Contact Lens & Anterior Eye 35 (2012) 247–259

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Contact Lens & Anterior Eye

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Review

Transport and interaction of cosmetic product material within the ocular surface:
Beauty and the beastly symptoms of toxic tears
Adeela Malik ∗ , Charles Claoué
Barking, Havering and Redbridge University Hospitals NHS Trust, Ophthalmology Department, Queen’s Hospital, Rom Valley Road, Romford, Essex RM7 0AG, United Kingdom

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

Article history: Eye cosmetics such as mascara, eye shadow and eyeliner are used extensively to highlight the eyes, and
Received 10 January 2012 are normally applied external to the ocular surface. Adverse reactions of cosmetics within the ocular
Received in revised form 23 July 2012 surface include mild discomfort, eyelid dermatitis, pre-corneal tear film instability, and keratitis. These
Accepted 24 July 2012
are attributed mainly to the preservative (benzalkonium chloride (BAC)) constituent of cosmetic product
material (CPM).
Keywords:
Transport of CPM from an external environment to any location on the ocular surface, essentially
Eye cosmetics
precedes the adverse interactions occurring at the location, and the control of these transport modes is
Dry eyes
Preservatives
therefore of clinical relevance.
Ocular surface The inter-transport of CPM across the TF occurs due to both diffusion and drift processes. Diffusion of
Adverse ocular effects neutral species is driven by concentration gradients, and the drift of cationic BAC is influenced by the
inherent electric field; determined by the distribution of the various ions secreted into the aqueous layer,
and the negative glycocalyx charge at the mucin layer.
In the presence of mucin deficiency, the corneal epithelium is exposed to invasion by both incident BAC
and lipophilic species. The transport of cationic BAC across the TF may be controlled by regulating the
secretion of various electrolytes at the lacrimal gland. This is of clinical significance in reducing corneal
epithelial adverse effects. However, the risks of adverse effects at the corneal surface due to invasion by
the lipophilic species remain. Patients with mucin deficiency, and especially those on eye ointment/drops
medication, should be discouraged from using cosmetics in a way likely to contaminate the TF.
© 2012 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction The chemical composition of eye cosmetics is complex, but is

Cosmetics [1–9] such as mascara, eye shadow and eyeliner are
used extensively world-wide to highlight and emphasise the eyes.
Most of these are applied away from the ocular surface (Fig. 1) but
some may exist precariously close to the eyelash margin. How-
ever adverse reactions [10–15] to these eye cosmetics, ranging from
simple irritation, keratitis, corneal epithelium inflammation, eye-
lid dermatitis and dry eye [16–18] symptoms have been reported.
This suggests migration of cosmetic product material (CPM) from
an external environment onto the ocular surface including the
pre-corneal tear film (TF). It is also obvious that adverse reac-
tions at any distal location on the ocular surface essentially occur
due to the transport of CPM from an external environment to this
location and the resulting chemical/biological interactions at the
location determine the nature of the adverse activity. Thus the con-
trol/suppression of CPM transport modes within the ocular surface
is of relevance in the prevention of adverse effects of eye cosmetics.
∗ Corresponding author. Tel.: +44 01708 435 000.
E-mail addresses: adeela15malik@gmail.com, adeelam@gmail.com (A. Malik).
well documented [1–9]. Additives such as fragrance and preserva-
tives in cosmetics are well known to give rise to toxic and allergic
reactions [11,19]. The current manufacturing trend is to avoid the
use of fragrance, but the inclusion of preservatives is necessary
in order to prevent growth of bacteria during storage and con-
trol of infection. Benzalkonium chloride (BAC) is the most common
preservative used in eye cosmetics [11,19–23].
Significant observed deterioration [24,25] in contact lenses dur-
ing wearing has also been attributed to the use of ocular cosmetics.
Mascara pigmentation of the bulbar conjunctiva is associated with
rigid gas permeable lens wear [26].
In this review, the expected CPM transport modes within the
various regions of the ocular surface will be discussed. Transport
driving factors and the resulting adverse effects are identified. For
completeness, the properties of popular eye cosmetics i.e. eyeliner,
mascara and eye shadow are also summarised.
The initial migration of CPM from the external environment
onto the immediate ocular surface i.e. adjacent to the eyelash mar-
gin, occurs [27,28] due to mechanical push, suction due to tear
surface tension or wrapping/blinking of the eyelids. Conjunctival
absorption, epithelial pigmentation and posterior blepharitis are

