scispace - formally typeset
Search or ask a question

Showing papers on "Toxicity published in 1977"


Journal ArticleDOI
01 Apr 1977-Cancer
TL;DR: A clinical trial was undertaken to improve the therapeutic index of cis‐plati‐num diammine dichloride with a concomitantly administered mannitol induced diuresis and CPDD administration, with Clinically significant responses in epidermoid carcinoma of the head and neck, adenocarcinomas of the ovary, and germ cell tumors of the testis.
Abstract: A clinical trial was undertaken to improve the therapeutic index of cis-platinum diammine dichloride with a concomitantly administered mannitol induced diuresis. Sixty patients, heavily pretreated, were entered; fifty-one are evaluable. The technique of concomitant osmotic diuresis and CPDD administration is described in detail. Doses ranged from 3 mg/kg to 5 mg/kg. At 5 mg/kg, dose-limiting renal, marrow and ototoxicity were seen, and resulted in one drug death. Marrow toxicity was moderate. Renal toxicity was limited to transient elevations in serum creatinine levels, except in some patients who had renal impairment prior to CPDD treatment. These patients had moderate renal toxicity. Serial treatments as frequently as once every 3 weeks were used to maintain responses. Serial high dose CPDD produced only mild renal dysfunction. Ototoxicity, usually subclinical, was quantitated audiometrically, and found to be dose related, but not clinically prohibitive at 4 mg/kg or less. The overall response rate (PR/MR) was 42%. Clinically significant responses in epidermoid carcinoma of the head and neck, adenocarcinoma of the ovary, and germ cell tumors of the testis were seen. All six responding patients with germ cell tumor of the testis, had been resistant to low dose (1mg/kg) CPDD. Two responding patients with ovarian adenocarcinoma had been resistant to alkylating agents.

605 citations


Journal ArticleDOI
TL;DR: Determination of methotrexate concentration in plasma identified patients at high risk of toxicity, a group that may benefit from supplemental leucovorin rescue.
Abstract: To correlate the pharmacokinetics and toxicity of methotrexate, we measured the drug's clearance from plasma after 395 high-dose, six-hour infusions given to 78 patients. After 375 infusions, 48 hour methotrexate levels fell within 2 standard deviations of the mean for nontoxic infusions, and myelosuppression did not occur. Methotrexate concentrations exceeded the range for nontoxic patients (mean +/- 2 standard deviations) after 20 infusions. Serious myelosuppression occurred after six of these 20 infusions, including five of 12 infusions associated with 48-hour drug concentrations above 9 X 10(-7) M. In seven patients with 48-hour concentrations above 9 X 10(-7) M, the absence of toxicity could be attributed to subsequent rapid clearance of the drug; four of these patients also received large doses of supplemental leucovorin (50 to 100 mg per square meter every six hours). Determination of methotrexate concentration in plasma thus identified patients at high risk of toxicity, a group that may benefit from supplemental leucovorin rescue.

366 citations


Journal ArticleDOI
01 Apr 1977-Cancer
TL;DR: The data presented indicate that a better therapeutic index has been achieved by osmotic diuresis with mannitol, and that the pharmocokinetics of the drug are unaltered.
Abstract: Cis-Dichlorodiammineplatinum (CPDD) NSC 119875 was given at toxic doses (3 mg/kg) to three groups of dogs. The renal toxicity was avoided with massive prehydration and with mannitol induced diuresis. The bone marrow toxicity was unaltered by either manipulation. The data presented indicate that a better therapeutic index has been achieved by osmotic diuresis with mannitol. Blood levels and urine levels measurements show that the pharmacokinetics of the drug are unaltered, the urinary concentration of drug being low in the first few hours, but with similar urinary drug recovery in all three groups.

