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PubMed1989

NTP Toxicology and Carcinogenesis Studies of N-Methylolacrylamide (CAS No. 924-42-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

N-Methylolacrylamide is a cross-linking agent used in adhesives, binders for paper, crease-resistant textiles, resins, latex film, and sizing agents. Toxicology and carcinogenesis studies were conducted by administering N-methylolacrylamide (98% pure) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. In vitro genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells; an in vivo bone marrow micronucleus test was performed with B6C3F1 mice. Neurobehavioral assays were performed during the 13-week studies. Sixteen-Day Studies: The doses of N-methylolacrylamide used ranged from 25 to 400 mg/kg. All rats that received 400 mg/kg died within 4 days, and 3/5 male rats that received 200 mg/kg also died before the end of the studies. Compound-related clinical signs seen with 200 mg/kg included ataxia, muscle tremors, and hyperirritability. Ataxia after dosing was observed from day 7 to the end of the studies for rats that received 100 mg/kg. The final mean body weight of male rats that received 100 or 200 mg/kg was 10% or 27% lower than that of the vehicle controls. The final mean body weight of female rats that received 200 mg/kg was 20% lower than that of the vehicle controls. Compound-related lesions in rats included hyperplasia of the bronchiolar and tracheal epithelium, dysplasia of the nasal and tracheal epithelium, centrilobular hepatocellular necrosis, lymphoid depletion of the spleen, and myelin degeneration of the lumbar ventral spinal nerve. All 5 male and 4/5 female mice that received 400 mg/kg N-methylolacrylamide died on the second day of the 16-day studies. The surviving female mouse in the 400 mg/kg group and the male and female mice in the 200 mg/kg groups were ataxic after they were dosed, starting on day 2. Weight changes were inconsistent among dose groups. Bronchial epithelial hyperplasia (mild) appeared to be dose related in males and females. Sinusoidal congestion of the liver and vacuolar degeneration of myocardial fibers were seen in males and females given 400 mg/kg. Thirteen-Week Studies: The doses of N-methylolacrylamide used ranged from 12.5 to 200 mg/kg. All rats that received 100 or 200 mg/kg died before the end of the studies. Rats that received 100 or 200 mg/kg had hind limb ataxia, which progressed to hind limb paralysis. Rats that received 50 mg/kg had hind limb ataxia beginning at week 8, which progressed to hind limb paresis by week 11. The final mean body weight of rats that received 25 or 50 mg/kg was 8% or 16% lower than that of the vehicle controls for males and 6% or 10% lower for females. In neurobehavioral assessments, decreased forelimb and hind limb grip strength was seen at doses as low as 25 mg/kg for female rats and at doses as low as 12.5 mg/kg for male rats. A decreased startle response was seen for females at doses as low as 25 mg/kg. The landing foot spread was significantly increased for male and female rats that received 50 mg/kg. Axon filament and myelin sheath degeneration of the brain stem, spinal cord, and/or peripheral nerves was seen in rats at increased incidences at 25 mg/kg and higher doses. Inflammation and/or hemorrhage and edema of the urinary bladder mucosa were seen with doses of 25 mg/kg or more in a few rats that had distended bladders at gross examination. All mice that received 200 mg/kg N-methylolacrylamide died before the end of the studies. Final mean body weights of dosed and vehicle control mice were similar. A decreased relative testis weight was observed for mice that received 12.5 mg/kg or more. The relative kidney weights for male mice receiving 50 or 100 mg/kg were greater than that for vehicle controls. Neurobehavioral studies indicated decreased forelimb grip strength in male and female mice at doses as low as 25 mg/kg. An exaggerated startle response was seen for female mice given 100 mg/kg. A reduction in rotarod performance was seen for male and female mice receiving 100 mg/kg and for male mice receiving 25 mg/kg. Hepatocellular necrosis anmale mice receiving 25 mg/kg. Hepatocellular necrosis and thymic lymphocytic necrosis were compound-related effects in mice given 200 mg/kg N-methylolacrylamide. Hemorrhage, necrosis, and mineralization of the zona reticularis of the adrenal gland were present in 3/10 female mice given 200 mg/kg, and cytoplasmic vacuolization of the adrenal cortex was seen with lower doses. Based on the results of these short-term studies, 2-year studies were conducted by administering 0, 6, or 12 mg/kg N-methylolacrylamide in water by gavage, 5 days per week for 103 weeks, to groups of 50 rats of each sex. Groups of 50 mice of each sex were administered 0, 25, or 50 mg/kg on the same schedule. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were within 6% of those of vehicle controls throughout most of the studies. Mean body weights of dosed mice were as much as 25% greater than those of vehicle controls for females and as much as 13% greater for males. The survival of female rats given 25 mg/kg per day was lower than that of vehicle controls after day 550, but survival of female rats given 50 mg/kg per day was not different from that of vehicle controls (vehicle control, 35/50; low dose, 22/50; high dose, 33/50). No differences in survival were observed between any other groups of rats or mice of either sex (male rats: 28/50; 22/50; 27/50; male mice: 30/50; 20/50; 21/50; female mice: 41/50; 35/50; 33/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: In rats, no biologically important nonneoplastic or neoplastic lesions were attributed to administration of N-methylolacrylamide. Higher doses might have increased the sensitivity of the studies to determine the presence or absence of a carcinogenic response. In mice, the incidences of adenomas of the Harderian gland were increased in males given either dose of N-methylolacrylamide and in females given the top dose (male: vehicle control, 1/48; low dose, 14/49; high dose, 29/50; female: 5/47; 8/45; 20/48). The incidences of carcinomas of the Harderian gland were not significantly increased by N-methylolacrylamide administration (male: 1/48; 0/49; 2/50; female: 0/47; 3/45; 2/48). The incidences of hepatocellular adenomas were increased in male and female mice given 50 mg/kg N-methylolacrylamide (male: 8/50; 4/50; 19/50; female: 3/50; 4/50; 17/49). The incidences of hepatocellular carcinomas were also marginally increased in dosed male mice (male: 6/50; 13/50; 12/50; female: 3/50; 3/50; 2/49). Hepatocellular adenomas and carcinomas (combined) occurred with positive trends, and the incidences in male and female mice receiving 50 mg/kg were increased compared with those in the vehicle controls (male: 12/50; 17/50; 26/50; female: 6/50; 7/50; 17/49). Chronic inflammation and alveolar epithelial hyperplasia of the lung were observed at increased incidences in mice given N-methylolacrylamide. Sentinel mice were seropositive for Sendai virus at 18 months. The incidences of alveolar/bronchiolar adenomas (3/49; 6/50; 11/50) and carcinomas (2/49; 4/50; 10/50) were increased in male mice given 50 mg/kg. Alveolar/bronchiolar adenomas or carcinomas (combined) occurred with a positive trend in male mice (5/49; 10/50; 18/50). The incidence of alveolar/bronchiolar adenomas or carcinomas (combined) was increased in female mice given the top dose of 50 mg/kg (6/50; 8/50; 13/49). Ovarian atrophy was observed at increased incidences in female mice receiving N-methylolacrylamide (3/50; 39/45; 38/47). The incidences of benign granulosa cell tumors were also increased in the dosed groups (0/50; 5/45; 5/47). The incidence of adenomas of the pars distalis in high dose female mice was significantly lower than that in vehicle controls (13/49; 5/14; 4/43). Genetic Toxicology: N-Methylolacrylamide was not mutagenic in S. typhimurium strains TA97, TA98, TA100, or TA1535 when tested with or without exogenous metabolic activation. N-Methylolacrylamide induced both sister chromatid exchanges (SCEs) and chromosomal aberrations in CHO cells with and without metabolic activation. No increase in micronucleated polychromatic erythrocytes (PCEs) was observed in the bone marrow of B6C3F1 mice after intraperitoneal injection of N-methylolacrylamide. Conclusions: Under the conditions of these 2-year studies, there was no evidence of carcinogenic activity of N-methylolacrylamide for male or female F344/N rats receiving doses of 6 or 12 mg/kg per day by aqueous gavage. There was clear evidence of carcinogenic activity of N-methylolacrylamide for male B6C3F1 mice, based on increased incidences of neoplasms of the Harderian gland, liver, and lung. There was clear evidence of carcinogenic activity of N-methylolacrylamide for female B6C3F1 mice, based on increased incidences of neoplasms of the Harderian gland, liver, lung, and ovary. In rats, because no biologically important toxic effects were attributed to N-methylolacrylamide administration, somewhat higher doses could have been used to increase the sensitivity of these studies for determining the presence or absence of a carcinogenic response. In female mice, ovarian atrophy was compound related. Synonyms: N-(hydroxymethyl)acrylamide; N-(hydroxymethyl)-2-propenamide; N-methanolacrylamide; monomethylolacrylamide

Journal Article↗
PubMed1989

NTP Toxicology and Carcinogenesis Studies of para-Chloroaniline Hydrochloride (CAS No. 20265-96-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

