Toxicity report series最新文献

Glyphosate is a systemic, broad-spectrum, post-emergence herbicide used for non-selective weed control. It was selected for study because of its widespread use, potential for human exposure, and the lack of published reports concerning comprehensive toxicity or carcinogenicity evaluations. Chemical disposition, 13-week toxicity, and mutagenicity studies of glyphosate were conducted. In disposition studies, male F344/N rats were administered an oral dose (5.6 or 56 mg/kg) of 14C-glyphosate. Blood, urine, fecal, and tissue samples were collected and analyzed for radioactivity. Within 72 hours after glyphosate dosing, 20-30% of the administered radioactivity was eliminated via urine, 70-80% via feces, and about 1% of the radioactivity remained in the tissues. Studies following oral, intravenous, and intraperitoneal administration of glyphosate indicated that the urinary radioactivity represented the amount of glyphosate absorbed and that the fecal radioactivity represented the amount unabsorbed from the gastrointestinal tract. In the 13-week toxicity studies, groups of 10 male and female F344/N rats and B6C3F1 mice were administered glyphosate in feed at 0, 3125, 6250, 12500, 25000, or 50000 ppm. Glyphosate administration induced increases in serum bile acids, alkaline phosphatase, and alanine aminotransferase activities in rats, suggesting mild toxicity to the hepatobiliary system. Clinical pathology measurements were not performed with mice. No histopathologic lesions were observed in the livers of rats or mice. There was no evidence of adverse effects on the reproductive system of rats or mice. Cytoplasmic alteration was observed in the parotid and submandibular salivary glands of rats and parotid salivary glands in mice. The salivary gland effects of glyphosate were demonstrated to be mediated through an adrenergic mechanism which could be blocked by the adrenergic antagonist, propanolol. Glyphosate was not mutagenic in Salmonella, and did not induce micronuclei in mice. The no-observed-adverse-effect level (NOAEL) for the salivary gland lesions was 3125 ppm in the diet for mice. A NOAEL could not be determined from the rat study. Synonyms: Glyphosate, technical grade; Glycine, N-(phosphonomethyl); N-phosphono-methyl glycine; N-(phosphonomethyl)glycine; MON 0573; MON 2139.

Trinitrofluorenone (TNF) is a major component of a toning formulation that at one time was used widely in certain photocopy processes. Because the principal route of exposure of humans to TNF probably would be dermal, studies were conducted to compare chemical absorption, distribution, excretion, and tissue retention, as well as toxicity in 14-day studies, by oral and dermal routes of exposure. Further, 13-week toxicity studies were carried out with TNF incorporated into the feed of rats and mice of both sexes. In genetic toxicity evaluations, TNF was found to be mutagenic in Salmonella typhimurium, with and without metabolic activation. In disposition and metabolism studies, excretion patterns following oral administration of radiolabeled TNF (in doses ranging between 1 and 100 mg/kg body weight) were similar; 20% and 70% of the administered dose appeared in urine and feces, respectively, during the first 72 hours. Residual radiolabel in tissues comprised less than 1% of the dose. The appearance in the feces of 60-70% of a 1 mg/kg i.v. dose provided evidence for substantial biliary excretion of TNF; studies of the radiolabeled materials extracted from urine and feces suggested that glucuronidation is a major biotransfomation of TNF and its metabolites. In the dermal exposure studies, groups of 5 F344/N rats and 5 B6C3F1 mice of each sex were administered TNF in acetone by topical application once a day, 5 days per week, for 14 days. Doses were 0, 7.5, 15, 30, 60, or 120 mg/kg body weight for rats and 0, 12.5, 25, 50, 100, or 200 mg/kg for mice. There were no deaths, no adverse clinical