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Nanotechnology and Applications in Cosmetics: General Overview

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 Food and Chemical Toxicology xxx (2015) 1e11

Contents lists available at ScienceDirect

Food and Chemical Toxicology

journal homepage: www.elsevier.com/locate/foodchemtox

Nanotechnology in cosmetics
Linda M. Katz, Kapal Dewan*, Robert L. Bronaugh
Office of Cosmetics and Colors, Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD 20740, USA

a r t i c l e i n f o a b s t r a c t

Article history: Nanomaterials are being used in cosmetic products for various effects. However, their use also raises
Received 26 May 2015 potential safety concerns. Some of these concerns can be addressed by determining the type of nano-
Received in revised form materials used, as well as stability, potential for skin absorption, route of exposure, and how they are
24 June 2015
formulated in cosmetic products. There has been considerable effort internationally to harmonize ap-
Accepted 25 June 2015
proaches in order to address definitional issues and safety concerns related to the use of nanomaterials in
Available online xxx
cosmetic products.
© 2015 Published by Elsevier Ltd.
Keywords:
Nanomaterials
Cosmetics
Safety of nanomaterials in cosmetics
Skin absorption

1. Introduction The FDA does not currently have a definition of a nanomaterial

Nanomaterials are currently being used in cosmetic products;
however, the actual number of nanomaterials being used depends
on how these materials are defined. Some nanomaterials may have
increased bioavailability or toxicity; therefore, the potential skin
absorption of these nanoparticles is an important consideration in
the determination of whether safety concerns exist. Issues about
the safety of a nanosized ingredient may also depend on its sta-
bility, since unstable nanomaterials will likely not be readily
absorbed. Regulation of nanomaterials used in cosmetics in the
United States is based on FDA's post-market authority over cos-
metics. Cosmetic regulation of nanomaterials as well as the Inter-
national Cooperation on Cosmetic Regulation (ICCR) process will be
described.
2. Use and safety of nanomaterials
2.1. Definition of nanomaterials in cosmetics
It is difficult to determine the number of nanomaterials used in
cosmetic products because the definition of what constitutes a
nanomaterial is currently evolving. The use of the prefix “nano” in
cosmetic advertising and labeling may not coincide with how the
term is used by regulatory authorities.
* Corresponding author.
E-mail address: Kapal.Dewan@fda.hhs.gov (K. Dewan).
but issued final guidance in June of 2014 to help provide regulatory
clarity in FDA's regulation of products containing nanotechnology
(Guidance for Industry Con, June 2014). FDA has developed certain
points to consider when attempting to identify applications of
nanotechnology in FDA regulated products: (1) whether a material
or end product is engineered to have at least one external dimen-
sion, or an internal or surface structure, in the nanoscale range
(approximately 1 nm to 100 nm) or (2) whether an engineered
material or end product exhibits properties or phenomena
including physical or chemical properties or biological effects that
are attributable to its dimension(s), even if these dimensions fall
outside the nanoscale range, up to one micrometer.
The European Union (EU) cosmetic regulation states that a
nanomaterial is an “insoluble or biopersistant and intentionally
manufactured material with one or more external dimensions, or
an internal structure, on the scale of from 1 to 100 nm” (Regulation
(EC) No 1223/2 and 9). Therefore, if stability and solubility are
considered, certain unstable classes of nanomaterials (liposomes,
solid lipid nanoparticles, and nanostructured lipid carriers) may not
be considered nanoparticles under this regulation.
Many of the nanomaterials found in cosmetic products that
claim to promote enhanced skin absorption may in fact be unstable
when applied to the skin and, therefore, unable to carry ingredients
beneath the surface layer of the skin. However, they may facilitate
skin absorption by promoting increased diffusion from the
cosmetic vehicle into the surface layer of skin (Schafer-Korting
et al., 2007). Only insoluble, stable nanoparticles, such as

http://dx.doi.org/10.1016/j.fct.2015.06.020
0278-6915/© 2015 Published by Elsevier Ltd.

