HEPTACHLOR/HEPTACHLOR
EPOXIDE
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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ATSDR/TP-88/16
TOXICOLOGICAJL PROFILE FOR
HEPTACHLOR/HEPTACHLOR EPOXTOE
Date Published — April 1989
Prepared by:
Dynamac Corporation
under Contract No. 68-D8-0056
for
Agency for Toxic Substances and Disease Registry (ATSDR)
U.S. Public Health Service
in collaboration with
U.S. Environmental Protection Agency (EPA)
Technical editing/document preparation by:
Oak Ridge National Laboratory
under
DOE Interagency Agreement No. 1857-B026-A1
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DISCLAIMER
Mention of company name or product does not consulate endorsement by
the Agency for Toxic Substances and Disease Registry.
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FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Lav 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
This public law (also known as SARA) directed the Agency for Toxic
Substances and Disease Registry (ATSDR) to prepare toxicological
profiles for hazardous substances which are most commonly found at
facilities on the CERCLA National Priorities List and which pose the
most significant potential threat to human health, as determined by
ATSDR and the Environmental Protection Agency (EPA). The list of the 100
most significant hazardous substances was published in the Federal
Register on April 17, 1987.
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each substance on the list. Each
profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute,
subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans."
This toxicological profile is prepared in accordance with
guidelines developed by ATSDR and EPA. The guidelines were published in
the Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by SARA.
The ATSDR toxicological profile is intended to characterize
succinctly the toxicological and health effects information for the
hazardous substance being described. Each profile identifies and reviews
the key literature that describes a hazardous substance's toxicological
properties. Other literature is presented but described in less detail
than the key studies. The profile is not intended to be an exhaustive
document; however, more comprehensive sources of specialty information
are referenced.
ill
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Foreword
Each toxicological profile begins with a public health statement
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement is material that
presents levels of significant human exposure and, where known,
significant health effects. The adequacy of information to determine a
substance's health effects is described in a health effects summary.
Research gaps in toxicologic and health effects information are
described in the profile. Research gaps that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of
the profiles is on health and toxicological information; therefore, we
have included this information in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested
private sector organizations and groups, and members of the public. We
plan to revise these documents in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been
reviewed by scientists from ATSDR, EPA, the Centers for Disease Control,
and the National Toxicology Program. It has also been reviewed by a
panel of nongovernment peer reviewers and was made available for public
review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
James 0. Mason, M.D., Dr. P.H.
Assistant Surgeon General
Administrator, ATSDR
iv
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CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT ARE HEPTACHLOR AND HEPTACHLOR EPOXIDE? 1
1.2 HOW MIGHT I BE EXPOSED TO HEPTACHLOR AND
HEPTACHLOR EPOXIDE? 1
1.3 HOW DO HEPTACHLOR AND HEPTACHLOR EPOXIDE
GET INTO MY BODY? 1
1.4 HOW CAN HEPTACHLOR AND HEPTACHLOR EPOXIDE
AFFECT MY HEALTH? 2
1.4.1 Brief Exposures at High Levels 2
1.4.2 Long-Term Exposures at Varying Levels 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE
BEEN EXPOSED TO HEPTACHLOR AND HEPTACHLOR EPOXIDE? 3
1.6' WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 3
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
MADE TO PROTECT HUMAN HEALTH? 5
2. HEALTH EFFECTS SUMMARY 7
2.1 INTRODUCTION 7
2.2 LEVELS OF SIGNIFICANT EXPOSURE 8
2.2.1 Key Studies and Graphical Presentations 8
2.2.1.1 Inhalation 8
2.2.1.2 Oral 9
2.2.1.3 Dermal 17
2.2.2 Biological Monitoring as a Measure of Exposure
and Effects 17
2.2.3 Environmental Levels as Indicators of Exposure
and Effects 18
2.2.3.1 Levels found in the environment 18
2.2.3.2 Human exposure potential 18
2.3 ADEQUACY OF DATABASE 18
2.3.1 Introduction 18
2.3.2 Health Effect End Points 19
2.3.2.1 Introduction and graphic summary 19
2.3.2.2 Description of highlights of graphs 22
2.3.2.3 Summary of relevant ongoing research 22
2.3.3 Other Information Needed for Human
Health Assessment 24
2.3.3.1 Pharmacokinetics and mechanisms
of action 24
2.3.3.2 Monitoring of human biological samples ... 24
2.3.3.3 Environmental considerations 24
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Cone
3.
4.
encs
CHEMICAL AND PHYSICAL INFORMATION
3 . 1 CHEMICAL IDENTITY
3 . 2 PHYSICAL AND CHEMICAL PROPERTIES
TOXICOLOGICAL DATA
4 . 1 OVERVIEW OF TOXICOLOGICAL DATA
4 . 2 TOXICOKINETICS
4.2.1 Overview
4.2.2 Absorption
4.2.2.1 Inhalation
4.2.2.2 Oral
4.2.2.3 Dermal
4.2.3 Distribution
4.2.3.1 Inhalation
4.2.3.2 Oral
4.2.3.3 Dermal
4.2.4 Metabolism
4.2.4.1 Inhalation
4.2.4.2 Oral
4.2.4.3 Dermal
4.2.5 Excretion
4.2.5.1 Inhalation
4.2.5.2 Oral
4.2.5.3 Dermal
4 . 3 TOXICITY
4.3.1 Lethality and Decreased Longevity
4.3.1.1 Overview
4.3.1.2 Inhalation
4.3.1.3 Oral
4.3.1.4 Dermal
4.3.2 Systemic/Target Organ Toxicity
4.3.2.1 Overview
4.3.2.2 Hepatotoxici ty
4.3.2.3 Neurologic effects
4.3.2.4 Adrenotoxicity
4.3.2.5 Renal toxic ity
4.3.2.6 Hematologic effects
4.3.3 Developmental Toxicity
4.3.3.1 Overview
4.3.3.2 Inhalation
4.3.3.3 Oral
4.3.3.4 Dermal
4.3.3.5 General discussion
4.3.4 Reproductive Toxicity
4.3.4.1 Overview
4.3.4.2 Inhalation
4.3.4.3 Oral
4.3.4.4 Dermal
4.3.4.5 General discussion
4.3.5 Genotoxicity
4.3.5.1 Overview
4.3.5.2 Review of data
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e •»
vi
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Contents
4.3.6 Carclnogenicity 61
4.3.6.1 Overview 61
4.3.6.2 Inhalation 61
4.3.6.3 Oral 62
4.3.6.4 Dermal 62
4.3.6.5 General discussion 72
4.4 INTERACTIONS WITH OTHER CHEMICALS 72
5. MANUFACTURE, IMPORT, USE, AND DISPOSAL 73
5.1 OVERVIEW 73
5.2 PRODUCTION 73
5.2.1 Manufacturing Process 73
5.2.2 Volume 73
5.2.3 Producers 74
5.3 IMPORT 74
5.4 USE 74
5.5 DISPOSAL 74
6. ENVIRONMENTAL FATE 75
6.1 OVERVIEW 75
6.2 RELEASES TO THE ENVIRONMENT 75
6.3 ENVIRONMENTAL FATE 75
6.3.1 Transport and Partitioning 75
6.3.2 Transformation and Degradation 75
6.3.3 Bioconcentration 76
7. POTENTIAL FOR HUMAN EXPOSURE 77
7.1 OVERVIEW 77
7.2. LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 77
7.2.1 Air 77
7.2.2 Water 77
7.2.3 Soil 78
7.2.4 Other 78
7.3 OCCUPATIONAL EXPOSURES 78
7.4 POPULATIONS AT HIGH RISK 79
8. ANALYTICAL METHODS 81
8.1 ENVIRONMENTAL MEDIA 81
8.2 BIOLOGICAL SAMPLES 81
8.3 GENERAL DISCUSSION 81
9. REGULATORY AND ADVISORY STATUS 85
9.1 INTERNATIONAL 85
9.2 NATIONAL 85
9.2.1 Regulations 85
9.2.2 Advisory Guidance 86
9.2.3 Data Analysis 87
9.2.3.1 Reference doses (RfDs) 87
9.2.3.2 Carcinogenic potency 88
9.3 STATE 88
9.3.1 Regulations 88
9.3.2 Advisory Guidance 88
10. REFERENCES 89
11. GLOSSARY 105
APPENDIX: PEER REVIEW 109
vii
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LIST OF FIGURES
1.1 Health effects from ingesting heptachlor/heptachlor
epoxide 4
2.1 Levels of significant exposure for heptachlor/heptachlor
epoxide-- inhalation 10
2.2 Effects of heptachlor/heptachlor epoxide--oral exposure 11
2.3 Levels of significant exposure for heptachlor/heptachlor
epoxide--oral 12
2.4 Availability of information on health effects of heptachlor/
heptachlor epoxide (human data) 20
2.5 Availability of information on health effects of heptachlor/
heptachlor epoxide (animal data) 21
4.1 Metabolic scheme for heptachlor in rats 37
ix
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LIST OF TABLES
3.1 Chemical identity of heptachlor and heptachlor epoxide 28
3.2 Physical and chemical properties of heptachlor and
heptachlor epoxide 29
4.1 Lowest reported LD50 for heptachlor and heptachlor
epoxide for various species 40
4.2 Microscopic hepatic effects of intermediate oral
exposure to heptachlor/heptachlor epoxide 44
4.3 Microscopic hepatic effects of chronic oral
exposure to heptachlor/heptachlor epoxide 46
4.4 NOAELs and LOAELs for suppression of body weight gain
by oral intake of heptachlor/heptachlor epoxide 48
4.5 Genotoxicity of heptachlor and heptachlor
epoxide (in vitro) 58
4.6 Genotoxicity of heptachlor and heptachlor epoxide (in vivo) .. 59
4.7 Cancer data sheet for derivation of potency of heptachlor
from hepatocellular carcinomas in female mice--I 63
4.8 Cancer data sheet for derivation of potency of heptachlor
from hepatocellular carcinomas in male mice--I 64
4.9 Cancer data sheet for derivation of potency of heptachlor
from hepatocellular carcinomas in female mice--II 65
4.10 Cancer data sheet for derivation of potency of heptachlor
from hepatocellular carcinomas in male mice--II 66
4.11 Cancer data sheet for derivation of potency of heptachlor
epoxide from hepatocellular carcinomas in female mice 67
4.12 Cancer data sheet for derivation of potency of heptachlor
epoxide from hepatocellular carcinomas In male mice 68
4.13 Cancer data sheet for derivation of potency of heptachlor
epoxide from hepatic carcinomas in female mice--I 69
4.14 Cancer data sheet for derivation of potency of heptachlor
epoxide from hepatic carcinomas in male mice 70
4.15 Cancer data sheet for derivation of potency of heptachlor
epoxide from hepatic carcinomas in female mice--II 71
8.1 Analytical methods for heptachlor and heptachlor epoxide
in environmental media 82
8.2 Analytical methods for heptachlor and heptachlor epoxide
in biological samples 84
xi
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1. PUBLIC HEALTH STATEMENT
1.1 WHAT ARE HEPTACHLOR AND HEPTACHLOR EPOXIDE?
Heptachlor is a man-made compound useful for the control of
termites. As a pure compound, heptachlor is a light tan solid that
smells something like camphor. Heptachlor epoxide is an oxidation
product of heptachlor formed by many plants and animals, including
people, after exposure to heptachlor. Heptachlor is present as an
impurity in the pesticide chlordane.
1.2 HOW NIGHT I BE EXPOSED TO HEPTACHLOR AND HEPTACHLOR EPOXIDE?
During the 1960s and 1970s, heptachlor was primarily used by
farmers to kill insects in seed grains and on crops, as well as by
exterminators and home owners to kill termites. During those years,
people could be exposed to heptachlor, usually as its oxidation product
heptachlor epoxide, through ingesting contaminated food and by the
misapplication of the chemical in homes.
Since late 1978, most uses of heptachlor have been phased out so
that this chemical is no longer available to the general public. In
August 1987, Velsicol Chemical Company, the only U.S. producer of
heptachlor, stopped selling this product. As of April 1988, heptachlor
can no longer be used for the underground control of termites. People
whose homes have been treated may continue to be exposed to this
chemical through the air over long periods of time.
Heptachlor epoxide remains in the soil for long periods of time.
One study showed that a crop grown in soil treated 15 years before with
heptachlor still contained heptachlor epoxide. Exposure can, therefore,
result from eating foods grown in soils treated a long time ago with
heptachlor.
Heptachlor and heptachlor epoxide may also be present at numerous
hazardous waste sices where workers and others on-site may be exposed.
It is also possible for people off-site to be exposed from the release
of heptachlor and heptachlor epoxide into the air or into neighboring
bodies of water.
1.3 HOW DO HEPTACHLOR AND HEPTACHLOR EPOZIDE GET INTO MY BOOT?
It is possible to breathe air containing very low levels of
heptachlor over long periods of time if one's house has been treated by
underground application. If the application is faulty, the level of
exposure would be expected to be increased.
Another way for heptachlor and heptachlor epoxide to enter the
human body is by eating foods or by drinking water or milk contaminated
with the compounds. Heptachlor is converted to heptachlor epoxide in the
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2 Section 1
body. However, since heptachlor cannot be used on farm crops anymore,
Che risk of exposure through these routes has been considerably reduce.
Residual heptachlor epoxide may still be present in soils or at
hazardous waste sites from which they may be transferred to crops or
food animals. If mothers have been exposed to heptachlor or heptachlor
epoxide, their breast-fed babies will ingest the compound in the milk.
Heptachlor or heptachlor epoxide may enter the body by penetrating
the skin. However, this route of exposure is extremely limited for the
general public since heptachlor is no longer available to the consumer.
Absorption through the skin is possible for those such as professional
exterminators who used heptachlor to treat houses for termites, and
workers at hazardous waste cleanup sites and at the manufacturing site.
1.4 HOV CAN HEPTACHLOR AND HZPTACHLOR EPOZIDE AFFECT MY HEALTH?
Heptachlor and heptachlor epoxide are clearly toxic to animals and
humans. How they affect your health would depend on how much you are
exposed to and for how long.
1.4.1 Brief Exposures at High Levels
Little information is available regarding human health effects from
brief exposures to high levels of heptachlor. Studies with animals have
shown that heptachlor and heptachlor epoxide are very toxic compounds. A
level of 100 milligrams of heptachlor per cubic meter of air (mg/m3) is
considered by the National Institute for Occupational Safety and Healt*
(NIOSH) to pose an immediate threat to life. This level of exposure
could only occur in an occupational setting.
Tremors and convulsions have been reported in laboratory animals
given heptachlor orally at high levels for short periods of time.
Similar effects have been seen in humans exposed to some related
pesticides at high levels.
1.4.2 Long-Term Exposures at Varying Levels
Little information is available with respect to health effects in
humans after long-term exposure to varying levels of heptachlor. Long-
term exposure to heptachlor or heptachlor epoxide may affect the liver.
Studies with animals fed heptachlor or heptachlor epoxide have shown
enlarged livers and damage to liver tissue, damage to kidney tissue, and
increased numbers of red blood cells. Tremors and convulsions are also
seen in animals in long-term exposure studies.
There is evidence that heptachlor and heptachlor epoxide are
associated with infertility and improper development of offspring.
Animal studies have shown that females were less likely to become
pregnant when both males and females were fed heptachlor. Baby rats born
to mothers fed relatively low doses of heptachlor showed a tendency to
develop cataracts shortly after their eyes opened.
Heptachlor fed to animals has caused liver cancer. The U.S.
Environmental Protection Agency (EPA) considers heptachlor and
heptachlor epoxide to be probable human cancer-causing agents based r
the results of studies with laboratory animals. The International Agv
for Research on Cancer (LARC) states that there is inadequate evidence
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Public Health Statement
that heptachlor causes cancer In humans,
it causes cancer in animals.
and only limited evidence that
1.3 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN
EXPOSED TO HEPTACHLOR AND HEPTACHLOR EPOXIDET
Heptachlor epoxide, the oxidation product of heptachlor, can be
measured in breast milk, body fat, or blood; however, there are
insufficient data to enable correlation of concentration levels in these
tissues with possible health effects.
1.6 WHAT LEVELS OP EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
Human data enabling correlation of levels of exposure to heptachlor
or heptachlor epoxide by any route with harmful health effects were not
found. Also, no information was found concerning harmful effects to
laboratory animals by breathing air contaminated with heptachlor or
heptachlor epoxide. The only information found, concerning harmful
effects of skin contact with the compounds for animals, was that
application of a solution of 195 to 250 milligrams per kilogram of body
weight (mg/kg) of heptachlor to the skin of rats caused death.
Figure 1.1 shows the relationship between exposure to heptachlor or
heptachlor epoxide and known health effects from eating foods or
drinking liquids containing heptachlor or heptachlor epoxide. The scale
on the graph represents exposure measured in milligrams of heptachlor or
heptachlor epoxide per kilogram of body weight per day (mgAg/day) .
The first column, called short-term exposure, shows the known
health effects from exposure to heptachlor or heptachlor epoxide for two
weeks or less. The second column, long-term exposure, shows known health
effects for exposures lasting over two weeks.
Levels of exposure may be calculated from cancer potency estimates
from the Carcinogen Assessment Group (GAG) of the EPA that may be
expected to cause a rate of 1 in 10,000 and of 1 in 10,000,000 following
ingestion. It must be emphasized, however, that these calculations based
on testing in animals represent the upper limit of the probable risk to
man; actual risks are likely to be much lower.
Risk
Dose
Heptachlor
Heptachlor epoxide
1 in 10,000
1 in 10,000,000
1 in 10,000
1 in 10,000,000
0.000022 mgAg/day
0.000000022 mgAg/day
0.000011
0.000000011
Since these numbers are extremely small, they have not been plotted in
Fig. 1.1.
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Section 1
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
EFFECTS
IN
ANIMALS
DOSE
(mg/kg/day)
1000
NERVE !
DEATH
TOXICITY
LIVER
TOXICITY
100
10
•1 0
01
0.01
EFFECTS
IN
HUMANS
QUANTITATIVE
DATA WERE
NOT
AVAILABLE
EFFECTS
IN
ANIMALS
KIDNEY -
TOXICITY
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
LIVER
TOXICITY <
BLOOD —
EFFECTS
INFERTILITY •
DOSE
(mg/kg/day)
1000
100
10
1 0
01
001
EFFECTS
IN
HUMANS
QUANTITATIVE DATA
WERE NOT AVAILABLE
Fig. 1.1. Health effects from ingesting hepUchlor /beptochlor epoxide.
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Public Health Statement 5
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
MADE TO PROTECT HUMAN HEALTH?
The government has set limits on exposure of individuals to
heptachlor and heptachlor epoxide from air in the workplace and from
contamination of food and water.
The EPA has cancelled the registration permitting the application
of heptachlor to crops or for seed treatment. The EPA has also set very
low levels of less than 0.1 part of heptachlor or heptachlor epoxide per
one million parts of grain or vegetable (0.1 ppm) in or on farm
products.
Most heptachlor exposures now involve workers who manufacture the
compound or workers at hazardous waste sites. The government has
established very strict limits for exposure in the workplace. The
Occupational Safety and Health Administration (OSHA) has established an
occupational exposure limit for heptachlor in air of 0.5 mg/m3. NIOSH
has recommended the same exposure limit. In addition, NIOSH has
recommended that workers who potentially may be exposed to heptachlor be
given a preemployment physical examination as well as periodic
reexaminations. These examinations should stress evaluations of the
eyes, nervous system, liver, and kidneys. Since heptachlor and
heptachlor epoxide have been shown to cause liver cancer in laboratory
animals, any exposure to them involves some potential risk.
The EPA in 1987 published health advisories for heptachlor and
heptachlor epoxide in drinking water; these advisories represent levels
of protection only for noncancer toxicity.
- 10-day health advisory--10 parts heptachlor per billion parts water
(ppb) based on heptachlor's ability to produce liver injury in a
10-kg child.
• Lifetime health advisory--17.5 ppb for heptachlor; 0.4 ppb for
heptachlor epoxide.
The National Academy of Sciences (NAS) published a health advisory in
1977 (based on cancer risk) recommending the following limits for long-
term exposure in drinking water: heptachlor, 0.0104 ppb; and heptachlor
epoxide, 0.0006 ppb.
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2. HEALTH EFFECTS SUMMARY
2.1 INTRODUCTION
This section summarizes and graphs data on the health effects
concerning exposure to heptachlor and heptachlor epoxide. The purpose of
this section is to present levels of significant exposure for heptachlor
and heptachlor epoxide based on key toxicological studies,
epidemiological investigations, and environmental exposure data. The
information presented in this section is critically evaluated and
discussed in Sect. 4, Toxicological Data, and Sect. 7, Potential for
Human Exposure.
This Health Effects Summary section comprises two major parts.
Levels of Significant Exposure (Sect. 2.2) presents brief narratives and
graphics for key studies in a manner that provides public health
officials, physicians, and other interested individuals and groups with
(1) an overall perspective of the toxicology of heptachlor and
heptachlor epoxide and (2) a summarized depiction of significant
exposure levels associated with various adverse health effects. This
section also includes information on the levels of heptachlor and
heptachlor epoxide that have been monitored in human fluids and tissues
and information about levels of heptachlor and heptachlor epoxide found
in environmental media and their association with human exposures.
The significance of the exposure levels shown on the graphs may
differ depending on the user's perspective. For example, physicians
concerned with the interpretation of overt clinical findings in exposed
persons or with the identification of persons with the potential to
develop such disease may be interested in levels of exposure associated
with frank effects (Frank Effect Level, FEL). Public health officials
and project managers concerned with response actions at Superfund sites
may want information on levels of exposure associated with more subtle
effects in humans or animals (Lowest-Observed-Adverse-Effect Level,
LOAEL) or exposure levels below which no adverse effects (No-Observed-
Adverse- Effect Level, NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels) are of interest to
health professionals and citizens alike.
Adequacy of Database (Sect. 2.3) highlights the availability of key
studies in the scientific literature on exposure to heptachlor and
heptachlor epoxide and displays these data in three-dimensional graphs
consistent with the format in Sect. 2.2. The purpose of this section is
to suggest where there might be insufficient information to establish
levels of significant human exposure. These areas will be considered by
the Agency for Toxic Substances and Disease Registry (ATSDR), EPA, and
the National Toxicology Program (NTP) of the U.S. Public Health Service
in order to develop a research agenda for heptachlor and heptachlor
epoxide.
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8 Section 2
2.2 LEVELS OF SIGNIFICANT EXPOSURE
2.2.1 Key Studies and Graphical Presentations
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the toxicology data
summarized in this section are organized first by route of exposure--
inhalation, ingestion, and dermal--and then by toxicological end points
that are categorized into six general areas--lethality, systemic/target
organ toxicity, developmental toxicity, reproductive toxicity, genetic
toxicity, and carcinogenicity. The data are discussed in terms of three
exposure periods--acute, intermediate, and chronic.
Two kinds of graphs are used to depict the data. The first type Ls
a "thermometer" graph. It provides a graphical summary of the human and
animal toxicological end points (and levels of exposure) for each
exposure route for which data are available. The ordering of effects
does not reflect the exposure duration or species of animal tested. The
second kind of graph shows Levels of Significant Exposure (LSE) for each
route and exposure duration. The points on the graph showing No-
Observed- Adverse -Effect Levels (NOAELs) and Lowest-Observed-Adverse-
Effect Levels (LOAELs) reflect the actual doses (levels of exposure)
used in the key studies. No adjustments for exposure duration or
intermittent exposure protocol were made.
Adjustments reflecting the uncertainty of extrapolating animal data
to man, intraspecies variations, and differences between experimental
versus actual human exposure conditions were considered when estimates
of levels posing minimal risk to human health were made for noncancer
end points. These minimal risk levels were derived for the most
sensitive noncancer end point for each exposure duration by applying
uncertainty factors. These levels are shown on the graphs as a broken
line starting from the actual dose (level of exposure) and ending with a
concave-curved line at its terminus. Although methods have been
established to derive these minimal risk levels (Barnes et al. 1987),
shortcomings exist in the techniques that reduce the confidence in the
projected estimates. Also shown on the graphs under the cancer end point
are low-level risks (10^ to W7) reported by EPA. In addition, the
actual dose (level of exposure) associated with tumor incidence is
plotted.
2.2.1.1 Inhalation
A plot of key data available for animals vs humans is not shown for
the inhalation route since the only point would be the odor threshold of
0.02 ppm in hunans.
Lethality. No key studies were found in the available literature.
In human case reports, convulsions and death were reported following
Inhalation of technical-grade chlordane, a compound that is structurally
similar to heptachlor and typically contains 10% of that chemical (CAG
1986).
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Health Effects Summary 9
Systemic/target organ toxicity. No key animal studies were found
in Che available literature. Human case reports described neurotoxic and
hematologic effects, following acute, intermediate, or chronic exposure
to technical-grade chlordane.
Developmental toxicity. No key studies were found in the available
literature. Available information on possible human developmental
toxicity from exposure to heptachlor is summarized in Sect. 2.2.1.2.
Reproductive tozicity. No key studies were found in the available
literature. Available information on possible human reproductive
toxicity from mixed pesticide or heptachlor exposure is summarized in
Sect. 2.2.1.2.
Genotoxicity. No information was found in the available literature
concerning genotoxic effects in humans or animals following inhalation
of heptachlor or heptachlor epoxide.
Carcinogenicity. No key animal studies were found in the available
literature. Information on oncogenic effects in humans following
exposures to mixtures of chemicals, including heptachlor, via
unspecified routes is summarized in Sect. 2.2.1.2.
Levels of exposure can be calculated from cancer potency estimates
generated by the EPA (CAG 1986) for lifetime risks of 10'4 to 10'7 for
cancer from exposure by the inhalation route (plotted on Fig. 2.1). The
calculations, based on testing in animals, represent the upper limit of
the probable risk to man; actual risks are likely to be much lower.
Concentration
(mg/m3)
Risk Heptachlor Heptachlor epoxide
10'4 7.7 x 10'5 3.8 x 10'5
10'5 7.7 x 10'6 3.8 x 10'6
10'6 7.7 x 10'7 3.8 x 10'7
10'7 7.7 x 10'8 3.8 x 10'8
It should be noted that the EPA CAG assessment of heptachlor and
heptachlor epoxide had not undergone peer review at the time this
profile was prepared.
2.2.1.2 Oral
Graphical representations of key data for the oral route of
exposure are shown at the end of this section for animals vs humans
(Fig. 2.2) and for different durations of exposure (Fig. 2.3).
