IPCS INCHEM Home

Endosulfan

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)0 - 0.006 mg/kg bw
   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)
    ENDOSULFAN

    International Programme on Chemical Safety
    Poisons Information Monograph 576
    Chemical

    1.  Name

        1.1  Substance

             Endosulfan

        1.2  Group

             Chlorinated "cyclodiene" insecticide

        1.3  Synonyms

             Benzoepin;
             Beosit;
             Bio 5,462;
             Chlorthiepin;
             Crisulfan;
             Cyclodan;
             Devisulphan;
             Endocel;
             Endosol;
             Endosulphan;
             Ensure;
             Ent 23,979;
             FMC 5462;
             Hildan;
             HOE 2,671;
             Insectophene;
             Kop-thiodan;
             Malux;
             Malix;
             Thifor;
             Thimul;
             Thiodan;
             Thiomul;
             Thionex;
             Thiosulfan;
             Thisulfan tiovel;
             Tiovel;

        1.4  Identification numbers

             1.4.1  CAS number:
                                    115-29-7

             1.4.2  Other numbers:
                                    RTECS  RB9275000
                                    ICSC   0742
                                    UN     2761
                                    EC     602 - 052 - 00 - 5
                                    NCIC   00566

                                    RCRA   Waste Number P050

                                    DOT ID & Guide 2761 151

                    - Transport Emergency Card: TEC ( R ) 61G41b

        1.5  Main brand names, Main trade names

             Beosit;
             Chlortiepin;
             Cyclodan;
             Devisulphan;
             Endocel;
             Endosol;
             Hildan;
             Insectophene;
             Malix;
             Rasayansulfan;
             Thifor;
             Thimul;
             Thiodan;
             Thionex;
             Thiosulfan;

        1.6  Main manufacturers, main importers

             Agr Evo; Excel; Hinolustan Insecticides; Makhteshim - Agan

    2.  SUMMARY

        2.1  Main risks and target organs

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

        2.2  Summary of clinical effects

             Poisoning by the endosulfan 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, 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 Valporate 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
             endosulfan 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 not to contaminate
             themselves.

    3.  PHYSICOCHEMICAL PROPERTIES

        3.1  Origin of the substance

             A synthetic product (Budavari et al., 1996)

        3.2  Chemical structure

             Structural names
    
             6,7,8,9,10, 10 - hexachloro - 1, 5, 5a, 6, 9, 9a - hexahydro
             - 6,9 - methano - 2,4,3 -= benzodioxathiepine 3 - oxide
             (IUPAC name) 
             Molecular formula: C9H6Cl6O3S
    
             Molecular weight:  406.9

        3.3  Physical properties

             3.3.1  Colour

                    Brown

             3.3.2  State/Form

                    Solid/Crystals

             3.3.3  Description

                    Endosulfan is brown coloured solid crystals. It
                    has a slight sulfur dioxide odor (NIOSH, 1998).
    
                    Endosulfan is a mixture of two stereoisomers: 
                    alpha - endosulfan, beta endosulfan.
    
                    Solubility: In water alpha endosulfan 0.32, 
                    beta - endosulfan 0.33 (both in mg/L, 22C). In ethyl
                    acetate, dichloromethane, toluene 200, ethanol c.65,
                    hexane c.24 (all in g/L, 20C), (Tomlin,1994)
    
                    Stability: Stable to sunlight. Slowly hydrolised in
                    aqueous acids and alkalis with the  formation of the
                    diol and sulfur dioxide (Tomlin, 1994)
    

                    Boiling Point: Decomposes.
    
                    Melting Point (technical) : 70 to 100C
                                  (pure)      : 106 C  (IPCS/CEC, 1999)
    
                    Density:  1.7
    
                    Vapour Pressure, Pa at 80C :1.2
    
                    Octanol/ Water partition coefficient as log  Pow: 3.55
                    - 3.62.  (IPCS/CEC, 1999).

        3.4  Hazardous characteristics

             The substance decomposes on heating, producing toxic
             fumes including sulfur oxides, chlorine fumes. Reacts with
             bases causing toxic (sulfur dioxides fumes) hazard. Attacks
             iron (IPCS/CEC;1999).

