*2.4.2.5.1. Introduction*

intensity of irradiation should be as uniform as possible. The material should be subjected to

The source of illumination should be either a tungsten light bulb or a warm white fluorescent light bulb that provides a level of illumination at the test site within the range of 450 to 550 lux

A series of UV radiation exposures expressed as joules per square meter is administered to the

A Colipa – FDA comparison is presented in Table 8. The FDA suggests some examples for SPF

on the estimated MEDu shall be exposed with incremental UV doses using a recommended geometric progression of either **1.12** or **1.25**.

that of the unprotected MED multiplied by the expected SPF of


For a product with an SPF of 8, given that the MED must correspond to the dose or to the median time, it will be surrounded with values obtained according to a geometric sequence at

Furthermore, 2 doses placed symmetrically in relation to the median dose are added, here:

the product.

Measure - 24 h after exposure - 24 h after exposure

**Colipa FDA**



previous time .


exposure.

other exposures placed

symmetrically around the middle

frequent radiometric controls.

140 Highlights in Skin Cancer

from 8 to 15.

**Table 8.** MED determination

0.9 x MED and 1.10 x MED

a rate of 1.25:

*2.4.2.4.3. Determining the MED in practice*

(FDA) or a xenon arc solar simulator with a filtering system.

each subject with an accurately-calibrated solar simulator.

Unprotected skin - a minimum of **5** sub-sites centred

Protected skin - The centre of the UV dose range is

0.64 x MED – 0.80 x MED – 1 MED – 1.25 Med – 1.56 MED

Although the protocol of determining the SPF is very clearly defined, both in Europe and in America, this is not the case concerning the UVA protection factor [52]. The two most fre‐ quently used methods are the IPD (Immediate Pigment Darkening) and PPD (Persistent Pigment Darkening) methods. Since 2007, taking the UVA protection in a sunscreen into account has become a necessity in Europe, with the establishing of 5 categories corresponding to no, low, medium, high and highest UVA protection [53].

## *2.4.2.5.2.- IPD and PPD methods*

These methods are based on the evaluation of the Meirowski phenomenon consecutive to the action of UVA rays. To do this, a halide lamp or a xenon arc lamp equipped with UVB filters is used. The subjects who are recruited have phototypes III and IV because they are likely to develop a tan in the evening. If the reading takes place at a maximum of 2 hours after irradi‐ ation, we refer to the IPD (immediate pigment darkening) method. If the reading is taken later, we can refer to it as the PPD (persistant pigment darkening) method [54, 55, 56].

The UVA-PF is defined according to:

UVA-PF = MIPDDprotected skin / DMIPDDunprotected skin

with MIPDD, Minimum Immediate Pigment Darkening Dose

or :

UVA-PF = MPPDDprotected skin / MPPDDunprotected skin

with MPPDD, the Minimal Persistent Pigment Darkening Dose.

*2.4.3. In vitro methods of determining the efficacy of sun products*

#### *2.4.3.1. Determining the SPF in vitro*

There is no official method in this field. All the methods which are proposed are spectropho‐ tometric methods based on the Beer Lambert law which links the absorbance of a sample to its concentration of active molecules. The principal of determining the SPF *in vitro* is based on measuring the transmittance of a sun product applied on various kinds of support. In the 1980's, Sayre and Agin studied different spectral light sources enabling them to correlate the results obtained respectively by *in vitro* and *in vivo* methods [58]. The first trials were carried out on supports such as certain animal skins (mice and pigs) or even on human skin. In 1989, Diffey and Robson tested a new substrate called Transpore® (3M, St Paul, US), a cheap adhesive system [59]. Its supple texture means that it must be placed on a rigid plate (such as quartz). The main disadvantage for its use is that it has varying sizes of pores depending on the part of the roll of the material which is used (which means that the first and last 60cm of the roll must be discarded and that the pores vary in size from one roll to the next. It is interesting for testing simple formulas, however, the results obtained are very different from those observed *in vivo* for formulas including complex mixtures of filters [60]. The quartz plates can also be used alone. They have 2 disadvantages: they are expensive and as they are not disposable, they must be rigorously cleaned between 2 series of measurements. Even though they are able to be used in research, they seem to be quite unsuitable for industrial use [61]. Skin substitutes (Vitroskin®) provide an interesting analogy with real skin, but they are expensive and they have a limited length of use once they have been rehydrated [62]. Different synthetic substrates are currently used, such as polyvinylchloride film (Saran Wrap®), Teflon [63] and polyme‐ thylmethacrylate (PMMA) [64, 65]. Whatever support is chosen, its efficacy in UVB light is determined by calculation, by effecting the convolution product of the spectrum of the source, of the spectrum transmitted through the sample and of the spectrum of the erythemogenic efficacy (figure 2) [66] and by integrating the area under the curve in the following formula:

$$SPF = \frac{\sum\_{290}^{400} E\_{\lambda} \mathcal{S}\_{\lambda} \Delta\lambda}{\sum\_{290}^{400} E\_{\lambda} \mathcal{S}\_{\lambda} T\_{\lambda} \Delta\lambda}$$

with E<sup>λ</sup> being the spectral erythemogenic efficacy (International Committee on Illumination), Sλ being solar spectral irradiance and Tλ being the spectral transmittance of the sample.

determines the rating. There are 4 categories (ratio ≥ 0.2 "low – 1 star" ; ratio ≥ 0.4 "medium –

**Figure 2.** Variations of weighting coefficients for each wavelength concerning erythema and non-melanoma skin can‐

About Suncare Products http://dx.doi.org/10.5772/55411 143

The technique and the quantity of the product applied on the skin play an important role in the obtained level of photoprotection. The same applies to the water-resistance of products [69] which is an important element to take into account when choosing a product which is going

The FDA and the Colipa propose protocols for determining the water-resistance of sun

The principal is the same in both cases. The subjects are immersed in a swimming pool or a jacuzzi, etc. On the other hand, the way of interpreting the results is not done in the same way

2 stars" ; ratio ≥ 0.7 "high – 4 stars" ; ratio > 0.95 "highest – 4 stars") [68].

**2.5. Determining water-resistance and photostability**

n‐melanoma skin cancer

*2.5.1.1. In vivo methods of determining water-resistance*

*2.5.1. Determining water-resistance*

in Europe and in the United States.

to be used on the beach.

Wavelength ‐‐‐‐‐Er

‐‐‐‐‐No

cer (Norme CEI 60335-2-27, 2002)

ythemal

products [70, 71].

#### *2.4.3.2. In vitro determination of the UVA-PF*

The Colipa published guidelines in 2007 for determining the UVA index *in vitro*. The initial UVA-PF is calculated using the UV absorbance spectrum which was adjusted to the labelled SPF. Sunscreen samples were then exposed to a single UV dose of 1.2 times the initial UVA-PF (in joules/m²). The final UVA-PF values for the samples were calculated from the adjusted absorbance spectrum after irradiation [67]. Other calculations made are those of the SPF/UVA-PF ratio, which must be lower than 3, and the critical wavelength λ<sup>c</sup> (the wavelength under which the product is 90% effective) which must be above or equal to 370 nm according to the recommendations of the AFSSaPS.

At the same time, the FDA suggested an *in vitro* method for determining the efficacy in UVA rays. The *in vitro* UVA proposed is based on measurement of UV transmission through a sunscreen film. The absorbance curve was obtained, in this case after pre-irradiation with a UV dose specified as two thirds of the SPF in Minimal Erythemal Doses (MEDs) (1 MED = 20 SED), and the mean absorbance in the UVA1 range from 340 to 400 nm and the entire UV range from 290 to 400 nm were determined. The ratio of mean UVA1 absorbance to mean absorbance

Wavelength ‐‐‐‐‐Er ythemal

out on supports such as certain animal skins (mice and pigs) or even on human skin. In 1989, Diffey and Robson tested a new substrate called Transpore® (3M, St Paul, US), a cheap adhesive system [59]. Its supple texture means that it must be placed on a rigid plate (such as quartz). The main disadvantage for its use is that it has varying sizes of pores depending on the part of the roll of the material which is used (which means that the first and last 60cm of the roll must be discarded and that the pores vary in size from one roll to the next. It is interesting for testing simple formulas, however, the results obtained are very different from those observed *in vivo* for formulas including complex mixtures of filters [60]. The quartz plates can also be used alone. They have 2 disadvantages: they are expensive and as they are not disposable, they must be rigorously cleaned between 2 series of measurements. Even though they are able to be used in research, they seem to be quite unsuitable for industrial use [61]. Skin substitutes (Vitroskin®) provide an interesting analogy with real skin, but they are expensive and they have a limited length of use once they have been rehydrated [62]. Different synthetic substrates are currently used, such as polyvinylchloride film (Saran Wrap®), Teflon [63] and polyme‐ thylmethacrylate (PMMA) [64, 65]. Whatever support is chosen, its efficacy in UVB light is determined by calculation, by effecting the convolution product of the spectrum of the source, of the spectrum transmitted through the sample and of the spectrum of the erythemogenic efficacy (figure 2) [66] and by integrating the area under the curve in the following formula:

