肼灌胃染毒在小鼠体内的毒物动力学

小鼠灌胃7和14mg/kg肼,血中肼浓度的时相为一级吸收一空模型,而消化道中肼的累积消除过程符合非线性动力学;静脉注射7mg/kg肼呈二室模型。肼经小鼠消化道吸收入血很快,吸收率为82～85％,但经灌胃进入消化道的肼却能够被全部消除,消除灌胃剂量的一半所需时间不到3min,至1h基本被全部消除;当血中吸收相基本结束时,灌胃剂量的79～83％已从消化道中被消除,与吸收率近似。肼在小鼠体内分布极快,呈周身分布,可能有“富集”部位。肼从小鼠体内消除快,物质蓄积性弱。     

Carcinogenicity and chronic toxicity of di-2-ethylhexyl terephthalate (DEHT) following a 2-year dietary exposure in Fischer 344 rats.

The carcinogenicity and chronic toxicity potential of di-2-ethylhexyl terephthalate (DEHT) was assessed in F-344 rats (50/sex/dose) by dietary exposure for 104 weeks. Exposure levels of 0, 1500, 6000 or 12,000 ppm resulted in average daily doses of 79, 324 and 666 mg/kg/day for males and 102, 418 and 901 mg/kg/day for females. Animals were observed daily for clinical signs and detailed physical examinations were performed weekly. Body weight and food consumption were measured at scheduled intervals. During weeks 103-104, urine and blood samples were collected and analyzed. Eyes were examined during week 104 using a binocular indirect ophthalmoscope. At necropsy, organs were weighed and examined macroscopically and microscopically. No histological effects were noted in any organ at any dose and there was no increase in the incidence of any tumor types. Toxic responses were confined to lower weight gains and food conversion efficiency in males and females ingesting 6000 or 12,000 ppm. The severity of a normal geriatric degenerative retinal change was exacerbated in females exposed to 6000 or 12,000 ppm and in males exposed to 12,000 ppm. Therefore, the no-observed effect level (NOEL) for tumorigenicity was 12,000 ppm and the NOEL for chronic toxicity was 1500 ppm.     

Acute and a 28-day repeated-dose toxicity study of total flavonoids from Clinopodium chinense (Benth.) O. Ktze in mice and rats

Clinopodium chinense (Benth.) O. Ktze (Labiatae), known as ‘Duanxueliu’ in the Chinese Pharmacopoeia, has been widely used as a traditional Chinese medicine for the treatment of hemorrhagic disease. Total flavonoids from Clinopodium chinense (Benth.) O. Ktze (TFCC), the most active ingredient, possess a variety of properties, such as antioxygenation. Until now, evidence-based toxicity data on TFCC has been limited. This study evaluated the acute (in mice and rat) and the 28-day repeated-dose (in rat) toxicity study of TFCC, respectively. In acute study, oral administration of TFCC to rats and mice did not induce toxicity or mortality up to the maximum doses of 4000 and 5000 mg/kg, respectively. In subacute toxicity study, we administered TFCC at daily doses of 70, 210, and 630 mg/kg for 4 consecutive weeks to rats via gavage. We observed no changes in food consumption, water intake, body weight, chemistry and hematological parameters, organ weight, gross pathology or histopathology. No animals from any group died. These findings indicate that TFCC is relatively nontoxic, and provide practical guidance for selecting a safe dose for further investigation of TFCC in animal studies or clinical trials.     

Developmental toxicity of Guthion in rats and mice

The purpose of this study was to assess the effects of Guthion, a pesticide with anticholinesterase activity, on development in rats and mice. A preliminary toxicity study with Guthion indicated that a 35-day LD₅₀ dose for virgin rats and a 10-day LD₅₀ dose for virgin mice was between 4 and 8 mg/kg/day for both species. On the basis of these data, doses of 0, 1.25, 2.5, and 5.0 mg/kg/day were selected for the developmental study, which consisted of two phases. During the first phase, pregnant rats and mice were treated for 10 days starting on gestational day 6. The high dose affected maternal welfare only in rats. Guthion did not significantly increase in a dose-related manner any of the specific anomalies observed in either rats or mice. During the second phase, pregnant rats were treated from gestational day 6 to postpartum day 21. Dams in the high dose group were more sensitive to Guthion later in gestation with the result that deaths and signs of anticholinesterase toxicity increased during this time. Guthion also adversely affected maternal welfare in this group. As a result of Guthion toxicity, only one litter survived until weaning. The inability to dissociate toxicity in adult and developing animals suggests that Guthion has little primary effect on the development of rats or mice.     

