Evaluation of subchronic toxicity of n-butyl acetate vapor.

The subchronic toxicity of n-butyl acetate (nBA), a common industrial solvent, was tested in rats in a 13-week inhalation study. Male and female Sprague-Dawley (SD) rats were exposed to concentrations of 0, 500, 1500 or 3000 ppm nBA for 6 h per day, 5 days per week for 13 consecutive weeks. Transient signs of sedation were observed only during exposure to the 1500 and 3000 ppm concentrations. Body weights for the 1500 and 3000 ppm groups were significantly reduced. Feed consumption values for the 1500 and 3000 ppm groups were significantly lower than the control group. Weights of the liver, kidneys and spleen were significantly lower for the 3000 ppm male group; testes and adrenal gland weights for the 1500 and 3000 ppm groups and the lung weight for the 3000 ppm male group were significantly higher than for the control group. Signs of irritation of the glandular stomach and necrosis in the non-glandular stomach were observed in 3000 ppm female rats. Degeneration of the olfactory epithelium along the dorsal medial meatus and ethmoturbinates of the nasal passages of some 1500 and all 3000 ppm rats was also seen. The severity was mild to moderate for the 3000 ppm group and minimal to mild for the 1500 ppm group. No effects were observed in the lungs of any group. The no-observed-effect level (NOEL) for this study is considered to be 500 ppm. The data presented here are relevant to the toxicity risk assessment of n-butanol due to the rapid hydrolysis of nBA in vivo.

Public trust and confidence in legal authorities: What do majority and minority group members want from the law and legal institutions?

Discussions of public trust and confidence in the police and the courts often assume that the key to public feelings is the public's evaluation of the outcomes that the public receives from these legal authorities. In the case of the courts, discontent is often assumed to be linked to issues of cost and delay-instrumental concerns about the outcomes delivered to the public by the courts. In the case of the police, the inability to effectively control crime is frequently seen as driving public evaluations. This article presents an alternative procedural justice based model that links public trust and confidence to views about the manner in which legal authorities treat the public. Drawing upon psychological research about public evaluations of institutions and authorities it is argued that the key issue that shapes public views is a process based evaluation of the fairness of the procedures that the police and courts use to exercise their authority. Analyses from several studies exploring the basis of public views support this procedural justice based model of public evaluation. In addition, the results provide suggestions about the elements of procedures that are central to public judgments about their fairness.

Proposed occupational exposure limits for select ethylene glycol ethers using PBPK models and Monte Carlo simulations.

Methoxyethanol (ethylene glycol monomethyl ether, EGME), ethoxyethanol (ethylene glycol monoethyl ether, EGEE), and ethoxyethyl acetate (ethylene glycol monoethyl ether acetate, EGEEA) are all developmental toxicants in laboratory animals. Due to the imprecise nature of the exposure data in epidemiology studies of these chemicals, we relied on human and animal pharmacokinetic data, as well as animal toxicity data, to derive 3 occupational exposure limits (OELs). Physiologically based pharmacokinetic (PBPK) models for EGME, EGEE, and EGEEA in pregnant rats and humans have been developed (M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 53-62; M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 63-73). These models were used to calculate estimated human-equivalent no adverse effect levels (NAELs), based upon internal concentrations in rats exposed to no observed effect levels (NOELs) for developmental toxicity. Estimated NAEL values of 25 ppm for EGEEA and EGEE and 12 ppm for EGME were derived using average values for physiological, thermodynamic, and metabolic parameters in the PBPK model. The uncertainties in the point estimates for the NOELs and NAELs were estimated from the distribution of internal dose estimates obtained by varying key parameter values over expected ranges and probability distributions. Key parameters were identified through sensitivity analysis. Distributions of the values of these parameters were sampled using Monte Carlo techniques and appropriate dose metrics calculated for 1600 parameter sets. The 95th percentile values were used to calculate interindividual pharmacokinetic uncertainty factors (UFs) to account for variability among humans (UF(h,pk)). These values of 1.8 for EGEEA/EGEE and 1.7 for EGME are less than the default value of 3 for this area of uncertainty. The estimated human equivalent NAELs were divided by UF(h,pk) and the default UFs for pharmacodynamic variability among animals and among humans to calculate the proposed OELs. This methodology indicates that OELs (8-h time-weighted average) that should protect workers from the most sensitive adverse effects of these chemicals are 2 ppm EGEEA and EGEE (11 mg/m(3) EGEEA, 7 mg/m(3) EGEE) and 0.9 ppm (3 mg/m(3)) EGME. These recommendations assume that dermal exposure will be minimal or nonexistent.

