Download EU Derogation Application Form For Copper CAS No 7440-50

EU Derogation Application Form For Copper
Appendix C Information on Efficacy
APPENDIX C
Contents:
Page 1: Preamble
Page 4: Mode of Action / Efficacy – Legionella
Page 5: Efficacy – Additional Pathogenic Organisms
CAS No 7440-50-8
EU Derogation Application Form For Copper
Appendix C Information on Efficacy
CAS No 7440-50-8
Preamble:
Copper has been known for its antifungal and biocidal properties for centuries. The historic use of
copper has been well documented Egyptian papyrus written between 2600 and 2200 BC describes
the application of copper to treat chest wounds and to purify drinking water. Later, Hippocrates
recommended the topical application of copper to treat leg ulcers, and, in the pre-antibiotic era of
the nineteenth and twentieth centuries, copper preparations were widely used in the treatment of
skin conditions, syphilis and tuberculosis.(1) As a fungicide copper sulfate has been used in
agriculture from the 1800’s for the control of potato blight and is still used today in the vine industry
as the preferred method of fungal control.
The use of copper is further illustrated by recent studies and trials into the use of copper surfaces in
hospitals and health care settings in infection prevention and control. As the prevalence of hospital
acquired infections increases the interest in this particular method of infection control has risen.
Studies on the use of copper surfaces abound and all show benefits albeit with limited effect. During
a study in the UK “A toilet seat, a set of tap handles and a ward entrance door push plate each
containing copper were sampled for the presence of micro-organisms and compared to equivalent
standard, non-copper-containing items on the same ward. Items were sampled once weekly for 10
weeks at 07:00 and 17:00. After five weeks, the copper-containing and non-copper-containing items
were interchanged. The total aerobic microbial counts per cm2 including the presence of ‘indicator
micro-organisms’ were determined. Median numbers of microorganisms harboured by the coppercontaining items were between 90% and 100% lower than their control equivalents at both 07:00
and 17:00.” (2) A similar study from Norway found that “Bacterial cells use different efflux systems to
detoxify the metal from the cytoplasm or periplasm. Despite this ability, bacteria are rapidly killed on
dry metallic copper surfaces.” (3) Despite these promising findings there is little doubt that although
beneficial, copper as a surface it is only successful in augmenting existing infection control measures.
Copper as a disinfectant has been used to treat and sterilize water. It is vital to note, however, that
regardless of efficacy that copper is not by any means the most effective biocide available. Oxidizing
agents such as Chlorine have far quicker killing times and agents such as peracetic acid will kill spores
of “difficult” microorganisms such as Clostridium difficile, which will resist both Chlorine and Copper.
Copper silver ionization is effective against waterborne pathogens, it is a wide ranging and basically
safe method of disinfection but nevertheless should only be viewed as one weapon in the ever
decreasing armory of defense against pathogenic and life threatening microbes. A review from 2010
pointed out that ”Hospital-acquired infections are a major challenge to patient safety. It is estimated
that in 2002, a total of 1.7 million hospital-acquired infections occurred (4.5 per 100 admissions), and
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Appendix C Information on Efficacy
CAS No 7440-50-8
almost 99,000 deaths resulted from or were associated with a hospital-acquired infection, making
hospital-acquired infections the sixth leading cause of death in the United States; similar data have
been reported from Europe. The estimated costs to the U.S. health care budget are $5 billion to $10
billion annually. Approximately one third or more of hospital-acquired infections are preventable.”
(4)
Further the continued emergence of bacterial resistance to antibiotics coupled with a sever lack of
new anti-microbial drugs must mean that any and all available methods of disinfection should be
used or at least be available for use should circumstance require. The number of new antibacterial
drugs approved in the USA between the years of 1983 and 1987 was 16, between the years 2003
and 2007 the number was 5 (5). This trend is worrying enough but the medical community is now
being forced to revert to treatment using polymyxins (polymyxin B, colistin) and pentacationic
lipopeptides to attempt to control the continued emergence of drug resistant gram negative
bacteria in spite of their nephrotoxicity. (6)
The importance of water borne pathogens in this emerging problem of nosocomial infections is high.
Of the organisms know to be capable of infecting patients through contact with hospital water
supplies the bacterial organisms excluding Legionella are:
Pseudomonas aeruginosa, Stenotrophmonas maltophilia, Serratia marcescens, Acinetobacter
baumannii, Aeromonas hydrophila,Burkholderia, Enterobacter,Flavobacterium, Serratia and
Chyseobacterium species.
Of the Mycobacterium organisms:
Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium xenopi, Mycobacterium kansasii
and Mycobacterium chelonae.
