Cosmetics Safety

Cosmetics are important chemical products in our daily lives, primarily including facial and body care products, hair dyes, nail polish, lipstick, perfume and deodorants (Zeliger, 2011). Today, cosmetic product consumers are seeking the safest and most effective products, and prefer fragrance-free, hypoallergenic, natural, environmentally friendly products that have not undergone animal testing and have been tested on appropriate human volunteers (Farris, 2014). In the development of new formulations for cosmetic products, it is possible to reach the desired safety standards through the work of researchers from different disciplines in evaluating not only the efficacy but also the safety of products (Rogiers & Pauwels, 2008). In Europe, cosmetics are regulated by the Cosmetic Products Directive (76/768/EEC), which emphasizes as its fundamental principle that the general toxicological profiles, chemical structures and exposure levels of all materials used must be taken into account. For all cosmetic products manufactured or imported in the United States, ensuring the safety of ingredients and the product prior to marketing is regulated by the Federal Food, Drug, and Cosmetic Act, the Fair Packaging and Labeling Act, and regulations published by the Food and Drug Administration (Zeliger, 2007; Gilbert, 2008; Farris, 2014). In evaluating the safety of cosmetic products; first, the toxicological profile of each substance in the product must be evaluated, and possible toxicological risks when applied to a healthy person under normal and foreseeable conditions of use are determined. Respiratory or oral exposure during or after application should not be disregarded, and the age of the target group, exposure and conditions of use should be taken into account (Brain & Walters, 2008; Kowcz et al., 2014).

The most important criterion in safety assessment is determining whether critical components are systematically available for use.

Researchers determine the safety margin of a cosmetic product by evaluating solid data on dermal absorption of cosmetic product content, systemic circulation loads and toxicological profiles (Kowcz et al., 2014; Scientific Committee on Consumer Safety (SCCS), 2016). There are numerous important epidemiological events documented in the literature. In 1972 in France, the addition of hexachlorophene to baby powders to reduce staphylococcal infections resulted in 204 infants becoming ill and 36 dying from respiratory failure (Thong, Freeman, & Maibach, 2008). In Sudan, poisonings occurred when henna was mixed with p-phenylenediamine to accelerate skin staining, and in Khartoum, more than 20 cases, mostly fatal, related to this combination were reported over two years (Thong, Freeman, & Maibach, 2008). The use of mercury as a preservative in creams resulted in facial pigmentation, increased mercury levels in blood and urine, and neuropsychiatric effects (Thong, Freeman, & Maibach, 2008). Similarly, numerous deaths in the 20th century were reported from arsenic compounds used as dyes in cosmetics (Gallo, 2008; Basha & Reddy, 2015). Cosmetics generally cause allergic or irritant contact dermatitis, with systemic side effects occurring particularly from irritant or hypersensitivity reactions (Thong, Freeman, & Maibach, 2008).

The major side effects and causative agents observed with cosmetics can be briefly summarized as follows;

Allergic contact dermatitis, an inflammatory skin disease characterized by erythema, edema and vesiculation seen as delayed skin reactions following cutaneous exposure to allergic chemicals, has become more common due to the entry of numerous new chemicals into the market. Infrequently used chemicals, upon entering the content of new and trendy cosmetics, begin to exhibit allergenic properties (Thong & Maibach, 2008a). For example; methylchlorolisothiazoline/methylisothiazoline was replaced with methyldibromoglutaronitrile, a biocide not reported to cause allergic contact dermatitis, but upon widespread use, methyldibromoglutaronitrile was found to be a strong contact allergen (Rice & Mauro, 2008). Phototoxicity (photoirritation and photoallergy); photoirritation is a nonimmunological skin reaction to active chemical caused by sun exposure, while photoallergy is an immunological reaction that involves a sensitization phase, occurs in sensitized individuals, requires minimal concentration of the photoallergen, and develops as a result of antibody or type IV delayed cell-mediated reaction. From cosmetics and dyes: acridine, eosin, erythrosine, fluorescein, methylene blue, methyl violet, orange red, p-phenylenediamine, rose bengal, toluidine blue; from deodorants and bacteriostatic agents: halogenated carbanilides, halogenated phenols, halogenated salicylanilides; from perfumes and bath products (volatile oils): essential oils, musk amber, bergamot oil, cedarwood oil, bitter orange oil, lavender oil, lemon oil, lime oil, rosemary oil, sandalwood oil, perfumes, fragrances; from spices: Rutaceae spp., Umbelliferae spp.; from sunscreen agents: benzophenones, cinnamates, oxybenzone, PABA esters, PABA-pabagel, pabanol, presun and others; from preservatives in sunscreen preparations: 6-acetoxy-2,4-dimethyl-m-dioxane can be given as examples of phototoxic and photoallergic chemicals (Thong & Maibach, 2008b). Phthalates used to maintain scent persistence in products such as soaps and shampoos and as plasticizers in products such as nail polish have been reported to adversely affect testosterone production, increase obesity risk associated with type 2 diabetes, and cause insulin resistance (Zeliger, 2011, The Association of Southeast Asian Nations (ASEAN), 2014).

