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.     

Lung Toxicity after 13-Week Inhalation Exposure to Nickel Oxide, Nickel Subsulfide, or Nickel Sulfate Hexahydrate in F344/N Rats and B6C3F1 Mice

Lung Toxicity after 13-Week Inhalation Exposure to Nickel Oxide,Nickel Subsulfide, or Nickel Sulfate Hexahydrate in F344/N Ratsand B6C3F₁ Mice. DUNNICK, J. K., ELWELL, M. BENSON, J. M., HOBBS,C. H., HAHN, F. F., HALY, P. J., CHENG, Y. S., AND EIDSON, A.F. (1989). Fundam. Appl. Toxicol. 12, 584–594. The relativetoxicity of nickel oxide (NiO), nickel sulfate hexahydrate (NiSO₄6H₂O)and nickel subsulfide (Ni₃S₂) was studied in F344/N rats andB6C3F₁ mice after inhalation exposure for 6 hr/day, 5 days/week,for 13 weeks. Exposure concentrations used (as mg Ni/m³ were0.4–7.9 for NiO, 0.02–0.4 for NiSO₄ 6H₂O and 0.11–1.8for Ni₃S₂. No exposure-related effects on mortality and onlyminor effects on body weight gain were seen in rats or mice.The most sensitive parameter for nickel toxicity was histopathologic change in the lungs of exposed animals where chronic activeinflammation, fibrosis, and alveolar macrophage hyperplasiawerez associated with nickel exposure. There was an exposure-related increase in lung weight in rats and mice. Equilibriumlevels of nickel in the lung were reached by 13 weeks of nickelsulfate and nickel subsulfide exposure, whereas lung levelsof nickel continued to increase throughout exposure to nickeloxide. Additional exposure-related histopathologic lesions intreated animals included atrophy of the olfactory epitheliumafter nickel sulfate and nickel subsulfide exposure. No nasallesions were seen after nickel oxide expo sure. Lymphoid hyperplasiaof the bronchial lymph nodes developed in animals exposed toall three nickel compounds. The order oftoxicity correspondedto the water solubility of the nickel compounds, with nickelsulfate being most toxic, followed by nickel subsulfide andnickel oxide.     

Inhalation Toxicity of 1,6-Hexanediamine Dihydrochloride in F344/N Rats and B6C3F1 Mice

1,6-Hexanediamine (HDA) is a high production volume chemicalwhich is used as an intermediate in the synthesis of paints,resins, inks, and textiles and as a corrosion inhibitor in lubricants.Two- and 13-week studies of the toxicity of the dihydrochloridesalt of HDA (HDDC) were conducted in male and female Fischer344/N rats and B6C3F₁ mice using whole-body inhalation exposure.Both species were evaluated for histopatho-logic and reproductiveeffects, and rats were examined for clinical chemistry and hematologicchanges. In the 2-week inhalation studies, animals were exposedto 10–800 mg HDDC/m³, 6 hr per day. All rats, all femalemice, and two of five male mice in the high-exposure group diedbefore the end of the study. Surviving mice in this group hada dose-dependent depression in body weight gain. Clinical signswere primarily related to upper respiratory tract irritationand included dyspnea and nasal discharge in both species. Treatment-relatedhistopathologic lesions included inflammation and necrosis ofthe laryngeal epithelium of both species and the tracheal epitheliumof mice, as well as focal inflammation and ulceration of therespiratory and olfactory nasal mucosa. In the 13-week inhalationstudies, animals were exposed to HDDC at concentrations of 1.6–160mg/ m³ for 6 hr per day, 5 days per week. In addition to thebase study groups, a supplemental group of rats at each exposurelevel was included to assess the effect of HDDC on reproduction.No treatment-related changes in organ weights or organ-to-body-weightratios occurred in rats, and no treatment-related clinical signsor gross lesions were seen in either species. Chemical-relatedmicroscopic lesions were limited to the upper respiratory tract(larynx and nasal passages) in the two highest exposure groupsand were similar in both species. These lesions included minimalto mild focal erosion, ulceration, inflammation, and hyperplasiaof the laryngeal epithelium, in addition to degeneration ofthe olfactory and respiratory nasal epithelium. HDDC causedno significant changes in sperm morphology or vaginal cytologyand no significant adverse effects on reproduction in rats ormice. Hematologic and clinical chemistry changes in rats wereminor and sporadic and were not accompanied by related histologicfindings. HDDC did not increase the frequency of micronucleatederythrocytes in mice. In summary, the toxicity of HDDC to ratsand mice was a result of the irritant properties of the chemical,was limited primarily to the nasal passages and upper airways,and was consistent with the effects of other irritant chemicalsadministered by inhalation.     