1367-0484/$ – see front matter © 2012 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.clae.2012.07.005
248 A. Malik, C. Claoué / Contact Lens & Anterior Eye 35 (2012) 247–259
Fig. 1. Interrelationship between various cosmetic product material (CPM), transport modes, driving factors/mechanisms, and the resulting adverse effects of eye cosmetics
within the ocular surface.
the typical expected adverse effects during this phase of transporta-
tion.
The subsequent interaction and transport of CPM across vari-
ous layers of the TF are largely determined by the characteristic
properties of its constituents, the chemistry of the individual TF
layer and the driving forces such as an electric field or concentra-
tion gradient. The distribution of +ve and −ve ions (electrolytes
secreted by the lacrimal gland) within the aqueous layer, in con-
junction with the −ve glycocalyx at the mucin, give rise to the
electric field, leading to drift of the charged species within the TF.
Due to the constant scavenging effect of the mucin (removal of
incident debris and pathogens), the net charge in the region at any
time and hence the electric field is difficult to predict. Concentra-
tion gradients, leading to diffusion processes, arise mainly due to
the aggregation of the neutral species within the medium. For the
purpose of the present work, CPM is considered as a mixture of BAC
(cationic polar molecules) and neutral lipophilic species.
The initial penetration of BAC across the lipid layer of the TF, in
the absence of an electric field, is concentration dependent. In vitro
experimental study [29] concerning interaction of BAC with lipids,
suggests that at low concentration <0.01%, adsorbed BAC within the
lipid layer exists as individual monomers and as micelles at higher
concentration >0.01%. Monomers are generally unable to penetrate
the lipid layer, but the few that do penetrate, alter its structure and
are trapped within the layer.
We suggest that cationic polar BAC, because of its affinity for
water/aqueous; preferentially align along the lower polar lipid
layer arrangement adjacent to the aqueous layer. Thereafter, the
majority of charged BAC species drift into the aqueous phase due to
the force of the electric field. Others, form neutral complexes with
polar lipids and are displaced as neutral species into the aqueous
phase. This process is probable, as charged cationic BAC is deficient
in electron and the polar lipid bilayer is ready to be ionised. It is
similar to ionisation of polar lipids in the presence of an ion that
facilitates the transfer of electrons leading to formation of free rad-
icals [30,31]. However due to the weak forces involved, complete
transfer of an electron does not occur, rather an electron is shared
between electron-deficient BAC and polar lipid to form neutral BAC
complex.
Both neutral and cationic BAC species thus exist within the aque-
ous layer beneath the lipid layer, and directly affect the osmolarity
and viscoelasticity of the TF, leading to dry eye symptoms.
Within the aqueous layer, the drift of the cationic BAC species
is dictated by the prevailing electric field, and the neutral species
diffuse according to the laws of passive diffusion governed by
concentration gradient. Net excess −ve charge within the TF
gives rise to a negative field that promotes drift of cationic BAC
towards the mucin layer, whereas net +ve charge leads to posi-
tive field that retards the drift of charged BAC towards the mucin
layer. Neutral BAC complexes after aggregation within the aque-
ous phase beneath the lipid layer move according to the laws of
diffusion.
Lipophilic species of CPM initially diffuse through the lipid
bilayer according to the laws of simple diffusion [32]. Thereafter
the diffusing neutral lipophilic species are insoluble within the
host aqueous layer and tend to aggregate beneath the lipid layer,
leading to passive diffusion within the aqueous phase, driven by
concentration gradient.
Further along the aqueous layer, the deep interposing mucin
layer acts as a barrier, and under normal circumstances the corneal
surface is protected from invasion by incident BAC and lipophilic
species.
However, in the presence of mucin deficiency, both BAC and
lipophilic species are able to interact with the corneal epithelium.
The interaction of the cationic BAC with the epithelium may
be reduced by creating net +ve charge within the aqueous layer
by enhancing the secretion of positive electrolytes at the lacrimal
gland, and this is of clinical significance particularly during mucin
deficiency.
However, in patients with mucin deficiency, adverse effects at
the corneal epithelium can occur due to lipophilic species alone i.e.
even with preservative-free cosmetics. These patients and espe-
cially those on eye ointment/drops medication should be informed
of the beastly aspects of cosmetics and discouraged from using
cosmetics in a way likely to contaminate the TF.
Fig. 1 illustrates the interrelationship between the various CPM
transport modes, the driving factors/mechanisms and the resulting
adverse effects of eye cosmetics within the ocular surface.
 A. Malik, C. Claoué / Contact Lens & Anterior Eye 35 (2012) 247–259
Fig. 2. Ocular surface and typical areas of application of popular eye cosmetics.
2. Eye cosmetics
Eye-mascara, eye-liner and eye-shadow are the three most pop-
ular types of eye cosmetics used predominantly by the human
female population worldwide. These products are normally applied
external to the ocular surface and are available in different forms
such as liquid, paste or powder to suit various skin conditions and
climatic environment. Fig. 2 illustrates the typical regions of appli-
cation of the various eye cosmetics in relation to the ocular surface.
2.1. Mascara
Mascara [6,33] is commonly used to enhance lashes. It may
darken, thicken, lengthen or define eyelashes. The main properties
and chemical composition of mascara are summarised in Table 1.
2.2. Eye shadow
Eye shadow [6,34] is applied on the eyelids and under the eye-
brows, to make a person’s eyes stand out while adding depth and
dimension. The main properties of eye shadow are summarised in
Table 2.
2.3. Eyeliner
Eyeliner [6,35] enhances the eyelashes on the upper and the
lower lids, and its main properties are summarised in Table 3.
2.4. Dyes for tinting of lashes and brows
Eyelash and eyebrow dyes are used to match the eyelash and
eyebrow colour with the hair colour. The procedure is illegal and
not approved by the FDA in the USA because of the risks involved
[6]. The dyes comprise toluenediamine and paraphenylenediamine
to provide a dark pigment [10]. The metallic dyes such as lead
acetate, silver acetate and sulphur are the safest and are gradual
in achieving colouring [36].
249
2.5. Eye makeup remover/solvent
Most eye makeup remover/solvents consist [13] of methyl
hydroxy cellulose, propylene glycol, sodium ether myristyl sul-
phate, hydrogenated castor, water and preservatives. These are not
normally allergenic, but could be a source of irritation and direct
toxicity to the tear film.
3. Preservatives used in eye cosmetic products
Benzalkonium chloride (BAC), thimerosol, chlorhexidine and
colophony are used [11] as preservatives in eye cosmetics and all
are capable of causing contact allergy. Thimerosol is used [9] pri-
marily in mascaras. Colophony or rosin (an extract derived from
pine) is occasionally used [6] in eye shadow and mascara. BAC or
chlorhexidine preservatives are used in sensitive-skin contact lens
products and eye cosmetics. It fulfils the European Pharmacopoeia
challenge test for inhibition of bacteria growth during storage of
ophthalmic formulations.
BAC is a quaternary ammonium salt with surfactant properties
and its molecules are charged (cationic) and polar. At water/air
surface and at low concentration (<0.01%) BAC molecules exist as
monomers and as micelles at high concentration (>0.01%) [29]. BAC
also causes cell hyperpermeabilty and in cell cultures, it induces
apoptosis at low concentrations and necrosis at high concentra-
tions.
Formaldehyde releasing preservatives are also effective addi-
tives to counter [11] contamination ‘on the shelf’ in cosmetics,
especially in preventing the growth of Gram-negative bacterial
organisms [14]. Under certain conditions, cosmetics can cause aller-
gic contact or irritant contact dermatitis [10–15,37].
4. Safety and regulation of cosmetic products
In the USA the production and safety of the cosmetics falls under
the Federal Food, Drugs and Cosmetic (FDA) Act 1938. FDA classi-
fies the cosmetics without actually regulating them. This allows a
250 A. Malik, C. Claoué / Contact Lens & Anterior Eye 35 (2012) 247–259

Table 1
Composition and properties of mascara.

