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HEXACHLOROCYCLOHEXANE
(MIXED ISOMERS)

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. PHYSICO-CHEMICAL 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 Odour:
   3.4 Other characteristics
4. USE
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description of use
   4.2 High risk circumstances of poisoning
   4.3 Occupationally exposed population
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion by route of exposure
7. TOXICOLOGY
   7.1 Mode of Action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adult
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in-vitro data
      7.2.4 Work place standards
      7.2.5 Acceptable Daily Intake
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
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 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscles
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      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 Relevant laboratory analysis and other investigations
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. Illustrative cases
   11.1 Case reports from the literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. Additional information
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. References
14. Author, reviewer, date, complete address

International Programme on Chemical Safety

Poisons Information Monograph 257

Chemical

1. NAME

1.1 Substance

Hexachlorocyclohexane is the correct name. The name Benzene Hexachloride is incorrectly used for 1,2,3,4,5,6- hexachlorocyclohexane. It should not be confused with hexachlorobenzene. The technical product is a mixture of isomers of this compound and related compounds that may vary in relative concentrations (Hayes, 1991). gamma- isomer is known as lindane.

1.2 Group

Organochlorine Insecticide

1.3 Synonyms

Benzahex; Benzex; BHC; Compound-666; DBH; DOL; Dolmix; ENT 8 601; FBHC; Gammexane; Gexane; HCCH; HCH; Hexablanc; Hexachlor; Hexachloran; Hexachlorocyclohexane; Hexafor; Hexamul; Hexapoudre; Hexyclan; Hexylan; Hilbeech; Kotol; Soprocide; Submar; TBH; Technical BHC; Technical HCH; Tri-6 (HSDB, 2000)

1.4 Identification Numbers

1.4.1 CAS number

608-73-1 (IARC, 1979) (Budavari, 1989)

1.4.2 Other numbers

UN NUMBER:

UN 2761; UN 2762; UN 2762; UN 2995; UN 2996

IUPAC NUMBER:

Not available

NCI NUMBER:

Not available

RTECS NUMBER

GV 3150000

OHM-TADS NUMBER

8100012

1.5 Main Brand Names/ Main Trade Names:

Agrocide, Ambrocide, Benesan, Benexane, Borer-Tox, Gamason (Hayes 1991)

1.6 Main Manufacturers/ Main Importers:

To be completed by each centre.

2. SUMMARY

2.1 Main risks and target organs

The main target organ is the central nervous system. Technical HCH is a mixture of alpha, beta, gamma and delta isomers and these isomers differ qualitatively and quantitatively in biological activity. The alpha and gamma isomers are central nervous stimulants and beta and delta are depressants. In a mixture of these isomers, one component may counteract the effect of another element and the final effect may depend on the composition (Gosselin, 1984). It also affects the heart and the liver (Ryan & Terry, 1996).

2.2 Summary of clinical effects

After ingestion, there is a latent period varying from about half hour to several hours (usually between 2 and 12 hours).

Symptoms include: hyperirritability and central nervous excitation with vomiting, faintness, tremor, restlessness, muscle spasms, ataxia and clonic and tonic convulsions. In infants and children, hyperpyrexia may be a consequence of the convulsions. Ensuing coma of variable duration can lead to respiratory failure and death within 24 hours. Second episodes of convulsions may occur after consciousness is regained. Possibility of retrograde amnesia. Pulmonary oedema was observed in two fatal paediatric intoxications (Gosselin, 1984).

The cardiovascular effect caused by technical grade HCH is ECG abnormalities. Its hepatic effects are from chronic exposure and include: increase in the enzymes lactate dehydrogenase, leucine aminopeptidase and gamma-glutamyl transpeptidase (Ryan & Terri, 1996).

Dermal exposure may cause occasional dermatitis and urticaria. Prolonged dermal or inhalation exposure may cause systemic intoxication (Clayton, 1981).

2.3 Diagnosis

Diagnosis is based on the history of exposure and clinical presentation especially CNS hyperirritability (Olson, 1990). Persistence of neurological and gastrointestinal disturbances might confirm the diagnosis. Blood levels may only be useful in order to confirm exposure and demonstrate the elimination of the chemical.

2.4 First-aid measures and management principles

Emesis is contraindicated because convulsions may occur soon.

Do not give milk, fat or oils.

Do not administer adrenergic amines, which may increase myocardial irritability.

Control convulsions with appropriate drug regimen (see Convulsions Treatment Guide).

Maintain a clear airway.

Aspirate secretions from airway.

Perform cardio-respiratory resuscitation.

In case of eye contact, irrigate eyes immediately with water or saline.

In case of skin contact, wash skin with copious amount of soap and water.

In case of ingestion, gastric lavage may be indicated; in severe cases, precede endotracheal intubation with a cuffed tube.

Administer activated charcoal.

Cathartics (not mineral oils) may be administered.

Monitor fluid and electrolyte balance.