Inhalation Toxicity Studies of Cobalt Sulfate in F344/N Rats and B6C3F1 Mice

Inhalation Toxicity Studies of Cobalt Sulfate in F344/N Ratsand B6C3F1 Mice. BUCHER, J. R., ELWELL, M. R., THOMPSON, M.B., CHOU, B. J., RENNE, R., AND RAGAN, H. A. (1990). Fundam.Appl. Toxicol. 15, 357–372. Groups of 10 F344/N rats andB6C3F1 mice of each sex were exposed to cobalt sulfate heptahydrateaerosols of 0, 0.3, 1.0, 3.0, 10, or 30 mg/m3, 6 hr per day,5 days per week, for 13 weeks. All rats and female mice andall but 2/10 male mice exposed at the top concentration survivedto the end of the studies. Polycythemia was observed in exposedrats but not in mice. Sperm motility was decreased in mice exposedat 3 mg/m3 (the lowest concentration evaluated) and at higherconcentrations, and increased numbers of abnormal sperm anddecreased testis and epididymal weights occurred in mice exposedto 30 mg/m3. Cobalt content in the urine of rats increased withincreasing atmospheric cobalt exposure. Primary histopathologiceffects were limited to the respiratory tract. Lesions in ratsand mice included degeneration of the olfactory epithelium,squamous metaplasia of the respiratory epithelium, and inflammationin the nose; inflammation, necrosis, squamous metaplasia, ulcers(rats), and inflammatory polyps (rats) of the larynx; metaplasiaof the trachea (mice); and fibro-sis, histiocytic infiltrates,bronchiolar epithelial regeneration, and epithelial hyperplasiain the alveoli of the lung. The most sensitive tissue was thelarynx, with squamous metaplasia observed in rats and mice atthe lowest exposure concentration of 0.3 mg/m3. Thus, a no-observed-adverse-effectlevel was not reached in these studies     

Inhalation Toxicity of Phosphine for Fischer 344 Rats and B6C3F1 Mice

Abstract

Because of the potential increased use of phosphine (PH₃) as a fumigant and the lack of adequate toxicity data, short-term inhalation studies were conducted to characterize the toxicity of PH₃ for Fischer 344 (F344) rats and B6C3F1 mice. Male rats and mice were exposed to 0, 1, 5, or 10 ppm PH₃ for up to 4 days, and males and females to 0, 1.25, 2.5, or 5 ppm for 2 wk. In the 4-day study, all rats died by the end of the third exposure to 10 ppm, and all mice were euthanized in moribund condition after the fourth exposure to 10 ppm. Clinical pathology data were obtained only for mice, due to early mortality of rats. There were no significant treatment-related effects in hematological indices in mice exposed to 1 or 5 ppm; at 10 ppm there was a moderate anemia, and leukocyte counts were significantly decreased. There were significant biologically relevant increases in serum activity of alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) and in the concentration of urine nitrogen (UN) at 10 ppm. Flectrophoretic evaluation of hemoglobin from mice exposed to 10 ppm did not reveal any differences in banding patterns from controls. Moribund mice euthanized after 4 exposures to 10 ppm had minimal to mild degeneration and necrosis of the renal tubule epithelium, minimal myocardial degeneration, and minimal to mild subcapsular foci of hemorrhage and necrosis in the liver. Bound PH₃ could not be detected in blood, lung, liver, or kidney of mice or lungs of rats exposed to 10 ppm for 3–4 days. There were no treatment-related mortalities in rats or mice exposed for 2 weeks. Lung weights of male rats and mice were significantly decreased and heart weights of female rats and mice were significantly increased after 2 wk of exposure to 5 ppm. Slight but statistically significant increases were observed in serum UN in male mice exposed to 5 ppm. There was no microscopic evidence of treatment-related effects in any of the tissues examined from rats or mice exposed to 5 ppm for 2 wk. Bound PH₃ could not be detected in blood, lung, liver, or kidney of mice or rats exposed to 5 ppm for 2 wk. These studies demonstrated that PH₃ inhalation does not cause a specific target organ toxicity in the B6C3F1 mouse or F344 rat, and that the primary hazard of subchronic inhalation in these species is lethality.     

