Regulatory Toxicology and Pharmacology 90 (2017) 214e221

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Regulatory Toxicology and Pharmacology

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Safety evaluation for ingredients used in baby care products:

Consideration of diaper rash
Susan P. Felter a, *, Andrew N. Carr b, Tingting Zhu c, Taryn Kirsch d, Gloria Niu e
a
Procter and Gamble, Central Product Safety, Mason, OH, United States
b
Procter and Gamble, Global Clinical Sciences, Cincinnati, OH, 45224, United States
c
Procter and Gamble, Central Product Safety, Beijing, China
d
Procter and Gamble, Central Product Safety, Schwalbach, Germany
e
Procter and Gamble, Global Clinical Sciences, Beijing, China

a r t i c l e i n f o a b s t r a c t

Article history: Diaper rash can adversely impact the barrier properties of skin, with potential implications for increased
Received 15 June 2017 absorption of chemicals through the skin, and this should be accounted for in any exposure assessment
Received in revised form used in the safety evaluation of consumer products used in the diaper (“nappy”) area. In the absence of a
7 August 2017
quantitative evaluation of the potential impact of diaper rash, a default assumption of 100% dermal
Accepted 10 September 2017
Available online 12 September 2017
penetration is often made for substances applied in the diaper area. We consider here the extent,
duration and severity of diaper rash and make a recommendation for conservative assumptions to
incorporate into exposure assessments. Using a time-weighted average, the potential impact of diaper
Keywords:
Diaper rash
rash is illustrated for substances that have varying degrees of absorption through healthy skin. Results
Compromised skin confirm that for assessments that already assume dermal absorption of 50% or higher, there is no impact
Dermal penetration on the overall exposure assessment. For substances that have a very low degree of dermal penetration
Safety assessment (1%) through healthy skin, the impact of rash is expected to be less-than four-fold. This can be refined
Risk assessment with additional data as there are many examples of poorly absorbed compounds for which dermal
penetration is still low even for compromised skin.
© 2017 Procter & Gamble Company. Published by Elsevier Inc. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction dermal penetration. This question is especially relevant to infant

skin in the nappy area since most infants experience diaper rash at
Cosmetics and personal care products are often used with direct some point, which, if sufficiently severe, can affect the barrier
application to the skin such that safety assessments must consider properties of skin. Thus, the implications of diaper rash on the
both the site-of-contact as well as systemic exposures for chemicals exposure assessment are important to consider.
absorbed through the skin. In estimating consumer exposure to As a quantitative estimation of the potential impact of diaper
products used on the skin, many safety assessments start with a rash has not been published, it is often recommended that a safety
default assumption of 100% dermal penetration. As the skin assessment of ingredients used in the nappy area be based on an
generally provides a significant barrier to dermal penetration of assumption of 100% dermal penetration. This is clearly a conser-
many substances, this initial assumption usually provides an op- vative assumption as diaper rash is not experienced continually,
portunity for refinement. An estimate of more realistic dermal and typically only a fraction of the skin is involved when rash is
penetration might come from in vivo data, ex vivo studies, or in present. Furthermore, even when diaper rash is present, the
silico modeling. Unless specifically designed otherwise, these severity is usually mild such that the skin retains a functional
methods all involve healthy skin, raising questions as to whether barrier. This paper provides a review of the literature as well as
the results are applicable to compromised skin, which can have historical P&G data on diaper rash, including the frequency and
diminished barrier integrity, resulting in the potential for increased severity of rash as well as the amount of skin involved and the time
to resolution. The implications of diaper rash for altering the
dermal penetration of chemicals is considered, recognizing that
this will depend on physical-chemical characteristics such that
* Corresponding author. Procter & Gamble, Mason, OH 45040, United States.
E-mail address: Felter.sp@pg.com (S.P. Felter). dermal penetration is not impacted to the same extent for all

http://dx.doi.org/10.1016/j.yrtph.2017.09.011
0273-2300/© 2017 Procter & Gamble Company. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
 S.P. Felter et al. / Regulatory Toxicology and Pharmacology 90 (2017) 214e221 215