Sunscreen agents, and particularly the acute toxic side effects of chemical UV absorbers, appear as contact irritation, allergic contact dermatitis, phototoxicity, photoallergy and skin pigmentation (Schauder & Ippen, 1997; Benson, 2008).

Compared to other sunscreen agents, p-aminobenzoic acid (PABA) has much higher risks of contact and photocontact allergy reactions due to staining and allergic contact reactions, and its use has been greatly reduced. PABA derivatives such as Padimate O and Padimate A, which was banned in the United States due to its phototoxic effects, have been reported to cause photosensitivity (Rigel, 2014). Padimate O generates free radicals in sunlight, causing DNA damage and increasing cancer risk (Zeliger, 2011). The sunscreen titanium dioxide absorbs approximately 70% of incoming UV rays, which creates free radicals causing serious cellular damage (Zeliger, 2011). In sunscreens, octyl salicylate has been reported to increase skin penetration of testosterone, estradiol and progesterone similar to Padimate O. These properties make them important in transdermal therapy while also raising concerns about increasing skin penetration of toxic compounds (Brain & Walters, 2008). In a study on experimental animals following exposure to the herbicide 2,4-dichlorophenoxyacetic acid 30 minutes after sunscreen application, herbicide penetration through hairless skin was observed, and when benzophenone and the insecticide N,N-diethyl-m-toluamide were applied simultaneously to porcine skin in vitro, their absorption was found to increase synergistically (Brain & Walters, 2008). From topical antiseptics, povidone iodine, sodium hypochlorite, acetic acid, hydrogen peroxide and chlorhexidine have been reported to demonstrate local cytotoxic effects in addition to bactericidal effects (Cross, 2008). Mercury compounds used as preservatives, formaldehyde, methyl and propyl p-aminobenzoic acids (PABA), butylhydroxyanisole, butylhydroxytoluene, benzoic acid and quaternary ammonium compounds have long been known to potentially have estrogenic activity.

Serious connections have been established between parabens and breast cancer (Brain & Walters, 2008; Zeliger, 2011). Methylparaben increases oxidative stress in the presence of UVB (Zeliger, 2011).

Soaps produced from hydrolysis of animal or vegetable oils with NaOH, which have low toxicities, may contain additives including chloroxylenol, phenol, triclosan, methylisothiazoline and other toxic substances for deodorant and antimicrobial properties (Zeliger, 2011). Surfactants (irritants) that simultaneously have both hydrophilic and lipophilic properties are widely used in soaps, shampoos, detergents, cosmetics and similar consumer products, and can easily penetrate the cornea's sandwich-like aqueous and lipid barriers, leading to eye toxicity (Fox & Boyes, 2008). Although alkanolamides (Diethanolamine (DEA) derivatives) used as viscosity and foam enhancers and entering rinse formulations have been reported to be safe, studies conducted by the National Toxicology Program (NTP) have indicated clear evidence that DEA, lauramide DEA and cocamide DEA caused liver tumors in mice (Brain & Walters, 2008). Silicon-based materials used as lubricants may show immunotoxic effects (Kaminski et al., 2008). Inhalation exposure to talc causes chronic talcosis with fibrosis effects (Witschi et al., 2008). Petrolatum and basic cream skin softeners were shown in an examination conducted on volunteers to increase the minimal erythema dose when volunteers were exposed to UV radiation (Zeliger, 2011). Natural (retinoic acid -tretinoin-) and synthetic (adapalene, bexarotene, tazarotene and alitretinoin) retinoids, vitamin A derivatives used against skin aging, may exhibit photoreactive properties and cause retinoid dermatitis (Sachs & Voorhees, 2014).