Toxicity and carcinogenicity studies of 4-methylimidazole in F344/N rats and B6C3F1 mice

4-Methylimidazole (4MI) is used in the manufacture of pharmaceuticals, photographic chemicals, dyes and pigments, cleaning and agricultural chemicals, and rubber. It has been identified as a by-product of fermentation in foods and has been detected in mainstream and side stream tobacco smoke. 4MI was studied because of its high potential for human exposure. Groups of 50 male and 50 female F344/N rats were fed diets containing 0-, 625-, 1,250-, or 2,500 ppm 4MI (males) or 0-, 1,250-, 2,500-, or 5,000 ppm 4MI (females) for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 30, 55, or 115 mg 4MI/kg body weight to males and 60, 120, or 250 mg 4MI/kg to females. Survival of all exposed groups of males and females was similar to that of the control groups. The mean body weights of males in the 1,250- and 2,500 ppm groups and females in the 2,500- and 5,000 ppm groups were less than those of the control groups throughout the study. Feed consumption by 5,000 ppm females was less than that by the controls. Clonic seizures, excitability, hyperactivity, and impaired gait were observed primarily in 2,500- and 5,000 ppm females. The incidence of mononuclear cell leukemia in the 5,000 ppm females was significantly greater than that in the controls. The incidences of hepatic histiocytosis, chronic inflammation, and focal fatty change were significantly increased in all exposed groups of male and female rats. The incidences of hepatocellular eosinophilic and mixed cell foci were significantly increased in 2,500 ppm males and 5,000 ppm females. Groups of 50 male and 50 female B6C3F1 mice were fed diets containing 0-, 312-, 625-, or 1,250 ppm 4MI for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 40, 80, or 170 mg 4MI/kg body weight to males and females. Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights of males and females in the 1,250 ppm groups and that in the 312- and 625 ppm females were less than those of the control groups. Feed consumption by exposed groups of male and female mice was similar to that by the controls. The incidences of alveolar/bronchiolar adenoma in all exposed groups of females, alveolar/bronchiolar carcinoma in 1,250 ppm males, and alveolar/bronchiolar adenoma or carcinoma (combined) in 1,250 ppm males and 625- and 1,250 ppm females were significantly greater than those in the control groups. The incidence of alveolar epithelial hyperplasia was significantly increased in the 1,250 ppm females. 4MI is carcinogenic inducing alveolar/bronchiolar adenoma and carcinoma in male and female mice. 4MI may also induce mononuclear cell leukemia in female rats. An erratum to this article can be found at     

Chronic studies evaluating the carcinogenicity of monomethylarsonic acid in rats and mice

Monomethylarsonic acid (MMA) was administered in the diet of male and female Fischer F344 rats and B6C3F1 mice in 2-year feeding studies according to US EPA guidelines. Rats were treated with 50, 400, or 1300 ppm MMA and mice were treated with 10, 50, 200, or 400 ppm MMA based on preliminary short-term studies. The highest dose in the male and female rat groups was reduced to 1000 ppm during week 53 and then further reduced to 800 ppm during week 60 due to high mortality in the male rats. There was no treatment-related mortality in the mice. The primary target organ for MMA-induced toxicity in rats and mice was the large intestine. Toxicity was more severe in rats compared to mice and in male rats compared to female rats. The maximum tolerated dose for chronic dietary administration of MMA in rats and mice was assessed as 400 ppm, and the no effect level with regard to intestinal toxicity was assessed as 50 ppm for rats and female mice and 200 ppm for male mice. There were no treatment-related neoplastic effects detected in either the rat or the mouse.     

