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.     

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.     

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.     

Subchronic Oral Toxicity of Ethylene Glycol Monobutyl Ether in Male Rats

Subchronic Oral Toxicity of Ethylene Glycol Monobutyl Etherin Male Rats. KRASAVAGE, W. J. (1986). Fundam Appl. Toxicol.6, 349–355. Adult male rats (Crl:COBS CD (SD)BR) weregiven undiluted ethylene glycol monobutyl ether (EGBE) by gavagein doses of 222, 443, or 885 mg/kg/day, 5 days/week over a 6-weekperiod. A dose-dependent decrease, which was statistically significantat the high dose, was seen in body weight gain. Feed consumptionwas also significantly reduced at the 885-mg/kg dose. The mostsignificant toxic effects produced by EGBE were on the red bloodcells including a significant dose-dependent decrease in hemoglobinconcentration. red blood cell counts, and mean corpuscular hemoglobinconcentration. Mean corpuscular hemoglobin and mean corpuscularvolume were increased at all dose levels. Effects secondaryto the red cell effects included increased spleen weights, spleniccongestion, and hemosiderin accumulation in the liver and kidneys.Relative liver weights and serum alkaline phosphatase (443-and 885-mg/kg doses) and serum alanine aminotransferase (885-mg/kgdose) levels were increased. Glucose was significantly reducedin the animals given 885 mg/kg/day. EGBE had no adverse effectson the testes, bone marrow, thymus, or white blood cells.     

Neuropathologic Findings in Young Male Rats in a Subchronic Oral Toxicity Study Using Triethyl Lead

This study was undertaken to ascertain the neuropathologic effectsof low level exposure of triethyl lead (3EL) to young male rats.Groups of 20 male Sprague—Dawley weanling rats were given3EL at 0, 0.05, 0.10, 0.20, 0.50, and 1.00 mg/kg body wt for91 days, 5 days/week by oral gavage. Lead acetate (PbHOAC) wasgiven at 200 mg/kg body wt/day as a positive control. Animals(five or six) were perfused with glutaraldehyde following barbiturateanesthesia at the termination of the experiment. These animalsand the remaining members of the group received a thorough grossand microscopic postmortem examination. Sections of the central,peripheral, and autonomic nervous systems were examined andlesions scored. No lesions were noted in the brain, but randomlydistributed light microscopic changes of spinal cord Walleriandegeneration were noted to increase in a dose responsive manner(p = 0.48; p < 0.01), with 3EL administration. Ultrastructuralexamination of selected sections of the lumbosacral nerves,revealed lesions characterized by reduced neurofilaments andneurotubules, and irregular lamellated axoplasmic dense bodiesin all animals receiving lead. Organolead was only detectedin animals receiving 3EL, but lead cat- ions were detected inall lead-treated animals. The brain lead levels of 1.00 mg/kg/dayand 200 mg Pb acetate positive control animals were equivalent.As distinctive ultrastructural lesions were seen in all ratstreated with 3EL, we suggest that the no observed adverse effectlevel (NOAEL) for 3EL be lowered to less than 0.05 mg/kg/day.Further studies using lower concentrations of 3EL are requiredto determine the ultrastructural NOAEL, to fully describe thedistribution of the lesions seen and to define the nature ofthe dense bodies.     

乳酸钠对大鼠的亚慢性经口毒性试验

目的观察大鼠连续经口给予乳酸钠后的毒性靶器官及其损害的可逆性。方法60只SD种大白鼠随机分为3个组,每组10只雌性和10只雄性大鼠,3组大鼠经口灌胃分别给予0、800、2000mg·kg^-1乳酸钠,给药体积1mL／100g,连续经口染毒90天。于第7周、第13周和恢复4周,每组剖杀部分大鼠做血液学、生化学、眼科、尿液检查,脏器湿重值、脏器系数值和解剖病理学观察。结果染毒各期高剂量组的血清生化学检查显示钠离子、钙离子数值升高,钾离子、氯离子数值降低;尿液检查发现尿比重（SG）数值降低,尿蛋白质（Pro）和尿胆红素（Bil）数值升高;解剖病理学发现7只大鼠膀胱腔内存在轻度蛋白样物质聚集;血清生化学检查低剂量组的钠离子和钙离子数值升高、恢复期高剂量组的钠离子数值仍然较高。结论乳酸钠能引起大鼠各期血液的无机离子和尿液蛋白出现明显的变化,对大鼠有一定毒性作用。     