chemicals. This is all considered in a holistic way to provide a technology has shown to provide increasingly good skin
summary of the implications of diaper rash for the exposure compatibility, leading to a decline in the frequency and severity
assessment of consumer products used in the nappy area of infants. of nappy dermatitis. However, irritant nappy dermatitis cannot
It is noted that this is only one part of the overall safety assessment; be completely avoided and might have an impact on dermal
consideration of infants and children as a potentially sensitive life absorption of substances ….
stage in safety assessments has recently been addressed (e.g., Felter
For the development of baby cosmetics and the risk assessment
et al., 2015; Neal-Kluever et al., 2014).
of products intended to be used in the nappy area, the potential
impact of irritation on dermal absorption of the chemical needs
2. Infant vs. adult healthy skin
to be considered by the safety assessor in the final quantitative
risk assessment of their products.”
The skin is the largest organ in the human body. It is comprised
of the epidermis, dermis and hypodermis, which allow for the in-
ternal and external regulation of the body. The epidermis consists Further guidance was not provided in terms of how a specific
of several layers which function as physical, chemical and immu- safety assessment should be done for the nappy area. Many man-
nological barriers (Elias, 2005, 2012). The outermost barrier is the ufacturers of products intended to be used for infants, including
stratum corneum, which mainly serves as a physical barrier and is diapers and wet wipes, start with an assumption that 100% of any
the primary regulator of percutaneous penetration. Although the chemical in contact with skin in the nappy area will be absorbed.
skin continues to develop and mature during the first year of life, However, this is clearly an over-exaggeration in many cases. This
the barrier properties of skin in a full-term neonate are comparable manuscript provides an analysis of the potential impact of diaper
to adult skin at or shortly after birth (Chiou and Blume-Peytavi, rash and makes recommendations for how this can be considered
2004; Fluhr et al., 2012; Telofski et al., 2012; Ludriksone et al., in the overall safety assessment process.
2014; Visscher et al., 2015). This conclusion is based primarily on
the results of trans-epidermal water loss (TEWL), which has been 3. The “Nappy Area”: consideration of skin under a diaper
used as a surrogate measure of skin barrier properties (Maibach
et al., 1984; Morgan et al., 2003). Investigators have shown that Diapers play an important role in infant hygiene, and the greater
even with the first few weeks after birth, TEWL measurements of absorbency of modern disposable diapers has led to an improve-
infant skin are in the same range as that of healthy adults (Hoeger, ment in skin health with a decreased frequency and severity of
2011; Kelleher et al., 2013). While there is not a simple correlation diaper rash (Odio and Thamen, 2014). These diapers are also con-
between TEWL and percutaneous absorption of chemicals, most structed with a breathable back sheet to help keep the skin drier.
studies evaluating TEWL and percutaneous absorption report a However, it is recognized that a diaper is not changed right away
positive correlation and conclude that overall the weight of evi- every time an infant urinates/defecates, so there can be increased
dence supports a relationship between these measures (Morgan hydration of the skin under a diaper compared to non-diapered
et al., 2003; Levin and Maibach, 2005).1 skin. However, under good hygiene practices of frequent diaper
It is recognized that the skin of full-term infants has barrier changes, the overall impact of diapering is quite minor and skin
properties comparable to adults2 and that minor differences are under a diaper in general stays quite healthy. Saadatmand et al.
within the range of inter-individual differences that are accounted (2017) developed a computer simulation of skin under a diaper
for by the default uncertainty factors used in quantitative safety and found that under normal diapering conditions (modeled as a 4-
evaluations (Felter et al., 2015). However, these statements are h wear period during the day and 8-h overnight), there can be
generally made with regard to healthy skin and little has been done short-term changes in the thickness (hydration level) of the skin
to explore the potential implications of diaper rash, as this has the but that these remain very close to baseline conditions (without a
potential to impact skin integrity. In fact, questions about exposure diaper) such that diapering per se is not expected to have a sig-
to chemicals in the nappy area of infants have been raised. The EU nificant impact on barrier properties of otherwise healthy skin. This
Scientific Committee on Consumer Safety (SCCS) Notes of Guidance leaves then the question of the impact of diaper rash, which occurs
for the Testing of Cosmetic Ingredients for their Safety Evaluation in most infants at some time during the diapering years.
(SCCS, 2016) concludes that an additional safety factor is not
needed for assessments of infants and children involving exposure 4. Diaper rash: implications for safety assessments
to intact skin. However, it was suggested that a specific safety
assessment is appropriate for cosmetic products used in the “nappy Diaper (or nappy) rash, also known as diaper dermatitis, is one
area” (diapered area) because of factors that may increase risk of the common skin disorders affecting babies. In most cases, the
relative to the rest of baby skin: rash is restricted to confined anatomic areas (e.g., genital, perianal)
and does not involve all (or even most) of the skin under a diaper.
“In the nappy area special circumstances are present resulting
The factors that lead to diaper rash are multi-factorial (physical,
from the close confining clothes and nappies, uncontrolled
chemical, enzymatic, and microbial factors) and are generally not
urination and defecation and resulting problems with potential
directly related to the diaper itself. If a soiled diaper is not changed
damage of the skin in the nappy zone. Modern nappy
right away, the presence of bile salts and other irritants in feces can
break down the protective lipids and proteins in the stratum cor-
1
neum. A mixture of urine and feces can increase the pH of the skin
This correlation is stronger when the analysis is focused on a single anatomical
(Berg et al., 1986; Fluhr et al., 2012), which can activate fecal en-
site. In studies conducted on the volar forearm of volunteers, Morgan et al. (2003)
found a linear relationship (r2 ¼ 0.996) between the number of tape strips (method zymes that can further contribute to skin irritation. Friction and
used to remove the stratum corneum) and the log of TEWL, and a similarly strong mechanical abrasion, especially if the skin is already compromised,
correlation between the absorption of penciclovir and TEWL (r2 ¼ 0.9283). can also lead to irritation. In addition, if a diaper is not changed
2
It is noted that in neonatal skin, dermal papillae are not yet observed and only frequently, extended periods of wetness can lead to over-hydrated
start to become apparent after one month (Miyauchi et al., 2016). This lack of
dermal papillae and its associated capillary loops in neonates could potentially even
skin which can leave it more vulnerable (Klunk et al., 2014; Visscher
minimize the ability for chemicals to be absorbed through neonatal skin and gain et al., 2015). Most rashes in the diaper area are simple cases of
entrance into the systemic circulation. irritant contact dermatitis (e.g., from frequent contact with urine
216 S.P. Felter et al. / Regulatory Toxicology and Pharmacology 90 (2017) 214e221

