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 of an Isomeric Mixture of Hydrochlorofluorocarbon (HCFC) 225 in Male Rats

A blend of the hydrochiorofluorocarbon isomers HCFC-225ca andHCFC-225cb has been proposed as a potential substitute for CFC-113,an important solvent and cleaning agent. The toxicity followingrepeated inhalation of an HCFC-225 isomer mixture was assessedin male Crl:CDBR rats. Three groups of 10 male rats were exposedto the test compound in air at design concentrations of 500,5000,and 13,000 ppm. Rats were exposed 6 hr/day, 5 days/week for2 weeks. A control group of 10 male rats was exposed to aironly. Decreased serum cholesterol, triglycerides, and glucose;dose-related increased mean absolute and relative liver weights;and microscopic hepatocellular hy pertrophy were present atall exposure concentrations. Hepatocellular hypertrophy correlatedultrastructurally to proliferation of peroxisomes. Clinicalchemical parameters and organ weight and morphologic changesin the liver were reversible following 14 days of recovery.     

Subchronic Inhalation Studies on Polychlorotrifluoroethylene (3.1 Oil)

Abstract

3.1 Oil, an oligomer of chlorotrifluoroethylene (CTFE), is an inert, nonflammable, saturated and hydrogen-free chlorofluorocarbon oil of interest to the Department of Defense (DOD) as a potential hydraulic fluid. To determine the potential subchronic inhalation toxicity of this CTFE oligomer, male and female F-344 rats were exposed to air only or to 0.25, 0.50, or 1.00 mg/l of CTFE oligomer in 65 6-h inhalation exposures over a 90-day period. A dose-dependent depression in body weight gains was noted in male rats only Serum alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase activities examined at the conclusion of the study indicated a treatment-related effect in the male test rats, but not the female test rats. Notable concentration-related increases (p < .07) in relative kidney and liver weights occurred in both sexes of rats at all test concentrations. The male rats showed slight to minimal hyaline droplet formation in the kidney proximal tubule epithelium. Pronounced cy-tomegaly of hepatocytes was the predominant lesion recognized.     

Toxicity of N-Methyl-2-pyrrolidone (NMP): Teratogenic, Subchronic, and Two-Year Inhalation Studies

Toxicity of N-Methyl-2-pyrrolidone (NMP): Teratogenic, Subchronic,and Two-Year Inhalation Studies. LEE, K. P., CHROMEY, N. C.,CULIK, R., BARNES, J. R., AND SCHNEIDER, P. W. (1987). Fundam.Appl Toxicol. 9,222–235. Pregnant rats were exposed toN-methyl-2-pyrrolidone (NMP) at atmospheric concentrations of0.1 and 0.36 mg/liter for 6 hr/day on Days 6 through 15 of gestation.Except for sporadic lethargy and irregular respiration in severalrats the first 3 days of exposure, there were neither abnormalclinical signs nor pathological lesions in the maternal rats.Exposure did not affect either the outcome of pregnancy or embryonalgrowth rate. No abnormal development was detected in the vitalorgans and skeletons of the fetuses. Rats were exposed to anaerosol-vapor mixture of NMP at concentrations of 0,0.1, 0.5,and 1.0 mg/liter for 6 hr/day, 5 days/week for 4 weeks. At 0.1and 0.5 mg/liter exposure levels, rats did not show any significantclinical signs or pathological lesions. However, lethargy, respiratorydifficulty, and excessive mortality were found in rats exposedto 1.0 mg/liter. These rats had focal pneumonia, bone marrowhypoplasia, and atrophy of lymphoid tissue in the spleen andthymus. These lesions were reversible in surviving rats following2 weeks of recovery. Increases in the relative and absolutenumbers of neutrophils were observed during exposure at 1.0mg/ liter, but returned to normal limits after 2 weeks of recovery.Rats were exposed to vapor of NMP at concentrations of 0, 0.04,or 0.4 mg/liter for 6 hr/day, 5 days/week for 2 years. Malerats at 0.4 mg/liter showed slightly reduced mean body weight.No life-shortening toxic or carci nogenic effects were observedin rats exposed for 2 years to 0.04 or 0.4 mg/liter of NMP.     

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.     

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.     

