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.

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)

Isopropanol: acute vapor inhalation neurotoxicity study in rats.

Five groups of 25 Fischer 344 rats of each sex were exposed for 6 h to isopropanol vapor at 0, 500, 1500, 5000 or 10,000 ppm. Behavioral observations for 10 rats of each sex were made prior to and 1, 6, and 24 h after exposure. Motor activity was evaluated for 15 rats of each sex prior to and immediately following exposure. Exposure to isopropanol caused a spectrum of transient effects indicative of narcosis at 10,000 ppm and sedation at 5000 ppm. Prostration or severe ataxia, decreased arousal, slowed or labored respiration, decreased neuromuscular function, hypothermia and loss of reflex function were observed 1 and 6 h after exposure to 10,000 ppm isopropanol vapor. Similar, but less severe, alterations were observed in animals in the 5000 ppm exposure group 1 h after exposure. Exposure concentration-related decreases in motor activity were observed in males and females in the 5000 and 10,000 ppm groups and slight decreases in motor activity were observed in males in the 1500 ppm group. Animals in the 1500 and 5000 ppm exposure groups recovered from these motor activity effects within 5 h. Based on this study, exposure of male and female rats to isopropanol vapor produces transient, concentration-related narcosis and/or sedation at concentrations of 5000 and 10,000 ppm and minor decreases in motor activity in males at a concentration of 1500 ppm. The no-observed-effect level (NOEL) for this was 500 ppm isopropanol.

Disposition and pharmacokinetics of isopropanol in F-344 rats and B6C3F1 mice.

The absorption, metabolism, disposition, and excretion of isopropanol (IPA) were studied in male and female rats and mice. Animals were exposed by i.v. (300 mg/kg) and inhalation (500 and 5000 ppm for 6 hr) routes; additionally, IPA was given by gavage to rats only in single and multiple 300 and 3000 mg/kg doses. In the rat approximately 81-89% of the administered dose was exhaled (as acetone, CO2, and unmetabolized IPA); approximately 76% of the dose in mice was exhaled after i.v. bolus but 92% was exhaled following inhalation. Approximately 3-8% of the administered dose was excreted in urine as IPA, acetone, and a metabolite tentatively identified as isopropyl glucuronic acid. Small amounts of radiolabel were found in feces and in the carcass. There were no major differences in the rates or routes of excretion observed either between sexes or between routes of administration. Additionally, repeated exposure had no effect on excretion. However, both the route of administration and the exposure or dose level influenced the form in which material was exhaled. Following exposure to 5000 ppm, a greater percentage of unmetabolized IPA was recovered in the expired air than following exposure to 500 ppm, implying saturation of metabolism.

Developmental neurotoxicity evaluation of orally administered isopropanol in rats.

Isopropanol was administered by gavage to timed-mated rats from Gestation Day (GD) 6 through Postnatal Day (PND) 21. Doses administered were 0, 200, 700, or 1200 mg/kg/day in a volume of 5 ml/kg. The dams were allowed to deliver and body weights and food consumption were recorded during gestation and lactation. Pups were counted, examined, sexed, and weighed on PND 0, 4, 7, 13, 17, 21, 36, 49, and 68. Litters were culled to eight pups (4:4 or 5:3 sex ratio) on PND 4 and litters without acceptable numbers of male and female pups were eliminated from the study. Pups were weaned on PND 22, and two pups from each litter and their dams were killed. Six of these pups from each dose group were perfused in situ for histopathological examination of the central and peripheral nervous system. Brains of the remaining pups were divided into four regions and weighed. Maternal liver and kidney weights were recorded. Weaned pups were assessed for day of testes descent or vaginal opening and for motor activity on PNDs 13, 17, 21, 47, and 58; auditory startle on PNDs 22 and 60; and active avoidance on PNDs 60-64. These pups were euthanized and examined on PND 68. One high-dose dam died on PND 15, but there were no other clinical observations or effects on maternal weight, food consumption, or gestation length. Pup survival, weight, sex ratio, and sexual maturation were unaffected. There were no biologically significant findings in the behavioral tests, no changes in organ weights, and no pathological findings that could be attributed to isopropanol exposure. In conclusion, there was no evidence of developmental neurotoxicity associated with isopropanol exposure as high as 1200 mg/kg/day.

