Chlordane

1. NAME	
   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 Confirmation Test(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)	

    CHLORDANE

    International Programme on Chemical Safety
    Poisons Information Monograph 574
    Chemical

    1.  NAME

        1.1  Substance

             Chlordane

        1.2  Group

             Chlorinated "cyclodiene" insecticide

        1.3  Synonyms

             Aspon;
             Belt;
             CD 68;
             Chlorindan;
             Chlorkil;
             Corodan;
             Cortilon neu;
             Dowchlor;
             HCS 3260;
             Kypchlor;
             M 140;
             Niran;
             Octachlor;
             Octoterr;
             Ortho-Klor;
             Synklor;
             Tat-Chlor 4;
             Topichlor;
             Toxichlor;
             Velsicol-1068.

        1.4  Identification numbers

             1.4.1  CAS number

                    57-74-9

             1.4.2  Other numbers

                    RTECS   PB9800000
                    ICSC    0740
                    UN      2996
                    EC      602-047-00-8
                    NCI     8931
                    Standard Transportation Number  49 131 70
                    EPA Hazardous Waste Number      UO36
                    DOT ID & Guide                  2762 131
                    Transport Emergency Card:       TEC(R)-61G41c
                    Chlordane [technical grade]     CAS12789-03-6
                    cis-Chlordane                   CAS12789-03-6
                    trans-Chlordane                 CAS 5103-74-2
                    gamma-Chlordane                 CAS 5566-34-7

        1.5  Main brand names, Main trade names

             Belt;
             Corodane;
             Chlortox;
             Niran;
             Octachlor;
             Octa-Klor;
             Sym-klor;
             Toxichlor.

        1.6  Main manufacturers, main importers

             Velsicol Chemical Corp.

    2.  SUMMARY

        2.1  Main risks and target organs

             Chlordane is a central nervous system stimulant. The
             liver and the kidney are the other organs significantly
             affected by chlordane. 

        2.2  Summary of clinical effects

             Poisoning by the chlordane 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.

        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. Treatment will be determined by
             clinical status.
    
             Analysis is difficult because of the complex nature of
             chlordane. 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
             chlordane has been ingested  not more than one 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 and  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
    
             1,2,4,5,6,7,8,8-octachloro-2,3,3a,4,7,7a-hexahydro-4,7-
             methanoindene (IUPAC)
    
             1,2,4,5,6,7,8,8-octachloro-3a,4,7,7a-tetrahydro-4,7-
             methanoindane
             1,2,4,5,6,7,8,8-=octachloro-2,3,3a,4,7,7a-hexahydro-4,7-
             methano-1 H-indene
             Structural formula
    
             Molecular formula  C10H6Cl8
             Molecular weight   409.8

        3.3  Physical properties

             3.3.1  Colour

                    Amber

             3.3.2  State/Form

                    Liquid-viscous fluid

             3.3.3  Description

                    Technical chlordane is a viscous, amber
                    coloured liquid.
    
                    It has a pungent, chlorine like odor (NIOSH, 1998)
    
                    Solubility: It is insoluble in water but soluble in
                    most organic solvents including acetone,
                    cyclohexanone, ethanol, deodorized kerosene,
                    isopropanol, trichloroethylene (Tomlin, 1994).
    
                    Boiling point at 0.27 kPa: 175 °C  (IPCS/CEC,
                    1999)
    
                    Melting point: 103 to 105 °C (IPCS, 1988)
    
                    Relative density (water=1): 1.59-1.63 (Budavari et
                    al., 1996)

                    Vapour pressure, Pa at 25 °C: 0.0013 (IPCS/CEC,
                    1999)
    
                    Octanol/water partition coefficient as log Pow: 2.78
                    (IPCS/CEC, 1999)
    
                    Viscosity 69 Poises at 25 °C (Budavari et al.,
                    1996)

        3.4  Hazardous characteristics

             The substance decomposes on heating and/or on burning
             and on contact with bases producing toxic fumes including
             chlorine, hydrogen chloride, and phosgene. Attacks iron,
             zinc, plastics, rubber and coatings (IPCS/CEC, 1999).
    
