TOXICITY OF COSMETICS

Cosmetics
Chemical components that are synthesized or obtained from natural sources are mixed together
to create cosmetics. Cosmetics serve a variety of functions. The body and skin can be cleansed or
protected using those made for personal care and skin care. Make up, or cosmetics intended to
improve or modify one's appearance, can be applied to cover up imperfections, accentuate
features like eyebrows and eyelashes, add color to the face, or completely transform the face to
resemble a new person, animal, or object. Cosmetics can also be made to give the body a scent.

India- As per Drugs and Cosmetics Act, 1940 and Rules, 1945-Cosmetic means any article
intended to be rubbed, poured, sprinkled or sprayed on, or introduced into, or otherwise applied
to, the human body or any part thereof for cleansing, beautifying ,promoting attractiveness, or
altering the appearance and includes any article intended for use as a component of cosmetic.

United States- Defines cosmetics as “articles intended to be rubbed, poured, sprinkled, or

sprayed on, introduced into, or otherwise applied to the human body or any part thereof for
cleansing, beautifying, promoting attractiveness, or altering the appearance, and articles intended
for use as a component of any such articles; except that such term shall not include soap”.

European Union- Defines cosmetics as “any substance or preparation intended to be placed in

contact with the various external parts of the human body (epidermis, hair system, nails, lips and
external genital organs) or with the teeth and the mucous membranes of the oral cavity with a
view exclusively or mainly to cleaning them, perfuming them, changing their appearance and/or
correcting body odors and/or protecting them or keeping them in good condition”.

History of cosmetics
The word ‘cosmetics’ arises from a Greek word ‘kosmeticos’ which means to adorn. Since that
time any material used for beautification or improvement of appearance is known as cosmetic.
The urge to adorn one’s own body and look beautiful has been an urge in the human race since
the tribal days. Earlier both males and females were equal competitors for improvement of
appearance. Males decorated themselves with animal parts and vegetable leaves etc. while
women did so by wearing any colored stones or flowers round their neck and the wrists. At a
later stage they employed colored earth for faces and bodies and still later colored ointments.
Bangles and necklaces made of backed earth also became common in the early civilization as
well as shells of various kinds obtained from nature. In digging up ancient Egyptian tombs much
light has fallen on the ancient practices of beautification. Pharaohian tombs have revealed that
colored earths were like malachite green. The copper ore was used as eye shadows. Lamp black
was common too for eyes. For dyeing of hairs red was also practiced. The dancing ladies applied
ointments perfumed with materials like myrrh to head so that when they danced the perfumed
ointment would flow down their bodies emitting pleasant smell all over. The history also records
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that when Jehu went to the town of Jezebel she painted her face and looked out from window.
The use of cosmetics in ancient Egypt reached heights with the famous queen Cleopatra who
tried to beguile Caesar and Antony the Romans when they visited Egypt. Shakespeare too
stressed the role of cosmetic wrote, “Had Cleopatara’s nose been longer, the shape of the world
would have been different.” The women of the world fee inspired when they have a mental
feeling that they are looking good. Hence, the practice of adornment or improvement of
appearance continued unabated across the countries. In modern days cosmetics are the rage and
are considered to be essential commodities of life. The role of cosmetics in everyday life met
greater acceptability after World War II. It was realized by social and medical scientists that
cosmetics not only adore but they exercise psychological effect on users and especially on the
skin. They keep the skin supple delaying the onset of wrinkling. They are also helpful in skin
infections and prevention of sunburns. In the last 3-4 decades the use of cosmetics has increased
exponentially not only among the females but also the male population. Hair dyes, powders,
creams are as popular with males as with females. Most countries have now laws to control,
manufacture, labeling, sale etc. of cosmetics in such a way that use of cosmetics harmful to
health is prevented. In India the Drugs Act 1940, has been renamed as Drugs and Cosmetics Act
in 1962 and contains some sections to exercise control over the manufacture, sale and use of
cosmetics

 Classification of cosmetics

The cosmetics are formulated as similar as pharmaceutical dosage forms like solids, semi-solids
or liquids or aerosol sprays. These are broadly classified in the following manner.

Cosmetics are classified mainly into four types-

1-Skin
(ⅰ)Face powder -.Though these are called face powder but it is applied to other parts of the body.
Powders and compacts are one of the important categories of skin care products. The body
powders are also known as dusting powder or talcum powder. Certain medicated powders are
mixed with active medicaments to prevent microbial growth on skin. Deodorant powders and
foot powders used for specific purposes. Face powders are widely used for face and body care.
These are very fine particles, shining having absorbent property, adhere to skin and spreads over
a large skin surface area. These powders contain talc, coloring agents, perfumes etc. to make the
skin pleasant to look and touch and give smooth feeling

(ⅱ)Creams –Vanishing creams, Cold creams, Sunscreens, Moisturizers.

Vanishing creams-These creams provide emollient and protective action to the skin against
environmental conditions by forming a neither greasy nor oily semi-occlusive residual film.
Vanishing creams are oil-in-water type emulsions. Vanishing creams are also known as day
creams as they are applied in the day times. They are named so as they spread as thin oil-less
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film when applied on the skin and this film is not visible to the naked eye. They are used to hold
powder on the skin and to improve adhesion.

Cold creams-Cold creams are applied on skin to provide smoothness and remove makeup. Cold
creams are named so due to the cooling effect they impart on application. Cold creams are oil-in-
water type emulsions added with certain fats (generally beeswax) and perfuming agents.

