MNAL
United States ECAO-CIN-423
Environmental Protection c
September, 1988
SEPA Research and
Development
DRINKING WATER CRITERIA DOCUMENT
FOR ENDRIN
Prepared for
HEALTH AND ECOLOGICAL CRITERIA DIVISION
OFFICE OF SCIENCES AND TECHNOLOGY
OFFICE OF WATER
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, OC 20460
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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DISCLAIMER
This document has been reviewed In accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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FOREWORD
Section 1412 (b)(3)(A) of the Safe Drinking Water Act, as amended In
1986, requires the Administrator of the Environmental Protection Agency to
publish maximum contaminant level goals (MCLGs) and promulgate National
Primary Drinking Water Regulations for each contaminant, which, In the
Judgment of the Administrator, may have an adverse effect on public health
and which Is known or anticipated to occur In public water systems. The
MCLG Is nonenforceable and 1s set at a level at which no known or antici-
pated adverse health effects In humans occur and which allows for an
adequate margin of safety. Factors considered In setting the HCLG Include
health effects data and sources of exposure other than drinking water.
This document provides the health effects basis to be considered In
establishing the MCLG. To achieve this objective, data on pharmacoklnetlcs,
human exposure, acute and chronic toxldty to animals and humans, epidemi-
ology and mechanisms of toxldty are evaluated. Specific emphasis Is placed
on literature data providing dose-response Information. Thus, while the
literature search and evaluation performed In support of this document has
been comprehensive, only the reports considered most pertinent In the deri-
vation of the MCLG are dted In the document. The comprehensive literature
data base In support of this document Includes Information published up to
1987; however, more recent data may have been added during the review
process. Editorial changes were also made 1n 1991 when this document was
finalized.
When adequate health effects data exist, Health Advisory values for less
than lifetime exposures (1-day, 10-day and longer-term, -10X of an
Individual's lifetime) are Included In this document. These values are not
used In setting the MCLG, but serve as Informal guidance to municipalities
and other organizations when emergency spills or contamination situations
occur.
Tudor Davles
Director
Office of Science and
Technology
James Elder
Director
Office of Ground Water
and Drinking Water
111
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DOCUMENT DEVELOPMENT
Annette M. Gatchett, Document Manager
Environmental Criteria and Assessment Office, Cincinnati
U.S. Environmental Protection Agency
Helen H. Ball, Project Officer
Environmental Criteria and Assessment Office, Cincinnati
U.S. Environmental Protection Agency
Authors
Shane S. Que Hee, Ph.D.
University of Cincinnati
Martha RadUe, Ph.D.
University of Cincinnati
Evelyn Uldner, B.S.
University of Clndnnnatl
Rita Schoeny, Ph.D.
University of Cincinnati
Ellen O'Flaherty, Ph.D.
University of Cincinnati
Stuart Baxter, Ph.D.
University of Cincinnati
Scientific Reviewers
Randall J.F. Bruins, M.S.
Annette Gatchett. B.S.
Richard Hertzberg, Ph.D.
Jennifer Orme, M.S.
William Bruce Pelrano, M.S.
Fred A. Reltman, B.S.
Environmental Criteria and Assessment
Office, Cincinnati
U.S. Environmental Protection Agency
Scientific Reviewers (cont.)
Margaret L. Chu, Ph.D.
Robert McGaughy, Ph.D.
William E. Pepelko, Ph.D.
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Washington, DC
Peter Gartslde, Ph.D.
Geraldlne Krueger, Ph.D.
University of Cincinnati
Keith Jacobson, Ph.D.
Life Systems, Inc.
Arlington, VA
Yogendra Patel, Ph.D.
Office of Drinking Water
U.S. Environmental Protection Agency
Washington, DC
Fumlo Matsumura
Dept. of Environmental Toxicology
and Toxic Substances
Research and Testing Program
University of California
Geraldlne L. Krueger
University of Cincinnati
Editorial Reviewers
Eriu Durden, B.S.
Judith Olsen, B.A.
Environmental Criteria and Assessment
Office, Cincinnati
U.S. Environmental Protection Agency
1v
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Document Preparation
Technical Support Services Staff: C. Cooper, P. Daunt, C. Fessler, K. Mann,
B. Zwayer, J. Moore. Environmental Criteria and Assessment Office, Cincinnati
Other Contributors: Becky Clark, Kay Irlon, Geraldlne Krueger, Lorraine
Mercer, Ted Morris, Jane Onslow, Maria Zlnam, University of Cincinnati
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TABLE OF CONTENTS
I. SUMMARY ........................... i-l
II. PHYSICAL AND CHEMICAL PROPERTIES ............... II-1
SPECTROSCOPIC PROPERTIES ................... 11-11
CHEMISTRY .......................... 11-11
ANALYTICAL METHODS ................ . ..... 11-12
SUMMARY ........................... 11-14
III. TOXICOKINETICS .................... .... III-l
ABSORPTION .......................... III-T
Oral .......................... III-l
INHALATION .......................... III-3
DERMAL ............................ III-3
DISTRIBUTION AND METABOLISM ................. III-4
Distribution In Human Tissues .............. III-4
Distribution 1n Animal Tissues ............. III-7
MECHANISMS OF TRANSPORT AND METABOLISM ............ 111-23
ELIMINATION ......................... 111-26
SUMMARY ........................... 1 11-33
IV. HUMAN EXPOSURE ........................ IV-1
V. HEALTH EFFECTS IN ANIMALS .................. V-l
ACUTE TOXICITY ........................ V-l
Experimental Lethality Studies ............. V-l
Environmental and Acddentlal Intoxication ....... V-7
Central Nervous System and Behavioral Effects ...... V-9
Cardiovascular Effects ................. V-10
Renal Effects ...................... V-12
Hepatic Effects ..................... V-12
SUBCHRONIC EFFECTS OF ENORIN ................. V-14
CHRONIC EFFECTS ......... . .............. V-20
TERATOGENICITY AND REPRODUCTIVE EFFECTS ........ ... V-29
Maimals ........................ . V-29
Birds ..................... ..... V-38
MUTAGENICITY ...... . .................. V-39
CARCINOGENICITY ........ ............... V-41
SUMMARY ........................... V-56
v1
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Page
VI. HEALTH EFFECTS IN HUMANS VI-1
ACUTE TOXICITY VI-1
Accidental and Intentional Poisonings VI-1
Effects of Occupational Exposures VI-3
Immunology VI-4
Ep1dem1olog1cal Studies VI-4
SUMMARY VI-10
VII. MECHANISMS OF TOXICITY VII-1
ACUTE TOXICITY VII-1
INTERACTIONS VII-5
SUMMARY VII-8
VIII. QUANTIFICATION OF TOXICOLOGICAL EFFECTS VIII-1
INTRODUCTION VIII-1
NONCARCINOGENIC EFFECTS VIII-6
QUANTIFICATION OF NONCARCINOGENIC EFFECTS VIII-10
Derivation of 1-Day HA VIII-10
Derivation of 10-Day HA VIII-11
Derivation of Longer-Terra HA VIII-11
Assessment of Lifetime Exposure and Derivation of DUEL . VIII-13
CARCINOGENIC EFFECTS VIII-14
EXISTING GUIDELINES, RECOMMENDATIONS AND STANDARDS VIII-17
SPECIAL CONSIDERATIONS VIII-19
SUMMARY VIII-21
IX. REFERENCES IX-1
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LIST OF TABLES
No. Title Page
II-l Nomenclature, Indexing Terras and Synonyms Currently
Used for Endrln II-3
II-2 Chemical Information Related to Some Endrln Degradation
Products II-4
II-3 CAS Indexing Terms and CAS RN for Endrln Metabolites. . . . II-5
II-4 Typical Composition of Technical Grade Endrln ....... II-6
II-5 Some Pesticide Mixtures 1n which Endrln 1s not the
Only Pesticide II-8
II-6 Analytical Methods for Determining Endrln or Endrln
Transformation Products 1n Tissues or Animal Fluids .... 11-13
III-l Evidence of Absorption Using Residue and Biological
Effect Data III-2
III-2 Endrln Concentrations Found 1n Victims of Endrln
Poisoning III-6
III-3 Distribution of Endrln and 12-KetoendMn at Day 148
In Sykes Hybrid III Hens (2 kg Initially) Fed 0.13 mg/kg
Diet by Capsule 111-10
III-4 Radioactivity In Tissues of Five Hens After a 148-Day
Period of Treatment with 0.3 yd/Day (as Capsules) 111-11
III-5 Endrln Distribution 1n Birds In the Post-1978
Literature 111-13
III-6 Distribution of Endrln and 12-KetoendMn in Experimental
Animals 111-17
III-7 Distribution of Radioactivity In Various Experimental
Animals after an Acute Oral Dose of Endrln 111-19
III-8 Analysis of Urine from Endrln Plant Workers 1n
England < 111-30
III-9 Estimated Half-Lives 1n Various Species for Elimination
of Endrln Administered by the Oral Route 111-32
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No.
V-l
V-2
V-3
V-4
V-5
V-6
V-7
V-8
V-9
V-10
V-ll
V-12
V-13
V-14
V-15
V-16
V-17
VI-1
VII-1
III-l
Title
Acute ToxUHy of Endrln 1n Experimental Animals
Median Lethal Doses 10 Days After Oral Administration
of Endrln and Its Metabolites to Rats
Endrln Short-Term Oral Dietary LCsg Values
Effects of Acute Endrln Exposure
Effects of Subchronlc Endrln Exposure
Mortality of Animals Exposed to 0.36 ppm (5.62 vg/m')
Endrln 'Vapor1
Effects of Oral Chronic Effects After Endrln Exposure . . .
Teratogenlclty and Reproductive Studies Performed
with Endrln 1n the 1960s
Reproductive Effects of Endrln for Studies Performed
since 1970
Negative Studies of the Carcinogenic Potential of Endrln. .
Incidence of Malignant Tumors In Male Rats Ingesting
Endln .
Incidence of Malignant Tumors 1n Female Rats Ingesting
Endln
Number of Osborne-Mendel Female Rats with Carcinomas. . . .
Number of Osborne-Mendel Male Rats with Carcinomas
Number of Osborne-Mendel Female Rats with Benign
Tumors
Number of Osborne-Mendel Male Rats Ingesting Endrln
with Benign Tumors
Analysis of Incidence of Primary Tumors In Osborne-Mendel
rats fed Endrln 1n the diet
Description of Plants Included In the Study of
Manufacturers of Organochlorlne (OC) Pesticides ......
Height Loss and Llpld Content (MeanX + S.E.) of Quail
Carcasses After Technical Chlordane, 98%-Pure Endrln,
and Chlordane-Endrln Treatments
Summary of Data Used to Derive HAs or DUEL
Page
V-2
V-6
V-8
V-15
V-21
V-23
V-30
V-32
V-34
V-42
V-45
V-46
V-49
V-50
V-52
V-53
V-57
VI-9
VII-7
VIII-U
1x
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LIST OF ABBREVIATIONS
ATP Adenoslne tMphosphate
bw Body weight
CC1. Carbon tetrachloMde
CMS Central nervous system
DHSO Dimethyl sulfoxlde
ONA Oeoxyrlbonuclelc add
dw Dry weight
DUEL Drinking water Equivalent Level
EC Electron capture
EEG Electroencephalogram
GABA Gamma -ami nobutyrlc add
GC Gas chromatography
GI Gastrointestinal
HA Health advisory
1.p. Intraperltoneal
1.v. Intravenous
LD50 Dose Lethal to 50% of the recipients
LDgo Dose lethal to 90X of the recipients
LDH Lactic dehydrogenase
LOAEL Lowest-observed-adverse-effect level
LOEL Lowest-observed-effect level
MEL Minimal effect level
MS Mass spectroscopy
NADPH N1cot1nam1de adenlne dlnucleotlde phosphate
(reduced form)
NAPH Nlcot1nam1de adenlne dlnucleotlde (reduced form)
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
PCAA Polychlorocycloalkane
ppm Parts per million
RfO Reference dose
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SGOT Serum glutamlc oxaloacetk transamlnase
SGPT Serum glutamlc pyruvlc transamlnase
ST5Q Survival time of 50% of the recipients
TBPS t-Buty1b1cyclophosphoroth1onate
TLC Thin-layer chromatography
TLV Threshold limit value
TWA Time-weighted average
ww Wet weight
x1
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I. SUMMARY
EndMn 1s an organochlorlne a11cycl1c pesticide first Introduced Into
the United States 1n 1951. It 1s produced by the epoxldatlon of Isodrln
obtained from the reaction of hexachlorocycloheptadlene and
cyclopentadlene. It has been produced 1n the United States by the Velslcol
Chemical Corporation. Endrln currently has United uses (1979 usage: 176
megagram) In the cotton growing regions of western Oklahoma, western Texas,
New Mexico, Arizona and California. It controls pale-western and army-cut-
worms and grasshoppers, as well as eastern pine voles, western meadow voles,
sugar cane beetle and 1s used to treat conifer seeds. Endrln 1s no longer
commercially available 1n the United States.
Endrln 1s a compound of low solubility 1n water, high solubility In non-
polar organic solvents, low vapor pressure (2.7x10~7 mm Hg at 25'C), high
absorptive potential 1n high organic-content soils, and a large octanol/
water coefficient (2.18x10').
The major analytical methods for endrln Include extraction, column
chromatography, gas chromatography/electron capture (GC/ECO) and gas
chromatography/raass spectrometry (6C/MS). Acidification or high
temperatures will decompose endrln. Endrln has low recoveries from waters
at pH 2 (23%), but >60X recoveries at pHs >7. In contrast. Us acid
decomposition product, endrln ketone, Is well recovered from waters at all
pHs. The photodecomposltlon product, the half-cage ketone, has also been
found In environmental media. Spills of endrln 1n the environment have been
detoxified by reaction with acidified zinc dust. Standard U.S. EPA and
NIOSH analytical methods are used for measuring endrln.
00630 1-1
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Endrln has occasionally been found In drinking water and In food;
measurable levels of endrln have not been detected 1n adipose tissue or the
blood of the general population. Endrln 1s absorbed through the skin, by
the lungs and by the gut, but no quantitative rates are known. Animals,
birds and humans who have been exposed to large amounts of endrln have shown
residues. In all warm-blooded species studied thus far, endrln Is quickly
metabolized and Us metabolites quickly eliminated. Endrln deposition in
tissues, especially fat, does occur at high doses In experimental animals
and 1n birds. Residues have been detected 1n liver, brain, kidneys and
fat. Endrln has a weighted average bloconcentratlon factor (6CF) of 3970
for the edible portion of all freshwater and estuaMne fish and shellfish
consumed by United States residents.
Poisoning Incidents have occurred 1n animals and man; convulsions In man
are known to occur above doses of 0.2 mg endMn/kg bw. Blood residues have
been found In humans grossly exposed to endrln In occupational and poisoning
Incidents. Endrln poisoning Incidents have been documented In Wales, the
United Arab Republic, Qatar, Pakistan and Saudi Arabia. The major toxicant
In mammals 1s considered to be the metabolite, 12-ketoendrln, but endrln
Itself Is considered the toxicant 1n birds; residues In brains are also
supportive of these hypotheses. Modes of elimination are species dependent,
but 1n mammals the measured and calculated half-lives of endrln derived
material are between 1 and 4 days. The major metabolite In mammals Is antl-
!2-hydroxyendr1n glucuronlde. Hydroxylatlon at the 3-pos1t1on, epoxlde
hydratlon and production of 12-ketoendrln also occur.
00630 1-2
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Endrln has been shown to penetrate the placenta! barrier In rats, mice
and hamsters. In rats, >50% of endrIn-derived material 1s eliminated within
1 day In the bile as glucuronldes, which after enterobacterlal degradation
and enterohepatlc circulation are eliminated as aglycones In the feces.
Excretion occurs slower In females than In males. Cows excrete free
ant1-!2-hydroxyendr1n conjugated 1n the urine as the sulfate. This also
occurs 1n hens. The antl.-12-hydroxyendrln has been detected as the
glucuronlde In the urine and feces of humans. Hens appear to eliminate
endrln faster than other birds; with endrIn Itself being excreted. Endrln
accumulates more 1n birds than 1n mammals.
Exposure to endrln 1n humans causes CMS effects, convulsions, and In
some cases, death. In endrln poisoning cases, electroencephalograms show
paroxysms of predominantly bilateral synchronous theta waves. In mild
poisoning, recovery 1s usually rapid and there have been no permanent
effects. This 1s consistent with short half-lives for elimination.
Epidemiology studies have corroborated the existence of convulsions and
other CMS effects In endrIn-exposed workers.
The acute oral LD,Q to mammals ranges from 2.3-43.4 mg endr1n/kg bw.
After dermal exposure ID., values range from 11-92 mg endr In/kg bw and are
vehicle-dependent. Inhalation exposure to 5.62 yg endrln/m£ for 7 hours
over 130 days Is not lethal to rats, hamsters and gu'nea pigs. Young
animals are more sensitive than adult animals to the effects of endrln. In
acute studies, sublethal endrln exposures elicited CNS effects Including
convulsions and behavioral changes. Depressed body weight gain was reported
during somewhat longer exposures (<1 month). In subchronlc and chronic
00630 1-3
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studies, dietary exposure of rats and dogs to endrln concentrations >1 ppm
reportedly elicited depressed body weight gain, elevated organ-to-body
weight ratios and/or early mortality.
Prenatal exposure to endrln caused adverse reproductive outcomes In
rats, mice and hamsters. In the latter two species, these outcomes Included
terata, reduced neonatal weight or fetal weight gain and mortality.
Further, evidence of altered behavioral development was reported In all
three species following prenatal endrln exposure.
Endrln was not nutagenlc In bacterial systems with or without metabolic
activation. There are four carclnogenldty bloassays for endrln which are
reported by their authors as negative. An NCI rat bloassay, however, upon
further analysis shows some evidence of tumorIgenlcity. Overall the animal.
studies are regarded as Inadequate I.e. Inconsistent to demonstrate or
refute a carcinogenic potential. Ep1dem1olog1c studies of which there are
several are also Inadequate because of nixed exposures and design
limitations.
The toxic and convulsant potencies of polychlorocycloalkane pesticides
(Including endrln) have been correlated with Inhibition of GABA-med1ated
functions 1n the CNS, particularly chloride 1on transport. Binding of
endrln or endrln metabolites to the SABA receptor may therefore be Involved
In the mechanism of acute endrln toxlclty. The mechanlsm(s) mediating
toxldty following chronic endrln exposure Is not known.
00630 1-4
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The occurrence of convulsions 1s believed to be related to blood-brain
permeability changes or to direct effects on the CMS. Although Inhibition
of membrane ATPases and mitochondria! ATPases from brain tissues have been
detected, which were species-dependent, sucdnyl chollne has prevented
convulsions 1n all species tested. Concentrations of cytochrorae P-450 1n
endMn-reslstant animals (mice, pine voles) may be greater than In suscept-
ible species (guinea pigs); gender may also be Important. The conversion of
endrln to antl- and sj^n-12-hydroxyendrlns, and conversion of the syn-Uomer
to !2-ketoendr1n may be dependent on the level and type of cytochrome P-450.
The acute ID,, values for all these unconjugated metabolites are lower
than for endrln Itself. L1p1d peroxldatlon may also play a role. The
correlation of urinary D-glucar1c add with endrln exposure and the glucuro-
nlde of an11-12-hydroxyendr 1 n 1n the urine In humans would support this
hypothesis. D-glucar1c acid has not been detected 1n human urine unless
ant 1-12-hydroxyendr1n levels 1n endrln equivalents were >0.13 mg/g
creatlnlne.
The U.S. EPA has set an Interim standard for endrln 1n finished drinking
water of 0.0002 rag/l. The. present ambient water quality criteria for the
protection of human health 1s 0.001 mg/i and for the protection of both
freshwater and saltwater aquatic life 1s 0.0023 vg/l. The World Health
Organization established as a guideline a maximum Intake of 2 wg/kg/day,
or 138.2 wg/day, for a 69.1 kg person. The proposed Index AHmentaMus
Commission's maximum residue limit 1n wheat 1s 20 vg/kg.
The threshold limit value (8-hour TLV/TUA) recommended by the American
Conference of Governmental Industrial Hyglenlsts (ACGIH) 1s 0.10 mg/m'
00630 1-5
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(0.10 yg/l), with a short-time exposure limit (15 minutes) of 0.30
mg/m3. Limits set by the Occupational Safety and Health Administration
are the same as those recommended by the ACGIH.
The 1-day health advisory (HA) for endrln 1n drinking water Is 0.05
mg/l for children. A NOAEL of 0.5 mg/kg bw/day based upon decreased loco-
motor activities 1n mice was used to derive the 1-day HA.
The 10-day HA for endrln Is 0.02 mg/l for children. A NOAEL of 0.150
mg/kg bw/day based upon depressed maternal body weight gain 1n rats was used
to derive the 10-day HA.
The longer-term HAs are 0.003 mg/l for children and 0.01 mg/l for
adults, based upon a NOAEL of 0.025 mg/kg/day for mild hlstopathologlc
changes 1n the livers of exposed dogs.
The DWEL for chronic exposure to endrln Is 0.01 mg/l. An RfO of
0.0003 mg/kg bw/day (verified by the U.S. EPA RfD Work Group on 4/20/88}
based upon a NOAEL of 0.025 mg/kg/day for mild hlstopathologlc changes 1n
livers of exposed dogs was used to derive this DWEL.
Using the criteria In the U.S. EPA guidelines for classification of
carcinogens, endrln 1s most appropriately classified In Group 0 (there 1s
Inadequate evidence to assess the potential carclnogenlclty for humans).
This classification 1s based on the nonposltlve but suggestive results 1n
some of the animal studies. The negative conclusions as reported by the
study authors of the four bloassays do not support a Group E classification,
1-6
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because of the Inadequacies of the studies. A U.S. EPA cardnogenlclty
Group D welght-of-evldence classification was verified by the CRAVE Work
Group on 10/19/88.
00630 1-7
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II. PHYSICAL AND CHEMICAL PROPERTIES
Endrln 1s an organochlorlne allcycllc pesticide, Introduced as an
Insecticide Into the United States In 1951. It has an empirical formula of
C12H8C16° and a IBolecular weight of 380.93. It 1s produced by the
epoxldatlon of a product (1sodr1n) obtained from the D1els-Alder reaction of
hexachlorocycloheptadlene and cyclopentadlene (Brooks, 1974a). The major
synthetic pathway 1s shown 1n Figure II-l. It has been manufactured In the
United States by the Velslcol Chemical Corporation. D1p1col1n1c acid at
levels of 0.5-500 ppm relative to endrln content 1s often utilized to
stabilize solid endrln against decomposition by metallic Impurities during
the epoxldatlon step (S1tt1g, 1977). The synonyms of endrln are provided 1n
Table II-l.
Chemical names and Indexing terms for the major chemical degradation
products of endrln are given 1n Table II-2, and for Us major metabolites In
Table II-3. The typical composition of technical grade endrln 1s provided
1n Table II-4. No other composition data were found In the literature
searched.
The 1979 usage of endrln In the United States was -175,500 kg (Anony-
mous, 1979). It was used as an Insecticide on cotton and small grains and
as a rodentldde 1n orchards (Elchers, 1980). UHh certain modifications
endMn's limited use still continues although widespread resistance of many
pests to 1t may account for further decline In Its usage (Federal Register,
1979). Its use 1s still permitted 1n the cotton growing regions of western
Oklahoma and western Texas, New Mexico, Arizona and California. Endrln 1s
used on small grains to control the following Insects: pale-western
00640 II-l
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ZZZ 2000/4000
0.5/3.0 Hours
r:
VII
•cttont/to«th*nol solvent; «Jov
rvactant •ddatier.
2.A;itatt, h**tir.e
•t 45°C for 1 hour
1 htxachlorocycloptr.taiitnt ZI
III •ettyltr.* ZV
V ey:loptr.t*ditnt VI
VZZ •ndrir.
noehlorocthyltnc
xaehl
iiodrin
FIGURE II-1
The Major Industrial Synthetic Pathway for Endrln
(Modified from S1tt1g, 1977)
00640
II-2
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TABLE II-l
Nomenclature, Indexing Terms and Synonyms Currently Used for EndMn
(SANSS data base, June 1983)
CAS RN 72-20-8* Molecular formula: C12H8C160
2,7:3,6-D1methanonaphth[2,3-b]ox1rene, 3,4,5,6,8,9,9-hexachloro-la, 2,2a,3,-
6,6a,7,7a-octahydro-(la a,2 B,2a 6,3 «, 6 a,6a 6,7 B,7a a)-(9CI)b
l,4:5,8-D1methanonaphthalene, l,2,3,4,10,10-hexachloro-6,7-epoxy-l,4,4a,5,-
6,7,8,8a-octahydro-endo,endo- (8CI)c
Compound 269
Endrex
EndrUol
Endrln
Endrln Isomer
Endrlne (FRENCH)
Experimental Insecticide 269
EN 57 (VAN)
ENT 17,251
Hexachloroepoxyoctahydro-endo,endo-dlmethanonaphthalene
Hexadrln
Mendrln
NCI-C00157
Oktanex
SO 3419
MLN: T E3 05 C555 A A- FO KUTJ AG AG BG JG KG LG ENDO ENOOd
l,2,3,4,10,10-Hexachloro-6,7-epoxy-l,4,4a,5,6,7,8,8a-octahydro-endo-l,4-endo-
5,8-dlmethanonaphthalene
l,2,3,4,10,10-Hexach1oro-6,7-epoxy-l,4,4a,5,6.7,8,8a-octahydro-l,4-endo,endo-
5,8-dlmethanonaphthalene
aChem1cal Abstracts Service Registry Number
bN1nth Collective Index, Chemical Abstracts
GE1ghth Collective Index, Chemical Abstracts
dW1swesser Line Notation
00640 II-3
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TABLE 11-2
Chemical Information Related to Some Cndrln Degradation Products
Common Chemical Names
and Molecular Formula
CAS Indexing Term and CAS RN
Comment
Reference
Endrln aldehyde
SO 7442
C12H8C160
Endrln ketone
A-ketoendrln
SO 2614
Ci2H8C160
No common chemical name
2.3,4,5.6-hexachloro-12-
oxopentacyclo[5.4.1.I"''
.05»9]tr1decane
Endrln alcohol
1.2,4-Methenocyclopenta[cd]pentalene-5-
carboxaldehyde. 2.2a,3.3.4.7-hexa-
chlorodecahydro-(l a.2 0.2a B. 4 B,4a
B. 5 B. 6a B,6b 0..7R)-
7421-93-4
2.5.7-Metheno-3H-cyclopenta[a]pentalen-
3-one. 3b, 4,5,6.6,6a-hexach1orodeca-
hydro-(2 a.3a B,3b B.4 0. 5 0. 6a B,
7 «.7a 8.8R)-
S3494-70-5
6.2.3.5-[1.2]propaned1yl[3]yl1dene-2H-
pentaleno(l,6-bc]furan, 2a,3,4,4,4a,
6b-hexachlorooctahydro-
659S6-39-0
1.5,2,4-Ethaned1y11denecyc1openta[cd]
pentalen-1(2H)-ol. 2.2a.3,3.4.8-hexa
chlorooctahydro-
Stereochemlcal configura-
tion of aldehyde revised;
structure confirmed with
"C and »H nmr spectral
data. Cpd Is produced by
thermal or photochemical
rearrangement of endrln
Principal product of
reaction of endrln with
H2S04
nmr spectra
Minor product (6-8X) of
acid catalyzed rearrange-
ment of endrln; single
crystal X-ray diffraction
and nmr data
iaC nmr spectra
Bird et al..
1978
Cox and
McKlnney.
1978
ApSlmon
et al., 1982
Cox and
McKlnney,
1978
ApSlmon
et al.. 1982
Cox and
McKlnney,
1978
33058-12-7
-------
TABLE II-3
CAS Indexing Terms and CAS RN for Endrln Metabolites
(from CHEHLINE. 1983}
Common Chemical Names
and Molecular Formula
CAS Indexing Term and CAS RN
12-KetoendMn
WL 41435
C12H6C1602
ant1-12-Hydroxyendr1n
WL 41434
C12H8C16°2
3-Hydroxyendr1n
C12H8C16°2
2,7:3,6-01methanonaphth(2,3-b)ox1ren-8-one,
3,4,5,6,9,9-hexachloro-la,2,2a,3,6,6a,7,7a-octa-
hydro-,(la o,2 B,2a 8,3 a,6 a,6a 6.7 B,7a <»)-
(9CI)
1,4:$,8-D1methanonaphthalen-9-one,
1,2,3,4,10,10-hexachloro-6,7-epoxy-l,4,4a,5,6,7,
8,8a-octahydro- (SCI)
28548-08-5
2,7:3,6-D1methanonaphth(2,3-b)ox1ren-8-o1,
3,4,5,6,9,9-hexachloro-la,2,2a,3,6,6a,7,
7a-octahydro-, (la a,2 6,2a 6,3 a,
6 *,6a 8.7 B.7a «)- (9CI)
l,4:5,8-01methanonaphthalen-9-ol,
l,2,3,4,10,10-hexachloro-6.7-epoxy-l,4,4a,5.6,7,
8.8a-octahydro- (SCI)
49748-76-7
2.7:3,6-01methanonaphth(2.3-b)ox1ren-2(laH)-o1,
3,4.5,6.9.9-hexachloro-2a.3,6,6a,7,7a-hexahydro-.
(la a.2 ».2a 8.3 a,6 a.6a 8.7 B,7a a)- (9CI)
57378-25-3
CI • Collective Index
00640
II-5
-------
TABLE II-4
Typical Composition of Technical Grade EndMn*
Component X (by weight)
EndMn 96.6
HEOD (dleldMn) 0.42
HHDN (aldrln) 0.03
Isodrln 0.79
Heptachloronorbornadlene 0.03
Heptachloronorbornene 0.08
4-Ketoendr1n 1.57
1,2,3,4,5-pentachloro-7-oxo-l,4,5,6-tetrahydro-l,4- 0.09
methanobenzene
Endrln aldehyde <0.05
Acidity (as HC1) 0.18
Unidentified 0.12
Hater content <0.1
Xylene Insoluble residue <0.5
•Adapted from Brooks, 1974a
00640 II-6
-------
cutworm, army cutworm, and grasshoppers. Additionally, 1t Is used to con-
trol the sugarcane beetle and pine voles In the eastern United States and
western meadow voles In the western United States and 1n the treatment of
conifer seeds (Federal Register, 1979). It 1s also used as a bird perch
toxicant (Hadler, 1982). EndMn has been generally coformulated to minimize
Us tendency to decompose In some common formulation carriers (Brooks,
1974a). Often, up to 15X (w/w) of hexamethylene tetramlne has been used for
this purpose. Endrln Is often coformulated with methyl parathlon In
emulslflable concentrates. A selected 11st of pestlddal mixtures 1n which
endMn 1s not the only pestlddal component Is provided 1n Table II-5. Pure
endrln appears to decompose above 245*C (Hetcalf, 1981), although technical
grade endrln (>92% endrln) decomposes above 200*C (Brooks, 1974a).
Presently, manufacture and use has been discontinued 1n the United States
(Merck Index, 1983).
Endrln 1s soluble In nonpolar solvents. The solubility of pure endrln
(1n g/100 mi at 25*C) Is as follows: acetone, 17; benzene, 13.8; carbon
tetrachlorlde, 3.5; xylene, 18.3; and water, 0.000023 (0.23 rog/l)
(Hetcalf, 1981). The equivalent solubilities for technical grade endrln
(55-57X chlorine content) Is as follows: acetone, 31; benzene, 51; carbon
tetrachlorlde, 51; Isopropanol, 3; methanol, 2; methyl ethyl ketone, 40;
toluene, 74; and xylene, 55 (Brooks, 1974a). The specific gravity of the
technical grade compound 1s 1.7 at 20*C. The vapor pressure of technical
grade endrln Is 2.7xlO"7 mm Hg at 25*C (Brooks, 1974a). Endrln appears to
obey a Freundllch adsorption Isotherm 1n the presence of an activated carbon
(200/400 mesh) aqueous slurry (U.S. EPA, 1980b). Kenaga (1980) has provided
the following physical constants for endrln at 25*C: water solubility,
00640 II-7
-------
o
o
o»
TABLE 11-5
Son* Pesticide Mixtures In which Endrln Is not the Only Pesticide
(Chcmname. 1983)*
CAS Registry Component CAS Registry
Number Numbers
Component Chemical Names
(endrln chemical name omitted)
Synonyms
53858 08-5 (50-29-3. 72-20-8. 298-00-0) 1.1'-(2.2.2-tr1chloroethyl1dene)b1s(4-
chlorobenzene)
00
58939-75-6 (72-20-8. 121-75-5)
59928824 (72-20-8.947-02-4)
64034 60-2 (57-13-6. 72-20-8)
8017-73-0 (60-57-1. 309-00-2)
(72-20-8)
8066-55-5 (72-20-8. 640-15-3)
Phosphorothlolc acid. 0.0-dlmethyl-O-
(4-nttrophenyl) ester
Butanedlolc acid, ((dlmethoxyphosphlno-
th1oyl)thlo)-. dlethyl ester
Phosphoramldlc acid. 1.3-d1th1olan-2-
ylldene-, dtethyl ester
urea
2.7:3.6-D1methanonaphth(2.3-b)ox1rene.
mixture with (l.«..4.a..4a.B..5.a.,
8.a..8a.B.)-1.2.3.4.10.10-hexachloro-
1.4.4a.5.8.8a-hexahydro-1.4:5.8-d1metha-
nonaphthalene
Phosphorodlthlolc acid. S-(2-(ethyl-
th1o)ethy1)-0.0-d1methyl ester, mixture
DDT-endrln-methyl para-
thlon mixture
Nalathlon-endrln
mixture
Cyolane-endrln mixture
Endrln-urea mixture
Leplt; Aldrln-dleldrln
mixture; Blnarln
Veldrln EE 922:Veldr1n;
Ekadrln; Thlometon-
endrln mixture
-------
o
o
TABLE 11-5 (cont.)
