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

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

2-Week Inhalation Study of N-Monomethylformamide in Rats

2-Week Inhalation Study of yV-Monomethylformamide in Rats. KENNEDY,G. L., JR., FERENZ, R. L., BURGESS, B. A., AND STULA, E. F.(1990). Fundam. Appl. Toxicol. 14, 810–816. N-Monomethylformamide(MMF) is a chemical intermediate with potential for inhalationexposure in humans. Human exposures to MMF have occurred incancer chemotherapy but have been limited due to liver damage.To assess the toxicity of MMF, groups of 15 male rats each wereexposed by nose-only inhalation, 6 hr/day, 5 days/week, for2 weeks to either 0 (control), 50, 130, or 400 ppm MMF. Fiverats per group were killed following the 10th exposure, fivewere killed after a 14-day postexposure recovery period, andfive rats were used to determine urinary MMF excretion. Parametersinvestigated were clinical observations and body weights, clinicalpathology, and gross and microscopic pathology including organweights. Liver damage occurred in rats exposed to either 130or 400 ppm. This was detected both by increases in serum enzymeactivity indicative of liver injury and by microscopic changesin the liver. The changes were more severe in the 400-ppm ratsand were partially reversible. Other organs were not adverselyaffected by inhalation of MMF. The amount of MMF excreted inthe urine was dependent on the exposure concentration and MMFwas present 14 days postexposure at the higher exposure levels.The no-observed-effect level under the conditions of this experimentwas 50 ppm.     

A Thirteen Week Repeated Inhalation Study of Ethylene Dibromide in Rats,,

A Thirteen Week Repeated Inhalation Study of Ethylene Dibromidein Rats. Nitschke, K.D., Kociba, R.J., Keyes, D.G. and McKenna,M.J. (1981). Fundam. Appl. Toxicol. 1:437–442. Male andfemale CDF (F 344) rats were exposed to 0, 3, 10 or 40 ppm ethylenedibromide (EDB), 6 hours/ day, 5 days/week for 13 weeks fora total of 67–68 exposures in 95–96 days. Scheduledsacrifices occurred after 1,6, and 13 weeks of exposure. Additionalrats were held for a recovery period of 88–89 days andsubsequently necropsied. Rats exposed to 3 ppm EDB showed noconsistent effect in any parameter measured. At 10 ppm, EDBcaused slight epithelial hyperplasia of the nasal turbinatesin animals necropsied after 1, 6 or 13 weeks of exposure; however,88 days after the last exposure to EDB, nasal turbinate changeswere not observed. Rats exposed to 40 ppm EDB exhibited a decreasein body weight gain throughout the 13-week exposure period,an increase in liver and kidney weights after 6 and 13 weeksof exposure, and hyperplasia and nonkeratinizing squamous metaplasiaof the respiratory epithelium of the nasal turbinates. Aftera recovery period of 88 days, there was a reversion to normalof the nasal turbinates in 19 of 20 rats and only an isolatedfocus of hyperplasia of the nasal epithelium in the one remainingrat. It is believed that this observation would have returnedto control limits if allowed a slightly longer recovery period.The most sensitive response associated with repeated subchronicexposure of rats to 10 or 40 ppm EDB involves pathologic changesin the respiratory epithelium of the nasal turbinates. Thesechanges regressed during a subsequent postexposure phase withno indication of a progression of the lesions. Since exposureof rats to 3 ppm EDB elicited no discernible response in anyof the tissues examined, 3 ppm was defined as the no-observable-effectlevel.     

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.     

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

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

Toxicological profile of hydrofluoropolyethers

Hydrofluoropolyethers (HFPE) are a family of linear oligomeric fluorinated fluids comprising a chain of difluoromethoxy and tetrafluoroethoxy repeating units with terminal OCF2H end groups, each of which contains an isolated hydrogen atom. These fluids have been designed as low environmental impact substitutes for perfluorinated organic substances in a number of applications including heat transfer and fire suppression agents, and as a solvent. The toxicological profile of these new fluids has been evaluated and is presented in this paper. Acute toxicity tests have been performed on Sprague-Dawley Crl: CD (SD) BR rats using oral, dermal, and inhalation routes. No deaths were recorded even at the highest tested concentrations, and the resultant LD50/LC50 values were >5000 mg/kg (oral), >2000 mg/kg (dermal), and >26,411 ppm (inhalation: reversible anaesthetic effects, e.g., lethargy, seen at this exposure concentration). Other short-term tests (skin and eye irritation, skin sensitisation, genotoxicity tests in vitro and in vivo, cardiac sensitisation) were also performed, and no hazardous properties were identified. Effects of repeated exposure by inhalation were examined in rats over test periods of 5, 14, 28, and 90 days. Effects on embryo-foetal development in the rat have also been studied. The 28-day, 90-day and developmental studies were performed using nominal HFPE concentrations of 1000, 3300, and 10,000 ppm (6h/day: actual exposures confirmed by test atmosphere analysis), and the highest tested concentration proved to be an NOAEL in each study. Major observed effects were elevated urinary (inorganic) fluoride levels and increased liver weights with centrilobular hepatocyte hypertrophy (considered an adaptive response, linked to hepatic metabolism of absorbed material).     

