The aim of this paper was to investigate the current status of read-across approaches in the Republic of Korea, Japan, and China in terms of applications and regulatory acceptance. In the Republic of Korea, over the last 6 years, approximately 8% of safety data records used for chemical registrations were based upon read-across, and a guideline published on the use of read-across results in 2017. In Japan, read-across is generally accepted for screening hazard classification of toxicological endpoints according to the Chemical Substances Control Law (CSCL). In China, read-across data, along with data from other animal alternatives are accepted as a data source for chemical registrations, but could be only considered when testing is not technically feasible. At present, read-across is not widely used for chemical registrations and regulatory acceptance of read-across may differ among countries in Asia. With consideration of the advantages and limitations of read-across, it is expected that read-across may soon gradually be employed in Asian countries. Thus, regulatory agencies need to prepare for this progression.

The labeling of all ingredients contained in consumer products has been requested by consumers concerned regarding their safety. Consequently, regulatory agencies have set guidelines for industries on how to provide safety information regarding the ingredients in their products. However, discordant opinions were raised from stakeholders, resulting in the formation of a risk communication forum among industries, regulatory agencies, consumer groups, and academia. There are several methods that might be utilized to provide ingredient information to consumers: (1) listing all ingredients on the label of products, (2) providing major ingredients on the label of products, (3) presenting all ingredients on the websites of each manufacturer, and (4) listing major ingredients on the label of products and the remainder of ingredients (not on the label) on the websites. Each method might have its own advantages and disadvantages with respect to providing the information regarding the names of the ingredients used in consumer products to the consumers. A continuous risk communication forum might be an effective tool to facilitate an improved understanding of chemical information, toxicological science, regulatory guidelines, labeling methods, and consumers' concern. This study suggests that risk communication efforts may be helpful and a good opportunity for stakeholders to exchange opinions and reach a harmonious conclusion on labeling of consumer products ingredients.

Detoxifying effects of hyperoxia, which is widely used in clinical practice, were investigated using HaCat cells (human keratinocytes) treated with benzo[a]pyrene (B[a]P) as a model agent to induce adverse effects in the skin. It is well-established that B[a]P may produce toxicities including cancer, endocrine disruption, and phototoxicity involving DNA damage, free radical generation, and down regulation of nuclear factor erythroid 2-related factor 2 (Nrf2). It is well-known that Nrf2 is associated increase of antioxidant enzyme catalase (CAT) or detoxification enzyme glutathione S-transferase (GST) in HaCat cells treated with B[a]P under optimal condition of hyperoxia (40% oxygenation) conditions. To further examine the underlying basis of this phenomenon, factors affecting the expression of Nrf2 were determined. Nrf2 was upregulated accompanied by a rise in p38 MAPK, sequestosome-1 (also known as p62) and NF-κB. In contrast, Nrf2 was downregulated associated with an elevation in glycogen synthase kinase 3 beta (GSK-3β) and peroxisome proliferator-activated receptor alpha (PPARα). Hyperoxia was also found to diminish DNA damage and generation of free radicals initiated in B[a]P-treated cells which was attributed to an significant rise of Nrf2, leading to elevated antioxidant activities or detoxification proteins including heme oxygenase 1 (HO-1), superoxide dismutase (SOD), glutathione peroxidase-1/2 (GPX-1/2), CAT, GST and glutathione (GSH). In addition, factors related to skin aging were also altered by hyperoxia. Data suggest that optimal hyperoxia exposure of 40% oxygenation may reduce cellular toxicity induced by B[a]P in HaCat cells as evidenced by inhibition of DNA damage, free radical generation, and down-regulation of Nrf2.

