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Hexane, n-

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS
      1.4.2 Other numbers
   1.5 Brand names/Trade names
   1.6 Manufacturers, importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Relevant laboratory analyses/sample collection
   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 Description
   3.4 Other characteristics
4. USES/HIGH RISK CIRCUMSTANCES OF POISONING
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High-risk circumstances of poisoning
   4.3 Occupationally exposed populations
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 by route of exposure
7. TOXICOLOGY
   7.1 Mode of action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults (volunteer and clinical case data)
         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) and other guideline levels
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL AND OTHER ANALYSES
   8.1 Sample
      8.1.1 Collection
      8.1.2 Storage
      8.1.3 Transport
   8.2 Toxicological Analytical Methods
      8.2.1 Tests for active ingredient
      8.2.2 Tests for biological sample
   8.3 Other laboratory analyses
      8.3.1 Biochemical investigations
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological or Haemostasiological investigations
      8.3.4 Other relevant biomedical analyses
   8.4 Interpretation
   8.5 References (in section 13)
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 by:
      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 Neurologic
         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 muscle
      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 Dermatologic
      9.4.9 Eye, ears, nose, throat: local effects
      9.4.10 Haematologic
      9.4.11 Immunologic
      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: pregnancy, breastfeeding, enzyme deficiencies
   9.5 Others
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses 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 treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion: alternatives, controversies and research needs.
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 and antisera
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEW(S), DATE, COMPLETE ADDRESSES
    1.  NAME

        1.1  Substance

             n-Hexane

        1.2  Group

             Aliphatic hydrocarbon

        1.3  Synonyms

             Hexyl Hydride
             Normal Hexane
             Hexane
             Hexanan
             Esani (Italian)
             Heksan (Polish)
             Hexanen (Dutch)

        1.4  Identification numbers

             1.4.1  CAS

                    CAS 110-54-3

             1.4.2  Other numbers

                    RTECS: MN 9275000
                    UN Number: 1208 (Ref: United Nations, 1989)
                    EC Number: 601-007-01-4

                    (Ref: Commission of the European Communities, 1987)

        1.5  Brand names/Trade names

             n-Hexane
             Skellysolve B

        1.6  Manufacturers, importers

             Importer: Produced by many companies and widely imported.

    2.  SUMMARY

        2.1  Main risks and target organs

             The target organs are: central and peripheral nervous
             system, respiratory system, heart, skin and eyes.  Chemical
             pneumonia usually occurs after ingestion and aspiration to
             the lungs.  CNS depression, convulsion, coma and death may
             follow acute exposures to large concentrations.
             

             Inhalation of hexane usually causes eye, nose, throat and
             respiratory irritation, which are rapidly reversible, when
             exposure is discontinued.
             
             Symptoms are more severe if ingestion or inhalation are
             associated with exposure to other hydrocarbons, which may
             potentiate the effects.
             
             Exogenous catecholamines may precipitate a fatal ventricular
             arrhythmia in the sensitized myocardium.
             
             Secondary risks:  the products resulting from n-hexane
             combustion (thermal decomposition) are CO and CO2.

        2.2  Summary of clinical effects

             Acute exposure to considerable concentrations of n-
             hexane may cause: cough, wheezing, bloody frothy sputum,
             headache, dizziness, tachycardia and fever.
             
             Gastrointestinal symptoms occur on ingestion.
             
             Exposure to high concentrations of n-hexane occurs usually by
             inhalation, and causes the following symptoms:
             
             -    Respiratory system: slow and shallow respiration;
                  aspiration of n-hexane may cause pulmonary oedema and
                  chemical pneumonia.
             
             -    Cardiovascular system: tachycardia.  Ventricular
                  dysrhythmia is rare.
             
             -    Central nervous systems: vertigo, giddiness, narcotic
                  syndrome.  In heavy exposure unconsciousness,
                  convulsions and coma may occur.
             
             -    Peripheral nervous system: chronic exposure may produce
                  important peripheral neuropathy (motor-sensory) and CNS
                  abnormalities.
             
             -    Gastrointestinal tract: nausea, vomiting and anorexia.
             
             -    Dermatitis and conjunctival irritation may occur.

        2.3  Relevant laboratory analyses/sample collection

             -    n-Hexane and its metabolites may be found in urine but
                  only in recent exposures.
             
             -    Biomedical analysis should be requested according to the
                  clinical state of the patient (at least blood, urine,
                  ECG and chest x-ray in case of poisoning).
             

             -    A sample of the product involved should be available for
                  analysis if needed.
             
             -    After chronic exposure, functional and neurological
                  studies should also be requested:
             
             -    electrophysiological studies may show decreased motor
                  sensory nerve conduction with an increased distal
                  latency period.
             
             -    electromyography may suggest neurogenic disease
             
             -    sural nerve biopsy (giant axonopathy and other
                  anatomical changes)

        2.4  First-aid measures and management principles

             In case of severe exposure by inhalation: move patient
             to fresh air, support respiratory and cardiovascular
             function.  Endotracheal intubation, oxygen and assisted
             ventilation may be necessary.  Avoid use of catecholamines,
             as cardiac dysrrhythmias are potential complications.
             
             Gastric aspirations and lavage may be considered only in the
             conscious patient and when ingestion has been superior to 2
             to 3 mk/kg or when n-hexane is associated with a more toxic
             substance.  The unconscious patient should be pre-
             intubated.
             
             In case of eye exposure, irrigation is required.
             
