Chronic Morpholine Exposure of Rats

Chronic Morpholine Exposure of Rats. HARBISON, R. D., MARINO,D. J., CONAWAY, C. C., RUBIN, L. F., AND GANDY, J. (1989). FundamAppl. Toxicol. 12,491–507. The chronic toxicity and carcinogenicpotential of morpholine were evaluated in 60 Sprague-Dawleyrats/sex/group receiving morpholine at mean inhalation exposureconcentrations of 0, 10, 50 and 150 ppm for 6 hr/day, 5 days/week,for 104 weeks. Survival, body weight gains, organ weights, hematology,and clinical chemistries were normal in exposed groups and comparableto those of the control animals. The incidences of palpabletissue masses and of histologically confirmed neoplasia werecomparable among all groups, including the control groups, andwere typical of the strain and age of the rats tested. In-lifeclinical examinations revealed increased incidences of irritationaround the eyes and nares, chromadacryorrhea, and urine stainson the fur, predominately in high-dose animals. Morpholine exposurewas associated with corneal irritation seen by ophthalmoscopicexamination and confirmed microscopically as keratitis limitedto the highest exposure group. Irritation of the maxillary andnasoturbinates as indicated by infiltration of neutrophils,focal squamous metaplasia of the turbinate epithelium, and necrosisof the turbinate bone was observed in high-dose animals. Therefore,chronic exposure of rats to morpholine for 2 years at concentrationsof 150 ppm or less revealed no carcinogenic potential or chronicsystemic toxicity. Consistent with its known irritating properties,morpholine produced only local irritation, which was limitedalmost exclusively to high-dose animals.     

Food Restriction during Organogenesis in Rabbits: Effects on Reproduction and the Offspring

Food Restriction during Organogenesis in Rabbits: Effects onReproduction and the Offspring. PETRERE, J. A., ROHN, W. R.,GRANTHAM, L. E., II, AND ANDERSON, J. A. (1993). Fundam. Appl.Toxicol. 21, 517–522. To assess the effects of markedly restricted food intake versusad libitum feeding or a slightly restricted feeding regimenduring the period of organogenesis we fed groups of 16–18pregnant rabbits Purina Certified High Fiber Chow ad libitum,150 g/day, 75 g/day, or 15 g/day on Gestation Days 6 to 18 inclusive.Prior to and after organogenesis the animals were provided foodad libitum (ad lib). Clinical observations, body weights, andfood and water consumption were recorded daily. On GestationDay 30 each doe was euthanatized and necropsied, and maternaland fetal data were collected. Each fetus was examined for external,visceral, and skeletal variations and malformations. Ossificationparameters were also evaluated. Statistical analyses were conductedin two ways, first comparing the restricted groups to the adlib group and second comparing the 15 and 75 g/day groups tothe 150 g/day group. During Days 6–18, the 15 and 75 g/daygroups had significantly decreased weight gain (actual weightloss), compared to the groups fed 150 g/day or ad lib. Waterconsumption was also significantly decreased in the 15 g/daygroup during this period, compared to the ad lib group. Whenfood was provided ad lib on Days 19–30 to the restrictedgroups, weight gain was significantly higher in the 15 and 75g/day groups than the group previously given 150 g/day and thead lib group. There were no differences in water consumptionduring that period. Abortion occurred in three 15 g/day animals.Pregnancy rate and numbers of corpora lutea, implantation sites,live and dead fetuses and resorptions, pre- and postimplantationloss, and placental weights were similar among groups. Fetalsex ratio and survival at term were comparable between the adlib group and the restricted groups. In the 15 g/day group,mean fetal weights were lower than those in the 150 g/day andthe ad lib groups. None of the fetuses from food-restricteddoes had external or visceral malformations, whereas two littermatesfrom the ad lib group had malformations of the heart or gallbladder.Except for a significant increase in the percentage of litterswith external or visceral variations in the 15 g/day group comparedto the 150 g/day group, there were no significant differencesbetween groups in the incidences of variations or malformations.Our findings agree with those in the literature in that abortionis increased and fetal weights are reduced when maternal foodintake is severely restricted during organogenesis. Contraryto a previous report also using 15 g/day during organogenesis[R. L. Clark, R. T. Robertson, C. P. Peter, J. A. Bland, T.E. Nolan, L. Oppenheimer, and D. L. Bokelman (1986). Fundam.Appl. Toxicol. 7, 292–286], we did not have an increasedincidence of fetal malformations. This study indicates thatthe influence of reduced food intake and body weight loss duringorganogenesis is equivocal in the induction of teratogenicityin rabbits.     

