Regulatory Toxicology and Pharmacology 53 (2009) 81–89

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Regulatory Toxicology and Pharmacology

journal homepage: www.elsevier.com/locate/yrtph

Safety evaluation of superabsorbent baby diapers

Kirstin Kosemund a, Harald Schlatter a, Jennifer L. Ochsenhirt b, Edburga L. Krause a,
Daniel S. Marsman b,*, Geetha N. Erasala b
a
Procter & Gamble Service GmbH, Schwalbach am Taunus, Germany
b
The Procter & Gamble Company, Winton Hill Business Center, 6280 Center Hill Ave, Cincinnati, OH 45224-1708, USA

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

Article history: Superabsorbent disposable baby diapers are sophisticated, well-engineered products that provide many
Received 9 September 2008 benefits including convenience, comfort, exceptional leakage protection, improved hygiene and skin care
Available online 1 November 2008 benefits compared with cloth diapers. Safety assurance is an integral part of the diaper development pro-
cess at Procter & Gamble, with the goal of ensuring safety for both caregivers and babies. A systematic,
Keywords: stepwise approach to safety assessment starts with a thorough evaluation of new design features and
Diaper rash materials, using the principles of general risk assessment including, as appropriate, controlled trials to
Contact dermatitis
assess clinical endpoints or independent scientific review of safety data. The majority of the diaper mate-
Infant diapers
Risk assessment
rials are polymers that are safe and do not have inherent toxicity issues. Trace amounts of non-polymeric
Diaper safety materials, such as colorants, are assessed based on their skin contact potential. New materials or design
features are introduced in marketed products only if they have been shown to be safe under the condi-
tions of recommended or foreseeable use. The product safety continues to be confirmed after launch by
means of in-market monitoring. This article provides a broad overview of human safety exposure-based
risk assessment used at Procter & Gamble for absorbent hygiene products.
Ó 2008 Elsevier Inc. All rights reserved.

1. Introduction innovations have transformed disposable diapers from a conve-

nience item into a product that improves the comfort and skin
Since the introduction of PampersÒ (Procter and Gamble, Cin- health of the infant (Adam, 2008).
cinnati, Ohio) in the US in 1961, the use of disposable diapers Benefits of the improvements in superabsorbent baby diapers
has increased in developed nations. Today, it is estimated that have been widely documented. Clinical evaluations have shown
90–95% of diapers used in these countries are disposable (Odio that these product improvements help to reduce skin over-hydra-
and Friedlander, 2000). European data indicate an average diaper tion and friction (key elements in diaper dermatitis) (Odio et al.,
change frequency of 4–5 diapers/day over a diapering period of 2000a,b; Campbell, 1987; Davis et al., 1989) and have
2.5 years (UK Environment Agency, 2005). The growth in the use demonstrated statistically significant reductions in the occurrence
of disposables has been accompanied by several improvements of diaper dermatitis in users of disposable baby diapers with super-
in the design of the diaper itself. The most important improvement absorbent core compared with users of cloth diapers or cellulose-
was the introduction of superabsorbent polymers (polyacrylates) only disposable diapers (Campbell, 1987; Davis et al., 1989;
as a component of the diaper core in the 1980s. Depending on Campbell et al., 1987; Seymour et al., 1987a,b; Lane et al., 1990;
the ionic strength of the fluid, these materials can absorb many Wilson and Dallas, 1990). A retrospective examination of clinical
times their own weight in aqueous liquids—in the case of tap trials performed before and after the widespread use of disposable
water, about 200 times (European Disposables and Nonwovens diapers with super-absorbent cores has demonstrated the reduc-
Association, 2007). Unlike traditional cellulose materials, polyacry- tion in the incidence of severe diaper dermatitis with modern dia-
lates have the ability to retain liquid in the diaper core, keeping it pers (Odio and Friedlander, 2000) and this overall reduction has
away from the baby’s skin, even under pressure. Other improve- been confirmed by physicians’ anecdotal reports (Spraker et al.,
ments have included features that permit faster acquisition of 2000). Additional advantages of superabsorbent diapers include
liquid, an apertured topsheet for efficient ‘‘liquid feces manage- the improvement of hygienic conditions (reduction of fecal
ment”, new materials that provide a cloth-like feel, breathable bacterial contamination) in day-care settings (Campbell et al.,
materials, improved fit, and flexible re-sealable fasteners. These 1988; Kubiak et al., 1993; Van et al., 1991a,b).
The many obvious advantages of today’s superabsorbent dis-
* Corresponding author. Fax: + 1 866 357 7849. posable baby diapers undoubtedly account for the high degree of
E-mail address: [email protected] (D.S. Marsman). consumer acceptance and satisfaction with the product. The

