Assessment of the Developmental Toxicity and Placental Transfer of 1,2-Dichloroethane in Rats

This study evaluates the developmental toxicity and placentaltransfer of 1,2-dichloroethane (DCE) in rats. Sprague–Dawleyrats were given 0–2.4 mmol DCE kg^-1 day^-1 by gavage, orwere exposed for 6 hr per day to 0–300 ppm DCE by inhalation,from Day 6 to 20 of gestation. Maternal toxicity was observedafter inhalation exposure to 300 ppm DCE and oral administrationof 2.0 or 2.4 mmol DCE kg^-1 There was no evidence of alteredgrowth nor teratogenic effects after either inhalation or oraladministration of DCE at any concentration tested. The timecourse disposition of ¹⁴C was examined over a 48-hr period in12- and 18-day pregnant rats after a single oral dose of 1.6mmol [¹⁴C]DCE kg^-1. Peak concentrations of radiocarbon occurredbetween 2 and 4 hr postdose. Conceptus (Day 12) and fetal (Day18) tissues accounted for 0.06 and 0.4% of the administereddose, respectively. Up to 4 hr, levels of radiocarbon in placentaand fetus were slightly less than in maternal plasma of 18-daypregnant rats and were two to five times higher at later periods.At 2 hr, unchanged DCE accounted for most of radioactivity (78–86%)recovered in maternal plasma, placenta, and fetus. Acidic metabolitesand radioactivity bound to macromolecules increased up to 24hr (0.01 µmol-eq DCE g^-1)in either placental or fetaltissues. Thereafter, their levels declined more slowly thanthose in the maternal plasma. Results from this developmentaltoxicity study in rats confirm embryonic exposure to radiocarbonassociated with [¹⁴C]DCE and/or its metabolites and has demonstratedthe lack of observable teratogenic effects.     

Olfactory toxicity of methyl iodide in the rat

 The monohalomethanes (methyl iodide, methyl bromide and methyl chloride) are widely used industrial methylating agents with pronounced acute and chronic toxicity in both experimental animals and man. Recently inhalation exposure of rats to methyl bromide has been shown to result in severe olfactory toxicity. This study examined the effects on the rat nasal cavity of inhalation of methyl iodide (100 ppm for 0.5 – 6 h), and demonstrated that methyl iodide is a more potent olfactory toxin than methyl bromide. Within the nasal cavity the olfactory epithelium was the principle target tissue, and it was only at high doses (600 ppm.h) that limited damage to transitional epithelium occurred. The squamous and respiratory epithelia were consistently unaffected. Within olfactory epithelium the sustentacular cells were the primary cellular target and damage to sensory cells appeared to be a secondary event. Methyl iodide induced olfactory damage was reversible, and 2 weeks after exposure almost complete repair had taken place. Received: 7 March 1995 / Accepted: 3 May 1995     

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.     

Derivation of an inhalation reference concentration based upon olfactory neuronal loss in male rats following subchronic acetaldehyde inhalation

Acetaldehyde inhalation induces neoplastic and nonneoplastic responses in the rodent nasal cavity. This experiment further characterizes the dose-response relationship for nasal pathology, nasal epithelial cell proliferation, and DNA-protein cross-link formation in F-344 rats exposed subchronically to acetaldehyde. Animals underwent whole-body exposure to 0, 50, 150, 500, or 1500 ppm acetaldehyde for 6 h/day, 5 days/wk for up to 65 exposure days. Respiratory tract histopathology was evaluated after 4, 9, 14, 30, and 65 exposure days. Acetaldehyde exposure was not associated with reduced body weight gain or other evidence of systemic toxicity. Histologic evaluation of the nasal cavity showed an increased incidence of olfactory neuronal loss (ONL) following acute to subchronic exposure to > or = 150 ppm acetaldehyde and increased olfactory epithelial cell proliferation following exposure to 1500 ppm acetaldehyde. The severity of the ONL demonstrated dose- and temporal-dependent behaviors, with minimal effects noted at 150-500 ppm acetaldehyde and moderately severe lesions seen in the highest exposure group, with increased lesion severity and extent as the exposure duration increased. Acetaldehyde exposure was also associated with inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium. These responses were seen in animals exposed to > or = 500 ppm acetaldehyde. Acetaldehyde exposure was not associated with increased DNA-protein cross-link formation in the respiratory or olfactory epithelium. A model of acetaldehyde pharmacokinetics in the nose was used to derive an inhalation reference concentration (RfC) of 0.4 ppm, based on the no-observed-adverse-effect level (NOAEL) of 50 ppm for the nasal pathology seen in this study.     