Thirteen-Week Inhalation Toxicity of 2- and 4-Chloronitrobenzene in F344/N Rats and B6C3F1 Mice

Toxicity studies were performed by exposing F344/N rats andB6C3F₁ mice to 2- and 4-chloronitrobenzene (CNB) by whole bodyinhalation 6 hr/day, 5 days/week, for 13 weeks. Animals wereevaluated for clinical chemistry (rats), hematology (rats),histopathology, and body/organ weights. Exposure concentrationswere 0, 1.1, 2.3, 4.5, 9, and 18 ppm for 2-CNB and 0, 1.5, 3,6, 12, and 24 ppm for 4-CNB. All rats in the 2-CNB study surviveduntil the end of the study. Two male mice in the 18-ppm groupin the 2-CNB study, however, died during Week 12; no deathsattributable to 4-CNB exposure occurred in rats or mice. Inboth studies, the mean body weight gains of exposed animalswere similar to those of the respective controls. In rats, inhalationexposure to 2- or 4-CNB resulted in methemoglobinemia leadingto a regenerative anemia and a variety of tissue changes secondaryto the oxidative erythrocyte injury. In the 2-CNB study, methemoglobinemiaresulted in a normocytic, normochiomic, responsive anemia, whereaswith 4-CNB, the methemoglobinemia was more severe and resultedin a niacrocytic, hyperchromic, responsive anemia. Alterationsof erythrocyte morphology were observed in both studies; changesincluded Heinz bodies, poikilocytes, and polychromasia. In rats,both isomers caused increases in serum activities of alanineaminotransferase and sorbitol dehydrogenase and increased bileacid concentrations. Microscopic liver changes included hemosiderindeposition in Kupffer cells (rats and mice exposed to 4-CNB),hepatocytomegaly (mice), and cytoplasmic basophilia (rats).Hepatocellular necrosis and chronic inflammation observed inmice were rather specific to the 2-CNB isomer, as only slightevidence of focal necrosis in the liver was observed in miceexposed to 4-CNB. Splenic lesions included hemosiderin accumulation,capsular fibrosis, and increased hematopoietic cell proliferation.Increased bone marrow hemosiderin and hematopoietic cell proliferationand kidney tubule hemosiderin deposition were also observed.Other findings, attributed to chemical exposure but not to thehematotoxicity, were described. Lesions included hyaline dropletnephropathy and degeneration of the testis in male rats exposedto 4-CNB, inflammation of the harderian gland in rats exposedto 4-CNB, hyperplasia of the nasal cavity epithelium in ratsexposed to 2-CNB, and hyperplasia of the forestomach epitheliumin mice exposed to 4-CNB; these lesions have not been describedpreviously in studies with these chemicals. Based on the exposureconcentrations evaluated, A no-observed-adverse-effect level(NOAEL) for histopathological injury in mice was 4.5 ppm for2-chloronitrobenzene and 6 ppm for 4-chloronitrobenzene; a NOAELwas not determined for rats.     

Thirteen-Week, Repeated Inhalation Exposure of F344/N Rats and B6C3F1 Mice to Ferrocene

Ferrocene (dicyclopentadienyl iron; CAS No. 102-54-5) is a relativelyvolatile compound used as a chemical intermediate, a catalyst,and an antiknock additive in gasoline. This organometallic chemicalis of particular interest because of its structural similaritiesto other metallocenes, some of which are carcinogenic. F344/Nrats and B6C3F₁ mice were exposed to 0, 3.0, 10, and 30 mg ferrocenevapor/m³, 6 hr/day, 5 days/week, for 13 weeks. During theseexposures, no rats or mice died, nor were any clinical signsof ferrocene-related toxicity observed. At the end of the exposures,male rats exposed to the lowest and highest level of ferrocenehad decreased body weight gains compared to filtered-air-exposedcontrol male rats, while body weight gains for all groups ofboth ferrocene- and filtered-air-exposed female rats were similar.Male mice exposed to ferrocene had no differences in body weightgains, compared to controls, but female mice had decreases inbody weight gains at the 10 and 30 mg/m³ exposure levels. Therewere exposure concentration- and exposure-time-related increasesin lung burdens of iron. The mean iron lung burden in rats exposedto 30 mg ferrocene vapor/m³ for 90 days was four times greaterthan the burden in control rats. No exposure-related changesin respiratory function, lung biochemistry, bronchoalveolarlavage cytology, total lung collagen, clinical chemistry, andhematology parameters were observed. This suggests that theaccumulations of iron in lung did not cause an inflammatoryresponse nor any functional impairment of the lung. There wereno indications of developing pulmonary fibrosis nor of any hematologictoxicity. No exposure-related gross lesions were seen in anyof the rats or mice at necropsy. Exposure-related histopathologicalterations, primarily pigment accumulations, were observedin the nose, larynx, trachea, lung, and liver of both species,and in the kidneys of mice. Lesions were most severe in thenasal olfactory epithelium where pigment accumulation, necrotizinginflammation, metaplasia, and epithelial regeneration occurred.Nasal lesions were observed in all ferrocene-exposed animalsand differed only in severity, which was dependent on the exposureconcentration. Histochernical stains of these target tissuesshowed the presence of iron ions. The results suggest that themechanism of ferrocene toxicity may be the intracellular releaseof ferrous ion through ferrocene metabolism, followed by eitheriron-catalyzed lipid peroxidation of cellular membranes or theiron-catalyzed Fenton reaction to form hydroxyl radicals thatdirectly react with other key cellular components, such as proteinor DNA.     

