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At least 109 records · Page 6Linked to original sources
PubMed1975

Chronic toxicity study of cyclamate: saccharin (10: 1) in rats.

Chronic rat feeding studies were conducted on a 10: 1 cyclamate/saccharin (C/S) mixture to supplement previous investigations which had established the safety of the individual components. The test mixture was fed at dietary levels designed to furnish 500, 1120, and 2500 mg/kg body weight to groups of 35 male and 45 female rats. The protocol included observations of physical condition, growth response, food efficiency, blood, urine, and postmortem pathology. Reproduction and lactation performance was examined through 2 litters. Teratology was also investigated. Since conversion to cyclohexylamine (CHA) was found to occur in many of the rats, particularly in the higher dosage groups, it was included as an added insult in the diets of about half the animals during the last quarter of the 2-year test period. The only positive finding in these studies which proved to have crucial significance was the occurrence of papillary carcinomas in the bladders of 12 of the 70 rats fed the maximum dietary level of the mixture (equivalent to about 2500 mg/kg body weight) for periods ranging from 78 to 105 weeks (except for one earlier death). This finding was the principal reason for the removal of cyclamates from the "generally recognized as safe" (GRAS) group of non-nutritive sweeteners by the U.S. Department of Health, Education and Welfare. In the opinion of the authors, the sequelae following this precipitate ban on cyclamates, prompted by a verbal report of the preliminary findings, warrant placing the study on record for the information of toxicologists and regulatory agencies throughout the world.

Animals↗
PubMed1975

Method for testing mutagenic effects of chemicals on spermatogonia of the Chinese hamster: results obtained with cyclophosphamide, saccharin, and cyclamate.

The action of different cyclophosphamide doses on spermatogonia of the Chinese hamster was examined. Two oral treatments at an interval of 24 h were carried out and spermatogonia were prepared for examination 24 or 48 h after the second dose. Accordingly the effects of 5 oral cyclophosphamide doses given on five consecutive days were tested on spermatogonia and preparations were made 24 or 72 h after the last treatment. The results so obtained form the basis of reference for findings following oral administration of saccharin sodium, sodium cyclamate, or trimethylphosphate. Male Chinese hamsters, 6-8 per group, were used, from each of which about 100 metaphases were evaluated. Preparation was carried out essentially according to Hoo and Bowles [Mutation Res. 13, 85-88 (1971)]. gaps, breaks, fragments, deletions and translocations were rated as structural aberrations. For every dose and every time of preparation the incidence of metaphases with aberrations, with or without gaps, and with translocations were assessed. The different experiments led to the following conclusions: 1. By analysis of spermatogonial metaphases of treated Chinese hamsters chemically induced chromosome aberrations can be proved with certainty. 2. Incidence of metaphases with translocations is a sensitive measure which is distinctly superior to the summary determination of all aberrations. In this way it was possible to show a mutagenic influence of 2 times 8 mg/kg cyclophosphamide p.o. 3. Following two cyclophosphamide doses administered at an interval of 24 h it was found that preparations of spermatogonia 48 h after the second dose was better suited for the evaluation than that at 24 h, for aberrations were more frequent with the same treatment. After five cyclophosphamide treatments at 24-h intervals, aberrations were somewhat more frequent 24 h after the last dose than at 72 h; in any case the values exceeded significantly the results of untreated controls. 4. A conclusive numeric chromosome analysis is not possible with the spermatogonia test, since a relatively high percentage of non-diploid cells is apparently of methodological origin. 5. Tests with 2 times 500 or 5 times 1000 mg/kg trimethylphosphate orally showed an increase in chromosome aberrations compared with controls indicating mutagenic effects in both cases; with 5 times 1000 mg/kg p.o., however, the figures were low as a result of marked mitotic inhibition. 6. The results of the spermatogonia test on Chinese hamsters revealed no mutagenic effects of saccharin sodium 2 times 5000 mg/kg orally, and of sodium cyclamate 5 times 2000 mg/kg orally. This is based on comparisons of the results both with untreated controls and positive controls treated with trimethylphosphate or cyclophosphamide.

Animals↗
PubMedDate not supplied

Carcinogenicity prediction and battery selection procedure: an in-depth analysis of cyclamate and its major metabolite cyclohexylamine.