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.     

Pulmonary Fibrosis Produced in F-344 Rats by Subchronic Inhalation of Aerosols of a 4000 Molecular Weight Ethylene Oxide/Propylene Oxide Polymer

Pulmonary Fibrosis Produced in F-344 Rats by Subchronic Inhalationof Aerosols of a 4000 Molecular Weight Ethylene Oxide/PropyleneOxide Polymer. KLONNE, D. R., DODD, D. E., Losco, P. E., TROUP,C. M., AND TYLER, T. R. (1988), Fundam Appl. Toxicol 10, 682–690.Inhalation of aerosols of the ethylene oxide/propylene oxidepolymer (U-5100) evaluated in this study has previously beenshown in acute and 2-week studies to produce toxicologic effectson the lungs, with increased lung weights and microscopic findingsof congestion and hemorrhage of pulmonary alveolar capillariesand necrosis of alveolar epithelial cells (D. R. KLONNE, D.J. NACHREINER, D. E. DODD, P. E. Losco, AND T. R. TYLER, 1987,Fundam. Appl. Toxicol. 9, 7737–784). In the present studies,F-344 rats were exposed 6 hr/day, 5 day/week for 2 weeks toaerosols at mean concentrations of 0,0.9, or 5.0 mg/m³ or for13 weeks to mean concentrations of 0, 0.3, 1.1, or 5.2 mg/m³.Following the 2-week study, minimal multifocal hemorrhage andeosinophilic proteinaceous debris in alveoli were observed inthe 0.9 mg/m³ group; similar lesions plus alveolar cell necrosiswere found in the 5 mg/m³ group. In the 13-week study, the 5.2mg/m³ group had a slight decrease in body weight gain, whileincreases in absolute and/or relative lung weights occurredfor both the 1.1 and 5.2 mg/m³ groups at the end of the exposureregimen and at the end of a 5-week recovery period. Histologiclesions of the lungs occurred in all U-5100-exposed groups andconsisted of hemorrhage, alveolar histiocytosis, interstitialpneumonia, and multifocal fibrosis. The incidence and severityof the pulmonary lesions were concentration related. At theend of the 5-week recovery period, there was little change inthe severity or incidence of the pulmonary lesions in the 1and 5 mg/m³ groups when compared to rats killed the day afterthe termination of exposures. In conclusion, exposure to aerosolsof U-5100 for 13 weeks produced generally slight but biologicallysignificant pulmonary fibrosis in rats at all the exposure concentrationstested in this study.     

Inhalation Fertility and Reproduction Studies with O,O'- Dimethylphosphorodithioate in Sprague-Dawley Rats

Inhalation Fertility and Reproduction Studies with O,O'-Dimethylphosphorodithioatein Sprague-Dawley Rats. HEYDENS, W. F., AND KRONENBERG, J. M.(1989). Fundam. Appl Toxicol. 12, 62–69. Groups of 15male and 35 female Sprague-Dawley rats were exposed to 0,0'-dimethylphosphorodithioate(DMPDT) 6 hr/day, 5 days/week for 11 weeks. Initial target concentrationswere 0, 4, 25, and 200 mg/m³ However, because of excessive toxicity,the high exposure level was reduced to 125 mg/m³ after 8 weeks.Exposed males were cohoused with two unexposed females immediatelyfollowing the exposure period and later mated to an additionaltwo unexposed females following a 16-week recovery period. Exposedfemales were cohoused with untreated males, and exposures wereresumed after mating and continued during gestation. Some femaleswere terminated at midgestation to assess fertility, while otherswere allowed to deliver their pups. F₁ animals were terminatedfor histological examination or mated to assess fertility. High-exposurelevel F₀ males were infertile after exposures, and there waslittle or no recovery. The fertility of low-exposure level maleswas not affected, but equivocal results were obtained at themid-exposure level. In this study, testicular lesions were observedonly in high level F₀ males. However, testicular lesions werealso noted in a few males exposed to 4 and 25 mg/³ in a concurrentsubchronic toxicity study. Female fertility was apparently unaffectedby exposure, and no treatment-related effects were noted inmales or females exposed in utero     