Please cite this article in press as: Katz, L.M., et al., Nanotechnology in cosmetics, Food and Chemical Toxicology (2015), http://dx.doi.org/
10.1016/j.fct.2015.06.020
2 L.M. Katz et al. / Food and Chemical Toxicology xxx (2015) 1e11
titanium dioxide, nanogold, nanosilver and polymers, are clearly
identified as nanoparticles that might enter into the body and
possibly cause safety issues directly.
2.2. Use of nanomaterials in cosmetics
Probably the most common claim for the use of nanomaterials
in cosmetics is to enhance the delivery of cosmetic ingredients into
the skin. The small size of lipid vesicles may enable these materials
to be absorbed more readily into skin (Cevc and Blume, 1992).
Scientific studies to substantiate these claims have provided
differing results. These may be due to study conditions such as
nanoparticle size and stability that make it difficult to achieve
consistent results even within the same laboratories. Differing
physicochemical properties of vesicles can likely affect their in-
teractions with skin (Honeywell-Nguyen et al., 2002). Some vesi-
cles may not penetrate the skin but may simply release their
ingredients onto the surface of the skin in a manner that facilitates
uptake and penetration into the surface layers of skin (Schafer-
Korting et al., 2007).
Nanomaterials also may be used to impart stability to formu-
lations that contain ingredients that may decompose due to
oxidation and other causes (Ourique et al., 2008). However, carrier
nanoparticles may have stability problems upon application to the
skin.
Nanoparticles of titanium dioxide and zinc oxide are used pre-
dominantly in sunscreen non-prescription drug products; however,
they may also be used in cosmetic products (where the resulting
product may be both a drug and a cosmetic depending on product
claims). These nanomaterials remain effective blockers of UV ra-
diation but also result in a transparent formulation that is pleasing
to the consumer.
Nanoparticles of silver are used in consumer products as anti-
bacterial or preservative agents. Cosmetic products in the US
cannot make antibacterial claims, since this claim is associated with
a physiological function, and, thus, its use is limited to drug prod-
ucts. Of note, nanosilver is not currently listed by the EU in Annex 5
of the Cosmetic Directive, which is the approved list for pre-
servatives allowed to be used in cosmetic products.
2.3. Skin absorption of nanomaterials
The potential skin absorption of nanomaterials is an issue that
must be addressed in order to help understand the safety and
usefulness of these materials in cosmetic products.
2.3.1. Insoluble nanomaterials
Quantum dots (QD) have been used by a number of investigators
as model compounds to study the skin absorption of nanomaterials.
They are stable particles and are highly fluorescent which enables
tracking of any skin permeation that occurs by using instruments
that measure this fluorescence.
Initial studies by Jessica Ryman-Rassmussen and coworkers
(Ryman-Rasmussen et al., 2006) were conducted with pig skin
assembled in diffusion cells. QDs with two different sizes and three
different surface charges were selected to determine the effect of
particle size and surface charge on skin penetration. Application to
skin was made in a pH 8.3 or pH 9.0 buffer supplied by the
manufacturer. Absorption into the skin was assessed by measuring
fluorescence of the particles using confocal microscopy. Spherical
QDs with each surface coating were found to penetrate through the
stratum corneum into the viable epidermis and dermis within 8 h.
The ellipsoidal QD with a glycol-amine coating was observed in the
epidermis within 8 h; whereas a carboxylic acid coating resulted in
a delay of epidermal penetration until 24 h. Recent additional
Please cite this article in press as: Katz, L.M., et al., Nanotechnology in cosmetics, Food and Chemical Toxicology (2015), http://dx.doi.org/
10.1016/j.fct.2015.06.020
studies (Prow et al., 2011) on the same QDs have shown that there is
generally no penetration of QDs through intact human stratum
corneum into the viable tissue below. The authors demonstrated
that the manufacturer's alkaline buffer (pH 8.3) facilitated
increased penetration of the uncharged PEG coated QDs into the
viable epidermis of human skin in diffusion cell studies (Prow et al.,
2011).
Titanium dioxide (TiO2) and zinc oxide (ZnO) nanoparticles tend
to agglomerate into particles larger than 100 nm and have been
generally found in various studies to remain on or near the surface
of the skin. Initially, in vitro studies were conducted to separately
examine the skin penetration of both TiO2 and ZnO (Gamer et al.,
2006). Two TiO2 formulations and one ZnO formulation were
applied to triplicate samples of skin in diffusion cells and studies
were run for 24 h. Stratum corneum layers were then removed by
cellophane tape stripping, and viable skin and receptor fluid were
analyzed for TiO2 and ZnO. Results showed that neither nano-
particle used in the sunscreen formulations was able to penetrate
porcine stratum corneum into the viable skin or receptor fluid.
The skin penetration of TiO2 formulations has been evaluated,
in vivo, in minipigs (Sadrieh et al., 2010). Three TiO2 particles were
used with the following sizes as measured by scanning electron
microscopy (SEM): uncoated submicron sized, 300e500 nm; un-
coated nanosized, 30e50 nm; and dimethicone/methacone copol-
ymer coated nanosized, 20e30 nm diameter and 50e150 in length.
Particles were applied at 5% by weight in a sunscreen formulation
at a concentration of 2 mg/cm2. At the end of the studies, the most
concentrated amounts of all three types of particles were found in
the surface layer of skin e the stratum corneum. Only isolated TiO2
particles were found in lower layers of the skin. The authors
concluded that the TiO2 particles studied did not penetrate intact
pig skin epidermis in a significant amount and, therefore, they are
unlikely to penetrate human skin.
The skin absorption of zinc oxide nanoparticles in a transparent
sunscreen formulation was examined using excised human skin in
diffusion cells (Cross et al., 2007). Less than 0.03% of the applied
zinc penetrated into the receptor fluid beneath the skin. No ZnO
nanoparticles were found in the stratum corneum or viable
epidermis as determined by electron microscopy. Further evidence
of a lack of significant ZnO nanoparticle skin penetration was ob-
tained in vivo with human volunteers (Zvyagin et al., 2008). A
commercially available sunscreen formulation containing ZnO
nanoparticles (about 15e30 nm in size) was applied in amounts to
simulate exposure conditions. Multiphoton microscopy imaging of
the surface of the skin and below was conducted immediately after
application and at 4 h and 24 h later. ZnO nanoparticles were
observed on the surface of the skin following application to the skin
and at 4 h. ZnO appeared to localize in skin folds and at the top of
hair follicle shafts without spreading to neighboring cells. None of
the nanoparticles were observed on the skin surface at 24 h, pre-
sumably due to bathing. No evidence of ZnO penetrating past the
stratum corneum into the viable epidermis was observed.
The skin absorption of both TiO2 and ZnO nanoparticles in
topical formulations was evaluated by in vivo and in vitro tech-
niques using skin from weanling Yorkshire pigs (Monteiro-Riviere
et al., 2011). The main purpose of this study was to determine if
mild skin damage from UV irradiation that might be seen with sun
exposure resulted in enhanced skin penetration of the nano-
particles. The skin for both in vivo and in vitro studies was pre-
treated with UV light prior to dosing with the nanoparticle
formulations. At the end of the in vitro absorption studies, TiO2 was
found in deeper layers of the stratum corneum in the damaged skin,
compared to normal skin, using transmission electron microscopy
(TEM). No penetration into the stratum corneum was observed for
ZnO nanoparticles with either normal or damaged skin. At the end
 L.M. Katz et al. / Food and Chemical Toxicology xxx (2015) 1e11
of the in vivo studies, TiO2 was found in deeper stratum corneum
layers than ZnO in both normal and damaged skin. However, there
was minimal penetration of either nanoparticle into the epidermis,
and no indication of systemic absorption of the nanoparticles in
these studies.
A few studies have been published concerning the ability of
other metal nanoparticles to penetrate skin. The absorption of sil-
ver nanoparticles through excised human skin was measured in
diffusion cells (Larese et al., 2009). The silver nanoparticles were
stabilized to prevent aggregation by coating them with poly-
vinylpirrolidone. Transmission electron microscopy (TEM) mea-
surements found the size of the particles to range between 25 and
48 nm. The skin in some cells was abraded with a hypodermic
needle according to the method of Bronaugh and Stewart
(Bronaugh and Stewart, 1985). The nanoparticles were applied in a
synthetic sweat solution resulting in an application of 70 mg/cm2
silver nanoparticles to the skin surface. Silver concentration in the
receptor fluid beneath the skin at the end of 24 h was 0.46 ng/cm2
with intact skin and 2.32 ng/cm2 with damaged skin. In addition to
the very low penetration through the skin, silver nanoparticles
could also be detected in the stratum corneum and the upper re-
gion of the viable epidermis by TEM analysis.
A publication from the same laboratory has shown that gold
nanoparticles are also absorbed in vitro into and through human
skin (Filon et al., 2011). The nanoparticles were as small as 12.6 nm
in diameter but tended to form aggregates. They were applied to
skin in a synthetic sweat solution at concentrations of 15 and 45 mg/
cm2 for the high and low doses respectively. Gold content in the
receptor fluid at the end of the 24 h experiments were 214 and
188 ng/cm2 for the respective doses. It appears that a small but
higher amount of nanogold was absorbed than nanosilver in the
experiments from the same laboratory. The authors recognized that
a possible confounding feature is that the dosing solutions
remained on the skin surface for the entire 24 h experiments in
both studies. The authors believe that this might result in a hy-
drating effect which could impact on skin absorption. The high dose
nanogold studies found less absorption of gold than the low dose
study e an effect that could have been caused by the different
volumes of dosing solution applied.
The skin absorption of metal nanoparticles less than 10 nm in
diameter was examined by Baroli et al. (Baroli et al., 2007).
Maghemite (diameter 5.9 nm) and iron (diameter 4.9 nm) nano-
particles were synthesized and their stability was assessed. Organic