signs, and no gross or microscopic changes related to treatment in either species, except for discoloration of skin at the site of application. Disposition studies with female rats showed that less than 10% of a dermal dose of 47 mg and less than 3% of a dermal dose of 400 mg were available systemically. In contrast, toxicity was observed in the 14-day feeding studies with TNF. Groups of 5 rats and 5 mice of each sex were fed diets containing TNF at concentrations of 0, 500, 1600, 5000, 16000, or 50000 ppm. There were no deaths of rats or mice, but body weight gains of rats receiving 50000 ppm were reduced by as much as 45%. Animals receiving diets with 5000 ppm or higher TNF had a black discoloration of the skin and hair and enlarged and/or dark thyroid glands. Mild follicular cell hypertrophy and pigmentation of the epithelium and colloid were noted in the thyroid gland. Among mice, the brain and gallbladder were dark; the spleen of females was dark and also enlarged by hematopoiesis. Thymic lymphoid depletion and atrophy of the seminal vesicles were present in top-dose male rats (50000 ppm). In 13-week studies, groups of 10 animals of each sex received diets containing TNF at concentrations of 0, 1000, 2000, 4000, 8000, or 16000 ppm for rats, and 0, 3125, 6250, 12500, 25000, or 50000 ppm for mice. No rats died, but the deaths of several mice in the 50000

Formic acid occurs in a variety of plants and fruits, mammalian tissues, and insect venoms. It is used industrially in preparing a variety of drugs, dyes, and chemicals; as a decalcifier; and in leather tanning. Formic acid also is an environmental contaminant of air and water and has been identified as the toxic intermediate (formate) in methanol poisoning. Two- and 13-week toxicity studies of formic acid were conducted in male and female F344/N rats and B6C3F1 mice by whole body inhalation exposure to formic acid vapors. In addition, in vitro genetic toxicity studies were performed with Salmonella typhimurium, with or without metabolic activation. Formic acid was not mutagenic in this assay. In 2-week studies, groups of 5 F344/N rats and 5 B6C3F1 mice of each sex were exposed to formic acid for 6 hours a day, 5 days a week, at concentrations of 0, 31, 62.5, 125, 250, or 500 ppm. Deaths occurred in animals exposed to 500 ppm (rats and mice) and 250 ppm (1 female mouse). Microscopic lesions in the respiratory and olfactory epithelia occurred in rats and mice exposed to 62.5 ppm and higher concentrations, with the severity related to the exposure concentration. The lesions consisted of squamous metaplasia, necrosis, and inflammation. Exposures had minimal or no effects on coagulation times, blood pH and electrolytes, or on concentrations and activities of urine analytes in rats during the 2-week studies. In 13-week studies, groups of 10 animals of each species and sex were exposed to formic acid at concentrations of 0, 8, 16, 32, 64, and 128 ppm for 6 hours a day, 5 days a week. Two mice, 1 male and 1 female, died in the 128 ppm groups. Body weight gains were significantly decreased in mice exposed to 64 and 128 ppm formic acid. Microscopic changes in rats and mice ranged from minimal to mild in severity and generally were limited to animals in the 128 ppm groups. Lesions related to exposure to formic acid consisted of squamous metaplasia and degeneration of the respiratory and olfactory epithelia, respectively. Hematologic and serum biochemical changes at interim and terminal time points were minimal to mild and, generally, were consistent with hemoconcentration. Overall, the effects of formic acid were consistent with those of irritant chemicals administered by inhalation exposure. The no-observed-adverse-effect level (NOAEL) for respiratory injury was 32 ppm in rats and mice. There was no significant evidence of systemic toxicity in these studies. Synonyms: Aminic Acid, Formylic Acid, Methanoic Acid, Hydrogen Carboxylic Acid.

