氰戊菊酯和甲苯对大鼠肺泡巨噬细胞联合毒性的形态学研究

以电镜和立体学测量相结合的方法,观察了氰戊菊酯与甲苯对大鼠肺泡巨噬细胞(PMφ)联合毒性的形态学变化。结果发现,二化合物在对PMφ的微丝、微管、线粒体、溶酶体和PMφ整体形态的超微结构毒性上均存在一定拮抗作用。     

浙贝母对甲状腺功能亢进模型鼠的保护作用研究

目的:研究浙贝母对甲状腺功能亢进(甲亢)模型鼠的保护作用。方法:采用甲状腺素复制甲亢模型鼠,并观察浙贝母对甲亢模型鼠三碘甲状腺素原氨酸(T3)、四碘甲状腺素原氨酸(T4)、环磷酸腺苷(cAMP)、环磷酸鸟苷(cGMP)以及耐缺氧能力的影响。结果:浙贝母具有显著降低甲亢模型大鼠T3、T4、cAMP的作用,且能显著提高甲亢模型小鼠的耐缺氧能力。结论:浙贝母具有较好对抗甲亢的作用。     

氰戊菊酯对大鼠外周神经,肌肉电生理及神经超微结构影响的研究

氰戊菊酯可使大鼠坐骨神经运动传导潜速率下降,股外侧肌肌电图中,轻收缩电位波幅下降,时限延长,重收缩电位波幅下降。严重中毒大鼠后期,在股外侧肌还可记录到神经性自发重复放电波。上述结果为临床FV中毒诊断提供了一定的实验依据。在形态上,FV可使坐骨神经内轴突髓鞘轻微变性水肿。     

杨梅多酚对大、小鼠血小板损伤的保护作用

目的 :研究杨梅多酚对大、小白鼠在化学和辐射损伤中血小板减少的影响。方法 :采用环磷酰胺和 60Co-γ射线致大、小白鼠血小板下降动物模型。结果 :杨梅多酚能提高血小板计数 ,在杨梅多酚组和病理模型对照组之间有显著性差异 (P<0.01) ;并能保护血液的止血功能。结论 :杨梅多酚对血小板损伤可起到治疗作用。     

Lack of Neuropathologic Consequences of Repeated Dermal Exposure to 2,4-Dichlorophenoxyacetic Acid in Rats

Lack of Neuropathologic Consequences of Repeated Dermal Exposureto 2,4-Dichlorophen- oxyacetic Acid in Rats. MATTSSON, J. L.,JOHNSON, K. A., AND ALBEE, R. R. (1986). Fundam. Appl. Toxicol.6, 175–181. A 24% aqueous solution of the dimethylaminesalt of 2,4-dichioro-phenoxyacetic acid (2,4-D amine) was appliedto the legs of male Fischer 344 rats 2 hr/day, 5 days/week,for 2 weeks. Because this concentration caused severe skin lesions,a second group of rats was treated similarly with a 12% solutionof 2,4-D amine for 3 weeks. The 12% solution caused only mildskin changes. The plasma 2,4-D content, at the end of exposure,was nearly five times greater in the rats exposed to the 24%solution than to the 12% solution (323 vs 66.5 µg/ml).The severe skin changes probably facilitated absorption in therats treated with the 24% solution. Rats treated with eitherconcentration weighed less than controls. Although histologicallynormal, kidneys of treated rats weighed more than controls.The increased kidney weights were attributed to physiologicaladaptation due to active excretion of absorbed 2,4-D. Lightmicroscopic examination of tissues, other than skin, revealedno differences between treated and control animals. There wereno nervous system pathologic changes although the rats wereexposed to sufficient amounts of 2,4-D amine to cause severeskin lesions, decreased body weights, and increased kidney weights.     

