Propylparaben

Propylparaben, a natural substance found in mango peel and cloudberries, has been used as a preservative in food, drugs and cosmetics for more than 60 years.

Scientific Research


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Table of contents:

1. Sources

1.1 In nature

Propylparaben is the ester of p-hydroxybenzoic acid and propanol. It appears as small colourless crystals or as a white powder that is both odourless and tasteless.[1]

It is produced naturally by the mango plant as an antifungal compound in mango peel,[2] and is found in small amounts in cloudberries along with methylparaben.[3] It is also synthesized by the fungus Verticillium albo-atrum.[4]

1.2 In food

Like methylparaben, propylparaben is generally considered as safe (GRAS) when used as a preservative in food up to a limit of 0.1%, including in fruit jelly, fruit preserves and jams. It is also permitted as an antifungal agent in food packaging materials with no limits or restrictions.[5] The Joint WHO/FAO Expert Committee on Food Additives (JECFA) considers a group daily intake of 0-10 mg/kg/day for the sum of methylparaben, ethylparaben and propylparaben acceptable,[6] but the European Food Safety Authority (EFSA) Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food has stated that propylparaben should not be included in the acceptable daily intake, although 0-10 mg/kg/day for the sum of methylparaben and ethylparaben is valid.[7]

Analyses of foodstuffs from both the United States and China have revealed that propylparaben is among the major parabens present in food, along with methylparaben and ethylparaben.[8][9] It has also been detected in foodstuffs imported into Malaysia,[10] and in fish from the Philippines and Poland.[11][12][13]

1.3 In pharmaceuticals

Parabens have been used in drug products since 1924. They are or have been used in suppositories, anaesthetics, eyewashes, pills, syrups, weight-gaining solutions, injectable solutions and contraceptives. Use concentrations vary, but maximum levels reportedly seldom exceed 1%. A 2004 listing of FDA-approved drug products revealed concentrations ranging from 0.0006% to 30%, with the majority at concentrations at <0.1%. The FDA has also specified 0.05% propylparaben for standard preparation A, a homosalate sunscreen used in SPF testing.[5]

1.4 In the environment

Propylparaben was a major paraben in indoor dust samples from Spain, the United States, China, Korea and Japan, where its measured concentration was as high as 110,800 ng/g.[14][15][16][17][18] It is also prevalent among paper products, especially sanitary wipes and currency bills. In one study, it was found in 69% of all paper products tested and accounted for approximately 16% of the total concentrations of parabens in these paper products overall.[19]

Propylparaben has also been detected in various aquatic environments due to contamination by sewage.[20][21][22] The concentration of propylparaben reached 3142 ng/L in Chinese rivers,[23] 69 ng/L in European rivers,[24] 207 ng/L in Japanese urban streams[20] and 57 ng/L in rivers in Southern India.[25]

1.5 In personal care products

Propylparaben is consistently one of the most popular parabens used in cosmetics, behind only methylparaben in frequency of occurrence and concentration.[26][27][28][29] In 2006, propylparaben was reported to be used in 7118 personal care products across a wide range of categories. These included baby products, bath products, makeup, hair products, nail care products, oral hygiene products, shaving products, skin care products and suntan products. More recent surveys have also found propylparaben in personal care products from the United States and China.[30][31][32]

An industry survey established in 2003 that the concentration of propylparaben used in such products ranged from 0.00002% to 0.7% then.[5] The maximum concentration of use appears to have dropped, as current surveys report maximum concentrations of 2720 μg/g and 1560 μg/g in the US and China, respectively, corresponding to about 0.3% and 0.15%.[31][32]

In 2010, the European Commission's Scientific Committee on Consumer Safety issued its opinion that the use of propylparaben and butylparaben as preservatives in cosmetic products is safe if the sum of their individual concentrations does not exceed 0.19%.[33] This means that some products in the US contain higher levels of propylparaben than what is permitted in Europe.[31]

