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    SULFADIMIDINE

    1.  EXPLANATION

         Sulfadimidine, which is also known as sulfamethazine, is widely
    used in veterinary medicine in combination with chlortetracycline and
    penicillin in pigs for maintenance of weight gain in the presence of
    atrophic rhinitis, growth promotion and increased feed efficiency.
    Sulfadimidine is also effective against a wide variety of diseases in
    food-producing animals. Common therapeutic uses in cattle include:
    treatment of bovine respiratory disease complex (shipping fever
    complex); necrotic pododermatitis (foot rot) and calf diphtheria;
    colibacillosis (bacterial scours); coccidiosis and acute mastitis and
    acute metritis. Common therapeutic uses in sheep include: treatment of
    pasteurellosis; bacteria pneumonia; colibacillosis (bacterial scours)
    and control and treatment of coccidiosis. Common therapeutic uses in
    pigs include: treatment of bacterial pneumonia; porcine colibacillosis
    (bacterial scours); bacterial swine enteritis; and reduction in the
    incidence of cervical abscesses. Common therapeutic uses in chickens
    include: control of infectious coryza; coccidiosis; acute fowl
    cholera; and pullorum disease. Common therapeutic uses in turkeys
    include: control of coccidiosis. This compound has not been evaluated
    previously by the Joint FAO/WHO Expert Committee on Food Additives.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

         Metabolism of sulfonamide drugs in animals includes conjugation
    at the N4-position (acetyl, sulfate, glucuronic acid, and glucose),
    conjugation at the N1-position (sulfate and glucuronic acid),
    removal of the p-amino group (formation of a desamino compound), ring
    hydroxylation, and conjugation of the ring hydroxylation products. The
    major residues in tissues from swine administered sulfadimidine are
    parent compound, N4-acetyl sulfadimidine, the N4-glucose conjugate
    of sulfadimidine, and desaminosulfadimidine. Dietary nitrite enhances
    the production of the desmanino metabolite. The intermediate leading
    to the desamino metabolite is weakly mutagenic in the Ames test
    (Paulson  et al., 1981; Paulson, 1986; Paulson  et al., 1987).

    2.2  Toxicological studies

    2.2.1  Acute toxicity

         No data are available.

    2.2.2  Short-term studies

    2.2.2.1  Mice

         Sulfadimidine was administered in the feed for 90 days to five
    groups of 12 male and 12 female weanling (3-4 weeks old) B6C3F1 SPF
    mice at dosages of 300, 600, 1200, 2400, or 3600 ppm. An additional
    group of 12 male and 12 female mice served as controls and received
    untreated feed. The primary objective of the study was to establish
    appropriate doses for a carcinogencity study. There was a slight
    depression in body weight gain in male mice at all doses and in female
    mice at doses of 600 ppm and above. There was a significant increase
    in the brain to body weight ratio at the 300, 1200, and 2400 ppm in
    male mice. No other biologically significant effects were noted (Heath
    & Littlefield, 1984a, 1984b; Littlefield, 1985a).

    2.2.2.2  Rats

         Sulfadimidine was administered continuously in the feed for 90
    days to five groups of 12 male and 12 female weanling (4-5 weeks old)
    Fischer 344 rats at dosages of 300, 600, 1200, 2400, or 3600 ppm. An
    additional group of 12 male and 12 female rats served as controls and
    received untreated feed. The animals were derived from a specific
    pathogen free breeding stock and were barrier maintained throughout
    the study. The primary objective of the study was to establish
    appropriate doses for a carcinogenicity study.

         There was an increased incidence of thyroid hyperplasia at all
    doses for male rats, progressing to 100% incidence at 3600 ppm. The
    incidence rates were 0/6, 1/8, 3/8, 5/8, 9/10, and 12/12 for the
    controls, 300, 600, 1200, 2400, and 3600 ppm dose groups,
    respectively. Ultrastructural changes in the thyroid included markedly
    dilated rough endoplasmic reticulum, altered microvilli, and
    diminished colloid droplets, involving thyroid follicular cells and
    compartmentalization of colloid within the follicular lumina. Thyroid
    gland enlargement was evident at necropsy in 12 of 24 rats receiving
    3600 ppm and in 1 of 24 rats receiving 2400 ppm. There was increased
    incidence of thyroid hyperplasia at 2400 and 3600 ppm in the females.
    Incidence rates were 9/11 and 10/11 in the 2400 and 3600 ppm dose
    groups, respectively. In addition, there was a slight reduction in
    body weight gain in the females in the 2400 and 3600 ppm dose groups.
    No other biologically significant effects were noted (Heath &
    Littlefield, 1984a, 1984b; Littlefield, 1985a).

