CAPTAN (addendum) First draft prepared by J.-J. Larsen Institute of Toxicology, National Food Agency of Denmark, Ministry of Health, Soborg, Denmark Evaluation for acceptable daily intake Biochemical aspects Absorption, distribution, and excretion Biotransformation Toxicological studies Short-term toxicity Genotoxicity Comments Toxicological evaluation References Explanation Captan was evaluated toxicologically by the Joint Meeting in 1963, 1965, 1969, 1973, 1977, 1978, 1982, 1984, and 1990 (Annex I, references 2, 3, 12, 20, 28, 30, 38, 42, and 59). Toxicological monographs were prepared in 1963, 1965, and 1969 (Annex I, references 2, 4, and 13), and monograph addenda were prepared in 1973, 1977, 1978, 1982, 1984, and 1990 (Annex I, references 21, 29, 31, 39, 43, and 61). Additional information on distribution, excretion, bio- transformation, genotoxicity, and short-term toxicity are reviewed in this monograph addendum. Evaluation for acceptable daily intake 1. Biochemical aspects (a) Absorption, distribution, and excretion The tissue distribution and excretion of a single oral dose of 10 mg/kg bw [14C-cyclohexene ring]-labelled captan was studied in five male and five female Sprague-Dawley rats (weighing 202-243 g), obtained from Charles River, Margate, Kent, United Kingdom. Urinary and faecal excretion of radiolabel was monitored over seven days, and the residual concentrations of radiolabel were then measured in selected tissues. The excretion profiles were similar for male and female rats, the urinary route predominating in animals of each sex; 81% of the administered radioactivity was excreted in the urine and 8-9% in the faeces over 48 h, and 69-73% in the urine and 23-25% in the faeces over 96 h. The residual concentrations in the tissue were negligible, the highest concentrations occurring in the kidneys (< 0.01% of the total radiolabel) after 48 h and in the blood (about 2 µg equivalents of captan per gram) after 96 h (Trivedi, 1990a,b) The effect of oral pretreatment with 10 mg/kg bw unlabelled captan for 14 days before an oral dose of 10 mg/kg bw [14C- cyclohexene ring]-labelled captan was studied in eight male and eight female Sprague-Dawley rats (weighing 192-260 g), obtained from Charles River, Margate, Kent, United Kingdom. The urinary and faecal excretion of radiolabel was monitored over seven days, and the residual concentrations of radiolabel were then measured in selected tissues. The excretion profiles of male and female rats were similar, the urinary route predominating: 88-91% of the administered radiolabel in the urine and 7-9% in the faeces over 48 h. The residual concentrations in tissues were neglible in animals of each sex, the highest concentrations occurring in the kidneys (0.04 µg/g). The pretreatment thus had little or no effect on the route or rate of elimination of radiolabelled substance (Bratt, 1990). (b) Biotransformation The fate of orally administed 14C-captan was studied in eight male and eight female Simonsen albino rats, received from Simonsen Laboratories, Gilroy, USA, weighing 185-200 g. The animals were given 100 mg/kg bw N-trichloro-[14C]-methylthio-4-cyclohexene-1,2- dicarboximide (0.34 mCi/mmol, aqueous suspension in 1 ml of 1% traganth gum and 005% Tween-20) by gastric intubation, and radiolabel was determined in urine, faeces, and expired air. Within 9 h, 50% of the dose had been excreted; the final distribution was 52% in urine, 23% in expired air, 16% in faeces, and 0.6% in tissues. The urinary metabolites were identified as thiazolidine-2-thione-4-carboxylic acid (19%), a salt of dithiobis(methane-sulfonic acid) (54%), and the disulfide monoxide derivative of dithiobis(methanesulfonic acid) (14%). 14C-Carbon dioxide was identified in expired air. Radioactive thiazolidine-2-thione-4-carboxylic acid was detected in the urine of rats treated simultaneously with captan and either [U-14C]cystine or reduced 35 S-glutathione. 