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Regulatory Toxicology and Pharmacology 81 (2016) 183e193

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Exposure Factor considerations for safety evaluation of modern
disposable diapers
Swatee Dey a, *, Mike Purdon a, Taryn Kirsch b, HansMartin Helbich b, Kenny Kerr a,
Lijuan Li a, Shaoying Zhou a
The Procter & Gamble Company, Cincinnati, OH, USA
Procter & Gamble Service GmDH, Schwalbach, Germany

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

Article history: Modern disposable diapers are complex products and ubiquitous globally. A robust safety assessment for
Received 28 June 2016 disposable diapers include two important exposure parameters, i) frequency of diaper use & ii) con-
Received in revised form stituent transfer from diaper to skin from direct and indirect skin contact materials. This article uses
25 August 2016
published information and original studies to quantify the exposure parameters for diapers. Using
Accepted 26 August 2016
Available online 28 August 2016
growth tables for the first three years of diapered life, an average body weight of 10e11 kg can be
calculated, with a 10th percentile for females (8.5e8.8 kg). Data from surveys and diary studies were
conducted to determine the frequency of use of diapers. The overall mean in the US is 4.7 diapers per day
with a 75th, 90th, and 95th percentile of 5.0, 6.0, and 7.0 respectively. Using diaper topsheet-lotion
Exposure based safety assessment transfer as a model, direct transfer to skin from the topsheet was 3.0e4.3% of the starting amount of
Disposable baby diapers lotion. Indirect transfer of diaper core materials as a measure of re-wetting of the skin via urine resur-
Exposure facing back to the topsheet under pressure was estimated at a range of 0.32e0.66% averaging 0.46%. As
Diaper safety described, a thorough data-based understanding of exposure is critical for a robust exposure based safety
Children assessment of disposable diapers.
© 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (

1. Introduction The major components of the modern disposable diaper are
inert polymers with a history of safe use in a number of absorbent
Disposable baby diapers have improved the lives of con- consumer products (Dey et al, 2014, 2016). The basic structure and
sumers in many parts of the world. It is estimated that the total composition of diapers have been previously reviewed (Kosemund
number of disposable diapers used during the first 3 years is et al., 2009). It consists of four functional layers (Fig. 1). The top-
4600e4800. The use of superabsorbent gelling materials has sheet is the layer in direct contact with the baby's skin, and is
resulted in diapers with the capacity to absorb many times their composed of soft, porous polypropylene developed to transfer
weight in fluid, and to keep the fluid away from the skin urine and other liquids quickly to the layers beneath. The topsheet
resulting in reduced skin hydration and pH changes, and re- may also contain a lotion (emollient) to help protect the skin from
ductions in the frequency and severity of diaper dermatitis (Odio over hydration and irritation (Baldwin et al., 2001). The acquisition
and Friedlander, 2000). In a recent review by Heimall et al. layer is composed of modified cellulose and polyester, and facili-
(Heimall et al., 2012), multiple expert opinion articles were cited tates the movement of liquid away from the skin to distribute it
recommending the use of super absorbent diapers as a key step evenly to the diaper core. The diaper core or absorbent layer con-
in preventing and treating diaper rash. sists of superabsorbent polymer gel that may be blended with
cellulose and contained within a cellulose or a porous polymer
nonwoven layer. Urine is locked and stored within its polymeric
structure even under pressure. The backsheet is the water-proof
Abbreviations: EBSA, Exposure Based Safety Assessment; QRA, Quantitative Risk
Assessment; BW, body weight; PERMID, Prolonged Exposure Rewet Method in outer layer of the diaper, typically made of soft textured, cloth-
Diapers; TWA, time-weighted average; FOU, frequency of use; LOW, length of wear; like polypropylene laminated with a polyethylene film. Its func-
SABAP, Speed of Acquisition with Balloon Applied Pressure. tion is to prevent liquid from leaking out of the diaper. Diapers also
* Corresponding author. 6280, Center Hill Ave, Cincinnati, OH 45224, USA.
contain additional features primarily designed to ensure a good fit,
E-mail address: (S. Dey).
0273-2300/© 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (

Kimber et al. 2011) and the Centers for Disease Control (CDC) (Centers for Disease Control and Prevention. comments are monitored for continued product safety assurance Although the BW is < 8 kg in the first 6 months of an infant's life. Using CDC data the the diaper constituents. 2015). changing exposure over time. diapering period of 3 years. Hazard assessment and dose-response BW for 3 months to 2 years was 10. and leg cuffs to prevent ments because it will take into account life stage differences in leakage. Diaper user biometric parameters 2. 1981. 2009 Rai et al. mate dermal exposure (mg/cm2/day) to assess skin sensitization bies) collected from published literature. For diaper In addition to the polymeric materials. Appropriate uncertainty factors is 9. 2015). the TWA for mean BW for a typical dia- ment is conducted prior to marketing the product to ensure a high pering age of 0e36 months for both genders combined is 11. uent transfer to skin (Table 1).. US EPA. The US EPA has pub- lished recommendations for body weight for exposure assessment of children 0e1.2 kg. Basic functional layers of a modern disposable diaper.2. 2). 2009. A time weighted average (TWA) is used The approach for safety assessment of baby diapers and other for exposure that is not constant at any one given time. under. 1e3. 2011). Daily inhalation rates for adults and children (10 years. because BWs in the diaper wearing children are transient and rapidly increasing. and the exposure dynamics of a 3-dimensional product like a disposable diaper is needed. For clinical in-use studies are conducted to confirm favorable skin EBSA we use 8 kg BW for the entire diapering period. the growth rate is rapid and is 3. intake for children 0e6 months and 0e12 months for assessing standing of potential local and systemic exposures. respectively.5 kg. 1 product have been recently reviewed where physiological and year old and new born babies) were estimated over a specified developmental differences that may result in differential sensi. This is con- compatibility when necessary. 2015) (Fig. 2014). under ‘in-use’ conditions. length of wear. 1976). Further. During this period. fastening systems and tapes. 1. 