Subchronic and developmental toxicity studies of n-butyl propionate vapor in rats.

Two inhalation studies were conducted to evaluate the possible subchronic and developmental toxic effects of n-butyl propionate. In the subchronic study, Sprague-Dawley rats (15/sex/group) were exposed to 0, 250, 750, or 1500 ppm vapor for 6 h/d, 5 d/wk for 13 wk. Five of the rats per sex per group were held after the final exposure for an 8-wk recovery period. Standard parameters of subchronic toxicity were measured throughout the study, and at the end of exposure and recovery periods, necropsies were performed, organs weighed, and tissues processed for microscopic examination. Exposure did not produce marked treatment-related deaths or adversely affect clinical signs, hematology, clinical chemistries, organ weights, or the histology of major visceral organs. The only systemic toxic effects were significant decreases in body weight, body weight gain, and feed consumption that occurred in 1500 ppm group rats. Morphologic changes were limited to the nasal cavity as evidenced by a concentration-related increased incidence and severity of olfactory epithelium degeneration in rats of the 750 and 1500 ppm groups. These degenerative microscopic alterations were primarily confined to the olfactory epithelium within the dorsal portion of the medial meatus, with lesser involvement of the olfactory mucosae overlying the tips of some of the adjacent ethmoturbinates. Both the systemic and nasal cavity effects appeared reversible after exposure ceased. In the developmental toxicity study, pregnant Sprague-Dawley rats (24/group) were exposed to 0, 500, 1000, or 2000 ppm vapor for 6 h/d on gestation d 6-15 and sacrificed on gestation d 20. All treatment-group dams exhibited significant reductions in body weight, body weight gain, and feed consumption. Gestational parameters were equivalent across all groups and there were no treatment-related developmental or teratogenic effects. The no-observed-adverse effects levels (NOAELs) determined for nbutyl propionate were 250 ppm for subchronic toxicity (based on the olfactory epithelium degeneration) and 22000 ppm for developmental toxicity (no developmental effects at top dose tested). Under the conditions of this study, a NOAEL was not determined for maternal toxicity.

A toxicokinetic study of inhaled ethylene glycol monomethyl ether (2-ME) and validation of a physiologically based pharmacokinetic model for the pregnant rat and human.

Exposures to sufficiently high doses of ethylene glycol monomethyl ether (2-methoxyethanol, 2-ME) have been found to produce developmental effects in rodents and nonhuman primates. The acetic acid metabolite of 2-ME, 2-methoxyacetic acid (2-MAA), is the likely toxicant, and, as such, an understanding of the kinetics of 2-MAA is important when assessing the potential risks to humans associated with 2-ME. A previously described physiologically based pharmacokinetic (PBPK) model of 2-ME/2-MAA kinetics for rats exposed via oral or iv administration was extended and validated to inhalation exposures. Pregnant Sprague-Dawley rats were exposed for 5 days (gestation days 11-15), 6 h/day, to 2-ME vapor at 10 and 50 ppm. Validation consisted of comparing model output to maternal blood and fetal 2-ME and 2-MAA concentrations during and following 5 days of exposure (gestation days 11-15). These concentrations correspond to a known no observed effect level (NOEL) and a lowest observed effect level (LOEL) for developmental effects in rats. The rat PBPK model for 2-ME/2-MAA was scaled to humans and the model (without the pregnancy component) was used to predict data collected by other investigators on the kinetics of 2-MAA excretion in urine following exposures to 2-ME in human volunteers. The partially validated human model (with the pregnancy component) was used to predict equivalent human exposure concentrations based on 2-MAA dose measures (maximum blood concentration, C(max), and average daily area under the 2-MAA blood concentration curve, AUC, during pregnancy) that correspond to the concentrations measured at the rat NOEL and LOEL exposure concentrations. Using traditional PBPK scale-up techniques, it was calculated that pregnant women exposed for 8 h/day, 5 days/week, for the duration of pregnancy would need to be exposed to 12 or 60 ppm 2-ME to produce maternal 2-MAA blood concentrations (C(max) or average daily AUC) equivalent to those in rats exposed to the NOEL (10 ppm) or LOEL (50 ppm), respectively.

A toxicokinetic study of inhaled ethylene glycol ethyl ether acetate and validation of a physiologically based pharmacokinetic model for rat and human.

