|This article needs additional citations for verification. (October 2012)|
|Jmol-3D images||Image 1|
|Molar mass||180.2 g/mol|
|Melting point||96 to 99 °C (205 to 210 °F; 369 to 372 K)|
|Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)|
|(what is: / ?)|
Propylparaben, the n-propyl ester of p-hydroxybenzoic acid, occurs as a natural substance found in many plants and some insects, although it is manufactured synthetically for use in cosmetics, pharmaceuticals and foods. It is a preservative typically found in many water-based cosmetics, such as creams, lotions, shampoos and bath products. As a food additive, it has the E number E216.
Propyl paraben, or propyl 4-hydroxybenzoate, belongs to the group of parabens. Propyl paraben has the CAS No. 94-13 3, and has the E number E216 when added as a food additive. Parabens, widely used as preservatives in a range of food and cosmetic products and in the pharmaceutical business, are alkyl esters of p-hydroxybenzoic acid. They have low toxicity and works as a broad-spectrum antimicrobial agent, why they are used as preservatives 1. You can find parabens in a large variety of products including but not limited to personal care products and in pharmaceuticals such as antibiotics and as food additives 2,3. In 2007, the WHO excluded propyl parabens from the list of chemicals acceptable for consumption due to the compound presenting possible estrogenic and reproductive effects. Propyl paraben is thus no longer allowed in products intended for oral consumption 4. It is however allowed in cosmetics and personal care products, with the total amount of parabens in the product not exceeding 0.8%, and propyl paraben not exceeding 0.4% of the total contents of the product.
There is little information available on the production, consumption and import quantities worldwide of propylparaben and in Sweden. The Danish Ministry of the Environment attempted in 2013 to collect information regarding the production and export of parabens to Scandinavian countries but failed to obtain any substantial information5. They concluded that the majority of the manufacturers are located in India and China, with a few manufacturing sites in Europe, USA and Asia. None of the major paraben production companies wanted to share information on the amounts produced when asked for it. The only data providing any clues to the world wide production rate of propyl paraben is the estimated 5 – 250 tons that are presumed to be produced in the USA annually 5. In 1995, 99% of all leave-on products contained parabens and 77% off all the rinse-off products as showed in a survey of 215 common products 6. A more recent study indicates that propylparaben is present in the majority of all personal care and cosmetics products that were investigated, including body lotions, deodorants and creams 7
PHYSIO-CHEMICAL PROPERTITES Parabens are virtually odorless and have a melting point substantially higher than ambient environmental temperatures, why it can be found as crystals or as white crystalline powders 7. It is very soluble in alcohol, with it’s octanol/water partition coefficient of 2.71. The vapor pressure of propylparaben is very low, and no spray applicators have been identified. It has a vapor pressure of 5.55 x 10-4 mm Hg 8. Parabens, which are esters of para-hydroxybenzoic acid that have different length of alkyl group attached at the para position of the benzene ring 9.
Table 1. The chemical and physical properties of propylparaben
Property Propylparaben Ref.
Molecular weight (g/mol) 180.21 10 Melting point (°C) 96.2-98 10 Density 1.0630 10 pKa 8.35 10 Kow 2.71 10 Molecular structure 10
Synonyms Propyl-4-hydroxybenzoate Benzyl salicylate, 2-hydroxybenzoic acid, benzyl ester, Propyl-p-hydroxybenzoate, E216
10 Vapor pressure (mm Hg) 5.55 x 10-4 8
KINETICS AND METABOLISM DATA
Uptake & Accumulation Absorption of intact parabens esters occur after dermal application through the skin 11. The potential of propyl paraben to cross the epithelium to allow for percutaneous absorption is greatly influenced by the oil/water phases of the formulation of which it is mixed with. Ethanol in products used as topical application has been shown to increase the absorption of parabens though the skin12. The addition of surfactants can also alter the percutaneous absorption13. As the length of the alkyl chain of different parabens increases, so does the hydrophobicity of the compound14. The greater the solubility the easier it is for the compound to cross through the epidermis14. Due to parabens being more soluble in oil the longer the alkyl length, parabens with long alkyl chains in oil-based formulations require a higher concentration to reach the same efficacy as those parabens with shorter alkyl lengths15.
