Parabens: A Comprehensive Review of Their Usage, Endocrine Disruption, And Regulatory Concerns

Abstract

A range of foods, cosmetics, and pharmaceuticals are kept fresher longer by using preservatives, which are chemicals that stop bacteria from growing. Paraben is currently utilized all over the world and is one of the most common preservatives in the products listed above. The human body quickly absorbs parabens. Human physiology makes it crucial to talk about their safety. Recent studies have classified since parabens belong to the class of endocrine disruptive chemicals (EDCs), it is crucial to accurately evaluate how they affect the human endocrine system. Fitness and bodily functioning are among the several negative effects of endocrine homeostasis disturbance. To demonstrate the latest developments in our knowledge of parabens' impact on the human endocrine system, we have gathered the body of research on their traits, incidence, and metabolism detailed in this review article.

Keywords

Introduction

Parabens, esters of p-hydroxybenzoic acid, are commonly used as antimicrobial preservatives in food packaging, cosmetics, and medicines. The EU permits up to 0.4% of a single paraben in cosmetic products, while mixes can be used at concentrations up to 0.8%. The FDA encourages manufacturers to follow these limits. According to the CDC’s National Report on Human Exposure to Environmental Chemicals, parabens, especially methyl, propyl, and butyl parabens, are widely found in the population, with 99.1% of individuals showing methyl paraben exposure [1, 2].

Parabens are used as excipients and preservatives in various pharmaceutical formulations, and while they are considered "generally recognized as safe" (GRAS) by the FDA, they are not subject to mandatory testing. The FDA tracks the maximum allowed concentrations of parabens in drug formulations, such as 0.04 mg of butyl paraben in prolonged-action tablets and 0.22 mg of methyl paraben in tablets [1-3].

Despite the GRAS status, quantifying urine concentrations of parabens in patients, especially following medication use, is important for understanding exposure.

A class of alkyl esters of p-hydroxybenzoic acid, parabens have gained widespread use because of their extended shelf life, low cost, chemical stability, and broad-spectrum antibacterial action. Butyl paraben, propyl paraben, ethyl paraben, and methyl paraben are among the parabens that are often utilized. In a variety of consumer goods, such as moisturizers, deodorants, shampoos, toothpastes, processed meals, and medications, these substances work as excellent preservatives because they prevent the growth of molds, yeasts, and bacteria [4, 5]. As demonstrated by bio monitoring studies that have found parabens in human urine, blood, breast milk, and even placental tissue, human exposure to parabens is almost universal due to their extensive use [6, 7].

Growing worries about the possible health dangers caused by parabens, especially their capacity to mimic estrogen and interfere with hormone signaling, have surfaced despite their regulatory clearance and GRAS status in many places. Although a clear causal connection has not yet been proven, the discovery of parabens in breast tumor cells has raised concerns about their potential involvement in the development of hormone-related malignancies [8, 9]. Additionally, research on animals indicates that parabens may disrupt thyroid function, sperm production, and reproductive development [10]. Because of safety concerns, certain nations have banned or restricted some parabens, and regulatory bodies including the U.S. Food and Drug Administration and the European Commission have reevaluated the permissible doses of parabens in consumer items [11, 12].

Figure 1: Balancing benefit and risks of paraben

2. DISCOVERY AND FURTHER HISTORY

• Early Use and Discovery (1920s– 1950s)

1. First synthesis: German scientist Max Giese produced parabens for the first time in the 1920s [10].
2. Early use in pharmaceuticals: Parabens were initially used as preservatives in pharmaceuticals, particularly in creams and ointments [11].
3. Introduction into cosmetics: In the 1950s, parabens were first used in toothpaste, lotions, and shampoos, as well as other personal hygiene products.[12]

• Pervasive Use and Growth (1960s-1990s)

1. Growing demand: In the 1960s and 1970s, the pharmaceutical and cosmetics industries expanded, which resulted in a significant rise in the demand for parabens.[13]
2. New applications: The new product categories that now contain parabens include food, beverages, and veterinary drugs.[14]
3. Regulatory approvals: The Scientific Committee on Consumer Safety of the European Union and the US Food and Drug Administration are among the agencies that have issued regulatory approvals for parabens licenses[15]

• Problems and Discussions (2000s–present)

1)    Endocrine disruption: Studies have indicated that parabens may interfere with endocrine function by mimicking estrogen [16].