Monitor acid-base balance.

3. PHYSICO-CHEMICAL PROPERTIES

3.1 Origin of the substance

As produced initially by photochlorination of benzene, HCH contains 14-77% of the gamma-isomer. Technical grade HCH was available commercially in the US and fortified HCH (FHCH) containing a varying mixture of at least 5 isomers, with a minimum of 40% gamma isomer. Typical isomer distribution is as follows (% by wt):gamma, 40-45; delta, 20-22; alpha, 18-22; beta, 4; epsilon and inerts, 1 (IARC, 1979).

In USA, all HCH registration has been changed administratively to lindane registrations. HCH is no longer produced in USA and cannot be sold for domestic use by EPA regulation as well as many other countries (FCH, 1984).

3.2 Chemical structure

Chemical name:

1, 2, 3, 4, 5, 6, -Hexachlorocyclohexane

Relative molecular weight:

290.85 (Lewis, 1997a; 1999)

Chemical formula:

C6H6Cl6

Isomers differ in the spatial positions of the chlorine atoms on the boat and chair forms.

3.3 Physical properties

3.3.1 Colour:

White or yellowish (Lewis, 1997a)

3.3.2 State/form:

solid flakes or powder (Lewis, 1999)

3.3.3 Odour:

persistent musty odour (Lewis, 1997a)

pH: no data

pKa: no data

Viscosity: not applicable

Solubility: Insoluble in water (FCH, 2000; Lewis, 1997a). Soluble in chloroform, ethanol, ether (ILO, 1983, Lewis, 1997a)

Boiling point: No data

Melting point: Vary widely with isomeric composition (Lewis, 1997a).

Flash point: not flammable.

Auto ignition point: not flammable.

Relative vapour density (air=1): no data

Vapour pressure: about 0.0317 mm Hg (20° C) (Lewis, 1999)

3.4 Other characteristics

4. USE

4.1 Uses

4.1.1 Uses

Previously used as an insecticide.

4.1.2 Description of use

The only known use of HCH is as an insecticide, formerly widely used especially in the control of cotton insects (Gosselin, 1984).

In some countries, it may be used for control of leaf hoppers, stem borers in lowland rice, as seed treatment for reduction of wireworm damage in winter and spring sown cereals and for control of pests of cereals, sugar beets and oilseed rape (FCH, 1984).

This product is in the list of UNEP/FAO prior inform consent procedure.

4.2 High risk circumstances of poisoning

Accidental ingestion of food contaminated with HCH has resulted in poisonings (Clayton, 1994).

Contamination of water has occurred from direct application of technical hexachlorocyclohexane or lindane to water for controlling mosquitoes, from the use of HCH in agriculture and forestry and, to a lesser extend, from occasional contamination of wastewater from manufacturing plants (WHO, 1984). Breastfed children can be exposed to HCH through breast milk (Amdur, 1991; UNEP/WHO, 1983).

The main sources of HCH in the human diet are milk, eggs, and other dairy products (WHO, 1984).

4.3 Occupationally exposed population

Production plant workers were exposed to HCH or lindane (Tomczak, 1981; Brassow, 1981)

Pesticide sprayers had been exposed during field spraying (Gupta, 1982).

Conjunctivitis and dermatitis have been reported but appeared to be unusual and were usually related to exceptionally heavy exposure (Hayes, 1991).

5. ROUTES OF ENTRY

5.1 Oral

Acute toxicity may follow ingestion of large amount of HCH. Sub chronic or chronic toxicity may occur after ingestion of contaminated water or food (Macnamara, 1970). Ingestion is not the main route of entry of HCH except in breastfeeding of babies.

5.2 Inhalation

Studies done on occupationally exposed subjects showed that HCH may be absorbed by inhalation but no report of acute poisoning by that route of exposure has been found (Chattopadhyay, 1988; Chandra, 1992; Nigam, 1986). Absorption of HCH in the lungs is possible when these materials are used as dust or liquid sprays (Clayton, 1994).

5.3 Dermal

HCH is readily absorbed through skin especially in occupational exposure (Chattopadhyay, 1988).

Serious accidental poisonings in general population occurred after dermal exposure to HCH (Clayton, 1994).

5.4 Eye

No data available.

5.5 Parenteral

No data available.

5.6 Others

No data available.

6. KINETICS

6.1 Absorption by route of exposure

HCH is absorbed from gastrointestinal tract, the lungs and the skin. Studies have demonstrated that absorption may vary from 80 to 95 % . Variation of dosage rates had no influence on the proportion absorbed but average absorption of the isomers differed from: alpha-HCH, 9.4 % ; beta-HCH, 90.7 % , gamma-HCH, 99.4 % ; delta-HCH, 91.9 % .

It is claimed that more rapid absorption of HCH occurs if it is administered with an alkyl surfactant. This increase in absorption is greater with single doses than with repeated doses (Clayton, 1981).