氰戊菊酯和甲苯对大鼠肺泡巨噬细胞联合毒性研究

氰戊菊酯和甲苯以4:5混合时,对大鼠肺泡巨噬细胞总数、FCR活性、吞噬杀菌功能及其在电镜下的形态和支气管肺泡灌洗液中的乳酸脱氨酶和酸性磷酸酶活性的毒效应上均存在明显的拮抗作用。     

复方苦参酊剂对炎症小鼠和大鼠的抗炎作用研究

摘 要 目的：考察复方苦参酊剂对炎症小鼠和大鼠的抗炎作用,为该药的新药申报奠定基础。 方法: 动物随机分为空白对照组、复方苦参酊剂低、中、高剂量组(33,66,110 mg·ml-1)、消肿止痛酊阳性药物组,分别采用二甲苯致小鼠耳廓肿胀模型、小鼠腹腔通透性模型、大鼠棉球肉芽肿增生模型、角叉菜胶致大鼠足趾肿胀模型,以耳廓肿胀度抑制率、毛细血管通透性、棉球肉芽肿增生、足趾肿胀度为检测指标,比较复方苦参酊剂低、中、高剂量组和空白对照组及阳性药组的差异。 结果: 与空白对照组相比,复方苦参酊剂高剂量组能显著降低小鼠耳肿胀度、降低小鼠腹腔灌洗液吸光度值、减少大鼠棉球肉芽肿的增生、抑制大鼠角叉菜胶引起的足跖肿胀（P＜0.05）。 结论: 复方苦参酊剂对炎症小鼠和大鼠均具有抗炎作用。     

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.     

Developmental Toxicity of Bromoxynil in Mice and Rats

Developmental Toxicity of Bromoxynil in Mice and Rats. ROGERS,J. M., FRANCIS, B. M., BARBEE B. D., AND CHERNOFF, N. (1991).Fundam. Appl. Toxicol 17, 442–447. The developmental toxicityof the wide-spectrum herbicide bromoxynil (bromoxynil phenol;3,5-dibromo-4-hydroxyphenyl cyanide) was evaluated in Sprague-Dawleyrats and Swiss-Webster mice, and the developmental toxicityof its octanoate ester (2,6-dibromo-4-cyanophenyl octanoate)was evaluated in Sprague-Dawley rats. Animals were treated fromDay 6 to Day 15 of gestation [presence of sperm or semen plug= 0 of gestation]. The doses administered were as follows: bromoxynilphenol in the mouse, 342, 114, and 38 µmol/kg/day; bromoxynilphenol and bromoxynil octanoate in the rat, 54, 18, and 6 µmol/kg/day.Some animals were killed on selected days during treatment formeasurement of organ weights sensitive to stress. In mice treatedwith bromoxynil phenol, maternal mortality was noted at 114and 342 µmol/kg/day, but surviving females gained weightnormally. Liver to body weight ratios increased with increasingdose, but no consistent effect was seen on adrenal, thymus,or spleen weights. Fetuses of mice treated with the highestdose of bromoxynil phenol were of lower weight and had a higherincidence of supernumerary ribs than controls. In rats, bromoxynilphenol and its octanoate ester at the highest doses used causedno mortality but resulted in only transient decreases in maternalweight gain and significantly increased the liver to body weightratio, but did not significantly alter adrenal, thymus, or spleenweight in the dams. No significant maternal effects were seenat lower doses. The highest doses of both compounds increasedthe incidence of supernumerary ribs in fetuses of treated rats,but did not induce other anomalies. Fetal weight was reducedin rats at the highest dose of bromoxynil octanoate, but noeffects on fetal weight were seen with bromoxynil phenol. Bromoxynilexposure produced a high incidence of supernumerary ribs atmaternally toxic doses in both rats and mice, although no evidenceof maternal stress per se was found. The mechanism and significanceof this effect require further study.     