0273-2300/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.yrtph.2008.10.005
82 K. Kosemund et al. / Regulatory Toxicology and Pharmacology 53 (2009) 81–89

convenience, fit, and comfort benefits compared with traditional The modern superabsorbent disposable diaper consists of three
cloth diapers are immediately evident, as are the benefits of drier basic functional product zones, as described below.
baby skin. Many consumers (and indeed many physicians) are
probably unaware of the rigorous and extensive safety programs 2.1. Direct skin contact materials
that have been designed and implemented to ensure that super-
absorbent diaper product innovations are safe and effective under The topsheet is the layer in direct contact with the baby’s skin.
practical use conditions. For example, the super-absorbent mate- It consists of a soft nonwoven synthetic sheet, composed of poly-
rial alone has been evaluated in numerous comprehensive studies propylene/polyethylene, either alone or as a blend, which allows
assessing safety aspects ranging from skin irritation, sensitization, liquids to pass through while remaining relatively dry and soft.
to possible systemic toxic effects, to accidental swallowing (Sprak- The main function of this layer is to transfer urine and other liquids
er et al., 2000). quickly to the layers beneath. In addition, the topsheet may carry a
Procter & Gamble is committed to the safety of its products to lotion to protect the skin from overhydration and irritation.
ensure that only products with an excellent safety profile are
placed on the market. The following detailed description presents 2.2. Indirect skin contact materials
the first in-depth discussion of Procter & Gamble’s human safety
risk assessment model applied to chemical safety of baby diapers. 2a. The acquisition/distribution layer is usually composed of a
Other safety evaluation routes which are followed but not dis- modified cellulose patch and a polyester-based layer sandwiched
cussed here address: between the topsheet and the core, which is not in direct con-
tact with the skin. Its main function is to facilitate the move-
 Environmental assessment including disposal of manufacturing ment of liquid away from the baby and to distribute it more
waste with recycling and reuse where possible and compatibil- evenly across the entire diaper core for efficient and maximal
ity with all local forms of solid waste handling (landfills, incin- absorbency.
eration) for consumer disposal of used product. 2b. The absorbent core is the inner-most layer of the diaper. It
 Physical hazard assessment to ensure product efficacy and typically consists of a blend of polyacrylate granules blended with
integrity. The focus for the physical hazard assessment in the fluff cellulose pulp (bleached by an elemental chlorine-free pro-
context of baby diapers is primarily choking and suffocation cess) and encapsulated by either a cellulose or polypropylene non-
but also to confirm the absence of hard edges or tight seams woven layer. The cellulose portion of the core functions to quickly
which might cause abrasions or red marks on the baby’s skin. absorb and transfer urine to the polyacrylate superabsorber. The
 Workers safety assessment for material handling and product superabsorber is able to absorb urine and to lock it within its poly-
making. meric structure to keep it away from baby’s skin, even under pres-
sure as when a baby sits on a full diaper.
The article is an example of human safety exposure-based risk
assessment for diapers. Similar approaches are used for other 2.3. Backsheet and fastening system
absorbent hygiene products.
3a. The backsheet is the water-resistant outer layer of the dia-
2. Anatomy of a disposable diaper per, typically made of a polyethylene film laminated with a soft-
textured, cloth-like polypropylene. Its function is to prevent liquid
While disposable diapers are offered in a variety of styles with from leaking out of the diaper into the outer clothing.
different consumer features, the basic ‘‘anatomy” of a disposable 3b. Additional elements include features primarily designed to
baby diaper remains essentially the same. The typical design ele- ensure a good fit to the diaper. Such design elements may include
ments and raw materials of today’s typical superabsorbent dispos- stretch side panels, fastening systems and tapes to improve fit, and
able diaper are shown in Fig. 1. leg cuffs to prevent leakage.

Inner Polypropylene-
topsheet Lotion (optional)

Fastening system
Outer Polyethylene-film

Inner leg cuff

Outer leg cuff

Absorbent core

Outside graphics

Fig. 1. Schematic representation of modern diaper design.

