The 500 Dalton Rule of Dermal Penetration and Cosmetic Science

In the year 2000 this article was published in a magazine called “Experimental Dermatology”

According to Google the article has been cited some 667 times which is quite a bit, maybe us Cosmetic Chemists should take note?

On first glance the article seems to be saying that an ingredient has to be smaller than 500 Dalton (a molecular weight of 500 or less) in order for it to penetrate the skin and that molecules larger than that would be unable to penetrate.  One might read that and then feel like running off to their ingredient supplier and demanding to know the molecular weight of all the ‘actives’ that they purchase.  One might even feel like the fact that molecular weight isn’t make so much of in cosmetic science is the reason why many products don’t really work and aren’t Authentic.  But to think or do that would be to miss the point of what a cosmetic is and can do.

The full article is only 5 pages including references so it isn’t such a big deal to do so. It basically looks into the fact that most topical allergens are molecularly small, less than 500 Daltons, and that molecules of that size or smaller can more easily fit through the gaps in between the corneocytes and thus into the deeper layers of the skin and through into the bloodstream.

Testosterone patches are a good example of an active that is less than 500 Daltons (testosterone is 288 Daltons) and that is able to penetrate the skin this way.

Here is some information I found online about a Testosterone patch called Androderm. 

Each Androderm® 2.5 mg/day Transdermal Patch contains 12.2 milligrams of testosterone and delivers 2.5 milligrams of testosterone over 24 hours.

Looking at this we see that only around 20% of the available Testosterone is absorbed in the 24 hours.  

It is available in packs of 60 patches.

Each Androderm® 5 mg/day Transdermal Patch contains 24.3 milligrams of testosterone and delivers approximately 5 milligrams of testosterone over 24 hours.

It is available in packs of 30 patches.

Other ingredients in the gel reservoir include:

• ethanol,
• purified water,
• glycerol,
• glycerol monooleate,
• methyl laurate,
• carbomer copolymer (type B), and sodium hydroxide.

The adhesive substance is laminate AR-7584.

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So this is a gel type base with the Testosterone suspended or emulsified into it (I’m not entirely sure exactly where it sits as I haven’t thought about it for long enough but anyway…). The base would be designed to facilitate the release of the Testosterone through the skin.  Often an excess of active on the outside of the cell helps to force some of it through the cell, this may be why only 20% of the available testosterone gets through.  If you think of it as like a crowd situation where the momentum of the crowd behind you pushes you along, it’s the same scenario here.

Ideally these other ingredients are left behind on the surface and even more ideally they do not cause any detrimental effects but one can see from reading more about the side effects of these patches that there can be some topical irritation for some people, no doubt from the occlusion and the contact with an alcoholic gel which may well disrupt the skins protective membrane.

So is this Testosterone Patch similar to a cosmetic?

In short NO.  Even though some of the ingredients are the same as what we might use in cosmetics the point of the product is where the differentiation starts.  A transdermal patch is designed to deliver one active through the skin and into the bloodstream.  A cosmetic product is (mostly) designed to protect the skin and beautify it from the outside in while still allowing the skin to function normally.  For the most part cosmetics are not fully occlusive and this is because the skin acts as an organ of excretion so blocking it in any way can help trap toxins at the skin surface and then cause congestion, irritation and inflammation.  Beyond that the very definition of a cosmetic tells us all we need to know about where actives should have to get to to work – the blood stream is not our target!

All of the actions we expect from our cosmetic products can and do take place on skin cells and do not require access to the blood stream to facilitate this action, indeed we should try to avoid that.

How does the 500 Dalton Rule Play Out In Cosmetic Science?

In short, in terms of cosmetic actives and cosmetic activity it doesn’t.  The long answer involves some consideration of potential irritants, things that might penetrate into the bloodstream and the whole notion of ‘safe’ cosmetics and so for that reason a long answer is somewhat useful.

A word about Hyaluronic Acid.

Arguably the most common active to have its weight discussed openly in public is Hyaluronic Acid, not least because it is often bought in Low Molecular Weight or High Molecular Weight versions.  Hyaluronic Acid is always heavier than 500 Daltons whether it is the low or high molecular weight version. In fact it is likely that Low Molecular Weight HA weighs up to 50,000 Dalton!  However, to put that into perspective High Molecular Weight HA can weigh up to 1.5 Million Dalton. The question is ‘does that matter?”   The answer is NO.

