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    DEXAMETHASONE

    First draft prepared by
    Dr F.X.R. van Leeuwen
    Toxicology Advisory Centre
    National Institute of Public Health and Environmental Protection
    Bilthoven, Netherlands

    1.  EXPLANATION

          Dexamethasone is a potent synthetic analogue of hydro-cortisone
    that has a long history of use in veterinary medicine for the
    treatment of a range of metabolic diseases and inflammatory
    disorders in companion and farm animals. Animal diseases in which
    dexamethasone is an effective treatment include inflammation,
    acetonaemia, non-specific skin disease, shock and stress. Its use in
    animals is primarily therapeutic. It is also used in human medicine
    for the treatment of a wide range of diseases. This wide range of
    therapeutic use reflects the broad spectrum of pharmacological
    actions of the corticosteroid hormones. The corticosteroids have
    effects on several important biochemical pathways and cellular
    transport mechanisms including, cellular sodium transport, glycogen
    synthesis and antiinflammatory responses.

          Dexamethasone had not been previously evaluated by the Joint
    FAO/WHO Expert Committee on Food Additives.

          The structure of dexamethasone is shown in Figure 1.

    FIGURE 1

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution and excretion

          Male Wistar albino rats were administered 0.23 mol [1,2-3H]
    dexamethasone/kg bw, i.p. Urine and faeces were collected up to 4
    days after treatment. Within 96 hours 74% of the dose was excreted,
    30% in the urine and 44% in the faeces (Rice  et al., 1974).

          Crl:SD(CD)BR rats were administered a single i.m. dose of 9 g,
    [1,2,4-3H]-dexamethasone/kg bw. Radioactivity was measured up to
    96 hours after administration in plasma (pre- and post-freeze
    dried), urine, faeces and expired air. Tritium exchange was measured
    in stored urine. Highest plasma levels were observed 6 hours after
    dosing (3.7 g equivalents/g), declining rapidly thereafter to 0.15
    g equivalents/g. Within 24 hours 41% of the radioactivity was
    excreted in the urine. After 96 hours a mean of 44% of the
    radio-activity was excreted. Tritium exchange was observed both in
    plasma and urine. Following freeze-drying, the mean loss of
    radioactivity 96 hours after dosing was 87% and 37% in plasma and
    urine, respectively (Stewart  et al., 1992).

          Dogs (mixed-breed) were administered dexamethasone alcohol or
    dexamethasone 21-isonicotinate as a solution i.v. or i.m. (1 mg/kg
    bw), or dexamethasone 21-isonicotinate as a suspension i.m. (0.1 or
    1 mg/kg bw). Plasma concentrations were determined with HPLC up to
    120 hours after treatment. The elimination half-life after i.v.
    administration was 120-140 minutes for both formulations. Following
    i.m. administration, absorption was rapid with peak plasma
    concentrations at 30-40 minutes for both solutions. Bio-availability
    after i.m. administration was 100% for dexamethasone alcohol but 40%
    for dexamethasone 21-isonicotinate. After i.m. administration of
    dexamethasone 21-isonicotinate as a suspension, dexamethasone was
    not detected in plasma, suggesting a long absorption phase (Toutain
     et al., 1983).

    2.1.2  Biotransformation

    2.1.2.1   In vitro

          The half-life of dexamethasone 21-isonicotinate was determined
    in human, rat, and rabbit sera. In rat and rabbit sera 90 and 99% of
    the ester was hydrolyzed after 10 minutes, respectively. The
    half-life of in human serum was about 90-100 minutes (Weisenberger,
    1972).

          Dexamethasone trimethylacetate was rapidly hydrolyzed to
    dexamethasone in bovine and equine whole blood; half-lives ranged
    from 10-30 minutes for both species (Houghton  et al., 1989).

          Dexamethasone dimethylbutyrate was hydrolyzed quickly in bovine
    plasma, with a half-life of about 1 hour (Coert  et al., 1988).

    2.1.2.2  Rats

          In the urine of rats administered 0.23 mol/kg bw [1,2-3H]-
    dexamethasone i.p., 10% of the administered radioactivity was
    associated with one polar metabolite of dexamethasone, likely to be
    6-hydroxy-dexamethasone (Rice  et al., 1974).