             Above 56 °C explosive vapor/air mixtures may be formed.
             Explosion hazard will depend on the solvent used or on the
             characteristics of the dust.

    4.  USES

        4.1  Uses

             4.1.1  Uses

                    Pesticide for use against invertebrate animals 

             4.1.2  Description

                    Chlordane is a persistent, non-systemic,
                    contact and ingested insecticide with some fumigant
                    action. It is used on land against formicidae,
                    coleoptera, noctuidae larvae, saltatoria, subterranean
                    termites (including Coptotermes spp.) and many other
                    insect pests. It also controls household insects,
                    pests of man and domestic animals, is used as a wood
                    preservative, a protective treatment for underground
                    cables and to reduce earthworm populations in lawns.
                    It may be applied to soil, directly to foliage or as a
                    seed treatment (Tomlin, 1994).
    
                    All U.S registrations of chlordane have been cancelled
                    (Reigart & Roberts, 1999).

                    Chlordane is on 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 can occur in children by chlordane 
             stored in the home or garage.
    
             Accidental exposure can occur among formulating plant
             workers.
    
             Suicide attempts.
    
             Exposure of the general population may occur in dwellings
             treated with chlordane for termite control.
    
             Individuals with a history of convulsive disorders would be
             expected to be at increased risk from exposure (Mackison et
             al., 1981).

        4.3  Occupationally exposed populations

             Factory workers involved in syntheses of
             chlordane,workers involved in formulating and dispensing
             chlordane and 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

             Chlordane vapor is absorbed by inhalation.

        5.3  Dermal

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

        5.4  Eye

             Exposure to vapors, dust and aerosols.

        5.5  Parenteral

             No data available.

        5.6  Other

             No data available

    6.  KINETICS

        6.1  Absorption by route of exposure

             In studies on 4 male rabbits, a combination of
             14C-alpha and gamma-chlordane (app. 1700 mg of each,
             administered orally in 4 doses at 4-day intervals), was well
             absorbed (Balba & Saha, 1978). Rats that breathed  [14C]
             chlordane vapor for 30 min retained 77% of the total inhaled
             (Stubbfield & Dorough, 1979).

        6.2  Distribution by route of exposure

             Studies using radio-labelled chlordane showed that after
             oral administration, the radioactivity was well distributed
             in tissues of rats (Barnett & Dorough, 1974) and rabbits
             (Balba & Saha, 1978). Rats, whether being treated with single
             oral doses of chlordane or fed diets containing this
             compound, retained the highest levels of residues in adipose
             tissue, followed by the liver, kidney, brain and muscle. More
             of the gamma-isomer was retained than of the alpha isomer.
             The tissue distribution of chlordane in rabbits was found to
             be similar to that in rats (Poonawalla & Korte, 1971; Balba &
             Saha, 1978).
    
             Human milk samples obtained from 1436 women residing in
             United States were analyzed by GLC . While chlordane was not
             detected in any of the  milk samples, its metabolite
             oxychlordane was found above the detection limit (95.8 ppb)
             in 74% of the samples (Savage et al., 1981).

        6.3  Biological halflife by route of exposure

             Serum half-life of 88 days was reported in one child 
             (Aldrich & Holmes, 1969). In another study, a half-life of 34
             days for the elimination of chlordane was calculated from
             kinetic studies of a patient who accidentally consumed a
             chlordane-containing pesticide (Olanoff et al., 1983).

        6.4  Metabolism

             Chlordane is metabolized very slowly (Gosselin et al.,
             1984). Most metabolites of chlordane are far less toxic than
             the parent material, but oxychlordane is more toxic with a
             LD50 in rats of 19.1 mg/kg (FAO/WHO, 1971).
    
