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1.
WRIGHT DOLLIS M.; HARDIN BRYAN D.; GOAD PHILLIP W.; CHRISLIP DAVID W. 《Toxicological sciences》1992,19(1):33-42
N,N-Diethyl-m-toluamide (mDET, DEET) is widely used as a topicalinsect repellent. It is the active ingredient in many consumerformulations, which usually contain 1025% mDET in analcohol base. More concentrated consumer products are also available,including some that are pure technical grade mDET. Persons livingor employed in mosquito-infested areas may have very high seasonalexposures to mDET. Because contradictory reports had been publishedon the reproductive and developmental toxicity of mDET, a seriesof studies was conducted in male and female Sprague-Dawley rats.All treatments were administered by daily subcutaneous injectionsof undiluted mDET. A dose finding study was done using 12 time-matedfemales per group treated on Gestational Days (GD) 615with 0.50, 0.62, 0.78, 0.92, or 1.2 ml mDET /kg/day. No femalessurvived 10 days of mDET dosing with 1.2 ml/kg/day. Deaths occurredin all other groups except the low dose (0.50 ml/kg/ day). Pregnantfemales treated on GD 615 with 0 or 0.30 ml/ kg/day wereused for the teratology study. Half of each group was euthanizedon GD 20: the second half was singly housed in nesting boxesand allowed to deliver litters. Live pups were counted and weighedsoon after birth on Postnatal Day (PD) 0 and again on PD 3,9, and 14. Proven fertile males were treated 5 days/week for9 weeks with 0, 0.30, 0.73, 1.15, or 1.80 ml mDET /kg/day fora male dose-finding study. Each group consisted of 20 males.No males survived the 1.80 ml/kg/day. Deaths occurred in allremaining dose groups except the 0.30 ml/kg/ day and controlgroup. Immediately following the final treatment of the maledose study, 11 males were randomly selected from the 0.30 and0.73 ml/kg/day groups. They were cohabited for 7 days with 4females per male during post-treatment Weeks 1 and 2. Half ofthe females were euthanized 1214 days after the lastday of cohabitation for a dominant lethal study; the remainingfemales were singly housed in nesting boxes and allowed to deliverlitters. Live pups were counted and weighed on PD 0 and 3. Therewas no evidence of reproductive or developmental toxicity inany of these assays, but there were signs of neuro-toxicityin treated adult male and female rats, which may relate to reportsof neurotoxicity in humans heavily exposed to mDET -containinginsect repellents, o 1992 society of Toxicology. 相似文献
2.
SCHOENIG GERALD P.; NEEPER-BRADLEY TERESA L.; FISHER LOUAN C.; HARTNAGEL RALPH E. JR. 《Toxicological sciences》1994,23(1):63-69
The potential for DEET to produce developmental toxicity wasevaluated in Charles River CD rats and New Zealand White rabbits.Rats were administered undiluted DEET by gavage on GestationalDays (gd) 615 at dosage levels of 0, 125, 250, and 750mg/kg/day. Rabbits were administered undiluted DEET by gavageon gd 618 at dosage levels of 0, 30, 100, and 325 mg/kg/day.Group sizes were 25 females per group for rats and 16 femalesper group for rabbits. Control rats and rabbits were ad ministeredcorn oil at the same dosage volumes administered in the high-doseDEET groups. In rats, maternal toxicity in the form of clinicalsigns including two deaths and depressed body weight and foodconsumption was observed at the high-dose level of 750 mg/kg/day.Rat fetal body weights per litter also were reduced at 750 mg/kg/day.In rabbits, maternal toxicity in the form of depressed bodyweight and food consumption was observed at the high-dose levelof 325 mg/kg/day. No maternal toxicity was observed at the low-or mid-dose groups for rats or rabbits. With the exception ofthe reduced fetal weights in rats at 750 mg/kg, there was noevidence of fetal toxicity, no effects on any of the gestationalparameters, nor were there any treat ment-related increasesin external, visceral, or skeletal variations or malformationsin the offspring from the rats and rabbits from these studies.1994 Society of Toxicology. 相似文献
3.
