Registration Dossier

Diss Factsheets

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
imilar to OECD Test Guideline 417 Toxicokinetics-distribution with acceptable deviations.
Justification for type of information:
1. HYPOTHESIS FOR THE CATEGORY APPROACH: The hypothesis is that properties are likely to be similar or follow a similar pattern because of the presence of a common metal ion, in this case tungstate.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES):
Source: Sodium tungstate
Target: Ammonium metatungstate
3. CATEGORY APPROACH JUSTIFICATION: See Annex 3 in CSR
4. DATA MATRIX: See Annex 3 in CSR
Cross-reference
Reason / purpose for cross-reference:
read-across: supporting information

Data source

Reference
Reference Type:
publication
Title:
Disposition and Clearance of Tungsten after Single-dose Oral and Intravenous Exposure in Rodents
Author:
McDonald JD, Weber WM, Marr R, Kracko D, Khain H and Arimoto R
Year:
2007
Bibliographic source:
Journal of Toxicology and Environmental Health, Part A, 70:829-836

Materials and methods

Objective of study:
distribution
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
: distribution
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Disodium wolframate
EC Number:
236-743-4
EC Name:
Disodium wolframate
Cas Number:
13472-45-2
Molecular formula:
Na2O4W
IUPAC Name:
Disodium dioxido(dioxo)tungsten
Details on test material:
- Test substance: Sodium tungstate dihydrate
- Supplier: Sigma-Aldrich (St. Louis, MO)
- Purity: 99.9%
- The identity of the W component of tungstate was confirmed by measuring isotopic abundance by ICPMS.
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
- Body weight: 240 - 265 g
- Supplier: Hilltop Labs

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: purified water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- Oral dose formulations were prepared on the day of administration by dilution of sodium tungstate dihydrate in purified water; these doses were selected to provide sufficient dose separation for the dose-response analysis of the disposition after oral administration.
- The doses span two log dilutions, and are all well within the tolerable concentration limits for W in rodents.
Duration and frequency of treatment / exposure:
single gavage administration
Doses / concentrations
Remarks:
Doses / Concentrations:
- Oral doses were prepared and administered at 1, 10, or 100 mg/kg.
No. of animals per sex per dose / concentration:
Four female rats were exposed per dose group. One animal per dose group was then sacrificed at each time point. Animals were sacrificed at 1, 2, 4 and 24 hours.
Control animals:
yes
Details on dosing and sampling:
COLLECTION OF SAMPLES:
- Animals were euthanized by an overdose of sodium pentobarbital administered by intraperitoneal injection.
- Plasma and tissues (intestine, liver, kidneys, femur, and uterus) were collected immediately after euthanasia (1, 2, 4 and 24 h after dosing).
- Plasma: blood was collected via cardiac puncture, placed in heparinized containers, and centrifuged at 2000 x g for 20 min.
- Tissues: liver, uterus, intestine (all three sections including contents), femur, and kidneys were harvested, weighed, placed in polypropylene containers, and stored at -70°C.

INSTRUMENTAL ANALYSIS:
- Tungsten concentrations were determined with the use of low-resolution ICP/MS following U.S. Environmental Protection Agency method 200.8
- When tissues and plasma were analyzed, the instrument response was recorded in micrograms of W per sample (ug/ sample).
- The data were then divided by the tissue weight to give micrograms of W per gram of tissue (ug/g), which is how the data in the current study are reported.
- In the case of plasma, direct weights were not recorded.
- Whole blood weights were recorded, and the amount of plasma was conservatively assigned a value of 55% of the whole blood weight.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
- As shown by comparisons of 100 mg/kg and 10 mg/kg oral doses and the 10 mg/kg and 1 mg/kg oral doses, W concentrations increased with dose but were not always proportional to dose.
- At 24 h, W was not completely eliminated at the mid and high doses but returned to baseline levels at the low dose.
- A statistically significant difference in the W concentrations in plasma compared with whole blood was not observed, indicating that the plasma profile is a good indicator of blood concentrations and that W partitions equally between red blood cells and plasma.
-the W concentration in each of the rat tissues, with few exceptions, increases at each time point to a maximum at 4 h before becoming greatly reduced at 24 h.
- Intestine and kidneys at the high dose and femur at the mid-dose have a lower W concentration at 2 than at 1 h, but the concentrations still rose at 4 h before decreasing at 24 h.
- The other exceptions are intestine at the low dose, which had the highest W concentration at 2 h, and liver at the low dose, which had a steadily decreasing concentration

Any other information on results incl. tables

No clinical abnormalities or gross tissue pathology were observed during tissue harvest from any of the studies.

Applicant's summary and conclusion

Conclusions:
As shown by comparisons of 100 mg/kg and 10 mg/kg oral doses and the 10 mg/kg and 1 mg/kg oral doses, W concentrations increased with dose but were not always proportional to dose. At 24 h, W was not completely eliminated at the mid and high doses but returned to baseline levels at the low dose. A statistically significant difference in the W concentrations in plasma compared with whole blood was not observed, indicating that the plasma profile is a good indicator of blood concentrations and that W partitions equally between red blood cells and plasma. The W concentration in each of the rat tissues, with few exceptions, increases at each time point to a maximum at 4 h before becoming greatly reduced at 24 h. Intestine and kidneys at the high dose and femur at the mid-dose have a lower W concentration at 2 than at 1 h, but the concentrations still rose at 4 h before decreasing at 24 h. The other exceptions are intestine at the low dose, which had the highest W concentration at 2 h, and liver at the low dose, which had a steadily decreasing concentration
Executive summary:

No toxicokinetics data of sufficient quality were available specifically on ammonium metatungstate (target substance). However, toxicokinetics data are available for Sodium tungstate (source substance), which are used for read-across. Due to similar water solubility for the target substance compared to the source substance, the resulting read-across from the source substance to the target substance is appropriate to estimate of potential toxicity for this endpoint. For more details, refer to the read-across category approach description in the Category section of this IUCLID submission or Annex 3 of the CSR.

Categories Display