Table of contents:
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.
1.2 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.
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. 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%). In addition, the maximum concentration of ethylparaben detected in these studies was 2770 μg/g of the product, corresponding to about 0.3%.
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. The Cosmetic Ingredient Review Expert Panel has also found ethylparaben to be safe for use in cosmetics at these use levels.
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. While ethylparaben was not detected in the aquatic environment of the Greater Pittsburgh Area in the United States, it was the main paraben observd in Indian rivers.
Parabens present in indoor air and dust are thought to originate from personal care products used in households. The concentration of ethylparaben detected in indoor air was 4 ng/m3 in a study in the US. 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.
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.
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%). 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. 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.
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. 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, which agreed with the findings of a Puerto Rican study among pregnant women.
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. 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. Indeed, 40% of ethylparaben crossed rabbit ear skin intact, compared to 20% for propylparaben, in one study. 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.
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. 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. The binary combination of methylparaben + ethylparaben also decreases their penetration rates through pig ear skin significantly. This reduction in transdermal penetration is beneficial for improving the toxicological risk of ethylparaben.
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.
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. The evidence indicates that in human skin, ethylparaben is hydrolyzed by the first isoform, carboxylesterase-1 (hCE1).
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.
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. 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.
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.
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. 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.
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%. 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, and a 5-year multi-center study involving 22,602 patch-tested patients found a 1.6% positive reaction rate. Parabens were also low frequency sensitizers (1.1%) in Australia, whereas in Singapore they were relatively more frequent sensitizers (2.58%).
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%.
4.4 Effects on male reproduction
Although 8 mg/ml of ethylparaben inactivated human sperm in vitro, 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.
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.
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. 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, 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.
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. In other words, the only paraben with weaker estrogenic activity than ethylparaben is methylparaben.
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. 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.
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.
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.
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.
4.6 Link to breast cancer
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. 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, 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. 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. Moreover, a population-based case-control study found that the risk of breast cancer did not increase with either antiperspirant or deodorant use.
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.
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. They have also been demonstrated to increase the migratory and invasive properties of human breast cancer cells 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, 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.
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