         An earlier 90 day study conducted in rats was not submitted for
    review. The study was conducted in 1973 in Long-Evans rats at dose
    levels of 2, 6, or 20 mg/kg bw/day. Littlefield (1985b) reported that
    definitive changes were seen at 20 mg/kg bw/day, slight changes were
    seen at 6 mg/kg bw/day, and no effects were seen at 2 mg/kg bw/day.

    2.2.2.3  Dogs

         Sulfadimidine was administered orally in gelatin capsules once
    daily, seven days a week, for 96 days to three groups of three male
    and three female beagle dogs at dosages of 2, 6, and 20 mg/kg bw/day.
    An additional group of three male and three female dogs served as
    controls and received empty gelatin capsules on a similar regimen. The
    dogs were 3-4 months of age at the beginning of the study. All animals
    were observed daily for signs of toxic or pharmacological effects.
    There were no dose related findings in symptomology, body weight, food
    consumption, ophthalmology, hematology, urinalysis, organ weight,
    organ to body weight ratio, or pathology. All dogs survived for the
    duration of the test (Smith, 1973).

    2.2.3  Longterm/carcinogenicity studies

    2.2.3.1  Mice

         Sulfadimidine was continuously administered in the feed to
    B6C3F1 mice for 12, 18, or 24 months at a dose equivalent to 30, 60,
    240, or 480 mg/kg bw/day. Another group of mice received no
    sulfadimidine in the feed and served as controls. The mice, derived
    from specific pathogen free mice, were 3 to 4 weeks old at the start
    of the study and were barrier maintained throughout the study. The
    experimental design is shown in Table 1.

    
    Table 1: Experimental design of study of sulfamidine in mice
                                                                                     

                           Scheduled time of sacrifice (months)

                                                                                     

    Dose (ppm)                     12                  18                  24

                             Male      Female    Male      Female    Male      Female
       0                      24         24       24         24      192        192
     300                      24         24       24         24       96        192
     600                                                              96         96
    1200                      24         24       24         24       96         96
    2400                                                                         96
    4800                      24         24       24         24       96         96
                                                                                     
    
         No significant effects were noted in clinical chemistry tests at
    any dose. Gross necropsy and histopathological examinations were
    conducted on 1705 of the 1728 animals in the study.

         In females, there was a slight dose-dependent depression in body
    weight. In males, a slight depression in body weight occurred only in
    the 4800 ppm dose group. There was no difference in food consumption
    in male or female mice throughout the study. In females, mortality was
    8, 8, 23, 11, 4, and 13% in the controls, 300, 600, 1200, 2400, and
    4800 ppm dose groups, respectively, In males, mortality was 8, 7, 6,
    9, 3, and 5% in the controls, 300, 600, 1200, 2400, and 4800 ppm dose
    groups, respectively.

         The appearance of follicular cell adenomas of the thyroid gland
    was the most notable neoplastic lesion associated with treatment with
    sulfadimidine. In females scheduled for sacrifice at 18 months, the
    incidence rates were 4% and 39% in the 300 and 4800 ppm dose groups,
    respectively, with none in the 1200 ppm dose group or controls. At 24
    months, the incidences in high-dose males and high-dose females were
    47% and 37%, respectively, compared to 2% and 4% in the respective
    control groups.

         In addition to the adenomas reported above, one female in each of
    the 600 and 4800 ppm dose groups and one male in the 2400 ppm dose
    group had a thyroid follicular cell carcinoma.

