1,2-epoxybutane

Neurotoxicity

Description of key information

Propylene oxide (PpO) and butylene oxide (BtO) are not known to produce neuropathy in humans; however, both produced ataxia of the hindleg and distal axonal degeneration of myelinated fibers of the lumbosacral primary sensory neuron in rats. Therefore, both must be considered to be neurotoxic. Although the concentration of PpO and BtO needed to produce neuropathy in rats is much greater than the exposure limits (100 ppm for PpO and not determined for BtO) recommended by the National Institute of Occupational Safety and Health, it cannot be excluded that the substances might cause neuropathies in humans at high concentrations too, but not at the derived DNELs/DMELs.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Effect on neurotoxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

neurotoxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: basic information given

Qualifier:

no guideline followed

Principles of method if other than guideline:

Based on preliminary studies, test rats were subjected daily to a 6-hr exposure to BtO at a concentration of 2000 ppm, four times a week for 5 months. Systematic clinical and histopathologic studies were performed.

GLP compliance:

not specified

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation

Duration of treatment / exposure:

5 months

Frequency of treatment:

6 h/day, 4 days/week

Dose / conc.:

2 000 ppm

No. of animals per sex per dose:

no data

Control animals:

yes

Remarks on result:

not measured/tested

Test rats developed mild ataxia in the hindleg in the second and third week of the fifth month of exposure. Test rats were sacrificed at the end of the fifth month of exposure along with the pair-fed control rats. In teased fiber preparations of peroneal, proximal, and distal sural nerves, nerve to soleus muscle, and proximal and distal dorsal caudal trunks, the difference in the frequency of the abnormality between test and control was not statistically significant. In epon-embedded sections, no abnormality of myelinated fibers in test compared with control was found in the limb nerves and the dorsal caudal trunk. Similarly, no abnormality was found in the sixth lumbar and the third sacral dorsal roots and dorsal root ganglion. On the other hand, in fasciculus gracilis, degeneration of myelinated fibers was found in all test rats at the third cervical segment, but not at the fifth thoracic segment. Morphometric evaluation of peroneal nerve and proximal and distal dorsal caudal trunks showed that the transverse fascicular area, myelinated fiber density, myelinated fiber number per nerve, and median and mean diameters of myelinated fibers were all similar between test and control.

The extent of the distribution of the distal degeneration of the myelinated axon in the fasciculus gracilis was analyzed. The centrally directed myelinated axon of the primary sensory neuron seemed to be dying or degenerating back to the fourth cervical segment and down to the third thoracic segment. The densities and the median diameters of myelinated fibers of the dorsomedì.an portion of the fasciculus gracilis at the third cervical and fifth thoracic segments were evaluated. Myelinated fiber density in test was significantly less than that in control only at the third cervical segment. Median diameter was similar between test and control in both segments.

In BtO intoxication, obvious axonal degeneration of myelinated fibers was preferentially found in the dorsal portion of the fasciculus gracilis, where the centrally directed myelinated axon of the lumbosacrococcygeal primary sensory neuron is distributed.

Conclusion

Propylene oxide (PpO) and butylene oxide (BtO) are not known to produce neuropathy in humans; however, both produced ataxia of the hindleg and distal axonal degeneration of myelinated fibers of the lumbosacral primary sensory neuron in rats. Therefore, both must be considered to be neurotoxic. Although the concentration of PpO and BtO needed to produce neuropathy in rats is much greater than the exposure limits (100 ppm for PpO and not determined for BtO) recommended by the National Institute of Occupational Safety and Health, PpO and BtO may cause neuropathies in exposed workers. Recognition of the neurotoxicity of both chemicals seems to be very important for better understanding the relationship between the chemicals and the distribution of morphologic alterations of the lumbosacral primary sensory neuron, one of the most vulnerable targets of the neurotoxic substances (Thomas, 1980).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Species:

rat

Effect on neurotoxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Test rats developed mild ataxia in the hindleg in the second and third week of the fifth month of inhalation exposure (Ohnishi, 1993). Test rats were sacrificed at the end of the fifth month of exposure along with the pair-fed control rats. In teased fiber preparations of peroneal, proximal, and distal sural nerves, nerve to soleus muscle, and proximal and distal dorsal caudal trunks, the difference in the frequency of the abnormality between test and control was not statistically significant. In epon-embedded sections, no abnormality of myelinated fibers in test compared with control was found in the limb nerves and the dorsal caudal trunk. Similarly, no abnormality was found in the sixth lumbar and the third sacral dorsal roots and dorsal root ganglion. On the other hand, in fasciculus gracilis, degeneration of myelinated fibers was found in all test rats at the third cervical segment, but not at the fifth thoracic segment. Morphometric evaluation of peroneal nerve and proximal and distal dorsal caudal trunks showed that the transverse fascicular area, myelinated fiber density, myelinated fiber number per nerve, and median and mean diameters of myelinated fibers were all similar between test and control.

The extent of the distribution of the distal degeneration of the myelinated axon in the fasciculus gracilis was analyzed. The centrally directed myelinated axon of the primary sensory neuron seemed to be dying or degenerating back to the fourth cervical segment and down to the third thoracic segment. The densities and the median diameters of myelinated fibers of the dorsomedì.an portion of the fasciculus gracilis at the third cervical and fifth thoracic segments were evaluated. Myelinated fiber density in test was significantly less than that in control only at the third cervical segment. Median diameter was similar between test and control in both segments.

In BtO intoxication, obvious axonal degeneration of myelinated fibers was preferentially found in the dorsal portion of the fasciculus gracilis, where the centrally directed myelinated axon of the lumbosacrococcygeal primary sensory neuron is distributed.