A chronic inhalation toxicity/oncogenicity study of methylethylketoxime in rats and mice.

To evaluate the oncogenic potential of methylethylketoxime (MEKO), CD-1 mice (50/sex/group) and F-344 rats (50/sex/group) were coexposed 6 h/day, 5 days/wk for 18 mo (mice) or 26 mo (rats) via whole-body inhalation exposures to target vapor concentrations of 0, 15, 75, and 375 ppm (actual concentrations of 0, 15 +/- 1, 75 +/- 2, or 374 +/- 10 ppm). Satellite groups of rats and mice (10/sex/group/interval) were exposed for 12 mo (mice) and 3, 12, or 18 mo (rats) to evaluate chronic toxicity. Methyl ethyl ketone (MEK), a possible hydrolysis product of MEKO, was present at less than 1%. Treatment-related effects included increased body weight (male rats only), methemoglobin formation, hematology and clinical chemistry changes, increased liver weight, and increased spleen and testes weights (rats only). A high incidence of cataracts and corneal dystrophy occurred in both control and MEKO-exposed rats, with an earlier appearance and slightly higher incidence for these ocular lesions in MEKO-exposed animals compared to controls. Degenerative and reparative changes of the olfactory epithelium in the nasal turbinates, primarily limited to the dorsal meatus, occurred in both rats (75 and 374 ppm) and mice (15, 75, and 374 ppm). In addition, in the mice, liver changes included increased incidences of pigment in reticuloendothelial cells, centilobular hypertrophy, granulomatous inflammation, and a slightly increased incidence of necrosis (75 and 374 ppm). An increase in hepatocellular carcinomas occurred in male mice at 374 ppm. Additional MEKO-related findings in the rat included congestion of the spleen with pigment in reticuloendothelial cells and extramedullary hematopoiesis and a decreased incidence of lymphoreticular mononuclear cell leukemia. Effects observed in the liver of the rats included decreases in the incidence of both peribiliary fibrosis and hyperplasia/proliferation of the biliary duct, an increase of spongiosis hepatis in males, and an increase in the incidence of intracytoplasmic vacuoles and hepatocellular basophilic foci. The effects on the liver were generally most profound in the high-exposure groups and, with the exception of the spongiosis hepatis, occurred in both sexes. An increase in hepatocellular adenomas occurred in the male rats at 75 and 374 ppm, and hepatocellular carcinomas in the male rats at 374 ppm. In both species, the liver tumors appeared relatively late in the life of the animals, with no significant increase in tumors at 12 mo of exposure in mice and at 18 mo of exposure in rats. Lifespan shortening was not observed, as MEKO-exposed animals survived generally as well as, or slightly better than, the controls.

Methyl bromide 1-year dietary study in dogs.

Average human exposure resulting from consumption of methyl I bromide (MB)-fumigated food has been estimated to be 0.00125 mg/kg/day. A 1-yr feeding study in beagle dogs was conducted as a safety study in which the high-dose diet was intended to yield a methyl bromide dose of at least 100 times the calculated human dietary exposure. Diets were fumigated with MB and fed to the dogs daily, except for weekends and holidays. MB consumption each feeding day was calculated as a time weighted average (TWA) that accounted for the rate of degassing from the fumigated diet and the rate of feed consumption during the feeding period. TWA compound consumption in the loss-, mid- and high-dose groups, respectively, averaged 0.06 ¿ 0.02, 0.13 ¿ 0.03 and 0.28 ¿ 0.08 mg/kg/day in males and 0.07 ¿ 0.03, 0.12 ¿ 0.03 and 0.27 ¿ 0.09 mg/kg/day in females. Clinical observations, body weight and feed consumption, ophthalmology, clinical pathology, urinalysis, organ weights and macroscopic and microscopic pathology were comparable in control and MB-treated dogs. Under the conditions of this study. the no-observed-effect level (NOEL) for MB was at least 0.28 mg/ kg/day, or approximately 200 times the expected average human dietary exposure.

Subchronic inhalation toxicity study of caprolactam (with a 4-week recovery) in the rat via whole-body exposures.