Reproductive Effects of Theophylline in Mice and Rats

Reproductive Effects of Theophylline in Mice and Rats. MORRISSEY,R. E., COLLINS, J. J., LAMB, J. C, IV, MANUS, A. G., AND GULATI.D. K. (1988). Fundam Appl. Toxtcol. 10, 525–536. Theophyllinewas administered by gavage in 13-week studies to B6C3F, mice(0, 75, 150, 300 mg/kg/day) and F344 rats (0, 37.5, 75, 150mg/kg/day) with significant reductions in male mouse terminalbody and testicular weights. Male rats also displayed reducedtesticular weight, as well as nonsignificant but dose-relateddecreases in body weight. There was a significant but non-dose-relateddecrease in female mouse body weight. In parallel studies ofB6C3F, mice and F344 rats, theophylline administered in thediet (0, 0.1, 0.2, 0.4%) produced significantly decreased terminalbody weights in male and female mice, but not rats. In rats,cauda epididymis weight was reduced at the high dose comparedto the control group, and there was an increase in abnormalsperm. These studies were followed by continuous breeding reproductiveassays in CD-I mice in which theophylline was administered infeed (0.0, 0.075, 0.15, and 0.30% calculated doses of 0, 125,265, and 530 mg/kg/day, respectively) to breeding pairs for14 weeks. There was a dose-dependent decrease in the numberof live pups produced per litter, a significant decrease inthe number of litters produced per pair (0.30%) and in the adjustedlive pup weight (0.30%), a decrease in the percentage of pupsborn alive (0.15 and 0.30%), and an increase in the number ofdays needed to produce each litter (0.30%). After 19 weeks ofcontinuous treatment at 0.307%, a crossover mating trial indicatedthat females and males were adversely affected by theophylline,as judged by the decreased percentage of pups born alive, thedecreased live pup weight, and the decreased number of livepups per litter relative to matings within the control group,but the effects in females were more extensive. Based on otherstudies, there is a suggestion that the observed changes infertility may be partially attributed to embryotoxicity.     

野马追对大、小鼠实验性高脂血症的防治作用

目的探讨野马追提取液对大、小鼠实验性高脂血症的防治作用。方法将大鼠和小鼠各60只分别随机分为大、小鼠空白对照组、高脂模型组、阳性对照组及野马追提取液高、中、低剂量组。除空白对照组外,小鼠各组给予相应的药物30d后腹腔注射75%蛋黄乳,大鼠各组喂高脂饲料同时给予相应的药物30d。各组均于末次给药后采血,测血清胆固醇、甘油三酯及高、低密度脂蛋白胆固醇(HDL-C、LDL-C)含量。结果野马追能明显降低实验性血清胆固醇、甘油三酯及LDL-C水平,并明显升高HDL-C水平。结论野马追对实验性大、小鼠高脂血症有明显防治作用。     

Prechronic Toxicity of o-Benzyl-p-chlorophenol in Rats and Mice

Prechronic Toxicity of o-Benzyl-p-chlorophenol in Rats and Mice.BIRNBAUM, L.S., DESKIN, R., GRUMBEIN, S.L., KURTZ, P., FOWLER,K.L., AND PETERS, A.C. (1986). Fundam. Appl. Toxicol. 7, 615-625.o-Benzyl-p-chlorophenol (BCP) is a major household and industrialgermicide. Its prechronic toxicity was evaluated in male andfemale F344 rats and B6C3F1 mice. Treatment was by gavage incorn oil. BCP was slightly toxic after acute oral exposure,with high mortality at 4000 and 2000 mg/kg in rats and mice.Exposure to 12 oral doses of BCP at 1000, 500, 250, 125, 62.5,or 0 mg/kg body wt resulted in dose-related cecal dilatationand nephrosis in both rats and mice. Doses for the subchronicstudies were based on the results of the 2-week studies. Tenanimals were treated per dose per sex. Rats received 480, 240,120, 60, 30, or 0 mg BCP/kg. Mice were treated with 1000, 800,650, 500, or 0 mg BCP/kg. Animals were dosed 5 days per weekfor 13 weeks. Clinical signs related to dosing included urogenitalstaining in rats and rough/oily haircoats in mice. No effectson growth rate were seen in rats, but growth was retarded atthe higher doses used in mice. Kidney weights increased in rats,and liver weights increased in mice. A decrease in thymus weightaccompanied by a depletion in thymic lymphocytes (rats) or thymicnecrosis (mice) occurred only in a high-dose animals. In bothspecies, the kidney was the major target organ. In rats, therewas an increase in incidence and severity of nephropathy andrenal tubule regeneration. The lesions in mice primarily involvedthe renal cortex and included necrosis, casts, chronic inflammation,and regeneration of the renal tubules. No effects of BCP exposurein rats were seen in a broad spectrum of hematology or urinalysisparameters. Minor decreases in blood urea nitrogen, creatinine,and alanine amino transferase were detected in male and femalerats. There were no biologically significant neurobehavioraleffects in rats or immunotoxic effects in mice due to exposureto BCP. Thus, the kidney is the major target Organ for BCP.     

