Methylparaben is used in cosmetics as an antimicrobial preservative. It is practically nonirritating and nonsensitizing to normal skin, and has only very weak estrogenic properties. It is considered to be safe for use in cosmetics up to a concentration of 0.4%.

Scientific Research

Caution: Please read's medical disclaimer.

Table of contents:

1. Sources

1.1 In nature

Methylparaben is the ester of the alcohol methanol and p-hydroxybenzoic acid, a compound produced in small quantities by all plants.[1] Methylparaben naturally occurs in some plants, including birthwort,[2] Guan pepper,[3] thale cress[4] and cloudberry.[5] It has also been detected in the herbaceous plants Oxalis tuberosa[6] and Andrographis paniculata,[7] and is known to be produced by 2 species of fungi[8][9] as well as by the honey bee in the production of royal jelly.[10]

While blueberries, blackberries, strawberries, olive and honeysuckle are often claimed to be natural sources of methylparaben, this is not technically correct. What the first 4 contain is p-hydroxybenzoic acid, the precursor and metabolite of methylparaben.[11][12][13][14] Honeysuckle actually contains 3,4,5-trihydroxybenzoic acid, also known as gallic acid.[15][16]

1.2 In food

Methylparaben is used as a preservative in foods due to its antimicrobial properties.[17][18][19] It is considered by the US FDA to be generally recognized as safe (GRAS) when used as a preservative in foods up to a concentration of 0.1%. This includes its use in fruit preserves, jams, and jellies, but it is not tolerated in milk from dairy animals.[20] In 2004, the European Food Safety Authority (EFSA) Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food reiterated its opinion of an acceptable daily intake of 0-10 mg/kg per day for the sum of methylparaben, ethylparaben and propylparaben.[21] The Joint WHO/FAO Expert Committee on Food Additives (JECFA) holds a similar view, but does not include propylparaben in the acceptable daily intake.[22]

Tests on foodstuffs from the US and China have revealed the prevalence of parabens in food. >90% of 267 food samples from the US, including beverages, dairy products, fats and oils, fish and shellfish, grains, meat, fruits, and vegetables contained parabens,[23] and >99% of 282 food samples from China, including cereals and cereal products, meat, fish and seafood, eggs, dairy products, bean products, fruits, vegetables, cookies, beverages, cooking oils and condiments, contained parabens.[24] Methylparaben was among the most common paraben analog found in both studies.[23][24] Other studies point to the presence of methylparaben in fish in streams and rivers affected by sewage.[25][26][27]

Based on the reported concentrations of parabens in foods in the United States and in China, the contribution of dietary intake to paraben levels has been estimated to be 5.5%, 2.6% and 0.42% for Chinese males, Chinese females, and United States adults, respectively.[28] In the Philippines, the estimated dietary human exposure to methyparaben, ethylparaben, propylparaben and butylparaben through fish meat intake was 2 μg/kg/day, 5000-times lower than the maximum acceptable daily intake (10 mg/kg/day).[29]

Methylparaben has been detected in human milk samples, with one study revealing its presence in 34.1% of defatted milk samples from 54 participating mothers. This was higher than ethylparaben (19.5%) and propylparaben (14.6%). The estimated median daily intake of parabens with human milk by infants was 192.5-301.3 ng/kg body weight/day. The maximum intake for methylparaben amounted to 1,314.9 ng/kg body weight/day however, indicating wide inter-individual variability.[30]

1.3 In pharmaceuticals

Parabens are also used as preservatives in pharmaceuticals, including suppositories, anaesthetics, eyewashes, pills, syrups, weight-gaining solutions, injectable solutions and contraceptives. Because preservatives are considered inactive ingredients, the US FDA does not include preservatives in its over-the-counter drug monographs. In 2004, methylparaben was found in concentrations ranging from 0.0014% to 70% in various drug products approved by the FDA. In addition, the FDA has specified 0.1% methylparaben for standard preparation B, a homosalate sunscreen used in SPF testing.[20]

1.4 In the urban environment

Parabens have been detected in paper products such as currency bills, tickets, business cards, food cartons, flyers, newspapers and sanitary wipes. Methylparaben was the predominant paraben analog found in these products, accounting for approximately 62% of the total paraben concentration in one study. On the basis of measured concentrations and the frequency of handling of paper products, the average daily intake of parabens through dermal exposure has been estimated to be 6.31 ng/day, with sanitary wipes contributing to the vast majority (>90%) of the exposures.[31]

Parabens have also been found in indoor dust in the US, China, Japan and Korea, at mean concentrations ranging from 1300-2890 ng/g among the four countries.[32] Methylparaben is again one of the most abundant parabens, a result that has been corroborated elsewhere.[33] Based on these measured concentrations, one study estimated a daily intake of 5.4 ng/kg body weight/day of parabens via dust ingestion, adding that the intake is 5-10 times higher in children than adults, and is highest for children in Korea and Japan.[32]

Another group in the US measured the median concentration of methylparaben in indoor air to be 2.9 ng/m3, leading to an estimated daily methylparaben intake through inhalation of 0.547 ng/kg body weight/day for adults and 1.91 ng/kg body weight/day for children.[34]

1.5 In personal care products

Like in food and pharmaceuticals, parabens also function as preservatives in cosmetics. According to the Cosmetic, Toiletry and Fragrance Association (now known as the Personal Care Products Council), cosmetic formulations may contain mixtures of parabens up to a concentration of 0.8%, or a single paraben up to a concentration of 0.4%.[20] This is the same as the maximum use concentrations authorized in the European Commission's Cosmetics Directive.[35]