    4.  USES

        4.1  Uses

             4.1.1  Uses

                    Pesticide for use against invertebrate animals

             4.1.2  Description

                    Endosulfan is a non-systemic insecticide and
                    acaricide with contact and stomach action. It is used
                    in the control of sucking, chewing and boring insects
                    and mites on a very wide range of crops, including
                    fruit (including citrus), vines, olives, vegetables,
                    ornamentals, potatoes, cucurbits, cotton, tea, coffee,
                    rice, cereals, maize, sorghum, oilseed crops, hops,
                    hazels, sugar cane, tobacco, alfalfa, mushrooms,
                    forestry, glasshouse crops, etc. Also controls tsetse
                    flies (Tomlin,1994).

        4.2  High risk circumstance of poisoning

             Accidental poisoning of children by endosulfan stored in
             the home or garage.
    
             Accidental exposure among formulating plant workers.
    
             Suicide attempts.
    

             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 endosulfan.
    
             Workers involved in formulating and dispensing
             endosulfan.
    
             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

             Endosulfan vapor is absorbed by inhalation.

        5.3  Dermal

             Endosulfan is readily absorbed after dermal contact, at
             a degree 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

             The percentage of endosulfan absorbed after oral dosing
             would appear to have been moderate to high. Single oral doses
             of  0.3 mg endosulfan and its two isomers administered to
             male Balb mice were not completely absorbed from the
             gastrointestinal tract but were excreted with the metabolites
             endosulfan sulfate and diol in the faeces. (IPCS,
             1998a).

        6.2  Distribution by route of exposure

             The autopsy and toxicological findings in a fatal case
             caused by ingestion of endosulfan dispersed in a colorless
             liquid containing about 55% of xylene (w/v) is reported by
             Bernardelli & Gennari  (1987). The following concentrations
             of endosulfan were found: blood 30 mg/L, gastric contents 0.5
             g in the total 50 mL, liver 20 mg/kg, kidney 2.0 mg/kg ,
             brain 0.3 mg/kg, xylene (solvent) was detected  only in
             stomach  contents  (0.4 g in the total 50 mL). 
    
             When endosulfan was fed to Balb c mice in the diet at a
             concentration of 10 ppm for up to 49 days, the sulfate
             metabolite was detected in the liver and visceral fat of all
             animals. Both isomers and the sulfate and diol metabolites of
             endosulfan were detected in the faeces, while the only
             endosulfan product detected in the  urine of these animals
             was the diol  metabolite. After a single dose of up to 0.3 mg 
             14C-labelled endosulfan to Balb/c mice, the highest
             concentrations, followed (in rank order) by visceral fat >
             urine > small intestine > kidney > brain> expired carbon
             dioxide > blood (Deema et al, 1966).
    
             At the end of a 24 - month study in which NMRI mice were
             given diets containing 0, 2, 6, or 18 ppm technical - grade
             endosulfan, the concentrations of endosulfan and its main
             metabolites endosulfan hydroxyether, sulfate, lactone, and
             diol were measured in the liver and kidneys. No endosulfan
             was detected in either the liver or the kidney. In mice given
             18 ppm endosulfan, the concentrations of the hydroxyether,
             lactone, and diol metabolites were at or below the level of
             detection (0.02 ppm), while the endosulfan sulfate
             concentrations were 0.1 to 0.2 ppm in kidney and 0.7 to 1.1
             ppm in liver. The tissue concentrations of endosulfan sulfate
             in mice at 2,6 and 18 ppm, respectively, were: kidney, 0.2 to
             0.4 ppm, 0.04 ppm and 0.1 to 0.2 ppm; and liver, 0.06 to 0.07
             ppm, 0.12 to 0.45 ppm, and 0.7 to 1.1 ppm (Leist, 1989).

             Following acute over-exposure , high endosulfan
             concentrations can temporarily be found in the liver; the
             concentration in the plasma decreases rapidly (IPCS,
             1984).

