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Universidad de Concepcin
Facultad de Ciencias Ambientales
Centro de ciencias ambientales EULA-Chile



research seminar




Benzoic acid, 4-hydroxy-, butyl ester





















Felipe Gonzlez Rodrguez
Sustancias txicas persistentes
03-06-14
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Index
C
Control ................................................................................................................................................................ 7
I
Introduction ........................................................................................................................................................ 3
P
Persistent overall parabens ................................................................................................................................ 6
Physical-Chemical Properties ............................................................................................................................. 5
R
References .......................................................................................................................................................... 8
S
sources and usage patterns ................................................................................................................................ 4
T
Toxic effects on human health and organisms in the environment ................................................................... 6










Introduction

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Parabens are esters of 4-hydroxybenzoic acid that have recently been reported to have adverse
effect on the male reproductive system in rodents. The toxicological database for the most
commonly used parabens is quite extensive and generally indicates a low degree of systemic
toxicity. In addition, several parabens have been recently reported to have estrogenic activity in
experimental cell systems and animal models. Butylparaben is included among the parabens
widely used as antioxidants and preservatives in foods, pharmaceuticals, and cosmetics. It is
regulated by the U.S. FDA as a synthetic flavoring and adjuvant. Human exposure to butylparaben
may occur via inhalation, eye or skin contact, or ingestion. Inhalation exposure causes irritation to
the respiratory tract. Contact with the eyes or skin can cause irritation, redness, pain, and/or
itchiness, but patch test results show that the sensitization potential of parabens is low. Ingested
butylparaben is rapidly absorbed from the gastrointestinal (GI) tract, metabolized, and excreted in
the urine. Large doses, however, may cause irritation to the GI tract. In mice, rats, rabbits, and
dogs, butylparaben was reported to be practically nontoxic. Results from one chronic feeding
study in mice showed that butylparaben caused a high incidence of amyloidosis, affecting the
spleen, liver, kidney, and/or adrenal gland. It was cytotoxic in isolated rat hepatocytes and
mitochondria and in other animal cells in vitro. Reproductive studies in mice and rats suggested
that maternal exposure to butylparaben in the diet results in adverse effects on the reproductive
system of F1 male offspring. Butylparaben was not mutagenic in several short-term bioassays (e.g.,
Ames test, Chinese hamster ovary cells, and comet assay) and was reported to be non-
carcinogenic in rats and mice.









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sources and usage patterns

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.
Physical-Chemical Properties

Chemically, they are esters of para-hydroxybenzoic acid,
commonly known as parabens. Among them include the methyl
parabens (e2189, propylparabeno (E216) or also butylparabeno.
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Therefore the difference between them depends on the alkyl group.
CAS Number: 000094-26-8
SMILES : O=C(OCCCC)c(ccc(O)c1)c1
CHEM : Benzoic acid, 4-hydroxy-, butyl ester
MOL FOR: C11 H14 O3
MOL WT : 194.23

Physical Property Value Units
Temp (deg
C)
Source
Melting Point 68.5 deg C EXP
pKa Dissociation Constant 8.47 (none) EXP
log P (octanol-water) 3.57 (none) EXP
Water Solubility 207 mg/L 20 EXP
Vapor Pressure
1.86E-
04
mm Hg 25 EST
Henry's Law Constant
8.45E-
09
atm-m3/mole 25 EST
Atmospheric OH Rate
Constant
1.55E-
11
cm3/molecule-sec 25 EST
Physical State
crystalline powder; small, colorless crystals or white powder;
finely divided solid

Budavari
(1996);
HSDB (2003)
Soluble in:
acetone, alcohol, ether, chloroform, glycerin (very slightly), and
propylene glycol

Budavari
(1996)

Parabens are stable in acidic solutions, in hot and cold water, and under conditions of sterilization.
They undergo hydrolysis in media above pH 7; in strong basic solutions, they hydrolyze to their
corresponding carboxylic acids. As the alkyl chain increases, so does resistance to hydrolysis, as
well as antimicrobial activity; water solubility and oil solubility, however, decrease (CIR, 1984).
Antimicrobical activity is retained across the pH range of 4 to 8 (Clariant, 2002a). Highly soluble
potassium salts of parabens were found to be more microbiocidal against more test organisms
than the parabens (Mizuba and Sheikh, 1987).
Although parabens are stable in air, butylparaben may form combustible dust concentrations.
When heated to decomposition, carbon monoxide and carbon dioxide may form (Mallinckrodt
Baker, Inc., 2003). Parabens interact with cosmetic ingredients, such as gelatin, polysorbates, and
cellulose esters; for example, 0.7% Tween 80 was found to deactivate butylparaben (CIR, 1984).

