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 Tetrahydrofuran Vapors in Rats and Mice

Subchronic Toxicity of Tetrahydrofuran Vapors in Rats and Mice.CHHABRA, R. S., ELWELL, M. R., CHOU, B., MILLER, R. A., ANDRENNE, R. A. (1990). Fundam. Appl. Toxicol. 14, 338–345.Tetrahydrofuran (THF), a four-carbon, cyclic ether, is widelyused as an industrial solvent. Groups of 10 rats and mice ofeach sex were administered THF vapor by whole body inhalationfor 13 weeks at exposure concentrations of 0, 66, 200, 600,1800, and 5000 ppm. The body weights and survival were not affectedby THF exposure, except in male mice at 5000 ppm concentrationwhich had reduced weight and three deaths. Clinical signs ofcentral nervous system (CNS) toxicity were observed in bothrats and mice at high dose levels. Rats of both sexes exposedto 5000 ppm were ataxic and mice exposed to 1800 or 5000 ppmappeared to be in a state of narcosis. There were no exposure-relatedgross necropsy findings in rats or mice. At 5000 ppm, decreasesin thymic and spleen weights in rats and mice of both sexesand increases in liver weights in both sexes of mice and infemale rats were observed. A minimal to mild centrilobular hepatocytomegalyoccurred in male and female mice exposed to 5000 ppm THF. Atrophyof the uterus and degeneration of the X zone in the adrenalcortex occurred in female mice exposed to 5000 ppm THF. THFexposure of rats was associated with minimal to mild acanthosisand inflammation in the forestomach. In conclusion, these studiessuggest that THF, like other commonly used organic solvents,causes narcosis in rats and mice. Although minimal exposure-relatedeffects were seen in the liver of both species, morphologicchanges were present only in mice. The stomach lesions werelimited to rats of both sexes and were most likely due to alocal irritant effect of TH F exposure.     

Subchronic Oral Toxicology of 4-Chloro-3-nitroaniline in the Rat

Subchronic Oral Toxicology of 4-Chloro-3-nitroaniline in theRat. O'DONOGHtJE, J. L (1986). Fundam. Appl. Toxicol. 6, 551–558.4-Chloro-3-nitroaniline was given to groups of 20 male and 20female rats by gavage at doses of 3.6, 18, or 90 mg/kg in a10% corn oil suspension. Doses were administered 5 days perweek for 90 days. The high dose resulted in reduced body weightgain in males, reduced feed consumption and fluctuating feedconsumption in both sexes, slight hemolytic anemia with Heinzbodies in both sexes, enlargement of the spleen due to congestion,hemosiderosis, and increased extramedullary hematopoiesis inboth sexes, inflammatory changes in the splenic capsules oftwo females, hemosiderin pigmentation of the liver in both sexes,bone marrow hyperplasia in both sexes, increased liver weightin females, and testicular atrophy. The middle dose produceda fluctuating feed consumption pattern in males, Heinz bodiesin both sexes, very slight anemia in females, splenic hemosiderosisin males, slightly increased splenic extramedullary hematopoiesisin females, hemosiderin pigmentation of the liver in males,and possibly increased liver weight in females, and inflammatorychanges in the splenic capsule of one male. The low dose producedHeinz bodies in males and possibly females although the Heinzbody counts of females were not statistically significant Theprimary toxicologic damage produced by 4-chloro-3-nitroanilineis hemolytic or Heinz body anemia and testicular atrophy. Thusthe toxicity of 4-chloro-3-nitroaniline is similar to that ofother aromatic nitro and amino chemicals.     

Chronic toxicity and carcinogenicity studies of ethylenediamine dihydrochloride by dietary incorporation in Fischer 344 rats.