The solvents ethylene glycol monoethyl ether acetate (EGEEA) and ethylene glycol monoethyl ether (EGEE), at sufficiently high doses, are known to be rodent developmental toxicants, exerting their toxic effects through the action of their metabolite 2-ethoxyacetic acid (2-EAA). Thus risks associated with exposure to these compounds are best evaluated based on a measure of the internal dose of 2-EAA. The goals of the work reported here were to develop physiologically based pharmacokinetic (PBPK) models of EGEEA and EGEE for pregnant rats and humans. These models were used to identify human exposure levels (ppm in air) equivalent to the rat no observed effect level (NOEL) and lowest observed effect level (LOEL) for developmental effects (Hanley et al., 1984). We exposed pregnant Sprague-Dawley rats to concentrations of EGEEA corresponding to the NOEL and LOEL. Maternal blood, urine, and fetal tissue concentrations of EGEE and 2-EAA measured in these experiments were used to validate the rat EGEEA and EGEE models. Data collected by other researchers were used to validate the capabilities of the rodent EGEEA and EGEE models to predict the kinetics in humans. The models for estimating circulating blood concentrations of 2-EAA were considered valid based on the ability of the model to accurately predict 2-EAA concentrations in rat blood, urine, and fetal tissue. The human inhaled concentration equivalent to the rat NOEL for EGEEA (50 ppm) was predicted to be 25 ppm using the maternal blood average daily area under the curve (AUC) and 40 ppm using the maximum concentration achieved in maternal blood (C(max)). The human inhaled concentration equivalent to the rat LOEL for EGEEA (100 ppm) was determined to be 55 ppm using the maternal blood average daily AUC and 80 ppm using the maternal blood C(max).

Family approach for estimating reference concentrations/doses for series of related organic chemicals.

The family approach for related compounds can be used to evaluate hazard and estimate reference concentrations/doses using internal dose metrics for a group (family) of metabolically related compounds. This approach is based upon a simple four-step framework for organizing and evaluating toxicity data: 1) exposure, 2) tissue dosimetry, 3) mode of action, and 4) response. Expansion of the traditional exposure-response analysis has been increasingly incorporated into regulatory guidance for chemical risk assessment. The family approach represents an advancement in the planning and use of toxicity testing that is intended to facilitate the maximal use of toxicity data. The result is a methodology that makes toxicity testing and the development of acceptable exposure limits as efficient and effective as possible. An example is provided using butyl acetate and its metabolites (butanol, butyraldehyde, and butyrate), widely used chemicals produced synthetically by the industrial oxo process. A template pharmacokinetic model has been developed that comprises submodels for each compound linked in series. This preliminary model is being used to coordinately plan toxicity studies, pharmacokinetic studies, and analyses to obtain reference concentrations/doses. Implementation of the family approach using pharmacokinetic modeling to obtain tissue dose metrics is described and its applications are evaluated.

Inhalation toxicity studies of aqueous dispersion resin.

Aqueous dispersion resin (ADR) is a water-based acrylate copolymer designed to allow a range of ethanol concentrations for hair-spray formulations. A series of inhalation (whole-body) aerosol toxicity studies, including acute, 9-day, and 90-day exposures, was conducted to determine any toxicological effects for ADR. An acute study of ADR was conducted for 4 h with a 14-day observation period. The maximum ADR aerosol concentration was 1.07 (+/- 0.04) mg/L with a mass medium aerodynamic diameter (MMAD) value of 1.46 microm and a geometric mean (sigma(g)) of 1.42. No deaths or exposure-related lesions were observed. Thus, the LC50 value was greater than 1.07 mg/L. For the 9-day study, each group contained 10 animals/sex and was exposed for 2 h/day. The mean exposure concentrations (+/- standard deviation) were 244 (+/- 39.6), 543 (+/- 71.9), and 843 (+/- 186.2) mg/m(3) for the 250-, 500-, and 1000-mg/m(3) groups, respectively. The mean MMADs were 2.83, 2.90, and 4.09 microm for the 250-, 500-, and 1000-mg/m(3) groups, respectively, with sigma(g) values ranging from 3.15 to 6.22. Unkempt fur and alopecia in the males and females from the 1000-mg/m(3) group at sacrifice were the only exposure-related clinical signs observed. Increased lung weights in the 500- and 1000-mg/m(3) exposure groups were found. Histopathological effects, such as alveolar histiocytosis and interstitial pneumonitis, were also noted in these two exposure groups. For the 90-day study, 10 animals per sex were included in each group with a 6-wk recovery group of 5 female rats/group. Exposures were conducted for 2 h/day. The mean exposure concentrations were 30.4 (+/- 2.3), 102 (+/- 11.6), and 308 (+/- 19. 3) mg/m(3) with mean MMADs of 3.09, 2.64, and 2.67 microm and sigma(g) values ranging from 3.54 to 3.90 for exposure concentrations of 30, 100, and 300 mg/m(3), respectively. The only findings at the 90-day sacrifice were increased lung weights for the males and females in the 300-mg/m(3) group and males in the 100-mg/m(3) group. For the 6-wk recovery sacrifice of the females, the lung weights for the 300- and 100-mg/m(3) groups were increased. Histopathological effects at the 90-day sacrifice included alveolar histiocytosis and lymphadenitis in the mediastinal lymph nodes in the 100- and 300-mg/m(3) exposure groups for males and females, while alveolar histiocytosis, intraalveolar cellular debris, lymphadenitis in the mediastinal lymph nodes, and/or interstitial pneumonitis were noted in these 2 exposure groups of the females after the 6-wk recovery period. Animals exposed for 90 days to 100 and 300 mg/m(3) for 2 h had increased lung weights. However, no effects were observed in the 30-mg/m(3) exposure group. Thus, under the conditions of the present 90-day study, a no-observable-effect level (NOEL) was found to be 30 mg/m(3).