三氧化二钴亚慢性吸入毒性研究

大鼠一次气管注入50mg三氧化二钴混悬液4个月后，可见肺纤维化改变，大鼠在中毒柜自然吸入0.1mg/m^3三氧化二钴3个月后，未见各项观察指标有明显改变；浓度达0.7mg/m^3时，动物出现贫血，血清铜蓝蛋白和唾液酸含量增高，肺脏器系数增大，提示亚慢性吸入三氧化二钴可能致肺纤维以及对血象产生影响。     

Subchronic Inhalation Toxicity of Dimethylformamide in Rats and Mice

ABSTRACT

Fisher F344 rats and B6C3F1 mice were exposed to concentrations of 0, 150, 300, 600 and 1200 ppm of dimethylformamide (DMF) for 6 hours a day, 5 days a week for 12 weeks. Detailed clinical observations were obtained weekly and body weights biweekly on all animals. Clinical chemistry and hematology evaluations were made on all rats and approximately half the mice at terminal sacrifice. Gross necropsy examinations were made on all animals. Histopathologic evaluations were conducted on selected tissues of animals of both species at all dose levels. Few overt signs of toxicity were seen in either rats or mice. There was a dose related depression in body weight gain in rats that was significant at the 1200 ppm level from the second week of study onwards. A total of 11 mice died or were sacrificed moribund during the study, 8 from the high dose and 2 from the 600 ppm dose level. Both clinical chemistry (in rats only) and gross necropsy observations, and histopathology of tissues indicate the possibility that liver may be the target in specific organ toxicity. The no-effect DMF dose was below the 150 ppm level for both rats and mice and the maximum tolerated dose was below the 600 ppm level.     

Subchronic Inhalation Toxicity of Methyl Isoamyl Ketone in Rats

Subchronic Inhalation Toxicity of Methyl Isoamyl Ketone in Rats.KATZ, G. V., RENNER, E. R., JR., AND TERHAAR, C. J. (1986).Fundam. Appl. Toxicol. 6, 498–505. Rats were exposed byinhalation, 6 hr/day, 5 days/week, to target vapor concentrationsof 2000, 1000, or 0 ppm of methyl isoamyl ketone (MIAK) for12 exposures spanning 16 days, and 2000, 1000, 200, or 0 ppmfor 69 exposures spanning 96 days. Body weights, hematology,and serum clinical chemistry determinations were comparableto controls in both inhalation studies. Clinical signs of toxicitywere lethargy and decreased aural response (2000 ppm, 2-weekstudy; 2000 and 1000 ppm, 90-day study) and nasal and eye irritation(2000 and 1000 ppm, 90-day study). In addition, the excretionof gel-like casts in seminal fluid was seen in males exposedto 2000 and 1000 ppm in both studies. increases in absoluteand relative liver and kidney weights were observed in bothsexes following exposure to 2000 and 1000 ppm in the 2-weekand 90-day studies. Liver weight increases were exposure dependentand in the 90-day study reflected hepatocyte hypertrophy observedon microscopic examination. Microscopic kidney changes werehyalin degeneration or hyalin droplet formation in males inthe 2-week (2000 and 1000 ppm) and 90-day (2000 ppm) studies;and minor to moderate regeneration of tubular epithelium (2000and 1000 ppm) in both studies. Minor tubular epithelium regenerationwas seen in females exposed to 2000 ppm for 90 days. The toxicityof MIAK following inhalation exposure was not as extensive orsevere as that resulting from a prior study in which male ratswere dosed orally with 2000 mg/kg/day (a dose comparable to2000 ppm) for 13 weeks. The 90-day inhalation exposure no-observed-effectlevel for toxicity was 200 ppm MIAK.     

