[Tinosorb constitutes a significant UVA upgrade for sunscreens.
Unfortunately this is currently available only in Europe and
Australia. Mexoryl gives some Canadian sunscreens a UVA advantage
over USA products. Vichy SPF 60 seem to be about as good as it gets in
Canada.]

Chemical & Engineering News
April 11,  2005
Volume 83, Number 15
pp. 18-22

 NEW-WAVE SUNSCREENS
Active ingredient makers are frustrated by the long list of
sunscreens and UV-A testing protocols that are still awaiting FDA
decisions

 MARC S. REISCH, C&EN NORTHEAST NEWS BUREAU

The rest of the world benefits from a variety of sunscreen active
ingredients and effectiveness rating systems that aren't available
in the U.S. The Food & Drug Administration has promised to give
U.S. consumers more options, but sunscreen ingredient suppliers
contend that the agency is dragging its feet.
For example, almost three years ago, chemical companies applied
to FDA for permission to sell three new sunscreen active
ingredients under expedited review procedures. They are still
waiting.

Six years ago, 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 is still 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,
which has long been in place to indicate the ability of sunscreens
to block UV-B. However, scientists believe that radiation from
the UV-A spectrum is responsible for skin wrinkling and, more
important, may contribute to skin cancer. UV-B light wavelengths
range from 290 to 320 nm; UV-A wavelengths, from 320 to 400 nm.

Until FDA provides UV-A testing guidelines, manufacturers can only
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 million
nonmelanoma cases of skin cancer diagnosed in the U.S. annually
are considered to be sun-related, according to the American Cancer
Society.

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

Personal care industry consultant David Steinberg accuses 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 says.

Many professionals in FDA are as frustrated as those in the
industry over the slow pace of approvals, Steinberg says.
Wrangling between Democrats and Republicans over who is to head
FDA, pressure on FDA 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 all made the agency
especially cautious.

Steinberg, who worked with one of the three companies to submit a
new sunscreen application to FDA, says it "should only take a
half-day to get approval." But it has been almost 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. And 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 FDA's TEA process for time and extent applications. FDA
put the TEA process in place early in 2002 to expedite listing
new sunscreens and other types of over-the-counter (OTC)
ingredients in FDA's monographs. Active ingredients with a
five-year history of extensive and safe OTC use in another country
are eligible for the 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, says Nadim A. Shaath, president of personal care
consulting firm Alpha Research & Development. Of those nine,
only five are extensively used. The others have one issue or
another associated with them. Aminobenzoic acid, for instance,
stains clothing and may cause adverse reactions in sensitive
individuals.

Seven UV filters listed in the U.S. monograph block UV-A rays,
Shaath says. But oxybenzone, for instance, is primarily a UV-B
filter that also blocks some UV-A rays. Menthyl anthranilate is
not a broad-spectrum UV-A 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 rarely used. 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 says. That list, in fact,
contains 28 approved sunscreens. Sun-kissed Australia has 26 on
its approved list, and Canada has 21. Since 1978, FDA has only
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 treat sunscreens as cosmetics, for which the regulatory
approval procedure is less onerous.

Until 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.
But a blockbuster sunscreen ingredient would only have sales of
about $10 million, Shaath says, far too little to justify the
kind of testing expenditures that would satisfy FDA.

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

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 may then 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, Shaath says.

"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." Harris adds that he expects approval "any day now."

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

Chaudhuri acknowledges that scientists have recently looked into
the possibility that 4-MBC might be an endocrine disrupter. But 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 methoxycinnimate, while it continues
to look into the matter.

"The U.S. is one of the most highly regulated markets," says 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
BASF Technical Service Manager Lee Mores. In other words, Mores
says, 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 will likely 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 says.

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

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 rules 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.

In a letter to 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-benzotriazolyl 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 an 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 absorbed radiation like an
organic compound and scattered and reflected 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, Osterwalder says, 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, he adds. 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 says. The earliest that
Ciba expects to see these two new sunscreens allowed for use in
the U.S. is in 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," says 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 is still too early
to qualify Parasol SLX using the TEA route, he says.

"Parsol SLX addresses safety issues we think will come up in the
future," Sit says. Octyl methoxycinnimate 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, Sit says. 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, he explains.

While new sunscreen actives are unlikely to find their way into
the U.S. market 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 R&D, 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, he says.

According to David Browning, Oxonica's health care business
director, because titanium dioxide is already listed in FDA's
monograph, Oxonica expects to introduce its Optisol sunblocker
in the U.S. soon.

BASF has also supplemented its existing line of titanium dioxide
with two coated microfine pigments manufactured by Sakai Chemical
Industry of Japan. "It is a better grade of titanium dioxide
because it is more transparent than existing grades," technical
services manager Mores says.

And EMD Chemicals' Chaudhuri says his firm expects to 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 effectively boost the
sunscreen's photostability.

Many involved in the sunscreen ingredients business contend that
FDA is ignoring their industry's needs. And 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.