Developmental toxicity evaluation of isopropanol by gavage in rats and rabbits.

Timed-pregnant CD (Sprague-Dawley) rats, 25/group, were dosed orally with aqueous isopropanol (IPA; CAS No. 67-63-0) solutions at 0, 400, 800, or 1200 mg/kg/day, once daily on Gestational Days (GD) 6 through 15 at a dosing volume of 5 ml/kg. Artificially inseminated New Zealand white rabbits, 15/group, were dosed orally with IPA at 0, 120, 240, or 480 mg/kg/day once daily on GD 6 through 18 at 2 ml/kg. Maternal body weights, clinical observations, and food consumption were recorded throughout gestation for both species. At scheduled euthanization for both species (GD 20, rats; GD 30, rabbits), fetuses were weighed, sexed, and examined for external, visceral (including craniofacial) and skeletal alterations. For both species, the pregnancy rate was high and equivalent across all groups; no dams or does aborted, delivered early, or were removed from study. In rats, two dams (8%) died at 1200 mg/kg/day and one dam (4%) died at 800 mg/kg/day. Maternal body weights and weight gain were equivalent across all groups, except for statistically significantly reduced gestational weight gain (GD 0-20; 89.9% of control value), associated with statistically significantly reduced gravid uterine weight at 1200 mg/kg/day (89.2% of control value). There were no treatment-related clinical signs or effects on maternal food consumption. All gestational parameters evaluated were equivalent across groups, including pre- and postimplantation loss, fetal sex ratios, and litter size. Twenty-two to 25 litters were examined per group. Fetal body weights per litter were statistically significantly reduced at the two highest doses (97.3 (n.s.), 94.7, and 94.3% of controls at 800 mg/kg/day and 92.1, 91.9, and 95.4% of controls at 1200 mg/kg/day for all fetuses and males and females separately). No evidence of increased teratogenicity was observed at any dose tested in rats. In rabbits, four does (26.7%) died at 480 mg/kg/day. Maternal body weights were statistically significantly reduced during treatment (GD 6-18) at 480 mg/kg/day (45.4% of control value) with a nonsignificant reduction in gestational weight change (GD 0-30; 77.3% of control value) at this dose. Profound clinical signs of toxicity and statistically significantly reduced maternal food consumption were observed at 480 mg/kg/day. All gestational parameters were equivalent across all doses administered. Thirteen to 15 litters were evaluated per group except for the 480 mg/kg/day group with 11 litters (due to maternal deaths). There were no treatment-related effects on pre- or postimplantation loss, fetal sex ratio, litter size, or fetal body weight/litter. Moreover, no evidence was found of increased teratogenicity at any dose tested in rabbits. Therefore, IPA was not teratogenic to CD rats or to NZW rabbits. The NOAELS for both maternal and developmental toxicity were 400 mg/kg/day in rats, and were 240 and 480 mg/kg/day, respectively, in rabbits.

In vitro and in vivo assays of isopropanol for mutagenicity.

To assess the mutagenic potential of isopropanol, an in vitro Chinese hamster ovary (CHO) cell/HGPRT gene mutation assay and a bone marrow micronucleus study in mice were conducted. In the CHO/HGPRT assay, concentration levels ranged from 0.5 to 5.0 mg/ml. No elevated mutant frequencies attributable to treatment were observed in the test under either activated or non-activated conditions. In the micronucleus assay, mice were injected intraperitoneally (IP) with either 350, 1,173, or 2,500 mg/kg of isopropanol at constant volumes of 10 ml/kg. No increased incidence of micronuclei was observed in bone marrow polychromatic erythrocytes (PCEs) harvested at 24, 48, or 72 hr post-dosing. In both assays, negative and positive control mutant frequencies were within historical control ranges. These results, in conjunction with previously published data, clearly demonstrate that isopropanol is not a mutagen.

Glycidyloxy compounds used in epoxy resin systems: a toxicology review.