2)    Breast cancer link: Some research has suggested Parabens and breast cancer may be related, while this association is still debatable.[17]

3)    Environmental issues: The impact of parabens on aquatic environments and their potential to contribute to antibiotic resistance have drawn criticism[18]

4)    Regulatory re-evaluations: In response to these concerns, regulatory agencies have reexamined the safety of parabens, leading to specific restrictions and suggestions [19].

3. SYNONYMS OF PARABENS

1.   Synonyms Esters of p-hydroxybenzoic acid [20].

2.   p-Hydroxybenzoates[21]

3.   Parahydroxybenzoate[22]

4.   Esters of hydroxybenzoic acid [23]

5.   Parabens (general word)[24]

• Particular Synonyms of Parabens:

1.     Methyl paraben: Methyl parahydroxybenzoate[25] and Methyl p-hydroxybenzoate[26]

2.     Ethyl paraben: Ethyl parahydroxybenzoate[27] and Ethyl p-hydroxybenzoate[28]

3.     Propyl paraben: Propyl parahydroxybenzoate, Propyl p- hydroxybenzoate[29]

4.     Butyl paraben, which includes butyl parahydroxybenzoate and butyl p- hydroxybenzoate[30]

4. DIFFERENT PARABEN TYPES

1.     Methyl paraben, also known as methyl p-hydroxybenzoate, is utilized in food, medicine, and cosmetics.[31]

2.     Ethyl paraben: Pharmaceutical, culinary, and cosmetic goods that include ethyl p- hydroxybenzoate [32].

3.     Propyl paraben: Used in food, medicine, and cosmetics, propyl p- hydroxybenzoateHowever,[33]

4.     butyl paraben, also known as butyl p-hydroxybenzoate, is utilized in medications and cosmetics[34]

5.     Isobutylparaben: Isobutyl p- hydroxybenzoate, which is utilized in medications and cosmetics [35].

6.     Isopropylparaben: Isopropyl p- hydroxybenzoate, which is utilized in medications and cosmetics [36].

7.     Benzyl paraben: A compound used in medicines and cosmetics that is benzyl p- hydroxybenzoate.[37]

8.     Phenyl paraben: Cosmetics and medications that contain phenyl p- hydroxybenzoate [38]

Figure 2: Paraben's Versatile Roles

5. PHYSICOCHEMICAL PROPERTIES:

Solubility: When an alkyl chain's length increases, parabens become less soluble in water; for instance, butyl paraben, which has a longer alkyl chain, is less water soluble than methyl paraben, which has the shortest alkyl chain. This development affects the use of parabens as more water-soluble parabens are preferred in aqueous formulations [39].

Antibacterial Activity: Parabens' ability to combat germs is influenced by the length of their alkyl chain. Longer alkyl chains in parabens seem to have stronger antibacterial action. Nevertheless, their diminished solubility might restrict their utility in specific formulations [40].

Parabens' high oil/water partition coefficient [41] indicates that they have a greater affinity for oil phases. Their distribution across the different stages of pharmaceutical and cosmetic formulations depends on this feature [42].

Molecular weight: ethyl: 40 methyl: 151.1 propyl: 166.6 butyl: 180.2

Melting points ?: ethyl: 6 methyl: 8  propyl: 13 butyl: 128

Boiling point?: ethyl: 125-128 Methyl: 118 Propyl: 98-115 butyl: 118

6. METHODS OF SYNTHESIS

 1. Chemical Reactants Para- hydroxybenzoic acid is the acid Alcohol is represented by the molecules methanol for methyl paraben and ethanol for ethyl paraben. Acid catalyst, including sulfuric acid [43]

2. Technique: Add para-hydroxybenzoic acid to the chosen alcohol in the proper molar ratio. Add an acid catalyst [44] in a catalytic amount to the mixture. While the reaction mixture is refluxing, heat it to facilitate esterification. The reaction mixture should be heated while under reflux to facilitate esterification. Continue to monitor the reaction until it is complete. The paraben product [45] should then be separated Using standard purification techniques after the reaction mixture has been neutralized. Example: Synthesis of Methyl paraben

The subsequent steps are part of a successful methyl paraben production process:

1. Reactants. Using aluminum sulfate as a catalyst, the acid para- hydroxybenzoic methanol hydrate[46]

2. Process: The ratio of methanol to para- hydroxybenzoic acid is 1:35 molar. Incorporate aluminum sulfate hydrate into the mixture. High pressure should be applied to the mixture in a reaction kettle. Stirring, heat the mixture to 130°C and leave it for 3 hours[47]

Following the reaction, heat and water are added to evaporate the unreacted methanol. To neutralize the mixture, use a solution of sodium hydroxide. The methyl paraben product will precipitate when the solution cools. Filter the product, wash it, and then allow it to dry to get methyl paraben that looks like white powder

3. The catalyst utilized in this process [48] is aluminum sulfate hydrate, which has a high catalytic activity, is simple to employ, and is environmentally benign. In the esterification process [49], alternate catalysts like thionyl chloride, dodecatungstophosphoric acid, or montmorillonite K10 clay can also be utilized to produce various paraben.

Figure 3: Paraben Synthesis Process

7. FUNCTION/USES:

Cosmetics: Statistics on the highest reported use concentration per product category are provided by the cosmetics industry in response to a study carried out by the Personal Care Products Council (Council). Contains information on the rates at which particular chemicals are used in cosmetics, gathered from manufacturers and shown by type of cosmetic product. According to a survey by the Personal Care Products Council (Council), the cosmetics industry reports the highest concentration of use for each product category. Data from the VCRP study in 2019 showed that methyl paraben was present in 11,739 formulations, 9,347 of which were leave-on formulations. Compared to the 8,786 usage recorded in 200644, 45, 46, this is more. With 9,034 registered applications, including 7,520 leave-on formulations, propyl paraben had the second- highest number of reported uses, up from 7,118 in 2006. None Except for benzyl paraben, which climbed from one documented use to more, all of the parabens previously examined in this safety evaluation have seen increases in reported usage since 2006.

The highest methyl paraben concentration ever discovered in lipsticks was 1% in 2006. The highest intake concentrations of the previously assessed parabens have stayed below 1%, and their consumption patterns are comparable to those documented in the earlier safety assessment. According to the industry survey and VCRP, each compound that has been reported to be in use has a frequency and concentration of utilization that is different from the substances that aren't being used.

Numerous parabens have been found to be found in items intended for accidental ingestion, applied close to the eye, utilized in infant products, or that come into touch with mucosal membranes [50, 51]. For instance, lipstick contains up to 0.35% methyl paraben, mascara has 0.8%, bath oils, tablets, and salts have 0.5%, and infant lotions, oils, and creams contain 0.4%. Certain parabens have been found to be inhalable in cosmetic sprays, such as hair sprays, hair color sprays, skin care products, moisturizing products, suntan products, deodorants, and other propellant and pump spray products45, 46. According to a survey conducted by the Council, a fragrance product can include up to 0.41% methyl paraben.

Non-cosmetic. Generally recognized as safe (GRAS) antibacterial agents in food are propyl paraben and methyl paraben, according to the US Food and Drug Administration. As artificial flavorings and adjuvants, butyl paraben, ethyl paraben, and propyl paraben can be added directly to food intended for human consumption. One indirect food additive that is used in adhesives and coatings is ethyl paraben. As antimitotic food additives, propyl paraben and methyl paraben have both received approval. The safety and efficacy of diaper rash products containing methyl paraben and propyl paraben have not been widely accepted due to a lack of data. The chemical preservative methyl paraben, which is used in animal medications, feeds, and related items, is GRAS at concentrations below 0.1%. In insecticides used as food preservatives, the residual amounts of propyl paraben and methyl paraben cannot be more than 0.1%. Many pharmaceutical formulations use excipients, or inert substances. Methyl paraben has been permitted at a maximum dose of 1.8 mg in tablet form and 2.6 mg/mL in oral solution, according to the US FDA database of inert substances. The highest authorized dosages of ethyl paraben are 0.6 mg granules and 0.6 mg/mL oral solution. The maximum amount of butyl paraben that can be used is 0.04 mg in a formulation for prolonged action tablets and 0.08 mg/mL in an oral solution60. According to a JECFA assessment, the cumulative daily intake (ADI) of ethyl paraben and methyl paraben ranges from 0 to 10 mg/kg.