with E<sup>λ</sup> being the spectral erythemogenic efficacy (International Committee on Illumination), Sλ being solar spectral irradiance and Tλ being the spectral transmittance of the sample.

The Colipa published guidelines in 2007 for determining the UVA index *in vitro*. The initial UVA-PF is calculated using the UV absorbance spectrum which was adjusted to the labelled SPF. Sunscreen samples were then exposed to a single UV dose of 1.2 times the initial UVA-PF (in joules/m²). The final UVA-PF values for the samples were calculated from the adjusted absorbance spectrum after irradiation [67]. Other calculations made are those of the SPF/UVA-PF ratio, which must be lower than 3, and the critical wavelength λ<sup>c</sup> (the wavelength under which the product is 90% effective) which must be above or equal to 370 nm according to the

At the same time, the FDA suggested an *in vitro* method for determining the efficacy in UVA rays. The *in vitro* UVA proposed is based on measurement of UV transmission through a sunscreen film. The absorbance curve was obtained, in this case after pre-irradiation with a UV dose specified as two thirds of the SPF in Minimal Erythemal Doses (MEDs) (1 MED = 20 SED), and the mean absorbance in the UVA1 range from 340 to 400 nm and the entire UV range from 290 to 400 nm were determined. The ratio of mean UVA1 absorbance to mean absorbance

*SPF* =

∑ 290 400

∑ 290 400

142 Highlights in Skin Cancer

*EλSλΔλ*

*EλSλTλΔλ*

*2.4.3.2. In vitro determination of the UVA-PF*

recommendations of the AFSSaPS.

 ‐‐‐‐‐No n‐melanoma skin cancer

**Figure 2.** Variations of weighting coefficients for each wavelength concerning erythema and non-melanoma skin can‐ cer (Norme CEI 60335-2-27, 2002)

determines the rating. There are 4 categories (ratio ≥ 0.2 "low – 1 star" ; ratio ≥ 0.4 "medium – 2 stars" ; ratio ≥ 0.7 "high – 4 stars" ; ratio > 0.95 "highest – 4 stars") [68].

#### **2.5. Determining water-resistance and photostability**

#### *2.5.1. Determining water-resistance*

The technique and the quantity of the product applied on the skin play an important role in the obtained level of photoprotection. The same applies to the water-resistance of products [69] which is an important element to take into account when choosing a product which is going to be used on the beach.

#### *2.5.1.1. In vivo methods of determining water-resistance*

The FDA and the Colipa propose protocols for determining the water-resistance of sun products [70, 71].

The principal is the same in both cases. The subjects are immersed in a swimming pool or a jacuzzi, etc. On the other hand, the way of interpreting the results is not done in the same way in Europe and in the United States.

In the United States, a product can display the words "water resistant" on the packaging and the SPF mentioned is the SPF obtained after 2 successive baths of 20 minutes. For the product to qualify as being "very water resistant", it must have undergone a test of 4 successive baths of 20 minutes.

retain more than 90% of their efficacy after irradiation in a solar simulator are deemed to be photostable. Eight filters (PABA, Oxybenzone, Phenilbenzimidazole sulfonic acid, Octocry‐ lene, Diethylhexylbutamidotriazine, 4-methylbenzylidene camphor, Benzophenone-5 and Methylene bis-benzotriazolyl tetramethylbutylphenol) appear to be interesting and likely to

About Suncare Products http://dx.doi.org/10.5772/55411 145

There are two categories of active ingredients, inorganic filters, also known as screens, and

