Toxicity repeat exposure studies

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. 

Subchronic Studies. Although short-term repeated exposure studies provide valuable information about toxicity over this time span, they may not be relevant for assessment of ha2ard over a longer time period. For example, the minimum and no-effects levels determined by short-term exposure may be significantly lower if exposure to the test material is extended over several months. Also, certain toxic effects may have a latency which does not allow their expression or detection over a short-term repeated-exposure period for example, kidney dysfunction or disturbances of the blood-forming tissues may not become apparent until subchronic exposure studies are undertaken. 

Results from animal stndies indicate that oral toxicity is more than ten times lower than via i.p. injections. There is cnrrently no evidence of cnmnlative toxicity from repeated exposure studies in experimental animals [3]. 

Substances are classified in Category 2 for specific target organ toxicity (repeated exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (See A.9.2.9) in order to help in classification. 

Hydraziae is toxic and readily absorbed by oral, dermal, or inhalation routes of exposure. Contact with hydraziae irritates the skin, eyes, and respiratory tract. Liquid splashed iato the eyes may cause permanent damage to the cornea. At high doses it can cause convulsions, but even low doses may result ia ceatral aervous system depressioa. Death from acute exposure results from coavulsioas, respiratory arrest, and cardiovascular coUapse. Repeated exposure may affect the lungs, Hver, and kidneys. Of the hydraziae derivatives studied, 1,1-dimethylhydrazine (UDMH) appears to be the least hepatotoxic monomethyl-hydrazine (MMH) seems to be more toxic to the kidneys. Evidence is limited as to the effect of hydraziae oa reproductioa and/or development however, animal studies demonstrate that only doses that produce toxicity ia pregaant rats result ia embryotoxicity (164). 

Types of Studies. Studies may be conducted in five specimens (in vivo) or in test tubes in vitro). Studies may be carried out by single exposure or by repeated exposure over variable periods of time. The design of any one study, including the monitoring procedures, is determined by a large number of factors, including the nature of the test material, route of exposure, known or suspected toxicity, practical use of the material, and the reason for conducting the study. 

Chronic Toxicity Studies. With the exception of tumorigenesis, most types of repeated exposure toxicity are detected by subchronic exposure conditions. Therefore, chronic exposure conditions are usually conducted for the following reasons if there is a need to investigate the tumorigenic potential of a material if it is necessary to determine a no-effects or threshold level of toxicity for lifetime exposure to a material and if there is reason to suspect that particular forms of toxicity are exhibited only under chronic exposure conditions. 

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. 

Several studies with rats support the AEGL-3 values. A 10-min exposure to aniline at 15,302 ppm resulted in no toxic effects, and a 4-h exposure at 359 ppm resulted in severe toxic effects but no deaths. Dividing these values by a total uncertainty factor of 100 and scaling across time using C%t=k results in values similar to those derived from the Kim and Carlson (1986) study. Studies with repeated exposures of rats resulted in additional effects on the blood and spleen, but concentrations up to 87 ppm, 6 h/d, 5 d/w for 2 w were not disabling or life-threatening. 

Data adequacy The key study was well conducted and documented. Supporting data include both human and animal studies. Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. Other effects in animal studies occurred at much higher concentrations or with repeated exposures the latter are not relevant for setting short-term exposures. No effects other than narcosis occurred in rats and mice exposed at 200,000 ppm for various periods of time. Adjustment by a total UF of 10 results in a higher value (20,000 ppm) than from the cardiac sensitization test with dogs. ... 

Earlier toxicity studies had suggested that the hazard from repeated ozone exposure might be reduced, inasmuch as animals became tolerant to the acute pulmonary edematogenic action of ozone. However, more recent studies, which demonstrated that tolerance to the ordinarily ozone-induced increase in susceptibility to infectious microorganisms or to the effects on respiratory mechanics does not develop, suggest that the tolerance phenomenon would have little protective value with respect to repeated exposure to ambient oxidant smog. 

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