Research

JAMA | Preliminary Communication Effect of Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients A Randomized Clinical Trial

Murali K. Matta, PhD; Robbert Zusterzeel, MD, PhD, MPH; Nageswara R. Pilli, PhD; Vikram Patel, PhD; Donna A. Volpe, PhD; Jeffry Florian, PhD; Luke Oh, PhD; Edward Bashaw, PharmD; Issam Zineh, PharmD, MPH; Carlos Sanabria, MD; Sarah Kemp, RN; Anthony Godfrey, PharmD; Steven Adah, PhD; Sergio Coelho, PhD; Jian Wang, PhD; Lesley-Anne Furlong, MD; Charles Ganley, MD; Theresa Michele, MD; David G. Strauss, MD, PhD

Visual Abstract

IMPORTANCE The US Food and Drug Administration (FDA) has provided guidance that Editorial sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic Supplemental content carcinogenicity and additional developmental and reproductive studies.

OBJECTIVE To determine whether the active ingredients (, , , and ) of 4 commercially available are absorbed into systemic circulation.

DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018.

INTERVENTIONS Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant.

MAIN OUTCOMES AND MEASURES The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule.

RESULTS Among 24 participants randomized (mean age, 35.5 [SD, 10.5] years; 12 [50%] women; 14 [58%] black or African American), 23 (96%) completed the trial. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash (1 participant with each sunscreen).

Geometric Mean Maximum Plasma Concentration, ng/mL (Coefficient of Variation, %) Avobenzone Oxybenzone Octocrylene Ecamsule Spray 1 4.0 (60.9) 209.6 (66.8) 2.9 (102) Not applicable Spray 2 3.4 (77.3) 194.9 (52.4) 7.8 (113.3) Not applicable Lotion 4.3 (46.1) 169.3 (44.5) 5.7 (66.3) Not applicable Cream 1.8 (32.1) Not applicable 5.7 (47.1) 1.5 (166.1)

CONCLUSIONS AND RELEVANCE In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in Author Affiliations: Author plasma concentrations that exceeded the threshold established by the FDA for potentially affiliations are listed at the end of this article. waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of Corresponding Author: David G. sunscreen ingredients supports the need for further studies to determine the clinical Strauss, MD, PhD, Division of Applied significance of these findings. These results do not indicate that individuals should refrain Regulatory Science, Office of Clinical from the use of sunscreen. Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03582215 Drug Administration, 10903 New Hampshire Ave, WO64-2072, JAMA. doi:10.1001/jama.2019.5586 Silver Spring, MD 20993 Published online May 6, 2019. ([email protected]).

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unscreens prevent skin damage by reflecting, absorb- ing, and/or scattering UV radiation and are regulated as Key Points over-the-counter (OTC) drug products in the United S Question What is the maximum plasma concentration of active 1-4 States. For some individuals, sunscreen products may be ap- ingredients of various types of sunscreen formulations under plied in substantial amounts multiple times every day over the maximal use conditions? course of a lifetime as both primary sunscreen products, start- Findings In this randomized clinical trial that included 24 healthy ing from an age of 6 months, and as ingredients in cosmetic participants and application of 4 commercially available sunscreen 5 products. Application to the skin can result in multiple grams formulations, maximum plasma concentrations (geometric mean of sunscreen being applied in a day, even with modest use.5 [coefficient of variation]) for the active ingredient avobenzone Although OTC sunscreen products are widely used, little is were 4.0 (60.9%), 3.4 (77.3%), 4.3 (46.1%), and 1.8 (32.1%) ng/mL known about systemic exposure for most active ingredients.6 for 2 different sprays, a lotion, and a cream, respectively. Understanding the extent of systemic exposure of these prod- Meaning The systemic absorption of sunscreen active ingredients ucts is important, as even a low percentage of systemic ab- supports the need for further studies to determine the clinical sorption (eg, 0.1%) could represent a significant systemic ex- significance of these findings. posure (eg, milligrams of ingredient being systemically absorbed per day).5 The clinical relevance of systemic expo- sure is not well understood. 2, 4, 6, 8, 9, 10, 12, and 14 hours after first sunscreen applica- The US Food and Drug Administration (FDA) guidance tion; day 2: 23, 28, and 33 hours; day 3: 47, 52, and 57 hours; titled “Guidance for Industry: Nonprescription Sunscreen Drug day 4: 71, 73, 74, 76, 78, 81, 82, 84, and 86 hours; day 5: 95 hours; Products Safety and Effectiveness Data” (sunscreen guidance)1 day 6: 120 hours; and day 7: 144 hours). Two milligrams of sun- recommends an assessment of the human systemic absorp- screen per 1 cm2 was applied to 75% of body surface area (area tion of sunscreen ingredients with a maximal usage trial7,8 and outside of normal swimwear; see Pharmacy Manual in Supple- a nonclinical safety assessment including dermal carcinoge- ment 1) 4 times per day for 4 days (at 0, 2, 4, and 6 hours on nicity and embryofetal toxicity. The FDA sunscreen guidance1 day 1; 24, 26, 28, and 30 hours on day 2; 48, 50, 52, and 54 hours and the proposed rule for the OTC sunscreen monograph6 note on day 3; and 72, 74, 76, and 78 hours on day 4; see Pharmacy that some nonclinical toxicology studies (ie, systemic carci- Manual in Supplement 1). This application regimen was cho- nogenicity and additional developmental and reproductive sen because sunscreens are labeled to be applied at least ev- studies) may be waived if results of an adequately conducted ery 2 hours and may be applied for multiple days in a row, such human pharmacokinetic maximal usage trial show a steady as might occur when outside in the sun. Plasma concentra- state blood level less than 0.5 ng/mL and an adequately con- tions of each active ingredient were assessed with validated ducted toxicology assessment does not reveal any potential liquid chromatography with tandem safety concerns.9,10 The objective of the current study was methods11 (eMethods 1-3 in Supplement 2). to determine the systemic exposure of active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) pre- Participants Population sent in 4 commercially available sunscreen products of dif- The study participants were enrolled from July to August 2018. ferent formulation types under maximal usage conditions. Participants were recruited by standard recruiting for a phase 1 healthy volunteer study (ie, email, text, online). Self- identified race/ethnicity was collected in an open-ended for- Methods mat and recorded by clinical staff as a standard component of a clinical trial.12 In addition, Fitzpatrick skin type13 was re- Study Design corded by clinical staff. Key inclusion criteria were ages 18 The study protocol was approved by the FDA Research in Hu- through 60 years with a body mass index of 18.5 to 29.9 man Subjects Committee and the clinical site’s local institu- (calculated as weight in kilograms divided by height in me- tional review board (Advarra [https://www.advarra.com]). All ters squared), negative test results for alcohol and drugs of participants provided written informed consent. The proto- abuse, and no known or suspected allergies or sensitivities to col and statistical analysis plan are available in Supplement 1. any components of the sunscreen formulations (additional de- This was an open-label, randomized, 4-group parallel study tails available in the study protocol in Supplement 1). conducted at a phase 1 clinical pharmacology unit in the United The major exclusion criteria were participants with bro- States to evaluate the effects of multiple applications of 4 dif- ken, irritated, or unhealed skin or active and active ferent topical sunscreen formulations (eTable 1 in Supple- autoimmune disease, anemia, or other chronic condition that ment 2) in healthy adult participants (Table 1;eTable2in affects blood sample collection. Additionally, participants using Supplement 2; deidentified participant data available in Supple- any of the listed sunscreen products or products containing ment 3). Study participants remained in the clinic for up to 7 the listed active ingredients were excluded from enrollment. days and were not exposed to direct sunlight during the study. The study product was weighed in advance and applied by a Randomization qualified study team member. Each group had 6 participants After screening, the 24 participants were randomized to par- (3 men, 3 women) who received a single formulation. Thirty ticipate in 1 of the 4 treatment groups (Figure 1). The random- blood samples were collected over 7 days (day 1: 0, 0.5, 1, 1.5, ization code was generated by a validated database system.

