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1
Overview of Cosmetics Reseacrh
at FDA
Nakissa Sadrieh, Ph.D.
Director, Cosmetics Division, OCAC/CFSAN/FDA
PCPC presentation October 2014
PCPC-October 2014
Outline
• Cosmetics regulations in the US
• Role of FDA research in the regulation of
cosmetics
• Examples of OCAC research
Strategic planning for future OCAC research
2 PCPC-October 2014
• Used by most consumers every day
• Examples: – Moisturizers, other skin preparations
– Hair care, hair dyes, hair straighteners
– Makeup, nail polishes
– Shaving preparations
– Perfumes and colognes
– Toothpastes, mouthwashes
– Face and body cleansers, deodorants
– Tattoos
• Multi-billion dollar industry
• Increasingly global industry
Cosmetics – Scope
PCPC-October 2014 3
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2
• Defined in the Federal Food, Drug, and
Cosmetic Act (FD&C Act), Section 201 (i)
• Articles intended for:
– Cleansing
– Beautifying
– Promoting attractiveness
– Altering the appearance
** Excludes “Soap” (alkali salt of fatty acid-CPSC)
Cosmetic
PCPC-October 2014 4
• Defined in FD&C Act, Section 201 (g)
• Articles intended
– For use in the diagnosis, cure, mitigation,
treatment, or prevention of disease
– To affect the structure or any function of
the body of man or other animals
Drug
PCPC-October 2014 5
• Cosmetics must not be adulterated or
misbranded
• The law does NOT provide for FDA pre-
market approval
• FDA’s authority is post-market only
Cosmetics – FDA’s Authority
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3
• OTC Drug – Monograph or product-
specific pre-market
approval required
– Pre-market evaluation of
safety & efficacy
– GMP regulations
– Establishments & products
must be registered
– Serious adverse events
must be reported
• Cosmetic – Pre-market approval not
required
– No pre-market clearance of
safety or efficacy
– GMP guidelines only
– Establishments & products
not required to be
registered
– Adverse events not
required to be reported
OTC Drug vs. Cosmetic
PCPC-October 2014 7
Requirements for Market • FDA Authority Over Cosmetics
o Under the FD&C Act, cosmetics must not be adulterated
(601) or misbranded (602)
o No pre-market approval of cosmetics, with the exception
of color additives
o Manufacturer bears responsibility for safety of marketed
products
o Manufacturer or distributors should have obtained all
data and information needed to substantiate the safety of
the product before marketing
8 PCPC-October 2014
• Limited legal authorities
• Competing agency priorities
• Significant changes in past 5-7 years – Manufacturing more global
– Alternatives to animal testing
– Increasingly sophisticated technology and complex ingredients
• Nanotechnology
• “Active” ingredients
• Botanicals
Cosmetics - Challenges
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• Safety Evaluation of ingredients
• Adverse Events evaluation and
analysis
• Compliance activities
• Development of Guidance and
Policies
• Research
Examples of Current Areas of
Emphasis
PCPC-October 2014 10
Importance of research in
OCAC • Because cosmetics do not have premarket review, FDA
depends on the following to carry out its mission:
– Published research
– Published position papers from international
regulators
– Industry publications
– Adverse events reports
– Enforcement actions
PCPC-October 2014 11
Cosmetics Research at FDA
A look at selected examples
12 PCPC-October 2014
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5
Reasons for doing cosmetics
research at FDA • To evaluate the safety of cosmetic ingredients
– Scientific interest/innovation/controversy
– Adverse events analysis
– Enforcement actions
• In response to inquiries:
– Citizen Petitions
– Stakeholders expectations
– Media interest
• In order to align with international regulators
13 PCPC-October 2014