CAS Registry Component CAS Registry
Number Numbers
Component Chemical Names
(endrln chemical name omitted)
Synonyms
8075-40-9 (72-20-8. 309-00-2)
37247-09-9 (50-29-3. 72-20-8)
37262-64-9 (72-20-8, 298-00-0)
37338-61-7 (72-20-8. Ml-66-2)
51602-20-1 (72-20-8. 21609-90-5)
59928-83-5 (72-20-8. 950-10-7)
61912-61-6 (72-20-8. 6923-22-4)
Nlxture with (l.a..4.a..4a.O..5.a.,
8.a..8a.B)-1.2.3.4.10.10-hexachloro-
1.4.4a.5.8.8a-hexahydro-1.4:5.8-d1metha-
nonaphthalene
Nlxture wtth 1.1'-(2.2.2-tr1ch1oroethy1-
Idene)b1s(4-chlorobenzene)
Phosphorothtolc acid. 0.0-dlmethyl-O-
(4-nttrophenyl) ester, mixture
Phosphoric acid. 3-(d1methylamtno)-1-
methyl-3-oxo-l-propenyl dimethyl ester.
mixture
Phosphonothlotc acid, phenyl-. 0-(4-
bromo-2.5-d1chlorophenyl) 0-methyl
ester, mixture
Phosphoramtdtc acid. (4-methy1-1.3-
dlthlolan-2-yltdene-. dlethyl ester.
mixture
Phosphoric acid, dimethyl-1-methyl-3-
(methylamlno)-3-oxo-l-propenyl ester.
(E)-. mixture
Aldrtn mixture with
endrln; Endlonal;
Nauxan; Tricot In
DOT-endrln mixture;
Endrln-DOT mixture
Endrln-methyl parathlon
mixture
Endrln-bldrln; Endrtn-
bldrln mixture; Endrln-
dlcrotophos
Endrln-leptophos
mixture
-------
TABLE 11-5 (cont.)
CAS Registry Component CAS Registry
Number Numbers
Component Cheatcal Names
(endrln chemical name omitted)
Synonyms
62588-93-6 (56-38-2. 72-20-8)
62815-24-1 (72-20-8. 13171-21-6)
63952-62-5 (72-20-8, 16752-77-5)
£ 63952-72-7 (72-20-8. 2104-64-5)
65437 77-6 (72-20-8. 7704-34-9)
Phosphorothlolc acid. 0,0-dlethyl-O-
(4-nltrophenyl) ester, mixture
Phosphoric acid. 2-chloro-3-(d1ethyl-
amlno)-1-methyl-3-oxo-l-propeny1
dimethyl ester, mixture
Ethanlmtdothlolc acid. N-(«methyl-
amtno)carbonyl)oxy)-, methyl ester,
mixture
Phosphonothtolc acid, phenyl-. 0-ethyl.
0-(4-n1trophenyl) ester, mixture
EndrIn-sulfur mixture
•Dialog Information Services. Inc.
-------
0.024 ppm (compare the 0.23 ppm value above); octanol/water partition
coefficient, 2.18xlOs; and a calculated organic soil adsorption constant
of 3.4x10*. Jarvlnen and Tyo (1978) reported the water solubility of
endrln at 200
Spectroscoplc Properties
Since endrln 1s not aromatic and does not contain conjugated double
bonds, it has a Iy of 148V1 era'* at the xmax at 225 nm
(TewaM and Sharma, 1978). Thus, ultraviolet/visible spectroscopy would be
neither sensitive nor useful analytically.
Infrared analysis 1s practical when utilizing the peak at 11.76 win and
baseline points at 11.50 and 11.97 & (Brooks, 1974b). The mass spectrum
1s diagnostic (Safe and Hutzlnger, 1973a). The molecular Ion (m/e 378) Is.
small with successive losses of Cl (m/e 343, 308). These latter peaks are
Intense enough to be utilized for specific 1on monitoring purposes. A Retro
Dlels-Alder process also occurs. Chemical 1on1zat1on mass spectrometry has
also been performed (Safe and Hutzlnger, 1973b). Cox and HcKlnney (1978)
measured the "C-NHR spectra of endrln, endrln aldehyde, endrln ketone and
endrln alcohol.
Chemistry
Endrln decomposes at temperatures above 200*C or when stored for long
periods, with endrln aldehyde and a pentacycllc aldehyde as decomposition
products (Brooks, 1974a). This process 1s Important for gas chromatographlc
analysis 1n metal columns (Phillips et al., 1962). Endrln undergoes epoxlde
ring opening and rearrangement 1n the presence of add or of metal cata-
lysts, I.e., Iron compounds (Brooks, 1974a). Endrln ketone Is the principal
00640 11-11
-------
product of add decomposition (ApSlmon et al., 1982). Endrln can undergo
the usual addition reactions, and also complex transannular rearrangements.
Uhen exposed to wavelengths of 253.7 and 300 nm and to sunlight, endrln In
hexane and cyclohexane decomposes to the following half-cage ketone, 1,8-exo-
9,n,ll-pentachloropentacyclo[6.2.1.13t6.02'7.04'10]dodecan-5-one, with 60%
conversion 1n 8 hours. This product has been Identified In environmental
samples (ZabHc et al., 1971). Photorearrangement 1s possible above 300 nm
1n the presence of appropriate photosensltlzers, e.g., silica gel (Iv1e and
Caslda, 1971a) and rotenone on bean leaves (Iv1e and Caslda, 1971b). For
the latter 'se jut not the former, endrln ketone and endrln aldehyde are
the major produ.::. The nomenclature, CAS Indexing terms and CAS RNs for
the major degradation products are given 1n Table II-2. The reaction of
acidified zinc dust with endrln has been suggested as a degradation pro-
cedure 1n the field (Butler et al., 1981).
Analytical Methods
The most recent analytical methods for endrln 1n animal tissues and
fluids are summarized In Table II-6. Most of the methods Involve extraction
to separate endrln from Us matrix, then cleanup or extraction before elec-
tron capture gas chromatography (EC/GC) or gas chromatography/mass spectrom-
etry (GC/MS). Heating above 200*C or acidification In any of the analytical
steps will cause degradation of the endrln as described In the chemistry
section. This may be the reason for the highly variable recoveries quoted
In the literature or for residues not being detected 1n the majority of
studies. For water analysis, 1f waters are already addle, probably most of
the endrln will have been degraded already to endrln ketone. In water at
25"C and pH 2, endrln recovery 1s 23%; at pH 7-10 Us recovery Is 88%
(Millar et al.. 1981). At 4*C and pH 2. however, the recovery 1s 92%; 85%
00640 11-12
-------
o
o
o>
TABLE 11-6
Analytical Methods for Determining Endrln or Endrln Transformation Products
In Tissues or Animal Fluids
Human Tissue or Fluid
Compound Determined
Method
Reference
Human urine
Human adipose tissue
tow milk
Bird brain
ant 1-12-hydroxyendrIn and
B-glucuronlde conjugate
endrln
endrln
endrln
oxidation of conjugate with meta
perlodate hydrolysis;hexane
extractlon/EC/GC
hexane extraction/gel permeation
chromatography cleanup/EC/GC
(100* recovery at 3.2 ppm)
hexane extraction/gel permeation
chromatography cleanup/EC/GC
(105X recovery)
extractlons/Florlsl! cleanup/
EC/GC (BOX recovery; detection
limit 0.5 ppb)
sodium sulfate/mllllng/soxhlet
extraction (dlethylether and
petroleum etherJ/EC/GC (70»6X
recovery; detection limit 0.05
ppm for a 1 g sample)
Baldwin and
Hutson. 1980
MacLeod et al.,
1982
Tessarl et al..
1980
Frank et al..
1979
Ludke. 1976
-------
of endMn aldehyde 1s recovered at pH 2, 7 or 10 at 4* or 25°C but 1s
degraded 1n the presence of chlorine at pH 10 (Millar et al., 1981).
Carbopack B columns have also been used to concentrate 8 ppb endMn from
water (Manganl et al., 1981), as have XAD-2 resins (Rees and Au, 1979). A
standard NIOSH method 1s available for monitoring airborne endMn In the
personal sampling mode (solid sorbent/battery powered pumps) (Taylor, 1980).
Summary
EndMn is an aliphatic organochloMne Insecticide with a molecular
weight of 380.93, water solubility of 0.024 ppm, specific gravity of 1.7 at
20*C, vapor pressure of 2.7xlO~7 mm Hg at 25'C and an octanol water parti-
tion coefficient of 2.18x10*. It was used predominantly to control cut-
worms and grasshoppers, but has also been used as a rodentklde In the
control of eastern pine voles and western meadow voles.
EndMn decomposes at temperatures >200*C Into endMn aldehyde and a
pentacycllc aldehyde. Adds or metals (Iron) will also decompose endMn
Into endMn ketones and aldehydes. Following extraction methods, endMn
levels In tissue and water analysis may be determined by EC/GC or GC/MS
techniques.
00640 11-14
-------
III. TOXICOKINETICS
This section refers only to data relevant to warm-blooded vertebrates.
Absorption
Endrln Is absorbed through the skin, by the lungs and by the gut (U.S.
EPA, 1980a). Rates of absorption have not been documented. That absorption
does occur Is demonstrated by the data In Table III-l concerning residue
levels and biological effects after exposure.
Oral. U1ld and domestic animals that have absorbed endrln through
1ngest1on of treated foliage can show residues 1n fat, blood and milk (see
Table III-l). Several poisoning Incidents have occurred through animal
feeds (Long et al., 1961; TerMere et al., 1958; Kllgemagl et al., 1958;
Hunter et al., 1960; U.S. EPA, 1980a). For an early review of poisoning
Incidents see Brooks (1969).
Animals and birds at the top of food chains as well as humans may be
particularly affected by the oral route of exposure If the chemical or Us
metabolites bloaccumulate. The weighted average BCF for endrln 1s 3970 for
the edible portion of all freshwater and estuarlne fish and shellfish
consumed by U.S. residents (U.S. EPA. 1980a).
Humans have Ingested endrIn-treated agricultural products (Carey et al.,
1979) as well as meat from domesticated and wild animals, birds and fish.
Poisoning of humans after accidental contamination of food has been
attributed to doses of 0.2 ng/kg bw (U.S. EPA. 1980a).
00650 III-l
-------
o>
in
o
TABLE II1-1
Evidence of Absorption Using Residue and Biological Effect Data
Route of
Absorption
Applied Dose
Residues
Biological
Effects
Reference
Oral
IV)
Inhalation/
deriul
Dermal
not known on
pasture
510 mg over 30
days to pigs
20 mg/day/cow
>0.2 mg/kg bw
In humans
•grossly exposed"
humans
animal mortality
data
Carworth Farm Strain
E (CFE) rats In acute
dose response experi-
ments
up to 24 pg/g
fat. 6.4-14
after 42 days
up to 2 pg/g fat
up to 0.2S |ig/g
milk
up to 10 ug/g
blood 400
fat
residues >1
blood
not reported
Not reported
Not reported
Not reported
Poisoning symptoms
In humans; convul-
sions
Convulsions at >0.2
mg/kg bw
Ratio of dermal to
acute oral L0$n for
20* emulslflable con-
centrate Is 1.6; and
for 2X dust Is 13
Long et al.. 1961
Hunter et al..
1960
U.S. EPA. 1980a
U.S. EPA. 1980a
Hayes. 1963
Coble et al.. 196?
Weeks. 1967
Cur ley et al.. 1970
Tewarl and Sharma.
1978; Rowley et
al.. 1987
Jager. 1970
Nulr. 1968
-------
Inhalation
Since the vapor pressure of technical endMn Is 2.7xlO~» on Hg at 21*C
(see Chapter II), this Is equivalent to a vapor density of 5.5 ng/m* of
air. Consideration of endrln's inhalation hazard to humans led the American
Conference of Governmental Industrial Hyg1en1sts (ACGIH, 1982) to set the
threshold limit value, 8-hour time weighted average (TLV-TUA), to be 0.10
mg/m> with a short-term exposure limit (STEL) for 15 minutes of 0.30
mg/m* (skin). The OSHA standard based on the 1968 ACGIH TLV 1s 0.10
mg/m* (skin) (NIOSH, 1978). Dermal absorption occurs concurrently with
air exposure as denoted by the "skin* designation.
Few blood residues have been found In endrln-exposed workers, except In
those grossly exposed (Jager, 1970). The absence of residues may Imply fast
metabolism or negligible absorption. In this case, fast metabolism Is
responsible.
Dermal
The most significant dermal exposures to endMn 1n the occupational
environment have occurred during field applications (Wolfe et al., 1963.
1967). Unfortunately, no residues have been reported to confirm absorption.
Both inhalation and dermal exposure have occurred during endMn manufacture
and distribution, but only grossly exposed workers have ever shown residues.
Nevertheless, convulsions have been reported In such workers (Jager, 1970).
The dermal acute ID5Q value for male CFE strain rats was 1.6 times
that for the oral acute value (diet) when the rats were exposed to a 20X
00650 III-3
-------
emulslMable concentrate (Hulr, 1968). Similarly, for exposure to a 20%
field strength dust, the ratio was 13 (Hulr, 1968), Illustrating the
Importance of the carrier 1n dermal absorption (see Chapter V). Such data
demonstrate that endrln Is absorbed through the skin of rats and 1s probably
also absorbed through human skin, as the •skin1 designation for the ACGIH
TLV-TWA Implies.
Distribution and Metabolism
In contrast to Us stereolsoner dleldrln, endrln 1s rapidly metabolized
In mammals and the metabolites are also quickly eliminated. Thus, the
distribution of endrln itself 1n tissues even after high doses may be below
detection limits. Under such conditions, distribution studies with radio-
labeled endrln may not reflect endrln distribution, but that of Us metabo-
lites. However at very high doses, e.g. human poisoning cases, gross occu-
pational exposures or 1n suicide cases, endrln can be detected In tissues.
Endrln appears to accumulate more In birds (excluding chickens) than In
mammals.
Distribution 1n Hunan Tissues. Endrln Is a relatively nonperslstent
pesticide 1n humans. Measurable levels of endrln have not been detected In
adipose tissue (Kutz et al., 1979) or the blood of the general population,
even In those areas where endrln was used extensively, such as India or the
lower Mississippi delta area (Brooks, 1974a). Endrln also has not been
found In the blood of workers who manufacture or formulate endrln (Hayes and
Cur ley, 1968; Baldwin and Hutson, 1980) except In the case of very high
levels of exposure (Jager, 1970).
00650 III-4
-------
Measurable tissue endrln concentrations are reached in cases of acute
poisoning. The time of sample collection 1s Important to these measure-
ments, as endrln residues decline rapidly 1n tissues after cessation of
exposure. Endrln concentrations as high as 10 tog/kg In blood and 400 mg/kg
1n fat have been reported (Hayes, 1963). In an Incident Involving three
acutely poisoned humans 1n the United Arab Republic 1n 1967, no endrln was
detected (<4 tig/kg) 1n cerebrosplnal fluid (Coble et al., 1967). The
serum, 30 minutes after one patient's convulsion, contained 53 ng endrln/
mi. After 20 hours the serum concentration was 38 ng/rai, and after a
further 10 hours, 21 ng/rai. In the same patient, the endrln level 1n a
24-hour urine sample after convulsion was 20 ng/mt. Levels of endrln much
lower than 10 mg/kg tissue were obtained In autopsies of 26 Saudi Arabians
poisoned by endrIn-contaminated bread (Weeks, 1967; Curley et al., 1970).
In the same Incident 874 people were hospitalized, and another 500-750
people were also exposed. Blood from the hospitalized patients contained
7-32 ng endrln/mi blood. Blood and urine samples taken from patients
29-31 days after the episode contained no detectable amounts of endrln. In
the Punjab province of Pakistan between July 14 and September 26, 1984.
there were 192 cases of probable endrln poisoning (Rowley et al., 1987).
Blood levels from 12 of 18 patients with convulsions had measurable levels
of endrln ranging from 0.3-254 ppb (0.3-254 tig/kg). No endrln was
detected in the urine (Rowley et al., 1987). Summary data are given In
Table III-2.
TewaM and Sharma (1978) studied the concentration of endrln by TIC/
ultraviolet spectrophotometry of autopsy materials of eleven cases of fatal
poisoning. These results are also summarized In Table III-2. High concen-
trations were found In fat-containing tissues, even for a time to death of 6
00650 III-5
-------
TABLE II1-2
EndMn Concentrations Found
1n Victims of EndHn Poisoning
Sample
Blood
Urine
Vomltus
Tissues (autopsy) from:
Stomach
Liver
Kidney
Spleen
Heart
Lung
Intestine
Endr
In Saudi Arabia3
(»g/kg)
0.007-0.032d
0. 004-0. 007d
5.24
0.16
0.685
0.116
NA
NA
NA
NA
1n Concentrations
In Pakistan* 1n
Ug/kg)
0.3-254
oe
NA
NA
1430
1760
NA
NA
NA
13,690
Su1ddesc
(mg/kg)
4.3-8.5
2.5-5.5
32.5-81.2
10.4-145
9.4-200
7.5-51.7
2.4-21.7
5.6-19.9
3.8-10.8
13.1-660
aCurley et al., 1970 (Includes first and third Oohar outbreaks and Hofuf
outbreak)
°Rowley et al., 1987 (192 cases of endrln poisoning)
cTewar1 and Sharma, 1978 (11 suicides)
dOn day of onset
«None detected 1n 12 patients
NA . Not analyzed
00650
III-6
-------
poisoning. These results are also summarized In Table III-2. High concen-
trations were found In fat-containing tissues, even for a time to death of 6
hours. There was some evidence to suggest that endrln In combination with a
fatty carrier, such as milk, caused death faster than when Ingested with
solid food. The levels quoted may be In error as endrln, 12-hydroxyendrln
or 12-ketoendMn were not separated.
Little 1s still known of the distribution and persistence of endrln
metabolites In human tissues. Baldwin and Hutson (1980) were unable to
detect ant 1-12-hydroxyendrln or 12-ketoendr1n 1n the blood of endrln workers
at a Shell manufacturing plant In England. The method used had a detection
limit of 2 ng/mi for both compounds.
By analogy with observations made In experimental animals, 1t may be
speculated that endrln and Its metabolites are rapidly eliminated. It Is
noteworthy In this regard that recovery from an acute poisoning episode Is
rapid, on the order of a day. (Davles and Lewis, 1956). so that If toxic
metabolites are formed In humans they are not persistent.
Distribution 1n Animal Tissues.
Birds — Researchers agree that orally dosed endrln Is absorbed
from the avlan gut and stored In various body tissues by both wild and
domestic species (Terrlere et al., 1959; Relchel et al., 1969).
After absorption of endrln, residues have been reported to be distribut-
ed among liver, brain, adipose, eggs, breast muscle and gonadal tissues.
00650 III-7
-------
Adipose tissues generally contained the highest concentration (Gregory,
1970; Terrlere et al., 1959), while brain tissues usually contained the
lowest (Rekhel et al., 1969).
Terrlere et al. (1959) examined the tissues and eggs of chickens exposed
to levels of 0.1, 0.25 and 0.75 rag endMn/kg feed. In one experiment,
1-month-old male Delaware X New Hampshire chicks were fed the various endrln
levels for 6 weeks and then sacrificed, while 6-month-old White Leghorn
pullets were exposed to the endrIn-fortified feed for 8 weeks and were
returned to the basal diet for 4 additional weeks. A repeat of the male
chick experiment using New Hampshire X Delaware chicks was also performed.
In all endrln exposures, the amount of adipose tissue was found to be meager
even though weight gain and feed consumption appeared to be normal. At a
level of 0.25 mg/kg feed or higher, definite deposition of endrln In the egg
tissue occurred within 2-4 weeks after exposure had ceased. Accumulation of
endrln In adipose tissue was found 1n both experimental groups with even the
lowest dietary level showing evidence of deposition. Analysis of breast and
tibia tissue revealed endrln deposition at both the 0.25 and 0.75 mg/kg feed
Intake levels.
The fat tissue of the plain chachalacas, Ortalls vetula. was analyzed by
Marlon (1976) for pesticide residues during 1971 and 1972. In four differ-
ent study areas 24 birds had an average endrln residue of 0.13+0.52 mg/kg
weight. There was no evidence that these birds died of endrln exposure.
Only 8 of the 24 birds sampled contained detectable endrln residues.
00650 II1-8
-------
The percentage of the dose retained by bobwhUe quail appears to be
dependent upon administration time and dose according to Gregory et al.
(1972). Analyses of whole birds fed equal doses of endrln-contamlnated
beans or beetles revealed retention of -16X of the total acute dose
Ingested, while 21X of the total chronic dose was retained. The residues
found 1n the body tissues during the acute and chronic experiments differed,
but not consistently. The average endrln content 1n adipose tissues 1n the
acute dosage group was 0.01 ML002 mg/kg ww, as compared with 0.010+0.001
mg/kg found 1n the chronic dosage group. Gonadal tissues from both groups
contained traces of endrln, while the concentration of liver residues 1n the
chronic test was 0.007 mg/kg and In the acute test, 0.004 mg/kg.
Baldwin et al. (1976) fed 10 Sykes Hybrid III hens (-2 kg) 0.13 rag
endr1n/kg diet by capsule over 148 days. At day 148, the levels of endrln
and !2-ketoendr1n were measured 1n muscle, liver, kidney and fat (Table
III-3). Levels of 12-ketoendMn, deltaketoendHn, antl- and syn-12-hvdroxy-
endMns were below detection. The distribution of l«C-endr1n provided at
0.3 pCVday for 148 days Is given 1n Table III-4 for day 148. These
results for radioactivity essentially are for endrln distribution Itself, as
supported by the data In Table III-3.
Ludke (1976) determined lethal brain residues for several compounds In
an Investigation of associated mortality with addltlvUy of chlordane and
endrln. Twenty male and female, 14-week-old, bobwhUe quail (Collnus
vlrg1n1anusl were fed diets containing 10 ppm chlordane for 10 weeks
followed Immediately by 10 ppm endrln 1n the diet for 10 weeks; 20 other
quail received 10 ppm endrln In the diet only (duration unspecified).
00650 III-9
-------
TABLE III-3
Distribution of Endrln and 12-KetoendMn at Day 148 1n Sykes
Hybrid III Hens (2 kg Initially) Fed 0.016 ng/kg Diet by Capsule*
Tissue
Breast meat
Leg meat
Liver
Kidney
Fat
Concentration
Endr1nb
<0. 0032-0. 001 3
0.017-0.095
0.013-0.20
0.035-0.13
0.32-1.21
(mq compound/kg ww)
12-Ketoendrln
<0.002
<0.003
<0.0006
<0.03
<0.0004
aSource: Baldwin et al., 1976
^Metabolites were considered absent 1f their concentrations were <10% of
the detected endrln value.
00650 111-10
-------
TABLE II1-4
Radioactivity 1n Tissues of Five Hens After a 148-Oay
Period of Treatment with 0.3 yd/Day (as capsules)*
Tissue Radioactive Residues
(ng endrln equivalent/kg w)
Breast neat 0.008-0.011
Leg meat 0.008-0.030
Fat 0.50-1.28
Liver 0.07-1.06
Kidney 0.13-0.23
Brain 0.017-0.050
Sciatic nerve 0.096-0.64
Bone marrow 0.14-0.58
Skin 0.13-0.39
Feathers 0.005-0.024
•Source: Baldwin et al., 1976
00650 111-11
-------
After 9-10 days on an uncontanlnated diet, survivors were sacrificed. In a
control group, eight quail given 10 ppra chlordane In their diet did not
experience arty mortality. All quail treated with endrln and with both
endrln and chlordane had significant loss In weight. This loss of weight
was associated with fat mobilization and Increasing brain residues. Birds
that died from endrln treatment alone had brain residues ranging from
0.34-1.84 ppm; survivors ranged from 0.28-0.62 ppm.
Birds that died from endrln exposure preceded by chlordane treatment had
brain residues ranging from 0.17-1.25 ppm; survivors ranged from 0.14-0.56
ppm. Brain residues of survivors were lower than those of dead birds and
approached significance (0.05
-------
brains. The year/number/levels 1n eggs were as follows: 1971, 3, 0.08-0.12
mg/kg ww; 1972, 12, 0.11-0.29; 1973, 21, 0.03-0.46; 1974, 25, NO-0.73; 1975,
30, 0.29-1.06; 1976, 25, NO-1.47.
In September 1978, ducks 1n Montana were found to contain up to 1.2
rog/kg ww endrln In their fat resulting from endrln applied on wheat crops to
destroy an Infestation of Army cutworms (Anonymous, 1979).
Table III-5 shows some typical residue levels found since 1977 In wild
and laboratory birds known to be exposed to endrln. These data Illustrate
that endrln 1s absorbed and then distributed throughout the body. No
12-ketoendMn was detected In the tissues of wild or domestic birds, unless
the birds had Ingested endrIn-killed fauna (Stkkel et al.. 1979a). The
connection of brain residues with lethality Is discussed 1n Chapter V.
Mammals — Little 1s known of the transport and distribution of
endrln 1n mammals. No evidence of storage 1n any particular tissue or
organ, other than fat, has been found. Residues of endrln ranging from
0.001-23.7 mg/kg ww, however, have been detected In a variety of mammalian
tissues.
Brooks (1969) reviewed studies showing that steers, lambs and hogs
receiving 0.1 mg endrIn/kg diet for 12 weeks had little tendency to deposit
endrln In body tissues. Continuous feeding of endrln at levels up to 2
mg/kg diet resulted In a maximum body fat concentration of 1 mg endr In/kg
ww. Cattle with only ambient environmental endrln exposure were analyzed
for the presence of endrln residues In their tissues by the U.S. Department
of Agriculture In 1967 (Spauldlng, 1972). Of the 2785 animals studied, 2783
00650 II1-13
-------
TABLE III 5
Endrln Distribution In Birds In the Post-1978 Literature
Species
Heron (wild)
Kestrel (wild)
(falco sparverlus)
Broadwlnged
hawk (wild)
(Buteo platypterys)
White pelican
(dead) (wild)
(Pelecanus
erythrorhynchos)
Pelican (wild)
Bobwhlte quail
(Collnus
vlrglnlanus)
Bullfinch
Crackles
(Qulscalus
qulscula)
Exposure Type
NR
NR
NR
NR
NR
S.8 tig/kg fed/
day/bird
0.15X endrln
(48 hours)
0.0375* endrln
(24 hours)
(via pear buds)
10 »g/kg diet
Tissue
carcass3
carcass
Gl tract
carcass
carcass
brain
brain
brain
liver
liver
carcass
brain
Concentration (number or
-------
TABLE III-5 (cont.)
o
o»
in
Species Exposure Type
Mallard* 10 mg/kg diet
(Anas (26 days)
platyrhynchos)
Quail (dead) 50 mg/kg diet
(Coturnlx
Japonlca)
Bald Eagle (dead)c20 mq/kg diet
(Hallaeetus
£ leucocephalus)
Z Eagle |wlld)« MR
Tissue
carcass
brain
liver
carcass
carcass
•uscle
brain
carcass
brain
Concentration (number or sex) Reference
(mg/kg ww)
1.4-1.9b at day 26 (2)
0.54-0.77»
1.1-1.9
1.1 (N)b on day 14-20 (4)
1.0 (f )b on days 13-15
1.5 (F)
0.63 (N)
0.92-1.2 (N/f)
0.5-2.5 (N)
0.71-1.2 (H)
Sttckel et al.. 1979a
Stlckel et al.. 1979a
Stlckel et al.. 1979b
Sttckel et al.. 1979b
aAfter head. skin. feet, wlngtlps and GI tract were removed
b!2-Ketoendrtn was below the detection Unit
°The lower 11«1t of detection was 0.10 ppn endrln
lower llMlt of detection was 0.05 ppm for endrln and 12-keto endrln.
detection for all Stickle et al. (1979a) referenced Materials.
NR - Not reported
Used as the Unit of
-------
contained no endMn residues; one animal contained between 0.01 and 0.1 mg
endrln/kg fat, and another contained between 0.11 and 0.5 rag/kg fat. By
1971, however, similar testing revealed that endMn Incidence 1n tissues was
Increasing. Of 2403 cattle tested, 42 had levels of 0.01-0.1 mg endrln/kg
fat (Spauldlng, 1972).
Long et al. (1961) reported high levels of storage 1n the adipose tissue
of six lambs using a dechloMnatlon method of analysis. Higher levels were
detected 1n the Internal fat surrounding the stomach and thoracic cavity
than 1n external fat deposits. Lambs were allowed to graze for 55 days on
pastures treated with 2% endrln granules, applied six times In Nay and June
at a rate of '1.1 kg endrln/acre. The lambs were then transferred to
untreated pasture; endrln In fat was measured after 0, 14 and 42 days. At
the start of grazing In untreated pastures, lambs had 18.3-23.4 mg endrln/kg
Internal fat and 11.5-14.0 mg/kg external fat. After 14 days, endrln levels
were surprisingly higher, with 20.3-23.7 mg/kg Internal fat, and 14.6-20.1
mg/kg external fat. Some loss did occur after 42 days. Internal fat levels
dropped to concentrations of 8.9-13.8 mg/kg fat, and external fat contained
only 6.4-11.0 mg/kg. These findings seem to contradict later reports by
Brooks (1969) of no storage and no retention. In the Long et al. (1961)
study, however, much higher levels of endrln were fed to younger animals;
younger animals have relatively more fat than adults. In addition the lambs
Initially were 1n "poor condition.' Sharraa and Gautam (1971) detected
endrln residues In the brain and liver tissue of calves. In the domestic
dog endrln was detected 1n the abdominal viscera (Reins et al., 1966) as
well as 1n fat (Richardson et al., 1967).
00650 111-16
-------
Richardson et al. (1967), using three 9-month-old beagle dogs fed 0.1 mg
endr1n/kg bw/day and two control animals fed uncontamlnated diet over the
128-day feeding period, found that endMn In jugular vein blood In each dog
reached a plateau at 3-8 rag/kg after 2 days of feeding. The distribution of
endMn 1n tissues after 128 days of feeding is provided 1n Table III-6.
Only the levels In fat were related to levels of endMn 1n blood. In con-
trast, administered dleldrln accumulated In the blood after 114-121 days.
Rats dosed at 8 vg of 14C-endrIn/day by the oral route achieved a
steady-state 1n the blood In 9-10 days (Brooks, 1969), but the label was
quickly eliminated after cessation of exposure.
Korte (1967) showed that conversion of endMn to metabolites was not
dependent on enterobacteMa but occurred In the liver, and 1n 1970 found
that the steady-state storage level after 6 days for female rats dosed at
0.4 mg l4C-endr1n/kg diet (16, 64 and 128 yg endMn/kg/bw) was about
twice that for males dosed similarly (27% vs. 14%, respectively) (Korte et
al., 1970). After 1.v. Injection of 200 t>g l«C-endrIn/kg 1n two doses,
male rats retained 5.2% and females 12.1% after 24 hours. This Illustrated
that the results for different genders were probably not due to gender-
dependent absorption variability. Baldwin et al. (1970) also found that
concentrations of endMn metabolites 1n female rats were dependent on the
duration of feeding (4 mg/endrln/kg feed over several weeks), whereas those
1n males were not. Walsh and Fink (1972) gave five Carworth Far* No. 1
adult mice 5 mg "C-endrln/kg bw by 1.v. using OffSO as a vehicle. After
10 minutes the radioactivity distribution was as shown 1n Table III-7.
EndMn was as penetrative to the blood-brain barrier as dleldrln; no endMn
was found In the bile up to 2 hours after administration.
00650 111-17
-------
TABU Ill-b
Otstrtkuttwi of fndrln and 12-Ketoendrtn In f Kperlewnm Anleu Is
J\ • — — — — — —
Concentration
IM coovound/kfl t Issue 1
An (Ml (Nuaber)
•eagle dog (3)
(9-aonlk-eld)
CM rat |t)
(faaale. 200-250 g)
CM rat (t)
M (aale. 200-2SO g)
i- Cff rat |3)
o> (Mle. 200-2SO g)
Holsteln cows (2)
•a It us nervegtcus (?)
(Ml*. 301 g. S33 g)
Nus ausculiis aeuse (k)
lose
(•I/kg kw)
0.1 ag/kg kw/day ever
120 days
2.S In arackls ell
2.5 In arackls ell
10 In aracklt ell
O.I ag/kg diet twice
dally for 21 days
SO In diaetkylsnirextde
dose net given
1 Issue
spleen*
fat*
auscle*
pancreas*
kearl*
liver*
kidney center*
blood*
fat*
liver"
kidney*
fat*
liver*
kidneys*
kralnc
rear leg at at*"
• ia^B»aj» eaajai i
liver4
kidney*
renal fat4
aownlal fat4
subcutaneous rat*
kraln*
kraln*
carcass*
fndrtn
0.12-2.t2
2SO-7tO
120-310
•1-280
12S-I70
11-04
30-02
1-0
S.4«»0.32
0.10»0.01
O.H
0.20*0.03
<0.004
0.02-0.11
0.001-0.002
0.001-0.002
0.000-0.011
0. 000* -0.0008
0.021-0.110
o.oso-o.oto
0.041-0.070
0.20 (533 g)
0.01-1.00
0.00-2.00
12-Ketoendrtn
7.27.0.47
o.otTo.oi
1.. 5,0. IS
o.soTo.oi
0.04"
0.2S-0.31
<0.0001
<0.0001
-------
1AILE Ill-t (cont.)
