Ethylparaben

Ethylparaben is an antimicrobial preservative that is considered safe for use in cosmetics up to a concentration of 0.4%.

Scientific Research


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Table of contents:

1. Sources

1.1 In food

Ethylparaben is the ester of p-hydroxybenzoic acid and ethanol. It is allowed as a component of adhesives intended for use in packaging, transporting or holding food. According to the Joint WHO/FAO Expert Committee on Food Additives (JECFA), the group acceptable daily intake for ethylparaben, methylparaben and propylparaben in foods is up to 10 mg/kg/day. The European Food Safety Authority Scientific Panel on Food Additives, Flavourings, Processing Adis and Materials in Contact with Food states that the acceptable daily intake for the sum of methylparaben and ethylparaben is up to 10 mg/kg/day, but that propylparaben should not be included in this acceptable daily intake.[1]

Investigations on foodstuffs from both the United States and China show that ethylparaben is among the predominant parabens in food from both countries, along with methylparaben and propylparaben.[2]

Ethylparaben was also detected in ~70% of analyzed fish samples from the Philippines, up to a concentration of 840 ng/g.[3][4]

1.2 In personal care products

Parabens function as preservatives in cosmetics. In 2002, 2679 cosmetic products were reported to the US FDA as containing ethylparaben. The products were from a wide range of categories including bath products, makeup, fragrances, hair products, nail care products, personal cleanliness products, products for shaving, skin care products and suntan products. An industry survey in 2003 revealed that the concentration of ethylparaben in personal care products ranged from 0.0002% to nearly 1% then.[1]

More recently, an analysis of 170 personal care products bought in New York found ethylparaben in 35% of baby care products, 28% of leave-on products and 10% of rinse-off products.[5] Tests on 52 personal care products from China revealed that ethylparaben was frequently present in face creams, face cleansers and body and hand lotions, with frequencies ranging from 50-73%, but was less common in shampoos (30%) and body washes (46%).[6] In addition, the maximum concentration of ethylparaben detected in these studies was 2770 μg/g of the product, corresponding to about 0.3%.[5][6]

Ethylparaben is authorized as a preservative in the European Commission's Cosmetics Directive at a maximum concentration of 0.4% when used individually, or at a total of 0.8% when used with other parabens.[7] The Cosmetic Ingredient Review Expert Panel has also found ethylparaben to be safe for use in cosmetics at these use levels.[1]

1.3 In the environment

The widespread use of parabens has resulted in their leaking into the environment. Parabens have been detected in aquatic environments as a result of discharges from wastewater plants.[8][9][10] While ethylparaben was not detected in the aquatic environment of the Greater Pittsburgh Area in the United States,[10] it was the main paraben observd in Indian rivers.[8]

Parabens present in indoor air and dust are thought to originate from personal care products used in households.[11][12] The concentration of ethylparaben detected in indoor air was 4 ng/m3 in a study in the US.[11] Ethylparaben has also been found in indoor house dust from Canada, Spain, the United States, China, Japan and Korea, though methylparaben and propylparaben usually predominate. The maximal measured concentration for ethylparaben was 3,110 ng/g.[11][12][13][14][15][16]

Ethylparaben has even been detected in a wide range of paper products such as sanitary wipes, paper currencies, flyers, tickets, envelopes, newspapers and printing paper, though typically at concentrations one order of magnitude lower than that of methylparaben.[17]

2. Exposure

Considering the prevalence of parabens, it is not surprising that the general population is widely exposed to them. A 2006 study measuring the urinary concentrations of 5 parabens in a demographically diverse group of 100 adults detected ethylparaben in 58% of the samples, which was lower than methylparaben (99%), propylparaben (96%) and butylparaben (69%), but higher than benzylparaben (39%).[18] A larger study conducted on the US population had similar results, finding ethylparaben in 42% of 2,548 urine samples but at a median concentration of at least one order of magnitude lower than those of methylparaben and propylparaben.[19] Ethylparaben was also found in all 109 urine samples from Chinese young adults, as well as in 39 consecutive patients in a primary care clinic in Western Canada.[20][21]

