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Ethinylestradiol

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 Manufacturers, 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 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   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. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   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
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES ETC.
   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 biomed. investigations etc.
   8.5 Overall Interpretation
   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 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, 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 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific 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), ETC.
    ETHINYLESTRADIOL

    International Programme on Chemical Safety
    Poisons Information Monograph 221
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Ethinylestradiol

        1.2  Group

        1.3  Synonyms

             Ethinyloestradiol; 
             Aethinyloestradiolum;
             Etinilestradiol;
             17 alpha-Ethynylestra-1,3,5(10)-triene-3,17 beta-diol;
             19-Nor-17 alpha pregna-1,3,5(10)-trien-20-yne-3,17 beta-diol

        1.4  Identification numbers

             1.4.1  CAS number

                    57-63-6

             1.4.2  Other numbers

                    No data available

        1.5  Main brand names, main trade names

             To be completed by centre using the monograph

        1.6  Manufacturers, Importers

             To be completed by centre using the monograph

    2.  SUMMARY

        2.1  Main risks and target organs

             Acute poisoning with ethinylestradiol results in mild,
             self limiting effects, usually involving the gastrointestinal
             tract. Chronic toxicity increases the risk of cardiovascular
             disease, including myocardial infarction, cerebrovascular
             disease, thromboembolic disease, gallbladder disease, and
             certain cancers in some people.

        2.2  Summary of clinical effects

             Acute poisoning with ethinylestradiol is mild and self
             limiting. Nausea, vomiting and occasionally vaginal
             breakthrough bleeding may occur. Chronic toxicity from
             ethinylestradiol, like other estrogens, increases the risk
             for stroke, myocardial infarction and thromboembolic disease
             in certain populations. Jaundice, hypertension, nasal
             congestion, headache, dizziness and fluid retention may
             occur. Endometrial, breast, and certain liver cancers may
             occur at a higher incidence than the general
             population.

        2.3  Diagnosis

             The diagnosis is based on a history of ingestion. Many
             patients may remain asymptomatic. No typical constellation of
             clinical findings aid the diagnosis. Laboratory analyses are
             not helpful.

        2.4  First aid measures and management principles

             Gut decontamination measures should be considered for
             all acute poisonings. Emesis is rarely indicated. Activated
             charcoal, given according to weight and age, may be
             appropriate. Cases of acute poisoning should otherwise be
             managed with supportive care, potentially including
             anti-emetic medication and or intravenous fluids for
             rehydration, if vomiting is excessive. Patients suffering
             from chronic toxicity should discontinue ethinylestradiol, in
             conjunction with the prescribing physician, and be managed on
             an individual basis, depending on clinical findings.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Synthetic steroid, prepared from estrone.

        3.2  Chemical structure

             Chemical name: 19-Nor-17 alpha pregna-1,3,5(10)-trien-20-yne-
                     3,17 beta-diol
    
             Molecular Weight: 296.39.

        3.3  Physical properties

             3.3.1  Colour

                    White to creamy or slightly yellowish-white.

             3.3.2  State/Form

                    Solid-crystals
                    Solid-powder.

             3.3.3  Description

                    Odorless.
                    Insoluble in water. Soluble 1 part in 6 parts of
                    ethanol, and 1 part in 4 parts of ether.
                    Melting point as a hemihydrate: 141 to 146C.

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    United States formulations have a shelf life of
                    36 months.

             3.4.2  Storage conditions

                    Storage at between 2 to 30C is preferred.

    4.  USES

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

                    The most frequent use is as the estrogen
                    component of combined oral contraceptives. Also used
                    for the treatment of menopausal and post menopausal
                    symptoms, especially the vasomotor effects. Used in
                    the treatment of female hypogonadism and as a
                    palliative treatment in malignant neoplasm of breast
                    and prostate. Also used in the treatment of some women
                    with acne, and in Turner's syndrome.

