Guideline For Risk Assessment

of Cosmetic Products

2016. 2. 25.

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 Table of Contents

Chapter 1. Purpose of Guideline for Risk Assessment of

Cosmetic Products ··········································· 6
1. Purpose ··························································································· 6

Chapter 2. General Principles of Cosmetic Product Safety ·· 7

1. General principles ······································································· 7
2. Cosmetic ingredients ··································································· 9
3. Finished product ······································································· 11

Chapter 3. Risk Assessment of Ingredients in Cosmetic

Products ························································· 12
1. Definition and principles of risk assessment ······················ 12
1.1. Definition of risk assessment ············································· 12
1.2. Principles of risk assessment ············································· 13
1.3. Reviewing necessity of risk assessment ·························· 15
1.4. Types of risk assessment for each risk factor ·············· 16
2. Methodology of risk assessment ··········································· 17
2.1. Preliminary review items for risk assessment ················ 17
2.2. Detailed procedures of risk assessment ························· 20
2.2.1. Hazard identification ······················································· 21
2.2.2. Hazard characterization ·················································· 22
2.2.3. Exposure assessment ······················································· 24
2.2.4. Risk characterization ························································ 27
2.2.5. Report preparation ·························································· 28
2.3. Re-assessment ········································································ 29

Chapter 4. References ·························································· 30

 Table of Contents

▣ Appendix ·········································································· 31
1. Cosmetic products risk assessment report form ··············· 32
2. General principles for computing margin of safety and
lifetime-cancer risk for cosmetic products risk assessment · 35
3. Cosmetic products exposure data ········································· 41
4. Collection method of toxicity data for cosmetic ingredient
risk assessment ·········································································· 47
5. Glossary of Terms ······································································ 64

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 History

Guideline for Risk Assessment of Cosmetic Products

Leg./Amend Approval
Comments
No. Date
Enactment of Guideline for Risk
B2-2011-4-005 2011.08.
Assessment of Cosmetic Products
Amendment of Guideline for Risk
B1-2013-4-002 2013.10.
Assessment of Cosmetic Products
Amendment of Guideline for Risk
B2-2016-4-001 2016.2.25.
Assessment of Cosmetic Products
 This guideline is written to provide general principles and methods

for risk assessment of cosmetic products from the current scientific

standard. It is the current view of the National Institute of Food and

Drug Safety Evaluation based on experience of risk assessment on

cosmetic products and opinion of professionals, and it may be amended

with advancement of science. Moreover, this guideline is not legally

enforceable, and suggested methods may be interpreted differently on a

case by case basis.

※ Guideline is a description of Ministry of Food and Drug Safety's opinion

on certain issues for the outside use (Regulation on Management of Ministry
ot Food and Drug Safety Guidelines (MFDS Rule))

※ If you have any feedback about this guideline, please contact us at the

number provided below.

National Institute of Food and Drug Safety Evaluation

Pharmaceutical and Medical Device Research Department T.043-719-4853 F.043-719-4855

Cosmetics Research Team

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 Purpose of Guideline for Risk Assessment of
Ⅰ
Cosmetic Products

1. Purpose

The purpose of this guideline is to present general principles of safety and

items, methodology, and procedure for evaluating the safety of cosmetic

ingredients in order to guarantee the safety of cosmetic products.

This guideline mainly concerns skin exposure due to cosmetic usage, and

contains information for risk assessment. We anticipate that it will be helpful

for consumers, cosmetic product manufacturers, and related organizations.

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 Ⅱ General Principles of Cosmetic Product Safety

1. General principles

1) A cosmetic product must not be harmful to the human body when used

according to the product guideline or indications, or when used under

predictable use conditions.

Cosmetics Act Article 2 (Definition) "Cosmetic product" refers to a product

that is rubbed or sprayed onto the human body or used with a similar

method to make the body more attractive by cleaning ㆍ beautifying it and to

brighten one's appearance or to maintain or enhance skin ㆍ hair health and has

a minimal effect on the human body. However, products that are classified as

medicine and medical supplies according to 「 Pharmaceutical Law 」 Article 2,

Item 4 are excluded.

※ Cosmetics Art Article 8 (Cosmetic Product Safety Criteria etc.) ③ The

Minister of Food and Drug Safety must quickly evaluate the risk of cosmetic

product ingredients that are known domestically or internationally to contain

harmful substances or that have raised concerns in terms of national health,

and determine whether or not they are harmful in accordance with the

ordinance of the Prime Minister. ④ When a risk assessment is completed

according to Clause 3, the Minister of Food and Drug Safety must designate

the raw ingredients of the corresponding cosmetic product as raw

ingredients that cannot be used in cosmetic manufacturing or determine its

use criteria.

2) Cosmetic products must not only be safe to consumers but also to experts

(hair stylist, skin care specialist etc.) who professionally use cosmetic

products.

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3) Since cosmetic products are mainly applied to the skin, skin irritancy and

sensitivity must be preferentially considered, as well as photic stimulation

or photosensitivity by light. Also, eye irritancy must be evaluated as

products that are applied to the scalp or face can enter the eye.

4) Depending on how a cosmetic product is used, systemic toxicity due to

skin absorption, carelessness (including exposure to children) or predictable

oral intake (lipstick, etc.) or inhalation toxicity (spray etc.) must be

considered.

5) Confirming the safety of a cosmetic product requires a holistic approach

for the entire cycle of the product from selecting the raw ingredients to

the use period.

6) A product's risk assessment may be different for each product, but it is

based on the toxicity data of each raw ingredient in general.

7) From a scientific perspective, not all ingredients require animal toxicity

data. For most ingredients, currently available data such as skin suitability

data should be reviewed first.

8) Considering that individual cosmetic product usage may vary, the risk of

cosmetic ingredients must be evaluated in a maximum usage environment

that can occur under normal conditions. If necessary, the risk must be

assessed not only for people with occupations that are frequently exposed

to cosmetics (e.g., celebrities and stylists), but also for children and babies.

Also, considering that various types of products may be simultaneously

used, the risk assessment should be conducted by considering the

combined risk when multiple cosmetic products are used simultaneously.

9) Cosmetic product manufacturers must do their best to obtain safety data

on the substances they use and use the data as much as possible.

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10) Safety documents may be utilized if tests were performed following

internationally recognized protocols, such as OECD guidelines, or based on

scientific basis.

11) This guideline may not be regarded as checklist during the risk

assessment of cosmetic products, and it is advisable to evaluate on a case

by cases following the characteristics of cosmetic product’s ingredients.

2. Cosmetic ingredients

1) Cosmetic products’ ingredients may be chemical substance or natural

substance. In cases, it may be single or mixture. In order to establish

safety of the final product, safety of the ingredients must be assured.

2) The ingredients used must not have been designated as a raw ingredient

that cannot be used in cosmetic product manufacturing by the Minister of

Food and Drug Safety and it must also be used appropriately within its

usage limit.

3) Sufficient measures must be taken to reduce trace amount of contaminants

such as heavy metal or unintentional remnant substances that can appear

during the manufacturing process or storage as much as possible. If

contaminants continue to exist even after such measures, its safety must be

reviewed in a case-by-case manner by considering skin exposure and the

exposure amount.

4) The physicochemical reactions and biological reactions are determined by

the chemical structure of the cosmetic ingredient and the chemical purity,

mutual interaction with other substances, and skin permeation can

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 influence the effectiveness, safety, and stability.

5) Extra caution must be taken toward the possibility of mutual interaction

between impurities (e.g., formation of nitrosamine), as well as the

possibility of substances extracted from plants and animals containing

agricultural pesticides, insecticides, metal substance, and biologically

harmful elements such as substances that cause transmissible spongiform

encephalopathy (TSE).

6) The skin permeation of cosmetic ingredients can influence its sensitivity

and systemic effect. The change in skin permeation can influence other

substances. In the sensitivity evaluation both the substance itself and its

vehicle must be considered together as the vehicle too may have an

influence.

7) The safety of the cosmetic product can differ depending on the exposure

conditions. Exposure conditions can vary depending on the form of the

cosmetic product, concentration, contact frequency and period, relevant

body surface area, and influence of sunlight. Risk assessments must

consider various predictable exposure conditions and must also include the

worst-case exposure conditions such as high concentration and high dose.

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3. Finished Product

1) The finished product must be safe during the usage period or until the

expiration date when stored under adequate conditions.

2) The safety of a product is reviewed by an expert by referring to the

toxicological characteristics of each component, experience of using

products of similar composition, and whether or not it contains new

substances.

3) Even though evaluation of the ingredients is the fundamental in

evaluating the safety of the final product, contamination of microorganism

during manufacturing, distribution and use must also be considered.

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 Ⅲ Risk Assessment of Cosmetic Products

1. Definition and principles of risk assessment

1-1. Definition of risk assessment

○ A series of processes that scientifically predict risk effects and probability

that may occur when the human body is exposed to risk elements existing

in cosmetic products, such as hazard identification, hazard characterization,

exposure assessment and risk characterization.

1) Hazard Identification : Process of scientifically confirming the potential

properties that may exhibit toxicity inside the human body

2) Hazard Characterization : Process of quantitatively calculating the

permissible dosage for human body exposure of risk elements based

on animal toxicity data and human toxicity data

3) Exposure Assessment : Process of calculating human body exposure level

based on quantitative data from risk elements exposed from the use of

cosmetic products

4) Risk Characterization : Process of determining the potential risk effect of

current exposure level on the health from the calculation of the risk based

on hazard identification, hazard characterization and exposure assessment

and includes the uncertainty assessment

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1-2. Principles of risk assessment

○ The following are the general principles necessary for conducting a risk

assessment.

1) A risk assessment is conducted in 4 steps: hazard identification, hazard

characterization, exposure assessment, and risk characterization.

