Disodium wolframate

Neurotoxicity

Description of key information

The neurotoxicity potential of sodium tungstate is reported by two publications by Sachdeva et al 2015 and Radcliffe et al 2009. An inhalation study reported that sodium tungstate is not appreciably transported via the olfactory pathway to the brain following a single 90-min exposure in rats, although this pathway is known to transport a number of other metals (Radcliffe et al, 2009). Sodium tungstate exposure was reported in one study to produced oxidative stress in brains from rats exposed. However, the study did not elucidate and correlate these oxidative changes with behavioral and functional alterations (Sachdeva et al, 2015).

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Link to relevant study records

Reference

Endpoint:

neurotoxicity: short-term oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Well documented scientfically sound study with sufficient information provided on materials and methods to evaluate results.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The effects of sodium tungstate on oxidative stress, few selected neurological variables like acetylcholinesterase, biogenic amines in rat brain regions (cerebral cortex, hippocampus and cerebellum)

GLP compliance:

not specified

Remarks:

Study has adequate and reliable coverage of the key parameters foreseen to be investigated in the corresponding test methods and adequate and reliable documentation of the study is provided

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

Male Wistar rats, weighing approximately 100–120 g were used in the study. Prior to the dosing, they were acclimatized for 7 days. Briefly, animals were kept in polypropylene cages with clean dust free rice husk. The animals were housed in stainless steel cages in an air-conditioned room with temperature maintained at 25 ± 2 °C and relative humidity 60 ± 10%. Animals’ rooms were illuminated with 300 lux light, alternating with 12 h darkness light from 06:00 to 18:00 h and vice versa. Rats were allowed standard chow diet throughout the experiment and water ad libitum.

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

Rats were divided into eight groups of 10 rats each and were treated as below for 3 months (five days a week):
Group I: Normal animal, received normal water
Group II: Sodium tungstate, 100 ppm in drinking water, daily
Group III: Quercetin alone, orally, once, daily (0.30 mM)
Group IV: N-acetylcysteine (NAC) alone, orally, once, daily (0.30 mM)
Group V: Flavonoid (naringenin) alone, orally, once, daily (0.30 mM)
Group VI: Sodium tungstate + Quercetin as in group II and group III, respectively
Group VII: Sodium tungstate + NAC (as in group II + group IV, respectively)
Group VIII: Sodium tungstate + Flavonoid (naringenin) (as in group II + group V, respectively)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

Daily

Dose / conc.:

100 ppm

Remarks:

nominal in water

No. of animals per sex per dose:

10 rats per group

Control animals:

yes, concurrent vehicle

Specific biochemical examinations:

- Amount of reactive oxygen species in blood was measured using 2′, 7′-dichlrofluorescein diacetate (DCF-DA) that gets converted into highly fluorescent DCF by cellular peroxides (including hydrogen peroxide). The supernatant fractions obtained were used to determine the following parameters in three different brain regions:
- Measurement of lipid peroxidation was conducted by the thiobarbituric acid reactive substances (TBARS).
- Tissue reduced glutathione (GSH) and oxidized glutathione (GSSG)
- Tissue glutathione peroxidase (GPx)
- Tissue glutathione-S-transferase (GST
- Brain acetyl cholinesterase (AChE) activity
- Brain monoamine oxidase (MAO) activity
- Brain biogenic amine levels (dopamine and nor epinephrin)

Neurobehavioural examinations performed and frequency:

None

Sacrifice and (histo)pathology:

Brains were quickly dissected out, placed on a glass plate resting over crushed ice for the separation of various regions (cortex, cerebellum and hippocampus). The brain parts were homogenized in phosphate buffer (pH 7.4).

Statistics:

The results are expressed as the mean ± SEM of number of observations. Comparisons of means were carried out using ANOVA followed by Bonferroni multiple comparison test to compare means between the different treatment groups

Clinical signs:

not specified

Mortality:

no mortality observed

Body weight and weight changes:

not specified

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

Haematological findings:

not specified

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Significant increase in oxidative stress variables.

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

effects observed, treatment-related

Description (incidence and severity):

- Brain ROS increased significantly in the cortex and hippocampus; however, an increasing trend was noticed in the cerebellum of rats on sodium tungstate exposure compared to normal animals.
- increase in GPXactivity in cerebellum compared to cortex and hippocampus on sodium tungstate exposure. GST activity on the other hand, significantly decreased in cortex, cerebellum and hippocampus.
- Depletion of dopamine (DA) in cortex and cerebellum was observed in sodium tungstate exposed rats as compared to normal control rats.
- Following sodium tungstate exposure, 5-HT levels were depleted in the cortex and marginally in the cerebellum.
- Sodium tungstate exposure produced an increase in Nor Epinephrie (NE) levels in hippocampus while there was a significant reduction in cortex and marginal fall in cerebellum compared to the NE levels of control rats.
- Sodium tungstate exposed animals showed an alteration in AChE activity in cortex and cerebellum compared to hippocampus.
- Sodium tungstate exposed animals showed a more pronounced alteration in AChE activity in cortex and cerebellum compared to hippocampus
- Co-administration of NAC and flavonoids with tungstate provided moderately effective in reducing brain ROS, moderately prevent effects in restoring GPX and GST activities in the different brain regions, recover the altered DA levels in cortex and cerebellum; and provided a significant recovery in the 5-HT level of the cortex and hippocampus, restored the altered NE levels in all the brain regions, and increase in the activity of acetylcholinesterase.

Key result

Dose descriptor:

conc. level:

Effect level:

100 ppm (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Tungstate exposure produced an increase in biochemical variables indicative of oxidative stress but no correlation was conducted with behavioral and functional alteration.

Remarks on result:

not determinable

Conclusions:

Tungstate exposure produced an increase in biochemical variables indicative of oxidative stress while, neurological alterations were more pronounced in the cerebral cortex compared to other regions. Co-administration of NAC and flavonoids with sodium tungstate significantly restored glutathione, prevented changes in the brain biogenic amines, reactive oxygen species (ROS) and TBARS levels in the different brain regions. The protection was more prominent in the animals co-administered with NAC. Further studies are required for elucidating and correlating the behavioral and functional alterations.

Endpoint conclusion

Endpoint conclusion:

no study available

Effect on neurotoxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Effect on neurotoxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The sodium tungstate neurotoxicity studies are more investigative reports conducted under no standard testing guidelines which limit their usability for regulatory purposes. Based on this, none of the data from these publications warrant any classification for sodium tungstate as a neurotoxicant per CLP as more information is needed.