2010. clearly provide evidence that under the majority of exposure . A TWA BW for children 3 months to 2 years was (1983)). health evaluation of exposure to CO2 (NIOSH. Surface area used to develop an appropriate diaper exposure assessment. It is not practical to assess diaper exposure for multiple age brackets and for a specific point in time. / Regulatory Toxicology and Pharmacology 81 (2016) 183e193 2. exposure assessment. Exposure assessment and risk characterization mating TWA BW for the first 3 years to estimate diaper exposure. This approach is expected to increase the accuracy of risk assess- such as. 8.8 kg and 12. consumer health servative since the TWA BW over 36 months is lower than 8 kg. According to EPA guidance when exposure is likely to occur it is appropriate to sum across time-weighted values for all age periods. 2005). This includes evaluation of all The 10th and 95th percentile TWA BW for both genders combined relevant toxicological endpoints. non-dietary hand-to-mouth behaviors and the weighted average and risk characterization. 3e6. 2010.1 kg and 13. Once marketed. This is depend on the potential biological effects of the constituents in consistent with the approach taken in this manuscript for esti- the raw materials.. diapers may also have a exposure the TWA BW provides a conservative assumption over the small amount of small molecular weight non-polymeric constitu. available human and experimental animal data. for eg. the con. dose-response assessment.2 kg (US EPA.. US EPA. skin effects. consistent (Kosemund et al. skin irritation and skin sensitization are mean. Body weight (BW) Diapers are used by babies approximately for 36 months or less (AAP. infant absorbent consumer products have been described previously BW changes every day. and it with EPA guidance we have chosen to use a TWA BW based on US follows the same risk assessment process established by the US EPA recommended average BWs for the diapering period of 0e36 National Academy of Sciences (National Academy of Science months (Table 2).6 kg respectively. So. 2003). published by the CDC (0e24 months and 24e36 months) (Centers In addition to a thorough assessment of the systemic endpoints of for Disease Control and Prevention. require an understanding of the consumers (children). 36 months (calculation not shown). 2014). These include diaper user biometric information. so the BW during majority of standing exposure via accurate consumer habits and practices data the diapering period is > 8 kg. The TWA BW from EPA is in are incorporated into the safe threshold levels of individual con.184 S.4 kg. In a review of the parameters such as frequency of use. This paper focuses on key parameters 2. ents or impurities at very low levels for which a thorough assess.. especially during the first few months of life. This is confirmed via adult skin patch test. Dey et al. and constit. 6e12 months. Based on US EPA data. Fig. Dey et al. The 10th percentile BW for females from this data set is 8. The overall cumulative exposure and risk (Arcus-Arth et al.1. including appropriate Appropriate assumption of skin surface area is needed to esti- body weight and surface area for a growing user population (ba..5 times faster than between 7 and For a robust exposure based safety assessment (EBSA). level of consumer safety assurance. reasonable agreement with the TWA BW based on growth data stituents to account for interspecies and intra-species differences. 2005. and a thorough under. TWA was also used for (Felter et al. risk assessment approach and consideration for children's 2011). and 1e2 and 2e3 years old (US EPA. It consists of a 4-step process that includes hazard used to determine ingestion of an environmental contaminant by identification. children gain weight rapidly. 2011). period of time based on a TWA of inhalation rates associated with tivity associated with early-life exposures have been discussed physical activities (ICRP.0 kg. as demonstrated by monthly body weight data on international growth standards published by US EPA Exposure Factors Handbook (US EPA. Human milk and lipid intake distribution was defined using TWA ditions under which diapers are used. as well as product related based on child specific dose per unit area. 10th and 95th percentile TWA BW for both genders for evaluated for additional safety assurance to ensure absence of local children 0e36 months is 10. exposure (US EPA.

4 12.1 9.7 5 4. given as mg or mg.2) þ (12  11.1 9 6 to <12 months 6 9. So. S.8 13.9 7.5 9.6) þ (3  7. 2.5 11.e.4) þ (6  9. which is considered interest (Kimber et al.9 9.3 11.5 12 11 17.3 13.8 4.3 11.1.2 9.5 11. / Regulatory Toxicology and Pharmacology 81 (2016) 183e193 185 Table 1 Exposure considerations for safety assessment of raw material constituents in baby diapers.2 1 to <2 years 12 11. 2.5 8.1 6.3 7.5 7. Dose per unit area of skin (mg/cm2/day): [Amt (mg) x FOU(#/day) (ITdirect% or ITindirect %) x DA%]/SA (cm2) ¼ Exposure (mg/cm2/day). calculations not shown) (Centers for Disease Control and Prevention.7) þ (3  6. Indirect skin contact (i. Exposure Parameters Abbreviation Definition. Table 2 Time-weighted average (TWA) of body weight for children 0e36 months (US EPA.7 9.7 4.1 8.8 5. Mean body weight during the first 2 years of life Figure adapted from monthly body weight data on international growth standards published by the Centers for Disease Control (CDC) (Centers for Disease Control and Prevention.1 9. it is assumed that the surface area is the area of the diaper part in contact with the skin. 1992) Birth to <1 month 1 4.6 13.4 9 7.3) þ (12  11. accounting for the surface area of contact per unit area of a chemical (e.0 11.8 14.6 12. Dey et al.7 9.6 11.1 17 17.4 5.1 9.4 7.1 13.8) þ (2  5.g.7 13.5)]/36 ¼ 9.6 3.9 6 5.1 14 14. TWA (10th) ¼ [(1  3.. Proportion of skin surface area in .9 4.5) þ (12  9.6 7. 2015).4) þ (12  13. 2010. Fig. Constituent transfer to skin Direct skin contact ITdirect % Constituent transfer to skin from materials in direct skin contact. 2008).0.5 Comparison to CDC data (from Fig.. conditions it is the surface area of contact.7 2 to <3 years 12 13.2 6.8 9.3 7.9 8.1) þ (6  7.2 10.8)]/36 ¼ 11. expressed as the dose to be a local effect.1 TWA body weight 11. mg/cm2) that has the greatest provides a reasonable estimate of the exposure to the constituent of impact on the acquisition of skin sensitization. TWA (Mean) ¼ [(1  4. Age group # Of Months in weight range Mean body weight (kg) 10th percentile body weight (kg) 95th percentile body weight (kg) Both genders Males Females Both genders Males Females Both genders Males Females EPA recommended body weights (US EPA.9 3. 2011).6 4 6. 2015) TWA body weight 10.5 12.6 7. rewetting) ITindirect % Constituent present in diaper core materials that dissolve in fluids and reflux back to the skin (re-wetting) Specific for the constituent raw material in the diaper Amount of constituent in product Amt Determined by product composition.3 9.9 1 to <3 months 2 5.2 Example of TWA calculation for mean and 10th percentile (both genders) for 0e36 months.4 11.3 3 to <6 months 3 7.2 6.2 10. as applicable to diapers General considerations Body weight TWA BW Time-weighted average body weight for children 0e36 months of age Skin surface area (exposed surface) SA For diapers. Dermal absorption DA Compound-specific (defaulted at 100% in the absence of data) Examples of EBSA calculations: Systemic dose (mg/kg/day): [Amt (mg)  FOU (#/day)  (ITdirect% or ITindirect %)  DA%]/TWA BW (kg) ¼ Exposure (mg/kg/day).9) þ (2  4. Specific for the product category Habits and practices (H&P) Frequency of use FOU Number of diapers used per day.