2) A risk assessment should use data that can reflect domestic situation, but

if domestic data does not exist or is insufficient, data from international

organizations or foreign countries may be used.

3) A risk assessment should consider the analysis method, sampling and

testing, and exposure frequency used over the entire supply and usage

process, including the manufacturing process of the cosmetic product.

4) A exposure assessment must be conducted under a realistic exposure

scenario considering various situations.

- However, in the case of groups that are sensitive to the substance being

assessed and high risk groups, acute, chronic, accumulated, complex

influences should be considered,

- In the case of vulnerable groups such as pregnant women and children,

more careful research and analysis are necessary, and the situations

should be sufficiently considered when preparing the exposure scenario.

5) Limits, uncertainties, and hypotheses that influence the results of the

evaluation should be suggested in the risk assessment report, and if there

is a difference in opinions between experts who participate in evaluation,

the minority's opinion should also be recorded.

6) While the data in the risk assessment report can be expressed quantitatively

or qualitatively considering uncertainties in scientific information, it should

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 be quantified to the extent that is scientifically possible.

7) The risk assessment report must be written in a format that can be easily

understood.

※ The above principles must be followed when conducting an evaluation.

However, there may be exceptions depending on the characteristics of
the risk element.

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1-3. Reviewing necessity of risk assessment

When risk assessment is When risk assessment is

necessary not necessary
- Setting usage prohibition based on

hazard

- Setting the usage limit based on the

margin of safety - If information on the risks

(anti-ultraviolet substances, sterilization is not sufficient, evaluate

substances) after collecting information

- Appropriateness of the standards for the - If harmful substances are

current usage limit substance illegally mixed in the

- Setting the standard for unintentional cosmetic product

contaminants - Functional cosmetic products

- Risk of cosmetics safety issue substances whose safety and validity

- Setting the priority of risk are proven and are already

management permitted

- To test that there is no significant

evidence of harmfulness to the human

body

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1-4. Types of risk assessment for each risk factor

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2. Methodology of risk assessment

2-1. Preliminary review items for risk assessment

1. Determine how to assign roles such as designating managers and

responsible persons for each step of the risk assessment.

2. Determine the purpose of the risk assessment.

3. Check the information necessary for risk assessment.

① What is the problem?

② Why did the problem occur?

③ How was the problem identified?

④ How serious is the problem?

⑤ Were there similar problems in the past? Or is it a new problem?

⑥ How does it influence the health of the human body?

⑦ How seriously does it affect the health of the human body?

⑧ Can the exposed group and the level of exposure be identified?

⑨ What were all of the relevant sources of exposure, and how much did each

source contribute to the problem?

⑩ Was the exposure period short-term or chronic? How often was it

exposed?

⑪ Are there currently regulations or safety management standards in

Korea or other countries?

4. Determine the subject of the risk assessment.

① Review the major exposure groups (sensitive groups such as children, high

exposure groups, main exposure groups, etc.) and determine the subject range

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 ② Establish strategy by referring to the standard guide acknowledged by

the risk assessment guideline and international organizations

5. Determine the range of risk assessment.

① The risk assessment on harmful substances are categorized into

carcinogenic risk assessment or non-carcinogenic risk assessment and is

determined by whether or not the substance is carcinogenic

② Determine the scenario depending on whether the product being

assessed is a raw ingredient or is a finished product

③ Understand how the measure will differ depending on the result of the

risk assessment

6. Determine the period of the risk assessment and notify the risk manager.

7. Review relevant data that are required when conducting risk assessment.

① The following must be considered for harmful substance monitoring

data

- Data must derive from recognized analysis tools, and it is best to utilize

the data produced for the purpose of assessing the risk - however, existing

data may be utilized.

- If the results of multiple experiments conducted separately are used in

a single risk assessment, only use the values whose homogeneity are

acknowledged by considering the testing purpose, range of sampling,

preprocessing method, analyzing device, and limit of quantification.

- If the value is lower than the limit of quantification, process it as zero

or LOQ/2 depending on the number of samples and the distribution of

values lower than the LOQ.

- Analysis data conducted for a specific purpose should be excluded from

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 the reference for general exposure assessment.

② If there is no new data, past data can be used when the limitations of

the evaluation or sufficient explanation in the document is provided.

③ For the body weight used for computing the human body exposure

amount, use the average body weight of the subject population group

on which the exposure assessment is conducted.

­ Average adult weight (19 years or older, 60kg)

④ For the usage amount of the cosmetic product, use data that is

appropriate for the characteristics of the risk element, purpose of the

risk assessment, and subject of the assessment.

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2-2. Detailed procedures of risk assessment

□ Background and purpose

- Explain the background of how the problem occurred, ripple effect,

seriousness and social impact.

□ Conducting risk assessment

- A risk assessment is conducted in 4 steps (hazard identification, hazard

characterization, exposure assessment, and risk characterization), and the

purpose, evaluation method, and result analysis for each step are

recorded.

□ Writing report and proposing management solution

- Document the results of the conducted risk assessment, and propose a

management solution depending on the purpose.

□ Review by expert advisory committee

- The expert advisory committee is composed of experts in each field, and

experts on clinical trials and statistics can be added ief needed.

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2-2-1. Hazard identification

1) Hazard identification is the procedure of the identifying hazard by

studying and analyzing the most current domestic and international

information about the harmful substance.

2) The toxicity data of the substance must consider all currently available

data. In vitro, in vivo, and clinical trial data, and even epidemiological

data should be included if available. The scientific evidence of toxicity

data must be stated.

3) Clinical trial and epidemiological data should preferentially use research

results of Asians, and more appropriately, Koreans.

4) The source and collection method of toxicological data are stated in detail

in Appendix 4) “Collection Method of Toxicological Data for Risk

Assessment of Cosmetic Ingredients”

Main contents Review method Note

○ Study physiochemical traits, use

temperature, amount used, use situation,

manufacturing process
○
○
Reports issued

Study source of exposure, exposure by international

○
period, human influence and organizations

biological data (absorption, distribution, (WHO, FAO, When worried

metabolism, excretion, in-body IPCS, IARC) and about exposure

accumulation) r e l a t e d to sensitive

Hazard
○
institutions (EPA, groups such as

Identifica Study toxicity data FDA, EC, Japan p r e g n a n t

tion - Short-term toxicity, long-term toxicity, Pension Service) w o m e n ,

carcinogenicity, mutagenicity, reproductive - Refer to sites in children, review

toxicity, immunotoxicology etc. relevant area data more

○
- If it has carcinogenicity, obtain evidence carefully

for carcinogenicity by reviewing the results International

of clinical trials and animal tests SCI level

papers

○ Human body epidemiological study

results, toxicokinetics

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2-2-2. Hazard characterization

1) Hazard characterization is a stage to establish toxic value (NOAEL,

BMDL) utilized in determining risk based on human or animal toxicity

data.

2) When using a cosmetic product, data with the same exposure route

should be preferentially used, but if there is no toxicity data with skin

exposure, oral or dermal exposure data can be used.

3) Hazard characterization data that are required for skin exposure can be

derived using the toxicity data shown in the table below.

4) Utilize toxicity data corresponding to skin exposure status

Exposure
Toxicity data(Dosage-reaction assessment data) Extrapolation to human
period

Apply when exposing for

Acute Acute Dermal Toxicity (24 hours)
1 day or 1 time

Short-ter Short-term Dermal Toxicity or Oral Toxicity (21~28 Apply when exposing

m days) => NOAEL identification for 1 day ~ 2 weeks

Subchron Subchronic Dermal Toxicity or Oral Toxicity (90 days) Apply when exposing

ic => NOAEL identification for 2 weeks ~ 7 years

Chronic Dermal NOAEL or Oral Toxicity => NOAEL Apply when exposing
Chronic
identification for 7 or more years

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 Main contents Review method Note

○ Study NOAEL, LOAEL, BMDL for

○ Use data from WHO, and developed

countries such as USA, Japan, Australia,

the substance

○
Canada

Apply uncertainty coefficient

- As a baseline, consider sensitivity of 1~10

for animals and human, and 1~10 between

humans. In addition, additional uncertainty

coefficient may be considered in following

○ Compute toxicity value (NOAEL, cases. Consider coefficient 3 when using

BMDL etc) from human toxicity test

lowest observed adverse effect level (LOAEL)
data or animal toxicity test data
is used in lieu of NOAEL, or coefficient 3
- When extrapolating animal test

may be additionally considered when data

data to human, apply an

uncertainty factor from 10 to from test period of less than subchronic

10,000
toxicity test (90 days) is available. However,
- Select the most sensitive toxicity
they should be determined on a case-by-case
end point from the most valid

basis, and the additional coefficient should be

toxicity test

between 1~10.

○ Use weight reduction, long-term weight

loss, structural change, and other

Hazard toxicity testing results and human

characte epidemiological results for selecting the

rization
○
toxicity end point

If it is not completely a carcinogen,

but data for setting NOAEL is

insufficient, recommend evaluation by

using BMDL
○ BMDL is computed based on dosage reaction

※ Provides software: (BMDS v.2.0,

-
modeling

The lower 95% confidence interval of BMD

○
www.epa.gov/NCEA/bmds)
is called BMDL
Evaluation method can differ
- From the graph that is extrapolated from
depending on whether or not
animal testing result, An amount that shows
genotoxicity, carcinogenicity exists
tumor occurrence rate of 5% BMDL5) or
- If the NOAEL value doesn't exist
10%(BMDL10) from the control is normally
because there is genotoxicity,
computed
carcinogenicity, use LOAEL or BMDL

values
○ Cancer Slope factor computation

-1
- slope(mg/kg bw/day) =risk/dose
- In the case of carcinogens,

compute cancer slope factor, Unit

Risk

○ If the exposure route is oral and ○ Can apply by considering bioavailabity

not skin, change into skin data when orally injecting

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2-2-3. Exposure Assessment

1) Exposure Assessment is a process of quantitatively calculating the human

body exposure from establishing a hypothetical scenario based on related

data such as amount of cosmetic products used.

