Received: 30 September 2019 Accepted: 1 October 2019

DOI: 10.1002/jat.3917

REVIEW ARTICLE

Review of the safety of application of cosmetic products

containing parabens

Natalia Matwiejczuk1 | Anna Galicka1 | Małgorzata M. Brzóska2

1
Department of Medical Chemistry, Medical
University of Białystok, Bialystok, Poland
2
Department of Toxicology, Medical
University of Białystok, Bialystok, Poland
Correspondence
Anna Galicka, Department of Medical
Chemistry, Medical University of Białystok,
Adama Mickiewicza 2A street, 15-222
Bialystok, Poland.
Email: angajko@umb.edu.pl
Abstract
Cosmetics are a source of lifetime exposure to various substances including para-
bens, being the most popular synthetic preservatives. Because the use of cosmetics
shows an increasing trend and some adverse health outcomes of parabens present in
these products have been reported, the present review focused on the safety of der-
mal application of these compounds. Special attention has been paid to the absorp-
tion of parabens and their retention in the human body in the intact form, as well as
to their toxicological characteristics. Particular emphasis has been placed on the
estrogenic potential of parabens. Based on the available published data of the con-
centrations of parabens in various kinds of cosmetics, the average ranges of systemic
exposure dose (SED) for methylparaben, ethylparaben, propylparaben, and
butylparaben have been calculated. Safety evaluations [margin of safety (MoS)] for
these compounds, based on their aggregate exposure, have also been performed.
Moreover, evidence for the negative impact of methylparaben on skin cells has been
provided, and the main factors that may intensify dermal absorption of parabens and
their impact on the skin have been described. Summarizing, the use of single cos-
metics containing parabens should not pose a hazard for human health; however,
using excessive quantities of cosmetic preparations containing these compounds
may lead to the development of unfavorable health outcomes. Due to the real risk of
estrogenic effects, as a result of exposure to parabens in cosmetics, simultaneous use
of many cosmetic products containing these preservatives should be avoided.

KEYWORDS

cosmetics, dermal absorption, estrogen potential, health effects, parabens, safety, skin,
systemic exposure

1 | I N T RO DU CT I O N 30 November 2009 on cosmetic products, these products are defined

as ‘any substance or mixture intended to be placed in contact with the
Cosmetic products are present in our daily lives and are necessary in external parts of the human body (epidermis, hair system, nails, lips,
the care of the skin, hair and nails. According to the Regulation and external genital organs) or with the teeth and the mucous mem-
(EC) No 1223/2009 of the European Parliament and of the Council of branes of the oral cavity with a view exclusively or mainly to cleaning

Abbreviations: BMI, body mass index; BP, n-butylparaben; BzP, benzylparaben; bw, body weight; E2, 17β-estradiol; ED50, median effective dose; EP, ethylparaben; ER, estrogen receptor; EU,
European Union; FTS, full-thickness skin membrane; GDM, gestational diabetes mellitus; HA, hyaluronic acid; hCE, human carboxylesterase; HEK, human embryonic kidney; HP, n-heptylparaben;
IBP, isobutylparaben; IPP, isopropylparaben; MMP, matrix metalloproteinase; MoS, margin of safety; MP, methylparaben; NOAEL, no-observed-adverse-effect level; PeP, n-pentylparaben;
PHBA, p-hydroxybenzoic acid; PhP, phenylparaben; PP, n-propylparaben; RF, receptor fluid; ROS, reactive oxygen species; SC, stratum corneum; SCCS, Scientific Committee on Consumer
Safety; SED, Systemic exposure dose; UV, ultraviolet; UVB, ultraviolet B.

176 © 2020 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/jat J Appl Toxicol. 2020;40:176–210.
SAFETY OF PARABENS IN COSMETICS
them, perfuming them, changing their appearance, protecting them,
keeping them in a good condition or correcting body odours’. In pur-
suance of the regulation of the European Union (EU), cosmetic prod-
ucts should be safe under normal or reasonably foreseeable
conditions of their use and should not endanger safety and health of
users. Cosmetic preparations, unlike medicines for external use,
should not affect the structure and function of tissues subjected to
application. Detailed cosmetics recipes, production process, and used
technologies influence the quality of the final products. Manufac-
turers should be aware that the preparations they release on the mar-
ket have to be completely safe. Safety of the cosmetic means that the
product not only does not contain prohibited chemical substances and
permitted substances in too high concentrations, but also requires
adequate microbiological purity and stability. A guarantee of microbio-
logical purity and stability is very important, therefore producers use
preservatives, usually choosing synthetic compounds, like parabens.
Parabens are the most popular synthetic preservatives used not
only in cosmetics, but also in foods and medicines. It was estimated
that most parabens present in the body come from dermal application
of cosmetics products (50 mg/day), while the amounts of these com-
pounds taken together with food (2.5 mg/day) and medicines
(25 mg/day) are significantly lower (Cashman & Warshaw, 2005; Soni,
Taylor, Greenberg, & Burdock, 2002). Because of the wide use of par-
abens, individuals will probably be exposed to these compounds dur-
ing a lifetime. From the chemical point of view, parabens are esters of
4-hydroxybenzoic acid, also known as p-hydroxybenzoic acid (PHBA),
among which methylparaben (MP), ethylparaben (EP), n-
propylparaben (PP), isopropylparaben (IPP), n-butylparaben (BP),
isobutylparaben (IBP), n-pentylparaben (PeP), n-heptylparaben (HP),
benzylparaben (BzP), and phenylparaben (PhP) can be distinguished.
In the available literature, these compounds may appear under differ-
ent names, e.g., nipagins, aseptins (Rastogi, Schouten, de Kruijf, &
Weijland, 1995; CIR, 2008). MP alone or combined with PP is the
TABLE 1 Physicochemical properties of the most common parabens used in cosmetics
Parameter MP
Chemical formula
Molecular weight, g/mol 152.16
CAS no. 99–76-3
PKa 8.17
Solubility in water at 25
C, g/100 mL 0.25


Solubility in water at 80 C, g/100 mL 2.00
Solubility in ethanol 32
LogPow 1.96
Melting point,
C 131
Boiling point,
C 270–280
177
most used paraben in cosmetics (Cowan-Ellsberry & Robison, 2009;
Dodson et al., 2012; Fisher et al., 2017; Golden, Gandy, & Vollmer,
2005; Guo, Wang, & Kannan, 2014; Pažoureková, Hojerová,
Klimová, & Lucová, 2013; Rastogi et al., 1995; Shen et al., 2007).
Parabens form small colorless hygroscopic crystals or powders
without a perceptible odor or taste (Neidig & Burrell, 1944). They are
characterized by numerous beneficial properties such as: high chemi-
cal stability within a wide range of pH and temperature, resistance to
hydrolysis, low production cost, and low frequency of sensitization or
irritation. Physicochemical properties of the most common parabens
used in cosmetics are presented in Table 1 (Golden et al., 2005; Soni
et al., 2005; Jewell et al., 2007). In addition, these compounds are bio-
degradable, do not change the consistency or color of the products,
and have been recognized by the USA Food and Drug Administration
(FDA) as safe. In a weakly acidic environment parabens are very effec-
tive in preventing the growth of yeast, mold, and to a lesser extent
bacteria. They show the most effective action against Gram-positive
(Gram+) bacteria, while their activity against mold and Gram-negative
(Gram−) bacteria is weaker (Doron, Friedman, Falach, Sadovnic, &
Zvia, 2001; Orth, Kabara, Denyer, & Tan, 2006). The antimicrobial
activity of parabens is related to the length of the alkyl chain of the
individual esters. The activity of parabens increases along with
increasing side-chain length. However, long-chain compounds are not
widely used due to their reduced solubility (Doron et al., 2001; CIR,
2008).
Parabens at the concentrations permitted to be used were con-
sidered safe, but many scientific reports contradict this and suggest
that everyday use of cosmetics containing these compounds can exert
harmful effects on the human body. Most of these data have been
related to the estrogenic properties of parabens with a longer aliphatic
chain, although short-chain esters can also exert estrogenic effects
(Sun et al., 2016), which may be connected with the development of
breast cancer (Darbre, 2006; Darbre et al., 2004; Darbre & Harvey,
EP PP BP
166.18 180.21 194.23
120–47-8 94–13-3 94–26-8
8.22 8.35 8.37
0.17 0.05 0.02
0.86 0.30 0.15
41 50 68
2.51 3.04 3.57
116–118 96–98 68–69
297–298 – –
178
2014; Harvey, 2003; Harvey & Everett, 2006, 2012), obesity
(Artacho-Cordon et al., 2017; Hu et al., 2013, 2016, 2017; Kolatorova
et al., 2018; Quirós-Alcalá, Buckley, & Boyle, 2018, 2019), an increase
in gestational age (Aker et al., 2019) and the risk of gestational diabe-
tes mellitus (GDM) (Li et al., 2019), or development of malignant mela-
noma (Darbre & Harvey, 2008). The anti-androgenic properties of
these compounds can contribute to a reduction of reproductive
potential (Garcia et al., 2017; Kang et al., 2002; Meeker, Yang, Ye, Cal-
afat, & Hauser, 2011; Oishi, 2001, 2002; Smarr et al., 2018; Tavares,
Martins, Oliveira, Ramalho-Santos, & Peixoto, 2009). In addition, in
some cases exposure to parabens via cosmetics may cause allergic
reactions (Cashman & Warshaw, 2005; Lee-Sarwar et al., 2018; Sav-
age, Matsui, Wood, & Keet, 2012; Spanier, Fausnight, Camacho, &
Braun, 2014).
Today, a huge amount of new cosmetic products flood the cos-
metics market and various mass media constantly encourage the use
of many promising cosmetic products to feel healthy and more
attractive, thus their daily use is constantly growing. The concentra-
tions of cosmetic ingredients are under the control of the producer,
but the consumer decides about the amount and frequency of use
of particular cosmetics. An average adult uses daily about nine cos-
metic products but >25% of women use ≥15 (Sedlewicz, 2005).
Because the use of cosmetics, being the main source of exposure to
parabens, shows an increasing trend and there are controversies
regarding the safety of these compounds for consumers, in the pre-
sent review our attention has been focused on the safety of applica-
tion of cosmetic products containing these compounds. As
knowledge of the risk of unfavorable actions of parabens present in
cosmetics is essential when developing formulations of these prod-
ucts and evaluating their safety, as well as when looking for possible
causes of unfavorable outcomes noted in consumers using cosmetics
containing parabens, toxicological characteristic of these compounds
are also presented and discussed in this review. Special attention has
been paid to the results of in vitro and in vivo studies on the absorp-
tion and biotransformation of parabens, as well as on the presence
of these compounds in the human body in their intact
(unhydrolyzed) form, which unambiguously proves the relationship
between the use of cosmetics and the accumulation of parabens.
Based on the available published data on the concentrations of para-
bens in various kinds of cosmetics and taking into account the rec-
ommendations of the Scientific Committee on Consumer Safety
(SCCS) for calculation of aggregate exposure for preservatives
through cosmetic use (SCCS, 2018), the average ranges of the sys-
temic exposure dose (SED) for MP, EP, PP, and BP have been calcu-
lated. Safety evaluations [margin of safety (MoS)] for these parabens,
based on their aggregate exposure, have also been performed. More-
over, the negative impact of MP on skin cells has been described
(Cha et al., 2015; Ishiwatari et al., 2007; Majewska, Zaręba, Sur-
 ski, & Galicka, 2017; Smith & Alexander, 2005). In addition,
az_ yn
attention has been focused on factors that may intensify dermal
absorption of parabens and their impact on the skin, including ultra-
violet B (UVB) radiation (Dubey et al., 2017; Handa et al., 2006). All
the above mentioned issues are discussed in the present review
MATWIEJCZUK ET AL.
article; however, the main concern has been directed towards dermal
exposure to parabens present in cosmetics and their safety for users
of these products. Particular emphasis has been on MP, being the
most often used paraben in cosmetics. In addition, in the recent
years the search for alternative preservatives to replace parabens or
to decrease their concentration and minimize the health risks for
users of cosmetics has become a scientific challenge.
Preparing the present review, we searched for data in biblio-
graphic databases such as PubMed, Scopus, Elsevier, ResearchGate,
etc., as well as toxicological and cosmetological databases (e.g., http://
ec.europa.eu, PubChem) using keywords such as: ‘parabens’, ‘esters of
4-hydroxybenzoic acid’, ‘methylparaben’, ‘ethylparaben’,
‘propylparaben’, ‘butylparaben’, ‘use of cosmetics’, ‘dermal absorption’,
‘accumulation in the skin’, ‘exposure’, ‘UVB radiation’, ‘safety’, ‘allergy’,
‘breast cancer’, ‘obesity’, ‘gestational diabetes mellitus’, ‘estrogenic
potential’, ‘anti-androgenic properties’, ‘skin cells’, ‘damage to
keratinocytes and fibroblasts’, stratum corneum’, ‘epidermis’, ‘dermis’,
‘collagen’, ‘EU Regulations’, ‘paraben alternatives’, etc.
2 | SKIN – THE FU N CT ION A ND
S I G N I F I CA N C E O F I T S CA R E
Skin is one of the most important and the largest organ of the human
body. Its average area in an adult human is from 1.5 to 2 m2, and the
mass along with the subcutaneous tissue can reach up to 20 kg (Fore,
2006; Lai-Cheong & McGrath, 2017; Richardson, 2003). As the outer-
most organ in the human body, it is constantly in contact with the
external environment and is the basic protective system. The thick-
ness of the skin is uneven and depends on many factors, such as the
area of the body, exposure to external factors (UV rays, injuries), and
age. The skin has a three-layer structure that ensures its flexibility and
durability. The epidermis is the outermost and thinnest layer. It is
made of the multilayered keratinized flat epithelium. Under the epi-
dermis is the dermis, which consists of dense connective tissue con-
taining collagen and elastin fibers. The dermis also contains nerve
fibers, blood vessels, and hair bulbs. In addition, there are also seba-
ceous and sweat glands. Human skin has many important functions
without which life would not be possible. It supports homeostasis and
maintains a balance between the body and the environment (Fore,
2006; Lai-Cheong & McGrath, 2017; Lee, Jeong, & Ahn, 2006;
Randall-Wickett & Visscher, 2006). The functions of skin can be
divided into the passive (e.g., protection) and the active (e.g., secretion
and sense). It protects the body from overheating, cold, heat, radia-
tion, reactive oxygen species (ROS), and chemicals (Lee et al., 2006;
Richardson, 2003; Romanovsky, 2014). In addition, protection against
the penetration of microorganisms and parasites is a very important
function of the skin, especially in the neonatal period and infancy
(Randall-Wickett & Visscher, 2006). Additionally, the skin exhibits
secretory and resorptive activities, is involved in the synthesis of vita-
min D3, hormones and melanin, and also plays an important role in the
immune system of the body (Fore, 2006; Lai-Cheong & McGrath,
2017; Richardson, 2003).
SAFETY OF PARABENS IN COSMETICS
The skin ages with age and under the influence of external fac-
tors. Aging of the skin is a complex biological process affected by
the combination of endogenous (metabolic processes, hormones,
genetic predispositions) and exogenous factors (chemicals, toxins,
ionizing radiation, UV radiation) (Cevenini et al., 2008; Farage,
Miller, Elsner, & Maibach, 2008; Farage, Miller, Elsner, & Maibach,
2013; Fisher, 2005; Fisher et al., 2002; Fore, 2006; Guinot, Malvy, &
Tenenhaus, 2002; Tobin, 2017). These factors may cause functional
and structural changes in the various layers of the skin. In addition,
they are also associated with changes in the appearance of the skin,
especially on the areas of the skin exposed to sunrays. The aging
skin intrinsically becomes thin, atrophic, finely wrinkled, and dry, in
contrast to the pre-aged skin in which photo-aging processes take
place. This skin usually shows thickened epidermis, mottled discol-
oration, deep wrinkles, laxity, dullness, and roughness. In each case,
the gradual loss of the skin elasticity leads to its sagging. These
changes are related, among others, to reduced content of collagen,
which is the most abundant extracellular matrix protein responsible
for the skin's tensile strength and mechanical properties (Frantz,
Stewart, & Weaver, 2010; Gelse, Poschl, & Aigner, 2003; Quan &
Fisher, 2015; Varani et al., 2006). In addition to collagen, the
amount of hyaluronic acid (HA), the key molecule responsible for
maintaining skin moisture, is reduced (Papakonstantinou, Roth, &
Karakiulakis, 2012).
Today, the appearance and condition of the human body are
becoming an extremely important aspect of life. Most people want
to adapt themselves to patterns of beauty promoted, accepted, and
imposed by a society. Therefore, growing attention has been paid to
maintaining healthy and beautiful skin. Furthermore, there is an
increasing interest in developing anti-aging strategies that are effec-
tive in relieving the symptoms of skin aging (Baumann, 2007;
Ganceviciene, Liakou, Theodoridis, Makrantonaki, & Zouboulis, 2012;
Bosch et al., 2015). Regular use of cosmetic formulations can
improve elasticity and smoothness of the skin, accelerate its regener-
ation, and thus temporarily change its condition (Campos, Gianeti,
Mercurio, & Gaspar, 2014; Ganceviciene et al., 2012; Holloway &
Jones, 2005; Ribeiro, Estanqueiro, Oliveira, Lobo, & Benefits, 2015).
This is due to the content of many active ingredients in the cosmetic
products (vitamins, polyphenols, flavonoids, peptides, growth fac-
tors), which exert numerous positive, direct or indirect (by reducing
the concentration of free radicals) effects on the skin (Baumann,
2007; Bosch et al., 2015; Campos et al., 2014; Gianeti, Mercurio, &
Campos, 2013; Lintner, Mas-Chamberlin, Mondon, Peschard, &
Lamy, 2009; Petruk, Del Giudice, Rigano, & Monti, 2018; Ribeiro
et al., 2015; Zillich, Schweiggert-Weisz, Eisner, & Kerscher, 2015)
and collagen synthesis (Galicka & Nazaruk, 2007; Nazaruk & Galicka,
2014). However, all these cosmetic products consist not only of the
active care ingredients, but also many chemical additives, among
which synthetic preservatives belong to an important group. Thus,
application of cosmetic preparations throughout a lifetime is a source
of repeated chronic exposure to numerous chemical compounds,
including parabens being the most often used preservatives in these
products.
179
3 | T H E EU R E G U LA T I O N S O F P A RA B E N S
I N C O S M E T I C P R O D U CT S
The EU recommendations for the safety of cosmetics and personal
care products were introduced in 1976 by the EU Cosmetic Directive
and the regulations are periodically updated. According to the Com-
mission Regulation (EU) No 358/2014 of 9 April 2014 amending
Annexes II and V to the Regulation (EC) No 1223/2009 of the
European Parliament and of the Council on cosmetic products,
4-hydroxybenzoic acid and its salts and esters, other than the esters
of isopropyl, isobutyl, phenyl, benzyl, and pentyl, are allowed to be
used at a maximum concentration of 0.4% (as acid) for single esters
and 0.8% (as acid) for mixtures of esters in ready-for-use preparations
(EC, 2014; CIR, 2008; EC, 2009). The same concentrations of para-
bens are accepted in the USA (CIR, 2008; FDA, 2012). IPP, IBP, PhP,
BzP, and PeP are prohibited in cosmetic products in accordance with
the current regulations of the EU (EC, 2014, EC, 2009). From
30 October 2014, only cosmetics that comply with the Commission
Regulation (EU) No 358/2014 may be placed on the EU market,
whereas from 30 July 2015 only products that comply with this Regu-
lation are allowed to be made available on the EU market. The EU
SCCS recommended that BP and PP should be prohibited in leave-on-
the-skin cosmetic products intended for use on the nappy area of chil-
dren aged <3 years (SCCS, 2011). Moreover, the SCCS has set maxi-
mum concentration limits of 0.14% for BP or PP (single esters and
their salts), 0.4% for MP or EP (single esters and their salts), and 0.8%
for mixtures of these four ingredients, wherein the sum of the individ-
ual concentrations of BP and PP cannot exceed 0.14% (EC, 2014, EC,
2009).
4 | ABSO RP TION AND R ETENTION OF
PARABENS – STUDIES ON ANIMAL AND
HU M A N SKI N SE CT I ON S
Many reports have proven that parabens can be quickly absorbed
through the intact skin and may be able to accumulate in body tissues.
Experiments carried out on animal and human skin sections demon-
strated that despite its lowest lipophilicity, MP has the ability to pene-
trate the skin to a greater extent than other parabens and to
accumulate in its non-metabolized form (Caon, Costa, de Oliveira,
Micke, & Simões, 2010; El Hussein, Muret, & Berard, 2007; Ishiwatari
et al., 2007; Jewell et al., 2007; Pažoureková et al., 2013; Pedersen,
Marra, Micoli, & Santi, 2007). Table 2 presents the results of chosen
studies on the dermal permeation and accumulation of parabens (with
particular emphasis on MP) in animal and human skin models. These
studies showed that the rate of paraben transport through the skin
depends on the length of the alkyl substituent and its occlusion-
forming capacity (Caon et al., 2010; Cross & Roberts, 2000; El Hussein
et al., 2007; Pedersen et al., 2007). The percentage of parabens per-
meating across the animal and human skin fragments was the highest
for MP, as the least lipophilic and the most water-soluble paraben,
and it was lower for EP, PP, and BP in accordance with their lower