t-Butyl perbenzoate (t-BP) is a relatively stable, lipid-soluble, organic peroxide widely used in the polymer industry. Studies were designed to determine the stability of t-BP in various biological media, its dermal absorption and distribution in intact animals, and the toxicity of t-BP when administered orally to both sexes of rats and mice for 14 days or 13 weeks. In genetic toxicity studies, t-BP was found to be mutagenic in Salmonella typhimurium strains TA100, TA1537, and TA98, with and without metabolic activation. t-BP-induced sister-chromatid exchange and chromosomal aberrations in Chinese hamster ovary cells in vitro but did not induce formation of micronuclei in peripheral blood in mice in the 13-week studies. Stability studies indicated t-BP was sufficiently stable in dose formulations to permit administration by gavage, intravenous injection, or dermally. However, t-BP degraded rapidly in blood, stomach contents, and liver homogenates, or in the presence of glutathione. Initial degradation products of t-BP are benzoic acid and t-butanol. Studies of t-BP disposition determined that approximately 16% of dermal doses administered to rats was absorbed and rapidly eliminated without tissue accumulation. Similarly, t-BP given intravenously was rapidly degraded and eliminated, primarily in urine, with no apparent accumulation in any tissue. Because dermal absorption was considered insufficient to administer a toxic dose, studies of t-BP toxicity were performed using gavage administration. Results of 14-day toxicity studies with 5 animals of each sex of rats and mice indicated that t-PB, administered by gavage in corn oil in doses ranging from 70 to 1112 mg/kg, produced no marked signs of systemic toxicity. Toxicity in mice, attributable to t- BP, was limited largely to increased stomach weights in males and females receiving the highest doses. This toxicity was characterized by forestomach epithelial hyperplasia, ulceration, and acute inflammation. Equimolar doses of the degradation products of t-BP (t-butanol and benzoic acid) also were administered in the 14-day studies to determine if t-BP toxicity could be attributed to the parent compound or products of its chemical degradation and/or metabolism. Results of these studies indicated that equimolar doses of t-butanol were not toxic in either sex or species. Some systemic toxicity of benzoic acid was observed in both sexes of mice, but not rats, receiving the highest dose (642 mg/kg). Toxicity was evidenced by the poor condition of dosed animals and in several deaths during the first week of the study. No lesions were observed microscopically, and it is speculated that this toxicity may have been due to acidosis. In the 13-week studies, t-BP was administered by gavage in water to 10 rats and 10 mice of each sex, at doses up to 500 mg/kg. The doses resulted in depressed body-weight gains in the highest dose groups and in dose-dependent increases in forestomach weights. Hyperplasia of

p-Chloro-alpha,alpha,alpha trifluorotoluene (CTFT) is a volatile, aromatic liquid used as a chemical intermediate in the manufacture of dinitroaniline herbicides. To evaluate the toxicity of CTFT, groups of F344/N rats and B6C3F1 mice of each sex were administered CTFT by gavage once a day for 14 consecutive days in either corn oil or in an experimental molecular complex vehicle, a-cyclodextrin (alpha-CD). Dose levels selected for CTFT with the alpha-CD vehicle were 10, 50, and 400 mg/kg; dose levels used with the corn oil vehicle were 10, 50, 400, and 1000 mg/kg. The toxicokinetics of CTFT also were compared by gavage with the different vehicles and by i.v. administration. In genetic toxicity studies, CTFT was not mutagenic in Salmonella typhimurium. The elimination of an intravenous dose of CTFT from blood is best described by a triexponential equation. The data best fit a 3-compartment kinetic model with a very rapid distribution phase. A biexponential equation was found to best fit the elimination of CTFT from blood following a gavage dose in either corn oil or an aqueous molecular complex suspension, alpha-CD. However, the biological half-life (t 1/2) was the same in both routes, approximately 20 hours. Absorption of CTFT from the alpha-CD vehicle was found to be much faster than from corn oil. The average t 1/2 of the absorption phase for a 10 mg/kg dose of CTFT in the alpha-CD and corn oil vehicles was 7 and 150 minutes, respectively. Despite the differences in absorption, no statistical difference was observed in the calculated area under blood