2) The types of cosmetic products are diverse and the usage methods vary

depending on those types. Therefore, exposure must be assessed by setting

an exposure scenario that considers how a product is used for each type

when conducting risk assessment of cosmetic products.

- For example, products such as lipstick that are used on the lips or around

the mouth must consider a certain level of intake, and products such as eye

shadow that are used around the eye must consider contact with conjunctiva.

- When used, shampoo and rinse are diluted with water. Although the applied

range is wide, these products are quickly washed away after use.

- Body lotions are applied to a wide range of the body and likely remain in

contact with the skin.

Exposure Assessment on Harmful Substances in Cosmetic Products

Main contents Method Note
○ Set the exposure scenario and evaluate the

exposure dosage in order to more clearly

evaluate who is the subject exposed to

danger and how s/he is exposed

- For human exposure dosage when used as

a single product or together with others, set

○ Compose an exposure the scenario by considering the oral, skin

Expos exposure route depending on the

scenario
ure characteristics for each product

assess - When computing human skin exposure

ment dosage, consider the skin area that can get

in contact when using the product (e.g.,

lips, nails, neck, etc.)

- For the pollution level of the harmful

substance, the exposure dosage can be

computed from considering the types of

○ Items to consider when

products, and amount used
- Number of daily use

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 writing exposure scenario - Amount to use for day or one session

- Skin absorption rate

- Customer type (e.g., children)

- Area of skin that gets in contact with the

product

- Application (e.g., rinsing product, rubbing

product)

○ The following shows the computation of systemic

exposure dosage (SED) when exposed to skin

- Systemic exposure dosage after a certain

amount of time can be derived from the

absorption rate based on the skin

absorption dosage per unit area or the

amount of the applied substance within

the product. When using the absorption

rate, the result value can differ depending

W h e n
on the dosage applied to the skin and

area. The two types of computation are computing

shown below. s y s t emi c

e xpos ur e

d o s a g e ,
1) Computing the systemic exposure dosage

t h e
based on the skin absorption dosage per

unit area ( μg/cm 2

) r emnant

index(RF)c

○ Systemic exposure dosage

SED =
DAa(μg/cm 2
) ×
10
-3
mg/ ×
μg SSA(cm 2
) ×F
(day
-1
)
an be

(SED) computation 60 kg considered.

(Refer to

SED (mg/kg bw/day)=Systemic Exposure Dosage Appendi x

μ 2
DAa ( g/cm ) = Amount of skin absorption
3)
2
SSA(cm ) = Skin surface area that processed the

cosmetic product in final

manufacturing step (Refer to Appendix

3 for skin surface area (SSA) value based

on body type)
-1
F(day ) = Frequency at which the cosmetic

product in its final manufacturing step is

exposed

60kg = Average adult weight

W h e n

computing
2) Computing the systemic exposure dosage
s y s t emi c
based on the amount of the applied
e xpos ur e
substance within the product (%)

d o s a g e ,

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 A(g/day) ×1000mg/g ×C (%)/100 ×DA p(%)/100
SED =
60 kg

SED (mg/kg bw/day)= Systemic Exposure Dosage

t h e
A (g/day) = 1-day usage of cosmetic product

: Refer to the amount to be used r e m n a n t

in 1-day depending on body index(RF)c

type in the Appendix

an be
C (%) = Concentration of the cosmetic
considered.
ingredient being studied at the part
(Refer to
where the cosmetic product in the

final manufacturing step is used Appendi x

DAp (%) = Skin absorption rate expressed as

3)

a percentage of the test does

when assumed to be used in real

usage condition

60 kg = Average adult weight

3) Following may be considered for infant and child product dosages.

① All infant and child products: consider ratio between weight and skin

area

- 2.3 times higher than an adult for a new-born

- 1.8 times higher if 6 months after birth

- 1.6 times higher if 12 months after birth

- 1.5 times higher if 5 years after birth

- 1.3 times higher if 10 years after birth

② Products that are likely to be used on the buttocks : When systematically

computing the exposure dose, assume 100% skin absorption rate

considering that the buttocks is a sensitive part.

③ All products that do not cover the buttocks : If data on skin absorption

cannot be used or only predictions through modeling exist, 100% skin

absorption rate can be applied.

④ ‘Rinsing’ product : Depending on its usage, the remnant index can be

measured for rinsing products, and if remnant factors cannot be used, 10%

remnant index can be applied.

⑤ Generally, uncertainty coefficient for infant and child under the age of 10

is already reflected in the between human variable, so additional

consideration is not needed.

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2-2-4. Risk characterization

1) It is a procedure to estimate the rate in which harmful reaction occurs in

human when exposed based on the amount exposed in hazard

characterization and exposure assessment.

2) The probability that harm can be caused due to exposure to harmful

substance by using the cosmetic product is shown as margin of safety

(MoS).

Margin of Safety(MOS) = NOAEL/SED

* SED = Systemic Exposure Dosage

3) Generally, it is regarded to have no risk if the computed value of the

margin of safety (MoS) is 100 or higher.

4) The risk level of carcinogens are determined using a dose-descriptor.

5) For the general method of computing margin of safety for risk level

assessment, refer to the example in the Appendix 2) “The General

Principles of Computing Margin of Safety and Lifetime-Cancer Risk for

Risk Assessment of Cosmetic Ingredients”

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2-2-5. Report preparation

1) The final report must systematically and clearly document the entire risk

assessment process. In the document, detailed data of the risk assessment

and overall opinions must be included, and the hypotheses made in the

process or conclusions, expert decision, uncertainties, limits or weaknesses

must be written.

Main points Review method Note

○ Summary, purpose, range, guideline, content,

method, conclusion and references for the

risk assessment should be written and

○ While it should be
○
relevant information should be attached

Characteristics of risks, scenarios in which

written based on the
they can occur, and validity of selecting the
risk assessment report
data used should be written as clearly and
format, the validity

○
simple as possible
of data selection,
Uncertainties, limits, and selected hypotheses
uncertainties and limits
that influence the result, as well as expected
Repor
must be clearly

○
t impacts should be written
documented Estimated risk values should be expressed
prepa

ration quantitatively or qualitatively by considering

scientific information and uncertainties, but

○
quantify within scientifically possible range

Propose a

management criteria

or

level
measure

that can
to

secure
the
○ Comparison with reference values of foreign

developed countries
a sufficient margin of

safety based on the

evaluation results

- 28 -
2-3. Re-assessment

1) If there are additional data that can be trusted, re-assessment can be

conducted.

- Re-assessment can be conducted if a new scientific fact is discovered or

the product is newly evaluated in a foreign country

- Re-assessment can be conducted if a new toxicological data are

announced

- 29 -
 Ⅳ References

1. Dooms-Goossens, Cosmetics as causes of allergic contact dermatitis, Cutis,

52, pp.316-320

2. Loprieno, N., Guidelines for safety evaluation of cosmetic products in the

EC countries, Fd. Chem. Toxic., 30, pp.809-815

3. Human testing for skin compatibility of products or skin tolerance of

potentially irritant cosmetic ingredients, SCAAT statement (ref 96/304),

Colipa, 1996, Brussels

4. B a r a tt M .D ., Q u a n tita tiv e S tr u c tu r e A c tiv ity R e la tio n s h ip s fo r s k in

corrosivity of organic acids, bases and phenols, Toxicology Letters, 1995,

75, pp.169-176

5. Howes, D., Guy R., Hadgraft J. et al., Methods for assessing percutaneous

absorption, ATLA, 24, pp.81-106

6. C o lip a / E F F A , G u id e lin e s on th e exchange of in fo r m a tio n b e tw e e n

fragrance suppliers and cosmetic manufacturers, Colipa, 1995

7. SCCNFP Notes of Guidance for the Testing of Cosmetic Ingredients and

their Safety Evaluation, 6th revision

8. World Medical Association, Declaration of Helsinki, 1964&1989(revised),

Fernay Voltaire, France

9. C IO M S/ W H O , International ethical guidelines for biom edical research

involving human subjects, 1993, CIOMS, Geneva

10. ASEAN Cosmetic Directive. ASEAN Guidelines for safety evaluation of

cosmetic products

11. CTFA, USA. CTFA Safety Evaluation Guidelines, 2007

12. SCCS's Notes of Guidance for the Testing of Cosmetic Substances and

Their Safety Evaluation 8th Revision

- 30 -
 [ Appendix ]

1. Cosmetic Products Risk Assessment Report Form

2. General Principles for Computing Margin of Safety and

Lifetime-Cancer Risk for Cosmetic Products Risk Assessment

3. Cosmetic Products Exposure Data

4. Collection Method of Toxicity Data for Cosmetic Ingredient

Risk Assessment

5. Glossary of Terms

- 31 -
Appendix) 1. Cosmetic Product Risk Assessment
Report Form

Title

<Abstract>
: Summary of the risk assessment

<Table of Contents>

1. Background and Purpose

: Describe Assessment Background and Purpose

2. Methods of Risk Assessment

: Short description of methods used in risk assessment

2.1. Hazard Identification

2.2. Hazard Characterization

2.3. Exposure Assessment

2.4. Risk Characterization

3. Results of Risk Assessment

3.1 Risk Characterization

3.1.1 ·
Physical chemical properties [substance name, IUPAC name, CA No.,

chemical formula, molecular weight, purity (analysis method),

structural formula(extraction method and refining process for extract),

physical image, melting point, boiling point, density, solubility, Log

POW, henry constant, synonym]