        6.3  Biological halflife by route of exposure

             The half lives for urinary and faecal elimination for
             males and female rats  were biphasic, with an earlier half
             life of 6 to 14 hour and a later half life of 33 to 67.5 hour
             (IPCS, 1998a).

        6.4  Metabolism

             Metabolism in animals is by oxidation and hydrolysis.
             When given to rats by various routes, endosulfan is
             metabolised to the sulfate, diol, hydroxyether, lactone,
             ether, hydroxy endosulfan carboxylic acid. Most endosulfan
             metabolites are polar and yet  to be identified (IPCS,
             1998a).

        6.5  Elimination and excretion

             After oral and intravenous administration of 
             14C - endosulfan  to male and female Wistar rats at a dose 
             of 2 or 0.5 mg/kg bw, respectively, >80% (intravenous) or 
             90% (oral) of the dose was eliminated in the urine and faeces 
             within seven days; elimination was essentially complete 
             within the first 1 - 2 days (IPCS, 1998a)
    
             14C-Endosulfan (alpha or beta isomer) was rapidly excreted
             by female rats after a single oral dose of 2 mg/kg bw or
             administration in the diet at a concentration of 5ppm. After
             a single dose, > 85% was excreted within 120 hours (> 70%
             after 48 hours), mainly in the faeces and to a lesser extent
             in the urine.  After dietary administration for 14 days ,
             followed by a 14 day recovery period, >72% of the
             administered dose was recovered. Biliary excreation of
             radiolabel in male rats given 1.2 mg/kg bw as a single dose
             approached 50% for the alpha isomer and 30 % for the ( isomer
             over 48 hours. There appeared to be little enterohepatic
             circulation. The largest proportion of the radiolabel
             administered was metabolized to highly polar products, most
             of which could not be extracted from faeces (28%) or tissues
             (71%). Of the extractable fraction, unidentifiable polar
             metabolites constituted 6.2 % in faeces and 13 % in urine.
             The apolar metabolites of endosulfan identified in faeces and
             urine were the diol, the lactone, the alpha-hydroxyether, and
             the sulphate (Dorough et al., 1978).

    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

                             In general, the doses of endosulfan
                             involved in cases of poisoning have been
                             poorly characterized. In a summary of case
                             reports (Lehr,1996), the lowest reported dose
                             that resulted in death was 35 mg/kg bw;
                             deaths have also been reported after
                             ingestion of 295 and 467 mg/kg bw, within 1
                             hour of ingestion in some cases. Intensive
                             medical treatment within 1 hour was reported
                             to be successful after ingestion of doses of
                             100 and 1000 mg/kg bw. The clinical signs in
                             these patient were consistent with those seen
                             in laboratory animals, dominated by tonic
                             clonic spasms. In a case which a dose of 1000
                             mg/kg bw was ingested, neurological symptoms
                             requiring anti-epileptic theraphy were still
                             required one year after exposure (IPCS,
                             1998a).

                    7.2.1.2  Children

                             No data available.

             7.2.2  Relevant animal data

                    Acute oral LD50 for rats80 mg/kg  (IPCS, 1998b)
    
                    Acute oral LD50 for mice14 - 35 mg/kg
    

                    Acute dermal LD50 for rabbits290 mg/kg
    
                    Inhalation LC50 (1 hour) for rats > 21 mg/L air;
    
                             (4 hours) male rats 0.0345 mg/L
    
                             (4 hours) female rats 0.0126 mg/L  (Tomlin,
                             1994)
    
                    NOEL     30 mg/kg (2 year feeding trials in rats)

             7.2.3  Relevant in vitro data

             7.2.4  Workplace standards

                    OSHA PEL:        none
    
                    TLV                     0.1 mg/m3 (as TWA) (ACGIH
                                            2000)
    
                    NIOSH  REL: Ca TWA      0.1 mg/m3  (skin)

             7.2.5  Acceptable daily intake (ADI)0 - 0.006 mg/kg bw

        7.3  Carcinogenicity

             Endosulfan is not carcinogenic (IPCS, 1998a)

        7.4  Teratogenicity

             Adequate data not available (IPCS, 1984)

        7.5  Mutagenicity

             Endosulfan was not mutagenic in E. coli or S.
             Typhimurium (Fahrig, 1976; Moriya et al., 1982). It did not
             induce mitotic conversion in Saccharomyces cerevisae (Fahrig,
             1976). However, in one study technical grade endosulfan was
             reported to induce reverse mutations, cross overs, and
             mitotic gene conversions in Saccharomyces cerevisiae (Yadav
             et al., 1982).
    
