Testing Information

Testing Status of Agents at NTP

CAS Registry Number: 94-26-8 Toxicity Effects

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Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 1

Names (NTP)

  • n-Butyl-p-hydroxybenzoate
  • BUTYLPARABEN
  • Butyl paraben

Human Toxicity Excerpts

  • HUMAN EXPOSURE STUDIES: Methylparaben, ethylparaben, propylparaben, and butylparaben were each applied to the backs of 50 humans at concentrations of 5, 7, 10, 12, and 15% in propylene glycol. Test compounds were applied daily for 5 days, and patches were then removed and the sites scored. The concentrations of individual parabens that produced no irritation were methylparaben, 5%; ethylparaben, 7%; propylparaben, 12%; and butylparaben, 5%. Higher concentrations produced some evidence of irritation. In a repeated insult patch test (RIPT), each Paraben at the "no effect" concentration above was applied to the skin of 50 subjects (25M/25F) for 4 to 8 hrs every other day for 3 weeks (10 applications). Following a 3-week rest, the materials were reapplied at induction concentrations for 24 to 48 hrs. No sensitization was reported. [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 60, June 2006. ]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: ... As constituents of antibacterial ointments, dermatological preparations, and proprietary lotions and skin creams ... /parabens/ are recognized causes of severe and intractable contact dermatitis ... Patients sensitive to one paraben show cross-sensitivity to the others. /Parabens/ [Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980., p. 969]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: It may cause ... hypersensitivity ... manifested as dermatitis. [Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1090]**PEER REVIEWED**
  • SIGNS AND SYMPTOMS: All ... parabens are capable of sensitizing skin and inducing cutaneous allergic responses, although incidence of such reactions is low. ... /Methylparaben/ [Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1096]**PEER REVIEWED**
  • ALTERNATIVE and IN VITRO TESTS: An in vitro test was set up to assess the release of lysosomal enzymes from cells and the effect on this process of the commonly used preservatives, parabens. Human peripheral lymphocytes, cultivated in vitro for 24 hr in the presence or absence of phytohemagglutinin (PHA; 5 mg/L), were used. After 1 day of incubation, PHA treatment caused an increased release (from 220 to 500%) of the lysosomal enzymes N-acetyl-beta-D-glucosaminidase, beta-D-glucuronidase, alpha-L-fucosidase and alpha-D-galactosidase. This enhancement was analytically reliable, and detectable with 1-5 ug of cell protein. Leakage of lactate dehydrogenase (LDH) underwent only a 20% increase on PHA treatment, indicating that the increased release of lysosomal enzymes was presumably due to secretion, not to cell damage. In PHA-stimulated lymphocytes, methyl-, ethyl-, propyl- and butyl-parabens caused a concentration-dependent diminution of the secretion of lysosomal enzymes. Butyl-paraben appeared to be the most potent inhibitor, causing a 45-50% inhibition at 0.06 mmol/L. ... Parabens did not influence the release of LDH, suggesting that they affected particularly the secretion of lysosomal enzymes. ... [Bairati C et al; Clin Chim Acta 224 (2): 147-57 (1994) ]**PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: ... The estrogenic effects of four parabens (methylparaben, ethylparaben, n-propylparaben, n-butylparaben) in estrogen-dependent MCF7 human breast cancer cells /are reported/. Competitive inhibition of 3-H-estradiol binding to MCF7 cell estrogen receptors could be detected at 1,000,000-fold molar excess of n-butylparaben (86%), n-propylparaben (77%), ethyl-paraben (54%) and methylparaben (21%). At concentrations of 10-6 M and above, parabens were are able to increase expression of both transfected (ERE-CAT reporter gene) and endogenous (pS2) estrogen-regulated genes in these cells. They could also increase proliferation of the cells in monolayer culture, which could be inhibited by the antiestrogen ICI 182,780, indicating that the effects were mediated through the estrogen receptor. However, no antagonist activity of parabens could be detected on regulation of cell proliferation by 17beta-estradiol at 10-10 M. Molecular modeling has indicated the mode by which paraben molecules can bind into the ligand binding pocket of the crystal structure of the ligand binding domain (LBD) of the estrogen receptor alpha (ERalpha) in place of 17beta-estradiol; it has furthermore shown that two paraben molecules can bind simultaneously in a mode in which their phenolic hydroxyl groups bind similarly to those of the meso-hexoestrol molecule ... [Byford JR et al; J Steroid Biochem Mol Biol 80 (1): 49-60 (2002) ]**PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: Estrogenic activities of the phenolic preservatives methylparaben, ethylparaben, propylparaben, butylparaben, isopropylparaben and isobutylparaben were examined by assaying estrogen-receptor (ER)-dependent proliferation of MCF-7 cells. All the compounds stimulated the proliferation to about the same level as the maximal cell yield attained with 3×10-11 M 17beta-estradiol, but at a concentration in the order of 10+5 to 10+7 higher than 17beta-estradiol. The cell-proliferative effects of parabens were completely suppressed by anti-estrogen ICI 182,780. MCF-7 cells treated with