Heptachlor (EHC 38, 1984)

INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

ENVIRONMENTAL HEALTH CRITERIA 38

HEPTACHLOR

This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.

Published under the joint sponsorship of
the United Nations Environment Programme,
the International Labour Organisation,
and the World Health Organization

Draft prepared by Professor D. Beritc-Stahuljak and Professor
F. Valic (University of Azgreb, Croatia) using texts made
available by Dr R. Millischer (ATOCHEM, Paris, France),
Dr. S. Magda (Kali-Chemie, Hanover, Germany), Mr D.J. Tinston
(ICI Central Toxicology Laboratory, United Kingdom), Dr. H.J.
Trochimowicz (E.I. Du Pont de Nemours, Newark, Delaware, USA)
and Dr G.M. Rusch (Engineered Materials Sector, Allied-Signal Inc.,
Morristown, New Jersey, USA).

World Health Orgnization
Geneva, 1984

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR HEPTACHLOR

1. SUMMARY AND RECOMMENDATIONS

1.1. Summary
1.1.1. Identity and analytical methods
1.1.2. Uses and sources of exposure
1.1.3. Environmental concentrations and exposures
1.1.4. Kinetics and metabolism
1.1.5. Studies on experimental animals
1.1.6. Effects on man
1.2. Recommendations

2. IDENTITY, PROPERTIES AND ANALYTICAL METHODS

2.1. Identity
2.2. Properties and analytical methods
2.2.1. Physical and chemical properties
2.2.2. Analytical methods

3. SOURCES OF ENVIRONMENTAL POLLUTION, TRANSPORT
AND DISTRIBUTION

3.1. Sources of pollution
3.1.1. Industrial production and uses
3.2. Transport and distribution
3.2.1. Air
3.2.2. Water
3.2.3. Soil
3.2.3.1 Bacterial degradation
3.2.3.2 Abiotic degradation

4. ENVIRONMENTAL LEVELS AND EXPOSURES

4.1. Environmental levels
4.1.1. Air
4.1.2. Water
4.1.3. Soil
4.1.4. Food
4.2. General population exposure
4.2.1. Exposure of infants
4.2.2. Occupational exposure

5. KINETICS AND METABOLISM

5.1. Animal studies
5.2. Human studies

6. STUDIES ON EXPERIMENTAL ANIMALS

6.1. Short-term exposures
6.2. Long-term exposures
6.3. Reproduction studies and teratogenicity
6.4. Mutagenicity
6.5. Carcinogenicity
6.6. Other studies

7. EFFECTS ON MAN

7.1. General population exposure
7.2. Occupational exposure and epidemiological studies
7.3. Treatment of poisoning

8. EFFECTS ON THE ENVIRONMENT

8.1. Toxicity for aquatic organisms
8.2. Toxicity for terrestrial organisms
8.3. Toxicity for microorganisms
8.4. Bioaccumulation and biomagnificiation
8.5. Population and community effects
8.6. Effects on the abiotic environment
8.7. Appraisal

9. PREVIOUS EVALUATIONS OF HEPTACHLOR BY INTERNATIONAL BODIES

10. EVALUATION OF HEALTH RISKS FOR MAN AND EFFECTS ON THE ENVIRONMENT

10.1. Heptachlor toxicity
10.2. Exposure to heptachlor
10.3. Evaluation of overall environmental effects
10.4. Evaluation of risks for human health and the environment

TASK GROUP MEETING ON ENVIRONMENTAL HEALTH CRITERIA FOR
ORGANOCHLORINE PESTICIDES OTHER THAN DDT (CHLORDANE, HEPTACHLOR,
MIREX, CHLORDECONE, KELEVAN, CAMPHECHLOR)

Members

Dr Z. Adamis, National Institute of Occupational Health,
Budapest, Hungary

Dr D.A. Akintonwa, Department of Biochemistry, Faculty of
Medicine, University of Calabar, Calabar, Nigeria^a

Dr R. Goulding, Chairman of the Scientific Sub-committee, UK
Pesticides Safety Precautions Scheme, Ministry of
Agriculture, Fisheries & Food, London, England (Chairman)

Dr S.K. Kashyap, National Institute of Occupational Health
(Indian Council of Medical Research), Meghaninager,
Ahmedabad, India

Dr D.C. Villeneuve, Environmental Contaminants Section,
Environmental Health Centre, Tunney's Pasture, Ottawa,
Ontario, Canada (Rapporteur)

Dr D. Wassermann, Department of Occupational Health, The
Hebrew University, Haddassah Medical School, Jerusalem,
Israel (Vice-Chairman)

Representatives of Other Organizations

Dr C.J. Calo, European Chemical Industry Ecology and
Toxicology Centre (ECETOC)

Mme van der Venne, Commission of the European Communities (CEC)

Dr D.M. Whitacre, Internation Group of National Associations
of Agrochemical Manufacturers (GIFAP)

Secretariat

Dr M. Gilbert, International Register for Potentially Toxic
Chemicals, United Nations Environment Programme, Geneva,
Switzerland

Mme B. Goelzer, Division of Noncommunicable Diseases, Office
of Occupational Health, World Health Organization, Geneva,
Switzerland

Dr Y. Hasegawa, Division of Environmental Health,
Environmental Hazards and Food Protection, World Health
Organization, Geneva, Switzerland

------------------------------------------------------------
^a Unable to attend.

Secretariat (contd.)

Dr K.W. Jager, Division of Environmental Health, Internation
Programme on Chemical Safety, World Health Organization,
Geneva, Switzerland (Secretary)

Mr B. Labarthe, International Register for Potentially Toxic
Chemicals, United Nations Environment Programme, Geneva,
Switzerland

Dr I.M. Lindquist, International Labour Organization, Geneva,
Switzerland

Dr M. Vandekar, Division of Vector Biology and Control,
Pesticides Development and Safe Use Unit, World Health
Organization, Geneva, Switzerland

Mr J.D. Wilbourn, Unit of Carcinogen Identification and
Evaluation, International Agency for Research on Cancer,
Lyons, France

NOTE TO READERS OF THE CRITERIA DOCUMENTS

While every effort has been made to present information in the
criteria documents as accurately as possible without unduly
delaying their publication, mistakes might have occurred and are
likely to occur in the future. In the interest of all users of the
environmental health criteria documents, readers are kindly
requested to communicate any errors found to the Manager of the
International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland, in order that they may be
included in corrigenda, which will appear in subsequent volumes.

In addition, experts in any particular field dealt with in the
criteria documents are kindly requested to make available to the
WHO Secretariat any important published information that may have
inadvertently been omitted and which may change the evaluation of
health risks from exposure to the environmental agent under
examination, so that the information may be considered in the event
of updating and re-evaluation of the conclusions contained in the
criteria documents.

* * *

A detailed data profile and a legal file can be obtained from
the International Register of Potentially Toxic Chemicals, Palais
des Nations, 1211 Geneva 10, Switzerland (Telephone no. 988400 -
985850).

ENVIRONMENTAL HEALTH CRITERIA FOR HEPTACHLOR

Following the recommendations of the United Nations Conference
on the Human Environment held in Stockholm in 1972, and in response
to a number of World Health Resolutions (WHA23.60, WHA24.47,
WHA25.58, WHA26.68), and the recommendation of the Governing
Council of the United Nations Environment Programme, (UNEP/GC/10, 3
July 1973), a programme on the integrated assessment of the health
effects of environmental pollution was initiated in 1973. The
programme, known as the WHO Environmental Health Criteria
Programme, has been implemented with the support of the Environment
Fund of the United Nations Environment Programme. In 1980, the
Environmental Health Criteria Programme was incorporated into the
International Programme on Chemical Safety (IPCS). The result of
the Environmental Health Criteria Programme is a series of criteria
documents.

A WHO Task Group on Environmental Health Criteria for
organochlorine pesticides other than DDT met in Geneva from 28
November to 2 December, 1983. Dr K.W. Jager opened the meeting on
behalf of the Director-General. The Task Group reviewed and
revised the draft criteria document on heptachlor and made an
evaluation of the health risks of exposure to heptachlor.

The drafts of this document were prepared by Dr D.C. Villenueve
of Canada and Dr S. Dobson of the United Kingdom.

The efforts of all who helped in the preparation and
finalization of the document are gratefully acknowledged.

* * *

Partial financial support for the publication of this criteria
document was kindly provided by the United States Department of
Health and Human Services, through a contract from the National
Institute of Environmental Health Sciences, Research Triangle Park,
North Carolina, USA - a WHO Collaborating Centre for Environmental
Health Effects.

1. SUMMARY AND RECOMMENDATIONS

1.1. Summary

1.1.1. Identity and analytical methods

Heptachlor is a white crystalline solid with a mild camphor
odour. It is used as an insecticide.

Gas chromatography with electron capture detection is the
method most commonly used for heptachlor determination.

1.1.2. Uses and sources of exposure

Heptachlor has been used for more than 30 years as a stomach
and contact insecticide, mainly in the control of termites and soil
insects. In its country of origin, the USA, its use is now
restricted to underground termite control. In several other
countries, approved uses have been gradually withdrawn.

Exposure of the general population is mainly through residues
in food, but in most countries these residues have decreased
considerably over the years and exposures are gener-ally far below
the advised acceptable daily intake. In areas where heptachlor is
used, there may be some additional intake from volatilisation of
sprayed heptachlor and from well-water.

A significant source of heptachlor for infants is breast milk,
in which the levels of heptachlor can be considerably higher than
those in dairy milk.

In certain occupational exposures, heptachlor is known to have
exceeded the TLV or MAC.

1.1.3. Environmental concentrations and exposures

Heptachlor is fairly stable to light and moisture and it is
not readily dehydrochlorinated. Volatilization is the major
mechanism of transport of topically-applied heptachlor. Its half-
life in the soil in temperate regions ranges between 3/4 - 2 years,
depending on the type of soil, and may be less in tropical regions.
It is not likely to penetrate into groundwater but contamination of
surface water and sludge can occur. Several metabolites, formed by
microbial action, have been found in soil, sludge, and water.
Epoxidation is an important metabolic route leading to
heptachlorepoxide, which is of comparable toxicity to heptachlor
but more stable in biological systems.

Bioaccumulation and biomagnification occur and bioconcentration
factors of 200 - 37000X have been reported from water into hydro-
biota.

Heptachlor has been shown to be toxic for aquatic life, but its
toxicity is highly species variable. Marine crustacea and younger
life stages of both fish and invertebrates are most sensitive.
Insufficient information is available on its toxicity for
terrestrial species.

1.1.4. Kinetics and metabolism

Heptachlor is readily absorbed following ingestion and skin
contact and is transported throughout the body. Heptachlor
epoxide, the most persistent metabolite, is rapidly formed and can
be found in the body, mainly in adipose tissue. The toxicity of
heptachlor epoxide is similar to that of heptachlor. Figures for
its half-life in the rat are contradictory; in chickens it is of
the order of 4 weeks. Excretion takes place via both urine and
faeces, but detailed information is lacking. Human milk can be a
major excretion route for heptachlor residues.

1.1.5. Studies on experimental animals

According to the classification of Hodge & Sterner (1956), the
acute toxicity of heptachlor is moderate (acute oral LD₅₀ for the
rat 40 - 162 mg/kg). WHO (1984) classified the technical product
as moderately hazardous. Toxic symptoms are related to
hyperexcitability of the central nervous system and include tremors
and convulsions. Death may follow respiratory failure. At non-
lethal acute exposures, heptachlor is hepatotoxic.

Proliferation of the smooth endoplasmatic reticulum and
induction of the mixed-function oxidases in liver cells is one of
the earliest indications of prolonged exposure to heptachlor.

At high exposure levels, heptachlor can interfere with
reproduction and the viability of offspring. Cataracts were
observed in both parents and progeny in the rat.

There were no indications of teratogenicity in rats, rabbits,
chickens, and beagle dogs.

Heptachlor is not generally active in short-term tests designed
to detect genetic activity. There is evidence that it may have
effects on cell to cell communication, which is a property of
promoting agents.

There is limited evidence that both heptachlor and heptachlor
epoxide are carcinogenic for mice.

1.1.6. Effects on man

There are no reports of cases of poisoning in man. Although no
adverse effects have been reported in workers manufacturing or
using heptachlor, epidemiological studies are insufficient to judge
the carcinogenic hazard of heptachlor for man.

1.2. Recommendations

1. Figures relating to current production and use
of heptachlor should be made available.

2. More information on human exposure to heptachlor
from sources such as breastmilk and applications
for termite control are required.

3. Further research is required in order to better
assess the significance for man of the carcinogenic
findings in mice.

4. Continuing epidemiological studies should be
made on workers who, in the past, have been exposed
to heptachlor.

2. IDENTITY, PROPERTIES AND ANALYTICAL METHODS

2.1. Identity

Molecular formula: C₁₀H₅Cl₇

CAS chemical name: 1,4,5,6,7,8,8-heptachloro-3_a,4,7,7_a-
tetrahydro-4,7-methano-1H-indene

Common trade names: Aahepta, Agroceres, Basaklor, Drinox,
E 3314, GPKh, Heptachlorane, Heptagran,
Heptagranox, Heptamak, Heptamul,
Heptasol, Heptox, Rhodiachlor, Soleptax,
Velsicol 104

CAS registry number: 76-44-8

Relative molecular mass: 373.3

2.2. Properties and Analytical methods

2.2.1. Physical and chemical properties

Heptachlor is a white crystalline solid with a mild odour of
camphor, a melting point of 93°C (46 - 74°C for the technical
product) and a density of 1.65 - 1.67 g/ml at 25°C. It has a
boiling point of 135 - 145 °C and vapour pressure of 4 x 10^-4 mm Hg
at 25°C.

