| 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|
| 2.1 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|
| 4.1 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|
| 6.1 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|
| 7.1 Mode of action|
| 7.2 Toxicity|
| 7.2.1 Human data|
| 18.104.22.168 Adults|
| 22.214.171.124 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|
| 126.96.36.199 Toxicological analyses|
| 188.8.131.52 Biomedical analyses|
| 184.108.40.206 Arterial blood gas analysis|
| 220.127.116.11 Haematological analyses|
| 18.104.22.168 Other (unspecified) analyses|
| 8.1.2 Storage of laboratory samples and specimens|
| 22.214.171.124 Toxicological analyses|
| 126.96.36.199 Biomedical analyses|
| 188.8.131.52 Arterial blood gas analysis|
| 184.108.40.206 Haematological analyses|
| 220.127.116.11 Other (unspecified) analyses|
| 8.1.3 Transport of laboratory samples and specimens|
| 18.104.22.168 Toxicological analyses|
| 22.214.171.124 Biomedical analyses|
| 126.96.36.199 Arterial blood gas analysis|
| 188.8.131.52 Haematological analyses|
| 184.108.40.206 Other (unspecified) analyses|
| 8.2 Toxicological Analyses and Their Interpretation|
| 8.2.1 Tests on toxic ingredient(s) of material|
| 220.127.116.11 Simple Qualitative Test(s)|
| 18.104.22.168 Advanced Qualitative Confirmation Test(s)|
| 22.214.171.124 Simple Quantitative Method(s)|
| 126.96.36.199 Advanced Quantitative Method(s)|
| 8.2.2 Tests for biological specimens|
| 188.8.131.52 Simple Qualitative Test(s)|
| 184.108.40.206 Advanced Qualitative Confirmation Test(s)|
| 220.127.116.11 Simple Quantitative Method(s)|
| 18.104.22.168 Advanced Quantitative Method(s)|
| 22.214.171.124 Other Dedicated Method(s)|
| 8.2.3 Interpretation of toxicological analyses|
| 8.3 Biomedical investigations and their interpretation|
| 8.3.1 Biochemical analysis|
| 126.96.36.199 Blood, plasma or serum|
| 188.8.131.52 Urine|
| 184.108.40.206 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|
| 220.127.116.11 Central nervous system (CNS)|
| 18.104.22.168 Peripheral nervous system|
| 22.214.171.124 Autonomic nervous system|
| 126.96.36.199 Skeletal and smooth muscle|
| 9.4.4 Gastrointestinal|
| 9.4.5 Hepatic|
| 9.4.6 Urinary|
| 188.8.131.52 Renal|
| 184.108.40.206 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|
| 220.127.116.11 Acid-base disturbances|
| 18.104.22.168 Fluid and electrolyte disturbances|
| 22.214.171.124 Others|
| 9.4.13 Allergic reactions|
| 9.4.14 Other clinical effects|
| 9.4.15 Special risks|
| 9.5 Other|
| 9.6 Summary|
| 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|
|14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)|
International Programme on Chemical Safety
Poisons Information Monograph 576
Chlorinated "cyclodiene" insecticide
1.4 Identification numbers
1.4.1 CAS number:
1.4.2 Other numbers:
EC 602 - 052 - 00 - 5
RCRA Waste Number P050
DOT ID & Guide 2761 151
- Transport Emergency Card: TEC ( R ) 61G41b
1.5 Main brand names, Main trade names
1.6 Main manufacturers, main importers
Agr Evo; Excel; Hinolustan Insecticides; Makhteshim - Agan
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.
The diagnosis is based on the history of exposure
(dermal, inhalational or gastrointestinal) and signs of
central nervous system hyperexcitability including
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
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
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
3. PHYSICOCHEMICAL PROPERTIES
3.1 Origin of the substance
A synthetic product (Budavari et al., 1996)
3.2 Chemical structure
6,7,8,9,10, 10 - hexachloro - 1, 5, 5a, 6, 9, 9a - hexahydro
- 6,9 - methano - 2,4,3 -= benzodioxathiepine 3 - oxide
Molecular formula: C9H6Cl6O3S
Molecular weight: 406.9
3.3 Physical properties
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, 22°C). In ethyl
acetate, dichloromethane, toluene 200, ethanol c.65,
hexane c.24 (all in g/L, 20°C), (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 100°C
(pure) : 106 °C (IPCS/CEC, 1999)
Vapour Pressure, Pa at 80°C :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
Pesticide for use against invertebrate animals
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
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.