The glycidyloxy compounds constitute an important group of chemicals used extensively in the formulation of epoxy resin systems employed in coatings, electronics, structural composites, and adhesives. Although extensive toxicological data are available on glycidyloxy compounds, use and understanding of the data have been hampered by two major problems: (1) proper identification and complexity of the epoxy systems in question, and (2) absence of meaningful classification of epoxy materials. This paper provides a classification scheme with CAS numbers and reviews the mammalian toxicology of the most common glycidyloxy derivatives used in epoxy resin systems based on both published and proprietary information. Although the toxicity of many of the glycidyloxy compounds used in epoxy resin systems can be characterized as low, the diversity of compounds found within this group precludes broad generalizations for the class. This comprehensive account should facilitate a clearer understanding of the potential health effects and allow for easier comparison among compounds containing the glycidyloxy moiety.

Subchronic feeding study of decarboxyfenvalerate in rats.

Groups of 30 male and 30 female Fischer-344 rats were fed dietary concentrations of 0, 30, 100, 300, 3000, or 10,000 ppm decarboxyfenvalerate (DC-FEN) for up to 13 wk. An interim kill of 10 rats/sex X group was performed at 7 wk. Following 7 or 13 wk of dietary treatment, groups of rats were necropsied, which included evaluation of hemocellular, hemochemical, and uretic parameters, selected absolute and relative organ weights, and macroscopic and microscopic observations. DC-FEN did not affect mortality. Body weight was decreased in male rats fed 10,000 ppm DC-FEN. Statistically and toxicologically significant differences in clinicopathologic parameters were observed at either the highest or two highest exposure levels. Some statistically significant differences were noted in some hemocellular and/or hemochemical parameters at either 100 or 300 ppm. These subtle changes were either not dose-related, inconsistent, or not of sufficient difference to be determined to have biological significance. Absolute and relative liver weights of male and female rats fed greater than or equal to 300 ppm DC-FEN were all higher than control values except for absolute weights in female rats (300 ppm) at the interim kill. Consistent significant increases in absolute or relative kidney weights were observed in male and female rats fed 3000 or 10,000 ppm DC-FEN. Other statistically significant differences in absolute and/or relative organ weights were seen primarily where the higher doses had caused decreased carcass weight. Macroscopic treatment-related liver enlargement (hepatomegaly) was observed in male and female rats fed 3000 or 10,000 ppm DC-FEN. Only one female rat fed 300 ppm DC-FEN had hepatomegaly at the terminal kill. Significant treatment-related microscopic effects were limited to glomerulonephrosis in male and female rats fed 10,000 ppm and hepatocellular hypertrophy and other associated liver changes in male and female rats fed 3000 or 10,000 ppm DC-FEN. Liver effects at doses less than 3000 ppm were indicative of a physiologic adaptive response and were not toxicologically significant. Therefore, the biologically significant no-effect level was 300 ppm.

Effect of vitamin E and other amelioratory agents on the fenvalerate-mediated skin sensation.

Previous investigations have demonstrated that dermal exposure to fenvalerate or other synthetic pyrethroid insecticides can produce a skin sensory response characterized by an itching/tingling sensation in humans and animals. The objective of this investigation performed in guinea pigs was to establish treatments which would be effective against pyrethroid-mediated skin sensation. Two classes of agents were tested. Barrier agents, which block penetration of substances through the skin, did not significantly reduce the fenvalerate-mediated skin sensations. Post-treatments with steroidal Dermolate, antihistamine Delamine or anti-inflammatory aspirin did not significantly reduce the pyrethroid-mediated skin sensation. However, Bicozene (a local anesthetic cream) and Tashan (a vitamin A, D, and E-containing cream) were effective in reducing the pyrethroid-mediated skin sensations. Prior (30 min and 5h) dermal application of vitamin E was found to be effective in significantly reducing the fenvalerate-mediated skin sensation; even when applied 29 h prior to fenvalerate exposure, there appeared to be a reduced skin response. Piperonyl butoxide (PBO), a pesticide synergist, reduced the fenvalerate skin sensations when applied either directly to the skin or in conjunction with the pyrethroid.