Type Application Composition Remarks/disadvantages

Mascara is available as cake or Applied to eyelashes to: darken, Cake preparation:
liquid thicken or define eyelashes Pressed together soap and waxes
(paraffin, carnauba or bees wax)
Liquid preparation:
Non water resistant:
Preservatives, waxes, resins, pigments
(oil in water emulsion), thickening
additives (nylon, rayon fibres,
hydrolysed animal protein) and
polyvinylpyrrolidone (to resist
smudging).
Mascaras designed to lengthen or curl
the eyelashes contain nylon/rayon
micro fibres with ceresin and
methylcellulose as stiffeners.
Water resistant preparation:
As above plus water resistant agent:
dodecane
Liquid mascara is produced as water resistant
or non water resistant product.
Water washable mascara is easy to wash away
with soap and water. Water resistant mascara
need special eye make-up remover (Section
2.5) and this could be hazardous especially
with sparse lashes.
Excessive use of particles in the mascara
composition, poses a risk to contact lens
wearers.
Mascara is dispensed in a tube with a
dispenser brush.
It is advisable not to share mascara with
others;
Pseudomonas aeruginosa infections have been
reported [3] from contaminated mascaras,
trauma to the eye or bad hygiene.

Table 2
Composition and properties of eye shadow.

Type Application Composition Remarks/disadvantages

Available as: powder, cream, stick,
and pencil. It comes in many
colours and textures. Choice of
colours allowed [24], regulated
[23] by Food, Drug and Cosmetic
Act 1938
Applied on the eyelids and under
the eyebrows to make eyes stand
out. It provides depth and
dimension
Powder:
It consists of pressed powder on cake
(hydrated magnesium silicate) as a base.
Kaolin (hydrated aluminium silicate,
titanium dioxide and calcium carbonate)
and potato starch are added to cake to
attain coverage and absorption of oil from
the skin of the eye.
Zinc stearate is used to attain [6]
smoothness and adhesion to the eyelid.
Micronized titanium dioxide, zinc oxide
and silicone derivatives are used as
pigments. Binders (lanolin, mineral oils,
isopropyl stearate) are added to the cake to
avoid flaking and also to aid dispersion of
pigmenting agents.
Cream:
Water resistant product and contains
anhydrous formulations of pigments in
petrolatum, cocoa butter or lanolin.
Pencil:
Consists of talc (as filler), mica, sericite
(fine grained mica), magnesium stearate,
colourants, preservatives, and magnesium
stearate (dry binder). Ingredients pressed
together at high pressure.
Powder:
Typical chalk like appearance of the
shadow is now out of fashion. Bismuth
oxychloride and mica are added for a
frosted or sparkling appearance, and fish
scale essence for a pearly or shinny look.
Addition of copper, brass, gold or silver
powders provide iridescent finish, but
these ingredients may leach out and pose
problems for contact lens wearers.
Preservatives and rubber tipped applicator
can cause adverse reactions. Thus these
products are not suitable for dermatitic
skin. Patients with seborrheic blepharitis
or otopic dermatitis are vulnerable to
contact or irritant dermatitis.
Cream:
Suitable for dry or wrinkled skin.
Unsuitable for oily skin. Hypoallergenic
formulations of this product contain no
lanolin or its derivatives.
Pencil:
The product is stiff and inappropriate for
recent eye surgery patients, but suitable
for oily skins.

Table 3
Composition and properties of eyeliner.

Type Application Composition Remarks/disadvantages

Liquid:
Available as: liquid pencil and Enhances the eyelashes on the
Comprises pigments, water, cellulose gum,
cake upper and lower lids
thickeners (magnesium and aluminium
silicate), and water soluble styrenebutadiene
latex or a polymer ammonium acrylate.
Pencil:
Consists of natural and synthetic waxes
combined with oils and pigments
Cake:
Same as eye shadow, but includes surfactants
to promote the formation of paste when
powder is mixed with water
Liquid:
The product contains a brush inside a
cylindrical container. As water soluble latex
needs preservative, thus liquid liners can cause
dermatitis.
Pencil:
As there is no fragrance or preservative in this
type of liner, there is no risk of contact
dermatitis.
 A. Malik, C. Claoué / Contact Lens & Anterior Eye 35 (2012) 247–259 251

