TECHNICAL REPORT DATA
(fltae ntd liaaucnom on tht men* btfort eomplttiitgl
IT. Wc»"QP»T NO.
EPA/600/8-88/034
2.
3. RE CLIENT'S ACCESSION NO.
PB88-180229/AS
M. TITLE AND SUBTITLE
6. REPORT DATE
Health Effects Assessment for alpha- and beta-Endo-
sulfan
«. PERFORMING ORGANIZATION CODE
T. AUTHOR(S)
•. PERFORMING ORGANIZATION REPORT NO.
ERrORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
13. TYPE OF REPORT AND PERIOD COVERED
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
14. SPONSORING AGENCY CODE
EPA/600/22
SUPPLEMENTARY NOTES
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 12991 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, RfD$ 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 RfO is an estimate of an exposure level that would not
toe expected to cause adverse effects when exposure occurs for a significant portion
c»f the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
fnfralation data if available.
T.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
6.IOENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
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Public
19. SECURITY CLASS (Thit Rtportj
Unclassified
21. NO. OF PAGES
20. SECURITY CLASS (THUftgt)
Unclassified
22. PRICE
KM P«* 2220.1 (••*. 4-77)
COITION i» OMOLKTI
A
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EPA/600/8-88/034
Hay, 1987
HEALTH EFFECTS ASSESSMENT
FOR ALPHA- AND BETA-ENDOSULFAN
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI. OH 45268
Iwvironciental Protect!-,n /i£ei
-------
DISCLAIMER
This document has been reviewed 1n 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 <*- and
B-endosulfan. All estimates of acceptable Intakes and carcinogenic potency
presented 1n this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
TOXLINE. CANCERLINE and the CHEMFATE/ CATALOG data bases. The basic litera-
ture searched supporting this document 1s current up to Hay, 1986. Secon-
dary sources of Information have also been relied upon 1n 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 Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria for Endosulfan.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Mater Regulations and Standards, Washington, DC. EPA
UO/5-80-046. NTIS PB81-117574.
U.S. EPA. 1986a. Integrated Risk Information System (IRIS).
Reference Dose (RfD) for Oral Exposure for Endosulfan. Online
(verification date 6/11/86; data Input pending). Office of Health
and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH.
The Intent 1n these assessments 1s to' suggest acceptable exposure levels
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 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 1s not the endpolnt of
concern). The first, RfO$ (formerly AIS) or subchronlc reference dose, 1s
an estimate of an exposure level that would not bo 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 llfespan).
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 In 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$i) and oral (RfO$o)
exposures.
111
-------
The RfD (formerly AIC) 1s similar 1n concept and addresses chronic
exposure. It 1s 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 (19805) 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 noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained In U.S.
EPA (1983).
For compounds for which there 1s sufficient evidence of cardnogenldty
RfOg and RfO values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer 1s a
process that Is 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 1f 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.
An RfDso of 0.01 rag/day was calculated for endosulfan from a LOAEL for
nephrotoxldty 1n rats 1n a 2-generat1on reproduction study (Huntingdon
Research Centre, 1984). An RfQg of 0.001 mg/day was calculated from the
same study. Mice appeared to be more sensitive than rats or dogs to the
effects of endosulfan. A CS of 50 based on mortality 1n mice was calculated
from a 73-week oral study.
Data were not available for Inhalation toxIcHy of endosulfan. The oral
studies In rats and mice are Inadequate to clearly assess the carcinogenic
potential of endosulfan.
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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 1n 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 Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith 01 sen 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.
4.
5.
6.
ENVIRONMENTAL FATE AND TRANSPORT
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
ORAL
INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS '
CARCINOGENICITY "
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK
6.1.
ASSESSMENT
SUBCHRONIC REFERENCE DOSE (RfDS)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDci)
Page
1
. . . 3
. . . 3
. . . 3
4
4
. . . 4
. , . 6
. . . 6
. . . 6
. . . 9
. . . 9
. . . 9
. . . 11
11
. . . 12
. . . 12
. . . 12
. . . 12
. . . 13
. . . 13
. . . 14
. . . 15
16
16
. . . 16
. . . 17
V11
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TABLE OF CONTENTS (cont.)
Page
6.2. REFERENCE DOSE (RfD) ................... 17
6.2.1. Oral (RfDn) ................... 17
6.2.2. Inhalation (RfD) ................ 20
7, REFERENCES ............................ 21
APPENDIX ............................... 28
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LIST OF ABBREVIATIONS
AOI Acceptable dally Intake
CNS Central nervous system
CS Composite score
DMSO Dimethyl sulfoxide
LOAEL Lowest-observed-adverse-effect level
LOEL Lowest-observed-effect level
MED Minimum effective dose
NOEL No-observed-effect level
ppm Parts per million
RfD Reference dose
RfDj Inhalation reference dose
RfDg Oral reference dose
RfDjj Subchronlc Inhalation reference dose
RfD$g Subchronlc oral reference dose
RQ Reportable quantity
RVd Dose-rating value
RVe Effect-rating value
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected physical and chemical properties and environmental fate of
a- and B-endosulfan are listed 1n Table 1-1.
