TECHNICAL REPORT 7ATA
frlfae rt»d tiuovcnom on the reverse >:fore completing)
1. REPORT NO.
2.
3. RECIPIENT'S ACCESSION NO
PB88-180278/AS
4. TITLE AND SUBTITLE
Health Effects Assessment for heptachlor
6. REPORT DATE
«. PERFORMING ORGANIZATION COO£
7. AUTHOR(S)
I. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/OR A NT N O.
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
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 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, RfD5 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.IDENTIFIERS/OPEN ENDED TERMS |c. COSATI Field/Group
18. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (Tttu Report/
21. NO. OF PAGES
20. SECURITY CLASS (Thispage/
Unclassified
22. PRICE
EPA Form 2220-1 (R«*. 4-77) PMKVIOUI EDITION is OBSOLETE
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EPA/600/8-88/042
June, 1987
HEALTH EFFECTS ASSESSMENT
FOR HEPTACHLOR
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 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
preliminary Interim assessment of adverse health effects associated with
heptachlor. 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
environmental data were located through on-Hne literature searches of the
TOXLINE and the CHEMFATE/DATALOG data bases. The basic literature searched
supporting this document 1s current up to May, 1986. Secondary 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 Assess-
ment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria for Heptachlor.
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
440/5-80-052. NTIS PB81-117632.
U.S. EPA. 1987. Drinking Water Criteria Document for Heptachlor,
Heptachlor Epoxlde and Chlordane. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Drinking Water,
Washington, DC. Final Report.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
for noncardnogens 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 chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, 1s
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 In ambient air or water where lifetime
exposure 1s 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 (RfO$i) and oral (RfD$0)
exposures.
111
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The RfD (formerly AIC) Is similar In concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the "hfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD 1s route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfOi) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained In U.S.
EPA (1984).
For compounds for which there 1s sufficient evidence of cardnogenldty
RfD$ and RfD 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 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, If appro-
priate, based on oral and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n 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 Inter-
pretation and use of the quantitative estimates presented.
Heptachlor has been shown to be carcinogenic following oral administra-
tion 1n mice and rats. Based on the geometric mean of the Incidence of
hepatocellular carcinoma 1n mice 1n the two studies, a human q-|* of 4.5
(mg/kg/day)"1 has been derived (U.S. EPA, 1986c). The carcinogenic
potential of heptachlor following Inhalation exposure has not been studied
so that an Inhalation q-)* cannot be derived.
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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 Waste
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
Page
1. ENVIRONMENTAL CHEMISTRY AND FATE
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
2.2. INHALATION .
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
1
3
3
3
. . . . . 4
4,
4
5
5
5
8
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
8
9
9
. 11
11
11
11
11
. 11
16
18
19
20
V11
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TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT 22
6.1. SUBCHRONIC REFERENCE DOSE (RfDs) 22
6.2. REFERENCE DOSE (RfD) 22
6.3. CARCINOGENIC POTENCY (q-|*) 22
6.3.1. Oral .• 22
6.3.2. Inhalation 22
7. REFERENCES 27
APPENDIX: Oral Summary Table for Heptachlor 1n Male Mice 36
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LIST OF ABBREVIATIONS
AAOI Adjusted acceptable dally Intake
ADI Acceptable dally Intake
bw Body weight
CBI Confidential Business Information
CS Composite score
DNA Deoxyr1bonucle1c add
HA Health advisory
LCso Concentration lethal to 50% of recipients
1050 Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
PEL Permissible exposure limit
ppm Parts per million
RfD Reference dose
RfDj Inhalation reference dose
RfDg Oral reference dose
RfD$ Subchronlc reference dose
RfD$j Subchronlc Inhalation reference dose
RfD$Q Subchronlc oral reference dose
SMR Standardized mortality ratio
TLV Threshold limit value
THA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTY AND FATE
Selected physical and chemical properties and environmental fate of
heptachlor are listed In Table 1-1.
The atmospheric half-life of vapor phase heptachlor Is based on the
estimated rate constants for Its reactions with photochemlcally generated
hydroxyl radicals and ozone (U.S. EPA, 1986a). Degradation by direct
photolysis 1s not reflected In this half-life value, although 1t may also be
a significant removal mechanism (NLM, 1986). The part of heptachlor that
remains sorbed onto atmospheric aerosols will show a longer half-life.
Monitoring data Indicate that bloconcentratlon 1n aquatic organisms and
adsorption to suspended solids and sediments are Important fate processes of
heptachlor In aqueous systems (Callahan et al., 1979; IARC, 1979).
Hydrolysis 1s reported to be the dominant degradation pathway of heptachlor
1n the free state In water (Callahan et al., 1979). The half-life In the
sorbed state will be conslderally longer, however. This Is reflected by the
half-life value of 38 days estimated by Zoeteman et al. (1980).
Heptachlor strongly adsorbs to soils, 1s relatively persistent and
remains primarily within the top few Inches of the soils to which It 1s
applied. Degradation products In soil Include 1-hydroxychlordene, hepta-
chlor epoxlde, a- and 8-chlordane and nonachlor. Reported removal rates
of heptachlor and Us degradation product heptachlor epoxlde range from
5.25-79.554 mean loss from soil/year (Sanborn et al., 1977). If the compound
strongly adsorbs to soils, significant portions will not be available for
hydrolysis, which may account for Its longer half-life 1n soils compared
with surface waters.
0085h -1- 11/26/86
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TABLE 1-1
Selected Physical and Chemical Properties and
Environmental Fate of Heptachlor
Property
Value
Reference
CAS number
Chemical class:
Molecular weight:
Vapor pressure:
Hater solubility:
Log octanol/water
partition coefficient:
or
B1oconcentrat1on factor:
Half-lives In
Air:
Water:
Soil:
76-44-8
chlororganlc pesticide
373.35
3xlO~* mm Hg (25°C)
5.6x10-2 mg/l (25-29°C)
3.87
9500 fathead minnow
3800 mosquito fish
3.1x10* mosquito larvae
3.7x10* snail
2.1x10* alga
36 minutes
(vapor phase) estimated
1-3 days
38 days (river)
9-10 months
years
U.S. EPA, 1980a
U.S. EPA, 1980a
Hansch and Leo, 1985
Velth et al, 1979
Callahan et al., 1979
Callahan et al., 1979
Callahan et al., 1979
Callahan et al., 1979
U.S. EPA, 1986a
Callahan et al., 1979
Zoeteman et al., 1980
IARC, 1979
Sanborn et al., 1977
0085h
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11/26/86
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2. ABSORPTION FACTORS IN HUMANS AND ANIMALS
2.1. ORAL
An abstract of a Russian study (Mlzyukova and Kurchatlov, 1970) reviewed
In U.S. EPA (1980a) reported that heptachlor administered to rats Intra-
gastMcally In a single oral dose of 120 mg/kg bw was detected 1n the blood
within 0.5-1 hour of administration. Further quantitative data concerning
the absorption of heptachlor following oral administration could not be
located In the available literature.
