Dermal toxicity of a medium-boiling (154-378 degrees C) coal liquefaction product in the rat--Part I

The subchronic dermal toxicity of a medium-boiling coal liquefaction product (CLP, 154-378 degrees C) was investigated in the rat. CLP was applied to the shaved backs of rats at dose levels of 50, 100, 200, or 400 mg/kg body weight.d, 7 d/wk for a period of 13 wk. Control groups received 0.4 ml/kg of normal saline. Signs of dermal irritation were observed at sites of application in males dosed at 200 and 400 mg/kg body weight and were characterized by thickened, focally necrotic and ulcerative skin. All animals survived the full length of the treatment period. Growth depression was observed in males at all dose levels, but no significant decrease in weight gain was observed in females. An increase in liver/body weight ratios was observed in all treatment groups of both sexes. The organ/body weight ratios for the spleen, heart, kidney, and brain were also increased in the upper dose groups of both sexes. Treatment with CLP caused a dose-dependent decrease in hemoglobin and packed cell volume in both sexes of all dose groups. The number of erythrocytes was decreased and that of neutrophils was increased in some CLP-treated groups of both sexes. There was a mild myeloid hyperplasia with increased myeloid/erythroid ratios in the 200- and 400-mg/kg groups of both sexes. Hepatic microsomal ethoxyresorufin deethylase activity was increased in all treatment groups of females, and in males dosed at 100 mg/kg and higher. In the renal tubules mild treatment-related histological changes occurred, which consisted of eosinophilic inclusions, increased cytoplasmic volume, and pyknosis. These changes were noted in the high-dose groups of both sexes. These data indicate that the medium-boiling CLP could produce systemic toxicity when applied dermally at 50 mg/kg body weight.d.     

Subacute inhalation toxicity of a medium-boiling coal liquefaction product (154-378 degrees C) in the rat [Part III

The short-term inhalation toxicity of a medium-boiling coal liquefaction product (CLP) was investigated in the rat. Groups of 5 male and 5 female Sprague-Dawley rats were exposed to CLP aerosols at 25 mg/m3 (low dose) or 100 mg/m3 (high dose) 6 h/d, 5 d/w, for 4 wk. The control group was exposed to filtered air while the positive control received diesel fuel aerosols at 100 mg/m3. Male rats exposed to high-dose CLP aerosols exhibited growth depression and increased hepatic aminopyrine demethylase activity compared to control animals. High-dose females had decreased hemoglobin content and hematocrit values. These biochemical and hematological effects were not observed in animals of either sex treated with the diesel fuel. No other biochemical and hematological changes were observed. Mild histological changes occurred in the liver and thyroid of rats treated with CLP and diesel fuel aerosols. Based on the data presented, inhalation of CLP aerosols resulted in toxicological effects that were similar to those caused by dermal exposure.     

Systemic Toxicity of the Heavy Fraction of a Coal Coprocessing Product in Male Rats Following Subchronic Dermal Exposure

The systemic toxicity of a coal coprocessing product [heavygas oil II (HGOII)] following subchronic, dermal exposure inmale Sprague-Dawley rats was investigated. HGOII was appliedto the dorsal skin daily at doses of 8.7, 20.8, 50.0, or 120.0mg/ kg body weight (bw) for 13 weeks. Another group of ratstreated with a medium boiling coal liquefaction product (CLP)served as positive controls. Growth suppression and decreasedfood consumption were noted in the groups exposed to HGOII at20.8 mg/kg and higher, and to CLP starting at the third weekof treatment. Relative liver, kidney, and brain weights in the20.8 mg/kg HGOII group and up were higher than those of thecontrol. Increased spleen weight was observed in all HGOII-treatedgroups. CLP treatment also caused increased relative kidneyand brain weights. Serum cholesterol was elevated in the HGOII-treatedgroups starting at 8.7 mg/kg while increased uric acid and lactatedehydrogenase were observed at 20.8 mg/kg and up. Decreasederythrocyte, hemoglobin, and platelet counts were observed at20.8 mg/kg and higher. All HGOII-treated groups had elevatedreticulocytes. These biochemical and hematological changes werenot observed in the CLP-treated group. Mild to marked histologicalchanges were observed in the thyroid, thymus, liver, spleen,and bone marrow of HGOII groups. In contrast, morphologicalchanges were relatively mild in CLP-treated animals. Data fromthe present study demonstrated that the hematological endpointswere sensitive to the liquid fuels and that HGOII was more toxicthan CLP. Based on the growth rate and biochemical, hematological,and morphological changes, the no observable adverse effectlevel for HGOII is judged to be below 8.7 mg/kg bw in the rat.     