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Randomization was conducted in block sizes of 4 and in- Table 1. Study Participant Demographics and Product Characteristics cluded equal numbers of women and men in each treatment group. This study was unblinded to investigators and partici- Fitzpatrick Participant Age, y Sex BMIa BSA, m2b Skin Typec pants because of the distinct differences between formula- Spray 1 (3% Avobenzone, 6% Oxybenzone, 2.35% Octocrylene, 0% Ecamsule)d tions (ie, spray vs lotion or cream), although participants and S1.1 30 Female 23 1.67 3 investigators did not know which spray or which lotion vs S1.2 27 Male 20.1 1.72 6 cream they received. Allocation concealment was not per- S1.3 58 Male 21.8 1.82 2 formed, and bioanalytical laboratory personnel were not S1.4 47 Female 27.1 1.83 3 blinded to allocation. S1.5 56 Female 23.8 1.91 3 S1.6 39 Male 28.6 2.06 5 Outcomes Mean 42.8 24.1 1.84 The prespecified primary outcome was the maximum plasma Spray 2 (3% Avobenzone, 5% Oxybenzone, 10% Octocrylene, 0% Ecamsule)d concentration of avobenzone over days 1 through 7. Avoben- zone is one of the primary UVA filters in the OTC sunscreen S2.1 46 Female 22.2 1.61 4 monograph,6 and systemic exposure data for this compound S2.2 22 Female 22.7 1.61 5 did not exist. The secondary outcomes were the maximum S2.3 33 Female 22.2 1.65 6 plasma concentrations of oxybenzone, octocrylene, and ecam- S2.4 33 Male 21.4 1.89 5 sule over days 1 through 7. S2.5 26 Male 29 1.98 6 Along with the primary and secondary outcomes, other ex- S2.6 42 Male 26.2 2.06 3 ploratory pharmacokinetic parameters were calculated, in- Mean 33.7 24.0 1.80 cluding time of maximum concentration overall and on days Lotion (3% Avobenzone, 4% Oxybenzone, 6% Octocrylene, 0% Ecamsule)d 1 and 4, area under the curve (AUC) of plasma concentration L.1 31 Female 22.2 1.36 3 vs time overall and on days 1 and 4, trough concentration or L.2 29 Female 26.6 1.65 4 residual concentration each day, and terminal half-life (time L.3 46 Male 23.8 1.83 4 required for active ingredient concentration to decrease by 50% L.4 30 Male 24.1 1.99 5 during the terminal or final decline phase). All adverse events, L.5 40 Female 26.7 2.06 5 whether serious or nonserious and whether related to the study L.6 31 Male 29.1 2.19 4 drug, were recorded by study personnel and adjudicated by Mean 34.5 25.4 1.85 the principal investigator. No adverse events of special inter- Cream (2% Avobenzone, 0% Oxybenzone, 10% Octocrylene, 2% Ecamsule)d est were specified. C.1 51 Female 28.1 1.65 5 Two post hoc assessments were performed. The number C.2 23 Male 23.7 1.85 6 and percentage of participants with plasma concentrations of C.3 24 Male 22.8 1.9 6 active ingredient exceeding 0.5 ng/mL were summarized based C.4 33 Female 27.1 1.91 5 on day-1 observations. In addition, accumulation with repeat C.5 33 Male 29.2 2.06 6 dosing was assessed by the log-transformed ratio of maxi- C.6 23 Female 29.1 2.13 5 mum plasma concentration and AUC on day 4 vs 1. Mean 31.7 26.7 1.92 Statistical Analysis Abbreviations: BMI, body mass index; BSA, body surface area. Because this was an exploratory study to assess general meth- a Calculated as weight in kilograms divided by height in meters squared. odology for a sunscreen maximal usage trial and no prior data b Calculated using the Mosteller formula: BSA = [height × weight/3600]1/2, 2 existed on the systemic absorption of avobenzone, the sample where BSA is expressed in m , height in cm, and weight in kg. c size was determined empirically with reference to the sun- Fitzpatrick Skin Type score was self-assessed by adding up the score for 7 genetic disposition, reaction to sun exposure, and tanning habits. Summed screen guidance recommendation for pilot studies. Data are scores from 0 to 7 indicate type 1; scores from 8 to 16, type 2; scores from 17 to reported with standard descriptive statistics for all demo- 25, type 3; scores from 25 to 30, type 4; scores greater than 30, type 5 or 6. graphics (arithmetic means) and pharmacokinetic para- d Maximum allowed on US market is 3% avobenzone, 6% oxybenzone, 10% meters (geometric mean, coefficient of variation, confidence octocrylene, and 2% ecamsule. See eTable 1 in Supplement 2 for a complete list of ingredients. intervals, minimum, and maximum). Terminal half-life is re- ported only for participants with 3 or more concentration val- ues in the terminal portion of the curve and an adjusted coef- ratio; 90% CIs were chosen because they are standard in phar- ficient of determination (R2) greater than 0.70. macokinetic studies.14,15 Exposures on day 4 vs day 1 were con- In post hoc analyses, accumulation with repeat dosing was sidered not significantly different if the lower bound of the 90% assessed by log-transforming AUC and maximum plasma con- CI for all exposure metrics included 1. centration from day 1 and 4 for each product and active ingre- Plasma concentrations below the limit of quantitation were dient. Data were analyzed using a linear-mixed effects model assigned as zero during calculation of pharmacokinetic para- with fixed effects for day (day 4 vs day 1) and random effects meters. No adjustments for multiplicity were made in the sta- for participant. Point estimates and corresponding 2-sided 90% tistical analyses. Because of the potential for type 1 error due CIs were obtained from the model and exponentiated to pro- to multiple comparisons, findings for analyses of secondary vide estimates of the geometric mean ratio and 90% CI of the outcomes, exploratory pharmacokinetic parameters, and post