The only assessment found on the amount of absorption of propyl parabens through the skin after dermal application is the assessment done by the industry itself, where they assess that the amount of unreacted butylparaben absorbed through the skin is approximately 1% of the content in the formulations in the part of the product that has contact with the skin 16. Propylparaben and butylparaben are structurally very similar, and the comparison between the two compounds has been used before due to the lack of data12. The study does however not provide satisfactory information about the solvent that was used, and the reliability of this data is therefore questioned.
It was long believed that parabens were completely metabolized by esterases in the body and completely excreted via the urine, but new research provides evidence that this is not the case. Nakazawa showed that the main metabolite, para-hydroxybenzoic acid could be found in all examined patients’ blood as well as in all the milk samples that were tested17. Furthermore, Oishi showed that some parabens could be absorbed and stored in tissues without being hydrolyzed by esterases in the body 18. It has been shown that the bioavailability of parabens is greatly increased by oil-in-water preparations 19, but to what extent propyl paraben is actually bioavailable is an unanswered question. Barr et al. (2012) reports that a number of paraben esters were detected in breast tissue samples following mastectomies. They found measurable levels of parabens in the tissue closest to the armpit, including propylparaben. 17.5% of the women who had parabens in their breast tissue claim to have never used underarm cosmetics that contain parabens, which would indicate that the parabens found in their tissues were taken up by the oral route or that propyl parabens do not only accumulate at the site of exposure.
Comments: All absorption should occur through dermal application since propyl paraben is prohibited as a food additive 4, but exposure to propyl paraben might occur through other routes. It is very difficult to determine uptake, metabolism and biological availability and half-life for propyl paraben since there is little research done on the subjects. It is clear that the vehicle matters for both absorption and bioavailability, but no reliable data applicable for this risk assessment could be extracted from these studies.
Distribution The highest concentrations of propyl paraben found in humans were detected in female breast tissue following mastectomies. The concentrations of parabens were in this uncontrolled study using 20 breast cancer patients 20.6 ± 4.2 ng g−1 breast tissue, with propyl paraben accounting for 2.6 ng g−1 breast tissue 20. Propyl paraben was the third most common paraben found in the tissues. The parabens were found in very close proximity to the area of application of cosmetics (i.e. deodorant) in the breast tissue, indicating that the propylparaben esters accumulate at the site of application rather than being distributed to the entire system 21. Other than this study there are no indications of any studies that parabens would accumulate in organs or tissues of the body.
Comments: Most studies indicate that propyl paraben is not distributed to other sites than the site of exposure, but the possibility that it can be distributed to other tissues and compartments within the body cannot be completely excluded.
Biotransformation & Excretion In a study performed by Lakeram et al. (2007) it was concluded that various parabens, including propylparaben, are metabolized into p-hydroxybenzoic acid by esterases in the gut, and liver if ingested orally. Furthermore, they concluded that pre-systemic metabolism in the intestine of orally ingested parabens may limit systemic exposure to parabens esters22. The biotransformation of propyl paraben includes hydrolysis of the ester bond by four carboxyl esterases that can be found in the skin and in the subcutaneous fat. The hydrolization produces para-hydroxybenzoic acid, the main metabolite of all parabens, and the respective side chains for each paraben 23. Even though it is believed that most metabolism of propyl paraben occurs at the site of exposure, but it has also been concluded that dermal application of propylparaben can allow for parabens to escape metabolism and action of the esterases. This is concluded because the metabolic process by esterases in the gut and liver would produce p-hydroxybenzoic acid, and intact paraben esters have been found both in urine and in human breast cancer tissue 21,24.
