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    SULFADIMIDINE

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

    1.  EXPLANATION

        Sulfadimidine is a sulfonamide used to treat a variety of
    bacterial diseases in humans and other species and to promote growth
    in food-producing animals. It had been previously reviewed at the
    thirty-fourth Meeting of the Committee (Annex 1, reference 85), when
    a temporary ADI of 0-4 g/kg bw/day was established based on a NOEL
    of 2.2 mg/kg bw/day for thyroid follicular cell hyperplasia in the
    rat and applying a safety factor of 500. A toxicological monograph
    was published after the Meeting (Annex 1, reference 86). At that
    time the Committee was aware of additional studies in progress
    concerning the mechanism of action of sulfadimidine on the thyroid
    gland and requested that the results of those studies should be
    submitted by 1991. At the thirty-eighth Meeting (Annex 1, reference
    97) the final reports were not available and the Committee extended
    the temporary ADI.

        At its present meeting these studies and additional information
    regarding genotoxicity and embryotoxicity and teratogenicity were
    reviewed and are summarized in this monograph addendum.

    2.  BIOLOGICAL DATA

    2.1  Toxicological studies

    2.1.1  Special studies on embryotoxicity and/or teratogenicity

    2.1.1.1  Rats

        Groups of pregnant CD rats were dosed by gavage with 0, 540,
    680, or 860 mg sulfadimidine/kg bw/day on days 6-15 of gestation.
    Dams were killed on day 20 of gestation. Observations included
    clinical signs, mortality, maternal body and liver weight, the
    number of resorptions, live and dead fetuses, litter size, and fetal
    weight. All fetuses were subjected to gross, skeletal, and visceral
    examinations.

        One dam from the low-dose group died during the study. In all
    treated dams the incidences of alopecia, rough coat, light-coloured
    faeces, and urine stains were increased. Maternal body-weight gain
    was decreased and relative liver weight was increased in all treated
    dams. In the high-dose group, fetuses had decreased body weights and
    the number of malformed fetuses/litter was increased. The incidence
    of gross or visceral malformations of fetuses/litter was increased
    at 860 mg/kg bw/day with the predominant malformations being cleft
    palate, hydroureter, and hydronephrosis. The incidence of
    hydroureter and hydronephrosis was also elevated in the mid-dose
    group. The NOEL for embryo- and fetotoxicity was 540 mg/kg bw/day
    (Wolkowski-Tyl  et al., 1982).

    2.1.1.2  Rabbits

        Groups of pregnant female New Zealand white rabbits were orally
    administered sulfadimidine (by gavage) at 0, 600, 1200, 1500, or
    1800 mg/kg bw/day on days 6 to 19 of gestation. Dams were killed on
    day 30 of gestation. No effects were observed on the number of
    corpora lutea, implantation sites or implantation loss, number of
    live fetuses sex distribution/litter, or fetal body weight. The
    incidences of gross, visceral, or skeletal malformations were not
    increased. No treatment-related effects were observed on the weight
    or gross appearance of the kidneys. A dose-related occurrence of
    clinical signs such as alopecia, pink or red ears, and weepy eyes
    was observed in treated dams. Maternal mortality was 3.0, 6.0, 4.0,
    20, and 19% in the 0, 600, 1200, 1500, and 1800 mg/kg bw/day
    treatment groups, respectively. Maternal body-weight gain was
    significantly decreased at 1200, 1500, and 1800 mg/kg bw/day. A
    dose-related increase in the percent resorptions and fetal
    deaths/litter was observed. The NOEL for embryotoxicity was 1200
    mg/kg bw/day (Wolkowski-Tyl  et al. , 1982).

    2.1.2  Special studies on genotoxicity

        The results of  in vitro and  in vivo genotoxicity studies on
    sulfadimidine are summarized in Table 1.

    2.1.3  Special studies on thyroid function

    2.1.3.1   In vitro

        The addition of 0, 10, or 80 g/ml sulfadimidine to normal rat
    serum did not affect the TSH, T3, or T4 concentrations. However,
    addition of 80 g/ml sulfadimidine resulted in a significant (28%)
    increase of rT3 (Braverman & DeVito, 1991).