and feces) that are responsive to topical treatments and parental improvements in disposable diapers (Adam, 2008; Clark-Greuel
education on proper diapering practices. It is also recognized that et al., 2014; Blume-Peytavi et al., 2014). Disposable diapers were
while good hygiene and frequent diaper changes will reduce the first introduced to consumers in 1950's with the primary benefit of
probability of developing diaper rash, it can occur even when good convenience, but not necessarily skin health. In the past 30 years,
diapering practices are followed. along with new materials and advanced technologies, the dispos-
Diaper rash is generally an episodic inflammatory reaction, with able diapers have been designed to provide better dryness, less
a mean duration of 2e3 days, and occurring most commonly in leakage, and better skin protection (Odio and Friedlander, 2000;
infants ages 9e12 months (Visscher and Hoath, 2006; Blume- Counts et al., 2014).
Peytavi et al., 2014), although other investigators have found it
more commonly in younger infants (Longhi et al., 1992). The ma- 4.1. Prevalence and severity of diaper rash
jority of infants and young children are affected by diaper rash at
some point during diaper-wearing years. Its severity may vary from Published literature on the prevalence of diaper rash is highly
quite mild (e.g., characterized as small areas of slight erythema) to variable, with reports in the incidence ranging from as low as 15% to
severe (e.g., characterized by the presence of large areas of ery- over 50% (Adalat et al., 2007; Blume-Peytavi et al., 2014; Phillip
thema and confluent papules, pustules and/or disrupted skin et al., 1997). To understand the implications of diaper rash on the
integrity), although most occurrences are considered mild and the potential for increased dermal penetration of substances in contact
incidence of the moderate to severe rash is reported to be very low with the skin, one needs to have information on the frequency,
(Visscher and Hoath, 2006; Liu et al., 2011; P&G internal data). severity, amount of skin involved, and duration of diaper rash.
To aid the clinical assessment of diaper rash, a grading scale was Development of diaper rash is greatly impacted by caregiver habits
developed, validated and published by Procter & Gamble (Odio and practices such that its prevalence varies significantly in
et al., 2000) (Table 1). The 7-point grading scale provides a different regions of the world. Unfortunately, most of the published
detailed description of the whole spectrum of rash severity that literature is limited in terms of the data collected and reported.
ranges from Grade 0 (none) to Grade 3.0 (most severe) (includes 0.5 Even when details are available, there are few longitudinal studies
increments) based on clinical features of erythema intensity and that follow the development and resolution of a rash incidence over
area, presence of papules and pustules, and disruption of skin time, such that statistical information on rash commonly provides
integrity. The four anatomical locations assessed include perianal, information on only a snapshot in time. Furthermore, if the data
genital, intertriginous and buttocks areas which represent the most come from a hospital or clinical setting where care is sought for a
common affected skin sites, although in some cases rash may also sick child, it is not known whether the reported incidence of diaper
appear at waistbands and legs. Not surprising, the perianal area rash is reflective of a healthy population.
usually shows the highest severity and frequency in terms of diaper A meta-analysis was conducted including four clinical studies
rash; however, rash in the genital area oftentimes draws a lot of conducted between 2004 and 2006 by Procter & Gamble and
attention and concerns from the caregivers. included a total of 281 infants from Germany and the U.S. (P&G,
Over the last few decades, the incidence of diaper dermatitis has unpublished data). It is noted that infants who presented with
been on the decline. This is due to improved cleaning habits, the use diaper rash during the recruitment for these studies were excluded,
of topical skin products, and most of all, technological raising the possibility that infants more prone to diaper rash could

