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Query: UMLS:C0023380 (
lethargy
)
5,697
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
1-Amino-2,4-dibromoanthraquinone (ADBAQ), an intermediate in the production of commercial dyes for wool, silk, and synthetic fibers, was selected for toxicology and
carcinogenesis
studies in two rodent species. In advance of the 2-year studies, 13-week studies were conducted in male and female F344/N rats and B6C3F1 mice which were fed a diet containing ADBAQ at concentrations of 0, 0.25, 0.50, 1.00, 2.50, and 5.00%. ADBAQ stained the skin and fur red at all doses in rats and at 1.00% and higher concentrations in mice.
Lethargy
and emaciation were noted at the 2.50% and higher doses in rats of both sexes. In general, the absolute weight of the liver and the liver/organ weight ratios increased in both sexes and species at all doses. Treated rats developed a chronic toxic hepatitis characterized by hepatocytomegaly, centrilobular vacuolar degeneration and necrosis, regenerative nodules, acute necrotizing cholangitis, bile duct hyperplasia, chronic active inflammation in periportal areas, and focal pigmentation. The hepatopathy occurred at all doses in males and at 0.50% and higher in females and correlated with elevations of serum glutamic-pyruvic and glutamic-oxaloacetic transaminases, leukocytosis, and neutrophilia. Hyaline droplet degeneration in the proximal convoluted tubules of the kidneys occurred in male rats, and uterine atrophy was observed in female rats at 1.00% and higher. Anemia occurred in both sexes of rats at all doses and thymic atrophy was observed in both sexes of high-dose rats. In male mice minimal dose-related lesions in the liver included centrilobular glycogen depletion at 1.00% and higher and pigmentation at all doses. At comparable doses, ADBAQ was considered to be markedly toxic in rats and of minimal nonlife-threatening toxicity in mice.
...
PMID:Thirteen-week toxicology studies of 1-amino-2,4-dibromoanthraquinone in Fischer 344/N rats and B6C3F1 mice. 395 25
2-Ethylhexanol (2EH) is a weak nongenotoxic hepatic peroxisome proliferator in the rat. It is a high-volume chemical intermediate in the preparation of the plasticizers bis-(2-ethylhexyl) adipate (DEHA), bis-(2-ethylhexyl) phthalate (DEHP), and tris-(2-ethylhexyl) phosphate (TEHP), which are weak hepatocellular tumorigens in female mice. In consequence, the oncogenic potential of 2EH was evaluated in male (M) and female (F) rats and mice (50 animals/sex/group). Oral gavage doses of 2EH in 0.005% aqueous Cremophor EL (polyoxyl-35 castor oil) were given five times a week to rats: 0 (water), 0 (vehicle), 50, 150, and 500 mg/kg for 24 months, and to mice: 0 (water), 0 (vehicle), 50, 200, and 750 mg/kg for 18 months. Statistical comparisons of data were made between vehicle controls and treatment groups. There were no differences of biological significance between data from vehicle and water control groups. In rats, there were no dose-related changes at 50 mg/kg. There was reduced body weight gain at 150 mg/kg (M, 16; F, 12%) and 500 mg/kg (M, 33; F, 31%) and an increased incidence of
lethargy
and unkemptness. There were dose-related increases in relative liver, stomach, brain, kidney, and testis weights at sacrifice. Female rat mortality was markedly increased at 500 mg/kg. There was marked aspiration-induced bronchopneumonia in rats at 500 mg/kg; hematologic, gross, and microscopic changes, including tumors, were otherwise comparable among all rat groups. In mice at 50 and 200 mg/kg there were no dose-related changes and essentially no time-dependent or time-independent adverse trends in liver tumor incidence at the 5% significance level. At 750 mg/kg mouse body weight gain was reduced (M, 26; F, 24%), and mortality increased (M and F, 30%) versus vehicle controls. At 750 mg/kg there was a slight increase in nonneoplastic focal hyperplasia in the forestomach of mice (M 5/50, F 4/50) versus vehicle controls (M 1/50, F 1/50). There were increases in mouse relative liver (F, 21%) and stomach (M, 13%; F, 19%) weights at 750 mg/kg. There was a 12% incidence of hepatic basophilic foci and an 18% incidence of hepatocellular carcinomas in male mice at 750 mg/kg, not statistically significant compared with either control by Fisher's exact test. There was a 12% incidence of hepatic basophilic foci and a 10% incidence of hepatocellular carcinomas in female mice at 750 mg/kg, statistically significant (p < 0.05) compared with vehicle but not with water controls by Fisher's exact test. There were no metastases. Time-dependent and -independent statistical analyses showed an adverse trend in the incidence of hepatocellular carcinomas in male and female mice, correlated with toxicity (expressed as mortality) at 750 mg/kg. The time-adjusted incidence of hepatocellular carcinomas in male mice (18.8%) was within the historical normal range at the testing facility (0-22%), but that in females (13.1%) lay outside the normal range (0-2%). Under the conditions of these studies 2EH was not oncogenic in rats, but there were weak adverse trends in hepatocellular carcinoma incidence in mice at high dose levels which may have been associated with toxicity. The major effects of chronic dosing were mortality in female rats at 500 mg/kg and in male and female mice at 750 mg/kg, accompanied by reductions in body weight gain in rats at 150 and 500 mg/kg and in mice at 750 mg/kg. Direct comparison of any tumorogenic effects of 2EH given alone to female mice with those due to 2EH formed in vivo from DEHA, DEHP, or TEHP is limited by the high mortality caused by 2ER in female mice at equivalent doses of 2EH. While 2EH may be a contributing factor in the hepatocellular
carcinogenesis
in female mice associated with the chronic administration of DEHA and DEHP, it is unlikely to be the entire proximate carcinogen.
...