        4.2  Therapeutic dosage

             4.2.1  Adults

                    Combined contraceptive: 20 to 50 g orally per
                    day. Menopausal and postmenopausal symptoms: 10 to 50
                    g orally per day. Female hypogonadism: typically 50
                    g orally three times per day for 14 consecutive days
                    in every 4 weeks.
                    Malignant prostate cancer: 0.15 to 2 mg orally per
                    day.
                    Malignant neoplasm of the breast: 1 mg orally three
                    times per day.

             4.2.2  Children

                    No data available

        4.3  Contraindications

             Contraindications are those of the use of estrogens in
             general, and include the following:
    
             1. Known or suspected carcinoma of the breast, except in
             selected patients being treated for metastatic disease.
             2. Known or suspected estrogen dependent neoplasia.
             3. Known or suspected pregnancy.
             4. Undiagnosed abnormal genital bleeding.
             5. Active thrombophlebitis or thromboembolic disease.
             6. A past history of thrombophlebitis, thrombosis or
             thromboembolic disease associated with the previous use of
             estrogen containing compounds (Physicians GenRx, 1997).

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             This is the main route of exposure. Generally exposure
             may be either intentional overdose or therapeutic over
             prescribing. Ethinylestradiol is readily absorbed by this
             route.

        5.2  Inhalation

             No data available

        5.3  Dermal

             No data available

        5.4  Eye

             No data available

        5.5  Parenteral

             No data available

        5.6  Other

             No data available

    6.  KINETICS

        6.1  Absorption by route of exposure

             Ethinylestradiol is rapidly and completely absorbed from
             the gastrointestinal tract. The ethinyl substitution in the
             C17 position inhibits first-pass metabolism. Bioavailability
             is reported at 40% (Kanarkowski 1988, Goebelsmann 1986,
             Physicians GenRx, 1997).

        6.2  Distribution by route of exposure

             Extensively plasma protein bound, mainly to albumin.
             Unboundmolecules distribute widely in the tissues due to
             their lipophilic nature. Volume of distribution is stated as
             3.8 L/Kg. Peak plasma concentrations occur initially at 2 to
             3 hours after oral ingestion. A second, 12 hour peak, is
             thought to represent extensive enterohepatic circulation
             (Hardman 1996, Kanarkowski 1988, Goebelsmann 1986, Physicians
             GenRx 1997).

        6.3  Biological half-life by route of exposure

             Biological half life is approximately 7.7 hours
             following a single oral therapeutic dose. (Kanarkowski 1988,
             Goebelsmann 1986). Elimination phase half life is reported
             between 13 and 27 hours (Hardman 1996).

        6.4  Metabolism

             Compared to other estrogens, metabolism is slow. Primary
             route of biotransformation is via 2-hydroxylation and the
             formation of 2- and 3-methyl ethers (Hardman 1996).
             First-pass metabolism occurs primarily in the gut wall (Back
             1982).

        6.5  Elimination by route of exposure

             Some enterohepatic circulation of sulfate and
             glucuronide metabolites does occur, hence some is excreted
             via the feces. Excretion is also via the kidneys (Reynolds,
             1993).

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    Generally, the mechanism of how
                    ethinylestradiol exerts its toxic and adverse effects
                    are based on the principles outlined in 7.1.2.
                    However, a 2 to 3 fold increase in the incidence of
                    gallbladder disease is reported with the use of

                    estrogens. This is thought due to an increased
                    saturation of bile with cholesterol and a reduction of
                    bile acid secretion. Also, many studies have been
                    performed investigating the adverse effects of
                    estrogens, including ethinylestradiol, on coagulation.
                    These have used estrogens alone, and estrogens in
                    combination with progestins. However a consensus of
                    the net outcome of physiologic or pharmacological
                    doses has not occurred as yet (Beller, 1994).