 K. Kosemund et al. / Regulatory Toxicology and Pharmacology 53 (2009) 81–89 83

In some products, aesthetics such as colorants or scents may be lished in 1983, by the National Academy of Sciences (National
added. The functional elements may vary depending on the style of Academy of Sciences, 1983). It describes the approach as a four-
diaper, the manufacturer, and consumer preference. step process: hazard identification, dose–response assessment,
exposure assessment and risk characterization. A robust RA is a
3. Risk assessment framework key component of a comprehensive risk management decision
which also incorporates aspects of public perception of risks, regu-
Materials used in diapers are mainly of polymeric nature. These latory aspects, and other issues.
materials are safe and no inherent toxicity issues are associated. The RA paradigm has been applied widely by regulatory agen-
However as for any product, there will be low levels of non-poly- cies and institutions to assess health endpoints related to exposure
meric components that may be introduced into the product for to chemicals present in food, air or drinking water. Slightly differ-
example from process aids used in the making process, or they ent approaches and terminology for risk assessment is used; how-
could be aesthetic ingredients such as colorants or scents that ever, the basic principles are the same (US EPA, 1993, 2002;
are added at low levels. To provide a high level of safety assurance International Programme on Chemical Safety, 1999; Organisation
we focus on the assessment of such substances prior to consumer for Economic Co-operation and Development, 2007). Another area
studies or widespread human exposure in the marketplace. where RA is used is to assess for potential site-of-contact effects
Although the exact process may vary depending upon the compo- such as allergic reactions following dermal exposure (Felter et al.,
nents and design of the product, the following paragraphs provide 2003, 2002; Gerberick et al., 2001a; RIFM QRA Expert group,
an example of the typical safety qualification of a material in- 2006). The four RA elements established by the National Academy
tended to be used in a baby diaper product. of Sciences (1983) are explored in more detail below as they apply
As a first step the complete compositions of each new material to the safety qualification of materials for baby diapers.
proposed for use in the diaper are obtained. Details may include
component information from secondary and tertiary suppliers. 4. Exposure assessment
Data are entered into a comprehensive, proprietary database for
access by safety assessors. After all components of the new mate- The key to an accurate and robust assessment of exposure to a
rial are known, an in-depth safety evaluation is completed. particular substance present in a baby diaper is a deep understand-
The process for this evaluation utilizes an approach known as ing of the habits and practices of caregivers and babies, as well as
an exposure-based risk assessment in which the inherent hazards experience in the intended and actual consumer use of disposable
of the raw materials and low level components are evaluated baby diapers. This actual-use experience forms the foundation for
within the context of the potential for human exposure, given characterizing exposure relating to product use such as frequency
the intended use of the material in a diaper. A simplistic represen- and duration. Understanding the way diapers are designed and
tation of the evaluation process followed prior to marketing can be manufactured helps guide the toxicologist to properly evaluate
found in Fig. 2. the potential exposure of the consumer to the materials present
The risk assessment (RA) process by nature is an iterative pro- in a diaper.
cess, whereby conservative default assumptions are commonly In keeping with the iterative nature of RA, Procter & Gamble’s
used in the first tier (e.g., an exaggerated assumption is that a exposure assessment starts with conservative default assump-
chemical is completely released from a diaper or fully absorbed tions that are commonly used in the first tier. The assessment
from the body following dermal exposure), and the assessment then may be refined as needed by replacing these conservative
may be refined if needed by replacing conservative default default assumptions with actual data. In assessing the safety of
assumptions with new data. The RA paradigm was broadly estab- diapers, consideration is given to both the baby and the

Diaper Risk Assessment

Chemical
Composition

Exposure assessment Exposure Data Hazard Identification Hazard Data

Refinement Refinement

Risk Characterization Dose-Response

Assessment

Exposure Based Risk Assessment

Physical Hazard Risk Assessment

Clinical data to Favorable Outcome
confirm skin benefits Environmental & Worker’s
Safety

In-market
Market Monitoring

Fig. 2. Diagram of the risk assessment process.

