Opinion on preservative EcoG+.
Date: 2017-03-01
Institutions: Directorate-General for Health and Food Safety
Subjects: consumer protection, cosmetic product, directive (EU), packaging product, scientific research, toxic substance

SCCS/1577/16 
Final version of 6 October 2016 

Scientific Committee on Consumer Safety 

SCCS 

OPINION ON 

preservative EcoG+  

The SCCS adopted this opinion at its 2nd plenary meeting  

on 6 October 2016 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final version of the Opinion on Eco G+ 

SCCS/1577/16 

About the Scientific Committees 
Two independent non-food Scientific Committees provide the Commission with the scientific 
advice  it  needs  when  preparing  policy  and  proposals  relating  to  consumer  safety,  public 
health  and the  environment. The Committees  also  draw  the  Commission's  attention  to  the 
new or emerging problems which may pose an actual or potential threat.  
They  are:  the  Scientific  Committee  on  Consumer  Safety  (SCCS),  the  Scientific  Committee 
on  Health,  Environmental  and  Emerging  Risks  (SCHEER)  The  Scientific  Committees  review 
and  evaluate  relevant  scientific  data  and  assess  potential  risks.  Each  Committee  has  top 
independent  scientists  from  all  over  the  world  who  are  committed  to  work  in  the  public 
interest. 

In  addition,  the  Commission  relies  upon  the  work  of  the  European  Food  Safety  Authority 
(EFSA), the European Medicines Agency (EMA), the European Centre for Disease prevention 
and Control (ECDC) and the European Chemicals Agency (ECHA).  

SCCS 
The  Committee,  on  request  of  Commission  services,  provides  Opinions  on  questions 
concerning  health  and  safety  risks  (notably  chemical,  biological,  mechanical  and  other 
physical risks) of non-food consumer products (e.g. cosmetic products and their ingredients, 
toys, textiles, clothing, personal care and household products such as detergents, etc.) and 
services (e.g.: tattooing, artificial sun tanning, etc.). 

Scientific Committee members  
Ulrike  Bernauer,  Laurent  Bodin,  Leonardo  Celleno,  Qasim  Chaudhry,  Pieter  Jan  Coenraads, 
Maria  Dusinska,  Jeanne  Duus-Johansen,  Janine  Ezendam,  Eric  Gaffet,  Corrado  Lodovico 
Galli,  Berit  Granum,  Eirini  Panteri,  Vera  Rogiers,  Christophe  Rousselle,  Maciej  Stepnik, 
Tamara Vanhaecke, Susan Wijnhoven 

Contact 
European Commission 
Health and Food Safety 
Directorate C: Public Health, Country Knowledge and Crisis Management  
Unit C2 – Country Knowledge and Scientific Committees 
L-2920 Luxembourg 
SANTE-C2-SCCS@ec.europa.eu   

© European Union, 2016 

ISSN: 1831-4767 

Doi:10.2875/111316 

        ISBN 978-92-79-65655-2 

       EW-AQ-17-001-EN-N 

The  Opinions  of  the  Scientific  Committees  present  the  views  of  the  independent  scientists 
who  are  members  of  the  committees.  They  do  not  necessarily  reflect  the  views  of  the 
European  Commission.  The  Opinions  are  published  by  the  European  Commission  in  their 
original language only. 

http://ec.europa.eu/health/scientific_committees/consumer_safety/index_en.htm 

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ACKNOWLEDGMENTS 

SCCS members listed below are acknowledged for their valuable contribution to the 
finalisation of this Opinion.  

(Chairperson) 

Dr U. Bernauer   
Dr L. Bodin 
Dr L. Celleno  
Prof. Q. Chaudhry 
Prof. P.J. Coenraads 
Prof. M. Dusinska 
Prof. J. Duus-Johansen 
Dr J. Ezendam 
Dr E. Gaffet  
Prof. C. L. Galli 
Dr B. Granum 
Prof. E. Panteri 
Prof. V. Rogiers   
Dr Ch. Rousselle  
Dr M. Stepnik  
Prof. T. Vanhaecke  
Dr S. Wijnhoven 

The additional contribution for the drafting of the preliminary Opinion of former members of 
the SCCS (2013-2016) and external experts listed below is gratefully acknowledged.  

Former SCCS Members 
Prof. G. H. Degen 
Dr. W. Lilienblum 
Dr. E. Nielsen 
Prof. T. Platzek   
Dr. J. van Benthem 

(Rapporteur) 

Former SCCS External experts 
Prof. A. Bernard  
Prof. A. M. Giménez-Arnau  
Dr. E. Mirkova 

This  Opinion  has  been  subject  to  a  commenting  period  of  a  minimum  four  weeks  after  its 
initial  publication.  Comments  received  during  this  time  were  considered  by  the  SCCS  and 
discussed in the subsequent plenary meetings. 
For this Opinion, comments received resulted in editorial changes.   

Keywords: SCCS, scientific opinion, preservative, EcoG+, directive 76/768/ECC, CAS 7440-
22-4, EC 231-131-3 

Opinion  to  be  cited  as:  SCCS  (Scientific  Committee  on  Consumer  Safety),  Opinion  on 
preservative EcoG+, 16 March 2016, final version of 6 October 2016. 

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TABLE OF CONTENTS 

ACKNOWLEDGMENTS ........................................................................................... 3 

1. 

2. 

3. 

BACKGROUND ............................................................................................. 5 

TERMS OF REFERENCE.................................................................................. 5 

OPINION..................................................................................................... 6 

3.1. 

Chemical and Physical Specifications....................................................... 6 

3.2. 

Function and uses ................................................................................ 9 

3.3. 

Toxicological Evaluation ........................................................................ 9 

3.4. 

Calculation of exposure....................................................................... 18 

4. 

5. 

6. 

CONCLUSION ............................................................................................ 25 

MINORITY OPINION.................................................................................... 25 

REFERENCES ............................................................................................. 26 

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1.  BACKGROUND 

Submission I for the preservative with the name EcoG+ was submitted by June 2012.  

The  proposed  new  preservative  'EcoG+'  is  silver-containing  phosphate  glass,  a  powder 
consisting  of  small  glass  beads.  'EcoG+'  is  intended  to  be  mixed  with  glass  beads  and  an 
appropriate  polymer  and  used  to  manufacture  composite  materials  for  cosmetic  product 
packaging.  The  substance  intended  to  be  released  into  the  cosmetic  product  is  the  silver 
ion. 'EcoG+' therefore acts as an inert carrier, into which the silver ion is dispersed. 
'EcoG+'  is  mixed  with  glass  beads  and  a  suitable  polymer  to  form  a  composite  packaging 
material,  a  proportion  of  the  glass  matrix  remains  at  the  surface  of  the  material.  The 
achieved  level  of  the  active  component  (i.e.  silver)  in  'EcoG+'  is  2%;  the  proportion  of 
'EcoG+'  envisaged  for  use  in  the  packaging  material  is  3%.  On  use  of  the  composite 
material as cosmetic product packaging, small amounts of silver ions are released into the 
cosmetic product, where it is intended to have a preservative function. 

The  typical  use  of  'EcoG+'  is  envisaged  to  be  a  level  of  1.4-2.0%  in  cosmetics  packaging. 
The  maximum  achieved  level  of  silver  ion  in  'EcoG+'  is  2%,  therefore  the  maximum 
achieved level of silver present in the cosmetic packaging material is 420-600 ppm. 

The information is subject of the attached Submission I. 

Submission II that updates the previously submitted dossier (submission I) was submitted 
by  the  applicant  in  February  2014,  in  response  to  specific  questions  for  clarifications  from 
the SCCS.  

2.  TERMS OF REFERENCE 

1.  Does  SCCS  consider  release  of  silver  ions  from  "EcoG+"  as  component  in  packaging 
material  safe  for  use  as  preservative  with  a  concentration  of  maximum  2.0 %  in  the 
cosmetic packaging material, taking into account the scientific data provided? 

2. 

And/or  does  the  SCCS  recommend  any  further  restrictions  with  regard  to  the  use  of 
"EcoG+" as preservative in cosmetics packaging? 

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3.  OPINION 

This  draft  contains  information  as  provided  in  submission  I  (of  2012)  and  the  update 
(submission II of 2014). 

3.1. Chemical and Physical Specifications 

3.1.1. 

Chemical identity 

EcoG+  is  a  composite  material  consisting  of  three  components,  i.e.  (1)  silver-containing 
phosphate  glass  powder,  (2)  glass  beads  and  (3)  an  appropriate  polymer  (for  example 
polypropylene,  PP),  as  detailed  in  Table  1,  below.  The  inclusion  of  glass  beads  is  not 
required  for  the  antimicrobial  activity  of  EcoG+  and  it  is  envisaged  that  some  packaging 
may contain components (1) and (3) only. 

Table 1 Components of EcoG+ 
Component  
Silver glass powder containing 1.4-2.0% Ag+  
Glass beads  
Polymer (polypropylene)  
Silver ion    

Function    
Active component  
Inert carrier  
Inert carrier  
Active component  

Typical composition 

3% 
≤52% 
≥45% 

420-600 ppm 

The silver glass powder (Million Guard PG721ST) contains a level of 1.4-2.0% silver ion and 
is  mixed  with  the  other  components  of  EcoG+  (glass  beads  and  polymer)  to  a  maximum 
level  of  3%.  The  level  of  silver  ion  achieved  in  the  EcoG+  packaging  is  therefore  420-600 
ppm. 
As  described  above,  EcoG+  contains  three  components;  i.e.  silver-containing  phosphate 
glass powder, glass beads and an appropriate polymer. EcoG+ therefore acts as a carrier for 
the active component, the silver ion, which is intended to be released in small amounts into 
the  cosmetic  product  contained  within  the  EcoG+  packaging.  The  species  ultimately 
released  into  the  cosmetic  product  is  the  silver  ion;  the  silver  released  into  the  cosmetic 
product  is  not  in  the  form  of  colloidal  silver  or  nanosilver.  Additionally,  although  silver 
nitrate is used as the source of silver, it is important to note that the silver ion is released 
into the cosmetic product without the nitrate counterion. This is because any nitrate present 
is destroyed by the very high temperatures used in the manufacture of EcoG+ glass and is 
liberated during the manufacturing process as nitrogen gas. 

