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Propylene glycol

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Hazardous characteristics
4. USES
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstance of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY
   7.1 Mode of Action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake (ADI)
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
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 toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central Nervous System (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ears, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Others
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    PROPYLENE GLYCOL

    International Programme on Chemical Safety
    Poisons Information Monograph 443
    Chemical

    1.  NAME

        1.1  Substance

             Propylene glycol

        1.2  Group

             Alcohol

        1.3  Synonyms

             1.2-propylene glycol;
             Alpha-beta-dioxypropan;
             alpha-propylene glycol;
             dowfrost;
             glicol propilenico;
             glikol propylenowy;
             methylethylene glycol;
             Methylglycol;
             monopropylene glycol;
             PG 12;
             propandiol-1.2;
             propane-1.2-diol;
             propilenoglicol;
             propylene glycol USP;
             Propylenglykol;
             Sirlene;
             solar winter ban;
             trimethyl glycol;

        1.4  Identification numbers

             1.4.1  CAS number

                    57-55-6

             1.4.2  Other numbers

                    NIOSH TY 2000000

        1.5  Main brand names, main trade names

             To be completed by each centre.

        1.6  Main manufacturers, main importers

             To be completed by each centre.

    2.  SUMMARY

        2.1  Main risks and target organs

             Relatively non-toxic in acute exposure.  It is primarily
             a CNS depressant in high doses.  On rare occasions stupor and
             unconsciousness occurred after parenteral administration). 
             After chronic exposure, seizures in man and renal and hepatic
             damage in animals have been described.

        2.2  Summary of clinical effects

             Ocular exposure causes mild ocular irritation with
             hyperaemia; chronic or prolonged skin and mucous membranes
             exposure may also cause irritation; gastrointestinal
             disturbances, nausea and vomiting have been observed after
             ingestion.
    
             Rapid intravenous injection of preparations of drugs
             containing propylene glycol as a solvent (in significant
             amounts) may cause unconsciousness, arrhythmias and even
             cardiac arrest.
    
             Chronic exposure may cause lactic acidosis, hypoglycaemia,
             stupor, and seizures; renal and hepatic damage have been
             observed only in animals.

        2.3  Diagnosis

             Is based on history of exposure (ingestion, inhalation
             or parenteral administration) and irritation and/or CNS
             effects.
    
             Symptomatology is dose-dependent, ranging from drowsiness to
             stupor, deep unconsciousness, and coma.  Other signs include
             hyperosmolality of serum, lactic acidosis, and hypoglycaemia
             (Martin & Finberg, 1970).
    
             The serum concentration may be measured by gas liquid
             chromatography but it is not helpful clinically.  There is a
             direct relationship between the serum level of propylene
             glycol and the osmolar gap (mg/dl = 84.6 + 78  osmolar gap
             in mOsm/kg).
    
             Some procedures of ethylene glycol measurement in the
             biological fluids also measure propylene glycol. This may
             lead to misdiagnosis of the severe condition of ethylene
             glycol poisoning in a patient who has been given drugs

             containing, as a solvent, the relatively innocuous propylene
             glycol.
    
             Acid-based parameters, glycaemia, serum electrolytes, serum
             lactates and osmolality should be monitored.

        2.4  First-aid measures and management principles

             Considerable toxicity is unlikely after an acute
             exposure, with the exception of rare but dramatic arrhythmias
             including cardiac arrest after rapid i.v. injection of drugs
             containing large amounts of propylene glycol solvent.  In
             such cases, regular acute cardiological monitoring should be
             undertaken.  Other treatment should be supportive.
    
             Ethanol or 4-methylpyrazole administration are absolutely not
             needed.
    
             Metabolic acidosis should be monitored, especially after
             prolonged exposure.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Synthetic, manufactured by various ways, but recently by
             hydration of propylene oxide (Faith, Keyes & Clark's
             Industrial Chemicals, 1975).

