Dioxybenzone

THE REST OF THE WORLD benefits from a variety of sunscreen active ingredients and effectiveness rating systems that are not available in the U.S. The Food and Drug Administration has promised to give American consumers more options, but sunscreen ingredient suppliers contend that the agency is dragging its feet.

For instance, three years ago, chemical companies applied to the FDA for permission to sell three new sunscreen active ingredients under expedited review procedures. They are still waiting. Six years ago, the FDA promised manufacturers and formulators that it would advise them on an acceptable measuring system to let consumers know how effectively a sunscreen formulation blocks UV-A rays. The industry still is waiting.

Today, consumers buying sun protection lotions and creams can get some sense of how these products protect them from sunburn-causing UV-B rays by reading the sun protection factor (SPF) rating. However, scientists believe that radiation from the UV-A spectrum is responsible for skin wrinkling and, more important, may contribute to skin cancer.

Until the FDA provides UV-A testing guidelines, manufacturers merely can indicate that their lotions and creams offer UV-A protection. Consumers have no idea of how effective a sunscreen product is in protecting them against the cancer-causing rays of the sun. That would be useful information because most of the more than 1,000,000 nonmelanoma cases of skin cancer annually diagnosed in the U.S. are considered to be sun-related, according to the American Cancer Society.

The FDA says its reviews have taken longer than expected to ensure "that they reflect the current understanding of medicine and science in the field." However, the frustration among sunscreen makers and formulators over the agency's lack of action is palpable. In 1999, the FDA issued a "final" sunscreen monograph--the do's and don'ts of sunscreen labeling and formulation. The agency has not "finalized" the document. Proposed UV-A testing and labeling roles are due later this year, the agency promises.

Personal care industry consultant David Steinberg accuses the FDA of "foot-dragging." He attributes the delays in the UV-A testing protocols and the slow approval of new sunscreen ingredients to a highly politicized atmosphere at the agency. "It's politics, not science, that has gone wrong," Steinberg maintains.

Many professionals in the FDA are as frustrated as those in the industry over the slow pace of approvals, Steinberg claims. Wrangling between Democrats and Republicans concerning FDA leadership, pressure to speed approval of new drugs, and the controversy over approved drugs with serious problems--such as Vioxx and the COX-2 inhibitor class--have made the agency especially cautious.

The l-o-n-g wait

Steinberg, who worked with one of the three companies to submit a new sunscreen application to the FDA, says it "should only take a half-day to get approval." Yet, it has been three years since Symrise, Germany's Merck, and BASF submitted requests to allow use of three ingredients in sunscreen formulations in the U.S.

Symrise, formed in 2002 through the merger of Haarmann & Reimer and Dragoco, asked for approval of isoamyl methoxycinnamate. Merck sought approval for 4-methylbenzylidene camphor, while BASF requested approval for octyl triazone. All would add to the arsenal of UV-B sunscreens available to product formulators.

Each of the companies submitted applications in August, 2002, under the FDA's TEA process for time and extent applications. The FDA put TEA in place early in 2002 to expedite listing new sunscreens and other types of over-the-counter (OTC) ingredients in the FDA's monographs. Active ingredients with a five-year history of extensive and safe OTC use in another country are eligible for fast-track FDA review.

Compared with many other countries, the U.S. has few useful UV-B filters and even fewer UV-A filters. Of the 16 filters now listed for use in U.S. sunscreen formulations, nine are basic UV-B filters, points out Nadim A. Shaath, president of the personal care consulting firm Alpha Research & Development. Of those nine, only five are used extensively. The others have one issue or another associated with them. Aminobenzoic acid, for instance, stains clothing and may cause adverse reactions in those with sensitive skin.

Seven UV filters listed in the U.S. monograph block UV-A rays, Shaath notes. Yet, oxybenzone, for instance, primarily is a UV-B filter that also blocks some UV-A rays. Menthyl anthranilate is not a broad-spectrum UVA filter. Avobenzone provides broad-spectrum UV-A blockage but quickly loses potency on the skin if not formulated properly. Sulisobenzone and dioxybenzone are difficult to solubilize and are used rarely. Two physical blockers, titanium dioxide and zinc oxide, are difficult to incorporate into formulations.