Comparative Toxicity and Carcinogenicity of Two Chlorinated Paraffins in F344/N Rats and B6C3F1 Mice

The toxicity and carcinogenicity of chlorinated paraffins containingC12 with 60% Cl, and C23 with 43% C1, were assessed in prechronicand 2-year gavage studies using F344/N rats and B6C3F1 miceof both sexes. Single administrations of chlorinated paraffinswere nonle thal in rats and mice, but repeated-dose and 2-yearstudies demonstrated toxic responses that differed with theparaffins. The C23,C143% paraffin produced a granulomatous inflammationin the liver of female rats in 13-week studies, while the C12,Cl60% paraffin caused deaths of rats and mice in 16-day studiesand marked liver enlargement in 13-week studies. In 2-year studies,the C23,C143% paraffin caused hepatic and lymphatic granulomatousinflammation and hyper plasia in both sexes of rats, and wasassociated with marginal increases in adrenal medullary pheochromocytomasin female rats and hepatocellular neoplasms in female mice andwith clear increases in malignant lymphomas in male mice. TheCl 2,Cl60% paraffin caused marked liver enlargement in ratsand increased the severity of nephropathy in male rats and theincidence of nephropathy in female rats. Cl2,Cl60% also causedhepatocellular neoplasms in both sexes of rats and mice: kidneytubular cell adenomas and adenocarcinomas in male rats, thyroidfollicular cell neoplasms in female rats and female mice, anda marginal increase in mononuclear cell leukemia in male rats.Thus, the short-chain, heavily chlorinated paraffin appearsto have a greater potential for chronic toxicity and carcinogenicitythan the longer-chain, lightly chlorinated paraffin. Both paraflinshave been reported to be nonmutagenic in bacteria. (NationalToxicology Program (1986) Technical Report, NIH Publications86-2561 and 86-2564).     

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.     

Toxicity and Carcinogenicity of 2,3-Dibromo-1-propanol in F344/N Rats and B6C3F1 Mice

2,3-Dibromo-1-propanol is a metabolite of the flame retardanttris(2,3-dibromopropyl) phosphate, previously shown to be amutagen and carcinogen in experimental animals. Toxicology andcarcinogenesis studies of 2,3-dibromo-1-propanol were conductedby applying the chemical in 95% ethanol to the interscapularskin of male and female F344/N rats and B6C3F₁ mice 5 days aweek for 13 weeks in the prechronic study and 48–55 weeks(rats) or 36–42 weeks (mice) in the carcinogenicity study.In the 13-week study, 10 rats and 10 mice of each sex receiveddoses of 0, 44, 88, 177, 375, or 750 mg/kg. Deaths associatedwith chemical application occurred only in the high-dose (750mg/kg) male mice. Chemical-related lesions were seen in thekidney of male rats, liver of female rats, and liver and lungof both sexes of mice. Based on the toxicity observed in the13-week study, 50 rats of each sex received doses of 0, 188,or 375 mg/kg and 50 mice of each sex received 0, 88, or 177mg/kg in the carcinogenicity study. The planned 2-year studywas terminated early because of reduced survival of rats relatedto chemical-induced neoplasia and because of the appearanceof antibodies to lymphocytic choriomeningitis virus in sentinelmice. Nearly all dosed rats had malignant neoplasms at one ormore sites, while only one control male and one control femalehad malignant neoplasms. In rats, neoplasms induced by 2,3-dibromo-1-propanoloccurred in the skin, nasal mucosa, Zymbal's gland, oral mucosa,esophagus, forestomach, intestines, liver, kidney, mammary gland(females), clitoral gland (females), spleen (males), and mesothelium(males). In mice, chemical-induced neoplasms occurred in theskin, forestomach, liver (males), and lung (males).     

