The Fate of Inhaled Azodicarbonamide in Rats

The Fate of Inhaled Azodicarbonamide in Rats. Mewhinney, J.A., AYRES, P. H., BECHTOLD, W. E., DUTCHER, J. S., CHENG, Y.S., BOND, J. A., MEDINSKY, M. A., HENDERSON, R. F., AND BIRNBAUM,L. S. (1987). Fundam. Appl. Toxicol. 8, 372–381. Azodicarbonamide(ADA) is widely used as a blowing agent in the manufacture ofexpanded foam plastics, as an aging and bleaching agent in flour,and as a bread dough conditioner. Human exposures have beenreported during manufacture as well as during use. Groups ofmale F344/N rats were administered ADA by gavage, by intratrachealinstillation, and by inhalation exposure to determine the dispositionand modes of excretion of ADA and its metabolites. At 72 hrfollowing gavage, 30% of the administered ADA was absorbed whereasfollowing intratracheal instillation, absorption was 90%. Comparisonbetween groups of rats exposed by inhalation to ADA to achievebody burdens of 24 or 1230 µg showed no significant differencesin modes or rates of excretion of [¹⁴C]ADA equivalents. ADAwas readily converted to biurea under physiological conditionsand biurea was the only ¹⁴C-labeled compound present in excreta.[¹⁴C]ADA equivalents were present in all examined tissues immediatelyafter inhalation exposure, and clearance half-times on the orderof 1 day were evident for all tissues investigated. Storagedepots for [¹⁴C]ADA equivalents were not observed. The rateof buildup of [¹⁴C]ADA equivalents in blood was linearly relatedto the lung content as measured from rats withdrawn at selectedtimes during a 6-hr inhalation exposure at an aerosol concentrationof 25 µg, ADA/liter. In a study extending 102 days afterexposure, retention of [¹⁴C]ADA equivalents in tissues was describedby a two-component negative exponential function. The resultsfrom this study indicate that upon inhalation, ADA is rapidlyconverted to biurea and that biurea is then eliminated rapidlyfrom all tissues with the majority of the elimination via theurine.     

Developmental Toxicity Evaluation of Inhaled Methyl Isobutyl Ketone in Fischer 344 Rats and CD-1 Mice

Developmental Toxicity Evaluation of Inhaled Methyl IsobutylKetone in Fischer 344 Rats and CD-1 Mice. Tyl, R. W., FRANCE,K. A., FISHER, L. C., PRITTS, I. M., TYLER, T. R., PHILLIPS,R. D., and MORAN, E. J. (1987). Fundam. Appl. Toxicol. 8, 310–327.Pregnant Fischer 344 rats and CD-1 mice were exposed to methylisobutyl ketone vapor (CAS No. 108-10-1) by inhalation on GestationalDays 6 through 15 at concentrations of 0, 300, 1000, or 3000ppm (mean analytical values of 0, 305, 1012, and 2997 ppm, respectively).The animals were sacrificed on Gestational Day 21 (rats) or18 (mice), and live fetuses were examined for external, visceral,and skeletal alterations. In rats, exposure to 3000 ppm resultedin maternal toxicity expressed as clinical signs, decreasedbody weight and body weight gain, increased relative kidneyweight, and decreased food consumption, and in fetotoxicityexpressed as reduced fetal body weight per litter and reductionsin skeletal ossification. In mice, exposure to 3000 ppm resultedin maternal toxicity expressed as exposure-related increasesin deaths (12.0%, 3/25 dams), clinical signs, and increasedabsolute and relative liver weight, and in fetotoxicity expressedas increased incidence of dead fetuses, reduced fetal body weightper litter, and reductions in skeletal ossification. No treatment-relatedincreases in embryotoxicity or fetal malformations were seenin either species at any exposure concentration tested. Therewas no evidence of treatment-related maternal, embryo, or fetaltoxicity (including malformations) at 1000 or 300 ppm in eitherSpecies.     

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.     