          Male Wistar albino rats were administered [3H]-dexamethasone
    orally at a dose of 1.14 nmol/kg bw. Thirty-one percent of the
    administered radioactivity was excreted in the urine within 4 days
    (most of it within the first 24 hours) as unconjugated metabolites.
    Unchanged dexamethasone accounted for 14%, 6-hydroxydexamethasone
    for 7.4%, and 20-dihydrodexamethasone for 1.1% of the urine
    radioactivity. Twenty-five percent of the administered dose was
    eliminated in the faeces. Another group of rats was pretreated with
    phenytoin 16 hours before dexamethasone treatment. The pretreatment
    reduced the rate of total radioactivity excreted in the urine within
    24 hours, but the total urinary and faecal excretion after 96 hours
    was not significantly reduced (English  et al., 1975).

    2.1.2.3  Pigs

          Four hours after the s.c. administration to pigs of
    [1,2-3H]-dexamethasone-21-trimethylacetate, less than 1% of total
    plasma radioactivity was extractable as unchanged
    [3H]-dexamethasone-21-acetate. The plasma concentration of
    dexamethasone was highest (about 3 ng/ml) at 4 hours, declining
    rapidly to about 0.5 ng/ml at 24 hours, and slowly thereafter.
    Measurable amounts of dexamethasone (>0.2 ng/ml) were still present
    at day 5 (Horner, 1989).

    2.1.2.4  Humans

          No parent compound could be detected in urine of patients after
    oral administration of a small dose of dexamethasone (<4 mg/day)
    for a few weeks. However, 60% was recovered as
    6--hydroxy-dexamethasone and 5-10% as
    6--hydroxy-20-dihydrodexamethasone. After the administration of
    about 15 mg dexamethasone/day metabolism occurred by an additional
    route involving epoxidation and subsequent hydrolysis, resulting in
    glycol formation in ring A (Seutter, 1975).

    2.1.3  Special studies on macromolecular binding

          The binding of dexamethasone to proteins in rat, dog, cow, and
    human plasma has been studied  in vitro by an equilibrium dialysis
    technique. Approximately 85, 73, 74, and 77% was bound in rat, dog,
    cow, and human plasma, respectively. Dexamethasone was mainly bound
    to the albumin fraction of human plasma (Peets  et al., 1969).

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

          The results of an acute toxicity study is summarized in Table
    1.

    2.2.2  Short-term toxicity studies

    2.2.2.1  Rats

          Groups of 15 rats were given daily s.c. injections of 0.5 ml
    vehicle or 50 g/kg bw dexamethasone for 6 weeks. Body- weight gain
    was significantly decreased in treated rats. Adrenal weights were
    also decreased. Post-mortem examination revealed no pathological
    organ changes. Only a summary of this study was available
    (Ueberberg, 1964).

          In 3 experiments, groups of 15 rats/sex were given 0.125 mg/kg
    bw (6 days/week), 0.25 mg/kg bw (5 days/week), or 0.4 mg/kg bw (5
    days/week) dexamethasone in tablets for 181-185 days. The control
    groups (10 rats/sex/group) received placebo tablets. All mid- and
    high-dose animals received 20 mg tetracycline*HCl once a week
    beginning on the 39th experimental day.

          Dose-related deaths occurred as follows: 4/30 at the low-dose,
    14/30 at the mid-dose and 26/30 at the top-dose. Post mortem
    examination in all cases showed severe infections. In all dose
    groups, body-weight gain was decreased, relative kidney weight was
    increased and relative adrenal and thymus weights were decreased. In
    the bone marrow the number of neutrophilic forms of leucocytes was
    increased and the number of eosinophils was decreased in all
    experimental groups as compared to controls. Detailed
    histopathological findings of the mid- and high-dose groups were not
    presented (Intervet, undated I).

          Groups of 20 male and 20 female Wistar rats were administered
    s.c. 0, 40, or 79 g/kg bw/day dexamethasone for 13 weeks. An
    additional group of 5 male and 5 female rats was given 79 g/kg
    bw/day dexamethasone s.c. for 13 weeks, then kept for a 7-week
    recovery period. Haematological and biochemical examinations were
    performed on 5 rats/sex after 10 weeks.