SCHOENIG GERALD P.; HARTNAGEL RALPH E. JR.; SCHARDEIN JAMES L.; VORHEES CHARLES V. 《Toxicological sciences》1993,21(3):355-365
The neurotoxic potential of N,N-diethyl-m-toluamide (DEET) wasevaluated following acute oral administration or following multigenerationplus chronic dietary administration to the rat. For the acutestudy, rats were administered undiluted DEET at dose levelsof 50, 200, or 500 mg/kg by gavage. A dose level of 500 mg/kgwas considered to be the highest practical dose that could beevaluated in this study based upon observations of overt toxicityat 500 mg/kg and mortality at 1000 mg/ kg in a dose range-findingstudy. The two measures of neurotoxicity evaluated in the acutestudy were functional observational battery (FOB) and motoractivity measurements. An apparent treatment-related effectin thermal response time (increased) was noted for both sexes1 hr after dosing at the 500 mg/kg dose level. A questionableeffect on rearing activity (decreased) also was noted at thesame dose level. For the multigeneration plus chronic dietaryadministration study, rats were administered DEET at dietaryconcentrations of 0, 500, 2000, or 5000 ppm continuously overtwo generations and then chronically for 9 months. A dietaryconcentration of 5000 ppm meets the criteria for a maximum tolerateddose (MTD) based on traditional chronic toxicology assessments.Evaluations included FOB, motor activity, discriminative acquisitionand reversal in an Mmaze, acoustic startle habituation, passiveavoidance acquisition and retention, and microscopic examinationof central and peripheral nervous tissue. The only effect thatwas considered to be possibly treatment-related was a slightincrease in exploratory locomotor activity at the 5000 ppm doselevel. Based on the results of these studies, the nervous systemdoes not appear to be a selective target when DEET is administeredto rats either as a single oral dose at high dose levels orchronically at the MTD. 相似文献
4.
Acute, subchronic, and chronic toxicity studies were conductedwith isomazole, a new (investigational) inotropic agent withsignificant vasodilator properties. When given acutely to eitheryoung adult rats or mice, the oral median lethal dose was approximately135 or 525 mg/kg, respectively. Clinical signs of toxicity wereleg weakness, hypoactivity, tremors, clonic convulsions, andataxia. Fischer 344 rats (15/sex/group) were fed diets containingisomazole in concentrations of 0, 0.03, 0.1, or 0.3% for 3 monthswith no resulting mortality or clinical signs of toxicity. Theaverage daily intake of the compound was approximately 0, 20,65, or 198 mg/kg in both sexes. Body weight gain, food consumption,and efficiency of food utilization were significantly reducedonly in males in the 198 mg/kg dose group. There were no changesof toxicological significance in any of the hematology, clinicalchemistry, or urine parameters. Isomazole produced significantincreases in hepatic p-nitroanisole O-demethylase activity andrelative liver weight primarily at the 65 and 198 mg/kg treatmentlevels. These effects were consistent with induction of thehepatic drug-metabolizing enzyme system. Histopathologic findingsconsisted of centrilobular fat deposition in the livers of 9of 15 males in the 198 mg/kg dose group, and periarteritis inthe adventitia of small and medium-sized arteries in the mesenteryin 3 of 30 and 12 of 30 animals from the 65 and 198 mg/kg dosegroups, respectively. The plasma levels of isomazole had a tendencyto drop after 90 days compared to Day 2 in all dose groups andwas more apparent in male rats. There was no accumulation ofeither isomazole or the two metabolites in the serum over the3-month period. The average daily intake of isomazole was 0,12, 30, or 76 mg/kg/day in the 6-month rat study(l0 animals/sex/group)and 0, 10, 26, or 68 mg/kg/day in the 1-year rat study (20 animals/sex/group).Qualitatively, no findings occurred in the 6-month and 1-yearstudy which differed from those in the 3-month study. 相似文献
5.
Acute Toxicity of Pesticides in Adult and Weanling Rats 总被引:4,自引:2,他引:2
Acute Toxicity of Pesticides in Adult and Weanling Rats. GAINES,T. B., AND LINDER, R. E. (1986). Fundam. Appl. Toxicol. 7, 299-308.LD50 values were determined for 57 pesticides administered bythe oral or dermal route to adult male and female Sherman rats.Thirty-six of the chemicals were also tested by the oral routein one sex of weanlings. Nine pesticides tested by the oralroute (bufencarb, cacodylic acid, dialifor, deltamethrin, dicamba,diquat, quintozene, phoxim, pyrazon) and four tested by thedermal route (bufencarb, chlordimeform, dichlofen-thion, leptophos)were more toxic to females than to males whereas famphur and2,4,5-T (oral route) were less toxic to females. Eighteen ofthe test chemicals were more toxic to the adult than to theweanling and four compounds (leptophos, methidathion, pyrazon,and sulfoxide) were more toxic to the weanling. In additionalstudies the variability of the LD50 value over a 1-year periodwas examined for two typical insecticides. Six consecutive bimonthlyoral LD50 determinations for parathion and DDT in adults ofboth sexes indicated that the LD50 values were little affectedby the time of year that the tests were done. 相似文献
6.