Subchronic Studies of Doxylamine in Fischer 344 Rats

Subchronic Studies of Doxylamine in Fischer 344 Rats. JACKSON,C. D., AND BLACK WELL, B.-N. (1988). Fundam. Appl. Toxicol.10,243–253. Doxylamine succinate was administered as anadmixture in the feed to male and female Fischer 344 rats foreither 14 or 90 days. The 14-day study included dose levelsof 0, 100, 250, 500, 1000, or 2000 ppm doxylamine. Except fora 7% decrease in final body weight in female rats in the 2000ppm group, there were no significant clinical observations madein the 14-day study. Microscopic lesions judged to be treatment-relatedwere limited to cytoplasmic vacuolization in the livers. Thelesions were more numerous in the higher dose groups of malesand present only in the 2000 ppm group of females. Dose levelsof 0, 162, 405, 1012, 2530, and 6325 ppm doxylamine were administeredin the 90-day study. There were no deaths during the study.Final body weights were decreased 13.3% in males of the 6325ppm group and 5.2, 10.1, and 14.4% in females in the 1012, 2530,and 6325 ppm groups, respectively. Liver/brain weight ratioswere increased in all treated male groups and in the two highestdose groups of females. Other organ weight changes were decreasesand believed to result from general reduction in weight gainin those groups where the decreases occurred. Treatment-relatedhistological changes were identified in the liver and parotidsalivary gland. Cytoplasmic vacuolization or fatty change ofthe liver was found in all groups of males but was more severein the higher dose groups. In females, these liver lesions wereobserved only in the two highest dose groups. A dose-relatedchange in the parotid salivary gland, consisting of cytomegalywith basophilic and coarsely granular or vacuolated cytoplasm,was observed.     

Comparative Hepatotoxicity of Two Polychlorotrifluoroethylenes (3.1 Oils) and Two Chlorotrifluoroethylene (CTFE) Oligomers in Male Fischer 344 Rats

Comparative Hepatotoxicity of Two Polychlorotrifluoroethylenes(3.1 Oils) and Two Chlorotrifluoroethylene (CTFE) Oligomersin Male Fischer 344 Rats. DELRASO, N. J., GODIN, C. S., JONES,C. E., WALL, H. G., MATTIE, D. R., AND FLEMMING, C. D. (1991).Fundam. Appl. Toxicol. 17, 550–562. Polychlorotrifluoroethylene(3.1 oil) is a nonflammable hydraulic fluid composed of chlorotrifluoroethylene(CTFE) oligomers of different carbon chain lengths (C5 to C9),primarily six (trimer) and eight (tetramer) carbons. Four testgroups of Fischer 344 rats(l6 rats/group) were orally gavageddaily over a 2-week period at doses of 1.25 g/kg with 3.1 oilcontaining a 55:45 ratio of trimer and tetramer(3.1 oil-C₆:C₃),3.1 oil composed of 95% trimer (3.1 oil-C₆), pure tetramer,and pure trimer. Four rats per treatment group were terminatedafter 1, 3, 7, and 14 doses. Rats dosed with either 3.1 oil-C₆:C³or pure tetramer demonstrated significant weight losses, increasedliver weights, increased rates of liver fatty acid ß-oxidation,pronounced hepatomegaly and altered hepatocellular architecture,and elevated serum liver-associated enzymes. Rats dosed witheither 3.1 oil-C₆ or only pure trimer demonstrated significantincrease in liver weight and moderate liver histopathologicchanges. Compositional analyses of the ratio percentage of trimerto tetramer present in 3.1 oil-C₆:C₃ (55:45) were found to bealtered when measured in the liver (32:68). Differential CTFEoligomer toxicity was indicated by effects on liver, body weight,and peroxisomal ß-oxidation and may allow for lesstoxic formulations of 3.1 oil to be generated by reducing oreliminating the tetramer component.     