Subchronic inhalation neurotoxicity study of amyl acetate in rats.

An inhalation toxicity study was conducted with rats to examine the potential for amyl acetate vapor to produce alterations in nervous system structure and function following repeated exposure. The study was performed as part of a USEPA Toxic Substances Control Act (TSCA) Section 4e Enforceable Consent Agreement for amyl acetate. Rats (CD) were exposed to amyl acetate vapor at concentrations of 0, 300, 600 or 1200 ppm, 6 h per day, 4 or 5 days per week, for at least 65 exposures. Treatment groups consisted of 15 rats per gender for the control and 1200 ppm groups and 10 rats per gender for the 300 and 600 ppm groups. Evaluations included clinical observations before, during and after each exposure, weekly detailed clinical examinations, weekly body weight and food consumption measurements and monthly functional observational battery and motor activity measurements conducted on non-exposure days. Neuropathology examination of the central and peripheral nervous system was performed at the end of the study. Exposure to amyl acetate did not result in overt clinical signs of toxicity or changes in body weight or food consumption. Transient, subtle decreases in general activity level during the 6-h exposure period were noted for animals in the 600 and 1200 ppm groups during the first 2 weeks of the study. Functional observational battery evaluations, automated motor activity measurements and neuroanatomy were unaffected by exposure. The no observed-effect level for subchronic neurotoxicity for this study was at least 1200 ppm, which is greater than an order of magnitude above the occupational threshold limit value (8-h, time-weighted average) for amyl acetate (100 ppm).

The effect of repeated methyl iso-butyl ketone vapor exposure on schedule-controlled operant behavior in rats.

Methyl iso-butyl ketone (MiBK), a commercial solvent, was selected by the US Environmental Protection Agency (US EPA) for testing under the Multi-Substance Rule for the Testing of Neurotoxicity (US EPA, 1993) using schedule-controlled operant behavior (SCOB) to determine if subchronic exposure to MiBK vapor had the potential to alter behavior as an indicator of neurotoxicity. Food-restricted and ad libitum-fed Sprague-Dawley male rats were exposed to 0, 250, 750, or 1500 ppm MiBK for 6 h/day, 5 d/wk for 13 weeks. SCOB testing of food-restricted animals, using a multiple fixed ratio (FR)/fixed interval (FI) schedule (FR20:FI120), was conducted prior to each exposure to maintain the operant behavior; the data from Weeks -1, 4, 8, and 13 were evaluated for evidence of neurotoxicity. SCOB testing was also evaluated for two weeks following the cessation of exposures. Ad libitum-fed animals were included to assess systemic effects using routine indicators such as changes in body weight, food consumption, and organ weight. No significant differences were seen in fixed-ratio run rate, FR pause duration, fixed-interval response rate, and index of curvature values at any concentration. Animals exposed to 750 and 1500 ppm MiBK exhibited clinical signs associated with transient reduced activity levels, but only during exposure. No signs of reduced activity were observed immediately after exposure for either group. No other treatment-related abnormalities were observed during exposure. Food-restricted animals did not demonstrate any increased or decreased sensitivity to the CNS depressive effects of MiBK relative to the ad libitum-fed animals. No treatment-related body weight differences were observed within either the food-restricted groups or the ad libitum-fed groups, although body weights of the former were clearly depressed compared with those of the latter. Relative and absolute liver, and relative kidney weights were significantly greater for the 750 and 1500 ppm ad libitum-fed animals. No differences in kidney weight were observed for food-restricted animals, but absolute and/or relative liver weights were significantly higher for all the treated food-restricted groups. The results of this study indicate that repetitive exposures to high concentrations of MiBK vapors do not result in adverse effects on operant behavior in the rat.