84 K. Kosemund et al. / Regulatory Toxicology and Pharmacology 53 (2009) 81–89

caregiver. Because skin integrity is similar in babies and adults, Using a lotion transfer factor provides a useful estimate for
and exposure/kg body weight and exposure/person are known most topsheet ingredients, since it is reasonable to assume that a
to be greater for babies, if the safety margin is sufficient to sup- lotion will have maximum opportunity to transfer to the skin. Lo-
port exposure to babies, then a lower exposure to the caregiver tion is deliberately applied to the outer surface of the topsheet and
is considered acceptable. is intended to be delivered to the skin while other topsheet mate-
In order to refine exposure assumptions, chemical and physical rials are typically incorporated into large polymers and must mi-
analyses may be performed under conditions that simulate the grate to the top before they can be transferred. Most ingredients
exposure in question. For example, release of a chemical present that are tightly integrated into the polymeric matrix do not mi-
in a diaper material when it comes into contact with urine may grate or transfer very readily, so using the lotion transfer estimate
be simulated to understand whether the baby wearing the diaper would lead to a highly conservative risk assessment. Per this con-
would be exposed to that chemical under a real in-use situation. servative assessment, if the margin of safety is considered to be
This simulation can be useful if extraction conditions (such as rel- insufficient, further analytical testing may be carried out to deter-
evant extraction media) are well defined. In addition, a variety of mine the actual release from the matrix and transfer rate of the
mathematical models have been developed to estimate exposure chemical in the raw material.
levels for specific exposure scenarios. The lotion transfer factor may also be the default value used for
A key principle for diaper exposure assessments is the fact that some other diaper materials with partial or indirect contact with
disposable diapers are a solid product based primarily on solid and the skin, such as the puckered or corrugated leg cuff materials.
inert polymeric materials. Thus, the majority of chemicals are of Although elastics are not in contact with the skin, exposure can
limited concern since they are large polymers which are usually in- theoretically result due to sweat or humidity facilitating migration
ert and not absorbed through the skin (Krause et al., 2006). The of raw materials to the skin. In this case, the lotion transfer factor is
remaining substances for further evaluation are the non-polymeric used even though actual values are expected to be much lower.
ones. For relevant exposure to the skin, these ingredients must be
released from the polymer and migrate to the surface of the diaper 4.2. Materials with indirect skin contact
to be available for dermal exposure. An assessment of this release
and migration from the polymer is important in order to obtain a This category includes raw materials beneath the topsheet that
realistic exposure estimate. When no data are available, a conser- are not in direct contact with the skin, but may contain ingredients
vative default value of 100% migration of the free fraction is typi- that have the potential to migrate or resurface and come into con-
cally assumed. tact with the skin. The relevant diaper structures in this category
A diaper is a three-dimensional product featuring different are the acquisition layer and absorbent core, which consist of
materials with different functions and exposures to these materials superabsorber, polyester, modified cellulose fibers, pulp and adhe-
range from continual direct skin contact to very transient or negli- sives. These materials typically require a carrier to reach the skin,
gible skin contact (Fig. 3). Potential exposure of the skin to non- for example the retrograde migration of urine. Typical values for
polymeric substances is sorted into three categories, depending retrograde fluid migration range between 0.25% and 2.5% depend-
upon the type of material and the exposure that is possible, based ing on the test system, product design and fluid loading, and diaper
upon design of the diaper (Herrlein, 1996). change frequency (Krause et al., 2006; Herrlein, 1996; Herrlein
et al., 1998).
4.1. Direct skin contact materials
4.3. Materials with negligible skin contact
This category consists of raw materials in direct and close con-
tact with the skin. Materials in this category primarily include the This category includes the raw materials of the backsheet and
topsheet, barrier leg cuffs, and ingredients such as lotion that can the fastening system which have no or transient contact with the
be transferred from the topsheet or cuffs to the skin. Studies using baby’s skin. Data from historical experience, comparison with pre-
a lotion ingredient tracer (stearyl alcohol) in older, mobile babies vious raw material composition, product integrity standards, and
showed that only a limited amount (i.e., less than 10%) of a proto- analytical leachability evaluation can frequently be used to support
type lotion was transferred from the topsheet to the skin (Odio the assumption for no or negligible skin exposure to material
et al., 2000b). Accordingly, for ingredients contained in or added ingredients.
to a direct skin contact raw material, a transfer factor may be used Exposure assessment also takes into consideration a baby’s
to calculate the level of ingredient available to come in contact body weight, age, and the daily number of diaper changes. Habits
with the skin. and practices data are used to determine health protective values

Direct skin contact

(Higher transfer rate)
Skin side
Indirect skin contact
via retention of wetness
surfacing to the skin
(Lower transfer rate)

Outside of diaper
Limited skin contact/exposure
(Negligible transfer rate)

Fig. 3. Illustration of types of exposure encountered with material components of the diaper.
 K. Kosemund et al. / Regulatory Toxicology and Pharmacology 53 (2009) 81–89 85

