This report was published by Dalia Mizikovsky.
Funding for this report was provided by Advance NanoTek Limited. Brisbane
Sunscreen is often used as the primary defense against sun damage and its harmful effects . Despite the continuous increase in the use of sunscreen worldwide , most of the active ingredients lack the necessary safety data . A Maximum Usage trial (MUsT) conducted by the US Food and Drug Administration (FDA) tested six active UV filters across four sunscreen formulations found that all organic UV filters tested showed systematic absorption . These findings regarding systemic absorption of organic UV filters, raise unevaluated safety concerns on potential carcinogenic, reproductive and developmental effects [3,4].
These findings led the US FDA to re-evaluate the GRASE status of active ingredients in sunscreen . GRASE is a measure used by the US FDA, which allows “drugs” to be sold over the counter without approved new drug applications, because they are generally recognized as safe and effective.
In a proposed rule, published on February 26, 2019 in the Federal Register – The Daily Journal of the United States Government  the FDA declared its review produced sufficient evidence that Zinc Oxide and Titanium Dioxide, two inorganic UV filters used in sunscreen products met GRASE standards . Trolamine Salicytate and Aminobenzoic acid (PABA) were determined by the FDA as not meeting GRASE standards , stating that the harm outweighed the benefit of their use .
In its proposed rule, the US FDA highlighted that for 12 organic UV filters, there was insufficient safety information to conclusively determine the GRASE status (Table 1) . In this report, we will review the results of the MUsT, in addition to other literature which has investigated the safety of organic UV filters.
For non-prescription sunscreen products, the US FDA regulation for plasma concentration of a topically applied substance must be below 0.5 ng/ml in order to forego toxicology testing .
The threshold value of 0.5 ng/mL is based on the principle that that level would approximate the highest plasma level below which the carcinogenic risk of any unknown compound would be less than 1 in 100,000 after a single dose .
Table 1. Active sunscreen ingredients (UV filters) and their GRASE status as established in the proposed rule by the Food and Drug Administration on February 26, 2019 .
The MUsT found that every organic UV filter tested exceeded this threshold after a single application (Table 2) . Furthermore, the concentration of the organic UV filters accumulated with subsequent application and remained above 0.5ng/ml in at half of the participants for at least 3 days after ceasing application . Two of the UV filters, benzophenone-3 and homosalate were still measured to be above the 0.5 ng/ml threshold on day 21 of the study, 17 days after ceasing application . Octocrylene had plasma concentrations that were 33-fold and 25-fold higher than the other UV filters tested at day 1 and day 4 of the MUsT respectively .
Previous studies have also identified the presence of organic UV filters in other relevant biological samples, such as urine [8, 9], breast milk , the placenta , and cord blood . It should be noted that physiological concentrations vary depending on the demographic sampled. Levels of UV filters in human samples are usually low [2, 5].
Table 2. Maximum Usage trial conducted by the Food and Drug Administration for six organic UV filters. Sunscreen was applied once on day 1, and 4 times a day for the subsequent 3 days. Blood samples were collected multiple times per day for days 1 to 4, and then once on days 5 to 7, day 10, day 14 and day 21. 
Dermal absorption is not the only relevant route of exposure to organic UV filters . UV filters also accumulate in bodies of water, benzophenone derivatives reaching concentrations of 300ng/ml in rivers, and at lower levels in sea and lake water due to the higher dilution factor [13, 14]. Furthermore, small amounts of organic UV filters were found in tap and groundwater, suggesting ingestion as an additional route of exposure . Swimming pools are another zone of major concern. They act as ‘sinks’ for organic UV filters, and their chlorine byproducts, with concentrations reported as 2.85, 1.9, 1.78 and 0.95 g/L for EHMC, OC, 4-MBC and BP3 respectively .
Biological Activities of Organic UV Filters
Endocrine disruption by organic UV filters has been characterised in a range of in vitro and in vivo animal and human studies, finding that many organic UV filters possessed some endocrine activity . Benzophenones, camphor derivatives, and cinnamate derivatives, three of the major classes of organic UV filters, have all been shown to possess estrogenic and androgenic disruptive effects, and to interact with the progesterone receptor in animal and in vitro studies [16-21]. Additionally, both benzophenones and cinnamate derivatives have been found to disturb the thyroid hormone receptor, and benzophenones the thyroid peroxidase enzyme [21-23]. These findings are reinforced by human studies, where small but significant changes in the relevant hormones were observed after topical application of sunscreen . The low amplitude of the changes was partially attributed to robustness against endocrine changes in adults .
Minor endocrine changes are unlikely to be of detriment to adults . However, children, whose developmental milestones are dependent on the correct endocrine signaling, are far more vulnerable to endocrine disruption [24, 25]. Exposure to organic UV filters can begin as early as in utero with maternal use of sunscreen . Maternal exposure to endocrine disrupting chemicals can affect the foetus via direct action if the foetus is exposed via placental transfer, or indirectly by the disruption of maternal hormones . Placental transfer is likely, given the lipophilic nature of many organic UV filters . Indeed, organic UV filters have been detected in the placenta, amniotic fluid, and cord blood [11, 29].
A human study from 2008, titled, Prenatal phenol and phthalate exposures and birth outcomes,  which investigated the effect of maternal urine concentration of benzophenone-3 on maternal hormones and birth outcomes found that the presence of benzophenone-3 was positively associated with birthweight in boys, and negatively associated with birthweight in girls . A more recent study from 2018  found a significant association between maternal urine and serum concentration of 4-hydroxybenzophenone (4-HBP), and decreased birth weight, head circumference and abdomen circumference . Additionally, urine concentration of 4-HBP was positively correlated with maternal triiodothyronine (T3), thyroxine (T4) and insulin-like growth factor 1(IGF-1) . 4-HBP is one of the known metabolites of benzophenones, in addition to a commercially used organic UV filter, so a proportion of the serum and urine concentration may originate from other benzophenone filters .
There are several studies of the developmental toxicity of organic UV filters using animal models which report significant effects from UV filter exposure [30-34].In one rat model, organic UV filters 4-methylbenzylidene camphor and 3-benzylidene camphor was administered in food to the parent generation pre-mating, during pregnancy, and during lactation and then to the offspring until adulthood . It was found that exposure to the organic UV filters was associated with delayed puberty and enhanced prostate growth in males, and altered uterine gene expression in females . Adult organ weights were altered in both sexes . There are numerous other animal model studies of developmental toxicity of organic UV filters which report significant effects from UV filter exposure [32-36].
In addition to exposure to organic UV filters in utero, young children are also exposed through frequent topical application in a bid to prevent sun damage . The absorption and resulting serum concentration of organic UV filters, though not evaluated, may be higher in children than adults since children have a greater skin surface area to volume ratio . Moreover, in the MUsT conducted by the FDA, it was proposed that the limiting factor for serum concentration of organic UV factors was skin absorption, rather than elimination or breakdown of the compounds .
Endocrine disruptors can have a major impact on fetal growth, and pubertal development, in addition to being associated with conditions such as obesity . However, the effects of organic UV filters are not limited to endocrine action, several studies suggesting potential neurotoxic  and carcinogenic effects . Moreover, recent evidence has shown that the breakdown products of organic UV filters may be hazardous, opening up another avenue that requires investigation .
Further safety testing must be conducted, including thorough toxicology studies on all organic UV filters, and their prominent breakdown products. Without this comprehensive information, a decision regarding their safety for further use cannot be made [3, 7].
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