Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: expert statement based on physical-chemical properties and toxicological profile

Data source

Reference
Reference Type:
other: expert statement
Title:
Toxicokinetic statement
Author:
Prof. Dr. Ursula Stephan
Year:
2018

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
expert statement based on physical-chemical properties and toxicological profile
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tris(pentane-2,4-dionato-O,O')vanadium
EC Number:
236-759-1
EC Name:
Tris(pentane-2,4-dionato-O,O')vanadium
Cas Number:
13476-99-8
Molecular formula:
C15H21O6V
IUPAC Name:
tris(pentane-2,4-dionato-O,O')vanadium

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Tissue absorption of Vanadium from oral doses has been reported to be very low. However there is little information on the absorption and distribution of vanadium from different salts. Parker and Sharma (1978) gave 5 or 50 ppm vanadium as vanadyl sulfate or sodium ortho- vanadate ad libitum for 3 months in the drinking water of rats being fed lab chow. Tissue concentration of rats fed 5 ppm of the either vanadium salts were similar to control; however, the tissues of animals fed 50 ppm had markedly elevated vanadium concentrations. The highest concentrations was in the kidney, follow by bone, liver and muscle. Tissue concentrations of vanadium in animals given 50 ppm sodium orthovanadate were higher than in animals receiving similar doses of vanadyl sulfate. These differences presumably were due to differences in solubility, in absorption, or in metabolism, especially elimination, of the compounds. The vanadium content of tissue tended to plateau after 3 weeks on the feeding regimen exept for the kidney were the concentration increased until the ninth week of the study.

Since Al(OH)3 restricts absorption of phosphorus and since the oxy anions of vanadium and phosphorus are very similar, the effect of Al(OH)3 on intestinal absorption of vanadium were examined. Accumulation of 48 vanadium in the tissue was reduced in rats gavaged with 1 ml of Al (OH)3 containing 5µmol Na3 VO4 and
1 µCi 48 vanadium compared to animals receiving the dose in 1 ml of saline. Tissue levels of 48 vanadium were consistently higher in controls than in Al(OH)3 treated animals. Equivalent doses of Al(OH)3 had no effect on tissue levels of 48 vanadium injected intraperitoneally; thus at appeared that Al(OH)3 reduced intestinal VO3 absorption (Wiegmann,1982).