Anlaal (Hunter)
foltfen Syrian Matter
(21)» (feaile)
CO
(fe
rat (27)"
•ale. 115-200 g)
(29)*
""'
Dose
(•g/kV ow)
l.S day via corn oil
over 11 days
2.S day via corn oil
over 11 days
O.IS day
0.30 day
0.44 day (all doses via
corn oil over 13 days)
1 Issue
liver'
fetal tissue' (10)*
liver'
fetal tissue' (7)*
liver •
fetal tissue!
liver*
fetal tissue*
liver*
fetal tissue* (ftp
Concentration
(•a conpound/kfl tissue)
••ference
fndrln 12-Ketoendrln
1.45 p Chernoff ot al.. •
0.021*0.004 p 1979
2.SS p
7S»3ft p
0.052-0.074 Kavlock el al..
-------
TAIL! III-?
Distribution of Radioactivity In Various Experimental Animals After an Acute Oral DOS* of fndrln
o
0
c»«
cr>
o
, ,
M
1
l^t
s
AntMl Spec Us Admin. Sei
•out*
Adult rat oral II
(CFE strain)
r
Adult mice t.v. N
(Cf no. i)
Mult rabbit oral N
(Outcn strain}
Cow (Holsteln) oral f
"
-
Ooio
J«g/koj
2.S
2.5
s.o
2.12
0.1 mg/kg tftot
(twice dally
for 21 days)
Carrltr
aracMs
oil
(1 a*)
arackti
oil
n •»!
dliwthyl-
sulfoildo
oltvo oil
(10 M)
corn oil;
adoilnts-
Itrod as
captulo
!
AnlMl TIM of
Heights Analysis
(a)
200-2SO at day 3
<»)
200-250 at day 3
(M
not given at 10 Minutes
15
2.2 kg at day 13
n;»
450-tSO kf at day 21
*
Percentage of Radioactivity Administered found
In Remaining
Urine Feces Liver Kidney fat Skin Carcass Total
2.15 M 1.2 O.M 1.T 2.3 12.2 M.9
T.50 3? 2.0 0.35 1.0 4.0 20.1 17.2
•A MA 52* M 21* HA 23«>b NA
5.2«.c
37.3 49.2 M .HA NA 13.5 100
55-57 19-21 0.*-1.5 111 0.0 HA 3.1-5.3 00-91
Major organs
Reference
•
Hutson
ot al.. 1975
Ualsh and
Fink. 1972
Oedford et
al.. 197Sb
Oaldwln
ot al.. 1976
*«g/kg tissue basis
••rain level
clleod level
HA - Hot analyied; N . Mlo; F • feaale; l.v. - Intravenous
-------
Hutson et al. (1975) showed that endMn administered in the diet to 6
male and 6 female rats (200-250 g) was quickly metabolized and then elimi-
nated as conjugates. The amount of conjugate was shown to be gender-depen-
dent, confirming the earlier work of Korte (1967), Korte et al. (1970) and
Baldwin et al. (1970). Three days after an acute oral dose of 2.5 mg
endr1n/kg bw In arachls oil by oral gavage, the fat, liver and kidneys of
male rats contained the levels shown 1n Table III-6 and 31% of the adminis-
tered dose was still retained by the animals. For females the corresponding
levels are again provided 1n Table III-6; 56X of the administered dose was
still retained. Female rats accumulated more endrln than male rats, but
mostly In fat and skin. Uhen 3 male rats were administered 60 mg endrln/kg
bw by gavage, the brains of the dead animals (after 7-22 hours) contained
0.02-0.11 mg endr1n/kg tissue and levels of 0.25-0.31 mg 12-ketoendrln/kg
tissue. The brain levels of delta-ketoendMn, 3-hydroxyendrln, syn-12-?
hydroxyendrln and ant 1-12-hydroxyendr1n were <5 wg/kg tissue. Distribu-
tion of radio-labeled 14C-endr1n in the experiments for both genders Is
provided 1n Table III-7.
Baldwin et al. (1976) dosed two Holsteln cows (500 kg) with 0.1 mg
"C-endr1n/kg diet twice dally for 21 days. At day 21, the tissue levels
of endrln and !2-ketoendr1n In Table III-6 were found. Endrln constituted
the vast majority of the residues In rear leg and lumbar meat, the liver,
kidney and In renal, oraental and subcutaneous fat. 12-Ketoendrln was
detected 1n the fat but not the lean meat. Some ant 1 -12-hydroxyendr In was
detected (0.020 mg/kg ww) In the subcutaneous fat of one cow. .Otherwise,
the amounts of antl- and s^n-12-hydroxyendr1ns and 3-hydroxyendrln were
below detection limits. The distribution of radlolabeled endrln Is
00650 111-21
-------
provided 1n Table III-7 for the residues 3 weeks after administration.
Minor residues remained 1n the major organs. All of the tissue residues
were essentially endrln Itself (see Table III-6).
Stlckel et al. (1979a), using two old, large rats (Rattus norveqlcus;
381 g and 533 g), administered a dose of 50 mg endMn/kg bw In a DMSO
carrier. 12-Ketoendr1n was detected In the brains and carcass of both rats
and endrln was also found In the carcass of the fatter animal (see Table
III-6). One male (542 g) and one female (331 g) rat were also fed a diet
containing 150 mg endrln/kg diet until death (16 days for the male; 24 days
for the female). No endrln was detected 1n the brain or carcass of either
animal. The levels of !2-ketoendr1n In the brain and carcass were 0.18 and
0.28 m/kg tissue for the male; and 0.13 and 0.13 for the female, respec-
tively. The number of animals 1n the rat experiments 1s too small for
statistical purposes but the results do agree In general with those of
Hutson et al. (1975). Stlckel et al. (1979a) also found that the residues
of endrln In the brains and carcasses of 6 white mice killed by eating
endrln-treated pine seed, and pooled In groups of three, varied from
0.70-1.00, and 0.88-2 mg endr1n/kg tissue, respectively. The corresponding
figures for 12-ketoendr1n were 0.04-0.08 and 0.07-0.10 mg/kg tissue. The
lower limit of detection for endrln and 12-ketoendr1n 1n homogenized duck
tissue was 0.05 ppm.
Bedford et al. (1975b), 1n experiments on male adult rabbits (Dutch
strain; 2.2 kg) Involving an acute oral dose of 2.12 mg endr1n/kg bw, found
low levels of endrln In the carcass at day 13 (13* retention) (see Table
III-7). At day 49. only 3.2% remained 1n the body.
00650 111-22
-------
EndMn and 12-ketoendrln were detected and confirmed by GC/MS in the
liver and fetal tissue of the hamster (Chernoff et al., 1979). Timed preg-
nant Golden Syrian hamsters (LVG strain) were housed two per cage at 22-24'C
under controlled lighting (16-hour light) after successful copulation. The
animals were fed commercial lab chow and water ad lib. The endrln was
administered at day 4 or at day 8 after copulation by gastric Intubation In
a corn oil vehicle. Single dose exerlments on nonpregnant and pregnant
animals were at 0, 0.5, 1.5, 5.0, 7.5 and 10 mg/kg bw (the number of preg-
nant animals were 76, 10, 34, 50, 34 and 24, respectively). In multiple
dose experiments, the doses were 0, 0.75, 1.5, 2.5 and 3.4 mg/kg/day (the
number of surviving animals were 50, 19, 21, 12 and 2, respectively). At
sacrifice (day 15) the 2.5 and 1.5 mg/kg/day dose groups yielded the endrln
levels given 1n Table III-6. These results Indicated that endrln crosses
the placental barrier in hamsters. Although the authors stated that
12-ketoendrln crossed the placental barrier, It Is uncertain whether
12-ketoendrln was formed from endrln 1n the fetus or penetrated the
placental barrier from the mother.
A similar type of study on rats was also performed by the same group
(Kavlock et al., 1981). Again 12-ketoendr1n and endrln were found In
maternal liver and In the fetus. Pregnant CO rats (175-200 g) were exposed,
as 1n the Chernoff et al. (1979) study, to endrln doses of 0.450, 0.300.
0.150, 0.075 and 0 mg/kg/day on days 7-20 of gestation, and killed on day 21
of gestation. The number of pregnant animals studied for the respective
doses were 12, 29, 27, 14 and 29. The results for the three highest doses
are contained 1n Table III-6. Although 12-ketoendr1n was Identified, It was
not quantUated. The average ratio of peak height of 12-ketoendrln to that
00650 111-23
-------
of endrln was 0.19 (range 0.07-0.47) for maternal livers and 0.35 (range
0.07-0.71) for the fetus. In the hamster fetus the ratio was 3.2*0.6 (10
fetuses) at a maternal dose of 1.5 ng/kg/day. Thus 1n the rat, passage of
endrln through the placenta will occur above a critical concentration
threshold In the blood produced by an oral dose between 0.300 and 0.450
mg/kg/day.
Mechanisms of Transport and Metabolism
The metabolic pathway for endrln 1n mammals 1s complex (Figure III-1)
and varies from species to species. In all species the unsubstUuted
methylene bridge (C,-) 1n endrln (compound I 1n Figure III-l) Is preferen-
tially attacked to form mostly antl- and lesser amounts of syn-12-hydroxy-
endrln, the latter being quickly oxidized by mlcrosomal mono-oxygenases to
produce 12-ketoendr1n (compound IV In Figure III-1). To a smaller extent
hydroxylatlon at the 3-pos1ton also probably occurs, and the epoxlde func-
tional group 1s probably hydrated. Syn- and antl-12-hydroxyendrln are most
Hkely Interconvertible in vivo probably by !2-ketoendr1n. Hydroxylatlon at
C-3 and C-4 1s Inhibited by the presence of the bulky hexachlorlnated
fragment (Hutson, 1981). Studies 1n rats (Cole et al., 1970) have Indicated
that "C-radlolabeled-endMn 1s quickly metabolized to the antl-12-
hydroxyendrln (compound II In Figure III-l), which Is excreted 1n the bile
(70% within 24 hours) as the glucuronlde (Hutson et al., 1975)r After
enterobacterlal deconjugatlon and enterohepatlc circulation, elimination
occurs as the aglycone (-45X) In the feces together with two other minor
metabolites, 3-hydroxyendrln (compound V In Figure III-l) and 4,5-trans.-
d1hydro1sodr1nd1o! (compound VI 1n Figure III-l). The major urinary metabo-
lite In male rats (only 1-2X of the administered dose) Is !2-ketoendr1n
00650 111-24
-------
(VI)
FIGURE III-1
Blotransforraatlon of Endrln In Manuals
Source: Hutson, 1981
00650
111-25
-------
(compound IV In Figure III-l). This metabolite 1s produced by the action of
mlcrosomal mono-oxygenases on sjtn-12-hydroxyendMn (compound III 1n Figure
III-l) (Hutson and Hoadley, 1974), which, 1n turn, 1s formed by attack at
the unsubstHuted methylene functional group of endrln. The primary
hydroxylatlon rates In the liver for the rat and rabbit are 50:7:1.5:1 and
40:5:4:1, respectively, for ant1-C-12. C-3, nn-C-12 and C-4 1n that order
(Bedford and Hutson, 1976). In the rabbit the major metabolite Is still
ant1-!2-hydroxyendr1n. but 1t Is conjugated with sulfate and eliminated 1n
the urine (Bedford et al., 1975b). Some ^n-12-hydroxyendrln sulfate was
also found 1n the urine as were the glucuronlde conjugates of the antl- and
s_yji-l2-hydroxyendr1n, 3-hydroxyendr1n, and the 4.5-trans-d1ol (compound VI
1n Figure III-l). The reason for this variability 1s related to the
molecular weight thresholds for biliary excretion of anlons In the rat and
rabbit; e.g., 325+50 and 475+50, respectively (H1rom et al., 1972). The
threshold for man Is between these values but Is closer to that of the
rabbit.
The rapid metabolism has been explained In terms of the sterlc Influence
of the epoxlde anlon on C-12-hydroxylatlon 1n promoting antl-C-12-hydroxyla-
tlon. The bulky hexachloMnated fragment Inhibits attack at C-3 and C-4.
Antl-12-hydroxyendr1n has been detected 1n the feces of factory workers
and Us B-glucuronlde has been detected In the urine (Baldwin and Hutson,
1980). The levels of the latter appear to be dose-dependent. The toxic
metabolite 12-ketoendrln was not detected 1n the urine and feces, neither
was 3-hydroxyendr1n (compound V In Figure III-l) or the dlol (compound VI In
Figure III-l).
00650 111-26
-------
These transformations are of Interest because syn- and ant_U12-hydroxy-
endrln and 12-ketoendrln all have lower LQ values than endrtn Hself.
As these metabolites are produced quickly they could be responsible for the
toxic effects elicited by endrln administration. 12-Ketoendrln has been
suggested as the acute toxicant (Bedford et a!., 1975a).
Elimination
Endrln 1s rapidly eliminated both In animals and 1n humans. The urine
1s the major excretory route 1n cows and rabbits but 1s of minor Importance
In the rat. Endrln Is both metabolized and excreted unchanged In propor-
tions that vary with species and gender.
When "C-labeled endrln was given orally and by 1.v. to rats, the Ice to
metabolite of endrln and other hydrophHlc metabolites were present 1n trace
amounts 1n the urine (Klein et al., 1968). After a single 1.v. dose of
14C-endr1n, 90% of the label was eliminated 1n the bile by the second day
(Cole et al., 1970).
Baldwin et al. (1970) found that endrln was metabolized 1n the rat to at
least three metabolites. One metabolite, !2-ketoendr1n, was found 1n the
urine. The other two metabolites were excreted In the feces and were not
found In body tissues. The second metabolite was an Isoroer of
12-hydroxyendrln. This Isomer had the hydroxyl group antl with respect to
the epoxy group. According to Korte et al. (1970), 12-hydroxyendrln
accounted for 95X of the radioactivity excreted by rats. The third
metabolite was a monohydroxylated endrln. but 1t was not substituted at
carbon 12 (Baldwin et al.. 1970). The unsubstUuted methylene bridge was
00650 111-27
-------
thus hydroxylated, and the corresponding ketone was found In adipose tissue,
liver and brain.
Rabbits excreted radioactivity after 1.v. administration of 14C-
labeled endrln mainly in the urine and only as metabolites (Korte et al.,
1970). Four metabolites were found In order of decreasing polarity In the
ratio of 1:1:3:1. The second most polar one was Identical to the
12-hydroxyendr1n, which was the main metabolite found 1n rats. The biolog-
ical half-life of endrln In male rats receiving 0.4 mg/kg diet was 2-3 days;
In females, -4 days (Korte et al., 1970). Following l.v. Injection of 200
vg of 14C-labeled endrIn/kg bw In two doses, male rats retained 5.2X and
females 12.IX of the radioactivity after 24 hours. The radioactivity was
totally excreted as metabolites (Korte et al.. 1970), When "Clabeled
endrln was fed to male and female rats, the males excreted 60% of 1t 1n the
feces within the first 24 hours, and the females only 39X; <1X was excreted
In the urine. Of the total radioactivity excreted 1n the feces. 70-75X
occurred 1n the form of hydrophlllc metabolites. Twenty-four hours after
the last dose only metabolites were excreted (Korte et al., 1970).
The elimination and distribution of »4C-1abe1ed endrln administered
acutely to rats (Hutson et al., 1975), mice (Walsh and F1nk, 1972), rabbits
(Bedford et al., 1975b) and cows (Baldwin et al., 1976) are provided In
Table III-7.
Hutson et al. (1975) showed that 55-57X of "C-endMn was eliminated,
mostly as the glucuronlde of antl-12-hvdroxyendrln. 1n the bile within 24
hours of administration to rats of 0.76-1.53 mg »*C-endr1n/kg bw. Other
minor components (<10X) were the glucuronldes of 3-hydroxy- and 12-keto-
00650 111-28
-------
endrln. Hale rats eliminated 69X of the label within 3 days whereas female
rats eliminated 45X. Feces from male and female rats fed for 2 weeks on
endrln diets contained the following: endrln (11X), ant1-!2-hydroxyendr1n
(83X), iyji-12-hydroxyendrln (<0.01X), 3-hydroxyendrln (5X), 12-ketoendrln
(IX) and delta-ketoendMn (<0.01X). Day 1 urine samples contained
17:2:0:1:10:0 proportions for males, while those from females contained 1-2%
endrln but no 12-ketoendMn, the major component being 12-hydroxyendMn-
0-sulfate.
Only traces of 12-ketoendMn were found In male rabbit urine 6 days
after oral dosing and none In rabbit feces (Bedford, et al., 1975b), even
though SOX of "C-label was excreted In the urine. Nearly all (>99.5X) of
the 14C-label In feces within 24 hours was endrln Itself, and endrln
metabolites were excreted slowly over several days. Excretion of the label
was 87X completed within 13 days. The following compounds were found In
urine up to 24 hours: 12-ketoendMn (7X), the glucuronlde of antj.-12-hy-
droxyendrln (21X), ant1-!2-hydroxyendr1n sulfate (53X), syn-12-hydroxvendrln
sulfate and 3-hydroxyendrln sulfate (14X); the glucuronlde of trans-4.5-
d1hydro-1sodr1n-4,5-d1ol glucuronlde (2X), and other minor glucuronldes
(3X). These components accounted for 40X of the single oral Intake of
l4C-endr1n. While the bulk of endrln metabolites are excreted directly by
the rat 1n the bile (Hutson et al., 1975), mostly as glucuronldes, the
rabbit excretes then directly as sulfates In the urine (Bedford et al.,
1975b). This behavior 1s consistent with Molecular weight thresholds for
biliary excretion, which are 32S±50 1n the rat and 475+50 In the rabbit
(H1rom et al., 1972).
00650 II1-29
-------
The molecular weight threshold for biliary excrtlU"' n man lies between
those of the rat and the rabbit but 1s closer to that or the rabbit. While
metabolism of endrln 1n humans has not been studied systematically, antl-12-
hydroxyendrln as the glucuronlde has been found 1n boil feces and urine of
endrln workers (Baldwin and Hutson, 1980) (Table 111-8}. 12-Ketoendrln was
not detected (Hutson, 1981). Thus, available Information suggests that
endrln 1s probably metabolized similarly In humans and 1n rats and rabbits.
though the proportion and the type of conjugation products differ. Baldwin
et al. (1976) showed that the sulfate conjugate of ant1-12-hydroxyendr1n was
the major metabolite In hens. Endrln was the only other excretion product
In feces, generally at levels 25-35% less than the sulfate conjugate of
ant1-l2-hvdroxyendr1n. which generally was at levels of 4-20 mg of endrln
equivalents/kg (Baldwin et al., 1976). Cows probably excrete the glucuron-
lde In the bile, but after enterohepatlc circulation the free metabolite 1s
excreted 1n the urine and feces (see Table III-7). 12-Ketoendrln Is also
excreted 1n the urine of cows to the extent of 2-26% of the total adminis-
tered "C-endrln (Baldwin et al., 1976). During dally treatment a steady-
state of "C-label In the urine of cows 1s attained at about day 9.
A brief half-life on the order of a day for humans Is .consistent with
the lack of persistence of endrln In human tissues (Coble et al., 1967), and
with the rapidity with which plateau concentrations are reached In other
mammals on chronic exposure, I.e., <1 week for blood endrln (Richardson et
al., 1967). This observation suggests that the biological half-life of
endrln In the dog 1s also on the order of 1-2 days.
00650 II1-30
-------
TABLE III-8
Analysis of Urine fron EndMn Plant Workers 1n England3
Worker Concentration of Total .12-KetoendMnc
ant1-!2-hydroxyendr1nb (vq/mi)
Ug/mi)
1
2
3
4
5
6
7
0.010
0.14
0.098
0.040
0.021
0.098
0.011
NR
0.13
NR
NR
NR
0.075
0.015
antl-12-Acetoxyendrln
after Acetylatlon
Expressed as Alcohol
tug/mi)
NR
0.13
NR
0.037
0.024
NR
NR
aSource: Baldwin and Hutson, 1980
Measured after 8-glucuron1dase cleavage
cProduced after oxidation
NR . Not reported
00650
111-31
-------
Two cows given 0.1 ng **C-endr1n/kg diet twice dally for 21 days
excreted the label 1n the milk and a steady-state was attained In 4-6 days,
mostly as free endrln. The antl- and s_£n-12-hydroxyendMn, 3-hydroxyendr1n
and !2-ketoendr1n were below detection limits (Baldwin et al.t 1976). The
estimated half-life Is 2-3 days.
In August, 1976, a Canadian dairy herd was treated with endrln for
control of files; 25 animals developed poisoning symptoms, and one cow and
one calf died (Frank et al., 1979). The next day after the poisoning a
composite milk sample contained 0.40 ppra endrln (8.7 ppm 1n the mllkfat).
After 34 days the levels were 0.0026 ppm (0.056 ppm in the milk fat). M11k
from Individual cows on day 13 contained endrln levels ranging from
0.031-0.16 ppm In whole milk. The residues were analyzed by EC/GC and by
TLC, or by two column EC/GC.
Estimations of the 50% disappearance time of endrln are presented 1n
Table III-9 for a variety of animal species. These data have been estimated
from the data presented In the cited references. Endrln 1n sheep and cattle
appears to have a longer half-life than 1n the rest of the species.
Another study Involved 50 mallard drakes (960-1360 g; 1 year old) fed 20
ppm endrln for 13 days (Heinz and Johnson, 1979). Groups of five ducks each
were sacrificed at 2, 4, 6, 8, 16, 32 and 64 days after the end of dosing.
Endrln was monitored 1n the blood and carcasses. The carcass lost 50% of
Its endrln In 3 days; the second half-life required an additional 8.9 days,
and 1t took 32.9 days to lose 90X of the original amount administered. On a
11pld-welght basis the first half-life of elimination was 2.2 days; the
00650 111-32
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TABLE II1-9
Estimated Half-Lives in Various Species for Elimination
of EndMn Administered by the Oral Route*
Species
Estimated Half-Life (dose)
Reference
Rat (H or F)
Rat (M) (1.v.)
(F) d.v.)
Rat (M)
(F)
Rabbit (M)
Dog (M)
Man
Sheep
Cattle
Mallard duck
Hen
Cow
2 days (16 vg/kg)
6 days (128 tig/kg)
2-3 days (200 vg/kg)
3-4 days (200 wg/kg)
2-3 days (2.5 mg/kg)
4 days (2.5 mg/kg)
<1 day (2.12 mg/kg)
T3 days 1n feces alone (2.12 mg/kg)
49 days 1n urine alone (2.12 mg/kg)
1-2 days (0.1 mg/kg/day)
1-2 days 1n blood serum
1.8-8.2 weeks
1.8-8.2 weeks
3 days (subchronk feeding)
1 month from fat (chronic feeding)
2-3 days
Korte, 1967;
Korte et al.. 1970
Korte, 1967;
Korte et al.. 1970
Hutson et al., 1975
Bedford et al., 19755
Richardson et al., 1967
Coble et al., 1967
Robinson, 1962
Robinson, 1962
Heinz and Johnson,. 1979
Cunwlngs et al., 1966
Baldwin et al., 1976
*These half-lives are based on the 1nU1al quick excretion.
tratlon was performed unless otherwise Indicated.
M » male; F • female
Acute admlnls-
00650
111-33
-------
second took an additional 6.7 days and a 90% loss of the administered amount
took 24.8 days. For blood the first and second half-times and the 90% loss
time on a wet weight basis were 1.7, 5.2 and 19.1 days, whereas on a llpld
basis, these values were 1.4, 4.3 and 15.9 days, respectively.
Cunnings et al. (1966) fed egg laying White Leghorn hens a combination
of endrln, Undane, dleldrln, DDT and heptachlor epoxlde at levels of 0.05,
0.15 or 0.45 ppm of each compound In the feed. After 14 weeks the birds
were returned to the basal diet for 32 days. Hens 1n the 0.45 ppm group
accumulated -3.4 ppm endrln In the fat and required about a month to reduce
the level to 50%. This Increase In half-life may reflect the presence of
the other pesticides. However, Baldwin et al. (1976) showed that hen eggs
concentrated J4C-endr1n during a dosing program of 0.13 mg endrln/kg.diet
over a period of 148 days to the extent of 0.11-0.18 mg endrln equivalent/kg
yolk. The label was Identified entirely as free endrln. Thus, accumulation
In eggs 1s a major pathway of elimination for hens.
Summary
The major route of absorption for humans appears to be through food.
The average dietary Intake 1n 1973 was 0.5 ng/kg bw/day. Special groups at
risk appear to be occupational workers 1n the pesticide manufacturing and
formulating Industries. Industrial and field workers may be exposed by both
dermal and respiratory routes. Several episodes of accidental and suicidal
endrln poisoning 1n humans have occurred. Poisoning has been caused by oral
doses of endrln as low as 0.2 mg/kg. Endrln levels In drinking water are
usually <100 ng/i. Endrln poisoning may occur In humans at blood
00650 111-34
-------
levels of 50-100 ng endMn/mi blood. These data Indicate endrln can be
absorbed In humans. Quantitative absorption rate data are not available for
mammals.
Fat appears to be the major storage tissue for endrln In lambs and
birds. The weighted average BCF In the edible portion of all freshwater and
estuarlne aquatic organisms 1s 3970.
The unsubstltuted methylene group of endrln Is preferentially and
quickly attacked to form mostly antl- and lesser amounts of syn-12-hydroxy-
endrln. The latter Is rapidly oxidized by mlcrosomal mono-oxygenases to
produce !2-ketoendr1n. Hydroxylatlon at the 3 position and epoxlde hydra-
tlon may occur to a small extent. Syn- and ant1-!2-hydroxyendr1n are likely
to be Interconvertible ,1^ vivo, with 12-ketoendrln as a possible
Intermediary metabolite.
Endrln residues have been found In such organs as the liver, brain and
kidneys and In the fat of birds, dogs, cows, rats, mice and hamsters. No
12-ketoendrln has been found 1n tissues of birds. Endrln appears to
penetrate the blood-brain barrier 1n rats and hens but less readily In the
cow, and the placental barrier In rats, mice and hamsters, although much
less efficiently for rats. 12-Ketoendrln may also penetrate the placental
barrier of these three species.
In rats >50% of the endrln metabolites are eliminated In the bile within
1 day as glucuronldes that, after enterobacterlal degradation and
entherohepatlc circulation, are eliminated as aglycones 1n the feces.
00650 111-35
-------
12-KetoendMn 1s the major urinary metabolite. Females excrete endrln
metabolites more slowly than males. Cows excrete free 12-hydroxyendrln
after enterohepatk circulation. !2-Ketoendr1n Is the only other major
metabolite In cow urine.
Though the major metabolite 1s still arvU-12-hydroxyendMn 1n male
rabbits, 1t Is conjugated as the sulfate and excreted directly In the urine.
This also occurs 1n hens.
The ant1-12-hydroxvendr1n has been detected as Us glucuronlde In the
urine and feces of humans.
Hens appear to eliminate endrln faster than most other birds. The
sulfate conjugate of anU.-12-hydroxyendrln 1s the major metabolite In hen
feces. The only other metabolite 1s endrln Itself. Endrln does appear to
accumulate more In birds than 1n mammals.
00650 111-36
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IV. HUMAN EXPOSURE
This chapter will be submitted by the Science and Technology Branch,
Criteria and Standards Division, Office of Drinking Water.
00660 IV-1
-------
IV. HUMAN EXPOSURE
Humans nay be exposed to chemicals such as endrln from a variety of
sources, Including drinking water, food, ambient air, occupational settings
and consumer products. This analysis of human exposure to endrln Is limited
to drinking water, food and ambient air because those media are considered
to be sources common to all Individuals. Even 1n limiting the analysis to
these three sources, 1t must be recognized that Individual exposure will
vary widely based on many personal chokes and on several factors over which
there 1s little control. Where one lives, works and travels, what one eats,
and physiologic characteristics related to age, sex and health status can
all profoundly affect dally exposure and Intake. Individuals living in the
same neighborhood or even 1n the same household can experience vastly
different exposure patterns.
Detailed Information concerning the occurrence of and exposure to endrln
1n the environment 1s presented 1n another document entitled "Occurrence of
Pesticides 1n Drinking Water, Food, and Air1 (Johnston et al., 1984). This
chapter summarizes the pertinent Information presented 1n that document In
order to assess the relative source contribution from drinking water, food
and air.
In the Exposure Estimation section of this chapter, available Informa-
tion 1s presented on the range of human exposure and Intake for endrln from
drinking water, food and ambient air for the 70-kg adult male.. It 1s not
possible to provide an estimate of the number of Individuals experiencing
specific combined exposures from those three sources. However, the Summary
00660 IV-1
-------
section of this chapter provides some Insight Into the relative contribu-
tions of the three sources, especially drinking water, to the range of
Intake values suggested by the available data.
Exposure Estimation
Drinking Mater. Levels of endrln 1n drinking water vary from one
location to another. The highest level of endrln monitored 1n the available
studies was 0.008 wg/l 1n New Orleans (U.S. EPA, 1975, as dted 1n
PelUzzaM, 1978), well below the Maximum Contaminant Level (NCL) of 0.2
yg/l. Analysis of the National Screening Program for Organlcs In Drink-
ing Water (NSP) (Boland, 1981} suggests that median levels of endrln In
drinking water would be below 0.1 vg/l, since none of 116 systems
sampled contained a level of endrln above 0.1 vg/l. In addition, analy-
sis of the Rural Hater Survey (RWS) (U.S. EPA, 1984) suggests that median
levels of endrln 1n drinking water systems would be <0.008 vg/l, since
none of 92 systems sampled contained a level of endrln >0.008 vg/l-
Endrln may not be present 1n drinking water In some areas. The available
monitoring data are not sufficient to determine regional variations 1n
levels of exposure to endrln.
The dally Intake of endrln from drinking water was estimated using the
assumptions presented In Table IV-1 and the values presented above. The
estimates 1n Table IV-1 Indicate that the dally Intake of endrln from drink-
Ing water ranges from 0.0-0.0028 vg/kg/day. However, the values presented
do not account for variances In Individual exposure or uncertainties In the
assumptions used to estimate exposure.
00660 IV-2
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TABLE IV-I
Estimated Dally Intake of Endrln from Drinking Hater*
Drinking water concentration (v9/i) Intake (vg/kg/day)
0.0 0.0
0.008 0.0002
0.1 0.0028
•Assumptions: 70-kg man consuming 2 i of water/day.
00660 IV-3
-------
Diet. Data are limited on the dietary Intake of endrln In the United
States. For fiscal year 1979, the only positive value for endrln In an FOA
market basket study on toddlers (FOA, 1982a,b). In this study, an estimated
dietary Intake of 0.0001 yg/kg/day was calculated based on endrln levels
1n an oil and fat composite (FOA, 1982b).
Additional data were obtained on the estimated total dietary Intake of
endrln for adults 1n the years 1974-1979 and for Infants and toddlers In the
years 1975-1979 (Table IV-2). The average total Intakes for adults, Infants
and toddlers over the years studied was 0.000008, 0.00004 and 0.00016 vg/
kg/day, respectively.
Using the above data, the dally adult Intake of endrln 1s estimated to
be 0.000008 yg/kg/day. This value does not account for variances 1n
Individual exposure.
It 1s expected that dietary levels of endrln vary somewhat with geo-
graphical location, with higher levels occurring 1n foods from areas near
the sources of endrln exposure. However, because of Insufficient data, no
estimates could be made of variations 1n Intake by geographical region.
EPA has established a tolerance of zero for endrln In and on the follow-
ing raw agricultural commodities: sugar beets, sugar beet tops, broccoli,
Brussel sprouts, cabbage, cauliflower, cotton seed, cucumbers, eggplant,
peppers, potatoes, summer squash and tomatoes (40 CFR 180.131, July 1, 1981).
00660 IV-4
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TABLE IV-2
Estimated Total Dally Dietary Intake of EndMn
for Adult Hale, Infant, and Toddler
Year
1974
1975
1976
1977
1978
1979
Average*
Adult
male*
NO
Tracec
NO
0.00004C
NO
NO
0.000008
Intake (vg/kg/day)
Infant5
(6 months)
NO
N0<*
NO
0.0002
NO
0.00004
Toddlerb
(2 years)
NO
0.0007
NO
NO
0.0001
0.00016
aFrom FDA 1981, except as noted.
bFrom FDA 1980b, 1982b.
Calculated based on Information 1n Johnson and Manske 1977 and
FDA 1980a.
^Appears to be an error since a positive value was reported 1n
Johnson et al. 1981.
eTrace values were not Included 1n the calculation; nondetected
values were assumed to be equal to zero.
NO > None detected.
00660
IV-5
-------
Air. Levels of endrln 1n the atmosphere also vary from one loca:lon
to another. The highest level of endrln reported was 39.3 ng/m» (0.0393
wg/m») In the-Mississippi Delta 1n 1972-1974 (Arthur et al., 1976).. In
a national study the highest level of endrln reported was 19.2 ng/m1
(0.0192 vg/m») 1n Tennessee 1n 1971 (Kutz et al., 1976). Typical
levels, however, are somewhat lower. An estimated mean level of endrln 1n
ambient air, based on the Information In Kutz et al. (1976), 1s 0.2 ng/ra»
(0.0002 wg/m»). (However, this estimate 1s based on data from 1970-1972
and obtained 1n sampling locations with potentially high concentrations of
pesticides 1n ambient air.) Additionally, concentrations of endrln are
below the limits of detection in some areas and may be as low as 0.0
ng/m3. The available monitoring data are not sufficient to determine
regional variations 1n levels of exposure to endrln.
The dally respiratory Intake for endrln from air was estimated using the
assumptions presented In Table IV-3 and the values presented above. The
estimates 1n Table IV-3 Indicate that dally endrln Intake from air ranges
from 0.0-0.013 vg/kg/day. These values do not account for variances 1n
Individual exposure or uncertainties 1n the assumptions used to estimate
exposure.
Summary
This section considers the relative contribution of drinking water, food
and ambient air to the total human exposure from these three sources. The
data presented here Indicate the potential total exposure to endrln that
could occur 1f a population was exposed to specific combinations of endrln
concentrations 1n drinking water, food and ambient air.