The carcinogenicity prediction and battery selection (CPBS) method can be used to predict the probable carcinogenicity of a chemical based on the results of a battery of short-term assays. The method uses Bayesian statistics and the estimated performance characteristics of the assays (i.e., sensitivity and specificity). For routine use, the prior probability of carcinogenicity (or of noncarcinogenicity) is assumed to be unknown and is assigned a nondiscriminatory value of 0.5, i.e., the chemical is assumed to have an equal probability of being a carcinogen or a noncarcinogen, which implies that the expert's intuition regarding the chemical's potential as a carcinogen, based on structural features, known metabolic transformation, or potential electrophilicity, is not taken into consideration. In the present study, it is shown with cyclamate and its metabolite cyclohexlamine that when a battery of assays is used, assigning values to the prior probability between 0.1 and 0.9 has no significant effect on the predicted carcinogenicity. In the view of the fact that the performance of short-term tests is calibrated against known carcinogens and noncarcinogens, and since in the available data bases there is a preponderance of carcinogens, it may be argued that the estimation of sensitivities may be biased toward elevated values. It is shown, however, that when a battery of assays is used, assigning decreased values to the sensitivity does not result in significant effects on the predicted activity of the two test chemicals. Frequently, in the compilation of short-term results within a single assay, different laboratories may report varying results. Heretofore the "consensus result" was derived by majority rule. Because the variability in results may have biological significance, and in view of the fact that for a widely used sweetner one might be even more risk-adverse, a modification of Bayes's formula was derived to take these differences into consideration when calculating the probable carcinogenicity of cyclamate and its major metabolite.

Biotransformation↗
PubMed1977

[Subchronic toxicologic studies using cyclamate-Na in dogs].

2 male and 2 female beagle dogs were fed cyclamate-Na in daily doses of 0 (control), 150, 500, 1500 mg/kg of body weight with the diet. Liquid feces occurred only after feeding 1500 mg/kg/day during the first few days of the experiment. Haematological, clotting and clinical chemistry parameters were unchanged in the groups up to the level of 1500 mg/kg/day. No effects were noted in carbohydrate and fat metabolism, nor in ECG or blood pressure. Gross pathology and histopathology did not reveal any change in any dose group. Daily fed doses of cyclamate-Na up to 1500 mg/kg body weight were well tolerated for three month in the dog.

Animals↗
PubMed1984

Investigations on the carcinogenicity of the artificial sweeteners sodium cyclamate and sodium saccharin in rats in a two-generation experiment.

In a two-generation experiment oral lifelong administration of a 2% and a 5% mixture of sodium cyclamate and sodium saccharin in the feed did not result in carcinogenic effects in Sprague-Dawley rats (70-78 rats/group). In particular, no tumors of the urinary tract were detected, apart from one female rat with a papilloma of the urinary bladder (2% group). A sugar-receiving group, as well as an untreated control group did not yield any unexpected results. Stone formation in the urinary bladder was considerably increased in the group receiving sodium cyclamate and saccharin at 5% concentration.

Animals↗
PubMed1978

Saccharin, cyclamate, and human bladder cancer. No evidence of an association.

An epidemiologic study designed to elucidate the possible roles of the artificial sweeteners saccharin and cyclamate in human urinary bladder cancer was recently completed. The previous intake of each of these substances among 519 patients with histopathologically confirmed bladder cancer and an equal number of matching controls in metropolitan Baltimore did not differ significantly in frequency, quantity, or duration. These normal findings persisted after simultaneous adjustment for the effects of smoking, occupation, age, diabetes mellitus, and a number of other potentially confounding factors. They are substantiated by the failure of the relative risk of bladder cancer to increase with increasing exposure to artificial sweeteners. It is concluded that neither saccharin nor cyclamate is likely to be carcinogenic in man, at least at the moderate dietary ingestion levels reported by the patient sample.

Cyclamates↗
PubMed1982

Effect of the suspected tumor promoters saccharin, cyclamate, and phenol on nerve growth factor binding and response in cultured embryonic chick ganglia.

The suspected bladder tumor promoters saccharin and cyclamate reversibly inhibited nerve growth factor-induced neurite outgrowth in embryonic chick sensory ganglia, and active concentrations of these artificial sweeteners inhibited binding of 125I-labeled mouse submaxillary gland nerve growth factor as well. The skin tumor promoter phenol also reversibly inhibited neurite outgrowth, while comparable concentrations of the nonpromoting but structurally related compounds benzene and fluorobenzene did not. However, in contrast to findings with saccharin and cyclamate, phenol had little, if any, effect on binding of radioactive nerve growth factor.

Animals↗
PubMed1991

The superoxide dismutase activities of two higher valent manganese complexes, MnIV desferrioxamine and MnIII-cyclam.

A green manganese desferrioxamine complex is rapidly formed at room temperature upon stirring freshly precipitated manganese dioxide in a solution of the ligand. Spectral studies and low-temperature ESR indicate that this compound, which has been previously described as a manganese(III) complex, is better characterized as containing tetravalent manganese. The complex appears to form oligomers in solution. The extinction coefficient at 635 nm is 137 +/- 6 M-1 cm-1 (per manganese) at pH 7.8 and 88 +/- 4 M-1 s-1 at pH 6.6 after purification by chromatography. The superoxide dismutase activity was measured and compared to that of mononuclear manganese(III) 1,4,8,11-tetraazacyclodecane (cyclam). The catalytic rate constants for superoxide dismutase activity are 1.7 x 10(6) M-1 s-1 and 2.9 x 10(6) M-1 s-1 for the desferrioxamine and the cyclam complexes, respectively.