         There was some indication of an increased incidence of
    hepatocellular ademona or carinoma. However, the authors concluded
    that this effect was without biological significance because the
    background rate for this lesion had traditionally been high and the
    incidences across the doses at the 24-month sacrifice appeared random
    except for the 600 and 4800 ppm dose groups.

         The US National Toxicology Program convened a Pathology Working
    Group to review the neoplastic lesions of the thyroid gland reported
    in this study. In a number of cases the Pathology Working Group
    concluded that a follicular cell adenoma was more properly diagnosed
    as a follicular cell hyperplasia. The incidences of thyroid follicular
    cell adenomas were reduced to 32% and 26% in high-dose males and
    females, respectively (Hildebrandt, 1988).

         The significant non-neoplastic lesions observed in both males and
    females included thyroid gland follicular cell hyperplasia,
    hematopoietic cell proliferation (red pulp) of the spleen, and
    pigmentation of the spleen (red pulp). Also noted in the females only
    were pigmentation of the lymph nodes (cortex mandibular) and acinus
    hyperplasia of the mammary gland.

         The Pathology Working Group concluded that the thyroid follicular
    cell hyperplasias reported in this study were more properly classified
    as thyroid follicular cell hypertrophy because an increase in cell
    numbers could not be documented by routine light microsocopy. This
    change in diagnosis does not change the interpretation of the study
    (Littlefield, 1988a).

    2.2.3.2  Rats

         Sulfadimidine was continuously administered in the diet to
    Fischer 344 rats for 3, 12, 18, or 24 months at a dose of 10, 40, 600,
    1200 or 2400 ppm. Another group of rats received no sulfadimidine and
    served as controls. The rats used in this study were from the F1a
    generation of dosed Fischer 344 rats (specific pathogen free) used in
    the 3-generation reproduction study reported in section 2.2.4.2). The
    animals were allocated to the study under barrier conditions as
    weanlings, were continued on the same dose as their respective dams,
    and were maintained in the barrier throughout the study. The
    experimental design is summarized in Table 2.

         The average dose over the course of the 24-month study were 0,
    0.6, 2.4, 29.8, 59.7, or 121.4 mg/kg bw/day for females and 0, 0.5,
    2.2, 26.3, 52.5, or 105.0 mg/kg bw/day for males based on measurements
    of food consumption, body weight, and analysis of the sulfadimidine
    concentration in the diet.

        Table 2: Experimental design of study of sulfadimidine in rats

    Scheduled time of sacrifice (months)
                                                                                               

    Dose (ppm)           3                   12                  18                  24

                   Male      Female    Male      Female    Male      Female    Male      Female
       0           15         15       15         15       15         15       180        180
      10           15         15       15         15       15         15        90         90
      40           15         15       15         15       15         15        90         90
     600           15         15       15         15       15         15        90         90
    1200           15         15       15         15       15         15        90         90
    2400           15         15       15         15       15         15        90         90
                                                                                               
    
         Blood samples were taken at the 12- and 24-month sacrifice for
    clinical chemistry and hematology measurements. Gross necropsies and
    histopathological examination of tissues were conducted for 1793 of
    the 1800 animals on test. In males at 24 months, cholesterol was
    depressed at all dose levels and lymphocyte counts were elevated,
    although only at 2400 ppm was the difference from the control animals
    significant. In females at 12 months, hemoglobin was depressed at all
    dose levels.

         The brain, liver, heart, thyroid gland, kidneys, testicles, and
    ovaries were weighed at the 12-, 18-, and 24-month sacrifices. The
    thyroid gland was also weighed at the 3-month sacrifice. The data show
    changes in the weights of thyroid, liver, heart and kidney. There was
    a significant trend for increased thyroid weight in both sexes and at
    each sacrifice interval, except for females at 24 months. Significant
    differences from the controls in thyroid weight were seen in all 2400
    ppm dose groups except the females at 24 months and the males at 18
    and 24 months. The liver weight was depressed at 24 months in females
    at the 2400 ppm dose and in males at the 1200 and 2400 ppm dose. The
    heart weight was depressed at 24 months in females at all doses. The
    kidney weight was depressed at 24 months in both sexes in the 600,
    1200, and 2400 ppm dose groups. Calculation of organ/body weight
    ratios showed differences that correlated with the changes in absolute
    weight. In addition, the authors stated that the brain/body weight
    ratio at 24 months was significantly different in both males and
    females at all dose levels, but the data were not included in the
    report.