If we look at this graph we see that Low Molecular Weight HA is around the same weight as Keratin and Elastin but is lighter than a common type of Collagen.  That means that in the grand scheme of things Low Molecular Weight HA is actually about the same weight as the structural stuff we have in our dermis.  But again this is somewhat irrelevant as the HA you put ONTO your skin does not end up in the dermis, not the Low or the Regular HA.

Hyaluronic Acid works as an osmotic delivery system that can push water-soluble actives deeper into the skin by forming a highly hydrated reservoir on the surface of the skin.  The main difference between the low and regular weight HA is in how thick it can get when you hydrate it and how it feels on the skin.  Both work well as osmotic pumps.  This situation would be quite different if we were looking at injecting HA as a dermal filler.

So what’s the go with Molecular Weight and Cosmetic Science?

Where the world of 500 Daltons and under and Cosmetic Science cross is in the realm of potential allergens.  While it is true that a cosmetic formula SHOULD be designed to keep ingredients away from the bloodstream there is always the potential that something applied topically can get in deeper and if or when it does it could cause issues ranging from an allergic reaction through to a toxicity.

The most common allergens in cosmetics are from the perfumes and preservatives we use and it is here that we will look next.

Perfumes and Essential Oils and the 500 Dalton Rule.

However we fragrance our products, be it with essential oils or synthetics, we are introducing a whole mixture of small aromatic components to the skin.  These aromatics are volatile (they move), indeed if they weren’t volatile we wouldn’t be able to smell them.  They have the potential to be quite irritating and further to that can act as penetration enhancers for other things especially if present at high enough levels.

Here are some of the aroma chemicals highlighted as being among the most likely to cause a skin reaction. No differentiation is made between those found naturally in Essential Oils and those from synthetic origin.

Citral MW 152.23 found in Lemon Myrtle, Lemongrass, Tea Tree, May Chang, Melissa, Verbena, Basil and a little in Lemon, Bergamot and Orange.

Benzyl Alcohol MW 108.14  found in Tolu Balsam, Benzoin and a little in violet Leaf and Jasmine Absolute.

Cinnamaldehyde MW 132.16 found in Cassia Leaf and Bark and Cinnamon Bark, a little (1%) In Cinnamon Leaf.

Eugenol MW 164.20 found in Clove Bud and Leaf, Cinnamon Leaf, Pimento Leaf and Berry, Basil.

Geraniol MW found in Bergamot, Thyme, Palmarosa, Rose, Citrnoella, Thyme.

 

Knowing that these ingredients above are allergens and given that they are all well under the 500 Daltons weight limit one could be tempted to draw the conclusion that it is because of their weight that they are a problem but again that would be unreasonable.  Pretty much all of the aromatic compounds we use or come across in life are molecularly small but not all are as allergenic as the above.

To further put this into perspective while the above are some of the aroma chemicals most likely to cause an allergic reaction they are all classified as weak allergens and in most cosmetic products the concentration of these particular aroma chemicals would naturally fall well below the sensitivity threshold which is often 2-3% of the active.  Essential oils and fragrances are often used at below 1% in most cosmetics.

An example of a much ‘safer’ in terms of dermal irritation aroma chemcial is Fenchone  Molecular Weight 152.23.

Fenchone is found in Spanish Lavender at concentrations up to 50%, in Fennel and Cedarwood.  According to Tisserand and Young’s “Essential Oil Safety” a study applying 4% to humans found it to be non irritating and non sensitizing.

So if the 500 Dalton mark isn’t the measure of allergenic potential what is?

I suppose the take-home message from this is that size isn’t everything.  Some of the aroma chemicals that can cause skin sensitisation or allergic response may be prone to oxidation and in cases like Linalool this is exactly what happens. Linalool (MW 154.25) oxidises to form hydroperoxides which are much more irritating than the starting point chemical. These hydroperoxides can form when the cosmetic or perfume oxidises meaning that unless cosmetics containing Lavender oil contain antioxidants and are packaged appropriately they can become quite a bit more irritating over time.