2.2. INHALATION
Oorough (1982) exposed rats to 14C-labeled heptachlor vapor at a very
low concentration for 1 hour. The total compound Inhaled did not exceed 50
wg heptachlor; the rats retained -87.9%. The protocol followed and
measurements made by which the authors estimated percent retention were not
specified 1n this report.
From July 1 to October 4, 1972, Arthur et al. (1975) placed 10 rabbits/
sex 1n open-air cages to expose them to the ambient air of Stonevllle, MS,
an area of heavy Insecticide use. Control rabbits, 10/sex, were housed
Indoors In an area of low pesticide use. Average air levels of heptachlor
epoxlde (heptachlor was either not measured or not detected) 1n open air
were 1.86 mg/m3; levels 1n the Indoor air were not measured. Residues of
heptachlor epoxlde In adipose tissue were 0.039 ppm In test rabbits as
compared with 0.016 ppm 1n controls. The average respiratory Intake of
heptachlor epoxlde In rabbits from the Stonevllle area was calculated at
0.002 yg/day.
0085h -3- 09/04/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. NCI (1977) conducted an oral subchronlc study to determine
dose levels of heptachlor to be administered to Osborne-Mendel rats and
B6C3F1 mice for cardnogenldty testing. Groups of five male and five
female rats and equal numbers of mice were fed diets containing technical
grade heptachlor (-73% heptachlor, 22% transchlordane, 5% nonachlor) .'at
concentrations of 0, 20, 40, 80, 160 or 320 ppm (rats) and 0, 20, 40 or 80
ppm (mice) for 6 weeks. After the dosing period, rats and mice were main-
tained on heptachlor-free diets for 2 weeks. The only parameters examined
were food consumption, body weight gain and mortality.
In rats, no effects on body weight gain or food consumption were
observed at <40 ppm In the diet. Female rats fed 80 ppm In the diet had
reduced body weight during the first week. Four female rats fed diets
containing 160 mg/kg died, while two male and five female rats fed at 320
ppm died.
In mice, the highest dose tested (80 ppm) resulted 1n the deaths of five
males and two females. No deaths and no effects on body weight gain or food
consumption occurred In mice fed diets containing 20 or 40 ppm.
Shaln et al. (1977) fed diets containing heptachlor (99.8% pure) to
groups of 42 male Sprague-Oawley rats for 90 days, at an average dose of 0
or 1.29 mg/kg bw/day. In six randomly selected cages, 12 rats showed a
statistically significant decrease 1n mean weekly weight gain (p<0.01).
This study was designed to determine the effects of pesticides on prostate
homeostasls; therefore, hlstologlcal examinations of other organs were not
conducted. Twenty-four hours before sacrifice, rats were castrated.
0085h -4- 09/04/86
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Cytoplasmlc, but not nuclear, androgen receptor sHe content of the ventral
prostate was significantly Increased. .Ventral prostate protein content was
reduced to 13% of levels found In controls and cell number was reduced to
18% of control.
Klnoshlta and Kempf (1970) fed rats heptachlor In their diets at various
(unspecified) dose levels for 13 weeks. Dose-related Increases 1n the
activities of three hepatic nulcrosomal enzymes (phosphorothloate detoxifica-
tion enzymes, o-demethylase and N-demethylase) were observed. The no-effect
level for enzyme Induction was reported to be ~1 ppm 1n the diet.
3.1.2. Inhalation. Pertinent data regarding the subchronlc toxldty of
heptachlor following Inhalation exposure could not be located In the
available literature.
3.2. CHRONIC
3.2.1. Oral. Several long-term feeding studies of heptachlor and
heptachlor epoxlde designed as cardnogenlcHy studies provide chronic
toxlcologlcal data. Except for the NCI (1977) and Reuber (1977a,b, 1978)
reports. Information concerning the other studies was obtained from a review
by Epstein (1976).
In an unpublished study by IROC (1973), groups of 100 male and 100
female CD-I mice were fed diets containing a 25:75 mixture of heptachlor:
heptachlor epoxlde at 0, 1, 5 and 10 ppm (mg/kg diet) for 18 months. At 6
months, 10 mice/sex/group were killed. Decreased body weight gain was
observed In females fed at the 10 mg/kg diet level. At 6 and 18 months,
mean liver weights showed significant dose-related Increases 1n both male
and female mice, with the greatest Increase 1n the males. Survival,
although underestimated as a result of the Interim kill, was 29% for males
0085h -5- 11/26/86
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and 30% for females at the highest dose and 51-66% for all other groups.
Including controls. Dose-related increases In liver weights were observed
1n both male and female mice at termination.
Davis (1965) fed groups of 100 male and 100 female C3H mice diets con-
taining heptachlor at 0 or 10 ppm (10 mg/kg diet) for 2 years. Low survival
was observed 1n both treated (30%) and control (34%) mice. A 2-fold
Increase over controls 1n the Incidence of hepatic hyperplasla was observed
In the test mice. Reevaluatlon of the slides by four other pathologlsts
resulted 1n more lesions being classified as hepatomas. In a review of the
tissue specimens from the Davis (1965) study, Reuber (1977a, 1978) found
hepatic vein thrombosis and cirrhosis 1n treated but not 1n control mice;
10% of males and 15% of females had hepatic vein thrombosis and 6% of treat-
ed mice had venous occlusion with recent liver Infarcts. Thrombosis of the
cardiac atrium was also present 1n some mice with hepatic vein thrombosis.
The prevalence of cirrhosis was 5/77 treated females and 2/86 treated males.
WHherup et al. (1955) fed .groups of 20 male and 20 female SF rats diets
containing 0, 0.5, 2.5, 5.0, 7.0 or 10.0 ppm (mg/kg) heptachlor for 10
weeks. Mortality 1n the test groups was not dose-related. Body weight
loss, decreased food consumption and Increased liver weights were observed
1n treated males, but not In females. These changes were greatest 1n males
fed diets containing 10 ppm. Liver lesions described as "chlorinated hydro-
carbon" type and considered to be nonneoplastlc were noted 1n 50% of females
and 17% of males fed the 10 ppm diet, and 1n 17% of females and 38% of males
fed the 7 ppm diet. These Hver lesions were not observed In rats fed diets
containing <5.0 ppm.
