Absorption, Distribution and Excretion
By the oral route, parabens are rapidly absorbed, metabolized, and excreted. The metabolic reactions and conversions in mammals vary with the chain length of the ester, the animal species, route of administration, and quantity tested. The metabolism of parabens in humans appears to be most closely related to that of dogs. The rate of metabolite excretion appears to decrease with increasing molecular weight of the ester. /4-Hydroxybenzoates (Parabens)/
After methyl paraben is intravenously infused into the dog, nonhydrolyzed methyl paraben is found in brain, spleen, and pancreas. In liver, kidney, and muscle, it is immediately hydrolyzed to p-hydroxybenzoic acid ... Six hours after oral administration of 1.0 g/kg to dogs, the peak plasma concentration of free and total methyl paraben (630 and 867 ug/cu cm) is reached. After 48 hr, the vast majority was eliminated.
The excretion and metabolism of methylparaben were monitored in 6 preterm infants after they had received multiple doses of a gentamicin formulation containing paraben preservatives. The recovery of the paraben from urine averaged 82.6%. The urinary excretion ranged from 13.2 to 88.1%.
... a study /was conducted/ using human volunteers in which the levels of methylparaben in the stratum corneum were measured. Cosmetic emulsions containing 0.15, 0.25, and 0.5% (w/v) methylparaben were applied one time to the forearm (42 sq cm) of one male and one female subject. At 1, 2, 5, and 12 hr after application, a small area was cleaned of emulsion using wet cotton and methylparaben was extracted by application of a glass cylinder (3.1 sq cm) with 0.5 mL ethanol for 25 min. Methylparaben concentrations were determined in the ethanol solvent using HPLC (for the 1, 2, and 5 hr durations) and GC/MS for other treatments. ... For the single application, methylparaben reached its peak 1 - 2 hr after application (peak was slightly higher for each higher use concentration) and returned to baseline after 12 hr. /In another study,/ healthy Japanese adults (one male, eleven female) applied a lotion only (6 subjects) or a lotion and an emulsion (6 subjects) containing Methylparaben (concentration not stated) twice a day for 1 month. Concentrations of methylparaben in the stratum corneum were determined as above using GC/MS before the first application, at 1, 2, 3, and 4 weeks, and 2 days after stopping. ... Repeated applications resulted in an increase in methylparaben concentration in the stratum corneum over time for both the lotion application and the lotion plus emulsion application. After 2 days, methylparaben had returned to pretreatment levels.
For more Absorption, Distribution and Excretion (Complete) data for METHYLPARABEN (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
In mice, rats, rabbits, or dogs methylparaben is excreted in the urine as unchanged benzoate, p-hydroxybenzoic acid, p-hydroxyhippuric acid (p-hydroxybenzoylglycine), ester glucuronides, ether glucuronides, or ether sulfates.
By the oral route, parabens are rapidly absorbed, metabolized, and excreted. The metabolic reactions and conversions in mammals vary with the chain length of the ester, the animal species, route of administration, and quantity tested. The metabolism of parabens in humans appears to be most closely related to that of dogs. The rate of metabolite excretion appears to decrease with increasing molecular weight of the ester. /4-Hydroxybenzoates (Parabens)/
/This study examined/ the metabolic fate of methylparaben in rabbits. The compound was given by gastric intubation, and urine was analyzed by paper chromatography. Three major metabolites, p-hydroxybenzoic acid, p-hydroxyhippuric acid, and p-carboxyphenyl glucuronide, as well as two minor metabolites, p-hydroxybenzoyl glucuronide and p-carboxyphenyl sulfate, were identified. Rabbits given orally 0.4 or 0.8 g/kg methylparaben, ethylparaben, propylparaben, or butylparaben excreted only 0.2 to 0.9% of the unchanged ester by 24 hr. Urinary excretion of p-hydroxybenzoic acid was slower with increasing carbon chain length of the paraben alkyl group. Excretion of the conjugated acid was approximately that of the free acid. At 24 hr following paraben administration, 25 to 39% was recovered as p-hydroxybenzoic acid, 15 to 29% as the glycine conjugate, 5 to 8% as the ester glucuronide, 10 to 18% as the ether glucuronide, and 7 to 12% as the sulfate.