Peak values are reached in 2-5 days. After intraperitoneal injection, 34% of dose was recovered in faeces, mostly unchanged, and 5% in urine (Gosselin, 1984)

6.2 Distribution by route of exposure

It has been shown that all isomers of HCH are distributed to all organs within 5 minutes after intraperitoneal injection (Nakajima, 1970). All isomers of HCH are preferentially stored in fat but over 30 times more isomer beta than gamma is stored at equivalent dosage levels.

It seems that there is a greater and more prolonged storage of the beta isomer (Amdur, 1991).

HCH have been detected in human milk and blood (IARC, 1979). Transplacental passage has been established. (IARC, 1979; Roncevic, 1987)

6.3 Biological half-life by route of exposure

Intraperitoneally administered HCH was eliminated in rats at a rate of 5 to 10 % of a dose per day. (Amdur, 1991).

Whole body elimination half-lives for beta-isomers may vary from 37-71 days in rats (Richter, 1981).

6.4 Metabolism

Mammalian biotransformation of HCH isomers involves formation of chlorophenols (trichlorophenol, tetrachlorophenol and pentachlorophenol) that are then conjugated with sulphuric and glucuronic acids (National Research Council, 1977). Hepatic oxidative enzymes are induced by HCH (Gosselin, 1984). Increased liver enzymes have been reported in individuals exposed to technical grade HCH principally by inhalation in a pesticide formulating plant (Kashyap, 1986). In animal experiments, ingestion of alpha, beta, and gamma-HCH and technical grade HCH results in some degree of increased microsomal activity (Tryphonas & Iverson, 1983).

6.5 Elimination and excretion by route of exposure

Trichlorophenol, tetrachlorophenol and pentachlorophenol and their conjugates of sulphuric and glucuronic acids are found in urine.

When single doses of 36Cl- labelled alpha-HCH and lindane were given intraperitoneally to rats at levels of 200 mg/kg bw and 40 mg/kg bw, respectively, approximately 80% of the total radioactivity was excreted in the urine and 20% in the faeces (IARC, 1979).

In rats, 65% of an intraperitoneal dose of 14C-alpha-HCH was excreted in the urine and 16 % in the faeces within 4 weeks (IARC, 1979).

beta-HCH is less efficiently excreted than other HCH isomers and is eliminated 5 times more slowly from the body than the other isomers.

HCH is also excreted in human milk. Although alpha, beta and gamma isomers were all found as residues in human milk, the alpha and gamma isomers are more rapidly metabolised and the beta isomers accounted for 90% of total HCH isomer residue (Amdur, 1991).

7. TOXICOLOGY

7.1 Mode of Action

HCH isomers differ quantitatively and qualitatively in biological activity. The alpha and gamma HCH isomers are central nervous system stimulants causing violent epileptiform convulsions. The beta and delta isomers are mainly depressant (Gosselin, 1984; Lewis, 1999).

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 or Ca2+ - ATPase activity may also be involved, as well as phosphokinase activities (Hayes 1991). A major site of action of HCH and its isomers appear to be at the synapse in the rat (Hayes and Laws, 1991).

It seems that HCH and its isomers could act on the GABA receptor-linked chloride channel although the mechanism is highly complex and is still not completely elucidated (Hayes & Laws, 1991). In the nervous system, gamma-HCH is thought to interfere with the gamma-aminobutyric acid (GABA) system by interacting with the GABA-A receptor-chloride channel complex at the picrotoxin binding site. Thus the seizures caused by gamma-HCH can be antagonized by GABA-A mimetics. Other suggestive data concerning mechanisms by which HCH causes neurological effects in animals includes enhanced synaptic activity, altered GABA functional activity, and inhibition of Na+ -K+-ATPase. (ATSDR, 1994, Ratra et. al, 2001).

In the liver, gamma-HCH is thought to act by interfering with hepatic oxidative capacity and glutathione metabolism. Another possible mechanism for hepatic toxicity is the increased lipid metabolism. Inhibition of Mg2+ATPase activity has been observed in rat liver tissue, suggesting an ATPase enzyme sensitivity to the action of gamma-HCH. The researchers suggested that some toxic effects appearing in mammals as a result of gamma-HCH exposure may arise from its influence on this ATPase activity. (ATSDR, 1994).

7.2 Toxicity

7.2.1 Human data

7.2.1.1 Adult

The dangerous acute dose of the technical mixture has been estimated at about 30 g (Lewis, 1999).

The mean lethal dose of technical HCH may be about 400 mg/kg when ingested by man (Gosselin, 1984).

Inhalation of more than 400 µg/kg within 3 days may cause toxic effects.

7.2.1.2 Children

The fatal poisoning of a 5 years old girl weighting 22 Kg was caused by an accidental ingestion of 4.5 g of hexachlorocyclohexane as a 30 % solution in an unspecified organic solvent. This represents a dosage of 180 mg/kg.

