Subchronic Toxicity of Inhaled Technical Grade 1,3-Dichloropropene in Rats and Mice

Subchronic Toxicity of Inhaled Technical Grade 1,3-Dichloropropenein Rats and Mice. Stott, W. T., Young, J. T., Calhoun, L. L.,and Battjes, J. E., (1988). Fundam. Appl. Toxicol. 11,207–220.In order to provide a comprehensive subchronic inhalation toxicitystudy of the soil fumigant, technical grade 1,3-dichloropropene(DCPT), male and female Fischer 344 rats and B6C3F1 mice wereexposed to 0, 10, 30,90, or 150 ppm DCPT vapors 6 hr/day, 5days/ week for 13 weeks. The primary target tissues of inhaledDCPT were identified as the nasal mucosa of both sexes of ratsand mice, and the urinary bladder of female mice. In addition,depressed growth rates of all animals exposed to 90 or 150 ppmDCPT (up to 20% in rats and 12% in mice) resulted in a varietyof alterations in hematologjc and clinical chemistry parameters,and changes in organ weights relative to controls. Nasal mucosaleffects consisted of a dose-related slight degenerative effectof nasal olfactory epithelium or a mild hyperplasia of the respiratoryepithelium or both in all animals exposed to 90 or 150 ppm and2 of 10 male rats exposed to 30 ppm DCPT. Some focal areas ofrespiratory metaplasia were also noted in high exposure groupmice. Urinary bladder effects consisted of a diffuse, moderatehyperplasia of the transitional epithelium in female mice exposedto 90 or 150 ppm DCPT. No treatment-related effects were observedin rats or mice exposed to 10 ppm DCPT vapors.     

1,3-Dichloropropene: Two-Generation Inhalation Reproduction Study in Fischer 344 Rats

1,3-Dichloropropene: Two-Generation Inhalation ReproductionStudy in Fischer 344 Rats. BRESLIN, W. J., KIRK, H. D., STREETER,C. M., QUAST, J. F.,AND SZABO, J. R. (1989). Fundam. Appl Toxicol.12, 129–143. This study evaluated the effects of inhaledtechnical-grade 1,3-dichloropropene (DCPT) on reproduction andneonatal growth and survival. Groups of 30 male and 30 femaleFischer 344 rats, approximately 6 weeks of age, were exposedvia inhalation to 0, 10, 30 or 90 ppm DCPT for 6 hr/day, 5 days/week,for two generations. The parental f₀ and f₁ generations wereeach bred twice. Reproductive and neonatal parameters evaluatedincluded indices of fertility and pup survival, gestation length,litter size, pup body weight, and pup sex ratio. Gross and histologicexaminations were conducted on all f₀ and f₁ adults. In addition,randomly selected f_1b and f_2b weanlings were given gross examinations.Parental effects were limited to rats exposed to 90 ppm DCPTand included decreased body weights and histopathologic effectson the nasal mucosa of adult male and female rats. The histopathologiceffects consisted of slight, focal hyperplasia of the respiratoryepitheium and/or focal degenerative changes in the olfactoryepithelium. No adverse effects on reproductive parameters orneonatal growth or survival were observed in the f_1a, f_1b, f_2a,or f_2b litters even at an exposure concentration which producedeffects in adult animals. Based on these results, it is concludedthat inhalation exposure of rats up to 90 ppm DCPT for two successivegenerations did not adversely affect the reproductive and neonatalparameters evaluated.     

Evaluation of the Effects of Inhalation Exposure to 1,3-Dichloropropene on Fetal Development in Rats and Rabbits

Evaluation of the Effects of Inhalation Exposure to 1,3-Dichloropropeneon Fetal Development in Rats and Rabbits. HANLEY, T. R., Jr.,JOHN-GREENE, J. A., YOUNG, J. T., CALHOUN, L. L., AND RAO, K.S. (1987). Fundam. Appl. Toxicol. 8, 562–570. 1,3-Dichloropropene(DCP), which has found widespread use as a soil fumigant, wasevaluated for its potential effects on embryonal and fetal developmentin rats and rabbits. Pregnant Fischer 344 rats and New ZealandWhite rabbits were exposed to 0, 20, 60, or 120 ppm of 1,3-dichloropropenefor 6 hr/day during gestation Days 6–15 (rats) or 6–18(rabbits). Exposure-related decreases in maternal weight gainand feed consumption were observed in rats at all treatmentlevels. Decreased weight gain was also observed among rabbitsat 60 and 120 ppm. A slight, but statistically significant,increase in the incidence of delayed ossification of the vertebralcentra in rats exposed in ulero to 120 ppm of DCP was consideredof little toxicologic significance in light of the maternaltoxicity observed at this exposure concentration. No evidenceof a teratogenic or embryotoxic response was observed in eitherspecies at any exposure level tested. Thus, it was concludedthat DCP was not teratogenic at exposure levels up to 120 ppmin either rats or rabbits.     

Ethyl Chloride: A Two-Week Inhalation Toxicity Study and Effects on Liver Non-Protein Sulfhydryl Concentrations