Table 1
Procter & Gamble global diaper grading scale.

Score Severity Descriptor

0 None Skin is clear (may have some very slight dryness and/or a single papule but no erythema)
0.5 Slight Erythema: Faint to definite pink in a very small area (<2%).
May also have a single papule and/or
May also have:
Skin Integrity: Some very slight dryness.
1.0 Mild Erythema: Faint to definite pink in a small area (2e10%) or
Definite redness in a very small area (<2%) and/or
Papules: A few scattered papules (2e5)
May also have:
Skin Integrity: Some very slight dryness
1.5 Mild/Mod Erythema: Faint to definite pink in a larger area (>10%) or
Definite redness in a small area (2e10%) or
Very intense redness in a very small area (<2) and/or
Papules: Slightly scattered papules covering a single or multiple areas (<10%)
May also have:
Skin Integrity: Moderate dryness or scaling
2.0 Moderate Erythema: Definite redness in a large area (10e50%) or
Very intense redness in a very small area (<2) and/or
Papules/Pustules: Single to several areas (10e50%) of papules, with 0e5 pustules
May also have:
Skin Integrity: Some slight desquamation or edema
2.5 Mod/Severe Erythema: Definite redness in very large area (>50%) or
Very intense redness in a small area (2e10%) and/or
Papules/Pustules: Larger areas (>50%) of multiple papules or numerous pustules or both
May also have:
Skin Integrity: Moderate desquamation and edema
3.0 Severe Erythema: Very intense redness in larger area (>10%) and/or
Skin Integrity: Severe desquamation, edema, erosion and ulceration
May also have:
Large areas of numerous confluent papules or numerous pustules/vesicles
 S.P. Felter et al. / Regulatory Toxicology and Pharmacology 90 (2017) 214e221 217