TABLE 2 Dermal permeation and retention studies of methylparaben (MP), ethylparaben (EP), propylparaben (PP) and butylparaben (BP) in animal and human skin models
Skin/subject/cosmetic/
amount/exposure time
Frozen (intact and stripped) and
fresh ear full-thickness skin
(FTS)/6-month-old domestic
pigs/aqueous solution, hydrogel
or emulsion oil-in-water with
and without enhancer of
penetration/10
± 0.05 mg/cm2/24 h
Frozen ear FTS/young
pig/paraben solution in 20%
and 50% (v/v) ethanol or
PBS/2 mL/6 h
Frozen dorsal skin/5-month-old
female Yucatan micro pig/MP
solution/10 μL/15 min, 60 min,
120 min
FTS from fresh ears/6-month-old
rabbits/3 creams containing
parabens in different
proportions/2 mg/cm2/8 h
180
Paraben Main results and conclusions References
MP (0.1%) % of unmetabolized MP in intact (stripped) MP is not completely hydrolyzed. Pažoureková et al., 2013
FTS of total amounts of permeants The amount of unmetabolized MP is
Enhancer Hydrogel Emulsion oil-in-water higher after exposure of the skin
to emulsion than hydrogel. The
– 5.6 (4.9) 5.8 (6.3) permeability coefficient increases
urea 5.4 (5.4) 6.1 (6.8) with paraben water solubility for
transcutol 5.2 (5.6) 7.4 (7.4) emulsions, while it decreases for
gels.Penetration enhancers and
propylene glycol 5.5 (5.7) 7.1 (7.1) mechanical damage to the skin
increase MP absorption.
Freezing of pig ear skin only slightly
reduces the hydrolytic activity of
esterases.
MP, EP, PP, BP (0.1% each) Diffusive parameter D/H2/cm MP shows the highest permeation Caon et al., 2010
MP 0.111 ± 0.032 flux. An increase in the ethanol
concentration caused a higher
EP 0.059 ± 0.018 paraben accumulation in the
PP 0.073 ± 0.038 dermis than in epidermis, probably
BP 0.045 ± 0.001 due to greater permeation.
MP (0.1%) MP concentration (μg/g tissue) MP is not hydrolyzed completely Ishiwatari et al., 2007
15 min, 60 min, 120 min and its retention in the skin
increases in a time-dependent
SC 976 ± 104, 1651 ± 276, 2046 ± 193 way.
Epidermis 9.2 ± 0.6, 19.3 ± 1.5, 15.0 ± 3.4
Dermis 2.3 ± 0.2, 3.2 ± 0.7, 3.4 ± 0.6
MP (0.23–0.32%) % (approx.) of parabens permeation The percentage of paraben Pedersen et al., 2007
EP (0.0–0.1%) MP, EP, PP permeation was the greatest for
PP (0.04–0.19%) MP, and it was more affected by
60%, 40%, 20% paraben solubility and lipophilicity
MP retention in the skin (μg/g tissue) than paraben content and the
Epidermis, Dermis composition of creams.
MP retention was higher in the
Cream 253.0 ± 19, 19.3 ± 2.3 epidermis than in the dermis. The
Cream 76.2 ± 13.1, 5.8 ± 2.4 difference in retention, not
Cream 167.6 ± 46.7, 12.6 ± 3.8 associated with the difference in
permeation, can be related to the
different composition of the
creams.
(Continues)
MATWIEJCZUK ET AL.
TABLE 2 (Continued)
SAFETY OF PARABENS IN COSMETICS

Skin/subject/cosmetic/
amount/exposure time
Frozen dorsal skin/male
mini-pigs/parabens
solution/25 μg/cm2/6 and 24 h
Human breast skin/3 healthy
female (aged 28, 35, 37 years)/
parabens solution/25 μg/cm2/6
and 24 h
Paraben
MP, EP, PP, BP (100 μM each)
Main results and conclusions References
% of permeation and retention in skin Paraben absorption was similar in Jewell et al., 2007
6 h RM, 24 h RM, 24 h skin human and mini-pig skin, but
mini-pig skin hydrolyzed parabens
MP 2.84 ± 0.48, 35.76 ± 7.04, 23.96 ± 8.44
to a greater extent than the
EP, ND 5.12 ± 1.68, 37.0 ± 10.6 human skin. The % absorption and
PP 3.56 ± 0.36, 20.12 ± 5.0, 36.96 ± 7.8 hydrolysis was the greatest for
MP. The retention in the skin was
BP, ND 15.12 ± 2.76, 48.76 ± 24.48
higher for more lipophilic
parabens. Parabens were
associated with the dermal lipids.
MP 5.56 ± 1.4, 27.80 ± 3.92, 28.6 ± 11.52
EP 8.76 ± 1.64, 35.32 ± 4.84, 35.96 ± 10.6
PP 6.72 ± 2.0, 30.32 ± 11.64, 44.0 ± 19.1
BP 4.48 ± 1.84, 32.96 ± 10.68, 49.68 ± 12.36

Human abdominal skin/6 women
aged 35–45 years/body
lotion/12, 24 and 36 h
MP (0.1%) % of total permeated parabens MP penetrated the skin to the El Hussein et al., 2007
EP (0.08%) Single application, 3 applications greatest extent.
PP (0.2%) MP 0.057 ± 0.03, MP 0.6 ± 0.1 EP 0.045 ± 0.01, EP 0.3 ± 0.1 PP After three applications of
BP (0.15%) 0.028 ± 0.01, PP 0.2 ± 0.05 BP 0.007 ± 0.003, BP 0.04 ± 0.01 body lotion the increase in the
epidermis–dermis crossing was
noted for each paraben, but the
most important for MP.

