Butylparaben

Butylparaben has one of the strongest estrogenic activities among the parabens. It and propylparaben are considered safe for use in cosmetics as long as the sum of their concentrations stays below 0.19%.

Scientific Research


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Table of contents:

1. Sources

1.1 In nature

Butylparaben is produced naturally by a marine bacterial strain belonging to the Microbulbifer genus. This marine bacterium also produces p-hydroxybenzoic acid, heptylparaben and nonylparaben.[1]

1.2 In food

The US FDA permits the use of butylparaben as a flavour additive in food.[2] It has been detected in foodstuffs from both the United States and China,[3][4] as well as in fish samples from the Philippines.[5][6]

According to an estimate by the US Food and Drug Administation Center for Food Safety and Applied Nutrition, the consumption rate for butylparaben is 37 ng/day.[7]

1.3 In the environment

Butylparaben has been detected in some aquatic environments due to contamination by sewage.[8][9][10] The highest concentrations measured were 163 ng/L in Japanese urban streams,[8] 52 ng/L in riverine water from South Wales,[11] and 42 ng/L in a coastal lagoon in Portugal.[12] Butylparaben is relatively biodegradable in river water but highly stable against sunlight, contributing to its persistence in aquatic environments.[13]

Butylparaben was present in indoor air at a maximum concentration of 3.2 ng/m3 in one study[14] and in indoor dust at a maximum measured concentration of 3920 ng/g across several studies.[15][16][17][14][18]

Currency bills and numerous paper products also contain butylparaben, though methylparaben and propylparaben were the major paraben analogs detected.[19]

1.4 In personal care products

Butylparaben was used in at least 3001 personal care products in 2002, including baby products, bath products, makeup, hair products, nail care products, oral hygiene products, shaving products, skin care products and suntan products.[20] The concentrations of use of butylparaben in cosmetic products ranged from 0.00004% to 0.54% in 2003.[20]

More recent surveys analysing the contents of personal care products from the United States and China have also revealed the presence of parabens, including butylparaben.[21][22] An investigation of 170 personal care products from New York in 2012 revealed that butylparaben was present in 20% of rinse-off products, 26% of leave-on products and 25% of baby care products, with concentrations up to 2090 µg/g, or 0.2%.[21] Butylparaben was also present in 25% out of 52 personal care products purchased in Tianjin, China, at concentrations up to 160 µg/g, or 0.02%.[22]

Based on a quantitative risk assessment, the European Commission's Scientific Committee on Consumer Safety stated in 2010 that the use of propylparaben and butylparaben as preservatives in cosmetic products is safe as long as the sum of their individual concentrations does not exceed 0.19%. The Danish government, however, has introduced additional restrictions, disallowing the use of propylparaben, butylparaben, isopropylparaben and isobutylparaben in personal care products intended for children below the age of 3.[23]

2. Exposure

Human biomonitoring data suggest that exposure to parabens, including butylparaben, is routine for many populations.[24][25][26][27][28][29] Urinary concentrations of butylparaben are usually much lower compared to those for methylparaben and propylparaben however, indicating relatively lower exposure for butylparaben.[25][27][29] Butylparaben was detected more frequently and at higher concentrations in urine samples from women than men.[30][31]

Serum levels of butylparaben are usually below the detection limit, with one study measuring a maximum concentration not exceeding 1 µg/L.[32][33]

3. Topical bioavailability

The preferential use of higher chain-length parabens like butylparaben can increase the concentration of parabens in the aqueous phase of cosmetic formulations, which is necessary for preservative effectiveness.[34] Due to its more lipophilic nature, butylparaben is also less well absorbed percutaneously than other parabens, reducing the risk of systemic toxicity.[35] Nevertheless, studies have demonstrated that topically applied butylparaben can be systematically absorbed. Caucasian men who applied a cream containing 2% butylparaben to their whole bodies daily for a week saw increases in their serum levels of butylparaben after application,[33] and 0.32% of the applied dose was recovered in their urine.[36]

The entrapment of butylparaben within liposomes can influence its skin penetration while retaining its antimicrobial activity. Specifically, the percutaneous absorption of butylparaben decreases with an increase in the lipid content, as more butylparaben is retained within the vehicle.[37][38] It has also been shown that complexing butylparaben with a cationic β-cyclodextrin polymer significantly improves its antimicrobial activity because the complexes are adsorbed onto the surface of bacterial membranes via electrostatic attraction.[39]

