First draft prepared by
Dr F.X.R. van Leeuwen
Laboratory of Toxicology
National Institute of Public Health and Environmental Protection
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 µg/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
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
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).
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
184.108.40.206 In vitro
The addition of 0, 10, or 80 µg/ml sulfadimidine to normal rat
serum did not affect the TSH, T3, or T4 concentrations. However,
addition of 80 µg/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).
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
Ames testa S. typhimurium 0-1000 µg/pl ? negativeb Mortelmens
TA100, 1535, in DMSO et al., 1986
Chromosomal CHO cells 1081-5000 ? negativeb NTP, undated
aberration µg/ml in
HGPRT forward CHO-cells 0.5-7.0 mg/l 96.6% negativeb Young, 1988
Sister CHO, cells 167-2000 ? positiveb,d NTP, undated
chromatid µg/ml in negativeb,e
UDS human up to 100 ? negative Allred et al.,
fibroblasts µg/ml 1982
Chromosomal rat, bone po 750, 1500 ? negativeb Ivett, 1988
aberrations marrow and 3000
a Without and with metabolic activation.
b Appropriate positive controls were used.
c Lumpy precipitate formed at >1500 µg/ml but dissolved immediately; pH
at >1500 µg/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
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 µg/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 µg/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
µg/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
µg/kg feed hormone. T4 levels were increased at 2 and 4 weeks in
the groups receiving sulfadimidine and >20 µg/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
(mg/kg bw/day) THYROID FOLLICULAR CELLS
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 µg/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 µg/kg thyroid feed hormone prevented this increase. At
the high-dose of 40 µg/kg of feed, thyroid weight was significantly
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 µg/kg feed thyroid hormone at weeks 2, 4, and 13 and in the 30
µg/kg feed thyroid hormone group only at 13 weeks (McClain et al.,
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
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).
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
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.,
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).
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).
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
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
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 µg/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.
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:
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,
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,
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
Toxicologist 13(1), Abstract nr 144 of the 32nd annual meeting of
the Society of Toxicology.
DOWNING, J.C., KIRLEY, T.A., RICHTER, W.R. & McCLAIN, R.M. (1993). A
seven-day exploratory study to assess thyroid function in normal and
hypophysectomized rats treated with sulfamethazine. Study no. 05992.
Unpublished report (no 132014) of Toxicology and Pathology of
Hoffmann-La Roche, Nutley, NJ, USA. Submitted to WHO by the Animal
Health Institute, Alexandria, VA, USA.
DOWNING, J.C. & McCLAIN, R.M. (1993). An in vitro exploratory
study to assess the inhibition of thyroid gland peroxidase by
sulfamethazine. Study no. 06303. Unpublished report (no 132041) of
Toxicology and Pathology of Hoffmann-La Roche, Nutley, NJ, USA.
Submitted to WHO by the Animal Health Institute, Alexandra, VA, USA.
IVETT, J.L. (1988). Chromosomal aberrations in vivo in mammalian
bone marrow cells on CL 380. HLA Study no. 10346-0-451. Unpublished
report of Hazleton Laboratories, America, Inc. Submitted to the WHO
by the Animal Health Institute, Alexandria, VA, USA.
LIPMAN, J.M., REICHERT, J.A. & McCLAIN, R.M. (1993). The effect of
sulfamethazine on autoregulation in the FRTL-5 rat thyroid cell
line. Study no. 05686. Unpublished report (no. 132051) of Toxicology
and Pathology of Hoffmann-La Roche, Nutley, NJ, USA. Submitted to
WHO by the Animal Health Institute, USA.
MARKIEWICZ, V.R. (1991). 13-Week subchronic study with
sulfamethazine in Cynomolgus monkeys with a special evaluation of
thyroid function and morphology. Unpublished final report no.
2609-100 from Hazleton, Washington Inc., Vienna, VA, USA. Submitted
to WHO by the Animal Health Institute, Alexandria, VA, USA.
McCLAIN, R.M., CAPEN, C.C., AGARWALL A.K. and DOWNING J.C. (1993a).
A four-week exploratory study of dose-response characteristics for
the effects of sulfamethazine on thyroid function in rats. Study no.
05421. Unpublished report (no 127736) of Toxicology and Pathology of
Hoffman-La Roche Inc., Nutley, NJ, USA. Submitted to WHO by the
Animal Health Institute, Alexandria, VA, USA.
McCLAIN, R.M, AGARWAL, A., RICHTER, W.R. & DOWNING, J.C. (1993b). A
twenty-six week exploratory study to assess the effects of
low-iodine diet on thyroid function in rats. Study no. 05961.
Unpublished report (no. 131862) of Toxicology and Pathology of
Hoffmann-La Roche, Nutley, NJ, USA. Submitted to WHO by the Animal
Health Institute, Alexandria, VA, USA.
McCLAIN, R.M., RICHTER, W.R., AGARWAL, A.K. & DOWNING. J.C. (1993c).
A three-month study in rats to investigate the reversibility of the
effects of sulfamethazine on thyroid finction by treatment with
thyroid hormone (study no. 05724). Unpublished report no. 127737
from Toxicology and Pathology, Hoffmann-La Roche Inc., Nutley, NJ,
USA. Submitted to WHO by the Animal Health Institute, Alexandria,
MORTELMANS, K., HAWORTH, S., LAWLOR, T., SPECK, W., TAINER, B.,
ZEIGER, E. (1986). Salmonella mutagenicity tests II: Results from
the testing of 270 chemicals. Environ. Mutagen., 8 (suppl.7):
NTP, (undated). In vitro cytogenetic tests from SITEK Research
Laboratories. Unpublished study submitted to WHO by the National
Institute of Environmental Health Sciences, Research Triangle Park,
NC, USA. Performed for the US National Toxicology Program.
RICHTER, W.R. (1992). A three-month study in rats to investigate the
effects of sulfamethazine on thyroid function. Report on a random
and blind histopathologic evaluation of thyroid tissue. Unpublished
report no. 90-3547 from Bio/Dynamics, East Millstone, NJ, USA.
Submitted to WHO by the National Institute of Environmental Health
Sciences, Research Triangle Park, NC, USA.
WOLKOWSKI-TYL, R., JONES-PRICE, C., MARR, M.C. & KIMMEL, C.A.
(1982). Teratological evaluation of sulfamethazine (CAS no. 57-68-1)
in New Zealand white rabbits. Unpublished report project no.
31U-2077 from RTI, Research Triangle Park, NC, USA. Submitted to WHO
by the National Institute of Environmental Health Sciences, Research
Triangle Park, NC, USA.
YOUNG, R.R. (1988). Mutagenicity test on sulfamethazine, sodium, lot
number 860816, in the CHO/HGPRT forward mutation assay. HLA Study
10346-0-435. Test report of Hazleton Laboratories. Submitted to WHO
by the Animal Health Institute, Alexandria, VA, USA.