The Pulmonary Response and Clearance of Ludox Colloidal Silica after a 4-Week Inhalation Exposure in Rats

Rats were exposed to Ludox colloidal silica (CS) at concentrationsof 0, 10, 50, and 150 mg/m³ for 6 hr/day, 5 days/week for 4weeks. Rats were killed after 4 weeks of exposure and 10 daysor 3 months post exposure (PE). The exposure concentration of10 mg/m³ Ludox CS is considered to be the no-effect concentration.There were no exposure-related clinical signs in any group.After 4 weeks exposure, lung weights were increased significantlyin rats exposed to 50 and 150 mg/m³ Ludox CS, but lung weightswere similar to those of controls at 3 months PE. After 4 weeksexposure to 50 mg/m³ Ludox CS, a slight alveolar macrophageresponse, polymorphonuclear leukocytic infiltration, and TypeII pneumocyte hyperplasia in alveolar duct regions were present.After 3 months PE, these pulmonary lesions had almost disappearedwith removal of most dust-laden alveolar macrophages (AMs).The pulmonary response to 150 mg/m³ Ludox CS was similar incharacter but increased in magnitude from that seen at 50 mg/m³At 3 months PE, most particleladen AMs had disappeared and theremaining AMs were aggregated and sharply demarcated. A fewaggregates of particle-laden AMs appeared to transform intosilicotic nodules comprising macrophages, epithelioid cells,and lymphocytic infiltration in some animals. Some silicoticnodules showed reticular fiber networks with minute collagenfiber deposition. Tracheobronchial lymph nodes were enlargedwith aggregates of particle-laden AMs and hyperplastic histiocyticcells. Lung-deposited Ludox cleared rapidly from the lungs withhalf-times of approximately 40 and 50 days for the 50 and 150mg/m³ groups, respectively.     

Two-Year Inhalation Toxicity Study in Rats with Hydrochlorofluorocarbon 123

The potential chronic toxicity and oncogenicity of hydrochlo-rofluorocarbon123 (HCFC-123) was evaluated by exposing male and female ratsto 0, 300, 1000, or 5000 ppm HCFC-123 for 6 hr/day, 5 days/week,for 2 years. Clinical pathology was evaluated at 6, 12, 18,and 24 months. An interim termination and measurements of hepaticcell proliferation and beta-oxidation activity were conductedat 12 months. The terminal euthani-zation occurred at 24 months.Males and females exposed to 5000 ppm and females exposed to300 or 1000 ppm had lower body weights and body weight gains.Serum triglyceride and glucose concentrations were significantlydecreased at all exposure concentrations in both sexes. Serumcholesterol was also lower in 300, 1000, and 5000 ppm femalesand in 5000 ppm males. Alterations in serum protein concentrationsoccurred at 300, 1000, and 5000 ppm. Survival was higher in1000 and 5000 ppm males and females. At 24 months, increasedrelative liver weight occurred in 5000 ppm males, and decreasedabsolute kidney weight occurred in 5000 ppm males and in 1000and 5000 ppm females. Benign hepatocellular adenomas were increasedin 5000 ppm males and in all test groups of females. Hepaticcholangiofibromas were also increased in 5000 ppm females. Pancreaticacinar cell adenomas were increased in all test groups of males,and acinar cell hyperplasia was increased in the 1000 and 5000ppm males and females. Benign testicular interstitial adenomasand focal interstitial cell hyperplasia were also increasedin all male test groups compared to controls. Diffuse retinalatrophy was increased in all male and female test groups, butit was considered to be an indirect compound-related effect.Hepatic beta-oxidation activity (peroxisome proliferation) washigher in 300, 1000 and 5000 ppm males and 1000 and 5000 ppmfemales. Compound-related differences in the rate of hepaticcell proliferation were not observed at any exposure concentration.Decreased incidences of a variety of age-related lesions occurredat 1000 and 5000 ppm.     

