TECHNICAL REPORT DATA
ffltttte read Instructions on tfie reverse before completing]
1. REPORT NO.
EPA/600/8-88/030
3. RECIPIENT'S ACCESSION NO
PB88-179957/AS
4. TITLE AND SUBTITLE
6. REPORT DATE
Health Effects Assessment for Dieldrin
«. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
I. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
1V CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive .Order ]2991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfDs or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b-IOENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
18. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (This Report/
Unclassified
21. NO. OP PAGES
20. SECURITY CLASS (Thit pagei
Unclassified
22. PRICE
EPA F*m 2220-1 (R«v. 4-77) PREVIOUS EDITION i* OMOLCTC
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EPA/600/8-88/030"
August, 1987
HEALTH EFFECTS ASSESSMENT
FOR DIELORIN
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has been reviewed In accordance with the U.S.
Environmental 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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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with dleldrln.
All estimates of acceptable Intakes and carcinogenic potency presented In
this document should be considered as preliminary and reflect limited
resources allocated to this project. Pertinent toxlcologlc and environ-
mental data were located through on-Hne literature searches of the TOXLINE
and the CHEMFATE/OATALOG data bases. The basic literature searched support-
Ing this document Is current up to May, 1986. Secondary sources of Infor-
mation have also been relied upon In the preparation of this report and
represent large-scale health assessment efforts that entail extensive peer
and Agency review. The following Office of Health and Environmental Assess-
ment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for
Aldr1n/01eldr1n. Prepared by the Office of Health and Environ-
mental Assessment, Environmental Criteria and Assessment Office,
Cincinnati. OH. for the Office of Water Regulations and Standards,
Washington, DC. EPA 440/5-80-018. NTIS PB81-117301.
U.S. EPA. 1980b. Hazard Profile for Dleldrln. Prepared by the
Office of Environmental Health and Assessment. Environmental Cri-
teria and Assessment Office, Cincinnati, OH, for the Office of
Solid Waste, Washington, DC.
The Intent 1n these assessments Is to suggest acceptable exposure levels
for noncarclnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, RfO$ (formerly AIS) or subchronlc reference dose, Is
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants 1n ambient air or water where lifetime
exposure Is assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$j) and oral (RfO$o)
exposures.
111
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The RfD (formerly AIC) 1s similar 1n concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980c) for a discussion of this concept]. The
RfD 1s route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes Is Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained 1n U.S.
EPA (1984).
For compounds for which there 1s sufficient evidence of carclnogenlclty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980c). Since cancer Is a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data If available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
The risk assessment for dleldrln 1s based on positive results In
several cardnogenlcHy bloassays. The U.S. EPA (1986) calculated a human
carcinogenic potency factor {q-j*) of 16 (mg/kg/day)"1 based on the
geometric mean of 13 animals bloassays. No additional data were found 1n a
review of more recent literature or the CBI files, and this value 1s still
recommended.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Haste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
ORAL
INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
SUBCHRONIC .....
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
Page
. . . 1
. . . 3
. . . 3
. . . 3
, , . 4
, . . 4
. . . 4
. . . 5
. . . 5
. . . 5
. . . 7
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS.
4.
5.
3.4.
3.3.1. Oral
3.3.2. Inhalation. . .
TOXICANT INTERACTIONS
CARCINOGENICITY .....
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral. ....
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
. . . . 7
9
9
10
10
10
10
10
10
15
15
15
17
V11
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TABLE OF CONTENTS (cont.)
RISK ASSESSMENT
6.1. SU8CHRONIC REFERENCE DOSE (RfOs) 18
6.2. REFERENCE DOSE (RfD) 18
6.3. CARCINOGENIC POTENCY (q-|*) 18
6.3.1. Oral 18
6.3.2. Inhalation 18
REFERENCES 32
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LIST OF TABLES
No. Title Page
4-1 Summary of Carc1nogen1c1ty Data for DleldMn 11
4-2 Summary of Pertinent Cancer Studies on Dleldrln Reviewed
By U.S. EPA (19865) 13
6-1 Cancer Data Sheet for Derivation of Potency of Dleldrln
From Tumor Incidence 1n Mice (Thorpe and Walker 1973) ... 19
6-2 Cancer Data Sheet for Derivation of Potency of Dleldrln
From Tumor Incidence In Mice (Thorpe and Walker 1973) ... 20
6-3 Cancer Data Sheet for Derivation of Potency of Dleldrln
From Tumor Incidence 1n Mice (Thorpe and Walker 1977a ... 21
6-4 Cancer Data Sheet for Derivation of Potency of Dleldrln
From Tumor Incidence In Mice (Davis, 1965) 22
6-5 Cancer Data Sheet for Derivation of Potency of Dleldrln
From Tumor Incidence 1n Mice (Davis, 1965) 23
6-6 Cancer Data Sheet for Derivation of Potency of Dleldrln
From Tumor Incidence 1n Mice (Walker et al., 1972) 24
6-7 Cancer Data Sheet for Derivation of Potency of Dleldrln
From Tumor Incidence 1n Mice (Walker et al., 1972) 25
6-8 Cancer Data Sheet for Derivation of Potency of Dleldrln
From Tumor Incidence In Mice (Walker et al., 1972) 26
6-9 Cancer Data Sheet for Derivation of Potency of Dleldrln
From Tumor Incidence 1n Mice (Walker et al., 1972) 27
6-10 Cancer Data Sheet for Derivation of Potency of Dleldrln
From Tumor Incidence 1n Mice (Tennekes et al., 1981). ... 28
6-11 Cancer Data Sheet for Derivation of Potency of Dleldrln
From Tumor Incidence 1n Mice (Melerhenry et al., 1983). . . 29
6-12 Cancer Data Sheet for Derivation of Potency of Dleldrln
From Tumor Incidence 1n Mice (Helerhenry et al., 1983). . . 30
6-13 Cancer Data Sheet for Derivation of Potency of Dleldrln
From Tumor Incidence In Mice (Melerhenry et al., 1983). . . 31
1x
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LIST OF ABBREVIATIONS
»
CAS Chemical Abstract Service
CBI Confidential business Information
EEG Electroencephalogram
LOAEL Lowest-observed-adverse-effect level
LOEL Lowest-observed-effect level
NOAEL Lowest-observed-adverse-effect level
NOEL No-observed-effect level
ppb Parts per billion
ppm Parts per million
RfO Reference dose
RfDj Inhalation reference dose
RfDg Oral reference dose
RfD$ Subchronlc reference dose
RfD$I Subchronlc Inhalation reference dose
RfD$o Subchronlc oral reference dose
SGOT Serum glutamlc oxaloacetlc transamlnase.
SGPT Serum glutamlc pyruvlc transamlnase
TLV Threshold limit value
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected physical and chemical properties and half-lives for dleldrln
are listed 1n Table 1-1.