Table 4 The pre-corneal tear film is also a part of an elaborate ocu-

Typical concentration of benzalkonium chloride (BAK) preservative in various
products/applications.
Application
As a preservative for eye drops intended to
combat corneal dryness [86]
Contact wetting solutions [86]
Cosmetics safe concentration [82,83]
Antibiotic fluoroquinolones (catifloxacin)
ophthalmic solution 0.3% [81]
Clinical range
lar surface defence mechanism [43]. Lysozyme [44] is a natural
form of protection against Gram-positive pathogens like Bacillus,
BAK concentration (%) Staphylococcus and Streptococcus, and the conjunctiva is protected
0.01 by secreted lysozyme and defensins. Failure of these protective
barriers can lead to conjunctivitis.
0.002–0.005
0.1
0.005 (50 ␮g/ml) 5.1. Mucin layer
0.001–0.02
The inner mucin layer has a role in tear film spreading, ocular
surface wetting and it also prevents invasion of corneal epithelium
from foreign debris and pathogens. Mucins are heavily glycosylated
high molecular weight glycopropteins, where heavy glycosylation
imparts an overall negative charge to the glycoprotein [45–48].
Mucin is classified as either secretary or membrane-associated.
The former is produced by conjunctival goblet cells and the lat-
ter by conjunctival and corneal epithelial cells [49]. New evidence
suggests that mucin is also produced by the lacrimal gland [50–52].
Membrane-associated mucins form the glycocalyx (a dense
barrier to pathogen penetrance) at the epithelial cell-tear film inter-
face [46]. It contains a hydrophobic transmembrane domain that
anchors to the mucin on the apical surface of the epithelial cells
(a short cytoplasmic tail that extends into the cytoplasm) and an
extracellular domain that reaches into the tear film [53]. This hold-
ing of mucin to the ocular surface, creates water attraction, as
corneal surface is naturally water repellent.
Secreted mucins move easily over the membrane-associated
mucins (comprising glycocalyx), due to the repulsive forces result-
ing from their anionic character [54]. Secretary mucins moving
through the tear fluid collect debris that is removed via the naso-
lacrimal duct during blinking.