Ethylparaben has also been detected in human serum samples. A study in the US found that 53% of the tested samples contained ethylparaben, and that the median concentration was a relatively high 0.2 mg/ml.[22] Another study reported that ethylparaben was detected in 22% of plasma samples from 332 Norwegian women, with a median concentration of < 3 ng/ml. This study also found an association between the use of skin lotions and elevated native paraben levels in the plasma,[23] which agreed with the findings of a Puerto Rican study among pregnant women.[24]

3. Topical bioavailability

The penetration of parabens into human skin varies as a function of the alkyl chain length, with shorter-chain-length parabens penetrating better. This indicates that ethylparaben should penetrate the skin better than propylparaben, butylparaben and benzylparaben, but not as well as methylparaben.[25][26][27] However, the shorter the chain length, the less lipophilic the paraben and the more it crosses the skin layers, indicating that higher systemic exposure can be expected from ethylparaben than from propylparaben or butylparaben.[28] Indeed, 40% of ethylparaben crossed rabbit ear skin intact, compared to 20% for propylparaben, in one study.[27] Similarly, an experiment on excised human breast skin found that 44% of ethylparaben had been absorbed through the skin 24 hours after application, compared to 37% for propylparaben and butylparaben and 17% for benzylparaben.[29]

The skin permeation of ethylparaben can be modified by the use of penetration enhancers. A 0.025% suspension of N-dodecyl-2-pyrrolidone increased the skin permeability of ethylparaben slightly, but a mixture of 15% ethanol + 1% l-menthol had no effect on ethylparaben permeability, despite raising the skin permeability of methylparaben and butylparaben.[30] On the other hand, the polymeric additive poly(2-methacryloyloxyethyl phosphorylcholine-co-butylmetacrylate) (PMB) as well as niacinamide have been shown to reduce the skin permeation of ethylparaben through rat skin and rabbit ear skin respectively.[31][32] The binary combination of methylparaben + ethylparaben also decreases their penetration rates through pig ear skin significantly.[33] This reduction in transdermal penetration is beneficial for improving the toxicological risk of ethylparaben.[32]

Occlusion of the skin can both increase and decrease the penetration of parabens such as ethylparaben -- the effect is dependent on the vehicle used. Occlusion resulted in decreased penetration when the paraben is in an ointment vehicle, but led to increased penetration when the paraben was in an acetone or ethanol vehicle.[34]

Carboxylesterases that can hydrolyze parabens have been identified from extracts of human abdominal skin. The first was a carboxylesterase in subcutaneous fat that was maximally active with methylparaben and decreased in activity as the chain length increased, while both the second and third carboxylesterase (in subcutaneous fat and keratinocytes respectively) exhibited the opposite pattern, preferring butylparaben as a substrate and decreasing in activity with decreasing chain length.[35] The evidence indicates that in human skin, ethylparaben is hydrolyzed by the first isoform, carboxylesterase-1 (hCE1).[29]

The extent of ethylparaben hydrolysis in human skin appears low. When 25 µm/cm2 ethylparaben was applied to human breast skin, 11% remained on the skin surface, 36% remained unmetabolized within the skin, 44% penetrated through the skin as native paraben, and just 5% had been metabolized to p-hydroxybenzoic acid after 24 hours.[29]

4. Safety

4.1 Effects on skin cells

0.2 g/l ethylparaben has been shown to inhibit the incorporation of phosphate into the RNA and DNA of embryonic mouse fibroblasts.[36] In addition, a mixture of methylparaben and ethylparaben may be capable of inducing oxidative stress in the skin by reacting with singlet oxygen and glutathione in visible light to produce glutathione conjugates of hydroquinone.[37]

4.2 Skin irritation and sensitization

7% ethylparaben in propylene applied daily to the backs of humans for 5 days did not produce irritation, nor did it induce sensitization in a repeated-insult patch test.[38]

A report in 1968 concluded that overall, sensitization to parabens is not a problem in the United States on the basis of the results of repeated-insult patch tests.[39] This view has been affirmed elsewhere, with another study stating that the incidence of paraben contact sensitization in healthy Americans is low considering their extensive use.[40]