butylparaben and isobutylparaben exhibited a decrease in gene expression of ERalpha and an increase in that of progesterone-receptor (PR), but the effects of these parabens were not as prominent as those of 17beta-estradiol. Western blot analysis indicated that these parabens caused a slight decrease in expression of ER? protein. Competitive binding to human ERalpha and ERbeta in vitro revealed that the parabens with longer side-chains showed greater affinity for estrogen receptors, and that they had similar relative binding affinity (RBA) values to both ERalpha and ERbeta. RBA values were much smaller than that of diethylstilbestrol. In conclusion, parabens have ER-dependent estrogenic activities, and their effects on the intracellular signaling pathway might be different from that of 17beta-estradiol. [Okubo T et al; Food Chem Toxicol 39 (12): 1225-1232 (2001) ]**PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: The inhibition of the proteolytic activity of acrosin in human spermatozoa by butyl p-hydroxybenzoate was assessed by the gelatin substrate film method. Compared with a typical acrosin inhibitor, TLCK, the inhibitory activity of butyl p-hydroxybenzoate to acrosin was much more effective (20 times) than that of N-tosyl-L-lysyl chloromethyl ketone (TLCK), proving that butyl p-hydroxybenzoate was a potent acrosin inhibitor. The effect of butyl p-hydroxybenzoate on membrane function of human spermatozoa was evaluated using a sperm-tail hypoosmotic swelling test and supravital stain method. A good correlation (r = 0.92) was observed between the % spermatozoa with normal membrane function and the % live spermatozoa after treatment of the spermatozoa with butyl p-hydroxybenzoate for 1 min, indicating that the death of spermatozoa caused by butyl p-hydroxybenzoate is probably due to impairment of sperm membrane function. Both the inhibitory effect on acrosin and the adverse effect on membrane function suggest that butyl p-hydroxybenzoate could be developed as a new vaginal contraceptive. [Song BL et al; J Reprod Fertil 91 (2): 435-40 (1991) ]**PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: ... The effects of methylparaben, ethylparaben, propylparaben, and butylparaben on human and rabbit erythrocytes in vitro /were examined/. Butylparaben, at 0.02% induced hemolysis in 12% of the rabbit and 6% of the human erythrocytes. [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 32, June 2006. ]**PEER REVIEWED**
  • ALTERNATIVE and IN VITRO TESTS: In this work, the estrogenic effects of three classes of substances included in cosmetic formulations-parabens, ultraviolet (UV) screens, and musk fragrances-were studied. Their estrogenic activity was measured with the use of three reporter cell lines: HELN, HELN ERalpha, and HELN ERbeta. These three cell lines allowed for the measurement of estrogenic activity toward estrogen receptors alpha and beta (ERalpha and ERbeta, while taking nonspecific interactions into account. Eight of the 15 substances tested showed specific estrogenic activity with the following degree of potency on ERalpha butylparaben > propylparaben > homosalate = octyl-dimethyl-PABA = 4-methyl-benzylidenecamphor = octyl-methoxycinnamate > ethylparaben = galaxolide. Among these active substances, parabens activated ERalpha and ERbeta similarly ... Methylparaben, ethylparaben, musk moskene, celestolide, and cashmeran did not activate estrogenic responses up to 10(-5) M. [Gomez E et al; J Toxicol Environ Health A 68 (4): 239-51 (2005) ]**PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: Potent in vitro spermicidal activity of parabens against human spermatozoa was demonstrated. The pass point concn of the 4 parabens (methylparaben, ethylparaben, propylparaben, and butylparaben), at which all spermatozoa were immobilized and no immobilized spermatozoon revived after 30 min incubation in phosphate buffered glucose soln, was 6, 8, 3, and 1 mg/mL, respectively, as tested by the Harris' method. [Song B et al; Contraception 39 (3): 331-5 (1989) ]**PEER REVIEWED**
  • OTHER TOXICITY INFORMATION: ... Scientific data relevant to the safety evaluation of the use of hydroxy- and alkoxy-substituted benzyl derivatives as flavoring ingredients is evaluated. The group of hydroxy- and alkoxy-benzyl derivatives was reaffirmed as GRAS based, in part, on their self-limiting properties as flavoring substances in food; their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of hydroxy- and alkoxy-substituted benzyl derivatives as natural components of traditional foods is greater than their intake as intentionally added flavoring substances. /Hydroxy- and alkoxy-benzyl derivatives/ [Adams TB et al; Food Chem Toxicol 43 (8) 1241-71 (2005) ]**PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • LABORATORY ANIMALS: Acute Exposure: In guinea pigs, mild skin irritation was noted 48 hr after dermal application of a preparation containing 5% butyl paraben. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 6:672]**PEER REVIEWED**