Lethality, acute. No key studies were found for humans. Key oral
single-dose lethal doses in animals were as follows:
Rats--71 mgAg, heptachlor (Podowski et al. 1979)
60 mg/kg, heptachlor epoxide (Podowski et al. 1979)
Mice--70 mgAg, heptachlor (Gak et al. 1976)
30 mg/kg. heptachlor/heptachlor epoxide (25%:75%) (Arnold et
al. 1977)
Hamsters--100 mgAg. heptachlor (Gak et al. 1976)
-------
10 Section 2
(mg/m3)
1 r-
ACUTE
(S 14 DAYS)
QUANTITATIVE
DATA WERE
NOT
AVAILABLE
INTERMEDIATE
(15-364 DAYS)
QUANTITATIVE
DATA WERE
NOT
AVAILABLE
0.1 -
0.01 -
0.001 -
CHRONIC
* 365 DAYS)
CANCER
0.0001 -
0.00001 -
0.000001 -
HEPTACHLOR
He
10-4-,
10-5 -
io-6-
10~7 -
(
10-* -,
10-5-
,0--
10-7-
HEPTACHLOR
EPOXIDE
ESTIMATED
UPPER-BOUND
HUMAN CANCER
RISK LEVELS
0.0000001 -
0.00000001 «-
Fig. 2.1. LcTeto of significant exposure for beptacUor/lwptacUor epoxide— inhabdon.
-------
Health Effects Summary 11
ANIMALS
(mg/kg/diy)
100 i— I
HUMANS
10
01
HAMSTER. LOW(H)
RAT TREMORS AND CONVULSIONS. SINGLE DOSE (H)
MOUSE. ADRENAL TOXICITY 26 DAYS. CONTINUOUS (H)
HAT AND MOUSE LD» (H)
RATIO, (HE)
I MOUSE. HYPOACTTVITY. SINGLE DOSE (H/HE)
*l MOUSE. RENAL TOXICITY. 10 WEEKS. CONTINUOUS (H)
: I RAT. REDUCED SURVIVAL 6 WEEKS CONTINUOUS (H)
•l MOUSE. ATAXIA. 10 WEEKS. CONTINUOUS (H)
O I MOUSE. REPRODUCTIVE EFFECTS. SINGLE DOSE (H/HE)
I MOUSE. RENAL TOXICITY. 10 WEEKS. CONTINUOUS (H)
. • MOUSE. REDUCED SURVIVAL. 6 WEEKS. CONTINUOUS (H)
I MOUSE ATAXIA. 10 WEEKS CONTINUOUS (H)
01 RAT. REDUCED SURVIVAL. 6 WEEKS. CONTINUOUS. (H)
O MOUSE. REDUCED SURVIVAL. 6 WEEKS. CONTINUOUS (H)
• MOUSE REDUCED SURVIVAL. 80 WEEKS. CONTINUOUS (H)
i MOUSE. REDUCED SURVIVAL. IB MONTHS. CONTINUOUS (H/HE)
• 1 MOUSE. REDUCED SURVIVAL. 104 WEEKS. CONTINUOUS (HE)
O MOUSE. REDUCED SURVIVAL 90 WEEKS. CONTINUOUS (H)
' RAT. HEMATOLOQIC EFFECT. 28 DAYS. INTERMTTTENT (H)
RAT. HEPATOTOXJCITY. 7 DAYS. INTEHMTTTENT (H)
, RAT. EEG CHANGES. 3 GENERATIONS. CONTINUOUS (H)
O MOUSE. REDUCED SURVIVAL. 18 MONTHS. CONTINUOUS (H/HE)
• RAT. HEPATOTOXICITY 5 MONTHS. CONTINUOUS (H/HE)
f RAT HEPATOTOXICITY. 110 WEEKS. CONTINUOUS (H)
9< RAT REPRODUCTIVE AND DEVELOPMENTAL EFFECTS 60 DAYS. CONTINUOUS (H)
I RAT. REDUCED SURVIVAL. 2 YEARS. CONTINUOUS (H/HE)
MOUSE. HEPATOTOXICITY. 6 MONTHS AND 18 MONTr**. CONTINUOUS (H/HE)
RAT. HEPATOTOXICITY 110 WEEKS. CONTINUOUS (H)
RAT HEPATOTOXICrrY. 110 WEEKS. CONTINUOUS (H)
DOG. HEPATOTOXCITY. 2 YEARS. CONTINUOUS (HE)
• RAT. HEPATOTOXICrrY. 108 WEEKS. CONTINUOUS (HE)
• DOG. HEPATOTOXICrrY. 60 WEEKS CONTINUOUS (HE)
001
QUANTITATIVE DATA
WERE NOT AVAILABLE
H HEPTACHLOR
HE HEPTACHLOR EPOXIDE
• LOAELORLOEL
O NOAELORNOEL
Fig. 2.2. Effects of hcptacUor/hepUchlor epoxide—oral exposure.
-------
12 Section 2
ACUTE
(114 DAYS)
INTERMEDIATE
(1S-3MOAVS)
CHRONC
RMS DAYS)
DEVELOP- TARGET REPRO. REDUCED TARGET REPRO- REDUCED TARGET
l£THAUTY MENTAL ORGAN DUCTBH SURVIVAL ORGAN OUCTCN SURVIVAL ORGAN CANCER
1000 -
too -
X) -
01
001
0001
00001
0000001
0 0000001
000000001
r. m. H
O
• r H(UVER)
frH
• r WHE (UVER)
f m »«HE(UVER)
m H/ME
\
f" H
0
m.H
J.mHE
r H(UVER)
r.WHE*
rHE
r HE (UVER) •
-------
Health Effaces Summary 13
Lethality, intermediate. No information was found for humans.
Increased mortality was reported in both sexes of Osborne-Mendel
rats and B6C3F1 mice fed technical-grade heptachlor in the diet for 6
weeks, followed by a 2-week period of observation. The LOAEL for rats
(based on data for females) was 16 mgAg/day; the NOAEL was 8 mg/kg/day.
The LOAEL for mice (based on data for males or females) was 12
mgAg/day; the NOAEL was 6 mgAg/day (NCI 1977).
Lethality, chronic. No information was found for humans.
Increased mortality was reported in female CD rats fed
heptachlor/heptachlor epoxide (75%:25%) in the diet for up to 2 years.
The LOAEL was 0.25 mgAg/day; a NOAEL was not established (Jolley et al.
1966, as cited in Epstein 1976).
Increased mortality was reported in male and female C3H mice
(combined) fed heptachlor epoxide in the diet for up to 104 weeks. The
LOAEL was 1.5 mg/kg/day; a NOAEL was not established (Davis 1965, as
cited in Epstein 1976).
Increased mortality was reported in both male and female Charles
River CD-I mice fed diets containing heptachlor/heptachlor epoxide
(25%:75%) for up to 18 months. The LOAEL was 1.5 mgAg/day. and the
NOAEL was 0.75 mgAg/day (IRDC 1973, as cited in Epstein 1976).
Increased mortality was reported in female, but not male, B6C3F1
mice fed diets containing technical-grade heptachlor for 80 weeks,
followed by observation for 10 weeks. The LOAEL was 2.7 mgAg/day, and
the NOAEL was 1.35 mgAg/day (NCI 1977).
Systemic/target organ toxicity. acute. No key studies for humans
were found in the available literature. Case reports described
neurotoxic effects in humans following their exposure (route not
specified) to technical-grade chlordane, a compound structurally related
to heptachlor and typically containing heptachlor at concentrations up
to 10% (GAG 1986).
The liver appears to be the most sensitive target organ for the
acute oral toxic effects of heptachlor/heptachlor epoxide in animals.
Enan et al. (1982) reported that acute administration of heptachlor to
rats in the diet induced several effects compatible with hepatic damage
including increased liver weight and increased serum levels of
bilirubin, alkaline phosphatase, and urea. The LOAEL was 1 mgAg/day; a
NOAEL was not established. Frank microscopic damage to the liver,
including steatosis and necrosis, was reported to occur in rats at acute
oral heptachlor doses of 5 to 7 mgAg/day (Krampl 1971, Pelikan 1971).
Hypoactivity and some deaths were reported in mice given a single
gavage dose of heptachlor/heptachlor epoxide (25%:75%) at levels near
the LD50- The LOAEL was 30 mgAg! a NOAEL was not established (Arnold et
al. 1977). Tremors and convulsions were reported in rats given the acute
oral LD50 dose of heptachlor of 90 mgAg (Lehman 1951).
Systemic/target organ tozicity. intermediate. No key studies for
humans were found in the available literature.
-------
14 Section 2
The liver appears to be the most sensitive target organ for the
intermediate oral toxic effects of heptachlor/heptachlor epoxide in
animals. Jolle^ et al. (1966, as cited in Epstein 1976) reported
hepatocytomegaly in' rats that had been fed heptachlor/heptachlor epoxide
(75%:25%) for 5 months. The LOAEL was 0.38 mg/kg/day; a NOAEL was not
established. IRDC (1973, as cited in Epstein 1976) reported dose-related
incidences of hepatocytomegaly and increased mean liver weights in mice
that had been fed heptachlor/heptachlor epoxide (25%:75%) for 6 months.
The LOAEL was 0.15 mg/kg/day; a NOAEL was not established. Frank
microscopic damage to the liver, including steatosis, fibrosis, or
necrosis, was reported to occur following intermediate oral exposure of
rats, pigs, and sheep to heptachlor at a level of 2 or 5 mg/kg/day
(Halacka et al. 1975, Pelikan 1971) and mice to heptachlor at a level of
7.5 mgAg/day (Akay and Alp 1981).
Ataxia and whole-body tremors were reported during intermediate
oral exposure of mice to heptachlor. The LOAEL was 15 mg/kg/day, and the
NOAEL was 7.5 mgAg/day (Akay and Alp 1981).
Atrophy of the adrenal cortex, including hypertrophy, heavy lipid
accumulation, granulation, and cell degeneration with extensive
destruction and fibrosis, was reported following administration to mice
of heptachlor in the drinking water at a reported concentration of 100
ppm (80 mgAg/day) for up to 26 days (Akay et al. 1982). The validity of
the 100-ppm dose level can be questioned since the solubility of
heptachlor in water is 56 mg/L or 0.056 ppm (Worthing and Walker 1983),
implying either that the dose level was incorrectly reported or that '
heptachlor was present in suspension, thus bringing into question the
uniformity of dosing. In addition, the 80-mg/kg/day dose level was
calculated using the authors' stated water consumption rate of 20
cc/day/mouse Akay et al. (1982); this is in excess of the usual 4 to 7
mL/day/mouse water intake reported by Arrington (1972).
Kidney granulomas were reported following administration of
heptachlor in the diet of mice for 10 weeks. The LOAEL was 30 mgAg/day,
and the NOAEL was 15 mgAg/day (Akay and Alp 1981) .
Elevated white blood cell counts were reported in rats that had
been fed heptachlor at a concentration of 1 mgAg/day, 5 days/week, for
a total of 28 days (Enan et al. 1982). Spleen fibrosis and Increased
numbers of red and white blood cells in the spleen were reported in mice
that had been fed heptachlor at a concentration of 30 mgAg/day for 10
weeks; it was not clear whether these changes were induced by doses of
15 or 7.5 mgAg/day (Akay and Alp 1981).
Systemic/target organ toxicity, chronic. No key studies for humans
were found in the available literature. Case reports described
hematologic effects in humans following exposure (route not specified)
to technical-grade chlordane. which typically contains 10% heptachlor
(CAG 1986). The incidence of cerebrovascular disease was significantly
increased in workers engaged in the manufacture of chlordane,
heptachlor, and endrin (Wang and McMahon 1979b), but was not increased
in pesticide applicators and termite control operators principally
exposed to chlordane and heptachlor by the inhalation, oral, and/or
dermal routes (Wang and MacMahon 1979a). The observation of
-------
Health Effects Suznnary 15
cerebrovascular disease reported by Wang and HacMahon (1979b) has not
been confirmed in other studies.
The liver appears to be the most sensitive target organ for the
chronic oral toxic effects of heptachlor/heptachlor epoxide in animals.
Increased mean liver weights and liver lesions of the "chlorinated
hydrocarbon" type were reported in rats that had been fed heptachlor
alone for up to 110 weeks. The LOAEL was 0.25 mgAg/day, and the NOAEL
was 0.15 mgAg/day (Witherup 1955, as cited in Epstein 1976).
Significant, dose-related increases in liver-to-body-weight ratios were
reported in beagle dogs that had been administered heptachlor epoxide in
the diet for 60 weeks. The LOAEL was 0.0125 mgAg/day; a NOAEL was not
established (Kettering 1958, as cited in EPA 1987c). Hepatic cell
vacuolization and degeneration, hepatocytomegaly, and liver regeneration
were reported in rats fed heptachlor epoxide for up to 108 weeks. The
LOAEL was 0.025 mgAg/day; a NOAEL was not established (Uitherup 1959,
as cited in Epstein 1976). Dose-related incidences of hepatocytomegaly
and increases in mean liver weight were reported in mice that had been
fed heptachlor/heptachlor epoxide (25%:75%) for up to 18 months. The
LOAEL was 0.15 mg/kg/day; a NOAEL was not established (IRDC 1973, as
cited in Epstein 1976).
Decreases in body-weight gain were induced by chronic oral exposure
to heptachlor (rats, Uitherup et al. 1955, as cited in Epstein 1976;
mice, NCI 1977) and heptachlor/heptachlor epoxide (25%:75%) (mice, IRDC
1973, as cited in Epstein 1976).
Developmental toxlclty. No key studies for humans were found in
the available literature. However, heptachlor epoxide was found in the
blood and several tissues of human stillborn infants (Curley et al.
1969). No adverse effects on human fetal development were reported
following ingestion of heptachlor-contaminated cow's milk for 27 to 29
months by women of child-bearing age in Oahu, Hawaii (Le Marchand et al.
1986). Data from both studies are inadequate to determine whether
reported levels of heptachlor and heptachlor epoxide are associated with
any developmental effects in humans.
Green (1970) reported decreased postnatal survival in the progeny
of rats that were fed heptachlor at a level of 0.25 mgAg/day for 60
days and during gestation; no teratogenic effects were noted. The LOAEL
was 0.25 mgAg/day; a NOAEL was not established.
Reproductive toxlclty. No key studies for humans were found in the
available literature. Elevated levels of heptachlor epoxide, as well as
elevated levels of eight of ten other organochlorine pesticides for
which analytical data were available, were reported in the serum of
women with premature delivery (Uassermann et al. 1982), and heptachlor
epoxide has been reported in the blood and tissues of stillborn infants
(Curley et al. 1969). No adverse effects on human reproduction were
reported following ingestion of heptachlor-contaminated cow's milk for
27 to 29 months by women of child-bearing age in Oahu, Hawaii (Burch
1983, as cited In Le Marchand et al. 1986). These data are inadequate to
provide a clear assessment of the relationship between
heptachlor/heptachlor epoxide exposure and human reproductive toxicity.
-------
16 Section 2
In a mouse dominant lethal assay, no adverse effects on
reproductive capacity were reported for male mice that had been given
single oral doses of heptachlor at levels of 7.5 or 15 mg/kg. The NOAEL
was 15 mg/kg; a LOAEL was not established (Arnold et al. 1977). In male
and female rats fed heptachlor at a level of 0.25 mg/kg/day for 60 days
prior to and during gestation, reproductive performance was unaffected
in the first generation; in the second generation, however, all females
receiving heptachlor at this dose failed to become pregnant. The LOAEL
was 0.25 mg/kg/day; a NOAEL was not established (Green 1970).
Genotoxicity. No key studies for humans or animals were found in
the available literature. The weight of evidence does not support the
genotoxicity of heptachlor (Marshall et al. 1976, NTP 1987, Gentile et
al. 1982, Glatt et al. 1983, Telang et al. 1982). Although there are
some studies that suggest an in vitro somatic cell clastogenic effect,
these findings need confirmation (NTP 1987). Evidence that heptachlor
interferes with metabolic cooperation was demonstrated by independent
investigators in phylogenetically different cell systems (Kurata et al.
1982, Telang et al. 1982).
Carcinogenicity. Heptachlor/heptachlor epoxide is a probable human
carcinogen based on animal data, classified in Group B2 under EPA's
guidelines for carcinogen risk assessment (EPA 1986g).
No key studies for humans were found in the available literature.
Inconsistent oncogenic effects from human occupational or incidental
exposures to heptachlor in combination with other chemicals have been
reported (Infante et al. 1978, Wang and MacMahon 1979a and 1979b,
Ditraglia et al. 1981, Velsicol 1981, Environmental Health Associates
1983a and 1983b, WHO 1984). These data are inadequate to establish a
clear qualitative or quantitative assessment of the relationship between
heptachlor exposure and human cancer risk.
Oral exposure to heptachlor/heptachlor epoxide increased the
incidence of liver carcinomas in one strain of rats and three strains of
mice. From geometric means for the most sensitive species tested (mice),
the carcinogenic potencies are 4.5 per mg/kg/day for heptachlor and 9.1
per mg/kg/day for heptachlor epoxide. From data for the most sensitive
sex and strain (female C3H mice), the carcinogenic potencies are 14.9
per mg/kg/d*y for heptachlor and 36.2 per mg/lag/day for heptachlor
epoxide (GAG 1986).
Levels of exposure can be calculated from cancer potency estimates
generated by the EPA (GAG 1986), on the basis of oral careinogenieity
data for rats and mice for lifetime upper-bound risks of 10'4 to 10'7
for cancer from exposure by the oral route (plotted on Fig. 2.3). These
calculations, based on testing in animals, represent the upper limit of
the probable risk to man; actual risks are likely to be much lower.
Dose
Risk
10-5
10"6
ID'7
Heptachlor Heptachlor epoxide
2.2 x 10'5
2.2 x 10'6
2.2 x 10'7
2.2 x 10'8
1.1 x 10-5
1.1 x 10*6
1.1 x lO'7
1.1 x 10'8
-------
Health Effects Summary 17
It should be noted that the EPA CAG assessment of heptachlor and
heptachlor epoxide had not undergone peer review at the time this
profile was prepared.
• *•
2.2.1.3 Dermal
Plots of key data available for animals vs humans and for different
durations of exposure are not shown since the only points would be the
LD50S of 195 mg/kg in male rats and 250 mgAg in female rats.
Lethality. No key studies were found for humans. Key dermal LDsos
in animals were 195 mg/kg in male rats and 250 mgAg in female rats
(Gaines 1969).
Systemic/target organ tozicity. No key studies for humans or
animals exposed to heptachlor or heptachlor epoxide via the dermal route
were found in the available literature.
Developmental toxicity. No key studies for humans or animals
exposed to heptachlor or heptachlor epoxide via the dermal route were
found in the available literature. Available information on possible
human developmental toxicity from exposure to heptachlor is summarized
in Sect. 2.2.1.2.
Reproductive tozicity. No key studies for humans or animals
exposed to heptachlor or heptachlor epoxide via the dermal route were
found in the available literature. Available information on possible
human reproductive toxicity from mixed-pesticide or heptachlor exposure
is summarized in Sect. 2.2.1.2.
Genotoxicity. No information was found in the available literature
concerning genotoxic effects in humans or animals following dermal
exposure to heptachlor or heptachlor epoxide.
Carcinogenicity. No key studies were found in the available
literature on the oncogenicity of heptachlor or heptachlor epoxide in
humans or animals via the dermal route. Information on oncogenic effects
in humans following exposures to mixtures of chemicals, including
heptachlor, via unspecified routes is summarized in Sect. 2.2.1.2.
2.2.2 Biological Monitoring as a Measure of Exposure and Effects
Extremely sensitive analytical methods have been developed for the
detection of heptachlor and heptachlor epoxide in various media
(detection limits as low as 10 ng/L); these methods are summarized in
Sect. 8 (Tables 8.1 and 8.2). Although most methods were developed for
detecting heptachlor and heptachlor epoxide in environmental samples,
the technology is readily adaptable to biological samples including
breast milk, adipose tissue, and serum. These methods can be used to
determine whether exposure has occurred. However, no studies were found
correlating levels to which humans were exposed with actual body
burdens. No specific tests for the effects of heptachlor or heptachlor
epoxide were found.
-------
18 Section 2
2.2.3 Environmental Levels as Indicators of Exposure and Effects
2.2.3.1 Levels found in the environment
Data found concerning levels of heptachlor and heptachlor epoxide
were from the 1960s and 1970s when heptachlor was actively used in
agriculture. It has been shown that heptachlor epoxide can be
translocated from soil to a crop 15 years after the last known
application of heptachlor at a rate of 224 kg/ha (Nash and Harris 1973,
as cited in WHO 1984). Talekar et al. (1983) reported the persistence of
heptachlor epoxide (at a level of 0.06 ppm) in the soil throughout a
1-year observation period following application of a total of 48 kgAa
of heptachlor over a 2 -year period. No data were found to indicate that
heptachlor epoxide is present in present-day crops. Heptachlor has been
identified at hazardous waste sites at concentrations ranging from not
detected (ND) in migrating groundwater to 4,800 jigA In sediments (EPA
1985b).
2.2.3.2 Human exposure potential
Since the cancellation of most uses of heptachlor, the potential
for exposure via inhalation for farm workers has greatly diminished. In
one study of houses treated for termites, the heptachlor level in the
air was 1.00 ± 0.70 /ig/m3 one year after treatment (Wright and Leidy
1982) , indicating that exposure to heptachlor via inhalation is possible
for people whose houses have been treated with the compound for termite
control .
Levels of up to 0.6 MgA °f heptachlor in drinking water have bee
reported (EPA 1985a) . These water data are from the period when
heptachlor was used for agricultural insect control.
Heptachlor epoxide has been reported in soils, especially cropland
soils, at levels up to 1.08 mg/kg (Weirsma et al. 1972a, as cited in
IARC 1979). Studies have shown that heptachlor epoxide can translocate
into crops 5 to 15 years after the last known application of heptachlor
(Lichtenstein et al. 1970, Nash and Harris 1973, as cited in WHO 1984).
Levels in foodstuff were reported for the 1970s and have been reviewed
by IARC (1979), WHO (1984), and EPA (1985a) . The relevance of these data
to present-day residue levels of heptachlor and heptachlor epoxide in
food is not clear.
No reports of human health effects as a direct consequence of
exposure to heptachlor or heptachlor epoxide were found. Section 4
discusses health effects from exposure to technical -grade chlordane
containing up to 10% heptachlor.
2.3 ADEQUACY OF DATABASE
2.3.1 Introduct ion
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each of the 100 most significant
hazardous substances found at facilities on the CERCLA National
Priorities List. Each profile must include the following content:
-------
Health Effects Summary 19
"(A) An examination, summary, and interpretation of available
toxicological information and epidemlologlc evaluations on a
hazardous, substance in order to ascertain the levels of
significant human exposure for the substance and the
associated acute, subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and
chronic health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may
present significant risk of adverse health effects in humans."
This section identifies gaps in current knowledge relevant to
developing levels of significant exposure for heptachlor and heptachlor
epoxide. Such gaps are identified for certain health effect end points
(lethality, systemic/target organ toxicity, developmental toxicity,
reproductive toxicity, and carcinogenicity) reviewed in Sect. 2.2 of
this profile in developing levels of significant exposure for heptachlor
and heptachlor epoxide, and for other areas such as human biological
monitoring and mechanisms of toxicity. The present section briefly
summarizes the availability of existing human and animal data,
identifies data gaps, and summarizes research in progress that may fill
such gaps.
Specific research programs for obtaining data needed to develop
levels of significant exposure for heptachlor and heptachlor epoxide
will be developed by the ATSDR, NTP, and EPA in the future.
2.3.2 Health Effect End Points
2.3.2.1 Introduction and graphic summary
The following graphs summarize the availability of data for
lethality, systemic/target organ toxicity, developmental toxicity,
reproductive toxicity, and carcinogenicity. The first graph (Fig. 2.4)
is for human data and the second (Fig. 2.5) is for animal data.
The bars of full height indicate that there are data to meet at
least one of the following criteria:
1. For noncancer health end points, one or more studies are available
that meet current scientific standards and are sufficient to define
a range of toxicity from no-effect levels (NOAELs) to levels that
cause effects (LOAELs or FELs).
2. For human carcinogenicity, a substance is classified as either a
"known human carcinogen" or "probable human carcinogen* by both EPA
and the International Agency for Research on Cancer (IARC)
(qualitative), and the data are sufficient to derive a cancer
potency factor (quantitative).
-------
HUMAN DATA
V SUFFICIENT
' INFORMATION*
to
(t
r>
n
i—
§
J
SOME
INFORMATION
NO
INFORMATION
INHALATION
DERMAL
LETHALITY
ACUTE
INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOOENICITY
_/ TOXICITY TOXICITY
SYSTEMIC TOXICITY
'Sufficient Uiformalion exists to meet at toast one of the criteria for cancer or noncancer end points
Fig. 2.4. Availability of information on health «•' s of heptachlor/heptachlor epoxide (human data).
-------
ANIMAL DATA
SUFFICIENT
INFORMATION*
SOME
INFORMATION
NO
INFORMATION
ORAL
INHALATION
DERMAL
LETHALITY
ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOOENWITV
/ TOXKITV TOXICmr
I
sr
r>
to
SYSTEMIC TOXICITV
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points.
Fig. 2.5. Availability of information on health effects of heptachlor/heptachlor epoxide (animal data).
-------
22 Section 2
3. For animal carcinogenicity, a substance causes a statistically
significant number of tumors in at least one species, and the d&
are sufficient to derive a cancer potency factor.
4. There are studies which show that the chemical does not cause this
health effect via this exposure route.
Bars of half height indicate that "some" information for the end
point exists, but does not meet any of these criteria.
The absence of a column indicates that no information exists for
that end point and route.
2.3.2.2 Description of highlights of graphs
Humans. There is some evidence concerning human exposure to
heptachlor and reproductive (exposure route undetermined, judged to be
oral) or developmental (exposure route undetermined, judged to be oral)
effects. The data in these studies were inadequate to assess whether or
not human exposure to heptachlor/heptachlor epoxide can induce
reproductive or developmental toxicity.
Neurotoxicity, hematotoxicity, and increased incidences of tumors
of the skin, bladder, and lungs were reported following exposures of
humans to mixtures of heptachlor and other chlorinated cyclodiene
insecticides (primarily chlordane) or other chlorinated hydrocarbons.
Because the mixed exposures preclude the determination of whether or not
heptachlor was involved in the induction of these toxic effects, these
studies were excluded from consideration of data adequacy. In additic
the data in these studies were inadequate to provide a clear assessme*.
of whether or not human exposure to mixtures of heptachlor and other
chemicals can induce these toxic effects.
Animals. For the inhalation route, no data were available for any
category of toxicity. For the oral route, adequate data were available
for lethality and carcinogenicity, and some data were available for
developmental and reproductive toxicity and for systemic/target organ
toxicity of all durations of exposure. For the dermal route, some data
were available for lethality, but no data were available for any other
category of toxicity.
For systemic effects other than hepatotoxicity (neurotoxicity,
adrenal toxicity, renal toxicity, and hematologic effects), the database
is grossly inadequate.