3.1.1.1. 

Primary name and/or INCI name 

Phosphate glass / Silver ion  

3.1.1.2.  Chemical names 

Phosphate glass containing 1.4 to 2 % Ag / Silver  

3.1.1.3. 

Trade names and abbreviations 

‘EcoG+’  

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3.1.1.4.  CAS / EC number (silver) 

CAS: / 

7440-22-4  

EC:   / 

231-131-3  

3.1.1.5.  Structural formula 

       / 

Ag+  

3.1.1.6. 

Empirical formula (silver glass powder) 

subm II: 1/6 Ag2O･(P2O5･ZnO)m･(9CaO･2Al2O3･B2O3･Na2O)n 

m=10, n=0.2～0.4 

3.1.2. 

Physical form 

EcoG+ is a solid composite material containing silver glass powder (Million Guard PG721ST), 
glass  beads  and  a  suitable  polymer.  The  silver  ions  present  in  the  silver  glass  powder 
(Million  Guard  PG721ST)  will  disperse  throughout  the  structure  of  EcoG+.  The  dispersed 
silver ions will subsequently be released from EcoG+ and will be present (dissolved) in the 
aqueous component of the cosmetic product contained within the EcoG+ packaging. 

3.1.3. 

Molecular weight 

Calculation of molecular weight is not possible for ‘EcoG+’. The molecular weight of the 
silver ion (active component of the product) is 107.88 

3.1.4. 

Purity, composition and substance codes 

‘EcoG+’ is manufactured from the following components: 

Calcium dihydrogen phosphate 
Phosphoric acid 
Zinc oxide 
Zinc phosphate 
Boric acid 
Cerium oxide 
Aluminium hydroxide 
Sodium nitrate 
Silicon dioxide 
Silver nitrate [achieved level of 
silver: 2%] 

The silver nitrate used in the manufacture of silver glass is of high purity (>99%). In use 
(i.e. following incorporation into the cosmetic product packaging), silver ions are released 
from the glass matrix into the cosmetic product. 

3.1.5. 

Impurities / accompanying contaminants 

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The specification of the silver nitrate used for the manufacture of the silver glass is 
as follows: 
Purity 
Sulphates  
Chlorides  
Copper  
Iron  
Lead  

<20 ppm  
<5 ppm  
<2 ppm  
<2 ppm  
<10 ppm  

     >99% 

Impurities in silver nitrates (the source of silver present in ‘EcoG+’) are present at very low 
levels and will therefore not influence the toxicity of the product. 

3.1.6. 

Solubility 

EcoG+ is a solid composite material containing silver glass powder (Million Guard PG721ST), 
glass  beads  and  a  suitable  polymer.  The  silver  ions  present  in  the  silver  glass  powder 
(Million  Guard  PG721ST)  will  disperse  throughout  the  structure  of  EcoG+.  The  dispersed 
silver ions will subsequently be released from EcoG+ and will be present (dissolved) in the 
aqueous component of the cosmetic product contained within the EcoG+ packaging. 

3.1.7. 

Partition coefficient (Log Pow) 

Calculation of the Log Pow is not possible for the composite material ‘EcoG+’ or for the 
silver glass component Million Guard PG721ST. Calculation of Log Pow for the silver ion is 
also not relevant due to its insolubility in octanol. 

3.1.8. 

Additional physical and chemical specifications 

3.1.9. 

Homogeneity and Stability 

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‘EcoG+’  is  chemically  inert  and  is  therefore  stable  following  storage.  Due  to  the  nature  of 
the  active  component  (the  silver  ion),  studies  of  stability  in  cosmetic  products  are  not 
relevant. 

3.2. Function and uses 

EcoG+  is  a  composite  packaging  material  consisting  of  three  components;  silver  glass 
powder,  glass  beads  and  a  suitable  polymer  (see  above  3.1.1).  A  proportion  of  the  glass 
matrix remains at the surface of the material. The proportion of silver glass (Million Guard 
PG721ST) envisaged for use in the EcoG+ packaging material is 3%. The achieved level of 
the active component (i.e. the silver ion) in EcoG+ packaging is 420-600 ppm. During the 
proposed  use  of  the  composite  material  as  cosmetic  product  packaging,  small  amounts  of 
silver ions are released into the cosmetic product, where a preservative function is intended. 
EcoG+ packaging may be used with a variety of cosmetic product types. 

EcoG+  glass  containing  silver  ions  will  be  used  only  in  the  internal  parts  of  any  packaging 
(i.e. the parts of the packaging in direct contact with the cosmetic product) and will not be 
used on external parts potentially coming into contact with the hands of the consumer.  The 
external  parts  of  the  cosmetic  product  packaging  will  be  made  of  other  materials  that  will 
prevent  the  migration  of  silver  from  the  internal  layer  to  the  external  parts  of  the 
packaging. 

3.3. Toxicological Evaluation 

Due  to  the  nature  of  the  product,  its  intended  use  and  the  low  levels  of  silver  to  which 
consumers  are  predicted  to  be  exposed,  no  new  toxicity  data  have  been  generated  using 
‘EcoG+’.  Reference  is  made  to  existing  public  domain  data  on  the  toxicity  of  silver. 
Extensive toxicity data on silver, silver salts and silver compounds are available in the public 
domain and these data have been reviewed by various national and international bodies as 
part of the safety assessment of silver and silver compounds. An overview of the available 
data is presented in this dossier.  
The applicant has stated that the silver in EcoG+ is not present in the form of nanosilver.  
Several  investigations  have  demonstrated  the  continuous  release  of  silver  ions  from  the 
surface  of  silver  nanoparticles  and  metallic  silver  (Hadrup  and  Lam,  2014;  Chernousova  & 
Epple, 2013) and several studies showed similar responses of Ag+ ions and AgNPs on cells, 
suggesting that the toxicity can be due to release to free silver ions though there are also 
nano-specific responses (Beer et al., 2012; SCENIHR 2014; Huk et al. 2014, 2015; Butler et 
al.  2015).  Thus,  some  information  available  from  recent  studies  with  nanosilver  is  also 
included when suitable, and the Opinion of SCENIHR on nanosilver was also consulted with 
regard to toxicity studies (SCENIHR 2014).  

The safety assessment of EcoG+ is based on the release of silver ions from the packaging 
material. 

3.3.1. 

Acute toxicity 

No  data  have  been  generated  for  ‘EcoG+’;  adequate  public  domain  data  are  available  to 
address the acute toxicity of the silver ion to which consumers will be exposed. 

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Acute oral LD50 values for silver salts in mice are reported to be in the range 50-100 mg/kg 
bw (Faust, 1992; WHO, 2003). Acute oral LD50 values in the mouse of 100 mg/kg bw for 
colloidal silver and 129 mg/kg bw for silver nitrate; and acute oral LD50 values in the rat of 
125 mg/kg bw for silver cyanide and >2820 mg/kg bw for the insoluble silver oxide are also 
reported  (Faust,  1992).  The  US  EPA  (1992)  stated  that  sufficient  data  are  available  to 
conclude that the acute toxicity of silver is relatively low. 

A recent guideline- and GLP-compliant study of acute oral toxicity performed in the rat with 
nanosilver reports an LD50 value of >2000 mg/kg bw; no mortality or signs of toxicity were 
observed at the limit dose in this study (Kim et al., 2013). Juberg (1997) states that acute 
oral LD50 values of silver compounds including silver nitrate, silver oxide, silver fluoride and 
silver chloride are indicative of slight to moderate toxicity.  

Nanosilver  is  of  low  acute  dermal  toxicity  in  the  guinea  pig  (Korani  et  al.,  2011; 
Maneewattapinyo et al., 2011) and the rat (Kim et al., 2013), with no mortality or signs of 
toxicity  reported  in  the  rat  at  the  limit  dose  of  2000  mg/kg  bw.  No  additional  data  are 
identified  for  the  acute  dermal  toxicity  of  silver  or  silver  salts.  However  in  light  of  the 
negligible systemic availability of silver following dermal exposure, the acute dermal toxicity 
of ‘EcoG+’ can be predicted to be very low. 

No reliable data have been identified for the acute inhalation toxicity of silver or silver salts; 
however, inhalation exposure is not relevant to the proposed use of ‘EcoG+’.  

3.3.2 

Irritation and corrosivity 

3.3.2.1.  Skin irritation 

Some  salts  of  silver  (for  example  silver  nitrate)  are  known  to  be  corrosive  or  irritating 
(Juberg, 1997); however due to the chemical nature of ‘EcoG+’ and the low silver content, 
skin irritation is not predicted.  
Kim  et  al.  (2013)  report  an  absence  of  dermal  irritation  in  a  study  performed  with 
nanosilver in rabbits and in compliance with GLP and the OECD guideline 404. Samberg et 
al. (2010) studied effects of silver nanoparticles on porcine skin after topical dosing for 14 
days: Macroscopic observations showed no gross irritation in pig skin, whereas microscopic 
and  ultrastructural  observations  showed  areas  of  focal  inflammation  and  localisation  of 
nanoparticles on the surface and in the upper stratum corneum layers of the skin. 
The US EPA (EPA, 1992) conclude, based on animal data and experience of medical use of 
preparations containing silver, that sufficient data are available to conclude that silver itself 
is not a skin irritant.  