             7.1.2  Pharmacodynamics

                    Like other steroid hormones, ethinylestradiol
                    is thought to act primarily through the regulation of
                    gene expression. As a lipophilic hormone, it diffuses
                    readily through cellular membranes to bind to estrogen
                    receptors situated in the nucleus. Estrogen receptors
                    are found in the female reproductive tract, breast,
                    pituitary, hypothalamus, bone, liver and other tissues
                    (Evans, 1988). The receptor interacts with a
                    specialized nucleotide sequence, resulting in either
                    an increase or decrease in the transcription of
                    hormone-regulated genes. Tissues may vary in the way
                    in which they respond to receptor activation.
                    Desirable therapeutic effects, include its action on
                    the female reproductive tract, (usually in combination
                    with a progesterone), where ethinylestradiol
                    stimulates proliferation and differentiation in the
                    fallopian tube, and increase the tubal muscular
                    activity. Ethinylestradiol also increases the water
                    content of cervical mucus and favors contraction of
                    the uterine myometrium. Estrogens, including
                    ethinylestradiol, block resorption of bone, resulting
                    in a positive effect on bone mass (Prince, 1991;
                    Belchetz, 1994). Control of the vasomotor symptoms
                    associated with the perimenopausal period is thought
                    to occur because of a blocking of the central nervous
                    system outflow that regulates blood flow to cutaneous
                    vessels. Like other estrogens, ethinylestradiol has a
                    beneficial effect on plasma lipoprotein profiles,
                    slightly elevating serum triglycerides, reducing serum
                    cholesterol, increasing high-density lipoprotein
                    levels and reducing low-density lipoprotein levels.
                    This beneficial effect may be due to action at
                    estrogen receptors within the liver itself (Lobo,
                    1991; Walsh, 1994) This alteration in lipoproteins is
                    thought to be the basis for the beneficial effect on
                    cardiovascular disease, particularly myocardial
                    infarction, in postmenopausal women.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             No minimal lethal or toxic dose has
                             been established. There is no dose of
                             ethinylestradiol which is therapeutically
                             effective and side effect free. Present
                             recommendations state that with long term
                             therapy, the minimally effective dose should
                             be prescribed  0.015 mg only, for 25 days
                             per month (Horeman 1983).

                    7.2.1.2  Children

                             No data available.

             7.2.2  Relevant animal data

                    Yager et al. (1991) demonstrated a correlation
                    between the prolonged use of oral contraceptives and
                    the development of liver cancer in rats. Han and Liehr
                    (1994b) induced DNA breaks in hamster kidneys, but not
                    in livers, following 2 weeks of treatment with a
                    single 25 mg estradiol implant. Lacassagne (1936),
                    induced tumors of kidney, bone, testis, uterus and
                    breast, in animals exposed to estrogens.
                    LD50  Rats: 2952 mg/Kg
                    Mice: 1737 mg/Kg  the mode of death is not reported
                    (Goldenthal, 1971).

             7.2.3  Relevant in vitro data

                    No data available

        7.3  Carcinogenicity

             It is well established that the risk of endometrial
             hyperplasia and cancer is increased in women receiving
             unopposed estrogen replacement therapy, including
             ethinylestradiol. Data from the 1970's and 1980's reported a
             2 to 15 fold increase in the risk of endometrial carcinoma
             (Henderson, 1989). The higher the dose and the longer the
             length of therapy the greater the risk. However, the addition
             of progestogen to estrogen replacement therapy was protective
             (Rubin, 1990; Persson, 1989).
    
             More research is needed before a conclusion can be drawn on
             whether ethinylestradiol therapy, and other estrogens,
             increase the risk of breast carcinoma. Conflicting findings
             have been reported. A review of data from the 1970's and
             1980's suggests that there is a moderate increase in the risk

             of breast carcinoma, but this did not occur until after 5
             years of therapy (Henderson, 1989; Steinberg, 1991). A study
             of 1369 cases of recently diagnosed breast cancer and 1645
             controls among postmenopausal women showed no increase in
             overall risk for those women taking estrogens (Wingo,
             1987).
    
             Benign hepatic adenomas may be associated with the use of
             oral contraceptives (Baum, 1973). These lesions have not been
             reported with the use of ethinylestradiol alone, however
             should be considered if abdominal pain and tenderness suggest
             hepatic involvement.
    
             There is limited evidence regarding the incidence of
             colorectal cancer in individuals taking estrogen replacement
             therapy. Meta-analysis has reported no overall increase in
             risk (MacLennan, 1995).

