[Effect of protein deficiency in rats on captan toxictiy. I. Acute toxicity of captan].
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Animals↗
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[Effect of protein deficiency on captan toxicity in rats. II. Activity of selected enzymes in rat serum and liver depending on the dietary level of protein and captan].
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Animals↗
Inhibition of RNA polymerase by captan at both DNA and substrate binding sites.
RNA synthesis carried out in vitro by Escherichia coli RNA polymerase was inhibited irreversibly by captan when T7 DNA was used as template. An earlier report and this one show that captan blocks the DNA binding site on the enzyme. Herein, it is also revealed that captan acts at the nucleoside triphosphate (NTP) binding site, and kinetic relationships of the action of captan at the two sites are detailed. The inhibition by captan via the DNA binding site of the enzyme was confirmed by kinetic studies and it was further shown that [14C]captan bound to the beta' subunit of RNA polymerase. This subunit contains the DNA binding site. Competitive-like inhibition by captan versus UTP led to the conclusion that captan also blocked the NTP binding site. In support of this conclusion, [14C]captan was observed to bind to the beta subunit which contains the NTP binding site. Whereas, preincubation of RNA polymerase with both DNA and NTPs prevented captan inhibition, preincubation with either DNA or NTPs alone was insufficient to protect the enzyme from the action of captan. Furthermore, the interaction of [14C]captan with the beta and beta' subunits was not prevented by a similar preincubation. Captan also bound, to a lesser extent, to the alpha and sigma subunits. Therefore, captan binding appears to involve interaction with RNA polymerase at sites in addition to those for DNA and NTP; however, this action does not inhibit the polymerase activity.
Bacterial Proteins↗
Mammalian host- and fluid-mediated mutagenicity assays of captan and streptozotocin in Salmonella typhimurium.
The mutagenicity of captan and of streptozotocin was tested in vivo by reversion of hisG46 base-pair substitution histidine auxotrophs of Salmonella typhimurium in the peritoneal cavity or in blood, plasma or urine of rats or mice. Genetic response was determined by the frequency of revertants (quantitative test) or by the number of revertants per plate (semiquantitative test). In quantitative HMA captan gave negative results following 3 hourly 500 mg/kg s.c. doses or 1000 mg/kg oral dose in mice with the hisG46 mutant or 2000 mg/kg oral dose in rats with the hisG46, uvrB (TA1950) mutant. The positive control SZN induced many reversions at 0.5 mg/kg i.p. or 10 or 100 mg/kg oral doses. In semiquantitative in vivo blood or urine assays captan gave negative results after a 250 mg/kg oral dose with hisG46. SZN in the same experiment gave positive results in both semiquantitative and quantitative in vivo blood assays following 1000 mg/kg i.p. or 2000 mg/kg oral doses in the rat with TA1950. Rat blood mixed with captan for 45 min before adding TA1950 cells inactivated 1000 mug captan/ml but not 5000 mg/ml in the semiquantitative test. Corresponding figures in the quantitative test were 500 mu/ml and 1000 mug/ml. Rat plasma inactivated the mutagenicity of about 10 times less captan than rat blood. Human blood inactivated about as much captan as rat blood. The mutagenicity of captan was inactivated more efficiently than of SZN by blood. The results of the experiments suggested that captan's mutagenicity is probably inactivated by glutathione of the erythrocytes. Rat S-9 liver microsomal fraction also strongly decreased captan's mutagenicity in a semiquantitative test with the R factor, uvrB, hisG46 (TA100) mutant.
Administration, Oral↗
Effects of Captan on DNA and DNA metabolic processes in human diploid fibroblasts.
The fungicide Captan has been examined for its effects on DNA and DNA processing in order to better understand the genotoxicity associated with this agent. Captan treatment resulted in production of DNA single strand breaks and DNA-protein cross-links and elicited an excision repair response in human diploid fibroblasts. Captan was also shown to inhibit cellular DNA synthesis and to form stable adducts in herring sperm and human cellular DNA. Misincorporation of nucleotides into Captan-treated synthetic DNA templates was significantly elevated in an in vitro assay using E. coli DNA polymerase I, suggesting that DNA adduct formation by Captan could have mutagenic consequences. In sum, these studies demonstrate that Captan is capable of interacting with DNA at a number of levels and that these interactions could provide the basis for Captan's genotoxicity. The extreme cytotoxicity of this fungicide, however, could be due to other cellular effects since at the IC50 for cell killing, approximately 0.8 microM, none of the above genotoxic events could be detected by the methods employed.
