Absorption, Distribution and Excretion
Following oral administration, parabens are rapidly absorbed, metabolized, and excreted. Metabolic responses and transformations in mammals vary depending on ester chain length, animal species, route of administration, and test dose. The metabolism of parabens in humans appears to be most similar to that in dogs. The rate of metabolite excretion appears to decrease with increasing ester molecular weight. /4-Hydroxybenzoate (parabens)/ Following intravenous infusion of methylparaben into dogs, unhydrolyzed methylparaben was detected in the brain, spleen, and pancreas. In the liver, kidneys, and muscle, it is immediately hydrolyzed to parabens… Six hours after oral administration of 1.0 g/kg methylparaben to dogs, peak plasma concentrations of free and total methylparaben reached 630 and 867 μg/cm³, respectively. The vast majority was excreted after 48 hours.
Following multiple administrations of gentamicin preparations containing parabens as preservatives to six preterm infants, the excretion and metabolism of methylparaben were monitored. The mean recovery rate of parabens in urine was 82.6%. Urinary excretion rates ranged from 13.2% to 88.1%.
…A study using human volunteers measured the content of methylparaben in the stratum corneum. Cosmetic lotions containing 0.15%, 0.25%, and 0.5% (w/v) methylparaben were applied once to the forearm (42 cm²) of one male and one female subject. At 1, 2, 5, and 12 hours after application, a small area was wiped off with a damp cotton swab, and then methylparaben was extracted for 25 minutes using a glass graduated cylinder (3.1 cm²) containing 0.5 mL of ethanol. The concentration of methylparaben in ethanol solvent was determined using high-performance liquid chromatography (HPLC, for 1, 2, and 5-hour processing) and gas chromatography-mass spectrometry (GC/MS, for other processing). …After a single application, the concentration of methylparaben peaked 1–2 hours after application (the higher the concentration, the slightly higher the peak), and returned to baseline levels after 12 hours. /In another study,/healthy Japanese adults (1 male, 11 females) applied a lotion (6 subjects) or a combination lotion and emulsion (6 subjects) containing methylparaben (concentration not specified) twice daily for 1 month. The concentration of methylparaben in the stratum corneum was determined using gas chromatography-mass spectrometry (GC/MS) at time points: before first application, 1, 2, 3, and 4 weeks after application, and 2 days after discontinuation. …Repeated administration led to an increase in the concentration of methylparaben in the stratum corneum over time, whether the emulsion was used alone or in combination with other emulsions. After two days, the concentration of methylparaben returned to pre-treatment levels. For more complete data on the absorption, distribution, and excretion of methylparaben (7 types), please visit the HSDB record page. Metabolites/Metabolites In mice, rats, rabbits, or dogs, methylparaben is excreted in the urine as unmetabolized benzoate, para-hydroxybenzoic acid, para-hydroxyhippuric acid (para-hydroxybenzoylglycine), ester glucuronide, ether glucuronide, or ether sulfate. After oral administration, parabens are rapidly absorbed, metabolized, and excreted. Metabolic responses and transformations in mammals vary depending on ester chain length, animal species, route of administration, and test dose. The metabolism of parabens in humans appears to be most similar to that in dogs. The excretion rate of metabolites appeared to decrease with increasing ester molecular weight. /4-Hydroxybenzoate (p-hydroxybenzoate)/
/This study investigated the metabolic pathway of /methylparaben/ in rabbits. The compound was administered via gastric tube, and urine was analyzed by paper chromatography. Three major metabolites were identified: p-hydroxybenzoic acid, p-hydroxyhippuric acid, and p-carboxyphenyl glucuronide, as well as two minor metabolites: p-hydroxybenzoyl glucuronide and p-carboxyphenyl sulfate. Rabbits orally administered 0.4 or 0.8 g/kg of methylparaben, ethylparaben, propylparaben, or butylparaben excreted only 0.2% to 0.9% of the unmetabolized ester within 24 hours. The urinary excretion rate of p-hydroxybenzoic acid decreased with increasing alkyl carbon chain length of the p-hydroxybenzoate. The excretion rate of the bound acid was approximately the same as that of the free acid. Twenty-four hours after administration of parabens, of the recovered parabens, 25% to 39% were in the form of parabens as parabens acid, 15% to 29% as glycine conjugates, 5% to 8% as ester glucuronides, 10% to 18% as ether glucuronides, and 7% to 12% as sulfates. The metabolism of methylparaben, ethylparaben, and propylparaben was studied in rats. Animals were orally administered 100 mg of the esters. Blood and urine were collected periodically and analyzed by paper chromatography. Paraben metabolites were detected in urine 30 minutes after administration. Unmetabolized parabens were not detected. Excretion of metabolites peaked 90 minutes after administration; thereafter, excretion gradually decreased. Hydroxyhippuric acid appeared in urine 30 minutes after administration; its concentration then increased uniformly over the next 4 hours. Glucuronide and ether sulfate metabolites appear only within 30 to 75 minutes after ingestion. After 90 minutes, 67% to 75% of the total paraben dose is excreted as parabens, 10% to 12.5% as parahydroxyhippuric acid, and 8% to 10% as glucuronic acid derivatives. The concentration of free parabens in the blood is extremely low. The concentration rises continuously within 1 hour after ingestion, but then decreases and stabilizes within 1 to 2 hours after ingestion. The authors conclude that the detoxification process of parabens occurs in two phases: (1) absorption of parabens and excretion of parabens in urine; (2) metabolic detoxification via the conjugation of glucuronic acid, sulfonates, and glycine. For more complete metabolite/metabolite data on methyl parabens (10 metabolites in total), please visit the HSDB record page.