Subchronic Toxicity of Triethylenetetramine Dihydrochloride in B6C3F1 Mice and F344 Rats

Triethylenetetramine dihydrochloride (trien-2HCl; CAS No. 38260-01-04),a chelating agent used to treat Wilson's disease patients whoare intolerant of the drug of choice, was tested for subchronictoxicity in B6C3F1 mice and F344 rats. Mice and rats receivedtrien-2HCl in the drinking water at concentrations of 0, 120,600, or 3000 ppm for up to 92 days. Twenty mice and 18 ratsof each sex were assigned to each dose group fed either a cereal-based(NIH-31) or a purified (AIN-76A) diet, both containing nutritionallyadequate levels of copper. An additional control group of ratsand mice received a Cu-deficient AIN-76A diet. This low copperdiet resulted in Cu-deficiency symptoms, such as anemia, liverperiportal cytomegaly, pancreatic atrophy and multifocal necrosis,spleen hematopoietic cell proliferation, and increased heartweight, together with undetectable levels of plasma copper inrats but not in mice. Trien-2HCl lowered plasma copper levelssomewhat (at 600 and 3000 ppm) in rats fed the AIN-76A diet,but did not induce the usual signs of copper deficiency. Trien-2HClcaused an increased frequency of uterine dilatation at 3000ppm in rats fed AIN-76A diet that was not noted in females fedthe Cu-deficient diet. Trien-2HCl toxicity occurred only inmice in the highest dose group fed an AIN-76A diet. Increasedfrequencies of inflammation of the lung interstitium and liverperiportal fatty infiltration were seen in both sexes, and hematopoieticcell proliferation was seen in the spleen of males. Kidney andbody weights were reduced in males as was the incidence of renalcytoplasmic vacuolization. There were no signs of copper deficiencyin mice exposed to trien-2HCl. The only effect of trien-2HClin animals fed the NIH-31 diet was a reduced liver copper levelin both rat sexes, noted at 3000 ppm.     

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.     

Particle Clearance and Histopathology in Lungs of F344/N Rats and B6C3F1 Mice Inhaling Nickel Oxide or Nickel Sulfate

The goals of this study were to (1)determine the effects ofrepeated inhalation of relatively insoluble nickel oxide (NiO)and highly soluble nickel sulfate hexahydrate (NiSO₄ 6H₂O) onlung particle clearance, (2)investigate the effects of repeatedinhalation of NiO or NiSO₄ on the pulmonary clearance of subsequentlyinhaled ⁸⁵Sr-labeled microspheres, (3)correlate the observedeffects on clearance with accumulated Ni lung burden and associatedpathological changes in the lung, and (4)compare responses inF344 rats and B6C3F₁, mice. Male F344/N rats and B6C3F₁ micewere exposed whole-body to either NiO or NiSO₄ 6H₂O 6 hr/day,5 days/week for up to 6 months. NiO exposure concentrationswere 0, 0.62, and 2.5 mg NiO/m for rats and 0, 1.25, and 5.0mg NiO/ m for mice. NiSO₄ 6H₂O/m³ exposure concentrations were0, 0.12, and 0.5 mg NiSO₄ 6H₂ for rats and 0, 0.25, and 1.0mg NiSO₄ 6H₂O/m³ for mice. After 2 and 6 months of whole-bodyexposure, groups of rats and mice were acutely exposed nose-onlyto 63 (NiO-exposed animals only), ⁶³NiSO₄ 6H₂O (Ni SO₄ 6H₂Oanimals only), or to ⁸⁵Sr-labeled polystyrene latex (PSL) microspheres(both NiO- and NiSO₄ 6H₂O-exposed animals) to evaluate lungclearance. In addition, groups of rats and mice were euthanizedafter 2 and 6 months of exposure and at 2 and 4 months afterthe whole-body exposures were completed to evaluate histopathologicalchanges in the left lung and to quantitate Ni in the right lung.Repeated inhalation of NiO results in accumulation of Ni inlungs of both rats and mice, but to a greater extent in lungsof rats. During the 4 months after the end of the whole-bodyexposures, some clearance of the accumulated Ni burden occurredfrom the lungs of rats and mice exposed to the lower, but notthe higher NiO exposure concentrations. Clearance of acutelyinhaled ⁶³NiO was also impaired in both rats and mice, withthe extent of impairment related to both exposure concentrationand duration. However, the clearance of acutely inhaled ⁸⁵SrPSL microspheres was not impaired. The repeated inhalation ofNiO resulted in alveolar macrophage (AM) hyperplasia with accumulationof NiO particles in both rats and mice, chronic alveolitis inrats, and interstitial pneumonia in mice. These lesions persistedthroughout the 4-month recovery period after the NiO whole-bodyexposures were terminated. In contrast, repeated inhalationof NiSO₄ 6H₂O did not result in accumulation of Ni in lungsof either rats or mice and did not affect the clearance of ⁶³NiSO₄6H₂Oinhaled after either 2 or 6 months of NiSO₄ 6H₂O exposure. Clearanceof the ⁸⁵Sr-labeled microspheres was significantly impairedonly in rats exposed to the microspheres after 2 months of exposureto NiSO₄ 6H₂O Histopathological changes in rats were qualitativelysimilar to those seen in NiO-exposed rats. Only minimal histopathologicalchanges were observed in NiSO₄ 6H₂O mice. These results suggestthat repeated inhalation of NiO at levels resulting in AM hyperplasiaand alveolitis may impair clearance of subsequently inhaledNiO. The potential effects of repeated inhalation of solubleNiSO₄ 6H₂O on the clear ance of subsequently inhaled poorlysoluble particles are less clear.     

