Bulletin 912
Kathon® CG/ICP Preservative for Media
Biocide Applications
Kathon CG/ICP preservative is a highly effective, broadspectrum biocide with excellent compatibility and stability,
and low toxicity at in-use levels. At very low concentrations,
Kathon CG/ICP preservative eradicates bacteria, fungi,
and yeast cells for prolonged periods. It does not interfere
with most enzyme- or antibody-linked reactions or assay
indicators. The product as supplied easily can be neutralized with 10% sodium bisulfite solution and disposed of as
nonhazardous waste. In most cases Kathon CG/ICP can be
the preservative of choice for applications in which traditional antimicrobials, such as sodium azide or thimerosal,
have been used.
Key Words
● biocide ● preservative
● antimicrobial
●
bactericide
●
fungicide
Contents
Topic
solutions, it can release harmful vapors. A powder, sodium azide
is both hazardous and inconvenient to work with. Gentamicin
(and other antibiotics) offers protection against a specific group
of microorganisms. Combinations of antibiotics expand the
range of protection, but combinations become complicated and
expensive, and protection remains less than complete.
In contrast, Kathon CG/ICP preservative is a highly effective,
broad-spectrum biocide with excellent compatibility and stability, and low toxicity at in-use levels. At very low concentrations,
Kathon CG/ICP preservative eradicates bacteria, fungi, and yeast
cells for prolonged periods. It does not interfere with most
enzyme- or antibody-linked reactions or assay indicators. Furthermore, there are no disposal restrictions on this material when
it is used at recommended levels. The product as supplied easily
can be neutralized with 10% sodium bisulfite solution and
disposed of as nonhazardous waste. In most cases Kathon CG/
ICP can be the preservative of choice for applications in which
traditional antimicrobials have been used.
Features and Benefits
Page
Kathon CG/ICP preservative offers many performance advantages over other preservatives:
Introduction
1
Features and Benefits
1
Chemical Identification and Mechanism of Action
2
Applications and Use
3
Stability
3
Economical – Required concentrations generally are more costeffective than other commercial preservatives.
Efficacy Testing
5
Formaldehyde-free – Does not contain or generate formaldehyde.
Safety
5
Low use levels – Excellent microbe control at low concentrations.
Typical use levels are 6-15 ppm of the combined active components (0.04-0.10% of the product as supplied, volume/volume).
See Efficacy Testing for details.
Broad-spectrum antimicrobial activity – Controls the growth of
Gram-negative and Gram-positive bacteria, and fungi (molds
and yeasts).
Introduction
Many industrial, commercial, and research laboratories use a
variety of organic solutions every day: reagents, control solutions, buffer solutions, mobile phases, water baths, etc. Some of
these laboratories also offer organics-containing products for
sale. Many of these solutions are susceptible to contamination by
microorganisms.
Preservatives currently used to prevent microbe growth in these
solutions are less than ideal. Thimerosal is expensive, blocks some
chromogenic substrates, and, because it contains mercury, is
classified as toxic for disposal. Its use is banned in some countries,
including Japan. Sodium azide is primarily biostatic at levels
normally used, thus it might not kill all microorganisms in a
solution. It poisons some enzyme systems and, as with thimerosal, its use imposes restrictions on product disposal. In acidic
Low toxicity – Extensive testing shows Kathon CG/ICP preservative is safe to use at recommended levels.
Excellent compatibility – with common formulation ingredients.
Stable – Excellent stability over a wide pH range (2 to 8.5).
Easy to formulate – Supplied as an easy-to-use aqueous solution.
No side effects – Will not adversely affect a product’s physical
properties or performance.
Environmentally friendly – Does not persist in the environment;
breakdown products are essentially benign.
EPA-registered – Kathon CG/ICP preservative is registered with
the US EPA (EPA Reg. No. 707-166) for use in a wide variety of
applications.
T197912
©1997 Sigma-Aldrich Co.
