Combined repeated dose and reproductive/developmental toxicities of copper monochloride in rats

This study investigated the combined repeated dose and reproductive/developmental toxicity of copper monochloride in rats. The test substance was administered once daily by gavage at 0, 1.3, 5, 20, or 80 mg/kg/day. Male rats were dosed for a total of 30 days beginning 14 days before mating. Female rats were dosed from 2 weeks before mating to day 3 of lactation throughout the mating and gestation period. At 80 mg/kg/day, deaths were observed in 3 out of 12 females. There was a dose-dependent increase in the incidence of clinical signs and a reduction in the food consumption. Hematological and serum biochemical investigations revealed a decrease in the red blood cell, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin (MCH), and serum total protein levels and an increase in the white blood cell and platelets in males, and a decrease in the MCH and an increase in the platelets in females. Histopathological examination showed an increased incidence of squamous cell hyperplasia of the stomach in both genders as well as increased hematopoiesis of the femur in males. There was an increase in the number of icteric and runt pups at birth. At 20 mg/kg/day, there was an increase in the incidence of clinical signs and squamous cell hyperplasia of the stomach in both genders. At 5 mg/kg/day, an increase in the incidence of squamous cell hyperplasia of the stomach was observed in females. There were no adverse effects in the lowest group in both genders. Based on these findings, the no-observed-adverse-effect levels of copper monochloride were concluded to be 5 mg/kg/day in male rats and 1.3 mg/kg/day in female rats for general toxicity and 20 mg/kg/day for reproductive/developmental toxicity.     

4-Week repeated intravenous dose toxicity study of a new camptothecin anticancer agent CKD-602 in dogs.

CKD-602 is a new camptothecin derivative antitumor agent with a formula (7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin) developed by Chong Kun Dang Pharmaceutical Company in Korea. In the present study, the subacute toxicity of CKD-602 was investigated after 4-week repeated intravenous administration of the test chemical in beagle dogs. The test chemical was administered intravenously at dose levels of 0, 0.001, 0.005, or 0.01 mg/kg/day for 4 weeks to male and female dogs (n = 3 for male and female dogs for each dose). 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. In the high dose group, an increase in the incidence of abnormal clinical signs and a decrease in food and water intake and body weight gain were observed in both sexes. Hematological investigations revealed decreased white blood cells (WBC) in both sexes and reduced red blood cells (RBC), hemoglobin and hematocrit in females. Histopathological examinations revealed an increase in the incidence of atrophy of the sternal and femoral marrow and spleen in both sexes and atrophy of the thymus and mesenteric lymph node in males. No treatment-related adverse effects were observed in both sexes of the low and middle dose groups. In conclusion, the 4-week repeated intravenous dose of CKD-602 to beagle dogs caused increases in the clinical signs and histopathological changes, and decreases in the body weight gain, food and water intake, RBC, hemoglobin, hematocrit and WBC at the dose level of 0.01 mg/kg/day. In the present experimental conditions, the target organs were determined to be bone marrow, blood cells, spleen, thymus, and mesenteric lymph node. The no-observed-adverse-effect levels (NOAEL) for males and females were considered to be 0.005 mg/kg/day, respectively.     

Reproductive and Developmental Toxicity Screening Study of 4-Aminophenol in Rats

Twelve male and female rats per group were given 4-aminophenol (PAP) by gavage at 0, 20, 100, or 500 mg/kg/day. Males were dosed for a total of 49 days, beginning 14 days before mating. Females were dosed for a total of 40–60 days, from 14 days before mating to Day 3 of lactation throughout the mating and gestation periods. Four males and 2 females died at 500 mg/kg/day, and all surviving males and females showed brown urine at 100 mg/kg/day and above. Body-weight gain was lower in males and females at 500 mg/kg/day, and food consumption was decreased in males at 500 mg/kg/day and in females at 100 and 500 mg/kg/day. Absolute and relative weights of the testes and epididymides were decreased at 500 mg/kg/day. Histopathological examinations revealed decreased spermatocyte and spermatid levels in the testis, debris of germ cell in the epididymis lumen, basophilic tubules in the kidney, and deposits of hemosiderin in the red pulp and extramedullary hematopoiesis in the spleen in males at 500 mg/kg/day. Longer gestation period, decreased delivery index, and lower body weight of pups on postnatal day (PND) 0 and increased number of stillborns at 500 mg/kg/day were also observed. At this dose, the viability of pups on PND 4 was decreased markedly. No adverse effects on reproduction or development were detected at 20 and 100 mg/kg/day. These findings indicate that PAP is general and reproductive/developmental toxic, but is unlikely to be teratogenic, in rats.     