Little Is known about the fate of dleldrln In the atmosphere. Because
of Us low vapor pressure, dleldrln will probably remain associated with
partlculate matter In the atmosphere. Vapor phase photodegradatlon has been
noted but Us rate Is unknown (HSDB, 1986).
In water, dleldrln 1s expected to persist In sediments and bloconcen-
trate 1n aquatic organisms. Volatilization should be an Important pathway
for ultimate removal of dleldrln. The estimated volatilization half-lives
of unadsorbed dleldrln range from 6-9 hours to up to 72 days 1n ponds;
however, the actual volatilization half-life will exceed these estimated
values because of strong adsorption. In addition, direct photolysis of
dleldrln to photodleldrln may occur (half-life of -4 months or somewhat less
In the presence of photosensltlzers). In a modelling study of a reservoir,
1t was concluded that 40% of dleldrln In the 1n-flow was lost to the bottom
*
by sedimentation: 50% was released through the out-flow because of the
short detention time In the reservoir; and 10% was taken up by fish (HSDB,
1986).
In soil, dleldrln will persist for extremely long periods of time (5-25
years) (U.S. EPA, 1980a). Its low water solubility and strong adsorption to
soil make leaching Into most groundwater unlikely (HSDB, 1986).
0092h -1- 01/06/87
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TABLE 1-1
Selected Physical and Chemical Properties and Half-lives for Oleldrln
Property
Value
Reference
CAS number:
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Log octano.1/water
partition coefficient:
B1oconcentrat1on factor:
Soil adsorption
coefficient:
Half-lives:
Water
Soil
60-57-1
chlorinated pesticides
380.93
1.78xlO-7 mm Hg
at 20°C
0.186 mg/i. at 25-29°C
4.32, 5.48, 6.20
102-10« (various
aquatic species)
3-6000 (fish)
7.41xlOa
-300 days (lakes)
1-6 years (estimated)
(estimated from 95%
removal time)
U.S. £PA, 1980a
U.S. EPA, 1980a
Kanazawa, 1981;
Hawker and Connell, 1986;
Hanson and Leo, 1985
HSDB, 1986
HSOB, 1986
Zoeteman et al., 1980
U.S. EPA, 1980a
0092h
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01/06/87
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Heath and Vandekar (1964) reported that absorption of radlolabeled dlel-
drln by the upper gastrointestinal tract of rats begins almost Immediately
following an oral dose and that absorption varies with the solvent used.
Ahdaya et al. (1978) reported that gastrointestinal absorption of dleldrln
was the slowest of several compounds tested, while Delchmann (1981) and
Qualfe and FUzhugh (1967) reported that dleldrln was absorbed readily from
the gastrointestinal tract. Ahdaya and Guthrle (1982) found that 63.2% of
an oral dose of 1 mg/kg dleldrln In a 1:1:8 emulphor:ethanol:water mixture
was absorbed from the gastrointestinal tract within 60 minutes. When the
stomach was llgated, only 13.9% of the dose was absorbed 1n 60 minutes,
Indicating that absorption from the small Intestine was the primary route of
dleldrln uptake; however, Tanaka et al. (1981) reported that dleldrln was
absorbed slowly from the small Intestine.
2.2. INHALATION
Delchmann (1981) reported that dleldrln was readily absorbed from the
respiratory tract.
0092h -3- 09/20/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Hunter et al. (1969) administered HEOO, the pure compound
1n a formulation of dleldrln, to human subjects at doses of 10, 50 or 211
ug/day for 2 years. Although the focus of the study was pharmacodynamlcs,
several clinical parameters reflecting health of the subject were monitored.
No adverse effects on health of the subjects occurred at any dose level.
There are several subchronlc studies available 1n which dleldrln was
administered orally to laboratory animals. Bandyopadhyay et al. (1982)
administered 0 or 5 mg/kg/day dleldrln by gavage In corn oil to rats for 15
days and found hlstopathologlcal changes 1n the liver and kidneys of rats
given dleldrln. Den Tonkelaar and Van Esch (1974) conducted 2-week studies
with groups of 3-6 male rats receiving 0, 2, 5, 10, 20 or 50 ppm dleldrln 1n
the diet, and examined effects on hepatic mlcrosomal enzymes. They deter-
mined that 5 ppm was a LOEL and 2 ppm a NOEL for Induction of these enzymes.
Shakoorl et al. (1984) fed dleldrln 1n the diet to male rats at a dosage of
2 mg/kg/day for 6 months, and found that several serum biochemical param-
eters. Including S60T and SGPT activities, were significantly Increased 1n
the treated rats after the 6-month exposure. Walker et al. (1969) adminis-
tered dleldrln (>99% purity) 1n gelatin capsules to groups of five male and
five female beagle dogs at dosages of 0. 0.005 and 0.05 mg/kg/day for 2
years. Treated dogs were healthy, as Indicated by body weights, EEG
tracings, uMnalysls. and hematologlcal and clinical chemistry evaluations.
The high-dose dogs had significantly Increased liver weights relative to
controls, but no tissue lesions were found. FUzhugh et al. (1964) treated
14 mongrel dogs with dleldrln In the diet at dosages of 0.2-10 mg/kg/day, 6
0092h -4- 09/20/86
-------
days/week for up to 25 months. Gross toxic effects (weight loss, convul-
sions) and histopathologlcal changes Including fatty degeneration of "liver
and kidneys and reduced cellularHy of the bone marrow occurred at >0.5
mg/kg/day.
Smith (1973) and Van Gelder and Smith (1973) conducted subchronlc
behavioral experiments with squirrel monkeys receiving dleldrln at oral
doses of 0.1 or 0.01 mg/kg/day for 55 days. The higher dosage Impaired
learning behavior, but the lower dosage had no effect.
3.1.2. Inhalation. Subchronlc Inhalation studies with dleldrln could not
be located In the available literature.
3.2. CHRONIC
3.2.1. Oral. In a study of occupational exposure to dleldrln. Van Raalte
(1977) found that Intoxication occurred at blood levels of 280-290 ppb,
while 200 ppb (corresponding to a dally oral Intake of 2 mg/person/day) was
a NOEL.
FUzhugh et al. (1964) fed groups of 12 male and 12 female Osborne-
Mendel rats diets containing 0, 0.5, 2, 10, 50, 100 or 150 ppm dleldrln for
2 years. Growth was unaffected, but survival was reduced In a dose-related
manner at concentrations of >50 ppm. All treated rats had Increased rela-
tive liver weights and dose-related histopathologlcal liver lesions. Rats
at the higher doses had distended and hemorrhaglc urinary bladders and an
Increased Incidence of nephritis.
Hodge et al. (1967) reviewed a large number of subchronlc and chronic
studies, and attempted to define thresholds for a variety of toxic effects
In different species. The lowest dietary concentration found to cause
adverse effects was 0.5 ppm, which resulted In Increased relative liver
weight and histopathologlcal liver effects 1n female rats fed this diet for
0092h -5- 01/06/87
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2 years. Hodge et al. (1967) concluded that no NOEL had yet been determined
for these effects, which were the most sensitive Indicators of dleldrln
toxlclty. Dogs fed 1 ppm dleldrln In the diet for 15 months had Increased
relative liver weights. H1stopatholog1cal effects 1n liver occurred In dogs
at 8 ppm 1n the diet for 10 months but not at 3 ppm for 15 months. Mice fed
10 ppm dleldrln In the diet for 2 years also experienced hlstopathologlcal
effects 1n the liver.