35 S-Dithiobis(methanesulfonic acid) was excreted in the urine of rats treated simultaneously with sodium 35 S-sulfite and either captan or thiophosgene. The metabolism of captan thus appears to involve evolution of thiophosgene derived from the trichloromethylthio moiety. Thiophosgene is detoxified, at least in part, by three mechanisms: (i) oxidation and/or hydrolysis to carbon dioxide; (ii) reaction with a cysteine moiety to yield thiazolidine-2-thione-4-carboxylic acid; and (iii) reaction with sulfite to produce dithiobis(methanesulfonic acid). Degradation in the gastrointestinal tract appears to play a major role in the metabolism of captan (DeBaun et al., 1974). The metabolites of captan were measured in the urine and faeces of five male and five female Sprague-Dawley rats (weighing 192-260 g, obtained from Charles River, Margate, Kent, United Kingdom) treated with a single oral dose of 10 or 500 mg/kg bw [14C-cyclohexene ring]-labelled captan. Some of the animals that received the dose of ]0 mg/kg bw were pretreated with 10 mg/kg bw unlabelled captan for 14 days. Seven urinary metabilites were identified: 3-hydroxy-4,5- cyclohexene-1,2-dicarboximide (42%), 5-hydroxy-3,4-cyclohexene- 1,2-dicarboximide (6%), 6-hydroxy-1-amido-2-carboxy-4,5-cyclohexene (13%), 4,5-cyclohexene-1,2-dicarboximide (11%), 1-amido-2-carboxy- 4,5-cyclohexene (7%), 4,5-dihydroxy-1,2-dicarboximide (6%), and 4,5-epoxy-1,2-dicarboximide (5%). Two unidentified metabolites account:ed for 4 and 2%, respectively, of the urinary radiolabel. Radiolabel remaining at the origin of the thin-layer chromatography plates, which could not be matched to identified metabolites, accounted for 7% of the urinary radiolabel. No significant difference was noted between the sexes or between dosing regimes in the quantity of urinary metabolites. Faecal extracts obtained from rats dosed with 10 and 500 mg/kg bw captan contained 7 and 43% respectively, of an unidentified metabolite (possibly captan). 4,5-Cyclohexene-1,2- dicarboximide accounted for an average of 35% of the faecal metabolites. 3-Hydroxy-4,5- or 5-hydroxy-3,4-cyclohexene-1,2- dicarboximide were major faecal metabolites, the quantities depending on the treatment regime and sex. 4,5-Dihydroxy-1,2-dicarboximide, 1-amido-2-carboxy-4,5-cyclohexene, and polar metabolites were found in only relatively small amounts, and 4,5-epoxy-1,2-dicarboximide was not detected in faecal extracts (Lappin & Havell, 1990). The dermal and oral absorption and metabolism of captan were studied in a pilot study of two human volunteers, and the results were compared with earlier findings in rats (Krieger & Thongsinthusak, 1993). The usefulness of thiazolidine-2-thione-4-carboxylic acid and 4,5-cyclohexene-1,2-dicarboximide as biomarkers of occupational exposure was also evaluated. Both compouns were rapidly detected after dermal application of 15 mg captan (purity, 99.1%) dissolved in 1 ml chloroform (analytical reagent grade) to two healthy adult men weighing 84 and 150 kg. The concentration of 4,5-cyclohexene-1,2- dicarboximide in 12-h urine samples was 5-640 ppb (the lower limit was the minimal detectable limit), and the concentrations were stable for at least one year when the samples were stored at -20°C. Thiazolidine- 2-thione-4-carboxylic acid was also stable, but the minimal detectable limit was 50 ppb. The same two individuals took oral doses of 0.1 or 1 mg/kg bw, urine was collected at 12-h intervals for four days, and the samples were analysed for same two metabolites. Both were detected in urine within the first 24 h (Figure 1) but represented only small percentages of the dose of captan administered: thiazolidine-2-thione- 4-carboxylic, 4-9%, and 4,5-cyclohexene-1,2-dicarboximide, 1-3%, perhaps because there are alternative metabolic pathways. In an earlier study in rats (DeBaun et al., 1974) given captan at much higher oral doses (77-100 mg/kg bw), 4,5-cyclohexene-1,2-dicarboximide and thiazolidine-2-thione-4-carboxylic acid in the urine represented 13 and 19%, respectively, of the dose of captan. In the rats, 4,5-cyclohexene-1,2-dicarboximide was further metabolized by hydroxylation, epoxidation, rearrangement, and internal scission to products that were not assayed in the study of humans. Although the authors of the study in humans concluded that dermal and oral metabolism of captan are different in man and rats, the study did not demonstrate species differences. The significantly higher doses used in rats, the limited number of human volunteers, and the lack of information on other metabolites limited the conclusions that could be drawn.2. Toxicological studies (a) Short-term toxicity Mice Two groups of 15 male CD1 mice were fed diets containing 0 or 6000 ppm captan (purity, 89.4%) for up to 91 consecutive days. The concentration of captan was within 4% of nominal concentration, and the homogeneity and stability of the diet were satisfactory for the period