concentration versus time curves (AUC) obtained from rats dosed with CTFT in either vehicle. Blood concentrations of CTFT were proportional to dose, at levels as high as 400 mg/kg in both vehicles. The bioavailability of CTFT was shown to be complete in both vehicles, through comparing the AUC following oral and i.v. dosing. In 14-day toxicity studies, 1 of 10 female rats given the top dose of 1000 mg/kg CTFT in corn oil died on day 8; no deaths of male rats or of mice of either sex were attributable to the administration of CTFT. Body weight gains in all groups of rats and mice were similar with the exception of the top dose (1000 mg/kg) groups of male and female rats, which lost weight during the first week and resumed weight gain during the second. CTFT was found to accumulate in the kidneys of male rats, and there was a linear relationship between the kidney CTFT concentrations and the kidney levels of a2u-globulin, as determined by an ELISA assay. Microscopic changes in male rats included a dose-related toxic nephropathy consistent with that previously described as "hyaline droplet nephropathy." Dosed male and female rats also had hepatocyte hypertrophy and cytoplasmic vacuolization of the adrenal cortex. Clinical pathology findings suggested a mild anemia and cholestasis in rats. In contrast to rats, mice did not show appreciable CTFT concentrations in any tissue evaluated, suggesting a

Antimony potassium tartrate (APT) is a complex salt that until recently was used worldwide as an anti-schistosomal drug. APT was efficacious in humans only if administered intravenously at a near-lethal total dose of 36 mg/kg. Because unconfirmed epidemiologic studies suggested a possible association between APT treatment and bladder cancer, prechronic toxicity studies were initiated with APT to select a route of administration and appropriate doses in the event chronic studies were needed. To determine the most appropriate route for longer-term studies, toxicity and concentrations of tissue antimony were compared in F344/N rats and B6C3F1 mice that were administered APT in drinking water or by i.p. injection for 14 or 16 days. The animals were assigned to dose groups, 5/sex/species. Drinking water doses, estimated by water consumption, were 0, 16, 28, 59, 94, or 168 mg/kg in rats and 0, 59, 98, 174, 273, or 407 mg/kg in mice; i.p. doses were 0, 1.5, 3, 6, 11, or 22 mg/kg in rats and 0, 6, 13, 25, 50, or 100 mg/kg in mice. APT was poorly absorbed and relatively nontoxic when given orally. There was no mortality or histopathological lesions in rats or mice receiving doses of APT as high as 168 or 273 mg/kg, respectively. One mouse in the highest dose group (407 mg/kg) died, and there were treatment-related lesions in the liver and forestomach of most mice in this dose group. In contrast, i.p. administration of the drug was much more toxic, resulting in the deaths of rats administered 22 mg/kg; kidney and liver lesions were found in these rats. In mice, i.p. administration of APT caused deaths and liver lesions at dose levels one-fourth of those that caused similar effects by oral administration. All male and female mice injected with 100 mg/kg APT died; half of the female mice given 50 mg/kg APT died; additional deaths occurred with doses as low as 6 mg/kg. Hepatocellular necrosis and inflammation of the liver capsule were present in both sexes of mice in the 50 mg/kg dose groups. As a result of these findings, an i.p. dose regimen was selected for subsequent studies. Groups of ten male and female F344/N rats and B6C3F1 mice were given 0, 1.5, 3, 6, 12, or 24 mg/kg doses of APT 3 times per week for 13 weeks by i.p. injection. Rats were more sensitive than mice to the toxic effects of APT, exhibiting dose-related mortality and reduction in body weight. Four male rats in the 24 mg/kg dose died; body weights in both sexes of rats from this dose group and in male rats from the 12 mg/kg dose group were 10-20% below controls. No clinical signs of toxicity in the mice, nor gross or microscopic lesions, could be attributed to APT. Increased concentrations of antimony, considered to be dose-related, were detected in the blood, liver, kidney, spleen, and heart of rats, and in the liver and spleen of mice. In rats, hepatocellular degeneration and necrosis were associated with dose-related elevations in activities of the liver-specific serum enzymes, so