It is virtually insoluble in water (0.056 mg/litre) but fairly
soluble in organic solvents, e.g., ethanol (45 g/litre), xylene
(1020 g/litre), acetone (750 g/litre), benzene (1060 g/litre).

It is stable in daylight, air, moisture, and moderate heat
(160°C) but is oxidized biologically to heptachlor epoxide
(Whetstone, 1964).

Technical heptachlor contains about 72 - 74% 1,4,5,6,7,8,8-
heptachloro-3a,4,7,7a-tetrahydro-4, 7-methanoindene, 20 - 22%
gamma-chlordane, and 4 - 8% gamma-nonachlor (Suzuki et al., 1978).

2.2.2. Analytical methods

Various methods used in the determination of heptachlor and
heptachlor epoxide are summarized in Table 1.

Table 1. Methods for the determination of heptachlor and its epoxide
---------------------------------------------------------------------------------------------------------
Sample type Extraction/clean-up Method of Limit of Reference
detection detection detection
---------------------------------------------------------------------------------------------------------
Formulations:

liquids extract (carbon disulphide) GC/FID - Horwitz (1970)

solids extract (pentane) in Soxhlet GC/FID - Horwitz (1970)

ambient air trap in ethylene glycol, partition GC/ECD 0.1 ng/m³ Arthur et al. (1976);
and extract (methylene chloride), Sherma & Shafik
fractionation and clean-up through (1975)
silica gel, CC

sediments and centrifuge, extract solid GC/ECD 1 - 10 µg/kg Jensen et al. (1977)
sewage sluge (acetone), liquid/liquid partition,
transfer into trimethyl pentane,
treat to remove sulfur isolate in
trimethylpentane

soil extract (acetone-hexane) add GC/ECD - Townsend & Specht
benzene to extract, evaporate to (1975)
dryness, dissolve in hexane, CC

food extract (ethyl ether in petroleum GLC of photo- - Ward (1977)
ether), Florisil CC followed by UV derivatives
irradiation of sample and
standards

crops blend with water-acetonitrile, GC/ECD 10 µg/kg Carey et al. (1973)
decant, separate liquid,
concentrate, extract (hexane)
transfer to hexane, CC

fish, crabs, extract (hexane-acetone), dry, GC/ECD 4 µg/kg Albright et al.
shellfish filter, wash, filtrate (water), (1975)
distill, CC
---------------------------------------------------------------------------------------------------------

Table 1. (contd.)
---------------------------------------------------------------------------------------------------------
Sample type Extraction/clean-up Method of Limit of Reference
detection detection detection
---------------------------------------------------------------------------------------------------------
fruits, extract (acetonitrile), dilute GC/ECD, - Horwitz (1975)
vegetables, (water), extract (petroleum thermionic
dairy ether), CC
products

milk extract (diethyl ether and GC - Gabica et al. (1974)
hexane), partition into
acetonitrile, extract (hexane)

rice extract (water, acetonitrile and GC - Suzuki et al. (1979)
ethanol), extract (n-hexane),
clean-up AgNO₃-coated florisil, CC

water, rural extract (hexane), CC GC/ECD 10 ng/litre Sandhu et al. (1978)
potable

adipose extract (hexane), re-extract GC/ECD and - Clausen et al. (1974)
tissue (petroleum ether, chloroform- TLC
methanol, acetonitrile or acetone-
hexane), dry, dissolve (hexane),
CC

wildlife grind with sodium sulphate, GC/ECD 5 µg/kg White (1976)
tissue extract (ethyl ether, petroleum
ether) in Soxhlet, CC
---------------------------------------------------------------------------------------------------------
Abbreviations: CC - column chromatography; GC - gas chromatography; FID - flame-ionization detection;
ECD - electron capture detection; TLC - thin-layer chromatography.

3. SOURCES OF ENVIRONMENTAL POLLUTION, TRANSPORT AND DISTRIBUTION

3.1. Sources of Pollution

3.1.1. Industrial production and uses

Heptachlor is not known to occur naturally.

It was isolated in 1946 from technical chlordane in both the
USA and the Federal Republic of Germany (IARC, 1974, 1979).
Heptachlor, which was first introduced as a contact insecticide
under the trade names Velsicol 104 and E 3314, was registered in
the USA in 1952 as a commercial insecticide for foliar, soil, and
structural applications, and for the control of malaria.

Heptachlor is produced commercially by chlorination of
chlordene in the presence of a catalyst (IARC, 1974) such as
Fuller's earth (Whetstone, 1964). This reaction is usually carried
out at 0 - 5°C in carbon tetrachloride. The solvent is then
distilled off, and the residue recrystallized from methanol before
grinding (Melnikov, 1971). Formulations include: emulsifiable
concentrates, wettable powders, dusts, and granules containing
various concentrations of active material.

It is a non-systemic stomach and contact insecticide.

The use of heptachlor is confined almost exclusively to the
control of soil insects and termites. Production of heptachlor in
the USA in 1971 was estimated at 2.7 million kg. In the period
July 1975 - December 1976, an estimated 4.5 million kg were
produced in the USA where it was used as an insecticide (registered
from June 1971 for use on 22 crops) and applied both as a topical
foliar application and as a seed treatment: 58% on corn, 26.8% by
pest control operators, 13.2% as seed treatment, and 2% for
miscellaneous uses including fire ant control, use on pineapples,
and possibly on citrus fruits (IARC, 1979).

In 1970, the world use of heptachlor was as follows: Africa 5%,
Asia 15%, Canada and the USA 5%, Europe 60%, and South America 15%
(FAO/WHO, 1971). However, it would appear that world usage is
diminishing.

A USA Environmental Protection Agency cancellation proceeding
led to a settlement on contested uses. This settlement allowed for
the limited use of heptachlor according to crop, location, amount
allowed, and maximum time interval between applications. Its main
use is now in termite control (Peirano, 1980).

The use of heptachlor has been restricted in Italy and
Switzerland (IARC, 1974). In Japan (Environmental Protection
Agency, Japan, 1978), the only accepted use of heptachlor is for
termite control. Its use is restricted in the USSR (IRPTC, 1982).

3.2. Transport and Distribution

3.2.1. Air

Volatilization is the major mechanism of transport of topically
applied heptachlor. In one study, 90% of heptachlor was
volatilized from bare moist soil in 2 - 3 days following
application (Taylor et al., 1976). Fields treated with technical
heptachlor at 2.24 kg/ha gave rise to air concentrations around the
field as high as 244 ng/m³, immediately following application.
After 3 weeks, the concentrations still remained as high as 15.4
ng/m³ (Peirano, 1980).

3.2.2. Water

Heptachlor is quickly hydrolysed in water to form 1-
hydroxychlordene which in turn is degraded microbially to form 1-
hydroxy-2,3-epoxychlordene. Formation of 1-hydroxychlordene seems
to be one of the major degradation pathways in moist soil. It has
been shown that heptachlor epoxide is also metabolized to 1-
hydroxychlordene (Harris & Miles, 1975).

Heptachlor is not often found in surface waters but it has been
detected at levels of 5 - 30 ng/litre while heptachlor epoxide has
been detected at levels of 5 - 40 ng/litre (IARC, 1974).

3.2.3. Soil

The half-life of heptachlor in soil was 9 - 10 months when
used at recommended agricultural rates (Anonymous, 1976).
Vrochinshy et al. (1980) described a half-life of 2 years; it could
still be detected in soil 14 years after use. Small field plots,
treated with up to 224 kg heptachlor/ha, had residue levels of 95
g/kg, 16 years after the initial application (Nash & Harris, 1973).
Data from tropical regions suggest that soil dissipation of
heptachlor may be more rapid in tropical than in temperate regions
(Stickley, 1972; Kathpal et al., 1983).

Soil surveys in the USA have showed 1-hydroxychlordene to be a
major residue in soils from 5 areas, while only small amounts of
heptachlor epoxide and the hydroxy epoxide were present (the half-
life of 1-hydroxychlordene in soil is 3 weeks) (Brooks, 1974). It
has been reported that heptachlor can be altered in the soil
environment to either heptachlor epoxide and/or 1-hydroxychlordene
(Harris & Miles, 1975).

When heptachlor was applied to a grass pasture at 5.6 kg/ha,
4% of the heptachlor remained after 30 days. After 15 weeks, 2%
remained (Taylor et al., 1977). In another study, heptachlor was
applied to the soil at a rate of 2.24 kg/ha; the soil was
rotatilled to 15 cm and tobacco plants were planted 6 days later.
After 3 months, soil samples at 0 - 15 cm and 15 - 23 cm showed
heptachlor levels of 0.37 mg/kg and 0.04 mg/kg, respectively
(Townsend & Specht, 1975).

Tzapko et al. (1967) concluded from their studies that
heptachlor penetration into ground water was likely to be
insignificant.

3.2.3.1. Bacterial degradation

Some bacteria and fungi are able to metabolize heptachlor to
its epoxide. Some soil bacteria have the ability to metabolize
heptachlor to chlordene, while other bacteria and fungi are able
to metabolize chlordene to chlordene epoxide (Harris & Miles,
1975). Microorganisms isolated from soil were examined for their
ability to metabolize heptachlor. Twenty-six out of 45 bacteria
and 35 out of 47 fungi isolated from soil were able to metabolize
heptachlor to its epoxide. According to the author there are two
other pathways of degradation, i.e., chemical hydrolysis to 1-
hydroxychlordene, followed by microbial epoxidation to 1-hydroxy-
2,3-epoxychlordene and conversion to an unknown product; and
bacterial dechlorination of heptachlor to chlordene and then
oxidation to chlordene epoxide. The author states that the former
seems to be a major degradation route and that preliminary
laboratory studies indicate that the production of 1-hydroxy-
chlordene in soil is comparable to that of heptachlor epoxide.

3.2.3.2. Abiotic degradation

Heptachlor is stable to light (Worthing, 1979).

Under conditions of sunlight or ultraviolet (UV) light,
heptachlor 1-exo-hydroxychlordene or 1-4,5,6,7,8,8-hexachloro-
3a,4,7,7a-tetrahydro-4,7-methanionden-1-ol was photodegraded
forming a cyclic ketone 1,1a,2,2,3, exo-6-hexachloro-1a,2,3,3a,5a,
5b-hexahydro-1,3-methano-1 H-cyclobuta ( c,d) pentalen-4-one. The
structure of this photodegraded product was elucidated by spectral
data from mass spectrometry, infrared spectrometry and ¹H and ¹³C
nuclear magnetic resonance (Parlar et al., 1978).

4. ENVIRONMENTAL LEVELS AND EXPOSURES

4.1. Environmental Levels

4.1.1. Air

The typical mean concentration of heptachlor in ambient air in
the USA was approximately 0.5 ng/m³ (Peirano, 1980). Air samples
were taken from both rural and urban areas of 9 cities in the USA
for 2 weeks per month, over a 6-month period, in 1971. Heptachlor
was found in samples taken from 2 of the 9 cities at a maximum
level in each city of 19.2 ng/m³ (Stanley et al., 1971). Air
samples, taken from 1972-74 in a cotton-growing area of the USA,
had a maximum heptachlor level of 0.8 ng/m³ (Arthur et al., 1976).

4.1.2. Water

Heptachlor and heptachlor epoxide were observed in chemical
sewage sludges in Ontario at levels (combined) of up to 21.73
µg/litre (Liu et al., 1975). In the water and sediment in the
upper Great Lakes, in 1974, values for heptachlor levels in water,
heptachlor epoxide in water, heptachlor in sediment, and heptachlor
epoxide in sediment were 0.005 µg/litre, 0.005 µg/litre, and 0.001
mg/litre and 0.001 mg/litre, respectively (Glooschenko et al.,
1976).

In the major river basins of the USA, heptachlor was found at
levels ranging from 0.001 to 0.035 µg/litre in a study conducted in
1967 (Peirano, 1980).

Heptachlor was found in 18 different locations in Europe and
the USA in sediments, plant effluents, lakes, and rivers (Eurocop-
Cost, 1976; Shackelford & Keith, 1976). The results of a survey
conducted in the USA in the period 1958-65 showed that heptachlor
was present in 17% of the samples of drinking-water studied. The
average concentration was 3 ng/litre (Safe Drinking-Water Committee,
1977). Heptachlor and heptachlor epoxide were found in potable
water supplies in rural areas of South Carolina in 45.5 and 63.6%
of samples tested, with the range of residues varying from undetected
to 44 ng/litre for heptachlor and from undetected to 87 ng/litre
for heptachlor epoxide (Sandhu et al., 1978).

A study was conducted in the USA in 1977 to compare pesticide
residue levels in the rural drinking-water of 2 states (1 sample
taken per 100 houses). Heptachlor was found in 45.5% of samples
from one state and in 62.5% of samples from the other at mean
levels of 9 and 15 µg/litre, respectively (Sandhu et al., 1978).

In another study, the average heptachlor residues in tap water
from Ottawa and The Hague were shown to be less than 0.013 µg/litre,
and 0.01 µg/litre, respectively (Kraybill, 1977a). Mean
concentrations of heptachlor and heptachlor epoxide of 0.6 and 3.0
ng/litre were found in Ottawa drinking-water in 1976 (Williams et
al., 1978). Heptachlor levels as high as 0.46 µg/litre have been
detected in ambient water in Nova Scotia (Burns et al., 1975).