Individuals with a history of convulsive disorders would be
expected to be at increased risk from exposure (Mackison et
4.3 Occupationally exposed populations
Factory workers involved in syntheses of endosulfan.
Workers involved in formulating and dispensing
Public health workers involved in pest control.
5. ROUTES OF EXPOSURE
Ingestion occurs through accidental or deliberate
ingestion or accidental ingestion of contaminated
Endosulfan vapor is absorbed by inhalation.
Endosulfan is readily absorbed after dermal contact, at
a degree depending on the type on the type of solvent
Exposure to vapors, dust and aerosols.
No data available.
No data available.
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,
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,
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
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,
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).
7.1 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).
7.2.1 Human data
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,
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,
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
NIOSH REL: Ca TWA 0.1 mg/m3 (skin)
7.2.5 Acceptable daily intake (ADI)0 - 0.006 mg/kg bw
Endosulfan is not carcinogenic (IPCS, 1998a)
Adequate data not available (IPCS, 1984)
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
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).
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
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
126.96.36.199 Toxicological analyses
188.8.131.52 Biomedical analyses
184.108.40.206 Arterial blood gas analysis
220.127.116.11 Haematological analyses
18.104.22.168 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
22.214.171.124 Toxicological analyses
126.96.36.199 Biomedical analyses
188.8.131.52 Arterial blood gas analysis
184.108.40.206 Haematological analyses
220.127.116.11 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
18.104.22.168 Toxicological analyses
22.214.171.124 Biomedical analyses
126.96.36.199 Arterial blood gas analysis
188.8.131.52 Haematological analyses
184.108.40.206 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
220.127.116.11 Simple Qualitative Test(s)
18.104.22.168 Advanced Qualitative Confirmation Test(s)
22.214.171.124 Simple Quantitative Method(s)
126.96.36.199 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
188.8.131.52 Simple Qualitative Test(s)
184.108.40.206 Advanced Qualitative Confirmation Test(s)
220.127.116.11 Simple Quantitative Method(s)
18.104.22.168 Advanced Quantitative Method(s)
22.214.171.124 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
126.96.36.199 Blood, plasma or serum
188.8.131.52 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
8.5 Overall interpretation of all toxicological analyses and
9. CLINICAL EFFECTS
9.1 Acute poisoning
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).
Endosulfan is hazardous by inhalation to a
lesser extent than oral or dermal contact (IPCS,
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
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).
No data available
9.2 Chronic poisoning
No data available
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
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
Arrhythmias may occur owing to myocardial
sensivity to catecholamines (Olson, 1999).
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.
184.108.40.206 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
220.127.116.11 Peripheral nervous system
No data available
18.104.22.168 Autonomic nervous system
No data available.
22.214.171.124 Skeletal and smooth muscle
Rhabdomyolysis may occur.
Nausea, vomiting and diarrhea may
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 &
After ingestion renal injury may
develop (Olson, 1999).
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
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)
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
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).
No data available
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.
126.96.36.199 Acid-base disturbances
Metabolic acidosis may occur.
188.8.131.52 Fluid and electrolyte disturbances
No data available
No data available
9.4.13 Allergic reactions
No data available
9.4.14 Other clinical effects
9.4.15 Special risks
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)
No data available
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
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
If the patient vomited spontaneously, monitor respiratory
functions and watch for signs of pulmonary aspiration.
Remove and discard contaminated clothing. Wash exposed skin
including hair and nails with (soap and) copious amounts of
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.
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
Gastric lavage is indicated if patient seen within 1 hour of
In the case of ingestion of a solution, or an emulsifiable
concentrate, a risk of chemical pneumonitis following
10.4 Enhanced Elimination
Enhanced elimination is not indicated because of the
large volume of distribution of chlorinated hydrocarbon
10.5 Antidote treatment
There is no specific antidote
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
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,
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
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.,
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
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
Rescuers must take precautions not to contaminate
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).
ACGIH (2000) Threshold limit values for chemical substances
and physical agents and biological exposure indices. Cincinnati,
OH: American Conference of Governmental Industrial Hygienists.