00660 IV-6
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TABLE IV-3
Estimated Dally Respiratory Intake of Endrln*
A1r concentration Ug/m*) Intake Ug/kg/day)
0.0 0.0
0.0002 0.00007
0.0192 0.0063
0.0393 0.013
•Assumptions: 70-kg man Inhaling 23 m» of air/day (ICRP, 1975).
00660 IY-7
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Table IV-4 presents a general view of the total amount of endMn that
may be received by an adult male from air, food and drinking water. Four
separate exposure levels In air, three exposure levels 1n drinking water,
and one exposure level from foods are shown In the table.
The data 1n Table IV-4 have been selected from an Infinite number of
possible combinations of concentrations for the three sources. Whether
exposure occurs at any specific combination of levels Is not known; nor 1s
It possible to determine the number of persons that would be exposed to
endrln at any of the combined exposure levels. The data represent possible
exposures based on the occurrence data and the estimated Intake data.
A mean level for endrln In ambient air of 0.0002 vg/m* was esti-
mated. Assuming a level of 0.0002 yg/m» In ambient air and the esti-
mated endrln Intake of 0.000008 yg/kg/day from foods, drinking water would
be the predominant source of exposure to endrln for the adult male at drink-
Ing water levels >0.003 yg/l.
The total estimated Intake of endrln 1s <0.020 yg/kg/day. This value
Is much lower than the FAO/HHO and EPA acceptable dally Intake of 0.2 yg/
kg/day (FDA, 1981), but approaches a maximum safe level of 0.04 yg/kg/day
calculated by EPA (U.S. EPA, 1976).
The relative source contribution data are based on estimated Intake and
do not account for a possible differential absorption rate for endrln by
route of exposure. The relative dose received may vary with the Intake. In
addition, the effects of endrln on the body may vary by different routes of
exposure.
00660 IV-8
-------
TABLE IV-4
Estimated Daily Intake of Endrln from the Environment
by Adult Males
Estimated Total Intake 1n yg/kg/day (X From Drinking
Water) Based on a Concentration 1n A1r (yg/m1) of:
Concentration
1n Drinking
Mater (Hg/i
Low
(0.0)
Intermediate
(0.0002}
High
(0.0192)
High
(0.0393)
Low (0.0)
0.000008 (0%) 0,00008 (OX) 0.0063 (OX) 0.013 (OX)
Intermediate 0.0002 (100X) 0.0003 (67X) 0.0065 (3.IX) 0.013 (1.5X)
(0.008)
High (0.1)
0.0028 (100X) 0.0029 (97X) 0.0091 (31X) 0.016 (17.5X)
Intake from each source:
Drinking water: 0.0 yg/i:
0.008 yg/l:
0.1 yg/i:
A1r:
Food:
0.0 yg/ma:
0.0002 yg/m»:
0.0192 yg/m>:
0.0393 yg/m»:
0.000008 yg/kg/day
0.0 yg/kg/day
0.0002 yg/kg/day
0.0028 yg/kg/day
0.0 yg/kg/day
0.00007 yg/kg/day
0.0063 yg/kg/day
0.013 yg/kg/day
00660
IV-9
-------
References
Arthur, R.O., J.O. Cain and B.F. Barrentlne. 1976. Atmospheric levels of
pesticides 1n the Mississippi Delta. Bull. Environ. Contain. Toxlcol.
15(2): 129-134.
Boland, P.A. 1981. National screening program for organlcs In drinking
water. Part II. Data. Prepared by SRI International, Menlo Park, CA, for
Office of Drinking Water, U.S. EPA, Washington, DC. EPA Contract No.
68-01-4666.
FDA (Food and Drug Administration). 1980a. Compliance program report of
findings. FY 77 total diet studies — Adult (7320.73). Food and Drug
Administration, U.S. Department of Health. Education and Welfare, Washing-
ton, DC.
FDA (Food and Drug Administration). 1980b. Compliance program report of
findings. FY 77 total diet studies -- Infants and toddlers (7320.74). Food
and Drug Administration, U.S. Department of Health, Education and Welfare,
Washington, DC.
FDA (Food and Drug Administration). 1981. The FDA surveillance Index.
Bureau of Foods, Food and Drug Administration, Washington, DC.
FDA (Food and Drug Administration). 1982a. Compliance program report of
findings. FY 79 total diet studies ~ Adult (7305.002). Food and Drug
Administration, U.S. Department of Health and Human Services, Washington,
DC. FDA/BF-82/98.
00660 IV-10
-------
PDA (Food and Drug Administration). 1982b. Compliance program report of
findings. FY 79 total diet studies ~ Infants and toddlers (7305.002).
Food and Drug Administration, U.S. Department of Health and Human Services,
Washington, DC. FDA/BF-82/97.
Johnson, R.D. and 0.0. Hanske. 1977. Pesticide and other chemical residues
1n total diet samples (XI). Pestle. HonH. J. 11(3): 116-131.
Johnson, R.O., 0.0. Hanske, D.H. New and D.S. Podrebarac. 1981. Pesticide,
heavy metal, and other chemical residues In Infant and toddler. Total diet
samples - (II) -- August 1975-July 1976. Pestle. HonH. J. 15(1): 39-50.
Johnston, P., F. Letk1ew1cz, 0. Borum, N. Samba 1, G. Gerner, et al. 1984.
Occurrence of pesticides 1n drinking water, food and air. Interim draft
report. Prepared by JR8 Associates, McLean, VA, for Office of Drinking
Water, U.S. EPA, Washington, DC.
Kutz, F.W., A.R. Yobs and H.S.C. Yang. 1976. National pesticide monitoring
programs, in: A1r Pollution from Pesticides and Agriculture Processes, R.E.
Lee, Ed. CRC Press, Cleveland, OH. p. 95-136.
PelUzzaM, E.D. 1978. Preliminary assessment of halogenated organic con-
pounds 1n man and environmental media. Monthly Technical Progress Report
No. 5, April 1-Apr 11 30, 1978. Prepared by Research Triangle Institute.
Research Triangle Park, NC, for Office of Toxic Substances, U.S. EPA,
Washington, DC. EPA Contract No. 68-01-4731.
00660 IV-11
-------
U.S. EPA. 1975. Analytical report: New Orleans water supply study. Region
VI, U.S. EPA. EPA 906/9-75-003. (CHed In Pelllzzarl, 1978)
U.S. EPA. 1976. National Interim primary drinking water regulations.
Office of Hater Supply, U.S. EPA, Washington, DC. EPA-570/9-76-003.
U.S. EPA. 1984. Rural water survey. Computer data provided by Department
of Sociology, Cornell University, Ithaca, NY.
00660 IV-12
-------
V. HEALTH EFFECTS IN ANIMALS
Acute Toxldtv
Experimental Lethality Studies. EndMn 1s acutely toxic to a number
of species when administered by oral gavage 1n a solvent, In the diet, or
applied to the skin (Table V-1). The LD5Q varies with the species and
strain of animal used. An early comprehensive study of acute toxlclty In
mammals Included Carworth rats (male and female of two ages), 4 rabbits, 4
guinea pigs, 1 cat and 2 monkeys (Treon and Cleveland, 1955). Minimum
lethal oral doses were: monkeys, 1-3 ng/kg bw; cats and female rats, <5
mg/kg; male rats. 5-7 ag/kg; rabbits, 5-7 mg/kg; and male guinea pigs, 24-36
mg/kg. These data suggest that primates are one of the most sensitive
groups. Signs of Intoxication Included ataxla, tremors, labored breathing,
diarrhea and tonlc-clonlc convulsions.
The oral LD.. of endrln for 6-month-old male Sprague-Dawley rats was
reported to be 40 mg/kg bw by Speck and Maaske (1958). Groups of 8-12 rats
were given single doses of endrln (20-80 mg/kg bw) In peanut oil by gastric
Intubation. There was a latent period of 45-60 minutes before the onset of
convulsions, regardless of the dose. Deaths occurred within 24-72 hours.
Gross examination at autopsy revealed contracted spleens, congested lungs,
and bright red blood, along with reddened livers and viscera. No hlstologk
changes were apparent In sections of liver tissue. Electroencephalogram
recordings after acute doses showed Irregular slowing, Irregular spikes, and
convulsive discharges. The righting reflex was not abolished during convul-
sions unless the attack was terminal. PentobarbUal stopped convulsions but
did not prevent death. Trypan blue (2 mt of IX solution) given with 50 mg
endr1n/kg bw to 30 rats prevented convulsions and lowered the death rate up
00670 V-1
-------
TABLE V-l
Acute Lethality of EndMn in Experimental Animals
LD5Q In mg/kg bw
Animal
Species
Rat, young3
Rat. adu1ta
Rat, adulta
Rata
Rata
Rata
Rata
Rat
Rata
Rata
House6
Mousef
House
Hamster
Hamster
Route of
Administration
oral
oral
oral
oral
oral
dermal
dermal
dermal
oral
oral
l.v.
l.p.
1.p.
oral
oral
Formulation
MAMMALS
peanut oil
peanut oil
peanut oil
20% e.c.b
2% f.s.d.c
20X e.c.b
W f.s.d.c
OHSOd
arachls oil
DHSOd
corn oil
methoxytrl-
glycol
corn oil
corn oil
Male
28.8
43.4
40.0
6.6
2.5
10.9
31.5
15-18
5.6
NR
2.3
5.6
8
12
NR
Female
16.8
7.3
NR
3.4
6.6
NR
92
5.3
5.3
NR
NR
NR
17.0
18.6
Reference
Treon et al.,
1955
Treon et al.,
1955
Speck and
Maaske, 1958
Mulr, 1968
Hulr, 1968
Mulr, 1968
Hulr, 1968
Galnes, 1969
Bedford
et al., 1975a
Bedford
et al., 1975b
Walsh and
Fink, 1972
Graves and
Bradley, 1965
Cole and
Caslda, 1986
Cabral
et al., 1979
Chernoff
et al., 1979
00670
V-2
-------
TABLE V-1 (cont.)
Animal
Species
Rabbit
Rabbit
Guinea pig
Dog
(mongrel)
Cat
Monkey
Pigeon
Mallard
Mallard
Route of
Administration
oral
dermal for 24
hours
oral
1.V.
oral
oral
1.V.
oral
percutaneous
Formulation
peanut oil
dry, 100 -mesh
powder
peanut oil
95X ethanol
peanut oil
peanut oil
BIROS
NR
corn oil
corn oil
1050 In mg/kg bw
Reference
Male Female
7-10 NR Treon et al.,
1955
NR 130-160 Treon et al.,
1955
369 169 Treon et al.,
1955
2-39 NR Reins et al.,
1966
5n NR Treon et al.,
1955
39 39 Treon et al.,
1955
1.2-2.0 1.2-2.0 Revzln, 1966
NR 5.64 Hudson
et al., 1979
>140 NR Hudson
et al., 1979
"CFE
Emulsion concentration
cMeld strength dust
dD1methy1su1fox1de
eCarworth Farms No. 1 strain
Swiss-Webster and ICR strains of Swiss albino mice
Estimated
Minimum lethal dosage
NR - Not reported
00670
V-3
-------
to 80 hours post -treatment. All animals given endMn alone were dead at 200
hours after dosing and -7% of the trypan blue-treated rats survived. No
convulsions were seen In animals with the chorold plexus stained blue by the
dye. These observations suggested that the acute reaction may Involve
Increased blood-brain barrier permeability and that the concentration of
endrln had to reach a critical level In either the blood or brain tissues
before convulsions occurred.
Graves and Bradley (1965) calculated an 10.. of 5.6 mg/kg bw for
endrln In corn oil Injected Into the peritoneal cavity of Swiss-Webster and
ICR strains of Swiss albino mice. No mortality was seen In controls (13
mice) or at dosages of 1 mg/kg (8 mice) or 2 mg/kg (8 mice). Complete
mortality was obtained with dosages >10 mg/kg (8 mice). Observations of
survivors during an additional 6-day period revealed no further mortality.
Similar observations have been reported for humans when Individuals survived
the symptomatic stage (Curley et al., 1970).
Acute l.v. LOrQ values and median survival times (ST^) of male mice
(IQ/group) exposed to endrln were determined to be 2.3 mg/kg bw (2.0-2.6,
95X confidence limits), and 17.5 minutes (15.2-20.1, 95% confidence limits
at a dose of 3 mg/kg), respectively (Walsh and Fink, 1972). Endrln was
administered In OHSO. At an L09Q (5 mg/kg), the ST5_ was 11 minutes.
In adult male mice (Cfl strain), a latent period of no activity that fol-
lowed Injection ended abruptly with a first clonlc convulsion. Intermittent
clonlc seizures ended with the beginning of hind leg tonic activity. Post-
tonic activity Involved continual clonlc seizures, which terminated In some
00670 V -4
-------
cases in death. The dose that produced ataxla 1n 50% of the mice was 0.75
mg/kg (0.59-0.98, 95% confidence limits). The authors stated that the
mechanism of tpxldty may be due to effects on plasma membranes or mitochon-
dria! ATPases 1n the brain or both.
When endrln was applied as a 20% emulsion, acute dermal LD5Q values
for rats were about twice the size of acute oral ID,- values (Nu1r, 1968).
When endrln was applied as a field strength dust, the acute dermal LD5Q
value was more than an order of magnitude greater. However, both of these
endrln preparations were more toxic than endrln administered In peanut oil,
showing that LD.g values are vehicle dependent. Dermal administration of
endrln as a dry 100-nesh powder 1n contact for 24 hours under a rubber
sleeve with the Intact skin of female rabbits yielded an acute LO,Q
between 130 and 160 mg endrIn/kg bw and a minimum lethal dose between 66 and
94 mg/kg bw (Treon and Cleveland, 1955). Table V-l summarizes these
toxldty data.
Bedford et al. (1975a) determined the acute oral LD,Q values (based on
10-day mortality) for three metabolites of endrln that have been Identified
1n mammals (Baldwin et al.. 1970; Bedford et al., 1975a). Each metabolite
was more acutely toxic than the parent pesticide (Table V-2). Svn-12-hy-
droxyendMn and !2-ketoendr1n were about 5 times more toxic than the parent
compound In male rats; 1n females, 12-ketoendrln was 5 times and syn-12-hy-
droxyendrln 2 times more toxic than endrln. AnU.-12-hydroxyendrln was 2
times more toxic In male rats and equltoxlc to endrln 1n females. The most
rapidly lethal compound was 12-ketoendrln; mortality was observed within 20
hours of administration for both male and female rats. Endrln and the
Isomers of !2-hydroxyendr1n produced mortality In 4-6 days In male rats, and
00670 V-5
-------
TABLE V-2
Median Lethal Doses 10 Days After Oral Administration
of EndMn and Its Metabolites to Rats*
L050
Compound
Male Female
Endrln 5.6 (3.0-7.9) 5.3 (3.6-7.4)
antl-12-HydroxyendMn 2.4 (2.0-3.0) 5.5 (4.2-7.2)
sj£-12-Hydroxyendr1n 1.2 (0.6-1.7) 2.8 (0.8-4.0)
12-KetoendMn 1.1 (0.7-1.5) 0.8 (0.5-1.2)
aSource: Bedford et al., 1975a
^Administered by gavage 1n OMSO to CFE strain rats, 12-14 weeks of age,
divided Into groups of either 4 or 8 rats of each sex
cNumbers 1n parentheses are 95X confidence Units
00670 V-6
-------
5-8 days 1n female rats. The authors concluded that even though oxIdatWe
metabolism of endrln 1s responsible for the observed efficient elimination
from rats of subacute doses, oxldatlve products of endrln may also be
responsible for Us acute toxlcUy.
LCSQs, defined as the dietary dosage (dw) required to kill 50% of the
test animals 1n a specified period of time, have been reported for
short-tall shrews and Ulster rats (Table V-3).
Environmental and Accidental Poisoning. The meadow vole (Mlcrotus
pennsylvanlcus) 1s known to be sensitive to endrln as evidenced by the
virtual disappearance of the rodent population after Us habitat and food
supply were sprayed once with endrln (Wolfe et al., 1963). Panlcum and
canary seed contaminated with 2.20-4.80 ppm endrln caused the deaths of -320
cageblrds (finches, doves, quails) 1n an aviary. Birds began dying 2 days
after Introduction of the contaminated feed, with the greatest number of
mortalities occurring after 5 days of exposure. No gross or microscopic
lesions were found 1n 12 necropsled birds (Main, 1978). Wild birds such as
grackles, mallards and white pelicans have also died of endrln Intoxication
(Peterson and Ellarson, 1978). Two bald eagles possibly died of endrln
poisoning (Kaiser et al., 1980). Brains of the eagles contained 0.71 and
1.2 mg endr1n/kg ww; the known lethal range begins at -0.6 mg endr1n/kg ww.
Misuse of endrln In India was responsible for the death of one bullock and
symptoms of acute poisoning In three other anlaals (Pandey, 1978). The
bullocks were treated for tick Infestation with "concentrated1 endrln over
their entire bodies. Signs of poisoning occurred after 6 hours.
00670 V-7
-------
o
o
TABLE V-3
Cndrln Short-Terra Oral Dietary
Values
Species
Short-tailed
shrew
Rat. Ulstar
Rat. Ulstar
Sex/Age
F/180 days
N/105-150 days
F/105-150 days
M/30-75 days
F/30-75 days
N. F/1mmature
H. F/1mma.ture
Duration Number of
Animals
14 days 5
14 days 5
14 days 5
14 days 5
14 days 5
5 days 50°
5 days 50°
(ppm endrln In the diet]
174
87
152
87
152
60.1 (43-83)c
62.3 (45-85)c
Reference
!
Blus. 1978
Blus. 1978
Blus. 1978
Blus. 1978
Blus. 1978
HcCann et al. .
1981
HcCann et al. .
1981
Dietary dosage (dw) required to kill SOX of test animals In a specified period of time
D5 male and 5 female/group/concentratlon; five concentrations
C95* - Confidence limit
-------
EndMn poisoning was reported 1n 15 of a herd of 70 Sa'anen adult female
goats after they had been grazing In an uncultivated area of weeds later
found to contain endrIn-contaminated boxes (Rapaport et a!., 1979). Signs
Included fits of trembling affecting the whole body, convulsions, profuse
salivation and collapse with an Inability to rise. In most cases signs
subsided within a few Minutes but resumed within an hour or so. Treatment
with atroplne, proplonyl promazlne, fluid (saline and Ringers).
cortlcosterold (prednlsone) and carbachol was not effective. Within 16
hours, 8/15 goats died, with 2 more dying In the next 24 hours. Postmortem
examination revealed profuse blood-stained froth in the trachea, diffuse
hemorrhaglc enteritis, some petcchlae on the eplcardlum, adhesions between
the parietal and pulmonary pleurae and Cysterlcerus tenulcolUs cysts In the
abdomen, with fluid and pale Intestinal contents. Quantities of endr In
consistent with those found In poisoning cases were found In the content of
the rumen.
Central Nervous System and Behavioral Effects. Sprague-Oawley rats
administered single, oral endrIn doses ranging from 20-80 mg/kg bw were
susceptible to convulsions, which were sometimes followed by catatonic
behavior (Speck and Naaske. 1958). In addition, electroencephalograph (EEG)
patterns following endrln exposure exhibited Irregular slowing and spikes,
and frequent convulsive discharges.
EEG patterns In squirrel monkeys were examined following Intramuscular
endrln exposures of 0.2 mg/kg bw/day or higher for 7 days, and the results
were summarized In an abstract (Revzln, 1968). Increased amplitudes and
splklngs In EEG recordings were observed after 7 days of exposure at 0.2
mg/kg/day, and were reportedly more narked at high total dosages.
00670 V-9
-------
Following cessation of dosing, EEG patterns remained abnormal for at least 1
month.
Locomotor activities were measured 1n nonpregnant female CD-I nice and
CO rats 2-4 hours after a single endrln exposure by gastric Intubation
(Kavlock et al., 1981). Mice and rats were exposed to 0, 0.5, 1.5 or 4.5,
and 0, 0.5, 1.0 or 2.0 rag/kg bw, respectively. Locomotor activities were
significantly reduced at the two highest dose levels In both species, and at
0.5 rag/kg bw 1n rats, but not nice.
Cardiovascular Effects. In the early 1960s, little was known of
cardiovascular changes following acute exposure to lethal amounts of endrln.
Experiments with male and female dogs to Investigate these phenomena were
conducted on 30 dogs weighing from 10-19 kg (Emerson et al., 1964) Anes-
thesia was Induced with sodium pentobarbltal (30 mg/kg) and, In some cases,
sucdnylchollne was given to prevent convulsions. Endrln (10 mg/kg bw In
95% ethanol) was administered by 1.v. Infusion. Control animals received an
equivalent amount of ethanol. Convulsions started within 5-10 minutes after
the beginning of endrln Infusion 1n dogs not given sucdnylchollne. Obser-
vations Included bradycardla, an Initial drop In arterial blood pressure,
Increased body temperature, hemoconcentratlon, decreased venous blood pH,
and Increased leukocyte counts. Hemolysls was seen In every post-endrln
hematocrU. Cerebral venous pressure and cerebrosplnal fluid pressure
elevations were also prominent features of endrln poisoning. Uhen sucdnyl-
chollne was given, the results were similar except that arterial pressure
Increased Initially but later fell to hypotenslve levels. Blood pH also
00670 V-10
-------
decreased more and hemoconeentration was more pronounced. In controls,
succlnylchoHne-lnduced bradycardla was replaced by tachycardia In some
animals. The heart rate would then oscillate between bradycardla and tachy-
cardia. These authors concluded that most of the observed effects appeared
to be caused by endMn acting directly on the CNS, although some might have
resulted secondarily from altered cerebral hemodynamlcs.
Endr1n-1nduced convulsions terminating In death are accompanied 'by
marked changed 1n blood pressure and heart rate. Using SO mongrel dogs,
Reins et al. (1966) determined the relationship between venous return
(cardiac output), total peripheral vascular resistance and hypertension
after a lethal dose of endrln. All animals were treated with sucdnylcho-
Une to prevent convulsions. Endrln (10 mg/kg bw In ethyl alcohol) Induced
a rise 1n systemic arterial blood pressure, which depended primarily on
Increased cardiac output caused by an elevated venous return. Increased
levels of eplnephrlne and noreplnephrlne In blood plasma, rather than CNS
stimulation, may be the explanation for the narked alterations In systemic
hemodynamlcs. Total peripheral resistance did not change significantly 1n
either endr1n-1nfused dogs or control, animals Infused with the solvent.
ethyl alcohol. In a similar study with dogs, Hlnshaw et al. (1966) also
reported large Increases 1n blood catecholamlne concentrations, and In-
creased cardiac output. In contrast to the Reins et al. (1966) findings,
these Investigators reported that total peripheral resistance fell signifi-
cantly and that cardiovascular alterations were not significantly correlated
with blood catecholamlnes after endrln Intoxication. One major difference
00670 V-ll
-------
between the two studies was that Reins et al. (1966) used sucdnylchollne to
prevent convulsions; anesthesia was achieved with sodium pentobarbltal (30
mg/kg bw) 1n both studies.
Renal Effects. Renal function and hemodynaralcs were examined In
mongrel dogs following acute and chronic exposure to endrln (Reins et al.,
1964). In the acute studies, eight dogs were exposed to lethal endrln doses
(10 ng/kg) by Intravenous Infusion via the femoral vein, and an additional
four dogs received the same endrln dose by Injection Into the Intestinal
lumen. Following a 2-4 hour examination period, Mstologlcal examinations
were conducted. Endrln exposure elicited Increased renal vascular
resistance, decreased renal blood flow and glomerular filtration rate (GFR)
within 1-2 hours of exposure, although marked Individual variation was
noted. Since these renal alterations could be reversed by treatment with
phentolamlne, they were considered to result secondarily to endrln-Induced
systemic hypertension and effects on circulating humoral agents, rather than
from a direct toxic effect of endrln on the kidney. An Influence of
exposure route on these renal effects was not stated. However, convulsions,
hypertension and bradycandla, which developed 1n the Intravenously Infused
dogs, did not occur In those receiving endrln via the Intestinal lumen.
Hlstologkally, the dogs exhibited protein precipitation In Bowman's space
and the renal tubules, and 1/12 dogs developed renal tubular necrosis.
Congestion, degeneration and/or swelling were reported In the spleen, liver
and lungs, whereas the heart, pancreas and Intestine appeared normal.
Heoatlc Effects. Oral administration of endrln (15 wg/kg/day) for 3
successive days elicited significant (p<0.05) elevations of liver total
llplds. liver trlglycerldes and serum cholesterol In male Sprague-Dawley
00670 V-12
-------
rats. SGOT but not SGPT activities were also sightly elevated following
endMn exposure tBorady et al., 1983).
Significant elevations In hepatic oxldatlve demethylatlon of
dimethylnltrosaralne were elicited \r\ male Swiss albino mice exposed by oral
gavage to endrln (2 mg/kg/day) for 3 consecutive days (Hostafa et al.,
1983). The effects of oral endMn exposure on IWer mlcrosomal P-450
content, ethylmorphlne demethylase and aniline hydroxylase activities In
pine voles and ICR white mice have also been reported (Hartgrove et al.,
1977). A single dose of O.S or 2.0 mq/kg bw was administered to pine voles,
whereas mice received a single dose of 4.0 or 10.0 mg/kg bw. The period of
time between dosing and sacrifice was not reported. Aniline hydroxylase
activities were elevated In both pine voles and mice following endMn
exposure. EndMn elicited a decrease In ethylmorphlne demethylase activity
1n pine voles, but an Increase In this activity In the mice. An elevation
In total cytochrorae P-450 content was elicited In mice, but not pine voles.
Female guinea pigs were chosen for a study of the effects of endMn on
hepatic and renal mlcrosomal electron transport because of their sensitivity
to the toxic effects of the pesticide (Pawar and Kachole, 1978). Six
animals (600-650 g) were Injected 1.p. with endMn (3 mg/kg bw/day In safola
oil) for 3 successive days; six control animals were Injected with an
equivalent amount of oil. Hlcrosomes were prepared from liver and kidney
tissue 24 hours after the third Injection. The liver weights of endrln-
treated animals were Increased and mlcrosomal protein content was
decreased. Kidney weight was elevated, but renal mlcrosomal protein was not
affected. Decreased hepatic mlcrosomal HAOPH-llnked amlnopyrlne
00670 Y.-13
-------
N-demethylatlon was attributed to decreased levels of cytochrome P-450.
Endrln treatment Increased Vn vitro NADH-med1ated amlnopyMne
N-demethylat1on In renal mlcrosomes. A significant Increase In I1p1d
peroxldatlon 1n hepatic mlcrosomes was evident when NADPH or ascorbate was
the electron donor.
Four chlorinated hydrocarbons Including endrln were tested for their
possible Interference with heme synthesis In Japanese quail, a species
chosen because of high sensitivity to chlorinated organic: as determined by
urinary porphyMn concentrations (NagelsmU et al.t 1979). There was no
Indication that endrln was porphyrlnogenlc (1-3 or 5 mg/kg bw/day for 3 days
given orally In a capsule), which suggested that urinary porphyMn would not
reflect endrln exposure In exposed humans.
Effects of acute endrln exposure are summarized 1n Table V-4.
Subchronlc Effects of Endrln
Maternal body-weight and I1ver-to-body weight ratios were measured In
two studies concerning perinatal endrln toxlclty In hamsters, rats and
mice. Endrln was administered orally to golden Syrian hamsters on days 4-15
of pregnancy, 1n single dally doses of 0, 0.75, 1.5, 2.5 or 3.5 mg/kg/day
(Chernoff et al., 1979). Doses >1.5 mg/kg/day produced maternal lethality,
which was preceded by significant weight loss. Neither lethality nor
effects on maternal weight were elicited at 0.75 mg/kg/day.
Endrln was administered orally 1n single dally doses to CD rats on days
7-20 of gestation, and to CD-I mice on days 7-17 of gestation (Kavlock et
al., 1981). Doses of 0, 0.075, 0.150, 0.300 or 0.450 mg/kg/day were
00670 V-14
-------
1AIII «-«
iffectt of Acute fndrln tiposure
o
0
-J
o
1
I/I
Species/
Strain
Bogs/mongrel
Bogs/mongrel
Bogs/mongrel
Rat Spraguo-
Bawloy
Nice/Swiss
albino
NIce/ICR iditte
Voles/pine
Guinea pigs/
strain not
stated
Ntce/CB-1
Se«/
Mumber
male, female
gender not
stated/50 dogs
gender not
stated/S-7
experiments:
number of dog*
not clearly
stated
mile
•lie
gender not stated/
4-11 mice per
treatment group
gender not stated/
14-18 per treat-
ment group
feMle/i group
female
Dose/
Route I xposure
t.v. Infusion 10 mg/kg
t.v. Infusion 10 mg/kg. In
presence of
succlnylchollne
t.v. Infusion 3 mg/kg
oral IS mg/kg/day for
3 successive
days
oral ? mg/kg/day for
3 successive
days
oral 4.0 and 10 mg/kg/
bw. single dose;
tin* until sacrl-
oral O.S or 2.0 mg/kg
bw single dose;
tin* until sacri-
fice not reported
I. p. 3 mg/kg/day for
3 successive days
oral Intubation 0. O.S. l.S or
4.S mg/kg bw.
single dose
Comments
Convulsions, bradycardta. arterial blood
pressure fall, elevated body temperature.
hemolysts and other hemotologtcal changes
Arterial blood pressure Increase.
decreased heart rate
Increased cardiac output and Increased
blood catecholamlnes. fall In total.
perlpheal vascular resistance
ilevated total liver llplds. liver
trlglycerldes. serum cholesterol and
slightly elevated SG01
Increased oildattve demethy lat Ion of
dtmethylnttrosamlne
Increased hepatic cylochrome f-450
content, aniline hydroxylase and
ethylmorphlne demethylase actlvtles
Increased hepatic aniline hydreiylase
activity, decreased ethylmorphtne
demethylase activity
••created hepatic cytochrome P-450
and amlnopyrlne H-demethylatlon.
Increased liver weight
Reduced locomotor activity at l.S and 4.S
mg/kg bw
Reference
Emerson et al.. 19M
Reins et al.. 19M
Htnshaw et al.. 1944
•orady et al.. 1983
ftostafa et al.. 1983
Hartgrove et al.. 1977
Hart grove et al.. 1977
Pawar and Kachole. 1978
Kavlock et al.. 1981
Rats/Ct
Monkeys/Squirrel
fenale
3. gender not
stated
oral Intubation
Intramuscular
0. O.S. 1.0 or
7.0 or 4.0
•g/kg bw. single
dose
0.? mg/kg/day for
7 days
Reduced loconotor activity at all
exposure levels
Increased amplitudes and spiking In lit
recordings
Kavlock et al.. 1981
Rev*tn. 1968
-------
administered to rats; doses of 0, 0.5, 1.0, 1.5 or 2.0 mg/kg/day were given
to nice. Results from the range finding study are reported In Table V-4.
Mice and rats were killed on days 18 and 21 of gestation, respectively.
Fetal mortality, weight, degree of skeletal and visceral maturation, and
Incidence of skeletal and visceral anomalies showed no dose-related
effects. Maternal weight gain was significantly reduced In rats exposed to
0.300 mg/kg/day (p<0.01) and markedly reduced at 0.450 mg/kg/day, but did
not differ from controls at 0.75 or 0.150 mg/kg/day. Neither maternal
deaths nor elevations 1n Hver-to-body weight ratios occurred 1n exposed
rats. Elevated I1ver-to-body weight ratios were reported In the mice at all
exposure levels, and maternal lethality occurred at doses >1.5 mg/kg/day.
HepatoblHary function and hepatotox1c1ty have been assessed In rats
d1etar11y exposed to endrln (Young and Mehendale, 1986). Treatment groups
of six male and six female Sprague-Dawley rats were given a powdered chow
diet containing 0, 5 or 10 ppra endrln for 15 days. The total endrln doses
for the 15 days of exposure (and the corresponding dose expressed as
mg/kg/day) were 7.4*1.1 mg/kg (0.5 mg/kg/day) and 14.2^0.9 mg/kg (0.9
mg/kg/day) for males; the female endrln doses were 7.4*0.4 mg/kg (0.5
mg/kg/day) and 12.8+J.8 mg/kg (0.9 mg/kg/day) for 5 and 10 ppm, respec-
tively. On day 16, heptatotoxldty 1n all animals was assessed by serum
enzymology, and hepatoblHary function was assessed by measuring biliary
flow rates and excretion rates of phenolphthaleln glucuronld* (PG).
Serum enzyme levels were not significantly elevated In the endrln
exposure groups. In males exposed to 5 ppm endrln, PG excretion and bile
flow rates were reduced to 66 and 68% of control levels, respectively. At
00670 V-16
-------
10 ppm, PG excretion was reduced to 75X of control, but no significant
change 1n bile flow rate was observed. In females exposed to 5 ppm endrln,
the rate of PG excretion was 10% higher than control, whereas the rate of
bile flow was not significantly different than control. At 10 ppm, rates of
PG excretion and bile flow were elevated to 30% and 25X above control
levels, respectively. It was concluded that endrln had a sex-dependent
effect on hepatoblHary function.
In the only reported subacute study Involving dermal exposure (Treon et
al., 1955), three female rabbits/group were exposed to 100-mesh, dry endrln
powder 75 or 150 rag (equivalent to 67-91 rag/kg bw/day at the high-dose and
20-42 mg/kg bw/day at the low-dose) under a rubber sleeve 2 hours dally, 5
days/week. In the high-dose group the rabbits died after 19, 19 and 25
applications. At the low-dose 1 of 3 died after the 40th application.