Reproductive and developmental toxicity screening study of 4-aminophenol in rats

Twelve male and female rats per group were given 4-aminophenol (PAP) by gavage at 0, 20, 100, or 500 mg/kg/day. Males were dosed for a total of 49 days, beginning 14 days before mating. Females were dosed for a total of 40-60 days, from 14 days before mating to Day 3 of lactation throughout the mating and gestation periods. Four males and 2 females died at 500 mg/kg/day, and all surviving males and females showed brown urine at 100 mg/kg/day and above. Body-weight gain was lower in males and females at 500 mg/kg/day, and food consumption was decreased in males at 500 mg/kg/day and in females at 100 and 500 mg/kg/day. Absolute and relative weights of the testes and epididymides were decreased at 500 mg/kg/day. Histopathological examinations revealed decreased spermatocyte and spermatid levels in the testis, debris of germ cell in the epididymis lumen, basophilic tubules in the kidney, and deposits of hemosiderin in the red pulp and extramedullary hematopoiesis in the spleen in males at 500 mg/kg/day. Longer gestation period, decreased delivery index, and lower body weight of pups on postnatal day (PND) 0 and increased number of stillborns at 500 mg/kg/day were also observed. At this dose, the viability of pups on PND 4 was decreased markedly. No adverse effects on reproduction or development were detected at 20 and 100 mg/kg/day. These findings indicate that PAP is general and reproductive/developmental toxic, but is unlikely to be teratogenic, in rats.     

Subchronic Oral Toxicology of 4-Chloro-3-nitroaniline in the Rat

Subchronic Oral Toxicology of 4-Chloro-3-nitroaniline in theRat. O'DONOGHtJE, J. L (1986). Fundam. Appl. Toxicol. 6, 551–558.4-Chloro-3-nitroaniline was given to groups of 20 male and 20female rats by gavage at doses of 3.6, 18, or 90 mg/kg in a10% corn oil suspension. Doses were administered 5 days perweek for 90 days. The high dose resulted in reduced body weightgain in males, reduced feed consumption and fluctuating feedconsumption in both sexes, slight hemolytic anemia with Heinzbodies in both sexes, enlargement of the spleen due to congestion,hemosiderosis, and increased extramedullary hematopoiesis inboth sexes, inflammatory changes in the splenic capsules oftwo females, hemosiderin pigmentation of the liver in both sexes,bone marrow hyperplasia in both sexes, increased liver weightin females, and testicular atrophy. The middle dose produceda fluctuating feed consumption pattern in males, Heinz bodiesin both sexes, very slight anemia in females, splenic hemosiderosisin males, slightly increased splenic extramedullary hematopoiesisin females, hemosiderin pigmentation of the liver in males,and possibly increased liver weight in females, and inflammatorychanges in the splenic capsule of one male. The low dose producedHeinz bodies in males and possibly females although the Heinzbody counts of females were not statistically significant Theprimary toxicologic damage produced by 4-chloro-3-nitroanilineis hemolytic or Heinz body anemia and testicular atrophy. Thusthe toxicity of 4-chloro-3-nitroaniline is similar to that ofother aromatic nitro and amino chemicals.     

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.     

Oral toxicity of a tocotrienol preparation in rats.