and conditions of storage used. The animals were observed daily; body weights were recorded daily for the first week of the study and weekly thereafter. Food consumption was recorded throughout the study. Five animals per group were killed after 28, 56, and 91 days of treatment and examined post mortem. The small intestine (duodenum, ileum, and jejunum) was removed and prepared by a 'gut rolling' procedure, starting at the ileo-caecal junction. Sections were stained with haematoxylin and eosin or with antibodies to proliferating cell nuclear antigen and examined by light microscopy. Sections were evaluated for histopathological change, for proliferating cell nuclear antigen labelling index (percent cells in the crypts labelled with antigen), for mean number of crypt cells, and for the ratio of villus to crypt height. Body-weight loss was seen among treated mice during the first week of the study in association with significantly reduced food consumption. This was considered to reflect the unpalatability of the captan diets. Food consumption was similar to that of controls from week 2 until the end of the study, and the body-weight gain of treated mice was similar to that of controls for the remainder of the study. The body weights, however, were significantly lower than those of controls from week 2 until the end of the study. The only macroscopic findings in treated mice killed after 28 days was pronounced thickening of the duodenal mucosa. Similar but less pronounced effects were observed in treated mice killed after 56 or 91 days. Histopathological changes in the small intestine were recorded at all times in treated animals. The effects consisted of marked crypt-cell hyperplasia with concomitant atrophy of the associated villi and were limited to approximately the first 7 cm of the duodenum. A marked increase in the number of mitotic figures was seen within the hyperplastic crypts. There was also increased inflammatory cell infiltrate in the expanded lamina propria, limited to the area of the duodenum with diffuse cell hyperplasia. The inflammatory cells were predominately mononuclear and were most prominent at day 28. At later times, only occasional villi were affected by the inflammatory cell infiltrate. In addition to the diffuse hyperplasia seen at day 28, focal crypt hyperplasia, characterized by increased crypt profiles and focal flattening of the villi, was present in animals killed on days 57 and 92. Again, the effect was confined to approximately the first 7 cm of the duodenum. The proliferating cell nuclear antigen labelling index was increased in the crypt cells in the proximal duodenum, and the average number of cells per duodenal crypt was increased at all times in treated mice. The highest crypt cell number was seen at day 28, and there was a trend for the number of cells to decrease with increasing exposure to captan, the villus to crypt height ratio was biologically significantly reduced in treated mice at all times. Thus, in this study, prominent crypt-cell hyperplasia was produced within the first 28 days in the duodenum of mice fed a diet containing 6000 ppm captan. The effect was also present at 56 or 91 days but was diminished, probably by compensatory mechanisms (Allen, 1994). Groups of five male and five female CD1 mice (body weights, 33.8-35.2 g), received as weanlings (29-33 days old) from Charles River, Margate, Kent, United Kingdom, were fed diets containing 0, 400, 800, 3000, or 6000 ppm captan (purity, 89.4%) for 56 days. Analysis of the diets showed that the achieved dietary concentrations of captan were within 9% of target levels; the homogeneity (maximum deviation, 6.8%) and chemical stability of captan in the diet stored at room temperature over 24 days (87.5-100% of the initial concentration) or over 73 days at -20°C (85.2-109% of the initial concentration) were also satisfactory. Clinical signs, body weight, and food consumption were monitored daily for the first week and then weekly for the remainder of the study. At termination on day 57, the animals were sacrificed, and the small intestine was prepared for histopathology by a 'gut rolling' procedure, starting at the ileo-caecal junction and rolling forward to the duodenum. Duodenal hyperplasia was evaluated by (i) visual examination of routinely stained sections for histopathological changes, (ii) assessment of the mean number of cells in the crypt-cell population, (iii) measurement