Chemical Identification
and Mechanism of Action
The active components in Kathon CG/ICP preservative are two
isothiazolones, 2-methyl-4-isothiazolin-3-one and 5-chloro-2methyl-4-isothiazolin-3-one (Figure A, Table 1). The active
components have a unique mechanism of action that both
inhibits microbe growth and causes cell death. Within minutes
after contacting a microorganism, the active components penetrate the cell wall and inhibit specific enzymes in the cell,
inhibiting growth, macromolecule synthesis, and respiration,
and causing intracellular energy levels to decline rapidly (Figure
B). With energy production disrupted, the cell can no longer
synthesize chemicals for routine operation or repair. Ultimately
the cell dies. Some of the target enzymes are within the central
metabolic cycle of the cell, the Krebs cycle (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, succinate dehydrogenase, NADH dehydrogenase; see Figure C), affording microbes
little chance to develop resistance.
Because of the active molecules’ ability to penetrate the cell wall
Figure B.
Figure A. Active Components
in Kathon CG/ICP Preservative
Rapid Inhibition of Microbe Growth
(E. coli, ATCC Number 25922)
0.5
5-Chloro-2-methyl-4-isothiazolin-3-one
CAS No. 26172-55-4
Oppm Active
Components
Absorbance at 600nm
0.4
1ppm Active
Components
0.3
0.2
2.5ppm Active
Components
0.1
2-Methyl-4-isothiazolin-3-one
CAS No. 2682-20-4
0.0
-0.5
0.0
1.0
0.5
1.5
Hours From Time of Biocide Addition
796-0139
797-0018, 797-0019
Figure C. Action Points of Kathon CG/ICP
Preservative in the Krebs Cycle
Glucose
Table 1. Composition and Properties
of Kathon CG/ICP Preservative
Active Components
5-Chloro-2-methyl-4-isothiazolin-3-one
2-Methyl-4-isothiazolin-3-one
Inert Components
Magnesium salts (chloride, nitrate)
Water
Properties
Density
Specific Gravity
Viscosity (23°C)
Evaporation Rate
pH (1% aqueous solution)
Color
Odor
Typical Use Levels
Shelf Life (25°C)
Pyruvate
2H CO2
Acetyl-CoA
1.15%a
0.35% a
Citrate
Oxaloacetate
a
23.00%
75.50% a
10.0 lb/gallon
1.2 (g/cc)
5cps
<1 (Bu acetate = 1)
1.5-3.0b
light amber
mild aromatic
6-15ppm active
components (combined)
1 year
Malate
[cis-Aconitate]
KREBS
CYCLE
Isocitrate
CO2
α-Ketogluatrate
Fumarate
Succinate
Succinyl-CoA
2H
2H
CO2
2H
2H
NAD
Electron Transport Chain
Specific sites of Kathon biocide inhibition
796-0140
a
Typical values, not to be construed as specifications.
Investigators at Rohm and Haas Company have determined that the pH of
Kathon CG/ICP preservative drifts downward to a minimum of 1.7. The lower the
initial pH, the smaller the pH drift. There is no appreciable loss of active
components or magnesium salts due to this pH drift.
b
2
SUPELCO
Bulletin 912
rapidly and target only specific enzymes, Kathon CG/ICP preservative controls microbes at very low levels – 0.04% to 0.10%
(product as supplied, volume/volume). Low concentrations of
preservative which are immediately bacteriostatic require several hours to kill the cell, while higher concentrations exhibit
rapid microbiocidal effects (Figure D). This is a reflection of the
rate-driven nature of the damage process – higher concentrations of the active components both inflict damage at a greater
rate and overwhelm the cell’s repair functions faster than lower
concentrations.
Lethal damage can be measured in cells treated with Kathon
(E. coli, ATCC Number 25922)
101
% Survivors
2. Generation of a secondary electrophile by disulfide exchange and tautomerization to a thioacyl chloride.
3. Intracellular generation of free radicals as a result of the
severe metabolic disruption, which severely stresses the
cell’s radical defense mechanism.