Short-Term Toxicity of Bitumen Upgrading Products in the Rat Following Repeated Dermal Exposure

Light gas oil (B-LGO), heavy gas oil No. 1 (B-HGOI), and heavygas oil No. 2 (B-HGOII) fractions of bitumen upgrading products(BUPs) were applied on the dorsal skin of rats at 25 mg/kg bw/day(low dose), 100 mg/kg bw/day (intermediate dose), and 400 mg/kgbw/day (high dose) for 4 weeks. Control animals received normalsaline while positive controls received a medium boiling coalliquefaction product (CLP) at 100 and 400 mg/kg bw/day. Reducedfood consumption and growth suppression were observed in malesand females treated with B-HGOI, B-HGOII, and CLP, but onlyin males receiving B-LGO. Increased relative spleen, kidney,and liver weights were observed in animals treated with B-HGOI,B-HGOII, and CLP, but not in control or LGO groups. A dose-relatedincrease in absolute and relative liver weight was most markedin animals receiving B-HGOII where a significant increase wasobserved starting at the low dose, followed by those receivingB-HGOI and CLP. Appearance of pale foci on the splenic capsuleand increases in spleen/body weight ratio were limited to animalsreceiving B-HGOI and B-HGOII. Decreases in hematocrit and RBCand increase in percentage of reticulocytes were observed inanimals of both sexes receiving B-HGOI and B-HGOII. Female ratsappeared to be more severely affected because significant decreasesin hemoglobin and RBC were observed in animals receiving thelow dose of B-HGOII and the intermediate dose of B-HGO-I. Increasedserum cholesterol was observed in B-HGOII-treated females atall dose levels, and in males starting at the intermediate dose.Histological changes were observed in the thymus gland, wheremoderate to marked cortical atrophy was noted in male and femalerats receiving the high dose of B-HGOI and B-HGOII, and in thebone marrow, where the most significant abnormality was thepresence of focal myelofibrosis in some male rats treated withB-HGOI and B-HGOII. Mild to moderate histological changes werefound in the thyroid, liver, and spleen of rats of all treatmentgroups. Changes in the skin included moderate hyperkeratosisin fe males receiving high doses of B-LGO and in animals ofboth sexes receiving high doses of B-HGOI, and moderate to markedepidermal hyperplasia in rats receiving high doses of B-HGOI.Based on these multiple endpoints, the severity of systemictox icity was B-HGOII > B-HGOI > CLP B-LGO. The NOEL wasabout 25 mg/kg bw/day for B-LGO and lower than 25 mg/ kg bw/dayfor B-HGOI and B-HGOII.     

Rodent carcinogenicity with the thiazolidinedione antidiabetic agent troglitazone.

Carcinogenic potential of the thiazolidinedione antidiabetic troglitazone was assessed in 104-week studies in mice and rats. Mice were given 50, 400, or 800 mg/kg, male rats 100, 400, or 800 mg/kg, and female rats 25, 50, or 200 mg/kg. Vehicle and placebo controls were included. Survival was significantly decreased in both sexes of both species at high doses, but was adequate for valid evaluation of carcinogenicity. Hypertrophy and hyperplasia of brown adipose tissue was observed in both species at all doses, and fatty change and hypocellularity of bone marrow was noted in mice at all doses and in female rats at 50 and 200 mg/kg. Hepatocellular vacuolation was observed in mice at 400 and 800 mg/kg, and centrilobular hepatocellular hypertrophy occurred in rats at > or = 200 mg/kg. Ventricular dilatation, myocardial fibrosis, and atrial myocyte karyomegaly in male rats at 400 and 800 mg/kg and female rats at all doses were morphologically similar to spontaneous lesions, but incidence and severity were increased compared with controls. In mice, the incidence of hemangiosarcoma was increased in females at 400 mg/kg and in both sexes at 800 mg/kg. The incidence of hepatocellular carcinoma was increased in female mice at 800 mg/kg. Troglitazone exposure [AUC((0-24))] at the lowest dose associated with increased tumor incidence in mice was 16 times human therapeutic exposure at 400 mg daily. No tumors of any type were increased in rats at exposures up to 47 times therapeutic exposure.     