OKAMURA TAKEHIKO; GARLAND EMILY M.; JOHNSON LINDA S.; CANO MARTIN; JOHANSSON SONNY L.; COHEN SAMUEL M. 《Toxicological sciences》1992,18(3):425-441
Acute stomach, kidney, and bladder toxicity was evaluated inF344 rats after gastric gavage of tetraethylorthosilicate (TES)at daily doses of 0, 0.111, 0.223, and 0.333 g. Five rats ofeach sex at each dose were sacrificed after 1, 2, and 4 days.In TES-treated groups, silicate accumulated in the stomach glandsand the muscle layer of the forestomach and glandular stomach.Serum chemistries demonstrated acute onset of renal failure.In the kidneys, acute tubular necrosis, accumulation of silicates,and superficial necrotizing papillitis were observed. In therenal pelvis and bladder, there was urothelial simple hyperplasia,focal erosion of the mucosa, edema, and inflammation. Theseacute toxic changes were dose and time dependent, but significantsex differences were not observed. The microscopic changes inthe urothelium were similar to those observed following administrationof high doses of sodium saccharin to male rats in which urinarysilicate precipitate and crystals form. 相似文献
7.
目的观察紫蓝素静脉注射对大鼠产生的急性中毒反应,以评价其安全性。方法 60只大鼠随机分为紫蓝素组(700 mg.kg-1.d-1)、3%碳酸氢钠溶液组、0.9%氯化钠溶液组,各20只。记录每只大鼠毒性反应的症状及开始和消失时间,连续观察14 d。结果①紫蓝素组给药2 h后大鼠全身皮肤呈紫色,大便呈紫蓝色,尿液呈黄褐色,第5天恢复正常。整个实验过程无大鼠死亡。②紫蓝素组大鼠体质量显著低于另外两组。③第1天紫蓝素组大鼠摄食量明显低于另外两组。④紫蓝素组大鼠肾脏脏器系数显著高于另外两组。⑤紫蓝素可引起部分大鼠肾脏髓质区域不同程度增大,皮质和髓质交界区域部分肾小管扩张;个别大鼠肾盂扩张,肾小管内有大量紫蓝色沉着。结论紫蓝素大鼠静脉注射给药的最大耐受量>700 mg.kg-1.d-1,主要表现为肾脏毒性。 相似文献
8.
HALEY PATRICK J.; FINCH GREGORY L.; HOOVER MARK D.; CUDDIHY RICHARD G. 《Toxicological sciences》1990,15(4):767-778
The Acute Toxicity of Inhaled Beryllium Metal in Rats. HALEY,P. J., FINCH, G. L., HOOVER, M. D., AND CUDDIHY, R. G. (1990).Fundam. Appl. Toxicol. 15, 767778. We exposed rats onceby nose only for 50 min to a mean concentration of 800 µg/m³of beryllium metal (initial lung burden, 625 µg) to characterizethe acute toxic effects within the lung. Histological changeswithin the lung and enzyme changes within bronchoalveolar lavage(BAL) fluid were evaluated at 3, 7, 10, 14, 31, 59, 115, and171 days postexposure (dpe). Beryllium metal-exposed rats developedacute, necrotizing, hemorrhagic, exudative pneumonitis and intraalveolarfibrosis that peaked at 14 dpe. By 31 dpe, inflammatory lesionswere replaced by minimal interstitial and intraalveolar fibrosis.Necrotizing inflammation was observed again at 59 dpe whichprogressed to chronic-active inflammation by 115 dpe. This inflammationworsened progressively, as did alveolar macrophage and epithelialhyperplasia, becoming severe at 171 dpe. Low numbers of diffuselydistributed lymphocytes were also present but they were notassociated with granulomas as is observed in beryllium-induceddisease in man. Throughout the experiment, total numbers ofcells were elevated within the BAL samples due primarily toincreased numbers of neutrophils. Lymphocytes were not elevatedin BAL samples collected from beryllium-exposed rats at anytime after exposure. Lactate dehydrogenase (LDH), ß-glucuronidase,and protein levels were elevated in BAL fluid from 3 through14 dpe but returned to near normal levels by 31 dpe. LDH increasedonce again at 59 dpe and remained elevated at 171 dpe. ß-Glucuronidaseand protein levels were slightly, but not significantly, elevatedfrom 31 through 171 dpe. Results indicate that inhalation ofberyllium metal by rats results in severe, acute chemical pneumonitisthat is followed by a quiescent period of minimal inflammationand mild fibrosis. Progressive, chronic-active, fibrosing pneumonitisis observed later. Chronic beryllium lung disease of man isan immunologically mediated granulomatous lung disease, whereasberyllium-induced lung lesions in rats appear to be due to directchemical toxicity and foreign-body-type reactions. 相似文献
9.