3.1.2 Usage Status

3.1.3 Exposure Process

3.1.4 Toxicological Data

3.1.4.1 Kinetic Information

3.1.4.1.1. Absorption, Distribution, Metabolism, Excretion (ADME)

- 32 -
 3.1.4.1.2. Transderma Asborption Ratio

3.1.4.2 Acute Toxicity

3.1.4.3 Skin Irritation and Corrosiveness

3.1.4.3.1. Skin Irritation

3.1.4.3.1.1. Human Skin Irritation

3.1.4.3.1.2. Animal Skin Irritation

3.1.4.3.2. Mucous Membrane Irritation

3.1.4.3.3. Skin Sensitivity

3.1.4.3.3.1. Human Skin Sensitivity

3.1.4.3.3.2. Animal Skin Sensitivity

3.1.4.4. Repeated Administered Toxicity

3.1.4.5. Immuno-Toxicity

3.1.4.6. Neuro-Toxicity

3.1.4.7. Reproduced Toxicity

3.1.4.8. Genetic-Toxicity

3.1.4.9. Carcinogenicity

3.1.4.10. Phototoxicity

3.1.4.11. Miscellaneous (including clinical data)

3.1.5 National and International Regulations

3.2. Hazard Characterization

3.2.1. Confirm the Optimal NOAEL

3.3. Exposure Assessment

3.3.1 Transdermal Exposure Assessment (Calculate transdermal exposure

for the entire body, include formulas)

3.3.2 Exposure Scenario

3.4 Risk Characterization (Calculate MOS, include formulas)

4. Propose a Standard for Risk Management

: Propose a standard for harmful substance in cosmetic products after

comprehensive consideration of margin of safety with a long term

usage, etc.

4.1. Proposal for Risk Management

5. Conclusion

- 33 -
6. Foreign Assessment Cases
7. Limitations
8. References

- 34 -
Appendix) 2. General Principles for Computing
Margin of Safety and Lifetime-Cancer Risk for
Cosmetic Products Risk Assessment

Exposure is evaluated after collection of toxic data on cosmetic ingredients and

comprehension of relationship between dosage and toxicity.

Methods for gathering toxic information is described in Appendix 4, and the

information is used for analysis on dosage and reaction. In order to determine

exposure, various factors effecting exposure described in the Guideline for Risk

Assessment of Cosmetic Products must be considered in determining actual

consumer's exposure to harmful substances due to use of cosmetic products.

Next, in accordance with the methods below, compare the exposure to harmful

substance from use of cosmetic products and the end point of specific toxicity to

determine whether noticeable safety issues arise (calculate safety coefficient and

determine safety grade).

1) Definition

Dose : Amount of tested substance administered

Dosage : general term used for amount and administered intervals and duration

No Observed Adverse Effect Level (NOAEL) : Maximum dosage where harmful

effects were not observed as a result of a long-term toxicity research, such as

28-day toxic study on rat, mouse, dog, etc., 90-day toxic tests and chronic toxic

tests, carcinogenicity tests, teratogenic tests, reproduction-toxicity tests, etc.

NOAEL is expressed in mg/kg body weight/day, and in most cases, could be

acquired through researching toxicity related literatures.

Systematic Exposure Dosage (SED) : Cosmetic product ingredient's systematic

exposure dosage is an estimated amount to be absorbed into the blood flow per

weight over one day and effect the entire body, and is expressed in mg/kg body

weight/day. In this definition, 60kg is generally used as an average human weight.

- 35 -
During risk assessment of cosmetic products, it shall be referred to as skin

exposure dosage or skin body exposure dosage.

2) Margin of Safety

Investigation of risk characteristics, the last step in risk assessment of cosmetic

ingredients is determining the margin of safety (MoS). Generally, a substance's MoS

is the value derived by dividing NOAEL by SED.

NOAEL

MoS =

SED

Generally, MoS of over 100 is evaluated as being safe, and this value is derived

by multiplying animal and human disparity coefficient 10 and inter-human disparity

coefficient 10.

On the other hand, certain toxic materials calculate RfD based on NOAEL, and in

this case, uncertain elements are already included, so MoS is not separately

calculated. In which case, by directly comparing RfD and SED, it is evaluated as

safe when SED is smaller than RfD.

If cosmetic product's absorption rate from skin administration or oral

administration is unknown, SED is determined by assuming that 100% of the

capacity has been absorbed. In this case, the actual risk will be much less than the

calculated risk. In special circumstances, skin absorption rate may be estimated by

permeability coefficient, and if estimated numbers are used, more attention is

needed for risk assessment.

In calculating the margin of safety, for substances not used daily as compared to

NOAEL, the actual risk may be lower, and these factors, with basis, may be

considered in evaluation.

On the other hand, a new research may propose lower NOAEL not used

previously, and this may cause changes to the margin of safety, which must be

- 36 -
taken into account in risk determination.

Certain toxicity data uses BMDL and BMCL as toxic dose index. Benchmark Dose

(BMD) or Benchmark Concentration (BMC) indicates dose or concentration of toxic

materials that cause certain amount of harmful reactions as compared to control

materials, and in general, they cause over 5~10% reaction as compared to control

materials. In certain cases, margin of safety may be calculated using BMDL or

BMCL rather than NOAEL. In certain cases (especially the US EPA documents),

BMDL or BMCL is used in determining RfD (or RfC). In this case, rather than

calculating margin of safety, various coefficient of variability are used in calculating

RfD (RfC), and risks are determined by directly comparing RfD (RfC) and SED.

For carcinogen, when MoS or MOE （ Margin of exposure) is over 1x10 ,

6
it is

generally determined to be safe

(http://whqlibdoc.who.int/trs/WHO_TRS_930_eng.pdf).

3) Considering skin absorption in calculating Systematic Exposure Dosage

（SED)
SED could be calculated from skin absorption per unit area after being exposed to

the substance for a certain period of time or from absorption rate proportionate to

the amount of the applied substance. When using the absorption rate, the resulting

value is influenced by the amount applied to the skin and the area.

In most cases, the amount and applied area of the actually used cosmetic products

(1 mg/cm ) ² is less than that of during skin absorption tests (for solids, 1-5 mg/cm ²
, for liquids, 10 μL/cm ²
). By using absorption rate achieved from in vitro test

resulting using higher amount of cosmetic ingredients than the actual amount in

determining SED, SED will be calculated less than the actual. As such, in

indicating skin absorption rate in percentages, absorption rate achieved from in

vitro test must be presented as a percentage of actual amount used. Actual amount

used could be estimated with the standards (Appendix 3) for product's amount

used and skin area (SSA).

There are two methods in calculating SED depending on the skin absorption route

- 37 -
of the compound.

3-1) Calculating SED based on skin absorption amount per unit area (μ
g/cm2)

When observing after skin surface application of finalized cosmetic products

(including ingredient under study) in order to calculate SED, one must

consider not only the applied surface area but also the exposure frequency

and the retention factor. All other variables must also be considered when

designing the skin absorption test [SCCNFP/0750/03].

DAa(μg/cm 2
) ×
10
-3
mg/ ×
μg SSA(cm 2
) ×F (day
-1
)

SED =

60 kg

SED (mg/kg bw/day) = Systemic Exposure Dosage (SED)

DAa μg/cm
(
2
) = Skin Absorption Amount

2
SSA (cm ) = Skin surface area applied with finalized cosmetic product

(refer to appendix 3 for skin surface ares (SSA) value on

different types)

-1
F (day ) = Frequency of exposure of finalized cosmetic products

60kg = default human weight

3-2) Calculating SED based on amount of applied substances among

products (%)

Value calculated from in vitro study, using mimicking amount not over the actual

- 38 -
use limit, has value for skin absorption rate based on amount of applied substances

among products (%). Higher concentration skin absorption tests may result in

underestimation of skin penetration.

Formula for calculating SED is as follows :

A(g/day) × 1000mg/g ×C (%)/100 ×DA p(%)/100

SED =
60 kg

SED (mg/kg bw/day) = Systemic Exposure Dosage

A (g/day) = Amount of cosmetic products used in one day : refer to daily

dosage per cosmetic products in appendix

C (%) = Concentration of cosmetic ingredient of finalized cosmetic

products in used part

DAp (%) = Skin absorption rate expressed in percentage of tested amount

assumed to be actually used in real use conditions

60kg = Default human weight

SED needs to be appropriately adjusted if the application method is different

from the actual application method of the product type.

If the formula could effect the bio-availability of the compound's structural

material (i.e., use of liposome, etc.) and other data are not available, specific

substance's bio-availability must be assumed to be 100%.

Generally, in normal skin conditions, additional uncertainty factor for child is

unnecessary [SCCNFP/0557/02].

The Threshold of Toxicological Concern, TTC : For example, US FDA accepted that

1.5 ㎍/kg/day, as food concentration, does not threaten public health and could be

ignored. These TTC concepts, based on science, could be applied in risk

assessment.

For determination of lifetime cancer risk, T25 test method, TD50 (amount to cause

cancer in half of animals during an "average lifespan" of certain average test

- 39 -
period-test object on a target site) or Benchmark Dose (BMD) method could be

used to calculate the lifetime cancer risk ratio. For example, T25 is defined as a

ratio of naturally occurring cancer ratio during a specific animal species' average

lifespan, as corrected, and chronic dosage causing cancer on a specific tissue parts

of 25% of the test animals. Method for determining T25 is described in details in EC

1999 and Dybing et al. [1997]. Animal's dosage (T25) is converted into human

dosage (HT25) based on comparative metabolism rate using the following formula

[Sanner et al. 2001].

T25
HT25 =
(Human Weight/Animal Weight)0.25

Based on daily dosage, fLfetime Cancer Risk is calculated by linear extrapolation

according to the following formula.