The antimicrobial activity of parabens increases with the length of the alkyl chain, which suggests that methylparaben has the weakest antimicrobial activity of all parabens.[36] However, water solubility decreases with increasing alkyl chain length, which may be a more important factor in cosmetics because microbial replication generally occurs in the water phase of oil/water formulations.[37] Indeed, one study concluded that methylparaben is the most effective preservative among the parabens and recommended that it be used at the highest possible concentration, supplemented by ethylparaben only when there is some limitation on the concentration of methylparaben.[38]

In 2006, methylparaben was used in at least 8786 personal care products in the US across a wide range of product categories including baby products, bath products, makeup, hair products, nail care products, oral hygiene products, shaving products, skin care products and suntan products. An industry survey had earlier established in 2003 that the concentration of methylparaben used in such products ranged from 0.0003% to 1%.[20] 2 recent studies demonstrate that parabens are also commonly found in cosmetics and personal care products in China, including those meant for childen.[39][40]

The use of parabens in cosmetics and personal care products appears to have declined over the past decade. In 1995, tests on 215 cosmetic products revealed that nearly all (99%) of the leave-on cosmetics and 77% of the rinse-off cosmetics contained parabens.[41] This contrasts with a survey in 2011which found parabens listed in the ingredient labels of 44% out of 204 cosmetic products.[42] More recently, another survey in 2013 of 170 personal care products found that ~40% of rinse-off products and ~60% of leave-on products contained parabens.[43] Methylparaben remains one of the most common and abundant paraben used in personal care and cosmetic products,[41][44][45][42][39] but its concentration of use appears to have dropped, as recent surveys now report maximum concentrations on the order of 1000 μg/g of the product, or about 0.1%.[43][40]

According to the Personal Care Products Council, the daily use of cosmetic products that may contain parabens amounts to an estimated 17.76g for adults and 378mg for infants.[20] It has been separately estimated that the total dermal intake of parabens from personal care products for adult females is 31μg/kg-bw/day.[43]

2. Exposure

Given the ubiquity of parabens, several studies have sought to quantify paraben exposure in the general population. An analysis of 2,548 urine samples from a representative sample of the US population detected methylparaben in 99.1% of the samples. Adolescent and adult females had significantly higher concentrations of methylparaben than adolescent and adult males, as did non-Hispanic blacks compared to non-Hispanic whites, except at older ages.[46] These gender and ethnic differences in methylparaben levels have been reported elsewhere,[47][48] and are thought to be a reflection of the differences in the use of beauty, hair and/or skin care products, though potential differences in the diet cannot be ruled out as a contributor.[46] A later study supported this hypothesis, finding a significant association between the use of skin lotions and the concentrations of native parabens in the urine of postmenopausal women.[49]

An investigation of 109 urine samples collected from Chinese young adults detected methylparaben, ethylparaben and propylparaben in all samples, as well as a 2-fold greater urinary concentration of parabens in females than in males. Methylparaben was the predominant paraben, accounting for 57-98% of the total paraben concentration. Based on the measured urinary concentrations, daily intake of parabens by Chinese young adults was estimated to be 18.4 and 40.8 μg/kg bw/day for Chinese males and females, respectively, lower than the value reported for adults in the United States (74.7 μg/kg bw/day).[28] Both results have been replicated elsewhere.[50] The same was true when Chinese children and US children were compared. US children had a median paraben concentration of 54.6 ng/ml, more than 5 times the median level measured in Chinese children, which was 10.1 ng/ml. However, Chinese children had 2-3 times higher concentrations of p-hydroxybenzoic acid in the urine than US children. As a result, the daily intake of methylparaben for Chinese children was estimated at 0.5-0.7 mg/day, similar to that determined for US children.[50]

Exposure to parabens also appears to be a routine event for individuals in Denmark, Canada and Spain, as evidenced by the presence of parabens in urine samples from these countries.[51][52][53] Measurable levels of methylparaben were detected in 98% of urine samples from 60 Danish men, in addition to the majority of serum and seminal plasma samples.[51] All 39 patients in an western Canadian primary care clinic had methylparaben in their urine,[52] as did all 120 pregnant Spanish women who participated in an Environment and Childhood project.[53]

Women show more temporal variation of urinary paraben concentrations, possibly reflecting changes in their use of personal care products over time.[47] The levels of methylparaban and propylparaben, too, are slightly more variable in women than in men. In addition, urinary paraben concentrations are 25-45% lower during pregnancy for women,[48] with evidence suggesting that that concentrations decrease with each additional week of pregnancy.[47]

3. Topical bioavailability

3.1 Penetration

Methylparaben is able to penetrate animal skin. In an experiment, 60% of methylparaben that had been applied to excised rabbit ear skin were found across the skin after 8 hours of contact. This was much higher than ethylparaben and propylparaben, of which only 40% and 20% penetrated through the skin respectively.[54] Similarly, more methylparaben crossed human epidermis and dermis than ethylparaben, propylparaben and butylparaben because of its shorter alkyl chain and hence lower lipophilicity. Even for methylparaben however, the percentage that crossed human abdominal skin after 3 applications of a paraben-containing body lotion in 36 hours was a mere 0.6%.[55]

The vehicle influences the rate of methylparaben penetration. Flux from oil/water emulsions was higher than from water/oil emulsions in one study,[56] and the absorption rate of methylparaben was higher from emulsions than from hydrogels in another.[57] The use of colloidal microgels has also been demonstrated to slow the transport rate of methylparaben by 2/3-fold compared to a saturated solution,[58] and 2-hydroxypropyl-beta-cyclodextrin has been shown to suppress the percutaneous absorption of methylparaben through mouse skin in vivo by 66%.[59]