The Effects of Inhalation Exposure to Sulfuryl Fluoride on Fetal Development in Rats and Rabbits

Sulfuryl fluoride is a fumigant insecticide used for soils andpermanent structures. Pregnant Fischer 344 rats and New ZealandWhite rabbits were exposed to 0, 25, 75, or 225 ppm of sulfurylfluoride vapor via inhalation for 6 hr/day on Days 6–15and 6–18 of gestation, respectively. Among rats, maternalwater consumption was increased in the 225 ppm exposure group,but there were no indications of embryotoxicity, fetotoxicity,or tera-togenicity in any of the exposed groups. Among rabbits,maternal weight loss during the exposure period (Days 6–18)was observed in the 225 ppm group. Decreased fetal body weights,considered secondary to maternal weight loss, were also observedat 225 ppm. However, no evidence of embryotoxicity or teratogenicitywas observed among rabbits in any exposure group. Thus, inhalationexposure to sulfuryl fluoride was not teratogenic in eitherrats or rabbits exposed to levels of up to 225 ppm, and fetotoxiceffects (reduced body weights) were observed among fetal rabbitsonly at an exposure level that produced maternal weight loss.     

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.     

Assessment of Offspring Development and Behavior Following Gestational Exposure to Inhaled Methanol in the Rat

The prospect of widespread human exposure associated with itsuse as an alternative fuel has sparked concern about the toxicpotential of inhaled methanol (MeOH). Previous studies haverevealed congenital malformations in rats following inhaledMeOH (Nelson et al. (1985). Fundam. Appl. Toxicol. 5,727–736)but these studies did not include postnatal behavioral assessment.In the present study, pregnant Long–Evans rats were placedin exposure chambers containing 15,000 ppm MeOH or air for 7hr/day on Gestational Days (GD) 7–19. The total alveolardose of methanol was estimated at about 6.1 g/kg/day, for atotal dose of about 42.7 g/kg for the entire study. Maternalbody weights were recorded daily and blood methanol concentrationswere determined at the end of exposure on GD 7, 10, 14, and18. Following birth (Postnatal Day 0 [PND 0]), a number of testswere performed at various points in development, including:offspring mortality and body wt (PND 1, 3), motor activity (PND13–21, 30, 60), olfactory learning (PND 18), behavioralthermoregulation (PND 20–21), T-maze learning (PND 23–24),acoustic startle response (PND 24, 60), reflex modfficationaudiometry (PND 60), pubertal landmarks (PND 31–56), passiveavoidance (PND 72), and visual-evoked potentials (PND 160).Maternal blood MeOH levels, measured from samples taken within15 mm after removal from the exposure chamber, declined fromabout 3.8 mg/ml on the first day of exposure to 3.1 mg/ml onthe 12th day of exposure. MeOH transiently reduced maternalbody wt (4–7%) on GD 8–10, and offspring BW (5%)on PND 1. No other test revealed significant effects of MeOH.Prenatal exposure to high levels of inhaled MeOH appears tohave little effect on this broad battery of tests beyond PND1 in the rat.     

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.     