Immunotoxicological Insignificance of Fenitrothion in Mice and Rats

Fenitrothion was administered orally to mice or rats in dailydoses of up to of the LD50 for 14 days, and numbers of splenic plaque-forming cells against sheep redblood cells (SRBC-PFC), one of the most common immune parameters,were measured. Splenic SRBC-PFC number was suppressed by fenitrothiononly in rats which received 30 mg/kg body weight (bw) of thecompound. Other immune parameters, including the arthus reaction,delayed-type hypersensitivity, and activities of macrophagesand natural killer cells in rats, were not influenced by fenitrothion.Adrenal hyperfunction manifesting as increased organ weightand elevated plasma corticosterone level was noted along withstrong cholinergic signs in rats which received 30 mg/kg bwof fenitrothion. At lower doses such as 3 or 0.3 mg/kg bw offenitrothion, rats had no strong cholinergic signs, adrenalhyperfunction, or evidence of immunosuppression despite significantsuppression of systemic cholinesterase (ChE) activities. Inmice, no suppression of SRBC-PFC number or mixed lymphocytereaction was noted even at the highest dose (40 mg/kg bw) offenitrothion, at which significant suppression of systemic ChEactivities but no cholinergic signs were noted. These findingsstrongly suggest that the im-munosuppressive effect of fenitrothionnoted in rats was due to systemic, potent cholinergic stressand that fenitrothion has no immunotoxicity in mice and rats.     

Natural Products: Anti-hyperalgesic Effect of an Ethanolic Extract of Propolis in Mice and Rats

Propolis, or bee glue, which contains a complex mixture of secondary metabolites, has long been used in many countries for the management of several diseases. The purpose of this study was to evaluate, by means of several pharmacological models, the anti-hyperalgesic effect of propolis collected in the south of Brazil. The abdominal constrictions induced in mice by intraperitoneal injection of acetic acid (0.6%), kaolin (50 mg kg^?1) or zymosan (40 mg kg^?1) were inhibited to different extents by an extract of propolis (1–60 mg kg^?1) administered intraperitoneally 30 min earlier; mean ID50 (concentrations resulting in 50% inhibition) values were 2.7, 10.8 and 10.7 mg kg^?1, respectively, and maximum inhibition was 58 ± 5, 57 ± 10 and 51 ± 5%, respectively. Given orally (25–200 mg kg^?1, 1 h previously) propolis also inhibited the abdominal constrictions induced by acetic acid (maximum inhibition 43 ±5%). When injected intraperitoneally (3–60 mg kg^?1, 30 min previously), propolis attenuated both the neurogenic (first phase) and inflammatory (second phase) pain responses and paw oedema caused by intraplantar injection of formalin (2.5%); maximum inhibition was 32 ±5, 43 ±6 and 19 ±2%, respectively. Oral administration of propolis (25–200 mg kg^?1, 1 h previously) inhibited both phases and reduced the oedema formation associated with the second phase of the formalin test (maximum inhibition 22±5, 33 ±6 and 26±3%) and extract of propolis (3–30 mg kg^?1 i.p. or 25–100 mg kg^?1 p.o., respectively 30 min and 1 h previously) significantly inhibited capsaicin-induced pain with maximum inhibition of 39±8 and 41 ±8%, respectively. When assessed in the Randall–Sellito test of pain, the extract of propolis (3–30 mg kg^?1, i.p., 30 min previously) significantly reversed the hyperalgesia induced by intraplantar injection of bradykinin (3 nmol per paw) in rats (P < 0.01). In contrast with morphine the extract of propolis (. 100 mg kg^?1, 30 min previously) was ineffective when assessed in the tail-flick and hot-plate thermal assays. Naloxone (5 mg kg^?1 i.p.) reversed (P < 0.01) the effect of morphine (5 mg kg^?1 s.c.) by 70 and 94% respectively in the first and second phases of the formalin test, but did not interfere with the analgesic effect of propolis (10 mg kg^?1 i.p., 30 min previously). These results show that ethanolic extract of propolis, given systemically, has significant anti-hyperalgesic action when assessed in chemical, but not thermal, models of nociception in mice and rats. Its analgesic action seems to be unrelated to release or activation of the opioid system.     

