Exposure, subchronic

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. 

In additional EPA studies, subchronic inhalation was evaluated ia the rat for 4 and 13 weeks, respectively, and no adverse effects other than nasal irritation were noted. In the above-mentioned NTP chronic toxicity study ia mice, no chronic toxic effects other than those resulting from bronchial irritation were noted. There was no treatment-related increase ia tumors ia male mice, but female mice had a slight increase in bronchial tumors. Neither species had an increase in cancer. Naphthalene showed no biological activity in other chemical carcinogen tests, indicating Htde cancer risk (44). No incidents of chronic effects have been reported as a result of industrial exposure to naphthalene (28,41). 

Some nonmalignant respiratory effects have been observed in experimental animals during acute or subchronic exposures. Soluble and moderately soluble compounds were more toxic than were insoluble compounds and produced different effects. Sulfate and subsulftde produced fibrosis whereas nickel oxide did not. 

Inhalation is the chief route of worker exposure. Comparative data from acute or subchronic inhalation exposures with rats (98) indicate that nitromethane and nitroethane are the least toxic of the nitroparaffins by this route and do not induce methemoglobin formation. The nitropropanes are less well tolerated 2-nitropropane is more toxic than 1-nitropropane and is more likely to cause methemoglobinemia. 

Undiluted DMAMP, AMP-95, and AB cause eye bums and permanent damage, if not washed out immediately. They are also severely irritating to the skin, causing bums by prolonged or repeated contact. Of these three aLkanolarnines, only AMP has been studied in subchronic and chronic oral studies. The principal effect noted was the action of AMP on the stomach as a result of its alkalinity. The no-observed-effect level (NOEL) in a one-year feeding study in dogs was 110 ppm in the diet. In general, the low volatility and appHcations for which these products are used preclude the likelihood of exposure by inhalation. 

A commercially interesting low calorie fat has been produced from sucrose. Proctor Gamble has patented a mixture of penta- to octafatty acid ester derivatives of sucrose under the brand name Olestra. It was approved by the FDA in January 1996 for use as up to 100% replacement for the oil used in preparing savory snacks and biscuits. Olestra, a viscous, bland-tasting Hquid insoluble in water, has an appearance and color similar to refined edible vegetable oils. It is basically inert from a toxicity point of view as it is not metabolized or absorbed. It absorbs cholesterol (low density Hpoprotein) and removes certain fat-soluble vitamins (A, D, E, and K). Hence, Olestra has to be supplemented with these vitamins. No standard LD q tests have been performed on Olestra however, several chronic and subchronic studies were performed at levels of 15% in the diet, and no evidence of toxicity was found. No threshold limit value (TLV), expressed as a maximum exposure per m of air, has been estabhshed, but it is estimated to be similar to that of an inert hpid material at 5 mg/m. ... 

Subchronic exposures involve consecutive daily exposures to the test material for a period amounting to usually no more than 10—15% of the lifespan of the test species. 

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. 

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. 

Acceptable Intake for Subchronic Exposure (AIS) An estimate similar in concept to the subchronic RfD. but derived using a less strictly defined methodology. Subchronic RfDs have replaced AISs as the Agency s preferred alues for use in e ahiating potential noncarcinogenic health effects resulting from subchronic exposure to a chemical. 

Development of subchronic RfDs parallels the development of chronic reference doses in concept the distinction is one of e.xposurc duration. Appropriate studies are evaluated and a subchronic NOAEL is identified. The RfD is derived from the NOAEL by the application of the UFs and MF, as outlined above. When experimental data arc available only for shorter e.xposurc durations than desired, an additional uncertainly factor is applied. This is similar to the application of the uncertainly factor for duration differences when a chronic RfD is estimated from subchronic animal data. On the other hand, if subchronic data are missing and a chronic oral RfD derived from chronic data exists, the chronic oral RfD is adopted as the subchronic oral RfD. Ill this instance, there is no application of an uncertainly factor to account for differences in exposure duration. 

To assess die overall potential for non carcinogenic effects posed by several exposure pathways, the total haziird index for each exposure duration (i.e., chronic, subchronic, and shorter-term) should be calculated separately. This equation is described below ... 

Note that die total exposure hazard index is calculated separately for clironic, subchronic, and shorter-term exposure periods. 

Arito H, Takahashi M, Ishikawa T. 1994a. Effect of subchronic inhalation exposure to low-level trichloroethylene on heart rate and wakefulness-sleep in freely moving rats. Sangyo Igaku 36 1-8. 

EPA has derived both an oral reference dose (RfD) and an inhalation reference concentration (RfC) for chronic exposure to hydrogen sulfide. The RfD of 0.003 mg/kg/day is based on the NOAEL of 3.1 mg/kg/day for gastrointestinal disturbance in pigs in a study by Wetterau et al. (1964) (IRIS 1998). The NOAEL value of 3.1 mg/kg/day was divided by an uncertainty factor of 1,000 to account for interspecies extrapolation (10), sensitive individuals (10), and subchronic exposure (10) (IRIS 1998). 

The no-effect level from a subchronic (90-day) study is assigned an additional safety factor of 10 because of the shorter period of exposure (11). Hence... 

Ferguson and Bowman 1990 Gilbert and Rice 1987 Hopper et al. 1986 Krasovskii et al. 1979 Levin et al. 1988 Massaro and Massaro 1987 Overmann 1977 Rice 1985a). It appears that animals are affected at roughly the same blood lead levels as humans. Measured neurotoxic effects in animals include significantly delayed motor function and reflexes, decreased performance on learning tasks, and impaired spatial discrimination. Additional animal studies are needed to investigate the neurotoxic effects of subchronic inhalation exposures to establish external dose-effect relationships. 

Vyskocil A, Semscky V, Fiala Z, et al. 1995. Renal alterations in female rats following subchronic lead exposure. J Appl Toxicol 15 257-262. 

In the case of noncarcinogenic substances, there exists a threshold this is an exposure with a dose below which there would not be adverse effect on the population that is exposed. This is the reference dose (RfD), and it is defined as the daily exposure of a human population without appreciable effects during a lifetime. The RfD value is calculated by dividing the no observed effect level (NOEL) by uncertainty factors. When NOEL is unknown, the lowest observed effect level (LOEL) is used. NOEL and LOEL are usually obtained in animal studies. The main uncertainty factor, usually tenfold, used to calculate the RfD are the following the variations in interspecies (from animal test to human), presence of sensitive individuals (child and old people), extrapolation from subchronic to chronic, and the use of LOEL instead of NOEL. Noncancer risk is assessed through the comparison of the dose exposed calculated in the exposure assessment and the RfD. The quotient between both, called in some studies as hazard quotient, is commonly calculated (Eq. 2). According to this equation, population with quotient >1 will be at risk to develop some specific effect related to the contaminant of concern. 

Immunotoxicity. No information was found on the immunological effects of acrylonitrile in humans or animals by any route of exposure. Because no Immunopathological effects have been reported in subchronic and chronic studies involving multiple species, additional studies employing a more specific testing battery are not warranted at this time. 

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. 

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