A 90-Day Subcutaneous Toxicity and Fertility Study of a LHRH Antagonist in Rats

A 90-Day Subcutaneous Toxicity and Fertility Study of a LHRHAntagonist in Rats. SUNDARAM, K., DIDOLKAR, A. K., KEIZER-ZUCKER,A., DEJESUS, W., RIVIER, J., VALE, W., AND BARDIN, C. W. (1990).Fundam. Appl. Toxicol. 14, 734–744. [Ac-D2Nal¹,4Cl-DPhe²,D3Pal³,Arg⁵,DGlu⁶(anisole adduct),DAla¹⁰]-GnRH (Nal-Glu) is an antagonist ofLHRH and has the potential to be utilized as an antigonadalagent. A study was undertaken to evaluate the toxicologicaleffects of Nal-Glu in rats. Nal-Glu, dissolved in 5% mannitolin water containing 9 ml/liter benzyl alcohol, was administeredsubcutaneously. In subchronic studies, groups of 12 male and12 female rats received 0, 50, 250, or 1250 µg/kg bodyweight (BW) Nal-Glu for 90 days and were killed on Day 91. Additionalgroups of male and female rats were given the high dose of Nal-Glu(1250 µ/kg BW) or vehicle for either 30 or 90 days. Theirfertility was assessed by mating them with normal animals. Unlikesome other LHRH antagonists, Nal-Glu exhibited a low potencyfor causing in vitro histamine release from rat peritoneal mastcells. Furthermore, in acute In vivo studies, Nal-Glu was lessactive in the induction of peripheral edema. In the subchronicstudy, all doses of Nal-Glu were well tolerated and there wereno apparent systemic toxic effects. The pharmacological effectsof Nal-Glu were quite evident, however. Nal-Glu treatment ledto a significantly decreased body weight gain in the males anda significantly increased body weight gain in the females. Therewas a dose-dependent decrease in weights of gonads and reproductiveorgans in both the sexes. Some of the hematological and serologicalparameters were significantly different in Nal-Glu-treated animals.However, most of the values were within the normal range andare considered to be of no toxicological significance. Histopathologicalevaluations were made in the control and high-dose groups only.In the male, a seminiferous tubular degeneration and atrophyof the interstitial cells was seen. The prostate and seminalvesicles were also atrophied and the epididymides were devoidof spermatozoa. In the females, the ovaries and uteri were atrophic.The injection site of Nal-Glu-treated rats had inflammatorychanges indicative of a local irritating action of the drug.All other tissues had normal histomorphology. Both male andfemale rats became infertile when 1250 MgAg Nal-Glu was administeredfor 30 days. Normal fertility was restored 8 weeks after cessationof 90-day treatment. It is concluded that repeated administrationof Nal-Glu leads to reversible infertility in both male andfemale rats. Although it was irritating at the site of injection,Nal-Glu had no systemic toxicological effects.     

Application of Microencapsulation for Toxicology Studies: II. Toxicity of Microencapsulated Trichloroethylene in Fischer 344 Rats

