Absorption, Distribution and Excretion
Dioxybenzone is a derivative of benzophenone. In monkeys, percutaneous absorption of benzophenone was observed. Other derivatives of benzophenone are capable of crossing the skin via direct penetration through the intercellular laminae of the stratum corneum (SC) or by passive diffusion by high-concentration gradient into the systemic circulation, where they are transported to different tissues including liver and brain.
No pharmacokinetic data available.
No pharmacokinetic data available.
No pharmacokinetic data available.
Information on the cutaneous absorption, distribution, and elimination of most topically applied sunscreen agents is limited. Solvents used in sunscreen products affect the stability and binding of the drug to the skin; in general, alcoholic solvents allow for the most rapid and deepest epidermal penetration of sunscreens. It appears that sunscreen agents are absorbed by the intact epidermis to varying degrees. /Sunscreens/

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Metabolism / Metabolites
No pharmacokinetic data available.
The pharmacokinetics of benzophenone-3 (BZ-3) was studied in rats. Male Sprague-Dawley-rats were administered 0 or 100 mg/kg oxybenzone orally. Blood samples were collected from some rats for up to 20 hours post dosing and analyzed for plasma oxybenzone by high performance liquid chromatography. Urine, feces, and expired air samples were collected for up to 96 hours and analyzed for BZ-3 metabolites. Selected rats were killed 6 hours after dosing to determine the tissue distribution of BZ-3. The kinetic behavior of oxybenzone was investigated by applying the plasma BZ-3 data to standard pharmacokinetic models. The pharmacokinetic behavior of BZ-3 in the blood could be described by a two compartment model, the halflives for distribution and elimination being 0.88 and 15.90 hours, respectively. The absorption halflife was 0.71 hour. The maximum plasma concentration, 25.6 micrograms per milliliter, occurred 3 hours after dosing. The liver had the largest total concentration of BZ-3, 6.47% of the dose, followed by the kidney, spleen, intestines, and heart in that order. BZ-3 was detected in the testes only after acid hydrolysis and in only one of six rats; however, the concentration represented 1.8% of the dose. Approximately 60% of the dose was excreted in the urine and feces over 96 hours. Urine was the predominant route of excretion. Most of the excreted dose consisted of compounds conjugated with macromolecules. Enzyme hydrolysis of the urine samples with beta-glucuronidase showed that most of the excreted dose was conjugated with glucuronic-acid. Identified metabolites included 2,4-dihydroxybenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, and 2,3,4-trihydroxybenzophenone. The authors conclude that following oral administration, oxybenzone is rapidly absorbed from the gastrointestinal tract and distributed primarily to the liver, kidneys, and testes, indicating that the liver may be the major organ involved in BZ-3 elimination.
Metabolism of the ultraviolet absorber benzophenone-3 (BZ3) by Sprague-Dawley-rats was studied. Rats were fed 100 mg/kg BZ3 by gavage and blood, tissue, urine, and fecal samples were examined at various time points. BZ3 and its metabolites were identified in plasma as soon as 5 minutes after administration. 2,4-Dihydroxybenzophenone (DHB), 2,2'-dihydroxy-4-methoxybenzophenone, and 2,3,4-trihydroxybenzophenone were detected in the blood after 30 minutes. DHB was the major metabolite found in tissue, urine, and fecal samples. The parent compound and metabolites appeared bound to macromolecules or in conjugated forms in plasma, as free compounds and conjugates in tissues, and extensively conjugated in feces and urine. The primary route of elimination was urinary and O-dealkylation was found to be the major metabolic pathway.
The metabolism and fate of benzophenone-3 (BZ-3) was studied in male Sprague-Dawley-rats and male B6C3F1-mice after oral administration of 100mg/kg body weight. Blood samples were collected at 5 minutes to 20 hours after administration. For a tissue distribution study, tissue samples were obtained 6 hours after administration of the BZ-3. For urinary and fecal excretion studies, mice and rats were placed in glass metabolism cages for 96 hours after administration of BZ-3. In rats, BZ-3 exhibited a biphasic elimination in plasma with alpha and beta elimination half lives of 0.9 and 15.9 hours, as compared to a single phase elimination half life of 1.8 hours in mice. Absorption was faster and peak plasma concentrations were reached faster in mice than rats. In the tissues studied, accumulation of the parent compound was highest in the liver, with higher amounts in the rat than mouse. 2,4-Dihydroxybenzophenone (DHB) was the major metabolite in the tissues, with higher amounts detected in the rat than the mouse. In rats, the urine was the major route of excretion of BZ-3 and DHB. In mice, elimination was divided between the urine and feces, with 2,3,4-trihydroxybenzophenone (THB) as the primary metabolite. Trace amounts of 2,2'-dihydroxy-4-methoxybenzophenone (DHMB) were found in the urine and feces of both species. The peak excretion in the urine of both the parent compound and DHB was earlier in rats than in mice. Most of the excretion of the BZ-3 and DHB in the feces was complete within 24 hours for both species, although the total fecal excretion for the parent compound was almost double in mice than rats, and for DHB was significantly less in mice than rats. The authors postulate that variations in the absorption rates, distribution patterns, and metabolism of BZ-3 in rats and mice may be related to species specific quantitative and qualitative differences in enzyme activities.