7.2.2 Relevant animal data

Oral:

 

LDLo (Guinea pig)

1400 mg/kg

LD50 (Rat)

100 mg/kg

LD50 (Mouse)

59 mg/kg

LD50 (Chicken)

597 mg/kg

LD50 (Quail-laboratory)

120 mg/kg

LD50 (Bird-wild species)

56 mg/kg

Dermal:

 

LD50 (Rat)

900 mg/kg

(Lewis, 1996)

 

Inhalation:

 

LC50 (Rat)

690 mg/m3

(LOLI, 2000)

 

The beta isomer produces lameness of the CNS and a peculiar flaccidity of the entire musculature (Hayes, 1991).

In rats, the acute toxicity of isomers of HCH decreases in the order gamma < alpha < delta < beta. However, the toxicity of repeated doses decreases in the order beta < alpha < gamma < delta. The long-term toxicity of the different isomers is directly related to their adipose tissue storage and inversely related to their rate of metabolism (Hayes, 1991).

Significant decreases in total white blood cell counts and clotting time were reported in rats fed Vitamin A free diets containing technical HCH at a dose level of 50 mg/kg/day for 7 weeks (Joseph et al, 1992).

7.2.3 Relevant in-vitro data

No data available.

7.2.4 Work place standards

Australia:

TWA 0.5 mg/m3; Skin

Belgium:

TWA 0.5 mg/m3; Skin

Finland:

TWA 0.5 mg/m3; Skin; Carcinogen

Germany:

TWA 0.5 mg/m3; Skin

Hungary:

TWA 0.5 mg/m3; STEL 0.1 mg/m3; Skin

Poland:

MAC (TWA) 0.05 mg/m3

 

MAC (STEL) 0.4 mg/m3

Russia:

TWA 0.05 mg/m3; Skin; STEL 0.1 mg/m3; Skin

Switzerland:

TWA 0.5 mg/m3; Skin

United Kingdom:

TWA 0.5mg/m3; STEL 1.5 mg/m3; Skin;

(RTECS, 2000)

 

7.2.5 Acceptable Daily Intake

FAO/WHO did not allocate ADI for technical HCH.

7.3 Carcinogenicity

The International Agency for Research on Cancer (IARC) has evaluated hexachlorocyclohexanes. They are classified under Group 2B. Evidence for carcinogenicity to humans is inadequate and evidence for carcinogenicity to animals is sufficient. (IARC, 1984).

Several case reports indicate a relationship between exposure to HCH or lindane and the occurrence of aplastic anaemia. An increase in lung cancer mortality was observed in agricultural workers who had used hexachlorocyclohexane (unspecified) and a variety of other pesticides and herbicides. Data available are insufficient for any conclusion to be drawn.

Technical grade alpha and beta-HCH and gamma isomer (lindane) produced liver tumours in mice when administered orally; the technical grade also produced lymphoreticular neoplasms. In two studies in rats, an increased incidence of liver tumours was observed with the gamma isomer, and in one study in rats a few thyroid tumours were observed with the gamma isomer; other studies were considered to be inadequate. Technical grade HCH and the gamma isomer were cancer tested inadequately by skin application in mice. alpha-HCH enhanced the incidence of liver neoplasms induced in rats by N-nitrosodiethylamine (IARC, 1979; IARC, 1984).

7.4 Teratogenicity

HCH isomers have been shown to cross placenta in animals. They are also present in human umbilical cord blood with foetal concentrations proportional to maternal concentrations (IARC, 1979)

HCH isomers given to pregnant mice are concentrated in the spleen, thymus and kidney of foetus with evidence of immune system alteration in the offsprings (Das, 1990).

Developmental toxicity studies in human have not been reported.

7.5 Mutagenicity

Technical-grade HCH, but not gamma-HCH, induced dominant lethal mutations in mice; chromosomal aberrations were not found in bone marrow cells of mice exposed to technical grade or gamma-HCH in vivo. gamma-HCH did not induce unscheduled DNA synthesis in human cells in vitro and did not induce micronuclei or chromosomal aberrations in cultured rodent cells; it induced DNA strand breaks but not unscheduled DNA synthesis. It did not induce sex linked recessive lethal mutations. beta-HCH was not mutagenic to yeast, but the gamma isomer induced gene conversion. Neither gamma nor beta-HCH were mutagenic to bacteria, and gamma and beta-HCH did not cause DNA damage in bacteria (IARC, 1984).

7.6 Interactions

Xylene used as a solvent in commercial sheep-dip concentrate, enhances the toxicity of HCH (Clarke et. al, 1981)

Anything that causes mobilization of fat (starvation or administration of adrenaline, ACTH, or thyroid-stimulating hormone) will cause mobilization of highly fat soluble compounds and make them more readily available for metabolism and subsequent excretion (Hayes, 1991).

8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

To be prepared by analytical toxicology experts.

