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.
PAULSON, G.D., GIDDINGS, J.M., LAMOUREUX, C.H., MANSAGER, E.R., &
STRUBLE, C.B. (1981). The isolation and identification of
14C-sulfamethazine metabolites in the tissues and excreta of swine.
Drug Metab.Dispos., 9, 142-146.
PAULSON, G.D. (1986). The effect of dietary nitrite and nitrate on the
metabolism of sulfamethazine in the rat. Xenobiotica, 16, 53-61.
PAULSON, G.D., FEIL, V.J. & MacGREGOR, J.T. (1987). Formation of a
diazonium cation intermediate in the metabolism of sulfamethazine to
desaminosulfamethazine in the rat. Xenobiotica, 17, 697-707.
REED, J.R. & WOLKOWSKI-TYL, R. (1984). Sulfamethazine: reproduction
and fertility assessment in CD-1 mice when administered via the diet,
unpublished report No. NTP-84-092 from the National Institute of
Environmental Health Sciences, Research Triangle Park, North Carolina.
Submitted to WHO by the US Coordinator of the Codex Alimentarius, US
Department of Agriculture, Washington, D.C.
SMITH, J.M. (1973). A three month oral toxicity study of
sulfamethazine in beagle dogs, unpublished report No. 72R-780 from
BioDynamics Inc., East Millstone, New Jersey, to SmithKline and
French, Westchester, Pennsylvania. Submitted to WHO by the US
Coordinator of the Codex Alimentarius, US Department of Agriculture,
Washington, D.C.