Ethylenediamine dihydrochloride (EDA.2HCl) was incorporated into the diet and fed to Fischer 344 rats for 2 years at target doses of 0, 0.02, 0.10 or 0.35 g/kg/day (equivalent to 0.009, 0.045 and 0.158 g free EDA/kg/day). Two separate untreated control groups were used. Interim sacrifices were at 6, 12 and 18 months and the terminal sacrifice was at 24 months. Under the conditions of this study, EDA.2HCl was not carcinogenic in the Fischer 344 rat. Most toxic responses were observed at the 12-month sacrifice and thereafter. Reductions in mean body weight gain were observed in high dose group male rats throughout most of the study and in the high dose group of female rats after approximately 18 months. Conversely, there was a slight increase in the mean body weight gain for the medium level female rats from about day 21 until 21 months that was of equivocal biological significance. Increased mortality was observed in the high dose group of both sexes and the mid dose group of female rats. The cause of the decreased survival was unclear, but may have been related to the enhancement of background degenerative lesions such as chronic nephropathy. Throughout the study, male rats from the high dose group had decreased erythrocyte counts, haemoglobin concentration and haematocrit. The cause and biological significance of the haematological changes were unknown. Increased water consumption was observed in the high dose group of both sexes during the latter half of the study. Increased urine volume with concurrent decreased urine specific gravity was generally observed in the high dose group of both sexes in the last half of the study and suggested a possible alteration in kidney function. Altered urine volume and specific gravity persisted to termination in female rats only. Slight increases in absolute and relative kidney weights were also observed in the high dose group of female rats during the latter half of the study. Hepatocellular pleomorphism was observed in the high dose group of both sexes, especially the female rats, and may have contributed to increased mean liver weights observed primarily in female rats from the high dose group. Hepatocellular pleomorphism was first observed in female rats at 12 months but was not observed in male rats until the final sacrifice. Rhinitis and tracheitis were observed with greater frequency in the high dose group of male rats at 12, 18 and 24 months and in high dose group female rats at 18 months. At 24 months, rhinitis, but not tracheitis, persisted at a significantly greater frequency in high dose group female rats. The apparent no-observable-effect level (NOEL) of this study was at the lowest dose level, 0.02 g/kg/day (equivalent to 9 mg EDA/kg/day).     

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.     

Subchronic Toxicity of 3,3',4,4',5-Pentachlorobiphenyl in the Rat: I. Clinical, Biochemical, Hematological, and Histopathological Changes

The systemic, toxicity of 3,3',4,4',5-pentachlorobiphenyl (PCB126) following subchronic dietary exposure was investigatedin Sprague-Dawley rats. PCB 126 was administered to rats ofboth sexes at concentrations of 0.1, 1.0, 10, or 100 ppb intheir diet for 13 weeks. Another group of rats received a loadingdose of 5 µg PCB/kg body wt at the start of the feedingperiod followed by exposure to 10 ppb PCB diet for the sameperiod of time as the other groups. Growth suppression and decreasedfood consumption were observed in the highest dose groups ofboth sexes. Increased organ/body weight ratios for the liveroccurred in the 10 and 100 ppb groups of both sexes. Rats ofboth sexes exposed to the highest dose of the PCB also exhibitedincreased relative kidney, spleen, and brain weights. Hematologicaland most serum biochemical changes were confined to the 100ppb groups. These included elevated alkaline phosphatase, bilirubin,cholesterol, and aspartate aminotransferase, and decreased serumglucose, hemoglobin, erythrocytes, hematocrit, and platelets.A dose-dependent increase in liver ethoxyre-sorufin-O-deethylaseactivity was observed in rats of both sexes starting at 0.1ppb. A dose-dependent increase in liver uroporphyrin levelswas observed in both sexes and significant changes occurredin the female rats at 1.0 ppb and higher dose groups. Decreasedliver vitamin A was observed in the 10 ppb group and higherin both sexes. Kidney vitamin A was elevated in the 100 ppbgroup. No statistically significant changes were noted in concentrationsof brain biogenic amines. PCB 126 residues were 10-fold higherin liver than in fat. Treatment-related histopathological changeswere observed in the thymus, thyroid, bone marrow, and liverof rats exposed to the 10 ppb diet, but increased frequencyof mild changes was observed in most of these tissues at the1.0 ppb level. Based on the above data, the no adverse effectlevel was judged to be 0.1 ppb in the diet or 0.01 µg/kgbody wt/day.     