Sunscreens - Sunlight composed of various wavelengths ranging from ultraviolet light. Some
of which have negative effects on the human skin. Long term exposure of sun radiation could
make degenerative changes in the skin cells which leads to premature ageing, sunburns and
skin cancers. Sunscreens prevent or minimize the harmful effects of the solar radiations on
the skin. The application of sunscreens is an efficient method of protecting skin against
UV radiations.

Moisturizers - Moisturizers are widely used for both normal and dry skin. Application of these
preparations can increase the water content in the stratum corneum, hence exerting its most vital
action, which is moisturizing action aside from maintaining a normal skin pH, and allowing the
lipid bi layers in the skin to more easily normalize and re-establish their capacity to connect
corneocytes together and allow for moisture retention in the intercellular spaces. Subsequently,
the hydration interrupts the dry skin cycle, making the skin surface smooth, soft, pliable and
more extensible. In addition, some other plausible actions exerted by moisturizers include
anti-inflammatory action by blocking cyclooxygenase activity, anti mitotic action, anti pruritic
action via down regulation of cytokines, photo protective action, antimicrobial action and
wound healing.

(ⅲ)Colorants- Lipstick, Rouges.

Lipsticks- These are applied to skin on the face and lips and are called rouge and lipsticks.
Lipstick is used to impart an attractive color and glossy and moist appearance to the lips. These
are basically dispersions of coloring matter in a base consisting of a suitable blend of oils, fats
and wax suitably perfumed and blended.

Rouges- The rouge is defined as the cosmetic preparation used to give a desired color to the
cheeks. The usual colors are pale pink, blue, red, reddish brown etc.

2-Hair
(ⅰ)Shaving preparation- Shaving preparations are purely men’s cosmetics. These preparations
used for shaving of a hair to soften the beard and produces foam to facilitate the shaving by
razor. Shaving creams or soap is used before the shaving to moisten the hair and prevents
skidding of razor due to oily materials on hair and provides a good grip to the razor to cut the
hair from the root.

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(ⅱ)Shampoos- It is hair cleaning and glossing and conditioning agent. It mainly contains anionic
surfactants. These are basically water based products containing surfactants and some additional
substance. The water based products has the advantage of easy removal. The shampoos have the
side effect that the hair gets dried.

(ⅲ)Hair dyes- Hair dyes or colorants are used by both the genders to change the natural hair
color or to mask grey hair. An ideal hair dye should have the following properties:

-It should have a stable formulation.

-It should color the hair uniformly.

-It should impart a stable color to the hair.

-It should not result in the loss of natural shine of hair.

-It should not result in the loss of natural moisture of hair.

-It should not damage the hair shaft.

-It should be non-irritant, non-toxic, and non-sensitizing.

(ⅳ)Hair conditioner- The conditioners or hair creams are viscous emulsions or an oily mass,
applied to the hair. They are not generally perfumed and are white, off-white or uniform in their
shades. The conditioner provides smoothness and softness to the hair by moisturizing them. The
water used for moisturizing is almost futile, as it evaporates in the meantime. The primary
purpose of a hair conditioner is to reduce the magnitude of the forces associated with combing or
brushing of the hair.

3-Nail- The various preparations of nail care are nail polish or lacquers, removers, nail creams,
cuticle softeners and removers, nail whiteners and bleaches. The materials used are nail polish,
thinner, remover, nail creams etc .The lacquers are the most widely used nail cosmetic. The
product can vary from transparent uncolored to pink, metallic and many more shades of
attraction. These are also known as nail enamel or nail varnish. These materials give very good
look and should be glossy. These should be non-toxic and quick drying nature and easy to apply
with good adherence property and long lasting. The nail lacquers contain materials like film
formers, resins, solvents diluents and plasticizers, colors, perfumes, pearlescent pigments etc.
The lacquer removers are required to remove the old lacquers to put new or to change the color.
These are also called nail cleansers and it contains solvents like acetone, ethyl acetate, amyl
acetate, toluene along with some fatting agents. Nail creams are the agents which protect the nail
from brittleness. The composition of nail creams are lanolin, beeswax, petroleum jelly, perfume
and these agents give emollient effect and retain the moisture to give a good shiny appearance.

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4-Hygienic
(ⅰ)Dental preparation- Maintenance of shining teeth is very much essential. The products used
for cleaning the teeth and oral cavity are called dentifrices which include tooth paste and tooth
powder. Apart from cleaning the tooth these agents prevent formation of calculus, dental plaque,
tooth decay, reduce mouth odor and restore freshness of mouth.

The tooth cleansing agent when in a paste form is called tooth paste and when in powder form it
is tooth powder.

(ⅱ)Mouth washes and gargles- As the nomenclature says these are the preparations used to
wash the mouth and throat. These are the agents used to clean the oral cavity and throat and to
prevent microbial infection in this area and to reduce the microbial population producing bad
odor. It is also used to treat against mouth and throat infections.