There is no information on the bioaccumulation or half-life of parabens esters, or their metabolites, an issue brought to attention by Harvey & Everett 25. Excretion does occur in urine, both as metabolites and as intact parabens esters, but yet there is no reliable method by which one can correlate exposure and absorption with the excretion rates 24. There are many indications from a variety of different surveys that repeated applications of dermal cosmetics can cause propylparaben to accumulate in the skin and later be absorbed into body tissue, intact or as metabolites 21,26 . There are also suggestions that there are individual differences in the metabolism of the compound in individuals. TOXICITY AND MODE OF ACTION/MECHANISM OF TOXICITY
Acute toxicity after single administration There is very little information available on acute toxicity data regarding propyl paraben. No studies have been found that would be entirely appropriate to use for this report since they are all so old that they are not available on the Internet, or are written in foreign languages. Many of these acute toxicity findings have been used in other reports on propyl paraben 27, but the extraction and translation of these reports are outside of the scope of the authors’ abilities for this assessment. Table 2 shows a modified table taken from Soni et al. (2001) to serve as guidance on probable acute toxicity values. Notable is that the dose interval has not been given in any of the reports, and so these values should be considered with care. The lowest lethal dose-value found was an intraperitoneal dose of 650 mg / kg BW. The only acute toxicity value after an oral exposure or propyl paraben was 6322 mg / kg BW.
Toxicity after repeated oral administration In a dietary study where rats were fed food containing 2 and 8% propyl paraben (0.9±1.2 g/kg BW,d and 5.5±5.9 g/kg BW,d respectively) for 96-weeks, the food intake and weight of the animals were recorded regularly. The weights of different organs were noted following sacrifice of the test animals. No adverse treatment-related effects could be found at either doses 28. Another study examined the effects on weanling dogs that were fed propyl at the concentration of 0.5 g/ kg BW/day for a year. No toxicological effects could be found, not in behavior, weight or following microscopy of the animals’ organs 28.
In a study using hamsters, no treatment-related microscopic changes in the stomach or in liver weight could be found after being fed propyl paraben at a concentration of approximately 3.6 g / kg BW / day for 20 weeks 29. A significant response occurred, however, when looking at the labeling index of the urinary bladder, suggesting a proliferative response. A similar study also showed that rats being fed 4% methyl paraben for nine days increased the labeling index of the fore stomach epithelia 30. In a study that could be considered equivalent to above mentioned, no increase in labeling index could be found for the organs that previously had been reported 31. All of these findings were found in the prefundic fore stomach, a part of the digestive system that humans do not possess. Comments: Effects that have been observed following repeated administration though food during a prolonged amount of time include proliferative responses of the prefundic fore stomach in rodents. There are contradictory results of the labeling index, which has been used as an indicator of proliferation for similar test models and doses. The lowest dose that caused an effect after chronic exposure was 3.6 g / BW and day and increased the labeling index of the urinary tract in rodents.
Endocrine disruption All parabens, and their main metabolite p-hydroxybenzoic acid, have been found to exert estrogenic activity in a range of different studies including in vitro recombinant yeast assays and human estrogen receptor assays 26,32–34.The larger the alkyl group of the paraben, the greater the estrogenic response, with propyl paraben being the second most potent of the parabens with a 30 000 fold less potency than 17-b-estradiol. Butylparaben has a potency of 10 000 fold less than 17-b estradiol 35. It has been shown that parabens bind to rodent uterine estrogen receptors 36 as well as to human estrogen receptors37. Other than propyl paraben binding to the estrogen receptor, there are no studies to the authors’ knowledge examining endocrine disruption caused by propyl paraben, neither on animals nor on humans. Comments: There are strong indications that biologically relevant concentrations of propyl paraben in human breast tissue could provide estrogenic stimulus sufficient to induce breast cancer in humans. The potency of propyl paraben is estimated to be approximately 30 000 less than oestradiol35. Oestradiol however occurs in breast tissue in the pictogram per gram range 38 , but the concentrations found in the Barr et al. (2012) study were ranging up to one million-fold higher than normal oestradiol concentrations in the body. This means that propyl paraben in biologically relevant tissues very well could interact with estrogenic receptors. Additionally, when paraben esters are combined in mixtures there is an additive effect and the potency becomes higher than of the individual compounds alone 39,40. Although there is no study available providing indisputable evidence for endocrine disruption by propyl paraben, it must be noted that the insufficiency of available tests does not remove the possibility of propyl paraben being disruptive.