3.3.2.2.  Mucous membrane irritation 

Some  salts  of  silver  (for  example  silver  nitrate)  are  known  to  be  corrosive  or  irritating 
(Juberg, 1997); however due to the chemical nature of ‘EcoG+’ and the low silver content, 
eye irritation is not predicted.  
Kim et al. (2013) report an absence of ocular irritation in a study performed with nanosilver 
and in compliance with GLP and the OECD guideline 405. In another study with instillation 
of colloidal silver particles in the eyes of guinea pigs, some (1 of 4) animals of the high dose 
group (5000 ppm) showed conjunctivae irritation grade 1 during the first 24 h observation 
time  whilst  no  ocular  reaction  was  found  in  any  animal  48  hrs  post  exposure 
(Maneewattapinyo et al., 2011). 

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The  US  EPA  (1989)  concluded,  based  on  animal  data  and  experience  of  medical  use  of 
preparations containing silver, that sufficient data are available to conclude that silver itself 
is not an eye irritant. 

3.3.3. 

Skin sensitisation 

Despite  the  widespread  and  historic  use  of  silver  jewellery  and  dermal  exposure  to  silver 
and the widespread silver salts in cosmetics, medical and personal care products, reports of 
skin sensitisation are infrequent and often associated with contaminants (e.g. nickel in silver 
jewellery).  The  EPA  (1989)  concluded  that  sufficient  data  are  available  to  conclude  that 
silver itself is not a skin sensitiser. 

When  citrate-coated  silver  nanoparticles  (AgNP,  10  nm)  were  applied  in  the  guinea  pig 
maximization test (GPMT), a skin sensitisation test based on OECD TG 406 using 20 guinea 
pigs, a single animal showed discrete or patchy erythema (Kim et al., 2013). According to 
the  OECD  test  guideline,  substances  that  induce  a  positive  response  in  30%  or  more 
animals in the GPMT are considered as skin sensitisers. Hence, under the conditions of the 
test, silver nanoparticles did not have a skin-sensitising potential. 

3.3.4. 

Dermal / percutaneous absorption 

As an inorganic metal ion, the dermal absorption of silver is predicted to be very low based 
on its physicochemical properties (lipid solubility and molecular weight) and interaction with 
dermal  proteins  (Hostynek,  2003).  This  prediction  is  confirmed  by  observations  of  Skog  & 
Wahlberg  (1964)  who  report  the  dermal  absorption  of  silver  nitrate  through  intact  guinea 
pig skin to be less than 1% after 5 hours of exposure (based on the limits of detection), and 
Snyder  (1975),  who  reports  a  similar  finding  for  human  skin.  Clinical  and  experimental 
studies indicate that the dermal absorption of silver is ‘exceedingly low’ (Lansdown, 2010); 
this observation is attributable to the barrier properties of epidermal phospholipids and the 
irreversible  binding  of  free  silver  ions  to  keratin  sulphydryl  groups.  More  recent 
investigations  of  the  dermal  absorption  of  silver  from  impregnated  nanosilver  dressings  in 
burns  patients  report  a  level  of  dermal  absorption  of  0.1%  or  less,  even  in  severely 
damaged skin [US EPA assessment of data reported by Moiemen et al., 2011; US EPA slides 
19 and 20]. The authors indicate that this level of absorption is orders of magnitude higher 
than that measured in intact skin. 

Larese  et  al.  (2009)  studied  penetration  of  silver  nanoparticles  (AgNP)  in  vitro  using  full 
thickness  abdominal  human  skin.  AgNP  (25  nm  in  size)  coated  with  polyvinylpyrrolidone 
dispersed  in  ethanol  and  diluted  in  synthetic  sweat  were  applied  for  24  hours.  The 
experiments were conducted using both intact and abraded skin. Low, but detectable, AgNP 
absorption  through  intact  skin  was  seen,  with  0.0057%  passing  within  one  day  (according 
to Bachler et al. 2013). Penetration through damaged skin was five times greater than that 
through intact skin. Using transmission electron microscopy, AgNP could be detected (in the 
stratum corneum and upper layers of the epidermis (Larese et al., 2009). 

SCCS comment  
The level of 0.1% dermal absorption is considered to be relevant to ‘EcoG+’ and is used for 
calculations of systemic exposure to silver resulting from the use of this product as cosmetic 
packaging material. 

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3.3.5. 

Repeated dose toxicity 

The  principle  effect  of  repeated  exposure  to  silver  in  humans  and  experimental  animal 
species  is  argyria,  where  the  rate  of  absorption  of  silver  exceeds  the  rate  of  biliary  or 
urinary  excretion.  Argyria  is  characterised  by  the  deposition  of  inert  precipitates  of  silver 
selenide  and  silver  sulphide  and  may  be  observed  in  numerous  organs  and  tissues,  but  is 
not  associated  with  toxicity  (Greene  &  Su,  1987;  ATSDR,  1990;  Faust,  1992;  EPA,  1996; 
Juberg, 1997; WHO, 2003; Lansdown, 2010). Silver is widely distributed and consequently 
deposition  may  occur  in  any  organs,  however  the  liver  is  widely  identified  as  the  principle 
organ  of  silver  deposition  due  to  its  role  in  the  excretion  of  silver.  In  patients  with  high 
levels  of  hepatocellular  deposition,  silver  is  precipitated  as  inert,  lysosomally  bound 
deposits; findings are not associated with any evidence of liver malfunction or toxicity. 

Sub-acute (28-day) toxicity tests in the rat performed with nanoparticulate silver report an 
absence  of  overt  toxicity  even  at  a  dose  level  of  1000  mg/kg  bw/d  (Kim  et  al,  2008). 
Elevated serum alkaline phosphatase activity and cholesterol levels observed in this study at 
dose  levels  of  300  mg/kg  bw/d  and  above  are  indicative  of  mild  hepatotoxicity.  Renal 
deposits of silver are similarly not associated with marked organ toxicity; in animal studies 
silver  deposits  are  reported  on  the  glomerular  basement  membrane,  arteriolar  endothelia 
and laminae, without apparent structural damage. Renal toxicity was not observed in a sub-
chronic toxicity study in mice administered 65 mg/kg bw/d silver nitrate (Faust, 1992). 

A  slight  greyish  pigmentation  of  the  eyes  was  observed  in  albino  rats  receiving 
approximately 60 mg/kg bw/d silver for 218 days (WHO, 2003); pigmentation of additional 
organs  was  observed  in  these  animals  following  a  lifetime  exposure.  Rats  exposed  to  222 
mg/kg  bw/d  silver  for  37  weeks  showed  growth  depression  and  granular  silver  deposits  in 
the eyes (EPA, 1989; ATSDR, 1990). 

Faust  (1992)  also  notes  a  study  in  which  rats  were  administered  silver  nitrate  or  silver 
chloride over a lifetime at dose levels equivalent to 635-660 mg silver/day. Enlargement of 
the  left  vertical  of  the  heart  was  reported  in  addition  to  slight  thickening  of  the  basement 
membranes  of  the  kidney  glomeruli;  renal  effects  were  observed  in  the  absence  of  overt 
organ toxicity. Deposition of silver was also observed in the skin, eyes and several internal 
organs. A study in which rats were administered 0.1% silver nitrate in the drinking water to 
rats  for  218  days  (equivalent  to  approximately  89  mg/kg  bw/d  silver)  reported  effects  on 
the  cardiovascular  and  hepatic  systems.  A  statistically  significant  increase  in  the  incidence 
of  ventricular  hypertrophy  was  reported;  advanced  pigmentation  was  observed  in  body 
organs.  The  ventricular  hypertrophy  observed  in  this  study  was  not  attributed  to  silver 
deposition (EPA, 1989; ATSDR, 1990). 

More recent studies on the toxicity of silver nanoparticles have been reviewed elsewhere in 
more  detail  (e.g.  Fetrell  2014;  Hadrup  &  Lim  2014;  SCENIHR  2014).  Here  only  oral  and 
dermal investigations where also ionic silver was studied in parallel are summarised.   

Van der Zande et al. (2012) found no hepatotoxicity or immunotoxicity in a 28 day feeding 
study in rats exposed to silver nanoparticle (< 20 nm non-coated; <15 nm PVP coated) at 
90  mg/kg  of  bw  or  ionic  silver  (silver  nitrate)  at  9  mg/kg  of  bw/day.  In  another  28  day 
study of with oral administration of nanoparticulate or ionic silver at doses up to 9 mg/kg of 
bw/day, a decreased thymus weight was recorded following the administration of 9 mg/kg 
of bw/day of ionic silver (Hadrup et al., 2012b). In a 90-day study with oral administration 
of silver nanoparticles (60 nm) to rats, decreased body weight was observed at 500 mg/kg 
of bw/day for males only (Kim YS et al., 2010). The authors of a recent review (Hadrup & 

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Lam 2014) noted that in several other oral studies with nanosilver compounds, no effects on 
body weight were reported.  

Korani et al (2011) conducted a sub-chronic dermal toxicity study in guinea pigs where the 
shaved  skin  (10%  of  the  body  surface  area)  of  the  animals was  rubbed  five  times  a  week 
for 13 weeks with solutions containing silver nanoparticles (AgNP, 1000 or 10,000 μg/ml) or 
silver nitrate (AgNO3 at 100 μg/ml). The observed skin responses (inflammation, decreased 
thickness  of  epidermis  and  dermis)  were  dose-dependent  and  the  impact  of  AgNO3  was 
similar to that from the same dose of AgNP. Negative impacts from AgNP were also seen on 
the  liver  and  spleen,  including  overproduction  of  Kupffer  cells  and  degeneration  of 
hepatocytes  in  the  liver.  The  authors  comment  that,  based  on  their  results,  exposure  to 
>0.1 mg/kg (100 μg/ml dose) of AgNP may result in slight liver, spleen and skin damage. 