  • LABORATORY ANIMALS: Acute Exposure: Mucous membrane irritation: ... a product formulation containing 0.2% propylparaben and 0.1% butylparaben was applied to the genital mucosa of six albino rabbits. The single 0.1 mL application of the undiluted product produced no evidence of mucosal irritation during the 7-day observation period. [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 42, June 2006. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: ... Butyl paraben was administered to 4-week-old Crj:CD-1 mice assigned to groups of eight animals, at doses of 0.01%, 0.10%, and 1.00% in the diet for 10 weeks. The average butyl paraben intake from the calculated food consumption was 14.4+/-3.60, 146+/-35.9, and 1,504+/-357 mg/kg per day for the 0.01%, 0.10%, and 1.00% dietary butyl paraben groups, respectively. There were no treatment-related effects of butyl paraben on the liver, ventral prostates, seminal vesicles, and preputial glands (both in terms of absolute weight and relative to body weight) in any of the study groups. Both the absolute and relative weights of the epididymes were significantly higher in 1.00% group when compared with controls. A dose-dependent decrease of both round and elongated spermatid counts in stages VII-VIII seminiferous tubules was observed, and the elongated spermatid counts were significantly lower in all of the treated groups. The numbers of spermatogonia and spermatocytes did not differ from control values. The serum testosterone concentration decreased in a dose-dependent fashion and was significant at 1.00%. These data demonstrated that butyl paraben can exert an adverse effect on the male reproductive system at doses that are well below those of the accepted daily intake (ADI) in Japan. [Oishi S; Arch Toxicol; 76 (7): 423-9 (2002) ]**PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: Ethylparaben or butylparaben were fed to /24/ rats at concentrations of 2 or 8% in the diet for 12 weeks. Negative controls were included in the study. ... At 8% dietary concentration, ethylparaben reduced growth rate, decreased motor activity, and, in some cases, caused death within the first week. All males fed 8% butylparaben died before the twelfth week. Females fed this diet exhibited signs of toxicity. [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 39, June 2006. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: A study /was conducted/ using Crl:(WI) BR male rats. Four exposure groups (16 rats each) received Butylparaben at concentrations of 0, 100, 1000, and 10000 ppm in the diet for a minimum of 56 days. ... Actual consumed doses of Butylparaben were estimated to be 0, 10.9, 109.3, and 1087.6 mg/kg day. All rats were 21 days of age at the start of the study. Body weights, clinical observations, and feed consumption were recorded. At 21 days after the start of exposure (42 days of age), blood samples were collected (bi-weekly after the initial collection) and analyzed for LH, FSH, and testosterone. At the end of the study, all surviving rats were killed and a final blood sample taken and analyzed. Sperm evaluations (concentration, motility, and morphology) were made. One testis was collected for evaluation of daily sperm production (DSP). ... No effects of butylparaben consumption on body weights, weight gain, feed consumption, or organ weights were found. Two rats (one control and one in the 100 ppm group) were killed on days 32 and 44, respectively, because of lesions of the eye from retro-orbital bleeding. In those two animals, no other clinical observations were noted during the study or at necropsy. No other control or treatment animals had adverse clinical observations during the study or at necropsy. Histopathology of the testes using the semi-quantitative staging described above identified no cell or stage related changes in either control or treated animals, except that one rat given 10,000 ppm had a single cross-section (25 cross-sections obtained) of a seminiferous tubule with a loss of germinal epithelium. The authors interpreted the small area affected and the failure to find any equivalent findings in the testes of any other animal to suggest this effect was not treatment related. Histopathological evaluation of the adrenal, pituitary, or thyroid glands or the liver uncovered no treatment related effects. DSP was unaffected by butylparaben consumption. Likewise, no effect on sperm motility, count, or morphology was found. No consistent differences in LH, FSH, or testosterone levels were reported in the treatment groups compared to controls. In the 1000 and 10000 ppm groups at the second blood sample interval (3 weeks) there was a significant reduction in testosterone. At 9 weeks, the 10000 ppm group had an increased testosterone level. LH levels were reduced in the 100 and 10000 ppm groups at 5 weeks, but not at other doses. At 9 weeks, LH levels were increased in the 10000 ppm group. None of these findings were considered dose-related. These authors concluded that 10000 ppm was a NOEL for general toxicity, including specific male reproductive toxicity as determined by hormone level determinations and sperm analysis [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 49, June 2006. ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: Butyl p-hydroxybenzoate (n-BHB) and isobutyl p-hydroxybenzoate (i-BHB) were administered orally to ICR/Jcl mice at concentrations of 0.6 (maximum tolerated dose), 0.3 or 0.15% in the diet for up to 102 wk. Tumors were observed at various sites including the hematopoietic system, the lung and the soft tissue. However, at none of the sites did the tumor incidence or the time to death with tumors differ significantly from that in the untreated control group. [Inai K et al; Food Chem Toxicol 23 (6): 575-8 (1985) ]**PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Sprague-Dawley rats were administered butylparaben in 0.5% carboxymethylcellulose by oral gavage at dose levels of 0, 10, 100, or 1,000 mg/kg/day on gestation days (GD) 6-19 (sperm positive day = GD 0). Caesarean sections were performed on GD 20 and fetuses were evaluated for viability, growth, and external, visceral, and skeletal abnormalities. Each group consisted of 25 females, with at least 21 per group being pregnant. The highest dose level caused decreases in maternal weight gain during some of the measurement intervals and was statistically significant during the GD 18-20 interval. Maternal food consumption was significantly decreased in the highest dose group over the dosing period (GD 6-20). There were no differences from control in any of the developmental parameters measured, including embryo/fetal viability, fetal weight, malformations, or variations. Based on the results of this study, the maternal NOAEL for butylparaben was 100 mg/kg/day. Butylparaben does not have the potential to cause developmental toxicity in the Sprague-Dawley rat at oral dosages up to 1000 mg/kg/day. [Daston GP; Birth Defects Res B Dev Reprod Toxicol 71 (4): 296-302 (2004) ]**PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... To account for potential reproductive effects in male animals, butylparaben was administered to 3-week-old Wistar rats divided in groups of eight subjects, at doses of 0.00%, 0.01%, 0.10% and 1.00% with the animal's diet. After 8 weeks, the rats were killed by decapitation and the weights of the testes, epididymes, prostates, seminal vesicles and preputial glands were recorded. The absolute and relative weights of epididymes were decreased in a dose-dependent manner and the decrease was statistically significant at 0.10% and above. The cauda epididymal sperm reserve of all treated groups was significantly decreased. The sperm count of the group receiving the highest dose was 58.2% of control values. The daily sperm production (DSP) in the testis was also significantly lower in all treated groups when compared to controls. Serum testosterone concentration was lowered dose-dependently and was significant at 0.1% or more. The daily intake of butylparaben that caused these disruptions is similar to the lower level of acceptable daily intake (ADI) for parabens in the European Community (EC) and in Japan. [Oishi S; Toxicol Ind Health 17 (1): 31-9 (2001) ]**PEER REVIEWED** PubMed Abstract
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... Pregnant Sprague-Dawley rats were injected subcutaneously with 100 or 200 mg/kg of butylparaben (BP) from gestation day (GD) 6 to postnatal day (PND) 20. In the group exposed to 200 mg/kg of BP, the proportion of pups born alive and the proportion of pups surviving to weaning were decreased. The body weights of female offspring were significantly decreased at PND 49. The weights of testes, seminal vesicles and prostate glands were significantly decreased in rats exposed to 100 mg/kg of BP on PND 49. In contrast, the weights of female reproductive organs were not affected by BP. The sperm count and the sperm motile activity in the epididymis were significantly decreased at doses of 100 and 200 mg/kg of BP. In accordance with the sperm count in the epididymis, the number of round spermatids and elongated spermatids in the seminiferous tubule (stage VII) were significantly decreased by BP. Testicular expression of estrogen receptor (ER)-alpha and ER-beta mRNA was significantly increased in 200 mg/kg of BP treated group at PND 90. Taken together, these results indicated that maternal exposure of BP might have adverse effects on the F1 male offspring. [Kang KS et al; J Vet Med Sci. 2002, Mar; 64(3):227-35 ]**PEER REVIEWED** PubMed Abstract
  • GENOTOXICITY: In Chinese hamster cells, 60mg/mL butylparaben was not mutagenic. In addition, negative results were reported for butylparaben (up to 1000 mg/plate) in the Ames test using Salmonella typhimurium strains TA 92, TA 94, TA 98, TA 100, TA 1535, TA 1537, and TA 2637. /from table/ [FAO/WHO Joint Expert Committee on Food Additives; WHO Food Additives Series 48: Hydroxy- and alkoxy-substituted benzyl derivatives (2001). Available from Database Query page at: http://www.inchem.org/pages/jecfa.html as of March 2, 2007. ]**PEER REVIEWED**
  • ALTERNATIVE and IN VITRO TESTS: The estrogenic effect of butylparaben was investigated in a rainbow trout Oncorhynchus mykiss test system. Butylparaben was administered orally to sexually immature rainbow trout every second day for up to 10 days in doses between 4 and 74 mg/kg/2 days and in the water at 35 and 201 ug/L for 12 days. Plasma vitellogenin was measured before and during the exposures and the concentrations of butylparaben in liver and muscle were determined at the end of experiments. Increases in average plasma vitellogenin levels were seen at oral exposure to 9 mg butylparaben/kg/2 days. The ED50 values for increase in vitellogenin synthesis were 46, 29 and 10.5 mg butylparaben/kg/2 days, respectively, at day 3, 6 and 12. Exposure to 201 ug butylparaben/L increased vitellogenin synthesis, but exposure to 35 ug/L did not. Butylparaben showed little tendency to bioaccumulation in rainbow trout; less than 1 per thousand of the total amount of butylparaben administered orally at 51 mg/kg/2 days over the 12 days experimental period was retained in liver at the end of the experiment. After 12 days exposure to 35 and 201 ug butylparaben/L plasma concentrations were 9 and 183 ug/L, respectively, and for the fish exposed to 20 ug/L there