Indeed, patch test results from the North American Contact Dermatitis Group over the period 1984-2002 show that positive reactions to paraben mixtures ranged from 0.6% to 2.3%.[41][42][43][44][45] This is similar to the prevalence observed in Europe, where data on 4713 patients seen in 22 European clinics over 1 year revealed an overall positive reaction response to parabens in 1.08% of the cases,[46] and a 5-year multi-center study involving 22,602 patch-tested patients found a 1.6% positive reaction rate.[47] Parabens were also low frequency sensitizers (1.1%) in Australia,[48] whereas in Singapore they were relatively more frequent sensitizers (2.58%).[49]

4.3 Genotoxicity

When applied directly to Chinese hamster cells, ethylparaben resulted in a small (1-3%) increase in polyploid cell production, a form of chromosomal mutation. It was also judged to increase chromosomal aberrations such as chromatid breaks, chromatid gaps, chromosomal exchanges and ring formations, by 11%.[50][51]

4.4 Effects on male reproduction

Although 8 mg/ml of ethylparaben inactivated human sperm in vitro,[52] ethylparaben administered to male rats at doses of 0.1% and 1% for 8 weeks had no treatment-related effects on the weights of any part of the male reproductive organs, anti-spermatogenic effects, nor did it elicit changes in the levels of sex hormones.[53]

Male Drosophila melanogaster (fruit flies) exposed to up to 0.1% ethylparaben did show some reproductive toxicity however. The number of eggs laid and the number of offspring were reduced, and the time taken for the offspring to emerge from the eggs was prolonged.[54]

4.5 Potential endocrine disruptor

Several yeast bioassays show that ethylparaben has the ability to activate the human estrogen receptor, but that it is up to 6 orders of magnitude weaker than estradiol.[55][56][57][58] These findings agree with the results of 2 other studies in which the estrogenic activity of the parabens were assessed in vitro using the proliferation of human breast cancer cells. Maximum cell proliferation was seen at a concentration of ethylparaben that was ~6 orders of magnitude lower than that observed for estradiol in the first study,[59] whereas in the second study ethylparaben achieved the same stimulation on cell proliferation as estradiol only at a concentration that was ~7 orders of magnitude higher.[60]

Competitive binding assays have also revealed that parabens, including ethylparaben bind with equal relative affinity to estrogen receptors α and β, and that those with longer alkyl side-chains show higher affinity for the receptors.[61][62] In other words, the only paraben with weaker estrogenic activity than ethylparaben is methylparaben.[55][61][62]

A third method of testing for estrogenicity that has been employed for ethylparaben is the rodent uterotrophic assay. In one study, ethylparaben administered at a dose of 100 mg/kg/day did not increase uterine weights in a mouse uterotrophic assay, indicating that it is not a potent estrogen in vivo.[63] However, 2 studies conducted by a different group contradicted these findings, showing that ethylparaben produced significant increases in the uterine weights of rats and mice, albeit with a potency that was much lower than that of estradiol.[64][65]

An in vivo fish assay has also been used to determine the estrogenic effect of ethylparaben. This involved the intraperitoneal injection of ethylparaben into juvenile rainbow trout, and measuring the levels of vitellogenin, a molecular marker of exposure to estrogenic endocrine disruptive chemicals, in the plasma using an enzyme-linked immunosorbent assay. Ethylparaben only increased vitellogenin at the high dose level of 300 mg/kg, resulting in a level 60 times that observed at baseline. This compares to estradiol, which increased the levels of vitellogenin by a factor of 150 at a dose of just 1 mg/kg.[66]

Gene expression profiling of 120 estrogen-responsive genes revealed a small but significant positive correlation for ethylparaben. The correlation for ethylparaben was higher than that for methylparaben (which was negative) but lower than propylparaben and butylparaben, as expected. It was further noted that the gene expression profiles of propylparaben and ethylparaben were closer to each other than were the profiles of either compared with estrogen, suggesting that the expression of some genes are specific to the parabens.[67]

It has been argued that the inhibition of estrogen sulfotransferases (SULTs) in the skin by parabens can contribute to their estrogenic effect since it reduces the sulfation of estradiol, indirectly leading to higher levels of free estradiol. However, both methylparaben and ethylparaben inhibited SULTs in the skin to such a minor extent that the half maximal inhibitory concentrations could not be derived.[68]

Ethyparaben does not bind to androgen receptors[69] and does not appear to have agonist or antagonist activity at androgen receptors.[70]

