Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
16
Absorption rate - dermal (%):
1
Absorption rate - inhalation (%):
5.3

Additional information

Initial comment on grouping and read across

This dossier addresses the substance divanadium tris(sulphate) and is one of several dossiers prepared by the Vanadium Consortium for vanadium substances due for registration under Regulation (EC) No 1907/2006, covering also tri-, tetra and pentavalent vanadium substances of varying solubility. To avoid unnecessary (animal) testing, a comprehensive grouping and read-across concept has been developed, which is described in detail further below.Therefore, the remaining text in this chapter is generic for all vanadium substances and has not been adapted on a substance-specific basis.

Divanadium tris(sulphate) ismanufactured and marketed in the EU solely in solution. However, in a conservative approach, the toxicological assessment also considers the solid besides the soluble form where relevant (and more conservative).

Toxicological relevance of the counterion “sulfate”

The registrant is of the opinion that the toxicity of divanadium tris(sulphate) is driven by the vanadium moiety and that the sulfate anion does not contribute to the overall toxicity of divanadium tris(sulphate) to any relevant extent, for the following reasons:

Sulfate anions are abundantly present in the human body in which they play an important role for the ionic balance in body fluids. Sulfate is required for the biosynthesis of 3′-phosphoadenosine-5′-phosphosulfate (PAPS) which in turn is needed for the biosynthesis of many important sulfur-containing compounds, such as chondroitin sulfate and cerebroside sulfate. TheJoint FAO/WHO Expert Committee on Food Additives (JECFA) concludes that the few available studies in experimental animals do not raise any concern about the toxicity of the sulphate ion in sodium sulphate. Sodium sulphate is also used clinically as a laxative. In clinical trials in humans using 2-4 single oral doses of up to 4500 mg sodium sulphate decahydrate per person (9000 – 18000 mg per person), only occasional loose stools were reported. These doses correspond to 2700 - 5400 mg sulphate ion per person. High bolus dose intake of sulphate ion may lead to gastrointestinal discomfort in some individuals. No further adverse effects were reported (JECFA 2000, 2002). This position was adopted by the European Food Safety Authority (EFSA2004) without alteration.

Based on the above information, one can therefore safely assume that the sulfate anion in divanadium tris(sulphate) does not contribute to the overall toxicity of divanadium tris(sulphate). It is concluded that only the effect of “vanadium” is further considered in the human health hazard assessment of divanadium tris(sulphate).

Read-across concept

This grouping concept is based on the chemistry / composition of all substances and on experimental studies for (i) water solubility and (ii) in-vitro bioaccessibility studies: assessment of the solubility and speciation of vanadium substances in five different artificial physiological fluids. Robust summaries for these studies are provided in each registration dossier.The conclusions of this testing programme can be summarised as follows:

 

Bioaccessibility – Read-across

The dissolution of metallic vanadium and tri-, tetra and pentavalent vanadium substances was assessed in various artificial physiological media. These were selected to simulate relevant human-chemical interactions (as far as practical), i.e. for contact of a test substance with skin, or for a substance entering the human body by inhalation or by ingestion. There is not an internationally agreed guideline for these tests yet (e.g. OECD). However, similar tests have been conducted for several metal substances and alloys incl. steel in previous risk assessments or in recent preparation for REACH, and some results have been published (e.g. Stopford et al, 2003, Herting et al, 2006; Midander et al, 2007). The composition of these artificial test media has been discussed by Kuhn and Rae, 1988; Moss, 1979; Stopford et al, 2004; Herting et al, 2006; Midander et al, 2007 and references therein. This test programme included the following five media:

Phosphate-buffered saline (PBS, pH 7.4) is a standard physiological solution that mimics the ionic strength of human blood serum. It is widely used in research and medical health care (e.g. Hanawa, 2004; Okazaki and Gotoh, 2005) as reference test solution for comparison with data from simulated physiological conditions.

