Determination of the Sodium Methylparaben Content Based on Spectrum Fluorescence Spectral Technology and GA-BP Neural Network].
Wang ST, Chen DY, Hou PG, Wang XL, Wang ZF, Wei M.
Guang Pu Xue Yu Guang Pu Fen Xi. 2015 Jun;35(6):1606-10.

Validated Stability-indicating Reverse-phase Ultra-performance Liquid Chromatography Method for Simultaneous Determination of Sodium Methylparaben, Sodium Propylparaben and Ketorolac Tromethamine in Topical Dosage Forms.
Roy C, Chakrabarty J, Modi PB.
Indian J Pharm Sci. 2013 Mar;75(2):197-204.

Evaluating food additives as antifungal agents against Monilinia fructicola in vitro and in hydroxypropyl methylcellulose-lipid composite edible coatings for plums.
Karaca H, Pérez-Gago MB, Taberner V, Palou L.
Int J Food Microbiol. 2014 Jun 2;179:72-9. doi: 10.1016/j.ijfoodmicro.2014.03.027. Epub 2014 Mar 31.

Ultrasound-Assisted Surfactant-Enhanced Emulsification Micro-Extraction Followed by HPLC for Determination of Preservatives in Water, Beverages and Personal Care Products.
Jan-E S, Santaladchaiyakit Y, Burakham R.
J Chromatogr Sci. 2017 Jan;55(1):90-98. Epub 2016 Sep 12.

New sorbent in the dispersive solid phase extraction step of quick, easy, cheap, effective, rugged, and safe for the extraction of organic contaminants in drinking water treatment sludge.
Cerqueira MB, Caldas SS, Primel EG.
J Chromatogr A. 2014 Apr 4;1336:10-22. doi: 10.1016/j.chroma.2014.02.002. Epub 2014 Feb 8.

Sodium Methylparaben:  properties, uses, pros, cons, safety

Sodium methylparaben is the sodium salt of methyl p-hydroxybenzoate (a paraben) used as a preservative. In the food sector it is classified as additive E 219 and may also be described as “sodium salt of methyl p-hydroxybenzoate” or “sodium methyl p-hydroxybenzoate”. In the cosmetics sector, the label name follows INCI and is SODIUM METHYLPARABEN (the same in Italian and English). In the pharmaceutical sector, technical synonyms are commonly used, such as “sodium methyl 4-hydroxybenzoate” or “sodium methyl parahydroxybenzoate”. Functionally, it acts as an antimicrobial mainly against yeasts and molds, supporting microbiological stability and shelf life of formulations. Its use remains subject to sector- and concentration-specific regulatory limits, and formulators also consider compatibility, ph, and overall tolerability. 

Chemical Composition and Structure

Sodium Methylparaben is the sodium salt of methyl p-hydroxybenzoate. Its chemical structure includes a benzene ring, a hydroxyl group, and an ester group. The sodium form increases its water solubility, making it ideal for use in liquid products or aqueous formulations. E219 works by inhibiting microbial growth through the destabilization of microbial cell membranes.

Physical Properties

Sodium Methylparaben is a white, odorless crystalline powder that is highly soluble in water. Due to its high solubility, it is easily incorporated into various formulations, especially in water-containing products such as beverages, creams, lotions, and syrups.

Production Process
Sodium Methylparaben is produced through the esterification of p-hydroxybenzoic acid with methanol, followed by neutralization with sodium hydroxide to form the sodium salt. This process enhances the solubility of the compound, facilitating its inclusion in aqueous formulations.

The name defines the structure of the molecule:

• Sodium (Na). Sodium is an alkaline metal, a group of highly reactive elements found in group 1 of the periodic table. Sodium is soft and silvery-white in color. It is highly reactive, especially with water, and is commonly found in salts and minerals.
• Methylparaben refers to the methyl ester of p-hydroxybenzoic acid. Parabens are a type of preservative used in a variety of cosmetic and pharmaceutical products.

Description of the raw materials used in its production.

• Methylparaben acid - This is the primary active ingredient that, once neutralized, becomes the preservative known as Sodium Methylparaben. It has antimicrobial and fungicidal properties.
• Sodium hydroxide (or lye) - Used as a neutralizing agent. When added to methylparaben acid, it neutralizes it to form the salt, Sodium Methylparaben.
• Water - Serves as a solvent and reaction medium. It facilitates the mixing and reaction between the methylparaben acid and sodium hydroxide.