Disposition and Pharmacokinetics of Isopropanol in F-344 Rats and B6C3F1 Mice

The absorption, metabolism, disposition, and excretion of isopropanol(IPA) were studied in male and female rats and mice. Animalswere exposed by iv (300 mg/kg) and inhalation (500 and 5000ppm for 6 hr) routes; additionally, IPA was given by gavageto rats only in single and multiple 300 and 3000 mg/ kg doses.In the rat approximately 81–89% of the administered dosewas exhaled (as acetone, CO₂, and unmetabolized IPA); approximately76% of the dose in mice was exhaled after iv bolus but 92% wasexhaled following inhalation. Approximately 3–8% of theadministered dose was excreted in urine as IPA, acetone, anda metabolite tentatively identified as isopropyl glucuronicacid. Small amounts of radiolabel were found in feces and inthe carcass. There were no major differences in the rates orroutes of excretion observed either between sexes or betweenroutes of administration. Additionally, repeated exposure hadno effect on excretion. However, both the route of administrationand the exposure or dose level influenced the form in whichmaterial was exhaled. Following exposure to 5000 ppm, a greaterpercentage of unmetabolized IPA was recovered in the expiredair than following exposure to 500 ppm, implying saturationof metabolism.     

Use of Lung Toxicity and Lung Particle Clearance to Estimate the Maximum Tolerated Dose (MTD) for a Fiber Glass Chronic Inhalation Study in the Rat

Short–term toxicity and lung clearance were assessed inrats exposed by inhalation to size-selected fibrous glass (FG)for 13 weeks. Results from this study and from a recent FG chronicinhalation study are presented here as guidelines for the selectionof a maximum tolerated dose (MTD) for chronic inhalation studiesof fibers. Fischer 344 rats were exposed using nose–onlyinhalation chambers, 6 hr/day, 5 days/week, for 13 weeks toone of five concentrations of FG (36, 206, 316, 552, or 714fibers/cc; expressed gravirnetrically, 3, 16, 30, 45, or 60mg/m³) or to filtered air. Rats were then held for an additional10 weeks of postexposure recovery. Test fiber was size–selectedfrom glass wool having a chemical composition representativeof building insulation. Rats were terminated at 7, 13, 19, and23 weeks after the onset of exposure to evaluate pulmonary pathology,lung epithelium cell proliferation, lung fiber burden, and lunglavage cells and chemistry. The effect of fiber inhalation onlung clearance of innocuous microspheres was also evaluated:following fiber exposure, six rats/group were exposed to ⁸⁵Sr–labeled3.0-µm polystyrene microspheres by intratracheal inhalationand then monitored for whole–body radioactivity duringthe 10–week recovery period. Data from the short–termstudy support the choice of 30 mg/m³ as the MTD for the previouschronic FG study and also provide indicators of long–termlung toxicity and functional impairment that can be used toestimate the MTD for future chronic fiber inhalation studies.     

Teratological Assessment of Methanol and Ethanol at High Inhalation Levels in Rats

Teratological Assessment of Methanol and Ethanol at High InhalationLevels in Rats. NELSON, B. K., BRIGHTWELL, W. S., MACKENZIE,D. R., KHAN, A., BURG, J. R., WEIGEL, W. W., AND GOAD, P. T.(1985). Fundam. Appl. Toxicol. 5, 727–736. Alcohols arewidely used as industrial solvents. In spite of the fact thatethanol is a human teratogen, there has not been systematicinvestigation of the potential teratogenic effects of otheralcohols, particularly using the inhalation route of exposure,as would be appropriate in assessing occupational and environmentaltypes of experience. As part of a large teratological examinationof industrial alcohols, methanol and ethanol were administeredby inhalation to groups of approximately 15 pregnant Sprague-Dawleyrats. Methanol was administered at 20,000 ppm (20ME), 10,000ppm (10ME), 5000 ppm (5ME), and 0 ppm (MECO) for 7 hr/day onDays 1–19 of gestation (Days 7–15 for 20ME). Ethanolwas administered at 20,000 ppm (20ET), 16,000 ppm (16ET), 10,000ppm (10ET), and 0 ppm (ETCO) for 7 hr/day on Days 1–19of gestation. Dams were sacrificed on Day 20 (sperm=Day 0).One-half of the fetuses were examined using the Wilson techniquefor visceral defects, and the other half were examined for skeletaldefects. The highest concentration of methanol (20ME) producedslight maternal toxicity and a high incidence of congenitalmalformations (p < 0.001), predominantly extra or rudimentarycervical ribs and urinary or cardiovascular defects. Similarmalformations were seen in the 10ME group, but the incidencewas not significantly different from controls. No adverse effectswere noted in the 5ME group. Dams in the 20ET group were narcotizedby the end of exposure, and maternal weight gain and feed intakewere decreased during the first week of exposure. The 16ET damshad slightly depressed weight gain (p < 0.01) during thefirst week of exposure, but there were no significant effectson feed consumption. There was no definite increase in malformationsat any level of ethanol, although the incidence in the 20ETgroup was of borderline significance     