Wright et al. (1978) conducted long-term (-6 years) studies with groups
of five male rhesus monkeys receiving diets containing dleldrln at concen-
trations of 0.01-5.00 ppm. The only observed treatment-related hlstologlcal
effects were 'small changes associated with the hepatocellular endoplasmlc
retlculum.* The most sensitive effects were changes In hepatic mlcrosomal
monooxygenases, which occurred at dietary concentrations of 1.75 and 5 ppm.
The threshold for the Induction of these enzymes was 25-30 yg/kg/day,
which corresponded to a liver concentration of 6-7 ppm. In rats and mice,
liver dleldrln concentrations of this magnitude are associated with substan-
tial enzyme Induction and liver enlargement. The results of this study and
the absence of detectable liver changes In humans with high endogenous
dleldrln concentrations Indicate that the livers of primate species may be
relatively Insensitive to dleldrln-lnduced effects (Wright et al., 1978).
Reuber (1980) reported results of a chronic toxlclty study In which
groups of 12 male and 12 female Osborne-Mendel rats were fed diets contain-
ing 0.5, 2, 10, 50, 100 or 150 ppm dleldrln for 2 years. The Incidence and
severity of chronic nephritis was Increased In rats exposed to >50 ppm.
Many animals 1n the 100 and 150 ppm groups died from renal necrosis or
hepatic necrosis. High mortality of rats at >50 ppm prevented detection of
late-developing tumors In those groups.
0092h -6- 01/06/87
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Harr et al. (1970a) conducted a factorial experiment 1n which groups of
OSU-W1star rats were exposed to dietary dleldrln. The two factors Investi-
gated were dietary concentrations of dleldrln (0.08-40.0 ppra) and age of the
rats (28-750 days). Dleldrln treatment resulted In nonspecific neural and
vascular lesions, cranial edema and convulsions. No functional effects on
the neural or vascular system occurred at concentration <2.1 ppm.
3.2.2. Inhalation. Chronic Inhalation studies with dleldrln could not be
located In the available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Chernoff et al. (1975) and D1x et al. (1977) obtained
negative results In teratogenlclty studies using mice and rats. Chernoff et
al. (1975) administered 0, 1.5, 3.0 or 6.0 mg/kg/day dleldrln by gavage In
peanut oil to groups of 9-25 pregnant CD rats and groups of 6-16 pregnant
CO-1 mice on days 7-16 of gestation. The highest dose caused 41% mortality
In rats and Increased relative IVver weight and decreased body weight gain
1n mice. No teratogenlc effects were observed. The two highest doses were
associated with an Increased percentage of supernumerary ribs In mice. D1x
et al. (1977) administered 0, 1.5 or 4.0 rag/kg/day HEOO (purified dleldrln)
1n corn oil to pregnant CF1 mice by gavage on days 6-14 of gestation. No
compound-related maternal toxlclty, fetotoxlclty or teratogenlc effects were
observed.
Several studies have addressed possible reproductive effects of dleldrln
In rats and mice. Agarwal and Ahmad (1979) reported that 12.5 ppm dleldrln
In the diet caused reduced fertility and high pup mortality In rats and
mice. No other details were provided. Good and Ware (1969) found that
feeding a diet containing 5 ppm dleldrln to CFW Swiss mice for 120 days
beginning 30 days before mating resulted In reduced Utter size. No effects
0092h -7- 01/06/87
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on fertility or fecundity were noted. KepUnger et al. (1968) reported that
a dietary level of 25 ppra dleldrln caused "marked" effects on fertility,
gestation, viability, lactation or survival of mice 1n a multlgeneratlon
study. Significant but less severe effects occurred at 3 and 10 ppm dlel-
drln. Mo other details were provided. Harr et al. (1970b) conducted an
experiment In which groups of OSU-Wlstar rats were exposed to dietary dlel-
drln concentrations of 0.08-40.0 ppm for 39-750 days. The higher concentra-
tions caused mortality. Dleldrln exposure decreased the percentage of
females that conceived and therefore the number of nursing pups. The calcu-
lated maximum dietary concentration that did not cause any reproductive
effects (conception rate, pup survival. Utter size) was 0.24 ppm, a level
that was equivalent to 0.014 mg/kg/day according to the authors.
In a review of several unpublished studies, Hodge et al. (1967) reported
that the lowest dietary dleldrln concentration that caused reproductive
effects was 2.5 ppm, which caused Increased pup mortality and fewer preg-
nancies In rats. This was the lowest concentration tested In any of the
available studies at that time, and therefore, a NOAEL could not be deter-
mined. This concentration was higher than the LOAEL (0.5 ppm) reported for
Increased relative liver weights and hlstopathologlcal changes 1n the liver
In rats (Hodge et al., 1967). Dogs were somewhat less sensitive, with
Increased pup mortality at 25 ppm but not 8 ppm (Hodge et al., 1967).
Clegg (1979) reviewed studies concerning the reproductive effects of
pesticides. In one of these studies, rats fed 0.1 or 1 ppm dleldrln In the
diet were unaffected, but 2 ppm caused reduced survival to weaning In the
F- generation. In another study, 60 ppm dleldrln In the diet of rats
caused decreased mating success. A multlgeneratlon mouse study showed that
0092h -8- 01/06/87
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10 and 25 ppm dleldrln In the diet caused reduced survival and viability of
pups. Only "non-consistent reduction of lactation Index" was reported at 3
ppm, the lowest dose tested.
3.3.2. Inhalation. Pertinent studies concerning teratogenldty or repro-
ductive effects of Inhaled dleldrln could not be located In the available
literature.
3.4. TOXICANT INTERACTIONS
Several studies are available concerning effects of dleldrln admin-
istered In combination with other pesticides. Ehrlch et al. (1976) found
that an oral dose of 16 mg/kg dleldrln had no effect on the antlchoHnester-
ase action of dlchlorvos. Delchmann et al. (1969) reported results of sev-
eral studies that showed that dleldrln storage In adipose tissue of rats and
dogs was reduced when DOT was administered concurrently. Menzer (1970) fed
dleldrln to mice at a dietary concentration of 5 or 25 ppm for 7 or 14 days,
and then administered various organophosphate pesticides by Intraperltoneal
Injection. Dleldrln pretreatment decreased the toxlclty of B1dr1n« and
phosphamldon, slightly decreased the toxlclty of malathlon and Increased the
toxlclty of dlmethoate. Thomas et al. (1974) reported that simultaneous
administration of dleldrln and parathlon had similar effects on androgen
metabolism and hepatic mlcrosomal enzymes as dleldrln alone. Jones et al.
