Oral studies

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. 

Epoxy Phenol Novolak Resins. Acute oral studies indicate low toxicity for these resins (49). Eye studies indicate only minor irritation in animals (49). The EPN resins have shown weak skin-sensitizing potential in humans. 

Endosulfan residues are rapidly eliminated from tissues as suggested by a half-life of approximately 7 days estimated in a 14-day oral study in female rats (Dorough et al. 1978). Rapid elimination was also observed in a 28-day study in goats in which half-lives between 1.1 and 3.1 days were estimated for endosulfan residues in various organs and tissues (Indraningsih et al. 1993). 

In a chronic oral study in rats, observation of squinting and red discharge from the eyes were reported more frequently in trichloroethylene exposed rats as the study progressed (NCI 1976). Histopathological changes in the eyes were not reported in rats following chronic inhalation exposure (Maltoni et al. 1988) or in rats or mice following chronic oral exposure (Maltoni et al. 1986 NCI 1976 NTP 1988). Based on the limited data. 

With the exception of studies examining reproductive outcome in people exposed to trichloroethylene in drinking water (ATSDR 1997 MDPH 1994), intermediate-duration studies in humans following oral exposure were not available. Intermediate-duration oral studies of trichloroethylene in animals (Barret et al. 1991, 1992 Buben and O Flaherty 1985 Constan et al. 1995 Dawson et al. 1993 Goel et al. 1992 Isaacson et al. 1990 Mason et al. 1984 Merrick et al. 1989 NCI 1976 NTP 1988, 1990 Stott et al. 1982 Tucker et al. 1982 Zenick et al. 1984) are available, but did not adequately provide exposure levels that could be... 

In a single-dose oral study in male and female rats (Bucci et al. 1992), only 0.5% of the radioactivity from a dose of 660 mg/kg [14C]-radiolabeled diisopropyl methylphosphonate was found in the tissues 120 hours after dosing. The investigators indicated that no important tissue depot for diisopropyl methylphosphonate or its metabolites could be identified from the data obtained. 

No intermediate- or chronic-duration oral studies examining developmental effects in animals were located. 

The only oral study of hydrogen sulfide is a study in pigs in which decreased body weights were observed in pigs fed hydrogen sulfide in the diet at 6.7 mg/kg/day for 105 days (Wetterau et al. 1964). 

No effects were observed at a dose of 3.1 mg/kg/day. However, because this study lacks details and there is no supporting data, no intermediate-duration MRL was derived. Additional intermediate-duration oral studies of hydrogen sulfide are needed to provide support for this study. 

Developmental Toxicity. No information is available on developmental effects of acrylonitrile in humans by any route of exposure. Acrylonitrile is teratogenic and embryotoxic in rats both by the oral and inhalation routes of exposure. Developmental studies on other animal species have not been conducted. Because species differences for acute acrylonitrile toxicity and metabolism have been demonstrated, additional developmental studies in other species using various dose levels would be valuable in evaluating the potential for acrylonitrile to cause developmental effects in humans. Because the available oral study was conducted by gavage, additional studies are needed to determine if these effects will occur following ingestion of drinking water or food. 

Two oral studies in rodents demonstrated the carcinogenic potential of dimethylhydrazines. Results of an inhalation study in mice showing an increased tumor response following exposure to 1,1-dimethylhydrazine may be compromised by the contamination of the test article with dimethylnitrosamine. Both inhalation and oral slope factors for the dimethylhydrazines have been withdrawn from IRIS. 

No studies were located regarding cancer incidence in animals after inhalation exposure to hexachloroethane. EPA has derived an inhalation unit risk (cancer slope factor) of 1.4x102 (mg/kg/day) 1 for hexachloroethane (IRIS 1995). This inhalation unit risk was calculated using data from oral studies (see Section 2.2.2.8) and Figure 2-2. 

Chronic-Duration Exposure and Cancer. No studies were located in humans following chrome-duration exposure to hexachloroethane for any exposure route. No chronic animal studies were conducted using the inhalation route of exposure. In oral studies with rats, the kidney was identified as a primary target organ in males and females (NTP 1989). The kidney damage in male rats was the result of hyaline droplet nephropathy and, accordingly, was not suitable as the basis for an oral MRL. In contrast to acute- and intermediate-duration oral exposure, liver toxicity was not evident in rats following chronic oral exposure. There were no studies of chronic dermal exposure to hexachloroethane. 