2.3.2.3 Summary of relevant ongoing research
A Special Data Call-in (EPA 1986f) for termiticides by the EPA
requires registrants to provide the following chemical-specific
toxicology studies to support a more comprehensive risk assessment of
each termiticide:
• General metabolism studies, one in rats and one in mice, giving
special consideration to pharmacokinetics
• Battery of acute toxicity studies
-------
Health Effaces Summary 23
• Subchronic inhalation study--rats (1 year), guinea pigs or rats
(2 weeks)
• Chronic feeding--nonrodents and rats (heptachlor epoxide); non-
rodents (heptachlor)
• Oncogenicity--rats (heptachlor epoxide)
• Mutagenicity studies
• Teratogenicity--rats and rabbits
• Optic tissue pathology--rats
The status of these data requirements for heptachlor follows:
The metabolism data required from the registrant have also been
submitted, reviewed, and accepted. The mutagenicity data requirements
have not been fully satisfied, and additional mutagenicity studies are
being requested. The registrant submitted a subchronic inhalation study
that was invalid because chlordane was used rather than heptachlor;
moreover, the lowest dose tested in the study was 20 times higher than
the National Academy of Science (HAS) airborne guideline of 0.005 mg/m^,
the lowest dose level requested by the Data Call-in. An inhalation study
for heptachlor is required (EPA 1986f).
Public Health Service research grants have been awarded to the
following investigators for studies on heptachlor/heptachlor epoxide
(CRISP database 1987): (1) F. Matsumura to study effects on calcium-
regulating processes in the nervous system, liver, and heart of rodents,
guinea pigs, and some invertebrate species; (2) J.E. Casida to study
effects on the brains (neurotransmitter receptors, cholinergic
receptors) of rats, chickens, fish, insects, and humans; and (3) D.E.
Moreland to study mechanisms of action in rats, insects, and sheep with
respect to bioenergetics, biological transport, oxidative
phosphorylation, and membrane permeability.
A request for proposals concerning heptachlor has been issued
(Science 1987) indicating the following areas of research interest:
• Definition of exposure and exposed populations. Establishment of a
registry (in Hawaii).
• Body burdens of heptachlor and other chlorinated hydrocarbon
pesticides (in Hawaii).
• Epidemiological evaluation of heptachlor exposure to define current
and anticipated risk (in Hawaii).
• Metabolism of heptachlor and related substances. Biological effects
on heptachlor.
• Clinical management, surveillance, and treatment of exposed persons
(in Hawaii).
-------
24 Section 2
2.3.3 Other Information Needed for Human Health Assessment
2.3.3.1 Pharmacokinetics and mechanisms of action
• • • *
No information was found for the following:
• Absorption of heptachlor or heptachlor epoxide from the respiratory
tract,
• Quantitative data concerning dermal absorption of heptachLor or
heptachlor epoxide,
• Distribution of heptachlor or heptachlor epoxide following
inhalation exposure,
• Distribution of heptachlor or heptachlor epoxide following dermal
exposure,
• Metabolism of heptachlor or heptachlor epoxide following inhalation
exposure,
• Excretion of heptachlor or heptachlor epoxide by humans following
ingestion,
• Excretion of heptachlor or heptachlor epoxide following dermal
exposure.
2.3.3.2 Monitoring of human biological samples
Analytical methods are available to determine if a person has be""
exposed to heptachlor or heptachlor epoxide (see Sect. 8, Table 8 2)
These methods do not, however, differentiate between routes of expose
No information was found to correlate levels of heptachlor epoxide in
tissue with either level or duration of exposure.
No information was found to indicate that there is any ongoing
research to correlate levels of heptachlor epoxide in the body with
level or duration of exposure.
2.3.3.3 Environmental considerations
Numerous analytical methods are available for the determination of
heptachlor and heptachlor epoxide in environmental samples (see Sect. 8,
Table 8.1).
Data were not found for levels of heptachlor or heptachlor epoxide
in soil or foodstuff from agricultural lands treated with heptachlor
since the cancellation of agricultural uses of heptachlor.
Available data indicate that heptachlor is converted to heptachlor
epoxide in the environment. The data also indicate that heptachlor
epoxide is persistent in the environment. The environmental fate and
transport characteristics of heptachlor epoxide have been determined.
No data on interactions of heptachlor or heptachlor epoxide with
other chemicals in the environment were found. In vivo, there are
limited data to indicate that heptachlor acts as a promoter of
carcinogenesis.
-------
Health Effaces Summary 25
As part of a Special Data Call-in for tenniticides, the EPA has
requested the following studies concerning environmental levels of
heptachlor (EPA 1986f):
• Hydrolysis,
• Aerobic and anaerobic soil metabolism,
• Aerobic aquatic metabolism,
• Leaching and adsorption/desorption,
• Soil dissipation: field study,
• Photodegradation in water,
• Special monitoring study of heptachlor residues entering surface
water from sanitary sewers, sumps, and drainage tiles from home
foundations known to have been properly treated with heptachlor,
• Applicator exposure,
• Indoor air exposure,
• Avian acute oral toxicity,
• All product chemistry.
-------
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
The chemical formulae, structures, synonyms, and Identification
numbers for heptachlor and heptachlor epoxide are listed in Table 3.1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Physical and chemical properties of heptachlor and heptachlor
epoxide are given in Table 3.2.
-------
28 Section 3
Table 3.1. Chemical identity of heptachJor and heptachlor epoxide
Chemical name
Heptachlor
Heptachlor epoxide
Synonyms
Trade names
Chemical formula
Wiswesser line
notation
Chemical structure
Identification Numbers
CAS Registry No.
NIOSH RTECS No.:
EPA Hazardous
Waste No.
OHM-TADS No.
DOT/UN/NA/IMCO
Shipping Nos.
STCC No.
Hazardous Sub-
stances Data
Bank No.
National Cancer
Institute No.
1,4,5,6,7,8,8-Heptachloro-
3a.4,7,7a-tetrahydro-4,7-
methanomdene, hepta-
chlorodicyclopentadiene
Velsicol 104®
Drinox8
C10HSC17
L C555 A DU IUTJ AG
AG BG FG HG IG JG
Cl
1,4,5.6,7,8,8-Heptachloro-
2,3-epoxy-2,3,3a,4.7.7a-
hexahydro-4,7-methanomdene,
epoxyheptachlor
Velsicol 53-CS-17®
C10HSC17O
T D3 C555 A EO JUTJ
AG AG BG GO IG JG KG
Cl
Cl H
76-44-8 i 1024-57-3
PC0700000 PB9450000
P059 NAa
7216526 NA
UN2762, UN2995, UN2996, NA
UN2761, NA3761
49 606 30 NA
554 6182
10875-C NA
Cl H
"NA = Not available.
-------
Chemical and Physical Information 29
Table 3.2. Physical and chemical properties of heptachlor and
heptachlor epoxide
Property
Heptachlor
Heptachlor epoxide
Molecular weight
Physical state
Color
Odor/odor
threshold
Melting point
Boiling point
Autoignition
temperature
Solubility in
water
Organic solvents
Density
Log partition
coefficient(s)
373.5
Crystalline solid (pure),
waxy solid (technical-grade
product) (Worthing and
Walker 1983)
Light tan (Sittig 198S)
Camphorlike (Sittig 198S)
Odor threshold in water:
0 02 mg/kg (Vereschueren
1983)
95-96°C (pure)
46-74°C (technical-grade
product) (Worthing and
Walker 1983)
135-145°C@ 1.5 torr
(IARC 1979)
NA
56 mg/L @ 25-298C
(Worthing and Walker
1983)
1.65 kg/L cyclohexanone,
6.25 g/L ethanol,
263 g/L deodorized kero-
sene, 1.41 kg/L xylene @
20-30°C (Worthing and
Walker 1983)
1.57-1.59 (Verschueren
1983)
Hexane/water 5.05
(Hansch and Leo 1979)
389.4
Solid
NA"
NA
160-161.5°C(IARC 1979)
NA
Insoluble (IARC 1979),
0.35 ppm (Hayes 1982)
NA
NA
Hexane/water: 4.60
(Hansch and Leo 1979)
-------
30 Section 3
Table 3.2 (continued)
Property
Heptachlor
Heptachlor epoxide
Vapor pressure
Henry's law
constant
Refractive index
Flash point
Flammability limits
Conversion factors
Other
3.0 X 10~4 torr @ 25°C
(Wmdholz 1983)
NA
NA
NA
NA
1 mg/L = 65.1 ppm and
1 ppm = 15.35 mg/m3
at 25 °C and 760 torr
(CAG 1986)
Stable to light, moisture,
air and at temperatures
<261°C, not readily de-
hydrochlonnated, suscepti-
ble to epoxidation
(Worthing and Walker 1983)
NA
NA
NA
NA
NA
1 mg/L = 62.5 ppm and
1 ppm = 15.9 mg/m3
at 25°C and 760 torr
(CAG 1986)
NA
"NA = Not available.
-------
31
4. TOZICOLOGICAL DATA
The toxicity of heptachlor and heptachlor epoxide in animals has
been reviewed in Anonymous (1986), GAG (1986), Eisler (1968), IARC
(1979), NRC (1982), EPA (198Sa and 1987c), and WHO (1984). When not
provided elsewhere, conversions of parts per million test compound in
diet to milligram test compound per kilogram body weight per day
(abbreviated mg/kg/day) were made using the table of Lehman (1959) .
4.1 OVERVIEW OF TOZICOLOGICAL DATA
Though limited, data suggest that heptachlor is readily absorbed
from the gastrointestinal tract and may be absorbed from the skin. No
information was found on absorption via the lungs. A large portion of
the absorbed heptachlor is slowly eliminated, primarily via the bile
duct into the feces. Heptachlor is readily oxidized to heptachlor
epoxide in mammals. Unchanged heptachlor has been detected in human
milk. Heptachlor epoxide has been detected in human milk, several human
tissues, blood, and amniotic fluid. No relationship has been established
between the metabolism and the toxic effects of heptachlor or heptachlor
epoxide.
Acute lethality data were available for animals exposed via the
oral and dermal routes. Heptachlor/heptachlor epoxide may be classified
as very toxic via the oral route on the basis of acute animal data.
Intermediate or chronic oral exposure to these compounds also induced
mortality in animals. Heptachlor may be classified as very toxic to
extremely toxic via the dermal rouce on the basis of acute lethality
data in animals. In human case reports, convulsions and death were
reported following inhalation of technical-grade chlordane, which
typically contains 10% heptachlor.
On the basis of animal data, hepatotoxicity may be the most
sensitive systemic/target organ end point for heptachlor/heptachlor
epoxide; signs of toxicity in animals following short- or long-term oral
exposure include histologic evidence of severe liver damage, increased
liver weight, and increased levels of serum components indicative of
hepatic damage. Decreased body weight gain has often been reported in
conjunction with the induction of hepatotoxicity by intermediate or
chronic oral exposure to heptachlor/heptachlor epoxide.
Neurotoxic signs, including hypoactivity, tremors and convulsions,
ataxia, and changes in EEC patterns have been induced in animals by
acute, intermediate, or chronic oral intake of heptachlor/heptachlor
epoxide. Studies in rat brain suggest that the neurotoxic effects of
heptachlor/heptachlor epoxide may involve, in part (1) interference with
nerve action or release of neurotransmitters as the result of inhibition
of either Na+-K+ ATPase or Ca2+-Mg2+ ATPase activity or (2) Inhibition
of the function of the receptor for 7-aminobutyric acid (GABA). In human
-------
32 Section 4
case studies, signs of neurotoxicity (irritability, salivation,
lethargy, dizziness, labored respiration, muscle tremors, and
convulsions) were reported following exposure (route not specified) of
humans to technical-grade chlordane, which typically contains 10%
heptachlor. The incidence of cerebrovascular disease was significantly
increased in workers engaged in the manufacture of chlordane,
heptachlor, and endrin, but was not increased in pesticide applicators
and termite control operators exposed to chlordane and heptachlor by
unspecified routes.
Additional systemic/target organ toxicities observed in animals
during long-term oral exposures include renal toxicity, adrenotoxicity,
and hematologic effects. Intermediate and chronic inhalation exposure of
humans to mixtures of heptachlor with chlordane and other chemicals has
been associated with pancytopenia. leukemia, and aplastic, hemolytic,
and megaloblastic anemias.
Heptachlor epoxide was found in the blood and several tissues of
human stillborn infants. No adverse effects on human fetal development
were reported following ingestion of heptachlor-contaminated cow's milk
for 27 to 29 months by women of child-bearing age in Oahu, Hawaii. These
data are inadequate to provide a clear assessment of the relationship
between heptachlor/heptachlor epoxide exposure and human developmental
toxicity. Cataracts and decreased postnatal survival were reported in
the progeny of rats fed diets containing heptachlor. No developmental
toxicity data were available for animals for other routes of exposure.
Elevated levels of heptachlor epoxide, as well as elevated leve'
of eight of ten other organochlorine pesticides for which analytical
data were available, were reported in the serum of women with premature
delivery, and heptachlor epoxide has been reported in the blood and
tissues of stillborn infants. No adverse effects on human reproduction
(no decrease in fertility, no increase in fetal or neonatal deaths) were
reported following ingestion of heptachlor-contaminated cow's milk for
27 to 29 months by women of child-bearing age in Oahu, Hawaii. These
data are inadequate to provide a clear assessment of the relationship
between heptachlor/heptachlor epoxide exposure and human reproductive
toxicity. Male and female mice that received heptachlor in the diet for
10 weeks were unable to produce a new generation. Decreased pregnancy
rates were reported following oral administration of heptachlor to male
and female rats for two generations. In male and female rats fed
heptachlor, heptachlor epoxide, or a mixture of the two for three
generations, the number of resorbed fetuses increased and fertility
decreased with succeeding generations. No reproductive toxicity data
were available for animals for other routes of exposure.
Heptachlor and heptachlor epoxide, with or without a metabolic
activation system, tested negative in well-conducted microbial gene
mutation assays, and heptachlor was not mutagenic in an epithelial cell
line (ARL) derived from rat liver. Heptachlor, with metabolic
activation, was clastogenic in Chinese hamster ovary (CHO) cells, but
neither heptachlor nor heptachlor epoxide was clastogenic in male mouse
germinal cells in a dominant lethal assay. With the exception of a
single positive in vitro sister chromatid exchange (SCE) assay with
heptachlor in CHO cells (with or without metabolic activation). the
-------
lexicological Data 33
results of DNA repair assays suggest that heptachlor is unlikely to
elicit DNA repair mechanisms unless the cell has been preinitiated.
Heptachlor appears to be a promoter of hepatocarcinogenesis in mice.
Consistent with this finding, low concentrations of heptachlor inhibited
metabolic cooperation in Chinese hamster cells and rat liver cells, a
property common to many known promoters. Of note was the demonstration
of assay specificity for detection only of agents that interfere with
cell-to-cell communication (epigenetic effect), as opposed to chemicals
that induce a genotoxic effect. Overall, therefore, it may be postulated
that heptachlor acts through an epigenetic mechanism rather than one
that is genotoxic.
The ability of heptachlor to act as an inhibitor of intercellular
communication may also be a component in the mechanism of
systemic/target organ, developmental, and reproductive toxicities,
although this mechanism of action has not been verified experimentally.
Available epidemiological studies on heptachlor are considered to
be inadequate to establish a clear qualitative or quantitative
assessment of the relationship between heptachlor exposure and human
risk of developing cancer. Chronic oral exposure to heptachlor/
heptachlor epoxide increased the incidence of liver carcinomas in CFN
rats and C3H, CD-I, and B6C3F1 mice. Heptachlor/heptachlor epoxide is
classified as a probable human carcinogen, Group B2, under EPA's
guidelines for carcinogen risk assessment.
4.2 TOZICOKINETICS
4.2.1 Overview
Though limited, data suggest that heptachlor is readily absorbed
from the gastrointestinal tract and may be absorbed through the skin. A
large portion of the absorbed heptachlor is slowly eliminated, primarily
via the bile duct into the feces.
Heptachlor is readily oxidizea to heptachlor epoxide in mammals.
Heptachlor epoxide has been detected in various tissues of rats and
dogs, with the highest levels found in fat. The accumulation of
heptachlor epoxide in fat is dose dependent, and female rats accumulate
more than males.
Heptachlor epoxide has been detected in several human tissues,
blood, milk, and amniotic fluid at concentrations of <1 ppm. Unchanged
heptachlor was also detected in human milk samples.
4.2.2 Absorption
4.2.2.1 Inhalation
Human. No information was found.
Animal. One group of 20 rabbits (10 males, 10 female; strain not
reported) was housed outdoors in an area of high pesticide use; an
equal-sized group was housed inside a building in an area of low
pesticide use. The groups were on study for 3 months. The heptachlor
epoxide level in adipose tissue of the outdoor group was 0.039 ± 0.002
ppm; the level in the control group (indoor) was 0.016 ± 0.001 ppm. The
-------
34 Section 4
calculated average respiratory intake of heptachlor epoxlde was 0.002
ppm. The calculated average respiratory Intake of heptachlor epoxi.de w
0.002 A»g/day (Arthur et al. 1975).
4.2.2.2 Oral
Human. Members of farm families who consumed raw dairy products
from cattle fed heptachlor -contaminated feed had significantly
(P < 0.01) elevated serum levels of heptachlor metabolites (Stehr-Green
et al. 1986). Heptachlor epoxide levels in the cow's milk ranged up to
89.2 ppm (fat basis); mean levels in human serum were 0.81 ± 0.94 ppb
for heptachlor epoxide, 0.70 ± 0.75 ppb for oxychlordane , and 0.79 ±
0.60 ppb for trans -nonachlor.
Animal. Heptachlor is absorbed from the gastrointestinal tract as
indicated by the presence of heptachlor and/or its metabolites in the
urine (feces) and tissues of animals dosed orally, but quantitative data
are not available. Only 6% of the radioactivity from a dose of 14C-
labeled heptachlor was found in the urine while 60% was found in the
feces of male rats 10 days after dosing (Tashlro and Hatsumura 1978).
Thus, the available data strongly indicate that a large percentage is
absorbed from the gastrointestinal tract and eliminated via the bile
into the feces. Approximately 60% of the radioactivity eliminated in the
feces was present in metabolites of heptachlor (Tashiro and Hatsumura
1978).
4.2.2.3 Dermal
Human. No information was found.
Animal. Heptachlor is absorbed through the skin following topical
application as indicated by its dermal toxlcity to rats (LD50 - 195-250
Gaines 1969), but quantitative data are not available.
4.2.3 Distribution
4.2.3.1 Inhalation
Human. No information was found.
Animal. No Information was found.
4.2.3.2 Oral
Human. The routes of exposure leading to detectable levels of
heptachlor and heptachlor epoxide in humans are not known for certain.
Since the majority of data are from the period when heptachlor was
widely used in agriculture, making ingestion of heptachlor likely, human
tissue levels are presented in this section. Other routes of exposure
may have contributed to the overall body burden of heptachlor/heptachlor
epoxide. Data are insufficient to determine whether or not the observed
levels of heptachlor and heptachlor epoxide were associated with any
toxic effects.
Heptachlor epoxide has been detected in human tissues, blood, milk,
and anmiotic fluid at various concentrations. Zavon et al. (1969)
reported levels of heptachlor epoxide in the range of not detected (N
-------
lexicological Data 35
to 0.563 ppm in fat of deceased infants. Curley et al. (1969) reported
heptachlor epoxide levels in the liver (0.03-1.67 ppm), kidneys (0.19-
1.14 ppm), and adrenals (0.46-1.00 ppm) of deceased infants. Heptachlor
epoxide levels in extracted lipids from mothers and newborn infants were
adipose tissue (0.2856 ± 0.3109 ppm), maternal blood (0.2798 ± 0.4626
ppm), uterine muscle (0.4895 ± 0.5086 ppm). fetal blood (0.9959 ± 0.9458
ppm), placenta (0.5000 ± 0.3950 ppm). and amniotic fluid (0.6730 ±
1.1645 ppm) (Polishuk et al. 1977b). These data provide evidence of
transplacental transfer to the fetus.
Heptachlor was detected by Jonsson et al. (1977) in 3 of 51 human
milk samples at an average concentration of 0.019 ppm. Heptachlor
epoxide was detected in 12 of the 51 samples at an average concentration
of 0.0027 ppm. Other investigators have reported the presence of
heptachlor epoxide in human milk at concentrations ranging from ND to
0.46 ppm (Kroger 1972, Polishuk et al. 1977a, Strassman and Kutz 1977,
Savage et al. 1981, Takahashi 1981, Takei et al. 1983).
Unchanged heptachlor was not detected (detection limit - 0.06 ppm)
in adipose tissue (Barquet et al. 1981). Heptachlor epoxide has been
detected in adipose tissue at levels ranging from <0.0001 ppm to 1.12
ppm (Radomski et al. 1968, Burns 19-74, Vassermann et al. 1974, Greer et
al. 1980, Barquet et al. 1981). in tissue at 1-32 ppb (highest in bone
marrow and liver) (Klemmer et al. 1977), in liver and brain at trace to
0.05 ppm (detection limit not reported) (Radomski et al. 1968), in blood
at 0-9.9 ppb (detection limit not reported) (Mossing et al. 1985), and
in whole plasma at 0.0136 ± 0.0057 ppm (Polishuk et al. 1977a).
Animal. Radomski and Davidow (1953) studied the pharmacokineti.es
of heptachlor in rats. When rats were fed diets containing heptachlor
for 2 months or more the highest levels of heptachlor epoxide were found
in the fat with markedly lower levels in liver, kidneys, and muscles;
none was detected in the brain. Levels in all tissues were higher in
females than in males.
The rate of heptachlor epoxide accumulation in and elimination from
body fat was determined in male and female rats by Radomski and Davidow
(1953). Rats were placed on diets containing heptachlor for 12 weeks
then placed on untreated diets for 12 more weeks. In males, the
heptachlor epoxide level reached a maximum plateau at approximately 2 to
8 weeks; thereafter the levels decreased, and, by the end of week 6
postdosing, the heptachlor epoxide level was below the detection limit.
In females, the heptachlor epoxide level in fat was much higher than in
males by 2 weeks and throughout the remainder of the study. By the end
of week 8 postdosing, the heptachlor epoxide level in the fat was below
the detection limit.
4.2.3.3 Dermal
Human. No information was found.
Animal. No information was found.
-------
38 Section 4
4.3 TOXICITY
4.3.1 Lethality "and" Decreased Longevity
4.3.1.1 Overview
Inhalation. No key studies on Increased mortality In humans or
animals following inhalation exposure of any duration to
heptachlor/heptachlor epoxlde were found in the literature. In human
case reports, convulsions and death were reported following inhalation
of technical-grade chlordane, which typically contains 10% heptachlor.
Oral. Heptachlor/heptachlor epoxide may be classified as very
toxic (Toxicity Category II) via the oral route on the basis of acute
oral LD5QS in rats of 71 mgAg for heptachlor and 60 mg/kg for
heptachlor epoxide.
Studies in rodents and dogs have shown that heptachlor, heptachlor
epoxide, or a mixture of these compounds may induce increased mortality
in animals following intermediate or chronic oral exposures.
No data describing increased mortality in humans following oral
exposures of any duration to heptachlor/heptachlor epoxide were found in
the literature.
Dermal. Heptachlor may be classified as very toxic (Toxicity
Category II) to extremely toxic (Toxicity Category I) via the dermal
route on the basis of acute dermal LD50 in rats of 195 mg/kg in males
and 250 mgAg *•" females. Data were not available for classifying the
acute dermal lethality of heptachlor epoxide In animals or for assessing
the acute, intermediate, or chronic dermal lethality of
heptachlor/heptachlor epoxide in humans.
4.3.1.2 Inhalation
Human. No key studies describing increased acrtality in humans
following inhalation exposure of aiiy duration were found in the
literature.
Animal. No data describing increased mortality, in animals
following inhalation exposure of any duration were found in the
literature.
4.3.1.3 Oral
Human. No data describing increased mortality in humans following
oral exposure of any duration were found in the literature.
Animal, acute. Acute oral LDSQs for heptachlor in rodents (rats,
mice, hamsters, and guinea pigs) and rabbits were in the range of 40 to
162 mgAg (Ben-Dyke et al. 1970, Eisler 1968, Gaines 1969, Gak et al.
1976, Lehman 1951, RTECS 1983-84, Sperling et al. 1972, Sun 1972,
Podowskl et al. 1979).
Acute oral LDSOs for heptachlor epoxide in rodents (rats and mice1*
and rabbits were in the range 39 to 144 mgAg (Eisler 1968, RTECS
84, Sperling et al. 1972, Podowski et al. 1979).
-------
Toxicological Data 39
Data from key studies, defined as peer- reviewed studies that report
the lowest oral LD5Q for each species, are shown in Table 4.1.
Animal, intermediate. Increased mortality was reported following
intermediate oral .intake of heptachlor by rats (NCI 1977), mice (NCI
1977), and dogs (Lehman 1952).
Groups of 10 Osborne- Mendel rats (5/sex) and 10 B6C3F1 mice (5/sex)
were fed technical -grade heptachlor (73% heptachlor; 22% trans-
chlordane; 5% nonachlor) for 6 weeks, followed by a 2 -week period of
observation. Dietary concentrations were 20, 40, 80, 160, and 320 ppm
(NCI 1977).
Two of five male rats died at the 320-ppm level; no deaths were
reported at 160 ppm or at lower levels. The LOAEL for male rats was 320
ppm (32 mgAg/day), and the NOAEL was 160 ppm (16 mg/kg/day) . Five of
five females rats died at the 320-ppm level, and four of five died at
the 160 -ppm level; no deaths were reported at 80 -ppm or lower levels.
The LOAEL in female rats was 160 ppm (16 mgAg/day), and the NOAEL was
80 ppm (8
All male mice died at the 80 -ppm level; no deaths were reported at
levels of 40 or 20 ppm. Data were not reported for levels of 160 and 320
ppm. The LOAEL for male mice was 80 ppm (12 mgAg/day), and the NOAEL
was 40 ppm (6 mgAg/day) . Two of five female mice died at the 80 -ppm
level; no deaths were reported at levels of 40 or 20 ppm. Data were not
reported for levels of 160 and 320 ppm. The LOAEL for female mice was 80
ppm (12 mgAg/day), and the NOAEL was 40 ppm (6 mgAg/day).
Animal, chronic. Increased mortality was reported following
chronic oral intake of heptachlor by rats and mice (NCI 1977),
heptachlor epoxide by mice (Davis 1965, as cited in Epstein 1976),
heptachlor/heptachlor epoxide (75%: 25%) by rats (Jolley et al. 1966, as
cited in Epstein 1976), and heptachlor/heptachlor epoxide (75%: 25%) by
mice (IRDC 1973, as cited in Epstein 1976).