Docs rally for better sun protection
Advances still unavailable in United States

Jul 1, 2005
By: Beth Kapes
Dermatology Times

Vienna, Austria - While it is increasingly clear that ultraviolet A
radiation (UVA) defense is essential for immune protection, in the
United States, unlike many other parts of the world, there is a
lack of uniform standards for the assessment of UVA protectiveness
of sunscreen.

"Sunscreens with clearly defined broad spectrum protection is
needed (in the United States)," said Henry W. Lim, M.D., at the
10th World Congress on Cancers of the Skin, here. "We know that
sun protection factor (SPF) is a reflection of the protection
against the erythemogenic effect of UVB (rays). While there are
several methods to assess the protectiveness against UVA, these
have not yet been applied in the United States."

UVA filters approved by the U.S. Food and Drug Administration (FDA),
including avobenzone (Parsol 1789) and benzophenones, and
inorganic (physical) filters, namely, zinc oxide and titanium
dioxide, are the primary sunscreen actives used to protect against
skin damaging UVA. However, there are several filters with UVA
protection superior to the above available in other parts of the
world, including Canada, European Union, Mexico and Japan. Some
of these are currently undergoing the FDA approval process; as
such, they are not yet available in the United States.

New UVA filters Widely used and excellent UVA filters include
Mexoryl SX and Mexoryl XL (both patented by L'Oreal); two UVA
filters that have been approved in Europe in 1992 and 1999
respectively, and in Japan in 1999 and 2002. Sunscreens containing
these filters are available in Europe, Asia, Latin and South
America. Millions of units have been sold without any reported
adverse effects. Mexoryl SX provides long-lasting, effective
protection due to the virtually impervious nature of the molecule
to the action of solar energy, according to its manufacturer,
L'Oreal.

Additional superb UVA filters include Tinosorb M and Tinosorb S,
both manufactured by Ciba Specialty chemicals. Both are approved
in Europe, and Tinosorb M is also approved in Australia. Both are
photostable and have strong absorption in the UVB and UVA range.

"Mexoryl and Tinosorb are significantly better than what we have
now in the States for two reasons: one, both have significantly
better absorption in the UVA range; and two, from the data we
have now, both are photostable - they do not degrade following
exposure to light like many of the filters used currently," says
Dr. Lim, chairman and C.S. Livingood chair, department of
dermatology, Henry Ford Hospital, Detroit. "Recent studies show
that both types of Mexoryl are better than all (UVA) filters in
the U.S. in prevention of photo-induced conditions."

In several studies, the presence of Mexoryl SX and Mexoryl XL
rendered sunscreen products to be more efficient in preventing the
induction of lesions in patients with photosensitive lupus
erythematosus and in those with polymorphous light eruption, as
compared to sunscreens containing avobenzone and Ti02, as the UVA
filters (Stege, H, et al, Photodermatology Photoimmunology &
Photomedicine, Volume 16 Issue 6 , December 2000, and
Moyal, D, et al, J European Acad of Dermatology and Venereology,
Sept 1999, s 317).

"What's important is that we recognize UVA plays a significant
role in immune suppression, and that there are excellent UVA
filters available that would benefit our patients in the United
States," Dr. Lim says. "Mexoryl SX, Tinosorb M and Tinosorb S
are at various stages of the FDA-approval process. It is our hope
that this process will move forward in a timely manner."

Photodermatol Photoimmunol Photomed.2000 Dec;16(6):256-9
Evaluation of the capacity of sunscreens to photoprotect lupus
erythematosus patients by employing the photoprovocation test.
 Although sunscreens are widely used to photoprotect patients
with photosensitive lupus erythematosus (LE), standardized
controlled studies that can prove their efficacy for this
indication have been lacking. Therefore, in the present study,
the capacity of three different, commercially available
sunscreens to prevent the development of skin lesions that have
been induced in LE patients under standardized, reproducible
conditions by employing a provocative phototest was assessed. In
a double blind, intraindividual comparative study, 11 patients
with LE were photoprovoked according to a standard protocol. All
patients developed LE-specific skin lesions upon photoprovocation
with a combination of UVA plus UVB radiation. Each of the
sunscreens tested prevented the development of skin lesions in
this assay, but to various extents. Suncreen A (UVB: Octocrylene;
UVA: Mexoryl SX, Mexoryl XL, Parsol 1789; TiO2) was by far the
most effective by protecting in 11/11 patients. This protective
capacity was corroborated by studies in which strong ICAM-1 mRNA
expression was found in unprotected test areas, but not in
sunscreen A pretreated sites. In contrast to sunscreen A,
sunscreen B (UVB: Eusolex 6300, Parsol MCX, Uvinul T150,
Neohelipan; UVA: Parsol 1789; TiO2) protected in 5 patients and
sunscreen C (Eusolex 6300, Parsol MCX, Uvinul T150; UVA:
Parsol 1789; TiO2) in 3 out of 11 patients. These studies
indicate that the use of sunscreens is beneficial to LE patients
because it can prevent the development of UV radiation-induced
skin lesions. Effective protection, however, might vary
considerably between different sunscreens.