FTS, full-thickness skin; RM, receptor medium; ND, not detectable

181
182
solubility (Table 1) (Caon et al., 2010; El Hussein et al., 2007; Jewell
et al., 2007; Pedersen et al., 2007). Differences in paraben diffusion
may result from their interaction with intercellular lipids, which
increase with increasing paraben lipophilicity. After 8-h cream applica-
tion on rabbit skin, which is a good model of human skin, MP showed
the highest permeation, reaching 60% of the amount applied, followed
by EP (40%) and PP (20%) (Pedersen et al., 2007). Similarly, MP passed
through human skin in the highest amount (0.42 ± 0.1, 1.91 ± 1.1, and
0.22 ± 0.1 μg/cm2 after 12, 24, and 36 h, respectively) during one
application of body lotion, while more lipophilic parabens crossed the
skin layers to a lesser extent (for BP the values were 0.03 ± 0.004,
0.24 ± 0.1, and 0.21 ± 0.1 μg/cm2 after 12, 24, and 36 h, respectively)
(El Hussein et al., 2007). The maximum accumulation of parabens in
the receptor fluid (RF) was after 24 h from the time of a single applica-
tion of body lotion, whereas a significant increase in the amount of
permeated parabens at each time point (12, 24, and 36 h) after three
applications of the body lotion was demonstrated. For MP these
values were significantly higher (0.6 ± 0.17, 3.4 ± 0.7, and
5.6 ± 0.63 μg/cm after 12, 24, and 36 h, respectively) than for BP
2
(0.03 ± 0.01, 0.28 ± 0.09, and 0.6 ± 0.17, respectively) (El Hussein
et al., 2007). Despite the weaker BP passage through the skin as com-
pared with MP, the repeated application of cosmetics containing BP
may also lead to its accumulation in the skin (Darbre, 2001; El Hussein
et al., 2007).
The absorption and the percentage of unmetabolized parabens
remaining in the skin depend not only on their physicochemical prop-
erties but also on the type and composition of the formulations used
(Pažoureková et al., 2013; Pedersen et al., 2007; Pozzo & Pastori,
1996). According to Pedersen et al. (2007), the solubility and
lipophilicity of parabens influence their penetration through the skin
to a greater extent than the initial paraben concentration and the
composition of preparations, while the composition of the used for-
mulation plays a role in paraben retention. The percentage of MP
remaining in the skin at 8 h after cream application was 15% of the
applied dose in the case of two creams, containing MP, EP, and PP,
while for EP and PP the values were in the range of 7% to 9%. In the
case of a third cream, not containing EP, the percentage of parabens
retained in the skin was ~3% for both MP and PP (Pedersen et al.,
2007). The amount of unmetabolized MP found in the RF during 24-h
permeation through the frozen intact and stripped full-thickness skin
membrane (FTS) of pig ear was higher after their exposure to emul-
sion oil-in-water (0.34 ± 0.06 and 0.50 ± 0.07 μg/cm2, respectively)
than to hydrogel (0.22 ± 0.02 and 0.29 ± 0.02 μg/cm , respectively) or
2
aqueous paraben solution (0.20 ± 0.03 and 0.29 ± 0.04 μg/cm2,
respectively) (Pažoureková et al., 2013). The greater permeation rate
of MP from the emulsion was probably caused by the fact that the
emulsion is closer to the natural skin film than hydrogel or a MP solu-
tion. Penetration enhancers (ethanol, urea, transcutol, propylene gly-
col) and mechanical damage to the skin increase absorption of
parabens (Caon et al., 2010; Pažoureková et al., 2013) (Table 2). Expo-
sure of pig ear FTS to parabens (MP, EP, PP, and BP) dissolved in eth-
anol at a concentration of 20% (v/v) resulted in their greater retention
in the epidermis than in the dermis, while after the use of a higher
MATWIEJCZUK ET AL.
concentration of ethanol (50%, v/v) more intact parabens were
detected in the dermis, which indicates increased permeation of para-
bens (Caon et al., 2010).
Compared to the intact FTS, the stripped FTS of pig ear had a
slightly smaller sheet thickness (on average ~1%), but a seven-fold
higher transcutaneous electrical conductivity value, which resulted in
higher permeation of parent MP and its metabolite from all investi-
gated preparations (Pažoureková et al., 2013). At 24 h after using
these preparations, 2.9–7.6% of the applied dose (10 μg/cm2) of
unmetabolized MP in stripped FTS and 2.0–5.8% MP in intact FTS RF
was detected. The presence of enhancer [e.g., 5% (w/w) transcutol] in
emulsion caused 1.4-times faster permeation of the parent MP
through the stripped FTS than through the intact FTS. The steady
state flux (Jss) values of MP were 0.13 μg/cm2/h and 0.18 μg/cm2/h
through intact and stripped FTS of pig ear, respectively (Pažoureková
et al., 2013). The purpose of the stripping procedure of the skin was
to mimic the in vivo conditions of topical application of cosmetics
containing parabens to the human skin with damaged stratum cor-
neum (SC) due to various mechanical or disease reasons.
Although the results of tests on animal skin sections are difficult
to extrapolate to humans, the pig skin model seems to be the most
useful. However, the process of absorption of individual cosmetic
ingredients, including parabens, can be different in humans because it
is dependent on a number of physical and biologic factors such as:
age, skin condition (normal, abraded or diseased), skin temperature,
the area of application and contact time, frequency of application, skin
hydration and pretreatment (e.g., microdermabrasion), peripheral cir-
culation, physical characteristics of the penetrant, and the penetrant–
vehicle relationship (Hougeir & Kircik, 2012; Lopes, Garcia, & Bentley,
2015). Heating the skin, e.g., with a massage, can increase the pene-
tration of cosmetics components into its internal layers. In in vitro
experiments using human epidermis, a significantly enhanced epider-
mal retention of BP and epidermal diffusivity of MP were demon-
strated at temperatures ranging from 23 to 45
C (Akomeah, Nazir,
Martin, & Brown, 2004). There are large differences in the degree of
absorption of cosmetic ingredients in various parts of the body
(e.g., the rate of absorption on the face and scalp is much greater than
in other parts of the body). Skin thickness is also important and cer-
tainly the eyelids or skin under the eyes, which is extremely thin and
delicate, is more exposed to paraben action than the skin on the soles
of the feet, which is very thick. In addition, an increasing number of
cosmetics are composed of ingredients that change penetration of the
epidermis, e.g., pyrrolidones, glycols, sulfoxides, alcohols, proteases
(papain), and surfactants (Hougeir & Kircik, 2012; Lopes et al., 2015;
Shokri, Javar, & Ghadermazi, 2014; Williams & Barry, 2004). Lactic
acid, glycolic acid or menthol can be used to deliver the active ingredi-
ents of cosmetics to the dermis to stimulate endogenous collagen syn-
thesis, as exogenous collagen used in cosmetics cannot penetrate
through the skin because of a high molecular mass. In addition to spe-
cific substances facilitating penetration of the active ingredients via
the skin, there are many cosmetic treatments that provide a similar
effect. Microdermabrasion may be an example. It is a very common
procedure used in most beauty salons, which is based on the
SAFETY OF PARABENS IN COSMETICS
mechanical removal of the SC facilitating the transport of the ingredi-
ents used. Furthermore, treatments such as waxing and epilation can
affect the SC, which also contributes to the penetration of substances
contained in cosmetic preparations (Trivedi, Kroumpouzos, & Murase,
2017).
Skin diseases are an additional factor increasing the penetration
of parabens via the skin. In children with atopic dermatitis, absorption
of these preservatives may be facilitated due to the use of specific
softeners for the treatment of the pathologically altered skin
(Overgaard et al., 2017). Moreover, the damage to the skin barrier or
discontinuity of the epidermis, such as scratches, increase the pene-
tration of all substances contained in care products (Nielsen, Nielsen, &
Sørensen, 2007).
5 | U S E OF C O S M E T I CS B Y C O N S U M ER S
A S A SO U R C E OF E X P O S U R E T O P A R A B E N S
Cosmetics are the source of everyday, common, and usually long-term
exposure to various substances, being their ingredients, including par-
abens. In addition to basic skin care, a rising number of people (espe-
cially women) use make-up products, which constitute as much as
63% of all categories of cosmetics according to the California Safe
Cosmetics Program (CSCP) reports. In recent times, gender- and age-
based stereotypes regarding the use of cosmetics, including make-up
products, have become less pronounced. Both adult and adolescent
(aged 13–17 years) men now use more decorative cosmetics tradi-
tionally used by women to improve their appearance (Biesterbos
et al., 2013; Manová, von Goetz, Keller, Siegrist, & Hungerbühler,
2013). Similarly, older people wanting to keep a good appearance in
the society continue the use of cosmetics for old age.
Due to the fact that paraben-containing cosmetics are commonly
used, a large part of the general population is exposed to these com-
pounds throughout the lifetime. In a study performed in 1984, Elder
(1984) estimated parabens presence in >13 200 formulations. The
Danish study revealed the presence of these compounds in 99% of
leave-on-the-skin and in 77% of washable cosmetics at a concentra-
tion within the range of 0.01% to 0.87% (Rastogi et al., 1995). Simi-
larly, in the USA, parabens have been found in more leave-on-the-skin
cosmetics (60%) than in the washable products (40%) (Guo & Kannan,
2013). The Swedish study showed the presence of parabens in 44%
of rinse-off products such as: shampoo, conditioner, body wash, and
face cleanser (Yazar, Johnsson, Lind, Boman, & Lidén, 2011).
MP is found most frequently and in the highest concentrations
among all cosmetics containing parabens (Darbre et al., 2004; Guo
et al., 2014; Pažoureková et al., 2013). It should also be emphasized
that the permissible concentration of parabens accepted in cosmetics
(0.4% for MP or EP, 0.14% for PP or BP, and 0.8% for the mixture of
these four ingredients) is not always respected by manufacturers
(Table 3 and Tables S1-S4). In the USA, some personal care products
and lipstick tested contained up to 1.0% MP (CIR, 2008). Furthermore,
cosmetics unlabeled or labeled as ‘paraben free’ may contain them.
Makkliang et al. (2018) reported the presence of parabens in
183
unlabeled mouthwashes and toners. Although the detected concen-
trations of MP and PP in the unlabeled products were much lower
than in the labeled ones, the unlabeled toners contained one more
paraben than the labeled ones. This also applies to alternative prod-
ucts, e.g., the presence of MP was revealed at a concentration of
0.16% in an alternative sunscreen (Dodson et al., 2012).
The aggregate SED (cumulative internal exposure) to parabens
estimated in the present review based on the published concentra-
tions of MP, ET, PP, and BP determined in various categories of cos-
metics (Table 3) and according to the recommendations of the SCCS
for calculation of aggregate exposure to preservatives through cos-
metics use (SCCS, 2018), ranged from 0.0471 to 1.928 mg/kg body
weight(bw)/day (assuming 50% dermal absorption), of which the
majority (about 34–38%) was MP (Table 4). Among all cosmetics ana-
lyzed, body lotions mostly contributed to paraben exposure followed
by face cream and hand cream, while exposure to these compounds
from other products was clearly lower. These values of SED for partic-
ular parabens, as well as the aggregate exposure to all parabens are
very close to the values estimated by other authors. In the USA, the
SED values were estimated for MP, EP, and PP as 0.79, 0.13, and
0.34 mg/kg bw/day, respectively, for 23 personal care products
assuming 80% dermal absorption (Cowan-Ellsberry & Robison, 2009).
Similar SED values for these parabens (MP, EP, and PP) were also
obtained by Guo and Kannan (2013): 0.8, 0.2, and 0.3 mg/kg bw/day.
For children aged 0–3 years the internal aggregate exposure levels for
MP, EP, PP, and BP were as follows: 1.01, 0.2, 0.41, and 0.20 mg/kg
bw/day, respectively (Gosens, Delmaar, Ter Burg, de Heer, & Schuur,
2014). Because the calculations were performed by us in the present
paper, calculations of SED were made assuming rational daily applica-
tion of cosmetics (SCCS, 2018), it should be underlined that these
values may be underestimated, as some people use various kinds of
cosmetic more frequently during the day than has been described in
the SCCS recommendations. For example, among 306 women aged
19–65 years from various regions of the USA, the daily mean use of
face cream was 2.05 g (Loretz et al., 2005), while among 1059 French
women of the same age, the use was much higher and reached 6.6 g
(Gomez-Berrada, Ficheux, Dahmoul, Roudot, & Ferret, 2017). More-
over, some women use lipstick from several to a dozen times a day
and as high as 1% concentration in this product has been reported
(CIR, 2008).
To recognize whether the concentrations of parabens generally
detected in cosmetic and the internal exposure to these compounds
are safe for users of these product in the present study, apart from
SED, the MoS was calculated as well (Table 5). The cosmetic prepara-
tion may be recognized as safe when the MoS equals at least
100 (SCCS COLIPA noP822010). The performed calculations of the
MoS for the concentrations of MP, ET, PP, and BP occurring in cos-
metics present on the market show that in some cases these com-
pounds are present in cosmetic products at concentrations that do
not guarantee safety for their users.
Cosmetics are used starting from infancy. Among the age groups
examined (0–4, 5–8, and 9–12 years), the regular use of face cream
and body lotion was found to be very high in the youngest, although
 184

TABLE 3 The ranges of concentrations of methylparaben (MP), ethylparaben (EP), propylparaben (PP), and butylparaben (BP) in various categories of cosmetics

Range of paraben concentrations, %

Type of cosmetic product MP EP PP BP References

Rinse-off skin and hair cleaning products
Shower gel 0.00005–0.4 0.00001–0.015 0.0002–0.097 0.0022–0.0286
Hand wash soap 0.000451–0.0969 0.000084–0.0135 0.000038–0.0917 0.000013–0.000203 Wang & Chang, 1998; CIR Expert Panel, 2008; Uysal & Güray,
Shampoo 0.000145–0.4 0.000002–0.2 0.011–0.4 0.004–0.25 2008; Farajzadeh, Djozan, & Bakhtiyari, 2010;
García-Jiménez, Valencia, & Capitán-Vallvey, 2010; Melo &
Hair conditioner 0.00153–0.4 0.00051–0.6 0.00212–0.5 0.0085–0.25 Queiroz, 2010; Sanchez-Prado, Llompart, Lamas,
Leave-on skin and hair care products Garcia-Jares, & Lores, 2011; Chuto, Chaiyo, Siangproh, &
Body lotion 0.000035–0.63 0.000018–0.54 0.000014–0.4 0.00001–0.24 Chailapakul, 2013; Wang & Zhou, 2013; Youngvises et al.,
2013; Ahn, Park, & Yoo, 2014; Alvarez-Rivera, Llompart,
Face cream 0.01–0.68 0.0000026–0.54 0.000012–0.35 0.00001–0.54 Garcia-Jares, & Lores, 2014; Baranowska, Wojciechowska,
Hand cream 0.0704–0.4 0.001–0.4 0.0571–0.4 0.000072–0.4 Solarz, & Krutysza, 2014; Guo et al., 2014; Makkliang,
Deo non-spray 0.000042–0.3 0.002–0.1 0.000036–0.4 0.00004–0.09 Kanatharana, Thavarungkul, & Thammakhet-Buranachai,
2018; Norseyrihan, Noorashikin, Marinah, Shiuan, & Ruzita,
Hair styling 0.0484–0.3 0.0038–0.1 0.0058–0.1 0.0004–0.1 2018
Make-up products
Liquid foundation 0.1–0.7 0.00006–0.5 0.02–0.4 0.00006–0.2
Make-up remover 0.000011–0.4 0.000002–0.3 0.0062–0.15 0.0328–0.15
Lipstick 0.15–1 0.0002–0.2 0.1–0.62 0.000448–0.1
Eye make-up 0.1–0.5 0.00312–0.49 0.0161–0.5 0.00649–0.3
Mascara 0.165–0.54 0.00002–0.4 0.1–0.32 0.00002–0.21
Eyeliner 0.13–0.6 0.03–0.4 0.05–0.4 0.05–0.2
Oral care cosmetics
Toothpaste 0.000045–0.1633 0.000001–0.01302 0.0133–0.1885 0.015267–0.228783
Mouthwash 0.0000741–0.12 ND 0.000099–0.005 ND

ND, not detectable

The ranges of concentrations of methylparaben (MP), ethylparaben(EP), propylparaben (PP), and butylparaben(BP) in various categories of cosmetics estimated on the basis of data collected in the Tables S1-S4
MATWIEJCZUK ET AL.
T A B L E 4 Possible systemic exposure dose (SED) of methylparaben (MP), ethylparaben (EP), propylparaben (PP), and butylparaben (BP) estimated based on these compounds concentrations
detected in various categories of cosmetics1

Estimated daily exposure to Range of SED for particular parabens, mg/kg bw/day
cosmetics normalized by Aggregate SED range for
Type of cosmetic body weight [A], mg/kg all parabens, mg/kg
product bw/day MP EP PP BP bw/day
Rinse-off skin and hair cleaning products
SAFETY OF PARABENS IN COSMETICS

Shower gel 2.79 0.000000697–0.00558 0.000000139–0.0002092 0.00000279–0.001353 0.0000307–0.0004 0.000034326–0.0075422

