Reproduction Study of Dimethylacetamide following Inhalation in the Rat

Reproduction Study of Dimethylacetamide following Inhalationin the Rat. Ferenz, R. L., and Kennedy, G. L., Jr. (1986). Fundam.Appl Toxicol. 7, 132-137. Groups of 10 male and 20 female Crl:CD(SD)BRrats were exposed to vapors of dimethylacetamide (DMAC) at concentrationsof 0 (control), 30, 100, or 300 ppm. Exposures were conductedfor 6 hr/day, 5 days/week for 10 weeks (prebreeding), then 7days/week for 7 to 8 weeks (through breeding, gestation, andlactation). The exposure period was interrupted for female ratsbetween gestation Day 21 and postpartum Day 4. No compound-relatedeffects on body weight, survival, or clinical signs were detectedin parental rats. Liver weight to body weight ratios were increasedin groups where both males and females were exposed to 300 ppmbut not in groups where only males or only females were exposedto 300 ppm. No significant differences were observed betweencontrol and test rats with respect to mating performance, fertility,length of gestation, progeny numbers, structure, and viability.At 21 days postpartum, pups derived from matings involving exposureof both sexes to 300 ppm or exposure of parental females to300 ppm had lower body weights than did the controls. Grosspathologic examination of representative pups and evaluationof liver and gonad weight data did not reveal any DMAC-relatedchanges. It is concluded that reproduction in rats was not alteredby repeated inhalation exposure to up to 300 ppm DMAC.     

Chronic Toxicity/Oncogenicity of Dimethylacetamide in Rats and Mice Following Inhalation Exposure

The potential chronic toxicity and oncogenicity of dimethylacetamide(DMAC) was evaluated by exposing male and female rats and miceto 0, 25, 100, or 350 ppm DMAC for 6 hr/day, 5 days/week for18 months (mice) or 2 years (rats). Clinical pathology was evaluatedat 3, 6, 12, 18, and 24 (rats only) months. An interim euthanizationfor rats occurred at 12 months and hepatic cell proliferationin rats and mice was examined at 2 weeks and 3 and 12 months.No compound-related effects on survival were observed. Ratsexposed to 350 ppm had lower body weight and/or body weightgain. There were no compound-related effects on body weightor weight gain in mice at any concentration. There were no compound-relatedadverse effects on the incidence of clinical signs of toxicityin rats or mice. No hematologic changes were observed in eitherspecies. Serum sorbitol dehydrogenase activity was increasedin rats exposed to 350 ppm. Serum cholesterol and glucose concentrationswere significantly higher in 100 and 350 ppm female rats. Compound-relatedmorphological changes were observed in the liver. In rats, exposureto 100 or 350 ppm produced increased absolute and/or relativeliver weights, hepatic focal cystic degeneration, hepatic peliosis,biliary hyperplasia (350 ppm only), and lipofuscin/hemosiderinaccumulation in Kupffer cells. In mice, exposure to 100 or 350ppm produced increased absolute and relative liver weights (350ppm females only), accumulation of lipofuscin/hemosiderin inKupifer cells, and centrilobular single cell necrosis. Malerats exposed to 350 ppm also had significantly higher absoluteand relative kidney weights which correlated with the grossand microscopic changes resulting from a compound-related increasein severity of chronic progressive nephropathy. Female miceexposed to 350 ppm had an increased incidence of bilateral,diffuse retinal atrophy. No increase in hepatic cell proliferationwas seen in mice or rats at any exposure concentration. DMACwas not oncogenic under these experimental conditions in eitherthe rat or mouse. The NOAEL for male and female rats and miceis 25 ppm.     