Toxicity Summary
Identification and Uses: Methylparaben is a methyl ester of parabens. It is a stable, non-volatile compound used as an antimicrobial preservative in food, pharmaceuticals, and cosmetics. Human Exposure and Toxicity: Parabens have been reported to cause contact dermatitis in some individuals upon skin contact. Parabens are associated with numerous cases of contact sensitization caused by skin contact; however, the mechanism of this sensitization is unclear. Sensitization can occur when medications containing parabens are applied to damaged or broken skin. While there is a lack of rigorous evidence of sensitization from ingestion of parabens, there have been reports of allergic reactions from ingestion. Animal Studies: Acute toxicity studies in animals have shown that methylparaben is virtually non-toxic when administered orally and parenterally. In individuals with normal skin, methylparaben causes minimal irritation and sensitization. In long-term dosing studies, the reported no-observed-effect level (NOEL) is as high as 1050 mg/kg, and the projected no-observed-adverse-effect level (NOAEL) in rats is 5700 mg/kg. Methylparaben does increase chromosomal aberrations in Chinese hamster ovarian cells. No carcinogenicity was observed in subcutaneous injection or vaginal administration of methylparaben to mice or rats. Methylparaben is not teratogenic in rabbits, rats, mice, or hamsters and is not embryotoxic. Methylparaben had no effect in uterine nutrition studies conducted in two laboratories, but an effect was observed in other studies in another laboratory. An in vitro study showed that sperm motility was lost at concentrations as low as 6 mg/mL; however, an in vivo study showed that adding 0.1% or 1.0% methylparaben to the diet of mice did not produce sperm toxicity. Another study added methylparaben to the diet of rats, with an estimated average dose as high as 1141.1 mg/kg/day, and found no adverse effects on the testes. Ecotoxicity studies: Methylparaben was used to determine vitellogenin levels and perform DNA microarray analysis in medaka. The results showed that at a methylparaben concentration of 630 μg/L, vitellogenin levels significantly increased in male medaka; while at a methylparaben concentration of 10 μg/L, the expression levels of genes encoding proteins such as vitellogenin and chorionic villiogenin increased. Interactions… Using human intestinal cells (Caco-2 cells), it was observed that at 0.25-0.5% (v/v) ethanol concentrations potentially present in the human intestine, the rate of hydrolysis of parabens to parahydroxybenzoic acid was significantly reduced. In Caco-2 cell homogenates, 1.0-2.5% (v/v) ethanol concentration was the optimal concentration for transesterification to produce ethylparaben. This study investigated the effects of ethanol concentration (0–20%), time, pH (3–9), protein concentration (1–5 mg/mL), and substrate concentration (6.25–200 μM) on transesterification kinetics, as well as the effects of different alcohols. The Km and Vmax values for the transesterification reactions of methyl, propyl, butyl, heptayl, and octyl parabens with ethanol were 449.7, 165.7, 86.1, 24.2, and 45.9 μM, and 114.4, 37.5, 19.5, 7.5, and 7.6 μmol/hr/mg Caco-2 cell protein, respectively. The Vmax values for the transesterification reactions of methyl parabens with ethanol, propanol, and butanol were 114.4, 5.1, and 4.9 μmol/hr/mg, respectively. …The clinical or toxicological significance lies in the fact that transesterification reactions following co-ingestion of ester compounds with ethanol may provide a basis for a previously unrecognized drug-alcohol interaction. The authors investigated the effects of ultraviolet B (UVB) irradiation on methylbarabine (MP)-treated human skin keratinocytes. HaCaT