5.2. Aqueous layer

The aqueous layer creates a suitable environment for the epithe-

Fig. 3. Tear film models.
manufacturer to use ingredients or raw materials and market the
final product without the government approval.
In Europe, the text of European Pharmacopoeia for inhibition of
bacteria growth during storage of ophthalmic formulations is fol-
lowed. Table 4 summarises the recommended safe concentrations
of BAC preservative in various cosmetic preparations and proce-
dures.
The cosmetic industry utilises the Draize eye irritation test
[38–40] using animals (rabbits). These tests are highly subjective,
and different laboratories often yield different results. There are
also ethical concerns about the relevance of this test.
5. Pre-corneal tear film (TF)
Tears [41,42] are a complex solution of water, enzymes, proteins,
immunoglobulins, lipids, metabolites and exfoliated epithelial
and polymorphonuclear cells. The pre-corneal tear film (TF) is
composed of three main layers: mucin (inner layer), aqueous
(intermediate layer) and a lipid (outer oily layer). The current
understanding is that instead of the traditional three separate lay-
ers (Fig. 3A), tear film comprises two layers consisting of a lipid layer
supported by an aqueous-mucin gel layer [42], where the concen-
tration gradient of the mucin decreases away from the epithelium
(Fig. 3B).
lial cells of the ocular surface and transport of essential nutrients
and oxygen to the cornea. It also provides support for the cell
movement over the ocular surface including washing away of the
epithelial debris, toxic elements and foreign bodies. It is produced
by primary and accessory lacrimal glands activated by hormonal,
sympathetic and parasympathetic stimuli.
Aqueous layer consists of water, electrolytes, proteins, peptide
growth factors, immunoglobulins, cytokines, vitamins, antimi-
crobials, and hormones secreted by the lacrimal glands [55,56].
Reduced aqueous tear production leads to a decreased growth fac-
tor concentration in the tears.
Electrolytes comprise positively charged sodium, potassium,
magnesium and calcium ions, and negatively charged chloride,
bicarbonate and phosphate ions. The electrolytes determine the
osmolarity of tears, act as a buffer in maintaining a constant pH
and also contribute in maintaining epithelial integrity of the ocu-
lar surface [57,58]. An increase in osmolarity of the aqueous layer
is a global feature of dry eye syndrome and leads to damage to
the ocular surface directly or indirectly by triggering inflammation
[56–59].
Proteins in human tears are species-specific [60]. The pri-
mary defense system of the ocular surface is composed of the
non-specific immunity conferred by lysozyme, lactoferrin, ␤-
lysin, defensins and the specific immunity of antibodies [56].
In aqueous-deficient dry eye syndrome, the concentration of
lysozyme, lactoferrin and lipocalin are reduced, compromising the
integrity of the defense system [61,62]. Evidence suggests that
lipocalin when complexed with other tear components may be
responsible for the high viscosity and low surface tension of tears
[63–65].
252 A. Malik, C. Claoué / Contact Lens & Anterior Eye 35 (2012) 247–259
5.3. Meibomian lipids
Meibum, the anterior layer of the tear film, is a complex mixture
[66–72] of lipids of various classes (phospholipids, sphingolipids,
triglycerides, wax esters, cholesterol esters, free fatty acid and
hydrocarbons). It is produced by the meibomian glands located
within the tarsal plates. It is the main barrier to evaporation from
the ocular surface [73]. A smooth lipid layer is also essential for
refraction of light into the eye and the formation of sharp retinal
image.
The anterior lipid layer (meibum) of the tear film consists
[66,67] of two sub-layers: non-polar lipids and amphiphillic lipids.
A polar phase composed of mainly phospholipid and glycol-
ipids acts as a surfactant between the hydrophilic aqueous-mucin
layer and the thick nonpolar lipid layer [73,74]. The non-polar
phase comprising mainly wax, cholesterol esters and triglycerides,
provide the air-tear film interface and also retards evaporation
[73]. Recent research [72] suggests that phospholipids (the polar
constituents) hitherto considered as an important stabilising com-
pound for the entire film structure, are absent in meibum, and
instead an alternative group of very long chain amphiphilic com-
pounds: (O-acyl)-omega-hydroxy fatty acids stabilises the film
structure.
Normally polar lipids are short chain, capable of ionisation
and/or formation of hydrogen bonds with molecules of water. In a
two phase water/oil mixture they tend to accumulate in the aque-
ous phase. Non-polar lipids are poorly soluble in water and in a
water/oil biphase mixture congregate in the oil. Amphiphillic lipids
consist of both polar and non-polar groups and tend to accumulate
at oil/water interface, with their polar group facing aqueous layer
and the non-polar group submerged in the oil.
6. Adverse reactions of eye cosmetics
Presence of cosmetic product material (CPM) within and along
the ocular surface can lead to adverse effects [10] ranging from mild
discomfort (stinging, itching or burning without visible skin lesion)
to eyelid dermatitis, tear film instability, corneal epithelium inflam-
mation, severe corneal keratitis and posterior blepharitis [74,75].
Allergy, allergic contact dermatitis and toxicity are known
adverse effects of fragrance and preservatives used in cosmetic
materials. Accordingly, the use of fragrance (a collection of many
ingredients and the most common cause of allergy [16] in cos-
metics) is now avoided in CPM, but preservatives are retained to
prolong shelf life and inhibit infection.
Ocular toxicology due to various drugs, chemicals and herbs is
well recognised [76], as is necrosis and cellular apoptosis due to
preservatives in topical ophthalmic medications [22,23].
BAC preservative is used widely in CPM and eye drop prepa-
rations, and depending on the concentration, can lead to various
adverse effects. Table 4 illustrates the typical safe concentrations
recommended for use in various ocular preparations/applications
[77–81]. The cosmetic ingredient review (CIR) Expert Panel Reports
in USA and EU have been published [82,83]. Toxic effects of BAC on
the corneal epithelium [77] and conjunctival cells [78,79] can lead
to ocular disturbance.
Dry eye [17,18] is a very common disorder of the tear film.
Sufferers can experience watering of the eyes, which is in fact a
response to irritation caused by the destabilisation of the tear film.
Destabilisation of the tear film can arise due to the interaction of
the cosmetic product material (CPM), either with any one layer of
the tear film individually or collectively with the whole film.
In vivo studies [84–88] have reported that BAC adversely
decreases non-invasive tear break-up time and induces dry eye
symptoms.
Fig. 4. Dry spot: aqueous diffuses away from corneal surface.
Invoking surface chemistry analysis, a recent in vitro study [29]
has reported impaired lipid spread and formation of non-uniform
surface layer. The results are shown to correlate well with in vivo
findings [71] that a significant decrease of TF non-invasive break-up
time occurs in eyes treated with BAC-preserved timolol.
A significant hastening of corneal drying due to the effect of BAC,
in both man and rabbit has been reported [80]. It is suggested that
BAC being a cationic and polar detergent, probably solubilises the
lipid layer, promoting free evaporation of water vapour and thereby
hasten drying.
Corneal surface desiccation leads to tear film instability. Here,
any damage to corneal epithelial cells leads to loss of production of
delicate glycocalyx that binds mucin (wetting agent) to the corneal
epithelial surface. In the absence of mucin the naturally water
repellent corneal surface (hydrophobic) is exposed and the aque-
ous compounds of TF are forced away from the damaged area of
corneal surface, leading to dry-spots [Fig. 4].
In vivo [88] and in vitro [29,89] studies have reported barrier
dysfunction of the corneal epithelium after treatment of human
eyes with BAC preserved timolol.
It is also suggested that BAC may encourage dissolution of the
mucin layer adsorbed on the corneal epithelium surface, increasing
the surface tension at the epithelial surface and thus cause the tear
film to retreat from the affected areas, which then appear as dry
spots [90,91]. The water repellent corneal surface is exposed, when
mucins cannot attach, and the aqueous components of the tear film
are thus forced away from the damaged area leading to dry spots.
Another study [92] has reported that apart from straight inter-
action with TF compounds, BAC can exert toxicity by inducing
inflammation at the ocular surface, and once damaged, the corneal
surface loses its wettability leading to destabilisation of the tear
film.
Accumulation of mascara on the ocular surface can cause simple
pigmentation, involving the tarsal conjunctiva at the lower edge of
the upper lid [26], and can also involve uncommonly the bulbar
surface.
Allergic responses to mascara include an asymptomatic follic-
ular response of the tarsal conjunctiva [10]. Contact dermatitis of
the eyelid can also result from mascara use, precipitated by various
components of the mascara such as black iron oxide [93], colophony
[94] and nickel [95]. Thimerasol used in mascaras [6,11] also causes
contact allergy. Survival and growth of microorganisms in mascara
during use has also been reported [96,97].
Mascara applicators can cause mechanical corneal abrasion,
which may become secondarily infected by contaminated mascara,
particularly with Pseudomonas aeruginosa [98].
A major adverse reaction from the use of eyeliner is the risk [99]
of developing conjunctival pigmentation. It occurs when lacrimal
fluid causes the eyeliner applied to the lower lid margin to wash
into the conjunctival sac [13]. Eyeliner can also be a source of bac-
terial and fungal contamination especially with the use of liquid
products. Toxicity and lead poisoning due to use of some cosmetics
has been documented [100,101].
 A. Malik, C. Claoué / Contact Lens & Anterior Eye 35 (2012) 247–259 253

Fig. 5. Distribution and alignment of various charged species within the tear film [BAC+ : cationic benzalkonium chloride (micelles) preservative; Lp : neutral lipophilic
constituent of CPM].