2. Exposure

Human exposure to parabens is often assessed by measuring in urine the conjugated or free species of parabens or their metabolites.[34] In the US population, propylparaben has been found in the urine at median concentrations of 8.7 to 9.1 ng/ml.[34][35] Exposure appears to be markedly lower In Chinese young adults, where the median urinary concentration has been shown to be 3.6 ng/ml,[36] though elevated levels have been reported in some Chinese adult females and children.[37] Propylparaben has also been detected in urine samples from other populations including Danish men,[38] Canadian men and women,[39] pregnant Japanese women[40] and Norwegian women.[41]

In the US, propylparaben concentrations have been found to be higher and more variable in urine samples from women than men, and to be higher as well in samples from African Americans than Caucasians. These differences may be due to gender and ethnic differences in the use of personal care products, or may reflect pharmacokinetic differences.[42] Urinary propylparaben concentrations were also more variable during pregnancy.[43]

2 studies on human serum samples detected propylparaben at concentrations up to 67.4 µg/L and 5.5 µg/L in the US and Denmark, respectively. The difference may have arisen from a difference in exposure between genders, as the Danish study group consisted of only men.[44][38] Propylparaben has also been found in some human milk samples,[45][46] and the intake of propylparaben with human milk by infants estimated at 381.1 ng/kg body weight/day.[46]

3. Topical bioavailability

Due to its chain length, propylparaben penetrates better into the skin than butylparaben and benzylparaben, but not as well as methylparaben or ethylparaben.[47][48] In one study, 20% of propylparaben applied to rabbit ear skin was found across it after 8 hours of contact, compared to 40% for ethylparaben and 60% for methylparaben.[49] This agreed with another study on human skin, which showed that the more lipophilic the parabens, the less they crossed the skin layers.[50]

It is possible to inhibit the skin permeation of propylparaben to reduce its toxicological risk. The use of a colloidal microgel, for instance, can reduce the transport rate of propylparaben by one order of magnitude compared to the corresponding saturated solution.[51] The polymeric additive poly(2-methacryloyloxyethyl phosphorylcholine-co-butylmetacrylate) (PMB) and niacinamide can also decrease the permeation of propylparaben through the skin.[52][53] Combining methylparaben and propylparaben, too, appears to significantly reduce the permeation rates of both parabens through pig ear skin.[54]

Occlusion of the skin can influence the skin penetration of parabens as well, but its effect depends strongly on the employed solvent vehicle. Increases in epidermal flux were observed for acetone and ethanol vehicles, whereas a decrease was seen following occlusion of an ointment formulation in an in vitro experiment on human epidermis.[55]

Some propylparaben is likely metabolized to p-hydroxybenzoic acid by carboxylesterases during its passage through the skin.[56] In rats, all topically applied propylparaben appears to be metabolized to p-hydroxybenzoic acid since the native paraben was not detected in the plasma after dermal administration,[57] but this may not be the case in human skin as rat skin is known to hydrolyze parabens much more rapidly.[58] Experiments using excised human breast skin showed that 24 hours after applying propylparaben, 8% of the dose remained on the skin surface, 44% was unmetabolized within the skin, 37% had penetrated through the skin as native paraben, and 5% had penetrated through the skin after being converted to p-hydroxybenzoic acid. The data further suggests that propylparaben, like butylparaben and benzylparaben, is preferentially hydrolyzed by one carboxylesterase isoform, carboxylesterase-2.[59]

In 22 urine samples from adults, propylparaben was detected mostly as the conjugated species,[60] indicating that native propylparaben that is dermally absorbed into the systemic circulation is conjugated in the liver and other organs.

4. Safety

4.1 Effects on skin cells

Propylparaben has been tested in cultures of embroyonic mouse fibroblasts, where like methylparaben and propylparaben, it significantly decreased the biosynthesis of RNA and DNA.[61]

4.2 Skin irritation and sensitization

12% propylparaben in propylene glycol did not irritate the skin when applied to the backs of human volunteers for 5 days, nor sensitize the skin in a repeated-insult patch test.[62] This is despite the concentration being orders of magnitude higher than normal usage in cosmetic products.[5] Indeed, studies have stated that the incidence of paraben contact sensitization is low and that sensitization to parabens in general is not a problem in the United States.[63][64][65] Even patients who present with allergic contact dermatitis when paraben-containing pharmaceuticals are applied to eczematous or ulcerated skin can tolerate paraben-containing cosmetics applied to normal, unbroken skin, supporting the notion that parabens are nonirritating and nonsensitizing to undamaged skin.[66]