Exposure parameters related to product use usage. First.2 4 5 6 7 a Saudi Arabia 545 4 4 5 6 7 France b 587 4. 6. daily disposable diaper usage ranged from 0. 50% of responders reported 1 or fewer disposable diapers per day. a side panels/backears. estimate duration for which each size was worn. For di. Length of wear sure to diapers. a Interviewer administered. the diary data (Table 4) indicated an overall mean (all cm2/day. For comparison. Panelists were 3. Table 3 Diaper frequency of use by country (survey data). it is clear that for vey Data).1. Results indicate an in. cases transfer of constituents from diaper to skin is variable based Studies were conducted in the US (Cincinnati. Surveys were conducted via door-to-door interviews majority of the diapering period children use size 3 and 4 diapers among mothers of babies 0e36 months of age in India. etc) being assessed is 95th percentile of 7.1. and parts of the diaper intended for fit and to prevent leakage. In France.5 1 2 4 4 Philippines a 461 2. per unit area (US EPA Exposure Factor handbook. 90th. China. a Length of wear (LOW) of various diaper sizes were evaluated to representative global survey on disposable diaper use was con. measured for appropriate surface area to estimate exposure in mg/ However. 2012). A comparison of data from the US reveals that the mean FOU 2008. One limitation for this survey was the absence of diaper ment is mainly focused on small molecular weight non-polymeric size information. barrier leg cuffs or the waistband. In both analyzed (P & G Diaper H & P Diary Studies..3 to 5. No specific surface area for the different diaper compo.1. (Tables 4 and 5).5 diapers per day. and 7. Japan growth of children during the first 5 months after birth. 2008). 90th and apers. We considered both survey and diary data.1 ± 1. UK. The mean exposure since the time in each wet diaper will be less.. 2011.1. and the physical and chemical properties of were asked to use the test products for a period of 5 days.1 for babies using Size 2 diapers. 2010. in which the data were collected. OH). Country No. size and body weight per CDC growth chart. and participants on proximity to skin. with a 75th.186 S. Dey et al.0.e.3 0 0 1 2 China a 2267 1. the only components of the diaper that are verse relationship between FOU and diaper size.7. door-to-door. Transfer of lotion was assessed in an exper- 2008 environmental assessment in the UK cited an average daily imental setup to determine a conservative default for potential use for disposable diapers of 4. whereas diary data represent a real-time record of product usage where parents record each use.7 5 6 7 7 Germany b 567 4. diary data collected in 2010e2012 for sizes 2e5 were pathways: direct skin contact and/or indirect skin contact. Survey data are limited by the accuracy of the responder's recall and often under or overestimates 3.3 2 3 4 5 Russia a 722 3.5 for babies using Size 5 diapers (Table 4).0 nents have been reported here. of participants Diaper use per day Mean 50th percentile 75th percentile 90th percentile 95th percentile India a 285 0. based on 2001e2002 transfer of constituents from diaper parts in direct contact.2. the components (topsheet. 2011. head. In China. In addition. The survey results consumer products can be extrapolated from these data. In a modern diaper. A provide skin benefits. The country with the highest FOU Diapers are made primarily of inert large molecular weight was the US with a mean of 5. the 4. sizes) of 4.. and 95th percentile of 5.5 5 7 8 10 US b 972 5. Direct skin contact mothers of healthy children 0e48 months. a higher babies 0e48 months. these data are com- legs. / Regulatory Toxicology and Pharmacology 81 (2016) 183e193 children (total body and specific body parts i. In this case the survey data 3. considering length of wear and rapid Philippines.e. 10 and 10 diapers respectively for the US. Sharkey et al.2. Frequency of use (FOU) is a key parameter in evaluating expo. Russia and Saudi Arabia. back ear. i. constituents that can be potentially transferred to skin via two Second.9 and a 75th. Partici. The safety assess- (Table 3). 2009) is also included in Table 4 that diapers the topsheet is coated with a lotion (emollient) to help indicates an average change frequency of 4.9.. trunk. The area of skin exposed to specific differed between the survey and the diary study. Mothers recorded the average number of FOU for size 2 and below may not necessarily mean a higher disposable diapers worn by their child in a typical day. Boniol et al. arms. Overall. The mean number in direct contact with the skin are the diaper topsheet and those of diaper changes was 5. . Constituent transfer from diaper to skin use of disposable diapers. It is likely that this difference is related to the manner design of the diaper. Diaper frequency of use also lacked diaper size information.9 and a reported 50th percentile of 6 polymeric materials which are not bioavailable. Based on diaper ducted in 10 countries during 2007e2008 (P&G Global H & P Sur. the constituent.7 5 6 6 7 UK b 901 5 5 6 8 8 Japan b 326 5. since it varies based on the size and respectively. The lowest reported FOU was in India. pants kept a diary on a variety of performance characteristics including the number of diaper changes every day.0.16 per day. 2001). with 75% of responders indicating no 3. (Table 3) indicated a mean diaper change of 5. 3. 2012. sales figures (Aumo ^nier et al. In some previous report (Rai et al. using FOU and the US the survey was administered by mail to mothers of parameters for sizes 3e4 seems reasonable. genitalia and buttock etc. Hence.) are available for estimation of dose parable between the current study and previous studies.6 ± 2.. b Self-administered by mail.9 6 7 10 10 Parents recorded the average number of disposable diapers used each day. Germany.

