Masato Hatao, Ph.D.

Shiseido Research Center

May 7, 2015

Safety Assurance of Skin Care

Cosmetics

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 rinse–off 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 36（7）；590-595, 2014

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

Allergic contact dermatitis due to

Methylisothiazolinone

6

Nothing can be “Completely Safe

Material” nor “100% Safe Material”.

Only under certain conditions, “Safe

Material” exists. “Safe Cosmetics”, as

well.

What is “SAFE MATERIAL”.

7

Is the water safe material?

It depends on the condition.

8

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】

9

What is “Cosmetics” in Japanese Pharmaceutical Affairs Law？

Hair nurturing tonics

Hair dye

Perming agent

Whitening cosmetics.

etc.

Defined as their effects are mild on

human body.

Cosmetics Keep the skin

normal and healthy.

Enhance

attractiveness.

Quasi-drug Prevent the disease

condition.

Socially accepted

cosmetics

Drug Cure the disease.

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.

＜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)

Cosmetic Ingredients

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 Predictions Inspection

Guarantee

Prospective

Retrospective

･Information

on safety

･In vitro tests

・Existing in vivo

test results

･Tests on

Human

subjects ･Customers

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

･Complaints

info

-Medical tests

-New safety

info

･Confirm info

(re-testing)

･Modify

contents

guaranteed

●Complaints & ⇒ Confirm predictions

medical testing (& modify contents)

●New Safety info ⇒ Modify predictions

Safety assurance of cosmetic products

15

Toxicological Endpoints

１ Acute Toxicity Systemic toxicity by single dose.

２ Primary Skin Irritation Irritation potency by applying on the skin.

３ Repeated Skin Irritation Irritation potency by repeated application on the skin.

４ Skin Sensitization Allergenicity when applied on the skin.

５ Photo-toxicity Irritancy on the skin upon receiving photo irradiation.

６ Photo-sensitization Allergenicity on the skin upon receiving photo irradiation.

７ Eye Irritation Irritation on eye in case of accidental exposure.

８ Genotoxicity Toxicity on genes.

９ 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.

General Toxicological Endpoints aimed for Development of Cosmetics and Quasi-drugs

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 2013/3/11 2009/3/11

7th Amendment

issued

2004/9/11

Time limit for

legislation in

each country

【Testing ban】

・Ingredient：Complete 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 Photo–SH/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.

19

Hazard Identification

Dose-Response Assessment Exposure Assessment

Risk Characterization

Risk Management

(Warning labeling)

（Estimation of non-harmful concentration)

Risk Communication

(Post marketing surveillance)

Risk assessment of cosmetics

(Route, Concentration, Frequency, Period)

Risk Assessment

No Observed Adverse Effect Level Systemic Exposure Dosage

・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

Assessment

Evaluation based on

Toxicological data

Evaluation based on

the existing safety

information

In-house toxicological data

Safety information data obtained from suppliers

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

Safety Assessment Data Source

To obtain No Observed Adverse Effect Level (NOAEL)

– 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

Data Base Source

22

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

Determination of Systemic Exposure Dosage

23

THE SCCS„S NOTES OF GUIDANCE 8TH REVISION

Estimated daily amount applied (mg/kg/day)＝

（Daily application amount X Retention factor）/ 60kg

Estimated daily exposure levels for different cosmetic types

24

• 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.

Risk Assessment for Systemic Toxicity

NOAEL

SED UF(uncertainty factor)

Safe? Dangerous?