Chronic toxicity evaluation of Morinda citrifolia fruit and leaf in mice

Noni (Morinda citrifolia) leaf and fruit are used as food and medicine. This report compares the chronic toxicity of Noni fruit and edible leaf water extracts (two doses each) in female mice. The 6 months study showed the fruit extract produced chronic toxicity effects at the high dose of 2 mg/ml drinking water, evidenced through deteriorated liver histology (hepatocyte necrosis), reduced liver length, increased liver injury marker AST (aspartate aminotransferase) and albumin reduction, injury symptoms (hypoactivity, excessive grooming, sunken eyes and hunched posture) and 40% mortality within 3 months. This hepatotoxicity results support the six liver injury reports in humans which were linked to chronic noni fruit juice consumption. Both doses of the leaf extracts demonstrated no observable toxicity. The hepatotoxicity effects of the M. citrifolia fruit extract in this study is unknown and may probably be due to the anthraquinones in the seeds and skin, which had potent quinone reductase inducer activity that reportedly was 40 times more effective than l-sulforaphane. This report will add to current data on the chronic toxicity cases of Morinda citrifolia fruit. No report on the chronic toxicity of Morinda citrifolia fruit in animal model is available for comparison.     

Liver toxicity and carcinogenicity in F344/N rats and B6C3F1 mice exposed to Kava Kava

Kava Kava is an herbal supplement used as an alternative to antianxiety drugs. Although some reports suggest an association of Kava Kava with hepatotoxicity , it continues to be used in the United States due to lack of toxicity characterization. In these studies F344/N rats and B6C3F1 mice were administered Kava Kava extract orally by gavage in corn oil for two weeks, thirteen weeks or two years. Results from prechronic studies administered Kava Kava at 0.125 to 2 g/kg body weight revealed dose-related increases in liver weights and incidences of hepatocellular hypertrophy. In the chronic studies, there were dose-related increases in the incidences of hepatocellular hypertrophy in rats and mice administered Kava Kava for up to 1 g/kg body weight. This was accompanied by significant increases in incidences of centrilobular fatty change. There was no treatment- related increase in carcinogenic activity in the livers of male or female rats in the chronic studies. Male mice showed a significant dose-related increase in the incidence of hepatoblastomas. In female mice, there was a significant increase in the combined incidence of hepatocellular adenoma and carcinoma in the low and mid dose groups but not in the high dose group. These findings were accompanied by several nonneoplastic hepatic lesions.     

Telmisartan treatment attenuates arsenic-induced hepatotoxicity in mice

The protective effect of telmisartan, the angiotensin II-receptor antagonist, against liver toxicity induced by sodium arsenite (5 mg/kg/day, p.o., for 30 days) was investigated in mice. Telmisartan treatment (10 mg/kg/day, p.o.) was applied for 30 days, starting on the same day of arsenic administration. Telmisartan significantly reduced serum alanine aminotransferase level which was increased by sodium arsenite. Telmisartan significantly suppressed lipid peroxidation, and prevented the reduced glutathione depletion and nitric oxide elevation in the liver tissue resulted from arsenic administration. Also, the increase of arsenic ion, and the reductions of selenium and zinc ions in liver tissue were attenuated by telmisartan. Histopathological examination showed that liver tissue injury mediated by arsenic was ameliorated by telmisartan treatment. Immunohistochemical analysis revealed that telmisartan significantly decreased the arsenic-induced expression of inducible nitric oxide synthase, tumor necrosis factor-α, cyclooxygenase-2, nuclear factor-κB and caspase-3 in liver tissue. It was concluded that telmisartan may represent a potential option to protect the liver tissue from the detrimental effects of arsenic toxicity.     

Carcinogenicity of <Emphasis Type="Italic">ortho</Emphasis>-phenylenediamine dihydrochloride in rats and mice by two-year drinking water treatment

The carcinogenicity of ortho-phenylenediamine (o-PD) was examined by administrating o-phenylenediamine dihydrochloride (o-PD2HCl) in dinking water to groups of 50 F344/DuCrj rats and 50 Crj:BDF₁ mice of both sexes for 2 years. The drinking water concentration of o-PD2HCl was 0, 500, 1,000 or 2,000 ppm (wt/wt) for male rats; 0, 250, 500 or 1,000 ppm for female rats; 0, 500, 1,000 or 2,000 ppm for male mice; and 0, 1,000, 2,000 or 4,000 ppm for female mice. Two-year administration of o-PD2HCl produced a dose-dependent increase in the incidences of hepatocellular adenomas and carcinomas in rats of both sexes and in female mice, and hepatocellular adenomas in male mice. In mice, the incidences of hepatocellular adenomas were increased at the lowest dose used in both males and females. Metastasis from hepatocellular carcinomas of rats occurred predominantly in the lung. Incidences of transitional cell papillomas and carcinomas in the urinary bladder were noted in male rats administered 2,000 ppm, together with an increased incidence of papillary and/or nodular hyperplasia of transitional epithelium. In mice, the incidence of papillary adenomas in the gall bladder, which is rare in mice, was increased in both males and females administered 2,000 ppm. Thus, o-PD is carcinogenic in two species, i.e., rats and mice of both sexes.     

