In a 24-hour period, oxybenzone (benzophenone 3) (25 μM) increased relative RXRα protein levels by 49% and decreased relative RXRβ and RXRγ protein levels by 61% and 56%, respectively [3]. At 7 DIV, caspase-3 levels are increased in initial cultures of mouse neocortical cells by oxybenzone (25-100 μM; 24 hours). RXRα signaling is activated and RXRβ/RXRγ signaling is impaired in oxybenzone-induced apoptosis. In mouse embryonic neural cells, oxybenzone (25 μM; 24 hours) decreases HDAC and HAT activity and prevents global DNA methylation [3].

Western blot analysis [3]
Cell Types: 7 DIV mouse neocortical cells
Tested Concentrations: 25 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: Exposure to oxybenzone (25 μM) for 24 hrs (hours) diminished relative RXRβ and RXRγ protein levels by 61% respectively and 56%, respectively. OxyBenzone (25 μM) treatment increased relative RXRα protein levels by 49%.

Absorption, Distribution and Excretion
In vivo studies have shown that benzophenone is absorbed through the skin and excreted in the urine. …The distribution of benzophenone-3 in rats via oral, intravenous, and topical administration has been investigated. (14) Oral doses of C-benzophenone-3 were 3, 28, 293, and 2570 mg/kg, dermal doses were approximately 0.2, 0.6, 0.8, and 3.2 mg/kg, and intravenous dose was 4.6 mg/kg. A sunscreen lotion was used as an excipient for the 0.6 mg/kg dermal dose, while an alcoholic solution of the compound was used for the other dermal doses. Benzophenone-3 was well absorbed at all routes of administration and doses, with urinary excretion being the predominant route, followed by fecal excretion. Only trace amounts of benzophenone-3 were detected in tissues after 72 hours. Benzophenone-3 is one of five UV filters, and standard operating procedures have been established for rapid analysis of these filters in different skin layers. 4.9% benzophenone-3 was added to a cosmetic formulation (ingredient not specified) and applied at a dose of 3 mg/cm² to fresh transdermal skin sections (±344 μm) of human skin (six samples from different donors) and placed in a static diffusion cell. 3 mL of receptor fluid (pH 7.4) maintained at 32 °C consisted of 1% bovine serum albumin, 0.9% NaCl, 0.02% KCl, and 0.04% gentamicin dissolved in distilled water. Transepidermal water loss was recorded at each site using a transepidermal water loss analyzer (TEWL). After 16 hours of exposure, the skin was cleaned and dried with cotton swabs. Receptor fluid was collected, and the skin surface was peeled 16 times to determine stratum corneum (SC) content, after which the epidermis was separated from the dermis. Analysis was performed using isocratic reversed-phase high-performance liquid chromatography (RP-HPLC2) combined with ultraviolet detection. The quantitative results for benzophenone-3 are as follows: total dosage 147 μg/cm² (3 mg cream/cm², 4.9% benzophenone-3); stratum corneum (SC) 8.5 ± 3.3 μg/cm²; epidermis 0.3 ± 0.2 μg/cm²; dermis 0.4 ± 0.1 μg/cm²; receptor fluid 1.0 ± 0.4 μg/cm². The wash buffer recovery rate was 85.7% ± 4.5%; the overall recovery rate was 93.4% ± 3.1%. These results indicate that the stratum corneum absorbed most of the administered dose (5.8%), approximately 0.5% was absorbed by the active skin, and 0.7% was analyzed in the receptor fluid. …They estimated that, 16 hours after topical application of benzophenone-3 to freshly harvested human skin, its transdermal bioavailability was 1.7 μg/cm² (1.0 μg/cm² in receptor fluid, 0.4 μg/cm² in dermis, and 0.3 μg/cm² in epidermis), equivalent to 1.16% of the administered dose. A study investigating the urinary concentration of benzophenone-3 in human volunteers after topical application showed low bioavailability. Researchers applied 40 grams of a commercially available sunscreen containing 4% benzophenone-3 to an average body surface area of 2.0 square meters in 11 volunteers and collected urine samples over the following 48 hours. Although urine is the primary known route of excretion for absorbed and bioavailable substances, only 0.4% (equivalent to 9.8 mg per volunteer) of the applied dose was recovered in urine during the 48-hour sampling period. In this study, 32 volunteers were treated with a basic cream formulation of 2 mg/cm² for four consecutive days during the first week, followed by the same treatment during the second week with a sunscreen containing 30% UV filters (10% 4-methylbenzyl camphor, 10% benzophenone-3, and 10% ethylhexyl methoxycinnamate). Blood samples were collected at multiple time points on the first day of treatment and daily thereafter. The parent forms of all three compounds were detected in plasma (benzophenone-3 concentrations up to 300 ng/mL) and urine, indicating significant skin penetration, transdermal absorption, and urinary excretion in humans. More complete data on the absorption, distribution, and excretion of 2-hydroxy-4-methoxybenzophenones (22 in total) can be found on the HSDB record page. Metabolism/Metabolites…Describes the metabolism and distribution of benzophenone-3 in rats and mice after oral administration and transdermal administration (100 mg/kg body weight) in rats. The same metabolites were detected in all cases: 2,4-dihydroxybenzophenone (DHB), 2,2'-dihydroxy-4-methoxybenzophenone (DHMB), and 2,3,4-trihydroxybenzophenone (THB). These metabolites existed in both free and bound (glucuronidated or sulfonated) states. Benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) is widely used as a sunscreen