9. CLINICAL EFFECTS

9.1 Acute poisoning

9.1.1 Ingestion

Irritability and central nervous excitation: notably vomiting, restlessness, muscle spasm, ataxia, tonic and clonic convulsions. Subsequently, central nervous system depression leads to respiratory failure. Occasional dermatitis and urticaria may develop. Symptoms generally appears within 2 hours but sometimes as late as 12 hours (Gosselin, 1984).

9.1.2 Inhalation

Inhalation may cause irritation of nose and throat. There is no report of acute poisoning following inhalation of HCH in human.

9.1.3 Skin exposure

HCH is absorbed through the skin and may lead to poisoning.

9.1.4 Eye contact

Eye exposure may cause irritation.

No data on systemic toxicity following eye exposure.

9.1.5 Parenteral exposure

No data available.

9.1.6 Other

No data available.

9.2 Chronic poisoning

9.2.1 Ingestion

Chronic ingestion of HCH contaminated-bread has produced grand mal epilepsy (Clayton, 1994).

In animals, chronic ingestion of HCH induced marked histological changes in both the liver and the kidneys (Philip, 1989).

9.2.2 Inhalation

Workers exposed to HCH by inhalation showed paresthesia of the face and extremities, headache and giddiness and, a few of them also presented symptoms of malaise, vomiting, tremors, apprehension, confusion, insomnia, impaired memory and loss of libido (Nigam, 1986).

9.2.3 Skin exposure

Symptoms of chronic skin exposure in workers are the same as those following inhalation but more severe and more frequent (Nigam, 1986).

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

Apprehension, excitability, dizziness, headache, disorientation, weakness, paresthesia, muscle twitching, tremor, tonic and clonic convulsion and unconsciousness are the major manifestations. Soon after ingestion, nausea and vomiting commonly occur. When chemicals are absorbed by skin, apprehension, twitching, tremors, confusion and convulsions may be the first symptoms. Respiratory depression is caused by the pesticide and by the petroleum solvents in which these pesticides are usually dissolved. Rhabdomyolysis may occur. Even though convulsive activity may be severe, the prognosis is fairly good. Although fatalities have occurred following absorption of large amounts of some organochlorine, there is a substantial likelihood of complete recovery if convulsions can be controlled, and vital functions sustained. (US EPA, 1982).

9.4 Systematic description of clinical effects

9.4.1 Cardiovascular

Acute: Cardiac arrhythmias may occur (Morgan, 1989).

9.4.2 Respiratory

Acute: Irritation, cyanosis, pulmonary oedema and chemical pneumonitis may occur (Morgan, 1989) (Jaeger, 1984).

9.4.3 Neurological

9.4.3.1 CNS

Acute: CNS excitation: hyperexcitability, hyperreflexia, tremor, ataxia, agitation, convulsions.

In overdose, CNS depression is possible.

Chronic: Headache, dizziness, drowsiness, irritability, muscle twitching, myoclonic jerks and convulsions, anorexia, fatigue and malaise (Baker, 1990)

9.4.3.2 Peripheral nervous system

Paresthesia, numbness of extremities

Acute: Tremor and twitching are common.

9.4.3.3 Autonomic nervous system

No data available

9.4.3.4 Skeletal and smooth muscles

Rhabdomyolysis has been reported (Jaeger,1984)

9.4.4 Gastrointestinal

Nausea, vomiting and diarrhoea may occur following ingestion.

9.4.5 Hepatic

Acute: Hepatic oxidative enzymes are induced by HCH (Gosselin et. al, 1984).

Chronic: Hepatomegaly, liver cell changes were seen in rats (Philip et. al, 1989).

9.4.6 Urinary

9.4.6.1 Renal

Acute: renal failure is secondary to rhabdomyolysis.

Chronic: Histological changes in kidneys have been reported in animals (Philip et. al, 1989).

9.4.6.2 Others

No data available.

9.4.7 Endocrine and reproductive systems

Chronic: Toxicity for human testis with decreased hormone production is suggested by findings among lindane production workers exposed to HCH (Tomczak et. al, 1981)

In sub chronic oral dosing studies, female rats showed ovarian atrophy with doses of 250 mg/kg. There was considerable general toxicity at this dose as well. HCH were found in higher concentrations in follicular fluid and cervical mucus in women with fertility problems (Van Velsen et. al, 1986).

9.4.8 Dermatological

Skin irritation results from extensive contact with HCH. Dermatitis and urticaria may occur (CHRIS, 1994).

9.4.9 Eye, ear, nose, throat, local effects

Chronic: Elevated intra-ocular pressure and functional abnormalities in the central retinal artery of workers involved in the HCH synthesis have been reported (Sivickaja, 1982).

9.4.10 Haematological

Chronic: Repeated exposure may lead to agranulocytosis or aplastic anaemia, even fatal (Gosselin et. al, 1984).

9.4.11 Immunological

A statistically significant increase (app.18% ) in the level of IgM was noted in 19 workers exposed to technical grade HCH during formulation (Kashyap, 1986).