        In a rat thyroid follicular cell line, FRTL-5, the effect of
    sulfadimidine on thyroid follicular cell proliferation was studied
    in the presence and absence of TSH. Sulfadimidine (10-11 to 10-5
    M) treatment for 24 hours in the absence of TSH did not increase
    FRTL-5 cell proliferation. In the presence of TSH, sulfadimidine
    (>10-9 M) enhanced the proliferative effect as compared to TSH
    alone. A lag period of 16 to 24 hours was shown before the
    augmentation of the effects of sulfadimidine was observed (Lipman
     et al., 1993).

        The inhibition of thyroid gland peroxidase was studied in dog
    thyroid gland microsomes. Incubation with sulfadimidine resulted in
    a linear inhibition of thyroid peroxidase between concentrations of
    0.2 and 6 x 10-6 M (3 to 95% inhibition). The IC50 was
    calculated to be 1.2 x 10-6 M (Downing & McClain, 1993).

        Sulfadimidine competitively inhibits lactoperoxidase, an enzyme
    closely related to thyroid peroxidase. This observation might
    suggest that the primary mechanism for sulfonamide-induced
    hypothyroidism is competitive inhibition of thyroid
    peroxidase-mediated thyroid hormone synthesis (Doerge, 1993).

    2.1.3.2  Rats

        Three replicates of six groups of 5 Fischer 344 rats were fed
    diets containing sulfadimidine at concentrations of 0, 300, 600,
    1200, 2400, or 4800 mg/kg of feed (equal to 18, 36, 74, 148, or 275
    mg/kg bw/day), for 4 weeks. Blood samples were taken at weekly
    intervals for TSH levels. At the end of the study all thyroid glands
    were removed and weighed. TSH levels were significantly elevated in
    rats consuming the 2400, and 4800 mg/kg sulfadimidine diets. At 600
    and 1200 mg/kg feed a slight increase in TSH levels was seen.
    Thyroid weights at 4800 mg/kg feed were about 3 times controls
    (Cullison & Furrow, 1990).

        Table 1:  Results of genotoxicity assays on sulfadimidine
                                                                                       

    Test system   Test object      Concentration   Purity   Results      Reference
                                                                                       

     In vitro

    Ames testa     S. typhimurium  0-1000 g/pl       ?     negativeb    Mortelmens
                  TA100, 1535,     in DMSO                                et al., 1986
                  1537, 98

    Chromosomal   CHO cells        1081-5000          ?     negativeb    NTP, undated
    aberration                     g/ml in
    assaya                         DMSO

    HGPRT forward CHO-cells        0.5-7.0 mg/l     96.6%   negativeb    Young, 1988
    mutation
    assaya

    Sister        CHO, cells       167-2000           ?     positiveb,d  NTP, undated
    chromatid                      g/ml in                 negativeb,e
    exchange                       DMSOc
    assaya

    UDS           human            up to 100          ?     negative     Allred  et al.,
                  fibroblasts      g/ml                                 1982

     In vivo

    Chromosomal   rat, bone        po 750, 1500       ?     negativeb    Ivett, 1988
    aberrations   marrow           and 3000
                                   mg/kg bw
                                                                                       

    a    Without and with metabolic activation.
    b    Appropriate positive controls were used.
    c    Lumpy precipitate formed at >1500 g/ml but dissolved immediately; pH
         at >1500 g/ml was 6.85; pH of untreated medium was 7.1.
    d    Without metabolic activation.
    e    With metabolic activation, only one fixation time, no second
         independent study.
    
         Groups of 60 to 70 male rats (Fischer 344) were fed diets
    containing sulfadimidine sodium salt at concentrations of 0, 40,
    150, 600, 2400, or 4800 mg/kg feed (equal to 0, 2.2, 8.5, 34, 136,
    or 261 mg/kg bw/day) for 13 weeks. Groups of 20 rats/dose were
    killed at 4, 8, and 13 weeks. Ten control rats and 10 rats receiving

    2400 mg/kg sulfadimidine sodium salt in the feed were kept for a
    recovery period of another 13 weeks and then killed. Observations
    included clinical signs, body weight, food consumption, T3, rT3,
    T4 and TSH determinations, and gross post mortem examination.
    Thyroid and pituitary weights and histopathology on the thyroid and
    pituitary glands were evaluated in rats from the 0, 2400, and 4800
    mg/kg feed groups only.