Resulting hypersensitivity reactions due to eyelash and eye-

brow dyes such as toluenediamine and paraphenylenediamine,
may cause contact dermatitis, keratoconjunctivitis and blephari-
tis [74,75,102]. Severe allergic blepharoconjunctivitis induced by
dye for eyelashes has also been reported [74].
Stearamide DIBA (dihydroxyisobutylamine) stearate is used in
cosmetic formulations as a surfactant and opacifying agent. A report
[103] concerning the safety assessment of these products con-
cluded that stearamide DEA (35–40%), and stearamide MEA (5.27%)
are not ocular irritant, but 17% stearamide MEA was observed to
cause moderate ocular irritation. Another study [104] concerning
rabbit eye irritation due to several fatty acid esters, concluded that Fig. 6. Electric field (E) convention and the drift of mobile charges. (a) Net excess
in pure form all isopropyl and butyl esters caused some adverse +ve charge at the mucin layer leads to +ve electric field (E) and (b) net −ve charge at
reactions, but the activity reduced considerably with 10% aque- the mucin layer leads to −ve electric field (E). Large arrowheads represent the field
ous dispersion. Another study [105] concerning the effects of free direction. Small arrowheads represent the drift direction of various mobile charges
within the field: [+ve charges drift along the direction of the field, −ve charges drift
fatty acids (FFA) on meibomian lipid film (MLF), concludes that FFA, against the arrow-head representing the field].
namely oleic (OA) and linoleic (LA), disrupt and/or prevent the for-
mation of human MLF, and could contribute to the onset of dry eye
diseases associated with enhanced lipolytic enzyme activity such
as chronic blepharitis.
Electrical charges inevitably lead to electric field and for a distri-
In general the complications with coloured contact lenses (gain-
bution/collection of various charges the effective field is essentially
ing increased popularity as cosmetics) are the same as those
due to the net excess charge of the distribution.
encountered with general contact lens wear i.e. superior limbic ker-
In TF and in the presence of relatively immobile negative gly-
atoconjunctivitis [106–111], lens deposition, allergic conjunctivitis,
cocalyx charges at the mucin layer, the relatively mobile +ve and
peripheral infiltrates, microbial keratitis and neovascularisation. In
−ve ions secreted by the lacrimal gland into the aqueous phase,
particular P. keratitis, iridocyclitis, contact lens overwear syndrome
form a bilayer as illustrated in Fig. 5. Refs. [114,115] discuss the
and tight lens syndrome have been reported [112] with coloured
general phenomena of electrical charge bilayer or double layers at
cosmetic contact lens wear.
liquid/solid interfaces.
The phenomenon of TF degradation and corneal epithelium
As most of the inherent charges within the TF are located in the
inflammation is intimately related to the migration and transport
vicinity of mucin layer, it is therefore reasonable to assume that
of CPM across the ocular surface, as discussed in Section 7.
mucin is the centre of net charge concentration and also the origin
of the associated electric field.
Fig. 6 illustrates the electric field convention adopted in
7. Inherent charges and electric field within TF the present study and the resulting motion/drift of the various
free/mobile charges. According to this convention, +ve charges drift
Inherent charge distribution within the TF comprises mainly along the direction of the field (i.e. along the arrow representing the
negatively charged glycocalyx (the anionic polysaccharide moi- field) and −ve charges move against the direction of the field. This
eties of the glycocalyx) at the mucin layer, positively charged convention is consistent with two plate electrode arrangement,
ions (sodium, potassium magnesium and calcium) and negatively where the electric field direction points from anode to cathode, and
charged ions (chloride, bicarbonate and phosphate) secreted into positive mobile charges move in the direction anode to cathode and
the aqueous layer [55,56,113] by the lacrimal glands. the transition of negative charges is in the reverse direction.
254 A. Malik, C. Claoué / Contact Lens & Anterior Eye 35 (2012) 247–259
Negative electric field within TF (Fig. 6b) would arise due to
net negative excess charge in the vicinity of the mucin layer,
and positive cationic BAC species would thereby drift towards
the mucin layer/corneal epithelium. On the other hand; positive
field (Fig. 6a) arising due to net positive excess charge, would
impede transport of cationic BAC towards the mucin layer/corneal
epithelium.
However, due to constant scavenging effect of the mucin (i.e.
the removal of incident debris, particles and pathogens), the real
situation is dynamic, and the net charge within TF at any time is
determined by the net rates of production and removal of various
charge species and is difficult to predict.
However the inherent −ve charges (that in part determine
the electric field) within the TF, are being produced at more
than one source (glycocalyx and lacrimal glands), whereas +ve
charges are produced only at lacrimal glands. Thus it is reason-
able to assume that most of the time −ve charges predominate,
leading to −ve field (Fig. 6b) and this assists transition of any
migrating/drifting +ve species within TF towards the mucin/corneal
epithelium.
It is also obvious that deliberate enhanced secretion of +ve ions
(sodium, potassium, magnesium and calcium) at the lacrimal gland
would result in +ve electric field to impede inter-transport of any
cationic BAC towards the mucin layer/corneal epithelium within
the TF (Fig. 6a) and is of clinical relevance in reducing BAC adverse
interactions at the corneal epithelium.
8. Transport of cosmetic product material (CPM) across
ocular surface including tear film
As eye cosmetics are invariably applied external to the ocular
surface (Fig. 2), thus any interaction between the two must involve