Subchronic Oral Toxicity,Tissue Distribution and Clearance of Hexachloroethane in the Rat

ABSTRACT

Hexachloroethane (HCE) was fed to Fischer 344 rats at approximate doses of 0, 1, 15 or 62 mg/kg/day for 16 weeks. Selected tissues were assayed at termination for HCE content. Histopathological examination identified the kidney as the primary target organ with male rats more sensitive than female rats. The kidney concentration of HCE increased proportionately with dose in the males, but there were disproportionately small increases with dose in females. A group of male rats was given 62 mg/kg/day for 8 weeks to estimate tissue clearance. Clearance of HCE from fat, liver, kidney and blood occurred in an apparent first-order manner with a half-life of approximately 2.5 days. The apparent first-order elimination suggests that HCE metabolism and excretion were not saturated in rats given up to 62 mg/kg/day and suggests that, in the range of doses given, toxicity should be proportional to exposure concentration. The no-observable-effect level (NOEL) for toxicity was 1 mg/kg/day for male and female rats.     

Oral Subchronic Toxicity of a Lipid Extract from Roystonea regia Fruits in Mice

D-004 is a lipid extract of royal palm (Rosytonea regia) fruits that prevents prostate hyperplasia induced with testosterone in rodents. Previous studies have shown no D-004-related toxicity in rats, but no study in mice had been reported. D-004 (500, 1000, and 2000 mg/kg) was evaluated in a subchronic (eight weeks) study in NMRI mice. No evidences of treatment-related toxicity were detected. Thus, body-weight gain, clinical observations, food consumption, blood biochemical, hematology, organ-weight ratios, and histopathological findings were similar in control and treated groups. This study supports that D-004 orally administered up to 2000 mg/kg did not induce treatment-related toxicity.     

A Subchronic Toxicity Study of Octyl Acetate in Rats

A Subchronic Toxicity Study of Octyl Acetate in Rats. DAUGHTREY,W. C., EUTERMOSER, M., THOMPSON, S. W., AND BILES, R. W. (1989).Fundam. Appl. Toxicol 11, 313-320. The subchronic toxicity ofoctyl acetate was assessed following its administration to ratsvia oral gavage, 5 days per week for 13 weeks. Treated ratsreceived undiluted octyl acetate at doses of 0.1, 0.5, or 1.0g/kg. Control rats received distilled water at a dose of 1.0g/kg An interim termination was made after 45 days of dosingat which time five animals per sex per group were terminatedand necropsied. Blood samples were collected and liver tissueswere prepared for histological examination. After 13 weeks ofdosing all animals were terminated and necropsied. Blood sampleswere obtained and selected organs were weighed and preparedfor subsequent histological examination. Several treatment-relatedeffects were observed in the high-dose group (1.0 g/kg) animals.These effects included slight reductions in body weight andfood consumption, increased liver and kidney weights, and evidenceof hydrocarbon nephropathy in highdose males only. The significanceof these observations is discussed in the report. With the exceptionof increased liver weights in the mid-dose group, no other significanttreatment-related effects were observed in the mid- or low-dosegroups of animals. It is believed that the increases in liverweight which were observed are a compensatory response to anincreased metabolic load, and not a reflection of true hepatotoxicnty.The results of this study indicated that octyl acetate possessedan overall low degree of systemic toxicity when administeredorally to rats for 13 weeks     