Oral Toxicity of 1,2-Dichloropropane: Acute, Short-Term, and Long-Term Studies in Rats 总被引:1,自引:1,他引:0
BRUCKNER J. V.; MACKENZIE W. F.; RAMANATHAN R.; MURALIDHARA S.; KIM H. J.; DALLAS C. E. 《Toxicological sciences》1989,12(4):713-730
Oral Toxicity of 1,2-Dichloropropane: Acute, Short-Term, andLong-Term Studies in Rats. BRUCKNER, J. V., MACKENZIE, W. F.,RAMANATHAN, R., MURALIDHARA, S., KIM, H. J.,AND DALLAS, C. E.(1989). Fundam. Appl. Toxicol 12, 713730. The objectiveof this investigation was to characterize the acute and short-and long-term toxic potency of orally administered 1,2dichloropropane(DCP). In the acute and short-term studies, male rats of 250300g were gavaged with 0, 100,250,500, or 1000 mg DCP/kg in cornoil once daily for up to 10 consecutive days. Although ingestionof DCP caused body weight loss and CNS depression, few othertoxic effects were manifest 24 hr after a single dose of thechemical. Morphological changes were limited to liver centrilobularcells in 500 and 1000 mg/kg rats. Similarly, elevated activityof some serum enzymes cccurred only at these two highest doselevels. Hepatic nonprotein sulfhydryl (NPS) levels were decreasedand renal NPS levels increased at 24 hr. In the short-term studyresistance developed to DCP hepatotoxicity over the 10 consecutivedays of exposure, as reflected by progressively lower serumenzyme levels and by decreases in the severity and incidenceof toxic hepatitis and periportal vacuolization. Nucleolar enlargementin hepatocytes, however, was observed at all dosage levels at5 and 10 days. There were a number of manifestations of hemolyticanemia, including erythrophagocytosis in the liver, splenichemosiderosis and hyperplasia of erythropoietic elements ofthe red pulp, renal tubular cell hemosiderosis, and hyperbilirubinemia.Urinalyses and histopathology revealed no evidence of nephrotoxicity.In the long-term study, male rats initially weighing 180200g were gavaged five times weekly for up to 13 weeks with 0,100,250,500,or 750 mg DCP/kg. As over one-half the 750 mg/kg group diedwithin 10 days, the survivors were sacrificed. Histopathologicalchanges in the 750 mg/kg animals included mild hepatitis andsplenic hemosiderosis, as well as adrenal medullary vacuolizationand cortical lipidosis, testicular degeneration and a reductionin sperm, and increased number of degenerate spermatogonia inthe epididymis in some members of the group. Similar testicularand epididymal degenerative changes also were observed in some500 mg/kg animals after 13 weeks of dosing. There was a progressiveincrease in the number of deaths in the 500 mg/kg group, suchthat more than 50% were dead by 13 weeks. No deaths occurredin the 100 or 250 mg/kg groups. The DCP dosage regimen alsopduced a dose-dependent decrease in body weight gain. DCP exhibitedvery limited hepatotoxic potential and no apparent nephrotoxicpotential in the long-term study. Slight elevations in serumornithine-carbamyl transferase activity, periportal vacuolzation,and active fibroplasia in the liver were seen in the 500 mg/kg 相似文献
10.
BRUCKNER J. V.; MACKENZIE W. F.; MURALIDHARA S.; LUTHRA R.; KYLE G. M.; ACOSTA D. 《Toxicological sciences》1986,6(1):16-34
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, 1634. 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 300350g 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 200250 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 the200250-g rats than to the 300350-g rats. In thesubchronic study, rats initially 200250 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. 相似文献
11.