Inhalation Toxicity Study of Formamide in Rats

Formamide is a widely used solvent for the manufacture and processingof plastics, and the possibility for inhalation exposure existsfor workers. To assess the toxicity of repeated inhalation ofsublethal concentrations of formamide, three groups of 10 maleCrl:CD BR rats each were exposed nose-only for 6 hr/day, 5 days/weekfor 2 weeks to design concentrations of 100, 500, or 1500 ppmof formamide vapor in air. A control group of 10 male rats wasexposed simultaneously to air only. At the end of the exposureperiod, blood and urine samples were collected for clinicalanalyses, and 5 rats per group were killed for pathologic examination.The remaining 5 rats per group were retained for a 14-day postexposureobservation (recovery) period and then subjected to the sameclinical and pathologic examinations. Male rats exposed to 1500ppm had significantly depressed body weights and body weightgains during the exposure and recovery periods compared to controls.Clinical pathologic examinations revealed that decreased plateletand/or lymphocyte counts were observed in rats exposed to 500or 1500 ppm of formamide. Pathologic examinations revealed compound-relatedmicroscopic changes in the kidneys of rats exposed to 1500 ppmformamide. Minimal to severe necrosis and regeneration of renaltubular epithelial cells were observed principally in the outerstripe of the outer medulla and in cortical medullary rays.Based upon the hematologic and clinical chemical parametersmeasured, the no-observed-effect exposure concentration forrepeated inhalation of formamide was considered to be 100 ppm,under the conditions of this study. The findings of treatment-relatedmicroscopic lesions in the kidneys as well as increases in meanabsolute kidney weights and kidney-to-body weight ratios reflectthe target organ toxicity.     

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.     

Inhalation Toxicity of Methylglutaronitrile in Rats

Abstract

Methylglutaronitrile (MGN) is a high-boiling (263°C) solvent/intermediate used in the fiber industry. Twenty male rats per group were exposed nose-only to condensation aerosol/vapor concentrations of approximately either 5, 25, or 200 mg/m³ of MGN for 6 h/day, 5 days/week over a 4-week period. Ten rats/group were sacrificed one day after the final exposure and the remaining rats after a four-week recovery period. No effects were observed in clinical observations during the exposure period, but body-weight depression was observed in the 200 mg/m³ group. The 200 mg/m³ group showed minimal decreases in red blood cell count, hemoglobin, and hematocrit values accompanied by increases in reticulocytes. There were no other effects observed in clinical or pathologic evaluations in the study. A neurobehavioral battery of tests (including grip strength, functional observational battery, and motor activity tests) given at the end of the exposure and recovery periods showed no MGN effects. During the 4-week recovery, body weights in the 200 mg/m³ group returned to normal and the hematologic findings in all groups were normal. Based on the above findings of body weight depression at 200 mg/m³, the no-observed-adverse-effect level (NOAEL) for this study was considered to be 25 mg/m³.     

Inhalation Toxicity of Cyclododecatriene in Rats

ABSTRACT

Cyclododecatriene (CDDT, CAS No. 4904-61-4) was tested for its inhalation toxicity in rats following repeated exposures. Male rats were exposed nose-only to CDDT for 6 hr/day, 5 days/wk for a total of 9 exposures over 2 weeks. Particular attention was paid to neurotoxicologic endpoints. Concentrations of 0 (control), 5, 50, and 260 ppm were studied. The 260 ppm chamber contained both vapor and aerosol while the 5 and 50 ppm chambers were vapor only. Four groups of 10 rats each were used to measure standard clinical signs and growth, clinical pathology (including hematology, biochemistries, and urine analysis), and tissue pathology. Another 4 groups of similar size were used for neurotoxicity testing. In the standard toxicity groups, 1/2 of the rats were sacrificed 1 day following the 9th exposure; the other half underwent a 2-week recovery period prior to being sacrificed (recovery group). During the exposures rats inhaling 260 ppm had a diminished or absent response to an alerting stimulus. Irregular respiration and lethargy were observed in these rats immediately following exposure. These signs were rapidly reversible and were not seen prior to the subsequent exposure. Body weights in rats exposed to either 50 or 260 ppm were significantly lower than the corresponding controls. No compound-related clinical pathology changes were seen in any of the test groups and tissue pathology effects only occurred in the nasal tissue. In rats exposed to 260 ppm, minimal degeneration/necrosis of nasal olfactory epithelium was observed in rats examined immediately following the exposure period. This change was not seen in the recovery rats. Functional observational battery (FOB) assessments and motor activity (MA) evaluations conducted after the 4th and 9th exposures on rats from all test groups, and specific neuropathologic evaluation on perfused brain, spinal cord, and skeletal muscle from rats exposed to 260 ppm failed to demonstrate any specific neurotoxicity. Outward signs of sedation were seen at the top level tested. Under the conditions of this test, the no-observed-adverse-effect level (NOAEL) was determined to be 5 ppm based upon a reduced rate of body weight gain in the 50 ppm group. No specific neurotoxicity was detected and the histopathologic response was limited to reversible changes in the nasal epithelia in rats exposed to 260 ppm.     

