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Heptachlor

1. Heptachlor
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, Main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICOCHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Hazardous characteristics
4. USES
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstance of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological halflife by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. TOXICOLOGY
   7.1 Mode of action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake (ADI)
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative ConfirmationTest(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced Elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    HEPTACHLOR

    International Programme on Chemical Safety
    Poisons Information Monograph 578
    Chemical

    1.  Heptachlor

        1.1  Substance

             Heptachlor

        1.2  Group

             Chlorinated "cyclodiene" insecticide

        1.3  Synonyms

             Agroceres;
             3-Chlorochlordene;
             Drinox;
             Drinox H-34;
             E 3314;
             ENT 15,152;
             Eptachloro;
             GPKh;
             H-34;
             Heptachloor;
             Heptachlore;
             Heptagran;
             Heptomul;
             Rhodiachlor;

        1.4  Identification numbers

             1.4.1  CAS number

                    76-44-8

             1.4.2  Other numbers

                    RTECS            PC 0700000
                    ICSC             0743
                    UN               2761
                    EC               602 - 046 - 00 - 2
                    NCI              C - 00180

                    Standard Transportation Number  4960630

                    RCRA Waste Number:              P 059

                    DOT  ID & Guide:                2761 151

                    Transport Emergency Card:       TEC (R) - 61 641b

        1.5  Main brand names, Main trade names

             Drinox;
             Heptagram;
             Heptamul;

        1.6  Main manufacturers, main importers

             Velsicol Chemical Corp.

    2.  SUMMARY

        2.1  Main risks and target organs

             Heptachlor is a central nervous system stimulant. The
             liver is  the other organ significantly affected by
             heptachlor. 

        2.2  Summary of clinical effects

             Poisoning by the heptachlor and other cyclodiene
             insecticides is more likely to begin with the sudden onset of
             convulsions preceeded by vomiting. Seizures caused by
             cyclodienes may appear as long as 48 hours after exposure,
             and then may recur periodically over several days following
             the initial episode. Tonic-clonic convulsions usually are
             accompanied by confusion, incoordination, excitability, or,
             in some instances coma and hypotension. Respiratory failure
             may also occur. At non-lethal acute exposures, heptachlor is
             hepatotoxic.

        2.3  Diagnosis

             The diagnosis is based on the history of exposure
             (dermal, inhalational or gastrointestinal) and signs of
             central nervous system hyperexcitability including
             seizures.
    
             Blood levels are not clinically useful, but could help to
             confirm the exposure, although treatment will be determined
             by clinical status.
    
             The principal method for its qualitative and quantitative
             determination is gas-liquid chromatography with electron
             capture detection.

        2.4  First aid measures and management principles

             Treatment is symptomatic. It is aimed at controlling
             convulsions, coma, and respiratory depression.
             Cardio-vascular function must be observed.
    
             To control convulsions use clonazepam IV or diazepam IV or
             per rectum. Intravenous barbiturates may also be used. Once
             convulsions are controlled further treatment with  Phenytoin
             or  Sodium Valproate should be continued as long as
             required.
              Do not give fats, oils or milk since these will enhance
             absorption from the intestinal tract.
    
             If the patient is conscious and a large quantity of
             heptachlor has been ingested not more than 1 hour ago perform
             gastric lavage only after tracheal intubation. This should be
             followed by intragastic administration of a large amount of
             activated charcoal slurry and a laxative.
    
             In the case of skin contact remove and discard contaminated
             clothing and wash exposed skin including hair and nails with
             (soap and) copious amounts of water.

              Opiates, adrenaline and  nor-adrenaline should only be
             given with extreme caution.  Aminophylline, atropine or
              oily laxatives should not be administered.
    
             Rescuers must take precautions to avoid personal
             exposure.

    3.  PHYSICOCHEMICAL PROPERTIES

        3.1  Origin of the substance

             A synthetic product (Budavari et al., 1996)

        3.2  Chemical structure

             Structural names
    
             1, 4, 5, 6, 7, 8, 8 - Heptachloro - 3a, 4, 7, 7a - tetrahydro
             - 4, 7 - methanoindene (IUPAC)
    
             1, 4, 5,  6, 7, 8,  8  -  Heptachloro - 3a,  4, 7, 7a  - 
             tetrahydro -  4,  7 - methano - 1H - indene
    
             Molecular formula              C10H5CL7
    
             Molecular weight               373.4 

        3.3  Physical properties

             3.3.1  Colour

                    White to light tan

             3.3.2  State/Form

                    Solid crystals

             3.3.3  Description

                    Heptachlor is a white to light tan color solid
                    crystals.
                    It has a camphor - like odor (NIOSH, 1998)
    
                    Solubility:             In water 0.056 mg/L
                                            ( 25 - 29°C)
    
                    Soluble in many organic solvents, e.g. in acetone 75,
                    benzene 106, xylene 102, cyclohexanone 119,
                    carbontetrachloride 113, ethanol 4.5  ( all in
                    g/100mL) (Tomlin, 1994).
    
