Dermal Absorption of Silver 

from ActicoatTM Wound 

Dressings 

Moiemen, N.S., Shale, E., Drysdale, K.J., Smith, G., 

1

Moiemen, N.S., Shale, E., Drysdale, K.J., Smith, G., 

Wilson, Y.T., Rapini, R. Acticoat dressings and 

major burns: Systemic silver absorption. The 

Midlands Burn Centre, University Hospitals 

Birmingham Foundation Trust, United Kingdom. 

Epub. 2010 Oct. 18. Burns, 37, 27-35 (2011). 

MRID 48607501. 

October 20, 2011
Sequence of Presentations

 Introduction and Science Assessment

Jessica Ryman-Rasmussen, PhD, DABT

Health Effects Division, Office of Pesticide Programs

2

 Ethics Assessment

Kelly Sherman

Office of the Director, Office of Pesticide Programs
Introduction-1

 The Agency has pending registration applications for 

articles treated with nanosilver. 

 The Agency is interested in conducting quantitative 

risk assessments for these products.

 These assessments require quantitative estimates of 

dermal penetration of nanosilver. 

3
Introduction-2

 There are limited data available that quantitatively 

estimate dermal penetration of nanosilver. Most of 

these data are in vitro data: 

 The Agency does Agency does not consider not consider in vitro in vitro dermal penetration dermal penetration 

studies as sufficiently validated for stand-alone use.

 In vitro dermal penetration data are used in a weight-of-theevidence that includes animal in vivo and/or human data.

4
Introduction-3

 A recent study by Moiemen et al. (2011) allows 

quantitative estimation of dermal penetration of silver 

from nanosilver in human volunteers.

 The Agency thinks that use of dermal penetration 

estimates for silver from nanosilver in this study 

would likely overestimate any dermal penetration 

from treated articles because:

 Patients had severely damaged skin (major burns) 

 Calculation method for estimates assumes that all circulating serum 

silver results from dermal absorption of silver from the wound 

dressing or from silver deposited in the skin layers (and not from 

impaired clearance)

5
Use of Moiemen et al. Study

 The Agency is proposing to use the Moieman 

study, together with in vitro studies, in a 

weight-of-the-evidence to quantitatively 

estimate dermal penetration of silver from 

nanosilver applied to treated articles. 

 This is an upper-bound estimate (not a mean) and 

is largely based on severely damaged skin, a 

worst-case scenario. 

6
Study Information

 Conducted at The Midlands Burn Centre, UK 

 Study Objective:

 Confirm the safety of Acticoat use on burns 

7

(extensive)
Test Substance 

 ActicoatTM wound dressings containing SILCRYSTTM

silver nanoparticles 

 Three layers: inner core of rayon/polyester 

sandwiched between two layers of silver-coated low 

adherent polyethylene mesh:

 Calcium alginate-coated: 7 days antimicrobial 

efficacy

 Uncoated: 3 days antimicrobial efficacy

8
Study Methods

 Day of/before surgery:

 Medical history, burn details, photography, baseline serum 

silver, fill blood count, serum chemistry

 General anesthesia, burn and graft donor sites infiltrated 

with adrenaline

• Burns: tangentially shaved or excised 

• Grafting sites: split thickness skin (254 μm) harvested via dermatome 

 Burns and grafting sites dressed with ActicoatTM

• Surface area of wound estimated by total amount of ActicoatTM applied 

to wound

• Every 7 days until “healed” (95% closure), until 42 days, or when 

clinician determined treatment no longer required 
Endpoints 

 Blood silver levels 

 Study start (baseline), every 3 days until ActicoatTM

discontinued, after discontinuation of ActicoatTM (1, 3, 6, 9 

months) 

 Detected by ICPMS (inductively coupled plasma mass 

spectroscopy) 

• Does not distinguish silver ion from silver nanoparticles 

• Detection limits in blood not given: estimated at 0.1 μg Ag+/L based on 

baseline range of patients in this study and instrument detection limits 

described in EPA SW-846 Method 6020A

 Hematology, clinical chemistry, wound healing, 

clinical signs 

10
Clinical Results-1

Table 1-Extent of burn

Patient # TBSA (%) Partial 

thickness 

burn (%)

Full 

thickness 

burn (%)

Total 

burn (%)

Donor 

sitec

(%)

Graft 

sitec

(%)

TBSAb

(cm2)