             In vivo and in vitro studies in rats have revealed two routes
             of biotransformation of chlordane and shown that the
             metabolites include trans-chlordane,
             1,2,-didichlorochlordene, oxychlordane,
             1-hydroxy-2-chloro-2,3-epoxychlordene, chlordene
             chlorohydrin, and 1,2-trans-dihydroxydihydrochlordene, as
             well as metabolites of heptachlor (Tashiro & Matsumura, 1977;
             Briemfield & Street 1979). In vitro studies showed that the
             livers of rat and humans  had almost identical ability to
             degrade chlordane, except that human liver has little
             capacity to convert trans-nonachlor to trans-chlordane. This
             is consistent with the accumulation of trans-nonachlor in
             people but not in rats (Tashiro & Matsumura, 1978).

        6.5  Elimination and excretion

             Chlordane is excreted primarily in the faeces
             (Poonawalla & Korte, 1971).
    
             Elimination of radiolabelled chlordane (3:1 alpha- and 
             gamma-chlordane) and the individual isomers was studied in 
             rats. Single oral doses of 0.05, 0.2 and 1 mg/kg body weight 
             in corn oil were almost completely eliminated after 7 days; 
             24 hours after administration, 70 % of alpha- chlordane and 
             60 % of the gamma-isomer were excreted. Female rats excreted 
             more of the dose in the urine than the males (Barnett & 
             Dorough, 1974).

    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 (-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

                             Chlordane has not been a common
                             substance causing poisoning.  All established
                             cases have been associated with gross
                             exposure. In most instances, including those
                             with full recovery, convulsions appeared
                             within 0.5 to 3 hours after ingestion (Micks,
                             1954; Curley & Garretson, 1969; Aldrich &
                             Holmes, 1969) or after dermal exposure
                             involving spillage.
    
                             During an acute episode, a man experienced a
                             brief episode of oliguria with proteinuria,
                             hematuria and mild hypertension, all of which
                             returned to normal (Stranger & Kerridge,
                             1968)
    
                             One 30-year-old woman was exposed to
                             chlordane through carelessness and overuse
                             over a 1 to 4 week period. Myoclonic jerks
                             occurred only after a delay of a month,
                             although the patient previously suffered from
                             circumoral numbness, anorexia, nausea and
                             fatigue (Garretson et al., 1985). Malaise and
                             anorexia became the dominant symptoms for 6
                             months before treatment. Dysfunctional
                             bleeding was attributed to hepatic enzyme
                             induction by the chlordane and increased
                             metabolism of contraceptive medication.

                             In an episode of contamination of a public
                             water supply by chlordane (probably
                             intentional) many people were affected and
                             the water level in a residence  near the
                             point of intake was 6.600 ppm. Although
                             chlordane, its contaminants, or its
                             metabolites were not detected in residents, a
                             significant proportion reported
                             gastrointestinal symptoms, skin and eye
                             irritation and headaches (Morbidity and
                             Mortality Weekly Reports, 1981).
    
                             Two cases of chlordane poisoning were
                             reported in 1955. One was caused by
                             absorption of accidentally spilled chlordane,
                             40 minutes later the victim became confused
                             and suddenly began having convulsions. She
                             was dead on arrival to the physician's
                             office. The other was a suicide attempt where
                             the individual (female) swallowed 6 g of
                             chlordane (104 mg/kg body weight) and died 9´
                             days after the incident (Derbes et al.,
                             1955).
    
                             One man occupationally exposed to chlordane
                             developed episodes of paresthesia and later
                             twitching of the right hand and arm.
                             Additional episodes, beginning in the same
                             way, ended as grand mal convulsions followed
                             by unconsciousness. He has recovered without
                             treatment when he discontinued contact with
                             chlordane.
    
                             Topical skin application of about 30 g to an
                             adult resulted in death in 40 minutes (ACGIH,
                             1986).
    