for risk assessment (UK Environment Agency, 2005; EU Scientific human epidemiology data (e.g., from workplace exposure) may
Committee on Toxicity, Ecotoxicity and the Environment, 1998). exist that provide more information about the toxicological profile
If differences in the makeup of diaper dimensions exist for a certain of a chemical. Sometimes there are data on human sensitization on
age range or diaper size, the assessment can be further refined by exposed populations. More often however risk assessors have to
using the actual size/dimension values to define the absolute rely on non human data on extrapolation of data from laboratory
amount of chemical present in a material. animals. These data include in vitro and in vivo data from toxicity
Greater precision in the exposure estimate may be obtained by testing of the actual chemical. The major toxicological endpoints
analytical quantification of the release and migration of a specific to consider relevant in the diaper context include but are not
chemical ingredient. For example, synthetic urine and other prod- limited to systemic toxicity (acute, subchronic, or chronic toxicity,
ucts that may be on the baby’s skin (e.g., baby oil or mineral oil, reproductive and developmental toxicity, genetic toxicology,
saline/isopropanol disinfectant) can be evaluated in tests to mea- carcinogenicity, neurotoxicity) and local effects, (skin irritation,
sure the migration of chemicals from the substrate. Evaluation of allergic contact dermatitis).
exposure may also include consideration of the permeation of The safety data sought in this review process come from a vari-
the chemical through the skin and into the body. This permeation ety of sources, including reports of toxicology studies conducted
is effected by many factors, including the body site of exposure in-house or by the supplier and the published scientific literature.
(e.g. occlusion level), and condition of the skin (e.g., intact, hy- Animal toxicity testing has historically been the primary and
drated, or compromised by irritation) (Scientific Committee on most reliable way to confirm the safety of new ingredients and
Consumer Products, 2006). Because of these uncertainties and for products. Today, animal testing has been greatly reduced by in-
better comparison with data derived from toxicity studies (admin- creased use of historical data, the increased sophistication of com-
istered dose vs. absorbed dose), a conservative approach is used in puter models. This is in line with Procter & Gamble’s commitment
which reduction factors for skin permeation are not applied unless to establishing and applying the ‘‘Three Rs” (Replacement, Reduc-
data indicate that use of such factors is appropriate. tion, Refinement) as an overriding principle for hazard identifica-
tion in risk assessment. This includes the development and use of
5. Hazard identification new methods substituting the use of animals for safety testing
(Replacement), methods that result in using fewer animals to ac-
Another step in the risk assessment process is known as hazard quire necessary information (Reduction) and methods that alter
identification. It is the phase during which a toxicologist evaluates procedures to eliminate and minimize discomfort (Refinement).
the inherent toxicity of a chemical to identify whether it can cause Additional hazard identification tools are available or can be
an adverse health effect given the relevant route of exposure. For- developed. The qualitative structure-activity (SAR) relationships
mal descriptions of the purpose of hazard identification vary be- approach which incorporates molecular substructures or frag-
tween the US and in Europe, but each is based on assessing the ments related to the presence or absence of toxicity has enjoyed
toxic effects of the chemical in question. In addition to gathering broad acceptance in the field of genetic toxicology and carcinoge-
information on the raw material or ingredient(s) as such, it is nicity, and has been used to identify and eliminate from consider-
important to gather information on known or expected contami- ation a large number of reactive chemical substructures that are
nants of the ingredient and to conduct similar searches for hazard potentially mutagenic and carcinogenic. Other more sophisticated
information on the contaminant(s). As outlined previously, the developments include quantitative structure-activity relationship
majority of materials used in diapers are large polymers which (QSAR) (OECD, 2007; Veith, 2006; Jaworska et al., 2003; Eriksson
are chemically inert. They do not penetrate the skin and therefore, et al., 2003; Cronin et al., 2003a,b) and Physiologically Based Phar-
are of negligible concern. Special attention is given to trace level, macokinetic (PBPK) modeling (Jones et al., 2006). The latter is a
non-polymeric substances like process aids, aesthetic ingredients mathematical modeling technique for the characterization of a
such as colorants or scents or potential levels of monomers, sol- chemical’s pharmacokinetics in a complex biological system,
vents, and additives used in polymerization reactions or syntheses. which can be used in human health risk assessment and investiga-
Understanding the chemistry of the substance is often helpful in tion of toxicity. Such approaches provide strong support for the
this regard. The exact source must be considered, as different pur- toxicological ‘‘bridging” associative process within the develop-
ity grades may be available and different suppliers may provide ment of the chemical risk assessment.
material with different impurity profiles. The full complement of The hazard information contains critical contextual information
hazard identification information can be drawn from several specific to the mode of action, species differences in response,
sources, including data from toxicity testing, evaluation of chemi- route of exposure, and characteristics of the dose-response rela-
cal structure to identify structural alerts, and data from human tionship. For example, a chemical may pose a risk only if it is in-
experience. haled—for example, mineral oil is safe to apply to the skin, but
can be highly dangerous if it is inhaled. Any modification of this
6. Evaluation of potential risk scenario (e.g., lowered dose, shorter duration) would then alter
the hazard and redefine the risk.
The initial analysis of a substance focuses on the evaluation of
those physico-chemical parameters such as molecular weight 7. Dose–response
and solubility which help the assessor to predict for its likelihood
to migrate out of the diaper and be available for skin exposure or Dose–response evaluations assess the relationship between the
even to be bioavailable via skin permeation. dose of a chemical and the incidence or severity of an adverse
Should there be any evidence for skin exposure or bioavailabil- health effect in the exposed population. Rigorously reviewed
ity, the chemical is further screened for alerts of concern using a methods for all human safety endpoints are available to calculate
tiered approach: acceptable exposure levels of chemicals e.g. for contaminants in
In silico and in vitro methods are available to determine for food, air or drinking water. The same principles can be used for
example potential for DNA reactivity, sensitization or developmen- consumers which may be exposed to low levels of chemicals.
tal toxicity. Hazard potential can be further evaluated by using The threshold of toxicological concern (TTC) approach (Kroes
available human and laboratory animal data. Only occasionally et al., 2004, 2005) provides an acceptable method to determine a
86 K. Kosemund et al. / Regulatory Toxicology and Pharmacology 53 (2009) 81–89

