Animal data limitations

One study of hematological effects in dermally-exposed animals was located. Hematological parameters, including red blood cell count, white blood cell count, and hemoglobin, were unaffected by dermal exposure to 500 mg/kg/day of 1,1,1 -trichloroethane (uncovered) for 90 days in rabbits (Torkelson et al. 1958). A NOAEL derived from this study is recorded in Table 2-3. The scarcity of human and animal data limits the assessment of hematological effects that may be caused by dermal exposure to 1,1,1 -trichloroethane. 

The scarcity of human and animal data limits the assessment of renal effects which may be caused by dermal exposure to 1.1,1-trichloroethane. The NOAEL values for renal effects in rats and rabbits are recorded in Table 2-3. 

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Musculoskeletal Effects. Very limited data were available regarding the effects of endosulfan on the musculoskeletal system. However, the available animal data did not indicate that this system is adversely affected following either inhalation or oral exposure to endosulfan (FMC 1965, 1967 Hoechst 1984b, 1984c, 1988b, 1989a, 1989c). Thus, persons exposed to endosulfan would not be expected to experience adverse effects on the musculoskeletal system. 

Based on the limited human and animal data, it is not possible to predict whether or not triehloroethylene exposure at levels found in the environment and at hazardous waste sites can result in gastrointestinal effects. 

No animal or human data were available for inhalation exposure. There are no data regarding effects in humans after oral exposure. Information is available in animals regarding health effects following acute, intermediate, and chronic oral ingestion of diisopropyl methylphosphonate. The animal data obtained after oral exposure indicate that diisopropyl methylphosphonate is moderately toxic after acute bolus exposure but has a lower order of toxicity after intermediate and chronic exposures in food. No data were found on the toxicity of diisopropyl methylphosphonate after exposure in drinking water. Further, diisopropyl methylphosphonate is rapidly metabolized and excreted and does not accumulate. It does not appear to have reproductive or developmental effects. At the doses tested, it does not appear to be an acetylcholinesterase inhibitor, although this issue has not been resolved yet. Limited data are available for dermal exposure in humans and animals. Diisopropyl methylphosphonate does not appear to be a... 

No studies were found on the health effects of diisopropyl methylphosphonate in humans following inhalation or oral exposure. The results of the one study that was located in which humans were exposed dermally to diisopropyl methylphosphonate was confounded by concurrent exposure to other chemicals. Limited animal data are available on the health effects of diisopropyl methylphosphonate following oral and dermal exposures. 

Absorption, Distribution, Metabolism, and Excretion. There are no data available on the absorption, distribution, metabolism, or excretion of diisopropyl methylphosphonate in humans. Limited animal data suggest that diisopropyl methylphosphonate is absorbed following oral and dermal exposure. Fat tissues do not appear to concentrate diisopropyl methylphosphonate or its metabolites to any significant extent. Nearly complete metabolism of diisopropyl methylphosphonate can be inferred based on the identification and quantification of its urinary metabolites however, at high doses the metabolism of diisopropyl methylphosphonate appears to be saturated. Animal studies have indicated that the urine is the principal excretory route for removal of diisopropyl methylphosphonate after oral and dermal administration. Because in most of the animal toxicity studies administration of diisopropyl methylphosphonate is in food, a pharmacokinetic study with the compound in food would be especially useful. It could help determine if the metabolism of diisopropyl methylphosphonate becomes saturated when given in the diet and if the levels of saturation are similar to those that result in significant adverse effects. 

Mineral Oil Hydraulic Fluids. No studies regarding hepatic effects in humans following inhalation, oral, or dermal exposure to mineral oil hydraulic fluids were located. In an animal study, histopathological examination of the livers from rats exposed by inhalation to <1.0 mg/m3 of the water-in-oil emulsion hydraulic fluid Houghto-Safe 5047F for 90 days, 23 hours/day, showed no treatment-related lesions (Kinkead et al. 1991). Animal data for oral exposure are limited to one study where rats were exposed to MIL-H-5606 at 1,000 mg/kg/day for 26 days (Mattie et al. 1993). Increases in liver weight and peroxisomal beta-oxidation activity were observed. 

Obach et al. [27] proposed a model to predict human bioavailability from a retrospective study of in vitro metabolism and in vivo animal pharmacokinetic (PK) data. While their model yielded acceptable predictions (within a factor of 2) for an expansive group of compounds, it relied extensively on in vivo animal PK data for interspecies scaling in order to estimate human PK parameters. Animal data are more time-consuming and costly to obtain than are permeability and metabolic clearance data hence, this approach may be limited to the later stages of discovery support when the numbers of compounds being evaluated are fewer. 

