S Kapoor, S Saraf
cosmetic, ingredients, risk analysis, tools, toxicity
S Kapoor, S Saraf. Risk analysis tools for toxicological profile of cosmetics. The Internet Journal of Toxicology. 2007 Volume 5 Number 2.
Cosmetic products made up of mixtures of ingredients used by all age group of person to keep their skin healthier and fresh. Occasionally, undesirable sides effect both local and systemic may occur with the use of cosmetics. Claimed effects and safety of cosmetic products depends upon the ingredients incorporated. Study of risk assessment associated with ingredients is the best way to avoid future problems. By adopting proper methodologies and techniques risk factors of ingredients incorporated in cosmetics can be determined and managed at safety level. This paper enlightened the toxic effects associated with some of the cosmetic ingredients, with the tool used for risk analysis and management procedure. This review encourage the industrialist, cosmeticians, pharmacist and researchers to carry and publish more cosmetic toxicity studies, which would help to explore the myth of cosmetics in front of consumers that will beneficial in terms of human health.
Skin is the effective barrier to the environmental. Disturbances to this barrier lead to the development of various skin problems. Cosmetic products are widely used by every socio class of human being to cleanse, perfume, protect and change the appearance of skin. Most cosmetic products contain a combination of ingredients such as emulsifiers, preservatives, thickener, colour, fragrance, UV filters (sunscreens), humectants, occlusive agents and pH stabilizers. Sometimes the ingredients in cosmetics can have unintended side effects. Most serious side effects have been noticed from various studies for certain cosmetic ingredients. Thus, it is necessary to have the best knowledge possible about each ingredient used, both in relation to its characteristics as well as to its toxicological data, taking into account the many potential risks related to its cosmetic use. The safety of a cosmetic product is based on the safety of its ingredients, the latter being evaluated by toxicological testing (Pauwels and Rogiers, 2004). Toxicity testing has been concentrated on ingredients, and particularly on those that are intended to react with biological matrices and therefore are of most concern for human health. The Threshold of Toxicological Concern (TTC) is a concept that refers to the establishment of a level of exposure for all chemicals, whether or not there are chemical specific toxicity data, below which there would be no appreciable risk to human health (Kroes, 2005).
Some activist groups have targeted cosmetics as possible human health threats, claiming that cosmetic ingredients are not adequately tested for safety and may pose risks to consumers. The groups allege that industry practices related to safety testing are flawed, that there is little government oversight, and that cosmetics contain cancer-causing chemicals and other toxicants (Ross, 2006).
When a formulation is being considered for safety a risk assessment must consider the general toxicological profile of the ingredients and their level of exposure. More recently the toxicity and efficacy of cosmetics and their ingredients has been under the spotlight. So cosmetic which are used mainly for beautification purpose is not free from side effects that myth should be cleared in front of consumers. There are some ingredients that found to be toxic and banned by all legislations but highly used by cosmetic industry, about which common consumers even academicians, pharmacist, cosmetician and chemist are also not aware. Various regulatory bodies like Food and drug administration (FDA), European union (EU) e.t.c. has identified the cosmetic ingredients that are either approved or prohibited on the basis of the toxic effects produced by them (Table 1, 2 and 3). Results of toxicology and safety testing are not always publicly disclosed, cosmetic manufacturers have internal processes, programs, and testing protocols that are designed to ensure the safety of the products they produce.
The present paper describe about the key principle of risk assessment used for evaluation of toxicological profile of cosmetics with special reference to the methodologies and techniques used for managing risk at optimum level. Objective of this review to motivate all academicians, chemists, beauticians, pharmacist, industrialist and researchers to perform risk assessment study of cosmetics by adopting proper legislation and publish. This would be helpful to upgrade the knowledge, increased the trust and disclosed the myths of common consumers regarding cosmetic products.
Risk Assessment And Risk Management
Each cosmetic finished product is an individual and unique combination of ingredients. No ingredients, whether naturally occurring or manufactured, is absolutely free from potential toxic effects. To allow a better safety evaluation risk associated with cosmetic ingredients should be assessed and properly managed [WHO, 2001; EC, 2000]. General principles and practice aDApted for risk assessment process, is represented in Fig 1.
Hazard identification: It is based on the results of
Dose-response assessment: In this the relationship between the toxic response and the exposure of ingredient is studied. In the case of an effect with a threshold, the dosage at which no adverse effects are observed (NOAEL) is determined. If the NOAEL is not available, the LO(A)EL is used. In the case of non-threshold carcinogens, a dose-descriptor (e.g. T25) is determined [Dybing et al., 1997].