have been under-represented in the study populations. At the time described earlier, diaper rash grading scales developed and pub-
of enrollment of infants in these studies, four different anatomical lished by P&G do not include the abdomen or flanks (estimated to
sites in the diapered area (buttocks, genitals, the intertriginous area be 30e40% of the skin under a diaper) because diaper rash is quite
and the perianal area) were evaluated for each infant using the rare in that region. The buttocks account for about another 30%, and
scale described earlier. It is noted that the abdomen is not included the other three areas (genitals, intertriginous area, and perianal
as a grading site because diaper rash is rare in this region. When all area) each account for 10% of the total skin surface area under a
four sites were considered over a 4-week period, it was found that diaper. Rash is quite rare on the abdomen/flanks, so we can assume
96% of infants had no or only slight-to-mild diaper rash, 4% had that this skin is essentially healthy skin under a diaper. When rash
scores ranging from mild/moderate to moderate/severe, and none does occur, it is most frequently seen in the perianal and inter-
experienced severe diaper rash. The site with the least amount and triginous areas, and this is especially true for more severe rash. It is
lowest degree of severity of diaper rash was the buttocks, which is difficult to estimate the actual fraction of skin impacted based
the area representing the largest surface area of skin under a diaper. either on the literature (which is often lacking in details) or the data
Over 90% of infants had no rash on the buttocks, and none had a cited above which provide granular data per anatomical area, but
score greater than mild/moderate. not per infant. Therefore, a conservative estimate is made here of
In another large-scale international clinical study, baseline data the overall fraction of skin (per infant) that is impacted by rash. For
collected in infants in Germany and the U.S. also showed that mild rash, we assume that it covers up to 50% of the skin in any
moderate and severe diaper rash are relatively rare (Carr et al., 2017). anatomical site. If we assume that the anatomical site being graded
Each infant was assessed for presence of diaper rash in four represents a maximum of 30% of the total skin surface area (SSA)
anatomical sites (buttocks, genitals, intertriginous area, and perianal under a diaper, and up to 50% of that area could be impacted by
area) such that there was a total of over 1500 rash scores for rash, this equates to an overall fraction of 15% of the total SSA.
approximately 800 infants (about half in each country). The rash Moderate-to-severe rash is uncommon and when it does occur, is
score is a culmination of multiple inputs including erythema, pres- most commonly found in the perianal area, which is subject to the
ence/number of papules/pustules and area of anatomical site effec- most irritation from feces and urine. Rash involving a larger fraction
ted. Rash score combinations that were recorded at an incidence of of the skin (e.g., as the result of a yeast infection) is also uncommon
<2% were excluded from the analysis. Excluding those rare rash and is often treated with readily available ointments or barrier
score combinations, there were no rash scores greater than 1.5 in the creams to protect the skin while it heals (Stamatas and Tierney,
U.S. (mild-to-moderate rash) and in Germany, there were no scores 2014).
greater than 2 (‘moderate’) and less than 5% of events scored as 2.
Importantly, over half of all rash scores were 0 (‘none’) or 0.5 (‘slight’) 4.3. Duration of diaper rash
in both geographies, suggesting many babies were not experiencing
any detectable rash. Furthermore, where rash was recorded, most Compared to the incidence of diaper rash, less is known about
combinations impacted <2% of the skin area in any site. the duration of rash as this requires following infants over time. It is
P&G's grading scale includes considerations of both severity and commonly cited that the mean duration is 2e3 days (Odio and
amount of skin affected, with the data tabulated per anatomical site Thamen, 2014; SCCS, 2016; Ersoy-Evans et al., 2016), but this is
rather than per infant. Thus, when evaluating the impact of rash on expected to vary depending on the severity of the rash and amount
the potential for altered dermal penetration of chemicals in contact of skin involved, the underlying cause, good hygiene practices
with diapered skin, it is important to keep in mind that a “very including use of barrier creams to protect the skin, and other fac-
small area” of rash (defined as <2% in P&G's grading scale) refers to tors. Literature reports from hospitals or medical practices where
the fraction of skin in the specific anatomical site being assessed. parents have sought treatment for diaper rash are likely to involve
The abdomen and buttocks represent the largest surface areas and severe cases compared to mild cases of rash that resolve more
have the least amount of rash; in fact, the abdomen is not included quickly such that parents do not seek medical treatment.
in the rash scores. If a score of 0.5 is assigned to the genitals,
intertriginous area, or the perianal area, this means that faint to 4.4. Summary
definite pink was seen in a very small area (<2%) of the skin in that
anatomical area. While important to caregivers and to manufac- Although diaper rash is experienced by most infants at some
turers of diapers who strive to provide products that help ensure point during the diapering years, healthy skin under the diaper is
the healthiest skin possible, such a minor impact on the skin is not much more common. Furthermore, even when rash is present, it is
expected to have a meaningful impact on the overall skin integrity mostly graded as “mild” and generally impacts a relatively small
under a diaper. Similarly, a score of 1.0 might mean the presence of area of the skin overall. Severe diaper rash is relatively rare, and will
faint to definite pink in a small area (2e10%) or definite redness in a generally lead a caregiver to apply skin protectant ointments that
very small area (<2%) of the skin in that anatomical area, which is will contribute to maintaining the barrier function of the affected
still an overall very small fraction of the skin under a diaper. While skin. Based on the published literature on diaper rash and more
this large-scale clinical study provides quite granular data on the granular baseline data from P&G unpublished clinical studies, we
incidence and severity of diaper rash in different anatomic regions, propose that the following conservative assumptions be made
the data are not well suited for use in evaluating the impact of when evaluating the potential impact of diaper rash on the integ-
diaper rash on overall skin integrity under a diaper. They do, rity of the skin barrier:
however, support a strong argument that while infants do
commonly experience diaper rash during the diapering years, it is  An infant experiences diaper rash ~6 days/month (20% of the
quite rare that the rash is widespread and/or involves severely time).
damaged skin.  When rash is present, it involves 25% of the total surface area of
the diapered skin
4.2. Amount of skin impacted by diaper rash  When rash is present, 60% is assumed to be mild and 40% is
assumed to be moderate-severe.
To facilitate a quantitative evaluation of the impact of diaper
rash, it is important to consider the fraction of skin involved. As These assumptions are based on the high end of values in the
218 S.P. Felter et al. / Regulatory Toxicology and Pharmacology 90 (2017) 214e221

