|Grade||Level of Evidence|
|A||Multiple double-blind, controlled clinical trials.|
|B||1 double-blind, controlled clinical trial.|
|C||At least 1 controlled or comparative clinical trial.|
|D||Uncontrolled, observational, animal or in-vitro studies only.|
|Grade||Effect||Size of Effect||Comments|
20% topical zinc oixde ointment was more effective than an ointment containing 15% salicylic acid + 15% lactic acid in curing warts.
A zinc oxide cream was less effective than silicone gel in reducing the formation of keloid and hypertrophic scars in humans when used to treat surgical wounds.
Capable of blocking both UVA and UVB radiation, depending on particle size. Large particles are more effective at UVA protection, while nanosized particles provide greater UVB protection.
Helps improve allergic contact dermatitis, diaper dermatitis and atopic dermatitis.
Inhibited the loss of skin elasticity in mice exposed to UVA radiation daily for 15 weeks.
Mice protected by a zinc oxide sunscreen prior to UVA irradiation had more moisturized skin than the control mice.
Inhibited skin yellowing caused by UVA exposure in mice.
Mice irradiated with UVA had skin that sagged less if they had been protected by a zinc oxide sunscreen beforehand.
May enhance wound healing as it promotes the formation of granulation tissue and re-epithelialization as well as decreases inflammation and bacterial growth.
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Table of contents:
- 1. Sources
- 2. Skin penetration
- 3. Effects on the skin
- 4. Stability
- 5. Safety
Zinc oxide is an odourless, white or faintly yellowish powder. It occurs naturally as the mineral zincite, but can also be produced synthetically. Zinc oxide has widespread use in cosmetic products as a UV absorber, bulking agent, skin protector and cosmetic colourant. It also has applications in the pharmaceutical industry, in the rubber industry and as a food additive, among other uses.
The use of zinc oxide in sunscreens in the United States has risen steadily since the 1990s as recognition of the biological harm produced by UVA exposure increased. Only 3% of 59 sunscreens surveyed in 1997 contained zinc oxide, but this figure had risen to 12% by 2003 and further to 16% by 2009. Zinc oxide is also known to be a main component of some kohls, traditional eye cosmetics used in the Middle East.
2. Skin penetration
The cosmetic inelegance of conventional zinc oxide formulations (its poor spreadability and its leaving of a white film on the skin) led to the development of micronized zinc oxide. One study on mice found greater systemic absorption of zinc from the zinc nanoparticles compared to the larger particles, but another study on pig skin showed that virtually all of the applied microfine zinc oxide was on the skin surface or in the upper layers of the stratum corneum.
Most studies on human skin agree that topically applied nano-sized zinc oxide does not penetrate beyond the stratum corneum. A few studies found that zinc oxide accumulated in skin furrows, grooves, folds and the hair follicles, but seldom migrated from these locations into the viable epidermis or dermis. Of the studies that detected the penetration of zinc oxide nanoparticles through the skin, the extent of the penetration was usually minimal (<0.03% or <0.01% of the applied dose) and did not significantly affect the total amount of zinc in the blood, except in one case where a very high concentration of zinc oxide (40%) was used.
Since the stratum corneum is such an effective barrier to zinc oxide, it might be expected that the disruption of this barrier would increase the absorption of zinc oxide. Nevertheless, while sunburned skin and tape-stripped skin did have slightly enhanced penetration of zinc oxide nanoparticles, transdermal absorption has not been shown to occur. Even skin compromised by psoriasis or atopic dermatitis appeared impervious to the systemic absorption of zinc oxide. However, penetration enhancers such as ethanol, oleic acid and oleic acid-ethanol can increase the transdermal delivery of zinc oxide nanoparticles by raising the intercellular lipid fluidity or by extracting lipids from the stratum corneum.
3. Effects on the skin
Zinc oxide is not as effective as titanium dioxide in attenuating UVB and short-wave UVA radiation. For example, the mean sun protection factor (SPF) for 4 mg/cm2 applications of sunscreen formulations containing 5% ultrafine zinc oxide was ~4 in one study compared to ~5 for titatium dioxide. However, zinc oxide provides superior protection against long-wave UVA radiation compared to titanium dioxide. Zinc oxide's UVA attenuation capability is important because protection against UV-induced immunosuppression is known to be provided only by sunscreens filtering both UVA and UVB radiation.