1 ± 1. 2000).02 multiples ND Direct transfer measurements were conducted using a diaper with 0. 6-h and overnight wear times). The percentage of lotion transferred to collection tapes was calculated for those samples with a known number of diaper applications (i. Children who were routine users of Results of lotion transfer to skin are shown in Table 6.7 cm2 (1. Results from group 2 one tape section was removed after wearing a single lotion-treated indicate that transfer from a single overnight diaper was diaper for 3 h (3-h tape).2 ± 6. In the 6 h wear collections.5e11.101 gm lotion spread on a topsheet of 83.6 ± 5.5 21e36 15 42% Size 5 15.5e7.207 mg/cm2 lotion). A total of 60 from group 1 indicate that transfer from a single diaper (3-h wear) children were randomly assigned to one of two groups of 30 chil. or a total of 3. or 1.5 Girls Size 1 4e5.7 ± 17.88 and 169.7 ± 6.7 ± 7. One of the two tapes on each possible to calculate a percent transfer. Dey et al. The test product application until removal at the next day's visit to the laboratory was a diaper (Size 4) with 101 mg lotion spread on a topsheet of (24-h tape) (Odio et al.6 ± 5.3% 18 h 15 103.7 cm2. was 48. Diaper size (BW range) No. Diaper size Body weight rangea (Manufacturer's recommendation . 2010). were given a full-day supply of lotion-treated diapers and were Total lotion transfer was 103..5 5e21 16 44% Size 4 11.6 ± 2. Wear time N Amount of lotion transferred (mg/cm2) Number of diapers used % Lotion Transfer per Diaper Mean ± SEM Group 1 3h 24 48. the parents of each infant ad libitum use of multiple diapers over the course of 18 and 24 h.88 multiples ND 24 h 12 169..5 24e36 12 33% Size 5 15.7 ± 1. The child was diapered with a fresh test 52.5 5 6 6 3 Overall (all sizes) 650 4. data reported in of these children was removed and saved by the parent at bedtime Table 4 indicate that an average of 4.0% 6h 22 72. / Regulatory Toxicology and Pharmacology 81 (2016) 183e193 187 Table 4 Diaper frequency of use by size in the US (diary data). Paul.5 7e24 17 47% Size 4 11.5 5 6 7 4e5 Size 4 (10e17 kg) 150 4.82 2 3..7 ± 1.0% of the starting amount dren each.5 2e7 5 14% Size 3 7.5 5 6 7 4 Size 5 (14e18 kg) 150 4. 2000). St.5e15.7 ± 6. b Mean body weight (BW) based on CDC growth charts (Center for Disease Control and Prevention.e.5 0e2 2 6% Size 2 5. In the first treatment group. S. of lotion on the diaper topsheet. Table 5 Estimated Length of Wear (LOW) for each diaper size for children up to 36 months of age.82 mg/cm2.3% of the starting amount of lotion on the product for an additional 3 h and the second tape was removed (6-h diaper topsheet.without overlap) Using mean BWb c Age range (months) LOW (months) % Of total LOW Boys Size 1 4e5.02.5e7. c The % of total LOW is based on 3 years (36 months) exposure to diapers.5e17. 3-h.8 5 6 7 Parents kept a diary of disposable diaper usage for the performance consumer testing on diapers of various sizes.5e15.7 ± 17. two MN) were affixed to the lower buttocks of all infants (2 tapes/child. diapers transferred 72. Two lotion transfer data points were derived from tape).04 mg/cm2 or 4.5e11. 3M..04 1 4. 83.0% of the one on each side of the gluteal cleft).1 7 8 9 5e6 Size 3 (7e13 kg) 150 4. 2009 Mean ± SD 75th percentile 90th percentile 95th percentile Average change frequency Size 1 (4e6 kg) Not done e e e e 6 Size 2 (5e8 kg) 200 5.2 ± 6. Measurements for direct skin transfer of diaper components (18-h tape).7 ± 7. Without knowledge of the number of diapers used it is not 24 h for all normal diapering practices.4 ± 1. .0% Group 2 Overnight 20 52. or 4.5 a BW range for diaper sizes assumes size increases in the middle of the weight range overlap. In the second treatment group.5e17. respec- instructed to use the supplied product exclusively over the next tively. Sections of collection tape (Tegaderm™. The second tape was left undisturbed from initial have been previously described (Odio et al. However.88 mg/cm2 (Mean ± SE).207 mg/cm2.88 1 4.4 Size 4 diapers is used each Table 6 Direct transfer of lotion from diaper topsheet to skin.5 0e2 2 6% Size 2 5. starting amount of lotion on two diapers. of participants Diaper use per day Data reported in Rai et al. Results disposable diapers were recruited for participation.5 2e5 3 8% Size 3 7.

(2009). The diaper was laid flat on the SABAP equipment and wetted intermittently with 3 loads of normal saline (0.41 psi) was the equipment lid and applying a pressure of 0. This was repeated twice with the same collagen set re-applied to the same diaper after each saline load. PERMID. 3). Coffi Collagen. Man- itoba..2. 3.1. Estimation of lotion was reported by Goellner et al. This method uses a gravimetric approach where collagen is used as a skin mimic and takes into account a) the pressure an infant may apply to a diaper. following which the pre-weighted dry collagen sheets are laid on top to the diaper before closing the back and front for children 18e24 months (0.3 cm. Then the SABAP lid was closed and pressure was applied at 0. 1997)]. The Speed of Acquisition with Balloon Applied Pressure (SABAP) equipment was used to measure rewet via the PERMID method. Re-wetting is defined as the fraction of total liquid load that resurfaces back to the topsheet after absorption due to changes in surface pressure on the absorbent material. 4) (Internal data. and plopping down on their bottom (Fig. 3b). 3. Ber- gamo. small fraction of the constituents within the core of the diaper may have the potential to migrate to the topsheet surface by the phenomenon of re-wetting.9%) under a pressure of 0. (Goellner et al.2.41 psi over a 4-hr period (Fig.41psi (Fig. an updated rewet method in diapers has been established to mimic a more realistic diaper wear scenario (Prolonged Exposure Rewet Method in Diapers . This represents about a 2-fold exaggeration over the data reported by Odio et al.188 S. in the presence of urine. b) An aliquot of fluid being applied through the acquisition hole. If we assume 4. CA) linked to a computer program (FSA software. 3c). time till the next load. Rewet test using the SABAP equipment a) Test diaper on the SABAP equip- day for a diapered child the average pressure applied while lying on ment. Since sleeping is a major part of the Fig. 1981). Inc) were placed on the diaper to cover the core. Described in a European patent (Herrlein. 