Inhalation Toxicity of 1,3-Propanediol in the Rat

1,3-Propanediol (504-63-2) was studied to determine the potential effects following repeated inhalation exposures to rats. Rats were exposed 6 hr/day, 5 days/wk for 2 wk (9 exposures) to vapor or vapor/aerosol mixtures of either 0, 41, 650, or 1800 mg 1,3-propanediol/m³. In vivo responses were observed or measured daily. Clinical pathology and tissue pathology analyses were conducted after the 9th exposure and on half of each group following an 18-day recovery (nonexposure) period. All rats showed normal body weights. No unusual external signs of response were seen, and no deaths were encountered. Clinical pathology (blood counts, serum chemical parameters) and tissue pathology (gross pathology, organ weights, and histopathology) examinations in the 1,3-propanediol exposed rats were similar to those in the unexposed controls. The highest concentration tested, 1800 mg/m³, which was the highest concentration that could practically be generated, was the no-observed-effect level (NOEL) for this study. 1,3-Propanediol does not appear to pose a significant hazard via inhalation of either the vapor or a vapor/aerosol mixture.     

n-Butyl Acrylate: Prenatal Inhalation Toxicity in the Rat

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

Phase-Specific Developmental Toxicity in Mice Following Maternal Methanol Inhalation

Phase-Specific Development Toxicity in Mice Following MaternalMethanol Inhalation. BOLON, B., DORMAN, D. C., JANSZEN, D.,MORGAN, K. T., AND WELSCH, F.(1993). Fundam. Appl. Toxicol.21, 508–516. Methanol is toxic to embryos of mice and rats when inhaled bydams at high concentrations. The present studies examined methanol-induceddevelopmental toxicity following inhalation exposure (6 hr/day)of pregnant CD-1 mice to 5000, 10,000, or 15,000 ppm eitherthroughout organogenesis (GD 6–15), during the periodof neural tube development and closure (GD 7–9), or duringa time of potential neural tube reopening (GD 9–11). Transientneurologic signs and reduced body weights were observed in upto 20% of dams exposed to 15,000 ppm. Examination of near-termfetuses revealed embryotoxicity (increased resorptions, reducedfetal weights, and/or fetal malformations) at 10,000 and 15,000ppm, while 3-day exposures at 5000 ppm yielded no observableadverse effects. Terata included neural and ocular defects,cleft palate, hydronephrosis, deformed tails, and limb (pawand digit) anomalies. Neural tube defects and ocular lesionsoccurred after methanol inhalation between GD 7–9, whilelimb anomalies were induced only during GD 9–11; cleftpalate and hydronephrosis were observed after exposure duringeither period. These findings were consistent with prior reportsthat maternal methanol inhalation at high levels induces developmentaltoxicity in a concentration dependent manner. Furthermore, ourdata indicate that the spectrum of teratogenic effects dependedupon both the timing (i.e., stage of embryonic development)and the number of methanol exposures.     

1,1,1,2-Tetrafluoroethane: Repeat Exposure Inhalation Toxicity in the Rat, Developmental Toxicity in the Rabbit, and Genoxicity in Vitro and in Vivo

Subchronic and chronic studies were carried out in the rat anda developmental toxicity study in the rabbit with exposuresto 1,1,1,2-tetrafluoroethane (HFC 134a) by inhalation. In therat repeated exposure to 50,000 ppm HFC 134a for 13,52, and104 weeks elicited no effect on clinical condition, growth,and survival, or on a variety of hematological, clinical chemistry,and urinary parameters. Treatment-related pathological changeswere seen only at study termination at 2 years and were confinedto increased incidence of Leydig cell hyperplasia and adenomain male rats exposed to 50,000 ppm. The tumors, which were alsoseen in control animals, were benign and not life-threatening.A battery of in vitro and in vivo tests gave no evidence ofgenotoxic activity. With exposure to pregnant rabbits, the onlytreatment-related effects were of minimal maternal toxicityat high exposure concentrations; there were no effects on fetaldevelopment. It is concluded that HFC 134a is of very low toxicityand should be an acceptable alternative to CFCs.     

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 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.     