        3.2  Chemical structure

             1,2 propanediol: CH3CHOHCH2OH
    
             Gross formula:C3H8O2

        3.3  Physical properties

             3.3.1  Colour

                    Colourless

             3.3.2  State/Form

                    Liquid

             3.3.3  Description

                    Liquid at room temperature, thick and sweetish
                    like glycerol, colourless and odourless,
    
                    Boiling point:  188.2C
                    Freezing point: -39C
                    Flash point: 210 F (= 99C)

                    Autoignition temperature:  700C
                    Relative vapour density:  2.62
                    Vapour pressure:  0.08mm at 20C
                    Miscible with water and ethanol in all proportions,
                    soluble in 12 parts of ether, miscible with acetone,
                    chloroform and some essential oils.
                    Explosive limits:  not available
                    pH:  not available
                    viscosity: not available

        3.4  Hazardous characteristics

             Combustible and in the form of vapour explosive when
             exposed to heat or flame.  Combustion products are carbon
             dioxide and water but when heated to decomposition it
             produces acrid smoke and irritating fumes (Sax, 1989).
    
             No significantly dangerous substances are produced after
             contact with light, humidity or commonly available chemicals. 
             Propylene glycol may react with hydrofluoric acid + nitric
             acid + silver nitrate to form the explosive silver fulminate
             (Sax, 1989).

    4.  USES

        4.1  Uses

             4.1.1  Uses

             4.1.2  Description

                    Non-toxic antifreeze in breweries and dairies;
                    brake fluid; substitute for ethylene glycol and
                    glycerol; manufacture of synthetic resins.  Added to
                    foods as a humefactant or solvent for artificial
                    colouring or flavouring agents.  Is a component of
                    cosmetic preparations.
    
                    Solvent in many pharmaceuticals, including oral,
                    injectable or topical formulations (Smolinske et al,
                    1987).
    
                    Many oral and parenteral drug preparations contain
                    propylene glycol in significant amounts as a
                    solvent:
    
                    Trade Name              Amount of Propylene Glycol,
                                            W/v-mg/ml
    
                    Amidate                 362.6mg
                    Apresoline              103.6mg
                    Bactrim                 414.4mg

                    Berocca PN              259mg
                    Brevibloc               25% v/v
                    Dilantin                414.4mg
                    Dramamine               518mg
                    Dramocen                518mg
                    Embolex                 460mg
                    Hydrocortisone          800-900mg
                    Konakion                207mg
                    Lanoxin & Lanoxin Ped.  414.4mg
                    Librium                 207mg
                    Loxitane                725.2mg
                    Luminal Sodium          702.4mg
                    MVC9 Plus               3108mg
                    MVI-123                 108mg
                    Nitro-BID               45mg
                    Nembutal                414.4mg
                    Nitrostat               3108mg
                    Nitroglycerin           518mg
                    Pentobarbital Sodium    414.4mg
                    Phenobarbital Sodium    702.4mg
                    Phenytoin Sodium        3108mg or 414.4mg
                    Septra                  414.4mg
                    Tridil                  3108mg
                    Valium                  414.4mg
    
                    There is no evidence that propylene glycol has been a
                    substance of abuse. Its actions are similar to those
                    of ethanol (thrice weaker) although it is only
                    one-0third as potent; propylene glycol could be used
                    as an ethanol substitute if it becomes more readily
                    available or cheaper.

        4.2  High risk circumstance of poisoning

             Intoxication similar to that caused by ethanol might be
             expected if large amounts of propylene glycol were ingested. 
             In reported cases toxic signs appeared only after repeated
             doses of propylene glycol, used as a solvent in medicines,
             were ingested in small amounts or repeatedly applied to the
             skin (Glasgow et al, 1983; Martin & Finberg, 1970).
    
             Acute toxicity following i.v. injection of drugs dissolved in
             significant amounts of propylene glycol has been reported
             (Hegarty & Dundee, 1977; Demey et al, 1988).

        4.3  Occupationally exposed populations

             Workers of chemical plants producing propylene glycol;
             using it as a raw material in chemical processes; or as a
             solvent in the manufacture of drugs, cosmetics, and household
             chemicals.
    

             Estimated acceptable daily intake: up to 25 mg propylene
             glycol per kg body weight (Seventeeth Report of the FAO/WHO
             Expert Committee, 1974).

    5.  ROUTES OF ENTRY

        5.1  Oral

             Several oral drug formulations contain propylene glycol
             as a solvent but may cause poisoning only after repeated
             ingestion (Arulanantham & Genel, 1978; Martin & Finberg,
             1970).

        5.2  Inhalation

             Not relevant.