Toxicity and carcinogenicity studies of methylene blue trihydrate in F344N rats and B6C3F1 mice

Methylene blue trihydrate has a variety of biomedical and biologically therapeutic applications. Groups of 50 male and 50 female rats and mice were administered methylene blue trihydrate in 0.5% aqueous methylcellulose solution by gavage at doses of 0, 5, 25, or 50 mg/kg bw/day (rats) or 0, 2.5, 12.5, and 25 mg/kg bw/day (mice), 5 days per week for 2 years. In rats survival of all dosed groups was similar to that of the vehicle controls, whereas mice exhibited a dose-dependent increase in survival. Rats receiving 25 and 50 mg/kg bw/day and mice receiving 25 mg/kg bw/day developed mild anemia. The incidences of pancreatic islet cell adenoma and adenoma or carcinoma (combined) were increased in all dosed groups of male rats, but increases were statistically significant in 25 mg/kg bw/day males only and the dose–response was non-linear. There was a corresponding increase in the incidence of pancreatic islet cell hyperplasia but statistically significant only in the 50 mg/kg bw/day male rats. There were no significant increases in neoplastic transformation observed in the mice; however, positive trends were noted for adenoma or carcinoma (combined) of the small intestine and malignant lymphoma.     

Carcinogenicity of glycidamide in B6C3F1 mice and F344/N rats from a two-year drinking water exposure

Acrylamide is a contaminant in baked and fried starchy foods, roasted coffee, and cigarette smoke. Previously we reported that acrylamide is a multi-organ carcinogen in B6C3F₁ mice and F344/N rats, and hypothesized that acrylamide is activated to an ultimate carcinogen through metabolism to the epoxide glycidamide. We have now examined the carcinogenic effects of glycidamide administered at 0, 0.0875, 0.175, 0.35 and 0.70 mM in drinking water to the same strains of rodents for two years. In male and female mice, there were significant increases in tumors of the Harderian gland, lung, forestomach, and skin. Female mice also had an increased incidence of tumors of the mammary gland and ovary. In male and female rats, there were significant increases in thyroid gland and oral cavity neoplasms and mononuclear cell leukemia. Male rats also had increases in tumors of the epididymis/testes and heart, while female rats demonstrated increases in tumors of the mammary gland, clitoral gland, and forestomach. A similar spectrum of tumors was obtained in mice and rats administered acrylamide. These data indicate that, under the conditions of these bioassays, acrylamide is efficiently metabolized to glycidamide and that the carcinogenic activity of acrylamide is due to its conversion into glycidamide.     

吉林生晒参慢性毒性试验的初步比较研究

目的以慢性毒性试验研究吉林人参对Wistar大鼠的毒性作用情况。方法进行慢性毒性试验,给予含有不同剂量（8.0、6.5、5.0g/kgBW）吉林人参样品的饲料喂饲大鼠180d,在试验中期和末期分别检测并比较各组大鼠体重、脏器系数、血液学指标、血生化学指标、病理变化情况。结果试验中、末期各剂量组大鼠的各种指标与对照组比较,差异无显著性（P〉0.05）。有一些血液学及血生化学指标在试验中、末期间比较,差异具有显著性（P〈0.05）。结论在180d的慢性毒性试验中,食用吉林人参未对大鼠产生明显慢性毒性作用。     

Induction of thyroid and liver tumors by chronic exposure to 2-methylimidazole in F344/N rats and B6C3F1 mice