Ultimately……
• FDA does cosmetics research to support
policy development and regulatory
mandate:
– Guidance
– Regulations
– Enforcement actions
14 PCPC-October 2014
Mechanisms used for
Research • Laboratory based work:
– FDA
– Contract
– Collaboration
• Literature based work – Published papers
– Databases (internal, commercial)
• Computational/ in silico
15 PCPC-October 2014
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6
Examples of OCAC
Research • Ingredient surveys: analytical work
– FDA research laboratories
– FDA field offices
– Contractors
– Academia
• Adverse events analysis: epidemiology
• In vitro/in vivo research: toxicology
• In silico research: computational toxicology
(QSAR)
• Literature/database research: regulatory 16 PCPC-October 2014
PCPC-October 2014 17
Examples of cosmetic ingredient and
contaminant surveys conducted under
contract
PCPC-October 2014 18
Title Status Lead in Lipstick Completed
Heavy Metals in Cosmetics, I Completed
Heavy Metals in Cosmetics, II Completed
Asbestos in Talc Completed
Eye area Cosmetics for Microbial Contamination (Micro I) Completed
Assessment of Microbial Contamination of Eye Area Cosmetics Containing
Non-Traditional Preservatives (Micro II)
Ongoing
Methylisothiazolinone (MIT) and Methylchloroisothiazolinone (CMIT) in
Cosmetics
Ongoing
Tattoo and Permanent Make-Up - Injectable Cosmetics for Microbial
Contamination
Ongoing
Diethanolamine (DEA) in Cosmetic Products Ongoing
Natural Latex Protein Antigens in Cosmetic Products Ongoing
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Cosmetic Products Adverse
Events CAERS Year Number of Individual
Reports
Number of Suspect
Products
2011 291 318
2012 352 418
2013 293 314
2014 344 388
19 PCPC-October 2014
Adverse events analysis
• Leave on products versus rinse off:
– Products
– Reports
• Hair care versus skin care:
– Products
– Reports
PCPC-October 2014 20
Leave on versus rinse off-related
adverse events
PCPC-October 2014 21
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8
Skin care versus hair care-related adverse
events
PCPC-October 2014 22
In Silico research in OCAC
PCPC-October 2014 23
Available (Q)SAR Models for the Mechanism of Action (MOA), Physicochemical
Properties, ADME, and Toxicological Endpoints Relevant to the Safety
Assessments of Cosmetic Ingredients
Me
ch
an
ism
of
Ac
tio
n Q
SA
R
Ph
ys
ico
ch
em
ica
l p
rop
ert
ies
AD
ME
Ru
le o
f 5
Wa
ter
so
lub
ilit
y
Bio
av
aila
bilit
y (
ora
l)
Ph
arm
ac
ok
ine
tic
(o
ral)
In v
ivo
Co
rne
al p
en
etr
ati
on
(Ra
bb
it C
orn
ea
)
In v
ivo
De
rma
l p
en
etr
ati
on
(Hu
ma
n s
kin
)
In v
itro
De
rma
l p
en
etr
ati
on
(Hu
ma
n s
kin
)
Me
tab
olis
m
Es
tro
ge
n r
ec
ep
tor
bin
din
g
An
dro
ge
n r
ec
ep
tor
bin
din
g
En
do
cri
ne
sy
ste
m d
isru
pti
on
Ac
ute
ora
l to
xic
ity
(ra
t / m
ou
se
)
Ac
ute
de
rma
l to
xic
ity
CASE-Ultra (Multicase Inc.)
Leadscope Model Applier (Leadscope, Inc.)
ADMET-Predictor (Simulations-Plus, Inc.) ● ● ● ● ● ● * ● ● ● ●GastroPlus (Simulations-Plus, Inc.) ●Percepta (Advanced Chemistry Development, ACD, Inc.) ● ● ● ● ● ● ● ● ● ●Symmetry (Prous Institute for Biomedical Research) ●SciQSAR (SciMatics, Inc.) *Derek Nexus (Lhasa Limited) ● ●Meteor Nexus (Lhasa Limited) ●● = Commercial (Q)SAR Models * = In-house (Q)SAR Models
SOFTWARE (DEVELOPER)
ENDPOINTS
10/31/2014
9
Table (continued)
Sk
in irr
ita
tio
n
Sk
in c
orr
os
ion
Sk
in s
en
sit
iza
tio
n
Ey
e irr
ita
tio
n
Ey
e c
orr
os
ion
Ba
cte
ria
l m
uta
ge
n (
Am
es
as
sa
y)
Eu
ca
ryo
te m
uta
ge
n
Eu
ca
ryo
te c
las
tog
en
Eu
ca
ryo
te D
NA
da
ma
ge
CASE-Ultra (Multicase Inc.) ● ● ● ● ●Leadscope Model Applier (Leadscope, Inc.) ● ● ● ● ● ●ADMET-Predictor (Simulations-Plus, Inc.) * * ● * * ● ● ● ●Percepta (Advanced Chemistry Development, ACD, Inc.) ● ● ● ● ● ● ●Symmetry (Prous Institute for Biomedical Research)
SciQSAR (SciMatics, Inc.)
