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o-Benzyl-p-chlorophenol is an aryl halide biocide with widespread use in hospitals and households as a broad-spectrum germicide in disinfectant solutions and soap formulations for general cleaning and disinfecting. Human exposure to o-benzyl-p-chlorophenol occurs by absorption through the skin and mucous membranes and by ingestion. Toxicity and carcinogenicity studies were conducted by administering o-benzyl-p-chlorophenol (approximately 97% pure) in corn oil by gavage to male and female F344/N rats and B6C3F1 mice for 16-days, 13-weeks, and 2-years. Clinical pathology parameters were evaluated during the 2-year rat study. Genetic toxicity studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, L5178Y mouse lymphoma cells, and cultured human lymphoblast cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were administered o-benzyl-p-chlorophenol in corn oil by gavage at doses of 0, 62.5, 125, 250, 500, or 1,000 mg/kg body weight 5 days a week over a 16-day period. Two 1,000 mg/kg female rats died and these deaths were attributed to chemical administration. The mean body weight gains of 1,000 mg/kg males and females were significantly lower than those of the controls. Clinical findings in 1,000 mg/kg males and females included diarrhea and rough hair coat. Absolute and relative kidney and liver weights of 250, 500, and 1,000 mg/kg males and 1,000 mg/kg females were significantly greater than those of the controls. Absolute and relative thymus weights of 500 and 1,000 mg/kg males and 250, 500, and 1,000 mg/kg females were significantly lower than those of the controls. At necropsy, dilatation of the cecum was observed in male and female rats; the incidence generally increased with dose. The dilated cecum of some dosed rats had necrosis of the mucosal epithelium. Mild to moderate nephropathy was observed in all 1,000 mg/kg male and female rats. Minimal nephropathy occurred in one rat receiving 62.5 mg/kg, two rats each from the 125 and 250 mg/kg groups, and seven rats in the 500 mg/kg groups. The incidence and severity of nephropathy increased with dose. 16-DAY STUDY IN MICE: Groups of five male and five female mice were administered o-benzyl-p-chlorophenol in corn oil by gavage at doses of 0, 62.5, 125, 250, 500, or 1,000 mg/kg body weight 5 days a week over a 16-day period. Deaths occurred only in the 1,000 mg/kg groups, in which three males and all females died. Mean body weight gains of dosed male and female mice were generally similar to those of the controls. Clinical findings in male and female high-dose mice included rough hair coat and postural changes. Absolute and relative liver weights of 500 and 1,000 mg/kg males and 500 mg/kg females (the highest dose group of females surviving) were significantly greater than those of the controls. Necropsy findings included dilatation of the cecum. Nephropathy occurred in 500 and 1,000 mg/kg mice (500 mg/kg, 2/10; 1,000 mg/kg, 6/10). 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered o-benzyl-p-chlorophenol in corn oil by gavage at doses of 0, 30, 60, 120, 240, or 480 mg/kg body weight 5 days a week for 13 weeks. No deaths were attributed to o-benzyl-p-chlorophenol administration; however, the deaths of five male rats were attributed to gavage trauma. Mean body weight gains of all dosed rats were generally similar to those of the controls. Clinical findings included yellow-red staining of the urogenital region hair coat of all dosed females. The albumin/globulin ratios in 120, 240, and 480 mg/kg male rats increased with dose and were the result of net decreases in total globulin. Administration of o-benzyl-p-chlorophenol caused no significant alterations in hematologic or urinalysis parameters. Absolute and relative kidney weights were significantly greater and the absolute and relative thymus weights were significantly lower in 480 mg/kg male and female rats and in 240 mg/kg female rats. No gross lesions related to compound administration were observed at necropsy. Nephropathy of mild to moderate derate severity occurred in 480 mg/kg male and female rats and in 240 mg/kg male rats. Few or no lesions occurred in other dosed rats and none occurred in controls. 