Chronic Toxicity, Reproductive, and Teratogenic Studies of Hexazinone

Chronic Toxicity, Reproductive, and Teratogenic Studies of Hexazinone.Kennedy, G. L., Jr., and Kaplan, A. M. (1984). Fundam. Appl.Toxicol. 4, 960–971. Hexazinone [3-cydohexyl-6-(dimethylammino)-1-methyl-1,3,5-triazine2,4(1H,3H)-dione; CAS 51235-04-2] was tested for oral toxicityin rats (both 90-day and 2-year feeding studies), mice (8-weekand 2-year feeding studies), and dogs (90-day feeding study).The teratogenic potential was evaluated in rabbits and ratsand functional reproductive capacity was studied in rats. Ninety-dayfeeding of up to 1000 ppm produced no signs of a toxic responsein rats. Rats fed 5000 ppm had growth curves slightly inferiorto those of the controls as the only detectable difference.Extending the feeding period to 2 years produced decreased bodyweights in males fed 2500 ppm (top level tested) and in femalesfed either 1000 or 2500 ppm. All other indices of response,including the type and distribution of tumors, were similarin the test and control rats with the no-effect level being200 ppm. Eight-week feeding of up to 10,000 ppm in mice producedincreased liver weight only at the highest level without anyother changes. Two-year feeding of either 200, 2500, or 10,000ppm resulted in sloughing of the distal tip of the tail andincreased liver weights among mice fed 10,000 ppm. Hypertrophyof centrilobular hepatocytes and hyperplasic nodules were increasedin mice fed either 2500 or 10,000 ppm. No evidence of a tumorigenicresponse was evident The no-effect level was 200 ppm. Dogs fed5000 ppm for 90 days had decreased rate of body weight gainwith clinical enzyme changes suggestive of liver damage. Microscopicexamination of the liver failed to reveal any alterations anddogs fed either 200 or 1000 ppm were indistinguishable fromcontrols. The no-effect level in the dog was 1000 ppm. No evidenceof a teratogenic response was seen in either rats or rabbitsand reproduction capacity in rats fed up to 2500 ppm for threegenerations was unaffected     

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

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

Comparative inhalation toxicity of ethyltoluene isomers in rats and mice

The C9 alkylbenzenes, composed mostly of ethyltoluenes and trimethylbenzenes, comprise 75–90% of the naphtha fraction of crude oil. Occupational and environmental exposure to C9 alkylbenzenes occur via inhalation. We conducted short-term inhalation studies on the ethyltoluene isomers (2-, 3- or 4-) to select one isomer for more comprehensive studies. Male Hsd:Sprague Dawley rats and female B6C3F1/N mice (n?=?10) were exposed by nose-only inhalation to 2-, 3- or 4-ethyltoluene (0, 1000 or 2000?ppm) or cumene (a reference compound: 0, 500 or 1000?ppm) 3?h/day, 5?days/week, for 2?weeks. Clinical observations included abnormal gait and delayed righting reflex. Rats and mice exposed to 2000?ppm 2-ethyltoluene and mice exposed to 2000?ppm 4-ethyltoluene were euthanized early in moribund condition; no exposure-related deaths were observed with 3-ethyltoluene or cumene. Histopathology of selected tissues revealed that the nose and liver (rats and mice) and lung (mice only) to be toxicity targets. In the mouse lung, all compounds except 4-ethyltoluene produced bronchial and bronchiolar hyperplasia. In rats and mice, 2-ethyltoluene was the only compound to produce lesions in the nose and liver: in mice, squamous metaplasia and neutrophilic inflammation of the respiratory epithelium and atrophy and degeneration of the olfactory epithelium were observed in the nose and centrilobular hypertrophy and necrosis were observed in the liver. In rats, 2-ethyltoluene exposure produced atrophy of the olfactory epithelium in the nose and centrilobular necrosis in the liver. Based on mortality, body weight effects and histopathology, the 2-ethyltoluene isomer was the most potent isomer.     