Captan↗
Toxicologic studies of N-trichloromethylthio-4-cyclohexene-1,2-dicarboximide (captan): its metabolism by rat liver drug-metabolizing enzyme system.
The degree of toxicity caused in rats by captan (N-trichloromethylthio-4-cyclohexene-1,2-dicarboximide) administered intraperitoneally is greater than that induced by orally administered captan. With regard to its effect on the drug-metabolizing enzymes of rat liver, the activity of aniline hydroxylase and the level of cytochrome P-450 were found to decrease in the treated rats 24 h after a single oral dose (650 mg/kg). The loss was even greater in the animals receiving diethyl maleate 1 h prior to captan. Furthermore, usual increase in the activity of drug biotransformation enzymes seen after phenobarbital treatment appears to decrease in rats dosed with this funaicide. In vitro incubations of rat liver microsomes with captan resulted in a profound loss of cytochrome P-450 and the acitivty of benzphetamine N-demethylase as well as aniline hydroxylase. Although the inhibition of drug-metabolizing enzyme activity by captan was observed in microsomal incubations with or without NADPH, a detectable amount of carbonyl sulfide (COS) was found only in the incubations that contained captan plus NADPH. Carbonyl sulfide appears to arise from a captan-derived metabolite, thiophosgene (CSCl2), which decomposes to COS in aqueous solutions and in the presence of NADPH inhibits the activity of drug biotransformation enzymes.
Aniline Hydroxylase↗
Protective effect of glutathione on the in vitro inhibition of hepatic cytochrome P-450 by captan.
The in vitro effect of various concentrations of captan on hepatic microsomal cytochrome P-450 from pehnobarbital-pretreated rats was studied. The I-50 value, namely the concentration of the inhibitor necessary to produce 50% loss of cytochrome P-450 was determined from theplotted inhibition curve. The presence of ethylenediaminetetraacetic acid (EDTA) in microsomal incubations prior to the addition of captan failed to prevent the loss of cytochrome P-450 by captan. In contrast, reduced glutathione (0.5 mM) added to microsomal incubations before captan (0.1 mM) afforded almost complete protection of cytochrome P-450 from captan inhibition. These data indicate that the inhibitory effect of captan on vitally important drug-metabolizing enzyme system, of which cytochrome P-450 is a major component, can be prevented by prior presence of reduced glutathione (GSH) but not of EDTA.
Animals↗
Effects of the herbicide 2,4-DB and fungicide captan on reactions of mitochondria and chloroplasts.
The effects of the herbicide 4(2,4-dichlorophenoxy)butyric acid (2,4-DB) and fungicide N-(trichloromethyltio)-4-cyclohexene-1,2-dicarboximide (captan) on electron transport processes of mitochondria and chloroplasts have been investigated. Chloroplasts, isolated from spinach leaves (Spinacia oleracea L.), were treated with pesticide prior to the addition of electron acceptor and ADP. White potato (Solanum tuberosum L.) mitochondria were either incubated with pesticide before the addition of substrate, or they were treated with pesticide after the addition of substrate and ADP. Captan inhibited oxidation of malate by mitochondria and acted as an uncoupler. With succinate as sunstrate captan was found to stimulate state 4 respiration, as substrate captan was found to stimulate state 4 respiration, with the loss of coupled phosphorylation only at higher concentrations of fungicide. The herbicide 2,4-DB appeared to be 5 to 10 times less effective than captain. Both compounds inhibited phosphrylation-coupled succinate oxidation at higher concentrations and malate-coupled phosphorylation at lower concentrations. They acted as inhibitors of NADH-cytochrome c reductase. Both pesticides inhibited noncyclic electron transport in chloroplasts. The rate of ferricyanide reduction in the presence and absence of phosphorylating agents was reduced, and although the rate of ATP generation was reduced also, the P/2e ratio was not changed much under the influence of pesticides.
Butyrates↗
Personnel safety and foliage residue in an orchard spray program using azinphosmethyl and captan.
Residue levels of azinphosmethyl and captan were determined from blotter paper patches attached to the clothing of personnel participating in an orchard spray program. Average exposure of 1.74 mg/man/hr for azinphosmethyl and 1.94 mg/man/hr for captan were extrapolated from mean residue values obtained from analyzing the patches. Azinphosmethyl residue found on apple and peach foliage had been reached by 69% by the tenth day post-application, while captan residue had been reduced 50% for the same period. There was no evidence of a buildup of either azinphosmethyl or captan on treated foliage as the season progressed.