Groups of 20 to 24 female CD .rats were fed diets containing 5, 7.5,
10, or 12.5 ppm heptachlor/heptachlor epoxide (75%: 25%) for up to 2
years. Prior to mixing, heptachlor was 99.9% pure, and heptachlor
epoxide was 96.0% pure. Forty- seven females served as controls.
Mortality was increased in all test groups: control, 21%; 5 ppm, 39%;
7.5 ppm, 25%; 10 ppm, 43%; and 12.5 ppm, 50%. The LOAEL was 5 ppm (0.25
mgAg/day); a NOAEL was not established (Jolley et al. 1966, as cited in
Epstein 1976).
Groups of 100 male and 100 female C3H mice were fed diets
containing 0 or 10 ppm heptachlor epoxide (purity not indicated) for up
to 104 weeks. Survival data were reported for males and females
combined. Mortality was increased in the test group. Excluding the 18
control mice sacrificed for transplant studies, survival at 104 weeks
was 34% in controls and 9.5% in animals that received heptachlor
epoxide. The LOAEL was 10 ppm (1.5 mgAg/day); a NOAEL was not
established (Davis 1965, as cited in Epstein 1976).
Groups of 100 male and 100 female Charles River CD-I mice were fed
diets containing 0, 1, 5, or 10 ppm heptachlor/heptachlor epoxide
(25%: 75%) for up to 18 months; 10 males and 10 females from each group
-------
40 Section 4
Table 4.1. Lowest reported LDM for heptachlor and heptachlor
epoxide for various species
Species
Rats
Rats
Mice
Hamsters
Sex/strain
Male/Charles
River-derived
Male/Charles
River-derived
ND/ND"
ND/golden
Chemical
Heptachlor
Heptachlor
epoxide
Heptachlor
Heptachlor
LD50
(mg/kg)
71
60
70
100
References
Podowski et al. 1979
Podowski et al. 1979
Gak et al. 1976
Gak et al. 1976
"ND, no data.
-------
Toxicologies! Data 41
were killed at 6 months. Based on the adjusted numbers of mice at risk
after the 6-months sacrifice, survival was similar in the control,
1-ppm, and 5-ppm groups (51 to 66%) but was reduced in 10-ppm test group
to 29% in males and 30% in females. The LOAEL was 10 ppm (1.3
mg/kg/day), and the NOAEL was 5 ppm (0.75 mg/kg/day) (IRDC 1973, as
cited in Epstein 1976).
Groups of 50 male and 50 female B6C3F1 mice were fed diets
containing technical-grade heptachlor (73% heptachlor, 22% trans-
chlordane, 5% nonachlor) for up to 80 weeks at time-weighted average
(TWA) concentrations of 6.1 or 13.8 ppm for males and 9 or 18 ppm for
females. Following treatment, the animals were observed for 10 weeks.
There were no significant differences in survival between the control
and treated males. In females, there was a statistically significant
(P - 0.02) trend for increased mortality, due mainly to the effect of
the high dose. Data from the survival curves indicate that the LOAEL in
females was 18 ppm (2.7 mgAg/day). and the NOAEL was 9 ppm (1.35
nig/kg/day) (NCI 1977).
4.3.1.4 Dermal
Human. No data describing increased mortality in humans following
dermal exposure of any duration were found in the literature.
Animal, acute. Acute dermal LD5QS for heptachlor were 195 and 250
mg/kg (in xylene) in male and female Sherman rats, respectively (Gaines
1969), 119 mg/kg (vehicle not specified) in rats of unidentified sex and
strain (RTECS 1983-84), and approximately 2,000 mgAg (dry powder) in
rabbits (sex and strain not indicated) (Eisler 1968); data were not
found for heptachlor epoxide.
A key study of acute lethality is one that is peer reviewed and
reports the lowest LD50 for a given species.
Gaines (1969) reported acute dermal LD5QS for heptachlor (technical
grade, purity not indicated) of 19S mgAg in »ale and 25° mgAg in
female Sherman rats. Xylene was the solvent.
The mechanism for induction of lethality from acute exposure to
heptachlor/heptachlor epoxide may involve the abilities of these
compounds to (1) interfere with nerve action or release of
neurotransmitters as the result of inhibition of the activities of
Na+-K+ ATPase (Folmar 1978, Yamaguchi et ml. 1980) or Caz+-Mg2+ ATPase
(Yamaguchi et al. 1980) and (2) inhibit the function of the receptor for
7-aminobutyric acid, as discussed further under the section on
neurotoxicity (see Sect. 4.3.2.3) (Abalis et al. 1985, 1986; Matsumura
and Ghiasuddin 1983; Lawrence and Casida 1984; Bloomquist and Soderlund
1985; Cole and Casida 1986).
With intermediate or chronic exposures to heptachlor/heptachlor
epoxide, death may be mediated by systemic toxicity, particularly
hepatotoxicity; in the case of chronic exposures, death may also be
related to the presence of hepatic tumors.
-------
42 Section 4
4.3.2 Systemic/Target Organ ToxicIty
4.3.2.1 Overview
Animal data on the systemic/target organ toxicIty of heptachlor/
heptachlor epoxide were available only for the oral route.
Evaluation of the existing toxlcologlcal database for heptachlor/
heptachlor epoxide suggests that hepatotoxlclty may be the most
sensitive noncancer end point of toxlclty for these substances In
animals.
Neurotoxlc signs have been reported during short- and long-term
oral exposure of animals to heptachlor/heptachlor epoxide. In human case
reports, signs of neurotoxlclty (Irritability, salivation, lethargy,
dizziness, labored respiration, muscle tremors, and convulsions) were
reported following exposure (route not specified) of humans to
technical-grade chlordane, which typically contains 10% heptachlor. The
incidence of cerebrovascular disease was significantly increased in
workers engaged in the manufacture of chlordane, heptachlor, and endrin,
but was not increased in pesticide applicators and termite control
operators exposed to chlordane and heptachlor by unspecified routes.
Additional effects observed in animals during long-term exposures
include renal toxicity, adrenotoxicity, hematologic effects, and
decreased body weight gain. Intermediate and chronic inhalation exposure
of humans to mixtures of heptachlor with chlordane and other chemicals
has been associated with pancytopenia, leukemia, and aplastic,
hemolytic, and megaloblastic anemias.
4.3.2.2 Hepatotoxicity
Overview. Hepatotoxic effects of the short- and long-term oral
administration of heptachlor/heptachlor epoxide to animals included
histologic changes (necrosis, steatosis, hepatocytomegaly, or increased
numbers of lysosomes), increased liver weight, and increases in the
levels of serum components that are Indicative of hepatic damage (e.g.,
alkaline phosphatase, bilirubin, cholesterol, and glutamic-pyruvic
transaminase). Studies were available only for the oral route.
Inhalation, human. No data describing hepatotoxicity in humans
following inhalation exposure of any duration were found in the
literature.
Inhalation, animal. No data describing hepatotoxicity in animals
following inhalation exposure of any duration were found in the
literature.
Oral, human. No key studies describing hepatotoxicity in humans
following oral exposure of any duration were found In the literature.
In 45 individuals exposed for approximately 2 months to
contaminated raw milk products from cattle fed heptachlor-contaminated
feed, 23 to 31% had significantly (? < 0.01) elevated serum levels of
heptachlor metabolites. Results of liver function tests and assays for
hepatic microsomal enzyme Induction did not differ from those of the
control cohort (Stehr-Green et al. 1986). Exposure measurements were
-------
Toxicological Data 43
reported; inadequacies of analysis limit the use of these data (Frumkin
et al. 1987).
Oral, animal (acute). Adverse hepatic effects from acute oral
exposure to heptachlor have been demonstrated in rats. Microscopic
effects included liver necrosis (Krampl 1971), cell vacuolization
(Krampl 1971), and liver steatosis (Pelikan 1971). Other effects
compatible with hepatic damage from heptachlor include increased
relative liver weight (Pelikan 1971, Enan et al. 1982) and elevated
serum levels of aldolase (Krampl 1971), glutamic-pyruvic transaminase
(Krampl 1971), bilirubin (Enan et al. 1982), alkaline phosphatase (Enan
et al. 1982), and cholesterol (Enan et al. 1982).
Other liver effects from acute oral exposure of rats to heptachlor,
such as reduced liver glycogen, increases in gluconeogenic enzymes,
elevated blood sugar, and increases in microsomal drug-metabolizing
enzymes, have been reported (Enan et al. 1982, Gillett and Chan 1968,
Kacew and Singhal 1973, Den Tonkelaar and Van Esch 1974), but their
relevance to liver toxicity is uncertain.
The investigation of Enan et al. (1982) was selected by EPA (1985a
and 1987c) for derivation of a 10-day health advisory for heptachlor. A
group of 15 female white rats (strain not indicated) was fed heptachlor
(96%) 5 days per week for 4 weeks at a concentration of 10 ppm in the
diet (equivalent to 1 mg/kg/day; EPA 198Sa and 1987c, conversion
assumptions not given). Four animals were killed after receiving 1, 7,
or 28 daily doses. Controls were fed a diet containing corn oil, the
solvent used for addition of test compound to diet. Effects compatible
with hepatic damage from acute oral intake of heptachlor included
increased relative liver weight (7 days) and elevated serum bilirubin
(1, 7, and 28 days), alkaline phosphatase (1 and 7 days), and blood urea
(7 days). The liver was not examined histologically. The LOAEL was 1
mg/kg/day; a NOAEL was not established.
Oral, animal (intermediate). Adverse hepatic effects from
intermediate oral exposure to heptachlor or a mixture of heptachlor and
heptachlor epoxide have been demonstrated in rats, mice, pigs, and
sheep. Microscopic effects are shown in Table 4.2.
The following effects of intermediate oral exposure were also
compatible with hepatic damage: an increase in liver LDH5 (least anodic
isoenzyme of lactic dehydrogenase) in pigs treated with heptachlor
(Halacka et al. 1974); elevated serum bilirubin, blood urea, serum
cholesterol, serum alkaline phosphatase, and relative liver weight in
rats treated with heptachlor (Enan et al. 1982); enlarged livers and
increased relative liver weight in rats treated with heptachlor (Pelikan
1971); and increased liver weight in mice treated with
heptachlor/heptachlor epoxide (25%:75%) (IRDC 1973, as cited in Epstein
1976).
Other liver effects from intermediate oral exposure of animals to
heptachlor or heptachlor epoxide, such as reduced liver glycogen
(heptachlor in pigs, Dvorak and Halacka 1975; rats, Enan et al. 1982),
increased blood glucose (heptachlor in rats, Enan et al. 1982),
increases in microsomal drug-metabolizing enzymes (heptachlor and
heptachlor epoxide in rats, Kinoshita and Kempf 1970), and increased
-------
44 Section
Table 4.2. Microscopic hepatic effects of intermediate
oral exposure to heptachlor/heptachlor epoxide
Compound(s)
Heptachlor
Heptachlor
Heptachlor
Heptachlor
Heptachlor
Microscopic
findings
Liver necrosis
Liver necrosis
Liver fibrosis
Liver steatosis
Increased number of
Species
Mice
Rats, pigs,
sheep
Mice
Rats,
mice
Pigs
References
Akay and Alp 1981
Halackaet al. 197S
Akay and Alp 1981
Pelikan 1971,
Akay and Alp 1981
Halacka et al. 1974
lysosomes in
hepatocytes
Heptachlor
Heptachlor/
heptachlor
epoxide
(75%:25%)
Nuclear irregu-
larities
Centrilobular
hepatocytomegaly
Mice
Rats
Akay and Alp 1981
Jollcy et al. 1966,
as cited in Epstein
1976
-------
lexicological Data 45
agranular endoplasmic reticulun (heptachlor in pigs, Dvorak and Halacka
1975) and dose-related changes in biochemical values related to liver
function (heptachlor epoxide in dogs, IRDC 1971, as cited in EPA 1985a),
have been reported,, but their relevance to liver toxicity is uncertain.
Five female CD rats, an interim sacrifice group in a 24-month
study, were fed a diet containing 7.5 ppm heptachlor/heptachlor epoxide
(75%:25%) for 5 months. Prior to mixing, heptachlor was 99.9% pure, and
heptachlor epoxide was 96.0% pure. Seven females served as controls.
Hepatocytomegaly in excess of control levels was reported in the test
group (incidence and severity not given). The LOAEL was 7.5 ppm, or 0.38
mgAg/day; a NOAEL was not established (Jolley et al. 1966, as cited in
Epstein 1976).
Groups of 100 male and 100 female Charles River CD-I mice were fed
diets containing 0, 1, 5, or 10 ppm heptachlor/heptachlor epoxide
(25%:75%, purities not specified) for 18 months. At the 6-month interim
sacrifice of 10 males and 10 females, dose-related incidences of
hepatocytomegaly (data not given) were reported in all treated males and
in 5- and 10-ppm females. Mean liver weights were increased in 5- and
10-ppm males and in all treated females. The LOAEL was 1 ppm (0.15
mg/kg/day) ; a NOAEL was not established (IRDC 1973, as cited in Epstein
1976).
Oral, animal (chronic). Adverse hepatic effects of chronic oral
exposure to heptachlor, heptachlor epoxide, or a mixture of the two
compounds have been demonstrated in rats, mice, and dogs. Microscopic
effects are shown in Table 4.3.
Other effects compatible with hepatic damage from chronic oral
exposure to heptachlor or heptachlor epoxide include increased liver
weight in rats exposed to heptachlor (Uitherup et al. 1955, as cited in
Epstein 1976) or heptachlor epoxide (Witherup et al. 1959, as cited in
Epstein 1976), dose-related changes in biochemical values related to
liver function in dogs exposed to heptachlor epoxide (IRDC 1971, as
cited in EPA 1985a), increased relative liver weight in dogs exposed to
heptachlor epoxide (Kettering 1958, as cited in EPA 1987c), and
increased liver weight in mice exposed to heptachlor/heptachlor epoxide
(25%:75%) (IRDC 1973, as cited in Epstein 1976).
The investigation of Witherup et al. (1955) was selected by EPA
(1985a and 1987c) for derivation of a lifetime health advisory for
heptachlor. Heptachlor of unspecified purity was administered in the
diet to groups of 20 male and 20 female CF rats at concentrations of
1.5, 3r 5, 7, or 10 ppm for up to 110 weeks. Liver lesions
characteristic of chlorinated hydrocarbons (i.e., hepatocellular
swelling, homogeneity of the cytoplasm, and peripheral arrangements of
the cytoplasmic granules of cells in the central zone of liver lobules)
were increased in males and females of the 7- and 10-ppm groups. Mean
liver weights were increased in males in the 5-, 7-, and 10-ppm groups.
On the latter basis, EPA reported the LOEL to be 5 ppm (0.25 mg/kg/day)
and the NOEL to be 3 ppm (0.15 mg/kg/day)•
EPA (1987c) selected a Kettering Laboratory study (Kettering 1958)
for derivation of a lifetime health advisory for heptachlor epoxide.
Groups of three female and two male beagle dogs were administered diets
-------
46 Section
Table 4.3. Microscopic hepatic effects of chronic oral
exposure to beptachlor/heptachlor epoxide
Compound(s)
Microscopic
findings
Species
References
Heptachlor
Heptachlor
Heptachlor
epoxide
Heptachlor
epoxide
Heptachlor/
heptachlor
epoxide
(25%:75%)
Heptachlor/
heptachlor
epoxide
(75%:25%)
Hepatic cell vacuol- Rats
ization
Hepatic vein Mice
thrombosis
Hepatic vein Mice
thrombosis
Microscopic changes Dogs
in liver (NOS)
Hepatocytomegaly Mice
(mostly centri-
lobular)
Centrilobular Rats
hepatocytomegaly
Witherup et al.
19S9, as cited in
Epstein 1976
Reuber 1977
Reuber 1977
IRDC 1971, as cited
in EPA 198Sa
IRDC 1973, as cited
in Epstein 1976
Jolley et al. 1966,
as cited in Epstein
1976
-------
Toxicologies! Data 47
containing 0 0.5 2.5 5, or 7.5 ppm of heptachlor epoxide (purity not
given) for 60 weeks. Relative mean liver weights were significantly
increased (significance level not given) in treated animals compared
with controls, and the increases were dose related. The LOEL was 0 5 uom
(0.0125 mgAg/day); a NOEL was not established. '
Witherup et al. (1959, as cited in Epstein 1976) fed heptachlor
epoxide (purity not indicated) in the diet to groups of 25 male and 25
female CFN rats at concentrations of 0.5, 2.5, 5, 7.5, or 10 ppm for up
to 108 weeks. Hepatic cell vacuolization, which was centrilobular at low
doses and irregular at higher doses, was reported in all test groups
(incidences not given). Degeneration, hepatocytomegaly, and regeneration
were also reported (incidences not given). The LOAEL was 0.5 ppm (0 025
mgAg/day); a NOAEL was not established.
IRDC (1973, as cited in Epstein 1976) administered
heptachlor/heptachlor epoxide (25%:75%) of unspecified purity at
concentrations of 0, 1, 5, or 10 ppm in the diet to groups of 100 male
and 100 female Charles River CD-I mice for up to 18 months; 10 males and
10 females from each group were killed at 6 months. Dose-related
incidences of hepatocytomegaly (data not given), particularly involving
centrilobular cells, were reported in males and females of all test
groups. A dose-related incidence of nodular hyperplasia of the liver was
reported for the 5- and 10-ppm test groups. Mean liver weights were
significantly increased by 13% (P < 0.05) in females dosed at 1 ppm by
33% (P < 0.01) at 5 ppm, and by 89% (P < 0.01) at 10 ppm, and in males
by 38% (P < 0.01) at 5 ppm and by 169% (P < 0.01) at 10 ppm. The LOAEL
was 1 ppm (0.15 mgAg/day); a NOAEL was not established.
Dermal, human. No data describing hepatotoxicity in humans
following dermal exposure of any duration were found in the literature.
Dermal, animal. No data describing hepatotoxicity in animals
following dermal exposure of any duration were found in the literature.
General discussion. Oral epnsures to heptachlor/heptachlor epoxide
of any duration induced hepatotoxicity in rodents, as evidenced by
microscopic changes, increases in liver weight, and changes in serum
parameters indicative of liver damage. Although no direct evidence is
available, it is possible that the ability of heptachlor to inhibit
intercellular communication, as shown by in vitro evidence (see Sect.
4.3.5, Genotoxicicy), may be involved in the mechanism of
hepatotoxicity; also, the inhibition of intercellular communication and
the induction of toxic effects in the liver may play roles in the
hepatocarcinogenic process.
Suppression of body weight gain has often been reported in
conjunction with the induction of hepatotoxicity by intermediate or
chronic oral exposure to heptachlor/heptachlor epoxide. NOAELs/LOAELs
for the suppression of body weight gain by oral intake of these
compounds are given in Table 4.4.
4.3.2.3 Neurologic effects
Overview. Neurotoxic signs, including hypoactivity, tremors and
convulsions, ataxia, and changes in EEC patterns have been induced in
-------
48 Section
Table 4.4. NOAELs and LOAELs for suppression of body weight gain
by oral intake of beptachlor/heptachlor epoxide'
Species
Rats
Mice
Pigs
Rats
Rats
Rats
Mice
Strain/sex
Sprague-
Dawley/M
O.ASA/M.F
NA/ND
CF/M
Osborne-
Mendel/M
Osborne-
Mendel/F
CD-l/F
LOAEL
(mg/kg/
day)
1
7.5
5
0.075
3.9*
2.6*
1.5
NOAEL
(mg/kg/
day)
NE
NE
2
NE
1.9
1.3
0.75
Chemical,
duration
H,I
H.I
H,I
H,C
H,C
H,C
H/HE
(25%:75%),
C
References
Shain et al.
1977
Akay and Alp
1981
Halacka et al.
1974
Witherup et al.
1955, as cited in
Epstein 1976
NCI 1977
NCI 1977
IRDC 1973. as
cited in Epstein
1976
"Abbreviations: NE, not established; ND, no data; NA, not applicable; H, hepta-
chlor, HE, heptachlor epoxide; F, female; M, male; I, intermediate; C, chronic.
*Dose levels represent time-weighted averages.
-------
Toxicologies! Data 49
animals by acute, intermediate, or chronic oral intake of
heptachlor/heptachlor epoxide.
In human case, reports, signs of neurotoxicity (irritability,
salivation, lethargy, dizziness, labored respiration, muscle tremors,
and convulsions) were reported following exposure (route not specified)
of humans to technical-grade chlordane, which typically contains 10%
heptachlor. The incidence of cerebrovascular disease was significantly
increased in workers engaged in the manufacture of chlordane,
heptachlor, and endrin, but was not increased in pesticide applicators
and termite control operators exposed to chlordane and heptachlor by
unspecified routes.
Inhalation, human. No key studies describing neurologic effects in
humans following inhalation exposure to heptachlor were found in the
literature.
Human case reports which described acute neurological effects were
reported following exposure to technical-grade chlordane, which typically
contains 10% heptachlor (GAG 1986, EPA 1985a, EPA 1987c). These effects
included irritability, salivation, lethargy, dizziness, labored
respiration, muscle tremors, and convulsions. Reported dose levels
ranged from 10 to 104 mgAg body weight (EPA 1985a) . In all of these
cases, the effects observed cannot be attributed to heptachlor alone.
In a study of 16,126 pesticide applicators and termite control
operators principally exposed to chlordane and heptachlor by unspecified
routes, cerebrovascular disease was found to be significantly (? < 0.05)
decreased in termite control operators (Wang and MacMahon 1979a).
Incidence did not increase with increased estimated exposure. However,
incidence of cerebrovascular disease was found to be significantly
(? < 0.05) increased (17 cases) when compared to expected incidence (9.3
cases) among 1,403 workers engaged in the manufacture of chlordane,
heptachlor, and endrin (Wang and MacMahon 1979b). This increased
incidence of cerebrovascular disease was not correlated to length of
exposure or latency and was reported to occur only after termination of
employment (EPA 1985a). Methodological deficiencies limit the usefulness
of these data; quantitative exposure (concentration and duration) data
were not reported, the workers were exposed to multiple chemicals, and
there was no control for confounding factors. The increased incidence of
cerebrovascular disease reported by Wang and MacMahon (1979b) was not
found in a subsequent study of heptachlor and chlordane-manufacturing
workers (Ditraglia et al. 1981).
Inhalation, animal. No data describing neurologic effects in
animals following inhalation exposure of any duration were found in the
literature.
Oral, human. No key studies describing neurologic effects in
humans following oral exposure to heptachlor were found in the
literature. The occurrence of cerebrovascular disease in workers exposed
to mixtures of heptachlor with chlordane and endrin is discussed under
the inhalation route (Sect. 4.3.2.3).
Oral, animal (acute). Hypoactivity and some deaths (incidences not
given) were reported in CD-I male mice given a single gavage dose of
heptachlor/heptachlor epoxide (25%:75%. w/w) at levels of 30 to 100
-------
SO Section 4
mg/kg, values near the LD50- Prior to mixing, the purity of the
heptachlor was 73%; the purity of the heptachlor epoxide was not giver
The LOAEL was 30 mg/kg; a NOAEL was not established (Arnold et al.
1977).
Tremors anfl convulsions (incidences not given) were reported In
rats (sex and strain not indicated) given the acute oral LD50 dose (90
mg/kg) of heptachlor (purity not indicated). Neurotoxic signs appeared
30 to 60 min after dosing and lasted 2 days (Lehman 1951).
Oral, animal (intermediate). Heptachlor (purity not indicated) was
fed to groups of at least 10 female and 5 male O.ASA FIS mice for 10
weeks at concentrations of SO, 100, or 200 ppm in the diet. Controls
received diet without heptachlor. At 100 ppm, ataxia was reported in
half the females, and whole-body tremors were observed in some
(incidence not given). No neurotoxic signs were observed at 50 ppm, and
no information was given on effects at 200 ppm. The LOAEL was 100 ppm
(15 mg/kg/day). a"d the NOAEL was 50 ppm (7.5 mgAg/day) (Akay and Alp
1981).
Oral, animal (chronic). Statistically significant changes in EEC
patterns (? < 0.05) were reported in female Wistar rats administered
heptachlor in the diet at levels of 1 or 5 mgAg/day for three
generations. The LOAEL was 1 mgAg/day I a NOAEL was not established
(Formanek et al. 1976).
Dermal, human. No key studies describing neurologic effects in
humans following dermal exposure to heptachlor were found in the
literature. The occurrence of cerebrovascular disease in workers exposed
to mixtures of heptachlor with chlordane and endrin is discussed unde
the inhalation route (Sect. 4.3.2.3).
Dermal, animal. No data describing neurologic effects in animals
following dermal exposure of any duration were found in the literature.
General discussion. Investigations of heptachlor/heptachlor
epoxide effects in rat brain suggest that the neurotoxic effects of
these compounds may, in part, involve the following two processes:
(1) interference with nerve action or release of neurotransmitters as
the result of inhibition of the activities of Na+-K+ ATPase (Folmar
1978; Yamaguchi et al. 1980) or Ca2+-Mg2+ ATPase (Yamaguchi et al. 1980)
and (2) inhibition of the function of the receptor for 7-aminobutyric
acid (GABA) (Abalis et al. 1985 and 1986, Hatsumura and Ghlasuddin
1983). Heptachlor. heptachlor epoxide. and other cyclodiene insecticides
bind to the picrotoxin binding site of the GABA receptor in mammalian
brain synaptosomes or membrane vesicles (Hatsumura and Ghiasuddin 1983,
Abalis et al. 1985, Lawrence and Casida 1984) and inhibit GABA-
stimulated chloride uptake by the GABA receptor-chloride ionophore
complex in the central nervous system (Abalis et al. 1986, Bloomquist
and Soderlund 1985, Cant et al. 1987). The convulsant activity and
toxlcity of the chlorinated cyclodiene insecticides (including
heptachlor and heptachlor epoxide) are closely related to their potency
as inhibitors of the In vitro or in vivo binding of t-butylbicyclo-
phosphorothionate (TBPS) to the picrotoxinin binding site of the GABA
receptor (Cole and Casida 1986, Lawrence and Casida 1984).
-------
Toxicologies! Data 51
4.3.2.4 Adrenotoxicity
Overview. Microscopic changes in Che cortex of the adrenal gland
were reported following intermediate oral exposure of mice to
heptachlor. These changes were observed in one study but have not been
confirmed.
Inhalation, human. No data describing adrenotoxicity in humans
following inhalation exposure of any duration were found in the
literature.
Inhalation, animal. No data describing adrenotoxicity in animals
following inhalation exposure of any duration were found in the
literature.
Oral, human. No data describing adrenotoxicity in humans following
oral exposure of any duration were found in the literature.
