Long-term toxicity data

If data have already been generated for risk assessments, it may be possible to use these without further quality assessment (as is done in the European Union), but any new and relevant information should be considered scientifically. Usually, the lowest acute and long-term toxicity data for a species should be used (if the endpoint is relevant at the population level and is derived from a validated study). If valid data for the same endpoints and the same species exist, the geometric mean should be taken. This value is then used together with other species values to calculate the EQSs. Use of a mean value in this situation minimizes cumulative conservatism that is, always using the most conservative data point, especially when additional valid data are available, will lead to too much conservatism, giving rise to an EQS that may be unrealistically low. 

When there is acute toxicity test data (LC50 or EC50) available for the mixture as a whole, this data as well as information with respect to the classification of components for chronic toxicity should be used to complete the classification for tested mixtures as follows. When chronic (long-term) toxicity data (NOEC) is also available, this should be used as well. 

Results of acute, short-term and long-term toxicity studies, reproduction studies, developmental studies, genotoxicity studies, and studies of the toxicity of metabolites and impurities, and other adverse effects. Data on human toxicology, the no observable effect level, acceptable daily intake, and proposed and safety directions... 

Maltby et al. (2002) and Van den Brink et al. (2006a) compared SSDs based on acute and chronic laboratory toxicity data for aquatic test species exposed to pesticides. The SSDs were constructed with toxicity data for the most sensitive taxonomic group, because of the specific toxic mode of action of the pesticides selected. The SSDs were used to calculate the hazardous concentration to 5% of the species (HC5) by means of a log-normal distribution model, and comparisons were performed for 2 insecticides and 7 herbicides (Table 6.4). The log-normal model did not fit the diuron (herbicide) short-term L(E)C50 data or the atrazine (herbicide) long-term NOEC data. Consequently, the L(E)C50 HC5 value for diuron and the NOEC HC5 value for atrazine should be interpreted with caution, as well as their acute HC5-chronic... 

There are various approaches that have been adopted for the use of AFs with the available toxicity data. They differ from authority to authority in the species number and type required and in the factors that are applicable to the given toxicity data (acute versus chronic). The various factors are summarized in Table 4.6. These factors reflect uncertainty in intra- and interlaboratory variation, intra- and interspecies variation, extrapolation between short- and long-term toxicity, extrapolation of results from laboratory to field, the possibility of indirect effects such as interspecific reactions (e.g., loss of predators, affecting prey), and the fact that environmental contaminants are often present as complex mixtures. 

On the basis of available data, in the judgment of the panel, it is unlikely that administration of these anticholinergic compounds will have long-term toxicity effects or delayed sequelae. An ongoing... 

Additional studies on chlorine toxicity in animals and, possibly, on human volunteers are needed to better define the health effects of chlorine gas exposure at 0.5-5 ppm, 24 h/d up to 7-10 d. Long-term exposure data for humans and animals is needed to approximate a disabled submarine situation. These studies should include evaluation of short-term effects on pulmonary function and long term effects such as pulmonary fibrosis. As is the case for all irritant toxic gases reviewed in this report. 

The conduct of animal toxicity studies proceeds concurrently with and in advance of clinical studies. A certain amount of animal toxicity data is required for the IND. This often includes acute toxicity in two rodent species, mutagenicity screening studies, and one-month toxicity studies in a rodent and non-rodent species. After the clinical studies have begun, further animal studies are conducted, usually until the time for the NDA. These would include further mutagenicity studies, reproductive toxicity studies, and long-term toxicity studies, possibly including carcinogenicity studies. 

In the previous evaluations of substances in this group, studies of acute toxicity, short-term toxicity (14 days to 14 weeks), long-term toxicity and carcinogenicity, genotoxicity and reproductive toxicity were available. None raised safety concerns. The toxicity data available for this evaluation were supported by those from the previous evaluations. 

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