A study of the effects of heptachlor on the organoleptic
properties of water has revealed that a heptachlor concentration in
water of 0.07 mg/litre (and higher) gives it a strange odour but
does not change the taste of water. Heptachlor at concentrations of
0.1 mg/litre or less does not affect the odour or taste of raw and
boiled fish products. Concentrations of 0.01 and 0.05 mg/litre do
not inhibit the biochemical oxygen demand. The dynamics of the
development and decay of aquatic saprophytic microflora has shown
that a heptachlor concentration of 0.1 mg/litre does not inhibit
the processes of "ammoniation" and nitrification of organic
substances in model reservoirs (Chekal, 1965).

WHO has recommended a guideline value of 0.1 µg/litre for
heptachlor and heptachlor epoxide in drinking-water (WHO, 1982).

4.1.3. Soil

A survey conducted on crop soils in 37 states of the USA in
1971 revealed heptachlor residues in 4.9% of samples, while
heptachlor epoxide was detected in 6.9% of samples with maximum
values of 1.37 and 0.43 mg/kg, respectively (Carey et al., 1978).

In a study conducted in the USA in 1969, crop soils from
43 states and non-crop soils from 11 states were examined.
Heptachlor was found in 68 of the 1729 samples analysed, with
residue levels ranging from 0.01 to 0.97 mg/kg, all the samples
being from cropland areas (Wiersma et al., 1972a,c). In another
study, heptachlor was found in soil samples from 7 out of 16 farms
examined in 1971 at levels of up to 0.24 mg/kg (Harris & Sans,
1971), while levels in the range of 0.01 - 0.84 mg/kg were found in
soil samples from 6 out of 12 states (5.7% of sites examined) in
the Corn Belt region of the USA (Carey et al., 1973).

Heptachlor residue levels found in soil samples taken from 7
out of 8 cities in the USA in 1969 ranged from 0.01 to 0.53 mg/kg
(Wiersma et al., 1972b). Average heptachlor and heptachlor epoxide
concentrations found in soil samples from 8 cities in the USA
ranged from 0.01 to 0.02 mg/kg and 0.01 - 0.05 mg/kg, respectively
(IARC, 1974).

In streambed sediment and sediment from natural drainage
ditches, heptachlor has been found at levels as high as 174 and 4.7
µg/kg, respectively (Burns et al., 1975).

4.1.4. Food

The Joint meeting on Pesticide residues (JMPR) estimated the
acceptable daily intake of heptachlor plus heptachlor epoxide at
0 - 0.0005 mg/kg body weight (FAO/WHO, 1971). The same meeting
arrived at the following recommendations for practical residue
limits (FAO/WHO, 1971):

0.01 mg/kg for citrus fruit;
0.5 mg/kg for crude soya bean oil;
0.05 mg/kg for vegetables; and
0.15 mg/kg for milk and milk products.

It was calculated that the daily human intake of heptachlor
epoxide in the USA ranged from 0.29 to 0.64 µg/day during the
period 1971-74 (Peirano, 1980). The daily intake of heptachlor
epoxide from food in 1965 in the USA was 2 µg/day. In 1970, this
figure was 1 µg/day (Duggan & Corneliussen, 1972).

Market basket surveys carried out from 1972-73 in the USA
showed maximum values for heptachlor epoxide ranging from trace
to 2 µg/kg (Johnson & Manske, 1976), while from a study published
in 1969 in the United Kingdom, the heptachlor epoxide content in
the total diet was, in general, less than 0.0005 mg/kg; heptachlor
was not detected (Abbott et al., 1969). In a series of studies
conducted in the United Kingdom and the USA, analyses of total
diets were carried out. Heptachlor epoxide was present in small
amounts in fish, poultry, meat, and dairy products, and in trace
amounts in fruits, vegetables, oils, and cereals. The maximum
values in poultry, meat, and fish ranged from trace to 2 µg/kg
(Johnson & Manske, 1976). The US EPA has established tolerances
for total residue levels of both heptachlor and heptachlor epoxide
at 0.1 mg/kg in or on cabbage, lettuce, rutabagas, and snap beans,
and 0.0 mg/kg (zero) in or on a variety of 30 vegetable, field, and
fruit crops, meat, or milk (US EPA, 1976)

Heptachlor was not found in any foods examined from August 1972
to July 1973 in the frame of the total diet study conducted by the
US Food and Drug Administration (IARC, 1979). In a study conducted
in 20 cities in the USA in 1974-75, only 3 out of 12 food classes
contained detectable residues of heptachlor epoxide. Levels ranged
from 0.0006 to 0.003 mg/kg (Peirano, 1980). A study that started
in 1974 in the USA disclosed the following mean heptachlor and
heptachlor epoxide residues as µg/kg wet weight (Table 2) (Madarena
et al., 1980).

Within the framework of the Joint FAO/WHO Food Contamination
Monitoring Programme, the levels of heptachlor and heptachlor
epoxide residues in various food items sampled in 1980-82 have been
reported from: Austria, Canada, Denmark, Guatemala, Japan, the
Netherlands, and the USA. On the fat basis, the median levels
ranged from 0 (not detected) in butter and cattle fat in Denmark to
13 µg/litre in cow's milk in Japan. On the "as is" basis, median
levels ranged from 0 (not detected) in hen's eggs in Denmark to 4
µg/kg in fresh onions in Guatemala. For heptachlor epoxide only,
the median levels ranged from 0 (not detected) in butter and
pasteurized cow's milk to 0.30 µg/litre in raw cow's milk in the
Federal Republic of Germany (fat basis) (WHO, 1983).

A study of US game fish conducted in 1967-68 showed heptachlor
and/or heptachlor epoxide present in 32% of 590 fish samples in a
range from 0.01 to 8.33 mg/kg (Henderson et al., 1969). Fish have
been shown to accumulate heptachlor and heptachlor epoxide at
0.008 mg/kg from concentrations of 0.06 µg/litre water (Hannon et
al., 1970). In whole fish, residues of heptachlor plus heptachlor
epoxide in the range of 0.01 - 0.26 mg/kg have been found (IARC,
1974). Average values for heptachlor and heptachlor epoxide in
oysters in the USA were less than 0.01 mg/kg (Bugg et al., 1967).

Table 2. Heptachlor and heptachlor epoxide levels in food
-------------------------------------------------------------------
Level (µg/kg wet weight) in:
pork horse meat chicken beef turkey
-------------------------------------------------------------------
Heptachlor 1.25 1.06 3.27 0.10 0.65
Heptachlor epoxide 1.95 5.28 9.58 0.50 6.66
-------------------------------------------------------------------

Potatoes grown in soils treated with heptachlor dust at 1.5
kg/ha were found to contain residues of heptachlor and heptachlor
epoxide up to 151 days following application. Processing of the
potatoes failed to reduce the heptachlor and heptachlor epoxide
content below the tolerance level (0.1 mg/kg) (Misra et al., 1977).

Sandy loam plots of soil were treated in 1951 with heptachlor
at 0, 56, 112, or 224 kg/ha. Residue levels were examined 15 - 16
years later. In soils, after 16 years, 9.5% of the heptachlor
applied at the highest dose level remained. No heptachlor residues
were found in soybeans grown on this soil 15 years after application
of heptachlor, but heptachlor epoxide residue levels of 0.067 -
0.237 mg/kg were found (Nash & Harris, 1973). In Canada, an
average level of heptachlor of 0.001 mg/kg was found in milk fat
(Frank et al., 1979a,b). The level of heptachlor in milk-extracted
lipids in the USA was 0.002 mg/kg and that of heptachlor epoxide
0.036 mg/kg (Duggan, 1967). In the Federal Republic of Germany,
heptachlor epoxide residues were found at a level of 0.024 mg/kg
milk extracted lipids (Heeschen et al., 1976).

Where cows (both early and late in lactation) were administered
daily a mixture of aldrin, heptachlor, and beta-HCH at 1, 2, or 4
mg/day for 4 weeks, aldrin and heptachlor could not be detected in
the milk-extracted lipids or in adipose tissue (Vreman et al.,
1976). In cows fed heptachlor epoxide daily at 5 or 20 µg/kg for
27 days, maximum levels of 2.9, and 4.4 µg/kg, respectively, were
detected in the milk (Hardee et al., 1964). Maximum levels of
heptachlor and heptachlor epoxide found in milk and milk products
in Ireland in 1971-72 were 62 and 21 µg/kg fat, respectively
(Downey et al., 1975).

In a German study published in 1972, heptachlor and heptachlor
epoxide residues were determined for cheese, butter, pasteurized
milk, and human milk (Heeschen, 1972). The findings showed that
for the milk and milk products, the average total residue was less
than 0.05 mg/kg. Human milk residues were about 10 times higher,
being 0.1 and 0.34 mg/kg in milk fat for heptachlor and heptachlor
epoxide, respectively.

4.2. General Population Exposure

4.2.1. Exposure of infants

In a study conducted in Canada, heptachlor epoxide was detected
in human milk, evaporated milk, and prepared baby food formulae.
The ranges found are given in Table 3 (Ritcey et al., 1972).

The most significant source of exposure to heptachlor for
infants appears to be human milk where heptachlor levels can be
much higher than in dairy milk. Jensen (1983) recently reviewed
the levels of heptachlor and heptachlor epoxide in human milk and
his data are given in Table 4.

The WHO Collaborating Centre in Japan participating in the
Joint FAO/WHO Food Contamination Monitoring Programme reported that
the median and 90 percentile values of heptachlor and heptachlor
epoxide residues in human milk ("as is" basis) were below 0.50
µg/litre and 2.10 µg/litre, respectively, in 1980 and below 0.50
µg/litre and 1.90 µg/litre, respectively, in 1981. The
Collaborating Centre in Guatemala reported that the median and 90
percentile values of heptachlor epoxide only ("as is" basis) were 0
and 2 µg/litre, respectively, in 1979 (WHO, 1983).

Table 3. Heptachlor epoxide in human milk, evaporated milk, and
prepared baby food formulae
-------------------------------------------------------------------
Residue level (mg/litre) in:
Human milk Evaporated Prepared
milk baby formula
-------------------------------------------------------------------
On whole milk basis 0.001 - 0.023 0.001 - 0.001 0.001 - 0.007

On fat basis 0.01 - 1.19 0.01 - 0.02 0.01 - 0.05
-------------------------------------------------------------------

Heptachlor epoxide and other organochlorine insecticide levels
in breast milk samples from vegetarians were lower. The mean
heptachlor epoxide levels were only 1 - 2% of the average level in
breast milk of the US general population (Hergenrather et al.,
1981).

4.2.2. Occupational exposure

During spraying, heptachlor concentrations in air of 0.6 - 1
mg/m³ have been measured. These levels decreased to 0.007 mg/m³,
1 - 1 1/2 h later (Osetrov, 1960). During mechanical disinfection
of seeds, the same author reported workplace concentrations of 5
mg/m³.

Permissible levels of exposure to heptachlor in the workplace
air have been adopted in different countries (ILO, 1980). Examples
include 0.5 mg/m³ as a time-weighted average concentration in
Belgium, Finland, the Netherlands, and the USA (both OSHA and
ACGIH); 0.1 mg/m³ maximum permissible concentration in Bulgaria;
and 0.01 mg/m³ maximum allowable concentration in the USSR (ILO,
1980; IRPTC, 1982; INRS, 1983).

Table 4. Heptachlor and heptachlor epoxide in human milk^a
-------------------------------------------------------------------------------------------------------
Heptachlor and heptachlor
epoxide content in^b

AMERICAS:
Canada
Alberta (1966-70) 59 (5%) - - 0.002 (0 - 0.06) Currie et al. (1979)
Alberta (1977-78) 33 (94%) 2.0 - 0.03 (0 - 0.11) Currie et al. (1979)
Canada (1967-68) 147 2.7 3 ± 3 0.13 ± 0.14 Ritcey et al. (1972)
(< 1 - 23) (< 0.01 - 1.19)
Canada (1975) 100 2.2 1/1 (0 - 3) - Mes & Davies (1979);
FAO/WHO (1981)

El Salvador (1973-74) 40 (50%) - 3 - De Campos & Olszyna-
Marzys (1979)

Guatemala
Rural area (1971) 46 (50%) - 7 - De Campos & Olszyna-
Marzys (1979)
Mexico (1976) 620 - - 0.01^e (median) FAO/WHO (1981)
0.01 (median)

Uruguay (Montevideo) 10 - 2 - Bauza (1975)

USA
Arkansas/Mississippi 57 (35%) - 12/10 - Strassman & Kutz (1977);
(1973-74) (0 - 30) FAO/WHO (1981)
Colorado (1972) 40 (25%) - 3 ± 1/1 - Savage et al. (1973);
(tr - 5) FAO/WHO (1981)
Georgia (Atlanta) 15 - 1.7 - Curley & Kimbrough
(1968) (1969)
Hawaii (1979-80) 50 (100%) 3.2 - 0.035 Takahashi et al. (1981)
(0.001 - 0.16)
Mississippi (pest- 34 (100%) - 3 (< 1 - 20) 0.08 Barnett et al. (1979)
icide area) (1973-75) (0.02 - 0.37)
-------------------------------------------------------------------------------------------------------

Table 4. (contd.)
-------------------------------------------------------------------------------------------------------
Heptachlor and heptachlor
epoxide content in^b