Metabolism of Prolintane in Rats and the Effect of Prolintane Metabolites on General Activities in Mice

Abstract

1. The metabolism of prolintane in vivo has been investigated in rats; the pharmacological effects in mice of the metabolites from rats and rabbits have been examined.

2. In four rats receiving [³H]prolintane (50 mg/kg, intraperitoneal) about 57% of the radioactivity was excreted in the 48 h urine.

3. A pyrrolidine ring-opened metabolite (15% dose) and p-hydroxyprolintane (5% dose) were excreted as predominant metabolites together with traces of unchanged drug and oxoprolintane.

4. The general activities (ambulation and rearing) of mice were increased significantly by p-hydroxyprolintane and (ω — 1)-hydroxyprolintane as well as prolintane. Oxoprolintane was not effective on ambulation, but partially effective on rearing. However, PPGABA showed a depressant effect in mice rather than being stimulatory.     

黄芩苷对急、慢性肝损伤模型鼠的保护作用

目的:研究黄芩苷对急、慢性肝损伤模型鼠的保护作用。方法:腹腔注射10%CCl4橄榄油溶液(0.2 ml/100 g)以复制小鼠急性肝损伤模型。50只KM小鼠随机均分为正常对照(等容生理盐水)组、模型(等容生理盐水)组与黄芩苷高、中、低剂量(1.00、0.50、0.25 g/kg)组。灌胃给药,每天1次,连续6 d,末次给药12 h后复制模型。另外,腹腔注射硫代乙酰胺(TAA,200 mg/kg),每周2次,连续12周以复制大鼠慢性肝损伤模型。50只SD大鼠随机均分为正常对照(等容生理盐水)组、模型(等容生理盐水)组与黄芩苷高、中、低剂量(0.8、0.4、0.2 g/kg)组。复制模型同时灌胃给药,每天1次连续12周。测定鼠血清与肝匀浆中丙氨酸氨基转移酶(ALT)活性,并对鼠肝组织病理学进行评级。结果:与正常对照组比较,模型组鼠血清ALT活性增强,肝组织匀浆ALT活性减弱,差异有统计学意义(P<0.01);鼠肝组织病理程度严重。与模型组比较,黄芩苷高、中、低剂量组鼠血清ALT活性减弱,肝组织匀浆ALT活性增强,差异有统计学意义(P<0.01或P<0.05);鼠肝组织病理程度有一定改善。结论:黄芩苷对急、慢性肝损伤模型鼠具有一定保护作用,其机制与调节ALT水平、改善肝组织病理程度有关。     

Developmental Toxicity Evaluation of Acrylamide in Rats and Mice

Developmental Toxicity Evaluation of Acrylamide in Rats andMice. FIELD, E. A., PRICE, C. J., SLEET, R. B., MARR, M. C,MORRISSEY, R. E., AND SCHWETZ, B. A. (1990). Fundam. Appl. Toxicol.14, 502–512. Acrylamide (ACRL), a widely used industrialchemical with neurotoxic effects, was evaluated for developmentaltoxicity. ACRL in distilled water was administered once dailyby gavage on gestational days (gd) 6–17 to mice (0, 3,15, or 45 mg/kg) and on gd 6–20 to rats (0, 2.5, 7.5,or 15 mg/kg). Following termination (gd 17, mice; gd 20, rats)fetuses were examined for external, visceral, and skeletal malformations.Maternal toxicity during treatment was observed at the highestdose as reduced body weight gain in both species and hindlimbsplaying in treated mice only. Weight gain corrected for graviduterine weight was also reduced in rats at 7.5 and 15 mg/kg/day.Embryo/fetal toxicity was not observed in rats, but fetal weightwas reduced in mice administered 45 mg/kg/day. No increase inthe incidence of malformations was observed in either species;however, the incidence of variations (predominately extra rib)increased with dose. In summary, administration of ACRL duringorganogene-sis produced maternal and developmental toxicityat 45 mg/kg/day in mice and maternal, but not developmental,toxicity at doses 7.5 mg/kg/day in rats.     