             Skin decontamination should be done and contaminated clothes
             be removed.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             n-Hexane is a straight-chain saturated hydrocarbon
             obtained from certain petroleum fractions after various
             thermal or catalytic cracking steps.
             
             Commercial hexane may contain from 20 to 85% n-hexane and
             varied amounts of hexane isomer (2-methylpentane, 3-
             methylpentane, 2,3-dimenthylbutane), cyclopentane,
             cyclohexane and small quantities of pentane and heptane
             isomers, acetone, methyl ethyl ketone, dichloromethane and
             trichloroethylene (ACGIH, 1989; Perbellini, et al., 1980,
             1981).  Trace amounts of benzene (0.05%) may be present
             (Baker & Rickert, cited in IPCS draft, 1989).

        3.2  Chemical structure

             C6H14
             
             Molecular weight: 86.18
             (C= 83.62%     H= 16.38%)

        3.3  Physical properties

             3.3.1  Colour

                    Colourless

             3.3.2  State/form

                    Liquid

             3.3.3  Description

                    Boiling point:                     68.64 C
                    Melting point:                     -95 C
                    Flash point:                       -21.6 C (closed
                                                       cup)
                    Autoignition temperature:          225 C
                    Explosive limits(vol % in air):    LEL: 1%, VEL: 7.5%
                    Critical temperature:              234 C
                    Relative vapour density (air = 1)  2.97
                    Vapour pressure:                   20.0 kPa at 25 C
                    Evaporation rate:                  Rapid: specific
                                                       data not
                                                       available
                    Refractive index n20:              D    1.375
                    Saturation vapour concentration:   20% at 25 C
                    Solubility in water:               9.5 mg/L at 25 C;
                                                       Insoluble at C
                    Solubility in other liquids:       Miscible with
                                                       alcohol,
                                                       chloroform, ether
                                                       1-octanol/water
                                                       partition coefficient:
                                                       log Pow 25 C = 3.6
                    Ionization potential:              10.18 eV

        3.4  Other characteristics

             Commercial hexane is a mixture of hexane isomers with
             other hydrocarbons (e.g. cyclopentane, cyclohexane, pentane
             and heptane).
             
             Stable material: probably not sensitive to mechanical
             impact.
             

             Explosion data: vapour can be readily ignited by static
             discharge.  Liquid can accumulate static charge by flow or
             agitation.
             
             Incompatibility: strong oxidizing agents (e.g., peroxides,
             nitrates, perchlorates) can increase risk of fire and
             explosion.
             
             Corrosivity to metal: not corrosive.
             
             Hazardous decomposion product: none.
             
             Hazardous polymerization: does not occur.

    4.  USES/HIGH RISK CIRCUMSTANCES OF POISONING

        4.1  Uses

             4.1.1  Uses

             4.1.2  Description

                    Main uses are as: rubber and adhesive solvent
                    (shoe factory); extraction of vegetable oil (soybean,
                    callous seed, flaxseed); pharmaceutical and cosmetic
                    industries.
                    
                    It is also a cleaning agent for textiles, furniture
                    and leather products.  N-hexane is also used for:
                    determination of refracture index of minerals, filling
                    for thermometers, denaturant for alcohols.  May become
                    a substance of abuse to "sniffers".

        4.2  High-risk circumstances of poisoning

             Adults may be exposed in the workplace or in case of
             suicide attempts.
             
             "Glue-sniffing" or n-hexane sniffing may be a habit in
             teenagers and young adults.
             
             Accidental ingestion may occur in children.

        4.3  Occupationally exposed populations

             Laboratory workers which use the solvent for extraction
             procedures, chemists and pharmacists may be exposed.  The
             factory, glues/adhesives industry workers or people involved
             in printing and painting industry.

    5.  ROUTES OF ENTRY

        5.1  Oral

             Not frequent.

        5.2  Inhalation

             Is the most frequent route of exposure.

        5.3  Dermal

             Absorption may occur but is slow.

        5.4  Eye

             Absorption is minimal

        5.5  Parenteral

             No data available.

        5.6  Others

             Unknown

    6.  KINETICS

        6.1  Absorption by route of exposure

             The pharmacokinetics of n-hexane have been widely
             investigated in the rat, but much less in known in
             humans.
             
             n-hexane is absorbed following inhalation, ingestion, or by
             topical application to the skin.  In human volunteers about
             28% of inhaled n-hexane was taken up by the lungs (Court &
             Milks, 1982).  According to Mutti & Falzai (1984) alveolar
             retention is about 25% of the inhaled dose of n-hexane and
             the final absorption is 15% to 17% in relation to the total
             respiratory uptake.
             
             The n-hexane molecule crosses easily the alveolar-capillary
             membrane and enters the bloodstream.
             
             Alveolar uptake was greater in obese individuals.  Although
             the alveolar uptake rate decreased during physical exercise,
             the total uptake of n-hexane increased slightly as a result
             of the higher lung ventilation rate.  A net lung uptake of
             112 mg/8 h was reported in workers exposed to 180 mg/m3 (51
             ppm) n-hexane (Perbellini et al., 1985).  Alveolar air

             concentrations of n-hexane correlated with blood
             concentrations in industrial workers exposed to commercial
             hexane (Brugnone et al., 1984).
             
             It is poorly absorbed from the gastrointestinal tract as are
             other aliphatic compounds.
             
             Dermal absorption is very slow.  Although the percutaneous
             absorption of n-hexane in man has not been well studied, this
             route of exposure has been implicated in some case reports of
             peripheral neuropathy (Nomiyana et al., 1973; Takahashi et
             al., 1977).
             