Area/year Number of Fat (%) Whole milk Milk fat Reference
samples (mean) (µg/litre) (mg/kg)
(% positive)
-------------------------------------------------------------------------------------------------------
USA (contd.)
Mississippi (non- 6 (100%) - 2 (< 1 - 3) 0.05 Barnett et al. (1979)
pesticide area) (0.01 - 0.08)
(1973-75)
Missouri (St. Louis) 51 (24%) - 2.7 - Jonsson et al. (1977)
(1973)
Pennsylvania (Phila- 53 - - 0.16 Kroger (1972)
delphia) (1970) (0.06 - 0.46)
USA-NE (1975) 233 - - 0.07 ± 0.04 Savage (1976); Savage et
(0.018 - 0.030) al. (1981)
USA-SE (1975) 288 - - 0.13 ± 0.21 Savage (1976); Savage et
(0.019 - 2.05) al. (1981)
USA-MW (1975) 378 - - 0.09 ± 0.07 Savage (1976); Savage et
(0.016 - 0.73) al. (1981)
USA-SW (1975) 388 - - 0.08 ± 0.10 Savage (1976); Savage et
(0.015 - 1.09) al. (1981)
USA-NW (1975) 149 - - 0.07 ± 0.10 Savage (1976); Savage et
(0.019 - 0.95) al. (1981)
USA-Total (1975) 1436 (61%) - 1 (median) 0.09 ± 0.13 Savage (1976); Savage et
(0.016 - 2.05) al. (1981)
ASIA:
Israel (1975) 29^d 1.5 9 ± 5 0.72 ± 0.48 Polishuk et al. (1977)

Japan
Akita (1979) 29 (96.6%) - 0.5 - Sasaki et al. (1980)
(0 - 1.0)
Japan (1971) 108 - 1 (median) - FAO/WHO (1981)
Japan (1972) 283 - 1 (median) - FAO/WHO (1981)
Japan (1973) 112 - 1 (median) - FAO/WHO (1981)
Japan (1974) 131 - 1 (median) - FAO/WHO (1981)
Japan (1975) 49 - 1 (median) - FAO/WHO (1981)
Japan (1976) 31 - 0.3 (median) - FAO/WHO (1981)
Japan (1977) 13 - 0.2 (median) - FAO/WHO (1981)
Japan (1978) 26 - 2 (median) - FAO/WHO (1981)
-------------------------------------------------------------------------------------------------------

Table 4. (contd.)
-------------------------------------------------------------------------------------------------------
Heptachlor and heptachlor
epoxide content in^b

Area/year Number of Fat (%) Whole milk Milk fat Reference
samples (mean) (µg/litre) (mg/kg)
(% positive)
-------------------------------------------------------------------------------------------------------
ASIA (contd.):
Japan (1979) 33 - 0.5 (median) - FAO/WHO (1981)
Japan (36 prefect- 398 (42%) - 1.1 - Hayashi (1972b)
ures) (1971)

EUROPE:
Austria
Vienna (1977-78) 20/182 2.6 - 0.010/0.013 Gyimothi (1979); FAO/WHO
(1981)
Belgium
Belgium (1968) 20 (20%) - 2 (1 - 3) - Heyndrickx & Maes (1979)
Brussels (1976) 24 (100%) - 8.2 (2 - 24) 0.35 Van Haver et al. (1977)
(0.07 - 0.15)
North Belgium (rural 34 (100%) - 12.2 0.61 Van Haver et al. (1977)
area) (1976) (2 - 75) (0.09 - 0.84)
South Belgium (urban 20 (100%) - 1.4 (1 - 11) 0.11 Van Haver et al. (1977)
area) (1976) (0.02 - 3.0)
South Belgium (rural 24 (100%) - 1.3 (1 - 5) 0.16 Van Haver et al. (1977)
area) (0.07 - 0.17)

Denmark
Copenhagen (1982) 4^c/36 (100%) 2.9 - 0.05 Orbaek (1982)
(0.02 - 0.07)
France
France (1971-72) ^c - - 0.280 Luquet et al. (1975)
(0.06 - 1.30)
Lille (1970) 49c (27%) - 7 - Luquet et al. (1972)
Strassbourg 65 (20%) - - 0.08 De Bellini et al. (1977)
(1974-75)

Germany, Federal
Republic of
Bayern (1973-74) 137 (23.4%) 2.3 3 (1 - 7) 0.14 Rappl & Waiblinger
(0.03 - 0.37) (1975)
-------------------------------------------------------------------------------------------------------

Table 4. (contd.)
-------------------------------------------------------------------------------------------------------
Heptachlor and heptachlor
epoxide content in^b

Area/year Number of Fat (%) Whole milk Milk fat Reference
samples (mean) (µg/litre) (mg/kg)
(% positive)
-------------------------------------------------------------------------------------------------------
Germany, Federal 320 - - 0.11/0.94 DFG (1978); FAO/WHO
Republic of (1973-74) (0.01 - 0.63) (1981)
Germany, Federal 68 - - 0.03 (median) FAO/WHO (1981)
Republic of (1976)
Germany, Federal 654 - - 0.06/0.03 DFG (1978); FAO/WHO
Republic of (1976-77) (0.01 - 0.20) (1981)
Germany, Federal 494 - - 0.03 (median) FAO/WHO (1981)
Republic of (1977)
Germany, Federal 147 - - 0.03 (median) FAO/WHO (1981)
Republic of (1977)
Germany, Federal 435 - - 0.017 /median) FAO/WHO (1981)
Republic of (1978)
Germany, Federal 374 - - 0.014/1.008 FAO/WHO (1981); Heeschen
Republic of (1979) (0.001 - 0.20) & Tolle (1981)
Kiel (1971) 99 - - 0.34 Heeschen (1972)
(0.04 - 1.91)
Kiel (1971) 99 - - 0.10^c (0 - 0.49) Heeschen (1972)
Italy
Milano (1975) 30 (100%) 2.6 - 0.12 Cerutti et al. (1976)
(0.02 - 0.31)

Luxembourg (1973) 12 - - 0.15 (median) Gatti et al. (1974)
(0.01 - 0.33)

Netherlands
Leiden (1969) 50 (100%) 1.9 1.2 ± 0.7 0.06 ± 0.03 Tuinstra (1971)
(0.3 - 3.5) (median)
(0.03 - 0.15)
8 regions (1972) 202 3.4 3 (median) 0.08 ± 0.04/0.08 Wegman & Greve (1974);
FAO/WHO (1981)
Norway
Oslo (1975) 50 (36%) - 1.6 - Bakken & Seip (1976)
(0.6 - 2.6)
------------------------------------------------------------------------------------------------------- (0- 14)

Table 4. (contd.)
-------------------------------------------------------------------------------------------------------
Heptachlor and heptachlor
epoxide content in^b

Area/year Number of Fat (%) Whole milk Milk fat Reference
samples (mean) (µg/litre) (mg/kg)
(% positive)
-------------------------------------------------------------------------------------------------------
Spain
Madrid (1981) 20 - 1^e - Baluja et al. (1982)
Madrid (1981) 20 (77%) - 4 ± 4 Baluja et al. (1982)
(0 - 14)
Rural area (1979) 21 (100%) - - 2.56^e Lora et al. (1979)
(0.41 - 10.8)
Rural area (1979) 21 (9.5%) - - 0.017 (0 - 0-30) Lora et al. (1979)
Urban area (1979) 24 (100%) - - 2.46^e Lora et al. (1979)
(0.62 - 11.7)
Urban area (1979) 24 (12.5%) - - 0.051 (0 - 1.00) Lora et al. (1979)
Spain Total (1979) 45 - 39^e 2.51^e Lora et al. (1979)
Spain Total (1979) 45 - 0.3 0.035 Lora et al. (1979)

Switzerland
Basel (1971) 50 - - 0.07 Schüpbach & Egli (1979)
(0.02 - 0.45)
Basel (1978) 50 - 0.8 (median) 0.03 Schüpbach & Egli (1979);
(< 0.01 - 0.11) FAO/WHO (1981)
Switzerland (1973) 15 - 1 (median) - FAO/WHO (1981)
Switzerland (1974) 6 - 0.5^e - FAO/WHO (1981)
(median)
3 (median)
-------------------------------------------------------------------------------------------------------
^a From: Jensen (1983).
^b Results are expressed as means ± SD/medians, and ranges are listed in parentheses.
^c Pooled samples.
^d Colostrum.
^e Heptachlor.

5. KINETICS AND METABOLISM

5.1. Animal Studies

Heptachlor is readily absorbed via all routes of exposure,
and is readily metabolized to heptachlor epoxide by mammals (Hayes,
1963). Heptachlor epoxide is metabolized slowly and is the most
persistent metabolite; it is mainly stored in adipose tissue, but
also in liver, kidney, and muscle (FAO/WHO, 1967). Klein et al.
(1968) showed that the metabolism of heptachlor in rats gave rise
to heptachlor epoxide and a hydrophilic metabolite, 1-exo-
hydroxychlordene epoxide. Heptachlor epoxide was found in tissues,
urine, and faeces, while the hydrophilic metabolite was only
detected in the urine. In rabbits, approximately 80% of the
urinary radioactivity was derived from the hydrophilic metabolite
and 20% from the epoxide. Mizyukova & Kurchatov (1970) found
heptachlor epoxide following intragastric administration of
heptachlor to female albino rats. Matsumura & Nelson (1971)
isolated another metabolite from rat faeces which they identified
as a dehydrogenated derivative of 1-hydroxy-2,3-epoxychlordene.
Rats fed diets containing 30 mg heptachlor/kg were shown to have
maximum heptachlor epoxide concentrations in adipose tissue within
2 - 4 weeks. Twelve weeks after cessation of exposure, heptachlor
had completely disappeared from the adipose tissue (Radomski &
Davidow, 1953). The highest concentrations of heptachlor epoxide
were found in adipose tissue; markedly lower amounts were found in
the liver, kidney, and muscle, and none in the brain. A similar
pattern of distribution was found in the dog (Radomski & Davidow,
1953). Mizyukova & Kurchatov (1970) gave a single dose of 120 mg
heptachlor/kg body weight to female albino rats. Heptachlor was
found in all organs 1/2 - 1 h later. During 3 - 6 months, the
heptachlor epoxide level in adipose tissue remained unchanged.
During the first 5 days, excretion was mainly via the
gastrointestinal tract.

The accumulation of heptachlor epoxide in the adipose tissue of
laying hens was demonstrated by Kan & Tuinstra (1976). The
accumulation ratio (level in adipose tissue/level in feed) was 6
for heptachlor.

Broiler chickens were fed heptachlor in concentrations of 0.01,
0.03, 0.1, and 0.3 mg/kg diet for the first 8 weeks of life.
Residue concentrations in adipose tissue increased rapidly in the
first 2 weeks and then tended to form a plateau at concentrations
about five times higher than those in the diet. Residue
concentrations decreased by about half in the first 4 weeks after
cessation of exposure (Wagstaff et al., 1980). When groups of cows
were fed heptachlor at doses of 0.5 - 2.0 mg/cow per day for a
period of 8 weeks, the level of heptachlor epoxide in the adipose
tissue was found to be below 0.1 mg/kg (Vreman et al., 1977).
Phenobarbital pretreatment significantly enhanced the metabolism of
heptachlor in rats. It caused a 6 to 11-fold increase in the liver
heptachlor epoxidase activity (Miranda et al., 1973).

5.2. Human Studies

Although there is no direct evidence showing the conversion of
heptachlor to its epoxide in human beings, there is little doubt
that the epoxide that has been found in human tissues is derived
from heptachlor. Some levels of heptachlor epoxide in the blood
and fat of human beings from various countries are presented in
Table 5. Ritcey et al. (1973) noted that the heptachlor epoxide
levels in young Canadians were significantly lower than those in
the older group surveyed. Kutz et al. (1977) reported that, in the
USA, there was little racial difference in the levels of heptachlor
epoxide and other organochlorine compounds in human adipose tissue.
Studies carried out by Zavon et al. (1969) and Curley et al. (1969)
suggested that, in the USA at that time, trace quantities of
heptachlor were found in the adipose tissue of stillborn and
newborn babies at autopsy, and that the levels were slightly lower
than those found in the adult population.

Abbott et al. (1968) revealed that the levels of organochlorine
pesticides including heptachlor epoxide in males from Britain were
higher than those in females and that the levels compared
favourably with other countries in which similar surveys had been
done.

A study by Van Haver et al. (1978) on 29 samples of adipose
tissue from men and 44 from women showed average residue levels of
0.19 and 0.20 mg/kg in males and females, respectively.

The mean value of heptachlor epoxide in 60 post-mortem samples
of adipose tissue was 0.380 mg/kg. Comparison with results
performed 6 and 9 years earlier showed an increase in heptachlor
epoxide levels (Dejonckheere et al., 1978).

There is limited information available on blood levels of
heptachlor epoxide, but it has been confirmed that levels in the
blood are several orders of magnitude lower than those found in
adipose tissue.

Because of its high lipid content, milk is one of the major
excretion routes for organohalogenated compounds, including
heptachlor epoxide. An extensive survey carried out in the USA
indicated that women who had lactated after several births had
lower pesticide levels in milk than primiparae (Savage, 1976).
Heptachlor epoxide, together with DDT, dieldrin, and oxychlordane
were the most common pesticides found in human milk (Savage, 1976).
Whole milk had much higher levels of organochlorines than colostrum
and this finding was attributed to the higher lipid content of
whole milk (Miller et al., 1979).

The distribution of heptachlor epoxide, in mg/kg, in tissues
obtained from autopsied stillborn infants was: adipose tissue,
0.32; spinal cord, not detected (ND); brain, 0.13; adrenals, 0.73;
lungs, 0.17; heart, 0.80; liver, 0.68; kidney, 0.70; spleen, 0.35;
pancreas, ND; umbilical cord blood, 0.0011 (Curley et al., 1969).

