SULFADIMIDINE First draft prepared by Dr F.X.R. van Leeuwen Laboratory of Toxicology National Institute of Public Health and Environmental Protection Bilthoven, Netherlands 1. EXPLANATION Sulfadimidine is a sulfonamide used to treat a variety of bacterial diseases in humans and other species and to promote growth in food-producing animals. It had been previously reviewed at the thirty-fourth Meeting of the Committee (Annex 1, reference 85), when a temporary ADI of 0-4 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 2.1.1.1 Rats Groups of pregnant CD rats were dosed by gavage with 0, 540, 680, or 860 mg sulfadimidine/kg bw/day on days 6-15 of gestation. Dams were killed on day 20 of gestation. Observations included clinical signs, mortality, maternal body and liver weight, the number of resorptions, live and dead fetuses, litter size, and fetal weight. All fetuses were subjected to gross, skeletal, and visceral examinations. One dam from the low-dose group died during the study. In all treated dams the incidences of alopecia, rough coat, light-coloured faeces, and urine stains were increased. Maternal body-weight gain was decreased and relative liver weight was increased in all treated dams. In the high-dose group, fetuses had decreased body weights and the number of malformed fetuses/litter was increased. The incidence of gross or visceral malformations of fetuses/litter was increased at 860 mg/kg bw/day with the predominant malformations being cleft palate, hydroureter, and hydronephrosis. The incidence of hydroureter and hydronephrosis was also elevated in the mid-dose group. The NOEL for embryo- and fetotoxicity was 540 mg/kg bw/day (Wolkowski-Tyl et al., 1982). 2.1.1.2 Rabbits Groups of pregnant female New Zealand white rabbits were orally administered sulfadimidine (by gavage) at 0, 600, 1200, 1500, or 1800 mg/kg bw/day on days 6 to 19 of gestation. Dams were killed on day 30 of gestation. No effects were observed on the number of corpora lutea, implantation sites or implantation loss, number of live fetuses sex distribution/litter, or fetal body weight. The incidences of gross, visceral, or skeletal malformations were not increased. No treatment-related effects were observed on the weight or gross appearance of the kidneys. A dose-related occurrence of clinical signs such as alopecia, pink or red ears, and weepy eyes was observed in treated dams. Maternal mortality was 3.0, 6.0, 4.0, 20, and 19% in the 0, 600, 1200, 1500, and 1800 mg/kg bw/day treatment groups, respectively. Maternal body-weight gain was significantly decreased at 1200, 1500, and 1800 mg/kg bw/day. A dose-related increase in the percent resorptions and fetal deaths/litter was observed. The NOEL for embryotoxicity was 1200 mg/kg bw/day (Wolkowski-Tyl et al. , 1982). 2.1.2 Special studies on genotoxicity The results of in vitro and in vivo genotoxicity studies on sulfadimidine are summarized in Table 1. 2.1.3 Special studies on thyroid function 2.1.3.1 In vitro The addition of 0, 10, or 80 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). 2.1.3.2 Rats Three replicates of six groups of 5 Fischer 344 rats were fed diets containing sulfadimidine at concentrations of 0, 300, 600, 1200, 2400, or 4800 mg/kg of feed (equal to 18, 36, 74, 148, or 275 mg/kg bw/day), for 4 weeks. Blood samples were taken at weekly intervals for TSH levels. At the end of the study all thyroid glands were removed and weighed. TSH levels were significantly elevated in rats consuming the 2400, and 4800 mg/kg sulfadimidine diets. At 600 and 1200 mg/kg feed a slight increase in TSH levels was seen. Thyroid weights at 4800 mg/kg feed were about 3 times controls (Cullison & Furrow, 1990). Table 1: Results of genotoxicity assays on sulfadimidine Test system Test object Concentration Purity Results Reference In vitro Ames testa S. typhimurium 0-1000 µg/pl ? negativeb Mortelmens TA100, 1535, in DMSO et al., 1986 1537, 98 Chromosomal CHO cells 1081-5000 ? negativeb NTP, undated aberration µg/ml in assaya DMSO HGPRT forward CHO-cells 0.5-7.0 mg/l 96.6% negativeb Young, 1988 mutation assaya Sister CHO, cells 167-2000 ? positiveb,d NTP, undated chromatid µg/ml in negativeb,e exchange DMSOc assaya UDS human up to 100 ? negative Allred et al., fibroblasts µg/ml 1982 In vivo Chromosomal rat, bone po 750, 1500 ? negativeb Ivett, 1988 aberrations marrow and 3000 mg/kg bw a Without and with metabolic activation. b Appropriate positive controls were used. c Lumpy precipitate