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Figure 1. Flow of Participants in Study of Sunscreen Ingredient Absorption

88 Healthy volunteers assessed for eligibility

64 Not randomized 52 Excluded (not eligible) 33 Did not meet inclusion criteria 11 Declined to participate 8 Outside screening window 12 Eligible to be replacement participant

24 Participants randomized

6 Randomized to receive spray 1 6 Randomized to receive spray 2 6 Randomized to receive lotion 6 Randomized to receive cream 6 Received spray 1 as randomized 6 Received spray 2 as randomized 6 Received lotion as randomized 6 Received cream as randomized

0 Lost to follow-up 0 Lost to follow-up 0 Lost to follow-up 0 Lost to follow-up 0 Discontinued intervention 0 Discontinued intervention 0 Discontinued intervention 1 Discontinued intervention 1 Withdrew (adverse event [milia])

6 Included in analysis 6 Included in analysis 6 Included in analysis 6 Included in analysis

Randomization was conducted in block sizes of 4 and included equal numbers of women and men in each treatment group.

hoc assessments should be interpreted as exploratory. Stan- for all products and through day 7 for all products except the dard noncompartmental calculations of pharmacokinetic para- cream (Figure 2, Table 2;eTable3inSupplement 2). Geomet- meters and statistical analyses were performed in R version ric mean maximum plasma concentrations were 4.0 ng/mL 3.4.3 (R Foundation). (coefficient of variation, 60.9%) for spray 1; 3.4 ng/mL (coef- ficient of variation, 77.3%) for spray 2; 4.3 ng/mL (coefficient of variation, 46.1%) for lotion; and 1.8 ng/mL (coefficient of Results variation, 32.1%) for cream (Table 2). AUC and maximum plasma concentration increased from day 1 to day 4 for all 4 Twenty-four participants (mean age, 35.5 [SD, 10.5] years; 12 products (Table 2; eTable 5 in Supplement 2), consistent with [50%] women); 14 [58%] black or African American; 14 [58%] drug accumulation. All formulations had exposure exceed- Fitzpatrick skin type 5 or 6) were randomized to 4 sunscreen ing 0.5 ng/mL on day 1, with the majority of participants reach- products (Table 1, Figure 1). Spray 1 contained 3% avoben- ing that threshold within 6 hours after the first application zone, 6% oxybenzone, 2.35% octocrylene, and 0% ecamsule; (Table 3 and Figure 3). There was a long terminal half-life (mean spray 2 contained 3% avobenzone, 5% oxybenzone, 10% oc- range, 33-55 hours) (Table 2). tocrylene, and 0% ecamsule; the lotion contained 3% avoben- zone, 4% oxybenzone, 6% octocrylene, and 0% ecamsule; and Oxybenzone the cream contained 2% avobenzone, 0% oxybenzone, 10% oc- All 3 products with oxybenzone resulted in oxybenzone tocrylene, and 2% ecamsule (Table 1). exposure, with plasma concentrations exceeding 20 ng/mL All participants completed the study except 1 participant on day 7. Geometric mean maximum plasma concentra- receiving the cream, who discontinued on day 2 because of tions were 209.6 ng/mL (coefficient of variation, 66.8%) milia. The most common adverse event was rash, which for spray 1; 194.9 ng/mL (coefficient of variation, 52.4%) for developed in 1 participant (17%) in each group. Adverse spray 2; and 169.3 ng/mL (coefficient of variation, 44.5%) events, which included rash, milia, and pruritis, resolved for lotion (Table 2). AUC was numerically higher on day 4 in all participants (all adverse events are listed in eTable 4 in compared with day 1 for all 3 products, consistent with drug Supplement 2). accumulation, although only spray 1 and lotion had 90% CIs Approximately 17% of measures (91/540 samples) were be- excluding unity (Table 2; eTable 5 in Supplement 2). All par- low the lower limit of quantitation for spray 1, 13% (68/540 ticipants who received formulations containing oxybenzone samples) for spray 2, 13% (68/540 samples) for lotion, and 33% had plasma concentrations exceeding 0.5 ng/mL within 2 (167/501) for cream. All data from the 1 participant who dis- hours after a single application on day 1 (Table 3 and continued from the study were included in the analysis up Figure 3). There was a long terminal half-life (mean range, through the last available time point (47 hours). 24-31 hours) (Table 2).