In Europe, by contrast, the list of approved useful UV-A and UV-B sunscreens "goes on and on," Shaath reveals. That list, in fact, contains 28 approved sunscreens. Australia has 26 on its approved list and Canada, 21. Since 1978, the FDA only has allowed the addition of avobenzone and zinc oxide to the list. FDA treats sunscreen active ingredients like drugs for regulatory purposes, Shaath explains, while regulators in Europe and elsewhere regard sunscreens as cosmetics, for which the regulatory approval procedure is less onerous.

Until the FDA initiated the TEA process, the only way to get a sunscreen approved was to file a New Drug Application. That meant spending many millions of dollars to do the testing and studies necessary for drug approval in the U.S. Such a route might be cost-effective for a new cancer drug or antibiotic, where annual sales can be in the hundreds of millions of dollars. A blockbuster sunscreen ingredient, however, only would have sales of about $10,000,000, far too little to justify the kind of testing expenditures that would satisfy the FDA.

In fact, the total U.S. market for sunscreen lotions and potions at the producer level comes in at just about $640,000,000 a year, reports Carrie Bonner, a market manager at the consulting firm of Kline & Co. By comparison, annual pharmaceutical industry sales in the U.S. exceed $150,000,000,000.

In Europe, the approval process is swifter and less costly. Manufacturers of a new sunscreen ingredient submit standard irritation and sensitivity tests to the European Cosmetic, Toiletry & Perfumery Association, which then may recommend it for regulatory approval. The tests are not as costly as what is required in the U.S. After several years of provisional testing, a new ingredient can move onto a final list of approved ingredients. The list expands and contracts at a faster pace than in the U.S., depending on experience in use.

"We started with a new drug application seven years ago" to get FDA approval of isoamyl methoxycinnamate, says Karl Harris, director of regional business management at Symrise. "We switched to the TEA process when it became available. We're still waiting for approval."

Ratan K. Chaudhuri, director of cosmetics research and applications at EMD Chemicals, the U.S. affiliate of Germany's Merck, complains that his firm has yet to hear from the FDA about its application seeking U.S. approval for the use of 4-methylbenzylidene camphor (4-MBC). He is frustrated that a product with a 25-year history of use in Europe still cannot be sold in the U.S.

Chaudhuri acknowledges that scientists recently have looked into the possibility that 4-MBC might be an endocrine disrupter, although he points out that his own company's investigation found no estrogenic effects. Furthermore, the Scientific Committee for Cosmetic Products & Non-Food Products Intended for Consumers, a European Commission advisory body, has--for now--cleared 4-MBC and one other sunscreen ingredient, octyl methoxycinnamate, while it continues to look into the matter.

"The U.S. is one of the most highly regulated markets," emphasizes Folker Ruchatz, cosmetic solutions marketing manager for BASF, which is awaiting approval of its TEA to list octyl triazone in the sunscreen monograph. Octyl triazone is "an extremely photostable filter with strong UV-B absorbence characteristics," according to Lee Mores, technical service manager at BASF. In other words, Mores indicates, a little bit goes a long way.

In the meantime, BASF must bide its time before it can submit other new sunscreens for approval. In February, European authorities approved the firm's new UV-A absorber, diethylamino hydroxybenzoyl hexyl benzoate, but it likely will be at least five years before BASF can bring the ingredient to the U.S. "We're committed to introducing it in the U.S. as soon as regulators allow us," Ruchatz promises.

Aside from pushing through new active ingredients, it is important that the FDA publish acceptable testing methods and label requirements for UV-A protection, insists Julian P. Hewitt, sun care team leader for Uniqema. "We currently have no rules for determining or labeling products for UV-A protection."

Europeans, however, do have such a guideline. Many formulators have adapted the Boots PLC star rating system, which provides a measure of the ratio of UV-A to UV-B radiation absorbed from a simulated light source. For a five-star rating, a sunscreen's UV-A performance must be at least 90% as good as its UV-B efficiency.

Hewitt also points out that current FDA roles do not allow formulators to combine the organic UV-A sunscreen avobenzone with the inorganic sunscreen titanium dioxide. Such a combination, he says, might allow formulators to achieve desirable UV-A and UV-B benefits at lower cost. Uniqema sells a range of nanoparticle-size titanium dioxide products for sunscreens under the Solaveil trade name.