Short-term dermal toxicity and mutagenicity of coal coprocessing products in the rat.

The present study was conducted to determine the dermal toxicity of coal coprocessing products and to assess their potential health hazards. Groups of 10 male and 10 female Sprague-Dawley rats were administered dermally coal coprocessing products (light gas oil, LGO; heavy gas oil I, HGOI; heavy gas oil II, HGOII) at 1 g/kg body weight/d for 14 d. The control and positive control groups received normal saline and a coal liquefaction product (CLP) at the same dose level, respectively. Treatment with either the three fractions of coprocessing products or CLP caused decreased growth rate and food consumption in animals of both sexes. Liver enlargement occurred in groups treated with HGOI, HGOII, and CLP. Decreased serum glucose was observed in animals of both sexes treated with the three fractions and CLP. Treatment with HGOI and CLP caused an elevation of hepatic microsomal ethoxyresorufin deethylase activity in the rat of both sexes. The three fractions and CLP caused mild anemia. Mild treatment-related histological changes were observed in the liver, spleen, thyroid, bone marrow, and kidney. All three fractions of coprocessing products were tested for their mutagenicity in five strains of Salmonella typhimurium: TA98, TA100, TA1535, TA1537, and TA1538. HGOI, after metabolic activation, was found to be mutagenic in the strains of TA98, TA100, and TA1538. In contrast, HGOII was mutagenic in the five strains with or without metabolic activation. These data indicate that HGOI and HGOII are more toxic than LGO, and should be subjected to further studies to determine their long-term effects.     

Toxicological studies on a new cephamycin, MT-141. VIII. Its fertility test in rats

A fertility study of MT-141 was performed in SD rats with the intramuscular (i.m.) injections at the dose levels of 400, 800 and 1,600 mg/kg/day. The male rats were injected with MT-141 for 63 days before mating and during the mating period, while the female rats were injected with MT-141 from the 14th day before mating up to the day 7 of gestation. All pregnant rats were sacrificed on day 20 of gestation followed by external, visceral and skeletal observations of their fetuses. The results are summarized as follows. The suppression of body weight gain was observed in males given above 800 mg/kg/day i.m. and in females of all treated groups during early period of gestation. However, no significant differences were found between treated groups and the control with regard to copulation rate and conception rate. Though no defects were observed for visceral and skeletal specimens in the fetuses of treated groups, MT-141 produced a delayed ossification of forelimbs in the fetuses at the doses above 800 mg/kg/day and of sternebrae at the dose of 1,600 mg/kg/day. It is concluded from the above-mentioned results that the maximal "no 'effective" dose of MT-141 on the fertility is above 1,600 mg/kg/day i.m. in parental rats and less than 800 mg/kg/day i.m. for the fetuses.     

Effects of pyridoxine on implantation and pregnancy in Wistar rat

Pyridoxine hydrochloride was gavaged to 2 groups of pregnant Wistar rats from day 0 to 13 and day 6 to 15 of gestation at doses of 100, 200, 400 and 800 mg/kg. A higher number of implantations, live pups and corpora lutea were observed in the treated rats, but a significant reduction in the body weights of the pups was noticed in the groups treated with 400 and 800 mg/kg. No other adverse effects on implantation and pregnancy were noticed. No evidence of dismorphogenic effects was seen.     

Encephalopathy in rats and nephropathy in rats and mice after subchronic oral exposure to benzaldehyde

Male and female Fischer 344 rats and B6C3F1 mice were treated daily (5 days/wk) with benzaldehyde by gavage either in 12 doses of 0 (vehicle control), 100 (rats only), 200, 400, 800, 1600 or (for mice only) 3200 mg/kg body weight/day (followed by 2 days' observation without treatment), or for 90 days in doses of 0, 50, 100, 200, 400 or 800 mg/kg/day (rats) or 0, 75, 150, 300, 600 or 1200 mg/kg/day (mice). In the acute studies, benzaldehyde induced deaths and decreased body-weight gain in both sexes of rats given 800 or 1600 mg/kg/day and caused deaths in both sexes of mice given 1600 or 3200 mg/kg/day. In the 90-day studies, deaths occurred in both sexes of rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Body-weight gain was depressed in male rats on 800 mg/kg/day, in male mice on 600 mg/kg/day and in female mice on 1200 mg/kg/day. Necrotic and degenerative lesions were seen in the cerebellar and hippocampal regions of the brain in both sexes of rats given 800 mg/kg/day, but not in mice. Renal tubular necrosis occurred in male and female rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Mild epithelial hyperplasia or hyperkeratosis of the forestomach was seen in male and female rats on 800 mg/kg/day. In this limited study, the no-observed-toxic-effect doses of benzaldehyde administered by gavage were 400 mg/kg/day in male and female rats, 300 mg/kg/day in male mice and 600-1200 mg/kg/day in female mice.     