252 citations


Journal ArticleDOI
TL;DR: It is concluded that increases in the lung complement of SOD, GR, GP, and GSH in the neonatal rat during oxygen challenge may provide the mechanism for their increased tolerance to hyperoxia-induced lung injury as compared to the adults.
Abstract: Although immature animals have long been known to be less susceptible to O2, toxicity than adults, the basic mechanism(s) to explain this phenomenon remains unresolved. Two biochemical mechanisms for protection of the lung from O2-induced injury have been proposed: the glutathione (GSH) system in reducing toxic lipid peroxides and the superoxide dismutase (SOD) system in eliminating superoxide anion. Experiments were carried out to determine whether these lung defense systems respond differently in neonatal and adult rats exposed to toxic concentrations of O2. Neonatal rats (4 to 7 days old) and adult rats (250-300 g) wire continuouly exposed to either 96-98% )2 or room air in monitored exposure chambers. All the O2-exposed adult rats showed extensive pulmonary edema and 65% died within 3 days of O2 exposure. Neonatal rats, however, all survived up to 5 days of O2 exposure without gross evidence of lung edema. During the course of exposure animals were sacrificed for biochemical analysis and the data expressed on a per lung basis as % of control values. After 72 hours of O2, exposure neonatal rats showed increased activity of GSH (171%), GSH-peroxidase (GP) (126%), GSH-reductase (GR) (120%). glucose-6-phosphate dehydrogenase (G-6-PD) (139%), and SOD (114%). Adult rats, however, failed to show increases in pulmonary GSH, GP, GR, and SOD activity. Thus, the resistance of the neonatal lung to O2-induced injury may be due to the augmented activity of these protective enzyme systems. (Supported by GM 12675 and NIH 1F32 HL05415.)

191 citations


Book ChapterDOI
TL;DR: In this paper, the additive toxicity is defined by an index for two or more chemicals in combination, and the significance of index values near zero is assessed by substituting values from the 95 percent confidence intervals into the formula to determine whether the range for the additive indices overlaps zero (simple additive toxicity).
Abstract: Mixtures of chemicals or pesticides may produce unexpected effects; some are hazardous and some are beneficial. A method was divised in which individual toxic contributions of chemicals are summed, and the additive toxicity is defined by an index for two or more chemicals in combination. This linear index expresses the toxicity quantitatively: zero indicates simple additive toxicity, negative values indicate less than additive toxicity, and positive values indicate greater than additive toxicity. The significance of index values near zero is assessed by substituting values from the 95 percent confidence intervals into the formula to determine whether the range for the additive indices overlaps zero (simple additive toxicity). The range is derived by selecting values of the 95 percent confidence interval yielding the greatest deviation from the additive index. Mixtures of malathion and Delnav were found to be extremely toxic, and the additive index for the mixture against rainbow trout (Salmo gairdneri) was 7.20; that is, highly synergistic. Mixtures of copper, zinc, and nickel were additive in toxicity to rainbow trout. Mixtures of commercial synergizers sulfoxide or piperonyl butoxide with rotenone produced greater than additive toxicity against rainbow trout (indices = + 2.13 and 2.36).

159 citations


Journal ArticleDOI
TL;DR: This study clearly demonstrates the poor correlation between dose and plasma concentration and the strong relationship between toxicity and Plasma concentration and mandates that the relatively simple, rapid and inexpensive theophylline plasma measurement be used in all patients receiving IV aminophyllines for longer than 24 hours in order to prevent toxicity.
Abstract: Use of recommended IV aminophylline dosage regimens in 48 older, acutely ill, hospitalized patients with chronic obstructive pulmonary disease (COPD) resulted in excessive plasma theophylline concentrations in 29 percent of these patients.A mean dose of 0.89 mg/kg/hr produced a plasma concentration which ranged from 7 to 52 mcg/ml with a mean of 21.9 mcg/ml. Plasma theophylline concentration was determined spectrophotometrically from plasma samples drawn at least 12 hours after a loading dose and initiation of a constant infusion. Severity of toxicity strongly correlated with the plasma theophylline concentration in 18 patients. Nausea and/or vomiting preceded life-threatening drug-induced arrhythmias and seizures less than half the time. Tachycardia was found to be the most consistent symptom associated with toxicity. These patients had lower plasma clearances than otherwise healthy younger adult asthmatics and healthy volunteers. Toxicity and identifiable risk factors for excessive plasma levels strongl...