Ethyl Chloride: A Two-Week Inhalation Toxicity Study and Effectson Liver Non-Protein Sulfhydryl Concentrations. Landry, T.D.,Ay res, J.A., Johnson, K.A. and Wall, J.M. (1982). Fundam. Appl.Toxicol. 2:230-234. Male and female Fischer 344 rats (6/sex/exposureconcentration)and male beagle dogs (2/exposure concentration)exposed to 0, 1600,4000 or 10 000 ppm ethyl chloride (EtCI)for 6 hr/da, 5 da/wk for 2 weeks showed no toxicologically significanttreatment-related effects on body weights; clinical chemistry,hematology, or urinalysis parameters; neurology (dogs only wereexamined); gross pathology or histopathology. The only treatment-relateddifferences in organ or relative organ weights (in rats or dogs)were slight, but statistically significant increases in liverto body weight ratios of male rats exposed to 4000 or 10 000ppm EtCI (4.9 and 7.5% respectively). Liver non-protein sulfhydryl(NPSH) concentration was measured in male Fischer rats and maleB6C3F1 mice that were exposed for 6 hours to 0,1600,4000 or10 000 ppm EtCl (mice were exposed to 0 or 4000 ppm EtCl only).Liver NPSH, measured 1/2 hr post exposure, was less than controlvalues in 4000 ppm exposed rats (88% of control value), 4000ppm exposed mice (64%), and 10 000 ppm exposed rats (89%). Theslight decreases in rat liver NPSH seem consistent with theincreased liver to body weight ratios. The toxicity data indicatethat 2-week repeated exposures to EtCl concentrations that wereup to 10 times the current A.C.G.I.H. T.L.V. (1000 ppm) causedminimal treatment-related effects in dogs and rats.     

Comparative Inhalation Toxicity of Nickel Sulfate to F344/N Rats and B6C3F1 Mice Exposed for Twelve Days

Comparative Inhalation Toxicity of Nickel Sulfate to F344/NRats and B6C3F₁ Mice Exposed for Twelve Days. BENSON, J. M.,BURT, D. G., CARPENTER, R. L., EIDSON, A. F., HAHN, F. F., HALEY,P. J., HANSON, R. L., HOBBS, C. H., PICKRELL, J. A., AND DUNNICK,J. K. (1988). Fundam. Appl. Toxicol 10, 164-178. Groups of F344/Nrats and B6C3F, mice were exposed to aerosols of nickel sulfatehexahydrate (NiSO₄-6H₂O) 6 hr/day for 12 days to determine theshort-term inhalation toxicity of this compound. Target exposureconcentrations were 60, 30, 15, 7, 3.5, and 0 mg NiSO₄.6H₂O/m³.Endpoints evaluated included clinical signs, mortality, quantitiesof Ni in selected tissues, effect on mouse resistance to tumorcells, and pathological changes in tissues of both rats andmice. All mice exposed to 7 mg NiSO₄ 6H2O/m³ or greater and10 rats exposed to 15 mg NiSO₄ 6H2O/m³ or greater died beforethe termination of exposures. Quantities of Ni remaining inlungs of rats at the end of the exposure were independent ofexposure concentration. Lung burdens of Ni in mice were approximatelyone-half that in lungs of rats. Exposure of female mice to 3.5mg NiSO₄ 6H2O/m³had no effect on resistance to tumor cells asdetermined by spleen natural killer cell activity. Histopathologicalchanges were seen in tissues of rats and mice exposed to aslow as 3.5 mg NiSO₄ 6H2O/m³. Lesions related to NiSO₄ 6H2O/m³exposureoccurred in lung, nose, and bronchial and mediastinal lymphnodes. Results indicated that exposure of rats and mice to amountsof NiSO₄ 6H2O/m³aerosols resulting in Ni exposure concentrationsonly eight times greater than the current threshold limit valuefor soluble Ni (0.1 mg/m³) for as little as 12 days can causesignificant lesions of the.     

Toxicology and carcinogenesis studies of tetralin (CAS No. 119-64-2) in F344/N rats and B6C3F1 mice (inhalation studies)