p-Chloroaniline has a large production volume and is used as a dye intermediate. Toxicology and carcinogenesis studies of p-chloroaniline (greater than 99% pure) were conducted by administering p-chloroaniline hydrochloride in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Vehicle controls were given deionized water by gavage. All doses were calculated as p-chloroaniline; the chemical was administered as the hydrochloride after dissolution in water containing molar equivalents of hydrochloric acid. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Hematologic parameters were measured at the end of the 13-week studies and at 6, 12, 18, and 24 months in the 2-year studies. Supplemental studies of the distribution and disposition of p-chloroaniline were conducted in male F344 rats. Sixteen-Day and Thirteen-Week Studies: In the 16-day studies, male and female rats and mice received 25, 50, 100, or 400 mg/kg of body weight. The vehicle controls received deionized water. All rats and mice that received 200 or 400 mg/kg died during the first 6 days of the studies. Some deaths occurred in each of the lower dose groups of mice. Splenic enlargement was observed at necropsy in rats administered 25, 50, or 100 mg/kg. Congestion of the spleen and hemosiderin deposition in the renal cortical tubular epithelial cells were observed at 100 mg/kg in male and female rats. Compound-related lesions in mice included hemosiderosis of the liver Kupffer cells and congestion of the spleen. In the 13-week studies, 10 rats of each sex were administered doses of 0, 5, 10, 20, 40, or 80 mg/kg. All male rats lived to the end of the 13-week studies. One of 10 female rats that received 80 mg/kg died from unknown causes. The final mean body weights of rats that received 80 mg/kg were 16% lower than that of vehicle controls for males and 4% lower for females. In the 13-week studies in mice, 10 animals of each sex were administered doses of 0, 7.5, 15, 30, 60, or 120 mg/kg. Deaths in mice were not related to p-chloroaniline hydrochloride administration. The final mean body weights of dosed and vehicle control mice were similar. In both rats and mice, no chemically related effects on organ weights were observed at necropsy, except for the spleen, which was enlarged as a function of increasing dose. Methemoglobin was increased in dosed groups and resulted in a secondary anemia, the severity of which was dose related. Compound-related lesions observed histologically, including pigmentation (hemosiderin) in the kidney, spleen, and liver and hematopoiesis in the liver and spleen, reflected the response to the hemolytic anemia and methemoglobinemia induced by p-chloroaniline hydrochloride. Based on these results, groups of 50 rats of each sex were administered 2, 6, or 18 mg/kg p-chloroaniline hydrochloride in water by gavage, 5 days per week for 103 weeks. Groups of 50 mice of each sex were administered 3, 10, or 30 mg/kg on the same schedule. Metabolism and Disposition Studies in Rats: The metabolism and disposition studies in F344/N rats showed that metabolic and excretory pathways were not saturated by p-chloroaniline administered orally at doses ranging from 0.3 to 30 mg/kg. p-Chloroaniline was rapidly metabolized and excreted primarily in urine with a half-life of approximately 2 hours. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were generally within 5% of those of vehicle controls throughout the studies. The survival of the low and mid dose groups of male rats and of the low and high dose groups of female rats was significantly greater than that of the vehicle controls (male: vehicle control, 18/49; low dose, 32/50; mid dose, 32/50; high dose, 21/50; female: 27/50; 39/50; 36/50; 37/50). The increased survival was attributed to the decreased incidences of mononuclear cell leukemia. Mean body weights of high dose male and female mice were generally within 5% of those of vehiclwithin 5% of those of vehicle controls throughout the studies. The survival of the mid dose group of male mice was lower than that of the vehicle controls after week 99 (male: 43/50; 36/50; 29/50; 35/50; female: 39/50; 42/50; 44/50; 41/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Fibrosis of the spleen was increased in dosed male and high dose female rats (male: vehicle control, 3/49; low dose, 11/50; mid dose, 12/50; high dose, 41/50; female: 1/50; 2/50; 3/50; 42/50). Cellular infiltration of lipocytes (fatty metaplasia) was observed in the spleen at increased incidences in high dose rats (male: 0/49; 0/50; 0/50; 24/50; female: 0/50; 0/50; 0/50; 11/50). The incidence of uncommon sarcomas of the spleen in high dose male rats was significantly greater than that in the vehicle controls (fibrosarcomas, osteosarcomas, or hemangiosarcomas, combined: 0/49; 1/50; 3/50; 38/50). Many of these tumors metastasized to one or more sites. In female rats, one fibrosarcoma of the spleen was found in a mid dose animal, and one osteosarcoma of the spleen was found in a high dose animal. The historical incidence of splenic connective tissue sarcomas (all types) in water gavage vehicle controls is 1/298 (0.3%) for male rats and 0/297 for female rats. The historical incidence of hemangiosarcomas in water gavage controls is 0/300 for male rats and 1/297 (0.3%) for female rats. Adrenal medullary hyperplasia was observed at an increased incidence in high dose female rats (4/50; 4/50; 7/50; 24/50). Marginally increased incidences of pheochromocytomas were seen in high dose male (13/49; 14/48; 15/48; 26/49) and female (2/50; 3/50; 1/50; 6/50) rats. The historical incidence of pheochromocytomas in water gavage vehicle control male F344/N rats is 121/299 (40% ± 16%); the historical incidence in water gavage vehicle control female F344/N rats is 20/295 (7% ± 2%). The incidences of mononuclear cell leukemia in dosed male and female rats were lower than those in vehicle controls (male: 21/49; 3/50; 2/50; 3/50; female: 10/50; 2/50; 1/50; 1/50). The incidences of malignant lymphomas in dosed male and female mice were lower than those in vehicle controls (male: 10/50; 3/49; 9/50; 3/50; female: 19/50; 12/50; 5/50; 10/50). Hematologic and methemoglobin measurements were made on blood samples collected from 15 randomly selected male and female rats per dose group at 6, 12, 18, and 24 months. In general, the high dose group at various intervals showed mild hemolytic anemia and dose-related increases in methemoglobin. In rats, compound-related nonneoplastic lesions were seen histopathologically in the bone marrow, spleen, and liver. These lesions included bone marrow hyperplasia, hepatic hemosiderosis, and splenic fibrosis and suggest compound-related effects on the hematopoietic system in general, the erythropoietic system specifically, and mesenchymal cells in the spleen. In male mice, the incidence of hemangiosarcomas of the liver or spleen in high dose male mice was greater than that in the vehicle controls (4/50; 4/49; 1/50; 10/50). The historical incidence of hemangiomas or hemangiosarcomas at all sites (combined) in water gavage vehicle control male B6C3F1 mice is 11/350 (3% ± 3%). The incidences of hepatocellular adenomas or carcinomas (combined) were increased in dosed male mice (11/50; 21/49; 20/50; 21/50), primarily due to increased incidences of hepatocellular carcinomas (3/50; 7/49; 11/50; 17/50). Hepatocellular carcinomas metastasized to the lung in 1/50 vehicle control, 1/49 low dose, 2/50 mid dose, and 9/50 high dose male mice. The historical incidence ofhepatocellular neoplasms in water gavage vehicle controls is 106/347 (31 ± 6%). Genetic Toxicology: p-Chloroaniline was mutagenic in S. typhimurium strains TA98 and TA100 in the presence of exogenous metabolic activation; no increase in revertant colonies was observed in strains TA97, TA1535, or TA1537. p-Chloroaniline induced trifluorothymidine (Tft) resistance in mouse L5178Y lymphoma cells with and without metabolic activation. In cultured CHO cells, treatment with p-chloroaniline produced significant increases in sister chromatid exchanges (SCEs) both with and without metabolic activation (S9); chromosomal aberrations were significantly increased only in the presence of S9. Audit: The data, documents, and pathology materials from the 2-year studies of p-chloroaniline 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 water gavage studies, there was clear evidence of carcinogenic activity of p-chloroaniline hydrochloride for male F344/N rats, as indicated by increased incidences of uncommon sarcomas of the spleen. Pheochromocytomas of the adrenal gland may also have been associated with chemical administration. There was equivocal evidence of carcinogenic activity of p-chloroaniline hydrochloride for female F344/N rats, as indicated by the presence of uncommon sarcomas of the spleen in one mid and one high dose animal and the increased incidence of pheochromocytomas of the adrenal gland. There was some evidence of carcinogenic activity of p-chloroaniline hydrochloride for male B6C3F1 mice, as indicated by increased incidences of hepatocellular neoplasms and of hemangiosarcomas of the liver or spleen. There was no evidence of carcinogenic activity of p-chloroaniline hydrochloride for female B6C3F1 mice administered 3, 10, or 30 mg/kg by gavage for 2 years. The incidences of mononuclear cell leukemia in male and female rats and of malignant lymphomas in male and female mice were decreased by administration of p-chloroaniline hydrochloride. Compound-related splenic fibrosis was present in male and female rats. Synonyms: 1-amino-4-chlorobenzene hydrochloride; 4-chlorophenylamine hydrochloride; 4-chlorobenzeneamine hydrochloride

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of d-Limonene (CAS No. 5989-27-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of d-limonene, a naturally occurring monoterpene found in many volatile oils, especially in citrus oils, were conducted because of its widespread use as a flavor and fragrance additive for food and household cleaning products and its increasing use as an industrial solvent. The d-limonene used in these studies was more than 99% pure and was administered in corn oil by gavage. Short-term studies were conducted in F344/N rats and B6C3F1 mice to identify toxic effects and affected sites and to help establish doses for the 2-year studies. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y cells, and Chinese hamster ovary (CHO) cells. The doses selected for the 16-day studies ranged from 413 to 6,600 mg/kg for both rats and mice; deaths and reduction in body weight gain occurred at the two highest doses. No compound-related clinical signs or histopathologic lesions were observed in any of the surviving dose groups. In the 13-week studies, doses of d-limonene ranged from 150 to 2,400 mg/kg for rats and from 125 to 2,000 mg/kg for mice. Deaths occurred in the high dose group of each species and sex. Greater than 10% reductions in body weight gain were observed in the two highest dose groups of male rats and male mice and the high dose female rats. Rough hair coats and decreased activity were observed at the two highest doses in both rats and mice. There were no chemical-related histopathologic lesions in female rats or in mice of either sex. A compound-related increased severity of nephropathy was observed in the kidney of male rats. This lesion was characterized by degeneration of epithelial cells in the convoluted tubules, granular casts in the outer stripe of the outer medulla, and epithelial regeneration. These lesions have been described as reasonably characteristic of the hyaline droplet nephropathy that is associated with an accumulation of liver-generated a2u-globulin in the cytoplasm of tubular epithelial cells. Two-year studies of d-limonene were conducted by administering 0, 75, or 150 mg/kg d-limonene in corn oil by gavage to groups of 50 F344/N male rats, 5 days per week for 103 weeks; groups of 50 female F344/N rats were administered 0, 300, or 600 mg/kg. These doses were selected based on compound-related, potentially life-threatening kidney lesions observed in males at 300 mg/kg and higher and on the large number of deaths of female rats at 2,400 mg/kg. Groups of 50 male B6C3F1 mice were administered 0, 250, or 500 mg/kg according to the same schedule; groups of 50 female B6C3F1 mice were administered 0, 500, or 1,000 mg/kg. These doses were selected based on the deaths observed for both male and female mice at 2,000 mg/kg during the 13-week studies and the body weight depression in male mice at 1,000 mg/kg and higher. Mean body weights of rats dosed with d-limonene were similar to those of vehicle controls throughout the studies. Survival of the high dose female rats after week 39 and of the vehicle control male rats after week 81 was significantly reduced (survival at week 104-- male: vehicle control, 29/50; low dose, 33/50; high dose, 40/50; female: 42/50; 40/50; 26/50). Mean body weights of dosed and vehicle control male mice were similar throughout the studies. Mean body weights of high dose female mice were notably lower than those of the vehicle controls after week 28. Survival of the low dose group of male mice was significantly lower than that of vehicle controls at the end of the study (33/50; 24/50; 39/50). No difference in survival was observed between vehicle control and dosed female mice (43/50; 44/50; 43/50). In the 2-year studies, the kidney was confirmed as the primary target organ for chemically related lesions. No lesions were observed in female rats. For males, the nonneoplastic lesions included exacerbation of the age-related nephropathy, linear deposits of mineral in the renal medulla and papilla, and focal hyperplasia of the transitional epithelium overlying the renal papilla. Uncommon tubular cell adenomas and adenocarc and adenocarcinomas of the kidney also occurred in dosed male rats, and this effect was supported by a dose-related increased incidence of tubular cell hyperplasia, as shown in the table below. INCIDENCES OF MALE RATS WITH RENAL LESIONS IN THE TWO-YEAR GAVAGE STUDY OF d-LIMONENE Site/Lesion Vehicle Control 75 mg/kg 150 mg/kg Renal papilla Mineralization 7/50 43/50 48/50 Epithelial hyperplasia 0/50 35/50 43/50 Kidney Tubular cell hyperplasia 0/50 4/50 7/50 Tubular cell adenoma 0/50 4/50 8/50 Tubular cell adenocarcinoma 0/50 4/50 3/50 In subsequent 21-day studies, male and female F344/N rats were administered d-limonene at doses ranging from 75 to 1,200 mg/kg. Microscopic examination of the kidney sections from these rats indicated a compound-related increase in intracytoplasmic granules in the proximal convoluted tubules of dosed male rats but not of female rats. The granules were shown to contain a2u-globulin by an immunohistochemical strain. a2u-Globulin was shown to be increased in kidney homogenates from dosed male rats by an ELISA test. In mice, no chemically related increases in neoplasms were observed. The incidence of neoplasms of the anterior pituitary gland in high dose female mice was lower than that in vehicle controls (adenomas or carcinomas, combined:vehicle control, 12/49; high dose, 2/48). Cells with an abnormal number of nuclei (8/49; 32/50) and cytomegaly (23/49; 38/50) were observed in the liver of high dose male mice. Genetic Toxicology: d-Limonene was not mutagenic in four strains of S. typhimurium (TA98, TA100, TA1535, or TA1537), did not significantly increase the number of trifluorothymidine (Tft)-resistant cells in the mouse L5178Y/TK± assay, and did not induce chromosomal aberrations or sister chromatid exchanges (SCEs) in cultured CHO cells. All assays were conducted in the presence and absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of d-limonene for male F344/N rats, as shown by increased incidences of tubular cell hyperplasia, adenomas, and adenocarcinomas of the kidney. There was no evidence of carcinogenic activity of d-limonene for female F344/N rats that received 300 or 600 mg/kg. There was no evidence of carcinogenic activity of d-limonene for male B6C3F1 mice that received 250 or 500 mg/kg. There was no evidence of carcinogenic activity of d-limonene for female B6C3F1 mice that received 500 or 1,000 mg/kg. An increased severity of spontaneous nephropathy, increased incidences of linear mineralization of the renal medulla and papilla, and hyperplasia of the transitional epithelium of the renal papilla were present in dosed male rats. Synonyms: cyclohexene; 4-isopropenyl-1-methyl; 1-methyl-4-(1-methylethenyl)cyclohexene; p-mentha-1,8-diene; carvene; cinene; cajeputene