3. The most amount represents 3. (2000). 2008). Winnepeg. 3 Sorisole. Here. Vista Medical. lying on back. 3a). .4 diapers are used in a 24-h period the transfer conditions for an average 18e24 month old child.41 psi for the appropriate amount of considered for experimentation.. Globe Packaging Co. Indirect skin contact Diaper core constituents beneath the topsheet are not in direct contact with the skin.2. c) Collagen sheet being removed after completion of fluid loads A wetting scenario was chosen to simulate realistic diaper wear for gravimetric measurements. b) a representative urine load during diaper wear.1. lying on stomach. After the application of the first load of saline a set of 4 stacked rectangular collagen sheets (43 cm  10. Children (n ¼ 174) ranging in age from 2 weeks to 52 months (diaper size newborn to size 6) completed the study. A percent rewet based on the total volume (180 ml) of saline added to the diapers was calculated.4 comprehensive information on urine volume and voiding patterns diapers (calculation not shown in table). However. Rewet from diaper core has been described previously (Rai et al. 82 min and at 164 min with 5 min of acquisition time after each load). manometer. Dey et al. / Regulatory Toxicology and Pharmacology 81 (2016) 183e193 day.2.r. c) the gap between urine voids.PERMID) for EBSA purposes.2% of the starting amount of lotion on 4.2.Via Fatebenefratelli. pneumatic pistons and acquisition hole with electrodes [FKV S. The liquid transferred was determined gravimetrically by weighing the collagen sheets before (dry sheets) and after completion of the experiment (wetted due to rewet) (Fig. Rai et al.3. 3. Baldwin. Rewet parameters. Saline was loaded at 60 ml per load at an interval of 82 min (at 0 min. A summary of transfer using a higher percentile FOU of diapers will further reduce the percent lotion transfer. Pressure applied by the pneumatic cushion in turn applies pressure on the diaper (Fig. Infant pressure was measured using a sensor mat (Force Sensing Array. 3. recommended the use of 7% in exposure calculations for the direct transfer of materials from diaper topsheets.2. Vista Medical) that measures pressure applied to the mat. d) exposed surface area and e) diaper wear time.2. Italy. It is a pneumatic box with a latex membrane.2.2. Pressure exerted by the child was measured in four positions: sitting upright. pressure regulator. Rewet study. 2009).

plopping measurements were not attempted on very young children.9 15 10. during actual diaper in use conditions only a ations for solubility potential of the chemical and b) the rewet small portion of the diaper is under-pressure (either back or front of parameters are based on older diaper wearing infants (18e24 the diaper or when baby is sitting).1 50 2e4 5.58 10 20. et al.9 ± 8. For plopping. The rewet was measured for the entire diaper core sur.0 52 12e18 10. coverage which was acknowledged as a shortcoming.25% rewet was used based on Control diapers were analyzed where dry collagen sheets were data and recommendation by the European Disposables and Non- placed on the dry diapers with a 4 mm mesh nylon screen between wovens Association (EDANA. of Voids per day (#) Volume per void (ml) Volume per day (ml) Voids during Time between voids when (months) (kg) participants mean þ SD mean þ SD mean þ SD sleepa (#) awakeb (min) 0e1 3.0 56 6e12 8. S.1 102 Adapted from Goellner et al.7 ± 6.7 24 15. and plopping down on their bottom (with the assistance of the child's caregiver). gain as the transfer of the diaper constituent without consider- face area. Hence the applied pressure months) with larger urine volume and higher pressure exerted from the baby will not be on 100% of the diaper surface area at all during in use which would result in a higher rewet.1 378 ± 77 7. where a default of 0.97 18 18.6 19. the pressure was measured for 10 s starting once the child settled into position.5 ± 5. Age Weight No. Table 7 Urination patterns among infants. lying on stomach. the pressure was recorded immediately for 1 s. So.3 610 ± 172 3. The currently described rewet method provides a reasonably conservative default estimate for exposure to constituents not in direct contact with the skin because a) the gravimetric measure of 3.2. times.6 25. a Calculated based on the total number of voids per day and portion of time spent sleeping.4 82 24e32 13. An 0. lying on back. Rewet results.4 ± 7.32 to 0.1 ± 5. The pressure exerted by each child was measured in four positions: sitting upright.4.82 14 19.4 30. the rewet ranged from with voiding every 82 min was used for experimental purposes.2.8 ± 6.1 63. For the sitting and lying down positions.26 39 20. so the percent transfer was adjusted by 50% and deemed . b Calculated based on the total number of voids while awake and portion of time spent awake.. However.4 ± 2.66% averaging at 0. Pressure applied by infants during various activities by Age A pressure mat was calibrated to 10 psi. (2009).5 ± 5.7 57. A void volume of 60 ml reasonable for exposure assessments.1 ± 4.4 27. 2005).9 ± 3.6 28. Due to physical limitations.6 873 ± 287 2.1 505 ± 150 3. This was done to normalize account prolonged exposure time and a larger surface area any weight gain of the collagen sheets due to absorption of mois. Rewet results for the older infant pressure and urine volume parameters were used as a current study are fairly consistent with an earlier report by Rai conservative approach that would cover younger infants as well.5 52 4e6 6.8 ± 3. Eleven different diapers were tested in the collagen sheets before and after use assumes the saline weight triplicate.3 ± 4.1 79.9 782 ± 213 2.1 ± 4. Current values are slightly the collagen stack and the diaper surface (~2 mm gap) to determine higher probably because the previous method did not take into non-contact absorption of water vapor.9 863 ± 300 2. ture from the atmosphere. Participants included 174 children ranging in age from 2 weeks to 52 months. 4.5 68 18e24 12.3 ± 14.01 21 13.8 49 1e2 5 9 20. relevant variables is presented in Table 7.1 ± 19.5 556 ± 140 7. Dey et al. (1981). / Regulatory Toxicology and Pharmacology 81 (2016) 183e193 189 Fig.46% (Table 8).8 496 ± 145 4.3 ± 21.