PMID:Oncogenicity testing of 2-ethylhexanol in Fischer 344 rats and B6C3F1 mice. 899 51
Oxazepam is one of a number of benzodiazepines used therapeutically as a sedative-hypnotic and antianxiety agent. Toxicology and
carcinogenesis
studies were performed by administering oxazepam (greater than 99% pure) in feed to male and female Swiss-Webster and B6C3F1 mice for 14 weeks, 57 weeks (Swiss-Webster), or 2 years (B6C3F1). Neurobehavioral assessments were performed during the studies. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells, and peripheral blood samples were analyzed for frequency of micronucleated normochromatic erythrocytes. Supplemental studies were performed to compare the metabolism and toxicokinetics of oxazepam in the two mouse strains, to evaluate the effect on liver cell replication rates, to perform clinical pathology assessments, and to examine the mutation spectrum and frequency of activated H-ras oncogenes in liver neoplasms from the 2-year study with B6C3F1 mice. 14-WEEK STUDY IN SWISS-WEBSTER MICE: Groups of 10 male and 10 female Swiss-Webster mice received oxazepam in feed at concentrations of 0, 625, 1,250, 5,000, 10,000 ppm for 14 weeks. One 625 ppm male and one 10,000 female were killed moribund before the end of the study, and the condition of the female mouse was attributed to oxazepam exposure. Mean body weight gains of exposed groups were similar to those of the controls. Exposed mice displayed chemical-related sedation and
lethargy
during the first study week, but appeared normal thereafter. In the neurobehavioral studies, reductions in grip strength were evident in both male and female mice at week 2 and persisted in males through week 11. An antianxiety effect was detected in exposed mice in measures of motor activity, startle response, and reactions to thermal stimulus. At necropsy, absolute and relative liver weights were increased in an exposure-related manner and were approximately two-fold greater in 10,000 ppm mice than in controls. Centrilobular hepatocellular hypertrophy was present only in exposed mice, and the severity increased with dose. 14-WEEK STUDY IN B6C3F1 MICE: Groups of 10 male and 10 female B6C3F1 mice received oxazepam in feed at concentrations of 0, Groups of 10 male and 10 female Swiss-Webster mice 625, 1,250, 2,500, 5,000, or 10,000 ppm for 14 weeks. received oxazepam in feed at concentrations of 0, There were no deaths that were clearly related to 625,1,250, 2,500, 5,000, or 10,000 ppm for 14 weeks. oxazepam exposure. Mean body weight gains of One 625 ppm male and one 10,000 ppm female were exposed groups were similar to those of the controls. Exposed mice displayed chemical-related sedation and
lethargy
during only the first study week. In neurobehavioral studies, reductions in grip strength were evident in males at week 2 but were no longer observed at week 12. An antianxiety effect was noted in exposed mice in measures of motor activity, startle response, and reactions to a thermal stimulus (females). At necropsy, absolute and relative liver weights were increased in an exposure-related manner and were approximately two-fold greater in 10,000 ppm mice than in controls. Centrilobular hepatocellular hypertrophy was present only in exposed mice, and the severity increased with dose. CHRONIC STUDIES: Groups of 60 male and 60 female Swiss-Webster and B6C3F1 mice received oxazepam in feed at concentrations of 0, 2,500, or 5,000 ppm. Additional groups of 60 male and 60 female B6C3F1 mice received 125 ppm in feed to allow for study of a group with projected serum concentrations of oxazepam similar to those achieved in humans taking a therapeutic dose. Ten male and 10 female B6C3F1 mice per group were evaluated at 15 months. Average daily oxazepam consumption varied throughout the studies, and the overall daily average ranged from 10 to 29 mg/kg body weight for the 125 ppm groups, 234 to 512 mg/kg for the 2,500 ppm groups, and 444 to 1,085 mg/kg for the 5,000 ppm groups. Serum oxazepam concentrations determined at 57 weeks in Swiss-Webster mice and at the 15-month interim evaluation of B6C3F1 mice 1 mice were approximately 1 ug/mL in the 125 ppm groups, 4 to 7 μg/mL in the 2,500 ppm groups, and 7 to 10 μg/mL in the 5,000 ppm groups. Neurobehavioral assessments during the chronic studies of each strain of mice were confounded by the poor survival and deteriorating condition of mice with hepatic neoplasia. However, within the limitations of the studies, there were no notable changes in the types of behaviors observed compared to those observed in the 14-week studies, nor was there an enhancement in the degree to which they were exhibited. 57-Week Study in Swiss-Webster Mice: Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: At 57 weeks, survival of exposed mice was significantly lower than that of controls (males: O ppm, 45/60; 2,500 ppm, 19/60; 5,000 ppm, 10/60; females: 47/60, 28/59, 17/59), causing the study to be terminated. Mean body weights of exposed males were similar to controls until week 17; afterwards, mean body weights of exposed male groups were lower than those of controls. Final mean body weights of exposed males were 9% lower than that of the controls. The mean body weight of 2,500 ppm females was greater than that of the controls throughout the study. Females receiving 5,000 ppm had a mean body weight greater than that of the controls early in the study; after week 29, the mean body weight of this group was similar to that of the controls. Feed consumption by exposed males and females was slightly lower than that by the controls, and females in all groups, including controls, consumed slightly more feed than males throughout the study. Dietary levels of 2,500 and 5,000 ppm oxazepam resulted in average daily compound consumption levels of 270 and 570 mg/kg for males and 320 and 670 mg/kg for females. Hypoactivity and sedation were observed in exposed mice during the first week of the study. There were no other clinical findings associated with oxazepam exposure. Pathology Findings: Systemic amyloidosis was the principal cause of death in mice dying before the study was terminated. The lower survival of mice receiving oxazepam was attributed to an increase in the extent and severity of amyloid deposits in many organs, including the heart and kidney. Atrial thrombosis and pulmonary lesions consistent with chronic heart failure occurred at higher incidences and with greater severity in exposed mice. The incidence of hepatocellular adenomas (males: 1/60, 35/60, 50/60; females: 0/60, 22/59, 47/59) and carcinomas (males: 0/60, 5/60,19/60; females: 1/60, 1/59, 11/59) were increased in exposed mice. The incidences of eosinophilic foci were also increased in exposed mice (males: 0/60, 22/60, 22/60; females: 0/60, 20/59, 14/59), and there was evidence of increased centrilobular hepatocyte hypertrophy (males: 12/60, 46/60, 47/60; females: 3/60, 51/59, 53/59). 2-Year Study in B6C3F1 Mice: Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of mice receiving 2,500 and 5,000 ppm was significantly lower than that of controls (males: O ppm, 45/50; 125 ppm, 44/50; 2,500 ppm, 15/50; 5,000 ppm, 0/50; females: 39/50, 41/50, 2/50, 0/50). Mean body weight gains of exposed male and female mice were similar to controls until about week 15 when weight gains for mice exposed to 2,500 or 5,000 ppm slowed in relation to controls, resulting in weight gains approximately 30% to 40% lower than those of the controls throughout the remainder of the study. Mean body weight gain of male mice exposed to 125 ppm was similar to that of the controls, while that of female mice receiving 125 ppm was 10% to 15% lower than that of the controls after about week 45. Feed consumption by exposed males and females was similar to that by controls. Dietary levels of 125, 2,500, and 5,000 ppm resulted in average daily oxazepam consumption levels of 12, 310, and 690 mg/kg body weight for males and 15, 350, and 780 mg/kg for females. In the 5,000 ppm groups,
lethargy