Pyrethroid-mediated skin sensory stimulation characterized by a new behavioral paradigm.

Occupational exposures to pyrethroids have been associated with skin sensory effects characterized by transient itching/tingling sensations. This effect had not been detected in "Draize" skin irritation tests and exists in the absence of visible skin irritation. The objective of this investigation was to develop an animal model to study this phenomenon. Guinea pigs were treated with pyrethroid solutions on one side of their shaved back and control substances on the other side. The animals responded by licking, rubbing, scratching, or biting the test sites and activity was quantified by counting the number of times the animals responded to pyrethroid or control treated sites. Animals responded to pyrethroid more than to control substances and this behavioral activity was apparently maximum during the first hour and essentially over by the fourth hour after treatment. The sensory response did not directly correlate with overt visible signs of skin irritation. However, a chemical irritant (oil of mustard) was able to restimulate the behavioral activity when applied within 24 hr after pyrethroid application. Skin sensory stimulation produced by cyano-containing synthetic pyrethroids was significantly greater than that produced by a non-cyano-containing pyrethroid. This behavioral model provides a quantitative means to evaluate pyrethroid nonerythematous skin sensory stimulation.

Six-month feeding study of fenvalerate in dogs.

Groups of six male and six female Beagle dogs were fed diets containing 0, 250, 500, or 1000 ppm fenvalerate for a period of 6 months. Prominent in-life observations related to treatment were emesis, head shaking, biting of the extremities, ataxia, and tremors. One high-dose male dog was sacrificed in extremis during the study period. Mean body weights of 1000-ppm female dogs were significantly lower than those of controls. Red blood cell counts and hematocrit and hemoglobin values in high-dose male and female dogs were significantly lower than those of controls at most sampling intervals. Serum cholesterol and alkaline phosphatase levels were also increased primarily in the high-dose group. Ophthalmic examination revealed changes in retinal vessel tortuosity in some mid- and high-dose dogs. Hepatic multifocal microgranulomata were observed in control and treated dogs microscopically. These changes increased in incidence and severity with dose and were considered to be related to treatment. Histiocytic cell infiltrate in mesenteric lymph nodes in some 500- and 1000-ppm female and 1000-ppm male dogs was the only other treatment-related microscopic effect.

Uptake and release of 14C-morphine by pulmonary endothelium and cultured pulmonary endothelial cells.

1. Isolated perfused rabbit lungs and cultured pulmonary endothelial cells take up radiolabeled [14C]morphine in proportion to the amount of labeled drug in the medium. 2. The accumulated label is readily released from the isolated lungs by perfusion with unlabeled morphine or naloxone, but not by perfusion with Krebs-Ringer solution, sucrose or thiopental. 3. Thiourea also enhances efflux of radioactivity, suggesting that the release is not related to interaction with specific opiate receptors. 4. Uptake of [14C]morphine by cultured rabbit or human endothelial cells is unaffected by morphine or naloxone, and the release of radioactivity is not enhanced by these agents. 5. None of the drugs used caused pulmonary edema in the isolated lung preparation, and they did not cause the release of lactic dehydrogenase from cultured endothelial cells. 6. It is concluded that morphine can be taken up by pulmonary endothelium, but it is probably not bound to specific receptors, and it does not injure the endothelial cells.

Cyanide concentrations in blood after amygdalin (laetrile) administration in rats.

Toxic amounts of cyanide are released into the blood of rats following the oral administration of amygdalin (laetrile); cyanide blood concentrations and toxicity are markedly less when amygdalin is given intravenously. Analysis of the time course of cyanogenesis suggests that cyanide could accumulate in blood after repeated oral doses of amygdalin.

Distribution of clozapine in the rat: localization in lung.