A risk assessment was performed for three types of phthalates, benzyl butyl phthalate (BBP), dibutyl phthalate (DBP), and di(2-ethylhexyl)phthalate (DEHP) unintentionally contaminated in cosmetics. A total of 100 products of 8 types of cosmetics were analyzed employing gas chromatography-mass spectrometry (GC-MS). By applying the maximum detected values of phthalates based on the worst exposure cases, their systemic exposure dosage (SED) was calculated. Accordingly, DEHP was identified as the main unintentional phthalates contaminants (0.10-600.00 ppm) in the cosmetics, with an SED of 3.37 x 10(-9) -3.75 x 10(-4) mg/kg/day. In the non-cancer risk assessment, a margin of safety (MOS >= 100, safe) of 1.28 x 10(4)-1.42 x 10(9) was estimated. In the cancer risk assessment, the lifetime cancer risk (LCR <= 10(-5), safe) was determined to be 8.81 x 10(-12) -9.79 x 10(-7). Based on the results of both risk assessments, the levels of unintentional phthalates contaminants in cosmetics were deemed safe. Some phthalates are widely used as plasticizers and are essential for daily life; however, various toxicities, including endocrine disruption, have been reported. Therefore, even under these "worst case" assumptions, an adequate margin of safety is shown such that this might be a low priority for further work although exposure to unintentional phthalates contaminants through cosmetics should be considered as part of cumulative exposure.

As the use of cosmetics has greatly increased in a daily life, safety issues with cosmetic ingredients have drawn an attention. Drometrizole [2-(2′-hydroxy-5′-methylphenyl)benzotriazole] is categorized as a sunscreen ingredient and is used in cosmetics and non-cosmetics as a UV light absorber. No significant toxicity has been observed in acute oral, inhalation, or dermal toxicity studies. In a 13-week oral toxicity study in beagle dogs, No observed adverse effect level (NOAEL) was determined as 31.75 mg/kg bw/day in males and 34.6 mg/kg bw/day in females, based on increased serum alanine aminotransferase activity. Although drometrizole was negative for skin sensitization in two Magnusson-Kligman maximization tests in guinea pigs, there were two case reports of consumers presenting with allergic contact dermatitis. Drometrizole showed no teratogenicity in reproductive and developmental toxicity studies in which rats and mice were treated for 6 to 15 days of the gestation period. Ames tests showed that drometrizole was not mutagenic. A long-term carcinogenicity study using mice and rats showed no significant carcinogenic effect. A nail product containing 0.03% drometrizole was nonirritating, non-sensitizing and non-photosensitizing in a test with 147 human subjects. For risk assessment, the NOAEL chosen was 31.75 mg/kg bw/day in a 13-week oral toxicity study. Systemic exposure dosages were 0.27228 mg/kg bw/day and 1.90598 mg/kg bw/ day for 1% and 7% drometrizole in cosmetics, respectively. Risk characterization studies demonstrated that when cosmetic products contain 1.0% of drometrizole, the margin of safety was greater than 100. Based on the risk assessment data, the MFDS revised the regulatory concentration of drometrizole from 7% to 1% in 2015. Under current regulation, drometrizole is considered to be safe for use in cosmetics. If new toxicological data are obtained in the future, the risk assessment should be carried out to update the appropriate guidelines.

As the use of cosmetics has greatly increased in a daily life, safety issues with cosmetic ingredients have drawn an attention. Drometrizole [2-(2'-hydroxy-5'-methylphenyl)benzotriazole] is categorized as a sunscreen ingredient and is used in cosmetics and non-cosmetics as a UV light absorber. No significant toxicity has been observed in acute oral, inhalation, or dermal toxicity studies. In a 13-week oral toxicity study in beagle dogs, No observed adverse effect level (NOAEL) was determined as 31.75 mg/kg bw/day in males and 34.6 mg/kg bw/day in females, based on increased serum alanine aminotransferase activity. Although drometrizole was negative for skin sensitization in two Magnusson-Kligman maximization tests in guinea pigs, there were two case reports of consumers presenting with allergic contact dermatitis. Drometrizole showed no teratogenicity in reproductive and developmental toxicity studies in which rats and mice were treated for 6 to 15 days of the gestation period. Ames tests showed that drometrizole was not mutagenic. A long-term carcinogenicity study using mice and rats showed no significant carcinogenic effect. A nail product containing 0.03% drometrizole was nonirritating, non-sensitizing and non-photosensitizing in a test with 147 human subjects. For risk assessment, the NOAEL chosen was 31.75 mg/kg bw/day in a 13-week oral toxicity study. Systemic exposure dosages were 0.27228 mg/kg bw/day and 1.90598 mg/kg bw/day for 1% and 7% drometrizole in cosmetics, respectively. Risk characterization studies demonstrated that when cosmetic products contain 1.0% of drometrizole, the margin of safety was greater than 100. Based on the risk assessment data, the MFDS revised the regulatory concentration of drometrizole from 7% to 1% in 2015. Under current regulation, drometrizole is considered to be safe for use in cosmetics. If new toxicological data are obtained in the future, the risk assessment should be carried out to update the appropriate guidelines.