Gamble’s solution (GMB, pH 7.4) mimics interstitial fluid within the deep lung under normal health conditions (Stopford et al, 2004)

Artificial lysosomal fluid (ALF, pH 4.5) simulates intracellular conditions in lung cells occurring in conjunction with phagocytosis and represents relatively harsh conditions (Stopford et al, 2004).

Artificial gastric fluid (GST, pH 1.5) mimics the very harsh digestion milieu of high acidity in the stomach (ASTM D5517).

Artificial sweat solution (ASW, pH 6.5) simulates an exposure scenario in contact with human skin, i.e. the hypo-osmolar fluid, linked to hyponatraemia (loss of Na+from blood), that is excreted from the body when sweating. This fluid is recommended in the available standard for the testing of nickel release from nickel containing products (EN1811, 1998).

Vanadium substances were incubated with freshly made solutions at a solid to liquid ratio of 0.1 g/L. This loading is similar to the loading in transformation/dissolution testing in environmental media according to OECD Series No. 29. Two exposure periods (2h and 24h) were used, and exposure times were strictly controlled to enable modelling of the dissolution process as a rate over time. The relative surface area of the test substances was determined by BET-absorption measurements. These absorption measurements allow for an assessment of the dissolution process in relation to sample surface area and total sample mass.

 

After cessation of the incubation period, the remaining solid material was separated from the supernatant, pH was measured and the supernatant solutions were analysed for dissolved vanadium concentrations by appropriate, validated analytical methods (i.e. ICP-MS).Speciation analysis of V(IV) and V(V) was performed by HPLC coupled to ICP-MS. The concentration of possible further species (i.e. V(III)) was determined indirectly by subtracting the amount of V(IV) and V(V) from the total amount of vanadium.

 

Table: Transformation/dissolution of vanadium substances in physiological relevant media

Dissolved V [%]

2-h exposure time

Dissolved V [%]

24-h exposure time

Vanadium metal

Phosphate-buffered saline (PBS, pH 7.4)

 0.4 % pentavalent V

 1.3 % pentavalent V

Gamble’s solution (GMB, pH 7.4)

 0.4 % pentavalent V

 0.8 % pentavalent V

Artificial lysosomal fluid (ALF, pH 4.5)

 1.2 % tetravalent V

 1.4 % tetravalent V

Artificial gastric fluid (GST, pH 1.5)

 1.2 % tetravalent V

 1.6 % tetravalent V

Artificial sweat solution (ASW, pH 6.5)

 ≤ DL

 0.6 % pentavalent V 

 0.7 % tetravalent V

 1.2 % pentavalent V

Trivalent vanadium compound (i.e. V2O3)

Phosphate-buffered saline (PBS, pH 7.4)

 5 % pentavalent V

 9 % pentavalent V

Gamble’s solution (GMB, pH 7.4)

 1 % tetravalent V

 3 % pentavalent V

 6 % pentavalent V

Artificial lysosomal fluid (ALF, pH 4.5)

 14 % tetravalent V

 16 % tetravalent V

Artificial gastric fluid (GST, pH 1.5)

 9 % tetravalent V

 4 % pentavalent V

 11 % tetravalent V

 5 % pentavalent V

Artificial sweat solution (ASW, pH 6.5)

 3 % tetravalent V

 5 % pentavalent V

 13 % tetravalent V

 12 % pentavalent V

Tetravalent vanadium compound (i.e. VOSO4)

Phosphate-buffered saline (PBS, pH 7.4)

 29 % tetravalent V

 68 % pentavalent V

 

100 % pentavalent V

Gamble’s solution (GMB, pH 7.4)

 100 % pentavalent V

100 % pentavalent V

Artificial lysosomal fluid (ALF, pH 4.5)

 94 % tetravalent V

 15 % pentavalent V

 90 % tetravalent V

 11 % pentavalent V

Artificial gastric fluid (GST, pH 1.5)

 74 % tetravalent V

 32 % pentavalent V

 74 % tetravalent V

 50 % pentavalent V

Artificial sweat solution (ASW, pH 6.5)

