|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|
Absorbs in the entire UVB spectrum but only part of the UVA spectrum. Does not protect against UV-induced DNA damage or immunosuppression.
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Table of contents:
- 1. Sources
- 2. Exposure
- 3. Skin penetration
- 3. Effects on the skin
- 4. Stability
- 5. Safety
1.1 In nature
1.1 In personal care products
Oxybenzone is very commonly used in personal care products. Surveys of 114 and 117 such products collected from the United States and China found it in 81% of the samples analyzed, at concentrations up to 0.148%. The highest levels were in skin lotions (including sunscreen lotions), followed by makeup products. Personal care products collected from the US contained higher concentrations of oxybenzone than those collected from China.
Oxybenzone may also exist in hair care products, as it has the ability to protect against hair damage caused by sunlight and to attenuate the fading of artificial hair colour through UV absorption.
1.2 In aquatic environments
Oxybenzone washed from the skin during recreational water activities and bathing can directly or indirectly (through wastewater treatment plant effluents) pollute aquatic environments. It has been detected in Spanish coastal waters and river waters, seawater from Italy, river water from Switzerland, surface waters from Japan and recreational waters from Slovenia. It has also been recovered from marine sediment extracts from the Southern California Bight in the US.
Fortunately, oxybenzone can undergo photodegradation by direct photolysis and by reacting with hydroxyl radicals and the triplet states of chromophoric dissolved organic matter, leading to a predicted half-life of several weeks under summertime conditions in Italian surface waters. The white rot fungus Trametes versicolor can also efficiently remove oxybenzone by more than 99% in less than 24 hours.
1.3 In food and water
Oxybenzone present in aquatic environments can end up in tap water as well as bio-accumulate in fish, as has been shown in Spain. Oxybenzone has also been used as an ultraviolet stabilizer in plastic surface coatings for food packaging, to prevent photodegradation.
Human exposure to oxybenzone is prevalent. A 2003-2004 survey of US residents found oxybenzone in 96.8% of the 2,517 urine samples, at a mean concentration of 22.9 µg/L. Females had significantly higher mean concentrations of oxybenzone compared to males, probably because women and girls use more sunscreens and personal care products. Mean concentrations also varied among the different ethnic groups. Non-Hispanic whites appeared to be more highly exposed than Mexican Americans and non-Hispanic blacks, which was thought to be a result of increased sunscreen use among people with lighter skin pigmentation. The latter finding was similar to that in a previous study on US girls aged 6-8 years, which found that whites had higher mean concentrations of oxybenzone than Hispanics and blacks. Serum and urine burdens of oxybenzone are also higher in individuals of higher socioeconomic status in the US.
Oxybenzone was also detected in the majority of urine samples from Danish men, women and children, in urine samples from the Belgian population, and in both urine and semen samples from Spain. Interestingly, there was no significant difference in oxybenzone concentrations between males and females in Belgium, but Belgian adolescents had significantly higher oxybenzone levels than adults, which could not be reasonably explained. Measured oxybenzone concentrations were markedly lower in Denmark, Belgium and Spain than in the US, which was considered a reflection of the more frequent inclusion of oxybenzone in sunscreen products in North America.
Fetuses may also be exposed to oxybenzone, since urine samples from pregnant women in the US, Puerto Rico, Spain, France and China have been shown to contain oxybenzone. In fact, oxybenzone was present at detectable levels in 61% of the amniotic fluid samples analyzed in a study of 97 pregnant women.
3. Skin penetration
In vitro studies on human epidermal membranes indicate that oxybenzone can pass into and through the skin in significant amounts, more so than other chemical sunscreens like octinoxate, octocrylene, octisalate, avobenzone and padimate O. When oxybenzone was applied to the inner forearm of human volunteers, 4% of the dose was found in the stratum corneum after 30 minutes, and nearly 35% was absorbed by the skin after 4 hours under occlusion.
In vivo studies have also confirmed the transdermal absorption of oxybenzone, showing its appearance in human plasma and urine following dermal exposure. A single application led to up to 0.4% to 2% of the applied dose detected in urine, but repeated whole-body applications can cause accumulation.
The effect of UV irradiation on the cutaneous absorption of oxybenzone is inconsistent -- one study found no significant difference between irradiated and un-irradiated skin, another found that simulated solar radiation decreased the diffusion through pig skin but did not affect the total absorbed dose, and a third found that both UVA and UVB enhanced oxybenzone flux and skin uptake.