         Mean body weight was slightly decreased throughout the
    treatment period in rats consuming diets containing 2400 and 4800
    mg/kg sulfadimidine sodium salt. Thyroid weight was increased in
    these same dose groups at all time points. Pituitary weights were
    increased only at week 13. In the recovery group, only the thyroid
    weight remained elevated over the controls. Significant increases in
    TSH concentrations were observed in animals fed the 2400 and 4800
    mg/kg feed diets; highest concentrations were observed after 4 weeks
    (especially at the high dose) and declined thereafter. In the
    high-dose group, T4 concentrations were significantly decreased
    compared to control values at weeks 4 and 8, while T3 values were
    significantly decreased at weeks 4, 8, and 13 (T4 was slightly
    decreased after 13 weeks of treatment). After the recovery period
    TSH concentrations were depressed compared to controls.
    Dose-dependent vacuolation of chromophobe cells of the pituitary
    gland was observed in animals from the two highest dose groups. This
    effect was found to regress with time. Complete recovery was
    observed after the withdrawal period. Hyperplasia and hypertrophy of
    the thyroid were also observed in the two highest dose groups. In
    rats fed diets containing 600 mg/kg sulfadimidine, hyperplasia and
    limited hypertrophy were seen in some rats at weeks 4 and 8 but not
    at week 13. There was complete recovery of the changes noted in the
    thyroid after the recovery period. The NOEL in this study was 150
    mg/kg feed, equal to 8.5 mg/kg bw/day (Braverman & DeVito, 1991;
    Richter, 1992; Bio/dynamics, 1992).

         In an exploratory study groups of 20 rats/sex (Charles River
    CD; 10-12 weeks old) were orally administered (via dietary
    admixture) sulfadimidine at dosages of 0, 1, 2.5, 5, 10, 25, 50,
    100, 200, 400, or 600 mg/kg bw/day for 4 weeks. At two weeks, five
    rats from each group, and at 4 weeks 15 rats from each group were
    killed. Parameters evaluated included clinical signs, mortality,
    body weight, food consumption, T3, rT3, T4 and TSH, gross post
    mortem examination, thyroid weight, and histopathology of the
    thyroid gland from all rats (sacrificed after 4 weeks of treatment)
    of all groups. A 'thyroid functional morphology index' was
    determined. This index was based on the size of the follicles, the
    amount and functional properties of follicular colloid, and the
    follicular-cell height. The total score ranged from 0 to 4.

         One death occurred in the 10 and 600 mg/kg bw/day dose groups.
    Neither death was considered to be treament-related. Significant and
    dose-related decreases in body-weight gain and food consumption
    occurred in the 400 and 600 mg/kg bw/day dose groups. At both 2 and
    4 weeks plasma T4 and T3 levels decreased significantly at doses
    >200 mg/kg bw/day (94% and 60% reduction at 600 mg/kg bw/day for
    T3 and T4, respectively). Plasma TSH levels were increased
    >200 mg/kg bw/day at both 2 and 4 weeks. A tendency for increase
    in this parameter was also seen at 100 mg/kg bw/day. A significant
    and dose-related increase in absolute and relative thyroid gland
    weight occurred at dosages of >200 mg/kg bw/day. At 2 weeks of
    treatment thyroid weight of animals treated with 600 mg/kg bw/day
    increased more than 2-fold and after 4 weeks more than 2.5 fold.
    Histopathology findings included a dose-related increase in the
    'thyroid functional morphology index' starting with 0.07 at 10 mg/kg
    bw/day and increasing to 3.8 at 600 mg/kg bw/day. Both hypertrophy
    and hyperplasia of thyroid follicular cells were dose-related with
    an incidence range of 1/14 at 10 mg/kg bw/day to 14/14 at 600 mg/kg
    bw/day for hypertrophy, and 13/15 at 200 mg/kg bw/day to 14/14 at
    600 mg/kg bw/day for hyperplasia (see Table 2). The NOEL in this
    study was 5 mg/kg bw/day (McClain  et al., 1993a).