54 % tetravalent V

51 % pentavalent V

 32 % tetravalent V

 72% pentavalent V

Pentavalent vanadium compound (i.e. NaVO3)

Phosphate-buffered saline (PBS, pH 7.4)

 100 % pentavalent V

100 % pentavalent V

Gamble’s solution (GMB, pH 7.4)

 93 % pentavalent V

100 % pentavalent V

Artificial lysosomal fluid (ALF, pH 4.5)

 65 % tetravalent V

 40 % pentavalent V

100 % tetravalent V

Artificial gastric fluid (GST, pH 1.5)

 4 % tetravalent V

 90 % pentavalent V

 6 % tetravalent V

 90 % pentavalent V

Artificial sweat solution (ASW, pH 6.5)

 5 % tetravalent V

 89 % pentavalent V

 5 % tetravalent V

 99 % pentavalent V

Pentavalent vanadium compound (i.e. V2O5)

Phosphate-buffered saline (PBS, pH 7.4)

 97 % pentavalent V

 98 % pentavalent V

Gamble’s solution (GMB, pH 7.4)

 99 % pentavalent V

100 % pentavalent V

Artificial lysosomal fluid (ALF, pH 4.5)

 91 % tetravalent V

100 % tetravalent V

Artificial gastric fluid (GST, pH 1.5)

100 % pentavalent V

 90 % pentavalent V

Artificial sweat solution (ASW, pH 6.5)

 95 % pentavalent V

 94 % pentavalent V

  

The results of this bioaccessibility testing programme can be summarised as follows:

 

Solubility

The readily soluble vanadium substance such as VOSO4, NaVO3, and V2O5dissolve practically completely in all physiological media already after only a short period of time, rendering them to be expected of similar and extensive bioavailability. In contrast, only 7 - 20% of V2O3dissolves in all physiological media, which makes it somewhat less available. Finally, metallic vanadium releases only 0.5 – 1.6% of vanadium into the surrounding media.

 

Speciation

Upon dissolution, all vanadium substances more or less finally transform to the pentavalent form in all media except ALF; here, even the pentavalent forms are converted almost completely to the tetravalent species already after a short period of time.

 

Conclusions

In bioaccessibility tests of tri-, tetra- and pentavalent vanadium substances and metallic vanadium, tetra- and pentavalent forms dissolved completely within 2h in various media selected to simulate relevant human-chemical interactions (i.e. PBS mimicking the ionic strength of blood, artificial lung, lysosomal, and gastric fluid as well as artificial sweat). However, only < 2% of metallic vanadium and <20% of V2O3went into solution.For metallic vanadium, it may be hypothesised that the oxide layer covering the particles goes more or less immediately into solution, whereas after this initial dissolution process vanadium remains practically inert. Similar observations were made for V2O3, suggesting that also in this case an oxidised layer covers the particle surface, resulting in a higher initial release rate that levels off during the initial 2h incubation period. Despite differences in solubility, the bioaccessibility data suggest the following:

 · All vanadium substances upon dissolution transform predominantly into pentavalent forms in physiological media, with the exception of ALF in which tetravalent V was the predominant species present after 2 and 24h.

·      Metallic vanadium is rather inert in physiological media, but any dissolved material transforms rather quickly to tetra- or pentavalent vanadium species, which are the main species in all physiological media tested.

·      Trivalent vanadium transforms to the higher (IV) and (V) oxidation states immediately upon dissolution. More specifically, trivalent vanadium dissolves only to pentavalent forms in PBS and GMB, and predominantly to tetravalent forms in ALF and ASW.

·      Tetravalent vanadium dissolves into pentavalent forms in PBS and GMB, and predominantly to tetravalent forms in ALF and GST.

·      As expected, pentavalent vanadium substances are released and retained as pentavalent forms in physiological media, with the exception of ALF in which tetravalent V dominates after 2h and is the only form present after 24h.