Niacinamide and the polymeric additive poly(2-methacryloyloxyethyl phosphorylcholine-co-butylmetacrylate) (PMB) can inhibit the penetration of butylparaben as well,[40][41] while other substances such as unsaturated fatty acids, limonene, menthol and ethanol act as penetration enhancers.[42][43][44] Heat and occlusion can also affect the delivery and retention of butylparaben.[45][46]

Part of the dermally absorbed butylparaben is metabolized to p-hydroxybenzoic acid by carboxylesterases in the skin.[47][48][49] This cutaneous metabolism affects its skin permeation highly, with the total flux increasing as the metabolic rate increases due to the creation of a steeper concentration gradient across the stratum corneum.[50][51] The extent of metabolism in human skin varies in different studies however. 1 found that nearly 50% of butylparaben applied to dermatomed human skin remained unmetabolized after penetrating through the skin, but 2 later studies using full-thickness skin found p-hydroxybenzoic acid together with barely detectable levels of native butylparaben in the receptor fluid, suggesting a near-complete first-pass metabolism.[20] Yet another study utilizing excised human breast skin showed that 24 hours after applying butylparaben, 3% of the dose was still on the skin surface, nearly 50% was in the skin, 37% had crossed the skin as the native paraben, and just 6% had been metabolized to p-hydroxybenzoic acid.[48]

4. Safety

4.1 Skin irritation and sensitization

5% butylparaben produced no irritation or sensitization when applied to the skin of 50 human volunteers.[52] Parabens are overall weak sensitizers with positive reaction rates in patch tests of usually around 1-3%, as evidenced by multiple studies in North America,[53][54][55][56][57] Europe[58][59][60] and in the Asia-Pacific.[61][62]

4.2 Genotoxicity

When 1% butylparaben is combined with potassium nitrate or sodium nitrite and irradiated for 5 days, butyl-3-nitro-4-hydroxybenzoate is formed. This reaction product has been found to be mutagenic in an assay used to detect DNA-damaging agents, though butylparaben itself was nonmutagenic in the same assay.[63][64]

Another experiment showed that butylparaben induced a slight (1-3%) increase in polyploid cell production in Chinese hamster cells in vitro, but did not increase chromosomal aberrations.[65] However, this contradicts the findings of a more recent study, which demonstrated that butylparaben caused detectable DNA damage and induced chromosomal aberrations together with sister-chromatid exchanges in Chinese hamster ovary cells.[66]

4.3 Effects on reproduction

1 mg/ml butylparaben is capable of completely inactivating human sperm in vitro.[67] When up to 1% dietary butylparaben was administered to male rats, the weights of the epididymides, the cauda epididymal sperm reserve, sperm production and serum testosterone levels were lowered.[68] A similar experiment on male mice found that dietary butylparaben decreased spermatid counts and serum testosterone concentrations, but did not significantly affect the numbers of spermatogonia or spermatocytes. Also, unlike the study on rats, the weights of the epididymides were significantly higher in the 1% group when compared with controls.[69] A repeat study on male rats attempted to refute these findings,[70] but was criticized by the Scientific Committee for Consumer Safety to be scientifically unacceptable.[71]

A reproductive epidemiology study on 132 men attending an infertility clinic between 2000-2004 found no relationship between the urinary concentration of butylparaben and hormone levels or conventional semen quality parameters, but observed a statistically significant positive association between butylparaben concentration and sperm DNA damage as measured by a Comet assay.[72]

Studies on prepubertal rats indicate that butylparaben can disrupt the Sertoli cell vimentin filaments, which may lead to the precocious release of spermatogenic cells from underlying Sertoli cells. The released cells may then undergo apoptosis owing to the loss of support provided by the Sertoli cells.[73][74] Another possible explanation for the reduced sperm counts induced by butylparaben may be related to its causation of DNA hypermethylation in epididymal sperm, as evidenced by a study on rats.[75] It has also been hypothesized that the effect of parabens on male fertility has to do with the interaction between parabens and mitochondrial function in the testis.[76]