         The body weight gain was similar in all groups for approximately
    20 weeks, at which time the rate of gain in the high dose group
    animals decreased and their body weights from this point to the end of
    the study were less than the other groups. From approximately 65 weeks
    until the end of the study, the average body weight of the control

    group was greater than any of the dosed groups. There was no
    significant difference in food consumption on a body weight basis
    between any of the groups. The dosed animals had a lower mortality
    rate than the control group. After 24 months, the mortality rates in
    the females were 41, 36, 35, 26, 19, and 19% in the control, 10, 40,
    600, 1200, and 2400 ppm dose groups, respectively. In the males, the
    mortality after 24 months was 37% in the controls, while all dose
    groups has a mortality in the range of 24 to 28%.

         Histopathological examination of the tissues revealed a
    neoplastic response only in the thyroid gland. In females scheduled
    for sacrifice at 18 months, follicular cell adenomas were observed
    only in the 40 and 2400 ppm dose groups. The incidence rate was 7% in
    both groups. In males scheduled for sacrifice at 18 months, follicular
    cell adenomas were observed in only the control, 600 ppm, and 2400 ppm
    dose groups, with incidence rates of 7, 7, and 14%, respectively.

         The report of the Pathology Working Group on this study is not
    yet available.

         Since mortality in the control animals was higher than in the
    dosed animals, the question arises as to whether a larger number of
    control animals might have developed tumors of the thyroid had they
    lived as long as the dosed animals. To examine this question the data
    for only those animals that were sacrificed at 24 months were
    analyzed. These data are shown in Table 3.

        Table 3: Incidence of follicular cell adenocarcinomas in ratssacrificed at 24 months
                                                                                         

                                            Dose, ppm

                 Control       10         40        600        1200        2400
                                                                                         

    Females       1/113       0/56       0/58       1/66       4/73        6/74
     (0.9%)        (0%)       (0%)      (1.5%)     (5.5%)     (8.1%)

    Males         0/118       1/66       0/66       1/65       1/70        7/68 
                   (0%)      (1.5%)      (0%))     (1.5%)     (1.4%)      (10.3%)
                                                                                         
    
         In the thyroid gland of both males and females, dose responses
    were noted for increases in follicular cell hyperplasia, focal
    cellular changes of the follicular cell, and follicle cyst
    (multilocular) (Littlefield, 1988b).

    2.2.4  Special studies on reproduction

    2.2.4.1  Mice

         The effect of sulfadimidine on fertility was assessed in a
    continuous breeding assay. Three groups of 20 male and 20 female CD-1
    mice were given sulfadimidine at a dose of 0.25, 0.5, or 1.0% of the
    diet. Another group of 38 male and 38 female mice served as controls.
    The mice were continuously exposed to sulfadimidine during the 7-day
    premating and 98-day cohabitation period. At the conclusion of this
    phase of the study, cross-over matings were performed with the
    parental mice. Three treatment groups were formed for the cross-over
    mating trial: control male x control female; high dose male x control
    female; control male x high dose female. At the conclusion of the
    cross-over mating period, the control and high dose male and female
    parental mice were subjected to gross necropsy and the reproductive
    organs were subjected to histopathological examination.

         The effects observed in the group receiving 1% sulfadimidine
    included a significant decrease in the number of litters and in the
    number of male and female live pups per litter, a significant decrease
    in male and female live pup weights (adjusted for the total number of
    pups per litter), and a significant increase in the proportion of live
    male pups per total live pups per litter. In the male mice receiving
    1% sulfadimidine, there was a significant decrease in the prostate and
    seminal vesicle weights (although the prostate weight was not
    significantly decreased after adjustment for body weight). In the
    female mice, body weight was significantly depressed relative to the
    control group. In both male and female mice, liver weights adjusted
    for body weight were significantly elevated relative to controls. No
    significant difference was found in the percent motile sperm, sperm
    concentration, or percent abnormal sperm in the cauda epididymis in
    the group fed 1% sulfadimidine versus the control group. Reproductive
    tract (ovaries, oviducts, uterus, and vagina), pituitary, and brain
    weight were unaffected in female mice fed 1% sulfadimidine versus the
    female mice in the control group. No treatment-related
    histopathological effects were observed in the pituitary or
    reproductive organs of male and female mice in the group fed 1%
    sulfadimidine.

