Acute toxicity determination

In the pharmaceutical industry, acute toxicity testing has uses other than for product safety determinations. First, as in other industries, acute toxicity determinations are part of industrial hygiene or occupational health environmental impact assessments (Deichmann and Gerarde, 1969). These requirements demand testing not only for finished products but frequently of intermediates as well. These issues and requirements, however, are discussed in Chapter 2 and are not directly addressed here. 

The QSAR paradigm has been shown to be particularly useful in environmental toxicology, especially in acute toxicity determinations of xe-nobiotics (223). There has recently been an emphasis on "transparent, mechanistically comprehensive QSAR for toxicity," a move that is welcomed by many researchers in the field (224, 225). Cronin and Schultz developed QSAR 1.101 to describe the polar, narcotic toxicity of a large set of substituted phenols. A number of phenols with ionizableor reactive groups (e.g., —COOH, SIO, — NH2, or — NHCOCHg) were omitted from the final analysis (226). 

Rosen, H., Blumenthal, A., Panasevlch, R., McCollum, J. 1963 Dlmetti l Sulfoxide DMSOJ as a Solvent In Acute Toxicity Determinations. Proc. Soc. Exp. Biol. Mad. 120 511-514. 

With the recent development of reliable microbiological tests for acute toxicity determination, such as the Microtox test (Bulich et al. 1981) and the resazurin test (Thomson etal. 1986), convenient tools became available for the investigation of larger series of chemicals in relatively short time and independent of local biological species and environments. It has also been demonstrated that these tests are generally quite representative of such... 

The LD50 is the statistically derived single dosage of a substance that can be expected to cause death in 50% of the sample population. It is therefore an indicator of acute toxicity, usually determined by ingestion using rats or mice, although other animals may be used. LD50 is also determined by other routes, e.g. by skin absorption in rabbits. The values are affected by species, sex, age, etc. 

In a recent study [72] DOSS is ranked as relatively nontoxic. The acute toxicity, LD50, of DOSS in mice was determined to be 2.64 g/kg, which is somewhat lower than the two earlier reported values of 3.98 g/kg [98] and 4.80 g/kg [99]. Also a lower value (1 g/kg) is given [94]. Similar values were found for rat toxicity. Toxicity was also evaluated for horses and pigs [100]. The oral LD50 was determined to be 0.065 g/kg. 

Acute Toxicity. The LD50 following oral administration of parathion, either in propylene glycol solutions or in aqueous suspensions of the 15% wettable powder, has been determined for rats, mice, and guinea pigs. The lethal dose was approximated for rabbits and dogs. The results of these experiments are summarized in Table I. Statistical evaluation was by the method of Wilcoxon and Litchfield (11). 

The purified tetraethyl pyrophosphate is a colorless, odorless, water-soluble, hygroscopic liquid (24, 4 )- It possesses a very high acute toxicity (28), exceeding that of parathion, and is rapidly absorbed through the skin. There is no spray-residue problem, however, for tetraethyl pyrophosphate hydrolyzes even in the absence of alkali to nontoxic diethyl phosphoric acid. Hall and Jacobson (24) and Toy (47) have measured its rate of hydrolysis, which is a first-order reaction. Its half-life at 25° C. is 6.8 hours and at 38° C. is 3.3 hours. Coates (10) determined the over-all velocity constant at 25° C. k = 160 [OH-] + 1.6 X 10 3 min.-1 Toy (47) has described an elegant method for preparing this ester as well as other tetraalkyl pyrophosphates, based upon the controlled hydrolysis of 2 moles of dialkyl chlorophosphate ... 

Lazar (http //lazar.in silico.de/predict) is a k-nearest-neighbor approach to predict chemical endpoints from a training set based on structural fragments [43]. It derives predictions for query structures from a database with experimentally determined toxicity data [43]. Model provides prediction for four endpoints Acute toxicity to fish (lethality) Fathead Minnow Acute Toxicity (LC50), Carcinogenicity, Mutagenicity, and Repeated dose toxicity. 

Brieger H, Rieders F, Hodes WA. 1951. Acrylonitrile spectrophotometric determination, acute toxicity and mechanism of action. Arch Ind Health Occup Toxicol 6 128-140. 

Douglas, M.T., D. 0. Chanter, I.B. Pell, and G.M. Burney. 1986. A proposal for the reduction of minimal numbers required for the acute toxicity to fish test (LC50 determination). Aquat. Toxicol. 8 243-249. 

The acute toxicity of bromocriptine mesilate has been determined in the mouse as 230 and 2620 mg/kg i.v. and p.o., respectively. In the rabbit, the corresponding values were 12 and >1000 mg/kg (2). Thus, bromocriptine proved less toxic than the nonhydrogenated ergot alcaloids by one order of magnitude, resembling the behaviour of the dihydrogenated derivatives. 

EEC Directive 92/69/EEC (1992) Official Journal of the EEC L383 A Methods for the determination of ecotoxicity C.2. Acute toxicity for Daphnia... 

Humans exposed at high concentrations of some halogenated hydrocarbons can develop cardiac arrhythmias. The cardiac sensitization test in dogs is considered an effective determination of potential cardiac sensitization in humans. Cardiotoxicity was observed at concentrations well below those associated with any acute toxic signs but only in the presence of greater-than-physiological doses of exogenous epinephrine. 

For acute toxicity, corrosivity and skin and eye irritation, values for the NOEL (or NOAEL or LOAEL) are not derived. Therefore, the only option is to determine whether the substance has an inherent capacity to cause such effects and to make a qualitative risk assessment to evaluate the likelihood of an adverse effect occurring in use. 

Acute toxicity should be determined in three species subacute or chronic studies should be by the route to be used clinically. Suitable mutagenicity studies should also be... 

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