Endosulfan sulfate Is a potential major transformation product of
a- and B-endosulfan In water and soil (Callahan et al.t 1979; Sanborn et
a!., 1977). The dominant pathways for removal of a- and B-endosulfan from
water at pH <7 are not known. The estimated oxidation half-life for the
Isomers 1n water Is 70 days at 20°C, and the estimated hydrolysis at pH 5.5,
7 and 8 Is 170, 35 and 3.5 days, respectively (Callahan et al., 1979). The
hydrolysis half-life of endosulfan at 30'C varies from 0.5 hours to 90 days
1n the pH range of 9.0-4.5 (Singh et al., 1986). Therefore, hydrolysis Is
Important In waters at pH >7. The a- and B-endosulfan Isomers should
strongly adsorb to soil and remain primarily within the upper few centi-
meters. Technical endosulfan Is >95% pure and Is composed of two steMo-
Isomers, a- and B-endosulfan (U.S. EPA, 1980a). The technical product
consists of "70% a-endosulfan and -30% B-endosulfan.
0065h -1- 07/29/86
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TABLE 1-1
Selected Physical and Chemical Properties and Half-Lives
for a- and B-Endosulfan
Property
Value
Reference
CAS number:
Chemical class:
Molecular weight:
Melting point:
Vapor pressure:
Hater solubility:
Log octanol/water
partition coefficient:
Soil adsorption
coefficient:
Half-lives In water:
a-: 959-98-8
Q-: 33213-65-4
chloroorganlc pesticide
406.95
o-: 108-110°C
B-: 207-209°C
<*- and 8- mixture:
IxlO'5 mm Hg at 25°C
a-: 0.32 mg/i at 20*C
B-: 0.33 mg/t, at 20'C
a-: 3.83
Bloconcentratlon factor: a-:
B-:
17-999 (algae)
1336-5763 (snail)
30-304 (fish)
44-3863 (algae)
8174-39,457 (snail)
90 and 388 (fish)
Half-lives 1n soil:
Technical grade: 328-2755 (fish)
a- and B-: 2900 (estimated)
<1-170 days (dependent on pH)
a-: 60 days
B-: 800 days
Callahan
et al.f 1979
Callahan
et al.. 1979
Worthing,
1983
Hansch and
Leo, 1985
Callahan
et al., 1979
Cal iahan
et «n., 1979
U.S, EPA.
1980a
Lyman
et crl., 1982
lal ahan et
al., 1979;
Singh
et al., 1986
Sanborn
et al., 1977
0065h
-2-
04/23/87
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
The <*- and B- Isoroers of [14C]-endosulfan were administered to rats
separately as single 2 rog/kg oral doses 1n corn oil (Dorough et al.t 1978).
No appreciable differences were observed 1n the fecal (or urine) elimination
of radioactivity of the two Isomers. Approximately 11 and 13%, 55 and 62%
and 68 and 75% of the administered radioactivity was eliminated 1n the feces
at 24, 48 and 120 hours after treatment with the »- and B- Isomers,
respectively. Analyses of bile collected for 48 hours showed that -47% of
the a-endosulfan dose and 29% of the B-endosulfan dose was eliminated by
this route. Enterohepatlc circulation was not demonstrated, since bile duct
cannulatlon did not alter the amount of radioactivity excreted Into the
urine. These data and the results of bile duct cannulatlon experiments at
48 hours suggest that gastrointestinal absorption of endosulfan was on the
order of 40%.
Ma1er-8ode (1968) Indicated that undiluted endosulfan Is slowly and
Incompletely absorbed from the mammalian gastrointestinal tract. Further
Information was not provided.
2.2. INHALATION
Pertinent data regarding the absorption of a- or B-endosulfan follow-
ing Inhalation exposure could not be located 1n the available literature.
0065h -3- 07/29/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
Toxldty studies of endosulfan typically evaluated the technical grade
products, which are mixtures of the a- and 8- Isomers.
3.1. SUBCHRONIC
3.1.1. Oral. Gupta and Gupta (1977) administered dally gavage doses of
0, 1.0, 2.5 and 5.0 mg/kg to rats for 7-15 days. At the 2.5 and 5.0
mg/kg/day levels, relative liver weight Increased and pentobarfoltol-lnduced
sleeping time decreased, Indicating possible Induction of hepatite mlcrosomal
enzymes; however, no effects on organ weights or sleeping time occurred at 1
mg/kg/day. In another experiment, Den Tonkelaar and van Esch (1974) deter-
mined NOELs for Induction of various liver mlcrosomal enzymes 'in male rats.
For endosulfan, the NOEL and LOEL for Induction were 50 and 200 ppm In the
diet administered for 2 weeks. The authors stated that this value agrees
with a NOEL of 50 ppm for h1stopatholog1cal liver abnormalities In a long-
term experiment from an unspecified unpublished report. Assuming a rat
consumes food equivalent to 5% of Us body weight/day (U.S. EPA, 19805), the
NOEL and LOEL are 2.5 and 10 mg/kg/day, respectively.
Female rats administered a diet containing 50 ppm (2.5 mg/kg/day) for 28
days exhibited no effects on body weight gain, relative liver or kidney
weights or Induction of liver mlcrosomal oxldase enzymes (Dorough et al.,
1978). Oral administration of 2.5 or 7.5 mg/kg/day for 60 days resulted 1n
Increased relative liver and lung weights 1n male rats (Ansarl et al.,
1984). In another study, rats given oral dosages of 5 mg/kg/day for 30 days
showed signs of toxlclty (hyperexcltabHlty, tremor, dyspnea and saliva-
tion), which disappeared after 3-4 days; however, there were no changes 1n
relative organ weights or biochemical, limited histologlcal, hematologlcal
Q065h -4- 10/24/86
-------
and fertility parameters (Olkshlth et al., 1984). These authors also
reported NOELs of 0.75 and 2.5 mg/kg/day In males and 0.25 and 0.75 mg/kg/
day In females. ACGIH (1986) reported that rats tolerated oral doses up to
3.2 mg/kg/day for 3 months without Injury, but additional Information
regarding this study (Czech, 1958) was not reported.