to protect human skin and hair from damage caused by ultraviolet (UV) radiation. This study investigated the metabolism of BP-3 in rat and human liver microsomes, as well as the estrogenic and antiandrogenic activities of its metabolites. When BP-3 was incubated with rat liver microsomes in the presence of NADPH, in addition to the previously detected metabolites 5-hydroxylated BP-3 (5-OH BP-3), 4-demethylated metabolite (2,4-diOH BP), and 2,3,4-trihydroxybenzophenone (2,3,4-triOH BP), 2,4,5-trihydroxybenzophenone (2,4,5-triOH BP) and 3-hydroxylated BP-3 (3-OH BP-3) were newly identified. In studies of recombinant rat cytochrome P450, 3-OH BP-3 and 2,4,5-triOH BP were mainly generated by CYP1A1. BP-3 can also be metabolized by human liver microsomes and CYP isoenzymes. In estrogen reporter gene (ER) assays using estrogen-responsive CHO cells, 2,4-dihydroxybenzoic acid (2,4-diOH BP) exhibited stronger estrogenic activity, 2,3,4-trihydroxybenzoic acid (2,3,4-triOH BP) showed similar activity, while the activities of 5-hydroxybenzoic acid-3 (5-OH BP-3), 2,4,5-trihydroxybenzoic acid (2,4,5-triOH BP), and 3-hydroxybenzoic acid-3 (3-OH BP-3) were all lower than those of benzoic acid-3 (BP-3). Researchers investigated the active structures of a series of 14 benzoic acid-3 derivatives. Estrogenic activity was enhanced when benzoic acid-3 was incubated with liver microsomes from untreated rats or rats treated with phenobarbital, 3-methylcholanthrene, or acetone in the presence of NADPH. However, dexamethasone-treated rat liver microsomes exhibited decreased estrogenic activity due to reduced production of inactive 5-hydroxybenzoic acid-3 and active 2,4-dihydroxybenzoic acid. Incubation of BP-3 with liver microsomes also reduced its anti-androgenic activity. This study aimed to investigate the pharmacokinetics of benzophenone-3 (BZ-3) administered orally at 100 mg/kg body weight to male Sprague-Dawley rats. Urine and fecal analyses indicated that urine was the primary route of excretion, followed by feces. Further analysis of urine samples revealed that the binding of BZ-3 to glucuronic acid was the primary systemic elimination pathway. This study also investigated the in vivo distribution of benzophenone-3 (BZ-3) after transdermal administration to Sprague-Dawley rats. Three metabolites were identified in plasma, with 2,4-dihydroxybenzophenone (DHB) and 2,2'-dihydroxy-4-methoxybenzophenone (DHMB) being the major metabolites detected, while 2,3,4-trihydroxybenzophenone (THB) was present in very low amounts. Tissue distribution studies showed that THB was the major metabolite in all tissues examined, followed by DHB (both free and bound). The highest concentration was found in the liver, followed by the kidneys, spleen, and testes. Benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) is widely used as a sunscreen to protect human skin and hair from damage caused by ultraviolet (UV) radiation. This study investigated the metabolism of BP-3 in rat and human liver microsomes, as well as the estrogenic and antiandrogenic activities of its metabolites. When BP-3 was incubated with rat liver microsomes in the presence of NADPH, in addition to the previously detected metabolites 5-hydroxylated BP-3 (5-OH BP-3), 4-demethylated metabolite (2,4-diOH BP), and 2,3,4-trihydroxybenzophenone (2,3,4-triOH BP), 2,4,5-trihydroxybenzophenone (2,4,5-triOH BP) and 3-hydroxylated BP-3 (3-OH BP-3) were newly identified. In studies of recombinant rat cytochrome P450, 3-OH BP-3 and 2,4,5-triOH BP were mainly generated by CYP1A1. BP-3 can also be metabolized by human liver microsomes and CYP isoenzymes. In estrogen reporter gene (ER) assays using estrogen-responsive CHO cells, 2,4-dihydroxybenzoic acid (2,4-diOH BP) exhibited stronger estrogenic activity, 2,3,4-trihydroxybenzoic acid (2,3,4-triOH BP) showed similar activity, while the activities of 5-hydroxybenzoic acid-3 (5-OH BP-3), 2,4,5-trihydroxybenzoic acid (2,4,5-triOH BP), and 3-hydroxybenzoic acid-3 (3-OH BP-3) were all lower than those of benzoic acid-3 (BP-3). Researchers investigated the active structures of a series of 14 benzoic acid-3 derivatives. Estrogenic activity was enhanced when benzoic acid-3 was incubated with liver microsomes from untreated rats or rats treated with phenobarbital, 3-methylcholanthrene, or acetone in the presence of NADPH. However, dexamethasone-treated rat liver microsomes exhibited reduced estrogenic activity due to decreased production of inactive 5-hydroxybenzoic acid-3 and active 2,4-dihydroxybenzoic acid. Incubation of BP-3 with liver microsomes reduced its anti-androgenic activity. Elimination pathway: In vivo studies showed that benzophenone is absorbed through the skin and excreted in the urine. Biological half-life: ...This study aimed to investigate the pharmacokinetics of benzophenone-3 (BZ-3) administered orally at 100 mg/kg body weight to male Sprague-Dawley rats. ...The elimination pattern was biphasic, with α-phase and β-phase elimination half-lives of 0.88 hours and 15.90 hours, respectively. ...This study also investigated the in vivo distribution of benzophenone-3 (BZ-3) after transdermal administration to Sprague-Dawley rats. Blood samples were collected at different time intervals, and the parent compound and its metabolites were analyzed by high-performance liquid chromatography (HPLC). Absorption was rapid…the absorption half-life was 3.45 hours…plasma clearance was biphasic, with different half-lives (α phase 1.3 hours, β phase 15.05 hours)…