Effects of Subchronic Exposure of Rats to 2-Methoxyethanol or 2-Butoxyethanol: Thymic Atrophy and Immunotoxicity

Effects of Subchronic Exposure of Rats to 2-Methoxyethanol and2-Butoxyethanol: Thymic Atrophy and Immunotoxicity. Exon, J.H., Mather, G. G., Bussiere, J. L., Olson, D. P., and Talcott,P. A. (1991) Fundam. Appl Toxicol. 16, 830–840. Male Sprague–Dawleyrats were exposed to either 2000 or 6000 ppm of 2-methoxyethanol(ME) or 2-butoxyethanol (BE) and females were exposed to either1600 or 4800 ppm of these compounds in the drinking water for21 days. Body weights were decreased in male rats exposed tothe high doses of both chemicals, while body weights of femalesexposed to either dose of BE were decreased. Male and femalerats exposed to either concentration of ME had a dose-relatedreduction in thymus weights. Testis weight was significantlylower in male rats exposed to the high dose of ME. Dose-relatedincreases in natural killer (NK) cell cytotoxic activities anddecreases in specific antibody production were observed in allrats treated with ME. Rats exposed to the low dose of BE alsohad enhanced NK cell activity. Splenocyte production of interferon-was decreased in male rats exposed to either dose of ME andin females treated with the high dose of ME. Spleen cell numberswere reduced in males exposed to the high dose of ME and femalesgiven either dose of ME. It appears that the immune system isa sensitive target of ME but not BE. The effects of ME on immunefunction differ depending on the immune parameter assessed.Enhanced NK cell activity may partially explain the observationsof others that certain glycol ethers have antitumor effectsin vivo.     

Subacute oral toxicity of 2-butyne-1,4-diol in rats.

2-Butyne-1,4-diol was given to male and female Wistar Imp:DAK rats by oral gavage for 28 consecutive days in daily doses of 1, 10 or 50 mg kg-1 day-1. After 28 days all animals were necropsied. Blood samples were obtained and selected organs were weighed and prepared for histological examination. Treatment-related effects in the high-dose group consisted of: fatal cases in both sexes; depressed body weight gain in males; increase of absolute and/or relative weights of liver and kidneys in both sexes; decreased red blood cell count, haematocrit value and haemoglobin concentration in female rats and elevated reticulocyte count and leukocyte count in both sexes; increased total serum protein content in females, elevated glucose concentration in males and higher activity of sorbitol dehydrogenase in both sexes; and histopathological evidence of hepatotoxicity and nephrotoxicity in decedents, and hepatic and splenic changes in survivors. Minor hepatic, splenic and erythrocytic changes were also found in some females given the middle dose. The dose of 1 mg kg-1 day-1 was considered to be the no-observed-effect level (NOEL), and 10 mg kg-1 day-1 the lowest-observed-effect level (LOEL).     

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.     

Subchronic Inhalation of Diethylamine Vapor in Fischer-344 Rats: Organ System Toxicity

Subchronic Inhalation of Diethylamine Vapor in Fischer-344-Rats:Organ System Toxicity. LYNCH, D. W., MOORMAN, W. J., STOBER,P., LEWIS, T. R., AND IVERSON, W. O. (1986). Fwidam. Appl. Toxicol.6, 559–565. Male and female Fischer 344 (F-344) rats wereexposed at 0, 25, or 250 ppm diethylamine (DEA) vapor, 6.5 hrper day, 5 days per week, for 24 weeks in order to assess cardiacand other organ system toxicity. Scheduled sacrifices were performedfollowing 30, 60, and 120 days of exposure. During the first2 weeks of exposure, the rats exposed at 250 ppm DEA did notgain weight. After 2 weeks, however, the rate of weight gainof these rats was greater than that of controls. Nevertheless,mean body weights for both sexes of rats exposed at 250 ppmDEA remained depressed compared to controls throughout the study.Sneezing, tearing, and reddened noses were seen in rats exposedat 250 ppm DEA. Histopathologic examinations revealed lesionsof the nasal mucosa of rats exposed at 250 ppm DEA (rats exposedat 25 ppm were not evaluated). These lesions of the respiratoryepithelium consisted of squamous metaplasia, suppurative rhinitis,and lymphoid hyperplasia. There were no pronounced treatment-relatedeffects on organ weights, hematology, or clinical chemistryindices except for blood urea nitrogen which was elevated inrats of both sexes exposed at 250 ppm DEA for 24 weeks. In contrastto the highdose animals, no treatment-related effects were observedin rats intermittently exposed at 250 ppm DEA for up to 24 weeks.No evidence of cardiotoxicity was seen in rats exposed to eitherDEA concentration for up to 24 weeks.     