and sedation were observed in a few mice during the first week of study. Pathology Findings: The early deaths of many of the B6C3F1 mice exposed to oxazepam were attributed to a marked increase in the incidences of hepatoblastoma (males: 0/49, 2/50, 21/50, 13/50; females: 0/50, 1/50, 8/50, 8/50), hepatocellular adenoma (males: 17/49,18/50, 34/50, 32/50; females: 25/50, 35/50, 35/50, 36/50), and hepatocellular carcinoma (males: 9/49, 5/50, 45/50, 50/50; females: 9/50, 5/50, 49/50, 44/50). Moderate hypertrophy of centrilobular hepatocytes occurred in mice receiving 2,500 and 5,000 ppm (males: 0/49, 2/50, 26/50, 43/50; females: 0/50, 2/50,11/50, 29/50). An increase in the incidence of follicular cell hyperplasia of the thyroid gland occurred in all exposed groups of mice (males: 4/49, 22/50, 49/50, 47/50; females: 16/50, 34/50, 49/50, 44/50), and thyroid gland follicular cell adenoma was increased in exposed females (0/50, 4/50, 5/50, 6/50). Testicular atrophy occurred in the 2,500 and 5,000 ppm groups (1/50, 0/50, 25/50, 38/50), and the incidence of epididymal Iymphocyte infiltration was increased in all exposed groups (2/50,14/50, 33/50, 21/50). The frequency of hepatocellular neoplasms with an activated H-ras oncogene in the B6C3F1 mice and the mutation spectrum of the H-ras gene were determined. The mutation spectrum of the H-ras genes in the relatively few neoplasms from exposed mice that did have an activated H-ras did not differ from the spectrum of mutations observed in neoplasms from controls, but the proportion of neoplasms with an activated H-ras gene decreased with increasing oxazepam dose. While 11 of 19 (58%) neoplasms from control mice had an activated H-ras gene, only 1 of 40 neoplasms from mice receiving 2,500 or 5,000 ppm oxazepam exhibited a similar molecular lesion. Thirteen of 37 (35%) neoplasms from mice in the 125 ppm group had an activated H-ras oncogene, suggesting that, although the incidence of all liver neoplasms was not statistically increased compared to controls, there was an increase in a similar subset of neoplasms (lacking an activated H-ras) that occurred with increased incidence at higher doses. SUPPLEMENTAL STUDIES: Because exposure to oxazepam caused increased incidences of liver neoplasms, supplemental short-term studies were performed. Oxazepam given in feed to male B6C3F1 mice at 25, 125, 2,500, or 5,000 ppm for up to 13 weeks was found to cause a dose-related increase in nuclear labeling index in studies measuring the incorporation of bromodeoxyuridine into replicating liver cells. This increase was statistically significant at all but the 25 ppm exposure level and was limited to mice evaluated at 15 days. Cell replication rates in most groups evaluated at 30 days and after were similar to control rates. There was minimal evidence suggestive of hepatocyte necrosis either by light microscopy or in clinical chemistry measures. There was, however, evidence of cholestasis, likely due to physical obstruction of bile canaliculi by swollen hepatocytes. The metabolic fate and toxicokinetics of oxazepam were evaluated in each strain of mice and were compared to published data from human studies. Both mice and humans form glucuronides of oxazepam and form 3- and 4-hydroxy and methoxy derivatives of the phenyl group. Oxidative metabolism of the phenyl group appears to be more prevalent in mice than is reported for humans. Elimination half-lives of parent compound do not differ between Swiss-Webster and B6C3F1 mice and are similar to values reported for humans. GENETIC TOXICOLOGY: Oxazepam was not mutagenic in any of several strains of Salmonella typhimurium, nor did it induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro tests were performed with and without S9 metabolic activation. Results from an in vivo mouse peripheral blood micronucleus test performed on the B6C3F1 mice used in the 14-week study were also negative. CONCLUSIONS: Under the conditions of these feed studies, there was clear evidence of carcinogenic activity of oxazepam in male and female Swiss-Webster mice based on increased incidences of hepatocellular adenoma and carcinoma. There was clear evidence of carcinogenic activity of oxazepam in male and female B6C3F1 mice based on increased incidences of hepatoblastoma and hepatocellular adenoma and carcinoma. Increased incidences of hyperplasia of thyroid gland follicular cells in male and female B6C3F1 mice and of follicular cell adenomas in female B6C3F1 mice were also related to oxazepam exposure. Administration of oxazepam to Swiss-Webster mice resulted in centrilobular hepatocellular hypertrophy and increased incidences and severity of systemic amyloidosis. Administration of oxazepam to B6C3F1 mice also resulted in centrilobular hepatocellular hypertrophy. Synonyms: 7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2 H - 1,4-benzodiazepin-2-one Trade Names: Tazepam, Wy-3498, Serax
...
PMID:NTP Toxicology and Carcinogenesis Studies of Oxazepam (CAS No. 604-75-1) in Swiss-Webster and B6C3F1 Mice (Feed Studies). 1259 20
NTP Toxicology and
Carcinogenesis
studies of a-methylbenzyl alcohol (greater than 99% pure), a cosmetic ingredient and food flavoring agent, were conducted by administering the chemical in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. a-Methylbenzyl alcohol was nominated for study by the National Cancer Institute because of the potential for widespread human exposure. Sixteen-Day and Thirteen-Week Studies: The doses used in the 16-day studies for rats and mice ranged between 125 and 2,000 mg/kg. Six of 10 rats and all mice dosed at 2,000 mg/kg died. In addition, because 7/9 mice dosed at 1,000 mg/kg died, the doses selected for the 13-week studies for mice (47-750 mg/kg) were half those used for rats (93-1,500 mg/kg). In the 13-week studies, deaths of 1/10 male and 3/10 female rats dosed at 1,500 mg/kg were compound related; none of the mice died. Body weight gain was reduced in rats at 1,500 mg/kg; there were no significant histopathologic lesions in either rats or mice. The only compound-related effects were ataxia, labored breathing, and
lethargy
for up to 30 minutes after dosing in rats and mice given the two highest doses and increases in liver weight to body weight ratios for male rats given the three highest doses and for female rats at all doses. Based on the pattern of mortality and the effects on body weight gain in the short-term studies, doses of 375 and 750 mg/kg a-methylbenzyl alcohol were administered in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 rats and 50 mice of each sex. Two-Year Studies: Significant reduction in body weight gain commenced at weeks 20-30 in high dose male and female rats, and body weights were 20%-30% below those of vehicle controls at study termination. In the low dose groups, body weight reduction occurred only in male rats during the last 10 weeks of the study. After 80 weeks, 60% of the high dose rats and 80%-100% of the low dose and vehicle control rats were alive; thereafter, the number of deaths in the chemically exposed groups increased sharply so that, at the end of 2 years, final survival for vehicle control, low dose, and high dose rats was 35/50; 8/50; and 1/50 for males and 34/50, 25/50, and 11/50 for females. There were a large number of gavage accidents in these studies (1, 9, and 8 for male rats and 1, 4, and 14 for female rats), but these accidents did not contribute to the increase in mortality after week 80, as all but 4 of these occurred earlier. Mortality in the last quarter of the study was thought to be due to the effects of cumulative toxicity of a-methylbenzyl alcohol on a renal excretory system already compromised by aging. Renal nephropathy that commonly occurs during aging was found in all groups of rats, but the severity was greater in male rats dosed with a-methylbenzyl alcohol. In addition, a collection of nonneoplastic lesions (parathyroid hyperplasia, calcification of the heart and glandular stomach, and fibrous osteodystrophy of bone) was found in the dosed male rats; these lesions were probably secondary to mineral imbalance arising from renal dysfunction. Since survival was poor in low and high dose male and high dose female rats, the sensitivity of the study for detecting a carcinogenic effect in these groups was reduced. Despite this limitation, there were dose-related increases in the incidences of renal tubular cell adenomas or adenocarcinomas (combined) in male rats (vehicle control, 0/50; low dose, 2/50; high dose, 5/50). In addition, transitional cell papillomas of the urinary bladder were observed in one high dose male and two high dose female rats. In mice, a reduction in body weight gain was apparent in the high dose groups of males and females. Final survival rates in mice were similar among groups (male: 39/49; 40/50; 28/50; female: 41/50; 41/50; 38/50). No neoplastic or nonneoplastic lesions were attributed to a-methylbenzyl lesions were attributed to a-methylbenzyl alcohol administration in mice of either sex. Genetic Toxicology: a-Methylbenzyl alcohol was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested in the presence or absence of exogenous metabolic activation. a-Methylbenzyl alcohol produced a positive response without activation in the mouse L5178Y/TK+/- lymphoma assay for induction of trifluorothymidine resistance; it was not tested with activation. In cytogenetic tests with CHO cells, a-methylbenzyl alcohol induced chromosomal aberrations in the presence, but not the absence, of metabolic activation; no induction of sister chromatid exchanges was observed in CHO cells after exposure to a-methylbenzyl alcohol. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activityof a-methylbenzyl alcohol for male F344/N rats, as shown by increased incidences of renal tubular cell adenomas and adenomas or adenocarcinomas (combined). There was no evidence of carcinogenic activity for female F344/N rats administered 375 or 750 mg/kg. Renal toxicity characterized by severe nephropathy and related secondary lesions was observed in the dosed rats, and excessive mortality occurred during the last quarter of the studies. Poor survival reduced the sensitivity of the studies for detecting the presence of a carcinogenic response both in chemically exposed groups of male rats and in the high dose group of female rats. There was no evidence of carcinogenic activity of a-methylbenzyl alcohol for male or female B6C3F1 mice administered 375 or 750 mg/kg for 2 years. Synonyms: styrallyl alcohol; styralyl alcohol; a-methylbenzenemethanol; phenylmethylcarbinol; 1-phenethyl alcohol
...
