Quaternary ammonium
QUATERNARY AMMONIUM COMPOUNDS
International Programme on Chemical Safety
Poisons Information Monograph G022 (Group PIM)
Chemical
1. NAME
1.1 Substance
Quaternary ammonium compounds
1.2 Group
Benzalkonium Chloride
Benzethonium Chloride
Cetalkonium Chloride
Cetrimide
Cetrimonium Bromide
Cetylpyridinium Chloride
Glycidyl Trimethyl Ammonium Chloride
Stearalkonium Chloride
1.3 Synonyms
Group:
QAC
Cationic surfactant
Cationic detergent
Benzalkonium Chloride:
Alkyldimethylbenzylammonium chlorides;
Zephiran chloride (R);
Alkyldimethyl quaternary ammonium chlorides;
Hyamine 3500;
Benzethonium Chloride:
Diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride;
Hyamine 1622(R)
Cetalkonium Chloride:
Benzylhexadecyldimethylammonium chloride;
Cetyldimethylbenzylammonium chloride;
Hexadecyldimethylbenzylammonium chloride;
Triton K 12;
Cetrimide
Trimethyltetradecylammonium bromide + dodecyl and
hexadecyltrimethylammonium bromide
Cetrimonium Bromide:
Hexadecyltrimethylammonium bromide
Cetyltrimethylammonium bromide
Retarder LA
Cetylpyridinium Chloride:
1-Hexadecylpyridinium chloride;
CPC
Glycidyltrimethylammonium chloride:
(2,3-epoxypropyl) trimethylammonium chloride
Stearalkonium Chloride:
Benzyl dimethyl stearyl ammonium chloride;
Stearyldimethylbenzylammonium chloride;
1.4 Identification numbers
1.4.1 CAS number
Benzalkonium Chloride CAS 8001-54-5
1.4.2 Other numbers
Benzethonium Chloride CAS 121-54-0
Cetalkonium Chloride CAS 122-18-9
Cetrimide CAS 8044-71-1
Cetylpyridinium Chloride (anhydrous) CAS 123-03-5
Stearalkonium Chloride CAS 122-19-0
Cetrimonium Bromide CAS 57-09-0
2. SUMMARY
2.1 Main risk and target organs
Quaternary ammonium compounds can cause toxic effects by
all routes of exposure including inhalation, ingestion,
dermal application and irrigation of body cavities. Exposure
to diluted solutions can cause mild and self-limited
irritation. Concentrated solutions of quaternary ammonium
compounds are corrosive and can cause burns to the skin and
the mucous membranes. They can produce systemic toxicity due
to their curare-like properties. They can also cause allergic
reactions.
2.2 Summary of clinical effects
Mild to severe caustic burns of the skin and mucous
membranes can occur depending on the agent and the
concentration. Other signs may include: nausea, vomiting,
abdominal pain, anxiety, restlessness, coma, convulsions,
hypotension, cyanosis and apnoea due to respiratory muscle
paralysis; death may occur within 1 or 3 hours after
ingestion of concentrated solutions. Haemolysis and
methaemoglobinemia have been reported infrequently.
2.3 Diagnosis
Diagnosis depends essentially on prior history and
presentation of specific signs and symptoms. These may
include gastrointestinal symptoms, pain, burning sensation or
local ulceration depending on the site of exposure and the
concentration of the solution.
2.4 First-aid measures and management principles
First aid measures include eyes and skin decontamination
by immediate and prolonged irrigation with copious amounts of
water or saline.
Treatment is symptomatic and supportive. There is no specific
antidote.
Most ingestions of diluted solutions are benign, and mild
irritation is self-limited. Only clinical observation and
symptomatic treatment are usually necessary. Emesis and
gastric decontamination are not indicated.
After ingestion of concentrated solutions or large amounts,
monitor and support respiratory and cardiovascular function.
Early oesophagoscopy should be performed to assess the
severity of burns.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of substance
Quaternary ammonium compounds or cationic detergents are
synthetic derivatives of ammonium chloride (Arena et al.,
1964).
3.2 Chemical structure
General formula:
R1 R3
N. . . . . . . . . . X
R2 R4
Where R1-4 represent(s) alkyl or aryl substituents and X
represents a halogen, such as bromide, iodide, or chloride
(Dreisbach & Robertson, 1987; Budavari, 1996).
3.3 Physical properties
3.3.1 Colour
See 3.3.3
3.3.2 State/Form
See 3.3.3
3.3.3 Description
The quaternary ammonium compounds show a
variety of physical, chemical, and biological
properties and most compounds are soluble in water
miscible solvents.