There are reports on possible silver-induced neurotoxic effects in rodents: One study found 
that  0.015%  silver  nitrate  in  the  drinking  water  for  125  days  (14  mg  Ag/kg  of  bw/day) 
induced  hypoactivity  in  argyric  mice  after  a  10  day  silver  withdrawal  period  (Rungby  & 
Danscher, 1984). An earlier study by these authors found an increase in liveliness observed 
in rats given 0.01 % silver nitrate in the drinking water (6 mg Ag/kg bw/day) for 4 months 
(Rungby  &  Danscher,  1983).  Hadrup  et  al.  (2012c)  investigated  the  effects  of  oral 
administration of ionic and 14 nm nanoparticulate silver for 28 days on neurotransmitters in 
rats: Alterations in noradrenaline, dopamine and 5-hydroxytryptamine concentrations were 
found in the brain at doses of 2.25 mg/kg bw/day of nanoparticulate silver and 9 mg/kg of 
bw/day  of  ionic  silver  (as  Ag-acetate).  In  another  study,  with  intraperitoneal  injection  of 
silver nanoparticles (25 nm, non-coated) at doses of 10, 25, and 50 mg/kg bw for 7 days, 
the  exposure  did  not  affect  cognitive  outcome  or  hippocampal  neurogenesis  in  adult  male 
mice (Liu P et al., 2013). 

3.3.6. 

Mutagenicity / Genotoxicity:  

ATSDR  (2003)  concluded  that  the  mutagenicity  data  for  silver  were  inconsistent,  but 
indicated the ability of the silver ion to bind to isolated DNA in vitro, causing strand breaks 
and affecting the fidelity of DNA replication.  

Studies  of  reverse  mutation  in  S.  typhimurium  and  E.  coli  are  negative.  WHO  reported  a 
negative rec-assay with B. subtilis and a positive result  in a DNA repair assay  at cytotoxic 
concentrations in cultured primary rat hepatocytes. Kim et al. (2013) reported an absence 
of genotoxicity in an Ames test and a study of chromosomal aberration in mammalian cells 
in  vitro,  both  performed  in  compliance  with  GLP  and  current  OECD  guidelines.  Nishioka 
(1975) showed that silver chloride induced no mutagenicity in bacteria, and Eliopoulos and 
Mourelatos  (1998)  found  no  mutagenicity  of  silver  iodide  by  the  Ames  test.  Recent  tests 
with ionic silver (AgNO3) in another Ames test with five bacterial strains were also negative 
(Butler  et  al.  2015).  It  should,  however,  be  noted  that  silver  is  strongly  bactericidal,  and 
consequently Ames test data are of limited value to conclude on silver mutagenicity. 

Eliopoulos  and  Mourelatos  (1998)  have  shown  that  silver  iodide  induces  sister  chromatic 
exchanges in human lymphocytes in concentrations 0.1 µg/ml and above (when dissolved in 
acetone)  and  in  concentrations  1  µg/ml  and  above  (when  dissolved  in  polyacrylamide 
suspension).  In  the  same  study,  AgNO3  was  used  as  positive  control  and  induced  sister 
chromatid  exchanges  (concentration  above  1  µg/g  bw)  in  P388  lymphocyte  leukemia  cells 
that  were  cultured  in  the  mouse  peritoneal  cavity.  Concentration-dependent  chromosomal 
damaging  effects  were  also  observed  in  human  T-cell  and  monocyte  cell  lines  (Jurkat  and 
THP-1 cells) after exposure to silver nitrate (Butler et al. 2015).  

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Both  silver  ions  (Ag⁺ )  as  well  as  silver  nanoparticles  (AgNPs)  induced  DNA  damage  (strand 
breaks,  DNA  adducts,  DNA  oxidation)  (8-oxodG)  in  vitro  (Foldbjerg  et  al.,  2011;  Huk  et  al., 
2014  and  2015)  and  micronucleus  formation  in  CHO  cells  in  a  concentration-dependent 
manner  (Jiang  et  al.,  2013).  Micronucleus  induction  has  been  detected  also  in  the  TK6 
lymphoblastoid  cell  line  following  incubation  with  5  nm  AgNPs,  but  only  at  a  cytotoxic 
concentration  of  25  µg/mL  (Hadrup  et  al.,  2012c;  Li  et  al.,  2012).  AgNPs  (50  nm,  80  nm 
and  200  nm)  induced  mammalian  gene  mutation  in  hprt  gene  in  V79  cells  in  very  low 
concentrations (Huk et al., 2014). These authors also showed that small (8 nm) nanosilver 
particles  with  different  charges  and  surface  compositions  (six  different  capping  agents) 
induced gene mutations in V79 cells (Huk et al., 2014). 

In an in vivo study with oral dosing, no micronucleus induction was found following 28 days 
of 60 nm AgNP administration to rats (Kim et al., 2008). Also genotoxicity testing by an in 
vivo  micronucleus  assay  in  an  inhalation  study  with  rats  exposed  to  AgNP  for  90  days  did 
not  reveal  genotoxicity  (Kim  et  al.  2011).  Additionally,  Li  et  al.  (2014)  studied  PVP-  and 
silicon-coated AgNPs for micronucleus, in a pig-A gene mutation assay and the comet assay. 
Both  the  PVP-  and  silicon-coated  AgNPs  induced  oxidative  DNA  damage  in  mouse  liver. 
However,  none  of  the  treatments  resulted  in  a  significant  increase  of  either  mutant 
frequencies  in  the  pig-A  gene  or  the  percent  of  micronucleated  reticulocyte  over  the 
concurrent controls, indicating no mutagenicity and clastogenicity. 

Silver ions are released from silver nanoparticles. Several studies showed similar responses 
of  Ag+  ions  and  AgNPs  on  cells,  suggesting  that  the  toxicity  can  be  due  to  release  to  free 
silver ions though there are also nano-specific responses (Beer et al., 2012; SCENIHR 2014; 
Huk et al. 2014, 2015; Butler et al. 2015). However, the rate of silver ion dissolution from 
AgNPs  differs  depending  on  surface  properties  (silver  charge  and  capping  agent)  and 
storage  conditions  as  shown  in  the  recent  study  of  Izak-Nau  et  al.  (2015).  Thus  storage 
conditions,  surface  properties  as  well  attachment  of  Ag+  ions  to  container  walls  can  be  a 
significant  contributor  to  the  contradictory  toxicity  results  observed  in  the  literature  for 
identical  nanoparticles  (Izak-Nau  et  al.  2015).  As  the  amount  of  silver  released  differs 
depending on particle surface properties and storage conditions, both positive and negative 
data on AgNPs must be regarded as inconclusive and not generalisable. 

SCCS Conclusion   
The  genotoxicity  of  Ag+  ions  was  investigated  for  all  the  three  endpoints  of  genotoxicity: 
gene  mutations,  chromosome  aberrations  and  aneuploidy,  although  results 
from 
mammalian cell gene mutation tests were not provided. The available tests were not always 
performed according to present standards and the data obtained are generally inconclusive. 
Ames test data are of limited value due to strong bactericidal properties of Ag+ ions. Gene 
mutation tests in mammalian cells are not provided. Results on chromosomal damage show 
negative and positive results.  
As Ag+ ions are released from silver nanoparticles and as one of the toxicity mechanism of 
silver  nanoparticles  (AGNPs)  is  via  Ag+  ions,  the  genotoxicity  of  AgNPs  was  considered  as 
well.  Genotoxicity/ mutagenicity data on AgNPs are also inconclusive, showing both positive 
and  negative  effects.  Due  to  different  amounts  of  Ag+  ions  released  from  different  AgNPs, 
these data can only be tentatively considered.  
As  the  main  mechanism  of  genotoxicity  of  silver  ions  is  via  ROS  production,  which  is  an 
indirect  and  concentration  dependent  process,  and  since  the  concentrations  of  silver  ions 
present in cosmetic products are low, the SCCS has no concern with regard to human risk. 
Also due to the low dermal penetration of silver ions, systemic genotoxicity is not expected.   

3.3.7. 

Carcinogenicity 

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There is some indication from old reports that the subcutaneous implantation of silver metal 
foils in rodents may cause the induction of local fibrosarcomas. However, such tumours are 
attributable  to  solid-state  carcinogenesis  and  are  not  of  relevance  to  the  human  risk 
assessment.  This  applies  also  to  contradictory  findings  of  tumours  following  subcutaneous 
and  intramuscular  injection  of  colloidal  silver  in  rats,  i.e.  routes  of  exposure  with  no 
established  human  relevance.  ATSDR  (1990)  conclude  that  animal  toxicity  and  human 
occupational  studies  using  more  relevant  routes  of  exposure  have  not  provided  indications 
of carcinogenicity, and silver is not expected to be carcinogenic in humans. The EPA (1989) 
concludes  that  silver  is  not  classifiable  with  respect  to  carcinogenicity  since  animal 
carcinogenicity  data  on  silver  are  inadequate  due  to  the  phenomenon  of  solid-state 
carcinogenesis. 
The weight of evidence therefore indicates that silver is not carcinogenic. 

3.3.8. 

Reproductive toxicity 

Data  on  the  reproductive  toxicity  of  silver  are  limited;  however  the  ATSDR  concludes  that 
‘existing evidence’ does not point to a strong effect of the silver ion on reproduction and no 
historical  evidence  to  indicate  an  effect  of  silver  on  reproduction  in  humans.  While 
subcutaneous injection of silver nitrate has been reported to cause reversible damage to the 
testes  in  rats  (Hoey,  1966),  no  effects  on  spermatozoa  or  fertility  were  observed  in  a 
drinking water study. 
A  high-quality  developmental  toxicity  study  performed  in  the  rat  with  silver  acetate  (NTP, 
2002) concludes a NOAEL for developmental toxicity of 100 mg/kg bw/d, the highest dose 
level  tested.  Indications  of  slight  maternal  toxicity  were  observed  at  this  dose  level;  more 
severe  maternal  toxicity  was  observed  at  a  dose  level  of  160  mg/kg  bw/d  in  a  screening 
study. Published data (Shavlovsky et al., 1995) indicate an effect of silver on development 
at  maternally  toxic  dose  levels  and  secondary  to  copper  deficiency  caused  by  the 
displacement of copper by silver from ceruloplasmin. 

