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EC number: 231-834-5 | CAS number: 7758-11-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- Study on analogous substance submitted as supporting data only.
Data source
Reference
- Reference Type:
- publication
- Title:
- Early Events Involving Glomerular Calcification Induced by Dibasic Sodium Phosphate Solution in Rats
- Author:
- Tsuchiya N, Torii M, Narama I, Matsui T
- Year:
- 2 008
- Bibliographic source:
- J Toxicol Pathol 21:229-37; DOI: 10.1293/tox.21.229
Materials and methods
- Objective of study:
- distribution
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Male Sprague-Dawley rats were treated with disodium hydrogenorthophosphate (409.6 mg/kg bw/day) by injection into the tail vain. Urinalysis was carried out on days 1, 3, 5 and 8 of dosing, and rats were sacrificed on days 2, 4 and 9 for histopathological and electron microscopic examination of the kidneys.
- GLP compliance:
- no
Test material
- Reference substance name:
- Disodium hydrogenorthophosphate
- EC Number:
- 231-448-7
- EC Name:
- Disodium hydrogenorthophosphate
- Cas Number:
- 7558-79-4
- Molecular formula:
- H3O4P.2Na
- IUPAC Name:
- disodium hydrogen phosphate
- Details on test material:
- - Name of test material (as cited in study report): dibasic sodium phosphate, Na2HPO4g.
- Analytical purity: >=99% (supplier information)
- Supplier: Kanto Chemical Co. Inc. Tokyo, Japan
Constituent 1
- Radiolabelling:
- no
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Clea Japan Inc. (Shiga, Japan)
- Age at study initiation: 5 weeks (35 days)
- Housing: individually in plastic cages in an animal room under controlled conditions
- Diet (e.g. ad libitum): pelleted diet (CA-1, Clea Japan Inc., Tokyo)
- Water (e.g. ad libitum): ad libitum by automatic watering system after filtration (30- and 3-µm pore filter) followed by UV-irradiation
- Acclimation period: 1 week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23±3°C
- Humidity (%): 50±20%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- intravenous
- Vehicle:
- physiological saline
- Details on exposure:
- The rats were administered 360 mM disodium hydrogenorthophosphate at 4 mL/kg bw/min for 2 minutes once daily via the tail vain through a polypethylene catheter connected to a plastic syringe mounted on an infusion pump (STC-525, Terumo Corp., Tokyo).
- Duration and frequency of treatment / exposure:
- once daily for up to 8 days
Doses / concentrations
- Remarks:
- Doses / Concentrations:
360 mmol/L, equivalent to 409.6 mg/kg bw/day
- No. of animals per sex per dose / concentration:
- 5
- Control animals:
- yes, concurrent vehicle
- Positive control reference chemical:
- no
- Details on study design:
- HISTOPATHOLOGY:
Rats were euthanized by exsanguination by cutting both the abdominal aorta and vena cava under pentobarbital sodium anesthesia. And were then necropsied. The kidneys were removed and weighed together (Mettler PM400). Organs listed in Table 2 were microscopically examined. These organs were fixed in 10% neutral buddered formalin, processed routinely and embedded in paraffin. Paraffin sections were prepared and stained with hematoxylin and eosin (H&E). The kidney sections were also stained with von Kossa and periodic acid Schiff (PAS) reagents and periodic acid methenamine-silver (PAM) stain.
IMMUNOHISTOCHEMISTRY:
Kidney sections were subjected to indirect immunoperoxidase staining using the following primary antibodies:
- PCNA (proliferating cell nuclear antigen)
- Podoplanin (specific for podocytes and parietal cells)
- Desmin
For electron microscopic observation, kidneys that were excised from 2 animals per group at each time point were fixed in 3% glutaraldehyde and 2% osmic acid and embedded in epoxy resin. Ultrathin sections were stained with uranyl acetate and lead citrate and examined under an electron microscope (JEM-1010, JEOL Ltd., Tokyo). - Statistics:
- Statistical significance was analyzed by Student’s t-test for body and kidney weights and the Mann-Whitney test for immunohistochemistry. All data are expressed as means ±SD.
Results and discussion
Toxicokinetic / pharmacokinetic studies
- Details on distribution in tissues:
- CLINICAL SIGNS AND MORTALITY
No abnormal clinical signs were observed in any group.
BODY WEIGHT AND WEIGHT GAIN
No body weight changes were observed in any group.
URINALYSIS
Increased urinary protein was first detected on day 3 in 2 out of 10 treated rats (100 mg/dL/4 h). Almost all treated animals had increased urinary protein excretion on day 5 with values ranging from 100 – 1000 mg/dL/4 h. By day 8, all treated rats showed moderate to severe proteinuria. In the control group, although several rats had minimal to mild proteinuria, no time course increase was observed.
Data are summarized in table 1.