Tocotrienols are added as antioxidants to food. As there have been no reports of toxicological evaluation, a 13-week oral toxicity study was performed in Fischer 344 rats of both sexes at dose levels of 0 (group 1), 0.19 (group 2), 0.75 (group 3) and 3% (group 4) of a preparation in powdered diet. Suppression of body weight gain was observed in group 4 males. On hematological examination, significant decrease in mean corpuscular volume (MCV) was observed in all treated males. Platelets were significantly reduced in group 3 and 4 males. Hemoglobin concentration, MCV, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration were significantly decreased in group 3 and 4 females and hematocrit in group 4 females. On serum biochemical examination, increase in the albumin/globulin ratio (A/G) and alkaline phosphatase in all treated males, elevated alanine transaminase in group 4 of both sexes and increases in asparagine transaminase and gamma-glutamyl transaminase in group 4 females were observed. With regard to relative organ weights, liver weights in group 4 of both sexes and adrenal weights in all treated males demonstrated an increase, and ovary and uterus weights in group 4 females were reduced. Histopathologically, slight hepatocellular hypertrophy in group 3 and 4 males, and reduction of cytoplasmic vacuolation in the adrenal cortical region in group 4 males were observed. Because of pathological changes in male liver and hematological changes in females, the no-observed-adverse-effect level (NOAEL) was concluded to be 0.19% in the diet (120 mg/kg body weight/day for male rats and 130 mg/kg body weight/day for female rats). As a decrease in MCV, an increase in the A/G, elevation of alkaline phosphatase and increase in adrenal weight were observed in all treated males, a no-observed-effect level (NOEL) could not be determined in this examination.     

Subchronic and chronic toxicity of ingested 1,3-dichloropropene in dogs

The potential toxicologic effects to dogs of 1,3-dichloropropene (1, 3-D), a soil fumigant used for the control of nematodes, were investigated. The 13-week subchronic toxicity study consisted of male and female beagle dogs (4/sex/dose group) given approximately 0, 5, 15, or 41 mg 1,3-D/kg body wt/day (approximately equivalent amounts of cis and trans isomers) via their diets. The 1-year chronic toxicity study consisted of male and female beagle dogs (4/sex/dose group) provided diets delivering approximately 0, 0.5, 2. 5, or 15 mg/kg body wt/day. The test material was stabilized in the feed by microencapsulation in a starch/sucrose matrix (80/20). In both the 13-week and the 1-year studies, the primary effect of 1,3-D in male and female dogs ingesting a dosage of >/=15 mg/kg/day was hypochromic, microcytic anemia. The anemia was regenerative, with increased erythropoietic activity characterized by polychromasia of erythrocytes and increased numbers of reticulocytes in peripheral blood. In the 13-week study, the anemia in dogs given 41 mg/kg/day progressively worsened over time, while the anemia in dogs given 15 mg/kg/day remained relatively constant between 42 and 90 days of dosing. Partial reversal of the anemia of high-dose animals occurred during a 5-week recovery period following the 13-week dosing regimen. In the 13-week study, terminal fasted body weights of males given 15 or 41 mg/kg/day were decreased 3 and 28%, respectively, and body weights of females given 5, 15, or 41 mg/kg/day were decreased 4.5, 12, and 24%, respectively, relative to controls. Males given 5 mg/kg/day for 13 weeks had no change in body weights relative to controls. In the 1-year study, the hypochromic microcytic anemia in dogs given 15 mg/kg/day remained relatively constant in severity between 3 and 12 months of treatment. Histopathologic alterations associated with anemia in the 1-year study consisted of increased hematopoiesis of the bone marrow and increased extramedullary hematopoiesis of the spleen. Body weights of males given 15 mg/kg/day were 5-12% lower than controls during the first 13 weeks of the study and 13-19% lower than controls during the remaining 9 months. Body weights of females given 15 mg/kg/day were 5-14% lower than controls over the majority of the dosing period. Males and females given 0.5 or 2.5 mg/kg/day for 1 year had no change in body weights relative to controls. A no-observed-effect level of 2.5 mg/kg/day was established for male and female dogs from the 1-year study.     