0085h -6- 09/04/86
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In a study by Jolley et al. (1966), groups of 25 female CD rats received
a 75:25 mixture of heptachlor:heptachlor epoxlde In their diets at concen-
trations of 5, 7.5, 10 or 12.5 mg/kg diet for 2 years. A group of 54
control rats were fed Insecticide-free diets. Spontaneous lesions were
observed 1n all groups and Included multiple cell type hypertrophy,
telanglectasla 1n the anterior pituitary and adrenal hypertrophy. Liver
weights were Increased over control levels 1n rats fed at 7.5, 10.0 and 12.5
mg/kg diet.
In the NCI (1977) study, groups of 50 male and 50 female Osborne-Mendel
rats and groups of 50 male and 50 female B6C3F1 mice were fed diets contain-
ing technical grade heptachlor (-73% heptachlor, 22% transchlordane, 5% non-
achlor) for up to 80 weeks. Controls for the rats consisted of 10 matched
and 60 pooled untreated rats/sex (controls from concurrent and recent
bloassays of other related compounds). For mice, male controls consisted of
20 matched and 100 pooled, while female controls consisted of 10 matched and
80 pooled controls. Despite a preliminary subchronlc dose range-finding
study, the doses used In this study had to be adjusted because of developing
symptoms of toxlclty. Low-dose male rats were fed a TWA dose of 38.9 mg/kg
diet, high-dose male rats were fed TWA diets of 77.9 mg/kg. Female low- and
high-dose rats received TWA doses of 25.7 and 51.3 diet, respectively.
Treated diets were provided for 80 weeks, followed by 30 weeks of observa-
tion. Male low- and high-dose mice received TWA doses of 6.1 and 13.8 mg/kg
diet and female low- and high-dose mice received TWA doses of 9.0 and 18.0
mg/kg diet. Treated diets were fed for 80 weeks, followed by a control diet
for 10 weeks of observation.
0085h -7- 11/26/86
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Mean body weights of high-dose rats were consistently depressed,
especially 1n males. Growth rates of the low-dose groups were similar to
controls. Adverse clinical signs Including loss of body weight, rough and
discolored hair and palpable masses developed In both treated and untreated
groups. After 80 weeks, vaginal bleeding developed In some female rats from
both treated groups. A dose-related but not significant Increase 1n
mortality was observed In male rats. A linear trend test for mortality was
significant (p=0.04) In female rats.
No differences 1n body weight gains were observed In mice. Sores and
hair loss were observed In both treated and control mice during the first
year. Abdominal dlstentlon and hair loss were prevalent In high-dose
females. Mortality In male mice was similar to controls. In females, there
was a significant positive linear trend for mortality, which was due
predominately to the difference 1n mortality between the treated groups.
3.2.2. Inhalation. Pertinent data regarding the effects of heptachlor
following chronic Inhalation exposure could not be located 1n the available
literature.
3.3. TERATOGEMICITY AMD OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. MestHzova (1967), 1n a study of the effects of heptachlor
on the fertility of rats (strain unspecified), fed heptachlor (98.1% pure)
In the diet at an "applied dose" of 6 mg/kg bw. It 1s not clear whether
this was a dally dose or a total dose administered over the duration of the
treatment. A marked reduction 1n the litter size 1n F, generations and 1n
one F- generation was observed. Mortality 1n suckling pups was high;
during the first week after birth, a mean percent mortality of exposed pups
was 46% as compared with 12% 1n controls. Cataracts developed 1n pups as
well as In treated adults.
0085h -8- 11726/86
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3.3.2. Inhalation. Pertinent data regarding teratogenlc or other repro-
ductive effects of heptachlor following Inhalation exposure could not be
located 1n the available literature.
3.4. TOXICANT INTERACTIONS
Cote et al. (1985) fed groups of 50 male and 50 female Sprague-Oawley
rats a mixture of 15 chemicals, Including heptachlor, 1n the diet for 91
days. The levels of chemicals fed to the rats were 1, 10, 100 or 1000 times
the water quality objectives for persistent substances from the 1978 Great
Lakes Water Quality Agreement. Results showed no dose-related toxlcologlcal
changes. Food consumption was significantly lower for females during week
.12, though body weight was not affected. The parameters examined Included
body weight, organ weights, gross and hlstopathologlcal examination of
organs and hematologlcal and biochemical determinations.
The remaining Interaction studies examined the effect of various pre-
treatments on heptachlor toxldty. Sperling and Ew1n1ke (1969) found that
pretreatment of adult male rats with an oral dose of 1.8 g turpentine/kg
bw/day for 3 days reduced the oral LD,Q of heptachlor from 112 to 70 mg/kg
bw. Intraperltoneal Injections of phenobarbltal, a known Inducer of mlcro-
somal enzymes, decreased the LD5Q of heptachlor In neonatal Sprague-Dawley
rats from 531 mg/kg bw 1n untreated rats to 133 mg/kg bw 1n pretreated rats
(Harbison, 1975).
Scheufler and Rozman (1984) Injected male Sprague-Oawley rats IntrapeM-
toneally with trans-st1lbeneox1de, a phase II enzyme Inducer, at 4 mg/kg/on
4 consecutive days. These rats were then given [14C] heptachlor (2 mg/kg)
Intravenously. Trans-stlllbeneoxlde significantly Increased (p<0.05) the
cumulative excretion of heptachlor-deMved material 1n the feces, but had no
effect on urinary excretion of heptachlor.
0085h -9- 11/26/86
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A series of experiments (Webb and Miranda, 1973; Miranda and Webb, 1974;
Miranda et al., 1973; Weatherholtz et al., 1969) Investigated the effects of
quantity and the quality of dietary protein on heptachlor toxldty 1n
weanling rats. Heptachlor, administered 1ntraper1toneally, was more toxic
to weanling rats fed 10% protein diets, when the protein was hlgh-qualHy
casein rather than low-quality gluten. This effect was more pronounced In
rats fed diets containing 18% protein (Webb and Miranda; 1973). Rats fed
the gluten diet had reduced body weight, low mlcrosomal protein content and
lower activities of heptachlor epoxldase than rats fed the casein diet. It
was suggested that metabolism of heptachlor to heptachlor expoxlde was
Inhibited by low protein diets.
0085h -10- 11/26/86
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4. CARCINOGEMICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the carcinogenic potential of
heptachlor In humans following oral exposure could not be located 1n the
available literature.
