Absorption, Distribution and Excretion
Bisphenol F (BPF), as an endocrine disruptor (EDC) pollutant, poses a significant threat to the environment. To assess the protein-level toxicity of BPF, this study employed various spectroscopic techniques to investigate the effects of BPF on human serum albumin (HSA) at three temperatures: 283 K, 298 K, and 308 K. The results showed that BPF effectively quenched the intrinsic fluorescence of HSA through static quenching. Measurements of the number of binding sites, binding constant, thermodynamic parameters, and binding subdomains indicated that BPF can spontaneously bind to the IIA subdomain of HSA via hydrogen bonds and van der Waals forces. Furthermore, the presence of BPF significantly altered the conformation of HSA. This study provides accurate and complete fundamental data, contributing to elucidating the in vivo binding mechanism of bisphenol F (BPF) to human serum albumin (HSA) and aiding in understanding its impact on protein function during blood transport and distribution.
This study investigated the distribution of bisphenol F (4,4'-dihydroxydiphenylmethane, BPF) in female Sprague-Dawley rats. Pregnant and non-pregnant rats were administered a single dose of 7 or 100 mg/kg [(3)H]BPF by gavage and housed in metabolic cages for 96 hours. BPF residues were primarily excreted in the urine (43-54% of the administered dose), containing at least six different metabolites; a small amount was excreted in the feces (15-20% of the administered dose). Sulfate esterase treatment and subsequent high-performance liquid chromatography analysis showed that the main metabolite in the urine (accounting for more than 50% of the radioactivity in the urine) was a sulfate conjugate of BPF. After 96 hours, BPF residues were detected in all tissues examined, with the highest residues in the liver (0.5% of the administered dose). In pregnant rats administered the drug on day 17 of gestation, BPF residues were detected in the uterus, placenta, amniotic fluid, and fetus (0.9-1.3% of the administered dose). At the end of the study, a significant amount of radioactive material remained in the digestive tract (8-10% of the administered dose). Following a single oral administration of [(3)H]BPF, 46% of the radioactive material was excreted via bile within 6 hours. In rats, BPF and/or its metabolites likely undergo enterohepatic circulation, which may explain the high level of residual excretion 4 days after BPF administration. This bisphenol is effectively absorbed by female rats and distributed to the reproductive tract, and its residues can cross the placental barrier in late pregnancy.

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Metabolism/Metabolites
Bisphenol F [4,4'-dihydroxydiphenylmethane] (BPF) has a wide range of industrial applications (lining coatings, adhesives, plastics, beverage and food can coatings). Free monomers of this bisphenol can be released into the environment and enter the food chain, potentially leading to human exposure to low doses of BPF. This synthetic compound has been reported to have estrogenic activity. A study on the distribution and metabolism of BPF in rats showed that BPF forms multiple metabolites and involves multiple biotransformation pathways. In this study, we investigated the in vitro biotransformation of radiolabeled BPF using subcellular fractions of rat and human livers. BPF metabolites were isolated and purified using high-performance liquid chromatography (HPLC) and analyzed by mass spectrometry (MS), mass spectrometry (MS(n)), and nuclear magnetic resonance (NMR). Many of these metabolites were identified for the first time in mammals and humans. BPF is metabolized to the corresponding glucuronides and sulfates (liver S9 fraction). In addition to these phase II biotransformation products, various hydroxylated metabolites and structure-related nonpolar metabolites are generated. These phase I metabolic pathways dominate in liver microsomal incubation experiments and are also present in liver S9 fraction incubation experiments. The formation of the major metabolites, namely meta-hydroxylated BPF and ortho-hydroxylated BPF (catechol BPF), depends on P450 enzymes, as does the formation of less polar metabolites (identified as BPF dimers). The formation of catechols and dimer metabolites corresponds to the biotransformation pathway shared by bisphenol F (BPF), other bisphenol compounds, and estradiol. Bisphenol A (BPA) and bisphenol F (BPF) are widely used in the manufacture of plastics and epoxy resins. Both compounds are known to exist in the environment and are food contaminants, thus humans are exposed to them over a long period, albeit at low levels. However, the metabolic pathways and potential bioactivations of these compounds in human cell lines are not fully elucidated. In this study, researchers used a novel and highly efficient genotoxicity assay based on histone H2AX phosphorylation to investigate the biotransformation capacity of BPA and BPF in human cells (intestinal cell line: LS174T, hepatocellular carcinoma cell line: HepG2, and kidney cell line: ACHN), focusing on the cytotoxicity and genotoxicity of these two bisphenols. Both BPA and BPF were extensively metabolized in the HepG2 and LS174T cell lines, with stronger biotransformation capacity observed in intestinal cells than in hepatocytes. Both cell lines produced glucuronide and sulfate conjugates of BPA. Conversely, the ACHN cell line lacked the ability to metabolize either of these bisphenol compounds. Researchers tested the cytotoxicity of BPA, BPF, and the BPF metabolite dihydroxybenzophenone (DHB) in rats. In the three cell lines used, similar toxicity ranges were observed: DHB exhibited weak cytotoxicity, BPF moderate cytotoxicity, and BPA was the most cytotoxic of the tested compounds. No genotoxicity was found in either BPA or DHB in any cell line. BPF showed significant genotoxicity in HepG2 cells. These results indicate that certain human cell lines can extensively metabolize bisphenol compounds and confirm the genotoxicity of bisphenol F. Bisphenol F (BPF) is present in the environment and is also a food contaminant. Therefore, human exposure to BPF is possible, and it is necessary to assess this risk. Studies have shown that BPF has genotoxic and endocrine-disrupting properties in the human hepatocellular carcinoma cell line (HepG2), which is a model system for studying the toxicity of exogenous substances. This study investigated the ability of HepG2 cells to biotransform BPF, as metabolism may affect the observed effects of BPF, and compared this metabolic capacity with that of human hepatocytes. Cells were incubated with (3)H-BPF for 24 hours. The culture medium was then concentrated, and the metabolites were separated by high performance liquid chromatography and identified by mass spectrometry. The HepG2 cell line metabolized BPF to a large amount of the corresponding sulfate. BPF is metabolized to sulfate and glucuronide in human hepatocytes, but there are inter-individual differences. The metabolism of BPF in HepG2 cells and human hepatocytes suggests the existence of a detoxification pathway. Therefore, the metabolic capacity of the two cell models is different. Therefore, it is important to simultaneously determine the biotransformation capacity of the model used to infer in vivo effects when assessing the toxic effects of a substance in vitro.