The metabolism of methylparaben, ethylparaben, and propylparaben was studied in rats. Animals were given orally 100 mg of ester. Blood and urine were collected regularly and analyzed by paper chromatography. Paraben metabolites were identified in the urine 30 minutes after dosing. No unchanged paraben was detected. Ninety minutes after dosing, excretion of metabolites was maximum; thereafter, excretion decreased. p-Hydroxyhippuric acid appeared in the urine after 30 minutes; its concentration then increased evenly during the next 4 hr. The glucuronide and ethereal sulfate metabolites appeared only between 30 and 75 minutes postingestion. After 90 minutes, 67 to 75% of the total paraben dose was excreted as p-hydroxybenzoic acid, 10 to 12.5% as p-hydroxyhippuric acid, and 8 to 10% as glucuronyl derivatives. The concentration of free p-hydroxybenzoic acid in the blood remained extremely low. A continuous rise occurred within the first hour, but the concentration thereafter decreased and leveled off 1 to 2 hr after ingestion. The authors concluded that there were two stages of paraben detoxification: (1) absorption of paraben and excretion in urine of p-hydroxybenzoic acid, and (2) metabolic detoxification by glucuronic-, sulfo-, and glycino-conjugation.
For more Metabolism/Metabolites (Complete) data for METHYLPARABEN (10 total), please visit the HSDB record page.

Toxicity Summary
IDENTIFICATION AND USE: Methylparaben is a methyl ester of p-hydroxybenzoic acid. It is a stable, non-volatile compound used as an antimicrobial preservative in foods, drugs and cosmetics. HUMAN EXPOSURE AND TOXICITY: Parabens are reported to cause contact dermatitis reactions in some individuals on cutaneous exposure. Parabens have been implicated in numerous cases of contact sensitivity associated with cutaneous exposure; however, the mechanism of this sensitivity is unknown. Sensitization has occurred when medications containing parabens have been applied to damaged or broken skin. Allergic reactions to ingested parabens have been reported, although rigorous evidence of the allergenicity of ingested paraben is lacking. ANIMAL STUDIES: Acute toxicity studies in animals indicate that methylparaben is practically non-toxic by both oral and parenteral routes. In a population with normal skin, methylparaben is practically non-irritating and non-sensitizing. In chronic administration studies, no-observed-effect levels (NOEL) as high as 1050 mg/kg have been reported and a no-observed-adverse-effect level (NOAEL) in the rat of 5700 mg/kg is posited. Methylparaben did increase chromosomal aberrations in a Chinese Hamster ovary cell assay. Methylparaben was noncarcinogenic when injected subcutaneously in mice or rats, or when administered intravaginally in rats. Methylparaben was nonteratogenic in rabbits, rats, mice, and hamsters. It is not embryotoxic. Methylparaben failed to produce any effect in uterotrophic assays in two laboratories, but did produce an effect in other studies from another laboratory. In one in vitro study, sperm were not viable at concentrations as low as 6 mg/mL methylparaben, but an in vivo study of 0.1% or 1.0% methylparaben in the diet of mice reported no spermatotoxic effects. Methylparaben was studied using rats at levels in the diet up to an estimated mean dose of 1141.1 mg/kg per day with no adverse testicular effects. ECOTOXICITY STUDIES: Medaka vitellogenin assays and DNA microarray analysis were carried out for methylparaben and found induction of significant vitellogenin in male medaka at 630 ug/L of methylparaben, while the expression levels of genes encoding proteins such as choriogenin and vitellogenin increased for concentrations at 10ug/L of methylparaben.

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Interactions
... Using human intestinal (Caco-2) cells, it was observed that hydrolysis of parabens to p-hydroxybenzoic acid is reduced markedly by ethanol concentrations that can occur in the human intestine, 0.25-0.5% (v/v). Ethanol concentrations of 1.0-2.5% (v/v) were optimal for transesterification to ethylparaben in Caco-2 cell homogenates. The kinetics of the transesterification reaction with regard to ethanol concentration (0-20%), time, pH (3-9), protein concentration (1-5 mg/mL) and substrate concentration (6.25-200 uM) as well as the effects of different alcohols were studied. The Km and Vmax values for transesterification with ethanol for methyl, propyl, butyl, heptyl and octyl parabens were 449.7, 165.7, 86.1, 24.2 and 45.9 uM and 114.4, 37.5, 19.5, 7.5 and 7.6 umol/hr/mg Caco-2 cell protein, respectively. The Vmax values for transesterification of methylparaben with ethanol, propan-1-ol, butan-1-ol were 114.4, 5.1 and 4.9 umol/hr/mg, respectively. ... The clinical or toxicological implication is that, following co-ingestion of ester compounds with ethanol, transesterification could provide the basis for a previously unrecognized drug-alcohol interaction.
... /The authors/ investigated the effects of ultraviolet-B (UVB) exposure on methylbaraben (MP)-treated human skin keratinocytes. HaCaT keratinocyte was cultured in MP-containing medium for 24 hr, exposed to UVB (15 or 30 mJ/cm2) and further cultured for another 24 hr. Subsequent cellular viability was quantified by MTT-based assay and cell death was qualified by fluorescent microscopy and flow cytometry. ... Practical concentrations of MP (0.003%) had a little or no effect on cellular viability, oxidative stress, nitric oxide (NO) production, lipid peroxidation and activation of nuclear transcription factors in HaCaT keratinocytes. Low-dose UVB also had little or no effect on these parameters in HaCaT keratinocytes. However, UVB exposure significantly increased cell death, oxidative stress, NO production, lipid peroxidation and activation of transcription factors in MP-treated HaCaT keratinocytes. These results indicate that MP, which has been considered a safe preservative in cosmetics, may have harmful effects on human skin when exposed to sunlight.
