n-Hexane Medical Guidelines
STATE OF CALIFORNIA
DEPARTMENT OF HEALTH SERVICES
DEPARTMENT OF INDUSTRIAL RELATIONS
MEDICAL GUIDELINES
HESIS
HAZARD EVALUATION SYSTEM AND INFORMATION SERVICE
850 Marina Bay Pkwy
Building P, 3rd Floor
Richmond, CA 94804
n-Hexane (Revised July 2000)
(866) 282-5516
TABLE OF CONTENTS:
Sources
Pharmacokinetics
Clinical Presentation
Diagnosis
Biological Monitoring
Treatment
Prognosis
What you should do
References
Sources: n-Hexane is a petroleum distillate used as a solvent in vegetable oil
extraction, and in cleaners, degreasers, glues, spray paints, paint
thinners, coatings, silicones, and greases. These n-hexane-containing
products are often used by workers in the food processing, printing,
manufacturing, painting, and automotive repair industries as well as
anywhere petroleum distillates are used.
Commercial or technical grade hexane (the form used in most products)
contains varying amounts of n-hexane (20-80%) along with other related
compounds, and should be treated as pure n-hexane. Pure n-hexane is
used in laboratories. Both n-hexane and mixed hexanes are often
referred to as "hexane" and sometimes as "petroleum distillate" and are
listed on Material Safety Data Sheets (MSDSs) with the CAS # 110-54-3.
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Pharmacokinetics: n-Hexane can enter the body via inhalation, ingestion, and dermal
absorption. Inhalation of n-hexane vapors or aerosols is the main route
of occupational exposure. Dermal absorption is usually minor.
When n-hexane is inhaled, 10% is immediately eliminated unchanged
through the lungs. The remaining portion is absorbed and metabolized
by the liver microsomal monooxygenase system, ultimately forming the
major metabolite, 2,5-hexanedione (2,5-HD). 2,5-HD reacts with the e -
amino groups of lysine in proteins, leading to the characteristic nerve
damage.
2,5-HD is excreted in the urine and is not normally stored in the body;
however, if exposure to n-hexane is prolonged or high, 2,5-HD can
remain in the body and cause nerve damage. Since the urinary
elimination half-life of 2,5-HD is 13 14 hours, 2,5-HD can accumulate in
the body during the workweek if n-hexane products are used on a daily
basis.
Clinical Presentation: Symptoms of peripheral neuropathy develop after a few months to a year
of repeated overexposure to n-hexane. Longer nerves and thicker fibers
are more susceptible to toxin-induced neuropathy; thus the symptoms
usually begin in the feet or legs. The first symptoms are sensory and
consist of tingling, numbness, burning, or prickling sensations in the feet
or toes. The symptoms are usually symmetric and graded distally,
although symptoms may appear in one foot first or may be more
pronounced in one foot. If overexposure to n-hexane continues, the
dysesthesias spread in a centripetal, symmetrical manner. Ankle jerks
are lost and weakness of dorsiflexion of the toes develops. Patients may
have difficulty walking on their heels and may have a slapping gait. If the
dysesthesias reach the upper shin, they begin to appear in the fingertips.
When the dysesthesias reach the elbows and thighs, a tent-shaped area
of hypesthesia may occur in the lower abdomen. With progression, this
broadens with the apex extending rostrally toward the sternum. At this
point, patients cannot stand, walk, or hold objects. If the neuropathy
continues further, the patient may become paralyzed.
The severity of nerve damage is related to 2,5-HD concentrations in the
body and prolonged usage. The extent of nerve damage may also
depend on the history of exposure to other neurotoxic chemicals. Using
acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone, or lead
acetate in combination with n-hexane can amplify the neurotoxic effects
of n-hexane. MEK intensifies the metabolic processing of n-hexane,
leading to a quicker, more pronounced initial motor weakness.
Some patients have also experienced CNS complaints such as
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headache, dizziness, nausea, anorexia, giddiness, and/or drowsiness,
and mucosal irritation with short-term overexposure. These symptoms
are usually temporary and disappear within minutes to hours after
removal from exposure. Health effects on other organ systems have not
been noted in human studies.