Table: Conclusion on bioavailability factors of different vanadium substances for risk characterisation and read-across purposes

Substance

Bioavailability (%)

Solubility

metallic vanadium

< 2

slightly soluble/insoluble

V2O3

< 20

sparingly soluble

VOSO4

100

soluble

NaVO3

100

soluble

V2O5

100

soluble

In-vivo absorption factors:

 Oral absorption:

 The published animal data on oral absorption of vanadium substances are summarised in the table below:

 Table: Animal data on oral absorption of vanadium substances

Vanadium substance

Test species

Absorption [%]

Comments

Route

Reference

 

 

Pentavalent

 

 

V2O5

rat

2.6
design/reporting inadequate,
sampling/analysis and mass balance incomplete,
72h sampling period
(bladder and intestinal content not subtracted)

Oral (gavage)

Conklin et al. 1982

NH3VO3

rat

4.2
design incomplete only 24h urinary excretion considered for result

Oral (gavage)

Al-Bayati et al. 1991

Na3VO4

rat

17.5
(based on urinary secretion), design/reporting inadequate,
sampling/analysis and mass balance incomplete,
120h sampling period, (bladder content not subtracted)

Oral (gavage)

Wiegmann et al. 1982

NaVO3

rat

16.5
(based on balance of faecal excretion)
admin via food (100ppm), design incomplete,

7d feeding/sampling,analysis incomplete
(bladder and intestinal content not subtracted)

Oral (food)

Adachi et al. 2000

NaVO3

rat

39.7
(based on balance of faecal excretion),

admin via food (0.1-25ppm), design incomplete,
14d feeding/sampling, analysis incomplete
(bladder and intestinal content not subtracted)

Oral (food)

Bogden et al. 1982

 

 

Tetravalent

 

 

VOCl2

rat

2.6
not assignable, (only abstract available)

intragastric

Sollenberger et al. 1981

VOSO4

rat

16.0
highly relevant
rel. bioavailability assessed based on comparison of AUC after iv vs oral admin,120h sampling period, radiotracer analysis

Oral (gavage)

Azay et al. 2001

 

According to EFSA (2004), “the low concentration of vanadium normally present in urine compared with the daily intake and the faecal levels indicate, that less than 5% of ingested vanadium is absorbed (WHO, 1996). The results of animal studies are in general in agreement with this conclusion. Uptake of radioactive vanadium pentoxide given orally to rats was 2.6% of the administered dose (Conklin et al., 1982). Other studies in rats have indicated that amounts greater than 10% can be absorbed from the gastrointestinal tract under some conditions (Bogden et al., 1982; Wiegmann et al., 1982).“

 

For pentavalent vanadium, the studies by Conklin et al. (1982), Al-Bayati et al. (1991) and Bogden et al. (1982) are considered incomplete because of study design (administration and analytical procedure) and sampling period. The studies by Wiegmann et al. (1982) and Adachi (2000), despite limitations in their design, allow a reasonable assessment of oral absorption of pentavalent V forms and yield a consistent picture of ca. 16% oral absorption.

 

For tetravalent absorption, the study by Sollenberger et al. (1991) cannot be assessed, whereas the study by Azay et al (2001) has a very reliable study design (AUC determination after concurrent i.v. and g.i. administration), yielding an oral absorption of 16% for tetravalent V, in line with the value obtained for pentavalent vanadium.

 

Thus, in-vivo data are available on soluble tetra- and pentavalent vanadium substances (V2O5, NaVO3, and VOSO4), suggesting an oral absorption value of 16%. For the trivalent vanadium trioxide, this value is also adopted for lack of substance-specific information, albeit recognising that this constitutes a somewhat conservative value in view of the moderate bioaccessibility. For vanadium metal, the very poor bioavailability (i.e., approx. 100-fold less than for soluble tetra- and pentavalent vanadium substances) supports assuming a default oral absorption factor of 1%.

 

Dermal absorption:

 

According to WHO (1988), absorption by this route is generally considered to be very low for vanadium substances.