             Endosulfan did not induce chromosomal abbreviations in bone
             marrow cells or spermatogonia of male rats treated with 5
             daily oral doses of 11 to 55 mg/kg body weight (Dikshith and
             Datta, 1978).
    

             An increased number of micronuclei induced in the bone marrow
             erythrocytes of mice treated with endosulfan in the drinking
             water (43.3 mg/litre) for 2 consecutive days was not
             statistically significant (Usha Rani et al., 1980). Negative
             results were observed in a dominant lethal test in mice
             (Canada, National Research Council, 1975). 

        7.6  Interactions

             The report of Arnold et all (1996) indicated that even
             estrogens of low potency, such as endosulfan, could have
             important effects because of interactions with other
             chemicals. The estrogenic properties of combinations of
             chemicals were screened in a system in which the human
             estrogen receptor sequence is incorporated into the yeast
             genome. Combinations of two weak environmental estrogens,
             such as dieldrin, endosulfan, and toxaphene, were 1000 times
             more potent in human estrogen  receptor - mediated
             transactivation than any chemical alone. This result was not
             produced in another laboratory in which the same assay was
             used or in a uterotropic assay in which sexually immature
             rats were treated with endosulfan or dieldrin alone or in a
             combination of three successive days and the uterine mass
             weighed on the following day. Both chemicals were inactive in
             either assay, and there was no evidence of synergism (Ashby
             et al., 1997). In a further study with the human estrogen
             receptor assay, however, 0.1 mmol/L endosulfan increased the
             activity of beta-galactosidase (Ramamoonthy et al., 1997).
    
             More doubt was cast upon the thesis of synergism by an
             independent study in which endosulfan and dieldrin showed no
             additive effect in displacing 3H-17(-estradiol from rat
             uterine estrogen receptors or in inducing the proliferation
             of MCF-7 breast cancer cells.  The weak proliferative
             potential described by Soto et al. (1994, 1995) was, however,
             confirmed in this assay in vitro. Endosulfan or dieldrin
             alone at 3 mg/kg bw per day or in combination, injected
             intraperitoneally daily for three days, did not stimulate
             uterotrophic activity and had no effect on pituitary
             prolactin or other endocrine related end-points in immature
             female rats, indicating that these weakly estrogenic
             compounds did not interact  in a synergistic fashion in
             binding to estrogen receptors or in activating estrogen
             receptors-dependent responses in mammalian tissues or cells.
             (Wade et al., 1997). The paper in which synergism was 
             originally proposed was later withdrawn, since the results
             could not be reproduced, even in the same laboratory
             (McLachalan, 1997). Overall, these suggest that concomitant
             exposure to weakly estrogenic compounds probably does not
             result in reproductive toxicity related to estrogen
             action.

    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

                    Endosulfan acts as a potent stimulant of the
                    central nervous system. The clinical picture in all
                    cases of human poisoning cases involved gagging,
                    vomiting, diarrhea, agitation, tonic clonic
                    convulsions, foaming at the mouth, dyspnea, apnea,
                    cyanosis and loss of consciousness. In an unsuccessful
                    attempted suicide, three stages were observed: an
                    acute cardiac and convulsive stage, a subacute
                    pulmonary and convulsive stage, and finally a slow
                    recovery (Shemesh et al., 1989).

             9.1.2  Inhalation

                    Endosulfan is hazardous by inhalation to a
                    lesser extent than oral or dermal contact (IPCS,
                    1988)

             9.1.3  Skin exposure

                    Endosulfan is hazardous by skin contact
                    especially liquid formulations (IPCS, 1988) 

             9.1.4  Eye contact

                    Contact with eyes may cause ocular irritation.
                    Other effects may be due to the solvent
                    present.