    
    Table 1.  Acute toxicity of dexamethasone
                                                                    

    Species   Sex    Route      LD50      Reference
                              (mg/kg bw)
                                                                    

    Mouse     M      i.p.     577         Engelhardt, 1963
                                                                    
    
           In all treated males, ALAT activity and total cholesterol
    concentrations were increased. Lipid levels were only incidentally
    raised. Plasma corticosteroid levels and hepatic glycogen were
    decreased in a dose-related manner. In treated males, adrenal
    glycogen levels were increased and in males as well as in females
    dose-related reductions in adrenal corticosteroids were observed.
    Post mortem examination found adrenal and thymus glands that were
    markedly smaller with reduced weights when compared to controls. In
    some animals no thymus tissue could be found. Compared to the
    controls, body weights and most organ weights of treated rats were
    lower. Microscopic examination revealed marked changes in the thymus
    and the adrenal glands. The adrenal cortex was narrowed due to loss
    of the regular structuring of the cells or cell columns, in addition
    to a reduction in lipids. The thymus from the treated rats showed
    atrophy of the medullary and cortical tissues. After the recovery
    period no significant changes compared to the controls were observed
    (Bauer  et al., 1969a; results of male rats partly reported in
    Segro, 1970).

    2.2.2.2  Dogs

           In a limited study, groups of 4 female beagle dogs were orally
    administered a 2 or 8 mg dexamethasone tablet/day (6 days/week) for
    26 weeks. No control group was used. Instead, values from previous
    studies were used for comparison. One low-dose dog died (not related
    to treatment) during the study and 3 high-dose dogs died, of which 2
    were due to retro-oesophageal abcesses or gastric ulcers. At
    post-mortem examination all remaining dogs were found to have
    infections. Alopecia was seen in 1 dog in each dose group. Atrophy
    of the lymphatic organs was seen in all dogs, adrenal weight was
    decreased, and in the high-dose group the thymus had almost
    disappeared (Intervet, undated II).

           Groups of mongrel dogs (3 male and 2 female dogs/group) were
    orally administered placebo tablets or 125 g/kg bw/day
    dexamethasone 7 days/week for 6 weeks. No treatment-related effects
    were observed on clinical signs, body-weight, liver and renal

    function tests, urinalysis, or post mortem examination. After 6
    weeks blood glucose values were increased in treated animals.
    Relative adrenal weights were decreased. In the adrenals, the zona
    fasciculata was narrowed in treated dogs. Lipid observed in the
    adrenal cortical zones of the controls was not present in treated
    dogs. Total 17-ketosteroid excretion in the urine was higher in all
    treated groups (Ueberberg, 1963).

           Groups of 3 male and 3 female beagle dogs were administered
    daily i.m. doses of 0, 40, or 79 g/kg bw dexamethasone for 13
    weeks. Additionally, 2 groups of 3 male and 3 female dogs were given
    daily i.m. doses of 79 g/kg bw dexamethasone for 13 weeks, then
    kept for a 4-week recovery period. One female dog from the recovery
    group died 14 days after cessation of dosing. No effects were
    observed on food consumption or haematological parameters. Decreased
    body-weight gain was observed in all treated dogs. ALAT activity was
    increased in 1 out of 3 female dogs in both the 40 g/kg bw/day and
    79 g/kg bw/day groups. Activity returned to normal after the
    recovery period. Total lipid levels in serum were increased in all
    treated dogs without any dose-dependence. By the end of the recovery
    period total lipid levels had decreased, but were still elevated
    relative to control levels in all treated dogs. Plasma corticoid
    levels were decreased in dogs receiving 79 g/kg bw/day
    dexamethasone but returned to normal by the end of the recovery
    period. Increased triglyceride levels in the adrenals and increased
    liver glycogen were observed in all treated dogs (without
    dose-relationship). The increased adrenal triglyceride levels was
    still apparent after the recovery period. Liver weights were
    increased in a dose-related manner and honey comb distention was
    seen in some hepatic cells. These effects reversed after treatment
    was ceased. In all treated dogs, the adrenal weights were lower than
    in the controls. Histological examination revealed diminution of the
    fascicular and reticular zones of the adrenal cortex without a clear
    demarcation between the different zones. After the recovery period
    the adrenal weights returned to normal. No thymus or only remnants
    of the thymus were found in some treated dogs. When the thymus was
    found in recovery animals, it did not differ histologically from the
    controls (Bauer  et al., 1969b).