3.3.9. 

Toxicokinetics 

3.3.9.1.  Absorption 

Studies  in  humans  and  animals  indicate  that  silver  compounds  are  absorbed  by  the 
inhalation  and  oral  routes  and  poorly  by  the  dermal  route.  Absorbed  silver  is  distributed 
widely  throughout  the  body.  Data  on  the  extent  of  oral  absorption  is  variable  but  is 
generally  accepted  to  be  relatively  low.  Juberg  (1997)  reports  oral  absorption  values  for 
silver  in  animal  studies  of  less  than  10%;  WHO  (2003)  states  that  up  to  5%  of  colloidal 
silver  can  be  absorbed  after  oral  exposure.  Important  factors  in  the  absorption  of  silver 
include  the  presence  and  extent  of  silver-binding  proteins  and  the  solubility  of  the  silver 
species  (Juberg  1997).  Lansdown  (2010)  states  that  passive  gastrointestinal  absorption  of 
the free silver ion is unlikely to be significant due to its reactivity with sulphydryl, carboxyl, 
hydroxy and protein ligands on mucosal surfaces and cell debris. Silver readily reacts with 
organic  constituents  of  food,  which  further  limits  its  absorption  from  the  gastrointestinal 
tract. The extent of oral absorption is therefore variable but is estimated not to exceed 5-
10%  and  is  thought  likely  to  be  influenced  by  factors  such  as  the  presence  of  food  and 
gastrointestinal transit time (ATSDR, 1990). 

3.3.9.2.  Distribution 

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The  systemic  distribution  of  orally  absorbed  silver  is  limited  by  extensive  biliary  excretion 
(first-pass  effect)  (Juberg,  1997).  Absorbed  silver  is  extensively  bound  to  serum  proteins 
including  albumin  and  ceruloplasmin.  Soluble  silver  ions  may  be  deposited  in  tissues  as 
insoluble  salts  such  the  silver  chloride  or  silver  phosphate  (ATSDR,  1990);  these  insoluble 
salts  are  subsequently  transformed  to  silver  selenide  and  silver  sulphide.  Dermal  silver 
deposits  in  one  case  of  argyria  were  identified  as  being  primarily  composed  of  silver 
sulphide (Buckley et al, 1965). The characteristic blue or grey discoloration of skin exposed 
to  sunlight  in  humans  with  argyria  may  be  caused  by  the  photoreduction  of  deposited 
insoluble  silver  salts  to  metallic  silver  (ATSDR,  1990).  Studies  in  the  rat  have  also 
characterised silver deposits in internal organs as the silver sulphide (Berry & Galle 1982). 

While deposition of silver has been observed in many organs and tissues, the liver and skin 
are  identified  as  the  main  storage  centres  for  silver  in  the  body  (ATSDR,  1990;  Faust, 
1992). Exposed experimental animals and humans show granular deposits containing silver 
in both pigmented and non-pigmented skin. 

In  studies  using  injection  of  radiolabelled  metallic  silver  and  silver  nitrate  in  the  rat,  the 
highest  concentrations  of  silver  were  identified  in  the  gastrointestinal  tract,  liver,  blood, 
kidney,  muscle,  bone  and  then  skin.  The  proportion  of  silver  distributed  to  the  tissues  is 
positively  correlated  with  the  dose  administered  (ATSDR,  1990).  Lansdown  (2010)  states 
that there is no convincing evidence for the passage of silver across the blood-brain-barrier 
or blood-CSF-barrier. 

3.3.9.3.  Metabolism 

Systemically absorbed silver may bind to plasma proteins and is deposited in tissues as the 
insoluble  silver  chloride  and  phosphate,  which  are  subsequently  reduced  to  silver  sulphide 
or silver selenide (ATSDR, 1990). Silver chloride deposited in exposed areas of skin may be 
photochemically reduced to metallic silver and subsequently oxidised by the tissue to form 
the black silver sulphide, resulting in skin discoloration. 

3.3.9.4. 

Excretion 

Excretion of silver in experimental animals is mainly via the bile, with little urinary excretion 
(Juberg,  1997;  WHO,  2003).  Biliary  excretion  is  also  the  major  route  in  humans,  with 
urinary  excretion  of  minor  importance  (Lansdown,  2010).  Silver  binds  to  and  induces  the 
expression  of  metallothioneins  in  the  liver,  thereby  facilitating  its  biliary  excretion. 
Cumulative  excretion  of  silver  in  experimental  animals  (mice,  rats,  monkeys  and  dogs) 
ranged from 90-99%, with retention of up to 10%. Similar retention is observed in humans. 
Half-lives of approximately 50 days are reported for silver (Faust, 992; Juberg, 1997; WHO, 
2003).  Whole-body  retention  studies  in  mice  and  monkeys  following  oral  dosing  with 
radiolabelled  silver  nitrate  indicate  that  silver  excretion  in  these  species  follows  a 
biexponential  profile  with  biological  half-lives  of  0.1  and  1.6  days  in  mice  and  0.3  and  3 
days  in  monkeys.  In  similarly  exposed  rats  and  dogs,  silver  excretion  followed  a 
triexponential profile with biological half-lives of 0.1, 0.7, and 5.9 days in rats and 0.1, 7.6, 
and 33.8 days in dogs (Furchner et al, 1968). Saturation of the elimination pathway in the 
liver  occurring  with  chronic  or  high  level  acute  exposure  leads  to  excretion  in  the  faeces 
decreasing and deposition in tissues increasing. Faust (1992) and ATSDR (1990) reported a 
study in dogs using intratracheal administration of metallic silver, the lung clearance of the 
metallic  silver  was  accompanied  by  increased  silver  in  the  stomach  and  liver  due  to  the 
mucociliary escalator and consequent ingestion. Dissolution of the silver into the blood was 
the main route of clearance from the lungs. Within 30 days, approximately 90% of the dose 
was excreted in the faeces. 

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3.3.10.  Photo-induced toxicity 

The  assessment  of  phototoxicity  is  appropriate for  substances  absorbing  light  in  the  range 
290-700  nm  and  is  relevant  for  organic  substances  rather  than  simple  inorganic  ions  such 
as silver. 
Previously, the SCCS assessed studies with topical application of a silver citrate containing 
formulation (FAT 81’034/B) followed by UV irradiation (SCCS/1274/09): Treatment did not 
induce  any  photosensitising  reactions  in  guinea  pigs  and  revealed  no  photoirritation  when 
the formulation was applied at concentrations up to 1% (corresponding to 0.01 % silver).   

3.3.11.  Human data 

Silver  has  no  known  physiological  function  (Faust,  1992).  The  WHO  (1977)  estimates  the 
oral intake of silver for humans from dietary sources to range from 27-88 μg/day; a small 
but measurable amount of silver is accumulated by individuals over their lifetime. 

The US EPA (1996) considers the critical effect in humans exposed to silver to be argyria, a 
medically benign but probably permanent blue-grey discoloration of the skin resulting from 
the deposition of silver in the dermis and possibly also from the silver-induced production of 
melanin. Silver is uniformly deposited in the skin but increased pigmentation is pronounced 
in  areas  exposed  to  sunlight  due  to  photo-activated  reduction  of  the  metal.  Although  the 
deposition  of  silver  is  permanent,  it  is  not  associated  with  systemic  health  effects  (EPA, 
1996) and no pathologic change or inflammatory reactions have been shown to result from 
silver  deposition  (Greene  &  Su,  1987).  Lansdown  (2010)  also  notes  that  argyria  is  not 
associated with cellular or tissue damage and is widely considered not to be of toxicological 
significance.  Following  prolonged  dermal  contact  or  exposure,  argyria  may  be  dermal  and 
localised;  widespread  argyria  (including  the  skin)  has  been  observed  following  the 
prolonged  use  of  high  levels  of  colloidal  silver  by  humans  and  in  experimental  animals 
administered  silver  compounds.  Silver  deposits  observed  in  argyria  are  extracellular  or 
intracellular (lysosomal) and may be more marked in light-exposed areas of the skin due to 
the  stimulation  of  melanin  production  by  silver  (Greene  &  Su,  1987;  Wadhera  &  Fung, 
2005). Argyrosis, pigmentation of the cornea and conjunctivae resulting from the deposition 
of insoluble inert silver complexes has been reported following industrial (ocular) exposure 
to  silver  compounds  (for  example  in  soldering)  and  following  the  historical  use  of  colloidal 
silver  to  treat  ocular  infection.  Similarly  to  argyria,  deposits  of  silver  selenide  and  silver 
sulphide are associated with proteins of the conjunctivae and cornea but are not associated 
with cellular damage. Following systemic absorption, the deposition of silver is apparent in 
internal organs; however the evidence indicates that silver does not cross the blood-brain-
barrier  or  the  blood-CSF-barrier  (Lansdown, 2010).  Relatively  high  concentrations  of silver 
are reported in the liver and may be associated with transient changes in clinical chemistry 
parameters  but  not  with  any  evidence  of  pathological  damage  in  patients  with  severe 
argyria or in animal models. 