                    Boiling Point:          at  0.2 kPa: 135  to 145°C
                    (IPCS/CEC, 1999)
    
                    Melting Point :         95  to  96°C  (IPCS/CEC,
                    1999)
                    Relative Density:       (water = 1): 1.65 to 1.67
    
                    Vapour Pressure:        Pa at 25°C: 0.053
    
                    Octanol/water partition coefficient as log Pow: 5.27
                    to 5.44

        3.4  Hazardous characteristics

             The substance decomposes on heating above 160°C
             producing toxic fumes including hydrogen chloride and other
             chlorine fumes. Reacts with strong oxidants. Attacks metals
             (IPCS/CEC,1999).

    4.  USES

        4.1  Uses

             4.1.1  Uses

                    Pesticide for use against invertebrate animals

             4.1.2  Description

                    Heptachlor is a non-systemic insecticide with
                    contact, stomach, and some respiratory action. It is
                    used to control termites, ants and soil insects in
                    cultivated and non cultivated soils. Applied as a seed
                    treatment, soil treatment, or directly to foliage.
                    Also used for control of household insects (Tomlin,
                    1994).
    
                    Heptachlor is registered in the United States  only
                    for underground use in power lines for fire ants
                    (Reigart and Roberts, 1999).
    
                    Heptachlor is on the list of 12 persistent
                    organochlorine pesticides (POP) identified by UNEP
                    Governing Council, for which international action is
                    required to reduce the risks to human health and the
                    environment. It is also subject to the prior informed
                    consent procedure of UNEP and FAO.

        4.2  High risk circumstance of poisoning

             Accidental poisoning of children by heptachlor stored in
             the home or garage.
    
             Accidental exposure among formulating plant workers.
    
             Suicide attempts.
    
             Exposure of the general population may occur in dwellings
             treated with heptachlor for termite control.
    
             Individuals with a history of convulsive disorders would be
             expected to be at increased risk from exposure (Mackison et
             al., 1981).
    
             Individuals with diseases of kidney, liver and lung
             (ITII,1988).

        4.3  Occupationally exposed populations

             Factory workers involved in syntheses of heptachlor.
    
             Workers involved in formulating and dispensing
             heptachlor.
    
             Public health workers involved in pest control.

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Ingestion occurs through accidental or deliberate
             ingestion or accidental ingestion of contaminated
             foodstuffs.

        5.2  Inhalation

             Heptachlor vapor is absorbed by inhalation.

        5.3  Dermal

             Heptachlor is readily absorbed after dermal contact, and
             the absorbtion is variable depending on the type on the type
             of solvent used.

        5.4  Eye

             Exposure to vapors, dust and aerosols.

        5.5  Parenteral

             Accidental or intentional.

        5.6  Other

             No data available.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Heptachlor is readily absorbed by the skin as well as by
             the lungs and gastrointestinal tract. It is only about twice
             as toxic orally as dermally. Rats retained 77% of heptachlor
             that they inhaled during a 30-minute period (Stubblefiled &
             Dorough, 1979).

        6.2  Distribution by route of exposure

             Heptachlor is readily metabolized into heptachlor
             epoxide in mammals. Heptachlor epoxide is the most persistent
             metabolite. It is mainly stored in adipose tissue, but also
             in liver, kidney and muscle. In rats, heptachlor epoxide was
             found in tissues, urine and faeces while the hydrophilic
             metabolite (1-exohydroxychlordene epoxide) was only detected
             in urine. Rats fed diets containing 30 mg heptachlor/kg were
             shown to have a maximum heptachlor epoxide concentrations in
             adipose tissue within 2 to 4 weeks. Twelve weeks after

             cessation of exposure, heptachlor completely disappeared from
             the adipose tissue. The highest concentration of heptachlor
             epoxide was found in adipose tissue; markedly lower amounts
             were found in the liver, kidney and muscle; and none in the
             brain (FAO/WHO, 1967). A similar pattern of distribution was
             found in the dog (Radomski & Davidow, 1953).The accumulation
             of heptachlorepoxide 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.

        6.3  Biological halflife by route of exposure

             When 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 decreased by
             about half in the first 4 weeks after cessation of exposure
             (Walgstaff et al., 1980).

        6.4  Metabolism

             Heptachlor is metabolized readily to heptachlor epoxide
             in mammals (Hayes, 1963). Heptachlor epoxide is metabolized
             quickly and is the most persistent metabolite.  Klein et al,
             (1968) showed  that the metabolism of heptachlor in rats gave
             rise to heptachlor epoxide and hydrophilic metabolite,
             1-exo-hydroxychlorene epoxide. Another metabolite of 
             heptachlor, a dehydrogenated derivative of 1-hydroxy -2, 
             3 - epoxy chlordene  was identified in rat faeces by 
             (Matsumura & Nelson, 1971).

        6.5  Elimination and excretion

             Heptachlor epoxide is excreted in faeces and urine while
             the hydrophilic metabolite is detected only in urine.  In
             rabbits, approximately 80% of the urinary radioactivity was
             derived from the hydrophilic metabolite and 20% from the
             epoxide (IPCS, 1984).