To determine the distribution of the antipsychotic agent, clozapin (CLZ), a fluorometric procedure for its estimation was devised, and the drug was measured in various tissues of rats after i.p. injection (20 mg/kg). In a 24-hour urine collection, less than 1% injected drug was found. After 1 hour, CLZ concentrations were greatest in lung, spleen, liver and brain (16-64 microgram/g). After 6 hours, CLZ levels in lung remained at 52 microgram/g, whereas concentrations in all other tissues declined to less than 7 microgram/g. When rat lung slices were incubated (O2, 37 degrees C) in CLZ solution (20 microgram/ml), the drug was taken up by the tissue against a concentration gradient, attaining a maximum tissue/medium ratio of 97 after 4 hours. When the concentration of CLZ was raised from 2 to 200 microgram/ml the 1-hour tissue/medium ratio declined from 89 to 21. Chlordiazepoxide, amphetamine and morphine depressed the 1-hour tissue/medium ratio of CLZ by 34 to 50%. CLZ uptake was also decreased 19% by anaerobic conditions and 25% by the presence of 2,4-dinitrophenol. The results suggest that the lung is a site of (active) transport and accumulation for CLZ and perhaps certain other basic drugs.

Quantitative changes in permeability of rat lung epithelium in lung edema.

The pulmonary absorption of 14C-labeled urea, mannitol, inulin, and dextran was measured in vivo in anesthetized rats with alpha-naphthylthiourea (ANTU)-induced (5 mg/kg, ip) lung edema. At 1 h after ANTU treatment, the absorption of mannitol was significantly increased; in 4-h ANTU-treated animals, the absorption of urea was unchanged, whereas the absorption of mannitol, inulin and dextran was increased markedly compared to controls. Although disappearance of each solute from control lungs could be described by a single, first-order rate, absorption time curves for mannitol and inulin showed at least two components in edematous lungs: a fast component(s) and a slower, first-order component; fast-component rates for the two saccharides appeared to be similar; the slow-component rate for each compound was not significantly different from its control rate. The results suggest that fast-component absorption in ANTU-treated rats represents a fraction of instilled solute which entered damaged areas of lung where the porosity of the absorbing membranes was markedly increased, whereas slow-component absorption occurred from normal areas of lung.

Characteristics of 45Ca uptake and efflux in rat lung slices.

The distribution and movements of 45Ca were investigated in lung slice preparations obtained from rats. The accumulation of 45Ca was measured in either 5.0 mM Ca2+, 0.5 mM Ca2+ or 0-Ca solutions. The 45Ca tissue to medium ratio was greatest in the 0-Ca solution; the presence of either 5.0 mM Ca2+ or 0.5 mM Ca2+ reduced this ratio 8- and 5-fold, respectively. Efflux of 45Ca indicated that there are at least two washout components. Exposure to either La3+ or Sr2+ (0.5 mM) during the washout resulted in a transient increase in 45Ca efflux (Sr2+ greater than La3+), whereas 0 degrees C slowed the loss of 45Ca. Uptake of 45Ca was increased by the metabolic inhibitor iodoacetic acid and inhibited in the presence of either La3+ or Sr2+. These findings indicate that the 45Ca accumulated within the lung is not readily depleted and a portion appears to accumulate at intracellular or less superficial sites or stores.

Effect of pulmonary edema on drug transport and binding in rat lung.

The pulmonary absorption and uptake of (35S)phenol red ((35S)PR was measured in anesthetized rats with alpha-naphthylthiourea- (ANTU) induced lung edema. When (35S)PR solution was injected through a tracheal cannula in control animals and the percentage of the tracheal cannula in control animals and the percentage of the dose unabsorbed plotted semilogarithmically against time, an apparent first-order absorption rate was obtained. In contrast, in rats with ANTU-induced edema, the absorption time curve showed at least two different first-order components. Increasing the concentration of (35S)PR from 0.01 to 3 mM resulted in a decrease in the percentage absorption of the compound in controls compared with a relatively constant percentage absorption in edematous lungs. (35S)PR uptake by lung slices from ANTU-treated rats was decreased in the presence of IAA and a N2 atmosphere, and the dye accumulated at a faster rate and to a greater extent than in controls. The results suggest that although energy-dependent drug transport mechanisms remain intact, the porosity of the absorbing membranes and the extent of drug binding in the lung are increased markedly in the presence of edema.