Dose In Male Rats Research Articles

Pharmacokinetics of 5-(4-(2-Carboxyethylcarbamoyle)-phenylazo) Salicylic Acid Disodium Salt Dihydrate (BX661A). (3): Distribution and Excretion in Rat after Single Oral and Intravenous Administration.

The distribution and excretion of radioactivity, and of the unchanged drug and major metabolites were investigated in rats after a single oral or intravenous administration of 14C-BX661A (labeled at 5ASA moiety: 14C-BX661A (5ASA), labeled at 4ABA moiety: 14C-BX661A (4ABA)) and non-labeled BX661A. 1. After oral administration of 14C-BX661A(5ASA) to fasted male rats, the radioactivity reached the highest level at 10 hr after administration in most tissues, except gastrointestinal tract. At this time point, the tissues showing higher level of radioactivity than that in plasma, were liver and kidney, except gastrointestinal tract. After administration of 14C-BX661A (4ABA), similar results were obtained. However, the levels of radioactivity were lower than those of 14C-BX661A (5ASA). 2. During 72 hr after oral administration of 14C-BX661A (5ASA) to fasted male rats, about 32 and 66% of the dose were excreted into the urine and feces, respectively. In female rats, about 45 and 55% of the dose were excreted into the urine and feces, respectively. While in 14C-BX661A (4ABA), the excretion of radioactivity into the urine and feces were about 7 and 88% of the dose in male rats, and the similar results were obtained in female rats. 3. During 72 hr after oral administration of BX661A to fasted male rats at a dose of 50, 100 and 200 mg/ kg, the excretion of the unchanged drug into the urine and feces were less than 0.6% of the dose. It was suggested that azo linkage of BX661A was almost completely cleavaged. Urinary excretion of 5ASA and Ac-5ASA accounted for 0.0-2.2% and 21.1-24.5%, and fecal excretion were 22.7-25.3% and 20.0-32.1% of the dose, respectively. On the other hand, urinary excretion of 4ABA and Ac-4ABA were less than 0.8 and 3.4-4.3% of the dose, respectively. Fecal excretion of 4ABA and Ac-4ABA were 67.3-78.5% and 2.7-5.1% of the dose, respectively. 4. During 72 hr after oral administration of BX661A to fasted female rats at a dose of 100 mg/kg, the fecal excretion of Ac-5ASA was significantly higher than those of male. Excretion pattern of another compounds were similar to those of male rats. 5. During 72 hr after intravenous administration of 14C-BX661A(5ASA) to fasted male rats, about 43 and 55% of the dose were excreted into the urine and feces, respectively. After administration of 14C-BX661A (4ABA), about 29 and 66% of the dose were excreted into the urine and feces, respectively. After intravenous administration of BX661A to fasted male rats, 29.5% of the dose was excreted into the urine as the unchanged drug within 8 hr. On the other hand, urinary excretion of Ac-5ASA was 11.5%, and fecal excretions of 5ASA, Ac-5ASA and 4ABA were 4.9, 19.3 and 29.0% of the dose during 72 hr, respectively. 6. After oral administration of 14C-BX661A to fasted male rats, the biliary excretions within 24 hr were 3-4% of the dose in both labeled compounds. After intravenous administration of 14C-BX661A (5ASA) to fasted male and female rats, the biliary excretion within 120 min was low in male rats compared with female (male: 67%, female: 80%). 7. Azo-bond of BX661A was easily reduced by reacting with human feces. After 90 min of reaction, the unchanged drug was not detected and the formation of 5ASA was observed. However, Ac-5ASA was not detected in the reaction mixture.

Nonclinical Toxicology Studies with Zidovudine: Reproductive Toxicity Studies in Rats and Rabbits