The synthesis process takes place in several stages:

• Preparation. Methylparaben is synthesized by esterification of p-hydroxybenzoic acid with methanol. This reaction is usually catalyzed by an acid and involves heating the reagents to promote the reaction.
• Neutralization. Methylparaben is neutralized with sodium hydroxide (NaOH) to produce sodium methylparaben with salt formation from the acid (Methylparaben ) and base (NaOH). The reaction is carried out in an aqueous solution.
• Crystallization. Sodium Methylparaben is isolated from the reaction mixture by crystallization. This involves cooling the reaction mixture to induce the formation of Sodium Methylparaben crystals.
• Filtration and drying. Sodium Methylparaben crystals are separated from the reaction mixture by filtration and dried to remove all remaining water.
• Quality control test. The final product is tested to ensure it meets the required specifications with tests for purity, moisture content and other physical and chemical properties.

Applications

• Food Industry: Sodium Methylparaben is used as a preservative in various packaged foods and beverages such as juices, jams, sauces, and confectioneries to extend their shelf life by preventing microbial growth.

• Cosmetics: In cosmetic products like creams, lotions, shampoos, and makeup, E219 is used to prevent bacterial and fungal contamination, ensuring product safety and efficacy.

• Pharmaceuticals: It is used as a preservative in syrups, mouthwashes, and liquid medicines to ensure that they remain free from contamination throughout their shelf life.

It is a preservative used in food, pharmaceuticals, cosmetics and more.

Cosmetics. The ingredient is labelled as Sodium Methylparaben

It is a restricted ingredient as V/12 a Relevant Item in the Annexes of the European Cosmetics Regulation 1223/2009. Substance or ingredient reported:  4-Hydroxybenzoic acid and its Methyl- and Ethyl-esters, and their salts. Maximum concentration in ready for use preparation: 0,4% (as acid) for single ester 0,8% (as acid) for mixtures of esters

• Preservative. Any product containing organic, inorganic compounds, water, needs to be preserved from microbial contamination. Preservatives act against the development of harmful microorganisms and against oxidation of the product.

Pharmaceuticals 

• Sodium Methylparaben is used as a preservative in oral solutions, such as those containing sodium valproate. An HPLC method was developed for the simultaneous determination of sodium valproate, methylparaben, and propylparaben in oral solutions

Safety in Use
Sodium Methylparaben is considered safe for use in food and cosmetic products at approved concentrations. However, like other parabens, its use has been the subject of debate due to potential links to skin sensitization or endocrine disruption. Most regulatory authorities, including the European Food Safety Authority (EFSA) and the Food and Drug Administration (FDA), consider Sodium Methyl p-Hydroxybenzoate safe when used within established limits.

Allergic Reactions
Some individuals may be sensitive to parabens, including Sodium Methylparaben. Allergic reactions, though rare, can include contact dermatitis, particularly in people with sensitive skin or a predisposition to allergies. It is recommended to test new products containing parabens on a small area of skin before widespread use.

Toxicity and Carcinogenicity
There is no conclusive evidence that Sodium Methylparaben is carcinogenic at approved concentrations for use in food and cosmetics. However, parabens have been the focus of scientific scrutiny for their potential effects on the endocrine system, as they can weakly mimic estrogen. Regulatory authorities closely monitor the use of parabens like E219, limiting their concentration in products to ensure consumer safety.

Environmental and Safety Considerations
Sodium Methylparaben is biodegradable and does not pose significant environmental risks when used in regulated amounts. However, the use of parabens is under increasing environmental scrutiny due to their potential accumulation in aquatic systems, which is why responsible use is advised.

Regulatory Status
Sodium Methylparaben is regulated and approved for use in the European Union and United States as a food and cosmetic preservative. Maximum allowable concentrations are set by food and cosmetic safety regulations to prevent adverse effects on human health.

Sodium Methylparaben as a preservative is widely used in our life, but health problems could arise if the human body absorbs it in quantity. So there are strict rules about the dosage of Sodium Methylparaben in each country (1).