Hand wash soap 3.33 0.00000751–0.001613 0.000001398–0.0002247 0.000000632–0.001527 0.000000216–0.00000338 0.000009756–0.00336808
Shampoo 1.51 0.00000109–0.00302 0.000000015–0.00151 0.000083–0.00302 0.0000302–0.001887 0.000114305–0.009437
Hair conditioner 0.67 0.00000513–0.00134 0.000001708–0.00201 0.0000071–0.001675 0.0000285–0.000837 0.000042438–0.005862
Leave-on skin and hair care products
Body lotion 123.20 0.000020944–0.38808 0.00001108–0.33264 0.00000862–0.2464 0.00000616–0.14784 0.000046804–1,11496
Face cream 24.14 0.0000041–0.08208 0.000000313–0.065178 0.00000145–0.042245 0.00000121–0.06518 0.000007073–0.254683
Hand cream 32.70 0.0115104–0.0654 0.0001635–0.0654 0.009336–0.0654 0.00001177–0.0654 0.02102167–0.2616
Deo non-spray 22.08 0.00000464–0.03312 0.0002208–0.01104 0.00000397–0.04416 0.00000442–0.009936 0.00023383–0.098256
Hair styling 5.74 0.001380–0.00861 0.000109–0.00287 0.00016646–0.00287 0.00001148–0.00287 0.00166694–0.01722
Make-up products
Liquid foundation 7.9 0.00395–0.02765 0.00000237–0.01975 0.00079–0.0158 0.00000237–0.0079 0.00474474–0.0711
Make-up remover 8.33 0.000000458–0.01666 0.000000083–0.012495 0.000258–0.006248 0.001366–0.00625 0.001624541–0.041653
Lipstick 0.90 0.000675–0.0045 0.0000009–0.0009 0.00045–0.00279 0.00000202–0.00045 0.00112792–0.00864
Eye make-up 0.33 0.000165–0.000825 0.0000103–0.0008085 0.0000265–0.000825 0.0000107–0.000495 0.0002125–0.0029535
Mascara 0.42 0.0003465–0.001134 0.000000042–0.00084 0.00021–0.000672 0.000000042–0.000441 0.000556584–0.003087
Eyeliner 0.08 0.000052–0.00024 0.000012–0.00016 0.00002–0.00016 0.00002–0.00008 0.000104–0.00064
Oral care cosmetics
Toothpaste 2.16 0.000000486–0.0017636 0.00000001–0.0001406 0.0001436–0.002036 0.0001649–0.002471 0.000308996–0.0064112
Mouthwash 32.54 0.00001206–0.019524 ND 0.0000161–0.0008135 ND 0.00002816–0.0203375
Total SED for particular parabens, mg/kg bw/day 0.0181360–0.6611396 0.000533658–0.516176 0.011524222–0.4379945 0.0016907–0.31244038 0.04710088–1.92775048
1
The possible systemic exposure doses (SED) of MP, EP, PP, and BP were estimated based on the published concentrations of these compounds detected in various categories of cosmetics (Table 3) and taking
into account the recommendations of the SCCS for calculation of aggregate exposure for preservatives through cosmetic use (SCCS, 2018). The value of SED was calculated using the following formula: SED = A
(mg/kg bw/day) × C (%)/100 × DA (%)/100; where A = estimated daily exposure to a cosmetic product per kg body weight (based upon the amount applied and the frequency of application) according to the
SCCS recommendations for calculation of aggregate exposure for preservatives through cosmetic use (SCCS, 2018); C = paraben concentration (MP, EP, PP or BP) determined in a cosmetic product; DA =
dermal absorption. Because dermal absorption of parabens reported by various authors ranges from 15 to 80% (Cowan-Ellsberry & Robison, 2009; Pedersen et al., 2007) according to the SCCS
recommendations for the safety assessment of cosmetics the rate of 50% was accepted for calculations (SCCS, 2018).
185
186
T A B L E 5 Safety evaluation for methylparaben (MP), ethylparaben
(EP), propylparaben (PP), and butylparaben (BP) based on aggregated
systemic exposure dose (SED) of these compounds2
Aggregated SED3, NOAEL4,
Paraben mg/kg bw/day mg/kg bw/day MoS2
MP 0.0181–0.6611 11.2 618.8–17.0
EP 0.0005–0.5162 250 500000–484.3
PP 0.0115–0.4380 3.3 287.0–7.53
BP 0.0017–0.3124 2 1176.5–6.4
2 2016; Kim, Lee, et al., 2018) and exceeded those previously reported
Margin of safety (MoS) was calculated from the formula:
MoS = NOAEL/SED; where NOAEL = no-observed-adverse-effect level
and SED = systemic exposure dose.
3
The range of values of SED for MP, EP, PP, and BP was estimated based
on the published concentrations of these compounds detected in various
categories of cosmetics daily used (Table 3 and 4).
4
For safety reasons, the lowest values of NOAEL described in the
available literature (Oishi, 2002; Hoberman et al., 2008; Boberg, Taxvig,
Christiansen, & Hass, 2010; Vo et al., 2010; SCCP COLIPA no P822010)
were used for the calculation of MoS
the products marked as intended for infants and safe to use also con-
tain potentially harmful ingredients, including parabens, to which the
skin of infants may be much more sensitive than adults (Manová et al.,
2013). In the USA, the dermal intake of parabens from personal care
products for infants and toddlers was calculated to be in the range of
0.0586–0.766 mg/kg bw/day, which was three-times higher than for
adult females (0.031 mg/kg bw/day) (Guo & Kannan, 2013). This dis-
proportion was even greater for individual cosmetic products. For
example, according to Gomez-Berrada et al. (2017) the exposure of
789 French infants (aged 0–3 years) to balm exceeded 6.3-times the
exposure value estimated in 1368 adults aged 18–69 years. In the
case of other most frequently used cosmetics (cream, shampoo,
shower gel, solid soap, cleansing lotion, emollient bath), exposure to
these preparations was also found to be 6–11-times higher in infants
than in adults. Pregnant women are usually unaware of the potential
unfavorable effects resulting from the use of cosmetics and they con-
tinue to apply them for the care of their body, while the fetus is par-
ticularly susceptible to endocrine disrupting agents, like parabens,
found also in the umbilical cord blood (Pycke, Geer, Dalloul, Abulafia, &
Halden, 2015).
It should be emphasized that the additional sources of the dermal
exposure to parabens, not included in the content of the present
review, are some hygiene articles such as sanitary wipes (including
baby wipes) and toilet paper, but also tickets, currency bills, business
cards, food cartons, and newspapers used in everyday life (Liao &
Kannan, 2014).
6 | A S S O C I A T I O N B E T W E E N T H E US E O F
COSMETICS AND THE INTACT PARABEN
C O N C E N T R A T I O N I N TH E B O D Y
The occurrence and accumulation of parabens in the human body in
the intact form have been confirmed by numerous studies performed
MATWIEJCZUK ET AL.
on volunteers using cosmetics containing parabens. Many studies rev-
ealed the presence of intact parabens in the skin, adipose tissue,
blood, serum, plasma, umbilical cord blood, placenta, breast milk of
lactating women, amniotic fluid, seminal fluid, urine, as well as in
healthy breast and breast tumor tissues, and the highest concentra-
tion of these compounds mostly reported for MP (Table 6 and 7). In a
Korean population, EP was found at the highest concentration
(median, 32.9 μg/L; maximum, 113 μg/L) in the urine, which was
about six-times higher than the concentration of MP (Kang et al.,
worldwide (China, Japan, Belgium, Germany, Greece, Sweden, Den-
mark, and the US) (summarized by Kim, Lee, et al., 2018) (Table 7).
Among studied populations, higher levels of parabens were detected
in children than in adults, in women than in men and in the pregnant
women than in non-pregnant ones. High concentrations of these
compounds were reported in the amniotic fluid of American women
(the maximum value for PP was 2130 ng/mL) (Philippat et al., 2013) or
in cord blood plasma of neonates from USA immigrants (the maximum
value for MP was 210 ng/mL) (Pycke et al., 2015) (Table 6). The
highest maximum concentration of parabens in tissues was found for
BP (26 469 ng/g) in the breast cancer tissue of Indian women
(Shanmugan et al., 2010).
The fact that parabens are detected in the human body in the
intact form suggests that they come from the dermal application of
cosmetics. This assumption is based on differences in the metabolism
of parabens supplied via the oral and dermal routes. Parabens entering
the body via the digestive tract are absorbed completely and hydro-
lyzed to PHBA by carboxylesterases [EC 3.1.1.1] in the intestine, liver,
and kidneys (Harville, Voorman, & Prusakiewicz, 2007; Janjua et al.,
2007; Jewell et al., 2007; Lakeram, Lockley, Sanders, Pendlington, &
Forbes, 2007). PHBA along with its glycine, glucuronic acid, ester, and
sulfuric acid conjugates are excreted in the urine. In humans there are
two isoforms of carboxylesterases (hCE) with dominance of hCE1 in
the liver and hCE2 in the small intestine (Imai, 2006); the latter also
dominates in the skin (Zhu, Hu, & Zeng, 2005). The substrate specific-
ity of hCE1 and hCE2 is different, MP and EP are preferentially hydro-
lyzed by hCE1, and PP, BP, and BzP by hCE2 (Imai, 2006). Both layers
of the human skin (epidermal and dermal) can hydrolyze parabens; the
epidermal layer contains an esterase that preferentially hydrolyses BP
(Lobemeier, Tschoetschel, Westie, & Hetmann, 1996). The presence
of parabens in the intact form may result from insufficient levels and
activities of the hCE necessary for a complete hydrolysis of dermally
applied parabens or their greater resistance to hydrolysis by the skin
esterases (Darbre, 2006; Lobemeier et al., 1996). in vitro studies rev-
ealed that hydrolysis of parabens in the human skin is much slower
than in the human liver, as well as in the skin and liver of rats (Harville
et al., 2007).
As cosmetics are often applied to large areas of the skin and sev-
eral products are used on the same body area, considerable amounts
of parabens can enter the body and accumulate in various tissues in
the unmetabolized form and, as a consequence, affect health to a
greater extent than those taken orally (Figure 1). Owing to the lack of
sufficient research showing a direct relationship between the
TABLE 6 The concentrations of methylparaben (MP), ethylparaben (EP), propylparaben (PP), and butylparaben (BP) detected in the human body

Paraben concentration in tissues (ng/g) and in fluids (ng/mL)

Body fluid/tissue Subject/age/population MP EP PP BP References

Skin tissue Japanese adults/n = 3 (application of emulsion on forearm) 6320 (after 1 h) – – – Ishiwatari et al., 2007
Adipose tissue Spanish adults/>16 years/n = 14 <LOD–1.78 (mean 0.60) <LOD–0.07 – – Artacho-Cordon et al., 2017
Chinese women/n = 87 6.3–224.7 18.6–588.1 17.6 0.5–479.0 Shen et al., 2018
Serum Caucasian men/21–36 years/n = 26 *135 Janjua et al., 2007
(application of cream with 2% BP on whole body) (after 3 h)
SAFETY OF PARABENS IN COSMETICS

Danish men/18–26 years/n = 60 0.89–59.6 <LOD–20.8 0.23–5.50 <LOD–0.87 Frederiksen, Jřrgensen, &
Andersson, 2011
American children/1–3 years/n = 936 1.6–138 <0.1–2.0 0.2–14.5 – Ye, Zhou, Wong, & Calafat, 2012
American lactating women/18–38 years/n = 34 5.4–42.1 – 5.4–42.1 – Hines et al., 2015
Spanish adults/>16 years/n = 14 0.19–2.13 <LOD – 0.33 <LOD–0.25 <LOD–0.22 Artacho-Cordon et al., 2017
Plasma Norwegian women/48–62 years/n = 332 9.4 3.0 2.0 – Sandanger et al., 2011
Czech men/n = 58 <LOD–16.0 <LOD–0.36 <LOD–0.75 ND Kolatorova-Sosvorova et al., 2017
Czech women/25–34/n = 27 0.073–1.078 0.024–0.157 – Kolatorova et al., 2018
Cord blood plasma Neonates USA immigrants/n = 38 0.89–210 <0.15–3.82 <0.27–31.8 <0.09–0.26 Pycke et al., 2015
American pregnant women/18–45 years/n = 34 ND 0.01–9.95 0.03–78.12 0.01–0.06 Geer et al., 2017
Blood Spanish adults/n = 6 0.82–6.1 3.8–15.0 – <LOD–3.6 Azzouz, Rascón, & Ballesteros,
2016
Indian pregnant women/20–38 years/n = 40 0.89–55.24 <LOD–11.24 1.08–63.58 0.47–10.22 Shekhar et al., 2017
Menstrual blood Spanish women/n = 25 0.9–45.5 0.8–16.0 0.4–9.0 0.4–1.0 Jiménez-Díaz et al., 2016
Placenta Spanish women/n = 50 0.2–10.0 0.2–5.3 0.2–1.7 0.2–0.6 Jiménez-Díaz et al., 2011
Spanish women 11.77 Valle-Sistac et al., 2016
Spanish women/n = 15 0.5–1.5 0.5–2.2 – – Vela-Soria et al., 2017
Amniotic fluid American pregnant women/18–40 years/n = 97 <LOD–827 <LOD–304 <LOD–2130 <LOD–179 Philippat et al., 2013
Indian pregnant women/20–38 years/n = 40 <LOD–44.77 < LOD – 6.07 1.03–60.87 <LOD–13.53 Shekhar et al., 2017
Human milk Milk purchased from Mother's 0.53–3.0 – <LOD–0.33 – Ye, Bishop, Needham, & Calafat,
2008
Milk Bank (San Jose, CA, USA)/n = 4 Schlumpf et al., 2010
Swiss women/32.2 years/n = 54 0.16–4.2 1.03–1.49 1.04–1.8 – Rodríguez-Gómez, Jiménez-Díaz,
Spanish women/n = 10 0.4–3.5 0.2–3.4 0.1–7.5 0.2–1.3 Zafra-Gómez, Ballesteros, &
Navalón, 2014
Spanish women/n = 10 1.2–7.8 0.7–15.0 0.7–43.5 0.6–14.5 Rodríguez-Gómez, Zafra-Gómez,
Camino-Sánchez, Ballesteros, &
Navalón, 2014
(Continues)
187
TABLE 6 (Continued)
188

Paraben concentration in tissues (ng/g) and in fluids (ng/mL)

Body fluid/tissue Subject/age/population MP EP PP BP References

Hines et al., 2015

Rodríguez-Gómez et al., 2015

American women/18–38 years/n = 34 0.5–2.3 – 0.1–0.6 – Azzouz et al., 2016
Spanish women/n = 10 1.26–16.3 0.97–18.1 1.02–12.6 1.06–12.1 Souza et al., 2016
Spanish women/n = 6 1.2–8.1 1.3–5.1 ND <LOD–0.3 Fisher et al., 2017
Brazil women/n = 16 10.8–39.8 11.5–29.6 ND 3.0–8.1 Vela-Soria et al., 2018
Canadian women/>18 years/n = 80 0.22–16.325 0.0023–2.183 0.0277–4.588 ND Dualde, Pardo, Fernández, Pastor,
Spanish women/n = 15 0.9–21 <LOD–4.05 0.4–12 <LOD–0.34 & Yusà, 2019

Spanish women/28–40 years/n = 10 <LOD–7.0 – <LOD–0.76 –

Seminal fluid Danish men/18–26 years/n = 60 <LOD–180 <LOD–5.65 0.39–35.5 <LOD–1.73 Frederiksen et al., 2011
Breast tissue Indian woman/n = 1 26.5 ND ND ND Shanmugan, Ramaswamy,
Radhakrishnan, & Tao, 2010
Breast tissue adjacent English women (mastectomies)/n = 160 tissue samples 0.2–5102.9 0.3–499.7 1.2–2052.7 0.2–95.4 Barr, Metaxas, Harbach, Savoy, &
to tumor Darbre, 2012
Breast tumor tissue Indian women/n = 9 41.0–1719 243–10 608 273–4490 535–26 469 Shanmugan et al., 2010
English women/n = 20 0.8–29.3 0.2–7.4 0.2–10.4 0.5–11.5 Darbre et al., 2004
Chinese women/n = 102 2.1–105.0 17.3–189.5 0.6–1.2 0.5–4533.7 Shen et al., 2018
*
the result may be overstated due to the use of a cream containing 2% BP; ND, not detectable; LOD, limit of detection
MATWIEJCZUK ET AL.
TABLE 7 The median (mean) concentrations of methylparaben (MP), ethylparaben (EP), propylparaben (PP), and butylparaben (BP) detected in the human urine

Urinary concentrations, ng/mL

Population (age, years) Country MP EP PP BP Median/mean References

Infants (0–2) Korea 7.03 23.6 0.719 <LOD Median Kim et al., 2018
Korea 79.6 2.4 3.4 <LOD Median Kim, Lee, et al., 2018
Belgium* 18.6 1.1 1.1 0.5 Median Kim, Lee, et al., 2018
Belgium* 34.8 2.3 2.1 0.8 Median Kim, Lee, et al., 2018
Children (3–12) Spain 150.0 8.1 21.5 1.2 Median Casas et al., 2011
SAFETY OF PARABENS IN COSMETICS