Of Fungal organisms:
Fusarium solani, Exophiala jeansemei, and Aspergillus fumigatus (7).
It is becoming more obvious and essential that any method of dealing with these types of infections
which is both effective and cost efficient be kept available.
With the rise in bacterial resistance to antibiotics, the urgency in dealing with water borne
pathogens at root source is now more than ever pressing. Techniques such as staff education and
improving standards of hand washing training can only go so far. Patients exposure to the above
pathogens occurs while showering, bathing and drinking (water or ice) and through contact with
contaminated medical equipment (e.g. tube feeds, endoscopes and respiratory equipment) rinsed
with water (7) .These forms of contact cannot reasonably be counteracted other than by dealing with
the issue at source.
Furthermore recent findings indicate that the incorrect or under use of disinfection agents can
induce antibiotic resistance in bacteria. In a study from Galway it was shown that sub lethal doses of
benzalkonium chloride, the active ingredient in common hand wipes, eye and ear drops, cleaning
EU Derogation Application Form For Copper
Appendix C Information on Efficacy
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products and house hold names such as Detol ® Lysol ® and Bactine ®, can induce bacterial
resistance to antibiotics in Pseudomonas aeruginosa (8).
All this points to a vital need to maintain all and any disinfection modalities. Bacteria evolve more
quickly than science or mankind can adapt to. They have the ability rapidly mutate and adapt so that
they can ameliorate the biocidal effect of antimicrobial agents. The conditions required for such
evolution are common knowledge: allow some to live and they will adapt. It is therefore wise to
allow all safe methods of microbial control to remain available.
In addition to uses in pathogenic control in health care settings copper silver ionisation has been well
established as an alternate method of maintaining bacteria quality in bathing water. For over thirty
years copper silver has been used effectively in both public and private swimming pools as a
bactericide, fungicide and algaecide. Many other effective means of ensuring safe quality bathing
water exist .Chlorine, bromine, ozone, ultra violet, chlorine dioxide and natural filtration using
aquatic plants are all viable means of keeping bathing water safe and copper silver by no means is
the most effective alternative. It is however a viable alternative and one which has benefits many
others simply do not.
Chlorine is by far the most used active in the swimming pool market and with good reason. As an
oxidising disinfectant it kills quickly and effectively the majority of bacteria with the noted exception
of Cryptosporidium (9). Chlorine is also known to cause health issues with long term exposure.
Chlorine is an accepted carcinogen. The WHO states that “in a 2-year bioassay, F344 rats and B6C3F1
mice were given chlorine in drinking-water at levels of 0, 70, 140, or 275 mg/litre (8, 13, or 24 mg/kg
of body weight per day for male rats; 5, 7, or 15 mg/kg of body weight per day for female rats; 8, 15,
or 24 mg/kg of body weight per day for male mice; and 1, 13, or 22 mg/kg of body weight per day for
female mice). Although there was a marginal increase in mononuclear-cell leukaemia in the groups
of female rats given 140 and 275 mg/litre, it was considered to be equivocal evidence of
carcinogenic activity because the incidence was significantly elevated compared with controls only
for the middle dose and the incidence of leukaemia in the concurrent controls was lower than the
mean in historical controls” and further states “It has been reported that asthma can be triggered by
exposure to chlorinated water. Episodes of dermatitis have also been associated with exposure to
chlorine and hypochlorite” and yet further states “An increased risk of bladder cancer appeared to
be associated with the consumption of chlorinated tapwater in a population-based, case–control
study of adults consuming chlorinated or non-chlorinated water for half of their lifetimes” (10)
More recent studies highlight not only the health issues regarding Chlorine but also the sever health
risks associated with chlorine by-products in a swimming pool environment. One study showed
“Regular attendance at chlorinated pools by young children is associated with an exposure
dependent increase in lung epithelium permeability and increase in the risk of developing asthma,
especially in association with other risk factors. We therefore postulate that the increasing exposure
of children to chlorination products in indoor pools might be an important cause of the rising
incidence of childhood asthma and allergic diseases in industrialised countries” (11). Another study
summarised as follows: “Disinfection is mandatory for swimming pools: public pools are usually
disinfected by gaseous chlorine or sodium hypochlorite and cartridge filters; home pools typically use
stabilized chlorine. These methods produce a variety of disinfection byproducts (DBPs), such as
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Appendix C Information on Efficacy
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trihalomethanes (THMs), which are regulated carcinogenic DBPs in drinking water that have been
detected in the blood and breath of swimmers and of nonswimmers at indoor pools. Also produced
are halogenated acetic acids (HAAs) and haloketones, which irritate the eyes, skin, and
mucousmembranes; trichloramine, which is linked with swimmingpool- associated asthma; and
halogenated derivatives of UV sun screens, some of which show endocrine effects. Precursors of DBPs
include human body substances, chemicals used in cosmetics and sun screens, and natural organic
matter. Analytical research has focused also on the identification of an additional portion of
unknown DBPs using gas chromatography (GC)/mass spectrometry (MS) and liquid chromatography
(LC)/MS/MS with derivatization. Children swimmers have an increased risk of developing asthma and
infections of the respiratory tract and ear. A 1.6- 2.0-fold increased risk for bladder cancer has been
associated with swimming or showering/bathing with chlorinated water. Bladder cancer risk from
THM exposure (all routes combined) was greatest among those with the GSTT1-1 gene. This suggests
a mechanism involving distribution of THMs to the bladder by dermal/inhalation exposure and
activation there by GSTT1-1 to mutagens. DBPs may be reduced by engineering and behavioral
means, such as applying new oxidation and filtration methods, reducing bromide and iodide in the
source water, increasing air circulation in indoor pools, and assuring the cleanliness of swimmers.”