4.1.2. Inhalation. Hang and MacMahon (1979) conducted a retrospective
mortality study of 1403 white male workers employed for >3 months 1n two
U.S. plants that produce chlordane and heptachlor. The total number of
deaths 1n the cohort was 113 as compared with 157 expected. The observed
Incidences of all types of cancer, except lung cancer, were less than
expected. Twelve members of the cohort died from lung cancer as compared
with 9 expected deaths (SMR=134). This Increase In lung cancer was not
statistically significant. Only one death from liver cancer was observed.
Although a statistically significant Increase In cerebrovascular disease was
observed (17 observed, 9.3 expected; SMR=183), the authors concluded that
cerebrovascular disease was not correlated to length of exposure or. latency
and occurred only after termination of employment and, therefore, was not
associated with exposure to heptachlor.
4.2. BIOASSAYS
4.2.1. Oral. Many of the reports concerning the carcinogenic potential
of heptachlor have not been published (Davis, 1965; IRDC, 1973; WHherup et
al., 1955; Jolley et al., 1966). Information concerning these studies was
obtained from a review by Epstein (1976) that was based on a statement of
suspension testimony at the Environmental Protection Agency Hearing on
Heptachlor/Chlordane, Washington, DC, August 26, 1975. Epstein (1976) also
presented the results of Independent statistical reanalyses and histologlcal
revaluations of these studies.
0085h -11- 09/04/86
-------
In a study by WHherup et al. (1955), groups of 20 male and 20 female CF-
rats were fed diets containing 1.5, 3.0, 5.0, 7.0 or 10.0 mg heptachlor/kg
diet for 110 weeks. Similar groups of rats served as controls. Benign and
malignant tumors were randomly distributed among test and control groups,
with greater Incidences 1n females, especially those fed 5.0 and 7.0 mg/kg
diet. Tumor types observed Included lymphomas, osteogenlc sarcomas, carci-
nomas of the thyroid and subcutaneous flbrosarcomas. In rats fed 7.0 and
10.0 mg/kg heptachlor, Hver lesions, described as "chlorinated hydrocarbon"
type, were observed at a high Incidence. These lesions were not believed to
be neoplastlc. The first statistical analysis Indicated that tumor
Incidences 1n treated rats were not statistically different from controls.
Reanalysls showed significant differences 1n the Incidences of tumors 1n the
treated female groups for any tumor (p=0.034), for malignant tumors In rats
fed 7.0 mg/kg diet (p=0.034) and for any tumor In rats fed 10.0 mg/kg diet
(p=0.017) (Epstein, 1976). Details concerning the types of statistical
tests used In these analyses were not provided.
Jolley et al. (1966) fed groups of 25 female CD rats a 75:25 mixture of
heptachloriheptachlor epoxlde at concentrations of 5.0, 7.5, 10 or 12.5 ppm
(mg/kg diet) for 2 years. A group of 54 female rats served as controls. At
necropsy, spontaneous tumors (e.g., mammary tumors, fIbroadenomas) were
observed with random frequency among treated and control groups. Malignant
lesions of the liver were not observed.
Davis (1965), 1n a study for the Food and Drug Administration, fed
groups of 100 male and 100 female C3H mice diets containing 0 or 10 ppm (10
mg/kg diet) heptachlor for 2 years. A large number of mice were lost or
discarded, sacrificed for transplant purposes or died prematurely, so no
statistical analysis of the data was made. A 2-fold Increase 1n benign
0085h -12- 11/26/86
-------
liver lesions 1n treated mice over controls was observed In the specimens
available for examination. Malignant Hver tumors occurred with less
frequency In treated mice as compared with control mice. Using the original
data and assuming that all missing control mice had tumors and all missing
treated mice did not, a statistical analysis was performed. By this method,
the Incidence of liver tumors In treated mice was not found to be statis-
tically significant from controls.
In a revaluation of slides from the Davis (1965) study, Reuber (1977b)
found the following liver carcinoma Incidences: 22/78 (28%) control males,
2/54 (4%) control females, 64/87 (73X) heptachlor males, 57/78 (73%)
heptachlor females. Statistical analysis of Reuber's results show a highly
significant Increased Incidence of liver carcinoma In all treated groups
when compared with controls (p=5xlO~§ males, p=lxlO~8 females). Reexam-
Inatlon of slides from 20 mice by three Independent pathologlsts resulted 1n
concurrence with Reuber's diagnoses; all diagnosed a high Incidence of
hepatic carcinoma (Epstein, 1976; Reuber, 1977b).
IRDC (1973) fed groups of 100 male and 100 female CD-I mice a 25:75
mixture of heptachlor:heptachlor epoxlde 1n the diet at 0, 1, 5 or 10 ppm
(mg/kg diet) for 18 months. In the original analysis, the Incidence of
nodular hyperplasla was highly significant for the 5 and 10 mg/kg level
males and females when compared with controls. The Incidence of hepatomas
was lower In the high-dose groups than 1n the 1 mg/kg diet group and
controls. A reexamlnatlon of the slides from this study (Reuber, 1977b)
found a greater Incidence of hepatic carcinoma, with a corresponding
decrease In the Incidence of hyperplasla and hyperplastlc nodules (Epstein,
1976). The Incidences of liver carcinoma found by Reuber (1977b) are shown
In Table 4-1. Five other pathologlsts reexamlned the slides from the IRDC
0085h -13- 11/26/86
-------
TABLE 4-1
Carcinogenic Potency of a 75:25 Mixture of Heptachlor Epox1de:Heptachlor
Administered In the Diet of CD-I Mice for 18 Months8
Sex
M
F
Dose
(mg/kg)
0
1
5
10
0
1
5
10
Target
Organ
liver
liver
liver
liver
liver
liver
liver
liver
Tumor Type
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
carcinoma
Tumor Incidence
(p value)b«c
0/62
2/68
18/68 (p=2x!0~*)
52/80 (p=
-------
(1973) study and agreed that the Incidence of hepatic-carcinoma was under-
diagnosed 1n the original examination (Epstein, 1976).
Epstein (1976) also reviewed an Italian study (Cabral et al., 1972) for
which an English abstract 1s available. In this study, a group of 95 Wlstar
rats, 10 days old, were given heptachlor (96.8X pure) In corn oil by gavage
at 10 mg heptachlor/kg bw on alternate days for a total of five doses.
Before weaning, 7 rats died, leaving 39 males and 49 females. Twenty femal-e
rats and nine males were sacrificed at 60 weeks, leaving 29 females and 30
males to be sacrificed between 106 and 110 weeks. Control rats, 19 males
and 27 females, received corn oil alone. The only statistically Increased
tumor Incidence was for endocrine tumors 1n the male test group (14/19
control vs. 27/30 treated; p=0.033) (Epstein, 1976). In addition, though
not statistically significant, rare "Upomatous" renal tumors were diagnosed
In two treated females.