Persistent overall parabens

In an assessment of the risk for the aquatic environment, several scenarios of parabens from
health care products or cosmetics transported with sewage water from the shower/bath to the
sewage treatment plant indicated that paraben concentrations in the sewage were at least a
factor of 100 to 1000 below the effect concentrations (acute or chronic effects); however, the risk
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was considered not conclusive, since data on chronic effect levels are few (Andersen et al., 2001).
In a study of the components in grey wastewater, butylparaben was included in a list of chemicals
in household products sold in Denmark; however, only ethylparaben and methylparaben were
detected at concentrations of 0.6 and 2.6 g/L, respectively (Eriksson et al., 2003). In surveys of
chemicals in the environment and wildlife in Japan, butylparaben was not found in surface water
or bottom sediment (Ministry of the Environment, 2003). However, in a survey of endocrine-
disrupting chemicals in indoor air and dust, butylparaben was detected in 8% (maximum
concentration of 3.2 ng/m3 [4.1 x 10-7 ppm]) and 22% (maximum concentration of 3.92 g/g
[0.0202 mmol/g]) of the air and dust samples of 120 and 118 homes, respectively, in Cape Cod,
MA (Rudel et al., 2003). The possibility exists for environmental release from the use of criosine
(0.56% butylparaben) as a biocide in oil
recovery packer fluid (Spectrum Laboratories, undated).

Persistence and bioaccumulation
Concern Reference
Not suspected to be persistent
Environment Canada Domestic Substance
List
Not suspected to be bioaccumulative
Environment Canada Domestic Substance
List


Toxic effects on human health and organisms in the environment


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
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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).

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 g/L), followed by n-propyl (9.1
g/L), ethyl (1.0 g/L), and butyl paraben (0.5 g/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 g/L and n-propyl
paraben from <0.2 to 7210 g/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 20052006 subsample (Calafat et al., 2010; Frederiksen et al., 2011).



Control

Butylparaben is regulated by the U.S. Environmental Protection Agency (EPA) under the Toxic
Substances Control Act (TSCA) and the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA).
In 1998 its pesticide registration status was listed as "cancelled" (U.S. EPA, 2003). Butylparaben is
also regulated by the FDA. It is permitted as a synthetic flavoring substance and adjuvant and is to
be used in the minimum quantity required to produce its intended effect [21 CFR 172.515] (FDA,
2003).
In Denmark, the maximum allowable concentration for parabens in food is 300 mg/kg as a
preservative. In cosmetics, up to 0.4% of a single paraben and no more than 0.8% of a paraben
mixture are permitted (Andersen et al., 2001). There is some concern in the European Union (EU)
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that parabens might occur in meats. Butylparaben and its sodium salt are not subject to residue
limits in foodstuffs of animal origin (CEC, 1999). The EU conditionally permitted the use of
parabens in foods, but they had to be combined with sorbates or sorbates and benzoates. A
temporary upper-limit acceptable daily intake (ADI) for methyl-, ethyl-, propyl-, and/or
butylparabens was set at 10 mg/kg bw. The European Commission Scientific Committee on Food
requested further studies and in 2000 decided to review data for parabens and benzoates. By
September 2002, no data for parabens had been submitted. The Committee questioned whether
parabens were still used in foods sold in the EU and recommended that the temporary ADI be
withdrawn (EC, 2003).
More recently, the European Food Safety Authority (EFSA) concluded that the ADI of up to 10
mg/kg should remain in place for the sum of methyl and ethyl paraben and their sodium salts on
the basis of a NOAEL of 1000 mg/kg; an ADI for the propyl ester could not be established because
of lack of a clear NOAEL. There is no evidence of demonstrable risk for the development of breast
cancer caused by the use of paraben-containing underarm cosmetics (SCCP, 2005a,b).



References:
- 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.
- Aeling JL, Nuss DD. Systemic eczematous "contact-type" dermatitis medicamentosa
caused by parabens. Arch Dermatol 1974;110:640.
- Oishi S. Effects of butylparaben on the male reproductive system in rats. Toxicol Indust
Health 2001;17:31-39.
- EC (Environment Canada). 2008. Domestic Substances List Categorization. Canadian
Environmental Protection Act (CEPA) Environmental Registry.