                             The acute lethal dose for man is estimated to
                             be 25 to 50 mg/kg body weight (IPCS, 1984).

                    7.2.1.2  Children

                             A 15-month-old girl ingested a
                             mouthful of chlordane suspension and after 3
                             hours, displayed tremors and incoordination
                             (Lensky & Evans, 1952).  Repeated seizures
                             developed and she was treated with ethyl
                             chloride, amobarbital and gastric lavage with
                             magnesium sulfate. The child recovered
                             completely and ataxia and excitability
                             disappeared after 2 to 3 weeks. At 26 years
                             of age, she was in excellent health and
                             appeared not to suffer any consequences from
                             the childhood episode (Taylor et al.,
                             1979).
    
                             A 2-year-old child had drunk an unknown
                             amount of a 74% formulation of chlordane
                             (Curley & Garretson, 1969). Vomiting preceded
                             convulsions, which were controlled by
                             phenobarbital; the EEG pattern was normal
                             within 40 hours and the child recovered.
    
                             A similar poisoning incident was observed
                             with a 4-year-old child (Aldridge & Homes,
                             1969). Convulsions were treated with
                             phenobarbital and the individual recovered.

                             After a 21-month-old child who had typical
                             convulsions following ingestion of an unknown
                             number of chlordane pellets  recovered; she 
                             had albuminuria and a positive urine culture;
                             to what extent chlordane may have influenced
                             the renal tract infection was unclear
                             (Canada, 1962). 

             7.2.2  Relevant animal data

                    Acute oral LD50 for rats 460 mg/kg (IPCS, 1998)
    
                    Acute oral LD50 for mice        430 mg/kg 
    
                    Acute oral LD50 for rabbits     300 mg/kg
    
                    Acute percutaneous LD50 for rabbits >200 but <2000
                    mg/kg (Tomlin, 1994), extremely irritating to their
                    eyes but produces only mild irritant to their
                    skin.

                    Inhalation LC50 (4 hour) (for exposure to an aerosol,
                    nominal concentration) >200 mg/L
    
                    NOEL for dogs 3 mg/kg diet.

             7.2.3  Relevant in vitro data

                    Sufficient human data are available

             7.2.4  Workplace standards

                    OSHA PEL TWA0.5 mg/m3  (skin)
    
                    TLV0.5 mg/m3 (as TWA) (ACGIH 1999)
    
                    NIOSH REL Ca TWA 0.5 mg/m3 skin
    
                    NIOSH IDLH  Potential occupational carcinogen
                                100 mg/m3

             7.2.5  Acceptable daily intake (ADI)

                    ADI     0.0005 mg/kg (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 demonstrate 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.
    
             Chlordane 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 chlordane and sufficient evidence in
             experimental animals for the carcinogenicity of chlordane.
             The overall evaluation of IARC on chlordane is Group 2B
             (possibly carcinogenic to humans).

        7.4  Teratogenicity

             No evidence of teratogenicity was found in animal
             studies (IPCS, 1984).

        7.5  Mutagenicity

             Alpha-chlordane, gamma chlordane and chlordene were
             tested in the Ames Salmonella microsome assay and were not
             mutagenic  (Simon et al., 1977). Chlordane was not mutagenic
             when tested using 5 different strains of Salmonella
             typhimurium in the Ames assay (Ergovich & Rachid, 1977). 
    
             More studies on animal and human cells in culture have shown
             that chlordane is not mutagenic or is only weakly mutagenic
             (Williams, 1979; Maslansky & Williams, 1981; Tong et al.,
             1981). Further work by Telang et al. (1982) showed that
             chlordane, 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.
    
             Chlordane and heptachlor did not cause dominant lethal
             effects in mice. Both compounds inhibited gap-junctional
             intercellular communication and induced gene mutations in
             rodent cells but did not induced unscheduled DNA synthesis.
             Neither chlordane nor heptachlor was mutagenic to bacteria
             and neither of these damaged bacterial or plasmid DNA (IARC,
             1991).