Toxicity and Carcinogenicity of Rotenone Given in the Feed to F344/N Rats and B6C3F1 Mice for up to Two Years

ABSTRACT

Toxicity and carcinogenicity studies of rotenone were conducted in F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were given rotenone in their diet for up to 103 weeks. The doses were 0, 38, and 75 ppm for rats and 0, 600, and 1,200 ppm for mice. Reduction in body weight gain occurred in male and female mice given rotenone. No effects on survival were observed for rats of either sex or female mice. Survival of male mice at 1,200 ppm was significantly greater than that of controls (47/50 vs. 29/50). There were no observed nonneoplastic effects due to rotenone, and for male and female mice no neoplasms were induced by rotenone. Parathyroid adenomas occurred at a higher incidence (4/44) in male rats at 75 ppm than in the controls (1/41). Because these tumors are rare (historical rate in NTP studies is 0.3%), the increase in the incidence of these benign tumors may have been related to rotenone administration. Hepatocellular neoplasms were reduced (p<0.01) in males receiving 1,200 ppm 1/50 relative to controls 12/47. Because this low rate of liver tumors is unusual in male B6C3F1 mice, this decrease was considered to be related to rotenone administration.     

Effect of Inhaled Azodicarbonamide on F344/N Rats and B6C3F1 Mice with 2-Week and 13-Week Inhalation Exposures

Effect of Inhaled Azodicarbonamide on F344/N Rats and B6C3F,Mice with 2-Week and 13-Week Inhalation Exposures. MEDINSKY,M. A., BECHTOLD, W. E., BIRNBAUM, L. S., BOND, J. A., BURT,D. G., CHENG, Y. S., GILLFTT, N. A., GULATI, D. K., HOBBS, C.H., AND PICK-RELL, J. A. (1990). Fundam. Appl. Toxicol 15, 308/319.Azodicarbonamide (ADA), a compound used in the baking and plasticsindustries, has been reported to cause pulmonary sensiti-zationand dermatitis in people. Two-week repeated and 13-week subchronicinhalation exposures of F344/N rats and B6C3F, mice to ADA wereconducted to determine the toxicity of inhaled ADA. The meanair concentrations of ADA in the 2-week studies were 207, 102,52, 9.4, or 2.0 mg/m3. No exposure-related mortality nor abnormalclinical signs were observed in rats or mice during or afterexposure. The terminal body weights were slightly depressedin the highest exposure group. Liver weights were lower in malerats exposed to 200 mg ADA/m3. No significant lesions were notedon either gross or histologic evaluation of rats or mice. Inthe 13-week subchronic study, the mean air concentrations ofADA were 204, 100, or 50 mg/m3. No mortality or clinical signsrelated to exposure were observed. The terminal body weightsof exposed rats were not significantly different from thoseof control rats but were significantly depressed in mice exposedto 100 or 200 mg ADA/m3. No histopathological lesions were notedin mice. Lung weights were increased and enlarged mediastinaland/or tracheobronchial lymph nodes were noted in rats exposedto 50 mg ADA/m3. No exposure-related lesions were observed microscopicallyin rats exposed to 100 or 200 mg ADA/m3. All rats in the 50mg ADA/m3 exposure group only had lung lesions that consistedof perivascular cuffing with lymphocytes and a multifocal typeII cell hyperplasia, suggesting a possible immune reaction toan antigen in the lung. Viral titers for rats exposed to 50mg ADA/m3 were negative for Sendai virus and pneumonia virusof mice, which produce similar lesions. The possibility of anunknown viral antigen causing this lesion cannot be eliminated.Lung tissue from male rats was analyzed for ADA and biurea,the major metabolite of ADA. No ADA was detected. The amountof biurea in the lungs increased nonlinearly with increasingexposure concentration, suggesting that clearance was somewhatimpaired with repeated exposures. However, even at the highestexposure concentration, this amount of biurea was less than1 % of the estimated total ADA deposited over the exposure period.In summary, ADA is rapidly cleared from the lungs, even wheninhaled at concentrations up to 200 mg/m3. Exposure to ADA forup to 13 weeks did not appear to be toxic to rodents     

