 (13*) 2 (5X) 

#FAEATHYEOID (19) (38) (29)

 

HYPBBPLASIA, NOS 1 OX)

 

REPRODUCTIVE SYSTEM 

*MAMMAB Y GLAND (24) (49) (48)

 

INFLAMMATION , ACUTE 1 (4X)

 

tPEOSTATE (23) (47) (44) 

INFLAMMATION , ACUTE 1 (2») 

INFLAMMATION , CHRONIC 1 (2%) 1 (2») 

#IESTIS (24) (49) (48)

 

ATECPHY, NOS 1 (4%) 

*EFIDIEYMIS (24) (49) (48)

 

STEATITIS 1 (2X)

 

NERVOU S SYSTEM 

tEBAI N (23) (48) (47) 

HYEROCEPHALUS , NOS 2 (9X) 

GLIOSIS 1 (4%) 1 (2%) 

NECROSIS, FOCAL 1 (2%) 

MALACI A 1 (2X) 

SPECIAL SENSE ORGAN S 

NON E 

MOSCULOSKEtETAL SYSTEM 

NONE 

BODY CAVITIES 

*MESENTERY (24) (49) (48) 

SIEATITIS 1 12%)

 

* NHBBEE OF ANIMALS WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUHBE E OF ANIMALS NECEOPSIED 

86 
TABLE C1.MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ALL OTHER SYSTEMS 

*MULTIEIE ORGANS 

HEMORRHAG E 

(24) (49) 

1 (2X) 

(48) 

SPECIAL MORPHOLOGY SUMMAR Y 

NO LESION REPORTED 

ACCIDENTAL DEATH 

AUTOLYSIS/NO NECROPSY 

NUMBE R OF ANIMALS WITH TISSUE

NUMBE R OF ANIMALS NECROPSIED 

 EXASINEC MICROSCOPICALLY 

87 
TABLE C2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

ADMINISTERED ALDICARB IN THE DIET

 

ANIHALS INITIALLY IN STODT

ANIMAL S NECROPSIED

ANIHALS EXAMINED HISTOPATHOLOGICALLY

INTEGUMENTARY SISTEH 

*SKIN

CYSI. NOS

RESPIRATORY SYSTEM 

*TRACHEA

INFLAMMATION , ACUTE

#LUNG

CONGESTION, NOS

HEtlCPKHAGE

INFLAMMATION , FOCAL

HEMATOPOIETIC SYSTEM 

fSPLEEN

CONGESTION, NOS

HEHCFRHAG E

NECROSIS, FOCAL

HYPERPLASIA, HEMATOPOIETIC

HEMJTOPOIESIS

CIRCULATORY SYSTEM 

fHEAET/ATKIUH 

THRCMBOSIS, NOS 

tMYOCAEDIUM 

FIBEOSIS, FOCAL 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

 25 50 50 

 25 50 50 

 25 50 50 

 (25) (50) (50) 

1 (2X) 

 (25) (45) (49) 

1 (2%) 

 (25) (48) (50) 

1 (2X) 

1 (2X) 

1 (4X) 1 (2%) 

 (23) (49) (50) 

2 (4X) 

1 (2X) 

1 (2X) 

1 (2X) 

2 (4X) 

(25) (50) (50) 

1 (4X) 

(25) (50) (50) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NBCEOPSIED
 

88
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

DIGESTIVE SYSTEM 

•SALIVARY GLAND	 (25) (50) (49) 

INFLAMMATION, NOS 2 (4X) 2 (4X) 

HYPERPLASIA, NOS 2 (4X) 2 (4X) 

•LIVER	 (25) (49) (50) 

INFLAMMATION, NOS 1 (2X) 

GRANULOMA, NOS 2 (8X) 1 (2X) 1 (2X) 

NECROSIS, FOCAL 1 C*X) 

METAMORPHOSIS FATTY 1 (4X) 1 (2X) 4 (8X) 

EASOPHILIC CYTO CHANGE 1 (<»X) 1 (2X) 

FOCAI CELLULAR CHANGE 4 (16X) 4 (8X) 5 (10X) 

HEMATOPOIESIS 2 (4X) 3 (6X) 

•BILE CUCT (25) (49) (50) 

HYPERPLASIA, NOS 3 (12X) 4 (8X) 2 (4X) 

