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 show oxybenzone is abosorbed transdermally (through the skin) and is excreted in the urine.
...The disposition of Benzophenone-3 in rats dosed orally, intravenously and topically, has been investigated. (14)C-Benzophenone-3 was administered orally at dosages of 3, 28, 293 and 2570 mg/kg, dermally at approximate dosages of 0.2, 0.6, 0.8 and 3.2 mg/kg and intravenously at a dosage of 4.6 mg/kg. The dermal dosage of 0.6 mg/kg involved the use of a sunscreen lotion as vehicle, while the other dermal dosage levels concerned alcoholic solutions of the compound. Through all routes and dosages, Benzophenone-3 appeared to be well-absorbed and urinary secretion clearly showed to be the major route of elimination, followed by the fecal route. Only trace amounts appeared to be measured in tissues after 72 hours.
Benzophenone-3 formed part of a battery of five UV filters for which standard operating procedures for their rapid analysis in various skin layers, were established. Benzophenone-3 was included at 4.9% in a cosmetic formulation (composition not stated) applied at 3 mg/sq cm on fresh dermatomed (+/- 344 um) human skin (6 samples from different donors) put on static diffusion cells. The 3 mL receptor fluid (pH 7.4) was maintained at 32 °C and consisted of 1% bovine serum albumin, 0.9% NaCl, 0.02% KCl and 0.04% gentamycin in distilled water. The transepidermal water loss (TEWL) was recorded at each site with a Tewameter. After an exposure time of 16 hours, the skin was washed and dried with cotton swabs. The receptor fluid was collected and 16 strippings were carried out on the skin surface to determine the stratum corneum (SC) content and subsequently the epidermis was separated from the dermis. Analysis was performed by isocratic RP-HPLC2 with UV detection. Benzophenone-3 quantification led to the following results: Total amount applied 147 ug/sq cm (3 mg cream/sq cm, 4.9% Benzophenone-3); Stratum corneum (SC) 8.5 +/- 3.3 ug/sq cm; Epidermis 0.3 +/- 0.2 ug/sq cm; Dermis 0.4 +/- 0.1 ug/sq cm; Receptor fluid 1.0 +/- 0.4 ug/sq cm; Washing solution 85.7% +/- 4.5%; Recovery 93.4% +/- 3.1%. The results indicate that the SC adsorbed the greatest proportion of the applied amount (5.8%), while about 0.5% was absorbed in the viable skin and 0.7% was analyzed in the receptor fluid. ... They estimate the dermal absorption of Benzophenone-3 in respect to bioavailability after topical application to freshly dermatomed human skin for 16 hours as 1.7 ug/sq cm (1.0 ug/sq cm receptor fluid, 0.4 ug/sq cm dermis, 0.3 ug/sq cm epidermis), corresponding to 1.16% of the applied dose.
The results of a study investigating the urinary content of Benzophenone-3 after topical application to human volunteers can be considered as an indication for low bioavailability. A commercial available sunscreen containing 4% Benzophenone-3 was topically applied in an amount of 40 g to the average body area of 2.0 sq m of each of 11 volunteers and urine samples were collected subsequently during 48 hours. Although the urine is known as the major excretion route for absorbed and bioavailable material, only 0.4% (corresponding a median of 9.8 mg/volunteer) of the applied Benzophenone-3 dose was recovered in the urine within the 48 hours sampling period.
In this study, 32 volunteers were treated with 2 mg/sq cm of a basic cream formulation on a daily basis for 4 days during the first week, followed by the same treatment regime with a sunscreen containing 30% of UV-filters in total (10% 4-Methylbenzylidene Camphor, 10% Benzophenone-3 and 10% Ethylhexyl Methoxycinnamate) during the second week. Blood was collected at several time intervals on the first day of treatment and subsequently on a daily basis. All three compounds were detected in their parent forms both in plasma (Benzophenone-3 up to 300 ng/mL) and urine, showing that there is a substantial skin penetration, dermal uptake and urinary excretion in humans.
For more Absorption, Distribution and Excretion (Complete) data for 2-Hydroxy-4-methoxybenzophenone (22 total), please visit the HSDB record page.

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Metabolism / Metabolites
...The metabolism and disposition of Benzophenone-3 when administered orally in rats and mice and dermally in the rat at a uniform single dosage of 100 mg/kg bw /were described/. The same metabolites /were/ detected in all cases: 2,4-Dihydroxybenzone (DHB), 2,2'-dihydroxy-4-methoxybenzone (DHMB) and 2,3,4-trihydroxybenzophenone (THB). They have been identified in their free and conjugated (glucuronidated or sulfonated) forms.
Benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) is widely used as sunscreen for protection of human skin and hair from damage by ultraviolet (UV) radiation. In this study, we examined the metabolism of BP-3 by rat and human liver microsomes, and the estrogenic and anti-androgenic activities of the metabolites. When BP-3 was incubated with rat liver microsomes in the presence of NADPH, 2,4,5-trihydroxybenzophenone (2,4,5-triOH BP) and 3-hydroxylated BP-3 (3-OH BP-3) were newly identified as metabolites, together with previously detected metabolites 5-hydroxylated BP-3 (5-OH BP-3), a 4-desmethylated metabolite (2,4-diOH BP) and 2,3,4-trihydroxybenzophenone (2,3,4-triOH BP). In studies with recombinant rat cytochrome P450, 3-OH BP-3 and 2,4,5-triOH BP were mainly formed by CYP1A1. BP-3 was also metabolized by human liver microsomes and CYP isoforms. In estrogen reporter (ER) assays using estrogen-responsive CHO cells, 2,4-diOH BP exhibited stronger estrogenic activity, 2,3,4-triOH BP exhibited similar activity, and 5-OH BP-3, 2,4,5-triOH BP and 3-OH BP-3 showed lower activity as compared to BP-3. Structural requirements for activity were investigated in a series of 14 BP-3 derivatives. When BP-3 was incubated with liver microsomes from untreated rats or phenobarbital-, 3-methylcholanthrene-, or acetone-treated rats in the presence of NADPH, estrogenic activity was increased. However, liver microsomes from dexamethasone-treated rats showed decreased estrogenic activity due to formation of inactive 5-OH BP-3 and reduced formation of active 2,4-diOH BP. Anti-androgenic activity of BP-3 was decreased after incubation with liver microsomes.
... This study was performed to investigate the pharmacokinetics of benzophenone-3 (BZ-3) after oral administration at 100 mg/kg bw in male Sprague-Dawley rats. ... Urine and feces analysis indicate that urine was the major route of excretion, followed by feces. Further analysis of urine samples also indicates that conjugation of BZ-3 with glucuronic acid was the major systemic elimination route for the compound.
... The disposition of benzophenone-3 (BZ-3) was investigated after dermal administration of 100 mg/kg bw in Sprague-Dawley rats. ... Three metabolites were identified in plasma, 2,4-dihydroxybenzophenone (DHB) and 2,2'-dihydroxy-4-methoxybenzophenone (DHMB) were the major metabolites detected in the plasma, while 2,3,4-trihydroxybenzophenone (THB) was detected in trace amounts. Tissue distribution studies revealed that THB was the major metabolite followed by DHB (both free and conjugated) in all tissues examined. The liver contained the highest amount followed by the kidney, spleen and testes, respectively.
Benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) is widely used as sunscreen for protection of human skin and hair from damage by ultraviolet (UV) radiation. In this study, we examined the metabolism of BP-3 by rat and human liver microsomes, and the estrogenic and anti-androgenic activities of the metabolites. When BP-3 was incubated with rat liver microsomes in the presence of NADPH, 2,4,5-trihydroxybenzophenone (2,4,5-triOH BP) and 3-hydroxylated BP-3 (3-OH BP-3) were newly identified as metabolites, together with previously detected metabolites 5-hydroxylated BP-3 (5-OH BP-3), a 4-desmethylated metabolite (2,4-diOH BP) and 2,3,4-trihydroxybenzophenone (2,3,4-triOH BP). In studies with recombinant rat cytochrome P450, 3-OH BP-3 and 2,4,5-triOH BP were mainly formed by CYP1A1. BP-3 was also metabolized by human liver microsomes and CYP isoforms. In estrogen reporter (ER) assays using estrogen-responsive CHO cells, 2,4-diOH BP exhibited stronger estrogenic activity, 2,3,4-triOH BP exhibited similar activity, and 5-OH BP-3, 2,4,5-triOH BP and 3-OH BP-3 showed lower activity as compared to BP-3. Structural requirements for activity were investigated in a series of 14 BP-3 derivatives. When BP-3 was incubated with liver microsomes from untreated rats or phenobarbital-, 3-methylcholanthrene-, or acetone-treated rats in the presence of NADPH, estrogenic activity was increased. However, liver microsomes from dexamethasone-treated rats showed decreased estrogenic activity due to formation of inactive 5-OH BP-3 and reduced formation of active 2,4-diOH BP. Anti-androgenic activity of BP-3 was decreased after incubation with liver microsomes.