Two screens could be used: titanium dioxide and zinc oxide which act by reflecting the ultraviolet rays. Both take the form of an inert, particularly photostable white powder [80, 81]. They were used for a long time in pigmentation, but were considered not to be very effective and were not very aesthetic due to the fact that they leave a white film on the skin sometimes called the "Pierrot's mask". The micronization of powders brought a solution to these 2 disadvantages [82, 83]. The reduction of the size of the particles from 200 nm to 15 nm makes the products more acceptable and coating them makes them disperse more easily in the chosen excipient. However, the reduction of the size of the particles raises certain questions, namely as to whether they can cross the skin barrier. Studies on pig skin show that micro-thin zinc oxide and titanium dioxide powders do not penetrate into the skin [84]. Similar results were obtained *in vivo* by the stripping method and showed that zinc oxide (Z-Cote Max® BASF) was restricted to the superficial layers of the epidermis, namely the *Stratum corneum* [85]. As for harmlessness, the results contrast. Some people argue that a risk exists, zinc oxide could have potentially genotoxic effects on human epidermal cells [86] and titanium dioxide could be cytotoxic and genotoxic on cell cultures (hamster ovary cells) [87]. For others, these ingredients are totally safe [88, 89]. Concerning efficacy, titanium dioxide proves to be the most efficient, as it gives an SPF value of 10 (Eusolex TS®) as opposed to 5 for zinc oxide (Z-Cote Max®) for the same incorporation percentage of 10%. It can be noted, however, that zinc oxide has a wider spectrum as it proves to be as efficient in the UVA field as in the UVB field, contrary to titanium

dioxide which is 2.5 times less efficient in UVA rays as in UVB rays [90].

It is a question of molecules which have one or more aromatic cycles associated with a substituent electron donor and/or an unsaturated hydrocarbon chain. These molecules are characterized by a chromophoric group which absorbs the incident photons' energy at certain wavelengths. It is said that the filters are selective, as they only absorb energy in a well-defined range of the UV spectrum. Each filter is thus characterized by its wavelength of maximum

stabilize the formulas they are incorporated into [79].

**2.6. Active ingredients**

*2.6.1. Inorganic filters or screens*

organic filters.

*2.6.2. Organic filters*

*2.6.2.1. Introduction*

absorption (λmax).

In Europe, a certain number of pre-requisites must be checked before the test is carried out to ensure that the incertitude is less than 17% of the average SPF. A percentage of water resistance is calculated by comparing the SPF obtained after 2 successive baths of 20 minutes and the initial SPF. If the percentage is higher than or equal to 50% of the initial SPF, then the product is declared as being "water resistant". In the same way, a product is declared as being "very water resistant" if after 80 minutes of immersion (4 periods of 20 minutes) the percentage of water resistance is higher than or equal to 50%. In both cases, the SPF displayed is the initial one (obtained before immersion).

#### *2.5.1.2. In vitro method of determining water resistance*

Very few studies exist concerning the development of *in vitro* techniques. Work by Choquenet et al can be quoted, which, by analogy with the Colipa method, provide the necessary conditions for distinguishing water resistant products from products which can be washed away with water [72]. The authors recommend immersing the PMMA plates, coated with the product which is to be tested, in a bath of distilled water, shaken gently (5 L.min-1) and at a temperature of 29 ± 2°C. The creams are applied to the PMMA plates and their SPF is measured using an integrating sphere spectrophotometer (Labsphère UV1000S) before and after immersion. As in the *in vivo* method, the product is deemed "water resistant" if the SPF after the bath is at least 50% of the initial SPF.

#### *2.5.2. Determining the photostability of sun products*

The photostability of sun products is an important criterion for two reasons: if the product is not photostable, its efficacy will decrease rapidly over time and the subject will thus no longer be sufficiently protected. Furthermore, the production of photo-oxidation products can lead to problems of skin tolerance [73]. It is advisable therefore to study the photodegradation profile of the filters incorporated into the excipients and to determine efficacy kinetics over time. Certain filters such as PABA [74] or benzophenones [75] are reputed to be very photo‐ stable. Other filters which are not very photostable, such as avobenzone, have a varying degree of stability according to the composition of the medium [76]. The filters can be studied alone or in a mixture, they can be irradiated after being placed on a glass plate in the UVB/UVA field and their photostability can be assessed by the dose of HPLC [77] or they can be studied *in vivo*. L'Oréal carried out an *in vivo* study in 2008 on 5 subjects. This study consisted in applying a product (SPF 15 ; FP-UVA 15) onto the volunteers' skin, formulated with 3 organic filters, octocrylene, avobenzone and Mexoryl SX®, irradiating them at doses ranging from 64 to 200% of the SPF, in retrieving the product from the skin and then dosing the filters. There was no significant difference between the rate of filters before and after irradiation, even for the high doses (200% SPF ie. 30 MED) [78]. A systematic study of the 18 UVB filters which are authorized in Europe enabled the filters to be ranked in ascending order of photostability. The filters which retain more than 90% of their efficacy after irradiation in a solar simulator are deemed to be photostable. Eight filters (PABA, Oxybenzone, Phenilbenzimidazole sulfonic acid, Octocry‐ lene, Diethylhexylbutamidotriazine, 4-methylbenzylidene camphor, Benzophenone-5 and Methylene bis-benzotriazolyl tetramethylbutylphenol) appear to be interesting and likely to stabilize the formulas they are incorporated into [79].