Eucalyptus oil used in dermatological conditions has weak mutagenic effects, dermal absorption is limited and can affect the barrier integrity of the upper skin layers (Carson et al., 2008).

From aromatic oils, antioxidant tea tree oil (weakly genotoxic and fetotoxic) and chamomile oil, used in food, cosmetics, toiletries and over-the-counter medicines, primarily for its aromatic, anti-inflammatory and sedative properties, have side effects of allergic contact or irritant dermatitis and can develop anaphylaxis (Carson et al., 2008; David et al., 2014). Ethyl carbamate, used as a solvent in cosmetic product manufacturing, has been reported to potentially be carcinogenic (Kotsonis & Burdock, 2008). Aliphatic hydrocarbons, lithium carbonate, ammonium, sodium and potassium thioglycollates, metal oxides, butylhydroxyanisole, methyl and propyl paraben, butylhydroxytoluene, organic peroxides, phenacetin, phenolphthalein, polyethylene glycol, cetyl alcohol, potassium dichromate, propylene glycol, quaternary ammonium salts, formaldehyde, sodium lauryl sulfate and other surfactants, and chemicals such as lead acetate are reported to carry risks when used in personal care and cosmetic products (Zeliger, 2011). In recent years, the number of reports on nanoparticles, which have started to be used in cosmetics and personal care products due to their high physicochemical properties, having extraordinarily large relative surface area and surface reactivity and potentially higher toxic effect potential than macro structures has been increasing daily (Miller, 2006; Kimbrell, 2007; Khanna et al., 2015; Viswanath & Kim, 2017). As particles partially decrease in size, the surface area/volume ratio increases, and the greater the surface area/volume ratio, the higher the chemical reactivity and potentially biological activity of a substance. Carbon fullerenes used in face creams and moisturizers, carbon nanotubes, and nanoparticulate metal oxides (titanium dioxide, zinc oxide) used in sunscreen, cosmetics and personal care products have caused greater chemical reactions and increased the production of reactive oxygen species (ROS) including free radicals that cause oxidative stress, inflammation and subsequently damage to proteins, membranes and DNA (Kimbrell, 2007; Viswanath & Kim, 2017).

The use of numerous chemicals and their increasing use day by day create risks to human and environmental health, making it imperative that toxicity evaluation of cosmetics be carried out in considerable detail and within a specific systematic framework.

With Directive 2003/15/EC, which is the 7th amendment to the EU Cosmetic Products Directive, animal testing has been prohibited since 27 February 2003, and toxicity evaluation of cosmetics is only possible through the use of alternative methods accepted by international organizations, primarily OECD guidelines, and through the use of very comprehensive and high-quality databases (Schäfer-Korting & Schreiber, 2008; Organisation for Economic Cooperation and Development (OECD), 2017). In November 2006, the Council of Ministers of the European Council adopted a decision on the cosmetovigilance system for monitoring undesirable effects of cosmetic products in Europe. This decision was taken to establish procedures for monitoring undesirable effects resulting from cosmetic products, assessing public health risks and taking corrective measures (Moretti & Velo, 2008). Cosmetovigilance is a public health monitoring procedure whose scope covers cosmetic products and targets public health. Cosmetovigilance addresses concerns related to products on the market by ensuring elimination or control of potentially hazardous substances (Vigan & Castelain, 2014). In Turkey, cosmetovigilance is conducted by the Medicines and Medical Devices Authority (Turkish Medicines and Medical Devices Authority (TİTCK), n.d.). In conclusion, considering the toxicological effects of cosmetics, which have simpler legal procedures than drugs, taking necessary measures and tightening controls is important for human health. For every preparation applied to the skin, including cosmetics, both systemic and local toxicological effects must be clarified. Acknowledgment: I would like to thank Prof. Dr. Gül Özhan, faculty member of Istanbul University Faculty of Pharmacy, for her support.   Tox. Pharm. Dr. Yağmur Emre Arıcan Istanbul University Faculty of Pharmacy Department of Pharmaceutical Toxicology