Parabens

Parabens are chemical preservative compounds that have been the subject of attention in the scientific literature as possible endocrine disruptors (particularly propylparaben and butylparaben), i.e. with the possibility of damaging the hormone-producing glands in our bodies, particularly in the breasts. The 2004 study by Darbre et al. showed that parabens remain in our bodies as intact esters (2). Following this study, some of the scientific literature in 2005 and 2006 cast doubt on Darbre's conclusions and claimed they were limited. However, both the US FDA and the European SCCP authorised in 2006 the use of a single paraben in cosmetic products at a concentration of 0.4% and the use of total parabens at a concentration of 0.8% (3). However, there is no shortage of studies that consider the restrictions unnecessary: M. G. Kirchhof et al. in 2013 found that parabens are among the safest and most well-tolerated preservatives and that current data do not support drastic regulations or personal exposure restrictions (4). Darbre in 2014 published a further study in which he showed how parabens can cause DNA damage (5).

Alternatives

Sodium Methylparaben studies

Typical optimal commercial product characteristics Sodium methylparaben

Appearance	White fine powder
Boiling Point	265.5ºC at 760 mmHg
Melting Point	>125°C
Flash Point	116.4ºC
pH	9.5-10.5 (1g/l, H2O)
Sulphate	≤0.12%
Chloride	≤350ppm
PSA	49.36000
LogP	1.61700
Water%	5.0 Max.
Heavy metal (Pb, ppm)	10 Max.
Safety

• Molecular Formula   C₈H₇O₃Na   C₈H₇NaO₃
• Molecular Weight   174.131 g/mol
• Exact Mass   174.029282
• UNII    CR6K9C2NHK
• CAS    5026-62-0
• EC Number: 225-714-1
• DSSTox Substance ID  DTXSID1042156
• IUPAC  sodium;4-methoxycarbonylphenolate
• InChI=1S/C8H8O3.Na/c1-11-8(10)6-2-4-7(9)5-3-6;/h2-5,9H,1H3;/q;+1/p-1  
• InChl Key      PESXGULMKCKJCC-UHFFFAOYSA-M
• SMILES   COC(=O)C1=CC=C(C=C1)[O-].[Na+]
• PubChem Substance ID 329769369
• MDL number MFCD00016470
• Beilstein Registry Number 4165000

Synonyms:

• Methyl 4-hydroxybenzoate sodium salt
• Sodium 4-(methoxycarbonyl)phenolate
• Sodium methylparaben
• Methylparaben sodium
• Methylparaben, sodium salt
• sodium;4-methoxycarbonylphenolate
• Sodium Methyl Parahydroxybenzoate
• sodium 4carbomethoxyphenolate
• Methyl p-hydroxybenzoate, sodium salt
• Sodium p-methoxycarbonylphenoxide
• Sodium methyl p-hydroxybenzoate
• Benzoic acid, 4-hydroxy-, methyl ester, sodium salt
• Sodium methyl 4-hydroxybenzoate
• sodium 4-methoxycarbonylphenolate
• Methyl p-hydroxybenzoate sodium
• Preserval MS
• Solparol
• Bonomold OMNa
• Methyl 4-hydroxybenzoate sodium salt
• Sodium 4-carbomethoxyphenolate

Bibliografia_______________________________________________

(1) Wang ST, Chen DY, Hou PG, Wang XL, Wang ZF, Wei M. Determination of the Sodium Methylparaben Content Based on Spectrum Fluorescence Spectral Technology and GA-BP Neural Network. Guang Pu Xue Yu Guang Pu Fen Xi. 2015 Jun;35(6):1606-10. 

(2) Darbre PD, Aljarrah A, Miller WR, Coldham NG, Sauer MJ, Pope GS. Concentrations of parabens in human breast tumours. J Appl Toxicol. 2004 Jan-Feb;24(1):5-13. doi: 10.1002/jat.958.

(3) https://www.fda.gov/cosmetics/cosmetic-ingredients/parabens-cosmetics

Cosmetic Ingredient Review Expert Panel. Final amended report on the safety assessment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben as used in cosmetic products. Int J Toxicol. 2008;27(Suppl 4):1-82.