Developmental Toxicity of Inhaled trans-1,2-Dichloroethylene in the Rat

The developmental toxicity of trans-1,2-dichloroethylene (t-DCE),a component of certain Freon cleaning agents, was examined inpregnant rats. t-DCE was administered by inhalation 6 hr dailyon Days 7–16 of gestation (the day copulation was confirmedwas termed Day 1 of gestation) at exposure levels of 0, 2000,6000, or 12,000 ppm. The offspring were then examined on Day22 of gestation. Overt maternal toxicity was expressed as asignificant reduction in weight gain at 12,000 ppm and in feedconsumption at 6000 and 12,000 ppm. During the exposure period,lacrimation and stained periocular hair, and signs of occularirritation, were observed in all groups. In addition, increasedincidences of alopecia, lethargy, and salivation were observedin the high-dose dams. Significant increases in the mean numberof resorptions per litter were seen in the litters of dams exposedto 6000 and 12,000 ppm of t-DCE; however, these values are withinthe range of historical controls and not considered to be treatmentrelated. The mean combined and female fetal weights were significantlyreduced in the litters of dams exposed to the highest concentration(12,000 ppm) of t-DCE. Marginal effects on feed consumption,unaccompanied by other changes and reflective of the patternseen at higher doses, were seen at 2000 ppm. Thus, marginalmaternal toxicity was seen at 2000 ppm and exposures to 6000ppm t-DCE or higher caused frank maternal toxicity while thefetus was affected only at 12,000 ppm. Therefore, t-DCE is notconsidered to be uniquely toxic to the rat conceptus.     

Lack of Selective Developmental Toxicity of Three Butanol Isomers Administered by Inhalation to Rats

Lack of Selective Developmental Toxicity of Three Butanol IsomersAdministered by Inhalation to Rats. NELSON, B. K., BRIGHTWELL.,W. S., KHAN, A., BURG, J. R., AND GOAD, P. T. (1989). Fundam.Appl Toxicol. 12,469–479. As part of an ongoing studyof the developmental toxicology of industrial alcohols, thisreport presents the results of the teratology assessments of1-butanol, 2-butanol, and t-butanol administered by inhalationto rats. Groups of approximately 15 Sprague-Dawley rats wereexposed at 8000, 6000, 3500, or 0 ppm 1-butanol, 7000, 5000,3500, or 0 ppm 2-butanol, or 5000, 3500, 2000, or 0 ppm t-butanolfor 7 hr/thy on Gestation Days 1–19 (sperm=0). In eachease, the highest concentration was selected to produce maternaltoxicity. Dams were sacrificed on Gestation Day 20, and fetuseswere individually weighed, tagged and examined for externalmalformations. One-half of the fetuses were stained and examinedfor skeletal abnormalities, and the other half were examinedfor visceral defects using the Wilson technique. For each butanolisomer examined, the highest concentration (and the intermediatein some eases) was maternally toxic, as manifest by reducedweight gain and feed intake. Even at a maternally toxic dose,and in spite of a dose-dependent reduction in fetal weightsfor each isomer, the only teratogenicity observed was a slightincrease in skeletal malformations (primarily rudimentary cervicalribs), seen with the highest concentration of 1-butanol. Thus,although teratogenicity was observed at 8000 ppm 1-butanol,and developmental toxicity was observed with each of the butylalcohol isomers studied, concentrations 50 times the currentpermissible exposure limits for these three butanol isomersdo not produce teratogenicity in rats.     

Acute Inhalation Toxicity of T-2 Mycotoxin in the Rat and Guinea Pig

Acute Inhalation Toxicity of T-2 Mycotoxin in the Rat and GuineaPig. CREASIA, D. A., THURMAN, J. D., WANNEMACHER, R. W., JR.,AND BUNNER, D. L. (1990). Fundam. Appl. Toxicol 14, 54–59.In this study, concentration-response parameters were determinedfor rats and guinea pigs systematically exposed to an aerosolof T-2 toxin. The LC50 for a 10-min exposure to T-2 toxin aerosolwas 0.02 mg T-2/liter air for rats and 0.21 mg T-2/liter airfor guinea pigs. Data from total T-2 deposition in rats andguinea pigs exposed to their respective LC50 aerosol concentrationgave an LD50 of 0.05 mg T-2/kg body weight for the rat and 0.4mg T-2/kg body weight for the guinea pig. These data show thatinhaled T-2 toxin is approximately 20 times more toxic to therat (0.05 mg T-2/kg body wt inhaled vs 1.0 mg T-2/kg body wtip) and at least twice as toxic to the guinea pig (0.4 mg T-2/kgbody wt inhaled vs 1-2 mg T-2/kg body wt ip) than ip administeredT-2 toxin. Histopathologic examination of major organs in boththe rat and guinea pig after respiratory exposure to T-2 toxinindicated that lesions were similar to those described aftersystemic administration of the toxin. Gross and microscopicalterations of respiratory tract tissue after T-2 aerosol exposurewere minimal and could not account for the increase in toxicity.     