The effect of occlusion on methylparaben penetration is strongly vehicle-dependent. While 6-7-fold increases in epidermal flux were observed for acetone and ethanol vehicles, a decrease was seen following occlusion of an ointment formulation. Moreover, occlusion of the ointment, but not the acetone or ethanol vehicles, led to a reduction in the epidermal retention of methylparaben.[60]

Penetration enhancers can markedly increase the permeation of methylparaben by perturbing the lipid lamella of the stratum corneum, making the lipid bilayer more fluid. In experiments on excised guinea pig dorsal skin, 1% I-menthol in 15% ethanol increased the permeability coefficient of methylparaben by about 16 times, and a 0.025% suspension of N-dodecyl-2-pyrrolidone increased the permeability coefficient of methylparaben by about 7 times.[61] Another study showed that Transcutol CG enhanced the epidermal-dermal diffusivity of methylparaben in pig ear skin.[57] Palmitoleic acid, linoleic acid and oleic acid at concentrations ranging from 5-20% in benzyl alcohol also increased the penetration of methylparaben through human skin.[62] Surprisingly, 4-cyanophenol, which is not expected to act as a permeation enhancer, increased both the dermal penetration rate and stratum corneum uptake of methylparaben,[63] and niacinamide increased the flux of methylparaben across rabbit ear skin.[64] On the other hand, the polymeric additive PMB inhibits the skin permeability of methylparaben.[65] It has also been discovered that the combination of methylparaben + ethylparaben, as well as of methylparaben + propylparaben significantly reduces the permeation rate of methylparaben through pig ear skin.[66]

Other factors that can affect the absorption and skin retention of methylparaben include heat (temperature) and the time of storage.[56][67]

In 2013, the European Commission's Scientific Committee on Consumer Safety (SCCS) reiterated that it would use a dermal absorption value of 3.7% for parabens in its margin of safety calculations until better data on humans becomes available.[68] This figure originated from the mean dermal absorption of 37% measured in split-thickness skin, using a correction factor of 10 to account for skin metabolism.[35]

3.2 Metabolism

A portion of the methylparaben that is absorbed is hydrolyzed by carboxylesterases in the skin to p-hydroxybenzoic acid.[69] In fact, a carboxyesterase that prefers methylparaben has been detected in an extract from human subcutaneous fat tissue.[70]

The extent of hydrolysis varies in different animal skins. Native methylparaben was not detected in the plasma at all after topical application in rats in one study.[71] Similarly, when 0.1% methylparaben was applied to intact pig ear skin, only a small amount of unmetabolized methylparaben (2 to 5.8% of the applied dose) penetrated through the skin after 4 hours. A much larger amount of p-hydroxybenzoic acid (37-73%) was found in the receptor fluid, indicating that most methylparaben is hydrolyzed during its passage through the skin.[57] Still, it is important to note that results from experiments on animal skin may not be representative of human skin. Rat skin is known to hydrolyze parabens much more quickly and completely than human skin, for instance.[72] An experiment utilizing dermatomed rat skin and human skin samples illustrates this difference, showing that 24% methylparaben was unmetabolized after crossing rat skin, compared to 60% for human skin.[73]

An in vivo study in which a 0.15% methylparaben emulsion was applied to the forearm of human volunteers found that 18% of the applied dose remained unmetabolized in the stratum corneum after 1 hour and rapidly declined thereafter. Methylparaben did appear to accumulate in the stratum corneum over time with repeated applications every 12 hours in this study, but its concentration also decreased quickly back to the baseline level within 2 days after the subjects stopped using the formulations.[74]

Part of the absorbed methylparaben may also be transesterified to ethylparaben in the presence of ethanol, as shown in an experiment on the excised skin of a Yucatan micropig.[75] In addition, because human biomonitoring studies show the presence of paraben conjugates in addition to free parabens in the urine,[46][50] it is assumed that some of the parabens dermally taken up into the systemic circulation are converted to paraben conjugates in the liver and other organs.

Comparatively, methylparaben and ethylparaben seem to be hydrolyzed more quickly in the skin than propylparaben, butylparaben or benzylparaben.[69]

3.3 Systemic exposure

Topical administration of methylparaben should be safer compared to oral and subcutaneous administration as <50% of the dose was absorbed in rats, resulting in a much lower systemic exposure compared to the other routes.[71]

Mechanical damage of the skin can increase the rate of systemic availability of both methylparaben and p-hydroxybenzoic acid. This has led to the suggestion that it should not be included in products intended for skin where the barrier function is compromised.[57]

3.4 Elimination

Irregardless of the route of administration, the major pathway of elimination for methylparaben is through the urine.[71] Methylparaben is primarily excreted in human urine as the glucuronide and sulfate conjugates.[76] The data suggests that a single dose of methylparaben is rapidly cleared, and not selectively stored in organs or tissues.[35]

4. Safety

4.1 Effects on skin cells

Methylparaben has been shown to significantly reduce RNA and DNA biosynthesis in cultures of embryonic mouse fibroblasts.[77] Normal human keratinocytes cultured in media containing 0.001% or 0.003% methylparaben for 1 month were larger and flatter and had decreased proliferating ability, characteristic of senescent cells. The cells also had reduced expressions of hyaluronan synthase 1 and 2 mRNAs and type IV collagen, the levels of which are known to decline with aging. Furthermore, the expression of the differentiation markers involucrin and HSP27 were increased. These findings suggest that methylparaben may influence the aging and differentiation of keratinocytes.[74]

4.2 Skin irritation and sensitization

Parabens are weak sensitizers with an expected sensitization rate of around 1%.[78][79] They are among the least sensitizing preservatives in commercial use, with reports of paraben-induced allergic contact dermatitis often attributable to the application of parabens on damaged rather than normal, unbroken skin.[80]