Application of Microencapsulation for Toxicology Studies. II.Toxicity of Microencapsulated Trichloroethylene in Fischer 344Rats. MELNICK, R. L., JAMESON, C. W., GOEHL, T. J., MARONPOT,R. R., COLLINS, B. J., GREENWELL, A., HARRINGTON, F. W., WILSON,R. E., TOMAS-ZEWSKI, K. E., AND AGARWAL, D. K. (1987). Fundam.Appl. Toxicol. 8, 432–442. Gelatin–sorbitol microcapsulescontaining 44.1% trichloroethylene (TCE) were prepared and mixedin NIH-07 rodent meal diet and provided at microcapsule concentrationsof 0 (untreated control group), 1.25,2.5, 5.0, or 10% (equivalentto 0, 0.55, 1.10, 2.21, or 4.41% TCE, respectively) to groupsof 10 male F344 rats for 14 days. An additional control groupreceived diets containing 5% empty capsules. For comparisons,TCE dissolved in corn oil was administered by gavage to differentgroups of 10 male rats for 14 consecutive days at dose levelsadjusted to correspond to those in the feed study. Treatment-relateddeaths occurred only in the highest dose group of the gavagestudy. Body weight gain and feed consumption were reduced inhigh-dose groups of both the feed and gavage studies. Therewas no measurable loss of TCE in feed sampled from the cagesduring the study. Dose-related increases in organ (liver andkidney) weight/body weight ratios, individual cell necrosisin the liver, and hepatic microsomal NADPH cytochrome c re-ductaseand peroxisomal palmitoyl-CoA oxidase and catalase activitieswere found in both the dosed-fed and gavage groups. Inductionof cytochrome P-450 occurred only in the dosed-feed study. Therewere no significant compound-related pathologic lesions observedin the kidneys, the only other organ examined microscopically.Differences in lethality, cytochrome P-450 levels, and inductionof microsomal or peroxisomal enzyme activities were attributedto differences in the method of dosing (gavage versus dosed-feed).The demonstration of no significant loss of TCE from the feedand of similar toxic effects produced by microencapsulated TCEvia feed and TCE in corn oil via gavage indicate that microencapsulationcan provide an excellent alternative exposure route for studyingthe oral toxicological properties of volatile chemicals, suchas TCE, in rats.     

Comparative Inhalation Toxicity of Nickel Subsulfide to F344/N Rats and B6C3F1 Mice Exposed for 12 Days

Comparative Inhalation Toxicity of Nickel Subsulfide to F344/NRats and B6C3F₁ Mice Exposed for 12 Days. BENSON, J. M., CARPENTER,R. L., HAHN, F. F., HALEY, P. J. HANSON, R. L., HOBBS, C. H.,PICKRELL, J. A., AND DUNNICK, J. K. (1987). Fundam Appl. Toxicol.9, 251–265. Groups of F344/N rats and B6C3F₁ mice wereexposed to aerosols of nickel subsulfide (Ni₃S₂) 6 hr/day for12 days not including weekends. Actual exposure concentrationswere within 3% of target (target 10.0, 5.0, 2.5, 1.2, 0.6,and 0.0 mg Ni₃S₂/m³). Nickel lung burdens of exposed rats andmice increased linearly with exposure concentration. Two malerats and all mice exposed to 10.0 mg Ni₃S₂/m³ died before theend of the exposures. Exposure to Ni₃S₂ had no elfect on thenatural killer cell activity of mouse spleen cells. Lesionsin rats and mice related to inhalation of Ni₃S₂ were found inthe nasal epithelium, lung, and bronchial lymph nodes. The mostextensive lesions were found in the lung and included necrotizingpneumonia. Emphysema developed in rats exposed to 5.0 or 10.0mg Ni₃S₂/m³ while fibrosis developed in mice exposed to 5.0mg Ni₃S₂/m³ Degeneration of the respiratory epithelium and atrophyof the olfactory epithelium of the nose occurred in rats exposedto as low as 0.6 mg Ni₃S₂/m³ and mice exposed to 1.2 mg/m³ Resultsindicate that inhalation exposure of rats and mice to Ni₃S₂/aerosol concentrations near the current threshold limit value(TLV) for nickel compounds (1 mg/m³ for Ni metal and roastingfume and dust and 0.1 mg/m³ as Ni for soluble compounds) canproduce lesions in the respiratory tract. Atrophy of lymphoidtissues (spleen, thymus, and bronchial lymph nodes) was foundin animals of the highest exposure concentration. Degenerationof the testicular germinal epithelium was also observed in miceand rats that survived 5.0 or 10.0 mg/m³ exposure concentrations.     