and chemical structure as well as the diaper core was analyzed (Table 9). tions.64 3. skin of children with approach could also be to understand the potential exposure to diaper dermatitis showed higher TEWL (104 ± 67 g/m2/hr) finished product constituents by extraction of the collagen sheet to compared to non-diaper rash skin and non-diapered skin indi- detect transferred chemicals via total rewet using PERMID and cating that diaper rash skin can be vulnerable due to loss of stratum quantifying the detected constituents for safety assessment.67 0. 1982.42 7. compound-specific physical/chemical properties. averaging at 0.22 8.32 0. semi occlusive) triplicate for the amount of extractable acrylic acid from the (Hoang. a All samples were tested in triplicates. acrylic acid (AA) and internal standard.33 3.29 3. in the areas of lesional diapered skin. Normal saline was loaded onto the test diaper in 3 aliquots of 60 ml each (180 ml total).99 1.64 5 5. Comparison of the mean default rewet of 0.19% (Dey et al.30 2.92 ± 0.11 3. acrylic acid-13C3 compromised by diaper rash. Differences be- matographic (HPLC) analysis on a Water's YMC-ODS-AQ column. The amount of liquid that transferred to the collagen sheets was determined gravimetrically.62 3.2.07 0.32 2 5.36 4 5. and UVB damage has shown by analyzing pure SAP via GC/MS. non-lesional diapered skin. Diaper types Weight of collagen sheet Re-wetting moisture on collagen sheet (g)a Normalized % Rewet e Full diaper (total % Rewet e 50% of diaper (size 4) (g)a collagen weight volume 180 ml) contact area Initial (dry Post (wet Wt difference in wet & Wt difference of pre and post collagen) collagen) dry collagen blank collagen 1 5. Infants with diaper dermatitis were measured the amount of residual AA in the SAP.77 0.25 2.32 3. as acrylic acid is present only in the SAP the degree of damage to the skin.49 9 5. 2011).99 ± 0.17 1.83 1.18 0.34 0.31 0.56 4.64 0. although a good alter. normal skin (Gattu and Maibach. 2015b).09 0. The total extractable acrylic acid was estimated via diaper rash.2. 2001.04 Re-wetting was evaluated as described in Section 3. 1992).19 ± 0.26 9. This corneum resulting in increased TEWL (Stamatas et al. 1992).97 1. Dermal absorption increased dermal penetration of constituents (McCormack et al. as indicated by similar TEWL. However. Aliquots were added at 82 min intervals. that diapered skin area without rash (about 85e90% of diapered It is important to point out that in most cases it may be area) is normal and has similar barrier function (TEWL 47 ± 29 g/ impractical to generate chemical-specific rewet data for every m2/hr) as non-diapered skin area (outer thigh. use of modern disposable diapers (Stamatas et al. Collagen sheets on control diapers (blank) were used to normalize any weight gain of the collagen sheets due to absorption of moisture from the atmosphere. such as the mo- a residual monomer in the super absorbent gel (SAP) present in the lecular weight. estimating a default rewet value via moderate.21%. barrier function of diapered skin area vs.27 8. For example.65 ± 0.. full-term and premature infant autopsy abdominal in the diaper components is important to predict exposure.72 0.27 0.91 5.15 0. Acrylic acid .67 2.96 1.27 0.14 0.10 1. The Compromised skin conditions as in contact dermatitis and estimate of acrylic acid is a good example to compare with the diaper dermatitis could potentially increase dermal penetration of default rewet value since here chemical specific rewet value can be constituents.75 0.190 S.46 ± 0. Five diapers were tested in exposure condition (skin health. The values (Fluhr et al. skin compromised material of the core. Wong et al.74 0.284 8. Dey et al. Akin et al..32 8.33 11 4.30 1. authors indicated that all cases of dermatitis were either mild to native when needed.35 7 5.40 1.28 2. It is well understood that intact skin in healthy full- collagen sheets..4% .004e1. keeps moisture away from the baby skin in the diaper area (Adam. polarity. The collagen extracted values variable penetration properties which were modest in magnitude. when no chemical specific rewet value can be established.27 9. 2011).37 3.97 0.. non-diapered skin showed considering AA is readily soluble in water. / Regulatory Toxicology and Pharmacology 81 (2016) 183e193 Table 8 Percent re-wet from diapers during simulated 4 h wear. Targeted chemical analysis using PERMID (acrylic acid) important parameters to understand exposure are: i) the amount of the constituent in the product and ii) dermal absorption of these For targeted chemical analysis PERMID can be used followed by constituents (Table 1).01 5.81 4. were compared with the total extractable amount to estimate with only slightly higher dermal penetration rate compared to transfer.637 11. occlusive vs.34 ± 0. Several other studies even indicate that compromised skin does not necessarily result in 5.96 3.41 1. 2011.40 0.37 Mean ± SD 5.03 1. A comparison penetration of alcohols af- Understanding the systemic bioavailability of the constituents ter 6 h in adult.53 2.16 3. The degree of impact depends on the constituent and accurately measured. This example confirms that and control (non-diapered skin on the outer thigh).41 8.46% is a conservative estimate.28 9.39 3 5. 2012).13 9. Dey et al. The dermal absorption is dependent on analysis of the collagen sheet for the specific chemical.66 6 5. skin in the diaper area may be analyte. The may be resource intensive to do routinely. mechanical irritation.25 2. Transfer of AA based on the quantitation limit and Stamatas et al.11 1.20 1.54 2. and hydration that may affect dermal absorption. In a study conducted by (10 mg/diaper). or occlusion were subjected to reversed-phase high performance liquid chro. mechanical.61 2.28 1.76 10... However. 2015a).20 ± 0. ranged from 0. TEWL 48 ± 30 g/m2/ starting material as disclosed by the supplier. and no severe cases were observed probably due to the the gravimetric method is considered a reasonable alternative. An alternative hr).. 2011). The collagen sheets were extracted with 100 ml of term infants' exhibit similar skin barrier properties based on TEWL analytical reagent grade water (ARW) by vortexing for 10 min. Results indicated acrylic acid was below level of quantitation 2008. Hence.93 4.59 8 5..21 0. 4..36 1.15 to 0.40 1.55 10 4.16 2.37 1. chemical.70 0. Two skin samples indicate a range of dermal penetration of 0. tween the diapered area and the non-diapered area have reduced Detection and quantitation was by tandem mass spectrometry (MS/ over time with the advent of modern diaper technologies that MS) operating under multiple reaction monitoring (MRM) condi.88 1.