A 28-day repeated dose toxicity study of ultraviolet absorber 2-(2'-hydroxy-3',5'-di-tert-butylphenyl) benzotriazole in rats

To examine the possible repeated-dose toxicity of an ultraviolet absorber, 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB), CD(SD)IGS rats were administered HDBB by gavage at a dose of 0 (vehicle: corn oil), 0.5, 2.5, 12.5, or 62.5 mg kg(-1) day(-1) for 28 days. At the completion of the administration period, a decrease in red blood cells, hemoglobin, and hematocrit was noted only in males at 2.5 mg/kg and more. Blood biochemical changes were noted at 0.5 mg/kg and more in males and at 62.5 mg/kg in females. Histopathologic changes were observed principally in the liver (vacuolar degeneration and hypertrophy of hepatocytes, bile duct proliferation, etc.) and in the heart (degeneration and hypertrophy of myocardium and cell infiltration). These changes were noted at 0.5 mg/kg and more in males and at 12.5 mg/kg and more in females. At higher doses, hypertrophy of tubular epithelium in the kidneys and diffuse follicular cell hyperplasia in the thyroids in both sexes and increased severity of basophilic tubules in the kidneys and extramedullary hematopoiesis in the spleen in males were also detected. After the 14-day recovery period, these changes mostly recovered in females but not in males. Based on these findings, no observed adverse effect level (NOAEL) was concluded to be less than 0.5 mg kg(-1) day(-1) in male rats and 2.5 mg kg(-1) day(-1) in female rats.     

Toxicity of 3,3',4,4'-tetrachloroazobenzene in rats and mice

The toxicity of 3,3',4,4'-tetrachloroazobenzene (TCAB) was evaluated in 13-week gavage studies in male and female F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included clinical chemistry, hematology, thyroid hormone analyses, and reproductive parameters. Groups of 10 rats and 10 mice of each sex were exposed to TCAB at dose levels of 0, 0.1, 1, 3, 10, or 30 mg/kg for 5 days a week for 13 weeks. In the rat studies, the major effects for both males and females included a 10% decrease in terminal body weight at 30 mg/kg/day, an increase in hematopoietic cell proliferation in the spleen at 10 and 30 mg/kg/day, and a responsive anemia at 10 and 30 mg/kg/day. A 15 to 30% decrease in platelet counts and a 20 to 40% decrease in thymus weights was observed at 10 and 30 mg/kg/day. An increase in liver weight up to 15% was found at 3 mg/kg/day and higher doses in males and at 10 and 30 mg/kg/day in females, respectively. An increase in spleen weights up to 15% was observed at 10 and 30 mg/kg/day in males and at 30 mg/kg/day in females. A marked decrease in circulating total thyroxine (TT4) was found in both males and females at all dose levels tested. TT4 could hardly be detected at 10 and 30 mg TCAB/kg/day. In addition, hyperplasia of the forestomach was increased at 3 mg/kg/day and higher doses in males and at 30 mg/kg/day in females. In the mouse studies, an increase in liver and spleen weight was observed up to approximately 25% in both males and females at 10 and 30 mg/kg/day. Hyperplasia of the forestomach was observed at 1 mg/kg/day and higher doses in both males and females. In males, a 30% decrease in thymus weights at 30 mg/kg/day and a 60% decrease in epididymal sperm density at 3 and 30 mg/kg/day was observed. Also in males, centrilobular hypertrophy of hepatocytes and an increase in hematopoietic cell proliferation in the spleen was observed at 3 mg/kg/day and higher doses. Based on the current study and information in the literature, TCAB has dioxin-like properties. Comparison of the effects of TCAB in the present study and in the literature to those with 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) indicates that TCAB is from two to six orders of magnitude less potent than TCDD depending on the end point.     

Subchronic toxicity of plant sterol esters administered by gavage to Sprague-Dawley rats.

The purpose of this study was to investigate the potential subchronic toxicity of plant sterol esters by a 13-week repeated oral dose in Sprague-Dawley rats. The test article was administered once daily by gavage to male and female rats at dose levels of 0, 1000, 3000 and 9000 mg/kg/day for 13 weeks. At the end of treatment period, 10 rats/sex/group were sacrificed, while six rats/sex in the negative control and highest dose groups were sacrificed after a 4-week recovery period. 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. Slight decreases in body weight gain were noted at lower doses but were only statistically different from the control animals in the highest dose group. In histopathological examinations, an increase in the incidence of cardiomyopathy with mononuclear cell infiltration was observed in males of the 9000 mg/kg group. Decreased body weight gain and increased incidence of cardiomyopathy observed in the highest dose group were not recovered until the end of the recovery period. There were no adverse effects on mortality, clinical signs, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, necropsy findings and organ weights in any treatment group. Based on these results, it was concluded that the 13-week repeated oral dose of plant sterol esters resulted in the suppression of body weight gains in both sexes and cardiomyopathy in males at a dose level of 9000 mg/kg/day. The target organ was determined to be heart in males, but not in females. The no-observed-adverse-effect level (NOAEL) was considered to be 3000 mg/kg/day for both sexes.     