This study was designed to assess the potential subchronic inhalation toxicity of caprolactam when administered as a 3-micron aerosol from an aqueous solution to Sprague-Dawley CD rats (10/sex/group) via whole-body exposure. The study was enhanced with the inclusion of motor activity measurements and a functional observational battery to assess the neurotoxic potential of caprolactam. The rats were exposed at least 65 times over a 13-week period for 6 h per day, 5 days per week, to target concentrations (3 microns, mass median aerodynamic diameter) of 0, 25, 75, and 250 milligrams per cubic meter (mg/m3). An additional 10 animals/sex/group were similarly exposed and then held for a 4-week recovery period. Exposure levels were determined gravimetrically six times daily; one daily sample was analyzed by high-pressure liquid chromatography. No deaths were observed in the study during the exposure or recovery periods. Treatment-related responses such as labored breathing and nasal discharge were seen during many of the exposures. Similar responses as well as moist rales were seen during the nonexposure periods during the 13 weeks of exposure. However, these responses abated during the 4-week recovery period. There were no clearly treatment-related responses observed with ophthalmoscopic examinations, body weight measurements, food consumption measurements, neurobehavioral evaluations, clinical pathology evaluations, organ weight measurements, or macroscopic pathology examinations. Microscopic findings that were considered related to exposure to the test material were seen in the nasoturbinal tissues (hypertrophy/hyperplasia of goblet cells in the respiratory mucosa and intracytoplasmic eosinophilic material in epithelial cells of the olfactory mucosa) of the two higher-exposure group animals and in the laryngeal tissues (squamous/squamoid metaplasia/hyperplasia of the pseudostratified columnar epithelium covering the ventral seromucous gland) of all three exposure group animals. These changes were considered to be adaptive responses to an irritant (caprolactam). The keratinization of the metaplastic epithelium in the larynx was considered to be an adverse effect. By the end of the 4-week recovery period, there was complete regression of the keratinization in the larynx, but recovery of the adaptive nasoturbinal effects had not completely resolved. In conclusion, the whole-body exposure of Sprague-Dawley rats to caprolactam as a respirable aerosol for 6 h/day, 5 days/week, for 13 weeks at gravimetrically determined levels of 24, 70, and 243 mg/m3 resulted in respiratory tract effects (laryngeal) at the highest exposure level with complete recovery within 4 weeks postexposure. The results indicate that the no-observed-adverse-effect level for caprolactam is 70 mg/m3, based on upper respiratory effects, with 243 mg/m3 representing a no-observed-effect level for systemic toxicity, neurotoxicity, and lower respiratory tract effects.

Methyl bromide: 1-year dietary study in dogs.

Average human exposure resulting from consumption of methyl bromide (MB)-fumigated food has been estimated to be 0.00125 mg/kg/day. A 1-yr feeding study in beagle dogs was conducted as a safety study, in which the high-dose diet was intended to yield a methyl bromide dose of at least 100 times the calculated human dietary exposure. Diets were fumigated with MB and fed to the dogs daily, except for weekends and holidays. MB consumption each feeding day was calculated as a time weighted average (TWA) that accounted for the rate of degassing from the fumigated diet and the rate of feed consumption during the feeding period. TWA compound consumption in the low-, mid- and high-dose groups, respectively, averaged 0.06 +/- 0.02, 0.13 +/- 0.03 and 0.28 +/- 0.08 mg/kg/day in males and 0.07 +/- 0.03, 0.12 +/- 0.03 and 0.27 +/- 0.09 mg/kg/day in females. Clinical observations, body weight and feed consumption, ophthalmology, clinical pathology, urinalysis, organ weights and macroscopic and microscopic pathology were comparable in control and MB-treated dogs. Under the conditions of this study, the no-observed-effect level (NOEL) for MB was at least 0.28 mg/kg/day, or approximately 200 times the expected average human dietary exposure.

Subchronic and chronic inhalation toxicity of antimony trioxide in the rat.