Comparative Toxicity of Arsine Gas in B6C3F1 Mice, Fischer 344 Rats, and Syrian Golden Hamsters: System Organ Studies and Comparison of Clinical Indices of Exposure

Comparative Toxicity of Arsine Gas in B6C3F₁ Mice, Fischer 344Rats, and Syrian Golden Hamsters: System Organ Studies and Comparisonof Clinical Indices of Exposure. BLAIR, P. C, THOMPSON, M. B.,MORRISSEY, R. E., MOORMAN, M. P., SLOANE, R. A., AND FOWLER,B. a. (1990). Fundam. Appl. Toxicol. 14, 776–787. In orderto examine possible species differences in response to arsineexposure, multiple inhalation studies consisting of acute (1-day),subacute (14- and 28-day), and subchronic (90-day) exposuresto this agent were conducted using three different species ofrodents. Evaluations of hematopoietic organs and alterationsin the heme biosynthetic pathway were the focus of these studies.Species used were B6C3F₁ mice (exposed 1, 14, or 90 days), Fischer344 rats (exposed 14, 28, or 90 days), and Syrian Golden hamsters(exposed 28 days). All arsine exposures were at concentrationsof 0.5, 2.5, or 5.0 ppm except for 90-day studies, in whichconcentrations were lowered to 0.025, 0.5, or 2.5 ppm. No changesin body weight gain were observed in either sex of mice or hamsters.The only decrease in body weight gain occurred in male ratsexposed to 5.0 ppm arsine for 28 days. Significant exposure-relatedincreases in relative spleen weights occurred in both sexesof mice and rats in the 0.5 (except 14-day female rats), 2.5,and 5.0 ppm exposure groups from all studies and in hamstersin the 2.5 and 5.0 ppm exposure groups. Generally, increasesin relative liver weight occurred in fewer exposure groups andwere of a lesser magnitude than increases in spleen weight.Other parameters affected included decreased packed cell volumes(mice, rats, and hamsters), hematol-ogy profiles (rats), andan increase in 6-aminolevulinic acid dehydratase activity inall species. Arsenic content was measured in livers of ratsafter 90 days of exposure. Concentrations increased in relationto atmospheric concentrations of arsine. Histopathological changesincluded increased hemosiderosis and extramedullary hematopoiesisin spleen and intracanalicular bile stasis (mice only) in liver.Additionally, bone marrow hyperplasia was observed in rats.Effects on other organs were not observed, suggesting that thehematopoietic system is the primary target for arsine. In conclusion,we have determined that the effects of arsine exposure uponmice, rats, and hamsters are similar. Most importantly, eventhough no effects on the hematopoietic system were observedfollowing a single exposure to 0.5 ppm arsine which is 10 timesthe Threshold Limit Value (TLV) set by the American Conferenceof Governmental Industrial Hygienists, repeated exposure to0.025 ppm (one-half the TLV) caused a significant anemia inrats.     

Pretreatment with Drinking Water Solutions Containing Trichloroethylene or Chloroform Enhances the Hepatotoxicity of Carbon Tetrachloride in Fischer 344 Rats

Pretreatment with Drinking Water Solutions Containing Trichloroethyleneor Chloroform Enhances the Hepatotoxicity of Carbon Tetrachloridein Fischer 344 Rats. Steup, D. R., Wiersma, D., McMillan, D.A., and Sipes, I. G. (1991). Fundam. Appl. Toxicol. 16, 798–809.Previous studies have demonstrated that various compounds, includingthe common groundwater contaminants trichloroethylene (TCE)and chloroform (CHCl³), can produce a synergistic toxic responsewhen coadministered with the model hepatotoxicant carbon tetrachloride(CCI₄. This phenomenon has not, however, been demonstrated followingadministration of these compounds in drinking water. Initialexperiments indicated that Fischer 344 (F-344) rats were significantlymore sensitive to these effects than the more commonly utilizedSprague–Dawley strain. To establish the suitability ofthis strain as a model, a variety of indicators of hepatotoxicitywas evaluated and compared to histological evidence of injury24 hr after dosing with CCl₄ or a combination of CCl₄ + TCE.Plasma alanine aminotransferase (ALT) activity was the mostreliable indicator of hepatic injury and was well-correlatedwith the histologic data. Dose–response studies utilizingsimultaneous ip dosing confirm the sensitivity of the F-344rat, demonstrating synergistic toxicity at doses as low as 0.165mmol/kg of CCl₄ and 0.6 mmol/kg of TCE. Synergism was also detectedfollowing simultaneous ip administration of 1 mmol/kg CCl₄ and0.5 mmol/kg of CHCl₃. To evaluate the effects of drinking waterexposure, rats were pretreated for 3 days with solutions containingTCE (0–40 mM) or CHCl₃ (0–8 mM) stabilized with1% Emulphor (EL-620P) as their only source of fluids. A single,ip dose of CCl₄ (1 mmol/kg) was then administered and 24 hrlater animals were killed for examination of liver histologyand determination of ALT activity. Although none of the pretreatmentswere detectably hepatotoxic, rats which drank 15 and 40 mm TCEor 8 mm CHCl₃ exhibited an enhanced response to CCl₄     