NCI (1978) conducted preliminary subchronlc studies 1n which groups of
five male and five female Osborne-Mendel rats and five male and five female
B6C3F1 mice were exposed for 6 weeks to the following endosulfan concentra-
tions In the diet: rats - 0, 178, 316, 562, 1000 and 1780 ppm; mice - 0,
3.2, 5.6, 10, 18 and 32 ppm. The animals were observed for an additional 2
weeks. In male rats, body weights were depressed 9% at 562 ppm and 10% at
1000 ppm. In male and female mice, body weights were depressed at >5.6 ppm.
One female died at 5.6 ppra, one male died at 10 ppm and, at the higher
concentrations, mortality Increased In both sexes of mice with Increasing
dosage. In rats, dose-related body weight depression occurred 1n males only
at concentrations >562 ppm; deaths occurred In males at 1780 ppm and females
at 316 and 562 ppm, but mortality did not appear to be dose-related.
Indices other than body weight and mortality were not evaluated. If 1t Is
assumed that rats and mice consume food equivalent to 5 and 13% of their
body weight In food/day, respectively (U.S. EPA. 1980t>), the rat 178 ppm
NOEL reflects 8.9 mg/kg/day dosage and the mouse 3.2 ppm NOEL reflects 0.4
mg/kg/day dosage.
U.S. EPA (1982) summarized several unpublished Hazleton Laboratories and
FMC Corp. studies, which appear to be the same as those described briefly by
Maler-Bode (1968), ACGIH (1986) and Vettorazzl (1975). One of these was a
subchronlc study by Baran (1967), 1n which groups of four male and four
female beagle dogs were fed diets containing 0, 3, 10 or 30 ppm technical
0065h -5- 10/24/86
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grade endosulfan for 2 years. One male and one female from each group were
sacrificed after 1 year and the remaining dogs at the end of the experiment.
No treatment-related effects on gross pathology, hlstopathology,, hematology,
clinical chemistry or urine chemistry were observed. If It 1s assumed that
a dog consumes an amount of food equivalent to 2.5% of Us body weight/day
(U.S. EPA, 1986b), the 30 ppm NOEL Is equivalent to 0.75 mg/kg/day. The
U.S. EPA (1982) evaluation of this study concluded that 1t was deficient
because H did not report food consumption, body weight and organ weight
data. There were also some discrepancies In the data (for example, leuco-
cyte counts at 18 and 21 months were reported for a dog that supposedly died
after 15 months). In another subchronlc dog study (Keller, 1959a) described
by U.S. EPA (1982), groups of mongrel dogs were given endosulfan 1n gelatin
capsules at dosages of 0, 0.075, 0.25 or 0.75 mg/kg/day, 6 days/week for 1
year. No effects on growth, organ weight, biochemical and hematologlcal
parameters or urine chemistry were observed, and there were no differences
In gross pathology or hlstopathology between treated dogs and controls. The
NOEL of 0.75 mg/kg/day 1n this study Is equivalent to the 30 ppm dietary
NOEL of Baran (1967). U.S. EPA (1982) concluded that this was an adequate
subchronlc oral study In dogs.
3.1.2. Inhalation. Pertinent data regarding the toxic effects of sub-
chronic Inhalation were not located In the available literature.
3.2. CHRONIC
3.2.1. Oral. An NCI (1378) cardnogenesls bloassay was conducted In
which technical grade endo&ulfan (98.8% pure) was administered In the diets
of Osborne-Mendel rats arid B6C3F1 mice. Groups of 50 an1mals/sex/spec1es
received the endosulfan-contalnlng diets for 78 weeks, followed by an
observation period of H weeks for mice or 33 weeks for rats. Groups of 20
0065h -6- 12/17/86
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anlmals/sex/specles served as matched controls. The TWA endosulfan concen-
trations In the diet were as follows: male rats, 408 or 952 ppm; female
rats, 223 or 445 ppm; male mice, 3.5 or 6.9 ppm; and female mice, 2.0 or 3.9
ppm.
High dose-related early mortality occurred 1n both groups of treated
male rats (NCI, 1978). Ten low-dose males survived past week 80 and were
sacrificed In week 82. Six high-dose males survived past week 71 and were
sacrificed 1n week 74. H1stopatho1og1cal effects of treatment 1n rats
Included high Incidences of toxic nephropathy 1n both sexes and testlcular
atrophy In males. These effects occurred at both dosage levels and appeared
to be dose-related. The survival of the female rats was not affected by
treatment.
High early mortality, starting at week 19, occurred among treated male
mice and appeared to be dose-related, but' the association between Increased
dosage and elevated mortality was not significant according to NCI (1978).
The data are difficult to Interpret because of high mortality among the male
control mice (11/20 died at week 72, possibly because of fighting).