rewetting) ITindirect 1% or chemical specific data Specific for the constituent raw material in the diaper Amount of constituent in product Amt Determined by product composition. gram (EEC 793/93) (Institute for Health and Consumer Protection. present as a salt form (sodium acrylate) which does not penetrate water-loss (Dey et al.086 mg/day Total available acrylic acid/kg BW/day 0. 1994) 0.20 323 15 4845 BQL 0.76 to 1. / Regulatory Toxicology and Pharmacology 81 (2016) 183e193 191 Table 9 Experimental % rewet and QRA for acrylic acid in diaper SAP.The RfD of 0. Indirect skin contact (i. as applicable to diapers General considerations Body weight TWA BW 8 Kg Time-weighted average body weight for children 0e36 months of age Skin surface area (exposed surface) SA For diapers. The hazard profile of tration is increased in compromised skin conditions it is not acrylic acid was evaluated by the European Risk Assessment Pro- increased to 100%.21 380 15 5700 BQL 0.19%  100%  1 mg/1000 mg ¼ 0. or oral mature infants (McCormack et al. SAP is a polymerized form of acrylic 3. tion model using human ex-vivo skin to estimate penetration for Safety assessment for Acrylic acid: The superabsorbent polymer intact and compromised skin barrier conditions indicated that (SAP) is one of the main absorbent components of the diaper core overall penetration of [14C]-PEG-7phosphate applied as a baby wipe (indirect skin contact). Acrylic acid (mg/kg) SAP (15 g/Size 4) Acrylic acid/Diaper (mg/diaper) LOQ < 10 mg/Diaper % Acrylic Acid/Diapera 325 15 4875 BQL 0. Skin barrier monomer. For a complete safety evaluation of the constituent. the critical effect was decreased pup weight in appropriate exposure routes and the duration and frequency of use the F1 and F2 generations at the mid dose of 240 mg/kg/day. Systemic Exposure (mg/kg/day) ¼ [Amount of constituent x Frequency of use (FOU)  Transfer Factor (direct or indirect eTF)  Dermal absorption (DA)]/Body weight. The exposure pa. surface area is specific to the diaper part in contact with the skin (Variable by size and design) Specific for the product category Habits and practices (H&P) Frequency of use FOU Mean 90th %tile 95th %tile 4. 6. Exposure Parameters Abbreviation Definition. Table 10 Exposure Parameters for risk assessment of raw material constituents in baby diapers.5 mg/kg/day Margin of Safety (MOS) ¼ RfD/consumer exposure 0.4 6 7 Constituent transfer to skin Direct skin contact ITdirect 4% Constituent transfer to skin from materials in direct skin contact.. The US EPA reference dose (RfD) for acrylic acid has been determined as 0.15 AVERAGE 0.e. Dermal absorption DA Compound-specific or conservative estimate based on phys/chem properties in the absence of data Table 11 Exposure Based Safety Assessment for Acrylic Acid (AA) in Diapers.19e4.42% for highly-compromised skin (premature skin mimic) acid.27% for intact skin and with high molecular weight. although dermal pene.5 mg/kg/day. S.21 433 15 6495 BQL 0. In a urine wetted diaper most of the acrylic acid is deficiency was characterized by tape stripping and transepidermal.011 mg/kg/day RfD of acrylic acid (US EPA. Overall diaper exposure model 1994). of the product.6% in full-term infants and 0.. 2002) and the US Environmental Protection Agency (US EPA.18 340 15 5100 BQL 0...04e35. and appropriate exposure based on results in a chronic reference dose of 0. Total amount fo SAP in pad 15 g Amount of free acrylic acid (extractable monomer) 500 ppm (manufacturer's upper limit) Diaper e Frequency of Use/day 6 Rewet Factor (%) 0. reasonably foreseeable use.011 ¼ 45 in adults. inhalation. Application of standard 10X it is important to understand the concentration range of the con.19% Dermal absorption 100% Weight of baby 8 kg Total available acrylic acid/day 500 mg/g monomer x 15 g  6  0. toxicity study in rats with acrylic acid administered via drinking rameters took into account specific exposed consumer (children). skin as easily as acrylic acid (Rai et al.5/0. water. uncertainty factors for interspecies and intraspecies extrapolation stituent in the product. Therefore. given as mg or mg. 2015b). The EBSA for SAP is mainly for the residual acrylic acid under repeat and single dose applications respectively. intended use of the product (dermal exposure.086/8 ¼ 0. In this study. resulting in a NOAEL of 53 mg/kg/day.5 mg/kg/day was based All of the above exposure parameters described is used in the on the US EPA two-generation reproductive and developmental safety assessment of diapers (Tables 10 and 11). 1982).5% in pre.5 mg/kg/day. 0. Use of this . An in vitro skin penetra. It is made up of inert polymeric material lotion constituent ranged from 0.19 a Maximal rewet percent is based on QL (10 mg/diaper) as actual value (this is conservative and real value could be lower). 2009). ingestion) vs.002e1. Dey et al.