Acute and subacute dermal toxicity of Break-Free CLP: a weapons cleaning and maintenance compound

Break-Free CLP((R)) is a commercial cleaning, lubricating and preserving compound used in both the military and civilian sectors for maintenance of small- and large-caliber weapons. Like many commercial mixtures, there is very little information available on the toxicity of Break-Free CLP. Studies were conducted to characterize the biological effects of single or repeat dermal application of Break-Free CLP to the clipped backs of CD-1 mice. Break-Free CLP was applied neat, 50 microl three times of week for up to 2 weeks. Foci of epithelial ulceration were observed in skin sections from 22% of Break-Free CLP-treated animals in conjunction with markedly thickened epithelium suggesting that robust epithelial regeneration was occurring in these animals. Skin histopathology of Break-Free CLP-treated animals closely matched the histopathology from mice treated repeatedly with 2% croton oil in acetone (dermal irritation positive control). Serum alkaline phosphatase activity was significantly (P < 0.05) lower for mice treated with Break-Free CLP, 2% croton oil or 7,12-dimethylbenz[a]anthracene (DMBA) compared with negative and vehicle control mice. Skin nitric oxide (NO) levels were not significantly elevated for mice treated with Break-Free CLP but were significantly elevated for mice treated with dermal irritation positive control compound DMBA. The cumulative skin changes in Break-Free CLP-treated animals support conducting a subchronic dermal application study. The observed decreases in serum alkaline phosphatase activity suggest that future studies should include the liver and bone as possible target organs. Additionally, dermal penetration studies could provide key health risk assessment information for characterizing the potential health risks associated with chronic dermal exposure to Break-Free CLP.     

Evaluation of the dermal subchronic toxicity of diphenyl ether in the rat.

Diphenyl ether (DPE) was investigated to determine the dermal absorption parameters and subchronic toxicity of this fragrance ingredient. For the absorption, distribution and elimination study, Sprague-Dawley rats received a dermal application of [14C]DPE under a semi-occlusive dressing for 6 h. DPE was diluted in diethyl phthalate (DEP) to administer a total application volume of 2 ml/kg and concentrations of 0.5, 5 and 50% (approximately equal to 10, 100 and 1000 mg DPE/kg body weight). Approximately 17.7% of the administered dose was eliminated in the urine, with small amounts also found in the feces (1.18-3.79%). At 72 h post-dosing, approximately 0.2% of the applied dose was retained in the body with low levels also measured in the liver, kidney and gastrointestinal tract (approximately equal to 0.04, 0.02 and 0.3%, respectively). The 13-week subchronic toxicity study was performed with groups of 12 Sprague-Dawley rats/sex/dose that received semi-occluded daily dermal applications of DPE for 6 h/day. All groups were dosed at a constant 2 ml/kg body weight volume of DPE in the DEP vehicle at concentrations to administer 0, 100, 300 or 1000 mg DPE/kg body weight/day. At the high dose level, there was a slight reduction in body weight gain in males (13%), increase in albumin (5-6%) and phosphate (10-15%) levels in both sexes, a reduction of cholesterol in females (14%), an increase in kidney (17%) and brain (8%) weights in males, and an increase in liver weight (18-19%) in both sexes. No histopathological lesions were seen in any organ examined. At 300 mg/kg body weight/day, the only notable findings were an increase in liver weight (10%) in both sexes and a slight increase in albumin (5%) in females. In addition, skin irritation reactions at the site of application were observed in all DPE dose groups. The systemic no-observed-effect level (NOEL) in this study is 100 mg/kg body weight/day. Owing to mitigating factors, the systemic findings were judged to lack biological significance and the no-observed-adverse-effect level (NOAEL) was determined to be 1000 mg/kg body weight/day.     