Cytogenetic Evaluation of Bone Marrow Cells from Rats Exposed to Styrene Vapor for One Year

Cytogenetic Evaluation of Bone Marrow Cells from Rats Exposedto Styrene Vapor for One Year. Sinha, A.K., Jersey, G.C., Linscombe,V.A., Adams, R.L., Mueller, A.M. and McClintock, M.L. (1983).Fundam. Appl. Toxicol.. 3:95-98. This report presents the cytogeneticfindings in bone marrow cells of rats exposed to styrene vapor.Male and female Sprague-Dawley rats were exposed to 0,600 and1000 ppm of styrene vapor by inhalation 6 hr per day, 5 daysa week, for a period of one yr. Blind scoring of metaphase spreadsprepared from bone marrow cells collected at the end of thelast exposure revealed that neither the 600 ppm nor the 1000ppm exposures to styrene vapor produced an incidence of chromosomalanomalies higher than those occurring spontaneously. It is interpretedthat styrene is non-clastogenic within the present exposureregimen.     

Olfactory and hepatic changes following inhalation of 3-trifluoromethyl pyridine in rats

Rats exposed by inhalation to 3-trifluoromethylpyridine (3-FMP) for 10, 30 or 90 days showed an unusual response in the nasal passages. Focal histological change including reduction in the number of cell layers, disorganisation, vacuolation and minimal necrosis was confined to the olfactory epithelium. Axon bundles and the olfactory bulb were unaffected but there was loss of PAS staining affinity in Bowman's glands. The onset of the lesion showed a very steep dose-relationship approximating a quantal response; no effects were seen after 90 days exposure to 0.1 ppm but the changes were fully developed after 30 days exposure to 0.5 ppm. There was no marked progression with either increased exposure concentrations (up to 329 ppm) or with increased duration of exposure (10-90 days). The respiratory epithelium was generally unaffected apart from a mild irritant response seen only after 90 days. Exposures also resulted in a response in the liver. Centrilobular and midzonal vacuolation was observed at 10 and 30 days following exposures at or above 5 ppm 3-FMP and the severity increased with concentration. The lesion regressed with time even when exposure continued and only minimal changes were evident after 90 days, probably indicating an adaptive response. This work demonstrates the high organ specificity of 3-FMP, particularly for the olfactory epithelium.     

Subchronic Studies of Doxylamine in Fischer 344 Rats

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

Final report on the safety assessment of methoxyisopropanol and methoxyisopropyl acetate as used in cosmetics