Cytochrome c Group↗
PubMed1984

Biodistribution of lipophilic 99mTc complexes of cyclam derivatives.

Several n-alkyl-cyclam derivatives were synthesized which form stable single component cationic chelates with 99mTc. These results suggest that the cyclam moiety in these derivatives complexes 99mTc in the same manner as the underivatized macrocycle. Biodistribution studies in mice show that all of these chelates are cleared from circulation by both the kidneys and liver. The ratio and rates of clearance by these organ systems is related to lipid solubility. None of the lypophilic-cationic-99mTc agents show any significant myocardial uptake. Also, these chelates show no significant ability to penetrate the blood-brain-barrier.

Animals↗
PubMed1990

Therapeutic effectiveness of 2,3,2 tet, cyclam and EDTA in toads exposed to lethal doses of nickel and cobalt.

1. In the course of the present investigation, three chelating agents (2,3,2 tet, cyclam or EDTA) were tested for their therapeutic effect on nickel and cobalt poisoned toad. 2. Our results showed that EDTA appears to be superior to the two other ligands, which have been proved to be chemical ligands for Ni and Co in vitro. 3. EDTA was able to prevent disturbances in the activities of serum aspartate and alanine aminotransferases, alkaline phosphatase, total protein, urea, uric acid and blood glucose level. 4. Our results suggest caution in the use of 2,3,2 tet or cyclam in human Ni and Co intoxication.

Animals↗
PubMed2005

[Ni(cyclam)(mu(1,3)-dca)2Cu(mu(1,5)-dca)2]: a genuine 3D bimetallic coordination polymer containing both mu(1,3)- and mu(1,5)-bidentate dicyanamide bridges and a ferromagnetic interaction between copper(II) and nickel(II) ions.

The structure of [Ni(cyclam)(mu(1,3)-dca)2Cu(mu(1,5)-dca)2], a genuine 3D dicyanamide-bridged bimetallic coordination polymer, is made up of 2D [Cu(mu(1,5)-dca)2]n layers connected by [Ni(cyclam)(mu(1,3)-dca)2] bridging moieties; it exhibits a ferromagnetic exchange interaction between copper(II) and nickel(II) ions through the mu(1,3)-bidentate dicyanamide bridges.

Journal Article↗
PubMed2005

Synthesis, characterization, and x-ray crystal structures of cyclam derivatives. 8. Thermodynamic and kinetic appraisal of lead(II) chelation by octadentate carbamoyl-armed macrocycles.

En route toward the development of hybrid organic-inorganic extracting materials incorporating lead-selective chelators and their implementation in water purification processes, the lead(II) binding properties of three N-carbamoylmethyl-substituted 1,4,8,11-tetraazacyclotetradecanes (cyclams) have been fully investigated by spectroscopic (IR, UV-vis, MALDI-TOF MS, (1)H and (13)C NMR), X-ray crystallographic, potentiometric, and kinetic methods. Solution NMR studies revealed that the Pb(2+) ion is entrapped in a molecular cage constituted by the four macrocyclic nitrogen and four amidic oxygen atoms. Protonation and lead binding constants determined in aqueous solution were shown to be linearly dependent, so that all three derivatives possess a similar affinity at any pH value. Thermodynamic and kinetic parameters revealed the crucial role played by the intramolecular hydrogen bonds also evidenced in the crystal structure of the tetraacetamide derivative L(1), which involve the lone pair of each macrocyclic tertiary amine and one amidic hydrogen atom belonging to the appended arm. In contrast to L(1), the absence of such intramolecular interactions for N-(dimethyl)carbamoylmethyl- and N-(diethyl)carbamoylmethyl-substituted cyclams (L(2) and L(3), respectively) accounts for the 2-3 orders of magnitude enhancement of their proton and lead binding affinities. Stopped-flow kinetic measurements enabled unraveling the formation process of the three lead(II) complexes that proceeds in a single rate-limiting step according to the Eigen-Winkler mechanism, while the apparent rate constants were found to increase in the order L(3) < L(2) << L(1) as a consequence of the more acidic character of L(1). A common proton-assisted dissociation mechanism has been found for the three lead(II) complexes, which involves the rapid formation of a protonated, six-coordinate intermediate followed by either a unimolecular decomposition or a bimolecular attack of a second hydronium ion.

Carbamates↗
PubMed1999

Magnetic Behavior and Crystal Structure of [Fe(cyclam)(NCS)(2)](TCNQ)(2): An Unusual One-Dimensional (TCNQ)(2)(-) Radical-Ion System.