Applications and Use
102
Kathon CG/ICP preservative has a shelf life of one year as
supplied, mixes easily with prepared organic solutions over a
wide pH range, and is not a health hazard at recommended use
levels.* The material is supplied in liquid form in a wide range of
volumes. These features make Kathon CG/ICP preservative the
excellent antimicrobial choice for all sizes of laboratories and
manufacturers of non-clinical reagents. Among its many applications, it is an ideal preservative for protecting reagents, control
solutions, buffers, and chromatographic mobile phases.
5ppm Active
Components
100
25ppm Active
Components
10 -1
Long-term protection in organic solutions is accomplished with
levels of the active components between 3ppm and 22.5ppm
(combined) (0.04-0.10% of the product as supplied). Typical use
levels fall in the range of 6-15ppm (combined) active components. It is usually advisable to treat a solution with a higher level
of preservative than the minimum effective dose (Table 2), to
extend the solution’s shelf life.
10 -2
100ppm Active
Components*
10 -3
0
15
30
45
60
75
90
Minutes After Biocide Addition
796-0142
*For demonstration only; 100ppm is very much above the recommended use range.
Figure E.
Pathways to Lethality
O
N
O
PROTEIN
HS
NCH3
CH3
CI
S
S
S
PROTEIN
Active Component
RSH
Disruption of
Metabolism
RS
RS
S
PROTEIN
NCH3
CI
O
CI
NCH3
S
OH
Death
PROTEIN
SH
NH2
The active components in Kathon CG/ICP preservative have a
history of successful use as preservatives. However, there are
some circumstances under which we advise potential users to
confirm biocide stability prior to large-scale use:
Amines – The presence of amines, particularly secondary amines,
has a deleterious effect on the stability of Kathon CG/ICP
preservative. The problem can be avoided by reducing the pH of
796-0144
SUPELCO
Since the components of organic solutions vary considerably,
and may affect the stability and efficacy of a preservative, we urge
commercial manufacturers to confirm the efficacy of Kathon CG/
ICP preservative in their own applications.
Temperature – As a general rule, a rise in temperature accelerates
the rate of degradation of chemicals, and the isothiazolones in
Kathon CG/ICP preservative are no exception. Temperatures in
excess of 55°C should be avoided during manufacturing an
organic solution once the preservative has been incorporated.
SH
Irreparable Damage
Some reagents are sold in concentrated form, and require a
limited shelf life after opening and dilution by the user. Reagents
such as these can incorporate higher levels of Kathon CG/ICP
preservative, but special labeling may be required to inform the
user of potential skin sensitization effects. For guidelines under
these circumstances, contact Supelco’s Technical Service chemists at 800-359-3041 or 814-359-3041.
Stability
O
Radical Cascade
Bulletin 912
1. Covalent modification via direct electrophilic attack.
These multiple pathways contribute to the ability of low levels of
the preservative to control microbe growth, and further reduce
the likelihood of resistance development.
Figure D. Microbiocidal Activity of Kathon
CG/ICP Preservative
CI
CG/ICP preservative by following the loss of protein thiols. There
is good correlation between the loss of viability and the loss of
these molecules. Data generated at Rohm and Haas Company
indicate that Kathon CG/ICP preservative operates via multiple
pathways (Figure E) that result in the lethal loss of protein thiols:
*Carefully follow the precautions for handling the concentrated product.
3
an amine-containing solution to less than 7, which will convert
the amines to their acid salts.
Reducing Agents – Some reducing agents are detrimental to
isothiazolone stability. In our experience, use levels of Kathon
CG/ICP preservative are stable in the presence of up to approximately 50ppm bisulfite (expressed as SO2).
pH – Kathon CG/ICP preservative is stable and effective over a
wide pH range: 2 to 8.5. At pH above 8.5 the stability of the
preservative is reduced.