        7.4  Teratogenicity

             No specific data available for ethinylestradiol. Reports
             suggest a link between fetal exposure to female sex hormones
             and congenital abnormalities. These include heart defects,
             and limb defects (Levy, 1973; Nora, 1973; Janerich, 1974).
             Janerich (1974) estimated the increased risk at 4.7 fold for
             developing limb defects in infants exposed to in-utero sex
             hormones. Other estrogens, namely diethylstilbestrol, have
             been associated with the development of vaginal and cervical
             adenocarcinoma in female offspring of mothers who had taken
             this drug during the first trimester (Greenwald, 1971;
             Herbst, 1971). Diethylstilbestrol ingestion during pregnancy
             is also associated with a number of other abnormalities in
             male offspring, including, smaller testes and urogenital
             abnormalities (Ross, 1983; Whitehead, 1981). Although no
             studies relating ethinylestradiol directly to these findings
             were identified, the pharmacological similarities in this
             class of compounds suggest caution should be used.

        7.5  Mutagenicity

             No specific data available for ethinylestradiol. After 2
             weeks Han and Liehr, (1994), induced DNA breaks in hamster
             renal cells, but not in hepatocytes, with 25 mg estradiol
             implants. Roy and Pathak (1995) have shown rat liver nuclei
             converted diethylstilbestrol to histone-binding metabolites.
             In vivo modification in the chromatin histone proteins by
             diethylstilbestrol metabolites may influence gene
             function.

        7.6  Interactions

             Increased ethinylestradiol and 17-beta-estradiol effect,
             probably via a decreased first pass metabolism, has been
             seen, with the concurrent use of grapefruit juice (Weber,
             1996). Possible antidepressant toxicity may occur with
             estrogens or oral contraceptives, the mechanism of which is
             not fully established. Krishnan (1984) reports on this case
             which suggests that estrogens may facilitate the development
             of akathisia. Also, a possibility for corticosteroid
             toxicity, through an unknown mechanism, has been reported on
             (Legler, 1986). A decrease in estrogen effect is seen with
             phenytoin use, secondary to induction of hepatic enzymes and
             increased metabolism (Notelovitz, 1981). Through a similar
             mechanism, smoking is thought to reduce the clinical efficacy
             of estrogens, including ethinylestradiol (Jensen, 1985).
             Increased serum concentration and possible toxicity of
             estrogens may be seen with 1 gram/day of vitamin C, secondary
             to decreased metabolism (Morris, 1981).

        7.7  Main adverse effects

             The main adverse effects of ethinylestradiol given in
             therapeutic dose are directly related to its estrogenic and
             metabolic effects. They include water and sodium retention,
             which may result in edema, weight gain and tender breast
             enlargement. Changes in libido, and withdrawal vaginal
             bleeding is also reported. Liver function impairment,
             jaundice and gallstones may occur. Headache, depression,
             dizziness, glucose intolerance, and a sensitivity to contact
             lenses are described. Large doses may produce hypercalcemia
             when used in the treatment of metastatic carcinoma. Nausea,
             vomiting and diarrhea are not uncommon. Dermatological
             effects include chloasma, melasma, rashes and urticaria.
             Erythema multiforme and erythema nodosum occur. Hypertension
             and thromboembolic disease are reported (Reynolds, 1993;
             Cornbleet, 1977; Fedorkow, 1989). Some cancers occur at a
             higher incidence, see 7.3.

    8.  TOXICOLOGICAL ANALYSES ETC.

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                             Specific levels of ethinylestradiol
                             are not available.

                    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 biomed. investigations etc.

        8.5  Overall Interpretation

             Sample collection
             Ethinylestradiol levels are not available. Estradiol levels
             are available, however the clinical relevance of these to
             poisoning from ethinylestradiol is unknown.
    
             Biomedical analysis
             Not relevant.
    
             Toxicological analysis
             Not relevant.
    
             Other investigations
             Generally no laboratory analysis would be needed following
             acute poisoning. In chronic toxicity laboratory work should
             be performed according to the individual patient needs.