139 citations


Journal ArticleDOI
TL;DR: Bone marrow toxicity occurred in 4 of 15 patients treated with 5-fluorocytosine for serious fungal infections and one patient with acute renal failure and prolonged high levels of 5-FC developed marrow aplasia and died of bacterial sepsis.
Abstract: Bone marrow toxicity occurred in 4 of 15 patients treated with 5-fluorocytosine (5-FC) for serious fungal infections. The development of marrow toxicity appeared to be related to serum 5-FC levels of 125 mug/ml or greater. In three patients, accumulation of toxic levels of 5-FC was related to diminished renal function. One patient with acute renal failure and prolonged high levels of 5-FC developed marrow aplasia and died of bacterial sepsis. Three patients experienced leukopenia, which was readily reversed when the dosage of 5-FC was decreased and the serum concentration was lowered. With careful monitoring of serum 5-FC concentration and renal function, the dose-related toxic effects of 5-FC on the marrow can be avoided.

135 citations


Journal ArticleDOI
TL;DR: Lifetime ingestion by rats of 0.2 mg/kg/day of hexachlorobutadiene caused no discernible ill effects, but slight degrees of primarily renal toxicity occurred with 2 mg/ kg/day; 20 mg/ kilograms/day caused multiple toxic effects, including renal tubular neoplasms.
Abstract: Lifetime ingestion by rats of 0.2 mg/kg/day of hexachlorobutadiene caused no discernible ill effects. Slight degrees of primarily renal toxicity occurred with 2 mg/kg/day; 20 mg/kg/day caused multiple toxic effects, including renal tubular neoplasms

120 citations


Journal ArticleDOI
TL;DR: It was demonstrated that the sulphydryl compounds β-mercaptoethylamine-HCl, cysteine and methionine significantly increased the survival rate of mice given a lethal dose of ethanol.

109 citations


Journal ArticleDOI
TL;DR: Nitrite in calcium-free artificial seawater (100 mg NO2- liter-1) was highly toxic but did not induce appreciable methemoglobinemia and adding calcium to this medium decreased the acute toxicity of nitrite.
Abstract: The relative toxicity of nitrite to chinook salmon fingerlings (Oncorhynchus tshawytscha) in both freshwater ([Ca++] = 32 mg liter-1) and natural seawater (32.5‰, [Ca++] = 396 mg liter-1) was measured by 48-h static bioassay. The percentage of hemoglobin oxidized to methemoglobin was also determined. In freshwater, the 48-h median lethal nitrite concentration was 19 mg liter-1. In natural seawater, 1,070 mg liter-1 nitrite caused only 10% mortality in 48 h. In freshwater with 27 mg NO2- liter-1, 44% methemoglobin occurred with 70% mortality. In natural saltwater with 815 mg NO2- liter-1, 74% methemoglobin occurred with 10% mortality. Adding calcium sulfate to the freshwater decreased the toxicity of nitrite but did not reduce methemoglobinemia. Nitrite in calcium-free artificial seawater (100 mg NO2- liter-1) was highly toxic but did not induce appreciable methemoglobinemia. Adding calcium to this medium decreased the acute toxicity of nitrite. These results suggest nitrite toxicity mortalities r...

103 citations


Journal ArticleDOI
TL;DR: It is suggested that parenterally administered cadmium-thionein is taken up by the renal tubules and catabolized, probably by the lysosomes of the tubular cells, with the liberation of Cd 2 + ions.

Journal Article
TL;DR: TdR offers significant protection against MTX toxicity and deserves further clinical study, as determined by labeling indices and cytofluorographic analyses.
Abstract: Continuous i.v. thymidine (TdR) was given to 12 patients with metastatic cancer in an attempt to prevent methotrexate (MTX) toxicity. MTX was infused in 27 courses with progressive dose increase from 80 mg/sq m for 24 hr to 6 g/sq m for 72 hr. TdR at 8 g/sq m/day was infused concurrently and continued 24 to 48 hr beyond MTX infusion. The median pretreatment serum TdR level was 0.19 micron. With TdR infusion, the median level was 1.5 micronM. Serum TdR fell with a half-time of 8 to 10 min after a pulse dose or cessation of infusion. Spinal fluid TdR equaled serum TdR levels after 2 hr of infusion. Less than 2% of administered TdR appeared in urine. MTX serum levels were proportional to dose infused, ranging from 80 to 100 micronM with 2 g/sq m/day. The half-time for MTX clearance from serum was 4 to 8 hr. Spinal fluid MTX reached equilibrium at 3 to 12% of serum levels by 4 hr. Bone marrow dysfunction during MTX infusion was prevented by TdR as determined by labeling indices and cytofluorographic analyses. Toxicity was not seen in patients with normal MTX clearance using 48-hr infusions of MTX where TdR was continued for an additional 48 hr after the MTX infusion had ended. However, 3 of 6 courses of MTX at 6 g/sq m over 72 hr led to toxicity. Toxicity was reversible in 2 patients, 1 of whom was retreated with a similar dose duration of MTX without toxicity when TdR was continued beyond the end of the MTX infusion for 48 hr instead of the usual 24 hr. The 3rd patient with toxicity died of progressive disease and thrombocytopenia 19 days after treatment. No TdR-related toxicity or unusual MTX toxicity was detected. Antitumor effects were noted in 4 patients. TdR offers significant protection against MTX toxicity and deserves further clinical study.

