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, Nigeriaa

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-3a,4,7,7a-
                           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 milka
-------------------------------------------------------------------------------------------------------
                                               Heptachlor and heptachlor 
                                               epoxide content inb               

Area/year               Number of     Fat (%)  Whole milk    Milk fat          Reference
                        samples       (mean)   (µg/litre)    (mg/kg)
                        (% positive)
-------------------------------------------------------------------------------------------------------
AFRICA:
 Kenya (1979)           33            -        0.5 (median)  -                 FAO/WHO (1981)

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           -        -             0.01e (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 inb               

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)          29d           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 inb               

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)    4c/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 inb               

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            -        -             0.10c (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 inb               

Area/year               Number of     Fat (%)  Whole milk    Milk fat          Reference
                        samples       (mean)   (µg/litre)    (mg/kg)
                        (% positive)
-------------------------------------------------------------------------------------------------------
 Spain                                                                                             
  Madrid (1981)         20            -        1e            -                 Baluja et al. (1982)
  Madrid (1981)         20 (77%)      -        4 ± 4                           Baluja et al. (1982)
                                               (0 - 14)
  Rural area (1979)     21 (100%)     -        -             2.56e             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%)     -        -             2.46e             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            -        39e           2.51e             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             -        0.5e          -                 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 organismsa
---------------------------------------------------------------------------------------------------------
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  20b               96-h    130        Henderson et al.
 minnow                   heptachlor                               LC50               (1959)
 (Pimephales               (72%)
  promelas)     stat   U   technical   25    8.2  400b              96-h    78         Henderson et al.
                          heptachlor                               LC50               (1959)

Bluegill       stat   U   technical   25    7.1  20b               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        Concentrationa   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 heptachlora
---------------------------------------------------------------------------------------------------------
Organism            Flow/  Grade       Temp   Sal    pH  Duration  Concentration  Organ       Reference
                    stat               (°C)   o/oo                 factorb
---------------------------------------------------------------------------------------------------------
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   technicalc  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 - 1700a    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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MAGNANI, B., POWERS, C.D., WURSTER, C.F., & O'CONNORS, H.B.
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MATSUMURA, F. & NELSON, J.O.  (1971)  Identification of the
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    See Also:
       Toxicological Abbreviations
       Heptachlor (HSG 14, 1988)
       Heptachlor (ICSC)
       Heptachlor (PDS)
       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)