Tetralin is used as an industrial solvent primarily for naphthalene, fats, resins, oils, and waxes; as a solvent and stabilizer for shoe polishes and floor waxes; as a solvent for pesticides, rubber, asphalt, and aromatic hydrocarbons (e.g., anthracene); as a dye solvent carrier in the textile industry; as a substitute for turpentine in lacquers, paints, and varnishes; in paint thinners and as a paint remover; in alkali-resistant lacquers for cleaning printing ink from rollers and type; as a constituent of motor fuels and lubricants; for the removal of naphthalene in gas distribution systems; and as an insecticide for clothes moths. Tetralin was nominated by the National Cancer Institute for carcinogenicity and disposition studies because of its structure, high production volume, and high potential for worker and consumer exposure. Male and female F344/N rats and B6C3F1 mice were exposed to tetralin (at least 97% pure) by inhalation for 2 weeks, 3 months, or 2 years; male NCI Black Reiter (NBR) rats were exposed to tetralin by inhalation for 2 weeks. Male NBR rats do not produce 2u-globulin; the NBR rats were included to study the relationship of 2u-globulin and renal lesion induction. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male (F344/N and NBR) and five female (F344/N) rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 12 exposures. All rats survived to the end of the studies. The final mean body weight of female rats exposed to 120 ppm and mean body weight gains of female rats exposed to 30 ppm or greater were significantly less than those of the chamber controls. Final mean body weights of exposed groups of male NBR rats and mean body weight gains of all exposed groups of male rats were significantly less than those of the chamber controls. Dark-stained urine was observed in all 120 ppm rats. Squinting, weeping, or matted fur around the eyes were noted in the majority of F344/N rats exposed to 120 ppm. The 2u-globulin concentrations in the kidney of male F344/N rats were significantly greater in all exposed groups than in the chamber control group. The absolute kidney weight of 60 ppm females and the relative kidney weights of male F344/N rats exposed to 30 ppm or greater and female rats exposed to 15 ppm or greater were significantly increased. The absolute liver weight of 120 ppm NBR male rats and the relative liver weights of male and female rats exposed to 60 or 120 ppm were significantly increased. In the nose, the incidences of mononuclear cell cellular infiltration were generally significantly increased in all exposed groups of rats, and incidences of olfactory epithelium degeneration and glandular hypertrophy occurred in all male F344/N rats exposed to 120 ppm. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 13 exposures. All mice survived to the end of the study. Mean body weights of male and female mice were similar to those of the chamber controls. Dark-stained urine was observed in most of the exposed mice. The absolute and relative liver weights of 60 and 120 ppm males and 30 and 120 ppm females and the relative liver weights of 60 ppm females were significantly greater than those of the chamber controls. In the nose, the incidences of olfactory epithelium atrophy were significantly increased in 60 and 120 ppm males and females. Glandular dilatation occurred in all 120 ppm females, and glandular hyperplasia occurred in all 120 ppm males and females. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. The same exposure concentrations were given to additional groups of 10 male and 10 female clinical pathology study rats for up to 6 weeks and five male renal toxicity rats for 2 weeks. All rats survived to the end of the study. During the first 4 weeks of exposure, dark-stained urine was observed in the catch pans of rats exposed to 30, 60, or 120 ppm. Tetralin induced a minimal decrease in the erythron in both sexes that resulted in a hematopoietic response. Tetralin increased urine aspartate aminotransferase and urine lactate dehydrogenase activities (males and females) and glucose/creatinine ratio (males), suggestive of renal injury. The absolute kidney weights of 60 and 120 ppm females and the relative kidney weights of males and females exposed to 15 ppm or greater were significantly greater than those of the chamber controls. Concentrations of 2u-globulin in the kidney of exposed male rats were generally greater than those of the chamber controls at all time points and greater at 6 and 14 weeks than at 2 weeks. There were significantly increased incidences of olfactory epithelium necrosis in rats exposed to 30 ppm or greater and of olfactory epithelium regeneration in 60 and 120 ppm rats. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of 120 ppm males were significantly less than those of the chamber controls. Dark-stained urine was observed in the catch pans of mice exposed to 30, 60, or 120 ppm during the first month of the study. Tetralin induced a minimal decrease in the erythron in both sexes that resulted in a hematopoietic response. The relative liver weights of 120 ppm males and 30 ppm or greater females were significantly greater than those of the chamber controls. Incidences of olfactory epithelium metaplasia in 60 and 120 ppm males and females, respiratory epithelium hyaline droplet accumulation in 120 ppm males and 60 and 120 ppm females, cytoplasmic eosinophilic granules within the transitional epithelium lining the urinary bladder in all exposed groups of males and females, and ovarian atrophy and uterine atrophy in 60 and 120 ppm females were significantly increased. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to tetralin at air concentrations of 0, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Additional groups of five male and five female rats were exposed to the same concentrations for 12 months. Survival of all exposed groups of rats was similar to that of the chamber controls. Mean body weights of 120 ppm females were 6% less than those of the chamber controls after week 29. Dark-stained urine was observed in all exposed groups of rats. Creatinine-adjusted levels of all urinary metabolites increased with increasing exposure concentration in males and females. In the standard evaluation of the kidney, there were slightly increased incidences of cortical renal tubule adenoma in male rats. In the combined analysis of single and step sections, the incidence of cortical renal tubule adenoma was significantly increased in the 120 ppm group. In the combined analysis, there was also a significantly increased incidence of renal tubule hyperplasia in the 120 ppm group. In 120 ppm males in the standard evaluation, the severity of chronic nephropathy was increased and the incidence of transitional epithelial hyperplasia in the renal pelvis was significantly increased. Three hepatocellular adenomas occurred in 120 ppm females, and one hepatocellular carcinoma each was observed in the 60 and 120 ppm groups. The incidences of uterine stromal polyp and endometrium hyperplasia were significantly increased in 120 ppm females. Incidences of interstitial cell adenoma and germinal epithelium atrophy of the testis in 30 and 120 ppm males were significantly greater than those in the chamber controls. The incidences of olfactory epithelium degeneration, metaplasia, basal cell hyperplasia, suppurative inflammation, and mineralization (except 30 ppm females) in the nose were significantly increased in all exposed groups of rats. The incidences of glandular dilatation were significantly increased in 120 ppm males and all exposed groups of females. The incidences of respiratory epithelium chronic inflammation were significantly increased in males exposed to 60 or 120 ppm and all exposed groups of females. The incidences of lens cataract in 120 ppm females were significantly increased. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to tetralin at air concentrations of 0, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Additional groups of five male and five female mice were exposed to the same concentrations for 12 months. Survival of 60 and 120 ppm female mice was significantly greater than that of the chamber controls. The mean body weights of all exposed groups of male and female mice were similar to those of the chamber controls by the end of the study. Dark-stained urine was observed in all exposed groups of male mice and in females exposed to 60 or 120 ppm. Creatinine-adjusted levels of all urinary metabolites increased with increasing exposure concentration in males and females. The incidence of hemangiosarcoma of the spleen was increased in 120 ppm females and exceeded the historical control range for inhalation studies. The incidences of olfactory epithelium atrophy, respiratory metaplasia, glandular hyperplasia, and suppurative inflammation in exposed groups of mice were significantly greater than those in the chamber controls. Transitional epithelium cytoplasmic eosinophilic granules were present in the urinary bladder of all exposed mice. (ABSTRACT TRUNCATED)     

Inhalation Toxicity of Butylene Oxide

Inhalation Toxicity of Butylene Oxide. Miller, R.R., Quast,J.R., Ayres, J.A. and McKenna, M.J. (1981). Fundam. Appl. Toxicol.1:319–324. Exposure of male and female Fischer 344 ratsand B6C3F1 mice to 0,400,800 or 1600 ppm butylene oxide vapors6 hours per day, 5 days per week, for a total of 9 days duringa 2-week interval revealed a definite species difference insensitivity to these high concentrations of the test material.All mice in the 1600 ppm group were dead prior to the 3rd dayof exposure while all rats exposed to 1600 ppm survived untilscheduled sacrifice with no obvious signs of distress exceptfor a pronounced retardation of growth. Inflammatory and degenerativechanges in the nasal mucosa were detected histopath-ologicallyin rats in the 1600 ppm group. Myeloid hyperpla-sia in the bonemarrow, and elevated mean white blood cell counts for male andfemale rats in the 1600 ppm group may possibly have been relatedto the inflammatory nasal lesions or to generalized stress.A subchronic inhalation toxicity study in which Fischer 344rats and B6C3F1 mice were exposed to 0,75,150 or 600 ppm for13-weeks resulted in no treatment-related mortalities. Slightgrowth retardation, particularly for female rats and mice, wasapparent for animals in the 600 ppm group. Histopathologic examinationsrevealed treatment-related lesions of the nasal mucosa in bothrats and mice in the 600 ppm group. There were no histopathologicobservations in rats or mice in the 75 or 150 ppm groups whichwere considered to be related to exposure to the test material.     