Toxicity Summary
Identification and Uses: 2-Hydroxy-4-methoxybenzophenone (benzophenone-3; BP-3) is available in crystalline or powder form. It is used as a UV absorber and stabilizer, particularly in plastics and coatings. It can also be used as a broad-spectrum UV filter, with concentrations up to 10% in sunscreen products, either alone or in combination with other UV filters. It not only prevents sunburn but also protects the skin from the photodynamic, photosensitizing, and phototoxic effects of various drugs. Human Studies: Photosensitivity to the UV blocker benzophenone-3 has been reported. Animal Studies: Benzophenone-3 did not cause skin sensitization in mice. Mice were given concentrations of 0, 3125, 6250, and 12500 μM benzophenone-3. Dysfeeding at concentrations of 25,000 ppm and 50,000 ppm was also administered for 13 weeks. The following effects were observed: 554 mg/kg body weight/day: No adverse reactions were observed. 1,246 mg/kg body weight/day: Increased liver weight. 2,860 mg/kg body weight/day: Increased liver weight. 6,780 mg/kg body weight/day: Decreased body weight gain in both males and females; increased liver weight; mild hepatocyte cytoplasmic vacuolation. 16,238 mg/kg body weight/day: Decreased body weight gain in both males and females; mild kidney damage in males; increased liver weight; mild hepatocyte cytoplasmic vacuolation; decreased sperm density and increased proportion of abnormal sperm in males; prolonged estrous cycle in females. In rat developmental studies, the following effects were observed: 204 mg/kg body weight/day: No abnormalities were observed in the studied reproductive parameters. 828 mg/kg body weight/day: No abnormalities were observed in the studied reproductive parameters. 3458 mg/kg body weight/day: Males: Decreased weight of the right tail, testis, and epididymis; decreased sperm count in tail tissue; Females: prolonged estrous cycle. Based on in vivo and in vitro studies, benzophenone-3 is an endocrine disruptor. In a photomutagenic assay of Salmonella typhimurium, benzophenone-3 did not induce gene mutations. In Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538, benzophenone-3 was not mutagenic, regardless of microsomal activation. Ecotoxicity studies: Benzophenone-3 interfered with the aggressive behavior of male fighting fish, indicating that the compound has endocrine disrupting activity. Oxybenzone absorbs UVA ultraviolet radiation, preventing it from reaching the skin. Interactions: Benzophenone-3 (BZ-3; 2-hydroxy-4-methoxybenzophenone, oxybenzone)...is permeable to the skin and detectable in urine. Its concentration ranges from 0.4% to 2%. This appears to be the major metabolic pathway in rats. To investigate the total amount of BZ-3 in urine after repeated full-body application of sunscreen and to observe whether ultraviolet radiation affected its excretion... 25 volunteers applied commercially available sunscreen containing 4% BZ-3 morning and evening for five consecutive days. Urine samples were measured during the five days of sunscreen application and again five days after the last application. They were divided into group A (unexposed group) and group B. Group B received ultraviolet radiation based on skin color: UVA dose from 400 to 707 J/cm², and UVB dose from 0.46 to 2.0 J/cm². The BZ-3 content in urine was analyzed using high-performance liquid chromatography (HPLC). ...The total amount of BZ-3 excreted by the volunteers ranged from 1.2% to 8.7% (average 3.7%). No significant difference was found between the two groups (P < 0.99, t-test)...
