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Toxicological information

Neurotoxicity

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Administrative data

Endpoint:
neurotoxicity: sub-chronic oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
no data available
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well reported study.

Data source

Reference
Reference Type:
publication
Title:
Effects of vanadium on activity and learning in rats
Author:
Sanchez, D. J.; et al.
Year:
1998
Bibliographic source:
Physiol. Behav. 63, 345-350

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The effects of vanadate administration on activity and learning were assessed in rats.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Test material form:
other: solid
Details on test material:
- Name of test material (as cited in study report): Sodium metavanadate
- Physical state: solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: animals were obtained from Criffa (Barcelona, Spain).
- Weight at study initiation: 200-220 g
- Diet: ad libitum, standrad rat chow
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 40-60
- Air changes (per hr):
- Photoperiod: 12 hours dark/light cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- Solutions of metavanadate were prepared in drinking water and given to animals at a volume of 0.20 mL/kg body weight.

Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
8 weeks treatment + 3 weeks pos exposure period
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg body weight/day
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
4.1 mg/kg body weight/day
Basis:
nominal conc.
(1.71 mg V/kg/day)
Remarks:
Doses / Concentrations:
8.2 mg/kg body weight/day
Basis:
nominal conc.
(3.42 mg V/kg/day)
Remarks:
Doses / Concentrations:
16.4 mg/kg body weight/day
Basis:
nominal conc.
(6.84 mg V/kg/day)
No. of animals per sex per dose:
48 animal were randomly assigned to 3 treatment groups (12 animals respectively), or to an untreated control group.
Control animals:
yes
Details on study design:
Dose selection rationale:
- The choice of the doses was dictated by previous results, which indicated that the administration of similar amounts of sodium metavanadate to rats was effective in normalising blood glucose levels (Domingo, J.L.; et al. 1995).
- Moreover, no remarable tocix effects were apparent when similar quantities of sodium metavanadate were administered to rats for 6 weeks in order to evaluate the efficacy of various chelating agents on distribution and urinary excretion of vanadium (Gomez, M.S.; et al. 1991).

Examinations

Observations and clinical examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: no further details are given

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No
Specific biochemical examinations:
no data
Neurobehavioural examinations performed and frequency:
Behavioral testing was initiated after the cessation of vanadate administration.

Open-Field Activity:
- General motor activity was measured in an open-field apparatus consisting of a wood 76.2x76.2-cm square and surounded by a 47-cm high dark wall.
- During the test, rats were allowed to move freely around the open-field and to explore the environment for 15 minutes.
- The path of the animals was recorded by a vidoe camera. The vidoe tracking programme Etho Vision was used to measure the total distance travelled, the number of horizontal movements, the total time in movement and the number of rearings as a measure of vertical activity.

Active Avoidance:
- Animals were tested for two-way shock avoidance learning in an Ugo Basile automatic reflex conditioner.
- An auditory (70dB, 670Hz) and a light stimulus (10W) administered as a maximum of 11 seconds served as the conditioned stimulus (CS). 1 second later, a 0.4mA scrambled current electric shock was administered for a maximum time of 10 seconds and served as the unconditioned stimulus (US).
- Total time for each trial was 22 seconds and the time between 2 consecutive trials was equal to 4 seconds.
- 50 trials were given each day, and the animals were tested at the same time of the day for 3 consecutive days.
- The total number of avoidances (number of crossings during US), the total number of intercrossings (total number of crossings during the entire trial) and the latency period (as time before the first crossing) were recorded.
- The first session was preceded by 10 minutes of accommodation to the box.
Sacrifice and (histo)pathology:
- At the end of the testing period (3 weeks), rats were euthanised under diethyl ether anesthesia.
- The following organs and tissues were removed for vanadium analyses: liver, spleen, kidneys, brain, bone (femur) and muscle (gastrocnemius).
Other examinations:
no data
Positive control:
not stated
Statistics:
Body weight, tissue vanadium concentrations and open-field activity data were analysed by one-way ANOVA followed by LSD (least significant difference) method for multiple comparison. Active avoidance data were evaluated with a two-way ANOVA (groupxsession) with repeated measures. Whenever the assumption of sphericity was rejected (p<0.005), to avaoid corrections, all F ratios involving repeated measures factors were calculated using a MANOVA. Significant treatment-related interactions were further analysed using the simple effect at each level of interaction. Multiple regression analysis was performed to assess associations between quantitative variables. A level of p<0.05 was used to indicate statistical significance.

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Clinical biochemistry findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Other effects:
not examined
Description (incidence and severity):
Migrated information from 'Further observations for developmental neurotoxicity study'



Details on results (for developmental neurotoxicity):Not applicable, since no developmental neurotoxicity was evaluated. (migrated information)
Details on results:
BODY WEIGHT AND WEIGHT GAIN
- At the end of the first week of treatment, there were no significant differences in body weight between control and vanadium-treated animals.
- A significant reduction in weight gain was subsequently observed in the group given 16.4 mg vanadate/kg bw/day for 8 weeks. This reduction was also noted at sacrifice 3 weeks after the end of the exposure period.

NEUROBEHAVIOUR
- The results of the behavioral testing showed that oral vanadate administration resulted in significant reductions in both general activity and learning in all dose groups.
- No clear dose-response relationship was found.

OTHER FINDINGS:
- A persistent presence of vanadium was observed in all tissues measured.
- Tissue levels of V in liver, spleen, kidney, brain, bone, and muscle were dose-dependently increased 3 weeks after cessation of treatment.

Effect levels

Dose descriptor:
other: reduction in general activity and learning
Effect level:
4.1 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Behavioural testing resulted in significant reductions in both general activity and learning at all dose levels; no clear dose-response relationship was found.
Remarks on result:
other:

Applicant's summary and conclusion

Conclusions:
Adult male rats were given 0, 4.1, 8.2 and 16.4 mg/kg bw/day sodium metavanadate orally by gavage for 8 consecutive weeks. Vanadium exposure caused an observable, but not significant, effect on body weight gain, while a persistent presence of vanadium was observed in all tissues. The results of the behavioural testing show that oral vanadate administration resulted in significant reduction in both general activity and learning. A NOAEL could not be derived. Tissue levels of V in liver, spleen, kidney, brain, bone, and muscle were found dose-dependently increased 3 weeks after cessation of treatment.