Inhalation Teratology Studies of n-Butyl Mercaptan in Rats and Mice

Inhalation Teratology Studies of n-Butyl Mercaptan in Rats andMice. THOMAS, W. C., SECKAR, J. A., JOHNSON, J. T., ULRICH,C. E., KLONNE, D. R., SCHARDEIN, J. L., AND KIRWIN, C. J. (1987).Fundam. Appl. Toxicol. 8, 170–178. n-Butyl mercaptan (n-BM)is used as a solvent and a chemical intermediate. Pregnant CharlesRiver CD-1 mice and COBS CD rats were randomly assigned to acontrol group and to three n-BM-exposed groups of 25 rats and25 mice each. The animals were exposed by whole-body inhalationto mean n-BM concentrations of 10, 68, or 15 2 ppm on a 6-hrdaily exposure schedule. Rats were exposed on Gestation Days6–19 and mice on Gestation Days 6–16. The controlgroup was exposed to filtered air only on a comparable regimen.Cesarean sections were performed on all surviving mice on GestationDay 17 and on all rats on Gestation Day 20. Seventeen of then-BM-treated mice died: 8 at the 68-ppm level and 9 at the 152-ppmlevel; none of the n-BM-treated rats died. An increased postimplantationloss and increased early resorption occurred in mice exposedat 68 and 152 ppm, indicating embryotoxicity. An increased incidenceof cleft palate was observed in mice exposed to 10 or 68 ppmwhich was not statistically significant. Total fetal abnormalitieswere statistically significantly different from controls at68 ppm where maternal lethality was observed when based on thefetal unit although not when based on the litter unit. Ratsexposed to 152 ppm or less demonstrated no terata.     

Two-Week, Repeated Inhalation Exposure of F344/N Rats and B6C3F Mice to Ferrocene

Two-Week, Repeated Inhalation Exposure of F344/N Rats and B6C3F¹Mice to Ferrocene. SUN, J. D., DAHL, A. R., GILLETT, N. A.,BARR, E. B., CREWS, M. L., EIDSON, A. F., BECHTOLD, W. E., BURT,D. G., DIETER, M. P., AND HOBBS, C. H. (1991). Fundam. ApplToxicol. 17, 150-158. Ferrocene (dicyclopentadienyl iron; CASNo. 102-54-5) is a relatively volatile, organometallic compoundused as a chemical intermediate, a catalyst, and as an antiknockadditive in gasoline. It is of particular interest because ofits structural similarities to other metallocenes that havebeen shown to be carcinogenic. F344/N rats and B6C3F, mice wereexposed to 0, 2.5, 5.0, 10, 20, and 40 mg ferrocene vapor/m3,6 hr/day for 2 weeks. During these exposures, there were nomortality and no observable clinical signs of ferrocene-relatedtoxicity in any of the animals. At the end of the exposures,male rats exposed to the highest level of ferrocene had decreasedbody-weight gains relative to the weight gained by filteredair-exposed control rats, while body-weight gains for all groupsof both ferrocene- and filtered air-exposed female rats weresimilar. Male mice exposed to the highest level of ferrocenealso had decreased body-weight gains, relative to controls,while female mice had relative decreases in body-weight gainsat the three highest exposure levels. Male rats had a slightdecrease in relative liver weight at the highest level of exposure,whereas no relative differences in organ weights were seen infemale rats. Male mice had exposure-relative decreases in liverand spleen weights, and an increase in thymus weights, relativeto controls. For female mice, relative decreases in organ weightswere seen for brain, liver, and spleen. No exposure-relatedgross lesions were seen in any of the rats or mice at necropsy.Histopathological examination was done only on the nasal turbinates,lungs, liver, and spleen. The only exposure-related findingwas histopathologic lesions in the nasal turbinates of bothspecies. These lesions were primarily centered in the olfactoryepithelium and were morphologically diagnosed as subacute, necrotizinginflammation. Nasal lesions were observed in all ferrocene-exposedanimals and differed only in severity, which was dependent onthe exposure concentration. In vitro metabolism studies of ferroceneshowed that nasal tissue, particularly the olfactory epithelium,had 10 times higher "ferrocene hydroxylating" activity thandid liver tissue from the same animals. These results suggestthat the mechanism of ferrocene toxicity may be the intracellularrelease of ferrous ion through ferrocene metabolism, followedby iron-catalyzed lipid peroxidalion of cellular membranes.     