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Acute poisoning effects are mild and self
                    limiting. Nausea, vomiting and break through vaginal
                    bleeding have been reported following oral
                    contraceptive overdose. Nasal congestion, visual
                    disturbances, headache and hypertension have also been
                    reported in association with estrogen overdose (AHFS
                    1997; Eden 1990; Punnonen, 1983).

             9.1.2  Inhalation

                    No data available

             9.1.3  Skin exposure

                    No data available

             9.1.4  Eye contact

                    No data available

             9.1.5  Parenteral exposure

                    No data available

             9.1.6  Other

                    No data available

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Gallbladder disease, glucose intolerance,
                    edema, leg cramps, porphyria cutanea tarda, chloasma,
                    gynecomastia,  thromboembolism, hypertension,
                    myocardial infarction, depression, psychosis, and
                    liver impairment have been reported with the prolonged
                    therapeutic use of estrogen containing contraceptives
                    or other estrogen medications (AHFS, 1997; Kane, 1969;
                    Kern, 1978; Pittman, 1974; BCDSP, 1973; Wynn, 1986;
                    Slone, 1981; CGSSYW, 1975; RCGP, 1978).

             9.2.2  Inhalation

                    No data available

             9.2.3  Skin exposure

                    No data available

             9.2.4  Eye contact

                    No data available

             9.2.5  Parenteral exposure

                    No data available

             9.2.6  Other

                    No data available

        9.3  Course, prognosis, cause of death

             Based on data from exposure to ethinylestradiol and
             other estrogen compounds acute poisoning from
             ethinylestradiol would be expected to result in mild, self
             limiting symptoms and signs. Death from exposure to this
             medication has not been reported. Secondary complications
             from the long term use of ethinylestradiol may result in
             death from myocardial infarction, stroke or cancer.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Varying degrees of systemic hypertension are
                    reported with the therapeutic use of estrogen
                    products, including those containing ethinylestradiol.
                    This is occasionally clinically significant (AHFS,
                    1997; Pittman, 1974). Hypertension has also been
                    reported following an estrogen implant overdose (Eden
                    1990). Myocardial ischemia, myocardial infarction,
                    thromboembolic disease, and fluid retention are also
                    associated with the therapeutic use of estrogen
                    products in the premenopausal age group (BCDSP, 1973;
                    AHFS, 1997; Pittman, 1974; Mann, 1975; RCGP, 1981;
                    RCGP, 1978; Slone, 1981). More recent studies suggest
                    that the use of hormone replacement therapy in the
                    post menopausal group may be protective against
                    cardiovascular disease (Henderson, 1991).

             9.4.2  Respiratory

                    Respiratory effects from acute overdose of
                    ethinylestradiol are not reported. Todd (1985)
                    reported on a 22 year old female with a history of
                    systemic lupus erythematosus who developed pulmonary
                    hypertension after beginning the oral contraceptive
                    pill. Pulmonary emboli are reported in patients taking
                    ethinylestradiol containing oral contraceptive
                    medication therapeutically (Fiechtner, 1978; AHFS,
                    1997).

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System (CNS)

                             Headache, dizziness, psychosis and
                             mental depression are reported with the
                             therapeutic use of ethinylestradiol
                             containing oral contraceptives (AHFS 1997;
                             Herzberg, 1971; Kane 1969; Dennerstein,
                             1978). The risk of stroke in those taking
                             ethinylestradiol containing medication

                             therapeutically is dependent on the
                             menopausal state. Premenopausal women seem to
                             have a higher incidence, while those taking
                             hormone replacement therapy, i.e.
                             postmenopausal women, have no increased risk,
                             or a reduced risk (Reynolds, 1993; Finucane,
                             1993; CGSSYM, 1975). Punnonen (1983) reported
                             on a 19 year old female who ingested 160 mg
                             of estradiol valerate. She demonstrated
                             temporary electroencephalogram changes and
                             headache.

                    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

                             No data available.