        5.3  Dermal

             When applied as a topical formulation it may
             occasionally irritate the skin and cause hypersensitivity
             reactions (Fisher,1978; Adams & Maibach, 1985).
    
             Mild lactic acidosis has been reported in an infant treated
             topically with a cream for burns containing propylene glycol
             (Yu et al, 1985).  Serum hyperosmolality occurred in patients
             with burns when large areas of damaged skin were covered with
             sulfadiazine cream containing propylene glycol (Kulich et al,
             1980; Fligner et al, 1985).

        5.4  Eye

             Eye irritation without further sequelae has been
             reported (Reinhardt et al, 1978).

        5.5  Parenteral

             Generalized symptoms and signs of propylene glycol
             poisoning were reported after intramuscular or intravenous
             injections of drugs containing significant amounts of
             propylene glycol as a solvent. The drugs involved were
             solutions of benzodiazepines (Hegarty & Dundee, 1977),
             nitroglycerin (Demey et al, 1984; Demey et al, 1988), and
             phenytoin (Karliner, 1967; Voigt, 1968).

        5.6  Other

             Ear: There is a risk that instillation of propylene
             glycol into the middle ear in patients with defects of the
             tympanic membrane may cause cochlear toxicity, according to
             animal data (Morizono et al, 1980).

    6.  KINETICS

        6.1  Absorption by route of exposure

             Oral: As with ethanol, absorption occurs rapidly. The
             peak plasma level occurs within one hour after oral
             administration (Yu et al, 1985).
    
             Inhalation:  Not relevant.
    
             Dermal: Absorption may be rapid:  in an infant with burns who
             received cream containing propylene glycol for ten
             consecutive days, cardiopulmonary arrest occurred one hour
             after the cream had been re-administered after a two-day
             drug-free interval (Fligner et al, 1985).
    
             Eye: Immediate local irritation immediate; systemic
             absorption not reported.
    
             Parenteral:  Absorption is immediate.

        6.2  Distribution by route of exposure

             After oral administration, the mean volume of
             distribution is 0.58 (range 0.41-0.77) L/kg (Yu et al,
             1985).
    
             Inhalation:  Not relevant
    
             Dermal:  Not available
    
             Eye:  Not relevant
    
             After intravenous infusion, the volume of distribution is
             36-62L (Speth et al, 1987).

        6.3  Biological half-life by route of exposure

             Oral:  Mean half-life in premature infants was 19.3
             hours (range 108-30.5) (Glasgow et al, 1983), no data
             available in adults.
    
             Dermal:  16.9 hours in an8-month-old infant (Fligner et al,
             1985).
    
             Parenteral:  2.4-5.2 hours [17, 22] 1.4-3.3 hours (mean
             2.3+/-07h) (Speth et al, 1987).

        6.4  Metabolism

             Propylene glycol undergoes metabolic oxidation to
             pyruvic acid,acetic acid, lactic acid, and propionaldehyde
             (Miller & Bazzano, 1965; Ruddick, 1972).

        6.5  Elimination by route of exposure

             The route of elimination depends on the dose
             administered, not on the route of exposure.  It is mainly
             excreted in the urine as the glucuronide conjugate but 12-45%
             is excreted unchanged (Ruddick, 1972).  Renal clearance
             decreases with dose (390 mL/min/1.73 m2 at a dose of 5 g/day,
             but only 144 mL/min/1.73 m2 at a dose of 21 g/day) (Speth et
             al, 1987).

    7.  TOXICOLOGY

        7.1  Mode of Action

             The toxicity of propylene glycol is mainly due to the
             parent compound and not to its metabolites. Propylene glycol
             has an irritatant effect on direct contact with eyes, mucous
             membranes and possibly after prolonged contact with skin.
    
             Propylene glycol causes CNS depression similar to that caused
             by ethanol but it is only one-third as potent. Cardiotoxic
             effects include arrhythmias and cardiac arrest.  Renal and
             hepatic damage has been reported in animals (Seidenfeld &
             Hanzlik, 1932), but there are no clinical data confirming
             this effect.
    