Toxicity
The extent to which a chemical or specific combination of chemicals might harm an organism is
known as toxicity. A full organism, such as an animal, bacterium, or plant, can be affected by
toxicity, as can an organism's substructure, such as a cell or an organ, such as the liver
(hepatotoxicity). On occasion, the term is used in daily speech to refer to poisoning.

toxicity studies for cosmetic products

Before 1938, the concept of cosmetics was different, cosmetology was regarded as the style of
selling dreams rather than objective, efficacy and regulation of cosmetics was not under drugs.
Sometimes safety for the consumers was also problematic. Later cosmetics was regulated
through the federal food and drug cosmetic act (FD&C) by the United States Food and Drug
Administration (US FDA). US FD&C Act 1940, 201(i) has defined cosmetics as “articles
intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to
the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance”.
US FDA also states that cosmetic products should contain generally regarded as safe ingredients
i.e., they should not contain harmful substances . The role of chemicals in modern nations has
expanded significantly in the second half of this century. In the present world economy, all sorts
of industrial production utilize the chemicals obtained either from natural sources (e.g., plants,
animals and microorganisms) or through the synthetic process. These chemicals are toxic to the
human body. Preservatives and fragrances used in cosmetics are also toxic and can cause cancer,
mutation, reproductive toxicity and endocrine disruption. Heavy metals are also added to
cosmetics for various purposes; these heavy metals are very toxic. At low concentrations, some
of these heavy metals can cause internal body organ damage. Various abnormalities including

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cancer, respiratory diseases, intellectual retardation and failure in organ function were reported
due to metal poisoning.

According to the National Institute of occupational safety and health (NIOSH) report 1989
around 2983 chemicals are used in cosmetics products.

Out of all 884 were found to be toxic

778 were found to cause acute toxicity

313 were causing biological mutation

376 were found to cause skin irritation and eye irritation

218 were causing re productivity complications and

148 were carcinogenic.

From this data, it became essential to perform toxicity studies on cosmetic products. The primary
purpose of toxicity study on cosmetic products/other chemicals is to obtain biological
information, required for the estimation of toxic adverse effects of the cosmetics produced after
human exposure.

Regulatory requirements for cosmetics safety studies

The U.S. FDA does have an important role in the control and maintenance of cosmetic products
in commerce. The FDA can ban, or limit ingredients based on safety concerns, cooperate with
manufacturers to undertake countrywide product recalls, enforce warning labels on goods, audit
cosmetics manufacturing facilities, issue warning letters, confiscate illicit items, and punish
offenders. Subsequently, the FD&C is a key piece of legislation governing cosmetics sold in the
United States. It outlaws the sale of adulterated or misbranded cosmetics and keeps note of any
infractions concerning cosmetic ingredients, pollutants, manufacturing, packaging, or shipping
and handling. Furthermore, several EU Regulations and Guidance Documents (GDs) relevant to
the safety evaluation of industrial chemicals and cosmetic goods define the information required
to assess possible detrimental effects of industrial chemicals and cosmetic products on the
environment and human health. These rules are as follows –

Regulation (EC) No 1223/2009: of the European Parliament and the Council of 30 November
2009 on cosmetic products.

SCCS/1602/18: Scientific Committee on Consumer Safety (SCCS) Notes of Guidance (NOG)

for the Testing of Cosmetic Ingredients and their Safety evaluation, 10th revision Besides these
regulations, the cosmetic sector is responsible for ensuring that its formulas and products are safe
for customers. Cosmetic companies typically achieve this through a variety of mechanisms,
including

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(a) industry standards for good manufacturing practice,

(b) the use of ingredients that have undergone safety testing and have been used in cosmetic
formulations for decades without evidence of adverse effects,

(c) global regulatory standards, and

(d) ongoing evaluation and testing of currently used and new ingredients.

Approaches for toxicity studies

Fig- Different approaches for toxicity studies of cosmetics products.

There are two approaches for toxicology studies mechanistic and descriptive. Mechanistic
toxicity study is based on the biochemical process by which a toxic effect is produced while the
descriptive toxicity study is based on various analytical techniques such as pathology,
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physiology, and pharmacology. Most of the toxicity studies performed today are descriptive and
involve the use of animals. The animals used in the toxicity studies are always killed and
examined at the end of the tests. Usually, rabbits, guinea pigs, and albino rats are selected for
toxicity studies. The toxicity studies performed on cosmetic products are - acute toxicity, skin
irritation/corrosion, skin sensitization, repeated dose dermal toxicity, photo toxicity, ocular
toxicity, and carcinogenicity.

Acute toxicity

The goal of acute toxicity studies of cosmetics products is to determine the potential toxicity of
chemicals (present in cosmetic products) to humans and other life forms. Acute toxicity studies
are conducted to determine the potency of toxic chemicals in terms of the median lethal dose
(LD50). LD50 is a value that represents the estimated dose causing 50% of animals’ death
exposed under fixed conditions of the test. Rats are the most commonly used animal for this
study. As per directive 92/69/EEC for oral, inhalational and acute toxicity studies at least ten rats
(five males and five females) are to be selected and exposed to chemicals at different dose levels
(at least three). As per commission directive 93/21/EEC, a chemical agent that produces LD50 at
a dose < 50mg/kg in rabbits or rats exposed by dermal route or at LC50 at a dose <0.5mg/l in a
rat exposed by inhalation for four hours. Clinical signs of toxicity include bleeding from the
mouth, diarrhea, convulsions, seizures, paralysis and death.

Skin irritation/ corrosion

Skin irritation is the reversible damage of the skin produced after the application of test
substance (chemicals) for up to 4h, while skin corrosion is the irreversible damage of the skin
produced after the application of test substance for up to 4h, as visible necrosis through the
epidermis and into the dermis. The goal of estimating the potency of chemicals to induce
irritation or corrosion is to evaluate whether information from human experience, animal studies,
in-vitro studies or from physiological data provides proof that the chemical is likely to be
corrosive or skin, eye, and respiratory irritant. Rabbits are most commonly used for this purpose.
Two rabbits are selected and exposed to the chemicals for 4h. Chemicals are exposed to the
water-moistened body under semi-occlusive patches. Erythema, scar, and Oedema are observed
at a predetermined interval of 1, 24, 48, 72 h after path removal, up to 14 days.