Castor oil is a natural oil derived from the seeds of the castor bean, Ricinus communis. It is comprised largely of triglycerides with a high ricinolin content. Toxicity studies with castor oil were performed by incorporating the material at concentrations as high as 10% in diets given to F344/N rats and B6C3F1 mice of both sexes for 13 weeks. Genetic toxicity studies also were performed and were negative for mutation induction in Salmonella typhimurium, for induction of sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, and for induction of micronuclei in the peripheral blood erythrocytes of mice evaluated at the end of the 13-week studies. Exposure to castor oil at dietary concentrations as high as 10% in 13-week studies did not affect survival or body weight gains of rats or mice (10 per sex and dose). There were no biologically significant effects noted in hematologic analyses in rats. Mild increases in total bile acids and in serum alkaline phosphatase were noted at various times during the studies in rats receiving the higher dietary concentrations of castor oil. Liver weights were increased in male rats receiving the 10% dietary concentration and in male and female mice receiving diets containing 5% or 10% castor oil. However, there were no histopathologic lesions associated with these liver changes, nor were there any compound-related morphologic changes in any organ in rats or mice. No significant changes were noted in a screening for male reproductive endpoints, including sperm count and motility, and no changes were observed in the length of estrous cycles of rats or mice given diets containing castor oil. Thus, no significant adverse effects of castor oil administration were noted in these studies. Synonyms: Ricinus Oil, oil of Palma Christi, tangantangan oil, phorboyl, Neoloid.

Ethylbenzene is commonly used as a solvent and chemical intermediate and as an additive in some motor fuel formulations. Inhalation toxicology studies of ethylbenzene (99% pure) were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to ethylbenzene vapor at chamber concentrations of 0, 100, 250, 500, 750, or 1000 ppm, 6 hours per day, 5 days per week for 13 weeks. No rats or mice died during the 13-week exposure. Body weight gains were slightly lower in the high dose groups of male and female rats, but the differences were not statistically significant. Absolute and relative kidney, liver, and lung weights were increased in the exposed rats, while weight increases occurred only in the livers of exposed mice. Chemically related histopathologic changes were not observed in any tissues of rats or mice. No changes were observed in the evaluation of sperm or vaginal cytology in rats or mice. Ethylbenzene was not mutagenic in Salmonella and did not induce chromosomal aberrations or sister chromatid exchanges in Chinese hamster ovary (CHO) cells in vitro, though it did induce trifluorothymidine resistance in mouse lymphoma cells at the highest concentration tested. Micronuclei assays in peripheral blood of mice were negative. Thus, there appears to be only minimal evidence of toxicity in F344/N rats and B6C3F1 mice exposed to ethylbenzene by inhalation at concentrations as high as to 1000 ppm for 13 weeks. Synonyms: EB, ethyl benzene, ethylbenzol, phenylethane. (NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.)

Cresols are monomethyl derivatives of phenol, and are found as constituents of coal tar, in various industrial solvents and resins, and in some essential oils. In 28-day toxicity studies, F344/N rats and B6C3F1 mice of both sexes were given o-cresol, m-cresol, p-cresol, or m/p-cresol (60:40) at concentrations from 300 ppm to 30,000 ppm in the diet. In 90-day studies, o-cresol or m/p-cresol (60:40) were added to the diet in concentrations as high as 30,000 ppm to F344/N rats and 20,000 ppm (o-cresol) or 10,000 ppm (m/p-cresol) to B6C3F1 mice. In the 28-day studies, all rats survived (5 per sex per dose), but some mice given o-cresol at 30,000 ppm, or m-cresol or p-cresol at 10,000 ppm or 30,000 ppm died before the end of the studies. Feed consumption was depressed during the first study week in all high- dose groups of animals and weight gains were generally less than controls in groups given 10,000 or 30,000 ppm in the four 28-day studies. Increased relative liver weights and kidney weights were noted in both rats and mice given concentrations of cresols as low as 3,000 ppm. However, there were no consistent microscopic changes associated with these weight increases. Bone marrow hypoplasia and uterus, ovary and occasional mammary gland atrophy were seen primarily at the highest dietary concentration, but also at 10,000 ppm with certain cresols. An effect specific