Route of Elimination: In vivo studies show oxybenzone is abosorbed transdermally (through the skin) and is excreted in the urine.

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Biological Half-Life
... This study was performed to investigate the pharmacokinetics of benzophenone-3 (BZ-3) after oral administration at 100 mg/kg bw in male Sprague-Dawley rats. ... The elimination pattern was biphasic with alpha and beta half-lives of elimination of 0.88 and 15.90 hr, respectively.
... The disposition of benzophenone-3 (BZ-3) was investigated after dermal administration of 100 mg/kg bw in Sprague-Dawley rats. Blood samples were collected at various intervals and the parent compound and its metabolites were analyzed by HPLC. Absorption was rapid ... The half-life of absorption was 3.45 hr... . Disappearance from the plasma was biphasic with different half-lives (1.3 for alpha phase and 15.05 hr for beta phase) ... .

Toxicity Summary
IDENTIFICATION AND USE: 2-Hydroxy-4-methoxybenzophenone (Benzophenone-3; BP-3) forms crystals or powder. It is used as an ultraviolet light absorber and stabilizer, especially in plastics and paints. It is also used as a broad-band UV filter in concentrations of up to 10% in sunscreen products alone or in combination with other UV filters. It serves not only to prevent sunburn but also to protect against the photodynamic, photosensitizing, and phototoxic effects of various drugs. HUMAN STUDIES: Photosensitivity to the UV-blocking agent benzophenone-3 has been reported. ANIMAL STUDIES: Benzophenone-3 was not a skin sensitizer in mice. Mice received benzophenone-3 in concentrations of 0; 3,125; 6,250; 12,500; 25,000 and 50,000 ppm in the diet for 13 weeks. The following effects were noted: 554 mg/kg bw/day: no adverse effects noted. 1,246 mg/kg bw/day: increased liver weight. 2,860 mg/kg bw/day: increased liver weight. 6,780 mg/kg bw/day: decreased body weight gain in males and females; increased liver weight; minimal cytoplasmic vacuolisation of hepatocytes. 16,238 mg/kg bw/day: decreased body weight gain in males and females; minimal renal lesions in males; increased liver weight; minimal cytoplasmic vacuolization of hepatocytes; decreased sperm density and increased abnormal sperm in males; increased estrous cycle length in females. In developmental studies in rats, the following effects were noted: 204 mg/kg bw/day: no deviations among the reproductive parameters studied. 828 mg/kg bw/day: no deviations among the reproductive parameters studied. 3,458 mg/kg bw/day: males: decreased right caudal, testicular and epididymal weights; decreased sperm number per caudal tissue females: prolonged cycle length. Benzophenone-3 is an endocrine-disrupting chemical based on in vivo and in vitro testing. Benzophenone-3 did not induce gene mutations in a Salmonella typhimurium photomutagenicity test. In Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 benzophenone-3 was nonmutagenic with and without microsomal activation. ECOTOXICITY STUDIES: Benzophenone-3 can disrupt agonistic behavior of male fighting fish, indicating the endocrine disrupting activity of this compound.
Oxybenzone absorbs UV-A ultraviolet rays, preventing them from reaching the skin.

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Interactions
Benzophenone-3 (BZ-3; 2-hydroxy-4-methoxybenzophenone, oxybenzone) ... penetrates the skin and can be found in the urine. The amount varies between 0.4% and 2%. This seems to be the main metabolic pathway in rats. ... To investigate the total amount of BZ-3 excreted in the urine after repeated topical whole-body applications of a sunscreen and to see if UV radiation has any effect on the amount excreted... 25 volunteers applied a commercially available sunscreen containing 4% BZ-3 morning and night for 5 days. Their urine was measured during those 5 days and during a further 5 days after the last application. They were divided into groups A (unirradiated) and B. Group B received UV radiation according to skin type: UVA between 400 and 707 J/sq cm, and UVB between 0.46 and 2.0 J/sq cm. BZ-3 in urine was analysed with a high-performance liquid chromatography method. ... The volunteers excreted 1.2-8.7% (mean 3.7%) of the total amount of BZ-3 applied. There was no significant difference between the two groups (P < 0.99, t-test)...