    2.2.3  Long-term toxicity/carcinogenicity studies

           No information available.

    2.2.4  Reproduction studies

           No information available.

    2.2.5  Special studies on embryotoxicity and teratogenicity

    2.2.5.1  Mice

           In a special study 0.15 mg dexamethasone/day (equal to 6 mg/kg
    bw/day) was administered s.c. to pregnant A/J mice on days 11-14
    post-conception. The mice were killed on day 18. The incidence of
    cleft palate was 93% (Walker, 1971).

    2.2.5.2  Rats

           Groups of 20 pregnant SPF-FW 49 Biberach rats were administered
    dexamathasone s.c. at dose levels of 0, 20, 40 or 79 g/kg bw/day on
    days 6-15 of gestation. Females were killed on gestation day 21. One
    female died intercurrently, the cause of death could not be
    resolved. All treated females failed to gain weight and had lower
    food consumption during treatment, but they gained weight after
    cessation of treatment. Total food consumption, however, remained
    lower in all treated animals compared to controls. The mean number
    of implantations was higher in all treated groups than in the
    control group. Resorption rates were higher in a dose-related manner
    and the number of live offspring was lower in the two highest dose
    groups. Litter weight was decreased in a dose-related manner. Both
    the variation and malformation rates were increased, but with no
    apparent dose-relationship. Retarded ossification of the sternebrae
    and hydronephrosis occurred most frequently (Lehmann, 1969a).

           Daily doses of 0.05, 0.2, or 0.8 mg dexamethasone/day (equal to
    250, 1000 or 4000 g/kg bw/day) were administered s.c. to pregnant
    Holtzmann rats on days 12-15 post-conception. The dams were killed
    at day 19. A high frequency of cleft palate (53%) was observed in
    litters of rats in the highest dose group. No cleft palates were
    observed at lower doses (Walker, 1971).

           Groups of 20 pregnant rats (Morini Wistar) were given daily
    s.c. injections of 0, 40, or 79 g dexamethasone/kg bw/day on days
    6-15 of gestation. Maternal body-weight gain and food consumption
    were decreased in all treated dams. Compared to the controls, the
    resorption rate was increased and fetal weights were decreased.
    Hydronephrosis was seen in 4 fetuses, 2 at 40 and 2 at 79 g/kg
    bw/day (Segro, 1970).

           In a poorly reported study, groups of 10 pregnant rats (SPF,
    strain SD-JCL) were given daily s.c. doses of 0, 20, 40, or 80 g
    dexamethasone/kg bw/day on days 6-15 of gestation. Mortality and
    body weights were recorded. The dams were killed on day 21 of
    pregnancy and the fetuses were delivered by caesarean section.
    Maternal body weight was decreased in treated animals. In all
    treated rats pre- and post-implantation losses were increased. No
    effects were observed on fetal weight. Cleft palate was seen in one

    fetus of the control group. One fetus in the 20 g/kg bw/day dose
    group had thoracoschisis. The occurrence of 14th rib was observed in
    the control group (25%) as well as in all dose groups. There was no
    marked difference relative to controls, but a slight dose-related
    effect was observed (incidences ranged from 20 to 28.4% in the
    treated groups). Deformity of the sternum was observed in 1/85 rats
    in the 20 g/kg bw/day dose group (Umemura  et al., 1972).

           In a pilot study groups of Virgin Lati:Han Wistar pregnant rats
    (10/group) were orally administered (by gavage) doses of 0, 10, 50,
    250, or 1250 g dexamethasone/kg bw/day on days 7 to 16 of
    gestation. Mortality, body weight, and food consumption were
    recorded. All dams were killed on day 21 and fetuses were delivered
    by caesarean section. Observations included the number of corpora
    lutea, implantations, fetus and placenta weight, and sex of viable
    fetuses. All fetuses were examined for skeletal and visceral
    abnormalities.