1.01

25 y/o male

30 27 3 30 0 0 5971.3

1.02

43 y/o male

66 15 32 47 22 28 9099.9

11

43 y/o male

1.03

56 y/o male

37 21 4 25 12 13 4887.7

1.04

22 y/o 

female

71 1 70 71 0

d

26 13710.9

1.05

31 y/o male

31 22 0 22 10 11 4718.1

1.06

44 y/o male

55 18 12 30 24 16 6360.5

MEDIAN 46 20 8 31 11 14 6166

y/o = year old

TBSA = Total body surface area

a

Percentage of TBSA affected. 

b

Estimated using patients’ %TBSA, height, and weight.

c

Percentage of total body surface area affected. 

d

The first grafting procedure for this patient used IntegraTM. 
Clinical Results-2

 Hematology/clinical chemistry

 Changes consistent with severe burns

 Not attributed to ActicoatTM

 Clinical signs

 32 adverse events reported, 31 unrelated

 1 possibly related to ActicoatTM (graft loss)

• Not considered serious

• Agency considers graft a restorative treatment and not a 

target organ of toxicity 

12
Clinical Results-3

 Healing sufficient for all participants except patient 1.04

 Patent 1.04 died: 4 serious events. 

 Withdrawn from study after grand mal seizure (fluconazole), overwhelming 

pseudomonas sepsis secondary to chest infection.

 Post mortem showed brain sepsis .

 Confirmed clinican’s view that ActicoatTM is safe for use on 

major burns

13
Serum Silver-During Treatment-1

14

No relationship between maximum silver level and burn TBSA
Serum Silver-During Treatment-2

15

Maximum serum levels approx 9 days.

Stay at max or decay to steady-state.
Serum Silver-Discontinue Treatment

16

Biphasic: fast phase by 12 days.

Median half-life 46.4 days (1.5%/day).
Serum Silver-Quantify Exposure

17

No apparent relationship between silver exposure and 

maximum serum levels (could be due to burn vascularity). 
Determination of Systemic 

Absorption of Silver from ActicoatTM

 Estimated the Area Under the Curve (AUC) 

during treatment with wound dressing (AUCT)

 Estimated AUC after discontinuation of wound 

dressing treatment (AUCD)

 Estimated total AUC by adding AUCT and 

AUCD

18
Dermal Absorption Factor-1

 Divided by the total AUC by the theoretical 

maximum cumulative exposure to silver 

 Multiplied this value by 100 to get the 

percentage absorbed

 Values were ≤0.1% 

19
Dermal Absorption Factor-2

 0.1% provides a conservative, upper-bound 

estimate

 Highest value observed 

 Based on severely damaged skin

 Calculation method assumes that all serum silver results 

from absorption and not from other processes (e.g. impaired 

clearance)

 Orders of magnitude higher than those observed in vitro 

with intact or mildly damaged human skin

20
Study Limitations

 Small sample size, no statistical analysis

 Difficult to recruit patients for this kind of study due to 

wound severity 

 No physicochemical characterization of SILCRYSTTM

 May frustrate comparison with other kinds of nanosilver 

because physicochemical properties not provided

 Detection limits for silver in serum for ICPMS not 

provided. Little detail on how ICPMS was performed. 

 Calculation method for half-life of serum elimination 

of silver not provided. 
Conclusion

Less than 0.1% penetration of silver from 

nanosilver is anticipated from textile products 

that are in direct contact with intact (healthy) 

skin. 

22
Ethics Assessment of

Moiemen et al. (2011)