Oral, animal. Ten female albino mice (strain not indicated) were
given heptachlor (89% purity) at a dose level of 100 ppm (80-mg/kg/day)
in the drinking water for up to 26 days. Six untreated females served as
controls. The adrenal glands from all treated animals showed cortical
atrophy. After 11 days of treatment, slight hypertrophy was reported in
the zona glomerulosa; after 26 days of treatment, cortical cells showed
hypertrophy, heavy lipid accumulation, granulation, and cell
degeneration with extensive destruction and fibrosis (Akay et al. 1982).
The validity of the 100-ppm dose level can be questioned since the
solubility of heptachlor in water is 56 mg/L or 0.056 ppm (Worthing and
Walker 1983), implying either that the dose level was incorrectly
reported or that the heptachlor was present in suspension, thus bringing
into question the uniformity of dosing. In addition, the 80-mg/kg/day
dose level was calculated using the authors' stated water consumption
rate of 20 cm3/day/mouse (Akay et al. 1982); this is in excess of the
usual 4 to 7 mL/day/mouse water intake reported by Arrington (1972).
Dermal, human. No data describing adrenotoxicity in humans
following dermal exposure of any duration were found in the literature.
Dermal, animal. No data describing adrenotoxicity in animals
following dermal exposure of any duration were found in the literature.
General discussion. The induction of adrenal toxicity by
heptachlor, reported In a single study, has not been confirmed by other
investigators. No information was found on the mechanism of action.
4.3.2.5 Renal toxicity
Overview. Kidney granulomas were reported in mice following
intermediate oral exposure to heptachlor. This effect was observed in
one study but has not been confirmed.
Inhalation, human. No data describing renal toxicity in humans
following inhalation exposure of any duration were found in the
literature.
Inhalation, animal. No data describing renal toxicity in animals
following inhalation exposure of any duration were found in the
literature.
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52 Section 4
Oral, human. No data describing renal toxicity in humans follow'
oral exposure of any duration were found in the literature.
Oral, animal. Heptachlor (purity not indicated) was fed to groups
of at least 10 female and 5 male O.ASA Fl5 mice for 10 weeks at
concentrations of 50, 100, or 200 ppm in the diet. Controls received
diet without heptachlor. The kidneys of the mice receiving 200 ppm
heptachlor had granulomas containing mononuclear cells, histiocytes, and
eosinophilic granulocytes (incidences not given). The LOAEL was 200 ppm
(30 mgAg/day). and the NOAEL was 100 ppm (15 mgAg/day) (Akay and Alp
1981).
Dermal, human. No data describing renal toxicity in humans
following dermal exposure of any duration were found in the literature.
Dermal, animal. No data describing renal toxicity in animals
following dermal exposure of any duration were found in the literature.
General discussion. The induction of renal toxicity by heptachlor,
reported in a single study, has not been confirmed by other
investigators. No information was found on the mechanism of action.
4.3.2.6 Hematologic effects
Overview. Spleen fibrosis and increased numbers of leukocytes in
the blood and spleen and erythrocytes in the spleen were reported
following intermediate oral exposure of rodents to heptachlor. These
effects were observed at the high dose; data were insufficient to
determine if they were seen at lower doses.
Inhalation, human. No key studies describing hematologic effect.
in humans following inhalation exposure to heptachlor were found in the
literature.
Intermediate and chronic multichemical exposure of humans by
inhalation of heptachlor, chlordane, and other chemicals has been
associated with several hematologic effects (GAG 1986, EPA 1985a). These
include aplastic anemia, hemolytic anemia, megaloblastic anemia,
pancytopenia, and leukemia (Infante et al. 1978, EPA 1985a).
Quantification of exposures was not reported. A separate case-control
study suggests that there is no increased risk of aplastic anemia to
people in pesticide-exposed occupations (Wang and Grufferman 1981).
Again, quantification of exposure was not reported.
Inhalation, animal. No data describing hematologic effects in
animals following inhalation exposure of any duration were found in the
literature.
Oral, human. No key studies describing hematologic effects in
humans following oral exposure to heptachlor were found in the
literature. Information concerning exposure to undetermined
concentrations of multiple chemicals is discussed under the inhalation
route (Sect. 4.3.2.6).
Oral, animal (intermediate). Administration of heptachlor (96%) at
a concentration of 1 mgAg/day in the diet 5 days/week for a total of 28
doses induced a significant (P < 0.05) elevation (1.7-fold) of the wh
blood cell count in rats (Enan et al. 1982).
-------
ToxlcoLogical Daca S3
Heptachlor (purity not indicated) was fed to groups of at least 10
female and 5 male O.ASA Fl5 mice for 10 weeks at concentrations of 50,
100, or 200 ppm in the diet. Controls received diet without heptachlor.
Spleen fibresis and increased numbers of red blood cells (RBCs) and
eosinophilic white blood cells (WBCs) in the spleen were induced at 200
ppm; it was not clear whether increased spleen RBCs and WBCs were
induced by the two lower-dose levels (Akay and Alp 1981).
Dermal, human. No key studies describing hematologic effects in
humans following dermal exposure to heptachlor were found in the
literature. Information concerning exposure to undetermined
concentrations of multiple chemicals is discussed under the inhalation
route (Sect. 4.3.2.6).
Dermal, animal. No data describing hematologic effects in animals
following dermal exposure were found in the literature.
General discussion. In rodents, spleen fibrosis was induced by
oral exposure to a high dose of heptachlor; the induction of hematologic
effects was minimal at lower doses. No information was found on the
mechanism of action.
4.3.3 Developmental Tozicity
4.3.3.1 Overview
Heptachlor epoxide has been found in tissues of stillborn infants.
A study was conducted of women of child-bearing age who ingested
heptachlor-contaminated milk; however, the resulting data were
considered inadequate to establish a relationship between exposure and
human developmental toxicity.
Cataracts and decreased postnatal survival were reported in the
progeny of rats fed diets containing heptachlor. These effects are
included as an indication of the kinds of developmental effects reported
in the literature; data were insufficient to further evaluate these
studies. No data were available for other routes of exposure in animals.
4.3.3.2 Inhalation
Human. No key studies describing human developmental toxicity
following inhalation exposure to heptachlor were found in the
literature. However, transplacental transfer of heptachlor epoxide and
possible concentration in fetal tissues have been indicated. Heptachlor
epoxide concentrations in fetal blood (0.9959 ppm) have been found to
exceed concentrations in maternal blood (0.2798 ppm) (Polishuk et al.
1977b). In addition, heptachlor epoxide has been reported in stillborn
infant brain, adrenal, lung, heart, liver, kidney, spleen, and adipose
tissues (Curley et al. 1969). Data concerning route, duration, and
extent of exposure were not provided.
Animal. No information was found.
4.3.3.3 Oral
Human. No key studies describing human developmental toxicity
following oral exposure to heptachlor were found in the literature.
-------
54 Section 4
Le Marchand et al. (1986) reported no adverse effects on human fetal
development following ingestion of milk containing heptachlor for 27
29 months among women of child-bearing age in Oahu, Hawaii. Milk fat
levels of heptachlor measured in Hawaii during this time, which ranged
from 0.12 to 5.00 ppm, were compared with EPA's "worst case" estimates
on record of 0.10 to 1.20 ppm. Burch (1983, as cited in Le Marchand et
al. 1986) reported no increase in fetal or neonatal deaths or incidence
of low-birth-weight infants in this study cohort. Twenty-two of the 23
major congenital malformations evaluated were found to be decreased in
the study population when compared with control cohorts. One
malformation (anomalies of the abdominal wall) was found to be slightly
increased in the study cohort during the period of known exposure
compared with the control cohorts; however, data for this malformation
were not available prior to study initiation. It was therefore not
possible to compare the incidence of this anomaly prior to exposure with
the incidence during exposure. The inadequacies of this study were (1)
milk fat residue levels of heptachlor were not reported for Oahu
specifically, and (2) milk fat residue levels of heptachlor were not
measured in the control population.
Transplacental transfer of heptachlor epoxide following exposure
via an unidentified route is discussed under the inhalation route (Sect.
4.3.3.2).
Animal. Cataracts were observed in progeny of rats fed 6.9
mgAg/day of heptachlor for 3 months prior to mating (FAO/WHO 1967. as
cited in WHO 1984). Mestitzova (1967) reported that rats fed an "appl<
dose" of 6 mg/kg heptachlor produced progeny in which increased
mortality and cataracts were noted shortly after eye opening. This stu.
was included as an indication of the kinds of developmental effects that
have been observed; data were insufficient to further evaluate these
studies.
Three unpublished three-generation studies with rats yielded
inconsistent results. In one study (Witherup et al. 1955, as cited in
WHO 1984), intermediate dose levels of heptachlor or heptachlor epoxide
increased postnatal mortality, but the highest dose had no effect. In
another study (Witherup et al. 1976b, as cited in WHO 1984), increased
postnatal mortality in rats was seen at the highest dose only in the
second generation. In a third study (Witherup et al.' 1976a, as cited in
WHO 1984), results for rats receiving a mixture of heptachlor and
heptachlor epoxide were not considered by the investigators to be
compound related.
Eisler (1968) reported two three-generation studies in rats. The
animals (male and female) were fed either a mixture of heptachlor and
its epoxide (ratio not specified) at 0.3, 3, or 7 ppm, or heptachlor at
0.3, 3, 6, or 10 ppm. Over 7,000 rats were examined in the two studies;
no anatomical anomalies were observed. F3 pups had no histological
changes in their viscera. The mixture, fed during lactation, did not
retard postnatal development. No other results were reported.
Male and female Sprague-Dawley rats (number not reported) were fed
diets containing 5 ppm (0.25 mgAg/day) heptachlor (purity not report '
for 60 days prior to and during gestation (Green 1970). Postnatal
survival in the Fl progeny was reduced. Only 19/122 offspring of tret.
-------
Toxicologies! Data 55
rats survived 21 days postpartum compared to 179/288 offspring of
controls. The LOAEL was 0.25 mg/kg/dayi a NOAEL was not established.
4.3.3.4 Dermal
Huaan. No key studies describing human developmental toxicity
following dermal exposure to heptachlor were found in the literature.
Transplacental transfer of heptachlor epoxide following exposure via an
unidentified route is discussed under the inhalation route (Sect.
4.3.3.2).
Animal. No information was found.
4.3.3.5 General discussion
Although no direct evidence is available, it is possible that che
ability of heptachlor to inhibit intercellular communication, as shown
by in vitro evidence (see Sect. 4.5, Genotoxicity), may be involved in
the mechanism of developmental toxicity.
4.3.4 Reproductive Toxicity
4.3.4.1 Overview
Heptachlor epoxide has been found in tissues of stillborn infants.
A study was conducted of women of child-bearing age who ingested
heptachlor-contaminated milk. The resulting data from both were
considered inadequate to establish a relationship between exposure and
human reproductive toxicity.
Male and female mice that received heptachlor in the diet for 10
weeks were unable to produce a new generation. Decreased pregnancy rates
were reported following oral administration of heptachlor to male and
female rats for two generations. In male and female rats fed heptachlor,
heptachlor epoxide, or a mixture of the two for three generations, the
number of resorbed fetuses increased and fertility decreased with
succeeding generations. No reproductive toxicity data were available for
other routes of exposure for animals.
4.3.4.2 Inhalation
Human. No key studies describing adverse reproductive effects in
humans following inhalation exposure to heptachlor were found in the
literature. Wassermann et al. (1982) detected significantly higher
levels of heptachlor epoxide in the serum of a group of women with
premature delivery than in the serum of a control group with normal
delivery. However, serum levels of eight of the ten organochlorlne
pesticides for which analytical data were obtained were all
significantly higher in the premature delivery group; route, duration,
and level of exposure were not reported. Heptachlor epoxide has been
reported in stillborn infant brain, adrenal, lung, heart, liver, kidney,
spleen, and adipose tissue, indicating transplacental transfer of
heptachlor (Curley et al. 1969).
Animal. No information was found.
-------
56 Section 4
4.3.4.3 Oral
Human. No key studies describing adverse reproductive effects in
humans following oral exposure to heptachlor were found in the
literature. Burch (1983, as cited in Le Marchand et al. 1986) reported
no adverse effects on human reproduction (no decrease in fertility, no
increase in fetal or neonatal deaths) among women of child-bearing age
following ingestion of heptachlor-containing milk for 27 to 29 months.
It was not established, however, that the levels of heptachlor ingested
by the "exposed" group were higher than the levels ingested by the
control group. Other information concerning possible reproductive
effects from heptachlor exposure via unspecified routes are presented
under the inhalation route (Sect. 4.3.4.2).
Animal. Epstein et al. (1972) administered heptachlor or its
epoxide to male mice that were then bred to untreated females;
preimplantation losses and resorptions were within control limits.
Male and female mice that received 50, 100, or 200 ppm (7.5, 15, or
30 mgAg/day. respectively) heptachlor in the diet for 10 weeks were
unable to produce a new generation (Akay and Alp 1981). No microscopic
alterations were found in ovaries or testes. This study was included as
an indication of the kinds of reproductive effects that have been
observed. Failure of mice to produce offspring following dosing with
heptachlor has not been confirmed.
In two three-generation studies with rats (male and female) fed
diets containing either heptachlor, heptachlor epoxide, or a mixture
the two, the number of resorbed fetuses increased and fertility
decreased with succeeding generations, in some cases to zero (Cerey and
Ruttkay-Nedecka 1971, Ruttkay-Nedecka et al. 1972). The results reported
by these authors have not been confirmed.
In a dominant lethal assay, 8 male CD-I mice received single oral
doses of 7.5 or 15 mg/kg heptachlor/heptachlor epoxide (25%:75%) and
were bred with three untreated females each week for 6 weeks (Arnold et
al. 1977). No adverse effects on reproductive capacity were reported.
The NOAEL was 15 mg/kg; a LOAEL was not established.
Male and female Sprague-Dawley rats (number not reported) were fed
a diet containing 5 ppm (0.25 mg/kg/day> heptachlor (purity not
reported) for 60 days and then during gestation (Green 1970). Females
killed on gestation day 21 showed no significant reproductive effects.
In a second phase of the study, however, rats receiving 5 ppm (0.25
ing/kg/day) for two generations showed decreased pregnancy rates. In the
first generation, 18/25 heptachlor-treated females (compared to 30/32
controls) became pregnant. In the second generation, none of 12 females
receiving heptachlor became pregnant. The LOAEL was 0.25 mg/kg/day: a
NOAEL was not established.
4.3.4.4 Dermal
Human. No key studies describing adverse reproductive effects in
humans following dermal exposure to heptachlor were found in the
literature. Information concerning possible reproductive effects fro.
-------
lexicological Data 57
heptachlor exposure via unspecified routes is presented under the
inhalation route (Sect. 4.3.4.2).
Animal. No information was found.
4.3.4.5 General discussion
When male mice were fed diets containing heptachlor or heptachlor
epoxide in a dominant lethal study, no effects on reproduction were
noted. On the other hand, when both sexes of mice or rats were fed diets
containing either heptachlor or heptachlor epoxide in multigeneration
studies, resorptions were increased relative to controls and fertility
was markedly decreased, in some instances to zero. These results seem to
indicate that heptachlor or heptachlor epoxide has the greatest effect
upon the female reproductive tract and/or upon the fetuses residing
therein. No studies were found where only female rodents were dosed.
4.3.5 Genotoxic ity
4.3.5.1 Overview
Heptachlor and heptachlor epoxide, with or without metabolic
activation, tested negative in well-conducted microbial gene mutation
assays, and heptachlor was not mutagenic in an epithelial cell line
(ARL) derived from rat liver. Heptachlor, with metabolic activation, was
clastogenic in Chinese hamster ovary (CHO) cells, but neither heptachlor
nor heptachlor epoxide induced a dominant lethal effect in male mouse
germinal cells. Heptachlor (with or without metabolic activation) was
positive in an in vitro CHO cell SCE assay. The results of unscheduled
DNA synthesis (UDS) assays with heptachlor were negative (primary
hepatocytes from mouse, rat, or hamster) except when preinitlated cells
(virally transformed human cell line) were used as the target.
Heptachlor inhibited metabolic cooperation in Chinese hamster lung cells
and rat liver epithelial cells.
4.3.5.2 Review of data
Tables 4.5 and 4.6 summarize the findings of relevant genetic
toxicology assays with heptachlor or heptachlor epoxida. Only those
studies considered acceptable by today's criteria or those reporting a
positive response are Included.
These studies are categorized into gene mutation (Category 1),
chromosome aberrations (Category 2), other mutagenic mechanisms
(Category 3), and epigenetic mechanisms (Category 4).
Gene mutation (Category 1). Heptachlor and heptachlor epoxide,
with or without activation, tested negative in well-conducted gene
mutation assays. Inconclusive evidence for a mutagenic effect (single
dose only, weak response, questionable control values) was reported for
heptachlor in two strains of Salmonella (TA98 and TAlOO) following
activation with S-9 fractions from Arochlor 1254-induced rats and one
strain (TA1535) following activation with a IS fraction from maize (Zea
mays inbred B37, Gentile et al. 1982).
-------
58 Section 4
TaMe 4.5. Gcoocoxkity of bepuchlor and beptachlor epoxidc (in vitro)
End point
Gene mutation
Chromosomal
aberrations
(somatic cells)
Sister chromaud
exchange
Unscheduled DNA
synthesis
Gap junction
inhibition
Compound
Heptachlor
Heptachlor
(technical grade)
Heptachlor epoxide
Heptachlor
(technical grade)
Heptachlor
Heptachlor
Heptachlor
Heptachlor
Heptachlor
Heptachlor epoxide
Heptachlor
Heptachlor
Species
Salmonella lyphimunum
strains TA98. TAIOO. TA1S3S.
TA1536, TA1537, TAI538
S. lyplumunum
strains TA98. TAIOO. TA1S3S
S lyphimunum
strains TA98, TAIOO, TA1S3S,
TA1S36. TA1537, TAI538
Zea mays
Adult rat liver (ARL)
epithelial cells
Chinese hamster ovary
(CHO) cells
CHO cells
Mouse, rat, hamster
primary hepatocytes
SV-40 transformed
human fibroblasts (VA-4)
SV-40 transformed
human fibroblasts (VA-4)
Chinese hamster V79
(6TG» and 6TG*)
ARL
(HGPRT* and HGPRT")
Result
with activation/
without activation
-/-
+ /-
-/-
-/NA"
+/-
+/+
(significant at
2 doses: f < 0.05
(significant at
3 doses; f < O.OS
+ ^
(Dose related)
(Dose related)
References
Marshall et al 1976,
NTP 1987
Gentile et al 1982
Marshall et al 1976,
Glatt et al. 1983
Gentile et al. 1982
Telang et al. 1982
NTP 1987
NTP 1987
Maslansky and
Williams 1981.
Probst et al 1981
Ahmed et al 1977
Ahmed et al 1977
Kurata et al. 1982
Telang et al 1982
"NA - Not applicable.
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lexicological Data 59
Tabk4.6. GcMCoxfchy of hepucUor aid bepocUor cpoilde (hi Hro)
End point
Dominant lethal
assay
Compound
Heptachlor
Heptachlor/heptachlor
epoxide (25% 75%)
Heptachlor epoxide
Species
Swiss mice
CD-I mice
Swiss mice
Route
Oral
•P"
Oral
>P
Oral
>P
Result References
— Epstein et aL 1972
- Arnold et al. 1977
- Epstein et al 1972
"ip — intrapentoneal.
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60 Section 4
Qualitative results presented by Gentile et al. (1982) indicated
that commercial-grade heptachlor caused a significant increase
(P < 0.05) in back mutations in Zea mays, leading to the conclusion th_.
heptachlor is presumptively mutagenic to corn.
Telang et al. (1982) demonstrated that heptachlor, assayed up to a
cytotoxic dose was not mutagenic in a mammalian liver cell system (rat
liver epithelial cells obtained from F344 rats. ARL) derived from the
only organ in which heptachlor induces tumors in vivo.
Structural chromosome aberrations (Category 2). The in vitro CHO
cell assay performed by NTP (1987) indicated that S-9-activated
heptachlor was clastogenic. No in vivo somatic cell assay has been
published. The dominant lethal assay results presented in Table 4.2 show
that neither heptachlor nor heptachlor epoxide is clastogenic in male
germinal cells (Epstein et al. 1972, Arnold et al. 1977).
Other mutagenic mechanisms (Category 3). NTP (1987) reported
nonactivated and S-9-activated heptachlor increased the frequency of
sister chromatid exchange in CHO cells. Heptachlor did not induce UDS in
primary hepatocytes from mouse, rat, or hamster (Haslansky and Williams
1981, Probst et al. 1981). In contrast, both heptachlor and heptachlor
epoxide induced significant dose-related increased UDS in a virally
transformed human cell line (Ahmed et al. 1977). These assays were
seriously compromised by technical deficiencies and have not been
confirmed.
Epigenetic effects (Category 4). Heptachlor induced inhibition of
gap junctional intercellular communication (metabolic cooperation)
between Chinese hamster V79 6-thioguanine-sensitive (6TGS) cells and
6-thioguanine-resistant (6TGr) cells (Kurata et al. 1982). The effect
was dose related (2.5 to 10 mg/mL) and included a cytotoxic level.
Telang et al. (1982) evaluated heptachlor at the same end point but used
a different mammalian cell line--rat liver epithelial cells. Heptachlor,
assayed up to a cytotoxic dose, »_•:. positive, and the effect was clearly
dose related. Of note was the demonstration of assay specificity to
detect only agents which interfere with cell-to-cell communication
(epigenetic) in contrast to chemicals which induce a genotoxic effect.
Four doses of the lipophilic procarcinogen/promutagen benzo[a]pyrene, up
to a cytotoxic dose, caused no interference with cell-to-cell
communication. The findings of Kurata et al. and Telang et al. are of
singular importance because they demonstrated that heptachlor interfered
with gap junction-mediated communication between contiguous cells in two
phylogenetically different mammalian cell lines. Moreover, this
constitutes independent confirmation of an alternative mechanism of
action for heptachlor.
General discussion. No compelling evidence of a mutagenic effect
in relevant biological systems was uncovered. Clastogenic activity in
mammalian somatic cells (in vitro) was observed but should be
independently verified before reaching a definitive conclusion. There
was no evidence of a clastogenic effect in male mouse germinal cells.
The results of DHA repair assays have been negative except for one assay
using SV-40 transformed human cells; however, this study is considered
to be equivocal. A single SCE study reported positive results, but ir
requires confirmation.
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Toxicological Data 61
4.3.6 Carcinogenicity
4.3.6.1 Overview
Chronic oral exposure to heptachlor increased the incidence of
liver carcinomas in C3H and B6C3F1 mice. Chronic oral exposure to
heptachlor epoxide increased the incidence of liver carcinomas in CFN
rats and C3H, CD-I, and B6C3F1 mice.
Available epidemiological studies on heptachlor are considered to
be inadequate to establish a clear qualitative or quantitative
assessment of the relationship between heptachlor exposure and the risk
of developing cancer in humans. Summaries and reviews of the animal and
epidemiological studies can be found In CAG (1986), Reuber (1978) and
WHO (1984).
Heptachlor/heptachlor epoxide is classified as a probable human
carcinogen. Group B2, under the EFA's guidelines for carcinogen risk
assessment. The EPA CAG assessment of heptachlor and heptachlor epoxide
had not undergone peer review at the time this profile was prepared.
4.3.6.2 Inhalation
Human. No key studies describing carcinogenic effects in humans
following exposure to heptachlor by inhalation were found in the
literature.
Evidence has shown that inhalation and skin absorption are the
principal routes of heptachlor exposure for the industrial worker.
However, secondary exposures for these individuals may occur through
ingestion (NCI 1977).
In a study of 16,126 pesticide applicators and termite control
operators principally exposed to chlordane and heptachlor, cancer of the
skin and bladder was increased (but P > 0.05) in both groups (Wang and
MacMahon 1979a). Apparent increases were noted in cancer of the lung
among pesticide applicators only. This study provides inadequate
evidence of the carcinogenicity of heptachlor because of methodological
deficiencies. Quantitative exposure (concentration and duration) data
were not reported; multiple chemical exposures were studied; 42 deaths
were classified without death certificates; no individual follow-up was
conducted; and there was no control of confounding factors. A follow-up
of this study in 1982 indicated that cancer of the bladder was slightly
Increased among termite control operators, whereas cancers of the lung
and skin were slightly increased among pesticide applicators; these
increases were not significant (WHO 1984). Termite control operators
were assumed to have had a greater exposure to heptachlor and chlordane.
In a study of 1,403 workers engaged in the manufacture of
chlordane, heptachlor, and endrin, lung cancer incidence appeared to be
increased for the entire study cohort, but significantly (P < 0.01)
increased for workers less than 35 years of age at occupation initiation
and leas than 50 years of age at the time of observation (Vang and
MacMahon 1979b, CAG 1986). Twelve mortalities from lung cancer were
observed. One death from liver cancer was reported. The increased
incidences of skin and bladder cancer among pesticide applicators of the
former study (Vang and MacMahon 1979a) were not reflected in this study
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62 Section 4
cohort. Methodological deficiencies included a lack of quantitative
exposure data, mixed exposures, small cohort size, and the inclusion o*.
workers with little potential for exposure (office workers). This latter
factor may have underestimated the cancer incidence of the manufacturing
workers.
Ditraglia et al. (1981) conducted a study of 2,100 manufacturing
workers from four pesticide plants, one of which produced heptachlor,
endrin, and other chemical products. At this plant, no statistically
significant increases were observed, although the incidences of
intestinal, bladder, urinary, and respiratory cancer appeared elevated.
The lack of quantitative exposure data, mixed exposures, small cohort
size, no adjustment of confounding variables, and inclusion of minimally
exposed workers in the study cohort limit the usefulness of these data
(GAG 1986).
In a study of 783 workers engaged in the manufacture of heptachlor
and chlordane in 1976-1977, and a subsequent follow-up in 1980-1981. no
increase in cancer incidence or mortality from cancer was reported
(Velsicol 1981). An industrial hygiene survey indicated a heptachlor
concentration in the plant atmosphere of 0.025 to 0.202 mg/or1 (Netzel
1981). As in previous studies, the lack of individual quantitative
exposure data for the study cohort, mixed exposures, limited follow-up,
and no adjustment of confounding variables limit the usefulness of these
data.
In a study of 3,496 chemical workers involved in the manufacture of
agricultural chemical products including heptachlor, no evidence of
increased cancer risk was found (Environmental Health Associates 1983t
1983b).
Animal. No data describing carcinogenicity in animals following
inhalation exposure of any duration were found in the literature.
4.3.6.3 Oral
Human. Epidemiological studies of carcinogenicity from
occupational exposure to mixtures of chlordane, heptachlor, and other
chemicals are described under inhalation (Sect. 4.3.6.2).
Animal. Heptachlor/heptachlor epoxide increased the incidence of
liver carcinomas in CFN rats and C3H. CD-I, and B6C3F1 mice. EPA's CAG
(GAG 1986) presented summaries of the nine data sets (Tables 4.7-4.15)
that showed significant increases In the incidence of hepatocellular
carcinomas in treated groups compared with controls.