Safety Assurance Flow

Genotoxicity

Systemic Toxicity

Repeated Dosage Toxicity

Reproductive & Developmental

Toxicity

Local Toxicity

Sensitization QRA

Skin Irritation

Eye Irritation

Photo Safety

＋/ー

Maximum

Concentration

Maximum

Concentration

Maximum

Concentration

in the formula

Launch in

the market

Post Marketing

Surveillance

Human Testing

Patch Test

Sensory Irritation Test

Home Use Test

Long-Term Dosage 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

Safety Assurance of Final Products: Implementation Standards for Human Test

Testing in humans Toxic endpoint to confirm Purpose of the test

irritation Sensory

irritation

sensitization others

Home use test ✔ ✔ insufficient Unexpected

adverse reaction

Assurance

Patch testing ✔ Assurance

Sensory Irritation test ✔ Assurance

Eye instillation Test ✔ Development for

formula

ROAT（Repeat Open

Application Test)

✔ Induction of

dryness

Development for

formula

RIPT(Repeated Insult

Patch Test)

✔ (insufficient) Claim

substantiation

Comedogenicity Test comedogenicity Claim

substantiation

Ophthalmologist Test insufficient insufficient insufficient Unexpected

adverse reaction

Claim

substantiation

Photo-irritation Test ✔（UV) Application of SCF

mark

Photo Maximization Test ✔(UV) insufficient Marketing

(display on product)

Human Tests on Finished Products

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.

Patch Testing

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 Sensitive Skin (Shiseido)

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 Products for Children

Safety Predictions Inspection

Guarantee

Prospective

Retrospective

･Information

on safety

･In vitro tests

・Existing in vivo

test results

･Tests on

human

subjects ･Customers

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

･Complaints

info

-Medical tests

-New safety

info

･Confirm info

(re-testing)

･Modify

contents

guaranteed

●Complaints & ⇒ Confirm predictions

medical testing (& modify contents)

●New Safety info ⇒ Modify predictions

Safety assurance of cosmetic products

32

Marketing

Function

Other risk information

from customers

Periodical

report

Direction

Significant adverse effects

Evaluation

Planning of

action

Decision of

action

Proposal

Direction 【Action】

・Caution for Use

・Formulation Renewal

・Recall

Direction

Feedback

Feedback

Archive of Action Records

Safety Control

Supervisor Marketing

Supervisor

General

Conduct action

Quality Assurance Supervisor

Education, Training，Self-inspection

Study Report, Literature

information

Flow of Post Marketing Surveillance, GVP（Good Vigilance Practice）

Collection

President, relevant executives, heads of related depts. ( )

Quarterly report at Management Meeting

社 内 各 部 門

活用

商品

施策

売り場

づくり

など

社 内 各 部 門

活用

商品

施策

売り場

づくり

など

Information on alerts

Interoffice memorandum; info on feedback from customers

Analysis report

Counter

Shiseido website Reflect customer feedback in

products and services

e.g., new products, improvements, activity tools,

sales pitches, etc.

Customer service section (Japan, China,

Taiwan, Hong Kong)

Request investigations Give results of investigations

Quality assurance

dept. Analyze

Each corporate dept.

Counter BCs

(iPad)

(Japan)

Account

executives

(Japan)

Quality

control staff

(in each

country) Cu

sto

me

rs a

rou

nd

the

wo

rld

Cloud service ＳＮＳ

Praises

Inquiries

Requests

Complaints

Alerts

Mirror

Feedback

from

customers

Da

ta serv

ice FAQ

Japanese, Chinese, English

(worldwide)

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

Analysis report

Customer information-analyzing function

Shiseido Computer Center

Japanese version

database

Chinese version

database

English version

database

Database for

analysis

Customer Customer service section

Affiliates in Japan and overseas

Customer information inputting

Customer service support

Chinese TS version

database

Global real-time sharing of information

English SHK version

database

English version

Japanese version

Chinese version

Chinese TS version

English SHK version

■Mirror System: System configuration diagram

Customer information analysis

Mirror

Product investigations: Requesting & responding

Customer service request

Safety Predictions Inspection

Guarantee

Prospective

Retrospective

･Information

on safety

･In vitro tests

・Existing in vivo

test results

･Tests on

human

subjects ･Customers

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

･Complaints

info

-Medical tests

-New safety

info

･Confirm info

(re-testing)

･Modify

contents

guaranteed

●Complaints & ⇒ Confirm predictions

medical testing (& modify contents)

●New Safety info ⇒ Modify predictions

Safety assurance of cosmetic products

Nothing is more important than SAFETY for us

because our products are for you

FINE