Subchronic Toxicity of Tetramethylsuccinonitrile

Subchronic Toxicity of Tetramethylsuccinonitrile. JOHANNSEN,F. R., AND LEVINSKAS, G. J. (1986). Fundam Appl. Toxicol. 7,41-48. The acute rat oral LD50 for tetramethylsuccinonitrile (TMSN)is 38.9 ± 7.4 mg/kg. A series of three 90-day subchronictoxicity studies were conducted with Sprague-Dawley-derivedalbino rats. In each study, rats were administered corn oilsolutions of TMSN by intubation. In the first study, groupsof 15 male and 15 female rats were given 0, 1, 3, or 10 mg/kgTMSN. Significant reductions in weight gain were observed at10 and 3 mg/kg/day. Survival, demeanor, food consumption, hematology,and urinalysis were not affected. Except for a reduction infasting blood glucose in the 10 mg/kg test group, no effectswere observed in clinical pathology parameters. Absolute andrelative liver weights were increased at 10 mg/kg (both sexes)and 3 mg/kg (males). Both absolute and relative kidney weightswere increased and treatment-related morphological lesions,characterized as tubular nephrosis, were observed in all testgroups of males, but not in females. Other TMSN-related microscopicobservations were limited to liver changes in both sexes at10 mg/kg. Two subsequent 90-day studies, each conducted with15 male rats per group, used levels of 0, 0.001, 0.01, 0.1,0.3, or 1.0 mg/kg/day TMSN. Renal weight increases were observedat 1.0 mg/kg TMSN. Microscopic renal lesions similar to thoseseen in the first study were observed down to 0.1 mg/kg TMSN.A no-effect level was established at 0,01 mg/kg TMSN. No treatment-relatedmicroscopic lesions of the kidney were observed in groups ofmale rats given 3.0 mg/kg TMSN by gavage for 90 days and thenremoved from treatment for 14 days. Thus, tubular nephrosisproduced by subchronic exposure to TMSN is reversible in themale rat. Groups of 15 male rats also were exposed to 1,5, or10 ppm TMSN in drinking water for 90 days. No adverse effectson in vivo parameters or clinical pathology were observed. Increasesin kidney weights were seen at 10 and 5 ppm TMSN. Histopathologicchanges characteristic of tubular nephrosis were noted in ratsfrom all treatment groups. Dogs administered capsules containingTMSN for 90 days at levels equivalent to 0.3, 1.0 and 3.0 mg/kg/dayexhibited slight suppressions of body weight gain at the twohigher dosage levels and a small increase in blood thiocyanateat 3 mg/kg. No other functional or morphological changes relatedto treatment were observed in any organs evaluated, includingliver and kidney.     

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。     

The Subchronic Oral Toxicity of the {beta}-Isomer of Hexachiorocyclohexane in Rats

The Subchronic Oral Toxicity of the ß-Isomer of Hexachlorocyclohexanein Rats VAN VELSEN, F. L., DANSE, L. H. J. C., VAN LEEUWEN,F. X. R., DORMANS, J. A. M. A., AND VAN LOGTEN, M. J. (1986).Fundam. Appl. Toxicol. 6, 697–712. The 13-week oral toxicityof ß-HCH, a non pesticidal isomer of hexachlorocyclohexane,was investigated in rats with doses of 0,2, 10, 50, or 250 mg/kgfeed. Parameters studied comprised clinical signs, growth andfood intake, biochemistry, hematology, organ weights, and histopathology.In all dose groups liver effects comprising increase of organweight, centrilobular hepatocytic hypertrophy, and proliferationof smooth endoplasmic reticulum or increased activity of microsomalenzymes, were observed. In the 50 mg/kg group the weights ofthymus and testes were affected. In the highest dose group,progressive clinical signs leading to the unscheduled sacrificeof approximately 50% of the rats were observed. Moreover, inthe males of this group atrophy of the testes, characterizedby a reduced size of the seminiferous tubules and a decreasednumber of interstitial cells was observed in association withspermatogrnic arrest. The females in this group showed atrophyof the ovaries with impaired oogenesis and focal hyperplasiaand metaplastic changes of the endometrial epithelium. Theseeffects are discussed with respect to a possible estrogenicaction of ß-HCH.     