           Maternal body-weight gain was decreased at doses of 50 g/kg
    bw/day and above and thymus involution was observed at the same dose
    levels. In the highest dose group, post-implantation mortality was
    increased. Most fetuses that died within the last 24 hours were
    malformed. Fetal weight was decreased at doses of 250 and 1250 g/kg
    bw/day. In the 2 highest dose groups retrognathia and cleft palate
    of variable severity were observed. Hydrops fetalis and umbilical
    hernia was found only at 1250 g/kg bw/day. Thymus hypoplasia was
    observed at 50, 250, and 1250 g/kg bw/day (4, 2, and 59%,
    respectively). The NOEL in this study was 10 g/kg bw/day (Druga,
    1993a).

           In the main Segment II study, groups of Virgan Lati:Han Wistar
    rats were orally administered (by gavage) 0, 20, 200, or 1000 g
    dexamethasone in methylcellulose/kg bw/day on days 6 to 15 of
    gestation. Mortality, body weight, and food consumption were
    recorded. All dams were killed on day 20. The visera of the dams
    were examined grossly and the thymus was removed and weighed.
    Observations included the number of corpora lutea, implantations,
    length of umbilical cord, fetus and placenta weight, and sex of
    viable fetuses. All fetuses received external, skeletal, and
    visceral examinations.

           Maternal body weight and body-weight gain and food consumption
    were decreased at 200 and 1000 g/kg bw/day. Thymus involution was
    observed at the same dose levels. Post-implantation mortality was
    increased at the highest dose. Fetal weight was decreased at 200 and
    1000 g/kg bw/day. Umbilical cord length was reduced at 200 and 1000
    g/kg bw/day and the length, thicknesss, and index of the femur were
    markedly lower at 1000 g/kg bw/day. High-dose fetuses showed an
    increased incidence of malformations, including hydrops fetalis,
    retrognathia, cleft palate, umbilical hernia of variable severity,

    split sternum, malformed vertebrae, malformed upper limb bones, and
    micromelia. Thymus hypoplasia was observed at 20, 200, and 1000
    g/kg bw/day (4, 2, and 16%, respectively). In the high-dose group,
    dystrophy of gonads was also observed. A no-effect level was not
    observed in this study (Druga, 1993b).

    2.2.5.3  Rabbits

           Dexamethasone, as one glucocorticoid in a series of 6, was
    administered i.m. at dose levels ranging from 0.1 to 4 mg/day (equal
    to 25 to 1000 g/kg bw/day) to pregnant rabbits on days 13.5-16.5
    post-conception. Litter resorptions were observed at 750 and 1000 g
    dexamethasone/kg bw/day. Cleft palate was observed at >62 g/kg
    bw/day. No effects on resorption or cleft palate were observed at 25
    g/kg bw/day (Walker, 1967).

           In a comparative study, groups of 15 pregnant rabbits ("SPF
    Himalyan"/Biberach) were administered s.c. 0, 20, 40, or 79 g
    dexamethasone/kg bw/day on days 6-18 of gestation. The dams were
    killed on day 29 of pregnancy. During dosing maternal body weight
    remained stationary or was reduced, particularly in the second half
    of the dosing period. A dose-related increase in resorption rate and
    number of runts was observed. A dose-related decrease in fetal
    weight was also observed. The incidence of flexure of the forefeet
    and of malformations (palatoschisis, gastroschisis, exencephaly,
    encephalocele and menigocele, anotia, and ectrodactyly) was
    increased in a dose-related manner in all treatment groups.
    Malformations of the extremities such as haemibrachia, hypoplasia of
    tibia and fibula, and acheiria were observed (Lehmann, 1969b).

           In a similar study, groups of 15 pregnant New Zealand white
    rabbits were given daily s.c. injections of 0, 40, or 79 g
    dexamethasone/kg bw/day on days 6-18 of gestation. Compared to the
    control group all treated dams had reduced body weight and their
    resorption rates were increased. No treatment-related effect on
    gross malformations was observed (Segro, 1970).

    2.2.6  Special studies on endocrine toxicity

           Groups of Cpb:WU rats (10/sex/group) were orally administered
    (by gavage) doses of 0, 0.3, 1, 3, 10, 30, or 100 g dexamethasone/
    kg bw/day for 90 days. Observations included clinical signs, body
    weight, water consumption, haematology, IgG/IgM determinations,
    gross post mortem examination, adrenal and thymus weight,
    histopathology, ACTH stimulation test (4 rats/sex/group), and
    corticosteroid determinations.