Avobenzone Octocrylene All 4 sunscreen products resulted in avobenzone exposures, All 4 products resulted in octocrylene exposures, with plasma with plasma concentrations exceeding 0.5 ng/mL on day 1 concentrations exceeding 0.5 ng/mL, starting from day 1 and

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Figure 2. Pharmacokinetic Profiles of Each Active Ingredient by Product for the Study Duration

A Spray 1 Avobenzone Oxybenzone Octocrylene Ecamsule 550 550 550 550 Participant 100 100 100 100 S1.1 S1.2 S1.3 S1.4 10 10 10 10 S1.5 S1.6 Product did not contain 1 1 1 1

Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ecamsule

0.1 0.1 0.1 0.1 0 50 100 150 0 50 100 150 0 50 100 150 0 50 100 150 Time, h Time, h Time, h Time, h

B Spray 2 Avobenzone Oxybenzone Octocrylene Ecamsule 550 550 550 550 Participant S2.1 100 100 100 100 S2.2 S2.3 S2.4 10 10 10 10 S2.5 S2.6

Product did not contain 1 1 1 1

Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ecamsule

0.1 0.1 0.1 0.1 0 50 100 150 0 50 100 150 0 50 100 150 0 50 100 150 Time, h Time, h Time, h Time, h

C Lotion Avobenzone Oxybenzone Octocrylene Ecamsule 550 550 550 550 Participant L.1 100 100 100 100 L.2 L.3 L.4 10 10 10 10 L.5 L.6

Product did not contain 1 1 1 1

Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ecamsule

0.1 0.1 0.1 0.1 0 50 100 150 0 50 100 150 0 50 100 150 0 50 100 150 Time, h Time, h Time, h Time, h

D Cream Avobenzone Oxybenzone Octocrylene Ecamsule 550 550 550 550 Participant 100 100 100 100 C.1 C.2 C.3 C.4 10 10 10 10 C.5 Product did not contain C.6 oxybenzone 1 1 1 1 Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration,

0.1 0.1 0.1 0.1 0 50 100 150 0 50 100 150 0 50 100 150 0 50 100 150 Time, h Time, h Time, h Time, h

Vertical shaded regions indicate the 6-hour window (eg, at 0, 2, 4, and 6 hours) of oxybenzone, 0.4 ng/mL for octocrylene, and 0.2 ng/mL for ecamsule. All samples sunscreen application; solid horizontal lines indicate the 0.5-ng/mL plasma below the LLOQ were set to 0.1 ng/mL for plotting individual profiles. Spray 1, spray concentration threshold; dashed horizontal lines indicate lower limit of 2, and lotion did not contain ecamsule; cream did not contain oxybenzone. quantitation (LLOQ). LLOQs were 0.2 ng/mL for avobenzone, 0.4 ng/mL for Geometric mean pharmacokinetic profiles are shown in eFigure 1 in Supplement 2.

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Table 2. Pharmacokinetic Parameters of Sunscreen Active Ingredients (All Data)