Twenty-Eight-Day Inhalation Toxicity Study of Silver Nanoparticles in Sprague-Dawley Rats

The antibacterial effect of silver nanoparticles has resulted in their extensive application in health, electronic, and home products. Thus, the exposed population continues to increase as the applications expand. Although previous studies on silver dust, fumes, and silver compounds have revealed some insights, little is yet known about the toxicity of nano-sized silver particles, where the size and surface area are recognized as important determinants for toxicity. Thus, the inhalation toxicity of silver nanoparticles is of particular concern to ensure the health of workers and consumers. However, the dispersion of inhalable ambient nano-sized particles has been an obstacle in evaluating the effect of the inhalation of nano-sized particles on the respiratory system. Accordingly, the present study used a device that generates silver nanoparticles by evaporation/condensation using a small ceramic heater. As such, the generator was able to distribute the desired concentrations of silver nanoparticles to chambers containing experimental animals. The concentrations and distribution of the nanoparticles with respect to size were also measured directly using a differential mobility analyzer and ultrafine condensation particle counter.     

Subchronic Inhalation Toxicity of Tetramethoxysilane in Rats

Sprague-Dawley rats were exposed 6 hr/day, 5 days a week, for28 days to tetramethoxysilane (TMOS) at concentrations of 0,1, 5, and 10 ppm (Phase I study) and to 0, 15, 30, and 45 ppm(Phase II study). All of the rats exposed to 45 ppm TMOS diedor were sacrificed in a moribund state during the 28-day studyperiod. Statistically significant changes were observed in foodconsumption, body weights, and clinical chemistry parametersin the animals exposed to 30 ppm TMOS. Males exposed to 15 ppmTMOS showed a significant decrease in total protein. No effectswere seen in rats exposed to 1, 5, and 10 ppm TMOS. Histopathologicallesions related to TMOS exposure were observed in the respiratorytract tissues and eyes of rats exposed to 15, 30, and 45 ppmTMOS. The principal types of lesions observed were ulceration,inflammation, and necrosis of epithelium. At 45 ppm, changesat these sites were severe and present in all animals. Changesat 30 ppm, while occurring in all rats, were much less severethan those seen at 45 ppm. At 15 ppm, the changes were minimaland occurred only in three males and five females. The dataof this study showed that TMOS has a steep dose-response curvewith no observable effects at 10 ppm, very minimal effects at15 ppm, moderate to severe effects at 30 ppm, and severe effectsand lethality at 45 ppm.     