(12) In addition Chlorine and all other pool disinfectants require the use of additional chemicals such
as aluminium sulphate as a flocculent, copper sulphate as an algaecide (yes we are aware of the
irony), acids and bicarbonates as pH regulators. Copper silver ionization does not require any
additional chemical additions thus reducing both health and environmental risks to two simple
actives. All told there is enough evidence to suggest that Chlorine, while being effective, is not
without its drawbacks. At the very least viable safe alternatives should remain available.
In a final use, that of cooling water, copper silver ionisation is again not the sole or best modality
available in the strictest sense of best. It does however present a system where by exact dosages
required are controllable to ensure public safety from cooling towers, Air conditioning systems and
HVac systems and the inherent risk from airborne Legionella. Again in this instance there are
alternatives on the market but copper silver, due to its ability to penetrate and break up biofilm is
more effective. In addition to controlling biofilm and Legionella in cooling towers copper silver will
also control algae and fungi within cooling systems and it is unique in this multi-faceted ability to
control a full spread of microbial contaminants.
This ability to control a range of microbial organisms, from fungal to viral, lends the use of copper
silver to a further seldom mentioned advantage over other modalities. In being multi active copper
silver ionisation can reduce energy consumption dramatically. In the health care setting its use
avoids the need for energy expensive thermal treatments; in the cooling tower sector it increases
cooling efficiency by biofouling control and in the swimming pool sector has proven to be more cost
effective in the long term than the alternatives for an array of reasons not least being extending the
life of the pool water and filtration media.
In short Copper silver ionisation presents a viable alternative to control pathogenic waterborne
diseases and pathogens which has proven itself on the market and in supported studies to be safe,
controllable and effective.
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Appendix C Information on Efficacy
CAS No 7440-50-8
Information on Efficacy:
Mode of Action: The biocidal and antimicrobial properties of copper have been of interest to science
roughly since the mid 1800’s. Many studies on exactly how copper deactivates or kills microbes have
been carried out but the exact molecular mechanisms which give copper its antimicrobial properties
are still under investigation. What is known is that copper antimicrobial mechanisms are complex
and vary in mode of and site of action. To date it has been shown that copper binds with Sulphur
based enzyme structures (13), catalyses the generation of reactive oxygen species which in turn
damage cell DNA, (14) copper reduces the metabolic capacity of cells, copper will damage bacterial
cell walls and cause result in lysis (16 & 17) and more recent studies have shown that copper is also
toxic to viruses and bacteriophages and interestingly that water has been shown to mediate in the
toxicity (18).Thus copper is toxic to microorganisms in a multifaceted manner and has been shown
to be effective against a whole range of organisms for bacteria to virus to fungus.
Efficacy against Waterborne Pathogens – Specific Studies:
Copper silver ionisation as distinct from copper itself has been the subject of interest for over twenty
years in the area of controlling waterborne pathogens. The main topic of research has been the area
of Legionella control where copper silver has been well established. Indeed several worldwide health
care organisations, including the HSE in Ireland, include copper and silver ionisation as part of
recommended practice (19). The following table details some of the studies completed:
Reference
World Health
Organisation
(2007) (20)
Study Type
Real World
Lee K.