Derek Nexus (Lhasa Limited) ● ● ● ● ● ● ● ●Toxtree (Non commercial and freely available) ● ● ● ● ● ● ●● = Commercial (Q)SAR Models * = In house (Q)SAR Models
SOFTWARE (DEVELOPER)
TOXICOLOGICAL END POINTS
Skin and Eye
Ca
rcin
og
en
icit
y
Re
pe
ate
do
se
to
xic
ity
De
ve
lop
me
nta
l to
xic
ity
Re
pro
du
cti
ve
to
xic
ity
Genotoxicity
Kro
es
TT
C d
ec
isio
n t
ree
Ph
oto
-in
du
ce
d t
ox
icit
y
In-House c/r-QSAR Models Planned for the
Development/Validation in Near Future
Sk
in irr
ita
tio
n
Sk
in s
en
sit
iza
tio
n
In v
itro
De
rma
l p
en
etr
ati
on
(H
um
an
sk
in)
Ey
e irr
ita
tio
n
Symmetry (Prous Institute for Biomedical Research) * * * *
* = In house (Q)SAR Models
SOFTWARE (DEVELOPER)
TOXICOLOGICAL END POINTS
(Q)SAR Software Used to evaluate 3
ingredients
• Software programs utilized:
– ADMET Predictor : Simulations-Plus, Inc. (www.simulations-plus.com)
– Percepta: Advanced Chemistry Development Labs, Inc. (www.acdlabs.com)
– CASE-Ultra: MultiCASE Inc. (www.multicase.com)
– Leadscope Model Applier: Leadscope, Inc. (www.leadscope.com).
– SciQSAR: SciMatics Inc. (www.scimatics.com).
– Derek Nexus: Lhasa Ltd. (www.lhasalimited.org)
– Toxtree: Ideaconsult Ltd. (www.toxtree.sourceforge.net)
10/31/2014
10
Abbreviations in QSAR result summary
+ –
+ –
P N
+ –
I O
Log Kp In Vitro Skin Permeability coefficient through human skin
+a
+p
+
*PA
% Confidence in prediction of skin irritation is based upon 21 QSAR models
Inconclusive / Outside of the applicability domain
Included in training set with actual positive in Mouse Lymphoma
Predicted positive in Mouse Lymphoma
Predicted positive in in vitro but in literature it is negative ( in vivo bone marrow)
Predicted positive either in Mouse Lymphoma cell or in vitro test
Included in training set with actual positive / negative class
Predicted positive / negative
Predicted positive alert / No alert
Outside model's applicability domain and predicted positive / negative
Poorly Absorbed
Eqv Equivocal
❸ % Confidence in prediction of skin sensitization is based upon only three QSAR models
**
SUMMARY: (Q)SAR RESULTS
SKIN ABSORPTION
-3.45 13.75 PA – – – + – – – –
-2.65 0.29 PA + + + + + + + +
-2.88 -0.23 PA – +p O – – + + EqvINGREDIENT - 3
INGREDIENT - 2
CA
RC
INO
GE
NIC
ITY
Lo
g K
p (
ME
DIA
N V
AL
UE
S IN
Cm
/h)
Lo
g P
(A
CD
PE
RC
EP
TA
)
SK
IN A
BS
OR
PT
ION
BA
CT
ER
IAL
MU
TA
GE
NE
SIS
(A
ME
S A
SS
AY
)
EU
CA
RY
OT
E M
UT
AG
EN
ES
IS
EU
CA
RY
OT
E C
LA
ST
OG
EN
ES
IS
EU
CA
RY
OT
E G
EN
ET
IC T
OX
ICIT
Y
GE
NO
TO
XIC
ITY
(S
UM
)
INGREDIENT - 1
CH
EM
ICA
L N
AM
E
GENOTOXICITY
SK
IN S
EN
SIT
IZA
TIO
N
SK
IN IR
RIT
AT
ION
Examples of FDA analytical research
• Prostaglandin analogs in cosmetic
products
• Skin whiteners
• Arbutin stability
30 PCPC-October 2014
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11
• In 2008, the US FDA approved the use of LatisseTM as a prescription drug for the
treatment of hypotrichosis (inadequate lashes)
• The ingredient responsible for eyelash enhancement is the prostaglandin,
bimatoprost, which activates prostamide F2α receptors found in the hair follicle
• Bimatoprost is also marketed under the trade name, Lumigan®, for the treatment
of ocular hypertension/glaucoma
Prescription Prostaglandin Analogs
• Prostaglandin analogs traditionally used for treatment of ocular
hypertension/glaucoma
• Side effects include conjunctival hyperemia, excessive tearing, inflammation,
coloring of iris, skin pigmentation, and increase in eyelash length, thickness,