             9.4.4  Gastrointestinal

                    Nausea and vomiting may occur following acute
                    overdose of ethinylestradiol containing oral
                    contraceptives (AHFS, 1997). Parker (1983) described a
                    young female who developed acute pancreatitis
                    associated with the ethinylestradiol containing
                    contraceptive medication.

             9.4.5  Hepatic

                    Hepatic impairment is not reported following
                    acute overdose of ethinylestradiol. Hepatobiliary
                    effects are associated with the therapeutic use of
                    ethinylestradiol containing contraceptive medications.
                    These include elevated liver function tests,
                    cholestatic jaundice, and gallbladder disease,
                    especially cholelithiasis (Kern, 1978; BCDSP, 1973;
                    AHFS, 1997; Fedorkow, 1989). Liver tumors are
                    discussed in 7.3.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             No data available

                    9.4.6.2  Other

                             No data available

             9.4.7  Endocrine and reproductive systems

                    Breakthrough vaginal bleeding is reported
                    following acute overdose of ethinylestradiol
                    containing contraceptives(Physicians GenRx, 1997;
                    AHFS, 1997). Glucose intolerance may occur with the
                    therapeutic use of estrogens (Wynn, 1986). Breast
                    tenderness is reported with routine use of oral
                    contraceptives (AHFS, 1997). Baron et al. (1983)
                    reported on a male employed by a pharmaceutical
                    company involved in the manufacture of
                    ethinylestradiol containing oral contraceptive
                    medication who developed a prolactin secreting
                    adenoma.

             9.4.8  Dermatological

                    The therapeutic use of ethinylestradiol
                    containing medication has been associated with the
                    development of chloasma, melasma, erythema multiforme,
                    erythema nodosum, and porphyria cutanea tarda
                    (Physicians GenRx 1997; AHFS, 1997; Sixel-Dietrich
                    1985).

             9.4.9  Eye, ear, nose, throat: local effects

                    Nasal congestion was reported by Eden (1990)
                    following an estrogen implant overdose. This may also
                    occur with the therapeutic use of ethinylestradiol
                    containing medications (AHFS, 1997). Contact lens
                    irritation has been reported with the therapeutic use
                    of ethinylestradiol containing oral contraceptives
                    (Goldberg 1970).

             9.4.10 Haematological

                    Hematological effects with acute overdose of
                    ethinylestradiol are not reported. Therapeutic use of
                    ethinylestradiol containing medication has been
                    associated with a decrease in antithrombin III, and an
                    increase in factors VII, III, IX and X. The exact
                    clinical significance of these changes is not known
                    (AHFS, 1997).

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No data available.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No data available.

                    9.4.12.3 Others

                             The therapeutic use of
                             ethinylestradiol containing medication may
                             also elevate triglyceride levels (Wynn,
                             1986). Slight increases in triglyceride,
                             phospholipid and cholesterol levels were
                             reported by Punnonen (1983), following an
                             overdose of 160 mg of estradiol
                             valerate.

             9.4.13 Allergic reactions

                    Some formulations of ethinylestradiol contain
                    FD & C Yellow No. 5, (tartrazine), which may induce
                    allergic reactions in sensitive individuals (Product
                    Information 1992).

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    Ethinylestradiol has a pregnancy category of
                    X. Because of the potential for mutagenicity and
                    teratogenicity ethinylestradiol should not be used
                    during pregnancy (See 7.4 and 7.5). The effects of
                    single acute overdose involving ethinylestradiol on
                    the developing fetus are unknown. Ethinylestradiol is
                    excreted in breast milk. Jaundice and breast
                    enlargement have been reported in infants of nursing
                    mothers concurrently using estrogens (AHFS,
                    1997).

        9.5  Other

             Not relevant.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Acute poisoning from ethinylestradiol is mild and self
             limiting, and as such treatment is essentially supportive.
             However, as in all poisoned patients initially attention
             should be given to resuscitative measures, and evaluation of
             the patients condition and vital signs. Consideration should

             be given to the possibility of concurrent co-ingestions.
             Given that gastrointestinal upset usually accompanies acute
             poisoning, there may be a need for anti-emetics and or fluid
             replacement. In those patients where chronic poisoning is
             suspected, treatment depends on the individuals findings, but
             may involve the management of acute thromboembolic events,
             stroke, myocardial infarction and hypertension.