Survival of the male mice at the end of the experiment was 15% for controls,
28% for the low-dose and 10% for the high-dose group. NCI (1978) concluded
that deaths among the high dose male mice were not attributable to a "common
cause" and that no specific hlstopathologlcal lesions, Including toxic
nephropathy. occurred at higher Incidences In treated males than In control
males. U.S. EPA (1980a), however, reported that endosulfan treatment was
toxic to the kidneys of male mice In the NCI (1978) bloassay. Inspection of
the NCI (1978) data reveals an Increased Incidence of hydronephrosls 1n low-
dose male mice, but not 1n high-dose male mice or 1n female mice; none of
the mice had toxic nephropathy. NCI (1978) did not discuss the finding of
0065h -7- 10/24/86
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hydronephrosls 1n low-dose male mice. Survival and Incidences of hlsto-
pathological lesions In female mice were not affected by treatment.
Other than the NCI (1978) bloassay, the only studies concerning chronic
endosulfan toxlclty are an unpublished rat study (Keller, 1959b), discussed
briefly In ACGIH (1986). Haler-Bode (1968) and U.S. EPA (1982). and a
carclnogenlclty study 1n mice (BRL, 1968). In the Keller (1959b) study,
groups of 25 male and 25 female Wlstar rats were fed diets containing 0, 10,
30 or 100 ppm technical grade endosulfan for 2 years. General appearance,
behavior, food consumption or hematologlcal parameters were not affected.
Survival of high-dose females was significantly reduced. High-dose males
exhibited slight to moderate growth depression and Increased relative kidney
weights. H1stopatholog1cal effects consisting of renal tubule dilatation,
formation of albuminous casts, focal Interstitial nephritis and degeneration
of tubule eplethellum occurred In the kidneys and hydropic cells with pale
eos1noph1!1c cytoplasmlc Inclusions occurred In the livers of high-dose
males. The results of this study Indicated that a dietary concentration of
30 ppm (1.5 mg/kg/day) was a NOEL. U.S. EPA (1982), however, concluded that
this study was an Inadequate evaluation of chronic toxlclty because the
number of animals surviving 2 years and the number of animals examined were
limited and because of the lack of blood and urine chemistry analyses.
In the BRL (1968) study, survival In one or both sexes of two strains of
mice treated by gavage with 1.0 or 2.15 ppm technical grade endosulfan 1n
gelatin from 7-28 days of age and subsequently with 3 or 6 ppm, respective-
ly. In the diet for -18 months was very poor compared with gelatin-treated
controls. Survival after 18 months was 16/18, 9/18 and 1/18 In the control,
low-dose and high-dose B6C3F1 males, respectively; 18/18. 9/18 and 1/18 In
the B6C3F1 females; 18/18. 16/18 and 6/18 In the B6AKF1 males; and 15/18,
0065h -8- 10/24/86
-------
12/18 and. 8/18 1n the 86AKF1 Females. Decreased survival was not due to
tumors, but any additional Information regarding toxlclty was not reported
since this study was designed primarily to Investigate carclnogenlcHy.
3.2.2. Inhalation. Pertinent data regarding the toxic effects of chronic
Inhalation exposure to endosulfan were not located In the available
literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Teratogenldty of endosulfan has not been demonstrated 1n
oral studies with rats and rabbits. Fetotoxlc effects occurred, but only at
dosages that produced maternal toxlclty.
Gupta et al. (1978) administered 0, 5 or 10 mg/kg endosulfan by gavage
to groups of 20-32 albino rats on days 6-14 of gestation. Markedly
Increased numbers of resorptlons and a dose-related Increase 1n maternal
mortality occurred In the treated rats, but gross abnormalities were not
observed In the fetuses.
In an unpublished teratogenlclty study (Raltech Scientific Services,
1980) conducted with rats, adverse effects on the fetus were noted at 6
mg/kg. These effects Included reduced size and weight, and skeletal,
visceral and external anomalies. The dams, however, had decreased body
weights and signs of CMS stimulation. The NOEL for fetotoxlclty was 2
mg/kg. No other details. Including the route of administration, were
provided In the U.S. EPA (1982) summary of this study.
U.S. EPA (1982) also described another unpublished study (Raltech
Scientific Services, 1982) In which groups of pregnant rabbits received oral
dosages of 0.3, 0.7 or 1.8 mg/kg/day on days 6-28 of gestation. Maternal
toxlclty was apparent 1n the high-dose group; effects Included hyperactlv-
Ity, rapid breathing, convulsions and death. No treatment-related effects
0065H -9- 10/24/86
-------
1n number.of corpora lutea. Implantation efficiency, litter size, sex ratio
of offspring, mean fetal length, fetal weight or numbers of live and
resorbed fetuses were observed; however, "common skeletal variations and
anomalies11 (unspecified) occurred In all groups. U.S. EPA (1982) did not
clarify If a control group was used In thts study but concluded that a NOEL
for maternal toxlclty of 0.7 mg/kg/day was defined.
Dose-related testlcular atrophy occurred 1n rats that were treated with
408 or 952 ppm (TWA) endosulfan In the diet for up to 82 weeks (NCI, 1978).
Vettorazzl (1975) mentioned a 3-generatlon rat study In which 50 ppm endo-
sulfan In the diet had no effect on reproduction or survival, but no details
were provided.