Methyl Isocyanate Subchronic Vapor Inhalation Studies with Fischer 344 Rats

Methyl Isocyanate Subchronic Vapor Inhalation Studies with Fischer344 Rats. DODD, D.E., AND FOWLER, E.H. (1986). Fundam. Appl.Toxicol. 7, 502-522. Groups of Fischer 344 rats were exposedto 3.1, 0.6, 0.15, or 0.0 (control) ppm of methyl isocyanate(MIC) vapor 6 hr per day for two 4-day sessions separated bya 2-day rest. There were no deaths during the study. The ratswere killed the morning following the last exposure day. The3.1 -ppm-exposed rats had decreased body weight, food consumption,and blood oxygen saturation (males only). Increased hemoglobinconcentration (males only) and lung weights were also observedin this group of rats. Multiple histologic lesions, limitedto the respiratory tract, were observed in rats of the 3.1-ppmgroup only. The lesions consisted of necrosis, suppurative inflammation,squamous metaplasia, and intraluminal and submucosal fibroplasia(bronchi and bronchioles only) which extended from the anteriornasal cavity to the terminal bronchioles. In a second study,rats were exposed to 3.0 ppm MIC, 6 hr per day, for either oneor two 4-day sessions and sacrificed on postexposure Days 1,15,43,and 85. All rats survived the 4- or 8-day exposure regimen,although significant decreases in body weight and encrustationof the eyes, nose, or mouth area were observed. During the first15 days postexposure, male mortality was 63%; only 6% of theMIC-exposed females died. The cause of death was interpretedto be a combination of pulmonary vascular and inflammatory changescoupled with anorexia. For survivors, recovery from the necrotizingand irritating effects of MIC vapor was observed. Squamous metaplasiaof respiratory epithelium, observed in rats sacrificed at theend of the exposure period, was replaced by tall pseudostratifiedcolumnar (regenerative) epithelium beginning in the bronchiand bronchioles as well as the distal trachea. Collagen maturationand condensation of the intraluminal and submucosal fibroplasiaoccurred during the postexposure period. The results of theseinvestigations support the current threshold limit value forMIC of 0.02 ppm.     

Evaluation of Subchronic Inhalation Toxicity of Dimethyl Disulfide in Rats

This study was carried out to investigate the potential subchronic inhalation toxicity of dimethyl disulfide (DMDS) via whole-body exposure in F344 rats. Groups of 10 rats of each sex were exposed to DMDS vapor by whole-body exposure at concentrations of 0, 5, 25, or 125 ppm for 6 h/day, 5 days/wk for 13 wk. All the rats were sacrificed at the end of treatment period. During the test period, clinical signs, mortality, body weights, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights, and histopathology were examined. At 25 ppm, a decrease in the body weight gain, food intake, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and blood urea nitrogen (BUN) was observed in the males, but not in the females. However, at 125 ppm, a decrease in the body weight gain, food intake, and thymus weight and an increase in the weights of adrenal glands were observed in both genders. Serum biochemical investigations revealed a decrease in the AST, ALT, BUN, creatine phosphokinase (CPK), and triglyceride levels and an increase in the glucose level. In contrast, no treatment-related effects were observed in the 5 ppm group. The toxic potency of DMDS was slightly higher in males than that in females. In these experimental conditions, the target organ was not determined in rats. The no-observed-adverse-effect concentration (NOAEC) was found to be 5 ppm, 6 h/day for male rats and 25 ppm, 6 h/day for female rats.     

Subchronic Inhalation and Oral Toxicity of Hydrogenated Terphenyls in Rats

The subchronic toxicity of a commercial blend of partially hydrogenatedterphenyl was evaluated in rats by inhalation and oral routesof exposure. Animals were exposed to target concentrations of0, 10, 100, or 500 mg/m³ for 6 hr/day, 5 days/week or were offereddiets daily with concentrations of 0, 50, 200, or 2000 ppm.Each study lasted approximately 14 weeks. The study designsincluded observations for clinical signs, body weights, ophthalmicexams, hematology and clinical chemistry, major organ weights,and gross and histopathology. No treatment-related effects werenoted in the ophthalmic exams. Body weights were slightly depressedin high-dose males from the inhalation study and high-dose femalesin the dietary study. Liver and liver/body weights were increasedin high-dose animals of both sexes and high-and mid-dose malesin the dietary and inhalation studies, respectively. In thehigh-dose females of the dietary study, kidney and kidney/bodyweights were increased with increased adrenal and adrenal/bodyweights were also observed. No compound-related gross lesionsnor pathological correlates to the organ weight changes wereobserved in either study. The no-adverse effect levels wereconsidered to be 100 mg/m³ and 200 ppm (15.9 mg/kg) for theinhalation and dietary studies, respectively. These data indicatethat a wide margin of safety exists for hydrogenated terphenylworkplace exposure.     