was a positive correlation between concentrations of vitellogenin and butylparaben in the plasma. On the assumption that butylparaben removed from the water phase during water exposure were taken up into the fish, butylparaben uptake rates in the fish exposed to 35 and 201 ug butylparaben/L were 13 and 78 mg/kg/day, respectively. [Alsley B et al; Aquat Toxicol 72 (4): 295-304 (2005) ]**PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: ... In a receptor-binding assay, butylparaben was able to compete with 3H-estradiol for binding to the rat estrogen receptor with an affinity approximately 5 orders of magnitude lower than that of diethylstilbestrol, and between 1 and 2 orders of magnitude less than nonylphenol. In an in vitro yeast-based estrogen assay, the four most widely used parabens (namely methyl-, ethyl-, propyl-, and butylparaben) were all found to be weakly estrogenic with the most potent (butylparaben) being 10,000-fold less potent than 17 beta-estradiol. The estrogenic activity of parabens was inhibited by 4-hydroxy tamoxifen in vitro, illustrating the requirement of these chemicals to interact with the estrogen receptor in order to activate the yeast. When administered orally to immature rats, the parabens were inactive. However, subcutaneous administration of butylparaben produced a positive uterotrophic response in vivo, although it was approximately 100,000 times less potent than 17 beta-estradiol. [Routledge EJ et al; Toxicol Appl Pharmacol 153 (1): 12-19 (1998) ]**PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: Effects of alkyl p-hydroxybenzoates (APHBs), which are used as preservatives, on ion channels were investigated in rat pheochromocytoma PC12 cells. Methyl p-hydroxybenzoate (MPHB; 300 uM) and butyl p-hydroxybenzoate (BPHB; 300 uM) inhibited Ba2+ current passing through Ca2+ channels, and facilitated the inactivation of the Ba2+ current. K+ current obtained with a depolarizing voltage-step was also suppressed by 300 microM MPHB or 300 microM BPHB. The extent of the suppression of the K+ current was not affected by extracellular Cd2+, suggesting that the suppression of the K+ current is not a secondary effect arising from the Ca2+ channel inhibition. An inward current activated by acetylcholine (ACh; 100 microM) was abolished by 300 uM BPHB, and it was partially blocked by 300 uM MPHB. In contrast to the ACh-activated current, an inward current activated by ATP (30 uM) was markedly potentiated by 300 uM BPHB. The results suggest that APHBs exert significant effects on the voltage- and ligand-gated channels. ... [Inoue K et al; Neuropharmacology 33 (7): 891-6 (1994) ]**PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: The widely used phenolic preservatives ethylparaben, propylparaben, butylparaben and their common metabolite p-hydroxybenzoic acid were tested for their ability to evoke an estrogenic response in vivo. Yolk protein induction in sexually immature rainbow trout was used as an estrogen-specific endpoint after repeated injections of the compounds. All tested parabens were estrogenic in doses between 100 and 300 mg/kg, while the metabolite showed no activity. ... butylparaben had an estrogenic potency comparable to that previously found for bisphenol A. [Pedersen KL et al; Pharmacol Toxicol 86 (3): 110-3 (2000) ]**PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: ... Evidence of the estrogenicity /of parabens (Pbens)/ using a morphometric analysis of uteri from mice treated with the preservatives methylparaben (MePben), ethylparaben (EtPben), propylparaben (PrPben), and butylparaben (BuPben) compared with estradiol (E2) /is presented/. Different groups of adult ovariectomized (Ovx) CD1 mice were subcutaneously (sc) treated daily for three days with two different equimolar doses (362 and 1086 uL/kg) of the Pbens: MePben (55 and 165 mg/kg), EtPben (60 and 180 mg/kg), PrPben (65 and 195 mg/kg), BuPben (70 and 210 mg/kg), E2 (10 ug/kg; 0.036 uL/kg), and vehicle (propyleneglycol; V, 10 mL/kg). On the fourth day, uteri were dissected, blotted, weighed, and placed in a fixative solution for 24 hr. The paraffin embeded uteri were cut to obtain 7 microm thick transversal sections. Luminal epithelium heights (LEH), glandular epithelium heights (GEH), and myometrium widths (MW) were measured. The highest Pbens dose was able to produce uterotrophic effects (38 to 76%) compared to E2 efects (100%). The relative uterotrophic potency to E2 (100) was from 0.02 to 0.009. Significant increases (P<0.05) in LEH, GEH, and MW as compared with V were obtained: LEH from 87 to 113% (E2 153%), GEH from 10 to 40% (E2 60%), and MW from 35 to 43% (E2 88%). These results confirm that Pbens at the doses assayed here induce estrogenic histological changes in the uteri of Ovx mice. [Lemini C et al; Toxicol Ind Health. 20 (6-10): 123-32 (2004) ]**PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: ... The effects of methylparaben, ethylparaben, propylparaben, and butylparaben on human and rabbit erythrocytes in vitro /were examined/. Butylparaben, at 0.02% induced hemolysis in 12% of the rabbit and 6% of the human erythrocytes. [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 32, June 2006. ]**PEER REVIEWED**