Subchronic Inhalation Toxicity of Hexamethylenediamine in Rats

Four groups of 15 male and 15 female Sprague-Dawley-derived(CD) rats each were exposed to aqueous hexamethylenediamine(HMD) aerosols for 6 hr/thy, 5 days/week for 13 weeks at meananalytical concentrations of 0, 12.8, or 51 mg/m³ Because ofexposure-related deaths in a group of male and female rats similarlyexposed to 215 mg/m³ HMD, this group was terminated during theseventh week of the study. Signs of respiratory and conjunctivalirritation were observed in rats at both the 51 and 215 mg/m³HMD test levels. Body weight gain was significantly reducedin both sexes exposed to 215 mg/m³ HMD. At the 5-week studyinterval, slight hemopoietic stimulation of peripheral bloodparameters was observed in rats of both sexes exposed to 215mg/m³ HMD. Treatment-related microscopic lesions were seen onlyin rats exposed to 215 mg/m³ MD and were confined to the trachea,nasal passages, and lungs. The noeffect level in this studyis considered to be 12.8 mg/m³ HMD.     

Methylene Chloride: A 2-Year Inhalation Toxicity and Oncogenicity Study in Rats

Methylene Chloride: A 2-Year Inhalation Toxicity and OncogenicityStudy in Rats. Nit-schke, K. D. Burek, J. D., Bell, T. J., Kociba,R. J., Rampy, L. W. and McKenna, M. J. (1988). Fundam. Appl.Toxicol. 11, 48-59. Male and female Sprague-Dawley rats wereexposed to 0, 50, 200, or 500 ppm methylene chloride for 6 hr/day,5 days/week for 2 years. Blood carboxyhemoglobin levels wereelevated in a dose-dependent (less than linear) manner in ratsexposed to 50–500 ppm methylene chloride Histopathologiclesions related to methylene chloride exposure were confinedto the liver and mammary tissue of rats. An increased incidenceof hepatocellular vacuolization was observed in male and femalerats exposed to 500 ppm methylene chloride. Female rats exposedto 500 ppm methylene chloride also had an increased incidenceof multinucleated hepatocytes and number of spontaneous benignmammary tumors/ tumor-bearing rat (adenomas, fibromas, and fibroadenomaswith no progression toward malignancy); the incidence of benignmammary tumors in female rats exposed to 50 or 200 ppm methylenechloride was comparable to historical control values. No increasein the number of any malignant tumor type was observed in ratsexposed to concentrations as high as 500 ppm methylene chloride.Additional groups of female rats were exposed to 500 ppm methylenechloride for the first 12 months or the last 12 months of the24-month study. The response observed in female rats exposedto 500 ppm for the first 12 months was the same as that observedin female rats exposed to 500 ppm for 2 years. Conversely, theresponse observed in female rats exposed to 500 ppm during thelast 12 months of the study was similar to that observed incontrol animals. Based upon the results of this study, the no-adverse-effectlevel for chronic inhalation exposure of Sprague-Dawley ratswas judged to be 200 ppm methylene chloride.     

One-Month Inhalation Toxicity Study of Tulobuterol Hydrochloride in Rats and Dogs

Tulobuterol hydrochloride (HCl) has ß₂-adrenergicagonist activity and is under development for use in the treatmentof chronic obstructive lung disease. The purpose of this studywas to determine the toxicity of inhaled tulobuterol HCl inrats and dogs. Rats were whole-body exposed to aerosol gravimetricconcentrations of 0, 0.03, 0.22, or 1.1 mg/ liter of tulobuterolHCl, 60 min/day for 28 days. Dogs were exposed (via insufflation)to estimated daily doses of 0, 0.2, 1.0, or 6.0 mg/kg for anequal period. Plasma levels of tulobuterol were determined followingexposure on Days 1, 8, and 28 using a high-pressure liquid chromato-graphicmethod developed for this study. Results indicated that plasmatulobuterol levels were highly correlated with tulobuterol doses(p < 0.0001 for rats and dogs). No dose-related changes inbody weight food consumption, hematological, or serum chemistryparameters were observed in either species. Anterior nasal cavitylesions were observed by light microscopy in rats exposed to0.22 and 1.1 mg/liter tulobuterol HCl at an incidence of 14and 93%, respectively. These lesions involved the nasal septum,turbinates, and/or the dorsolateral wall of the nasal cavityand consisted of suppurative rhinitis and necrosis. The correspondingmean plasma tulobuterol levels on Day 28 in mid- and high-doserats were approximately 1000 and 15,000 ng/ml. Nasal lesionswere not observed in rats allowed to recover for 2 weeks. Nogross or microscopic lesions were detected in lungs or othertissues of either species. These results indicate that the insufflationof high doses of tulobuterol HCl aerosol for 1 month was generallywithout toxicity in dogs and that the local nasal ussue injuryobserved in rats exposed to high concentrations of aerosolizedtulobuterol HCl was reversible.     