Serum – The presence of strong nucleophiles can have a deleterious effect on Kathon CG/ICP preservative, but this reaction is
dependent on the concentration of the nucleophile, pH, and
other components of the solution.
Stability in Biological Buffers
Biological buffers such as Tris, TES, HEPES, etc. may contain
amines that are aggressive to Kathon CG/ICP preservative at pH
>7. Degradation of the preservative can be minimized by reducing the pH to 7 or lower, to protonate the free amines and convert
them to less aggressive acid salts.
Stability in Enzyme Conjugates
Kathon CG/ICP preservative is unaffected by the presence of
many enzymes. There was virtually no loss of the preservative’s
active components in horseradish peroxidase or alkaline phosphatase preparations treated with 250ppm preservative after six
months of storage at temperatures of -4°C to 18°C.
Stability in Lyophilization
Kathon CG/ICP preservative is not recommended for use in
lyophilized products. Data from several trials indicate that the
active components evaporate during the lyophilization process
and thus are not available for protecting the product on reconstitution.
Degradation Products
Kathon CG/ICP preservative may degrade in the presence of high
pH, high temperature, reducing agents, and aggressive nucleophiles, as discussed above. In each situation the degradation
pathway will be similar. Degradation products include small
organic acids (acidic, formic), carbon dioxide, chloride ion, and
elemental sulfur. None of these degradation products will have
significant impact on the environment.
Stability Testing
The level of active components in Kathon CG/ICP preservative,
as supplied and in formulated products, can be determined by
HPLC analysis. Contact Supelco for analytical methods (publication number 196904) and working standards.
Table 2 – Microorganisms Controlled with Kathon CG/
ICP Preservative: Minimum Effective Levels
(As Supplied and Combined Active Components)c
Organism (ATCCd Number)
Concentration (ppm)
Product As
Active
Supplied Components
Gram-Negative Bacteria
Achromobacter parvulus (4335)
Alcaligenes faecalis (8750)
Azotobacter vinelandii (12837)
Enterobacter aerogenes (3906)
Escherichia coli (11229)
Flavobacterium suaveolens (958)
Nitrobacter agilis (14123)
Proteus vulgaris (8427)
Pseudomonas aeruginosa (15442)
Pseudomonas cepacia (Gibraltar 165)
Pseudomonas fluorescens (13525)
Pseudomonas oleoverans (8062)
Salmonella typhosa (6539)
Shigella sonnei (9292)
150
150
300
600
300
300
50
150
300
300
150
2
2
5
5
8
9
0.1
5
5
0.75
2
5
5
2
Gram-Positive Bacteria
Bacillus cereus mycoides (R&H L5e)
Bacillus subtilis (R&H B2e)
Brevibacterium ammoniagenes (6871)
Cellulomonas sp. (21399)
Sarcina lutea (9341)
Staphylococcus aureus (6538)
Staphylococcus epidermidis (155)
Streptococcus pyrogenes (624)
Streptomyces albus (3004)
150
150
150
300
150
150
600
2
2
2
6
5
2
2
9
1
Fungi – Yeasts
Aspergillus foetidus (16878)
Aspergillus niger (9642)
600
Aspergillus oryzae (10196)
300
Aureobasidium (Pullularia)
pullulans (9348)
300
Candida albicans (yeast; 11651)
300
Chaetomium globosum (6205)
600
Cladosporium resinae (11274)
300
Gliocladium fimbriatum (QM7638)
600
Lentinus lepideus (12653)
Lenzites trabea (11539)
Mucor rouxii (R&H L5-83e)
300
Penicillium funiculosum (9644)
300
Penicillium variabile glaucum (USDAf) 150
Phoma herbarum pigmentivora (12569) 150
Pullularia (Aureobasidium)
pullulans (9348)
300
Rhizopus stolonifer (10404)
300
Rhototorula rubra (yeast; 9449)
150
Saccharomyces cerevisiae (yeast; 2601) 150
Trichophyton mentagrophytes
interdigitale (95332)
300
8
9
5
5
5
9
5
9
4
6
5
5
2
2
5
5
2
2
5
c
Bacteriostatic and fungistatic tests performed by serially diluting test compounds
in trypticase soy broth and 1:100 inoculation with 24-hour broth cultures of test
bacterium or yeast, or a fungal spore suspension prepared from 7 to 14 day culture
slants washed with 7mL deionized water. Minimum inhibitory concentration levels
determined visually after 2 days incubation at 37°C for bacteria or 7 days incubation
at 28-30°C for fungi.