Effects of Chronic Treatment with the Leukotriene D4 Antagonist Compound LY171883 on Fischer 344 Rats and Rhesus Monkeys

Effects of Chronic Treatment with the Leukotriene D4 AntagonistCompound LY171883 on Fischer 344 Rats and Rhesus Monkeys. HOOVER,D. M., BENDELE, A. M., HOFFMAN, W. P., FOXWORTHY, P. S., ANDEACHO, P. I. (1990). Fundam. Appl. Toxicol. 14, 123–130.One-year toxicity studies were done to evaluate potential toxiceffects associated with chronic exposure of rats and monkeysto the leukotriene antagonist LY171883. Rats were fed dietarydoses of 0.0, 0.01, 0.03, or 0.1%, equivalent to approximately0, 5, 15, or 50 mg/kg of body weight/day. Monkeys were givendaily nasogastric gavage doses of 0, 30, 75, or 175 mg/kg ofbody weight. No treatment-related effects occurred in physical,behavioral, ocular, food consumption, or uri-nalysis parametersin either species. Mild dose-related hepatotoxicity occurredin rats given approximately 15 or 50 mg/kg of LY 171883. Thehepatotoxicity was characterized by liver enlargement associatedwith induction of hepatic peroxisomal ß-oxidationand microsomal drug metabolism. Male rats also had hepatocellularfatty change, centrilobular hypertrophy of hepa-tocytes, andincreased levels of serum alanine transaminase and total bilirubin.Other effects in rats included minimal decreases in hematocritvalues, decreases in serum triglycerides and cholesterol, andincreased kidney weight The monkeys tolerated daily oral dosesof LY 171883 up to 175 mg/kg with only minor increases in hepaticmicrosomal enzyme activity and slightly increased liver andkidney weights in males. No effects occurred in monkeys given30 mg/kg. There was no induction of hepatic peroxisomal enzymesor pathologic abnormalities in monkeys treated with LY 171883.The peroxisomal inductive effect was apparently a species-relatedeffect separate from the pharmacologic activity of leukotrieneantagonism.     

Subchronic Inhalation of Diethylamine Vapor in Fischer-344 Rats: Organ System Toxicity

Subchronic Inhalation of Diethylamine Vapor in Fischer-344-Rats:Organ System Toxicity. LYNCH, D. W., MOORMAN, W. J., STOBER,P., LEWIS, T. R., AND IVERSON, W. O. (1986). Fwidam. Appl. Toxicol.6, 559–565. Male and female Fischer 344 (F-344) rats wereexposed at 0, 25, or 250 ppm diethylamine (DEA) vapor, 6.5 hrper day, 5 days per week, for 24 weeks in order to assess cardiacand other organ system toxicity. Scheduled sacrifices were performedfollowing 30, 60, and 120 days of exposure. During the first2 weeks of exposure, the rats exposed at 250 ppm DEA did notgain weight. After 2 weeks, however, the rate of weight gainof these rats was greater than that of controls. Nevertheless,mean body weights for both sexes of rats exposed at 250 ppmDEA remained depressed compared to controls throughout the study.Sneezing, tearing, and reddened noses were seen in rats exposedat 250 ppm DEA. Histopathologic examinations revealed lesionsof the nasal mucosa of rats exposed at 250 ppm DEA (rats exposedat 25 ppm were not evaluated). These lesions of the respiratoryepithelium consisted of squamous metaplasia, suppurative rhinitis,and lymphoid hyperplasia. There were no pronounced treatment-relatedeffects on organ weights, hematology, or clinical chemistryindices except for blood urea nitrogen which was elevated inrats of both sexes exposed at 250 ppm DEA for 24 weeks. In contrastto the highdose animals, no treatment-related effects were observedin rats intermittently exposed at 250 ppm DEA for up to 24 weeks.No evidence of cardiotoxicity was seen in rats exposed to eitherDEA concentration for up to 24 weeks.     