A 10-year overview of results of preservatives patch testing in Europe showed a relatively flat percentage of positive reactions to parabens, varying from 0.5% to 1%,[81] and a 5-year multicenter study in Germany alone found a 1.6% positive reaction rate from patch test data from 22,602 patients tested with a 15% paraben mix in petrolatum.[82] Similarly, patch test results from the North American Contact Dermatitis Group consistently showed a positive reaction response to parabens between 0.6% to 2.3% from 1984-2002.[83][84][85][86][87]

Patch test results from Singapore from 2006-2011 revealed a sensitization frequency of 2.58% for parabens,[88] while in Australia parabens were among the least frequent sensitizers (1.1%).[89]

4.3 Phototoxicity

Although one study found more apoptotic and necrotic cells in methylparaben-treated cultures of human keratinocytes compared to the control,[74] another study indicated that methylparaben itself may not be cytotoxic, because it did not increase the number of apoptotic or necrotic cells in cultures of human keratinocytes that were not exposed to UV radiation. Methylparaben did increase the number of necrotic cells produced as a result of UV radiation exposure, however, possibly attributable to its enhancement of UVB-induced reactive oxygen species and nitric oxide production, NF-kB and AP-1 activation, and lipid peroxidation.[90] This is supported by another study which indicated that methylparaben and ethylparaben may induce oxidative stress in the skin by reacting with singlet oxygen and glutathione in visible light to produce glutathione conjugates of hydroquinone.[91]

UV irradiation of methylparaben isolated in solid argon has been shown to result in its conversion into highly reactive methylparaben radical and isomeric ketenes.[92] In another experiment, 2 major photoproducts were detected after sunlight irradiation of an aqueous solution of methylparaben. These were p-hydroxybenzoic acid and 3-hydroxy methylparaben. Both were inactive in an in vitro DNA damage assay, but the latter can be metabolized in the skin to form protocatechuic acid, which does cause distinct DNA damage.[93]

4.4 Genotoxicity

The results of 3 different assays evaluating the genotoxicity of methylparaben were reported in 1974. The first was a host-mediated assay that showed that methylparaben did not induce significant increases in mutant or recombinant frequencies with S. typhimurium or S. cerevisiae. The second, a cytogenic assay, found that methylparaben did not induce detectable abberations in the chromosomes of either rat bone marrow cells in metaphase or human lung cells in anaphase. The third, a dominant lethal assay, likewise did not find methylparaben to be mutagenic.[20] Methylparaben did increase chromosomal aberrations by 15% in a test on Chinese hamster cells however.[94]

4.5 Potential endocrine disruptor

Methylparaben has the weakest estrogenic activity and the lowest affinity for estrogen receptors among the parabens.[95] It was approximately 7 orders of magnitude weaker than estradiol in activating human estrogen receptors in one study.[96] Another study found that it increased uterine weights in female rodents in vivo after oral, subcutaneous or dermal administration, but that its relative uterotrophic potency was much lower than estradiol.[97] Other uterotrophic assays have failed to find a estrogenic effect for methylparaben, confirming that it is not a potent estrogen in vivo.[96][98] Moreover, gene expression profiling of 120 estrogen-responsive genes revealed a negative correlation coefficient for methylparaben.[99]

There are conflicting results on the estrogenic activity of p-hydroxybenzoic acid, a major metabolite of methylparaben. One study found that p-hydroxybenzoic acid injected subcutaneously into female mice led to a dose-dependent estrogen-like effect, as evidenced by significant increases in uterine weights.[100] However, other uterotrophic assays were not able to confirm this effect, showing that uterus weights in female mice administered p-hydroxybenzoic acid were not significantly increased or were even significantly decreased compared to controls.[20][98]

It has been hypothesized that parabens' inhibition of estrogen sulfotransferases (SULTs) in the skin elevates estrogen levels, contributing to their estrogenic effect. Methylparaben is a weak inhibitor of SULTs (the weakest amongst the parabens), whereas p-hydroxybenzoic acid displayed no inhibitory activity towards SULTs.[101]

Methylparaben was not found to bind to androgen receptors,[102][103] nor to inhibit androgen sulfation,[101] but it did inhibit testosterone-induced transcriptional activity by 40% at a concentration of 10µm in a cell-based assay.[104]

Finally, it is important to note that endocrine disruption per se is not a toxic endpoint in itself, but a mechanism by which toxic effects may occur. Furthermore, endocrine effects are usually reversible, and it is possible that the effects of very low potency estrogens such as methylparaben may be irrelevant at low exposures.[105]

4.6 Effects on male reproduction

Methylparaben inactivated human sperm in vitro at a concentration of 6 mg/ml in one study. Because this was the lowest concentration tested, it is possible that methylparaben may also inactivate sperm at lower concentrations.[106] However, male rats fed up to 1% methylparaben in the diet did not exhibit any statistically significant differences in the weight of the testes, epididymides, prostates, seminal vesicles or preputial glands, nor were their sperm counts, sperm motility, the distribution pattern of sperm developmental stages or the serum levels of their reproductive hormones affected.[107][108] It has been suggested that this may be due to rapid metabolism of the parabens by esterases in vivo.[108]

In the early-to-mid 2000s, the link between the use of paraben-containing underarm cosmetics and breast cancer was promoted through a number of publications. It was noticed that the underarm area is directly adjacent to the breast and that the upper outer quadrant of the breast, which is close to where underarm cosmetics are applied, is the most frequent site of breast cancer.[109][110] Moreover, estrogens are known to be involved in breast cancer, and parabens, which had been reported to be present in the vast majority of cosmetic products, had been shown to exert weak estrogenic effects[111] as well as to exist in human breast tumours, albeit at low levels.[112] These papers raised public interest and concern over the role of estrogenic ingredients such as methylparaben in breast cancer.[113]

