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Description of key information

State of the art toxicokinetic studies are not available. 

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicokinetic profile of elemental Tellurium

Although daily uptake of Tellurium can be estimated with approximately 100 µg per person [1], its physiological role, if any, cannot be conclusively explained at the time being.

It needs to be acknowledged that essentiality may have a specific influence on toxicokinetic behavior because it is known that for essential elements specialized systems (like transport proteins) exist to allow for stable homeostatic conditions.

 

Absorption and bioavailability

All available data hint for a rather poor absorption of elemental Tellurium after oral uptake, i.e. systemic absorption was measured in human studies with elemental Tellurium, but also with tetra- or hexavalent Tellurium salts and is stated with 10 to 25 % of the applied dose [3].

In rats and rabbits absorption after oral exposure was determined with 10 to 40 % of applied dose.

 

The dermal absorption after application onto the skin is unknown [1] as is the case for human respiratory absorption [4].

 

For the determination of equitoxic potency of various Tellurium moieties (in this case elemental Tellurium and Tellurium dioxide) and hence definition of the NOAEL and furtheron derivation of DNELs the relative bioavailability is the most important figure.

 

For this purposein vitro studies with elemental Tellurium (Te) and Tellurium dioxide (TeO2) were conducted [5,6,7,8] to assess their behavior in a physiological environment with regard to any toxicokinetic differences.

Therefore bioavailability simulating inhalation and oral uptake was measured by the substance`s solubility in artificial alveolar fluid and in artificial saliva and gastrointestinal fluid respectively.

 

The results indicate that Tellurium dioxide is of approximately three times higher solubility than elemental Tellurium (see following table for measured solubility data):

 

 

Tellurium [mg/L]

Tellurium dioxide [mg/L]

 

Mean solubility in

artificial alveolar fluid after 72 hours

238.4 ± 16.1

799.1 ± 7.3 (Te)

999.4 ± 9.1 (Tellurium dioxide)

 

 

Factor

 

3.35 (based on Te)

 

Mean solubility in

artificial gastrointestinal fluid

56.68 ± 1.46

 156.7 ± 13.2 (Te)

196.03 ± 16.5 (Tellurium dioxide)

 

 Factor

 2.76 (based on Te)

 

 

 

Due to the unavoidable inaccuracies of these types of studies the obtained figures should be rounded for their practical use, i.e. the bioavailability for Tellurium dioxide can be estimated to be threefold higher compared with elemental Tellurium in different body fluids.

 

It is a well accepted fact, that suchin vitrostudies with inorganic substances may underestimate thein vivobioavailability, because living cells do possess active transport systems to control for homeostatic reasons the uptake of for example essential elements. Nevertheless thein vitrodata does clearly allow for a comparative insight into the bioavailability of different redox-species of an element and are therefore suitable for comparing study results with different Tellurium compounds in particular since the element Tellurium is not thought to be essential.

Despite total lack of information, the relative absorption after dermal exposure compared with oral exposure may be estimated by using data from other metals:

The Health Risk Assessment Guidance for Metals (HERAG) proposes for dermal absorption after exposure to dust or other dry metal compounds a default value of 0.1 % [9].

From this it follows that the dermal systemic bioavailability of elemental Tellurium may be estimated to be 10 % of the oral bioavailability (based on 10 % oral uptake) which results in a systemic bioavailability of 1 % of the external dermal dose. This figure clearly exceeds the above mentioned 0.1 % as typical for other metals and can therefore be considered a very conservative approach.

 

The figure of 1 % of dermal uptake of elemental Tellurium will be used further in the exposure considerations.

 

 

Distribution

The majority (90 %) of Tellurium in the blood stream enters erythrocytes; the remainder is bound to plasma proteins [4]. Tellurium may therefore accumulate in red blood cells in the form of dimethylated Tellurium.

 

Tellurium can cross the placenta and blood-brain barrier as well as the fetal blood-brain barrier. [6,13].

 

Concentrations of Tellurium were < 5 µg/L in blood, < 1 µg/L in saliva and < 0.5 µg/L in urine; the body “load” for an adult person is 600 mg Tellurium.

Highest tissue concentrations have been found in the kidneys [4], but also in liver, bone, brain and testes [10].

 

The half-life time of Tellurium in humans is estimated to be 3 weeks [3].

 

 

Metabolism

Ingested Tellurium is transformed, methylated and then effluxed into the blood stream where accumulation into red blood cells as dimethylated Tellurium takes place [11].

 

Trimethylated Tellurium was detected in blood serum and in urine as a main metabolite, but not in red blood cells.

 

Based on speciation studies it was found that all inorganic Tellurium is first reduced to Telluride (Te2-) and thereafter methylated [10,11].

 

Since concentrations of “free” Tellurium seem to be extremely low in various media it is obvious that absorbed Tellurium is taken up and converted to the Telluride moiety in cells from which it is released into the blood stream as dimethylated Tellurium for further distribution and predominantly renal excretion.

 

Excretion

Loss of systemically available Tellurium for humans is approximately 80 % in urine, approximately 16 % in feces and approximately 2 % in exhaled air [3] as dimethylated Tellurium resulting in a typical garlic odour [10].

Excretion in urine seems to take place via Trimethyltelluronium [12].

 

But the excretion pattern seems also to depend on the chemical form and mode of administration because in rats the main route of excretion is via feces (60 to 80 %) [4].