9.4.12 Metabolic

9.4.12.1 Acid-base disturbances

Acute: Severe metabolic acidosis may be a consequence of convulsions.

9.4.12.2 Fluid and electrolyte disturbances

No data available.

9.4.12.3 Others

Acute: Hyperpyrexia may occur in infant and children.

9.4.13 Allergic reactions

No data available.

9.4.14 Other clinical effects

No data available.

9.4.15 Special risks

Pregnancy: HCH passes through the placenta.

Breast-feeding: HCH has been found in breast milk (UNEP/WHO, 1983).

9.5 Other

9.6 Summary

10. MANAGEMENT

10.1 General principles

In case of ingestion, do not induce vomiting and do not give milk, fat or oils by mouth.

Open and maintain at least one intravenous route.

Control the convulsions (see Convulsion Treatment Guide).

Administer activated charcoal.

Maintain clear airways.

Monitor CPK levels and myoglobinuria.

Atropine and adrenaline should be avoided in case of ECG changes.

10.2 Relevant laboratory analysis and other investigations

10.2.1 Sample collection

To be completed by analytical committee.

10.2.2 Biomedical analysis

10.2.3 Toxicological analysis

To be completed by analytical committee.

10.2.4 Other investigations

10.3 Life supportive procedures and symptomatic/specific treatment

Make a proper assessment of airway, breathing, circulation and neurological status of the patient.

Control convulsions using appropriate drug regimen.

Oxygen, intravenous dextrose and thiamine should also be given.

Lidocaine (1mg/kg bw as intravenous infusion followed by 2 – 4 mg/min as continuous infusion) may be indicated in the case of myocardial dysrrhythmias.

Monitor vital signs including ECG changes.

Protect airway in case of convulsions.

10.4 Decontamination

In case of skin contact: Remove and discard contaminated clothing. Wash skin with (soap and) copious amount of water for several minutes.

In case of ingestion, do not induce emesis.

Perform gastric lavage in case of ingestion.

Administer activated charcoal 50 – 100 g and cathartic that has been shown to reduce absorption of HCH.

10.5 Elimination

Enhanced elimination procedures of already absorbed HCH are not indicated.

10.6 Antidote treatment

10.6.1 Adults

Not available.

10.6.2 Children

Not available.

10.7 Management discussion

Since HCH is present in measurable amounts in the blood, fat and human milk along with PCBs and many other organochlorine insecticides, interactions and long-term effects of these contaminants on human health still need to be studied.

11. Illustrative cases

11.1 Case reports from the literature

In Greece, seventy-nine persons were poisoned by a 40% dry powder of HCH or the same powder mixed with either water or a petroleum solvent which was sprinkled on ground, walls and over clothing, bedding and bodies of people. Symptoms were related to gastrointestinal tract and CNS. Eighteen were seriously affected but all survived (Danopoulos, 1953).

A woman who washed two calves with a HCH solution showed severe convulsions but survived. Her arms and hands had been wet to the elbows with the materials. One day after admission, a concentration of 4.95 mg/100 ml of HCH was found in urine (Heiberg, 1955).

An 8 year old boy ate about a dozen of chocolate biscuits which had been sprayed with a product containing 4% HCH. His condition was critical for 48 hours but he recovered fully after 72 hours (Macnamara, 1970).

Eight cases of HCH poisoning followed ingestion of food containing 4% HCH. Three of the victims suffered convulsions, coma, pulmonary oedema and death. Serious illness in the other victims was believed to have been prevented by vomiting (Nag D, 1977).

In a village in Uttas, India, eight persons were poisoned after ingesting wheat bread containing 0.005% HCH. Symptoms reported are grand mal epilepsy and all survived victims. It was found that wheat flour had been contaminated with HCH during storage (Clayton, 1981).

Occupational exposure to HCH in 45 males working in manufacture of hexachlorocyclohexane, including handlers (production workers likely to have the most exposure) and non-handlers (factory operator) has been studied. Exposure occurred primarily via skin. Subjective symptoms included paresthesia, headache, giddiness, vomiting, apprehension and insomnia (Chattopadhyay, 1988).

11.2 Internally extracted data on cases

To be completed by each centre.

11.3 Internal cases

To be completed by each centre.

12. Additional information

12.1 Availability of antidotes

Not applicable.

12.2 Specific preventive measures

Any individual coming into contact with HCH should be instructed in safe handling procedures and in need for strict personal hygiene. He should also be provided with protective equipment (special protective clothing, face shield or goggles) (HSDB, 2000).

12.3 Other

Toxic for aquatic and terrestrial life; bio accumulates. Do not spill in motorways.