Table 5. Concentrations of heptachlor epoxide in human blood and adipose tissue
--------------------------------------------------------------------------------------
Country Number Blood Adipose Tissue Reference
of (µg/kg) (mg/kg)
samples
--------------------------------------------------------------------------------------
Argentina 52 0 - 0.73 Garcia Fernandez et al. (1975)
Argentina 0.2 (m) Astolfi et al. (1973)
Argentina 0.16 (f) Astolfi et al. (1973)
Argentina 36 0.34 0.19 Garcia Fernandez et al. (1975)

Australia 185 0-95 (5.5) Siyali (1972)
Australia 52 0-64 (3.1) 0 - 0.73 Siyali (1972)
Australia 81 ND - 0.5 Siyali (1972)

Canada 32 0.004 - 1.81 Larsen et al. (1971)
Canada 221 0.01 - 0.2 (0.04) Ritcey et al. (1973)

Denmark 0.12 Jensen & Clausen (1979)
Denmark 0.08 Jensen & Clausen (1979)

England (0 - 0.40) 0.045 (m) Abbott et al. (1968)
England (0 - 0.08) 0.032 (f) Abbott et al. (1968)

USA 1092 0.08 - 0.7 (0.09) Kutz et al. (1977)
USA 52 ND - 0.563 (0.173) Zavon et al. (1969)
--------------------------------------------------------------------------------------

6. STUDIES ON EXPERIMENTAL ANIMALS

Because of the rapid transformation of heptachlor into
heptachlor epoxide in the mammalian body, the toxicity data
concerning the two substances will be discussed together.

The toxicity and the residue data on heptachlor including
some unpublished studies have been reviewed several times by
international bodies such as FAO/WHO, IARC, IRPTC, and CEC. For
their conclusions, refer to section 8.4.

The USSR literature on the toxicity of heptachlor has been
reviewed by IRPTC (1982).

6.1. Short-Term Exposures

The acute toxicity of heptachlor in several animal species
according to different routes of exposure, is summarized in Table
6. The symptoms associated with heptachlor poisoning include
hyper-excitability, tremors, convulsions, and paralysis. Liver
damage may occur as a possible late manifestation (Gleason et al.,
1969).

The acute toxicity of heptachlor epoxide is greater than that
of heptachlor; for instance, the intravenous lethal doses for
heptachlor and heptachlor epoxide are 40 and 10 mg/kg body weight,
respectively (FAO/WHO, 1967).

The acute oral LD₅₀ values of 4 other heptachlor metabolites
(chlordene, 3-chlordene, 1-hydroxychlordene, and chlordene epoxide)
were found to be greater than 4600 mg/kg body weight (Mastri et
al., 1969).

When technical grade heptachlor was fed to broiler chickens
during the first 8 weeks of life at dietary levels up to 0.3 mg/kg,
no adverse effects on health were observed (Wagstaff et al., 1977).

Heptachlor was fed to adult male rats at a level of 20 mg/kg
diet for 12 weeks (Shain et al., 1977). Effects were noted on body
weight gain and food consumption and the cytoplasmic androgen
receptors of the ventral prostate were less numerous than in
controls.

Rats fed heptachlor at 0, 5, or 10 mg/kg body weight for 8
months showed proliferation of the smooth endoplasmic reticulum and
an increased number of mitochondria in liver cells, even at 5 mg/kg
(Stemmer & Hamdi, 1964).

Table 6. Acute toxicity of heptachlor
-------------------------------------------------------------------
Species Sex Route of LD₅₀(mg/kg Reference
administration body weight)
-------------------------------------------------------------------
rat M oral 40 NIOSH (1978)

rat M oral 100 Hayes (1963)

rat F oral 162 Hayes (1963)

rat M dermal 195 Hayes (1963)

rat F dermal 250 Hayes (1963)

rat NS dermal 119 NIOSH (1978)

rat NS ip 27 NIOSH (1978)

rat NS percutaneous 195 - 250 FAO/WHO (1963)

rat NS oral 80 - 90 Gleason et al.
(1969)

mouse NS oral 68 NIOSH (1978)

mouse NS iv 40 FAO/WHO (1967)

rabbit NS oral 80 - 90 Gleason et al.
(1969)

guinea-pig NS oral 116 NIOSH (1978)

hamster NS oral 100 NIOSH (1978)

chicken M oral 62 Sherman & Ross
(1961)
-------------------------------------------------------------------

6.2. Long-Term Exposures

Rat

Four groups of 10 male and 20 female rats were given daily oral
doses of pure heptachlor, at 0, 5, 50, or 100 mg/kg body weight,
starting at about 4 months of age (Pelikan et al., 1968).
Administration was continued for 200 days or until the animals
died. By the tenth day, all the animals in the groups fed 50 or
100 mg/kg had died. On day 200, the surviving animals in the 5
mg/kg group and the control group were sacrificed for autopsy.
Prior to death, the 50 and 100 mg/kg groups became irritable and
had accelerated respiration by the second day. Convulsions
preceded deaths. In the group given 5 mg/kg, no clinical
abnormalities were seen until the 50th day, when hyper-reflexia,
dyspnoea, and convulsions were observed. Two males and two females

in this group died before completion of the study, compared with
only one female in the controls. Weight gain was not affected by
administration of 5 mg/kg. Gross pathology revealed changes in the
liver, kidney, and spleen. Histological examination showed fatty
degeneration of the liver cells and moderate fatty infiltration of
the epithelium of the renal tubules, as well as hyperplasia of the
smooth endoplasmic reticulum of the parenchymatous cells of the
liver in the group fed 5 mg/kg.

The addition of heptachlor (up to 45 mg/kg diet) or its epoxide
(up to 60 mg/kg) or both to the diet of rats for 140 days produced
microscopic liver changes, e.g., enlarged centrilobular cells
showing big nuclei with prominent nucleoli, cytoplasmic fat
droplets, and occasional cytoplasmic margination (Stemmer & Jolley,
1964). In a study involving 269 rats, it was demonstrated that
these changes regressed after withdrawal of the pesticide.
Electron microscopic studies demonstrated an increase in rough and
smooth endoplasmic reticulum (Stemmer & Hamdi, 1964).

Groups of 10 rats (males or females) were fed diets containing
heptachlor epoxide at 5, 10, 20, 40, 80, 160, or 300 mg/kg for 2
years (Velsicol Corp., unpublished data, 1959). Concentrations of
80 mg/kg or higher resulted in 100% mortality in 2 - 20 weeks. All
the female animals given 40 mg/kg died within a period of 54 weeks.
This concentration had no effect on the mortality of the male
animals up to 104 weeks. Diets containing 20 mg/kg or less did not
produce any signs of illness in male or female rats during a 2-year
period, but an increase in liver weight was observed in male rats
dosed with more than 10 mg/kg and in females administered 5 mg/kg.

In groups of 20 CFW strain rats fed heptachlor epoxide in the
diet at 10, 20, and 40 mg/kg for 2 years, significant increases in
mortality were observed only in females at the 40 mg/kg level
(Velsicol Corp., unpublished data, 1959). Liver weights in the
females were slightly increased. Tumour incidence was lower in the
treated groups than in the controls and was independent of the
content of heptachlor epoxide in the diet.

Groups each comprising 25 male and 25 female rats were fed 0,
100, 250, 500, 1000, or 2000 mg of the heptachlor metabolite 1-
hydroxychlordene per kg diet for up to 224 days (Ingle, 1965). A
rat of each sex was sacrificed at intervals for autopsy. After
receiving the test diet for 110 days, 3 females from each dose
level were selected and mated with males from the same dose level.
Growth and food consumption were normal at all levels, and
mortality appeared to be unaffected by the test compound. At 2000
mg/kg, the compound may have produced intestinal irritation.
Within the one generation, no adverse effects were observed on
fertility, litter size, litter weight, or survival and growth of
the young at any dose level. Gross pathological findings were
limited to one hepatoma in a female fed 2000 mg/kg and one in a
male fed 500 mg/kg; one female at 100 mg/kg had a parotid gland
tumour. A breast tumour was seen in a control animal.
Histopathology revealed changes in the liver only, which, at 1000
and 2000 mg/kg, showed slight to moderate cytoplasmic margination;

this was also evident, to some extent, in the controls and lower-
level groups. It was doubtful whether the hepatic cell enlargement
that occurred was related to 1-hydroxychlordene.

The Joint Meeting on Pesticide Residues (JMPR) reviewed the
toxicity data on heptachlor in its 1970 meeting (FAO/WHO, 1971) and
concluded on the following "no-effect-levels":

- rat: 5 mg/kg diet (equivalent to 0.25 mg/kg body
weight per day); and

- dog: 2.5 mg/kg diet (equivalent to 0.06 mg/kg body
weight per day).

Dogs

Heptachlor administered orally to dogs at 5 mg/kg per day
caused all the animals to die within 21 days; at 1 mg/kg per day, 3
out of 4 dogs died within 424 days, and one was still living at 455
days (Lehman, 1952b).

Three dogs given heptachlor epoxide orally, at 2, 4, or 8 mg/kg
body weight per day for 5 days a week, died after 22, 10, and 3
weeks, respectively. Daily oral doses of 0.25 and 0.5 mg/kg body
weight did not produce any signs of illness during 52 weeks, but
0.25 mg/kg, estimated to be equivalent to 6 mg/kg diet, was
reported to be the minimal dose producing a pathological effect
(Velsicol Corp., unpublished data, 1959).

Diets containing 0.5, 2.5, 5.0, or 7.5 mg heptachlor epoxide
per kg diet were given to groups of 5 dogs (2 males and 3 females,
23 - 27 weeks of age) for 60 weeks (Velsicol Corp., unpublished
data, 1959). No deaths attributed to heptachlor epoxide occurred.
The weights of the male dogs increased in inverse proportion to the
concentration of the compound in the diet. The weights of the
females were normal. Liver weights were increased at 5 mg/kg and
above. Degenerative liver changes were seen in only 1 dog at 7.5
mg/kg diet.

Pigs

Pigs were dosed orally with heptachlor at levels of 2 or 5
mg/kg per day for up to 78 days (Dvorak & Halacka, 1975).
Ultrastructural changes were observed in the liver of the low-dose
group, after 78 days. These changes consisted of glycogen
depletion and proliferation of agranular endoplasmic reticulum. At
the higher dose level, similar changes were seen as early as 27
days after the start of exposure.

6.3. Reproduction Studies and Teratogenicity

The continuous exposure of rats to doses of either heptachlor
or its epoxide exceeding 7 mg/kg increased the mortality rate of
the pups during the suckling period, though 10 mg/kg fed to 3
generations of rats did not produce any adverse effects on
reproductive capacity, growth, or survival (Witherup et al.,
unpublished data, 1955).

Male and female rats fed exclusively on diets containing a
mixture of heptachlor and heptachlor epoxide (3:1) at 0, 0.3, 3,
or 7 mg/kg were mated throughout three succeeding generations
(Witherup et al., 1976a). The number of pregnancies in the F₁ and
F₂ generations was slightly reduced in the 0.3 mg/kg group, but not
in the higher dose level groups. There was a slight increase in
the mortality rate of the pups in the second and third week after
birth in the 3 mg/kg group. The compound did not exert any
statistically significant effect on the fertility of the
progenitors or the ability of the progeny to survive.

In a study by Witherup et al. (1976b), male and female rats
were fed exclusively on diets containing heptachlor at 0, 0.3, 3,
6, or 10 mg/kg throughout three generations, and allowed to
reproduce (Witherup et al., 1976b). Mortality of the pups was
slightly increased in the 10 mg/kg group during the second and
third weeks after birth, only in the 2nd generation. No adverse
effects were reported at the lower dose levels.

The feeding of rats at 1 - 10 mg/kg body weight per day during
a 3-generation reproduction study resulted in an increased number
of resorptions and in lower viability and lactation indices (Cerey
& Ruttkay-Nedecka, 1971; Ruttkay-Nedecka et al., 1972). Cataracts
were observed in test animals. Heptachlor has also been shown to
block or shorten the estrous cycle in rats (Cerey et al., 1977).

In a 3-generation reproduction study, a group of 80 rats was
given heptachlor at 6.9 mg/kg body weight, daily, for 3 months
before mating (FAO/WHO, 1967a). Cataracts were found in 6.8% of
the young and became obvious between the 19th and 26th day after
birth. Among the parents, 15.2% of the animals were affected,
and the lesions appeared after 4 - 9 months. Another effect was a
decrease in litter size.

Twenty-four male and 24 female adult beagle dogs were used for
a 2-generation reproduction and teratology study with heptachlor
epoxide. The treated dogs were fed the compound at 1, 3, 5, 7, or
10 mg/kg diet. No differences in body weight or food consumption
were seen between control and treated dogs. All but one of the F₁
pups at the 10 mg/kg dietary level died between birth and 10 weeks
of age. Abnormal haematological values were reported in some pups
at the 1, 3, and 7 mg/kg levels. Elevated liver enzyme values were
also noted in some animals at the 3, 5, and 7 mg/kg levels. No
compound-related abnormalities were observed in pups from the F₁
and F₂ generations. An increase in liver weight among P₂(F₁) dogs
from the 7 mg/kg level was the only organ weight variation

considered compound related. Finely granular "ground glass"
cytoplasm in liver parenchymal cells of some P₂(F₁) dogs at the
5, 7, and 10 mg/kg dietary levels was also reported (IRDC, 1973).

Pregnant female rabbits were treated orally with heptachlor
epoxide at 0 (22 animals) or 5 mg/kg body weight/day (20 animals)
from day 6 to 11 of gestation (Wazeter et al., 1969) and fetuses
recovered by Caesarean section on day 28. There were no
behavioural abnormalities apparent in the offspring, and body
weight gain was not affected by heptachlor epoxide. There were no
deaths. No compound-related effects were observed with respect to
numbers of viable and non-viable term fetuses, resorptions,
implantation sites, corpora lutea, and non-gravid females. A
significant increase in fetal weight was evident in the treated
group; this increase was considered to be compound-related.
Survival time was not considered to be affected by heptachlor
epoxide. There were no teratogenic effects attributable to the
compound.