A Dynamic Closed-Loop Recirculating Inhalation Chamber for Conducting Pharmacokinetic and Short-Term Toxicity Studies

A Dynamic Closed-loop Recirculating Inhalation Chamber for ConductingPharmacokinetic and Short-term Toxicity Studies. Paustenbach,D.J., Carlson, G.P., Christian, J.E., Born, G.S. and Rausch,J.E. (1983).Fundam. Appl. Toxicol. 3:528–532. Tests forevaluating the hazard of inhalation exposure generally requirelarge quantities of the chemical of interest. This paper describesan inhalation technique that involves a dynamic closed-looprecirculating system which uses only small amounts of toxicantsince the test atmosphere to which the animals are exposed isrecycled. Carbon dioxide and water are continually removed whilethe oxygen and test substance absorbed by the animals are replenished.The approach described is different from other closed-loop chamberssince the test substance is continuously added to the chamberand the air concentration is continuously measured. The techniquewas successfully used to expose 20 adult rats for up to 12 consecutivehours to 100 ppm of ¹⁴C-carbon tetrachloride yet only 2–3mL of test material were consumed. The inhalation chambers werefabricated from standard 40-liter cylindrical glass bell jars.A high number of air changes (35–40 equivalent chambervolumes per hour) permitted exposure of as many as five adultrats per 10 liters of chamber volume. This closed-loop approachshould prove to be especially useful for evaluating the riskof exposure to very expensive materials or when only limitedquantities of a test material are available. These systems mayalso be used to expose rats and other small animals to radioisotopesin studies which evaluate the uptake, distribution, metabolism,and excretion of volatile xenobiotics.     

Accumulation of Cd(II) in the CNS Depending on the Route of Administration: Intraperitoneal, Intratracheal, or Intranasal

The uptake and subsequent neuronal transport of certain heavymetals in the olfactory mucosa may be a major means by whichthese compounds gain access to the CNS. To contrast olfactoryversus blood-borne routes of exposure, three groups (n = 4)of adult Long-Evans rats were exposed to solutions of radiolabeledCdCl₂. Exposure was by one of three routes: unilateral intranasalinstillation (IN), intratracheal lavage (IT), or intraperitonealinjection (ip). The dose level for the intranasal route was30 µl of 1 µM CdCl₂ labeled with 1 µCi ¹⁰⁹Cd.For IT and ip, the dose was 30 µl of 1 µM CdCl₂diluted to 300 µl in saline and labeled with 1 µCi¹⁰⁹Cd. Rats were euthanized 24 hr after exposure, tissue sampleswere taken, and radioactivity was counted. Cd levels were lowin the olfactory bulbs of rats exposed either intratracheallyor intraperitoneally. However, in rats intranasally exposed,Cd levels were nearly 40 higher in olfactory bulbs ipsilateralto the exposed side than in those on the contralateral side.With all routes of exposure, Cd levels in brain samples wereonly slightly elevated. These results suggest that for certainairborne toxicants, especially those that are excluded fromthe CNS by the blood-brain barrier, the olfactory system mayprovide a direct route of entry into the CNS.     