conservative estimate of exposure levels below which there is very ly intake), or other risk value that has already incorporated areas of
low probability of risk for consumers when chemicals are present data extrapolation and uncertainty. With these incorporated
at very low levels. This approach has been used for decades to sup- uncertainty factors, a MOS equal to or greater than 1 can be consid-
port safe exposures to indirect food additives in the absence of ered to be acceptable.
complete chemical-specific human toxicological data. Over the In the best case, risk assessment indicates that the ingredient or
years, the method has been refined and additional work has been product is safe for its intended use and that an adequate margin of
done to extend the underlying database so that it can be used more safety exists even if the diaper is misused in a foreseeable way.
broadly. Blackburn et al. (2005) and Kroes et al. (2007) have specif- Once this determination is made, the product is ready to continue
ically addressed the use of TTC for cosmetics and other personal its journey towards the store shelves. In some cases, data gaps are
care products. identified that result in the design of an additional safety testing
For exposures that exceed a TTC-based limit, quantitative meth- program. If the initial risk assessment leads to unfavorable results
ods of risk assessment have been established by a number of inter- and the safety of the ingredient cannot be confirmed for the in-
national/regulatory agencies (National Academy of Sciences, 1983; tended use, then a suitable alternative to the ingredient in question
US EPA, 1993, 2002; International Programme on Chemical Safety, is sought. As noted previously, it is often not the material itself that
1999; Organisation for Economic Co-operation and Development, raises any concern, but rather the presence of contaminants that
2007). These quantitative risk assessment methods are used to must be controlled. This process can include working with new
support human safety from a variety of exposures ranging from materials or suppliers to find ingredients that meet the product’s
contaminants in the air and drinking water, to pesticides and other technical needs while ensuring the safety of consumers. For the
contaminants in food. Procter & Gamble applies these same conser- estimation of risk, conservative default assumptions are used often
vative, health-protective methods to assure the safety of consumer for elements of the process. Numerous conservative default
products, including diapers. An in-depth review of these methods assumptions have already been described in the Exposure section.
is beyond the scope of this document. Briefly, however, these For hazard characterization at very low exposure levels, the thresh-
methods most commonly involve extrapolating toxicity data from old of toxicological concern approach described earlier is used. In
laboratory animal studies to establish an acceptable exposure limit cases in which the initial safety margin estimate is lower than de-
for humans that takes into account (e.g., through the application of sired, more accurate data may be obtained to refine many of these
conservative uncertainty factors) differences between species and conservative default assumptions. For example, actual skin perme-
the potential for sensitive subpopulations. In addition, uncertainty ation studies or dermal penetration modeling can be conducted to
factors may be applied to account for sub-chronic to chronic (expo- refine the estimation of systemic exposure.
sure duration) extrapolation, or for the adequacy or completeness
of the database (e.g. lack of a reproductive/developmental toxicity 9. New material testing and clinical studies
study). In addition, there may be other areas of data extrapolation
for which uncertainty factors have not been established, but which Since skin contact is the predominant type of exposure during
should still be considered in a risk assessment. These areas include baby diaper use, clinical skin irritation tests may be conducted to
route-to-route extrapolation (e.g. using data from an oral toxicity confirm that new materials or new diaper designs do not nega-
study to conduct a risk assessment for a product applied to the tively affect skin health in the diaper area. The relevant clinical
skin), vehicle or matrix effects in extrapolations from test condi- endpoints include parameters such as skin dryness, skin pH, and
tions to diaper-relevant conditions, and accounting for the biolog- the absence of rash and mechanical irritation (Adam, 2008). In or-
ical or micro-environmental differences of the intimate diaper der to ensure an adequate level of safety for even the most sensi-
area. As described above for exposure assessment, dose-response tive user, these tests normally are conducted under conditions
assessment is also an iterative process. A first-tier assessment gen- that exaggerate potential in-market exposure both in terms of test
erally utilizes conservative (health-protective) default assump- concentration and duration of exposure. To assess the skin irrita-
tions, recognizing that these can be refined with data as tion potential, an appropriate Human Patch Application Test may
appropriate. be conducted (Andersen et al., 1994; Rhein et al., 1990; Shellow
and Rapaport, 1981; Bowman et al., 2003).
8. Risk characterization and final risk assessment Allergic contact dermatitis is another important area of concern
when evaluating the safety of raw materials coming in contact
Risk characterization is the final step in RA, integrating expo- with the skin (Gerberick et al., 2001b). The approach for conduct-
sure assessment, hazard identification and characterization and ing skin sensitization risk assessments utilizes the same quantita-
dose-response assessment, into advice suitable for use in deci- tive risk assessment approach as described in the above
sion-making or risk management. There are two terms commonly paragraphs. International industry associations such as the Re-
used in risk characterization: margin-of-exposure (MOE) and mar- search Institute for Fragrance Materials and the International Fra-
gin-of-safety (MOS). grance Association have formally adopted the RA approach as the
core strategy for primary prevention of skin sensitization to these
8.1. margin-of-exposure (MOE) materials in consumer products. Based on deep understanding of
the biology associated with induction of skin sensitization, the sci-
A MOE is a comparison of the estimated human exposure to an ence of structure-activity relationship and RA for skin sensitization
experimental or extrapolated dose such as a NOAEL, LOAEL, or has matured to provide substantial guidance in the determination
benchmark dose. It does not take into account any areas of data of the safe level of a sensitizing ingredient in a consumer product.
extrapolation or uncertainty. The output of the assessment is the comparison of the anticipated
consumer exposure level (CEL) to the acceptable exposure level
8.2. margin-of-safety (MOS) (AEL). The AEL/CEL represents a Margin of Safety (MOS with its
embedded conservatism and safety factors, and provides the nec-
A MOS is a comparison of the estimated human exposure to a essary reassurance of safety for ingredients which may contain
risk value for which the risk causing adverse effects is considered trace levels of materials with sensitization potential (e.g., perfume
to be minimal such as an RfD (reference dose), ADI (acceptable dai- raw materials). Generally, an MOS greater than 1 is considered
 K. Kosemund et al. / Regulatory Toxicology and Pharmacology 53 (2009) 81–89 87