Teratologic Evaluation of Inhaled Epichlorohydrin and Allyl Chloride in Rats and Rabbits

Teratologic Evaluation of Inhaled Epichlorohydrin and AllylChloride in Rats and Rabbits. John, J.A., Gushow, T.S., Ayres,J.A., Hanley, T.R., Jr., Quast, J.F. and Rao, K.S. (1983). Fundam.Appl Toxicol. 3:437–442. Pregnant Sprague-Dawley ratsand New Zealand white rabbits were exposed to vapors of epichlorohydrin(ECH) at concentrations of 0, 2.5 or 25 ppm or to allyl chloride(AC) at concentrations of 0, 30, or 300 ppm. Exposures werefor 7 hr/day on days 6 through 15 (rats) or 6 through 18 (rabbits)of gestation. Maternal effects including decreased body weightand food consumption were observed among rats inhaling 25 ppmof ECH. No evidence of an adverse effect to the embryo or fetuswas observed among rats or rabbits following exposure to ECH.In the AC study maternal toxicity occurred in both rats andrabbits treated at 300 ppm. These consisted of depressed weightgain during gestation and increases in liver weight (both species)and kidney weights (rats only). Fetuses from rats exposed to300 ppm of AC had a slight delay in skeletal development butthere were no other signs of embryotoxicity. Thus, ECH and ACwere not teratogenic or embryolethal in rats or rabbits followinginhalation exposure to concentrations which induced effectsin the maternal animals.     

Immunotoxicologic Assessment of Subacute Exposure of Rats to Carbon Tetrachloride with Comparison to Hepatotoxicity and Nephrotoxicity

Immunotoxicologic Assessment of Subacute Exposure of Rats toCarbon Tetrachloride with Comparison to Hepatotoxicity and Nephrotoxicity.SMIALOWICZ, R.J., SIMMONS, J. E., LUEBKE, R. W., AND ALLIS,J. W. (1991). Fundam. Appl. Toxicol 17, 186-196. The immunotoxicity,hepatotoxicity, and nephrotoxicity of subacute exposure to carbontetrachloride (CCI4) were evaluated in young adult (8-9 weeksold) male Fischer 344 rats dosed by gavage with CCI4 for 10consecutive days at 0, 5, 10, 20 or 40 mg/kg/day. Two days followingthe last treatment rats were evaluated for alterations in immunefunction by monitoring the following; body and lymphoid organweights; mitogen and mixed leukocyte reaction lymphoproliferativeresponses; natural killer cell activity; and cytotoxic T lymphocyteresponses. A separate group of similarly dosed rats was immunizedwith sheep red blood cells (SRBQ on Day 9 of dosing, and theprimary antibody response was assessed 4 days later. Hepaticand renal toxicity were assessed 2 days after the last treatmentby monitoring organ weights, serum indicators of hepatic andrenal damage, and hepatic cytochrome P450 levels, as well asby histological evaluation. Significant increases in relativeliver weights were observed in rats dosed at 40 mg/kg/day. Histologically,these livers displayed mild to moderate vacuolar degenerationand minimal to mild hepatocellular necrosis. In addition, serumlevels of aspartate aminotransferase and alanine aminotransferasewere elevated at this dosage, as well as at 20 mg/kg/day. Therewere no renal effects observed at these dosages of CCU. In addition,no consistent alterations were observed in the immune parametersexamined in these same animals nor in the rats immunized withSRBC. Furthermore, there was no difference in the antibody responseto SRBC in another set of rats dosed at 40, 80, or 160 mg/kg/dayCCI⁴. These results indicate that CCU is not immunotoxic inthe rat at dosages that produce overt hepatotoxicity.     