Effect of Different Levels and Periods of Lead Exposure on Tissue Levels and Excretion of Lead, Zinc, and Calcium in the Rat

Effect of Different Levels and Periods of Lead Exposure on TissueLevels and Excretion of Lead, Zinc, and Calcium in the Rat.Victery, W., MILLER, C. R., ZHU, S.-Y., AND GOYER, R. A. (1987).Fundam. Appl. Toxicol. 8, 506–516. Influence of lead ontissue content and urinary excretion of lead, zinc, and calciumin rats was studied following various exposure periods. Weanlingmale rats were fed a trace mineral-sufficient diet with either0, 200, 500, or 1000 ppm lead (as acetate) in drinking waterfor 4, 8, or 12 weeks. Blood lead ranged from 40 to over 100µg/dl; kidney lead was highest at 4 weeks. Urinary leadexcretion was highest at 4 weeks and declined with longer exposure.Urinary zinc excretion correlated positively with lead excretionat the lower excretion rates but plateaued at higher lead excretionrates. After 12 weeks exposure at each lead dose employed, decreasedzinc concentration was observed in testes, bone, and brain.Plasma, erythrocyte, and kidney zinc were not affected, whilepancreas and liver zinc were slightly elevated. Urine calciumwas increased significantly only in rats exposed to 1000 ppm,possibly reflecting renal cell damage as determined by elevatedrenal calcium levels. These results indicate that lead doseis more important than exposure period for determining kidneylead levels, while urinary lead excretion rate is both doseand time dependent. Blood lead clearance values are relativelyindependent of dose and fall as exposure continues. Essentialtrace metal balance for zinc, especially, and to a lesser extentfor calcium, is affected by the dose and length of chronic leadexposure.     

Chronic toxicity and oncogenic dose-response effects of lifetime oral acrylonitrile exposure to Fischer 344 rats

Acrylonitrile (AN) was administered in the drinking water for approximately 2 years to groups of 100 male and 100 female Fischer 344 rats at nominal concentrations of 1, 3, 10, 30, and 100 ppm. Two groups, each of 100 males and 100 females, were used as untreated controls. Average daily intake was 0.1, 0.3, 0.8, 2.5 or 8.4 mg AN per kg body weight per day, respectively, for treated male rats and 0.1, 0.4, 1.3, 3.7, or 10.9 mg AN per kg per body weight per day, respectively, for dosed females. Clinical biochemistry, interim necropsies, organ weights and microscopic evaluation of tissues and organs were performed on groups of ten rats per sex per group at months 6, 12, and 18 and at study termination. Females were sacrificed in the 24th month and males were terminated after 26 months of dosing. A consistent decrease in survival, lower body weight and reduced water intake, as well as small reductions in hematological parameters, were observed in both sexes of the 100 ppm group. Elevated numbers of early deaths were observed in groups of males receiving 10 ppm AN and females receiving 30 ppm AN. Organ:body weight ratios at various study intervals were consistently elevated in the high dose group and likely were related to lower body weights. At these same intervals, mean absolute weights were either comparable to controls or only slightly elevated and few changes in weight ratios were seen when organ weights were compared with brain weights. No biochemical changes suggested a treatment-related effect. An increase in urine specific gravity in 100 ppm male rats was reflective of a decrease in liquid intake at this level. The only significant non-neoplastic finding observed histologically was a dose-related increase in hyperplasia/hyperkeratosis in squamous cells of the forestomach in male and female rats given 3 ppm and higher AN. This observation correlated with the induction of treatment-related squamous cell tumors (papillomas and carcinomas) of the forestomach seen primarily in rats at 3 ppm AN and higher. Mammary gland carcinomas were observed only in female groups. Both sexes given 10 ppm AN or more in their drinking water for their lifetime had astrocytomas of the brain/spinal cord and adenomas/carcinomas of the Zymbal's gland.     

Two-year toxicity and oncogenicity study with acrylonitrile incorporated in the drinking water of rats