SAILLENFAIT A. M.; SABATE J. P.; LANGONNE I.; CEAURRIZ J. DE 《Toxicological sciences》1991,17(2):399-408
Difference in the Developmental Toxicity of Ethylenethioureaand Thm N,N'-Substituted Thiourea Derivatives in Rats. SAILLENFAIT,A. M., SABATE, J. P., LANGONNE, I., AND DE CUURRIG J. (1991).Fundam. Appl Toxicol 17, 399408. Sprague-Dawley ratswere administered ethylenethiourea (ETU), 1,3-dimethyl-2-thiourea(DMT), 1,3-dibutyl-2-thiourea (DBT), or 1,3-diphenyl-2-thiourea(DPT) by gavage from Days 6 to 20 of gestation. Daily dosagelevels (mg/kg/day) were ETU at 0, 15, 25 and 35; DMT at 0, 15,25, 50, 100, and 200; DBT at 0, 15,25, 50, 100, and 200; andDPT at 0,25, 50, 100, and 200. There was evidence of maternaltoxlcity at all doses of DMT and at doses 50 mg DBT/kg/day.DPT was embryolethal at 200 mg/kg/day. Fetotoxicity was observedat doses 15 mg DMT/kg/day, 15 mg DBT/kg/day, and 100 mg DPT/kg/day.ETU was the only chemical tested that proved to be teratogenic. 相似文献
12.
Dimethylethanolamine: Acute, 2-Week, and 13-Week Inhalation Toxicity Studies in Rats 总被引:1,自引:0,他引:1
KLONNE DENNIS R.; DODD DAROL E.; PRITTS IRVIN M.; NACHREINER DONALD J.; FOWLER EDWARD H.; TROUP CATHERINE M.; HOMAN ELTON R.; BALLANTYNE BRYAN 《Toxicological sciences》1987,9(3):512-521
Dimethylethanolamine (DMEA) is a volatile, water-soluble aminethat has applications in the chemical and pharmaceutical industries.These studies evaluated the acute and subchronic inhalationtoxicity of DMEA. Acute (4-hr) exposures of Wistar rats to DMEAvapor resulted in an LC5O value (95% confidence limits) of 1641(8623125)ppm. Clinical signs of nasal and ocular irritation, respiratorydistress, and body weight loss were observed in rats exposedto 1668 ppm DMEA and higher. In the 2-week study, F-344 ratsexposed to 98, 288, or 586 ppm DMEA for 9 days (6 hr/day) duringan 11-day period also exhibited signs of respiratory and ocularirritation (except the 98 ppm group). All animals of the 586ppm group and 4 of 15 male rats of the 288 ppm group died. Bodyweight values for the 288 ppm group were reduced to about 75%of preexposure values, while the 98 ppm group gained 35% lessweight than controls. Statistically significant differencesin clinical pathology parameters (288 ppm group) and in organweight values (288 and 98 ppm groups) probably resulted fromthe decreased food consumption and not from specific targetorgan toxicity. In the groups evaluated histologically (the98 and 288 ppm groups) the eye and nasal mucosa were the primarytarget organs. In the 13-week subchronic study, F-344 rats wereexposed to 0, 8, 24, or 76 ppm DMEA for 6 hr/day, 5 days/weekfor 13 weeks. The principal exposure-related changes were transientcorneal opacity in the 24 and 76 ppm groups; decreased bodyweight gain for the 76 ppm group; and histopathologic lesionsof the respiratory and olfactory epithelium of the anteriornasal cavity of the 76 ppm group and of the eye of several 76ppm group females. Rats maintained for a 5-week recovery periodonly exhibited histological lesions of the nasal tissue, withthe lesions being decreased in incidence and severity. DMEAacts primarily as an ocular and upper respiratory tract irritantand toxicant at vapor concentrations of 76 ppm, while 24 ppmor less produced no biologically significant toxicity in rats.Thus, 24 ppm was considered to be the no-observable-effect level. 相似文献
13.