Tests with animals showed, that vanadium pentoxide (and five other vanadium compounds in the valence states IV and V) were very fast and with a high extend absorbed by the lung after intratracheally application. From the given doses were 30% to 50% absorbed after few minutes to some hours: 30% of the administered dose were accumulated in the lung 10 days after application. Repeated application shows accumulation in the lung too.
After oral application only 2%-3% were absorbed.
Details on distribution in tissues:
Trace amounts of vanadium injected intravenously, as either the (III), (IV), or (V) oxidation state accumulated in the liver, kidney, spleen and testis up to 96 hours. Vanadium concentration in other tissues measured was declining at this time. Subcellular analyses on the liver indicated that 43% of the vanadium was found in nuclei and debris, 37% with the mitochondria, 10% with the microsomes, and 11% with the supernatant.
Accumulation of vanadium in the tissue of rats seemed to be directly related to the level of intraperitoneal dose of vanadyl trichloride in the range of 0,1 to 2 mg/kg body weight. At the high level of 8 mg/kg body weight, vanadium accumulated more rapidly in deposition organs such as bone, kidney and liver. Overall, 48 vanadium was distributed in the following order: bone>kidney>liver>spleen> intestine>stomach> muscle>testis>lung> brain. Subcellular distribution analysis indicates that vanadium was associated with the high-molecular weight proteins in the soluble fraction of liver and was also associated with nuclei, mitochondria and microsomes (Sharma et al, 1980)
Details on excretion:
The main route of excretion of intravenously injected 48 vanadium was the urine. At 96 hours, 46% of the dose had been excreted in the urine and 8,6% in the faeces. Bile seemed to contribute to the intestinal elimination of vanadium when plasma vanadium levels were high; however, in the period of 0-6 hours after injection of pentavalent
48 vanadium, the renal excretion was 5-10 times higher than biliary excretion.
An animal test with female F344rats, exposed with 1or 2 mg/m3 Vanadium pentoxide for a time of 14 days resulted in a half-life of 4.4 to 5.0 days. Female rats exposed for 2 years with 0, 0.5, 1, or 2 mg/m3 vanadium pentoxide aerosole incorporated 130, 175,308µg vanadium. At the day 542 after beginning of the experiment 10 to 13% of the mentioned amount. The concentration of vanadium in the lung increased until day 173 (after beginning), then the amount in the lung decreased. The half-life for the lung clearance resulted in 37, 59, and 61 days. The difference to the first short-term experiment could be an alteration of the lung function caused by the Vanadium content.
In an similar experiment with female mice, exposed for 14 days with 2 or 4 mg/m3 vanadium pentoxide the half-life was estimated with 2 to 3 days. The same experiment with 3 groups of female mice exposed with 1,2, or 4 mg/m3 vanadium pentoxide for 2 years resulted in a half-life of 6,11 and 14 days for the lung clearance.. At the day 535 of exposure 2-3 % vanadium of the dose (of 153,162 and 252µ g vanadium) were found.
In a group of workers, exposed to vanadium - concentrations of 0,36, to 32,9 µg/m3 the urine concentration of 0,83 µg vanadium /g kreatine at the end of the shift. The excretion of 60 to 70 µg vanadium is an sign for workplace concentration of 0.05 mg/m3 vanadium..
After only one exposure, rats excreted 40% with the urine of the vanadium dose, intratracheally administered. The main route of excretion of intravenously injected, vanadium was the urine.
At 96 hours, 46 % of the dose had been excreted in the urine and 8.6% in the faeces (Hopkins and Tilton, 1966). Bile seemed to contribute to the intestinal elimination of vanadium when plasma vanadium levels were high; however, in the period of 0-6 hours after injection of pentavalent vanadium, the renal excretion was 5-10 times higher than biliary excretion (Sabbioni, 1981).
When Ammonium metavanadate was given orally at rats 80% of the vanadium was found in the faeces over a period of 6 days. A similar result was received with Sodium metavanadate, fed at rats: 59.9 ± 18.9% were excreted with the faeces.

Metabolite characterisation studies

Details on metabolites:
Vanadium tris (acetylacetonate) is a complex compound. The Vanadium is coordinated with the oxygen of the acetlyacetonate. The complex is instable in contact with (wet) air or water and forms the vanadyl cation. It is known that the biological active species of vanadium are the vandylcation and the vanadatate anion. Vanadium can exist with the valence states: 0, 2+, 3+, 4+, and 5+ is capable to change the valence states, depending of the pH and the vanadium concentration. The vanadium cations and the vanadate-anions can form some hydrates in aqueous medium (e.g. under physiological conditions too). The hydrates exist (as tri-, hexa- , deca-hydrates (and other hydrates) in an equilibrium, depending from the conditions.
This chemical behaviour explains the difficulties in the estimation of the toxicological interactions in the organisms.

Any other information on results incl. tables

Vanadyl compounds

Uptake

 

Tissue absorption of Vanadium from oral doses has been reported to be very low. However there is little information on the absorption and distribution of vanadium from different salts. Parker and Sharma (1978) gave 5 or 50 ppm vanadium as vanadyl sulfate or sodium ortho- vanadate ad libitum for 3 months in the drinking water of rats being fed lab chow. Tissue concentration of rats fed 5 ppm of the either vanadium salts were similar to control; however, the tissues of animals fed 50 ppm had markedly elevated vanadium concentrations. The highest concentrations was in the kidney, follow by bone, liver and muscle. Tissue concentrations of vanadium in animals given 50 ppm sodium orthovanadate were higher than in animals receiving similar doses of vanadyl sulfate. These differences presumably were due to differences in solubility, in absorption, or in metabolism, especially elimination, of the compounds. The vanadium content of tissue tended to plateau after 3 weeks on the feeding regimen exept for the kidney were the concentration increased until the ninth week of the study.

