The Dalton 500 Rule

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 Dalton 500 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 the skin. This "rule" explains why some ingredients just seem to 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.

The skin is composed of three 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 tissues, hair follicle and sweat glands. Fianlly the deepest layer is the subcutaneous fat or hypodermis.

Epidermis

The epidermis is further divided 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 skincare to work, it must first traverse the outermost layer of the stratum corneum.

Stratum Corneum Barrier Function

The stratum corneum is made up of 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 because the cell membranes are hydrophobic. This means they repel water. Some water-soluble molecules may be able to penetrate through the openings of the hair follicle and sweat glands. Howver this only makes up a total of 0.1% of your body surface.

Size and Charge

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

How did they come up with this rule?

The inventors of the 500 Dalton rule investigated the molecular weight of allergens that cause allergic contact dermatitis and the most commonly used topical drugs in dermatology. They found that all the allergens and drugs had a molecular weight of less than 500 daltons. An allergen must be able to penetrate the skin to cause an immune response. Same with a topical drug. Therefore, in normal human healthy skin, 500 daltons is the upper limit of penetration.

Some new drugs may be able to penetrate by modifying the molecular structure. In people with atopic dermatitis (eczema) The barrier function 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 does not 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're 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 on products that have no hope of penetrating the outermost skin layer.

Example of Small and Big Molecules

For example, retinoic acid has a molecular weight of 300 daltons. This means it can easily penetrate the skin. Retinol 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, but 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 the fine lines. The hyaluronic acid plumps up water and fills in the fine lines. If you stop using the hyaluronic acid, your wrinkles reappear right away.

References:

1. Billch andreas et al. "Novel cyclosporin derivatives featuring enhanced skin penetration despite increased molecular weight". Bioorganic medicinal & organic chemistry9 (2005): 3157-3167

2. Bos, Jan D.and Marcus MHM Meinardi. " The 500 Dalton rule for skin penetration of chemical compounds and Drugs". Experimental dermatology

3. (2000): 165-169.3 Harding, C. R. et al. "The cornified cell envelope: an important marker of the stratum corneum maturation in healthy and dry skin." International journal of cosmetic science4 (2003): 157-167

4. https://www.futurederm.com/what-exactly-is-the-500-dalton-rule/

5. https://aad.org/publidkids/skin/-the-layer-of-your-skin

6. https://barefacetruth.com/2015/03/31/hyaluronic-acid-yes-size-does-matter/

7. https://www.isclinical.com/skincare_magento/images/Your_5kin.png