13-WEEK STUDIES IN MICE: In the first 13-week study, groups of 10 male and 10 female mice were administered o-benzyl-p-chlorophenol in corn oil by gavage at doses of 0, 30, 60, 120, 240, or 480 mg/kg body weight 5 days a week for 13 weeks. Survival, mean body weight gains, and clinical findings of dosed animals were similar to those of the controls throughout the study. The Pathology Working Group confirmed that no microscopic lesions were observed that could definitively be associated with o-benzyl-p-chlorophenol administration. On the basis of these findings, a second 13-week study was performed using higher doses. In the second 13-week study, groups of 15 male and 15 female mice were administered o-benzyl-p-chlorophenol in corn oil by gavage at doses of 0, 500, 650, 800, or 1,000 mg/kg body weight 5 days a week for up to 13 weeks. Five male and five female mice from each group were evaluated after 2 weeks, with the remainder (up to 10 per sex) evaluated at the end of the study. One 500 mg/kg mouse, three 650 mg/kg mice, 14 mice receiving 800 mg/kg, and 19 mice administered 1,000 mg/kg died before the end of the study. Mean body weight gains of dosed male and female mice that received 500 or 800 mg/kg were lower than those of the controls. Absolute and relative liver weights of 800 mg/kg males and all surviving dosed females were significantly greater than those of the controls. Absolute and relative kidney weights of 500, 650, and 800 mg/kg male mice were slightly lower than those of the controls, and those of female mice were similar to those of the controls. The incidence and severity of nephropathy increased with time and with increasing dose of o-benzyl-p-chlorophenol. Significant nephropathy was present at all doses, with mild nephropathy present at the 500 mg/kg dose. Acute necrotizing, suppurative inflammation of the olfactory epithelium was noted in all dose groups, with severity increasing with dose. These lesions were considered to be directly related to the caustic nature of o-benzyl-p-chlorophenol following retrograde exposure after gavage, with the presence of foreign material likely due to retrograde migration of the chemical. 2-YEAR STUDY IN RATS: Groups of 80 male and 80 female rats were administered o-benzyl-p-chlorophenol in corn oil by gavage 5 days a week for 103 weeks. The doses were 0, 30, 60, or 120 mg/kg body weight for male rats and 0, 60, 120, or 240 mg/kg body weight for female rats. After 3 and 15 months, 7 to 10 male and 8 to 10 female rats were evaluated for organ weights and clinical pathology, and control and high-dose rats were evaluated for histopathology. Survival, Body Weights, and Clinical Findings: Survival of dosed male and female rats was similar to that of the controls. Mean body weights of dosed rats were generally similar to those of the controls. No chemical-related clinical findings were observed except yellow staining of the urogenital area hair coat in dosed female rats; staining was observed earlier in high-dose female rats. Pathology Findings: Severe, time- and dose-related nephropathy was observed in male and female rats, occurring as early as 3 months after the beginning of chemical administration (females). In male rats dosed for as long as 2 years, secondary hyperparathyroidism developed, with parathyroid gland hyperplasia, mineralization of the kidney and glandular stomach, and fibrous osteodystrophy occurring in the high-dose group. The severity of these lesions was greater in males. The kidney was the only organ in which chemical related increased incidences of neoplasms may have occurred. One renal tubule adenoma occurred in a control male rat, one renal tubule adenoma and one transitional cell carcinoma occurred in high-dose female rats, and one transitional cell carcinoma occurred in a mid-dose female. One renal tubule carcinoma was observed in a high-dose male rat. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice were administered o-benzyl-p-chlorophenol in corn oil by gavage at doses of 0, 120, 240, or 480 mg/kg body weight 5 days a week for 103 weeks. Ten male and 9 or 10 female mice were evaluated after 3 and 15 months for organ weights and histopathology; the remaining 50 male and 50 female mice were evaluated at the end of the study. Survival, Body Weights, and Clinical Findings: Survival of high-dose male and female mice was lower than that of the controls, which was associated in part with dose-related increases in the incidence and severity of nephropathy. The final mean body weights of all dosed males and mid- and high-dose females were lower than those of the controls. Chemical-related clinical findings included emaciation, abnormal posture, rough hair coat, and hypoactivity. Pathology Findings: Nephropathy occurred in most dosed males and females, and the incidence and severity increased with time and dose. Fibrous osteodystrophy of bone, mineralization of the glandular stomach, and squamous hyperplasia of the forestomach occurred in male and female mice. In the standard evaluation, the combined incidence of renal tubule