Journal Article↗
PubMed1989

NTP Toxicology and Carcinogenesis Studies of Chloroethane (Ethyl Chloride) (CAS No. 75-00-3) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Toxicology and carcinogenesis studies of chloroethane (99.5% pure), an alkylating agent and chemical intermediate, as well as a topical and inhalation anesthetic, were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to chloroethane by whole-body inhalation once for 4 hours or for 6 hours per day, 5 days per week for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium. Single-Exposure, Fourteen-Day, and Thirteen-Week Studies: In the single-exposure and 14-day inhalation studies, all rats and mice exposed to 19,000 ppm chloroethane survived. The animals were not exposed at lower concentrations. No clinical signs of toxicity were seen. In the 14-day studies, final mean body weights of exposed male rats and exposed mice were higher than those of controls. Mean body weights of exposed and control female rats were similar. In the 13-week studies, rats and mice were exposed to 0, 2,500, 5,000, 10,000, or 19,000 ppm chloroethane. No compound-related deaths occurred in rats or mice. The final mean body weight of rats exposed to 19,000 ppm was 8% lower than that of controls for males and 4% lower for females. Final mean body weights of exposed mice were generally higher than those of controls. No compound-related clinical signs or gross or microscopic pathologic effects were seen in rats or mice. The liver weight to body weight ratios for male rats and female mice exposed to 19,000 ppm were greater than those for controls. Although no chemically related toxic effects were observed in the short-term studies, concerns about potential flammability and explosion led to the selection of 0 and 15,000 ppm as the exposure concentrations for rats and mice for the 2-year studies. Body Weight and Survival in the Two-Year Studies: Mean body weights of exposed male rats were 4%-8% lower than those of controls after week 33. Mean body weights of exposed female rats were generally 5%-13% lower than those of controls throughout the study. Although survival of male rats and exposed female rats was low at the end of the studies (male: control, 16/50; exposed, 8/50; female: 31/50; 22/50), no statistically significant differences in survival were observed between exposed and control groups of either sex. Survival at week 90 for male rats was 37/50 (control) and 31/50 (exposed) and for females, 43/50 (control) and 33/50 (exposed). The high incidence of mononuclear cell leukemia may have contributed to the high mortality. Mean body weights of exposed male mice were up to 13% higher than those of controls throughout the study. Mean body weights of exposed and control female mice were generally similar throughout the study. The survival of the exposed groups of both male (after day 330) and female (after day 574) mice was significantly lower than that of controls (final survival-- male: 28/50; 11/50; female: 32/50; 2/50). The majority of exposed female mice died as a result of uterine carcinomas. Male mice, and particularly exposed mice, died early as a result of an ascending urinary tract infection. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Malignant astrocytomas of the brain were seen in three exposed female rats, and gliosis was observed in a fourth. The historical incidence of glial cell neoplasms in untreated control female F344/N rats is 23/1,969. The highest incidence observed in an untreated control group is 3/50. Trichoepitheliomas (1/50), sebaceous gland adenomas (1/50), basal cell carcinomas (3/50), and squamous cell carcinomas (2/50) of the skin were observed only in exposed male rats. Keratoacanthomas occurred in four control and two exposed male rats. Exposure of female mice to chloroethane caused a high incidence of uterine carcinomas of endometrial origin (control, 0/49; exposed, 43/50). One control female did have a uterine carcinoma, although it was not of endometrial origin. The tumors observed in 34 exposed females were highly malignant, invading the uterine myometrium and metastasizing to a wide variety of organs, primarily lung (23), ovary (2 a wide variety of organs, primarily lung (23), ovary (22), lymph nodes (18), kidney (8), adrenal gland (8), pancreas (7), mesentery (7), urinary bladder (7), spleen (5), and heart (4), and to a lesser extent, colon, stomach, gallbladder, small intestine, ureter, and liver. Two marginally increased incidences of other neoplasms were observed in exposed male and female mice. The incidence of hepatocellular carcinomas in exposed female mice was greater than that in controls (3/49; 7/48). One other exposed female had a hepatocellular adenoma. The incidence of alveolar/bronchiolar neoplasms of the lung in exposed male mice was greater than that in controls (adenomas or carcinomas, combined: 5/50; 10/48). Genetic Toxicology: Chloroethane, tested within the closed environment of a desiccator, was mutagenic with and without exogenous metabolic activation in S. typhimuriumstrain TA1535; in strain TA100, a positive response was observed only with activation. No mutagenic activity was observed in S. typhimurium strain TA98 with or without metabolic activation. Conclusions: Under the conditions of these 2--year inhalation studies, there was equivocal evidence of carcinogenic activity of chloroethane for male F344/N rats, as indicated by benign and malignant epithelial neoplasms of the skin. For female F344/N rats, there was equivocal evidence of carcinogenic activity, as indicated by three uncommon malignant astrocytomas of the brain in the exposed group. The study of male B6C3F1 mice was considered to be an inadequate study of carcinogenicity because of reduced survival in the exposed group. However, there was an increased incidence of alveolar/bronchiolar neoplasms of the lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, as indicated by carcinomas of the uterus. A marginally increased incidence of hepatocellular neoplasms was observed in the exposed group. Synonyms: monochloroethane; chloroethyl; ether hydrochloric; ether muriatic; aethylis; aethylis chloridum; ether chloridum; ether chloratus Trade Names: Kelene; Chelen; Anodynon; Chloryl Anesthetic; Narcotile

