Registration Dossier

Toxicological information

Neurotoxicity

Currently viewing:

Administrative data

Endpoint:
neurotoxicity: sub-chronic oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Axonal Atrophy Is a Specific Component of 2,5-Hexandedione Peripheral Neuropathy
Author:
E.J. Lehning, K.S. Dyer, B.S. Jortner, R.M. LoPachin
Year:
1995
Bibliographic source:
Toxicology and Applied Pharmacology, 135, 1995, 58-66

Materials and methods

Test guideline
Qualifier:
no guideline followed
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
Aldrich Chemical Company, 97% purity

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
Taconic Farms, GErmantown, NY, 250-275 g bw, Purina Rodent Lab Chow, water ad lib.,

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
0.4 % (w/v), maximum concentration tolerated without severe reduction in daily water consumption
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
77, 86 and 103 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0.37 g/kg/d
Basis:
actual ingested
No. of animals per sex per dose:
one dose, male animals only
Control animals:
yes, concurrent vehicle
Details on study design:
Index of hexanedione-induced neurological deficits: hindlimb weakness as indicated by performance on a treadmill.
Rats were sacrificed when developping hindlimb weakness. Sciatic nerve and posterior tibial nerve were analyzed.

Examinations

Observations and clinical examinations performed and frequency:
Index of hexanedione-induced neurological deficits: hindlimb weakness as indicated by performance on a treadmill.
Neurobehavioural examinations performed and frequency:
Sciatic nerve and posterior tibial nerve were analyzed after sacrifice.
Sacrifice and (histo)pathology:
ketamine and xylazine
Positive control:
No
Statistics:
ANOVA

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
reduced body weight gain
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
approx. 30 % reduction
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
hindlimb weakness
Neuropathological findings:
effects observed, treatment-related
Description (incidence and severity):
Sciatic nerve and posterior tibial nerve

Effect levels

Dose descriptor:
other: axonal atrophy
Effect level:
ca. 370 mg/kg bw/day
Based on:
test mat.
Sex:
male
Remarks on result:
other:

Applicant's summary and conclusion

Conclusions:
Axonal atrophy is a specific, functionally relevant neuropathic component of hexanedione neuropathy.
Male SD rats receiving 370 mg/kg bw day (oral application) developped hindlimb weakness after 77-103 days.
Examination of the sciatic nerve and posterior tibial nerve show axonal swelling and atrophy.