formed at >1500 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 independent study. Groups of 60 to 70 male rats (Fischer 344) were fed diets containing sulfadimidine sodium salt at concentrations of 0, 40, 150, 600, 2400, or 4800 mg/kg feed (equal to 0, 2.2, 8.5, 34, 136, or 261 mg/kg bw/day) for 13 weeks. Groups of 20 rats/dose were killed at 4, 8, and 13 weeks. Ten control rats and 10 rats receiving 2400 mg/kg sulfadimidine sodium salt in the feed were kept for a recovery period of another 13 weeks and then killed. Observations included clinical signs, body weight, food consumption, T3, rT3, T4 and TSH determinations, and gross post mortem examination. Thyroid and pituitary weights and histopathology on the thyroid and pituitary glands were evaluated in rats from the 0, 2400, and 4800 mg/kg feed groups only. Mean body weight was slightly decreased throughout the treatment period in rats consuming diets containing 2400 and 4800 mg/kg sulfadimidine sodium salt. Thyroid weight was increased in these same dose groups at all time points. Pituitary weights were increased only at week 13. In the recovery group, only the thyroid weight remained elevated over the controls. Significant increases in TSH concentrations were observed in animals fed the 2400 and 4800 mg/kg feed diets; highest concentrations were observed after 4 weeks (especially at the high dose) and declined thereafter. In the high-dose group, T4 concentrations were significantly decreased compared to control values at weeks 4 and 8, while T3 values were significantly decreased at weeks 4, 8, and 13 (T4 was slightly decreased after 13 weeks of treatment). After the recovery period TSH concentrations were depressed compared to controls. Dose-dependent vacuolation of chromophobe cells of the pituitary gland was observed in animals from the two highest dose groups. This effect was found to regress with time. Complete recovery was observed after the withdrawal period. Hyperplasia and hypertrophy of the thyroid were also observed in the two highest dose groups. In rats fed diets containing 600 mg/kg sulfadimidine, hyperplasia and limited hypertrophy were seen in some rats at weeks 4 and 8 but not at week 13. There was complete recovery of the changes noted in the thyroid after the recovery period. The NOEL in this study was 150 mg/kg feed, equal to 8.5 mg/kg bw/day (Braverman & DeVito, 1991; Richter, 1992; Bio/dynamics, 1992). In an exploratory study groups of 20 rats/sex (Charles River CD; 10-12 weeks old) were orally administered (via dietary admixture) sulfadimidine at dosages of 0, 1, 2.5, 5, 10, 25, 50, 100, 200, 400, or 600 mg/kg bw/day for 4 weeks. At two weeks, five rats from each group, and at 4 weeks 15 rats from each group were killed. Parameters evaluated included clinical signs, mortality, body weight, food consumption, T3, rT3, T4 and TSH, gross post mortem examination, thyroid weight, and histopathology of the thyroid gland from all rats (sacrificed after 4 weeks of treatment) of all groups. A 'thyroid functional morphology index' was determined. This index was based on the size of the follicles, the amount and functional properties of follicular colloid, and the follicular-cell height. The total score ranged from 0 to 4. One death occurred in the 10 and 600 mg/kg bw/day dose groups. Neither death was considered to be treament-related. Significant and dose-related decreases in body-weight gain and food consumption occurred in the 400 and 600 mg/kg bw/day dose groups. At both 2 and 4 weeks plasma T4 and T3 levels decreased significantly at doses >200 mg/kg bw/day (94% and 60% reduction at 600 mg/kg bw/day for T3 and T4, respectively). Plasma TSH levels were increased >200 mg/kg bw/day at both 2 and 4 weeks. A tendency for increase in this parameter was also seen at 100 mg/kg bw/day. A significant and dose-related increase in absolute and relative thyroid gland weight occurred at dosages of >200 mg/kg bw/day. At 2 weeks of treatment thyroid weight of animals treated with 600 mg/kg bw/day increased more than 2-fold and after 4 weeks more than 2.5 fold. Histopathology findings included a dose-related increase in the 'thyroid functional morphology index' starting with 0.07 at 10 mg/kg bw/day and increasing to 3.8 at 600 mg/kg bw/day. Both hypertrophy and hyperplasia of thyroid follicular cells were dose-related with an incidence range of 1/14 at 10 mg/kg bw/day to 14/14 at 600 mg/kg bw/day for hypertrophy, and 13/15 at 200 mg/kg bw/day to 14/14 at 