    7.  TOXICOLOGY

        7.1  Mode of action

             Chlorinated hydrocarbon insecticides act by altering the
             electrophysiological and associated enzymatic properties of
             nerve cell membranes, causing a change in the kinetics of Na+
             and K+ ion flow through the membrane. Disturbances of calcium
             transport of Ca+2-ATPase activity may also be involved, as
             well as phosphokinase activities (Hayes & Laws, 1991).
    

             The cyclodiene compounds antagonize the action of the
             neurotransmitter gamma-aminobutyric acid (GABA), which
             induces the uptake of chloride ions by neurons. The blockage
             of this activity by cyclodiene insecticides results in only
             partial repolarization of the neuron and a state of
             uncontrolled excitation (Klassen & Watkins, 1999).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             There is no information on cases of
                             accidental or suicide poisoning with
                             heptachlor.

                    7.2.1.2  Children

                             There is no information on the case
                             of accidental or suicide  poisoning with
                             heptachlor.

             7.2.2  Relevant animal data

                    Acute oral LD50 for rats100 mg/kg  (IPCS, 1998)
    
                    Acute oral LD50 for guinea pigs116  mg/kg
                    (Tomlin, 1994)
    
                    Acute oral LD50 for mice 68  mg/kg (Tomlin, 1994)
    
                    Acute percutaneous LD50 for rabbits  >2000 mg/kg
    
                    Acute percutaneous LD50 for rats 119-250 mg/kg
    
                    Inhalation LC50 (4 hour) (for rats exposed to
                    heptachlor in an aerosol > 2.0 but <200 mg/L
                    air.
    
                    NOEL                    in rats     7 mg/kg diet
                                            in dogs     1 mg/kg diet
                                            ( 2 generation reproduction
                                            study)

             7.2.3  Relevant in vitro data

                    Heptachlor induced human myeloblastic leukemia
                    has been studied. Similar to 12 - 0
                    - tetradecanoylphorbol, 13 - acetate, a known tumor
                    promoter, heptachlor induced cell adherence and
                    formation of extended cytoplasmic  pseudopodia in ML -
                    1 cells. The growth of ML -1 was slightly stimulated
                    by low concentrations (<30 nM) of heptachlor. A dose
                    responsive cell death was also observed with ML - 1
                    cells were treated with heptachlor at concentrations
                    greater than 80 uM. Examination by light microscopy of
                    the cells treated with 80 uM heptachlor revealed a
                    gradual appearance of differentiation characteristics
                    in the culture. On day 3 of the treatment, 41%  of the
                    cells remained unchanged as ML -1, 39% of the cells
                    showed changes and apparent cells differentiation, and
                    20% of the cells were induced to differentiate to
                    monocyte- or macrophage- like cell type. Electron
                    microscopy also revealed cellular differentiation and
                    the presence of monocyte - and macrophage-like cell
                    types (22%) was confirmed by positive esterase
                    staining (Chuang et al., 1991)

             7.2.4  Workplace standards

                    OSHA PEL TWA            0.5 mg/m3 (skin) (ACGIH 2000)
    
                    TLV                     0.05 mg/m3 (as TWA)
    
                    NIOSH  REL              Ca TWA 0.5 mg/m3 skin
    
                    NIOSH IDLH              Potential occupational
                                            carcinogen 35 mg/m3

             7.2.5  Acceptable daily intake (ADI)

                    ADI              0.0001 (PTDI) (IPCS, 1997)

        7.3  Carcinogenicity

             Case reports of leukaemia and other blood dyscrasias
             have been associated with exposure to chlordane/heptachlor,
             primarily in domestic situations (Furie & Trubowitz,
             1976).
    

             Mortality from lung cancer was slightly elevated in two
             cohort studies of pesticide applicators; and one of
             chlordane/heptachlor manufacturers. Termite control operators
             probably have greater exposure to chlordane than other
             pesticide applicators.  However, in one study of applicators,
             the excess occurred only among workers who were not engaged
             in termite control (Mac Mahon et al., 1988). In the other
             study of applicators, the relative risk for lung cancer among
             workers engaged in termite control was similar to that of
             workers engaged in other pest control. Inconsistencies in
             these findings make it difficult to ascribe the excesses to
             exposure to chlordane.
    
             Small excess risks for other cancers, including leukaemia,
             non-Hodgkin's lymphoma and soft tissue sarcoma and cancers of
             the brain, skin, bladder and stomach were observed, with
             little consistency among studies (IARC, 1991). 
    
             Chlordane, technical-grade chlordane, heptachlor,
             technical-grade heptachlor, heptachlorepoxide and a mixture
             of heptachlor and heptachlorepoxide have been tested for
             carcinogenicity by oral administration in several strains of
             mice and rats. These studies uniformly demonstrated increases
             of hepatocellular neoplasms in mice of each sex. Increases in
             the incidence of thyroid follicular-cell neoplasms were
             observed in rats treated with chlordane and technical-grade
             heptachlor. An increased incidence of malignant fibrous
             histiocytomas was observed in one study in male rats treated
             with chlordane. A small increase in the incidence of liver
             adenomas was seen in one study in male rats treated with
             technical grade chlordane.
    