keratinocytes were cultured in MP-containing medium for 24 hours, then exposed to UVB (15 or 30 mJ/cm²) for another 24 hours. Cell viability was then quantified using the MTT assay, and cell death was identified by fluorescence microscopy and flow cytometry. Actual concentrations of MP (0.003%) had little effect on cell viability, oxidative stress, nitric oxide (NO) production, lipid peroxidation, and nuclear transcription factor activation in HaCaT keratinocytes. Low doses of UVB had little effect on these parameters in HaCaT keratinocytes. However, UVB irradiation significantly increased cell death, oxidative stress, NO production, lipid peroxidation, and transcription factor activation in MP-treated HaCaT keratinocytes. These results suggest that MP, considered a safe preservative in cosmetics, may have harmful effects on human skin when exposed to sunlight. A recent study hypothesized that succinylcholine-related increases in intracranial pressure (ICP) are caused by paraben preservatives in multi-dose vials. The authors tested this hypothesis in a standard cat model to determine the effects of equal volumes of preservative-free succinylcholine, succinylcholine containing propyl and methyl esters (both from multi-dose vials), five times the dose of the two preservatives, and saline on ICP. Preservatives alone increased ICP by 0.08 ± 0.08 mmHg (± standard error; not statistically significant). Saline had no effect on ICP. Preservative-free and preservative-containing succinylcholine increased ICP by 4.2 ± 0.10 mmHg and 3.8 ± 0.07 mmHg, respectively (P < 0.01 compared to preservatives alone and saline alone). The 99% confidence upper limit for the increase in intracranial pressure (ICP) induced by preservative alone was 0.42 mmHg. This result (in the authors' opinion) suggests that parabens do not cause or significantly enhance succinylcholine-related ICP increases. This study aimed to evaluate the effects of barnyard grass extract (GT) or methylparaben (MP) on histopathological changes and two oxidative stress biomarkers in rats with subchronic exposure to bisphenol A (BPA). Adult female Wistar rats were orally exposed to BPA (50 mg/kg), BPA+GT (35 mg isoflavones/kg), or BPA+MP (250 mg/kg) for 90 days. Plasma and liver, kidney, thyroid, uterus, ovary, and mammary gland tissue samples were collected at 30, 60, and 90 days after exposure. Lipid peroxidation and the generation of hydroxyl radicals in vivo were assessed by histological analysis and the detection of malondialdehyde and 2,3-dihydroxybenzoic acid. Compared with BPA or BPA+MP treatment, GT treatment resulted in less histopathological changes in the liver and kidneys. Mild thyroid receptor antagonism was observed only after BPA+MP treatment. Abnormal follicle development increased over time, and the number of corpora lutea decreased. No significant histological changes were found in the uterus. The mammary glands showed specific estrogen-stimulated changes at all stages. Both MP and GT exhibited antioxidant properties, reducing lipid peroxidation and BPA-induced hydroxyl radical generation. GT L. extract mitigated the toxic effects of BPA and was shown to have antioxidant and detoxifying effects. MP possessed antioxidant properties but was either ineffective or exacerbated by BPA-induced histopathological changes.
For more complete interaction data on methylparabens (7 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 21.8% to 79% methylparaben in physiological saline >5600 mg/kg.
Oral LD50 in rats: 2100 mg/kg in 0.85% methylparaben saline suspension.
Oral LD50 in mice: 8.0 g/kg (data from table).
Intraperitoneal LD50 in mice: 0.96 g/kg (data from table).
For more complete non-human toxicity data for methylparaben (9 types in total), please visit the HSDB record page.