Skin sensitization

According to OECD test guideline for skin sensitization OECD TG406, “Skin sensitization
(allergic contact dermatitis) is an immunological mediated cutaneous reaction to a chemic,
substance”, and is characterized by Pruritic, Oedema, erythema, papules or a combination of
these in the human. The goal of estimating the skin sensitization potency of chemicals is to
evaluate whether exposure of the chemical to the human initiates allergic reactions and whether
the chemical has a skin sensitization potential when exposed to the animal. Skin sensitization is
mainly performed on guinea pigs and mice. The mouse ear swelling test (MEST) or local

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(auricular) lymph node assay (LLNA) was performed on the surface of the mouse ear. When a
guinea pig is used for testing, the chemical is applied on the surface or injected under the skin.

Repeated dose dermal toxicity

As per the OECD TG 410, the dose in a dermal test is the amount of a test substance applied to
the skin. The dose is expressed as a weight (gm, mg) or as the weight of test substance per unit
weight of test animal (mg/kg). Repeated dose animal toxicity study provides information on
possible health issues, arising from repeated exposure to the chemical by dermal route over a
specific period. Rats, guinea pigs or rabbits are used for this study. The test substance is applied
daily to several groups of test animals in graduated dose, one dose per group for 21 days/28 days.
Animals are observed daily to detect the sign of toxicity, during the period of application.

Photo toxicity

As per OECD test guideline for photo toxicity OECD TG 432, photo toxicity is defined as a
“toxic response from a substance applied to the body which is either elicit or increased (apparent
at lower dose level) after subsequent exposure to light or that is induced by skin irritation after
systemic administration of substance” . Photo toxicity is produced when the skin applied with a
chemical/product come in contact with sunlight or UV radiation because chemical forms toxic
decomposition products following exposure to the sunlight or UV radiation. Guinea pig and mice
are most commonly used. The erythemal dose is predetermined, and the product is applied to the
skin of the test animal. This is usually done under a patch for a period of 24h or 48h after a
specified time patch is removed and one site irradiated with UV radiation (UV-A and UV-B).
after 24h of patch removal, both sites (irradiated and non-irradiated) are evaluated and compared
with control.

Ocular toxicity studies

Ocular damage may produce due to accidental or normal contact with the chemicals present in
cosmetic products employed for human skincare. The Draize test is used to evaluate qualitative
alteration produced in the eyes of examined animals. Most commonly rabbit is used for ocular
toxicity. According to the Draize test method, several test animals are applied with test
substances in a single dose to one eye. The second untreated eye is used as a control. The degree
of irritation produced in the treated eye is evaluated and compared with the control eye.

Carcinogenicity

The substances which induce tumors (benign or malignant) are known as a carcinogenic
substances. When they are ingested, inhaled, injected or dermal applied, they may increase their
malignancy or shorten the time of tumor occurrence. Two categories of carcinogens are known:
One is genotoxic (induce cancer through interaction with the DNA and induce mutations) and
another is non-genotoxic (induce cancer through a mechanism other than DNA damage, like

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hormonal effects). Most commonly, two species of rodent’s mice and rats are used for the
carcinogenicity study. Carcinogenicity testing requires more animals than another toxicity
testing. At least 100 animals (50 male and 50 female) rodents are used for each of 3 doses. The
latency period of tumor formation in rodent’s animals is 1 or 2 years. Test substance should be
administered 7 days a week for a fraction of life span comparable to the fraction of human life
span over which the substance is likely to be used. Generally, the period of dosing should be 24
months for rats and 18 months for mice. Observation should include macroscopic changes
observed at autopsy and detailed histopathology of organs and tissues.

Eye irritation test

The international EC/Home Office validation study of alternatives to the Draize eye irritancy test
did not achieve the expected objectives but triggered the organization of an ECVAM workshop
on the practical aspects of validation and the preparation of a pre validation schedule, as well as
the planning of the COLIPA study. Limited results were obtained from a small number of
protocols in COLIPA's first international validation phase of alternatives to the Draize test,
where prediction models had been prepared for each test. 28 COLIPA has organized discussions
on the second experimental validation phase. Since the analysis of the results of the first phase
revealed the variability of the in vivo data, COLIPA envisages using specific test materials,
authorizing a more mechanistic approach. Currently there are no validated alternative methods
capable of replacing the OECD 405 in vivo eye irritancy test and COLIPA does not expect
significant progress to emerge from the second validation phase in the near future. However, one
might consider encouraging a flexible approach by attempting to evaluate the potential of certain
categories of ingredients acting via common mechanisms by comparison with the data available
for appropriate control substances.

Toxico kinetics Studies

Toxicokinetic studies may be required for safety assessment if there is significant absorption.
Toxicokinetic studies are also of importance in extrapolating both in vitro and in vivo animal
data to man.

Metabolism Studies

In some cases the metabolic fate of the cosmetic ingredient, that is absorbed into the biological
system of the human body, can have an important bearing of its toxic potential, its disposition in
the body and its excretion.

Long-term toxicity studies

The objective of long-term studies is to determine the effects of a cosmetic ingredient in a

mammalian species following prolonged and repeated exposure. In these tests, effects which

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require a long latency period or which are cumulative become manifest (e.g. carcinogenicity,
impairment of fertility, reproductive disorders).

Finished products

The in-house experience acquired by the major cosmetics firms is particularly interesting in the
domain of in vitro testing on finished products. However, no in vitro alternative test method has
yet been successful in a validation study. The SCCNFP confirms the view that evaluation of the
safety of finished products can in general be based on knowledge of the ingredients' toxicity,
provided supplementary information is available in certain cases:

− when the vehicle used in the formulation is different to the solvents used in the toxicity tests
and when there is a likelihood of an increase in skin penetration or skin irritation;

– when a new, potentially toxic substance is liable to be created through the combination of
ingredients present in the finished product.