Journal Article↗
PubMed1989

NTP Toxicology and Carcinogenesis Studies of Diphenhydramine Hydrochloride (CAS No. 147-24-0) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Diphenhydramine hydrochloride is a widely used antihistaminic drug in human and veterinary medicine. Toxicology and carcinogenesis studies were conducted by feeding diets containing USP-grade diphenhydramine hydrochloride (greater than 99% pure) to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, dietary concentrations ranged from 620 to 10,000 ppm for rats and from 310 to 5,000 ppm for mice. All rats that received diets containing 10,000 ppm and 9/10 rats that received diets containing 5,000 ppm died before the end of the studies. The final mean body weights of rats receiving 1,250 or 2,500 ppm were 12%-13% or 30%-34% lower than those of controls. Feed consumption by rats at the three highest concentrations was more than 30% less than that by controls. All mice receiving 5,000 ppm, 4/5 males and 4/5 females receiving 2,500 ppm, and 4/5 males receiving 1,250 ppm died before the end of the studies. The final mean body weights of mice that received 1,250 or 2,500 ppm were lower than the initial weights. All dosed rats and mice were hyperactive and sensitive to sound and/or touch. In the 13-week studies, dietary concentrations of diphenhydramine hydrochloride ranged from 156 to 2,500 ppm for rats and from 78 to 1,250 ppm for mice. All rats lived to the end of the studies. The final mean body weights of rats receiving 1,250 or 2,500 ppm were about 15% or 35% lower than those of controls. The final mean body weight of female rats receiving 625 ppm was 9% lower than that of controls. Increased activity was observed for all male and female rats receiving 1,250 and 2,500 ppm. Cytoplasmic vacuolization of the liver, characteristic of fat accumulation, was observed in male and female rats receiving 313-2,500 ppm. The severity of this change increased with increased dose. For mice, 1/10 males receiving 313 ppm, 2/10 males receiving 625 ppm, and 8/10 males receiving 1,250 ppm died before the end of the studies. The final mean body weights of mice that received 625 or 1,250 ppm were about 9% or 16% lower than those of controls. No compound-related histopathological effects were observed in mice. Based on the mortality and body weight effects of diphenhydramine hydrochloride in the short-term studies, dietary concentrations selected for the 2-year studies were 0,313, and 635 ppm diphenhydramine hydrochloride for male rats and 0, 156, and 313 ppm for female rats and male and female mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed and control rats were similar throughout the studies, and mean body weights of dosed mice were 3%-13% lower than those of controls throughout most of the studies. No significant differences in survival were observed between any groups of rats or mice of either sex (male rats: control, 29/50; low dose, 32/50; high dose, 24/50; female rats: 35/50; 32/50; 36/50; male mice: 29/50; 30/50; 24/48; female mice: 37/50; 39/50; 32/50). The estimated average daily feed consumption by dosed rats and dosed mice was similar to that by controls. The average amount of diphenhydramine hydrochloride consumed per day was approximately 13 or 27 mg/kg for low dose or high dose male rats, 7 or 15 mg/kg for low dose or high dose female rats, and 21 or 46-47 mg/kg for low dose or high dose male and female mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: For three high dose male rats, astrocytomas were found in brain sections taken by routine sampling procedures. Gliomas, containing neoplastic astrocytes and oligodendrocytes, were found in one control and one additional high dose male rat. The incidence of glial cell tumors in high dose male rats (4/50) exceeded the highest incidence in historical controls in the Program (2/50). The historical incidence of glial cell tumors is less than 0.7% in approximately 2,000 untreated control male F344/N rats. Three addiless than 0.7% in approximately 2,000 untreated control male F344/N rats. Three additional sections of brain were prepared from the residual fixed tissues of each male and female rat. One additional astrocytoma in a high dose male rat and one astrocytoma in a high dose female rat were observed in these sections. Adenomas of the anterior pituitary gland in female rats occurred with a significant positive trend; the incidences in low dose male and high dose female rats were marginally greater than those in controls (male: control, 11/49; low dose, 21/50; high dose, 14/49; female: 23/50; 26/50; 35/50). The incidence of alveolar/bronchiolar adenomas in low dose male rats was slightly greater than that in controls (0/49; 5/50; 3/50). The incidences of alveolar/bronchiolar adenomas or carcinomas (combined) in dosed male rats were not significantly different from that in controls (1/49; 6/50; 5/50) but exceeded the highest incidence in historicalcontrols (4/49). The historical incidence of alveolar/bronchiolar neoplasms in untreated control male F344/N rats is approximately 2.2%. Adenomatous hyperplasia of the lung was not increased in incidence in dosed male rats compared with controls. The incidences of granulomas of the liver were increased in dosed rats (male: 0/49; 3/50; 4/50; female: 8/50; 15/49; 18/50). At no site were the incidences of neoplastic lesions in dosed mice considered to be compound related. Cytoplasmic vacuolization (fatty metamorphosis) of the liver was observed at an increased incidence in high dose female mice (0/49; 1/49; 8/49). Genetic Toxicology: Diphenhydramine hydrochloride was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested in either the presence or absence of exogenous metabolic activation. Exposure to this chemical did not induce trifluorothymidine (Tft) resistance in mouse L5178Y lymphoma cells with or without metabolic activation. In cytogenetic tests with cultured CHO cells, diphenhydramine hydrochloride induced chromosomal aberrations in the absence, but not the presence, of exogenous metabolic activation (S9); no induction of sister chromatid exchanges (SCEs) was observed in these cells with or without S9. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of diphenhydramine hydrochloride for male F344/N rats, based on marginally increased incidences of uncommon brain neoplasms (astrocytomas or gliomas) and of alveolar/bronchiolar neoplasms. There was equivocal evidence of carcinogenic activity for female F344/N rats, based on a marginal increase in the incidence of pituitary gland adenomas. There was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 156 or 313 ppm diphenhydramine hydrochloride. Synonyms: 2-diphenylmethoxy-N,N-dimethylethanamine hydrochloride; 2-(benzhydryloxy)-N,N-dimethylethylamine hydrochloride; b-dimethylaminoethyl benzhydryl ether hydrochloride; benzhydramine hydrochloride Trade Names: Alleran; Benadryl

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Iodinated Glycerol (Organidin(R).) (CAS No. 5634-39-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of iodinated glycerol (Organidin(R)., a complex mixture prepared by the reaction of iodine with glycerol and found to contain 33% 3-iodo-1,2-propanediol as the major component) were conducted because of human exposure to iodinated glycerol as an expectorant and its possible relationship to the formation of alkyl iodides, e.g., methyl iodide, a suspected animal carcinogen. These studies were conducted by giving iodinated glycerol in water by gavage (5 days per week) to groups of F344/N rats and B6C3F1 mice for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted with iodinated glycerol in Salmonella typhimurium, mouse L5178Y lymphoma cells, Chinese hamster ovary (CHO) cells, and B6C3F1 mice (in vivo bone marrow micronucleus test). Also, 3-iodo-1,2-propanediol was tested in S. typhimurium and B6C3F1 mice (in vivo micronucleus assay). Sixteen-Day and Thirteen-Week Studies: Sixteen-day studies were conducted by giving iodinated glycerol at doses up to 1,000 mg/kg to rats and up to 500 mg/kg to mice. All female rats and 4/5 male mice in the highest dose group died before the end of the studies; there were no dose-related effects on body weights of male or female rats or male mice at the end of the studies. The forestomach of 2/5 female mice that received 500 mg/kg was thickened and granular. Thirteen-week studies were conducted by administering iodinated glycerol at doses up to 500 mg/kg to rats and mice. During these studies, 3/10 female rats and 1/10 female mice that received 500 mg/kg died. Final mean body weights of rats and mice that received 500 mg/kg were 4% lower than those of vehicle controls for males and 6%-7% lower for females. Kidney tubular cell lesions, including cortical necrosis, regeneration, and calcification, were observed at increased incidences in the highest dose group of female rats. Lymphoid hyperplasia of the stomach was observed in dosed male and female rats. Kidney tubular cell regeneration was also observed in dosed female mice. Inflammation or abscesses of mild-to-moderate severity and hyperplasia, acanthosis, and/or hyperkeratosis of mild-to-moderate severity were observed in the forestomach of the highest dosed group of female mice. Body Weight and Survival in the Two-Year Studies: Two-year studies were conducted by administering 0, 125, or 250 mg/kg iodinated glycerol in deionized water by gavage, 5 days per week for 103 weeks, to groups of 50 male F344/N rats and 50 male B6C3F1 mice. Groups of 50 female F344/N rats and 50 female B6C3F1 mice were administered iodinated glycerol on the same schedule at lower doses of 0, 62, or 125 mg/kg because of the increased severity of kidney and stomach lesions in the 13-week studies. Mean body weights of high dose male rats were 5%-10% lower than those of vehicle controls from week 43 to week 68 and 10%-13% lower from week 72 to the end of the studies. Mean body weights of low dose male rats and high dose female rats were 4%-9% lower than those of vehicle controls from week 88 to the end of the studies. The survival of the high dose group of male rats was considerably lower than that of the vehicle controls after week 86. No other significant differences in survival were observed between any groups of rats of either sex (male: vehicle control, 28/50; low dose, 20/50, high dose, 2/50; female: 31/50; 30/50; 27/50). Mean body weights of dosed and vehicle control male mice were similar. Mean body weights of high dose female mice were 6%-8% lower than those of vehicle controls from week 40 to week 64 and were 9%-13% lower thereafter. No significant differences in survival were observed between any groups of mice of either sex (male: 36/50; 40/50; 32/50; female: 40/50; 33/50; 38/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The incidence of mononuclear cell leukemia were increased in dosed male rats (vehicle control, 14/50; low dose, 29/50; high dose, 24/50). Follicular cell carcinomas of the thyroid gland in male rats occurred at an increased incidence in low dose male rats (0/49; s of the thyroid gland in male rats occurred at an increased incidence in low dose male rats (0/49; 5/49; 1/49). Reduced survival of high dose male rats may have been responsible for the decreased tumor incidence in this group relative to that in the low dose group. Follicular cell carcinomas were observed in one low dose and one high dose female rat. Follicular cell carcinomas of the thyroid gland have been observed in 3/293 water gavage vehicle control male F344/N rats and in 10/1,904 untreated control male F344/N rats. Adenomas of the nasal cavity were observed in two high dose male rats. Adenomas of the nasal cavity have not been observed in 300 water gavage vehicle control male F344/N rats or in 1,936 untreated control male F344/N rats. Squamous metaplasia and focal atrophy of the salivary glands were observed at increased incidences in dosed rats (squamous metaplasia--male: 0/48; 47/50; 48/49; female:1/49; 48/50; 49/50; focal atrophy--male: 1/48; 10/50; 30/49; female: 0/49; 4/50; 11/50). In dosed female mice, adenomas of the anterior pituitary gland were increased (10/47; 15/45; 24/46). The incidences of adenomas of the harderian gland in dosed female mice were increased (6/50; 8/40; 13/50). A carcinoma of the harderian gland was observed in another high dose female mouse. Dilatation of the thyroid gland follicle and follicular cell hyperplasia were observed at increased incidences in dosed mice (dilatation--male: 0/48; 28/50; 32/50; female: 4/48; 11/48; 10/48; hyperplasia--male: 3/48; 46/50; 34/50; female: 2/48; 25/48; 35/48). The incidences of follicular cell adenomas were 3/48, 6/50, and 0/50 for males and 2/48, 3/48, and 4/48 for females. Hyperkeratosis and acanthosis of the forestomach were observed at increased incidences in high dose male mice (hyperkeratosis: 0/49; 0/49; 5/50; acanthosis: 0/49; 1/49; 5/50). Squamous cell papillomas were observed in female mice (1/49; 2/50; 5/49). The historical incidence of forestomach squamous cell neoplasms is 4/339 (1.2%) in water gavage vehicle control female B6C3F1 mice and is 18/1,994 (0.9%) in untreated control female B6C3F1 mice. Squamous cell neoplasms were not observed in male mice. Genetic Toxicology: Treatment of the base-substitution mutant S. typhimurium strains TA100 and TA1535 with iodinated glycerol in a preincubational protocol with and without S9 resulted in a dose-related increase in the number of revertant colonies; no increase in revertants was observed with the frame-shift mutant strains TA98 or TA1537. 3-Iodo-1,2-propanediol was also mutagenic in TA100 with or without S9; it was not mutagenic in TA98. Iodinated glycerol increased the number of trifluorothymidine-resistant cells in mouse lymphoma L5178Y/TK± assay in the absence of exogenous metabolic activation; it was not tested with activation. Iodinated glycerol induced sister chromatid exchanges (SCEs) and chromosomal aberrations in CHO cells without S9; with S9, the frequency of SCEs was increased more than without S9 but no chromosomal aberrations were induced. No increase in micronucleated polychromatic erythrocytes was observed in the bone marrow of B6C3F1 mice after injection with either iodinated glycerol or 3-iodo-1,2-propanediol. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity for male F344/N rats administered iodinated glycerol, as indicated by increased incidences of mononuclear cell leukemia and follicular cell carcinomas of the thyroid gland. Adenomas of the nasal cavity in two high dose male rats may have been related to the administration of iodinated glycerol. There was no evidence of carcinogenic activity for female F344/N rats administered 62 or 125 mg/kg iodinated glycerol by gavage for 103 weeks. There was no evidence of carcinogenic activity for male B6C3F1 mice administered 125 or 250 mg/kg iodinated glycerol by gavage for 103 weeks. There was some evidence of carcinogenic activity for female B6C3F1 mice administered iodinated glycerol, as indicated by increased incidences of adenomas of the anterior pituitary gland and neoplasms of the harderian gland. Squamous cell papillomas of the forestomach may have been related to the administration of iodinated glycerol. Significant nonneoplastic lesions considered related to exposure of iodinated glycerol were squamous metaplasia and focal atrophy of the salivary gland in male and female rats. Dilatation of the thyroid gland follicle and follicular cell hyperplasia were observed in male and female mice. Synonyms or Trade Names: Organidin®.; iodopropylidene glycerol

Journal Article↗
PubMed1988

NTP Toxicology and Carcinogenesis Studies of 2-Amino-4-Nitrophenol (CAS No. 99-57-0) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

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.

