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