Neurotoxicity evaluation of rats after subchronic inhalation exposure to isobutanol.

The subchronic neurotoxic effects of isobutanol were studied by exposing Sprague-Dawley rats to isobutanol vapor concentrations of 0, 250, 1000, and 2500 ppm for 6 hrs/day, 5 days/wk, for 3 months. A comprehensive set of neurotoxicity tests (functional observational battery, motor activity, perfusion fixation neuropathology, and schedule-controlled operant behavior) including an assessment of complex behavior dependent on learning and memory was conducted. In addition, full histopathology and blood chemistry evaluations were conducted in order to assess any potential functional/behavioral effects in the context of other possible systemic toxicities. There were no morphological or behavioral effects indicative of a specific, persistent or progressive effect of isobutanol on the nervous system at exposure concentrations up to 2500 ppm. A slight decrease in response to external stimuli was observed during exposures at all concentrations. These effects are likely transient effects of acute exposure to isobutanol.

Evaluation of subchronic neurotoxicity of n-butyl acetate vapor.

n-Butyl acetate, a common industrial solvent, was selected by the US EPA as a chemical of concern for neurotoxicity as part of the Multisubstance Rule for the Testing of Neurotoxicity. The neurotoxic potential of n-butyl acetate was investigated in Sprague-Dawley rats using a functional observational battery, motor activity, neurohistopathology, and schedule-controlled operant behavior (SCOB) as indicators of neurotoxicity. Animals were exposed to concentrations of 0, 500, 1500, or 3000 ppm of n-butyl acetate for 6 hours per day for 65 exposures over 14 weeks. Functional observational battery and motor activity values for ad libitum-fed male and female rats were measured during Weeks -1, 4, 8, and 13. SCOB testing of food-restricted animals, using a multiple fixed ratio/fixed interval schedule, was conducted daily prior to each exposure to maintain the operant behavior; the data from Weeks -1, 4, 8, and 13 were evaluated for evidence of neurotoxicity. Transient signs of sedation and hypoactivity were observed only during exposure to the 1500 and 3000 ppm concentrations. The only signs of systemic toxicity were reduced body weights for the 3000 ppm ad libitum-fed groups and occasionally for the female 1500 ppm ad libitum-fed group. No evidence of neurotoxicity was seen during the functional observational battery examinations. Motor activity for the 3000 ppm male group was significantly (p < or = 0.05) higher than for the control group only during Week 4. No significant differences were observed among groups for Weeks 8 and 13. No significant differences in motor activity values were observed for female rats. No significant differences were seen in operant behavior at any test vapor concentration. Microscopic evaluations of sections from the brain, spinal cord (cervical and lumbar regions), dorsal and ventral spinal roots, dorsal root ganglia, sciatic nerve, and tibial nerve of animals in the control and 3000 ppm groups did not indicate any treatment-related effects. In conclusion, there was no evidence of cumulative neurotoxicity based on the functional observational battery, motor activity, neurohistopathology, and schedule-controlled operant behavior endpoints. The data presented here are relevant to the neurotoxicity risk assessment of n-butanol due to the rapid hydrolysis of n-butyl acetate in vivo.

Dermal absorption and pharmacokinetics of isopropanol in the male and female F-344 rat.

Isopropanol (IPA), as a 70% aqueous solution, was applied under occluded conditions to the shaved backs of male and female Fischer F-344 rats for a period of 4 hr. Maximum analyzed blood concentrations of IPA were attained at 4 hr and decreased steadily following removal of the test material. Blood concentrations were below the limit of quantification at 8 hr. Acetone (ACE) blood levels rose steadily during the 4-hr exposures and continued to rise following removal of the test material, reaching peak analyzed levels at 4.5 hr (male) and 5 hr (females). ACE blood concentrations were below the limit of quantification at 24 hr. Basic pharmacokinetic parameters were similar for male and female rats with mean, first-order elimination half-lives for IPA and ACE of 0.8 to 0.9 hr and 2.1 to 2.2 hr, respectively. Following iv administration of [14C]IPA, 50-55% of the dose was eliminated as 14CO2 with lesser amounts recovered as expired volatiles or in urine. Total recoveries following iv administration were 83% for both males and females. Following a 4-hr dermal exposure to [14C]IPA (70% aqueous solution), 84-86% of the dose was recovered from the application site. Dermal absorption rates were calculated by two independent methods. The values obtained were 0.78 +/- 0.03 and 0.85 +/- 0.04 mg/cm2/hr for males and 0.77 +/- 0.13 and 0.78 +/- 0.16 mg/cm2/hr for females. Calculated permeability coefficients of 1.37 to 1.50 x 10(-3) cm/hr for males and 1.35 to 1.37 x 10(-3) cm/hr for females indicate that in the rat, IPA is rapidly absorbed dermally when applied under occluded conditions.