China* 3.66 0.62 1.49 0.03 Median Kim, Lee, et al., 2018
Denmark 3.0 0.4 0 – Median Frederiksen et al., 2013
Korea 10.8 (aged 32.6 (aged 0.511 (aged <LOD (aged Median Kim, Lee, et al., 2018
3–6 years) 3–6 years) 3–6 years) 3–6 years)
7.81 (aged 24.6 (aged <LOD (aged <LOD (aged Median
7–12 years) 7–12 years) 7–12 years) 7–12 years)
Korea 71.6 8.82 3.61 Median Kim, Lee, et al., 2018
Belgium* 18.6 1.1 1.1 0.33 Median Kim, Lee, et al., 2018
Belgium* 9.1 0.7 0.8 0.5 Median Kim, Lee, et al., 2018
USA* 51.8 0.15 0.99 – Median Kim, Lee, et al., 2018
Sweden 5.3 0.66 1.9 <LOD Median Larsson et al., 2014
USA 5.4 2.1 <LOD Mean Quirós-Alcalá et al., 2018
USA 44.1 5.1 Mean Quirós-Alcalá et al., 2019
Adolescents (13–18) Korea 5.43 32.9 <LOD <LOD Median Kim, Lee, et al., 2018
Korea 135 21.7 6.54 0.33 Median Kim, Lee, et al., 2018
Belgium* 18 1.1 4.2 <LOD Median Kim, Lee, et al., 2018
Adult general population USA 43.9 1.0 9.1 0.5 Median Ye, Bishop, Reidy, Needham, & Calafat, 2006
(≥19) USA 63.5 0 8.7 0 Median Calafat, Ye, Wong, Bishop, & Needham,
2010
Denmark 17.7 1.98 3.6 0.19 Median Frederiksen et al., 2011
USA 112 – 24.2 0.7 Median Smith et al., 2012
China* 19.5 0.09 4.3 0 Median Kim, Lee, et al., 2018
Korea 19.5 48.9 3.12 <LOD Median Kim, Lee, et al., 2018
Korea 254 53.4 24.0 1.97 Median Kim, Lee, et al., 2018
Germany 42.6 1.0 2.2 <LOD Median Moss et al., 2014
India 6.28 0.25 0.39 – Median Honda, Robinson, & Kannan, 2018
USA 5.8 – 2.4 – Mean Quirós-Alcalá et al., 2018
(Continues)
189
TABLE 7 (Continued)
190

Urinary concentrations, ng/mL

Population (age, years) Country MP EP PP BP Median/mean References

USA 56.5 < LOD 7.1 <LOD Mean Quirós-Alcalá et al., 2019

Spain 104 1.78 14.2 <LOD Mean Artacho-Cordon et al., 2017

Adult men (≥19) USA 27.4 – 3.45 0 Median Meeker et al., 2011
China 3.8 1.4 2.2 – Median Ma et al., 2013
Canada 26 10.4 3.1 0.4 Median Darbre & Harvey, 2014
USA 23.2 – 2.30 – Median Nassan et al., 2017
Korea 112 32.7 47.4 – Median Honda et al., 2018
Adult women (≥19) China 10.0 1.6 7.0 – Median Ma et al., 2013
Denmark 14.0 0.9 1.7 – Median Frederiksen et al., 2013
Canada 25.5 10.2 2.8 0.3 Median Darbre & Harvey, 2014
Sweden 40 2.4 18 <LOD Median Larsson et al., 2014
USA visit 1st/2nd visit 1st/2nd visit 1st/2nd visit 1st/2nd Mean Hines et al., 2015
143/125 5.3/1.0 28.6/41.3 1.4/2.9
Pregnant women (≥19) Spain 191.0 8.8 29.8 2.4 Median Casas et al., 2011
Puerto Rico 153 – 36.7 0.4 Median Meeker et al., 2013
Japan 75.8 7.5 20.2 0.6 Median Shirai, Suzuki, Yoshinaga, Shiraishi, &
Mizumoto, 2013
Korea 209.1 (aged 21.9 (aged 28.8 (aged 0 (aged Median Darbre & Harvey, 2014
22–29 years) 22–29 years) 22–29 years) 22–29 years)
169.9 (aged 65.6 (aged 6.3 (aged 0 (aged
30–39 years) 30–39 years) 30–39 years) 30–39 years)
Korea 39 38 6.6 <LOD Median Kim, Lee, et al., 2018
Japan* 134 7.53 20.2 0.59 Median Kim, Lee, et al., 2018
Canada 75.8 15.13 25.50 3.28 Mean Fisher et al., 2017
USA 94.86 – 1st/3rd trimester 1st/3rd trimester Mean Braun et al., 2014
(Boston) 1st/3rd trimester – 31.8/39.9 0.8/1.1
USA 146/164 1.44 75.3 0.39 Median Pycke et al., 2015
(Brooklyn) 279
*
concentrations of parabens are summarized by Kim et al., 2018b; LOD, limit of detection
MATWIEJCZUK ET AL.
SAFETY OF PARABENS IN COSMETICS
F I G U R E 1 Schematic representation of the differences between dermal (A) and oral (B) exposure to parabens.* R (alkyl group): methyl (-CH3)
in methylparaben, ethyl (-CH2CH3) in ethylparaben, propyl (-CH2CH2CH3) in propylparaben, butyl (-CH2CH2CH2CH3) in butylparaben. PHBA, p-
hydroxybenzoic acid [Colour figure can be viewed at wileyonlinelibrary.com]
quantity, frequency, type, composition, and combination of cosmetics
used and the concentration of parabens accumulated in the human
body, depending on age, gender, and ethnicity, it is impossible to
assess reliably the extent of exposure to parabens via cosmetics. To
our knowledge, only a few studies have been conducted under strict
control or on the basis of volunteer questionnaires related to the use
of cosmetics (Table 8). In one of them, Japanese volunteers (two men
and a women) only once applied emulsions (0.15 g each) containing
0.15, 0.25, and 0.5% (w/v) of MP on a forearm area of 42 cm2,
whereas another group (one man and 11 women) applied only a lotion
(six subjects) or the lotion and emulsion (six subjects) to both forearms
twice a day for 1 month (Ishiwatari et al., 2007). After an hour from a
single application of emulsion containing 0.15% MP, ~18% of the
applied dose of MP was detected in the SC and the amount increased
in a dose-dependent manner; however, after 12 h this concentration
decreased to 0.028% of the applied quantity of MP. Repeated applica-
tion of cosmetic products (twice a day for 1 month) was associated
with increased accumulation of the intact MP in the SC with time and
the number of cosmetics used during the experimental period, but
dropped to the baseline level after 2 days from stopping the use of
these products. In the group of volunteers applying the lotion and
emulsion containing MP on the skin, paraben concentration in the SC
was higher in comparison to the group applying only the lotion
(Ishiwatari et al., 2007).
191
Janjua et al. (2007) and Janjua et al. (2008) carried out a 2-week
single-blinded study on 26 healthy young Caucasian male volunteers
who everyday applied to the whole body skin a basic cream without
parabens (control week) and a cream containing 2% (w/w) of BP
(treatment week) in the same amount (2 mg/cm2). The amount of BP
excreted in the urine was 2.6 ± 0.1 mg/24 h in the treatment week
and this represented 0.32% of the applied dose of paraben (Janjua
et al., 2008). The concentration of BP in the serum was 135 ± 11 μg/L
after 3 h from the time of BP-containing cream application (Janjua
et al., 2008). These results showed that this paraben applied to the
skin with cosmetic preparations for everyday use is absorbed and
remains in its intact form; however, the concentration of BP used in
these studies exceeded the standards acceptable for use. Several
studies were based on volunteer questionnaires about the categories
and frequency of cosmetics use (Table 8). Although it is not known
whether all the cosmetics used contained parabens and in what quan-
tities, a relationship between the use of cosmetics, as reported by vol-
unteers, and the concentration of parabens detected in their tissues
and fluids was demonstrated. The percentage of parabens identified
and their concentrations determined in the tested samples were the
highest for MP and PP, but they varied depending on the cosmetics
used and the subjects (age, gender, pregnancy, and ethnicity).
According to Fisher et al. (2017), pregnant Canadian women (n = 31)
reported the use of 1653 personal care products in the past 24 h
 192

TABLE 8 Correlations between the use of cosmetics and the concentrations of intact parabens: methylparaben (MP), ethylparaben (EP), propylparaben (PP), and butylparaben (BP) in the body

Subject (n)/age, years/cosmetics (type, area,

amount, frequency of the use) Body tissue/fluid Paraben concentration and detection, % The main results and conclusions References
2
Japanese volunteers (two men and a woman)/ stratum corneum (SC) MP (pmol/cm ) MP was not hydrolyzed completely and Ishiwatari et al., 2007
emulsion/forearm/single application 1 h 6320 retained in the skin. Paraben retention in
SC increased after repeated application and
12 h 10 with the use of more cosmetics.
Japanese volunteers (1 man and 11 women)/aged 1 week ~ 15 Stopping use of cosmetics caused the
20–50/lotion (n = 6); lotion and emulsion (n = 6)/ 4 weeks ~ 95 decrease in the MP concentration.
forearm/repeated application/twice a day for
1 month 2 days after stopping ~2

Caucasian young male volunteers (n = 26)/cream serum BP ± SEM BP was detected in the serum within a few Janjua et al., 2007
containing 2% BP/whole body/2 mg/cm2/2 weeks 3 h 135 ± 11 μg/L hours after application of body cream on Janjua, Frederiksen,
the whole body. Skakkebæk, Wulf, &
urine total BP ± SEM Maximum BP excretion in urine of all subjects Andersson, 2008
2.6 ± 0.1 mg (24 h) occurred 8–12 h after application of the
cream.
Women who gave birth to child at the University milk ng/L ± SEM (%) The highest frequency of detection of Schlumpf et al., 2010
Women's Hospital Basel (n = 54)/median age MP 2.18 ± 2.02 (25.9) parabens in defatted human milk was for
32.3/questionnaire on cosmetic use MP and decreased with paraben increasing
EP 1.26 ± 0.23 (14.8) lipophilicity.
PP 1.42 ± 0.38 (11.1) The concentration of EP increased with the
BP 0 (58) age of the mother.

Participants in the Norwegian Women And Cancer plasma ng/mL (%) The concentrations of parabens in plasma, Sandanger et al., 2011
Study (n = 332)/aged 48–62/self-reported use of MP 9.4 (63) especially MP, were significantly associated
cosmetics with the use of cosmetic products.
EP 2.4 (22) Repeated use of skin care products increases
PP 4.0 (29) the skin exposure to the intact parabens.
BP –
Pregnant women from Puerto Rico (n = 105)/aged urine ng/L (%) Cosmetics and make-up products were Meeker et al., 2013
18–40/self-reported use of cosmetics in the 48 h MP 140 (100) positively associated with the
prior urine collection concentration of all parabens in urine. The
PP 30 (99.3) use of hand or body lotion was correlated
BP 1.0 (58) with 2–3-times higher paraben
concentrations.
Pregnant women (n = 170) from a fertility clinic in urine 1st trimester μg/L (%) There was a relationship between the number Braun et al., 2014
Boston/self-reported cosmetic use within the past MP 146 (100) of cosmetic products used and the urinary
24 h concentration of parabens.
PP 39.9 (99) The increase in the individual paraben
BP 1.1 (72) concentrations was depended on the type
of cosmetics used.
(Continues)
MATWIEJCZUK ET AL.
TABLE 8 (Continued)

Subject (n)/age, years/cosmetics (type, area,

amount, frequency of the use) Body tissue/fluid Paraben concentration and detection, % The main results and conclusions References
Swedish mother–child couples/(95 mothers aged 45 urine Mothers, Children The level of all parabens was higher in Larsson et al., 2014
and 97 children (47 boys and 50 girls) aged 6–11/ mg/L (%) mothers than the children's urine, but MP
diary on cosmetic use dominated in both groups.
MP 37.8 (100), 6.8 (86) The correlation between the use of cosmetics
PP 13.9 (88), 2.1 (62) and the concentration of parabens in urine
EP 3.1 (95), 0.7 (77) was specific to the type of cosmetic and
tested group.
SAFETY OF PARABENS IN COSMETICS

Lactating North Carolina women (n = 34, for milk milk Detection (%) MP was detected in 100% of all samples Hines et al., 2015
n = 9)/aged 18–38/questionnaire on cosmetic use urine milk urine serum (milk, urine, and serum), other parabens
were more often detectable in urine than in
serum MP 100 100 100 serum. In milk samples BP was undetectable.
EP 50 73 38 There were significant correlations between
PP 100 97 56 the type of cosmetic product and the
individual paraben concentration in the
BP 0 81 9 samples tested.
Adult–child pairs participating in the Study of Use of urine μg/L Concentration of MP, PP and BP in the urine Philippat, Bennett, Calafat,
Products and Exposure Related Behavior/adults Adults, Children was positively correlated with the total & Picciotto, 2015
(n = 90) aged 32–45, children (n = 83) aged 4–7/ number of different cosmetic products
questionnaire on cosmetics use MP 59.1–97, 26.5–36 used in the past 24 h in adults.
PP 7.5–16, 2.7–3.5
BP ≤ LOD–0.5, ≤ LOD
mg/L (%)
Caucasian (born in Canada) pregnant women urine MP 33.62 (100) The concentrations of parabens (mainly MP) Fisher et al., 2017
(n = 31)/median age 34/a diary of cosmetic use in urine and milk increased with the
24 h prior to and during the urine collection EP 2.72 (90) frequency of the use of cosmetic products.
PP 5.15 (96) It was higher in the urine in the morning than
at night.
BP 0.17 (72) The correlation between the type of cosmetic
use and the individual paraben
concentration was specific to the sample
Pregnant women (n = 56)/median age 34/cosmetics milk MP 0.22 (82) tested.
used on breast during collection of milk at EP < 0.1 (57)
2–3 months postpartum PP < 0.1 (66)
BP – (<1)
Caucasian male (n = 400)/aged 18–55/questionnaire urine mg/L (%) The use of body care products was associated Nassan et al., 2017
on cosmetic use within the past 6 and 24 h MP 28 (99) with higher urinary concentrations of
parabens, mainly of MP. The highest
PP 2.86 (90) increase in individual paraben level was
BP 0.26 (31) detected within 6 h of urine collection and
was associated with the type of cosmetics
used.
193

(Continues)
194 MATWIEJCZUK ET AL.

before and during the 24-h spot urine collection, had a significantly
higher geometric mean concentration of parabens in their urine than
the women who did not use cosmetics at this time. Women classified
Kim, Lee, et al., 2018 as ‘High Product Category Users’ (the maximum number of cosmetics
used during 48 h was 82) had 2–4-times higher concentrations of par-
References

abens than ‘Low Product Category Users’. Similarly, other authors

reported that the concentration of paraben in the skin, blood, milk,
and urine increased along with the quantity and frequency of using
cosmetic products, which was most clearly demonstrated for MP
In the Korean population the use of personal

(Ishiwatari et al., 2007; Meeker et al., 2011, Sandanger et al., 2011;

care products was related to the highest

regardless of the age and gender of the

among all parabens EP concentrations

Braun et al., 2014; Larrson et al., 2014; Fisher et al., 2017; Nassan
et al., 2017).
The main results and conclusions

In addition, the association between the type of cosmetic and the

increase in the concentrations of particular parabens in the body in
individual studies has been demonstrated. The use in the past 24 h of
shampoo and hair conditioner by pregnant Caucasian women born in
cosmetic users.

Canada was connected with a higher (72–84%) concentration of BP in

the urine (Fisher et al., 2017). In a study by Philippat et al. (2015)
among adult–child pairs from North California, the use of hair care
products in the past 24 h was also associated with higher urinary con-
centration of BP, but only in children. In adults the use of hair care
products (including hair conditioner, hair gel, hair spray, moose, hair
Paraben concentration and detection, %

bleach, relaxer, and perm) correlated with higher concentration of MP

in the urine (Philippat et al., 2015). A similar correlation between hair
styling products use and MP concentration, but in the serum, was
MP 9.10 (11.1), 11.6 (19.2)
μg/L night (morning) urine

EP 99.1 (19.4), 97.4 (19.2)

reported among lactating North Carolina women (Hines et al., 2015).