of the bromodeoxyuridine labelling index (percent cells labelled with bromodeoxyuridine as a ratio to the total number of cells in the crypts), and (iv) measurement of the ratio of villus to crypt height. The stomach, jejunum, and ileum were evaluated for histopathological changes only. The body-weight gains of mice fed 3000 or 6000 ppm were lower than those of controls throughout the study, and there was a slight reduction at 400 and 800 ppm, although this was confined to the first few days. A similar pattern of change was seen in food consumption and was consistent, at least in part, with a reduction in the palatability of the diet containing captan. Captan induced a morphologically discernible diffuse hyperplasia of the crypt cells, which was localized to the first 7 cm of the duodenum after the pylorus of the stomach, at 3000 and 6000 ppm in males and at 800, 3000, and 6000 ppm in females. There was an increase in the crypt-cell labelling index at 3000 and 6000 ppm in animals of each sex and an increased incidence in the numbers of cells in the crypt-cell population at dietary levels of 800 ppm and above. In addition, a decrease in the villus to crypt height ratio was seen at 3000 and 6000 ppm in both males and females. These changes were accompanied by mononuclear inflammatory cells in the lamina propria. Mild crypt-cell hyperplasia in the jejunum of male mice was seen at 3000 and 6000 ppm, and there was mild hyperplasia of the forestomach epithelium with hypertrophy of the gastric pits of the glandular portion of the stomach in males at 3000 ppm and in animals of each sex at 6000 ppm. The NOAEL was 400 ppm on the basis of pathological changes including duodenal hyperplasia (Tinston, 1995). Rats The effect of captan on preneoplastic enzyme-altered liver foci was studied in groups of 15 male Fischer 344 rats, six weeks old, given 200 mg/kg bw N-nitrosodiethylamine intraperitoneally and two weeks later fed 4000 ppm (equivalent to 200 mg/kg bw) captan (purity, 90.5%) for six weeks and then sacrificed. The rats underwent a partial hepatectomy at week 3. A small increase in the number of glutathione S-transferase (placental form)positive foci was seen, but the effect was reported to be borderline. There was no effect on mortality or body-weight gain (Cabral et al., 1991). (b) Genotoxicity The potential for captan to interact with DNA was studied in vivo in Swiss ICR-derived CD-1 mice and Osborne-Mendel rats which received a suspension of 14C-trichlormethyl-captan (radiochemical purity, 96-98%; specific activity, 19 mCi/mmol) by gavage. DNA was isolated from various tissues and radiolabel was assayed by scintillation spectrometry. Male mice receiving 1600 mg/kg bw and male and female rats given 300 mg/kg bw of labelled captan were sacrificed 4 or 24 h after treatment, and DNA was extracted from the liver and testis. No significant disintegration was found to be associated with the DNA from either organ. Rats were not used in subsequent experiments because the amount of radiolabelled material with high specific activity was not sufficient to treat both mice and rats. Radiolabel was associated with DNA in all of the organs from mice that were examined (stomach, duodenum, intestine, kidney, liver, testis) 24 h after oral administration of 156 mg/kg bw labelled captan (50-56 mCi/mmol). No correlation was seen between the level of captan-DNA associations and the site of tumour formation. Since information on the spectrum and structure of the captan-induced DNA modifications in specific tissues after administration of captan was not available, the authors were not able to correlate the observed associations with proposed mechanisms of carcinogenesis. Dialysis used to investigate the nature of the captan-DNA interactions in vivo indicated that up to 90% of the detected radioactivity represented either non-covalently associated captan or covalent associations that were hydrolysed non-enzymatically, releasing soluble, labelled nucleotides. The exact nature of the remaining captan-DNA associations was not known (Selsky & Matheson, 1981). The effect of captan on microtubules and micro filaments was studied in vitro in tubulin prepared from porcine brain and in cultured mouse fibroblasts. Turbidometry at 350 nm showed that captan caused a dose-dependent inhibition of tubulin assembly after incubation. At equimolar concentration with tubulin (30 µmol/litre), captan