Journal Article↗
PubMed1988

NTP Toxicology and Carcinogenesis Studies of 2-Amino-5-Nitrophenol (CAS No. 121-88-0) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

2-Amino-5-nitrophenol is used as a colorant in semipermanent hair dyes and in the manufacture of C.I. Solvent Red 8, an azo dye for synthetic resins, lacquers, and wood stains. 2-Amino-5-nitrophenol was nominated for toxicology and carcinogenesis studies by the National Cancer Institute because of widespread human exposure associated with its use in hair dyes. Toxicology and carcinogenesis studies were conducted by administering 2-amino-5-nitrophenol (98% pure) by gavage in corn oil 5 days per week to groups of F344/N rats and B6C3F1 mice of each sex in 16-day, 13-week, and 2-year studies. In the 2-year studies, male and female rats were given doses of 0, 100, or 200 mg/kg and male and female mice were given doses of 0, 400, or 800 mg/kg. Sixteen-Day and Thirteen-Week Studies: During the 16-day studies, F344/N rats of each sex received 0, 156, 313, 625, 1,250, or 2,500 mg/kg 2-amino-5-nitrophenol by gavage in corn oil vehicle. One of the five males that received 2,500 mg/kg, 1/5 females that received 1,250 mg/kg, and 2/5 females that received 313 mg/kg died before the end of the studies. Final mean body weights of rats that received 1,250 or 2,500 mg/kg were 11% and 30% lower than that of vehicle controls for males and 9% and 13% lower for females. B6C3F1 mice of each sex received doses of 0, 313, 625, 1,250, 2,500, or 5,000 mg/kg 2-amino-5-nitrophenol. Two of five males and 5/5 females that received 5,000 mg/kg, 3/5 males and 3/5 females that received 2,500 mg/kg, 3/5 females that received 1,250 mg/kg, 1/5 females that received 625 mg/kg, and 2/5 male vehicle controls died before the end of the studies. Final mean body weights of chemically exposed mice were not different from those of the vehicle controls. Rats that received 625, 1,250, or 2,500 mg/kg and male mice that received 5,000 mg/kg had loose stools. In 13-week studies, F344/N rats and B6C3F1 mice of both sexes received 0, 100, 200, 400, 800, or 1,600 mg/kg 2-amino-5-nitrophenol by gavage in corn oil. Five of 10 male and 2/10 female rats that received 1,600 mg/kg, 1/10 male and 3/10 female rats that received 800 mg/kg, and 1/10 male rats that received 400 mg/kg died before the end of the studies. Final mean body weights of males that received 400, 800, or 1,600 mg/kg were 10%, 25%, and 43% lower than that of vehicle controls. The final mean body weight of females that received 1,600 mg/kg was 16% lower that of vehicle controls. Four of 10 male and 3/10 female mice that received 1,600 mg/kg died before the end of the 13-week studies. The final mean body weight of male mice that received 1,600 mg/kg was 11% lower than that of vehicle controls; male and female mice that received 1,600 mg/kg appeared lethargic. During the 13-week studies, acute/chronic perivasculitis of vessels of the cecum and colon was observed in rats that received 400, 800, or 1,600 mg/kg and in mice that received 1,600 mg/kg. Body Weight and Survival in the Two-Year Studies: Mean body weights of rats receiving 200 mg/kg were 5%-10% lower than those of vehicle controls after week 33 for males and 4%-5% lower than those of vehicle controls after week 93 for females. Survival of male rats was significantly lower than that of vehicle controls after week 99 for the 100 mg/kg dose group and after week 75 for the 200 mg/kg dose group (final survival: vehicle control, 33/50; 100 mg/kg group, 16/50; 200 mg/kg group, 4/50). Survival of female rats was comparable to that of vehicle controls (30/50; 32/50; 29/50). Loose or poorly formed stools were observed for male rats and occasionally for females that received 200 mg/kg. Mean body weights of mice that received 800 mg/kg were 8%-11% lower than those of vehicle controls between weeks 29 and 74 for males and 8%-13% lower than those of vehicle controls after week 69 for females; mean body weights of mice that received 400 mg/kg were greater than those of vehicle controls after week 69 for males and 5%-9% lower than those of vehicle controls after week 69 for females. Survival of mice that received 800 mg/kg was significantly reduced compared with that of ose of vehicle controls after week 69 for females. Survival of mice that received 800 mg/kg was significantly reduced compared with that of vehicle controls after week 20 for males and week 22 for females and was not considered adequate to evaluate a carcinogenic response (final survival--male: vehicle control, 31/50; 400 mg/kg group, 36/50; 800 mg/kg group, 12/50; female: 37/50; 36/50; 10/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Pigmentation was present at increased incidences in all groups of chemically exposed animals and was characterized by varying amounts of an orange, granular pigment present in the fibrous connective tissue of the lamina propria, in the submucosa, and around vessels in the submucosa of the cecum and colon. Pigmentation of the rectum was observed at increased incidences in male rats that received 100 mg/kg, male and female rats that received 200 mg/kg, and both groups of chemically exposed mice. No pigmentation was found in the intestines of vehicle control rats or mice. Associated with pigmentation was an increased incidence of acute/chronic inflammation in the cecum and colon of all groups chemically exposed rats and mice; this inflammation was similar to that observed in the 13-week studies but was of greater severity. Acute/chronic inflammation was also present in the rectum of male rats that received 100 mg/kg, male and female rats that received 200 mg/kg, and male mice that received 800 mg/kg. The incidence of pancreatic acinar cell adenomas was significantly increased (P≤0.002) in male rats that received 100 mg/kg 2-amino-5-nitrophenol (vehicle control, 1/50; 100 mg/kg, 10/50; 200 mg/kg, 3/49); the increase was considered to be associated with chemical exposure. The reduced survival of male rats that received 200 mg/kg markedly reduced the sensitivity of this group for detecting the presence of neoplasms. The incidences of adenomas or carcinomas (combined) of the preputial or clitoral glands were marginally increased in male or female rats that received 200 mg/kg 2-amino-5-nitrophenol (preputial gland: 3/50; 2/50; 5/50; clitoral gland: 3/50; 3/50; 7/50). Neoplasms found in the intestinal tract of 3/50 male rats that received 100 mg/kg (one leiomyoma of the small intestine, one adenocarcinoma of the jejunum, one leiomyoma of the cecum), 2/50 male rats that received 200 mg/kg (one lipoma and one osteosarcoma of the cecum), and 1/50 female rats that received 200 mg/kg (one leiomyoma of the cecum) were not considered to be the result of chemical exposure. No compound-related neoplasms were found in mice exposed to 2-amino-5-nitrophenol in the 2-year studies. Genetic Toxicology: 2-Amino-5-nitrophenol was mutagenic in Salmonella typhimurium strains TA98, TA100, and TA1537 when tested in a preincubation protocol with and without exogenous metabolic activation, and it exhibited equivocal mutagenic activity in strain TA1535 in the presence of induced liver S9. 2-Amino-5-nitrophenol induced forward mutations in mouse L5178Y lymphoma cells in the absence of metabolic activation; it was not tested with S9. An increase in chromosomal aberrations and sister chromatid exchanges was observed in cultured Chinese hamster ovary (CHO) cells following incubation with 2-amino-5-nitrophenol both in the presence and absence of exogenous metabolic activation. Data Audit: The data, documents, and pathology materials from the 2-year studies of 2-amino-5-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 for male F344/N rats that received 100 mg/kg 2-amino-5-nitrophenol, as shown by the increased incidence of acinar cell adenomas of the pancreas. Reduced survival of male F344/N rats that received 200 mg/kg decreased the sensitivity of this group for detecting a carcinogenic response. There was no evidence of carcinogenic activity for female rats that received 100 or 200 mg/kg per day. Marginally increased incidences of preputial or clitoral gland adenomas or carcinomas (combined) occurred in male and female F344/N rats administered 200 mg/kg 2-amino-5-nitrophenol. There was no evidence of carcinogenic activity for B6C3F1 mice that received 400 mg/kg 2-amino-5-nitrophenol; reduced survival of B6C3F1 mice that received 800 mg/kg caused this group to be considered inadequate for detecting a carcinogenic response.

Journal Article↗
PubMed1988

NTP Toxicology and Carcinogenesis Studies of 4-Hexylresorcinol (CAS No. 136-77-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