             Peak blood levels occur in less than 1hour following
             inhalation or percutaneous exposure (Graham et al.,
             1987).

        6.2  Distribution by route of exposure

             n-hexane has great affinity for high lipid content
             tissues and is rapidly metabolized to hydroxylated compounds
             before being converted to 2,5-hexanedione.
             
             The thermodynamic distribution coefficient of n-hexane
             between the organism and the atmosphere was calculated to be
             = 12 (Filser et al., 1987).

        6.3  Biological half-life by route of exposure

             Mutti et al., (1984) found that the respiratory
             elimination of n-hexane in recently exposed workers was
             biphasic.  They reported that the median half-lives of the
             fast and slow phases were 11 minutes and 99 minutes,
             respectively.

        6.4  Metabolism

             At the first step of the exudative metabolism by
             cytochrome P-450, the carbons 1, 2 and 3 of n-hexane molecule
             are hydroxylated and form hexanols in different proportions
             (in all species of animals).
             
             n-hexane is metabolized by the mixed function oxidase system
             in the liver (Graham et al., 1987) forming alcohols which are
             conjugated to glucuronic acid or converted to carbon monoxide
             (Finkel, 1983).  1-Hexanol and 3-Hexonal are less toxic
             metabolites.  The former is oxidated to hexanoic acid, which
             undergoes the usual lipid metabolism.  3-Hexanol, a minor
             metabolite, has not been fully investigated (Boudene, 1988). 
             2-Hexanol is the most important metabolite.
             

             According to experimental studies carried out in animals (Di
             Vincenzo et al., 1976) and in men (Perbellini et al., 1980)
             the metabolism of n-hexane and methyl-n-butyl ketone is
             closely connected.
             
             2-Hexanol is the main metabolite; it gives origin to 2,5-
             hexanedione which is responsible for the neurological
             damage.
             
             Perbellini et al., (1980) reported that 2,5-hexanedione was
             found in urine as the main n-hexane metabolite.
             
             2-hexanol and 2,5-hexanedione were identified as n-hexane
             metabolites also in animals (Di Vincenzo et al., 1976).  The
             last metabolite was found as a methyl-n-butylketone
             metabolite in human serum (Di Vincenzo et al., 1978).
             
             Perbellini et al., (1981) suggest that 2,5-hexanedione and,
             secondly, 2-hexonal might be used as a reliable indicator for
             monitoring environmental exposure to n-hexane, because these
             metabolites are not detectable in urine of unexposed
             people.
             
             Fedthe & Bolt (1987) detected 5,5-dihydroxy-2-hexanone as an
             n-hexane metabolite.  In relation to 2,5-hexanedions, the
             amount detected was about 10 times higher in rat's urine and
             4 times higher in the urine of humans.  This metabolite may
             be the result of a detoxification route (Fedtke & bolt,
             1987).
             
             Workers exposed to n-hexane for about 7 hours/day without
             protective devices had the following metabolites in urine: 2-
             hexanol, 2-methyl-2-pentanol, 3-methyl-2-pentanol,
             cyclohexanol, cyclohexanone and thichloroethanol (each one:
             0.1mg/L), gamma-valerolactone (0.25 mg/L) and 2,5-hexanedione
             (0.4 mg/L) (Governa et al., 1987).
             
             In humans exposed to concentrations of up to 200 ppm, steady
             state blood levels were dose-dependent; accumulation occurred
             in humans exposed to as little as 1 ppm.

        6.5  Elimination by route of exposure

             Filser et al., (1987) found that only 17% (in rat) and
             20% (in man) of inhaled n-hexane was exhaled unchanged.
             
             Mutti et al., (1984) found that approximately 10%  of the
             total uptake (mean: 166 mg) of unchanged n-hexane was
             excreted from the lungs and about 3 mg/g creatinine of 2,5
             hexanedione was detected in urine of workers exposed to 50
             ppm in air, during the post-exposure period.
             

             Although these authors and others (Iwata et al., 1983;
             Perbillini et al., 1981) observed a close relation between
             mean daily exposure and urinary excretion of 2,5-hexanedione,
             for Mutti et al., (1984) it was not possible to measure this
             metabolite at exposure levels lower than 50 mg/m3
             (approximately 14 ppm) at the end of the working day.
             
             Governa (1987) proposed that urinary concentrations of 2,5-
             hexanedione can serve as a predictive measurement for early
             detection of neurotoxic lesions at preclinical stages.

    7.  TOXICOLOGY

        7.1  Mode of action

             Damage to the respiratory tract and circulatory
             disturbances are probably due to the same mechanism as for
             similar solvents.
             
             The rapidity of onset and the extent of the chemical
             pneumonitis is due to n-hexane's low viscosity, which allows
             rapid spread over large areas of the lung.  After the first
             24 hours, the extent of pulmonary compromise is related to
             severity: 30% or more of lung infiltration requires
             approximately 2 to 4 weeks for resolution.  Long-term
             pulmonary effects have not been observed.
             
             Hadjiivanova et al., (1987) reported important alterations in
             the quantity and composition of pulmonary surfactant in rats
             after short-term exposure (4260 ppm) of n-hexane.
             
             The lungs of the rats exposed to hexane at different
             concentrations showed a direct toxic effect on pneumocytes;
             fatty degeneration, change of alveolar bodies of type II
             pneumocytes and increased detachment of cells (Schnoy et al.,
             1982).
             
             The CNS and behavioural effects observed after exposures to
             n-hexane are due to its lipid-containing cells.  Neural
             membrane modifications and reduction of the brain's oxidative
             metabolism may explain the neurobehavioural changes and CNS
             depression.
             