coatings were applied to both nanoparticles to prevent irreversible
aggregation. Absorption studies were conducted with excised hu-
man skin in diffusion cells and the location of nanoparticles in skin
was determined by electron microscopy. The studies found that
both nanoparticles were able to penetrate the skin into the stratum
corneum layer and into the hair follicle openings. They diffused into
the lower layer of the stratum corneum; however, only in rare in-
stances were the nanoparticles found in the viable epidermis.
2.3.2. –Soluble nanomaterials
Liposomes have been widely used in cosmetic products for a
number of years for the purpose of increasing the delivery of in-
gredients into the skin. Cevc was the first to develop flexible lipo-
somes (called transfersomes) which were claimed to be more
effective than rigid liposomes in the delivery of ingredients through
skin (Cevc and Blume, 1992; Cevc et al., 1995). The same principle of
creating a flexible liposome to enhance delivery was applied by Van
den Bergh using the micelle-forming surfactant
octaoxyethylenelaurate-ester (PEG-8-L) to create flexibility in the
liposomes synthesized (van den Bergh et al., 1999). Vesicle diam-
eter was between 100 and 150 nm, as determined by dynamic light
scattering. The rationale behind the use of flexible liposomes is in
Please cite this article in press as: Katz, L.M., et al., Nanotechnology in cosmetics, Food and Chemical Toxicology (2015), http://dx.doi.org/
10.1016/j.fct.2015.06.020
3
their ability to change shape as they pass through small spaces in
the skin, which may be advantageous in their ability to promote
absorption. Subsequent studies from the same laboratory were
conducted on flexible liposomes prepared with either PEG-8-L or
Tween 20 as the micelle forming surfactant (Honeywell-Nguyen
et al., 2002). After separate application of flexible and rigid lipo-
some formulations to the skin of human volunteers, the stratum
corneum layers were sequentially removed by cellophane tape
stripping after 1 h. Intact liposomes prepared with either surfactant
were seen on the skin surface and as deep as the ninth tape strip.
This indicated that some intact flexible liposomes could penetrate
deep into the stratum corneum. It cannot be determined from the
electron micrographs if sufficient numbers of flexible liposomes
can penetrate into the stratum corneum to result in a biological
effect. Intact rigid liposomes were not found on the skin surface.
Instead, extensive liposome vesicle fusion was observed resulting
in lipid bilayers that were visible on the skin surface. No evidence
was found of rigid liposomes penetrating into the stratum
corneum.
Solid lipid nanoparticles (SLN) and nanostructured lipid carriers
(NLC) are also believed to decompose on the skin surface and
release their contents (Schafer-Korting et al., 2007; Kuchler et al.,
2009; Weichers and Musee, 2010). SLN are made with lipids solid
at room temperature and NLC are prepared with a mixture of solid
and liquid lipids (Schafer-Korting et al., 2007). Both types of
nanoparticles are prepared using high pressure homogenization.
The amount of active ingredient that can be carried by an SLN varies
with solubility properties of the ingredient but can be roughly
about 1% of the final formulation (Schafer-Korting et al., 2007). NLC
preparations generally can contain higher levels of active in-
gredients but SLN preparations can sometimes improve chemical
stability. Increased delivery of the lipophilic dye Nile Red was
shown in SLN compared with NLC and a conventional cream
formulation (Kuchler et al., 2009). Evaporation of water following
application of the SLN and NLC nanoparticles to the skin surface
triggers formation of a lipid film on the surface of skin which is
thought to promote diffusion of ingredients into the skin (Schafer-
Korting et al., 2007).
2.3.3. Polymers (soluble/insoluble nanomaterials)
The use of dendrimers and other polymers is being explored as a
method of delivery of ingredients into and through the skin. Poly-
mers have the advantage of relatively small size and stability and
can be soluble or insoluble nanoparticles depending on their
structure. Unlike lipid vesicles, soluble polymer nanoparticles are
stable and do not disintegrate on or near the surface of the skin.
Enhanced skin absorption of indomethacin was observed by the
addition of polyamidoamine (PAMAM) dendrimers to aqueous
formulations applied to rat skin (Chauhan et al., 2003). The den-
drimers were found to substantially increase the solubility of the
hydrophobic indomethacin in the formulations used. Dendrimers
that have potentially many binding sites per molecule could be
more effective than other solubility enhancing chemicals. In vitro
skin penetration of indomethacin was enhanced by the 0.2% con-
centration of the generation 4 dendrimer with surface amino
groups (G4-NH2) by a factor of 4.5 compared to the pure drug
suspension. In vivo absorption from a transdermal patch was found
to increase 2.7% with the 0.2% dendrimer formulation. The authors
suggested that the increases in penetration of indomethacin from
the PAMAM dendrimer formulations were based solely on in-
creases in solubility of the drug in the formulations and not on
delivery of the drug into the skin by the dendrimer.
PAMAM dendrimers were found to enhance the delivery into
skin of 5-fluorouracil (5-FU)e a model compound for hydrophilic
compounds (Venugganti and Perumal, 2009). The effects of
4 L.M. Katz et al. / Food and Chemical Toxicology xxx (2015) 1e11
dendrimer surface charge, size, and concentration on in vitro pig
skin absorption was examined. Skin was pretreated with the den-
drimers for 24 h and then the dendrimers were removed. The
control solution of 5-FU in isopropyl myristate was applied and the
skin permeability constant was determined. The smallest sized
dendrimers (generation-2) were most effective in increasing
penetration of 5-FU compared with the control solution only. The
permeability constant of 5-FU was increased by 2.5 and 1.9 fold
respectively with the cationic and neutral dendrimers. The
enhancement was only 1.5-fold with the negatively charged den-
drimer. Penetration of dendrimers into the skin was limited to the
“first few layers of skin” presumably because of their large molec-
ular weight.
Dendritic core multishell (CMS) neurotransmitter nanoparticles
were synthesized and evaluated for their ability to enhance the skin
absorption of a model dye (Nile Red) into excised pig skin. The CMS
nanoparticles were found to be 20e30 nm in size by photon cor-
relation spectroscopy. The dye was added to an aqueous solution of
the CMS polymer which was then stirred vigorously for 72 h and
then filtered to remove insoluble residues of the dye. Penetration of
the Nile Red dye into the stratum corneum and the viable epidermis
was increased by the CMS nanoparticles by 8-fold and 13-fold
respectively when compared to the cream formulation. Accumu-
lation of nanoparticles in the furrows of the skin surface suggests
that the mechanism of enhanced delivery is the facilitation of the
mixing of the lipids from both the nanoparticles and the skin sur-
face (Kuchler et al., 2009).
Polycaprolactone (PCL) nanocapsules are polymer nanoparticles
that have been used by L'Oreal and others to encapsulate in-
gredients for use in cosmetic products (Clemmensen et al., 2007).
Particle size can vary with the method of synthesis but has been
reported to be in the range of 100e200 nm (Ourique et al., 2008;
Clemmensen et al., 2007). An allergic reaction to retinyl palmitate
in a cosmetic product was attributed to possible enhanced skin
absorption in these nanocapsules since retinyl palmitate is nor-
mally only a weak skin sensitizer (Clemmensen et al., 2007). Reti-
noic acid (tretinoin) was encapsulated in PCL nanocapsules to
determine if photostability could be enhanced (Ourique et al.,
2008). Tretinoin-loaded nanocapsules resulted in a doubling of
photostability to between 85 and 100 min when compared with the
control methanol solution. The skin absorption of the sunscreen
agent benzophenone-3 (BZ3) was examined following PCL encap-
sulation since BZ3 can be absorbed through the skin with potential
adverse effects (Marcato et al., 2011). Skin absorption into and
through human skin in diffusion cells was reduced 70e80% when
BZ3 was applied in the nanocapsules.
Lipoic acid is a supplement with antioxidant properties that can
be measured in the laboratory by its inhibitory effects on lipid
peroxidation (Kulkamp et al., 2011). PCL nanocapsules have been
shown to increase the antioxidant activity of lipoic acid as
compared to the activity of lipoic acid in a control solution
(Kulkamp et al., 2011). The beneficial effect of PCL encapsulation is
thought to be due to stabilization of the lipoic acid in combination
with a slow, prolonged release of the compound.
2.4. Safety of nanomaterials
The skin is the primary route of exposure to nanomaterials in
the use of cosmetic products. As we have seen from the discussion
in the previous section, there are still some uncertainties in the
ability of nanomaterials to penetrate the surface layer of skin (the
stratum corneum) into the viable layers of skin where toxicological
concerns could arise. Furthermore, it is in the viable skin where
nanoparticles could be taken up by blood vessels for systemic
distribution.
Please cite this article in press as: Katz, L.M., et al., Nanotechnology in cosmetics, Food and Chemical Toxicology (2015), http://dx.doi.org/
10.1016/j.fct.2015.06.020
Larger particles that tend to agglomerate, such as TiO2 and ZnO,
do not appear to present a hazard due to a lack of significant skin
absorption (Gamer et al., 2006; Sadrieh et al., 2010; Cross et al.,
2007; Zvyagin et al., 2008; Monteiro-Riviere et al., 2011). Howev-
er, smaller particles less than 10 nm in size have been shown to
occasionally reach the viable skin layers (Baroli et al., 2007).
However, the pathway of penetration of even a few nanoparticles
through intact skin is not clear. These particles are still much larger
than 500 Da, which is the approximate size of the upper limit of
molecules that can be significantly absorbed through skin (Bos and
Meinardi, 2000). For example, a generation 2 PAMAM dendrimer
has a diameter of only 2.9 nm yet the molecular weight is 3256 Da
(Tomalia et al., 1990). This demonstrates that even very small nano-
molecules can have extremely large molecular weights in com-
parison to those of molecules known to penetrate the skin.
Absorption studies have been conducted on damaged skin to
determine if enhanced penetration of nanoparticles could be
facilitated by conditions that alter the barrier properties (e.g. cuts,
scrapes, severe sunburn, and certain skin diseases such as eczema).
Repeated stripping of the surface of the skin with cellophane tape is