13. References

Amdur MO, Doull J & Klaassen CD (1991) Casarett and Doull’s Toxicology, 4th ed., Pergamon Press, New York, NY, USA

ATSDR: Profile for Alpha-, Beta-, Gamma-, and Delta-Hexachlorocyclohexane (Update), US Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, Atlanta, GA, 1994

Baker ST & Wilkinson CF (1990) The Effects of Pesticides on Human Health, Advances in Modern Environmental Toxicology, volume XVIII, Princeton Scientific Publishing Co, Princeton, NJ, USA

Bennett H (1986) Concise chemical and Technical Dictionary, 4th ed., Chemical Publishing Co, New York, NY, USA

Brassow HL, Baumann K & Lehnert G (1981) Occupational Exposure to Hexachlorocyclohexane- II. Health Conditions of Chronically Exposed Workers, Int.Arch.Occ.Environ.Health 49(1), 81-87

Budavari S, O’Neil MJ, Smith A & Heckelman PE (1989) The Merck Index, 11th ed., Merck & Co, Rahway, NJ, USA

Chandra H, Pangtey BS, Modak DP, Singh KP, Gupta BN, Bharti RS & Srivastava SP (1992) Biological Monitoring of Chlorinated Pesticides Among Exposed Workers of Mango Orchards: A case Study in Tropical Climate, Bull. Environ.Cont.Toxicol.48(2), 295-301

Chattopadhyay P, Karnik AB,Thakore KN, Lakkad BC, Nigam SK & Kashyap SK (1988 Health Effects Among Workers Involved in the Manufacture of Hexachlorocyclohexane, J.Soc.Occ.Med. 38(3), 77-81

CHRIS: CHRIS Hazardous Chemical Data. US Department of Transportation, US Coast Guard, Washington, DC. Micromedex, Inc, Englewood, CO (expires October 31, 2000).

Clarke, M. L., D. G. Harvey and D. J. Humphreys, Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981)

Clayton GD & Clayton FE (Eds): Patty's Industrial Hygiene and Toxicology, Volume 2B. Toxicology, 4th ed. John Wiley & Sons, New York, NY, 1994.

Danopoulos E, Mellisinos K & Katsas G: Serious poisoning by hexachlorocyclohexane, clinical and laboratory observations on five cases. Arch Ind Hyg 1985; 7:582-587.

Das SN, Paul BN, Saxena AK & Ray PK (1990) Effect of in utero Exposure to Hexachlorocyclohexane on the Developing Immune System of Mice, Immunopharmacol. Immunotoxicol. 12(2), 293-310

FCH: Farm Chemicals Handbook (1984) Meister Publishing Co, Willoughby, OH, USA

FCH: Farm Chemicals Handbook (2000) Meister Publishing Co, Willoughby, OH, USA

Gosselin RE, Smith RP, Hodge HC (1984), Cinical Toxicology of Commercial Products, 5th ed, Williams and Wilkins, Baltimore, MD, USA

Gupta SK, Parikh JR, Shah MP, Chatterjee SK & Kashyap SK (1982) Changes in Serum Hexachlorocyclohexane (HCH) Residues in Malaria Spraymen after Short-Term Occupational Exposure, Arch. Environ. Health 37(1), 41-44

Hawley GG (1981) The Condensed Chemical Dictionary, 10th ed., Van Nostrand Reinhold Co, New York, NY, USA

Hayes WJ Jr & Laws ER Jr (1991) Handbook of Pesticide Toxicology, 3 vol. Academic Press Inc., San Diego, CA, USA

HSDB: Hazardous Substances Data Bank. National Library of Medicine (2000), Bethesda, Maryland

Heiberg OM, Wright HN, Benzene Hexachloride poisoning. AMA Arch. Ind. Health 1955; 11, 457-458.

IARC (1979) IARC Monographs: Some Halogenated Hydrocarbons Vol. 20, 609 pp

IARC Monographs (1984): An Updating of IARC Monographs Volumes 1 to 42 Supplement 7 440 pp IARC

International Labour Office (1983) Encyclopedia of Occupational Health and Safety, Vol 2, 2538 pp

IPCS (1989) Environmental Health Criteria for Beta-Hexachlorocyclohexane, WHO, Geneva, Switzerland

Jaeger U, Podczeck A, Haubenstock A et al: Acute oral poisoning with lindane-solvent mixtures. Vet Human Toxicol., 1984; 26:11-14.

Joseph P, Shivanandappa T, Narasinhamurthy K, Krishnakumari MK, Effect of Vitamin A on hexachlorocyclohane (HCH) toxicity in the rat. Gen Pharmacol; 1992; 23 (6) .

Kashyap SK Health Surveillance and Biological Monitoring of Pesticides Formulators in India, Toxicology Letters, 1986; vol 33 nos 1/3, pp 107-114.

Lewis RJ: Sax's Dangerous Properties of Industrial Materials, 10th ed. Van Nostrand Reinhold Company, New York, NY, 2000.

LOLI(R): The Regulated Chemicals List of Lists, Compiled by ChemADVISOR, Inc, Pittsburgh, PA (CD-ROM Version), Micromedex, Inc, Englewood, CO, (edition expires 10/31/00).