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Biological Half-Life
No pharmacokinetic data available.

Toxicity Summary
IDENTIFICATION AND USE: 2,2'-Dihydroxy-4-methoxybenzophenone (dioxybenzone) is a solid, which is used as a benzophenone sunscreen agent. Many sunscreens contain UVA-absorbing avobenzone or a benzophenone (such as dioxybenzone, oxybenzone, or sulisobenzone), in addition to UVB-absorbing chemical ingredients (some of which also contribute to UVA protection). HUMAN STUDIES: There are no human toxicity studies available. Although it has been suggested that benzophenone derivatives may protect against photosensitivity reactions to photosensitizing drugs (e.g., chlordiazepoxide, chlorpromazine, demeclocycline, hydrochlorothiazide, nalidixic acid, nystatin, sulfisoxazole), most clinicians agree that these sunscreens provide, at most, only limited protection for patients who are sensitive to these drugs. ANIMAL STUDIES: Dioxybenzone was nonmutagenic when assayed directly and was weakly mutagenic with metabolic activation in Salmonella strain TA1537. Dioxybenzone was not mutagenic in vivo in the mouse micronucleus test. In mice, signs of toxicity including decreased activity, piloerection, and exophthalmus were observed at doses of 166-5000 mg/kg. Dioxybenzone given orally delayed skin tumors and inhibited tumor incidence and tumor burden in the two-stage mouse skin carcinogenesis model. ECOTOXICITY STUDIES: Dioxybenzone was more toxic to the two tested coral species than other benzophenone derivatives.

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Protein Binding
No pharmacokinetic data available.