  • ALTERNATIVE and IN VITRO TESTS: Evidence /is presented/ for the in vivo and in vitro bioactivities and receptor binding affinities of methylparaben (MePben), ethylparaben (EtPben), propylparaben (PrPben), and butylparaben (BuPben) compared with those of estradiol (E2). Estrogenicity was studied using the uterotrophic assay in immature (Im) and adult ovariectomized (Ovx) CD1 mice, and in immature female Wistar rats (IW). Animals were subcutaneously (sc) treated for three consecutive days with different molar equivalent doses ranging from 3.62 to 1086 uL/kg body weight of parabens (Pbens), E2 (0.036 uL/kg), or vehicle. Pbens increased uterine weight in Im and Ovx animals and their relative uterotrophic effect to E2 (100) (RUEE2) were from 34 to 91. The relative uterotrophic potencies related to E2 (100) (RUPE2) of these compounds were from 0.003 to 0.007. The E2 ED50 for CD1 animals able to increase the uterine weight was 7 ug/kg (0.9-55 confidence limits); and that of Pbens ranged from 18 to 74 mg/kg. In IW rats, the ED50 were from 33 to 338 mg/kg. All Pbens, except MePb, competed with [3H]E2 for the estrogen receptor binding sites. The uterotrophic effects of Pbens in Im mice have a positive correlation with the side-chain length of the ester group of these compounds. ... The NOELs values for Pbens uterotrophic activity in Im were from 0.6 to 6.5 mg/kg per day; and Ovx from 6 to 55 mg/kg. The NOELs IW ranged from 16.5 to 70 mg/kg indicating that Im were more susceptible than Ovx and IW to these effects. The data shown here confirm the estrogenicity of Pbens. [Lemini C et al; Toxicol Ind Health 19 (2-6): 69-79 (2003) ]**PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: ... Immature B6D2F1 mice were treated with oral or subcutaneous doses of the test compounds for three consecutive days. p-Hydroxybenzoic acid and butyl p-hydroxybenzoate were also tested by the subcutaneous route in a rat uterotrophic assay. A significant increase in the uterus weight at day 4 was considered an estrogenic effect. In the mouse assay, none of the compounds tested produced any estrogenic response at dose levels up to 100 mg/kg body weight per day, for ethyl p-hydroxybenzoate even at a dose level of 1000 mg/kg body weight per day. In immature Wistar rats, subcutaneous administration of butyl p-hydroxybenzoate produced a weak estrogenic response at 600 mg/kg body weight per day. [Hossaini A et al; Food Chem Toxicol 38 (4): 319-23 (2000) ]**PEER REVIEWED** PubMed Abstract
  • ALTERNATIVE and IN VITRO TESTS: The GE-Amersham CodeLink 20 K human expression microarray system was used to profile the expression of 19881 genes in MCF7 human breast cancer cells following a 7-day exposure to 5 × 10-4 m methylparaben, 10-5 m n-butylparaben and 10-8 m 17beta-estradiol. At these concentrations, the parabens gave growth responses in MCF7 cells of similar magnitude to 17beta-estradiol. The study identified genes which are upregulated or downregulated to a similar extent by methylparaben, n-butylparaben and 17beta-estradiol. However, the majority of genes were not regulated in the same way by all three treatments. Some genes responded differently to parabens from 17beta-estradiol, and furthermore, differences in expression of some genes could be detected even between the two individual parabens. Therefore, although parabens possess estrogenic properties, their mimicry in terms of global gene expression patterns is not perfect and differences in gene expression profiles could result in consequences to the cells that are not identical to those following exposure to 17beta-estradiol. [Pugazhendhi D et al; J Appl Toxicol 27(1): 67-77 (2007) ]**PEER REVIEWED**
  • IMMUNOTOXICITY: Twenty albino guinea pigs /were given/ intradermal injections of Freund's complete adjuvant on Days 0 and 9; at which time 5 percent Butylparaben was applied under 48-hr occlusive patches to the clipped dorsal skin every other day for 3 weeks (10 applications). Twelve days after the last induction patch was removed, the test material was applied as a challenge patch for 48 hrs to a previously untested site. One, 7, 24, and 48 hrs after removal of the patch, the sites were scored and the skin examined microscopically for evidence of sensitization. Six of the 20 animals reacted to the challenge patch containing 5% butylparaben in olive oil. The mean erythema score was 1.70 (max. score = 4). Tissue from two of the six animals showed "pathologic aspects" under microscopic examination, and the lesions were considered clearly allergic. In the worst case, spongiosis, squamous crust, and lymphocytic infiltration were observed. [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 41, June 2006. ]**PEER REVIEWED**
  • IMMUNOTOXICITY: Methylparaben, ethylparaben, propylparaben, and butylparaben (at 0.1%) were each injected intracutaneously into the shaved dorsal skin of 10 guinea pigs per ingredient according to the Draize method. Injections were made three times weekly for 3 weeks (10 injections). Two weeks after the final induction injection, a challenge injection was administered into an adjacent site and observed 24 hours later. There were no reactions in the animals to any of the Parabens. It was observed that these ingredients are nonsensitizing. [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 42, June 2006. ]**PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Mouse (dd-strain) oral 13200 mg/kg [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 36, June 2006. ]**PEER REVIEWED**
  • LD50 Mouse oral 5.0 g/kg [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 6:672]**PEER REVIEWED**
  • LD50 Mouse ip 230 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 637]**PEER REVIEWED**