Single dose oral toxicity study of BMY-28100 in juvenile rats and dogs

In order to investigate the single dose oral toxicity of BMY-28100 in juvenile animals, the drug was administered in single doses to 4-day-old and 14-day-old Crj: CD (SD) rats of both sexes at a dose of 2,000 mg/kg, and to 4-week-old beagle dogs of both sexes at doses of 500, 1,000 and 2,000 mg/kg by oral route. The results obtained are summarized as follows: 1. In rats, decreases of the body weight gain were observed for male and female rats treated with the drug on postnatal day 4 through 5 days and 3 days after dosing, respectively. There were no apparent drug-related toxic signs. No deaths occurred during the observation period. Enlargement of the cecum was found in a few rats of both sexes administered the drug on postnatal day 4 or 14. 2. In dogs, watery-mucous diarrhea observed at 2 to 3 hours after dosing in all dose groups was not dose-related. This finding lasted in some dogs till 4 days after dosing. An increased incidence of emesis was induced in all males at 2,000 mg/kg and all females of all dose groups except one female at 2,000 mg/kg. Body weights increased normally for all dogs, but one male at 1,000 mg/kg showed a transient decrease in food consumption. No drug-related histopathological changes were found. Based upon these results, BMY-28100 at 2,000 mg/kg induced no apparent toxic changes in the present experimental conditions. Therefore, the single dose oral toxicity of the drug in juvenile animals appeared to be very slight and generally similar to that in adults.(ABSTRACT TRUNCATED AT 250 WORDS)     

A subchronic oral toxicity study on pyrroloquinoline quinone (PQQ) disodium salt in rats

A subchronic oral toxicity study on pyrroloquinoline quinone (PQQ) disodium salt was performed in rats. Sprague-Dawley rats were randomly divided into four groups (10 rats/sex/group) and administered with PQQ disodium salt at doses of 0 (control), 100, 200 and 400 mg/kg bw/day by gavage for 13 weeks. Daily clinical observations and weekly measurement of body weights and food consumption were conducted. Blood samples were obtained on day 46 and day 91 for measurement of hematology and serum biochemical parameters. Animals were euthanized for necropsy, selected organs were weighted and recorded. Histological examination was performed on all tissues from animals in the control and PQQ disodium salt treatment groups. No mortality or toxicologically significant changes in clinical signs, body weight, food consumption, necropsy findings or organ weights was observed. Differences between treated and control groups in some hematological and serum biochemical examinations and histopathological examination were not considered treatment-related. The no-observed-adverse-effect-level (NOAEL) of PQQ disodium salt in rats was considered to be 400 mg/kg bw/day for both sexes, the highest dose tested.     

Toxicological studies of a new cephamycin, MT-141. III. Its chronic toxicity in rats

The chronic toxicity of MT-141 was studied in male and female Wistar rats with 182-time intramuscular injections of 50, 100, 200, 400, 800 and 1,600 mg/kg/day and the following results were obtained. MT-141 at all dosage levels caused no lethal effect on rats. However, it induced local inflammatory changes at the site of injection, such as hemorrhage, infiltration of round cells and fibrosis particularly at high doses. MT-141 at a high dose of 1,600 mg/kg/day decreased the gain of body weights in male rats but not in female rats. MT-141 increased the water intake in male and female rats from 8th day till last day after treatments with the doses more than 800 mg/kg/day. This compound also softened the feces and distended the cecum. MT-141 at the highest dosage level of 1,600 mg/kg/day increased the weight of kidney in male and female rats. Electron-microscopic findings revealed dissociation of basal infolding and dilatation of endoplasmic reticulum in renal epithelial cells of rats treated with the doses more than 800 mg/kg/day. These results suggest that MT-141 may induce renal toxicity in rats at these doses. The administration of MT-141 changed some toxicological parameters in gross and histopathological examinations and analyses of blood, serum and urine. However, the changes were accidental, independent on the dose and within physiological variations. It is concluded from above-mentioned results that the maximal "no effective" dose of MT-141 is 400 mg/kg/day in male and female rats.     