Zidovudine (ZDV) was evaluated for adverse effects on reproduction and fetal development in animal test species. Standard preclinical tests for reproduction and fertility, developmental toxicity, and postnatal toxicity were conducted in CD (Sprague–Dawley) rats and a developmental toxicity study was conducted in New Zealand white rabbits. In an additional study, reproductive outcome was characterized in female rats given ZDV before, during, or after mating and drug levels in the plasma and milk of lactating rats were determined. Finally, drug exposure data including observed peak plasma concentrations (Cmax) and area under the concentration–time curve (AUC) were evaluated for pregnant rats and rabbits. In a reproduction/fertility study in CD rats, toxicity to the early rat embryo, manifested as an increase in early resorptions and a decrease in litter size, was noted following dosage of the parental animals with 75 or 225 mg ZDV/kg bid. A dose of 25 mg/kg bid was a no-effect level in rats. At the time of mating, male rats had been dosed for 85 days, and females had been dosed for 26 days. To further evaluate the effects of ZDV on reproduction, dosing of male rats was continued to 149 days when they were mated a second time to virgin, untreated females. All reproductive parameters were normal in the untreated females from this second mating, indicating that the embryotoxic effect of the drug was not likely mediated by a genotoxic or other effect in the male. A separate study in female CD rats given 225 mg/kg bid for various periods pre- or postconception suggests that the toxic effect of ZDV is primarily to the early rodent embryo. Early embryo death did not occur in rats or rabbits in standard developmental (teratology) studies; however, pregnant New Zealand white rabbits given 250 mg/kg bid during gestation Days 6–18 showed reduced weight gain, anemia, and an increase in late fetal deaths. No other evidence of developmental toxicity was noted in either species, and ZDV was not teratogenic in rats or rabbits given up to 250 mg/kg bid during the period of major organogenesis. At this dose,Cmaxvalues in rats and rabbits were approximately 234 and 150 times higher, respectively, than the mean steady-state serum concentration in adults following chronic oral administration of 250 mg every 4 hr. In both the reproduction/fertility study and a peri- and postnatal study in rats, liveborn offspring showed no adverse effects on survival, growth, or developmental measurements.

Absorption, Tissue Distribution, Excretion, and Metabolism of 3H- and 14C-Labeled Emamectin Benzoate in Rats

Male and female rats were administered a single high (20 mg/kg, oral) or low (0.5 mg/kg, oral or intravenous) dose of radiolabeled 4‘‘-deoxy-4‘‘-(epi-methylamino)avermectin B1a (MAB1a) benzoate. The bioavailability of MAB1a benzoate (low dose) in male and female rats was 43% and 63%, respectively. More than 98% of the total radioactivity was found in feces, with <0.4% in urine and <1.6% in the tissues. The total radioactive residues (TRR) in feces and tissues consisted of MAB1a and a single N-demethylated metabolite. The TRR contents (ppb parent equivalent) of kidney, liver, fat, muscle, spinal cord, and brain at day 1 post low oral dose in male rats were 437, 355, 241, 109, 30, and 8 ppb, respectively, and in female rats 260, 244, 192, 90, 11, and 5 ppb, respectively. The TRR contents of these tissues from both male and female rats declined to very low levels (≤12 ppb) by day 7. The TRR content of tissues at day 7 post high dose was relatively high (8−2033 ppb). Lung and spleen had higher residue contents in comparison to other tissues. Daily pretreatment with the compound for 14 days had no effect on the tissue residue levels and metabolism. Keywords: Emamectin; MK-0244; 4‘‘-deoxy-4‘‘-(epi-methylamino)avermectin B1a; 4‘‘-deoxy-4‘‘-epi-aminoavermectin B1a; residues; metabolism; HPLC

Nonclinical Toxicology Studies with Zidovudine: Reproductive Toxicity Studies in Rats and Rabbits