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Interactions
Amiodarone hydrochloride is currently being investigated in the United States as a cardiac antiarrhythmic agent. Previous reports from Europe indicate that amiodarone occasionally causes a cutaneous photosensitivity reaction that may be associated with a peculiar blue-gray discoloration of the skin. In addition, corneal microdeposits of yellow-brown granules may occur. We report observations on a case of amiodarone photosensitivity and corneal deposits developing in a patient shortly after amiodarone therapy was begun. Symptoms included burning and stinging of the skin, with redness and swelling that developed immediately after sun exposure. Phototesting showed that the photoactivating wavelengths were primarily in the long-wave UV-A spectrum between 350 and 380 nm. Prior application of a 10% dioxybenzone sunscreen greatly reduced the phototest reaction. Four weeks after the patient stopped taking amiodarone, the UV-A sensitivity was still present but diminished, and by ten weeks it had disappeared. During this time, the corneal deposits were reduced in number. All ten patients we have treated so far with amiodarone for cardiac arrhythmias have shown a similar photosensitivity, indicating that this is probably a phototoxic reaction.
Sunscreens are widely utilized due to the adverse effects of ultraviolet (UV) radiation on human health. The safety of their active ingredients as well as that of any modified versions generated during use is thus of concern. Chlorine is used as a chemical disinfectant in swimming pools. Its reactivity suggests sunscreen components might be chlorinated, altering their absorptive and/or cytotoxic properties. To test this hypothesis, the UV-filters oxybenzone, dioxybenzone, and sulisobenzone were reacted with chlorinating agents and their UV spectra analyzed. In all cases, a decrease in UV absorbance was observed. Given that chlorinated compounds can be cytotoxic, the effect of modified UV-filters on cell viability was examined. Chlorinated oxybenzone and dioxybenzone caused significantly more cell death than unchlorinated controls. In contrast, chlorination of sulisobenzone actually reduced cytotoxicity of the parent compound. Exposing a commercially available sunscreen product to chlorine also resulted in decreased UV absorbance, loss of UV protection, and enhanced cytotoxicity. These observations show chlorination of sunscreen active ingredients can dramatically decrease UV absorption and generate derivatives with altered biological properties.
BACKGROUND: Sunscreen compounds with added benefit of skin cancer prevention have both public and commercial interests. Our earlier study using the Epstein-Barr virus early antigen in vitro assay reported on skin cancer chemoprevention potential of benzophenone sunscreens. We now report the in vivo antitumor activity of two of the benzophenone sunscreens which tested positively in the in vitro assay, octabenzone (UV-1) and dioxybenzone (UV-2), in the two-stage mouse skin carcinogenesis model using (+/-)-(E)-4-methyl-2-[-(E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) as inducer and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) as promoter. MATERIALS AND METHODS: Pathogen-free, female hairless mice of HOS:HR-1 strain, 15 animals per control and test groups, were used. Skin tumors were induced by a single dose of NOR-1 (390 nmol in 100 uL of acetone). One week later, TPA (1.7 nmol in 100 uL of acetone) was applied to skin twice weekly for 20 weeks as tumor a promoter. The test compounds UV-I or UV-2 were administered at 0.0025% to mice through drinking water ad libitum, starting one week prior to and stopping one week after tumor initiation. All animals were examined weekly for the development of skin papillomas. RESULTS: In both UV-1- and UV-2-treated mice, a two-week delay in tumor appearance, and significant inhibition (p<0.001) of tumor incidence (50% and 60%, respectively) and tumor burden (papilloma inhibition/mouse, 50% and 70%, respectively) were observed when compared to the positive control group. UV-2 (dihydroxy derivative) was a more potent inhibitor of skin tumor than UV-1 (monohydroxy derivative), which followed their antioxidant activity ranking. CONCLUSION: The results affirm the skin cancer chemoprevention potential of orally-ingested benzophenone sunscreens in mice and warrant studies in humans to validate synergistic protection achievable by complementation of oral and topical sunscreen usage.
This study aimed to qualify photosafety screening on the basis of photochemical and pharmacokinetic (PK) data on dermally applied chemicals. Six benzophenone derivatives (BZPs) were selected as model compounds, and in vitro photochemical/phototoxic characterization and dermal cassette-dosing PK study were carried out. For comparison, an in vivo phototoxicity test was also conducted. All of the BZPs exhibited strong UVA/UVB absorption with molar extinction coefficients of over 2000 M(-1) x cm(-1), and benzophenone and ketoprofen exhibited significant reactive oxygen species (ROS) generation upon exposure to simulated sunlight (about 2.0 mW/sq cm); however, ROS generation from sulisobenzone and dioxybenzone was negligible. To verify in vitro phototoxicity, a 3T3 neutral red uptake phototoxicity test was carried out, and benzophenone and ketoprofen were categorized to be phototoxic chemicals. The dermal PK parameters of ketoprofen were indicative of the highest dermal distribution of all BZPs tested. On the basis of its in vitro photochemical/phototoxic and PK data, ketoprofen was deduced to be highly phototoxic. The rank of predicted phototoxic risk of BZPs on the basis of the proposed screening strategy was almost in agreement with the results from the in vivo phototoxicity test. The combined use of photochemical and cassette-dosing PK data would provide reliable predictions of phototoxic risk for candidates with high productivity.
The sunscreen protection factor (SPF) is essentially a factor that accounts for all the variables (UV absorption range, maximum absorbance, molar absorptivity, concentration, pH, solvent) that determine the effectiveness of a sunscreen product. SPFs are derived by dividing the minimum dose of sunlight needed to produce erythema (MED) on sunscreen-protected skin by that dose producing the same effect on unprotected skin. The US Food and Drug Administration's (FDA) approved method for determining SPFs relies on a solar simulator. Sunlight generally cannot be used because it is too variable. However, some clinicians believe that use of a solar simulator on a small number of test subjects may not provide an accurate indication of a product's effectiveness. Sunscreens with SPFs of 2 to less than 4 afford only minimum protection against sunburn but permit suntanning; SPFs of 4 to less than 8 allow moderate sunburn protection and UVB exposures of 4-8 times longer than unprotected skin but permit some suntanning; SPFs of 8 to less than 12 provide high sunburn protection and allow UVB exposures of 8-12 times longer than unprotected skin and permit limited suntanning; SPFs of 12 to less than 20 provide very high sunburn protection and UVB exposures of 12-20 times longer than unprotected skin and permit little or no suntanning; and SPFs of 20-30 provide ultra high sunburn protection, offering the most protection and permitting no suntanning. Effective May 21, 2001, the FDA is condensing these categories into 3 broader groups of sunscreen products and has generalized the category designations. Sunscreens with SPFs of 2 to less than 12 afford minimal protection against sunburn and tanning; SPFs of 12 to less than 30 allow moderate sunburn or suntan protection; and SPFs of 30 and above provide high protection against sunburn or tanning. /Sunscreens/