Phthalates are used for industrial plasticizers to impart flexibility and durability to polyvinyl chloride. Despite widespread use of phthalates, reported endocrine-disrupting properties raise safety concerns for consumers. Since phthalates are permitted as excipients in controlled-release capsules and enteric coatings, patients taking drugs containing these chemicals may potentially be at some health risk. In this study, 102 distinct pharmaceutical products were analyzed by gas chromatography/mass spectrometry to determine phthalate content and maximal phthalate exposure rate was calculated. In 102 drug samples, di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and diethyl phthalate (DEP) were detected in 9.8, 27.45, and 5.88% of cases, respectively. The highest level of DEP was found in extended-release (ER) capsules with concentrations ranging from 935.5 to 1535.37 ppb. The highest levels of DBP (1.32-7.07 ppb) were detected in tablets, whereas highest level (7.07 ppb) of DEHP was found in suspension preparations. The phthalate hazard index (HI) (human exposure tolerable daily intake) was calculated for each sample, but no sample exhibited an HI value exceeding 1; the minimum value taken to indicate a serious health risk. Thus, no apparent serious health risk from phthalate exposure arises from taking these medications. The low HI values suggest that phthalate contamination in pharmaceuticals may not pose an apparent significant risk to humans. However, the sources of phthalate present in pharmaceutical products still needs to be investigated and verified through on-site inspections in manufacturing processes in order to minimize human exposure. It is recommended that measures be taken to prevent phthalate contamination in pharmaceuticals.

BACKGROUND/AIM:The study focused on identifying the mechanisms or drugs that might sensitize resistant KBV20C human oral squamous carcinoma cells overexpressing P-glycoprotein (P-gp) to antimitotic drug treatment.MATERIALS AND METHODS:Five HIV protease inhibitors (atazanavir, nelfinavir, darunavir, lopinavir, and ritonavir) were tested to identify drugs that could be used at a relatively low dose for sensitizing antimitotic drug-resistant KBV20C cells. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action.RESULTS:Co-treatment with nelfinavir or lopinavir had a high sensitizing effect on vincristine-treated KBV20C cells. Nelfinavir and lopinavir reduced cell viability, increased G2 phase arrest, and up-regulated apoptosis when used as a co-treatment with vincristine. We also demonstrated that eribulin co-treatment with nelfinavir and lopinavir similarly increased sensitization of KBV20C cells. Only lopinavir was found to have a high P-gp-inhibitory activity (similar to verapamil). Interestingly, nelfinavir had very low P-gp-inhibitory activity, suggesting that vincristine-nelfinavir sensitization is independent of the P-gp-inhibitory effect of nelfinavir. We also demonstrated this same combination mainly caused sensitization due to late apoptosis in P-gp-overexpressing drug-resistant KBV20C cells.CONCLUSION:Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repositioned HIV protease inhibitors nelfinavir and lopinavir. In particular, the sensitizing effect of co-treatment with nelfinavir on antimitotic drug-resistant cancer cells was found to be strong and independent of P-gp-inhibitory activity. As P-gp inhibition can be toxic to normal cells, selecting nelfinavir may be safer for normal cells in patients with drug-resistant cancer.

Frequent air travelers and airplane pilots may develop various types of illnesses. The environmental risk factors associated with air travel syndromes (ATS) or air travel-related adverse health outcomes raised concerns and need to be assessed in the context of risk management and public health. Accordingly, the aim of the present review was to determine ATS, risk factors, and mechanisms underlying ATS using scientific data and information obtained from Medline, Toxline, and regulatory agencies. Additional information was also extracted from websites of organizations, such as the International Air Transport Association (IATA), International Association for Medical Assistance to Travelers (IAMAT), and International Civil Aviation Organization (ICAO). Air travelers are known to be exposed to environmental risk factors, including circadian rhythm disruption, poor cabin air quality, mental stress, high altitude conditions, hormonal dysregulation, physical inactivity, fatigue, biological infections, and alcoholic beverage consumption. Consequences of ATS attributed to air travel include sleep disturbances (e.g., insomnia), mental/physical stress, gastrointestinal disorders, respiratory diseases, circulatory-related dysfunction, such as cardiac arrest and thrombosis and, at worst, mechanical and terrorism-related airplane crashes. Thus safety measures in the cabin before or after takeoff are undertaken to prevent illnesses or accidents related to flight. In addition, airport quarantine systems are strongly recommended to prepare for any ultimate adverse circumstances. Routine monitoring of environmental risk factors also needs to be considered. Frequently, the mechanisms underlying these adverse manifestations involve free radical generation. Therefore, antioxidant supplementation may help to reduce or prevent adverse outcomes by mitigating health risk factors associated with free radical generation.