Agricultural Workers' Diseases↗
Cytogenetic and dominant lethal studies on captan.
Possible mutagenic activity of captan was investigated by in vitro and in vivo cytogenetic studies and by the dominant lethal study in mice. In vitro cytogenetic study with cultured human diploid cells revealed a significant increase in the frequency of cells showing stickiness and a severe mitotic inhibition at concentrations of 3.0 and 4.0 microgram of captan per ml. although no chromosomal aberrations were observed. In in vivo cytogenetic study, no chromosomal aberrations were induced in the bone marrow cells of rats treated orally with captan at a single dose of 500, 1000 or 2000 mg/kg or at five consecutive doses of 200, 400 or 800 mg/kg/day. Dominant lethal study also failed to show any mutation induction after treatment of male mice with daily oral dose of 200 or 600 mg of captan per kg bw for five days.
Animals↗
Evidence of reduced poly-B-hydroxybutyrate biosynthesis in free-living nitrogen-fixing bacteria, Azotobacter chroococcum, following acquired resistance to the fungicide captan.
Some biological activities of Azotobacter chroococcum, strain Azcap 1, (spontaneous mutant, captan resistant up to 300 micrograms/ml) were assayed on RM medium with and without the presence of the fungicide. Comparisons were also carried out with Az. chroococcum sensitive strains Azwt, Azcan 10 and 14. The hydrolysis of captan, incorporated in agar plates of RM at 100 micrograms/ml, was rapid, since on 4-day plates, no effect was found on the strain Azwt, while on freshly prepared ones its growth was completely blocked. As for Azcap 1, grown on RM only, the behaviour was similar to that of sensitive strains, whereas when grown on captan the results of experiments showed: (i) a lag of approximately 12 h to reach the maximum nitrogen-fixing activity; (ii) delay of 12-24 h in the full consumption of glucose present in the medium, although the invertase activity did not present differences; (iii) high ATP culture content during the 50 h of the experiment; (iv) approximately 6-10-fold lower production of PHB (poly-B-hydroxybutyrate); (v) lack of typical encystment phase, for the tested 96 h and reduced viability in developing colonies on agar RM medium. In contrast, when captan was added to cultural medium at sublethal concentration, 50 micrograms/ml for sensitive strain Azwt and 200 micrograms/ml for Azcap 1, the amount of glutathione produced (to remove the fungicide toxicity) was several times higher for the former.
Azotobacter↗
Alterations of nucleic acid and protein syntheses in vivo in the chick embryo mediated by captan.
1. The objective of this investigation was to measure the effects of captan on DNA, RNA and protein biosyntheses in limbs of developing chick embryo, in vivo. 2. Captan (12p.p.m.) was injected into the egg on day 4 of incubation and macromolecular syntheses were measured on days 8--14. 3. Total DNA content was unaffected by captan, but incorporation of [3H]thymidine was inhibited over the entire time range; the period of peak specific activity (day 11) was inhibited in treated samples to 67% of control. 4. Total RNA content was reduced in the earlier days but returned to normal by day 14, whereas incorporation of [3H]uridine was lowered throughout the period. The timing of peak specific activity for RNA synthesis was delayed by 2 days in treated eggs and was inhibited by 32% when peak days were compared. 5. Total protein concentration was slightly lowered by captan treatment in the mid-range of the days measured and the incorporation of [3H]valine was retarded in the early days; peak periods of synthesis were similar in magnitude but were shifted from days 9--10 in control to day 11 in treated embryos.
Animals↗
Relative toxicity of aldrin, fenvalerate, captan and diazinon to the freshwater food-fish, Clarias batrachus.
The median lethal concentrations (LC50S) of aldrin, fenvalerate, captan and diazinon were determined for Clarias batrachus by trimmed Spearman-Karber method. The potency ratios of toxicity among them were analysed by parallel-line bioassay with quantal responses. The LC50S for 40 day of exposure of aldrin, fenvalerate, captan and diazinon were 0.00036, 0.0094, 0.5473 and 2.4186 ppm respectively. These values were lower than those obtained for an exposure of 96 hour. It shows the greater toxicity of the pesticides in a long-term exposure. The relative toxic potency of aldrin fenvalerate, captan and diazinon was in a ratio of 6807:241:4:1 respectively. Thus the chemically different groups of pesticides exhibit an order of toxicity as aldrin greater than fenvalerate greater than captan greater than diazinon for the freshwater catfish, Clarias batrachus. It infers that the catfish is most sensitive to aldrin and least sensitive to diazinon. The comparison of the sensitivity of various species tested against these pesticidal chemicals has also been done to review the available information.