In an unpublished 2-generatlon reproduction study In the rat (Huntingdon
Research Centre, 1984), exposure with dietary levels of 0, 3, IS and 75 ppm
endosulfan produced litter loss In the F* at both maitngs at 3 and 15 ppm
levels. At 75 ppm the effect was comparable with the control. In the F,.
generation there was a compound-related Increase In litter loss over
controls at both matings. There were no dose-related or compound-related
effects on reproductive performance, except for decreased Utter weight at
75 ppm In the F. and F_. Utters. TeratoTogtcal events were also not
observed In any of the dosages tested In the above study. Interestingly,
however, yellowish discoloration of the cells of the proximal convoluted
tubules of the kidney was found In traces In F,. males at all doses, and
In minimal amounts In males at 75 ppm only. In addition, granular clumped
pigment was observed In trace amounts In these cells; suggesting some
destructions of red blood cells In the hematopoletlc system occurring at all
doses tested In males. Therefore, the lowest dose, 3 ppm endosulfan or 0.15
mg/kg/day (based on food consumption at the rate of 554 g bw), represents a
LOAEL.
0065h -10- 10/24/86
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3.3.2. Inhalation. Pertinent data regarding the reproductive and devel-
opmental toxlclty of endosulfan by Inhalation exposure were not located In
the available literature.
3.4. TOXICANT INTERACTIONS
Two human fatalities Involved endosulfan Ingested with alcohol, although
dlroethoate was also used In one formulation (Demeter and Heyndrlckx, 1978).
Increased gastrointestinal absorption of endosulfan In the presence of
alcohols has been reported (Lendle, 1956). These data were Interpreted as
suggesting that synerglsm between alcohol and endosulfan Is likely (Demeter
and Heyndrlckx, 1978).
Dose-dependent Increased activities of amlnopyMne-N-demethylase and
aniline hydroxylase In endosulfan-treated rats suggest that endosulfan 1s an
Indueer of the mixed-function oxldase system (Agarwal et al., 1978).
0065h -11- 10/24/86
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data regarding the carclnogenlclty of endosulfan to humans
exposed orally or by Inhalation were not located 1n the available literature.
4.2. BIOASSAYS
4.2.1. Oral. An NCI (1978) bloassay of endosulfan provided no evidence
that endosulfan 1s carcinogenic. This assay was conducted with rats and
mice that were exposed 1n the diet. High early mortality occurred In the
males of both species, apparently because of toxic nephropathy In the rats
(see Section 3.2.1.). Significant Increases In the Incidence of tumors at
any site did not occur among dosed rats or mice of either sex. No conclu-
sions regarding the carclnogenlclty of endosulfan In the male rats or mice
could be drawn. because the shortened Hfespans precluded evaluation of the
occurrence of late-developing tumors. In a review of this study, U.S. EPA
(1980a) concluded that the NCI (1981) bloassay was a stringent test for
carclnogenlclty and that the negative results were valid. Reuber (1981)
re-examined hlstologlcal sections from this study and concluded that endo-
sulfan was carcinogenic, although no dose-related trends 1n the Incidence of
any particular type of tumor were found.
Endosulfan was also tested for carclnogenlclty In mice by BRL (1968).
Thlodrin, a 96X pure mixture of endosulfan Isomers, was administered to
B6C3F1 and B6AKF1 strains of mice by stomach tube at 1 or 2.15 mg/kg/day 1n
gelatin from days 7-28 of age to "18 months, followed by administration In
the diet at concentrations of 3 and 6 ppm, respectively. Both treatment
groups consisted of 18 male and 18 female mice of each strain. BRL (1968)
concluded that there was a statistically significant (p»Q.05) Increase
relative to controls In the Incidences of pulmonary adenomas and total
D065h -12- 10/24/86
-------
tumors 1n mice treated orally with endosulfan. The Incidences 1n both
strains, sexes and dose groups were pooled 1n this analysis; however, 1n a
summary of the data and results of this study, Innes et al. (1967) classi-
fied endosulfan as a compound "which did not cause a significant Increase 1n
tumors after oral administration." U.S. EPA (1980a) did not address this
apparent discrepancy explicitly, but Instead reported the conclusions of
Innes et al. (1967) and relied heavily upon the more recent NCI (1978)
bloassay to evaluate the possible cardnogenlclty of endosulfan.
4.2.2. Inhalation. Pertinent data regarding the cardnogenlclty of
endosulfan by Inhalation were not located In the available literature.
4.3. OTHER RELEVANT DATA
Endosulfan has yielded mixed results In various mutagen1c1ty assays
using Salmonella tvphlmurlum (Dorough et al., 1978; U.S. EPA, 1980a), while
negative results were obtained 1n Sacchardmyces cerevlslae. Esther 1ch.|a coll
and Serratla roarcescens (U.S. EPA, 1980a). Endosulfan was mutagenlc In
Drosophlla reelanogaster 1n the sex-linked recessive lethal and sex-chromo-
some loss tests (Velazquez et al., 1984). In mice fed endosulfan (43.3
mg/kg), there was no significant Increase 1n the frequency of polychromatic
erythrotytes with mlcronuclel (Rani et al., 1980); however, endosulfan
produced a significant Increase In frequency of sister chromatld exchanges
In cultured human lymphold cells (Sobtl et al., 1983).
BRL (1968) administered a 2.15 mg/kg dose of endosulfan in OMSO to
groups of 18 male and 18 female 28-day-old B6C3F1 and B6AKF1 mice by subcu-
taneous Injection. The mice were sacrificed after an 18-month observation
period and examined for pulmonary adenomas. The Incidence of adenomas 1n
treated rats did not differ significantly from that 1n controls.