Sprague-Dawley rats (80 per sex per control and 48 per sex in each treatment group) were given drinking water formulated to contain 0, 35, 100, or 300 ppm acrylonitrile (AN) for up to 2-years. An additional ten rats per sex per group were added for a 1-year interim necropsy. The equivalent doses of AN consumed were 0, 3.4, 8.5, and 21.3 mg/kg per day for males and 0, 4.4, 10.8, and 25.0 for females. Rats were closely monitored clinically with body weight, feed and water consumption measured at numerous intervals. Hematology, clinical chemistry, and urinalysis were evaluated six times. All rats were necropsied when moribund, found dead, or at scheduled termination, with extensive histopathology of all rats. Numerous adverse toxic and oncogenic effects were observed in both sexes of all AN treatment groups. Decreased water consumption, feed consumption, and concomitant body weight suppression occurred within days of study initiation and persisted throughout the study in all treatment groups. An early onset of Zymbal gland tumors in high dose male and female rats, and in the mammary gland of all treated groups of females, was detected in-life. Hematology, clinical chemistry, and urinalysis, repeatedly evaluated, were without significant biological effects, except for an increased urine specific gravity due to the rats lower water intake. Organ weights at study termination were not significantly affected. Mortality was high in all female treated groups, with no surviving male or female 300 ppm rats during the last 2 months of the study. The most significant findings in this study were detected following gross and microscopic examination of an extensive list of tissues from all rats in the study. Nontumorous and tumorous lesions were found at an increased and/or decreased rate in a number of tissues of both sexes at all treatment levels. The primary nontumorous histopathologic effects of AN exposure occurred in the forestomach and the central nervous system of rats of both sexes and involved all treatment groups. A statistically significant increased incidence of tumors in one or more dose levels of either sex occurred in the central nervous system, Zymbal gland, forestomach, tongue, small instestine, and mammary gland. A no-observed-effect level (NOEL) was not identified in this study for toxicity or oncogenicity in either sex.     

Subchronic Toxicity Studies of t-Butyl Alcohol in Rats and Mice

The purpose of this study was to evaluate the toxicity of t-butylalcohol, an important commodity chemical, an additive to unleadedgasoline, and a contaminant of drinking water. Ninety-day toxicitystudies were conducted in B6C3F1 mice and Fischer 344 (F344)rats of both sexes using dosed water. Dose levels of t-butylalcohol were 0, 0.25, 0.5, 1, 2, and 4% (w/v). Lethality wasobserved at the 4% level of both sexes and species. Weight-gaindepression was present in all dose levels of male rats; 4% femalerats; 1, 2, and 4% male mice; and 2 and 4% female mice. Waterconsumption was increased at lower dose levels in male ratsand decreased in the higher dose levels of both sexes of ratsand female mice. Clinical signs in rats were ataxia in bothsexes and hypoactivity in males. Clinical signs in mice wereataxia, abnormal posture, and hypoactivity. In rats, urine volumeswere reduced, in association with crystalluria. Gross lesionsat necropsy were urinary tract calculi, renal pelvic and ureteraldilatation, and thickening of the urinary bladder mucosa. Microscopiclesions were hyperplasia of transitional epithelia and inflammationof the urinary bladder. In male rats treated with t-butyl alcohol,microscopic renal changes were suggestive of -2/i-globulin nephropathy.No-effect levels for the urinary tract lesions were 1% in malerats and mice (803.7 mg/kg/day for the male rats and 1565.8mg/kg/day for the male mice) and 2% in female rats and mice(1451.5 mg/kg/day for the female rats and 4362.9 mg/kg/day forthe female mice). The results indicate that in rodents the urinarytract is the target organ for t-butyl alcohol toxicity, andmales are more sensitive to t-butyl alcohol toxicity than females.     

Toxicological evaluation of New Zealand deer velvet powder. Part I: acute and subchronic oral toxicity studies in rats.

Potential toxic effects of acute and subchronic dosage regimens of deer velvet powder have been assessed in rats following OECD guidelines. In the acute study, rats of both sexes were exposed to a single dose of 2 g/kg body weight. There was no mortality or other signs of toxicity during 14 days' observation. Furthermore, no significant alteration either in relative organ weights or their histology was discernible at terminal autopsy. In the 90-day subchronic study, deer velvet was administered in 1 g/kg daily doses by gavage to rats. A control group of rats received water only. There was no effect on body weight, food consumption, clinical signs, haematology and most parameters of blood chemistry including carbohydrate metabolism, liver and kidney function. No significant differences were seen between the mean organ weights of the adrenal, kidney and brain in rats treated with deer velvet and control rats. However, there was a significant difference (P<0.05) in the group mean relative liver weight (3.52 +/- 0.30 vs 3.81 +/- 0.26 g/100 g body weight) of deer velvet-treated and control male rats. The gross necropsy and pathological examination of rats treated with deer velvet did not reveal any abnormalities in tissue morphology. Based on these results, it may be concluded that rats had no deer velvet treatment-related toxicological and histopathological abnormalities at the doses administered, despite the observed minor changes in liver weight.     