        10.2 Life supportive procedures and symptomatic/specific
        treatment

             Life supportive measures are generally not required.
             However, in all poisoned patients one should make a proper
             assessment of the airway, breathing, circulation and
             neurological status of the patient. A clear airway should be
             maintained. Aspirate secretions from the airway and
             administer oxygen if required. Endotracheal intubation should
             be performed on an individual basis. Control convulsions with
             appropriate drug regimen. Open and maintain at least one
             intravenous route. Administer intravenous fluids on an
             individual basis. Monitor vital signs. Correct hypotension
             and/or hypertension as required. Ethinylestradiol should be
             discontinued, after consultation with the prescribing
             physician, if signs of chronic toxicity occur.

        10.3 Decontamination

             Given the relatively benign course of ethinylestradiol
             poisoning the induction of emesis or the use of gastric
             lavage is rarely indicated, unless other more toxic
             co-ingestants are involved. Administer a single dose of
             activated charcoal following an acute poisoning. The amount
             should be adjusted according to patient age and size.

        10.4 Enhanced elimination

             No data available. No reports of the use of methods to
             enhance the elimination of ethinylestradiol or other estrogen
             products were found. Given its relatively benign course in
             acute poisoning, it is unlikely that such methods would be
             warranted.

        10.5 Antidote treatment

             10.5.1 Adults

                    No antidote exists.

             10.5.2 Children

                    No antidote exists.

        10.6 Management discussion

             Acute poisoning following ethinylestradiol exposure is
             uncommon, mild, and self limiting. Following consideration to
             the use of methods to decontaminate the gut the treatment is
             essentially supportive. Patients with evidence of chronic
             poisoning should stop taking ethinylestradiol, after
             consultation with the prescribing physician. Their treatment
             is on an individual basis, depending on clinical
             findings.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Punnonen (1983) reported on a 19 year old female who
             ingested 160 mg of estradiol valerate. Her estradiol level
             was elevated at 2 nmol/L, as was her serum cholesterol,
             triglycerides and phospholipids. An electroencephalogram,
             (EEG), demonstrated subcortical disturbance. At one week post
             ingestion her EEG was normal.

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             These relate primarily to chronic toxicity.
             Ethinylestradiol should be taken only under the supervision
             of a physician, who should undertake periodic medical
             examinations to check for adverse reactions or signs of
             chronic toxicity. Patients with recognized contraindications
             (See 4.3) should avoid its use. Patients with a history of
             pregnancy induced jaundice should be prescribed
             ethinylestradiol with caution. As should patients with a
             history of psychosis, mental depression, liver impairment,
             and metabolic bone disease. Because estrogens may enhance
             epiphyseal plate closure, ethinylestradiol should be used
             carefully in young patients. Patients with known tartrazine
             allergy should not be prescribed those brands of
             ethinylestradiol containing this coloring. Ethinylestradiol
             has no known risk of abuse (Product Information,
             1992).

        12.2 Other

             No data available.

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    14. AUTHOR(S), ETC.

        Author: John Fergus Kerr MBBS
        Toxicology Treatment Program
        University of Pittsburgh Medical Center
        Room NE-583, MUH
        200 Lothrop Street
        Pittsburgh, Pennsylvania, USA, 15213.
        Tel: 412-6486800
        Fax: 412-6486855
    
        Date: 1997
    
        Co-author: John G. Benitez MD MPH
        Toxicology Treatment Program
        University of Pittsburgh Medical Center
        Room NE-583, MUH
        200 Lothrop Street
        Pittsburgh, Pennsylvania, USA, 15213.
        Tel: 412-6486800
        Fax: 412-6486855
    
        Peer review: INTOX-10 Meeting, Rio, Brazil, September 1997 (Drs
        Cobaugh
    


    See Also:
       Toxicological Abbreviations