(1974) found that addition of 100 ppm dleldrln to a diet containing 900 ppm
hexachlorophene reduced mortality of rats fed hexachlorophene alone for 8
weeks from 100% to <4%. The authors speculated that the modification of
hexachlorophene toxlclty by dleldrln may have been due to enzyme Induction.
Another study reported effects of chemicals other than pesticides on
dleldrln toxlclty. Uzoukwu and Sleight (1972) found that sodium nitrite did
not potentiate dleldrln toxlclty In guinea pigs.
0092h -9- 01/06/87
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4. CARCINOGENICITY
4.1. HUNAN DATA
4.1.1. Oral. Human oral carclnogenlclty studies could not be located In
the available literature.
4.1.2. Inhalation. Jager (1970) and Versteeg and Jager (1973) reported
results of studies of 233 pesticide workers exposed to aldrln, dleldrln,
endrln and telodrln for 4-13 years 1n Holland. No adverse health effects,
Including cancer, attributable to pesticide exposure were detected. Van
Raalte (1977) conducted a follow-up study, presumably of the same group of
workers, and found no adverse health signs and no Increase In cancer Inci-
dence. The author suggested that these results Indicated that dleldrln Is
not a human carcinogen. In reviewing this study, however, U.S. EPA (1980a)
noted that the total number of subjects 1n this study was small and that the
observation times may have been too short (I.e., <20 years).
4.2. BIOASSAYS
4.2.1. Oral. U.S. EPA (1980a) reviewed and evaluated several studies of
the carclnogenlclty of dleldrln (Table 4-1). U.S. EPA (1986b) reviewed the
studies shown In Table 4-2. Mice appeared to be the species most sensitive
to dleldrln carclnogenlclty; the liver was the principal organ affected.
Results from rat studies were generally negative. Of the studies discussed
by U.S. EPA (1986b), the Thorpe and Walker (1973) bloassay In mice was
determined to be the most useful for risk assessment.
In the Thorpe and Walker (1973) study, diets containing 10 ppm dleldrln
(>99X pure) were fed to groups of 30 CF, mice of both sexes for 110
weeks. The control group consisted of 45 mice of both sexes. The mice were
bred and maintained In Individual cages under specific-pathogen-free
conditions. Treatment commenced at 4 weeks of age; all survivors were
sacrificed after the 110-week exposure. Moribund animals were sacrificed
0092h -10- 08/24/87
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0092h
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09/20/86
-------
TABLE 4-2
Summary of Pertinent Cancer Studies on Mice Using Dleldrln
Reviewed By U.S. EPA (1986b)
Sex, Strain
Female, CF-j
Female, CF]
Hale, CF-|
Hale, CF-]
Hale, B6C3F]
Tumor Site
and Type
liver,
carcinoma
liver,
carcinoma
liver.
carcinoma
liver,
carcinoma
liver,
carcinoma
Potency
(mg/kg/day)'1
28.60
25.00
24.81
22.02
9.13
Potency Index
(mmol/kg/day)-1
1.1x10*
9.5xl03
9.5x103
8.4xl03
3.5xlO»
Reference
Walker et
al,, 1972
Davis and
FUtzhugh,
1962,
Walker et al.,
1972
Davis and
Fltzhugh,
1962,
NCI, 1978a
0092h
-13-
08/24/87
-------
during the study; all animals were grossly examined. The sections of brain,
heart, lungs, liver, kidneys, and testes or ovaries, and all macroscopic
lesions were processed and microscopically examined. In the mice fed
dleldrln, liver enlargement was detected after 50 weeks 1n both sexes with
mortality Increased after 22 months. Liver lesions were arbitrarily
classified as Type A or Type B.
Dleldrln Induced a statistically significant Increase (p<0.01) In the
Incidence of liver tumors In both sexes as compared with controls.
Metastases were found only In the lungs of animals with Type B tumors. As
In a previous study by Walker et al. (1972), Type B tumors were not detected
1n female controls and were present In only a small proportion (4% of male
controls.
In contrast to the earlier study of Walker et al. (1972), tumor
Incidences versus time were presented. Liver tumors appeared much earlier
1n the treated animals than In controls 1n that 50 and 100% of all
dleldrln-treated females and males, respectively, that died by 17 months had
liver tumors; no liver tumors, however, were found 1n controls at that time.
In the NCI (1977a) studies, groups of 50 male and 50 female B6C3F1 mice
were fed diets containing 2.5 or 5 ppm technical grade dleldrln for 80
weeks, followed by a 10- to 13-week observation period before sacrifice.
Matched control groups consisted of 20 untreated males and 10 untreated
females. Pooled controls consisted of the matched controls plus untreated
mice from bloassays with other chemicals (92 males and 79 females). There
was a significant positive dose-related trend In the Incidence of hepato-
cellular carcinomas 1n male mice when pooled controls were used for compari-
son. Incidences were 17/92 for pooled controls, 12/50 for low-dose mice and
16/45 for high-dose mice.
0092h -14- 08/24/87
-------
In the Walker et al. (1972) study, groups of 300, 125, 125 and 200 CF1
mice of each sex were fed diets containing 0, 0.1, 1.0 or 10.0 ppm dleldrln
(99+% purity), respectively, for 132 weeks. There was a dose-related
Increase In Individual and combined Incidences of benign and malignant liver
tumors In both sexes. In males, combined liver tumor Incidences were
reported as 20% for controls, 26% for low-dose, 31% for middle-dose and 94%
for high-dose mice. In females, combined liver tumor Incidences were
reported as 13% for controls, 27% for low-dose, 37% for middle-dose and 92%
for high-dose mice. Survival of high-dose mice was reduced relative to
controls.
4.2.2. Inhalation. Inhalation studies of the carclnogenldty of dleldrln
could not be located In the available literature.
4.3. OTHER RELEVANT INFORMATION
Dleldrln has given negative results In mutagenlclty assays with micro-
organisms. Including Salmonella typh1mur1um with or without metabolic
activation (U.S. EPA, 1980a; Ashwood-Smlth, 1981). Ashwood-Smlth (1981)
reported that mutagenlclty findings In several mammalian studies were
equivocal because of a lack of positive controls or a dose-response rela-
tionship or both. Bldwell et al. (1975) and Dean et al. (1975) reported
that dleldrln gave negative results In several mammalian mutagenlclty assays.
4.4. WEIGHT OF EVIDENCE
IARC (1982) classified dleldrln as a Group 3 compound. I.e., a compound
that could not be classified according to Us carclnogenldty. This classi-
fication probably reflects categorizing the evidence for carclnogenldty In
animals as "limited,* based on the observation that the only tumor type con-
sistently associated with treatment was liver tumors 1n mice, which are
0092h -15- 08/24/87
-------
known to have a high background Incidence. According to the U.S. EPA
classification scheme (U.S. EPA, 1986a), dleldrln belongs In Group 82, I.e.,
Probable Human Carcinogen, which reflects sufficient evidence for carclno-
genldty to animals there being multiple studies with liver tumor responses
In mice which withstand the downgrading provisions of the U.S. EPA cancer
guidelines. Also, some evidence of carcinogenic activity 1s seen 1n a
second species, the rat (U.S. EPA, 1986b).