A safe cosmetic is a stable cosmetic.

To summarise I’d see the 500 Dalton rule as being somewhat interesting and worth keeping in mind with regards to the potential for your cosmetic fragrance to irritate (avoiding a fragrance would avoid all of these ‘small’ chemicals) but that it is in no way the most important thing to consider, not least because all aromatics used in cosmetics are this small.  Oxidative stability is far more important.

 

What about non-aromatic and non-active chemicals used in cosmetics?

Look at this:

Glycerin:     92.09 Dalton

Argirelene:  889 Dalton

Matrixyl:  578 Dalton

Ethanol: 46 Dalton

Water: 18 Dalton

Caprylic/Capric Triglyceride: 408 Dalton

Lactic Acid: 90 Dalton

L Ascorbic Acid: 176 Dalton

Retinol: 286 Dalton

Retinol Palmitate: 524 Dalton

Phenoxyethanol: 138.16 Dalton

Potassium Sorbate: 150.22 Dalton

From the list above you can see the average cosmetic product contains a range of small ingredients, many of which have a weight of less than 500 Dalton.  Glycerin and water are good examples of very small molecules that are not known for their dermal penetration and are known for their skin compatibility and low irritancy – people don’t get allergic to water or glycerin but may feel uncomfortable if their skin is hyper-hydrated (especially internal skin membranes) or if their barrier has been eroded as with a carpet burn or similar.

Argirelene and Matrixyl are two synthetic peptides manufactured by the cosmetic industry to improve the look and function of the skin.  Both are pushing the limits of ‘smallness’ but both have some degree of efficacy data behind them meaning they do something and you can see a result from using them.

Retinol absolutely is biologically active but it is way larger than glycerin or phenoxyethanol (a preservative).  Retinyl Palmitate  is metabolised THROUGH the skin so what you pop onto the surface isn’t what gets into the bloodstream, the skin breaks it down as it goes.

Talking of Retinol, the most biologically active version to be widely prescribed is Tretinoin which chemically is All-trans Retinoic Acid.

Retinyl Palmitate > Retinol > Retinal (Retinaldehyde) > Retanoic Acid

The skin can break down the Retinyl Palmitate to Retanoic Acid and allowing it to do so rather than just applying Retanoic Acid directly is a gentler but slower way to get results.

If we map the molecular weights of this conversion we get the following:

Retinyl Palmitate ( 524.86) > Retinol (286.45) > Retinal (284.44) > Retanoic Acid (300.44)

We see the size of the biologically active molecule go up and down, indeed the most biologically active form of the Vitamin A is slightly larger than the two middle steps.  Even though these molecular weights are tiny it does focus the attention on what really matters in terms of efficacy and authentic cosmetics and that’s this:

• What is your target?
• Where is your target?
• What is the solubility of your active?
• What concentration is required for an effect?

With Retinyl Palmitate it is of no consequence that we start with a molecule that is larger than 500 Dalton as the skin does the breaking down.

I found it interesting to note that this study found between 5-8% of the topical dose of Tretanoin was traceable in the bloodstream – and that’s an active that the skin is designed to soak up and metabolise. 

With Hyaluronic Acid it is of no consequence that we start with a hugely heavy and long molecule because it drives things into the cell from the outside.

With aroma chemicals the size is clearly not the only (or even most important) factor when trying to work out its allergy potential.

With Glycerin and Water we know that in spite of their tiny molecular size, these are two of the safest cosmetic ingredients around (in general).

So how should the Cosmetic Chemist relate to the 500 Dalton Rule?

Unintentional dermal penetration is clearly something for the cosmetic chemist to avoid.  There is no doubt that size can be a contributing factor to dermal penetration but it is not the ONLY factor and often in something as complex as a cosmetic formula, formulated for topical action, it is of minor importance.  For these reasons I would argue that the Cosmetic Chemist should focus more on understanding and having an appreciation for the four things above – target, location, solubility and concentration – and relegate ‘molecular size’ as of minor consequence.  I believe that the quest for safe and authentic cosmetic products is best achieved if one focuses on creating sensible and stable products rather than on the avoidance or adoption of things with small molecular weights.

Size isn’t everything.

Amanda x