600 mg/kg bw/day for hyperplasia (see Table 2). The NOEL in this study was 5 mg/kg bw/day (McClain et al., 1993a). Groups of 35 male rats [CDF (F344)/CrLBR] were fed diets containing 0 or 2400 mg sulfadimidine/kg feed (equivalent to 120 mg/kg bw/day) for 13 weeks. Supplemental thyroid hormone (T4/T3: molar ratio 9:1) was incorporated into the sulfadimidine diet at concentrations of 10, 20, 30, or 40 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 SULFADIMIDINE (mg/kg bw/day) THYROID FOLLICULAR CELLS Hypertrophy Hyperlasia 0 0/15 0/15 1 0/15 0/15 2.5 0/15 0/15 5 0/15 0/15 10 1/14a 0/14a 25 2/15 0/15 50 11/15 0/15 100 13/14b 0/14b 200 15/15 13/15 400 15/15 15/15 600 14/14a 14/14a a One rat died during the experiment. b The thyroid gland was missing from one rat. At the high-dose of 40 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 decreased. Treatment with a combination of thyroid hormone and sulfadimidine reduced the diffuse hypertrophy and diffuse hyperplasia observed with sulfadimidine alone in a dose-related manner. Reduced follicular activity (flattened epithelium and distended follicles) was observed in rats consuming diets containing 40 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., 1993c). Groups of 6 normal and 6 hypophysectomized male rats (CDF (F-344/CrlBR; 11 weeks of age) were fed diets containing sulfadimidine at concentrations of 0, 2400, or 4800 mg sulfadimidine/kg feed (equivalent to 120 and 240 mg/kg bw/day) for 7 days, then all rats were killed. Observations included clinical signs, mortality, body weight, food consumption, plasma measurements of T3, rT3 and T4, thyroid weight, and histopathology of the thyroid. One hypophysectomized rat in the 2400 and two normal rats in the 4800 mg/kg feed groups died. None of the deaths was considered to be treatment-related. Treated hypophysectomized rats had lower body-weight gains and food consumption than treated normal rats. The decrease in plasma T3, rT3, and T4 concentrations observed in normal rats was significant and dose-related in both dose groups. In hypophysectomized rats plasma concentrations of T3, rT3, and T4 were decreased by 84, 82 and 92%, respectively, as compared to the levels in normal control rats. These low levels were not affected by sulfadimidine treatment. Absolute and relative thyroid weights increased significantly in normal rats consuming diets containing 2400 and 4800 mg sulfadimidine/kg feed. In the hypophysectomized rats, relative thyroid weights tended to be slightly less than those of normal controls, but no effects of sulfadimidine treatment were found. Follicular-cell hypertrophy and hyperplasia were observed in normal sulfadimidine-treated rats. Thyroids of hypophysectomized rats had a less active appearance. Sulfadimidine treatment, however, did not induce histological changes in hypophysectomized rats (Downing et al., 1993). To investigate the effects of a low-iodine diet on thyroid function, groups of 40 male rats (CDF (F-344)/CrL BR; 10-12 weeks old) were administered modified Remington control or Remington low-iodine diets for 13 weeks. The control diet contained 0.26 mg iodine/kg feed and the low-iodine diet contained <0.1 mg iodine/kg feed. Ten rats/group were assigned to a recovery group and allowed to recover for 13 weeks on a control diet. Another ten rats from each group were killed after 4, 8, or 13 weeks of treatment or after 13 weeks of recovery. No significant effect on plasma T3 levels was observed with the low-iodine diet; normal values were maintained throughout the experiment. Plasma T4 levels were reduced in a time-related manner in rats fed the low-iodine diet. After 13 weeks of treatment, plasma T4 levels were about 8% of controls. Reverse T3 levels decreased significantly in the low-iodine group. This decrease was also time-related. After 4 weeks of treatment the levels were about 15% of control values and after 8 and 13 weeks the levels were at or below the detection limit. Plasma TSH levels increased in a time-dependent manner. After 13 weeks on low iodine treatment, TSH increased almost 6-fold over control values. In the low-iodine treatment group there was a time-related increase in absolute and relative thyroid weight (about 5-fold) at 13 weeks. After 13 weeks recovery, TSH levels returned to normal, plasma T4 and rT3 levels were significantly elevated to about 150% when compared to controls, and the increased absolute and relative thyroid weights were diminished, although they were still increased compared to the controls. Histopathology of thyroid glands from animals fed low-iodine diet after 4, 8, and 13 weeks showed hypertrophy of follicular epithelium, expressed by the presence of columnar epithelium. Diffuse hyperplasia was also present, the severity of which increased with time. After the 13 week recovery period the hypertrophy and hyperplasia disappeared almost completely. In 3 animals focal cystic hyperplasia was present, and in one animal a follicular cell adenoma was found (McClain et al., 1993b). 