to the p- cresol and m/p-cresol studies was atrophy and regenerative changes in the nasal epithelia and forestomach, presumably a direct result of the irritant effects of the chemical or its vapors. Results of reproductive tissue evaluations and estrus cycle characterizations with o-cresol and m/p-cresol gave no indication of adverse effects to the male reproductive system, but the estrus cycle was lengthened in rats and mice receiving the higher concentrations of o-cresol and rats receiving m/p-cresol. In the 90-day studies, no deaths of rats (20 per sex per dose) or mice (10 per sex and dose) could clearly be related to administration of either o-cresol or m/p-cresol. Hematology, clinical chemistry, and urinalysis results were generally unremarkable in all studies, although an accumulation of bile acids in high-dose rats was considered evidence of a deficit in hepatocellular function resulting from ingestion of the chemical. Results of microscopic analyses were consistent with findings in the 28-day studies, and revealed evidence of mild bone marrow hypocellularity in rats and forestomach hyperplasia in mice given diets containing the higher concentrations of o-cresol. Evidence of nasal irritation was present in rats and mice receiving feed containing m/p-cresol. Additional lesions in rats receiving m/p-cresol included bone marrow hypocellularity and uterine atrophy. The cresol isomers exhibited a generally similar pattern of toxicities in rats and mice. Dietary concentrations of 3,000 ppm appeared to be minimal effect levels for increases in liver and kidney weights and deficits

Toxicology studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to pentachlorobenzene (99%percnt; pure) in feed for 15 days or 13 weeks. Exposure concentrations were 0, 100, 330, 1,000, 3,300, or 10,000 ppm pentachlorobenzene in the 15-day studies (five animals of each sex per group per species). All rats that received 10,000 ppm and all mice that received 3,300 or 10,000 ppm died. Of the exposed rats that survived to the end of the studies, males had an accumulation of abnormal hyaline droplets in the renal cortical epithelium and males and females had centrilobular hepatocellular hypertrophy. Chemical-related lesions were not observed in exposed mice. Exposure concentrations were 0, 33, 100, 330, 1,000, or 2,000 ppm pentachlorobenzene in the 13-week studies (10 animals of each sex per group per species). No compound-related deaths occurred. Body weights of exposed rats but not of mice were lower than those of controls. In male rats, dose-related histologic lesions included renal tubular epithelial hyaline droplet formation and medullary granular casts and mineralization. This spectrum of renal lesions in male rats is consistent with the entity described as "hydrocarbon or hyaline droplet nephropathy." Exacerbation of spontaneous nephropathy characterized by renal tubular cell regeneration and homogeneous intratubular protein casts was seen in rats of each sex. Urinary protein concentration was increased in male and female rats in the 1,000- and 2,000-ppm groups; this change was especially prominent in males. Urinary glucose concentration was increased in male rats in the 330- to 2,000-ppm groups and in female rats in the 1,000 and 2,000-ppm groups. Centrilobular hepatocellular hypertrophy was observed in exposed male and female rats. Unidentified yellow-brown pigment granules were present in hepatocytes and renal tubular epithelium in exposed animals of each sex but were more prominent in females. These granules possibly contained porphyrins. The only exposure-related histologic lesion in mice of either sex was centrilobular hepatocellular hypertrophy. Significant, but not dose-related, increases of liver porphyrin concentrations were observed in exposed male rats; female rats in the 2,000-ppm group also had increased liver porphyrin concentrations. Liver porphyrin concentrations were significantly increased in the 1,000- and 2,000-ppm groups of mice of each sex. Increased sorbitol dehydrogenase concentrations in exposed rats and mice of each sex were attributed to mild hepatocyte injury. Minimal thyroid follicular cell hypertrophy was also present in male and female rats in the 1,000 and 2,000-ppm groups. Free thyroxin and total thyroxin concentrations were significantly decreased in exposed male and female rats; these data indicate moderate hypothyroxinemia in exposed animals. Hematologic findings in exposed rats included decreased hematocrit, hemoglobin concentration, erythrocyte count (males), mean corp