Registration Dossier

Toxicological information

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Admitted to hospital in February 1998
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Report is a case study examining the effects of exposure to 1-bromopropane in one human case. The patient was lost to follow up and not enough information was presented within the literature to allow full assessment of the reliability of the data source.

Data source

Reference
Reference Type:
publication
Title:
Encephalomyeloradiculoneuropathy following exposure to an industrial solvent
Author:
Sclar. G.
Year:
1999
Bibliographic source:
Clinical Neurology and Neurosurgery 101 (1999) pp 199-202

Materials and methods

Study type:
clinical case study
Endpoint addressed:
not applicable
Test guideline
Qualifier:
no guideline available
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
1-bromopropane (CAS # 106-94-5; > 95.5 % by weight)
butylene oxide (CAS # 106-88-7; < 0.5 %),
1,3-dioxolane (CAS # 646-06-0; < 2.5%)
and nitromethane (CAS # 75-52-5; < 0.25%).

2 proprietry ingredients were also present, one of which was denoted as a saturated terpene blend.

Results and discussion

Clinical signs:
The patient, a 19-year-old Hispanic male without significant past medical history, was transferred to hospital in February, 1998, after 1 week at another institution. In mid-January he had developed numbness and mild but progressive weakness of the proximal lower extremities and right hand. On admission, he could not stand without assistance. Other symptoms included a transient dysphagia and urinary difficulties. Just prior to developing these symptoms, he had been employed for 2 months as a metal stripper. This occupation involved the use of an industrial solvent used as a degreasing and cleaning agent.

About the time the symptoms began, the man had noted darkening of the skin of his right hand, which was preferentially exposed to this solvent. Protective gloves had been used as a precaution, but may not have been sufficient to keep out the solvent, and may have enhanced dermal uptake by occlusion effect.

Results of examinations:
Prior to admission, a brain MRI revealed a non-enhancing lesion, without mass effect, in the right corona radiata. Lumbar puncture revealed normal protein, glucose, cell count and the absence of oligoclonal banding. He was treated with three grams of i.v. solumedrol, for presumptive multiple sclerosis. This was without effect, but he was still taking 75 mg of oral prednisone daily on transfer to our hospital.

Neurologic exam on admission revealed the patient to be alert and oriented. Speech was fluent, and language function was normal. Extraocular eye movements were full with no nystagmus. The pupils were 4 mm, equal, round and reactive to light and accommodation. The remaining cranial nerves were grossly intact. Mild (4+/5) weakness of the right biceps and triceps was present, but all other upper extremity muscle groups were rated 5/5, and tone was normal. Upper extremity reflexes were all at 2+.

There was dramatic and symmetric weakness of all lower extremity muscle groups. Distally the dorsi- and plantar flexors were rated 0/5, quadriceps 3/5, hamstrings 2+ /5, and iliopsoas 2+ /5. Tone was mildly increased. The knee reflexes were 3+, while the ankle jerks were diminished (trace to absent) and the plantar reflexes neutral. Sensation was profoundly affected in a stocking distribution. Pinprick and position sense were both markedly decreased-absent at the toes and ankles. Vibration sense was deficient (the right hand and both lower extremities, with the right leg being more affected then the left).

A gadolinium enhanced MRI of the brain revealed several patchy areas of increased T2 signal in the periventricular white matter, mostly outside the corpus callosum and asymmetrically distributed (more prominent on the right). There was no evidence of mass effect or abnormal enhancement, while MRI imaging of the spinal cord revealed enhancement at multiple thoracic and lumbar levels in the region of the neural formina, in the proximity of the nerve root ganglia.

All four extremities were studied using standard nerve conduction techniques and a Dantec Counterpoint system. These studies included two motor nerve conductions with F wave response latencies and two sensory nerve conductions per extremity.

Lower extremity distal motor latencies markedly prolonged (range: 8.0-9.6 ms), but only for the peroneal segment below the knees were the motor conduction velocities mildly slowed (left: 39.3, right: 38.3 ms). The right F-EDB and both F-AHs were prologned (57.6 - 62 ms). The left F-EDB could not be obtained. There was marked slowing of all the lower extremity sensory conduction velocities sural-left: 36.2, right: 31.8 ms; superficial peroneal-left: 31.2, right: 29.4 ms) but the corresponding sensory evoked response amplitudes were all normal except for the left sural (mildly attenuated at 3.1 µV). The lower extremity motor-evoked response amplitudes were within normal limits.

The distal motor latencies, motor and sensory conduction velocities, motor evoked response amplitudes and F-response latencies were within normal limits for both arms. Sensory evoked response amplitudes for the right arm were within normal limits, but were attenuated compared with the left (right-median: 10, ulnar: 10.6, left-median: 23.3, ulnar: 23.0 µV). There was no evidence of conduction block or temporal dispersion for either the upper or lower extremities.