Journal ArticleDOI
TL;DR: The cytotoxicity of the nitroimidazole Ro 7-0582 to tumor cells has been studied in vivo using two transplantable tumors, the EMT6 tumor in BALB/c mice and the MDAH/MCa4 tumor in C3H mice.
Abstract: The cytotoxicity of the nitroimidazole Ro 7-0582 to tumor cells has been studied in vivo using two transplantable tumors, the EMT6 tumor in BALB/c mice and the MDAH/MCa4 tumor in C3H mice. It was found that a high dose of Ro 7-0582 (1 mg/g) was toxic to approximately 90% of the tumor cells, that the toxicity only occurred when the tumor contained hypoxic cells, and that the toxicity was directed at both hypoxic and well-oxygenated cells. Also, there was little or no selective toxicity to irradiated, as opposed to unirradiated, tumor cells. The relative contributions of cytotoxicity and radiosensitization were evaluated in a tumor cure experiment for the MDAH/MCa4 tumor in C3H mice injected with 1 mg/g of Ro 7-0582. Calculations showed that in the absence of cytotoxicity the dose modification factor due to radiosensitization alone would have been 2.02 rather than the value of 2.30 observed. No toxicity was observed at the lower dose of 0.3 mg/g.

Journal ArticleDOI
Karl Schärer1
TL;DR: When growth is markedly reduced in a toxicity experiment alterations of this kind in the organ weight: body weight ratios have to be expected as a physiological response of the organism to decreased feed intake.

Journal ArticleDOI
TL;DR: Rhesus monkeys were intoxicated with methyl alcohol, using an initial dose of 2 gm/kg and subsequent doses were administered in order to maintain an attenuated and prolonged state of intoxication, which developed metabolic acidosis with the accumulation of formic acid in the blood and a corresponding decrease in blood bicarbonate.
Abstract: Rhesus monkeys were intoxicated with methyl alcohol, using an initial dose of 2 gm/kg and subsequent doses were administered in order to maintain an attenuated and prolonged state of intoxication. Arterial blood samples were drawn for methyl alcohol, formate, PO2, PCO2, and pH, which were monitored periodically throughout the course of the experiment. With the use of these procedures monkeys developed metabolic acidosis with the accumulation of formic acid in the blood and a corresponding decrease in blood bicarbonate. These animals served as models, which allowed for ocular evaluation for early signs related to methyl alcohol poisoning. A mechanism to explain toxicity is proposed and discussed.

Journal ArticleDOI
TL;DR: It is suggested that toxicity and DNA damage may result from the actions of toxic intermediates in the metabolic reduction of nitrofurans.

Journal ArticleDOI
01 Dec 1977-Diabetes
TL;DR: This study suggests that streptozotocin's beta cell toxicity is mediated through recognition by the beta cell, and 3-O-Methyl glucose and, to a lesser but significant extent, glucose were shown to protect against the strepto-SZ toxkity, whereas mannitol did not.
Abstract: D-glucose in the pyranose (ring) form exists as two anomers. The alpha-anomer is more effective than the beta-anomer in promoting insulin secretion, suppressing that of glucagon, and protecting beta-cells against alloxan toxicity. Streptozotocin (SZ), a beta cell toxin, is composed of a cytotoxic moiety, 1-methyl 1-nitrosourea, attached to carbon-2 of glucose and exists as either of two anomers in the pyranose form. In 24-hour-fasted male rats, predominantly alpha- or predominantly beta-SZ was injected intravenously and plasma glucose levels were obtained 48 hours later. The alpha-anomer produced significantly greater beta-cell necrosis at doses of 30, 35, and 40 mg./kg. body weight. At higher doses, no differences between the alpha and beta anomers were observed. 3-O-Methyl glucose (3-OMG) protected against both SZ anomers; however, the alpha-SZ remained more toxic. Larger doses of glucose protected against the lower doses of SZ and, under such conditions, the individual glucose anomers appeared equally potent. Finally, mannitol at comparable molar concentrations was ineffective in protecting against the SZ toxicity. This study suggests that streptozotocin's beta cell toxicity is mediated through recognition by the beta cell. In addition, 3-OMG and, to a lesser but significant extent, glucose were shown to protect against the streptozotocin toxicity, whereas mannitol did not.