2,2'-dihydroxy-4-methoxybenzophenone is a yellow powder. (NTP, 1992)
2,2'-Dihydroxy-4-methoxybenzophenone is a member of benzophenones.
Dioxybenzone, or benzophenone-8, is an organic compound derived from [DB01878] that is used as a sunscreen agent. It absorbed UV-B and UV-AII rays. Dioxybenzone is an approved sunscreen ingredient in concentrations up to 3%.

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Drug Indication
Indicated for use as an active sunscreen agent.

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Mechanism of Action
Emitted by the sun, UVA-II rays, which range at 320–400 nm and are not absorbed by the ozone layer, and UVB rays, which range 290–320 nm and are partially absorbed by the ozone layer and exert a damaging effect on human skin, including basal cell carcinoma and melanoma. As a chemical filter, dioxybenzone absorb these rays to prevent their penetration into the skin and attenuate long-term skin damage caused by UV radiation from the sun. In a rat uterine cytosolic estrogen receptor (ER) competitive binding assay, dioxybenzone was not found to be a ER-binder.

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Therapeutic Uses
/EXPL THER/ BACKGROUND: Sunscreen compounds with added benefit of skin cancer prevention have both public and commercial interests. Our earlier study using the Epstein-Barr virus early antigen in vitro assay reported on skin cancer chemoprevention potential of benzophenone sunscreens. We now report the in vivo antitumor activity of two of the benzophenone sunscreens which tested positively in the in vitro assay, octabenzone (UV-1) and dioxybenzone (UV-2), in the two-stage mouse skin carcinogenesis model using (+/-)-(E)-4-methyl-2-[-(E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) as inducer and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) as promoter. MATERIALS AND METHODS: Pathogen-free, female hairless mice of HOS:HR-1 strain, 15 animals per control and test groups, were used. Skin tumors were induced by a single dose of NOR-1 (390 nmol in 100 uL of acetone). One week later, TPA (1.7 nmol in 100 uL of acetone) was applied to skin twice weekly for 20 weeks as tumor a promoter. The test compounds UV-I or UV-2 were administered at 0.0025% to mice through drinking water ad libitum, starting one week prior to and stopping one week after tumor initiation. All animals were examined weekly for the development of skin papillomas. RESULTS: In both UV-1- and UV-2-treated mice, a two-week delay in tumor appearance, and significant inhibition (p<0.001) of tumor incidence (50% and 60%, respectively) and tumor burden (papilloma inhibition/mouse, 50% and 70%, respectively) were observed when compared to the positive control group. UV-2 (dihydroxy derivative) was a more potent inhibitor of skin tumor than UV-1 (monohydroxy derivative), which followed their antioxidant activity ranking. CONCLUSION: The results affirm the skin cancer chemoprevention potential of orally-ingested benzophenone sunscreens in mice and warrant studies in humans to validate synergistic protection achievable by complementation of oral and topical sunscreen usage.
Sunscreen agents are used to prevent sunburn and premature aging of the skin, and to reduce the incidence of solar or actinic-induced keratoses, skin cancers, tanning, and other harmful effects of the sun. Some data suggest that carcinogenesis and photoaging can occur at doses of UV radiation below that required to produce a sunburn (i.e., suberythemal doses). Most clinicians agree that the liberal and regular use of an effective sunscreen is therapeutically desirable and not just cosmetically desirable, especially in light-skinned people with blue eyes, red hair, and/or freckles who are most susceptible to the acute and chronic harmful effects of sunlight. /Sunscreens/