adequate to allow the material to be used in a marketed product, et al., 1995). Consequently, Quality Assurance parameters are
while an MOS below 1 is not appropriate for product release to established as part of the product release criteria and the products
market without additional safety work. For those materials with are manufactured according to Good Manufacturing Practice to
an MOS less than 1, the toxicologist may consider reformulation, their integrity. Since accidental exposure through ingestion of dia-
reevaluation of assumptions used in the exposure assessment or per parts is considered a foreseeable scenario, the level of systemic
further research to generate more safety data. exposure and risk is also routinely assessed. The safety assess-
It should be noted that there is insufficient scientific rationale to ments routinely conducted for raw materials generally are also suf-
apply any additional infant uncertainty factor for higher suscepti- ficient for this unique situation and primarily include evaluation of
bility of infant skin (SCCNFP, 2002; Renwick et al., 2000). Structural existing data in the literature relating to systemic exposure to the
and functional skin barrier properties have been shown to be equal ingredients. Technical assessments include evaluation of the po-
between full term neonates, infants and adults. Several studies and tential risk of an acute ingestion. For example, in the case of the
observations support the conclusion that newborns and young in- super absorbent polymers found in the core of the diaper, a risk
fants are even less susceptible to skin sensitization owing to an assessment taking into account acute and subchronic toxicity data
immature or developing immune system, respectively. This posi- demonstrates that accidental ingestion of the small superabsorber
tion is supported by several pieces of information related to epi- granules would not lead to an increased health risk for the baby.
dermal skin biology: While not recommended, accidental ingestion of this material will
1. Epidermal thickness, density of epidermal cell layers and cel- not result in aggregation that causes choking or suffocation, nor
lular structure are identical between adults and newborns (Fact will it result in any internal toxic responses to this inert polymer
Book, 1996; Fairley and Rasmussen, 1983; Holbrook, 1982). The re- or any low-level contaminants that might be present (Greim,
duced thickness of neonatal skin relative to adult skin, particularly 1998). Even under rare product failure situations, such as when
the dermis which has smaller collagen fibre bundles and immature superabsorber may come in contact with the skin, sufficiently high
elastic fibers (Rook et al., 1992), is irrelevant when considering the margins of safety exist for such an accidental exposure.
potential for induction or elicitation of a sensitization response
since sensitization processes are initiated in the epidermis and 11. Scientific review
not the dermis.
2. Full-term newborn infants have a functional stratum cor- In order to help ensure that the most up-to-date information
neum and a mature skin barrier function equal to adults (Fact and sound scientific judgment have been employed in the safety
Book, 1996; Kalia et al., 1998; Cunico et al., 1977; West et al., assurance program, safety assessors may decide to gather objective
1981) Importantly, structural and functional cellular constitution feedback and input from external experts in pertinent disciplines
required to build up a mature stratum corneum is already present before introducing major changes to a product.
in the late pregnancy (Hammarlund and Sedin, 1979; Harpin and
Rutter, 1983). Age-dependent studies have shown clear evidence 12. In-market monitoring
that skin barrier remains virtually constant from infancy to late
adulthood (Leveque et al., 1984; Ghadially et al., 1995). The final element of a complete safety strategy for diapers is the
3. In vivo as well as in vitro studies have shown that percutane- monitoring, recording and follow up of safety-related comments
ous absorption of chemicals is similar in infants and adults (Ras- from caregivers in the market. This tool provides continuous con-
mussen, 1978; Wester and Maibach, 1982; McCormack et al., sumer feedback, enabling the manufacturer to be aware of any