4.3.6.4 Dermal
Human. Epidemiological studies of carcinogenicity from
occupational exposure to mixtures of chlordane, heptachlor, and other
chemicals are described under inhalation (Sect. 4.3.6.2).
Animal. No data describing carcinogenicity In animals following
dermal exposure of any duration were found in the literature.
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Toxlcologlcal Data 63
Table 4.7. Cancer data sheet for deriTation of potency of beptachlor
from nepatoceUular carcinomas in female mice—I
Compound
Species, strain, sex
Body weight
Length of experiment
Length of exposure
Tumor site and type
Route, vehicle
Human potency (qf)
Heptachlor
Mouse, C3H, female
0.030 kg (assumed)
24 months
24 months
Liver carcinoma
Oral, diet
14.9 per mg/kg/day
Experimental
animal dose
(ppm)
0
10
Average
animal dose
(mg/kg/day)
0.00
1.43a
Equivalent
human dose
(mg/kg/day)
0.000
0.108
Tumor incidence
(No. responding/
No. examined)
2/54
57/78
"Lowest exposure level associated with increased tumors in
experimental animals.
Source: Davis 1965, as diagnosed by Reuber 1977b. Extracted
from CAG 1986.
-------
64 Section 4
Table 4.8. Cancer data sheet for derivation of potency of beptachlor
from hepatocellular carcinomas in male mice—I
Compound
Species, strain, sex
Body weight
Length of experiment
Length of exposure
Tumor site and type
Route, vehicle
Human potency (q*)
Heptachlor
Mouse, C3H, male
0.030 kg (assumed)
24 months
24 months
Liver carcinoma
Oral, diet
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
"Lowest exposure level associated with increased tumors in
experimental animals.
Source: Davis 196S, as diagnosed by Reuber I977b. Extracted
from CAC 1986.
-------
Toxicological Data 65
Table 4.9. Cancer data sheet for derivation of potency of heptachlor
from hepatocellular carcinomas in female mice—II
Compound
Species, strain, sex
Body weight
Length of experiment
Length of exposure
Tumor site and type
Route, vehicle
Human potency
Technical-grade heptachlor
Mouse, B6C3F,, male
0.030 kg (assumed)
90 months
80 months
Liver, carcinoma
Oral, diet
0.83 per mg/kg/day
Experimental
animal dose
(ppm)
0
18.0
Average
animal dose
(mg/kg/day)
0.00
2.34fl
Equivalent
human dose
(mg/kg/day)
0.000
0.18
Tumor incidence
(No. responding/
No. examined)
2/10
30/42
"Lowest exposure level associated with increased tumors in
experimental animals.
Source: NCI 1977b. Extracted from CAG 1986.
-------
66 Section 4
Table 4.10. Cancer data sheet for derivation of potency of heptachlor
from bepatocellnlar carcinomas in male mice—II
Compound
Species, strain, sex
Body weight
Length of experiment
Length of exposure
Tumor site and type
Route, vehicle
Human potency (q*)
Technical-grade heptachlor
Mouse, B6C3F,, male
0.030 kg (assumed)
90 months
80 months
Liver, carcinoma
Oral, diet
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
"Lowest exposure level associated with increased tumors in
experimental animals.
Source: NCI 1977b. Extracted from CAG 1986.
-------
lexicological Data 67
Table 4.11. Cancer data sheet for derivation of potency of beptachlor
epoxide from hepatocellular carcinomas in female mice
Compound
Species, strain, sex
Body weight
Length of experiment
Length of exposure
Tumor site and type
Route, vehicle
Human potency (q(*)
Heptachlor epoxide
Mouse, C3H, female
0.030 kg (assumed)
24 months
24 months
Liver carcinoma
Oral, diet
36.2 per mg/kg/day
Experimental
animal dose
(ppm)
0
10.0
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)
2/54
77/81
"Lowest exposure level associated with increased tumors in
experimental animals.
Source: Davis 1965, as diagnosed by Reuber 1977b. Extracted
from CAG 1986.
-------
68
Section 4
Table 4.12. Cancer data sheet for derivation of potency of heptachlor
epoxide from hepatocellular carcinomas in male mice
Compound
Species, strain, sex
Body weight
Length of experiment
Length of exposure
Tumor site and type
Route, vehicle
Human potency (q")
Heptachlor epoxide
Mouse, C3H, male
0.030 kg (assumed)
24 months
24 months
Liver carcinoma
Oral, diet
27.7 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
73/79
"Lowest exposure level associated with increased tumors in
experimental animals.
Source: Davis 1965, as diagnosed by Reuber 1977b. Extracted
from CAG 1986.
-------
Toxicological Data 69
Table 4.13. Cancer data sheet for derivation of potency of heptachlor
epoxide from hepatic carcinomas in female mice—I
Compound
Species, strain, sex
Body weight
Length of experiment
Length of exposure
Tumor site and type
Route, vehicle
Human potency (q*)
25.75 mixture of heptachlor/heptachlor epoxide
Mouse, CD-I, female
0.030 kg (assumed)
19 months
18 months
Liver, carcinoma
Oral, diet
1.04 per mg/kg/day
Experimental
animal dose
(ppm)
0
1
5
10
Average
animal dose
(mg/kg/day)
0
0.13
0.65
1.30°
Equivalent
human dose
(mg/kg/day)
0
0.01
0052
0 10
Tumor incidence
(No. responding/
No. examined)
6/76
1/70
6/65
30/57
"Lowest exposure level associated with increased tumors in experimental
animals.
Source: IRDC 1973b, as Devaluated by Reuber. Extracted from CAG
1986.
-------
70 Section 4
Table 4.14. Cancer data sheet for derivation of potency of heptachlor
epoxide from hepatic carcinomas in male mice
Compound
Species, strain, sex
Body weight
Length of expenment
Length of exposure
Tumor site and type
Route, vehicle
Human potency (qf)
25.15 mixture of heptachlor/heptachlor epoxide
Mouse, CD-I, male
0.030 kg (assumed)
19 months
18 months
Liver, carcinoma
Oral, diet
6.48 per mg/kg/day
Experimental
animal dose
(ppm)
0
1
5
10
Average
animal dose
(mg/kg/day)
0
0.13
0.65"
1.30
Equivalent
human dose
(mg/kg/day)
0
0.010
O.OS2
0.10
Tumor incidence
(No. responding/
No. examined)
0/62
2/68
18/68
52/80
"Lowest exposure level associated with increased tumors in expenmental
animals.
Source: IRDC 1973b, as reevaluated by Reuber. Extracted from CAG
1986.
-------
lexicological Daca 71
Table 4.15. Cancer data sheet for derivation of potency of heptachlor
epoxide from hepatic carcinomas in female mice—II
Compound
Species, strain, sex
Body weight
Length of experiment
Length of exposure
Tumor site and type
Route, vehicle
Human potency (q")
Heptachlor epoxide
Rat, CFN, female
0.350 kg (assumed)
108 weeks
108 weeks
Liver, carcinoma
Oral, diet
5.76 per mg/kg/day
Experimental
animal dose
(ppm)
0
0.5
2.5
5.0
75
100
Average
animal dose
(mg/kg/day)
0
0.025
0.125
0250"
0.375
0.500
Equivalent
human dose
(mg/kg/day)
0
0.0043
0.021
0.043
0.064
0.085
Tumor incidence
(No. responding/
No. examined)
0/17
3/22
3/18
7/22
3/21
5/19
"Lowest exposure level associated with increased tumors in
experimental animals.
Source: Witherup et al. 1959, as reevaluated by Reuber.
Extracted from CAG 1986.
-------
72 Section 4
4.3.6.5 General discussion
Low concentrations of heptachlor have been shown to inhibit
metabolic cooperation in Chinese hamster cells (Kurata et al. 1982) and
rat liver cells (Telang et al. 1982) in vitro, a property common to many
known promoters. It is postulated, therefore, that heptachlor may act
through an epigenetic rather than a genotoxic mechanism. Data exist that
demonstrate a correlation between interference with metabolic
cooperation and tumor promotion. The assumption that heptachlor may
possess promoter activity is further supported by the action of the test
material on preinitiated virally transformed cells and by the evidence
from in vivo studies indicating that heptachlor is a promoter of
hepatocarcinogenesis in mice (Williams and Numoto 1984). The multistage
concept of carcinogenesis was first formalized by Friedewald and Rous
(1944), who coined the now classic terms "initiation" and "promotion" to
denote, respectively (1) the production of potentially tumorigenic cells
by limited exposure to a carcinogen, and (2) the completion of the
neoplastic transformation as the result of subsequent treatment with
appropriate agents that are not intrinsically carcinogenic. Complete
carcinogens are considered to be those compounds that are capable of
both initiation and promotion.
4.4 INTERACTIONS WITH OTHER CHEMICALS
Williams and Numoto (1984) reported that heptachlor (purity 97.6%),
when administered in the diet at 5 or 10 ppm for 25 weeks, promoted the
development of hepatocellular foci and hepatocellular neoplasms in male
B6C3F1 mice previously initiated with 20 ppm diethylnitrosamine given
the drinking water for 14 weeks.
-------
73
5. MANUFACTURE, IMPORT, USE, AMD DISPOSAL
5.1 OVERVIEW
One company manufactured heptachlor in the United States; however,
as of August 1987, this company voluntarily stopped selling chlordane
and heptachlor. No information was found concerning the importation of
heptachlor. Heptachlor epoxide is not produced commercially in the
United States; no importation data were found. Methods of disposal
include high-temperature incineration and burial in a hazardous waste
landfill.
5.2 PRODUCTION
5.2.1 Manufacturing Process
Heptachlor is prepared by the free-radical chlorination of
chlordene in benzene containing from 0.5 to 5.0% of fuller's earth. The
reaction is run for up to 8 h. The chlordene starting material is
prepared by the Diels-Alder condensation of hexachlorocyclopentadiene
with cyclopentadiene (Sittig 1980).
Heptachlor epoxide is an oxidation product of heptachlor; it is not
produced commercially in the United States (IARC 1979).
5.2.2 Volume
Heptachlor and heptachlor epoxide were not reported in the public
portion of the Toxic Substances Control Act Chemical Substance Inventory
(TSCA Inventory) (EPA 1987a). Since the chemicals are used solely as
pesticides, reporting in the TSCA Inventory is not required.
The Chemical Economics Handbook (CEH) reported the production of
2.0 million pounds of heptachlor for the year 1974, 1.3 million pounds
for 1978, 0.4 million pounds for 1980, and 0.1 million pounds for 1982
(CEH 1984). Sales of chlordane and heptachlor in the United States were
voluntarily stopped by the sole U.S. producer in August 1987 (The
Washington Post 1987).
The U.S. International Trade Commission (USITC) did not report the
domestic production volume of heptachlor separately for the years 1981
through 1985 (USITC 1982a, 1983a, 1984a, 1985, 1986); only yearly totals
were reported for all cyclic insecticides. The USITC reports production
volume data only for chemicals for which three or more manufacturers
report volumes that exceed certain minimum output levels.
-------
74 Section 5
5.2.3 Producers
The following company was listed as a producer of heptachlor Ln the
United States:
Farley Northwest Industries, Inc., (SRI International
subsidiary Velsicol Chemical Corp., 1986, USITC 1986)
Memphis, Tennessee
5.3 IMPORT
The USITC did not report separate import data for heptachlor for
the years 1981, 1982, and 1983 (USITC 1982b, 1983b, 1984b). The U.S.
Department of Commerce did not report separate importation data for
heptachlor for the years 1983, 1984, and 1985 (USDOC 1984-1986).
No information was found on the importation of heptachlor epoxide.
5.4 USE
The only registered uses for heptachlor in the United States are
for subterranean termite control by methods other than pressure rodding
(EPA 1987d, 1987e), the dipping of roots or tops of nonfood plants for
insect control (Vindholz 1983), and treatment of power and telephone
pedestals for fire ant control (EPA 1986f).
5.5 DISPOSAL
Heptachlor and heptachlor epoxide are Resource Conservation and
Recovery Act (RCRA) hazardous wastes and hazardous constituents (EPA
1986c); as such they must be disposed of in secure landfills in
compliance with all federal, state, and local regulations. They may also
be incinerated at 1,500°F for 0.5 s for primary combustion and at
3,200°F for 1.0 s for secondary combustion, with adequate scrubbing of
incinerator exhaust and disposal of ash (Sittig 1985).
-------
75
6. ENVIRONMENTAL FATE
6.1 OVERVIEW
Heptachlor and heptachlor epoxide are persistent in the
environment, with half-lives in soil of 2 and 14 years, respectively.
Heptachlor epoxide has been found in food crops grown in soils last
treated with heptachlor 15 years before. Both heptachlor and heptachlor
epoxide have been shown to bioconcentrate in aquatic organisms,
especially in fish and mollusks.
6.2 RELEASES TO THE ENVIRONMENT
Information on point source and nonpoint source releases of
heptachlor and heptachlor epoxide was not found. However, based on the
registered use of heptachlor as an insecticide for non-pressure-injected
subterranean termite control and for the dipping of roots and tops of
ornamental (nonfood) plants, it may be assumed that heptachlor could be
released to the environment.
6.3 ENVIRONMENTAL FATE
6.3.1 Transport and Partitioning
Release of heptachlor to the environment from its use as an
insecticide or from disposal will result in its transport into surface
waters and/or soils. A computer fate model, developed using heptachlor
released to water, predicts that it will partition from water into
sediment and then into aquatic biota (Simon and Parker 1984).
The evidence suggests that heptachlor may be found in the
atmosphere. Taylor et al. (1976, as cited in WHO 1984) found that 90% of
the heptachlor applied to moist, bare soil volatilized within 2 to 3
days following its application.
While transport through the water column is likely for heptachlor
(Simon and Parker 1984), its penetration into groundwater will probably
be insignificant (Tzapko et al. 1967, as cited in WHO 1984).
Information on transport and compartmentalization of heptachlor
epoxide was not found.
6.3.2 Transformation and Degradation
The degradation of heptachlor and heptachlor epoxide has been well
studied, as reviewed by WHO (1984) and EPA (1985a). Heptachlor may be
subject to oxidation and biodegradation in the environment (EPA 1985a,
Simon and Parker 1984, Lichtenstein et al. 1970, Eichelberger and
Lichtenberg 1971, Petrasak et al. 1983).
-------
76 Section 6
Heptachlor epoxide is not very susceptible to biodegradation,
photolysis, oxidation, or hydrolysis in the environment (Mabey et al.
1981, as cited in EPA 1985a; Callahan et al. 1979, as cited in EPA
198Sa). The resistance to degradation may account for an estimated
half-life of 2 years in soil and the persistence of heptachlor epoxide
in a field for up to 14 years after the last application of heptachlor
(Vrochinsky 1980, as cited in WHO 1984).
Lichtenstein et al. (1970) found that potatoes grown in soil that
had been treated with heptachlor at 5 lb/5-in. acre for 5 consecutive
years contained 0.002 ppm heptachlor, 0.054 ppm heptachlor epoxide,
0.015 ppm 7-chlordane, 0.004 ppm a-chlordane, and 0.002 ppm nonachlor 5
years after the last heptachlor application.
Soybeans, grown in soil treated 15 years previously with heptachlor
at 224 kg/ha, contained no heptachlor residues but did have residues of
heptachlor epoxide ranging from 0.067 to 0.237 mg/kg (Nash and Harris
1973, as cited in WHO 1984). Talekar et al. (1983) reported the
persistence of heptachlor epoxide at a level of 0.06 ppm in the soil
throughout a 1-year observation period following application of a total
of 48 kg/ha of heptachlor over a 2-year period.
6.3.3 Bioconcentration
Geyer et al. (1982) found that exposure of the mussel (Hytilus
edulis) for 4 days to heptachlor epoxide at 1.95 mg/L resulted in a
bioconcentration factor (BCF) of 1,700 (log BCF - 3.23). Hawker and
Connell (1986) determined the log BCFs for heptachlor and heptachlor
epoxide in several moHusks: heptachlor had a log BCF of 3.41 for the
soft clam (Hya arenaria) and 3.93 for the oyster (Crassotrea vi.rgi.ni.ca);
heptachlor epoxide had a log BCF of 3.23 for the mussel (Mytilus edulis)
and 2.93 for the oyster.
Bioconcentration factors have also been determined for fish: in
the pinfish (Lagodon rhoaboides) the log BCF was 3.71 for heptachlor and
3.46 for heptachlor epoxide, and in the sheepshead minnow (Cyprinodon
variegatus) the log BCFs were 4.33 and 3.65 for heptachlor and
heptachlor epoxide, respectively (Zaroogian et al. 1985).
-------
77
7. POTENTIAL FOR HUMAN EXPOSURE
7.1 OVERVIEW
Data concerning potential human exposure to heptachlor and
heptachlor epoxide are from the era when heptachlor was actively used as
an agricultural insecticide. More recent data were not available The
exposure data, especially exposure from residues in foods, combined with
environmental persistence data indicate that human exposure to
heptachlor or heptachlor epoxide could occur if food crops were
inadvertently grown in a contaminated site. Since the discontinuation of
the use of heptachlor on agricultural products, exposure is more likely
to occur from the inhalation of vapors or direct contact with residual
heptachlor from improper residential pesticide application and the
accidental contamination of dairy and meat products.
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
7.2.1 Air
Little data are available on concentrations of heptachlor and
heptachlor epoxide in air after the use of heptachlor as an agricultural
pesticide was restricted. However, during its period of maximum usage
heptachlor was found in ambient air in the United States at a mean
concentration of approximately 0.5 ng/m3 (Peirano 1980, as cited in WHO
1984). A survey of 16 states between 1970 and 1972 detected heptachlor
in 42% of 2,479 air samples with a mean concentration of 1.0 ng/m3 in
positive samples; the maximum concentration found was 27.8 ng/m3 in
Tennessee (Kutz et al. 1976, as cited in EPA 1985a).
Three houses in North Carolina were treated with a termiticide
containing both chlordane (0.5%) and heptachlor (0.25%). Immediately
after treatment, the average atmospheric heptachlor level was 1.41 ±
0.64 Mg/m3. At 12 months posttreatment, the heptachlor level in the'air
was 1.00 ± 0.70 pg/m3 (Wright and Leidy 1982).
An air monitoring study in houses treated with heptachlor has been
conducted; however, at the time this report was prepared, data were not
available for release to the public by EPA (Jaquith 1987).
7.2.2 Water
Heptachlor and heptachlor epoxide have been found in ambient waters
at concentrations ranging from 0.001 /*g/L to 0.5 Mg/L (IJC 1983, STORE!
1987). A range of drinking water concentrations for heptachlor, based on
regional surveys conducted in the 1970s, was reported as 0 005 to 0 6
Mg/L (EPA 1985a).
-------
78 Section 7
7.2.3 Soil
During the years that heptachlor was used as an agricultural
pesticide, substantial levels of It and of heptachlor epoxlde were
present In soil, particularly In soil used for crops. In 1969,
heptachlor was detected In 68 of 1,729 cropland soils at levels of 0.01
to 0.97 mg/kg; however, It was not detected In noncrop soils (Ulersma et
al. 1972a, as cited In IARC 1979). In the same survey, heptachlor
epoxlde was found In 139 of the 1,729 cropland soil samples at
concentrations of 0.01 to 1.08 mg/kg and In 2 of 199 noncropland soil
samples at 0.01 mg/kg- In a study of corn belt region soils of the
United States, heptachlor was found In 5.7% of samples, and heptachlor
epoxlde was found In 8% of samples at concentrations of 0.01 to 0.84
mg/kg and 0.01 to 0.31 mg/kg. respectively (Carey et al. 1973, as cited
In IARC 1979). Heptachlor has also been detected In urban environments;
In 1969, the soil of seven of eight cities surveyed had heptachlor
levels of 0.01 to 0.53 mgAg (Wlersma et al. 1972b, as cited In IARC
1979).
Heptachlor and heptachlor epoxlde have been detected In sediments
from streams and rivers at concentrations ranging from 0.1 Mg/kg to 100
(STORE! 1987).
Heptachlor has been Identified In soils (up to 38 A»g/L) and
sediments (up to 4,800 pg/L) from Comprehensive Environmental Response,
Compensation, and Liability Act (CERCLA) hazardous waste sites (EPA
1985b).
7.2.4 Other
Heptachlor and heptachlor epoxlde have been Identified in
foodstuffs, although the data are almost exclusively from studies
conducted prior to 1980 when heptachlor was still being used as an
agricultural pesticide. Both IARC (1979) and WHO (1984) present reviews
of heptachlor and heptachlor epoxide levels in foods. The Total Diet
Study, conducted by the Food and Drug Administration (FDA) between 1972
and 1973, found no heptachlor in any of the foods tested (Johnson and
Hanske 1976, as cited in IARC 1979). A study of 20 U.S. cities two years
later (1974-75) found heptachlor epoxlde in 3 of 12 food classes
examined at levels of 0.6 to 3.0 pg/kg (Peirano 1980 / as cited in WHO
1984). Market basket surveys in 30 cities found similar results:
heptachlor epoxide was present at up to 2 /ig/kg in 21 samples of dairy
products and in 24 samples of meat, fish, and poultry; 1 sample of
potatoes had trace levels of the compound (Johnson and Manske 1976, as
cited in IARC 1979).
7.3 OCCUPATIONAL EXPOSURES
An industrial hygiene survey conducted at a plant manufacturing
heptachlor detected the compound at levels of 0.025 to 0.202 mg/m3 in
workplace air; breathing- zone samples were not taken (Netzel 1981).
Because use of heptachlor is Halted to underground termite and
fire ant control and ornamental plant applications, much of the
widespread occupational exposure to the compound has been eliminated.
The Quarterly Hazard Summary Report (NIOSH 1980) estimated 566,911
-------
Potential for Human Exposure 79
workers in 119 occupations were exposed to heptachlor in generic
formulations based on a 1972 to 1974 survey. Since that time, heptachlor
use has been drastically reduced. Given the current restrictions on
heptachlor use, occupational exposure can still be expected for
exterminators, ornamental plant pesticide applicators, and waste-sice
cleanup personnel. Documentation of exposure levels encountered in these
occupations was not found.
7.4 POPULATIONS AT HIGH RISK
FDA comparisons for fiscal years (FY) 1977 and 1979 (FDA 1980a,b,
1982a,b, as cited in EPA 198Sa) of estimated dietary intake of
heptachlor epoxide by geographic region indicate that toddlers and
infants from the north central region of the United States are at
greater risk of heptachlor epoxide exposure than those in other sections
of the country. In FY 1979, average infant intake was approximately
0.021 pg/kg/day, whereas north central infant intake was 0.041
Mg/kg/day. Toddlers across the United States ingested an average of
0.018 /ig/kg/day, in comparison to 0.051 Mg/kg/day ingested by north
central toddlers. Similar results were reported for FY 1977. It should
be noted that these estimates are for a period when heptachlor was
widely used for agricultural insect control.
Jensen (1983, as cited in WHO 1984) reported that the
concentrations of fat-soluble contaminants in breast milk are expected
to be considerably higher than in whole blood since the blood flow to
the breast is much more rapid than the rate of milk secretion. Infant
exposure to heptachlor from human milk may be significant. Heptachlor
epoxide was found in the breast milk of 63% of 1,436 nursing women
sampled in 1980 (mean concentration in milkfat 91.4 ppb) (Savage et al.
1981). Fifty-four nursing mothers studied in Hawaii (1979-1980)
exhibited heptachlor epoxide in their milk, with a mean concentration in
milkfat of 0.036 ppm (Takei et al. 1983).
A possibly significant area of exposure risk involves people,
especially military personnel (NRC 1982), whose homes have been treated
with heptachlor for termite control. Given its volatility, it may be
possible for the compound to reach significant atmospheric
concentrations in the home.
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81
8. ANALYTICAL METHODS
8.1 ENVIRONMENTAL MEDIA
Analytical methods for the detection of heptachlor and heptachlor
epoxide in environmental media, including air, soil, water, food, and
solid waste are presented in Table 8.1.
8.2 BIOLOGICAL SAMPLES
Analytical methods for the detection of heptachlor and heptachlor
epoxide in biological samples are shown in Table 8.2.
8.3 GENERAL DISCUSSION
Sample preparation steps vary, but, in general, involve a gross
extraction of a heptachlor-containing fraction (usually lipids for
biological samples) and a single- or multistep cleanup. The clean-up
steps chosen depend to a large extent on the lipid content of the
sample.
The method of detection and quantification of heptachlor and
heptachlor epoxide in environmental and biological samples is gas
chromatography (GC) with either electron capture (EC) or mass
spectrometry (MS) detection.
-------
co
ro
TIM
Sample type
Air
Ambient
(NIOSH method S287)
Water
Rural poUble
Soil
Seduncnu and sewage
tludgc
Soil
Soil
Soil
Soil
Food
FruiU. vegetables.
dairy product*.
vegetable oili
eS.1. AHUyocal MMMMi lor MptacHor BM M
Extraction/cleanup'
Adsorb on Chromosorb 102.
detorb with toluene
Extract (hexane). CC
Centrifuge, extract solid (acetone).
liquid/liquid partition, transfer into
tnmethylpcntanc. treat to remove sulfur.
isolate in inmethylpentaoe.
Add acetone, extract (petroleum ether or
hexane), filter, wash (water) to remove
acetone. CC
Extract (hexane-uopropanol). filter.
wash (water) to remove isopropanol.
filler, dry
Extract (accione-hexane). add benzene to
extract, evaporate to dryness, dissolve
in hexane. CC
Wet sample, extract (hexane-uopropanol).
filter, wash (water) to remove isopropanol.
dry
Extract (acclonilnle). dilute (water).
extract (petroleum ether). CC
Limit of
Detection" detection" References
GC/ECD 0 1 jig/m' NIOSH 1979
GC/ECD lOng/L Sandhu el al 1978
GC/ECD 1-10 ng/kg Jensen el al 1977
GC/ECD 1 jig/kg Harris and Sans
1971
GC/ECD 10 jig/kg Wiersma ct al
I972a,b
GC/ECD NR Townsend and Spechi
1975
GC/ECD 10 fig/kg Carey el al 1973
GC/ECD. NR Horwiu 197$
thermionic
detection
(0
O
r»
8
CD
-------
TlMc8.l(C
-------
84 Section 8
Sample type
Biological
Adipose tissue
Wildlife tissues
Blood serum
Plant tissues
Extraction/cleanup4
Extract (hexane), re-extract (petroleum
ether, cbloroform-methanol. acetomtnle
or acetone-bexane), dry, dissolve (hexane). CC
Grind with sodium sulfate. extract (ethyl
ether-petroleum ether) in Soxhlet. CC
Extract (chloroform-methanol). filter, add
solvent, dissolve (petroleum ether). CC
Blend in acetomtnle, extract (hexane).
wash (water), evaporate to dryness. dissolve
(hexane). CC
Detection"
GC/ECD
and TLC
GC/ECD
GC/ECD, TLC
GC/ECD
Limn of
detection0
10 ppb
5Mg/kg
Ippb
NR
References
Clausen et al 1974,
EPA 1980
White 1976
Polishuk et aL I977a.