a frequently used technique to remove the stratum corneum.
Abrasion of the skin surface is a more severe procedure that
removes much of the epidermal layer including the stratum cor-
neum. The flexing or rubbing the surface of skin has also been
studied as a means of facilitating particle absorption (Tinkle et al.,
2003). Tinkle and coworkers observed that beryllium particles
(0.5e1.0 mm) penetrated into human epidermis following repeated
mechanical flexing of the skin in a 1 h in vitro study (Tomalia et al.,
1990). Quantum dots (QDs) have frequently been used as model
compounds in studies to assess barrier integrity because of relative
stability, ease of detection, and fluorescent properties.
Zhang and Monteiro-Riviere (Zhang and Monteiro-Riviere,
2008) examined the effects of the above techniques on the skin
penetration of two QDs. The hydrodynamic diameters of QD565
and QD655 were 14 nm and 18 nm, respectively. Neither QD was
found to penetrate into the stratum corneum when applied to rat
skin assembled in diffusion cells with or without skin flexing. Both
QDs were found only on the surface of the viable epidermis after
studies conducted for 8 or 24 h. Only removal of the epidermis by
skin abrasion prior to dosing resulted in penetration of the QDs into
the dermal layer of skin after 24 h.
No penetration of a different QD with a polymer coating (total
diameter approximately of 37 nm) was observed through intact and
tape-stripped hairless mouse skin (Gopee et al., 2009). Studies were
conducted in vivo and absorption was assessed by measurement of
QDs in lymph nodes and the liver. Some penetration into internal
organs was found following application of QDs to abraded skin.
Significant penetration of small (approximately 4 nm) QDs was
not observed past the stratum corneum layer of skin, even after a
five or ten minute massaging of the surface of the skin following
application. Subsequent studies following removal of most of the
stratum corneum by tape-stripping resulted in some penetration of
QDs into deeper layers of skin but only when the studies were
accompanied by a ten minute skin surface massage (Gratieri et al.,
2010).
QDs were also used to examine possible penetration of a
nanomaterial in vivo through hairless mouse skin exposed to ul-
traviolet radiation (Mortensen et al., 2008). The QD565 had a hy-
drodynamic diameter of approximately 30 nm in the 75% glycerol
solution used for application. Minimal penetration of the QDs was
observed with intact mouse skin but appeared to increase slightly
in the UV irradiated animals after the 8 and 24 h studies. These
studies (in this and the previous three paragraphs), using various
methods to create skin damage, illustrate the importance of the
skin barrier in preventing or reducing possible toxicity from dermal
 L.M. Katz et al. / Food and Chemical Toxicology xxx (2015) 1e11
exposure to nanomaterials.
Nanomaterials may exhibit unique biochemical properties
compared with microparticles of the same chemical, since a
nanomaterial has a large fraction of its atoms on the surface of
the particle (larger surface area to mass ratio). These unique
chemical properties may result in unique bioactivity (Castranova,
2011). It therefore becomes important to understand which
chemical properties are ones that might be of most importance in
predicting a biological response from a nanomaterial. Regarding
TiO2 and pulmonary toxicity, bioactivity has been shown to
depend on the size of individual nanomaterials as well as the
agglomeration state (Mortensen et al., 2008). The in vitro effect of
nanomaterials on rat liver cells in culture was evaluated to
determine if any cellular morphological changes could be
observed (Hussain et al., 2005). Silver nanoparticles were toxic in
the mitochondrial function test and membrane leakage test;
whereas, other similarly sized nanoparticles of molybdenum,
aluminum, iron oxide and titanium dioxide were not toxic at the
lower dose. The study suggested that nanomaterial toxicity was
not a function solely of size of the particle but depended on other
chemical properties.
Further studies have been conducted to look more closely at
potential toxicity of nano and micro sized particles of the same
chemical. Effects of silver nanoparticles (35 nm) and micro-sized
particles (1.6 mm) were examined for their effects on the mortal-
ity of neonatal Daphnia Magna aquatic invertebrates (Gaiser et al.,
2011). Neonates were exposed to the particles for 96 h in an
aqueous suspension. Survival rates of the neonates exposed to 0.1.
mg/l silver particles demonstrated that the nanoparticles were
twice as toxic as the microparticles. The potential acute toxicity of
copper particles was examined in mice following a single oral
gavage (Zhen et al., 2006). LD50 values for copper nanoparticles
(23.5 nm) and copper microparticles (17 mm) were 413 and
>5000 mg/kg body weight respectively. Damage to the livers and
kidneys of nanoparticle treated mice was observed histopatholog-
ically and from blood biochemistry examination. Male mice were
found to exhibit more severe symptoms to nanocopper than female
mice. There were generally no significant toxic effects observed in
microparticle treated animals.
The toxicity of silica particles was evaluated in a 10 week mouse
feeding study. The approximate diameter of silica nanoparticles
was 30 nm and the microparticles were about 30 mm in size. No
significant effects were observed in the overall health of the ani-
mals at the end of the study. However, animals in the nanosilica
group exhibited signs of liver damage as evidenced by elevated
aniline aminotransferase (ALT) and aspartate aminotransferase
(AST) levels in the blood (So et al., 2008). In another silica feeding
study in mice, however, similar effects in animals treated with
either the nanoparticles (10e20 nm) or the microparticles (45 mm)
were observed. Non-specific lesions were seen in organs removed
from the mice treated with either size particle indicating a low level
of toxicity. No details were provided on the doses administered to
the mice or the length of the feeding studies (Cha and Myung,
2007).
Some indication has been provided of potential increased
toxicity with nanoparticles compared with that of microparticles
although the examples cited are not directly related to cosmetic
exposure. The importance of an understanding of skin absorption, if
any, of these nanoparticles is emphasized (Nafisi et al., 2014) so that
an accurate assessment of exposure can be determined. The view
that nanoparticles may present a greater risk of toxicity than mi-
croparticles is based on the fact that nanoparticles could be more
readily absorbed through membranes or possibly more reactive
because of their small size. However, there are some that feel that
toxicity of insoluble particles may be independent of size and that
Please cite this article in press as: Katz, L.M., et al., Nanotechnology in cosmetics, Food and Chemical Toxicology (2015), http://dx.doi.org/
10.1016/j.fct.2015.06.020
5
most will not create increased toxicity at the nanoscale level
(Zvyagin et al., 2008). The authors suggest that caution should be
used in interpreting toxicity data from nanoparticles since any
observed effects might be due to the presence of insoluble particles
in cells and not necessarily on the size of these particles (Zvyagin
et al., 2008).
The EU's Scientific Committee on Consumer Products stated in
their most recent nanomaterials safety evaluation that soluble
nanoparticles may not require new safety studies because con-
ventional risk assessment methodologies may be satisfactory
(Scientific Committee o and January 9, 2012). However, there is no
discussion of the situation that could occur if a soluble nano-
material promotes increased absorption of another ingredient.
Presumably, new safety studies may be needed if they are not
available to support the safety of the ingredient at the enhanced
exposure levels.
Inhalation is less important than skin absorption as a route of
exposure for most cosmetics; however, the possibility of health
concerns from inhalation of nanomaterials should not be ignored.
Much of the research in this area has been conducted based on
concerns about occupational exposure. Nanomaterials have been
shown to cause significant adverse effects both in vitro and in an-
imals from deposition of particles in regions of the lung
(Castranova, 2011). A growing database is described containing
physiochemical properties of a nanoparticle and its bioactivity in
pulmonary toxicology.
Nanomaterials used in cosmetic products may indirectly create
safety concerns when they are transferred to the environment in
waste water due to consumer bathing (Weichers and Musee, 2010).
Nanomaterials in cosmetics are not likely to be significantly
excreted in human waste because of poor absorption through the
skin into the body. (However, nanomaterials parenterally admin-
istered to animals have been shown to be readily excreted (Cho
et al., 2009; Chen et al., 2010)). As nanomaterials become more
widely used in consumer products and by other industries, there
may be exposure to humans from polluted water, air and even
manufacturing establishments. Only limited information is avail-
able on nanowaste generation and further discussion of this issue is
beyond the scope of this chapter.
3. Regulatory aspects
Regulation of nanomaterials in cosmetics in the United States
FDA's mission is to ensure that the products it regulates, such as
drugs, biologics, vaccines, and devices, are effective, safe, and
properly labeled for use, and that foods and cosmetics are safe and
properly labeled. In the case of drugs, biologics, vaccines, devices,
and foods, FDA has premarket authority by which ingredients and
finished products can be assessed prior to marketing. For cosmetics,
FDA's authority is post-market only, meaning that the Agency does
not evaluate the safety of ingredients, finished products, or the
specifics of labeling prior to marketing. FDA exercises its post-
market authority within a “risk management” framework which
is applied on a case-by-case basis.
In 2007, FDA issued its FDA Nanotechnology Task Force Report
(Nantotechnology, July 2007), following public meetings and in-
ternal discussions aimed at gaining a better understanding of the
nature of the science at that time. The conclusion of that report
was: “The Task Force believes FDA should continue to pursue
regulatory approaches that take into account the potential
importance of material size and the evolving state of the science.
As a result of the discussion, the Task Force did not recommend
adoption of a formal definition of nanotechnology for regulatory
purposes but left room for discussion with the Agency of products
6 L.M. Katz et al. / Food and Chemical Toxicology xxx (2015) 1e11

