Hazardous substances genotoxicity

For substances like genotoxic carcinogens or mut enic substances Category I or n (according to the EU classification for hazardous substances), a NOAEL or LOAEL cannot be establish. To minimise exposure to tfa substances, TRK values were established, reflecting the airborne concentration of a hazardous substances which can be achieve with the available techniques . ... 

Safety/Toxicity Cytotoxicity, carcinogenicity,22 chronic toxicity,25 environmental toxicity,2 genotoxicity,25 hazardous substance,2 hematological effects,22 immunotoxicity,2 marine toxicity, 2 mutagenicity,5o neurotoxicity, phytotoxicity, soil toxicity, testicular effects ... 

The National Institute for Occupational Safety and Health (NIOSH) of the United States describes in the section Determining whether a drug is hazardous how human and animal data on carcinogenicity, reprotoxicity and genotoxicity are interpreted for their list of hazardous substances [8]. 

Pyrethrins (I) Pyrethrins induce the formation of liver and thyroid tumors by mechanisms that appear to be similar to those of other non-genotoxic, mitogenic substances, e.g., phenobarbital, which produce tumors in rodents, and these tumors are not predictive of hazard in humans at relevant exposures [99]... 

A survey is made of European Union directives regulating the use of hazardous chemicals and other industrial materials. A list is presented of carcinogenic, mutagenic and genotoxic substances covered by Directive 97/10/ CE. 

Useful data for the hazard assessment may also be obtained from studies on toxicokinetics (including metabolism), in vitro studies on macromolecule binding, from knowledge of the reactivity and electrophilicity of a substance, and from the presence or absence of structural alerts for genotoxicity. 

Routine genotoxicity tests are not designed in order to derive no-effect levels. However, the magnitude of the lowest dose with an observed effect (i.e., the LOEL) may, on certain occasions, be a helpful tool in the hazard assessment. Specifically, it can give an indication of the potency of the test substance. Modified studies, with additional dose levels and improved statistical power may be useful in this regard. 

There have been many epidemiological studies on coffee intake and human cancer. Since we have indentified one of major genotoxic substance in coffee, thorough experimental studies are urgently required to evaluate the hazards of coffee. 

In the effects assessment step the relationship between the level of exposure and the incidence, nature, and severity of an (adverse) effect following the exposure is determined. For most types of effects, it is assumed that there is a minimum dose or concentration below which adverse effects will not occur the no effect level or threshold. To determine the threshold, different doses are tested, for most chemical hazards usually in laboratory animals. In toxicology, the highest tested dose without adverse effects is called the no observed adverse effect level (NOAEL). Based on the NOAEL established in an experimental study, a human limit value can be calculated, taking into account uncertainties and differences in experimental design and circumstances. Uncertainties and differences are accounted for by uncertainty factors (e.g., for interspecies differences, intraspecies variability, and exposure duration). For some types of substances, it is assumed that every level of exposure can result in adverse effects, in which case no threshold would exist. This, for instance, is assumed to apply for genotoxic carcinogens. 

This hazard class is primarily concerned with chemicals that may cause mutations in the germ cells of humans that can be transmitted to the progeny. However, mutagenicity/genotoxicity tests in vitro and in mammalian somatic cells in vivo are also considered in classifying substances and mixtures within this hazard class. 

Roex, E.W.M., Traas, T.P. and Slooff, W. (2001) Ecotoxicological hazard assessment of genotoxic substances, Report no. 601503022. RIVM (National Institute of Public Health and the Environment), Bilthoven, The Netherlands. 

For a new substance that is to be initially supplied at the base-set level (greater than 1 tonne per annum), information regarding acute and repeated-dose toxicity, skin and eye irritation, skin sensitization and genotoxicity is necessary. Testing to identify any respiratory sensitization hazard is not required, although structure-activity considerations may lead to classification as sensitizing and assignment of R42 (May cause sensitization by inhalation), as described previously for isocyanates. There is also the option to apply the safety phrase S22 ( Do not breathe dust ) in the absence of R42, and this has been done, for example, with certain new, dusty chlorotriazinyl dyestuffs. 

In an exceptional situation the actual exposure can be determined (see Sect. 26.5.3), the hazards of the substance has been defined sufficiently (see Sect. 26.3.5) and above all, the exposure limit to the substance has been set by the competent authority. This may apply for instance to working with ethanol, see also Sect. 26.7.2. In such an ideal situation it is possible to claim completely safe working conditions or, in case of genotoxic and sensitising substances, safe with a societally accepted minor health risk (see Sect. 26.7.2). In practice for pharmacy preparation and reconstitution medicines hardly any exposure limits exist at the moment. In most situations risk mitigation means ... 

FCSN) in 1997 (FDA 2013a) with the Food and Drug Administration Modernization Act of 1997 (FDA 2009). An important exception is made for genotoxic carcinogens [the Delaney Clause (FDA 2002)], known to damage DNA by mutation or chromosome aberration for such substances the risk is considered higher due to their inherent hazard, and permitted exposure levels are lower. 

FDA uses a tiered approach for hazard identification. When a substance s exposure is estimated to be below the TOR (1.5 pg/person per day), in silico analysis is considered sufficient, while for higher exposures in vitro genotoxicity (mutagenicity, chromosome aberration) assays are commonly required. In Europe, any FCS that requires authorization needs to be screened for genotoxicity. A default requirement for endocrine disraption screening is currentiy not in place in the U.S. or the E.U. 

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