Single-dose toxicity studies

It is necessary to determine the toxicity of a drug. The maximum tolerable dose and area under the curve are established in rodents and nonrodents. There are two types of toxicity studies single dose and repeated dose. Single... 

In the United States, as an alternative to 2-week studies, single dose toxicity studies with extended examinations can support single dose human trials. 

In the EU and the USA, two week studies are the minimum duration. In Japan, 2 week non-rodent and 4 week non-rodent studies are needed. In the USA, as an alternative to 2-week studies, single dose toxicity studies with extended examinations (hematology, clinical chemistry, urinalysis, macroscopic and microscopic pathology) can support single dose human trials. 

Berger et al. (212) studied the toxicity of single doses of dlethylamlnoett l benzllate In mice and monkeys and Its general actions on several functional systems. In the monkey, an Intravenous dose of 1 mg/kg resulted in mydriasis and some decrease In voluntary movement. A dose of 2 mg/kg Induced ataxia with occasional convulsive Jerks. A dose of 6 mg/kg Induced Intermittent clonic convulsions In one monkey the convulsive state lasted for about 10 min and was followed by a depressed state lasting for over an hour. Pupillary dilatation, the effect of longest duration, sometimes persisted for as long as 20 h. 

Acute Toxicity Studies. These studies should provide the following information the nature of any local or systemic adverse effects occurring as a consequence of a single exposure to the test material an indication of the exposure conditions producing the adverse effects, in particular, information on dose—response relationships, including minimum and no-effects exposure levels and data of use in the design of short-term repeated exposure studies. 

Dichloroethane is one of the more toxic chlorinated solvents by inhalation (49). The highest nontoxic vapor concentrations in chronic exposure studies with various animals range from 100 to 200 ppm (50,51). 1,2-Dichloroethane exhibits a low single-dose oral toxicity in rats LD q is 680 mg/kg (49). Repeated skin contact should be avoided since the solvent can cause defatting of the skin, severe irritation, and moderate edema. Eye contact may have slight to severe effects. 

Contact or ingestion of cyanamide must be avoided, and precautions taken to prevent inhalation of dust or spray mist. In rat studies cyanamide-100 toxicity ranges from a single oral dose LD q of 280 mg/kg to a single dermal dose LD q of 590 (420—820) mg/kg. The compound is, therefore, considered to be moderately toxic both by ingestion in single doses and by single-skin appHcations. An aqueous paste of the product is corrosive to rabbit skin. Small quantities of the dry product produced severe irritation when introduced into the conjunctival sac of the rabbit eye. 

Diglycidyl Ether of Bisphenol A. The Hquid DGEBPA-based resins exhibit low acute toxicity with a single-dose oral LD q value in rats of >2000 mg/kg (40). The potential for absorption of DGEBPA through the skin in acutely toxic amounts is low. LD q values of >800 mg/kg for acute dermal toxicity have been obtained from studies using both the pure and commercial DGEBPA (41,42). 

Substantial toxic effects in the liver have been seen in acute studies in animals. Prout et al. (1985) administered single doses of 10-2,000 mg/kg trichloroethylene to rats and mice. Blood level kinetics of trichloroethylene and its metabolites revealed that trichloroethylene was metabolized more quickly in the mouse, and thus, at high doses, the mouse was exposed to greater concentrations of trichloroethylene metabolites than the rat. Hepatic hypertrophy and centrilobular swelling were observed in mice treated with... 

Single-dose oral toxicity studies in rats, mice, and cattle indicate that signs of diisopropyl methylphosphonate intoxication include decreased activity, ataxia, tympanitis, and prostration within 1-4 hours after dosing (Hart 1976 Palmer et al. 1979). Mink that received 1,852 mg/kg/day diisopropyl methylphosphonate in their feed displayed aggressive behavior. However, it was concluded that this behavior was probably due to hunger resulting from the unpalatability of the feed (Aulerich et al. 1979). 

Developmental Toxicity. A single rat study, which found no adverse effects, addressed the developmental effects of diisopropyl methylphosphonate (Hart 1980). Additional data that utilize a greater range of doses in a few different species may be helpful. 

Acute lethality studies in animals exposed by inhalation, ingestion, or dermal contact to several mineral oil hydraulic fluids indicate that mineral oil fluids are not potent toxicants. Mineral oil hydraulic fluids produced no deaths in rats after 4-hour exposures to aerosol concentrations of 110-210 mg/m3 or gavage administration of single doses <5,000 mg/kg (Kinkead et al. 1987a, 1988). Rabbits, likewise, did not die after single 24-hour exposures to occluded dermal doses of several mineral oil hydraulic fluids <2,000 mg/kg (Kinkead et al. 1985, 1987a, 1988). 

Mineral Oil Hydraulic Fluids. There is limited information on the toxicity of mineral oil hydraulic fluids in humans. A single case report of a child accidentally ingesting a single dose of automotive transmission fluid provides limited information on death and systemic effects. A case-control study provides some information on the carcinogenicity of mineral oil hydraulic fluids. The study population was exposed via inhalation and dermal routes. An occupational exposure study provides information on neurotoxicity following chronic dermal exposure. Information on the toxicity of mineral oil hydraulic fluids is limited to a series of inhalation, oral, and dermal acute-duration exposures. These studies provide information on death, systemic effects, and neurotoxicity by inhalation, oral, and dermal routes, and immunotoxicity following dermal exposure. 

The single-dose toxicity studies were performed in two mammalian species, rat and mouse, by the route used in clinical practice, that is oral, as well as that ensuring adequate systemic exposure to the drug, that is intravenous. The subacute (3 months) toxicity studies were correctly carried out in the two animal species (rat, dog) in which also the pharmacokinetics was studied. Since in accordance with the International Conference on Harmonization (CPMP/ICH/286/95), 3-month toxicity studies support clinical trials for up to 1 month s duration (the longest duration of drug administration in clinical use), chronic toxicity studies have not been performed. 

---