Toxicity Summary
Identification and Uses: Bisphenol F is a mixture of isomers and oligomers. It is widely used in the manufacture of epoxy resins and coatings, including varnishes, paints, linings, adhesives, plastics, pipes, dental sealants, and food packaging. Human Studies: A retrospective analysis of patch testing results for plastic and adhesive allergens was conducted. A total of 444 patients underwent patch testing, with the specialist series using up to 56 plastic and adhesive allergens and the baseline series using up to 5. Positive reaction rates were compared with other patch test reports. Of all patients, 97 (22%) experienced irritation, and 201 (45%) experienced at least one allergic reaction. The highest sensitization rates were observed with bis(2-dimethylaminoethyl) ether 1%, benzoyl peroxide 1%, epoxy resins, bisphenol F 0.25%, 2-hydroxyethyl methacrylate 2%, and 2-hydroxyethyl acrylate 0.1%. Using a specialized series of detection methods, a total of 193 patients with plastic and adhesive allergies were identified, of whom 162 were not identified by baseline series detection alone. Occupational exposure to bisphenol F (BPF) occurs through inhalation of dust and skin contact with the compound in workplaces where BPF is produced or used. Monitoring data show that the general population can be exposed to BPF through inhalation of indoor dust, ingestion of carbonated beverages, and skin contact with consumer products containing BPF resins and coatings. BPF primarily causes necrotizing changes in human peripheral blood mononuclear cells. BPF exhibits anti-androgenic activity in human cell lines. At non-cytotoxic concentrations, BPF effectively induces DNA fragmentation in HepG2 cells, but did not elicit a positive response in the micronucleus assay. Animal studies: Oral administration of BPF to young rats for at least 28 days did not detect significant endocrine-mediated changes, therefore concluding that BPF has no endocrine-mediated effect. The primary effect of this chemical is hepatotoxicity based on clinical biochemical indicators and liver weight, but no histopathological changes were observed. Female rats administered bisphenol F experienced weight loss, accompanied by decreased serum total cholesterol, glucose, and albumin levels. When the estrogenic activity of bisphenols was assessed using a recombinant yeast assay, bisphenol F was the most potent among the compounds in this group. In the Ames assay, bisphenol F did not induce any gene mutations in the bacteria.

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Interactions
Based on the recombinant yeast assay, the estrogenic activities of BPA, BPAF, BPAP, and BPF were tested. Six mixtures were designed based on the results, each with an equivalent toxicity ratio (EC10 or EC50). The EC50 values for BPA, BPAF, BPAP, and BPF were 6.81 × 10⁻⁶ mol/L, 7.44 × 10⁻⁷ mol/L, 1.43 × 10⁻⁵ mol/L, and 7.52 × 10⁻⁶ mol/L, respectively, indicating that the estrogenic activity of the four bisphenols was in the order BPAF > BPA > BPF > BPAP. Experiments show that different combined effects are produced when BPA is mixed with BPAF, BPAP, and BPF in different proportions. ...

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Non-human toxicity values
Oral LD50 in rats: 4950 mg/kg

[1]. New Phenolic Derivatives from Galeola faberi. Planta Med. 1993 Aug;59(4):363-5.

Bisphenol F is a bisphenol with a methane structure in which two hydrogen atoms are replaced by 4-hydroxyphenyl groups. It is an environmental food contaminant and an exogenous estrogen. It is a diarylmethane and also a bisphenol. 4,4'-Methylenediphenol has been reported to be detected in Dracocephalum ruyschiana, Galeola faberi, and other organisms for which relevant data are available.

C13H12O2

200.2332

200.083

620-92-8

4,4'-Dihydroxydiphenylmethane-d10;1794786-93-8

12111

White to off-white solid powder

1.2±0.1 g/cm3

390.0±22.0 °C at 760 mmHg

162-164 °C

192.9±16.9 °C

0.0±0.9 mmHg at 25°C

1.635

2.73

2

2

2

15

157

0

PXKLMJQFEQBVLD-UHFFFAOYSA-N

InChI=1S/C13H12O2/c14-12-5-1-10(2-6-12)9-11-3-7-13(15)8-4-11/h1-8,14-15H,9H2

4-[(4-hydroxyphenyl)methyl]phenol

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 (~499.40 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.49 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 (12.49 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 (12.49 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.)