4-Hexylresorcinol, which is used as an anthelmintic and antiseptic, was nominated by the National Cancer Institute for study. Toxicology and carcinogenesis studies were conducted by administering 4-hexylresorcinol (greater than 99% pure) 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. Sixteen-Day and Thirteen-Week Studies: In the 16-day studies, groups of five rats and five mice of each sex were administered 0, 31.3, 62.5, 125, 250, or 500 mg/kg 4-hexylresorcinol. Survival was not affected. Decreased body weights were seen in male rats that received 250 or 500 mg/kg 4-hexylresorcinol. No other effects were observed. In the 13-week studies, groups of 10 rats and 10 mice of each sex were administered 0, 62.5, 125, 250, 500, or 1,000 mg/kg of the chemical, 5 days per week. All rats and male mice and 9/10 female mice that received 1,000 mg/kg died before the end of the studies. Final mean body weights of male rats that received 250 or 500 mg/kg were 22% or 38% lower than that of the vehicle controls; final mean body weights of female rats that received 250 or 500 mg/kg were 16% or 9% lower. No compound-related gross or microscopic pathologic effects were observed in rats. No body weight effects were observed for mice. Mild to moderate nephropathy was dose related in male and female mice. Based on these results, 2-year toxicology and carcinogenesis studies of 4-hexylresorcinol were conducted by administering 0, 62.5, or 125 mg/kg to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 7%-11% lower than those of the vehicle controls throughout the study. Mean body weights of low dose male and dosed female rats were similar to those of the vehicle controls. The body weights of dosed male and dosed female mice were comparable to those of vehicle controls except during the last 16 weeks of the studies, when body weights were 6%-16% lower in the dosed groups. No significant differences in survival were observed between any groups of rats or mice of either sex (male rats: vehicle control, 30/50; low dose, 29/50; high dose, 33/50; female rats: 28/50; 32/50; 30/50; male mice: 36/50; 26/50; 30/50; female mice: 35/50; 32/50; 35/50). Nonneoplastic and Neoplastic Lesions in the Two-Year Studies: Two astrocytomas and an oligodendroglioma were observed in high dose male rats, a glioma was observed in one low dose male rat, and an oligodendroglioma was observed in one vehicle control male rat. These neoplasms were not considered to be related to 4-hexylresorcinol administration. Focal medullary hyperplasia of the adrenal gland was observed at increased incidences in dosed male mice (5/50; 16/50; 10/49). Pheochromocytomas in male mice occurred with a marginal upward trend (1/50; 2/50; 5/49). Historically, these neoplasms are observed in about 1% of corn oil vehicle control B6C3F1 male mice. The incidences of neoplasms of the harderian gland in male mice were slightly increased over those in the vehicle controls (adenomas or carcinomas, combined: 0/50; 4/50; 3/50). Decreases were observed in the incidences of mononuclear cell leukemia in dosed male (12/49; 7/50; 1/50) and female (16/50; 3/50; 2/50) rats, hepatocellular adenomas or carcinomas (combined) in dosed male mice (21/50; 9/50; 9/50), and circulatory system tumors in male (10/50; 4/50; 2/50) and female (6/50; 2/49; 0/50) mice. These decreased incidences of tumors in rats and mice are considered to be possibly related to 4-hexylresorcinol administration. The incidences and severity of nephropathy (male: 39/50; 43/50; 47/50; female: 7/50; 40/49; 47/50) and incidences of osteosclerosis (male: 5/50; 5/50; 15/50; female: 21/50; 25/49; 40/50) were increased in both dosed male and female mice and are considered to be related to chemical exposure. Genetic Toxicology: 4-Hexylresorcinol was not mutagenic for Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without S9 metabolic activation. 4-Hexylre, TA1535, or TA1537 with or without S9 metabolic activation. 4-Hexylresorcinol induced forward mutations at the TK locus in mouse L5178Y cells in the presence of S9; no response was observed in the absence of metabolic activation. In cytogenetic assays with cultured Chinese hamster ovary (CHO) cells, 4-hexylresorcinol caused an increase in the frequency of sister chromatid exchanges (SCEs) in the absence of metabolic activation; no induction of SCEs was observed in the presence of S9. Chromosomal aberrations were not induced in CHO cells with or without metabolic activation. Data Audit: The data, documents, and pathology materials from the 2-year studies of 4-hexylresorcinol were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented appropriately 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 4-hexylresorcinol for male or female F344/N rats given doses of 62.5 or 125 mg/kg. There was equivocal evidence of carcinogenic activity of 4-hexylresorcinol for male B6C3F1 mice, as shown by marginally increased incidences of pheochromocytomas (and hyperplasia) of the adrenal medulla and of harderian gland neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice given doses of 62.5 or 125 mg/kg 4-hexylresorcinol. Decreased incidences of three tumors types were considered related to 4-hexylresorcinol administration: mononuclear cell leukemia in male and female rats, hepatocellular neoplasms in male mice, and circulatory system tumors in male and female mice. Synonyms: 4-hexyl-1,3-benzenediol; 4-hexyl-1,3-dihydroxybenzene

Journal Article↗
PubMed1988

NTP Toxicology and Carcinogenesis Studies of Trichloroethylene (CAS No. 79-01-6) in Four Strains of Rats (ACI, August, Marshall, Osborne-Mendel) (Gavage Studies).

Trichloroethylene is an industrial solvent used primarily for vapor degreasing and cold cleaning. It was selected for study because of its industrial use and for potential for human exposure. (An estimated 3.5 million workers are exposed to trichloroethylene.) In an earlier study trichloroethylene (stabilized with epichlorohydrin and 1,2-epoxybutane) administered by gavage caused hepatocellular carcinomas in male and female B6C3F1 mice. Trichloroethylene administration did not increase the incidence of tumors in male or female Osborne-Mendel rats. However, the survival of dosed rats was reduced, thereby compromising the sensitivity of the study to detect a carcinogenic effect. The studies described in this report were conducted to compare the sensitivities of four strains of rats (ACI, August, Marshall, and Osborne-Mendel) to diisopropylamine-stabilized trichloroethylene. The results of the present studies demonstrate that long-term administration of trichloroethylene produces nephrotoxicity in four strains of rats and that the susceptibilities of these strains to the nephrotoxic effects of the chemical are similar. Because of chemically induced toxicity, reduced survival, and incomplete documentation of the experimental data, the studies are considered inadequate for either comparing or assessing trichloroethylene-induced carcinogenesis in these strains of rats. Toxicology and carcinogenesis studies of trichloroethylene (more than 99% pure, stabilized with 8 ppm diisopropylamine) were conducted by administering the chemical in corn oil gavage at doses of 0, 500, or 1,000 mg/kg per day, 5 day per week, for 103 weeks to groups of 50 male and 50 female ACI, August, Marshall, and Osborne-Mendel rats. The doses were selected on the basis of results from 13-week gavage studies in which groups of 10 male and 10 female ACI, August, and Marshall rats received daily doses or trichloroethylene (male: 125-2,000 mg/kg; female: 63-1,000 mg/kg). Doses for Osborne-Mendel rats were selected to conform with doses used in an earlier carcinogenicity study in that strain (TR-2). In the 13-week studies, male ACI and August rats receiving 2,000 mg/kg trichloroethylene and male and female Marshall rats receiving 1,835 mg/kg had final mean body weights 12%-17% lower than those of the vehicle controls. All other dose groups had body weights comparable to those of the vehicle controls. Three male August rats dosed with 2,000 mg/kg died. Histopathologic evaluation of tissues revealed no lesions attributable to trichloroethylene administration in the 13-week studies. This absence of histopathologic findings did not accurately predict the nephrotoxic effects of long-term administration of trichloroethylene to rats. Body Weight and Survival in the Two-Year Studies: In the 2-year studies, all dosed groups exhibited some reduction in mean body weights relative to the vehicle controls. Survival relative to vehicle controls was significantly reduced in 7/16 dosed groups (see page 6 of the Technical Report). Also, the survival of high dose male Marshall rats was reduced by a large number of accidental deaths. Nephrotoxicity, reduced survival, and central nervous system toxicity (characterized by sedation, loss of consciousness, tremors, and convulsions) showed that the doses of trichloroethylene selected for the 2-year studies were too high. Renal Effects in the Two-Year Studies: Trichloroethylene caused tubular cell cytomegaly in 82%-100% of all dosed animals. In addition, trichloroethylene produced toxic nephropathy (which was distinguishable from age-related nephropathy) in 17%-80% of the dosed animals. Cytomegaly, karyomegaly, or toxic nephropathy was not found in untreated or vehicle control animals. Trichloroethylene administration was also associated with increased incidences of renal tubular cell adenomas and adenocarcinomas. The incidences of renal lesions are shown in the following table (see page 7 of Technical Report). Other Pathologic Effects in the Two-Year Studies: An increased incidence of interstitial cell tumors of the testis was observinterstitial cell tumors of the testis was observed in high dose male Marshall rats (untreated control, 16/46; vehicle control, 17/46; low dose, 21/48; high dose, 32/48; P=0.002). The incidences of pheochromocytomas of the adrenal gland were significantly reduced in male ACI, female August, female Marshall, and male and female Osborne-Mendel rats. Genetic Toxicology: Trichloroethylene did not cause mutations in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without metabolic activation. In Chinese hamster ovary cells, trichloroethylene did not induce chromosomal aberrations; the results for sister chromatid exchanges were considered positive. Trichloroethylene was mutagenic to mouse L5178Y lymphoma cells in the presence of rat liver S9. Data Audit: Audits of the experimental data for these 2-year studies of trichloroethylene were conducted by the National Toxicology Program (see Appendix Q of the Technical Report). The results of the audits revealed evidence that the doses of trichloroethylene were too high. In addition, there was insufficient documentation of animal breeding, clinical observations, environmental conditions, and analytical chemistry data. Also, individual animal identification was not always verifiable. Conclusions: Under the conditions of these 2-year gavage studies of trichloroethylene in male and female ACI, August, Marshall, and Osborne-Mendel rats, trichloroethylene administration caused renal tubular cell cytomegaly and toxic nephropathy in both sexes of the four strains. However, these are considered to be inadequate studies of carcinogenic activity because of chemically induced toxicity, reduced survival, and deficiencies in the conduct of the studies. Despite these limitations, tubular cell neoplasms of the kidney were observed in rats exposed to trichloroethylene and interstitial cell neoplasms of the testis were observed in Marshall rats exposed to trichloroethylene. Synonyms: acetylene trichloride; 1-chloro-2,2-dichloroethylene; 1,1-dichloro-2-chloroethylene; ethinyl trichloride; ethylene trichloride; 1,1,2-trichloroethylene; trichloroethene Trade names of formulations: Algylen; Anamenth; Benzinol; Blacosolv; Blancosolv; Cecolene; Chlorilen; Chlorylea; Chorylen; Circosolv; Crawhaspol; Densinfluat; Dow-Tri; Dukeron; Fleck-Flip; Flock Flip; Fluate; Gemalgene; Germalgene; Lanadin; Lethurin; Narcogen; Narkogen; Narkosoid; Nialk; Perma-A-Chlor; Perm-A-Clor; Petzinol; Philex; Threthylen; Threthylene; Trethylene; Tri; Triad; Trial; Triasol; Trichloran; Trichloren; Triclene; Tri-Clene; Trielene; Trielin; Triklone; Trilen; Trilene; Triline; Trimar; Triol; TRI-plus; TRI-plus M; Vestrol; Vitran; Westrosol Target Organs & Incidences from 2-year Studies

Journal Article↗
PubMed1987

NTP Toxicology and Carcinogenesis Studies of Ethylene Oxide (CAS No. 75-21-8) in B6C3F1 Mice (Inhalation Studies).