           Significant decreases in body-weight gain (more pronounced in
    males than in females) were observed at doses of >10 g/kg
    bw/day. In males of the same groups sluggishness and erected fur
    were observed, which were considered to be treatment-related. WBC

    and  differential WBC counts were significantly decreased in rats at
    >10 g/kg bw/day. WBC counts were also significantly reduced in
    females at 3 g/kg bw/day. IgG and IgM levels were significantly
    decreased at 100 g/kg bw/day. Decreases in adrenal and thymus
    weights were observed and accompanied by histopathological changes,
    including atrophy and structural disorganization, at >10 g/kg
    bw/day. In the same dose groups dose-related decreases in
    corticosterone levels with or without ACTH stimulation were
    observed. The Committee concluded that the NOEL in this study was at
    1 g/kg bw/day (De Jong & Coert, 1987).

           Rats (6/group) were administered a dose of 0, 0.5, 1, 1.5, 2,
    or 4 g dexamethasone/kg bw/day by gavage for 1 and 7 days. Five
    hours after the last application the rats were killed and blood and
    liver samples were taken. Tyrosine amino transferase (TAT) activity
    in the supernatant of liver homogenates was measured and serum
    corticosterone concentrations were determined. TAT activity was
    increased in a dose-dependent manner at 2 and 4 g/kg bw/day and a
    significant decrease in serum corticosterone was seen at 4 g/kg
    bw/day. The NOEL in this study was 1.5 g/kg bw/day (Kietzman, 1991;
    Bette & Kietzmann, 1991).

    2.2.7  Special studies on genotoxicity

           The results of genotoxicity studies are summarized in Table 2.

    2.2.8  Special studies on immune response

         The influence of dexamethasone-21-isonicotinate on the course
    of experimental bacterial infections of mice and their therapy, on
    the phagocytotic activity of the reticulo-endothelial system and the
    serum protein picture was investigated. No clear effect on
    antibiotic therapy was observed. Dexamethasone-21-isonicotinate
    decreased the activity of Celasin C and penicillin G-procain against
    streptococcal infections and improved the activity of both
    substances against staphylococcal infections. No quantitative effect
    was observed upon serum albumin, alpha1, alpha2, 1, 2 or
    gamma-globulins of mice both 48 hours after a single s.c. treatment
    or 24 hours after 5 days of treatment (once a day s.c.) with 75,
    150, or 300 g dexamethasone 21-isonicotinate/kg bw (Goeth &
    Lechner, 1978).

    2.3  Observations in humans

           The corticosteroid suppressive effect of dexamethasone is well
    known and used for the definitive diagnosis of Cushing syndrome in
    human patients. People with Cushing syndrome suffer from a chronic
    over-production of cortisol resulting from an over-production of
    ACTH. In the "low- and high-dose dexamethasone suppression test" the
    subjects receive 0.5 or 2 mg dexamethasone orally every 6 hours for

    
    Table 2:  Results of genotoxicity assays on dexamethasone and
              dexamethasone-21-isonicotinate
                                                                                   

    Test system   Test object      Concentration   Purity  Results     Reference
                                                                                   

     In vitro

    Ames testa     S.typhimurium   10-1000         99%     negativec   Baumeister,
                  TA98, 100,       g/pl                               1988a
                  1535, 1537
                   E. coli , WP2

    Fluctuation   Mouse            12.5-400        99.4%   negativee   Clements,
    assayb,d      lymphoma         g/ml                               1992
                  L5178Y cells

     In vivo

    Micronucleus  NMRI mice        i.v. 5 mg/kgf   97.5%   negativeg   Baumeister,
    testsa                                                             1988b
                                                                                   

    a    Test substance: dexamethasone 21-isonicotinate.
    b    With and without metabolic activation.
    c    Appropriate positive controls were used.
    d    Test substance: dexamethasone.
    e    4-Nitroquinoline and benzo(a)pyrene were used as positive controls.
     f    The initial dosage (107.5 mg/kg) had to be reduced due to acute
         toxicity (tonic convulsions, deaths) of the excipient 1,
         2-propylenglycol.
    g    Cyclophosphamide was used as positive control.
    