PP ≤LOD (0.8), 0.9 (1.8)

In a Korean population, the use of bath products (shampoo, hair con-

BP 20.4 (−), 34.0 (−)

ditioner, body wash) was related to a higher EP concentration in the

Males, Females

urine regardless of the age of the users (Kim, Lee, et al., 2018), which
is consistent with the highest maximal concentration of this com-
pound (0.6%) found in hair conditioner (Table 3). In Caucasian males,
the use of liquid soap and body wash was associated with an increase
in BP concentration in the urine (Nassan et al., 2017). In the users of
bar soap lower urinary concentrations of MP, PP, and BP were found
Body tissue/fluid

in both adults and children (Philippat et al., 2015). There was a strong
association between lipstick use and the concentrations of MP and PP
in the serum of Brazilian women (Tahan, Santos, Albuquerque, & Mar-
urine

tins, 2016) and between the use of make-up products and PP concen-
tration in the breast milk of pregnant Canadian women (Fisher et al.,
2017). In Swedish mothers and children (aged 6–11 years), the use of
(n = 170) aged 2–18, adults (n = 91) aged ≥19/

numerous make-up products was associated with higher concentra-

Korean volunteers, mother–child pairs/children
Subject (n)/age, years/cosmetics (type, area,

tions of MP and PP in the urine (Larrson et al., 2014). The results are
questionnaire on cosmetic use within the

consistent with the reported highest maximal concentration of these

parabens (1% of MP and 0.62% of PP) found in the lipstick and 0.7%,
0.6%, and 0.5% of MP found in the liquid foundation, eyeliner and eye
amount, frequency of the use)

make-up, respectively (Table 3). In women from North California, the

(Continued)

use of colored cosmetics including foundation, blush, eye shadow, eye

previous 1–2 months

LOD, limit of detection

liner, and mascara was correlated with increased BP concentration in

the urine, whereas the use of facial cleaning products was associated
with higher urinary PP concentration (Philippat et al., 2015). Based on
TABLE 8

the analysis of data from a questionnaire, Hines et al. (2015) found

significant correlations between the use of nail polish and MP concen-
tration in the urine and PP concentration in the urine and serum. In
SAFETY OF PARABENS IN COSMETICS
adults reporting the use of deodorants and mouthwashes, BP concen-
tration in the urine was increased (Philippat et al., 2015), but in the
users of the cologne the urinary concentration of MP was higher
(Braun et al., 2014). The use of toothpaste among Korean adults was
associated with higher concentrations of MP and PP in the night-time
urine (Kim, Lee, et al., 2018). The maximum concentrations of MP, EP,
and BP (0.54–0.68%) in body lotions and face creams exceeded the
permissible concentrations (Table 3). In American pregnant women
the use of lotion was associated with higher concentrations of BP and
PP in the urine (Braun et al., 2014; Meeker et al., 2013). In Swedish
mothers and children (aged 6–11 years), the use of lotion was corre-
lated with an increased MP concentration (Larrson et al., 2014).
In many published studies in which any data on the use of cos-
metics have been collected from the participants, the authors also
suggest that the intact parabens detected in the human body come
from the exposure of the skin to the cosmetic products. Among the
studies performed in the USA (Ye et al., 2006), Denmark (Casas et al.,
2011), Spain (Frederiksen et al., 2011), Japan (Shirai et al., 2013) or
China (Ma et al., 2013), the highest concentrations of MP were found
in pregnant women from Spain (191 ng/mL) and Japan (62.6 ng/mL).
A significantly lower paraben concentration was found in the urine
samples of young adult Chinese (Ma et al., 2013). Despite the lack of
data on cosmetics use (type, amount, and frequency) among the par-
ticipants, the authors found a relationship between the concentration
of intact paraben in the urine and the rate of the use of cosmetics in
these countries. In Denmark, Spain, and Japan, the rate of the use of
cosmetics per capita was 7.1-times higher than in China and 1.4-times
higher than in the USA (Ma et al., 2013). Significantly higher concen-
trations of MP and PP in the urine have been demonstrated in females
compared to males in both adults and adolescents (Calafat et al.,
2010; Heffernan et al., 2015; Honda et al., 2018; Nassan et al., 2017;
Smith et al., 2012). Smith et al. (2012) showed that the concentrations
of MP and PP were 4.6- and 7.8-times, respectively, higher in women
than in men. These results may be related to markedly more frequent
use of a greater number of personal care and make-up products by
females than by males (Biesterbos et al., 2013; Manová et al., 2013).
7 | U N F A V O R A B LE H E A L T H E FF E C T S O F
E X P O S U R E T O P A R A B E N S V I A C O S M ET I C S
Many results of in vitro and in vivo studies (summarized by Harvey &
Everett, 2006; Darbre & Harvey, 2008, 2014; Boberg et al., 2010;
ska, 2018) indicate that
Nowak, Ratajczak-Wrona, Górska, & Jabłon
parabens possess estrogenic activity. The estrogen activity of para-
bens increases with increasing alkyl chain length, branching in the
alkyl chain, and the presence of an aromatic ring in the chain
(Darbre & Harvey, 2008). Exposure of estrogen-dependent human
breast cancer cells (MCF-7) to parabens (MP, EP, PP, and BP) at con-
centrations of ≥10−6 M resulted in increased expression of estrogen-
regulated genes and cell proliferation to a similar extent as 17β-
estradiol (E2) at a concentration of 10−10 M, and these effects were
mediated through estrogen receptors (ERs) (Byford et al., 2002). The
195
study of Okubo et al. (2001) showed that parabens (MP, EP, PP, BP,
IPP, and IBP) had similar relative binding affinity to both of the human
ERs, ERα and ERβ. MP and EP exerted weaker effects on cell prolifera-
tion (maximum at a concentration of ~10−4 M) than PP and BP whose
maximum effect was at a concentration of ~10−5 M, which can be
related to greater binding affinity to ERs of parabens with longer side-
chains (Gomez et al., 2005; Okubo, Yokoyama, Kano, & Kano, 2001).
In addition to the ability to bind to ERα and ERβ, and to change
the expression of estrogen-regulated genes, parabens have been
reported to have an inhibitory effect on the activity of estrogen sul-
fotransferase in human skin cytosolic fractions and normal human epi-
dermal keratinocytes (Prusakiewicz, Harville, Zhang, Ackermann, &
Voorman, 2007). Similarly to ER affinity, the potency to inhibition of
estrogen sulfation increased along with the paraben ester chain length
and for BP the half maximal inhibitory concentration (IC50) in the skin
cytosol was 37 ± 5 μM. Recently, it was reported that parabens inter-
fered with estrogen metabolism in human embryonic kidney (HEK-
293) cells by inhibition of the activity of 17β-hydroxysteroid dehydro-
genase types 1 and 2, which regulate the local balance between
potent and weakly active estrogen levels (Engeli et al., 2017).
Studies performed in vivo on immature and adult ovariectomized
CD1 mice and immature female Wistar rats showed higher
estrogenicity of parabens than reported in vitro (Lemini et al., 2003).
In animals subcutaneously treated for 3 days with MP, EP, PP, and BP
in doses ranging from 3.62 to 1086 μmol/kg bw caused an increase in
uterine weight. The median effective dose (ED50) of parabens to
increase uterine weight in CD1 mice ranged from 18 to 74 mg/kg, and
that of E2 was 7 μg/kg; in Wistar rats, the ED50 ranged from 33 to
338 mg/kg. The estrogenicity of MP and EP at doses close to the
acceptable daily intake (0–10 mg/kg bw for the sum of these com-
pounds) was also reported by Sun et al. (2016). After 3 days of
intragastric administration with 20 mg/kg bw/day of MP and 4 and
20 mg/kg bw/day of EP, the uterine weight in immature female
Sprague-Dawley rats significantly increased. Although these results
cannot be directly extrapolated to humans exposed to parabens via
their application with cosmetics to the skin, the concentration of MP
(17635 ± 5592 ng/mL) in the urine of rats treated with the same dose
of MP (20 mg/kg bw/day), in which in vivo estrogenic effects were
observed (Sun et al., 2016), was similar to the highest urinary level of
MP reported in woman (15 100 ng/mL) and in men (23 200 ng/mL)
(Smith et al., 2012). The authors using molecular docking simulation,
showed the interaction between parabens and the pocket that binds
to the human α-ER (hERα) agonist. They suggested that estrogenic
activity of MP and EP demonstrated in vivo at doses close to the
acceptable daily intake in humans may be associated with estrogen-
related diseases (Smith et al., 2012).
There are many reports suggesting a relationship between the
presence of parabens in the breast tissue in their intact form and the
increased risk of the breast tumor development (Darbre, 2001, 2006;
Harvey, 3003; Darbre et al., 2004, Harvey & Everett, 2006, 2012;
Darbre & Harvey, 2008, 2014). Because of the area (the upper outer
quadrant of the breast) of tumor development and a lot of evidence
that intact parabens accumulated in the body come from cosmetics, it
196
has been speculated that the presence of parabens in the breast
tumor is associated with the application of antiperspirant/deodorant
products under the arms and on the adjacent area of the breast. The
concentrations of parabens detected in breast tumor tissues differ sig-
nificantly depending on the ethnicity of women and the method used
for measurement of these compounds. The concentration of parabens
determined in Indian and Chinese women dramatically exceeded the
concentration determined in English women (Table 6). For example,
the maximum concentration of BP in English women (n = 20) was
11.5 ng/g (Darbre et al., 2004), whereas in Chinese (n = 102) and
Indian (n = 9) women the maximum BP concentrations were 4 533.7
and 26 469 ng/g, respectively (Shanmugan et al., 2010; Shen et al.,
2018). The authors included in their study one healthy breast tissue
sample (Shanmugan et al., 2010) in which they detected only MP at a
relatively low concentration (26.5 ng/g) compared to the concentra-
tions found in tumor tissues (range 41.0–1719 ng/g). Barr et al. (2012)
measured the concentration of parabens in unaffected breast tissues
adjacent to tumor (n = 160) and found a wide range of concentrations
especially for MP (0.2–5102.9 ng/g) and PP (1.2–2052.7 ng/g), while
the concentration of BP was the lowest (0.2–95.4 ng/g). As estrogenic
activity of parabens is known to increase with an increase in the
length of the linear alkyl chain from MP to BP, the presence of BP at
the highest concentration in cancerous tissues (Shen et al., 2018;
Shanmugam et al., 2010) and its lack in the healthy breast tissue
(Shanmugan et al., 2010), as well as the lowest amount (in comparison
to other parabens) in unaffected breast tissues adjacent to tumor
(Barr et al., 2012) (Table 6) suggest it may be involved in tumor
development.
Based on the comparison analysis of the concentrations of partic-
ular paraben esters measured in unaffected breast tissues and in
breast cancer tissues, converted to estrogen equivalents (Table 9),
according to the previously published calculations (Darbre & Harvey,
2014; Harvey & Everett, 2006), it may be concluded that the highest
concentrations of BP (802.1 pg/g tissue) detected in breast tumor tis-
sue exceeds 14.5-times the endogenous estrogen level of 55.3 pg/g
reported by Clarke et al. (2001) in human breast tissue. According to
calculations performed by Harvey and Everett (2006) and Darbre and
Harvey (2014) significant estrogenic potential of parabens (>20% of
the endogenous estrogen level) can be achieved from a single applica-
tion of body care lotion to the breast/chest area. In the present paper,
these calculations have been expanded to include basic hygiene prod-
ucts used on the breast and underarms such as shower gel and deo
non-spray, as well as sunscreen lotion/creams with addition to body
lotions (Table 10). The evaluated estrogenic potential of MP, EP, PP,
and BP (Table 10) was comparable or even markedly higher of that
reported by Darbre and Harvey (2014). It is important to underline
that estrogenic potential of parabens may be reached even if it is cal-
culated based on the use of only chosen cosmetics applied on the
chest and around the armpits (Table 10). It should be added that the
calculations presented in the present review were carried out
according to the recommendations of the SCCS (2018) for estimation
of the daily exposure to cosmetic products and the minimum number
of cosmetics used by average women populations was taken into
MATWIEJCZUK ET AL.
T A B L E 9 Calculated estrogenic potential of parabens:
methylparaben (MP), ethylparaben (EP), propylparaben (PP), and
butylparaben (BP) detected in the breast tissue
Range of concentrations*
Estrogen equivalents of
Breast tissue Paraben ng/g tissue measured paraben, pg/g
Normal MP 0.2–5102.9 2 × 10−4–5.1
EP 0.3–499.7 1.8 × 10−3–3.0
PP 1.2–2052.7 1.2 × 10−2–20.5
BP 0.2–95.4 6.1 × 10−3–2.9
Tumor MP 0.8–1719 8 × 10−4–1.7
EP 0.2–10 608 1.2 × 10−3–63.5
PP 0.2–4490 2 × 10−3–44.9
BP 0.5–26 496 0.015–802.1
Estrogenic potency of MP, EP, PP, and BP is lower than that of estradiol
by 1 000 000, 167 000, 100 000, and 33 000, respectively (Darbre &
Harvey, 2014; Harvey & Everett, 2006). Calculated values are estrogen
equivalents comparing the concentrations measured in the human breast
tissue. Estrogenous concentration of estradiol in normal breast tissue is
55.3 pg/g, whereas its concentration in human breast tumor tissue is
348 pg/g (Clarke, Leonessa, Welch, & Skaar, 2001).
*
the range of concentration was estimated on the basis of results
presented in Table 6
account. However, considering the more frequent use of the body
care lotion together with many other cosmetic products such as body
sprays, breast-firming creams, breast-enhancing creams, shaving cre-
ams, aftershave lotions, depilators, cellulite reducing creams all con-
taining parabens, the estrogenic potential could be much higher.
According to a study by Fisher et al. (2017) pregnant Canadian women
recorded the use of 1653 cosmetic products (the minimum number
was three and the maximum was 82 per person) during 48 h. Thus,
based on the above evaluations of the estrogenic potential of para-
bens and taking into account the possible real daily cosmetics applica-
tion, it can be concluded that the use of cosmetic preparations by
women may be a source of exposure to parabens in amounts
possessing estrogenic action. Despite many published controversial
articles on the lack of a direct relationship between the use of cos-
metics containing parabens on the breast and the increased risk of
breast cancer, the growing amount of data on the presence of para-
bens in breast tissue in the recent years (determined with the use of
much more sensitive methods) should be recognized as alarming
regarding the safety of the common use of these compounds as pre-
servatives in cosmetics. The high concentrations of parabens present
in the blood of pregnant women (Shekhar et al., 2017), as well as in
umbilical cord blood (Geer et al., 2017; Pycke et al., 2015), placenta
(Jiménez-Díaz et al., 2011; Vela-Soria et al., 2017), or amniotic fluid
(Philippat et al., 2013; Shekhar et al., 2017) (the highest concentration
of 2130 ng/mL for PP was noted in the amniotic fluid of American
women) (Table 6) may be associated with the unconscious exposure
of fetuses in the womb of mothers to the adverse action of parabens.
It should be considered that estrogenic potential of parabens present
at the same concentration may be about 30-times higher in children
T A B L E 1 0 Calculated estrogenic potential for human dermal absorption of parabens: methylparaben (MP), ethylparaben (EP), propylparaben (PP), and butylparaben (BP) in cosmetics most often
applied to the breasts and around them5