90-Day repeated-dose toxicity study of licorice flavonoid oil (LFO) in rats

Licorice flavonoid oil (LFO) is a new functional food ingredient consisting of licorice hydrophobic polyphenols in medium-chain triglycerides (MCT). As part of a safety evaluation, a 90-day oral toxicity study in rats was conducted using an LFO concentrate solution (2.90% glabridin). Male and female animals were assigned to one of 12 groups (10 males or females per group) and received corn oil (negative control), MCT (vehicle control), or 400, 600, 800 or 1600 mg/kg of the LFO concentrate solution. In conclusion, LFO concentrate solution induced an anticoagulation effect in both sexes, although there was a clear sex difference. Based on these findings, it is concluded that the no-observed-adverse-effect level (NOAEL) for the LFO concentrate solution is estimated to be 800 mg/kg/day for female rats, and approximately 400 mg/kg/day for male rats.     

Toxicology and carcinogenesis studies of bis(2-chloroethoxy)methane (CAS No. 111-91-1) in F344/N rats and B6C3F1 mice (dermal studies)

Bis(2-chloroethoxy)methane is used as a solvent and the starting agent in the production of fungicides and polysulfide polymers. Bis(2-chloroethoxy)methane was nominated for study by the National Institute of Environmental Health Sciences because of its widespread use as a starting material to produce polysulfide elastomers, and because there were no 2-year carcinogenicity studies reported in the literature. Male and female F344/N rats and B6C3F1 mice received dermal applications of bis(2-chloroethoxy)-methane in ethanol (greater than 98% pure) for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, rat bone marrow cells, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were dermally administered 0, 12.5, 25, 50, 100, or 200 mg bis(2-chloroethoxy)methane/kg body weight in ethanol, 5 days per week for 16 days. All rats survived to the end of the study. Mean body weights of dosed rats were similar to those of the vehicle control groups. There were no histopathologic lesions related to bis(2-chloroethoxy)methane administration. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were dermally administered 0, 12.5, 25, 50, 100, or 200 mg bis(2-chloroethoxy)methane/kg body weight in ethanol, 5 days per week for 17 days. All mice survived to the end of the study. Mean body weights of dosed mice were similar to those of the vehicle control groups. There were no histopathologic lesions related to bis(2-chloroethoxy)methane administration. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were dermally administered 0, 50, 100, 200, 400, or 600 mg bis(2-chloroethoxy)methane/kg body weight in ethanol, 5 days per week for 14 weeks. Additional clinical pathology groups of 10 male and 10 female rats were administered the same doses for 23 days. All core study 600 mg/kg males and females and two 400 mg/kg females died before the end of the study. The cause of death was considered to be related to the cardiotoxic effect of bis(2-chloroethoxy)methane. There were no significant differences between final mean body weights of dosed rats and those of the vehicle control groups; the mean body weight gain of 400 mg/kg males was significantly less than that of the vehicle controls. Clinical findings included prostration and ataxia in 600 mg/kg rats during the first week of the study and nasal/eye discharge, lethargy, ataxia, and abnormal breathing in 400 and 600 mg/kg females beginning week 5. An enlarged heart was noted in one 100 mg/kg female rat. Relative kidney weights of 100, 200, and 400 mg/kg males were significantly greater than that of the vehicle control group. Increased incidences and severities of myofiber cytoplasmic vacuolization and interstitial mononuclear cell infiltration in the heart occurred in 400 and 600 mg/kg male and female rats and in 200 mg/kg females. Increased incidences and severities of myofiber necrosis occurred in 600 mg/kg males and females; one female each in the 200 and 400 mg/kg groups also had this lesion. Three 600 mg/kg males had atrial thrombosis. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were dermally administered 0, 50, 100, 200, 400, or 600 mg bis(2-chloroethoxy)methane/kg body weight in ethanol, 5 days per week for 14 weeks. Except for three 600 mg/kg females, all mice survived to the end of the study. Mean body weights of dosed and vehicle control mice were similar. One 600 mg/kg female that died early exhibited lethargy, abnormal breathing, and tremors, and one animal had clonic seizures. One 600 mg/kg female that died early had focal erosion of the glandular stomach and a focus in the duodenum found to consist of acute suppurative inflammation and thrombosis. Absolute and relative kidney weights of 400 and 600 mg/kg males and 600 mg/kg females were significantly greater than those of the vehicle control groups. Absolute liver weights of 400 and 600 