The International Association of Environmental Mutagenesis and Genomics Societies (IAEMGS) is a global organization that promotes applied and basic research on environmental mutagenesis and genomics. IAEMGS is composed of 13 national and regional societies of environmental mutagenesis and genomics and the total membership is approximately 4000. IAEMGS convenes the general assembly every four years during each International Conference on Environmental Mutagens (ICEM) for communication among members of participating societies and discussion on future directions. The latest general assembly was held during the 12th ICEM/5th Asian Conference on Environmental Mutagens (ACEM) in November 2017 in Incheon, Korea. This report summarizes the topics and discussions in the general assembly.

The endocrine disrupting actions of di(2-ethylhexyl) phthalate (DEHP) on testicular functions are postulated to involve excess free radical generation. Thus the aim of this study was to examine the ability of antioxidant vitamins C and E to prevent DEHP-induced testicular disruption in male Sprague-Dawley (SD) rats. SD male rats were administered DEHP alone or DEHP with vitamin C and/or vitamin E for 30days. DEHP alone increased the levels of testosterone (T) and reduced estradiol (E-2) concentrations. Supplementation with antioxidant vitamins diminished or restored serum T levels noted in DEHP-treated rats to control values. In contrast vitamins C and E increased E-2 levels to control in rats administered DEHP. Antioxidants significantly improved the decreased testicular levels of reduced glutathione and activity of superoxide dismutase compared to DEHP-treatment alone. Co-treatment of vitamins C and E also markedly improved the reduced epididymal sperm head counts and elevated levels of malondialdehyde (MDA) or 8-hydroxydeoxyguanosine (8-OHdG) induced by DEHP treatment. These results support the concept that the adverse actions of DEHP may be related to increased free radical generation while co-treatment with vitamins C and E significantly blocked the actions of DEHP on male testicular functions.

Risk assessment and hormone evaluation were carried out for di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP), endocrine disrupting chemicals (EDCs), in 302 Korean children (n = 223) and adolescents (n = 79) (< age 19). Urinary and serum concentrations of DEHP, MEHP (mono(2-ethylhexyl) phthalate), DBP, MBP (monobutyl phthalate), and PA (phthalic acid, a common final metabolite of phthalates) were detected in children and adolescents. Daily exposure levels were estimated to be 16.45 ± 36.50 μg/kg b.w./day for DEHP, which is one-third of the tolerable daily intake (TDI) value (50 μg/kg b.w./day), but 14 out of 302 participants had a hazard index (HI = intake/TDI) value >1. The mean daily exposure level of DBP was 1.23 ± 1.45 μg/kg b.w./day, which is one-eighth of the TDI value (10 μg/kg b.w./day), but 1 out of 302 participants had a HI value > 1. Positive correlations were observed between serum DBP or MEHP, and serum estradiol (E2) and/or luteinizing hormone (LH) in prepubescent children. In addition, serum MBP levels were found to be negatively correlated with serum triiodothyronine (T3) or thyroxine (T4) in male participants, and serum DEHP levels with serum thyroid stimulating hormone (TSH) in female adolescents. Low-density lipoprotein (LDL) levels were positively correlated with serum PA levels in children and adolescents. DEHP, DBP or its metabolites may be associated with altered hormone levels in children and adolescents. Data suggest that exposure levels of DEHP and DBP in Korean children need to be reduced to levels below TDI to protect them from EDC-mediated toxicities. Abbreviations: DBP: dibutyl phthalate; DEHP: di(2-ethylhexyl) phthalate; E2: estradiol; EDC: endocrine disrupting chemical; EFSA: European Food Safety Authority; FSH: follicle stimulating hormone; HDL: high density lipoprotein; HI: hazard index; LDL: low density lipoprotein; LH: luteinizing hormone; MEHP: mono(2-ethylhexyl) phthalate; MBP: monobutyl phthalate; PA: phthalic acid; PPAR: peroxisome proliferator-activated receptor gamma; PVC: polyvinyl chloride; T3: triiodothyronine; T4: thyroxine; TDI: tolerable daily intake; TG: triglyceride; TSH: thyroid stimulating hormone; UPLC/MS/MS: Ultra Performance Liquid Chromatography/Tandem Mass Spectrometry; WWF: World Wildlife Fund.