Inhalation Developmental Toxicity Study of Propylene Oxide in Fischer 344 Rats

The developmental toxicity potential of propylene oxide (PO)was evaluated in Fischer 344 rats following inhalation exposure.Four groups of 25 mated female rats were exposed to 0, 100,300, and 500 ppm of PO for 6 hr per day on Gestation Days 6through 15, inclusive. Cesarean sections were performed on allfemales on Gestation Day 20 and the fetuses removed for morphologicalevaluation. Exposure to propylene oxide did not adversely affectsurvival, appearance, or behavior at any of the exposure levelstested. Maternal body weight gain and food consumption werereduced significantly among the females at the 500 ppm levelduring the exposure period. No exposure-related effects werenoted with respect to maternal water consumption, organ weights,cesarean section, or fetal morphological observations with thesole exception of increased frequency of seventh cervical ribsin fetuses at the maternally toxic exposure level of 500 ppm.In summation, the no-observable-adverse-effect level (NOAEL)of propylene oxide. when administered to Fischer 344 rats viawhole-body inhalation exposure, was considered to be 300 ppm.     

Pulmonary and Pleural Responses in Fischer 344 Rats Following Short-Term Inhalation of a Synthetic Vitreous Fiber: II. Pathobiologic Responses

The pleura is a target site for toxic effects induced by a varietyof fibrous particulates, including both natural mineral andman made vitreous fibers. We examined selected cytological andbio chemical indicators of inflammation in both the pleuralcompart ment and pulmonary parenchyma in F344 rats followinginhala tion of RCF-1, a kaolin-based ceramic fiber. Male F344rats were exposed by Inhalation to 89 mg/m³ (2645 WHO fibers/cc)RCF-1 6 hr/day for 5 consecutive days. In lung parenchyma, cytologicaland biochemical inflammatory responses occurred rapidly followingexposure. In contrast, pleural responses were delayed in onsetand of a much smaller magnitude than those observed in lung.At both Day 1 and Day 28 postexposure, increased quantitiesof lactate dehydrogenase, N-acetyl glucosaminidase, alkalinephosphatase, albumin, and neutrophils were present in bronchoalveolarlavage fluid. These responses were attenuated at the lattertime point. No significant responses were detected in pleurallavage fluid until 28 days following exposure, at which timeelevated numbers of macrophages and eosinophils, but not neutrophils,were observed. Increased albumin and fibronectin were also observed in PLF at this latter time point. These findings demonstratethat the onset of pleural and pulmonary responses followinginhalation of RCF-1 are temporally separated and that pleuralinjury may increase in severity with time following exposure.The increase in severity of pleural inflammation found in thepostexposure period cannot be readily explained by fiber translocation.     

Subchronic Inhalation Toxicity of 1,1,1,3-Tetrachloropropane in Rats

The purpose of this study was to evaluate the inhalation toxicityof 1,1,1,3-tetrachloropropane (TCP), an intermediate in productionof chlorinated silicone fluids. Male and female Sprague- Dawleyrats were exposed 6 hr/day, 5 days/week, for days to TCP atconcentrations of 0, 25, 75, or 225 ppm (Phase study) and to0, 1, 5, or 10 ppm (Phase II study). Phase II of study was conductedbecause a no-observed-effect level was not achieved in PhaseI. No animals died during the study. Clinical signs of toxicityincluded oral, nasal, and/or ocular discharge. No statisticallysignificant differences were observed in either body weightsor food consumption between exposed and control animals. Clinicalpathology did not indicate any treatment related effects. Absoluteand relative liver and kidney weights were increased in maleand female rats exposed to 225 ppm TCP, and heart weights wereincreased in male rats exposed to 225 ppm TCP. The liver andheart weight changes were supported by the findings of microscopiclesions in these organs. These lesions consisted of multifocal/focalmyofiber degeneration necrosis with adjacent chronic myocarditisin the heart and multifocal single-cell necrosis in the liverparenchyma. The liver lesions had essentially resolved at theend of a 28-day recovery period but the heart lesions were stillpresent in male rats in the recovery group exposed to 225 ppmTCP. No treatment-related effects were observed in animals exposedto 1, 5, or 10 ppm TCP. The data of this study showed that theno-observable-effect level for TCP was 10 ppm in male and femaleCD rats.     