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Drug Warnings
Because the absorptive characteristics of skin of children younger than 6 months of age may differ from those of adults and because the immaturity of metabolic and excretory pathways of these children may limit their ability to eliminate any percutaneously absorbed sunscreen agent, sunscreen products should be used in children younger than 6 months of age only as directed by a clinician. It is possible that the characteristics of geriatric skin also differ from those of skin in younger adults, but these characteristics and the need for special considerations regarding use of sunscreen preparations in this age group are poorly understood. /Sunscreens/
If skin irritation or a rash occurs during use of a sunscreen product, use of the sunscreen should be discontinued and the sunscreen washed off. If irritation persists, a physician should be consulted. Contact of sunscreen agents with the eyes should be avoided. If the sunscreen comes in contact with the eyes, the affected eye(s) should be flushed thoroughly with water. /Sunscreens/
Little information is available regarding the safety of chronic sunscreen usage, but commercially available physical and chemical sunscreens appear to have a low incidence of adverse effects. Derivatives of PABA, benzophenone, cinnamic acid, and salicylate and 2-phenylbenzimidazole-5-sulfonic acid have caused skin irritation including burning, stinging, pruritus, and erythema on rare occasions. Skin irritation produced by padimate A appears to be dose related. /Sunscreens/
Although it has been suggested that benzophenone derivatives may protect against photosensitivity reactions to photosensitizing drugs (e.g., chlordiazepoxide, chlorpromazine, demeclocycline, hydrochlorothiazide, nalidixic acid, nystatin, sulfisoxazole), most clinicians agree that these sunscreens provide, at most, only limited protection for patients who are sensitive to these drugs. /Benzophenone derivatives/
Even when using a sunscreen, prolonged sunlight exposure should be avoided and protective clothing should be worn by all persons, particularly those that are fair-skinned, blue-eyed, or blond. Until a protective tan develops, initial sunlight exposures should be limited to short periods, which may be gradually lengthened. /Sunscreens/

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Pharmacodynamics
Dioxybenzone is a sunscreen agent and chemical UV filter that absorbs UV-B rays and UV-AII rays to limit their penetration into human skin. In a screening protocol consisting of the _in vitro_ EBV-EA activation assay followed by the _in vivo_ confirmation test in the two-stage mouse skin cancer model utilizing NOR-1 as inducer and TPA as promoter of tumour, dioxybenzone exhibited a significant chemopreventive activity against mouse skin carcinogenesis which correlated with their antioxidant potency. There is some evidence that suggests some benzophenones and their hydroxylated metabolites act as weak estrogens in the environment; however similar effect of dioxybenzone has not been established.

C14H12O4

244.24

244.073

131-53-3

Dioxybenzone-d3

8569

Yellow powder

1.3±0.1 g/cm3

375.0±0.0 °C at 760 mmHg

73-75 °C(lit.)

146.0±18.6 °C

0.0±0.8 mmHg at 25°C

1.624

3.93

2

4

3

18

292

0

O(C([H])([H])[H])C1C([H])=C([H])C(=C(C=1[H])O[H])C(C1=C([H])C([H])=C([H])C([H])=C1O[H])=O

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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 (409.43 mM)
H2O: 1 mg/mL (4.09 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.24 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 (10.24 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 (10.24 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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 (Please use freshly prepared in vivo formulations for optimal results.)