• PANCREA S (24) (49) (50) 

ATRCEHY, NOS 1 (2X) 1 (2X) 

ATROPHY, FOCAL 2 (4X) 

•STOMACH	 (24) (48) (49) 

INFLAMMATION , CHRONIC 4 (8X) 2 (4X) 

•CECUM (24) (49) 

INFLAMMATION, ACUTE 1 (2X) 

URINARY SYSTEM
 

• KIDNE Y (24) (49) (50) 

INFLAMMATION, CHRONIC 5 (21X) 14 (29X) 22 (44X) 

ENDOCRINE SYSTEfl 

•PITUITARY (25) (48) (48) 

CYST, NOS 2 (8X) 1 <2X) 

MULTIPLE CYSTS 1 (2X) 

HEMORRHAG E 1 (4X) 

HEMORRHAGIC CYST 2 (8X) 1 (2X) 

HYPERPLASIA, NOS 1 ("X) 1 (2X) 1 (2X) 

&NGIECTASIS 1 (2X) 

# NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECSOPSIED
 

89
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

*ADEENA L CORIfiX (2U) (47) (46) 

LIFCIDCSIS 2 (4%) 

•THYRCJD (24) (44) (47) 

HYPEPPLASIA, C-CELL 4 (17X) 3 (7%) 3 (6X) 

f PA SA THYROID (18) (34) (34) 

HYFEEPLASIA, NOS 1 (3%) 

REPRODUCTIVE SYSTEM 

*MAMMAF Y GLAN D (25) (50) (50) 

GALACTOCELE 1 (2%) 

HYPEPPLASJA, NOS 1 (2X) 

tUTERUS/ENDOMETRIUM (24) (47) (49) 

HYPEBPLASIA, CYSTIC * (9X) 2 (4%) 

fOVAR Y (25) (47) (48)

 

STEATITIS 1 (2X) 

NERVOUS SYSTEM 

iflRAIN (25) (49) (50)

 

HYEEOCEPHALUS, NOS 1 (2X)

 

SPECIAL SENSE ORGANS 

NONE 

BOSCULCSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NONE 

ALL OTHER SYSTEMS
 

ADIPOSE TISSUE
 

IHFLAHHAIIOH. CHRONIC
 

* NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECBOPSIED
 

90
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL MORPHOLOGY SOBMARY 

NO LESION REPORTED 

# NUMBE R OF ANIMALS WIT H 1ISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMALS NECPOPSIED 

91 

APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN MICE ADMINISTERED ALDICARB IN THE DIET
 

93
 

TABLE 01.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

ADMINISTERED ALDICARB IN THE DIET 

ANIMALS INITIALLY IN STUDY

ANIMALS NECROPSIED

ANIMALS EXAMINE D HISTOPATHOIOGICALLY

INTEGOMENTAP Y SYSTEM 

*SKIN

ULCEE, NOS

*SOBCUI TISSUE

INFLAMMATION , FOCAL GEANOLOMATO U

RESPIRATOR Y SYSTEM 

NONE 

HEBATOEOIE1IC SYSTEM 

tSFLEE N

HYFEPPLASIA, LYMPHOID

*LY«PH NODE


INFIAMMATION, NOS


tMESENTFRIC L. NODE


INFIAMMATION, NOS


CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVE SYSTEM
 

*LIVEF
 

INFLAMMATION. MULIIFOCAL
 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

 25 50 50 

 24 50 49 

 24 50 49 

 (24) (50) (49) 

2 (4X) 

 (24) (50) (49) 

1 (4%) 

 (24) (49) (49) 

1 (2X) 2 (4X) 

 (23) (50) (47) 

2 (4*) 

 (23) (50) (47) 

1 (2X) 

(24) (49) (49) 

* NUMBEE OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBEF OF ANIMALS NECEOPSIED
 