Fischer 344 rats were exposed by inhalation to Sb2O3 (antimony trioxide) dust at exposure levels of 0, 0.25, 1.08, 4.92, and 23.46 mg/m3 for 6 hr/day, 5 days/week for 13 weeks followed by a 27-week observation period. Subsequently, an inhalation oncogenicity study was conducted at exposure levels of 0, 0.06, 0.51, and 4.50 mg/m3 for 12 months followed by a 12-month observation period. The Sb2O3 in the subchronic study had a mass median aerodynamic diameter (MMAD) of 3.05 +/- 0.21 microns (mean +/- SD) with a geometric standard deviation (GSD) of 1.57 +/- 0.06. In the chronic study, the MMAD was 3.76 +/- 0.84 and the GSD was 1.79 +/- 0.32. Except for the eyes, no adverse clinical observations were attributed to Sb2O3 in either study. In the subchronic study, corneal irregularities were seen after about 2 weeks of exposure and did not abate during the observation period. In the chronic study, ophthalmoscopic evaluation at 24 months revealed a dose-related increase in cataracts of 11, 24, 28, and 32% (both sexes combined) for each group, respectively. Body weights were significantly lower (6%) than the control group's weights in the 23.46 mg/m3 males in the subchronic study. These rats did not recover this weight during the 27-week observation period. Body weights of the females in both studies and males in the chronic study were unaffected. There were no Sb2O3 effects on clinical chemistry or hematology in either study. Mean absolute and relative lung weights were significantly increased in the 4.92 and 23.46 mg/m3 groups in the subchronic study. The 23.46 mg/m3 group's lung weights did not recover to control levels during the 27-week observation period. Lung weights for rats in the chronic study were unaffected. Microscopic changes in the lungs in the subchronic and chronic study were limited to subacute-chronic interstitial inflammation, increased numbers of alveolar-intraalveolar macrophages, foreign material in the alveolar-intraalveolar macrophages in the peribronchial and perivascular (chronic study only) lymphoid aggregates and in the peribronchial lymph nodes, granulomatous inflammation/granulomas, and fibrosis. In the chronic study, any observed neoplasms occurred with comparable incidence among all groups and were within the historical range for controls. Clearance of Sb2O3 from the lung was burden dependent and was reduced by 80% in the 4.50 mg/m3 group in the chronic study. The previously reported studies, which found Sb2O3 to be a carcinogen, were run at higher lung burdens. Under the exposure conditions of the current study, Sb2O3 was not a carcinogen.

Assessment of ocular toxicity in dogs during 6 months' exposure to a potent organophosphate.

Exposure to anticholinesterase pesticides has been associated with the development of ocular toxicity in humans and animals, ranging from blurred vision to degeneration of the optic nerve. Based on the concern for human safety, the US Environmental Protection Agency has recently required additional studies for this class of compounds, focusing on biochemical, functional and histopathological evaluation of the ocular system. This study was designed to determine the effects on the eye of ethyl parathion, a highly toxic organophosphate, when administered orally to 30 beagle dogs (five of each sex per group) at doses of 2.4, 7.9 or 794 micrograms kg-1day-1 for 6 months. Control animals received corn oil. Routine ophthalmoscopic and slit lamp examinations, refraction and intraocular pressure determinations and electroretinograms were performed as functional assessments at various intervals over the study. Plasma and erythrocyte cholinesterase were determined at weeks 1, 6, 14, 20 and 26, while brain, retinal and ocular muscle cholinesterase were measured at week 26 only. Histopathological examination of the retina, optic nerve, ocular muscle and ciliary body was conducted at termination. Plasma and erythrocyte cholinesterase was markedly depressed at 7.9 and 794 micrograms kg-1day-1 as early as week 1. Retinal cholinesterase was decreased (37-55%) from control values in the 794 micrograms kg-1day-1 group only. Ocular muscle cholinesterase was comparable in treated and control groups at termination. No functional impairment of the eye was noted over the 6-month study.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxicity of calcium sodium metaphosphate fiber. II. Chronic inhalation and oncogenicity study.

Male and female Fischer 344 rats (80/sex/group) were exposed to CSM fiber 6 hr/day, 5 days/week at target-exposure levels of 0, 1, 5, or 25 mg/m3 for 24 months, corresponding to 0, 27, 80, and 513 fibers/cc, respectively. Number and size of the airborne fibers were determined during the course of the study. At 3 and 12 months, 10 rats/sex/group were euthanized and at 18 and 24 months 5 rats/sex/group were euthanized. In addition, 5 rats/sex/group were removed from exposure at 18 months and maintained for a 6-month recovery period. All animals surviving at the completion of the exposure period were maintained in a clean environment for up to 5 additional months. Clinical laboratory examinations were performed on 10 animals/sex/group at 3, 12, and 24 months. The number of fibers in the lung were also determined at 3, 12, 18, and 24 months. Body weight and survival did not appear to be affected by treatment. There were no biologically significant effects on clinical parameters. There was a dose-related increase in lung weight during the exposure period which was generally reversible during the recovery periods. There also was a dose-related increase in the number of fibers/milligram of lung, but no increase in lung fiber burden after the first 3 months. The number of fibers in the lungs of animals exposed to CSM fiber for 18 months and allowed 6-month recovery period showed a decrease especially at the high dose. No increase in tumors (benign or malignant) was observed in this study. Microscopic changes considered reflective of an irritant response were observed in the nasal turbinates notably at the 5 and 25 mg/m3 levels. Histological changes were also observed in the lungs at the 5 and 25 mg/m3 levels. The incidence and/or severity of histopathological changes in the 1 mg/m3 group was considered to be essentially comparable to controls.