In the NCI (1977) study, technical .grade heptachlor (-73% heptachlor,
22% trans-chlordane and 5% monochlor) was fed to groups of 50 Osborne-Mendel
rats and 50 B6C3F1 mice/sex for 80 weeks, followed by observation periods.
The dosing schedules were presented 1n Section 3.2.1. TWA high- and low-
dose diet concentrations were 77.9 and 38.9 ppm (mg/kg diet), respectively,
for male rats; 51.3 and 25.7 ppm, respectively, for female rats; 13.8 and
6.1 ppm, respectively, for male mice; and 18.0 and 9.0 ppm, respectively,
for female mice. Ten rats/sex served as matched controls and 60 rats/sex
served as pooled controls. For mice, 20 male and 10 female matched controls
and 100 male and 80 female pooled controls were used. Comprehensive hlsto-
loglcal examinations were performed on major organs and gross lesions of all
rats and mice that died spontaneously, were killed when moribund or were
killed at the end of the study, except when precluded because of cannibalism
or autolysls.
0085h -15- 11/26/86
-------
The results In rats showed -no statistically Increased (Fisher exact
test, life-table method) tumor Incidences. No hepatocellular carcinomas
were observed In any of the rats. Cholanglocardnoma was diagnosed In the
liver of one low-dose male. Neoplastlc nodules of the liver, considered by
the Investigators to represent a cancerous condition (NCI, 1977) were found
In all treated and control groups. The Incidences were 2/58 (3%) pooled
controls, 1/10 (10%) matched controls, 3/44 (7%) low-dose, 6/49 (12%) hlgti-
dose for males and 5/59 (8%) pooled controls, 1/10 (10%) matched controls,
9/48 (18%) low-dose and 5/46 (11%) high-dose for females. Other tumors
observed 1n the rats were folUcular-cell and C-cell carcinoma of the
thyroid In male and females, mammary tumors In females and two endometrlal
stromal sarcomas 1n the high-dose female group.
In heptachlor-treated B633F1 mice, hepatocellular carcinoma was the most
frequently observed neoplasm. The Incidence 1n high-dose males was signifi-
cantly different when compared with matched controls (p=0.001 or p=0.0007 by
two simple proportion analyses; p=0.002 by life-table method). In low-dose
males, the Incidence of hepatocellular carcinoma was lower than In the
control group. In female mice, high-dose females showed a significant
(p<0.005) Increase In hepatocellular carcinoma as compared with controls. A
highly significant (p<0.0001) dose-related Increase between the low- and
high-dose female groups was also observed. This dose-related Increase 1s
mainly a result of the large difference between the high- and low-dose
groups. The Incidence of hepatocellular carcinoma 1n mice 1s shown In
Table 4-2.
4.2.2. Inhalation. Pertinent data regarding the carcinogenic potential
of heptachlor In laboratory animals following Inhalation exposure could not
be located In the available literature.
0085h -16- 09/04/86
-------
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4.3. OTHER RELEVANT DATA
Heptachlor has tested negative 1n the reverse mutation assay In 10
strains of Salmonella typhlmurlum and 1n three strains of Escherlchla coll
without metabolic activation (Morlya et al., 1983; Probst et al., 1981;
Marshall et al., 1976) and 1n the rec assay 1n two strains of Bacillus
subtnis In which no activating system was used (Shlrasu et al., 1976).
Gentile et al. (1982) reported positive results for reverse mutation In S.
typhlmurlum strains TA98 and TA100 at 10 yg technical grade heptachlor/
plate with S-9 metabolic activation. A commercial formulation of heptachlor
was negative 1n these strains. Both technical and commercial grade hepta-
chlor were negative for mltotlc gene reversion In Saccharomyces cerevlslae
with and without S-9 metabolic activation (Gentile et al., 1982).
Heptachlor was also negative In the recessive lethal assay 1n Drosophlla
melanogaster (Benes and Sram, 1969) and for unscheduled DNA synthesis In
rat, mouse and hamster primary hepatocy.tes (Probst et al., 1981; Maslansky
and Williams, 1981).
The dominant lethal assay 1n CD-I mice receiving heptachlor by gavage or
1ntraper1toneal Injection was negative (Arnold et al., 1977)*. The dominant
lethal assay 1n rats fed heptachlor at 1 or 5 mg/kg diet for 3 generations
resulted In Increased numbers of resorbed fetuses (Cerey et al., 1973). An
Increased number of chromosome aberrations In the bone marrow of these rats
was also noted. Heptachlor was positive (p<0.05) for unscheduled DNA syn-
thesis In SV-40 transformed human flbroblasts (VA-4) with, but not without,
the S-9 fraction at 100 and 1000 WM heptachlor (Ahmed et al., 1977).
0085h -18- 09/04/86
-------
4.4-. HEIGHTOF EVIDENCE
Heptachlor has been shown to be carcinogenic In mice (NCI, 1977; Davis,
1965; Reuber, 1977b; IROC, 1973; Epstein, 1976) and rats (WHherup et a!.,
1955; Epstein, 1976). This ev1den.ce of carclnogenlcHy Is sufficient to
classify 1t 1n welght-of-evldence Group 82, probable human carcinogen,
according to the U.S. EPA classification scheme .for carclnogenlcHy (U.S.
EPA, 1986b).
0085h -19- 06/22/87
-------
5. REGULATORY STANDARDS AND CRITERIA
U.S. EPA (1978) cancelled the registrations of most pesticide products
containing heptachlor (and chlordane) as defined 1n the notice of Intent to
Cancel (U.S. EPA, 1974). The exceptions are "the use of heptachlor or
chlordane through subsurface ground insertion for termHe control and the
dipping of roots or tops of nonfood plants."
U.S. EPA (1975a) proposed 0.0001 mg/l of heptachlor and heptachlor
epoxlde as the Interim primary drinking water standard. This level was
deleted 1n the final U.S. EPA (1975b) regulations because the EPA was
Involved In the suspension and cancellation proceedings.
FHPCA (1968) set a permissible surface water criteria for public water
supplies at 0.018 mg/l for heptachlor and heptachlor epoxlde. The
criteria for fish and other aquatic life based on an LC5Q of 0.0002 mg/i
for heptachlor would be very low; therefore, 1t 1s recommended (FHPCA, 1968)
that heptachlor should not be used near an aquatic environment.