being developed by manufacturers to see what areas might be

Wording of conditions of
deficient or might need further guidance or regulatory modifi-
cations. As a result of this Report and further interest in nano-
products, FDA has developed a “Final Guidance for Industry

use and warnings

Considering Whether an FDA-Regulated Product Involves the
Application of Nanotechnology” (Guidance for Industry Con,
2576).
For most regulated product areas under FDA's jurisdiction, FDA's

i
authority has been felt to be adequate to deal with new technology
through its pre-market approval process. One of the notable ex-
ceptions has been in the area of cosmetics. Cosmetics products, as
noted above, are not subject to pre-market approval, and the reg-
ulatory authority for cosmetics lies within the Federal Food, Drug,
and Cosmetic Act (sections 601 and 602) (Federal Food), stating that

Other
cosmetics shall not be adulterated nor misbranded. In order to

h
address the issues of nanotechnology in cosmetics, FDA developed
a separate guidance for the safety of nanomaterials in cosmetic

Maximum concentration
products, which was published in June 2014. This final guidance on
Nanotechnology, “Guidance for Industry: Safety of Nanomaterials

in ready for use

b) 1.7% (acid)
a) 2.5% (acid)
in Cosmetic Products” (Guidance for Industry) provides guidance to

c) 0.5% (acid)
preparation

0.5% (acid)

0.5% (acid)
industry and other stakeholders regarding FDA's thinking about the

2% (acid)
safety assessment of nanomaterials in cosmetics and is intended to
assist interested parties in identifying potential safety issues and

g
how to assess them.