             Heptachlor has been evaluated by the International Agency for
             Research on Cancer (IARC, 1979; 1987; 1991). It was concluded
             that there is inadequate evidence in humans for the
             carcinogenicity of heptachlor and sufficient evidence in
             experimental animals for the carcinogenicity of heptachlor.
             The overall evaluation of IARC on heptachlor is Group 2B
             (possibly carcinogenic to humans).

        7.4  Teratogenicity

             Heptachlor was not tetratogenic in the tests conducted
             but  at higher exposure levels it may interfere with
             reproduction and the viability of the offspring (IPCS,
             1984).

        7.5  Mutagenicity

             Gene mutation assays indicate that heptachlor is not
             mutagenic in bacteria (Probst et al, 1981; Shirasu et al,
             1976; Moriya et al., 1983) or mammalian liver cells (Telang
             et al., 1982). Negative results were reported in two dominant
             lethal assays using male germinal cells (Epstein et al.,
             1972; Arnold et al., 1977). DNA repair assays indicate that
             heptachlor is not genotoxic in rodent hepatocytes (Maslansky
             & Williams, 1987; Probst et al., 1981) but showed qualitative
             evidence of unscheduled DNA synthesis in human fibroblasts
             (Ahmed et al., 1977).

        7.6  Interactions

             Phenobabital pretreatment significantly enhance the
             metabolism of heptachlor in rats. It causes a 6 to 11-fold
             increase in the liver heptachlor epoxidase (Miranda et al.,
             1973).

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative ConfirmationTest(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                    8.3.1.2  Urine

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Heptachlor is a potent stimulant of the central
                    nervous system. Poisoning by the cyclodienes is more
                    likely to begin with the sudden onset of convulsions,
                    and is often not preceded by the premonitory
                    manifestations seen with DDT. Seizures caused by
                    cyclodienes may appear as late as 48 hours after
                    exposure, and then may recur periodically over several
                    days following the initial episode (Reigart & Roberts,
                    1999).

             9.1.2  Inhalation

                    Heptachlor may be absorbed by inhalation.
                    Symptoms are basically the same as by
                    ingestion.

             9.1.3  Skin exposure

                    Is a significant route of exposure. Symptoms
                    are basically the same as by ingestion.

             9.1.4  Eye contact

                    Heptachlor is an eye irritant.

             9.1.5  Parenteral exposure

                    No data available.

             9.1.6  Other

                    No data available.

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    No data available.

             9.2.2  Inhalation

                    No data available

             9.2.3  Skin exposure

                    No data available

             9.2.4  Eye contact

                    No data available

             9.2.5  Parenteral exposure

                    No data available

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             Typical, severe poisoning by heptachlor is characterised
             by onset of violent convulsions within 0.5 to 3 hours and
             either death or the start of recovery within a few hours to a
             day (Hayes & Laws, 1991). Seizures caused by heptachlor may
             appear as long as 48 hours after exposure, and then may recur
             periodically over several days following the initial episode
             (Reigart & Roberts, 1999). Nausea and vomiting occur before
             signs of central nervous system activity has appeared.
             Convulsions may and may not be the first clear indication of
             illness. Convulsions usually are accompanied by confusion,
             incoordination, excitability, or, in some instances, coma.
             Respiratory failure may also occur.  Death may follow
             respiratory failure (IPCS, 1984).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Arrhythmias may occur owing to myocardial
                    sensivity to catecholamines (Olson, 1999).

             9.4.2  Respiratory

                    The effects of heptachlor on the respiratory
                    system are secondary to the effects on the nervous
                    system (Hayes & Laws, 1991).

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             Central nervous system excitation is
                             the primary toxic effect seen in humans.
                             Convulsions can occur suddenly after a
                             massive overdose. Convulsions often last
                             about a minute and may recur at intervals of
                             about 5 min. Convulsions usually are
                             accompanied by confusion, incoordination,
                             excitability, or, in some instances, coma.
                             

                    9.4.3.2  Peripheral nervous system

                             Paraesthesia,  No further data
                             available.

                    9.4.3.3  Autonomic nervous system

                             No data available.

                    9.4.3.4  Skeletal and smooth muscle

                             Rhabdomyolysis may occur.

             9.4.4  Gastrointestinal

                    Nausea and vomit may occur.

             9.4.5  Hepatic

                    Heptachlor is a potent inducer of hepatic
                    microsomal enzymes (Hart et al., 1963). 
    

                    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 (IPCS, 1984).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             After ingestion renal injury may
                             develop (Olson, 1999)

                    9.4.6.2  Other

                             No data available.