             9.1.5  Parenteral exposure

                    The intravenous administration of a small dose
                    of endosulfan (1mL) in xylene caused the rapid onset
                    of severe grand mal seizures in a 28 year-old woman
                    with a past history of epilepsy. She developed liver
                    dysfunction, proximal myopathy secondary to
                    rhabdomyolysis, and renal failure. (Pulmonary
                    complications and neurological sequelae were minimal
                    with the patient making a full recovery over three
                    months) (Grimmett et al., 1996).

             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 endosulfan 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 endosulfan 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 be seen
             before signs of central nervous system activity has appeared.
             Syncope may be the earliest sign of endosulfan
             toxicity.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 endosulfan on the respiratory
                    system are secondary to the effects on the nervous
                    system (Hayes & Laws, 1991).  Dyspnea along with apnea
                    and cyanosis may occur.

             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.
                             Syncope may be the earliest sign of
                             endosulfan toxicity.

                    9.4.3.2  Peripheral nervous system

                             No 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, vomiting and diarrhea may
                    occur.

             9.4.5  Hepatic

                    Dorough et al. (1978) could not detect any
                    induction of hepatic cytochrome P-450 or epoxidase
                    activity toward aldrin after treatment of female rats
                    with endosulfan (50 ppm of diet) for 28 days. On the
                    other hand, Tyagi et al (1986) have observed that
                    multiple dosing of male rats (7.5 mg/kg body weight)
                    did affect these parameters to a small degree (Hayes &
                    Laws, 1991).

             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

                    In an in vivo study of estrogenic effects
                    conducted by Raizado et al (1991), endosulfan did not
                    change the weights of the uterus, cervix, or vagina,
                    while estradiol  propionate produced large increases.
                    The increased weights seen with the combined treatment
                    were similar to those with estradiol propionate
                    alone.
    

                    As part of a study intended to optimize investigations
                    of estrogenic activity, endosulfan and nine other
                    chemicals with known or suspected estrogenic activity 
                    were tested in three assays: competitive binding to
                    the mouse uterine estrogen receptor, transcriptional
                    activation in HeLa cells transfected  with plasmids
                    containing an estrogen receptor and a response
                    element, and the uterotropic assay in mice. There was
                    no evidence from any of these tests that endosulfan
                    was estrogenic (Shelby et al., 1996)

             9.4.8  Dermatological

                    Skin irritation results from extensive contact
                    with organochlorine pesticides or with the white
                    petroleum distillate vehicles.
    
                    When dermal irritancy of technical - grade endosulfan
                    (purity 98.6%) was tested according to EEC  Guideline
                    B.4 (Acute toxicity skin irritation of Directive
                    92/69/EEC), no signs of systemic toxicity were
                    observed (Bremmer, 1997a).

             9.4.9  Eye, ear, nose, throat: local effects

                    May cause redness and pain in the eyes
                    (IPCS/CEC, 1999).
    
                    When the ocular irritancy of technical grade
                    endosulfan (purity, 98.6%) was tested on rabbits
                    according to EEC guideline B.5 (Acute toxicity eye
                    irritation of Directive 92/69/EEC) it was found not
                    irritating to the eye (Bremmer, 1997b).

             9.4.10 Haematological

                    No data available

             9.4.11 Immunological

                    The absence of immunotoxic effects in a large
                    number of bioassays with endosulfan suggested that it
                    does not have an adverse effect on  the immune
                    function of laboratory animals. However, in two
                    studies, rats given endosulfan in the diet at 30 or 50
                    ppm for 6 weeks or 20 ppm for 22 weeks had reduced
                    serum titres of tetanus toxoid antibody and reduced
                    immunoglobins G and M, and inhibition of migration of
                    both, leukocytes and macrophages. These findings have
                    not been confirmed. 