EPA 1980
Townsend and Specht
1975
"GC/ECD - gas chromatography/electron capture detection. CC - column chromatography: TLC • thin-layer chromato^
phy; NR - not reported.
Source Adapted from I ARC (1979)
-------
85
9. REGULATORY AND ADVISORY STATUS
9.1 INTERNATIONAL
The World Health Organization (WHO) has recommended an acceptable
daily intake of heptachlor plus heptachlor epoxide in food of 0 to 0.5
mg/kg body weight (WHO 1984). WHO has also recommended a guideline
concentration of 0.1 mg/L in drinking water (EPA 1987c).
9.2 NATIONAL
9.2.L Regulations
The Occupational Safety and Health Administration (OSHA) has
established an 8-h time-weighted average (TWA) permissible exposure
limit for heptachlor of 0.5 mg/m3 with the notation "skin" (OSHA 1985).
Cancellation of most uses of heptachlor was announced in the
Federal Register (EPA 1978) in 1978. Uses that were cancelled and their
effective dates of cancellation are:
• Field corn treatment--August 1, 1980;
• Seed treatment--September 1, 1982 (barley, oats, wheat, and rye corn),
July 1, 1983 (sorghum);
• Citrus--Florida--December 31, 1979;
• Pineapples--December 31, 1982;
• Narcissus bulbs--December 31, 1980.
Heptachlor and heptachlor epoxide are not regulated by EPA under
the Clean Air Act. Heptachlor is regulated as a hazardous substance
under Section 311 of the Federal Water Pollution Control Act (Clean
Water Act), with a reportable quantity of 1 Ib (0.454 kg) for discharges
into publicly owned treatment works (EPA 1986a). Heptachlor and
metabolites are listed under Section 307 of the Federal Water Pollution
Control Act as toxic pollutants (EPA 1986d).
Effluent guidelines have been established for heptachlor and
heptachlor epoxide under the Clean Water Act for the following
industrial point-source categories (EPA 1988a): electroplating, steam
electric, asbestos, timber products processing, metal finishing, paving
and roofing, paint formulating, ink formulating, gum and wood,
pesticides, and carbon black.
Tolerances for residues of heptachlor and heptachlor epoxide in or
on various raw agricultural commodities were set at 0, 0.01, 0.02, or
-------
86 Section 9
0.1 ppm under Section 408 of the Pesticide Residue Amendment to the
Federal Food, Drug, and Cosmetic Act as administered by the EPA (EPA
1986b). In 1985 the EPA proposed a rule to revoke the tolerances for
heptachlor and hcfptachlor epoxide and replace them with an action level
of 0.02 ppm based on the detection limits for heptachlor/heptachlor
epoxide using the FDA multiresidue analytical method (EPA 1985c).
Heptachlor is listed under RCRA as an acute hazardous waste (Waste No.
P059), and heptachlor and heptachlor epoxide are listed as RCRA Appendix
VIII hazardous constituents (EPA 1986c) .
Heptachlor and heptachlor epoxide are regulated as hazardous
substances under CERCLA, with a reportable quantity of 1 Ib (0.454 kg)
for releases of each from vessels and facilities (EPA 1986c).
The EPA initiated a Label Improvement Program (LIP) to reduce the
potential risk from pesticide application in 1981. For heptachlor, the
label changes included specific precautions concerning application near
domestic water supplies, near heating ducts, and around structures with
subfloor crawl spaces. The label must also warn against yearly
retreatment (EPA 1986f).
As a result of a risk/benefit review of the chlorinated cyclodiene
pesticides (including heptachlor), the EPA issued a Special Data Call-in
for the termiticides requiring the following information to be submitted
(EPA 1986f).
• A one-year indoor air monitoring study in homes of various
construction types that were treated for subterranean termite
control in accordance with label instructions as revised by EPA's
termiticide LIP;
• General metabolism studies, one in rats and one in mice, giving
special consideration to pharmacokinetics;
• Five short-term mutagenicity (gene mutation) assays;
• A subchronic inhalation study in rats to assess the potential toxic
response from the inhalation route of exposure.
Based on the results of the first indoor air monitoring study, a
settlement agreement was reached between EPA and Velsicol. Under the
terms of that agreement, registration of heptachlor as a termiticide was
canceled pending the results of a new air monitoring study. In addition,
certain application methods (e.g., pressure injection) may not be used.
If other application methods can be developed, and if the subsequent air
monitoring study provides adequate data to determine that human health
risks are sufficiently low, then the registration for use as a
tenniticide will be reinstated. Otherwise, the cancellation will stand
(EPA 1988b).
No other federal regulations relating to heptachlor and heptachlor
epoxide were found.
9.2.2 Advisory Guidance
The American Conference of Governmental Industrial Hygienists
(ACGIH) has adopted an 8-h TWA threshold limit value (TLV) for exposu
to heptachlor of 0.5 mg/m3 (ACGIH 1986b). The ACGIH recommendation
-------
Regulatory and Advisory Status 87
includes a "skin" notation to indicate the potential for absorption of
the compound by the cutaneous route, including via mucous membranes and
eyes, either by airborne or direct contact. This TWA limit was
considered to be sufficiently low to prevent systemic poisoning (ACGIH
1986a).
The National Institute for Occupational Safety and Health (NIOSH)
has recommended a permissible exposure limit for heptachlor of 0.5
mg/m3, and has recommended the designation of 100 mg/m^ as the airborne
concentration immediately dangerous to life or health (NIOSH/OSHA 1978) .
In addition, NIOSH has recommended that workers who potentially may be
exposed to heptachlor be given a preemployment physical examination as
well as periodic reexaminations. These examinations should stress
evaluations of the eyes, nervous system, liver, and kidneys (NIOSH/OSHA
1981).
The ACGIH has not adopted a TWA-TLV for heptachlor epoxide, and
NIOSH has not recommended a permissible exposure limit for the compound.
The Office of Drinking Water of the EPA has issued the following
health advisories for heptachlor and heptachlor epoxide in drinking
water (EPA 1987c) ; these levels represent protection only for noncancer
toxicity end points:
• One day: insufficient data to establish;
• Ten day: 10 Mg/L;
• Longer term: insufficient data to establish;
• Lifetime: 17.5 Mg/L (heptachlor), 0.4 jig/L (heptachlor epoxide).
The National Academy of Sciences has issued a health advisory level
for chronic exposure to heptachlor (0.0104 ppb) and heptachlor epoxide
(0.0006 ppb) from drinking water (EPA 1987c) .
The EPA has established a National Ambient Water Quality Criterion
for heptachlor of 0.28 ppb, and has proposed maximum contaminant level
goals for heptachlor and heptachlor epoxide of 0 in drinking water; the
concentration in drinking water, with an upper-bound lifetime cancer
risk of 10*6, was calculated as 0.0104 /ig/L for heptachlor and 0.00065
for heptachlor epoxide (EPA 1985b) .
9.2.3 Data Analysis
9.2.3.1 Reference doses (RfDs)
The EPA has calculated a reference dose (RfD) for heptachlor of
0.0005 mg/kg/day (EPA 1987c) based on a study with CF rats fed various
dose levels of heptachlor (Witherup et al. 1955, as cited in Epstein
1976); see Sect. 4.2.2.3.
The EPA has calculated an RfD for heptachlor epoxide of 0.000013
mg/kg/day (EPA 1987c) based on a study in dogs (Kettering 1958, as cited
in EPA 1987c); see Sect. 4.2.2.3.
-------
88 Section 9
9.2.3.2 Carcinogenic potency
q_*. EPA has calculated carcinogenic potency (q^*) values for
heptacfilor and heptachlor epoxide. The methodology used by the EPA for
calculating the q *s is described by Anderson et al. (1983). The details
of the derivation of q * values for heptachlor and heptachlor epoxide
are given by CAG (1986J.
Briefly, oral exposure to heptachlor/heptachlor epoxide increased
the incidence of liver carcinomas in one strain of rats and three
strains of mice. From geometric means of cancer potencies calculated for
studies for the most sensitive species tested (mice), the q^s are 4.5
per mg/kg/day for heptachlor and 9.1 per mg/kg/day for heptachlor
epoxide. From data for the most sensitive sex and strain (female C3H
mice), the q *s are 14.9 per mg/kg/day for heptachlor and 36.2 per
mg/kg/day for heptachlor epoxide (CAG 1986).
IARC (1979) classified heptachlor as Group 3: inadequate evidence
of carcinogenicity in humans and limited evidence of carcinogenicity in
animals. The IARC (1979) position on heptachlor epoxide is that there is
limited evidence that it is carcinogenic in experimental animals.
The EPA has classified heptachlor/heptachlor epoxide as a Group B2
carcinogen based on animal studies: probable human carcinogen. This
classification is for compounds for which there is inadequate evidence
from human studies and sufficient evidence from animal studies (EPA
1986g).
Methods used by other agencies. No information was found.
9.3 STATE
9.3.1 Regulat ions
The State of California has established Applied Action Levels
(AALs) for drinking water for heptachlor (0.02 ppb) and heptachlor
epoxide (0.10 ppb) (EPA 1987b).
Use of heptachlor has been banned by Minnesota, Massachusetts, and
New York (P6.TC News 1987).
9.3.2 Advisory Guidance
No information was found.
-------
89
10. REFERENCES
Abalis IM, Eldefrawi ME, Eldefrawi AT. 1985. High-affinity
stereospecific binding of cyclodiene insecticides and 7-hexachloro-
cyclohexane to 7-aminobutyric acid receptors of rat brain Pestic
Biochem Physiol 24:95-102.
Abalis IM, Eldefrawi ME, Eldefrawi AT. 1986. Effects of insecticides on
GABA-induced chloride influx into rat brain microsacs. J Toxicol Environ
Health 18:13-23.
ACGIH (American Conference of Government Industrial Hygienists). 1986a.
Documentation of the Threshold Limit Values and Biological Exposure
Indices. 5th ed. Cincinnati, OH, p. 296.
ACGIH (American Conference of Government Industrial Hygienists). 1986b.
TLV's. Threshold Limit Values and Biological Exposure Indices for 1986-
1987. Cincinnati, OH, pp. 5, 20.
Ahmed FE, Hart RW, Lewis NJ. 1977. Pesticide induced DNA damage and its
repair in cultured human cells. Mutat Res 42:161-174.
Akay MT, Alp U. 1981. The effects of BHC and heptachlor on mice.
Hacettepe Bull Nat Sci Eng 10:11-22.
Akay MT, Kolankaya D, Ozgur KC. 1982. Histological changes in adrenal
glands of female mice treated by heptachlor. Hacettepe Bull Nat Sci Eng
Albright LJ, Northcote TG, Oloffs PC, Szeto SY. 1975. Chlorinated
hydrocarbon residues in fish, crabs, and shellfish of the Lower Fraser
River, Its estuary, and selected locations in Georgia Strait, British
Columbia--1972-73. Pestic Monit J 9:134-140 (cited in IARC 1979).
Anderson EL. 1983. Quantitative approaches in use to assess cancer risk
Risk Anal 3(4):277-295.
Anonymous. 1986. Chemical review: heptachlor. Dangerous Prop Ind Mater
Rep 6:16-49.
*Key studies.
-------
90 Section 10
* Arnold DW, Kennedy GL, Jr, Keplinger ML, Calandra JC, Calo CJ. 1977.
Dominant lethal studies with technical chlordane, HCS-3260, and
heptachlor: heptachlor'epoxide. J Toxicol Environ Health 2:547-555.
Arrlngton LR. 1972. The laboratory animals. In: Introductory Laboratory
Animal Science. Danville, IL: The Interstate Printers and Publishers,
pp. 7-11, 181-184.
Arthur RD, Cain JD, Barrentine BF. 1975. The effect of atmospheric
levels of pesticides on pesticide residues in rabbit adipose tissue and
blood sera. Bull Environ Contamin Toxicol 14(6):760-764.
Arthur RD, Cain JD, Barrentine BF. 1976. Atmospheric levels of
pesticides in the Mississippi delta. Bull Environ Contam Toxicol
15:129-134 (cited in IARC 1979).
Barnes D et al. 1987. Reference dose (RfD): Description and use in
health risk assessments. Appendix A in Integrated Risk Information
System Supportive Documentation. Vol. 1. Washington, DC: Office of
Health and Environmental Assessment, Environmenal Protection Agency.
EPA/600/8-86/032a.
Barquet A, Morgrade C, Pfaffenberger CD. 1981. Determination of
organochlorine pesticides and metabolites in drinking water, human blood
serum, and adipose tissue. J Toxicol Environ Health 7:469-479.
Ben-Dyke R, Sanderson DM, Noakes DN. 1970. Acute toxicity data for
pesticides. World Rev Pestic Control 9:119-127.
Bloomquist JR, Soderlund DM. 1985. Neurotoxic insecticides inhibit GABA
dependent chloride uptake by mouse brain vesicles. Biochem Biophys Res
Commun 133:37-43.
Burch TA. 1983. An Investigation of the Possible Effect of Heptachlor
Contamination of Milk on Pregnancy Outcome of Oahu Women Residents
(Based on Data for Six-Month Intervals from 1968 through 1982). Hawaii
State Department of Health, R and S Report 46 (cited InvLeMarchand et
al. 1986).
Burns JE. 1974. Pesticides in people. Organochlorine pesticide and
polychlorinated biphenyl residues in blopsied human adipose tissue--
Texas 1969-72. Pestic Monit J 7(3/4):122-126.
GAG (Carcinogen Assessment Group). 1986. Carcinogenicity Assessment of
Chlordane and Heptachlor/Heptachlor Epoxlde. Washington, DC: Office of
Health and Environmental Assessment, Environmental Protection Agency.
Callahan MA, Slimak MW, Gabel NW, et al. 1979. Water-Related
Environmental Fate of 129 Priority Pollutants. Vol. II. Washington, DC:
Office of Water Planning Standards, Office of Water Waste Management,
Environmental Protection Agency. EPA 440/4-79-029b (cited in EPA 1985).
-------
References 91
Carey AE, Wiersma GB, Tai H, Mitchell WG. 1973. Organochlorine pesticide
residues in soils and crops of the Corn Belt region, United States 1970
Pestic Monit J 6:369-376 (cited in IARC 1979).
CEH (Chemical Economics Handbook). 1984. Stanford Research Institute.
Menlo Park, CA: SRI International. Sections 573.3001Z; 573.3004 Y-Z;
573.3005 D-E, I-J, M-N.
Cerey K, and Ruttkay-Nedecka J. 1971. The influence of heptachlor on rat
fertility and growth. Z Versuchstierkd 13:243-244.
Clausen J, Braestrup L, Berg 0. 1974. The content of polychlorinated
hydrocarbons in Arctic mammals. Bull Environ Contain Toxicol 12:529-534
(cited in IARC 1979).
Cole LM, Casida JE. 1986. Polychlorocycloalkane insecticide-induced
convulsions in mice in relation to disruption of the GABA-regulated
chloride ionophore. Life Sci 39:1855-1862.
Curley A, Copeland MF, Kimbrough RD. 1969. Chlorinated hydrocarbon
insecticides in organs of stillborn and blood of newborn babies. Arch
Environ Health 19:628-632.
* Davis HJ. 1965. Pathology report on mice fed aldrin, dieldrin,
heptachlor, or heptachlor epoxide for two years. Internal FDA Memorandum
to Dr. A.J. Lehman (July 19) (cited in Epstein 1976).
Den Tonkelaar EM, Van Esch GJ. 1974. No-effect levels of organochlorine
pesticides based on induction of microsomal liver enzymes in short-term
toxicity experiments. Toxicology 2:371-380.
Ditraglia D, Brown DP, Namekata T, Iverson N. 1981. Mortality study of
workers employed at organochlorine pesticide manufacturing plants. Scand
J Work Environ Health 7 (Suppl 4):140-146.
Dvorak M, Halacka K. 1975. Ultrastructure of liver cells in pig at
normal conditions and after administration of small doses of
heptachlorine. Folia Morphologica (Prague) 23:71-76.
Eichelberger JW, Lichtenberg JJ. 1971. Persistence of pesticides in
river water. Environ Sci Techno1 5:541-548.
Eisler M. 1968. Heptachlor: Toxicology and safety evaluation. Ind Med
Surg 840-844.
* Enan EE, El-Sebae AH, Enan OH. 1982. Effects of liver functions by
some chlorinated hydrocarbon insecticides in white rats. Meded Fac
Landbouwwet Rijksuniv Gent 47(1):447-457.
Environmental Health Associates. 1983a (October 26). Cause-Specific
Mortality Among Employees of the Chevron Chemical Company Facility at
Richmond. Office of Toxic Substances. Microfiche 0295.
-------
92 Section 10
Environmental Health Associates. 1983b (November 11). Cause-Specific
Mortality Among Employees of Chevron Research Company. Office of Toxic
Substances, Microfiche 0295.
EPA (Environmental Protection Agency). Velsicol Chemical Co. et al.
1978. Consolidated heptachlor/chlordane cancellation proceedings. Fed
Regist 43:12372-12375.
EPA (Environmental Protection Agency). 1980. Analysis of Pesticide
Residues in Human and Environmental Samples. EPA-600/8-80-038, Section
3, E, p. 1.
EPA (Environmental Protection Agency). 1985a. Drinking Vater Criteria
Document for Heptachlor, Heptachlor Epoxide, and Chlordane. EPA-6001X-
84-197-1.
EPA (Environmental Protection Agency). 1985b. National primary drinking
water regulations; synthetic organic chemicals, inorganic chemicals and
microorganisms; proposed rule. Fed Regist 50(219):46981, 46982, 46996,
46997.
EPA (Environmental Protection Agency). 1985c. Revocation of heptachlor
tolerances; proposed rule. Fed Regist 50:50643-50646.
EPA (Environmental Protection Agency). 1986a. Designation of hazardous
substances and determination of reportable quantities for hazardous
substances. 40 CFR 116 and 117, Sections 116.4 and 117.3, pp. 32-37,
43-46.
EPA (Environmental Protection Agency). 1986b. Tolerances and exemptions
from tolerances for pesticide chemicals in or on raw agricultural
commodities. 40 CFR 180, Sections 180.1, 180.104, 180.319; pp. 248. 260,
285-286, 348-349.
EPA (Environmental Protection Agency). 1986c. Identification and listing
of hazardous waste and designation, reportable quantities, and
notification. 40 CFR 261 and 302, Sections 261.33 and Appendix VIII,
302.4, and 302.6; pp. 380-381, 398, 860, 885, 935.
EPA (Environmental Protection Agency). 1986d. Effluent guidelines and
standards. Part 401. General provisions. 40 CFR Subchapter N--, Section
401.15, pp. 5, 8-9.
EPA (Environmental Protection Agency). 1986e. Test Methods for
Evaluating Solid Waste. 3rd ed. Washington, DC: Office of Solid Waste
and Emergency Response. SW-846, pp. 8080-1-8080-27, 8250-1-8250-32.
EPA (Environmental Protection Agency). 1986f. Guidance for the
Registration of Pesticide Products Containing as the Active Ingredient
Heptachlor. Office of Pesticide Programs, December 31, 1986. EPA
Chemical Code No. 0175, pp. 5-8, 15.
-------
References 93
EPA (Environmental Protection Agency). 1986g. Guidelines for
carcinogenic risk assessment. Fed Regist 51(185):33992-34003.
EPA (Environmental. Protection Agency). 1987a. Computer Printout (CICIS):
1977 Production Statistics for Chemicals in the Nonconfidential Initial
TSCA Chemical Substance Inventory. Washington, DC: Office of Pesticides
and Toxic Substances.
EPA (Environmental Protection Agency). 1987b. Updated Drinking Water
Standards and Health Advisory Table. San Francisco, CA: EPA-Region IX.
EPA (Environmental Protection Agency). 1987c. Heptachlor and Heptachlor
Epoxide. Health Advisory. Washington, DC: Office of Drinking Water.
EPA (Environmental Protection Agency). 1987d. Memorandum of
Understanding [EPA and Velsicol]. Washington, DC: Office of General
Council.
EPA (Environmental Protection Agency). 1987e. Supplement to the
Memorandum of Understanding [EPA and Velsicol]. Washington, DC: Office
of General Council.
EPA (Environmental Protection Agency). 1988a. Analysis of Clean Water
Act effluent guidelines pollutants. Summary of the chemicals regulated
by industrial point source category. 40 CFR 400-475, draft. Washington,
DC: Office of Water.
EPA (Environmental Protection Agency). 1988b. Chlordane/heptachlor
termiticides; notice of cancellation and existing stocks determination
and notice of intent to suspend. Fed Regist 53(68):11797-11805.
Epstein SS. 1976. Carcinogenicity of heptachlor and chlordane. Sci Total
Environ 6:103-154.
Epstein SS, Arnold E, Andrea J, Bass W, Bishop Y. 1972. Detection of
chemical mutagens by the dominant lethal assay in the mouse. Toxlcol
Appl Pharmacol 23:288-325.
FAO/WHO (Food and Agriculture Organisation/World Health Organization).
1967. Pesticide Residues in Food. Joint Report of the FAO Working Party
on Pesticide Residues and the WHO Expert Committee on Pesticide
Residues. Geneva: World Health Organization, Technical Report Series 370
(cited in WHO 1984).
FDA (Food and Drug Administration). 1980a. Compliance Program Report of
Findings. FY77 Total Diet Studies--Adult (7320.73). Washington, DC: U.S.
Department of Health, Education, and Welfare (cited in EPA 1985).
FDA (Food and Drug Administration). 1980b. Compliance Program Report of
Findings. FY77 Total Diet Studies--Infants and Toddlers (7320.74).
Washington. DC: U.S. Department of Health, Education, and Welfare (cited
in EPA 1985).
-------
94 Section 10
FDA (Food and Drug Administration). 1982a. Compliance Program Report o
Findings. FY77 Total Diet Studies--Adult (7305.002). Washington, DC:
U.S. Department of Health and Human Services (cited in EPA 1985).
FDA (Food and Drug Administration). 1982b. Compliance Program Report of
Findings. FY79 Total Diet Studies--Infants and Toddlers (7305.002).
Washington, DC: U.S. Department of Health and Human Services (cited in
EPA 1985).
Folmar LC. 1978. In vitro inhibition of rat brain ATPase, pNPPase, and
ATP-32Pi, exchange by chlorinated-diphenyl ethanes and cyclodiene
insecticides. Bull Environ Contam Toxicol 19(4):481-488.
Fonnanek J, Vanickova M, Plevova J, Holoubkova E. 1976. The effect of
some industrial toxic agents on EEC frequency spectra in rats. Adverse
Eff Environ Chem Psychotropic Drugs 2:257-268.
Friedewald WF, Rous P. 1944. The initiating and promoting elements in
tumor production. An analysis of the effects of tar, benzpyrene, and
methylcholanthrene on rabbit skin. J Exp Med 80:101-126.
Frumkin H, Chute CG. 1987. The health effects of heptachlor. J Am Med
Assoc 257(14):1900.
* Gaines TB. 1969. Acute toxicity of pesticides. Toxicol Appl Pharmacol
14:515-534.
* Gak JC, Grillot C, Truhaut R. 1976. Use of the golden hamster in
toxicology. Lab Animal Sci 26(2):274-280.
Gant DB, Eldefrawi ME, Eldefrawi AT. 1987. Cyclodiene insecticides
inhibit GABA receptor-regulated chloride transport. Toxicol Appl
Pharmacol 88:313-321.
Gentile JM, Gentile GJ, Bultman J, Sechriest R, Wagner ED, Plewa MJ.
1982. An evaluation of the genotoxic properties of insecticides
following plant and animal activation. Mutat Res 101:19-29.
Geyer H, Sheehan P, Kotzias D, Freitag D, Korte F. 1982. Prediction of
ecotoxicological behaviour of chemicals: Relationship between physico-
chemical properties and bioaccumulation of organic chemicals in the
mussel Mytllus edulis. Chemosphere 11(11):1121-1134.
Gillett JW, Chan TM. 1968. Cyclodiene insecticides as inducers,
substrates, and inhibitors of microsomal epoxidation. J Agric Food Chem
16:590-593.
Glatt H, Jung R, Oesch F. 1983. Bacterial mutagenicity investigation of
epoxides: Drugs, drug metabolites, steroids, and pesticides. Mutat Res
11:99-118.
-------
References 95
* Green VA. 1970. Effects of pesticides on rat and chick embryo. In:
Henphill D, ed. Trace Substance Environmental Health 3, Proc 3rd Ann
Conf, University of Missouri (1969), pp. 183-209.
Greer ES, Miller DJ, Burscato FN, Holt RL. 1980. Investigation of
pesticide residues in human adipose tissue in the Northeast Louisiana
area. J Agric Food Chem 28:76-78.
Halacka K, Dvorak M, Rysanek K, Svejda J. 1974. Influence of low
perorally administered doses of heptachlor on liver tissue of
experimental animals. Scr Med Fac Med Univ Brun Purkynianae 47(6):365-
372.
Halacka K, Dvorak M, Rysanek K, Jagos P, Cerny E. 1975. Effect of small
orally administered doses of heptachlor on ultrastrueture of hepatocytes
and their enzyme systems in experimental animals. Cesk Hyg 20:286-291.
Hansch C, Leo A. 1979. Substituent Constants for Correlation Analysis in
Chemistry and Biology. New York, NY: John Wiley and Sons, p. 247.
Harris CR, Sans UV. 1971. Insecticide residues in soils on 16 farms in
southwestern Ontario-1964, 1966, and 1969. Pestic Monit J 5:259-267
(cited in IARC 1979).
Hawker DV, Connell DV. 1986. Bioconcentration of lipophilic compounds by
some aquatic organisms. Ecotox Environ Safety 11:184-197.
Hayes WJ, Jr. 1982. Pesticides Studied in Man. Baltimore, MD: Williams
and Wilkins, pp. 233-234, 264-267, 269-272, 275-281.
Hopper ML. 1982. Automated gel permeation system for rapid separation of
industrial chemicals and organophosphate and chlorinated pesticides from
fats. J Agric Food Chem 30:1038-1041.
Horwitz W, ed. 1975. Official Methods of Analysis of the Association of
Official Analytical Chemists, 12th ed. Washington, DC: Association of
Official Analytical Chemists, pp. 475-484 (cited in IARC 1979).
IARC (International Agency for Research on Cancer). 1979. Heptachlor and
heptachlor epoxide. In: IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans. Vol. 20. Lyon, France: IARC,
pp. 129-154.