migration of CPM from an external environment onto the ocular
surface.
A randomised study [27] designed to monitor the initial migra-
tion of CPM into the anterior of the ocular surface in the close
vicinity of the lid-margin, concluded that CPM can migrate easily
onto the ocular surface when applied close to the eyelash mar-
gin. Wrapping of the eyelids (extreme forced eyelid closure or
excessive blinking), or drawing-in of the CPM due to the sur-
face tension effect of the tear meniscus, have been suggested
as possible mechanisms. The study also showed that the CPM
migration increased with time and was exacerbated by eye drop
instillation.
This initial encounter of the migrated CPM with the imme-
diate conjunctiva in the proximity of the eyelash, can lead
to tarsal conjunctiva pigmentation and posterior blepharitis
[74,75].
A further spread of CPM into the distal regions of the conjuncti-
val epithelium, and inter-transport across the tear film culminating
in interaction with the corneal epithelium is expected. The for-
mer is essentially a surface transport phenomenon along the upper
layer of TF, driven by hydrodynamic forces generated by blinking
or wrapping of the eyelid. The latter is essentially a diffusion and
drift transport phenomena of CPM leading to adverse effects such
as lipid layer destabilisation, dry eye syndrome, corneal epithelium
inflammation and keratoconjunctivitis [10–18].
CPM consists of a variety of species such as pigments, oils, waxes,
preservatives (BAC is the most widely used preservative), microfi-
bres, powder, mica, stearates, lipophilics and lubricants/diluents. In
this review, the transport of BAC type preservative and lipophilic
(i.e. oils, fatty acids, stearates) constituents of CPM, in the pres-
ence of inherent charged particles within TF, has been considered in
detail. BAC molecules incident at the upper layer of TF, are cationic
and polar, while the incident lipophilic species are neutral and apo-
lar.
The interaction of CPM with various layers of the TF is
largely determined by the CPM characteristics and the chem-
istry/composition of the individual layer concerned [116–120]. The
dynamic aspects of TF and the role of lipid layer in tear evapora-
tion is well recognised [121,122] and more recently the interaction
between meibomian gland secretions with polar lipids [123] has
been clarified.
In vitro experimental studies [29] concerning the interaction
of BAC with meibum lipid layer, show that at lower concentra-
tion (<0.01%) BAC exists as individual monomers and micelles are
formed at concentrations exceeding 0.01%. The study also con-
cluded that at high concentration, BAC micelles penetrate the lipid
layer, whereas at low concentrations, the individual monomers of
BAC are unable to penetrate and are trapped within the lipid layer.
Explanation is that the cationic polar BAC molecules adsorb like
individual monomers within the meibum lipid (hydrophobic) sur-
face, and spontaneously separate out into heterogeneous structure
of BAC-enriched fluid and thick lipid islands. The in vitro experi-
mental setup used in this study (i.e. interaction between BAC and
human tears, meibum and rabbit corneal cell lipid extract at the
air/water interface) was however free from any electric field, and
it appears that in the presence of negative electric field (Fig. 7b)
low concentration cationic BAC monomers would drift and pen-
etrate the lipid layer. Ref. [88] suggests that in vivo, trapping of
BAC molecules within the lipid layer would be effectively screened
from the rapid aqueous tear turnover and consequently leads to
long-term adverse effects.
Fig. 7 illustrates the transport and interaction of cationic BAC
preservative and lipophilic components of CPM across the lipid
layer of the TF, assuming −ve electric field across the tear film.
We suggest that initially, polar BAC species because of their
affinity for water/aqueous pass through the top non-polar layer
of the lipid arrangement and align along the lower polar bilayer of
the arrangement. In the presence of negative electric field (Fig. 6b),
the majority of the cationic BAC species drift out into the aqueous
layer beneath the lipid layer in a process akin to electrophoresis
[114,115,124–128]; and the others form neutral complexes with
the polar bilayer of the lipid arrangement. The cellular origin and
role of mucin in tear films is discussed in Ref. [129,50,130–137]. The
requisite electric field arises due to the inherent charge distribution
within TF as discussed in Section 7. Relatively the electric charge
on BAC monomers (i.e. BAC at low concentration) is less compared
to that on BAC micelles (i.e. BAC at high concentration), and con-
sequently the electric driving force on BAC monomers is also less
compared to that on micelles. Consequently, the intertransport of
BAC monomers across the lipid layer is a weak process compared
to that of BAC micelles.
During transition through the lipid layer, some of the charged
cationic BAC species may also form neutral complexes with the
polar sub-layer of the lipid arrangement. This is probable, as
the charged cationic BAC is deficient in electron and polar lipid
bilayer is ready to be ionised. The process is similar to ionisa-
tion of polar lipids in the presence of an ion that facilitates the
transfer of electron leading to formation of free radicals [30,31].
However due to weak forces involved, complete transfer of an
electron does not occur, but an electron is shared between electron-
deficient BAC and polar lipid to form a neutral complex. It is
also expected that during this process, local rearrangement of the
pre-existing weak coupling between the polar lipids and the aque-
ous phase also takes place. However, the heterogeneous neutral
complexes so formed, are displaced into the adjacent aqueous
layer.
Consequently, both charged BAC and neutral complexes of BAC
exist within the aqueous phase beneath the lipid layer.
 A. Malik, C. Claoué / Contact Lens & Anterior Eye 35 (2012) 247–259 255

