“Apply by massaging onto skin” or “rub until absorbed” are seemingly innocuous directions of use found on many skincare products, but with potentially significant impact on their safety assessment. The safety assessment of substances is governed by the intrinsic toxicology profile of the substance, and the exposure to said substance. The later for skincare products is mostly dictated by the level of absorption through skin. Many factors affect percutaneous penetration rates through skin – at least 15 factors of percutaneous penetration exist that should be considered when investigating dermal absorption profiles of chemicals.
The physiochemical property of compounds is one of the most recognized and pervasive factors, influencing chemical interactions with skin layers, ability to penetrate, and diffusion characteristics. Condition of skin exposure such as dose, duration, surface area and frequency are other factors involved in determining amount absorbed. Rubbing is one variable that has been understudied but may play an important role in understanding overall exposure rates, chemical toxicity, dermal absorption, and skin’s barrier abilities. This is particularly pertinent for cosmetics given the relevance of rubbing/massaging of skincare products once applied on the skin.
But I found studies indicating no effect on dermal absorption!
Most of the publicly available studies involve drugs. However, the principles are applicable to cosmetic ingredients. Briefly, rubbing
has been shown to increase absorption in some instances and not in others. Early research by McMaster et al. (1985) showed no influence of massaging on hydrocortisone cream dermal absorption in animals after application to the naked retroauricular area of the guinea pig and the abdomen of the rhesus monkey (McMaster et al., 1985). Further information for this study could not be found.
Draelos (2015) also found no effect with rubbing in the application of triamcinolone spray in 50 patients with eczema (Draelos, 2015). It should be highlighted that Draelos (2015) investigated the degree of improvement in the patients after applying a medication with or without rubbing it into the skin, and not levels of drug in the patients. As such, it was not a direct measure of whether or not rubbing increased exposure to the drug and therefore should not carry too much weight.
Okay, so what about studies indicating effects on dermal absorption?
Although the above studies noted no difference in penetration and efficacy in regard to rubbing, other studies demonstrated the opposite. Treffel et al. (1993) showed that while application of 5 µg/cm2 of caffeine on excised human skin was unaffected by pressured application (0.25 bar over atmospheric pressure for 30 minutes), application of 240 µg/cm2 of caffeine under pressure significantly increased permeation, specifically 1.8 times higher (Treffel et al., 1993).
Ishii et al. (2010) conducted penetration studies of another corticoid, triamcinolone acetonide, in a white petrolatum ointment base. 1% triamcinolone acetonide ointment (100 mg/0.95 cm2) was applied on excised hairless rat skin after 30s massage at a pressure of 1.87-3.12 N/cm2, and amount permeated over 24 hours was quantified using high performance liquid chromatography. The total amount of triamcinolone acetonide permeated over 24 hours was 9 times higher in experiments with a pre-treatment rub in comparison to those without. Furthermore, skin impedance (the response of a specific skin region to an externally applied electrical current) was three times higher without 30s rubbing, demonstrating the ability of massage to reduce skin barrier function (Ishii et al., 2010).
Hasler-Nguyen and Fotopoulos (2012) also conducted skin penetration studies of an anti-inflammatory medication, diclofenac, in excised human skin. They demonstrated that application of 5 mg/cm2 1.16% diclofenacdiethylamine gel, followed by 45 seconds of rubbing, increased diclofenac penetration through human skin up to five-fold after 8 hours. Such application, in addition to increasing skin penetration, also resulted in higher accumulation in skin (Hasler-Nguyen and Fotopoulos, 2012).
What about substances relevant to cosmetics
Perhaps the most interesting example of how rubbing may affect dermal absorption of substances is that of salicylic acid. The substance has faced significant scrutiny as a cosmetic ingredient, and permissible limits are likely to be lower than the current limits indicated below (or use in certain products scrapped entirely):
Table 1: current maximal limits of salicylic acid in cosmetic products
| Category | Current maximum permissible level |
| Rinse-off products | 3.0% |
| Other products except body lotion, eye shadow, mascara, eyeliner, lipstick, roll-on deodorant | 2.0% |
| Body lotion, eye shadow, mascara, eyeliner, lipstick, roll-on deodorant | 0.5% |
The latest SCCS opinion on salicylic acid is beyond the scope of this blog but can be found here. Back to rubbing and dermal absorption – in their attempt to identify methods to simulate rubbing of topical formulations, Nguyen at al. (2017) identified that while there was no statistically significant difference between the amount of salicylic acid in receptor fluid after 24h following rubbing for 15s compared to control, rubbing did result in increased 
delivery of salicylic acid into the stratum corneum as well as viable epidermis and dermis. Specifically, the authors used full-thickness pig skin and a gel consisting of 2% salicylic acid, 38% denatured alcohol, and water (Nguyen et al., 2017).