PMID:NTP Toxicology and Carcinogenesis Studies of a-Methylbenzyl Alcohol (CAS No. 98-85-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1269 35
N,N-Dimethylaniline is used as a chemical intermediate in the synthesis of dyestuffs. Toxicology and
carcinogenesis
studies were conducted by administering N,N-dimethylaniline (greater than 98% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 2 weeks, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. Two-Week and Thirteen-Week Studies: In the 2-week studies, doses were 94-1,500 mg/kg; deaths of rats and mice were observed in groups given doses of 750 or 1,500 mg/kg. The final mean body weights of male rats that received 375 or 750 mg/kg were 15% or 47% lower than that of vehicle controls; final mean body weights of other groups of rats and mice were similar to those of vehicle controls. Compound-related clinical signs observed included cyanosis in rats and
lethargy
and tremors in rats and mice. Splenomegaly occurred in nearly all dosed groups of rats and mice, and the incidences were dose related. In the 13-week studies, doses were 32-500 mg/kg; no compound-related deaths occurred. The final mean body weights of male rats that received 250 or 500 mg/kg were 15% or 27% lower than that of vehicle controls. The final mean body weights of all groups of dosed female rats and male and female mice were within 12% of those of vehicle controls. Compound-related clinical signs included
lethargy
in rats and mice and cyanosis in rats. Splenomegaly was observed in all dosed groups of rats and mice; the severity was dose related. Compound-related extramedullary hematopoiesis and hemosiderosis occurred in the kidney or testis of dosed rats and liver and spleen of dosed rats and mice. Two-year studies were conducted by administering 0, 3, or 30 mg/kg N,N-dimethylaniline in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 rats of each sex. The lower dose was selected to be one-tenth the higher dose to increase the likelihood that one dose would cause only a minimal nonneoplastic response. Groups of 50 mice of each sex were administered 0, 15, or 30 mg/kg on the same schedule. Body Weight and Survival in the Two-Year Studies: Mean body weights of vehicle control and dosed rats and mice were similar throughout the studies. Survival rates of all respective groups were similar after 2 years, except for the lowered survival of vehicle control female rats (vehicle control, 21/50; low dose 32/50; high dose, 36/50). This may reflect the large number (24/50) of vehicle control female rats killed when observed to be in a moribund state. Final survival for other groups was as follows: male rats--29/50; 32/50; 28/50; male mice-- 34/50; 30/50; 34/50; female mice--35/50; 39/50; 33/50. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: In these 2-year studies, the spleen was the expected site of chemical-related effects. Fatty metamorphosis and fibrosis in the spleen of high dose male rats were increased (fatty metamorphosis: vehicle control, 0/49; low dose, 1/49; high dose, 10/50; fibrosis: 5/49; 2/49; 22/50). Splenic hemosiderosis and hematopoiesis were present at an incidence greater than 85% in all groups of rats; however, the severity of the lesions was greater in dosed groups than in vehicle controls. Sarcomas of the spleen were seen in 3/50 high dose male rats, and an osteosarcoma was seen in another high dose male rat. One additional high dose male rat had a sarcoma of the thymus. Splenic sarcomas are uncommon in corn oil vehicle control male F344/N rats (NTP historical incidence 3/2,081, 0.1%), and thus, these neoplasms in high dose male rats (4/50, 8%) were considered to be chemically related. Lower incidences of mononuclear cell leukemia (which apparently originates in the spleen) were seen in dosed male and female rats than in vehicle controls (male: 13/50; 4/50; 3/50; female: 11/50; 7/50; 0/50). The incidence of squamous cell papillomas of the forestomach in high dose female mice was marginally greater than that in vehicle controls (2/50; 2/50; 8/50). No malignant forestomacin vehicle controls (2/50; 2/50; 8/50). No malignant forestomach neoplasms were observed. Genetic Toxicology: N,N-Dimethylaniline was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of exogenous metabolic activation. In the mouse lymphoma assay, N,N-dimethylaniline produced a positive response with and without metabolic activation. In CHO cells, N,N-dimethylaniline induced both sister chromatid exchanges (SCEs) and chromosomal aberrations in the presence of exogenous metabolic activation. Without activation, an increase in chromosomal aberrations was observed, but no increase in SCEs occurred. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of N,N-dimethylaniline for male F344/N rats, as indicated by the increased incidences of sarcomas or osteosarcomas(combined) of the spleen. There was no evidence of carcinogenic activity of N,N-dimethylaniline for female F344/N rats given 3 or 30 mg/kg body weight by gavage for 2 years. There was no evidence of carcinogenic activity of N,N-dimethylaniline for male B6C3F1 mice given 15 or 30 mg/kg body weight by gavage for 2 years. There was equivocal evidence of carcinogenic activity of N,N-dimethylaniline for female B6C3F1 mice, as indicated by an increased incidence of squamous cell papillomas of the forestomach. Both rats and mice could have tolerated doses higher than those used in these studies. There were decreased incidences of mononuclear cell leukemia in dosed male and high dose female rats. Compound-related splenic fibrosis, hemosiderosis, and fatty metamorphosis were increased in male rats. Synonyms: dimethylaminobenzene; N,N-dimethylbenzeneamine; dimethylaniline; dimethylphenylamine; N,N-dimethylphenylamine
...
PMID:Toxicology and Carcinogenesis Studies of N,N-Dimethylaniline (CAS No. 121-69-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1269 81
Tribromomethane, a chemical intermediate and solvent, has been identified as a drinking water contaminant resulting from water chlorination. Toxicology and
carcinogenesis
studies were conducted by administering tribromomethane (95%-97% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex once or for 14 days, 13 weeks, or 2 years. Single-Administration, Fourteen-Day, and Thirteen-Week Studies: All rats that received 2,000 mg/kg and 3/5 males and 3/5 females that received 1,000 mg/kg tribromomethane died before the end of the single-administration studies. All mice that received 2,000 mg/kg, 4/5 males and 2/5 females that received 1,000 mg/kg, and 1/5 males that received 500 mg/kg died before the end of the studies. Shallow breathing was observed for rats and male mice that received 1,000 or 2,000 mg/kg tribromomethane. In the 14-day studies, all rats that received 600 or 800 mg/kg and 1/5 males that received 400 mg/kg tribromomethane died before the end of the studies. The final mean body weight of male rats that received 400 mg/kg was 14% lower than that of vehicle controls. One of five male mice that received 600 mg/kg and 1/5 female mice that received 800 mg/kg died before the end of the studies. Final mean body weights of dosed and vehicle control mice were comparable. None of the rats died before the end of the 13-week studies (doses ranged from 12 to 200 mg/kg). Final mean body weights were comparable for dosed and vehicle control rats. All male rats that received 100 or 200 mg/kg tribromomethane and all female rats that received 200 mg/kg were
lethargic