EMG of selected lower extremity muscles revealed increased insertional activity only in the left extensor digitorum longus, and no sustained spontaneous activity in any of the muscles studied. Non-quantitative studies showed a tendency toward prolonged duration (i.e. 17-20 ms) for numerous MUPs (i.e. motor unit potentials). In several muscles satellite potentials amplitudes and morphologies varied from discharge to discharge. No MUPs could be recruited in the right tibialis anterior or left EDB muscles. In most muscles, recruitment was full, but with a noticeable lag between the onset of patient effort and muscle recruitment.

Somatosensory-evoked potential studies revealed normal amplitudes and latencies for the arms (median nerve stimulation), but no cortical potentials could be obtained following bilateral peroneal stimulation, suggesting a lesion at the dorsal column or lemniscal level. The lumbar latency values (left: 12.2, right: 10.6 ms) suggested an additional abnormality on the left, at or distal to the lumbar cord. Brainstem auditory and visual evoked potentials were within normal limits.

Lumbar puncture produced clear colorless fluid with an opening pressure of 230 mm Hg (31.5 cm H2O). Protein (0.28 g/L), glucose (3.6 mmol/L), and lactic acid (1.6 meq/L) determinations and cell counts (RBC = 12 c/µL, WBC = 0 c/µL) were all within normal limits, as were myelin basic protein levels, Lyme titers, CSF ACE level, HSV PCR, and antibody determinations for CMV, VCA, echo, Coxsackie, and polio viruses, except for the finding, now, of one oligoclonal band. Lumbar puncture and serology were negative for VDRL, cryptococcal antigen, CSF bacterial, fungal and AFB cultures, ANA titer, IgM for EBV, and ANCA C & P antibodies (IgG for EBV was positive). Serum B12 (1.25 ng/mL) and folate (17.2 ng/mL) levels were elevated. Total serum cholesterol was elevated (2.6 and 2.83 g/L).

Effectivity of medical treatment:
The patient continued on tapering doses of prednisone. Intermittent hypertension developed, and was treated with hydrochlorothiazide and quinapril. He received physical and occupational therapy and by the time of discharge (3/6/1998) displayed remarkable improvement in lower extremity strength. Right plantarfiexor strength remained 0/5, left improved to 2/5, dorsiflexors were both 3/5, iliopsoas muscles 4+ /5, the quadriceps were 5/5, and hamstring muscles 4/5.
Outcome of incidence:
Unfortunately following discharge the patient was lost to follow-up.

Any other information on results incl. tables

The patient, a 19-year-old Hispanic male without significant past medical history, was transferred to hospital in February, 1998, after 1 week at another institution. In mid-January he had developed numbness and mild but progressive weakness of the proximal lower extremities and right hand. On admission, he could not stand without assistance. Other symptoms included a transient dysphagia and urinary difficulties. Just prior to developing these symptoms, he had been employed for 2 months as a metal stripper. This occupation involved the use of an industrial solvent used as a degreasing and cleaning agent.

About the time the symptoms began, the man had noted darkening of the skin of his right hand, which was preferentially exposed to this solvent. Protective gloves had been used as a precaution, but may not have been sufficient to keep out the solvent, and may have enhanced dermal uptake by occlusion effect.

Prior to admission, a brain MRI revealed a non-enhancing lesion, without mass effect, in the right corona radiata. Lumbar puncture revealed normal protein, glucose, cell count and the absence of oligoclonal banding. He was treated with three grams of i.v. solumedrol, for presumptive multiple sclerosis. This was without effect, but he was still taking 75 mg of oral prednisone daily on transfer to our hospital.

Neurologic exam on admission revealed the patient to be alert and oriented. Speech was fluent, and language function was normal. Extraocular eye movements were full with no nystagmus. The pupils were 4 mm, equal, round and reactive to light and accommodation. The remaining cranial nerves were grossly intact. Mild (4+/5) weakness of the right biceps and triceps was present, but all other upper extremity muscle groups were rated 5/5, and tone was normal. Upper extremity reflexes were all at 2+.

There was dramatic and symmetric weakness of all lower extremity muscle groups. Distally the dorsi- and plantar flexors were rated 0/5, quadriceps 3/5, hamstrings 2+ /5, and iliopsoas 2+ /5. Tone was mildly increased. The knee reflexes were 3+, while the ankle jerks were diminished (trace to absent) and the plantar reflexes neutral. Sensation was profoundly affected in a stocking distribution. Pinprick and position sense were both markedly decreased-absent at the toes and ankles. Vibration sense was deficient (the right hand and both lower extremities, with the right leg being more affected then the left).

A gadolinium enhanced MRI of the brain revealed several patchy areas of increased T2 signal in the periventricular white matter, mostly outside the corpus callosum and asymmetrically distributed (more prominent on the right). There was no evidence of mass effect or abnormal enhancement, while MRI imaging of the spinal cord revealed enhancement at multiple thoracic and lumbar levels in the region of the neural foramina, in the proximity of the nerve root ganglia.

All four extremities were studied using standard nerve conduction techniques and a Dantec Counterpoint system. These studies included two motor nerve conductions with F wave response latencies and two sensory nerve conductions per extremity.