Overall, paraben sensitization of around 1% is expected in routine patch testing with paraben esters.[67] Studies from Europe in the 1990s and early 2000s show positive reactions to parabens in patch test data ranging from 1.1% to 1.6%.[68][69][70] Data from the North American Contact Dermatitis Group found positive reaction response rates varying from 0.6% to 2.3% in the period from 1984-2002.[71][72][73][74][75] In Australia parabens were among the least frequent sensitizers with a positive reaction rate of 1.1%.[76] The figure is higher in Singapore and the United Arab Emirates however, with data revealing a sensitization frequency of 2.58% for the former from 2006-2011 and a sensitization frequency of 5.1% for the latter from 1989-1996.[77][78]

4.3 Genotoxicity

2 studies published in 1975 independently found that propylparaben was nonmutagenic with and without metabolic activation.[79][5] A year later, 2 additional studies evaluating the genotoxicity of propylparaben were published. The first used an in vivo cytogenic assay, an Ames or modified Ames test and a bacterial repair test, and found propylparaben to be nongenotoxic in all assays except the repair test.[80] The other study used a modified Ames test in which propylparaben in DMSO was added to cultures of 2 strains of S. typhimurium and 1 strain of E. coli, and found that propylparaben was mutagenic only in one of the S. typhimurium strains with metabolic activation.[81]

Propylparaben also increased polyploid cell production slightly (1-3%) in Chinese hamster cells in vitro, though it did not induce significant chromosomal aberrations.[82] Another experiment on Chinese hamster ovary cells found that it induced chromosomal aberrations together with sister-chromatid exchanges however.[83]

4.4 Potential endocrine disruptor

Most studies agree that propylparaben has estrogenic activity as shown in numerous in vivo and in vitro assays,[84][85][86][87][88][89][90][91] though one found an antiestrogenic potential in juvenile zebrafish.[92] It is important to note, however, that its estrogenic potency is markedly lower than that of estradiol, by about 4-5 orders of magnitude.[84][85][87][93][94] Like the other parabens, propylparaben binds with equal relative affinity to estrogen receptors α and β.[95][96][97]

It has been suggested that the inhibition of estrogen sulfotransferases (SULTs) in the skin by parabens may elevate estrogen levels, contributing to their estrogenic effect. Experiments show that propylparaben and butylparaben inhibit SULT activity in the skin cytosol, with half maximal inhibitory concentrations (IC50) of 36 µg/ml and 7.2 µg/ml respectively.[98] 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, since available data indicate that the concentrations of free propylparaben and butylparaben in human bodily fluids are 1-3 orders of magnitude lower than the IC50 values of the parabens, and that the IC50 values in the human liver are similar to those in human skin.[33]

Importantly, propylparaben has the highest estrogenic potency (20x higher than methylparaben, ethylparaben and butylparaben) in pregnant Japanese women when both the abundance in the urine and the relative estrogenic activity of each compound is taken into consideration.[40]

Propylparaben seems to have antiandrogenic activity in addition to its estrogenic activity. At a concentration of 10 μm, it inhibited the transcriptional activity of testosterone by 33% in a cell-based bioassay.[99] This may be attributable to its partial inhibition of testosterone binding to androgen receptors.[100] However, since this concentration is ~100,000 times that of the concentration of testosterone used, it is clear that propylparaben's binding affinity for the androgen receptor, if any, is orders of magnitude lower than that of testosterone.[99]

4.5. Effects on reproduction

Male rats fed propylparaben in the diet at 0.01%, 0.1% and 1% for 4 weeks had reduced cauda epipdidymal sperm reserves and sperm concentrations compared to controls at the 0.1% and 1% levels. Sperm counts in the testes were statistically reduced compared to controls for all concentrations of exposure as well, and serum testosterone was significantly decreased at the 1% level.[101] This may be due to direct inactivation by propylparaben, as has been demonstrated in vitro on human sperm.[102] It has also been hypothesized that parabens may interfere with mitochondrial function in the testis, resulting in a decrease in reproductive potential.[103] Propylparaben has also exhibited antiandrogenic activity,[99][100] which may be relevant as androgens play a critical role in the development of the male reproductive tract, sexual accessory organs, spermatogenesis and maturation of spermatozoa.[104]