The hypothesis was also controversial within the scientific community and opened a discussion on the evidence linking the use of underarm cosmetics to a higher incidence of breast cancer. Several important deficiencies in the study design were raised, including but not limited to the lack of control tissue, the use of blank samples that were contaminated with parabens, the high variability in the individual blank values and the lack of studies of the donors' exposure to consumer paraben-containing products and whether they were using any paraben-containing cancer drugs. In addition, it was noted that methylparaben, which was present at the highest level in breast tumours, had shown the lowest estrogenicity in vitro and in vivo, that existing epidemiological data indicated an absence of an association between underarm cosmetics and breast cancer, and that the majority of underarm cosmetics do not actually contain parabens as preservatives.[114][115][116]

In response, the original authors stated that they had never intended to link tumour grade, quadrant incidence of breast tumours or underarm cosmetic use in patients. They also acknowledged that their study on the concentrations of parabens in breast tumours could not identify the route or entry or source of the parabens, and that they had not claimed that the presence of the parabens had caused the breast tumours.[117][118][119][120]

After reviewing the evidence, the European Commission's Scientific Committee on Consumer Products concluded in 2005 that there was insufficient data to establish a clear link between the use of paraben-containing underarm cosmetics and breast cancer. They noted that although breast cancer tumours occur most frequently in the upper quadrant of the breast, which is closest to the armpit, a clear relationship has been found with the amount of gland tissue present at that location. Also, they considered an exchange process from the armpit to the breast tissue highly speculative, since it is clinically well-established that the circulation of blood and lymph goes from the breast towards the armpit and not vice-versa. Finally, they also noted that parabens, including methylparaben, were orders of magnitude less potent than estradiol, the predominant and strongest naturally occurring estrogen in the body.[121]

However, more recent research indicate that parabens exist in human breast tissue at concentrations sufficient to stimulate the proliferation of human breast cancer cells,[122] that they can increase the migratory and invasive properties of human breast cancer cells,[123] and that they can induce anchorage-independent growth of human breast epithelial cells, a property closely related to transformation and a predictor of tumour growth in vivo.[124] Neither the Cosmetic Ingredient Review Expert Panel nor the European Commission's Scientific Committee on Consumer Safety have re-evaluated the safety of parabens in cosmetics taking into account these new information