(4) Kirchhof MG, de Gannes GC. The health controversies of parabens. Skin Therapy Lett. 2013 Feb;18(2):5-7.

(5) Darbre PD, Harvey PW. Parabens can enable hallmarks and characteristics of cancer in human breast epithelial cells: a review of the literature with reference to new exposure data and regulatory status. J Appl Toxicol. 2014 Sep;34(9):925-38. doi: 10.1002/jat.3027.

Abstract. A framework for understanding the complexity of cancer development was established by Hanahan and Weinberg in their definition of the hallmarks of cancer. In this review, we consider the evidence that parabens can enable development in human breast epithelial cells of four of six of the basic hallmarks, one of two of the emerging hallmarks and one of two of the enabling characteristics. In Hallmark 1, parabens have been measured as present in 99% of human breast tissue samples, possess oestrogenic activity and can stimulate sustained proliferation of human breast cancer cells at concentrations measurable in the breast. In Hallmark 2, parabens can inhibit the suppression of breast cancer cell growth by hydroxytamoxifen, and through binding to the oestrogen-related receptor gamma may prevent its deactivation by growth inhibitors. In Hallmark 3, in the 10 nm–1 μm range, parabens give a dose-dependent evasion of apoptosis in high-risk donor breast epithelial cells. In Hallmark 4, long-term exposure (>20 weeks) to parabens leads to increased migratory and invasive activity in human breast cancer cells, properties that are linked to the metastatic process. As an emerging hallmark methylparaben has been shown in human breast epithelial cells to increase mTOR, a key regulator of energy metabolism. As an enabling characteristic parabens can cause DNA damage at high concentrations in the short term but more work is needed to investigate long-term, low-dose mixtures. The ability of parabens to enable multiple cancer hallmarks in human breast epithelial cells provides grounds for regulatory review of the implications of the presence of parabens in human breast tissue. Copyright © 2014 John Wiley & Sons, Ltd.

Harvey PW. Parabens, oestrogenicity, underarm cosmetics and breast cancer: a perspective on a hypothesis. J Appl Toxicol. 2003 Sep-Oct;23(5):285-8. doi: 10.1002/jat.946. PMID: 12975767.

Harvey PW, Everett DJ. Significance of the detection of esters of p-hydroxybenzoic acid (parabens) in human breast tumours. J Appl Toxicol. 2004 Jan-Feb;24(1):1-4. doi: 10.1002/jat.957. PMID: 14745840.

Hager E, Chen J, Zhao L. Minireview: Parabens Exposure and Breast Cancer. Int J Environ Res Public Health. 2022 Feb 8;19(3):1873. doi: 10.3390/ijerph19031873. 

Abstract. There is increasing recognition that environmental exposure to chemicals, such as endocrine-disruptive chemicals (EDCs), contributes to the development of breast cancer. Parabens are a group of EDCs commonly found in personal care products, foods, and pharmaceuticals. Systemic exposure to parabens has been confirmed by the ubiquitous detection of parabens in human blood and urine samples. Although evidence from in vivo and epidemiological studies linking parabens exposure to breast cancer is limited, the current evidence suggests that parabens may negatively interfere with some endocrine and intracrine targets relevant to breast carcinogenesis. So far, most studies have focused on a single paraben's effects and the direct modulating effects on estrogen receptors or the androgen receptor in vitro. Recent studies have revealed that parabens can modulate local estrogen-converting enzymes, 17β-hydroxysteroid dehydrogenase 1 and 2 and increase local estrogen levels. Also, parabens can crosstalk with the human epidermal growth factor receptor 2 (HER2) pathway and work with ER signaling to increase pro-oncogenic c-Myc expression in ER+/HER2+ breast cancer cells. Future studies investigating paraben mixtures and their crosstalk with other EDCs or signaling pathways both in vitro and in vivo in the context of breast cancer development are warranted.

Petric Z, Ružić J, Žuntar I. The controversies of parabens - an overview nowadays. Acta Pharm. 2021 Mar 1;71(1):17-32. doi: 10.2478/acph-2021-0001.