Methylene Chloride: A Two-Year Inhalation Toxicity and Oncogenicity Study in Rats and Hamsters

Methylene Chloride: A Two-Year Inhalation Toxicity and OncogenicityStudy in Rats and Hamsters. BUREK, J. D., NITSCHKE, K. D., BELL,T. J., WACKERLE, D. L., CHILDS, R. C., BEYER, J. E., DITTENBER,D. A., RAMPY, L. W., AND MCKENNA, M. J. (1984). Fundam. Appl.Toxicol. 4, 30–47. A long-term study was conducted todetermine the possible chronic toxicity and oncogenicity ofmethylene chloride. Rats and hamsters were exposed by inhalationto 0, 500, 1500, or 3500 ppm of methylene chloride for 6 hrper day, 5 days a week, for 2 years. No exposure-related cytogeneticeffects were present in male or female rats exposed to 500,1500, or 3500 ppm. Females rats exposed to 3500 ppm had an increasedmortality rate while female hamsters exposed to 1500 or 3500ppm had decreased mortality rates. Carboxyhemoglobin valueswere elevated in rats and hamsters exposed to 500, 1500, or3500 ppm with the percentage increase in hamsters greater thanin rats. Minimal histopathologic effects were present in thelivers of rats exposed to 500, 1500, or 3500 ppm. Decreasedamyloidosis was observed in the liver and other organs in hamstersexposed to 500, 1500, or 3500 ppm. While the number of femalerats with a benign tumor was not increased, the total numberof benign mammary tumors was increased in female rats in anexposure-related manner. This effect was also evident in malerats in the 1500- and 3500-ppm exposure groups. Finally, malerats exposed to 1500 or 3500 ppm had an increased number ofsarcomas in the ventral neck region located in or around thesalivary glands. Therefore, in this 2-year study, some effectswere observed in male and female rats exposed to 500, 1500,or 3500 ppm of methylene chloride. In contrast, hamsters exposedto the same exposure concentrations had less extensive spontaneousgeriatric changes, decreased mortality (females), and lackedevidence of definite target organ toxicity.     

A Subchronic Inhalation Toxicity Study in Rats Exposed to Silicon Carbide Whiskers

To determine whether inhaled silicon carbide whiskers (SiC)cause lung damage in rats, four groups (50 males/50 femaleseach) of rats were exposed to air only or to one of three concentrationsof SiC 6 hr/day, 5 days/week for 13 weeks. Half (25 males/25females/group) were euthanized at the end of exposure, the remainder26 weeks later. Mean concentrations were 0, 630, 1746, and 7276SiC whiskers/ml (0.09, 3.93, 10.7, and 60.5 mg/m3). Althoughthere were no concentration-related changes in body weight,clinical chemistry, or hematological data attributable to SiC,lung weights were increased in the high concentration exposuregroup at both euthanization times. In all whisker-exposed groups,after 13 weeks of exposure, the incidence of the following lungand lymph node lesions was higher than in controls: inflammatorylesions; bronchiolar, alveolar, and pleural wall thickening;focal pleural fibrosis in lung; and reactive lymphoid hyperplasiain bronchial and mediastinal lymph nodes. After 26 weeks ofrecovery, lung inflammatory lesions had decreased and fewerrats had enlarged lymph nodes, but the incidence of alveolarwall thickening, focal pleural wall thickening, and adenomatoushyperplasia of lung had increased further. Incidence and severityappeared to be dose-related. Therefore, until longer term studiesare undertaken and it is established whether the above observedlesions will progress to more severe pathological entities,it is prudent to adopt stringent handling procedures for siliconcarbide whiskers.     