         Groups of 35 male rats [CDF (F344)/CrLBR] were fed diets
    containing 0 or 2400 mg sulfadimidine/kg feed (equivalent to 120
    mg/kg bw/day) for 13 weeks. Supplemental thyroid hormone (T4/T3:
    molar ratio 9:1) was incorporated into the sulfadimidine diet at
    concentrations of 10, 20, 30, or 40 g/kg of feed. These
    sulfadimidine/thyroid hormone feeds were administered to groups of
    35 rats each. Ten rats/group were killed at weeks 2 and 4 and the
    remaining 15 rats were euthanized at week 13. No effects were
    observed on clinical signs and no deaths occurred.

         Body weights were reduced compared to the controls throughout
    the treatment period in rats receiving diets containing the
    sulfadimidine + 40 g/kg feed thyroid hormone. All treated groups
    showed reduced food consumption at week 2 that returned to normal at
    week 4, except for the groups receiving sulfadimidine + 30 or 40
    g/kg feed thyroid hormone diets. At the end of the treatment period
    food consumption was reduced only in rats receiving sulfadimidine
    alone. T3 levels were significantly decreased at week 2 in all
    dose groups. This effect was more pronounced with an increasing dose
    of thyroid hormone. At 4 and 13 weeks the decrease was significant
    in animals consuming diets containing sulfadimidine with >20
    g/kg feed hormone. T4 levels were increased at 2 and 4 weeks in
    the groups receiving sulfadimidine and >20 g/kg feed thyroid
    hormone, but were less pronounced at the highest dose. After 13
    weeks T4 levels were increased in all dose groups. Reverse T3
    levels were not consistently affected by treatment. Administration
    of thyroid hormone prevented the TSH increase observed in the rats
    receiving sulfadimidine only, in a dose- and time-dependent manner.

        Table 2:  Incidence of histopathologic changes in rats treated for
          4 weeks with sulfadimidine
                                                                                   

    SULFADIMIDINE
    (mg/kg bw/day)                      THYROID FOLLICULAR CELLS
                                                                                   

                                     Hypertrophy          Hyperlasia
                                                                                   

          0                              0/15                0/15

          1                              0/15                0/15

          2.5                            0/15                0/15

          5                              0/15                0/15

          10                             1/14a              0/14a

          25                             2/15                0/15

          50                            11/15                0/15

          100                           13/14b               0/14b

          200                           15/15               13/15

          400                           15/15               15/15

          600                           14/14a              14/14a
                                                                                   

    a     One rat died during the experiment.
    b     The thyroid gland was missing from one rat.
    
    At the high-dose of 40 g/kg feed hormone, TSH levels were even
    decreased (60-70% compared to controls) at 2, 4, and 13 weeks.
    Thyroid weight was increased in rats administered sulfadimidine
    alone at all the time points. Supplemental treatment of the feed
    with 20 or 30 g/kg thyroid feed hormone prevented this increase. At
    the high-dose of 40 g/kg of feed, thyroid weight was significantly
    decreased.

         Treatment with a combination of thyroid hormone and
    sulfadimidine reduced the diffuse hypertrophy and diffuse
    hyperplasia observed with sulfadimidine alone in a dose-related
    manner. Reduced follicular activity (flattened epithelium and
    distended follicles) was observed in rats consuming diets containing
    40 g/kg feed thyroid hormone at weeks 2, 4, and 13 and in the 30
    g/kg feed thyroid hormone group only at 13 weeks (McClain  et al.,
    1993c).

          Groups of 6 normal and 6 hypophysectomized male rats (CDF
    (F-344/CrlBR; 11 weeks of age) were fed diets containing
    sulfadimidine at concentrations of 0, 2400, or 4800 mg
    sulfadimidine/kg feed (equivalent to 120 and 240 mg/kg bw/day) for 7
    days, then all rats were killed. Observations included clinical
    signs, mortality, body weight, food consumption, plasma measurements
    of T3, rT3 and T4, thyroid weight, and histopathology of the
    thyroid.

