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Biomonitoring Summary

Parabens

Methyl paraben CAS No. 99-76-3
Ethyl paraben CAS No. 120-47-8
n-Propyl paraben CAS No. 94-13-3
Butyl paraben CAS No. 94-26-8

General Information

Parabens are short alkyl chain esters of para-hydroxybenzoic acid (PHBA), of which four were measured in the National Biomonitoring Program: methyl, ethyl, n-propyl, and butyl (n- and iso-butyl) parabens. These chemicals are widely used as preservatives in cosmetics and in such personal care products as shampoos, hair and shaving products, facial and skin cleansers, and lotions. The amount allowed depends on whether a mixture of parabens (up to 0.8%) or a single paraben (up to 0.4%) is used; however, amounts less than 0.3% are typically included in such products (CIR, 2008). The most frequently used parabens, methyl and n-propyl, can be added (up to 0.1%) as antimicrobials to prevent food spoilage in such items as baked goods, beverages, syrups, jellies, jams, and preserves; these parabens, as well as ethyl paraben, can be used in food packaging (Soni et al., 2001, 2002, and 2005). At maximum concentrations rarely exceeding 0.1%, parabens are allowed as preservatives in various pharmaceutical products (CIR, 2008). Parabens also occur naturally in some foods, including specific fruit juices and wine (Soni et al., 2005). Production and usage of products containing parabens can result in their release to the environment through various waste streams. Parabens do not persist in the environment, and they are degraded by photolysis in the air and biodegraded in water.

General population exposure occurs with use of paraben-containing personal care products or consumption of foods or pharmaceuticals containing parabens. Dermal application of lotions and cleansers may result in small amounts of parabens being absorbed through the skin and reaching the blood stream (Janjua et al., 2008). Enzymes in the skin rapidly metabolize parabens to PHBA, the primary metabolite, reducing the dose that reaches the blood stream. Parabens penetrate the epidermis to an extent that is inversely proportional to the length of the ester side chain (e.g, in order of increasing penetration, butyl > propyl > ethyl > methyl) (CIR, 2008). When a butyl paraben-containing cream was applied to human skin, less than 1% of the dose was recovered in the urine (Janjua et al., 2008). A study found that premature infants excreted from 13 to 88% of a methyl paraben dose (used as a preservative in an intravenous medication), and most of the urinary methyl paraben was conjugated to sulfate and, to a lesser extent, glucuronide (Hindmarsh et al., 1983). In general, ingested parabens are rapidly absorbed in the gastrointestinal tract, promptly hydrolyzed by the liver, and then conjugated to sulfate and glucuronide and eliminated in the urine within hours (Soni, 2001 and 2002). In animal studies, PHBA is a major metabolite of parabens, but it is also normally found in human urine as a decomposition product of the endogenous amino acid tyrosine and in a wide variety of plant foods. In vitro studies suggest that parabens may be metabolized to PHBA in the intestine and subsequently re-esterified to another paraben or to the parent paraben (Lakeram et al., 2006). Parabens do not accumulate in the skin or other body organs.

Human health effects from parabens at low environmental doses or at biomonitored levels from low environmental exposures are unknown. Parabens were not found to be acutely toxic nor was toxicity noted when they were administered for several weeks by oral or intravenous routes to animals (CIR, 2008; Matthews et al., 1956). In animal studies, parabens were found to be non-allergenic, and they did not sensitize skin (Adler-Hradecky and Kelentey, 1960; Sokol, 1952). When applied topically, parabens may produce irritation in previously sensitized or damaged skin in humans and in laboratory animals; sensitized individuals may also react to parabens (Aeling and Nuss, 1974; Fisher et al., 1971; Marzulli et al., 1968; Smith, 1991). In addition, chronic skin reactions have been reported, including urticaria and angioedema (Soni et al., 2001). Despite evidence that parabens are non-allergenic, sporadic human cases have been reported of anaphylactic reactions following paraben exposure (CIR, 2008; Nagel et al., 1977).