Product type, body parts

a) Rinse-off products,
b) Oral care products
c) Leave-on products
International perspectives on regulation of nanomaterials in
Conditions

cosmetics

The International Cooperation on Cosmetics Regulation (ICCR), f

composed of regulators from Canada, the European Commission, 217-468-9/218-235-4/

209-481-3/209-045-2/
224-387-2/202-259-7/
202-284-3/219-020-8/
205-252-7/204-401-3/

201-176-3/241-503-7/
223-795-8/209-166-0/
Japan, and the United States, was formed in 2007 to address areas of

213-361-6/202-293-2

200-618-2/208-534-8

206-323-5/205-290-4
cosmetic-related concerns, with a goal to cooperate or harmonize,
whenever possible. The mission of this group is to remove regu-
latory obstacles among regions, while maintaining the highest level
EC number

of consumer protection.
Nanotechnology has been an ongoing topic for discussion, and
e

has been broken down into the following topics: criteria, safety, and
582-25-2/553-70-8/4337-

4075-81-4/557-27-7/327-
1205-50-3/939-48-0/93-

nanomaterial characterization. Working group reports are posted

66-0/93-58-3/93-89-0/
1863-63-4/2090-05-3/

2315-68-6/136-60-7/

Propionic acid and its salts Propionic acid/ammonium 79-09-4/17496-08-1/

on each regulatory website as they are completed. In 2010, the
65-85-0/532-32-1

Nanotechnology working group of ICCR described a nanomaterial

62-8/137-40-6
as “a substance used in a cosmetic is considered a nanomaterial if it
CAS number

is an insoluble ingredient, intentionally manufactured, with one or

more dimensions in the realm of 1e100 nm in the final formulation
99-2

and is sufficiently stable and persistent in biological media to allow

d

for the potential of interaction with biological systems” (Report of

benzoate/propyl benzoate
benzoate/ethyl benzoate/
Substance identification

the Joint). The finished work products of the safety and character-
butyl benzoate/calcium

propionate/magnesium
Ammonium benzoate/

magnesium benzoate/
mea-benzoate/methyl

propionate/potassium
Benzoic acid; Sodium
ingredients glossary

benzoate/potassium
isopropyl benzoate/

ization working groups have been finalized and can be found on the
propionate/calcium

propionate/sodium
isobutyl benzoate/
Name of common

benzoate/phenyl

ICCR website (Report of the Joint).

In 2011, 2012, and 2013 the ICCR Working Group on Currently
List of preservatives allowed in cosmetic products

propionate
benzoate

Available Methods for Characterization of Nanomaterials submitted

their reports to ICCR. These reports (Report of the Joint) contain
c

listings of the current most relevant methods for the character-

Salts of benzoic acid other

ization of nanomaterials for possible use in cosmetic products. Each

reference number 1 and
than that listed under

esters of benzoic acid

method was evaluated in terms of the parameter it measured, the

Chemical name/INN

Benzoic acid and its

sensitivity of the measurement, and the underlying principles

involved in the determination. In addition, in 2013 the ICCR
sodium salt

Working Group on Nanomaterial Safety posted its report on Safety

Approaches to Nanomaterials in Cosmetics. Relevant scientific
publications, reports, and opinions were evaluated with the
b

conclusion that the overall risk from nanomaterials in cosmetic

Reference
Annex V

number

ingredients were no different from that seen in conventional in-

gredients and that there is a need for more research into finished
1a

3
a

products (Report of the Joint).

Please cite this article in press as: Katz, L.M., et al., Nanotechnology in cosmetics, Food and Chemical Toxicology (2015), http://dx.doi.org/
10.1016/j.fct.2015.06.020
 Salicylic acid (1) and its Salicylic acid/calcium
10.1016/j.fct.2015.06.020
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salts salicylate/magnesium
salicylate/mea-salicylate/
sodium salicylate/
potassium salicylate/tea-
salicylate
4 Hexa-2,4-dienoic acid and Sorbic acid/calcium
its salts sorbate/sodium sorbate/
potassium sorbate
5 Formaldehyde, Formaldehyde/
paraformaldehyde (3) paraformaldehyde
6 Moved or deleted
7 Biphenyl-2-ol, and its salts O-phenylphenol/mea O-
phenylphenate/potassium
O-phenylphenate/sodium
O-phenylphenate
8 Pyrithione zinc (4) Zinc pyrithione
9 Inorganic sulphites and Sodium sulfite/
hydrogensulphites (5) ammonium bisulfite/
ammonium sulfite/
potassium sulfite/
potassium hydrogen
sulfite/sodium bisulfite/
sodium metabisulfite/
potassium metabisulfite
10 Moved or deleted
11 Chlorobutanol Chlorobutanol
12 bis Butyl 4-hydroxybenzoate Butylparaben/
and its salts propylparaben/sodium
propoylparaben/sodium
Propyl 4-hydroxybenzoate butylparaben/potassium
and its salts butylparaben/potassium
propylparaben
12 4-Hydroxybenzoic acid 4-hydroxybenzoic acid/
and its salts and esters, methylparaben/potassium
other than the esters of ethylparaben/potassium
isopropyl, isobutyl, paraben/sodium
phenyl, benzyl and pentyl methylparaben/sodium
ethylparaben/
ethylparaben/sidium
paraben/potassium
methylparaben/calcium
paraben
13 3-Acetyl-6-methylpyran- Dehydroacetic acid/
2,4(3H)- dione and its salts sodium dehydroacetate
14 Formic acid and its sodium Formic acid/sodium
salt formate
15 3,30 -Dibromo-4,40 - Dibromohexamidine
hexamethylene isethionate
dioxydibenzamidine
69-72-7/824-35-1/18917- 200-712-3/212-525-4/ Not to be used in products Not to be used for children
89-0/59866-70-5/54-21- 242-669-3/261-963-2/ for children under 3 years under 3 years of age (2)
7/578-36-9/2174-16-5 200-198-0/209-421-6/ of age, except for
218-531-3 shampoos
110-44-1/7492-55-9/ 203-768-7/231-321-6/ 0.6% (acid)
7757-81-5/24634-61-5 231-819-3/246-376-1
50-00-0/30525-89-4 200-001-8/- a) Oral products a) 0.1% Not to be used in aerosol
(free formaldehyde) dispensers (sprays)
b) Other products b) 0.2%
(free formaldehyde)
90-43-7/132-27-4/ 201-993-5/205-055-6/ 0.2% (as the phenol)
13707-65-8/84145-04-0 237-243-9/282-227-7
13463-41-7 236-671-3 a) Hair products a) 1.0% a) Only in rinse-off
product
b) Other products b) 0.5% b) Not to be usee in oral
L.M. Katz et al. / Food and Chemical Toxicology xxx (2015) 1e11
products
7757-83-7/10192-30-0/ 231-821-4/233-469-7/ 0.2% (as free SO2)
10196-04-0/10117-38-1/ 233-484-9/233-321-1/
7773-03-7/7631-90-5/ 231-870-1/231-548-0/
7681-57-4/16731-55-8 231-673-0/240-795-3
57-15-8 200-317-6 0.5% Not to be used in aerosol Contains chlorobutanol
dispensers (sprays)
94-26-8/94-13-3/35285- 202-318-7/202-307-7/
0.14% (as acid) for the Not to be used in leave-on Fri leave-on products
69-9/36457-20-2/38566- 252-488-1/253-/049-7/ sum of the individual product designed for designed for children
94-8/84930-16-5 254-/009-1/284-597-5 concentrations application on the nappy under three years of age:

0.8% (as acid) for area of children under “Do not use on the nappy
mixtures of substances three years of age. area”
mentioned in entry 12 and
12a, here the sum of the
individual concentrations
of butyl and
propylparaben and their
salts does not exceed
0.14%
99-96-7/99-76-3/36457- 202-804-9/202-785-7/ 0,4% (as acid) for single
19-9/16782-08-4/5026- 253-048-1/240-830-2/ ester 0.8% (as acid) for
62-0/35285-68-8/120-47- 225-714-1/252-487-6/ mixtures of esters
8/114-63-6/26112-0-2/ 204-399-4/204-051-1/
69959-44-0 247-464-2/274-235-4
520-45-6/4418-26-2/ 208-293-9/224-580-1/- 0.6% (as acid) Not to be used in aerosol
16807-48-0 dispensers (sprays)
64-18-6/141-53-7 200-579-1/205-488-0 0.5% (as acid)
93856-83-8 299-116-4 0.1%
(continued on next page)
7
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Reference Chemical name/INN Substance identification Conditions Wording of conditions of

number use and warnings
Name of common CAS number EC number Product type, body parts Maximum concentration Other
ingredients glossary in ready for use
preparation

a b c d e f g h i

and its salts (including

isethionate)
16 Thiomersal Thimerosal 54-64-8 200-210-4 Eye products 0.007% (of Hg) If mixed Contains Thiomersal
with other mercurial
compounds authorized by
this Regulation, the
maximum concentration
of Hg remains fixed at
0.007%
17 Phenylmercuric salts Phenylmercuric acetate/ 62-38-4/94-43-9 200-532-5/202-331-8 Eye products 0.007% (of Hg) If mixed Contains Phenylmercuric
(including borate) phenylmercuric benzoate with other mercurial compounds
compounds authorized by
this Directive, the
maximum concentration

L.M. Katz et al. / Food and Chemical Toxicology xxx (2015) 1e11
of Hg remains fixed at
0.007%
18 Undec-10-enoic acid and Undecylenic acid/ 112-38-9/6159-41-7/ 203-965-8/-/222-264-8/ 0.2% (as acid)
its salts potassium undecylenate/ 3398-33-2/1322-14-1/ 215-331-8/282-908-9/
sodium undecylenate/ 84471-25-0/56532-40-2 260-247-7
calcium undecylenate/
mea-undecylenate/tea-
undecylenate
19 5-Pyrimidinamine, 1,3- Hexetidine 141-94-6 205-513-5 0.1%
bis(2-ethylhexyl)
hexahydro-5-methyl-
20 5-Bromo-5-nitro-1,3- 5-bromo-5-nitro-1,3- 30007-47-7 250-001-7 Rinse-off products 0.1% Avoid formation of
dioxane dioxa ne nitrosamines
21 Bronopol 2-bromo-2-nitropropane- 52-51-7 200-143-0 0.1% Avoid formation of
1,3-diol nitrosamines
22 2,4-Dichlorobenzyl Dichlorobenzyl alcohol 1777-82-8 217-210-5 0.15%
alcohol
23 1-(4-Chlorophenyl)-3- Triclocarban 101-20-2 202-924-1 0.2% Purity criteria:3,30 , 4, 40 -
(3,4-dichlo ophenyl)urea Tetrachloroazo
(6) benzene<1 ppm; 3,30 , 4,40 -
Tetrachloroazo
xybenzene<1 ppm
24 Chlorocresol P-chloro-M-cresol 59-50-7 200-431-6 Not to be used in products 0.2%
applied on mucous
membrane
25 5-Chloro-2-(2,4- triclosan 3380-34-5 222-182-2 (a) Toothpastes, hand (a) 0.3%
dichlorophenoxy phenol) soaps, Body soaps/
Shower gels,
Deodorants (non-
spray), Face
powders and
blemish concealers.
Nail products for
cleaning the
fingernails and
toenails before the
application of
artificial nail
systems.
(b) Mouthwashes (b) 0.2%
26 Chloroxylenol chloroxylenol 88-04-0/1321-23-9 201-793-8/215-316-6 0.5%
27 N,N00 -Methylenebis[N0 -[3- Imidazolidinyl 39236-46-9 254-372-6 0.6%
(hydro ymethyl)-2,5-
 dioxoimidazolidin- -yl]
10.1016/j.fct.2015.06.020
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urea]
28 Poly(methylene),. Polyaminopropyl 32289-58-0/27083-27-8/ e 0.3%
alpha.,.omega.-bis biguanide 28757-47-3/133029-32-0
[[[(aminoimin methyl)
amino]iminomethyl]amin
]-, dihydrochloride
29 2-Phenoxyethanol Phenoxyethanol 122-99-6 204-589-7 1.0%
30 Methenamine Methenamine 100-97-0 202-905-8 0 15%
31 Methenamine 3- Quaternium-15 4080-31-3 223-805-0 0.2%
chloroallylochloride
32 1-(4-Chlorophenoxy)-1- Climbazole 38083-17-9 253-775-4 0.5%
(imidazo-1-yl)-3,3-
dimethylbutan-2-one
33 1,3-Bis(hydroxymethyl)- DMDM hydantoin 6440-58-0 229-222-8 0.6%
5,5-dim hylimidazolidine-
2,4-dione
34 Benzyl alcohol (7) Benzyl alcohol 100-51-6 202-859-9 1.0%
35 1-Hydroxy-4-methyl-6- 1-hydroxy-4-methyl-6-(2, 50650-76-5/68890-66-4 -/272-574-2 a) Rinse-off products a) 1.0%
(2,4,4-trin ethylpentyl)-2 4,4-trimethylpentyl)-2 b) Other products b) 0.5%
pyridon and its pyridon, piroctone