             The peripheral neuropathy has been studied in detail and
             numerous theories are postulated.
             
             The nerve damage is basically an axonal swelling with
             accumulation of neurofilaments along the nerve fibres.  This
             occurs initially on the proximal sides of the nodes of
             Ranvier in distal parts of the fibres and progresses
             proximally along the nerves and internodal regions.
             

             The distal part of the nerve degenerates and myelin may
             disintegrate around the swelling with the axon remaining
             intact (producing secondary demyelination).
             
             Another theory suggests that reduction of energy production
             in the axon results in disruption of axonal transport,
             alteration of protein structure, and inadequate proteolysis
             of neurofilaments in the nerve terminal.
             
             A chemical theory on the origin of damage was proposed by
             Graham et al., (1985) who attributed the accumulation of
             neurofilaments to protein crosslinking at the amine
             groups.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults (volunteer and clinical case data)

                            Inhalation of 5000 ppm of n-hexane  
                            for 10 minutes resulted in vertigo and
                            giddiness. Exposure to 2000 ppm for the same
                            length of time did not cause symptoms
                            (Patty, cited in IPCS draft, 1989).

                    7.2.1.2  Children

                             Probably comparable to similar
                             compounds, but no particular data
                             available.

             7.2.2  Relevant animal data

                    Most of the relevant animal data refer to the
                    central and peripheral neurological damage, but some
                    other studies have been done.  It is interesting to
                    remark that rabbits are not sensitive to n-hexane's
                    neurological effects.
                    
                    Male rats exposed repeatedly to high concentrations of
                    n-hexane in a pattern similar to human "sniffing"
                    (drug abuse) showed neurotoxic levels of 2,5-
                    hexanedione.  Those levels increased after repeated
                    daily exposures, suggesting induction of liver
                    microsomal enzymes synthesizing 2,5-hexanedione from
                    hexane.  The minimal sustained plasma levels which
                    induce neurotoxicity are less than 50 mg/mL in the rat
                    (Howd et al., 1982).
                    
                    Nylen et al., (1989) observed a severe atrophy
                    involving the seminiferous tubules with loss of the
                    nerve growth factor in the immunoreactive germ cell
                    line of rats after 61 days of exposure  to 1000 ppm of

                    n-hexane.  Permanent testicular damage was found in
                    some animals which had a total loss of the germ cell
                    line lasting up to 14 months after the post-exposure
                    period.  Simultaneous administration of n-hexane (1000
                    ppm) with toluene (1000 ppm) or xylene (1000 ppm) did
                    not cause germ cell line alterations or testicular
                    atrophy.

             7.2.3  Relevant in vitro data

                    In vitro toxicity of n-hexane and 2,5-
                    hexanedione has been evaluated in the isolated
                    perfused rabbit heart (Raje, 1983).  The force of
                    cardiac contraction was significantly reduced
                    following 1 hour of perfusion with 9.6 mg/L n-hexane
                    and with 0.35% v/v of 2,5-hexanedione.
                    
                    Spinal neurone cell cultures exposed to n-hexane and
                    butanone (methyl-ethyl-ketone) developed the neural
                    swelling faster than when exposed only to n-hexane
                    (Veronesi et al., 1984).

             7.2.4  Workplace standards

                    The US standard is the time-weighted average
                    (TWA) = 500 ppm although the ACGIH recommended not
                    more than 100 ppm.  Industrial exposures for more than
                    6 months to 190 ppm have been associated with
                    polyneuropathy (Wang et al., 1986).  Several values
                    are enlisted:
                    
                    OSHA/TWA (1989)       500 ppm, 1800 mg/m3
                    
                    NIOSH/OSHA (1985)     100 ppm
                                          510 ppm/15 min ceiling
                    
                    ACGIH TLV (1989)      50 ppm, 180 mg/m3
                                          other isomers 500 ppm,
                                          1800 mg/m3
                    
                    ACGIH STEL (1989)     other isomers 1000 ppm,
                                          1800 mg/m3

                    IDLH                  5000 ppm
                    
                    Conversion factor:    1 ppm n-hexane in air =
                                          3.25 mg/m3.

             7.2.5  Acceptable daily intake (ADI) and other guideline
                    levels

                    No data available.


        7.3  Carcinogenicity

             Human data are not available.  Animal tests are negative.

        7.4  Teratogenicity

             No data on teratological effects available, but a study
             in pregnant rats showed n-hexane blood concentrations in the
             fetus equal to that found in maternal blood (Court & Milks,
             1982).

        7.5  Mutagenicity

             No data available

        7.6  Interactions

             Simultaneous exposure with other solvents (especially
             with ketones) increases n-hexane toxicity in humans and
             animals.  Methyl-n-butylketone is by itself responsible for
             an identical neuropathy to that observed by n-hexane.
             
             Toluene, butanone and n-hexane are common components of glue. 
             Butanone (methyl-ethyl-ketone = CH3-CO-C2H2) increases
             n-hexane neurotoxicity both in humans and experimentally
             (Veronesi et al., 1984).
             
             Toluene seems to decrease n-hexane's neurotoxic effect, as it
             may reduce the oxidative metabolism and increase the
             generation of  2hexanol (Iwata et al., 1984).
             
             2-Butanone (methyl-ethyl-ketone, MEK, CH3-CO-C2H2) increases
             n-hexane neurotoxicity.  Rats exposed to n-hexane (9000 ppm)
             and butanone (1000 ppm) develop a more severe and early
             polyneuropathy than rats exposed only to n-hexane (10 000
             ppm) (Altenkirch et al., 1978).  The biochemical mechanism is
             not well understood.
             