Calibration Study on Subchronic Inhalation Toxicity of Man-Made Vitreous Fibers in Rats

This 3-mo inhalation study investigated the biological effects of a special-purpose glass microfiber (E-glass microfiber), the stone wool fiber MMVF21, and a new high-temperature application fiber (calcium-magnesium-silicate fiber, CMS) in Wistar rats. Rats were exposed 6 h/day, 5 days/wk for 3 mo to fiber aerosol concentrations of approximately 15, 50, and 150 fibers/ml (fiber length >20 µm) for E-glass microfiber and MMVF21. For the CMS fiber only the highest exposure concentration was used. During a 3-mo postexposure period, recovery effects were studied. In the highest exposure concentration groups, gravimetric concentrations were 17.2 mg/m 3 for E-glass microfiber, 37 mg/m 3 for MMVF21, and 49.5 mg/m 3 for the CMS fiber. After 3 mo of exposure, lung retention of fibers longer than 20 µm per lung was 17 × 10 6 for E-glass microfiber, 5.7 × 10 6 for MMVF21, and 0.88 × 10 6 for CMS. After 3 mo of recovery the concentration of the long fiber fraction was decreased to 38.4%, 63.9%, and 3.0% compared to original lung burden for the E-glass microfiber, MMVF21, and CMS, respectively. Biological effects measured included inflammatory and proliferative potential, histopathology lesions, and the persistence of these effects over a recovery period of 3 mo. Generally, observed effects were higher for E-glass microfiber when compared to MMVF21. The following clear dose-dependent effects on E-glass microfiber and MMVF21 exposure were observed as main findings of the study: increase in lung weight, in measured biochemical parameters and polymorphonuclear leukocytes (PMN) in the bronchoalveolar lavage fluid (BALF), in cell proliferation (BrdU-response) of terminal bronchiolar epithelium, and in interstitial fibrosis. The values observed in the proliferation assay on the carcinogenic E-glass microfiber indicate that this assay has an important predictive value with regards to potential carcinogenicity. Surprisingly, for the biosoluble CMS fiber, fibrogenic potential was detected in this study. The results of the CMS exposure group indicate that effects may be dominated by the presence of nonfibrous particles and that fibrosis may not be a predictor of carcinogenic activity of fiber samples, if the fiber preparation contains a significant fraction of nonfibrous particles. In summary, this study demonstrates the importance of fiber dust contamination by granular components. For future subchronic studies a longer posttreatment observation period would be advisable.     

Dipropylene Glycol Monomethyl Ether: A 13-Week Inhalation Toxicity Study in Rats and Rabbits

Dipropylene Glycol Monomethyl Ether. A 13-Week Inhalation Studyin Rats and Rabbits. LANDRY, T. D., AND YANO, B. L. (1984).Fundam. Appl. Toxicol. 4, 612–617. Fischer 344 rats (10/sex/exposureconcentration) and New Zealand White rabbits (7/sex/exposureconcentration) were exposed to 0, 15, 50, or 200 ppm (0, 91,303, or 1212 mg/m3) of dipropylene glycol monomethyl ether (DPGME)for 6 hr/day, 5 days/week for 13 weeks. Criteria of responseincluded general observations, body weights, clinical chemistry,hematology, urinalyses (rats only), necropsy, organ weights,and histopathology. There were no effects attributed to exposureto DPGME at any exposure concentration in either male or femalerats or rabbits. The highest concentration tested (200 ppm)was approximately 40% of a saturated DPGME atmosphere. Basedon the low vapor pressure of DPGME, and results in this 13-weekstudy, DPGME appears to have a low subchronic vapor inhalationtoxicity hazard.     