d
American Type Culture Collection.
e
Rohm & Haas collection.
f
United States Department of Agriculture collection.
4
SUPELCO
Bulletin 912
Efficacy Testing for Commercial Products
The two tests described here will enable you to estimate the
ability of Kathon CG/ICP preservative to protect your product.
Use the Protection Testing Procedure to determine the level of
Kathon CG/ICP preservative needed to prevent microbial growth.
Two levels of the preservative generally are tested, with the levels
selected based on application needs, such as the time period over
which preservation is required (e.g., 1 week or 1 year), how harsh
the product environment is toward the preservative (e.g., pH,
amine or reducing agent content), and the type and level of
microbial contamination the product may encounter in manufacturing, storage, or use. Use the Preservative Stability Test to
determine the stability of Kathon CG/ICP preservative in your
product, to estimate how long the preservative will be effective.
Protection Testing Procedure
1. Treat samples of the product with the test level(s) of Kathon
CG/ICP preservative. Reserve an aliquot of unpreserved
product as a control, to demonstrate the ability of the
product to support microbial growth.
2. Inoculate the preservative-treated and control samples with
a high level of inoculum (106 – 107 total colony forming
units/mL of sample). Prepare the inoculum mixture from
among the organisms listed in Table 3 or, for a truer
evaluation of performance, use the microbe(s) most likely to
occur in your product (e.g., by inoculating samples with
naturally contaminated product).
3. Incubate the inoculated samples at 25°C for two weeks.
4. Determine microbe levels in the samples by streaking an
aliquot of each sample onto a tryptic soy broth agar (TSBA)
plate, incubating the plates at 30°C for one week, then
examining and rating them as indicated in Table 4.
5. Inoculate each sample a second time, incubate at 25°C for
another two weeks, and streak onto TSBA plates. Incubate
the plates at 30°C for one week, then examine and rate them
as described in step 4. A Kathon CG/ICP preservative level is
deemed effective if no microbial growth (<10 CFU/mL) is
detected after each inoculation.
Table 3. Inoculum for Evaluating
Protection by Kathon CG/ICP Preservative
Microorganism
Gram-Negative Bacteria
Pseudomonas aeruginosa
Pseudomonas cepacia
Gram-Positive Bacterium
Staphylococcus aureus
Yeast
Candida albicans
Fungus
Aspergillus niger
ATCC No.
15442
17765
6538
0
T (trace)
1+
2+
3+
4+
SUPELCO
Bulletin 912
Preservative Stability Test
This test typically is performed on uninoculated samples.
1. Treat samples of the product with the test level(s) of Kathon
CG/ICP preservative. Divide each sample into two vials.
Store one vial in an incubator at 25°C; store the second in a
dry bath at 45°C.
2. Analyze the samples at various time intervals after introducing the preservative, using the HPLC methods described in
Supelco publication 196904 (available on request). A typical
analysis schedule is: immediately after introduction of the
preservative, after two weeks and after four weeks at 45°C,
and after 4 weeks at 25°C. Other storage temperatures and
analysis schedules can be substituted to address specific
needs. Any significant loss of the active agents (i.e., >20%)
over the test period, under the conditions you choose, is a
clear indication that additional work should be done to
determine and/or improve stability.
Note that while the stability test results are an indicator of the
length of time Kathon CG/ICP preservative will effectively preserve the product, a specific shelf life cannot be extrapolated
from these limited results.