Gaul & Staud (1935) reported 70 cases of argyria following the medical use of organic and 
colloidal silver, including 13 cases of generalised argyria following the intravenous injection 
of  silver  arsphenamine.  Argyria  was  found  to  develop  after  a  total  dose  of  4-8  g  in  some 
patients,  while  in  others,  argyria  did  not  develop  until  after  a  total  dose  of  10-20  g.  The 
authors  confirmed  that  the  degree  of  the  discoloration  in  skin  biopsies  was  directly 

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proportional  to  the  amount  of  silver  present.  They  concluded  that  argyria  may  become 
clinically  apparent  after  a  total  accumulated  (intravenous  dose)  of  approximately  8  g  of 
silver arsphenamine. Based on cases presented in this study, the EPA use the lowest dose 
resulting  in  argyria  in  one  patient  of  4  g  silver  arsphenamine  (equivalent  to  1  g  silver)  as 
the minimal effect level for argyria. East et al (1980) report a case of argyria in a 47-year- 
old woman who had taken excessively large oral doses of silver acetate over a period of 2.5 
years. Symptoms of argyria appeared after the first 6 months of exposure. The total body 
burden of silver was estimated to be 6.4 g; the total body burden and the concentration of 
silver in the skin were estimated to be 8000 times higher than normal. 
Workers exposed to silver as a consequence of work in the manufacturing and packaging of 
silver  nitrate;  mining,  smelting,  polishing  and  hammering  of  silver  have  been  reported  to 
show  generalised  argyria.  Localised  argyria  may  also  be  manifested  as  isolated  areas  of 
pigmentation occurring at the tracheobronchial junction the smaller bronchi (Faust, 1992).  
The  inhalation  of  silver  at  concentrations  that  produce  argyria  can  also  cause  respiratory 
tract irritation.  
Large  oral  doses  of  silver  nitrate  have  been  reported  to  cause  abdominal  pain,  diarrhoea, 
vomiting,  shock,  convulsions  and  death  (Faust,  1992);  however  effects  are  attributable  to 
the corrosive properties of this form of silver. The estimated fatal dose in humans is 10 g. 

Juberg  (1997)  notes  that  acute  occupational  exposure  to  high  airborne  concentrations  of 
silver  nitrate  has  been  associated  with  local  irritant  reactions,  however  findings  are 
attributable to the corrosive properties of this salt rather than silver per se. The author also 
states  that the  results of  several  occupational  epidemiology  studies  have  not  revealed  any 
adverse  health  effects  in  workers  exposed  by  inhalation  to  metallic  silver,  soluble  and 
insoluble salts of silver for periods of 5-20 years. Studies demonstrated pigmentation of the 
skin, eyes (conjunctivae) and mucous membranes and elevated silver concentrations in the 
blood,  faeces  and  hair  but  no  evidence  of  haematological  change  or  clinical  chemistry 
indications of organ damage. 

Workers exposed to silver nitrate and silver oxide dusts for up to 10 years were reported to 
have experienced sneezing, stuffiness and running nose or sore throat, coughing, wheezing, 
chest  tightness  and  abdominal  pain  (Drake  and  Hazelwood,  2005).  Granular  silver-
containing  deposits  correlated  with  the  duration  of  employment  and  some  people 
experienced  decreased  night  vision.  Another  group  of  workers  manufacturing  metal  silver 
powder  also  reported  a  decrease  in  night  vision.  Conjunctival  argyria  was  seen  in  21%  of 
silver  reclamation  workers  exposed  to  silver  and  insoluble  silver  compounds,  while  25% 
exhibited  corneal  argyria  and  many  of  the  workers  manifested  pigmentation  of  the  nasal 
septum. 
While isolated cases of immediate or delayed contact dermatitis have been reported, silver 
is  not  considered  to  be  highly  allergenic  (ATSDR,  1990;  Faust,  1992).  Following  the 
accidental inhalation of radiolabelled silver by a worker, silver was found mainly in the liver; 
ciliary  action  removed  the  silver  from  the  lungs  followed  by  ingestion,  with  elimination 
mainly in the faeces and limited urinary excretion (Faust, 1992; ATSDR, 1990). 

The dermal absorption of silver compounds in intact human skin is low, but may be greater 
in burns patients (ATSDR, 1990). Silver was detected in the urine, blood, and body tissue of 
humans with seriously burned skin following treatment with topical preparations containing 
silver  nitrate.  Distribution  into  muscle,  liver,  spleen,  kidney,  heart  and  bones  has  been 
demonstrated following the topical application of silver nitrate for the treatment of burns. 

3.4. Calculation of exposure 

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3.4.1. 

Silver ion migration from containers 

Achieved levels of silver resulting from the use of ‘EcoG+’  
The  levels  of  silver  likely  to  be  attained  in  cosmetic  products  stored  in  EcoG+  packaging 
have been investigated in two preliminary studies and a more detailed study.  

Study 1 
A  study  of  migration  of  silver  from  a  cosmetic  container  manufactured  using  ‘EcoG+’  was 
performed; the container was filled with distilled water and silver concentrations measured 
by ICP atomic emission spectroscopy. The achieved levels of silver were 56 ppb after 2 days 
and 73 ppb after 7 days.  

Table 4.1   Migration of silver ions from EcoG+ into distilled water 

Time point  
2 days  
7 days  

Silver concentration (ppb) 
56 ppb 
73 ppb 

NOTE: The composition of the container used in this study is not given.  

Study 2 
A  further  study  (Taiki  2012)  was  performed  over  a  period  of  two  months  using  cosmetic 
containers  filled  with  distilled  water,  tap  water  or  an  aqueous  dilution  (1/500)  of  nutrient 
broth. Silver concentrations were measured at various time points using inductively coupled 
plasma emission spectroscopy. 

Table 4.2   Achieved levels of silver  

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It  can  be  seen  from  the  results  of  this  study  that  the  kinetics  of  silver  migration  were 
comparable for the three simulants investigated. Maximal silver concentrations (~ 35 ppb) 
were  seen  up  to  approximately  Day  14.  Silver  levels  subsequently  remained  relatively 
constant at a level of approximately 32 ppb.  
Taiki 
2012 

Ref. 

NOTE: The liquid dispenser used in this study consisted of polypropylene (58%), glass bead 
(40%) and silver glass (1.5%).    
Containers manufactured with EcoG+ can contain higher amounts of silver glass (3%). The 
test was apparently conducted at neutral pH.   

Study 3 
A further study of achieved silver concentrations (TAIKI Corporation, 2014) was performed 
in  order  to  assess  the  influence  of  product  pH  on  the  level  of  silver  release  from  cosmetic 
containers  manufactured  from  90%  polypropylene,  9%  glass  and  1%  silver  glass. 
Containers were filled with an aqueous buffer solution containing 0.1% sodium chloride and 
0.05% citrate; the pH of the buffer solution was adjusted to 4.0, 5.0 or 6.0 by the addition 
of  sodium  citrate  solution.  Containers  were  maintained  either  at  room  temperature  or  at 
elevated  temperature  (40°C  and  75%  relative  humidity)  for  a  period  of  four  weeks.  Silver 
levels in the buffer were measured by ICP optical emission spectrophotometry. The results 
of these analyses are shown below. 

Table 4.3   Achieved levels of silver  

Silver  concentrations  in  the  buffer  solution  after  4  weeks  were  slightly  higher  for  the  jars 
stored at elevated temperature. There was no clear effect of pH on silver concentration. 

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NOTE: The cosmetic jar used in this study consisted of polypropylene (90%) with 10% 
EcoG+ resin that contained 10 % of silver glass. 

Overview of migration data 
The silver ions present in the silver glass component (Million Guard PG721ST) of the EcoG+ 
packaging  will  migrate  within  the  packaging  and  will  subsequently  also  migrate  into  the 
aqueous phase of any cosmetic product contained within the packaging. Migration of silver 
ions into the cosmetic product may potentially be influenced by the pH or presence of other 
ionic  species  in  the  aqueous  phase  of  the  product.  The  available  data  show  that  the 
concentration  of  silver  achieved  in  the  product  is  relatively  low,  and  that  a  maximum 
concentration  is  achieved  within  approximately  30  days.  The  silver  concentration  achieved 
in the cosmetic product is governed by an equilibrium. Reduction of the product content in 
the container through usage will not therefore result in a higher level of silver in the residual 
product. 

NOTE:  The  migration  of  silver  ions  from  ‘EcoG+’  packaging  material  has  not  been  tested 
with typical cosmetic formulations (w/o or o/w), however it is assumed not to be higher in 
those cosmetic formulations. 

The following calculations are based on a silver ion concentration of 0.03 µg/mL in cosmetic 
products stored in EcoG+ packaging material.  

Systemic Exposure Dose  
Systemic  exposure  to  silver  resulting  from  the  proposed  use  of  the  product  is  calculated 
using the following parameters:  

•  The global daily exposure value for preservatives of 17.4 g/day (269 mg/kg bw/d) for 

all cosmetic products which may be applied on the skin (SCCS, 2016)  

•  An estimate of the level of silver attained in cosmetics of 0.03 µg/mL (TAIKI data)  

•  Dermal absorption of 0.1% (Moiemen et al., 2011 and US EPA 2011)  

Using  these  parameters  results  in  an  estimated  systemic  exposure  of  approximately 
0.000008 μg/kg bw/d silver following the use of ‘EcoG+’.  

The  value  of  0.1%  for  dermal  absorption  of  silver  is  derived  from  serum  levels  in  persons 
with  severely  damaged  skin  (burn  patients)  during  treatment  with  silver-rich  wound 
dressings (Moiemen et al., 2011; US EPA 2011). This value is a conservative upper-bound 
estimate and orders of magnitude higher than those measured in vitro with intact or mildly 
damaged human skin (Larese et al. 2009). 

Reference values 
All published reviews concur that the relevant (critical) effect of silver exposure is argyria. 
Toxicological reference values for silver have been derived by the EPA, WHO and EFSA. 

The  US  EPA  uses  a  systemic  lifetime  (systemic)  exposure  of  1  g  silver  as  starting  point1; 

1 The EPA (1989) used the study of Gaul & Staud to derive a minimal (lifetime exposure) NOAEL of 1 g silver (systemic). This 
level of systemic exposure is calculated to be equivalent to an oral reference dose (RfD) of 0.00056 mg/kg bw/d (0.56 μg/kg 
bw/d) following correction for the extent of oral absorption (5 %), bodyweight (70 kg), exposure over a lifetime of 70 years 
(25500 days) and an uncertainty factor of 3  

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this  is  calculated  to  be  equivalent  to  a  systemic  exposure  level  of  0.00056  mg/kg  bw/d 
(0.56 μg/kg bw/d) assuming a lifetime of 70 years and a bodyweight of 70 kg.  