Developmental Toxicity of Boric Acid in Mice and Rats

Boric acid (BORA), an ingredient of many cosmetics, pharmaceuticals,and pesticides, was tested for developmental toxicity in timed-pregnantSwiss mice and Sprague-Dawley rats (n = 26–28/group).BORA (0, 0.1, 0.2, or 0.4% in feed) was provided throughoutgestation to attain steady-state exposure as early as possibleduring prenatal development. Average doses (mg/kg/day) were248, 452, or 1003 in mice, and 78, 163, or 330 in rats. To limitprenatal mortality, BORA (0.8% or 539 mg/kg/day) was providedto an additional group of rats on Gestational Days (GD) 6 to15 only. On GD 17 (mice) or 20 (rats), fetuses were weighedand examined for malformations (external, visceral, skeletal).Mouse dams exhibited mild renal lesions (0.1%), increased waterintake and relative kidney weight (0.4%), and decreased weightgain (0.4%) during treatment. There was a reduction of fetalbody weight (0.2%) and an increased incidence of resorptionsand malformed fetuses per litter (0.4%). Morphological changesincluded an increased incidence of short rib XIII (a malformation)and a decreased incidence of rudimentary or full rib(s) at lumbarI (an anatomical variation). Maternal rats exhibited increasedliver and kidney weights at 0.2%, altered water and/or foodintake at >0.2%, and decreased weight gain at >0.4%. Averagefetal body weight/litter was reduced at all doses. Prenatalmortality was increased only at 0.8%. The incidence of fetalmalformations was significantly increased at 0.2%. The mostfrequently observed malformations were enlarged lateral ventriclesof the brain and agenesis or shortening of rib XIII. In rats,the no-observable-adverse-effect level (NOAEL) for maternaltoxicity was 78 mg/kg (0.1%), while in mice the low dose of248 mg/kg (0.1%) approached the maternal NOAEL with mild renallesions in only 2 of 10 females. Embryo/fetal toxicity occurredin all groups of rats at 78 mg/kg (0.1%) while the NOAEL fordevelopmental toxicity in mice was 248mg/kg (0.1%). Thus developmentaltoxicity occurred below maternally toxic levels in rats as wellas in the presence of maternal toxicity in mice and rats.     

Subchronic Inhalation Toxicity of Dimethylformamide in Rats and Mice

ABSTRACT

Fisher F344 rats and B6C3F1 mice were exposed to concentrations of 0, 150, 300, 600 and 1200 ppm of dimethylformamide (DMF) for 6 hours a day, 5 days a week for 12 weeks. Detailed clinical observations were obtained weekly and body weights biweekly on all animals. Clinical chemistry and hematology evaluations were made on all rats and approximately half the mice at terminal sacrifice. Gross necropsy examinations were made on all animals. Histopathologic evaluations were conducted on selected tissues of animals of both species at all dose levels. Few overt signs of toxicity were seen in either rats or mice. There was a dose related depression in body weight gain in rats that was significant at the 1200 ppm level from the second week of study onwards. A total of 11 mice died or were sacrificed moribund during the study, 8 from the high dose and 2 from the 600 ppm dose level. Both clinical chemistry (in rats only) and gross necropsy observations, and histopathology of tissues indicate the possibility that liver may be the target in specific organ toxicity. The no-effect DMF dose was below the 150 ppm level for both rats and mice and the maximum tolerated dose was below the 600 ppm level.