 

In the absence of measured data on dermal absorption, current guidance suggests the assignment of either 10% or 100% default dermal absorption rates. In contrast, the currently available scientific evidence on dermal absorption of metals (predominantly based on the experience from previous EU risk assessments) yields substantially lower figures, which can be summarised briefly as follows:

 

Measured dermal absorption values for metals or metal substances in studies corresponding to the most recent OECD test guidelines are typically 1 % or even less. Therefore, the use of a 10 % default absorption factor is not scientifically supported for metals. This is corroborated by conclusions from previous EU risk assessments (Ni, Cd, Zn), which have derived dermal absorption rates of 2 % or far less (but with considerable methodical deviations from existing OECD methods) from liquid media.

 

However, considering that under industrial circumstances many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a factor 10 lower default absorption factor may be assigned to such “dry” scenarios where handling of the product does not entail use of aqueous or other liquid media. This approach was taken in the in the EU RA on zinc. A reasoning for this is described in detail elsewhere (Cherrie and Robertson, 1995), based on the argument that dermal uptake is dependent on the concentration of the material on the skin surface rather than it’s mass.

 

The following default dermal absorption factors for metal ions are therefore proposed (reflective of full-shift exposure, i.e. 8 hours):

From exposure to liquid/wet media:        1.0 %

From dry (dust) exposure:                         0.1 %

 

Divanadium tris(sulphate) is manufactured and marketed in the EU solely in solution and thus the default dermal absorption factors from exposure to liquid/wet media of 1.0 % applies.

This approach is consistent with the methodology proposed in HERAG guidance for metals (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal substances; EBRC Consulting GmbH / Hannover /Germany; August 2007).

Inhalation absorption:

The fate and uptake of deposited particles depends on the clearance mechanisms present in the different parts of the airway. In the head region, most material will be cleared rapidly, either by expulsion or by translocation to the gastrointestinal tract. A small fraction will be subjected to more prolonged retention, which can result in direct local absorption. More or less the same is true for the tracheobronchial region, where the largest part of the deposited material will be cleared to the pharynx (mainly by mucociliary clearance) followed by clearance to the gastrointestinal tract, and only a small fraction will be retained (ICRP, 1994). Once translocated to the gastrointestinal tract, the uptake will be in accordance with oral uptake kinetics.

In consequence, the material deposited in the head and tracheobronchial regions would be translocated to the gastrointestinal tract without any relevant dissolution, where it would be subject to gastrointestinal uptake at a ratio of 16% (regardless of whether the ingested material is either tetra- or pentavalent). In contrast, the material that is deposited in the pulmonary region may be assumed by default to be absorbed to 100%. This absorption value is chosen in the absence of relevant scientific data regarding alveolar absorption although knowing that this is a conservative choice. Thus, the following predicted inhalation absorption factor can be derived for divanadium tris(sulphate). For further information on particle size, see IUCLID section 4.5.

 

 

Deposition fractions

Absorption

factors

 

d50 [µm]

Head [%]

TB [%]

PU [%]

Head/TB (=GI) [%]

PU

[%]

Absorption factor via inhalation [%]

V2(SO4)3 (i)

>2000

33.2

0.0

0.0

16

100

5.32

(i) Divanadium tris(sulphate) is manufactured and sold in solution only and as such is not inhaled. However, for pre-cautionary considerations, the solid product is being assessed and inhalability was nevertheless assumed.

Biological function

A number of vanadium dependent enzymes have been found in lower organisms, such as bacteria and algae. In higher animals and humans, however, no specific biochemical function has yet been identified for vanadium. Nevertheless, the possibility has been considered that vanadium might play a role in the regulation of some enzymes, such as the Na+/K+exchanging ATPase, phosphoryl-transfer enzymes, adenylate cyclase and protein kinases. Therefore, its role in hormone, glucose, lipid, bone and tooth metabolism has also been discussed (WHO, 1996).Vanadium substances have been shown to mimic the action of insulin in isolated cell systems, animal models and diabetic patients. Therefore, their use in the therapy of diabetes mellitus has been considered (Shechter, 1990; Shamberger, 1996).Vanadium has also been suggested as an aid in body building, but there is no evidence that it is effective (Fawcett et al., 1996).Altogether, vanadium has not been shown to be essential for humans and does not have a nutritional value. Even though some signs of vanadium deficiency have been reported in goats and rats (WHO, 1996), vanadium deficiency has not been identified in humans.