    2 consecutive days. In normal healthy persons cortisol production,
    determined as 17-hydroxycorticosteroid or 17-ketosteroid excretion
    in urine, is suppressed, whereas in patients with Cushing syndrome
    cortisol production is not suppressed. No significant clinical side
    effects of this dexamethasone suppression test were reported (Crapo,
    1979).

    3.  COMMENTS

           Information from studies on dexamethasone, including data on
    kinetics, metabolism, acute and short-term toxicity, developmental
    toxicity, and genotoxicity, was available for assessment.

           Toxicokinetic studies revealed rapid absorption after i.m.
    administration to dogs and rats with peak plasma levels found after
    30 minutes and 6 hours, respectively. Dexamethasone is rapidly
    excreted in urine and faeces. Dexamethasone esters are rapidly
    hydrolyzed in serum. Biotransformation in rats and humans is
    comparable and involves mainly hydroxylation to 6-hydroxy- and
    20-dihydro-dexamethasone. However, there was additional evidence
    that at high (therapeutic) doses in people, dexamethasone is
    metabolized by an additional route involving epoxidation.

           Following repeated oral administration of dexamethasone to rats
    and dogs in short-term toxicity studies the main target organs were
    the thymus and the adrenal gland. Corticosteroid concentrations in
    plasma and hepatic glycogen were reduced, whereas serum lipid levels
    were increased. In rats dosed orally with 0.3, 1, 3, 10, 30, or 100
    g dexamethasone/kg bw/day for 90 days, thymus involution and
    morphological changes in the adrenal gland and a decrease in
    corticosterone and white blood cell counts were observed in male and
    female rats at doses above 10 g/kg bw/day. Due to the decrease in
    white blood cell counts in female rats at 3 g/kg bw/day this dose
    was considered to be a marginal effect level. In a study with rats
    orally dosed with 0.5, 1, 1.5, 2, or 4 g/kg bw/day dexamethasone
    for 7 days the corticosterone concentration was reduced in the
    highest-dose group and the activity of tyrosine aminotransferase in
    the liver was increased in a dose-related manner at 2 and 4 g/kg
    bw/day. The NOEL in this study was 1.5 g/kg bw/day.

           No reproduction studies with dexamethasone were available but
    an increase in pre- and post-implantation loss and a reduction in
    fetal weight were observed in teratogenicity studies in mice, rats,
    and rabbits receiving dexamethasone by injection. In these studies
    malformations such as hydrops fetalis, cleft palate, exencephaly,
    and encephalocele were observed at maternally toxic dose levels.

           In oral teratogenicity studies with rats using dose levels
    ranging from 10 to 1250/kg bw/day, maternal toxicity was found at 50
    g/kg bw/day and above. At doses at and above 1000 g/kg bw/day,
    dexamethasone caused structural malformations (hydrops fetalis,
    cleft palate). Thymus involution and a decrease in body weight were
    observed in fetuses, resulting in an overall NOEL for embryotoxicity
    in rats of 10 g/kg bw/day.

           Long-term toxicity/carcinogenicity data were not available.

    4.  EVALUATION

           Based on its long history of use in human medicine and because
    dexamethasone was negative in  in vitro gene mutation assays with
    bacteria and mammalian cells and in an  in vivo micronucleus test
    with mice, the Committee was not concerned about the carcinogenic
    potential of dexamethasone.

           Using a safety factor of 100 the Committee established an ADI
    of 0-0.015 g/kg bw/day for dexamethasone based on a NOEL of 1.5
    g/kg bw/day for the induction of tyrosine aminotransferase activity
    in rat liver. Due to the careful selection of the dose levels in
    this study the Committee did not round this figure.

    5.  REFERENCES

    BAUER, O., LEHMANN, & UEBERBERG, H. (1969a) Rat study to screen
    pyridine-4-carboxylic acid-(dexamethasone-21')-ester (HE 111) for
    subacute toxicity in comparison with dexamethasone. Unpublished
    report d.d. 12 June 1969 from Dr. K. Thomas GmbH, Dept. of
    Experimental Pathology and Toxicology, Biberach, Germany. Submitted
    to WHO by Boehringer Ingelheim Vetmedica GmbH, Ingelheim, Germany.