SED
Lifetime Cancer Risk =
HT25/0.25

Unit for SED is mg/kg bw/day.

- 40 -
Appendix) 3. Cosmetic Products Exposure Data

1. Average exposed skin area for each type of products and estimated daily
exposure level based on Copila data are as follows.

Table 1. Average exposed skin area for each type of products [Bremmer et al.

2005(RIVM); US EPA 1997]

Skin Area (RIVM)

EPA Isometric
Product Type Area 2
Parameter Area (cm )
2
(cm )

Hair Care

Area of Both Hands + 1/2

Shampoo 1440 1430
Head Area

Area of Both Hands + 1/2

Hair Conditioner 1440 1430
Head Area

Hair Spray 565 Women's 1/2 Head Area 555

1/2 Area of Both Hands,

Hair Styling Gel 1010 1010
1/2 Head Area

1/2 Area of Both Hands,

Hair Styling Mousse 1010 1010
1/2 Head Area

Semipermanent
580 1/2 Head Area 590
Hairdye (Lotion)

Oxidative/
580 1/2 Head Area 590
Permanent Hairdye

Hair Bleach 580 1/2 Head Area 590

Hair Fixing Lotion 580 1/2 Head Area 590

Bath and Shower

Handwash Liquid
860 Area of Both Hands 840
Soap

Handwash Solid
860 Area of Both Hands 840
Soap

Liquid Shower Soap 17500 Entire Body Area 19400

Solid Shower Soap 17500 Entire Body Area 19400

Bubble Bath 16340 Body Area - Head Area

Bathing Salt 16340 Body Area - Head Area

Bath Oil 16340 Body Area - Head Area

Skin Care

Facial Cream 565 Women's 1/2 Head Area 555

- 41 -
 Body Area - Women's
Body Lotion 15670
Head Area

Hand Lotion 860 Area of Both Hands 840

Peel-off/Scrubbing Gel 565 Women's 1/2 Head Area 555

Facial Masque 565 Women's 1/2 Head Area 555

Body Area - Women's

Body Masque 15670
Head Area

Skin Whitening
565 Women's 1/2 Head Area 555
Lotion

Make-up and Nail Care

Liquid Foundation 565 Women's 1/2 Head Area 555

Make-up Remover 565 Women's 1/2 Head Area 555

Eye Shadow 24

Mascara 1.6

Eye-liner 3.2

Eye Make-up Remover 50

Nail Polish 4

Nail Polish Remover 11

Lipstick, Lip Cream 4.8 cf) Ferrario et al. 2000

Deodorant

Deodorant Stick
200 Both Armpits
Type/ Roll-on Type

Deodorant Spray1) 200 Both Armpits

Foot Care

Limited Foot Cream 1170 Feet Area 1120

Anti-Bacterial Foot
1170 Feet Area 1120
Cream

Fragrances

Eau de Toilette Spray 200

Perfume Spray 100

Men's Cosmetics

Shaving Cream 305 Men's 1/4 Head Area 325

After Shave 305 Men's 1/4 Head Area 325

- 42 -
 Sun Care Cosmetics

Sunblock Lotion 17500 Total Body Area 19400

Sunblock Cream 17500 Total Body Area 19400

Baby Care

Baby Cream 190

Baby Oil 190

Baby Powder 190

Miscellaneous

Hair Removal Cream 5530 Women's Leg Area 5460

Massage Oil 16340 Body Area - Head Area

Bath Oil 16340 Body Area - Head Area

Face Painting for 1/2 Child's Head Area

475 496
Children (4.5 y.o.)

Face Painting for

580 1/2 Head Area 650
Adults

1) Only skin exposure is considered here.

- 43 -
Table 2. Estimated daily exposure level based on Colipa data [SCCNFP/0321/02;

Hall et al. 2007, 2011]

Calculated
Daily
Daily
Dosage Calculated
Dosage
Est. Daily per Retention Daily
Product Type 1 per
Dosage(g) Weight Factor Dosate
Weight
(mg/kg (g/day)
(mg/kg
bw/day)
bw/day)

Bath and Shower

Shower Gel 18.67 279.20 0.01 0.19 2.79

2 3
Handwash Soap 20.00 - 0.01 0.20 3.33

Hair Care

Shampoo 10.46 150.49 0.01 0.11 1.51

2
Hair Conditioner 3.92 - 0.01 0.04 0.60

Hair Styling Products 4.00 57.40 0.1 0.40 5.74

35mL
Not
Semi-permanent Dye (per
2 - 0.1 calculat -
and Lotion applicat
ed
ion)

100mL
Not
Oxidized/ Permanent (per
2
- 0.1 calculat -
Dye applicat 4
ed
ion)

Skin Care

Body Lotion 7.82 123.20 1.0 7.82 123.20

Facial Cream 1.54 24.14 1.0 1.54 24.14

Hand Cream 2.16 32.70 1.0 2.16 32.70

Make-up

Liquid Foundation 0.51 7.90 1.0 0.51 7.90

2
Make-up Remover 5.00 - 0.1 0.50 8.33

2
Eye Shadow 0.02 - 1.0 0.02 0.33

2
Mascara 0.025 - 1.0 0.025 0.42

2
Eyeliner 0.005 - 1.0 0.005 0.08

Lipstick, Lip Care 0.057 0.90 1.0 0.057 0.90

- 44 -
 Deodorant

Non-spray Deodorant 1.50 22.08 1.0 1.50 22.08

Aerosol Spray

Deodorant
1.43 20.63 1.0 1.43 20.63
(Ethanol-based
5
Products)

Aerosol Spray

Deodorant
0.69 10.00 1.0 0.69 10.00
(Non-ethanol-based

Products)

Mouth Care

Toothpaste (Adult) 2.75 43.29 0.05 0.138 2.16

Mouth Wash 21.62 325.40 0.10 2.16 32.54

1
Retention Factor is a factor used by SCCNFP to correct the wash and dilution

effect from using the products (shower gel, shampoo, etc.) on wet skin or hair

[SCCNFP/0321/00]

2
Product type not included in the Colipa study : Value derived from dividing the

existing daily dosage by average human weight of 60 kg

3
Danish Ministry of the Environment, Environmental Protection Agency : Survey of

liquid hand soaps, including health and environmental assessments.

4
Daily exposure amount not calculated due to low exposure frequency

5
Steiling et al. (publication in preparation); results presented to the SCCS.

Ethanol-based products means products containing ethanol as a main ingredient

- 45 -
2. For sunblocks, daily dosage of 17.0 g/day may be applied, assuming twice
daily usage for Korean male's average surface area of 16,822 cm2 6 with
amount of 0.5 mg/cm2.
6
Survey of skin surface area for the risk assessment (Ministry of Food and Drug
Safety, 2010)
3. In special cases such as sterilized preservatives, individualized product type's
exposure value may not reflect the overall exposure of these compounds. This
is because a single consumer will certainly use several other cosmetic products
that also contain similar compounds. SCCNFP proposes using total amount used
during a person's entire day from all cosmetic products used for exposure value
[SCCNFP/0321/00]. In prediction considering current exposure data and worst-case
scenario, for surveying consumers using cosmetic product sets containing same
sterilized preservatives, 15.1 g/day or 234 mg/kg bw/day value must be used in
calculating margin of safety (Table 3). Sunblock products were not included in the
table below because they are used only during certain period in a year.

Table 3. Calculation of total exposure to sterilized preservatives from the use of

cosmetic products

Exposure Type Product g/day mg/kg bw/day

Shower Gel 0.19 2.79

Wash off Skin and Hair Handwash Soap 0.20 3.33

Cleansing Products Shampoo 0.11 1.51

Hair Conditioner 0.04 0.67

Body Lotion 7.82 123.20

Facial Cream 1.54 24.14

Leave-on Skin and Hair
Hand Cream 2.16 32.70
Care Products
Non-spray Deodorant 1.50 22.08

Hair Styling 0.40 5.74

Liquid Foundation 0.51 7.90

Make-up Remover 0.50 8.33

Eye Make-up 0.02 0.33

Make-up Products
Mascara 0.025 0.42

Lipstick 0.06 0.90

Eyeliner 0.005 0.08

TOTAL ± 15.1 234

- Currently, although no base exposure value for risk assessment from inhalation

of volatile substance from cosmetic ingredients is concretely described, some

examples could be found in SCCS risk assessment data [SCCS/1501/12].

- 46 -
Appendix) 4. Collection Method of Toxicity Data
for Cosmetic Ingredient Risk Assessment

Following procedure is available for researching toxic and risk information on

relevant cosmetic ingredients.

▢ Toxicity and Risk Information Search

1 Ingredient and General Information

- Name confirmation process could be easily omitted, but it is an important

process for increasing accuracy and efficiency of the search results. Ingredient

and substance could be confirmed using the below representative name search

sites.

< Representative Name Expression and Search Sites

for Ingredients and Substances >
○ CAS2) number : http://www.cas.org/expertise/cascontent/index.html
○ IUPAC3) name : http://www.iupac.org/Publications
○ CA Index Name from the CAS Chemical Registry System : www.cas.org
○ INN4)
○ Common name
○ INCI name5)
○ EINECS6) or ELINCS number7)
- It is suggested to utilize SciFinder (fee based) or ChemIDplus (free), which

allows synonym and similar number searches, for the initial name search because

2) Chemcal Abstracts Service

3) International Union of Pure and Applied Chemistry
4) International Non-proprietary Name
5) International Nomenclature of Cosmetic Ingredients
6) European Inventory of Existing commercial Chemical Substance
7) European List of Notified Chemical Substances

- 47 -
 various name expressions are used on various search sites.