Although percutaneous absorption of oxybenzone does not seem to increase in intrinsically or extrinsically aged skin, absorption varies depending on the anatomical site and is higher for facial skin compared to the skin of the back. Laser skin resurfacing can increase the skin deposition of oxybenzone by several-fold, as it reduces the barrier function of the skin.
Percutaneous absorption involves 2 processes, the release of the solute from its vehicle to the skin followed by the permeation of the solute through the skin. Both processes can potentially be modulated by the formulation vehicle through vehicle-solute and vehicle-skin interactions. Vehicle-solute interactions influence the rate and extent of solute release from the vehicle. For example, an oil-in-water emulsion where oxybenzone is likely to exist in the internal phase, should exhibit a slower release rate than a water-in-oil emulsion, where oxybenzone is in the external phase. A vehicle for which oxybenzone has high affinity, such as coconut oil, will also show a slower release. Vehicle-skin interactions on the other hand result in penetration enhancement or retardation. Ethanol, for instance, is thought to enhance penetration by extraction of stratum corneum lipids. Polyethylene glycol 400 has the potential to increase the vehicle-skin partitioning of oxybenzone and therefore its dermal absorption. The inclusion of propylene glycol or thickening agents that increase the viscosity of formulations may also promote the penetration of oxybenzone.
For single phase solvents, it has been reported that oxybenzone penetration can be minimized by choosing vehicles with a vehicle solubility parameter substantially different from the solubility parameter of the membrane. A comparison of 5 different vehicles found that a mixed ethanol:oil-based formulation, which is used for some commercial sunscreen spray formulations, led to significantly higher retention of oxybenzone in the epidermis. Other studies show that oxybenzone is better retained in the upper layers of the skin when formulated in an emulsion gel than when formulated in petrolatum.
Encapsulating oxybenzone within solid lipid microspheres or microparticles, nanoparticles, and nanocapsules is another viable strategy to decrease the penetration of oxybenzone in the skin and avoid systemic absorption, as is cyclodextrin complexation, though there are exceptions.
3. Effects on the skin
Oxybenzone's absorption profile spans from 270 to 350 nm, with absorption peaks at 288 and 350 nm. This encompasses the entire UVB spectrum but only part of the UVA spectrum, which explains why oxybenzone provides relatively weak UVA protection compared to avobenzone. In a comparison of 18 sun filters all at the highest concentration allowed by European legislation, oxybenzone also had one of the lowest efficacies.
Alone, oxybenzone can diminish the UV-induced formation of sunburn cells, physical damage to the skin structure and inflammation, but it is unable to inhibit thymine dimer formation or immunosupression. Combinations of oxybenzone with other UV filters can be effective in preventing DNA damage, inflammation and immunosuppression caused by UV radiation. However, a sunscreen containing oxybenzone, octinoxate and octisalate could not completely protect the skin against UV-induced oxidative stress parameters such as glutathione depletion and matrix metalloproteinase-9 (MMP-9) secretion, and sunscreens containing octinoxate, padimate O and oxybenzone failed to protect against the UV-induced increase in melanoma incidence in mice.
The photoprotective effect of oxybenzone can be enhanced by the choice of an appropriate vehicle, such as an emulsion-gel that helps retain oxybenzone in the superficial skin layers, by encapsulation within nanoparticles or nanocapsules that can scatter or reflect UV radiation, by complexation with cyclodextrins, by loading onto microspheres, microparticles or liposomes, by adsorption on a mesoporous silica drug carrier, and by the addition of antioxidants such as vitamin C, vitamin E and melatonin.
It is noteworthy that the oxybenzone in some commercial sunscreens may be prone to recrystallization after being applied to the skin, which may interfere with its UV-light absorbing function. Exposing oxybenzone to chlorine, a disinfectant in swimming pools, also leads to the loss of UV protection.
3.2 Prevent photoaging
The major histopathologic change in the dermis of photoaged skin is the accumulation of massive amounts of abnormal elastic tissue, termed solar elastosis. In mice, a SPF 15 sunscreen containing oxybenzone and octinoxate inhibited elastin gene induction by 57% in response to PUVA treatment, an indication of protection against photoaging. It is not clear however whether oxybenzone alone has this effect.
Although it has been proposed that oxybenzone is rapidly photo-oxidized to its semiquinone following UV irradiation, this claim contradicted other published stability data and has been contested, with other groups showing that oxybenzone is actually quite photostable.
In fact, oxybenzone can stabilize the UVA filter avobenzone, retinol, and the topical corticoid desonide. It does undergo significant photodegradation in the presence of the physical sunscreen titanium dioxide, but its stability can be improved via combination with octocrylene or by encapsulation.