Lower extremity distal motor latencies markedly prolonged (range: 8.0-9.6 ms), but only for the peroneal segment below the knees were the motor conduction velocities mildly slowed (left: 39.3, right: 38.3 ms). The right F-EDB and both F-AHs were prologned (57.6 - 62 ms). The left F-EDB could not be obtained. There was marked slowing of all the lower extremity sensory conduction velocities sural-left: 36.2, right: 31.8 ms; superficial peroneal-left: 31.2, right: 29.4 ms) but the corresponding sensory evoked response amplitudes were all normal except for the left sural (mildly attenuated at 3.1 µV). The lower extremity motor-evoked response amplitudes were within normal limits.

The distal motor latencies, motor and sensory conduction velocities, motor evoked response amplitudes and F-response latencies were within normal limits for both arms. Sensory evoked response amplitudes for the right arm were within normal limits, but were attenuated compared with the left (right-median: 10, ulnar: 10.6, left-median: 23.3, ulnar: 23.0 µV). There was no evidence of conduction block or temporal dispersion for either the upper or lower extremities.

EMG of selected lower extremity muscles revealed increased insertional activity only in the left extensor digitorum longus, and no sustained spontaneous activity in any of the muscles studied. Non-quantitative studies showed a tendency toward prolonged duration (i.e. 17-20 ms) for numerous MUPs (i.e. motor unit potentials). In several muscles satellite potentials amplitudes and morphologies varied from discharge to discharge. No MUPs could be recruited in the right tibialis anterior or left EDB muscles. In most muscles, recruitment was full, but with a noticeable lag between the onset of patient effort and muscle recruitment.

Somatosensory-evoked potential studies revealed normal amplitudes and latencies for the arms (median nerve stimulation), but no cortical potentials could be obtained following bilateral peroneal stimulation, suggesting a lesion at the dorsal column or lemniscal level. The lumbar latency values (left: 12.2, right: 10.6 ms) suggested an additional abnormality on the left, at or distal to the lumbar cord. Brainstem auditory and visual evoked potentials were within normal limits.

Lumbar puncture produced clear colorless fluid with an opening pressure of 230 mm Hg (31.5 cm H2O). Protein (0.28 g/L), glucose (3.6 mmol/L), and lactic acid (1.6 meq/L) determinations and cell counts (RBC = 12 c/µL, WBC = 0 c/µL) were all within normal limits, as were myelin basic protein levels, Lyme titers, CSF ACE level, HSV PCR, and antibody determinations for CMV, VCA, echo, Coxsackie, and polio viruses, except for the finding, now, of one oligoclonal band. Lumbar puncture and serology were negative for VDRL, cryptococcal antigen, CSF bacterial, fungal and AFB cultures, ANA titer, IgM for EBV, and ANCA C & P antibodies (IgG for EBV was positive). Serum B12 (1.25 ng/mL) and folate (17.2 ng/mL) levels were elevated. Total serum cholesterol was elevated (2.6 and 2.83 g/L).

The patient continued on tapering doses of prednisone. Intermittent hypertension developed, and was treated with hydrochlorothiazide and quinapril. He received physical and occupational therapy and by the time of discharge (3/6/1998) displayed remarkable improvement in lower extremity strength. Right plantarfiexor strength remained 0/5, left improved to 2/5, dorsiflexors were both 3/5, iliopsoas muscles 4+ /5, the quadriceps were 5/5, and hamstring muscles 4/5. Unfortunately following discharge the patient was lost to follow-up.

Applicant's summary and conclusion

Conclusions:
A 19-year-old male developed complaints including weakness of the lower extremities and right hand, numbness, dysphagia and urinary difficulties following a 2 month exposure to an industrial solvent constituted mainly of 1-bromopropane, but also containing butylene oxide, 1,3-dioxolane, nitromethane, and other components. Nerve conduction studies revealed evidence of a primary, symmetric demyelinating polyneuropathy. Evidence of CNS involvement came from gadolinium enhanced MRI scans of the brain, showing patchy areas of increased T2 signal in the periventricular white matter, similar scans of the spinal cord revealing root enhancement at several lumbar levels, and SSEP studies. The patient's symptoms had started to resolve following the discontinuation of the exposure, before he was lost to follow-up. Similar findings have been reported following 1-bromopropane exposure in rats, leading to a hypothesis that the patient's symptoms may have been due to 1-bromopropane-induced neurotoxicity.
Executive summary:

A 19-year-old male developed complaints including weakness of the lower extremities and right hand, numbness, dysphagia and urinary difficulties following a 2 month exposure to an industrial solvent constituted mainly of 1-bromopropane, but also containing butylene oxide, 1,3-dioxolane, nitromethane, and other components. Nerve conduction studies revealed evidence of a primary, symmetric demyelinating polyneuropathy. Evidence of CNS involvement came from gadolinium enhanced MRI scans of the brain, showing patchy areas of increased TZ signal in the periventricular white matter, similar scans of the spinal cord revealing root enhancement at several lumbar levels, and SSEP studies. The patient's symptoms had started to resolve following the discontinuation of the exposure, before he was lost to follow-up. Similar findings have been reported following 1-bromopropane exposure in rats, leading to a hypothesis that the patient's symptoms may have been due to 1-bromopropane-induced neurotoxicity.