published data as well as P&G's extensive clinical database. While 5.1. Impact of the extent and nature of skin damage on dermal
difficult to quantify, each assumption is conservative; when taken absorption
together, the overall degree of conservatism is compounded.
A number of investigators have evaluated the impact of various
forms of skin damage (e.g., mechanical, chemical, and disease-
5. Dermal absorption: influence of skin barrier compromise induced), on the potential for a range of substances to be absor-
and physical-chemical characteristics bed. Several literature reviews on in vitro and in vivo dermal
penetration studies through compromised skin have been pub-
The potential for a chemical to be absorbed through the skin lished (Kezic and Nielsen, 2009; Gattu and Maibach, 2010, 2011;
depends on many factors related to the exposure conditions, the Chiang et al., 2012). In five publications dealing with skin
overall health of the skin, and the physical-chemical properties of damaged by solvents (acetone, 1,1,1-trichloroethane or sodium
the chemical being evaluated. Under the same exposure conditions, lauryl sulfate), an enhancement factor ranging from 2 to 46 was
some compounds are essentially completely absorbed while others reported. Interestingly, the highest and lowest values were by the
are very poorly absorbed. In the absence of data, it is common to same investigator (Benfeldt, 1999) using the same penetrant (sali-
have a starting assumption of 100% dermal absorption for most cylic acid), but the solvents were different. In nine publications
organic molecules, recognizing that this can often be refined. There dealing with skin with an intrinsically compromised barrier
are a number of in vivo, in vitro and in silico models for estimating (various skin diseases), an enhancement factor ranging from 1.5 to
dermal penetration (reviewed in Dumont et al., 2015). Data from 3 was reported. The greatest variability was seen in four publica-
these models will reflect the impact of physical-chemical proper- tions reporting on the impact of mechanical damage induced by
ties of a chemical and can be used to refine a safety assessment. For tape stripping, ranging from 4-fold for hydrocortisone (Feldman
example, compounds with a molecular weight >500 Da and log and Maibach, 1965) to 440e1300-fold for the hydrophilic phar-
Pow less than 1 or greater than 4, a default value of 10% dermal maceuticals aciclovir and peniciclovir (Morgan et al., 2003). In this
absorption is generally considered appropriate (SCCS, 2010). latter publication, the stratum corneum was completely removed
These models generally assume exposure to healthy skin. Ex- (to glistening). Importantly, these drugs are very poorly absorbed
periments can also be done (primarily in vitro) to assess the po- through intact skin. If one assumes that 100% was absorbed through
tential for penetration through damaged skin (e.g., Dey et al., 2015), the tape-stripped skin and this represented a 1300-fold increase
but these are resource intensive such that it is not practical to do over intact skin, then the absorbed fraction through intact skin
this for all chemicals. When these data are available, they can be would have been <0.1%. Overall, the body of literature using
included directly in a safety assessment; for cases where they are compromised human skin models was summarized by Gattu and
not, we propose a conservative default approach that allows one to Maibach (2010, 2011) as showing a “modest but clear enhance-
consider the severity of the skin damage as well as the physical- ment in absorption with enhancement favoring hydrophilic mole-
chemical properties of the chemical being assessed. cules.” They go on to conclude that “in general, enhancement was
There are very few published data on absorption of chemicals modest on the order of 1 magnitude of 10 implying that despite
through infant skin, and especially through skin with diaper rash. In mechanical, chemical, biocidal damage and clinical disease, not all
one clinical pharmacology study, Eichenfield and Bogen (2007) barrier properties are removed.”
evaluated the potential for systemic absorption of the antifungal Specifically relevant to an ingredient being studied for use in a
miconazole nitrate through the skin of infants with moderate to baby wipe lotion, Dey et al. (2015) measured the penetration of
severe diaper dermatitis. Of 24 infants, 19 received 0.25% micona- [14C]-PEG-7 phosphate (phosphated polyethylene glycol) in an
zole nitrate ointment and 5 received 2% miconazole nitrate cream ex vivo human skin model compromised by tape stripping, with 20
for 7 days. The investigators indicated that the ointment was tape strips resulting in moderately compromised skin and 25e30
applied at least 5 times per day such that the infants “received tape strips resulting highly compromised skin (as determined by
substantial repeated exposure” (not quantified). Blood samples TEWL measurements). Baby wipe lotion containing radiolabeled
were collected prior to treatment and after 7 days. In infants PEG-7 phosphate was applied either five times (5 mg/cm2) or once
receiving the ointment with 0.25% miconazole nitrate, blood con- (25 mg/cm2) to intact skin and compromised skin. As expected
centrations were nondetectable (<1 ng/ml) in 15/18 infants and based on its molecular weight (~417) and high water solubility, the
minimal (3.0e3.8 ng/ml) in two infants (samples for one infant mean penetration of PEG-7 phosphate through intact skin was low
were missing). In infants receiving the cream with 2% miconazole (0.76e1.27%). Absorption through the tape stripped skin was
nitrate, blood concentrations were nondetectable in 1/5 infants and increased 4- to 6-fold (mean ranging from 3.19 to 4.48%). Impor-
ranged from 5.2 to 7.4 ng/ml in the other 4 infants. While a lack of tantly, while there was a clear increase in dermal penetration in this
quantitative information on the amount applied to the infants compromised skin model, it was still quite low under all conditions.
prevents these data from being used to estimate dermal absorption,
the authors concluded that systemic absorption of 0.25% micona- 5.2. Impact of physico-chemical properties on dermal absorption
zole nitrate through skin with diaper rash was “minimal” and that it
was safe to use in the treatment of moderate to severe diaper rash. It is well-recognized that physico-chemical properties have a
This underscores the fact that even skin with moderate to severe significant impact on the potential for a substance to be absorbed
rash still presents a significant barrier to systemic absorption of through the skin. Smaller molecules that are soluble in both lipid
substances that are known to have poor absorption through and water (log P values in the range of 1e2) are generally associated
healthy skin. with the highest potential for absorption whereas those with a
If the barrier function of skin is sufficiently compromised, the molecular weight greater than 500 and Log Pow <-1 or >4 h are
skin becomes more permeable and there is a potential for increased associated with much lower dermal absorption, which becomes
absorption of chemicals through the skin. However, the degree to increasingly diminished as the molecular weight increases or the
which dermal absorption is impacted is highly variable and de- compounds becomes highly hydrophilic or hydrophobic (EC, 2004).
pends on the extent of damage to the skin as well as physical- The stratum corneum provides the first barrier to substances on
chemical properties of the chemical being evaluated. These are the skin, and is particularly resistant to the absorption of hydro-
each considered below. philic compounds. Therefore, when the stratum corneum is
 S.P. Felter et al. / Regulatory Toxicology and Pharmacology 90 (2017) 214e221 219

