Registration Dossier

Toxicological information

Neurotoxicity

Currently viewing:

Administrative data

Endpoint:
neurotoxicity
Remarks:
other: in-vitro
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Very detailed investigation on the mechanism of sulphite toxicity.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
A mechanism of sulfite neurotoxicity.
Author:
Zhang, X.; et al.
Year:
2005
Bibliographic source:
J. Biol. Chem. 279, 43035-43045

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
In this study the increase in reactive oxygen species (ROS) was assayed in Neuro-2a, PC12, HepG2 cell lines and human foetal liver cells exposed to 5-500 µM freshly prepared sulphite for 30 min was examined.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): sodium sulfite
- Molecular formula (if other than submission substance): Na2SO3
- Molecular weight (if other than submission substance): 126 g/mol
- Other: sodium sulfite was obtained from Merck, Germany
No further information given.

Test animals

Species:
other: in-vitro system, rat brain mitochondria used were prepared from Wistar rats
Strain:
other: not applicable
Sex:
not specified
Details on test animals and environmental conditions:
not applicable

Administration / exposure

Route of administration:
other: not applicable
Vehicle:
other: not applicable
Doses / concentrations
Remarks:
Doses / Concentrations:
5-500 µM sodium sulfite
Basis:
other: in-vitro applied concentration
No. of animals per sex per dose:
not applicable

Results and discussion

Results of examinations

Clinical signs:
not examined
Description (incidence and severity):
not applicable
Mortality:
not examined
Description (incidence):
not applicable
Body weight and weight changes:
not examined
Description (incidence and severity):
not applicable
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
not applicable
Food efficiency:
not examined
Description (incidence and severity):
not applicable
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
not applicable
Ophthalmological findings:
not examined
Description (incidence and severity):
not applicable
Clinical biochemistry findings:
not examined
Description (incidence and severity):
not applicable
Behaviour (functional findings):
not examined
Description (incidence and severity):
not applicable
Gross pathological findings:
not examined
Description (incidence and severity):
not applicable
Neuropathological findings:
not examined
Description (incidence and severity):
not applicable
Other effects:
not examined

Effect levels

Dose descriptor:
NOAEL
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Any other information on results incl. tables

- Exposure of Neuro-2a, PC12, HepG2 and human foetal liver cells to micromolar concentrations of sodium sulphite caused an increase in reactive oxygen species and a decrease in ATP.

- Likewise, the biosynthesis of ATP in intact rat brain mitochondria from the oxidation of glutamate was inhibited by micromolar concentrations of sulphite.

- The glutamate-driven respiration increased the mitochondrial membrane potential, and this was abolished by sulphite, but the increases of the potential by malate and succinate were not affected.

- Sulphite inhibits the formation of NADH from exogenous NAD and glutamate added to rat brain mitochondrial extracts.

- Pre-incubation of mitochondria with sulphite blocked the reduction of NAD.

- Glutamate dehydrogenase in rat brain mitochondrial extracts was inhibited dose-dependently by sulphite as was the activity of a purified enzyme.

- The authors proposed that the glutamate dehydrogenase is one target of action of sulphite, leading to a decrease in α-ketoglutarate and a diminished flux through the TCA cycle accompanied by a decrease in NADH through the mitochondrial electron transport chain, a decreased mitochondrial membrane potential, and a decrease in ATP synthesis. 

 

Applicant's summary and conclusion

Conclusions:
In the described study, exposure of Neuro-2a, PC12, HepG2 and human foetal liver cells to 5-500 µM sodium sulfite caused an increase in reactive oxygen species and a decrease in ATP. Sulfite inhibited dose-dependently the glutamate dehydrogenase (GDH) in rat brain mitochondrial extracts. It was concluded that the GDH inhibition by sulfite leads to a decrease in α-ketoglutarate and a diminished flux through the TCA cycle accompanied by a decrease in NADH through the mitochondrial electron transport chain, a reduction in the mitochondrial membrane potential, and a decreased ATP synthesis.