Exposure assessment: Study in which the amount and the frequency of human exposure to the product is determined.
Risk characterization: It is used to examine the probability of the ingredient/molecule to cause the damage to human health and its potency to produce damage.
Risk Management is a decision-making process in which the optimal steps are selected for reducing a risk produced by ingredients to an acceptable level. Risk management (Fig 2) procedure is often controlled by legislation, which lays down allowable limits of exposure and puts specific duties on management and workers [Beck et al., 1994; Dayan, 1999; Loprieno, 1999; Rogiers, 2002a; Masson, 1999; Sanner 2001].
Risk analysis of cosmetic ingredients should be carried out by performing physicochemical analysis, toxicological analysis (SCCNFP/0690/03, 2003) and microbial contamination examination.
A small molecular weight hydrophobic compound is more likely to penetrate through the skin than a high molecular weight hydrophilic compound and a highly volatile compound could cause significant inhalation exposure when present in a product applied to the skin. Hence, physical and chemical properties of cosmetic ingredients should be seen as they may be able to predict certain toxicological properties. The basic and minimal specifications such as chemical identity, physical form , molecular weight (M.W), purity of the chemical, characterization of the impurities or accompanying contaminants, solubility, partition coefficient (Log Po/w) of any ingredient should be considered and the information obtained from study of above points must be included in each toxicological dossier.
Toxicological profile analysis
The assessment of the toxicological potential is the most important step in the hazard evaluation of a cosmetic ingredient and consists in a series of distinct toxicity studies. This study carried out in terms of evaluations of distinct toxicological parameters which are as follows.
1) Acute toxicity
It is evaluated to describe the adverse effects on health, which may result from a single exposure to a substance via the oral, dermal or inhalation route [ECB, 2003]. The
2) Irritation and corrosivity
This is evaluated in terms of skin irritation, skin corrosivity and mucous membrane irritation produced by cosmetic ingredients.
a) Skin irritation and skin corrosivity
Skin irritation tests have been developed to assess the potential of a certain substance to cause redness and edema after a single topical application and skin corrosion tests assess the potential of a substance to cause irreversible necrosis through the epidermis and into the dermis, following the application of a test substance for the duration period of 3 minutes up to 4 hours. Corrosive reactions are notified by formation of ulcers, bleeding, and scabs. At the end 14 days, discoloration of the skin, alopecia, and scars will be observed to assess the extent of skin corrosion reactions [OECD, 1981]. Validated
b) Mucous membrane irritation
Mucus membrane irritation will be accessed by determining occular irritation produced by cosmetic ingredients after a single application. Occular irritation tests have been developed to assess the potential of a certain substance to cause chemosis, discharge, redness to the conjunctiva, swelling of the iris and opacity to the cornea. Classical
3) Skin sensitization
A skin sensitizer is an agent that is able to cause an allergic response in susceptible individuals. Three common
4) Dermal / percutaneous absorption
Human exposure to cosmetic ingredients occurs mainly via the skin. In order to reach the circulation cosmetic ingredients must cross a number of cell layers of the skin. The in vivo and in vitro dermal / percutaneous absorption studies have been described by several international bodies [ECETOC, 1993; US EPA, 1996]. Dermal / percutaneous absorption is the amount of dermally applied substance remaining in the residual skin (excluding the stratum corneum) plus the amount of dermally applied substance which has transpassed the skin and is detected in the receptor fluid. The sum is considered to be systemically available [Bronaugh, 2005].
5) Repeated dose toxicity
Repeated dose toxicity comprises the adverse general toxicological effects occurring as a result of repeated daily dosing with exposure to, a substance for a specific part of the expected lifespan of the test species [ECB, 2003]. The 28-day and 90-day oral toxicity tests in rodents are the most commonly used repeated dose toxicity tests and often give a clear indication on target organs and type of systemic toxicity. Currently no validated or generally accepted alternative methods are available for replacing animal testing.
Mutagenicity refers to the induction of permanent transmissible changes in the amount or structure of the genetic material of cells or organisms. Genotoxicity is a broader term and refers to potentially harmful effects on genetic material that are not necessarily associated with mutagenicity. Several
Substances are defined as carcinogenic if they induce tumours, increase their incidence, malignancy when they are inhaled, ingested, dermally applied or injected [ECB, 2003].