The findings of this study do indicate an increase in the dermal delivery of salicylic acid following rubbing given that the dermis and epidermis compartments are considered as bioavailable in line with SCCS guidance. It should be highlighted that while total recovery of salicylic acid was below required levels (85 – 115%), sublimation of salicylic acid during evaporation of organic solvents has been reported. Given that major components in salicylic acid gel are water and 38% denatured alcohol, sublimation can be a possible explanation for the results of the recovery of salicylic acid in this study. The study method does deviate from current OECD test guidelines, but nevertheless further highlights the potential impact of rubbing on increased exposure to dermally applied substances.
Dermal absorption – is it just about massaging?
Made it this far? Want more? I have saved the best for last. This example highlights how not only rubbing but also skin condition impact dermal absorption, with an interesting outcome. Kaushik et al. (2021) wanted to compare the influence of direct and indirect skin hydration as well as massage on the dermal penetration efficacy of the substance, Nile red. While not used in cosmetics or as a drug but in cell biology to stain lipids in cells, Nile red was used as a lipophilic drug surrogate and was incorporated into Vaseline (petroleum jelly) and measured in the skin by epifluorescence microscopy. The formulation was applied with and without massage (finger massage with saturated glove for 20s) onto either dry skin or pre-hydrated, moist skin excised from pigs. One would expect that with the occlusive properties of Vaseline, massage, and enhanced skin hydration, an increase in dermal absorption would occur. While massage increased Nile red permeation by 18% and penetration by 5%, application with massage on the hydrated skin decreased permeation by 29% and penetration by 18% compared to control (no massage and dehydrated skin).
Various reasons were identified for causing the effect observed, underlining the many factors at play that affect dermal absorption. Firstly, it was found that Vaseline undergoes syneresis (the extraction or expulsion of a liquid from a gel) after topical application. The expulsed mineral oil forms a film on top of the skin, and parts of it penetrate into the skin. Nile red, which is lipophilic and dissolved in the mineral oil, enters the skin with the mineral oil, i.e., via a solvent drag mechanism. Secondly, it was found that massage squeezes the skin and causes the expulsion of water from deeper layers of the stratum corneum. The expulsed water can act as a water barrier that prevents the penetration of lipophilic compounds and could potentially promote the penetration of hydrophilic compounds (Kaushik et al., 2021).
The last study, or any of the other studies listed here, should not be considered singularly but in a weight-of-evidence highlighting that while massaging may increase dermal absorption and therefore change the calculus of the safety assessment given that exposure has increased, absorption of a substance through skin is multifaceted with more factors (i.e., skin hydration, skin treatment, and the penetration of excipients from the vehicle that can modify the structure of skin properties to name a few) that must also be considered. As with all things toxicology, a case-by-case evaluation is needed with each case and their unique elements being assessed individually.
Owing to expertise in a number of relevant fields. kriTOX can help you define the best strategy for your products. Please click here should you need more information about cosmetic ingredient services.
Published by Boris Krivoshiev, PhD – Founder and Principal Toxicologist at kriTOX
References
Draelos, Z.D. (2015). Triamcinolone spray: no‐rub application as effective as rub application. J. Cosmet. Dermatol. 14, 286–290.
Hasler-Nguyen, N., and Fotopoulos, G. (2012). Effect of rubbing on the in vitro skin permeation of diclofenac-diethylamine 1.16% gel. BMC Res. Notes 5, 1–5.
Ishii, H., Todo, H., and Sugibayashi, K. (2010). Effect of sebum and ointment rubbing on the skin permeation of triamcinolone acetonide from white petrolatum ointment. Biol. Pharm. Bull. 33, 876–880.
Kaushik, V., Ganashalingam, Y., Schesny, R., Raab, C., Sengupta, S., and Keck, C.M. (2021). Influence of Massage and Skin Hydration on Dermal Penetration Efficacy of Nile Red from Petroleum Jelly—An Unexpected Outcome. Pharmaceutics 13, 2190.
McMaster, J., Maibach, H.I., Wester, R.C., and Bucks, D.A.W. (1985). Does rubbing enhance in vivo dermal absorption (Marcel Dekker: New York).
Nguyen, H.X., Puri, A., and Banga, A.K. (2017). Methods to simulate rubbing of topical formulation for in vitro skin permeation studies. Int. J. Pharm. 519, 22–33.
Treffel, P., Panisset, F., Humbert, P., Remoussenard, O., Bechtel, Y., and Agache, P. (1993). Effect of pressure on in vitro percutaneous absorption of caffeine. Acta Derm. Venereol. 73, 200–202.