It has been hypothesized recently that succinylcholine-associated increases in intracranial pressure (ICP) are caused by the paraben preservatives contained in multidose vials. /The authors/ tested that hypothesis in a standard feline model to determine the effects on ICP of equal-volume injections of preservative-free succinylcholine, succinylcholine with preservatives from multi-dose vials that contain both propylparaben and methylparaben, these preservatives alone at five times the dose contained in the succinylcholine, and normal saline. The preservatives alone increased ICP by 0.08 +/- 0.08 mm Hg (+/- standard error; not significant). Normal saline had no effect on ICP. Preservative-free succinylcholine and succinylcholine with preservatives increased ICP by 4.2 +/- 0.10 and 3.8 +/- 0.07 mm Hg respectively (P less than 0.01 compared to the preservatives alone and normal saline). The 99% upper confidence limit for the increase in ICP induced by the preservatives alone was 0.42 mm Hg. This result suggests /, to the authors/ that parabens do not cause or substantially augment the ICP increase associated with succinylcholine administration.
To evaluate the influence of an extract of Genista tinctoria L. herba (GT) or methylparaben (MP) on histopathological changes and 2 biomarkers of oxidative stress in rats subchronicly exposed to bisphenol A (BPA). Adult female Wistar rats were orally exposed for 90 d to BPA (50 mg/kg), BPA+GT (35 mg isoflavones/kg) or BPA+MP (250 mg/kg). Plasma and tissue samples were taken from liver, kidney, thyroid, uterus, ovary, and mammary gland after 30, 60, and 90 d of exposure respectively. Lipid peroxidation and in vivo hydroxyl radical production were evaluated by histological analysis along with malondialdehyde and 2,3-dihydroxybenzoic acid detection. The severity of histopathological changes in liver and kidneys was lower after GT treatment than after BPA or BPA+MP treatment. A minimal thyroid receptor antagonist effect was only observed after BPA+MP treatment. The abnormal folliculogenesis increased in a time-dependent manner, and the number of corpus luteum decreased. No significant histological alterations were found in the uterus. The mammary gland displayed specific estrogen stimulation changes at all periods. Both MP and GT revealed antioxidant properties reducing lipid peroxidation and BPA-induced hydroxyl radical generation. GT L. extract ameliorates the toxic effects of BPA and is proved to have antioxidant potential and antitoxic effect. MP has antioxidant properties, but has either no effect or exacerbates the BPA-induced histopathological changes.
For more Interactions (Complete) data for METHYLPARABEN (7 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral >5600 mg/kg for 21.8 to 79% methylparaben in saline.
LD50 Rat oral 2100 mg/kg for methylparaben as a 0.85% saline suspension.
LD50 Mouse oral 8.0 g/kg /From table/
LD50 Mouse ip 0.96 g/kg /From table/
For more Non-Human Toxicity Values (Complete) data for METHYLPARABEN (9 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 4-hydroxybenzoate ester resulting from the formal condensation of the carboxy group of 4-hydroxybenzoic acid with methanol. It is the most frequently used antimicrobial preservative in cosmetics. It occurs naturally in several fruits, particularly in blueberries. It has a role as a plant metabolite, an antimicrobial food preservative, a neuroprotective agent and an antifungal agent.
Methylparaben is used in allergenic testing.
Methylparaben is a Standardized Chemical Allergen. The physiologic effect of methylparaben is by means of Increased Histamine Release, and Cell-mediated Immunity.
Methylparaben has been reported in Nigrospora oryzae, Hypericum ascyron, and other organisms with data available.
Methylparaben is found in alcoholic beverages. Methylparaben is an antimicrobial agent, preservative, flavouring agent. Methylparaben is a constituent of cloudberry, yellow passion fruit, white wine, botrytised wine and Bourbon vanilla. Methylparaben has been shown to exhibit anti-microbial function Methylparaben belongs to the family of Hydroxybenzoic Acid Derivatives. These are compounds containing an hydroxybenzoic acid (or a derivative), which is a benzene ring bearing a carboxylic acid. (A3204).
See also: Butylparaben; ethylparaben; methylparaben (component of) ... View More ...

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Mechanism of Action
...The mechanism of cytotoxic action of parabens may be linked to mitochondrial failure dependent on induction of membrane permeability transition accompanied by the mitochondrial depolarization and depletion of cellular ATP through uncoupling of 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.)