IJC. 1983. An inventory of chemical substances identified in the Great
Lakes Ecosystem. Vol. 1-Summary. Report to the Great Lakes Water Quality
Board. Windsor, Ontario: International Joint Commission, 175 pp.
Infante PF, Epstein SS, Newton WA, Jr. 1978. Blood dyscrasias and
childhood tumors and exposure to chlordane and heptachlor. Scand J Work
Environ Health 4:137-150.
IRDC (International Research and Development Corporation). 1971. [No
title.] Unpublished report to EPA (cited in EPA 1985).
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96 Section 10
* IROC (International Research and Development Corporation). 1973.
Eighteen month oral carcinogenic study in mice. Unpublished report to
Velsicol Chemical Corporation, September 26 (cited in Epstein 1976).
• *
Jaquith D. 1987. (Environmental Protection Agency.) Personal
communication on status of EPA review of Velsicol air monitoring study
on heptachlor to L. Keifer of Dynamac Corporation, July 10.
Jensen AA. 1983. Chemical contaminants in human milk. Residue Rev 89:1-
128 (cited in WHO 1984).
Jensen S, Renberg L, Reutergardh L. 1977. Residue analysis of sediment
and sewage sludge for organochlorines in the presence of elemental
sulfur. Anal Chem 49:316-318 (cited in IARC 1979).
Johnson RD, Manske DD. 1976. Pesticide residues in total diet samples
(IX). Pestic Monit J 9:157-169 (cited in IARC 1979).
* Jolley WP, Stemmer HL, Pfitzer EA. 1966. The effects of feeding diets
containing a mixture of heptachlor and heptachlor epoxide to female rats
for 2 years. Unpublished report from the Kettering Laboratory to
Velsicol Corporation, January 28 (cited in Epstein 1976).
Jonsson V, Liu GJK, Armbruster J, Kettelhut LL, Drucker B. 1977.
Chlorohydrocarbon pesticide residues in human milk in Greater St. Louis,
Missouri 1977. Am J Clin Nutr 30:1106-1109.
Kacew S, Singhal RL. 1973. The influence of p,p-DDT, chlordane,
heptachlor, and endrin on hepatic and renal carbohydrate metabolism and
cyclic AMP-adenyl cyclase system. Life Sci 13:1363-1371.
* Kettering Laboratory. 1958. 60-Week Dog Feeding Study (cited in EPA
1987c as EPA 1958).
Kinoshita FK, Kempf CK. 1970. Quantitative measurement of hepatic
microsomal enzyme induction after dietary intake of chlorinated
hydrocarbon insecticides. Toxicol Appl Pharmacol 17:288.
Klemmer HW, Budy AM, Takahashi W. 1977. Hunan tissue distribution of
cyclodlene pesticides-Hawaii 1964-1973. Clin Toxicol 11(1):71-82.
Kosmatyi ES, Bublik LI. 1974. Use of a chromatopolarographic method in
pesticide analysis (Russ.). Ukr Khim Zh 40:1316-1318 [Chem Abstr
82:137835p] (cited in IARC 1979).
Krampl V. 1971. Relationship between serum enzymes and histological
changes in liver after administration of heptachlor in the rat. Bull
Environ Contain Toxicol 5:529-536.
Kroger M. 1972. Insecticide residues in human milk. J Pediatr
80(3):401-405.
-------
References 97
Kurata H, Hirose K, Umeda M. 1982. Inhibition of metabolic cooperation
in Chinese hamster cells by organochlorine pesticides. Gann 73:217-221.
Kutz FW, Yobs AR, Yang HSC. 1976. National pesticide monitoring
programs. In: Lee RE, ed. Air Pollution from Pesticides and Agriculture
Processes. Cleveland, OH: CRC Press (cited in EPA 1985a).
Lawrence LJ, Casida JE. 1984. Interactions of lindane, toxaphene, and
cyclodienes with brain-specific t-butylbicyclophosphorothionate
receptor. Life Sci 35:171-178.
Lehman AJ. 1951. Chemicals in foods: A report to the Association of Food
and Drug Officials on current developments. Part II. Pesticides.
Association of Food and Drug Officials. US Q Bull 15:122-133.
Lehman AJ. 1952. Chemicals in foods: A report to the Association of Food
and Drug Officials on Current Developments. Part II. Pesticides. Section
III: Subacute and chronic toxicity. Association of Food and Drug
Officials. US Q Bull 16:47-53.
Lehman AJ. 1959. Appraisal of the safety of chemicals in foods, drugs,
and cosmetics. Association of Food and Drug Officials.
Le Marchand L, Kolonel LN, Siegel BZ. Dendle WH, III. 1986. Trends in
birth defects for a Hawaiian population exposed to heptachlor and for
the United States. Arch Environ Health 41(3):145-148.
Lichtenstein EP, Schultz KR, Fuhremann TV, Liang IT. 1970. Degradation
of aldrin and heptachlor in field soils during a ten-year period
translocation into crops. J Agric Food Chem 18:100-106.
Mabey VR, Smith JH, Podoll RP, et al. 1981. Aquatic Fate Process Data
for Organic Priority Pollutants. Washington, DC: Monitoring Data Support
Division, Office of Water Regulations and Standards. EPA 440/4-81-014
(cited in EPA 1985a).
Marshall TC, Dorough HW, Swim HE. 1976. Screening of pesticides for
mutagenic potential using Salmonella cyphlmurium mutants. J Agric Food
Chem 24(3):560-563.
Maslansky CJ, Williams GM. 1981. Evidence for an epigenetic mode of
action in organochlorine pesticide hepatocarcinogenicity: A lack of
genotoxicity in rat, mouse, and hamster hepatocytes. J Toxicol Environ
Health 8:121-130.
Matsumura F, Ghiasuddin SM. 1983. Evidence for similarities between
eyelodiene-type insecticides and picrotoxinin in the action mechanisms.
J Environ Sci Health B18:l-14.
Mestitzova M. 1967. On reproduction studies and the occurrence of
cataracts in rats after long-term feeding of the insecticide heptachlor.
Experientia 23:42-43.
-------
98 Section 10
Mossing ML, Redetzke KA, Applegate HG. 1985. Organochlorine pesticides
in blood of persons from El Paso, Texas. J Environ Health 47(6):312-313
Nash RG, Harris UG. 1973. Chlorinated hydrocarbon insecticide residues
in crops and soil. J Environ Qual 2:269-273 (cited in WHO 1984).
* NCI (National Cancer Institute). 1977. Bioassay of heptachlor for
possible carcinogenicity. CAS. No. 76-44-8. Technical Report Series 9.
Bethesda, MD: Carcinogen Bioassay and Program Resources Branch,
Carcinogenesis Program, Division of Cancer Cause and Prevention, NCI,
National Institutes of Health. DHEV Publication (NIH) 77-809.
Netzel NR. 1981. Industrial Hygiene Survey. Velsicol Chemical
Corporation, Memphis, Tennessee Plant. Office of Toxic Substances.
Microfiche 200S01.
NIOSH/OSHA (National Institute for Occupational Safety and
Health/Occupational Safety and Health Administration). 1981.
Occupational Health Guidelines for Chemical Hazards. U.S. Department of
Health and Human Services. DHHS (NIOSH) Publication 81-123, pp. 1-5.
NIOSH (National Institute for Occupational Safety and Health). 1979.
NIOSH Manual of Analytical Methods. Vol. 5. U.S. Department of Health,
Education, and Welfare. DHEV (NIOSH) Publication 79-141, pp. S287-1-
S287-9.
NIOSH/OSHA (National Institute for Occupational Safety and
Health/Occupational Safety and Health Administration). 1978. Pocket
Guide to Chemical Hazards. U.S. Department of Health, Education, and
Welfare. DHEW (NIOSH) Publication 78-210, pp. 106-107.
NIOSH (National Institute for Occupational Safety and Health). 1980. The
Quarterly Hazard Summary Report (March).
NIOSH (National Institute for Occupational Safety and Health). 1985.
Pocket Guide to Chemical Hazards. U.S. Department of Health and Human
Services. DHHS (NIOSH) Publication 85-114, pp. 132-133.
NRG (National Research Council). 1982. An Assessment of the Health Risks
of Seven Pesticides Used for Termite Control. Prepared for Department of
the Navy, Washington, DC. NTIS PB 83-136374.
NTP (National Toxicology Program). 1987. Unpublished results from B.
Tainer, Toxicology Research Testing Programs, Cellular Genetic
Toxicology Branch, NTP, to J. Rowland, Dynamac Corporation, April 15.
OSHA (Occupational Safety and Health Administration). 1985. OSHA Safety
and Health Standards for General Industry. 29 CFR 1910. Subpart Z. U.S.
Department of Labor, Washington, DC: U.S. Government Printing Office.
Peirano WB. 1980. Heptachlor-Maximum Acceptable Limit in Drinking Wat
Washington DC: Environmental Protection Agency (A criteria document
prepared for the World Health Organization) (cited in WHO 1984).
-------
References 99
Pelikan Z. 1971. Short-tern intoxication of rats by heptachlor
administered in diet. Arch Belg Med Soc Hyg Med Trav Med Leg 29(7)-462-
470.
Petrasek AC, Kug«lman IJ, Austern BM, Pressley TA. Winslow LA, Wise RH.
1983. Fate of toxic organic compounds in wastewater treatment plants
Water Pollut Control Fed 55:1286-1296.
* Podowski AA, Banerjee BC, Feroz M, Dudek HA, Willey RL, Khan MAQ.
1979. Photolysis of heptachlor and cis-chlordane and toxicity of their
photoisomers to animals. Arch Environ Contain Toxicol 8:509-518.
Polishuk ZW, Ron M, Wassermann M, Cucos S, Wassermann D, Lemesch C.
1977a. Pesticides in people. Organochlorine compounds in human blood
plasma and milk. Pestic Monit J 10(4):121-129.
Polishuk ZW, Wassermann D, Wassermann M, Cucos S, Ron M. 1977b.
Organochlorine compounds in mother and fetus during labor. Environ Res
13:278-294.
Probst GS, McMahon RE, Hill LE, Thompson CZ, Epp JK, Neal SB. 1981.
Chemically induced unscheduled DNA synthesis in primary rat heptocyte
cultures: A comparison with bacterial mutagenicity using 218 compounds
Environ Mutat 3:11-32.
P&TC News. 1987. Pesticide & Toxic Chemical News. Boschwitz Bill Would
Ban Four Termiticides. Washington, DC: Food Chemical News, Inc. (July
8) .
Radomski JL, Davidow B. 1953. The metabolite of heptachlor, its
estimation, storage and toxicity. J Pharmacol Exp Therap 107:266-272.
Radomski JL, Deichmann WB, Clizer EE, Rey A. 1968. Pesticide
concentrations in the liver, brain, and adipose tissue of terminal
hospital patients. Food Cosmet Toxicol 6:209-220.
Reuber MD. 1977. Hepatic vein thrombosis in mice ingesting chlorinated
hydrocarbons. Arch Toxicol 38:163-168.
Reuber MD. 1978. Carcinomas and other lesions of the liver in mice
ingesting Organochlorine pesticides. Clin Toxicol 13(2):231-256 [Also
available as Reuber, MD. 1979. Toxicol Annu 3:231-256).
RTECS. 1983-84 (Suppl). Registry of Toxic Effects of Chemical
Substances. National Institute for Occupational Safety and Health, U.S.
Department of Health and Human Services, pp. 1178-1179.
Ruttkay-Nedecka J, Cerey K, Rosival L. 1972. Evaluation of the chronic
toxic effect of heptachlor. Kongr Chen Pol'nohospod 2:C27.
Sandhu SS, Warren WJ, Nelson P. 1978. Pesticidal residue in rural
potable water. J Am Water Works Assoc 70:41-45 (cited in IARC 1979).
-------
100 Section 10
SARA (Superfund Amendments and Reauthorization Ace). 1986. Section IK
Health-Related Authorities. HR 2005.
Savage EP, Keefe TJ, Tessari JD, et al. 1981. National study of
chlorinated hydrocarbon insecticide residues in human milk, USA. I.
Geographic distribution of dieldrin, heptachlor, heptachlor epoxide,
chlordane, oxychlordane, and mirex. Am J Epidemiol 113(4):413-422.
Science. 1987. Request for Proposals. Hawaii Heptachlor Health Effects
Research Program. Science 237 (4812):313.
Shain SA, Shaeffer JC, Boesel RV. 1977. The effect of chronic ingestion
of selected pesticides upon rat ventral prostate homeostasis. Toxicol
Appl Pharmacol 49(1):115-130.
Simon J, Parker FL. 1984. Fate of heptachlor. In: Veziroglu TN, ed. The
Biosphere: Problems and Solutions. Amsterdam: Elsevier Science
Publishers, pp. 453-460.
Sittig M, ed. 1980. Pesticide Manufacturing and Toxic Materials Control
Encyclopedia. Park Ridge, NJ: Noyes Data Corporation, pp. 165-171, 445-
448.
Sittig M. 1985. Handbook of Toxic and Hazardous Chemicals and
Carcinogens. 2nd ed. Park Ridge, NJ: Noyes Publications, pp. 480-482.
Sperling F, Ewenike HKU, Farber T. 1972. Changes in LD50 of parathion
and heptachlor following turpentine pretreatment. Environ Res 5:164-171.
SRI International. 1986. Directory of Chemical Producers, United States
of America. Menlo Park, CA: Stanford Research Institute, p. 861.
Stehr-Green PA, Schilling RJ, Burse VW, et al. 1986. Evaluation of
persons exposed to dairy products contaminated with heptachlor. J Am Med
Assoc 256(24):3350-3351.
STORET. 1987. Water Quality Control Information System (STORET) [data
base]. Washington, DC: Office of Water and Hazardous Materials,
Environmental Protection Agency.
Strassman SC, Kutz FW. 1977. Insecticide residues in human milk from
Arkansas and Mississippi 1973-74. Pestic Monit J 10(4):130-133.
Sun Y-P. 1972. Correlation of toxicity of insecticides to the house fly
and to the mouse. J Econ Entomol 65(3):632-635.
Takahashi W, Saidin D, Takei G, Wong L. 1981. Organochloride pesticide
residues in human milk in Hawaii 1979-1980. Bull Environ Contain Toxicol
27:506-511.
Takei GH, Kauahikaua SM, Leong GH. 1983. Analyses of human milk sampl"
collected in Hawaii for residues of organochlorine pesticides and
polychlorobiphenyls. Bull Environ Contain Toxicol 30:606-613.
-------
References 101
Talekar NS, Kao HT, Chen JS. 1983. Persistence of selected insecticides
in subtropical soil after repeated biweekly applications over two years.
J Econ Entomol 76:711-716.
Tashiro S, Matsumura F. 1978. Metabolism of trans-nonachlor and related
chlordane components in rat and man. Arch Environ Contain Toxicol 7:113-
127.
Taylor AW, Glotfelty DE, Glass BL, Freeman HP, Edwards WM. 1976.
Volatilization of dieldrin and heptachlor from a maize field. J Agric
Food Chem 24:625-631 (cited in WHO 1984).
Telang S, long C, Williams GM. 1982. Epigenetic membrane effects of a
possible tumor-promoting type on cultured liver cells by the non-
genotoxic organochlorine pesticide chlordane and heptachlor.
Carcinogenesis 3(10):1175-1178.
Townsend LR, Specht HB. 1975. Organophosphorus and organochlorine
pesticide residues in soils and uptake by tobacco plants. Can J Plant
Sci 55:835-842 (cited in IARC 1979).
Tzapko W, Rogovsky GF, Kurinov VN. 1967. On the possibility of
hexachlorane and heptachlor penetrating into subsoil water. In: Hygiene
of Settlements. Kiev: Zdorovie Publishers, pp. 93-95 (cited in WHO
1984) .
USDOC (U.S. Department of Commerce). 1984. Bureau of the Census. Report
FT 246/Annual 1983.
USDOC (U.S. Department of Commerce). 1985. Bureau of the Census. Report
FT 246/Annual 1984.
USDOC (U.S. Department of Commerce). 1986. Bureau of the Census. Report
FT 246/Annual 1985.
USITC (U.S. International Trade Commission). 1982a. Synthetic Organic
Chemicals, United States Production and Sales 1981. Washington, DC: U.S.
Government Printing Office. Publication 1292.
USITC (U.S. International Trade Commission). 1982b. Imports of Benzenoid
Chemicals and Products 1981. Washington, DC: U.S. Government Printing
Office. Publication 1272.
USITC (U.S. International Trade Commission). 1983a. Synthetic Organic
Chemicals, United States Production and Sales 1982. Washington, DC: U.S.
Government Printing Office. Publication 1422.
USITC (U.S. International Trade Commission). 1983b. Imports of Benzenoid
Chemicals and Products 1982. Washington, DC: U.S. Government Printing
Office. Publication 1401.
-------
102 Section 10
USITC (U.S. International Trade Commission). 1984a. Synthetic Organic
Chemicals, United States Production and Sales 1983. Washington, OC: U..
Government Printing Office. Publication 1588.
USITC (U.S. International Trade Commission). 1984b. Imports of Benzenoid
Chemicals and Products 1983. Washington, DC: U.S. Government Printing
Office. Publication 1548.
USITC (U.S. International Trade Commission). 1985. Synthetic Organic
Chemicals, United States Production and Sales 1984. Washington, DC: U.S.
Government Printing Office. Publication 1745.
USITC (U.S. International Trade Commission). 1986. Synthetic Organic
Chemicals, United States Production and Sales 1985. Washington, DC: U.S
Government Printing Office, Publication 1892, pp. 235, 241.
Velsicol. 1981. Epidemiologic study of employees of Velsicol Chemical
Corporation plant, Memphis, Tennessee, January 1952-December 1979.
Conducted by Shindell and Associates, Milwaukee, WI. Office of Toxic
Substances, Microfiche 0454.
Verschueren K. 1983. Handbook of Environmental Data on Organic
Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Company.
pp. 702-706.
Vrochinsky KK, Gemetchenko MM, Merezhko AI. 1980. Hydrobiological
Migration of Pesticides. Moscow: Moscow University Press, pp. 8-14, 3'
37, 59-63, 87-94, 119-120 (cited in WHO 1984).
Wang HH, Grufferman S. 1981. Aplastic anemia and occupational pesticide
exposure: A case-control study. J Occup Med 23(5):364-366.
Wang HH, MacMahon B. 1979a. Mortality of pesticide applicators. J Occup
Med 21(11):741-744.
Wang HH, MacMahon B. 1979b. Mortality of workers employed in the
manufacture of chlordane and heptachlor. J Occup Med 21(11):745-748.
s.
The Washington Post. 1987. Maker ends sale of chlordane. Washington, DC:
The Washington Post Company (August 12).
Wassermann M, Tomatis L, Wassermann D, et al. 1974. Pesticides in
people. Epidemiology of organochlorine Insecticides in the adipose
tissue of Israelis. Pestic Monit J 8(1):1-7.
Wassermann M, Ron M, Bercovici B, Wassermann D, Cucos S, Pines A. 1982.
Premature delivery and organochlorine compounds: Polychlorinated
biphenyls and some organochlorine insecticides. Environ Res 28:106-112.
White DH. 1976. Nationwide residues of organochlorines in starlings,
1974. Pestic Monit J 19:10-17 (cited In IARC 1979).
-------
References 103
WHO (World Health Organization). 1984. Environmental Health Criteria 38.
Heptachlor. Geneva, Switzerland: WHO.
Wiersma GB, Tai H(> Sand PF. 1972a. Pesticide residue levels in soils, FY
1969-National Soil's Monitoring Program. Pestic Monit J 6:194-228 (cited
in IARC 1979).
Wiersma GB, Tai H, Sand PF. 1972b. Pesticide residue levels in soil from
eight cities-1969. Pestic Monit J 6:126-129 (cited in IARC, 1979).
Williams GM, Numoto S. 1984. Promotion of mouse liver neoplasms by the
organochlorine pesticides chlordane and heptachlor in comparison to
dichlorodiphenyltrichloroethane. Carcinogenesis 5(12):1689-1696.
Windholz M, ed. 1983. The Merck Index. 10th ed. Rahway, NJ: Merck and
Company, p. 673.
* Witherup S, Cleveland FP, Shaffer FG, Schlecht H, Musen L. 1955. The
Physiological Effects of the Introduction of Heptachlor into the Diet of
Experimental Animals in Varying Levels of Concentration. Unpublished
report to Velsicol Corporation (August 17) (cited in WHO 1984).
* Witherup S, Cleveland FP, Stemmer K. 1959. The Physiological Effects
of the Introduction of Heptachlor Epoxide in Varying Levels of
Concentration to the Diet of CFN Rats. Unpublished report from the
Kettering Laboratory to Velsicol Corporation (November 10) (cited in
Epstein 1976).
Witherup S, Stemmer KL, Taylor P, Hull L. 1976a. The Effects Exerted
upon the Fertility of Rats and upon the Viability of Their Offspring by
the Introduction of Heptachlor into their Daily Diets. Cincinnati, OH:
The Kettering Laboratory (Report prepared for the Velsicol Chemical
Corporation) (cited in WHO 1984).
Witherup S, Stemmer KL, Taylor P, Hull L. 1976b. The Effects Exerted
upon the Fertility of Rats and upon the Viability of their Offspring by
the Introduction of Heptachlor into their Daily Diets. Cincinnati, OH:
The Kettering Laboratory (Report prepared for the Velsicol Chemical
Corporation) (cited in WHO 1984).
Worthing CR, Walker SB, eds. 1983. The Pesticide Manual. A World
Compendium. 7th ed. Lavenham, Suffolk, Great Britain: The Lavenham Press
Limited. 306 pp.
Wright CG, Leidy RB. 1982. Chlordane and heptachlor in the ambient air
of houses treated for termites. Bull Environ Contain Toxicol 28:617-623.
Yamaguchi I, Matsumura F, Kadous AA. 1980. Heptachlor epoxide: Effects
on calcium-mediated transmitter release from brain synaptosomes in rat.
Biochem Pharmacol 29(12):1815-1823.
-------
104 Section 10
Yang HSC, Wiersma GB, Mitchell WG. 1976. Organochlorine pesticide
residues in sugarbeet pulps and molasses from 16 states, 1971. Pescic
Monit J 10:41-43 (cited in I ARC 1979).
Zaroogian GE, Heltshe JF, Johnson H. 1985. Estimation of
bioconcentration in marine species using structure-activity models.
Environ Toxiocol Chem 4:3-12.
Zavon MR, Tye R, Latorre L. 1969. Chlorinated hydrocarbon insecticide
content of the neonate. Ann NY Acad Sci 160:196-200.
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105
11. GLOSSARY
Acute Exposure--Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Bioconcentration Factor (BCF)--The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surrounding
water at the same time or during the same time period.
Carcinogen--A chemical capable of inducing cancer.
Ceiling value (CL)--A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure--Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity--The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity--Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
Frank Effect Level (FEL)--That level of exposure which,produces a
statistically or biologically significant increase in frequency or
severity of unmistakable adverse effects, such as irreversible
functional impairment or mortality, in an exposed population when
compared with its appropriate control.
EPA Health Advisory--An estimate of acceptable drinking water levels for
a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH)--The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape-impairing symptoms or irreversible
health effects.
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106 Section 11
Intermediate Exposure--Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Inmunologic Toxieity-The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In vitro--Isolated from che living organism and artificially maintained,
as in a test tube.
In vivo--Occurring within the living organism.
Key Study--An animal or human toxicological study that best illustrates
the nature of the adverse effects produced and the doses associated with
those effects.
Lethal Concentration(LO) (LCLO)--The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration(50) (LCso)--A calculated concentration of a
chemical in air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal Dose(LO) (LDLO)--The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Dose(SO) (LDSO)--The dose of a chemical which has been calculated
to cause death in 50% of a defined experimental animal population.
Lowest-Observed-Adverse-Effect Level (LOAEL)--The lowest dose of
chemical in a study or group of studies which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.
Lovest-Observed-Effect Level (LOEL)--The lowest dose of chemical in a
study or group of studies which produces statistically or biologically
significant increases in frequency or severity of effects between the
exposed population and its appropriate control.
Malformations--Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level--An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen--A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
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Glossary 107
Neurotoxicity--The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOAEL)--That dose of chemical at which
there are no statistically or biologically significant increases in
frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
No-Observed-Effect Level (NOEL) --That dose of chemical at which there
are no statistically or biologically significant increases in frequency
or severity of effects seen between the exposed population and its
appropriate control.
Permissible Exposure Limit (PEL) --An allowable exposure level in
workplace air averaged over an 8-h shift.
qj*--The upper-bound estimate of the low-dose slope of the dose- response
curve as determined by the multistage procedure. The q * can be used to
calculate an estimate of carcinogenic potency, the incremental excess
cancer risk per unit of exposure (usually j*g/L for water, mg/kg/day for
food, and Mg/m3 for air) .
Reference Dose (RfD)--An estimate (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population to a
potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
uncertainty factors that reflect various types of data used to estimate
RfDs and an additional modifying factor, which is based on a
professional judgment of the entire database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ)--The quantity of a hazardous substance that is
considered reportable under CERCLA. Reportable quantities are: (1) 1 Ib
or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-h period.
Reproductive Tozicity--The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
Short-Term Exposure Limit (STEL)--The maximum concentration to which
workers can be exposed for up to IS min continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TUA may not be exceeded.
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108 Section 11
Target Organ Toxlclty--This term covers a broad range of adverse effe
on target organs or physiological systems (e.g., renal, cardiovascular
extending from those arising through a single limited exposure to those
assumed over a lifetime of exposure to a chemical.
Teratogen--A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV)--A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.
Time-weighted Average (TWA)--An allowable exposure concentration
averaged over a normal 8-h workday or 40-h workweek.
Uncertainty Factor (UF)--A factor used in operationally deriving the RfD
from experimental data. UFs are intended to account for (1) the
variation in sensitivity among the members of the human population,
(2) the uncertainty in extrapolating animal data to the case of humans,
(3) the uncertainty in extrapolating from data obtained in a study that
is of less than lifetime exposure, and (4) the uncertainty in using
LOAEL data rather than NOAEL data. Usually each of these factors is set
equal to 10.
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109
APPENDIX: PEER REVIEW
A peer review panel was assembled for heptachlor/heptachlor
epoxide. The pannel consisted of che following members: Dr. Sheldon D.
Murphey, University of Washington; Dr. Michael J. Norvell, M. J. Norvell
Assoc., Inc.; and Dr. Jean Scholler, Scholler Assoc., Inc. These experts
collectively have knowledge of heptachlor/heptachlor epoxide's physical
and chemical properties, toxicokinetics, key health end points,
mechanisms of action, human and animal exposure, and quantification of
risk to humans. All reviewers were selected in conformity with the
conditions for peer review specified in the Superfund Amendments and
Reauthorization Act of 1986, Section 110.
A Joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and determined which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile, with a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.
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