             9.4.7  Endocrine and reproductive systems

                    A dosage of 6.9 mg/kg/day for 3 days
                    significantly reduced fertility of rats and also the
                    survival of young during the first weeks by about one
                    third; this effect was found more sensitive than tests
                    of the liver and kidney function (Mestizovā & Beno,
                    1966, Mestitzovā 1967). Essentially similar results
                    were reported for dosages of 5 and 10 mg/kg/day, and
                    some fetal anomalies as well as resorptions were 
                    encountered. A dosage of 1 mg/kg/day apparently was
                    harmless to reproduction (Rosival et al., 1972)
                    Yamaguchi et al, (1987) found no increases in fetal
                    mortality or malformation when heptachlor was
                    administered to pregnant rats (days 7 - 17) at doses
                    up to 20 mg/kg/day.
    
                    Induction of hepatic microsomal enzymes may result in
                    hormonal disturbances because of accelerated
                    metabolism of endogenous  steroids (Street et
                    al.,1969).
    
                    Accumulation of heptachlor, a major component of a
                    technical chlordane in ovary, uterus and adrenals in
                    non-pregnant rats within 30 after an oral dose of 120
                    mg/kg heptachlor. In pregnant rats, levels were
                    markedly elevated in the uterus compared to non
                    pregnant rats; the higher accumulation is believed to
                    be a result of a slower metabolic turnover of
                    heptachlor. These results indicate that chlordane or
                    some of its components/metabolites have an increased
                    affinity towards reproductive organs during pregnancy
                    and may have potential to adversely affect
                    reproductive processes (Rani et al., 1992).

             9.4.8  Dermatological

                    Skin irritation results from extensive contact
                    with organochlorine pesticides or with the white
                    petroleum distillate vehicles.

             9.4.9  Eye, ear, nose, throat: local effects

                    It was reported by Mestitzova (1967) that
                    heptachlor at a dosage of 6.9 mg/kg/day increased the
                    incidence of cataracts in rats, especially young once
                    born to treated mothers.

             9.4.10 Haematological

                    Blood disorders (leukemias, production
                    defects, and thrombocytopenie purport) have been
                    catalogued following home termite treatment with
                    chlordane and heptachlor, but proof of a direct effect
                    is lacking (Epstein & Osonoff, 1987).

             9.4.11 Immunological

                    No data available

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Metabolic acidosis may
                             occur.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No data available

                    9.4.12.3 Others

                             No data available

             9.4.13 Allergic reactions

                    No data available

             9.4.14 Other clinical effects


             9.4.15 Special risks

                    Pregnancy
    
                    In one study with rats chlordane or some of its
                    components/metabolites show an increased affinity
                    towards reproductive organs during pregnancy and may
                    have potential to adversely affect reproductive
                    processes. See 9.4.7 (Rani et al., 1992)
    
                    Breast feeding
    
                    Several investigators detected heptachlor epoxide
                    levels ranging from non-detectable to 0.46 ppm in
                    human milk (Kroger,1972; Polishuk et al., 1977;
                    Strassman & Kutz, 1977; Savage et al., 1981)
    
                    Concentrations of heptachlor in the milk of women in
                    various populations have been reported. Restrictions
                    on the use of the organochlorine insecticides (DDT,
                    aldrin, dieldrin, heptachlor and chlordane) have
                    resulted in reduced concentrations of these chemicals
                    in breast milk and adipose tissue as compared with
                    previous studies. The concentration of heptachlor in
                    breast milk did not pose a hazard to breast fed
                    infants (Stevens et al., 1993). In one study of 1436
                    women residing in the United states heptachlor was
                    found in less than 2%, but heptachlor epoxide, its
                    metabolite, was found 63% of the samples (detection
                    limit 91.4 ppb  for heptachlor epoxide) (Savage et
                    al., 1981).

        9.5  Other

             No data available

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             The condition of the patient in a particular case is
             decisive whether the first attention should be given to
             removal of the poison or to sedation of the patient. 

             Treatment is symptomatic, aimed at controlling convulsions,
             coma, and respiratory depression.
    
             Cardiovascular function needs to be observed. If heptachlor
             has been ingested less than one hour ago, gastric lavage may
 
             be indicated preceded by endotracheal intubation followed by
             activated charcoal slurry.
    
              Opiates should only be administered with extreme caution
             because of their depressive effects on the respiratory
             centre.  Adrenaline  and nor-adrenaline should only be
             administered with extreme caution, because they may sensitise
             the myocardium and thus provoke serious cardiac arrhythmias.
              Aminophylline, atropine or  oily laxatives should not be
             administered.

        10.2 Life supportive procedures and symptomatic/specific treatment

             Make a proper assessment of airway, breathing,
             circulation and neurological status of the patient.
    
             Monitor vital signs.
    
             Maintain a clear airway. Support ventilation using
             appropriate mechanical device. Administer oxygen.
    
             Open and maintain at least one IV route. Administer IV fluids
             if necessary.
    
             To control convulsions use clonazepam IV or diazepam IV or
             per rectum. Intravenous barbiturates may also be used.Once
             convulsions are controlled further treatment with  Phenytoin
             or Sodium  Valproate should be continued for a further two
             to four weeks. (See  the Treatment Guide on Convulsions).
    
             Monitor blood pressure and ECG. Control cardiac dysrrhythmias
             with proper drug regimen and/or electrophysiologic
             procedures.
    