             The metabolites are relatively non-toxic:  lactic acidosis
             and serum hyperosmolality may occur.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             The estimated acceptable daily
                             intake is 25  mg/kg (17th Report of the Joint
                             FAO/WHO Expert Committee on Food Additives,
                             1974).  Single oral doses of 1.5 g/kg (used
                             in the treatment of glaucoma) caused
                             dizziness (Goldsmith, 1978).  Lactic acidosis
                             and coma with hyperosmolality were seen in an
                             elderly patient with a propylene glycol serum
                             concentration of 910 mg/dl after IV
                             administration of nitroglycerin dissolved in 
                             propylene glycol (Demey et al,
                             1984).

                    7.2.1.2  Children

                             Doses of 60 ml of propylene glycol
                             caused stupor in infants (Martin & Finberg,
                             1970).  Administration of 3 g/day in a
                             premature infant weighing 800 g resulted in
                             hyperosmolality; the serum concentration of
                             propylene glycol was 930  mg/dl (Glasgow et
                             al, 1983).

             7.2.2  Relevant animal data

                    LD50  oral, rat = 20g/kg 
                    iv, rat = 68g/kg
                    oral, dog = 22g/kg (Sax, 1989)

             7.2.3  Relevant in vitro data

             7.2.4  Workplace standards

                    No ACG/IH TLV-TWA, OSHA PEL, or IDLH values
                    have been established for this agent (ACGIH, 1989;
                    NIOSH, 1985).

             7.2.5  Acceptable daily intake (ADI)

                    25 mg/kg as food additive (17th Report of the
                    Joint FAO/WHO Expert Committee on Food Additives,
                    1974).

        7.3  Carcinogenicity

             No data available.

        7.4  Teratogenicity

             No teratogenic effects were seen in the rabbit
             (Schumacher et al, 1968).

        7.5  Mutagenicity

             No data available.

        7.6  Interactions

             No data available.

    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 
             toxicological investigations

             Sample collection
    
             To be filled by the Analytical Group.
    
             Biomedical analysis
    
             Gasometric blood measurements (pH and bicarbonates) are
             necessary, serum osmolality, glucose, BUN, serum lactate and
             electrolytes may be helpful. If the patient is vomiting,
             serum electrolytes should be monitored. 
    
             Toxicological analysis
    
             To be filled by the Analytical Group.  Its attention is
             called to the false positive results of colorimetric tests
             for Ethylene glycol if Propylene glycol (e.g. administered as
             drug solvent)  is present in the blood (Robinson et al,
             1983).
    

             Other investigations
    
             No data available

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Symptomatology is dose-dependent, ranging from
                    drowsiness to stupor, deep unconsciousness, and
                    coma.
    
                    Other signs include hyperosmolality of serum, lactic
                    acidosis, and hypoglycaemia (Martin & Finberg,
                    1970).

             9.1.2  Inhalation

                    Not relevant.

             9.1.3  Skin exposure

                    Absorption through intact skin is minimal, but
                    may become important in infants with skin lesions
                    (Fligner  et al., 1985).
    
                    Local irritation and hypersensitivity reactions may
                    occur (Fisher, 1978; Adams & Maibach, 1985).  Systemic
                    effects are less marked than after oral ingestion and
                    are more likely after repeated administration.
                    However, there is evidence that systemic effects may
                    immediately follow local application (Fligner et al.,
                    1985).

             9.1.4  Eye contact

                    Eye irritation has been reported (Reinhardt et
                    al, 1978).

             9.1.5  Parenteral exposure

                    Toxic effects have been reported after IV
                    injection or instillation of drugs dissolved in
                    propylene glycol. Propylene glycol may cause
                    hypotension; bradycardia, and  QRS and T abnormalities
                    on the ECG; arrhythmia and cardiac arrest; and serum
                    hyperosmolality and lactic acidosis (Karliner, 1967;
                    Demey et al, 1988).  Haemolysis may occur after i.v.
                    administration (Demey et al, 1988).

             9.1.6  Other

                    Not relevant 

        9.2 Chronic poisoning

             9.2.1  Ingestion

                    Most of the reported cases are of sub-acute
                    poisoning, since toxicity was observed usually after
                    several days of of administration of propylene glycol
                    as a solvent in  oral, parenteral or topical
                    formulations of drugs.
    
                    Grand mal seizures occurred in an 11-year old boy
                    after taking a medication containing propylene glycol
                    over one year (Arulanantham & Genel, 1978).  CNS
                    depression has been reported in patients taking
                    phenytoin dissolved in propylene glycol; this did not
                    recur when the solvent had been changed (Yu et al,
                    1985).
    