Methoxyisopropanol and Methoxyisopropyl Acetate, commonly known as propylene glycol monomethyl ether (PGME) and propylene glycol monomethyl ether acetate (PGMEA), respectively, have fragrance, solvent, and viscosity-decreasing functions in cosmetics, although only Methoxyisopropanol is in current use at concentrations ranging from 4% to 35%. Methoxyisopropanol is easily absorbed into the bloodstream upon inhalation or ingestion. The acetate ester is readily metabolized to Methoxyisopropanol in the body, which is excreted unchanged in the expired breath or in the urine as free or conjugated Methoxyisopropanol, or as the primary metabolite propylene glycol. In acute oral toxicity studies, the LD(50) values of Methoxyisopropanol were 4.6 to 9.2 g/kg in rats, with similar low acute toxicity in other animal species. Inhalation exposures of rats, mice, and rabbits to 3000 ppm Methoxyisopropanol for 6 h per day for 9 days to 13 weeks produced increased relative liver weights, signs of central nervous system (CNS) depression, and in some cases, elevated serum alkaline phosphatase, alanine aminotransferase, or hepatocellular hypertrophy, but the kidneys were unaffected. The no observed adverse effect level (NOAEL) for 13-week inhalation exposures to Methoxyisopropanol was 1000 ppm in rats and rabbits. In a 90-day dermal exposure study using rabbits, 10 ml/kg undiluted Methoxyisopropanol produced narcosis and increased kidney weights and the NOAEL was 7.0 ml/kg. Chronic (2-year) daily inhalation exposures of rats and mice to 3000 ppm Methoxyisopropanol produced signs of liver toxicity (rats and mice) and some evidence of renal toxicity in rats. The only observation at 1000 ppm was dark foci of the liver in male rats. For female rats and male and female mice, the NOAEL of this chronic inhalation study was 1000 ppm Methoxyisopropanol. Methoxyisopropanol and Methoxyisopropyl Acetate were found to be nonirritating to slightly irritating and non-sensitizing in rabbit and guinea pig skin. Repeated applications of undiluted Methoxyisopropanol to the eyes of rabbits produced transient slight to moderate irritation. Pregnant rats exposed to 200 or 600 ppm Methoxyisopropanol by inhalation on gestation days 6 to 17 had no effects on maternal health or normal fetal development. Adult male rats exposed to these concentrations had no effects on the reproductive organs. Pregnant rats and rabbits exposed to 500 to 3000 ppm Methoxyisopropanol by inhalation during gestation had no significant embryotoxic or fetotoxic effects, althougth CNS depression and reduced body weight gain were observed in the 3000 ppm group. In a two-generation inhalation study using rats, continuous inhalation of 3000 ppm Methoxyisopropanol produced CNS depression, prolonged estrous cycles, reduced fertility indices, reduced pup weights and pup survival, and delayed sexual development, with a NOAEL for reproductive and developmental effects of 1000 ppm. In a continuous breeding protocol using mice, 2.0% Methoxyisopropanol in drinking water produced reduced growth, reduced relative epididymis weight, reduced relative prostate weight, and increased liver weight (females only) in offspring, with a NOAEL at a 1% concentration. Exposure of mice or rats to 300 ppm to 3000 ppm Methoxyisopropanol by inhalation produced no signs of carcinogenicity. Methoxyisopropanol was negative for mutagenicity or genetic toxicity in the bacterial reverse mutation assay (100 mM), and in the Siberian hamster embryo assay (concentrations not reported). In other assays, 100 mM Methoxyisopropanol increased sister chromatid exchanges in V79 cells. In human inhalation exposure studies of 1 to 7 h duration, 50 to 75 ppm Methoxyisopropanol vapor had an objectionable odor; 150 ppm was slightly irritating to the eyes and throat; 250 ppm produced eye irritation, lacrimation, blinking, rhinorrhea, and headache; 300 ppm was mildly irritating to the eyes, nose, and throat; 750 ppm was extremely irritating; and 2050 ppm produced extreme discomfort with severe lacrimation, blepharospasm, and painful breathing. None of the concentrations tested impaired motor coordination or performance on neurological tests. The irritating effects subsided within 15 min to 24 h of removal from the inhalation chamber. The National Institute of Occupational Safety and Health (NIOSH) recommended an 8-h time-weighted average for occupational exposure of 100 ppm. A margin of safety of 500 was determined, based on a calculated exposure from the normal use of nail polish remover products (100% absorption) and the NOAEL for reproductive toxicity. The absorption of Methoxyisopropanol through the nail is likely to be low, suggesting this margin of safety is conservative. Because Methoxyisopropanol is volatile, exposure by inhalation is possible, but the odor becomes objectionable at 50 to 75 ppm in air. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that Methoxyisopropanol and Methoxyisopropyl Acetate are safe for use in nail care products in the practices of use and concentration as described in this safety assessment.     

The acute,genetic, developmental and inhalation toxicology of trans-1,3,3,3-tetrafluoropropene (HFO-1234ze)

HFO-1234ze is being developed as a refrigerant, propellant, and foam-blowing agent because it has a very low global warming potential (less than 10), as contrasted to the hydrofluorocarbons with values of over 500. Several toxicology studies were conducted to develop a toxicology profile for this material. There was no lethality in mice and rats receiving single 4-hour exposures up to 103,300 or 207,000 ppm, respectively. Exposures up to 120,000 ppm did not induce cardiac sensitization to adrenalin. Rats were exposed to HFO-1234ze at levels of 5,000, 20,000, and 50,000 ppm 6 hours/day 5 days/week for 2 weeks. Predominate findings of increased liver and kidney weights and histopathological changes in the liver and heart suggested that these organs were the targets for HFO-1234ze toxicity. In a 4-week study at 1000, 5000, 10,000, and 15,000 ppm, the only organ showing treatment-related effects was the heart. In a 90-day study with exposures of 1500, 5000, and 15,000 ppm 6 hours/day 5 days/week, again, the heart was the only target organ. The findings consisted of focal and multifocal mononuclear cell infiltrates in the heart. There was no evidence of fibrosis, and, when compared to the 2- and 4-week studies, there did not appear to be an increase in severity with length of exposure. HFO-1234ze was inactive in a mouse and rat micronucleus assay, an Ames assay, and an unscheduled DNA synthesis assay and was not clastogenic in human lymphocytes. It was also not a developmental toxin in either the rat or rabbit, even at exposure levels up to15,000 ppm.     