A 90-Day Vapor Inhalation Toxicity Study of Decalin

A 90-Day Vapor Inhalation Toxicity Study of Decalin. GAWORSKI,C. L., HAUN, C. C, MACEWEN, J. D., VERNOT, E. H., BRUNER, R.H., AMSTER, R. L., AND COWAN, M. J., JR. (1985). Fundam. Appl.Toxicol. 5, 785–793. A subchronic 90-day inhalation studywas conducted to determine the toxic effects of decalin, a commonlyused industrial solvent. Experimental groups consisting of maleand female beagle dogs, male and female Fischer-344 rats, andfemale C57BL/6 mice were continuously exposed to decalin concentrationsof 5 or 50 ppm. An unexposed control group was also maintained.All dogs and a portion of each rodent group were sacrificedand examined at exposure termination, while the remaining rodentswere held for observation up to 21 months postexposure. No distinctexposure-related lesions were noted in dogs. Dog body weights,organ weights, and blood clinical pathology were also normal.At exposure termination hepatocellular cytoplasmic vacuolizationwas noted in female mice exposed to both concentrations. Thisliver tissue change was reversible and was not a significantfinding in female mice examined during the 21-month postexposureobservation period. In male rats, decalin exposure producednephropathy characterized by hyaline droplets, necrosis, andintratubular casts. Accentuated tubular degeneration and medullarymineralization were noted in exposed rats held for long-termpostexposure observation. There was no associated abnormal increasein mortality nor alterations in serum, blood urea nitrogen,or creatinine levels. Female rats were free of decalin-inducedrenal damage. There was a slightly greater incidence of commonlyoccurring pituitary tumors in both mice and rats; however, thetumor incidence was not dose related. The results of this studysuggest that the toxic effects of decalin are similar to thosepreviously described for other hydrocarbon solvents and fuels.     

Comparative Toxicity and Carcinogenicity Studies of Tetracycline and Oxytetracycline in Rats and Mice

Comparative Toxicity and Carcinogenicity Studies of Tetracyclineand Oxytetracycline in Ratsand Mice. DIETZ, D. D., ABDO, K.M., HASEMAN, J. K., EUSTIS, S. L., AND HUFF, J. E. (1991). FundarmAppl Toxicol. 17, 335–346. Two-year toxicity and carcinogenicitystudies of oxytetracycline hydrochloride and tetracycline hydrochloride,two structurally similar and widely used antibiotics, were performedin F344/N rats and B6C3F1 mice. Rats and mice were continuouslyexposed via their diet to the following levels of antibiotic:oxytetracycline HCl—rats 0, 25,000, or 50,000 ppm; mice0, 6,300, or 12,500 ppm; tetracycline HCI—rats and mice0, 12,500, or 25,000 ppm. On a milligram per kilogram of bodyweight basis these exposures represent doses that are 20 to140 times daily human therapeutic doses. Dose-related increasedsurvival was noted among oxytetracycline-treated male rats andtetracycline-treated female rats and male mice, while treatment-relatedreduced body weight gain occurred in oxytetracycline- and tetracycline-treatedmice. Microscopic changes Included fatty metamorphosis and focalcellular change in livers of oxytetracycline-treated male ratsand basophilic cytoplasmic and clear cell change in livers oftetracycline-treated male rats. The only neoplastic changeswere a marginally increased trend in phmchromocytoma of theadrenal medulla ( equivocal evidence only) among oxytetracyclineexposedmale rats (12/50 controls, 19/50 low dose, 24/50 high dose)and an increased incidence of pituitary adenoma or adenocarcinomaamong high-dose oxytetracycline-treated female rats (20/50 controls,32/50 high dose). Although oxytetracycline and tetracyclineappeared to increase the inadence of pituitary hyperplasia inhigh-dose male and female rats, respectively, the total incidenceof proliferative changes (hyperplasia, adenoma, and adenocarcinoma)was not affected by antibiotic exposure. The results from thesestudies therefore support the notion that neither antibioticis careinogenic in rodents. There were several negative trendssuggesting possible protective effats by both these tetracyclineanalogs against certain spontaneous neoplastic and nonneoplasticchanges.     

A 90-Day Vapor Inhalation Toxicity Study of Methyl Ethyl Ketone

A 90-Day Vapor Inhalation Toxicity Study of Methyl Ethyl Ketone.Cavender, F.L., Casey, H.W., Salem, H., Swenberg, J.A. and Gralla,E.J. (1983). Fundam. Appl. Toxicol. 3: 264–270. Male andfemale Fischer 344 rats were exposed to 0, 1250, 2500, or 5000ppm methyl ethyl ketone (MEK) vapors 6 hours per day, 5 daysper week for 90 days. The 90-day exposures had no adverse effecton the clinical health or growth of male or female rats exceptfor a depression of mean body weight in the 5000 ppm exposuregroup. The 5000 ppm animals had a slight but significant increasein liver weight, liver weight/body weight ratio, and liver weight/brainweight ratio at necropsy. Serum glutamic-pyruvic transaminase(SGPT) activity in the 2500 ppm female rats was elevated whilethe 5000 ppm female rats exhibited significantly decreased SGPTactivity. In addition, alkaline phosphatase, potassium and glucosevalues for the 5000 ppm female rats were increased. Specialneuro-pathological and routine pathological studies did notreveal any lesions that could be attributed to MEK exposure.     

Carcinogenicity and Toxicity of Inhaled Nitrobenzene in B6C3F1 Mice and F344 and CD Rats

The potential carcinogenicity and toxicity of inhaled nitrobenzenewere evaluated following chronic (2-year) exposure in mice andrats. Male and female B6C3F1 mice were exposed to 0, 5, 25,or 50 ppm nitrobenzene, while male and female F344 rats andmale CD rats were exposed to 0, 1, 5, or 25 ppm nitrobenzene.All exposures were for 6 hr/day, 5 days/week excluding holidays,for a total of 505 days over 2 years. Survival was not adverselyaffected by nitrobenzene exposure, and only mild exposure-relateddecreases in body weights (<10% of control) were occasionallynoted. Nitrobenaene exposure resulted in increased incidenceof neoplasia in male B6C3F1 mice (pulmonary alveolar/bronchiolarand thyroid follicular cell neoplasms), female B6C3FI mice (mammarygland neoplasms), male F344 rats (hepatocellular and renal neoplasms),female F344 rats (endometrial stromal neoplasms), and male CDrats (hepatocellu lar neoplasms). In addition, there were marginalincreases in the incidence of hepatocellular neoplasia in femaleB6C3F1 mice and thyroid follicular neoplasia in male F344 rats.Groups of nitrobenzene-exposed mice and rats with increasedincidence of renal and thyroid neoplasia also had increasedincidences of hyperplasia in these tissues. Toxicity resultingfrom chronic inhalation of nitrobenzene was manifested by methemoglobinemia,anemia, and adaptive or degenerative changes in the nose, liver,and testis. The results indicate that inhaled nitrobenzene iscarcinogenic and toxic in mice and rats, and that the spectrumof these responses in animals is dependent on species, sex,and genetic background.     