         One hypophysectomized rat in the 2400 and two normal rats in
    the 4800 mg/kg feed groups died. None of the deaths was considered
    to be treatment-related. Treated hypophysectomized rats had lower
    body-weight gains and food consumption than treated normal rats. The
    decrease in plasma T3, rT3, and T4 concentrations observed in
    normal rats was significant and dose-related in both dose groups. In
    hypophysectomized rats plasma concentrations of T3, rT3, and
    T4 were decreased by 84, 82 and 92%, respectively, as compared to
    the levels in normal control rats. These low levels were not
    affected by sulfadimidine treatment. Absolute and relative thyroid
    weights increased significantly in normal rats consuming diets
    containing 2400 and 4800 mg sulfadimidine/kg feed. In the
    hypophysectomized rats, relative thyroid weights tended to be
    slightly less than those of normal controls, but no effects of
    sulfadimidine treatment were found. Follicular-cell hypertrophy and
    hyperplasia were observed in normal sulfadimidine-treated rats.
    Thyroids of hypophysectomized rats had a less active appearance.
    Sulfadimidine treatment, however, did not induce histological
    changes in hypophysectomized rats (Downing  et al., 1993).

         To investigate the effects of a low-iodine diet on thyroid
    function, groups of 40 male rats (CDF (F-344)/CrL BR; 10-12 weeks
    old) were administered modified Remington control or Remington
    low-iodine diets for 13 weeks. The control diet contained 0.26 mg
    iodine/kg feed and the low-iodine diet contained <0.1 mg iodine/kg
    feed. Ten rats/group were assigned to a recovery group and allowed
    to recover for 13 weeks on a control diet. Another ten rats from
    each group were killed after 4, 8, or 13 weeks of treatment or after
    13 weeks of recovery.

         No significant effect on plasma T3 levels was observed with
    the low-iodine diet; normal values were maintained throughout the
    experiment. Plasma T4 levels were reduced in a time-related manner
    in rats fed the low-iodine diet. After 13 weeks of treatment, plasma
    T4 levels were about 8% of controls. Reverse T3 levels decreased
    significantly in the low-iodine group. This decrease was also
    time-related. After 4 weeks of treatment the levels were about 15%
    of control values and after 8 and 13 weeks the levels were at or
    below the detection limit. Plasma TSH levels increased in a
    time-dependent manner. After 13 weeks on low iodine treatment, TSH
    increased almost 6-fold over control values. In the low-iodine
    treatment group there was a time-related increase in absolute and
    relative thyroid weight (about 5-fold) at 13 weeks. After 13 weeks
    recovery, TSH levels returned to normal, plasma T4 and rT3
    levels were significantly elevated to about 150% when compared to
    controls, and the increased absolute and relative thyroid weights
    were diminished, although they were still increased compared to the
    controls. Histopathology of thyroid glands from animals fed
    low-iodine diet after 4, 8, and 13 weeks showed hypertrophy of
    follicular epithelium, expressed by the presence of columnar
    epithelium. Diffuse hyperplasia was also present, the severity of
    which increased with time. After the 13 week recovery period the
    hypertrophy and hyperplasia disappeared almost completely. In 3
    animals focal cystic hyperplasia was present, and in one animal a
    follicular cell adenoma was found (McClain  et al., 1993b).

    2.1.3.3  Pigs

         The study described here consisted of two separate studies, run
    consecutively. In the first study 2 groups of 5 intact male weanling
    pigs received diets containing 0, or 5000 mg sulfadimidine/kg of
    feed (equivalent to 0 or 200 mg/kg bw/day). A positive control group
    was fed a diet containing propylthiouracil at 400 mg/kg of feed.
    Blood samples were collected at two-week intervals for 12 weeks. In
    the second study 4 groups of 5 animals were used. Two groups were
    fed unmedicated feed and two groups were fed diets containing 2000
    mg sulfadimidine/kg of feed (equivalent to 80 mg/kg bw/day). One of
    the two groups was pair-fed and the other  ad lib. Blood samples
    in this study were collected at weekly intervals for 4 weeks. In
    both studies blood was analyzed for TSH, T4, and T3 levels.