2-Methylimidazole (2MI) has been identified as a by-product of fermentation and is detected in foods and mainstream and side-stream tobacco smoke. It is used in the manufacture of pharmaceuticals, photographic chemicals, dyes and pigments, agricultural chemicals, and rubber. Carcinogenicity studies of 2MI were conducted because of its high potential for human exposure and a lack of carcinogenicity data. Groups of male and female Fischer 344/N rats were fed diets containing 0, 300, 1,000, or 3,000 ppm (males) or 0, 1,000, 2,500, or 5,000 ppm (females) 2MI for 106 weeks and groups of male and female B6C3F1 mice were fed 0, 625, 1,250, or 2,500 ppm 2MI for 105 weeks. Animals in each group were sacrificed at 8 days, 14 weeks, and 6 months for determinations of serum thyroid hormone and liver enzyme levels and histopathological examinations and at 2 years for evaluations of neoplastic lesions. In rats, 2MI administration reduced serum thyroxine and triiodothyronine and increased thyroid stimulating hormone levels. 2MI administration also increased total hepatic UDP-glucuronosyltransferase levels. At 2 years, the incidences of thyroid follicular cell hyperplasia, adenoma or carcinoma (combined), as well as follicular mineralization were increased. The incidences of hepatocellular adenoma or carcinoma (combined) in the two highest dose groups of males and females were also increased. The incidences of mixed cell focus in males and females were also significantly increased. In mice, the incidences of thyroid follicular cell hypertrophy and hyperplasia were significantly increased in the high dose males and females. The incidence of thyroid follicular cell adenoma in the 2,500 ppm males was significantly greater than that in the control group. The incidences of hepatocellular adenoma or carcinoma (combined) were significantly increased in all exposed groups of males and in the 2,500 ppm females. Significant increases in incidences were also observed in spleen hematopoietic cell proliferation in both sexes and bone marrow hyperplasia, chronic active inflammation of the epididymis, sperm granuloma, and germinal epithelial atrophy of the testis in males. Under these experimental conditions, carcinogenic activity of 2MI was demonstrated in male and female rats and mice.     

Acute, subacute toxicity and genotoxic effect of Bio-Quinone Q10 in mice and rats

In the present study, the acute, subacute and genetic toxicity of Coenzyme Q10 (CoQ10) in the form of Bio-Quinone (Pharma Nord, Denmark) was assessed. LD(50) of CoQ10 by oral treatment was greater than 20g/kg body weight in both female and male mice. Genotoxicity was assessed in mice by Ames test in Salmonella typhimurium strains TA97, TA98, TA100 and TA102, by bone marrow micronucleus test and sperm abnormality. Thirty-day subacute toxicity was conducted with oral daily dose at 0, 0.56, 1.13 and 2.25g/kg body weight in rats. No significant changes in body weight, food intake, behavior, mortality, hematology, blood biochemistry, vital organ weight, sperm abnormality, mutagenicity and micronucleus formation were observed and no clinical signs or adverse effects were detected by administration of CoQ10. These results support the safety of CoQ10 for oral consumption.     

Developmental toxicity evaluation of gallium nitrate in mice

Gallium nitrate, a drug with antitumor activity, is presently undergoing clinical trials as a chemotherapeutic agent for the treatment of certain malignancies. Since there are very limited published animal toxicity data available, this study was conducted to investigate the potential adverse developmental effects of this drug. Pregnant Swiss mice were administered intraperitoneally gallium nitrate at 12.5, 25, 50, and 100 mg/kg/day on days 6, 8, 10, 12, and 14 of gestation. Monitors for maternal toxicity were body weight, food consumption and clinical signs. At sacrifice (day 18) maternal weight, liver and kidney weights, and gravid uterine weights were measured. Gestational parameters monitored were numbers of total implants, resorptions, postimplantation losses, and dead fetuses. Live fetuses were sexed, weighed, and examined for external, internal and skeletal malformations and variations. Maternal toxicity was noted in all the gallium nitrate-treated groups. Embryo/fetal toxicity was evidenced by a decrease in the number of viable implants, a reduction in fetal weight, and an increase in the number of skeletal variations (12.5, 25, 50 and 100 mg/kg). No significant increase in the incidence of malformations was observed at 12.5, 25, or 50 mg/kg. The no-observable-adverse-effect level (NOAEL) for both maternal and developmental toxicity of gallium nitrate was <12.5 mg/kg.     

百草枯对小鼠的急性毒性试验

目的 观察百草枯(Paraquat,PQ)对小鼠的急性毒性,计算其半数致死量(LD50).方法 给小鼠灌服不同浓度的PQ溶液,通过观察小鼠的活动和毒性反应,记录小鼠的死亡数,用概率单位法计算LD50.结果 给药后不同时间内,小鼠出现自由活动减少,濒死时呼吸频率加快、张口呼吸、鼻翼扇动等中毒症状,死亡高峰在2 h内,死亡原因为多脏器损伤.♂小鼠LD50=106.99 mg·kg-1,95%可信限范围为97.01～118.03 mg·kg-1;♀小鼠LD50=86.40 mg·kg-1,95%可信限范围74.54～100.14 mg·kg-1.结论 PQ属于中等毒农药,♀小鼠更敏感.     