Acute Inhalation Studies with Methyl Isocyanate Vapor. I. Methodology and LC50 Determinations in Guinea Pigs, Rats, and Mice

Acute Inhalation Studies with Methyl Isocyanate Vapor. I. Methodologyand LC50 Determinations in Guinea Pigs, Rats, and Mice. DODD,D. E., FOWLER, E. H., SNELLINGS, W. M., PRITTS, I. M., AND BARON,R. L. (1986). Fundam. Appl. Toxicol. 6, 747–755. Groupsof male and female Fischer 344 rats, B6C3F1 mice, and Hartleyguinea pigs were exposed once for 6 hr to mean concentrationsof 10.5, 5.4, 2.4, 1.0, or 0 (control) ppm of methyl isocyanate(MIC)vapor. Rats and mice were also exposed to 20.4 ppm of MIC.No deaths occurred in animals exposed to 2.4 or 1.0 ppm. Themajority of deaths for the 20.4- and 10.5-ppm groups occurredduring postexposure Days 1 through 3, while at 5.4 ppm deathswere observed throughout the 14-day postexposure period. The6-hr LC50 values (with 95% confidence limits) were 6.1 (4.6to 8.2) ppm for rats, 12.2 (8.4 to 17.5) ppm for mice, and 5.4(4.4 to 6.7) ppm for guinea pigs. Notable clinical observationsduring and immediately following MIC exposure were lacrimation,perinasal/perioral wetness, respiratory difficulty (e.g., mouthbreathing), decreased activity, ataxia, and hypothermia. Thefrequency of clinical signs decreased during the second postexposureweek. Body weight losses were common in all species followingMIC exposures of 2.4 ppm or greater. At 1.0 ppm, only femalemice had body weight depression. Recovery of body weight losswas observed in the 5.4- (guinea pigs only), 2.4-, and 1.0-ppmconcentration groups. The lungs of all animals that died werediscolored. Following microscopic examination of the respiratorytract, deaths were attributed to pulmonary edema and congestion.In a separate study, Fischer 344 rats and Hartley guinea pigswere exposed once for 4 hr to mean concentrations of 36.1, 25.6,15.2, or 5.2 ppm of MIC vapor. In general, the results weresimilar to those of the single 6-hr exposure Study.     

Histopathology of Acute Toxic Response in Rats and Mice Exposed to Methyl Chloride by Inhalation

Histopathology of Acute Toxic Response in Rats and Mice Exposedto Methyl Chloride by Inhalation. Morgan, K.T., Swenberg, J.A.,Hamm, T.E., Jr., Wolkowski-Tyl, R. and Phelps, M. (1982). Fundam.Appl. Toxicol. 2:293-299. Both sexes of one strain of rat (F344),two strains of mice (C3H and C57BL/6) and the cross (B6C3F1)of these 2 strains of mice were exposed by inhalation to methylchloride for 6 hours per day for up to 12 days. Methyl chlorideconcentrations in air were 0, 500, 1000, or 2000 ppm for mice,and 0, 2000, 3500 or 5000 ppm for rats. All male B6C3F1 miceexposed to 2000 ppm were dead or moribund by day 2, and allmale and female mice in the remaining 2000 ppm groups were moribundby day 5. Prior to death many of these mice exhibited ataxia,and hematuria with the latter occurring mainly in females. Treatmentassociated lesions in mice included hepatocellular degenerationand necrosis, degeneration and necrosis of proximal convolutedtubules and/or basophilic tubules in the renal cortex, and focalareas of necrosis of the internal granular layer of the cerebellum.Brain lesions were most severe in female C57BL/6 mice, whilehepatocellular degeneration was most severe in male C57BL/6and B6C3F1 strains. Approximately 50% of the male and femalerats exposed to 5000 ppm were killed in extremis on day 5. Theprincipal clinical signs, which were confined to the 5000 and3500 ppm groups, included severe diarrhea, incoordination ofthe fore-limbs, and in a small number of animals, hind limbparalysis and convulsions. In rats, lesions were observed inthe liver, kidney and brain which resembled those seen in micebut were generally less severe. Lesions observed in tissuesexamined only in rats included vacuolar degeneration of thezona fasciculata of the adrenal glands and degenerative changesin the seminiferous tubules and epididymis. Rats appeared torespond in a similar manner to mice but were more resistantto methyl chloride toxicity. These findings demonstrate species,strain and sex differences in susceptibility to methyl chloride.     