                    Sinus arrhythmia, tachypnea, tachycardia, stupor and
                    hypoglycaemia occurred in a 15-month-old boy who
                    received 7.5 ml of propylene glycol as a solvent in
                    vitamin C syrup (Martin & Finberg, 1970).

             9.2.2  Inhalation

                    Not relevant

             9.2.3  Skin exposure

                    Most of the reported cases are of sub-acute
                    poisoning, since toxicity was observed usually after
                    several days of of administration of propylene glycol
                    as a solvent in oral, parenteral or topical
                    formulations of drugs. 
    
                    Local irritation and hypersensitivity reactions may
                    occur (Trancik & Maibach, 1982). Serum hyperosmolality
                    may also occur after percutaneous absorption (Kulich
                    et al, 1980; Bekeris et al, 1979).

             9.2.4  Eye contact

                    Eye irritation is an acute, not a chronic
                    effect (Reinhardt et al, 1978).

             9.2.5  Parenteral exposure

                    Most of the reported cases are of sub-acute
                    poisoning, since toxicity was observed usually after
                    several days of of administration of propylene glycol
                    as a solvent in oral, parenteral or topical
                    formulations of drugs.  Seizures believed to be due to
                    propylene glycol solvent were seen in infants
                    receiving parenteral multivitamins (MacDonald et al,
                    1987).  Lactic acidosis and hyperosmolality have been
                    reported (Glasgow et al, 1983;  Demey et al, 1984;
                    Demey et al, 1988).

             9.2.6  Other

                    Not relevant.

        9.3  Course, prognosis, cause of death

             The course of poisoning is usually benign but ingestion
             of large amounts may be as dangerous as severe ethanol
             intoxication.  Large doses ingested or injected may cause
             severe arrhythmia, including cardiac arrest, resulting in
             sudden death (Karliner, 1967; Russell & Bousvaros, 1968;
             Voigt,1968).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Acute:  Rapid intravenous injection may cause
                    arrhythmia, even cardiac arrest.  Bradycardia, QRS and
                    T abnormalities may occur (Gellerman & Martinez, 1967;
                    Demey et al, 1988).
    
                    Chronic:  No data available.

             9.4.2  Respiratory

                    Acute:  No adverse respiratory effects have
                    been reported but in extremely severe intoxication
                    respiratory disturbances may occur due to CNS
                    depression.
    
                    Chronic:  No data available.

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System (CNS)

                             Acute: Depression of the CNS may
                             appear as drowsiness, stupor, and rarely as
                             coma (Martin & Finberg, 1970; Demey et al,

                             1984;  Demey et al, 1988; Yu et al, 1985;
                             Goldsmith, 1978). 
    
                             Chronic:  Seizures have been reported
                             (Arulanantham & Genel, 1978; Mac Donald et
                             al, 1987).

                    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

                             Hypotonia has been reported.

             9.4.4  Gastrointestinal

                    No data available.

             9.4.5  Hepatic

                    Acute: Hepatotoxicity has been observed in
                    animals (Seidenfeld & Hanzlik, 1932).
    
                    Chronic: No data available.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Acute: Pre-existing renal failure
                             aggravates propylene glycol poisoning and
                             worsens lactic acidosis (Cate & Hendrick,
                             1980).  Renal toxicity has been reported in
                             animals (Seidenfeld & Hanzlik, 1932) but have
                             not been reported clinically.
    
                             Chronic:  No data available.

                    9.4.6.2  Others

                             No data available.

             9.4.7  Endocrine and reproductive systems

                    No data available.

             9.4.8  Dermatological

                    Acute:  No data available.
    
                    Chronic:  Irritation of skin and mucous membranes is
                    usually negligible but may become marked especially if
                    propylene glycol is incorporated into impermeable pads
                    (Trancik & Maibach, 1982).  Hypersensitivity reactions
                    have been reported (Hannuksela & Forstrom, 1978; Unger
                    & Sklaroff, 1967).

             9.4.9  Eye, ears, nose, throat: local effects

                    Acute:  Local irritation of the eye may occur
                    without any serious sequelae (Reinhardt et al,
                    1978).
    
                    Administration of drugs with propylene glycol as a
                    solvent into the ear should be avoided in patients
                    with defects in the ear drum since it may cause
                    cochlear toxicity (Morizono et al, 1980).
    