Ethylene oxide is a major industrial chemical used primarily as an intermediate in the manufacture of other chemicals; e.g., ethylene glycol, a major component of automotive and other antifreeze products. Exposure to ethylene oxide is greatest in the health care industry, where an estimated 75,000 workers are potentially exposed. Ethylene oxide was nominated for toxicology and carcinogenesis studies in B6C3F1 mice because of its extensive production; the potential for human exposure in the workplace, from medical devices, or from food; the positive results of genetic toxicology assays; and the previous use of only F344/N rats in inhalation carcinogenicity studies. Two inhalation studies reported in 1984 by Snellings et al. and by Lynch et al. demonstrated carcinogenic responses in F344/N rats. Results were similar in both studies and consisted of increased incidences of mononuclear cell leukemia, peritoneal mesotheliomas, and primary brain tumors. Experimental Design: Toxicology and carcinogenesis studies of ethylene oxide (greater than 99% pure) were conducted by exposing groups of 50 B6C3F1 mice of each sex to air containing 0, 50, or 100 ppm ethylene oxide, 6 hours per day, 5 days per week for 102 weeks. These doses were selected because, in 14-week studies, all mice exposed at 600 ppm died within 1 week, and all mice exposed at 400 ppm died by week 4. Rhinitis was observed in both sexes exposed at 200, 400, and 600 ppm as was renal tubular degeneration in both sexes at 100, 200, and 400 ppm. The latter effects observed at 100 ppm were slight and deemed not to be life threatening in 2-year studies. Two-Year Studies: Survival of exposed and control mice was comparable in the 2-year studies (male: control, 28/50; low dose, 31/50; high dose, 34/50; female: 25/50; 24/50;31/50). Final mean body weights in exposed mice were 95%-102% of those of the controls. No compound-related clinical signs were observed. Those neoplastic lesions that occurred at elevated incidences in mice exposed to ethylene oxide are reported in the following table (see page 6 of the Technical Report). In male mice, alveolar/bronchiolar carcinomas, alveolar/bronchiolar adenomas, and papillary cystadenomas of the harderian gland occurred with positive trends. In female mice, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, papillary cystadenomas of the harderian gland, malignant lymphomas, and uterine adenocarcinomas occurred with positive trends. Mammary gland tumors also were increased in exposed female mice. Data Audit: An audit of the experimental data was conducted for the 2-year studies of ethylene oxide. No data discrepancies were found that influenced the final interpretations. Conclusions: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity for B6C3F1 mice as indicated by dose-related increased incidences of benign or malignant neoplasms of the lung and benign neoplasms of the harderian gland in both male and female B6C3F1 mice following exposure to ethylene oxide vapors at 50 and 100 ppm. In female mice, ethylene oxide caused additional malignant neoplasms of the uterus, mammary gland, and hematopoietic system (lymphoma). Synonyms: oxirane; EO; ETO; dihydrooxirene; dimethylene oxide; 1,2-epoxyethane; oxane; a,beta-oxidoethane

Journal Article↗
PubMed1987

NTP Toxicology and Carcinogenesis Studies of Boric Acid (CAS No. 10043-35-3) in B6C3F1 Mice (Feed Studies).

Boric acid is a component of cosmetics and pharmaceuticals and is also used in numerous industrial processes. Earlier long-term studies did not demonstrate a carcinogenic effect in Sprague-Dawley rats. Because of potential widespread human exposure, corroborative evidence was sought in a second species. Toxicology and carcinogenesis studies were conducted by feeding technical-grade boric acid (99.7% pure) to groups of male and female B6C3F1 mice for 14 days, 13 weeks, and 2 years. In the 14-day studies (five mice per group), mortality occurred in mice fed 25,000 ppm, 50,000 ppm, or 100,000 ppm boric acid; hyperplasia and/or dysplasia of the forestomach was also seen in these dose groups. No compound-related gross pathologic or histopathologic effects were seen in male or female mice exposed at concentrations up to 12,500 ppm in feed. In the 13-week studies, groups of 10 male and 10 female mice were fed boric acid at concentrations up to 20,000 ppm; 8 male mice and 1 female mouse receiving 20,000 ppm and 1 male receiving 10,000 ppm boric acid died before the end of the studies. Male and female mice receiving 20,000 ppm boric acid weighed 23% and 18% less, respectively, than did the controls at the end of the studies. Testicular atrophy in 8/10 male mice, hyperkeratosis and acanthosis of the stomach in 8/10 male and female mice, and extramedullary hematopoiesis of the spleen in all male and female mice receiving 20,000 ppm boric acid indicated that the testis, stomach, and spleen were potential target organs in the 2-year studies. Based on these results, 2-year toxicology and carcinogenesis studies were conducted by feeding diets containing boric acid at concentrations of 0, 2,500, or 5,000 ppm to groups of 50 male and 50 female mice. Survival of high dose male mice after week 63 and of low dose mice after week 84 was lower than that of the controls (final survival: control, 41; low dose, 30; high dose, 22), which may have reduced the sensitivity of the carcinogenicity study; the numbers of female mice (33; 33; 37) that survived to the end of the studies were considered adequate for toxicologic evaluation. Body weight gain was reduced in each sex after week 30; mean final body weights were 7% and 13% below control values for exposed male mice and 7% and 20% below those of controls for exposed female mice. No chemically related clinical signs were reported. At the top dose, boric acid caused an increased incidence of testicular atrophy (control, 3/49; low dose, 6/50; high dose, 27/47) and interstitial cell hyperplasia (0/49; 0/50; 7/47) inmale mice. The testicular atrophy was characterized by variable loss of spermatogonia, primary and secondary spermatocytes, spermatids, and spermatozoa from the seminiferous tubules. The seminiferous tubules contained primarily Sertoli cells and variable numbers of spermatogonia. In some mice, there were accumulations of interstitial cells, indicating hyperplasia. In low dose male mice, there were increased incidences of hepatocellular carcinomas (5/50; 12/50; 8/49) and hepatocellular adenomas or carcinomas (combined) (14/50; 19/50; 15/49) and an increased incidence of subcutaneous tissue fibromas, sarcomas, fibrosarcomas, or neurofibrosarcomas (combined) (2/50; 10/50; 2/50). No increased incidence of subcutaneous tissue neoplasms was seen in male mice receiving 5,000 ppm. Because the incidence of subcutaneous tissue tumors is variable in historical controls, because there was no corresponding increase in the high dose male mice, and because the incidence of hepatocellular tumors was not significant by the incidental tumor test and was within the historical control range, neither of these tumors was considered to be related to the administration of boric acid. Boric acid was not mutagenic in the Salmonella/microsome assay with Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537. Boric acid was negative in the mouse lymphoma L5178Y/TK+/- assay and did not induce sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells. All assays were preformed with anhamster ovary cells. All assays were preformed with and without metabolic activation. The data, documents, and pathology materials from the 2-year studies of boric acid 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. Under the conditions of these 2--year feed studies, there was no evidence of carcinogenicity of boric acid at doses of 2,500 or 5,000 ppm for male or female B6C3F1 mice. Testicular atrophy and interstitial cell hyperplasia were observed in high dose male mice. The decrease in survival of dosed male mice may have reduced the sensitivity of this study. Synonyms: orthoboric acid; boracic acid

Journal Article↗
PubMed1987

NTP Toxicology and Carcinogenesis Studies of Bromodichloromethane (CAS No. 75-27-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Bromodichloromethane (99% pure), one of several trihalomethanes commonly formed after chlorination of water, was selected for study because no carcinogenicity data were available for this compound and because chloroform, a related trihalomethane, had been found to cause tumors in rodents. The general population might be exposed to bromodichloromethane in drinking water supplies, in swimming pools, and in a variety of food substances. Single-administration, 14-day, 13-week, and 2-year studies were conducted in F344/N rats and B6C3F1 mice. The chemical was administered by gavage in corn oil because human exposure is primarily oral. Additional studies were performed to evaluate the potential for genetic damage in bacteria and mammalian cells. Results of the Short-Term Studies: In the single-administration studies, the chemical was administered at doses of 150-2,500 mg/kg per day. All rats and female mice at 1,250 and 2,500 mg/kg and all male mice at 600, 1,250, and 2,500 mg/kg died; 2/5 male rats, 1/5 female rats, and 2/5 female mice at 600 mg/kg died; all animals at lower dose levels survived. In the 14-day studies, rats received doses of 38-600 mg/kg, and mice received doses of 19-300 mg/kg per day. One female rat at 38 mg/kg and one female rat at 600 mg/kg died. Weight loss or decreased weight gain was seen at 300 and 600 mg/kg in male and female rats. All male mice at 150 and 300 mg/kg died, and one female mouse at 300 mg/kg died; no weight effects were observed in surviving mice. Dose-related necropsy findings included reddened renal medullae in male rats at 600 mg/kg and in male mice at 150 and 300 mg/kg. Clinical signs seen in high dose groups after dosing were hyperactivity in rats and lethargy in mice. In the 13-week studies, male and female rats received doses of 19-300 mg/kg per day, male mice received doses of 6.25-100 mg/kg per day, and female mice received doses of 25-400 mg/kg per day. Five of 10 male rats and 2/10 female rats at 300 mg/kg died. None of the mice died. Final body weights of male and female rats at 150 and 300 mg/kg were lower than those of vehicle controls (45%-88% of vehicle control weights); final body weights of male mice at 100 mg/kg and female mice at 400 mg/kg were 92% and 94% of those of the vehicle controls. Centrilobular degeneration in the liver and degeneration and necrosis of the kidney were seen in male rats at 300 mg/kg; centrilobular degeneration was seen in female rats at 300 mg/kg; degeneration andnecrosis of the kidney were seen in male mice at 100 mg/kg, and centrilobular degeneration of the liver was seen in female mice at 200 and 400 mg/kg. Experimental Design of the Two-Year Studies: The 2-year toxicology and carcinogenesis studies of bromodichloromethane were conducted by administering the chemical in corn oil by gavage, 5 days per week for 102 weeks, to groups of 50 male and female rats at doses of 0, 50, or 100 mg/kg per day; to groups of 50 male mice at doses of 0, 25, or 50 mg/kg per day; and to groups of 50 female mice at doses of 0, 75, or 150 mg/kg per day. The study in male rats was restarted because at 10.5 months into the original study, a temperature elevation killed 45/50 vehicle control male rats. Survival and Body Weight in the Two-Year Studies: Final survival of dosed rats was comparable to that of vehicle controls (male: vehicle control, 28/50; low dose, 36/50; high dose, 28/50; female: 34/50; 27/50; 41/50). Mean body weights of high dose male and female rats were decreased during the last 1.5 years of the study; final mean body weights of high dose male and female rats were 88% and 79% of the vehicle control mean weights. Final mean body weights of low dose male and female rats were comparable to those of the vehicle controls. Final survival of dosed male mice was comparable to that of the vehicle controls (34/50; 32/50; 42/50). At week 84, survival of female mice was greater than 50% in all dose groups. After week 84, survival of dosed and vehicle control female mice was reduced (final survival: 26/50; 13/50; 15/50), and this decreased survival was ass6/50; 13/50; 15/50), and this decreased survival was associated with ovarian abscesses (8/50; 19/47; 18/49). The final mean body weight of high dose male mice was 95% that of the vehicle controls; the final mean body weight of low dose male mice was comparable to that of the vehicle controls. Mean body weights of the high dose female mice were decreased during the last 1.5 years of the study; the final mean body weight was 75% that of the vehicle controls. The final mean body weight of the low dose female mice was 91% that of the vehicle controls. Nonneoplastic Effects in the Two-Year Studies: Compound-related nonneoplastic lesions included cytomegaly and tubular cell hyperplasia of the kidney and necrosis and fatty metamorphosis of the liver in male rats; eosinophilic cytoplasmic change, clear cell change, focal cellular change, and fatty metamorphosis of the liver and tubular cell hyperplasia of the kidney in female rats; fatty metamorphosisof the liver, renal cytomegaly, and follicular cell hyperplasia of the thyroid gland in male mice; and follicular cell hyperplasia of the thyroid gland in female mice. Neoplastic Effects in the Two-Year Studies: Bromodichloromethane caused compound-related increases in the incidences of neoplasms of the large intestine and kidney in male and female rats, the kidney in male mice, and the liver in female mice, as shown in the table (see page 5 of the Technical Report). The neoplasms of the large intestine and kidney are uncommon tumors in F344/N rats and B6C3F1 mice. Administration of bromodichloromethane was also associated with a decrease in the tumors of the adrenal glands in male rats, the pituitary and mammary glands in female rats, and the pituitary gland in female mice. Genetic Toxicology: Bromodichloromethane was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 when tested by the preincubational protocol at concentrations up to 1,000 ug/plate with or without metabolic activation. The compound was not mutagenic in the mouse lymphoma L5178Y/TK± assay in the presence of S9 but did induce forward mutations in the system in the presence of metabolic activation from rat liver S9. Cytogenetic tests with Chinese hamster ovary cells demonstrated no induction of chromosomal aberrations orsister chromatid exchanges following treatment with bromodichloromethane in either the presence or absence of metabolic activation. Data Audit: An audit of the experimental data was conducted for the 2-year toxicology and carcinogenesis studies of bromodichloromethane. No discrepancies were found that influenced the final interpretations of the results of these studies. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats and B6C3F1 mice as shown by increased incidences of tubular cell adenomas and adenocarcinomas in the kidney and adenocarcinomas and adenomatous polyps in the large intestine in male and female rats, increased incidences of tubular cell adenomas and adenocarcinomas in the kidney of male mice, and increased incidences of hepatocellular adenomas and carcinomas in female mice. Synonym: dichlorobromoethane

