Documents Management Branch (HFA-305) Food and Drug Administration 5630 Fishers Lane, Rm 1061 Rockville, MD 20852 IN RE: Sunscreen Final Monograph Dear Madam or Sir, Our comments concern sunscreen photostability and its implications for arriving at a valid UVA testing

But the evidence is now overwhelming that excessive exposure to any part of the solar W spectrum, including WA II (320-340 nm) and WA I (340-400 nm), is harmful. Apart from its possible role in melanoma, WA has been shown to cause a wide variety of chemical and biological effects including generation of reactive oxygen species, DNA damage, lipid peroxidation, increase in elastin fibers, collagen cross-linking, epidermal thickening, and an increase in the number of dermal cysts.‘0-16 Following iwadiation with full spectrum W atmbenzone sumcreem that conmin diethylbsCy2,Gnaphthalate demonstrate impnmed photostability compared to those without. FuU spectrum W protection Traditional sunscreen design focuses on attenuating the sunburn component of UV radiation, principally in the 290 to 320 nm range, sometimes extending to 340 nm (see sidebar on traditional sunscreen design). In our laboratories, we approach sunscreen design from two simple premises: Nab Bestnzhlung mit Vollspektn4m W-Licbt uerbmerten AKhWlZOnSonnencremes, die Diethylbexyl2, GNaphthalat enfbielten, im Vmgla’cb mit Sonnemchutmitteln ohm? Dietbylhexyl2,GNdphthalat die Photostabilitiit. l All sun protection derives from W radiation attenuation. l The best sun protection derives from radiation attenuation across the entire solar UV spectrum, from 290 nm to 400 nm. Our objective, therefore, is to facilitate the formulation of sunscreens that reliably artenuate well over 90% of all solar UV radiation. As we see it, sunscreens that perform to this level provide their users with full spectrum protection. Suite f3 l’imzdiation ci rayo* ultraviolet d plein spectra, les lotions sohires ir l’auobenzone, contenant le dit%ylbex$2 et le G naphthalate, d&nontmt me pbotostabilit6 ame%w5e cornpar aux lotions qui ne continennent pas ces ingtidients. Logo de aplicar radiaci6n cm todo el espectro de radmci6n ultravioleta, 10s filtros solares de avobenzona que contienen naftalato de dzoctilo exbibieron mayorfotoestabilidad que aquellos prodautos que no lo contenian. solve the question raised at the American Academy of Dermatology Consensus Conference held February 4, 2000. This conference brought the medical, regulatory and scientific communities together to try and reach a consensus on WA protection by sunscreens. One conclusion was that SPF must remain as a way to advise consumers on WB protection. The participants also agreed that WA protection is required in all sunscreens and that a simple label must be developed to show consumers the level of protection. Because the term “broad spectrum” has been used and mis-used,‘Z applying this term to products that protect against both WB and UVA has become muddled and should be abandoned. We suggest using full spectrum as a permitted claim provided the product attenuates more than 90% of all solar W radiation. Products that .do not offer this protection could not be labeled as either full spectrum or broad spectrum. Achieving full spectrum protection: Achieving full spectrum protection in a sunscreen requires the incorporation of W filters that, alone or in combination, absorb throughout the solar W spectrum. It also requires W filters that provide the needed magnitude of attenuation within the concentration limits as defined by country regulations and/or cosmetic acceptability (see sidebar on organic W filters). A major obstacle to delivering full spectrum protection is the dearth of acceptable W filters that provide significant attenuation across the entire WA range from 320 nm to 400 nm. Only avobenzone is currently approved for general use in the US.h It absorbs broadly enough and with sufficient magnitude to attenuate more than 90% of UVA radiation. Avobenzone needs help to remain photostable; the very radiation it absorbs can cause it to undergo chemical reactions that degrade its absorbance.23-25 Avobenzone: A Powerful Tool Absorbance of WA and WWhen the FDA approved avobenzone for general use in sunscreens in 1997, formulators in the US joined their counterparts in the rest of the world in having available an extremely powerful tool to attenuate W mdiation.2” The maximum permitted level in the US is 3.0%, in the EU 5.0% and in Japan 10.0%. Unquestionably, in terms of breadth and magnitude of absorbance and its nearly 20.year history of safe use around the world, avobenzone is the leading candidate to extend sun protection throughout the WA portion of the spectrum. An often overlooked property of avobenzone is its significant absorbance of WB (Figure 3). In fact, our data indicates that at 306 nm, avobenzone absorbs almost twice as well on a molar basis as ethylhexyl salicylate (formerly octyl salicylate). At 320 nm, avobenzone’s molar absorptivity is about equal to oxybenzone’s molar absorptivity at the same wavelength.” Avobenzone maintains a significant magnitude of absorbance throughout the UVB band. Analyzing sunscreenphotostability: In the laboratory, in vitro experiments were conducted to evaluate the absorbance of various avobenzone formulations both before and after irradiation with 10 MED from a solar simulator.’ For general reference, 10 MED is equivalent to approximately two hours of sunlight. Absorbance is defined as log (l/T) where T (transmittance) is the ratio of radiation detected after passage through the test vehicle to radiation emitted by a radiation source. Attenuation is defined as l-T, or, when referred to as a percentage, as 100(1-T). For reference, absorbance of 2 equals 99% attenuation, absorbance of 1.52 equals 97% attenuation, and absorbance of 1 equals 90% attenuation. Transmittance data for the sample formulations was obtained by a transmittance analyzerd. The analyzer’s softwaree integrated the area under the absorbance curve and reported the percentages of radiation attenuation. Figure 4 illustrates both the promise of avobenzone and its problem. Before irradiation, the 1% avobenzone sunscreen attenuates 75% of the UVB radiation, and 81% of the WA radiation. Following irradiation, attenuation falls to 57% of UVB and 56% of WA. Attenuation of WI3 is reduced by 24% and attenuation of WA is reduced by 30% by the 10 MED exposure. Photostabilizing wit& DEHN: Figure 5 illustrates what happens ‘, Ambenzene is auailablejrom several suppliers under the trade names Pan01 1789 (Rochs Vitnnains, Parsippany, NJ, Solmom BMBM CFmtarom, Ha@ Bay. ha&, Neo Ueliopan Type 357 ~Haarman and Reimer, Holrminden~ Germanyj, E~m~lex 9020 CEMerck. Darmstadt, Gernzanyl, c~nd rivinul BMDM (BASF, Ludwi&mfen, Geinzany~ when DEHN is substituted for another ester in the formula at 4%. Except for the substitution, this formulation is identical in every way to the one depicted in Figure 4. Before irradiation, this formulation attenuates 82% of the UVB radiation and 80% of the UVA. After irradiation with 10 MED, attenuation of WB is 80% and UVA is 77%. For both UVB and UVA, loss of attenuation is less than 4%. As we shall see, some very good things happen to sunscreen formulations when avobenzone is formulated with DEHN. But first, let’s discuss the chemistry and photochemistry of this material. Diethylhexyl 2,6-Naphthalate DEHN is the diester of 2,6-naphthalene dicarboxylic acid, and 2ethylhexanol, a branched C8 primary alcohol. Figure 6, on page 40, shows the molecular structure: molecular formula, and molecular weight of DEHN. The physical properties of this molecule’” can be inferred to a large extent from its structure. It is a semi-viscous (546 cSt at 25°C by the Kinematic method) liquid at room temperature and has a freeze point of less than 5X It has a high refractive index of 1.53. Its specific gravity is 1.02. It is quite lipophilic. It is insoluble in water, propylene glycol and glycerin. It is freely soluble in most oils such as mineral oil, castor oil, and typical cosmetic esters Although it may seem unexpected and fortuitous, DEHN is an excellent solvent for lipophilic solids such as the UV filters oxybenzone (benzophenone-31, avobenzone, and ethylhexyl triazone (formerly octyl triazone). Figure 7 shows the UV absorbance of DEHN. In the solar UV range, it has a peak absorbance (h-,,,,J of 294 nm and a molar absorptivity (E) of about 9,000. It has two small peaks at 332 and 350 nm, and molar absorptivity at those peaks of about 1,000 and 2,000, respectively. As shown in Figure 7, on page 40, the solar UV absorbance of DEHN is very weak. By comparison, the absorbance of ethylhexyl methoxycinnamate exceeds .80 at 310 nm, and the absorbance of avobenzone is approximately 1.1 at 355 nm. The ability of DEHN to photostabilize avobenzone is a function of its capacity to act as an acceptor of triplet energy (see sidebar on photochemistry of photostability). Avobenzone has a triplet energy of about 60 kcalimol.” Based on published values for similar compounds, DEHN has a triplet energy of 57-60 kcal/mol and, therefore, may behave as an acceptor of avohenzone’s triplet energy Work is ongoing to provide a more precise characterization of the photophysical properties of DEHN. Its triplet energy and other properties of interest will be published in due course. Sunscreen Applications Table 2 shows the formulas for several model sunscreens used in the experiments described below. The first two sunscreens, marked A and B, both contain 3% avobenzone, and no other UV filters at all. DEHN has been added to Formula B at 4%, and not to Formula A. So basically we have two matched formulas, a negative control and a positive control. Figures 9 and 10 show the absorbance profiles of these two formulas before and after 10 MED exposures. It is very important to note that 3% 1.20E-04