                    Chronic:  No data available.

             9.4.10 Haematological

                    Acute:  Rapid intravenous injection of drugs
                    dissolved in propylene glycol may cause haemolysis
                    (Demey et al, 1984).
    
                    Chronic: No data available.

             9.4.11 Immunological

                    In vitro, 1% propylene glycol is cytotoxic to
                    natural killer cells (Denning & Webster,
                    1987).

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Acute:  Lactic acidosis, with an
                             increase of serum lactate up to 15.5 mEq/L
                             [43] occurs when large doses are absorbed
                             regardless of the route of exposure (Demey et
                             al, 1984; Demey et al, 1988; Fligner et al,
                             1985; Cate & Hendrick, 1980;  Kelner &
                             Bailey, 1985).
    
                             Chronic:  No data available.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No data available.

                    9.4.12.3 Others

                             Hyperosmolality occurs after marked
                             absorption of propylene glycol regardless of
                             the route of exposure (Glasgow et al, 1983;
                             Demey et al, 1988; Kulich et al, 1980;
                             Bekeris et al, 1979; Fligner et al,
                             1985).
    
                             There is a good correlation between the
                             osmolar gap and the serum propylene glycol
                             concentration. An estimation of the serum
                             propylene glycol concentration may be
                             calculated from the osmolar gap. 1 g of
                             propylene glycol has an osmotic effect of
                             13.1 mOsm/L. In a case reported by Fligner et
                             al (1985) the following correlation between
                             osmolality and propylene glycol concentration
                             was found: 
    
                             propylene glycol level =84.6 + (78  osmolar
                             gap in mOsm/kg H20). 
    
                             Hypoglycaemia has been described in a little
                             boy after treatment with an oral vitamin C
                             preparation dissolved in propylene glycol
                             (Martin & Finberg, 1970).  No effects on the
                             reproductive system have been
                             reported.

             9.4.13 Allergic reactions

                    Acute:  Hypersensitivity reactions affecting
                    the skin may occur (Hannuksela & Forstrom, 1978; 
                    Adams & Maibach, 1985).
    
                    Chronic:  No data available.

             9.4.14 Other clinical effects

                    No data available

             9.4.15 Special risks

                    No data available

        9.5  Others

             No data available

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Acute or chronic poisoning rarely need action other
             than to withdraw the patient from the source of exposure and
             observe until the symptoms disappear.
    
             After exposure to large doses, coma, seizures and/or cardiac
             arrhythmias necessitate monitoring of vital functions and
             intensive care measures.  Since the metabolites of propylene
             glycol are less toxic than the parent substance, inhibition
             of the metabolism of propylene glycol by ethanol or 4-methyl
             pyrazole is unnecessary. Lactic acidosis does not usually
             justify alkalinisation. 

        10.2 Life supportive procedures and symptomatic treatment

             Acute or chronic poisoning rarely need action other
             than to withdraw the patient from the source of exposure and
             observe  until the symptoms disappear.  After large doses,
             coma,  seizures and/or cardiac arrhythmias necessitate
             monitoring of vital functions and intensive care
             measures.

        10.3 Decontamination

             In case of eye exposure wash with copious amounts of
             water.  Remove gastric contents by inducing vomiting or
             lavage only after ingestion of large doses (>100 ml) and
             very recent ingestion.

        10.4 Enhanced elimination

             No enhanced elimination procedures are needed.

        10.5 Antidote treatment

             10.5.1 Adults

                    Antidotes are not needed.  Ethanol and
                    4-methylpyrazole have no place in the treatment of
                    propylene glycol poisoning.

             10.5.2 Children

                    Antidotes are not needed.  Ethanol and
                    4-methylpyrazole have no place in the treatment of
                    propylene glycol poisoning.

        10.6 Management discussion

             Not relevant.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Case 1
    
             A 6 month-old infant sustained a deep second to third degree
             burn of the anterior part of the chest (8% of the total body
             area).  Initial therapy included topical silver sufadiazine
             for six days.  On the tenth day after the burn, erythema and
             desquamation occurred over more than 70% on his total body
             surface area.  The desquamation was diagnosed as toxic
             epidermal necrolysis and was considered equivalent to a
             superficial and deep second-degree burn.  Treatment with
             topical silver sulfadiazine and dicloxacillin was begun, 78%
             of the total body surface area was covered with the
             preparation.  The infant was alert, with a temperature of
             38.4C, pulse rate 132/min, respirations, 28/min, and weight
             9.3kg. Continued topical therapy consisted of application
             twice daily of gauze impregnated with 600 to800g of silver
             sufadiazine.
    