Developmental Toxicity of Oral and Inhaled Vinyl Acetate in the Rat

Vinyl acetate (VA) is used almost exclusively as an industrialchemical in polymerization, copolymerization, or as a chemicalintermediate. The present studies were undertaken as part ofa collaborative effort by the VA producers of Western Europe,Japan, and the United States to provide animal toxicology datafor risk assessment. To assess the potential of VA causing developmentaltoxicity in rodents, groups of 23 or 24 Crl:CD(SD)BR rats weregiven 0, 200, 1000, or 5000 ppm VA in drinking water or exposed6 hr/day to 0, 50, 200, or 1000 ppm VA vapors on Days 6–15of gestation (both routes approximating 0, 25, 100, or 500 mg/kg/day).Administration of VA in the drinking water produced no evidenceof maternal or developmental toxicity. A significantly loweredwater intake was observed in dams from the 5000 ppm VA groupand probably reflected unpalatability of the VA water solutionat the highest dose level. In the inhalation study, maternaltoxicity was evident by a marked reduction in weight gain ofdams exposed to 1000 but not 200 or 50 ppm VA. Fetal toxicitywas evident by a statistically significant decrease in meanfetal weight and mean crown-rump length in fetuses from the1000-ppm VA group. In addition, there was a statistically significantincrease in the incidence of minor skeletal alterations in fetusesfrom dams exposed to 1000 ppm VA. Delayed ossification was themain skeletal alteration. In summary, pregnant rats were relativelyinsensitive to the effects of VA administered in the drinkingwater at a concentration level as high as 5000 ppm. However,VA did adversely affect both the dam and the conceptus at aninhaled concentration of 1000 ppm, but not at lower exposurelevels. These results indicate that VA is not uniquely toxicto the conceptus. The no-observed-effect level for the dam andconceptus under these experimental conditions was greater than5000 ppm for the drinking water study and was 200 ppm for theinhalation study.     

Evaluation of the Developmental and Reproductive Toxicity of Chlorpyrifos in the Rat

Chlorpyrifos (O,O-diethyl-O-(3,5,6-trichloro-2-pyridyl)-phosphorothioate),an organophosphate insecticide, was evaluated for its potentialto produce developmental and reproductive toxicity in rats followingoral exposure. Pregnant Fischer 344 rats were given doses of0 (corn oil vehicle), 0.1, 3.0, or 15 mg chlorpyrifos/kg/day,by gavage, on Gestation Days 6 through 15. Maternal effectsnoted at the two higher dose levels included decreased cholinesteraselevels at 3.0 mg/kg/day and cholinergic signs (excessive salivationand tremors), decreased cholinesterase levels, and decreasedbody weight gain at 15 mg/kg/day. No maternal effects were apparentat 0.1 mg/kg/day. Although maternal toxicity was observed atthese two higher exposure levels, no developmental effects werenoted at any dose. In a two-generation reproduction study, Sprague-Dawleyrats were maintained on diets supplying 0, 0.1, 1.0, or 5.0mg chlorpyrifos/kg/day. Parental effects included decreasedplasma, and erythrocyte cholinesterase at 1.0 mg/kg/day, anddecreased plasma, erythrocyte, and brain cholinesterase andhistopathologic alterations of the adrenal zona fasciculataat 5.0 mg/kg/day. The histopathologic alterations of the adrenalwere characterized as very slight to slight vacuolation (consistentwith fatty change) in males, and very slight vacuolation and/oraltered tinctorial properties in females. No effects on thereproductive or fertility indices or on the histopathology ofreproductive tissues were observed at any dose level, and noneonatal effects were observed at 0.1 or 1.0 mg/kg/ day in theF1 or F2 litters. Parental toxicity at the high dose was accompaniedby decreased pup body weight and increased pup mortality inthe F1 litters only. These data show that oral administrationof chlorpyrifos to rats at parentally toxic dose levels wasnot embryolethal, embryo/fetotoxic, or teratogenic and did notadversely affect fertility or the function or structure of thereproductive organs. Although effects on neonatal growth andsurvival were observed at a maternally toxic dose level in onegeneration, this effect was not observed in the subsequent generationand, therefore, may not have been related to treatment.     