In addition, a mineral sunscreen containing zinc oxide and titanium dioxide has been shown to inhibit both the UVB-induced formation of pyrimidine dimers and the single-strand breaks caused by UVA radiation. The latter attests to the genomic protection capability of zinc oxide against UVA, since titanium dioxde does not block UVA radiation.
Reducing the particle size from micro to nano increases the UVB protection afforded by metal oxides, as measured by higher SPF values, but at the expense of long-wave UVA absorption. This may account for why a sunblock preparation containing nano-sized zinc oxide and titanium dioxide was only effective in preventing UVB-induced damage but not UVA-specific damage in an experiment, compared to an organo-mineral sunblock containing Tinosorb M, octinoxate, zinc oxide and titanium oxide, which was able to prevent both types of damage. To ensure a high and balanced UV protection, a zinc oxide dispersion with large mean size (that provides adequate UVA protection) can be combined with a titanium dioxide dispersion with a mean particle size in the range of 110-130 nm, which is very effective in UVB absorption. Alternatively, a zinc oxide dispersion containing both small nanosized and large microsized particles can also achieve balanced UVA + UVB protection.
Primary particles of nano-sized zinc oxide tend to cluster to form aggregates and agglomerates. The UV absorption profile of nano-sized zinc oxide is largely dependent on the size of the aggregates; large agglomerates are not as effective providing the desired UV protection. Hence, dispersing agents are usually used to maintain the fine aggregate size and prevent the reformation of agglomerates.
Zinc oxide's photoprotective efficacy can be enhanced by by loading onto solid lipid nanoparticles that themselves have UV blocking potential, and by the addition of some natural substances to the formulation. Ascorbic acid for instance appears to enhance the deposition of zinc oxide nanoparticles on the skin surface without increasing its permeation through the skin layers, whereas Teucrium polium L. extract has its own UV absorption spectrum, contributing to its synergistic action.
3.2 Prevention of photoaging
2 studies have demonstrated the efficacy of sunscreens containing zinc oxide to inhibit UV-induced changes in the skin that are related to photoaging. In the first study, hairless mice irradiated with UVA every day for 15 weeks after application of a sunscreen containing 10% silicone-coated zinc oxide + 3% octinoxate had skin that was significantly more elastic, more moisturized, less thick and sagged less compared to the positive controls. The increase in skin yellowness induced by UVA exposure was also completely inhibited in these mice. Biopsies revealed that skin elastase activity was significantly lower in these mice, which helps prevent the loss of 3D structure of the elastic fibres and therefore explains the inhibition of skin sagging. These results suggest that zinc oxide can partially, but not entirely, reduce photoaging. The second study was conducted on an ex vivo human skin model, and found that a sunscreen containing zinc oxide and titanium dioxide improved the elastic fiber and collagen network in the dermis.
3.3 Anti-microbial effect
3.4 Improved healing
Topical zinc oxide appears to improve the healing of wounds caused by surgery, experimental excision and burns. The most authoritative of these was a randomized, double-blind, placebo-controlled multicenter trial that evaluated topical zinc oxide versus placebo mesh for acute open wounds following pilonidal disease excision. The wounds of those treated with zinc oxide had a median healing time that was 8 days shorter than those treated with the placebo (54 days compared to 62 days), but the difference was not statistically significant, indicating that larger clinical trials are needed to show the definitive effects of topical zinc oxide on wound healing.
At a cellular level, zinc oxide has been shown to promote granulation tissue formation, re-epithelialization, and to decrease bacterial growth and inflammation. Zinc oxide has also been demonstrated to increase the gene expression of insulin-like growth factor-1 (IGF-1) and to mobilize copper and selenium to the site of injury, which may be 2 mechanisms by which it enhances wound healing,
3.5 Dermatitis treatment
Zinc oxide has been shown to attenuate allergic contact dermatitis, albeit not as successfully as tea tree oil or topical corticosteriods like clobetason butyrate. It is also able to treat diaper dermatitis when combined with allantoin and cod liver oil, dexpanthenol or petrolatum. Zinc oxide has even been incorporated into specially designed textiles to support the treatment of atopic dermatitis.
