Prediction of ADME-Tox properties and toxicological endpoints of triazole fungicides used for cereals protection

Ionut Mădălin Gridan; Alecu Aurel Ciorsac; Adriana Isvoran

doi:10.5599/admet.668

Prediction of ADME-Tox properties and toxicological endpoints of triazole fungicides used for cereals protection

ADMET & DMPK ◽

10.5599/admet.668 ◽

2019 ◽

Vol 7 (3) ◽

pp. 161-173 ◽

Cited By ~ 2

Author(s):

Ionut Mădălin Gridan ◽

Alecu Aurel Ciorsac ◽

Adriana Isvoran

Keyword(s):

Endocrine Disruption ◽

Skin Sensitization ◽

Mutagenic Potential ◽

Computational Tools ◽

Triazole Fungicides ◽

P Glycoprotein ◽

Carcinogenic Potential ◽

Predictive Study ◽

Harmful Effects ◽

Good Oral Bioavailability

Within this study we have considered 9 triazole fungicides that are approved to be used in European Union for protecting cereals: cyproconazole, epoxiconazole, flutriafol, metconazole, paclobutrazole, tebuconazole, tetraconazole, triadimenol and triticonazole. We have summarized the few available data that support their effects on humans and used various computational tools to obtain a widely view concerning their possible harmful effects on humans. The results of our predictive study reflect that all triazole fungicides considered in this study reveal good oral bioavailability, are envisaged as being able to penetrate the blood brain barrier and to interact with P-glycoprotein and with hepatic cytochromes. The predictions concerning the toxicological endpoints for the investigated triazole fungicides reveal that they. reflect potential of skin sensitization, of blockage of the hERG K+ channels and of endocrine disruption, that they have not mutagenic potential and their carcinogenic potential is not clear. Epoxiconazole and triadimenol are predicted to have the highest potentials of producing numerous harmful effects on humans and their use should be avoided or limited.

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3 Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate

Journal of the American College of Toxicology ◽

10.3109/10915818409010517 ◽

1984 ◽

Vol 3 (3) ◽

pp. 101-130 ◽

Cited By ~ 5

Keyword(s):

Hepatocellular Adenoma ◽

Final Report ◽

Mutagenic Potential ◽

Patch Tests ◽

Body Weight Reduction ◽

Dermal Irritation ◽

Carcinogenic Potential ◽

Mild Irritant ◽

Dioctyl Adipate ◽

Skin Sensitizer

Dioctyl Adipate, the diester of octyl alcohol and adipic acid, and Diisopropyl Adipate, the diester of isopropyl alcohol, are used in cosmetics as emollients and bases. These two ingredients have a low acute oral and percutaneous toxicity. Undiluted Dioctyl Adipate and Diisopropyl Adipate were, at most, only very mild, transient eye irritants. Primary dermal irritation tests indicated that Dioctyl Adipate was a very mild irritant and Diisopropyl Adipate was minimally irritating. Dioctyl Adipate was not a skin sensitizer in guinea pigs. An Ames test for the mutagenic potential of Dioctyl Adipate was negative. An assay of the carcinogenic potential of Dioctyl Adipate produced no untoward effects and was noncarcinogenic to rats. Mice studies indicated a dose- related body weight reduction and a higher incidence of hepatocellular adenoma and carcinoma than controls. In a lifetime study Dioctyl Adipate caused no skin tumors when 10 mg was applied weekly to the back skin of mice. The teratogenicity potential of Dioctyl Adipate is reviewed. Clinical assessment of Dioctyl Adipate in formulations showed, at most, minimal erythema and papules when applied under occlusion. No UV sensitization occurred. Undiluted Diisopropyl Adipate produced no irritation in 24 h patch tests, but was moderately irritating in a 21-day cumulative irritancy test. Formulations containing up to 20% Diisopropyl Adipate caused minimal to mild irritation, no sensitization and no photosensitization. On the basis of available data, it is concluded that Dioctyl Adipate and Diisopropyl Adipate are safe as presently used in cosmetics.

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Mutagenic and Cytotoxicity LQB 123 Profile: Safety and Tripanocidal Effect of a Phenyl-t-Butylnitrone Derivative

BioMed Research International ◽

10.1155/2017/2483652 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8

Author(s):

Mauricio Peixoto Cupello ◽

Francis Monique Saraiva ◽

Pedro Ippolito ◽

Andréia da Silva Fernandes ◽

Rubem Figueiredo Sadoko Menna-Barreto ◽

...