Benzalkonium chloride occurs as a white or yellowish
white amorphous powder, a thick gel, or gelatinous
flakes. It is hygroscopic, soapy to the touch and has
a moldy aromatic odour and very bitter taste.
Practically insoluble in ether; and very soluble in
acetone, ethanol (95%), methanol, propanol and water
(Wade & Weller, 1994). Aqueous solutions of
benzalkonium chloride foam when shaken, have a low
surface tension and possess detergent and emulsifying
properties (Wade & Weller, 1994).
3.4 Hazardous characteristics
See 3.3.3.
4. USES/CIRCUMSTANCES OF POISONING
4.1 Uses
4.1.1 Uses
4.1.2 Description
Quaternary ammonium compounds are the active
ingredients in disinfectants and sanitizers for homes,
farms, hospitals, offices and public transportation
vehicles. They are also used as algaecides and
slimicides for swimming pools, industrial water
reservoirs, and farm ponds. They are included in the
last rinse in laundering by some hospitals, diaper
services and various institutions.
Quaternary ammonium compounds are used in a variety of
topical preparations in the treatment of minor
infections of the eye, mouth and throat and as
preservative in preparations for external use.
Cetrimide and benzalkonium chloride are used as
antiseptics for cleansing wounds, skin and burns
(Reynolds, 1996).
Quaternary ammonium compounds are also used as surface
active agents. These compounds are strongly adsorbed
by many substances. The positive charge imparts
antistatic properties to wool, cotton, and other
cellulosic fibres as well as certain synthetic fibres.
The compounds are used in hair conditioners, as
softeners for textiles and paper products, and as
pigment dispersers (Rietschel, 1995).
The concentration of quaternary ammonium compounds may
vary from 0.005 % to 25 % or more.
4.2 High risk circumstances
Accidental poisoning can occur when quaternary ammonium
compounds are stored in ordinary containers, and should be
stored in distinctive bottles (never in soft drink bottles)
in a safe place (Adelson & Sunshine, 1952).
Accidental poisoning has been infrequently described after
irrigation of body cavities (Gilchrist, 1979; Baraka et al.,
1980; Momblano et al., 1984).
Repeated occupational exposure after handling quaternary
ammonium compounds as powders or solutions can produce
sensitization (Shmunes & Levy, 1972; Oritiz-Frutos et al.,
1996; Placucci et al., 1996; Krogsrud & Larsen, 1997).
4.3 Occupationally exposed populations
Physicians, nurses, dentists, veterinarians,
pharmacists, and laboratory workers (Rietschel, 1995;
Placucci et al., 1996). Housework and cleaning
professionals.
5. ROUTES OF EXPOSURE
5.1 Oral
This is the most common route of entry (Vale & Meredith,
1985).
5.2 Inhalation
Quaternary ammonium compounds are commonly used in
inhalers and nasal sprays as a wetting agent and as a
preservative (Kuboyama et al., 1997; Beasley et al.,
1998).
5.3 Dermal
Accidental spillage of quaternary ammonium compounds on
skin and clothes is common because these compounds are
present in various household preparations eg, shampoos, dish
washing material, disinfectants, cleaning agents, and eye and
nasal preparations. Dermal absorption is very low except
through damaged skin (Nicola et al., 1997; Fisher & Stillman,
1972).
5.4 Eye
This route of entry may occur (Reynolds, 1996).
5.5 Parenteral
Haemolysis after intravenous injection of quaternary
ammonium compounds has been reported (Reynolds, 1996).
5.6 Others
Irrigation of body cavities:
- intra-uterine administration may cause haemolysis
(Reynolds, 1996)
- irrigation with cetrimide solutions in the treatment of
hydatid cysts has produced systemic toxicity (Gilchrist,
1979; Baraka et al., 1980; Momblano et al., 1984).
6. KINETICS
6.1 Absorption by route of exposure
Oral exposure:
Quaternary ammonium compounds are poorly absorbed by oral
route (Craig & Stitzel, 1994).
Dermal exposure:
Systemic effects from percutaneous absorption through intact
skin are rare (Wilson & Burr, 1975).
Parenteral:
Systemic absorption is possible. (Wilson & Burr, 1975).
6.2 Distribution by route of exposure
No data available
6.3 Biological half-life by route of exposure
No data available
6.4 Metabolism
No data available
6.5 Elimination and excretion
Poorly absorbed by oral route and therefore relatively
large amounts of the agent are eliminated in faeces (Craig &
Stitzel, 1994).
7. TOXICOLOGY
7.1 Mode of action
Local corrosive injury may result from the caustic
nature of these compounds.
Quaternary ammonium compounds have curare-like depolarising
properties (Van Berkel & de Wolff, 1988).