#### **2.6. Active ingredients**

In the United States, a product can display the words "water resistant" on the packaging and the SPF mentioned is the SPF obtained after 2 successive baths of 20 minutes. For the product to qualify as being "very water resistant", it must have undergone a test of 4 successive baths

In Europe, a certain number of pre-requisites must be checked before the test is carried out to ensure that the incertitude is less than 17% of the average SPF. A percentage of water resistance is calculated by comparing the SPF obtained after 2 successive baths of 20 minutes and the initial SPF. If the percentage is higher than or equal to 50% of the initial SPF, then the product is declared as being "water resistant". In the same way, a product is declared as being "very water resistant" if after 80 minutes of immersion (4 periods of 20 minutes) the percentage of water resistance is higher than or equal to 50%. In both cases, the SPF displayed is the initial

Very few studies exist concerning the development of *in vitro* techniques. Work by Choquenet et al can be quoted, which, by analogy with the Colipa method, provide the necessary conditions for distinguishing water resistant products from products which can be washed away with water [72]. The authors recommend immersing the PMMA plates, coated with the product which is to be tested, in a bath of distilled water, shaken gently (5 L.min-1) and at a temperature of 29 ± 2°C. The creams are applied to the PMMA plates and their SPF is measured using an integrating sphere spectrophotometer (Labsphère UV1000S) before and after immersion. As in the *in vivo* method, the product is deemed "water resistant" if the SPF after

The photostability of sun products is an important criterion for two reasons: if the product is not photostable, its efficacy will decrease rapidly over time and the subject will thus no longer be sufficiently protected. Furthermore, the production of photo-oxidation products can lead to problems of skin tolerance [73]. It is advisable therefore to study the photodegradation profile of the filters incorporated into the excipients and to determine efficacy kinetics over time. Certain filters such as PABA [74] or benzophenones [75] are reputed to be very photo‐ stable. Other filters which are not very photostable, such as avobenzone, have a varying degree of stability according to the composition of the medium [76]. The filters can be studied alone or in a mixture, they can be irradiated after being placed on a glass plate in the UVB/UVA field and their photostability can be assessed by the dose of HPLC [77] or they can be studied *in vivo*. L'Oréal carried out an *in vivo* study in 2008 on 5 subjects. This study consisted in applying a product (SPF 15 ; FP-UVA 15) onto the volunteers' skin, formulated with 3 organic filters, octocrylene, avobenzone and Mexoryl SX®, irradiating them at doses ranging from 64 to 200% of the SPF, in retrieving the product from the skin and then dosing the filters. There was no significant difference between the rate of filters before and after irradiation, even for the high doses (200% SPF ie. 30 MED) [78]. A systematic study of the 18 UVB filters which are authorized in Europe enabled the filters to be ranked in ascending order of photostability. The filters which

of 20 minutes.

144 Highlights in Skin Cancer

one (obtained before immersion).

the bath is at least 50% of the initial SPF.

*2.5.2. Determining the photostability of sun products*

*2.5.1.2. In vitro method of determining water resistance*

There are two categories of active ingredients, inorganic filters, also known as screens, and organic filters.