 

Since Al(OH)3 restricts absorption of phosphorus and since the oxy anions of vanadium and phosphorus are very similar, the effect of Al(OH)3on intestinal absorption of vanadium were examined. Accumulation of 48vanadium in the tissue was reduced in rats gavaged with 1 ml of Al (OH)3 containing 5µmol Na3VO4 and

1 µCi48vanadium compared to animals receiving the dose in 1 ml of saline. Tissue levels of48vanadium were consistently higher in controls than in Al(OH)3 treated animals. Equivalent doses of Al(OH)3 had no effect on tissue levels of 48vanadium injected intraperitoneally; thus at appeared that Al(OH)3 reduced intestinal VO3 absorption (Wiegmann,1982).

 

Tests with animals showed, that vanadium pentoxide (and five other vanadium compounds in the valence states IV and V) were very fast and with a high extend absorbed by the lung after intratracheally application. From the given doses were 30% to 50% absorbed after few minutes to some hours: 30% of the administered dose were accumulated in the lung 10 days after application. Repeated application shows accumulation in the lung too.

After oral application only 2%-3% were absorbed.

Tissue Distribution of vanadium

 

Trace amounts of vanadium injected intravenously, as either the (III), (IV), or (V) oxidation state accumulated in the liver, kidney, spleen and testis up to 96 hours. Vanadium concentration in other tissues measured was declining at this time. Subcellular analyses on the liver indicated that 43% of the vanadium was found in nuclei and debris, 37% with the mitochondria, 10% with the microsomes, and 11% with the supernatant.

Accumulation of vanadium in the tissue of rats seemed to be directly related to the level of intraperitoneal dose of vanadyl trichloride in the range of 0,1 to 2 mg/kg body weight. At the high level of 8 mg/kg body weight, vanadium accumulated more rapidly in deposition organs such as bone, kidney and liver. Overall,48vanadium was distributed in the following order: bone>kidney>liver>spleen> intestine>stomach> muscle>testis>lung> brain. Subcellular distribution analysis indicates that vanadium was associated with the high-molecular weight proteins in the soluble fraction of liver and was also associated with nuclei, mitochondria and microsomes (Sharma et al, 1980)

 

Metabolism

 

Vanadium tris (acetylacetonate) is a complex compound. The Vanadium is coordinated with the oxygen of the acetlyacetonate. The complex is instable in contact with (wet) air or water and forms the vanadyl cation. It is known that the biological active species of vanadium are the vandylcation and the vanadatate anion. Vanadium can exist with the valence states: 0, 2+, 3+, 4+, and 5+ is capable to change the valence states, depending of the pH and the vanadium concentration. The vanadium cations and the vanadate-anions can form some hydrates in aqueous medium (e.g. under physiological conditions too). The hydrates exist (as tri-, hexa- , deca-hydrates (and other hydrates) in an equilibrium, depending from the conditions.

This chemical behaviour explains the difficulties in the estimation of the toxicological interactions in the organisms.

 

 

Excretion

 

The main route of excretion of intravenously injected 48vanadium was the urine. At 96 hours, 46% of the dose had been excreted in the urine and 8,6% in the faeces. Bile seemed to contribute to the intestinal elimination of vanadium when plasma vanadium levels were high; however, in the period of 0-6 hours after injection of pentavalent

 48vanadium, the renal excretion was 5-10 times higher than biliary excretion.

An animal test with female F344rats, exposed with 1or 2 mg/m3Vanadium pentoxide for a time of 14 days resulted in a half-life of 4.4 to 5.0 days. Female rats exposed for 2 years with 0, 0.5, 1, or 2 mg/m3 vanadium pentoxide aerosole incorporated 130, 175,308µg vanadium. At the day 542 after beginning of the experiment 10 to 13% of the mentioned amount. The concentration of vanadium in the lung increased until day 173 (after beginning), then the amount in the lung decreased. The half-life for the lung clearance resulted in 37, 59, and 61 days. The difference to the first short-term experiment could be an alteration of the lung function caused by the Vanadium content.

In an similar experiment with female mice, exposed for 14 days with 2 or 4 mg/m3   vanadium pentoxide the half-life was estimated with 2 to 3 days. The same experiment with 3 groups of female mice exposed with 1,2, or 4 mg/m3 vanadium pentoxide for 2 years resulted in a half-life of 6,11 and 14 days for the lung clearance.. At the day 535 of exposure 2-3 % vanadium of the dose (of 153,162 and 252µ g vanadium) were found.