Recently, it has been reported that the skin absorption of N,N-diethyl-m-toluamide (DEET) and oxybenzone (OBZ) mutually enhances each other, with DEET and OBZ being the active ingredients in mosquito repellent and sunscreen, respectively. To directly assess the reported enhancing effect, we used human urinary metabolites as biomarkers; furthermore, we sought to determine the optimal method for simultaneous use of these two products without increasing each other's absorption. We employed four skin application methods: DEET alone (S1), oxadazole alone (S2), DEET followed by oxadazole (S3), and DEET followed by oxadazole (S4). The study found significant differences between the different methods (p = 0.013), primarily attributed to the difference between S1 and S4, indicating that applying DEET before oxadazole to the skin significantly increased DEET absorption. Applying the two products in the reverse order (S3) did not result in a significant increase in DEET absorption. Regarding the permeability of oxadiazine, no significant differences were observed between the methods. In summary, the study confirms that applying DEET to the skin before applying oxadiazine enhances DEET absorption. If sunscreen and insect repellent must be used simultaneously, it is recommended to apply sunscreen (OBZ) first, wait 15 minutes, and then apply insect repellent (DEET). Organic ultraviolet (UV) filters are widely used in various products, including cosmetics, to prevent UV damage to tissues and industrial materials. Their widespread use has raised concerns about potential adverse effects on human health and aquatic ecosystems, which accumulate these pollutants. To enhance sun protection, UV filters are often used in mixtures. This study investigated the toxicity of a binary mixture of 4-methylbenzyl camphor (4MBC), octyl methoxycinnamate (OMC), and benzophenone-3 (BP-3) by assessing the mortality rate of midge larvae. Furthermore, molecular endpoints were analyzed, including changes in the expression levels of genes related to the endocrine system (ecdysone receptor EcR) and genes related to stress response (heat shock protein 70 hsp70). The results showed that the mortality rate induced by the binary mixture was similar to that induced by the individual compounds; however, some differences existed in the median lethal concentration (LC50) between the groups. Gene expression analysis revealed that EcR mRNA levels were elevated in the presence of 0.1 mg/L 4MBC, but returned to normal after exposure to mixtures of 4MBC with 0.1, 1, and 10 mg/L BP-3 or OMC. Conversely, hsp70 mRNA levels were elevated after exposure to the tested combinations of 4MBC with BP-3 or OMC. These data suggest that 4MBC, BP-3, and OMC may have antagonistic effects on EcR gene transcription and synergistic effects on hsp70 gene activation. This is the first experimental study to reveal the effects of UV filter mixtures on complex patterns in invertebrates. Data indicate that the interactions within these chemical mixtures are highly complex and have varying effects on different endpoints. The increasing incidence of skin cancer in recent years has highlighted the importance of protecting the skin from ultraviolet (UV) radiation. Chemical sunscreens, such as benzophenone-3 (BP-3), are widely used in sunscreen formulations. BP-3 is a commonly used broad-spectrum chemical sunscreen, but studies have shown that its topical application can cause adverse reactions. Therefore, there is a need to develop innovative sunscreen formulations to improve user safety. Lipid carriers appear to be a good alternative for formulating chemical sunscreens, reducing their skin permeability while maintaining good photoprotective capabilities. This study aims to compare the transdermal absorption and skin bioavailability of BP-3 loaded in solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), nanostructured polymer lipid carriers (NPLC), and nanocapsules (NC). This study also investigated the particle size, zeta potential, and in vitro sun protection factor (SPF) of the nanoparticle suspensions. The results showed that the polymeric lipid carrier composed of NPLC and NC significantly reduced the skin permeability of BP-3 while exhibiting the highest SPF value. This study confirms the great potential of NPLC and NC in the formulation of chemical UV filters. For more complete data on 2-hydroxy-4-methoxybenzophenone (7 interactions in total), please visit the HSDB record page. Non-human toxicity values: Rat oral LD50: 7400 mg/kg; Mouse intraperitoneal LD50: 300 mg/kg; Rat oral LD50: >12.8 g/kg; Rabbit dermal LD50: >16.0 g/kg