Estrogen equivalents absorber

Estrogen equivalents absorbed per

Range of paraben concentration Amount of paraben daily Estrogen equivalents of day assuming on area 500 cm3,
SAFETY OF PARABENS IN COSMETICS

Paraben Type of cosmetic in cosmetics. %6 applied to the breast, mg Dermal absorption, mg absorbed paraben, ng pg/g breast tissue
MP body lotion 0.000035–0.63 0.0399–718.2 0.01995–359.1 0.01995–359.1 0.0399–718.2
deo non-spray 0.000042–0.3 0.042–300 0.021–150 0.021–150 0.042–300
sunscreen 0.000036–0.26 0.036–260 0.018–130 0.018–130 0.036–260
shower gel 0.00005–0.4 0.00036–2.86 0.00018–1.43 0.00018–1.43 0.00036–2.86
EP body lotion 0.000018–0.54 0.02052–615.6 0.01026–307.8 0.0614–1843.1 0.1228–3686.2
deo non-spray 0.002–0.1 2–100 1–50 5.988–299.4 11.976–598.8
sunscreen 0.0213–0.54 21.3–540 10.65–270 63,77–1616.8 127.54–3233.6
shower gel 0.00001–0.015 0.0000715–0.10725 0.000036–0.0536 0.00021–0.321 0.00042–0.642
PP body lotion 0.000014–0.4 0.01596–456 0.008–228 0.08–2280 0.16–4560
deo non-spray 0.000036–0.4 0.036–400 0.018–200 0.18–2000 0.36–4000
sunscreen 0.00005–0.3 0.05–300 0.025–150 0.25–1500 0.5–3000
shower gel 0.0002–0.097 0.00143–0.69355 0.0007–0.347 0.007–3.47 0.014–6.94
BP body lotion 0.00001–0.24 0.0114–273.6 0.0057–136.8 0.1727–4145 0.3454–8290
deo non-spray 0.00004–0.09 0.04–90 0.02–45 0.6061–1363.64 1.212–2727.3
sunscreen 0.00001–0.54 0.01–540 0.005–270 0.1515–8181.82 0.303–16363.6
shower gel 0.0022–0.0286 0.01573–0.2045 0.0079–0.1023 0.2394–3.1 0.479–6.2
5
To evaluate the amount of particular parabens applied daily to the skin it has been recognized according to the RIVM (2006; available at: https://www.rivm.nl/bibliotheek/rapporten/320104001.pdf) that 1 mg
of body lotion, deo non-spray, sunscreen, and shower gel is applied to the 1 cm2 of the skin. Taking into account that body lotion, deo non-spray, and sunscreen are leave-on-the-skin products (retention
factor = 1), whereas shower gel is a rinse-off-the skin product (retention factor = 0.01), and the daily frequency of their application is 2.28, 2, 2, and 1.43 (SCCS, 2018), respectively, it has been estimated that
the daily application of these cosmetics on the breast area (500 cm2; Darbre & Harvey, 2014) reaches 1140, 1000, 1000, and 715 mg, respectively. Estrogenic potency of MP, EP, PP, and BP is lower than that
of estradiol by 1 000 000-, 167 000-, 100 000-, and 33 000-times, respectively (Darbre & Harvey, 2014; Harvey & Everett, 2006). Calculated values are estrogen equivalents comparing the concentrations
measured in human breast tissue. Estrogenous concentration of estradiol in normal breast tissue is 55.3 pg/g, whereas its concentration in human breast tumor tissue is 348 pg/g (Clarke et al., 2001).
6
The ranges of concentrations of parabens in body lotion, deo non-spray, sunscreen and shower gel were taken from the published literature (CIR, 2008; Melo & Queiroz, 2010; Haunschmidt, Buchberger,
Christian, Klampfl, & Hertsens, 2011; Sanchez-Prado et al., 2011; Baranowska et al., 2014; Youngvises et al., 2013; Wang & Zhou, 2013; Alvarez-Rivera et al., 2014; Guo et al., 2014; Norseyrihan et al., 2018)
197
198
than in adults when the concentration of endogenous estradiol in the
blood of women (180 pM) exceeds 32-times the child's concentration
(5 pM) (Boberg et al., 2010). Except from fetal exposure to parabens
through the transport of these compounds via the umbilical cord, the
risk of parabens reaching infants via breast milk can also be high. The
concentrations of parabens in the milk of lactating women are col-
lected in Table 6.
In addition to ERs, parabens can act as antagonists of androgen
receptors (Chen et al., 2007; Satoh, Nonaka, Ohyama, & Nagai, 2005).
MP, PP, and BP at 10 μM, inhibited testosterone-induced transcrip-
tional activity in HEK-293 cells by 40%, 33%, and 19%, respectively
(Chen et al., 2007). Anti-androgenic properties of parabens may be
the cause of male reproductive disorders observed under the influ-
ence of these compounds in animal models (Oishi, 2001, 2002)
because androgens play an important role in the development of the
male reproductive system, and in spermatogenesis and maturation of
spermatozoa. In rats exposed to PP in a dose comparable to the
upper-limit of daily paraben intake (10 mg/kg bw/day) acceptable in
the EU and Japan, the serum testosterone concentration and daily
sperm production were decreased (Oishi, 2002). The changes in the
concentration of testosterone in the serum and in daily sperm produc-
tion, as well as the decrease in the absolute and relative weights of
epididymides were detected in rats exposed to 0.1% BP (Oishi, 2001).
Oral exposure of adult male Sprague-Dawley rats to BP in the doses
of 0, 10, 100, and 1000 mg/kg/day for 28 days induced an epigenetic
effect on spermatogenic germ cells in the testis (Park, Nah, Lee, Oh, &
Gye, 2012). The subcutaneous exposure of young male rats to BP had
a toxic impact on the reproductive system, including an increase in
the prostate relative weight and changes in sperm morphology, as well
as in the histology of the sexual organs (Garcia et al., 2017). These
alterations could affect the capacity for fertilization of the animals.
The relationship between BP concentration in the urine and damage
to sperm DNA was also demonstrated in American male partners
(n = 137) attending an infertility clinic (Meeker et al., 2011). Similarly,
among 501 male partners of couples planning to become pregnant
the urinary concentrations of MP, EP, and BP were associated with
diminished sperm count and several sperm motility parameters (Smarr
et al., 2018). Furthermore, the positive association between the uri-
nary level of BP and XY18 disomy and between PP and chromosome
13 disomy was found in 156 Polish men who attended an infertility
clinic for diagnostic purposes (Jurewicz et al., 2017). The
aneuploidogenic properties of BP and its ability to induce polyploidy
were shown in CHO-K1 Chinese hamster ovary cells (Tayama,
Nakagawa, & Tayama, 2008).
Recently, research involving zebrafish, which is genetically similar
to humans, are becoming very popular. The comprehensive study con-
ducted by Bereketoglu and Pradhan (2019) showed many significant
adverse outcomes of MP and PP on early developmental stages of
zebrafish. Both MP at a concentration of ≥100 μM and PP at ≥10 μM
were toxic to the embryos in a concentration-dose manner and led to
developmental abnormalities such as spinal defects, pericardial edema,
and pigmentation defects, but PP showed higher toxicity. Further-
more, 1 μM MP and 10 μM PP affected the expression of genes
MATWIEJCZUK ET AL.
encoding proteins involved in the stress response, cell cycle, DNA
damage, inflammation, and fatty acid metabolism. Therefore, parabens
can induce oxidative stress, DNA damage, cell apoptosis, and disrup-
tions of lipid and endocrine metabolisms (Bereketoglu & Pradhan,
2019).
Parabens with estrogenic and anti-androgenic properties (Boberg
et al., 2010; Chen et al., 2007; Darbre & Harvey, 2008; Oishi, 2001,
2002) influencing the level of thyroid hormones (Berger et al., 2018;
Koeppe, Ferguson, Colacino, & Meeker, 2013) can also promote
adipogenesis. Hu et al. (2013) reported the adipogenic effect of para-
bens (BP and BzP) on murine 3 T3-L1 and human adipose-derived
multipotent stromal cells (hADSC) mediated through glucocorticoid
receptor and/or peroxisome proliferator-activated receptor gamma
(PPARγ). Parabens were also shown to modulate the mRNA expres-
sion of adipokines, adiponectin, and leptin and to promote adipose
conversion of human adipose-derived multipotent stromal cells
(Hu et al., 2013). The same authors reported that in an in vitro mouse
experimental model, MP and BP also induced changes in gene expres-
sion related to adipocyte differentiation and lipogenesis in adipose tis-
sue (Hu et al., 2016). Moreover, exposure to both parabens
significantly decreased procollagen type 1 N-terminal propeptide
(P1NP) level in the serum but had no effect on C-terminal telopeptide
of type I collagen (CTX-I) level, which suggests their negative influ-
ence on bone formation, but not on bone resorption. Kolatorova et al.
(2018) found significantly higher concentrations of parabens in the
plasma of healthy women with a high body mass index (BMI) (median
MP 353 pg/mL and PP 84 pg/mL) as compared to those with lower
BMI (median MP 255 pg/mL and PP 59 pg/mL). Positive associations
were found between the plasma concentration of MP and adipsin
level, and negative associations between MP and glucagon, leptin, and
plasminogen activator inhibitor 1 (PAI-1) levels. The above results sug-
gest that parabens may play a role in the development of obesity,
which is a risk factor for GDM. Parabens may influence glucose
metabolism through estrogen-dependent signaling and alter the func-
tion of pancreatic β cells. Exposure to these compounds during preg-
nancy can increase insulin resistance and subsequently the risk of
GDM. According to Li et al. (2019), higher urinary levels of PP and
summed estrogenic activity of parabens (MP, EP, PP, BP, and BzP)
were significantly associated with an increasing prevalence of GDM in
overweight/obese pregnant women.
In addition, in some cases exposure to parabens via cosmetics
may cause allergic reactions (Cashman & Warshaw, 2005; Lee-Sarwar
et al., 2018;Savage et al., 2012 ; Spanier et al., 2014). In the partici-
pants (aged 6–18 years) of the National Health and Nutrition Exami-
nation Survey (NHANES), performed in the USA, the urinary
concentrations of MP, PP, and BP were positively associated with aer-
oallergen sensitization (Savage et al., 2012; Spanier et al., 2014). Fur-
thermore, there was a negative correlation between the
concentration of MP and nonatopic asthma or wheeze and lack of
association between PP concentration and atopic asthma or wheeze
(Savage et al., 2012). There was no consistent relationship in a study
of mother–child pairs (n = 467) between the concentration of paraben
in the maternal plasma or in the urine of children at age 3 and 4 years
SAFETY OF PARABENS IN COSMETICS
and pediatric asthma, recurrent wheezing or allergic sensitization
(Lee-Sarwar et al., 2018). In a more recently published review article,
the authors recognized parabens as one of the least allergenic preser-
vatives (Fransway et al., 2019).
8 | E F F EC T O F P A RA B E N S O N CU L T U R ED
SKIN CELLS: KERATINOCYTES AND
FIBROBLASTS
To date, there have been few reports on the effect of MP on
human skin cells cultures and the main components of the skin
(Table 11). Most studies conducted on skin keratinocytes and fibro-
blasts demonstrated toxic effects of MP used in the concentrations
range of 0.001% to 0.3%, on cell viability and proliferation (Cha
et al., 2015; Dubey et al., 2017; Handa et al., 2006; Ishiwatari
et al., 2007; Majewska et al., 2017; Smith & Alexander, 2005). An
increase in the number of apoptotic and necrotic cells was noted
with exposure to MP (Dubey et al., 2017; Ishiwatari et al., 2007;
Majewska et al., 2017). In turn, Carvalho et al. (2012) and Spindola
et al. (2018) reported a slight toxic effect of MP on fibroblasts at a
concentration <1%.
Ishiwatari et al. (2007) treated neonatal human epidermal
keratinocytes with 0.001% and 0.003% MP and reported, in addition
to the decreased cell viability and proliferation, reduced expression of
hyaluronan 1 and 2 synthases and type IV collagen at the mRNA level.
It can therefore be assumed that synthesis of HA, the key molecule
responsible for maintaining skin moisture (Papakonstantinou et al.,
2012) and collagen, which is the most abundant structural protein
responsible for the skin's tensile strength and mechanical properties
(Frantz et al., 2010; Gelse et al., 2003; Quan & Fisher, 2015; Varani
et al., 2006), can be also reduced. In the studies on the influence of
MP on the human skin fibroblasts, conducted by our research team,
we also found a significant decrease in the expression of the main skin
collagen types I, III and VI at both the gene and protein levels
(Majewska et al., 2017). The inhibition of collagen biosynthesis dem-
onstrated in our study could be caused, at least partially, by the MP-
induced inhibition (in a dose-dependent manner) of the activity of
prolidase, which catalyzes the last step in collagen degradation pro-
cess and recovers proline to collagen re-synthesis (Surazynski, Miltyk,
Palka, & Phang, 2008). Furthermore, activation of pro-matrix
metalloproteinase (MMP)-2 under the influence of MP suggests
increased collagen degradation (Majewska et al., 2017). Cha et al.
(2015) reported a relationship between decreased collagen type I
expression and the increased expression of MMP-1 in MP-treated
human fibroblasts (at a concentration of 0.01–0.04%) and in mouse
skin after topical application of MP (400 mg/mL). Although MMP-1
possesses specific activity against collagen type I, it was reported that
also MMP-2, in addition to its capacity to degrade gelatin, is involved
in degradation of native type I collagen (Aimes & Quigley, 1995).
Therefore, increased activity of MMP-2, under the influence of MP,
may be associated with decreased collagen concentration in skin cells.
The concentrations used in our study were higher (0.01%, 0.03%, and
199
0.05%) as compared to the ones used by other authors (Dubey et al.,
2017; Handa et al., 2006; Ishiwatari et al., 2007). In our more recent
study, lower MP concentrations of parabens (MP in combination with
PP to reflect more real exposure of the skin to these compounds)
were used and we also found a significant impact on cell survival and
proliferation, as well as on collagen biosynthesis in human skin fibro-
blasts (results in preparation for publication).
The topical application of MP (400 mg/mL) to mouse dorsal skin
for 8 weeks (3 times/week) resulted in a cell senescence phenotype
(Cha et al., 2015). The skin in MP-treated mice was dry and pale, with
increased fine wrinkles and roughness compared with the control
mice, which could be associated with a decrease in collagen type I.
Handa et al. (2006) proved that MP (0.003–0.3%) may intensify
the harmful influence of UVB radiation on human skin keratinocytes,
which leads to increased production of free radicals, synthesis of nitric
oxide, lipid peroxidation, and oxidative stress (Fisher et al., 2002;
Matsumura & Ananthaswamy, 2004). Furthemore, MP can also con-
tribute to pigmentation changes in the skin, which in turn can even
lead to skin cancer (Alexiades-Armenakas, 2008). Similar results were
observed in keratinocyte cultures treated with MP (concentration in
the range of 5 × 10−4–0.01%) exposed to UVB (0.6 mW/cm2) (Dubey
et al., 2017) (Table 11).
The above results suggest that long-term skin exposure to para-
bens alone, and especially together with UVB, to which the general
population is exposed during the lifetime, may lead to the develop-
ment of different unfavorable changes in the skin.
9 | STRATEGIES TO REDUCE ADVERSE
H E A L T H E F F E C T S D U E T O S K I N E X P OS U R E
TO COSMETICS CONTAINING PARABENS
Today, not only researchers but also a rising number of consumers
question the safety of parabens in cosmetics. Much attention has
been attracted to cosmetics that do not contain parabens and are
marked as paraben free. Harley et al. (2016) reported a reduction in
the urinary concentrations of MP (by 43.9%) and PP (by 45.4%) in
100 adolescent girls who switched cosmetics containing parabens to
paraben-free products for just 3 days. However, despite being
unmarked, cosmetic products may contain parabens (Dodson et al.,
2012; Makkliang et al., 2018) or other chemical preservatives, such as
isothiazolinones, formaldehyde or halogen organic compounds, with
undesirable effects on the skin (Halla et al., 2018; Hectorne &
Franshway, 2006; Jong et al., 2007). These compounds can more
often cause allergic reactions, and some of them, like formaldehyde,
can be dangerous to health because of its causal relationship with
cancer (Sasseville, 2004). In order to minimize the use of harmful syn-
thetic substances, natural preservatives of plant origin have been the
subject of intensive scientific research and attract the attention of the
cosmetics industry.
Plant extracts and essential oils are added to many cosmetics and
personal hygiene products aimed at purifying, nutrition, beautifying,
and perfuming of the human body mainly because of their well-known
200 MATWIEJCZUK ET AL.