2.1.3.3 Pigs The study described here consisted of two separate studies, run consecutively. In the first study 2 groups of 5 intact male weanling pigs received diets containing 0, or 5000 mg sulfadimidine/kg of feed (equivalent to 0 or 200 mg/kg bw/day). A positive control group was fed a diet containing propylthiouracil at 400 mg/kg of feed. Blood samples were collected at two-week intervals for 12 weeks. In the second study 4 groups of 5 animals were used. Two groups were fed unmedicated feed and two groups were fed diets containing 2000 mg sulfadimidine/kg of feed (equivalent to 80 mg/kg bw/day). One of the two groups was pair-fed and the other ad lib. Blood samples in this study were collected at weekly intervals for 4 weeks. In both studies blood was analyzed for TSH, T4, and T3 levels. In the first study, from week 4 onwards, the sulfadimidine and the positive control groups consumed less than half as much feed as the control group, resulting in body weights that were half those of control animals. Thyroid weights for the sulfadimidine-treated group averaged five times those for control animals. Average TSH levels were 48 and 14 times the controls for sulfadimidine-treated and positive control groups, respectively. T4 levels were inversely proportional to the TSH values, dropping to 4% of controls by week 2. In the second experiment all groups had comparable body weights. The TSH values in the sulfadimidine-treated groups were considerably elevated (about 25 times the control values) and the T4 values were about 10 times lower than controls. Histopathological examination of animals from the first experiment showed follicular cell hyperplasia of the thyroid gland and chromophobe cell hyperplasia of the pituitary gland. In the second study only the thyroid glands were examined and the presence of follicular cell hyperplasia was reported (Cullison et al., 1990a). Groups of 5 male weanling pigs received diets containing 0, 125, 250, 500, or 1000 mg sulfadimidine/kg feed (equivalent to 0, 5, 10, 20, or 40 mg/kg bw/day) for 4 weeks. Blood samples were taken weekly and analyzed for TSH, T4, and T3 levels. At the end of the experiment the thyroid glands were removed, weighed, and examined histologically. At the highest dose, average TSH levels increased markedly, and peaked at week 3 at about 10 times the controls. There was a considerable difference in the response of the five animals. T4 levels inversely mirrored those for TSH in the highest-dose group, showing a maximum decrease to about half the control value at week 3. T4 levels varied considerably, but individual animals showed good correlation between decreases in T4 and increases in TSH. Thyroid weights of animals in the highest-dose group increased remarkably, averaging 17 grams versus 4 grams for controls. Thyroid follicular hypertrophy or follicular cell hypertrophy and hyperplasia was noted in the 250 mg/kg feed dose group and higher. The NOEL in this study was 125 mg/kg feed, equivalent to 5 mg/kg bw/day (Cullison et al., 1990b). 2.1.3.4 Monkeys Groups of Cynomolgus monkeys (4/sex/group) were orally administered doses of 0, 30, 100, or 300 mg sulfadimidine sodium/kg bw/day for 13 weeks. No effects were observed on clinical signs, mortality, body weight, food consumption, ophthalmoscopy, electro-cardiogram, myeloid to erythroid ratio, gross pathology, pituitary weight or histopathology. In particular, no depression of T3 or T4, increase in TSH, increase in thyroid weight or notable changes in the thyroid morphology were observed. The highest dose, 300 mg/kg bw/day was the NOEL (Markiewicz, 1991). 