0092h -16- 12/10/87
-------
5. REGULATORY STANDARDS AND CRITERIA
The U.S. EPA (1980a) derived cancer-based ambient water quality criteria
for dleldrln using data from the Walker et al. (1972) mouse study. The
recommended criteria corresponding to an Incremental Increase In excess
lifetime cancer risk of 10~>, 10~» and 10~7 were 0.71, 0.071 and
0.0071 ng, respectively. These estimates were made to protect against dlel-
drln exposure through Ingestlon of contaminated water and aquatic organisms.
Estimates made for the consumption of aquatic organisms only are 0.76, 0.076
and 0.0076 ng/l, respectively.
Vettorazl (1975) reported an FAO/WHO ADI of 0.0001 mg/kg/day for aldrln
plus dleldrln. ACGIH (1986) and OSHA (1983) have recommended 0.25 mg/m3
as a criterion for dleldrln In the atmosphere. In recommending this TLV,
ACGIH (1986) noted that the TLV was believed to be sufficiently low to
prevent systemic toxlclty.
OQ92h -17- 08/24/87
-------
6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
Because dleldrln 1s classified as a carcinogen, no RfDSQ or ..
will be derived.
6.2. REFERENCE DOSE (RfO)
Because dleldrln 1s classified as a carcinogen, no RfDQ or RfD. will
be derived.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. Thirteen data sets are suitable for quantitative risk
estimation. The most sensitive sex and strain tested Is male CF, mice In
the Thorpe and Walker (1973) study shown In Table 6-1. From these data
(Tables 6-1 through 6-13) the potency can be estimated at 55 per mg/kg/day.
The most sensitive species tested 1s mice. There are 13 potency
estimates, ranging from 55 down to 7 per mg/kg/day, with a geometric mean of
16 per mg/kg/day. Therefore the potency for the general population or human
q,* 1s estimated at 16 per mg/kg/day.
These estimates are plausible upper bounds for the Increased cancer risk
from dleldrln, meaning that the true risk 1s not likely to exceed these
estimates and may be lower. This estimate of oral carcinogenic potency Is
adopted for the purposes of this document.
Review of the CBI file for dleldrln did not reveal any Information that
would modify this assessment.
6.3.2. Inhalation. Data are Insufficient to calculate an Inhalation
q * for dleldrln.
0092h -18- . 08/24/87
-------
TABLE 6-1
Cancer Data Sheet for Derivation of Potency of OleldMn
from Tumor Incidence In
Compound: dleldrln
Species, Strain, Sex: mouse, CF-j, male
Body Weight: 0.030 kg (assumed)
Length of Experiment: 110 weeks
Length of Exposure: 110 weeks
Tumor Site and Type: liver
Route, Vehicle: oral, diet
Human Potency (ql*): 55 per mg/kg/day
Experimental
Dose (ppm)
0
10
Average Dally
Dose (mg/kg/day)
0.00
1.30
Human Equivalent
Dose (mg/kg/day)*
0.000
0.098
Tumor
Incidence*
11/45
30/30
tSource: Thorpe and Walker, 1973
*Note: To calculate human potency, a tumor Incidence of 29/30 was used and
the dose was adjusted to 29/30 of the.above value.
0092h -19- 08/24/87
-------
TABLE 6-2
Cancer Data Sheet for Derivation of Potency of D1eldr1n
from Tumor Incidence 1n Mice*
Compound: dleldrln
Species, Strain, Sex: mouse, CF-j, female
Body Weight: 0.030 kg (assumed)
Length of Experiment: 110 weeks
Length of Exposure: 110 weeks
Tumor Site and Type: liver
Route, Vehicle: oral, diet
Human Potency (ql*): 26 per mg/kg/day
Experimental
Dose (ppm)
Average Dally
Dose (mg/kg/day)
Human Equivalent
Dose (mg/kg/day)
Tumor
Incidence
0
10
0.00
1.30
0.000
0.104
10/44
26/30
^Source: Thorpe and Walker, 1973
0092h
-20-
08/24/87
-------
TABLE 6-3
Cancer Data Sheet for Derivation of Potency of 01eldr1n
from Tumor Incidence In M1cet
Compound: technical-grade dleldrln
Species, Strain, Sex: mice, B6C3F-), male
Body Weight: 0.030 kg (assumed)
Length of Experiment: 93 weeks
Length of Exposure: 80 weeks
Tumor Site and Type: liver, carcinoma
Route, Vehicle: oral, diet
Human Potency (ql*): 9.8 per mg/kg/day
Experimental
Dose (ppm)
Transformed
Dose (mg/kg/day)
Human Equivalent
Dose (mg/kg/day)*
Incidence
No. Responding/
No. Examined
0
2.5
5
0
0,325
0.65
0
0.026
0.052
17/92
12/50
16/45
tSource: Thorpe and Walker, 1977a
*Note: Human equivalent doses were multiplied by 80/93 to reflect exposure
less than the duration of the experiment.