        7.6  Interactions

             Chlordane has been shown to exert a protective effect
             against several organophosphorus and carbamate insecticides
             (Williams, 1967; Street, 1969; Williams 1970).
    
             Protein deficiency has been shown to double the acute
             toxicity of chlordane in rats (Boyd, 1972). Chlordane has
             also shown to increase the hepatotoxic effects of carbon
             tetrachloride in the rat (Stenger et al., 1975;Mahon, 1977;
             1979).

    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 Confirmation Test(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

                             "Basic analyses"
    
                             "Dedicated analyses"
    
                             "Optional analyses"

                    8.3.1.2  Urine

                             "Basic analyses"
    
                             "Dedicated analyses"
    
                             "Optional analyses"

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

                    "Basic analyses"
    
                    "Dedicated analyses"
    
                    "Optional 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

                    Following ingestion of chlordane some patients
                    have experienced nausea and vomiting before signs of
                    central nervous system overactivity appeared. However
                    a convulsive fit could be the first clear indication
                    of illness. Convulsions often last about a minute and
                    may recur at intervals of about 5 minutes. Convulsions
                    usually are accompanied by confusion, incoordination,
                    excitability, or in some instances, coma. Respiratory
                    failure may also occur (Olanoff et al., 1983).

             9.1.2  Inhalation

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

             9.1.3  Skin exposure

                    Skin is a significant route of exposure, and
                    may even result in death (ACGIH, 1986). Symptoms are
                    basically the same as by ingestion.

             9.1.4  Eye contact

                    Contact with the eyes may cause ocular
                    irritation and pain (IPCS, CEC, 1999).

             9.1.5  Parenteral exposure

                    No data available.

             9.1.6  Other

                    Symptoms were relatively mild in a poisoning by
                    rectally administered chlordane involving a dose of
                    0.53 to 1.9 mg/kg (Marquart, 1982).

        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

                    Recent evidence indicates that neurotoxicity, a
                    known human endpoint in acute exposures may be a
                    relevant endpoint in chronic human exposures. No
                    chronic animal studies have examined neurotoxicity
                    (Kilburn & Thornton, 1995).

        9.3  Course, prognosis, cause of death

             Typical, serious poisoning by chlordane is characterized
             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 chlordane 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 may  occur
             before signs of central nervous system activity have
             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 (Olanoff
             et al., 1983). Death may follow respiratory failure (IPCS,
             1984).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

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

             9.4.2  Respiratory

                    The effects of chlordane 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 of the extremities has
                             been reported in a man accidentally exposed
                             to chlordane (Barnes, 1967).

                    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

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

             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

                    Induction of hepatic microsomal enzymes may
                    result in hormonal disturbances because of accelerated
                    metabolism of endogenous steroids (Street et al.,
                    1969).
    
                    At concentrations above 30 mg per kg of fodder,
                    chlordane interferes with reproduction in rats and
                    mice (IPCS, 1988).
    
                    No multi-generational reproductive studies, by any
                    route, exist for technical chlordane. Several items
                    within the current chlordane database suggest that
                    reproductive effects could be a relevant endpoint for
                    chlordane. The study of Cassidy et al. (1994)
                    indicates alterations in reproductive-related
                    behaviour in male rats as a consequence of chlordane
                    exposure.

                    Accumulation of a major component of a technical
                    chlordane (heptachlor) 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

                    May cause redness and pain in the eyes
                    (IPCS/CEC, 1999).

             9.4.10 Haematological

                    Case reports of leukaemia and other blood
                    dyscrasias have been associated exposure to chlordane.
                    The bone marrow showing evidence of dyserythropoiesis,
                    eosinophilia and megaloblastosis was reported after
                    extensive exposure with recovery after 4 months
                    (Furie, 1976)

             9.4.11 Immunological

                    Altered immune competence was reported in the
                    offspring off mice whose mothers had received
                    chlordane at a rate of 8.0 mg/kg/day throughout
                    gestation but not in young whose mothers received 0.16
                    mg/kg/day (Cranmer et. al., 1979, Spyker-Cranmer et
                    al., 1982).

