Systemic exposure in rabbits

For these 49 MMP-8 inhibitors the systemic exposure in rabbits following oral administration... 

Fig. 9. Correlation of VolSurf descriptors with systemic exposure after oral administration in rabbits for 49 structurally diverse MMP-8 inhibitors. Left. Predicted versus experimental systemic exposure -log(AUC(orai)) from the 4 component PLS model. Right PLS loadings showing the importance of VolSurf descriptors to the prediction of the systemic exposure in rabbits.

The analysis of PLS coefficients from the final model allows to assess the importance of individual descriptors contributing to the systemic exposure in rabbits following oral administration in this series. The corresponding PLS coefficient plot is shown in... 

Solid 1,4-dichlorobenzene was noted to produce a burning sensation when held closely to the skin for an excessive period of time, but it does not produce irritation or systemic effects (Hollingsworth et al. 1956). One study was located regarding the systemic effects in rabbits after dermal exposure to... 

No studies were located regarding respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, dermal/ocular, or other effects in humans after dermal exposure to hexachlorobutadiene. Liver, kidney, and dermal/ocular effects were reported in animals. These effects are discussed below. All LOAEL values for systemic effects in rabbits after acute-duration exposure are recorded in Table 2-3. 

Other Systemic Effects. In rabbits exposed dermally to isophorone at doses up to 3160 mg/kg, no systemic pathological effects were found by gross necropsy (Hazleton Labs 1964), but histological examinations were not performed. In this study, the site of application was occluded for 24 hours to prevent evaporation of isophorone from the skin. No significant differences between pre-exposure and post-exposure levels of serum electrolytes, blood glucose and sulfhydride radicals, SGOT,... 

Toxicology. The nitroparaffins have minimal effects by way of actual contact. There were neither systemic effects nor irritation in dermal studies in rabbits. Human exposure of a prolonged or often-repeated nature has led to low grade irritation attributable to removal of oil from the skin, an effect produced by most organic solvents. Eye irritation potential of all four nitroparaffins has been deterrnined in rabbits. Other than a transient slight redness and some lachrymation, no effects were noted. The average Draize score was 0.0. The acute oral toxicity, LD q, of all four nitroparaffins has been deterrnined in the rat (Table 8). 

Contact with hexachloroethane vapors at a concentration of 260 ppm was apparently irritating to the eyes of dogs because the animals kept their eyes closed during all exposure periods (Weeks et al. 1979). In rats, a red exudate was observed about the eyes after 4 weeks of exposure to hexachloroethane vapors, and in rabbits, after a single dermal exposure to a water paste of hexachloroethane (Weeks et al. 1979). The red exudate did not appear until after 4 weeks of exposure to hexachloroethane vapor and, thus, may be a systemic effect rather than the effect of direct contact of the eye with hexachloroethane. 

The only reports regarding systemic effects in humans after dermal exposure to -hexane are two studies describing dermal effects and ocular effects in volunteers. Ocular effects in rabbits and body weight effects in guinea pigs have also been reported. 

Target Organ Toxicity. -Hexane exposure is documented to cause toxicity in peripheral nerves of humans (both sensory and motor). In rats, -hexane exposure causes toxicity in the peripheral and central nervous system and in male reproductive tissues. Effects on respiratory tissue have been observed in mice and rabbits. The toxic agent in nervous system and reproductive tissues is believed to be the -hexane metabolite 2,5-hexanedione (Graham et al. 1995). 

Intermediate-Duration Exposure.No studies are available on the adverse health effects from intermediate-duration exposure in humans by any route. Studies in animals indicate that exposure to endrin via inhalation can be lethal and causes effects on the nervous and respiratory systems, the liver, the brain, adrenals, and kidneys (Treon et al. 1955). Since systemic effects were observed at levels which caused death, data are not sufficient to derive an intermediate-duration inhalation MRL. Animal studies also demonstrate that oral intermediate-duration exposure can lead to death in several species (rat, mouse, hamster, rabbit, monkeys, cat) (Treon et al. 1955). Endrin was lethal in rabbits following dermal exposure (Treon et al. 1955). No other treatment-related disorders are known. Additional studies for oral and dermal routes using a range of exposure levels would be useful in identifying potential target tissues. 

Animal data include an inhalation study in rabbits that resulted in an increased incidence of retroesophageal right subclavian artery in the fetuses (Hayes et al. 1985), and an oral study in rats that resulted in an increased incidence of an extra rib (NTP 1987). The data were considered sufficient to derive an acute-duration inhalation MRL of 0.8 ppm, based on a NOAEL of 300 ppm for lack of developmental effects in rabbits. It would be useful to have additional information on the developmental effects of 1,4-dichlorobenzene by inhalation and oral exposure in relation to maternal toxicity. There are currently no data available for the dermal route. Information on the developmental effects of dermal exposures would be useful if dermal absorption and systemic distribution of 1,4-dichlorobenzene could be demonstrated in toxicokinetic studies. 

McKee RH, Kapp RW Jr, Ward DP. 1985. Evaluation of the systemic toxicity of coal liquefaction-derived materials following repeated dermal exposure in the rabbit. J Appl Toxicol 5(6) 345-351. 

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