Journal ArticleDOI
TL;DR: Rats exposed to aerosolized superoxide dismutase failed to modify either the time course or the cumulative toxicity of 100 per cent O2, suggesting that the primary site of production and of damage due to O2-induced free radicals must be within the intracellular space.
Abstract: Superoxide (O2-.) is a highly toxic free radical that may be an important component of pulmonary O2 toxicity. The primary defense against this free radical is superoxide dismutase. Rats were exposed to aerosolized superoxide dismutase, and it failed to modify either the time course or the cumulative toxicity of 100 per cent O2. Because the aerosolized enzyme can be expected to be delivered only to the extracellular space of the lung, it is suggested that the primary site of production and of damage due to O2-induced free radicals must be within the intracellular space.

Journal Article
TL;DR: Ultrastructural morphometric and biochemical changes in liver mitochondria of fetal rats whose mothers were exposed to methyl mercury hydroxide in their drinking water at concentrations of 0, 3, 5, or 10 p.m. for 4 weeks prior to mating and through day 19 of pregnancy are described.

Journal ArticleDOI
TL;DR: The genetic differences in teratogenicity observed were predicted in advance, on the basis of known differences in polycyclic hydrocarbon metabolism regulated by the Ah locus, and it is proposed that this animal model system might be useful in investigating human genetic Differences in susceptibility to drug-induced aplastic anemia.
Abstract: The balance between cytochrome(s) P1-450 and other forms of P-450 in the liver, and probably many nonhepatic tissues as well, appears to be important in the toxicity, carcinogenicity, mutagenicity, and teratogenicity of numerous compounds. Thus, allelic differences in a single gene — the Ah locus —can have profound effects on the susceptibility of mice to drug toxicity and cancer. There is evidence for the Ah locus in the human.

Journal ArticleDOI
TL;DR: It is concluded that the metabolic products of CPA for cytotoxicity as expressed as cystitis and lethality are different from the alkylating agents, which appear to affect immunological phenomena.

Journal ArticleDOI
TL;DR: Biological factors have been found which can cause variable toxicity of colony and clonal isolates of Anabaena flos‐aquae (Lyngb.) de Bréb.
Abstract: Biological factors have been found which can catise variable toxicily of colony and clonal isolates of Anabaena flos-aquae (Lyngb.) de Breb. when cultured in the laboratory. These factors help to explain some of the variable toxicity of and animal .susceptibility to A, ilos-aquae blooms in nature. Two bacteria in the Enterobacteriaceae isolated from a toxic waterbloom, depressed toxin production in selected bacteria-free toxic clones of A. flosaquae. These toxin-depressing bacteria decreased culture toxicity 3-fold from 80 to 240 mg/kg (intraperitoneal in male mice). Many colony isolates from, a toxic bloom had minimum lethal dosages (LD^i,^) greater than 240 mg/kg. This was because they were composed of mixtures of toxic and nontoxic filaments. The oral LD^^^„ of the toxin from A. flosaqtiae clonal isolate NRC-44-1 varied significantly for 6 different animal species. Using these oral LD,,,fn it is estimated that a surface-concentrated bloom of toxic A, flos-aquae, having a biomass density of 20 mg/rnl dry lueight, would cause death of ducks or calves when 20 ml/kg was consumed whereas a monogastric animal such as a rat would require 80 ml/kg.

Journal ArticleDOI
TL;DR: The preparation and growth characteristics of a novel mixed hepatocyte-fibroblast culture system is described together with its use as a test for metabolism-mediated cytotoxicity using cyclophosphamide as the compound under test and the relevance of incorporating microsomal suspensions as metabolizing components into the various toxicity tests currently available is discussed.