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Absorption, Distribution and Excretion

  • By the oral route, parabens are rapidly absorbed, metabolized, and excreted. The metabolic reactions and conversions in mammals vary with the chain length of the ester, the animal species, route of administration, and quantity tested. The metabolism of parabens in humans appears to be most closely related to that of dogs. The rate of metabolite excretion appears to decrease with increasing molecular weight of the ester. /4-Hydroxybenzoates (Parabens)/ [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 6:639]**PEER REVIEWED**
  • After butyl paraben is intravenously infused into the dog, nonhydrolyzed butyl paraben is found in brain, spleen, and pancreas. In liver, kidney, and muscle, it is immediately hydrolyzed to p-hydroxybenzoic acid. Six hours after oral administration of 1.0 g/kg to dogs, the peak plasma concentration of free and total butyl paraben (15 and 141 ug/cu cm) is reached. After 48 hr, butyl paraben is eliminated. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 6:672]**PEER REVIEWED**
  • Skin penetration of methyl, ethyl, propyl and butyl parabens through excised guinea pig dorsal skin was examined, and effects of the penetration enhancers, l-menthol plus ethanol itself and N-dodecyl-2-pyrrolidone, were observed. Permeability of coefficients of the parabens correlated with n-octanol/water partition coefficients. Addition of 1% l-menthol in 15% ethanol about sixteen times increased the permeability coefficient of methyl paraben, whereas this enhancer decreased that of butyl paraben to about one fifth of the control value. A similar, though weaker, tendency was observed for the effects of 15% ethanol itself. 0.025% suspension of N-dodecyl-2-pyrrolidone increased the permeability coefficient of methyl paraben about seven times, whereas it did not change that of butyl paraben significantly. Therefore, dependency of the permeability coefficients of the parabens on n-octanol/water partition coefficients almost disappeared in the presence of this compound. A spin label study with stratum corneum lipid liposomes revealed that increase of fluidity of the lipid bilayer by these penetration enhancers corresponded with their enhancement effects on skin penetration of methyl paraben. Perturbation of stratum corneum lipid lamella thus seems to be related with their enhancement of the absorption of hydrophilic paraben. [Kitagawa S et al; Chem Pharm Bull (Tokyo) 45 (8): 13454-7 (1997) ]**PEER REVIEWED** PubMed Abstract
  • Intravenous (IV) injections at 50 mg/kg Methylparaben, Ethylparaben, Propylparaben, or Butylparaben were administered to groups of three or more fasted dogs. Similarly, these compounds were administered orally at a dose of 1.0 g/kg. Blood and urine were analyzed at predetermined intervals. Immediately following IV injection, very little ester remained in the blood. Metabolites were detectable in the blood up to 6 hr postinjection and 24 hr postingestion. Recovery of all esters but Butylparaben ranged from 58 to 94% of the administered dose. Absorption was essentially complete. Recovery of Butylparaben after oral administration was 40% and 48 after IV administration. The authors considered this finding a result of less effective hydrolysis of Butylparaben. Dogs given 50 mg/kg were then killed and the distribution of esters and metabolites to organs was determined. Pure ester was recovered only in the brain, spleen, and pancreas. High concentrations of metabolites were detected in the liver and kidneys. With in vitro assays, it was found that esterases in the liver and kidneys of the dog were extremely efficient in hydrolyzing Parabens --- complete hydrolysis after 3 minutes for all Parabens except Butylparaben, which took 30 to 60 minutes. No accumulation of Parabens was observed in the tissues of dogs given orally 1 g/kg/day Methylparaben or Propylparaben for 1 year. The rate of urinary excretion of esters and metabolites in these dogs increased to such an extent that after 24 hr, 96 % of the dose was excreted in the urine. This is contrasted with dogs given a single dose of paraben in which the 96 % excretion level was not attained until 48 hr. When 10 % Methylparaben or Propylparaben in hydrophilic ointment was applied to the skin of a white rabbit for 48 h, esters and metabolites were not detected in the kidneys. [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 28, June 2006. ]**PEER REVIEWED**
  • ... Parabens in an ointment vehicle (15% in Vaseline) /were applied/ to the skin of each of three healthy humans. Presence of residual parabens on the skin was determined at 1 and 8 hr. One hour after application, parabens were identified; at 8 hr, they were not detected. /Parabens/ [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 23 June 2006. ]**PEER REVIEWED**
  • The effect of cutaneous metabolism on the skin penetration of drugs was analyzed based on a two-layer skin diffusion/metabolism model. In vitro permeation studies of propylparaben and butylparaben with or without an esterase inhibitor, diisopropyl fluorophosphate (DFP), were performed. Pretreatment of the skin with DFP prolonged the lag time for the penetration of intact parabens. Additionally, DFP significantly decreased the total flux of butylparaben, but not that of propylparaben. Model analysis of the penetration profiles revealed that DFP inhibits the cutaneous metabolism without affecting any other processes. To comprehensively understand the relationships among lipophilicity, metabolic rate, and skin permeation of drugs, simulation studies were performed with newly derived equations concerning the permeability coefficient and the lag time for the penetration of both intact and metabolite forms. ... The permeation of lipophilic compounds such as butylparaben is more highly affected by cutaneous metabolism in the viable layer because these compounds easily penetrate the stratum corneum layer. Consequently, the balance between the permeability of drug across the stratum corneum and the dermis has been implicated to impose a significant influence on the percutaneous absorption of drugs subjected to cutaneous metabolism. [Seko N et al; Biol Pharm Bull 22 (3): 281-7 (1999) ]**PEER REVIEWED** PubMed Abstract