A 90-Day Vapor Inhalation Toxicity Study of Methyl Ethyl Ketone

A 90-Day Vapor Inhalation Toxicity Study of Methyl Ethyl Ketone.Cavender, F.L., Casey, H.W., Salem, H., Swenberg, J.A. and Gralla,E.J. (1983). Fundam. Appl. Toxicol. 3: 264–270. Male andfemale Fischer 344 rats were exposed to 0, 1250, 2500, or 5000ppm methyl ethyl ketone (MEK) vapors 6 hours per day, 5 daysper week for 90 days. The 90-day exposures had no adverse effecton the clinical health or growth of male or female rats exceptfor a depression of mean body weight in the 5000 ppm exposuregroup. The 5000 ppm animals had a slight but significant increasein liver weight, liver weight/body weight ratio, and liver weight/brainweight ratio at necropsy. Serum glutamic-pyruvic transaminase(SGPT) activity in the 2500 ppm female rats was elevated whilethe 5000 ppm female rats exhibited significantly decreased SGPTactivity. In addition, alkaline phosphatase, potassium and glucosevalues for the 5000 ppm female rats were increased. Specialneuro-pathological and routine pathological studies did notreveal any lesions that could be attributed to MEK exposure.     

Subchronic Oral Toxicity of Glyoxal via Drinking Water in Rats

Subchronic Oral Toxicity of Glyoxal via Drinking Water in Rats.Ueno, H., Segawa, T., Hasegawa, T., Nakamuro, K., Maeda, H.,Hiramatsu, Y., Okada, S., and Sayato, Y. (1991). Fundam. Appl.Toxicol. 16, 763–772. The subchronic oral toxicity ofglyoxal via drinking water and the effect on in vivo proteinsynthesis in tissues following a single treatment with thissubstance were assessed in Sprague–Dawley male rats. Animalsreceived drinking water containing glyoxal levels of 2000, 4000,and 6000 mg/liter ad libitum for 30, 60, and 90 days in PhaseI. In Phase II, the high-dose and control-1 groups fed the dietad libitum, and a diet-limited control-2 group given the sameamount of diet as consumed by the high-dose group were maintainedfor 90 and 180 days. The study designs included observationsof clinical signs, body weights, major organ weights, grossand histopathological examinations, serum clinical chemistry,and biochemical examinations such as glyoxalase activity andglutathione content in selected tissues. Body weight gain andorgan weights significantly decreased with dosage. Althoughconsumption of food and water was also depressed in the exposedgroup, the reduction of body weight gain was greater in thehigh-dose group than in the diet-limited control 2 group. Histopathologicalexaminations revealed only a slight papillary change in thekidneys from the high-dose group at both 90 and 180 days terminationsin Phase II. The induction of both glyoxalase I and II was observedin liver and erythrocytes at 30-day termination of the exposedgroups. Serum enzyme and protein levels were significantly reducedby the mid- and/or high-dose exposures. With a single oral high-dosetreatment of glyoxal, a great decline in the incorporation ofL-[³H]leucine was shown particularly in the liver, and thisprobably led in part to a reduction in the serum protein levelsin rats following subchronic exposure to glyoxal. These dataindicated an overall low degree of systemic toxicity to ratsexposed subchronically to glyoxal via drinking water.     

Inhalation Studies in Rats Exposed to Dimethylacetahide (DMAc) from 3 to 12 Hours Per Day

ABSTRACT

Male rats were exposed by inhalation from 10 to 300 ppm Dimethylacetamide (DMAc) for either 3, 6, or 12 hrs/day for a total of 10 exposures (5 exposures, 2 rest days, 5 exposures). Rats were observed daily for signs of DMAc-related effects, growth was monitored by body weights, clinical laboratory tests and microscopic examination of the liver, testes epididymides, and nasal passages were conducted. One half of the rats in each group was allowed a 14-day post-exposure period to evaluate the reversibility of DMAc-induced changes. No clinical signs of toxicity or DMAc-related gross changes at necropsy were seen in any of the rats although 1 rat exposed to 300 ppm for 12 hours per day died following the seventh exposure. Slight (< 5%) decreases in body weight gain were seen in rats exposed to 300 ppm for 6 or 12 hrs/day. Serum cholesterol levels were elevated in rats exposed to either 100 or 300 ppm (all exposure durations) and in rats exposed to 30 ppm for 12 hours. Total serum protein concentrations were increased in rats exposed for 12 hours/day to either 30, 100, or 300 ppm. Hepatocellular hypertrophy together with margination of hepatocellular cytoplasmic contents and lipid-like cytoplasmic vacuolation in hepatocytes were seen microscopically only in rats exposed for 12 hours/day to 300 ppm. Recovery from these liver changes was not complete after 14-day post-exposure period. No evidence of either testicular damage or irritation to the upper respiratory tract was seen.     