Chronic toxicity and carcinogenicity studies of olestra in Fischer 344 rats.

Two 2-year feeding studies were carried out in Fischer 344 rats with olestra, a mixture of the hexa-, hepta- and octaesters of sucrose formed with long-chain fatty acids. Olestra was fed at 0, 0.99, 4.76 or 9.09% (w/w) of the diet in the first study, and at 0 or 9.09% (w/w) of the diet in the second. Daily observations, feed consumption and body weights, ophthalmoscopic examinations, organ weights, serum chemistry, haematology, urinalysis and histopathological evaluations revealed no evidence of any adverse effects associated with olestra ingestion. Relative to controls, there was a higher incidence of basophilic liver foci in olestra-fed female rats at 12 months. At 24 months, foci were observed in most animals in all groups but were more numerous in olestra-fed females. The foci were not associated with hepatic tumours, alterations in liver function, or increases in liver weight and therefore not considered to represent a toxic response to olestra. Isolated statistically significant differences in mortality, mononuclear cell leukaemia, and pituitary adenomas were observed but were not considered to be related to olestra ingestion since they were not reproducible across the two studies, generally not dose responsive, not consistent between sexes, and the incidences were within the ranges for historical and contemporary laboratory controls. The results of the two studies show that olestra was not toxic or carcinogenic when fed to rats at up to 9% of the diet for 24 months.

Subchronic inhalation toxicity of methanol.

The subchronic inhalation toxicity of methanol was evaluated in rats and monkeys. Animals were exposed to 0, 500, 2000, and 5000 ppm methanol vapor for 6 h/d, 5 d/w, for 4 wk. The only treatment-and dose-related effect noted was that of mucoid nasal discharge in rats, which was considered reflective of upper respiratory tract irritation. No consistent treatment-related effects were found for organ or body weights or for histopathologic or ophthalmoscopic examinations. Overall, these findings support the use of the present American Council of Governmental Industrial Hygienists threshold limit value (TLV) of 200 ppm and short-term exposure limit (STEL) of 250 ppm for exposure to methanol vapor.

A 26-week inhalation toxicity study with formaldehyde in the monkey, rat, and hamster.

This inhalation study involved simultaneous exposure of five groups of 6 male Cynomolgus monkeys, 20 male and 20 female Fischer 344 rats, and 10 male and 10 female Syrian golden hamsters for 22 hr per day, 7 days per week for 26 weeks to formaldehyde gas. The cumulative mean exposure concentrations were 0, 0, 0.19, 0.98, and 2.95 ppm for the two control groups, low-, mid-, and high-level exposure groups, respectively. There was no treatment-related mortality during the study. In monkeys, the most significant findings were hoarseness and congestion and squamous cell metaplasia in the nasal turbinates of the 2.95-ppm exposure group. There were no signs of toxicity in the lower-level exposure groups. In the rat, the only observations of possible responses to exposure were found in the 2.95-ppm exposure group. These findings consisted of squamous metaplasia in the nasal turbinates, decreased body weights starting during the second week of the study, and decreased liver weights. In contrast to monkeys and rats, hamsters did not show any significant responses to exposure even at 2.95 ppm. It was concluded that nearly continuous exposure of monkeys and rats for six months at a level of 2.95 ppm of formaldehyde clearly elicited an effect while exposures below this level did not appear to demonstrate an effect. It further appeared that the monkey and rat were more sensitive to formaldehyde exposure than the hamster.

Toxicology studies of fenbufen.

The acute, subacute, and chronic toxicity of gamma-oxo[1,1'-biphenyl]-4-butanoic acid (fenbufen), a new orally and parenterally effective non-steroidal antiinflammatory, analgesic, and antipyretic agent, was investigated in mice, rats, and dogs. In these studies, the gastrointestinal and renal changes associated with toxic doses of fenbufen resembled those described for this class of drug. In coadministration studies, there were no evidences of specific adverse interactions when fenbufen was given with dicoumarol or with triamcinolone; however, coadministration of acetylsalicylic acid (ASA) and fenbufen resulted in decreased plasma concentrations of fenbufen-related materials and a possible increase in the incidence of gastrointestinal hemorrhages or ulcers.