3. COMMENTS In a teratogenicity study with rats orally dosed with 0, 540, 680, or 860 mg sulfadimidine/kg bw/day, the incidences of cleft palate and minor visceral malformations were increased at the two highest doses, giving a NOEL of 540 mg/kg bw/day. In a similar study in rabbits with dose levels up to 1800 mg/kg bw/day no malformations were observed, but dose-related increased incidences of resorptions and fetal death were observed. The NOEL for embryotoxicity was 1200 mg/kg bw/day. A range of in vitro and in vivo genotoxicity tests were generally negative. A positive result was obtained with a sister chromatid exchange assay in the absence of metabolic activation. The protocol did not meet current standards. In several short-term toxicity studies with rats administered sulfadimidine in the diet up to a dose of 600 mg/kg bw/day an increase in thyroid weight, decreases in plasma concentrations of the thyroid hormones T3, and T4, and an increase in TSH were observed. These changes were accompanied by hypertrophy and hyperplasia of thyroid follicular cells. The overall NOEL in these studies was 5 mg/kg bw/day. In pigs administered sulfadimidine in the diet for four weeks at doses of 0, 5, 10, 20, or 40 mg/kg bw/day, similar effects were observed with a NOEL of 5 mg/kg bw/day. In monkeys orally administered 0, 30, 100, or 300 mg/kg bw/day sulfadimidine no effects on the thyroid gland were observed. The Committee noted that the available studies dealt with relevant and sensitive end-points with respect to the toxic effects of sulfadimidine on the thyroid gland, and concluded that the tumours seen at high dose levels of sulfadimidine are due to enhanced hormonal stimulation of the thyroid gland through elevated TSH levels and not to a direct action of sulfadimidine. The significance of the formation of the reactive diazonium intermediate formed in the GI tract by bacterial action was also considered. Because the diazonium ion covalently binds to intestinal contents the Committee concluded that it was not of toxicological concern. 4. EVALUATION Considering all available information, including the studies evaluated at the thirty-fourth meeting (Annex 1, reference 85), the Committee established an ADI of 0-50 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. 5. REFERENCES ALLRED, L.E., OLDHAM, J.W., MILO, G.E., KINDIG, O., CAPEN, C.C. (1982). Multiparametric evaluation of the toxic responses of normal human cells treated in vitro with different classes of environmental toxicants. J. of Ecotox. and Environm. Health , 10: 143-156. BRAVERMAN, L.E. & DeVITO, W.J. (1991). A three-month study in rats to investigate the effects of sulfamethazine on thyroid function: effect on serum TSH, T3, T4 and reverse T3 concentrations. Unpublished report no. UM-90-201-013 from the University of Massachusetts Medical School, Division of Endocrinology Laboratory, Worcester, MA, USA. Submitted to WHO by the Animal Health Institute, USA. BIO/DYNAMICS (1992). A three-month study in rats to investigate the effects of sulfamethazine on thyroid function. Unpublished final report no. 90-3547 from Bio/dynamics, NJ, USA. Submitted to WHO by the Animal Health Institute, Alexandria, VA, USA. CULLISON, R. & FURROW, R. (1990). Evaluation of the dose-dependent effects of sulfamethazine on rat thyroid stimulating hormone (TSH) levels. Unpublished report from the Division of Veterinary Medical Research Center for Veterinary Medicine, US Food and Drug Administration. Final report for DVMR study 312.04. Submitted to the WHO by the US FDA, Rockville, MD, USA. CULLISON, R., FURROW, R., WAGNER, D., ELSASSER, T. (1990a). The effect of sulfa drugs on the swine thyroid. Unpublished report from the Division of Veterinary Medical Research Center for Veterinary Medicine, US Food and Drug Administration. Final report for DVMR studies 312.01 and 312.02 Submitted to WHO by the US FDA, Rockville, MD, USA. CULLISON, R., FURROW, R., WAGNER, D., ELSASSER, T. (1990b). Estimation of the sensitivity of the swine model for the goitrogenic effects of drugs. Unpublished report from the Division of Veterinary Medical Research Center for Veterinary Medicine, US Food and Drug Administration. Final report for DVMR study 312.03. Submitted to WHO by the US FDA, Rockville, MD, USA. DOERGE, D.R. (1993). Inhibition of thyroid hormone synthesis as a mechanism for sulfonamide-induced thyroid toxicity. The 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. 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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, VA, USA. 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): 1-119. 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.
See Also: Toxicological Abbreviations Sulfadimidine (WHO Food Additives Series 25) SULFADIMIDINE (JECFA Evaluation)