Journal ArticleDOI
TL;DR: Patients with cancer and concomitant infections with either herpes virus hominis or varicella zoster virus were treated with polyinosinic·polycytidylic acid to determine the reliability of rIn·rCn to induce interferon production, and the toxicity of the drug.
Abstract: Twenty-four patients with cancer and concomitant infections with either herpes virus hominis or varicella zoster virus were treated with polyinosinic·polycytidylic acid (rIn·rCn) to determine: (1) the reliability of rIn·rCn to induce interferon production, and (2) the toxicity of the drug. Seven additional patients with herpes zoster were observed as controls. Two lots of rIn·rCn were used; Lot 1 was consistently effective in stimulating serum interferon at doses of 9 and 12 mg/kg, whereas Lot 2 was effective at doses of 3–12 mg/kg. There was no correlation between rIn·rCn doses within these ranges and the resultant interferon levels. Generally, peak serum interferon occurred within the first day. Toxicity to rIn·rCn consisted of fever in 21/24 patients, mild elevation of liver enzymes in 8/24 patients, and laboratory abnormalities of coagulation in 9 patients. The coagulation abnormalities appeared linearly related to the dose of rIn·rCn used. All these abnormalities were reversible, and none were considered severe or lifethreatening. Sincer rIn·rCn was effective in stimulating interferon and since toxicity was considered acceptable, a randomized double-blind study was initiated to determine whether rIn·rCn is effective in the treatment of herpes zoster.

Journal Article
TL;DR: Pulmonary parenchymal or pleural reactions to chemotherapeutic agents used in the management of patients with malignant diseases are being recognized with increasing frequency and appear to be direct toxic effects of the drugs.
Abstract: Pulmonary parenchymal or pleural reactions to chemotherapeutic agents used in the management of patients with malignant diseases are being recognized with increasing frequency. Alkylating agents, asparaginase, bleomycin, methotrexate and procarbazine have all been implicated. Some of the reactions, such as the rare procarbazine pleuritis and pneumonitis, represent hypersensitivity phenomena. Others, such as alkylating agent pulmonary toxicity, appear to be direct toxic effects of the drugs. The severity of the toxicity is variable. The appearance of these pulmonary changes must be differentiated from tumor progression or a variety of possible infections. The awareness of possible pulmonary toxicity is of great importance since early discontinuation of the agent following the first hint of pulmonary toxicity may allow partial or complete reversal of the process. Continued therapy in the face of drug-related pulmonary toxicity may enhance the likelihood of irreversible pulmonary compromise with respiratory failure and death.

Journal ArticleDOI
TL;DR: Findings indicate that saturated FFA toxicity may be due to the deposition of saturated fats within the ER with subsequent interference with cellular metabolism, and the early accumulation of triglyceride and FFA in these cells.

Journal ArticleDOI
TL;DR: The dose of clofibrate administered to hemodialysis patients can be adjusted to avoid toxicity and provide the desired therapeutic effect by monitoring serum CPK and TG levels.
Abstract: A daily dose of 1.5 to 2.0 gm of clofibrate lowers serum triglyceride (TG) levels in patients with normal renal function but causes muscle toxicity and elevated creatine phosphokinase (CPK) levels in patients with long-term renal failure. Plasma clofibrate disappearance is prolonged as much as seven times normal in severely uremic patients. A marked reduction in the standard 14 gm/wk clofibrate dose to a total dose of 1.0 to 1.5 gm/wk effectively lowered serum TG levels (--28%, p less than 0.02) in hypertriglyceridemic hemodialysis patients without toxicity. The serum clofibrate level at this dose was comparable to that in hypertriglyceridemic nonuremic patients receiving 14 gm/wk of clofibrate. The dose of clofibrate administered to hemodialysis patients can be adjusted to avoid toxicity and provide the desired therapeutic effect by monitoring serum CPK and TG levels.


Journal ArticleDOI
TL;DR: The results suggest that paraquat alone is not hepatotoxic in mice; however, Se deficiency or diethyl maleate pretreatment may shift the organ specific toxicity of paraquats toward the liver.

Journal ArticleDOI
A. Michael Kaplan1, Sherman H1
TL;DR: Methomyl exhibited a low order of chronic oral toxicity even though it exhibited high acute oral toxicity, and when applied dermally to rabbits, aqueous suspensions of methamyl exhibited low acute toxicity.