Journal Article↗
PubMedDate not supplied

[Evolution of industrial toxicology toward vanishing doses and the human genome].

BACKGROUND: This article aims to discuss the influence that the application of the recent discoveries in genomics will have on the theory and practice of industrial toxicology in developed post-industrial countries. It is stressed that the recent advances in toxicogenomics can be integrated into the existing wealth of knowledge on the toxic properties of industrial chemicals to improve the efficacy of prevention of toxicological risk. METHODS AND RESULTS: The understanding of the biochemical and physiological mechanisms underlying susceptibility or resistance to the toxic effects of industrial xenobiotics, and in particular to carcinogens, allows us to split the epidemiologically derived relationship linking the frequency of disease in the exposed population to the level of workplace contamination into a set of sequential sub-relationships linking: a) the exposure level to that of workplace contamination; b) the internal dose to the exposure level; c) the biological effect (e.g., measured through biochemical markers of early effect) to the internal dose; d) the frequency of disease to that of observation of early biochemical effects. Each of the cited relationships is affected by a degree of uncertainty due to the variability of biological response among the examined individuals, which in turn requires a definition of the statistical limits for the association functions between the variables. As a consequence, the possibility of investigating the individual biochemical and physiological steps in the causal mechanism that links toxic exposure to disease does not necessarily lead to an increase in the information potential of biological monitoring, since the uncertainty due to inter-individual variability is amplified through the sequence of causal relationships to the point that the data from biological monitoring become valueless with regard to the prediction of the frequency or probability of disease. This is particularly true when exposure to 'low doses' is investigated, as is now increasingly frequent in post-industrial developed countries, where workplace contamination is now greatly reduced to levels which may be borderline with those in the general environment. Thus at the low-dose end of the range of contamination and exposure values there is an area where, for statistical reasons consequent to the heterogeneity of examined populations, a quantitative prediction of internal exposure due to environmental contamination, of biological adverse effects due to exposure levels and of frequency of disease due to the extent or frequency of biological effects is no longer reliably possible. This in turn impairs the preventive efficacy of biological monitoring. CONCLUSIONS: A closer integration between industrial toxicology and state-of-the-art molecular genetics derived from the recent sequencing of the human genome is the way to overcome the limitations described. In particular, the individual subjects in the examined populations can be classified with regard to some genetically controlled characters relevant to the biotransformation of xenobiotics and to DNA repair and the statistical analysis of data can be performed on more homogeneous subpopulations, in order to decrease inter-individual variability of biochemical and physiological response. This in turn increases the predictive power of the biological markers, both of dose and effect, and improves the efficacy of prevention, e.g., by highlighting oversensitive subpopulations or lifestyles which can increase the risk of occupational and environmental disease.

Carcinogens, Environmental↗
PubMed1991

[A study on toxicological information search--an example from a study on food additives].

The information search method for toxicological evaluation of food additives was examined. Both a survey of the existence of critical reviews or specific databases for toxicological evaluation and the performance of preliminary online-search are important for a comprehensive and effective search. Examples of file selection and search scheme examination are reported. The results are considered to be generally applicable to toxicological information search for other groups of chemicals.

Database Management Systems↗
PubMed2003

[Amphetamine and derivatives related death in the aspect of forensic toxicology].

Amphetamine and derivatives are the crucial theme in the problems of forensic toxicology. The paper is based on the study of 20 cases of deaths in which amphetamine and/or derivatives were involved as the cause of death. Toxicological examinations of the autopsy specimens were performed with the use of HPLC/MS method in chemical positive ionization mode (APCI) after liquid--liquid extraction. The toxicological findings obtained in particular cases indicate that the majority of cases under consideration were complex. Among all 20 cases only two, probably suicidal deaths, were a result of amphetamine abuse. Some of them which were violent deaths (murder, gun-shot, hanging, drowning) of people under the influence of drugs. The majority of cases which were probably fatal accidents caused by the interaction of various mixtures of xenobiotics which included also opiates, cocaine, benzodiazepines besides amphetamine and derivatives. The concentrations of xenobiotics detected in these cases fit a relatively large range. One case is worth mentioning. This is a death of a permanent amphetamine user who survived two weeks with hematoma in brain in which amphetamine was detected postmortem. The report also discuss amphetamine and derivatives metabolic problems and contains useful data for medico-legal purposes.

Adult↗
PubMed2004

NTP toxicology and carcinogenesis studies of triethanolamine (Cas No. 102-71-6) in B6C3F1 mice (dermal studies).

UNLABELLED: [structure--see text] Triethanolamine is widely used in the manufacturing of household detergents and polishes, textiles, agricultural herbicides, mineral and vegetable oils, paraffin and waxes, pharmaceutical ointments, petroleum demulsifiers, synthetic resins, plasticizers, adhesives, and sealants. It is used as a chemical intermediate for anionic and nonionic surfactants, a vulcanization accelerator, a humectant and softening agent and in many other industrial applications. The National Cancer Institute nominated triethanolamine for study because of its widespread use in cosmetics and other consumer products, its high potential for worker exposure due to its many industrial uses, and its potential for conversion to the carcinogen N-nitrosodiethanolamine. Previous 3-month and 2-year studies of triethanolamine were conducted by the National Toxicology Program in F344/N rats and B6C3F1 mice; results from the 2-year rat study indicated equivocal evidence of carcinogenic activity based on a marginal increase in the incidence of renal tubule adenoma (NTP, 1991). Interpretation of the results from the 2-year study in mice was complicated by Helicobacter hepaticus infection, prompting a repeat 2-year study in mice. Male and female B6C3F1 mice received triethanolamine (greater than 99% pure) by dermal application for 2 years; a study of absorption, distribution, metabolism, and excretion was performed in additional mice. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse peripheral blood erythrocytes. 2-YEAR STUDY: Groups of 50 male and 50 female mice received dermal applications of 0, 200, 630, or 2,000 mg/kg (males) and 0, 100, 300, or 1,000 mg/kg (females) triethanolamine in acetone, 5 days per week, for 104 (males) or 104 to 105 (females) weeks. Survival of all dosed groups was similar to that of the vehicle control groups. Body weights of 2,000 mg/kg males were less than those of the vehicle controls from weeks 17 to 37 and at the end of the study; body weights of dosed groups of females were similar to those of the vehicle controls throughout the study. Treatment-related clinical findings included skin irritation at the site of application, which increased with increasing dose and was more severe in males than in females. Gross lesions observed at necropsy included nodules and masses of the liver in dosed females. The incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were significantly increased in all dosed groups of females. The incidence of hemangiosarcoma of the liver in 630 mg/kg males was marginally increased. The incidences of eosinophilic focus in all dosed groups of mice were greater than those in the vehicle controls. Gross lesions observed at necropsy included visible crusts at the site of application in all dosed groups of mice. Treatment-related epidermal hyperplasia, suppurative inflammation, ulceration, and dermal chronic inflammation occurred at the site of application in most dosed groups of mice, and the incidences and severities of these lesions generally increased with increasing dose. GENETIC TOXICOLOGY: Triethanolamine was not mutagenic in any of the in vitro or in vivo tests. It did not induce mutations in Salmonella typhimurium, and no induction of sister chromatid exchanges or chromosomal aberrations was noted in cultured Chinese hamster ovary cells exposed to triethanolamine. These in vitro tests were all conducted with and without S9 metabolic activation. Triethanolamine did not induce sex-linked recessive lethal mutations in germ cells of adult male Drosophila melanogaster exposed by feeding or injection. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples of male or female mice that received dermal applications of triethanolamine for 13 weeks. CONCLUSIONS: Under the conditions of this 2-year dermal study, there was equivocal evidence of carcinogenic activity of triethanolamine in male B6C3F1 mice based on the occurrence of liver hemangiosarcoma. There was some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of hepatocellular adenoma. Exposure to triethanolamine by dermal application resulted in increased incidences of eosinophilic focus of the liver in males and females. Dosed mice developed treatment-related nonneoplastic lesions at the site of application.

Adenoma, Liver Cell↗
PubMed2004

[25 years of toxicology in Luxembourg, contributions by the National Health Laboratory].

A historical overview of the Institution and a retrospective of the most interesting works undertaken in the toxicology department as well as the methodology used in analytical clinical and forensic toxicology will be outlined. The main activities of the department are toxicological investigations of biological specimens of intoxicated patients as well as material involved in intoxication cases asked by sanitary and governmental authorities. Scientific research activities in the department as well as development and validation of analytical methodology will be reported.

Humans↗