Reproductive toxicity It has been shown that propyl paraben causes adverse effects on the male reproductive system 41. In a study performed on rats given dietary supplements of propyl paraben for 4 weeks at the onset of spermatogenesis, it was shown that sperm concentration in the cauda epididymal sperm reserves decreased in a dose-dependent manner. Propylparaben also affected the secretion of testosterone, lowering it significantly to 64,6% of the control value, at a dose of 1290 mg/kg BW*d. The daily sperm production also decreased at the dose of 12.4 mg/kg BW*d, and possibly at lower doses as well. There were no observed treatment-related effects on any of the reproductive organs, however the body weight was slightly significantly lower for the treatment group treated with 1.00% propyl paraben in their diet. Growth inhibition has in the past been used as measures of estrogenic effects 42,43, however, contradictory results exist where the body weight is not affected by a even higher propyl paraben in the diet 28.
In an in vitro study on the spermicidal activity of propyl paraben it was found that the spermicidal potency of propyl paraben was 3 mg/ml solution 44. The study showed that propyl paraben is an effective spermicide. Comments: No reproductive tests running over several generations were found. All the studies found were performed on the male reproductive system. No tests were found using humans, but as the reproductive systems of rats are similar to that of humans, the studies presented above are considered satisfactory regarding the quality and the quantity of evidence. As testosterone controls the development of the male reproductive system and spermatogenesis 45, the studies presented are considered adequate evidence for propyl paraben exerting reproductive effects. The lowest concentration at witch an effect was seen for reproductive toxicity was 12.4 mg/ kg BW / day, but this value may be lower as all concentrations were positive for the endpoint ‘Decrease of daily sperm production’.
Carcinogenicity There are no studies that indicate the development of cancer after exposure to propyl paraben.
Comments: To date there is no evidence that personal care products containing propyl paraben induces breast cancer, but it is worth noting that there also are no studies that have been conducted to explore this possibility, as eloquently pointed out by Harvey & Everett (2012). They argue that there is a “false reassurance [of parabens not being carcinogenic] by masking the inadequacies of empirical evidence and knowledge”. The study on propyl paraben concentrations in breast cancer patients performed by Barr et al. 2012 showed a clear correlation between the placement of breast cancer tissue and the area on the breast that is frequently exposed to dermal cosmetics and concentrations of parabens, including propyl paraben.
Genotoxicity and mutagenicity Propylparaben has been shown to cause oxidative stress coupled with DNA damage using an in vitro system with mammalian cells 46. Using kidney cells from the green monkey, mechanistically relevant endpoints were examined following a 24-hour exposure of propylparaben. The exposure to propyl paraben caused changes in the cell-proliferation rates, which was shown by a significant dose-dependent decline of cells in the M-phase after a 24-hour exposure of 500μM (90.1 mg/L) propylparaben. The amount of mitotic cells for this dose was four times as low than in the control. The decline in cell-proliferation was explained by a cell-cycle arrest in the G0/G1 phase. Furthermore, they found nuclear γ-H2AX foci in treated groups, which is an early indicator of the occurrence of double stranded DNA breaks. EC50-values could not be obtained in this study due to the highest concentration tested was not potent enough 46.
Propylparaben caused detectible RNA-damage using comet assays. It also induces chromosome aberrations and sister-chromatic exchanges 47. For chromosome aberrations the EC34=2.0 μM (0.36 mg/L) and EC7= 1.0 μM (0.18 mg/L) in CHO-K1 cell cultures after a one hour exposure 47.
In an Ames test used to evaluate the mutagenicity of propyl paraben in yeast cells propyl paraben was found non-mutagenic, both with or without previous metabolic activation for doses ranging between 0.0025 to 0.15% propyl paraben in solution of the suspension tests48.
Comments: Propyl parabens can induce mutagenic responses for concentrations at 1.0 μM (0.18 mg/L) or higher in vitro, although contradictory results exist. No tests have been found that examine genotoxicity and mutagenicity on germ cells.
Acute dermal toxicity/irritation after a single exposure A formulation containing 0.2% propyl paraben and methyl paraben, respectively, was applied topically to rabbits covering 10% of their body surface at doses of 2mg/cm2 and 6 mg/cm2. After the singe exposure the rabbits, both in the control group and in test groups, were exposed to UV-light every day for 4 min at 6 inches away from a UV light with a spectrum of 2800 and 4000 A. In total two control groups and three test groups containing six to eight animals each. Persistent moderate erythema, mild desquamation and slight edema were noted for both doses, with occasional bleeding and epidermal lesions. The higher dose was slightly more irritating than the lower dose, but the exposure to UV-light did not affect the test results. No other toxicological effects than the dermal ones were noted, such as body weigh gain or food consumption 49. A formulation containing 0.2% propyl paraben and 0.1% butyl paraben was applied at a dose of 0.1 ml to the genital mucosa of rabbits, and there was no evidence of toxicological effects or irritation of the skin following the 7 day observation period 49. Comments: The tests above do not only contain propyl paraben but also another paraben as the active substance. Since all parabens are structurally similar, the tests will be considered appropriate since it will be in accordance with a more careful approach rather than disregarding them as invalid. It is worth noting that the rabbits were shaved and that the study does not comment on whether the skin could have been irritated before the start of the study.