L.M. Katz et al. / Food and Chemical Toxicology xxx (2015) 1e11
monoethanolamine salt olamine
36 Moved or deleted
37 2,20 -Methylenebis(6- Bromochlorophene 15435-29-7 239-446-8 0.1%
bromo-4-chl rophenol)
38 4-Isopropyl-m-cresol O-Cymen-5-OL 3228-02-2 221-761-7 0.1%
39 Mixture of 5-Chloro-2- Methylchloroisothiazo 26172-55-4, 2682-20-4, 247-500-7, 220-239-6 Produit a ricer 0.0015% (of a mixture in
methyl-isothiazol-3(2 H)- linone and 55965-84-9 the ratio 3:1 of 5-Chloro-
one and 2- Methylisothiazolinone 2-methyl -isothiazol-
Methylisothiazol-3(2H)- 3(2H)-o ne and 2-
one with magnesium Methylisothiazol
chloride and magnesium
3(2H)-one
nitrate
40 2-Benzyl-4-chlorophenol Chlorophene 120-32-1 204-385-8 0.2%
41 2-Chloroacetamide Chloroacetamide 79-07-2 201-174-2 0.3% Contains chloroacetamide
42 N,N'-bis(4-chlorophenyl)- Chlorhexidine/ 55-56-1/56-95-1/18472- 200-238-7/200-302-4/ 0.3% (as chlorhexidine)
3,12-dii mino-2,4,11,13- chlorhexidine 51-0/3697-42-5 242-354-0/223-026-6
tetraazatetradecan Diacetate/chlorhexidine
ediamidine and its Digluconate/
digluconate, diacetate and chlorhexidine
dihydrochloride Dihydrochloride
43 1-Phenoxypropan-2-ol (8) Phenoxyisopropanol 770-35-4 212-222-7 Only for rinse-off products 1.0%
44 Alkyl (C12eC22) trimethyl Behentrimonium chloride 17301-53-0/57-09-0/112- 241-327-0/200-311-3/ 0.1%
ammonium bromide and (1)/cetrimonium bromide/ 02-7/1119-94-4/112-00- 203-928-6/214-290-3/
chloride cetrimonium chloride (2)/ 5/1120-02-1/112-03-8 203-927-0/214-294-5/
laurtrimonium bromide/ 203-929-1
laurtrimonium chloride/
steartrimonium bromide/
steartrimonium chloride
(2)
45 4,4-Dimenthyl-1,3- Dimethyl oxazolidine 51200-87-4 257-048-2 0 1% pH > 6
oxazolidine
46 N-(Hydroxymethyl)-N- Diazolidinyl urea 78491-02-8 278-928-2 0.5%
(dihydrox methyl-1,3-
dioxo-2,5-imidazolidinyl-
4)-N0 -(hydroxymethyl)
urea
47 Benzenecarboximidamide, Hexamidine/hexamidine 3811-75-4/659-40-5/ -/211-533-5/299-055-3/- 0.1%
4,40 -(1,6- diisethionate/hexamidine 93841-83-9/-
hexanediylbis(oxy))bis-, diparaben/hexamidine
and its salts (including paraben
isothionate and p-
hydroxybenzoate)
(continued on next page)

9
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Reference Chemical name/INN Substance identification Conditions Wording of conditions of

number use and warnings
Name of common CAS number EC number Product type, body parts Maximum concentration Other
ingredients glossary in ready for use
preparation

a b c d e f g h i

48 Glutaraldehyde (Pentane- Glutaral 111-30-8 203-856-5 0.1% Not to be used in aerosols Contains glutaral (9)
1,5-dial) (sprays)
49 5-Ethyl-3,7-dioxa-1- 7-ethylbicyclooxazolidine 7747-35-5 231-810-4 0.3% Not to be used in oral
azabicyclo[3.3.0] octane products and in products
applied on mucous
membranes
50 3-(p-Chlorophenoxy)- Chlorphenesin 104-29-0 203-192-6 0.3%
propane-1,2 -diol
51 Sodium Sodium 70161-44-3 274-357-8 0.5%
hydroxymethylamino hydroxymethylglycinate
acetate
52 Silver chloride deposited Silver chloride 7783-90-6 232-033-3 0.004% (as AgCl) 20% AgCl (w/w) on TiO2.
on titanium dioxide Not to be used in products

L.M. Katz et al. / Food and Chemical Toxicology xxx (2015) 1e11
for children under 3 years
of age, in oral products and
in eye and lip products
53 Benzenemethanaminium, Benzethonium chloride 121-54-0 204-479-9 a) Rinse-off products 0.1%
N,N-dimethyl-N-[2-[2-[4- b) Leave-on products
(1,1,3,3, other than oral
-tetramethylbutyl) products
phenoxy]ethoxy ]ethyl]-,
chloride
54 Benzalkonium chloride, Benzalkonium chloride/ 8001-54-5/63449-41-2/ 264-151-6/293-522-5/ 0.1% (as benzalkonium Avoid contact with eyes
bromide and saccharinate benzalkonium bromide/ 91080-29-4/68989-01-5/ 273-545-7/270-325-2/ chloride)
(10) benzalkonium 68424-85-1/68391-01-5/ 269-919-4/263-080-8/
saccharinate 61789-71-7/85409-22-9 287-089-1
55 Methanol, Benzylhemiformal 14548-60-8 238-588-8 Rinse-off products 0.15%
(phenylmethoxy)-
56 3-Iodo-2- Iodopropynyl 55406-53-6 259-627-5 a) Rinse-off products a) 0.02% Not to be used in oral and Not to be used for children
propynylbutylcarbamate butylcarbamate b) Leave-on products b) 0.01% lip products a) Not to be under three years of age
c) Deodorants/ c) 0.0075% used in products for (11) b) and c) Not to be
antiperspirants children under 3 years of used for children under
age, except in bath three years of age (12)
products/shower gels and
shampoos b) Not to be
used in body lotion and
body cream (13) b) and c)
Not to be used in products
for children under 3 years
of age
57 2-Methyl-2H-isothiazol- Methylisothiazolinone 2682-20-4 220-239-6 0.01%
3-one
58 Ethyl Lauroyl Arginate HCl 60372-77-2 434-630-6 0.4% Not to be used in lip
(preservative) products, oral products
and spray products
59 1,2,3-Propanetricarboxylic Citric acid (and) silver 460-890-5 0.2% corresponding to Not to be used in oral
acid, 2-hydroxy-, citrate 0,0024% of silver producrs and eye products
monohydrate and 1,2,3-
Propanetricarboxylic acid,
2-hydroxy-silver(1þ) salt,
monohydrate

1. For the purposes of this list: ‘Salts’ is taken to mean: salts of the cations sodium, potassium, calcium, magnesium, ammonium and ethanolamines; salts of the anions chloride, bromide, sulphate, acetate. ‘Esters’ is taken to
mean: esters of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl.
2. All finished products containing formaldehyde or substances in this Annex and which release formaldehyde must be labeled with the warning ‘contains formaldehyde’ where the concentration of formaldehyde in the finished
product exceeds 0.05%.
 L.M. Katz et al. / Food and Chemical Toxicology xxx (2015) 1e11
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