2 papers published in 2003 hypothesized that underarm cosmetics may be linked to breast cancer by drawing upon observations that the armpit is directly adjacent to the upper outer quadrant of the breast, that this quadrant is the most frequent site of carcinoma, that estrogens are known to be involved in breast cancer and that parabens are weakly estrogenic and are included in many cosmetic products.[71][72] This hypothesis was supported by data showing that an earlier age of breast cancer diagnosis was associated with more frequent use of antiperspirants or deodorants and underarm shaving,[73] as well as data demonstrating the presence of intact parabens in human breast tumours. Specifically, methylparaben was measured at a 12.8 ng/g level, while ethylparaben, propylparaben and butylparaben were found at 2.0 to 2.6 ng/g.[74] The latter study was, however, criticized for a number of important deficiencies in the study design, including the fact that paraben concentrations were not measured in control tissue, the use of blank samples that were contaminated with parabens, the high variability in the individual blank values, and the lack of consideration of the tissue donors' exposure to consumer products or pharmaceuticals containing parabens. It was also pointed out that methylparaben, the most frequently occurring paraben detected in the breast tissue, had shown the lowest estrogenicity in in vitro and in vivo studies, and that the majority of underarm cosmetics do not actually contain parabens as preservatives.[75][76][77] Moreover, a population-based case-control study found that the risk of breast cancer did not increase with either antiperspirant or deodorant use.[78]

After reviewing the scientific literature, 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 underarm cosmetics (with or without parabens) and breast cancer. The Committee also noted that hormones do not play a significant role in the pathogenesis of a significant proportion of breast cancers, that a clear relationship exists between the amount of gland tissue at the upper quadrant of the breast, which explains the more frequent occurrence of breast cancer tumours at that location, and that the circulation of blood/lymph goes from the breast towards the armpit, not the other way around, making the transfer of parabens from the armpit towards the breast tissue highly speculative.[79]