Zidovudine (ZDV) was evaluated for adverse effects on reproduction and fetal development in animal test species. Standard preclinical tests for reproduction and fertility, developmental toxicity, and postnatal toxicity were conducted in CD (Sprague-Dawley) rats and a developmental toxicity study was conducted in New Zealand white rabbits. In an additional study, reproductive outcome was characterized in female rats given ZDV before, during, or after mating and drug levels in the plasma and milk of lactating rats were determined. Finally, drug exposure data including observed peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) were evaluated for pregnant rats and rabbits. In a reproduction/fertility study in CD rats, toxicity to the early rat embryo, manifested as an increase in early resorptions and a decrease in litter size, was noted following dosage of the parental animals with 75 or 225 mg ZDV/kg bid. A dose of 25 mg/kg bid was a no-effect level in rats. At the time of mating, male rats had been dosed for 85 days, and females had been dosed for 26 days. To further evaluate the effects of ZDV on reproduction, dosing of male rats was continued to 149 days when they were mated a second time to virgin, untreated females. All reproductive parameters were normal in the untreated females from this second mating, indicating that the embryotoxic effect of the drug was not likely mediated by a genotoxic or other effect in the male. A separate study in female CD rats given 225 mg/kg bid for various periods pre- or postconception suggests that the toxic effect of ZDV is primarily to the early rodent embryo. Early embryo death did not occur in rats or rabbits in standard developmental (teratology) studies; however, pregnant New Zealand white rabbits given 250 mg/kg bid during gestation Days 6–18 showed reduced weight gain, anemia, and an increase in late fetal deaths. No other evidence of developmental toxicity was noted in either species, and ZDV was not teratogenic in rats or rabbits given up to 250 mg/kg bid during the period of major organogenesis. At this dose, Cmax, values in rats and rabbits were approximately 234 and 150 times higher, respectively, than the mean steady-state serum concentration in adults following chronic oral administration of 250 mg every 4 hr. In both the reproduction/fertility study and a periand postnatal study in rats, liveborn offspring showed no adverse effects on survival, growth, or developmental measurements.

Health effects of inhaled tertiary amyl methyl ether and ethyl tertiary butyl ether

Government specifications on the oxygen content of motor gasoline sold in certain areas of the USA have resulted in commercialization of the oxygenate fuel additives tertiary amyl methyl ether (TAME) and ethyl tertiary butyl ether (ETBE). TAME and ETBE were evaluated in 4-week rat inhalation studies sponsored by Amoco Corporation. Target vapor concentrations were 0, 500, 2000, or 4000 ppm for 6 h per day, 5 days per week, for 4 weeks. TAME exposure at 4000 ppm resulted in 25% mortality, apparently as a consequence of severe CNS depression. Body weight gain was decreased in the TAME high dose male rats. In contrast, no ETBE exposed animals died during the study and no changes in body weight gain were observed. Significant effects on functional observational battery (FOB) parameters were only found in the TAME high and mid-dose groups immediately after exposure. All affected FOB parameters were normal by the next day. Both TAME and ETBE exposures significantly increased relative liver weights in the high and mid-dose groups. However, no treatment-related histopathologic findings were noted for either compound. Clinical chemistry and hematology findings were absent with ETBE exposure and minimal with TAME exposure. The results indicate that 500 ppm was a NOAEL for both compounds in these studies.

N-Nitro- L-arginine attenuates development of tolerance to antinociceptive but not to hormonal effects of morphine

The effect of N-nitro- L-arginine methyl ester on thyrotropin (TSH), growth hormone (GH) and prolactin levels in serum was studied after a single dose in male rats. The effect of repeated N-nitro- L-arginine methyl ester on the development of tolerance to the multiple effects of morphine was also examined. N-Nitro- L-arginine methyl ester (25 mg/kg i.p.) decreased cold-stimulated (rats were kept 30 min at +4°C) TSH levels but did not alter basal TSH, GH or prolactin levles. Acute or repeated N-nitro- L-arginine methyl ester treatments were not antinociceptive alone, neither did they modify the effect of acute morphine. A 5-day treatment with increasing doses of morphine induced antinociceptive tolerance. This was attenuated by N-nitrol- L-arginine methyl ester co-administration on the 3rd day, less so on the 5th day. Repeated morphine produced tolerance to the effect on TSH (decrease) and prolactin (increase) levels, but sensitization to the GH-elevating effect, measured after a 4-day delay. A 5-day treatment with N-nitro- L-arginine methyl ester did not modify the development of tolerance to the hormonal effects of morphine. In the case of TSH, it is difficult to draw a conclusion because the 5-day N-nitro- L-arginine methyl ester and morphine treatment generally decreased basal TSH levels. Sensitization to the hyperthermic effect of morphine occurred after a 4-day delay and this was not altered by N-nitro- L-arginine methyl ester. These results suggest that both intric oxide-dependent and independent mechanisms are involved in the development of tolerance to the various effects of morphine.

Studies on the Metabolic Fate of Felodipine. (V): Absorption, Distribution, Metabolism and Excretion after a Single Oral Administration to Dogs.