#### *2.6.1. Inorganic filters or screens*

Two screens could be used: titanium dioxide and zinc oxide which act by reflecting the ultraviolet rays. Both take the form of an inert, particularly photostable white powder [80, 81]. They were used for a long time in pigmentation, but were considered not to be very effective and were not very aesthetic due to the fact that they leave a white film on the skin sometimes called the "Pierrot's mask". The micronization of powders brought a solution to these 2 disadvantages [82, 83]. The reduction of the size of the particles from 200 nm to 15 nm makes the products more acceptable and coating them makes them disperse more easily in the chosen excipient. However, the reduction of the size of the particles raises certain questions, namely as to whether they can cross the skin barrier. Studies on pig skin show that micro-thin zinc oxide and titanium dioxide powders do not penetrate into the skin [84]. Similar results were obtained *in vivo* by the stripping method and showed that zinc oxide (Z-Cote Max® BASF) was restricted to the superficial layers of the epidermis, namely the *Stratum corneum* [85]. As for harmlessness, the results contrast. Some people argue that a risk exists, zinc oxide could have potentially genotoxic effects on human epidermal cells [86] and titanium dioxide could be cytotoxic and genotoxic on cell cultures (hamster ovary cells) [87]. For others, these ingredients are totally safe [88, 89]. Concerning efficacy, titanium dioxide proves to be the most efficient, as it gives an SPF value of 10 (Eusolex TS®) as opposed to 5 for zinc oxide (Z-Cote Max®) for the same incorporation percentage of 10%. It can be noted, however, that zinc oxide has a wider spectrum as it proves to be as efficient in the UVA field as in the UVB field, contrary to titanium dioxide which is 2.5 times less efficient in UVA rays as in UVB rays [90].

#### *2.6.2. Organic filters*

#### *2.6.2.1. Introduction*

It is a question of molecules which have one or more aromatic cycles associated with a substituent electron donor and/or an unsaturated hydrocarbon chain. These molecules are characterized by a chromophoric group which absorbs the incident photons' energy at certain wavelengths. It is said that the filters are selective, as they only absorb energy in a well-defined range of the UV spectrum. Each filter is thus characterized by its wavelength of maximum absorption (λmax).

#### *2.6.2.2. The main families and their characteristics*

PABA (λmax = 309 nm) is now banned in Europe due to the fact that it is highly allergenic [91]. Its derivatives (PEG-25 PABA and Octyldimethyl PABA) are less allergenic and are still authorized in Europe. They are some examples of the few hydrosoluble filters available. According to the grafting which was carried out, the efficacy is variable. Octyldimethyl PABA (Padimate O) enables an SPF value of 9 to be attained for 8% of incorporation, and PEG-25 PABA gives an SPF of 4 for 10% [92].

Mexoryls® and more precisely Mexoryl SX® are derivatives of camphor. The latter is the only Mexoryl® of the series to be authorized in the United States. It is presented as an interesting filter regarding protection from skin damage caused by UVA rays both *in vitro*

About Suncare Products http://dx.doi.org/10.5772/55411 147

Concerning UVA filters, avobenzone is widely used and its lack of stability can be compen‐ sated for by combining it with other filters. Encapsulation, although fuelling many publica‐ tions, has not enabled any industrial application so far [105, 106]. Neoheliopan AP® and Uvinul

It is a pity that 3-benzylidene camphor (limited to 2%) is still authorized in Europe, as at this dose it is almost inefficient and it is also suspected of being an endocrine disruptor [107, 108].

Although a certain number of authors claim that the toxicity of organic filters is irrefutable, the same cannot be said for the others. The potential endocrine effect of certain filters is not conclusive and the controversy concerning parabens which has shaken the scientific com‐ munity [109] lead us to believe that in the field, it is necessary to be prudent and indispensable ingredients for photoprotection should not be too hastily discredited. However, confronted with these threats, it would be advisable to find new filters, especially using plants as a source, as well as ingredients which could complete the action thanks to their original properties. We could mention, for example, boldine, an alkaloid from the boldo tree, which has been known for a long time for its antioxidant properties [110] and more recently for a potential photoprotective effect [111]. Aromatic compounds contained in certain lichens [1 chloropan‐ narine, epiphorelic acid I and II, calicine) prove *in vitro* to be of a level of efficacy comparable to that of OMC [112]. Flavonoids, natural colorants of many plants prove to be an interesting family too with chlorogenic acid in particular (SPF = 10), baicaline (SPF = 8), luteoline (SPF = 7), apigenine (SPF = 7), puerarine (SPF = 6) for a usage dose of 10% [113]. Coming from the sea, mycosporine-like aminoacids seem to be interesting in particular with a potential photopro‐