An-Shoei Yang Tung-Chuan Chiang Fu-Fa Hsu Mei-Hsiu Liao Lie-Hang Shen 《Drug and chemical toxicology》2013,36(4):529-533
S-3-iodo-N-(1-ethyl-2-pyrrolidinyl)methyl-2-hydroxy-6-methoxybenzamide (IBZM) is one of the several benzamide derivatives showing a high affinity for the central nervous system (CNS) D2 dopamine receptor. Carrier-free [123I]IBZM is potentially useful as a nuclear medicine imaging agent for investigating the CNS D2 dopamine receptor in humans. This study describes the acute toxicity of IBZM and S-N-(1-ethyl-2-pyrrolidinyl)methyl-2-hydroxy-6-methoxybenzamide (BZM) in the rats. Treated rats were administered with IBZM at dose levels of 1 and 5 μg/kg and BZM at dose levels of 250 and 1250 μg/kg with dose volumes of 1 and 5 mL/kg. The control rats were administered 5 mL/kg of vehicle control. The rats were observed for 14 days. Observations included general demeanor, clinical signs, mortality, body weights/total body weight gains, and gross necropsy findings. None of the animals died during the 14-day study period. In female rats, the body weight gained at the first week of BZM treatment at a dose level of 1250 μg/kg and the total body weight gains of both IBZM treated groups were significantly higher than the control group (p < 0.05). 相似文献
14.
Masato Okamoto Taizo Kita Hirotsugu Okuda Takeshi Tanaka Toshikatsu Nakashima 《Basic & clinical pharmacology & toxicology》1994,75(1):1-6
Abstract: Acute toxicity of nicotine was examined in old (24 months) and young (6 weeks) Wistar rats. There were no significant age differences in the mortality and convulsive responses induced by an intraperitoneal injection of nicotine (24.5 mg/kg). The lethal nicotine levels in blood and cortex and the latent period to death in old rats were larger than those in young rats. Cortical and blood nicotine levels 15 min. after the nicotine injection in old rats were also higher than those in young rats. Nicotine significantly increased dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid levels in striatum and hippocampus in young rats, but not those in old rats. Moreover, nicotine-induced elevations in blood levels of corticosterone in old rats were also less than those in young rats. On the other hand, the cytochrome P-450 content, the nicotine oxidase activity and the flavin-containing monooxygenase activity in liver showed age-related decreases in the young, the middle-aged (12 months) and the old rats. These results indicate that the acute toxicity of nicotine in old rats reflects the decreases in hepatic nicotine metabolism and in brain sensitivity to nicotine. 相似文献
15.
Fengying Sun Zhengxing Su Cheng Sui Chao Zhang Lijia Yuan Qingfan Meng Lirong Teng Youxin Li 《Basic & clinical pharmacology & toxicology》2010,107(2):656-662
Abstract: The objective of this study was to investigate the acute toxicity, pharmacokinetics and pharmacodynamics of paliperidone derivatives (PDs) compared with paliperidone and risperidone. The i.g. LD50 and i.v. maximum tolerated doses of PD1, PD5 and PD6 were greater than those of paliperidone and risperidone in mice. Pharmacokinetic study showed that PDs were quickly metabolized to paliperidone to take effect in the treatment of schizophrenia in rats after i.g. administration. Only traces of the parent substances were found. Pharmacodynamic study showed that PDs significantly reduced MK‐801‐induced hyperlocomotion in mice. The electrocardiogram (ECG) was recorded at 0, 5, 10, 15, 20, 25, 30, 45 and 60 min. in anaesthetized rats after i.v. injection of 0.21, 0.59, 1.69 μmol/kg drugs. Heart rate reduction had a linear relation with dose after i.v. injection of PDs, paliperidone and risperidone. No significant change in the ECG parameters was found in all groups after administration of the low dose. Although the reductions in heart rate and the corrected QT interval (QTc) were observed in all drugs at the high dose, PD5 and PD6 were associated with smaller effects on the ECG parameters than other compounds, including paliperidone and risperidone. Therefore, PD5 and PD6 could be potential candidates for the treatment of schizophrenia. 相似文献
16.