and darkness
• “Eyelash-enhancing” effects spurred the production of new cosmetic products
containing prostaglandins
• A number of new eyelash-enhancing cosmetic products containing other
prostaglandin analogs were placed on the market
• Up until now, no analytical method had been reported for the detection and
quantitation of prostaglandins in cosmetics
3
Market Survey Results
• 31 products were analyzed for all
16 prostaglandin analogs (LC-MS/MS)
• 13 of 31 products tested positive and
concentrations ranged from 27.4 – 297 µg/g
• Only 4 of the 16 prostaglandin analogs
were found in the products surveyed
• Different lots numbers were analyzed and
concentrations were consistent between lots
• The concentrations of the prescription
products were all calculated to be within
9% of the labeled concentration
• The concentration levels found in the
cosmetic products is similar to that found in
the prescription drugs
Product Prostaglandin
Calc. Conc. (%RSD) (µg/g)
Product 1 Taf EA 133 (11.3)
Product 2 Taf EA 141 (8.04)
Product 3 Taf EA 91.6 (10.6)
Product 4 Bima IE 172 (4.90)
Product 5 Bima IE 206 (5.98)
Product 6 Clo IE 42.5 (1.40)
Product 7 Clo IE 68.9 (6.78)
Product 8 Clo IE 90.0 (3.89)
Product 9 Clo IE 63.6 (6.44)
Product 10 Clo IE 27.4 (6.68)
Product 11 Clo IE 60.2 (5.09)
Product 12 17-PTPF2α MA 132 (2.07)
Product 13 17-PTPF2α MA 297 (1.19)
Prescription Product 1
Trav 36.6 (8.05)
Prescription Product 2
Lat 50.3 (7.63)
Prescription Product 3
Bima 290 (4.15)
12
10/31/2014
12
Research on Skin Whiteners
• Study objective: to develop an HPLC-UV method to
quantitate vitamin C, α-arbutin, β-arbutin, kojic acid,
nicotinamide, hydroquinone, resorcinol, 4-
methoxyphenol and 4-ethoxyphenol
• 59 different types of skin lightening products were
analyzed, including creams, lotions, serums, foams,
gels, masks, bar soaps, tablets and capsules
PCPC-October 2014 34
PCPC-October 2014 35
β-artutin 29%
α-artutin 17%
ascorbic acid 14%
kojic acid 14%
nicotinamide 20%
hydroquinone 17%
resorcinol 5%
Others (N.D.) 24%
Total Products Number = 59
Distribution of individual analytes in skin
lightening products
Arbutins research
• Arbutin is the glycoside derivative of hydroquinone
– β-arbutin is commonly found in species of several plant families
in nature
– α-arbutin can be obtained by biotransformation or by chemical
routes
• β- and α-arbutin popular skin whitening agents because
of ability to interfere with melanin synthesis
• Biological activity is related to inhibition of tyrosinase
enzymes in melanocytes
PCPC-October 2014 36
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13
Conclusions of Arbutin research
• Of 33 Skin lightening products claimed to contain arbutin:
• 52% contained β-arbutin and 30% contained α-arbutin
• 21% did not contain detectible levels of β-arbutin or α-arbutin
• Both α- and β-arbutin were found stable to mild chemical conditions up to 6
months, while readily hydrolyzing to hydroquinone in extreme conditions of
heat and pH
• Both α- and β-arbutin were found unstable in vivo, with and half-life of 8 h in
both cases, but the formation of hydroquinone was minimal if not absent
within the tested conditions
• No anomerization of either α- or β-arbutin was observed in any of the tested
experimental conditions
PCPC-October 2014 37
PCPC-October 2014 38
Safety research
3D Reconstructed Human Skin
• Testing biologic activity of chemicals yields high
concordance with in vivo assays