Acute, Subacute, and Subchronic Inhalation Toxicity Studies of Respirable Polymeric Methylene Diphenyl Diisocyanate (Polymeric MDI) Aerosol in Rats

Short-term inhalation toxicity studies with respirable polymericmethylene diphenyl diisocyanate (polymeric MDI) aerosol wereperformed in rats. The 4-hr LC50 was found to be 490 mg polymericMDI/m³ (95.5% <4.3 µm). Exposure of (4-week-old) ratsto 0, 2.2, 4.9, or 13.6 mg polymeric MDI/m³ (95% < 5 µm)for 2 weeks resulted in mortality, severe growth retardation,and elevated lung weights at 13.6 mg/m³ at 4.9 mg/m³ slightgrowth retardation and slightly elevated lung weights were observed.A 13-week study with 6-week-old rats exposed to 0.35, 1.4, or7.2 mg polymeric MDI/m³ (95% < 5 µm) revealed transientgrowth retardation and a slightly increased number of pulmonaryalveolar macrophages occasionally accompanied by increased numbersof mononuclear cells and fibroblasts in alveolar septa onlyat 7.2 mg/ m³ In a second 2-week study with 4 or 6-week-oldrats exposed to 14.1 mg polymeric MDI/m³ (95% < 5 µm),4-week-old rats died earlier and in greater numbers than 6-week-oldrats. In a second 13-week study with 6-week-old rats, usingexposure concentrations of 0, 4.1, 8.4, and 12.3 mg polymericMDI/ m³ (95% < 5 µm) and including a 4-week recoveryperiod, 12.3 mg/ m³ induced mortality, growth retardation, severerespiratory distress, increased lung weights, degeneration andhyperplasia of the nasal epithelium, accumulations of macrophagesin the lungs and mediastinal lymph nodes, and focal inflammatorychanges in the lungs. Rats exposed to 8.4 mg/ m³ showed respiratorydistress, lower body weights in males, increased lung weights,and similar, but much less severe, histopathological changesin the respiratory tract and mediastinal lymph nodes. Most ofthe histopathological changes seen at the higher concentrationswere also seen at 4.1 mg/m³ but to a very minor degree and ina few rats only. At the end of the 4-week posttreatment periodthe microscopical changes in nose, lungs, and mediastinal lymphnodes were still present but generally to a much less degreethan at the end of the exposure period. It was concluded thatthe dose-effect curve for repeated exposures of rats to respirablepolymeric MDI is very steep, and that the "no-observed-adverse-effectlevel" of polymeric MDI was 1.4 mg/m³ the actual no-adverse-effectlevel being lower than but most probably very close to 4.1 mg/m³.     

Subchronic Inhalation Toxicity Study of Caprolactam (with a 4-Week Recovery) in the Rat via Whole-Body Exposures

This study was designed to assess the potential subchronic inhalationtoxicity of caprolactam when administered as a 3-µm aerosolfrom an aqueous solution to Sprague-Dawley CD rats (10/sex/group)via whole-body exposure. The study was enhanced with the inclusionof motor activity measurements and a functional observationalbattery to assess the neurotoxic potential of caprolactam. Therats were exposed at least 65 times over a 13-week period for6 h per day, 5 days per week, to target concentrations (3 µm,mass median aerodynamic diameter) of 0, 25, 75, and 250 milligramsper cubic meter (mg/m³). An additional 10 animals/sex/groupwere similarly exposed and then held for a 4-week recovery period.Exposure levels were determined gravimetrically six times daily;one daily sample was analyzed by high-pressure liquid chromatography.No deaths were observed in the study during the exposure orrecovery periods. Treatment-related responses such as laboredbreathing and nasal discharge were seen during many of the exposures.Similar responses as well as moist rales were seen during thenonexposure periods during the 13 weeks of exposure. However,these responses abated during the 4-week recovery period. Therewere no clearly treatment-related responses observed with ophthalmoscopicexaminations, body weight measurements, food consumption measurements,neurobehavioral evaluations, clinical pathology evaluations,organ weight measurements, or macroscopic pathology examinations.Microscopic findings that were considered related to exposureto the test material were seen in the nasoturbinal tissues (hypertrophy/hyperplasiaof goblet cells in the respiratory mucosa and intracytoplasmiceosinophilic material in epithelial cells of the olfactory mucosa)of the two higher-exposure group animals and in the laryngealtissues (squamous/squamoid meta-plasia/hyperplasia of the pseudostratifiedcolumnar epithelium covering the ventral seromucous gland) ofall three exposure group animals. These changes were consideredto be adaptive responses to an irritant (caprolactam). The keratinizationof the metaplastic epithelium in the larynx was considered tobe an adverse effect. By the end of the 4-week recovery period,there was complete regression of the keratinization in the larynx,but recovery of the adaptive nasoturbinal effects had not completelyresolved. In conclusion, the whole-body exposure of Sprague-Dawleyrats to caprolactam as a respirable aerosol for 6 h/day, 5 days/week,for 13 weeks at gravimetrically determined levels of 24, 70,and 243 mg/m³ resulted in respiratory tract effects (laryngeal)at the highest exposure level with complete recovery within4 weeks postex-posure. The results indicate that the no-observed-adverse-effectlevel for caprolactam is 70 mg/m³, based on upper respiratoryeffects, with 243 mg/m³ representing a no-observed-effect levelfor systemic toxicity, neurotoxicity, and lower respiratorytract effects.     