1982). concerns by users and to maintain a high standard of product qual-
4. The skin is less reactive to potent contact sensitizers in early ity and consumer satisfaction. This is accomplished by including
infancy than it is later in life (Rietschel and Fowler, 1995). Allergic the manufacturer’s local contact details on every product (e.g., a
dermatitis to poison ivy-oleoresin as well as to certain topical med- toll-free telephone number or local address). Trained consumer
ications is rare in early life (Epstein, 1971). The skin reactivity to relations personnel and safety personnel monitor these calls to
2,4-dinitrochlorobenzene has been shown to be very low in neo- ensure that any alleged safety concerns are investigated and
nates and low in babies up to 3 months of age compared with addressed by appropriate follow up.
adults. Importantly, the sensitization incidence in 9-month-old in-
fants was shown to be equal to adults, however at a 30 times high-
er dose per unit area concentration than that required to achieve 13. Conclusion
equal sensitization incidences in adults (Cassimos et al., 1980). This
observation supports the conclusion that infants are not more sus- Each year, millions of consumers and caregivers rely on the
ceptible to sensitization than adults, and might well be less suscep- superabsorbent disposable diaper as a convenient, effective and
tible given equivalent exposures. Babies may be less susceptible to safe product. The major components of diapers are inert poly-
sensitization because of the immaturity of their immune systems, mers that are inherently safe and all materials are carefully as-
which has been shown to have limited immune cell function, re- sessed before introducing into marketed products. Procter &
duced cytokine release, limited antibody synthesis, and deficiency Gamble has established a systematic approach for evaluating
of cell-mediated immunity (Gotoff, 1996). diaper safety as an integral part of the product development
process. The approach follows the principles of general risk
assessment including hazard identification, dose–response
10. Accidental ingestion assessment, exposure assessment and risk characterization and,
controlled trials to assess relevant clinical endpoints and/or inde-
On rare occasions, misuse of diapers can lead to the ingestion of pendent scientific review, as appropriate. Additionally, post-mar-
diaper components. In these situations, the immediate concern is keting surveillance with consumer feedback provides added
the potential choking or suffocation hazard associated with physi- assurance that safe, quality products serve babies and caregivers
cal components of the product. Therefore, the structural integrity around the world. The continued safe marketing of diaper prod-
of the baby diapers is assessed by objective criteria to ensure the ucts for over 45 years bears testimony to the company’s rigorous
integrity and safety of the product for the consumer (Olsen, and conservative safety assessment strategy that is described in
1998; van Prooijen and de Winter, 1996; Krische, 1997; Rimell this manuscript.
88 K. Kosemund et al. / Regulatory Toxicology and Pharmacology 53 (2009) 81–89

Conflict of interest statement Greim, H. (Ed.), 1998. Occupational Toxicants. Deutsche Forschungsgemeinschaft.
Wiley-VCH, Weinheim, New York,Chichester,Brisbane, Singapore, Toronto, pp.
1–29.
The authors are employees of Procter & Gamble. Hammarlund, K., Sedin, G., 1979. Transepidermal water loss in newborn infants. III.
Relation to gestational age. Acta. Paediatr. Scand. 68, 795–801.
Harpin, VA., Rutter, N., 1983. Barrier properties of the newborn infant’s skin. J.
Acknowledgments
Pediatr. 102, 419–425.
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The authors thank Dr. Ralf Adam for his contributions to the European Patent EP0797967 A1..
Herrlein, M.K., Robertson, M.C., Berk, A., Kleinsteuber, U., Plischke, M., 1998. Method
safety assessment program. Lisa Bosch assisted in the preparation
for assessing Disposable absorbent articles, PCT World Patent A61F 13/15.
of this manuscript. International Publication number WO 98/58606.
Holbrook, K.A., 1982. A histological comparison of infant and adult skin. In:
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