Scientific References

  1. Viitanen PV, et. al. Metabolic engineering of the chloroplast genome using the Echerichia coli ubiC gene reveals that chorismate is a readily abundant plant precursor for p-hydroxybenzoic acid biosynthesis. Plant Physiol. (2004)
  2. Wu TS, Ou LF, Teng CM. Aristolochic acids, aristolactam alkaloids and amides from Aristolochia kankauensis. Phytochemistry. (1994)
  3. Pereda-Miranda R, et. al. Methyl 4-hydroxy-3-(3'-methyl-2'-butenyl)benzoate, major insecticidal principle from Piper guanacastensis. J Nat Prod. (1997)
  4. Walker TS, et. al. Metabolic profiling of root exudates of Arabidopsis thaliana. J Agric Food Chem. (2003)
  5. Baardseth P, Russwurm H. Content of some organic acids in cloudberry (Rubus chamaemorus L.) Food Chem. (1978)
  6. Bais HP ,Vepachedu R, Vivanco JM. Root specific elicitation and exudation of fluorescent β-carbolines in transformed root cultures of Oxalis tuberosa. Plant Physiol Biochem. (2003)
  7. Li W, et. al. p-Hydroxybenzoic acid alkyl esters in Andrographis paniculata herbs, commercial extracts, and formulated products. J Agric Food Chem. (2003)
  8. El Aissami A, et. al. Contribution to the study of the chemical composition of Verticillium albo-atrum secretions in liquid media. Mycopathologia. (1998)
  9. Macías M, et. al. Phytotoxic compounds from the new coprophilous fungus guanomyces polythrix. J Nat Prod. (2000)
  10. Ishiwata H, et. al. Determination and confirmation of methyl p-hydroxybenzoate in royal jelly and other foods produced by the honey bee. Food Addit Contam. (1995)
  11. Sellappan S, Akoh CC, Krewer G. Phenolic compounds and antioxidant capacity of Georgia-grown blueberries and blackberries. J Agric Food Chem. (2002)
  12. Céspedesa CL, et. al. Phytochemical profile and the antioxidant activity of Chilean wild black-berry fruits, Aristotelia chilensis (Mol) Stuntz (Elaeocarpaceae). Food Chem. (2010)
  13. Huang WY, et. al. Survey of antioxidant capacity and phenolic composition of blueberry, blackberry, and strawberry in Nanjing. J Zhejiang Univ Sci B. (2012)
  14. Aziz NH, et. al. Comparative antibacterial and antifungal effects of some phenolic compounds. Microbios. (1998)
  15. Gazdik Z, et. al. Use of liquid chromatography with electrochemical detection for the determination of antioxidants in less common fruits. Molecules. (2008)
  16. Jurikova T, et. al. Phenolic profile of edible honeysuckle berries (genus lonicera) and their biological effects. Molecules. (2011)
  17. Karaca H, et. al. Evaluating food additives as antifungal agents against Monilinia fructicola in vitro and in hydroxypropyl methylcellulose-lipid composite edible coatings for plums. Int J Food Microbiol. (2014)
  18. Siegel M. Fungistatic activity of methylparaben and propylparaben. Antibiot Chemother (Northfield Ill). (1953)
  19. Nes IF, Eklund T. The effect of parabens on DNA, RNA and protein synthesis in Escherichia coli and Bacillus subtilis. J Appl Bacteriol. (1983)
  20. 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)
  21. Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food. Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food on a Request from the Commission related to para hydroxybenzoates. The EFSA Journal. (2004)
  22. Joint FAO/WHO Expert Committee on Food Additives. Toxicological recommendations and information on specifications. Sixty-seventh meeting. (2006)
  23. Liao C, Liu F, Kannan K. Occurrence of and dietary exposure to parabens in foodstuffs from the United States. Environ Sci Technol. (2013)
  24. Liao C, Chen L, Kannan K. Occurrence of parabens in foodstuffs from China and its implications for human dietary exposure. Environ Int. (2013)
  25. Yamamoto H, et. al. Aquatic toxicity and ecological risk assessment of seven parabens: Individual and additive approach. Sci Total Environment. (2011)
  26. Renz L, et. al. A study of parabens and bisphenol A in surface water and fish brain tissue from the Greater Pittsburgh Area. Ecotoxicology. (2013)
  27. Jakimska A, et. al. Development of a liquid chromatography-tandem mass spectrometry procedure for determination of endocrine disrupting compounds in fish from Mediterranean rivers. J Chromatogr A. (2013)
  28. Ma WL, et. al. Urinary concentrations of parabens in Chinese young adults: implications for human exposure. Arch Environ Contam Toxicol. (2013)
  29. Ramaswamy BR, et. al. Determination of preservative and antimicrobial compounds in fish from Manila Bay, Philippines using ultra high performance liquid chromatography tandem mass spectrometry, and assessment of human dietary exposure. J Hazard Mater. (2011)
  30. Schlumpf M, et. al. Exposure patterns of UV filters, fragrances, parabens, phthalates, organochlor pesticides, PBDEs, and PCBs in human milk: correlation of UV filters with use of cosmetics. Chemosphere. (2010)
  31. Liao C, Kannan K. Concentrations and composition profiles of parabens in currency bills and paper products including sanitary wipes. Sci Total Environment. (2014)
  32. Wang L, et. al. Occurrence and human exposure of p-hydroxybenzoic acid esters (parabens), bisphenol A diglycidyl ether (BADGE), and their hydrolysis products in indoor dust from the United States and three East Asian countries. Environ Sci Technol. (2012)
  33. Ramírez N, Marcé RM, Borrull F. Determination of parabens in house dust by pressurised hot water extraction followed by stir bar sorptive extraction and thermal desorption-gas chromatography-mass spectrometry. J Chromatogr A. (2011)
  34. Rudel RA, et. al. Phthalates, alkylphenols, pesticides, polybrominated diphenyl ethers, and other endocrine-disrupting compounds in indoor air and dust. Environ Sci Technol. (2003)
  35. Scientific Committee on Consumer Safety. Opinion on parabens, 2010. SCCS. (2010)
  36. Murrell WG, Vincent JM. The esters of 4-hydroxybenzoic acid and related compounds. IV. The bacteriostatic action of n-alkyl 4-hydroxybenzoates. J Soc Chem Ind. (1950)
  37. Atkins F. Some aspects of creams in cosmetics. Manuf Chem. (1950)
  38. O'Neill JJ, Mead CA. The parabens: Bacterial adaptation and preservative capacity. J Soc Cosmet Chem. (1982)
  39. Wang P, et. al. Investigation of parabens in commercial cosmetics for children in Beijing, China. J Cosmet Sci. (2013)
