Ascorbic acid (AsA) has multifunctional effects on skin beauty regarding the prevention and improvement of pigmentation and wrinkles. However, AsA not only has poor stability both in aqueous solutions and in cosmetic formulations, but it also influences the stabilities of formulations. To express the efficacy of AsA in/on the skin, it is important to develop a novel AsA derivative which overcomes those disadvantages. We synthesized 3-O-glyceryl ascorbate (3GA) by introducing a glycerol group into the C-3 position of AsA. 3GA has high stability in formulations. We then investigated the chemical and biological effects of 3GA. 3GA has a scavenging ability against various reactive oxygen species (ROS) assessed by the ESR spin-trapping method. HaCaT keratinocytes pretreated with 3GA have suppressed intracellular ROS levels both under physiological conditions and following exposure to H₂O₂ or UVB. In addition, HaCaT cells pretreated with 3GA were protected from cell damage induced by H₂O₂, UVB and ONOO^-. In reconstructed human epidermal equivalents, topical application of 3GA markedly reduced the generation of intracellular ROS after UVB irradiation. Taken together, 3GA is an effective AsA derivative that is stratum corneum permeable, does not interfere with the stability of cosmetic formulations, and is able to reduce intracellular ROS levels caused by oxidative stress.

Neuregulin 1 (NRG1), one of neurotrophic factors, plays an important role in the differentiation and development of nerve cells and glia cells. Recently, it was reported that NRG1 is expressed in dermal fibroblasts and regulates the constitutive color of human skin. Furthermore, effects of NRG1 on the melanogenesis in melanocytes became apparent. In this study, the relationship between skin pigmentation induced by UV rays and NRG1 was investigated. It is known that reactive oxygen species (ROS) are generated in UV-irradiated skin and enhance the melanogenesis. H₂O₂, one of ROS, exposure enhanced NRG1 expression on mRNA and protein level in dermal fibroblasts. Although culture supernatant of H₂O₂ exposed fibroblasts upregulated mRNA expression of melanogenesis related-factors in melanocytes, these changes were suppressed by NRG1 neutralizing antibody. Moreover, NRG1 exposure increased mRNA expression of melanogenesis related-factors in melanocytes. On the basis of these results, it was considered that ROS induced by UV rays enhance NRG1 production in dermal fibroblasts and this NRG1 upregulates melanogenesis in melanocytes and consequently induces skin pigmentation. Although most of the existing studies on the accelerating mechanism of melanogenesis focus on the epidermal-derived factors, NRG1 is produced by dermal fibroblasts and gets involved in melanogenesis. Therefore, NRG1 is considered to be a novel dermal-derived factor inducing skin pigmentation after UV rays exposure.

Recently we have experienced two outbreaks of health hazard from cosmetics that were voluntary recalled. One is an outbreak of immediate wheat allergy due to epicutaneous sensitization to a hydrolyzed wheat protein, contained in a facial soap. A total of 2,111 patients have been registered. Most of the patients are females, and half of them had anaphylaxis after eating wheat. The other is an outbreak of Rhododenol-induced leukoderma, and more than 19,000 patients were reported. Rhododenol is a quasi-drug ingredient for lightening cosmetics, and is a phenol compound. The Patch Test Material Research Committee of the Japanese Society for Dermaoallergology and Contact Dermatitis was set up in 2007, and has been performing two nation-wide studies. One of them is an epidemiological study on allergic contact dermatitis, which was done first as the paper-based case-registration questionnaire study started in 2010. Cosmetics were the most responsible products of allergic contact dermatitis, 67% of all, and the common causative items were hair dyes, skin lotions, and shampoos. The cases from the facial soap containing the hydrolyzed wheat protein and cosmetics for lightening skin including Rhododenol were reported in our study. We have made ‘Skin Safety Case Information Network of Cosmetics and Other Products: SSCI-Net.' The aim of this network is to get real-time information of skin health hazards from cosmetics and decrease the risk and hazard as soon as possible by the industry–academic–government information network.

The skin permeation can explain with Fick's diffusion model. Skin concentration depends on partition coefficient between skin and vehicle and concentration in vehicle. However it is changed with various factors, activity of ingredient in vehicle, effect of other ingredients on skin, the change of formulation after application and so on. Thus, if the same concentration of active ingredient is in the formulation, the skin concentration or skin absorption is not always the same. It is important to know the skin penetration and permeation of cosmetic ingredient for the assessment of not only toxicity but also efficacy.

Animal welfare and EU Cosmetic Directive/Regulation call for the implementation of non-animal test methods for safety assessments of cosmetic ingredients. Thus, the ethical and legislative demands have triggered intense research in the field of alternative methods. A number of scientific innovations have been made to assess skin irritation, eye irritation, and skin sensitization. The aim of this review article is to summarize various promising methods developed.

Recently there were typical reports about the serious side-effect syndromes for the medicated cosmetics in Japan. One side-effect symptom was due to medicated soap with the hydrolyzed wheat powder so-called as “Cha No Sizuku Sekken.” This symptom was called as the food-dependent exercise-induced anaphylaxis (FDEIA). Another side-effect symptom was caused to rododendrol (4-(4-hydroxyphenyl)-2-bunanol, HPBol) as the whitening agent. HPBol happened the serious side-effect of vitiligo against many users. In this report, I explain to describe the position of quasi drugs in Japan and to make clear to both the distribution of molecular weight about the hydrolyzed wheat powder described by Dr. Yoshiaki Ikarashi and the cause of giving the side-effect of rododendrol described by Takumi Akiyama.