Evaluation of the Subacute and Subchronic Toxicity of Inhaled EDS Hydrotreated Naphtha in the Rat

Evaluation of the Subacute and Subchronic Toxicity of InhaledEDS Hydrotreated Naphtha in the Rat. MCKEE, R. H., AND HINZ,J. P. (1987). Fundam Appl. Toxicol 9, 120–130. Inhalationstudies were conducted to assess the subacute and subchronictoxicity of EDS hydrotreated naphtha (HN). In the subacute toxicitystudy, male and female Sprague-Dawley rats were exposed to variousconcentrations of HN vapor (0 2, 1.0, and 5.0 g/m³) 6 hr/dayfor 5 consecutive days. Following 2 recovery days, the animalswere exposed for 4 additional days and then sacrificed on the12th study day. In the subchronic toxicity study, a similarprotocol was utilized, however, the animals were exposed 5 days/weekfor 13 weeks. Following a 2-week recovery period, the animalswere sacrificed. Parameters examined in both studies includedsurvival, growth, clinical observations, urinalysis, blood chemistryat necropsy, and microscopic examination of selected tissues.There was some evidence of systemic effects associated withrepeated inhalation exposure to HN, although these effects weremild and were primarily confined to the high-exposure groups.The major systemic effect appeared to be renal toxicity in malerats as evidenced by increased urinary excretion of renal epithelialcells, creatinine, glucose, and protein and decreased urineosmolality. However, the absence of consistent pathologic changesin the kidneys of these animals suggested that the lesions wereeither slight or reversible during the 2-week recovery period.     

n-Butyl Acrylate: Prenatal Inhalation Toxicity in the Rat

n-Butyl Acrylate: Prenatal Inhalation Toxicity in the Rat. Merkle,J. and Klimisch, H.-J. (1983). Fundam. Appl. Toxicol. 3:443–447.n-Butyl acrylate was examined for its prenatal toxicity in Sprague-Dawleyrats. Inseminated rats were exposed to concentrations of 0,25, 135 and 250 ppm for a duration of 6 hours per day from the6th to 15th day post coitum. Subsequently the animals were heldto the 20th day post coitum. During the inhalation period concentrationsof 135 and 250 ppm n-butyl acrylate led to maternal toxicity(delayed body weight gain depending on the concentration, clinicalsigns of irritation). At the end of the exposure period thesigns subsided. The same concentrations induced embryo-lethality(increased number of dead implantations depending on the concentration).25 ppm of n-butyl acrylate did not lead to maternal toxicityor embryolethality. Under the conditions chosen, a teratogeniceffect of the test substance was not detected at any concentration.     

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.     

A Subchronic Dermal Exposure Study of Diethylene Glycol Monomethyl Ether and Ethylene Glycol Monomethyl Ether in the Male Guinea Pig

A Subchronic Dermal Exposure Study of Diethylene Glycol MonomethylEther and Ethylene Glycol Monomethyl Ether in the Male GuineaPig. HOBSON, D. W., D'ADDARIO, A. P., BRUNER, R. H., AND UDDIN,D. E. (1986). Fundam. Appl. Toxicol 6, 339–348. Diethyleneglycol monomethyl ether (DEGME) has been selected as a replacementanti-icing additive for ethylene glycol monomethyl ether (EGME)in Navy jet aircraft fuel. This experiment was performed todetermine whether DEGME produced similar toxicity to EGME followingdermal exposure. Male guinea pigs were dermally exposed to 1.00,0.20, 0.04, or 0 (control) g/kg/day EGME for 13 weeks, 5 days/week,6 hr/day. Another group of animals was similarly exposed to1.00 g/kg/day EGME. Body weights as well as testicular and splenicweights were reduced as a result of exposure to EGME. DEGME-exposedanimals exhibited decreased splenic weight in the high- andmediumdose (1.00 and 0.20 g/kg/day) exposure groups only. Hematologicchanges in EGME-exposed animals included mild anemia with increasederythrocytic mean corpuscular volumes and a lymphopenia withincreased neutrophils. Similar hematological changes were notobserved in any animals exposed to DEGME. Serum creatine kinaseactivity was increased in animals exposed to EGME, and serumlactate dehydrogenase activity was increased in EGME and 1.00g/kg/day DEGME-exposed animals. In general, DEGME produced minimaltoxicological changes following dermal exposure, whereas thetoxicological changes observed following similar exposure toEGME were much more profound.     

