JOURNAL OF COSMETIC SCIENCE 90 INTRODUCTION Sensitive skin is prevalent among consumers. In surveys in the United States, Europe, and Asia, almost half of people reported having sensitive skin (1–4). The symptoms of sensitivity are varied, including stinging, redness, roughness, scaling, and itching (5–8). Certainly, direct contact to skin irritants can trigger sensitivity responses. Also, airborne materials such as smoke and chemicals can become trapped in fabrics and, thus, elicit skin responses when the fabrics contact the skin (9–12). Thus, frequent cleaning of clothes is important to dramatically reduce exposure of the skin to these irritating materials (9–11). Although clean clothes are important to help avoid skin sensitivity issues from environ- mental irritants, indirect exposure through detergent residues on fabrics may also con- tribute to the problem (5,13). In addition, extensive direct exposure to detergent may occur during hand-laundering, and during prewashing and pretreating of fabrics before using a commercial washing machine. Ingredients such as dyes and perfumes are fre- quently reported triggers of sensitive skin, and as such, several commercially available laundry detergents designed for sensitive skin (known as “free detergents”) are formu- lated without these ingredients. Notably, 80% and 97% of dermatologists in the United States and Canada, respectively, recommend the use of free detergents to their patients with sensitive skin. (US data are based on IQVIA (Durham, NC) ProVoice January 2018 cumulative 12-mo data. Canadian data are based on an Internet survey conducted in January 2018 of 150 dermatologists licensed to practice in Canada.) Although out- right contact dermatitis from laundry detergents is a rare event, occurring in less than 1% of sensitive-skin patients (14,15), it is still important to understand the potential for irritation from detergent products because these products do come into direct and indirect contact with the skin. Although there are many methods to evaluate detergent effects on the skin, from simple laboratory tests to in vitro evaluations such as cell culture, the most relevant to real-world skin responses are observations in controlled clinical studies (5). Recently published work (16,17) proposes using a specifi c set of in vitro methods (zein protein denaturation test, cell culture cytokine release test, and corneosurfametry measure of protein and lipid deg- radation) as suffi cient to assess product mildness of laundry detergents designed for sensi- tive skin. By contrast, in this report, we describe clinical mildness comparisons of direct and indirect exposure to the two U.S. market-leading, commercially available free laun- dry detergents, both of which are designed for sensitive skin and which have markedly different pH values. (U.S. market leadership is based on 2017 retail sales, Nielsen laun- dry detergent category.) Both products are formulated as liquid detergents and as laundry detergent pacs encased in a dissolvable membrane. We conducted two clinical studies: one a mini-immersion, repeat insult test modeling direct exposure to the skin during hand-laundering of garments using dilutions of the liquid formulations of the two deter- gents and the other a patch test modeling prolonged exposure to detergent residues on fabrics after machine washing using either the liquid or pac formulations of the two de- tergents. Although laundry formulations are complex and many factors and ingredient components can play a role in skin mildness, pH has been cited as a concern for irritation in sensitive-skin individuals (18,19). Therefore, we explored whether pH differences may help explain the skin mildness effects observed in the clinical studies by analyzing the pH and reserve alkalinity of the liquid formulas and the pH of fabrics washed with the liquid formulas.

MILDNESS OF LAUNDRY DETERGENTS DIFFERING IN pH 91 MATERIALS AND METHODS CHEMICALS Commercial laundry detergents All Free Clear® (AFC), All Free Clear Mighty Pacs® (AFCMP), Tide Free and Gentle® (TFG), and Tide Pods Free and Gentle® (TPFG) were purchased at a U.S. retail outlet in the United States in 2017. Tide® and All® are manufac- tured by the Procter & Gamble Company (P&G, Cincinnati, OH) and Sun Products Corp. (Wilton, CT), respectively. Active Wheel® (AW Hindustan Unilever Ltd., Mumbai, India) was purchased in India in 2017. Ivory Bar® soap (IB P&G) was purchased at a U.S. retail outlet in 2017. ReagentPlus® (≥98.5%) grade sodium lauryl sulfate (SLS which is also known as sodium dodecyl sulfate) was manufactured by, and purchased from Sigma Chemical Com- pany (St. Louis, MO). All other chemicals were United States Pharmacopeia (USP) grade. CLINICAL STUDY METHODS Protocols for the two randomized (right–left and site), balanced, double-blind arm studies described in the following paragraphs were reviewed and approved by independent insti- tutional review boards. The studies were supervised by an independent dermatologist, and were monitored by P&G personnel to ensure that they were conducted in compliance with the protocol and with Good Clinical Practices as specifi ed under 21 Code of Federal Regulations (CFR) 321.66. Before participating in the studies, each subject signed a written informed consent that contained all the basic elements outlined in 21 CFR 50.25. REPEAT INSULT FOREARM TEST (RIFT) This mini-immersion, repeat insult method is a 1-d study modeling the skin effects of exposure to detergents during hand-laundering. It was conducted in Beijing, China, in August of 2017. For the study, 80 female subjects (ages 20–45 years) in general good health with self-described sensitive skin were recruited, and all of them completed the study without adverse events. The subjects were instructed to not use lotions or cosmetic products on their forearms for 3 d before the start of the study and for the duration of the test. During that time, they were provided with commercial IB soap for washing and bathing. They were also instructed not to expose their forearms to soap or water in the 3 h before the visit on the day of the study. On the day of the study, subjects were acclimated for at least 15 min under controlled temperature and humidity conditions (21° ± 2°C and 45–55% relative humidity) im- mediately before the start of the study and remained in that environment for the duration of the study (approximately 5 h). After the 15 min of acclimation, visual grading was carried out by two trained graders using grading scales: erythema (0–4 scale) and skin dryness (0–5 scale). Then, noninvasive instrumental measurements were carried out in the following order: corneometry with a Corneometer® CM 825 (Courage and Khazaka Electronic, Cologne, Germany), transepidermal water loss (TEWL) with a Delfi n VapoMeter (Kuopio, Finland), and pH with a Hanna Instruments HI99181 skin pH meter (Woonsocket, RI). These measurements were repeated 40 min after each of the subsequent four expo- sures to test treatments, which was just before the subsequent treatment.