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.     

Acute Inhalation Toxicity of T-2 Mycotoxin in Mice

Acute Inhalation Toxicity of T-2 Mycotoxin in Mice. Creasia,D. A., THURMAN, J. D., JONES, L. J., III, NEALLEY, M. L., YORK,C. G., WANNEMACHER, R. W., Jr., and BUNNER, D. L. (1987). Fundam.Appl. Toxicol. 8, 230–235. Experiments were conductedto study the acute inhalation toxicity of T-2 mycotoxin in bothyoung adult and mature mice. For a 10-min aerosol exposure,the 24-hr LC50 of T-2 mycotoxin in young adult mice was 0.08± 0.04 mg T-2/liter air and that for mature mice was0.325 ± 0.1 mg T-2/liter air. Deaths among mice exposedto the higher aerosol concentrations used in this study (i.e.,1.5 to 2.4 mg T-2/liter air) occurred in less than 5 hr. Generalclinical symptoms in these animals immediately postexposurewere tremors, lethargy, stilted gait, and, in some animals,prostration. In experiments separate from the concentration-responsestudies, total deposition of T-2 aerosol and selective retentionof T-2 in the respiratory tract and nasal turbinates were determinedanalytically from ³H-labeled T-2. When total deposition of T-2was quantitated, there was excellent agreement between thatamount of T-2 deposited and that amount of T-2 predicted fromcalculations based on aerosol size and animal minute volume.Based on the aerosol deposition data, the LD50 values of T-2mycotoxins was 0.24 mg/kg for young adult mice and 0.94 mg/kgfor mature mice. For mice, inhalation of T-2 mycotoxin is atleast 10 times more toxic than systemic administration (LD50 4.5 mg/kg) and at least 20 times more toxic than dermal administration(LD50 > 10 mg/kg).     

The Effects of Allyl Isovalerate on the Hematopoietic and Immunologic Systems in Rodents

The Effects of Allyl Isovalerate on the Hempatopoietic and ImmunologicSystems in Rodents. HONG, H. L., HUFF, J. E., LUSTER, M. I.,MARONPOT, R. R., DIETER, M. P., HAVES, H. T., AND BOORMAN, G.A. (1988). Fundam. Appl. Toxicol. 10, 655–663. FemaleB6C3F1 mice plus male and female Fischer 344/N rats were gavagedwith allyl isovalerate (AIV) in corn oil at 0, 31,62, or 125(mice) and 0, 31. 62, 125, or 250 (rats) mg/kg body weight forfive daily exposures per week for a 2-week period. Hematologic,immunologic, and histopathologic studies were performed 48 to72 hr following the final treatment. AIV exposure had no effecton hematology or bone marrow cellularity in mice or rats. AIVexposure at 250 mg/kg was toxic to rats causing reduced weightgain and hepatotoxicity. In vivo and in vitro studies revealedthat pluripotent hematopoietic stem cells (CFU-S) and granulocyte-macrophageprogenitors (CFU-GM) in the bone marrow were decreased in thetreated mice. Hematopoietic suppression was correlated withthe reduction in the hexose monophosphate shunt metabolism ofbone marrow cells but the Embden-Meyerhof pathway and tncarboxylicacid pathway enzymes did not appear to be affected. Examinationof host resistance following Plasmodium and Listeria challengedid not demonstrate significant differences between treatedand control mice, nor were there other effects on the immunesystem. This suggests that the myelotoxic effects were minimaland of a degree that would not alter host resistance.     