3.6 Warts treatment
Warts are a common dermatological problem caused by human papilloma virus (HPV) infection. In a randomized, double-blind and controlled trial of 44 patients with warts, half were given an ointment containing 20% zinc oxide, and half received an ointment containing 15% salicylic acid + 15% lactic acid. Of the patients that completed the study, 50% of those in the zinc oxide-treated group were completely cured and 18.7% failed to respond, compared with 42% and 26% respectively, in the group treated with salicylic acid + lactic acid, demonstrating the superiority of the topical zinc oxide treatment.
3.7 Other treatments
Randomized trials indicate that zinc oxide can be used in the treatment of oral herpes and intertrigo. There has also been a case report of a 50% zinc oxide paste leading to nearly complete remission of Hailey-Hailey disease, an autosomal dominant condition characterized by outbreaks of rashes and blisters in the skin.
Uncoated microfine zinc oxide has been evaluated for its photostability through measurement of its absorption curves after exposure to 0 and 30 joules /cm2 of solar-simulated UV. The absorption curve was unchanged, demonstrating that zinc oxide is completely photostable. Moreover, uncoated, dimethicone-coated and silica-coated versions of microfine zinc oxide did not react with the organic sunscreen octinoxate under irradiation, an indication of its low photoreactivity. Coatings can also make zinc oxide particles hydrophobic, rendering them more compatible with water-resistant systems.
When zinc oxide sunscreens were irradiated by UVB light, a significant increase in zinc ions was observed, indicating that UV radiation induces the dissociation of zinc. There is also concern over the photocatalytic activity of zinc oxide, which can adversely affect skin cells.
Although zinc oxide nanoparticles and non-nano forms up to a concentration of 25% as a UV filter in sunscreens are considered by the European Union's Scientific Committee of Consumer Safety to not pose a risk of adverse effects in humans after dermal application, zinc oxide is currently not a permitted UV filter in the European Union.
The US FDA however allows for the use of zinc oxide as a sunscreen active ingredient up to a maximum concentration of 25%.
5.1 Adverse skin reactions
Large and microfine zinc oxide is not toxic, irritating or sensitizing to the skin. A repeated dose dermal toxicity study on rats found that nano-sized zinc oxide lowered the collagen content of rat skin however, which was suggested to be due to partial dissolution and penetration of the nanoparticles, followed by the induction of reactive oxygen species (ROS).
Although these dermal toxicity / irritation studies suggest that zinc oxide is relatively innocuous to the skin, their results stand in stark contrast to the multitude of in vitro studies that have shown the negative effects of zinc oxide on skin cells. For example, zinc oxide nanoparticles have been shown to increase cell death in fibroblasts, keratinocytes and melanoma cells and to cause DNA damage in keratinocytes and melanoma cells. Prolonged treatment of keratinocytes with zinc oxide nanoparticles led to reduced mitochondrial activity, loss of normal cell morphology and disturbances in cell-cycle distribution as well.
Nitrite present in perspiration and cosmetics can enhance the photocatalytic damage wrought by zinc oxide nanoparticles under UV irradiation by breaking amino acid residues and promoting protein oxidation and nitration.
The molecular mechanisms underlying the toxicity of zinc oxide nanoparticles remain unclear. It has been hypothesized that zinc oxide absorbs UV radiation in nanoparticle form, leading to photocatalysis and the production of reactive oxygen species (ROS). These ROS swamp the cells' redox defense system, thereby initiating cell death. However, there is also evidence that indicates that the zinc ions that dissociate from zinc oxide under UV irradiation is responsible for inducing ROS generation, mitochondrial dysfunction and cell death. It has also been suggested that the elevated levels of ROS is in part a result of the cytotoxic response, rather than a causal factor, since the addition of antioxidants reduced ROS without affecting cytotoxicity and intracellular ROS is mainly produced after zinc oxide particles of the dissolved zinc ions enters the cells.