Developmental toxicity study of inhaled acrylic acid in New Zealand White rabbits.

In range-finding and definitive developmental toxicity studies, timed pregnant New Zealand White rabbits were exposed to acrylic acid (CAS No. 79-10-7) vapour for 13 consecutive days during pregnancy. In the range-finding study, eight pregnant does/group were exposed to 30, 60, 125 or 250 ppm acrylic acid vapour on gestation days (gd) 10-22 of pregnancy. Monitors of toxicity included body weight measurements, daily food consumption measurements and clinical observations. Three of the eight does/group were killed on the day following the last exposure (gd 23), and the remaining does were killed and autopsied on gd 29. At autopsy, special attention was given to gross observation of maternal nasal turbinates, and nasal turbinates from all does were evaluated histologically. No evaluation of foetuses was performed in the range-finding study. In the definitive study, 16 does/group were exposed to concentrations of 25, 75 or 225 ppm acrylic acid vapour from gd 6 to 18, the major period of organogenesis. Monitors of maternal toxicity included clinical observations and measurements of body weight and daily food consumption measurements. Does were killed and autopsied on gd 29. Maternal liver and kidney weights were measured and external, visceral and skeletal evaluations of foetuses were conducted. Maternal nasal turbinates were not evaluated histologically in the definitive study. Effects in does from both studies included consistent concentration-related reductions in food consumption and body weight gains throughout the exposure period at concentrations of acrylic acid vapour above 60 ppm. Characteristic clinical signs of sensory irritation, including perinasal and perioral wetness and severe nasal congestion, were noted in does from both studies at or above vapour concentrations of 75 ppm. Gross observation of nasal turbinates immediately following exposures in the range-finding study indicated colour changes in the nasal turbinates of does in the 60 and 250 ppm groups. Colour changes in the nasal turbinates were noted in one doe from the 250 ppm exposure group killed on gd 29. Pertinent autopsy findings in the does from the definitive study included ulceration of the nasal turbinates of a single doe in the 225 ppm group. Histological evaluation of turbinates from does killed the day following exposures in the range-finding study revealed lesions in the nasal epithelium in all acrylic acid-exposed groups. The severity of the lesions was concentration related. Microscopic evaluation of turbinates from does killed on gd 29 showed the presence of nasal lesions in the 60, 125 and 250 ppm groups. However, the nasal tissues had recovered considerably during the post-exposure interval. Despite the severe effects on the nasal mucosa of does in both studies, there was no evidence of developmental toxicity including teratogenicity at any exposure concentration used in the definitive study.

The psychology of legitimacy: a relational perspective on voluntary deference to authorities.

People within organized groups often internalize their feelings of obligation to obey group rules and the decisions of group authorities. They believe that group authorities and rules are legitimate and, hence, entitled to be obeyed. Because of this belief, group members voluntarily accept and obey rules and decisions from group authorities. This review draws on evidence from studies of authorities in political, legal, managerial, educational, and family settings to explore why people view as legitimate and voluntarily defer to group authorities. Two theories about legitimacy are contrasted: resource-based theories, represented by instrumental models, and identification-based theories, represented by the relational model. The findings provide strong support for the existence of a relational component of legitimacy, suggesting that authorities draw an important part of their legitimacy from their social relationship with group members. The findings also show that there is an instrumental component to legitimacy. Hence, the psychology of legitimacy involves both instrumental and relational elements.

Pharmacokinetics and material balance studies of diethylenetriamine trihydrochloride in the Fischer 344 rat following oral, endotracheal or intravenous dosing.

The metabolism and disposition of diethylenetriamine trihydrochloride (DETA.3HCl) were studied with regard to route of administration and dosage effects. Male Fischer 344 rats were administered 50 or 500 mg kg(-1) of [1,2-(14)C]-DETA.3HCl orally or endotracheally, and the fate of the 14C-radioactivity was followed for 48 h. The DETA.3HCl was readily absorbed from the gut or the lung, with bioavailabilities of 95% and 90%, respectively. It was distributed throughout the body, with the kidney attaining the highest concentration (about 2.5-5 times that of blood). The apparent volume of distribution determined from plasma concentration data following intravenous dosing (50 mg kg[-1]) was 486 ml kg(-1), consistent with distribution in the total body water. Urine and feces were the major routes of excretion, with only a small fraction eliminated as CO2. Excretion was quite rapid, with over 96% of the dose eliminated within 48 h. The principal component in the urine was unchanged DETA, suggesting that DETA.3HCl was not extensively metabolized. While the major metabolites has not been identified, there was evidence that DETA.3HCl was neither metabolized to ethylenediamine nor to the acid conjugates. There was indication that the metabolism of DETA.3HCl was saturated at 500 mg kg(-1), as there was a shift to a higher proportion of unchanged DETA excreted in the urine. There were no significant differences in material balance or pharmacokinetic parameters among animals receiving DETA.3HCl by the oral or endotracheal routes of administration.

