Hazard assessment of nitrosamine and nitramine by-products of amine-based CCS: alternative approaches.

Carbon capture and storage (CCS) technologies are considered vital and economic elements for achieving global CO2 reduction targets, and is currently introduced worldwide (for more information on CCS, consult for example the websites of the International Energy Agency (http://www.iea.org/topics/ccs/) and the Global CCS Institute (http://www.globalccsinstitute.com/)). One prominent CCS technology, the amine-based post-combustion process, may generate nitrosamines and their related nitramines as by-products, the former well known for their potential mutagenic and carcinogenic properties. In order to efficiently assess the carcinogenic potency of any of these by-products this paper reviews and discusses novel prediction approaches consuming less time, money and animals than the traditionally applied 2-year rodent assay. For this, available animal carcinogenicity studies with N-nitroso compounds and nitramines have been used to derive carcinogenic potency values, that were subsequently used to assess the predictive performance of alternative prediction approaches for these chemicals. Promising cancer prediction models are the QSARs developed by the Helguera group, in vitro transformation assays, and the in vivo initiation-promotion, and transgenic animal assays. All these models, however, have not been adequately explored for this purpose, as the number of N-nitroso compounds investigated is yet too limited, and therefore further testing with relevant N-nitroso compounds is needed.

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Improvement of the Cramer classification for oral exposure using the database TTC RepDose--a strategy description.

The present report describes a strategy to refine the current Cramer classification of the TTC concept using a broad database (DB) termed TTC RepDose. Cramer classes 1-3 overlap to some extent, indicating a need for a better separation of structural classes likely to be toxic, moderately toxic or of low toxicity. Groups of structurally similar compounds of high toxicity in Cramer class 1 and of moderate to low toxicity in Cramer class 3 were identified and reassigned to the appropriate Cramer class according to their observed toxicological potency in in vivo studies. This refinement results in a better discrimination of Cramer classes 1 and 3 and an increased number of substances in Cramer class 2. The TTC values are 8.7 µmol/person/d (class 1), 6.72 µmol/person/d (class 2) and 0.28 µmol/person/d (class 3). Assuming a median molecular weight of 220 g/mol for the compounds of the TTC RepDose DB, the corresponding TTC values are 1930, 1478 and 63 µg/person/d for classes 1, 2 and 3 respectively. The derived thresholds are close to the TTC values initially proposed by Munro with 1800, 540 and 90 µg/person/d for classes 1, 2 and 3 respectively. Additional structural classes are discussed with a view to further refinement of the current Cramer classification scheme.

Evaluation of inhalation TTC values with the database RepDose.

The thresholds of toxicological concern (TTCs) define limit values for substances of unknown toxicity below which dietary intake is considered to be of no concern to human health. The TTC concept has already been used for risk assessment of e.g. food contaminants or flavoring substances and is in discussion to be applied to other classes of compounds such as cosmetic ingredients, household products, non-relevant metabolites in drinking water, and impurities in pharmaceuticals. The present publication aimed to evaluate whether the current TTC concept can also be applied to define limit values for inhalation exposure, using a data set of 203 industrial chemicals from the database RepDose. It has been shown, that the NOEC values in classes 1, 2, and 3 are distributed over six orders of magnitude resulting in a considerable overlap between the distribution curves for the three classes. Inhalation thresholds for Cramer classes 1 (compounds likely to be of low-toxicity), 2 (compounds likely to be of moderate toxicity), and 3 (compounds suspect for high toxicity) were analyzed close to the approach described by Munro for oral TTCs. The 5th percentiles NOEC of Cramer classes 1-3 result in thresholds of 1.5×10(-3) ppm for Cramer class 1 and 2.2×10(-5) ppm for Cramer class 3. A threshold could not be derived for class 2 because of the small number of compounds available. If calculated as body doses, the inhalation thresholds for classes 1 and 3 (71 and 4 µg/person/d, respectively) are considerably lower than the oral thresholds derived by Munro (1800 and 90 µg/person/d). It has been shown that one reason for this difference is the high sensitivity of the respiratory tract to local effects. In a next step, the values obtained were further refined. If organophosphates or compounds with structural alerts for genotoxicity are excluded, the TTC in Cramer class 1 increases, whereas the TTC in Cramer class 3 remains the same. Based on these analyses two inhalation TTCs for non-genotoxic compounds are proposed: 3.6×10(-3) ppm (180 µg/person/d) for Cramer class 1 and 2.4×10(-5)ppm (4 µg/person/d) for Cramer class 3.

Derivation of the minimal magnitude of the Critical Effect Size for continuous toxicological parameters from within-animal variation in control group data.

Assuming that temporal fluctuations in physiological parameters (e.g. haematology, biochemistry) in individual healthy non-exposed animals are non-adverse, the minimal magnitude of the Critical Effect Size (CES) for a number of continuous parameters of toxicity studies was derived. A total of 36 studies (19 pharmaceutical preclinical studies in dogs and 17 chemical risk assessment studies in rats) were analysed to determine within-animal variation in their control groups. Minimal CES-values were derived for each group of studies, differentiating where necessary between strains and sexes, using the 2.5 percentile (lower limit) and/or 97.5 percentile (upper limit) of the distribution of the within-animal variation around the mean of each parameter. We concluded that minimal CES-values for continuous clinical chemistry and haematology parameters should be established separately per species, strain, sex and study duration investigated. Grouping of minimal CES-values, leading to more or less "general" values, seems possible for those parameters that are subject to tight homeostatic control and consequently show little within-animal variation. Nearly a quarter of the proposed CES-values is 5%, nearly a quarter range from 6% to 10%, a quarter is 15% or 20%, and nearly 30% of the proposed values is 20% of the mean of the control animals.