Additional research surfaced in 2013 and 2014 showing that parabens sometimes exist in human breast tissue at concentrations sufficient to drive the growth of human breast cancer cells.[80][81][82] They have also been demonstrated to increase the migratory and invasive properties of human breast cancer cells[83] and to induce anchorage-independent growth of human breast epithelial cells, a property closely related to transformation and a predictor of tumour growth in vivo,[84] but 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. 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)
  2. Liao C, Liu F, Kannan K. Occurrence of and dietary exposure to parabens in foodstuffs from the United States. Environ Sci Technol. (2013)
  3. Kim JW, et. al. Multiresidue analytical method for the determination of antimicrobials, preservatives, benzotriazole UV stabilizers, flame retardants and plasticizers in fish using ultra high performance liquid chromatography coupled with tandem mass spectrometry. J Chromatogr A. (2011)
  4. 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)
  5. 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)
  6. Guo Y, Wang L, Kannan K. Phthalates and parabens in personal care products from China: concentrations and human exposure. Arch Environ Contam Toxicol. (2014)
  7. Scientific Committee on Consumer Safety. Opinion on parabens, 2013. SCCS. (2013)
  8. Ramaswamy BR, et. al. GC-MS analysis and ecotoxicological risk assessment of triclosan, carbamazepine and parabens in Indian rivers. J Hazard Mater. (2011)
  9. Yamamoto H, et. al. Aquatic toxicity and ecological risk assessment of seven parabens: Individual and additive approach. Sci Total Environment. (2011)
  10. 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)
  11. Rudel RA, et. al. Phthalates, alkylphenols, pesticides, polybrominated diphenyl ethers and other endocrine-disrupting compounds in indoor air and dust. Environ Sci Technol. (2003)
  12. Canosa P, et. al. Pressurized liquid extraction with in-cell clean-up followed by gas chromatography-tandem mass spectrometry for the selective determination of parabens and triclosan in indoor dust. J Chromatogr A. (2007)
  13. 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)
  14. Canosa P, et. al. Determination of parabens and triclosan in indoor dust using matrix solid-phase dispersion and gas chromatography with tandem mass spectrometry. Anal Chem. (2007)
  15. Fan X, et. al. Simultaneous quantitation of parabens, triclosan, and methyl triclosan in indoor house dust using solid phase extraction and gas chromatography-mass spectrometry. J Environ Monit. (2010)
  16. 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)
  17. Liao C, Kannan K. Concentrations and composition profiles of parabens in currency bills and paper products including sanitary wipes. Sci Total Environment. (2014)
  18. Ye X, et. al. Parabens as urinary biomarkers of exposure in humans. Environ Health Perspect. (2006)
  19. Calafat AM, et. al. Urinary concentrations of four parabens in the U.S. population: NHANES 2005-2006. Environ Health Perspect. (2010)
  20. Ma WL, et. al. Urinary concentrations of parabens in Chinese young adults: implications for human exposure. Arch Environ Contam Toxicol. (2013)
  21. Genuis SJ, et. al. Paraben levels in an urban community of Western Canada. ISRN Toxicol. (2013)
  22. Ye X, et. al. Automated on-line column-switching HPLC-MS/MS method for measuring environmental phenols and parabens in serum. Talanta. (2008)
  23. 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)
  24. Meeker JD, et. al. Distribution, variability, and predictors of urinary concentrations of phenols and parabens among pregnant women in Puerto Rico. Environ Sci Technol. (2013)
  25. Hansen J, Möllgaard B. Penetration and transformation of the parabens in human skin in vitro. Contact Dermatitis. (1990)
  26. Pozzo AD, Pastori N. Percutaneous absorption of parabens from cosmetic formulations. Int J Cosmet Sci. (1996)
  27. Pedersen S, et. al. In vitro skin permeation and retention of parabens from cosmetic formulations. Int J Cosmet Sci. (2007)
  28. El Hussein S, et. al. Assessment of principal parabens used in cosmetics after their passage through human epidermis-dermis layers (ex-vivo study). Exp Dermatol. (2007)
  29. 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)
  30. 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)
  31. 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)
  32. Nicoli S, et. al. Association of nicotinamide with parabens: effect on solubility, partition and transdermal permeation. Eur J Pharm Biopharm. (2008)
  33. Caon T, et. al. Evaluation of the transdermal permeation of different paraben combinations through a pig ear skin model. Int J Pharm. (2010)
  34. 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)
  35. Lobemeier C, et. al. Hydrolysis of parabenes by extracts from differing layers of human skin. Biol Chem. (1996)
  36. 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)
  37. 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)
  38. Sokol H. Recent developments in the preservation of pharmaceuticals. Drug Standards. (1952)
  39. Marzuilli FN, Carson TR, Maibach HI. Delayed contact hypersensitivity studies in man and animals. Proc Joint Conf Cosmet Sci. (1968)
  40. Fisher AA. The role of topical medications in the management of stasis ulcers. Angiology. (1971)
  41. 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)