Isopropanol: summary of TSCA test rule studies and relevance to hazard identification.

The toxicity of isopropanol (IPA) has been extensively studied as a result of a Test Rule under Section 4 of the Toxic Substances Control Act. In general, the data showed that IPA has a low order of acute and chronic toxicity; does not produce adverse effects on reproduction; is neither a teratogen, a selective developmental toxicant, nor a developmental neurotoxicant; and is not genotoxic or an animal carcinogen. IPA is, however, a potential hazard for transient central nervous system depression at high exposure levels. In addition, IPA produced effects to several rodent toxicity endpoints at high dose levels (i.e., motor activity, male mating index, and exacerbated renal disease) which are of unclear relevance to human health. The data generated by these studies confirmed that IPA acts as a typical short-chain alcohol in mammalian biological systems. It produces a significant narcotic effect upon exposure at high levels for extended periods of time, with no irreversible effects even after repeated exposure, which is consistent with other short-chain alcohols. The metabolism of IPA appears equivalent across species with rapid conversion to acetone and carbon dioxide. Overall, these studies demonstrate IPA exposure is a low potential hazard to human health. This information will allow for an improved assessment of the human health risks from IPA exposure.

Oncogenicity testing of 2-ethylhexanol in Fischer 344 rats and B6C3F1 mice.

2-Ethylhexanol (2EH) is a weak nongenotoxic hepatic peroxisome proliferator in the rat. It is a high-volume chemical intermediate in the preparation of the plasticizers bis-(2-ethylhexyl) adipate (DEHA), bis-(2-ethylhexyl) phthalate (DEHP), and tris-(2-ethylhexyl) phosphate (TEHP), which are weak hepatocellular tumorigens in female mice. In consequence, the oncogenic potential of 2EH was evaluated in male (M) and female (F) rats and mice (50 animals/sex/group). Oral gavage doses of 2EH in 0.005% aqueous Cremophor EL (polyoxyl-35 castor oil) were given five times a week to rats: 0 (water), 0 (vehicle), 50, 150, and 500 mg/kg for 24 months, and to mice: 0 (water), 0 (vehicle), 50, 200, and 750 mg/kg for 18 months. Statistical comparisons of data were made between vehicle controls and treatment groups. There were no differences of biological significance between data from vehicle and water control groups. In rats, there were no dose-related changes at 50 mg/kg. There was reduced body weight gain at 150 mg/kg (M, 16; F, 12%) and 500 mg/kg (M, 33; F, 31%) and an increased incidence of lethargy and unkemptness. There were dose-related increases in relative liver, stomach, brain, kidney, and testis weights at sacrifice. Female rat mortality was markedly increased at 500 mg/kg. There was marked aspiration-induced bronchopneumonia in rats at 500 mg/kg; hematologic, gross, and microscopic changes, including tumors, were otherwise comparable among all rat groups. In mice at 50 and 200 mg/kg there were no dose-related changes and essentially no time-dependent or time-independent adverse trends in liver tumor incidence at the 5% significance level. At 750 mg/kg mouse body weight gain was reduced (M, 26; F, 24%), and mortality increased (M and F, 30%) versus vehicle controls. At 750 mg/kg there was a slight increase in nonneoplastic focal hyperplasia in the forestomach of mice (M 5/50, F 4/50) versus vehicle controls (M 1/50, F 1/50). There were increases in mouse relative liver (F, 21%) and stomach (M, 13%; F, 19%) weights at 750 mg/kg. There was a 12% incidence of hepatic basophilic foci and an 18% incidence of hepatocellular carcinomas in male mice at 750 mg/kg, not statistically significant compared with either control by Fisher's exact test. There was a 12% incidence of hepatic basophilic foci and a 10% incidence of hepatocellular carcinomas in female mice at 750 mg/kg, statistically significant (p < 0.05) compared with vehicle but not with water controls by Fisher's exact test. There were no metastases. Time-dependent and -independent statistical analyses showed an adverse trend in the incidence of hepatocellular carcinomas in male and female mice, correlated with toxicity (expressed as mortality) at 750 mg/kg. The time-adjusted incidence of hepatocellular carcinomas in male mice (18.8%) was within the historical normal range at the testing facility (0-22%), but that in females (13.1%) lay outside the normal range (0-2%). Under the conditions of these studies 2EH was not oncogenic in rats, but there were weak adverse trends in hepatocellular carcinoma incidence in mice at high dose levels which may have been associated with toxicity. The major effects of chronic dosing were mortality in female rats at 500 mg/kg and in male and female mice at 750 mg/kg, accompanied by reductions in body weight gain in rats at 150 and 500 mg/kg and in mice at 750 mg/kg. Direct comparison of any tumorogenic effects of 2EH given alone to female mice with those due to 2EH formed in vivo from DEHA, DEHP, or TEHP is limited by the high mortality caused by 2ER in female mice at equivalent doses of 2EH. While 2EH may be a contributing factor in the hepatocellular carcinogenesis in female mice associated with the chronic administration of DEHA and DEHP, it is unlikely to be the entire proximate carcinogen.