Twenty-eight days repeated oral dose toxicity study of gemifloxacin in Wistar albino rats

The purpose of this study was to investigate the potential toxicity of gemifloxacin by 28-day repeated oral dose in Wistar albino rats. The test article, was administered daily by gavage to male and female rats at dose levels of 0, 50, 100, 200 mg/kg/day. At the end of treatment period, 12 rats/sex/group was sacrificed, while six extra rats/sex in the vehicle control and highest dose groups sacrificed after 14 days recovery period. During the treatment and recovery periods, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, phototoxicity, hematology, serum biochemistry, synovial fluid biochemistry, electrocardiogram (ECG), gross findings, organ weights, microscopic examination of synovial fluid, and histopathology were examined. Hematological and serum biochemical investigations revealed a dose-dependent increase in the total white blood cell (WBC), total bilirubin (T-BIL), glucose (GLU), alanine aminotransferase (ALT) and significant decreases in total protein (TP) were observed in both sexes at the same dose, at the end of treatment period, but the levels returned toward normal during the recovery period. Histopathology of talar joint showed that erosion of the articular surface of that joint in both sexes at the end of treatment period at the dose level of 200 mg/kg/day. Degenerative changes in tendinocytes were observed in Achilles tendon of both sexes at the high dose level at the end of treatment period. In histopathological study shows partial effacement of liver architecture and focal ulceration in gastric mucosa at the high dose level at the end of treatment period. Based on these results, it was concluded that 28 days repeated oral dose of gemifloxacin caused increases in the liver weight, WBC count, T-BIL, glucose level, ALT, decreasing the TP, cause chronic hepatitis and acute gastritis, erosion of the articular surface of joint and histopathologic changes in Achilles tendon in rats at the dose level of 200 mg/kg/day.     

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.     

A 90-Day Subcutaneous Toxicity and Fertility Study of a LHRH Antagonist in Rats

A 90-Day Subcutaneous Toxicity and Fertility Study of a LHRHAntagonist in Rats. SUNDARAM, K., DIDOLKAR, A. K., KEIZER-ZUCKER,A., DEJESUS, W., RIVIER, J., VALE, W., AND BARDIN, C. W. (1990).Fundam. Appl. Toxicol. 14, 734–744. [Ac-D2Nal¹,4Cl-DPhe²,D3Pal³,Arg⁵,DGlu⁶(anisole adduct),DAla¹⁰]-GnRH (Nal-Glu) is an antagonist ofLHRH and has the potential to be utilized as an antigonadalagent. A study was undertaken to evaluate the toxicologicaleffects of Nal-Glu in rats. Nal-Glu, dissolved in 5% mannitolin water containing 9 ml/liter benzyl alcohol, was administeredsubcutaneously. In subchronic studies, groups of 12 male and12 female rats received 0, 50, 250, or 1250 µg/kg bodyweight (BW) Nal-Glu for 90 days and were killed on Day 91. Additionalgroups of male and female rats were given the high dose of Nal-Glu(1250 µ/kg BW) or vehicle for either 30 or 90 days. Theirfertility was assessed by mating them with normal animals. Unlikesome other LHRH antagonists, Nal-Glu exhibited a low potencyfor causing in vitro histamine release from rat peritoneal mastcells. Furthermore, in acute In vivo studies, Nal-Glu was lessactive in the induction of peripheral edema. In the subchronicstudy, all doses of Nal-Glu were well tolerated and there wereno apparent systemic toxic effects. The pharmacological effectsof Nal-Glu were quite evident, however. Nal-Glu treatment ledto a significantly decreased body weight gain in the males anda significantly increased body weight gain in the females. Therewas a dose-dependent decrease in weights of gonads and reproductiveorgans in both the sexes. Some of the hematological and serologicalparameters were significantly different in Nal-Glu-treated animals.However, most of the values were within the normal range andare considered to be of no toxicological significance. Histopathologicalevaluations were made in the control and high-dose groups only.In the male, a seminiferous tubular degeneration and atrophyof the interstitial cells was seen. The prostate and seminalvesicles were also atrophied and the epididymides were devoidof spermatozoa. In the females, the ovaries and uteri were atrophic.The injection site of Nal-Glu-treated rats had inflammatorychanges indicative of a local irritating action of the drug.All other tissues had normal histomorphology. Both male andfemale rats became infertile when 1250 MgAg Nal-Glu was administeredfor 30 days. Normal fertility was restored 8 weeks after cessationof 90-day treatment. It is concluded that repeated administrationof Nal-Glu leads to reversible infertility in both male andfemale rats. Although it was irritating at the site of injection,Nal-Glu had no systemic toxicological effects.     