             On day 12, cardiorespiratory arrest occurred approximately
             one hour after a debridement bath and a dressing change; no
             medication had been given other than 15mg of oral
             diphenhydramine given four hours before the arrest.  An acute
             respiratory acidosis was reflected by a pH of 7.28 and a 
             PC02 of 50 mmHg.  After resuscitation, the results of
             neurological examination reflected substantial hypoxic
             damage.
    
             The next day, the measured serum osmolality was 388 mOsm/kg
             H20 with a simultaneously calculated serum osmolality of 314
             mOsm/kg H20, so the osmolal gap was 74 mOsm/kg H20.  During
             the course of the day, the serum osmolality increased to 420
             (osmolal gap to 130) mOsm/kg H20.  The following day the
             serum propylene glycol was 771 mg/dL.  No source of serum
             propylene glycol other than silver sufadiazine was detected
             and this medication contained 76.7 mg/g of propylene glycol. 
             During the preceding 79 hours of hospitalization, 3,400 g of
             the preparation had been applied resulting in a total
             propylene glycol dose 9 g/kg/24 hr.  Silver sulfadiazine
             therapy was discontinued and the serum osmolality gradually

             decreased to 298 mOsm/kg H20; blood lactate was 58 mmol/L,
             alkalinising therapy was never required.
    
             Mechanical ventilation continued for three weeks.  The
             patient's later course was marked by severe, persistent
             hypoxic encephalopathy (Fligner et al, 1985).
    
             Case 2
    
             A 15-year-old was admitted for removal of the Wilm's tumour. 
             Surgery was followed by administration of actinomycin D and 
             radiotherapy.  The postoperative course was complicated by
             spiking fever and gastrointestinal bleeding, but by 40 days
             after admission he was afebrile, eating well, and gaining
             weight.  He received ascorbic acid in large doses as a
             preparation suspended in propylene glycol, 250 mg thrice a
             day (7.5 ml), beginning on the 48th hospital day. Eight days
             after starting vitamin C therapy he was noted to have a 
             sinus arrhythmia and two days later he was found unresponsive
             with tachypnoea, tachycardia, and diaphoresis.  He awoke soon
             without further treatment.  The cerebrospinal fluid was
             normal, blood glucose was 70 mg/dL.  Several similar episodes
             occurred during the following 3 days, and serum glucose was
             41 and 42 mg/dl, respectively, during the periods of
             unresponsiveness.  On one of those occasions he regained
             consciousness after having received an i.v. infusion of a
             solution containing 10 g of glucose.  The fasting blood
             glucose on the following day was 48, and the 2 hour
             postprandial level was 42 mg/dL.
    
             At that time, vitamin C therapy was stopped and no further
             episodes occurred.  A fasting blood glucose was84 mg/dl and a
             glucose tolerance test normal 2 days after the therapy had
             been discontinued (Martin & Finberg, 1970).

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Avoiding production of pharmaceuticals containing
             amounts of propylene glycol which may cause acute or chronic
             poisoning when the drug is administered in therapeutic doses
             parenterally, orally, or on the skin.
    
             In the occupational setting the recommendations are: keep
             away from flame (it is combustible), no smoking, ventilate
             areas, use goggles.

        12.2 Other

             No data available.

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    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
        ADDRESS(ES)

        Author:      Janusz Szajewski, MD
                     Warsaw Poison Control Centre
                     Szpital Praski
                     03-701 Warszawa
                     Poland
    
                     Tel:    48-22-190897/196654
                     Fax:    48-22-196943
                     Tlx:    813601 sbtpl
    
        Date:        August 1991
    
        Peer Review: Newcastle-upon-Tyne
                     United Kingdom
    
        Date:        February 1992
    
        Review:      IPCS
    
        Date:        May 1994
    



    See Also:
       Toxicological Abbreviations
       Propylene glycol (ICSC)
       PROPYLENE GLYCOL (JECFA Evaluation)
       Propylene glycol (SIDS)