At levels producing maternal toxicity, parabens were not teratogenic in animal studies (Daston, 2004; Elder, 1984, Moriyama et al., 1975). Butyl paraben may alter male reproductive organ size and sperm numbers and activity, but animal studies have been inconsistent (Fisher et al, 1999; Oishi, 2001; Taxvig et al, 2008). Other parabens have not shown reproductive toxicity in animal studies (CIR, 2008; Shaw and deCatanzaro, 2009). The estrogenic activity of parabens is extremely weak: butyl paraben, the most potent of the group, is 10,000 to 100,000 times less potent than naturally occurring estradiol (Golden et al., 2005). Safety assessments of maximum estimated paraben exposures have concluded that estrogenic effects are unlikely in humans. (CIR, 2008; Elder, 1984; Golden, 2005; Soni et al., 2001 and 2002).

Parabens were non-mutagenic in several in vitro assays, although methyl and ethyl paraben increased chromosomal abnormalities in some animal cell assays (CIR, 2008). Parabens have not been found to be animal carcinogens. Neither NTP nor IARC has evaluated parabens with respect to human carcinogenicity. The FDA classifies methyl and n-propyl paraben as Generally Recognized as Safe (GRAS) for addition to foods, up to 0.1% (21 CFR 184.1490), and allows these and butyl paraben up to specified amounts as additives and preservatives in specific foods (21 CFR 172.515) (Soni et al., 2005).

Biomonitoring Information

Levels of urinary parabens reflect recent exposure. In a small convenience sample of U.S. adults, methyl and n-propyl paraben were detected in 99% and 96% of urine specimens, respectively (Ye et al., 2006). The highest median paraben value was methyl (43.9 µg/L), followed by n-propyl (9.1 µg/L), ethyl (1.0 µg/L), and butyl paraben (0.5 µg/L). In the NHANES 2005-2006 subsample, median values observed for the overall population were similar to those in the earlier convenience sample (Calafat et al., 2010). Urinary levels of methyl and n-propyl paraben were highly correlated, and their concentrations ranged widely, with methyl paraben from <1.0 to 17,300 µg/L and n-propyl paraben from <0.2 to 7210 µg/L (Calafat, et al., 2010). When adjusted for age, sex, and race/ethnicity, geometric mean methyl paraben levels were higher in non-Hispanic blacks than in non-Hispanic whites except at ages greater than 60 years (Calafat et al., 2010). Females had three times higher adjusted geometric mean levels of methyl paraben and seven times higher adjusted geometric mean levels of n-propyl paraben than males (Calafat et al., 2010). In a small sample of Danish males, methyl, ethyl, n-propyl, and butyl parabens were detected in 80% or more of the urine specimens. Median values of each paraben were similar to the corresponding values for males in the NHANES 2005–2006 subsample (Calafat et al., 2010; Frederiksen et al., 2011).

Finding a measurable amount of one or more parabens in urine does not imply that the levels cause an adverse health effect. Biomonitoring studies on levels of parabens provide physicians and public health officials with reference values so that they can determine whether people have been exposed to higher levels of parabens than are found in the general population. Biomonitoring data can also help scientists plan and conduct research on exposure and health effects.

References

Adler-Hradecky C, Kelentey B. On the toxicity and local analgetic effect of p-hydroxybenzoic acid esters. Arch Int Pharmacodyn Ther 1960;128:135-42.

Aeling JL, Nuss DD. Systemic eczematous "contact-type" dermatitis medicamentosa caused by parabens. Arch Dermatol 1974;110:640.

Calafat AM, Ye X, Wong L-Y, Bishop AM, Needham LL. Urinary concentrations of four parabens in the U.S. population: 2005-2006. Environ Health Perspect 2010;118:679-85.

Cosmetic Ingedient Review Expert Panel (CIR). 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;27(Suppl 4): 1-82.

Daston GP. Developmental toxicity evaluation of butylparaben in Sprague-Dawley rats. Birth Defects Res (Part B) 2004;71:296-302.