Subchronic and Chronic Inhalation Toxicity of Antimony Trioxide in the Rat

Fischer 344 rats were exposed by inhalation to Sb₂O₃ (antimonytrioxide) dust at exposure levels of 0, 0.25, 1.08, 4.92, and23.46 mg/m³ for 6 hr/day, 5 days/week for 13 weeks followedby a 27-week observation period. Subsequently, an inhalationon-cogenicity study was conducted at exposure levels of 0, 0.06,0.51, and 4.50 mg/m³ for 12 months followed by a 12-month observationperiod. The Sb₂O₃ in the subchronic study had a mass medianaerodynamic diameter (MMAD) of 3.05 ± 0.21 microns (mean± SD) with a geometric standard deviation (GSD) of 1.57± 0.06. In the chronic study, the MMAD was 3.76 ±0.84 and the GSD was 1.79 ± 0.32. Except for the eyes,no adverse clinical observations were attributed to Sb₂O₃ ineither study. In the subchronic study, corneal irregularitieswere seen after about 2 weeks of exposure and did not abateduring the observation period. In the chronic study, ophthalmoscopicevaluation at 24 months revealed a dose-related increase incataracts of 11, 24, 28, and 32% (both sexes combined) for eachgroup, respectively. Body weights were significantly lower (6%)than the control group's weights in the 23.46 mg/m³ males inthe subchronic study. These rats did not recover this weightduring the 27-week observation period. Body weights of the femalesin both studies and males in the chronic study were unaffected.There were no Sb₂O₃ effects on clinical chemistry or he-matologyin either study. Mean absolute and relative lung weights weresignificantly increased in the 4.92 and 23.46 mg/m³ groups inthe subchronic study. The 23.46 mg/m³ group's lung weights didnot recover to control levels during the 27-week observationperiod. Lung weights for rats in the chronic study were unaffected.Microscopic changes in the lungs in the subchronic and chronicstudy were limited to subacute-chronic interstitial inflammation,increased numbers of alveolar-in-traalveolar macrophages, foreignmaterial in the alveolar-in-traalveolar macrophages in the peribronchialand perivascular (chronic study only) lymphoid aggregates andin the peribronchial lymph nodes, granulomatous inflammation/granulomas,and fibrosis. In the chronic study, any observed neoplasms occurredwith comparable incidence among all groups and were within thehistorical range for controls. Clearance of Sb₂O₃ from the lungwas burden dependent and was reduced by 80/ in the 4.50 mg/m³group in the chronic study. The previously reported studies,which found Sb₂O₃ to be a carcinogen, were run at higher lungburdens. Under the exposure conditions of the current study,Sb₂O₃ was not a carcinogen.     

Inhalation Teratology and Reproduction Studies with 1, 1-Dichloro-2,2,2-Trifluoroethane(HCFC-123)