Geometric Mean (Coefficient of Variation %) [Range] Spray 1 Spray 2 Lotion Cream Avobenzone Overall Maximum plasma 4.0 (60.9) [1.6-8.3] 3.4 (77.3) [1.0-7.3] 4.3 (46.1) [2.8-9.3] 1.8 (32.1) [1.1-2.7] concentration, ng/mLa Time to maximum 77.0 [57.0-82.0] 67.5 [14.0-86.0] 67.5 [33.0-95.0] 69.0 [33.0-86.0] concentration, hb Maximum plasma concentration, ng/mLa Day 1 1.6 (43) [1.0-3.0] 1.5 (92.9) [0.4-4.4] 2.4 (69.4) [1.0-5.2] 1.0 (43.8) [0.5-1.6] Day 4 3.8 (68.9) [1.4-8.3] 3.1 (70.2) [1.0-6.4] 3.5 (58.6) [2.0-9.3] 1.7 (40.4) [1.0-2.7] Residual concentration 0.9 (62.4) [0.4-1.8] 0.7 (70) [0.3-1.6] 1.2 (69.5) [0.6-3.4] 0.3 (73.2) [0.2-0.7] at day 7, ng/mL Terminal half-life, hc 54.6 (57.0) [29.8-114.0] 45.2 (68.0) [27.6-128.1] 35.4 (13.4) [31.3-40.8] 33.0 (48.0) [22.4-68.4] Oxybenzone Overall Maximum plasma 209.6 (66.8) [83.3-532.0] 194.9 (52.4) [89.3-350.1] 169.3 (44.5) [103.3-274.6] NA concentration, ng/mLa Time to maximum 57.0 [8.0-78.0] 32.5 [6.0-82.0] 21.5 [8.0-57.0] NA concentration, hb Maximum plasma concentration, ng/mLa Day 1 155.4 (56.4) [70.9-271.1] 162.2 (81.8) [46.1-350.1] 149.5 (38.4) [97-270.2] NA Day 4 177.6 (70.6) [75.2-532.0] 163.0 (46.3) [89.3-299.2] 118.1 (40.6) [69.8-186.4] NA Residual concentration 34.4 (51.4) [15.6-56.1] 20.9 (52.0) [9.8-42.4] 24.5 (78.0) [14.0-86.8] at day 7, ng/mL Terminal half-life, hd 30.6 (19.1) [25.4-43.5] 23.5 (13.0) [20.9-28.9] 27.1 (33.8) [20.9-48.1] NA Octocrylene Overall Maximum plasma 2.9 (102.0) [1.0-9.8] 7.8 (113.3) [2.5-20.4] 5.7 (66.3) [2.8-13.4] 5.7 (47.1) [2.9-10.3] concentration, ng/mLa Time to maximum 74.5 [8.0-82.0] 65.0 [14.0-84.0] 54.5 [33.0-78.0] 72.0 [33.0-81.0] concentration, hb Maximum plasma concentration, ng/mLa Day 1 0.8 (53.0) [0.5-1.7] 3.7 (125.7) [1.1-18.5] 2.6 (65.6) [1.2-6.3] 2.9 (39.9) [1.6-4.2] Day 4 2.6 (108.5) [1.0-9.8] 6.2 (83.1) [2.5-17.6] 3.9 (65.8) [1.7-9.2] 4.9 (48.7) [2.4-8.5] Residual concentration 0.6 (28.4) [0.4-0.9] 1.2 (66) [0.6-2.6] 1.7 (87.3) [0.5-4.4] 1.3 (50.9) [0.8-2.6] at day 7, ng/mL Terminal half-life, he 84.4 (53.3) [59.3-120.2] 43.3 (50.7) [26.9-75.2] 45.2 (20.7) [36.9-55.6] 45.9 (27.9) [33.9-62.8] Ecamsule Overall Maximum plasma NA NA NA 1.5 (166.1) [0.5-12.1] concentration, ng/mLa Time to maximum NA NA NA 28.0 [8.0-86.0] concentration, hb Maximum plasma concentration, ng/mLa Day 1 NA NA NA 1.2 (177.3) [0.4-12.1] Day 4 NA NA NA 0.7 (33.2) [0.5-1.1] Residual concentration NA NA NA NA at day 7, ng/mL Terminal half-life, h NA NA NA NA Abbreviation: NA, not applicable. c Reported for only a subset of participants: spray 1 (n = 5), spray 2 (n = 5), a Maximum active ingredient concentration observed over the study duration. lotion (n = 3), and cream (n = 5). Day 1 values are the maximum concentration over the interval of 0 to 23 d Reported for only a subset of participants: spray 1 (n = 6), spray 2 (n = 5), hours. Day 4 values are the maximum concentration over the interval of 71 to and lotion (n = 5). 95 hours. e Reported for only a subset of participants: spray 1 (n = 2), spray 2 (n = 4), b Reported as median (range); denotes the time of maximum active ingredient lotion (n = 3), and cream (n = 4). concentration observed over the study duration.

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Table 3. Number and Percentage of Study Participants With Plasma Active Ingredient Concentrations Exceeding 0.5 ng/mL at Select Time Points on Day 1 by Product and Active Ingredient

Participants With Active Ingredient Concentrations >0.5 ng/mL on Day 1, No./Total (%) 2ha 4ha 6ha 8 h Any Time Avobenzone Spray 1 0/6 (0) 2/6 (33) 4/6 (67) 6/6 (100) 6/6 (100) Spray 2 0/6 (0) 2/6 (33) 4/6 (67) 5/6 (83) 5/6 (83) Lotion 1/6 (17) 3/6 (50) 5/6 (83) 6/6 (100) 6/6 (100) Cream 0/6 (0) 2/6 (33) 1/6 (17) 5/6 (83) 6/6 (100) Oxybenzone Spray 1 6/6 (100) 6/6 (100) 6/6 (100) 6/6 (100) 6/6 (100) Spray 2 6/6 (100) 6/6 (100) 6/6 (100) 6/6 (100) 6/6 (100) Lotion 6/6 (100) 6/6 (100) 6/6 (100) 6/6 (100) 6/6 (100) Octocrylene Spray 1 0/6 (0) 0/6 (0) 2/6 (33) 3/6 (50) 4/6 (67) Spray 2 1/6 (17) 3/6 (50) 6/6 (100) 6/6 (100) 6/6 (100) Lotion 0/6 (0) 2/6 (33) 6/6 (100) 6/6 (100) 6/6 (100) a The second, third, and fourth Cream 1/6 (17) 5/6 (83) 6/6 (100) 6/6 (100) 6/6 (100) administration of product on day 1 Ecamsule occurred at 2, 4, and 6 hours, respectively, after the blood sample Cream 0/6 (0) 1/6 (17) 1/6 (17) 3/6 (50) 5/6 (83) was obtained.