Prenatal Toxicity of Xylene Inhalation in the Rat: A Teratogenicity and Postnatal Study

Technical xylene (cas.nr. 1330-20-7) was investigated for development toxicity in a teratology and in a postnatal study. Rats (Mol: WIST) were exposed to 500 p.p.m. 6 hr per day on days 4 to 20 of gestation. There were no signs of maternal toxicity. In the teratology study, no exposure-related differences were found except for delayed ossification of os maxillare. In the postnatal study, the xylene-exposed pups had a higher body weight and an impaired performance on a motor ability test (Rotarod). Due to the possibility of direct toxic effects of xylene on the developing central nervous system, further studies are needed to investigate dose-effect relationship for this type of effects.     

Chronic Toxicity and Oncogenicity Inhalation Study with Vinyl Acetate in the Rat and Mouse

Vinyl acetate was evaluated for chronic toxicity and oncogenicityin male and female rats and mice in a 104-week study. Targetconcentrations were 0, 50, 200, and 600 ppm. The study includedinterim terminations at approximately 53 and 83 weeks and agroup whose exposure was terminated at 70 weeks and alloweda 15-week recovery period. Over the course of the exposures,body weight gain was consistently depressed in all 600 ppm groupsand in the 200 ppm mice. Except for female rats of the 600 ppmexposure group, recovery animals showed significant improvementsin weight gain relative to controls. There were no changes inhematological parameters of either species that could be unequivocallyrelated to treatment. The only effect noted on clinical chemicalparameters during the study were decreases in blood glucosein the 600 ppm females. There were no adverse effects on survivalin either species. Increases in lung weight were noted in ratsand mice primarily in the 600 ppm groups. These changes wereassociated with bronchial exfoliation, macrophage accumulation,and fibrous plaques and buds extending into the airway lumen,and bronchial/bronchiolar epithelial disorganization. The mostsignificant histopathological changes were noted in the nasalcavity. In the olfactory epithelium of both rats and mice, themain nonneoplastic changes included epithelial atrophy, regenerativeeffects (squamous metaplasia and respiratory metaplasia of olfactoryepithelium), basal cell hyperplasia, and epithelial nest-likeinfolds. No nonneoplastic changes were observed in the respiratoryepithelium of rats, while squamous metaplasia at the naso/maxilloturbinateregion was prevalent in mice. Nonneoplastic changes were similarin the recovery groups. Oncogenic responses to vinyl acetateexposure were mainly confined to the nasal cavity in rats andincluded endo- and exophytic papillomas, squamous cell carcinoma,carcinoma in situ in olfactory regions, and endophytic papillomain respiratory regions. Squamous cell carcinomas were also foundeither in areas normally covered by cuboidal epithelium or areasof unknown origin. One squamous cell carcinoma was found inthe larynx of a rat of the 600 ppm groups. One squamous cellcarcinoma was found in the lung of a mouse of the 600 ppm group.The no-observable- adverse-effect level for all effects was50 ppm in both species. The tumorigenic response appears tobe nonlinear. The nonlinear dose response and the unique natureof the rodent nasal cavity suggest that specific risk extrapolationmodels should be developed for vinyl acetate.     

Toxicity of n-C9 to n-C13 Alkanes in the Rat on Short Term Inhalation

Abstract: Male Sprague Dawley rats were exposed to inhalation of n-C9 to n-CI3 alkanes close to air saturation at 20$dG (4438, 1369, 442, 142 and 41 p.p.m., respectively) for 8 hours and observed for the following 14 days. In addition, exposure to higher and lower concentrations of n-C9 was performed. The concentration of alkane in the brain after exposure exceeded that of blood for the lower alkanes, while the higher alkanes possessed a brain/blood ratio equal to or less than unity. Gross ataxia, general and focal seizure and spasms were observed in animals exposed to n-C9 in the range from 5280 to 3560 p.p.m. No toxic effects were observed in animals exposed to 2414 p.p.m. of n-C9 or to the other alkanes. An LC50 value for n-C9 of 4467±189 p.p.m. was estimated. Despite the clinical improvement in animals surviving the n-C9 exposure of 4438 p.p.m. (6/10), severe cerebellar damages were found at autopsy at the end of the observation period, with a loss of Purkinje cells as the most prominent feature. Immediate post mortem examination (4/ 10) showed marked vascular congestion of the liver as well as slight fatty degeneration but no cerebellar damage. No abnormalities were observed in animals exposed to the other alkanes. The significant distribution in the brain of the n-C9 alkane, the clinical signs of cerebellar dysfunction and the damage of cerebellar neurons would suggest CNS to be a possible target organ for the toxic effects of the n-C9 alkane.     