0092h
-21-
08/24/87
-------
TABLE 6-4
Cancer Data Sheet for Derivation of Potency of D1eldr1n
from Tumor Incidence 1n
Compound: dleldrln
Species, Strain, Sex: mice, C3H, male
Body Weight: 0.030 kg (assumed)
Length of Experiment: 2 years
Length of Exposure: 2 years
Tumor Site and Type: liver, carcinoma
Route, Vehicle: oral, diet
Human Potency (ql*): 22 per mg/kg/day
Experimental
Dose (ppm)
Transformed
Dose (mg/kg/day)
Human Equivalent
Dose (mg/kg/day)
Incidence
No. Responding/
No. Examined
0
10
0
1.3
0
0.104
22/73
62/71
"^Source: Davis, 1965
0092h
-22-
08/24/87
-------
TABLE 6-5
Cancer Data Sheet for Derivation of Potency of Dleldrln
from Tumor Incidence In M1cet
Compound: dleldrln
Species, Strain, Sex: mice, C3H, female
Body Weight: 0.030 kg (assumed)
Length of Experiment: 2 years
Length of Exposure: 2 years
Tumor Site and Type: liver, carcinoma
Route, Vehicle: oral, diet
Human Potency (ql*): 25 per mg/kg/day
Incidence
Experimental Transformed Human Equivalent No. Responding/
Dose (ppm) Dose (mg/kg/day) Dose (mg/kg/day) No. Examined
00 0 2/53
10 1.3 0.104 62/71
tSource: Davis, 1965
0092h -23- 08/24/87
-------
TABLE 6-6
Cancer Data Sheet for Derivation of Potency of D1eldr1n
from Tumor Incidence In M1cet
Compound: dleldrln
Species, Strain, Sex: mice, CF-|, male
Body Weight: 0.030 kg (assumed)
Length of Experiment: 33 months
Length of Exposure: 24 months
Tumor Site and Type: liver, carcinoma
Route, Vehicle: oral, diet
Human Potency (ql*): 25 per mg/kg/day
Experimental
Dose (ppm)
Transformed
Dose (mg/kg/day)
Human Equivalent
Dose (mg/kg/day)
Incidence
No. Responding/
No. Examined
0
0.1
1.0
10.0
0
0.013
0.13
1.3
0
0.001
0.01
0.104
58/288
32/124
34/111
165/176
tSource: Walker et al., 1972
0092h
-24-
08/24/87
-------
TABLE 6-7
Cancer Data Sheet for Derivation of Potency of Dleldrln
from Tumor Incidence 1n Mice*
Compound: dleldrln
Species, Strain, Sex: mice, CF-|, male
Body Weight: 0.030 kg (assumed)
Length of Experiment: 33 months
Length of Exposure: 24 months
Tumor Site and Type: liver, carcinoma
Route, Vehicle: oral, diet
Human Potency (ql*): 28 per mg/kg/day
Experimental
Dose (ppm)
Transformed
Dose (mg/kg/day)
Human Equivalent
Dose (mg/kg/day)
Incidence
No. Responding/
No. Examined
0
0.1
1.0
10.0
0.0013
0.013
0.13
1.3
0.0001
0.001
0.01
0.104
39/297
24/90
32/87
136/148
tSource: Walker et al., 1972
0092h
-25-
08/24/87
-------
TABLE 6-8
Cancer Data Sheet for Derivation of Potency of D1e1dr1n
from Tumor Incidence In N1cet
Compound: dleldrln
Species, Strain, Sex: mouse, CF-j, male
Body Weight: 0.030 kg (assumed)
Length of Experiment: 128 weeks
Length of Exposure: 128 weeks
Tumor SHe and Type: liver
Route, Vehicle: oral, diet
Human Potency (ql*): 15 per mg/kg/day
Experimental
Dose (ppm)
0
1.25
2.5
5
10
20
Average Dally
Dose (mg/kg/day)
0.00
0.16
0.33
0.65
1.30
2.60
Human Equivalent
Dose (mg/kg/day)
0.000
0.012
0.025
0.049
0.098
0.196
Tumor
Incidence
9/78
6/30
13/30
26/30
5/11
12/17
tSource: Walker et al., 1972
0092h
-26-
08/24/87
-------
TABLE 6-9
Cancer Data Sheet for Derivation of Potency of D1eldr1n
from Tumor Incidence 1n Nice*
Compound: dleldrln
Species, Strain, Sex: mouse, CF-j, female
Body Weight: 0.030 leg (assumed)
Length of Experiment: 128 weeks
Length of Exposure: 128 weeks
Tumor Site and Type: liver
Route, Vehicle: oral, diet
Human Potency (ql*): 7.1 per mg/kg/day
Experimental
Dose (ppm)
0
1.25
2.5
5
10
20
Average Dally
Dose (mg/kg/day)
0.00
0.16
0.33
0.65
1.30
2.60
Human Equivalent
Dose (mg/kg/day)
0.000
0.012
0.025
0.049
0.098
0.196
Tumor
Incidence
8/78
5/30
12/28
18/30
9/17
8/21
tSource: Walker et al., 1972
0092h
-27-
08/24/87
-------
TABLE 6-10
Cancer Data Sheet for Derivation of Potency of Dleldrln
from Tumor Incidence In M1cet
Compound: dleldrln
Species, Strain, Sex: mouse, CF-), male
Body Weight: 0.030 leg (assumed)
Length of Experiment: 110 weeks
Length of Exposure: 110 weeks
Tumor Site and Type: liver
Route, Vehicle: oral, diet
Human Potency (ql*): 18 per mg/kg/day
Experimental
Dose (ppm)
Average Dally
Dose (mg/kg/day)
Human Equivalent
Dose (mg/kg/day)
_Tumor
Incidence
0
10
0.00
1.30
0.000
0.104
25/252
113/139
"^Source: Tennekes et al., 1981
0092h
-28-
08/24/87
-------
TABLE 6-11
Cancer Data Sheet for Derivation of Potency of Dleldrln
from Tumor Incidence In H1cet
Compound: dleldrln
Species, Strain, Sex: mouse, C57BL/6J, male
Body Weight: 0.030 kg (assumed)
Length of Experiment: 132 weeks
Length of Exposure: 85 weeks
Tumor Site and Type: Hver, hepatocellular carcinoma
Route, Vehicle: oral, diet
Human Potency (ql*): 7.4 per mg/kg/day
Experimental
Dose (ppm)
0
10
Average Dally
Dose (mg/kg/day)
0.00
1.30
Human Equivalent
Dose (mg/kg/day)*
0.000
0.104
Tumor
Incidence
0/69
21/71
^Source: Helerhenry et al., 1983
*Note: Human Equivalent doses were multiplied by 85/132, to reflect exposure
less than the duration of the experiment.
0092h -29- 08/24/87
-------
TABLE 6-12
Cancer Data Sheet for Derivation of Potency of Dleldrln
from Tumor Incidence In M1cet
Compound: dleldrln
Species, Strain, Sex: mouse. C3H/He, male
Body Weight: 0.030 kg (assumed)
Length of Experiment: 132 weeks
Length of Exposure: 85 weeks
Tumor Site and Type: liver, hepatocellular carcinoma
Route, Vehicle: oral, diet
Human Potency (ql*): 8.5 per mg/kg/day
Experimental Average Dally Human Equivalent Tumor
Dose (ppm) Dose (mg/kg/day) ' Dose (mg/kg/day)* Incidence
0 0.00 0.000 6/50
10 1.30 0.104 19/50
^Source: Helerhenry et al., 1983
*Note: Human Equivalent doses were multiplied by 85/132, to reflect exposure
less than the duration of the experiment.
0092h -30- 08/24/87
-------
TABLE 6-13
Cancer Data Sheet for Derivation of Potency of Dleldrln
from Tumor Incidence 1n M1cet
Compound: dleldrln
Species, Strain, Sex: mouse, B6C3F], male
Body Weight: 0.030 kg (assumed)
Length of Experiment: 132 weeks
Length of Exposure: 85 weeks
Tumor SHe and Type: liver, hepatocellular carcinoma
Route, Vehicle: oral, diet
Human Potency (ql*): 11 per mg/kg/day
Experimental
Dose (ppm)
Average Dally
Dose (mg/kg/day)
Human Equivalent
Dose (mg/kg/day)*
Tumor
Incidence
0
10
0.00
1.30
0.000
0.104
3/76
26/62
tSource: Helerhenry et al., 1983
*Note: Human Equivalent doses were multiplied by 85/132, to reflect exposure
less than the duration of the experiment.
Q092h
-31-
08/24/87
-------
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986.
Documentation of the Threshold Limit Values, 4th ed. Cincinnati, OH.
p. 196.