Oral (gavage), in utero and postnatal exposure of Sprague-Dawley rats to low doses of tributyltin chloride. Part 1: Toxicology, histopathology and clinical chemistry.

Tributyltin (TBT) is a biocide that contaminates foods, especially shellfish. TBT is an endocrine disrupter in several marine species and is neurotoxic and immunotoxic in mammals. We have examined the effects of exposure to low doses of tributyltin chloride (TBTC) from day 8 of gestation until adulthood. Pregnant rats were gavaged daily with 0, 0.025, 0.25 or 2.5 mg TBTC/kg body weight from day 8 of gestation until weaning. Stomach contents of suckling pups contained undetectable levels of TBT and dibutyltin (DBT) levels were detectable only in the highest TBTC dose used, indicating negligible lactational transfer to pups. Post weaning, pups were gavaged daily with the same dose of TBTC administered to their mothers and sacrificed on post-natal days (PND) 30 (males and females), 60 (females) and 90 (males). TBTC had no effects on dams' body weights, food consumption, litter size, sex ratio or survival of pups to weaning. However, all doses of TBTC significantly affected parameters of the growth profile of the pups (mean body weights, average slope, curvature) and the ratio of weekly food consumption to weekly body weight gain indicated enhanced food conversion to body mass in females but a decreased conversion in males. Liver, spleen and thymus weights were also affected by TBTC. In male pups dosed at 2.5 mg/kg/day, reduced serum thyroxine levels were evident, indicating that the thyroid is a target for TBTC toxicity. No histopathological lesions were seen in the liver but elevated serum alanine aminotransferase, gamma-glutamyl transferase and amylase indicated hepatotoxicity. Significant decreases in liver weights in female pups exposed to 0.025 mg/kg/day TBTC were observed at PND 60. Decreases in spleen and thymus weights also pointed towards toxic effects of TBTC on the immune system. The 0.025 mg/kg/day TBTC should have been a no affect dose and yet this dose caused significant effects on growth profiles, decreased liver weights and elevated serum GGT levels in females.     

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.     

Toxicological studies on (2"R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic. Subacute toxicity study in rats

(2"R)-4'-O-Tetrahydropyranyladriamycin X HCl (THP), a new anthracycline antitumor antibiotic, was administered to Sprague-Dawley rats intraperitoneally for 13 weeks. In rats receiving 0.4 mg/kg/day, piloerection, emaciation, loose feces and thickening of the injection site were evident, and 7 males and 2 females died after week 12. Inferior body weight gain was observed in both sexes starting week 4 approximately 6. The food consumption also decreased. Hematological examination revealed lower counts of total leucocyte and lymphocyte. At termination there were lower spleen, thymus and testes weights, thickening of the walls of the intestine and stomach, gastric ulceration, presence of ascitic fluid, and congestion and thickening at the injection site. Decreases in the lymphocyte populations of the thymus, spleen and lymph nodes were observed microscopically. A decrease in the number of hematopoietic cells in the bone marrow and a degeneration of the germinal epithelium in the testes were also seen, as were gastrointestinal disturbances. These treatment-related effects were mainly confined to rats receiving 0.4 mg/kg/day and to a lesser extent, to rats receiving 0.1 mg/kg/day. The effects on rats receiving 0.025 mg/kg/day were only at the microscopic level. No rats receiving 0.006 mg/kg/day were toxicologically affected.     