         Exposure of breeding pairs of CD-1 mice to 0.25 or 0.5%
    sulfadimidine in the diet during the continuous breeding phase of the
    study had no effect on fertility or reproductive performance. These
    animals were not necropsied. Thus it is not known whether these
    animals exhibited the same organ weight changes as observed in the
    animals fed 1% sulfadimidine (Reed & Wolkowski-Tyl, 1984). 

    2.2.4.2  Rats

         Fischer 344 rats, derived from specific pathogen free rats, were
    dosed with sulfadimidine in the feed for three generations, with two
    litters per generation, at dose levels of 600, 1200, or 2400 ppm. Each
    group initially contained 45 animals/sex. A separate control group of
    90 animals/sex was fed untreated feed and served as controls.

         There was a significant decrease in average body weight across
    all generations for 21-day old male pups in all dose groups compared
    to controls. In addition, there was a significant decrease in average
    body weight across all generations for 21-day old female pups in the
    2400 ppm dose group. There was a significant increase in the
    proportion of animals dying prior to weaning in the 2400 ppm dose
    group compared to controls.

         There were no significant dose-related changes in litter size,
    sex ratios, fertility, or stillbornes. Histopathological examination
    of two male and two female F3b rats revealed no neoplastic or
    non-neoplastic lesions (Littlefield 1988c).

    2.2.5  Special studies on embryotoxicity and teratogenicity

         Rats

         The conceptuses examined in this study were from the second
    litter of the third generation of Fischer 344 rats (F3b) exposed
    continuously to 0, 600, 1200, or 2400 ppm sulfadimidine in the feed
    (section 2.2.4.2). The control, low, mid, and high dose groups
    contained 29, 22, 24, and 28 dams, respectively. Dams were weighed on
    gestation days 0, 7, 14, and 29 and were observed daily for early
    delivery, morbidity, or mortality. Maternal weight gain during
    gestation was not affected in any dose group indicating that the high
    dose did not induce overt material toxicity. Mortality did not occur
    in any group. One animal in the control group and two animals in the
    1200 ppm dose group delivered prematurely. Dams were sacrificed by
    asphyxiation with CO2 on day 20 of gestation. Under the conditions
    of the study, exposure of Fischer 344 rats to sulfadimidine prior to
    and during gestation did not produce embryo/fetotoxicity or a
    teratogenic effect.

         Examination of gravid uteri at sacrifice revealed no significant
    differences among treatment groups in the incidence of resorptions,
    dead or malformed fetuses, or in the average body weight of live
    fetuses per litter. The number and percent of fetal external and
    visceral variations per litter and the number of skeletal and total
    variations per litter were not significantly altered among dose
    groups. However, the percent of variations per litter were
    significantly increased among dose groups. Because of the normally
    high incidence of skeletal variations at this stage of development in
    the rat, the authors concluded that the latter effect was not

    biologically significant. The total number of implantations/litter
    were significantly reduced across experimental groups in a positive
    dose-related trend. However, because the prevalence for
    post-implantation loss between controls and dose groups was not
    significantly altered, the authors concluded that the trend toward
    decreased implantations with increased dose was not biologically
    significant (Bates & LaBorde, 1987).

    2.2.6  Special studies on thyroid function

    2.2.6.1  Rats

         Fischer 344 rats (aged 3-9 weeks) were divided into 6 treatment
    groups with 3 subgroups for serial sacrifice at 12, 18, or 24 months.
    Sulfadimidine was administered continuously in the feed at doses of 0,
    10, 40, 600, 1200, or 2400 ppm. Each treatment subgroup sacrificed at
    12- or 18-months consisted of 15 animals/sex, while the subgroups
    receiving sulfadimidine and sacrificed at 24 months consisted of 30
    animals/sex. The control subgroup sacrificed at 24 months consisted of
    60 animals/sex. After feeding for 12, 18, or 24 months the animals
    were fasted for approximately 18 hours, anesthetized with CO2, and
    bled to obtain blood for thyroid and pituitary hormone measurements.
    The animals were then sacrificed by CO2 asphyxiation and the thyroid
    weight was determined.