0065h -13- 10/24/86
-------
4.4. HEIGHT OF EVIDENCE
Endosulfan has been tested for carclnogenldty In rats (NCI. 1978) and
mice (NCI, 1978; BRL, 1968; Innes et al.t 1967) In chronic oral studies with
negative and Inconclusive results. U.S. EPA (1980a) concluded that endo-
sulfan was not carcinogenic. Given the Inconcluslveness of one NCI bloassay
and the difference of opinion about the BRL assay, the criteria for two
clearly negative studies 1s not met and the animal data base Is Judged to be
Inadequate. Endosulfan 1s, therefore, most appropriately classified In EPA
Group 0 (U.S. EPA, 1986c).
0065h -14- 12/17/86
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5. REGULATORY STANDARDS AND CRITERIA
U.S. EPA (1980a) derived an RfO for endosulfan of 0.028 rag/day for a 70
kg human from the low dietary concentration (2 ppm) In the NCI (1978) study
In mice. This RfO was used as the basis for an ambient water quality
criterion of 75 yg/l. The FAO/WHO (Vettorazzl, 1975) has adopted an RfO
of 0.0075 mg/kg/day for a- and 8-endosulfan and endosulfan sulfate, based
on the NOEL of 0.75 mg/kg/day In dogs exposed 6 days/week for 1 year
(Keller, 1959a).
ACGIH (1986) currently recommends a TLV-TWA of 0.1 vq/m3 for occupa-
tional atmospheric exposure to endosulfan.
0065h -15- 12/17/86
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfO$)
6.1.1. Oral (RfOSQ). NCI (1978) conducted 6-week range-finding studies
with groups of five male and five female B6C3F1 mice that were exposed to 0,
3.2, 5.6, 10, 18 or 32 ppm endosulfan 1n the diet and to Osborne-Mendel rats
that were similarly exposed to 0, 178, 316, 562, 1000 or 1730 ppm. Body
weight depression and mortality occurred 1n the mice at >5.6 ppm (see
Section 3.1.1.). In the rats, body weight depression occurred 1n the males
at >562 ppm, but was not observed 1n the females, and deaths occurred at
1780 ppm In the males and at 316 and 562 ppm In the females. The mouse and
rat NOELs (3.2 and 178 ppm, respectively) correspond to 0.4 and 8.9
mg/kg/day dosages (see Section 3.1.1.).
Other subchronlc oral toxldty studies have been conducted with rats
that were exposed to endosulfan for 7-60 days (see Sections 3.1.1. and
3.3.1.). The Huntingdon Research Centre study (1984) reported yellowish
discoloration of cells along with clumped pigments In trace amounts In these
cells of the proximal convoluted tubules of kidneys of males exposed at all
dosages tested (3, 15 and 75 ppm). The lowest dose, 3 ppm endosulfai or
0.15 mg/kg/day In males, represents a LOAEL.
Dogs that were exposed to endosulfan 1n capsules at doses of 0.075, 0.25
or 0.75 mg/kg/day, 6 days/week for 1 year showed no treatment-related
effects on growth, organ weights, b1ochem1cal/hematolog1ca1/ur1ne chemistry
parameters or gross hlstopathology (Keller, 1959a; Baran, 1967) (see Section
3.1.1.).
The LOAEL of 0.15 mg/kg/day from the Huntingdon Research Centre (1384)
rat study Is the most appropriate basis for calculation of an RfD™ for
endosulfan because rats appear to be the most sensitive species and the
0065h -16- 05/13/87
-------
lowest adverse effect level (0.15 mg/kg/day, corresponding to 3 ppm 1n the
diet) Is below the NOELs In the rat and mice studies (see Section 3.1.1.).
The high- est NOEL from the dog studies (0.75 mg/kg/day) (Keller, 1959a;
Baran, 1967) 1s supportive of the mouse 0.4 mg/kg/day NOEL, but less well
defined, because of a shortage of LQEL data. Using the rat LOAEL of 0.15
mg/kg/day with an uncertainty factor of 1000 results 1n an RfDSQ of
0.00015 mg/kg/day, or 0.01 mg/day for a 70 kg man.
The CBI literature contains a 13-week diet study that defines a LOAEL of
10 ppm for rats (0.64 mg/kg/day for males and 0.75 mg/kg/day for females,
using reported food consumption and body weight data) for hematologlcal
effects. The LOAEL of 0.15 mg/kg/day for rats (Huntingdon Research Centre,
1984) 1s comparable with the LOAEL for hematologlcal effects In the CBI; the
recommended RfO-Q 1s appropriate as calculated.
6.1.2. Inhalation (RfOg,). The lack of pertinent Inhalation toxlclty
data for endosulfan precludes calculation of an RfD.,.
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDp). An RfDQ of 0.004 mg/kg/day was calculated for
endosulfan from the chronic diet NOEL of 2 ppm for female mice 1n the NCI
(1978) bloassay with an uncertainty factor of 100 (U.S. EPA, 1980a). It
appears that the higher NOEL of 3.9 ppm In the female mice was not used as
the basis for the RfD because this Is above the low dose for male mice (3.5
ppm) that was associated with nephrotoxldty (U.S. EPA, 1980a). In the
calculation of the RfD, the 2 ppm NOEL was converted to a dally dosage of
0.4 mg/kg/day by assuming that a mouse consumes an amount of food equivalent
to 20% of Its body weight (5 g food/25 g body weight) dally (U.S. EPA.
1980a). Current methodology, however, assumes that a mouse consumes an
amount of food equivalent to 13% of Its body weight/day (U.S. EPA, 1980b).