A risk assessment of benzalkonium chloride (BAC) was conducted based upon its toxicological profile and exposure evaluation. Since 1935, BAC has been used in a wide variety of products such as disinfectants, preservatives, and sanitizers. It is well-established that BAC is not genotoxic nor does it display tumorigenic potential, but safety concerns have been raised in local usage such as for ocular and intranasal applications. The Foundation of Korea Cosmetic Industry Institute (KCII) reported that in a hair conditioner manufactured as a cosmetic or personal product in South Korea, BAC was present at concentrations of 0.5-2%. The systemic exposure dosage (SED) was determined using the above in-use concentrations and a risk assessment analysis was conducted. The Margin of Safety (MOS) values for hair conditioners were calculated to be between 621 and 2,483. The risk of certain personal and cosmetic products was also assessed based upon assumptions that BAC was present at the maximal level of regulation in South Korea and that the maximal amount was used. The MOS values for the body lotion were all above 100, regardless of the application site. Collectively, data indicate that there are no safety concerns regarding use of products that contain BAC under the current concentration restrictions, even when utilized at maximal permitted levels. However, a chronic dermal toxicity study on BAC and comprehensive dermal absorption evaluation needs to be conducted to provide a more accurate prediction of the potential health risks to humans.

The detoxifying effect of pyridoxine against acetaminophen (APAP)-induced hepatotoxicity was investigated. HepG2 cells were co-treated with APAP and pyridoxine to compare with betaine or methionine for 24 h. LDH, ALT and AST activities were measured to determine direct cells damage in vitro and in vivo. Lipid peroxidation, antioxidant enzymes activity, and glutathione level were measured. Cytochrome c releaseand procaspase-3, cleaved caspase-3, Bcl-2, or Bax protein levels were measured to determine APAP-induced apoptotic cell death. Pyridoxine treatment significantly increased cell viability and decreased leakage of LDH activity against APAP-induced hepatotoxicity in HepG2 cells. ALT and AST activities were dose-dependently reduced by pyridoxine treatment compared to APAP-treated group. Significant increases in activities of GST and GPx were observed after co-treatment with APAP and pyridoxine. Although APAP-induced Nrf2 and HO-1 expression levels were gradually reduced in HepG2 cells by pyridoxine treatment, induction of antioxidant enzymes activities were dose-dependently increased. These protected effects of pyridoxine against APAP-induced hepatoxicity were closely associated with suppression of APAP-induced oxidative stress and apoptotic cell death in HepG2 cells. These data indicated that the protective action of pyridoxine against hepatic cell injuries was involved in the direct antioxidant activity which provides a pivotal mechanism for its potential hepatoprotective action.

Certain cosmetic colorants are irritant to skin or aggravate dermatitis. Thymic stromal lymphopoietin (TSLP) plays an important role in the initiation and progress of skin inflammation and atopic dermatitis by triggering Th2 immune responses. However, the effects of cosmetic colorants on TSLP production are unknown yet. Therefore, we investigated whether cosmetic colorants regulated TSLP production and dermatitis. Lithol Rubine B (LR-B, Pigment Red 57) and its calcium salt (LR-BCA), commonly used cosmetic colorants, potentiated phorbol-12-myristate-13-acetate-induced TSLP production in keratinocytes. In addition, the topical exposure to LR-B or LR-BCA on mouse ear upregulated a TSLP inducer (MC903)-induced TSLP production and Th2 cytokine expression. Dermatitis symptoms and serum IgE and histamine levels were also aggravated by LR-B or LR-BCA, implicating the role of increased TSLP expression in acute dermatitis. LR-B or LR-BCA induced IκBα degradation and NF-κB activation in keratinocytes, leading to TSLP expression. Collectively, our results demonstrate that LR-B and LR-BCA increase TSLP expression and Th2 immune responses, thereby aggravating acute dermatitis in the compromised skin. The results further suggest that certain cosmetic colorants such as LR-B may aggravate dermatitis under pro-inflammatory conditions by upregulating TSLP production.