disrupted, there is generally a greater enhancement of the ab- can be refined further based on physical-chemical properties or
sorption of hydrophilic compounds (Morgan et al., 2003; Nielsen, other modeling or data. For example, it is well-documented that
2005; Gattu and Maibach, 2011). There is also a greater impact on disruption of the stratum corneum has a greater impact on the
smaller molecules, less so for larger molecules (Jakasa et al., 2006). absorption of hydrophilic and smaller molecular weight com-
This explains the dramatic increase in the dermal absorption of the pounds; if evaluating the potential impact of diaper rash on the
hydrophilic chemicals peniciclovir (log Kow 2.1) and acyclovir absorption of a larger lipophilic compound, the initial assumptions
(log Kow 1.8) reported by Morgan et al. (2003) after removing the we recommend can be refined if needed as it is clear that even in
stratum corneum by tape stripping. This is also consistent with the the presence of significant rash, absorption will likely not approach
findings of Borra s-Blasco et al. (2004) who evaluated seven model 100%.
drugs with log P values ranging from 0.95 to 4.2. Pre-treatment of
the skin with the irritant SLS did not increase the permeability
coefficients for most of the lipophilic compounds (log P  3), 6.1. Case studies
whereas for those with log P < 3, an increase in permeability was
found to relate both to the concentration of SLS used and the lip- To illustrate the impact of diaper rash on estimates of systemic
ophilicity of the compound tested. exposure to an ingredient used in a cosmetic product used in the
nappy area, we consider hypothetical examples of an ingredient
applied to the skin at a rate of 100 mg/day (spread over the surface
6. Implications of diaper rash for safety assessments of the diapered skin). For chemicals already expected to be absor-
bed at a high rate, an assumption of 100% dermal penetration is
While diaper rash is a common experience during the diapering appropriate for both healthy skin and rash skin. Thus, there is no
years, it is also true that most of the time the skin under a diaper is impact on the overall assessment for chemicals already known or
healthy. When rash is present, it is mild in nature and only involves assumed to be well-absorbed through the skin. For chemicals that
a fraction of the skin. We present recommendations here for how are less-well absorbed, it is expected that the presence of diaper
the potential for diaper rash can be considered when doing a safety rash can have an impact on dermal penetration, but this will
assessment for products used in the nappy area. Importantly, this is depend on the severity of the rash (designated here as “mild” or
only relevant for assessments that aren't already based on a con- “severe”) and the physical-chemical properties of the substance
servative assumption of 100% dermal penetration. For those as- being evaluated. We consider a scenario for ingredients repre-
sessments, there is no impact of diaper rash since an assumption is senting a range of physical-chemical properties that would result in
already made that 100% of the chemical is absorbed through the a very low (1%), low (10%), or moderate (50%) degree of penetration
skin. Where a refinement is needed, one can use a tiered approach, through healthy skin. Dermal penetration through skin with mild
starting with conservative assumptions and refining those as rash is conservatively estimated to be increased 10-fold, while
needed. It is also noted that these assumptions are for a product dermal penetration through skin with moderate-severe rash is
used in the entire nappy area (e.g., a cleaning wipe or a diaper it- conservatively assumed to be 100%. It is noted that this can be
self); if a product is used in a more limited way (e.g., only applied to refined with experimental data obtained using a compromised skin
skin with diaper rash), this should be considered in the assessment. model. For example, the fore mentioned study by Dey et al. (2015)
We summarized earlier a set of conservative assumptions that used a tape-stripped ex vivo skin model showed dermal
regarding diaper rash: penetration of PEG-7 phosphate was still less than 5% even through
compromised skin.
 An infant experiences diaper rash ~6 days/month (20% of the Table 2 illustrates the calculations involved to estimate the
time). quantitative impact of diaper rash on the absorption of an ingre-
 When rash is present, it involves 25% of the total surface area of dient with very low (1%) absorption through healthy skin.
the diapered skin For this example, the assumptions employed above result in a
 When rash is present, 60% is assumed to be mild (15% of the total (time weighted average) absorbed amount of 3.25 mg, or 3.25%
diapered skin) and 40% is assumed to be moderate-severe (10% of the applied dose. This is ~ 3-fold higher than what one would
of the diapered skin). expect for all healthy skin (100 mg  1% ¼ 1 mg), but about 30-fold
lower than what one would calculate if one assumed 100% dermal
For skin with mild rash, based on our review of the literature penetration (100 mg  100% ¼ 100 mg). Results of similar modeling
(summarized in Section 5.1), we propose that an initial assessment are summarized below in Table 3 for compounds that are expected
assume a 10-fold increase in dermal penetration and that for skin to penetrate through healthy skin at low-level (10%) or moderate-
with severe rash, we propose that an initial assessment assume level (50%). The increase is less than 1.5-fold for compounds ex-
100% dermal penetration. These values might be appropriate for pected to penetrate at a low level, and almost negligible for com-
some substances but will still be very conservative for others and pounds expected to penetrate healthy skin at a moderate level.

