# Dermal Absorption of Silver

fro m ActicoatTM 

# Wo und 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 Fo undation 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 not consider in vitro dermal penetration Agency does not consider in vitro 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 Acticoat TM 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 Acticoat TM 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

site c (%) Graft site c (%) 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 va scularity).

# Determination of Systemic Absorption of Silver from Acticoat TM  

### Estimated the Area Under the Curve (AUC) during treatment with wound dressing (AUCT

### )  

### Estimated AUC after discontinuation of wound dressing treatment (AUC D

### )  

### Estimated total AUC by adding AUCT 

### and AUC D 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 SILCRYST TM 

###  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

Ke lly 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 inf ormation sheet 

# • Provided at least 24 hours to review the inf ormation sheet

32 

# • After 24 hours, the subjects (or their representatives) were given an opportunit y to discuss the study and ask questions of the investigator or research study nurse

# Informed Consent — 2 • 3 subjects initially signed the consent f orms 

# • 1 subject provided ve rbal consent 

# • Ve rbal 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?