Combined repeated dose and reproductive/developmental toxicity screening test of the nitrophenolic herbicide dinoseb, 2-sec-butyl-4,6-dinitrophenol, in rats

In a combined repeated dose toxicity study with reproduction/developmental toxicity screening test, Crj:CD(SD)IGS rats were dosed with dinoseb, 2-sec-butyl-4,6-dinitrophenol, by gavage at 0 (vehicle), 0.78, 2.33, or 7.0 mg/kg bw/day. Six males per group were dosed for a total of 42 days beginning 14 days before mating. Twelve females per group were dosed for a total of 44-48 days beginning 14 days before mating to day 6 of lactation throughout the mating and gestation period. Recovery groups of six males per group and nonpregnant six females per group were dosed for 42 days followed by a 14-day recovery period. No deaths were observed in males of any dose group or in females of the recovery groups. At 7.0 mg/kg bw/day, eight females died and two animals were moribund during late pregnancy, and a significant decrease in body weight gain was found in both sexes. Hematocrit was significantly higher at 0.78 mg/kg bw/day and above in the main group males at the end of administration period. Reduction in extramedullary hematopoiesis in the spleen was significant at 2.33 mg/kg bw/day in the main group females. Sperm analysis revealed a decrease in sperm motility and an increase in the rates of abnormal sperm, abnormal tail, and abnormal head at 7.0 mg/kg bw/day. A number of dams delivered their pups and of dams with live pups at delivery was significantly lowered in the 7.0 mg/kg bw/day group. Based on these findings, the LOAEL for males and NOAEL for females were 0.78 mg/kg bw/day, and the NOAEL for reproductive/developmental toxicity was considered to be 2.33 mg/kg bw/day.     

Ten- and ninety-day toxicity studies of 1,2-dichlorobenzene administered by oral gavage to Sprague-Dawley rats

Ten- and ninety-day toxicity studies of 1,2-dichlorobenzene (DCB) were conducted in male and female Sprague-Dawley rats to meet the needs of the U.S. Environmental Protection Agency for toxicity data on this chemical for use in their determination of possible health risks related to human exposure. 1,2-Dichlorobenzene was administered at doses of 37.5, 75, 150, and 300 mg/kg/day (10-day), and 25, 100, and 400 mg/kg/day (90-day) in corn oil by oral gavage; control animals received corn oil. At time of sacrifice, gross necropsies were performed and selected tissues were weighed and prepared for histological evaluation. Blood was taken for hematology and clinical chemistries. In the 10-day study, exposure of 300 mg DCB/kg body weight to male rats resulted in a statistically significant decrease in final body weight, organ weights (heart, kidneys, spleen, testes, and thymus), and relative organ weights (spleen and thymus). A significant increase in absolute and relative liver weights was also noted in this dose group. Males also displayed significant increases in water consumption (300 mg/kg group), ALT (300 mg/kg) and leukocyte count (150 and 300 mg/kg). A significant increase in the incidence of hepatocellular necrosis was seen in the 300 mg/kg group of males compared to controls. In the 90-day study, male rats exposed to 400 mg DCB/kg displayed a statistically significant decrease in body weight, organ weight (spleen), and relative organ weight (spleen). The absolute weights of kidney and liver and the relative weights for heart, kidney, liver, lung, brain, and testes were increased significantly for this dose group. The absolute and relative weights of both the kidney and liver were significantly increased in the female 400 mg/kg dose group. The only clinical chemistry parameters statistically different than control were increased ALT (100 and 400 mg/kg groups), BUN and total bilirubin in the male 400 mg/kg group and total bilirubin in the 400 mg/kg female group. Histopathological evaluation showed hepatocellular lesions associated with DCB treatment which included centrolobular degeneration and hypertrophy, and single cell necrosis in male and females receiving 400 mg DCB/kg. The NOAEL observed in this study is 25 mg/kg/day.     