. The incidences of cytoplasmic vacuolization of hepatocytes in dosed male rats were slightly increased compared with that in vehicle controls. The severity of this lesion was increased in the 200 mg/kg group. One of 10 female mice that received 100 mg/kg tribromomethane died before the end of the 13-week studies. The final mean body weight of mice that received 400 mg/kg was 8% lower than that of vehicle controls for males and was comparable to that of vehicle controls for females. Cytoplasmic vacuolization of hepatocytes was observed in the liver of 5/10 male mice that received 200 mg/kg and in 8/10 male mice that received 400 mg/kg tribromomethane. Based on these results, 2-year studies of tribromomethane were conducted by administering 0, 100, or 200 mg/kg tribromomethane in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 F344/N rats of each sex and 50 female B6C3F1 mice. Male B6C3F1 mice were administered 0, 50, or 100 mg/kg tribromomethane on the same schedule. Body Weights and Survival in the Two-Year Studies: Mean body weights of high dose male and female rats were 10%-28% lower than those of vehicle controls throughout the second year of the studies. Survival of the high dose group of male rats was significantly lower than that of the vehicle controls after week 91; no significant differences in survival were observed between any groups of female rats (male: vehicle control, 34/50; low dose, 30/50; high dose, 11/50; female: 34/50; 28/50; 28/50). Reduced survival for male rats given 200 mg/kg tribromomethane lowered the sensitivity of this group to detect a carcinogenic response. Mean body weights of dosed and vehicle control male mice were comparable throughout the study. Mean body weights of dosed female mice were 5%-16% lower than those of vehicle controls from week 28 to the end of the study. No significant differences in survival were observed between any groups of male mice; the survival of both dosed groups of female mice was significantly lower than that of the vehicle controls after week 77 (male: 41/50; 37/50; 36/50; female: 25/49; 15/50; 20/50). Reduced survival in all groups of female mice was partly due to a utero-ovarian infection; nonetheless, survival of all groups of female mice was at least 50% by week 92. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Uncommon adenomatous polyps or adenocarcinomas (combined) of the large intestine (colon or rectum) were induced in three male ratarge intestine (colon or rectum) were induced in three male rats (vehicle control, 0/50; low dose, 0/50; high dose, 3/50) and in nine female rats (0/50; 1/50; 8/50); the historical incidence of neoplasms of the large intestine is less than 0.2% in approximately 2,000 corn oil vehicle control male F344/N rats, and none has been observed in approximately 2,000 corn oil vehicle control female F344/N rats. Three of the neoplasms of the large intestine (one in the high dose male rats and two in the high dose female rats) were adenocarcinomas. Focal or diffuse fatty change of the liver was observed at increased incidences in dosed rats (male: 23/50; 49/50; 50/50; female: 19/50; 39/49; 46/50). Active chronic inflammation was observed at increased incidences in dosed male and high dose female rats (male: 0/50; 29/50; 23/50; female: 9/50; 8/49; 27/50). The incidence of necrosis of the liver was increased in high dose male rats (7/50; 3/50; 20/50) and decreased in dosed females (11/50; 3/49; 2/50). Mixed cell focus was observed at increased incidences in dosed female rats (8/50; 25/49; 28/50). Other nonneoplastic lesions observed at increased incidences in dosed rats included chronic active inflammation and squamous metaplasia of the ducts of the salivary gland (squamous metaplasia-- male: 0/50; 15/50; 31/48; female: 0/49; 10/49; 16/50; chronic active inflammation--male: 0/50; 16/50; 25/48; female: 0/49; 9/49; 18/50), squamous metaplasia of the prostate gland (2/49; 6/46; 12/50), ulcers of the forestomach (male: 1/49; 5/50; 10/50), and chronic active inflammation of the lung (male: 1/50; 7/50; 15/50). Pigmentation of the spleen was also observed at an increased incidence in high dose female rats. The salivary gland and lung lesions were characteristic of infection by rat coronavirus, a virus to which a positive serologic reaction was observed early in the studies. The incidence of follicular cell hyperplasia of the thyroid gland was increased in high dose female mice (5/49; 4/49; 19/47), and fatty change of the liver was increased in both dosed groups of female mice (1/49; 9/50; 24/50). No chemically related adverse effects were observed in male mice. Neoplastic lesions that occurred at lower incidences in dosed animals compared with those in vehicle controls included preputial gland neoplasms in male rats (10/41; 5/38; 1/34), uterine stromal polyps in female rats (10/49; 9/50; 2/50), anterior pituitary gland adenomas in male and female rats (male: 12/50; 12/48; 2/45; female: 29/48; 12/46; 16/48), mammary gland fibroadenomas in female rats (22/50; 17/50; 6/50), and alveolar/bronchiolar neoplasms in male mice (11/50; 7/50; 2/49). Other than concomitant decreases in body weights, no other reasons are obvious to correlate these decreases with chemical administration. Genetic Toxicology: Tribromomethane exhibited equivocal mutagenicity in Salmonella typhimurium strain TA100 in the absence of exogenous metabolic activation and in strains TA97 and TA98 when exposure occurred in the presence of hamster S9; tribromomethane produced no increases in revertant colonies in TA1535 or TA1537 with or without exogenous metabolic activation. Tribromomethane induced trifluorothymidine (Tft) resistance in mouse L5178Y cells with and without metabolic activation. When tested incultured Chinese hamster ovary (CHO) cells for cytogenetic effects, tribromomethane produced an increase in both sister chromatid exchanges (SCEs) and chromosomal aberrations in the absence, but not in the presence, of exogenous metabolic activation. Tribromomethane caused sex-linked recessive lethal mutations in Drosophila when administered to adult males by feeding; no induction of mutations was observed when tribromomethane was administered by abdominal injection. Results of tests for reciprocal translocations in adult male Drosophila exposed to tribromomethane by feeding were negative. In vivo tests for cytogenetic effects in bone marrow cells of male B6C3F1 mice demonstrated that intraperitoneal injection of tribromomethane induced an increase in SCEs but no increase in chromosomal aberrations. Intraperitoneal injection of tribromomethane also induced an increase in the incidence of micronucleated polychromatic erythrocytes in the bone marrow of B6C3F1 mice. Audit: The data, documents, and pathology materials from the 2-year studies of tribromomethane have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of tribromomethane for male F344/N rats and clear evidence of carcinogenic activity for female F344/N rats, based on increased incidences of uncommon neoplasms of the large intestine. Reduced survival for male rats given 200 mg/kg tribromomethane lowered the sensitivity of this group to detect a carcinogenic response. Chemically related nonneoplastic lesions included fatty change and active chronic inflammation of the liver in male and female rats, minimal necrosis of the liver in male rats, and mixed cell foci of the liver in female rats. There was no evidence of carcinogenic activity for male B6C3F1 mice given 50 or 100 mg/kg tribromomethane or for female B6C3F1 mice given 100 or 200 mg/kg; male mice might have been able to tolerate a higher dose. Survival of female mice was reduced, partly due to a utero-ovarian infection. Synonym: bromoform
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PMID:NTP Toxicology and Carcinogenesis Studies of Tribromomethane (Bromoform) (CAS No. 75-25-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1270 34
Toxicology and
carcinogenesis
studies of technical-grade benzyl alcohol (99% pure), a textile dye additive, solvent, and food flavoring agent, were conducted by administering the chemical by gavage in corn oil vehicle to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Short-Term Studies: In 16-day studies, all five male and five female rats and mice dosed with 2,000 mg/kg benzyl alcohol died. Two of five male and 3/5 female rats and 1/5 male and 2/5 female mice dosed with 1,000 mg/kg died. Rats and mice of each sex in the two highest dose groups were
lethargic