[1]. Evaluation of the health aspects of methyl paraben: a review of the published literature. Food Chem Toxicol. 2002 Oct;40(10):1335-73.

[2]. Disruption of normal adipocyte development and function by methyl- and propyl- paraben exposure. Toxicol Lett. 2020 Nov 1;334:27-35.

[3]. Methylparaben protects 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells and improved behavioral impairments in mouse model of Parkinson's disease. Neurotoxicology. 2013 Jan;34:25-32.

[4]. Propylparaben inhibits mouse cultured antral follicle growth, alters steroidogenesis, and upregulates levels of cell-cycle and apoptosis regulators. Reprod Toxicol. 2019 Oct;89:100-106.

Methylparaben is a product of the condensation of the carboxyl group of 4-hydroxybenzoic acid with methanol, belonging to the 4-hydroxybenzoic acid esters. It is one of the most commonly used antibacterial preservatives in cosmetics. Methylparaben is naturally found in many fruits, especially blueberries. It has multiple functions, including as a plant metabolite, antibacterial food preservative, neuroprotective agent, and antifungal agent. Methylparaben is used in allergen testing. Methylparaben is a standardized chemical allergen. Its physiological effects are achieved by increasing histamine release and cell-mediated immunity. Methylparaben has been reported to be detected in Hypericum oryzae, St. John's wort, and other organisms with relevant data. Methylparaben is also present in alcoholic beverages. It is an antibacterial agent, preservative, and flavoring agent. Methylparaben is one of the ingredients in cloudberries, passion fruit, white wine, botrytized wine, and bourbon vanilla. Methylparaben has been proven to have antibacterial properties. Methylparaben belongs to the hydroxybenzoic acid derivative family. These compounds contain hydroxybenzoic acid (or its derivatives), which refers to a benzene ring with a carboxylic acid group (A3204).
See also: Butylparaben; Ethylparaben; Methylparaben (ingredient)...View more...

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Mechanism of Action
...The cytotoxic mechanism of action of parabens may be related to mitochondrial dysfunction, which depends on the induction of membrane permeability switching, accompanied by mitochondrial depolarization and cellular ATP depletion caused by uncoupling through oxidative phosphorylation.

C8H8O3

152.15

152.047

99-76-3

Methyl paraben-d4;362049-51-2;Methyl Paraben-13C6;1581694-95-2

7456

White to off-white solid powder

1.2±0.1 g/cm3

265.5±13.0 °C at 760 mmHg

125-128 °C(lit.)

116.4±12.6 °C

0.0±0.6 mmHg at 25°C

1.547

1.87

1

3

2

11

136

0

LXCFILQKKLGQFO-UHFFFAOYSA-N

InChI=1S/C8H8O3/c1-11-8(10)6-2-4-7(9)5-3-6/h2-5,9H,1H3

methyl 4-hydroxybenzoate

Nipagin; Maseptol; Methylparaben

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 (~657.25 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (16.43 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 (16.43 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 (16.43 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.)