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Zinc compounds release, depending on their solubility, zinc cations which determine the biological activity of the respective zinc compounds.

Sufficient data is available on the soluble zinc compounds zinc chloride and zinc sulphate and on the slightly soluble zinc compounds ZnO and ZnCO3.

Zinc is an essential trace element which is regulated and maintained in the various tissues mainly by the gastrointestinal absorption and secretion during high and low dietary zinc intake and because of the limited exchange of zinc between tissues, a constant supply of zinc is required to sustain the physiological requirements. The zinc absorption process in the intestines includes both passive diffusion and a carrier-mediated process. The absorption can be influenced by several factors such as ligands in the diet and the zinc status. Persons with adequate nutritional levels absorb 20-30% and animals absorb 40-50%. Persons that are zinc deficient absorb more, while persons with excessive zinc intake absorb less.

For the soluble zinc compounds, the available information suggests an oral absorption value of 20%. This value can be considered as the lower bound range at adequate nutritional levels. The oral absorption of the slightly soluble zinc oxide has been shown to be 60% of that of the soluble zinc compounds. This corresponds to approximately 12-18%. No oral absorption information is available for the remaining slightly soluble and insoluble zinc compounds (i.e. Zn(OH)2, Zn3(PO4)2, ZnCO3, Zn, ZnS). However, considering that these substances have lower water solubility than ZnO, it can be conservatively assumed that the oral absorption of these compounds is ≤ 12%.

Animal data suggests that there is pulmonary absorption following inhalation exposure. Half-life values of 14 and 6.3 hours were reported for dissolution of zinc oxide. The absorption of inhaled zinc depends on the particle size and the deposition of these particles therefore data was provided on the particle size distribution of zinc aerosol from three different industry sectors. The particle size distribution data was evaluated by using a multiple path particle deposition (MPPD) model. This model revealed that for zinc aerosols the largest part of the deposition is in the head region and much less in the tracheobronchial and pulmonary region. Although most of the material deposited in the head and tracheobronchial region is rapidly translocated to the gastrointestinal tract, a part will also be absorbed locally.

Based on data for local absorption of radionuclides in the different airway regions, it can be assumed that the local absorption of the soluble zinc compounds will be approximately 20% of the material deposited in the head region, 50% of the material deposited in the tracheobronchial region and 100% of the material deposited in the pulmonary region. For the slightly soluble and insoluble zinc compounds a negligible absorption can be assumed for materials deposited in the head and the tracheobronchial region. 100% of the deposited slightly or insoluble zinc compounds are assumed to be absorbed in the pulmonary tract. The deposited material will be cleared via the lung clearance mechanisms into the gastrointestinal tract where it will follow oral absorption kinetics. Therefore the inhalation absorption for the soluble zinc compounds is a maximum of 40% and for the slightly soluble and insoluble zinc compounds inhalation absorption is at a maximum of 20%. These values can be assumed as a reasonable worst case, because they are considered to cover existing differences between the different zinc industry sectors with respect to the type of exercise activities (and thus breathing rate) and particle size distribution.

The available information from in vivo as well as the in vitro studies suggests the dermal absorption of zinc compounds through intact skin to be less than 2%.In vitro studies that estimated dermal absorption values only on the basis of the zinc levels in the receptor medium without taking into account the zinc present in the stratum corneum appear to underestimate absorption values derived from in vivo studies. Such zinc trapped in the skin layers may become systemically available at a later stage. Quantitative data to evaluate the relevance of this skin depot are however lacking. Given the efficient homeostatic mechanisms of mammals to maintain the total body zinc and the physiologically required levels of zinc in the various tissues to be constant, the anticipated slow release of zinc from the skin is not expected to disturb the homeostatic zinc balance of the body. Considering the available information on dermal absorption, the default for dermal absorption of all zinc compounds (solutions or suspensions) is 2%. Based on the physical appearance, for dust exposure to zinc and zinc compounds a 10-fold lower default value of 0.2% is a reasonable assumption.

Zinc appears to be distributed to all tissues and tissue fluids and it is a cofactor in over 200 enzyme systems. The excretion of zinc is primarily via faeces, but also via urine, saliva, hair loss, sweat and mothers-milk.

Zinc oxide nanomaterial:

 

Toxicokinetics according to OECD 417 under non-GLP conditions were examined as part of repeated Dose Inhalation Toxicity Studies. In the 14-day-inhalation-study (Bellmann, 2011) one day after end of exposure, in the high dose group of Z-COTE® HP1 the absolute Zn content was slightly increased (statistically significant) to 365% in the lung as compared to the clean air control group. In all other organs the Zn levels were very close to the control values. The deposited mass of Z-COTE®HP1 in the 10-day exposure period was approx. 290 μg/lung, the analytical results thus demonstrating a practically complete dissolution of the retained test item. After the 14-day recovery, some statistivally significant increases were detected, however, as these values were close to controls and not dosedependent, they are considered as incidental findings. Overall, no relevant amounts of increased ZCOTE-HP1 (NM-111) were detected in any body compartment demonstrating the rapid elimination. The absolute Zn content following exposure to NM-110 and NM-113 in lung were in the same order but not significantly increased.

In the 90-day repeated dose inhalation toxicity study with male Wistar rats exposed (nose only) to coated nanoscaled ZnO (Z-COTE HP1) and non-coated microscaled ZnO, the toxicokinetics analytical results revealed practically complete dissolution of the retained test substance. Overall, no relevant amounts of increased nanoscaled ZnO were detected in any body compartment demonstrating the rapid elimination (Creutzenberg, 2013).

ZnO nanoparticles of approximately 50 nm in size (TEM evaluation) were compared to ZnO microparticles showing at least one diameter >100 nm (TEM evaluation). After oral and intraperitoneal administration for both ZnO nanoparticles and microparticles, Zn could be observed in serum indicating uptake from the GI–tract, either as particulate materials or as dissolved Zn ions. For ZnO nanoparticles the systemic availability was somewhat higher compared to that of ZnO microparticles as indicated by Zn measurements by ICP-MS. Zn showed a higher distribution in the liver, spleen and lung after treatment with ZnO nanoparticles compared to treatment with ZnO microparticles (Li et al 2012).

 

There are no indications for significant, if any, penetration of nanoparticles through the skin, most likely only a minimal amount of Zn ions released from the nanoparticles may be available for systemic exposure.

The in vivo study according to current standards OECD Guideline 427 (Creutzenberg, 2011) shows that coated ZnO nanoparticles (Z-COTE® HP1) are not absorbed after dermal application in rats. This result is supported by other literature data. Studies in volunteers with ZnO nanoparticles in sun-blocking formulations or in vitro experiments using coated or uncoated nanoparticles have shown that ZnO nanoparticles are not able to penetrate the stratum corneum (Zvyagin et al. 2008).There isno evidence that ZnO nanoparticles penetrate through intact or sunburned skin.In view of the discussion above, it is assumed that penetration of the skin, if any, is caused by Zn ions released from ZnO nanoparticles.

 

Overall, there was no indication of nano-specific toxicity. The observed biological effects are mainly caused by dissolved Zn-ions.