Ultraviolet unrest

In a letter to the FDA in 2000, Ciba Specialty Chemicals argued that the agency should include two of its new sunscreens in a final sunscreen monograph. The firm had developed two broad-spectrum, organic microfine UV-A and UV-B sunscreens now used in Europe and elsewhere: bis-ethylhexyloxyphenol methoxyphenol triazine and methylene bis-benzotriazoyl tetramethylbutylphenol. Ciba trade named the two Tinosorb S and Tinosorb M, respectively.

Tinosorb M is the first of a new class of sunscreens that combine the benefits of an organic and inorganic filter. "The idea came to us seven or eight years ago," explains Uli Osterwalder, global marketing manager for UV Protection and Actives. Ciba scientists developed an organic filter that absorbs radiation like an organic compound and scatters and reflects radiation like an inorganic material.

Ciba developed Tinosorb M as a large, photostable, organic molecule with performance characteristics typical of titanium dioxide and zinc oxide, but it is easier to formulate with and has higher transparency. Company scientists used similar criteria to develop Tinosorb S, relying instead on chemistry from light stabilizers used in plastics. Tinosorb M is intended for use in aqueous dispersions, whereas Tinosorb S is for oil-phase sun-care formulations. Because the sunscreen particles are relatively large, scientists reasoned there would be little chance that Tinosorb M and S could be absorbed through the skin and pose a threat to human health.

"We checked both Tinosorb M and S for estrogenic activity, and they were both negative," Osterwalder contends. The earliest that Ciba expects to see these two new sunscreens allowed for use in the U.S. is 2006, when the company will be eligible to submit data to FDA for approval under the TEA process.

Another company with products sitting on the sidelines is DSM, which acquired a stable of sunscreen ingredients as part of its 2003 acquisition of Roche's vitamins and fine chemicals business. "The U.S. has effectively closed the door on newer and better technologies," asserts Fintan Sit, global marketing manager for DSM Nutritional Products.

Even before the acquisition, Roche had launched a new UV-B filter, dimethicodiethylbenzal malonate, for use everywhere in the world--except the U.S. Sit says the cost of filing a New Drug Application in the U.S. for the filter, known as Parsol SLX, is too high--and without five years of data, it still is too early to qualify using the TEA route. "Parsol SLX addresses safety issues we think will come up in the future," Sit relates.

Octyl methoxycinnamate and 4-MBC came under suspicion a few years ago because people thought these materials might penetrate the skin. Parsol SLX, like the new Ciba filters, is larger than conventional sunscreens. It is made of organic chromophores attached to a polysiloxane chain. While the silicone chain has an affinity for skin, it does not penetrate the skin's surface and keeps the sunscreen active ingredients on top.

While new sunscreen actives are unlikely to be on the U.S. market anytime soon, sunscreen ingredient suppliers are doing all they can to tweak approved sunscreens or improve the usefulness of existing sunscreen actives. For instance, Oxonica, spun out of England's University of Oxford, recently introduced an ultrafine titanium dioxide sunscreen doped with 0.7% manganese. According to Gareth Wakefield, vice president of research and development, the manganese changes the rutile pigment's electronic structure, eliminating its potential to generate free radicals. The manganese also makes the pigment a better UV-A filter than undoped titanium dioxide. Because titanium dioxide already is listed in the FDA's monograph, Oxonica expects to introduce its Optisol sunblocker in the U.S. soon--at least that is the hope of David Browning, the company's health care business director.

BASF also has supplemented its existing line of titanium dioxide with two coated micro fine pigments manufactured by Sakai Chemical Industry of Japan. "It is a better grade of titanium dioxide because it is more transparent than existing grades," maintains Mores. Meanwhile, EMD Chemicals probably will introduce a stabilizer that will boost the effectiveness of the UV-A sunscreen avobenzone. The stabilizer, diethyl hexyl syringylidene malonate, is a singlet oxygen quencher that will enhance the sunscreen's photostability.

Many involved in the sunscreen ingredients business contend that the FDA is ignoring their industry's needs. Indeed, as long as the agency remains preoccupied with other matters, U.S. consumers will be among the last to benefit from the latest sun care products.

Marc S. Reisch is senior correspondent in the Northeast News Bureau of Chemical & Engineering News, from which this article was adapted.

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