The absorption, distribution, metabolism and excretion of 14C-nizatidine were studied after a single oral or intravenous administration of 5 mg/kg to rats.1. The blood levels of radioactivity reached a maximum concentration at 30 min after oral administration, corresponding to 668 and 426 ng equivalent of nizatidine/ml, and then declined within the first 6 hr with half-lives of 1.43 and 1.38 hr in male and female rats, respectively. The half-lives in the ranges of 8-24 hr were 10.3 hr in male, and 15.4 hr in female.2. The blood level of radioactivity declined biexponentially with half life of 0.66 hr in the first 4 hr and 27.0 hr in the range between 6 hr and 48 hr after intravenous administration in male rats.3. Male rats excreted 68.0 % of the dose in urine and 27.1 % of the dose in feces until 120 hr after oral administration. Until 120 hr after intravenous administration, male rats excreted 84.2 and 16.2 % of the dose in urine and feces, respectively. The biliary excretion within 48 hr after oral administration was 20.2% of the dose in male rats, while the excretion of the radioactivity reabsorbed, as a percent of the dose, was 5.8% in bile and 30.3% in urine until 48 hr after intraduodenal injection.Female rats excreted 59.7 % of the dose in urine and 39.1 % of the dose in feces until 120 hr after oral administration.4. The radioactivity levels in the tissues except the testis reached a maximum concentration at 30 min after oral administration in male rats, and relatively high radioactivity was found the kidney, small intestine, liver, urinary bladder and stomach. The other tissues contained nearly the same concentrations of radioactivity as plasma, or somewhat lower. At 120 hr after oral administration, the radioactivity in most tissues was not detectable.5. The plasma protein binding in vitro was 12.8-16.9% at concentrations range between 0.1 and 10 μg/ml, and that in vivo was 20.6, 26.2 and 41.8% in the plasma sample collected 0.5, 2 and 6 hr after administration, respectively.6. In the fractions of plasma and urine collected in male and female rats after oral administration, the unchanged drug, N-desmethyl and S-oxide metabolites were the main components and the other minor compounds, M-3 and M-5, were also detected in the urine. In the fractions of bile in male rats, M-2, M-4, M-5 were detected with the unchanged drug, N-desmethyl and S-oxide metabolites.

Studies on the Metabolic Fate of Neticonazole. (I): Absorption, Distribution, Metabolism and Excretion in Rats after a Single Subcutaneous Administration.

The absorption, distribution, metabolism and excretion of 14C-neticonazole (14C-SS717) were studied in rats after a single subcutaneous administration of 25mg/kg.1. Blood levels of the radioactivity reached the maximum of 2.Olμg equiv. of SS717/ml (male) or 1.59μg equiv. of SS717/ml (female) at 4hr after dosing, and then declined slowly during 4 ?? 24hr with half-lives of 21 and 15hr in male and female rats, respectively. The elimination half-lives at the terminal phase (48 ?? 168hr) were 64hr (male) and 58hr (female).2. Within 120hr after dosing in male rats, 65.4 and 29.5% of the dose were excreted in the urine and feces, respectively. No sex difference was observed in the excretion of radioactivity.3. Biliary excretion of the radioactivity within 48hr after dosing was 51.9 and 46.7% in male and female rats. respectively. In male rats, 46. 7 and 2.0% of the dose were excreted in the urine and feces, respectively, while the excretion of radioactivity in female rats was 49. 6% of the dose in the urine and 2.7% of the dose in the feces. Also, the partial reabsorption of biliary excreta occurred from the intestinal tract.4. Maximum levels of the radioactivity in most of tissues were reached at 4hr after dosing in male rats, and a high level of the radioactivity was observed in the adrenal gland, liver, kidney, aorta, fat and harderian gland. The distribution of radioactivity in the stomach was also visualized by the whole body autoradiography.5. The extent of in vitro binding of 14C-SS717 to plasma proteins was 98.7 ?? 99.0% in rats, and 99.2-99.7% in human. The percent of in vivo binding of 14C-SS717 and/or its radioactive metabolites to the rat plasma proteins were 62.0-79.3% within 24hr after dosing.6. In the plasma samples drawn from male rats at lhr after dosing, the percent of radioactivity of the unchanged drug was 20.5% and that of U-1 ?? U-3, U-5, U-6 and M3 metabolites were 1.9 ?? 7.8%. Subsequently, the unchanged drug declined gradually, but the most of metabolites increased until 4hr after dosing and thereafter declined.In the urine excreted within 24hr after dosing, the percent of radioactivity of U-2 and U-6 metabolites were 17.1 and 14.1%, respectively, and that of U-1, U-3 ?? U-5 and five unknown metabolites were 0.5 ?? 9.7%. In the bile sample excreted within 24hr after dosing, the percent of radioactivity in U-2, U-5, U-6 and six unknown metabolites were 0. 2-2.2%. Meanwhile, in the enzymatically hydrolyzed samples, that of U-5, U-3, U-2, U-6 and 12 unknown metabolites were 0.59.5%, however, the most of those were observed for the first time.