after dosing. Other toxic responses to benzyl alcohol in these dose groups included blood around the mouth and nose, subcutaneous hemorrhages, and blood in the urinary and gastrointestinal tracts of rats and blood in the urinary bladder of mice. Animals administered lower doses of benzyl alcohol (125, 250, or 500 mg/kg) had no compound-related histologic lesions. Doses selected for the 13-week studies were 0, 50, 100, 200, 400, and 800 mg/kg for rats and mice. Eight of 10 male rats dosed with 800 mg/kg died during weeks 7 and 8; four of these deaths were described as gavage related. Rats dosed with 800 mg/kg exhibited clinical signs indicative of neurotoxicity including staggering, respiratory difficulty, and
lethargy
. Hemorrhages occurred around the mouth and nose, and there were histologic lesions in the brain, thymus, skeletal muscle, and kidney. In mice, deaths were scattered among all dose levels, but none occurred in vehicle controls. Four male and six female mice died after being dosed; all deaths but one were described as gavage related. Staggering after dosing also occurred during the first 2 weeks of the studies in mice dosed with 800 mg/kg. Some of the deaths in the rats and mice may have been caused by a combination of the gavage procedure and chemical toxicity, since there was evidence that benzyl alcohol induced neurotoxic effects. There were reductions in relative weight gain in male rats dosed with 800 mg/kg benzyl alcohol, in female rats dosed with 200 mg/kg or more, in male mice dosed with 400 or 800 mg/kg, and in female mice dosed with 200 mg/kg or more. No notable changes in body weight gain or compound-related histopathologic lesions were observed in rats or mice from the lower dose groups. Based on mortality, reduction in relative body weight gain, and the histopathologic lesions, doses selected for 2-year studies in rats were 0, 200, and 400 mg/kg. Doses selected for 2-year studies in mice were 0, 100, and 200 mg/kg, based on mortality and depression in relative body weight gain. Body Weight and Survival in the Two-Year Studies: Fifty animals of each species and sex were administered benzyl alcohol in corn oil by gavage 5 days per week for 103 weeks. Administration of benzyl alcohol did not affect survival in male rats (final survival rates: vehicle control, 28/50; low dose, 27/50; high dose, 24/50) but reduced survival of dosed female rats by half (36/50; 18/50; 17/50). Many of the early deaths were considered related to the gavage procedure. Survival in mice was not affected by benzyl alcohol administration (male: 34/50; 33/50; 35/50; female: 26/50; 32/50; 36/50). No effect of benzyl alcohol on body weight gain in rats or mice was observed. In the third month of the studies, clinical signs of sialodacryoadenitis virus infection were observed in rats. A positive serologic reaction for rat coronavirus was observed in sentinel animals at 6 months and again at 18 months. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: No apparent compound-related nonneoplastic responses were observed. Dose-related negative trends in the incidences of anterior pituitary gland neoplasms were seen in female rats (vehicle control, 29/50; low dose, 17/47; high dose, 9/49) and of harderian gland adenomas in male mice (8/50; 3/50; 2/50). Adenomas of the adrenal cortex occurred at an increased incidence in high dose male mice (0/48; 0/44; 3/48), but this slight increase was not considered to be related to chemical expcal exposure. Genetic Toxicology: Benzyl alcohol was not mutagenic when tested by the preincubational protocol in the presence or absence of exogenous metabolic activation in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537. In the mouse L5178Y/TK± lymphoma assay, benzyl alcohol induced an increase in trifluorothymidine (Tft)-resistant cells in the absence, but not in the presence, of S9; the effect was associated with toxicity. In cytogenetic assays with Chinese hamster ovary (CHO) cells, treatment with benzyl alcohol produced an increase in sister chromatid exchanges (SCEs) which was judged to be equivocal both with and without S9; a significant increase in chromosomal aberrations was observed after exposure to benzyl alcohol in the presence, but not the absence, of S9. Audit: The data, documents, and pathology materials from the 2-year studies of benzyl alcohol have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of benzyl alcohol for male or female F344/N rats dosed with 200 or 400 mg/kg. Survival in both dose groups of female rats was 50% that of vehicle controls, primarily due to an increased number of gavage-related deaths. There was no evidence of carcinogenic activity of benzyl alcohol for male or female B6C3F1 mice dosed with 100 or 200 mg/kg for 2 years. Synonyms: benzenemethanol; phenylcarbinol; phenylmethanol; a-hydroxytoluene; benzenecarbinol; phenolcarbinol; a-toluenol
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PMID:NTP Toxicology and Carcinogenesis Studies of Benzyl Alcohol (CAS No. 100-51-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1272 82
2-Amino-4-nitrophenol is used to color semipermanent hair dyes and in the manufacture of mordant dyes for leather, nylon, silk, wool, and fur. 2-Amino-4-nitrophenol was nominated by the National Cancer Institute for toxicology and
carcinogenesis
studies because of widespread human exposure associated with its manufacture and use. Toxicology and
carcinogenesis
studies were conducted by administering 2-amino-4-nitrophenol (98% pure) in corn oil by gavage, 5 days per week, to groups of F344/N rats and B6C3F1 mice of each sex in 15-day, 13-week, and 2-year studies. Fifteen-Day and Thirteen-Week Studies: During the 15-day studies, rats and mice received doses of 0, 313, 625, 1,250, 2,500, or 5,000 mg/kg. All rats that received 2,500 or 5,000 mg/kg and all female rats that received 1,250 mg/kg died before the end of the studies. Final mean body weights of chemically exposed rats surviving to the end of the studies were comparable to those of vehicle controls. Diarrhea was observed in all groups of exposed rats except those receiving 313 mg/kg. All mice that received 2,500 or 5,000 mg/kg, 2/5 males and all females that received 1,250 mg/kg, and 1/5 females that received 313 mg/kg died before the end of the studies. Final mean body weights of exposed mice surviving until the end of the studies were comparable to those of vehicle controls. In 13-week studies, F344/N rats and B6C3F1 mice of each sex received 2-amino-4-nitrophenol at doses of 0, 62.5, 125, 250, 500, or 1,000 mg/kg. All rats that received 1,000 mg/kg and 2/10 males and 2/10 females that received 500 mg/kg died before the end of the studies. The final mean body weight of male rats that received 500 mg/kg was reduced 10% compared with that of vehicle controls; final mean body weights of all other surviving exposed rat groups were comparable to those of vehicle controls. Diarrhea and
lethargy
were observed for rats that received 500 or 1,000 mg/kg. All male mice and most females that received 1,000 mg/kg and 4/10 females that received 500 mg/kg died before the end of the studies. Final mean body weights of chemically exposed mice were comparable to those of vehicle controls. No compound-related clinical signs were observed in mice during the studies. Mineralization of the renal cortex and degeneration of the renal tubular epithelium were observed in male and female rats that received 1,000 mg/kg and in males that received 500 mg/kg. Degeneration and necrosis of the renal tubular epithelium was observed in 5/10 male and 3/10 female mice that received 1,000 mg/kg. Body Weight and Survival in the Two-Year Studies: In the 2-year studies, rats and mice received 2-amino- 4- nitrophenol at doses of 0, 125, or 250 mg/kg. Mean body weights of male rats that received 250 mg/kg were 8%-10% lower than those of vehicle controls throughout most of the 2-year study. Mean body weights of female rats were comparable to those of vehicle controls. Soft stools and occasional diarrhea were observed in chemically exposed rats starting 6 months after the beginning of the studies. Survival of male rats that received 250 mg/kg was markedly lower than that of vehicle controls after week 89 (final survival: vehicle