         Male and female rats fed sulfadimidine at 1200 or 2400 ppm for
    12, 18, or 24 months showed significantly greater thyroid weights when
    compared to controls. The serum T3 levels were not significantly
    different for males or females after any exposure period. Serum T4
    levels were significantly lower for females dosed at 1200 or 2400 ppm
    for 18 months and for males dosed at 600, 1200, or 2400 ppm for 24
    months. However, the decrease in serum T4 levels did not show a
    consistent dose response trend. The serum TSH levels were not
    significantly different for males or females after any exposure
    period. There no significant differences in T3 uptake for males or
    females after any exposure period.

         The authors reported a significant decrease in the total thyroid
    hormone to pituitary hormone ratio (T3 + T/TSH) in male and female
    animals receiving doses of sulfadimidine of 600 ppm and above for 18
    and 24 months, except for females dosed at 2400 ppm for 24 months
    (Fullerton  et al., 1987).

    2.3  Observations in man

         A general discussion of adverse reactions to sulfonamide therapy
    in man is found in the thirty-fourth Report of the Joint FAO/WHO
    Expert Committee on Food Additives.

    3.  COMMENTS

         In the carcinogenicity study in mice, thyroid follicular-cell
    adenomas occurred in male and female mice at a dietary level of 4800
    ppm. In the corresonding study in rats, thyroid follicular-cell
    adenomas and adenocarcinomas occurred in females at a dietary level of
    2400 ppm and in males at a dietary level of 1200 or 2400 ppm.

         It was concluded that the thyroid follicular-cell tumors observed
    in mice and rats were most probably the result of perturbation of the
    thyroid-hypothalamus-pituitary axis and that humans would not be at
    carcinogenic risk if exposure to sulfadimidine was below the NOEL for
    a sensitive parameter of thyroid function.

         In the carcinogenicity study in mice, the NOEL for thyroid
    follicular-cell hypertrophy was 86 mg/kg bw/day for females and 68
    mg/kg bw/day for males. In the corresponding study in rats, the NOEL
    for thyroid follicular-cell hyperplasia was 2.4 mg/kg bw/day for
    females and 2.2 mg/kg bw/day for males.

         In the study on thyroid function in rats, the NOEL for increased
    thyroid weight was 30 mg/kg bw/day for females and 26 mg/kg bw/day for
    males at 12, 18 and 24 months. In this study, the serum concentrations
    of triiodothyronine and thyroid-stimulating hormone were highly
    variable and were not significantly different either at any dose or at
    any time. The concentration of thyroxine in the serum was decreased in
    females given sulfadimidine at 1200 or 2400 ppm in the diet for 18
    months and in males given 600, 1200 or 2400 ppm in the diet for 24
    months. However, the decrease did not show a consistent dose-response
    trend.

         The NOELs for reproductive and teratogenic effects in the rat
    were 120 mg/kg bw/day, which was the highest dose tested. The NOEL for
    reproductive effects in the mouse was 720 mg/kg bw/day. In this study,
    a significant decrease in the number of litters and in the number of
    live pups per litter, a significant decrease in live pup weight, and
    a significant increase in the proportion of male pups among the live
    pups per litter were observed at the highest dose level.

         A temporary ADI of 0-0.004 mg/kg bw/day was established based on
    the NOEL of 2.2 mg/kg bw/day for thyroid follicular-cell hyperplasia
    in male rats and a safety factor of 500. This safety factor was used
    because the evaluation of the carcinogenicity studies had not been
    finalized and additional studies were being undertaken to examine
    further the effects of sulfadimidine on the thyroid gland and the
    possibility of hypersensitivity reactions.

         The Committee was also aware of additional studies in progress on
    the effect of sulfadimidine on the thyroid in various animal species,
    and requested that the results of these studies should be submitted by
    1991.