             If the patient vomited spontaneously, monitor respiratory
             functions and watch for signs of pulmonary aspiration.

        10.3 Decontamination

             Skin contact
             Remove and discard contaminated clothing.  Wash exposed skin
             including hair and nails with (soap and) copious amounts of
             water.
    
             Eye contact
             Irrigate exposed eyes with copious amounts of water or
             saline. Saline is preferable but do not delay the irrigation
             if only water is readily available.
    

             Ingestion
             Inducing vomiting is contraindicated because of the risk of
             abrupt onset of seizures. If the patient is conscious perform
             gastric lavage for large ingestion, avoiding aspiration into
             the lungs. This should be followed by intragastric
             administration of a large amount of activated charcoal slurry
             containing  50 to 200g of powder . Do not give fats, oils or
             milk as these will enhance poison  absorption from the
             intestinal tract.
    
             Gastric lavage is indicated if patient seen within 1 hour of
             ingestion.
    
             In the case of ingestion of a solution, or an emulsifiable
             concentrate, a risk of chemical pneumonitis following
             aspiration exist.

        10.4 Enhanced Elimination

             Enhanced elimination is not indicated because of the
             large volume of distribution of chlorinated hydrocarbon
             insecticides.

        10.5 Antidote treatment

             10.5.1 Adults

                    There is no specific antidote

             10.5.2 Children

                    There is no specific antidote.

        10.6 Management discussion

             Clonazepam or diazepam are drugs of first choice, but
             also barbiturates may be helpful administered slowly by
             intravenous or intramuscular injection , e.g. phenobarbitone
             (Shell Agriculture, 1990). Major side effects of the
             treatment with barbiturates are sedation, respiratory
             depression, hypotension, shock, apnoea and laryngospasm
             (KNMP, 1996).

             When convulsions are under control and do not recur, it is
             recommended that treatment be continued with regular
             antiepileptic drugs such as  Phenytoin (or Sodium 
              Valproate), for 2 to 4 weeks (Shell Agriculture,
             1990).

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Rescuers must take precautions not to contaminate
             themselves.
    
             The manufacture of heptachlor has ceased in many countries.
             Disposal of any remaining stocks should be done with care to
             avoid contamination of the environment. Disposal can be done
             by burning the remaining stock in a proper incinerator
             designed for chlorinated hydrocarbon insecticide waste
             disposal. Seek further advice from the local distributor or
             poisons centre.

        12.2 Other

             Heptachlor is fairly stable to light and moisture and
             it is not readily dehydrochlorinated. Its half-life in the
             soil in temperate region 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 heptachlor epoxide,  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 hydrobiota.
    
             Heptachlor has been shown to be a toxic for aquatic life, but
             its toxicity is highly species variable. Marine crustacea and
             younger life stages both fish and invertebrates are most
             sensitive. Insufficient information is available on its 
             toxicity for terrestrial species (IPCS, 1984).

    13. REFERENCES

        ACGIH (2000) Threshold limit values for chemical substances
        and physical agents and biological exposure indices. Cincinnati,
        OH: American Conference of Governmental Industrial Hygienists.
    
        Ahmed FE, Hart RW, Lewis NJ (1977)  Pesticide induced DNA damage
        and its repair in cultured human cells. Mutat Res 42:161-174.
    
        Arnold DW, Kennedy GL, Jr, Keplinger ML, Calandra JC, Calo CJ
        (1977)  Dominant lethal studies with technical chlordane HCS-3260,
        and heptachlor:heptachlor epoxide. J Toxicol  Environ Health  2:
        547-555.
    
        Budavari S ed. (1996) The Merck Index: an encyclopedia of
        chemicals, drugs, and biologicals, 12th ed. Rahway, New Jersey,
        Merck and Co., Inc.
    
        Chuang LF, Hinton DE, Cheng AT, Cheung RY (1991)  Induction
        differentiation in human myeloblastic leukemia ML - 1 cells by
        heptachlor, a chlorinated hydrocarbon insecticide. Toxicol Appl
        Pharmacol 109 (1): 98-107.
    
        Epstein SS and Ozonoff (1987) Leukemias and blood dyscrasias
        following exposure to chlordane and heptachlor. Teratogen
        Carcinogen Mutagen , 527-540.
    
        Epstein SS, Arnold E, Andrea J, Bass W,  Bishop Y (1972) Detection
        of chemical mutagens by the dominant lethal assay in the mouse.
        Toxicol Appl Pharmacol  23: 288-325.
    
        FAO/WHO (1967) Heptachlor. In: 1966 Evaluation of some pesticide
        residues in food, Rome, Food and Agriculture Organization of the
        United Nations.
    
        Furie B and Trubowitz S (1976) Insecticides and blood dyscrasias.
        Chlordane exposure and self-limited refractory megaloblastic
        anemia. J Am Med Assoc 235:1720 - 1722.
    
        Hart LG, Shultice RW, Fouts JR (1963) Stimulatory effects of
        chlordane on hepatic microsomal drug metabolism in the rat.
        Toxicol Appl Pharmacol 5:371-386.
    