Paraquat Pharmacokinetics Using a Subcutaneous Toxic Low Dose in the Rat

Paraquat Pharmacokinetics Using a Subcutaneous Toxic Low Dosein the Rat. M. S. DEY, R. G. BREEZE, W. L. HAYTON, A. H. KARARA,AND R. I. KRIEGER. 1990. Fundam. Appl. Toxicol. 14, 208–216.The pharmacokinetics of paraquat were examined at a dose whichproduced lung disease but avoided renal damage. Following singlesc injections of l4CH3-paraquat (72 µmol/kg) in male Sprague-Dawleyrats, blood was sampled via indwelling jugular cannulas. Noncannulatedrats were exsanguinated by cardiac puncture during a 7-day testperiod. Blood, liver, kidney, lung, brain, heart, spleen, gitract, injection site, adrenals, body, urine, and feces wereanalyzed for total radioactivity. Histology of lung after 7days revealed (+1) paraquat lung disease. No evidence of renaldamage was observed. Paraquat was rapidly absorbed. Peak bloodconcentrations of 58 nmol/ml were measured at 20 min. Peak lungand kidney paraquat concentrations at 40 min were 65 and 359nmol/g, respectively. Paraquat pharmacokinetics (NONLIN) werebest described by a two-compartment open model; the mean biologicalhalf-life was 40.9 hr. Eighty-five percent of the dose was eliminatedin urine by 7 days. The body contained 79% of the remainingradioactivity. The residual radioactivity is associated withprolonged paraquat excretion and, perhaps, progressive lungdisease.     

Application of Microencapsulation for Toxicology Studies: II. Toxicity of Microencapsulated Trichloroethylene in Fischer 344 Rats

Application of Microencapsulation for Toxicology Studies. II.Toxicity of Microencapsulated Trichloroethylene in Fischer 344Rats. MELNICK, R. L., JAMESON, C. W., GOEHL, T. J., MARONPOT,R. R., COLLINS, B. J., GREENWELL, A., HARRINGTON, F. W., WILSON,R. E., TOMAS-ZEWSKI, K. E., AND AGARWAL, D. K. (1987). Fundam.Appl. Toxicol. 8, 432–442. Gelatin–sorbitol microcapsulescontaining 44.1% trichloroethylene (TCE) were prepared and mixedin NIH-07 rodent meal diet and provided at microcapsule concentrationsof 0 (untreated control group), 1.25,2.5, 5.0, or 10% (equivalentto 0, 0.55, 1.10, 2.21, or 4.41% TCE, respectively) to groupsof 10 male F344 rats for 14 days. An additional control groupreceived diets containing 5% empty capsules. For comparisons,TCE dissolved in corn oil was administered by gavage to differentgroups of 10 male rats for 14 consecutive days at dose levelsadjusted to correspond to those in the feed study. Treatment-relateddeaths occurred only in the highest dose group of the gavagestudy. Body weight gain and feed consumption were reduced inhigh-dose groups of both the feed and gavage studies. Therewas no measurable loss of TCE in feed sampled from the cagesduring the study. Dose-related increases in organ (liver andkidney) weight/body weight ratios, individual cell necrosisin the liver, and hepatic microsomal NADPH cytochrome c re-ductaseand peroxisomal palmitoyl-CoA oxidase and catalase activitieswere found in both the dosed-fed and gavage groups. Inductionof cytochrome P-450 occurred only in the dosed-feed study. Therewere no significant compound-related pathologic lesions observedin the kidneys, the only other organ examined microscopically.Differences in lethality, cytochrome P-450 levels, and inductionof microsomal or peroxisomal enzyme activities were attributedto differences in the method of dosing (gavage versus dosed-feed).The demonstration of no significant loss of TCE from the feedand of similar toxic effects produced by microencapsulated TCEvia feed and TCE in corn oil via gavage indicate that microencapsulationcan provide an excellent alternative exposure route for studyingthe oral toxicological properties of volatile chemicals, suchas TCE, in rats.