control, 32/50; 125 mg/kg group, 24/50; 250 mg/kg group, 10/50). Survival of female rats was comparable among all groups (final survival: 25/50; 27/50; 31/50). Mean body weights of male and female mice that received 250 mg/kg were comparable to those of vehicle controls; the mean body weights of female mice that received 125 mg/kg were as much as 17% greater than that of vehicle controls. Survival of all mouse groups was comparable during the 2-year studies (final survival: male-- 28/50; 29/50; 23/50; female--28/50; 31/50; 30/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Pigmentation of the small and large intestines was present in exposed rats but not in vehicle controls. Ulcers and erosive lesions of the digestive tract were observed in male rats that received 250 mg/kg and to a lesser extent in male rats that received 125 mg/kg. A carcinoma of the colon occurrkg. A carcinoma of the colon occurred in one male rat that received 250 mg/kg; no other neoplasms were observed in the gastrointestinal tract of rats. No pigmentation, ulcers, or erosive lesions were found in the digestive tract of mice. The severity of nephropathy was markedly greater in exposed male rats than in vehicle controls. Associated with the nephropathy were nonneoplastic lesions indicative of reduced renal function and secondary hyperparathyroidism, including parathyroid hyperplasia, mineralization of various organs, and fibrous osteodystrophy. Renal tubular cell hyperplasia (1/50; 4/48; 5/50) and renal cortical (tubular cell) adenomas (0/50; 1/48; 3/50) occurred in male rats. Renal cortical adenomas are infrequently observed in male F344/N rats (historical incidence, 0.5%). More preputial gland adenomas or carcinomas (combined) were observed in low dose male rats than in vehicle controls (3/50; 10/48; 3/50), whereas the incidences of clitoral gland neoplasms were decreased in dosed female rats (9/50; 6/50; 1/49). Hemangiomas or hemangiosarcomas (combined) occurred in male mice that received 2-amino-4-nitrophenol (0/50; 1/50; 5/50); each tumor was present at a different site. The historical control incidence is 11% at the study laboratory and 6% in 2-year NTP studies. Genetic Toxicology: 2-Amino-4-nitrophenol was mutagenic in Salmonella typhimurium strains TA98 and TA100 with metabolic activation. 2-Amino-4-nitrophenol was not mutagenic in strains TA1535 or TA1537. 2-Amino-4-nitrophenol was mutagenic in the mouse lymphoma L5178Y/TK± assay without metabolic activation. It was not tested with activation. 2-Amino-4-nitrophenol induced sister chromatid exchanges (SCEs) and chromosomal aberrations in Chinese hamster ovary cells in the presence and absence of metabolic activation. Audit: The data, documents, and pathology materials from the 2-year studies of 2-amino-4-nitrophenol were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of 2-amino-4-nitrophenol for male F344/N rats, as shown by increased incidences of renal cortical (tubular cell) adenomas. The incidences of renal tubular cell hyperplasia were also increased in male rats exposed to 2-amino-4-nitrophenol. The survival of male rats that received 2-amino-4-nitrophenol was reduced compared with survival of vehicle control male rats. There was no evidence of carcinogenic activity of 2-amino-4-nitrophenol for female F344/N rats or for male or female B6C3F1 mice that received 125 or 250 mg/kg per day.
...
PMID:NTP Toxicology and Carcinogenesis Studies of 2-Amino-4-Nitrophenol (CAS No. 99-57-0) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1272 86
The technical grade of xylenes (mixed) (hereafter termed xylenes) contains the three isomeric forms and ethylbenzene (percentage composition shown above). The annual production for 1985 was approximately 7.4 x 108 gallons. Xylenes is used as a solvent and a cleaning agent and as a degreaser and is a constituent of aviation and automobile fuels. Xylenes is also used in the production of benzoic acid, phthalate anhydride, and isophthalic and terephthalic acids as well as their dimethyl esters. Toxicology and
carcinogenesis
studies of xylenes were conducted in laboratory animals because a large number of workers are exposed and because the long- term effects of exposure to xylenes were not known. Exposure for the present studies was by gavage in corn oil. In single-administration studies, groups of five F344/N rats and B6C3F1 mice of each sex received 500, 1,000, 2,000, 4,000, or 6,000 mg/kg. Administration of xylenes caused deaths at 6,000 mg/kg in rats and mice of each sex and at 4,000 mg/kg in male rats. In rats, clinical signs observed within 24 hours of dosing at 4,000 mg/kg included prostration, muscular incoordination, and loss of hind limb movement; these effects continued through the second week of observation. Tremors, prone position, and slowed breathing were recorded for mice on day 3, but all mice appeared normal by the end of the 2- week observation period. In 14- day studies, groups of five rats of each sex were administered 0, 125, 250, 500, 1,000, or 2,000 mg/kg, and groups of five mice of each sex received 0, 250, 500, 1,000, 2,000, or 4,000 mg/kg. Chemical- related mortality occurred only at 2,000 mg/kg in rats and at 4,000 mg/kg in mice. Rats and mice exhibited shallow breathing and prostration within 48 hours following dosing at 2,000 mg/kg. These signs persisted until day 12 for rats, but no clinical signs were noted during the second week for mice. In 13- week studies, groups of 10 rats of each sex received 0, 62.5, 125, 250, 500, or 1,000 mg/kg, and groups of 10 mice of each sex received 0, 125, 250, 500, 1,000, or 2,000 mg/kg. No deaths or clinical signs of toxicity were recorded in rats. However, high dose male rats gained 15% less weight and females 8% less weight than did the vehicle controls. Two female mice died at the 2,000 mg/kg dose.
Lethargy
, short and shallow breathing, unsteadiness, tremors, and paresis were observed for both sexes in the 2,000 mg/kg group within 5- 10 minutes after dosing and lasted for 15- 60 minutes. Two- year toxicology and
carcinogenesis
studies were conducted by administering 0, 250, or 500 mg/kg xylenes in corn oil by gavage to groups of 50 F344/N rats of each sex, 5 days per week for 103 weeks. Groups of 50 B6C3F1 mice of each sex were administered 0, 500, or 1,000 mg/kg xylenes on the same schedule. Although the mortality was dose related in male rats (final survival: vehicle control, 36/50; low dose, 26/50; high dose, 20/50), many of the early deaths in the dosed males were gavage related. Body weights of the high dose male rats were 5%- 8% lower than those of the vehicle controls after week 59. The mean body weights of low dose and vehicle control male rats and those of dosed and vehicle control female rats were comparable. Survival rates of female rats and both sexes of dosed mice were not significantly different from those of the vehicle controls. The mean weights of dosed male and female mice were comparable to those of the vehicle controls. Hyperactivity lasting 5- 30 minutes was observed in high dose mice after dosing, beginning after week 4 and continuing through week 103. At no site was the incidence of nonneoplastic or neoplastic lesions in dosed rats or mice of either sex considered to be related to the administration of xylenes. Neither xylenes nor any of its components (o- xylene, m-xylene, p- xylene, or ethylbenzene) were mutagenic when tested with or without metabolic activation in Salmonella typhimurium strains TA100, TA1535, TA97, or TA98 with the preincubation protocol. In addition, ethylbenzene was tested in cytogenetic assays using cultured Cetic assays using cultured Chinese hamster ovary cells both with and without metabolic activation; neither sister- chromatid exchanges nor chromosomal aberrations were induced by ethylbenzene. An audit of the experimental data was conducted for the 2-year studies of xylenes. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity of xylenes (mixed) for male or female F344/N rats given 250 or 500 mg/kg or for male or female B6C3F1 mice given 500 or 1,000 mg/kg.
...
