1-bromopropane

Neurotoxicity

Description of key information

Three studies investigating the potential neurotoxic effects from exposure to 1-bromopropane were conducted. These results indicated that 1-bromopropane may have neurotoxic potential for humans.

Additional information

In a study of effect on the neural behavior of rats by means of investigating sex preference through smelling the urine of the opposite sex in the 1-bromopropane exposure groups, no result dependent upon the test material and exposure concentration was detected.

Another study aimed to clarify the dose-dependent effects of 1-bromopropane on the nervous system. Forty-four Wistar male rats were randomly divided into 4 groups of 11 each. The groups were exposed to 200, 400, or 800 ppm of 1-bromopropane or only fresh air 8 hours per day for 12 weeks. Grip strength of forelimbs and hind limbs, maximum motor nerve conduction velocity (MCV), and distal latency (DL) of the tail nerve were measured in 9 rats of each group every 4 weeks. The other 2 rats of each group were perfused at the end of the experiment for morphological examinations. The rats of the 800-ppm group showed poor kicking and were not able to stand still on the slope. After a 12-week exposure, forelimb grip strength decreased significantly at 800 ppm and hind limb grip strength decreased significantly at both 400 and 800 ppm or after a 12-week exposure. MCV and DL of the tail nerve deteriorated significantly at 800 ppm. Ovoid or bubble-like debris of myelin sheaths was prominent in the unraveled muscular branch of the posterior tibial nerve in the 800-ppm group. Swelling of preterminal axons in the gracile nucleus increased in a dose-dependent manner. Plasma creatine phosphokinase (CPK) decreased dose-dependently with significant changes at 400 and 800 ppm. 1-Bromopropane induced weakness in the muscle strength of rat limbs and deterioration of MCV and DL in a dose-dependent manner, with morphological changes in peripheral nerve and preterminal axon in the gracile nucleus. 1-Bromopropane may be seriously neurotoxic to humans and should thus be used carefully in the workplace.

To ascertain the neurotoxicity of 1-bromopropane, two doses of 1-bromopropane (3.7 and 11.0 mmol/kg), and a dose of 2,5-hexanedione (2,5-HD) as a positive reference (2.6 mmol/kg) dissolved in olive oil were subcutaneously injected into rats once a day, 5 d/wk for 4 weeks. A control group were injected with olive oil alone. The maximum motor conduction velocity (MCV) and the motor latency (ML) in rat tail nerve, as indexes of the electrophysiological changes, were investigated for 4 weeks.

From 2 weeks after the injections, the MCV in the 1-bromopropane treated groups began to decrease in a dose-dependent fashion. These dose-related decreases continued, and the MCV in the group injected with 1-bromopropane (11.0 mmol/kg) decreased significantly compared with that in the control group.

The ML in the 1-bromopropane treated groups increased in reverse correlation with the MCV decreases. The changes in ML occurred earlier than the MCV changes in the 1-bromopropane treated groups. The potency of the peripheral neurotoxic changes induced by 1-bromopropane at the doses used in the present study was weaker than that observed in the positive reference 2,5-HD (2.6 mmol/kg) group.

A full Functional Observation Battery (FOB) addressing potential neurotoxic effects was conducted as part of the 90 day repeat dose inhalation study, and that no clear treatment-related findings were observed during FOB on any occasion tested. Occasional statistically significant differences between the control and treated groups were attributed to intergroup variation. With respect to motor activity, no significant differences were detected between the control and treated groups during the study.

Justification for classification or non-classification

According to section 3.2.8 of Directive 67/548/EEC, volatile substances which cause clear symptoms of central nervous system (CNS) depression by inhalation and which are not already classified with respect to acute inhalation toxicity (R20, R23, R26, R68/20, R39/23 or R39/26) should be classified as R67: Vapours may cause drowsiness and dizziness.

The key acute oral rat study by Clauzeau (1993) used a limit dose of 2000 mg/kg and reported clinical signs suggesting effects on the CNS on day 1, but no effects on day two, and no macropathology. Other acute studies reported clinical signs consistent with CNS disturbance (Paster 1978a oral; Schorsch 1997 inhalation; Moon 1998 inhalation; Labbe 1997 inhalation) which indicate effects in a lipophilic tissue at a distance from the site of exposure. Therefore, based on effects on the CNS, n-propyl bromide most likely passes through the gastrointestinal (GI) tract and the alveoli of the lungs to produce systemic exposure. However, the CNS effects were limited to the immediate post-dosing period, indicating that n-propyl bromide did not accumulate, consistent with its properties of water solubility.

In addition, human CNS effects have been reported. 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.

Taking the above into account, n-propyl bromide is officially classified as R67 on Annex I of Directive 67/548/EEC and as a STOT SE Category 3 on Annex VI of the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.