totally inhibited microtubule formation; at lower concentrations (5-30 µmol/litre), captan also promoted disassembly of preformed microtubules. These effects were confirmed by electron microscopy. Immunofluorescent microscopy of cultured mouse fibroblasts showed that captan also depolymerized microtubules, and the extent of microtubule disassembly was concentration- and time-dependent. While a 3-h incubation of the cells with 10 mmol/litre captan was required to completely disturb the microtubular structures, a 12-h incubation with 5 µmol/litre was required to produce the same effect. Recovery of microtubules was observed when preincubated cells were washed extensively. The effect of captan on microtubules was considered to be specific, since in equimolar concentrations in vitro it did not interact with G-or F-actin isolated from rabbit muscle or with the fluorescent actin pattern in mouse fibroblasts incubated with 10 mmol/litre captan for up to 12 h. Microfilaments typical of untreated cells were seen in captan-treated fibroblasts. Thus, captan interacts at equimolar concentrations with tubulin, affecting the assembly and disassembly of microtubules in isolated tubulin and cultured mammalian cells (Stournaras et al., 1991). Groups of 100 male CD-1 mice were given a single dose of 890 mg/kg bw of 35 S-captan (radiochemical purity, 95%; specific activity, 888 MBq/mmol per litre), 82 mg/kg bw of 14C-1-methyl-1- nitrosourea (positive control), or a vehicle formulation by gavage. Six hours after sacrifice, the stomach, jejunum, liver, and bone marrow were sampled, and DNA was extracted from each tissue and purified; the radiolabel associated with these DNA extracts was then measured. Radiolabel was shown to be associated with DNA extracts originating from all tissues of mice treated with captan or the positive control but not from those given the vehicle. Covalent binding indexes (micromoles of captan bound per mole of nucleotide divided by millimoles of captan administered per kilogram body weight) of 2.8, 38, 38, 46, and 91 were determined for DNA from bone marrow, liver, stomach, dudenum, and jejunum, respectively. Selected tissues were further purified in order to determine whether the radiolabel in the extracts was associated with DNA. Radiolabel in liver extracts from captan-treated mice, but not from positive control mice, was found at the base of the tube, away from the main DNA fraction. In contrast, radiolabel associated with DNA from the jejunum and duodenum of captan-treated animals clearly separated at a higher position on the density gradient than the main DNA fraction. Although captan was associated with DNA in all of the organs examined, this study did not indicate whether the association was covalent (Pritchard & Lappin, 1991). When 14C-captan (radiochemical purity, 95-98%) was incubated at 25°C with calf thymus DNA, about 0.3% of the radiolabel was associated with the DNA. In the absence of glutathione, this association was present at time zero and did not increase with time, suggesting that the radiolabel represents loosely bound, unextracted material rather than covalently bound adducts. In the presence of glutathione, the amount of radiolabel associated with DNA appeared to increase initially but rapidly reached a constant level, which again was independent of time. In both cases, the level of associated radiolabel was dependent on the concentration of captan but was unaffected by pH. Because of the high levels of associated radiolabel at time zero, the lack of effect of time and pH, and the low radiochemical purity of the captan used, it could not be concluded that captan binds to DNA to any significant extent under these conditions. These results also preclude identification of the DNA adducts. After incubation of 14C-captan with each deoxynucleoside or DNA base in the presence or absence of glutathione, no reaction was seen with captan, as measured by high-performance liquid chromatography and scintillation counting of the eluent. Groups of 6-12 male CD-1 mice weighing 30-40 g (6-8 weeks old) were each given a single dose of 3 mmol/kg bw 35 S-N-acetylcysteine, 2-oxo-[35 S]-thiazolidine-4-carboxylate, 2-thioxo-[35 S]- thiazolidine-4-carboxylate, or 35 S-captan in vehicle by gavage; another group of male mice was given the vehicle alone. Six hours after treatment, the mice were killed, their livers were removed and homogenized, and DNA extracts were