             2-Propanol (isopropanol, (CH3)2CHOH) enhances the induction
             of n-hexane-metabolizing enzymes and increases the 2-hexanol
             concentration in the liver and kidney (Zahlsen et al., 1984). 
             The effect of monoketones (ketone, a metabolite of
             isopropanol or MEK) may be due to a transient decrease of the
             energy generating process in the axon through a reversible
             combination of the ketones with glyceraldehyde-3-phosphate
             dehydrogenase or another enzyme involved in anaerobic
             glycolysi (Boudene, 1988).
             
             Methyl isobutyl ketone (MIBK, C6H120) mixed with n-hexane
             significantly increased aniline hydroxylase and cytochrome P-
             450 activity in the liver of exposed hens (Abou Donia et al.,
             1985).  The latter effect suggests that MIBK potentiates the
             neurotoxic effect of n-hexane.
             

             Carbon tetrachloride toxicity may be increased by ketone
             metabolites of n-hexane (Charbonneaum et al., 1986).
             
             The effect of sympathomimetic drugs combined with that of
             acute n-hexane exposure may induce cardiac arrhythmias.

    8.  TOXICOLOGICAL AND OTHER ANALYSES

        8.1  Sample

             8.1.1  Collection

             8.1.2  Storage

             8.1.3  Transport

        8.2  Toxicological Analytical Methods

             8.2.1  Tests for active ingredient

             8.2.2  Tests for biological sample

        8.3  Other laboratory analyses

             8.3.1  Biochemical investigations

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological or Haemostasiological investigations

             8.3.4  Other relevant biomedical analyses

        8.4  Interpretation

        8.5  References (in section 13)

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Nausea, vomiting, and irritating of nasal and
                    oropharyngeal mucosa.  Headache, CNS depression and
                    coma may develop.  Severe chemical pneumonitis and
                    even pulmonary oedema may result from aspiration of n-
                    hexane into the lungs.  Tachycardia and, rarely,
                    ventricular arrhythmia.


             9.1.2  Inhalation

                    Brief exposure (10 minutes at 1500 ppm) can
                    cause upper respiratory irritation, nausea and
                    headache.  Dizziness and drowsiness occur at 5000 ppm
                    and massive exposure may cause unconsciousness,
                    convulsions and death.  Exposures below 500 ppm do not
                    usually induce CNS depression.  Tachycardia and,
                    rarely, ventricular arrhythmia.

             9.1.3  Skin exposure

                    Direct contact may cause irritation.

             9.1.4  Eye contact

                    Eye irritation did not occur in volunteers
                    exposed to 500 ppm hexane vapour for 3 to 5 minutes
                    (Nelson, cited in IPCS draft, 1989), but vapour
                    exposure at higher concentrations can cause eye
                    irritation.  Pain may occur if there is direct contact
                    with the liquid.
                    
                    N-hexane splashed into the eye may cause corneal
                    opacification and lipolysis and loss of epithelial
                    cells.

             9.1.5  Parenteral exposure

                    Unknown

             9.1.6  Other

                    Unknown

        9.2  Chronic poisoning by:

             9.2.1  Ingestion

                    No data available

             9.2.2  Inhalation

                    Dizziness, weakness, weight loss, anaemia,
                    nervousness, pain in the limbs, peripheral numbness
                    and paraesthesia occur, preceding sensori-motor
                    ascending polyneuropathy.  CNS symptoms including
                    dysarthria, motor incoordination and visual
                    difficulties may be masked by the
                    polyneuritis.


             9.2.3  Skin exposure

                    Produces local erythema, oedema and burns.

                    Symptoms of systemic toxicity as for inhalation may
                    occur.

             9.2.4  Eye contact

                    Local irritation

             9.2.5  Parenteral exposure

                    No data available

             9.2.6  Other

                    No data available

        9.3  Course, prognosis, cause of death

             Course and prognosis

             The main symptoms of exposure are neurological.  After acute
             inhalation, vertigo, drowsiness and fatigue occur immediately
             and are followed by headache and CNS depression or coma if
             exposure continues.  Pulmonary and cardiac effects may occur
             subsequently.
             
             Causes of sudden death are the following:
             
             -   Anoxic death may be produced by either airway occlusion
                 or aspiration pneumonia "sniffers" who frequently use a
                 plastic bag over the head may suffocate.
             
             -   Respiratory depression caused by the solvent may involve
                 the cerebral respiratory centre leading to respiratory
                 arrest.
             
             -   Cardiac arrhythmia may occur, due to the lowering of the
                 myocardial threshold to the arrhythmogenic effects of
                 catecholamines which is favoured by hypoxia.
             
             -   Sudden death may rarely occur in industrial accidents
                 associated with anaesthetic effects noted at high levels
                 of exposure in enclosed areas, but "sniffers" constitute
                 the main group at risk.
             
             Peripheral neuropathy occurs after prolonged, repeated
             inhalation.
             

             The effects are first seen between several months to one year
             after the beginning of long-term hexane exposure.  Among glue
             sniffers, the course may be subacute, heading to PNS
             involvement within 2 months.
             