  42. Marks JG et. al. North American Contact Dermatitis Group standard tray patch test results (1992 to 1994). Am J Contact Dermat. (1995)
  43. 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)
  44. Marks JG Jr, et. al. North American Contact Dermatitis Group patch-test results, 1996-1998. Arch Dermatol. (2000)
  45. Marks JG Jr, et. al. North American Contact Dermatitis Group patch-test results, 1998 to 2000. Am J Contact Dermat. (2003)
  46. 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)
  47. Schnuch A, et. al. Patch testing with preservatives, antimicrobials and industrial biocides. Results from a multicentre study. Br J Dermatol. (1998)
  48. Chow ET, et. al. Frequency of positive patch test reactions to preservatives: The Australian experience. Australas J Dermatol. (2013)
  49. Cheng S, et. al. Contact sensitivity to preservatives in Singapore: frequency of sensitization to 11 common preservatives 2006-2011. Dermatitis. (2014)
  50. Ishidate M Jr, et. al. Cytotoxicity test on medical drugs--chromosome aberration tests with Chinese hamster cells in vitro. Eisei Shikenjo Hokoku. (1978)
  51. Ishidate M Jr, et. al. Primary mutagenicity screening of food additives currently used in Japan. Food Chem Toxicol. (1984)
  52. Song BL, Li HY, Peng DR. In vitro spermicidal activity of parabens against human spermatozoa. Contraception. (1989)
  53. Oishi S. Lack of spermatotoxic effects of methyl and ethyl esters of p-hydroxybenzoic acid in rats. Food Chem Toxicol. (2004)
  54. Zhao X, Li Y, Gu W. Reproductive toxicity of ethylparaben on male Drosophila melanogaster. Wei Sheng Yan Jiu. (2014)
  55. Routledge EJ, et. al. Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic. Toxicol Appl Pharmacol. (1998)
  56. Miller D, et. al. Estrogenic activity of phenolic additives determined by an in vitro yeast bioassay. Environ Health Perspect. (2001)
  57. Schultis T, Metzger JW. Determination of estrogenic activity by LYES-assay (yeast estrogen screen-assay assisted by enzymatic digestion with lyticase). Chemosphere. (2004)
  58. Morohoshi K, et. al. Estrogenic activity of 37 components of commercial sunscreen lotions evaluated by in vitro assays. Toxicol In Vitro. (2005)
  59. Okubo T, et. al. ER-dependent estrogenic activity of parabens assessed by proliferation of human breast cancer MCF-7 cells and expression of ERalpha and PR. Food Chem Toxicol. (2001)
  60. Byford JR, et. al. Oestrogenic activity of parabens in MCF7 human breast cancer cells. J Steroid Biochem Mol Biol. (2002)
  61. Satoh K, et. al. Competitive binding of some alkyl p-hydroxybenzoates to human estrogen receptor alpha and beta. Yakugaku Zasshi. (2000)
  62. Gomez E, et. al. Estrogenic activity of cosmetic components in reporter cell lines: parabens, UV screens, and musks. J Toxicol Environ Health A. (2005)
  63. Hossaini A, Larsen JJ, Larsen JC. Lack of oestrogenic effects of food preservatives (parabens) in uterotrophic assays. Food Chem Toxicol. (2000)
  64. Lemini C, et. al. In vivo and in vitro estrogen bioactivities of alkyl parabens. Toxicol Ind Health. (2003)
  65. Lemini C, et. al. Morphometric analysis of mice uteri treated with the preservatives methyl, ethyl, propyl, and butylparaben. Toxicol Ind Health. (2004)
  66. Pedersen KL, et. al. The preservatives ethyl-, propyl- and butylparaben are oestrogenic in an in vivo fish assay. Pharmacol Toxicol. (2000)
  67. 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)
  68. Prusakiewicz JJ, et. al. Parabens inhibit human skin estrogen sulfotransferase activity: possible link to paraben estrogenic effects. Toxicology. (2007)
  69. Fang H, et. al. Study of 202 natural, synthetic, and environmental chemicals for binding to the androgen receptor. Chem Res Toxicol. (2003)
  70. 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)
  71. Darbre PD. Underarm cosmetics and breast cancer. J Appl Toxicol. (2003)
  72. Harvey PW. Parabens, oestrogenicity, underarm cosmetics and breast cancer: a perspective on a hypothesis. J Appl Toxicol. (2003)
  73. McGrath KG. An earlier age of breast cancer diagnosis related to more frequent use of antiperspirants/deodorants and underarm shaving. Eur J Cancer Prev. (2003)
  74. Darbre PD, et. al. Concentrations of parabens in human breast tumours. J Appl Toxicol. (2004)
  75. Golden R, Gandy J. Comment on the publication by Darbre et al. (2004). J Appl Toxicol. (2004)
  76. 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)
  77. Flower C. Observations on the paper by Darbre et al. (2204). J Appl Toxicol. (2004)
  78. Mirick DK, Davis S, Thomas DB. Antiperspirant use and the risk of breast cancer. J Natl Cancer Inst. (2002)
  79. Scientific Committee on Consumer Products. Extended Opinion on Parabens, Underarm Cosmetics and Breast Cancer. SCCP. (2005)
  80. Barr L, et. al. Measurement of paraben concentrations in human breast tissue at serial locations across the breast from axilla to sternum. J Appl Toxicol. (2012)
  81. 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)
  82. Wróbel A, Gregoraszczuk EŁ. Effects of single and repeated in vitro exposure of three forms of parabens, methyl-, butyl- and propylparabens on the proliferation and estradiol secretion in MCF-7 and MCF-10A cells. Pharmacol Rep. (2013)
  83. 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)
  84. Khanna S, Darbre PD. Parabens enable suspension growth of MCF-10A immortalized, non-transformed human breast epithelial cells. J Appl Toxicol. (2013)