Diagnosis: Symptom description
Begin by asking the patient to describe the symptoms and how they
initially appeared. Patients with peripheral neuropathy will usually
describe a neuropathy that begins in the feet and spreads in a graded,
symmetrical and centripetal fashion. Ask the patient how the disease
progressed. Did the symptoms get worse over a few days or many
years? Patients affected by n-hexane will describe disease progression
over several weeks to a year. Symptoms that evolve over a period of
more than five years usually suggest a genetic disorder.
Occupational history
Description of all jobs held
Work exposures
Specific exposures to solvents, pesticides, and/or heavy metals (e.
g. methyl n-butyl ketone, carbon disulfide, acrylamide, mercury,
lead, and organophosphates)
Clustering of symptoms in other workers
Medical history
The clinical presentation of n-hexane-associated neuropathy cannot
usually be distinguished from other causes such as diabetes, renal
failure, vitamin deficiency, or paraproteinemic neuropathy. Therefore, it is
important to rule out these disorders. A complete medical history can aid
in ruling out certain causes. Questions should be asked regarding the
following:
Viral illnesses such as polio
Medications
Occurrence of symptoms among family members
Alcohol intake
Pre-existing medical conditions or disorders such as diabetes
The following tests should also be considered to rule out other causes:
Complete blood count
Erythrocyte sedimentation rate
Urinalysis
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Chest x-ray
Postprandial blood glucose
Serum and urine protein electrophoresis
Vitamin B12
Creatinine
Thyroid-stimulating hormone
Diagnostic tests
The somatosensory system can be examined by tests of primary
sensation. The pinprick test can be used to determine the patients sense
of pain. A wisp of cotton can be used to determine the sense of touch
(avoid touching hairy skin). A flask filled with warm water at about 35-36?br>
C and cool water at
28-32?C can be used to determine the ability to distinguish thermal
sensation. A tuning fork or vibrometer can be used to determine sense of
vibration. Care should be taken in interpreting these results since these
subjective tests are dependent on patient response. Therefore, it is best
to have the patient close or cover their eyes. Also, patients should not be
pressed to undergo this examination if they are fatigued. Test results are
also dependent on the limb temperature, so be certain that the ambient
temperature is controlled to maintain a limb temperature of 72?F.
Electrodiagnosis can determine the difference between axonal and
demyelinating disorders, but cannot distinguish between toxic and
nontoxic etiologies. Axonal degeneration usually shows a reduction in
amplitude of evoked conduction action potentials with relative
preservation of nerve conduction velocities. Demyelination shows a
slowing of the nerve conduction velocity, dispersion of evoked compound
action potentials, conduction block, and marked prolongation of distal
latencies. n-Hexane neurotoxicity causes both axonal degeneration and
demyelination and thus can present mixed electrodiagnostic findings.
Nerve conduction tests usually show decreased motor and sensory
nerve conduction velocities.
Nerve biopsies are useful for hexacarbon neuropathies since the results
are distinctive. Results show axonal swellings with secondary retracted
myelin sheaths filled with massive neurofilament accumulations that are
tightly pressed together. Some unmyelinated axons have glycogen
granule accumulations in the axonal lumen. The sural nerve at the ankle
is the preferred site.
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Biological As mentioned previously, 2,5-HD, the proximate neurotoxin, is excreted
Monitoring: in the urine and can be measured by a specialty laboratory. However,
2,5-HD leaves the body quickly, so the testing must be performed within
2-3 days of n-hexane exposure. The best time for obtaining a urine
sample would be at the end of the shift at the end of the workweek.
Creatinine determination is important because the concentration of 2,5-
HD depends on urine output.
Previous studies determined that exposure to 50 ppm resulted in
4 mg/L 5 mg/L (adjusted for specific gravity) 2,5-HD. It should be noted
that almost everyone is exposed to n-hexane and the general population
has 2,5-HD urine levels of below 1 mg/L.
Treatment: The patient should be removed from further exposure. There is no other
useful treatment.