Keyword(s):

Mammalian Cells ◽

High Selectivity ◽

Peritoneal Macrophages ◽

Parasite Growth ◽

Selectivity Index ◽

Mutagenic Potential ◽

Intracellular Amastigotes ◽

In Vivo Tests ◽

Harmful Effects

The therapeutic options for Chagas disease are limited and its treatment presents a number of drawbacks including toxicity, drug resistance, and insufficient effectiveness against the chronic stage of the disease. Therefore, new therapeutical options are mandatory. In the present work, we evaluated the effect of a phenyl-tert-butylnitrone (PBN) derivate, LQB 123, againstTrypanosoma cruziforms. LQB 123 presented a trypanocidal effect against bloodstream trypomastigotes (IC50=259.4±6.1 μM) and intracellular amastigotes infecting peritoneal macrophages (IC50=188.2±47.5 μM), with no harmful effects upon the mammalian cells (CC50values greater than 4 mM), resulting in a high selectivity index (CC50/IC50> 20). Additionally, metacyclic trypomastigotes submitted to LQB 123 presented an IC50of about191.8±10.5 μM and epimastigotes forms incubated with different concentrations of LQB 123 presented an inhibition of parasite growth with an IC50of255.1±3.6 μM. Finally, we investigated the mutagenic potential of the nitrone by theSalmonella/microsome assay and observed no induction of mutagenicity even in concentrations as high as 33000 μM. Taken together, these results present a nonmutagenic compound, with trypanocidal activity against all relevant forms ofT. cruzi, offering new insights into CD treatment suggesting additional in vivo tests.

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Clotrimazole, Pregnancy and Endocrine Disruption: A Narrative Review

Current Opinion in Gynecology and Obstetrics ◽

10.18314/cogo.v4i1.2087 ◽

2021 ◽

Vol 4 (1) ◽

pp. 418-423

Author(s):

Conradi P

Keyword(s):

Pregnant Women ◽

Endocrine Disruptors ◽

Endocrine Disruption ◽

Surface Waters ◽

Endocrine Disruptor ◽

Human Medicine ◽

Internet Research ◽

Healthy Newborn ◽

Harmful Effects ◽

In Pregnancy

Background: Clotrimazole is an antifungal drug commonly used in human medicine. It is considered to be safe in pregnancy. Besides this medical assumption ecotoxicology has developed over the last years an awareness of pharmaceuticals which have been detected in surface waters and are of concern for the biosphere. Some of those drugs are endocrine disruptors. So is clotrimazole.Methods: Selective internet research on this subject incorporating medical and ecotoxicological positions.Conclusions: Ecotoxicology and human medicine postulate divergent positions about the harmful effects of clotrimazole. Medicine bases its assumption on thousands of healthy newborn babies whose mothers were treated with clotrimazole during pregnancy. This argument is easy to refute as clotrimazole is an endocrine disruptor and possible consequences of exposure during sensitive periods of pregnancy will only show up much later in life. As a result medicine is challenged to incorporate ecotoxicological concerns into its advice for pregnant women.

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Inhibition of P-glycoprotein transport: a mechanism for endocrine disruption in the channel catfish?

Marine Environmental Research ◽

10.1016/j.marenvres.2004.03.015 ◽

2004 ◽

Vol 58 (2-5) ◽

pp. 205-208 ◽

Cited By ~ 7

Author(s):

K.M. Kleinow ◽

G.C. Hummelke ◽

Y. Zhang ◽

P. Uppu ◽

C. Baillif

Keyword(s):

Endocrine Disruption ◽

Channel Catfish ◽

P Glycoprotein ◽

Glycoprotein Transport

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Application of toxicogenomics to the endocrine disruption issue

Pure and Applied Chemistry ◽

10.1351/pac200375112419 ◽

2003 ◽

Vol 75 (11-12) ◽

pp. 2419-2422 ◽

Cited By ~ 4

Author(s):

T. Shirai ◽

Makoto Asamoto

Keyword(s):

Gene Expression ◽

Risk Management ◽

Endocrine Disruption ◽

Epidemiological Data ◽

Risk Identification ◽

Short Term ◽

Carcinogenic Potential ◽

Short Period ◽

Genomic Scale ◽

Active Substances

Toxicogenomics can be expected to be a useful method for detecting the carcinogenic potential of endocrine active substances (EASs) in the short term with the generation of understanding of mode-of-action and mechanisms when a reliable database with information about proteomics and informatics is established. At present, there are no concrete epidemiological data supporting any exogenous EAS contribution to hormone-related organ carcinogenesis in humans. However, with the establishment of appropriate animal models and analysis of genomic-scale gene expression, risk identification and evaluation should be facilitated within a relatively short period, and this approach eventually promises to contribute a great deal of risk management regarding EASs.

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