Developmental Toxicity Study of Clarified Slurry Oil (CSO) in the Rat

Pregnant CD rats were exposed dermally to 0.05, 1, 10, 50, and250 mg/kg/day of Clarified Slurry Oil (CSO) on Days 0–19of gestation to determine its potential developmental toxicity.Untreated and vehicle controls were included in the study. Day20 of gestation Caesarean-derived fetuses were examined forgross, external, and visceral or skeletal alterations. Dosagesof 1 mg/kg/day and higher significantly decreased maternal bodyweight, body weight gain, feed consumption, gravid uterine weight,and live litter size and significantly increased resorptionrate. These dosages also significantly reduced fetal weightsand retarded development of the brain, kidney, thoracic andcaudal vertebrae, metacarpals, and hindpaw phalanges in dosagegroups with live fetuses (high dosage group dams resorbed allconceptuses). The 50- and 250-mg/kg/day dosage group dams hadonly placentas and/or dark red viscous fluid in the uterus orvagina and significant body weight loss (associated with resorption).The highest dosage also caused emaciation, slight dehydration,and swollen dark anogenital areas. These results indicate thatCSO produces adverse developmental effects at maternally toxicdosages. The maternal and developmental NOAELs (no observedadverse effect levels) were 0.05 mg/kg/day. In a second study,groups of 10 mated female rats were exposed to "pulse" exposuresand dosages of 1, 50, or 250 mg/kg/day of CSO applied dermallyfor 2- or 3-day intervals that spanned the gestation period.All dosages reduced maternal feed consumption and body weightgain during the treatment period. Dosages of 50 and 250 mg/kg/dayalso produced early resorptions when administered on Days 6through 8 and 9 through 11 of gestation. However, no increasein fetal alterations occurred, indicating that the effects onembryo–fetal development were due to early death and notto the death of malformed conceptuses.     

Evaluation of the Potential for Developmental Toxicity in Rats and Mice following Inhalation Exposure to Tetrahydrofuran

Sprague-Dawley rats and Swiss (CD-1) mice were exposed to 0,600, 1800, or 5000 ppm THF (a four-carbon cyclic ether, widelyused as an industrial solvent) vapors, 6 hr/day, 7 days/week(6–19 days of gestation (DG) for rats; 6–17 DG formice). Body weights of pregnant rats in the 5000 ppm group werereduced at euthanization. There were no effects on the percentageof live rat fetuses/litter or on the fetal sex ratio. Fetalbody weight was significantly reduced for the 5000 ppm group,but the incidence of abnormalities was not increased. Mice inthe 1800 and 5000 ppm groups were sedated during exposure; approximately27% of the mice in the 5000 ppm group died. Mean body and uterineweights of mice were reduced for the 1800 and 5000 ppm groupsat euthanization (18 DG), but adjusted maternal weight gainwas not affected at 1800 ppm. There was a reduction in the percentageof live fetuses/litter for the mice in 1800 and 5000 ppm groups(95% resorptions in the 5000 ppm group). Fetal weight and sexratio in mice were not affected. An increase in the incidenceof reduced sternebral ossifications was correlated to THF concentration,although differences between groups were not statistically significant.There were no increases in the incidences of other malformationsor variations. These results suggest that THF may be embryotoxicin mice, but if the conceptus survives, development as assessedby this experimental design continues in a normal fashion. Theno-observable-adverse-effect level (NOAEL) for maternal toxicitywas 1800 ppm in both rats and mice. The NOAEL for developmentaltoxicity was 1800 ppm in rats and 600 ppm in mice.     

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.