        Hayes, WJ. (1963) Clinical handbook on economic poisons. Emergency
        information for treating poisonings, Atlanta,Georgia, US
        Department of Health, Education and Welfare, Public Health Service
        (PHS Publication No. 476).
    
        Hayes WJ (Jr) and Laws ER (Jr) (1991) Handbook of pesticide
        toxicology. Academic Press Inc. p. 816 - 822.
    

        IARC (1991) IARC Monograph: Occupational Exposures in Insecticide
        Application and Some Pesticides. Vol. 53 p. 115-179.
    
        IARC (1987) IARC Monographs: An updating of IARC Monographs Vol. 2
        to 42 Supplement 7 440 pp.
    
        IPCS (1984) Environmental Health Criteria Monographs 38.
        Heptachlor. World Health Organization.
    
        IPCS (1997) Inventory of IPCS and other WHO pesticide evaluations
        and summary of toxicological evaluations performed by the Joint
        Meeting on Pesticide Residues (JMPR). WHO/PCS/98.1. World Heath
        Organization. Geneva.
    
        IPCS (1998) The WHO Recommended classification of pesticides by
        hazards and guidelines to classification 1998-1999.
        WHO/PCS/98.21/Rev.1. World Health Organization, Geneva.
    
        IPCS/CEC (1999) International Chemical Safety Cards: 0743.
        Heptachlor (Technical Product).
    
        ITII (1988) Toxic and hazardous industrial chemicals safety
        manual. The International Technical Information Institute, Tokyo,
        Japan.
    
        Kan, CA and Tuinstra, LGM.  (1976)  Accumulation and excretion of
        certain organochlorine insecticides in broiler breeder hens. J
        Agric Food Chem  24: 775-778.
    
        Klaassen CD and Watkins JB (1999) Casarett and Doull's toxicology:
        the basic science of poisons. 5th ed. New York, MacGraw-Hill 
        Publishing Company 542-547.
    
        Klein W, Korte F, Weisgerber I, Kaul R, Mueller W,  Djirsarai A. 
        (1968).  The metabolism of endrin, heptachlor,and telodrin. Qdal 
        Pldt Mater Veg (Den Haag), 15: 225-238.
    
        KNMP (1996) Informatorium Medicamentorum 1996 deel 1, Koninklijke
        Nederlandse Maatschappij ter bevordering der Pharmacie,
        's-Gravenhage.
    
        Kroger M. (1972)  Insecticide residues in human milk. J Pediatr
        80: 401-405.
    
        Kroger M. (1972)  Insecticide residues in human milk. J Pediatr
        80: 401-405.
    
        Mackison FW, Stricoff RS, Partridge LJ (1981) NIOSH/OSHA-
        Occupational Health Guidelines for Chemical Hazards. DHHS (NIOSH)
        Publication No. 81-123 (3 vols.), Washington, DC: U.S. Government
        Printing Office.
    

        MacMahon B, Monson RR, Wang HH, Zengh TZ (1988) A second follow-up
        of mortality in a cohort of pesticide applicators. J Occup Med 30
        (5): 429-32.
    
        Mahon DC and Oloffs PC (1979)  Effects of sub-chronic low-level
        dietary intake of chlordane on rats with cirrhosis of the liver. 
        J Environ Sci  Health,  B14: 227-246.
    
        Maslansky CJ and Williams GM  (1981)  Evidence for an epigenetic
        mode of action in organochlorine pesticide hepatocarcinogenicity: 
        A lack of genotoxicity in rat, mouse and hamster hepatocytes.  J
        Toxicol. Environ  Health,  8: 121-130.
    
        Matsumura F and Nelson JO  (1971)  Identification of the major
        metabolite product of heptachlor epoxide in rat feces. Bull
        Environ Contam Toxicol., 5: 489-492.
    
        Mestitzova M (1967) On reproduction studies and the occurrence of
        cataracts in rats after long-term feeding of the insecticide
        heptachlor. Experientia 23, 42-43.
    
        Mestitzova M and Beno M (1966) Toxicologic characteristics of
        small repeated doses of heptachlor. Prak Lek 18, 153-157.
    
        Micks DW (1954) Potential health hazards of organic insecticides.
        Tex State J Med, 50, 148-153. 
    
        Miranda CL, Webb RE,  Ritchey SJ  (1973)  Effect of dietary
        protein quality, phenobarbital and SKD 525-A on heptachlor
        metabolism in the rat. Pestic Biochem Physiol 3: 456-461.
    
        Moriya M, Ohta T, Watanabe K, Miyazawa T, Kato K,  Shirasu U
        (1983) Further mutagenicity studies on pesticides in bacterial
        reversion assay systems. Mutat Res;116, 185-216.
    
        NIOSH (1998) Pocket Guide to Chemical Hazards. U.S. Department of
        Health and Human Services. Public Health Service. Centers for
        Disease Control and Prevention. National Institute for
        Occupational Safety and Health.
    
        Olson KR ed. (1999) Poisoning and drug overdose. Appleton and
        Lange. P.133-134.
    