Table 2
Quantitative impact of diaper rash on the absorption of ingredient with very low (1%) absorption through healthy skin.

Presence of Diaper x Fraction of Skin Condition Dermal Absorption (Ingredient Applied ¼ 100 mg/ Amount absorbedb (Time Weighted Average, mg/
Rash Timea day) day)

No 0.80 100% Healthy skin 100 mg  1% ¼ 1 mg/day 0.8 mg

Yes 0.20 75% Healthy Skin 0.75 [100 mg  1%] ¼ 0.75 mg/day 2.45 mg
15% Mild Rash 0.15 [100 mg  10%] ¼ 1.5 mg/day
10% Moderate- 0.10 [100 mg  100%] ¼ 10 mg/day
Severe
Total ¼ 12.25 mg/day Total ¼ 3.25 mg
a
~6 days/month with some diaper rash.
b
Fraction of Time x Total Dermal Penetration.
220 S.P. Felter et al. / Regulatory Toxicology and Pharmacology 90 (2017) 214e221

Table 3
Quantitative impact of diaper rash on absorption of compounds with low (10%) or moderate (50%) degree of dermal penetration through healthy skin.

Degree of Absorption through Healthy Amount that would be absorbed through all healthy skin (applied Amount absorbed through skin with diaper
Skin dose ¼ 100 mg) rash

Low (10%) 10 mg 14.5 mg

Moderate (50%) 50 mg 52.5 mg

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Conflict of interest statement Gattu, S., Maibach, H.I., 2011. Modest but increased penetration through damaged
skin: an overview of the in vivo human model. Skin. Pharmacol. Physiol. 24 (1),
The authors are all employed by Procter & Gamble, which 2e9.
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manufactures and markets disposable diapers.
(Eds.), Harper's Textbook of Pediatric Dermatology, third ed. Blackwell Pub-
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for polyethylene glycols through skin compromised by sodium lauryl sulphate.
Exp. Dermatol 15 (10), 801e807.
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online at http://dx.doi.org/10.1016/j.yrtph.2017.09.011. loss values: a reference data set. Pediatr. Dermatol 30, 712e716.
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