Fig. 7. Transport of cosmetic product material (CPM) across the meibum lipid layer, assuming −ve electric field (E) across the tear film (TF) BAC+ : cationic preservative and
LP : neutral lipophilic species of CPM.

Fig. 8. Transport of cosmetic product material (CPM) within the aqueous layer in the presence of −ve glycocalyx and the secreted ions by the lacrimal gland into the aqueous
layer (assuming negative field due to net excess resulting negative charge at the mucin layer). [All species move towards corneal epithelium, but are screened by the mucin.
BAC+ : high cationic benzalkonium chloride preservative; LP : neutral Lipophilic species of CPM and E: electric field].

Lipophilic species of CPM penetrate the lipid layer accord-
ing to the laws of simple diffusion. Simple diffusion of lipophilic
or hydrophilic solutes through a lipid membrane is determined
by the partition coefficient and permeability coefficient of the
solute, whereas the passive diffusion of particles in a medium
is determined by the diffusion coefficient and the concentration
gradient of the particles within the medium [138,139]. Gen-
eral aspects of transport, diffusion and permeation of water and
electrolytes through lipid bilayer have also been discussed in
Refs. [140–145].
The relative penetration rates of BAC and lipophilic species
through the lipid layer is determined by the relative permeability
of the lipid layer. Structurally, the lipophilic constituents of CPM
(oils, stearates and solvents) are neutral apolar molecules, whereas
BAC preservatives are cationic polar molecules [29], and the per-
meability of neutral apolar molecules in lipids is several orders of
magnitude higher than that of cationic polar molecules [142–145].
Fig. 8 illustrates the transport modes of BAC and lipophilic
species within the aqueous layer in the presence of negative elec-
tric field. Here, the negative field could arise due to excess negative
charge at the mucin layer due to either predominance of glycoca-
lyx or reduced secretion of +ve electrolytes. In this configuration all
incident positively charged particles drift under the action of the
electric field towards the mucin layer, and the neutral species of
CPM (i.e. lipophilic and neutral complexes of BAC) diffuse passively
towards the mucin layer, driven by the concentration gradient.
However, all these particles/species are prevented from reaching
the corneal epithelium surface, as the main function [132] of the
mucin is to prevent adhesion of debris and pathogens to the ocular
surface.
Fig. 9 illustrates the motion of various CPM constituents within
the aqueous layer post dry-spot formation i.e. in the absence of Gly-
cocalyx and receding aqueous phase, with no electric field within
the hot-spot region. Here, the charged BAC species lying at the outer
256 A. Malik, C. Claoué / Contact Lens & Anterior Eye 35 (2012) 247–259
Fig. 9. Inter-transport of cosmetic product material (CPM) within the tear film (TF) during dry-spot activity (i.e. dissolution of mucin or damaged epithelial surface cells)
[preferentially lipophilic species (LP ) and BAC neutral complexes reach and interact with corneal epithelium]. BAC+ cationic benzalkonium chloride preservative.
periphery of reduced space-charge accumulation may still be influ-
enced by the electric field generated within the adjoining normal
regions (with normal distribution of mucin and glycocalyx), and the
trajectory of the charged BAC bends towards the normal glycocalyx
region. Charged BAC lying within the central core of the dry-spot
region drifts randomly within the aqueous phase in the absence of
any electrical force.
In the absence of an electric-field, the intertransport of charged
BAC species across the lipid layer of the TF is reduced and pos-
sibly occurs according to the processes suggested by in vitro
experimental studies of Ref. [29]. The formation of neutral BAC
complexes and the penetration of the lipophilic species through
the lipid layer is however unaffected by the lack of electric
field.
The lipophilic species that have initially penetrated through the
lipid layer are poorly soluble in the host aqueous layer, and are
subject to partitioning at local pH, between the complex mix of
aqueous layer comprising electrolytes, proteins and metabolites.
However, the aggregation of these species, including that of neu-
tral BAC species beneath the lipid layer within the aqueous phase,
gives rise to passive diffusion driven by concentration gradient.
Thus, in the presence of mucin deficiency (vitamin A deficiency)
[146] or dry spots [54,55], diffusing lipophilic species and neutral
complexes of BAC preservative reach the corneal epithelial sur-
face leading to adverse reactions. This suggests that the integrity of
mucin layer/gradient is crucial. In the presence of mucin deficiency,
even preservative-free cosmetics can lead to adverse effects at the
corneal epithelium.
Other species such as lipocalin, a lipid binding protein [147,148],
is also capable of adsorbing to and penetrating into the meibomian
lipid layer.
Some antibiotics and chemotherapeutic agents diffuse
[149] through the lipid bilayer, where the functional group(s)
become charged by protonation or deprotonation at physiological
pH.
The accumulation or influx of particulate matter within the
aqueous layer directly affects the osmolarity, and viscoelasticity of
the tear film [150,151], leading to TF instability. Besides determin-
ing the osmolarity of tears, electrolytes such as sodium, potassium,
magnesium, calcium, chloride, bicarbonate, and phosphate, also act
as a buffer to maintain a constant pH and contribute in maintain-
ing epithelial integrity of the ocular surface [57,58]. An increase in
osmolarity of the aqueous layer is a global feature of dry eye syn-
drome and damages the ocular surface directly and indirectly by
triggering inflammation [56,59].
Fig. 1 summarises the various CPM transport modes expected
within the ocular surface due to the use of eye cosmetics, includ-
ing the underlying driving forces/mechanisms and the resulting
adverse effects within the ocular surface.
9. Conclusion
The majority of adverse effects due to the use of eye cosmetics,
stem from the transport of CPM within the ocular surface, and the
control of CPM transport in this region is of relevance in preventa-
tive therapy.
Initial migration of CPM from the external environment, onto
the ocular surface adjacent to the lash line, can give rise to simple
tarsal conjunctival pigmentation and posterior blepharitis. Inter-
transport of BAC and lipophilic constituents of CPM across the TF,
can lead to dry eye symptoms, corneal epithelial inflammation and
keratconjuntivitis.
The motion/drift of charged cationic BAC species across the TF
is influenced by the presence of an electric field, determined by the
distribution of inherent charges within the TF, comprising mainly
a −ve glycocalyx at the mucin layer, and electrolytes secreted into
the aqueous phase by the lacrimal gland. A negative electric field
(due to excess negative charge at the mucin layer) assists drift of
cationic BAC towards mucin/corneal epithelium, whereas a positive
field (due to excess positive charge at the mucin layer) impedes
such motion.
In vitro experimental studies suggest that in the absence of an
electric field, the inter-transport of BAC preservative across the
lipid layer of TF is concentration dependent. At low concentration
(<0.01%) the individual monomers are absorbed within the lipid
layer, and at high concentration (>0.01%) BAC micelles penetrate
the lipid layer
The transport of lipophilic constituents of CPM across the lipid
layer of the TF is dictated by the processes of simple diffusion. The
transport of both lipophilic and neutral species across the aqueous
phase is largely due to passive diffusion determined by concentra-
tion gradients.
Inter-transport of cationic BAC across the TF may be impeded by
enhancing the secretion of +ve ions at the lacrimal gland to achieve
retarding electric field across TF, and this is of clinical significance.
The roll of mucin layer/gradient is crucial in the prevention of
adverse effects at the corneal epithelium. During mucin deficiency,
all incident constituents of CPM are able to interact with the corneal
epithelium. Thus during mucin deficiency, even preservative-free
 A. Malik, C. Claoué / Contact Lens & Anterior Eye 35 (2012) 247–259
cosmetics can lead to adverse effects, where the neutral and
lipophilic species of CPM are able to interact freely with the epithe-
lium.
Patients with mucin deficiency, and especially those on eye oint-
ment/drops medication, should be warned of the beastly aspects
of cosmetics and discouraged from using them in a way likely to
contaminate the TF.
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