Benzalkonium chloride may cause bronchoconstriction by
releasing spasmogenic mediators from the mast cells within
the broncheal wall and stimulating cholinergic and
noncholinergic nerves to produce bronchoconstriction (Graf et
al., 1995; Hallen & Graf, 1995).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Human fatalities can occur following
an oral dose of 100 to 400 mg/kg or a
parenteral dose of 5 to 15 mg/kg (Ellenhorn
et al., 1997). According to Arena (1964), the
fatal dose of quaternary ammonium compounds
was estimated to be 1 to 3 g.
7.2.1.2 Children
No data available
7.2.2 Relevant animal data
LD50 of benzalkonium chloride varies according
to the species of animal and also depends on the route
of exposure (Wade & Weller, 1994).
Guinea pig, oral: 200 mg/kg
Mouse, ip 10 mg/kg
Mouse, iv 10 mg/kg
Mouse, oral 175 mg/kg
Mouse, sc 62 mg/kg
Rat, ip 14.5 mg/kg
Rat, iv 13.9 mg/kg
Rat, oral 240 mg/kg
Rat, sc 400 mg/kg
Rat, skin 1.56 g/kg
Nasal lesions were induced by the intranasal
administration of 0.5 to 0.10% of benzalkonium
chloride in rats (Kuboyama et al., 1997). Extensive
inner ear destruction occurred after a comparatively
short period of middle ear exposure to quaternary
ammonium compounds in guinea pigs (Aursnes,
1982).
7.2.3 Relevant in vitro data
Tanada et al. (1991) studied the adsorption
removal of benzalkonium chloride by granular activated
carbon for medical waste water treatment; they found
significant correlation between the amount of
benzalkonium chloride adsorbed in less than 1000 ppm
of equilibrium concentration and the micropore volume
of activated carbon.
7.2.4 Workplace standards
No data available
7.2.5 Acceptable daily in take (ADI) and other guideline
levels
No data available
7.3 Carcinogenicity
No data available
7.4 Teratogenicity
No data available
7.5 Mutagenicity
No data available
7.6 Interactions
Some studies indicate that the presence of alcohol
potentiates the lethal effect (Adelson & Sunshine,
1952).
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall interpretation of all toxicological analyses and
toxiclogical investigations
Specific laboratory determination for quaternary
ammonium compounds are not usually available or necessary for
the treatment of the patient. In severe cases, a complete
blood count (haemoglobin, red blood cells, leukocytes with
differential count), methaemoglobin determination, glucose,
electrolytes, renal and hepatic function and arterial blood
gases should be performed; chest X-ray and ECG should also be
obtained.
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Serious toxicity is unlikely with
benzalkonium chloride because of the low
concentrations found in most preparations (Vale &
Meredith, 1985). However, in higher concentrations,
mild to severe caustic burns can occur on the lips,
tongue, mouth, throat, hypopharynx, oesophagus,
stomach depending on the agent and concentration of
the solution (Chataigner et al., 1991; Chan, 1994).
They may be accompanied by hypersalivation, vomiting,
haematemesis, diarrhoea and confusion (van Berkel & de
Wolff, 1988). Metabolic acidosis may also occur
(Arena, 1964). In severe cases there may be
hypotension, shock, respiratory paralysis,
convulsions, coma and cardiorespiratory arrest
(Mathieu-Nolf et al., 1985). Fatalities have been
reported (Chataigner et al., 1991; Hitosugi et al.,
1998).
9.1.2 Inhalation
Prolongation of mucociliary clearance occurred,
shortly after application of benzalkonium chloride but
there was no detectable effect on nasal mucosal
function after two weeks of regular use (McMahon et
al., 1997).
Some studies state that benzalkonium chloride
containing nasal preparations can cause nasal
stiffness, nasal mucosa swelling, and
bronchoconstriction in asthmatic patients (Reynolds,
1996).
9.1.3 Skin exposure
Dermal burns have been reported with
concentrated cetrimide, including solutions of 12 and
17.5% (Mercer, 1983; Nicola et al., 1997).
1% solution of cetrimide produced necrosis when
applied to the dermis of a 77-year old woman (August,
1975).
Caustic action can occur with benzalkonium chloride
with preparation diluted 1:2,000 or 1:5,000, and with
dilution of at least 1:20,000 (Wilson & Burr,
1975).
9.1.4 Eye contact
Eye exposure may result in mild discomfort
(0.1% solution) to very serious corneal damage (10%
solution) depending on the agent and the
concentration. High concentrations of benzalkonium
chloride can cause ocular toxicity in human eyes
(Reynolds, 1996). Some investigations indicate that
quaternary ammonium compounds can cause ocular
inflammation (Swan, 1944; Rietschel, 1995).