         In the first study, from week 4 onwards, the sulfadimidine and
    the positive control groups consumed less than half as much feed as
    the control group, resulting in body weights that were half those of
    control animals. Thyroid weights for the sulfadimidine-treated group
    averaged five times those for control animals. Average TSH levels
    were 48 and 14 times the controls for sulfadimidine-treated and
    positive control groups, respectively. T4 levels were inversely
    proportional to the TSH values, dropping to 4% of controls by week
    2.

         In the second experiment all groups had comparable body
    weights. The TSH values in the sulfadimidine-treated groups were
    considerably elevated (about 25 times the control values) and the
    T4 values were about 10 times lower than controls.

         Histopathological examination of animals from the first
    experiment showed follicular cell hyperplasia of the thyroid gland
    and chromophobe cell hyperplasia of the pituitary gland. In the
    second study only the thyroid glands were examined and the presence
    of follicular cell hyperplasia was reported (Cullison  et al.,
    1990a).

         Groups of 5 male weanling pigs received diets containing 0,
    125, 250, 500, or 1000 mg sulfadimidine/kg feed (equivalent to 0, 5,
    10, 20, or 40 mg/kg bw/day) for 4 weeks. Blood samples were taken
    weekly and analyzed for TSH, T4, and T3 levels. At the end of
    the experiment the thyroid glands were removed, weighed, and
    examined histologically. At the highest dose, average TSH levels
    increased markedly, and peaked at week 3 at about 10 times the
    controls. There was a considerable difference in the response of the
    five animals. T4 levels inversely mirrored those for TSH in the
    highest-dose group, showing a maximum decrease to about half the
    control value at week 3. T4 levels varied considerably, but
    individual animals showed good correlation between decreases in T4
    and increases in TSH. Thyroid weights of animals in the highest-dose
    group increased remarkably, averaging 17 grams versus 4 grams for
    controls. Thyroid follicular hypertrophy or follicular cell
    hypertrophy and hyperplasia was noted in the 250 mg/kg feed dose
    group and higher. The NOEL in this study was 125 mg/kg feed,
    equivalent to 5 mg/kg bw/day (Cullison  et al., 1990b).

    2.1.3.4  Monkeys

         Groups of Cynomolgus monkeys (4/sex/group) were orally
    administered doses of 0, 30, 100, or 300 mg sulfadimidine sodium/kg
    bw/day for 13 weeks. No effects were observed on clinical signs,
    mortality, body weight, food consumption, ophthalmoscopy,
    electro-cardiogram, myeloid to erythroid ratio, gross pathology,
    pituitary weight or histopathology. In particular, no depression of
    T3 or T4, increase in TSH, increase in thyroid weight or notable
    changes in the thyroid morphology were observed. The highest dose,
    300 mg/kg bw/day was the NOEL (Markiewicz, 1991).

    3.  COMMENTS

         In a teratogenicity study with rats orally dosed with 0, 540,
    680, or 860 mg sulfadimidine/kg bw/day, the incidences of cleft
    palate and minor visceral malformations were increased at the two
    highest doses, giving a NOEL of 540 mg/kg bw/day. In a similar study
    in rabbits with dose levels up to 1800 mg/kg bw/day no malformations
    were observed, but dose-related increased incidences of resorptions
    and fetal death were observed. The NOEL for embryotoxicity was 1200
    mg/kg bw/day.

         A range of  in vitro and  in vivo genotoxicity tests were
    generally negative. A positive result was obtained with a sister
    chromatid exchange assay in the absence of metabolic activation. The
    protocol did not meet current standards.

         In several short-term toxicity studies with rats administered
    sulfadimidine in the diet up to a dose of 600 mg/kg bw/day an
    increase in thyroid weight, decreases in plasma concentrations of
    the thyroid hormones T3, and T4, and an increase in TSH were
    observed. These changes were accompanied by hypertrophy and
    hyperplasia of thyroid follicular cells. The overall NOEL in these
    studies was 5 mg/kg bw/day. In pigs administered sulfadimidine in
    the diet for four weeks at doses of 0, 5, 10, 20, or 40 mg/kg
    bw/day, similar effects were observed with a NOEL of 5 mg/kg bw/day.
    In monkeys orally administered 0, 30, 100, or 300 mg/kg bw/day
    sulfadimidine no effects on the thyroid gland were observed.