95
 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

INFLAMMATION, GRANULOMATOUS
 

NECROSIS, NOS
 

NECROSIS, FOCAL
 

HYPERPLASIA, NODULAR
 

NODULAR REGENERATION
 

*EILE DUCT
 

DILATATION, NOS
 

#EEYEBE PATCH
 

HYPHRPLASIA, LYMPHOID
 

tJEJUNUM
 

HYPIBPLASIA, LYMPHOID
 

URINARY SYSTEM
 

tKIDNEY
 

INFLAMMATION, FOCAL
 

INFLAMMATION, INTERSTITIAL
 

tURINARY BLADDER
 

INFLAMMATION, CHRONIC
 

HYPERPLASIA, EPITHELIAL
 

ENDOCRINE SYSTEM
 

tPITUITARY
 

CYST, NOS
 

REPRODUCTIVE SYSTEM
 

*EEEPUTIAL GLAND
 

MOLTIPLE CYSTS
 

INFLAMMATION, NOS
 

tPROSTATF
 

INFLAMMATION, SUPPURATIV5
 

*SEMINAL VFSICLE
 

HYPEPPLASIA. CYSTIC
 

MATCHED
 

CONTROL
 

1 (4X)
 

1 (4X)
 

(2U)
 

(20)
 

1 (5X)
 

(20)
 

(24)
 

(22)
 

(22)
 

(24)
 

(21)
 

(24)
 

1 (4X1
 

LOW DOSE
 

1 (2%)
 

1 (2X)
 

1 <2X)
 

(49)
 

1 (2X)
 

(45)
 

(45)
 

1 (2X)
 

(50)
 

1 (2X)
 

(45)
 

(44)
 

1 (2X)
 

(50)
 

1 (2%)
 

2 (4%)
 

(37)
 

(50)
 

HIGH DOSE
 

1 (2*)
 

1 (2X)
 

1 (2X)
 

(49)
 

(48)
 

(48)
 

(49)
 

1 (2X)
 

1 (2X)
 

(47)
 

1 (2X)
 

1 (2X)
 

(45)
 

(49)
 

(43)
 

1 (2X)
 

(49)
 

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

96
 
___ ___ _ _ _

TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

NEBVOUS SYSTEH 

IBRAI N (2<0 (50) (<»7) 

INFLAMMATION , ACUTE 1 (2%) v__.__ _—^«.... «•_»*._ *__.• *_ -.— — ——•—•»»•—••»— —»» — •—•••— ••— •— — —^•""•••"•"•— ••» »••— -•—*— — »—• 

SPECIAL SENSE ORGAN S 

NON E 

BUSCULCSKEIETAL SYSTEH 

NONE 

BODY CAVITIES 

NCNE 

ALL OTHER SYSTEMS 

NONE 

SPECIAL BOPFHOLOGY SUMHAR Y 

NO LESION REPORTED 13 17 13 

ACCICENTAL DEATH 1 

AUTCLXSIS/NO NECROPSY 1 

t NUMBE R OF ANIMALS WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBED OF ANIBALS HECROPSIED 

97 
TABLE 02.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

ADMINISTERED ALDICARB IN THE DIET

 

ANIMALS INITIALLY IN STUDY

ANIMALS NECPOPSIED

ANIMALS EXAMINE D HISTOPATHOLOGICALLY

INTEGUMENTAR Y SYSTEM 

NONE 

RESPIRATOR Y SYSTEM 

*LUNG/ALVEOLI

HEMCBRHAG E

HEMATOFOIETIC SYSTEM 

ISFLEEK

ANGIECTASIS

HYPERPLASIA, LYMPHOID

fMESENTEFIC L. NODE

INFLAMMATION , NOS

HYPERPLASIA, LYBPHOID

CIRCULATOR Y SYSTEM 

NONE 

DIGESTIVE SYSTEM 

tLIVER 

HEMORRHAGE 

INFLAMMATION , MULTIFOCAL 

NECROSIS, NOS 

NECROSIS, FOCAL 

fPANCREAS 

DHATA TIQN/DUCTS 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

 25 50 50 

 25 50 50 

 25 50 50 

 (25) (50) (50) 

1 (2%) 

 (24) (49) (50) 

1 (2%) 

1 (2S) 2 (4%) 

 (20) (47) (48) 

1 (2«) 

1 (2%) 1 (2X) 

(25) (49) (48) 

1 (2%) 

1 (2X) 1 (2X) 

1 12%) 

1 <2X) 

(24) (50) (49) 

1 (4X) 2 (481 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROFSIED
 

98
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) ____ __ _______•_ ._*_».._ _ __ __ _ _________•«____-*«» — —•— — —•-.•,._.____«»•-«_ — _ ••« —••——— J..— ••>, 