Propylene Glycol Monomethyl Ether: A 13-Week Inhalation Toxicity Study in Rats and Rabbits

Propylene Glycol Monomethyl Ether: A 13-Week Inhalation ToxicityStudy in Rats and Rabbits. Landry, T.D., Gushow, T.S. and Yano,B.L. (1983). Fundam. Appl. Toxicol. 3:627–630. Fischer344 rats (10/sex/exposure concentration) and New Zealand Whiterabbits (7/sex/exposure concentration) were exposed to 0, 300,1000, or 3000 ppm (0, 1.09, 3.62, or 10.9 mg/L) of propyleneglycol monomethyl ether (PGME) for 6 hr/da, 5 da/wk, for 13weeks. Minimal effects were observed in animals exposed to 3000ppm. Indications of a transient central nervous system depressionwere observed in rats and rabbits exposed to 3000 ppm. Therewere also small increases (6 to 8%) in mean relative liver weightsof 3000 ppm exposed male and female rats relative to controls.Minimal histologic effects were observed in the livers of 3000ppm exposed female rats. These were suggestive of hepatocellularhypertrophy but were without evidence of degenerative changes.There was an increase in the urinary pH of male rats exposedto 3000 ppm PGME for 4 weeks, but this was not evident after12 weeks of exposure. There was no indication of histopathologicaleffects in the kidneys of either species, and there were nohematological effects. No treatment-related effects were foundin either rats or rabbits exposed to 300 or 1000 ppm.     

Inhalation Toxicity of Sulfuryl Fluoride in Rats and Rabbits

Inhalation Toxicity of Sulfuryl fluoride in Rats and Rabbits.EISENBRANDT, D. L., AND NITSCHKE, K. D. (1989). Fundam Appl.Toxicol 12, 540–557. The inhalation toxicity of the structuralfumigant sulfuryl fluoride (SO₂F₂) was evaluated in rats andrabbits. Exposures for a preliminary 2-week study were 6 hr/day,5 days/week, to 0, 100, 300, or 600 ppm SO₂F₂ Nine often ratsat 600 ppm died or were moribund between the second and sixthexposures. Extensive kidney lesions were present in all ratsexposed to 600 ppm, whereas only minimal renal changes werenoted in rats at 300 ppm. Upper and lower respiratory tissueswere inflamed in the single rat that survived the 2-week exposureto 600 ppm. Rabbits exposed to 600 ppm SO₂F₂ were hyperactiveand one animal had a convulsion. Exposure to 300 or 600 ppmfor 2 weeks resulted in vacuolation and/or malacia in the cerebrumof all rabbits and most of these rabbits also had moderate inflammationof nasal tissues; a few rabbits at 600 ppm had inflammationof the trachea or bronchi. A subsequent 13-week study evaluatedrats and rabbits exposed to 0, 30, 100, or 300 ppm SO₂F₂ (337ppm TWA for rabbits). Rabbits initially were exposed to a highconcentration of 600 ppm; however, convulsions were noted intwo animals after nine exposures and the concentration subsequentlywas reduced to 300 ppm. Vacuolation and/or malacia were observedin the cerebrum of all rabbits at the highest concentration;one rabbit exposed to 100 ppm also had cerebral vacuolation.Rabbits at the highest concentration, as well as one rabbitexposed to 100 ppm, had inflammation of the nasal tissues. Ratsexposed to 300 ppm SO₂F₂ for 13 weeks had mottled incisor teeth,minimal renal effects, pulmonary histiocytosis, inflamma tionof nasal tissues, and cerebral vacuolation. Also, rats exposedto 100 ppm SO₂F₂ for 13 weeks had mottled teeth. fluoride toxicitywas suggested by mottled teeth in rats as well as elevationof serum fluoride levels in rats and rabbits exposed to SO₂F₂for 13 weeks. Although repeated exposure of rats and rabbitsto 100–600 ppm SO₂F₂ resulted in toxicity ofthe kidneys(rats only), brain, and respiratory system, no effects weredetected in animals exposed to 30 ppm for 13 weeks.