Subchronlc and chronic endrln toxldty were evaluated 1n Carworth rats,
beagle dogs and an unspecified species of rabbit (Treon et al., 1955). Four
of five female rabbits that were orally administered 1 mg/kg/day endrln 5
days/week died during the 10-week exposure period. Mortality occurred 1n
3/3 male rats after oral administration of endrln at 5 mg/kg/day. Mortality
occurred In 2/5 females but no deaths occurred 1n males at the 2 mg/kg/day
dose level. All treated animals developed hypersens1t1v1ty to stimuli and
weight loss but generally male rats were less affected than female rats.
Height gains 1n groups of 20 male and 20 female rats (Initial age 28 days)
given diets containing 0, 1, 5, 25, 50 or 100 pom endrln for 20 and 40 weeks
were also reported. In 5 ppm males, weight gain was significantly reduced
at 20 but not 40 weeks of exposure. At 25 ppm, significant weight gain
00670 V-17
-------
reduction was observed at both 20 and 40 weeks. In contrast, female weight
gain was significantly elevated at >5 ppm following both 20 and 40 weeks of
exposure.
Beagle dogs were administered diets containing 4-50 ppm endrln for
periods ranging from -1-10 months. Mortality occurred at exposure >5 ppm.
After -6 months of exposure to 4 ppm, the I1ver-to-body weight ratio was
elevated, and liver-, kidney- and brain-to-body weight ratios were elevated
In dogs exposed to 8 ppm. Dogs that died during endrln exposure exhibited
degenerative lesions In brain, heart, liver and kidneys. In addition to
pulmonary hyperemla and edema. The renal damage was particularly severe
(Treon et al., 1955).
Sprague-Oawley rats were fed diets containing various concentrations of
endrln for up to 16 weeks (Nelson et al., 1956). The endrln concentrations
were 0, 1, 5, 25, 50 and 100 ppm, and were administered to groups of 10 rats
(5 of each gender). Mortality occurred within 4 weeks 1n males and females
fed concentrations >5 and 25 ppm, respectively. For the 100 ppm group, this
mortality was 100X. After 16 weeks, some mortality had occurred In all male
exposure groups, but only 1n female groups exposed to >25 ppm.
Dose-related weight loss was reported 1n animals exposed for up to 8
weeks. Serum alkaline phosphatase was consistently elevated froa weeks
10-16 among survivors fed 25 or 50 ppm; this elevation occurred but was not
persistent at the lower exposure levels. HypersensHlvHy to various
stimuli was reported at all exposure levels, but was most pronounced and
followed by convulsions at the higher (25-100 ppm) exposures only. These
00670 V-18
-------
animals also exhibited dysenteric symptoms, Intermittent blindness and
slight nasal bleeding. The nasal bleeding also occurred In the 1 and 5 ppm
exposure groups. The latency to hypersens1t1v1ty, nasal bleeding,
dysenteric symptoms and blindness was not reported.
Endrln (3.5 mg/kg bw/day) was administered to groups of male Sprague-
Dawley rats by oral gavage 5 days/week for periods ranging from 1 week to 7
months (Speck and Maaske, 1958). After 1 week of exposure, 4/30 animals
died. Surviving animals exhibited an elevated respiration rate,
excitability or Irritability, and were predisposed to convulsions following
auditory stimulation. Irregular EEG recordings were also observed following
1 week of exposure.
EEG changes were minimal 1n the chronic groups. However, after 3 months
of exposure, livers appeared spotty with zones of basophlllc cells around
the central and portal veins. Furthermore, plasma specific gravity was
significantly reduced following 3 months of endrln exposure; this effect was
reversible upon discontinuation of endrln exposure.
Cattle and sheep were not affected by 5 ppm In the feed Ingested over a
112-day period (Radeleff, 1956). Chickens (7 days old) were not made excit-
able by a ration containing 1.5 and 3 ppm endrln for 42 days. This was not
so for concentrations of 6-12 ppm endrln; decreased weight gains were also
shown at these concentrations (Sherman and Rosenberg, 1954).
Feeding studies were conducted to estimate the maximum tolerated doses
of endrln 1n Osborne-Hendel rats and B6C3F1 mice for a National Cancer
00670 V-19
-------
Institute study of cardnogenlclty (NCI, 1979). EndMn was first dissolved
1n acetone and then added to the feed. Corn oil was added to all feed (2%
of final weight of feed) as a dust suppressant. Five males and five females
were given food with or without endrln for 6 weeks, followed by observation
for 2 weeks.
For rats, endrln was added to the feed In 2-fold Increasing concentra-
tions, ranging from 2.5-80 ppm (NCI, 1979). There were no deaths at 10 ppm
and mean weight gains were not different from controls. At 20 ppm, one
animal of each sex died, but weights of survivors were not significantly
affected. In the same 1979 NCI subacute study, mice were given feed
containing from 2.5-20 ppm endrln. At 10 ppm, 3 males and 4 females died In
the group of 10 mice. No mortality occurred In the 5 ppm group; mean weight
gains were comparable with that of controls. In these subacute exposures,.
Increased mortality was the only toxic effect reported other than
hyperexc1tab1l1ty In male mice receiving >5 rag/kg diet.
Effects of subchronlc endrln exposure are summarized In Table Y-5.
Chronic Effects
In a series of experiments, Treon et al. (1955) explored the effects of
endrln 1ngest1on 1n a number of species Including rats, rabbits and dogs.
Included 1n this study was the only report found of an Inhalation exposure
of animals to 'vapors' of endrln (Table V-6). No convulsions were reported
among this group of animals. Pathological findings were similar to those
observed following other routes of administration.
00670 V-20
-------
UBlf V-S
fffects of Subchronlc fndrln Iipoture
Species/Strain
Rabbit/not
stated
Rat/Carworth
Rat/Carworth
Rogs/beagle
Sex/Nutter
Route
f/S oral
H/t and f/S oral
M/20 and f/20 oral
15 total animals oral
Dose/E xposure
Regimen
1 mg/kg/day. S
days/weeks for
10 weeks
2 mg/kg/day
dteti contained
0. 1. 5. 25. 50
or 100 ppm endrlii
for 20-40 weeks
dtots contained
4-50 DOM endrln
for 1-10 Months
Comments
4/5 rabbits died
2/5 female rats died; no deaths In Mies
Reduced weight gain In rats exposed
at >$ ppm.
Mortality In some animals >5 pom.
Elevated liver -to -body weight ratio
at 4 OP*, elevated liver-, kidney- and
Reference
Ireon ot al.. 1955
Treon et al.. 1955
Ireon et al.. 1955
Treon ot al.. 1955
Rabbits
3f/group
Rats/Sorague- N/5 and f/5
Oawley
Rats/Sorague-
Rawley
derMl
oral
Rats/Osborne
Nendel
H/5 and f/5
oer' group
oral gavage
oral
20-4? or »7-91
•g/kg/day
2 hours/day. 5
days/week for up
to 0 weeks
dietary eiposure
at 0. 1. 5. 25. 50
or 100 ppni for up
to It weeks
3.5
5 days/week for
1 week to 1 Months
diets contained
0. 2.5. 5. 10. 20.
40 or RO pp* for
t weeks, followed
by 2 weeks of
observation
brain-to-body weight ratios at 0 ppe.
Mortality In both eiposwo'groups after
19-40 applications.
Mortality In SOON Male rats In all
exposure levels and In females exposed
to >25 ppa. Nasal bleeding In 1 or 5 ppm
exposure groups. Height loss, elevated
seruo) alkaline photphatase. dysenteric
symptom and Interoilttent blindness.
4/30 died after 1 week of exposure.
abnormal 116 patterns In survivors.
After 3 months exposure, spotty livers
with tones of basophlllc cells, reduced
plasma specific gravity.
No deaths or weight gain effects at
<10 PPM. Mortality occurred at 20 op*.
weights of survivors were unaffected.
Treon ot al.. 1955
Nelson et al.. 1956
Speck and Maaske.
195R
NCI. 1919
-------
1ARII V-S fcont.)
fffects of Subchrenlc fndrln Exposure
Species/Strain
Htco/RtC3M
Sex/Number
N/5 and f/5
Route
oral
Pose/E xposure
Regimen
diet contained
Comments
Ho deaths or weight gain effects at
Reference
NCI. 1979
Hamsters/golden 20-3W per
Syrian exposure group
oral
Rats/CD
15-30* per
exposure group
oral
i
is*
Mice/CIO
20-MF per
exposure group
oral
Rats/Sprague-
Oawley
H/» and F/
per group
oral
0. ?.5. 5. 10 or
20 ppm endrtn for
4 weeks, followed
by 2 weeks of
observation
single dally doses
of 0. 0.75. 1.5.
2.5 or 3.5 mg/kg
bw were adminis-
tered to pregnant
hamsters on days
4-15 of gestation
single dally doses
of 0. 0.075. 0.150.
0.300 or 0.450
mg/kg bw were ad-
ministered to preg-
nant rats on days
7-M of gestation
single dally doses
of 0. 0.5. 1.0. 1.S
or ?.0 mg/kg bw
were administered
to pregnant mice
on days 7-17 of
gestation
diets contained
0. 5 or 10 pom
endrln for 15 days.
Approximate corre-
sponding mg/kg/
day doses were 0.
0.5 and 0.9. res-
pectively
1.5 mg/kg/day.
Chernoff et al.. 1979
Depressed maternal weight gain at 0.300
and 0.450 mg/kg bw.
Kavlock et al.. 1981
Lethality and/or depressed maternal weight
gain at doses >1.0 mg/kg bw/day. Elevated
liver-to-body weight ratio at all
exposure levels.
Altered hepatoblllary function which
was se«-dependent.
Kavlock et al.. 1901
Young and Nehendale.
198b
-------
TABLE V-6
Mortality of Animals Exposed to 0.36 ppn (5.62 ng/m») Endrln '
Species
Cat
Guinea pig
Hamsters
Rats
Rabbits
Mice
No. of
Exposure
(days)
130
130
101-130
130
118
107
No. Dead/
No. Exposed
0/1
0/2
0/2
0/3
2/4
1/3
Dally Inhalation
Volume
(ii' /day)
0.15
0.074
0.037
0.26
1.6
0.05
vg Endr1nc
(7 -hour day)
0.25
0.12
0.061
0.43
2.6
0.082
aSource: Treon et al., 1955
^Exposed by Inhalation 7 hours/day, 5 days/week for 185 days
cThe original paper does not provide any weight data for these species In
these experiments.
00670
V-23
-------
Treon et al. (1955) fed groups of 20 male and 20 female Carworth rats
diets containing 0, 1, 5, 25, 50 or 100 ppm endrln for 2 years. Rats
receiving 50 or 100 ppn exhibited hypersensUWHy to external stimuli,
occasional convulsions and liver degeneration. In addition, after 80 weeks
of treatment, Increased mortality 1n rats was noted at 25, 50 and 100 ppm in
males and at 50 and 100 ppm 1n females. Effects on body weight were
reported at 20 and 40 weeks. Females at 5 and 25 ppm appeared to have a
greater rate of body weight gain than controls, while body weights In males
appeared to be slightly depressed at these levels. At >50 ppm, rats of both
sexes appeared to have a slightly Increased rate of body weight gain, but
since mortality was high In these groups, the survivors may have been the
larger rats. Hales at 5 and 25 pom had Increased relative liver weights
compared with controls, while rats at 1 ppm were not different from controls.
Treon et al. (1955) also conducted a study with beagle dogs 1n which
groups of 1-4 were fed diets containing 0-50 ppm endrln for up to 18
months. All dogs fed 10-50 ppm (0.49-4.00 mg/kg/day) died, and >50* of
those fed 5-8 ppm (0.20-0.65 mg/kg/day) died. Actual endrln Intakes were
reported by the authors. All dogs receiving <4 ppm (0.15-0.21 mg/kg/day)
survived, but growth was affected 1n the 4 ppm groups. The 3 ppm (0.12-0.25
mg/kg/day) group had significantly higher relative kidney and heart weights
than controls. Dogs fed 1 ppm endrln were similar to controls 1n all
parameters, Including gross pathology and hlstopatholoqy. According to the
authors, the dogs (two males and two females) on the 1 ppa diet actually
consumed 0.045-0.120 mg/kg/day.
In a 2-year dog study, beagle dogs (7/sex/group) received diets
containing 0, 0.1, 0.5, 1.0, 2.0 or 4.0 ppm endrln for >2 years (U.S. EPA,
00670 V-24
-------
1987). Interim sacrifices (2 dog/sex/group) were performed at 6 and 12
months. Parameters monitored Included growth, food consumption, behavior,
serum and urine chemistry, organ weights and hlstopathology of all major
organs. Animals treated at the 2 and 4 ppm dose levels experienced
convulsions, slight Increase 1n relative liver weights, and mild
hlstopathologkal changes 1n liver cells. Because of the effects observed
1n the dogs consuming diets containing 2 ppm endrln (0.05 mg/kg/day), this
level was considered the LOAEL. No adverse effects were observed In dogs
receiving diets containing <1 ppm endrln. Therefore, 1 ppm (0.025
mg/kg/day) was considered the NOAEL.
Renal function and hemodynamlcs were examined 1n mongrel dogs following
acute and chronic exposure to endrln (Reins et al., 1964). In the chronic
study, five female dogs were given endrln (1 mg/kg) by Intramuscular
Injection 5 days/week until death or sacrifice. Results concerning renal
function were reported as Inconclusive due to marked Individual variation,
and hlstologlcal evaluation of the renal tubules, as well as the brain,
pancreas, heart and Intestines, showed no definitive pathological changes.
However, chronic endrln exposure elicited congestion and occasional
hemorrhage In the lungs, and adrenal I1p1d depletion and congestion.
Oelchmann et al. (1970) conducted a chronic study for the primary
purpose of providing Information on the possible carclnogenldty of endrln.
aldrln and dleldrln. Carcinogenic outcomes of chronic studies are reported
1n the Carclnogenldty section. Endrln dissolved 1n corn oil was added to
ground Purina rat chow and administered to Osborne-Hendel rats (SO males and
50 females) at 1, 3 or 6 ppm for 10 weeks and at 2, 6 or 12 ppm until death
00670 V-25
-------
or 31 months. There was no significant effect on mean body weight or weight
gain In endrln-treated rats. Two hundred rats (100/sex) were fed an uncon-
tamlnated diet. No mention was made whether corn oil was added to the
control diet. Signs of toxldty observed during the course of the experi-
ment were limited to episodes of tremors and clonlc convulsions with
•outcries.1 These signs were dose related; however, the statement was made
1n general for all three Insecticides. The mean survival rate for 12 ppm
endrln-treated male rats was 17.6+6.9 months, and for 2 ppm treated rats,
18.U4.9 months; mean survival for control rats was 19.7+4.8 months (statis-
tical analysis not reported). The mean survival of female rats was about
the same or slightly longer. Liver-to-body weight ratios were not signifi-
cantly different from those observed 1n control animals. H1sto1og1c changes
In the livers of rats fed endrln (2, 6 or 12 ppm) were similar to those
receiving the control diet with the exception of a moderate Increase In the
Incidence of centrllobular cloudy swelling; there was also an Increase 1n
cloudy swelling of the renal tubular epithelium.
Male and female Osborne-Hendel rats (24/group) were fed diets containing
0, 0.1, 1, 5, 10 or 25 ppm endrln for 2 years (Reuber, 1978). Although this
study was intended to be a cardnogenlclty bloassay, data on the total
Incidence and severity (none, mild, moderate or severe) of chronic
Interstitial nephritis that developed 1n both control and exposed groups
were also reported. There appeared to be a trend toward Increased Incidence
and severity of nephritis with Increasing endrln exposure, particularly 1n
the males exposed to >1 ppm. The author concluded that endrln exposure
Induced dose-related Increases In the Incidence and severity of chronic
00670 V-26
-------
nepnritls 1n the males. However, statistical evaluation of these data was
not reported, and such an evaluation appeared necessary In order to justify
this conclusion.
The NCI (1979) conducted a chronic study with Osborne-Mendel rats and
B6C3F1 mice to determine the possible carclnogenldty of endrln. EndMn was
added to feed as described 1n subacute effects. Fifty animals of each sex
constituted a treatment group of rats or mice. Ten animals of each sex were
matched controls and data from 40 or 50 untreated animals from similar
bloassays were pooled for statistical evaluation.
Groups of rats (100 each) were administered one of two doses of endrln
for 80 weeks (NCI, 1979), and then observed until survivors were sacrificed
at 110-114 weeks. Hale rats received 2.5 or 5 ppm endrln In the diet.
There was neither a significant effect on mean body weight nor a significant
dose-related trend In mortality. Clinical signs usually associated with
aging were observed earlier In dosed rats than 1n controls: alopecia,
diarrhea, eplstaxls, tachypnea, pale mucous membranes, hematurla, rough hair
coats and dermatitis. Thyroid hyperplasla and pituitary cysts were observed
1n exposed animals, but not In matched controls. However, the spontaneous
occurrence of these lesions In aged Osborne-Hendel rats was described as not
uncommon. Testlcular atrophy was reported 1n 8/42 and 14/45 low- and
high-dose rats, respectively; none was reported 1n matched controls.
Mice were administered endrln In the diet for 80 weeks and observed
until sacrifice at 90-91 weeks. Initial doses of 2.5 or 5 ppm were not well
tolerated by male mice and were reduced to 1.2 and 2.5 ppm (NCI, 1979). The
00670 Y-27
-------
TWA was calculated to be 1.6 and 3.2 ppn. Female mice were kept at the 2.5
or 5 ppn level. Mean body weights were similar to corresponding controls
and there was no dose-related trend 1n mortality 1r female mice. Survival
was decreased In high-dose male mice; a large number of the low-dose males
died following the accidental overdose at 66 weeks and survival could not be
determined. Before the overdose, clinical signs Included alopecia,
diarrhea, eplstaxls, rough hair coats, tachypnea, hematurla and discolored
urine. After about 4 months, all of the high-dose male group appeared
hyperexdtable, and doses for males were lowered as Indicated above.
Lowering the dose did not change the hyperexdtable behavior In the majority
of the group. In the last half of the first year, clinical signs were
apparent 1n both sexes: abdominal distension, alopecia and rough hair
coats. Because of an error at week 66, excessive amounts of endrln were
given to the 1.2 ppm dosed male mice which caused animals to be
hyperexdtable until termination. Researchers determined that a rather fine
line exists between endrln levels causing CMS toxldty and those virtually
nontoxlc.
KreHzer (1980) determined whether behavioral effects would be produced
by endrln at levels below those that produced overt signs of Intoxication.
Adult male bobwhlte quail, Collnus vlrqlnlanus. were fed endrln dissolved In
propylene glycol and blended Into feed at levels of 0.1 and 1.0 ppm. An
equal amount of propylene glycol was added to the feed of controls. There
were four controls and four birds at each treatment level for all tests that
measured performance on nonspatlal discrimination reversal tasks. Birds
were dosed (beginning at the age of 3 days) for 138, 185 and 240 days before
Tests 1, 2 and 3, respectively. The fourth test began after 267 days of
00670 V-28
-------
aoslng followed by 25 days of untreated feed, and the fifth test after 278
days of dosing followed by 50 days of untreated feed. EndMn-treated birds
made from 36-139% more errors than did controls (p<0.025). The difference
between acquisition error scores of controls and treated birds Increased
exponentially over the first four tests. The 0.1 ppm diet dosed birds made
significantly more errors than the 1.0 ppm birds after reversal of black and
white patterns used for discrimination to receive a reward. There was no
explanation for this effect. Endrln effects were reversed after 50 days of
untreated feed. The principal effects of endrln was to Impair the birds'
ability to solve a novel problem. Mean brain residues In endrln-treated
birds were 0.075 mg endMn/kg ww for the 0.1 ppm dose and 0.35 mg endrIn/kg
ww for the 1.0 ppm dose.
Jager (1970) published an extensive review of the epidemiology and
toxicology of long-term exposure to aldMn, dleldrln, endrln and telodMn.
In a discussion of endrln toxldty 1n animals, Jager concluded that even
though endrln 1s a stereolsomer of dleldrln, 1t differs from dleldrln In the
following respects: higher acute toxkHy, more rapid metabolism, and less
persistence 1n vertebrates. The endrln LD5Q varied with the vehicle and
experimental species used, endrln being 4-5 times more acutely toxic than
dleldrln. The dietary NOEL for endrln In chronic feeding studies In the rat
and the dog was 1 ppm endrln 1n the diet.
The effects of chronic endrln exposure are summarized 1n Table V-7.
Teratoqenldty and Reproductive Effects
Mammals. Two studies of endrln toxldty 1n rodents were conducted 1n
the 1960s at doses that were toxic to the mother. Endrln was added to the
00670 V-29
-------
IARIE v-?
Summary of Oral Chronic Effects After fndrln (xpoture
o
o
Species/Strain
Rats/Carworth
Sex/Hunter
MU/S-20
per group
Dote/I iposure
Regimen
diets contained 0,
1. 5. 2S. SO or 100
ppm endrln for 2 years
Comments
Mortality at >2S ppm. Elevated liver-
to-body weight In males exposed to >S ppm.
lesser but nonsignificant elevations at
1 ppm In males, and 1-5 ppm In females.
Reference
Treon et al.. 19SS
Dogs/beagle
Rats/Otborne-
Hendel
M/50 and f/SO
N/SO and F/50
Rats/Osborne-
NeHdel
Rats/Osborne-
Mtce/RtOM
Rats/long-
Evans
N/24 and f/24
per group
M/50 and f/SO
per group
N/SO and f/SO
per group
N/7 and f/7
per group
diets contained 0-SO
p|M for 1R-19 months
diets contained 2. 4
or 12 ppm endrln
until death or for
31 Months
diets contained 0.
0.1. 1. S. 10 or 24
ppa endrln for 2 years
diets contained IMA
endrln levels of 2.S
or S ppm for males.
and 3 or * ppm for
females for 110-114
weeks
diets contained TIM
endrln dotes of l.t
and 3.2 ppm for
•ales or 2.S and S
ppo) for f MM lei. for
90-91 weeks
diets containing 0. 0.1
O.S. 1.0. 2.0 or 4.0
for >2 years
Enlarged kidneys and hearts at 3
not 1
but
Early mortality In oiposed groups relative
to controls. Mo effects on body weight gain
or liver-to-body weight ratios. Moderately In-
creased Incidence of cloudy swelling In
centrllobular liver tones and In renal
tubular epithelium. Also, moderate
Increases In Incidence of lung congestion
and focal hemorrhages.
Chronic Interstitial nephritis, tending
toward Increased Incidence and severity
with Increasing dose.
Clinical signs associated with aging
appeared earlier In dosed rats than In
controls. Testlcular atrophy was reported
In exposed males, but not In matched
controls.
Recreated survival In high-dose males.
Mypereicltablltty In high-dose males.
Clinical signs Including alopecia.
abdominal distension and rough hair coats
were reported In dosed groups prior to
controls.
Convulsions, slight Increase In relative
liver weight and mild htstopathologtcal
changes In liver cells at 2 and 4 ppm.
Ho adverse effects at 1 ppm.
Treon et al.. 19SS
Oelchmann et al.. 1970
Reuber. 1970
NCI. 1979
NCI. 1979
U.S. EPA. 19876
-------
feed of Sprague-Dawley rats (Green, 1969) and of CFW Swiss mice (Good and
Uare, 1969) at 5 ppm and fed to the animals before and during gestation
(Table V-8). .Green (1969) reported Increased early resorptlon of embryos
and Good and Uare (1969) reported Increased maternal mortality and signifi-
cantly smaller Utter size, also Indicating Increased resorptlon.
At about the same time, Morris (1968) studied the effects of endrln
feeding on field-captured deer mice (Peromyscus manlculatus osgoodD for
parental survival, fertility, Utter size and survival of young to weaning
(see Table V-8). Reproductive performance was recorded for 6 months before
a 7-month feeding program was Initiated (0, 1, 2, 4 and 7 ppm endrln In the
diet). Postnatal mortality of the young appeared to be the major effect of
endrln on the offspring of deer nice; however, soft and skeletal tissues
were not examined for the Incidence of nalformations. Survival of parents
was significantly decreased at endrln levels >2 ppm.
A single oral dose of endrln, 5 mg/kg bw (1/2 L05Q), administered by
Intubation to pregnant Syrian golden hamsters, caused a marked and statis-
tically significant Increase In fetal deaths In animals treated on day 7 or
8 of gestation (Ottolenghl et al., 1974). In these studies (Table V-9), two
control groups were used, one group receiving the corn oil vehicle and a
second group receiving no treatment. Comparisons of litters from pesticide
treated hamsters were made with the corn oil-treated group for evaluation of
the Incidence of embryoddal and teratologlcal effects by using the Hann-
Uhltney U-test. Ounnett's multiple comparisons test was used to evaluate
differences 1n fetal weight. A statistically significant Increase In the
Incidence of fused Mb and cleft palate (p<0.01) occurred In Utters from
00670 V-31 'VI* u:
-------
g
o»
-J .
o
TABLE V-8
Teratogentctty and Reproductive Studies PerforMed with Endrln In the 1960s
Species
< Sprague-Dawley
w rats
CfW Swiss Mice
Deer Mice
(PeroMyscus
Manlculatus
Sex
females
Males and
females
14 parental
pairs/dose
Dose
(PP-)
5
5
2
4
7
Feeding Procedure
60 days before and
during gestation
4 Months before and
during gestation
At Intervals over
7 -Month period
Effects Reference
Increase In fesorptlons Green. 1969
Parental Mortality (1/3) Good and Ware.
Significantly smaller 1969
litter size
Parental Mortality Morris. 1968
Significant decrease
In survival of off-
osqoodl)
spring at 21 days
-------
dams treated on day 7, 8 or 9 and sacrificed on day 14 of gestation. A
significant Increase 1n open eye and webbed foot occurred only 1n Utters
from dams treated on day 8. Fetal weight was reduced 1n all treated
Utters. The association of webbed foot and open eye with low fetal weight
suggests that these effects may be an expression of growth retardation
(Ottolenghl et al.. 1974).
OttolengM et al. (1974) also examined the effects of orally adminis-
tered endrln 1n corn oil (day 7, 8 or 9 of gestation) on the fetuses of CD-I
mice (see Table V-9). The frequency and gravity of defects produced by a
single dose of 2.5 mg/kg bw (1/2 LD5Q) administered to mice on day 9 of
gestation were less pronounced than those seen In hamsters at 5 mg/kg.
Abnormalities Included an Increased Incidence of eye opening (p<0.5) and a
low occurrence of cleft palate. No significant effects were found. with
regard to fetal survival or fetal weight.
«
A single dose of endrln 1n corn oil administered to Syrian golden
hamsters by oral gavage on day 8 of gestation produced menlngoencephaloceles
at doses above 1.5 mg/kg bw and fused ribs at doses above 5.0 mg/kg (see
Table V-9). Open eyes, cleft palate and webbed foot were not observed. No
significant effects were noted 1n either maternal mortality and weight gain
or fetal mortality and weight gain. In a multiple dose study, the adminis-
tration of endrln on days 5-14 of gestation produced maternal lethality at
doses >1.5 mg/kg bw/day. Fetal toxldty (Including Increased mortality,
reduced fetal weight and reduced skeletal ossification) resulted at doses
above 0.75 mg/kg/day (see Table V-9). Endrln crossed the placenta and was
Identified 1n the fetus. 12-KetoendMn was found 1n both mother and fetus
but not quantified (Chernoff et al., 1979).
00670 V-33
-------
1AMI V-9
Reproductive Iffects of fndrtn for Studies Perforated Sine* 1910
0
Species
•olden syrlan
hamsters
•olden syrlan
hamsters
(LV6 strain)
•olden syrlan
hamsters
-e flV6 strain)
£ •olden syrlan
hamsters
•olden syrlan
hamsters
ۥ rats
C» rats
ۥ rats
C» rats
Route of
Adnlnls- nose
tratton |mg/kg/day)
oral S
gavage
•ral >«.7S
•ral >1.5
gavage
•ral >*.•
gavage
•ral 1.5
gavage
gastric •••75
gastric •.!$
Intubation
gastric 9.3
Intubation
gastric 0.450
Vehicle toy of Mo. of
Gestation titters
corn oil 7 7
corn oil 5-14 19
corn oil 5-14 71
corn oil • 50
34
74
corn oil 5-14 13
corn oil 7-70 14
corn oil 7-70 77
corn oil 7-70 79
corn oil 7-70 17
Iffects
fetal death (37X of Implantations).
growth retardation, congenital abnor-
Mlltles In ?W of fetuses treated on
day •: open eye. 77k; webbed foot.
1M; cleft pal'te. 5*; cleft lip. 1«;
fused ribs. M
Harked Mternal toitctty; bypeacttv-
tty. tremors, reduced weight gain.
lethality; fetal toitctty; In-
creased mortality, reduced fetal
weight, reduced skeletal ossification
Significant Mternal lethality and
weight reductions, mentngoencephale-
celes In fetuses of two Utters
fused ribs and menlngoencephaloceles;
no overt embryolethal or maternotoilc
effects
Persistent elevation of locomator
activity In offspring; nonlocomotor
behavior of offspring unaffected;
SIX of dams died during dosing period.
Mo effect on Mternal weight gain or
fetus
Mo effect on Mternal weight gain or
fetus
Significant decrease In Mternal
weight. Mo effect on fetus.
•TV decrease In Mternal weight gain.
no apparent effect on the fetus
Reference
•ttolenghl
et at.. 1974
Chernoff
et al.. 1979
Chernoff
et al.. 1979
Chernoff
et al.. 1979
•ray et al..
1901
Kavlock
et al.. 19«1
Kavlock
et al., 19fl
Kavlock
et al.. 1981
Kavlock
et al.. 1981
-------
1ABII V-9 (cont.)
in
Spec tes
» rats
«-l mice
CO-1 ate*
Cl-l mice
CI-1 mice
C8-1 mice
C8-1 mice
Ci-1 mice
M.I mice
'v
1CR/SIN ale*
Route of
Adminis-
tration
oral
»*•'«•
oral
gavage
gastric
Intubation
gastric
Intubation
gastric
Intubation
gastric
Intubation
gastric
Intubation
gastric
Intubation
gastric
Intubation
tailrlc
Intubation
Dose Vehicle Day of
(•g/kg/tfay) Gestation
0.07S corn oil 1 tnrougb
0.1S day IS
0.30
2.5 corn oil 9
O.S corn oil 1-17
1.0 corn oil 1-1?
l.S corn oil 1-11
7.0 corn oil 1-11
single oose
2 corn oil •-!?
•
1 corn oil •
*
2 MS 14-11
2.2 corn oil 8-1?
Ho. of
litters
13
13
S
10
31
32
12
2
11
14
U
MS
24
iffeett
Pupi 30X «oro active In the Mies than
controls or 0.01S Mg/kg endrln dose
groups; at 90 days of age. no endr In-
Induced differences were apparent;
did not affect pup survival or growth.
Congenital abnormalities: open eye;
cleft palate
Maternal liver enlargement
•educed maternal weight gain; decrease
In fetal weight and skeletal and vis-
ceral maturation
Maternal lethality; no teratogenlc
effect or embryo lethality; decreased
locomotor activity, reduced weight
gain In pups; activity levels depressed
after first and third doses but no sig-
nificant difference after tenth dose.
No dose-related evidence of open eyes
and cleft palate
Reduced maternal weight, reduced
fetal weight
Reduced maternal weight gain, fetal
weight, percent of supernumary
ribs, sternal and caudal ossifications.
Eiencephaly and fused ribs were observed
In a few offspring.
Reduced locomotor activity In figure
eight mates.
Reduced neonatal weight
Reference
Cray et al..
1981
Ottolenghl
et al.. 1914
Kavlock
et al.. 1901
Kavlock
et al.. 1981
Kavlock
et al.. 1981
Kavlock
et al.. 1981
Cher no ff and
Kavlock. 1982
Kavlock
et al.. 198S
Gray et al..
1981
Setdenberg et
al.. 1986
MS • Mot stated
-------
In the hamster, exposure to endMn 1n corn oil at 1.5 nxj/kg bw/day on
days 5-14 of gestation produced a significant elevation 1n locomotor activ-
ity of offspring that was still present at 125 days of age (see Table V-9).
Nonlocomotor behavior of the offspring (Including rearing In the open field,
running wheel activity and mounting) were not altered by treatment. Dams
were markedly hypoactlve using the same testing conditions 1n which the pups
were hyperactive. More than half of the group receiving 1.5 mg/kg/day died.
Rats exposed on days 7 through 15 of gestation to endrln at 0.15 or 0.30
mg/kg/day were 30% more active than controls before weaning but not as
adults. These doses did not kill the dams or affect pup survival or
growth. In this study, a dose of 0.075 mg/kg/day appeared to have no effect
on behavior. Behavioral effects may be of special concern In view of the
persistence of endrln In the environment and Us capability for magnifica-
tion 1n the food chain (Gray et al., 1981).
Kavlock et al. (1981) found that endrln was not teratogenk or embryo-
lethal In the CO rat or CD-I mouse when administered by gastric Intubation
at maternally-toxic dose levels throughout the period of organogenesls (see
Table V-9). However, evidence of fetal toxldty (depressed fetal weight and
caudal vertebrae number; elevated supraocdpUal score) was reported among
offspring of mice exposed to 1.0 or 1.5 mg endrIn/kg/day. Adult female rats
tolerated 2-3 times less endrln than did adult mice or hamsters, but the rat
1s the only one of the three species In which endrln did not Induce
fetotoxkHy. The difference In fetal sensitivity was attributed to lower
levels of 12-ketoendrln present 1n the rat fetus than observed In the
hamster fetus. More recently, fetal outcomes were examined following oral
exposure of CD-I mice to a low (7 mg/kg) or moderate (9 mq/kg) maternally
toxic dose of endrln on day 8 of gestation (Kavlock et al., 1985).