ORGAN WEIGHTS
There were no statistically significant differences in the kidney weights of the phosphate-treated rats in comparison with the control group. No data were provided by the authors to corroborate this result.
HISTOPATHOLOGY: NON-NEOPLASTIC
No significant changes were observed in the saline control group. The first renal lesions were observed on day 4 of treatment as minimal focal deposition of calcium salts within the parietal epithelial cells. After 8-day repeated dosing, focal calcification of the glomerular basement membrane, mesangium, and parietal epithelial cells were evident. Hypertrophy and increased mitotic figures were also visible.
There were no lesions observed in the other organs including the bone and parathyroid.
The results are summarized in table 2.
IMMUNOHISTOCHEMISTRY
There were no differences in podoplanin expression or the number of PCNA-positive cells between the treated and untreated rats on days 2 and 4.
On day 9, the number of podoplanin-positive podocytes and parietal epithelial cells were significantly lower and desmin expression was significantly higher compared to control values.
The results are summarized in table 2.
ELECTRON MICROSCOPY
After single administration of disodium hydrogenorthophosphate, a number of small vacuoles were observed within the Bowman’s space. High-density particles (calcium phosphates?) adhered to the membranes of the vacuoles and clusters of debris were found within the Bowman’s space.
On day 4, low-density lamellar structures were observed within the Bowman’s space, the glomerular basement membrane and the mesangial matrix. Some of these structures protruded into the vascular cavity and the podocytes lining the glomerular basement membrane exhibited hypertrophy. Bowman’s space was filled with large amounts of debris.
On day 9, degeneration of the podocytes was more severe and lamellar structures accumulated partially within parietal epithelia, podocytes and glomerular basement membrane.
The results are summarized in table 2.
Metabolite characterisation studies
- Metabolites identified:
- not measured
Any other information on results incl. tables
Table 1: Detection of proteinuria by urinanalysis.
Treatment |
Day 1 |
Day 3 |
Day 5 |
Day 8 |
||||
|
Control |
Treated |
Control |
Treated |
Control |
Treated |
Control |
Treated |
Nr. of animals |
9 |
15 |
6 |
10 |
3 |
5 |
3 |
5 |
Negative |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Minimal |
4 |
11 |
6 |
4 |
2 |
0 |
3 |
0 |
Mild |
5 |
4 |
0 |
4 |
1 |
1 |
0 |
0 |
Moderate |
0 |
0 |
0 |
2 |
0 |
3 |
0 |
1 |
Marked |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
4 |
a) Minimal: <15 mg/dL; Mild: 30 mg/dL; Moderate: 100 mg/dL; Marked: > 300 mg/dL;
Table 2: Findings for disodium hydrogenorthophosphate treated rats
Findings |
|
Days of administration |
||
|
|
Single |
3 days |
8 days |
Urinalysis |
Proteinuria |
- |
P |
P |
Microscopy |
Calcification:parietal epithelial cells |
- |
P |
P |
Calcification: Glomerular basement membrane / podocytes |
- |
- |
P |
|
Calcification: Mesangium |
- |
- |
P |
|
Hypertrophy of parietal epithelial cells |
- |
- |
P |
|
Proliferation and/or activation of parietal epithelial cells |
P |
P |
P |
|
Decrease of podoplanin expression in parietal epithelial cells |
- |
- |
P |
|
Decrease of podoplanin expression in podocytes |
- |
P |
P |
|
Desmin expression in glomeruli |
- |
- |
P |
|
Electron microscopy |
Small vacuoles in Bowman’s space and podocytes |
P |
- |
- |
Lamellar body deposition |
- |
P |
P |
|
Effacement / degeneration of podocytes |
- |
P |
P |
|
Increase of microvilli |
- |
P |
P |
|
Thickening of glomerular basement membrane |
- |
- |
P |
|
Electron-dense capillary endothelium |
P |
P |
P |
P: present; - not present
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
The detected glomerular changes are consistent with the onset of proteinuria, which were considered due to protein leakage secondary to glomerular injury characterized by degneratoin of podocytes. On day 9 of treatment, calcification was observed in all parts of glomeruli. - Executive summary:
To investigate the early changes involved in glomerular calcification, 409 mg/kg bw/day disodium hydrogenorthophosphate was administered to rats via the tail vein for up to 8 days. Urinalysis was carried out on days 1, 3, 5, and 8 of the treatment and rats were sacrificed on days 2, 4, and 9 for histopathological and electron microscopic examination of the kidneys.
Following single dosing, there were no gross or pathological findings but electron microscopy revealed a number of vacuoles within the Bowman’s space. On day 4, minimal focal mineralization was observed within the parietal epithelial cells. Lamellar structures with effacement of podocytes, an increased number of microvilli and large amounts of debris filling the Bowman’s space were the main electron microscopic changes on days 4 and 9. Increased urinary protein expression correlated well with the glomerular changes. These results suggest that the onset of glomerular calcification is preceded by primary podocytes damage.
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