Chronic Nephropathy and Renal Carcinogenicity of o-Benzyl-p-chlorophenol in F344/N Rats and B6C3F1 Mice

o-Benzyl-p-chlorophenol, an aryl halide biocide, was evaluatedin male and female F344/N rats and B6C3F₁ mice in a series ofsubchronic and 2-year toxicity and carcinogenicity studies.Kidney was the primary target of toxicity in the 13-week gavagestudies in rats and mice, with increased nephropathy noted aslow as 240 mg/kg in male rats. Considering the nephropathy tobe dose-limiting, the chronic (2-year) study was conducted atlower doses (male rats: 30, 60, or 120 mg/kg; female rats: 60,120, or 240 mg/kg; male and female mice: 120, 240, or 480 mg/kg;in corn oil; n=50/group). Survival and body weights of dosedrats were similar to controls in the 2-year study. Survivalof high-dose male and female mice, and body weights of all dosedmale and mid- and high-dose female mice, were lower than controls.The incidence and severity of nephropathy increased with doseand length of treatment in both rats and mice. There was anincreased incidence of renal tubule adenomas or carcinomas inboth the mid- and high-dose male mice. Despite similar evidenceof nephropathy, however, there were no increased incidencesof neoplasms in female mice or in male or female rats. Thisstudy suggests therefore that while nephrotoxicity may havebeen a necessary component, factors other than the marked nephrotoxicityof o-benzyl-p-chloro-phenol were critical to the developmentof renal carcinogenesis induced in only male mice.     

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.     

Four-Day Repeated Inhalation and Recovery Study of Methyl lsocyanate in F344 Rats and B6C3F1 Mice

F344 rats and B6C3F1 mice of both sexes were exposed by inhalationto 0, l,and 3 ppm methyl isocyanate (MIC) for 4 consecutivedays (6 hr/day) followed by a recovery period of 91 days. Fivemice and rats/sex/group except the 3 ppm group (5 rats/ sexon Day 7 and 2 males on Day 28) were killed on Days 7, 28, 49,and 91 after the exposure and examined histopathologically.Forty-nine of 56 male rats, 51 of 56 female rats, and 1 of 56male mice in the 3 ppm group died by 28 days; early death animalswere also examined histologically. Exposure-related changesoccurred in rats and mice of both sexes in the 3 ppm group only.Lesions of the nasal cavity in rats and mice were characterizedby regeneration of the olfactory and respiratory epithelia secondaryto epithelial erosion. By Day 28 the olfactory and respiratoryepithelia in mice appeared normal, while in rats incompleteregeneration of the olfactory epithelium was still present.Regeneration of the respiratory epithelium in the trachea ofrats occurred in the 3 ppm group and the epithelium appearedto return to normal by Day 28. Lung lesions in rats consistedof mural and/or intraluminal fibrosis secondary to extensiveerosion of the respiratory epithelium in the major bronchi tothe terminal bronchioles. Acute inflammation of the small airways,occasional hyaline membranes of alveolar walls, and pulmonaryatelectasis were also seen. Alveolar fibrosis was observed inrats found dead from Day 14 on and in male rats killed on Day28. Atrophy of the thymus and spleen, atrial thrombosis of theheart, and hepatocellular necrosis were frequently seen in ratsdying following MIC exposure. The lung lesions in mice werequalitatively similar to those in rats, but were restrictedto the major bronchi. Minimal intraluminal or mural fibrosiswas still present in mice on Day 91. In a separate study, asingle 6-hr exposure of five male rats to 3 ppm MIC was followedby a recovery period of 7 days. The lesions of the respiratorysystem were essentially the same as those in the 3 ppm groupkilled on Day 7 after the 4-day repeated exposure of MIC, butthe alveolar lesions were more severe.     