※ SciFinder : http://scifinder.cas.org/
ChemIDplus : http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?CHEM/
- CAS registry number is the best search method as it is organized systematically

and realistically, and is built based on the most data.

- General information could be searched on other portal sites.

․ Search published data using search engine on world wide web.

․ Use main search sites, such as Naver, Daum, Google, Yahoo and MSN, to

search using key words and identify data.

․ Reliability cannot be guaranteed on searched results, so must use caution in

evaluating the results.

- 48 -
 2 Identify Laws and Reguations
- Must identify regulations on cosmetic product ingredients.

< Laws on Cosmetic Products

of Each Country >
❏ Korea
○ www.mfds.go.kr > Information Data > Regulatory Data
❏ EU
○ Cosmetics Regulation(No 1123/2009)
: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:2009R1223:20130711:en:PDF
○ Directive 76/768/EEC(EU, 1976)
: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1976L0768:20100301:en:PDF

❏ USA
○ Title 21 Code of Federal Regulations, Cosmetic Products
: http://www.fda.gov/cosmetics/guidancecomplianceregulatoryinformation/actsrulesregulations /
regulationsfederalregisterdocuments/ucm126613.htm/

❏ Japan
○ Pharmaceutical and Medical Device Agency
: http://www.pmda.go.jp/operations/shonin/info/iyakubugai.html(Japanese)
○ Ministry of Health, Labour and Welfare (MHLW) Laws
: http://www.mhlw.go.jp(Japanese)

- In addition to regulations, other helpful information on possible ingredients for

cosmetic products are found.

※ Food Additive Authorization :

http://ec.europa.eu/enterprise/sectors/chemicals/documents/classification/laboratory-

practice/foodstuffs_en.htm

Annexes I, Biocidal Products Directive(EU, 1998) :

http://ec.europa.eu/dgs/jrc/index.cfm

Annex I Plant Protection Products Directive :

http://ec.europa.eu/food/plant/protection/resources/publications_en.htm

- 49 -
 3 Toxic Data Search
- In order to first identify risk status, one must confirm which substances

are discussed among professional by researching international committees'

websites (SCCS, CIR).

※ http://ec.europa.eu/health/ph_risk/committees/04_sccp/sccp_opinions_en.htm

http://ec.europa.eu/health/ph_risk/committees/sccp/sccp_opinions_en.htm

http://www.cir-safety.org/

- Confirm CAS number of the substance from TOXNET (http://nlm.nih.gov/),

and perform more research on chemical and physical characteristics from

other search sites.

※ http://toxnet.nlm.nih.gov/

- Research substance's research status and current status from PubMed

(www.pubmed.com). Results could be identified using Keyword search and

conditional search. There may be limitations to research as some results

require payment of fee for access.

- Vast amount of data could be supplied from search websites such as IARC,
IPSC, US EPA and US NTP, but TOXNET could provide all data on certain

substances.

※ IARC : www.iarc.fr

IPSC : http://ipsc.jrc.ec.europa.eu/

US EPA : http://www.epa.gov/

US NTP : http://ntp-server.niehs.nih.gov/

- When detailed information or additional data are needed on searched

toxicity information, fee-based database must be utilized.

- Data from research institutes, such as CIR and KOSMET, are recommended,

and HSDB8) and PubMed, where free search is possible.

8) Hazardous Substances Data Bank, http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

- 50 -
Search Sites on Safety Information Relating to Cosmetic Products
No. Site Name Address Range Comment Note
▪ Higher effectiveness when

World Wide Web, list of search results match the

TM
1 Google http://www.google.be/ links conforming to keyword keyword Free

search ▪ accuracy of data not

▪
guaranteed

Higher effectiveness when

World Wide Web, list of search results match the

2 Yahoo! http://www.yahoo.com/ links conforming to keyword keyword Free

search ▪ accuracy of data not

▪
guaranteed

Higher effectiveness when

World Wide Web, list of search results match the

3 MSN search http://www.msn.com/ links conforming to keyword keyword Free

search ▪ accuracy of data not

guaranteed

http://eur-lex.europa.eu/en/index

.htm(Legislation, case-law, Laws and regulations

Hard to access information
consolidated versions) including treaties, legislative
4 EUR-Lex without exact wording of the Free
http://ec.europa.eu/enterprise/sec laws, case laws, EU
laws
tors/chemicals/reach/index_en.ht directives, etc.

m (proporsal)

5 Directorate General (DG) http://ec.europa.eu/about/ds_en. Helpful information on Developed over the past couple Free

- 51 -
 of years and important factor in
Enterprise, cosmetic cosmetic products to be
htm follo-up action to EU's cosmetic
section release and related regulations
product legislation

http://ec.europa.eu/dgs/health_co In addition to links to

nsumer/index_en.htm committee comments, such Important source of information

Directorate General http://ec.europa.eu/health/ph_ris as SCCP, provides overview for including SCC(NF)P

Health and Consumer k/committees/04_sccp/sccp_ of EU legislations related to comments, but must be careful
6 Free
Protection opinions_en.htm(SCCP) consumer rights and because cosmetic product

(DG SANCO) http://ec.europa.eu/health/ph_ris protection of citizen's health, ingredient's name may appear

k/committees/sccp/sccp_ such as food and other different from INCI name.

opinions_en.htm(SCCNFP) manufactured goods

EU risk assessment process

and related information on

hazardous and

manufacturing substances Provides information on EU's

are available in addition to legislation and related

7 JRC ScienceHub https://ec.europa.eu/jrc/ Free
links to latest information information such as development

on all legal, physical, directions on chemical substances.

chemical, toxicology and

environmental ecological

toxicology tests

The personal care CTFA changed to PCPC.

Information on risks of
products http://www.personalcarecouncil.o Provides information on risk
8 cosmetic products and Fee
council(formerly CTFA), rg/ assessment on cosmetic products'
consumer. Connected to CIR.
PCPC compound ingredients. Only fee

- 52 -
 paying members are provided

with detailed information.

Assessment results are focused on

CIR (Cosmetic cosmetic product ingredients, and

Risk assessment on cosmetic
9 Ingredient Review) http://www.cir-safety.org/ does not provide detailed Free
product ingredients
conclusions-U.S.CTFA information on the assessment

itself.

http://www.nlm.nih.gov/

http://www.nlm.nih.gov/database

s/(Free charge)

http://www.ncbi.nlm.nih.gov/entr

ez/query.fcgi?db=PubMed

(PubMed) Medical library, such as

http://toxnet.nlm.nih.gov/ PubMed, with freely usable

TOXNET is appropriate for wide
(TOXNET) information. In addition,
range of toxicity information
U.S. National Library of http://chem.sis.nlm.nih.gov/chemi variety of toxicity
10 search because the database is Free
Medicine dplus/(ChemIDplus) information are provided,
organized systematically and
http://toxnet.nlm.nih.gov/cgi-bin/ such as ChemIDplus, HSDB,
search is easy.
sis/htmlgen?HSDB(HSDB) TOXLINE, CCRIS, DART,

http://toxnet.nlm.nih.gov/cgi-bin/ etc.

sis/htmlgen?TOXLINE(TOXLINE)

http://toxnet.nlm.nih.gov/cgi-bin/

sis/htmlgen?CCRIS(CCRIS)

http://toxnet.nlm.nih.gov/newtox

net/dart.htm(DART)

- 53 -
 http://toxnet.nlm.nih.gov/html/M

ulti.htm(Multi-database)

▪ Links to current laws,

regulations and cases of

the US
http://www.epa.gov/

http://www.epa.gov/epahome/la
▪ Information on health

effects when exposed to

wregs.htm (laws)

http://www.epa.gov/iris/(IRIS)
various substances

environment(Integrated
in the

Risk
▪ Reliable information on

http://www.epa.gov/hpvis/index. chemical substances being sold

Information System, IRIS)

United States
html(HPVIS)

http://www.epa.gov/pesticides/sc
▪ Provide environmental
in the US.

11 Environmental

Agency
Protection

(U.S. EPA)
ience/handler-exposure-data.html
ecology

information
and

on
toxicity

mass
▪ Maybe different from EU's
Free

(Exposure data) classification and regulatory

produced chemical
http://www.epa.gov/ebtpages/hu system.
products in the US (High
matoxicity.html(human toxicity)
production Volume
http://www.epa.gov/epahome/St
Information System, HPVIS)
andards.html(Test

guidelines)
methods and
▪ Provide information on

diversity of individuals

during risk assessment,

human toxicity, such as

- 54 -
 exposure information, and

general test methods and

guidelines

Provide assessment report

on chemical substance's, Information is very trustworthy

U.S. National Toxicology including toxicology, because NTP possesses own test
12 http://ntp-server.niehs.nih.gov/ Free
Program (NTP) molecular biology and program, and performs overall

causation, effect on public tests on risk assessment.

health

Provide information on risks

http://www.who.int/ipcs/en/ of chemical substances,

International Programme CICADs is sufficient to gather
http://www.who.int/ipcs/publica effects on human and
13 on Chemical Safety information on risk of chemical Free
tions/cicad/en/index.html environment and review of
(IPCS) substances.
(CICAD) chemical substances, based

on science

Australian National
Recommended for safe use
Industrial Chemicals Access to reference material on
according to physico-
Notification and http://www.nicnas.gov.au/chemic environmental ecological toxicity
14 chemical, environmental Free
Assessment Scheme al-information research and original report
ecological toxicity and
(NICNAS) -Chemical including useful explanation
exposure data
Assessment Reports

European Centre for Report on chemical ECETOC reports represent

15 Ecotoxicology and http://www.ecetoc.org/index.php susbtances, including basic know-how of many chemical Free

Toxicology of Chemicals research, manufacturing, risk companies and reliable/useful

- 55 -
 assessment, toxicology and

(ECETOC) environmental ecologial information

toxicology

Brought shock to the cosmetics

The International
Recommended for toxicology industry with the provided
Fragrance Association
16 http://www.ifraorg.org/ information and ingredients information; however the Free
(IFRA) Code and
on 130 perfumes research results were not made
Standards
public and needs improvements.