Acute, 9-Day, and 13-Week Vapor Inhalation Studies on Ethylene Glycol Monohexyl Ether

Acute, 9-Day, and 13-Week Vapor Inhalation Studies on EthyleneGlycol Monohexyl Ether. KLONNE, D. R., DODD, D. E., PRITTS,I. M., TROUP, C. M., NACHREINER, D. J., and BALLANTYNE, B. (1987).Fundam. Appl. Toxicol. 8, 198–206. At ambient conditions,the low vapor pressure of ethylene glycol monohexyl ether (EGHE)allows for a maximum vapor concentration of approximately 85ppm. In an acute inhalation study on Wistar albino rats, a 4-hrexposure to 83 ppm EGHE produced no clinical signs, body weighteffects, mortality, or macroscopic lesions in thoracic or abdominalorgans. Fischer 344 rats exposed for 9 days (6 hr/day) overan 11-day period, to 0 (control), 19, 41, or 84 ppm EGHE haddecreased body weight gains and increased liver to body weightvalues at 84 ppm EGHE. No alterations of the hematology parametersor the morphology of the testes or liver were observed. In asubsequent study, rats were exposed to mean EGHE concentrationsof 0 (control), 20, 41, or 71 ppm for 6 hr/day, 5 days/week,for 13 weeks. Urogenital wetness was observed in all EGHE-exposedgroups of females and in males of the 71-ppm group. Decreasedbody weight gains were observed in both sexes of the 71-ppmgroup, and a slight decrease was also observed in females ofthe 41-ppm group. Increased absolute and/or relative liver weightswere observed in both sexes of the 71-ppm group and to a lesserextent in the 41-ppm group. Possibly related to these findingsin the liver were decreases in serum transaminases (aspartateand alanine aminotransferase) and sorbitol dehydrogenase, withan increase in alkaline phosphatase observed in the 71-ppm groupof female rats. However, there were no gross or histopathologiclesions found to indicate impairment of the liver. Increasesin absolute and/or relative kidney weights were primarily observedin the 41-and 71-ppm groups of males but no gross or histopathologiclesions were found to explain these findings. The principalEGHE-related effect observed in animals maintained for a 1-monthrecovery period after cessation of exposures was a continuedincrease in the absolute and/or relative liver weights of the71-ppm group. Hematologic abnormalities and testicular atrophyobserved with some shorter chain alkyl glycol ethers were notobserved with EGHE. Based on the data from the 13-week inhalationstudy, subchronic inhalation exposure to 71 ppm EGHE producedminimal but biologically significant toxicity, while exposureto 41 ppm EGHE is considered to be a concentration at whichno biologically significant toxic effects were observed.     

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.     

Age-Dependent Pharmacokinetic Changes of Ethylenediamine in Fischer 344 Rats Parallel to a Two-Year Chronic Toxicity Study

Age-Dependent Pharmacokinetic Changes of Ethylenediamine inFischer 344 Rats Parallel to a Two-Year Chronic Toxicity Study.YANG, R. S. H., TALLANT, M. J., AND MCKELVEY, J. A. (1984).Fundam. Appl. Toxicol. 4, 663–670. As part of a 2-yearchronic toxicity study, the phannacokinetics of ethylenediamine(EDA) was studied in Fischer 344 rats of both sexes at day zero(naive animals), 6 months (controls and high level animals),and 18 months (controls and high level animals). The rats, whichwere randomized along with the rest of the animals on the toxicitystudy, were taken for pharmacokinetic experiments at the specifiedtime. A single per os (po) dose of 50 mg [¹⁴C]EDA - 2HCI/kgwas given to each rat and the plasma kinetics was followed fora 24-hr period. Five pharmacokinetic parameters (absorptionrate constant, terminal half-life, area under the curve, volumeof distribution, and ^l4CO₂ production rate constant) were comparedwith respect to age, sex, and chronic dosing. There were noapparent age-, sex-, and/or chronic dosing-related differencesin absorption rate constant and terminal half-life. However,age-related changes in area under the curve (AUC) were evident.The older rats had higher values (generally two- to threefold)for AUC than the younger rats. This age-related difference inAUC is closely associated with the volumes of distribution (V_dof the animals of varying ages. On the basis of liters per kilogram,the V_d's of the older rats are approximately one-fourth to one-halfof those for the younger (zero day) rats. The ¹⁴CO₂ productionrate constant was derived from the rate of formation of ¹⁴CO₂as a result of [¹⁴C]EDA - 2HCl dosing. The comparison of thisconstant under the various experimental conditions suggestssex-related differences. The findings of this study demonstratedage-, and to a lesser extent, sex-related differences. Chronicdosing-related changes are minimal These results are discussedin light of the chronic toxicity findings.     