Recently, there has been a wave of care products and make-up with SPF on the market, their SPF being mainly around 15. The justification for this is found in publications which state that there is a beneficial effect of using filters on a daily basis in order to prevent skin ageing and in particular using a mixture of avobenzone (1.5%) - ecamsule (1.5%) - octocrylene (4%) [117]. Even if we know very well that UV rays are responsible for actinic ageing, the daily use of products containing filters does not seem to be a good thing. It appears that filters, even though they are active, sometimes have adverse effects. They must be kept, therefore, for use in sun care products, all the more so as these other care products are not sun care products, so do not have to obey the same rules, namely those concerning the SPF / UVA-PF ratio and the critical

and *in vivo* [103, 104].

*2.6.3. Molecules of interest*

A+® are not authorized in the United States yet.

tective effect in the UVA field [114, 115, 116].

wavelength [118].

**3. Care products and make-up with SPF**

Cinnamates are the most widely used UVB filters. As an example, we can give octylmethox‐ ycinnamate (OMC) (λmax = 310 nm). Indeed, it is found in a large number of products on the market. Cinnamates are well tolerated, even though they are linked with the notion of being endocrine disruptors. It should be remembered however, that OMC has 140,000 times less affinity for α receptors and 500,000 times less affinity for β oestrogen receptors than βestradiol, the standard oestrogen [93] and that its uterotrophic effects in animals is judged to be very low [94]. Cinnamic esters are quite efficient filters as they generate approximately 1 SPF unit per percentage of use [92].

Salicylates are poor photoprotectors. We can mention in particular homomenthyl salicylate or homosalate (λmax = 306 nm) which, when incorporated into the recommended excipient at 8%, constitutes the FDA standard and which enables an average SPF of 4.47 (4.47 ± 1.279) to be reached. It is practically non-existent in European products. Certain publications report that octisalate (or octyl salicylate) has a proliferative effect on MCF-7 cells in breast cancer [95].

Benzophenones are wide spectrum filters which give 2 maxima of absorption in UV rays, one of 285 nm and the other close to 325 nm. As examples, we can mention benzophenone-3 (or oxybenzone) and benzophenone-4 and 5. Although they are not very efficient filters (SPF of 3 to 10% for oxybenzone and 4 to 5% for benzophenone-4), they are interesting, however, because they are very stable. Their low substantivity is a disadvantage, as is their poor tolerance (frequent allergic reactions for oxybezone) [96, 97]. Questions are being raised in other respects, as there could be a potentialization of the transdermic penetration of oxybenzone by a frequently associated repellent, DEET (NN diethyl-m-toluamide) but opinions are divided [98, 99]. What is certain is that oxybenzone is a filter which is found in the organism after topical application. It is known that 1 to 2% of the oxybenzone contained in a formula is absorbed after 10 hours. It is advised that these products should not be applied over large surfaces and that repeated applications should be avoided [100]. As for formulation, certain ingredients such as Transcutol® (diethylene glycol monoethyl ether) could be looked for, which increase substantivity without favouring crossing the skin barrier [101]. These are not therefore filters that should be rejected, but rather filters that should be used with care.

Triazines and derivatives (Bemotrizinal or Tinosorb S® -305 and 360 nm- and Bisoctrizole or Tinosorb M® -310 et 340 nm) are safe from a toxicological point of view [102]. They are marketed by a company called Ciba and are synergic. It is thus particularly interesting to combine them in the same formula. Bisoctrizole is both the best UVB and the best UVA filter on the market [92].

Mexoryls® and more precisely Mexoryl SX® are derivatives of camphor. The latter is the only Mexoryl® of the series to be authorized in the United States. It is presented as an interesting filter regarding protection from skin damage caused by UVA rays both *in vitro* and *in vivo* [103, 104].

Concerning UVA filters, avobenzone is widely used and its lack of stability can be compen‐ sated for by combining it with other filters. Encapsulation, although fuelling many publica‐ tions, has not enabled any industrial application so far [105, 106]. Neoheliopan AP® and Uvinul A+® are not authorized in the United States yet.

It is a pity that 3-benzylidene camphor (limited to 2%) is still authorized in Europe, as at this dose it is almost inefficient and it is also suspected of being an endocrine disruptor [107, 108].

#### *2.6.3. Molecules of interest*

*2.6.2.2. The main families and their characteristics*

PABA gives an SPF of 4 for 10% [92].

percentage of use [92].