Butylparaben led to myometrial hypertrophy when fed to peripubertal female rats,[77] though it did not influence the number of corpora lutea in mature female rats.[78]

4.4 Developmental toxicity

Pregnant rats injected subcutaneously with 100 or 200 mg/kg of butylparaben from gestation day 6 to postnatal day 20 had a lower proportion of pups born alive (both doses) and a lower proportion of pups surviving to weaning (200 mg/kg dose). Moreover, the body weights of female offspring were significantly decreased, whereas for male offspring the sperm counts and sperm motile activity in the epididymis were significantly decreased.[79] Other studies agree that exposure to butylparaben in utero and during lactation has adverse effects on the reproductive system in male offspring, including reduced anogenital distance, delayed preputial separation, reduced reproductive organ weights, lower sperm production and sperm counts, and changes in the levels of testosterone, estradiol, FH and LSH.[80][81] However, a separate study in which pregnant rats were fed butylparaben by oral gavage at levels up to 1000 mg/kg/day and caesarean sections were performed on gestation day 20, did not find any differences from control in embryo/fetal viability, fetal weight, malformations or variations.[78]

The impact of butylparaben on the brains of pups has also been examined. In one study, female rats were orally and subcutaneously administered butylparaben from early pregnancy till weaning, and its effects on the behaviour, brain neurotransmitters and brain derived neurotrophic factor (BDNF) were compared with those of a valproic acid (VA) autistic-rat model. Compared to the controls, the male offspring exposed to butylparaben showed similar social and learning and memory behavioral deficits as in the VA rat model. Some similar alterations in the monoamine content, amino acids and BDNF factor were also observed between the 2 groups, suggesting that prenatal exposure to butylparaben induced autism-like symptoms in the offspring.[82]

4.5 Potential endocrine disruptor

Butylparaben has demonstrated estrogenic activity in numerous assays.[83][84][85][86][87][88] Although it has greater affinity for estrogen receptors than methylparaben, ethylparaben and propylparaben,[89][90][91][77] its estrogenic potency is still 3-4 orders of magnitude weaker than that of estradiol.[83][85][86][92] In one uterotrophic assay in mice for instance, butylparaben exposure ranging from 0.735 to 35 mg/day did not affect uterine mass, unlike 500 ng/day of estradiol which consistently increased uterine mass.[93]

The estrogenic effect of parabens has been linked to their inhibition of human skin estrogen sulfotransferase (SULT) activity, which can lead to an increase in estrogen levels. Among the parabens butylparaben is the most potent inhibitor of skin estrogen sulfation. Its half maximal inhibitory concentration (IC50) for estradiol was 37 µm, and it completely blocked skin sulfation of estradiol at a concentration of 1 mM. It also inhibited the sulfation of estrone, though its IC50 value for estrone SULT activity was slightly higher than that for estradiol. Moreover, its potency increased 3-fold in a culture of human keratinocytes compared to skin cytosol, suggesting that it may have a stronger effect in vivo.[94] Based on this study, the European Commission's Scientific Committee on Consumer Safety deemed it scientifically plausible that the concentrations of free propylparaben and butylparaben could markedly inhibit SULTs, but only in the cells of the skin area of the topical application. A marked inhibition of systemic SULTs by parabens was regarded as unlikely, because the available data indicated that concentrations of free propylparaben and butylparaben in human bodily fluids were orders of magnitude lower than the IC50 values of the parabens, and IC50 values in the liver were similar to those in the skin.[23]

Research also indicates that butylparaben can act with other environmental estrogens such as bisphenol A and nonylphenol to give estrogenic responses that are additive.[95]

Interestingly, the laccase enzyme from the white rot fungus Trametes versicolor can degrade butylparaben and hence remove its estrogenic activity in the presence of the redox mediator 1-hydroxybenzotriazole (HBT).[96]

Butylparaben appears to have some antiandrogenic activity, as 190 µm butylparaben partially inihibted testosterone binding to androgen receptors by ~40% in one study,[97] and 10 µm butylparaben was found to inhibit the transcriptional activity of testosterone by 19% in a cell-based assay.[98]

