May 7, 2015

Safety Assurance of Skin Care

Cosmetics

Masato Hatao, Ph.D.

Shiseido Research Center

Safety assurance for cosmetics is highly

appreciated more than ever!
Recent incidence of severe adverse effects by
cosmetics.
Advancement of science enable us to detect
new threat with respect to safety of chemicals.
Regulation change requires safety assessment
without using animals.

Anaphylaxis by cosmetics?
Wheat-dependent exercise-induced anaphylaxis
(WDEIA) due to Hydrolyzed wheat protein in a soap
product. Even a rinseoff product caused immediate
type allergy in consumers.

Okumura & Chinuki, J. Jpn. Hair Sci. Assoc. 44, 2,58-62, 2012

Severe adverse effect in whitening cosmetics in

Japan
The number of Rhododenol induced-leukoderma (white spots)
patients was reportedly at least 18909.
The special Committee on the Safety of Cosmetics Containing Rhododenol in the
Japanese Dermatological Association Jpn. J. Dermatol. 124 (11) ; 2095-2109, 2014

Shiomi et.al. Hifubyou-sinryou 367590-595, 2014

Allergic contact dermatitis due to

Methylisothiazolinone
4. CONCLUSION
SCCS/1521/13
Revision of the opinion on methylisothiazolinone (P94)
31
1. On the basis of the new evidence in relation to sensitising potential,
does the SCCS consider Methylisothiazolinone (MI) still safe for
consumers, when used as a preservative in cosmetic products up to
concentration limit of 100 ppm? If no, it is asked for the SCCS to
revise this concentration limit on the basis of information provided.
Current clinical data indicate that 100 ppm MI in cosmetic products is not
safe for the consumer.
For leave-on cosmetic products (including wet wipes), no safe
concentrations of MI for induction of contact allergy or elicitation have been
adequately demonstrated.
For rinse-off cosmetic products, a concentration of 15 ppm (0.0015%) MI is
considered safe for the consumer from the view of induction of contact
allergy. However, no information is available on elicitation.
2. Does the SCCS have any further scientific concerns with regard

What is SAFE MATERIAL.

Nothing can be Completely Safe

Material nor 100% Safe Material.
Only under certain conditions, Safe
Material exists. Safe Cosmetics, as
well.
6

Is the water safe material?

It depends on the condition.

7

To what extent should safety be covered

Ordinary situation

Foreseeable miss use.

No adverse effects

Insignificant limited
adverse effects upon
receiving quick
remedy.
Cited from Homepage of Japan Soap & Detergent Association

What is Cosmetics in Japanese Pharmaceutical Affairs Law

Cosmetics

Drug
Cure the disease.

Quasi-drug
Prevent the disease
condition.

Keep the skin

normal and healthy.
Enhance
attractiveness.

Hair nurturing tonics

Socially accepted
Hair dye
cosmetics
Perming agent
Whitening cosmetics.
etc.

Defined as their effects are mild on

human body.
9

Definition of Cosmetics in Japanese Pharmaceutical Affairs Law

The term cosmetics used in this law refers

to articles with mild action on the human
body, which are intended to be applied to
the human body through rubbing, sprinkling
or other similar methods, aiming to clean,
beautify and increase the attractiveness,
alter the appearance or to keep the skin or
hair in good condition.

Cosmetic Ingredients
Standards for Cosmetics
Basic Rule: Those which may cause infection or introduce health hazard is
prohibited.
Positive List:
Preservatives: Appendix 3 (EU ANNEX V)
UV filters: Appendix 4
(EU ANNEX VI)
Tar Color: Ministry of Health and Welfare Ordinance (EU ANNEX IV)
No.30 of 1966 (Red 219 & Yellow 204 for hair & nail products)
Limitation of Other Items: Appendix 2 (EU ANNEX III)
Negative List:
Drugs, any ingredients that do not meet the Standards for Biological Materials,
Class I Specified Chemical Substances provided in the Law Concerning the
Evaluation of Chemical Substances and Regulation of Their Manufacture, etc.
Article 2, Paragraph 2 (Law No.117 of 1973), or Class II Specified Substances
provided in the same law Article 2, paragraph 3 or the material determined by
MHLW
Other Items: Appendix 1 (EU ANNEX II)

Definition of Quasi-drug
The term quasi-drug used in this law refers to articles
intended for the uses specified in the following items. These
articles shall be those which have mild action on the human
body similar articles designated by the Ministry of Health,
Labor and Welfare.
(1) To prevent nausea or other discomfort, or bad breath or
body odor.
(2) To prevent heat rash, feastering, etc.
(3) To prevent the loss of hair, or to grow or remove hair.
(4) To exterminate or prevent rats, flies, mosquitoes, fleas, etc.
in order to ensure the health and hygene of humans or
animals.
All the ingredients in quasi-drug shall be evaluated and shall
be permitted by MHLW.