  40. Guo Y, Wang L, Kannan K. Phthalates and parabens in personal care products from China: concentrations and human exposure. Arch Environ Contam Toxicol. (2014)
  41. Rastogi SC, et. al. Contents of methyl-, ethyl-, propyl-, butyl- and benzylparaben in cosmetic products. Contact Dermatitis. (1995)
  42. Yazar K, et. al. Preservatives and fragrances in selected consumer-available cosmetics and detergents. Contact Dermatitis. (2011)
  43. Guo Y, Kannan K. A survey of phthalates and parabens in personal care products from the United States and its implications for human exposure. Environ Sci Technol. (2013)
  44. Shen HY, et. al. Simultaneous determination of seven phthalates and four parabens in cosmetic products using HPLC-DAD and GC-MS methods. J Sep Sci. (2007)
  45. Msagati TA, et. al. Analysis and quantification of parabens in cosmetic products by utilizing hollow fibre-supported liquid membrane and high performance liquid chromatography with ultraviolet detection. Int J Cosmet Sci. (2008)
  46. Calafat AM, et. al. Urinary concentrations of four parabens in the U.S. population: NHANES 2005-2006. Environ Health Perspect. (2010)
  47. Tillett T. Here today, here tomorrow? Urinary concentrations of parabens over time. Environ Health Perspect. (2012)
  48. Smith KW, et. al. Predictors and variability of urinary paraben concentrations in men and women, including before and during pregnancy. Environ Health Perspect. (2012)
  49. Sandanger TM, et. al. Plasma concentrations of parabens in postmenopausal women and self-reported use of personal care products: the NOWAC postgenome study. J Expo Sci Environ Epidemiol. (2011)
  50. Wang L, et. al. Characteristic profiles of urinary p-hydroxybenzoic acid and its esters (parabens) in children and adults from the United States and China. Environ Sci Technol. (2013)
  51. Frederiksen H, Jørgensen N, Andersson AM. Parabens in urine, serum and seminal plasma from healthy Danish men determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). J Expo Sci Environ Epidemiol. (2011)
  52. Genuis SJ, et. al. Paraben levels in an urban community of Western Canada. ISRN Toxicol. (2013)
  53. Casas L, et. al. Urinary concentrations of phthalates and phenols in a population of Spanish pregnant women and children. Environ Int. (2011)
  54. Pedersen S, et. al. In vitro skin permeation and retention of parabens from cosmetic formulations. Int J Cosmet Sci. (2007)
  55. El Hussein S, et. al. Assessment of principal parabens used in cosmetics after their passage through human epidermis-sdermis layers (ex-vivo study). Exp Dermatol. (2007)
  56. Pozzo AD, Pastori N. Percutaneous absorption of parabens from cosmetic formulations. Int J Cosmet Sci. (1996)
  57. Pažoureková S, et. al. Dermal absorption and hydrolysis of methylparaben in different vehicles through intact and damaged skin: using a pig-ear model in vitro. Food Chem Toxicol. (2013)
  58. Lopez VC, Hadgraft J, Snowden MJ. The use of colloidal microgels as a (trans)dermal drug delivery system. Int J Pharm. (2005)
  59. Tanaka M, et. al. Effect of 2-hydroxypropyl-beta-cyclodextrin on percutaneous absorption of methyl paraben. J Pharm Pharmacol. (1995)
  60. Cross SE, Roberts MS. The effect of occlusion on epidermal penetration of parabens from a commercial allergy test ointment, acetone and ethanol vehicles. J Invest Dermatol. (2000)
  61. Kitagawa S, Li H, Sato S. Skin permeation of parabens in excised guinea pig dorsal skin, its modification by penetration enhancers and their relationship with n-octanol/water partition coefficients. Chem Pharm Bull (Tokyo). (1997)
  62. Nanayakkara GR, et. al. The effect of unsaturated fatty acids in benzyl alcohol on the percutaneous permeation of three model penetrants. Int J Pharm. (2005)
  63. Romonchuk WJ. Mechanism of enhanced dermal permeation of 4-cyanophenol and methyl paraben from saturated aqueous solutions containing both solutes. Skin Pharmacol Physiol. (2010)
  64. Nicoli S, et. al. Association of nicotinamide with parabens: effect on solubility, partition and transdermal permeation. Eur J Pharm Biopharm. (2008)
  65. Hasegawa T, et. al. Decrease in skin permeation and antibacterial effect of parabens by a polymeric additive, poly(2-methacryloyloxyethyl phosphorylcholine-co-butylmetacrylate). Chem Pharm Bull (Tokyo). (2005)
  66. Caon T, et. al. Evaluation of the transdermal permeation of different paraben combinations through a pig ear skin model. Int J Pharm. (2010)
  67. Akomeah F, et. al. Effect of heat on the percutaneous absorption and skin retention of three model penetrants. Eur J Pharm Sci. (2004)
  68. Scientific Committee on Consumer Safety. Opinion on parabens, 2013. SCCS. (2013)
  69. Jewell C, et. al. Hydrolysis of a series of parabens by skin microsomes and cytosol from human and minipigs and in whole skin in short-term culture. Toxicol Appl Pharmacol. (2007)
  70. Lobemeier C, et. al. Hydrolysis of parabenes by extracts from differing layers of human skin. Biol Chem. (1996)
  71. Aubert N, Ameller T, Legrand JJ. Systemic exposure to parabens: pharmacokinetics, tissue distribution, excretion balance and plasma metabolites of 14C-methyl-, propyl- and butylparaben in rats after oral, topical or subcutaneous administration. Food Chem Toxicol. (2012)
  72. Harville HM, Voorman R, Prusakiewicz JJ. Comparison of paraben stability in human and rat skin. Drug Metab Lett. (2007)
  73. Fasano WJ. Methylparaben and butylparaben: In vitro dermal penetration and metabolism in rat and human skin. E. I. du Pont de Nemours and Company, Haskell Laboratory (Du Pont-13966). (2004)
  74. Ishiwatari S, et. al. Effects of methyl paraben on skin keratinocytes. J Appl Toxicol. (2007)
  75. Oh SY, et. al. The effect of ethanol on the simultaneous transport and metabolism of methyl p-hydroxybenzoate in excised skin of Yucatan micropig. Int J Pharm. (2002)
  76. Ye X, et. al. Parabens as urinary biomarkers of exposure in humans. Environ Health Perspect. (2006)
  77. Krauze S, Fitak B. Influence on preservatives on the biosynthesis of nucleic acids and on the protein content of animal cells in tissue culture. Mitt Geb Lebensmittelunters Hyg. (1971)
  78. Menné T, Hjorth N. Routine patch testing with paraben esters. Contact Dermatitis. (1988)
  79. Menné T, et. al. Contact sensitization to 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one (MCI/MI). A European multicentre study. Contact Dermatitis. (1991)
