Carcinogenicity categorization of chemicals—new aspects to be considered in a European perspective

Bolt, Hermann M.; Foth, Heidi; Hengstler, Jan G.; Degen, Gisela H.

doi:10.1016/j.toxlet.2004.04.004

Cited by 177 publications

(100 citation statements)

References 74 publications

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“…To provide greater emphasis to the Expert Panel's WoE conclusion, Table 4 provides a comparison between a set of characteristics found in confirmed genotoxic carcinogens (Bolt et al 2004;Petkov et al 2015) and the genotoxic activity profiles for glyphosate, AMPA, and GBFs. There is virtually no concordance between the two sets of characteristics.…”

Section: Genotoxicity Classification and Moamentioning

confidence: 99%

Genotoxicity Expert Panel review: weight of evidence evaluation of the genotoxicity of glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid

Brusick¹,

Aardema²,

Kier

et al. 2016

Critical Reviews in Toxicology

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published a monograph concluding there was strong evidence for genotoxicity of glyphosate and glyphosate formulations and moderate evidence for genotoxicity of the metabolite aminomethylphosphonic acid (AMPA). These conclusions contradicted earlier extensive reviews supporting the lack of genotoxicity of glyphosate and glyphosate formulations. The IARC Monograph concluded there was strong evidence of induction of oxidative stress by glyphosate, glyphosate formulations, and AMPA. The Expert Panel reviewed the genotoxicity and oxidative stress data considered in the IARC Monograph, together with other available data not considered by IARC. The Expert Panel defined and used a weight of evidence (WoE) approach that included ranking of studies and endpoints by the strength of their linkage to events associated with carcinogenic mechanisms. Importantly, the Expert Panel concluded that there was sufficient information available from a very large number of regulatory genotoxicity studies that should have been considered by IARC. The WoE approach, the inclusion of all relevant regulatory studies, and some differences in interpretation of individual studies led to significantly different conclusions by the Expert Panel compared with the IARC Monograph. The Expert Panel concluded that glyphosate, glyphosate formulations, and AMPA do not pose a genotoxic hazard and the data do not support the IARC Monograph genotoxicity evaluation. With respect to carcinogenicity classification and mechanism, the Expert Panel concluded that evidence relating to an oxidative stress mechanism of carcinogenicity was largely unconvincing and that the data profiles were not consistent with the characteristics of genotoxic carcinogens. ARTICLE HISTORY

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Section: Genotoxicity Classification and Moamentioning

confidence: 99%

Genotoxicity Expert Panel review: weight of evidence evaluation of the genotoxicity of glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid

Brusick¹,

Aardema²,

Kier

et al. 2016

Critical Reviews in Toxicology

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“…Some of these known impurities are potential mutagens or carcinogens and genotoxic impurities are those have potential to cause cancer in humans. 2,3 Keeping in view of its consequence, European Medicines Agency and ICH [ICH M7] have framed guidelines genotoxic impurities in the drug substance. 4,5 These guidelines proposed a threshold limit of toxicological concern value (1.5 µg/day) of genotoxic impurities in the drug substance.…”

Section: Introductionmentioning

confidence: 99%

A Selective and Sensitive Method Development and Validation by Lc–ms/MS Approach for Trace Level Quantification of Three Potential Genotoxic Impurities in Pantoprazole Sodium Drug Substance

2017

RJC

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A novel reverse-phase selective and sensitive liquid chromatography coupled with tandem mass spectrometric (LC-MS/MS) method was developed and validated for the trace analysis of N-(4-hydroxyphenyl) acetamide (GTI-A), N-(4-(difluoromethoxy) phenyl) acetamide (GTI-B) and 4-(difluoromethoxy)-2-nitroaniline (GTI-C) which are potential genotoxic impurities in pantoprazole drug substance. The optimized method utilizes a positive ion electrospray ionization in multiple reaction monitoring (MRM) detection modes with purosphere star RP 18 e (100 mm×4.6 mm, 3.0 µm) column. Solution-A was 0.1% formic acid in 1000 ml of water used as a buffer and solution-B was acetonitrile. The flow rate was 1.0 mL/min and gradient program was developed for rapid analysis and elution mode was monitored by a mass spectrophotometer. The method was validated as per International Conference on Harmonization (ICH) guidelines and the method capability for quantification was found to be 0.5 ppm with respect to sample concentration of 1mg/mL in pantoprazole sodium. The correlation coefficient obtained for all the three impurities was >0.9997 and the accuracy of the method was ranged between 96.3% and 104.3%.

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“…Pharmaceutical genotoxic impurities (PGIs) may induce genetic mutations, chromosomal breaks (rearrangements) and they have potential to cause cancer in human [3][4]. Therefore exposure to even low levels of such impurities present in final active pharmaceutical ingredient (API) may be of significant toxicol importance [5].…”

Section: Introductionmentioning

confidence: 99%

Development and Validation of LC-MS/MS Method for the Analysis of P-Toluenesulfonicacid, In Antiviral Drug Acyclovir

Reddy¹

2015

IJIRSET

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A sensitive and selective liquid chromatographic-tandem mass spectrometric (LC/MS/MS) method was developed and validated for the trace analysis (>1 ppm level) of p-Toluenesulfonicacid, a genotoxic impurity, in acyclovir drug substances. The chromatographic separation was achieved on Symmetry C-18 (150 X 4.6mm, 3.5µm) column using a mobile phase consisting of 5 mM ammonium acetate and methanol (70:30 v/v) at flow rate of 0.4 mL /min. The API-4000 LC/MS/MS was operated on an electrospray in negative mode. The selected ion monitoring (SIM) mode was used during the analytical run and it is able to quantitate up to 1.5 ppm of p-Toluenesulfonicacid. The newly developed method was validated as per achieved on International Conference on Harmonization (ICH) guidelines

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Carcinogenicity categorization of chemicals—new aspects to be considered in a European perspective

Cited by 177 publications

References 74 publications

Genotoxicity Expert Panel review: weight of evidence evaluation of the genotoxicity of glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid

Genotoxicity Expert Panel review: weight of evidence evaluation of the genotoxicity of glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid

A Selective and Sensitive Method Development and Validation by Lc–ms/MS Approach for Trace Level Quantification of Three Potential Genotoxic Impurities in Pantoprazole Sodium Drug Substance

Development and Validation of LC-MS/MS Method for the Analysis of P-Toluenesulfonicacid, In Antiviral Drug Acyclovir

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