Post on 12-Jan-2016
description
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