In this presentation, Skin Care Cosmetics

include both cosmetics and a part of
quasi-drug products

Safety assurance of cosmetic products

Retrospective

Prospective

Safety

Predictions

Inspection

Guarantee
Information
on safety
In vitro tests
Existing in vivo
test results

Tests on
Human
subjects

To predict safety of
human testing
Limited human testing To predict safety of
full scale human
testing
Non-human testing

Customers

Confirm info
(re-testing)
Modify
contents
guaranteed

Complaints
info
-Medical tests
-New safety
info

Complaints &
Confirm predictions
medical testing (& modify contents)
New Safety info Modify predictions

General Toxicological Endpoints aimed for Development of

Cosmetics and Quasi-drugs
Toxicological Endpoints

Acute Toxicity

Systemic toxicity by single dose.

Primary Skin Irritation

Irritation potency by applying on the skin.

Repeated Skin Irritation

Irritation potency by repeated application on the skin.

Skin Sensitization

Allergenicity when applied on the skin.

Photo-toxicity

Irritancy on the skin upon receiving photo irradiation.

Photo-sensitization

Allergenicity on the skin upon receiving photo irradiation.

Eye Irritation

Irritation on eye in case of accidental exposure.

Genotoxicity

Toxicity on genes.

Human patch test

Confirmation of non-irritancy potentials by application on human

skin.

10

Repeated dose toxicity

Investigating systemic effects by multi-dose.

11

Reproductive &
Developmental toxicity

Investigating the effect of reproductive organs and next generation.

12

ADME

Absorption, Distribution, Metabolism, Elimination.

15

Toxicological Endpoints

Evaluation method

Acute Toxicity

OECD TG420, TG423, TG425, (TG402, TG403)

Primary Skin Irritation

OECD TG404, in vitro 3D (OECD TG431)

Sensitization

GPMT (OECD 406), LLNA (OECD 429), DPRA

(OECD 442C), KeratinoSens (OECD 442D), etc.

Photo-toxicity

in vitro 3T3 NRU (OECD TG432)

Photo-sensitization

Adjuvant & Strip

Eye-irritation

Draize (OECD TG405) BCOP (OECD TG437), ICE

(OECD438)

Genotoxicity Test

OECD TG471, 473, 474, 487

Repeated Dose Toxicity

OECD TG407, 408, 409, 410, 411, 412, 413, 422, 452,
453,

Reproductive & Developmental

OECD TG414, 415, 416, 421, 422, 443

ADME

OECD TG417, 427, 428

EU Regulation
2003/3/11

7th Amendment
issued

2004/9/11

2009/3/11

2013/3/11

Time limit for

legislation in
each country

Testing ban
IngredientComplete ban in EU
area
Marketing ban
Ingredients & Final Products
evaluated by animal testing are
prohibited
Exemption: ADME,
Reproductive, Repeated Dose
toxicity

Marketing ban
Ingredients &
Final Products
evaluated by
animal testing are
prohibited

Toxicological Endpoints

Evaluation method

Acute Toxicity

in vitro Cell viability LD50

Primary Skin Irritation

in vitro 3D (OECD TG431)

Sensitization

in vitro h-CLAT, -SH, ARE, DPRA (OECD 442C),

KeratinoSens (OECD 442D),

Photo-toxicity

in vitro 3T3 NRU (OECD TG432)

Photo-sensitization

in vitro PhotoSH/NH2, PhotoARE, Photo-apoptosis

Photo hCLAT

Eye-irritation

BCOP (OECD TG437), ICE (OECD438)

Genotoxicity Test

OECD TG471, 473, 474, 487

Repeated Dose Toxicity

NA

Reproductive & Developmental

NA

Dermal Absorption

in vitro Skin Permeation (OECD TG428)

Safety evaluation must be conducted using publicly accepted

method when it is used for quasi-drug submission.