Abstract. Effects of paraben toxicity, i.e., endocrine-disruption properties, are in the focus of researchers for decades, but still - they are a hot subject of debate. Parabens are aliphatic esters of p-hydroxybenzoic acid, which are widely used as antimicrobial agents for the preservation of cosmetics, pharmaceuticals and foods. Mostly used parabens are methyl-, ethyl-, propyl- and butylparaben. Although the toxicity of parabens is reported in animals and in in vitro studies, it cannot be taken for granted when discussing hazards for human health due to an unrealistic exposure -safety profile. Many studies have demonstrated that parabens are non-teratogenic, non-mutagenic, non-carcinogenic and the real evidence for their toxicity in humans has not been established. For now, methyl-, ethyl- and propylparaben are considered safe for use in cosmetics and pharmaceuticals within the recommended range of doses. Regarding alternatives for parabens, a variety of approaches have been proposed, but every substitute would need to be tested rigorously for toxicity and safety.

Byford JR, Shaw LE, Drew MG, Pope GS, Sauer MJ, Darbre PD. Oestrogenic activity of parabens in MCF7 human breast cancer cells. J Steroid Biochem Mol Biol. 2002 Jan;80(1):49-60. doi: 10.1016/s0960-

Abstract. Parabens (4-hydroxybenzoic acid esters) have been recently reported to have oestrogenic activity in yeast cells and animal models. Since the human population is exposed to parabens through their widespread use as preservatives in foods, pharmaceuticals and cosmetics, we have investigated here whether oestrogenic activity of these compounds can also be detected in oestrogen-sensitive human cells. We report on the oestrogenic effects of four parabens (methylparaben, ethylparaben, n-propylparaben, n-butylparaben) in oestrogen-dependent MCF7 human breast cancer cells. Competitive inhibition of [3H]oestradiol binding to MCF7 cell oestrogen receptors could be detected at 1,000,000-fold molar excess of n-butylparaben (86%), n-propylparaben (77%), ethyl-paraben (54%) and methylparaben (21%). At concentrations of 10(-6)M and above, parabens were are able to increase expression of both transfected (ERE-CAT reporter gene) and endogenous (pS2) oestrogen-regulated genes in these cells. They could also increase proliferation of the cells in monolayer culture, which could be inhibited by the antiestrogen ICI 182,780, indicating that the effects were mediated through the oestrogen receptor. However, no antagonist activity of parabens could be detected on regulation of cell proliferation by 17 beta-oestradiol at 10(-10)M. Molecular modelling has indicated the mode by which paraben molecules can bind into the ligand binding pocket of the crystal structure of the ligand binding domain (LBD) of the oestrogen receptor alpha (ERalpha) in place of 17beta-oestradiol; it has furthermore shown that two paraben molecules can bind simultaneously in a mode in which their phenolic hydroxyl groups bind similarly to those of the meso-hexoestrol molecule. Future work will need to address the extent to which parabens can accumulate in hormonally sensitive tissues and also the extent to which their weak oestrogenic activity can add to the more general environmental oestrogen problem.

Darbre PD, Aljarrah A, Miller WR, Coldham NG, Sauer MJ, Pope GS. Concentrations of parabens in human breast tumours. J Appl Toxicol. 2004 Jan-Feb;24(1):5-13. doi: 10.1002/jat.958. PMID: 14745841.

Nowak K, Ratajczak-Wrona W, Górska M, Jabłońska E. Parabens and their effects on the endocrine system. Mol Cell Endocrinol. 2018 Oct 15;474:238-251. doi: 10.1016/j.mce.2018.03.014. Epub 2018 Mar 27. PMID: 29596967.

Wei F, Mortimer M, Cheng H, Sang N, Guo LH. Parabens as chemicals of emerging concern in the environment and humans: A review. Sci Total Environ. 2021 Jul 15;778:146150. doi: 10.1016/j.scitotenv.2021.146150. Epub 2021 Feb 27. PMID: 34030374.

Charles AK, Darbre PD. Combinations of parabens at concentrations measured in human breast tissue can increase proliferation of MCF-7 human breast cancer cells. J Appl Toxicol. 2013 May;33(5):390-8. doi: 10.1002/jat.2850. Epub 2013 Jan 31. PMID: 23364952

Darbre PD, Harvey PW. Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks. J Appl Toxicol. 2008 Jul;28(5):561-78. doi: 10.1002/jat.1358.  PMID: 18484575.