00670 V-36
-------
Statistically significant (p<0.05) reductions In fetal weight and number of
sternal and caudal ossifications were reported at 7 mg/kg, but not 9 mg/kg
endrln. Significant reductions 1n the percent of supernumary ribs (p<0.05)
were reported for both doses. Exencephaly and fused ribs were observed In
2/157 and 3/184 fetuses examined. These data were Interpreted as Indicative
of a low but significantly elevated Incidence of terata following endrln
exposure.
Chernoff and Kavlock (1982) assayed 28 compounds of known teratogenlc
potential by an In vivo teratology screening procedure (see Table V-9).
Endrln was administered by oral gavage (2 mg/kg bw) to 25 gravid CD-I mice
on days 8-12 of gestation. Dams were allowed to give birth, and Utter size
and weight on postpartum days 1 and 3 were compared with concurrent
controls. Results Indicated significantly reduced maternal weight and
reduced fetal weight on postpartum day 1. In a similar screening study,
reduced neonatal weight, but not viability, was reported following exposure
of ICR/SIM mice to endrln (2.2 mg/kg/day) by oral Intubation on days 8-12 of
gestation (Seldenberg et al., 1986).
Behavioral development of CD-I mouse offspring prenatally exposed to
endrln has also been evaluated by measuring figure eight maze reactive
locomotor activity (Gray et al., 1986). Endrln (2 mg/kg bw) was
administered by oral gavage to pregnant females on days 14-18 of gestation,
and locomotor activities were measured In offspring 22, 58 and 200 days
after birth. Locomotor activity was less than the control at days 58 and
200; this effect was statistically significant (p<0.05) at day 58 only.
00670 V-37 03/1 i:/
-------
Birds. A disastrous die-off of brown pelicans, which reduced the
population from 400 to 250 birds, occurred In Louisiana In May and June
1975. Several months earlier, a die-off of -100 white pelicans occurred
near the same area. Shell thickness of pelican eggs from 1971 through 1976
averaged 6.7-13.5X less than the mean thickness for eggs collected before
1947. Statistical analysis of data on residues 1n eggs Indicated that there
were significant differences In DOT and DOE mean concentrations for several
years but no pronounced trend. PC6 residues remained essentially the same.
DleldMn residues Increased significantly during the study; endrln residues
increased significantly through 1975, and then dropped sharply In 1976.
Endrln has been considered the major factor In the d1e-offs because endrln
residues were detected In brains of several pelicans and because the die-off
In 1975 coincided with the peak 1n endrln residues In pelican eggs. The
effect of endrln on reproductive success 1s unknown, but the egg with the
highest residues (1.47 mg/kg ww) contained an embryo that died while pipping
(Blus et al., 1979).
On the basis of further studies, the critical level of endrln In brown
pelican eggs was roughly estimated at >0.5 wg/g. More exact determination
was not possible because of the small population. Of the avlan species
studied, the brown pelican was the most sensitive to organochloMne
contaminants, particularly DOE and endrln (Blus, 1982). In mallard ducks
dletarlly exposed to 0.5 or 3.0 ppm endrln, egg production, fertility and
hatchabllUy were not affected, but embryo survival was reduced In the 3.0
ppm treatment group (Roylance et al., 1985). A similar study reported no
adverse reproductive outcomes for mallards dletarlly exposed to 1 ppm
endrln, but equivocal evidence of poor reproduction at 3 ppm exposure (Spann
00670 V-38
-------
et al., 1986). However, application of endrln directly to mallard eggs at
doses greater or less than the 1C elicited reduced growth and
malformations In surviving embryos (Hoffman and Albers, 1984).
HutaqenlcUy
Endrln was one of 228 pesticides tested for mutagenlcHy 1n a Salmonella
typhlmurlum reverse mutation assay using strains TA1536, TA1537, TA1538,
TA98 and TA100 (Ames et al., 1975). Endrln was not mutagenlc for any of the
above bacterial strains, nor for Escherlchla coll HP2 her. These in vitro
assays were done both with and without addition of rat hepatic homogenates
(S9) to supply mammalian metabolic enzymes (HoMya et al., 1983). The
National Toxicology Program (U.S. DHHS, 1982) also reported endrln to be
nonmutagenlc for Salmonella, although no details of testing procedures were
given. A third study utilized a modification of the standard reverse
mutation assay wherein the Salmonella strains were streaked on agar plates
poured so as to obtain a concentration gradient of the test compound.
Endrln was not mutagenlc for any of the above strains nor for the following:
his G46. his C3076. or his D3052 (Probst et al., 1981). Similarly, endrln
was not mutagenlc In the absence of S-9 1n S. typhlmulrum strains TA98,
TA100, TA1535 or TA1537. Further, mutagenlcUy was not observed In TA98 or
TA100 1n the presence of S-9, nor 1n TA98 plus S-9 and TCPO, an epoxlde
hydratase Inhibitor (Glatt et al., 1983).
Endrln exposure of primary rat or hamster hepatocytes did not result 1n
Increased unscheduled DNA synthesis (Probst et al., 1981; Williams, 1980).
This nonrepllcatlve ONA synthesis 1s regarded as an Indicator of repair of
ONA damage. Endrln (as well as DOT, rnUex. kepone, hexachlorocyclopenta-
dlene, heptachlor and chlordane) produced no Increases over control numbers
00670 V-39
-------
of mutants at the hypoxanthlne-guanlne phosphorlbosyl transferase (HGPRT)
locus when tested In adult rat liver epithelial cells (Williams, 1980;
Telang et al., 1981). Genotoxlclty was not elicited by a variety of
organochlorlne pesticides Including endrln tested Jhi vitro 1n a hepatocyte
primary culture ONA repair assay using hepatocytes from male Fischer F344
rats (300-375 g), CD-I mice (25-35 g) and Syrian hamsters (85-130 g)
(Maslansky and Williams, 1981). The potent procarclnogen, dlmethyl-
benzanthracene, was the positive control and OMSO was the solvent control.
The lack of endr1n-1nduced genotoxldty agrees with the negative
mutagenldty 1n sensitive mlcroblal assays.
Adult DrosophUa were exposed to endrln by abdominal Injection, and the
Muller-5 test for recessive lethal mutation on the X-chromosome was done.
The authors noted no positive responses for endrln or any other chlorinated
pesticide tested (Benes, 1969).
In an abstract, Grant (1973) reported that among a number of organo-
chlorlne pesticides, endrln, aldrln, chlordane, dleldrln, DDT, heptachlor
and llndane, all caused chromosome breakage. The organisms and dosage
routes were not described. 01ksh1th and Oatta (1973) reported the effects
of endrln on rat chromosomes. Male albino rats (200-250 g), treated
Intratestkularly with 0.25 mg endrln (In saline) per testls and sacrificed
10 days after dosing, exhibited chromosomal aberrations In germinal tissue.
Abnormalities Included breaks, fragments, ring formation, stickiness and
chromatln bridges.
Endrln, 10~«, 10~» and 10'* H, did not significantly affect
s1ster-chromat1d exchange frequencies 1n both activated and nonactlvated
00670 V-40
-------
human lymphold cells of the LA2-007 cell line over 48 hours (Sobtl et al.,
1983). However, slster-chroraatld exchange frequencies were significantly
elevated In 15 central mud minnows per exposure following exposure of
5.4x10"" to 5.4x10'* M endrln 1n aquaria water for 2 weeks (Vlgfusson
et al., 1983).
Carc1noqen1c1ty
Endrln has been examined for carc1nogen1c1ty 1n mice (B6C3F1, C57B1/6J,
C3D2F1/J and C3HF strains), rats (Os borne-Mendel, Sprague-Oawley). and dogs
(beagle and mixed breeds). Reuber (1979) has strongly claimed cardno-
genlclty for rats, and less strongly for other animal species; however
evidence accumulated to date remains somewhat conflicting since results have
been negative for most studies. In studying mice and dogs, clear conclu-
sions have been much more difficult to reach, owing to toxldty problems and
the Inadequate numbers In most Investigations. The following studies are
summarized 1n Table V-10.
The first study of endrln cardnogenldty was conducted by Treon et al.
(1955). Endrln was administered to 28-day-old rats, 20 males and 20
females/group, In doses of 0, 1, 5, 25, 50 or 100 ppm endrln In the feed for
106 weeks. The 100 ppm dose approximated 10 mg/kg bw/day. Doses >25 ppm
for females and >50 ppm for males resulted In significant mortality by 106
*eeks so that few animals remained at these higher doses for pathological
examination. Signs of overt toxldty (hypersensltlvUy to external stimuli.
or occurrence of convulsions) were not evoked at doses <25 ppm. The authors
reported that the Incidence of neoplasla was no greater among experimental
animals than among controls In the tissues studied (liver, kidney, brain,
00670 V-41 08/1 3/3
-------
1AMI ¥-10
•tfittv* SMI** »f Ik* CcrclMffMlc r*te*M«l »f I Mr I*
•
1 '
N»
ft*. !•
JtetMl Str«t» Or**
tot CirMrtk 20
20
OikwM- SO*
_^^
w*ftJB* BW** *^^^
NM*1 SO*
NIC* cstoi/M 100
100
CJMM/J 10t
100
OUV1 SO*
SM tovtt
N «r«1
r ira^i
N *r«1
ft «r«1
c«ra vll}
ft wal
f (Ct«4»
N «r«1
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ft «r«1
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fSlvlMMl
cam •!!
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2. *. 1? »f»
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-------
heart, adrenal gland, spleen, skin. lung, and other unidentified tissues).
No primary data were presented. Subsequent Independent assessment of hlsto-
loglcal specimens led to the report (Reuber, 1979) that one animal Ingesting
25 ppm had a carcinoma of the pituitary and one Ingesting 50 ppro a broncho-
genie carcinoma. No malignancies were originally reported In untreated rats
although these (and endMn-treated animals) were later reported to have
developed benign tumors of the breast and retlculum sarcomas.
In addition to the above, three Independent studies were conducted with
the same species (rats. Osborne-Mendel) under similar conditions. Delchmann
et al. (1970) found that animals Ingesting endrln dissolved In corn oil and
admixed with ground Purina chow developed malignant tumors; however, similar
Incidences occurred In control animals. In this study, Osborne-Mendel wean-
ling rats, 50 male and 50 female per treatment and 100 male and 100 female
per control group were administered 1, 3 or 6 ppm endrln In the feed for 10
weeks and then twice those concentrations until sacrifice, the tlae of which
varied considerably (5-29 months). Hale animals treated with final doses of
2, 6 or 12 ppm showed 15, 9 and 24% Incidences, respectively, of malignant
tumors, compared with 18% 1n controls. In females the corresponding Inci-
dence of malignancies was 21, 11 and 22%, with 24% 1n control animals. The
predominant tumor type In both sexes In all groups was malignant lymphoma.
In this study excess cancer Incidence In animals Ingesting endrln was not
reported 1n the liver, endocrine organs or reproductive tissues, as was
observed 1n the previous studies. The authors concluded that endrln fed for
a lifetime to albino rats was neither tumoMgenie nor carcinogenic.
In a second Osborne-Mendel rat study reported by Reuber (1978), 22-day-
old male and female rats, 24/group, were fed 0, 0.1, 1.0, 5, 10 and 25 ppm
00670 V-43 -•- - '
-------
endrln admixed In corn oil wUh the diet (IX) for 104 weeks. Owing to high
and early mortality 1n the highest concentration group, additional groups of
animals Ingesting this concentration were subsequently established. Some of
the tissues studied on sacrifice were lung, spleen, kidney, heart, liver,
pancreas, stomach, small Intestine, colon, kidney, adrenals, thyroid, ovary,
leg muscle, leg bone, bone marrow, bladder and prostate. In male rats,
endHn Induced hyperplastlc nodules 1n the liver. For both nodules and
•malignant lesions" (defined as the sum of carcinomas and sarcomas), endrln
appeared most active at a dose of 0.1 ppm. The tabulated data were often
confusing. The Incidence of malignant hepatic neoplasla 1n males and
females was relatively low (Tables V-11 and V-12). No malignant tumors In
the liver were observed 1n control animals of either sex. In addition to
developing liver lesions, endrln-treated rats of both sexes developed
neoplasms at a number of other sites. In males these Included retkulum
cell sarcomas of the lungs and lymph nodes and some rare malignant tumors,
as well as carcinomas of the thyroid and renal cortex. The observations
showed no preferred cancer site (greater than two Instances) although
frequencies never exceeded 13% for a spedf'.c site at a given dose. In
females, carcinomas and lelomyosarcomas of the mammary gland, stromal cell
sarcomas of the uterine endometrlum, retlculum cell sarcoma of the lung and
hepatic Kupffer cell sarcoma were observed (see Table V-12). The preferred
cancer sites 1n this study were the mammary gland, the thyroid and the
uterus, In that order. On the basis of the above findings, the author
concluded that endrln was a carcinogen. The data appear more conclusive for
female rats than for male rats. Doses below 5 mg/kg appeared to elicit few
overt signs of toxUHy In the animals. Inherent difficulties are encoun-
tered when Interpreting Reuben's (1978) report. Statistics were based on
00670 V-44 'JfiVi*.
-------
o
o
TABLE ¥-11
Incidence of Malignant Tutors In Hale Rats Ingesting Endrln*
Endrln
Concentration
(p|M feed)
0
0.1
1
5
10
25
No. AnlMls
Examined
15
16
10
10
20
19
Liver
Carclnou
0
2
0
0
1
1
SarcoM
0
0
0
0
1
0
Lung
SarcoM
0
1
0
0
0
1
HaMUry
Carclnou
0
0
0
1
0
0
Gland
SarcoM
0
1
1
0
1
0
Other
CarctnoM SarcoM
0 0
4° 3C
id }9
0 0
0 if
ig 2"
Total
Malignant
Twwrs
0
11
3
1
4
5
'Source: Reuber. 1970
^wo thyroid, adenocarc InoM (site unknown) and adrenal cortex
cTwo In lyaph nodes and one In the stoMch
dStOMCh
eKtdney
rHeMngtoendothel1al
flThyrold
Lynph node and osteogenlc
-------
TABLE V-12
Incidence of Malignant Tumors In female Rats Ingesting Endrln*
Endrln
Concentration
(ppm feed)
0
0.1
1
5
10
25
Liver
No. Animals
Examined
23
23
23
20
18
19
Carcinoma
0
0
0
1
0
1
Sarcoma
0
1
0
0
1
0
Lung
Sarcoma
0
0
1
1
0
0
Mammary
Carcinoma
6
10
14
13
8
1
Gland
Sarcoma
1
2
0
0
1
2
Other Total
Carcinoma
2b
0
2d
0
>
5'
Malignant
Sarcoma Tumors
0 9
le 14
1C 18
0 15
0 11
lc 10
'Source: Reuber. 1978
Papillary adenocarclnoma. site unknown
cUterus
Thyroid and colon
'Adrenal cortex
four In thyroid and one In the adrenal cortex
-------
the number of animals with malignant tumors. From the data, the reader
cannot Justify the numbers reported In the text; also one animal may develop
more than one lesion.
In a study by NCI (1979), 35-day-old male Osborne-Hendel rats were, fed a
diet Incorporating endrln Initially dissolved 1n acetone to a level of 2.5
or 5.0 ppm diet. Females (50) were fed a diet containing 0, 3.0 or 6.0 ppm
technical grade endrln for 80 weeks and surviving animals were sacrificed at
111-114 weeks. There were 10 control rats of each sex. The tissues
utilized for hlstopathology were the following: skin, lungs and bronchi,
trachea, bone and bone marrow, spleen, lymph nodes, heart, salivary gland,
liver, pancreas, stomach, Intestines, kidneys, bladder, pituitary, adrenal,
thyroid, parathyroid, mammary gland, prostate or uterus, testls or ovary and
brain. Comparing Incidences of malignant tumor formation 1n Individual
tissues between control and treated animals, the authors of the study con-
cluded that endrln was not carcinogenic 1n either sex. Malignant tumors
that were observed 1n two or more male animals per group (4X Incidence In
treated animals) were hematoma of the kidney (4% at the high dose), adrenal
carcinoma (4% at the low dose), Islet cell carcinoma of the pancreas (6X at
the high dose) and fibrous hlstocytoma (4X at the high dose). The Increased
Incidence of Islet cell carcinomas 1n the high dose group was statistically
significant compared with controls applying the Cochran-Armltage, but not
the Fisher exact test. Cancer Incidence at other sites was not
statistically significant. In female animals, two or more animals had
malignancies 1n the pituitary (4X at the low dose) and adrenal (14% at the
low and 6X at the high dose but 11X 1n controls). None of these Increased
Incidences were statistically significant, but the Increases of pituitary
00670 V-47
-------
adenomas, and combined Increased Incidences of adenomas and carcinomas of
the adrenal were significant. Data Interpretation in this study was
complicated by the use of only 10 matched controls per gender.
The opposite conclusions to those made above were reached, however, by a
later reviewer of this study (Reuber, 1979) after re-examination of the
pathology slides, and based on comparisons of cumulated cancer Incidences at
different sites, I.e., endocrine and reproductive tissues, or control vs.
treated groups. In males and females, Increased cancer Incidence compared
with controls was thereby observed for both doses of endMn for endocrine
organs (pituitary and adrenal glands) and the liver. In addition, females
showed an Increase In Incidence of malignant tumors of the ovary, uterus.and
mammary gland. In males, the numbers of animals with malignant tumors
(carcinomas and sarcomas) were 67X and 64X at the low and high dose,
respectively, compared with 10% 1n the control groups. In females, the
corresponding values were 74 and 82% compared with 40% In the control
groups. In female rats, 74 and 67% of animals Ingesting the low and high
dose, respectively, had carcinomas of the endocrine organs, compared with
10% of untreated animals. In male rats, the corresponding Incidences were
36 and 42% 1n treated and 10% 1n control animals. Statistically significant
Increases 1n carcinoma Incidence In the pituitary (43% low-dose, 30% high-
dose, 0% control) and adrenal glands (33, 31 and 0%, respectively) were
observed In female rats at both endrln doses (Table V-13), and 1,< the pitu-
itary gland of males at the lower dose (29% coapared with 0% In controls)
(Table V-14). In female rats, 40 and 28% developed malignant tumors of the
reproductive system at the low and high endrln doses, respectively, compared
with 10% of control animals (see Table V-13). Hepatocellular carcinoma
00670 V-48
-------
o
o
TABLE V-13
Nunber of Osborne-Hendel Feoale Rats with Carcinomas*
Oose
(pp» endrln In the diet)
0 Matched
Pooled
2.78
5.56
Low » high dose
Number
Examined
10
49
46
46
92
Endocrine
1
11
34
31
65
(10X)b
(23X)
<74X)C
(67X)h
(71X)"
Pituitary
0
6
20
14
34
(12X)
(43X)d
(30X)1
(37X)n
Adrenal
0
0
15
14
29
<33X)e
(31X)J
<32X)J
Reproductive
System
1 (10X)
3 (6X)
17 <40X)f
13 (28X)k
30 (33X)f
L
0
0
1
4
5
Iver
(W)
<9X)
(5X)
Total No. with
Carcinomas
1 <10X)
5 (JOX)
29 (63X)g
35 (76X)1
64 (10%)
'Sources: NCI. 1979; Reuber. 1979
Percentage of anlaals examined with tiwor of tissue specified
cp<10~», one-sided test
dp<10~*. one-sided test
ep<5x!0~*. one-sided test
p<3xlO~*. one-sided test
9p . 2x10"». one-sided test
hp<)0~». one-sided test
V . 2.7xlO~». one-sided test
Jp<1.2xlO"». one-sided test
kp - 3.4xlO~*. one-sided test
p - 1.8xlO~», one-sided test
"p<10~». one-sided test
np = 7xlO~«. one-sided test
-------
o
o
TABLE V-14
Number of Osborne-Mendel Hale Rats with Carcinomas*
I
in
O
Dose
(ppm endrln In the diet)
0 matched
Pooled
2.5
5.0
Low * high dose
Number
Examined0
10
49
45
45
90
Endocrine
1 (10X)
5 (10*)
17 (36*)
19 (42*)
36 (40*)
Pituitary
0
3 (6*)
13 (29*)c
7 (16X)
30 (22*)«
Adrenal
1 (10*)
1 (2*)
1 (2*)
« (9*)
5 (6X)
Liver
0
0
1 (2*)
2 (4*)
3 <3*)
Total No. with
Carcinomas
1 (10*)
4 (6*)
24 (53X)d
22 (49X)d
44 (49X)d
'Sources: NCI. 1979; Reuber. 1979
Percentage of number examined
cp • 0.003, one-sided test
VO.000.009) one-sided test
ep • 0.001. one-sided test
-------
Incidences observed In low and high-dose endrln-treated female rats, com-
pared with controls, were 2, 9 and OX, respectively, but were not statisti-
cally significant. The corresponding figures for male rats were 2, 4 and
OX, respectively and also not significant. Female rats therefore appeared
to be more susceptible than male rats at the various target sites mentioned
above. The Incidences of benign tumors In male or female rats were not
reported to be significantly different from values In controls or any endrln
dose (Tables V-15 and V-16).
Re-evaluation of the tissue sections by Reuber (1979) thus has resulted
In dramatically Increased tumor Incidences In both control and exposed
groups. Reuben's criteria for classifying tissues as tumorlgenlc appear to
differ from those of other Investigators. Until differences between
Reuber's criteria and those of others 1s resolved It will be difficult to
draw conclusions from his findings.
In a study with mice (WUherup et al., 1970), males and females of the
C57B1/6J and C302F1/J strains Ingested Purina mouse chow admixed with endrln
dissolved 1n 95X ethanol to give concentrations of 0, 0.3 or 3.0 ppm 1n the
diet. For both strains, 100 males and 100 females constituted each treat-
ment group and two control groups. Tissues analyzed histopathologlcally
were the following: heart, lungs, liver, spleen, kidneys, GI tract, lymph
nodes, urinary bladder, gonads, pancreas, thyroid, thymus, adrenals, brain,
pituitary, spinal cord, eyes, bone marrow, nasal passages, skin and periph-
eral blood smears. In this lifetime study (up to 119 weeks) the overall
Incidence of neoplasms found In each strain and diet group was not Influ-
enced by the content of endrln In the dally diet. The authors concluded
00670 V-51 lG/':/38
-------
I
w«
IVJ
TABLE V 15
NiMber of Osborne-Nendel Female Rats with Benign Tuw>rsa
Dose
(ppa endrln In the diet)
0 Matched
Pooled
2.78
5.56
Low *• high dose
NiMber
Examined
10
49
46
46
92
Endocrine
4 (40X)
14 (30X)
6 (13X)
10 (22%)
16 (17X)
Pituitary
1 <10X)
6 (12X)
3 (7%)
7 |15X)
10 HIX)
Adrenal
2 (20X)
3 <6X)
8 (18X)
13 (28X)
21 (23X)
Reproductive
Syste*
0
4 (W)
9 (20X)
3 (7X)
12 (13X)
Liver
0
1 (»)
9 (20X)
14 (30X)
23 (25X)
lotalb
3 (30X)
14 (29X)
2 (4X)
5 (11X)
7 (8X)
'Sources: NCI. 1979; Reuber. 1979
bTotal nunber of anlMls bearing benign tuaors
-------
c*
TABLE V-16
NiMber of Osborne-Mendel Male Rats Ingesting Endrln with Benign Tuw>rsa
Dose
(ppa endrln In the diet)
0 Mtched
Pooled
2.5
5
Low * high dose
NiMfcer
Examined
10
49
45
45
90
Endocrine11
2 (20X)«
14 (49X)
19 (49X)
16 (36*)
35 (39X)
Pituitary0
1 (10X)
8 (16X)
5 (W)
10 (2?X)
15 (17X)
Adrenal*
2 (20X)
3 (**)
12 (27X)
3 (11*)
15 (17X)
Llverc
1 (Itt)
4 (8X)
13 (29X)
6 (1W)
19 (21X)
Total*
5 (50X)
17 (49X)
10 (22%)
9 (20X)
19 (21X)
'Sources: NCI, 1979; ReiK«r. 1979
bAdenoMS
cHyperplast1c nodules
^Total nunber of anlMls bearing benign tuwtrs
•Statistical analysis (one-sided t test) revealed no statistical significance for any experimental group
compared with controls
-------
that wnen endrln was added to the dally diet of C5781/6J Inbred mice and
C302F1/J hybrid nice 1n the amounts of 3.0 and 0.3 pom. the pesticide was
not carcinogenic to the animals. Reuber 1n his Independent analysis of the
slides of this study came to the opposite conclusion for the 0.3 ppra dose
(Reuber. 1979).
•
In an NCI study (1979), female B6C3F1 mice 35 days of age Ingested
endrln admixed with the diet for 80 weeks at concentrations of 0, 2.5 or 5.0
ppm and 0, 1.6 and 3.2 pom for aales. All surviving nice were killed at 90
or 91 weeks. Each treated group contained 50 animals and each control group
10 animals. In male nice, two or more animals per treated group had hepato-
cellular carcinoma (16X at the high dose) compared with one (10X) 1n the
control group. A corresponding number of mice with malignancies was not
observed 1n females. Significant Incidences for any site In either sex were
not observed. Because of the high mortality In the treated groups, hlsto-
loglcal examination was limited to only one section of the liver and since
the numbers of control animals were only 10, an Independent reviewer stated
(Reuber, 1979) that no conclusions could be reached from this study.
Four bloassays for cardnogenldty were done 1n rats and three were on
mice. These bloassays were done at different Institutions, namely Food and
Drug Administration (FOA) during 1955-1957 as Devaluated by Reuber (1978).
the National Cancer Institute (NCI, 1979). the University of Cincinnati
(Ketterlng Laboratory) (Ultherup et al.. 1970), and the University of H1am1
(Oelchmann et al.. 1970). All the bloassays on rats and mice were reported
as negative by those authors. There were, however, deficiencies 1n the
studies which 1s explained below, which render the findings Inadequate to
properly assess the carcinogenic potential 1n animal test systems.
00670 V-54
-------
In the FDA rat (Osborne-Hendel) study the animals at highest dose (25
ppm) did not survive well and additional animals were started In that dose.
The remainder of the groups lived for the programmed two year study. It
also appeared that every animal came to autopsy and not all sections from
grossly observed animals were studied microscopically. In spite of some
deficiencies there were a sufficient number of animals In the studies
particularly 1n the aspect of liver and kidney, In all experimental and
control groups (Reuber, 1978). This study was originally reported as
negative. It was reevaluated by- a panel of pathologist whose report was
referenced In a CAG document (U.S. EPA. 1978). One pathologist considered
the finding positive (Table V-ll and V-12) but did not provide slide by
slide tabulation of his findings and did not distinguish between primary
and/or metastatlc tumors In the liver. A second pathologist whose original
finding Indicated that the study was negative, provided slide by slide
tabulation of diagnosis which was confirmed by the panel review. In the FDA
mice (C3HF1) study the survival was very poor In both control and
experimental group.
The KetteMng study used two strains of mice (C5781/6J and C3D2F1/J).
The C57B1/6J strain exhibited mainly leukemia and liver tumors with low
Incidence. These tumors appeared equally 1n the experimental and control
groups and the latent period of tumor formation was similar. But In the
C302F1/J strain, the Incidence of liver tumors 1n the dose group (3 ppm) was
slightly higher In the female than In controls and the latent period of
tumor formation was decreased than other groups (HUherup et al., 1970).
00670 V-55
-------
The NCI bloassay was done In Osborne-Hendel rats and B6C3F1 mice. These
studies were reported as negative. A primary reviewer for NCI noted that
the negative findings could be a reflection of the high toxlclty of endrln,
which only permitted the administration of relatively low chronic dosages.
Furthermore, the reviewer observed that an accidental overdose among low
dose male mice resulted In early death of several animals 1n this treatment
group and the study was marred by a small (10) If matched controls; however,
this deficiency was compensated by the use of pooled controls (see Table
V-17). There were significant Increases In hemangloma In low dose male
rats, adrenal adenoma and/or carcinoma In high dose 1n males, pituitary
adenomas In the high dose female, adrenal adenoma and/or carcinoma 1n low
dose female rats as compared to the pooled controls. Although, the
islet-cell carcinoma In male rats had a significant trend but no
statistical significance at either dose group, the NCI concluded that these
tumors could not be clearly considered related to the admlnstratlon of
endrln (NCI, 1979). Although NCI concluded that the bloassays of endrln
were not carcinogenic, the responses noted above can not be totally Ignored.
Endrln was not mutagenlc 1n any bacterial strains but exhibited
chromosomal aberration 1n germinal tissues. Endrln 1s also structurally
related to aldrln, dleldHn, chlordane, chlorendlc acid and heptachlor which
t
are known to carcinogenic 1n animals. The available cancer epldemlologtc
data Involving several studies 1s Inadequate to demonstrate or refut, a
carcinogenic hazard because of study design limitations and/or mixed
exposures. Using the criteria 1n the U.S. EPA (1986) guidelines for
classification of carcinogens, endrln 1s most appropriately classified In
Group 0; I.e. a chemical for which there 1s Inadequate evidence to assess
the potential carclnogenlclty for humans. This classification Is based on
00670 V-56 - :
-------
TABLE V-17
Analysis of Incidence of Primary Tumors In Osborne-Hendel
rats fed EndMn In the diet
Sex Site
Hale Hemangloraa
P Values*
Adrenal
Carcinoma
P Values*
Adrenal-
Adenoma or
Carcinoma
P Values*
Pancreatic
Islet Cell
Carcinoma
Female Pituitary-
Adenoma
P Values*
Adrenal-
Carcinoma
P Values*
Adrenal:
Adenoma or
Carcinoma
P Values
Pooled
Control
0/49(0)
NS
0/44(0)
NS
2/44(5)
P.O. 028
0/46(0)
P.Values
0.039
4/44(9)
P.O. 01 5
2/46(4)
NS
4/46/(9)
NS
Matched
Control
0/10(0)
NS
0/9(0)
NS
2/9(22)
NS
0/10
2/7(29)
NS
1/9(11)
NS
3/9(33)
P.O. 041
Low
Oose
5/46(11)
P.O. 024*
2/46(4)
NS
4/46(9)
NS
0/45
11/47(23)
NS
7/49(14)
NS
14/49(33)
P.O. 004*
High
Oose
3/47(6)
NS
0/44(0)
NS
8/44(18)
P.O. 045*
3/47(6)
13/45(29)
P.O. 016*
3/47(6)
NS
7/47(15)
NS
Source: NCI, 1979
NS » Non significant
* - Significant with respect to pooled control
* » Beneath the Incidence of tumors In the control groups Is the
probability level for the Cochran ArmHage test when P <0.05, otherwise
not significant (NS) Is Indicated.
00670
V-57
-------
the nonposUlve but suggestive results In some of the animal studies. The
negative conclusions as reported by the study authors of the four bloassays
do not support a Group E classification, because of the Inadequacies of the
studies. A Group 0 we1ght-of-ev1dence 1s thought to be the best classifi-
cation until additional studies can be done to clarify the situation.
Later studies suggested that endrln or Us rapidly-produced metabolites
might act as promoters, although some have produced conflicting evidence.
Ito et al. (1980) showed that endrln (25 ppm 1n diet) promotes the develop-
ment of preneoplastlc changes 1n rat liver after Initiation with N-nHroso-
dlethylamlne or N-2-fluorenylacetam1de. Maslansky and Williams (1981)
showed that endrln (10"» to 10"* M) was not genotoxk In the hepatocyte
primary culture (HPCJ/DNA repair assay utilizing hepatocytes from male
Fischer F344 rats, male CO-1 mice and male Syrian hamsters. ONA repair was
observed 1n response to a positive control 1n all three systems. Thus, the
mechanism of the weak hepatocardnogenldty of endrln may reflect an epl-
genetlc mechanism, probably Involving a promotional rather than a genotoxk
effect. Kurata et al. (1982) demonstrated that endrln above 5 mg/i 1n the
HGPRT system using wild-type 6-th1oguan1ne-sens1t1ve V79 Chinese hamster
cells and mutant 6-th1oguan1ne-res1stant cells Inhibited metabolic coopera-
tion (reciprocal exchange of material between cells In contact), as do
recognized '.uraor promoters. A concentration of 20 mg endr1n/i caused 80%
Inhibition whereas 10 mg endMn/l elicited -25% Inhibition. On the other
hand, Miller et al. (1981), 1n an abstract, reported that endrln (0-40 u«)
did not change the frequency of transformation of C3H lOTl/2 cells by
3-methylcholanthrene or benzo(a)pyrene (0-10 mg/1) after a 3-hour Incu-
bation.
00670 V-58
-------
Summary
The acute oral LO,Q of endMn given to mammals by oral gavage ranged
from 2.3 mg/kg to 43.4 mg/kg bw (see Table V-l). The L05Q following
dermal exposures ranged from 10.9-92 mg/kg bw and was vehicle-dependent. A
lone Inhalation study Indicated that 130 seven-hour exposures to 0.36 ppm
endrln "vapor* were not fatal to rats, hamsters and guinea pigs; however,
two of four rabbits died after 188 exposures and one of three mice died
after 107 exposures (see Table V-5). Young animals appeared to be more
sensitive to dietary endrln than older animals (see Table V-3). Metabolites
of endrln were more acutely toxic In rats than the parent compound (see
Table V-2), with !2-ketoendr1n being the most toxic 1n both male and female
rats and having acute oral LO,Qs of 1.1 and 0.8 mg/kg bw, respectively.
The acute oral LO.. values for endrln Itself were 5.6 and 5.3 mg/kg bw,
respectively, In this same study.
Short-term endrln exposures reportedly elicit CMS effects, Including
convulsions (Emerson et al., 1964), reduced locomotor activity (Kavlock et
al., 1981), and altered EEG recordings (Revzln, 1968). Reported hepatic
effects Include elevated liver weight, Uplds and tMgycerldes, and changes
In cytochrome P-450 content and P-450-med1ated enzyme activities (Hartgrove
et al., 1977; Pawar and Kachole, 1978; Borady et al., 1983; Nostafa et al.,
1983). Endrln also elicits changes 1n cardiac output, blood pressure,
hemolysls and other hematologlcal parameters (Emerson et al., 1964; Hlnshaw
et al., 1966; Reins et al., 1966).