             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
    
                    Concentrations of chlordane 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 chlordane 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 chlordane was not found in any of the samples,
                    and its metabolite oxychlordane was found above the
                    detection limit (95.8 ppb) in 74% of the samples
                    (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 chlordane
             has been ingested less than one hour ago, gastric lavage
             after endotracheal intubation may be indicated, 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 barbituratesmay 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 has 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 is seen within one 
             hour after ingestion.
    
             In the case of ingestion of a solution, or an emulsifiable
             concentrate, a risk of chemical pneumonitis following
             aspiration exists.

        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

             The use of activated charcoal in the treatment of an
             acute chlordane intoxication is fully established. Repeated
             dosing may be beneficial as it partially interrupts the
             entero-hepatic circulation (Hayes & Laws, 1991).

             Clonazepam or diazepam are the drugs of first choice, but   
             barbiturates also 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,
             as required. (Shell Agriculture, 1990). 

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             After a 21-month-old child who had a typical convulsion
             following ingestion of an unknown number of chlordane
             "pellet" was essentially recovered, she was found to have
             albuminuria, and a positive urine culture; to what extend
             chlordane may have influenced the renal tract infection was
             unclear (Canada, 1962)
    
             A woman working at a formulating plant who accidentally
             spilled a solution of chlordane and DDT on her belly and
             thighs became confused and suddenly began having convulsions
             after 40 minutes. She was dead before she was taken to the
             physician's office (Derbes, 1955).
    
             One 30-year-old woman was exposed to chlordane  by careless
             handling and overuse over a 1 to 4 week period. Myoclonic
             jerks occurred only after a delay of a month, although the
             patient previously suffered from circumoral numbness,
             anorexia, nausea and fatigue. Fatigue and anorexia became the
             dominant symptoms for 6 months before treatment (Garretson et
             al., 1985).

    12. Additional information

        12.1 Specific preventive measures

             Rescuers must take precautions not to contaminate
             themselves.
    
             The manufacture of chlordane 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

             Chlordane is persistent and rather immobile in soil,
             this substance may be hazardous to the environment; special
             attention should be given to fish in tropical areas. It is
             strongly advised not to let the chemical enter into the
             environment (IPCS, CEC, 1999)

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

        Author:     Dr Nida Besbelli
                    IPCS
                    World Health Organization
                    1211 Geneva 27
                    Switzerland

                    Tel:     41 22 791 4287
                    Fax:     41 22 791 4848
                    E-mail:  besbellin@who.ch

        Prepared: June 2000

        Reviewer: Janusz Szajewski, MD
        Warsaw Poisons Centre
        Tel/fax +48 (22) 839 06 77
        e-mail: szajewsk@waw.pdi.net
        June 2000

        Peer review: INTOX 12 Meeting, 7 - 11 November 2000
        Drs J. Szajewski, C.Alonzo, R. Fernando.

    See Also:
       Toxicological Abbreviations
       Chlordane (EHC 34, 1984)
       Chlordane (HSG 13, 1988)
       Chlordane (PDS)
       Chlordane (FAO Meeting Report PL/1965/10/1)
       Chlordane (FAO/PL:1967/M/11/1)
       Chlordane (FAO/PL:1969/M/17/1)
       Chlordane (AGP:1970/M/12/1)
       Chlordane (WHO Pesticide Residues Series 2)
       Chlordane (WHO Pesticide Residues Series 4)
       Chlordane (Pesticide residues in food: 1977 evaluations)
       Chlordane (Pesticide residues in food: 1982 evaluations)
       Chlordane (Pesticide residues in food: 1984 evaluations)
       Chlordane (Pesticide residues in food: 1986 evaluations Part II Toxicology)