Studies on the Metabolic Fate of Betamethasone Butyrate Propionate. (IV). Absorption, distribution and excretion in rats and rabbits.

3H-BBPをラットおよびウサギに0.25mg/kgで経皮(非密封法)，あるいは1mg/kgで皮下投与し，その吸収，分布，排泄について検討し，以下の結果を得た．1．軟膏またはクリームを正常皮膚動物に経皮投与した際，全身系への経皮吸収率は雄性ラットでは約3～5%，雌性ラットでは約14%，また雄性ウサギでは約14%であった．損傷皮膚雄性ラットでは約30～50%であった．2．正常皮膚動物における血液または血漿中放射能濃度の最高到達時間および最高値は雄性ラット:24時間，0.6～0.8ng/ml，雌性ラット:8時間，4.7ng/ml雄性ウサギ:13時間，3.0ng/mlであった．また，損傷皮膚雄性ラットでは5時間，8.6～15.7ng/mlであった．3．主排泄経路はラットでは糞であったが，ウサギの尿糞中排泄率の割合はほぼ同じであった．4．正常皮膚雄性ラットにおける組織内放射能濃度は，投与後8時間あるいは24時間に最高濃度を示し，肝臓，腎臓副腎，貯精嚢および膀胱に高い濃度が認められた．各組織からの消失は緩慢であり，特に血液かbの消失が遅延した．塗布部皮膚のミクロオートラジオグラムより，BBPの経皮吸収経路として付属器官を経由するルートと経表皮ルートが確認された．5．正常皮膚雄性ラットに7回反復投与した際，毎回投与後24時間における血液および組織中放射能濃度は，投与回数に伴い上昇する傾向を示した．7回投与後の血液および組織中からの放射能の消失は緩慢であったが，7回投与後の尿および糞中排泄率は単回投与群と相違が認められなかった．6．妊娠ラットに3H-BBPを皮下投与した際の全身オートラジオグラムより，胎盤通過性が確認されたものの，放射能が胎仔組織に残留する傾向は認められなかった．

Absorption, distribution and excretion of 14C-benidipineHCl in rats.

Absorption, distribution and excretion of 14C-benidipine · HCl(KW-3049) were studied in rats after a single oral (1.0mg/kg) or intravenous (0.1mg/kg) administration and after repeated oral dosing for 21 days (1mg/kg).And, plasma unchanged drug levels were determined after repeated oral dosing of KW-3049 (1mg/kg) for 21 days to rats.1. Plasma levels reached the maximum of 126.4ng equiv./ml (male) or 246.6ng equiv./ml (female) at 0.5hr after oral dosing and the elimination half-lives at the terminal phase were 20.3hr and 30.Ohr in male and female rats, respectively.2. The highest level of radioactivity was found in the liver at 0.1hr after intravenous dosing. The level of radioactivity in central nervous system was the lowest.3. Maximum levels in most tissues were reached at 0.5hr after oral dosing. The liver had the highest level of radioactivity except the gastro-intestinal tract. The central nervous system had the lowest level of radioactivity.4. After intravenous or oral dosing in male rats, 18 or 19% of the dose was excreted in the urine and 84 or 74% of the dose in the feces, respectively. After oral dosing in female rats, 24 and 72% of the dose was excreted in urine and feces, respectively.5. Biliary excretion of radioactivity was 34% within 48hr after oral dosing.6. In the case of the repeated oral dosing for 21 days of KW-3049, plasma level of unchanged drug showed no change. The level of radioactivity in plasma after repeated daily dosing of 14C-KW-3049 increased by repeated dosing untill 14th dosing. Its level after final dose was 1.3 times higher than that after a single dose. Some tissues showed two to three times higher levels of radioactivity after repeated dosing. Excretion of radioactivity into the urine and feces was almost constant during repeated administration, and was 6 and 88%, respectively.