Pulmonary Response to Toner upon Chronic Inhalation Exposure in Rats

Pulmonary Response to Toner upon Chronic Inhalation Exposurein Rats. MUHLE, H., BELLMANN, B., CREUTZENBERG, O., DASENBROCK,C., ERNST, H., KILPPER, R., MACKENZIE, J. C., MORROW, P., MOHR,U., TAKENAKA, S., AND MERMELSTEIN, R., Fundam. Appl. Toxicol.17, 280–299. A chronic inhalation study of a test tonerwas conducted by exposure of groups of F-344 rats for 6 hr/day,5 days/week for 24 months The test toner was a special Xerox9000 type xerographic toner, enriched in respirable-sized particlescompared to commercial toner, such that it was about 35% respirableaccording to the ACGlH criteria. The target test aerosol exposureconcentrations were 0, 1.0 (low), 4.0 (medium), and 16.0 (high)mg/m³. Titamum dioxide (5 mg/m³) and crystalline silicon dioxide(1 mg/m³), used as negative and pasitive controls for fibrogenicity,were also evaluated. Inhalation of the test toner or the controlmaterials showed no signs of overt toxicity. Body weight, clinicalchemistry values, food consumption, and organ weights were normalin the toner- and TiO₂-exposed groups, except for a 40% increasein lung weight in the toner highexposure group. All of the changesin the toner-exposed groups were restricted to the lungs orassociated lymph nodes. A chronic inflammatory response wasevident from the bronchoalveolar lavage parameters for the tonerhigh-exposure group. The incidence of primary lung tumors wascomparable among the three toner-exposed groups and the TiO²-exposed,and air-only controls, as well as consistent with historicalbackground levels A mild to moderate degree of lung fibrosiswas observed in 92% of the rats in the toner high-exposure group,and a minimal to mild degree of fibrosis was noted in 22% ofthe animals in the toner high-exposure group. The pulmonarychanges in the toner high-exposure group were smaller in magnitudethan those found in the crystalline silica-exposed group. Thecomparative fibrogenic potency of TiO², toner, and SiO² wasestimated to be 1:5:418 using a dasimetric model and assuminga common mechanistic basis. There were no pulmonary changesof any type at the toncr low-exposure level, which is most relevantin regard to potential human exposures The lung alterationsin the toner high-exposure group are interpreted in terms of"lung overloading," a generic response of the respiratory systemto saturation of its detoxification capacity. The maximum tolerateddose (MTD) criterion was met at the toner high (16 mg/m³)-exposurelevel.     

Developmental Toxicity Evaluation of Inhaled Nitrobenzene in CD Rats

Developmental Toxicity Evaluation of Inhaled Nitrobenzene inCD Rats. TYL, R. W., FRANCE, K. A., FISHER, L. C., DODD, D.E., PRITTS, I. M, LYON, J. P., O'NEAL, F. O., and KIMMERLE,G. (1987). Fundam. Appl. Toxicol. 8, 482–492. PregnantCD (Sprague–Dawley) rats were exposed to nitrobenzenevapor (CAS Registry No. 98-95-3) at 0, 1, 10, and 40 ppm (meananalytical values of 0.0, 1.06, 9.8, and 39.4 ppm, respectively)on gestational days (gd) 6 through 15 for 6 hr/day. At sacrificeon gd 21, fetuses were evaluated for external, visceral, andskeletal malformations and variations. Maternal toxicity wasobserved: weight gain was reduced during exposure (gd 6–9and 6–15) to 40 ppm, with full recovery by gd 21, andabsolute and relative spleen weights were increased at 10 and40 ppm. There was no effect of treatment on maternal liver,kidney, or gravid uterine weights, on pre- or postimplantationloss including resorptions or dead fetuses, on sex ratio oflive fetuses, or on fetal body weights (male, female, or total)per litter. There were also no treatment-related effects onthe incidence of fetal malformations or variations. In summary,during organogenesis in CD rats, there was no developmentaltoxicity (including teratogenicity) associated with exposureto nitrobenzene concentrations that produced some maternal toxicity(10 and 40 ppm) or that produced no observable maternal toxicity(1 ppm).     