Histopathology of Acute Toxic Responses in Selected Tissues from Rats Exposed by Inhalation to Methyl Bromide

Histopathology of Acute Toxic Responses in Selected Tissuesfrom Rats Exposed by Inhalation to Methyl Bromide. HURTT, M.E., MORGAN, K. T., AND WORKING, P. K. (1987). Fundam. Appl.Toxicol. 9, 352–365. To determine and characterize thehistological changes induced in selected tissues from the Fischer344 rat by acute inhalation exposure to methyl bromide (MeBr),groups of 10 male rats(11–13 weeks old) were exposed to0, 90, 175, 250, or 325 ppm MeBr 6 hr/day for 5 days. Animalswere anesthetized with phenobarbital then perfusion-fixed 1–2hr after the last exposure or in extremis (325 ppm, 4 days)with Karnovsky's fixative and selected tissues were processedfor light microscopy. With the exception of the nasal passages,tissues were selected on the basis of previous studies withmethyl chloride (MeCl). The nose was examined as part of ongoingresearch of nasal toxicity in this laboratory. The principalclinical signs, confined to the 250 and 325 ppm groups, werediarrhea, hemoglobinuna, and, in a few cases, gait disturbancesand convulsions. A dose-dependent vacuolar degeneration of thezona faseiculata of the adrenal glands, cerebellar granule celldegeneration, and nasal olfactory sensory cell degenerationwere seen in all concentration groups except at 90 ppm. Cerebralcortical degeneration and minor alterations in testicular histologywere seen only in the 325 ppm group. Hepatocellular degenerationwas confined to the 250 and 325 ppm groups. No changes wereseen in the kidneys or epididymides. This study demonstratesthat MeBr has similar target organs to MeCl suggesting thatsimilar mechanisms of toxicity may be operational. However,important differences in the nature of cellular responses tothese chemicals may facilitate studies on their mechanisms ofactions.     

Developmental Toxicity Evaluation of Inhaled 2-Ethoxyethanol Acetate in Ficher 344 Rats and New Zealand White Rabbits

Developmental Toxicity Evaluation of Inhaled 2–EthoxyethanolAcetate in Fischer 344 Rats and New Zealand White Rabbits. Tyl,R. W., Pritts, I. M, France, K. A., Fisher, L. C, and Tyler,T. R. (1988). Fundam. Appl. Toxicol. 10, 20–39. PregnantFischer 344 rats and New Zealand white rabbits were exposedto 2–ethoxyethanol acetate (EEA; CAS No. 111–15–9)vapor by inhalation on Gestational Days 6 through 15 (rats)or 6 through 18 (rabbits) at concentrations of 0, 50, 100,200,or 300 ppm, 6 hr/day. The animals were terminated on Gesta–tionalDay 21 (rats) or 29 (rabbits) and fetuses were examined forexternal, visceral, and skeletal malformations and variations.In rabbits, exposure to 100–300 ppm resulted in maternaltoxic–ity: decreased weight gain at 100–300 ppm,clinical signs at 200–300 ppm, alterations in hema–tologyat 100–300 ppm, reduced gravid uterine weight at terminationat 200–300 ppm, and elevated absolute liver weight at300 ppm. Developmental toxicity was observed at 100–300ppm: an increased incidence of totally resorbed litters at 200–300ppm, an increase in nonviable fetuses at 300 ppm, and a decreasein viable implants (live fetuses) per litter at 200–300ppm. The incidence of fetal malformations (external, visceral,and skeletal) was increased at 200–300 ppm. The incidenceof total malformations was 100% at 300 ppm and significantlyincreased at 200 ppm. Reduced fetal ossification was observedat 100–300 ppm. In rats, exposure to 100–300 ppmalso resulted in maternal toxicity: reduced weight gain andreduced food consumption at 200–300 ppm and elevated relativeliver weight and alterations in hematology at 100–300ppm. Absolute maternal liver weight was increased at all EEAexposure concentrations; relative liver weight was increasedat 100–300 ppm. Developmental toxicity was observed at100–300 ppm: increased nonviable implantations/litter(300 ppm), reduced fetal body weight/litter (200–300 ppm),and increased incidence of external (300 ppm), visceral, andskeletal (100–300 ppm) variations indicative of toxicity.The incidence of visceral, skeletal, and total malformationswas increased at 200–300 ppm. In conclusion, in both species,inhalation exposure to EEA during organogenesis produced maternaltoxicity at 100–300 ppm and developmental toxicity at100–300 ppm, including teratogenicity at 200–300ppm. At 50 ppm in both species, there was no evidence of maternalor developmental toxicity, including teratogenicity.     