             The first symptoms are symmetrical numbness and paesthesia in
             the distal extremities, most notably in feet or hands. 
             Headache, anorexia and dizziness may precede or coincide with
             neuropathy.  Improvement of symptoms is noted after cessation
             of exposure and mild cases may recover completely.  The
             disease may progress even for 1 to 4 months after
             discontinuing exposure.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Tachycardia may occur.  N-hexane may decrease
                    the myocardial threshold to the arrhythmogenic effects
                    of endogenous and exogenous catecholamines, causing
                    dysrrhythmias, predominantly ventricular arrhythmias
                    and, very rarely, sudden death due to ventricular
                    fibrillation.

             9.4.2  Respiratory

                    Aspiration may cause chemical pneumonia, cough,
                    wheezing and pulmonary irritation may progress to
                    pulmonary oedema with hypoxia, bloody sputum, and
                    fever.  Slow and shallow respiration may be noted. 
                    After exposure to high concentrations, respiratory
                    arrest might occur.

             9.4.3  Neurologic

                    9.4.3.1  CNS

                             Acute exposure to n-hexane may cause
                             CNS depression, coma and convulsions.  Acute
                             CNS effects may be due to hypoxia following
                             aspiration and/or directly result from
                             inhalation or ingestion.
                             
                             Neuropsychiatric disability may follow
                             chronic inhalation.  Axons are affected after
                             chronic inhalation exposure, but symptoms may
                             be obscured by the polyneuritis.  During the
                             recovery phase of the polyneuritis,
                             dysarthria, blurred vision, ataxia and
                             spasticity become evident.
                             

                             Cranial nerve neuropathy has been reported by
                             Yamamura from a Japanese survey where 33 of
                             93 exposed workers presented cranial nerve
                             paralysis (Lolin, 1989).  Optic atrophy has
                             been reported in a few cases.

                    9.4.3.2  Peripheral nervous system

                             Sensory or sensorimotor
                             polyneuropathy represents the main effect
                             after chronic exposure and is characterized
                             by insidious onset.  Large and long axons are
                             affected early (the sciatic nerve is
                             especially vulnerable).  Pain in the limbs
                             weakness and muscle wasting occur, as well as
                             sensory loss in a "stocking and glove"
                             pattern.  The conduction velocity is
                             moderately slowed.
                             
                             The distribution is symmetrical and initially
                             involves only hands and feet.  In more severe
                             cases, weakness and weightloss are seen.  The
                             patient may have abdominal pain, cramps in
                             the legs and loss of ankle reflexes.  Hand
                             muscular weakness may make seizing objects or
                             pinching difficult.  Pure motor neuropathy is
                             unusual.  Loss of pinprick and touch
                             sensation is limited to hands and feet.  In
                             some cases, weakness and atrophy increase and
                             progress to involve the proximal muscle
                             groups.
                             
                             Axonal regeneration may take months or years. 
                             Residual disability can occur (Cavanagh,
                             1979; Schaumburg and Spencer,
                             1979).

                    9.4.3.3  Autonomic nervous system

                             Glue sniffers have shown autonomic
                             disturbances such as hyperhydrosis of the
                             hands and feet, which may be followed by
                             anhydrosis.

                    9.4.3.4  Skeletal and smooth muscle

                             Muscular atrophy may appear
                             subsequently to poly-neuropathy.


             9.4.4  Gastrointestinal

                    Nausea, vomiting, abdominal pain and diarrhoea
                    occur after ingestion.  Symptoms resulting from
                    ingestion generally develop within 6 hours of
                    exposure.

             9.4.5  Hepatic

                    Fatty changes in the liver may occur after
                    chronic exposure.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Protenuria in the exposed workers in
                             the shoe industry (Caudarella et al., 1981)
                             were significantly higher when compared to
                             control group, but no effects on serum
                             creatinine levels were detected.

                    9.4.6.2  Others

                             No data available

             9.4.7  Endocrine and reproductive systems

                    No data available in humans.
                    
                    Serious lesions, some of them causing sterility, were
                    reported in rats exposed to n-hexane (Nylen et al.,
                    1989; De Martino et al., 1987).

             9.4.8  Dermatologic

                    Irritation of skin, erythema, oedema and
                    chemical burns.

             9.4.9  Eye, ears, nose, throat: local effects

                    Eye irritation did not occur in volunteers
                    exposed to 1760 mg/m3 (500 ppm) of hexane vapour for
                    3-5 minutes (Nelson et al., 1943).  Higher
                    concentrations would produce irritation.

             9.4.10 Haematologic

                    Leucocytosis is observed.  Aplastic anaemia
                    may occur in chronic exposure to n-hexane contaminated
                    with benzene.

             9.4.11 Immunologic

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No data available.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No data available

                    9.4.12.3 Others

                             No data available

             9.4.13 Allergic reactions

                    A skin test done in 25 subjects with undiluted
                    n-hexane applied (25% solution) was negative (Kligman,
                    cited in IPCS draft, 1989).
                    
                    Prolonged occlusive skin contact for 1 to 5 hours with
                    liquid n-hexane caused erythema and, after 5 hours,
                    blistering (Oettel, cited by IPCS draft, 1989).  In
                    another study, 0.l mL of n-hexane was rubbed into skin
                    daily for 18 days and neither erythema nor oedema were
                    observed (Wahlberg, 1984a, 1984b).

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks: pregnancy, breastfeeding, enzyme
                    deficiencies

                    No data available

        9.5  Others

             No data available.

    10. MANAGEMENT

        10.1 General principles

             In cases of skin and/or eye contact only
             decontamination and clinical observation are needed, although
             in some cases, ophthalmological advice is required.
             

             If important amounts have been ingested and/or inhaled:
             maintain open airway, provide respiratory assistance if
             necessary.  Oxygen is indicated.  Treatment is symptomatic
             and supportive.  There is no antidote.
             