             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
    
                    A 21-year-old woman 5-month pregnant ingested an
                    unknown amount of endosulfan to provoke abortion.
                    Neither fetal movement or heart tones were audible as
                    early as four hours after the clinical symptoms
                    occurred. Such low concentrations of endosulfan in the
                    blood of the mother as 0.47 microgram/g of the poison
                    caused relatively quick fetus death (Sancewicz -Pach
                    et al, 1997) 
    
                    Breast feeding

        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 endosulfan
             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 fluid 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 powder. Do not give fats, oils or milk
             as these will enhance 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 by slow
             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

             A professional agricultural pilot who, following an
             emergency landing , was soaked with Methomyl (a carbamate)
             and Endosulfan (an organochlorine)  leaking from  his
             aircraft. He developed cholinergic symptoms within an hour of
             the accident, which settled spontaneously, but he suffered a
             toxic-clonic seizure some 6 hours later while in the
             hospital. The seizure was attributed to exposure to the
             organochlorine, however, subsequent EEG recordings
             demonstrated foci of non-specific epileptiform activity in
             the frontal lobes. The pilot made a full recovery and has
             remained seizure-free without treatment (Cable & Doherty,
             1999).
    
             Eighteen cases of endosulfan poisoning by accidental
             overexposure, during spray, was reported in Northern India
             between October 1995 to September 1997. Nausea, vomiting,
             abdominal discomfort, tonic and clonic convulsions,
             confusion, disorientation and muscular twitching were
             cardinal manifestations. None of the patients were affected
             to their illness. All the patients avoided preventive
             measures and developed toxicity both due to inhalation and
             absorption through skin (Chugh et al., 1998).
    
             A case of nonacidental endosulfan intoxication in a
             previously healthy 43-year-old male patient is reported by
             Boereboom et al. (1998). On admission the patient has a few
             symptoms, but refractory seizures began 1 hour after
             ingestion. The patient died on the fourth day after admission
             showing clinical signs of cerebral herniation confirmed at
             autopsy.
    
             A 21-year-old woman, 5-month pregnant ingested an unknown
             amount of endosulfan to provoke abortion. Gynecological
             examination and abdominal ultrasonography revealed
             longitudinal pelvic presentation of the fetus. Neither fetal
             movement or heart tones were audible as early as four hours
             after the clinical symptoms occurred. Such low concentrations
             of endosulfan in the blood of the mother as 0.47 microgram/g
             of the poison caused relatively quick fetus death (Sancewicz
             et al, 1997).
    

             A teenage girl with acute endosulfan poisoning developed
             psychosis , generalized tonic--clonic seizures myoclonic
             jerks, cortical blindness and limb rigidity. Serial magnetic
             resonance  imaging (MRI) showed bilateral reversible lesions
             localized caudate nucleus, putamen and occipital cortex,
             internal capsule and thalamus were spared (Pradhan et al.,
             1997)
    
             A 28 year old woman with a past history of epilepsy presented
             with refractory grand mal seizures after injecting 1 mL of
             thiodan intravenously. She developed liver dysfunction,
             proximal myopathy secondary to rhambomyolysis and renal
             failure. The seizures were terminated with midazolam and
             thiopentone. Mechanical ventilation was required for nine
             days. Renal and liver dysfunction resolved with supportive
             measures only. Hemodialysis was not required. Pulmonary
             complications and neurological sequelae were minimal with the
             patient making full recovery (Grimmett et al., 1996).
    
             A case of generalized seizures following ingestion of 20 cc
             of endosulfan (Endocel) was reported by Sood et al  (1994).
             The patient, a young male of 25 years presented signs due to
             involvement of the cholinergic neuronal system and of status
             epilepticus. He made a complete recovery.
    
             Six patients with acute endosulfan intoxication were reported
             by Blanco-Coronado et al (1992). The symptoms of nausea,
             vomiting, headache, and dizziness began 2.7 +/- 0.25 hour
             after ingestion; in four cases the patients had been
             hospitalized,  although asymptomatic. All had severe
             metabolic acidosis with high anion gap and hyperglycemia;
             five out of six had thrombocytopenia, in three of them
             pulmonary aspiration occurred and five required mechanical
             ventilation. The only fatality was due to acute renal
             failure, disseminated intravascular coagulation, thrombosis
             of  the pulmonary arteries and aorta, and cardiogenic shock.
             In this patient the blood endosulfan was 2.85 mg/L versus
             mean of 0.48 mg/L in the survivors. 
    