Based  on  the  epidemiological  and  pharmacokinetic  data,  WHO  (2003)  derives  a  human 
NOAEL (lifetime oral intake) for silver of 10 g, corresponding to 0.39 mg Ag/person/day or 
0.0065  mg/kg  bw/d.  Assuming  a  gastrointestinal  absorption  of  silver  of  5%,  this  is 
equivalent to a systemic reference value of 0.000325 mg/kg bw/d (0.325 µg/kg bw/d). 

EFSA has evaluated silver-based preservatives for use in food-contact materials on the basis 
of human and animal data and has derived a group restriction limit of 0.05 mg Ag/kg food, 
which corresponds to a worst-case exposure of 0.05 mg Ag/person/day or 0.00083 mg/kg 
bw/day.  Assuming  a  gastrointestinal  absorption  of  silver  of  5%,  this  is  equivalent  to  a 
systemic reference value of 0.0000415 mg/kg bw/d (0.0415 µg/kg bw/d). 

The  (oral  and  systemic)  reference  values  for  silver  are  listed  in  a  table  (below)  for  a 
comparison to the systemic silver exposure dose resulting from use of EcoG+ as packaging 
material and related MOS calculations. 

Table 4.4   Exposure and Safety Calculations  

Comparison  of  the  SED  for  silver  resulting  from  the  proposed  use  of  EcoG+  to  the 
toxicological  reference  values  derived  by  the  EPA,  WHO  and  EFSA  shows  Margin  of  Safety 
(MoS) values well in excess of 100. Therefore the proposed use of EcoG+ is not considered 
to  result  in  adverse  health  effects  in  consumers  using  cosmetic  products  stored  in  EcoG+ 
packaging. 

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3.4.2. 

Discussion 

Physicochemical properties 
EcoG+ is a solid composite material containing silver glass powder (Million Guard PG721ST), 
glass  beads  and  a  suitable  polymer.  The  silver  ions  present  in  the  silver  glass  powder 
(Million  Guard  PG721ST)  will  disperse  throughout  the  structure  of  EcoG+.  The  dispersed 
silver ions will subsequently be released from EcoG+ and will be present (dissolved) in the 
aqueous component of the cosmetic product contained within the EcoG+ packaging. 

When  containers  made  with  EcoG+  were  used  to  study  migration  of  silver  ions  into 
simulants (aqueous buffer solutions), the achieved levels were about 30 ppb (0.03 µg/mL).   

Toxicity of silver (local and systemic) 
Some  salts  of  silver  (for  example  silver  nitrate)  are  known  to  be  corrosive  or  irritating 
[Juberg, 1997]; however only at very high concentrations (>1000 ppm). The very low levels of 
ionic  silver  attained  in  cosmetic  products  stored  in  ‘EcoG+’  packaging  materials  will  not 
result in skin irritation or in mucous membrane irritation.  
Overall,  the  acute  and  chronic  toxicity  of  oral  or  parenteral  administered  silver  and  silver 
salts is relatively low, although accidental and self-inflicted poisonings can occur with ionic 
or colloidal silver [Lansdown, 2010; Hadrup & Lam 2014].  
The  principle  effect  of  repeated  exposure  to  silver  in  humans  and  experimental  animal 
species  is  argyria,  where  the  rate  of  absorption  of  silver  exceeds  the  rate  of  biliary  or 
urinary excretion resulting in blue-grey discoloration of the skin. Argyria is characterised by 
the  deposition  of  inert  precipitates  of  silver  selenide  and  silver  sulphide  and  may  be 
observed  in  numerous  organs  and  tissues,  but  is  not  associated  with  toxicity.  Argyrosis, 
pigmentation of the cornea and conjunctivae resulting from the deposition of insoluble inert 
silver  complexes  has  been  reported  following  industrial  (ocular)  exposure  to  silver 
compounds  (for  example  in  soldering)  and  following  the  historical  use  of  colloidal  silver  to 
treat ocular infection [Drake & Hazlewood 2005; Lansdown, 2010]. 
Available data in animals do not  point to a specific effect of the silver  ion on development 
and  reproduction  (only  at  maternally  toxic  doses),  and  there  is  no  historical  evidence  to 
indicate an effect of silver on reproduction in humans.  

All published reviews concur that the relevant (critical) effect of silver exposure in humans 
is  argyria,  a  medically  benign  but  probably  permanent  blue-grey  discoloration  of  the  skin 
resulting  from  the  deposition  of  silver  in  the  dermis  and  possibly  also  from  the  silver-
induced  production  of  melanin  [ATSDR,  1990;  Faust,  1992;  EPA  1996;  Juberg,  1997;  WHO,  2003; 
Lansdown, 2010].  

Mutagenicity and genotoxicity 
The  genotoxicity  of  Ag+  ions  was  investigated  for  all  the  three  endpoints  of  genotoxicity: 
gene  mutations,  chromosome  aberrations  and  aneuploidy,  although  results 
from 
mammalian cell gene mutation tests were not provided. The available tests were not always 
performed according to present standards and the data obtained are generally inconclusive. 
Ames test data are of limited value due to strong bactericidal properties of Ag+ ions. Gene 
mutation tests in mammalian cells are not provided. Results on chromosomal damage show 
negative and positive results.  
As Ag+ ions are released from silver nanoparticles and as one of the toxicity mechanism of 
silver  nanoparticles  (AGNPs)  is  via  Ag+  ions,  the  genotoxicity  of  AgNPs  was  considered  as 
well.  Genotoxicity/ mutagenicity data on AgNPs are also inconclusive showing both positive 
and  negative  effects.  Due  to  different  amounts  of  Ag+  ions  released  from  different  AgNPs, 
these data can only be tentatively considered.  
As  the  main  mechanism  of  genotoxicity  of  silver  ions  is  via  ROS  production,  which  is  an 
indirect  and  concentration  dependent  process,  and  since  the  concentrations  of  silver  ions 

23 

 
 
 
 
 
 
 
 
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present  in  cosmetic  products  is  low,  the  SCCS  has  no  concern  with  regard  to  human  risk. 
Also due to the low dermal penetration of silver ions, systemic genotoxicity is not expected.   

Carcinogenicity  
Animal toxicity and human occupational studies using relevant routes of exposure have not 
provided  indications  of  carcinogenicity,  and  silver  is  not  expected  to  be  carcinogenic  in 
humans. 

Dermal absorption 
As an inorganic metal ion, the dermal absorption of silver is predicted to be very low based 
on its physicochemical properties (lipid solubility and molecular weight) and interaction with 
dermal  proteins  [Hostynek,  2003].  This  prediction  is  confirmed  by  an  in  vivo  study  [Skog  & 
Wahlberg 1964] reporting the dermal absorption of silver nitrate through intact guinea pig skin 
to  be  less  than  1%  (based  on  the  limits  of  detection)  as  well  as  clinical  and  experimental 
studies  indicating  that  the  dermal  absorption  of  silver  is  ‘exceedingly  low’  [Lansdown,  2010]. 
More  recent  investigations  of  the  dermal  absorption  of  silver  from  impregnated  nanosilver 
dressings  in  burns  patients  report  a  level  of  dermal  absorption  of  less  than  0.1%,  even  in 
severely  damaged  skin  [US  EPA  assessment  of  data  by  Moiemen  et  al.,  2011].  This  level  of 
absorption  is  orders  of  magnitude  higher  than  that  measured  in  vitro  with  intact  or  mildly 
damaged  human  skin  [Larese  et  al.  2009].  The  value  of  0.1%  is  a  conservative  upper-bound 
estimate,  which  will  be  used  in  the  calculation  of  systemic  exposure  resulting  from  dermal 
exposure to silver and margins of safety.  

Risk assessment 
All published reviews concur that the relevant (critical) effect of silver exposure is argyria. 
Toxicological  reference  values  for  silver  have  been  derived  by  the  EPA,  WHO  and  EFSA  in 
other regulatory contexts (drinking water regulation, release of silver ions from food-contact 
materials). The systemic silver reference values are a suitable basis for calculating margins 
of safety for exposure resulting from dermal exposure to silver ions used as preservative in 
cosmetic products. 

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4.  CONCLUSION 

1.  Does  SCCS  consider  release  of  silver  ions  from  "EcoG+"  as  component  in  packaging 
material  safe  for  use  as  preservative  with  a  concentration  of  maximum  2.0 %  in  the 
cosmetic packaging material, taking into account the scientific data provided? 

Safety assessment is based on the release of silver ion from the packaging material. 

SCCS considers the release of silver ions from "EcoG+" as a component in packaging 
material  safe  for  use  as  preservative  with  a  concentration  of  maximum  2.0 %  in  the 
cosmetic packaging material. 

2. 

And/or  does  the  SCCS  recommend  any  further  restrictions  with  regard  to  the  use  of 
"EcoG+" as preservative in cosmetics packaging? 

/  

5.  MINORITY OPINION 

None 

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6.  REFERENCES 

Submission I and II 

ATSDR  (1990).  Toxicological  Profile  for  Silver.  Agency  for  Toxic  Substances  and  Disease  Registry,  US 
Public Health Service. Available at: http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=539&tid=97  

Berry  JP  &  Galle  P  (1982).  Selenium  and  kidney  deposits  in  experimental  argyria.  Electron  microscopy 
and microanalysis. Pathologie Biologie 30 (3), 136–140.  

Buckley WR, Oster CF & Fassett DW (1965). Localized argyria. II. Chemical nature of the silver containing 
particles. Archives of Dermatology 92 (6), 697–705.  