Several publications advanced the hypothesis of a potential link between breast cancer and the use of paraben-containing underarm cosmetics in 2003 and 2004. The hypothesis was based upon observations that parabens are included in most cosmetic products, that underarm cosmetics are applied to an area directly adjacent to the upper outer quadrant of the breast, that this quadrant is the most frequent site of carcinoma in the breast, that estrogens are known to be involved in breast cancer, and that parabens exert weak estrogenic effects.[99][100] It was supported by data showing the presence of low levels of methylparaben, ethylparaben, propylparaben and butylparaben in human breast tumours,[101] that parabens exhibit estrogenic activity in human breast cancer cells,[102][103] and that earlier and more frequent use of antiperspirant/deodorant usage with underarm shaving were associated with an earlier age of breast cancer diagnosis.[104]

The hypothesis was controversial, and opened a discussion on the quality of the scientific evidence supporting it. It was found that the study measuring the concentrations of parabens in breast tumours had major flaws, such as the lack of control tissue, the use of blank samples contaminated with parabens, and the lack of consideration towards the tissue donors' exposure to consumer products and drugs containing parabens. Moreover, it was pointed out that most underarm cosmetics do not use parabens as preservatives, and that a previous case-control study had failed to find a relationship between breast cancer risk and antiperspirant/deodorant use.[105][106][107][108]

In 2005, the European Commission's Scientific Committee on Consumer Products (SCCP) stated its opinion that the data was inadequate to establish a clear link between the use of underarm cosmetics (with or without parabens) and breast cancer. In addition to the points made previously, they noted that the reason behind the more frequent occurrence of tumours in the upper quadrant of the breast is related to the amount of gland tissue present at that location, and that an exchange process from the armpit towards the breast tissue is highly speculative because the circulation of blood/lymph is known to go from the breast towards the armpits and other tissues and organs, not vice-versa.[109]

Newer research does provide more support for the hypothetical link between parabens and breast cancer. They show that parabens are unusually stable in human breast cancer tissues[110] and exist at concentrations sufficient to stimulate the proliferation of human breast cancer cells,[111][112] that they can increase the migratory and invasive properties of breast cancer cells,[113] 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,[114] and that they possess antagonist activities on human oestrogen-related receptor γ, a diagnostic biomarker and treatment target for breast cancer.[115] However, 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 by taking these new information into account.

4.7 Use in children

The Danish Minister of the Environment banned the use of propylparaben and butylparaben in cosmetic products for children up to 3 years of age in early 2011. Their decision opened the question of whether the same measure should be taken at the EU level, and as a result the European Commission's Scientific Committee on Consumer Safety (SCCS) was asked for its opinion on the scientific justification for the Danish measure.[23]

The scientific arguments for the higher risks of parabens in young children were summarized as follows. Firstly, newborns and young children have higher surface area to body weight ratios, which can cause higher exposure per kg body weight to dermally applied parabens.[116] Secondly, the half-lives of parabens may be much longer in newborns due to reduced expression of carboxylesterases and reduced glucuronidation activity. Thirdly, the nappy area is susceptible to nappy dermatitis, which may enhance the dermal absorption of parabens. Fourthly, target organ sensitivity may be enhanced in young children and effects induced in childhood may be more severe, since impaired organ development may be irreversible.[117] The Danish Environmental Protection Agency also considered that young children spend many hours in the sun and can therefore be exposed to a high amount of sunscreen products containing propylparaben and butylparaben.[118]

The last point was dismissed by the SCCS on the basis that over-exposure to sunscreens in young children is a form of product misuse rather than normal product usage. The SCCS also decided that no additional safety factor needed to be included for ingredients used in children's cosmetics, as an intra-species assessment factor of 10 had already been included in their margin of safety calculations for the parabens, which would cover the toxicokinetic and toxicodynamic differences between children and adults.

Overall, the SCCS reiterated its opinion that for general cosmetic products containing parabens, there was no safety concern in children, as their original margin of safety calculations were already based on very conservative assumptions of toxicity and exposure that were sufficient to address the existing uncertainties. However, they were unable to exclude a risk for children below 6 months of age and with respect to parabens in leave-on cosmetic products designed for application on the nappy area, in light of both the immature metabolism and the possibly damaged skin in this area due to nappy dermatitis.[23] These conclusions were reiterated in 2013.[119]

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