             Do not induce vomiting.
             
             Avoid the use of catecholamines.

        10.2 Relevant laboratory analyses and other investigations

             10.2.1 Sample collection

                    Collect urine or blood samples, in a tightly
                    closed receptacle (n-hexane is very
                    volatile).

             10.2.2 Biomedical analysis

                    -   Arterial blood gases should be monitored in case
                        of respiratory symptoms.
                    
                    -   Complete blood count.
                    
                    -   ECG monitoring.
                    
                    -   Chest x-rays should be done on admission and
                        repeated according to the clinical situation.
                    
                    -   Measure blood glucose (Hypoglycemia has been
                        reported rarely).
                    
                    -   Serum electrolytes determination and renal and
                        liver function tests may be needed.
                    
                    -   Electrodiagnostic after chronic exposure studies
                        include:  electromyography, nerve conduction
                        velocity (NCV, which shows progressive slowing),
                        visual evoked potentials and electroretinograms
                        (may indicate axonal degeneration in the CNS
                        visual tracts).
                    
                    -   Nerve-muscle biopsy (sural) may be useful in
                        chronic exposure.

             10.2.3 Toxicological analysis

                    n-hexane measured in urine of human exposure.
                    
                    Imbriani et al., (cited by Boudene, 1988) found a good
                    correlation between workplace air levels of n-hexane
                    and urinary concentration in exposed workers.
                    

                    Cu = 9.0669 x Ci + 0.8396
                    Cu(g/L) = urinary concentration of n-hexane
                    Ci(mg/m3) = workplace air level
                    
                    n-hexane metabolites in urine.

             10.2.4 Other investigations

                    Berthold CM (cited by Lolin Y, 1989) suggests
                    that electron-microscopic examination of sural nerve
                    biopsy materials should be used for detecting sub-
                    clinical neuropathy.

                    Neuro-behavioural studies may be of interest.

        10.3 Life-supportive procedures and symptomatic treatment

             Initial management depends on the severity of the
             illness: the respiratory function is of main concern after n-
             hexane aspiration on inhalation.
             
             A clear airway (naso or orotracheal intubation) and
             artificial respiration with oxygen should be provided in all
             patients with respiratory symptoms.  Arterial blood gases
             should be monitored.
             
             Respiratory tract symptoms are treated symptomatically. 
             Oxygen is given whenever respiratory symptoms occure and
             broncholytic treatment may be useful.  Arterial and other
             blood gases must be repeatedly monitored.  If signs of
             respiratory insufficiency appear, mechanical ventilation
             shall be considered at an early stage.  Positive and
             expiratory pressure has been claimed to be of value in these
             cases.
             
             In case of pulmonary oedema corticosteroides may be
             indicated.  Secondary bacterial infection is treated with
             antibiotics.
             
             CNS-depression, coma and convulsions are treated
             symptomaticly, including ensurance of clear airway, assisted
             ventilation and administration of anticonvulsive agents.
             
             Arrythmias are treated in accordance with general principles. 
             Any metabolic disturbances are corrected.
             
             Endogenous catecholamines should be avoided, and if used,
             they should be given in low dosage and under close
             cardiovascular supervision.
             
             Continuous positive airway pressure (CPAP) or positive end-
             expiratory pressure (PEEP) should be used when indicated.
             

             For treatment of pulmonary oedema corticosteroids are
             indicated.  Preventive treatment of chemical pneumonia with
             antibiotics may be controversial.
             
             Exogenous catecholamines should be avoided, as they may
             precipitate an ventricular dysrhythmia.  They should only be
             used in the lower dosage ranges with careful ECG monitoring
             for cardiac resuscitation.
             
             The rest of the treatment is supportive, and a close
             monitoring of vital signs is required.

        10.4 Decontamination

             In case of eye contact: flush immediately with room-
             temperature running water for at least 15 minutes.
             
             Skin contact:  remove clothing, wash the skin thoroughly with
             mild soapy water.
             
             Ingestion: rinse mouth copiously.  No decontamination is
             indicated if the n-hexane ingested does not contain relevant
             concentration of other toxic compounds.  If ingested n-hexane
             is contaminated with significant amounts of halogenated
             hydrocarbons) the substances must be removed from the
             gastrointestinal tract.  Gastric lavage should be done in a
             comatose patient only after intubation with a cuffed only
             endotracheal tube.
             
             Activated charcoal does not effectively absorb n-hexane and
             its presence in the stomach may induce vomiting and increase
             the risk of aspiration.

        10.5 Elimination

             No data available

        10.6 Antidote treatment

             10.6.1 Adults

                    No antidote available

             10.6.2 Children

                    No antidote available.

        10.7 Management discussion: alternatives, controversies and
             research needs.

             -  Induction of vomiting or gastric lavage are
                contraindicated, except when ingestion of n-hexane is over
                2 to 3 mL/kg or n-hexane contains another more toxic
                chemical (e.g. pesticide).  In this case, extreme caution
                should be taken to avoid aspiration, since small amounts
                of n-hexane will involve severe chemical pneumonitis
                (Ellenhorn & Barceloux, 1988).
             
             -  Mild observations of hepatic aminotransferase levels have
                been reported in exposed workers (Ellenhorn & Barceloux,
                1988).
             
             -  Dose-response relationship of n-hexane is still unclear. 
                Although peripheral neuropathy has been fully documented
                effects on the CNS need further studies.
             
             -  Genotoxic and teratogenic studies are still insufficient
                to draw valid conclusions.
             