Oxybenzone can inhibit cell growth and retarded cell cycle progression in cultured human cells. Chlorinated oxybenzone has also been shown to induce increased cell death. Nevertheless, these in vitro effects may not necessarily be relevant in vivo, as one study has found that the concentration of oxybenzone that penetrates to the viable epidermis of human skin is several times lower than those that cause toxicity in cultured human keratinocytes. There is also evidence to suggest that the cytotoxicity and phototoxicity of oxybenzone can be reduced by nanoencapsulation.
5.2 Pro-oxidant action
Topically applied oxybenzone leads to an increased production of reactive oxygen species under UV illumination and also appears to decrease the activity of the antioxidant enzyme superoxide dismutase. It has been suggested that the UV photo-oxidation of oxybenzone deactivates thioredoxin reductase, a central component of the thioredoxin system that is an important antioxidant defense. Fortunately, its inclusion in cyclodextrin complexes can markedly inhibit the formation of free radicals on exposure to UV light.
5.3 Contact allergy and contact dermatitis
While true photoallergic reactions to sunscreens is considered rare, oxybenzone is among the most common elicitors, as demonstrated by photopatch testing results from North America, Europe, and the Asia-Pacific. This may be due to its tendency to react with free amino acids or peptides of the human skin.
There are well over a dozen reports in the medical literature describing contact allergies and contact dermatitis to oxybenzone, including a few cases relating to skin eruptions, cheilitis and anaphylaxis. This is very likely because of its popularity as a sunscreen ingredient, as data from human repeat insult patch tests and photoallergy studies indicate that the mean rate of contact allergy to oxybenzone is just 0.07%.
Oxybenzone was weakly mutagenic in Salmonella studies and induced sister-chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells in the presence of a metabolic activation system. However, results from a Drosophila somatic mutation and recombination test (SMART) and an in vivo cytogenetic assay in rat bone marrow cells were both negative, supporting the conclusion that oxybenzone is not genotoxic in vivo.
5.5 Reproductive toxicity
Male rodents exposed to oxybenzone orally or dermally sometimes have altered reproductive parameters such as reduced epididymal sperm densities, but not always. A case-control study of 877 idiopathic infertile men and 713 fertile controls did not find a relationship between exposure to oxybenzone and idiopathic male infertility.
In Japanese medaka reproduction assays, female Japanese medaka exposed to µg/L levels of oxybenzone had significantly lower hatching success, indicating that oxybenzone can alter reproduction endpoints in fish.
Importantly, oxybenzone has been detected in human placental tissue samples, suggesting that prenatal exposure does occur. Higher maternal urinary concentrations of oxybenzone has been linked to decreased birth weight in girls, increased birth weight in boys and increased head circumference at birth.
5.6 Potential endocrine disruptor
Oxybenzone exerts uterotrophic effects in rats. It has also been shown to induce vitellogenin production and to alter the expression of various endocrine genes in fish. There have even been studies demonstrating the endocrine activities of oxybenzone on the insect Chironomus riparius, a reference organism in aquatic toxicology.
Specifically, oxybenzone appears to be a partial agonist towards estrogen receptors, and an antagonist towards androgen and progesterone receptors, though one study in 2005 concluded that oxybenzone was not estrogenic at a concentration of 100 µm.
In addition, there is evidence that oxybenzone or its metabolites stimulate proliferation of human breast cancer cells, providing further support of its estrogenic activity. Oxybenzone exposure was not significantly associated with age of menarche in adolescent girls however.
When creams containing 10% each of oxybenzone, octinoxate and 4-methylbenzylidene camphor (4-MBC) were applied to the whole bodies of 15 young men and 17 post-menopausal women, there were no biologically significant effects on thyroid hormone levels, indicating that the concentrations of the sunscreens absorbed were not sufficient to disturb the homeostasis of thyroid hormones in adult humans.
5.7 Alters absorption of herbicides and insect repellents
Oxybenzone can act as a dermal penetration enhancer, with 0.6% oxybenzone significantly increasing the total peentration of a moderately lipophilic herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D). Moreover, oxybenzone and the insect repellent N,N-diethyl-m-toluamide (DEET) show a synergistic permeation enhancement when applied concurrently.
Since the simultaneous application of oxybenzone and the insect repellent picaridin has the opposite effect (supression of the transdermal penetration of both compounds), it has been suggested that picaridin would be a better candidate for concurrent use with sunscreen preparations in terms of minimizing percutaneous permeation of the chemicals.
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