• Derived from normal (non-cancer, non-transformed)
human skin cells
• Highly differentiated to form normal layers of intact
epidermis
• Validated for Irritation and Micronucleus Tests
• Metabolically and mitotically active
10/31/2014
14
Assay to
measure skin
irritation
3D Reconstructed Human Skin
Micronucleus
assay detects
clastogens
Control (untreated) Positive Control (H2O2)
10X
20X
10X
40X
20X
40X
Comet Assay - Treat primary human skin cells (NHEK) with
compounds of interest and detect DNA damage
Comet Assay in NHEK Cells
NHEK cells treated with H2O2 as positive control: DNA damage can be
visualized and quantitated in
Comet assay conditions have been optimized, and NHEK primary human
skin cells will be exposed to potential chemicals of interest to assess
genotoxicity
(1)
(93)
(91)
(3)
Laboratory Validation results of Comet
Assay in NHEK Cells
10/31/2014
15
Future directions for OCAC
research
• Development of systematic processes for the
analysis of adverse events and for linkage of
specific cosmetic ingredients with adverse
events
• Risk assessment
43 PCPC-October 2014
Future strategy for OCAC research
• Develop models for specific testing needs
– Dermal penetration (baby skin versus adult skin)
– Sensitization/allergenicity
– In vitro toxicology for various endpoints (e.g. dermal penetration,
genotoxicity, eye area toxicity, inhalation toxicity)
• Areas for future focus:
– Allergens (fragrance allergens, latex, gluten…)
– Preservatives (parabens, MIT, …)
– Ingredients of interest (formaldehyde, hydroquinone, …)
– Botanicals
– Tattoos
– Ingredients that are pharmacologically “active”
44 PCPC-October 2014
Safety Research paradigm
• Hypothesis generation from:
– Adverse events analysis
– In silico modeling
– Literature survey/ public inquiry
• Testing via:
– Product surveys (contract, FDA laboratories)
– Establishing In vitro toxicology models developed for
safety assessment of cosmetic ingredients
– Establishment of collaborations/partnerships
45 PCPC-October 2014
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16
“Quality” research paradigm
• Use results of in-house testing and field operations to ensure:
– Lack of microbiological contamination
– Identification and qualification of impurities, degradants, heavy metal,
and other contaminants
– Product consistency through adoption of GMP principles:
• Manufacturing process controls
• Stability
• Microbial/endotoxin contamination
• Efficacy of preservatives
• Product/ingredient specifications
• Use data from laboratory surveys to quantitate select
ingredients in specific products of interest:
– Address presence and quantity of select ingredients in product labeling
46 PCPC-October 2014
Ultimate goal of OCAC research
• Impact on policy development:
– Guidance
– Rule making/regulations
– Product labeling
• Propagate research results:
– Publications
– Consumer updates on website and social media
• Focus future enforcement actions
– Inspections
– Warning letters
– Seizures PCPC-October 2014 47
Conclusions
• The goal of OCAC research is for FDA to
have:
– More public confidence in cosmetic product
quality AND safety
PCPC-October 2014 48
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17
Looking towards the future
• Prioritize research goals
• Use available resources to meet defined
research goals
• Leverage resources with collaborators to
maximize impact on public health:
– Academia
– Industry
PCPC-October 2014 49
Thank you
PCPC-October 2014 50
