Why should you care about the 500 Dalton rule?

Big Molecules Can’t Penetrate Skin

You may or may not have heard of a concept in skin care pharmacology called the 500 dalton rule. This rule was proposed in the year 2000 to describe the upper limit molecular weight for a molecule to be able to penetrate into skin. This “rule” explains why some ingredients seem to just sit on the skin, while other ingredients can seep right into the lower layers of the skin. To explain this concept a little better, we need some background on the layers of the skin.

Layers of the Skin

The skin is composed of 3 basic layers. The epidermis is the outermost layer and provides the waterproof barrier necessary to keep bad things like bacteria out. The dermis lies underneath the epidermis and contains the connective tissue, hair follicles, and sweat glands. Finally, the deepest layer is the subcutaneous fat or hypodermis.

layers of skin


The epidermis is further subdivided into 5 more layers. From top to bottom these are the: stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale.

For a medication or skin care product to work, it must first traverse that outermost layer, the stratum corneum. Thankfully for humans, this layer of skin is tough and waterproof for the most part. Unfortunately, this hampers our ability to deliver treatments via the skin.

Stratum Corneum Barrier Function

The stratum corneum is made up of dead keratinocytes that contain a lot of keratin and a cornified cell envelope. In order for a molecule to make it through, it will have to pass through or between the cells. Most molecules pass between cells. Molecules that attract fat (lipophilic) will pass more easily between the cells because cell membranes are hydrophobic. This means they repel water.

Some water-soluble molecules may be able to penetrate through the openings of the hair follicles and sweat glands. However, this only makes up a total of 0.1% of your body surface area.

500 Dalton Rule: Molecules <500 daltons in weight can penetrate skin.

Size and Charge

Barring the charge of the molecule, the biggest impediment to traversing the stratum corneum is the size of the molecule. Enter the 500 dalton rule. If a molecule is small (as in less than 500 daltons in molecular weight) then the molecule will be able to traverse the space between the dead keratinocytes in the stratum corneum and continue its merry way down into the deeper layers.

How did they come up with this rule?

The inventors of the 500 dalton rule investigated the molecular weights of allergens that cause allergic contact dermatitis and the most commonly used topical drugs in dermatology. They found that all of the allergens and drugs had a molecular weight of less than 500 daltons. An allergen must be able to penetrate the skin to cause its immune response. Same with a topical drug.

Therefore in normal, healthy human skin 500 daltons is the upper limit of penetration.

Some new drugs may be able to penetrate skin by modifying the original molecular structure. In people with atopic dermatitis (eczema) the barrier function of the skin is impaired. Thus they will be able to absorb larger molecules more readily.

How does the 500 dalton rule apply to skincare?

If you are applying a product that doesn’t need to penetrate to the lower layers of the skin, you don’t need to worry. Occlusive creams that prevent water loss from the skin will sit on the top layer and do their job. This includes moisturizers and serums.

If, however, you were hoping for more results at the molecular level, it pays to find out how big those molecules really are. You may be throwing money away for products that have no hope of penetrating the outermost skin layer.

Examples of Small and Big Molecules

For example, retinoic acid (aka my favorite prescription anti-aging molecule) has a molecular weight of 300 daltons. This means it can easily penetrate your skin. Retinol (my favorite non-prescription anti- aging molecule) has a molecular weight of 286 daltons.

On the other hand, topical hyaluronic acid is way too big to penetrate the skin. Hyaluronic acid can range in size from 5,000 to 20 million daltons. Not only is it very heavy, the molecule is also very big. This makes it even harder for it to traverse between skin cells. The effects of topical hyaluronic acid are more likely to be due to the optical illusion of having a water-loving molecule sit on your fine lines. The hyaluronic acid plumps up with water and fills in the fine lines. If you stop using the topical hyaluronic acid however, your wrinkles reappear right away.

What are some of your favorite products that claim to penetrate the skin? Did you do some research on their ingredients after reading this article?



  1. Billich, Andreas, et al. “Novel cyclosporin derivatives featuring enhanced skin penetration despite increased molecular weight.” Bioorganic & medicinal chemistry9 (2005): 3157-3167.
  2. Bos, Jan D., and Marcus MHM Meinardi. “The 500 Dalton rule for the skin penetration of chemical compounds and drugs.” Experimental dermatology3 (2000): 165-169.
  3. Harding, C. R., et al. “The cornified cell envelope: an important marker of stratum corneum maturation in healthy and dry skin.” International journal of cosmetic science4 (2003): 157-167.
  4. http://www.futurederm.com/what-exactly-is-the-500-dalton-rule/
  5. https://www.aad.org/public/kids/skin/the-layers-of-your-skin
  6. http://barefacedtruth.com/2015/03/31/hyaluronic-acid-yes-size-does-matter/
  7. http://www.isclinical.com/skincare_magento/images/Your_Skin.png

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