 

In conclusion above short description of the toxicokinetic behavior allows for the following:

  • Determination of relative bioavailabilities (threefold higher for Tellerium dioxide than elemental Tellurium) allows for definition of equitoxic potencies of elemental Tellurium versus Tellurium dioxide.
  • Because of utmost practical importance the dermal absorption of elemental Tellurium can be fixed due to a relatively robust estimation, i.e. 1 % of dermally applied dose.
  • Once absorbed all inorganic Tellurium seems to be converted to dimethylated (and also trimethylated) Telluride/Telluronium because concentrations of “free” Tellurium are extremely low and also only the di- and trimethylated Tellurium moieties have been detected.
  • Due to this unique metabolic behavior elemental Tellurium and Tellurium dioxide seem to belong into the same class of toxicants with regard to adverse effects which do not differ by mode of action but only by their potency due to differences in bioavailability (for comparison see also reference [2]).
  • Tellurium crosses the placenta barrier and fetuses may be therefore exposed to it.

Particles size an relevance of inhalation pathway

 

Tellurium is a solid substance, i.e. the inhalation characteristics are depending on the particle sizes.

 

The particle size distribution was determinedby light scattering, which allows a measurement of the volume based diameter (seeSiemens test report 20110372.02 (03/2012)).

 

Since inhalation of particles depends on the physical size and on the density, the aerodynamic diameter has to be defined. This parameter allows for a prediction of the likelihood of a particle to be respired and deposited in the human lung.

 

The physical particle diameter can be converted to the aerodynamic diameter in a first approach by the equation:

 

 DA≈ D√r/r0          (1)

(see: Attwood, David and Florence, Alexander: FASTtrack: Physical Pharmacy,   Pharmaceutical Press, 2nd ed. 2012)

(for spherical particle > 1µm)

 

with:

D:Particle diameter:

DA:Aerodynamic diameter:

r:Density of the disperse phase

r0:Unit density = 1 kg/dm3

 

 

For elemental Tellurium the statistical distribution of thephysical particlediameter D was stated with:

 

Particle diameter L10: 52.36 µm

(= 10 % < 52.36 µm; 90 % > 52.36 µm)

Particle diameter L50: 77.00 µm

Particle diameter L90: 112.98 µm

 

Converting D to DAfor elemental Tellurium with a relative density of 6.2 by use of equation (1) leads to:

 

DA≈ D x 2.5

Aerodynamic diameter LA10: 130.4 µm

(= 10 % < 130.4 µm; 90 % > 130.4 µm)

Aerodynamic diameterLA50: 192.50 µm

Aerodynamic diameterLA90: 282.45 µm

 

Since the test item consists of spherical dark-grey particles with a physical particle size clearly above 10 µm (see Graph x) the conversion should be considered as very precise.

 

The calculation shows, that the distribution as of Graph X is shifted to the right hand side and no measured particles are of an aerodynamic diameter below 10 µm.

 

But also a numerical solution by using the definition of “respirable fraction” according toEN 481 (1993) can be applied:

The value, where 50 % of particles in the air with an aerodynamic diameter DAare below 4 µm is defined as “respirable fraction”.

 

From this, that the measured particles are devoid of a relevant respirable fraction.

 

Both algorithms are demonstrating, that the measured particles of elemental Tellurium are classified as “not respirable”, because practically absence of particles with an aerodynamic diameter below 10 µm can be shown,

Based on this assessment the inhalation route is consideredno relevant application pathway for this substance and animal studies by inhalation are not required.

Dermal Absorption

In the evaluated scenarios only dry exposure to Tellurium dioxide dust is relevant.In the absence of measured data on percutaneous/dermal absorption, current guidance and practice in general suggests by default the assignment of either 10% or 100% dermal absorption rates:

- 10 % dermal absorption is used for molecular weights > 500 Da and log Pow < -1 or > 4,

otherwise:

 - 100 % dermal absorption is used.

For metals and their inorganic compounds, these considerations cannot be applied: The typical model for metals requires a metal compound to dissolve prior to its penetration of the skin by diffusive mechanisms the fact of which requires formation to the metal cation, for which in turn partition coefficients from n-octanol/water are irrelevant.

Just by default for metals only a figure of 100 % dermal absorption can be used in case of lack of any specific data.

In contrast, the currently available scientific evidence on the extent of dermal absorption of metals yields substantially lower figures than 100 %, as documented for example in a guidance document from US-EPA:

US-EPA estimated the dermal absorption of metals in its Guidance Document “Assessing Dermal Exposure from Soil” by (citation from: http://www.epa.gov/risk/assessing-dermal-exposure-soil):

“Suggested ABS factors based on the pharmacokinetic properties of chemicals appeared in Ryan et al, 1987. The proposed range for dermal absorption of inorganics from soil was 0.1% to 1%. This was also consistent with a review of the studies for cadmium, an inorganic, as assessed in EPA, 1992. Region 3 recommends accepting the 1% value as a conservative assumption of ABS for inorganics, in keeping with RAGS.”

ABS = Absorption factor (unitless)

RAGS = Risk Assessment Guidance for Superfunds

This is in line with the methodology proposed in the HERAG guidance for metals (HERAG fact sheet; 2007), where the following default dermal absorption factors for metal cations have therefore been proposed (epresentative for a full-shift exposure, i. e. 8 hours):

From exposure to liquid/wet media:                  1.0 %

From dry (dust) exposure:                                  0.1 %

Due to the fact, that it is unclear how similar tellurium is to those metals, which were used for the derivation of above figures, a dermal absorption for tellurium of 10 % is proposed. This leads to an additional Margin of Safety of 100 for the relevant exposure scenario to dry tellurium dust and is in line with good industrial practice.

Also recent publications for the assessment of elemental impurities in medicinal products do support this approach (see Teasdale A., Ulman K., Domoradzki J., Walsh P; 2015): “Conclusion: Although fragmentary in nature, existing data do nevertheless show that dermal exposure to metals is limited, often well below 10% of that observed when the same materials are administered orally.”