Longer exposure to endrln elicits mortality, depressed weight gain or
weight loss, and elevated organ-to-body weight ratios (Treon et al., 1955;
Nelson et al., 1956; Chernoff et al., 1979; Kavlock et al., 1981). Abnormal
00670 V-59
-------
EEG patterns, elevated serum alkaline phosphatase, reduced plasma specific
gravity and Intermittent blindness have also been reported, as well as
altered hepatoblHary function, following endrln exposure ranging from 2
weeks to several months (Nelson et al., 1956; Speck and Maaske, 1958; Young
and Nehendale, 1986).
Chronic endrln exposure causes mortality or early appearance of clinical
signs associated with aging (Treon et al., 1955; Oelchmann et al., 1970;
NCI, 1979). Organ-specific effects reported Include elevated organ-to-body
weight ratios, lung congestion and hemmorhage, swelling of renal tubules,
and chronic Interstitial nephritis (Treon et al.. 1955; Dlechmann et al.,
1970; Reuber, 1978). Prenatal exposure to endrln elicited terata, mortality
and/or reduced neonatal weight or weight gain 1n offspring of hamsters and
mice. These outcomes were not consistently observed In rats. However,
evidence of altered behavioral development, measured by maze locomotor
activity, was observed In offspring of rats, mice and hamsters following
prenatal endrln exposure.
Endrln was not mutagenlc In mlcroblal systems with or without metabolic
activation, and endrln exposure did not significantly affect
slster-chromatld exchange frequencies 1n a human lymphold cell line.
However, a significant elevation of slster-chromatld exchange frequency was
observed In minnows following endrln exposure.
Conclusions concerning endrln cardnogenlcUy have not been entirely
consistent. Endrln was determined to lack cardnogenkHy 1n Osborne-Mendel
rats and 86C3F1 mice under the conditions of an NCI (1979) bloassay. This
conclusion Is consistent with those of three previously reported studies
00670 V-60 "Vi 7/88
-------
concerning endrln carclnogenlcHy In rats and mice. In contrast, Reuber
(1979) has concluded that an Increased tumor Incidence Is elicited by
chronic endrln exposure, based on his Independent evaluation of the NCI
(1979) bloassay tissue sections, and on a separate study (Reuber, 1978).
00670 V-61
-------
VI. HEALTH EFFECTS IN HUMANS
Acute Toxldty
In September 1978, the U.S. Department of Health and Human Services
Issued an occupational health guideline for endrln (U.S. OHHS, 1978).
Symptoms of overexposure were described as follows:
Exposure to endrln may cause sudden convulsions which may occur
from 30 minutes to 10 hours after exposure. Headache, dizziness,
sleepiness, weakness and loss of appetite may be present for 2-4
weeks following this exposure. A number of deaths have occurred
from swallowing endrln. In less severe cases of endrln poisoning,
the complaints Include headache, dizziness, abdominal discomfort,
nausea, vomiting, Insomnia, agitation and mental confusion.
Electroencephalograms may show dysrhythmlc changes which frequently
precede convulsions; withdrawal from exposure usually results 1n a
normal, electroencephalogram within 1-6 months. In most cases,
recovery 1s rapid, but headache, dizziness, lethargy, weakness and
anorexia may persist for 2-4 weeks.
Accidental and Intentional Poisonings. Several Incidents of endrln
poisoning from contaminated flour have been reported In the literature. In
Hales, bread made from flour contaminated with endrln during shipment In a
railway car resulted In 59 poisoning cases with no deaths In 1956. The
bread contained up to 150 mg endr1n/kg bread and the smallest acute dosage
to elicit serious effects was calculated to be 0.2 mg/kg bw (Davles and
Lewis, 1956).
In 1967, explosive outbreaks of acute endrln poisoning occurred In Doha,
Qatar and Hofuf In Saudi a Arabia as a result of the tngestlon of food
prepared with endrln-contamlnated flour (Weeks, 1967; Curley et al., 1970).
Twenty-six persons died and 874 were hospitalized. Many others were prob-
ably poisoned to a lesser degree but did not seek medical aid. The concen-
tration of endrln 1n bread eaten by patients ranged from 48-1807 mg/kg
00680 VI-1 JCv'22/;"
-------
bread. Flour used to made the bread contained 2153-3367 mg endrIn/kg flour.
Coble et al. 41967} reported acute endrIn poisoning with sudden convulsions
In three Egyptians, following 1ngest1on of'bread made with contaminated
flour. In these cases, recovery was spontaneous. A serum endrIn concentra-
tion of 0.053 ppm was reported for one of these patients 5 hours after Us
apparent consumption 1n contaminated bread, and 30 minutes after a convul-
sion was observed.
In the Punjab province of Pakistan between July 14 and September 26,
1984 there were 194 cases of probable endrIn poisoning (Anonymous, 1984;
Rowley et al., 1987). Of the 194 cases, 19 (70%) deaths occurred among
persons between 1 and 9 years of age. Males and females were equally
affected. Symptoms Included sudden collapse, 'bilateral jerking of the
upper extremities followed by general tonic, clonlc contractions and
frothing and vomiting1. Older patients reported headaches and/or nausea and
minor muscular spasms about one-half hour before collapsing. Repeated
attacks were associated with hypoxla, pulmonary congestion and death. Serum
levels from 12 of 18 patients with convulsions had measurable levels of
endMn. Values from the 12 patients ranged from 0.3-254 ppb with a mean of
30.10 ppb. No endrln was detected 1n the urine of these 12 patients (Rowley
et al., 1987). A case-control study did not Implicate causative food or
environmental factors. However, a common food product, sugar, may have been
contaminated. One composite sugar sample taken from the hoaes of three
patients had endrln levels of 0.04 ppn (Rowley et al., 1987). The presence
of endrln In 57X of patients with seizures tested 1n Pakistan suggests that
endrln was the cause of this outbreak (Anonymous. 1984; Rowley et al., 1987).
00680 VI-2
-------
Cases of fatal endrln poisoning have been reported from Intentional
1ngest1on and accidental Ingest!on. TewaM and Sharma (1978) reported 11
fatal poisonings; the time periods from administration of the pesticide
(route not known 1n seven cases) to death ranged from 1-6 hours. Endrln
Ingestlon with milk or alcohol appeared to Increase toxldty as death
occurred within an hour or two. Increased toxldty was attributed by the
authors to more rapid absorption through the GI tract.
A pedlatrlc hospital In Mexico- reported endrln Intoxication 1n 33
patients ranging 1n age from 1-16 years (Hontoya Cabrera et al., 1982).
Accidental Ingestlon accounted for 22 cases, 7 were suicides and 4 were
attributed to criminal Intent. The accidental poisonings resulted from the
uncontrolled use of endrln In the home as a rodentldde.
A 19-year-old male who attempted suicide by Ingestlon of endrln devel-
oped severe pulmonary edema as well as CMS Involvement. Pulmonary edema was
thought to be due to chemical pneumonltls and aspiration pneumonia. The
authors believed that the use of PEEP (positive end-expiratory pressure) up
to 28 cm H.O In treatment of the pulmonary edema contributed to the
patient's complete recovery (Jedelkln et al., 1979).
Effects of Occupational Exposures. No Illnesses were noted In
seasonal workers dusting potatoes with 1% endrln dust at a calculated dermal
exposure of 2.0 rag/kg bw/day In combination with a calculated respiratory
exposure of 0.044 mg/kg bw/day (Wolfe et al., 1963). Also, no Illnesses
were noted when endrln was applied at 544-634 kg/acre as an emulslflable
00680 VI-3
-------
concentrate for nice control at a calculated dermal dose of 0.28 mg/kg/day
1n combination with a calculated respiratory exposure of 0.0011 mg/kg bw/day
(Wolfe et al., 1963).
Immunology. Thirteen pesticides Including endrln were tested for
their jjn vitro effects on human lymphocyte mltogenlc responses to phyto-
hemaglutlnln and neutrophll chemotaxls (Lee et al., 1979; Park and Lee,
1980). This study was undertaken 1n an effort to clarify the Imunosuppres-
slve effects of many pesticides. Endrln Inhibited the lymphocyte response
In whole blood 11.5X and 14.2% 1n mononuclear cells. Neutrophll chemotaxls
was Inhibited 21% (77*4 vs. 105*10 cells per high power field In control
cultures). In each case, Inhibition was not reported to be statistically
significant. All pesticides tested Inhibited lymphocyte responses to some
degree, and the authors suggested that the Inmunosuppresslve effect of
pesticides could be a direct effect of those chemicals on leukocytes.
Epldemloloqlcal Studies. Jager (1970) reported an epldemlologlcal
study conducted on 826 male workers at the Insecticide plant of Shell Neder-
land Chemle located at Pernls, Netherlands. A unit for the production of
endrln was begun 1n February 1957. During the first 2 years of plant opera-
tion seven cases of endrln Intoxication had occurred and were accompanied by
convulsive seizures. All were due to acute overexposure either following an
accident or to obvious neglect of precautions. Normal recovery was rapid,
usually within 1-3 days.
Concentrations of endrln In the blood of 45 operators from the endrln
plant were determined at least once a year from 1964-1968. The threshold
00680 VI-4 ""•'": '*'••
-------
level of endrln In the blood below which no sign or symptoms of Intoxication
were seen was 0.050-0.100 vg/rai. The half-life of endrln In the blood,
and thus 1n the body, was estimated to be -24 hours. Medical files and
routine medical examinations revealed no abnormalities other than those that
would be expected 1n any group of 233 long-term workers (4-13.3 years expo-
sure). Results of determination of alkaline phosphatase, SGOT, SGPT, LDH,
total serum proteins, and the spectra of serum proteins did not show any
changes that could be correlated with the Influence of the degree or dura-
tion of exposure to these Insecticides on these parameters. In all cases of
Intoxication characterized by typical EE6 changes, EEG patterns returned to
normal. In the study of the parameters of enzyme Induction, the data showed
that occupational exposure 1n endrln manufacturing may cause enzyme Induc-
tion In hydroxylatlng enzyme systems although this response appeared not to
affect the health of the workers. It was not known whether endrln or Its
manufacturing precursors were the causative agents (Jager, 1970).
A follow-up mortality study on 233 of these workers having at least 4
years of exposure by 1970 has recently been reported (Rlbbens, 1965). Of
these 233 workers who were occupationally exposed to aldrln, dleldrln,
endrln and/or TelodMn, 232 were accounted for. The mean and range of expo-
sure durations were 11 and 4-27 years, respectively. These periods, as well
as the exposure levels, were considered sufficient for meaningful mortality
evaluation. The total mortality of this population was 25, significantly
lower than the expected mortality of 38 based on death statistics of Dutch
men. Nine of 25 deaths were caused by neoplasms, versus 12 expected cancer
deaths; 3/9 neoplasms were lung tumors. The remaining six cases were
comprised of six different neoplasms, none of which were liver tumors.
00680 VI-5
-------
These results were concluded to reveal no evidence for specific cardnogen-
1c1ty of endrln, aldrln or dleldMn In this exposed population.
Hoogendara et al. (1962, 1965) conducted a parallel study at the same
plant. Of the 122 men exposed to all pesticides at the plant, 25 workers
had EEG abnormalities (Hoogendam et al., 1962). A worker was accidentally
covered with a 50% Isodrln solution 1n xylene. He experienced dizziness and
headache and profusely perspired 2 hours later. This worker suffered a
typical eplleptlforra convulsion 6 hours after the exposure, regained con-
sciousness within 10 minutes and rapidly recovered. There 1s some evidence
to suggest that Isodrln was partially converted to endrln 1n the liver of
this patient (Brooks, 1969). The EEGs of patients with endrln Intoxication
showed paroxysms of predominantly bilateral synchronous theta-waves. In the
other report (Hoogendam et al., 1965) three endrln workers suffered convul-
sive Intoxications, two being examined for recovery of abnormal EEGs. One
was exposed for 1.5 years and the other for 3 years. One recovered 1n 1
month, and the other In <6 months. The authors suggested that the prevail-
ing exposure 1n the manufacture of aldrln, dleldrln and endrln did not
disturb liver function since the levels of SGOT and SGPT returned to normal
In the four workers who Initially showed Increases.
Ottevanger and Van SUtert (1979) continued the enzyme Induction studies
of Jager (1970) on 29 endrln workers at the endrln manufacturing plant in
Pernls. The D-glucarlc add concentration 1n urine was considered to be a
useful test for enzyme Induction. After 7 days of exposure, levels of the
metabolite, antl.-12-hydroxyendrln. Increased (up to 0.360 mg/g creatlnlne)
accompanied by a sharp rise In D-glucarlc acid levels. After the long week-
end, the anU.-12-hydroxyendrln levels decreased, but 0-glucar1c add levels
00680 VI-6
-------
remained above normal. The normal values obtained after a 6-week shutdown
and maintenance period Indicated that enzyme Induction 1n endrln workers is
reversible. A urinary ant1-12-hydroxvendr1n level of 0.130 mg/g creatlnlne
was considered the threshold level below which enzyme Inductlo- does not
occur, although exceptions were noted.
VMJ-Standhardt et al. (1979) examined urinary excretion of D-glucar1c
add and total porphyrln 1n endrln workers. The excretion of D-glucarlc
add after working was significantly Increased compared with excretion after
a long weekend and with a control group. The results Indicated that
D-glucarlc add was a useful test for exposure to endrln, but porphyrln
excretion was not.
An ep1dem1olog1cal study was made of 216 patients with contact dermatl-
t1s In rural regions of Japan from 1968-1970 (Matsushita et al., 1980). All
participants except three were farmers. Exposure occurred mainly from
spraying operations. Chlorinated hydrocarbons (BHC and endrln) were thought
to be responsible for 9.7% of the cases. Inaoequate protection of the spray
personnel, poor health conditions and carelessness were largely responsible
for the dermatitis.
Wang and Grufferman (1981) performed a case control study of the associ-
ation between fatal aplastlc anemia and occupations entailing pesticide
exposure. They found no correlation between use of chlorinated hydrocarbon
pesticides, Including endrln, and aplastlc anemia mortality in the United
States from 1950 through 1975.
00680 VI-7
-------
OUraglla et al. (1981) conducted a retrospective cohort study to
examine the mortality of workers employed In the manufacture of chlordane,
heptachlor, DOT and aTdrln/dleldrln/endrln. The four plants selected for
study are described 1n Table VI-1. Workers '.elected for the study had been
employed at least 6 months; the personnel 1n contact with endrln were
located at plants 2 and 3, and numbered 30S and 1155, respectively.
The only major category where observed deaths were greater than expected
was 'nonmallgnant respiratory system disease1 at Plant 3 (22 observed vs.
10.4 expected: SMR-212) and for 'other respiratory diseases' (11 observed
vs. 5.2 expected: SHR-213, p<0.05). No statistically significant excesses
or deficits In mortality for any specific cancer site were noted. In Plant
3 there was a slight excess of cancer of the esophagus (2 observed vs. 0.85
expected), cancer of the rectum (3 observed vs. 1.24 expected), cancer of
the liver (2 observed, vs. 0.57 expected), and cancer of the lymphatic and
hematopoletlc system (6 observed vs. 4.09 expected). There was a deficit
for respiratory cancer (7 observed vs. 12.64 expected) at Plant 3. Addi-
tional analyses are necessary to determine 1f an excess 1n nonmallgnant
respiratory disease observed at Plant 3 was associated with specific occupa-
tional exposure. Since malignant respiratory disease was not reported at
Plant 2, which also manufactured endrln, endrln alone probably did. not
Induce the lethal respiratory disease reported at Plant 3 unless exposures
were much higher than those at Plant 2. However, OUraglla et al. (1981)
did not report exposure data.
00680 VI-8 Cc. :
-------
TABLE VI-1
Description of Plants Included In the Study of Manufacturers
of Organochlorlne (OC) Pesticides*
Plant 1
Plant 2
Plant 3
Plant 4
Starting date for OC
pesticide production
OC pesticides
produced
Other pesticides
produced
Other chemicals
at plant
Location
*Source: Dltraglla et
1946
Chlordane
None
Chlorine,
dlcyclo-
pentadlene
Illinois
al., 1981
1951
Heptachlor,
endrln
None
Chlorine,
chlorendlc
anhydride.
hexachloro-
cyclopenta-
dlene, vinyl
chloride
Tennessee
1946
Aldrln,
dleldrln,
endrln
Organo-
bromlnes;
organo-
phosphates
Numerous
precursors
Colorado
1947
Dlchloro-
d1phenyl-tr1-
chloroethane
(DDT)
None
Tr1-chloro-
acetaldehyde,
sulfurlc add,
nonochloro-
benzene
California
00680
VI-9
-------
Suarnary
Exposure to endrln 1s reported to cause CNS effects, convulsions and
death. In less severe poisoning, recovery Is usually rapid and there are no
permanent effects.
A number of cases of acute poisoning resulting from accidental or Inten-
tional Ingestlon of endMn have been reported. The approximate oral dose
producing convulsions Is between 0.2 and 0.25 mg/kg bw.
No potential hazard existed during typical dermal or respiratory expo-
sures encountered by seasonal agricultural workers exposed to endrln through
dusting and spraying operations.
No fatalities or permanent abnormalities were recorded 1n a 1970 eplde-
m1olog1cal study of 233 workers engaged In the manufacture of chlorinated
hydrocarbon Insecticides Including endrln for more than 4 years. Convul-
sions and CNS effects were observed In some workers. Exposure did not
elicit an elevation In total mortality of these workers through 1985.
Occupational exposure In endrln manufacturing may cause enzyme Induction In
hydroxylatlng enzyme systems, but this response appeared to be reversible
and to have no effect on the health of workers. Antl-12-hydroxyendrln
levels excreted 1n the urine of endrIn-exposed workers were correlated with
excretion of D-glucar1c add.
No correlation was found between mortality from aplastlc anemia and the
use of chlorinated pesticides Including endrln In the United States from
1950 through 1975, although no exposure data were provided to allow assess-
ment of the Importance of endrln 1n this study.
00680 VI-10 v«
-------
A mortality study of workers engaged 1n the manufacture of organochlo-
rlne pesticides did not Identify a specific cancer risk but further studies
were recommended.
00660 VI-11
-------
VII. MECHANISMS OF TOXICITY
Acute Toxlclty
The order of acute oral toxldty to endrln 1n various adult male species
1s monkey > rabbit > pheasant • quail > chicken » cattle « dog > hamster >
guinea pig - rat. Young animals and female animals are more susceptible
than adult males, at least 1n rats (Treon and Cleveland, 1955). Endrln and
Us metabolites are quickly eliminated except at grossly high doses, and the
total half life varies between 1 and 4 days (see Chapter IV). Doses of >0.2
mg endr1n/kg bw can cause convulsions (Jager, 1970); lethality to humans may
occur at doses >6 g/person (Reddy et al., 1966).
The unsubstltuted methylene group 1n endrln 1s rapidly attacked to
produce mostly antl- and some s^n-12-hydroxyendrln, the former being elimi-
nated as the sulfate in the urine of rabbits, female rats and hens, as the
aglycone 1n the feces of male rats, as the glucuronlde 1n the urine and the
feces of humans, and as the free metabolite 1n the urine of the cow (see
Chapter IV). The s^n-alcohol Is quickly transformed to !2-ketoendr1n, which
Is the most acutely toxic to rats of all endrln derivatives Including endrln
Uself (Bedford et al., 1975a). In fact, associations between lethality and
the presence of !2-ketoendr1n residues In the brain have been made for rats
(Hutson et al., 1975), rat fetuses (Kavlock et al., 1981) and hamster
fetuses (Chernoff et al.. 1979) but not for birds (SUckel et al., 197°a,b);
12-ketoendrln has been postulated as the ultimate toxicant, at lease In rats
(Bedford et al., 1975a). hamster fetuses (Chernoff et al.. 1979) and rat
fetuses (Kavlock et al., 1981).
00690 VII-1
-------
The CMS Is the major target system for acutely administered endrln.
Emerson et al. (1964) suggested that endrIn-Induced hyperexcUablllty and
convulsions were caused by a direct action of endrln on the motor cortex
and/or spinal cord. It was further suggested that endrln acted directly on
the medulla since the bradycardla that followed endrln exposure preceded
pressure Increases In the cerebrosplnal fluid and sagltal venous sinus,
which were also elicited by endrln exposure. Walsh and Fink (1972) suggested
that the mechanism of acute endrln toxldty Involved Induction of a bio-
chemical lesion In the CMS, followed by a time-dependent process culminating
In toxic manifestations. It was postulated that Interference with plasma
membrane or mitochondria! ATPase may be Involved In the mechanism. However,
Nehrotra et al. (1982) reported that although some ATPase activities of rat
brain and beef heart were Inhibited by cyclodlene pesticides (Including
endrln) Jjn vitro, these Inhibitions could not be easily related to the
toxldty of the compounds. For example, endrln was more toxic to rats than
aldrln, but ATPase activities were Inhibited to a greater extent by aldrln
relative to endrln.
A series of more recent studies suggests that mechanism of CNS disturb-
ance and toxldty for endrln are related to Interference with gamma-ami no-
butyric acid (GABA)-medlated functions. The toxic and convulsant potencies
In mice of a series of 14 polychlorocycloalkane (PCAA) Insecticides,
Including endrln, were determined and related to their .In. vivo potencies for
Inhibiting the mouse brain t-butylblcyclophosphorothlonate (TBPS) binding
site, which Is associated with GABA-regulated chloride transport (Cole and
Caslda, 1986). Following LD5Q estimations, male Swlss-Uebster mice were
administered LD5Q, L05Q/2 or LD50/* doses of each compound by Intra-
perltoneal Injection. Mice were sacrificed 30 Minutes later, brains were
00690 VII-2
-------
removed and binding of [>$S]TBPS to brain membranes was determined. For
endrln specifically, the LD50 was 8 mg/kg bw, and the percent Inhibitions
for LDjQ, LDjQ/2 and LD5Q/* doscs were 77±7» 39±6 and °*, respec-
tively. These data were consistent with two previous reports suggesting
binding of cyclodlene Insecticides (Including endrln) to the GABA receptor
(Lawrence and Caslda, 1984; Tanaka et al., 1984; Aballs et al., 1985). It
was concluded that the toxldty or convulsant activities of PCAA
Insecticides were correlated with in vivo disruption of the mouse brain TBPS
binding site.
Aballs et al. (1986) also reported that a GABA-Indue ted "Cl~ Influx
Into rat brain mlcrosacs Is reduced by Uj, vitro exposure to cyclodlene
Insecticides. Mlcrosacs exposed to endrln (1 jifl) exhibited an 82% reduc-
tion 1n "Cl~ Influx relative to control. These data were Interpreted
as supportive of previous suggestions that cyclodlene Insecticides (Includ-
ing endrln) Inhibit functions mediated by the GABA receptor.
Peripheral vascular effects of acute endrln exposure were examined In
partially Isolated forellmbs of 10 mongrel dogs (Emerson and H1nshawt 1965).
Following the surgical forel 1mb separation and, In 5/10 dogs, denervatlon of
the forellmb, endrln (10 mg/kg) was Intravenously Infused. After about 10
minutes of Infusion, Innervated 11mb vascular resistance Increased -80%;
this Increased resistance was accompanied by a decrease In limb blood flow.
S1m41ar results were observed In the denervated forellmbs after about 10
minutes of Infusion. However, In contrast to the Innervated limbs, vascular
resistance subsequently Increased steeply to high levels, and 11mb blood
flow virtually ceased. It was concluded that sympathetic 1nnervat1on was
not necessary for vascular resistance Increases following endrln exposure,
00690 VII-3
-------
and U was suggested that the vascular effects of endMn may be due to
circulating catecholamlnes.
Endrln toxldty may also be mediated through effects on membranee
permeability, since heraolysls has been observed for postendrln hematocrlts
In dogs (Emerson et al., 1964), and "hemorrhaglc enteritis1 has been noted
In rats and birds (Stlckel et al., 1979b).
Subchronk studies In human workers are consistent with a reversible
Induction of liver nlcrosomal activity, as denoted by urinary levels of
D-g1ucar1c add, which Is dependent on the level of cytochrome P-450
(Ottevanger and Van Slttert, 1979). 0-glucarlc add was not detected In
urine when ant1-!2-hydroxyendr1n urine levels were <0.13 mg/g of creatlnlne.
In rats (Treon et al., 1955), the only long-term degenerative changes In
the organs from fatally-poisoned animals studied occurred 1n the liver and
kidneys. The mechanisms responsible for such changes are not known.
Endrln was reported to lack cardnogenldty In several studies (Treon et
al.. 1955; Oelchmann et al., 1970; Ultherup et al., 1970; NCI, 1979), but
Reuber (1978, 1979) has concluded that endMn Is a carcinogen. It Is note-
worthy that endrln lacks genotoxldty 1n bacterial assays (Ames et al.,
1975; Horlya et al., 1983), and like other organochlorlne pesticides. In
rat, mouse and hamster hepatocytes (Maslansky and UllHams, 1981). In view
of these results, Haslansky and Williams (1981) proposed that the cardno-
genldty of organochlorlne pesticides reflects an eplgenetlc rather than a
genotoxlc mechanism. This proposal Is consistent with the observations of
00690 VII-4
-------
Kurata et al. (1982), which Indicated that organochlorlne pesticides
(Including endrln) Inhibited metabolic cooperation 1n Chinese hamster
cells. It was suggested that the pesticides that Inhibited metabolic
cooperation might be tumor promotors. Further, Ito et al. (1980) reported
that dietary endrln exposure (25 ppm for 6 weeks) elicited an Increase In
the area of hyperplastlc liver nodules In hepatectomlzed Fischer F344 rats
previously treated with d1ethyln1trosam1ne, although the number of nodules
was not affected by endrln. A classification system was also proposed;
endrln would be classified by this system as a weak promoter.
It Is emphasized that the discussion In the above paragraph should not
be construed as positive evidence for endrln tumor 1 gene11ty, but rather, as
evidence of a possible eplgenetk action of endrln. Conclusions concerning
endrln carclnogenldty are presented 1n the following chapter.
Interactions
Ludke (1976) demonstrated that prior treatment with a closely-related
Insecticide can Increase bird mortality. Fourteen-week-old male and female
white quail (Collnus v1rq1n1anusl were divided Into four groups; four birds
constituted the control group. All groups were fed turkey maintenance mash
with IX (w/w) propylene glycol mixed In the diet. Pesticides were dissolved
In propylene glycol and mixed Into the diet. Twenty-eight birds received 10
ppm technical chlordane In the diet for 10 weeks and 20 of these were Inert
fed 10 ppm 98% pure endrln In the diet for 6-10 days. A fourth group (N-20)
was fed 10 ppm endrln In the diet. No mortality occurred 1n the control
group nor In the group fed chlordane alone. For endrIn-fed birds, mortality
occurred on days 1 (1 bird), 6 (7), 9 (5) and 10 (2). For the chlordane-
endrIn-treated groups, mortality occurred on days 3 and 6-10 (14 birds) of
00690 VII-5
-------
endMn exposure, and survivors were sacrificed on days 9 and 10 of endrln
exposure. All surviving birds treated with endrln alone or chlordane-endrln
lost weight and showed depleted llpld content In the carcasses (Table
VII-1). Control and chlordane-treated birds showed no significant
decreases. Birds that survived exposure to chlordane-endrln or endrln alone
had lower brain residues of endrln than the dead birds. Birds dying of
endrln poisoning alone had brain residues ranging from 0.34-1.84 rag
endrIn/kg ww (survivors • 0.28-0.62 rag endMn/kg ww). In chlordane-endrln-
treated birds, the dead birds contained 0.17-1.25 rag endrln/kg brain,
whereas the survivors had 0.14-0.56 rag/kg brain. The latter two groups
differed at p<0.10. Dead or moribund birds treated with the two pesticides
contained significantly lower (p<0.025) endrln brain residues than the
corresponding birds treated with endrln alone. Thus, birds nay be more
vulnerable to a toxicant if the bird already carries a body burden of one or
more closely related chemicals. In this study, Mortality from endrln alone
was associated with as little as 0.34 rag endMn/kg brain.
Neena et al. (1978) Investigated endrln-lnduced toxldty In normal rats
and rats Irradiated with gamma radiation by dividing 128 male albino rats
(150-200 g) Into four equal groups. The control group received groundnut
oil 1.p.; group 2 received a single 1.p. Injection of 10 ag endrln/kg bw In
groundnut oil; group 3 served as Irradiated controls (900 rads); group 4
received 10 rag endrln/kg bw 0.5 hours after Irradiation. In both normal and
irradiated rats, endrln caused a significant Increase In SGOT, SGPT and
ATPase; add and alkaline phosphatase, sucdnlc dehydrogenase and glucose-6-
phosphatase decreased significantly during varying periods of 2-48 hours
after treatment. In Irradiated rats given endrln, the changes appeared
earlier and were more pronounced than In normal rats given endrln alone,
00690 VII-6
-------
TABLE VII-1
Weight Loss and Llpld Content (Mean X + S.E.) of Quail Carcasses After
Technical Chlordane, 98%-Pure Endrln, and Chlordane-EndMn Treatments*
Treatment
Chlordane
Endrln
Condition No. X Llpld % Weight Loss
None
10 ppm diet:
10 weeks
None
10 ppm diet:
10+ weeks
none
none
10 ppm diet:
6-10 days
10 ppm diet:
6-10 days
S
S
0
M
S
D
H
S
4
4
13
1
3
12
3
3
4.69+0.77
3.45+0.56
0.43+0.14
0.73"
2.73+0.97
0.39+0.06
0.2770.04
2.78+"l.29
0
0
32.2+2.4
68.6"
14.7+1.1
31.4+3.0
37.2711.7
19.U3.5
•Source: Ludke, 1976
S > Sacrificed, no apparent signs of toxldty; 0
(reduced activity and lowered appetite)
dead; M * moribund or sick
00690
VII-7
-------
except 1n the case of ATPase where endrln appeared to neutralize the effect
of radiation on the mitochondria! membrane. The study indicated that endrln
leads to Injury of liver and kidney tissues, and that this may occur sooner
after gamma Irradiation of rats.
Following 2 weeks of dietary exposure to 0, 5 or 100 ppm endrln, rats
were administered a single dose of CC1. (0.1 ml/kg) by Intraperltoneal
Injection, and hepatotoxldty was assessed the following day by determina-
tion of serum enzyme activities (Young and Hehendale, 1986). No signifi-
cant elevations In enzyme activities were observed following exposure to
endrln alone. Following exposure to CC1. alone, modest but significant
elevations 1n serum of male rats was reported for SGPT, SGOT and Isodtrate
dehydrogerase (ICO) activities. In females, CC1. exposure elicited
significant but modest elevations In SGOT and ICO activities and a more
substantial elevation 1n ornlthlne-carbanyl transferase (OCT) activity.
However, exposure to CC1. plus endrln elicited marked elevation In SGPT
and ICO activities 1n females relative to the untreated controls. Further,
these activities were statistically significantly higher than those of
animals exposed to CC1. alone. It was concluded that dietary endrln
pretreatment potentiated CC1. hepatotoxldty.
Summary
Acute exposure to endrln causes death, which Is preceded by convulsions
and other CMS disturbances. Acute toxlclty Is associated with the presence
of 12-ketoendMn, and this metabolite has been postulated to be the ultimate
toxicant. Evidence suggests that endrln (and other polychlorocycloalkene
Insecticides) may Induce convulsions and death by Interfering with GABA-
regulated functions 1n the CMS, particularly chloride transport. Increased
00690 VII-8 '••••'•••.-._
-------
vascular resistance that follows endrln exposure may be Mediated through
effects of circulating catecholamlnes. Studies of human workers exposed
subchronlcally to endrln suggest Induction of liver nlcrosomal enzymes.
Mechanisms of chronic endrln toxldty are not known.
As with other organochloMne pesticides, endrln lacks genotoxlclty In
bacterial systems and 1n rodent hepatocytes, but can Inhibit metabolic
cooperation 1n Chinese hamster cells. These observations are consistent
with, but do not necessarily Indicate, a capability of endrln to Influence
tumor development by eplgenetlc mechanisms.
Evidence for Interactions augmenting endrln toxldty exists for birds
carrying a body burden of closely related chemicals, and for rats pretreated
with gamma Irradiation. Pretreatment with endrln potentiated CC1.-Induced
hepatic Injury In rats.
00690 VII-9
-------
VIII. QUANTIFICATION OF TOXICOL06ICAL EFFECTS
Introduction
The quantification of lexicological effects of a chemical consists of
separate assessments of noncarclnogenlc and carcinogenic health effects.
Chemicals that do not produce carcinogenic effects are believed to have a
threshold dose below which no adverse, noncarclnogenlc health effects occur,
while carcinogens are assumed to act without a threshold.
In the quantification of noncarclnogenlc effects, a Reference Dose
(RfD), [formerly termed the Acceptable Dally Intake (ADI)] 1s calculated.
The RfD Is an estimate (with uncertainty spanning perhaps an order magni-
tude) of a dally exposure to the human population (Including sensitive
subgroups) that Is likely to be without an appreciable risk of deleterious
health effects during a lifetime. The RfD Is derived from a no-observed-
adverse-effect level (NOAEL), or lowest-observed-adverse-effect level
(LOAEL), Identified from a subchronk or chronic study, and divided by an
uncertainty factor(s) times a modifying factor. The RfD Is calculated as
follows:
RfD - (NOAEL or LOAEL) ,
[Uncertainty Factor(s) x Modifying Factor]
Selection of the uncertainty factor to be employed 1n the calculation of
the RfD 1s based upon professional judgment, while considering the entire
data base of lexicological effects for the chemical. In order to ensure
that uncertainty factors are selected and applied In a consistent manner,
00700 VIII-1
-------
the U.S. EPA (1988a) employs a modlfIcatlon to the guidelines proposed by
the National Academy of Sciences (HAS, 1977, 1980) "as follows:
Standard Uncertainty Factors (UFs)
Use a 10-fold factor when extrapolating from valid experimental
results from studies using prolonged exposure to average healthy
humans. This factor 1s Intended to account for the variation
1n sensitivity among the members of the human population. [10H]
Use an additional 10-fold factor when extrapolating fro> valid
results of long-term studies on experimental animals when
results of studies of human exposure are not available or are
Inadequate. This factor Is Intended to account for the uncer-
tainty 1n extrapolating animal data to the case of humans.