Aleksandrowicz DR (1997) Endosulfan poisoning and chronic brain
syndrome. Arch Toxicol 43 (1): 65 - 8.
Arnold SF, Klotz D M, Collins BM, Vonier PM, Guilette LJ,
McLachlan JA (1996) Synergistic activation of oestrogen
receptorwith combinations of environmental chemicals. Science
Ashby J, LeFevre P A , Odum J, Harris CA, Routledge EJ, Sumpter,
J.P. (1997) Synergy between synthetic oestrogens? Nature 385, 494.
Bernardelli BC, Gennari MC (1987) Death caused by ingestion of
endosulfan. J Forensic Sci 32 (4): 1109-12.
Blanco-Coronado JL, Repetto M, Geviestal RJ, Vicente JR, Yelamos
F, Lardelli A (1992) Acute intoxication by Endosulfan. J Toxicol
Clin Toxicol 30 (4): 575 -83.
Boereboom FT, Van Dijk A, Van Zoonen P, Meulenbelt J (1998)
Nonaccidental endosulfan intoxication: a case report with
toxicokinetic calculations and tissue concentrations. J Toxicol
Clin Toxicol 36 (4): 345 -52).
Bremmer JN (1997a) Endosulfan: Substance technical (code:
Hoe002671 00 ZD99 0008) Testing for primary dermal irritation in
therabbit. Unpublished Hoechst Marion Roussel preclinical
developmentstudy No. 96.0837. Hoechst document A58442. Submitted
to WHO by Hoechst Schering AgrEvo GmbH, Frankfurt-am-Main,
Bremmer JN (1997b) Endosulfan: Substance technical (code:
Hoe002671 00 ZD99 0008) Testing for primary eye irritation in the
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Hoechst Schering Agr Evo GmbH, Frankfurt-am-Main, Germany.
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chemicals, drugs, and biologicals, 12th ed. Rahway, New Jersey,
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Cable GC, Doherty S (1999) Acute carbamate and organochlorine
toxicity causing convulsions in an agricultural pilot: a case
report. Aviat Space Environ Med 70 (1): 68 -72).
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environmental quality (NRC Associate Committee on Scientific
Criteria for Environmental Quality, Report No. 11,Subcommittee of
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Dorough MW, Huhtanen K, Marshall TC, Bryant HE (1978) Fate of
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Lyons, France, International Agency for Research on Cancer (XIV +
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IPCS (1984) Environmental Health Criteria Monographs 40.
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IPCS (1998a) Inventory of IPCS and other WHO pesticide evaluations
and summary of toxicological evaluations performed by the Joint
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IPCS/CEC (1999) International Chemical Safety Cards: 0742
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Nederlandse Maatschappij ter bevordering der Pharmacie,
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HoechstSchering AgrEvo GmbH, Frankfurt-am-Main, Germany.
Leist KH. (1989) Endosulfan-substance technical (code: Hoe
002671 oi ZD97 0003). Carcinogenicity study in mice, 24 months
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Mackison FW, Stricoff RS, Partridge LJ (1981)
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Moriya M, Ohta T, Watanabe K, Miyazawa T, Kato K, Shirasu Y(1983)
Further mutagenicity studies on pesticides in bacterial reversion
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Olson KR ed. (1999) Poisoning and drug overdose. Appleton and
Pradhan S, Pandey N, Phadke RV, Kaur A, Sharma K, Gupta RK
(1997)Selective involvement of basal ganglia and occipital cortex
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Leonard L S, Gaido K W, Bocchinfuso W P, Korach K S, Safe S
(1997) Estrogenic activity of a dieldrin/toxaphene mixture in
themouse uterus, MCF-7 human breast cancer cells, and
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Reigart RJ, Roberts JR (1999) Recognition and Management of
Pesticide Poisonings. 5th ed.U.S. Environment Protection Agency
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Serrano, F O (1995) The E-screen assay as a tool to
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14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
Dr Nida Besbelli
World Health Organization
CH-1211 Geneva 27,
Telephone 41 22 791 4287
Facsimile 41 22 791 4848
Prepared: July 2000
Janusz Szajewski, MD
Warsaw Poisons Centre
Telephone 48 22 839 0677
Facsimile 48 22 839 0677
Peer review: INTOX 12 Meeting, 7 - 11 November 2000
Drs J. Szajewski, C.Alonzo, R. Fernando.