examined. The study indicated no significant covalent binding of captan to DNA, despite the very large doses administered. These studies provide no clear evidence for a reaction between captan or its breakdown products and DNA bases or deoxynucleosides. Furthermore, captan is, at best, an extremely weak genotoxin in vivo. Any binding of captan to DNA must be extremely low and would be impossible to measure by currently available methods. Thus, the tumours seen in mice must arise by a mechanism other than one involving direct interaction between captan and DNA (Provan et al., 1992). The genotoxicity of captan was also studied in vitro in cultured human foreskin fibroblasts. Treatment with 0.16- 1.7 µmol/litre captan reduced cloning ability and produced DNA single-strand breaks and DNA-protein cross-links; an excision repair response was elicited at 17-260 µmol/litre. Captan also inhibited cellular DNA synthesis at 3-17 µmol/litre and formed stable adducts in herring sperm DNA and human cellular DNA. Misincorporation of nucleotides into synthetic DNA templates was significantly increased after treatment with captan at 1-12 mmol/litre in vitro in the presence of Escherichia coli DNA polymerase I, suggesting that DNA adduct formation with captan could have mutagenic consequences. This study shows that captan can interact with DNA at a number of levels and that these interactions may provide the basis for a genotoxic effect. The extreme cytotoxicity of the compound could, however, be due to other cellular effects, since at the IC50 for cell killing (about 0.8 µmol/litre), none of the genotoxic events was seen (Snyder, 1992). Comments The excretion profiles of male and female rats were similar, the urinary route predominating. The residual tissue concentrations seven days after dosing were negligible in animals of each sex, the highest concentrations being found in the kidneys and blood. The metabolism of captan in rats appears to involve the evolution of thiophosgene, derived from the trichloromethylthio moiety. Thiophosgene is detoxified, at least in part, by three mechanisms: oxidation and/or hydrolysis to carbon dioxide; reaction with the cysteine moiety of glutathione to yield thiazolidine-2-thione-4-carboxylic acid; and reaction with sulfite to produce dithiobis(methanesulfonic acid). Degradation in the gastrointestinal tract appears to play a major role in the metabolism of captan. Studies on the hyperplasia induced by captan showed prominent crypt-cell hyperplasia within 28 days in the proximal duodenum of mice fed diets containing 6000 ppm captan for 91 days or 800, 3000, or 6000 ppm for 56 days. The NOAEL was 400 ppm, the lowest dose administered for 56 days, equivalent to 60 mg/kg bw per day, on the basis of duodenal hyperplasia. Captan has been adequately tested for genotoxicity in a range of assays, which demonstrate that it is mutagenic and clastogenic in vitro but not in vivo. The in-vitro responses are reduced or abolished by the presence of liver homogenates, serum, glutathione, or cysteine whenever these experimental modifications have been investigated. Studies of the genotoxicity of captan in mouse duodenum indicate that it does not bind covalently to DNA (although metabolic incorporation of the N-trichloromethylthio-carbon does occur) and nuclear aberrations are not induced. The Meeting concluded that captan does not present a significant genotoxic risk, owing to the presence of an efficient detoxification mechanism in vivo. There appear to have been no studies on the effects of captan on glutathione levels analogous to those conducted with folpet. Dietary studies of 4-8 weeks' duration have shown that irritation and consequent inflammation as well as hyperplasia occur in the proximal duodenum of mice. These data indicate that sustained proliferative stimulation of the proximal duodenum is a consequence of oral administration of captan. The Meeting concluded that this finding represents an important element in the process by which captan, which is not genotoxic in vivo, induces tumours in the mouse gastrointestinal tract. The information available to the present Meeting provides no basis for altering the existing ADI for captan, which is based on an NOAEL of 12.5 mg/kg bw per day determined in studies of reproductive toxicity in rats and monkeys, and a 100-fold safety factor. Toxicological evaluation Levels that cause no toxic effect Mouse: 400 ppm