Prenatal Toxicity of 2-Methoxypropylacetate-1 in Rats and Rabbits

Prenatal Toxicity of 2-Methoxypropylacetate-l in Rats and Rabbits.MERKLE, J., KLIMISCH, H.-J., and JÄCKH, R. (1987). Fundam.Appl. Toxicol. 8, 71–79. 2-Methoxypropylacetate-1 wasinvestigated in Wistar rats and Himalayan rabbits for embryotoxicpotential. Rats after inhalation exposure to 0, 0.6, 3.0, or14.9 mg/liter (approximately 0, 110, 550, or 2700 ppm, respectively)for 6 hr per day from gestation Days 6 through 15 exhibitedsome degree of maternal toxicity at 2700 and 550 ppm. At 2700ppm an increase of skeletal anomalies of the thoracic vertebraeamong the fetuses was observed and interpreted as an exposure-relatedslight teratogenic effect. In Himalayan rabbits exposed viainhalation to 0,0.2,0.8, or 3.0 mg/liter (approximately 0, 36,145, or 550 ppm, respectively) for 6 hr per day from gestationDays 6 through 18 teratogenicity was much more pronounced: at550 ppm, in the absence of clear maternal toxicity, the fetusesof all litters showed severe malformations. No maternal or fetaleffects were observed at 145 and 36 ppm. Dermal applicationof 1000 and 2000 mg/kg to Himalayan rabbits from gestation Days6 through 18 failed to produce maternal or fetal toxicity.     

Isobutyraldehyde Administered by Inhalation (Whole Body Exposure) for up to Thirteen Weeks or Two Years Was a Respiratory Tract Toxicant but Was Not Carcinogenic in F344/N Rats and B6C3F1 Mice

Isobutyraldehyde (a chemical structurally related to formaldehydeand used as a flavoring agent) was studied for toxicity andcarcinogenicity by exposing male and female F344/N rats andB6C3F₁ mice. Animals were exposed to isobutyraldehyde vapors6 h per day, 5 days per week for up to 13 weeks or 2 years.In the 13-week studies, groups of 10 male and 10 female F344/Nrats and B6C3F₁ mice were exposed to concentrations of 0, 500,1000, 2000, 4000, or 8000 ppm. Chemical-related body weightdepression and deaths occurred in rats and mice exposed to 4000and 8000 ppm. Necrosis of the epithelium accompanied with acuteinflammatory reaction was observed in the nasal turbinate, larynx,and trachea of rats exposed to 8000 ppm. Exposure of rats to4000 ppm resulted in metaplasia of the nasal respiratory epithelium,inflammation, degeneration of the olfactory epithelium, andosteodystrophy of the nasal turbinate bone. In the 13-week mousestudy, exposure to 8000 ppm or 4000 ppm resulted in necrosisof the epithelium lining of the nasal turbinates. Osteodystrophyof the nasal turbinate bone and squamous metaplasia of the nasalrespiratory epithelium were noted in mice exposed 4000 ppm.Degeneration of the olfactory epithelium was noted in malesexposed 2000 ppm and in females exposed to 4000 ppm. In the2-year studies, groups of 50 male and 50 male F344/N rats andB6C3F1 were exposed to concentrations isobutyraldehyde vaporsof 0, 500, 1000, or 2000 ppm 6 h per day, 5 days per week. Therewere no differences in survival rates or mean body weights betweenexposed groups and control rats. Survival of male mice exposedto 2000 ppm and mean body weights of female mice exposed to1000 or 2000 ppm were lower than those of the of the controls.No increase in neoplasm incidence was observed in rats and micein the 2-year studies that could be attributed to isobutyraldehydeexposure. Chemical-related nonneoplastic lesions were limitedto the nose of rats and mice. They included squamous metaplasiaof the respiratory epithelium (rats), suppurative inflammation(rats), and olfactory epithelial degeneration (rats and mice)at 1000 and 2000 ppm.     

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

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