Safety Profile of a Polyherbal Formulation (Gynocare capsules) in Female Rats by Subchronic Oral Toxicity Study

Gynocare capsules, is a polyherbal formulation, are used as uterine tonic and for treating gynaecological ailments like infertility, leucorrhea, and menstrual disorders. The formulation contains ingredients of herbal origin, such as, extracts of Ashoka, Vasaka, Durva, Chandan, Musk, and so on. It was evaluated for its safety at the therapeutic dose level by a repeated dose oral toxicity study in albino Wistar rats. The herbal formulation was administered orally at a therapeutic dose of 100 mg/kg/day, for 90 days. All animals were monitored daily for their health status and signs of abnormalities. The body weight, water consumption, and food intake were measured once weekly. At the end of the experimental period, various hematological and biochemical parameters were estimated and histopathologies of selected organs were conducted. The study resulted from the long-term oral administration of Gynocare capsules (100 mg/kg), did not cause any relevant signs of toxicity nor significant changes in the physical, hematological and biochemical parameters. However, statistically significant differences were seen in the relative organ weights of adrenal gland, ovary, and serum creatinine levels. The reduction in ovary weight revealed the possibility of the drug targeting the ovary. Moreover, no pathological features were identified in the treated group as monitored by the histopathological analysis of the internal organs. The study established that Gynocare capsules at the dose given (100 mg/kg) did not induce any remarkable or significant toxic effects, indicating that it was safe in rats following oral administration for 90 consecutive days.     

Toxicity of Cyclohexanone Oxime: II. Acute Dermal and Subchronic Oral Studies

Toxicity of Cyclohexanone Oxime. II. Acute Dermal and SubchronicOral Studies, GAD, S. C., DERELANKO, M. J., POWERS, W. J., MULDER,S., GAVIGAN, F., AND BABICH, P. C. (1985). Fundam. Appl. Toxicol.5, 128–136. Derrnal exposure of rabbits to cyclohexanoneoxime (CHO) for 24 hr at 0, 0.8, 2, and 5 g/kg caused dose-relatedreticulocytosis on the day after dosing as well as a decreasein hemoglobin in the 5-g/kg females 7 days postdosing. Gavageof rats 5 days a week for 13 weeks at levels of 0, 0.25, 2.5,and 25 mg/kg resulted in a dose-related decrease in erythrocytenumber, hemoglobin, and hematocrit, with an accompanying increasein circulating reticulocytes and nucleated erythrocytes, inboth sexes. Also seen were corneal opacities and an increasedincidence of Howell-Jolly bodies. Results suggested an increasederythropoiesis in the spleen and bone marrow. The data fromsatellite groups terminated at 30 and 60 days revealed no effectat the lower test level, but results from the end of the studyshowed a clear cumulative dose response down to the 0.25-mg/kglevel. Males were affected earlier and at lower doses than females.These results, along with those of a subacute study with a recoveryperiod, suggest that CHO induces an oxidative attack on erythrocyteswhich appears reversible upon cessation of exposure.     

Oral Toxicity of Carbon Tetrachioride: Acute, Subacute, and Subchronic Studies in Rats