Groups comprising 4 male and 20 female chickens were fed
heptachlor epoxide dietary levels of 0, 0.02, 0.1, or 0.2 mg/kg for
25 weeks (Wolvin et al., 1969). Body weight increase was not
affected by heptachlor epoxide. Mortality rates were low in all
groups, but a slightly higher incidence occurred in the 0.2 mg/kg
group. No abnormal behaviour was observed. The total weekly egg
production and mean weekly egg weights were not significantly
different in the test and control groups. Hatchability was
slightly decreased in the groups fed 0.1 and 0.2 mg/kg; viability
of the offspring was not affected. A 12% reduction in hatchability
resulted when 1.5 mg heptachlor was injected into fertile eggs
(Smith et al., 1970); however, no abnormal chicks resulted.
Japanese quail were given heptachlor in the diet at 10 and 50 mg/kg
(Shellenberger et al., 1966). There were no obvious adverse
effects on reproduction when the birds were 10 weeks of age.

6.4. Mutagenicity

Heptachlor was shown to be non-mutagenic in Salmonella
typhimurium and Escherichia coli in the presence or absence of
rat liver microsomal preparations (Marshall et al., 1976; Moriya et
al., 1983). Heptachlor was not active in the rec assay with
Bacillus subtilis (Shirasu et al., 1976).

Heptachlor did not induce X-linked recessive lethals in post-
meiotic germ-cells from Drosophila melanogaster (Benesh & Shram,
1969).

The ip administration of heptachlor at 5.2 mg/kg body weight to
male mice caused an increase in the frequency of chromosomal
aberrations in bone-marrow cells (Markaryan, 1966).

Rats fed 1 or 5 mg/kg heptachlor diet for 3 generations showed
an increased incidence of abnormal mitosis in bone-marrow cells in
the second and third generations (Cerey et al., 1973).

After a single intraperitoneal administration of heptachlor to
albino male mice at a dose of 5.2 mg/kg body weight in oil
solution, the cytogenic analysis of bone-marrow cells, performed 21
h after administration of heptachlor revealed an increase of up to
13.75% in the incidence of nuclear lesions, and up to 9.17%, in the
incidence of chromosome aberrations (Markaryan, 1966).

After a 7-month intragastric administration of heptachlor to
albino rats at doses of 1/30, 1/50, and 1/100 of LD₅₀ (LD₅₀= 82
mg/kg body weight), it was established that heptachlor doses of
1/30 and 1/50 of LD₅₀ elicited changes in the mitotic activity of
bone-marrow cells, inhibition of prophase, and chromosome adhesion.
Chromosome fragments were found in a few cells. A heptachlor dose
of 1/100 of the LD₅₀ exerted a slight effect on rat bone-marrow
cells (Kulakov & Efimenko, 1974).

Male mice dosed either orally or intraperitoneally with a
mixture of heptachlor and heptachlor epoxide (1:3) at levels of 7.5
or 15 mg/kg body weight failed to show any dominant lethal response
(Arnold et al., 1977).

Heptachlor was also negative in tests designed to monitor
testicular DNA synthesis in mice (Seiler, 1977) and in in vitro
breakage of plasmid DNA in E. coli (Griffin and Hill, 1978).

More recent studies on animal and human cells in culture have
shown that heptachlor is not mutagenic or only weakly mutagenic
(Maslansky & Williams, 1981; Tong et al., 1981). Further work by
Telang et al. (1982) showed that heptachlor was not mutagenic to an
adult rat liver cell line but inhibited cell to cell communication
in a rat liver 6-thioguanine resistant/sensitive cell line. Telang
et al. (1982) proposed that heptachlor was exhibiting properties
exerted by many promoting agents.

6.5. Carcinogenicity

CFN rats were fed heptachlor epoxide in the diet at
concentrations of 0.5, 2.5, 5, 7.5, or 10 mg/kg (FAO/WHO, 1967).
No differences were observed among the 5 experimental groups, and
the results can be considered together for all the test animals.
The incidence of tumour-bearing animals was 8/23 (34%) and 13/24
(54%) in the control males and females, respectively, and 65/111
(58%) and 92/114 (80%) in the test groups of males and females,
respectively. Again, many tumours were located in endocrine
organs. Liver tumours were observed in 7 males and 12 females in
the test groups only (overall incidence 19/225, i.e., 8.4%). Only
2 of the liver tumours were malignant.

Heptachlor dissolved in ethanol was added to the diet of CF
rats at 1.5, 3, 5, 7, and 10 mg/kg for 110 weeks. Each group
included 40 animals (20 of each sex). Mortality rates were
comparable in all groups. The number of tumour-bearing animals was
16/40 at 0 mg/kg, 9/40 at 1.5 mg/kg, 13/40 at 3 mg/kg, 12/40 at 5
mg/kg, 15/40 at 7 mg/kg, and 12/40 at 10 mg/kg. Most tumours were
found in the pituitary and other endocrine organs. No liver

tumours were recorded. No preferential tumour site was observed in
any particular group except for 4 thyroid tumours that were
observed in the 7 and 10 mg/kg groups (Witherup et al., unpublished
data, 1955).

In a study carried out on a total of 154 female rats, a
mixture of heptachlor and heptachlor epoxide (3:1) was added to the
diet at 0, 5, 7.5, 10, and 12.5 mg/kg, for 2 years (Velsicol Corp.,
unpublished data, 1959). Pituitary and mammary tumours were seen
at all dose levels and in the controls; the incidence of the
tumours varied from group to group but was not dose-related. At
the end of the 2 years, all groups including the controls showed
histological changes in the liver, i.e., hypertrophy, cytoplasmic
margination, and the appearance of lipid vacuoles in the
centrilobular cells. The severity of the changes was related to
the dose. At 12.5 mg/kg, regenerative liver changes were present.
The no-observed-adverse-effect level was 5 mg/kg.

Wistar rats were given 5 doses of heptachlor in corn oil by
stomach tube, at 10 mg/kg body weight, every second day, starting
at 10 days of age, until they were sacrificed (Cabral et al.,
1972). A sub-group of animals was sacrificed at 60 weeks of age,
the other sub-group between 106 and 110 weeks. Growth and survival
rates were similar in both test and control groups; the incidence
of tumours at different sites in males and females was comparable
in both groups.

Heptachlor was tested for carcinogenicity in Osborne-Mendel
rats by the National Cancer Institute (1977). Technical grade
heptachlor containing 72% heptachlor, 18% gamma-chlordane,
2% alpha-chlordane, 2% nonachlor, 1% chlordene, 0.2%
hexachlorobutadiene, and other minor impurities, was fed in the
diet at time-weighted average doses of 38.9 and 77.9 mg/kg for
male rats, and 25.7 and 51.3 mg/kg for female rats. All surviving
rats were killed at 110 - 111 weeks. Rats treated with high levels
of heptachlor showed decreased body weight gain. Mortality rates
were dose-related in female rats. No hepatic tumours were observed
in rats administered heptachlor. A statistically significant dose-
related trend in proliferative follicular-cell lesions of the
thyroid was found. The trend towards follicular-cell carcinomas
combined with adenomas was significant for the females. The trend
towards follicular-cell lesions remained significant when pooled
controls were used instead of matched controls and when the data
were subjected to life-table adjustment. It was concluded from
this study that heptachlor possibly caused thyroid tumours in rats
(NCI, 1977), notwithstanding the fact that in the judgement of the
(NCI) pathologist, the nature, incidence, and severity of the
proliferative thyroid lesions were not sufficient to indicate
clearly a carcinogenic effect of heptachlor on rats.

Epstein (1976) reported a study carried out by the FDA in 1965
in which male or female C3H mice were fed heptachlor or heptachlor
epoxide for 24 months. The incidences of hepatic nodular
hyperplasia and benign hepatomas were doubled in mice treated with
heptachlor and heptachlor epoxide. The incidence of hepatic

carcinomas was the same in heptachlor-treated and control groups,
but double in the group administered heptachlor epoxide. Following
histological re-evaluation, a significant excess of liver
carcinomas was found in males and females treated with heptachlor
or heptachlor epoxide. When all the malignant tumours were
considered, the incidence in the controls was approximately twice
that of the two test groups.

Epstein (1976) also reviewed an unpublished study carried out
in 1973 by the International Research and Development Corporation
(IRDC) under contract to the Velsicol Chemical Corporation, where
male and female Charles River CD-1 mice were fed a mixture of 75%
heptachlor epoxide and 25% heptachlor at levels of 1, 5, or 10
mg/kg diet for 18 months. A dose-related incidence of liver
tumours was observed in the test groups. Histological re-
evaluation showed an excess of liver carcinomas in females fed 10
mg/kg and in males fed 5 or 10 mg/kg.

In the 1977 study reported earlier, groups of B6C3F1 mice were
fed a technical mixture of heptachlor in the diet for 80 weeks at
time-weighted concentrations of 6 and 14 mg/kg. Liver carcinomas
were found in 34/47 males and 30/42 females receiving the higher
dose and in 11/46 males and 3/47 females in the lower dose groups.
It was concluded that heptachlor is carcinogenic for the liver of
mice.

A committee of the National Academy of Sciences (NAS) in the
USA was asked to review all available carcinogenicity data on
heptachlor as part of the cancellation hearings. Heptachlor was
found not to be carcinogenic in rats and the target organ site
for carcinogenic response in certain strains of mice was confined
to the liver. The committee concluded that "there are no adequate
data to show that these compounds are carcinogenic in humans, but
because of their carcinogenicity in certain mouse strains and the
extensive similarity of the carcinogenic action of chemicals in
animals and in humans, the committee concluded that chlordane,
heptachlor and/or their metabolites may be carcinogenic in humans.
Although the magnitude or risk is greater than if no
carcinogenicity had been found in certain mouse strains, in the
opinion of the committee the magnitude of risk cannot be reliably
estimated because of the uncertainties in the available data and in
the extrapolation of carcinogenicity data from laboratory animals
to humans" (NAS, 1977).

IARC (1979) in its evaluation of the carcinogenic risk from
exposure to heptachlor concluded: "There is sufficient evidence
that heptachlor is carcinogenic in mice." In 1982, another IARC
working group reviewed existing data on heptachlor and concluded
that there was limited evidence for the carcinogenicity of
heptachlor for experimental animals (IARC, 1982). Telang et al.
(1982) suggested that heptachlor had the properties of many
promoting agents.

6.6. Other Studies

Heptachlor, when administered to rats at 1 or 5 mg/kg diet for
3 generations, caused changes in their EEG spectra (Formanek et
al., 1976). Heptachlor has been shown to inhibit oxidative
phosphorylation in rat liver mitochondria (Nelson, 1975), to
increase serum esterase (EC 3.1) activity (Crevier et al., 1954),
and to induce hepatic mixed-function oxidases in rats (Krampl et
al., 1973; Den Tonkelaar & Van Esch, 1974; Krampl & Hladka, 1977;
Madhukar & Matsumura, 1979). With respect to the latter,
heptachlor was able to induce both aniline hydroxylase (EC 1.14.14)
and aminopyrine demethylase (EC 1.5.3) activity at levels as low as
2 mg/kg diet fed for a 2-week period (Den Tonkelaar & Van Esch,
1974). Work carried out in the USSR on the influence of heptachlor
on hepatic enzyme systems is reported in Onikienko & Petrun (1962)
and Petrun (1962).

Age was a modifying factor for the acute toxic effects of
heptachlor. Heptachlor was less toxic in newborn rats than in
adult rats (LD₅₀ newborn rat, 531 mg/kg; LD₅₀ adult, 71 mg/kg)
(Harbison, 1973, 1975). Phenobarbital enhanced the acute toxicity
of heptachlor in newborn rats (Harbison, 1973).

Heptachlor was less toxic in rats fed a dietary protein level
of 10% with unsupplemented gluten, than in animals fed diets
containing gluten plus amino acids or casein plus 0.2% DL-
methionine (Webb & Miranda, 1973). When the dietary protein level
was raised to 18%, heptachlor was twice as toxic for treated
animals compared with animals fed unsupplemented gluten.

7. EFFECTS ON MAN

7.1. General Population Exposure

There is no information on cases of accidental or suicidal
poisoning, and no adverse effects due to heptachlor have been
reported in the general population.

7.2. Occupational Exposure and Epidemiological Studies

After reviewing 25 previously-reported cases of blood dyscrasia
together with a small number of newly identified cases of aplastic
anaemia, leukaemia, or neuroblastoma in children in relation to
their possible association with chlordane or heptachlor exposure,
Infante et al. (1978) reported an anecdotal relationship. However,
in a case-control study, no association between blood dyscrasias
and occupational exposure to heptachlor was found (Wang &
Grufferman, 1981).

Wang & MacMahon (1979a,b) studied one cohort of workers engaged
in the manufacture of chlordane, heptachlor, and endrin and another
cohort of approximately 16 000 pesticide-spraying personnel,
including termite control workers. Both studies showed a deficit
of deaths from all cancers but small non-statistically significant
excesses of lung, skin, or bladder cancer.

In 1982, an IARC Working Group concluded that the above studies
were inadequate to evaluate the carcinogenicity of heptachlor for
human beings (IARC, 1982).

Shindell (1981) studied the mortality experience of 783 workers
engaged in the manufacture of chlordane and heptachlor. Workers
must have had a minimum of 3 months work experience during 1946-76.
No increase in mortality rate due to cancer was observed among 124
deaths. Taking into account length of employment (5, 10, 15, 20
years), SMRs for cancer were not increased.