0065h -17- 05/13/87
-------
Application of this food factor (0.13) to the dietary level of 2 ppra results
1n a dosage of 0.26 mg/kg/day, which corresponds to an RfO of 0,0026 mg/kg/
day when an uncertainty factor of 100 1s used. However, the 2-generat1on
rat study (Huntingdon Research Centre, 1984) provided LOAEL for nephrotoxlc-
1ty possibly, resulting from hematopoletlc effects In male rats exposed to
0.15 mg/kg/day. It would be therefore appropriate to apply an uncertainty
factor of 10,000 to this LOAEL to derive an RfDQ of 0.000015 mg/kg/day for
endosulfan. This number was derived by the Office of Pesticide Programs
(OPP) and verified by the Agency-wide RfO committee on June 11, 1986 (U.S.
EPA, 1986a).
The OPP previously reported a provisional RfO of 0.0075 mg/kg/day based
on a 1-year oral dog NOEL of 0.750 mg/kg/day (U.S. EPA, 1982). This RfD Is
Identical to that adopted by the FAO/WHO (Vettorazzl, 1975). The dog NOEL
1s not an appropriate basis for an RfO because It Is higher than the dosage
of endosulfan (NCI, 1978) that appeared to be associated with early mortal-
ity and hydronephrosls 1n male mice (I.e., 3.5 ppm 1n the diet, which 1s
equivalent to 0.46 mg/kg/day when a food factor of 0.13 1s applied) and Is
very close to the dosage (BRL, 1968) associated with Increased mortality In
both male and female mice (6 ppm 1n the diet, which 1s equivalent to 0.78
mg/kg/day). In addition, the mice were treated for nearly the entire
Hfespan, wnereas the dogs were treated for considerably less than their
Hfespans.
CSs for endosulfan can be calculated from the NCI (1978), BRL (1968) and
Keller (19f»9b) chronic oral bloassays conducted with rats and mice (see
Section 3.2.1.). Treatment-related mortality that was not attributed to
tumor development occurred at all dosages that produced effects 1n those
studies. The derivations of CSs from the lowest dosages producing mortal-
ity 1n these studies are presented 1n Table 6-1. Mortality In mice from the
0065h -18- 05/13/87
-------
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NCI (1978) study was not used as an endpolnt because H was not definitely
attributed to treatment. Fetotoxlclty 1n the Gupta et al. (1978) study (see
Section 3.3.1.) 1s also an appropriate basis for a CS calculation for
endosulfan.
Standard chronic toxldty RQ methodology was used to calculate the CSs.
This Involved using standard food consumption estimates to convert dietary
exposure Into mg/kg/day dosages and assumed or reported body weights and the
cube root of the body weight ratio approximation to convert the animal MEDs
to human MEDs (see Table 6-1). RV s of 10 and 8 most appropriately
c
reflect the mortality and fetotoxlclty, respectively. The highest CS (50)
1s calculated from the mortality 1n mice (BRL, 1968). reflecting the greater
susceptibility of mice compared with other test species to endosulfan.
6.2.2. Inhalation (RfDj). The lack of pertinent Inhalation toxlclty
data for endosulfan precludes calculation of an RfO, or CS.
QQ65h -20- 05/13/87
-------
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986.
Documentation of the Threshold Limit Values amd Biological Exposure Indices,
5th ed. Cincinnati. OH. p. 230.
Agarwal, O.K., et al. 1978. Effect of endosulfan on drug metabolizing
enzymes and I1p1d peroxldatlon In rat. J. Environ. Sc1. Health. C13: 49.
(Cited In U.S. EPA, 1980a)
Ansarl, R.A., M.K.J. S1dd1qu1 and P.K. Gupta. 1984. Tox1c1ty of endo-
sulfan: Distribution of a- and B-lsomers of racemlc endosulfan following
oral administration In rats. Toxlcol. Lett. 21(1): 29-33. (CA 101:20281)
Baran, J. 1967. Report to Niagara Chemical Division, FMC Corporation:
Two-year chronic oral toxlclty of thlodan technical - beagle dogs: IBT No.
C3758. (Unpublished study Including letter dated Dec. 5, 1967 from J.C.
Calandra to John F. McCarthy, received Dec. 7, 1967 under 7F0632; prepared
by Industrial Bio-Test Laboratories. Inc., submitted by FMC Corp., Phila-
delphia, PA. CDL:091100-A) MRID 00003741.
BRL (Blonetlcs Research Labs, Inc.) 1968. Evaluation of carcinogenic,
teratogenlc and mutagenlc activities of selected pesticides and Industrial
chemicals. Vol. 1. Carcinogenic study. National Cancer Institute. NTIS PB
223-159.
0065H -21- 10/24/86
-------
Callahan, M.A., M.W. Sllmak, N.W. Gabel, I.P. May. C.F. Fowler and J.R.
Feed. 1979. Water-related environmental fate of 129 priority pollutants -
Vol. I. U.S. EPA, Washington, DC. EPA 440/4-79-0298.
Czech, H. 1958. No title provided. Hedlcln v. Chemle. 6: 574. (Cited In
ACGIH. 1986}
Demeter, J. and A. Heyndrlckx. 1978. Two lethal endosulfan poisonings In
man. J. Anal. Toxlcol. 2: 68. (Cited In U.S. EPA, 1980a)
Den Tonkelaar, E.M. and C.J. Van Esch. 1974. No-effect levels of organo-
chlorlne pesticides based on Induction of mlcrosomal liver enzymes In short-
term toxldty experiments. Toxicology. 2: 371-380.