Dermal toxicity/irritation after repeated exposure In a study using rats, a formulation containing 0.3% propyl paraben was administered topically daily to the anterior shaved skin (10-15% of the total body surface) for 13 weeks. The application dose was approximately 4.12 g/ kg BW*d. There was a significant decrease in weight gain of the treated group, as well as significant gross histopathological changes limited to the area of exposure. Slight changes in hematologic and blood chemistry parameters were also noted, but these were not large enough to point to a cumulative systemic toxic effect49. Propyl paraben was applied to the backs of 50 humans at concentrations of 5,7,10 and 15% propyl paraben in propylene glycol. The test subjects were exposed daily for 5 consecutive days. The endpoint of this test was irritation of the skin and the 12% concentration did not produce and irritation, but the 15% did. The test was followed up by yet another, pro-longed, repeated insult patch test of 3 weeks with application every other day for the 12% concentration, and no sensitization was reported 50. The study did not indicate the amounts of formulation that was applied and thus the exact dose at which the test subjects were exposed cannot be given.
Table 4. Summary of dermal toxicity/irritation tests after repeated exposure. *Many of the studies only indicate the amount of active substance in the formulation, but not the amount of formulation that was applied to the test subjects, why a dose interval and a NOAEL is not possible to establish according to standards. Species Time of Exposure Amount of active substance in formulation Dose interval (g/kg BW/d) Endpoint Toxicity measure Ref. Rat 13 w 0.3% 4.12 Decrease in weight, histopathological changes NOAEL < 4.12 LOAEL = 4.12 49 Human 5 d 5 – 15% N/A* Dermal irritation NOAEL = 12%* LOAEL = 15%* 50 Human 3 w 12% N/A* Sensitization No effect 50
In a review study of Soni et al. (2001) about 20 studies performed on sensitization of propyl paraben and mixtures containing propyl paraben were reviewed. They concluded that sensitization due to parabens is not significant when the concentrations of propyl paraben are within 0.3 to 0.4% of the total amount of formulation27. In the sensitization tests that have been performed, the influx or parabens through the epidermis is very much dependent on the vehicle of the parabens. The amounts of ethanol and acetone in the mixture will affect how much that is absorbed into the skin 51. Most reports where allergic reactions have been found due to parabens happen after application to already damaged skin or after repetitive application at very high doses 52 27, not within the scope of what is allowed to be sold in the market today. Comments: Many of the studies only indicate the amount of active substance in the formulation, but not the amount of formulation that was applied to the test subjects, why a dose interval and a NOAEL is not possible to establish according to standards. There are no longer exposures performed on humans, thus the study done on rats is considered appropriate for further assessment. It would seem that rodents are more sensitive to propyl parabens than humans, but this cannot be ascertained by the information available.
Mode of action/mechanism of toxicity The cytotoxicity of propyl paraben is linked to mitochondrial failure due to induction of the mPT pore and depletion of ATP stores due to depolarization of the mitochondrial membranes and uncoupling of oxidative phosphorylation 27. The kidney and liver is extremely efficient in metabolizing propyl paraben by hydrolysis, and some metabolism is also believed to take place at the site of exposure after dermal absorption by esterases 49.
Sodium propyl p-hydroxybenzoate, the sodium salt of propylparaben, a compound with formula Na(C3H7(C6H4COO)O), is also used similarly as a food additive and as an anti-fungal preservation agent. Its E number is E217.
- Oishi (2002). "Effects of propyl paraben on the male reproductive system". Food Chemical Toxicology 40 (12): 1807–13. doi:10.1016/s0278-6915(02)00204-1. PMID 12419695.
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