9.1.5 Parenteral exposure
Intravenous administration of quaternary
ammonium compounds may cause haemolysis (Reynolds,
1996).
9.1.6 Other
Intra-uterine administration may cause
haemolysis (Reynolds, 1996).
Irrigation with cetrimide solutions in the treatment
of hydatid cysts has produced chemical peritonitis
(Gilchrist, 1979), methaemoglobinemia with cyanosis
(Baraka et al., 1980) and metabolic acidosis (Momblano
et al., 1984).
9.2 Chronic poisoning
9.2.1 Ingestion
Small amounts of quaternary ammonium compounds
are ingested from dish washing detergents used in the
kitchen. Repeated measurements and calculations
indicate an average oral intake of surfactants of
about 100 mg/man/year, this level does not cause
toxicity (Gloxhuber et al., 1974).
9.2.2 Inhalation
Occupational asthma has been reported after
prolonged exposure to benzalkonium chloride (Bernstein
et al., 1994).
9.2.3 Skin exposure
People exposed to quaternary ammonium compounds
can exhibit irritant contact dermatitis, particularly
with benzalkonium chloride (Shmunes & Levy, 1972;
Oritiz-Frutos et al., 1996; Placucci et al., 1996;
Krogsrud & Larsen, 1997).
9.2.4 Eye contact
No data available
9.2.5 Parenteral exposure
No data available
9.2.6 Others
No data available
9.3 Course, prognosis, cause of death
Poisonings due to diluted solutions usually are mild and
self-limited.
In high concentrations, mild to severe caustic burns can
occur. If there is improvement in symptoms after initial
treatment then the patient is likely to survive if adequate
treatment is continued. Death in case of heavy exposure is
usually related to cardiorespiratory collapse,
bronchoconstriction or acute pulmonary oedema (Ellenhorn,
1997). In severe cases death may occur within 1 or 3 hours
after ingestion (Chataigner et al., 1991; Hitosugi et al.,
1998).
9.4 Systemic description of clinical effects
9.4.1 Cardiovascular
In acute cases hypotension and cardiac arrest
can occur (Mathieu-Nolf et al., 1985; Nicola et al.,
1997).
9.4.2 Respiratory
In acute cases pulmonary oedema resulting from
aspiration, dyspnea and cyanosis due to paralysis of
the respiratory muscles, bronchoconstriction, cough
can occur (Adelson & Sunshine, 1952; Chataigner et
al., 1991; Chan, 1994).
Several cases of bronchoconstriction resulting from
nebulised benzalkonium chloride as a preservative in
corticosteroid preparations have been reported
(Beasley et al., 1986; Beasley et al., 1987; Beasley
et al., 1998)
Occupational asthma has been reported after prolonged
exposure to benzalkonium chloride (Bernstein et al.,
1994).
9.4.3 Neurological
9.4.3.1 Central nervous system
In acute exposure, central nervous
depression progressing to coma may occur and
can be preceded by excitement and convulsions
(Gloxhuber et al., 1974; Reynolds,
1996).
9.4.3.2 Peripheral nervous system
No data available
9.4.3.3 Autonomic nervous system
No data available
9.4.3.4 Skeletal and smooth muscle
Quaternary ammonium compounds have
depolarising muscle relaxant properties and
can produce paralysis of the respiratory
muscles (Reynolds, 1996).
9.4.4 Gastrointestinal
In acute exposure vomiting, diarrhoea, and
abdominal pain may occur. Ingestion of concentrated
solution may produce local ulceration on lips, mouth,
pharynx, oesophagus, stomach and intestines (Vale &
Meredith, 1985; Chataigner et al., 1991).
9.4.5 Hepatic
In acute exposure hepatic necrosis and elevated
liver function tests have been reported (Adelson &
Sunshine, 1952).
9.4.6 Acid-base
In acute and severe cases metabolic acidosis
has been reported (Adelson & Sunshine, 1952; Momblano
et al., 1984).
9.4.7 Hematological
Haemolysis and methaemoglobinaemia have been
reported in a woman following irrigation with 0.1%
cetrimide in the treatment of hydatid cysts (Baraka et
al., 1980).
Intra-uterine administration of quaternary ammonium
compounds may cause haemolysis (Reynolds,
1996).
10. MANAGEMENT
10.1 General principles
Treatment is symptomatic and supportive. There is no
specific antidote.
Most ingestions of diluted solutions are benign, mild
irritation is self-limited and only clinical observation and
symptomatic treatment are usually necessary. Gastric
decontamination is not indicated.