Pulmonary Retention of Inhaled Diesel Particles after Prolonged Exposures to Diesel Exhaust

Pulmonary Retention of Inhaled Diesel Particles after ProlongedExposures to Diesel Exhaust CHAN, T. L., LEE, P. S., AND HERING,W. E. (1984). Fundam. Appl. Toxicol. 4, 624–631. The effectof continuous exposure to diluted diesel exhaust on the pulmonaryretention of inhaled diesel particles was studied in male Fischer344 rats. Test animals were first exposed to clean air or diluteddiesel exhaust in exposure chambers at nominal particulate concentrationsof 250 µg/m³ or 6 mg/m³ for 20 hr/day, 7 days/week, forperiods lasting from 7 to 112 days, followed by a nose-onlyexposure to ^l4C-tagged diesel particles for 45 min. At preselectedtime intervals after the radioactive exposure, the ¹⁴C-activitiesin the lungs of groups of four animals were measured to determinethe clearance of the ^l4C-diesel particles up to 1 year. Thepulmonary retention of the radioactive diesel particles wasgreater in animals which had been preexposed to diesel exhaustThe slower alveolar clearance of particle-laden macrophagesand leukocytes can be described by a normal Diphasic clearancemodel. Since some of the macrophages were found sequesteredas aggregates in the pulmonary region, a slow-clearing residualcomponent was included in a modified lung retention model. Whenthese residual fractions were determined and excluded from theactive particulate transport within the lungs, normal alveolarclearance rates were calculated for the animals with a preexposurediesel particulate dose less than 0.8 mg. Slower clearance wasobserved at a dose of 6.5 mg and no clearance was evident ata dose of 11.8 mg in their lungs. In effect, the greater retentionof inhaled particles can be interpreted as-a sign of impairedlung clearance attributable to the prolonged exposures to highconcentrations of diesel exhaust gases and/or the presence ofaccumulated carbonaceous particles residing in sequestered macrophageaggregates in the lungs.     

Teratogenicity Study of N-Methylpyrrolidone after Dermal Application to Sprague-Dawley Rats

Teratogenicity Study of N-Metbylpyrrolidone after Dermal Applicationto Sprague-Dawley Rats. Becci, P.J., Knickerbocker, M.J., Reagan,E.L., Parent, R.A., and Burnette, L.W. (1982). Fundam. Appl.Toxicol. 2:73–76. Teratogenicity studies were performedin rats given N-methylpyrrolidone, a solvent used in chemicalprocessing. Dosages of 75,237 and 750 mg of N-methylpyrrolidone/kgbody weight/day were administered dermally to groups of 25 pregnantSprague-Dawley rats on days 6 through 15 of gestation. Additionally,the study used a positive dermal control. Hexafluoroacetone,was chosen based on its dermal teratogenic activity. An oralpositive control, aspirin, was included in order to add significanceto the data generated in the experimental positive dermal controlgroup. All animals were killed and subjected to uterine examinationon day 20 of gestation. Maternal toxicity was indicated at 750mg of N-methylpyrrolidone/kg by reduced body weight gain duringgestation. Treatment with N-methylpyrrolidone resulted in dose-dependentbrightly colored yellow urine and dry skin. Treatment at thehigh dosage level resulted in fewer live fetuses per dam, anincrease in the percentage of resorption sites and skeletalabnormalities. These effects could be the result of maternaltoxicity. There was no evidence of teratogenic effects nor effectson the dams at 75 and 237 mg/kg of body weight.     