Risk assessment of cosmetics

Risk Assessment
Hazard Identification

Dose-Response Assessment
Estimation of non-harmful concentration)

No Observed Adverse Effect Level

Exposure Assessment
(Route, Concentration, Frequency, Period)

Systemic Exposure Dosage

Risk Characterization

Risk Management
(Post marketing surveillance)

Risk Communication
(Warning labeling)

19

Safety Assessment Data Source

Evaluation based on
Toxicological data

In-house toxicological data

Safety information data obtained from suppliers

Assessment

Evaluation based on
the existing safety
information

Evaluation by reliable scientific bodies

General toxicology: CIR, SCCS
Carcinogenicity: RoC, IARC, EPA, Prop 65, ECHA
Repeated toxicity: NTP, EPA
Reproductive toxicity: NTP, Prop65, ECHA
Safety information DB: TOXNET, MEDLINE

Reliable publications/software

To obtain No Observed Adverse Effect Level (NOAEL)

CIR: Cosmetic Ingredient Review
SCCS: Scientific Committee on Consumer Safety
IARC: International Agency for Research on Cancer
ECHA: European Chemical Agency

RoC: Report on Carcinogen

EPA: Environmental Protection Agency
Prop.65: Proposition 65
NTP: National Toxicology Program

Data Base Source

JP (Japanese)
NITE (National Institute of Technological Evaluation
CERI (Chemicals Evaluation and Research Institute)

EU
SCCS opinions, EFSA opinions, and ECHA DB

US
CIR reports, NTP, EPA-IRIS, and Toxnet

International
IPCS, UNEP/ILO/WHO
Concise International Chemical Assessment Documents

IARC
RIFM DB
HERA (Human and Environmental Risk Assessments on
ingredients of household cleaning products)
by AISE and Cefic

Determination of Systemic Exposure Dosage

Amount of cosmetics per day, concentration of a substance in
the final product, dermal absorption and body weight should
be taken into consideration.
Calculation of SED
SED (mg/kg/day)
= A (mg/kg/day) C (%)/100 DAp (%)/100
SED (mg/kg/day) ; Systemic Exposure Dosage
A (mg/kg/day)Estimated daily exposure to a cosmetic
product
C (%)Concentration of a substance in a final cosmetic
product
DAp (%)Dermal absorption percentage
22

Estimated daily exposure levels for different cosmetic types

Estimated daily amount applied (mg/kg/day)
Daily application amount X Retention factor/ 60kg

23

THE SCCSS NOTES OF GUIDANCE 8TH REVISION

Risk Assessment for Systemic Toxicity

Estimation of No Observed Adverse Effect Level (NOAEL).
Not only hazard but also exposure amount should be taken
into consideration. Systemic Exposure Dosage (SED) is
dependent on dermal absorption, the amount of substance
applied, application area, frequency & length of
application.
Evaluation of safety by comparing NOAEL and SED.
Safe?

Dangerous?
NOAEL
SED
UF(uncertainty factor)
24

Safety Assurance Flow

Genotoxicity

Systemic Toxicity
Repeated Dosage Toxicity
Reproductive & Developmental
Toxicity

Maximum
Concentration

Human Testing

Local Toxicity
Sensitization QRA
Skin Irritation
Eye Irritation

Maximum
Concentration
in the formula

Maximum
Concentration

Patch Test
Sensory Irritation Test
Home Use Test
Long-Term Dosage Test

Photo Safety
Post Marketing
Surveillance

Launch in
the market

Safety Assurance of Final Products:

Implementation Standards for Human Test

Following items should be considered when new raw material is introduced in the
formula or under unexperienced usage in the market.
1) The market history of ingredients and safety assessment results
2) Product type
3) Application Method: rubbing, spray, leave on, rinse off
4) Concentration in a final product
5) Amount of used on the skin
6) Frequency of use
7) Whole application area
8) Application part
9) Exposure time
10) Foreseeable misuse
11) Special segmentation sensitive skin, children
12) Market history of similar formula products
13) Quantity likely to enter the body
14) Application on skin areas exposed to sunlight

Human Tests on Finished Products

Testing in humans

Toxic endpoint to confirm

Purpose of the test

irritation

Sensory
irritation

sensitization

others

Home use test

insufficient

Unexpected
adverse reaction

Patch testing

Assurance
Assurance

Sensory Irritation test

Assurance

Eye instillation Test

Development for
formula

ROATRepeat Open
Application Test)

RIPT(Repeated Insult
Patch Test)

Induction of
dryness

(insufficient)

Comedogenicity Test
Ophthalmologist Test

insufficient

Photo-irritation Test

UV)

Photo Maximization Test

(UV)

insufficient

insufficient

Development for
formula

Claim
substantiation
comedogenicity

Claim
substantiation

Unexpected
adverse reaction

Claim
substantiation
Application of SCF
mark

insufficient

Marketing
(display on product)

Patch Testing

Cosmetic or raw
material is applied on
a plaster for patch test.