Figure 4: Paraben usage varies across cosmetic and non-cosmetic applications

8. STOARAGE

The storage conditions

1. Store parabens in a moist, cold place away from heat sources and bright light[52]

The recommended temperature range for parabens is 15°C to 30°C (59°F to 86°F)[53]

2. Humidity control: Parabens should be stored in an environment with regulated humidity to prevent moisture absorption[54]

3. Objects for Storage

1. Tightly closed containers: Parabens should be stored in tightly closed containers to prevent exposure and disease.[55]

2. Glass or plastic containers: It's best to store parabens in items that are resistant to corrosion and chemical reactions. Labeling and dating: Label container with the contents, date of storage, and handling instructions.[56]

 9. ADVERSE EFFECT EVALUATION

1. Oral toxicity: Parabens have a moderate level of oral toxicity; in rats, their LD50 values fall between 2 and 8 g/kg[57]

2. Dermatological toxicity: Parabens have a low level of cutaneous toxicity; in rabbits, their LD50 values fall between 2 and 4 grams per kilogram. In rats, parabens have LC50 values between 2 and 4 mg/L [58], indicating that they are not hazardous when breathed. Toxicity, Both Chronic and Sub chronic Toxicology to reproduction Parabens have been shown in animal studies to affect the reproductive system's development and function [59].

Endocrine disruption:

Parabens replicate estrogen and affect endocrine function in animal experiments [60]. According to the International Atomic Research Commission, parabens are "not classifiable as to their carcinogenicity to humans98." both local and systemic Repercussions

1. Skin irritation: Parabens can cause signs of skin irritation, including redness, itching, and burning [61].

2. Allergic contact dermatitis: Parabens may cause allergic contact dermatitis in certain individuals.[62]

3. Systemic effects: Studies conducted on animals have shown that parabens affect the kidneys, liver, and reproductive system [63].

10. MARKETED PRODUCTS

Products for Personal Care and Cosmetics

1.   TRESemmé, Head & Shoulders, and Pantene Pro- V [58] are shampoos that include methyl paraben and propyl paraben.

2.   Conditioners: L’Oreal Paris [64], Garnier Fructis, and Redken all include methyl paraben and propyl paraben.

3.   Nivea, Neutrogena, and Olay [65] are examples of moisturizers that include methyl paraben and propyl paraben.

4.   Sunscreen: Coppertone, Banana Boat [66], and Hawaiian Tropic all include methyl paraben and propyl paraben.

5.   Cosmetics: Revlon [67], Maybelline, and L’Oreal Paris contain methyl paraben and propyl paraben. Drugs and Supplies

Topical medications:

1.   Bacitracin [68], neosporin, and hydrocortisone cream contain methyl paraben and propyl paraben.

2.   2. Ointments: Desitin [69], Aquaphor, and Vaseline include methyl paraben and propyl paraben.

3.   3. TheraTears [70], Visine, and Clear Eyes all contain methyl paraben and propyl paraben as components.

4.   Items of Food

5.   Drinks: A lot of energy drinks, sports drinks, and flavored waters include methyl paraben and propyl paraben [71].

6.   Processed foods: Some processed foods, such as pastries, ice cream, and baked goods, include methyl paraben and propyl paraben [72, 75-80].

CONCLUSION

Therefore, the development of better extraction and analytical techniques would enable more accurate and extensive evaluation of environmental contaminants in complicated matrices. To provide a more realistic assessment of these contaminants' true ecological and health danger, greater research into their acute and chronic toxicity is required. Lastly, packaging that educates customers about how cosmetics affect the environment may persuade them to use these goods more sensibly and wisely. The most sophisticated set of laws governing cosmetic items worldwide is the EU Cosmetics Regulation (Regulation 1223/2009/EC). Before being put on the market, all chemicals and cosmetics go through rigorous dermatological and toxicological testing. The evaluation considers the product's frequency of use (daily, weekly, or frequently throughout the day) as well as its possible users (child, pregnant woman, or anyone with sensitive skin). As well as the intended usage of the product. The Scientific Committee on Safety of Cosmetics, an independent advisory body of the European Commission made up of toxicologists, allergists, epidemiologists, and specialists, conducts additional toxicological tests for substances whose safety is questionable. In risk assessment. In some situations, the European Commission may decide to restrict or outright ban the use of a certain ingredient in cosmetics in accordance with the committee's recommendations. There are no dangerous substances in cosmetics that are legally sold in the European Union, including Poland that could endanger the health or safety of customers.

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