A 90-Day Inhalation Toxicity Study with Benomyl in Rats

A 90-Day Inhalation Toxiaty Study with Benomyl in Rats. WARHEIT,D. B., KELLY, D. P., CARAKOSTAS, M. C., AND SINGER, A. W. (1989).Fundam Appl Toxicol./ 12, 333-345. Benomyl [methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate,CAS Registry No. 17804-35-2] is a fungicide and the possibilityfor inhalation exposure exists for field workers. To assessthe toxicity of benomyl, groups of 20 male and 20 female CDrats were exposed nose-only 6 hr a day, 5 days a week, to concentrationsof 0, 10, 50 or 200 mg/m³ of a benomyl atmosphere. At the midpoint(approximately 45 days on test) and at the end of the exposureperiod, blood and urine samples for clinical evaluation werecollected from 10 rats/group/sex, and these animals were sacrificedfor pathological examination. Similar evaluations were performadon all remaining rats at the end of the 90-day test period.After approximately 45 days on test, compoundrelated degenerationof the olfactory epithelium was observed in all males and in8 of 10 female rats exposed to 200 mg/m³ benomyl. Two male ratsexposed to 50 mg/m³ had similar, although less severe, areasof olfactory epithelial degeneration. After approximately 90days of exposure, the remaining 10 rats/group/sex were sacrificedand examined. Of these rats, all of the males and females exposedto 200 mg/m³ had olfactory degeneration, along with 3 malesexposed to 50 mg/m³ of benomyl. No other observed lesions wereinterpreted to have been caused by the benomyl exposure. Inaddition, male rats exposed to 200 mg/m³ benomyl had depressedmean body weights compared to controls and this finding correlatedwith a reduction in food consumption. Based on pathologicalobservations, 10 mg/m³ represents the no-observable-effect level(NOEL) for the male rats, and 50 mg/m³ is the NOEL for the femalerats.     

Inhalation Toxicity of an Isomeric Mixture of Hydrochlorofluorocarbon (HCFC) 225 in Male Rats

A blend of the hydrochiorofluorocarbon isomers HCFC-225ca andHCFC-225cb has been proposed as a potential substitute for CFC-113,an important solvent and cleaning agent. The toxicity followingrepeated inhalation of an HCFC-225 isomer mixture was assessedin male Crl:CDBR rats. Three groups of 10 male rats were exposedto the test compound in air at design concentrations of 500,5000,and 13,000 ppm. Rats were exposed 6 hr/day, 5 days/week for2 weeks. A control group of 10 male rats was exposed to aironly. Decreased serum cholesterol, triglycerides, and glucose;dose-related increased mean absolute and relative liver weights;and microscopic hepatocellular hy pertrophy were present atall exposure concentrations. Hepatocellular hypertrophy correlatedultrastructurally to proliferation of peroxisomes. Clinicalchemical parameters and organ weight and morphologic changesin the liver were reversible following 14 days of recovery.     

Four-Week Inhalation Toxicity Study with Ludox Colloidal Silica in Rats: Pulmonary Cellular Responses

Four-Week Inhalation Toxicity Study with Ludox Colloidal Silicain Rats: Pulmonary Cellular Responses. WARHEIT, D. B., CARAKOSTAS,M. C, KELLY, D. P., AND HARTSKY, M. A. (1991). Fundam. Appl.Toxicol. 16, 590–601. This study was designed to complementa traditional subchronic inhalation toxicity study with Ludoxcolloidal silica. CD rats were exposed nose-only for 2 or 4weeks at concentrations of 0, 10, 50, and 150 mg/m³ Ludox (driedSiO₂). Additional groups of rats exposed for 4 weeks were givena 3-month recovery period. Following exposure and/or recovery,fluids and cells were recovered from the lungs by bronchoalveolarlavage (BAL) and measured for cellular and biochemical parameters.Additional groups of animals were processed for cell labelingstudies or lung deposition studies. Inhaled doses of Ludox colloidalsilica were measured after 4-week exposures and were found tobe 489 µg/lung (10 mg/m³ group), 2418 µg/lung (50mg/m³), and 7378 µg/lung (150 mg/m³), respectively. Resultsshowed that exposures to 150 mg/m³ Ludox for 2 or 4 weeks producedpulmonary inflammation along with increases in BAL protein,LDH, and alkaline phosphatase values (p<0.05) and reducedmacrophage phagocytosis. Inflammatory responses, evidenced byincreased numbers of neutrophils, were also measured in thelungs of the 50 mg/m³ group following 2 and/or 4 weeks of exposure.Most biochemical parameters for all groups returned to controlvalues following a 3-month recovery period. Autoradiographicstudies demonstrated that the labeling indices of terminal bronchiolarand lung parenchymal cells were generally increased in the 50and 150 mg/m³ groups after 2 and 4 weeks of exposure but, withone exception, returned to normal levels following a 3-monthpostexposure period. No significant alterations in any measuredparameters were detected in rats exposed to 10 mg/m³ Ludox atany time postexposure. The determination of a no-observable-effectlevel (NOEL) of 10 mg/m³ was consistent with results obtainedby conventional toxicology methods and affirms the utility ofthese biochemical, cellular, and autoradiographic techniquesfor providing a predictive screen to assess the toxicity ofinhaled particles.     

Inhalation Toxicity Study of Formamide in Rats

Formamide is a widely used solvent for the manufacture and processingof plastics, and the possibility for inhalation exposure existsfor workers. To assess the toxicity of repeated inhalation ofsublethal concentrations of formamide, three groups of 10 maleCrl:CD BR rats each were exposed nose-only for 6 hr/day, 5 days/weekfor 2 weeks to design concentrations of 100, 500, or 1500 ppmof formamide vapor in air. A control group of 10 male rats wasexposed simultaneously to air only. At the end of the exposureperiod, blood and urine samples were collected for clinicalanalyses, and 5 rats per group were killed for pathologic examination.The remaining 5 rats per group were retained for a 14-day postexposureobservation (recovery) period and then subjected to the sameclinical and pathologic examinations. Male rats exposed to 1500ppm had significantly depressed body weights and body weightgains during the exposure and recovery periods compared to controls.Clinical pathologic examinations revealed that decreased plateletand/or lymphocyte counts were observed in rats exposed to 500or 1500 ppm of formamide. Pathologic examinations revealed compound-relatedmicroscopic changes in the kidneys of rats exposed to 1500 ppmformamide. Minimal to severe necrosis and regeneration of renaltubular epithelial cells were observed principally in the outerstripe of the outer medulla and in cortical medullary rays.Based upon the hematologic and clinical chemical parametersmeasured, the no-observed-effect exposure concentration forrepeated inhalation of formamide was considered to be 100 ppm,under the conditions of this study. The findings of treatment-relatedmicroscopic lesions in the kidneys as well as increases in meanabsolute kidney weights and kidney-to-body weight ratios reflectthe target organ toxicity.