[10A]
• Use an additional 10-fold factor when extrapolating from less
than chronic results on experimental animals when there Is no
useful long-term human data. This factor Is Intended to
account for the uncertainty 1n extrapolating from less than
chronic NOAELs to chronic NOAELs. [10S]
• Use an additional 10-fold factor when deriving an RfD from a
LOAEL Instead of a NOAEL. This factor 1s Intended to account
for the uncertainty 1n extrapolating from LOAELs to NOAELs.
[10L]
Modifying Factor (MF)
• Use professional Judgment to determine another uncertainty
factor (HF) that 1s greater than zero and less than or equal to
10. The magnitude of the HF depends upon the professional
assessment of scientific uncertainties of the study and data
base not explicitly treated above, e.g.. the completeness of
the overall data base and the number of species tested. The
default value for the HF 1s 1.
The uncertainty factor used for a specific risk assessment Is based
principally i^on scientific judgment rather than scientific fact and
accounts fur possible Intra- and Interspedes differences. Additional
considerations not Incorporated 1n the NAS/OOU guidelines for selection of
an uncertainty factor Include the use of a less than lifetime study for
deriving an RfD, the significance of the adverse health effects and the
counterbalancing of beneficial effects.
00700 VII1-2
-------
From the RfD, a Drinking Hater Equivalent Level (DUEL) can be calcu-
lated. The DUEL represents a medium specific (I.e., drinking water)
lifetime exposure at which adverse, noncarclnogenlc health effects are not
anticipated to occur. The DUEL assumes 100% exposure from drinking water.
The DUEL provides the noncarclnogenlc health effects basis for establishing
a drinking water standard. For Ingest!on data, the DUEL Is derived as
follows:
DUEL . («") * (Body weight In kg) m
Drinking Uater Volume in i/day
where:
Body weight « assumed to be 70 kg for an adult
Drinking water volume - assumed to be 2 i/day for an adult
In addition to the RfD and the DUEL, Health Advisories (HAs) for expo-
sures of shorter duration (1-day, 10-day and longer-term) are determined.
The HA values are used as Informal guidance to municipalities and other
organizations when emergency spills or contamination situations occur. The
HAs are calculated using an equation similar to the RfD and DUEL; however,
the NOAELs or LOAELs are Identified from acute or subchronlc studies. The
HAs are derived as follows:
(MOAEL or LOAEL) x (bw) ,.
*-~———~-~~~~~~~*~~l~~ • mg/i
(UF) x ( I/day)
Using the above equation, the following drinking water HAs are developed
for noncarclnogenlc effects:
1. 1-day HA for a 10 kg child Ingesting 1 i water per day.
2. 10-day HA for a 10 kg child Ingesting 1 i water per day.
3. Longer-term HA for a 10 kg child Ingesting 1 i water per day.
4. Longer-term HA for a 70 kg adult Ingesting 2 i water per day.
00700 VIII-3
-------
The 1-day HA calculated for a 10 kg child assumes a single acute
exposure to the chemical and 1s generally derived from a study of <7 days
duration. The 10-day HA assumes a limited exposure period of 1-2 weeks and
1s generally derived from a study of <30 days duration. The longer-term HA
Is derived for both the 10 kg child and a 70 kg adult and assumes an
exposure period of -7 years (or 10% of an Individual's lifetime). The
longer-term HA Is generally derived from a study of subchronlc duration
(exposure for 10% of animal's lifetime).
The U.S. EPA categorizes the carcinogenic potential of a chemical, based
on the overall we1ght-of-evidence, according to the following scheme:
Group A: Human Carcinogen. Sufficient evidence exists from
epidemiology studies to support a causal association between
exposure to the chemical and human cancer.
Group B: Probable Human Carcinogen. Sufficient evidence of
cardnogenlclty In animals with limited (Group Bl) or Inade-
quate (Group 82} evidence 1n humans.
Group C: Possible Human Carcinogen. Limited evidence of
cardnogenlclty 1n animals In the absence of human data.
Group D: Not Classified as to Human Cardnogenlclty. Inade-
quate human and animal evidence of cardnogenlclty or for which
no data are available.
Group E: Evidence of Noncarclnogenldty for Humans. Mo
evidence of cardnogenldty 1n at least two adequate animal
tests In different species or In both adequate ep 1 dentlologle
and animal studies.
If toxlcologlcal evidence leads to the classification of the contaminant
as a known, probable or possible human carcinogen, mathematical models are
used to calculate the estimated excess cancer risk associated with the
Ingestlon of the contaminant In drinking water. The data used In these
00700 VIII-4
-------
estimates usually come from lifetime exposure studies using animals. In
order to predict the risk for humans from animal data, animal doses must be
converted to equivalent human doses. This conversion Includes correction
for noncontlnuous exposure, less than lifetime studies and for differences
1n size. The factor that compensates for the size difference Is the cube
root of the ratio of the animal and human body weights. It Is assumed that
the average adult human body weight Is 70 kg and that the average water
consumption of an adult human 1s 2 l of water per day.
For contaminants with a carcinogenic potential, chemical levels are
correlated with a carcinogenic risk estimate by employing a cancer potency
(unit risk) value together with the assumption for lifetime exposure from
Ingestlon of water. The cancer unit risk Is usually derived from a linear-
ized multistage model with a 95X upper confidence limit providing a low dose
estimate; that 1s, the true risk to humans, while not Identifiable, Is not
likely to exceed the upper limit estimate and, 1n fact, may be lower.
Excess cancer risk estimates may also be calculated using other models such
as the one-hit, Welbull, loglt and problt. There Is little basis In the
current understanding of the biological mechanisms Involved In cancer to
suggest that any one of these models Is able to predict risk more accurately
than any other. Because each model 1s based upon differing assumptions, the
estimates derived fur each model can differ by several orders of magnitude.
The scientific data base used to calculate and support the setting of
cancer risk rate levels has an Inherent uncertainty that Is due to the
systematic and random errors In scientific measurement. In most cases, only
studies using experimental animals have been performed. Thus, there 1s
00700 VIII-5 •--•/,"
-------
uncertainty when the data are extrapolated to humans. When developing
cancer risk rate levels, several other areas of uncertainty exist, such as
the Incomplete knowledge concerning the health effects of contaminants In
drinking wa*er, the Impact of the experimental animal's age, sex and
species, the nature of the target organ system(s) examined and the actual
rate of exposure of the Internal targets 1n experimental animals or humans.
Dose-response data usually are available only for high levels of exposure
and not for the lower levels of exposure closer to where a standard may be
set. Uhen there 1s exposure to more than one contaminant, additional
uncertainty results from a lack of Information about possible synerglstlc or
antagonistic effects.
Moncardnoqenlc Effects
Although the acute LD5Q for endrln has been determined for a number of
species, the available data for defining short-term health advisories (HAs)
1s more limited. In an abstract, Revzln (1966) reported an Increase 1n the
amplitude of the EEG and a tendency toward spiking after seven dally doses
of 0.2 mg/kg bw endrln 1n rats. No effects w«re noted, however, after 1 or
t
2 days exposure to the same dose level. Speck and Haaske (1958) reported
EEG changes and occasional convulsions after 1 week using dally oral doses
of 3.5 mg/kg bw 1n rats. It was not reported whether effects occurred at
lower doses (0.8 and 1.7 mg/kg bw), which were also employed.
Information on acute and subchronlc effects of endrln exposure 1s
available from perinatal toxlclty studies. Chernoff et al. (1979) reported
marked maternal toxlclty In Syrian golden hamsters at doses >1.5 mg/kg
•»*•
bw/day for 10 days. Kavlock et al. (1981) reported decreased locomotor
00700 VII1-6
-------
activities In adult female CD-I mice after single oral exposures to 1.5 or
4.5 mg/kg endMn, but not to 0.5 mg/kg endMn. In CD rats, single oral
endrln doses of 0.5, 1.0 or 2.0 mg/kg bw elicited a dose-related decrease 1n
locomotor activity. Pregnant CO-1 mice exposed to endrln doses of 0.5, 1.0,
1.5 or 2.0 mg/kg bw/day by oral gavage on days 7-17 of gestation exhibited
reduced weight gain at the three highest exposure levels and elevated llver-
to-body weight ratios at all exposure levels. Pregnant CD rats exposed to
endrln doses of 0.075, 0.150, 0.300 or 0.450 mg/kg/day by oral gavage on
days 7-20 of gestation exhibited decreased weight gain at the two highest
doses only; llver-to-body weight ratios were unaffected 1n all exposure
groups. Thus, 0.150 mg/kg/day may be considered as a NOAEL for a 14-day
oral endrln exposure.
s
Nelson et al. (1956) exposed Sprague-Dawley rats to 1, 5, 25, 50 and 100.
ppra endrln 1n the diet for up to 16 weeks. Body weights and serum alkaline
phosphatase, an Index of liver damage, were measured weekly. Following 4
weeks of exposure, 40% mortality had occurred at exposure levels >5 ppm 1n
males, and hypersens1t1v1ty to various stimuli and nasal bleeding had
occurred at the 1 and 5 ppm exposure levels. Body weight losses and
elevated serum alkaline phosphatase occurred at all exposure levels. By 10
weeks of exposure, mortality had occurred at all exposure levels In males
and to females at levels >25 ppm. Mortality within the groups remained the
same at week 16.
/-
NCI (1979) In a cancer range-finding study found decreases In body
weight gain 1n rats administered 20 ppm, but not 10 ppm In the diet for 6
weeks. In the same study decreased body weight gains were also reported In
mice administered 10 ppm, but not 5 ppm In the diet.
00700 VIII-7 •:•:.. ••j/cr-
-------
Treon et al. (1955) conducted subchronlc and chronic exposure studies on
both rats and dogs. Groups of 20 male and 20 female Carworth rats were
given diets containing 0, 1, 5, 25, 50 or 100 ppm endrln for up to 2 years.
Mortality was high at the 50 and 100 ppm exposure levels. Height gain was
decreased in the males exposed to 5 and 25 ppm, but not 1 ppm, for 20 weeks.
Liver-to-body weight ratios were Increased 1n male rats 1n the 5 and 25 ppm
groups, but not the 1 ppm group, after 2 years of exposure. Liver-to-body
weight ratios In the female rats exposed to 1 or 5 ppm endrln for 2 years
did not differ significantly from controls.
s
Treon et al. (1955) also conducted a study with beagle dogs In which
groups of 1-4 were fed diets containing 0-50 ppm endrln for up to 18 months.
All dogs fed 10-50 ppm (0.49-4.00 mg/kg/day) died, and >50% of those fed 5-8
ppm (0.20-0.65 mg/kg/day) died. Actual endrln Intakes were reported by the.
authors. All dogs receiving <4 ppm (0.18 mg/kg/day) survived, but growth
was affected 1n the 4 ppm groups. The 3 ppm (0.19 mg/kg/day) group had
significantly higher relative kidney and heart weights than controls. Dogs
fed 1 ppm endrln were similar to controls 1n all parameters. Including gross
pathology and hlstopathology. According to the authors, the dogs (two males
and two females) on the 1 ppm diet actually consumed 0.083 mg/kg/day.
Unite other chronic studies have been conducted with the primary Intent
of evaluating carcinogenic response, some toxldty data have also been
s-
reported. Oelchmann et al. (1970) administered endrln to rats at concentra-
tions of 2, 6 and 12 ppm In the diet for up to 37 months. A moderate
Increase 1n cloudy swelling of the liver and renal tubular epithelium along
00700 VIII-8
-------
with a moderate Increase 1n the Incidence of lung congestion and focal
hemorrhage was reported. Since the authors stated that the effects were not
dose-related, H Is assumed they occurred at the 2 ppm level as well as the
higher doses.
In an NCI (1979) study both mice and rats were chronically exposed to
endrln. The mice were administered a time-weighted-average (TWA) concentra-
tion 1n the diet of 1.6 and 3.2 ppm, while the rats received 3 and 6 ppm.
Neither mortality nor body weights were affected by either dose. However, a
variety of clinical signs usually associated with aging were observed
earlier 1n the exposed mice and rats. Although a NOAEL was not observed In
the Oelchmann et al. (1970) or the NCI (1979) studies, the results of these
Investigations provide strong support for a NOAEL no greater than 0.05 mg/kg
bw in rats and 0.13 mg/kg bw 1n mice (1 ppm 1n the diet).
In a 2-year dog study, beagle dogs (7/sex/group) received diets
containing 0, 0.1, 0.5, 1.0, 2.0 or 4.0 ppm endrln for >2 years (U.S. EPA,
1987). Interim sacrifices (2 dogs/sex/group) were performed at 6 and 12
months. Parameters monitored Included growth, food consumption, behavior,
serum and urine chemistry, organ weights and hlstopathology of all major
organs. Animals treated at the 2 and 4 ppm dose levels experienced convul-
sions, slight Increase 1n relative liver weights, and mild hlstopathologlcal
changes 1n liver cells. Because of the effects observed 1n the dogs
consuming diets containing 2 ppm endrln (0.05 •g/kg/day), this level was
considered the LOAEL. No adverse effects were observed 1n dogs receiving
diets containing <1 ppm endrln. Therefore. 1 ppm (0.025 mg/kg/day) was
considered the NOAEL.
00700 VIII-9
-------
Only one chronic nonmaramallan study appears to have been conducted to
u--
date. KreUzer (1980) measured behavioral effects of endrln In adult
bobwhlte quail (Collnus v1rq1n1anus) using nonspatlal discrimination
reversal tasks. The birds were fed 0.1 and 1.0 ppm endrln In the diet (0.01
and 0.10 rag/leg bw If H Is assumed the birds eat an amount equivalent to 10%
of bw/day) for up to 240 days. Significantly Increased error rates were
detected at both levels of exposure. While the results of this study
suggest a NOAEL lower than values determined from other chronic studies, It
1s uncertain how they relate to those of mammalian exposures. Acute ID,.
studies on pigeons (Revzln, 1966) suggest that some species of birds may be
more sensitive to endrln exposure than mammals.
Quantification of Noncardnoqenlc Effects
t
Derivation of 1-Oav HA. Previously the study by Revsln (1968) was
selected as the basis for the 1-day HA. In this study, Revsln reported
alterations 1n the EEG of squirrel monkeys after 7 dally doses of 0.2 mg/kg
endrln. Results of this study were provided as an abstract. Recently the
Science Advisory Board of the U.S. EPA (1988c) In their meeting discourage
the use of data from an abstract for the derivation of an HA level. Under
the circumstances, the Kavlock et al. (1981) study 1s considered for the
1-day HA. In a preliminary range finding study, Kavlock et al. (1981)
reported decreased locomotor activities 1n adult female CD-I mice following
single oral endrln doses of 1.5 or 4.5, but not 0.5 mg/kg bw. The 0.5 o^/kg
dose can be considered a NOAEL. The 1-day HA for a 10 kg child 1s derived
as follows:
i j u. O.S mq/kg x 10 kg n n, ...
1-day HA - ^ ^ ... ^ • 0.05 mg/l
1 t/day x 100
00700 VIII-10
-------
where:
0.5 mg/kg • NOAEL, based on locomotor activities 1n mice
(Kavlock et al., 1981)
10 kg . weight of protected Individual (child)
1 i/day • assumed water consumption by a child
100 « uncertainty factor, chosen In accordance with
NAS/OOW and Agency guidelines for use with a NOAEL
from a study In animals
Derivation of 10-Oav HA. Formerly the 10-day HA value was calculated
based on the results of the Nelson et al. (1956) study on rats. However,
revaluation of the study Indicated certain observations that should not be
Ignored. These observations Included body weight losses, hypersensUlvlty
to various stimuli, nasal bleeding and Increased alkaline phosphatase
activity at the lowest endrln level tested. In view of the noted
observations, It 1s prudent to consider the Kavlock et al. (1981) study for
*•
derivation of the 10-day HA. Kavlock et al. (1981) reported depressed
maternal weight gain 1n CD rats exposed to endrln doses of 0.300 or 0.450
but not 0.150 or 0.075 mg/kg/day for 14 consecutive days; 0.150 mg/kg/day
can be considered a NOAEL for a 10-day exposure. The 10-day HA for a 10 kg
child 1s derived as follows:
10-day HA - 0.150 mq/kq/day x 10 kq m Q2
* 1 I/day x 100
where:
0.150 mg/kg/day - NOAEL, based on weight gain changes In rats
(Kavlock et al., 1981)
10 kg . weight of protected Individual (child)
1 i/day • assumed water consumption by a child
100 « uncertainty factor, chosen 1n accordance with
NAS/OOW and Agency guidelines for use with a
NOAEL from a study In animals
00700 VIII-11
-------
Derivation of Longer-Tern HA. Subchronlc exposure data appropriate
for deriving longer-term HAs are extremely limited. Nelson et al. (1956)
reported body weight losses, hypersensltlvHy to various stimuli, nasal
bleeding and Increased alkaline phosphatase activity to levels of endrln >1
ppm In Sprague-Qawley rats. The reported LOAEL of 1 ppm endrln In the diet
corresponds to a dose of 0.05 rag/kg/day (assuming an average dally dietary
consumption of 5X of body weight for Sprague-Dawley rats In a subchronlc
study; U.S. EPA, 1*87). By 10 weeks of exposure, Mortality had occurred at
all exposure levels 1n males and to females at levels >25 ppm.
Treon et al. (1955) reported elevated kidney and heart-to-body weight
ratios 1n beagle dogs exposed for up to 18 months to diets containing 3 ppm,
but not 1 ppm endrln. At both doses, organ-to-body weight ratios for liver,
brain and spleen did not differ significantly from controls. Based on
measured food Intake, the dally dose for the 1 ppm dose group varied from
0.045-0.12 mg/kg bw. However, the dally Intake of 1 ppm endrln appears to
be suspect since this range overlaps with the 3 ppm range of exposure as
given In the published report. It 1s therefore recommended that the DUEL,
which 1s based on lifetime exposure (see Assessment of Lifetime Exposure and
Derivation of a DUEL Section), be used as a conservative basis for the
longer-term HA. This value 1s based on a chronic NOAEL of 0.025 mg/kg/day.
*•
The Nelson et al. (1956) study 1s precluded for use since a high rate of
mortality occurred In male rats at >0.05 mg/kg/day after 10 weeks.
The DUEL of 0.009 mg/i Is based on adult body weight and water
consumption and therefore 1s used directly for the longer-term HA for
adults. For the 10 kg child, the RfO upon which the DUEL Is based Is used
1n the following derivation.
00700 VIII-12
-------
longer -Term HA RfD x 10 ** °-0003
(child) 1 i/day 1 i/day
• 0.003 mg/i
where:
RfO . 0.0003 rog/kg/day
10 kg - assumed weight of exposed Individual (child)
1 i/day • assumed volume of water consumed/day by a 10
kg child
Assessment of Lifetime Exposure and Derivation of a DUEL. A review of
the literature, Including an unpublished study from the CBI files concerning
endMn and the various RfD values that have been promulgated by the
different branches of the Agency, has Indicated that the CBI study 1s the
most appropriate basis for an RfD (U.S. EPA, 1988b). In this 2-year dog
study, beagle dogs (7/sex/group) received diets containing 0, 0.1, 0.5, 1.0,
2.0 or 4.0 ppm endrln for >2 years. Animals treated at the 2 and 4 ppm dose
levels experienced convulsions, slight Increase 1n relative liver weights.
and mild histopathologlcal changes In liver cells. No adverse effects were
observed at <1 ppm endrln, therefore 1 ppm (0.025 mg/kg/day) was considered
the NOAEL. Using the above study, the derivation of the DUEL 1s as follows:
Step 1 - RfD Derivation
Rf0 . 0.025 mq/kq/day m
where:
0.025 mg/kg/day « NOAEL for oral exposure fn dogs (U.S.
EPA.1987)
100 • uncertainty factor appropriate for use with a
NOAEL (from animal data and to protect
sensitive members of the human population
00700 VIII-13
-------
Step 2 - DUEL Derivation
nun RfD x 70 fco 0.00025 roo/ko/day x 70 kg
DWcL • * • a—*——' • . 0.009 mg/l
2 I/day 2 l/day ^
where:
RfD . 0.00025 mg/kg/day
•
70 kg • assumed weight of protected Individual (adult)
2 i/day • assumed volume of water consumed by a 70 kg adult
The recommended lifetime DUEL for a 70 kg adult Is 0.009 mg/i endMn.
A summary of the data used to calculate the HAs and the lifetime DUEL Is
provided 1n Table VIII-1. The values derived for the HAs and DUEL represent
estimates of the concentration of endrln In drinking water that will not
cause adverse effects after 1-day, 10-day, longer-term or lifetime exposures.
Carcinogenic Effects
There are no clinical reports available relating endrln exposure to
induction of cancer In humans. DUraglla et al. (1981) conducted a retro-
spective cohort study to examine the mortality of workers employed In the
manufacture of chlordane, heptachlor, DOT and aldrln/dleldrln/endrln. No
statistically significant excess for any specific cancer site was noted.
However, since no exposure data are reported, the results of this study are
Inconclusive. While there Is no evidence Unking endrln to cancer Induction
In humans, the amount of data available 1s Insufficient to allow definite
conclusions to be drawn.
Four bloassays for carclnogenlcUy were done 1n rats and three were on
mice. These bloassays were done at different Institutions, namely Food and
Drug Administration (FOA) during 1955-1957 as Devaluated by Reuber (1978).
00700 ¥111-14
-------
o
o
o
o
TABLE VI11-1
Summary of Data Used to Derive HAs or DUEL
1
en
Criteria Dose Duration Effect
(•g/kg bw/day)
1-Day HA 0.5 1 day NOAEL: locomotor
activities In mice
10-Day HA 0.15 14 days NOAEL: decreases In
maternal weights In
rats
Longer-term HA 0.025 2 years NOAEL: htstologtcal
liver lesions and
occasional convulsions
DUEL 0.025 2 years NOAEL: hlstologlcal
liver lesions and
occasional convulsions
Value of HA or DUEL
Child Adult
(mg/t) (mg/t)
0.05 NC
0.02 NC
0.003 0.009
NC 0.009
Reference
Kavlock
et al.. 1981
Kavlock
et al.. 1981
U.S. EPA.
1987b
U.S. EPA.
1987b
NC . Not calculated
-------
the National Cancer Institute (NCI, 1979), the University of Cincinnati
(KetteMng Laboratory) (HHherup et al.. 1970), and the University of «1am1
(Dekhmann et al., 1970). All the bloassays on rats and nice were reported
as negative by those authors. There were, however, deficiencies 1n the
studies which 1s explained below, which render the findings Inadequate to
properly assess the carcinogenic potential 1n animal test systens.
In the FOA rat (Osborne-Hendel) study the animals at highest dose (25
pp(n) did not survive well and additional animals were started In that dose.
The remainder of the groups lived for the programmed two year study. It
also appeared that every animal came to autopsy and not all sections from
grossly observed animals were studied Microscopically. In spite of some
deficiencies there were a sufficient nunber of animals 1n the studies
particularly In the aspect of liver and kidney, In all experimental and
control groups (Reuber, 1978). This study was originally reported as
negative. It was reevaluated by a panel of pathologist whose report was
referenced 1n a CAG document (U.S. EPA, 1978). One pathologist considered
the finding positive (Table V-11 and V-12) but did not provide slide by
slide tabulation of his findings and did not distinguish between primary
and/or metastatlc tumors 1n the liver. A second pathologist whose original
finding Indicated that the study was negative, provided slide by slide
tabulation of diagnosis which was confirmed by the panel review. In the FOA
mice (C3HF1) study the survival was very poor In both control and
experimental group.
The KetteMng study used two strains of mice (C5781/6J and C302F1/J).
The C57B1/6J strain exhibited mainly leukemia and liver tumors with low
Incidence. These tumors appeared equally In the experimental and control
00700 VIII-16
-------
groups and the latent period of tumor formation was similar. But 1n the
C302F1/J strain, the Incidence of liver tumors 1n the dose group (3 ppm) was
slightly higher In the female than in controls and the latent period of
tumor formation was decreased than other groups (WUherup et a!., 1970).
The NCI bloassay was done In Osborne-Mendel rats and B6C3F1 nice. These
studies were reported as negative. A primary reviewer for MCI noted that
the negative findings could be a reflection of the high toxldty of endrln.
which only permitted the administration of relatively low chronic dosages.
Furthermore, the reviewer observed that an accidental overdose among low
dose male mice resulted In early death of several animals In this treatment
group and the study was marred by a small (10) 1f matched controls; however,
this deficiency was compensated by the use of pooled controls (see Table
V-17). There were significant Increases 1n hemangloraa In low dose male
rats, adrenal adenoma and/or carcinoma In high dose In males, pituitary
adenomas In the high dose female, adrenal adenoma and/or carcinoma In low
dose female rats as compared to the pooled controls. Although, the
Islet-cell carcinoma In male rats had a significant trend but no
statistical significance at either dose group, the NCI concluded that these
tumors could not be clearly considered related to the admlnstratlon of
endrln (NCI, 1979). Although NCI concluded that the bloassays of endrln
were not carcinogenic, the responses noted above can not be totally Ignored.
Endrln was not nutagenlc 1n any bacterial strains but exhibited
chromosomal aberration 1n germinal tissues. Endrln Is also structurally
related to aldMn, dleldrln, chlordane, chlorendlc acid and heptachlor which
are known to carcinogenic 1n animals. The available cancer epldemlologlc
00700 VIII-17
-------
data Involving several studies 1s Inadequate to demonstrate or refute a
carcinogenic hazard because of study design limitations and/or mixed
exposures. Using the criteria 1n the U.S. EPA (198?) guidelines for
classification of carcinogens, endrln 1s most appropriately classified In
Group 0; I.e. a chemical for which there Is Inadequate evidence to assess
the potential cardnogenlclty for humans. This classification 1s based on
the nonposltlve but suggestive results In some of the animal studies. The
negative conclusions as reported by the study authors of the four bloassays
do not support a Group E classification, because of the Inadequacies of the
studies. A Group D we1ght-of-ev1dence 1s thought to be the best classifi-
cation until additional studies can be done to clarify the situation.
Existing Guidelines. Recommendations and Standards
The U.S. EPA (1975) has set an Interim standard for endrln In finished
w
water of 0.0002 mg/i. The U.S. EPA (1980a) proposed an ambient water
criterion for endrln of 0.001 mg/1. This value was the same as the
maximum allowable concentration recommended at that time by the Public
Health Service.
The World Health Organization (FAO/WHO, 1973) established as a guideline
a maximum Intake of 2 vg/kg/day, or 138.2 yg/day, for a 69.1 kg person.
The proposed Index AHmentarlus Commission's maximum residue limit In wheat
w^"
1s 20 vg/kg (Bailey et al., 1982).
The threshold limit value (8-hour TLV/TWA) recommended by the American
Conference of Governmental Industrial Hyglenlsts Is 0.10 mg/ra» (0.10
00700 VIII-18
-------
vg/l), wHh a short time exposure limit {15 minutes) of 0.30 mg/m»
(ACGIH, 1982). The Occupational Safety and Health Administration limits are
the same, 0.10 mg/m' (29 CFR 1910-1000).
The history of recommendations concerning endrln 1s provided In the
Federal Register (1979). The U.S. EPA Issued a notice of rebuttable pre-
sumption against registration and continued registration (RPAR) of endrln-
contalnlng products (e.g., R1d-a-B1rd and Sorblklll) on July 27. 1976. It
Included three supportable risk presumptions — risk of significant popula-
tion reductions of nontarget organisms, acute toxlclty to wildlife, and
teratogenldty. After review, the Agency determined that the offsetting
economic, social or environmental benefits were still not great enough.
Thus, endrln use was cancelled In the following areas: on cotton 1n all
areas east of Interstate highway 35; on small grains to control all pests
other than army cutworm, the pale western cutworm and grasshoppers; on apple
orchards 1n the eastern United States to control meadow voles; on sugarcane
to control the sugarcane borer; and on ornamentals. Registration for new
uses of endrln was denied, as well as Us use In unenclosed bird perch
treatments. Limited use was allowed under specific conditions for the
following: on cotton west of Interstate 35; on small grains to control array
cutworms and pale western cutworms; on apple orchards In the eastern United
States to control the pine vole and In the western United States to control
meadow voles; on sugarcane to control the sugarcane beetle; for conifer seed
treatment; and use In enclosed bird perch treatments. New uses and regis-
tration of endrln under specified conditions were allowed as follows: as a
tree paint In Texas; on alfalfa and clover seed crops 1n Colorado; and on
small grains to control grasshoppers (In Montana). These determinations
were originally Issued on October 20, 1978 by the Agency.
00700 VIII-19
-------
In response to the endrln RPAR, the Agency determined that endrln was
unlikely to pose an oncogenlc risk to humans, and that the risk presumptions
for acute dermal toxldty and fatalities to endangered species had been
rebutted.
In the case of fish kills, signs stating 'Contaminated: No Fishing" must
be posted for 1 year after a fish kill, or for 6 months after lesser
contamination unless endrln residues In the edible portion of fish are <0.3
ppm ww.
The bird species deemed potentially at risk were the Arctic and American
peregrine falcons, bald eagles and brown pelicans. A NOEL of 1.5 mg/kg bw
was accepted for teratogenldty 1n the hamster. The LOEL 1n the hamster was
5 mg/kg. However, behavioral studies using quail have Indicated that either
quail are very sensitive to the effects of endrln or the endpolnts measured
are more sensitive than those used In the past.
Special Considerations
Endrln given to the dam at dose levels -10-fold In excess of the chronic
NOEL in adult nonpregnant animals has been associated with reduced fetal
weight In hamsters and mice. At levels comparable to the chronic NOEL,
endrln exposure resulted 1n Increased locomotor activity of offspring of
rats and hamsters. Thus, unborn children must be considered a potentially
sensitive group.
The general public In the Missouri and Mississippi basins between March
1964 and June 1967 were exposed to endrln In drinking water (Schafer et al.t
00700 VIII-20
-------
1969) and In 1976 In Ottawa, Canada (Williams et al., 1978). These situa-
tions occurred 1n agricultural areas. Acid drinking waters are more likely
U--
to contain endrln ketone than endrln Itself (ApSlmon et al., 1982), also
keeping In mind that endrln cannot be analyzed well 1n acid water, In
»
contrast to endrln ketone (Millar et al., 1981). Thus, people living In
areas of high endrln use have more potential for risk than have the general
population.
Farming communities and workers near areas of endrln application may be
exposed not only to endrln (Wolfe et al., 1963, 1967; U.S. EPA, 1971, 1979;
Arthur et al., 1976; Jeg1er7 1964), but also to the major product of
sunlight degradation, the half-cage ketone Identified also 1n environmental
samples (Zablk et al., 1971). Exposure to this product may Increase their
risk.
Workers exposed to endrln In occupational environments have been known
to suffer convulsions (Jager, 1970). Such workers are the best study
populations for monitoring signs of cancer. Poisoning episodes have also
been reported for endrIn-contaminated flour (Coble et al., 1967; Weeks,
1967; Curley et al., 1970).
Previous exposure to related compounds can Increase susceptibility to
the toxic effects of endrln. Pretreatment of quail with chlordane at
dosages less than the NOAEL (10 ppm 1n the diet for 10 weeks) resulted In
greater mortality In birds subsequently administered 10 ppm endrln 1n the
diet than In those administered endrln alone (Ludke, 1976). Of the birds
that died, the ones treated with endrln alone had lower brain endrln concen-
trations than In those pretreated with chlordane.
00700 VIII-21
-------
Raa'atlon may increase the response to endrln. Irradiation of rats with
gamma particles (900 rads) before Injection of 10 mg/lcg bw endrln to rats
resulted 1n a greater Increase In SGOT, SGPT, and a greater decrease In add
and alkaline phosphatase, sucdnk dehydrogenase and glucose-6-phosphatase
s- /'
than 1n rats treated with endrln alone (Heena et al., 1978).
Finally, stress may lower the threshold for the toxic effects of endrln.
The survival tiroes of female field nice (Peromyscus manlculatus) were
shorter during combined cold and starvation, at doses of endrln as low as 1
*-
ppm In the diet, than In stressed mice that received no endrln (Morris,
1968).
Summary
The NOAEL for acute exposure to endrln Is determined to be 0.5 Rig/kg
bw/day based upon locomotor activities 1n nice. Based upon this NOAEL, a
1-day HA for a 10 kg child of 0.05 og/i Is proposed.
The NOAEL for 14-day exposure to endrln Is determined to be 0.150 mg/kg
bw/day based upon body weight changes In rats. Utilizing this NOAEL a
10-day HA Is proposed to be 0.02 rog/i for a 10 kg child.
The NOAEL for a 2-year exposure to endrln 1s determined to be 0.025
mg/kg bw/day based upon histologlcal liver lesions In dogs. Utilizing this
NOAEL, longer-term HAs of 0.003 mg/l for children and 0.009 mg/i for
adults are proposed.
00700 YIII-22
-------
An RfO of 0.00025 mg/kg/day was derived based upon a NOAEL of 1 ppm
endrln In the diets of dogs exposed for 2 years and mild hlstopathologlcal
liver changes 1n exposed animals. Based on this RfO, a lifetime DUEL of
0.009 mg/l 1s proposed.
00700 VIII-23
-------
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*
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00710 IX-27 /?s,-
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