 

 

Metabolism

Vanadium is an element, and as such, is not subject to metabolisation as such. However, vanadium transforms rather quickly to predominantly pentavalent vanadium species upon dissolution which can be expected to represent the predominantspecies under all physiological circumstances perhaps except for inhalation and subsequent uptake by the lysosomes of macrophages.

 

Once systemically available, vanadium is subject to changes in speciation or valence, i.e. interconversion of the two oxidation states, the tetravalent form, vanadyl (VO2+) and the pentavalent form vanadate (VO3-). The anionic pentavalent form is reported to predominate in extracellular fluids whilst the cationic tetravalent vanadyl ion appears to be the most common intracellular form. Thus, in the oxygenated blood, it circulates as vanadate but in tissues, it is retained mainly as vanadyl. Depending on the availability of reducing agents, including reduced glutathione-SH, NADPH, NADH, and oxygen, vanadium may be reduced, reoxidised, and/or undergo redox cycling.

 

Chasteen et al. (1986) have verified the simultaneous presence of vanadium (IV) and (V) species in biological media (tissues, blood, urine and faeces) after dietary supplementation of rats with 15-25 ppm vanadyl sulfate for 180 days, as well as oral (gavage) administration of48V (100 µg V/kg bw) either as vanadyl sulfate or as ammonium vanadate. To avoid oxidation of vanadium (IV) to (V), dissection was performed under a nitrogen atmosphere, and excised tissues were frozen in liquid nitrogen. Most important is the conclusion that ingested vanadyl (IV) is retained as such during the gastric passage and eliminated via faeces or urine, with little absorption in the intestine. In contrast, vanadate (V) is apparently quantitatively reduced in the gastric milieu to (IV) vanadium. However, circulating vanadyl in blood appears to partly oxidise to the pentavalent state due to the oxygen tension. These conclusions appear to be in line with EFSA (2004) and ATSDR (1992).

 

According to EFSA (2004), “absorbed vanadium is transported in the serum mainly bound to transferrin. Extracellular vanadium is present in the form of vanadate (5+) and intracellular vanadium most likely in the vanadyl (4+) form.”

 

According to ATSDR (1992),Vanadium can reversibly bind to transferrin protein in the blood and then be taken up into erythrocytes. These two factors may affect the biphasic clearance of vanadium that occurs in the blood. There is a slower uptake of vanadyl into erythrocytes compared to the vanadate form. Five minutes after an intravenous administration of radiolabeled vanadate or vanadyl in dogs, 30% of the vanadate dose and 12% of the vanadyl dose is found in erythrocytes (Harris et al. 1984). It is suggested that this difference in uptake is due to the time required for the vanadyl form to be oxidized to vanadate.

When V+4 or V+5 is administered intravenously, a balance is reached in which vanadium moves in and out of the cells at a rate that is comparable to the rate of vanadium removal from the blood (Harris et al. 1984). Initially, vanadyl leaves the blood more rapidly than vanadate, possibly due to the slower uptake of vanadyl into cells (Harris et al. 1984). Five hours after administration, blood clearance is essentially identical for the two forms. A decrease in glutathione, NADPH, and NADH occurs within an hour after intraperitoneal injection of sodium vanadate in mice (Bruech et al. 1984). It is believed that vanadate requires these cytochrome P-450 components for oxidation to the vanadyl form. A consequence of this action is the diversion of electrons from the monooxygenase system resulting in the inhibition of drug dealkylation (Bruech et al. 1984).