lasting through day 7. Geometric mean maximum plasma con- Absorption of some sunscreen ingredients has been de- centrations were 2.9 ng/mL (coefficient of variation, 102%) for tected in other studies; however, significant data gaps exist.16-18 spray 1; 7.8 ng/mL (coefficient of variation, 113.3%) for spray In the recent FDA proposed rule for the OTC monograph,6 2 2; 5.7 ng/mL (coefficient of variation, 66.3%) for lotion; and active ingredients ( and ) were found 5.7 ng/mL (coefficient of variation, 47.1%) for cream (Table 2). to be generally recognized as safe and effective, while for AUC increased from day 1 to day 4 for all 4 products, and maxi- 12 active ingredients (, , , mum plasma concentration was numerically higher on day 4 , meradimate, octinoxate, octisalate, oc- compared with day 1 (Table 2; eTable 5 in Supplement 2), con- tocrylene, , , oxybenzone, and avo- sistent with drug accumulation. All participants who re- benzone) there were insufficient data to make a “generally rec- ceived the 3 products with the highest octocrylene product ognized as safe and effective” determination; thus, more data composition (spray 2, lotion, cream) had octocrylene plasma have been requested from the manufacturers. Avobenzone, concentrations exceeding 0.5 ng/mL within 6 hours of the first oxybenzone, and octocrylene were part of the present study; administration (Table 3 and Figure 3). There was a long termi- of note, ecamsule is marketed under a New Drug Application nal half-life (mean range, 42-84 hours) (Table 2). and is not part of the OTC monograph. Oxybenzone, along with some other sunscreen active Ecamsule ingredients including octocrylene, has been found in human The cream was the only product containing ecamsule. The geo- breast milk.19 In addition, oxybenzone has been detected in metric mean maximum plasma concentration was 1.5 ng/mL amniotic fluid, urine, and blood.6 Furthermore, some studies (coefficient of variation, 166.1%) (Table 2). Five of 6 par- in the literature have raised questions about the potential for ticipants had an ecamsule plasma concentration exceeding oxybenzone to affect endocrine activity.6,20 No prior plasma 0.5 ng/mL on day 1 (Table 3 and Figure 3). Some pharmacoki- concentration data existed for avobenzone or octocrylene, netic measures could not be calculated because 109 of 167 time while ecamsule use was shown to result in limited but points were below the assay limit of quantitation (0.2 ng/mL). detectable exposure in a study conducted under what would be considered submaximal usage conditions today.21 Cur- rently, multiple active ingredients lack nonclinical safety Discussion assessment data, including systemic carcinogenicity and additional developmental and reproductive studies to deter- This randomized clinical trial demonstrated systemic expo- mine the clinical significance of the level of absorption of sure of 4 commonly used sunscreen active ingredients on ap- sunscreen active ingredients. plication of sunscreen products under maximal use condi- This study was performed to demonstrate the feasibility tions consistent with current sunscreen labeling (ie, apply at of conducting a sunscreen maximal usage trial7 and obtain pre- least every 2 hours). All 4 sunscreen active ingredients tested liminary data on sunscreen active ingredients. It was not in- resulted in exposures exceeding 0.5 ng/mL. The clinical ef- tended to be a definitive maximal usage trial study. In this fect of plasma concentrations exceeding 0.5 ng/mL is un- study, a total of 6 participants per formulation was sufficient known, necessitating further research. to detect systemic exposure exceeding 0.5 ng/mL for the tested

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Figure 3. Pharmacokinetic Profile of Each Active Ingredient by Product for Day 1

A Spray 1 Avobenzone Oxybenzone Octocrylene Ecamsule 500 500 500 500 Participant 100 100 100 100 S1.1 S1.2 S1.3 S1.4 10 10 10 10 S1.5 S1.6 Product did not contain 1 1 1 1

Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ecamsule

0.1 0.1 0.1 0.1 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time, h Time, h Time, h Time, h

B Spray 2 Avobenzone Oxybenzone Octocrylene Ecamsule 500 500 500 500 Participant S2.1 100 100 100 100 S2.2 S2.3 S2.4 10 10 10 10 S2.5 S2.6

Product did not contain 1 1 1 1

Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ecamsule

0.1 0.1 0.1 0.1 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time, h Time, h Time, h Time, h

C Lotion Avobenzone Oxybenzone Octocrylene Ecamsule 500 500 500 500 Participant L.1 100 100 100 100 L.2 L.3 L.4 10 10 10 10 L.5 L.6

Product did not contain 1 1 1 1

Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ecamsule

0.1 0.1 0.1 0.1 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time, h Time, h Time, h Time, h

D Cream Avobenzone Oxybenzone Octocrylene Ecamsule 500 500 500 500 Participant C.1 100 100 100 100 C.2 C.3 C.4 10 10 10 10 C.5 C.6 Product did not contain oxybenzone 1 1 1 1 Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration, ng/mL Concentration,

0.1 0.1 0.1 0.1 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time, h Time, h Time, h Time, h

Vertical shaded regions indicate the 6-hour window (eg, arrows denote dosing at 0, oxybenzone, 0.4 ng/mL for octocrylene, and 0.2 ng/mL for ecamsule. All samples 2, 4, and 6 hours) of sunscreen application; solid horizontal lines indicate the below the LLOQ were set to 0.1 ng/mL for plotting individual profiles. Spray 1, spray 0.5-ng/mL plasma concentration threshold; dashed horizontal lines indicate lower 2, and lotion did not contain ecamsule; cream did not contain oxybenzone. limit of quantitation (LLOQ). LLOQs were 0.2 ng/mL for avobenzone, 0.4 ng/mL for Geometric mean pharmacokinetic profiles are shown in eFigure 2 in Supplement 2.