Aldrin↗
Dermal penetration of [14C]captan in young and adult rats.
Age dependence in dermal absorption has been a major concern in risk assessment. Captan, a chloroalkyl thio heterocyclic fungicide, was selected for study of age dependence as representative of this class of pesticides. Dermal penetration of [14C]captan applied at 0.286 mumol/cm2 was determined in young (33-d-old) and adult (82-d-old) female Fischer 344 rats in vivo and by two in vitro methods. Dermal penetration in vivo at 72 h was about 9% of the recovered dose in both young and adult rats. The percentage penetration was found to increase as dosage (0.1, 0.5, 2.7 mumol/cm2) decreased. Two in vitro methods gave variable dermal penetration values compared with in vivo results. A static system yielded twofold higher dermal penetration values compared with in vivo results for both young and adult rats. A flow system yielded higher dermal penetration values in young rats and lower penetration values in adults compared with in vivo results. Concentration in body, kidney, and liver was less in young than in adult rats given the same absorbed dosage. A physiological pharmacokinetic model was developed having a dual compartment for the treated skin and appeared to describe dermal absorption and disposition well. From this model, tissue/blood ratios of captan-derived radioactivity for organs were found to range from 0.35 to 3.4, indicating no large uptake or binding preferences by any organ. This preliminary pharmacokinetic model summarizes the experimental findings and could provide impetus for more complex and realistic models.
Administration, Cutaneous↗
Gas chromatographic determination of captan, folpet, and captafol residues in tomatoes, cucumbers, and apples using a wide-bore capillary column: interlaboratory study.
An interlaboratory study of the determination of captan, folpet, and captafol in tomatoes, cucumbers, and apples was conducted by 4 laboratories using wide-bore capillary column gas chromatography with electron capture detection. The 3 fungicides were determined using the Luke et al. multiresidue method modified to include additional solvent elution in the optional Florisil column cleanup step used with this method. The crops were fortified with each fungicide at 3 levels per crop. Mean recoveries ranged from 86.2% for a 25.1 ppm level of captan in apples to 115.4% for a 0.288 ppm level of captafol in apples. Interlaboratory coefficients of variation ranged from 3.4% (24.7 ppm folpet) to 9.7% (0.243 ppm captafol) for tomatoes; from 2.8% (2.0 ppm captafol) to 8.2% (24.8 ppm captan) for cucumbers; and from 1.5% (0.234 ppm folpet) to 22.1% (0.266 ppm captafol) for apples.
Captan↗
Gas-liquid chromatographic determination of captan and two metabolites in milk and meat.
A gas-liquid chromatographic (GLC) method has been developed for the determination of captan (N-trichloromethylthio-4-cyclohexene-1,2-dicarboximide) and 2 metabolites, tetra-hydrophthalimide (THPI) and tetrahydrophthalamic acid (THPMA), in milk and meat. The sample is extracted with ethyl acetate and is cleaned up by acetonitrile partition and silica gel chromatography where captan, THPI, and THPMA are separated. Captan is directly determined by GLC. THPI and THPMA are separately derivatized in an acetone solution of pentafluorobenzyl bromide. The resultant derivatives are purified separately on an Al2O3 column and quantitated by GLC, using an electron capture detector. Recoveries from milk samples fortified at 0.02-10 ppm ranged from 71 to 102%; recoveries from meat samples fortified at 0.04-10 ppm ranged from 75 to 99%.
Animals↗
[Resistance of earthworms Lumbricus terrestris and Allolobophora turgida to the fungicide captan 50 W.P].
Two species of earthworms were kept in Muck, Chicot and Ste-Sophie soils treated with captan 50 W.P. solutions of 700, 1 400 and 2 800 ppm. After a 42-day treatment period, L. terrestris had a 95% survival and A. turgida 100% survival. Using a gas chromatograph method, no captan was detected in tissue extracts of exposed earthworms. Based on the survival rate and the undetected presence of captan in earthworm tissues, we concluded that soil residues of this product are unlikely to be harmful to the animal's ecology.
Animals↗
Nonteratogenicity of captan in beagles.
Thirty and 60 mg/kg captan, administered in the diet during the entire gestation period or during gestation and an 8-week lactation period, caused no adverse effects in either mothers or progeny, and captan is thus judged to be nonteratogenic in beagles.
Animals↗