Compatibility testing of cosmetic finished products on human volunteers has been recommended
by SCCNFP in a recent opinion (SCCNFP/0068/98 Final - June 1999), see Annex 12

Toxic chemicals in cosmetics

Today's life is unimaginable without the use of many cosmetic and cosmeceutical products,
some of which have toxic chemicals that should be avoided. The role of toxicology in cosmetic
and cosmeceutical industry is to ensure that toxic ingredients are avoided and replaced with less
toxic, or even better, non-toxic chemicals. The importance of the campaign for safe cosmetics is
to raise awareness about toxic chemicals in cosmetics, promote safety standards and stimulate
the transformation of cosmetic industry into safe and non-toxic.

1,4-Dioxan-1,4-dioxane, a carcinogen linked to organ toxicity, may be found in as many as 22

percent of the more than 25,000 cosmetic products in the Skin Deep database. It is not marked on
ingredient labels because it is a contaminant produced during manufacturing. It is found in
products that create suds such as shampoos, liquid soaps, bubble baths, hair relaxers. 1,4-dioxane
is generated through a process called ethoxylation, in which ethylene oxide, a known breast
carcinogen, is added to other chemicals to make them less harsh. Research shows that 1,4-
dioxane readily penetrates the skin3. It is considered a probable human carcinogen by the U.S.
Environmental Protection Agency and is listed as an animal carcinogen by the National
Toxicology Program. It is included on California’s Proposition 65 list of chemicals known or
suspected to cause cancer or birth defects.

Acrylates -Acrylates (ethyl acrylate, ethyl methacrylate, and methyl methacrylate) are
ingredients found in artificial nail products (acrylic nails, nail enhancing polishes). Inhalation
and skin contact are two main exposure routes. Despite evidence of adverse skin, eye, and throat
reactions to these chemicals, they continue to be used in nail products. The International Agency

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of Research on Cancer (IARC) and U.S. Environmental Protection Agency (EPA) classify ethyl
acrylate as a possible human carcinogen. Workers in acrylic sheet manufacturing exposed to both
high and low levels of methyl methacrylate (MMA) were at an increased risk of colorectal
cancer. Orthopedic surgeons are chronically exposed to MMA and are proportionately more
likely to die from cancer, especially esophageal and myeloproliferative cancers, than general
surgeons. MMA inhalation is toxic to lungs and is associated with damage to nasal passages,
liver, and kidneys. Ethyl acrylate is toxic to the lungs, liver, kidneys, and gastrointestinal system.
Two studies showed that occupational exposure to MMA can cause symptoms of generalized
and peripheral nerve damage. Acrylates are skin, eye, and respiratory tract irritants, and can
cause workplaceinduced asthma (occupational exposure) and allergic contact dermatitis
(artificial nails that contain acrylates).

Benzophenon - Benzophenone is used in personal care products such as lip balm and nail polish
to protect the products from UV light. Derivatives of benzophenone, such as benzophenone-2
(BP2) and oxy benzene (benzophenone-3 or BP3) are common ingredients in sunscreen.
Benzophenone is persistent, bio accumulative and toxic. It is considered to be a possible human
carcinogen and possible endocrine disruptor. The European Food Safety Authority (EFSA)
classifies benzophenone as a known toxicant because it can cause liver hypertrophy in the rat at
lower doses. Oxy benzene can permeate across the skin and accumulate in blood, kidneys and
liver in rats, and may be hepatotoxic.

Butylated Compounds- Butylated hydroxyl anisole (BHA) and butylated hydroxyl toluene
(BHT) are used as preservatives in a variety of personal care products (lip and hair products,
makeup, sunscreen, antiperspirants, deodorants, fragrances, creams). According to European
Commission on Endocrine Disruption there is strong evidence that BHA is a human endocrine
disruptor. A study carried out in normal mammalian kidney cells found that exposure to BHA
caused specific damage at the cellular level and was found to exert a significant cytotoxic effect
even at low doses. IARC determined that there was only limited evidence of carcinogenicity for
products used on the lips. There is moderate evidence that BHT is a human respiratory irritant.

Carbon Black- Carbon black is a dark black powder used as a pigment in cosmetics such as
eyeliner, mascara, lipstick, nail polish, eye shadow, brush-on-brow, blushers, rouge, makeup and
fundation. IARC classifies carbon black as possible human carcinogen. Several human studies
indicate carbon black exposure may increase the risk of lung disease. Data from the study on rats
conducted by Kim and coworkers showed that carbon black exposure enhanced the
cardiovascular risk by inducing hyper homo cysteimia and platelet hyperactivity, although these
effects may be variable depending on particle size and exposure duration. Homocysteine may be
a potential biomarker for cardiovascular toxicity following carbon black exposure.

Coal Tar- Coal tar is a known human carcinogen found in shampoos and scalp treatments,
soaps, hair dyes and lotions. Occupational exposure to coal tar or coaltar pitch increases the risk
of skin cancer. Other types of cancer (lung, bladder, kidney and digestive tract cancer) have also

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been linked to occupational exposure to coal tar and coal-tar pitch. Pyridine, a coal tar
constituent, has been linked to neurological damage. Effects include emotional and sleep
disturbances, as well as loss of coordination.