Prechronic toxicity studies on 2-ethylhexanol in F334 rats and B6C3F1 mice.

Data on the subchronic toxicity of 2-ethylhexanol (2EH) were required to establish the dose vehicle and dose levels for oncogenicity studies. In preliminary studies 2EH was given subacutely (11 days) to male and female Fischer 344 rats and B6C3F1 mice as an aqueous emulsion by oral gavage (0, 100, 330, 1000, and 1500 mg/kg/day). Clinical observations were made, body weights, food consumption, clinical chemistries, hematologies, and selected organ weights were measured, and gross and micropathologies were performed. Target organs were the central nervous system, liver, forestomach, spleen, thymus, and kidney in rats and the central nervous system, liver, and forestomach in mice. 2EH was then administered by oral gavage to male and female F344 rats and B6C3F1 mice as an aqueous emulsion (0, 25, 125, 250, and 500 mg/kg/day) for 13 weeks. At 500 mg/kg/day in the rat there was reduced body weight gain (6% male, 7% female), increased relative liver (29% male, 15% female), kidney (16% male, 6% female), stomach (11% male, 16% female), and testes (6%) weights, and moderate gross and microscopic changes in the liver and forestomach. There were no behavioral effects or effects on the spleen or thymus. A no-effect level for target organ effects in the rat was 125 mg of 2EH/kg/day. At 500 mg of 2EH/kg/day in the mouse the only effects were increased relative stomach weights in males (13%) and a low incidence of gross and microscopic findings in the forestomach (male and female) and liver (female). A no-effect level for target organ effects in the mouse was 125 mg of 2EH/kg/day. 2EH was a peroxisome proliferator in the rat but not in the mouse at subchronic dose levels of 500 mg/kg/day. Dose levels in oncogenicity studies were set at 50 mg/kg/day for the absence of treatment-related effects in rats and mice, and 500 and 750 mg/kg/day, respectively, in rats and mice as high doses producing minimal toxicity without altering the life span.

Two-generation reproduction toxicity study with isopropanol in rats.

A two-generation reproduction toxicity study was conducted in rats with isopropanol. Thirty rats of each sex per group (P1) were dosed once daily by oral gavage with 0, 100, 500 or 1000 mg isopropanol kg-1 for at least 10 weeks prior to mating. Parental animals were mated within groups for up to 3 weeks. Parental females were dosed during mating, gestation and lactation; parental males were dosed during mating through delivery of their last litter sired. The P2 adults were selected from the F1 litters and were dosed for 10-13 weeks before mating to produce a single litter. Findings in the parental animals included increased lactation body weight gain in the mid- and high-dose females, increased liver and kidney weights in the mid- and high-dose groups of both sexes and centrilobular hepatocyte hypertrophy in some P2 males. There was also accumulation of hyaline droplets and other microscopic findings in the kidneys from the mid- and high-dose P1 males and from all treated groups of the P2 males. Increased mortality was observed in the high-dose F1 offspring during the early postnatal period, although no other clinical signs of toxicity were observed in the offspring of either generation. In addition, offspring body weight was reduced during the early postnatal period in the high-dose F1 males and in the high-dose F2 pups of both sexes. Eighteen out of 70 F1 weanlings in the 1000 mg kg-1 group died or were euthanized prior to P2 selection. No treatment-related post-mortem findings were observed in the offspring from either generation.(ABSTRACT TRUNCATED AT 250 WORDS)