        Polishuk ZW, Wassermann D, Wassermann  D, Cucos S, Ron M (1977)
        Organochlorine compounds in mother and fetus during labor. Environ
        Res 13: 278-294.
    
        Probst GS, McMahon, RE, Hill LE, Thompson CZ, Epp JK, Neal, S.B.
        (1981)  Chemical-induced unscheduled DNA synthesis in primary
        rat hepatocyte cultures: A comparison with bacteria mutagenicity
        using 218 compounds. Environ Mutat 3: 11-32.
    

        Radomski, JL. & Davidow, B.  (1953)  The metabolite of heptachlor,
        its estimation, storage and toxicity. J Pharmacol Exp Ther, 107:
        266-272.
    
        Rani BE, Karanth NG, Krishnakumari MK (1992) Accumulation and
        embriotoxicity of the insecticide heptachlor in the albino rat. J
        Environ Biol 13(2) 95-100.
    
        Reigart RJ, Roberts JR (1999) Recognition and Management of
        Pesticide Poisonings. 5th ed.U.S. Environment Protection Agency
        p.55-62.
    
        Rosival L, Cerey K, Ruttkayova, Vargova M and Tildyova K (1972)
        Recent achievements in pesticide toxicology studies.
        Egeszsegtudomany 16, 63-69.
    
        Savage EP, Keefe TJ, Tessari JD, Wheeler HW, Applehans FM, Goes
        EA, Ford SA (1981) National study of chlorinated hydrocarbon
        insecticide residues in human milk, USA. I. Geographic
        distribution of dieldrin, heptachlor, heptachlor epoxide,
        chlordane, oxychlordane and mirex. Am J Epidemiol: 113(4) 413-22.
    
        Shell agriculture (1990) Safety guide, Shell International
        Chemical Company Limited Crop Protection Division Shell Centre
        London, 35-36, 71-75.
    
        Shirasu Y, Moriya M, Kato K, Lienard F, Tezuka H, Teramoto S, Kada
        T (1977) Mutagenicity screening of pesticides and modification
        products: A basis of carcinogenicity evaluation. Cold Spring
        Harbor Conf Cell Proliferation 4.
    
        Stevens MF, Ebell GF, Psaila-Savona P (1993) Organochlorine
        pesticides in Western Australian nursing mothers. Med J Aust 1993
        Feb 15; 158(4):238-41.
    
        Strassman SC and Kutz FW (1977)  Insecticide residues in human
        milk from Arkansas and Mississippi 1973-1974. Pesticide Monit J
        10(4):130-133.
    
        Street JC, Mayer  FL, Wagstaff J (1969)  Ecological significance
        of pesticide interactions.  Ind Med Surg,  38: 409-414.
    
        Stubblefield WA and Dorough HW (1979) Quantitative administration
        of insecticide vapors to rats. Toxicol Appl  Pharmacol 48, A138.
    
        Telang S, Tong  C, Williams GM  (1982)  Epigenetic membrane
        effects of a possible tumour promoting type on cultured liver
        cells by the non-genotoxic organochlorine pesticides chlordane and
        heptachlor.  Carcinogenesis,  3: 1175-1178.
    

        Tomlin C ed. (1994) The Pesticide Manual. Incorporating the
        Agrochemicals Handbook. The British Crop Protection Publications
        p.171-172.
    
        Wagstaff, DJ., McDowell, JR., and  Paulin, HJ.  (1980) Heptachlor
        residue accumulation and depletion in broiler chick hens. Am J Vet
        Res., 41(5): 765-768.

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)

        Author:
    
        Dr Nida Besbelli
        IPCS
        World Health Organization
        CH-1211 Geneva 27,
        Switzerland
    
        Telephone   41 22 791 4287
        Facsimile   41 22 791 4848
        E-mail      besbellin@who.ch

        Prepared: June 2000
    
        Review:
        Janusz Szajewski, MD
        Warsaw Poisons Centre
        Poland
    
        Telephone   48 22 839 0677
        Facsimile   48 22 839 0677
        E-mail      szajewsk@waw.pdi.net
    
        Peer review: INTOX 12 Meeting, 7 - 11 November 2000
        Drs J. Szajewski, C.Alonzo, R. Fernando.
    




    See Also:
       Toxicological Abbreviations
       Heptachlor (EHC 38, 1984)
       Heptachlor (HSG 14, 1988)
       Heptachlor (ICSC)
       Heptachlor (PDS)
       Heptachlor (FAO Meeting Report PL/1965/10/1)
       Heptachlor (FAO/PL:CP/15)
       Heptachlor (FAO/PL:1967/M/11/1)
       Heptachlor (FAO/PL:1968/M/9/1)
       Heptachlor (FAO/PL:1969/M/17/1)
       Heptachlor (AGP:1970/M/12/1)
       Heptachlor (WHO Pesticide Residues Series 4)
       Heptachlor (WHO Pesticide Residues Series 5)
       Heptachlor (Pesticide residues in food: 1991 evaluations Part II Toxicology)
       Heptachlor (CICADS 70, 2006)