The patch test plaster is

applied on the forearm and is
left to stand for 24 hours.

Such skin reactions as

redness and swelling
are observed and
evaluated.

Patch test is performed on volunteers to ensure that

the irritation the product causes on human skin is
minimal.

Safety Assurance of Products for Sensitive Skin (Shiseido)

Definition of sensitive skin
Sensitive skin is defined as follows: Skin with high sensitivity to
skin sensitization, irritation or sensory irritation. The skin tends to
easily suffer from skin troubles due to cosmetics that ordinary
people can use without any skin trouble.
Careful selection of materials
We have List of ingredients previously formulated in products for
sensitive skin (Positive list) and Negative list which consists of
materials with concerns in terms of sensitization, irritation and
sensory irritation.
If the products for sensitive skin consist of materials carefully
selected based on these lists, we thereby assure safety of products
for sensitive skin.
Confirmation of finished products
Patch test of the finished product is basically performed on subjects
having sensitive skin in order to confirm tolerance for sensitive skin.

Safety Assurance of Products for Children

Definition of children
Children less than 2 or 3 years old except for a newborn in the view point of
physiology and pharmacokinetic properties of the skin.

Product type should be restricted

Product type should be basically restricted to skin care products since the other
product types are not suitable for children from ethical point of view.
Raw materials should be selected carefully
The products for children should be formulated in the same manner with
sensitive skin. We thereby assure safety of products for children.
If the raw materials are properly selected, it is not necessary to perform in use
test. However, in the case of products for atopic children, clinical test is
inevitable.

Safety assurance of cosmetic products

Retrospective

Prospective

Safety

Predictions

Inspection

Guarantee
Information
on safety
In vitro tests
Existing in vivo
test results

Tests on
human
subjects

To predict safety of
human testing
Limited human testing To predict safety of
full scale human
testing
Non-human testing

Customers

Confirm info
(re-testing)
Modify
contents
guaranteed

Complaints
info
-Medical tests
-New safety
info

Complaints &
Confirm predictions
medical testing (& modify contents)
New Safety info Modify predictions

Flow of Post Marketing Surveillance, GVPGood Vigilance Practice

Quality Assurance Supervisor
Safety Control
Supervisor
Collection Evaluation
Other risk information
Study Report, Literature
information

from customers

Periodical
report
Direction

Marketing
Supervisor
General

Significant adverse effects

Planning of
action

Marketing
Function
Direction

Conduct action
Feedback

Action
Caution for Use
Formulation Renewal
Recall

Proposal
Direction

Decision of
action

Feedback

Archive of Action Records

32

Education, TrainingSelf-inspection

Customer information: Feeding into an intra-company system for effective use

Quality
control staff
(in each
country)

FAQ
Japanese,
Chinese,
English
(worldwide)

Shiseido website

Counter

Interoffice memorandum; info on feedback from customers

Quality
Analyzeassurance
dept.

Request
investigations
Give results of
investigations

Analysis report

Analysis report

Cloud service

Reflect customer feedback in

products and services
e.g., new products,
improvements, activity tools,
sales pitches, etc.

Each corporate dept.

Account
executives
(Japan)

Praises
Inquiries
Requests
Complaints
Alerts

Quarterly report at Management Meeting

Data service

Counter BCs
(iPad)
(Japan)

Information on alerts

Feedback
from
customers

Customers around the world

Customer
service
section
(Japan,
China,
Taiwan,
Hong Kong)

President, relevant executives,

heads of)related depts.
(

Mirror

Mirror System: System configuration diagram

Global real-time sharing of information
Shiseido Computer Center

Affiliates in Japan and overseas

Customer

Customer service section

English version

Mirror
Customer information inputting

Japanese version

Customer service support

Chinese version
Product investigations: Requesting &
responding

English
version
database

Japanese
version
database

Chinese TS
version
database

Customer service request

Chinese
version
database

English SHK
version
database

Chinese TS version

Customer information analysis

Database for
analysis
English SHK version

Customer informationanalyzing function

Safety assurance of cosmetic products

Retrospective

Prospective

Safety

Predictions

Inspection

Guarantee
Information
on safety
In vitro tests
Existing in vivo
test results

Tests on
human
subjects

To predict safety of
human testing
Limited human testing To predict safety of
full scale human
testing
Non-human testing

Customers

Confirm info
(re-testing)
Modify
contents
guaranteed

Complaints
info
-Medical tests
-New safety
info

Complaints &
Confirm predictions
medical testing (& modify contents)
New Safety info Modify predictions

Nothing is more important

than SAFETY for us
because our products are
for you

FINE