         The Committee noted that the available studies dealt with
    relevant and sensitive end-points with respect to the toxic effects
    of sulfadimidine on the thyroid gland, and concluded that the
    tumours seen at high dose levels of sulfadimidine are due to
    enhanced hormonal stimulation of the thyroid gland through elevated
    TSH levels and not to a direct action of sulfadimidine.

         The significance of the formation of the reactive diazonium
    intermediate formed in the GI tract by bacterial action was also
    considered. Because the diazonium ion covalently binds to intestinal
    contents the Committee concluded that it was not of toxicological
    concern.

    4.  EVALUATION

         Considering all available information, including the studies
    evaluated at the thirty-fourth meeting (Annex 1, reference 85), the
    Committee established an ADI of 0-50 g/kg bw/day based on an
    overall NOEL of 5 mg/kg bw/day observed in rats and pigs for changes
    in thyroid morphology and applying a safety factor of 100.

         Although it was recognized that primates (including humans) are
    less susceptible than rats and pigs to the antithyroidal effect of
    sulfonamides, the Committee noted that in individuals sensitized to
    sulfonamides, hypersensitivity reactions may occur as a result of
    the ingestion of sulfadimidine residues in food of animal origin. In
    line with the previous evaluation (Annex 1, reference 85) the
    Committee therefore recommended that the MRLs should be set as low
    as practically achievable following good practice in the use of
    veterinary drugs. In doing so, the Committee also recognized that
    these concentrations would then be below the levels considered
    significant for microbiological concern.

    5.  REFERENCES

    ALLRED, L.E., OLDHAM, J.W., MILO, G.E., KINDIG, O., CAPEN, C.C.
    (1982). Multiparametric evaluation of the toxic responses of normal
    human cells treated  in vitro with different classes of
    environmental toxicants.  J. of Ecotox. and Environm. Health , 10:
    143-156.

    BRAVERMAN, L.E. & DeVITO, W.J. (1991). A three-month study in rats
    to investigate the effects of sulfamethazine on thyroid function:
    effect on serum TSH, T3, T4 and reverse T3 concentrations.
    Unpublished report no. UM-90-201-013 from the University of
    Massachusetts Medical School, Division of Endocrinology Laboratory,
    Worcester, MA, USA. Submitted to WHO by the Animal Health Institute,
    USA.

    BIO/DYNAMICS (1992). A three-month study in rats to investigate the
    effects of sulfamethazine on thyroid function. Unpublished final
    report no. 90-3547 from Bio/dynamics, NJ, USA. Submitted to WHO by
    the Animal Health Institute, Alexandria, VA, USA.

    CULLISON, R. & FURROW, R. (1990). Evaluation of the dose-dependent
    effects of sulfamethazine on rat thyroid stimulating hormone (TSH)
    levels. Unpublished report from the Division of Veterinary Medical
    Research Center for Veterinary Medicine, US Food and Drug
    Administration. Final report for DVMR study 312.04. Submitted to the
    WHO by the US FDA, Rockville, MD, USA.

    CULLISON, R., FURROW, R., WAGNER, D., ELSASSER, T. (1990a). The
    effect of sulfa drugs on the swine thyroid. Unpublished report from
    the Division of Veterinary Medical Research Center for Veterinary
    Medicine, US Food and Drug Administration. Final report for DVMR
    studies 312.01 and 312.02 Submitted to WHO by the US FDA, Rockville,
    MD, USA.

    CULLISON, R., FURROW, R., WAGNER, D., ELSASSER, T. (1990b).
    Estimation of the sensitivity of the swine model for the goitrogenic
    effects of drugs. Unpublished report from the Division of Veterinary
    Medical Research Center for Veterinary Medicine, US Food and Drug
    Administration. Final report for DVMR study 312.03. Submitted to WHO
    by the US FDA, Rockville, MD, USA.

    DOERGE, D.R. (1993). Inhibition of thyroid hormone synthesis as a
    mechanism for sulfonamide-induced thyroid toxicity.  The
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    See Also:
       Toxicological Abbreviations
       Sulfadimidine (WHO Food Additives Series 25)
       SULFADIMIDINE (JECFA Evaluation)