Macnamara BGP (1970) Benzene Hexachloride Poisoning, Brit. Med. J 3(5722) p.585

Nakajima E, Shindo H& Kurihara N (1970) Distribution of Alpha-, Beta-, and Gamma BHC-14 C in Whole Body Autoradiography in Mice, Radioisotopes 19(11), 532-538

National Institute of Occupational Safety and Health (NIOSH) (2000), Benzene Hexachloride, in Registry of Toxic Effects of Chemical Substances (RTECS)

Morgan D, Recognition and management of pesticide poisonings, 4th ed, U.S. Environmental Protection Agency, Washington, DC , 207pp. 1989.

Nag D, Singh GC & Senon S: Epilepsy epidemic due to benzahexachlorine. Trop Geogr Med 1977; 29:229-232.

National Research Council(1977) Drinking Water and Health, Volume 1, National Academy Press, Washington, DC, USA

Nigam SK, Karnik AB, Majumder SK, Viswerwariah K, Suryanarayana Raju G,

Muktha Bai K, Lakkad BC, Thakore KN & Chatterjee BB (1986) Serum Hexachlorocyclohexane Residues in Workers Engaged at a HCH Manufacturing Plant, Int. Arch.Occ.Enciton.Health 57(4), 315-320

Olson KR (1990)Poisoning and Drug Overdose, a Lange Clinical Manual, Prentice Hall International Inc., Norwalk, Connecticut, USA

Philip GH, Sriraman PK & Ramamurthi R (1989) Histopathological Changes in Liver and Kidney of Mus Booduga Following Oral Benzene Hexachloride (BHC) Feeding. Bull. Environ.Cont. Toxicol. 42(4),499-502

Richter E, Luger W, Klein W, Korte F & Weger N (1981) Excretion of Beta Hexachlorocyclohexane by the Rat as Influenced by Oral Paraffin, Squalene and Lutrol E 400, Ecotoxicol. Environ. Cont. Toxicol. 38(1), 117-124

Roncevic N, Pavkov S, Galetin-Smith R, Vukavic T, Vojinovic M & Djordjevic M (1987) Serum Concentrations of Organochlorine Compounds During Pregnancy and the newborn. Bull.Environ. Cont. Toxicol. 38(19), 117-124

RTECS: Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health, Cincinnati, OH (CD ROM Version), Micromedex, Inc, Englewood, CO, (edition expire 10/31/2000).

Ryan RP, Terry CE (eds) Toxicology Desk Reference, 4th edition, Volumes 1-3, Taylor & Francis, Washington, DC, 1997, 1455p.

Spencer EY (1982) Guide to the Chemicals Used in Crop Protection, 7th ed., Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada

SAX NI, Lewis RJ Jr (1989) Dangerous Properties of Industrial Materials, 7th ed., 3 volumes, Van Nostrand Reinhold, New York, NY, USA

Sivickaja II (1982) Features of the Action of Pesticides on the Eye (abstract), Gigiena truda I professional’nye zabolevanija, 4, 32-35

Tomczak S, Baumann K & Lehnert G (1981) Occupational Exposure to Hexachlorocyclohexane, Int. Arch. Occ. Environ.Health 48(3), 283-287

Tryphonas L, Iverson F, Sequential histopathologic analysis of alpha-hexachlorocyclohexane-induced hepatic megalocytosis and adenoma formation in the HPB mouse, J Natl Cancer Inst. 1983 Dec;71(6):1307-18.

U.S.EPA (1982) Management of Pesticide Poisoning, NTIS, USA

Van Velsen, Danse LH, Van Leeuwen FX, Dormans JA & Van Logten MJ (1986) The Subchronic Oral Toxicity of the Beta-Isomer of Hexachlorocyclohexane in Rats. Fund.Appl. Toxicol. 6,697-712

WHO (1984) Guidelines for Drinking Water Quality Vol.2 Health Criteria and other supporting Information Geneva, Switzerland

Worthing CR (1979) Pesticide Manual, 6th ed., British Crop Protection Council, Worcestshire, England

14. Author, reviewer, date, complete address

Author:

Dr N. Besbelli

Address:

Poison Center
Refik Saydam Hygiene Center
Cemal Gursel Cad. No 18 Sihhiye
06100 Ankara/TURKEY

Tel:

90 312 4337001

Fax:

90 312 4337000

E-mail:

besbelli@servis2.net.tr

Co-author:

Lyse Lefebvre
Pharmacienne

Address:

Institut National de Santé Publique du Québec
Direction de toxicologie humaine
2705, boul. Laurier
Sainte-Foy (Quebec)
CANADA
G1V 4G2

Tel:

(418) 654 2254

Fax:

(418) 654 2148

Peer Review:

Awang R; Besbelli N, Caldas, LQA;
17th. September 2001, Edinburgh


See Also:
        Alpha- and beta-hexachlorocyclohexanes (EHC 123, 1992)
        Hexachlorocyclohexane (IARC Summary & Evaluation, Volume 20, 1979)