Vanadium in the plasma can exist in a bound or unbound form (Bruech et al. 1984). Vanadium as vanadyl (Patterson et al. 1986) or vanadate (Harris and Carrano 1984) reversibly binds to human serum transferrin at two metalbinding sites on the protein. With intravenous administration of vanadate or vanadyl, there is a short lag time for vanadate binding to transferrin, but, at 30 hours, the association is identical for the two vanadium forms (Harris et al. 1984). The vanadium-transferrin binding is most likely to occur with the vanadyl form as this complex is more stable (Harris et al. 1984). The transferrin-bound vanadium is cleared from the blood at a slower rate than unbound vanadium in rats, which explains a biphasic clearance pattern (Sabbioni and Marafante 1978). The metabolic pathway appears to be independent of route of exposure (Edel and Sabbioni 1988).“

Placental transfer, and transfer via mother’s milk

„Analytical studies have shown very low levels in human milk (Byrne and Kosta 1978). Evidence from animal studies supports the occupational findings(ATSDR, 1992).

Distribution

Acute studies with rats showed the highest vanadium concentration to be located in the skeleton. Male rats had approximately 0.05% of the administered 48V in bones, 0.01% in the liver, and <0.01% in the kidney, blood, testis, or spleen after 24 hours (Edel and Sabbioni 1988). Conklin et al. (1982) reported that after 3 days, 25% of the absorbed vanadium pentoxide was detectable in the skeleton and blood of female rats. In female rats exposed to sodium metavanadate in the diet for 7 days, the highest concentrations of vanadium were found in bone, followed by the spleen and kidney (Adachi et al. 2000b); the lowest concentration was found in the brain.In a study byDaiet al., 1994 with non-diabetic and streptozotocin-diabetic rats given vanadyl sulfate in their drinking-water (0.5–1.5 mg/mL) for 1 year, vanadium concentrations were distributed in the following order: bone > kidney > testis > liver > pancreas > plasma > brain. Vanadium was found to be retained in these organs 16 weeks after cessation of treatment while plasma concentrations were below the limits of detection at this time.These findings appear to be in line with EFSA (2004) and ATSDR (2008).

 

According to EFSA (2004), “after administration by different routes to rats, the highest amounts were found in lungs (after intratracheal installation), bone, kidneys, liver and spleen. Studies on rats and mice showed a three-compartment model for elimination with plasma half-times of 15 minutes, 14 hours and 8.5 days (Lagerkvist et al., 1986).”

„Oral exposure for an intermediate duration produced the highest accumulation of vanadium in the kidney. Adult rats exposed to 5 or 50 ppm vanadium in the drinking water for 3 months had the highest vanadium levels in the kidney, followed by bone, liver, and muscle (Parker and Sharma 1978). The retention in bone may have been due to phosphate displacement. All tissue levels plateaued at the third week of exposure. A possible explanation for the initially higher levels in the kidney during intermediate-duration exposure is the daily excretion of vanadium in the urine. When the treatment is stopped, levels decrease in the kidney. At the cessation of treatment, vanadium mobilized rapidly from the liver and slowly from the bones. Other tissue levels decreased rapidly after oral exposure was discontinued. Thus, retention of vanadium was much longer in the bones (Edel et al. 1984; Parker and Sharma 1978). In rats exposed to approximately 100 mg/L vanadium in drinking water as vanadyl sulfate or ammonium metavanadate for 12 weeks, significant increases, as compared to controls, in bone, kidney, and liver vanadium levels were observed; no alterations in vanadium muscle levels were found (Thompson et al. 2002). The highest concentration of vanadium was found in the bone, followed by the kidney and liver. Tissue vanadium concentrations were significantly higher in rats exposed to ammonium metavanadate as compared to animals exposed to vanadyl sulfate.“(ATSDR, 2008)

Excretion

According to EFSA (2004), “studies on rats and mice showed a three-compartment model for elimination with plasma half-times of 15 minutes, 14 hours and 8.5 days (Lagerkvist et al., 1986).”