The compound [Fe(cyclam)(NCS)(2)](TCNQ)(2), where cyclam is 1,4,8,11-tetraazacyclotetradecane and TCNQ is a partially reduced 7,7,8,8-tetracyanoquinodimethane fragment, has been obtained from the corresponding thiocyanate by metathesis reaction. The compound crystallizes in the triclinic system, space group P&onemacr;, a = 7.832(3) Å, b = 8.008(2) Å, c = 15.501(3) Å, alpha = 79.85(2) degrees, beta = 85.11(2) degrees, gamma = 74.18(3) degrees, Z = 1. The crystalline lattice consists of one-dimensional TCNQ units, stacked along the a direction, and it is stabilized by interactions with the Fe(III) hexacoordinated complex cations. All of the TCNQ's are crystallographically equivalent, with bond parameters typical of partially reduced acceptors with a formal charge of 0.5 electron. Two different distances between adjacent TCNQ units are observed, i.e., 3.29 and 3.42 Å, indicating the presence of dimeric (TCNQ)(2)(-) in the chains. The temperature dependence of the magnetic susceptibility was described as due to two contributions: the first one comes from the Curie contribution of the Fe(III) complex while the second arises from the magnetic exchange interactions between the nearest neighbor TCNQ anions. The latter is typical of one-dimensional antiferromagnetic chains of S = (1)/(2) spins, localized on (TCNQ)(2)(-) units, and it could be fitted according to a one-dimensional Heisenberg antiferromagnet model.

Journal Article↗
PubMed2004

Four-arm oligonucleotide Ni(II)-cyclam-centered complexes as precursors for the generation of supramolecular periodic assemblies.

The development of a multiarm metal-centered DNA building block as a precursor for the construction of supramolecular assemblies has relied upon the preparation of a Ni(II)-1,4,8,11-tetrazacyclotetradecane ligand (cyclam) functionalized with four linkers. This complex can be incorporated into a support-bound DNA sequence and the remaining three linkers can then be elongated by DNA synthesis. The result is a Ni(II)-cyclam complex tethering four 20-mer DNA strands. This building block, designed to be tetrahedral in nature, can in principle be used to form tetrahedral assemblies. These assemblies can be designed to be of known size and composition or permitted to grow into complexes of essentially infinite size, ideally the macroscopic version of a crystal.

DNA↗
PubMed2005

Octahedral non-heme non-oxo Fe(IV) species stabilized by a redox-innocent N-methylated cyclam-acetate ligand.

The ligand 1,4,8-tri-N-methyl-1,4,8,11-tetraazacyclotetradecane-11-acetic acid (Me3cyclam-acetic acid) has been synthesized by Eschweiler-Clarke methylation of cyclam-acetic acid, and the iron(III) complex [(Me3cyclam-acetate)FeN3]PF6, 1, has been synthesized, which has been found to have significantly different properties than its unmethylated analogue, [(cyclam-acetate)FeN3]PF6, 2. Whereas the iron ion in 2 is low spin with S = 1/2, 1 is found to be high spin at temperatures above 100 K, though low-spin species are observed at lower temperatures, indicating a spin crossover phenomenon. The iron(II) species 1red is electrochemically more accessible than 2red since the Fe2+/3+ redox wave in 1 appears approximately 350 mV more positive than the corresponding wave in 2. Also, 1 displays a reversible Fe3+/4+ redox wave, which is irreversible in 2, denoting that the Fe(IV) species 1ox is kinetically stable. 1red and 1ox have been generated electrochemically in solution and studied spectroscopically. Mössbauer spectroscopy has confirmed that, in both reduction and oxidation, iron is the redox center, that 1red is high spin (S = 2), and that 1ox is low spin (S = 1), in contrast to 2red which is low spin and 2ox which could not be isolated.

Crystallization↗
PubMed2001

A mixed-valence manganese(III)-manganese(IV) di-mu-oxo complex, [(cyclam)MnO]2(ClO4)2(NO3).

The title dinuclear di-mu-oxo-bis[(1,4,8,11-tetraazacyclotetradecane-kappa(4)N)manganese(III,IV)] diperchlorate nitrate complex, [Mn(2)O(2)(C(10)H(24)N(4))(2)](ClO(4))(2)(NO(3)) or [(cyclam)MnO](2)(ClO(4))(2)(NO(3)), was self-assembled by the reaction of Mn(2+) with 1,4,8,11-tetraazacyclotetradecane in aqueous media. The structure of this compound consists of a centrosymmetric binuclear [(cyclam)MnO](3+) unit, two perchlorate anions and one nitrate anion. While the low-temperature electron paramagnetic resonance spectra show a typical 16-line signal for a di-mu-oxo Mn(III)/Mn(IV) dimer, the magnetic susceptibility studies also confirm a characteristic antiferromagnetic coupling between the electronic spins of the Mn(IV) and Mn(III) ions.

Journal Article↗