Acute-Duration Exposure. Information is available regarding the effects of acute-duration inhalation exposure of humans to acrylonitrile and the effects are characteristic of cyanide-type toxicity. Quantitative data are limited but are sufficient to derive an acute inhalation MRL. Further studies of humans exposed to low levels of acrylonitrile in the workplace would increase the confidence of the acute MRL. Studies in animals support and confirm these findings. No studies are available on the effects of acute-duration oral exposure in humans however, exposure to acrylonitrile reveals neurological disturbances characteristic of cyanide-type toxicity and lethal effects in rats and mice. Rats also develop birth defects. Animal data are sufficient to derive an acute oral MRL. Additional studies employing other species and various dose levels would be useful in confirming target tissues and determining thresholds for these effects. In humans, acrylonitrile causes irritation of the skin and eyes. No data are available on acute dermal exposures in animals. 

Exposure-response data from animal studies were used to derive acute exposure guideline level (AEGL) values for arsine. AEGL values derived with animal data which had complete exposure data were more scientifically valid than AEGLs estimated from limited anecdotal human data. The greater conser... 

Based upon the available data, derivation of AEGL-1 values was considered inappropriate. The continuum of arsine-induced toxicity does not appear to include effects consistent with the AEGL-1 definition. The available human and animal data affirm that there is a very narrow margin between exposures that result in little or no signs or symptoms of toxicity and those that result in lethality. The mechanism of arsine toxicity (hemolysis that results in renal failure and death), and the fact that toxicity in humans and animals has been reported at concentrations at or below odor detection levels (-0.5 parts per million (ppm)) also support such a conclusion. The use of analytical detection limits (0.01 to 0.05 ppm) was considered as a basis for AEGL-1 values but was considered to be inconsistent with the AEGL-1 definition. 

Several reports identified nonlethal effects in humans acutely exposed to arsine. These reports, however, lacked definitive exposure data but verified hematologic disorders leading to renal failure as critical effects of arsine exposure. Bulmer et al. (1940) (as cited in Elkins 1959) reconstructed an exposure incident at a gold extraction facility and estimated that subchronic (up to 8 mon) exposure to 0.12 ppm arsine resulted in jaundice and anemia (see Section 2.2.1). The lack of definitive exposure data for humans necessitates the use of animal data for quantitative estimation of AEGL values. Derivation of AEGL-2 values based upon limited human data (Flury and Zernik 1931) was considered but rejected because the data were poorly documented and inconsistent with other data showing lethality at lower cumulative exposures. 

Acute lethality data for inhalation exposure to monomethylhydrazine are available for monkey, dog, rat, mouse, and hamster. Based upon the available data, hamsters appear to be the most resistant species, and the squirrel monkey and beagle dog are the most sensitive. The lethality of monomethylhydrazine appeared to follow a linear relationship for exposures up to 1 h. Most animal data focus on lethality as the toxicity endpoint with very limited exposure-response information available regarding nonlethal effects. The most significant effect reported in the acute exposure studies was the notable hemolytic response that was reversible upon cessation of exposure. However, the preponderance of the data suggest that there is little margin between exposures associated with nonlethal, reversible effects and those that result in death. 

Limited animal data suggest little reproductive and developmental toxicity potential for monomethylhydrazine at doses that do not result in overt maternal intoxication. 

Data on acute exposures of humans to both isomers of dimethylhydrazine are limited to case reports of accidental exposures. Signs and symptoms of exposure include respiratory irritation, pulmonary edema, nausea, vomiting, and neurologic effects. However, definitive exposure data (concentration and duration) were unavailable for these accidents. The limited data in humans suggest that the nonlethal toxic response to acute inhalation of dimethylhydrazine is qualitatively similar to that observed in animals. No information was available regarding lethal responses in humans. In the absence of quantitative data in humans, the use of animal data is considered a credible approach for developing AEGL values. 

Immunotoxicity. No studies are available for any exposure route on the potential for hexachloroethane to cause immunotoxic effects in humans. Data in animals are limited to studies that evaluated lymphoid organs (e.g., spleen and thymus) as part of a comprehensive histopathological examination following oral and inhalation exposure to hexachloroethane (Gorzinski et al. 1985 Weeks et al. 1979). Adverse effects were not reported for these organs. 

Postgavage hyperactivity was noted in rats with an oral dose of 375 mg/kg/day (NTP 1989) and tremors occurred following a dose of 500 mg/kg/day (Weeks et al. 1979). Other available animal data are limited to the findings of histological examination of the brain and other nervous tissue following inhalation, oral, and dermal exposures (Gorzenski et al. 1985 NTP 1977, 1989 Weeks et al. 1979). No lesions were reported. 

In animal experiments exposures can be carefully controlled, and dose-response curves can be formally estimated. Extrapolating such information to the human situation is often done for regulatory purposes. There are several models for estimating a lifetime cancer risk in humans based on extrapolation from animal data. These models, however, are premised on empirically unverified assumptions that limit their usefulness for quantitative purposes. While quantitative cancer risk assessment is widely used, it is by no means universally accepted. Using different models, one can arrive at estimates of potential cancer incidence in humans that vary by several orders of magnitude for a given level of exposure. Such variations make it rather difficult to place confidence intervals around benefits estimations for regulatory purposes. Furthermore, low dose risk estimation methods have not been developed for chronic health effects other than cancer. The... 

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