10.2 Life-supportive procedures and symptomatic treatment
When clinically indicated, expansion of circulatory
blood volume, vasoactive drugs, supplemental oxygen,
artificial ventilation and treatment of seizures should be
promptly instituted.
Endoscopy should be performed as soon as possible and within
24 hours.
Symptomatic treatment may include bronchodilators,
antiemetics and methaemoglobinemia treatment when
indicated.
Treatment of contact dermatitis and other injuries should be
performed.
10.3 Decontamination
Ingestion
A significant ingestion is unlikely if spontaneous emesis has
already occurred. Do not induce emesis or perform gastric
lavage because of the risk for corrosive injury and
production of foam (AACT & EAPCCT, 1997).
For significant ingestions, consideration may be given to
aspirating the stomach contents; however, the risk of
gastrointestinal injury could be further compromised by this
procedure. If undertaken, this should be performed cautiously
through a thin, flexible nasogastric tube.
In severe cases, activated charcoal may be considered;
however, although there are in vitro data demonstrating the
adsorption of benzalkonium chloride by activated charcoal
(Tanada et al., 1991), its effective use in the medical
management of severe quaternary ammonium poisonings has not
been confirmed. Furthermore this may mask endoscopy
evaluation.
Eyes and skin
Irrigate with copious amounts of tepid water or saline.
Consult an opthalmologist if eye pain persists or if there is
significant corneal injury on fluorescein examination (Olson,
1999).
10.4 Enhanced elimination
Elimination methods have not been shown to be effective
(Olson, 1999).
10.5 Antidote treatment
10.5.1 Adults
There is no specific antidote
10.5.2 Children
There is no specific antidote
10.6 Management discussion
For significant ingestions, consideration may be given
to aspirating the stomach contents; however, the risk of
gastrointestinal injury could be further compromised by this
procedure. If undertaken, this should be performed cautiously
through a thin, flexible nasogastric tube.
Although there are in vitro data demonstrating the adsorption
of benzalkonium chloride by activated charcoal (Tanada et
al., 1991), its effective use in the medical management of
severe quaternary ammonium poisonings has not been confirmed.
Furthermore this may mask endoscopy evaluation.
11. ILLUSTRATIVE CASES
11.1 Case reports from the literature
Child, oral ingestion
Two and a half-month-old twins were mistakenly given an 11%
solution of benzalkonium chloride orally for candidiasis.
They had been prescribed a 1:50,000 dilution. Within 24 hours
both children had developed irritability, fever, anorexia,
dehydration, cough, circumoral erythema, drooling and
numerous oral and pharyngeal lesions. One twin developed
chemical pneumonitis. Both twins were given IV fluids and
antibiotic support and recovered (Nicola et al., 1997).
Children, oral ingestion
Five normal newborn breast fed babies were accidentally fed a
dilute antiseptic solution (chlorhexidine 0.05% with
cetrimide 1%) in place of sterile water, developing caustic
burns of the lips, mouth and tongue within minutes; one baby
became quite severely ill due to acute pulmonary oedema, but
all survived without sequele (Mucklow, 1988).
Adult, oral ingestion
While in a tavern, a 45-year-old woman, was served a drink
made up of 3/4 of an ounce of whisky and 2.5 ounces of
supposed ginger ale (but it was hyamine 2389). She swallowed
a mouthful (approximately 1 ounce) and immediately complained
of feeling ill and vomited. She died approximately 25 minutes
after ingesting the drink (Adelson & Sunshine, 1952).
Adults, skin exposure
Two physicians were reported to have become sensitized to
benzalkonium chloride from handling instruments soaked in the
disinfectant for cold sterilization. They developed allergic
conjunctivitis from the presence of benzalkonium chloride in
ophthalmic solutions (Fisher & Stillman, 1972; Rietschel,
1995).
Adult, skin exposure
A physician developed a severe allergic conjunctivitis from
an ophthalmic solution containing benzalkonium chloride. The
conjunctivitis became worse with the use of another
preparation containing this preservative (Fisher & Stillman,
1972).
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
Quaternary ammonium compounds should not be stored in
soft drink containers and should be stored in specific
bottles and in a safe place. While handling these compounds
care should be necessary.
12.2 Other
No data available
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14. AUTHOR(S), REVIEWER(S), ADDRESS(ES), DATE
Author: Satish Kumar Arugonda,
School of Pharmacy,
University of Otago,
Dunedin, New Zealand.
Date: 5th October,1998.
Peer review group: N Besbelli, D Cobaugh, L Fruchtengarten, B
Groszek, MO Rambourg-Schepens (coordinator), W Temple.
Date: July, 1999