    BAUER, O., PAPPRITZ, & UEBERBERG, H. (1969b) Investigation into the
    subacute toxicity of pyridine-4-carboxylic acid (dexamethasibe-21')
    ester (HE 111) in comparison with dexamethasone in dogs. Unpublished
    report No. AX-U-30 d.d.21-4-1969 from Dr. Karl Thomas, GmbH,
    Biberach, Germany. Submitted to WHO by Boehringer Ingelheim
    Vetmedica GmbH, Ingelheim, Germany.

    BAUMEISTER, M. (1988a) Mutagenicity study with HE III XX (Voren) in
    the  S. typhimurium and  E. coli/mammalian microsome assay (Ames
    Test). Unpublished report no. Gen Tox. 39/87 d.d. 5 February 1988
    from Dr. K. Thomas, GmbH, Dept. of Experimental Pathology and
    Toxicology, Biberach, Germany. Submitted to WHO by Boehringer
    Ingelheim Vetmedica GmbH, Ingelheim, Germany.

    BAUMEISTER, M. (1988b) Mutagenicity study with HE III XX (Voren) in
    the bone marrow micronucleus assay. Unpublished report no. Gen Tox.
    40/87 d.d. 8 February 1988 from Dr. K. Thomas, GmbH, Dept. of
    Experimental Pathology and Toxicology, Biberach, Germany. Submitted
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    BETTE, P. & KIETZMANN, M. (1991) Effect of dexamethasone on tyrosine
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    CRAPO, L. (1979) Cushings syndrome: A review of diagnostic tests.
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    CLEMENTS, J. (1992) Study to determine the ability of dexamethasone
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    lymphoma L5178Y cells using a fluctuation assay. Unpublished report
    no. 2TKREBSG.001 from Hazleton Microtest Limited, York, England.
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    COERT, A., HOEIJMAKERS, M., VAN RENS, P. (1988) The  in vitro
    hydrolysis of dexamethasone dimethylbutyrate in cows plasma.
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    De JONG, H. & COERT, A. (1987) The determination of the hormonal
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    The Netherlands.

    DRUGA. A. (1993a) Pilot teratology study (Segment II) of
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    DRUGA, A. (1993b) Teratology study (segment II) of dexamethsone in
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    ENGELHARDT, G. (1963). Pharmacological expos on substance HE III.
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    ENGLISH, J., CHAKRABORTY, J. & MARKS, V. (1975) The metabolism of
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    GOETH, H. & LECHNER, V. (1978) Investigation on the influence of
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    with antibiotics and sulphonamides as well as on the phagocytotic
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    HORNER, M.W. (1989) Pharmacokinetics of dexamethasone in pig plasma
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    report d.d. November 1989, Ciba Geigy Project no. 4. from
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    HOUGHTON, E., GRAINGER, L. & TEALE, P. (1989) The  in vitro
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    INTERVET, (undated I) Chronic oral toxicity study with dexamethasone
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    INTERVET, (undated II) Chronic oral toxicity study with
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    KIETZMAN, M. (1991) Report of a study in rats to investigate the
    effect of dexamethasone on tyrosine aminotransferase activity in the
    liver and on serum corticosterone levels. Veterinary College,
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    LEHMANN, (1969a) Reproduction study comparing the compound HEIII
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    by Boehringer Ingelheim Vetmedica GmbH, Ingelheim, Germany.

    LEHMANN, (1969b) Reproduction study on the substance HEIII versus
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    Germany. Submitted to WHO by Boehringer Ingelheim Vetmedica GmbH,
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    PEETS, E.A., STAM, M. & SYMCHOWICZ, C. (1969) Plasma binding of
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    SEGRO, G. (1970) Expertise on HE111 in rats and rabbits. Report d.d
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    UEBERBERG, H. (1963) Comparative experimental trials in dogs with
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    dexamethasone. Unpublished report no. AX-U-3 d.d.20-12-1963 from Dr
    Karl Thomas, GMBH, Biberach, Germany. Submitted to WHO by Boehringer
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    UEBERBERG, H. (1964) Comparative investigations in rats with
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    UMEMURA, M., KAST, A. & IIDA, H. (1972) Teratologica; testing of
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    WALKER, B.E. (1967) Induction of cleft palate in rabbits by several
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    50: 665.


    See Also:
       Toxicological Abbreviations
       DEXAMETHASONE (JECFA Evaluation)