REPRODUCTIVE AND REPEATED DOSE TOXICITY OF CYCLODODECATRIENE (CDDT) IN RATS FOLLOWING ORAL (GAVAGE) TREATMENT

ABSTRACT

Cyclododecatriene (CDDT, CAS No. 4904-61-4) was administered daily by oral gavage to groups of Crl:CD®(SD)IGS BR rats at dose levels of 0 (control), 30, 100, or 300 mg/kg/day. Female rats were dosed for four weeks premating, through mating, gestation, and lactation (a total of 55 to 63 days of treatment). Male rats were treated for 55 days (four weeks premating and through mating). Premating, body weights, food consumption, and clinical signs were recorded. Hematology, clinical chemistry, and urine analyses were conducted at the end of the premating period. A neurobehavioral test battery was conducted prior to and after four weeks of treatment. After the premating period, females were paired with males from the same groups for 1–2 weeks. Litters were delivered, pups were evaluated for structural integrity, and pup body weights were recorded on days 0 and 4 postpartum. Lactating females and their offspring were sacrificed on postpartum day 4. Selected organs were weighed and the tissues were examined microscopically from the lactating females. Offspring were examined for clinical abnormalities. A test substance-related reduction in body weight gain occurred in male rats administered 300 mg/kg/day. Decreased body weight gain in the 300 mg/kg/day males was accompanied by increased food consumption and decreased food efficiency. Females administered 100 or 300 mg/kg/day had test substance-related, significantly decreased body weight and body weight gain during gestation, that was accompanied by a significant increase in food consumption (300 mg/kg/day group only), and significantly decreased food efficiency. There were no test-substance related effects on clinical observations in males or females during the premating phase, or in females during gestation or lactation. Neurobehavioral parameters and motor activity were unaffected by CDDT-treatment. During this study, statistically significant treatment-related changes were observed in several clinical pathology parameters. The decreases in red cell mass (RBC, HGB, HCT) were minimal and, due to the magnitude, were not expected to result in biological effects. Similarly, minimally increased potassium and mildly decreased triglycerides were not of a magnitude to be biologically significant. Finally, changes in serum enzymes (AST, ALT, ALP), urea nitrogen, and serum protein occurred in directions that are not associated with toxicity. The changes in urine volume, urine concentration, and urea nitrogen may be the result of elevated glomerular filtration rate and altered tubular fluid flow, in the absence of any histopathological change. No effects on reproduction in parental males or females were produced by CDDT. Body weights of pups in the 300 mg/kg group were significantly decreased on postpartum days 0 and 4. There were no test-substance related effects on clinical observations, number of pups born, and the number of pups born alive, or the number of pups surviving through lactation day 4. The no-observed-adverse-effect level (NOAEL) for CDDT was 30 mg/kg/day based on decreased body weight and body weight gain, increased food consumption, and decreased food efficiency in females administered 100 or 300 mg/kg/day. The NOEL in pups was 100 mg/kg/day, based on decreased body weights of pups in the 300 mg/kg/day group during lactation.     

Evaluation of the toxic potentials of a new camptothecin anticancer agent CKD-602 on fertility and early embryonic development in rats

This study examined the potential adverse effects of a new camptothecin anticancer agent, CKD-602, on the fertility and early embryonic development of Sprague-Dawley rats. Ninety-six rats of each gender were divided into four groups: three treatment groups and a control group. CKD-602 was administered intravenously to male rats at 0, 4.7, 14, and 42 microg/kg from 63 days prior to mating until the end of the mating period, and to female rats from 14 days before mating until day 6 of gestation. All the males were sacrificed after the end of the 14-day mating period, while all the females were subjected to a caesarean section on day 15 of gestation. In the high dose group, a high incidence of hair loss was observed in both genders. A decrease in the level of food consumption, followed by a decrease in body weight gain was also observed in both genders. At the scheduled necropsy, the gross postmortem examinations revealed an increase in the incidence of thymic atrophy, paleness of the thoracic and abdominal organs in both genders and an increase in the serum testosterone concentration. In addition, there was a decrease in the thymus weight of the males and an increase in the liver, spleen, kidneys, lung, and heart weights of the females. There was an increase in the number of fetal deaths and post-implantation losses as well as a decrease in the litter size found at the caesarean section of the dams. No treatment-related effect on the histopathological findings, sexual cycle, pre-coital time, mating index, fertility index, pregnancy index, and sperm parameters was observed. There were no adverse effects on the general findings and reproductive performance of the parent animals and early embryonic development in the low and medium dose groups. Overall, the no-observed-adverse-effect levels (NOAELs) of CKD-602 are believed to be 14 microg/kg for both general toxicity and early embryonic development, and more than 42 microg/kg for the reproductive performance of the parent animals.     