23

Kelly Sherman

Office of Pesticide Programs
Introduction

 Research conducted in UK in 2006-2007, after 

promulgation of the 2006 Human Studies Rule

 This is considered an intentional exposure human 

toxicity study because it investigated the potential for 

24

adverse effects through blood biochemistry and 

hematology

 Study was located by EPA, not submitted to the 

Agency, so 40 CFR §26.1303 does not apply

 Information for ethics review obtained from the article and 

information provided by the investigators 
Value to Society

 This study provides data on dermal absorption 

of silver from nanosilver in ActicoatTM wound 

dressings

25

 EPA is currently lacking in vivo data on dermal 

absorption of silver from nanosilver

 The data could be used in EPA risk 

assessments for nanosilver products
Subject Selection

 Patients with burns covering greater than 20% 

TBSA, or their next of kin, were approached and 

asked about their interest in participating

 5 men, 1 woman; aged 22-56

26

 5 men, 1 woman; aged 22-56

 Pregnancy and lactation were exclusion criteria, but 

pregnancy testing was not performed on the female 

subject

 Appropriate inclusion and exclusion criteria
Vulnerable Group

 Subjects have severe burns

 Patients with burns of this severity are extremely 

ill and sometimes unconscious

 Protocol provided safeguards to protect these 

subjects from coercion or undue influence over 

their decision to participate

 24 hours to review materials before consent solicited

 Withdrawal permitted at any time for any reason

27
Risks

 No risks from use of Acticoat dressings

 Subjects would have received the same treatment 

even if not enrolled in the study

28

 Only study-related risks were from additional 

blood sampling
Risk Minimization

 “Extra” blood draws were avoided where possible

 An extra 15 mL of blood was collected when blood sampling 

occurred as part of normal medical treatment

 Patients likely to have sensitivity or complications 

were excluded. Exclusion criteria:

 Known sensitivity to silver and other related compounds

 Infected burns

 Known renal, hepatic, or neurological disease

 Known history of poor compliance with medical treatment

 Pre-existing dementia

29
Benefits & Risk:Benefit Balance

 Benefits 

 No benefits to subjects

 Societal benefit from knowledge about the safety 

of Acticoat when used for patients with major 

30

burns

 Risk:Benefit Balance

 Not discussed in article

 Risks were minimal, so the potential benefits to 

society outweigh the risks
Ethics Oversight

 Research was reviewed and approved by 

the Sandwell and West Birmingham Ethics 

Committee

31

 The committee was “fully complies” with 

the Standard Operative Procedures for 

Research Ethics Committees in the UK
Informed Consent

• Subjects (or their representatives) were 

provided with subject information sheet

• Provided at least 24 hours to review the 

information sheet

32

• After 24 hours, the subjects (or their 

representatives) were given an opportunity 

to discuss the study and ask questions of 

the investigator or research study nurse
Informed Consent—2

• 3 subjects initially signed the consent forms

• 1 subject provided verbal consent

• Verbal consent provided in the presence 

33

of a researcher and a nurse

• 2 subjects provided consent retrospectively; 

their representatives initially provided 

consent
Respect for Subjects

 Subjects offered complete freedom to 

withdraw at any time for any reason

 Not paid for participation

 Subjects’ privacy protected

34
Standards for Documentation

 The requirement at 40 CFR §26.1303 to 

document the ethical conduct of research 

submitted to EPA does not apply:



35

Study was located in the public literature, not 

submitted to EPA

 EPA located the study at its own initiative
Standards of Conduct

 FIFRA §12(a)(2)(P) does not apply

 Did not involve use of a pesticide

 40 CFR part 26 subparts A-L do not apply

 Neither conducted or supported by EPA

 Not conducted with the intention to submit the 

results to EPA

 International Standard

 Declaration of Helsinki (2004)

36
Compliance with Standards of Conduct

 Protocol states that research will be conducted in 

accordance with the Declaration of Helsinki

 Protocol received approval from the Sandwell and 

West Birmingham Local Research Ethics Committee

 Research was consensual, and was not intended to 

harm participants

 It appears from the published article that the conduct 

was consistent with the basic principles in the 

Declaration of Helsinki

37
Standards for EPA Reliance

 40 CFR §26.1703

 Prohibits reliance on data involving intentional exposure of 

pregnant or nursing women or of children

 40 CFR §26.1705

38

 Prohibits reliance on data unless EPA has adequate 

information to determine substantial compliance with 

subparts A through L for 40 CFR 26
Compliance with Standards of Acceptability

 40 CFR §26.1703

 All subjects were above the age of 18

 The female subject was not pregnant or nursing

39

 40 CFR §26.1705

 EPA has adequate information to conclude that the 

research was conducted under procedures at least 

as protective as those in subparts A though L of this 

part
Conclusion

If it is deemed scientifically valid and relevant, 

there are no barriers in FIFRA or in 40 CFR 

§26.1703 or 26.1705 to EPA’s reliance on the 

Moiemen et al. (2011) study in actions taken 

40

Moiemen et al. (2011) study in actions taken 

under FIFRA or §408 of FFDCA
Charge Questions

1. Is the Moiemen et al. (2011) study scientifically 

sound, providing reliable data?

2. If so, can the Moiemen et al. (2011) study be 

used to support the Agency's conclusion that the 

41

dermal absorption factor for silver from 

nanosilver on human skin is less than 0.1%?

3. Is there adequate information to support a 

determination that the study was conducted in 

substantial compliance procedures at least as 

protective as those at subparts A-L of 40 CFR 

part 26?