The obvious discrepancy between the results of these in vitro studies and those of the dermal toxicity / irritation studies may be due to the limited skin penetration of zinc oxide, rendering the photocatalytic process insignificant in vivo.
Nevertheless, various types of coatings can lower the cytotoxic effect of zinc oxide nanoparticles. Poly(methacrylic acid (PMAA)-coated and oleic acid-coated nanoparticles had reduced ROS production and cytotoxicity, and titanium dioxide shell coatings modulated the toxicity by curtailing the release of zinc ions and decreasing the contact area of the zinc oxide cores.
Despite negative results in various tests for genotoxicity and mutagenicity, zinc oxide nanoparticles have been shown to induce DNA damage in many cell lines, including human epidermal cells, human epithelial cells, human nasal mucosa cells, human liver cells and human skin melanoma cells. Its genotoxicity appears to be linked to an increase in tyrosine phosphorylation, and may be mediated through oxidative stress.
5.3 Reproductive toxicity
Zinc oxide nanoparticles seem to act as a testicular toxicant in male mice; following treatment with 50 and 300 mg/kg doses, epididymal sperm parameters including sperm number, motility and percentage of abnormality were significantly changed. In adidition, histopathological criteria such as epithelial vacuolization, sloughing of germ and detachment were significantly increased, and there were decreases in seminiferous tubule diameter and seminiferous epithelium height as well as maturation arrest. Rats exposed to 500 mg/kg of zinc oxide nanoparticles also showed increased fetal resorption, reduced numbers of born or live pups, and the pups had lower body weights.
5.4 Decreased absorption of herbicldes
Pre-treatment of hairless mouse skin with zinc oxide impeded the dermal penetration of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), unlike other sunscreen actives such as octinoxate, homosalate, octisalate and padimate-O.
5.5 Inhalation toxicity
According to the Technical Guidance Document on Risk Assessment of the European Chemical Council, aerosols with a Mass Medium Aerodynamic Diameter (MMAD) greater than 10–15 μm are not respirable for humans and will deposit in the upper regions of the lungs, whereas particles with a size less than 10–15 μm will reach the gas-exchange region of the lung. The US Silicones Environmental, Health and Safety Council (SEHSC) recommends that for a consumer aerosol application for any silicone-based material, the particle size MMAD should be at least 30 μm with no more than 1% of the particles having an aerodynamic diameter of 10 μm or less, so that virtually all aerosol particles will be trapped in the nasopharyngeal region and very few if any particles will be deposited in the tracheobronchial region.
One study investigating the influence of different parameters on the droplet size and size distribution of sprayable sunscreen emulsions found that it is possible to develop formulations with a low percentage (<5%) of emitted droplets below 30 μm in size by optimizing formulation parameters and using appropriate actuators and valves. Also, in all experiments the percentage of droplets below 10 μm was less than 0.1%. However, the Scientific Committee of Consumer Safety pointed out that this was based on a spray distance of 11 cm -- larger distances may allow for a short time lapse that enables the evaporation of aerosol liquid components, leading to smaller droplet sizes. Moreover, they noted that the dried residual particles spreading in the air also need to be taken into account for possible inhalation exposure, especially when high vapour pressure fluids such as alcohols are used in the generation of the aerosol.
In vivo studies of rodents show that inhalation of aerosolized zinc oxide nanoparticles can lead to lung inflammation, impairment and oxidative stress. The dissolution of the zinc oxide nanoparticles inside phagosomes may be the main cause of the induced lung injuries.
Human studies concluded that inhalation of fine and ultrafine zinc oxide particles at a concentration of 500 μg/m3 for 2 hours was below the threshold for acute systemic effects, but that inhaled concentrations of 2.5 mg/m3 and above over 2 hours can cause metal fume fever. However, the Scientific Committee of Consumer Safety does not consider the first study to be relevant for the evaluation of zinc oxide as a cosmetic ingredient in view of the different type of zinc oxide used, and stated in 2012 that the use of zinc oxide nanoparticles in spray products cannot be considered safe on the basis of the available information.
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