Landeen et
al(1989) (22)
Laboratory Assay
Josep Modol
et al (2007)
(24)
Conclusions
N/A
Effective when prescribed concentrations are maintained
11
years
No cases of hospital-acquired legionnaires’ disease were
diagnosed after the installation of the copper–silver
ionization system in 94% (15 of 16) of the hospitals. One
hospital did report a case of hospital-acquired legionnaires’
disease soon after the installation of the ionization system;
however, no cases had occurred from 1995 to 2002 in this
hospital
Recommendation
Janet E. Stout;
Victor L. Yu
(2003) (21)
Zeming Liu et
al (1998) (23)
Length
N/A
Real World Trial
8
months
Real World Trial
5 Years
Enhanced bacterial inactivation rates of agar-grown cultures
of L. pneumophila in well water systems were shown when
copper and silver were added to chlorinated water
In summary, one copper-silver ionization system was
successfully used to disinfect two hospital buildings
sequentially
After implementation of the copper-silver ionization
system, environmental colonization with Legionella species
decreased significantly, and the incidence of nosocomial
legionellosis decreased dramatically, from 2.45 to 0.18
cases per 1000 patient discharges
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Another trial in Germany concluded that copper silver ionisation was not effective in controlling
Legionella, and concluded “The effect was not significant (P = .071); therefore, it must be considered
that Legionella developed a tolerance to silver ions” (25). This was refuted later in another study
which stated “In a study performed in Germany, the failure of copper–silver ionization to control
Legionella was attributed by the authors to the emergence of Legionella resistant to copper–silver
ionization. However, careful analysis of the article showed that resistance to copper or silver ions was
never demonstrated for any Legionella strains isolated following copper–silver disinfection. The
apparent failure to control Legionella was more likely due to suboptimal ion levels and not to the
development of resistance” (21). Weather or resistance did indeed develop or weather levels of
silver were too low to be effective this study raises relevant points regarding the efficacy of copper
silver ionization.
Bacterial resistance to both copper and silver is known. It is further well accepted that given the
correct circumstances and conditions that bacteria will develop resistance to virtually all disinfection
modalities. With regard to copper and silver this may yet be the case and it is certainly the
experience of this author that the system is not without failings.
In the course of installing systems both in Ireland and abroad, factors which require attention during
the running of copper silver ionisations have become apparent. Just as Chlorine is subject to failure
at higher temperatures copper silver requires that pH be maintained and a level below 7.2 to ensure
success. Copper solubility is pH dependant and at levels above 6 copper begins to fall from solution
and eventually revert to colloidal form.
Further ensuring constant levels of copper and silver is vital not only to ensure efficacy but also, and
perhaps more importantly, to mitigate against bacterial resistance development.
Additional Pathogenic Efficacy:
Copper silver ionisation is valuable in more than controlling Legionella. Other waterborne
pathogenic organisms are also vulnerable to treatment using copper silver ionisation. A study on
planktonic and biofilm forming pathogens in 2010 summarised that “The study was to determine the
efficacy of copper-silver ionization against the formation of Pseudomonas aeruginosa,
Stenotrophomonas maltophilia, and Acinetobacter baumannii in biofilms and planktonic phases. At
concentrations below the EPA limits, ionization has potential to control the three waterborne
pathogens” (26). All three of the above microorganisms are known to cause disease and fatalities in
humans.
These pathogenic agents are not limited to bacterial infestations but also include fungal and viral
pathogens (29) .Of the organisms know to be capable of infecting patients through contact with
hospital water supplies the bacterial organisms excluding Legionella are:
Pseudomonas aeruginosa, Stenotrophmonas maltophilia, Serratia marcescens, Acinetobacter
baumannoo, Aeromonas hydrophila and Chyseobacterium species.
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Of the Mycobacterium organisms:
Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium xenopi, Mycobacterium kansasii
and Mycobacterium chelonae.
Of Fungal organisms:
Fusarium solani, Exophiala jeansemei, and Aspergillus fumigatus (28).
A study on fungal pathogens revealed that “The prevalence of fungi was significantly lower in ionized
than in nonionized water samples from health care facilities” (27) It is interesting to note that this
particular study was carried out in a hospital who had already installed a copper silver system for the
control of Legionella and that the study was prompted by the fact that “Since a copper and silver
ionization system was installed in our hospital in September 1999 for control of environmental
Legionella species, the number of consultations to the Infectious Diseases department regarding
fungal infection has markedly decreased” (27).
To summarise, a growing number of studies are pointing to copper silver being effective in
controlling waterborne pathogens. The technology has been established in the field of Legionella
control but has efficacy in the control of a spread of microorganisms. It is accepted that the efficacy
is subject to conditions of operation and that further more in-depth research on microorganisms
other than Legionella is required to fully prove the full efficacy of the system but copper silver is
working and keeping water free from pathogens in a number of applications without risk to human
health or the environment and as such is a key tool in the control of pathogenic agents.
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Appendix C Information on Efficacy
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