Absorption, Metabolism, and Excretion of N,N-Diethyl-m-toluamide Following Dermal Application to Human Volunteers 总被引:1,自引:0,他引:1
SELIM SAMI; HARTNAGEL RALPH E. JR.; OSIMITZ THOMAS G.; GABRIEL KARL L.; SCHOENIG GERALD P. 《Toxicological sciences》1995,25(1):95-100
The absorption, metabolism, and excretion of N,N-diethyl-m-toluamide(DEET) in male human volunteers following dermal applicationof |14C|DEET was studied. DEET was applied to two groups ofsix volunteers either as the undiluted technical grade materialor as a 15% solution in ethanol. The material was applied overa 4 x 6-cm area on the volar surface of the forearm and wasleft in contact with the skin for 8 hr, then rinsed off theskin. Application sites also were tape stripped at 1, 23, and45 hr after rinsing. Serial blood samples and all urine andfeces were collected for 5 days after application. Aliquotsof these materials were analyzed for total radioactivity inorder to define absorption and excretion patterns. Urine samplesalso were analyzed by HPLC to characterize the metabolic profileand/or to identify metabolites. Absorption of DEET as evidencedby plasma radioactivity occurred within 2 hr after dose application.Elimination of radioactivity from plasma was rapid and quantifiablelevels of radioactivity were observed in plasma for only 4 hrafter the end of the 8-hr exposure period. Urine was the principalroute of excretion of radioactivity and accounted for an averageof 5.61 and 8.33/ of the applied dose in the undiluted DEETand 15/ DEET in ethanol groups, respectively. Excretion of radioactivityin the feces was less than 0.08/ of the applied dose in bothgroups. DEET did not accumulate in the superficial layers ofthe skin as evidenced by low amounts of radioactivity in thetape strippings. The major fraction of the applied radioactivitywas recovered in the skin rinses. Absorbed DEET was completelymetabolized and six major metabolites were observed in urine.Two major urinary metabolites tenta tively were identified.Based upon the percentage of applied dose recovered in the excreta,dermal absorption of DEET ranged from 3 to 8% with a mean of5.6/ in the volunteers applied undiluted technical grade DEET.The corresponding values for the volunteers applied 15/ DEETin ethanol were 4 to 14/ and 8.4/, respectively. 相似文献
17.
Hkan Mrnstad 《Basic & clinical pharmacology & toxicology》1975,37(5):425-428
Abstract: The 24 hour LD50 dose for intraperitoneally injected sodium fluoride was determined in developing and young adult rats of both sexes. The developing animals tolerated two and a half times as much fluoride as the young adults when expressed as mg FVkg of body weight. There were no significant differences between the two sexes. The 24 hour LD50 values were: 4 day old females 45 (39–52), males 40 (34–48); 20 day old females 47 (39–57), males 51 (47–55); 60 day old females 30 (21–43), males 28 (17–42); 90 day old females 21 (17–26), males 20 (17–24) mg F-/kg of body weight. 相似文献
18.
Comparison of Systemic Toxicity between Botulinum Toxin Subtypes A1 and A2 in Mice and Rats
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Yasushi Torii Yoshitaka Goto Shinji Nakahira Shunji Kozaki Ryuji Kaji Akihiro Ginnaga 《Basic & clinical pharmacology & toxicology》2015,116(6):524-528
The adverse events caused by botulinum toxin type A (subtype A1) product, thought to be after‐effects of toxin diffusion after high‐dose administration, have become serious issues. A preparation showing less diffusion in the body than existing drugs has been sought. We have attempted to produce neurotoxin derived from subtype A2 (A2NTX) with an amino acid sequence different from that of neurotoxin derived from subtype A1 (A1NTX). In this study, to investigate whether A2NTX has the potential to resolve these issues, we compared the safety of A2NTX, a progenitor toxin derived from subtype A1 (A1 progenitor toxin) and A1NTX employing the intramuscular lethal dose 50% (im LD50) in mice and rats and the compound muscle action potential (CMAP) in rats. Mouse im LD50 values for A1 progenitor toxin and A2NTX were 93 and 166 U/kg, respectively, and the rat im LD50 values were 117 and 153 U/kg, respectively. In the rat CMAP test, the dose on the contralateral side, which caused a 50% reduction in the CMAP amplitude, that is, CMAP‐TD50, was calculated as 19.0, 16.6 and 28.7 U/kg for A1 progenitor toxin, A1NTX and A2NTX, respectively. The results indicate that A2NTX is safer than A1 progenitor toxin and A1NTX. 相似文献
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NAIR R. S.; AULETTA C. S.; SCHROEDER R. E.; JOHANNSEN F. R. 《Toxicological sciences》1990,15(3):607-621