mg/kg females were also significantly increased. Significantly increased incidences of myofiber cytoplasmic vacuolization occurred in 400 and 600 mg/kg females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were dermally administered 0, 75, 150, or 300 mg bis(2-chloroethoxy)methane/kg body weight in ethanol, 5 days per week for 105 weeks. Survival of all dosed groups of rats was generally similar to that of the vehicle controls. Mean body weights of dosed rats were similar to those of the vehicle controls throughout the study. Clinical findings in 300 mg/kg females that died during the first year of the study included abnormal breathing, lethargy, thinness, nasal discharge, and ataxia. Significantly increased incidences of degeneration of the olfactory epithelium in the nose occurred in all dosed groups of males and in 150 and 300 mg/kg females. The incidences of inflammation of the forestomach were significantly increased in 150 and 300 mg/kg males, and the incidence of ulcers was significantly increased in 300 mg/kg males. Increased incidences of cystic degeneration of the liver occurred in 150 and 300 mg/kg male rats; the incidence was significantly increased in the 300 mg/kg group. 2-YEAR STUDY IN MICE: Groups of 50 male mice were dermally administered 0, 150, 300, or 600 mg bis(2-chloroethoxy)methane/kg body weight in ethanol, 5 days per week for 105 weeks. Groups of 50 female mice were dermally administered 0, 100, 200, or 400 mg/kg in ethanol, 5 days per week for 104 weeks. Survival of 600 mg/kg male mice was significantly less than that of the vehicle control group. Mean body weights of dosed mice were generally similar to those of the vehicle controls throughout the study. Clinical findings observed in 600 mg/kg male mice that died during the first year of the study included lethargy and thinness. Myocardial heart changes were recorded according to the characteristic lesions of cardiomyopathy syndrome (necrosis, mononuclear cell infiltration, myocardial cell vacuolization, and interstitial fibrosis) separately, and in addition, where appropriate, they were also categorized as cardiomyopathy. Increased incidences of cardiomyopathy and mononuclear cell infiltration occurred in 600 mg/kg males and 400 mg/kg females; the incidences were significantly increased in 600 mg/kg males compared to the vehicle controls. Significantly increased incidences of cardiomyocyte vacuolization and interstitial fibrosis occurred in 600 mg/kg males. A few early deaths in the 600 mg/kg males were considered to be due, at least in part and probably exclusively, to bis(2-chloroethoxy)methane-induced cardiotoxicity. The incidence of ulceration of the forestomach was significantly increased in 600 mg/kg males. Significantly increased incidences of dermal inflammation and fibrosis and epidermal hyperplasia at the site of application occurred in 600 mg/kg male mice. GENETIC TOXICOLOGY: Bis(2-chloroethoxy)methane was mutagenic in S. typhimurium strains TA100 and TA1535 in the presence of exogenous metabolic activation enzymes (S9) in one study; results from a second bacterial mutagenicity test were judged to be equivocal based on responses observed in TA100 and in E. coli strain WP2 uvrA/pKM101 in the presence of S9. No mutagenicity was observed in other tester strains or in the absence of S9. Bis(2-chloroethoxy)methane did not increase the frequency of micronucleated reticulocytes in bone marrow of male F344/N rats following three daily treatments by gavage or micronucleated erythrocytes in peripheral blood of male or female mice after 3 months of dermal exposure. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of bis(2-chloroethoxy)methane in male or female F344/N rats administered 75, 150, or 300 mg/kg. There was no evidence of carcinogenic activity of bis(2-chloroethoxy)methane in male B6C3F1 mice administered 150, 300, or 600 mg/kg or in female B6C3F1 mice administered 100, 200, or 400 mg/kg. The administration of bis(2-chloroethoxy)methane for 2 years resulted in increased incidences of nonneoplastic lesions in the nose of male and female rats, the forestomach of male rats, the heart of male and female mice, and the forestomach and skin of male mice.     

Toxicity Studies of 1,3-Dichlorobenzene in Sprague-Dawley Rats

ABSTRACT

Male and female Sprague-Dawley rats received 1,3-dichlorobenzene daily by corn oil gavage for 10 or 90 consecutive days. The 10-day study doses were 0, 37, 147, 368 and 735 mg/kg; the 90-day study doses were 0, 9, 37, 147 and 588 mg/kg. In the 10-day study, there was a significant depression of body weight in both sexes at 735 mg/kg. Liver weights were significantly increased in both sexes at 368 and 735 mg/kg. Serum cholesterol levels were significantly elevated in both sexes at 368 and 735 mg/kg. Histopathological evaluation revealed centrolobular hepatocellular degeneration at 368 mg/kg in males and 735 mg/kg in females.