U.S. EPA (1980a) determined 2.8 ng/8. for heptachlor as the water
concentration corresponding to an Increased lifetime excess cancer risk of
10"5. This value was derived assuming a 70 kg human consumes 2 l of
water/day and 6.5 g of fish and shellfish with a bloconcentratlon potential
of 11,200. Using these assumptions, 97% of heptachlor exposure results from
the consumption of aquatic organisms. The value of 2.8 ng/i Is based on a
q * of 3.37 (mg/kg/day)"1 calculated from the Incidence of heptocellular
carcinoma 1n male B6C3F1 mice found 1n the NCI (1977) study with technical
heptachlor.
0085h -20- 09/04/86
-------
HAs based on noncardnogenlc effects of heptathlon have been determined
by U.S. EPA (1987). Ttie 1-day HA Is 0.010 and 0.035 mg/i for a child and
an adult, respectively. These values, also recommended as 10-day HAs, were
derived from a 14-day feeding study 1n rats by Enan et al. (1982). The
lifetime AADI for an adult was determined to be 0.0175 mg/l for a 70 kg
adult assuming 2 8. water consumption/day, or 0.0035 mg/i, assuming that
only 20% of the heptachlor Intake 1s from water. This lifetime value Is
based on an ADI (now referred to as RfO) of 0.035 mg/day for a 70 kg human
derived from a NOEL of 3 ppm (0.15 mg/kg bw/day) 1n a rat study by Hltherup
et al. (1955). FAO/WHO (1972) has recommended an ADI of 0.5 yg/kg bw for
heptachlor.
ACGIH (1986) adopted a TWA-TLV of 0.5 mg/m3 for heptachlor In workroom
air. The OSHA (1985) PEL for skin exposure In the workroom Is also 0.5
mg/m3 for heptachlor. NRC (1982) has recommended an Interim guideline for
airborne heptachlor In military housing of 2 yg/ma.
0085h -21- 06/22/87
-------
6. RISK ASSESSMENT
6.1. SUBCHflONIC REFERENCE DOSE (RfD$)
Because heptachlor has been shown to be carcinogenic, no RfDST or
RfOQn values for heptachlor win be derived.
ou
6.2. REFERENCE DOSE (RfD)
Because heptachlor has been shown to be carcinogenic, no RfDj or
RfDQ values for heptachlor will be derived.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. Four data sets showed significant Increases 1n the Inci-
dence of hepatocellular carcinomas 1n treated groups compared with controls.
Tables 6-1 through 6-4 present the tumor Incidence for these data sets. A
q,* of 4.5 (mg/kg/day)"1 has been calculated from the geometric mean of
these four data sets which showed an Increase In hepatocellular carcinoma 1n
mice (U.S. EPA, 1986c). This value will be recommended as the q * for the
purpose of this document and the data used to derive It are presented 1n
Tables 6-1 through 6-4. Data were not located within CBI files that would
modify this approach to risk assessment.
6.3.2. Inhalation. Pertinent data concerning the carcinogenic potential
of heptachlor following Inhalation exposure could not be located 1n the
available literature; therefore, an Inhalation q * cannot be calculated.
0085h -22- 06/03/87
-------
TABLE 6-1
Cancer Data Sheet for Derivation of Potency of Heptachlor 1n Male C3H Mice
Compound: heptachlor
Reference: Davis, 1965
Specles/straln/sex: mouse, C3H, male
Route/vehicle: oral, diet
Length of exposure (le) = 24 months
Length of experiment (Le) = 24 months
Body weight = 0.030 kg (assumed)
Tumor site and type: liver, carcinoma
Human Potency (q-|*) = 12.4 per mg/kg/day
Experimental
Animal Dose
(ppm)
0
10
Average
Animal Dose
(mg/kg/day)
0.00
1.43
Equivalent
Human Dose
(mg/kg/day)
0.000
0.108
Tumor Incidence
No. Responding/
No. Examined
22/78
64/87
0085h
-23-
02/04/87
-------
TABLE 6-2
Cancer Data Sheet for Derivation of Potency of Heptachlor 1n Female C3H Mice
Compound: heptachlor
Reference: Davis, 1965
Specles/straln/sex: mouse, C3H, female
Route/vehicle: oral, diet
Length of exposure (le) = 24 months
Length of experiment (Le) = 24 months
Body weight = 0.030 kg (assumed)
Tumor site and type: Hver, carcinoma
Human Potency (q-|*) = 14.9 per mg/kg/day
Experimental
Animal Dose
(ppm)
0
10
Average
Animal Dose
{mg/kg/day)
0.00
1.43
Equivalent
Human Oose
(mg/kg/day)
0.000
0.108
Tumor Incidence
No. Responding/
No. Examined
2/54
57/78
0085h
-24-
06/22/87.
-------
TABLE 6-3
Cancer Data Sheet for Derivation of Potency of Heptachlor
1n Male 86C3F1 Mice
Compound: Technical grade heptachlor
Reference: NCI, 1977b
Specles/straln/sex: mouse, B6C3F1, male
Route/vehicle: oral, diet
Length of exposure (le) = 80 weeks
Length of experiment (Le) = 90 weeks
Body weight = 0.030 kg (assumed)
Tumor site and type: liver, carcinoma
Human Potency (q-)*) = 2.79 per mg/kg/day
Experimental
Animal Dose
(ppm)
0
6.1
13.8
Average
Animal Dose
(mg/kg/day)
0
0.79
1.79
Equivalent
Human Dose
(mg/kg/day)
0
0.063
0.14
Tumor Incidence
No. Responding/
No. Examined
5/19
11/46
34/47
0085h
-25-
02/04/87
-------
TABLE 6-4
Cancer Data Sheet for Derivation of Potency of Heptachlor
1n Female B6C3F1 Mice
Compound: Technical grade heptachlor
Reference: NCI, 1977b
Specles/straln/sex: mouse, B6C3F1, female
Route/vehicle: oral, diet
Length of exposure (le) = 80 weeks
Length of experiment (Le) = 90 weeks
Body weight = 0.030 kg (assumed)
Tumor site and type: liver, carcinoma
Human Potency (q-|*) = 0.83 per mg/kg/day
Experimental
Animal Dose
(ppm)
0
9.0
18.0
Average
Animal Dose
(mg/kg/day)
0
1.17
2.34
Equivalent
Human Dose
(mg/kg/day)
0
0.094
0.18
Tumor Incidence
No. Responding/
No. Examined
2/10
3/47
30/42
0085h
-26-
02/04/87
-------
7. REFERENCES
ACGIH (American Conference of Government Industrial Hyg1en1sts). 1986.