             -  Use of corticosteroids may in chemical pneumonia be
                controversial.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from the literature

             The most significant report from literature are those
             describing the studies of occupationally exposed populations:
             Japanese sandal workers, Italian shoe industry, Taiwan press-
             proofing workers, tungsten carbide mills and extraction
             facilities.
             
             A review of the n-hexane induced polyneuropathy in industrial
             workers in Japan is given by Takeuchi (1993). It is suggested
             that urinary levels of 2,5-hexanedione could serve as an
             indicator for monitoring exposure to n-hexane (Takeuchi,
             1993).
             
             Neurological symptoms in the limbs were shown to be
             significantly increased in metal can manufacturing workers
             compared to unexposed workers (Bachmann  et al., 1993).
             
             In Italy twenty workers exposed over a long period to n-
             Hexane were shown not to have significant neurological
             anomalies. However, the amplitude of the sensory nerve action
             potentials (SNAP), recorded from the sural, median and ulnar
             nerves, were decreased compared to control groups (Pastore et
             al., 1994).
             

             Chemotaxis, measured with human polymorphonuclear leukocytes,
             was impaired in apparently healthy shoe workers exposed to n-
             hexane (Governa et al., 1994).
             
             Primary axonal polyneuropathy and secondary segmental
             demyelination was observed in 27 Turkish males exposed
             occupationally to n-hexane (Oge et al., 1994).
             
             Fifteen workers occupationally exposed to n-hexane for 5 to
             21 years were studied with evoked potentials and averaged
             extraocular retinograms.  Compared to a non-exposed group of
             10 controls, they had changes indicating cerebral dysfunction
             (Seppalainen et al., 1979).
             
             A report on 3 women who suffered motor polyneuropathy
             following occupational exposure to a glue containing 80.4% of
             n-hexane describe in detail the nerve changes.  Myelin
             sheaths and axons of large diameter fibres showed
             polymorphous changes and muscles showed degeneration atrophy
             and degenerative changes, with lymphocytic infiltrates and
             phagocytosis (Scelsi et al., 1980).
             
             Sanagi (cited in IPCS draft, 1989) investigated the effect of
             exposure to n-hexane in a factory producing a tungsten
             carbide ally where the materials were mixed with n-hexane and
             acetone by ball mills. Fourteen workers (concurrently
             exposed) aged less than 50 years with an exposure duration of
             1 to12 years (mean: 6.2 years) were studied and another group
             consisting of 5 workers (previously exposed) aged less than
             50 years with exposure durations of 1 to16 years (mean: 5.2
             years). The mean 8 hour time average concentration of n-
             hexane over a period of 2 years was 204 mg/m3 (58 ppm), and
             the average concentration for acetone was 22 to 69 ppm.
             Headaches, hyperaesthesia in the limbs, and muscle weakness
             were reported more often by the exposed group.  Three exposed
             workers complained of paraesthesias.  There was a slightly
             higher prevalence of diminished bicipital and patellar deep
             tendon reflexes in the exposed group.  There were significant
             effects on muscle strength and vibration sensation.
             Electrophysiological studies showed no signs of
             neuropathology in the workers, but in the concurrently
             exposed workers, conducting velocities in the posterior
             tibial nerve were significantly reduced.
             
             Huang & Chu (1989) studied evoked potentials, somatosensory
             brianstem auditory, and pattern-reversal visual evoked
             potentials (SEP, BAEP,, and PVEP) in 5 patients with chronic
             n-hexane polyneuropathy.  The results obtained were: in SEPs,
             the median central conducting (N13 to N20) was normal but the
             tibial central conduction (N22 to P40) was delayed.  The
             central conducting time (I to V interval) of the BAEP was
             also prolonged.  However, the P100 latency of the PVEP was

             normal.  These data indicate that the spinal cord and
             brainstem are primarily affected in chronic n-hexane
             intoxication.

        11.2 Internally extracted data on cases

        11.3 Internal cases

             (to be completed by PC)

    12. ADDITIONAL INFORMATION

        12.1 Availability of antidotes and antisera

             No antidote

        12.2 Specific preventive measures

             Limiting exposure, training and education of workers
             are the most important methods to prevent n-hexne effects in
             the occupational health context.
             
             Engineering controls are required.  Methods include
             mechanical ventilation (dilution and local exhaust).  A non-
             sparking grounded ventilation system separate from exhaust
             ventilation systems should be used.
             
             Personal protective equipment and respiratory protection
             should be available for emergencies, for work to be done in
             poorly ventilated areas or for specific maintenance
             operations.  Protective gloves resist n-hexane, but mixtures
             with other solvents (e.g. MEK) may allow penetration of
             gloves and other protective clothing.
             
             Disposal:  burn in a chemical incinerator equipped with an
             after burner and scrubber.  Extra care in igniting is
             necessary as this material is highly flammable.

        12.3 Other

             No data available

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    14. AUTHOR(S), REVIEW(S), DATE, COMPLETE ADDRESSES

        Author:     Hilda Triador
                    CIAT, Piso 7
                    Hospital de Clinicas
                    Montevideo
                    Uruguay
        
                    Tel:  598-2-804000
                    Fax:  592-2-470300
        
        Date:       February 1990
        
        Peer reivew:         Strasbourg, France, May 1990
                             Newcastle-upon-Tyne, United Kingdom, January
                             1991
        
        IPCS Review:         November 1990.
        
        Editor:              M.Ruse
        
        Finalised:  IPCS, April, 1997

    



    See Also:
       Toxicological Abbreviations
       Hexane, n- (EHC 122, 1991)