146 Highlights in Skin Cancer

filter on the market [92].

PABA (λmax = 309 nm) is now banned in Europe due to the fact that it is highly allergenic [91]. Its derivatives (PEG-25 PABA and Octyldimethyl PABA) are less allergenic and are still authorized in Europe. They are some examples of the few hydrosoluble filters available. According to the grafting which was carried out, the efficacy is variable. Octyldimethyl PABA (Padimate O) enables an SPF value of 9 to be attained for 8% of incorporation, and PEG-25

Cinnamates are the most widely used UVB filters. As an example, we can give octylmethox‐ ycinnamate (OMC) (λmax = 310 nm). Indeed, it is found in a large number of products on the market. Cinnamates are well tolerated, even though they are linked with the notion of being endocrine disruptors. It should be remembered however, that OMC has 140,000 times less affinity for α receptors and 500,000 times less affinity for β oestrogen receptors than βestradiol, the standard oestrogen [93] and that its uterotrophic effects in animals is judged to be very low [94]. Cinnamic esters are quite efficient filters as they generate approximately 1 SPF unit per

Salicylates are poor photoprotectors. We can mention in particular homomenthyl salicylate or homosalate (λmax = 306 nm) which, when incorporated into the recommended excipient at 8%, constitutes the FDA standard and which enables an average SPF of 4.47 (4.47 ± 1.279) to be reached. It is practically non-existent in European products. Certain publications report that octisalate (or octyl salicylate) has a proliferative effect on MCF-7 cells in breast cancer [95].

Benzophenones are wide spectrum filters which give 2 maxima of absorption in UV rays, one of 285 nm and the other close to 325 nm. As examples, we can mention benzophenone-3 (or oxybenzone) and benzophenone-4 and 5. Although they are not very efficient filters (SPF of 3 to 10% for oxybenzone and 4 to 5% for benzophenone-4), they are interesting, however, because they are very stable. Their low substantivity is a disadvantage, as is their poor tolerance (frequent allergic reactions for oxybezone) [96, 97]. Questions are being raised in other respects, as there could be a potentialization of the transdermic penetration of oxybenzone by a frequently associated repellent, DEET (NN diethyl-m-toluamide) but opinions are divided [98, 99]. What is certain is that oxybenzone is a filter which is found in the organism after topical application. It is known that 1 to 2% of the oxybenzone contained in a formula is absorbed after 10 hours. It is advised that these products should not be applied over large surfaces and that repeated applications should be avoided [100]. As for formulation, certain ingredients such as Transcutol® (diethylene glycol monoethyl ether) could be looked for, which increase substantivity without favouring crossing the skin barrier [101]. These are not therefore filters

Triazines and derivatives (Bemotrizinal or Tinosorb S® -305 and 360 nm- and Bisoctrizole or Tinosorb M® -310 et 340 nm) are safe from a toxicological point of view [102]. They are marketed by a company called Ciba and are synergic. It is thus particularly interesting to combine them in the same formula. Bisoctrizole is both the best UVB and the best UVA

that should be rejected, but rather filters that should be used with care.

Although a certain number of authors claim that the toxicity of organic filters is irrefutable, the same cannot be said for the others. The potential endocrine effect of certain filters is not conclusive and the controversy concerning parabens which has shaken the scientific com‐ munity [109] lead us to believe that in the field, it is necessary to be prudent and indispensable ingredients for photoprotection should not be too hastily discredited. However, confronted with these threats, it would be advisable to find new filters, especially using plants as a source, as well as ingredients which could complete the action thanks to their original properties.

We could mention, for example, boldine, an alkaloid from the boldo tree, which has been known for a long time for its antioxidant properties [110] and more recently for a potential photoprotective effect [111]. Aromatic compounds contained in certain lichens [1 chloropan‐ narine, epiphorelic acid I and II, calicine) prove *in vitro* to be of a level of efficacy comparable to that of OMC [112]. Flavonoids, natural colorants of many plants prove to be an interesting family too with chlorogenic acid in particular (SPF = 10), baicaline (SPF = 8), luteoline (SPF = 7), apigenine (SPF = 7), puerarine (SPF = 6) for a usage dose of 10% [113]. Coming from the sea, mycosporine-like aminoacids seem to be interesting in particular with a potential photopro‐ tective effect in the UVA field [114, 115, 116].