Studies on the metabolic fate of S-3460. (IV). Metabolism and protein binding.

The metabolism of 14C-S-3460 in rats, rabbits and mice was studied after subcutaneous administration at dose of 0.5 mg/kg. Plasma protein binding was also determined. 1. Plasma metabolites. The main metabolite was 21-hydroxy compound ((2)) and unchanged S-3460 was not detected in any of studied species. Other metabolites detected were 17, 21-dihydroxy compound ((4)) and 6, 7-dihydro and 17, 21-dihydroxy compound ((9)) in male and female rats, and other not identified metabolites. Almost the same amounts of (4) and (9) as well as (2) and unknovn compounds were presented in rabbits. Neither (4) nor (9) was detected in mice. 2. Urinary metabolites. In male and female rats, (4), (2), (9) and unknown metabolites each accounted for less than 1 % of the dose, but unchanged S-3460 was not detected. Almost equal amounts of (4), less of (2) and much more of (9) than that after a single dose were detected after repeated doses to male rats. In rabbits, the main metabolite (2) and many kinds of metabolites were detected but not the unchanged drug. 3. Biliary metabolites. Unknown metabolite Bf1 (13 % of the dose), conjugate of (2) (12 %), unknown metabolite Ba14 (8 %) and Ba22 (5 %) and many minor metabolites were detected in male rats. The main metabolite in female rats was the conjugate of (2), the amount of which was 2.5 times greater than that in male rats. 4. Plasma protein binding. Binding of 14C-S-3460 to rat and rabbit plasma in vitro was the same, 87 %, and to human plasma was about 97 %. Those in vivo were 85 to 88 % from 1 to 8 hr after dosing in male rats and rabbits.

Toxicity and carcinogenicity studies of phenylephrine hydrochloride in F344/N rats and B6C3F1 mice.

Phenylephrine HCl was incorporated into feed given to male and female F344/N rats and B6C3F1 mice in studies of 14 days, 12 weeks, and 2 years duration. In 12-week studies, body weight gains decreased with dose, and deaths of male rats and mice occurred at concentrations of 5,000 ppm and above; however, no organ-specific toxicity was evident. During 2-year studies, body weights of rats receiving diets at 620 and 1,250 ppm and mice at 1,250 and 2,500 ppm ranged up to 16% less than control. Survival of high dose male rats was substantially greater than controls. Survivals of other dose groups of rats and mice were similar to controls. Chronic focal inflammation of the liver, and inflammation of the prostate were increased in dosed rats. No increases in neoplasms were observed in rats or mice consuming diets containing phenylephrine HCl for 2 years. The incidences of mononuclear cell leukemia and pheochromocytomas of the adrenal gland were decreased in dosed male rats. Approximate time weighted average doses ranged up to 54 mg/kg/day for rats and 280 mg/kg/day for mice during the 2-year studies.

Plasma growth hormone (GH) response to intravenous GH-releasing factor (GRF) in adult rats: evidence for transient pituitary desensitization after GRF stimulation.