Ethanolamine Compounds- Ethanolamine compounds are present in soaps, shampoos, hair

conditioners and dyes, lotions, shaving creams, paraffin and waxes, household cleaning products,
pharmaceutical ointments, eyeliners, mascara, eye shadows, blush, make-up bases, foundations,
fragrances, and sunscreens. The European Commission prohibits d ethanolamine (DEA) in
cosmetics, to reduce contamination from carcinogenic nitrosamines that are formed after the
reaction of DEA with other ingredients. DEA and TEA (tri ethanolamine) have been found to be
hepato carcinogenic in female mice. Studies have found that DEA affects human male
reproductive health. It alters sperm structure, causing abnormalities that affect the sperm’s ability
to swim and fertilize the egg. DEA accumulates in the liver and kidney, causing organ toxicity. It
has also possible neurotoxic effects such as tremor. Another study suggests that memory function
and brain development in offspring could be permanently affected by mothers’ exposure to DEA.

Formaldehyde- Formaldehyde and formaldehyde-releasing preservatives are found in nail

polish, nail glue, eyelash glue, hair gel, hair-smoothing products, baby shampoos, body soaps,
body wash, and color cosmetics. Formaldehyde is a known human carcinogen. Studies of
workers exposed to high levels of formaldehyde, such as industrial workers and embalmers, have
found that formaldehyde causes myeloid leukemia, and cancers of the paranasal sinuses, nasal
cavity and nasopharynx. Formaldehyde is also the 2015 American Contact Dermatitis Society
contact allergen of the year.

Fragrance- The International Fragrance Association (IFRA) lists 3,059 materials that are
reported as being used in fragrance compounds. Of these 3,059 ingredients, some (such as
acetaldehyde, benzophenone, BHA, BHT, benzyl salicylic, benzyl benzoate, butoxyethanol,
butyl phenyl methyl propional, methyl chloride, methylene chloride, diethyl phthalate, essential
oil mixtures, methyl eugenol, formaldehyde, ethanolamines, methanol, oxy benzone, propyl
paraben, resorcinol, styrene, synthetic musks, titanium dioxide, 1,4-dioxane, ethyl benzene and
vinyl acetate) have evidence linking them to health effects including cancer, reproductive
toxicity, allergies and sensitivities.

Homosalate- Homosalate is a widely used chemical in sunscreens and skin care products with
sun protecting factor (SPF). It is a potential endocrine disruptor (impacts androgen and
progesterone systems) and it may enhance the absorption of pesticides in the body. In human
breast cancer cells homosalate exposure led to 3.5 times more cell growth and multiplication.

Hydroquinone- Hydroquinone is most commonly used in skin lighteners, products heavily

marketed towards women of color. It is also found in skin lighteners, facial and skin cleansers,
facial moisturizers, hair conditioners, and finger nail coating products. Hydroquinone decreases
the production and increases the degradation of melanin pigments in the skin, what increases the

13
skin’s exposure to UVA and UVB rays, and the consequence is increased risk of skin cancer.
Hydroquinone is linked to a skin condition called ochronosis in which the skin thickens and turns
bluish-grey. Exposure of the eye can cause pigmentation and permanent corneal damage.
Hydroquinone may be harmful if inhaled, causing irritation of the nose, throat and upper
respiratory tract. A study on occupational exposure of hydroquinone showed that subjects
exposed to hydroquinone had a higher prevalence of cough and decreased lung capacity
compared to their unexposed counterparts.

Heavy Metals- Heavy metals like lead, arsenic, mercury, aluminum, zinc, chromium and iron
are found in a wide variety of personal care products including lipsticks, whitening toothpaste,
eyeliners, nail colors, foundations, sunscreens, eye shadows, blushes, concealers, moisturizers,
and eye drops. Lead is a well-known and proven neurotoxin that has been linked to learning,
language and behavioral problems. Lead has been linked to reduced fertility in men and women,
hormonal changes and menstrual irregularities. Pregnant women are especially vulnerable
because lead crosses the placenta and may enter the fetal brain, and has also been linked to
miscarriage. Mercury is linked to nervous system toxicity, as well as reproductive, immune and
respiratory toxicity, and is a recognized environmental health concern by numerous national and
international government bodies. Mercury may also disrupt thyroid hormones. Aluminum-based
compounds vary in their toxicity, but some are linked to neurotoxicity, developmental and
reproductive toxicity, and cancer. Excess chromium levels (chromium is an essential trace
element in human body, it is important factor for enhancing insulin activity) are strongly linked
to immune and respiratory toxicity, as well as systemic toxicity.

MIT, CMIT-Methyl isothiazolinone (MIT) and methylchloroisothiazolinone (CMIT) are found

in shampoos, conditioners, hair colors, body wash, lotions, sunscreens, mascaras, shaving
creams, baby lotions, baby shampoos, hairsprays, makeup removers, liquid soaps and detergents.
Rats exposed to highly concentrated MIT (over 50%) showed a range of symptoms, including
significant body weight gain and death. Autopsies revealed that death was due to reddened lungs
and swollen intestines. MIT and CMIT are two of the most predominant contact allergens found
in cosmetic products. In vitro cell studies on MIT showed signs of neurotoxicity when cerebral
cortex cells were exposed to liquid MIT.

Mica- Mica is a naturally occurring mineral dust often used in makeup foundations, as filler in
cement and asphalt, and as insulation material in electric cables. Mica is a respiratory irritant.
Long-term inhalation of mica dust may cause lung scarring which leads to symptoms such as
coughing, shortness of breath, weakness, and weight loss.

Nail Polish Removers- Isopropyl acetone, methyl ethyl ketone, and n-methyl-pyrrolidone, are
commonly used as the solvent in nail polish removers. These chemicals are skin, eyes and
respiratory irritants. There is some evidence about possible carcinogenicity of isopropyl acetone.