Chronic Toxicity, Oncogenic Potential, and Reproductive Toxicityof p-Nitroaniline in Rats. NAIR, R. S., AULETTA, C. S., SCHROEDER,R. E., AND JOHANNSEN, F. R. (1990). Fundam. Appl. Toxicol 15,607621. Dose levels for these studies were selected mainlyon the basis of subchronic studies, although consideration wasalso given to workplace exposure levels and proposed mechanismof tumor formation with structurally similar compounds. Forthe chronic study, groups of 60 male and 60 female SpragueDawleyCD (Registered Trademark of Charles River Breeding Laboratories,Portage, Ml) rats were given 0, 0.25, 1.5, or 9.0 mg/kg/daypara-nitroaniline (PNA) by gavage in corn oil for a period of2 years. Parameters monitored included clinical observations,ophthalmoscopic exams, body weights, food consumption, hematology,clinical chemistry, and urinalysis at regular intervals throughoutthe study. All gross lesions and over 40 tissues were examinedhistologically for all control and high-dosage-level animals.Gross lesions, spleens, and livers of low- and mid-dosage groupswere also examined histologically. For the reproduction study,groups of 15 male and 30 female rats, designated as F0 generation,were given PNA at the same levels as the chronic study for 14weeks prior to mating and during mating, gestation, and lactation.Selected groups of 15 male and 30 female rats of the F1 generationreceived the same dose of PNA for 18 weeks prior to mating andduring mating, gestation, and lactation. F2 pups were observedthrough weaning at which time they were euthanized. Observationsmade during the study included body weights, food consumption,mating and fertility indices, pup and litter survival indices,and histopathology of selected tissues. In the chronic study,except for a slight decrease in survival of high-dose male ratslate in the study, survival in all treated groups was comparableto controls. Blood methemoglobin levels were elevated in themid- and high-dosage groups, while slight anemia was observedin the high-dosage group also. Spleen weights were significantlyincreased in the high-dosage groups. An accumulation of brownpigment was observed in the cytoplasm of the sinusoidal macrophagesor littoral cells of the liver and in the reticuloendothelialcells of the spleen. No treatment-related increase in tumorincidence was observed. In the reproduction study, no consistentpattern of effect from treatment between the F0 and F1 generationwas seen in mating, pregnancy, or fertility indices. Thus, administrationof PNA at levels which produced significant methemoglobin-emiaand low-level anemia in the rat and histological changes inthe spleen produced no tumors or reproducible effects on reproductiveperformance. 相似文献
20.
Assessment of the Developmental Toxicity, Metabolism, and Placental Transfer of N,N-Dimethylformamide Administered to Pregnant Rats 总被引:2,自引:0,他引:2
Saillenfait A. M.; Payan J. P.; Beydon D.; Fabry J. P.; Langonne I.; Sabate J. P.; Gallissot F. 《Toxicological sciences》1997,39(1):33-43
This study evaluates the developmental toxicity and placentaland milk transfer of N,N-dimethylformamide (DMF) in rats. Sprague-Dawleyrats were given 0, 50, 100, 200, and 300 mg DMF/kg/day, by gavage,on Gestational Days (GD) 6 through 20. Maternal toxicity wasindicated by depressions in weight gain and food consumptionat doses 100 mg/kg. Fetal toxicity was indicated by decreasedfetal body weight at doses 100 mg/kg, and by increased incidencesof two skeletal variations (absent or poorly ossified supraoccipitaland sternebrae) at 200 and 300 mg/kg. Thus, the maternal anddevelopmental no-observed-adverse-effect level was 50 mg/kg/day.The time course disposition of [14C]DMF was examined over a48-hr period in GD12- and GD18-pregnant rats after a singleoral dose of 100 mg [14C]DMF/kg Peak concentrations of radiocarbonoccurred within 1 hr after dosing. Embryonic (GD 12) and fetal(GD18) tissues accounted for 0.15 and 6% of the administereddose, respectively. Levels of radiocarbon in embryonic and fetaltissues were equal or slightly less than in maternal plasmaup to 8 and 24 hr, respectively, and higher thereafter. HPLCanalysis performed at intervals from 1 to 8 hr on GD12 and 124hr on GD18 indicated that unchanged DMF and metabolites werereadily transferred to the embryonic and fetal tissues, wheretheir levels were generally equal to those in maternal plasma.The parent compound accounted for most of the radioactivityuntil 48 hr and then decreased. N-Hydroxymethyl-N-methylformamide(HMMF) and N-methylformamide (NMF) were the predominent metabolitesand increased with time. Much lower concentrations were foundfor formamide and N-acetyl-S-(N-methylcarbamoyl)cysteine. Transferof radioactivity into milk was studied in dams given a singleoral administration of 100 mg [14C]DMF on Lactation Day 14.DMF, HMMF, and NMF were found in the milk at concentrationsequal to those in plasma. 相似文献