A Comparison of the Fate of Inhaled Methyl Chloroform (1,1,1-Trichloroethane) Following Single or Repeated Exposure in Rats and Mice

A Comparison of the Fate of Inhaled Methyl Chloroform (1,1,1-Trichloroethane)Following Single or Repeated Exposure in Rats and Mice. Schumann,A.M., Fox, T.R. and Watanabe, P.G. (1982). Fundam. Appl. Toxicol.2:27–32. Male Fischer 344 rats and B6C3F1 mice were exposedby inhalation to 1500 ppm of methyl chloroform (MC) 6 hours/day,5 days/week for approximately 16 months. On the last day ofrepeated exposure ¹⁴C-labeled MC was used. The fate of the ¹⁴C-MCin the repeatedly exposed animals was compared to a group ofrats and mice which had been exposed concurrently for 16 monthsto chamber air (age-matched controls) prior to receiving thesingle 6 hour exposure to 1500 ppm of ¹⁴C-MC. The routes ofexcretion and tissue concentration of ¹⁴C activity were similarbetween the singly and repeatedly exposed rats and mice. Themajor route of elimination of MC was exhalation of the parentchemical In the expired air and constituted approximately 97%of the total recovered radioactivity in rats and 92–94%in mice. The remaining radioactivity (3.9%) was recovered asmetabolized MC in the expired air (¹⁴CO₂) and as nonvolatileradioactivity in the urine, feces, carcass and cage wash. Micewere found to eliminate MC more rapidly via the pulmonary routeand to biotransform approximately 5-fold more MC on a body weightbasis than rats. Repeated exposure to MC did not significantlyaffect the disposition of MC compared to the singly exposedrats and mice. Thus even after long-term repeated exposure toMC, its biotransformation remains limited. Comparison of theresults of the present study to those obtained previously inyoung-adult rats and mice indicates that alterations in thepharmacokinetics of ¹⁴C-MC (increased body burden and decreasedrate of pulmonary elimination) occur with age but not priorrepeated exposure to MC.     

Inhalation Toxicity of Butylene Oxide

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

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

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

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

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

The Ototoxicity of Trichloroethylene: Extrapolation and Relevance of High-Concentration, Short-Duration Animal Exposure Data

Inhalation exposure to high concentrations of 1,1,2-trichloroethylene(TCE) has been shown to damage hearing in the mid-frequencyrange in the rat. The present study directly evaluated the adequacyof high-concentration, short-term exposures to TCE for predictingthe neurotoxicity produced by longer duration exposures. Adultmale Long-Evans rats (n = 10–12 per group) were exposedto TCE via inhalation (whole body) in 1-m³ stainless steel flow-throughchambers for 6 hr/day, 5 days/week. The following exposureswere used: 1 day (4000–8000 ppm), 1 week (1000–4000ppm), 4 weeks (800–3200 ppm), and 13 weeks (800–3200ppm). Air-only exposed animals served as controls. Auditorythresholds were determined for a 16-kHz tone 3–5 weeksafter exposure using reflex modification audiometry. Resultsreplicated previous findings of a hearing loss at 16 kHz forall exposure durations. The dBl5 concentrations (concentrationthat increases thresholds by 15 dB) for 16-kHz thresholds were6218, 2992, 2592, and 2160 ppm for the 1-day, 1-week, 4-weekand 13-week exposures, respectively. These data demonstratethat the ototoxicity of TCE was less than that predicted bya strict concentration time relationship. These data alsodemonstrate that simple models of extrapolation (i.e., C t= k, Haber's Law) overestimate the potency of TCE when extrapolatingfrom short-duration to longer-duration exposures. Furthermore,these data suggest that, relative to ambient or occupationalexposures, the ototoxicity of TCE in the rat is a high-concentrationeffect.