equivalent to 60 mg/kg bw per day (56-day study of toxicity) Rat: 250 ppm, equivalent to 12.5 mg/kg bw per day (study of reproductive toxicity) Dog: 100 mg/kg bw per day (66-week study of toxicity) Monkey: 12.5 mg/kg bw per day (study of developmental toxicity) Estimate of acceptable daily intake for humans 0-0.1 mg/kg bw Studies that would provide information useful for continued evaluation of the compound Further observations in humans References Allen, S.L. (1994) Captan: Investigation of duodenal hyperplasia in mice. Unpublished report No. CTL/L/5674 from Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom. Submitted to WHO by Zeneca Agrochemicals, Fenhurst, Haslemere, Surrey, United Kingdom. Bratt, H. (1990) Captan: Repeat dose study (10 mg/kg) in the rat. Unpublished report No. CTL/P/2958 from ICI Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom. Submitted to WHO by ICI Agrochemicals, Fernhurst, Haslemere, Surrey, United Kingdom. Cabral, R, Hoshiya, T., Hakol, K., Hasegawa, R. Fukushima, S. & Ito, N. (1991) A rapid in vivo bioassay for the carcinogenicity of pesticides. Tumori, 77, 185-188. DeBaun, J.R., Miaullis, J.B., Knarr, J. Mihailovski, A. & Menn, J.J. (1974) The fate of N-trichloro[14C]-methylthio-4-cyclohexene- 1,2-dicarboximide ([14C]captan) in the rat. Xenobiotica, 4, 101-119. Krieger, R.I. & Thongsinthusak, T. (1993) Captan metabolism in humans yields two biomarkers, tetrahydrophthalimide (THPI) and thiazolidine-2-thione-4-carboxylic acid (TTCA) in urine. Drug Chem. Toxicol., 16, 207-225. Lappin, G.J. & Havell, M.L. (1990) Captan: Biotransformation study in the rat. Unpublished report No. CTL/P/2951 from ICI Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom. Submitted to WHO by ICI Agrochemicals, Fernhurst, Haslemere, Surrey, United Kingdom. Pritchard, D.J. & Lappin, G.J. (1991) Captan: DNA binding study in the mouse. Unpublished report No. CTL/P/3380 from ICI Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom. Submitted to WHO by ICI Agrochemicals, Fernhurst, Haslemere, Surrey, United Kingdom. Provan, W.M., Eyton-Jones, H. & Green, T. (1992). The potential of captan to react with DNA. Unpublished report No. CTL/R/1131 from ICI Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom. Submitted to WHO by ICI Agrochemicals, Fernhurst, Haslemere, Surrey, United Kingdom. Selsky, C.A. & Matheson, D.W. (1981) The association of captan with mouse and rat deoxyribonucleic acid. Unpublished report No. T- 10435 from The in vitro Toxicology Section, Environmental Health Center, Stauffer Chemical Company, Farmington, Connecticut, USA. Submitted to WHO by ICI Agrochemicals, Fernhurst, Haslemere, Surrey, United Kingdom. Snyder, R.D. (1992) Effects of captan on DNA and DNA metabolic processes in human diploid fibroblasts. Environ. Mol. Mutag., 20, 127-133 Stournaras, C., Saridakis, I., Fostinis, Y & Georgoulias V. (1991) Interaction of captan with mammalian microtubules. Cell Biochem. Func., 9, 23-28 Tinston, D.J. (1995) Captan: Investigation of duodenal hyperplasia in mice. Unpublished report No. CTL/P/4532 from Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom. Submitted to WHO by ZENECA Agrochemicals, Fenhurst, Haslemere, Surrey, United Kingdom. Trivedi, S. (1990a) Captan: Excretion mid tissue retension of a single oral dose (10 mg/kg) in the rat. Unpublished report No. CTL/P/2820 from ICI Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom. Submitted to WHO by ICI Agrochemicals, Fernhurst, Haslemere, Surrey, United Kingdom. Trivedi, S. (1990b) Captan: Excretion and tissue retension of a single oral dose (500 mg/kg) in the rat. Unpublished report No. CTL/P/2862 from ICI Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom. Submitted to WHO by ICI Agrochemicals, Fernhurst, Haslemere, Surrey, United Kingdom.
See Also: Toxicological Abbreviations Captan (HSG 50, 1990) Captan (ICSC) Captan (PIM 098) Captan (FAO/PL:1969/M/17/1) Captan (WHO Pesticide Residues Series 3) Captan (WHO Pesticide Residues Series 4) Captan (Pesticide residues in food: 1977 evaluations) Captan (Pesticide residues in food: 1978 evaluations) Captan (Pesticide residues in food: 1980 evaluations) Captan (Pesticide residues in food: 1982 evaluations) Captan (Pesticide residues in food: 1984 evaluations) Captan (Pesticide residues in food: 1984 evaluations) Captan (Pesticide residues in food: 1990 evaluations Toxicology) Captan (IARC Summary & Evaluation, Volume 30, 1983)