Oral Toxicity of Carbon Tetrachloide: Acute, Subacute, and SubchronicStudies in Rats. BRUCKNER, J. V., MACKENZIE, W. F., MURALIDHARA,S., LUTHRA, R., KYLE, G. M., AND ACOSTA, D. (1986). Fundam.Appl. Toxicol. 6, 16–34. This investigation was conductedto characterize the acute, subacute, and subchronic toxic potencyof ingested carbon tetrachloride (CCl₄) In the first acute andsubacute toxicity study, male Sprague-Dawley rats of 300–350g were gavaged with 0, 20, 40, or 80 mg CCl₄/kg once daily for5 consecutive days, rested for 2 days, and dosed once dailyfor 4 additional days. Rats of 200–250 g were gavagedwith 0, 20, 80, or 160 mg CCl₄/kg according to the same dosageregimen in the second acute and subacute study. In the firstand second studies one group of rats at each dosage level wassacrificed for clinical chemistry and histopathological evaluationat 24 hr, 4 days, and 11 days after initiation of dosing. Single20- and 40-mg/kg doses had no apparent toxic effect at 24 hr,although 80 mg/kg caused mild hepatic centrilobular vacuolizationand significant increases in some serum enzyme levels. In general,there was progressively severe hepatic injury at each dosagelevel over the 11-day period. CCl₄ was more hepatotoxic to the200–250-g rats than to the 300–350-g rats. In thesubchronic study, rats initially 200–250 g were gavaged5 times weekly for 12 weeks with 0, 1, 10, or 33 mg CCl4/kgBody weight and clinical chemistry indices were monitored duringthe 12 weeks of dosing and 2 weeks after cessation of dosing,A dose of 1 mg/kg had no apparent adverse effect; 10 mg/kg producedslight, but statistically significant increases in sorbitoldehydrogenase activity and mild hepatic centrilobular vacuolization;33 mg/kg caused marked hepatotoxicity. Serum enzyme levels remainedelevated during the 12-week dosing period, but returned towardnormal within 13 days of cessation of CCl₄ exposure. Microscopicexamination of livers of the 33-mg/kg rats revealed cirrhosis,characterized by bile duct proliferation, fibrosis, lobulardistortion, parenchymal regeneration, hyperplastic nodules,and single-cell necrosis. The fibrosis was not reversed withinthe 13-day recovery period.     

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.     

A Chronic Toxicity and Oncogenicity Study in Rats and Subchronic Toxicity Study in Dogs on Ingested Vinylidene Chloride

A Chronic Toxicity and Oncogenicity Study in Rats and a SubchronicToxicity Study in Dogs on Ingested Vinylidene Chloride. Quast,J.F., Humiston, C.G., Wade, C.E., Ballard, J., Beyer, J.E.,Schwetz, R.W. and Norris, J.M. (1983). Fundam. Appl. Toxicol.3:55-62. The chronic toxicity and oncogenic potential of ingestedvinylidene chloride (VDC) was evaluated in a 2-year study onSprague-Dawley rats and the subchronic toxicity was evaluatedin beagle dogs in a 97-day study. The vinylidene chloride wasincorporated in the drinking water of the rats at nominal concentrationsof 50, 100 or 200 ppm. The time weighted average mg/kg bodyweight/day dosages of vinylidene chloride administered to themale and female rats over the 2-year period at the various meananalyzed concentrations were 7, 10 or 20 for the males and 9,14 or 30 for the females. Dogs were administered vinylidenechloride in peanut oil incorporated in a gelatin capsule atconcentrations which provided 6.25, 12.5 or 25 mg vinylidenechloride/kg body weight/day. There were no significant differencesbetween the groups of rats or dogs ingesting vinylidene chlorideand their corresponding control groups in the following parameters:appearance and demeanor, mortality, body weight, food consumption,hematology, urinalysis, clinical chemistry determinations, organweights and organ to body weight ratios. There were no significantdifferences in water consumption of the groups of rats ingestingvinylidene chloride and the controls. The sole treatment-relatedobservation in the rats, evident only upon microscopic examination,was in the liver. The observation was characterized by a minimalamount of hepatocellular swelling with midzonal fatty changewhich occurred in the females at all dose levels and in themales only at the 200 ppm level. No exposure-related neoplasticchanges occurred in the rats in any of the test groups. No exposure-relatedgross or histopathological changes were present in the tissuestaken from the dogs at the termination of the 97-day study.     

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.