The ability of human (h)GRF-(1-29)NH2 to stimulate GH secretion was studied in cannulated adult rats. In order to suppress endogenous GRF secretion and the inhibitory action of hypothalamic somatostatin (SRIF), rats were anesthetized with sodium pentobarbital. Intravenous administration of hGRF-(1-29)NH2 elicited a dose-dependent response of plasma GH, with 250 ng/kg being the smallest effective dose in male rats. In female rats, for each dose tested (250 to 70,000 ng/kg), the GH response represented only about 60% that of male rats. Repeated iv stimulations with hGRF-(1-29)NH2 at short time intervals (45 min) produced transient desensitization of pituitary responsiveness to GRF: a blunted GH response to the second and third stimulations was observed both in male and in female rats and for each dose tested. Similar blunted responses were also obtained with repeated injections of native hGRF-(1-44)NH2. The possibility that these blunted responses could be due to incomplete suppression of hypothalamic SRIF secretion by sodium pentobarbital was excluded by the use of rats that were passively immunized against SRIF; in these rats, it was shown that at least 65% of the inhibition of the GH response after the second GRF stimulation was unrelated to SRIF action. Similar transient desensitization to repeated hGRF-(1-29)NH2 stimulations was also observed in conscious rats that were passively immunized against SRIF. This occurrence of blunted responses was shown to be related to the length of the time interval between GRF stimulations, with longer intervals resulting in less or no desensitization. It appears thus that modulation of pituitary responsiveness to the action of GRF is mediated by at least two independent mechanisms in the rat: in addition to the inhibitory action imposed by hypothalamic SRIF, which induces periods of refractoriness to the action of GRF, it was shown in this study that in the pituitary level each GRF stimulation also induces a transient desensitization of somatotrophs for about 1 h. This period of refractoriness might not be due to excessive stimulation with GRF, since it was also observed with the lowest dose of hGRF-(1-29)NH2 that gave a significant release of GH. Finally, a sex difference was confirmed for the response of anesthetized adult rats to stimulation with hGRF-(1-29)NH2, reflecting a sex steroid-induced modification of pituitary responsiveness to GRF stimulation.

Chronic toxicity and oncogenicity studies of ethylene glycol in rats and mice

These studies were performed to assess the chronic toxicity and oncogenicity of ethylene glycol (EG) in rats and mice. Groups of 130 Fischer 344 rats and 80 CD-1 mice per sex were fed diets yielding approximate dosages of 1.0, 0.2, or 0.04 g/kg/day of EG. Two separate control groups in each study received no EG. Mortality rate was increased in high-dose male rats all of which died by 475 days. The following effects were also observed in high dose male rats: reduced body weight gain, increased water intake, increased blood urea nitrogen and creatinine, reduced erythrocyte count, reduced hematocrit and hemoglobin, increased neutrophil count, increased urine volume, reduced specific gravity and pH. Urinary calcium oxalate crystals and increased kidney weight were seen in all high-dose rats. Uric acid crystals were seen in the urine of high-dose female rats at 18 and 24 months. Histopathologic changes in high-dose male rats included tubular cell hyperplasia, tubular dilation, peritubular nephritis, parathyroid hyperplasia, and generalized soft tissue mineralization. Fatty change of the liver was seen in high- and intermediate-dose female rats. No clinical signs, or gross or microscopic evidence of toxicity was seen in mice at the dosages used. Water intake and clinical pathologic parameters were not measured in the mouse study. In these studies there was no evidence of an oncogenic effect of EG in rodents.

Toxicology and carcinogenesis studies of isophorone in F344 rats and B6C3F1 mice

Toxicology and carcinogenesis studies of isophorone were conducted by administering 0, 250, or 500 mg/kg body weight per day by gavage in corn oil to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days/week, for 103 weeks. Dosed male rats developed proliferative lesions of the kidney including hyperplasia, adenoma, and adenocarcinoma of the renal tubule, and epithelial hyperplasia of the renal pelvis. Non-proliferative kidney lesions observed in dosed male rats included mineralization, and a more severe nephropathy in low dose animals than in controls or high dose animals. Carcinomas of the preputial gland occurred in high dose male rats. No isophorone-related lesions were observed in female rats. In male mice, isophorone exposure may have been associated with an increase in hepatocellular neoplasms and mesenchymal neoplasms of the integumentum in high dose animals, and with a marginally increased incidence of lymphoma in low dose male mice. In mice, no non-neoplastic lesions in males or females, or neoplastic lesions in females were considered associated with isophorone administration.

Chronic oral toxicity and oncogenicity studies of flecainide, an antiarrhythmic, in rats and mice