Lack of immunotoxic effects of repeated exposure to atrazine associated with the adaptation of adrenal gland activation

T cell-dependent IgM antibody production and natural killer cell (NKC) activity were assessed in SD rats orally administered atrazine for 28 days to males (0, 6.5, 25, or 100 mg/kg/day) or females (0, 3, 6, or 50 mg/kg/day), or 30 or 500 ppm in diet (3 or 51 mg/kg/day). Anti-asialo GM1 antibodies (NKC) and cyclophosphamide (antibody-forming cell assay [AFC]) served as positive controls. Pituitary (ACTH, prolactin), adrenal (corticosterone, progesterone, aldosterone), and gonadal (androgens, estrogens) hormones were assessed after 1, 7, and/or 28 days of treatment. Food intake and body weights were significantly reduced in the highest dosed males, and transiently affected in females. Urinary corticosterone levels were not increased in atrazine-treated groups in either sex at any time point measured (10, 22, or 24 days). Corticosterone and progesterone were elevated in males after a single atrazine dose ≥6.5 mg/kg/day, but not after 7, 14, or 28 doses. There were no effects on adrenal, pituitary, or gonadal hormones in females. Atrazine did not suppress the AFC response or decrease NKC function after 28 days in males or females. Atrazine had no effect on spleen weights or spleen cell numbers in males or females, although thymus weights were elevated in males receiving the highest dose. The lack of immunotoxic effect of atrazine was associated with diminished adrenal activation over time in males, and no effects on adrenal hormones in females.     

Reproductive and repeated dose toxicity of cyclododecatriene (CDDT) in rats following oral (gavage) treatment

Cyclododecatriene (CDDT, CAS No. 4904-61-4) was administered daily by oral gavage to groups of Crl:CD (SD)IGS BR rats at dose levels of 0 (control), 30, 100, or 300 mg/kg/day. Female rats were dosed for four weeks premating, through mating, gestation, and lactation (a total of 55 to 63 days of treatment). Male rats were treated for 55 days (four weeks premating and through mating). Premating, body weights, food consumption, and clinical signs were recorded. Hematology, clinical chemistry, and urine analyses were conducted at the end of the premating period. A neurobehavioral test battery was conducted prior to and after four weeks of treatment. After the premating period, females were paired with males from the same groups for 1-2 weeks. Litters were delivered, pups were evaluated for structural integrity, and pup body weights were recorded on days 0 and 4 postpartum. Lactating females and their offspring were sacrificed on postpartum day 4. Selected organs were weighed and the tissues were examined microscopically from the lactating females. Offspring were examined for clinical abnormalities. A test substance-related reduction in body weight gain occurred in male rats administered 300 mg/kg/day. Decreased body weight gain in the 300 mg/kg/day males was accompanied by increased food consumption and decreased food efficiency. Females administered 100 or 300 mg/kg/day had test substance-related, significantly decreased body weight and body weight gain during gestation, that was accompanied by a significant increase in food consumption (300 mg/kg/day group only), and significantly decreased food efficiency. There were no test-substance related effects on clinical observations in males or females during the premating phase, or in females during gestation or lactation. Neurobehavioral parameters and motor activity were unaffected by CDDT-treatment. During this study, statistically significant treatment-related changes were observed in several clinical pathology parameters. The decreases in red cell mass (RBC, HGB, HCT) were minimal and, due to the magnitude, were not expected to result in biological effects. Similarly, minimally increased potassium and mildly decreased triglycerides were not of a magnitude to be biologically significant. Finally, changes in serum enzymes (AST, ALT, ALP), urea nitrogen, and serum protein occurred in directions that are not associated with toxicity. The changes in urine volume, urine concentration, and urea nitrogen may be the result of elevated glomerular filtration rate and altered tubular fluid flow, in the absence of any histopathological change. No effects on reproduction in parental males or females were produced by CDDT. Body weights of pups in the 300 mg/kg group were significantly decreased on postpartum days 0 and 4. There were no test-substance related effects on clinical observations, number of pups born, and the number of pups born alive, or the number of pups surviving through lactation day 4. The no-observed-adverse-effect level (NOAEL) for CDDT was 30 mg/kg/day based on decreased body weight and body weight gain, increased food consumption, and decreased food efficiency in females administered 100 or 300 mg/kg/day. The NOEL in pups was 100 mg/kg/day, based on decreased body weights of pups in the 300 mg/kg/day group during lactation.