Human and Risk assessment on Provides data provided by the

http://www.heraproject.com/Risk
17 Environmental Risk ingredients used in industry, but the number of Free
Assessment.cfm
Assessment (HERA) household products chemical substances is limited.

Provide research on cancer

International Agency for from chemical substances, Important information is

18 Research on Cancer http://www.iarc.fr/ such as cause of cancer, provided, but researched cosmetic Free

(IARC) mechanism and scientific ingredients is limited.

plan for conquering cancer

Report on safe work

Occupational Safety & environment, with continuous Provides information on various

19 Health Administration http://www.osha.gov/ focus on improvement of elements to become a safe work Free

(OSHA) work place for safety and environment.

health

Biochemistry, Bioengineering, Useful database to search topical

SciFinder-Chemical Organic and Inorganic information on various chemical

20 http://scifinder.cas.org/ Fee
Abstracts Service, U.S.A. Chemistry, Macromolecular issues. Provides program for easy

Chemistry, Physiological information search.

- 56 -
 Chemistry, Toxicology and

Environmental Science

Original reports are provided by

CIR (Cosmetic Review and evaluation of companies.

http://www.cir-safety.org/
21 Ingredient Review) full detailed risks of cosmetic Although supported by Fee
http://www.cosmeticsinfo.org/
reports-U.S.CTFA ingredients companies, is composed of

independent committee members.

Health laws, including

regulations related to
CTFA International
cosmetic products in the US, Useful in research global trend
Cosmetic Legal and http://www.personalcarecouncil.o
22 personal products industry of cosmetic ingredients, but only Fee
Regulatory Database rg/
and related company available to CTFA members
-CTFA
guidelines, CIR evaluation

and index of European INCI

Information on toxicology,
RTECS (Registry of
mutation, cancer, genetic
Toxic Effects of Criticized for lack of detailed
23 http://www.cdc.gov/niosh/ toxicity, long-term toxicity, Fee
Chemical review on useful documents.
legal maximum exposure
Substances)-U.S. NIOSH
amount, regulations

Chemical name, molecular

weight, structural formula,

Beilstein-Beilstein
http://www.beilstein-journals.org production method, Book or
24 Chemical Data and
/bjoc/home/home.htm physiochemical and Paper
Software, Germany
biological characteristics, and

organic chemistry, including

- 57 -
 existence in nature.

Information provided from

Beilstein's organic chemistry

book and carefully reviewed

reports by 176 journals.

Similar to Beilstein, but

provides reports focused on

inorganic and organic

Gmelin-Gmelin Institute
metallic chemistry from Data has not been updated since Book or
25 of Inorganic Chemistry,
carefully reviewed reports 1997. Paper
Germany
from 110 journals and books

on inorganic and organic

metallic chemistry

MSDS-OHS (Material Document

Safety Data template to

Document containing safety MSDS provides general toxicity
Sheet-Occupational be attached
26 information on over 59,000 and risk information, but does
Health& Safety)-MDL or included
substances and compounds not provide important toxicity
Information Systems, with
information on substances.
U.S.A. product

List of chemical substances List is useful for regulatory

Chemlist-Chemical https://www.cas.org/content/reg of countries, such as TSCA, purposes, but difficult to use as

27 Fee
Abstracts Service, U.S.A. ulated-chemicals (Added) DSL, NDSL, ECL, ENCS, environmental cological toxicity

EINECS, ELINCS, AICS, etc. data.

Kosmet (Cosmetic & http://www.ifscc.org/Resources/ Cosmetic product Very useful for focusing on
28 Fee
Perfume Science and KOSMET (Added) development, healthy skin, cosmetic products

- 58 -
 import of cosmetic products,

research on ingredients and

manufacturing analysis, safety

Technology)-IFSCC, U.K.
trends, physiochemical and

biological characteristics, safety

and packaging.

Pharmaceutical, biochemical

and toxicological effect on

chemical substances, other

than drugs.
TOXCENTER https://www.cas.org/legal/keeps
Reference documents on
(Toxicology Center) hare/non-participating/toxcenter
29 certified test materials, from Fee
-Chemical Abstracts http://www.stn-international.de/i
environmental toxicology of
Service, U.S.A. ndex.php?id=123 (Added)
chemical substances to human

toxicity of pharmaceuticals.

Information from CA plus,

Biosis, and Medline

Medline-U.S. National http://www.ncbi.nlm.nih.gov/site Information on all areas

30 Fee
Library of Medicine s/entrez/ (Pubmed) related to medicine

Documents on bio-

EMBASE (Excerpta pharmaceutical and

Medica medicinal treatment, such as

31 database)-Elsevier http://www.excerptamedica.com/ biological science, bio- Fee

Science B.V., the chemistry, medical, forensic

Netherlands science, pediatric science,

p h a r m a c e u t i c a l ,

- 59 -
 pharmacology, drug

economy, neuropsychiatry,

public health, biomedical

engineering, and environ-

mental science

IPA (International
https://www.lib.utexas.edu/index Topics related to pharma-
32 Pharmaceutical Fee
es/titles.php?id=205 (Added) ceutical and health
Abstracts)-ASHP, U.S.A.

General information on
HEALSAFE (Health and
environment, industry, job and
Safety Science
33 medical safety, and Fee
Abstracts)-Cambridge
information on transportation,
Scientific Abstracts, U.S.
aviation and space industry

Scientific documents on

variety of areas such as

SciSearch-Institute for science, technology and bio-

34 Scientific Information, medical Fee

U.S.A. Utilization index of published

science reports and currently

being published reports

Over 25 million documents,

CA (Chemical Abstracts) and documents from all areas,

35 Plus/ Search-Chemical http://www.videogateway.tv/cas/ such as chemistry, Fee

Abstracts Service, U.S.A. biochemistry and chemical

engineering

36 CSNB (Chemical Safety http://www.rsc.org/Publishing/C Provide information on Fee

- 60 -
 chemical substances, fire,

News Base)-The Royal explosion, storage,

Society of Chemistry, urrentAwareness/CSNB/ (Added) transportation, waste disposal,

U.K. test animal research, health,

safety, etc.

Over 20 of variety areas;

LIFESCI (Lifescience biotechnology, animal

Collection) -Cambridge behavioral science,

37 Fee
Scientific Abstracts, biochemistry, bio engineering,

U.S.A. ecology, genetics,

immunology, etc.

Research results, review and

US patents on wide range

38 Biosis-Biosis, U.S.A. of biological and bio-medical Fee

areas, from astro-biology to

zoology

Agricultural economy, rural area

sociology, zoology, chemistry,

AGRICOLA-National insectology, food and human

Agricultural Library, nutrition, forestry, national

39 http://agricola.nal.usda.gov/ Fee
U.S. Department of resources, pesticides, plant

Agriculture science, soil and fertilizer, water

resources, biology, ecology and

natural history

Chembank-U.S. http://chembank.broadinstitute.or IRIS, RTECS, HSDB, CD-ROM used by the most Fee &
40
Department of g/ OHMTADS, number of risk assessors CD-ROM

- 61 -
 Transportation, EPA,
CHRIS, TSCA Format
NIOSH and NLM

General characteristic, ratings,

IUCLID (International exposure limits in work place,

Fee &
Uniform ChemicaL http://iuclid.eu/index.php?fuseac physio-chemical characteristics,
41 Detailed information is limited CD-ROM
Information Database) tion=home.iuclidHome toxicology and eco-toxicology
on most Format
-ECB information on substances

submitted to ECB

Toxic reaction data on over Korea National Toxicology

80,000 chemical substances Program (KNTP) project that

http://www.nifds.go.kr/toxinfo/I from National Institute of operates program to oversee

42 Tox-Info
ndex Food and Drug Safety toxic material by establishing

Evaluation, under Ministry foundation for systematical

of Food and Drug Safety management of toxic substances

KRIS(Korea Risk http://nifds.go.kr > Risk Monitoring of various risk

43
information system) Information substances

http://www.nihs.go.jp/library/ha
Research results and
kkounen.htm(Research Report)
44 NIHS(JAPAN) outcomes of NIHS, monthly
http://www.nihs.go.jp/library/mo
report since September 2009
nthly_report.htm(Monthly Report)

Pharmaceuticals and http://www.pmda.go.jp/operation Approval information on

45 Medical Device Agency s/shonin/info/iyakubugai.html quasi-drug and cosmetic

(PMDA), JAPAN (Japanese) pdoructs

- 62 -
 Ministry of Health,
Information on various laws
46 Labour, and Welfare http://www.mhlw.go.jp(Japanese)
and standards
(MHLW), JAPAN

※ Reference : Marleen Pauwels and Vera Rogiers, Database search for safety information on cosmetics ingredients, Regulatory
Toxixology and Pharmacology, 49(2007):208-216.

- 63 -
Appendix) 5. Glossary of Terms

․Sensitization : Injection of heteroantigen within body for retention

of antibody. Generally refers to activation of immune reaction.

Sensitization.