East BW, Boddy K, Williams ED, MacIntyre D & McLay ALC (1980). Silver retention, total body silver and 
tissue  silver  concentrations  in  argyria  associated  with  exposure  to  an  anti-smoking  remedy  containing 
silver acetate. Clin. Exp. Dermatol. 5, 305-311.  

EFSA  (2004).  Opinion  of  the  Scientific  Panel  on  Food  Additives,  Flavourings,  Processing  Aids  and 
Materials  in  Contact  with  Food  (AFC)  on  a  request  from  the  Commission  related  to  a  4th  list  of 
substances for food contact materials (2004). The EFSA Journal 65, 1-17 

(1989). 

EPA 
http://www.epa.gov/iris/subst/0099.htm  

Integrated 

Risk 

Information 

System 

(IRIS). 

Silver 

(CASRN 

7440-22-4). 

Faust  R  (1992).  Toxicity  Summary  for  Silver,  Chemical  Hazard  Evaluation  and  Communication  Group, 
Biomedical  and  Environmental  Information  Analysis  Section,  Health  and  Safety  Research  Division,  Oak 
Ridge National Laboratory, Oak Ridge, Tennessee.  

Furchner JE, Richmond DR & Drake GA (1968). Comparative metabolism of radionuclides in mammals-IV. 
Retention of silver-110m in the mouse, rat, monkey and dog. Health Physics 15 (6), 505–514.  

Gaul  LE  &  Staud  AH  (1935).  Clinical  spectroscopy.  Seventy  cases  of  generalized  argyrosis  following 
organic  and  colloidal  silver  medication  including  a  biospectrometric  analysis  of  ten  cases.  J.  Am.  Med. 
Assoc. 104 (16), 1387-1390.  

Greene RM & Su WPD (1987). Argyria. Am. Fam. Phys. 36. 151-154.  

Hoey MJ (1966). The effects of metallic salts on the histology and functioning of the rat testes. J. Reprod. 
Fertil. 12, 461-471.  

Hostynek JJ (2003). Factors determining percutaneous metal absorption. Food and Chemical Toxicology 
41, 327-345.  

Juberg DR (1997). A Review of Toxicity and Epidemiological Data for Silver in Animal and Humans. 5th 
International Conference Proceedings: Transport, Fate and Effects of Silver in the Environment.  

Kim JS, Song KS, Sung JH, Ryu HR, Choi BG, Cho HS, Lee JK & Yu IJ (2013). Genotoxicity, acute oral and 
dermal  toxicity,  eye  and  dermal  irritation  and  corrosion  and  skin  sensitisation  evaluation  of  silver 
nanoparticles. Nanotoxicology 7(5):953-60. (doi:10.3109/17435390.2012.676099; Epub 2012 Apr 4) 

Kim YS, Kim JS, Cho HS, Rha DS, Kim JM, Park JD, Choi BS, Chang HK, Chung YH, Kwom IH, Jeong J, Han BS 
&  Yu  IJ  (2008).  Twenty-eight-day  oral  toxicity,  genotoxicity,  and  gender-related  tissue  distribution  of 
silver nanoparticles in Sprague-Dawley rats. Inhalation Toxicology 20 (6), 575-583. 

Korani M, Rezayat SM, Gilani K, Arbadi Bidgoli S & Adeli S (2011). Acute and subacute dermal toxicity of 
nanosilver in guinea pig. International Journal of Nanomedicine 6, 855-862.  

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Langsdown ABG (2010) A pharmacological and toxicological profile of silver as an antimicrobial agent in 
medical devices. Adv Pharmacol Sci, Article ID 910686, 16 pages; doi:10.1155/2010/910686 

Moiemen NS, Shale E, Drysdale KJ, Smith G, Wilson YT & Rapini R. (2011). Acticoat dressing and major 
burns: systemic silver absorption. Burns 37, 27-35.  

NTP (2002). Final Study Report Developmental Toxicity Evaluation for Silver Acetate (CASRN 563-63-3) 
Administered by Gavage to Sprague-Dawley (CD¨) Rats on Gestational Days 6-19. NTIS Report PB2002-
109209.  

Skog  E  &  Wahlberg  JE  (1964).  A  Comparative  Investigation  of  the  Percutaneous  Absorption  of  Metal 
Compounds in the Guinea Pig by Means of the Radioactive Isotopes: 51Cr, 58Co, 65Zn, 110mAg, 115mCd, 203Hg. 
Journal of Investigative Dermatology 43, 187-192.  

Snyder WS (1975). Report of the Task Group on Reference Man. Pergamon Press, Oxford, England, pp. 
407-708. (Cited in ATSDR, 1990).  

TAIKI Corporation (2012). Analysis of Concentration of Silver Ion Released from Ag-Eco-G Product (Liquid 
Dispenser). TAIKI Corporation Internal Report: 14th May 2012.  (2 pp) 

TAIKI Corporation (2014). Experimental Report. TAIKI Corporation Internal Report: 9th January 2014. 

US-EPA (2011) Dermal absorption of silver from Acticoat wound dressings (20 october 2011; slides with 
an assessment of the Moiemen et al. 2011 study)  

Wadhera A & Fung M (2005). Systemic argyria associated with ingestion of colloidal silver. Dermatology 
Online Journal 11 (1), 12.  

WHO (1997): Summary of Toxicological data of Certain Food Additives. WHO Food Additives Series No. 
12.  Twenty-first  Report  of  the  Joint  FAO/WHO  Expert  Committee  on  Food  Additives.  WHO  Technical 
Report Series No. 617.  

WHO,  2003,  Silver  in  Drinking  Water  Background  Document  for  Development  of  WHO  Guidelines  for 
Drinking-Water Quality, Geneva, Switzerland (WHO/SDE/WSH/03.04/14).  

Additional references added by SCCS 

Bachler  G,  von  Goetz  N,  Hungerbühler  K  (2013)  A  physiologically  based  pharmacokinetic 
model  for  ionic  silver  and  silver  nanoparticles.  International  Journal  of  Nanomedicine  8, 
3365-3382. 

Chernousova S, Epple M (2013) Silver as antibacterial agent: ion, nanoparticle, and metal. 
Angewandte Chemie 52, 1636-1653. 

Drake  PL,  Hazelwood  KJ  (2005).  Exposure-related  health  effects  of  silver  and  silver 
compounds: a review. Ann Occup Hyg 49(7):575-85. 

EFSA (2011) EFSA Panel on food contact materials, enzymes, flavourings and processing 
aids (CEF); Scientific Opinion on the safety evaluation of the substance, silver zeolite A 
(silver zinc sodium ammonium alumino silicate), silver content 2 – 5 %, for use in food 
contact materials. EFSA Journal 2011; 9(2):1999. [12 pp.] doi:10.2903/j.efsa.2011.1999. 
Available online: www.efsa.europa.eu/efsajournal.htm  

Fewtrell  L  (2014)  Silver:  water  disinfection  and  toxicity.  Centre  for  Research  into 
Environment  and  Health.  Aberysthwyth  University  ;  Aberythstwyth  2014.  Available  at: 
http://www.who.int/water_sanitation_health/dwq/chemicals/Silver_water_disinfection_toxic
ity_2014V2.pdf   

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Hadrup N, Lam HR (2014) Oral toxicity of silver ions, silver nanoparticles and colloidal silver 
– a review. Regulatory Toxicology and Pharmacology 68, 1-7. 

Hadrup N, Loeschner K, Bergstrom A, et al. (2012b). Subacute oral toxicity investigation of 
nanoparticulate and ionic silver in rats. Arch. Toxicol. 86 (4), 543–551. 

Hadrup N, Loeschner K, Mortensen A, et al. (2012c). The similar neurotoxic effects of 
nanoparticulate and ionic silver in vivo and in vitro. Neurotoxicology 33 (3), 416–423. 
http://dx.doi.org/10.1016/j.neuro.2012.04.008. 

Kim  JS,  Sung  JH,  Ji  JH,  Song  KS,  Lee  JH,  Kang  CS,  Yu  IJ  (2011)  In  vivo  Genotoxicity  of 
Silver Nanoparticles after 90-day Silver Nanoparticle Inhalation Exposure. Saf Health Work; 
2(1):34-8. doi: 10.5491/SHAW.2011.2.1.34. Epub 2011 Mar 31. 

Larese  FF,  D’Agostin  F,  Crosera  M,  Adami  G,  Renzi  N,  Bovenzi  M,  Maina  G  (2009)  Human 
skin penetration of silver nanoparticles through intact and damaged skin. Toxicology 255(1-
2):33–37.  

Liu  P,  Huang  Z,  Gu  N  (2013)  Exposure  to  silver  nanoparticles  does  not  affect  cognitive 
outcome or hippocampal neurogenesis in adult mice. Ecotoxicol Environ Saf 87: 124-130. 

Maneewattanapinyo  P,  Banlunara  W,  Thammachaoen  C,  Ekgasit  S,  Kaewamatawong  T 
(2011) An evaluation of acute toxicity of colloidal silver nanoparticles. J Vet Med Sci 73(11): 
1417-1423 

Rungby  J,  Danscher  G  (1983).  Localization  of  exogenous  silver  in  brain  and  spinal  cord  of 
silver exposed rats. Acta Neuropathol. 60(1-2):92-8. 

Rungby J, Danscher G (1984). Hypoactivity in silver exposed mice. Acta Pharmacol Toxicol 
(Copenh) 55(5):398-401. 

Samberg  ME,  Oldenburg  SJ,  Monteiro-Riviere  NA  (2010)  Evaluation  of  silver  nanoparticle 
toxicity in skin in vivo and keratinocytes in vitro. Environm Health Perspect 118:407-413  

Samberg  ME,  Orndorff  PE,  Monteiro-Riviere  NA  (2011)  Antibacterial  efficacy  of  silver 
nanoparticles  of  different  sizes,  surface  conditions  and  synthesis  methods.  Nanotoxicology 
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