Documentation of the Threshold Limit Values and Biological Exposure Indices,
5th ed. Cincinnati, OH. 296 p.
Ahmed, F.E., R.H. Hart and N.J. Lewis. 1977. Pesticide-Induced DNA damage
and Us repair 1n cultured human cells. Mutat. Res. 42: 161-174.
Arnold, D.W., G.L. Kennedy, Jr., M.L. KepUnger, J.C. Calandra and C.J. Calo.
1977. Dominant lethal studies with technical chlordane, HCS-3260 and hepta-
chlor:heptachlor epoxlde. J. Toxlcol. Environ. Health. 2: 547:555. (Cited
In U.S. EPA, 1987)
Arthur, R.O., J.D. Cain and B.F. Barrentlne. 1975. The effect of atmo-
spheric levels of pesticides on pesticide residues 1n rabbit adipose tissue
and blood sera. Bull. Environ. Contam. Toxlcol. 14: 760. (Cited 1n U.S.
EPA, 1987)
Benes, V. and R. Sram. 1969. Mutagenlc activity of some pesticides In
DrosophUa melanoqaster. Ind. Ned. 38: 50-52.
Cabral, J.R., M.C. Testa and B. Terradnl. T972. Lack of long-term effects
of the administration of heptachlor to suckling rats. TumoM. 58: 49-53.
(Italian with English abstract) (Cited 1n Epstein, 1976)
0085h -27- 06/22/87
-------
Callahan, M.A., H.W. Sllmak, N.W. Gabel, et al. 1979. Hater-Related
Environmental Fate of 129 Priority Pollutants. Chapter 29.
Cerey, K., V. Izakovlc and J. Ruttkay-Nedecka. 1973. Effects of heptachlor
on dominant lethality and bone marrow In rats. Mutat. Res. 21: 26. (CHed
In U.S. EPA, 1987}
Cote. M.G., G.L. Plaa, V.E. Valll and O.C. VUleneuve. 1985. Subchronlc
effects of a mixture of persistent chemicals found In the Great Lakes.
Bull. Environ. Contam. Toxlcol. 34(2): 285-290.
Davis, H.J. 1965. Pathology report on mice fed aldrln, dleldrln, hepta-
chlor or heptachlor epoxlde for two years. Internal FDA memorandum to Or.
A.J, Lehman, Ouly 19. (CHed 1n Epstein, 1976)
Dorough, H.H. 1982. Inhalation toxicology starting with the environment.
Environ. Toxlcol. Chem. 1(3): 213-220.
Enan, E.E., A.H. El-Schae and O.H. Enan. 1982. Effects of some chlorinated
hydrocarbon Insecticides on liver function In white rats. Meded. Far.
Landbouwwet., R. Ksunlv. Gent. 47(1): 447-457. (CHed 1n U.S. EPA, 1987)
Epstein, S.S. 1976. CarclnogenlcHy of heptachlor and chlordane. Sc1.
Total Environ. 6: 103.
FAO/WHO (Food and Agricultural Organization/World Health Organization).
1972. Evaluations of some pesticide residues In food. WHO Pestle. Residues
Ser. No. 2. Geneva. (CHed 1n U.S. EPA, 1987)
0085h . -28- 06/22/87
-------
FWPCA (Federal Water Pollution Control Administration). 1968. Water
quality criteria: Report of the National Technical Advisory Committee to the
Secretary of the Interior. U.S. GPO, Washington, DC. (CHed In U.S. EPA,
1987)
Gentile, J.M, G.J. Gentile, J. Bultman, R. SechMest, E.G. Wagner and M.J.
Plewa. 1982. An evaluation of the genotoxlc properties of Insecticides
following plant and animal activation. Mutat. Res. 101: 19-29.
Hansch C. and A.J. Leo. 1985. Medchem Project. Issue #26. Pomona
College, Claremont, CA.
Harbison, • R.O. 1975. Comparative toxldty of selected pesticides In
neonatal and adult rats. Toxlcol. Appl. Pharmacol. 32: 443. (Cited In
U.S. EPA, 1987)
IARC (International Association for Research on Cancer). 1979. Monograph
on the evaluation of the carcinogenic risk of chemicals to humans. Some
halogenated hydrocarbons. WHO, Lyon, France. 20: 129-135.
IRDC (International Research and Development Corporation). 1973. Unpub-
lished report to Velslcol Chemical Corp., 18-Month Oral Carcinogenic Study
1n Mice. September 26. (CHed In Epstein, 1976)
Jolley, W.P., K.L. Stemmer and E.A. PfHzer. 1966. The effects of feeding
diets containing a mixture of heptachlor and heptachlor epoxlde to female
rats for 2 years. Unpublished report from the Ketterlng Lab. to Velslcol
Corp. January 28. (Cited In Epstein, 1976)
0085h -29- 06/22/87
-------
Klnoshlta, F.K. and C.K. Kempf. 1970. Quantitative measurement of hepatic
mlcrosomal enzyme Induction after dietary Intake of chlorinated hydrocarbon
Insecticides. Toxlcol. Appl. Pharmacol. 17: 288.
Marshall, T.C., W. Dorough and H.E. Swim. 1976. Screening of pesticides
for mutagenlc potential using Salmonella typhlmuMum mutants. J. Agrlc.
Food Chem. 24: 560.
Maslansky, C.J and G.M. HIT Haras. 1981. Evidence for an eplgenetlc mode of
action In organochloMne pesticide hepatocardnogenlclty: Lack of genotoxlc-
1ty In rat, mouse and hamster hepatocytes. J. Toxlcol. Environ. Health. 8:
121-130.
Mestltozova, M. 1967. On reproduction studies on the occurrence of
cataracts In rats after long-term feeding of the Insecticide heptachlor.
ExpeMentla. 23: 42-43. (Cited 1n U.S. EPA, 1987)
Miranda, C.L. and R.E. Webb. 1974. Effect of diet and chemicals on
pesticide toxlclty In rats. PhlUpp. J. Nutr. 27: 30.
Miranda, C.L., R.E. Webb and S.J. RHchey. 1973. Effect of dietary protein
quality, phenobarbHal and SKF 525-A on heptachlor metabolism 1n the rat.
Pestle. Blochem. Physlol. 3: 456.
Mlzyukova, I.G. and G.V. Kurchatov. 1970. Metabolism of heptachlor.
Farmacol. Tokslkol. (Moscow). 33(4): 496-499. (Russ.) (CA 73:86885j)
(Cited In U.S. EPA, 1980a)
0085h -30- 06/22/87
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Morlya, M., T. Ohta, K. Watanabe, T. Mlyazawa, K. Kato and Y. Shlrasu.