Agarwal, S.P. and A. Ahmad. 1979. Effects of. pesticides on reproduction In
mammals. Pesticides. 12(4): 33-38. (Taken from PESTAB 18010527)
Ahdaya, S. and F.E. Guthrle. 1982. Stomach absorption of Intubated Insec-
ticides In fasted mice. Toxicology. 22(4): 311-317.
Ahdaya, S.M., P.V. Shah and F.E. Guthrle. 1978. Comparative penetration
(In vivo) of Insecticides through the skin and gastrointestinal tract of
mice. Toxlcol. Appl. Pharmacol. .45(1)): 320.
Ashwood-Smlth, M.J. 1981. The 'genetic toxicology of aldrln and dleldrln.
Mutat. Res. 86(2): 137-154.
Bandyopadhyay, S.K., R.K. T1war1, A. Ultra, B. Mukherjee, A. Banerjee and
C.C. Chatterjee. 1982. Effects of L-ascorblc add supplementation on
dleldrln toxlclty In rats. Arch. Toxlcol. 50(3-4): 227-232.
Bldwell, K., E. Waber, I. Nalnhold, T. Connor and M.S. Legator. 1975.
Comprehensive evaluation for mutagenlc activity of dleldrln. Mutat. Res.
31(5): 314.
0092h -32- 08/24/87
-------
Cabral, 3.R., R.K. Hall, S.A. Bronczyk and P. Shublk. 1979. A cardnogen-
Idty study of the pesticide dleldrln 1n hamsters. Cancer Lett. 6(4-5):
241-246.
Chernoff, N., R.J. Kavlock, J.R. Kathreln, J.M. Dunn and J.K. Haseman.
1975. Prenatal effects of dleldrln and photodleldMn In mice and rats.
Toxlcol. Appl. Pharmacol. 31: 302-308.
Clegg, D.J. 1979. Animal reproduction and cardnogenlclty studies 1n
relation to human safety evaluation. Dev. Toxlcol. Occup. Hed. 4: 45-59.
Davis, K.J. 1965. Pathology report on mice fed aldMn, dleldrln, hepta-
chlor or heptachlor epoxlde for two years. Int. Food Drug Admin. (Cited In
U.S. EPA, 1980a)
Davis, K.J. and O.G. FUzhugh. 1962. Tumor 1 gen 1c potential of aldrln and
dleldrln for mice. Toxlcol. AppT. Pharmacol. 4: 187-189.
Dean, B.J., S.M.A. Doak and H. Somervllle. 1975. Potential mutagenlclty of
dleldrln (HEOD) In mammals. Food Cosmet. Toxlcol. 13: 317-323.
Delchmann, U.B. 1981. Halogenated cyclic hydrocarbons. In.: Patty's
Industrial Hygiene and Toxicology, Vol 2B, 3rd ed., G.D. Clayton and F.E.
Clayton, Ed. John Wiley and Sons Inc., New York. p. 3603-3769.
Delchmann, W.B.. H. Ke^Hnger, I.S. Dressier and U.B. Salaf. 1969. Reten-
tion of dleldrln and DDT In the tissues of dogs fed aldrln and DDT Individ-
ually and as a mixture. Toxlcol. Appl. Pharmacol. 14(2): 205-213.
0092h -33- 08/24/87
-------
Delchmann, H.B., W.E. MacDonald, E. Blum, et al. 1970. TumoMgenlclty of
aldMn, dleldrln and endrln In the albino rat. Ind. Med. Surg. 39(10):
426-434.
Den Tonkelaar, E.M. and G.J. Van Esch. 1974. No effect levels of organo-
chloMne pesticides based on Induction of mlcrosomal liver enzymes In short-
term toxVclty experiments. Toxicology. 2(4): 371-380.
Dlx, K.M., C.L. Van Der Paum and H.V. McCarthy. 1977. Toxlclty studies
with dleldrln: Teratologlcal studies 1n mice dosed orally with HEOO.
Teratology. 16(1): 57-62.
Enrich, M., R. Quellette and S.O. Cohen. 1976. Toxlcologlc Interactions
Involving dlchlorvos (DDVP). Toxlcol. Appl. Pharamcol. 37(1): 105-106.
FHzhugh, O.G., A.A. Nelson and M.L. Qualfe. 1964. Chronic oral toxldty
of aldrln and dleldrln 1n rats and dogs. Food Cosmet. Toxlcol. 2: 551-562.
Good, E.E. and G.W. Ware. 1969. Effects of Insecticides on reproduction In
the laboratory mouse: IV. Toxlcol. Appl. Pharmacol. 14(1): 201-203.
Hansch C. and A.J. Leo. 1985. Medchem Project Issue No. 26. Pomona
College, Claremont, CA.
Harr, J.R., R.R. Claeys and N. Benedict. 1970a. Dleldrln toxicosis In
rats: Long-term study of brain and vascular effects. Am. J. Vet. Res.
32(10): 1853-1862.
0092h -34- 08/24/87
-------
Harr, J.R., R.R. Claeys, J.F. Bone and T.H. McCorcle. 1970b. DleldMn
toxicosis: Rat reproduction. Am J. Vet Res. 31: 181-189.
Hawker, O.H. and D.W. Connell. 1986. Bloconcentratlon of I1poph1l1c com-
pounds by some aquatic organisms. Ecotoxlcol. Environ. Safety. 11: 184-197.
Heath, D.F. and M. Vandekar. 1964. Tox1c1ty and metabolism of cHeldrln In
rats. Br. 0. Ind. Med. 21: 269. (Cited 1n U.S. EPA, 1980a)
Hodge, H.C., A.M. Boyce. W.B. Delchmann and H.F. KraybUl. 1967. Toxicol-
ogy and no-effect levels of aldrln and dleldrln. Toxlcol. Appl. Pharmacol.
10: 613-675.
HSOB (Hazardous Substance Data Bank). 1986. Report No. 322. On-line: 1986.
Hunter, C.G., J. Robinson and M. Roberts. 1969. Pharmacodynamlcs of
dleldrln (HEOD). Ingestlon by human subjects for 18 to 24 months, and post-
exposure for eight months. Arch. Environ. Health. 18(1): 12-21.
IARC (International Agency for Research on Cancer). 1982. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Chemicals
Industrial Processes and Industries Associated with Cancer In Humans. WHO,
IARC, Lyons, France. Supplement 4, p. 35-37.
Jager, K.H. 1970. Aldrln, 01eldr1n, Endrln and Telodrln. An Epldemlologl-
cal and lexicological Study of Long-Term Occupational Exposure. Elsevler
Publ. Co., New York. p. 60, 121-131. (Cited In IARC, 1974)
0092h -35- 08/24/87
-------
Oones, D.C., W.E. Davis, G.W. Newell, D.P. Sasmore and V.J. Rosen. 1974.
Modification of hexachlorophene tox1c1ty by dleldrln and Arochlor 1254.
Toxicology. 2(3): 309-318.