Eight-Week Toxicity Study of 60 Hz Magnetic Fields in F344 Rats and B6C3F1 Mice

Toxicity studies were performed by exposing F344/N rats andB6C3F1 mice (10 animals per sex per species per group) to transient-free,linearly polarized 60 Hz magnetic fields for 8 weeks. Targetedmagnetic fields strengths used were 0 gauss (G; sham controlfields did not exceed 0.001 G), 0.02 G, 2 G, and 10 G. Exposurewas whole-body and continuous for 18.5 hr per day, 7 days perweek. An additional group of rats and mice was exposed intermittently(1 hr on/1 hr off) to 10 G fields for the same period of time.Endpoints evaluated included morbidity, mortality, gross pathology,histopathology, body/organ weights, clinical chemistry (ratsonly), and hematology (rats only). All mice and all male ratssurvived until the end of the study. One female rat (2-G exposuregroup) died during Week 7 of the study; the death was not attributedto magnetic field exposure. In both studies, the mean body weightgains of exposed animals were similar to those of the respectivecontrols. There were no gross, histological, hematological,or biochemical lesions attributed to magnetic field exposure.Statistically significant increases in liver weight and liverto body weight ratio occurred in female rats of all exposuregroups but only at the termination. These data suggest that,for the variables evaluated in these studies, an 8-week exposureto linear-polarized, transientfree 60 Hz magnetic fields atfield intensities of up to 10 G is not associated with significanttoxicity in F344/N rats and B6C3F1 mice. Furthermore, therewas no toxicity observed in animals receiving intermittent (1hr on/l hr off) exposures to 10-G fields. A 2-year study inF344/N rats and B6C3F1 mice is nearing completion of the in-lifephase without overt toxicity in any exposed group. It is premature,however, to make any prediction concerning the possible influenceof exposure to 60 Hz magnetic fields on cancer rates.     

Toxicity and carcinogenicity of nitrofurazone in F344/N rats and B6C3F1 mice

Toxicology and carcinogenesis studies were conducted by feeding diets containing nitrofurazone (99% pure) to groups of F344/N rats and B6C3F1 mice for 14 days, 13 wk or 2 yr. In the 14-day studies, in which doses ranged from 630 to 10,000 ppm, nitrofurazone was more toxic to mice than to rats. Accordingly, in the 13-wk studies, doses for rats ranged from 150 to 2500 ppm and for mice from 70 to 1250 ppm. At the higher doses, convulsive seizures and gonadal hypoplasia were observed in both species. Evidence of toxicity in rats also included degenerative arthropathy. For the 2-yr studies, rats were exposed to 0, 310 or 620 ppm nitrofurazone and the survival of male rats given 620 ppm was lower than that of controls (33/50, 30/50 and 20/50 in the control, 310- and 620-ppm groups, respectively). Nitrofurazone administration increased the incidences of mammary gland fibroadenomas in female rats (8/49, 36/50 and 36/50 in the control, 310- and 620-ppm groups, respectively). In male rats it was associated with a marginal increase in sebaceous gland adenomas and trichoepitheliomas of the skin, mesotheliomas of the tunica vaginalis, and tumours of the perputial gland. Nitrofurazone caused testicular degeneration (atrophy of germinal epithelium and aspermatogenesis) in rats, and degeneration of vertebral and knee articular cartilage in rats of both sexes. In mice, dietary concentrations of nitrofurazone for the 2-yr studies were 0, 150 or 310 ppm. In mice of each sex, nitrofurazone administration induced stimulus-sensitive convulsive seizures, primarily during the first year of study. In male mice, there was no evidence of any chemically-related carcinogenic effects, but there was a treatment-related decrease in survival (39/50, 31/50 and 27/50 in the control, 150- and 310-ppm groups, respectively). In female mice nitrofurazone induced ovarian lesions with increased incidences of benign mixed tumours (0/47, 17/50 and 20/50 in control, low- and high-dose groups, respectively) and granulosa cell tumours (1/47, 4/50 and 9/50 in control, low- and high-dose groups, respectively).