14
Nanoparticles- Insoluble nano particles in cosmetic products are essentially used as UV-filters
or preservatives. Nanoparticles can be found in deodorants, toothpastes, shampoos, lotions,
foundation, anti-aging creams, and nail polish. Studies have indicated that low solubility
nanoparticles (such as titanium dioxide, zinc oxide, silver, fullerenes, silica, carbon black) tend
to be more toxic than larger particles of the same material. Inhalation of nano materials may lead
to inflammation and oxidative stress.

Nitrosamine- Nitrosamines can be found in nearly every kind of personal care product.
Nitrosamines are probable human carcinogens (group 2A). There is also some evidence of
endocrine disruption at very low doses. N-nitrosodiethanola mine, one form of nitrosamine,
accumulates in the liver, bladder and other organs and leads to chronic toxic health effects.

Parabens- Parabens are preservatives that can be found in shampoos, conditioners, lotions,
facial and shower cleansers and scrubs. Parabens are potential endocrine disruptors due to their
ability to mimic estrogen. Combined with other estrogenic chemicals parabens may potentially
influence the development of malignant melanoma through their estrogenic and genotoxic
activities. Some studies have also shown that parabens have potential developmental and
reproductive toxicity.

PABA-PABA(para-amino benzoic acid) and PABA derivatives are commonly used in

sunscreens as ultraviolet B (UVB) filters. Studies performed on rats and on thyroid tissue
samples suggest that PABA may disrupt thyroid activity by decreasing the levels of thyroxine.
UV radiation is more likely to damage DNA in the presence of PABA, and DNA damage to the
skin increases the risk of skin cancer.

Petroliam- Petrolatum, or petroleum jelly, derived from petroleum, is often used in personal care
products (such as lotions) as moisturizing agent. Petrolatum can be contaminated with toxic
chemicals called polycyclic aromatic hydrocarbons (PAHs). IARC lists 14 PAHs as probable or
possible carcinogens and one PAH as a known carcinogen.

Phenoxyethanol- Phenoxyethanol is used as a preservative in cosmetic products and also as a

stabilizer in perfumes and soaps. It can be found in moisturizers, eye shadows, foundation,
sunscreens, conditioners, mascaras, eye liners, shampoos, lip gloss, concealers, body wash, hand
creams, blush, hair colors, hair sprays, lip balms, lotions, nail polish, baby wipes, baby lotions
and soaps, soap (liquid and bar), shaving creams, deodorants, toothpaste, fragrance, hair removal
waxes, hand sanitizer and ultrasound gel. Exposure to phenoxyethanol has been linked to
reactions ranging from eczema to severe, life-threatening allergic reactions. Infant oral exposure
to phenoxyethanol can acutely affect nervous system function.

Polyacrylamide - Polyacrylamide is used as a stabilizer and binder in lotions and other products.
It can be found in facial moisturizers, anti-aging products, color cosmetics, lotions, hair products,
and sunscreens. Polyacrylamide can break down into acrylamide, which is a probable human
carcinogen, and can be associated with reproductive and developmental toxicity.

15
Phthalate Phthalates have been banned from cosmetics in the European Union, but still remain
prevalent in U.S. products such as color cosmetics, fragranced lotions, body washes and hair care
products, nail polish and treatment. These chemicals are linked to endocrine disruption,
developmental and reproductive toxicity, and possibly to cancer.

Resorcinol- Resorcinol is commonly used in hair dyes and acne medication. In higher doses it is
toxic and can disrupt the function of the central nervous system (convulsions are reported in
acute intoxication) and lead to respiratory problems (respiratory failure in acute intoxication). It
has also been shown that resorcinol can disrupt the thyroid function. It has been shown to have
two different effects: the inhibition of enzymes involved in thyroid hormone synthesis (leading
to hypothyroidism) and the activation of thyroid hormone receptors. A study of resorcinol’s
effects on cells, suggests that resorcinol acts like thyroid hormone and as an agonist at thyroid
hormone receptors at low doses.

Retinol-Retinol is the chemical name of the essential micronutrient vitamin A that can be found
in anti-aging creams and lotions, moisturizers, and foundation. Retinoic acid and retinyl
palmitate, in combination with sunlight, may increase skin cancer risk. The California EPA’s
Proposition 65 list identifies all-trans retinoic acid as a developmental toxicant.

Purpose of Guideline for Risk Assessment of Cosmetic Products

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.

General Principles of Cosmetic Product Safety

(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.

(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.

(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.

16
(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.

(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.

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.

17
(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 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.

(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.

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.

Risk Assessment of Cosmetic Products

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

18
(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.

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 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.

19
Detailed procedures of risk assessment
(1).Background and purpose - Explain the background of how the problem occurred, ripple
effect, seriousness and social impact.

(2).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.

(3).Writing report and proposing management solution - Document the results of the conducted
risk assessment, and propose a management solution depending on the purpose.

(4).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 if needed.

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.

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.

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.

20
(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.

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

NOAEL=No observed adverse effect level

(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, 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.

MOS = NOAEL/SED

Report preparation-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.

Re-assessment-If there are additional data that can be trusted, re-assessment can be conducted.

21
 - 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.

