Safety acute toxicity studies

Acute toxicity studies have been performed in various animals mice, rats, rabbits, cats, dogs, and macaques.18,20,35,36,40,44 Lethal doses of DMHP are extremely high, in comparison with the small doses required to produce its pharmacodynamic effects. For instance, the intravenous LD50 in mice is 63 mg/kg, whereas the minimal effective dose in 50% of the animals (MED50) is 0.075 mg/kg, for a safety factor of 840. The dose required to produce tranquilization in the unanesthetized dog is 0.05 mg/kg, and the minimal lethal dose is 10 mg/kg by the same route. The margin of safety in the dog is about 200. By comparison, the margin of safety of reserplne is 5.0. 

FDA (intended Standard safety Acute toxicity (rodent and Short-term use studies Short-/midterm studies... 

Beta-cyclodextrin has been the most studied of the cydodextrins. Results from numerous investigations have demonstrated its safety and metabolism. Table 22.4 shows the results of acute toxicity studies from various routes of administration. At the maximum dose of (3-cyclodextrin presented orally, no mortality related to it was... 

The toxicity of astemizole also appears to be remarkably low. An acute toxicity study in rats found that at 25,000 times the antihistaminic dose (2,560 mg/kg) the drug produced some transient sedation but no lethality up to 2 weeks after administration—an extreme safety margin. This raises the possibility that antihistamines may have intrinsic antiasthmatic activity, but at such doses that the toxicity of the first-generation drugs precluded such a use at safe doses. 

Toxicity studies on trifluoroethanol show acute oral LD q, 240 mg/kg acute dermal LD q, 1680 mg/kg and acute inhalation L(ct) Q, 4600 ppmh. Long-term subchronic inhalation exposure to 50—150 ppm of the alcohol has caused testicular depression in male rats, but no effects were noted at the 10 ppm level (32). Although the significance of the latter observations for human safety is unknown, it is recommended that continuous exposure to greater than 5 ppm or skin contact with it be avoided. 

Health and Safety Factors. Results of acute oral toxicity studies of 2-pyrrohdinone on white rats and guinea pigs show the LD q to be 6.5 ml,/kg. Skin patch tests on 200 human subjects indicate that 2-pyrrohdinone is a skin kritant, but there is no indication of sensitising action. It is a mild eye irritant (79). 

Elsberry, D. (1986). Screening approaches for acute and subacute toxicity studies. In Safety Evaluation of Drugs and Chemicals (Lloyd, W., Ed.). Hemisphere Publishing, Washington, D.C., pp. 145-151. 

Common Study Protocols. The dog is the most commonly used nonrodent species in safety assessment testing (i.e., acute, subchronic, and chronic studies). The exception to this is its use in developmental toxicity and reproductive studies. For developmental toxicity studies, the dog does not appear to be as sensitive an indicator of teratogens as other nonrodent species such as the monkey (Earl et al., 1973) or the ferret (Gulamhusein et al., 1980), and, for reproductive studies, the dog is not the species of choice because fertility testing is difficult to conduct (due to prolonged anestrus and the unpredictability of the onset of proestrus) and there is no reliable procedure for induction of estrus or ovulation. 

Safety Precautions. Because the phosphorus esters used In our studies exhibit varying (and sometimes unknown) degrees of acute toxicity, we recommend observing strict laboratory safety precautions when handling these materials. 

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... 

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