MATCHED 

CONTROL LOW DOSE HIGH DOSE
 

HYECELASIA, NOS	 1 (2X)
 

ATROPHY. NOS	 1 (2X)
 

#EEYEFS PATCH (20) (U5) (40)
 

HYEIEPLASIA, LYMPHOID 1 (3X)
 

*J£JUNUH (2C) (45) (40)
 

HYFEPPLASIA, LYMPHOID 1 (2X)
 

tILEUH	 (20) (45) (40)
 

HYPEFPLASIA, LYMPHOID	 1 (5%)
 

URINARY SYSTEM
 

#KIDNEY (24) (50) (50)
 

HYPEFPLASIA, LYMPHOID 3 (6X)
 

ENDOCRINE SYSTEM
 

tEITUITAHY (21) (40) (43)
 

ANGIECTASIS 1 (5%)
 

REPRODUCTIVE SYSTEM
 

*MAMMARY GLAND (25) (50) (50)

 

GALSCTOCELE 1 (2X)

 

•UTERUS	 (25) (50) (49) 

HYCFOMHTR A 1 (H%) 1 (2X) 

#UTERU£/ENDOMETRIU M (25) (50) (49)

 

HYPIEPLAS1A, CYSTIC 3 (6X)

 

tOVAE Y (23) (48) (46) 

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

NERVOU S SYSTEM 

NONE 

SPECIAL SENSE ORGAN S 

NONE 

t NUMBE B OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE E OF ANIMALS NECROPSIED 

99 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

MUSCULCSKELITAL SYSTEM 

NONE 

BODY CAVITIES 

*PERI1CNEAL CAVITY (25) (5P) (50) 

INFLAMMATION, GRANULOMATOUS 1 (2%) 

ALL OTHER SYSTEMS 

NOME 

SPECIAL MORPHOLOGY SUMMAR Y 

NO LESION REPORTED 8 21 21 — ———— — — ———-.———•.— — —_ —— _ _ ——— ———————«—— — _.— — —— — — — ._ — —_,— — — —_—_ «.*._ — — v —_ —_ — — ^ —_^«.«»^_-. 

» NUBBEE OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBEE OF ANIMALS NECROPSIED
 

100
 
APPENDIX E
 

ANALYSES OF FORMULATED DIETS FOR
 

CONCENTRATIONS OF ALDICARB
 

101
 
102

 
APPENDIX E
 

Analyses of Formulated Diets for
 

Concentrations of Aldicarb
 

A 10-g sample of the diet mixture was shaken with 125 ml of 

acetone at room temperature for 16 hours, then filtered through 

Celite with acetone washes. The acetone was removed by evaporation and the residue was transferred to a 10-ml volumetric flask. 

After appropriate dilutions with acetone, the solution was quantitatively analyzed for aldicarb by gas-liquid chromatography 

(flame potentiometric detector in the sulfur mode, 20% Carbowax 

20M column). Recoveries were checked with spiked samples, and 

external standards were used for calibration. 

Theoretical Sample Coefficient 

Dietary No. of Analytical of Variation Range 

Level (ppm) Samples Mean (ppm) (%) (ppm) 

2 9 1.77 20.1 1.14-2.35 

6 9 5.76 4.94 5.41-6.18
 

103 
104

 
Review of the Bioassay of Aldicarb* 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 DREW 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 cri­ tique is given on the bioassay of Aldicarb.
 

The reviewer for the report on the bioassay of Aldicarb said that
 

Aldicarb was not carcinogenic under the conditions of test. After a
 

brief description of the experimental design, he said that there was
 

no indication, either through weight depression or early mortality,
 

that the maximum tolerated dose levels had been tested. As a result,
 

he concluded that the chronic dosages were much too low and, therefore,
 

the study was an inadequate bioassay for the carcinogenicity of Aldicarb.
 

It was moved that the report on the bioassay of Aldicarb be
 

accepted with the notation that the results of the study do not reflect
 

a test of the maximum tolerated doses nor one-half those amounts. The
 

motion was seconded and approved unanimously.
 

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
 

105
 
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.
 

«UA GOVERNMENT PRINTING OFFICE: 1979 281-217/3157 1-3 

106 

NIH Publication No. 79-1391