GUIDELINES ON THE USE OF HUMAN VOLUNTEERS IN THE

TESTING OF POTENTIALLY CUTANEOUS IRRITANT COSMETIC
INGREDIENTS OR MIXTURES OF INGREDIENTS
Emphasis on consumer safety

According to the Cosmetics Directive “a cosmetic product put on the market within the
Community must not cause damage to human health when applied under normal or reasonably
foreseeable conditions of use” . In order to achieve this goal of product safety, toxicological data
on cosmetic ingredients are needed as outlined in the SCCNFP Notes of Guidance for Testing of
Cosmetic Ingredients for their Safety Evaluation 2nd Rev. (XXIV/1878/97). Among the data
mentioned, also human data are cited. However, the document does not specify these in detail.
Regarding skin irritation, the SCCNFP considers that at present human testing of cosmetic
ingredients or mixtures of ingredients should not be preferred to animal testing.

Animal tests for assessment of safety to be replaced by alternative methods

In the past, most of the toxicological data mentioned above have been generated by testing on
animals. However, according to Council Directive 76/768/EEC, the marketing of cosmetic
products containing ingredients or combinations of ingredients tested on animals after 30 June
2000 in order to meet the requirements of this Directive shall be prohibited. The Commission’s
general policy regarding research on animals supports the development of alternative methods to
reduce or replace animal testing when possible.

Testing of cosmetic ingredients in humans

In this context, the scientific and ethical considerations for testing cosmetic ingredients or
mixtures of ingredients in human subjects need to be defined more clearly. The skin irritancy
reaction in humans is not an absolute measure and must be related to appropriate controls
defining the range of response.

The SCCNFP stresses three points:

(1).Since tests in animals or validated alternative methods may be limited regarding their
predictive value for exposure of a human population, confirmatory safety tests in humans may be
necessary scientifically and ethically, provided that the toxicological profile of an ingredient or a

22
mixture of ingredients based on animal or alternative methods is available and that a high degree
of safety is to be expected.

(2).Confirmatory tests of ingredients or mixtures of ingredients in humans must be limited to

situations where no irreversible damaging effects are to be expected for the volunteers and where
the study goal is reasonably achievable with a study population of limited size.

(3).The recruitment of human volunteers should be in line with the “World Medical Association
Declaration of Helsinki” and “the Good Clinical Practice for trials on Medicinal Products in the
European Community”.

Initial considerations

Available chemical and physicochemical data and structure-activity relationships making use of
computer programs and databases for the prediction of skin irritation potential should be used.

Evaluation of irritation

Ingredients or mixtures of ingredients should be tested on animals and humans only at non-
corrosive concentrations. This decision may be based on pH and acid/alkaline reserve
measurements and on in vitro tests for skin corrosive. At the present, in vitro methods for the
assessment of irritancy have not yet been validated.

Confirmation by human volunteer testing

On the basis of a low irritation potential as proven by animal or future validated in vitro methods,
the skin tolerability of an ingredient or a mixture of ingredient can be confirmed by testing in
human volunteers. A number of test protocols are available such as open and closed patch tests,
single and repeated-exposure tests. They should be chosen on the basis of the relevant use pattern
of the ingredient or mixture of ingredients. In the open test, the tested ingredient or mixture of
ingredients is applied on the skin without occlusion for time periods between 15 min and 24 h. In
closed patch tests, diluted or undiluted products are applied under occlusive chambers over 24 or
48 hours. Cumulative or repetitive closed patch tests involve applications on the same test site
between 1 and 7 times per week over a period of 1 to 5 weeks. These repetitive tests allow the
assessment of cumulative irritation that is missed by single application tests. Controlled use or
repeated open application tests (ROAT) imply the repeated application of an ingredient or a
mixture of ingredients closely modeled to the use-situation. While these tests historically have
been assessed by clinical methods, non-invasive bioengineering technology such as measurement
of trans epidermal water loss or of blood flow may provide higher sensitivity and objectivity of
these tests and thereby reduce the exposure and risk to volunteers. However, neither the above
confirmatory tests nor the use of bioengineering methods have been validated according to

23
modern scientific criteria. The SCCNFP recommends the Commission to support further
research in this area.

Consumer market surveillance

The evaluation of irritation of an ingredient or mixture of ingredients is not finished with the
introduction of respective cosmetic products on the market, but it should continue by making use
of data generated by consumer market surveillance and other sources.

Ethical considerations

Confirmatory skin tolerance tests of cosmetic ingredients in humans are subject to ethical
concerns. In order to take account of these concerns, to minimize the risk to volunteers and to
safeguard their rights, test protocols should be submitted to an acknowledged ethical committee
and be in compliance with the followings :

- World Medical Association Declaration of Helsinki in its current revision. Human testing is to
be conducted and monitored under the direction of relevantly trained personnel to ensure the
health and well being of volunteer subjects involved in the testing. The health and welfare of the
subject has first priority and must be highly protected. Importantly, the human testing that is
conducted for chemicals and consumer products is associated with minimal risk as it is
conducted:

i) to supplement non-clinical information,

ii) to confirm that exposure will not cause significant harm, and/or,

iii) in a controlled fashion that minimizes subject risk.

- National regulations regarding human studies

- Good Clinical Practice for Trials on Medicinal Products in the European Community. The
investigator(s) in skin tolerability tests of cosmetic ingredients should fulfill the qualifications as
mentioned in the CPMP Working Party on Efficacy of Medicinal Products Note for Guidance on
Good Clinical Practice.

24
Conclusion
There is a need for the establishment of higher standards in cosmetology in a way of raising
awareness about toxic chemicals that should be avoided, promoting safety standards and
transforming cosmetic industry into safe and non-toxic. The role of toxicology in cosmetic and
cosmeceutical industry is to ensure that toxic ingredients are avoided and replaced with less
toxic, or even better, non-toxic chemicals.

25
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