8) Reproductive toxicity
Reproductive toxicity is used to describe the adverse effects induced by a substance on any aspect of mammalian reproduction. The most commonly performed
9) Toxicokinetic studies
Toxicokinetic studies explain e the time-dependent fate of a substance within the body. This includes absorption, distribution, biotransformation and its excretion [ECB, 2003]. In specific cases,
10) Photo-induced toxicity
It is measured in terms of photoirritation and photomutagenicity of cosmetic ingredients.
11) Human data vs / data
Tests in animals and alternative methods carried out for toxicity evaluation of ingredients are of limited predictive value with respect to human exposure. Therefore, a skin compatibility test with human volunteers is needed scientifically and ethically, to confirm that there are no harmful effects when applying a cosmetic product for the first time to human skin or mucous membranes.
In general, acute toxicity, irritation and corrosivity, skin sensitization, dermal / percutaneous absorption, repeated dose toxicity, mutagenicity/genotoxicity
III) Microbial examination
Preservatives are added as ingredients in cosmetic products to make the products free from microbial side effect. To evaluate the potency of preservative efficacy challenge test is widely used which determines that preservative are in sufficient quantity to keep the product free from toxic effect [BIS, 2006]. COLIPA has proposed the microbial limit for the purity of cosmetics
Methodologies and Techniques
(OECD), European Cosmetic, Toiletry and Perfumery Association (COLIPA), Cosmetics, Toiletries and Fragrances Association (CTFA), Bureau of Indian standard (BIS) and world health organization (WHO) guidelines. There are various in
Calculation of risk factors
Risk factors for a cosmetic ingredient are calculated in terms of Margin of Safety (MoS), Systemic Exposure Dosage (SED) and Life time cancer risk.
NO(A)EL : The No Observed (Adverse) Effect Level is the outcome of long-term toxicity studies, such as 28-day, 90-day tests .
SED: The Systemic Exposure Dosage of a cosmetic ingredient is the amount expected to enter the blood stream (and therefore be systemically available) per kg body weight and per day. It is expressed in mg/kg body weight/day.
This MoS value [Renwick, 1998] is used to extrapolate from a group of test animals to an average human being, and subsequently from average humans to sensitive subpopulations (Fig.3). These factors can be further subdivided as indicated in Fig .4 [WHO, 1994].
For testing skin absorption of product that mimics human exposure, normally 1-5 mg/cm2 for a solid and up to 10 µl/cm2 for liquids should be used
a) Dermal absorption in µg/cm
Calculations of the SED should preferably be based on the absolute amount bioavailable (µg/cm2) after a certain time period, based on the highest anticipated concentration.
SED (mg/kg bw/day) = Systemic Exposure Dosage
DAa(µg/cm2) = Dermal Absorption reported as amount/cm2
SSA (cm2) = Skin Surface Area expected to be treated with the finished cosmetic product
F (day-1) = Frequency of application of the finished product
60 kg = Default human body weight
b) Dermal absorption in percentage
Calculations of the SED may also be based on the percentage dermally absorbed, lowest concentration anticipated.
SED (mg/kg bw/day) = Systemic Exposure Dosage
A (g/day) = Amount of the cosmetic product applied daily
C (%) = Concentration of the ingredient under study in the finished cosmetic product on the application site
DAp (%) = Dermal Absorption expressed as a percentage
60 kg = Default human body weight
3) Lifetime cancer risk
Determination of the lifetime cancer risk is carried out in several distinct steps. The dose-descriptor T25 is defined as the chronic dose rate that will give 25% of the animal's tumours at a specific tissue site after correction for spontaneous incidence, within the standard life time of that species. The determination of T25 is described in details by Dybing et al. . From the experimental data an animal dose descriptor (T25) is determined and converted to a human dose descriptor (HT25) by using the following formula [Sanner et al. 2001]. Subsequently, the lifetime cancer risk is determined by linear extrapolation to the actual exposure dose. Finally, a commentary statement is generated stating whether an overall evaluation of all data available indicates that the actual risk may be higher or lower than the calculated risk.
SED represents the lifetime daily dose expressed in mg/kg bw/day.
As time progressed, through invasions and migrations and cultures merged there has been profound effect on the value of cosmetics. Cosmetic products are developed to be applied to human skin and external mucosa and to be used by the general public. Skin and mucous membrane irritation are the most frequently observed reactions.
Authors are thankful for the time to time guidance provided by professionals of Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, C.G.