Chronic oral toxicity and oncogenicity studies on flecainide acetate, an antiarrhythmic compound, were made in male and female rats and mice. The duration of compound administration was 18 months in mice and 24 months in rats, and dose levels for both species were 0, 60, 30, and 15 mg/kg/day. The treated rats had dose-related significant decreases in mean body weights at all dose levels while the treated mice had a small body weight reduction (nonsignificant) at the higher doses. The body weight effects could not be correlated with reduced food consumption. Chronic administration of flecainide did not produce chronic toxic changes in either species. Likewise, chronic compound administration did not adversely affect survival rates; in fact, the treated groups of rats had survival rates higher than those of the controls with the differences from controls being significant for the male rat groups. All of the tumors in all groups of animals (control and treated) were considered spontaneous in nature. The incidence of the various types of tumors in the treated groups of animals was not significantly increased when compared to the control groups, with one exception. Interstitial cell adenoma in the testes was the most common tumor of the male rats and the increased survival rate of the high dose male rats had a direct effect on the incidence of this tumor. Since the high dose mile rats had much better survival than the controls (90% vs 56%), a higher incidence of interstitial cell adenomas would be expected (more rats live longer, more rats with a late developing spontaneous tumor). Comparison of the incidence of interstitial cell adenomas in male rats which survived the 2-year study revealed no significant difference between controls and treated animals. Also when the incidence of interstitial cell adenomas was statistically evaluated with a life table approach, there was no indication of increased tumorigenic risk in the treated groups as compared to the controls.

The metabolic profile of sodium o-phenylphenate after subchronic oral administration to rats

We examined the metabolites of o-phenylphenol (OPP) in the urine of male and female rats dosed with 2% sodium o-phenylphenate (OPP-Na) in food from the age of 5 wk for 136 days. The urinary metabolites of OPP-Na produced during the 24 hr after OPP-Na feeding accounted for 55% of the dose in male rats and 40% in females. The main metabolites were OPP-glucuronide and 2,5-dihydroxybiphenyl (2,5-DHBP)-glucuronide. OPP metabolites in the free form accounted for only 1% of the total phenolic metabolites excreted. 2,5-DHBP was rapidly converted to the corresponding quinone in aqueous solvents but not in organic solvents. There was a clear sex difference in the proportions of urinary metabolites; the amount of 2,5-DHBP excreted by male rats in 24-hr urine was more than seven times that excreted by females. This result may be related to the finding that bladder tumours occur in male but not female rats fed OPP-Na in the diet (Hiraga & Fujii, Fd cosmet. Toxicol. 1981, 19, 303).

Effects of tri-n-butyl phosphate on the peripheral nervous system of the Sprague-Dawley rat.

Tri-n-butyl phosphate, a widely used plasticizer and solvent, was orally administered to male and female Sprague-Dawley rats for 14 consecutive days (low dose: 0.28 mL/kg; high dose: 0.42 mL/kg). Effects of this industrial chemical were investigated on the peripheral nervous system of these animals. A significant (P less than 0.05) reduction in conduction velocity of caudal nerve was observed in high dose male rats. Electron microscopic examination of sciatic nerve showed morphological changes such as retraction of Schwann cell processes surrounding unmyelinated fibres in both sexes of high dose groups.

Dichloroacetate, sodium: 3-Month oral toxicity studies in rats and dogs

Dichloroacetate (DCA) was administered daily for three consecutive months to rats by gavage at 125, 500, and 2000 mg/kg and to dogs in gelatine capsules at 50, 75, and 100 mg/kg. Rats of both sexes at 2000 mg/kg experienced 13.3% mortality rates. Among dogs one of three females at 75 mg/kg and one of four males at 100 mg/kg died. Compound-related effects experienced by both species included suppressed food consumption and body weight gain, hind limb weakness and/or paralysis (high dose groups), depressed erythroid hemograms, reduced blood levels of glucose, lactate, and pyruvate, vacuolation of myelinated white tracts in the cerebrum and to a lesser extent cerebellum, and degeneration of testicular germinal epithelium with syncytial giant cell formation. Species differences in reactions to DCA were also noted. High dose male rats frequently exhibited aspermatogenesis while DCA-treated dogs experienced prostate glandular atrophy, cystic mucosal hyperplasia in the gall bladder, hemosiderin-ladened Kupffer cells, and ocular lesions. The ocular lesions in dogs characteristically consisted of three components: (1) bilateral lenticular opacities; (2) injected bulbar conjunctivae and superficial corneal vascularization; and (3) tendency for keratoconjunctivitis sicca. In both species, a 1-month recovery period produced a general normalization trend. However, the lenticular opacities (dogs), gall bladder anomaly (dogs), brain lesions (both species), loss of testicular germinal epithelium (rats), and aspermatogenesis (rats) persisted or showed minimal improvement.