Background/Aim: The study focused on identifying the mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to halaven (HAL) or vincristine (VIC) treatment. Materials and Methods: Based on the relatively low dose or IC50 values for sensitizing anti-mitotic drug-resistant KBV20C cells, the aging-related drugs donepezil (DON) and sildenafil citrate (SID) were selected. Fluorescence-activated cell sorting (FACS), western blotting, and annexin V analyses were performed to investigate the mechanism of action of DON and SID in HAL-treated KBV20C cells. Results: DON or SID reduced cell viability, increased G2 arrest, and up-regulated the expression of the DNA damaging protein pH2AX when used as co-treatment with HAL. DON and SID induced both early and late apoptosis in KBV20C cells in response to HAL treatment, without increasing autophagy. VIC-DON and VIC-SID co-treatments increased sensitization of KBV20C cells, suggesting that DON and SID can be combined with other anti-mitotic drugs for sensitizing resistant cancer cells. When the sensitization efficacies of DON and SID were compared to that of the anti-psychotic repositioned drug fluphenazine (FLU), HAL-SID or HAL-FLU co-treatments were found to have better sensitization effects than HAL-DON suggesting that HAL-SID sensitization mechanism is different from that of HAL-DON. In addition, DON was found to have higher P-gp inhibitory activity than FLU or SID. Conclusion: These results suggest that HAL-FLU or HAL-SID sensitization in KBV20C cells involves both cytotoxic and P-gp inhibitory effects, whereas HAL-DON sensitization may involve only P-gp inhibitory activity of DON.

Many chemicals, including endocrine disruptors, are known to produce various toxicities such as developmental or reproductive toxicity, carcinogenicity, mutagenicity, immunotoxicity and neurotoxicity; this chapter discusses mutagenicity and carcinogenicity. Mechanisms of carcinogenesis due to exposure to endocrine disruptors may be associated with free radical generation and biomolecule (e.g., DNA, protein, lipid) damage after the dysregulation of hormones such as estrogen, testosterone, thyroid and insulin. Each subtype of ovarian carcinoma has different clinical characteristics, biological behaviors and responses to chemotherapy. Endometriosis is an estrogen-dependent disease characterized by the presence of endometrial glands and stroma outside the uterine cavity. It is a common gynecological disorder as well as a major cause of infertility. It also addresses vaginal cancer, testicular cancer and prostate cancer. The fact that epigenetic mechanisms may play a role in endocrine disruption helps to explain the transgenerational effects of chemicals. The epigenetic mechanism involves the alteration of DNA in the germ line that appears to transmit transgenerational adult-onset disease, including spermatogenic defects, prostate disease, kidney disease and cancer. Mechanisms of carcinogenesis due to exposure to endocrine disruptors may be associated with free radical generation and biomolecule (e.g., DNA, protein, lipid) damage after the dysregulation of hormones such as estrogen, testosterone, thyroid and insulin.

Ceramide 3 is used mainly as a moisturizer in various cosmetic products. Although several safety studies on formulations containing pseudo-ceramide or ceramide have been conducted at the preclinical and clinical levels for regulatory approval, no studies have evaluated the systemic toxicity of ceramide 3. To address this issue, we conducted a risk assessment and comprehensive toxicological review of ceramide and pseudo-ceramide. We assumed that ceramide 3 is present in various personal and cosmetic products at concentrations of 0.5–10%. Based on previously reported exposure data, the margin of safety (MOS) was calculated for product type, use pattern, and ceramide 3 concentration. Lipsticks with up to 10% ceramide 3 (MOS = 4111) are considered safe, while shampoos containing 0.5% ceramide 3 (MOS = 148) are known to be safe. Reported MOS values for body lotion applied to the hands (1% ceramide 3) and back (5% ceramide 3) were 103 and 168, respectively. We anticipate that face cream would be safe up to a ceramide 3 concentration of 3% (MOS = 149). Collectively, the MOS approach indicated no safety concerns for cosmetic products containing less than 1% ceramide 3.