The carcinogenic action of aristolochic acid in rats

Male and female Wistar rats treated orally with 0.1, 1.0 or 10.0 mg/kg/day aristolochic acid as its sodium salt (AA) developed a high incidence of tumours dependent on dose and time. After 3 months' treatment 1.0 and 10.0 mg/kg AA led to severe papillomatosis of the forestomach with occasional signs of malignancy. Three to 6 months later without further treatment the rats developed squamous cell carcinomas in the forestomach with formation of metastases. At the same time anaplasia of the tubular epithelium and mainly adenomas appeared in the renal cortex. The transitional epithelium of the renal pelvis and the urinary bladder showed hyperplasia, papillomas or carcinomas. For the low dose (0.1 mg/kg) the treatment with AA varied between 3 and 12 months. No tumours were observed in the first 6 months of the study. After 12 and 16 months, however, papillomas or squamous cell carcinomas also occurred in the forestomach. In addition, hyperplasia of the transitional epithelium of the renal pelvis was found while the renal cortex and the urinary bladder remained normal.This paper was presented in part at the 23rd Annual Meeting of the European Society of Toxicology, March 21–24, 1982, Tel Aviv, Israel     

Corneal lesions induced by the systemic administration of capsaicin in neonatal mice and rats

Summary Following a single subeutaneous injection of capsaicin to neonatal mice, a high incidence of corneal lesions with opacity developed after a long latency. The intensity of the lesions progressed for about 1 month in animals which had received a high dose (50 or 100 mg/kg) of capsaicin. Although the intensity gradually decreased thereafter, 50% of animals still exhibited a visible opacity 6 months after treatment. Similar corneal lesions were also produced in neonatal rats which had been injected with capsaicin. It is suggested that the corneal lesions induced by capsaicin may be due to destruction of the trigeminal nerve.     

Subchronic toxicity of chloral hydrate on rats: a drinking water study

The subchronic toxicity of chloral hydrate, a disinfection byproduct, was studied in rats following 13 weeks of drinking water exposure. Male (262 +/- 10 g) and female (190 +/- 8 g) Sprague-Dawley rats, ten animals per group, were administered chloral hydrate via drinking water at 0.2, 2, 20 and 200 ppm. Control animals received distilled water only. Gross and microscopic examinations, serum chemistry, hematology, biochemical analysis, neurogenic amine analysis and serum trichloroacetic acid (TCA) analysis were performed at the end of the treatment period. Bronchoalveolar fluids were collected at necropsy and urine specimens were collected at weeks 2, 6 and 12 for biochemical analysis. No treatment-related changes in food and water intakes or body weight gains were observed. There were no significant changes in the weights of major organs. Except for a mild degree of vacuolation within the myelin sheath of the optic nerves in the highest dose males, there were no notable histological changes in the tissues examined. Statistically significant treatment-related effects were biochemical in nature, with the most pronounced being increased liver catalase activity in male rats starting at 2 ppm. Liver aldehyde dehydrogenase (ALDH) was significantly depressed, whereas liver aniline hydroxylase activity was significantly elevated in both males and females receiving the highest dose. A dose-related increase in serum TCA was detected in both males and females starting at 2 ppm. An in vitro study of liver ALDH confirmed that chloral hydrate was a potent inhibitor, with an IC(50) of 8 micro M, whereas TCA was weakly inhibitory and trichloroethanol was without effect. Analysis of brain biogenic amines was conducted on a limited number (n = 5) of male rats in the control and high dose groups, and no significant treatment-related changes were detected. Taking into account the effect on the myelin sheath of male rats and the effects on liver ALDH and aniline hydroxylase of both males and females at the highest dose level, the no-observed-effect level (NOEL) was determined to be 20 ppm or 1.89 mg kg(-1) day(-1) in males and 2.53 mg kg(-1) day(-1) in females. This NOEL is ca. 1000-fold higher than the highest concentration of chloral hydrate reported in the municipal water supply.