Ethylene Glycol Monopropyl Ether: A Developmental Toxicity Study in Rabbits

Ethylene Glycol Monopropyl Ether A Developmental Toxicity Studyin Rabbits. KRASAVAGE, W. J., HOSENFELD, R. S., AND KATZ, G.V. (1990). Fundam. Appl. Toxicol. 15, 517–527. To determinethe potential developmental toxicity of ethylene glycol monopropylether (EGPE), groups of pregnant New Zealand white rabbits wereexposed to target concentrations of 0, 125, 250, or 500 ppmEGPE vapors for 6 hr a day on Days 6–18 of gestation.Maternal effects included a slight reduction in feed consumptionduring the first week of treatment at the 250- and 500-ppm exposurelevels and slightly reduced body weight gain at the 500-ppmlevel compared to those of the controls, but the differenceswere not statistically significant. One doe exposed to 500 ppmhad red-colored urine during the 24-hr period following thesecond exposure. Hemato-logic determinations, absolute and relativeorgan weights, and observations at necropsy revealed no treatment-relatedmaternal effects. Reproductive indices, i.e., pregnancy rate,number of corpora lutea, implantation sites, viable fetuses,early and late resorptions, fetal body weights, fetal sex ratio,and the gravid uterine and corrected body weights, were notaffected by exposures to EGPE. The occurrences of external andinternal soft tissue malformations and variations and the incidencesof skeletal malformations in the EGPE-exposed groups were notsignificantly different from those in the control group. Commonskeletal variations, in many instances, were seen less frequentlyin EGPE-exposed fetuses than in control fetuses. In those caseswhere the incidence of fetuses with a skeletal variation wasgreater for EGPE-exposed fetuses than that for control fetuses,the number of litters involved was not significantly differentfrom that of the control group. Thus, EGPE vapor concentrationsas high as 500 ppm did not produce teratoge-nicity or otherdevelopmental toxicity in the rabbit conceptus.     

Effects of Recombinant Murine Interferon-{gamma} on Pregnant Mice and Their Fetuses

Effects of Recombinant Murine Interferon- on Pregnant Mice andTheir Fetuses. KATO, I., KIMURA, S., FURUHASHI, T., NAKAYOSHI,H., TAKAYAMA, S., AND UENISHI, N. (1990). Fundam. Appl. Toxicol.14, 658–665. Recombinant murine interferon- (Rec-MuIFN-)was administered intramuscularly to C3H/HeNCrj mice on Days6-15 of gestation at dosage levels of 8 x 10⁵, 4 x 10⁶, and2 x 10⁷ u/kg/day. Dams were killed for examination of fetuseson Day 18 of gestation. Pregnant females that received 2 x 10⁷u/kg/day of Rec-MuIFN- showed uterine bleeding on Days 10–15of gestation and could not maintain their pregnancy. These damsdied on Days 13–17orwerekilled/ieWrem/sonDays 10–15for examination, and therefore no fetal data were availablefor this group. In the 2 x 10⁷ u/kg/day group, the mean absoluteweights of the lung and spleen increased and the mean absoluteweight of the liver, red blood cells (RBC), hematocrit, andhemoglobin decreased significantly. Surviving dams in the 8x 10³ and 4 x 10⁶ u/kg/day groups showed significant increasesin the mean absolute weights of the lung, liver, kidneys, andspleen and a decrease in platelet count. Significant increasesin the weights of the heart and ovaries and decreases in RBC,hematocrit, and hemoglobin were observed in the 4 x 10⁶ u/kg/daygroup. Histopathological examination revealed increased extramedullaryhema-topoiesis in the spleen of the 4 x 10⁶ and 2 x 10⁷ u/kg/daygroups. Fetuses showed no external, visceral, or skeletal malformationsand variations caused by the administration of Rec-MuIFN-7 inany of the treated groups. Although a slight but statisticallysignificant decrease in fetal body weight and a delay in ossificationwere seen in fetuses in the 4 x 10⁷ u/kg/day group, these findingswere considered to be the result of maternal toxicity and notfetal toxicity. No fetal effects were observed i n the 8 x 10⁵u/kg/day group.