  80. Hafeez F, Maibach H. An overview of parabens and allergic contact dermatitis. Skin Therapy Lett. (2013)
  81. Wilkinson JD, et. al. Monitoring levels of preservative sensitivity in Europe. A 10-year overview (1991-2000). Contact Dermatitis. (2002)
  82. Schnuch A, et. al. Patch testing with preservatives, antimicrobials and industrial biocides. Results from a multicentre study. Br J Dermatol. (1998)
  83. Storrs FJ, et. al. Prevalence and relevance of allergic reactions in patients patch tested in North America--1984 to 1985. J Am Acad Dermatol. (1989)
  84. Marks JG et. al. North American Contact Dermatitis Group standard tray patch test results (1992 to 1994). Am J Contact Dermat. (1995)
  85. Marks JG et. al. North American Contact Dermatitis Group patch test results for the detection of delayed-type hypersensitivity to topical allergens. J Am Acad Dermatol. (1998)
  86. Marks JG Jr, et. al. North American Contact Dermatitis Group patch-test results, 1996-1998. Arch Dermatol. (2000)
  87. Marks JG Jr, et. al. North American Contact Dermatitis Group patch-test results, 1998 to 2000. Am J Contact Dermat. (2003)
  88. Cheng S, et. al. Contact sensitivity to preservatives in Singapore: frequency of sensitization to 11 common preservatives 2006-2011. Dermatitis. (2014)
  89. Chow ET, et. al. Frequency of positive patch test reactions to preservatives: The Australian experience. Australas J Dermatol. (2013)
  90. Handa O, et. al. Methylparaben potentiates UV-induced damage of skin keratinocytes. Toxicology. (2006)
  91. Nishizawa C, et. al. Reaction of para-hydroxybenzoic acid esters with singlet oxygen in the presence of glutathione produces glutathione conjugates of hydroquinone, potent inducers of oxidative stress. Free Radic Res. (2006)
  92. Kuş N, Bayarı SH, Fausto R. Methylparaben isolated in solid argon: structural characterization and UV-induced conversion into methylparaben radical and isomeric ketenes. J Phys Chem B. (2013)
  93. Okamoto Y, et. al. Combined activation of methyl paraben by light irradiation and esterase metabolism toward oxidative DNA damage. Chem Res Toxicol. (2008)
  94. Ishidate M Jr, et. al. Cytotoxicity test on medical drugs--chromosome aberration tests with Chinese hamster cells in vitro. Eisei Shikenjo Hokoku. (1978)
  95. Satoh K, et. al. Competitive binding of some alkyl p-hydroxybenzoates to human estrogen receptor alpha and beta. Yakugaku Zasshi. (2000)
  96. Routledge EJ, et. al. Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic. Toxicol Appl Pharmacol. (1998)
  97. Lemini C, et. al. In vivo and in vitro estrogen bioactivities of alkyl parabens. Toxicol Ind Health. (2003)
  98. Hossaini A, Larsen JJ, Larsen JC. Lack of oestrogenic effects of food preservatives (parabens) in uterotrophic assays. Food Chem Toxicol. (2000)
  99. Terasaka S, et. al. Expression profiling of estrogen-responsive genes in breast cancer cells treated with alkylphenols, chlorinated phenols, parabens, or bis- and benzoylphenols for evaluation of estrogenic activity. Toxicol Lett. (2006)
  100. Lemini C, et. al. Estrogenic effects of p-hydroxybenzoic acid in CD1 mice. Environ Res. (1997)
  101. Prusakiewicz JJ, et. al. Parabens inhibit human skin estrogen sulfotransferase activity: possible link to paraben estrogenic effects. Toxicology. (2007)
  102. Fang H, et. al. Study of 202 natural, synthetic, and environmental chemicals for binding to the androgen receptor. Chem Res Toxicol. (2003)
  103. Satoh K, et. al. Androgenic and Antiandrogenic Effects of Alkylphenols and Parabens Assessed Using the Reporter Gene Assay with Stably Transfected CHO-K1 Cells (AR-EcoScreen System). J Health Sci. (2005)
  104. Chen J, et. al. Antiandrogenic properties of parabens and other phenolic containing small molecules in personal care products. Toxicol Appl Pharmacol. (2007)
  105. Harvey PW, Johnson I. Approaches to the assessment of toxicity data with endpoints related to endocrine disruption. J Appl Toxicol. (2002)
  106. Song BL, Li HY, Peng DR. In vitro spermicidal activity of parabens against human spermatozoa. Contraception. (1989)
  107. Oishi S. Lack of spermatotoxic effects of methyl and ethyl esters of p-hydroxybenzoic acid in rats. Food Chem Toxicol. (2004)
  108. Hoberman AM, et. al. Lack of effect of butylparaben and methylparaben on the reproductive system in male rats. Birth Defects Res B Dev Reprod Toxicol. (2008)
  109. Darbre PD. Underarm cosmetics and breast cancer. J Appl Toxicol. (2003)
  110. Harvey PW. Parabens, oestrogenicity, underarm cosmetics and breast cancer: a perspective on a hypothesis. J Appl Toxicol. (2003)
  111. Byford JR, et. al. Oestrogenic activity of parabens in MCF7 human breast cancer cells. J Steroid Biochem Mol Biol. (2002)
  112. Darbre PD, et. al. Concentrations of parabens in human breast tumours. J Appl Toxicol. (2004)
  113. Harvey PW, Darbre P. Endocrine disrupters and human health: could oestrogenic chemicals in body care cosmetics adversely affect breast cancer incidence in women? J Appl Toxicol. (2004)
  114. Golden R, Gandy J. Comment on the publication by Darbre et al. (2004). J Appl Toxicol. (2004)
  115. Jeffrey AM, Williams GM. The paper by Darbre et al. (2004) reports the measurement of parabens in 20 human breast tumors. J Appl Toxicol. (2004)
  116. Flower C. Observations on the paper by Darbre et al. (2204). J Appl Toxicol. (2004)
  117. Darbre PD, et. al. Reply to Robert Golden and Jay Gandy. J Appl Toxicol. (2004)
  118. Darbre PD, et. al. Reply to Alan M. Jeffrey and Gary M. Williams. J Appl Toxicol. (2004)
  119. Darbre PD, et. al. Reply to Christopher Flower. J Appl Toxicol. (2004)
  120. Harvey PW. Discussion of concentrations of parabens in human breast tumours. J Appl Toxicol. (2004)
  121. Scientific Committee on Consumer Products. Extended Opinion on Parabens, Underarm Cosmetics and Breast Cancer. SCCP. (2005)
  122. 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)
  123. Khanna S, Dash PR, Darbre PD. Exposure to parabens at the concentration of maximal proliferative response increases migratory and invasive activity of human breast cancer cells in vitro. J Appl Toxicol. (2014)
  124. Khanna S, Darbre PD. Parabens enable suspension growth of MCF-10A immortalized, non-transformed human breast epithelial cells. J Appl Toxicol. (2013)