 

Inhalation exposure:Occupational studies showed that urinary vanadium levels significantly increased in exposed workers (Gylseth et al. 1979; Kiviluoto et al. 1981b; Lewis 1959; Orris et al. 1983; Zenz et al. 1962). Male and female workers exposed to 0.1-0.19 mg/m3 vanadium in a manufacturing company, had significantly higher urinary levels (20.6μg/L) than the nonoccupationally exposed control subjects (2.7μg/L) (Orris et al. 1983). The correlation between ambient vanadium levels and urinary levels of vanadium is difficult to determine from these epidemiological studies (Kiviluoto et al. 1981b). In most instances, no other excretion routes were monitored. Analytical studies have shown very low levels in human milk (Byrne and Kosta 1978). Evidence from animal studies supports the occupational findings. Vanadium administered intratracheally to rats was reported to be excreted predominantly in the urine (Oberg et al. 1978) at levels twice that found in the feces (Khoads and Sanders 1985). Three days after exposure to vanadium pentoxide, 40% of the recovered 48V dose was cleared in the urine while 30% remained in the skeleton, and 2%-7% was in the lungs, liver, kidneys, or blood (Conklin et al. 1982). Epidemiological studies and animal studies suggest that elimination of vanadium following inhalation exposure is primarily in the urine“.(ATSDR, 1992).

 

Oral exposure:Since vanadium is poorly absorbed in the gastrointestinal tract, a large percentage of vanadium is excreted unabsorbed in the faeces in rats following oral exposure. More than 80% of the administered dose of ammonium metavanadate or sodium metavanadate accumulated in the feces after 6 or 7 days (Adachi et al. 2000b; Patterson et al. 1986). After 2 weeks of exposure, 59.1±18.8% of sodium metavanadate was found in the feces (Bogden et al. 1982). However, the principal route of excretion of absorbed vanadium is through the kidney in animals. Approximately 0.9% of ingested vanadium was excreted in the urine of rats exposed to sodium metavanadate in the diet for 7 days (Adachi et al. 2000b). An elimination halftime of 11.7 days was estimated in rats exposed to vanadyl sulfate in drinking water for 3 weeks (Ramanadham et al. 1991).“(ATSDR-Draft, 2008).

 

Hamel & Duckworth (1995) examined the mechanisms controlling metabolism and pharmacokinetics of oral V administration, i.e. the accumulation of V in various organs from rats fed a liquid diet for 18 days, containing no or supplemental V at varying concentrations given as sodium orthovanadate or vanadyl sulfate. Organs of non-supplemented animals contained widely varying concentrations (ng of V/g dry tissue weight) with brain < fat < blood < heart < muscle < lung < liver < testes < spleen < kidney. All organs accumulated V in a dose dependent manner, but not all organs were at steady state conditions after 18 days. Additional rats were fed both V substances, switched to control diet, and assayed at 0, 4 and 8 days to calculate organ halftimes of V. Insulin sensitive tissue tissues, including liver and fat, had shorter halftimes than tissues that are relatively less insulin sensitive, including spleen, brain and testes. Sodium orthovanadate and vanadyl sulfate fed rats showed similar accumulation and elimination patterns.Vanadium elimination halftimes in various tissues were 3.57–15.95 or 3.18–13.50 days following a one-week exposure to 8.2 mg V/kg/day as sodium metavanadate or vanadyl sulfate, respectively.

 

Table: Vanadium elimination halftimes in organs in rats exposed to 8.2 mg V/kg/day for 1 Week (Hamel & Duckworth, 1995)

 

Organ

Halftime (days)

Sodium metavanadate

Halftime (days)

Vanadyl sulfate

Liver                

3.57

3.18

Kidney

3.92

3.27

Fat

4.06

5.04

Lung

5.52

4.45

Muscle

6.11

4.49

Heart

7.03

5.05

Spleen

9.13

5.15

Brain

11.17

9.17

Testes

15.95

13.50

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