2011. 15 (Suppl. 2012. Toilet training your child: the Basics. duration of wear is less/diaper. as the ‘high-end exposure’. et al. S.cfm?section¼jedana_nonwovens&story¼testmethods. 2005.19%). The FOU of diaper sizes 3e5 is considered Gattu.. In addition. this submitted work.W. An Updated Lifecycle Assessment Study for Disposable and Reusable Nappies. and 100% dermal penetration (Table 11).J. Reg. Hoang. J. DC. 2008. S. No funding was received from any external source for any aspect of National Research Council. Studies BR11-06-05. Rev.. BR 1-07-8. surveys) across diaper sizes 3e5. 21 (3). Available at: http://www.. Report of the tive on the various conditions of exposure associated with diapers Task Group on Reference Man.T. An in vitro comparison of the permeability of adult Conflict of interest versus neonatal skin (Chapter 11). M. (80e86% of 3 years). Aumo ^nier.2016. CA. 53. Acid Risk Assessment. Child. a 90th percentile FOU Fluhr. 12e21. 37. nchs/data/series/sr_11/sr11_246. 1997.. high-end boundaries for exposure assess. 2015b. 1992. D. 2008. When developing EBSA for products intended for children. Method for assessing disposable absorbent structures. present in the SAP of disposable diapers. and specific habits and practices of Centers for Disease Control and Prevention.. et al. majority of the diapering period children wear diaper sizes 3e5 2e9. Risk Assessment in the Federal Government. et al. S. 52 (1). S. (0. 2002). Skin Protection Agency (US EPA. G. Matern. 55 (S1). Pharmacol. U. 1976. Criteria for a . Kosemund. 18e20. It provides updated information on consumer habits BR 12-06-02. New that have varied levels of skin contact due to its 3-D structure and York. Epidemiol. 2001. Dearman. http://www. et al. the EBSA must incorporate the po- Dey.cdc. Howard L. Patent # EP 0797967 A1... et al. 2015). Discussion and conclusions Baldwin. Skin benefits from continuous topical administration of a zinc oxide/petrolatum formulation by a novel disposable diaper. DC.. 357e365. Contemp. Br. Available at: http://cfpub. 53 (95). R. Human milk and lipid intake distributions human safety concerns for the residual acrylic acid that may be for assessing cumulative exposure and risk. 2016. account the type of product.. Maibach.A. Physiol.. et al. Avail- able at: http://www. Invest. EBSAs often use consumption by ‘high-end’ consumers to Dey. Pediatr. / Regulatory Toxicology and Pharmacology 81 (2016) 183e193 reference dose derived from oral data to support dermal risk Transparency document assessment is considered conservative since toxicokinetic studies in rats and mice have demonstrated that approximately 80e90% of Transparency document related to this article can be found AA is absorbed orally while dermal absorption after cutaneous online at http://dx. 17Se19S. European Disposables and Nonwovens Association. Clin.H. Pediatr... An in vitro skin penetration model for compromised skin: develop a conservative exposure assessment. contact and via re-wetting as urine resurfaces with changes in Dey. WHO Growth Standards. 149e164. Internal Data Baldwin. Assessment of health risks resulting from early-life expo- body weight of 8 kg which is less than the TWA body weight for sures: are current chemical toxicity testing protocols and risk assessment 0e3 yrs at 10th percentile (9. of 6 is recommended. 1992) and the European Scientific Pharmacol. 483e490. et al. S. Acrylic defines the upper. 461e464. Beginning at the bottom: evidence-based care of diaper of diapers may not necessarily increase the exposure since the dermatitis. K. J. H.. et al. 2015a.doi.. F. M. S. 2015. 1). et al. Pediatr. 2008. and takes into 20Growth%20Charts.1016/j. J. Dermatol Venereol. Effects of breathable disposable diapers: reduced prevalence of comprehensive risk assessment of acrylic acid using diaper EBSA Candida and common diaper dermatitis. All authors are employees of the Procter and Gamble Company. J. National Academy of Science. Exposure factor considerations for risk assessment of modern disposable diapers. (Eds. et al. 1e7. 81e89. Zeise. 1983.S. updated exposure parameters have been AAP. skin surface areas. Basketter. there is evi.. Neonatal Skin: Structure and Function. MCN Am. McCormack. Boistis. exposure parameters are used.M.192 S. penetration of 100% is used in the absence of data. Urination during the first three years of life.. Dose metrics in the acquisition robust EBSA to ensure continued consumer safety. Skin.epa. et al.. Dermatol 166. 90th https://www2.. Partners: Standard Test Methods for the Nonwoven Industry http://www. as well as age appropriate body weights and exposed Examination Survey(NHANES) (accessed April 6. Skin care of the diaper area. ments at or above the 90th percentile (World Health Organization.I.. and practices and product exposure scenarios to enable a more Kimber. data (vs.K.. Worldwide Strategic 2008). 2010.08. dence that dermal penetration even for a compromised skin Environmental Protection Agency.aap.. In: Society of Toxicology Meeting (SOT). Toxicol.. Dey et al. and safety Committee on Consumer Safety (SCCS. 2005. S. Based on the Adam. Proportion of skin surface area of children and young adults special care is required to ensure that appropriate and conservative from 2 to 18 years old. 7. et al. used for assessment of acrylic acid which includes a BW of 8 kg. The US Environmental estimating penetration of polyethylene glycols 14C-PEG-7 phosphate.. J. Infant Pressure Measurements. National Institute for Occupational Safety and Health (NIOSH). Tox Pharm. I. 10e16..cdc. Infant epidermal skin physiology: adaptation after birth. In conclusion. 45 (3). Environment Agency.. 15. 219e244. et al. Dermal Exposure Assessment: Principles and Applications. 28. Abstract # 505. Safety of disposable diaper materials: extensive evaluations tential amount of constituents transferred to the skin with direct validate use.eda- In the safety assessment of chemicals in diapers we use a experimental rewet transfer factor Module7/barton_schmitt_protocol_guide_for_parents_1. Modern diaper performance: construction. of skin sensitization: thresholds and importance of dose per unit area. and a MOS of 45. Science Report e SC010018/SR2. An EBSA for disposable diapers is Centers for Disease Control and Prevention. Dermatol 128. 1981.xml. Publisher Marcel Dekker. Regul. EPA/600/8e91/011B. J Dermatol. Washington.. Toxicol. materials. M.. This seems reasonable since infants grow 174e178. Nurs.nappyinformationservice. Acad. et al. 282e290. Felter. 2014. Pharmacol.. K. Krowech. The National Health and Nutrition product use.. 1981. 2002.htm. Nephron 28.J. 1982. R.yrtph. IARC publicaiton 23. 2008. Office of Health and Environmental Assess- barrier is not 100%. 2015. rapidly during the first 5 months after birth.. ment. 2003. Washington.017 administration is about 20e25% (ECB.. it can be concluded that there are no systemic Arcus-Arth. A. SCHO0808BOIR-E-E. The margin of safety (MOS) is determined by dividing the AEL by the consumer exposure level (CEL).. Bristol. ICRP (International Comminssion on Radiological Protection). Assignee: The Procter & Gamble Company.. Int. J. Akin. Although a default dermal Herrlein. 24. S.). Pergammon percentile FOU (6 diapers). 2008. The World Health Organization European Chemicals¼12188. 2012. Current. pp. this manuscript provides a detailed perspec. Pediatr. Diego. Dey. Modest but increased penetration through damaged for EBSA based on the LOW estimation which shows that during skin: an overview of the in vivo human model. National Academy Press. et al. European Union Risk Assessment Report.. Dermatol 18 (4)..pdfnhanes. Physiol.. 2012) use 90th percentile review.. In: ncea/cfm/recordisplay. J. The CEL needs to be below the AEL in order to be safe for References consumer use.. L. Also increased FOU Heimall. Environ. 39e45. Safety evaluation of superabsorbent baby diapers. Eur. 5e11.. Edward K. Dermatol 25 (4)..1 kg).org.pdf.P. Office for official publicaitons of the European Commu- nities. Based on more accurate diary methods adequate? Crit. San applied pressure. 2009.htm#The%20WHO% based on child specific exposure considerations. composition.pdf. NY. Expos Anal.. ISBN 92-894-1272-0.

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