HCFC 123 is one of the chemicals being developed as a replacementfor CFC 11 in refrigerant and solvent applications. Supplementingearlier rat teratology studies, a rabbit inhalation teratologystudy was conducted. In addition, one-generation and two-generationinhalation reproduction studies were conducted. In the teratologystudy, the pregnant rabbits were exposed to levels of 0 (control),500, 1500, and 5000 ppm, 6 hr per day from Days 6 through 18of gestation. Slight body weight losses and reduced food consumptionwere seen in does in all three exposure level groups. This responsefollowed an exposure-related pattern. There were no other signsof maternal toxicity. There was also no evidence of treatment-relatedeffects on the kits. A probe one-generation reproduction studywas conducted. In this study four groups of 12 male and 12 femalerats were exposed to vapors of HCFC 123 6 hr per day, 7 daysper week from 4 weeks prior to mating through weaning of theiroffspring. The exposure levels for this study were 0 (control),300, 1000, and 5000 ppm. There were no effects on mating andfertility, or on pup survival or birth weight. A two-generationstudy was subsequently conducted. In this study, five groupsof 32 male and female rats were exposed to HCFC 123 from 6 weeksof age through weaning. From the offspring of these animals,groups of 28 males and females were selected for the F₁ generation.These animals were exposed to HCFC 123 from weaning (4 weeksof age) through weaning of the F₁ generation. All exposureswere 6 hr per day, 7 days per week. The exposure levels forthis study were 0 (control), 30, 100, 300, and 1000 ppm. Therewere no effects on any of the fertility or reproductive indicesmeasured. As with prior studies, decreases in serum triglyceridelevels were seen. Pup survival and birth weight were unaffectedby treatment. Pup body weight gain was lower in all treatmentgroups during nursing, following an exposure-related pattern.Since weight gain for the F₁ animals was normal following weaning,this depression of body weight gain may be related to the depressionof serum triglycerides. In addition, liver weights of the adultrats exposed to levels of 100 ppm and higher of HCFC 123 werehigher than controls, histological examination revealed onlyhepatic enlargement and vacuolation. It was concluded that exposureto HCFC 123 did not cause reproductive effects although it dideffect the body weight gain of the offspring during lactation.     

Subchronic Oral Toxicity Studies with Erythritol in Mice and Rats

Erythritol is a sugar alcohol (polyol) with potential applications as a low-calorie, bulk sweetener. Ingested erythritol is efficiently absorbed and excreted unchanged via the urine since it is not metabolized systemically by the animal or human body. Erythritol was administered to four groups of 10 male and 10 female Swiss CD-1 mice and four groups of 15 male Wistar Crl:(WI) WU BR rats at dietary levels of 0, 5, 10, or 20% for 90 days. A fifth group of rats received a diet containing 20% erythritol on a time-restricted basis (6 hr/day), and a sixth group received a diet containing 20% mannitol for comparison. There were no treatment-related mortalities in either mice or rats. Soft stools and occasional diarrhea were observed in rats fed diets with 20% erythritol or mannitol but not in mice. Body weights were slightly yet significantly reduced in rats fed 20% erythritol or mannitol and in male mice of the 20% dose group. Erythritol intake in the high-dose group was approximately 12 g/kg body wt in rats and 44 and 45 g/kg body wt in male and female mice, respectively. Hematological and clinicochemical examinations of blood and plasma did not reveal any treatment-related effects. Urine output increased with increasing erythritol dose. In male and female mice of the 20% erythritol group, the creatinine-normalized urinary excretion of protein, K-glutamyltransferase (GGT), and electrolytes (Na⁺, K⁺, Ca²⁺, P_i, citrate) was significantly increased while urinaryN-acetylglucosaminidase (NAG) remained unchanged. At the 10% level, significantly increased urinary protein (both sexes) and GGT (males only) excretion were seen. In rats, the creatinine-normalized urinary excretion of GGT, NAG, and some electrolytes (Na⁺, K⁺, and Ca²⁺) was increased in some erythritol groups but a clear dose–response relationship was evident only for calcium. On termination of the study, cecal enlargement was seen in rats of the 10 and 20% dose groups and in mice of the 20% dose group. Increased relative and absolute kidney weights were observed in both sexes of mice in the 20% erythritol group, in male mice of the 5 and 10% groups, and in rats of the 10 and 20% erythritol groups. Histopathological examination did not reveal any treatment-related abnormalities in either mice or rats. In conclusion, the ingestion of erythritol for 90 days at dietary levels of up to 20% did not produce signs of toxicity in mice or rats. In particular, the morphological integrity of the kidneys was not adversely affected by the treatment in either species. The increases in urinary excretion of protein, GGT, NAG, and electrolytes were considered to result from extensive osmotic diuresis and a potential overload of the renal excretory system at the high dose levels employed.     

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.     

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.