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ingredients but not to delineate the absorption across the en- washout phase, the plasma concentration up to 17 days after tire potential population that uses sunscreens. the last dose, and the systemic exposure to additional com- The 0.5-ng/mL threshold is based on the principle that monly used sunscreen ingredients, including octinoxate, the level would approximate the highest plasma level below homosalate, and octisalate. which the carcinogenic risk of any unknown compound would be less than 1 in 100 000 after a single dose.1,6 This Limitations Threshold of Toxicological Concern (TTC) concept was first This study has several limitations. First, the study was con- adopted by FDA in the regulation of food packaging sub- ducted in indoor conditions without exposure to heat, sun- stances that can migrate into food.9 The threshold value light, and humidity, which may alter or modify the rate of ab- is also consistent with the TTC applied to pharmaceutical sorption of sunscreen active ingredients. While this is a drug substance impurities in the International Council for limitation, the study was designed to collect informative data Harmonisation “Guidance for Industry: M7 (R1) Assessment in a standardized manner to design subsequent studies. Sec- and Control of DNA Reactive (Mutagenic) Impurities in Phar- ond, the study was not designed to assess differences in ab- maceuticals to Limit Potential Carcinogenic Risk.”10 That sorption by formulation type, Fitzpatrick skin type, or partici- document recommends a TTC of 1.5 μg/d, when appropriate, pant age. However, as shown in the individual participant which was translated to 0.5 ng/mL for sunscreen active ingre- absorption profiles (Figure 2 and Figure 3), there was consis- dients, assuming a circulating plasma volume of approxi- tent absorption of multiple sunscreen active ingredients across mately 3 L. Application of this concept was considered the different formulation types, Fitzpatrick skin types, and ages acceptable during the determination of the “generally recog- in the study. Third, the study was conducted with multiple ap- nized as safe and effective” status of sunscreen active ingre- plications of sunscreen products as per the labeled dosage regi- dients because such ingredients will be supported by exten- men and not evaluated on single-dose application, so maxi- sive human use and absence of other pharmacologic or mum plasma concentration and additional pharmacokinetic toxicologic signals from the nonclinical assessment recom- characteristics after a single application were not determined mended in the FDA sunscreen guidance. Application of such in this study. a threshold concept might not be appropriate or clinically meaningful for chemicals or chemical classes with effects on the human body, beyond that intended as sunscreen. Conclusions While the current study was purposefully designed to represent maximal usage per sunscreen labels (ie, apply at In this preliminary study involving healthy volunteers, appli- least every 2 hours) to areas of the body outside of normal cation of 4 commercially available sunscreens under maxi- swimwear over multiple days as might occur at the beach, mal use conditions resulted in plasma concentrations that ex- absorption exceeding 0.5 ng/mL occurred on day 1 (Figure 3 ceeded the threshold established by the FDA for potentially and Table 3) and for 3 of the 4 active ingredients lasted until waiving some nonclinical toxicology studies for sunscreens. day 7 (Figure 2). A second phase of this study will use a dif- The systemic absorption of sunscreen ingredients supports the ferent design to investigate additional questions raised by need for further studies to determine the clinical significance this study, including the maximum plasma concentration of these findings. These results do not indicate that individu- after a single application, the skin concentration during the als should refrain from the use of sunscreen.

ARTICLE INFORMATION Author Contributions: Drs Matta and Strauss had Supervision: Patel, Sanabria, Wang, Furlong, Ganley, Accepted for Publication: April 12, 2019. full access to all of the data in the study and take Michele, Strauss. responsibility for the integrity of the data and the Conflict of Interest Disclosures: None reported. Published Online: May6,2019. accuracy of the data analysis. doi:10.1001/jama.2019.5586 Concept and design: Matta, Zusterzeel, Patel, Oh, Funding/Support: The study was funded by the US Author Affiliations: Division of Applied Regulatory Bashaw, Zineh, Sanabria, Adah, Coelho, Wang, Food and Drug Administration. Science, Office of Clinical Pharmacology, Office of Furlong, Ganley, Michele, Strauss. Role of the Funder/Sponsor: The FDA oversaw the Translational Sciences, Center for Drug Evaluation Acquisition, analysis, or interpretation of data: design and overall conduct of the study including and Research, US Food and Drug Administration, Matta, Zusterzeel, Pilli, Patel, Volpe, Florian, Kemp, overseeing the management, analysis, and Silver Spring, Maryland (Matta, Zusterzeel, Pilli, Godfrey, Wang, Michele, Strauss. interpretation of the data. The FDA also prepared, Patel, Volpe, Florian, Strauss); Office of Clinical Drafting of the manuscript: Matta, Zusterzeel, reviewed, and approved the manuscript for Pharmacology, Office of Translational Sciences, Sanabria, Strauss. submission for publication. Center for Drug Evaluation and Research, US Food Critical revision of the manuscript for important Additional Contributions: We are deeply grateful and Drug Administration, Silver Spring, Maryland intellectual content: Matta, Zusterzeel, Pilli, Patel, to the study participants and all the nurses and (Oh, Bashaw, Zineh); Spaulding Clinical Research, Volpe, Florian, Oh, Bashaw, Zineh, Kemp, Godfrey, physicians from Spaulding Clinical Research who West Bend, Wisconsin (Sanabria, Kemp, Godfrey); Adah, Coelho, Wang, Furlong, Ganley, Michele, contributed to the dosing and pharmacokinetic Division of Nonprescription Drug Products, Office Strauss. sample collection. We also thank Robert Gump, BS of Drug Evaluation IV, Office of New Drugs, Center Statistical analysis: Matta, Zusterzeel, Florian, (FDA), and Suresh Narayanasamy, PhD (FDA), for Drug Evaluation and Research, US Food and Wang. who performed this work as a part of their Drug Administration, Silver Spring, Maryland (Adah, Obtained funding: Wang, Michele, Strauss. normal duties. Coelho, Michele); Office of Drug Evaluation IV, Administrative, technical, or material support: Office of New Drugs, Center for Drug Evaluation Matta, Zusterzeel, Pilli, Patel, Bashaw, Zineh, Kemp, Data Sharing Statement: See Supplement 4. and Research, US Food and Drug Administration, Adah, Coelho, Wang. Silver Spring, Maryland (Wang, Furlong, Ganley).