In a group of workers, exposed to vanadium - concentrations of 0,36, to 32,9 µg/m3the urine concentration of 0,83 µg vanadium /g kreatine at the end of the shift. The excretion of 60 to 70 µg vanadium is an sign for workplace concentration of 0.05 mg/m3 vanadium..

After only one exposure, rats excreted 40% with the urine of the vanadium dose, intratracheally administered. The main route of excretion of intravenously injected, vanadium was the urine.

 At 96 hours, 46 % of the dose had been excreted in the urine and 8.6% in the faeces (Hopkins and Tilton, 1966). Bile seemed to contribute to the intestinal elimination of vanadium when plasma vanadium levels were high; however, in the period of 0-6 hours after injection of pentavalent vanadium, the renal excretion was 5-10 times higher than biliary excretion (Sabbioni, 1981).

When Ammonium metavanadate was given orally at rats 80% of the vanadium was found in the faeces over a period of 6 days. A similar result was received with Sodium metavanadate, fed at rats:  59.9 ± 18.9% were excreted with the faeces.

 

2,4 -Pentanedione

2,4-Pentadione (Acetylacetone, 2,4PD, CAS: 123-54-6), was investigated for its comparative kinetics in male Fisher 344 rats by a single intravenous (i.v.) injection of (4.3, 43, 148.5, and 430 mg/kg), or a 6-hr nose-only inhalation exposure (400) ppm to 14C-2,4-PD. For the i.v.-route, the plasma concentration of 14C-2,4-PD-derived radioactivity declined in a bioexponential fashion. The overall form of the 14C plasma concentration-time curves and derived toxicokinetic parameters indicated, that dose-linear kinetics occurred in the i.v. dose range 4.3- 148.5 mg/kg, but not with 430 mg/kg. Metabolism of 2,4PD was rapid and undetectable after 8 hr. 14C-2,4 PD derived radioactivity was eliminated mainly as 14CO2 and in urine. For the 4.3, 43 and 148.5 mg/kg doses 14CO2 elimination was relatively constant (36.8,38,8 and 42.3% in 48 hr samples respectively) and greater than urinary excretion ( 17.9, 14,3 and 29.6 %;48 h specimens). At 430 mg/kg i.v. there was a reversal of the excretion pattern, with urine 14C excretion (54.7%) becoming greater than that for 14CO2 (27.3%). Excretion in expired volatiles and faeces was small. Radiochromatograms of urine showed free 2,4 PD in the 12 hr samples, together with 7 other metabolites. Free 2,4PD and 6 of the metabolites decreased or were not detectable in a 24 or 48 h urine sample, but one peak (retention 7.9 min) increased progressively to become the major fraction (97%). Nose- only exposure to 400 ppm 14C-2,4PD produced a main decrease in breathing rate of 20.1%, which was constant and sustained throughout exposure, due to a lengethening of the expiratory phase of the respiratory cycle.14C-2,4-PD was rapidly absorbed during the first 3 hr of exposure, then began to plateau, but did not reach a steady-state. Post- exposure elimination of 14C from plasma followed a biexponential form with a t1/2 for the terminal disposition phase of 30.72 h. Post-exposure, plasma non-metabolized 2,4-PD declined rapidly to undetectable concentrations by 12 h. Radiolabel excretion was approximately equivalent in urine (37.6%) and expired 14CO2 (36.3%) . Urine radiochromatograms showed a minor 2,4PD contaminant (0.6-5.89% over 48 hr) along with 7 other peaks probably representing metabolites. The major metabolite peak was at 7.8 min retention, increasing from 41.1% (12 h) to 62.8% (48 h). Immediately post-exposure, radioactivity was present in all tissues examined, but on a concentration basis (microgram equiv/G) there was no preferential accumulation of 14C in any tissue organ.

Applicant's summary and conclusion

Executive summary:

These results show that vanadium compounds, administered intratracheally, in a significant amount will be absorbed in the lung. The vanadium will be distributed in the bones, kidney, liver, spleen and testes. When Vanadium compounds were inhaled, the main part of vanadium will be excreted with the urine and when vanadium compounds were administered orally the main part will excreted with the faeces.