In the 90-day study, body weights were significantly depressed in both sexes at 588 mg/kg. Normalization of food and water consumption by final body weight indicated that at 588 mg/kg both sexes had increased food and water consumption relative to controls. Absolute and relative liver weights were significantly increased in both sexes at 147 and 588 mg/kg. Relative kidney weights were significantly higher in both sexes at 588 mg/kg and in males at 147 mg/kg. Serum cholesterol and calcium levels were significantly elevated over controls in females at 37,147, and 588 mg/kg, and in males at all dose levels. Histopathological evaluation at 147 and/or 588 mg/kg demonstrated liver and thyroid lesions in both sexes, and pituitary and kidney lesions in males. A NOAEL was not firmly established.     

Toxicological study of pyridoxal isonicotinoyl hydrazone: acute and subchronic toxicity.

Pyridoxal isonicotinoyl hydrazone (PIH) is a highly effective iron chelator. Acute toxicity testing was performed in mice and rats of both sexes, with 10 mice or rats/sex/group. The LD50 values of PIH in both species were 5 and 1 g/kg given orally and intraperitoneally, respectively. Microscopic examination of tissues from the highest oral dose (6 g/kg) animals that survived 7 days revealed fatty degeneration in the liver. Subchronic toxicity was tested in rats of both sexes, with 8 males and 8 females/group. PIH doses of 100, 400 and 800 mg/kg were given orally for 90 consecutive days. Water was given to the control group. Hematocrit and blood chemistries were analysed at weeks 3, 6, 10 and 13. There were no changes in hematocrit and BUN. PIH at doses of 800 mg/kg caused a significant increase in serum alkaline phosphatase and transaminase levels at week 13. Microscopic examination showed hepatic degeneration in a dose-related fashion. Vascular congestion of the kidney and spleen was also found. No histopathological changes were detected in sections from the stomach and intestine.     

Short-term toxicity study in rats dosed with menthone

Menthone, a component of peppermint oil, was given p.o. to groups of 10 male and 10 female rats at dose levels of 0, 200, 400 and 800 mg/kg b.w./day, respectively, for 28 days. After 19 days the dose was reduced to 400 mg/kg b.w. in the female group receiving the highest dose. Analyses of plasma showed a dose-dependent decrease in creatinine content and a dose-dependent increase in alkaline phosphatase activity and bilirubin. The relative weights of liver and spleen were increased. Cyst-like spaces were seen histopathologically in the white matter of the cerebellum of the two highest dose groups. The no-effect level for menthone in this study was lower than 200 mg/kg b.w./day.     

26-Week repeated oral dose toxicity study of the new quinolone antibacterial DW-116 in Sprague-Dawley rats.

The purpose of this study is to investigate the potential subchronic toxicity of DW-116 by a 26-week repeated oral dose in Sprague-Dawley rats. The test article, DW-116, was administered daily by gavage to male and female rats at dose levels of 0, 5, 25 and 125 mg/kg/day. At the end of the treatment period, 12 rats/sex/group were sacrificed, while six extra rats/sex in the vehicle control and highest dose groups were sacrificed after a 4-week recovery. During the test period, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined. There was no treatment-related mortality. An increase in the incidence of post-dosing salivation was observed in both sexes of the highest dose group. At the scheduled autopsy, an increase in the liver weight was observed in males of the highest dose group in a dose-dependent manner. Hematological investigations revealed a dose-dependent increase in the total white blood cell (WBC) and lymphocyte counts in males treated with the 125 mg/kg dose. Total bilirubin and alanine aminotransferase (ALT) values were also increased in males at the same dose. These effects were completely reversible during the recovery period. There were no adverse effects on body weight, food and water consumption, ophthalmoscopy, urinalysis, necropsy findings and histopathology in any treatment group. Based on these results, it was concluded that the 26-week repeated oral dose of DW-116 caused increases in the liver weight, WBC counts, total bilirubin and ALT values in males at a dose level of 125 mg/kg/day. The target organ was determined to be the liver and WBC in males, but not in females. The no-observed-adverse-effect level (NOAEL) was considered to be 25 mg/kg/day for males and 125 mg/kg/day for females.