․Photosensitization : Acquired immune reaction by forming allergic

substances from chemical substance activated by light

․Photoallergy : Sensitivity occurring from chemical substance

activated by light

․Photoirritation : anti-immunological skin reaction induced from

light, and occurs from chemical substanced reacting to light

․Local tolerance : Localized decrease of efficacy and effects from

repeated exposure to drugs, mainly occurring in skin

․Acute toxicity : Toxicity outbreak from short-term exposure to

toxic substance, and usually occurs from exposure of less than 24

hours

․Acute Reference Dose (ARfD) : Maximum allowed dose from oral

intake when acutely exposed to toxic substance and does not

induce noticeable risk over the entire life-time

․Benchmark :
a. a statistical lower confidence limit of dosage showing altered

response pre-determined for efficacy (USEPA, 1995 : Benchmark

Dose)

b. (Also called benchmark concentration (BMC)) is a statistical

- 64 -
 lower confidence limit of dosage showing benchmark response

(BMR) to response ratio on negative effect compared to the

background(IRIS, 1999, Glossary of IRIS Terms)

c. Exposure to substance within dosage to increase incident rate

only at pre-determined small increment (typically 1~10%) of

probability with regards to certain toxicity. Or, dosage related

to pre-determined criterion or changes to biological effect.

(Ministry of Agriculture, Forestry and Fisheries and Ministry of

Health, Labour and Welfare (Japan), 2005; Standard Guideline

for Risk Management Related to Food Safety(Definition))

․Tolerance: Body showing less reaction than the original reaction due to

exposure to drugs, chemical substances and toxic substances, especially

from repeated exposure

․Exposure scenario : Hypothetical scenario of body exposure

process from production to actual use of a specific substance

․Margin of exposure (MOE) : NOAEL's ratio of estimated exposure

amount

․Control : Substance used as a standard substance, or sample

group, in research to judge research results

․Good Laboratory Practice : Standard used in laboratory tests

during testing of drug and toxic effects on animals and humans.

Generally applied during laboratory stages

․Chronic Toxicity : Toxicity presented through chronic

administration of a substance

- 65 -
․No Observed Adverse Effect Level (NOAEL) : Maximum dosage for

no observable adverse or toxicological effects on humans and

animals. Expressed as mg/kg body weight/day

․LC50 : Air concentration to cause death of 50% of the population

in acute exposure

․Developmental Toxicity) : Risk reaction occurring during

developmental period of subject due to exposed substances, such as

fetal death, deformity, growth inhibition, etc. Reversible or

irreversible reactions are possible

․Benchmark Dose (BMD) : Dosage of a specified substance

estimated to cause a level of response, defined in advance

(Benchmark Response Level, BMR), to a body

․Corrosive : Property causing issue necrosis after administration.

Corrosive in general acid

․Uncertainty Factor (UF) :

a. Used when NOAEL/LOAEL is convered to RfD, and generally

apply 10; (1) Variation within species, (2) Variation between

species, (3) Use of RfD based on different duration, or (4)

calculate RfD using NOAEL, not NOAEL. 〔 AIHA, 2000; Risk

Assessment principles for the Industrial Hygienist 〕 ;

b. Depending on the circumstances, one of the following two could

use this term. (i) Mathematical expression of uncertainty level

unable to be evaluated even with high level of precision. (ii)

Relating to food additives and contaminated substances,

coefficient applied to NOAEL to deduct ADI (ADI is calculated

by dividing NOAEL with MoS). Value of MoS changes

- 66 -
 depending on characteristic of toxic effect, size and type of

protected group, quality of relevant toxicological information.

〔 Duffus, 2000; Univ. Edinburgh Med School On-line Chemical

Safety Glossary 〕 ;

c, Coefficient used to deduct RfD and RfC from test data

(generally 10x). UF is used to consider uncertainty for (1)

sensitivity variable between human group members (i.e.,

intra-species variable or intra-human variable), (2) level of

uncertainty when animal data are used on humans (i.e.,

inter-species variable), (3) uncertainty in applying test data for

less than life-time exposure to life-time exposure, (4) uncertainty

when applying LOAEL, rather than NOAEL (5) uncertainty level

when applying animal data, even when the database is not

complete. 〔 IRIS, 1999; Glossary of IRIS Terms 〕 ;

d. Coefficient utilized for adjusting various uncertain sources, such

as estimating human effect using test animal data (i.e.,

inter-species variable, intra-species deviation, synergism), and

different exposure route (i.e., oral exposure vs. inhalation

exposure). 〔 REAP, 1995; Residential Exposure Assessment Projec

t 〕;

e. Coefficient used to deduct RfD from test data (generally 10x).

UF is used to consider uncertainty for (1) sensitivity variable

between human groups, (2) level of uncertainty when animal data

are used for human, (3) uncertainty in applying test data for less

than life-time exposure to life-time exposure, (4) uncertainty when

applying LOAEL rather than NOAEL. 〔 USEPA, 1995; Benchmark

Dose 〕〔 USEPA, 1997a:EPA Terms of Environment 〕〔 USDOE,

2000; RAIS Glossary 〕

․Reproductive Toxicity : Harmful effects on body or tissue causing

decrease in function of reproductive organs

- 67 -
․In Vivo Tests : Tests within a body. Generally refer to animal

and human tests

․Bioavailability : Ratio of substance working in a specified parts

within a body after administration

․In vitro Tests : Tests performed outside a body, in an artificial

environment

․Confidence Interval : Range of variable statistically estimated to

include a true value on a specified probability

․Passive Cutaneous Anaphylaxis Test : Intradermal injection of

antiserum, gained after sensitizing mouse or guinea pig with test

substnace, to a similar or different species of animal, then test

substance, mixed with evans blue, is injected to tail vein. The

formation of blue spot in the area of the injection is observed

inside the skin. Blue spot greater than 5mm is determined to be

benign.

․Margin of Safety (MOS) : Value derived from dividing NOAEL

of risk elements existing in cosmetic products by daily exposure

dosage

․Threshold Dose : Dose or exposure concentration just before the

appearance of effect

․Dose Descriptor : Value gained from body or environmental

toxicity tests, such as LC50 (value causing specific side effects) or

NOAEL (maximum dose not causing toxicity)

- 68 -
․Dose-response Relationship : Difference in effects due to variations

in the amount of administration of a substance. Provides

information related to substance's efficacy.

․Vehicle : Material, with no medical efficacy on its own, used to

deliver activated substances, such as solvents

․Gastro Intestinal Absorptivity (GIABS) : Final entire body

absorption rate of a substance administered orally

․Risk Assessment : Series of processes related to scientifically

estimating risk effects and occurrence probability from human

body's exposure to risk elements existing in cosmetic products,

including hazard identification, hazard characterization, exposure

assessment and risk characterization.

․Hazard : Substance's inherent toxicity

․Morbidity : Frequency of a certain disease appearing within a

group expressed in percentages

․In Silico : Term used in bioinformatics, it is a virtual experiment

using computers

․Acceptable Daily Intake (ADI) : Suggested amount of daily

intake of risk substances not to cause hazardous reactions

․Tolerable Daily Intake (TDI) : Allowed amount of daily intake of

toxic substances harmless to human body

- 69 -
․Good Clinical Practice (GCP) : Internationally used ethical and

scientific standards for design, performance, record and report of

clinical study with human

․Systemic Exposure Dosage (SED) : Systematic exposure dosage for

cosmetic ingredients is amount estimated, per body weight, to react

to the entire body through blood flow in a day and expressed in

mg/kg body weight/day. Also called skin exposure dosage or

skin body exposure dosage.

․Non-clinical : Other than clinical study on human, testing of

substances using testing methods within test tubes or test animals

․Endpoint : Measurable or observable properties of substances, and

toxicologically, indicates individualized biological effects, such as

general sensation, carcinogenicity, toxicity, etc., on specific organs

․Provisional Tolerable Weekly Intake (PTWI) : Allowed amount of

weekly intake of toxic substance not harmful to human body.

Generally applicable to toxic substance accumulating in human

body, such as heavy metal.

․Reference Dose (RfD) : Maximum oral intake amount of toxic

substance suggested by US EPA. Expressed as Reference

Concentration (RfC) for inhaled substances.

․Lowest Observed Adverse Effect Level (LOAEL) : Minimum

concentration where observation of toxicity of certain substance is

possible on test animals or human

․Target Organ : Organ showing toxic effect from a substance

- 70 -
․Skin Sensitization Test : Testing method for evaluating

immunological skin hypersensitivity reaction from repeated skin

exposure of a test substance (drugs for external use, cosmetic

products and other substances), such as local lymph node assay

(LLNA), Magunusson Kligman Guinea Pig Maximisation test

(GPMT) and Buehler test. LLNA uses inbred mouse, and is based

on increase of lymphocyte in local lymph node in use area of

target ingredient. This is an objective method to gain results from

stimulation index (SI), and expressed as a ratio between stimulation

arising from tested substance and stimulation of control animal.

Magunusson Kligman Guinea Pig Maximisation test is an immune

booster type test, and is determined from increase of allergic

reaction from intradermal injection of subject ingredient in

conditions using or not using Freunds' complete immune booster.

GPMT is thought to be equal in sensitivity as LLNA. Buehler test

is a method used only in localized areas and without the use of

immune boosters, and is less sensitive compared to GPMT. When

using Buehler test method, a reasonable scientific basis must be

presented.

․Skin Compatibility Test : Test method of measuring irritation on

skin from typical use condition or predictable over-use condition.

Subjective indicators, such as skin poking pain, itchiness, burning

sensation, etc., are included, in addition to objective indicators.

․Dermal Exposure : Exposure from contact between material

containing chemical substances and skin, and amount absorbed or

adhere to skin

․Primary Skin Irritation Study : Irritant test of substances with

- 71 -
 potential for skin contact, such as ointment applied in localized skin

area. White rabbit is used as test animal, and irritation is determined

by observing erythema, callous formation, edema formation in

localized (contacted) areas after application of drugs

․Limit Test : Acute toxicity test where if abnormal reaction is not

observed at a pre-determined maximum dose, no more high dosage

tests are performed

․Chemical Abstracts Service Index Number (CAS Number) :

Classification number of chemical substances by CAS

- 72 -