[1]. Prenatal exposure to benzophenone-3 (BP-3) induces apoptosis, disrupts estrogen receptor expression and alters the epigenetic status of mouse neurons. J Steroid Biochem Mol Biol. 2018;182:106-118.

[2]. Can oxybenzone cause Hirschsprung's disease?. Reprod Toxicol. 2019;86:98-100.

[3]. Benzophenone-3 Impairs Autophagy, Alters Epigenetic Status, and Disrupts Retinoid X Receptor Signaling in Apoptotic Neuronal Cells. Mol Neurobiol. 2018;55(6):5059-5074.

Therapeutic Uses
Sunscreen.
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Oxybenzone is listed in the database.
Ultraviolet Protectant.
Topical sunscreen that provides UVA/UVB protection and is FDA approved for concentrations up to 6%. For more complete data on the therapeutic uses of 2-hydroxy-4-methoxybenzophenone (9 in total), please visit the HSDB record page.

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Drug Warnings
...Benzophenone-3 undergoes a binding reaction in the body, making it soluble in water. However, it is not yet clear at what age this binding capacity fully matures, therefore physical sunscreens such as titanium dioxide and/or zinc oxide may still be more suitable for children.
Manufacturers of sunscreens using propellants warn that inhaling the fumes produced by these products can be harmful or even fatal. /Propellant/
Because the skin absorption characteristics of infants under 6 months of age may differ from those of adults, and their metabolic and excretory pathways are not yet fully developed, potentially limiting their ability to clear transdermal sunscreens, sunscreens should only be used on infants under 6 months of age under the guidance of a clinician. The skin characteristics of older adults may also differ from those of younger adults, but these characteristics and the special considerations for using sunscreens in this age group are not fully understood. /Sunscreen/
Limited information exists regarding the safety of long-term use of sunscreens, but commercially available physical and chemical sunscreens appear to have a low incidence of adverse reactions. Derivatives of para-aminobenzoic acid (PABA), benzophenone, cinnamic acid, salicylic acid, and 2-phenylbenzimidazole-5-sulfonic acid can cause skin irritation, including burning, stinging, itching, and erythema, in rare cases. /Sunscreen/
For more complete data on drug warnings for 2-hydroxy-4-methoxybenzophenone (8 in total), please visit the HSDB records page.

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Pharmacodynamics
Oxybenzophenone is an organic compound used in sunscreens; it is a derivative of benzophenone.

C14H12O3

228.2433

228.078

131-57-7

Oxybenzone-d5;1219798-54-5

4632

Light yellow to yellow solid powder

1.2±0.1 g/cm3

370.3±27.0 °C at 760 mmHg

62-64 °C(lit.)

140.5±17.2 °C

0.0±0.9 mmHg at 25°C

1.596

3.64

1

3

3

17

258

0

DXGLGDHPHMLXJC-UHFFFAOYSA-N

InChI=1S/C14H12O3/c1-17-11-7-8-12(13(15)9-11)14(16)10-5-3-2-4-6-10/h2-9,15H,1H3

(2-hydroxy-4-methoxyphenyl)-phenylmethanone

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~438.14 mM)
H2O : ~1 mg/mL (~4.38 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.95 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (10.95 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 5 mg/mL (21.91 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)