Dermal Toxicity and Carcinogenicity of 4-Vinyl-1 -cyclohexene Diepoxide in Fischer Rats and B6C3F1 Mice

Dermal Toxicity and Carcinogenicity of 4-Vinyl-1-cyclohexeneDiepoxide in Fischer Rats and B6C3F1 Mice. CHHABRA, R. S., HUFF,J., HASEMAN, J., JOKJNEN, M. P., AND HETJMANCIK, M. (1990).Fundam. Appl. Toxicol 14, 752–763. 4-Vinyl-l-cyclohexenediepoxide (VCHD) is used as a chemical intermediate and as areactive diluent for diepoxides and epoxy resins. Studies wereconducted by administering VCHD in acetone by dermal application,5 days per week for 105 weeks, to groups of 60 rats of eachsex at 0, 15, or 30 mg/animal. Groups of 60 mice of each sexwere administered 0, 2.5, 5, or 10 mg/animal on the same schedulefor up to 103 weeks. Ten animals from each group were humanelykilled, necropsied, and examined histopathologically duringMonth 15. At the 15-month evaluation, 2 of 10 male rats thatreceived 30 mg had a squamous cell carcinoma of the skin ator adjacent to the site of application. Squamous cell papillomasand carcinomas were seen in all mice that received 5 or 10 mg.Two of nine female mice given 10 mg had granulosa cell tumorsof the ovary, and one of nine female mice given 10 mg had anovarian papillary cystadenoma. In the 2-year studies, body weightand survival were lower in high-dose rats and mid- and high-dosemice than in vehicle controls. All high-dose male mice diedby Week 83; remaining high-dose female mice were killed duringWeek 84 for humane reasons. Squamous cell papillomas of theskin in dermally exposed male rats and squamous cell carcinomasand basal cell adenomas or carcinomas of the skin in exposedmale and female rats were increased. The incidence of squamouscell carcinomas of the skin was increased in male and femalemice at all dose levels. Mid- and high-dose female mice hadan increased incidence of benign or malignant granulosa celltumors and of benign mixed tumors of the Ovary.     

The Toxicity of Dimethylamine in F-344 Rats and B6C3F1 Mice following a 1-Year Inhalation Exposure

The Toxicity of Dimethylamine in F-344 Rats and B6C3F1 Micefollowing a 1-Year Inhalation Exposure (1985). BUCKLEY, L. A.,MORGAN, K. T., SWENBERG, J. A., JAMES, R. A., HAMM, T. E., JR.,and BARROW, C. S. Fundam. Appl. Toxicol. 5, 341–352. Dimethylamineis a widely used commodity chemical, for which there are fewchronic toxicity data. Male and female F-344 rats and B6C3F1mice were exposed by inhalation to 0, 10, 50, or 175 ppm dimethylamine(DMA) for 6 hr/day, 5 days/week for 12 months. Groups of 9–10male and female rats and mice were necropsied after 6 and 12months of exposure. No male mice were sacrificed at 12 monthsdue to a high incidence of early deaths in that group. The meanbody weight gain of rats and mice exposed to 175 ppm DMA wasdepressed to approximately 90% of control after 3 weeks of exposure.The only other treatment-related changes were concentration-relatedlesions in the nasal passages. Two distinct locations in thenose were affected: the respiratory epithelium in the anteriornasal passages, and the olfactory epithelium, especially thatlining the anterior dorsal meatus. There was focal destructionof the anterior nasoturbinate and nasal septum, local inflammation,and focal squamous metaplasia of the respiratory epitheliumin rats and mice. Mild goblet cell hyperplasia was observedonly in rats. The olfactory epithelium exhibited extensive lossof sensory cells with less damage to sustentacular cells. Therewas also loss of olfactory nerves, hypertrophy of Bowman's glands,and distension of the ducts of these glands by serocellulardebris in regions underlying degenerating olfactory epithelium.At the 175-ppm exposure level, rats had more extensive olfactorylesions than mice, with hyperplasia of small basophilic cellsadjacent to the basement membrane being present in rats butnot mice. After 12 months of exposure to 10 ppm DMA, minimalloss of olfactory sensory cells and their axons in olfactorynerve bundles was observed in the nasal passages of a few ratsand mice. These results indicate that the olfactory sensorycell is highly sensitive to the toxic effects of DMA, with minorlesions being produced in rodents even at the current thresholdlimit value of 10 ppm.     

Two-year inhalation carcinogenesis studies of methyl methacrylate in rats and mice: inflammation and degeneration of nasal epithelium

Methyl methacrylate (MMA), a liquid monomer, is used as a chemical intermediate in the manufacture of plexiglass and other acrylic products and as "bone cement" in orthopedic and dental surgery. Toxicology and carcinogenesis inhalation studies of MMA were conducted because of: (1) widespread human exposure; (2) evidence of mutagenicity; and (3) inadequacy of previously conducted long-term oral, dermal, and inhalation studies. Groups of 50 male F344/N rats were exposed to MMA by inhalation at 0, 500, or 1000 ppm, female F344/N rats at 0, 250, or 500 ppm, and male and female B6C3F1 mice at 0, 500, or 1000 ppm, 6 h a day, 5 days a week for 102 weeks. Survival rates of male and female rats and mice exposed to MMA were similar to those of their respective controls. Body weights were reduced in the low and high dose male (3-6% and 5-10%, respectively) and female (5-7% and 8-10%) rats exposed to MMA for more than 80 weeks and in male (7-19% and 6-17%) and female (0-13% and 0-17%) mice for more than 20 weeks. Inhalation exposure of MMA for 102 weeks did not induce any increased incidences of neoplasms in male or female rats or mice. Non-neoplastic lesions in the nasal cavity of MMA-exposed rats and mice were significantly increased and these included inflammation and degeneration of the olfactory epithelium of MMA-exposed male and female rats and inflammation, hyperplasia, cytoplasmic inclusions in the respiratory epithelium, and degeneration of the olfactory epithelium in male and female mice.     