PMID:NTP Toxicology and Carcinogenesis Studies of Xylenes (Mixed) (60% m-Xylene, 14% p-Xylene, 9% o-Xylene, and 17% Ethylbenzene) (CAS No. 1330-20-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1273 97
Nitrofurazone is a synthetic furan derivative, active against a broad spectrum of bacteria, which has been widely used in veterinary and human medicine. Toxicology and
carcinogenesis
studies were conducted by feeding diets containing nitrofurazone (99% pure) to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: Groups of five males and five females of each species were fed diets containing 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm for 14 consecutive days. Early deaths occurred in all groups of rats receiving 5,000 or 10,000 ppm nitrofurazone. The surviving rats in the lower two dose groups gained weight, but weight gain was decreased as the dose of nitrofurazone was increased. Feed consumption by rats of each sex was decreased at all doses above 630 ppm. In all dosed groups, clinical signs of toxicity included rough hair coats and
lethargy
. At doses of 2,500 ppm and above, rats of each sex exhibited intermittent episodes of seizures and
lethargy
. All mice that received 2,500, 5,000, or 10,000 ppm nitrofurazone and 3/5 males that received 1,250 ppm died before the end of the 14-day studies; the surviving dosed mice (except females at 630 ppm) lost weight. A dose-related decrease in feed consumption was observed at all doses above 630 ppm. Clinical signs included rough hair coats and convulsive seizures. In the 13-week studies, groups of 10 rats of each sex were given diets containing 0, 150, 310, 620, 1,250, or 2,500 ppm nitrofurazone. No deaths were observed and all animals gained weight, but the magnitude of weight gain was dose dependent with decrements in final mean body weight for the highest dose group reaching 55% in males and 36% in females. Other evidence of chemically related toxicity included convulsive seizures, osteoporosis, degenerative arthropathy, and gonadal hypoplasia in both sexes at the two highest doses. Groups of 10 mice of each sex were given diets containing 0, 70, 150, 310, 620, or 1,250 ppm nitrofurazone for 13 weeks. Early deaths were observed in the two highest dose groups of each sex. The final mean body weights of male and female mice in the 1,250-ppm groups were about 20% lower than those of the controls; weight gains of the other dosed mice were comparable to those of the controls. Stimulus-induced convulsive seizures were observed for all mice in the two highest dose groups. Testicular hypoplasia was observed in the two highest dose groups of male mice. Body Weight and Survival in the Two-Year Studies: Dietary concentrations for the 2-year studies were 0, 310, or 620 ppm for rats and 0, 150, or 310 ppm for mice (50 animals per dose group). Mean body weights of high dose male rats were lower than those of the controls after week 39; mean body weights of low dose male rats and of the controls were comparable throughout the study. Final mean body weights of low and high dose female rats were 9% and 21% lower than those of the controls. Dosed rats consumed less feed than did the controls. The average amount of nitrofurazone consumed per day was approximately 11-12 or 24-26 mg/kg by low or high dose male and female rats. The survival of the high dose group of male rats was lower than that of the controls after week 92 (final survival-- male: control, 33/50; low dose, 30/50; high dose, 20/50; female: 28/50; 37/50; 31/50). Mean body weights of dosed mice were similar to or somewhat greater than those of controls throughout most of the studies. The average daily feed consumption by dosed mice was similar to that of controls. The average amount of nitrofurazone consumed per day was approximately 14-16 or 29-33 mg/kg for low or high dose male and female mice. The survival of the high dose group of male mice was lower than that of the controls after week 88 (final survival-- male: 39/50; 31/50; 27/50; female: 39/50; 40/50; 35/50). In mice of each sex, nitrofurazone administration induced stimulus-sensitive convulsive seizures beginning at week 4 or 5 for high dose mice and week 24 for low dose female mice. These seizures were low dose female mice. These seizures were observed primarily in the first year of the study. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Degenerative changes involving the vertebral and femoro-tibial (knee) joints were observed at increased incidences in dosed rats. The degenerative changes primarily affected the articular cartilage and were similar to those seen in the 13-week studies. Degeneration of the sternal synchondroses was increased in high dose female rats. The osteoporosis seen in the 13-week studies was not observed in the 2-year studies. Testicular degeneration, characterized by atrophy of the germinal epithelium and aspermatogenesis, was observed at increased incidences in dosed male rats (control, 12/50; low dose, 49/50; high dose, 47/50). Adenomas of the sebaceous glands and trichoepitheliomas or sebaceous adenomas (combined) of the skin were observed in high dose male rats (0/50; 0/50; 5/50). Carcinomas of the preputial gland were increased in dosed male rats (1/50; 8/50; 5/50). The incidences of preputial gland adenomas or carcinomas (combined) in dosed male rats were not statistically greater than that in the controls (9/50; 16/50; 7/50). However, in the low dose group, the incidence is greater than the highest incidence observed in historical untreated control groups (9/50). In addition, hyperplasia of the preputial gland was observed in six low dose male rats in which neither adenomas nor carcinomas occurred. The incidence of mesotheliomas of the tunica vaginalis in low dose male rats was greater than that in the controls (0/50; 7/50; 2/50). Fibroadenomas of the mammary gland occurred at markedly increased incidences in dosed female rats (8/49; 36/50; 36/50). Three adenocarcinomas were also observed (1/49; 0/50; 2/50). Ovarian atrophy (7/47; 44/50; 38/50) and tubular cell hyperplasia of the ovary (1/47; 23/50; 21/50) were observed at markedly increased incidences in dosed female mice. The incidences of benign mixed tumors (0/47; 17/50; 20/50), granulosa cell tumors (1/47; 4/50; 9/50), and granulosa cell tumors or luteomas (combined) (3/47; 6/50; 9/50) of the ovary were increased in exposed female mice. Mononuclear cell leukemia in rats occurred with negative trends (male: 21/50; 23/50; 6/50; female: 15/49; 2/50; 2/50). In female mice, the incidences of adenomas or carcinomas (combined) of the anterior pituitary gland occurred with a negative trend (10/50; 7/50; 2/49). The incidences of testicular interstitial cell tumors were decreased in dosed male rats (45/50; 30/50; 28/50). Genetic Toxicity: Nitrofurazone was mutagenic in Salmonella typhimurium strains TA98 and TA100 both with and without exogenous metabolic activation. The responses in strains TA1535 and TA1537 were more varied: nitrofurazone was mutagenic in strain TA1535 only in the presence of S9 and produced no consistent increase in gene reversions in strain TA1537 with or without S9. In the absence of metabolic activation, nitrofurazone induced forward mutations at the TK+/- locus of mouse L5178Y lymphoma cells; the chemical was not tested with S9. Treatment of cultured Chinese hamster ovary cells with nitrofurazone in the absence of S9 produced a dose-related increase in sister chromatid exchanges and chromosomal aberrations; with S9, sister chromatid exchanges were increased, but no induction of chromosomal aberrations was observed. Audit: The data, documents, and pathology materials from the 2-year studies of nitrofurazone were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of nitrofurazone for male F344/N rats as shown by the occurrence of sebaceous gland adenomas and trichoepitheliomas of the skin, mesotheliomas of the tunica vaginalis, and preputial gland tumors. There was clear evidence of carcinogenic activity of nitrofurazone for female F344/N rats as shown by a markedly increased incidence of fibroadenomas of the mammary gland. There was no evidence of carcinogenic activity for male B6C3F1 mice fed diets containing nitrofurazone at concentrations of 150 or 310 ppm. There was clear evidence of carcinogenic activity of nitrofurazone for female B6C3F1 mice as shown by increased incidences of benign mixed tumors and granulosa cell tumors of the ovary. Administration of nitrofurazone was associated with decreased incidences of mononuclear cell leukemia in male and female rats, testicular interstitial cell tumors in male rats, and pituitary gland neoplasms in female mice. Convulsive seizures in mice of each sex, ovarian atrophy in female mice, testicular degeneration in rats, and degeneration of articular cartilage in rats were all associated with the administration of nitrofurazone. Synonyms: 5-nitro-2-furaldehyde semicarbazone; 2-[(5-nitro-2-furanyl)methylene]hydrazine carboximide Trade Names: Aldomycin; Amifur; Chemfuran; Coxistat; Furacin; Furacinetten; Furaplast; Furazol W; Furesol; Furracoccid; Mammex; Nefco; Nifuzon; Nitrofural; Vabrocid
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PMID:NTP Toxicology and Carcinogenesis Studies of Nitrofurazone (CAS No. 59-87-0) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1273 99
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