A prospective cohort study of women seeking fertility treatment in the US indicated that propylparaben may be associated with diminished ovarian reserve based on suggestive evidence of lower antral follicle counts and higher day-3 FSH levels with increasing urinary propylparaben tertiles, but emphasized the need for further studies to validate these findings.[105]

A potential link between breast cancer and the use of paraben-containing underarm cosmetics was considered in a number of papers published in 2003 and 2004. The authors of these papers observed 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.[106][107] This hypothesis was supported by data showing the presence of low levels of methylparaben, ethylparaben, propylparaben and butylparaben in human breast tumours,[108] that parabens exhibit estrogenic activity in human breast cancer cells,[109][110] and that earlier and more frequent use of antiperspirant/deodorant usage with underarm shaving were associated with an earlier age of breast cancer diagnosis.[111]

The hypothesis attracted both public and scientific interest, leading to 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.[112][113][114][115]

As a result, in 2005 the European Commission's Scientific Committee on Consumer Products opined that there was insufficient data 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 it is clinically well-established that the circulation of blood/lymph goes from the breast towards the armpits and other tissues and organs, not vice-versa.[116]

Newer research does provide more support for the hypothesis in the form of data showing that parabens exist in human breast tissue at concentrations sufficient to stimulate the proliferation of human breast cancer cells,[117][118] that they can increase breast cancer cells' migratory and invasive properties,[119] that they can also induce anchorage-independent growth of human breast epithelial cells, a property closely related to transformation and a predictor of tumour growth in vivo,[120] and that they possess antagonist activities on human oestrogen-related receptor γ, a diagnostic biomarker and treatment target for breast cancer.[121] However, to date neither the Cosmetic Ingredient Review Expert Panel nor the European Commission's Scientific Committee on Consumer Safety have conducted a re-evaluation of the safety of parabens in cosmetics that takes these new information into consideration.

4.7 Use in children

In 2011, the Danish Minister of the Environment banned the use of propylparaben and butylparaben in cosmetic products for children up to 3 years of age. Denmark's decision raised the question of whether the same measure should be taken at the EU level, and the European Commission's Scientific Committee on Consumer Safety (SCCS) issued another document later that year to clarify its opinion.[33]

In its document, the SCCS recognized several reasons in the scientific argumentation on the possible effects of endocrine disruptors in young children. Firstly, the immaturity of physiological functions in young children may mean that absorption and distribution factors are different from adults, which may cause ineffective inactivation and elimination kinetics and hence higher internal exposure to the same external dose compared to adults.[122][123][124] Secondly, young children have a higher body surface area to mass ratio, which may result in higher exposure per kg body weight.[122] Thirdly, potentially enhanced target organ sensitivity in young children and effects induced in childhood may be more severe, since impaired organ development may be irreversible.[124] Furthermore, the Danish Environmental Protection Agency 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.[125]

The SCCS rejected the last point as it considered the over-exposure to sunscreens in young children to be a form of product misuse rather than normal product usage. The SCCS also felt 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.

The SCCS also noted that ester cleavage of parabens can be assumed to be lower in the skin of children younger than 1 year old, due to differences in the expression of carboxylesterases. Moreover, glucuronidation activity is reduced in neonates, newborns and early infants up to 6 months of age, suggesting that these children may potentially be at higher risk due to the prolonged half-lives of parabens circulating in the body. This was supported by data showing that urine samples of hospitalized preterm neonates and newborns had 3-5 fold higher proportions of free methylparaben or propylparaben, compared to 2-5% in adults.[126]

Overall, the SCCS concluded that there was no safety concern in children with regards to general cosmetic products containing parabens, as their margin of safety calculations were based on very conservative assumptions of toxicity and exposure. However, a risk could not excluded 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.[33] These conclusions were reiterated in 2013.[127]

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