TABLE 11 The impact of methylparaben (MP) on cultured skin cells

Skin cells MP concentration, % Main results References

Neonatal keratinocytes (NHEKs) 0.001 # cell proliferation Ishiwatari et al.,
0.003 " number of apoptotic and necrotic cells, cell 2007
aging process
# expression of hyaluronian synthase (−1 and
−2) and type IV collagen mRNA
" expression of HSP27 and involucrin mRNA
Keratinocytes (HaCaT) exposed to UVB 0.003 # cell viability Handa et al., 2006
0.03 " oxidative stress, NO production, lipid
peroxidation, activity of transcription
0.3 factors NF-κB and AP-1
Keratinocytes (HaCaT) 5 × 10−4–0.01 MP # cell viability Dubey et al., 2017
irradiated with UVB " number of apoptotic cells: "expression of
(0.6 mW/cm2) pro-apoptotic (Bax, Apaf-1,
cytochrome C, caspase-3, caspase-12) and
#expression of anti-apoptotic Bcl-2
" intracellular ROS generation, disruption of
mitochondrial membrane integrity, lipid
peroxidation and DNA damage
Fibroblasts (CRL1747) 0.01 # cell viability and proliferation Majewska et al.,
0.03 " expression of pro-apoptotic caspase-3 and 2017
Bax
0.05 # expression of anti-apoptotic Bcl-2
# collagen biosynthesis, expression of
collagen type I, III and VI mRNA
# prolidase activity
" MMP-2 activity
Fibroblasts (CCD1072Sk) 0.01 no significant cytotoxic effects on cells Spindola et al., 2018
0.1
1.0
Fibroblasts (HDFs) 0.001 # cell viability (>0.01% MP) Carvalho et al., 2012
0.01 " number of apoptotic and necrotic cells
(1.0% MP)
0.1 " level of genotoxicity (1.0% MP)
1.0
Fibroblasts (nHDFs) 0.01 # the growth capability Cha et al., 2015
0.02 " expression of cellular senescence markers:
p53, p21WAF1, and p16INK4A
0.04 " intracellular ROS levels
# antioxidant enzymes, GPx1 (due to the
reduction of c-Jun expression) and SOD
mRNA
# ARE activity (anti-oxidant response
element)
# COL1A1 expression
" MMP1 expression
Embryonic mouse fibroblasts (Balb/C 3 T3 0.2 # cell viability Smith & Alexander,
clone A31) 0.4 2005
0.6

AP-1, activating protein 1; Apaf-1, apoptotic protease-activating factor-1; ARE, anti-oxidant response element; COL1A1, collagen type I α1 chain; GPx1,
glutathione peroxidase; (n)HDF, (neonatal) human dermal fibroblasts; HSP27, Heat shock protein 27; NHEKs, normal human epidermal keratinocytes; NF-κ
B, nuclear factor κ-light-chain-enhancer of activated B cells; NO, nitric oxide; p53, tumor protein 53; ROS, reactive oxygen species; SOD, superoxide
dismutase

properties such as: antioxidant, anti-inflammatory, protective against Ribeiro et al., 2015). In addition to their many beneficial properties,
UV, anti-aging, softening, maintaining skin moisture, reducing skin dis- the main advantage of many of them is their antibacterial activity.
coloration, stimulating wound healing, and having a pleasant aroma Several studies have shown the preservative effectiveness of natural
(Fatima, Alok, Agarwal, Singh, & Verma, 2013; Pawar et al., 2011; products such as: thymol, cinnamaldehyde, allyl isothiocyanate, citric
SAFETY OF PARABENS IN COSMETICS
acid, ascorbic acid, rosemary extract or rosemary acid, lavender, tea
tree, lemon oil, and chamomile oil, in cosmetic preparations (Dreger &
 ska, Sikora, &
Wielgus, 2013; Fatima et al., 2013; Kunicka-Styczyn
Kalemba, 2009; Sarkic & Stappen, 2018). Among various mechanisms
of essential oils antibacterial activity, disruption of permeabilization of
membranes is the most known (Dreger & Wielgus, 2013). The oils and
their components are often used externally in skin creams, lotions,
cleansers and oils, mouthwash products, toothpastes, decorative cos-
metics, lipsticks, shampoos, soaps, and perfumes. Some of them have
been proven to be effective preservatives and others act synergisti-
cally with synthetic preservatives (Herman, Herman, Domagalska, &
ska et al., 2009; Kunicka-
Młynarczyk, 2013; Kunicka-Styczyn
 ska, Sikora, & Kalemba, 2011; Maccioni, Anchisi, Sanna,
Styczyn
Sardu, & Dessi, 2002; Muyima, Zulu, Bhengu, & Popplewell, 2002;
Nostro et al., 2002, 2004). Cinnamon oil, used at the concentration of
2.5%, has been shown to have 3.5-times stronger antimicrobial activ-
ity than 0.4% MP against S. aureus, E. coli, and C. albicans growth
(Herman et al., 2013). However, when oil is applied alone, its antimi-
crobial activity is usually specific and insufficient. To achieve better
efficacy it is necessary to use higher concentrations of the oil, which
may cause allergenic reactions of the skin or other health problems.
The synergistic action of oils with chemical preservatives character-
ized by numerous beneficial properties such as: broad spectrum activ-
ity, physical and chemical stability, solubility in water/insolubility in
oil, low production cost, and low frequency of sensitization or irrita-
tion, makes it possible to minimize their concentration and at the
same time their undesirable effects on the skin. It was demonstrated
that MP used at 20- and 200-times lower concentrations than is usu-
ally used in cosmetic preparations, in combination with essential oils
exerted a preserving effect but not against all microorganisms
(Maccioni et al., 2002). However, this effect can be increased by the
combination of two or more essential oils. The addition of lavender,
tea tree and lemon oil to body milk made it possible to decrease
ska
8.5-fold the level of synthetic preservatives (Kunicka-Styczyn
et al., 2009). Natural products can be used as free, microencapsulated,
or transported by nanostructured carriers (Halla et al., 2018). The use
of nanotechnology can provide promising solutions. Encapsulated thy-
mol used at 12–25-times lower concentrations in cosmetic formula-
tions (lotion, gel, and cream) was as effective a preservative as MP at
the concentration of 4 mg/mL (Wattanasatcha, Rengpipat, & Wan-
ichwecharungruang, 2012).
Essential oils consist of terpenes with terpenoids, as well as aro-
matic and aliphatic compounds with a low molecular weight. There
are mostly two or three main compounds that determine the biologi-
cal properties of essential oils (Dreger & Wielgus, 2013; Sarkic &
Stappen, 2018). Anethole, with well-documented antibacterial and
antifungal properties, was reported as one of the major components
of anise and fennel fruit essential oils (De, De, Sen, & Banerjee, 2002),
possessing a number of valuable properties useful in cosmetology.
Anethole at low concentrations is able to induce collagen synthesis in
human skin fibroblasts and to protect collagen and glycosaminogly-
cans against changes caused by hydrogen peroxide (Andrulewicz-Bot-
 ska, Kuźmicz, Nazaruk, Wosek, & Galicka, 2019; Galicka,
ulin
201
Krętowski, Nazaruk, & Cechowska-Pasko, 2014). Furthermore,
anethole, as for many other components of essential oils, is a lipophilic
small and non-polar molecule that can easily penetrate the skin
(Sarkic & Stappen, 2018).
Plant extracts are a valuable source of many other natural anti-
microbial substances such as polyphenols and flavonoids (Cowan,
1999; Mukherjee, Maity, Nema, & Sarkar, 2011). In addition to their
preservative and antioxidant properties, our research team found
that some of them also have the ability to stimulate collagen bio-
synthesis in human skin fibroblasts (Galicka & Nazaruk, 2007;
Nazaruk & Galicka, 2014), and what is more, to prevent the nega-
tive effects of MP on collagen expression at the mRNA and protein
levels (results in preparation for publication), which have been dem-
onstrated in our previous study (Majewska et al., 2017) and by Cha
et al. (2015).
Seo et al. (2002) proposed chitosan and Inula helenium L. extract
as a good natural preservative system, which could be used in cos-
metic formulations. However, the use of natural substances has cer-
tain limitations such as a possible loss of activity after dilution,
dependence on pH, volatility, and strong odor of essential oils or the
limited spectrum of activity depending on the target species and the
form of microorganisms (Gram− bacteria, Gram+ bacteria,
mycobacteria, yeasts, molds) (Halla et al., 2018). The promoted natural
preservative (grapefruit seed extract) was reported to interact with
medicines mainly due to disturbing their metabolism (Brandin,
Myrberg, Rundlöf, Arvidsson, & Brenning, 2007).
Antimicrobial peptides are a rich and diverse group of natural
molecules that have been discovered in various plants and animals
(Kim, Jeong, Cho, Lee, & Kim, 2018; Mahlapuu, Håkansson, Ringstad, &
Björn, 2016). Peptides, such as defensins, cathelicidin, dermcidin, and
lactoferrin naturally occurring in the human skin play an important
role in the innate and/or adaptive immunity skin resistance and partic-
ipate in the repair of injured skin (Bardan, Nizet, & Gallo, 2004;
Yamasaki & Gallo, 2008). They possess antibacterial activity against a
wide range of microorganisms, including Gram−/Gram+ bacteria and
fungi (Hancock & Sahl, 2006) and belong to the new generation of
promising antimicrobials for use as food additives and in the pharma-
ceutical and cosmetic industries. They can be used as natural preser-
vatives in personal care products, such as balms and creams
(Rahnamaeian & Vilcinskas, 2015).
In the light of the evidence presented in the present review,
indicating the possibility of adverse health effects due to the use of
cosmetics containing parabens, it seems very important to look for
effective ways to reduce the use of parabens in cosmetology and
their concentration in cosmetics. As preservatives cannot be
completely eliminated from cosmetics and due to the concern of
consumers that alternative compounds may also have adverse
effects on their health, strategies aimed at decreasing the unfavor-
able outcomes of the widespread use of parabens not only in cos-
metics, but also in food and medicine, is of great importance. It
should be underlined that other synthetic preservatives or natural
alternatives to parabens are not completely safe or fully effective in
protecting cosmetics against the development of microorganisms,
202
which guarantees its safety in this respect. The best solution seems
to be searching for natural remedies that, when added in a small
safe amount, would allow either lowering the concentration of par-
abens used in cosmetics or lowering their unfavorable outcomes
noted at the concentration necessary to provide the microbiological
purity for cosmetic products.
10 | CO NC LUSIO NS
Although cosmetics have become part of our daily routine and their
use has increased significantly in recent years, their continuous long-
term use can cause various undesirable effects associated even with
serious health risks. Many studies conducted on the absorption, bio-
transformation, and accumulation of parabens with the use of animal
and human skin sections and with the participation of volunteers,
prove their existence in the body in a non-metabolized form. Consid-
ering their wide and extensive use over a large part of the human
lifespan and the new cosmetic products continuously being intro-
duced to the market, it is difficult to predict their possible negative
long-term outcomes. Apart from adults, this problem also concerns
children, adolescents, pregnant women and, above all, newborns
whose skin may be more sensitive to the action of parabens. Despite
the safety of children's cosmetics provided by the manufacturers, the
dermal intake of parabens from children's cosmetics was estimated to
be even higher than in adults. Most consumers do not know the com-
position of cosmetics and the action of their ingredients because they
pay more attention to the active ingredients that aim to improve the
appearance of the skin. Penetration enhancers added to increase the
effectiveness of the active cosmetic components, enhance simulta-
neously the degree of parabens penetration into the skin and can con-
tribute to their increased accumulation in the human body. The fact
that discontinuation of cosmetics use containing parabens or replace-
ment of them with other preservatives resulted in a decrease in their
concentration in the body, allows for the conclusion that dermal expo-
sure to cosmetic preparations containing parabens is an important
source of unhydrolyzed parabens in the human body. The few studies
carried out on cultured skin cells prove their undesirable effect on the
viability and proliferation of both keratinocytes and fibroblasts, as well
as on collagen expression, the skin's key protein.
It should be emphasized that the estimation of concentration of
unhydrolyzed parabens in the body does not reflect the total dermal
exposure to parabens because, similarly to the oral parabens intake,
some are hydrolyzed to PHBA and form various conjugates that are
not measured in most studies. The unequivocal determination of what
percentage of parabens is absorbed through the skin is difficult and
involves many factors that cannot be standardized. These factors
include the lack of the skin barrier in the case of cell cultures, individ-
ual differences in the metabolism and absorption via the skin of para-
bens, as well as the frequency and area of cosmetics application,
ethnicity, age, and the various patterns of co-use of these products.
Therefore, more large-scale population studies are required to evalu-
ate precisely the health risk posed by parabens entering the body
MATWIEJCZUK ET AL.
from cosmetics applied to the skin and mucous membrane, as well as
the research for alternative solutions to minimize the exposure of the
organism to these preservatives should be continued.
Summarizing the review of the available knowledge in the field of
safety of cosmetics containing parabens, it should be clearly empha-
sized that the use of single products of this kind should not pose a
hazard for human health. However, as the available data show, a sig-
nificant part of the general population use cosmetic products in exces-
sive quantities, which may cause exposure to parabens exceeding the
limit of safety and leading to the development of unfavorable health
outcomes. The assessment of the estrogenic potential of parabens
derived from cosmetics applied to the breasts and around them, per-
formed in the present review, confirms the possibility of an occur-
rence of such effects in humans. Particular attention should therefore
be paid to the estrogenic potential of these compounds. Due to the
real risk of estrogenic effects as a result of exposure to parabens from
cosmetics, consumers out of concern for their own health should
avoid the simultaneous use of many products containing these
preservatives.
CONFLIC T OF INT ER E ST
Authors declare none of conflicts of interest.
OR CID
Natalia Matwiejczuk https://orcid.org/0000-0003-2970-1508
Anna Galicka https://orcid.org/0000-0002-4027-989X
Małgorzata M. Brzóska https://orcid.org/0000-0002-3023-0056
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SUPPORTING INF ORMATION
Additional supporting information may be found online in the
Supporting Information section at the end of this article.
How to cite this article: Matwiejczuk N, Galicka A,
Brzóska MM. Review of the safety of application of cosmetic
products containing parabens. J Appl Toxicol. 2020;40:176–210.
https://doi.org/10.1002/jat.3917