In a retrospective cohort study on workers involved in the
production of chlorinated hydrocarbon pesticides, Ditraglia et al.
(1981) studied the workers in a plant manufacturing heptachlor;
these workers were also studied by Wang & MacMahon (1979a). SMRs
for all cancer deaths were lower than expected. The number of
workers studied was small and further follow-up of the cohort was
recommended by the authors.

MacMahon & Wang (1982) carried out a second follow-up study of
mortality rates in a cohort of pesticide-spraying personnel,
including termite control workers. Among 540 deaths for which the
cause was ascertainable, small excesses of bladder cancer in
termite operators and of skin and lung cancer in other operators
were observed, but these were not statistically significant.

In a follow-up mortality study of workers engaged in the
production of heptachlor from 1952-79, the vital status of 207
production workers was ascertained and records were obtained for
90.8% of the population. Three deaths had occurred, none from
cancer. No unusual morbidity was observed in persons still living
(Shindell & Associates, 1981).

7.3. Treatment of Poisoning

In case of overexposure, medical advice should be sought
forthwith.

(a) Treatment before person is seen by a physician

The person should stop work immediately. Contaminated clothing
should be removed, and the affected skin washed with soap and
water, if available, and flushed with large quantities of water.
If swallowed, vomiting should be induced, if the person is
conscious (WHO/FAO, 1975).

(b) Medical treatment

If the pesticide has been ingested, gastric lavage should
be performed with 2 - 4 litres of tap water followed by saline
purgatives (30 g sodium sulfate in 250 ml of water). Barbiturates
(preferably phenobarbitone or pentobarbitone) or diazepam should
be given im or iv in sufficient dosage to control restlessness or
convulsions. Mechanical respiratory assistance with oxygen may be
required. Calcium gluconate, 10% in 10 ml, should be injected iv
four hourly. Contraindicated are oily purgatives, epinephrine, and
other adrenergic drugs and central stimulants of all kinds
(WHO/FAO, 1975).

8. EFFECTS ON THE ENVIRONMENT

8.1. Toxicity for Aquatic Organisms

Data on the toxicity of heptachlor for aquatic organisms are
summarized in Table 7. Maximum levels of heptachlor to which
aquatic ecosystems could be exposed were calculated to be 0.0038
µg/litre as a 24-h average for salt water species, with 0.52
µg/litre maximum exposure at any time, and 0.0036 µg/litre as a 24-
h average for fresh water species, with 0.053 µg/litre maximum
exposure at any time (US EPA, 1980).

Generally, the acute toxicity of heptachlor is affected by
temperature and salinity. Eisler (1969), using 48-h tests on
the grass shrimp Palaemonetes vulgaris, showed a reduction in
mortality by increasing the salinity from 12 to 18 ^o/oo, but no
further reduction at salinities up to 36 ^o/oo. Mortality rates
increased with increasing temperature in the range 15 -30°C.
Bridges (1965) showed a relationship between temperature and 24-h
LC₅₀ in the redear sunfish. At 7.2°C, the heptachlor
concentration required to kill 50% of the fish in 24 h was
92 µg/litre; this concentration fell consistently over a range of
temperatures to 22 µg/litre at 29 °C. No clear effect of salinity
or temperature was found in studies on the mummichog Fundulus
heteroclitus (Eisler, 1970b).

Long-term exposure of fish to heptachlor usually reduces
survival at all life stages (Andrews et al., 1966; Hansen &
Parrish, 1977; Goodman et al., 1978) and induces a dose-related
growth decrease (Andrews et al., 1966). Adaptation or resistance
to heptachlor may develop since a natural population of mosquito
fish that received run-off from cotton fields treated with
pesticides were 4 times more resistant to heptachlor than newly-
exposed fish (Boyd & Ferguson, 1964).

Heptachlor at a concentration of 6.8 mg/litre in the
incubation medium was reported to give 50% inhibition of ATPase
from liver mitochondria and a concentration of 16.4 mg/litre gave
50% inhibition of Na⁺-K⁺ ATPase in bluegill brain homogenate (Yap
et al., 1975). In studies by Cutkomp et al. (1971), heptachlor at
15.6 mg/litre induced 58.6% inhibition of bluegill brain Na⁺-K⁺
ATPases, 65.6% inhibition of brain Mg²⁺ ATPase, and 66.3%
inhibition of muscle Mg²⁺ ATPase. Heptachlor induced 67%
inhibition of Na⁺-K⁺ ATPases at 37.35 mg/litre in rainbow trout
gill microsomes and 70% inhibition of Mg²⁺ ATPase (Davis et al.,
1972). Hiltibran (1974) also reported a reduction in oxygen
utilization and phosphate utilization by liver mitochondria from
bluegill at heptachlor concentrations of 37 mg/litre medium.

Table 7. Toxicity of heptachlor for aquatic organisms^a
---------------------------------------------------------------------------------------------------------
Organism Flow/ M/ Grade °C pH Sal Endpoint Para- Concen- Reference
stat U ^o/oo meter tration
(µg/litre)
---------------------------------------------------------------------------------------------------------
American flow M technical 30- 24.5- reduction 96-h 1.5 Schimmel et al.
oyster heptachlor 32 27 of shell EC₅₀ (1976a)
(Crassostrea (65%) deposition
virginica)

Cladoceran stat U 16 7.4- immobil- 48-h 42 Sanders & Cope
(Daphnia 7.8 isation EC₅₀ (1966)
pulex)

Scud, stat U technical 21 7.1 96-h 29 Sanders (1969)
2 months heptachlor LC₅₀
(Gammarus stat U 21 7.1 24-h 150 Sanders (1969)
lacustris) LC₅₀

Stonefly stat U technical 15.5 7.1 96-h 0.9 - Sanders & Cope
(naiads) heptachlor LC₅₀ 1.1 (1968)
(72%)

Hermit crab stat U heptachlor 20 8 24 96-h 55 Eisler (1969)
(Pagurus reference LC₅₀
long- stat U standard 20 8 24 24-h 470 Eisler (1969)
icarpus) LC₅₀

Pink shrimp flow M technical 27.5- 25.5- 96-h 0.11 Schimmel et al.
(Penaeus heptachlor 30 29.5 LC₅₀ (1976a)
duorarum) 44-
72 mm
---------------------------------------------------------------------------------------------------------

Table 7. (contd.)
---------------------------------------------------------------------------------------------------------
Organism Flow/ M/ Grade °C pH Sal Endpoint Para- Concen- Reference
stat U ^o/oo meter tration
(µg/litre)
---------------------------------------------------------------------------------------------------------
Fathead stat U technical 25 7.1 20^b 96-h 130 Henderson et al.
minnow heptachlor LC₅₀ (1959)
(Pimephales (72%)
promelas) stat U technical 25 8.2 400^b 96-h 78 Henderson et al.
heptachlor LC₅₀ (1959)

Bluegill stat U technical 25 7.1 20^b 96-h 26 Henderson et al.
(Lepomis heptachlor LC₅₀ (1959)
macrochirus) (72%)

American eel stat U heptachlor 20 8 24 96-h 10 Eisler (1970a)
(Anguilla LC₅₀
rostrata)

Spot flow M technical 23- 20- 96-h 0.85 Schimmel et al.
(Leiostomus heptachlor 26 21 LC₅₀ (1976a)
xanthurus) (65%)

Rainbow trout stat U technical 7.2 96-h 7.0 Macek et al.
(Salmo heptachlor LC₅₀ (1969)
gairdneri) (72%)
---------------------------------------------------------------------------------------------------------
^a A more comprehensive table listing different conditions and exposure times is available on request
from IRPTC, Geneva.
^b Hardness (mg/litre).
U = Nominal concentration.
M = Measured concentration.
Data on the toxicity of heptachlor epoxide are given in
Table 8. Heptachlor epoxide at a concentration of 16.2 mg/litre
incubation medium caused 44.9% inhibition of bluegill brain Na⁺-K⁺
ATPase, 16.7% inhibition of brain Mg²⁺ ATPase, and 46.7% inhibition
of muscle Mg²⁺ ATPase (Cutkomp et al., 1971).

8.2. Toxicity for Terrestrial Organisms

The LD₅₀s for heptachlor in birds are presented in Table 9.
These data emphasise the variability of toxicity among species.
When Japanese quail were fed heptachlor at 10 or 50 mg/kg diet from
hatch, there were no obvious adverse effects on growth after 16
weeks or on the reproductive success of these birds at 10 weeks of
age (Shellenberger & Newell, 1965). Injection of 1.5 mg
heptachlor/egg resulted in a 12% reduction in hatchability but no
abnormal chicks (Smith et al., 1970). There are no available data
on the toxicity of heptachlor for non-avian species.

Heptachlor epoxide was fed to groups of 4 male and 20 female
chickens at dietary levels of 0, 0.02, 0.1, or 0.2 mg/kg for 25
weeks (Wolvin et al., 1969). Body weight increase was not affected
by heptachlor epoxide. Mortality rates were low in all groups, and
a slightly higher mortality rate recorded for the group fed 0.2
mg/kg was of doubtful significance. No abnormal behaviour was
observed. Total weekly egg production and mean egg weights were
not affected by treatment. Hatchability was slightly decreased in
eggs from the group fed 0.1 and 0.2 mg/kg, but the viability of
hatched chicks was not affected.

8.3. Toxicity for Microorganisms

When various microorganisms, isolated from estuarine and
surface slicks, were exposed to heptachlor at concentrations up to
100 g/litre and provided with glucose as the main carbon source,
growth of two species was affected (Ahearn et al., 1977).

Table 8. Toxicity of heptachlor epoxide for aquatic organisms
-------------------------------------------------------------------------------------------------
Organism Size/ Flow/ Grade Temp pH Sal Parameter Concentration Reference
age stat (°C) ^o/oo (µg/litre)
-------------------------------------------------------------------------------------------------
Pink shrimp 62-81 flow 99% 24.2- 20 96-h LC₅₀ 0.04 Schimmel et al.
(Penaeus mm 26.5 (1976a)
duroarum)

Cladoceran 24 h stat unspec- 18-20 7.9 24-h LC₅₀ 120 Frear & Boyd
(Daphnia ified (1967)
magna)
-------------------------------------------------------------------------------------------------
Heptachlor was found to be "highly toxic" to plate cultures
of the fungus Rhizoctonia solani, even at low concentrations
(Richardson & Miller, 1960). Application of 10 µmol of heptachlor
to a liquid culture of a yeast Saccharomyces cerevisiae (haploid
strain, D273-10B) caused 100% inhibition of cell growth, when
nonfermentable energy sources were provided, and 13% inhibition
when fermentable energy sources were provided (Nelson & Williams,
1971). This suggested cell division was inhibited by specific
inhibition of oxidative metabolism. Technical heptachlor (74%
heptachlor) at 50 µg/litre caused a reduction in cell density in a
culture of the marine dinoflagellate Exuviella baltica resulting
in a reduction in chlorophyll a concentration (Magnani et al.,
1978). As levels of chlorophyll a per cell were not significantly
different in treated and untreated cultures, the observed
inhibition of C¹⁴ uptake per treated cell was probably due to
interference with chlorophyll function rather than its synthesis.

Table 9. Toxicity of heptachlor for birds
------------------------------------------------------------------------------------------
Species Sex Parameter Concentration^a Reference
(mg/kg)
------------------------------------------------------------------------------------------
Mallard, 3 months male acute oral LD₅₀ > 2000 Tucker & Crabtree (1970)

Bobwhite quail oral LD₅₀₊ 125 DeWitt & George (1960)

Bobwhite quail dietary LC₅₀ 450 - 700 Heath et al., unpublished
data (1970)

Ring-necked pheasant oral LD₅₀₊ 150 - 400 DeWitt & George (1960)

Pheasant dietary LC₅₀ 250 - 275 Heath et al., unpublished
data (1970)

Japanese quail dietary LC₅₀ 80 - 95 Heath et al., unpublished
data (1970)

Chicken, 7 - 14 days female acute oral LD₅₀ 62.4 Sherman & Ross (1961)
(New Hampshire)
------------------------------------------------------------------------------------------
^a Concentration in mg/kg body weight for oral dosing;
concentration in mg/kg diet for dietary dosing.

A haploid strain (D273-10B) of Saccharomyces cerevisiae in the
early log phase of growth was exposed to 10 µmol of heptachlor
epoxide (dissolved in dimethyl sulphoxide and added to the growth
medium) for 20 h (Nelson & Williams, 1971). Heptachlor epoxide
caused a 16% inhibition in growth when glucose (a fermentable
substrate) was the energy source provided, and a 79% inhibition
when lactate (a non-fermentable substrate) was the energy source.
This suggested that inhibition of yeast growth by heptachlor
epoxide was due to interference with oxidative metabolism.

8.4. Bioaccumulation and Biomagnification

Data on bioconcentration are summarized in Table 10. A
weighted average bioconcentration factor for the edible portion of
freshwater and estuarine aquatic organisms consumed by Americans
was calculated to be 11 200 (US EPA, 1980). Fish fed continuous
levels of heptachlor developed the highest residues at 56 days
(Andrews et al., 1966). Lethality through biomagnification was
demonstrated when crayfish died after feeding on tubificid worms
that had been exposed to heptachlor at 1.5 µg/litre (Naqvi, 1973).
However, worms placed in clean water after exposure to heptachlor
(even after exposure to the higher dose of 3.75 µg/litre) were not
lethal for crayfish. Although marine molluscs show a very high
concentration of heptachlor, residues are rarely found in wild
populations (Modin, 1969).

Data on the bioaccumulation of heptachlor epoxide are given in
Table 11.