Dlkshltn, T.S.S.. R.B. Ralzada, M.K. SMvastava and B.S. Kaphalla. 1984.
Response of rats to repeated oral administration of endosulfan. Ind.
Health. 22(4): 295-304. (CA 102:107828c)
Dorough, H.W., K. Huhtunen, T.C. Marshall and H.E. Bryant. 1978. Fate of
endosulfan In rats and toxlcologlcal considerations of apolar metabolites.
Pestle. Blochem. Physio!. 8: 241-252.
Gupta, P.K. and R.C. Gupta. 1977. Effect of endosulfan pretreatment on
organ weights and on pentobarbltol hypnosis 1n rats. Toxicology. 7:
283-288.
0065h -22- 10/24/86
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Gupta, P.K., S.V. Chandra and O.K. Saxena 1978. Teratogenlc and embryo-
toxic effects of endosulfan In rats. Acta Pharmacol. Toxlcol. 42: 150-152.
Hansch, C. and A.T. Leo. 1985. Medchem Project Issue No. 26. Pomona
College, Claremont, CA.
Huntingdon Research Centre. 1984. Effect of Endosulfan-Technlcal on
Reproductive Function of Multiple Generations 1n the Rat. Report submitted
by J.A. Edwards et al. to the Office of Pesticides Program, U.S. EPA.
Innes, J.R.M, B.M. Ulland, M.G. Valerlo. et al. 1967. Bloassay of pesti-
cides and Industrial chemicals for tumor1gen1city In mice. A preliminary
note. J. Natl. Cancer Inst. 42: 1101-1114.
Keller, J.G. 1959a. Final report: Repeated oral administration - dogs.
(Unpublished study received Feb. 9, 1960. under PP0237; Prepared by Hazleton
Laboratories, Inc. FMC Corp. Philadelphia, PA. COL:090365H) MRID 00003604.
(Cited In U.S. EPA, 1982)
Keller, J.G. 1959b. Final report: Two-year chronic feeding study - rats:
(thlodan technical). (Unpublished study received Feb.. 9, 1960, under
PP0237; Prepared by Hazleton Laboratories, Inc. FMC Corp., Philadelphia, PA.
COL:090265-E) MRIO 00003602. (Cited 1n U.S. EPA, 1982)
Lendle, L. 1956. Berlcht uber Untersuchungen von Hoe 2671 (Thlodan) der
Farbwerke Hoechst A.G.. July 1956. .In: Maler-Bode, 1968. (Ger.) (Cited 1n
U.S. EPA, 1980a)
0065H -23- 10/24/86
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Lyman, H.J., U.F. Reehl .and O.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Hethods. HcGraw-H1ll, New York. p. 4-9.
Maler-Bode. H. 1968. Properties, effect, residues, and analytics of the
Insecticide endosulfan (review). Residue Rev. 22: 2-44. (Cited 1n U.S.
EPA, 1980a)
NCI (National Cancer Institute). 1978. Bloassay of endosulfan for possible
careInogenlcity. NCI Carclnogenesls. Tech. Rep. Ser. No. 62. 54 p. [Also
publ. as DHEW (NIH) 78-1312]
Raltech Scientific Services. 1980. Final report: Teratology study with FHC
5462 In rats: Raltech Study No. 79041. (Unpublished study received Nov. 12.
1980 under 279-2306: FMC Corp., Philadelphia, PA. CDL:243707) MRID
GS014008. (Cited In U.S. EPA, 1982)
Raltech Scientific Services. 1982. Final report: Teratology study with FMC
5462 1n rabbits: Raltech Study No. 80070. (Unpublished study received Feb.
16. 1982, under 279-2306; FHC Corp.. Philadelphia. PA. CDL:246792) MRID
GS014023. (Cited 1n U.S. EPA. 1982)
Rani, M.V.U., O.S. Reddl and P.P. Reddy. 1980. Mutagenlclty studies
Involving aldrln, endosulfan, dlmethoate, phosphamldon, carbaryl and
ceresan. Bull. Environ. Contain. Toxlcol. 25(2): 277-82. (CA 93:198808f)
Reuber, H.D. 1981. The role of toxlclty 1n the carclnogenlcHy of endo-
sulfan. Scl. Total Environ. 20(1): 23-47.
0065h -24- 10/24/86
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Sanborn, J.R., 8.M. Francis and R.L. Metcalf. 1977. The degradation of
selected pesticides In soil: A review of the published literature. Office
of Research and Development, U.S. EPA, Cincinnati, OH. EPA 600/9-77-02.
p. 339-342.
Singh, N.C., T.P. Oasgupta, E.V. Roberts and A. Nanslngh. 1986. Kinetics
of hydrolysis of endosulfan and vamldothlon. Irr. ACS Nat. Meet. Dlv. Agro-
chemicals, New York.
Sobtl, R.C., A. Krlshan and J. Davles. 1983. Cytok1net1c and cytogenetlc
effect of agricultural chemicals on human lymphold cells \i\ vitro. II.
Organochlorlne pesticides. Arch. Toxlcol. 52: 221.-231.
U.S. EPA. 1980a. Ambient Water Quality Criteria for Endosulfan. Prepared
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 440/5-80-046. NTIS PB81-117574.
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Health Effect Assessment Chapters of the Consent Decree Water Criteria
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U.S. Envirormental Protection Agency
r s'sion 5, Library (5PL-16)
SSO S. Dearborn Stveet, Room 1670
Chiuago, IL 60604
0065h -27- 02/05/87
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