Mutual enhancement of dermal absorption of N,N-diethyl-m-toluamide (DEET) and oxybenzone (OBZ) has been reported recently with DEET and OBZ being active ingredients of insect repellent and sunscreen, respectively. To assess the reported enhancing effect directly, we used human urinary metabolites as biomarkers; besides, we also sought to determine the best way for concurrent use of these two products without extra absorption of either. Four dermal application methods were used: DEET only (S1), OBZ only (S2), DEET on top of OBZ (S3), and OBZ on top of DEET (S4). Among the study methods, there was a significant difference (p=0.013), which was attributed to the difference between S1 and S4, suggesting that applying OBZ over DEET on the skin lead to significantly higher absorption of DEET. Using both products in reverse order, (S3) did not result in extra DEET absorption significantly. As for OBZ permeation, no significant difference was observed among the methods. In summary, the enhancement of DEET absorption is confirmed for OBZ being applied over DEET on the skin; should concurrent use of both be necessary, applying sunscreen (OBZ) first and then insect repellent (DEET) with a 15-min interval is recommended.
Organic ultraviolet (UV) filters are used in a wide variety of products, including cosmetics, to prevent damage from UV light in tissues and industrial materials. Their extensive use has raised concerns about potential adverse effects in human health and aquatic ecosystems that accumulate these pollutants. To increase sun radiation protection, UV filters are commonly used in mixtures. Here, we studied the toxicity of binary mixtures of 4-methylbenzylidene camphor (4MBC), octyl-methoxycinnamate (OMC), and benzophenone-3 (BP-3), by evaluating the larval mortality of Chironomus riparius. Also molecular endpoints have been analyzed, including alterations in the expression levels of a gene related with the endocrine system (EcR, ecdysone receptor) and a gene related with the stress response (hsp70, heat shock protein 70). The results showed that the mortality caused by binary mixtures was similar to that observed for each compound alone; however, some differences in LC50 were observed between groups. Gene expression analysis showed that EcR mRNA levels increased in the presence of 0.1 mg/L 4MBC but returned to normal levels after exposure to mixtures of 4MBC with 0.1, 1, and 10 mg/L of BP-3 or OMC. In contrast, the hsp70 mRNA levels increased after exposure to the combinations tested of 4MBC and BP-3 or OMC mixtures. These data suggest that 4MBC, BP-3, and OMC may have antagonist effects on EcR gene transcription and a synergistic effect on hsp70 gene activation. This is the first experimental study to show the complex patterned effects of UV filter mixtures on invertebrates. The data suggest that the interactions within these chemicals mixtures are complex and show diverse effects on various endpoints.
For the last years, the increase of the number of skin cancer cases led to a growing awareness of the need of skin protection against ultraviolet (UV) radiations. Chemical UV filters are widely used in sunscreen formulations as benzophenone-3 (BP-3), a usually used broad spectrum chemical UV filter that has been shown to exercise undesirable effects after topical application. Innovative sunscreen formulations are thus necessary to provide more safety to users. Lipid carriers seem to be a good alternative to formulate chemical UV filters reducing their skin penetration while maintaining good photo-protective abilities. The aim of this work was to compare percutaneous absorption and cutaneous bioavailability of BP-3 loaded into solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), nanostructured polymeric lipid carriers (NPLC) and nanocapsules (NC). Particle size, zeta potential and in vitro sun protection factor (SPF) of nanoparticle suspensions were also investigated. Results showed that polymeric lipid carriers, comprising NPLC and NC, significantly reduced BP-3 skin permeation while exhibiting the highest SPF. This study confirms the interesting potential of NPLC and NC to formulate chemical UV filters.
For more Interactions (Complete) data for 2-Hydroxy-4-methoxybenzophenone (7 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 7400 mg/kg
LD50 Mouse ip 300 mg/kg
LD50 Rat oral > 12.8 g/kg
LD50 Rabbit dermal >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
Sunscreening Agents.
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Oxybenzone is included in the database.
Ultraviolet screen.
Topical Sunscreen Agent providing UVA/UVB coverage and approved for use by the FDA at concentrations up to 6%.
For more Therapeutic Uses (Complete) data for 2-Hydroxy-4-methoxybenzophenone (9 total), please visit the HSDB record page.

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Drug Warnings
... /Benzophenone-3/ undergoes conjugation in the body to make it water soluble. However, we do not know at what age the ability to conjugate is fully developed, and therefore for children physical filters such as titanium dioxide and/or zinc oxide might still be considered a more appropriate sunscreen component.
The manufacturers of sunscreen preparations with propellants warn that concentrating and subsequently inhaling the fumes from these preparations may be harmful or fatal. /Propellants/
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/
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. /Sunscreens/
For more Drug Warnings (Complete) data for 2-Hydroxy-4-methoxybenzophenone (8 total), please visit the HSDB record page.

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Pharmacodynamics
Oxybenzone 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.)