    4.  EVALUATION

              Level causing no toxicological effect
              Mouse: 600 ppm in the diet equal to 68 mg/kg bw/day
              Rat: 40 ppm in the diet, equal to 2.2 mg/kg bw/day.

              Estimate of temporary acceptable daily intake
              0-0.004 mg/kg bw/day.

              Further work or information required.
              Additional studies on the effect of sulfadimidine on the
              thyroid in various species.


    5.  REFERENCES

    BATES, H.K., & LABORDE, J.B. (1987). Developmental toxicity evaluation
    of sulfamethazine feeding to Fischer 344 rats, unpublished report No.
    423 from the National Center for Toxicological Research, Food and Drug
    Administration, Jefferson, Arkansas. Submitted to WHO by the US
    Coordinator of the Codex Alimentarius, US Department of Agriculture,
    Washington, D.C.

    FULLERTON, F.R., KUSHMAUL, R.J., SUBER, R.L., & LITTLEFIELD, N.
    (1987). Influence of oral administration of sulfamethazine on thyroid
    hormone levels in Fischer 344 rats.  J.Toxicol.Env. Health, 22,
    175-185.

    HEATH, J.E. & LITTLEFIELD, N. (1984a). Effect of subchronic oral
    sulfamethazine administration on Fischer 344 rats and B6C3F1 mice.
     J.Environ.Pathol.Toxicol. Oncol., 5, 201-214.

    HEATH, J.E. & LITTLEFIELD, N. (1984b). Morphological effects of
    subchronic oral sulfamethazine administration of Fischer 344 rats and
    B6C3F1 mice.  Toxicol.Pathol., 12, 3-9.

    HILDEBRANDT, P.K. (1988). Chairperson's report of the Pathology
    Working Group review, two-year dietary study of sulfamethazine in
    B6C3F1 mice. Pathco, Inc., Gaithersburg, Maryland. Submitted to WHO by
    the US Coordinator of the Codes Alimentarius.

    LITTLEFIELD, N. (1985a). 90-day study on sulfamethazine in B6C3F1
    mice, unpublished report No. 333 from the National Center for
    Toxicological Research, Food and Drug Administration, Jefferson,
    Arkansas. Submitted to WHO by the US Coordinator of the Codex
    Alimentarius, US Department of Agriculture, Washington, D.C.

    LITTLEFIELD, N. (1985b). 90-day study on sulfamethazine in Fischer 344
    rats, unpublished report No. 334 from the National Center for
    Toxicological Research, Food and Drug Administration, Jefferson,
    Arkansas. Submitted to WHO by the US Coordinator of the Codex
    Alimentarius, US Department of Agriculture, Washington, D.C.

    LITTLEFIELD, N. (1988a). Chronic toxicity and carcinogenesis study on
    sulfamethazine in B6C3F1 mice, unpublished report No. 418 from the
    National Center for Toxicological Research, Food and Drug
    Administration, Jefferson, Arkansas. Submitted to WHO by the US
    Coordinator of the Codex Alimentarius, US Department of Agriculture,
    Washington, D.C.

    LITTLEFIELD, N. (1988b). Chronic toxicity and carcinogenesis study on
    sulfamethazine in Fischer 344 rats, unpublished report No. 420 from
    the National Center for Toxicological Research, Food and Drug
    Administration, Jefferson, Arkansas. Submitted to WHO by the US
    Coordinator of the Codex Alimentarius, US Department of Agriculture,
    Washington, D.C.

    LITTLEFIELD, N. (l988c). Three-generation reproduction and toxicity
    study of sulfamethazine in Fischer 344 rats, unpublished reports Nos.
    419, 421, 422 from the National Center for Toxicological Research,
    Food and Drug Administration, Jefferson, Arkansas. Submitted to WHO by
    the US Coordinator of the Codex Alimentarius, US Department of
    Agriculture, Washington, D.C.

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    See Also:
       Toxicological Abbreviations
       Sulfadimidine (WHO Food Additives Series 33)
       SULFADIMIDINE (JECFA Evaluation)