Toxicity Sudies of Acetone Administered in the Drinking Water of Rodents

Toxicity Studies of Acetone Administered in the Drinking Waterof Rodents. DIETZ, D. D., LEININGER, J. R., RAUCKMAN, E. J.,THOMPSON, M. B., CHAPIN, R. E., MORRISSEY, R. L., AND LEVINE,B. S. (1991). Fundam Appl. Toxicol 17, 347–360. Two- andthirteen-week toxicity studies were conducted using male andfemale F344/N rats and B6C3F1 mice. Animals were exposed tothe following concentrations of acetone in their drinking water:two-week studm 0; 5000; 10,000; 20,000; 50,000; or 100,000 ppmacetone. Thirteen-week rat and female mouse studies 0; 2500;5000; 10,000; 20,000; or 50,000 ppm acetone. Thirteen week malemice were exposed to 0; 1250; 2500; 5000; 10,000; or 20,000ppm acetone. Depressed body weight gain was restricted to the50,000 and 100,000 ppm exposure groups. Male and female miceexposed respectively to 20,000 or 50,000 ppm acetone for 2 weeksdeveloped hepatocellular hypertrophy. This change was not apparentafter 13 weeks of exposure although relative and alsolute liverweight was increased in high dose female mice. Bone marrow hypoplasiawas observed In 5/5 high dose (100,000 ppm) male rats duringthe 2-week studies. Treatment of male rats for 13 weeks resultedin a variety of mild and subtle hematological changes that oftenoccurred at relatively low levels of exposure (5000 ppm) andresembled those seen during the clinical condition of megaloblasticanemia Changes characteristic of hypogonadism (depressed spermmotility and cauda epididymal and epididymal weight and elevatedincidence of abnormal sperm) were observed in male rats raceiving50,000 ppm acetone for 13 weeks. The incidence and severityof a kidney laion that is morphologically similar to the spontaneouslyoccurring nephropathy among aging F-344 rats were increasedat 20,000 and 50,000 ppm acetone, respectively, in 13-week malerats. In summary, the effects of acetone were either subtlein nature or occurred during very high levels of exposure confirmingacetone's low level of toxicity. The daily levels of acetoneexposure were often several-fold greater than possibly encounteredby humans during the accidental consumption of contaminatedgroundwater (250 ppm; 5 mg/day) and frequently exceeded maximumlevels reported following acute toxic exposures (2,500 mg/kg).     

Toxicology and carcinogenesis studies of 4-methylimidazole (Cas No. 822-36-6) in F344/N rats and B6C3F1 mice (feed studies)

4-Methylimidazole is used in the manufacture of pharmaceuticals, photographic chemicals, dyes and pigments, cleaning and agricultural chemicals, and rubber. It has been identified as a by-product of fermentation in foods and has been detected in mainstream and sidestream tobacco smoke. 4-Methylimidazole was nominated by the National Cancer Institute for a long-term study because of the high potential for human exposure. Male and female F344/N rats and B6C3F1 mice were exposed to 4-methylimidazole (99.5% pure) in feed for 2 years. Fifteen-day and 14-week toxicity studies of 4-methylimidazole in F344/N rats and B6C3F1 mice are reported in NTP Toxicity Report No. 67. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 0, 625, 1,250, or 2,500 ppm 4-methylimidazole (males) or 0, 1,250, 2,500, or 5,000 ppm 4-methylimidazole (females) (equivalent to average daily doses of approximately 30, 55, or 115 mg 4-methylimidazole/kg body weight to males and 60, 120, or 260 mg/kg to females) for 106 weeks. Survival of all exposed groups of male and female rats was similar to that of the control groups. Mean body weights of males in the 1,250 and 2,500 ppm groups and females in the 2,500 and 5,000 ppm groups were less than those of the control groups throughout the study; mean body weights of 1,250 ppm females were less after week 41. Feed consumption by 5,000 ppm females was less than that by the controls. Clonic seizures, excitability, hyperactivity, and impaired gait were observed primarily in 2,500 and 5,000 ppm females. The incidence of mononuclear cell leukemia in 5,000 ppm females was significantly greater than that in the controls, and the incidence exceeded the historical range in feed study controls. The incidences of hepatic histiocytosis, chronic inflammation, and focal fatty change were generally significantly increased in all exposed groups of male and female rats. The incidences of hepatocellular eosinophilic and mixed cell focus were significantly increased in 2,500 ppm males and 5,000 ppm females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were fed diets containing 0, 312, 625, or 1,250 ppm 4-methylimidazole (equivalent to average daily doses of approximately 40, 80, and 170 mg 4-methylimidazole/kg body weight to males and females) for 106 weeks. Survival of all exposed groups of male and female mice was similar to that of the control groups. Mean body weights of males and females in the 1,250 ppm groups were less than those of the control groups after weeks 17 and 12, respectively. Mean body weights of 312 and 625 ppm females were less after weeks 85 and 65, respectively. Feed consumption by exposed groups of male and female mice was generally similar to that by the controls. The incidences of alveolar/bronchiolar adenoma in all exposed groups of females, alveolar/bronchiolar carcinoma in 1,250 ppm males, and alveolar/bronchiolar adenoma or carcinoma (combined) in 1,250 ppm males and 625 and 1,250 ppm females were significantly greater than those in the control groups. The incidence of alveolar epithelium hyperplasia was significantly increased in 1,250 ppm females. GENETIC TOXICOLOGY: 4-Methylimidazole was not mutagenic in the S. typhimurium mutation assay when tested in strains TA97, TA98, TA100, and TA1535, with and without hamster or rat liver metabolic activation enzymes. No consistent or significant increases in the frequencies of micronucleated erythrocytes were seen in the bone marrow of male rats or mice treated with 4-methylimidazole by intraperitoneal injection, or in peripheral blood samples from male and female mice administered the compound in dosed feed for 14 weeks. CONCLUSIONS: Under the conditions of these 2-year studies, there was no evidence of carcinogenic activity of 4-methylimidazole in male F344/N rats exposed to 625, 1,250, or 2,500 ppm. There was equivocal evidence of carcinogenic activity of 4-methylimidazole in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of 4-methylimidazole in male and female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. Exposure to 4-methylimidazole resulted in nonneoplastic lesions in the liver of male and female rats and the lung of female mice and in clinical findings of neurotoxicity in female rats.