Elder RL, ed. Final report on the safety assessment of methylparaben, ethylparaben, propylparaben, and butylparaben. J Am Coll Toxicol 1984;3(5):147-209.

Fisher AA, Pascher F, Kanof NB. Allergic contact dermatitis due to ingredients of vehicles. A vehicle tray for patch testing. Arch Dermatol 1971;104:286-90.

Fisher JS, Turner KJ, Brown D, Sharpe RM. Effect of neonatal exposure to extrogenic compounds on development of the excurrent ducts of the rat testis through puberty to adulthood. Environ Health Perspect 1999;107:397-405.

Frederiksen H, Jorgensen N, Andersson A-M. Parabens in urine, serum and seminal plasma from healthy Danish men determined by liquid chromatography—tandem mass spectrometry (LC—MS/MS). J Expos Sci Environ Epidemiol 2011; 21:262-71.

Golden R, Gandy J, Vollmer G. A review of the endocrine activity of parabens and implications for potential risks to human health. Crit Rev Toxicol 2005;35:435-58.

Hindmarsh KW, John E, Asali LA, French JN, Williams GL, McBride WG. Urinary excretion of methylparaben and its metabolites in preterm infants. J Pharm Sci 1983;72:1039-41.

Janjua NR, Fredericksen H, Skakkebaek NE, Wulf HC, Andersson A-M. Urinary excretion of phthalates and paraben after repeated whole-body topical application in humans. Int J Androl 2008;31:118-30.

Lakeram M, Paine AJ, Lockley DJ, Sanders DJ, Pendlington R, Forbes B. Transesterification of p-hydroxybenzoate esters (parabens) by human intestinal (Caco-2) cells. Xenobiotica 2006;36:739-49.

Marzulli FN, Carson TR, Maibach JI. Delayed contact hypersensitivity studies in man and animals. Proc Joint Conf Cosmet Sci 1968. pp. 107-22.

Matthews C, Davidson J, Bauer E, Morrison JL, Richardson AP. p-Hydroxybenzoic acid esters as preservatives. II. acute and chronic toxicity in dogs, rats, and mice. J Am Pharm Assoc Sci Ed 1956;45:260-7.

Moriyama I, Hiraoka K, Yamaguchi R. Teratogenic effects of food additive ethyl-p-hydroxybenzoate studied in pregnant rats. Acta Obstet Gynaecol Japan 1975;22:94-106.

Nagel JE, Fuscaldo JT, Fireman P. Paraben allergy. JAMA 1977;237:1594-5.

Oishi S. Effects of butylparaben on the male reproductive system in rats. Toxicol Indust Health 2001;17:31-39.

Shaw J, deCatanzaro D. Estrogenicity of parabens revisited: impact of parabens on early pregnancy and an uterotrophic assay in mice. Reprod Toxicol 2009;28:26-31.

Smith JM. Adverse reactions to food and drug additives. Eur J Clin Nutr 1991;45 (Supp. 1):17-21.

Sokol H. Recent developments in the preservation of pharmaceuticals. Drug Standards 1952;20:89106.

Soni MG, Carabin IG, Burdock GA. Safety assessment of esters of p-hydroxybenzoic acid (parabens). Food Chem Toxicol 2005;43:985-1015.

Soni MG, Burdock GA, Taylor SL, Greenberg NA. Safety assessment of propyl paraben: a review of the published literature. Food Chem Toxicol 2001;39:513-32.

Soni MG, Taylor SL, Greenberg NA, Burdock GA. Evaluation of the health aspects of methyl paraben: a review of the published literature. Food Chem Toxicol 2002;40:1335-73.

Taxvig C, Vinggaard AM, Hass U, Axelstad M, Boberg J, Hansen PR, et al. Do parabens have the ability to interfere with steroidogenesis? Toxicol Sci 2008;106:206-13.

Ye X, Bishop AM, Reidy JA, Needham LL, Calafat AM. Parabens as urinary biomarkers of exposure in humans. Environ Health Perspect 2006;114:1843-6.


 
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