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REFERENCES bioavailability trial for topical dermatological 15. US Food and Drug Administration (FDA), 1. US Food and Drug Administration (FDA). products. Ther Innov Regul Sci. 2015;49(1):108-115. Department of Health and Human Guidance for Industry: Nonprescription Sunscreen 9. US Food and Drug Administration, HHS. Services. Guidance for Industry: Drug Products—Safety and Effectiveness Data. FDA Food additives: threshold of regulation of Bioavailability Studies Submitted in NDAs or website. https://www.fda.gov/downloads/drugs/ substances used in food-contract articles: final rule. INDs—General Considerations. FDA website. guidancecomplianceregulatoryinformation/ Fed Regist. 1995;60(136):36582-36596. https:// https://www.fda.gov/downloads/Drugs/ guidances/ucm473464.pdf. Published November www.govinfo.gov/content/pkg/FR-1995-07-17/pdf/ GuidanceComplianceRegulatoryInformation/ 2016. Accessed February 5, 2019. 95-17435.pdf. Accessed April 1, 2019. Guidances/UCM631943.pdf. Published February 2019. Accessed April 09, 2019. 2. US Food and Drug Administration, HHS. Labeling 10. International Conference on Harmonization and effectiveness testing: sunscreen drug products (ICH). Guidance for Industry: M7(R1) Assessment 16. Klimová Z, Hojerová J, Beránková M. for over-the-counter human use: final rule. Fed Regist. and Control of DNA Reactive (Mutagenic) Skin absorption and human exposure 2011;76(117):35620-35665. Impurities in Pharmaceuticals to Limit Potential estimation of three widely discussed UV filters in sunscreens—in vitro study mimicking real-life 3. Nash JF. Human safety and efficacy of Carcinogenic Risk. US Food and Drug Administration website. https://www.fda.gov/ consumer habits. Food Chem Toxicol. 2015;83:237- filters and sunscreen products. Dermatol Clin. 250. doi:10.1016/j.fct.2015.06.025 2006;24(1):35-51. doi:10.1016/j.det.2005.09.006 downloads/Drugs/ GuidanceComplianceRegulatoryInformation/ 17. Janjua NR, Kongshoj B, Andersson AM, Wulf HC. 4. 21 CFR §700.35: cosmetics containing sunscreen Guidances/UCM347725.pdf. Published March 2018. Sunscreens in human plasma and urine after ingredients. US Government Publishing Office Accessed April 01, 2019. repeated whole-body topical application. J Eur Acad website. https://www.govinfo.gov/content/pkg/ 11. US Food and Drug Administration (FDA), Dermatol Venereol. 2008;22(4):456-461. doi:10.1111/ CFR-2011-title21-vol7/xml/CFR-2011-title21-vol7- j.1468-3083.2007.02492.x sec700-35.xml. 2011. Accessed February 5, 2019. Department of Health and Human Services. Guidance for Industry: Bioanalytical Method 18. Gonzalez H, Farbrot A, Larkö O, Wennberg AM. 5. Wang J, Ganley CJ. Safety threshold Validation. FDA website. https://www.fda.gov/ Percutaneous absorption of the sunscreen considerations for sunscreen systemic exposure: downloads/drugs/guidances/ucm070107.pdf. benzophenone-3 after repeated whole-body a simulation study. Clin Pharmacol Ther. 2019;105 Published May 2018. Accessed February 5, 2019. applications, with and without ultraviolet (1):161-167. doi:10.1002/cpt.1178 12. US Food and Drug Administration (FDA), irradiation. Br J Dermatol. 2006;154(2):337-340. 6. US Food and Drug Administration (FDA). Department of Health and Human Services. doi:10.1111/j.1365-2133.2005.07007.x Sunscreen drug products for over-the-counter Guidance for Industry and Food and Drug 19. Schlumpf M, Kypke K, Wittassek M, et al. human use: proposed rule. Fed Regist. 2019;84 Administration Staff: Collection of Race and Exposure patterns of UV filters, fragrances, (38):6204-6275. https://www.govinfo.gov/content/ Ethnicity Data in Clinical Trials. FDA website. parabens, phthalates, organochlor pesticides, pkg/FR-2019-02-26/pdf/2019-03019.pdf. Accessed https://www.fda.gov/downloads/ PBDEs, and PCBs in human milk: correlation April 1, 2019. regulatoryinformation/guidances/ucm126396.pdf. of UV filters with use of cosmetics. Chemosphere. 7. US Food and Drug Administration (FDA), Published October 2016. Accessed April 16, 2019. 2010;81(10):1171-1183. doi:10.1016/j.chemosphere. Department of Health and Human Services. 13. Benson HA. Assessment and clinical 2010.09.079 Guidance for Industry: Maximal Usage Trails for implications of absorption of sunscreens across 20. Krause M, Klit A, Blomberg Jensen M, et al. Topical Active Ingredients Being Considered for skin. Am J Clin Dermatol. 2000;1(4):217-224. doi:10. Sunscreens: are they beneficial for health? an Inclusion in an Over-the-Counter Monograph: Study 2165/00128071-200001040-00003 overview of endocrine disrupting properties of Elements and Considerations. FDA website. 14. US Food and Drug Administration (FDA), UV-filters. Int J Androl. 2012;35(3):424-436. doi:10. https://www.fda.gov/downloads/Drugs/ 1111/j.1365-2605.2012.01280.x GuidanceComplianceRegulatoryInformation/ Department of Health and Human Services. Guidances/UCM608356.pdf. Published May 2018. Guidance for Industry: Statistical Approaches to 21. Benech-Kieffer F, Meuling WJA, Leclerc C, Roza Accessed February 05, 2019. Establishing Bioequivalence. FDA website. L, Leclaire J, Nohynek G. Percutaneous absorption https://www.fda.gov/downloads/drugs/guidances/ of Mexoryl SX in human volunteers: comparison 8. Bashaw ED, Tran DC, Shukla CG, Liu X. Maximal ucm070244.pdf. Published January 2001. with in vitro data. Skin Pharmacol Appl Skin Physiol. usage trial: an overview of the design of systemic Accessed April 09, 2019. 2003;16(6):343-355. doi:10.1159/000072929

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