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Metabolism/Metabolites

  • In mice, rats, rabbits, or dogs, butyl paraben is excreted in the urine as unchanged benzoate, p-hydroxybenzoic acid, p-hydroxyhippuric acid (p-hydroxybenzoylglycine), ester glucuronides, ether glucuronides, or ether sulfates. [Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 6:672]**PEER REVIEWED**
  • The penetration and metabolism of Butylparaben using viable, full-thickness human skin /is described/. ... A total of 21% of the radiolabel penetrated to the receptor fluid after 24 hr. ... the principle metabolite, hydroxybenzoic acid, was detected in the receptor fluid, with barely detectable levels of butylparaben and no ethylparaben, in this study of full-thickness skin. ... This work was repeated to again examine the penetration and metabolism of butylparaben (0.4%) in an oil/water emulsion applied to the same full thickness viable human skin ... A finite dose (10 :L/cm ) of the 2 emulsion was applied to the skin surface and remained in contact over a 24 hr period without occlusion. (14)C-butylparaben (labeled in the carbon ring) was measured in the receptor fluid. A mean value of 14.9% (+ or - 3.73%) of the radioactive label penetrated the full thickness human skin after 24 hr. The principle metabolite, hydroxybenzoic acid, was found in the receptor fluid (mean of 15.2% + or - 5.23%) of all 10 replications (skin donated from two individuals), but barely detectable levels of the parent Butylparaben (mean of 0.225% 0.063%) were found only in 5 of 10 replications. The authors interpreted these results to confirm the near complete first-pass metabolism of Butylparaben to p-hydroxybenzoic acid in human skin. [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 30, June 2006. ]**PEER REVIEWED**
  • ... A study /was conducted/ of the in vitro dermal penetration and metabolism of Methylparaben and Butylparaben in rat and human skin. For each paraben, an oil in water emulsion with both radiolabeled ( C in the carbon 14 ring) and non-radiolabeled paraben was prepared to a target concentration (0.8% for Methylparaben and 0.4% for Butylparaben). Skin samples (10 replicates for rat skin and 13 replicates for human skin) were mounted in flow-through diffusion cells. Test emulsions were applied evenly at 10 :L/cm , one time, with no occlusion. Samples of the receptor 2 fluid from a single skin were pooled, along with reference standards, were mixed with acetonitrile, filtered, and analyzed for Methylparaben, Butylparaben, and hydroxybenzoic acid using liquid chromatography coupled with mass spectroscopy. ... For Butylparaben, 52.3% was metabolized to hydroxybenzoic acid, with only 5.5% as unmetabolized Butylparaben. Metabolism was different in human skin ... For Butylparaben, 32.8% appeared as hydroxybenzoic acid and 49.7% as unmetabolized Butylparaben. [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 30, June 2006. ]**PEER REVIEWED**
  • ... An experiment /was conducted/ using full thickness human skin and Methyparaben and Butylparaben. /The authors/ noted that the parabens were converted to the alkyl alcohol and p-hydroxybenzoic acid, in a dose-dependent manner following Michaelis-Menton kinetics. They interpreted these findings as suggestive of enzymatic action in the skin. [Cosmetic Ingredient Review; Final Report of the Cosmetic Ingredient Review Expert Panel; Amended Safety Assesment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben; p. 29, June 2006. ]**PEER REVIEWED**

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TSCA Test Submissions

  • None found

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Footnotes

1 Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.

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Web page last updated on August 06, 2009