Prognosis: If the patient is removed from further exposure, the prognosis is usually
good. The patient may experience a worsening of symptoms within the
first few weeks, but improves afterward. Recovery usually takes a few
months to a few years depending on disease severity. Recovery in mild
to moderate cases is usually complete. Severe cases take longer to
recuperate and may not recover completely, possibly experiencing
residual muscle atrophy, spasticity, muscle cramps and
dyschromatopsia.
If the patient continues to be exposed, the neuropathy worsens,
ultimately developing into paralysis. Fortunately, death has not been
reported in humans.
What you should do:
Complete a Doctors First Report (DFR) of Occupational Illness.
Get the MSDS of the solvent product(s) that the patient is using.
Recommend that the patient inform their employer, if work-related, and provide documentation
for medical removal.
Contact HESIS at (866) 282-5516 if you have any questions.
References:
Altenkirch H, Wagner HM, Stoltenburg-Didinger G, Steppat R. Potentiation of hexacarbon neurotoxicity by methyl ethyl
ketone and other substances. Neurobehavioral Tox and Teratol 1982; 4:623-627.
Aratani J, Suzuki H, Hashimoto K. Measurement of vibratory perception threshold in workers exposed to organic solvents.
Env Research 1993; 61:357-361.
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Arlien-Soborg P. Solvent Neurotoxicity. Boca Raton: CRC Press; 1992.
Asbury AK. Diseases of the peripheral nervous system. In: Antony Fauci et al., editors. Harrisons Principles of Internal
Medicine. 14th ed. 2 v. New York: McGraw-Hill, Inc., Health Professions Division; 1998. p. 2457-2469.
Chang YC. Patients with n-hexane induced polyneuropathy: a clinical follow-up. Br J Ind Med. 1990; 47:485-489.
Fedtke N, Bolt HM. Detection of 2,5-hexanedione in the urine of persons not exposed to n-hexane. Int Arch Occup Env
Hlth 1986; 57:143-48.
Governa M, Calisti R, Coppa G, Tagliavento G. Urinary excretion of 2,5-hexanedione and peripheral polyneuropathies in
workers exposed to hexane. J Tox Env Health. 1987; 20:219-228.
Herskowitz A, Ishii N, Schaumburg H. n-Hexane neuropathy. NEJM. 1971;28:82-85.
Iwata M, Takeuchi Y, Hisanaga N, Ono Y. Changes of n-hexane metabolites in urine of rats exposed to various
concentrations of n-hexane and to its mixture with toluene or MEK. Int Arch Occup Env Hlth 1983; 53:1-8.
Liss GM, Midroni G, House RA. Occupational Peripheral Neuropathy. In: Occupational Medicine Secrets. Bowler MR,
Cone JE, eds. Hanley & Belfus, Inc: Philadelphia, 1999; p. 225-229.
Mutti A, Ferri F, Lommi G, Lotta S, Lucertini S, Franchini I. N-hexane induced changes in nerve conduction velocities
and somatosensory evoked potentials. Int Arch Occup Env Hlth 1982; 51:45-54.
Ralston WH, Hilderbrand RL, Uddin DE, Andersen ME, Gardier RW. Potentiation of 2,5-Hexanedione Neurotoxicity by
Methyl Ethyl Ketone. Tox. Applied Pharm. 1985. 81:319-327.
Sanagi S, Seki Y, Sugimoto K, Hirata M. Peripheral nervous system functions in workers exposed to n-hexane at a low
level. Int Arch Occup Environ Health. 1980; 47:69-79.
Seppalainen AM. Neurophysiological approaches to the detection of early neurotoxicity in humans. CRC Critical Reviews
in Toxicology. 1988; 18:245-298.
Wang J, Chang Y, Kao K, Huang C, Lin C, Yeh W. An outbreak of n-hexane induced polyneuropathy among press
proofing workers in Taipei. Am J Ind Med 1986; 10:111-118.
Yamamura Y. N-hexane polyneuropathy. Folia Psychiatrica et Neurologica Japonica 1969; 23:45-57.
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