1983. Further mutagenldty studies on pesticides In bacterial reversion
assay systems. Mutat. Res. 116(3-4): 185-216. (Cited In U.S. EPA, 1987)
NCI (National Cancer Institute). 1977. Bloassay of heptachlor for possible
cardnogenlcHy. NCI Cardnogenesls Tech. Rep. Ser. No. 9. Ill p. [Also
publ. as DHEH Publ. No. (NIH) 77-809]
NLM (National Library of Medicine). 1986. Hazardous Substances Database
Record Number 554.
NRC (National Research Council). 1982. An assessment of the health risks
of seven pesticides used for termite control. Prepared for Dept. Navy,
Washington, DC. NTIS PB 83-136374. (Cited 1n U.S. EPA, 1987)
OSHA (Occupational Safety and Health Administration. 1985. Safety and
Health Standards. Code of Federal Regulations. 29: 1000-1910.
Reuber, M.D. 1977a. Hepatic vein thrombosis 1n mice Ingesting chlorinated
hydrocarbons. Arch. Toxlcol. 38: 163-168.
Reuber, M.D. 1977b. Hlstopathology of carcinomas of the liver In mice
Ingesting heptachlor or heptachlor epoxlde. Expl. Cell Blol. 45: 147-157.
Reuber, M.D. 1978. Carcinomas and other lesions of the liver In mice
Ingesting organochlorlne pesticides. CUn. Toxlcol. 13(2): 231-256. [Also
available as Reuber, M.D., 1979, Toxlcol. Ann., 3: 231-256]
00»5h -31- 06/22/87
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Robst, G.S., R.E. McMahon, I.E. H111, C.Z. Thompson, J.K. Epp and S.B. Neal.
1981. Chemically-Induced unscheduled DNA synthesis In primary rat hepato-
cyte culture. A comparison with bacterial mutagenldty using 218 compounds.
Environ. Mutagen. 3(1): 11-32. (Cited 1n U.S. EPA, 1987)
Sanborn, J.R., B.M. Francis and R.L. Metcalf. 1977. The degradation of
selected pesticides In soil. A review of published literature. EPA
600/9-77-022. U.S. EPA, Cincinnati, OH. p. 616.
Scheufler E. and K. Rozman. 1984. Enhanced total body clearance of
heptachlor from rats by trans-stllbene oxide. Toxicology. 32(2): 93-104.
Shaln, S.A., J.C. Shaeffer and R.W. Boesel. 1977. The effect of chronic
Ingestlon of selected pesticides upon rat ventral prostate homeostasls.
Toxlcol. Appl. Pharmacol. 40(1): 115-130.
Shlrasu, Y., M. Morlya, K. Kato, A. Furuhashl and T. Kada. 1976. Mutagen-
ldty screening of pesticides In the m1crob1al system. Nutat. Res. 40:
19-30. (CHed 1n U.S. EPA, 1987)
Sperling, F. and H. Ew1n1ke. 1969. Changes In LD5Q of parathlon and
heptachlor after turpentine pretreatment (Abstr. No. 24). Toxlcol. Appl.
Pharmacol. 14: 622. (Cited 1n U.S. EPA, 1987)
U.S. EPA. 1974. Pesticide products containing heptachlor or chlordane.
Federal Register. 39: 41298.
0085h -32- 06/22/87
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U.S. EPA. 1975a. Primary drinking water proposed Interim Standards.
Federal Register. 40: 11990.
U.S. EPA. 1975b. National Interim primary drinking water regulations.
Federal Register. 4: 59566.
U.S. EPA. 1978. Consolidated heptachlor/chlordane cancellation proceed-
ings. Federal Register. 43: 12372.
U.S. EPA. 1980a. Ambient Water Quality Criteria for Heptachlor. 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 440/5-80-052. NTIS PB 81-117632.
U.S. EPA. 1980b. Guidelines and Methodology used 1n the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 49347-49357.
U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic ToxIcHy 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. Graphical Estimates Modeling System (GEMS), Fate of
Atmospheric Pollutants (FAP) Data Base. Computer printout Office of Toxic
Substances, U.S. EPA.
0085h -33- 06/22/87
-------
U.S. EPA. 1986b. Guidelines for Carcinogenic Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986c. Carc1nogen1c1ty Assessment of Chlordane and Heptachlor/
Heptachlor Epoxlde. Carcinogen Assessment Group, Office of Health and
Environmental Assessment, Washington, DC. December 1986 Final.
EPA-600/6-87/004.
U.S. EPA. 1987. Drinking Water Criteria Document for Heptachlor, Hepta-
chlor Epoxlde and Chlordane. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Drinking Water, Washington, DC. Final Draft.
VeHh, G.D., D.L. Delore and B.B. Bergstedt. 1979. Measuring and estimat-
ing the bloconcentratlon factor of chemicals In fish. J. F1sh Res. Board
Can. 36: 1040-1080.
Wang, H.H. and B. MacMahon. 1979. Mortality of workers employed In the
manufacture of Chlordane and heptachlor. 2. Occup. Med. 21: 745-748.
Weatherholtz, W.M., T.C. Cambell and R.E. Webb. 1969. Effect of dietary
protein levels on the toxlclty and metabolism of heptachlor. J. Nutr. 98:
90-94. (Cited 1n U.S. EPA, 1987)
Webb, R.E. and C.L. Miranda. 1973. Effect of the quality of dietary
protein on heptachlor toxlclty. Food Cosmet. Toxlcol. 11: 63-67.
0085h -34- 06/22/87
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Wither-up, S., P.P. Cleveland, F.G. Shaffer, H. Schlecht and L. Musen. 1955.
The physiological effects of the Introduction of heptachlor Into the diet of
experimental animals 1n varying levels of concentration. Unpublished report
from the KetteMng Lab. to Velslcol Corporation, August 17. (Cited 1n
Epstein, 1976}
Zoeteman, B.C.J., K. Harmsen, J.B.H.J. Llnders, C.F.H. Morra and W. Slooff.
1980. Persistent organic pollutants In river water and ground water of The
Netherlands. Chemosphere. 9: 231-249.
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APPENDIX
Oral Summary Table for Heptachlor 1n Male M1cea»b
Experimental Dose Effect q-|*
(mg/kg/day)
TWA dietary concentration heptocellular 4.5 (mg/kg/day)"1
of 0, 6.1, 10, 13.8 or 18 ppm carcinoma (geometric mean)
chronic exposure
aSource: U.S. EPA, 1986c
bNo Inhalation data was available; therefore, no Inhalation q-j* could be
calculated.
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