Studies using the inhalation route might be useful to determine the potential human health risk in populations that may be occupationally exposed to hexachloroethane vapors for long periods. Additional chronic oral studies may be useful to help further clarify the dose-response relationships and better characterize thresholds. Studies by the dermal route would not be useful until the rate and extent of absorption have been better characterized. 

Because inhalation exposure is limited by the properties of hexachloroethane, higher doses could be achieved using oral exposure. If an oral study is negative for reproductive effects at high doses, an inhalation study may not be necessary. 

There are no other acute oral studies of hexachloroethane which support this MRL. However, intermediate-duration oral studies of hexachloroethane in rats described further in the worksheet for the intermediate-duration oral MRL provide support that the liver is a target following oral exposure to hexachloroethane. 

Techniques of Oral Absorption. There are three major techniques for oral delivery of drugs to test animals. The most common way is by gavage, which requires that the material be in a solution or suspension for delivery by tube to the stomach. Less common materials may be given as capsules (particularly to dogs) or in diet (for longer-term studies). Rarely, oral studies may also be done by inclusion of materials in drinking water. 

An acute intravenous study can provide accurate rates of metabolism without interference from intestinal flora, plus rates of renal and biliary elimination, if urine and bile are collected. This route also avoids the variability in delivered dose associated with oral absorption and ensures that the maximum amount of radiolabel is excreted in the urine or bile for purposes of detection. Once IV data and parameters are available, they can be used with plasma concentrations from limited oral studies to compute intestinal absorption via the ratio of Areas Under the (plasma and/or urine) Curves or via simulations of absorption with gastrointestinal absorption models. 

In single dose oral studies with rats, endrin treatment was associated with an increased incidence (2.4-3.5-fold) in the number of DNA single strand breaks in hepatocytes (Bagchi et al. 1992a, 1993a, 1993c Hassoun et al. 1993). DNA damage was attributed to oxidative injury caused by endrin. 

A chronic oral MRL was not derived because of the limitations of the available studies. Human studies that described dietary exposure to cyanide through consumption of cassava lacked quantitative exposure information. The one available chronic oral study in rats found no treatment related effects (Howard and Hanzel 1955). 

For chronic exposure in animals, only one oral study in rats (hydrogen cyanide) was located (Howard and Hanzal 1955). However, the reliability of this study is low because of the unstable cyanide levels in their feed throughout the experiment due to evaporation of cyanide. Furthermore, no effects were found in the study besides nondose-related changes in weight gain in female rats, but not in male rats. No chronic studies in animals were located for the inhalation and dermal routes. Therefore, data are not sufficient to derive MRL values for chronic exposure. Additional chronic-duration studies in animals would be helpful to determine thresholds for target organs. 

The only information about the immunological effects of mirex exposure in animals was provided by one acute oral study in rats in which decreased spleen weight was reported (Buelke-Sam et al. 

Intermediate-duration oral studies in humans for mirex are lacking. A review of the animal oral intermediate toxicity data for mirex indicates that the available studies are not adequate to derive intermediate oral MRL for mirex. The most suitable study provides a LOAEL of 0.25 mg/kg/day for endocrine effects-dilation of rough endoplasmic reticulum cisternae of the thyroid of weanling Sprague-Dawley rats (Singh et al. 1985). Adjusting the LOAEL of 0.25 mg/kg/day determined from this study with a total uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for animal to human extrapolation, and 10 for interspecies variability) yields an intermediate oral MRL of 0.0003 mg/kg/day, which is lower than the chronic-duration oral MRL of 0.0008 mg/kg/day derived from an NTP (1990) study in rats (see chronic-duration MRL). Therefore, no oral intermediateduration MRL was developed for mirex. 

No information was located regarding the gastrointestinal toxicity of chlordecone in humans. Only very limited evidence of gastrointestinal effects has been observed in oral studies in experimental animals (Fujimori et al. 1983 Larson et al. 1979b). Thus, it is unlikely that chlordecone exposure would result in adverse effects on the gastrointestinal tracts of persons exposed to low levels at hazardous waste sites. 

Immunological Effects. No data on immunotoxicity of mirex in were located. The only information about the immunological effects of mirex exposure in animals was provided by one acute oral study in rats in which decrease spleen weight was reported (Buelke-Sam et al. 1983). Thus, it is uncertain whether persons exposed to mirex at hazardous waste sites might experience adverse effects on the immune system. 

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