Kanazawa, 0. 1981. Measurement of the bloconcentratlon factors of pesti-
cides by freshwater fish and their correlation with phys1cochem1cal proper-
ties or acute tox1c1t1es. Pestle. Sc1. 12: 417-424.
Kepllnger, M.L., W.B. Delchman and F. Sala. 1968. Effects of combinations
of pesticides on reproduction In mice. Ind. Med. Surg. 37(7): 525.
Menzer, R.E. 1970. Effect of chlorinated hydrocarbons In the diet on the
toxlclty of several organophosphorus Insecticides. Toxlcol. Appl.
Pharmacol. 16(2): 446-452.
Melerrhenry, E.F., B.H. Reuber, H.E. Gershwin, L.S. Hsleh and S.W. French.
1983. Dleldrln-lnduced mallory bodies In hepatic tumors of mice of
different strains. Hepatology. 3: 90-95.
NCI (National Cancer Institute). 1977a. Bloassay of aldrln and dleldrln
for possible carclnogenlcHy. NCI Cardnogenesls Tech. Rep. Ser. No. 21
(Also Published as NTIS PB-275 666.) NCI-CG-TR-21.
NCI (National Cancer Institute). 1977b. Bloassay of dleldrln for possible
carclnogenlcHy. NCI Carc1nogenes1s Tech. Rep. Ser. No. 22. (Also
published as NTIS PB-275-676)
0092h -36- 08/24/87
-------
OSHA (Occupational Safety and Health Administration). 1983. OSHA Safety
and Health Standards. 29 CFR 1910.1000.
Qualfe, J.S. and M.L. FHzhugh. 1967. Survey of quantitative relationships
between Ingestlon and storage of aldrln and dleldrln 1n animals and man.
Food Cosmet. Toxlcol. 5(1): 39-50.
Reuber, M.D. 1980. Significance of acute and chronic renal disease In
Osborne-Hendel rats Ingesting dleldrln or aldrln. Clln. Toxlcol. 17(2):
159-170.
Shakoorl, A.R., Y.6. Rasul and S.S. A11. 1984. The effect of long-term
administration of dleldrln on biochemical components In blood serum of
albino rats. Folia B1ol (CRACOW). 32(3.): 213-222.
Smith, R.M. 1973. Successive discrimination reversal and dleldrln toxldty
In the squirrel monkey (Sa1m1r1 sclureus). D1ss. Abstr. Int. B. 33(8):
3997.
Tanaka, R., S. Fujlsaua and K. Nakal. 1981. Absorption and protein binding
of carbaryl, dleldrln and paraquat In rats on a protein diet. J. Toxlcol.
Sc1. 6(1): 1-12.
Tennekes, H.A., A.S. Wright, K.M. D1x and 3.H. Koeman. 1981. Effects of
dleldrln, diet and bedding on enzyme function and tumor Incidence 1n livers
of male CF-1 mice. Cancer. Res. 41: 3615-3620.
0092H -37- 08/24/87
-------
Thomas, J.A., L.G. Scheln, H.D. Colby and W.J. Canady. 1974. Interaction
of dleldrln and parathlon on androgen metabolism 1n the prostate and on
hepatic p-450 activity In mice. Pharmacologist. 16(2): 229.
Thorpe, E. and A.I. Walker. 1973. Toxlclty of dleldrln (HEOD). II. Com-
parative long-term oral toxldty studies 1n mice with dleldrln, DOT, pheno-
barbHone, beta-BHC and gamma-BHC. Food Cosmet. Toxlcol. 11(3): 433-443.
Treon, J.F. and P.P. Cleveland. 1955. Toxlclty of certain chlorinated
hydrocarbon Insecticides for laboratory animals with special reference to
aldrln and dleldrln. Agrlc. Food Chem. 3(5): 402-408.
U.S. EPA. 1980a. Ambient Water Quality Criteria for Aldr1n/D1eldr1n. Pre-
pared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH, for the Office of Water
Regulations and Standards, Washington, DC. EPA 440/5-80-018. NTIS PB
81-117301.
U.S. EPA. 1980b. Hazard Profile for Dleldrln. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH, for the Office of Solid Waste, Washington, DC.
U.S. EPA. 1980c. Guidelines and Methodology for the Preparation of Health
Effect Assessment Chapters of the Ambient Water Quality Criteria Documents.
Federal Register. 45(231): 79347-79357.
0092h -38- 08/24/87
-------
U.S. EPA. 1984. Methodology and guidelines for reportable quantity deter-
mlnatlons based on chronic tox1c1ty data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH, for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986a. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986b. Draft Carcinogenic Risk Assessment for Aldrln and D1el-
drln. Carcinogenic Assessment Group, Office of Health Effects Assessment,
Washington, DC. EPA Contract No. 68-02-4131.
Uzoukwu, M. and S.D. Sleight. 1972. Dleldrln toxicosis: Fetotoxlcosls,
tissue concentrations and microscopic and ultrastructural changes In guinea
pigs. Am. J. Vet. Res. 33(3): 579-583.
Van Gelder, G.A. and R.M. Smith. 1973. Delayed acquisition of a successive
reversal behavioral task 1n d1eldr1n-dosed squirrel monkeys. Toxlcol. Appl.
Pharmacol. 25(3): 485.
Van Raalte, H.G.S. 1977. Human experience with dleldrln In perspective.
Ecotoxlcol. Environ. Saf. 1: 203. (CHed In U.S. EPA, 1980a)
Versteeg, 3.P.J. and K.W. Jager. 1973. Long-term occupational exposure to
the Insecticides aldrln, dleldrln, endrln and telodrln. Br. J. Ind. Med.
30: 201. (Cited In U.S. EPA, 1980a)
0092H -39- 08/24/87
-------
Vettorazzl. G. 1975. State of the art of the toxlcologlcal evaluation
carried out by the joint FAQ/WHO expert committee on pesticide residues. I.
Organohalogenated pesticides used 1n public health and agriculture. Residue
Reviews. 56: 107-134.
Walker, A.I.T., D.E. Stevenson, J. Robinson, E. Thorpe and M. Roberts.
1969. The toxicology and pharmacodynamlcs of dleldrln (HEOD): Two-year oral
exposure of rats and dogs. Toxlcol. Appl. Pharmacol. 15(2): 345-373.
Walker, A.KT., E. Thorpe and D.E. Stevenson. 1972. The toxicology of
dleldrln (HEOD): I. Long-term oral toxldty studies In mice. Food Cosmet.
Toxlcol. 11: 415-432.
Wright, A.S., C. Donntnger, R.D. Greenland, K.L. Stemmer and M.R. Zavon.
1978. The effects of prolonged Ingestlon of dleldrln on the'livers of male
rhesus monkeys. Ecotoxlcol. Environ. Saf. 1(4): 477-502.
Zoeteman, B.C.J., K. Harmsen, O.B.H.J. Llnders, C.F.H. Morra and W. Slooff.
1980. Perslstant organic pollutants In river water and groundwater of the
Netherlands. Chemosphere. 9: 243.
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