             The clinical course following endosulfan ingestion in a 
             suicidal attempt is described by Shemesh et al., (1988). The
             clinical picture comprised three stages: the acute cardiac
             and convulsive stage followed by pulmonary and convulsive
             stage and finally the slow recovery stage. 
    

             A case of acute poisoning by endosulfan  in  an  industrial
             worker, with residual  psychiatric syndrome is described by
             Aleksandrowicz (1979). The main route of exposure (not
             sufficiently explained in the paper) was most probably
             inhalation and dermal contact.The acute phase was manifested
             by reported  convulsions  and  impaired consciousness. After
             recovery  the patient became disoriented and agitated. The
             residual phase, 2 years  after initial hospitalization, was
             manifested by cognitive and emotional defects, severe
             impairment  of memory and inability to perform any but the
             simplest tasks. Psychological tests revealed gross impairment
             of visual - motor coordination. The differential diagnosis of
             chronic brain syndrome requires accurate history and milder
             cases of endosulfan poisoning may easily be overlooked or
             misdiagnosed 

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Rescuers must take precautions not to contaminate
             themselves.

        12.2 Other

             Degradation of endosulfan in soil and water by
             photolysis, chemical reactions and biotransformation  is
             governed by a wide range of climatic  factors  and the type
             of microorganisms present.
    
             Endosulfan does not appear to be a problem with regard to
             persistence. It is not readily bioaccumulated. In aquatic
             organisms, loss soon balances uptake and fairly low  plateau 
             level of residues is achieved.
    
             Endosulfan is hazardous in acute overexposed for some aquatic 
             species, especially fish. There has  been large-scale field
             experience with  endosulfan without any long-term adverse
             effects on the environment.
    
             Careful application to avoid overexposure of non-target
             organisms does not eliminate kills in local fish populations
             when endosulfan is applied to  wetland areas at recommended
             rates. Because there is little or no biomagnification,
             endosulfan, when applied at recommended rates,  is not
             hazardous to terrestial animals. Toxicity for bees is low to
             moderate. (IPCS, 1984).

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        pollutants. Environ Health Perspectives 103 (Suppl. 7),
        113-122.
    

        Tomlin C ed. (1994) The Pesticide Manual. Incorporating the
        Agrochemicals Handbook. The British Crop Protection Publications
        p.171-172.
    
        Usha Rani MV, Reddi OS, Reddy PP (1980) Mutagenicity studies
        involving aldrin, endosulfan, dimethoat, phosphamidon, carbaryl
        and Ceresan. Bull Environ Contam Toxicol 25, 277-282.
    
        Wade M G, Desaulniers D, Leingartner K, Foster  W G  (1997)
        Interactions between endosulfan and dieldrin on estrogen-mediated
        processes in vitro and in vivo. Reprod  Toxicol  11, 791-798. 
    
        Yadav AS, Vashishat RK, Kakar SN. (1982) Testing of endosulfan and
        fenitrothion for genotoxicity in Saccharomyces cerevisiae. Mutat.
        Res., 105, 403-407.

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

        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: July 2000
    
        Reviewer:
        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
       Endosulfan (EHC 40, 1984)
       Endosulfan (HSG 17, 1988)
       Endosulfan (PDS)
       Endosulfan (FAO Meeting Report PL/1965/10/1)
       Endosulfan (FAO/PL:1967/M/11/1)
       Endosulfan (FAO/PL:1968/M/9/1)
       Endosulfan (WHO Pesticide Residues Series 1)
       Endosulfan (WHO Pesticide Residues Series 4)
       Endosulfan (WHO Pesticide Residues Series 5)
       Endosulfan (Pesticide residues in food: 1982 evaluations)
       Endosulfan (Pesticide residues in food: 1989 evaluations Part II Toxicology)
       Endosulfan (JMPR Evaluations 1998 Part II Toxicological)