Safe Handling
Kathon CG/ICP preservative presents no toxicological problems
or health hazards at recommended use levels. However, the
following precautions must be observed when handling the
product as supplied.
Danger
As supplied, Kathon CG/ICP preservative is corrosive, and can
cause irreversible eye damage and skin burns. These effects may
not manifest themselves for several hours after contact. Kathon
CG/ICP preservative also can cause allergic skin reactions in
susceptible individuals. It may be harmful if swallowed or absorbed through the skin.
Do not get Kathon CG/ICP preservative in eyes, on skin, or on
clothing. Plant personnel handling the product as supplied
should wear splash goggles or a face shield, rubber gloves, and
an impervious apron and boots. Laboratory personnel should
wear a lab coat, safety glasses, and rubber gloves.
Avoid breathing the vapor or mist from the product as supplied,
and wash hands thoroughly after use, to prevent contamination
of food or drink. Take special care to avoid contaminating
surfaces that later might be contacted by unprotected personnel.
11651
6275
Table 4. Rating Streaked Plates for
Colony-Forming Units (CFU)
Score Assigned to Plate
To perform a simulated accelerated aging study, treat a second
set of samples with the preservative and place them in a dry bath
at 45°C. After four weeks, cool the samples to ambient temperature, then inoculate, incubate, plate, and examine, as described
in steps 2–4. Substitute other aging conditions to address
specific needs.
Estimated CFU/mL
<10
10 - <100
100 - <103
103 - <104
104 - <105
>105
Neutralizing Solution
Kathon CG/ICP preservative is quickly neutralized by solutions of
sodium bisulfate at acidic pH. To prepare a neutralizing solution,
dissolve 1lb sodium bisulfate in 1 gallon water (120g/L). The
solution should have a pH of 4.0-5.0 for maximum effectiveness.
If a neutralizing solution is permanently maintained, it should be
replaced weekly. Keep containers of neutralizing solution covered to reduce the release of sulfur dioxide and maintain solution
activity.
5
Tests indicate that Kathon CG/ICP preservative is completely
deactivated within 30 minutes when treated with at least 2
volume equivalents of neutralizing solution.
Note: Neutralizing solution should not be used to treat Kathon
CG/ICP preservative spilled on skin.
Cleanup of Equipment
Estimate the volume of Kathon CG/ICP preservative remaining in
a well-drained system, including vessels, lines, and pumps. Add
2 volumes of neutralizing solution for each estimated volume of
Kathon CG/ICP preservative, and circulate for 30 minutes. Drain
the solution to a chemical sewer and rinse the system with clean
water or detergent solution.
Material Safety Data Sheets
A material safety data sheet (MSDS) is available for this product.
This sheet contains pertinent information that you may need to
protect your employees and customers against any known
health or safety hazards associated with this product.
We recommend that you obtain copies of the MSDS from us
before using Kathon CG/ICP preservative in your facilities. We
also suggest that you contact your suppliers of other materials
recommended for use with Kathon CG/ICP preservative for
appropriate health and safety precautions before using them.
Ordering Information:
Kathon CG/ICP preservative is available in North America only.
For a comparable preservative available elsewhere, please
contact your Supelco distributor.
Kathon CG/ICP Preservative
Description
3 x 5mL
50mL
400mL
3.6 liters
15 liters
Cat. No.
500119
500127
500135
500143
500151
Microbe Cultures (for efficacy testing)
Contact: American Type Culture Collection
Rockville, MD 02060 USA
Customer Service/Ordering: 800-638-6597
Main Office: 301-881-2600
Trademarks
Kathon – Rohm and Haas Company
BULLETIN 912
For more information, or current prices, contact your nearest Supelco subsidiary listed below. To obtain further contact information, visit our website (www.sigma-aldrich.com), see the Supelco catalog, or contact
Supelco, Bellefonte, PA 16823-0048 USA.
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H
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