Po-Yung Lu et al. (1975) examined the fate and distribution of
¹⁴C-heptachlor and metabolites in food chain organisms in two
laboratory model ecosystems and in vitro by sheep liver microsomes.
They found that chlordene and heptachlor undergo rapid epoxidation
and are also hydroxylated at C₁ to form the corresponding hydroxy
analogues. Heptachlor epoxide, however, is highly stable in
biological systems. The rates of conversion and degradation of
these compounds are influenced by microsomal oxidases, photolysis,
and chemical hydrolysis. The relative balance of the epoxidation
and hydroxylation determines the magnitude of persisting residues
in the environment.

Table 10. Bioaccumulation of heptachlor^a
---------------------------------------------------------------------------------------------------------
Organism Flow/ Grade Temp Sal pH Duration Concentration Organ Reference
stat (°C) ^o/oo factor^b
---------------------------------------------------------------------------------------------------------
American oyster flow technical 10 days 17 600 tissues Wilson
(Crassostrea (1965)
virginica)

Fathead minnow, flow heptachlor 20 7.5 32 days 9500 whole body Veith et
adult (Pimephales al. (1979)
promelas)

Sheepshead minnow, flow technical^c 28 - 28 days 3600 whole body Goodman et
juvenile (Cyprin- heptachlor 32 al. (1978)
odon variegatus)

Spot, 20 - 40 mm, flow technical 23.5- 18.5- 24 days 1038 - edible Schimmel et
juvenile (Leiost- heptachlor 26.5 21.5 2816 tissue al. (1976b)
xanthurus)

Spot, 20 - 40 mm, flow technical 23.5- 18.5- 24 days 2154 - whole body Schimmel et
juvenile (Leiost- hetpachlor 26.5 21.5 5126 al. (1976b)
xanthurus)
---------------------------------------------------------------------------------------------------------
^a A more comprehensive table is available on request from IRPTC, Geneva.
^b Concentration of heptachlor in tissue: concentration of heptachlor in water.
^c Technical material: 65% heptachlor, 22% gamma-chlordane, 2% alpha-chlordane, 2% nonaclor, 9% others.

Table 11. Bioaccumulation of heptachlor epoxide
---------------------------------------------------------------------------------------------------------
Organism Flow/ Grade Temp Sal pH Medium Duration Concentration Organ Reference
stat (°C) ^o/oo factor
---------------------------------------------------------------------------------------------------------
Pink shrimp, flow 99% 24.2- 20 marine 96 h 200 - 1700^a whole Schimmel
62-81 mm 26.5 body et al.
(Penaeus duorarum) (1976b)

Fathead minnow, flow 20 7.5 fresh 32 days 14 400 whole Veith
adult body et al.
(Pimephales promelas) (1979)
---------------------------------------------------------------------------------------------------------
^a Concentration in tissue: concentration in water.

8.5. Population and Community Effects

In 4 farms surveyed after treatment with heptachlor at 2.24 kg
ai/ha, the following wildlife deaths were recorded: 53 mammals from
12 species, 222 birds from 28 species, 22 reptiles from at least 8
species, many fish from more than 8 different species, many
miscellaneous frogs and many crayfish (Smith & Glasgow, 1963).
There was considerable variation in the amounts of heptachlor and
its epoxide found in the tissues of these dead animals. During a
2-year study on the effects on wild birds of a programme of fire
ant control (in which heptachlor was applied at 0.28, 0.56, and
2.24 kg ai/ha), disappearance of arthropods and changes in bird
behaviour and mortality rates were recorded soon after application
of heptachlor (Ferguson, 1964). Nesting and ground dwelling
insectivorous birds were most severely affected. Fairly complete
recovery of bird and insect populations has frequently been
reported. In a study area that was part of approximately 10
million ha treated with heptachlor at 2.24 kg ai/ha, nesting
success of ten species of bird was 45.4% in the year following
application compared with a success rate of 65% in an untreated
area (Smith & Glasgow, 1963). Quail populations were still
depressed 3 years after application of 2.24 kg ai/ha (Rosene,
1965). Application of 0.56 kg/ha caused a temporary decline in
numbers. Bobwhite quail were introduced to areas immediately after
application of heptachlor at 2.24 kg, 1.40, 0.28, and 0.14 kg/ha.
Heptachlor at 1.40 and 2.24 kg/ha caused severe mortality among
pairs of adult birds introduced successively during the first 15
days of application (61% died when exposed to 2.24 kg ai/ha, 53% at
1.40 kg/ha, 15% at 0.28 kg/ha and there were no deaths at 0.14
kg/ha). After the first 15 days, the mortality rate declined
rapidly and was undetectable after 45 days (Kreitzer & Spann,
1968). In 2 months following an aerial application of heptachlor
granules in a forest preserve, more than 300 birds of various
species were found dead; 39 of these were banded birds, compared
with a normal yearly recovery of 3 - 4 banded birds (Bartel, 1960).
Considerable bird mortality was recorded following application of
granules containing 10% heptachlor at 33.6 kg/ha to control
sugarcane root weevil (Oberhau, 1971). The level of residues of
heptachlor in bird carcasses indicated death from heptachlor
poisoning.

In an aquatic ecosystem, application of heptachlor at 1
mg/litre caused a 94.4% decrease in productivity in natural
phytoplankton communities within 4 h of initial exposure (Butler,
1963).

8.6. Effects on the Abiotic Environment

No data are available on the effects of heptachlor on the
abiotic environment.

8.7. Appraisal

In some studies on the aquatic toxicity of heptachlor,
concentrations exceeding its solubility in water (56 µg/litre at
25 - 29 °C) have been used. Therefore, the dose to which organisms
were exposed is unknown. In studies where technical material has
been used, the toxic effects attributed to heptachlor may be due to
the other cyclodiene insecticides present in the formulation or be
influenced by synergistic or antagonistic interactions between
them.

Data on the toxicity of heptachlor epoxide are very sparse.
The few data that do exist indicate that it is equally toxic and
more persistent than the parent compound.

9. PREVIOUS EVALUATIONS OF HEPTACHLOR BY INTERNATIONAL BODIES

IARC (1979) concluded that there is sufficient evidence that
technical grade heptachlor is carcinogenic in mice and that there
is limited evidence that heptachlor epoxide is carcinogenic in
experimental animals. IARC (1982) later concluded that there is
limited evidence for the carcinogenicity of heptachlor in
experimental animals and that human data available "do not allow an
evaluation of the carcinogenicity of heptachlor or heptachlor
epoxide to humans to be made".

The Joint Meeting on Pesticide Residues (JMPR) reviewed
residues and toxicity data on heptachlor on several occasions in
1965, 1966, 1967, 1968, 1969, and 1970 (FAO/WHO, 1965, 1967b, 1968,
1969, 1970, 1971). In 1970, it estimated the acceptable daily
intake (ADI) for man at 0 - 0.0005 mg/kg body weight. This was
based on no-observed-adverse-effect levels of:

5 mg/kg diet, equivalent to 0.25 mg/kg body weight/day in
the rat, and

2.5 mg/kg diet, equivalent to 0.06 mg/kg body weight/day
in the dog.

WHO has recommended a guideline value of 0.1 µg/litre for
heptachlor and heptachlor epoxide in drinking-water (WHO, 1982).

WHO (1984) classified heptachlor as moderately hazardous.

The WHO/FAO (1975), in its series of data sheets on pesticides,
issued one on heptachlor. Based on a brief review of the use,
exposure, and toxicity of the compound, practical advice is given
on labelling, safe-handling, transport, storage, disposal,
decontamination, selection, training, and medical supervision of
workers, first aid, and medical treatment.

Regulatory standards established by national bodies in 12
different countries (Argentina, Brazil, Czechoslovakia, the Federal
Republic of Germany, India, Japan, Kenya, Mexico, Sweden, the
United Kingdom, the USA, and the USSR) and the EEC can be obtained
from the IRPTC (International Register of Potentially Toxic
Chemicals) Legal File (IRPTC, 1983).

IPRTC (1982), in its series "Scientific reviews of Soviet
literature on toxicity and hazards of chemical", issued a review on
heptachlor.

The CEC (1981) reviewed the data available on heptachlor in
1981.

10. EVALUATION OF HEALTH RISKS FOR MAN AND EFFECTS ON THE ENVIRONMENT

10.1. Heptachlor Toxicity

The acute toxicity of heptachlor is moderate (the oral LD₅₀ in
the rat ranges from 40 to 162 mg/kg body weight). It is readily
absorbed via all routes of exposure and rapidly metabolized. On
repeated exposure, heptachlor epoxide may accumulate in the body,
mainly in adipose tissue. Toxic symptoms are related to CNS-
hyperactivity and include tremors and convulsions. In experimental
animals, prolonged low-level exposure resulted in the induction of
hepatic microsomal enzymes and at a later stage in liver
hypertrophy with histological changes. At higher levels,
heptachlor is hepatotoxic (section 6.3).

Heptachlor was not a teratogen in the tests conducted but at
higher exposure levels it may interfere with reproduction and the
viability of the offspring.

Heptachlor is not generally active in short-term tests for
genetic activity. There is evidence that it may have an effect on
cell to cell communication which is a property of promoting agents.

There is limited evidence for the carcinogencity of heptachlor
and heptachlor epoxide in experimental animals. No cases of
adverse effects or occupational poisoning have been reported.

10.2. Exposure to Heptachlor

For the general population, food is the major source of
exposure to heptachlor, but residue intake in most countries is
below the advised acceptable daily intake. In areas where
heptachlor is used, inhalation and drinking of well-water may
account for some additional exposure.

Relatively high concentrations of heptachlor epoxide can be
found in human milk, especially in areas with high heptachlor
exposure in the general population.

Occupational exposure, especially via the skin and via
inhalation, can be considerable when the material is handled in
installations or in situations where safety precautions are
insufficient.

10.3. Evaluation of Overall Environmental Effects

In soil, heptachlor is persistent and relatively immobile.
Heptachlor itself may be lost from the soil by slow vapourisation,
by oxidation to heptachlor epoxide (a more persistent degradation
product of comparable toxicity), by photoconversion to photo-
heptachlor, or by conversion to less toxic metabolites by soil
bacteria. The rate at which heptachlor is lost by these various
mechanisms is influenced by climate, soil type, and management
practices (retention being longest in undisturbed soil).
Heptachlor shows little movement within the soil, the majority of

heptachlor residues being found in the top few centimetres. These
residues are most likely to be spread by dust particles in air
currents.

Although there is no indication of widespread contamination of
water by heptachlor, its residues have been found in fish from
various bodies of water. Heptachlor is not very soluble in
water and persists in aquatic ecosystems by being absorbed onto
sediments. It has been shown to be toxic to aquatic life, but its
toxicity is highly species variable. This is particularly so for
marine vertebrates where acute LC₅₀ values span three orders of
magnitude. Marine crustacea are particularly sensitive to
heptachlor; concentrations of 0.03 µg/litre may be lethal. Younger
life stages of both fish and invertebrates are the most sensitive
to heptachlor, "safe" concentrations being 0.1 and 0.01 µg/litre,
respectively. Evaluation of the toxicity of heptachlor for
wildlife depends solely on extrapolation from studies on game birds
and domestic species. In these animals, toxicity is variable, with
LD₅₀ values ranging from 6 to 531 mg/kg body weight. Heptachlor is
generally classified as a neurotoxin.

Uptake of heptachlor is fairly rapid. Superficially, clearance
of heptachlor in animals is rapid and complete, but the major
storage product, heptachlor epoxide, persists much longer. The
relative amount of heptachlor epoxide in tissues increases with
length of exposure. Few data are available on the toxicity of this
metabolite, but indications are that it is of comparable toxicity
to heptachlor. Its marked persistence in the environment and its
tendency to accumulate in body fat make it a serious environmental
hazard.

10.4. Evaluation of Risks for Human Health and the Environment

Although there is no evidence that incriminates heptachlor as a
human carcinogen, the suspicion, principally arising from the mouse
carcinogenicity studies, cannot be entirely put aside. Further
research is required to elucidate this problem. Nevertheless, in
the present state of knowledge, it is concluded that:

(a) As long as occupational hygiene procedures are
maintained to keep exposure levels to a minimum,
whether or not by the imposition of maximum allowable
concentrations, there is little reason to believe
that workers will be at risk from their handling or
contacts with heptachlor.

(b) For the general population, consumers should not
suffer any adverse effects from heptachlor residues
in food, provided that the intake is kept within the
ADI set by the Joint FAO/WHO Meeting.

In certain regions of the world, the exposure of
the general population to heptachlor may be augmented
by its use as a termiticide in buildings.

The intake of heptachlor residues transferred to
breast-fed infants through human milk, in areas of
high heptachlor use, remains a concern.

(c) Environmentally, heptachlor causes concern because of
the high sensitivity of several marine species to it
and because of the persistence of the metabolite
heptachlor epoxide in adipose tissue and in the
environment.

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    See Also:
       Toxicological Abbreviations
       Heptachlor (HSG 14, 1988)
       Heptachlor (ICSC)
       Heptachlor (PIM 578)
       Heptachlor (FAO Meeting Report PL/1965/10/1)
       Heptachlor (FAO/PL:CP/15)
       Heptachlor (FAO/PL:1967/M/11/1)
       Heptachlor (FAO/PL:1968/M/9/1)
       Heptachlor (FAO/PL:1969/M/17/1)
       Heptachlor (AGP:1970/M/12/1)
       Heptachlor (WHO Pesticide Residues Series 4)
       Heptachlor (WHO Pesticide Residues Series 5)
       Heptachlor (Pesticide residues in food: 1991 evaluations Part II Toxicology)
       Heptachlor (CICADS 70, 2006)