Measurement of Nuclear DNA Modification by 32P-Postlabeling in the Kidneys of Male and Female Fischer 344 Rats after Multiple Gavage Doses of Hydroquinone

Oral administration of hydroquinone (HQ) to male Fischer 344(F344) rats results in dose-related kidney toxicity beginningwith mild enzymuria by 1 week, significant cell proliferationby 6 weeks, and nephropathy and an increase in the incidenceof renal tubule adenomas after 2 years. Female F344 rats, B6C3F1mice, Sprague-Dawley rats, dogs, and humans are resistant tothe renal toxicity of HQ associated with repeated exposure.To determine the potential of HQ to induce covalent DNA adductsin the kidney, male and female F344 rats were given 0, 2.5,25, or 50 mg/kg HQ by gavage for 6 weeks, and nuclear DNA isolatedfrom kidneys was analyzed by the ³²P-postlabeling assay. At50 mg/kg, males, but not females, showed an increase in therate of excretion of N-acetyl-ß-D-glucosaminidase,indicative of proximal tubular damage. Analysis of nuclear DNApreparations by the postlabeling assay showed that HQ does notproduce covalent DNA adducts in the kidneys of male and femalerats. The assay's lower limit of detection is 1 adduct in 10⁹to 10¹⁰ DNA nucleotides. No treatment-related increases in backgroundradioactivity levels on the chromatograms were seen at locationscorresponding to the major in vitro adducts of HQ and p-benzoquinone.HQ treatment, however, resulted in the reduction of the levelsof certain endogenous adducts (I-compounds), the biologicalsignificance of which is unknown. The results indicate thatHQ does not produce covalent DNA adducts in the kidneys of maleand female rats after repeated oral administration at nephrotoxicdose levels, and suggest a nongenotoxic etiology of benign tumorsin the kidneys of male F344 rats treated with HQ.     

Modification of Gastrointestinal Tumor Development in Rats by Dietary Butylated Hydroxytoluene

Modification of Gastrointestinal Tumor Development in Rats byDietary Butylated Hydroxytoluene. Lindenschmidt, R. C., TRYKA,A. F., AND WITSCHI, H. (1987). Fundam. Appl. Toxicol. 8, 474–481.Male Fischer 344 rats were given two or four injections of 1,2-dimethylhydra-zine(DMH), 40 mg/kg sc, and then fed a diet containing 0.5% butylatedhydroxytoluene (BHT). Five months later, the animals treatedwith two doses of DMH had a significantly higher incidence ofcolon tumors than the animals fed a BHT-free control diet. Inanimals treated with four injections of DMH, the increase incolon tumor incidence was statistically not significant, butBHT appeared to produce a shift in tumor distribution. In asecond experiment, Fischer 344 rats were treated with 2 x 40mg/kg of DMH and fed a diet of 0.5 or 0.1% BHT for 6 months;these animals had a significantly increased incidence of smallintestinal tumors (duodenum, jejunum, and ileum) compared withanimals fed the control diet. In rats treated with DMH and givena diet of 0.5% butylated hydroxyanisole (BHA), overall incidenceof gastrointestinal tract tumors was higher than in controlanimals, although the difference was statistically not significant.Administration of N-nitroso-N-methylurea (NMU; 90 mg/kg givenorally) produced stomach and colon tumors; 0.5% BHT in the dietdid not modulate tumor incidence. It is concluded that dietaryBHT may enhance development of gastrointestinal tumors producedby DMH, but not by NMU, provided exposure to BHT occurs afterexposure to the carcinogen.     

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.     

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.     

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.