adenoma and carcinoma was increased in 240 mg/kg male mice. Six renal tubule adenomas and three renal tubule carcinomas occurred in dosed male mice. No renal neoplasms occurred in female mice. Due to the marginal increase in renal neoplasia, and the small size of renal neoplasms, an extended evaluation of the kidney was conducted. No significant alteration in the neoplasm incidences were observed in female mice. However, a dose-related increased trend of renal tubule adenoma was observed in male mice. Combination of the extended evaluation with the original evaluation resulted in an increased incidence of renal tubule adenomas in the 480 mg/kg males and an increased incidence of renal tubule adenomas or carcinomas in both the 240 and 480 mg/kg males. GENETIC TOXICOLOGY: o-Benzyl-p-chlorophenol did not induce gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 and did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These tests were performed with and without exogenous metabolic activation (S9). Positive results were obtained, however, in gene mutation tests conducted with LS178Y mouse Lymphoma cells and TK6 human lymphoblast cells in the absence of S9. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of o-benzyl-p-chlorophenol in male F344/N rats receiving 30, 60, or 120 mg/kg body weight. There was equivocal evidence of carcinogenic activity of o-benzyl-p-chlorophenol in female F344/N rats based on the occurrence of two rare renal transitional cell carcinomas. There was some evidence of carcinogenic activity of o-benzyl-p-chlorophenol in male B6C3F1 mice based on increased incidences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of o-benzyl-p-chlorophenol in female B6C3F1, mice receiving 120, 240, or 480 mg/kg. o-Benzyl-p-chlorophenol was nephrotoxic for male and female F344/N rats and B6C3F1 mice. The severity of nephropathy was increased in male and female rats and the incidence and severity of nephropathy was increased in male and female mice. The incidence and severity of nephropathy increased with length of treatment. Other lesions considered to be associated with the nephropathy and the secondary hyperparathyroidism in male rats and in male and female mice included fibrous osteodystrophy and soft tissue mineralization. Increased incidences of squamous cell hyperplasia of the forestomach were observed in mice. Synonyms: 2-benzyl-4-chlorophenol, 4-chloro-2-benzylphenol, 4-chloro-2-(phenylmethyl)phenol, 4-chloro-alpha-phenol o-cresol, p-chloro-o-benzylphenol, 2-hydroxy-5-chlorodiphenylmethane Trade names: Bio-Clave, Chlorophene, Clorofene, Clorophene, Ketolin H, Nipacide BCPR, Preventol BPR, Santophen 1, Septiphene
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PMID:NTP Toxicology and Carcinogenesis Studies of o-Benzyl-p-Chlorophenol (CAS No. 120-32-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1261 87

Manganese is the 12th most abundant element in the earth's crust. The base metal does not occur naturally, but is a component of more than 100 minerals, including sulfides, oxides, carbonates, silicates, phosphates, and borates. In addition to occurring in foods and drinking water, manganese occurs in the atmosphere from dust, volcanic activity, forest fires, and industrial emissions. Manganese (II) sulfate monohydrate was chosen for study because of its stability, solubility, and availability. Toxicology and carcinogenesis studies were conducted by administering manganese (II) sulfate monohydrate (97% pure) in feed to groups of male and female F344/N rats and B6C3F1 mice for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, germ cells of Drosophila melanogaster, and cultured Chinese hamster ovary cells. 14-DAY STUDY IN RATS: Groups of five male and five female rats received diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm manganese (II) sulfate monohydrate. All rats survived to the end of the study. Male rats exposed to 50,000 ppm had a mean body weight gain 57% lower and a final mean body weight 13% lower than those of the controls. The mean body weight gain of 50,000 ppm females was 20% lower and the final mean body weight was 7% lower than those of the controls. During the second week, 50,000 ppm males and females exhibited diarrhea. 14-DAY STUDY IN MICE: Groups of five male and five female mice received diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm manganese (II) sulfate monohydrate. One female mouse in the 25,000 ppm group died on day 1 of unknown causes; all other mice survived to the end of the study. Differences in body weights between exposed and control mice could not be attributed to chemical administration. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received diets containing 0, 1,600, 3,130, 6,250, 12,500, or 25,000 ppm manganese (II) sulfate monohydrate. Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 110 to 1,700 mg/kg body weight in males and 115 to 2,000 mg/kg in females. All rats survived to the end of the study. Mean body weight gains were marginally lower than that of controls in males exposed to 3,130 ppm or more; mean body weight gains were significantly lower than that of the controls in females exposed to 6,250,12,500, or 25,000 ppm. At the end of the study, absolute and relative liver weights of all exposed male rats and of 25,000 ppm female rats were significantly lower than those of controls. The total leukocyte count in males was similar between exposed and control rats; however, neutrophil counts of all exposed groups were greater than those of the controls, whereas lymphocyte counts of the 6,250, 12,500, and 25,000 ppm groups were significantly lower than those of the controls. Total leukocyte counts in 6,250,12,500, and 25,000 ppm females were significantly decreased because of a decrease in lymphocytes. Male rats also demonstrated marginal but significant increases in percent hematocrit and erythrocyte count in the 6,250,12,500, and 25,000 ppm groups. No clinical or histopathologic findings in rats were chemical related. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm manganese (II) sulfate monohydrate. Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 330 to 7,400 mg/kg body weight in males and 390 to 6,900 mg/kg body weight in females. No deaths were chemical related. The mean body weight gains of exposed male mice and of 50,000 ppm female mice were significantly lower than those of controls. The absolute and relative liver weights of 50,000 ppm males were significantly lower than those of controls. The percent hematocrit and hemoglobin concentration of males and females exposed to 50,000 ppm were lower than those of the controls, and the mean erythrocyte volumes were significantly lower than those of the controls. The total leukocyte counts of males in the 25,eukocyte counts of males in the 25,000 and 50,000 ppm groups were significantly lower than that of the controls. No clinical findings were attributed to manganese (II) sulfate monohydrate ingestion. Epithelial hyperplasia and hyperkeratosis of the forestomach occurred in three 50,000 ppm males. 2-YEAR STUDY IN RATS: Groups of 70 male and 70 female rats were fed diets containing 0, 1,500, 5,000, or 15,000 ppm manganese (II) sulfate monohydrate. Based on average daily feed consumption, these doses resulted in the daily ingestion of 60, 200, or 615 mg/kg body weight (males) or 70, 230, or 715 mg/kg (females). Eight to 10 rats from each group were evaluated at 9 and 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of 15,000 ppm male rats in the 2-year study was significantly lower than that of the control group. The deaths of males in the control and exposure groups were attributed to a variety of spontaneous neoplastic and nonneoplastic lesions; however, the greater number of deaths in the 15,000 ppm group resulted from increased incidences of advanced renal disease related to ingestion of manganese (II) sulfate monohydrate. The decreased survival of the 15,000 ppm males did not occur until approximately week 93 of the study; before week 93, survival was similar in all groups. Survival of exposed females was similar to that of the controls. The mean body weight of 15,000 ppm male rats was within 5% of the control group until week 89, by week 104, the mean body weight of 15,000 ppm males was 10% lower than that of the control group. The mean body weights of 1,500 and 5,000 ppm male rats and all exposed female groups were similar to those of the controls throughout the study. Feed consumption by all exposure groups was similar to that by the control groups. No clinical findings were attributed to manganese (II) sulfate monohydrate ingestion. Hematology, Clinical Chemistry, and Tissue Metal Concentration Analyses No differences in hematology and clinical chemistry parameters attributable to the ingestion of manganese (II) sulfate monohydrate occurred between exposed and control groups. At both the 9- and 15-month interim evaluations, tissue concentrations of manganese were significantly elevated in the livers of 5,000 and 15,000 ppm male and female rats, with an accompanying depression of hepatic iron. Pathology Findings: The ingestion of diets containing 15,000 ppm manganese (II) sulfate monohydrate was associated with a marginal increase in the average severity of nephropathy in male rats (0 ppm, 2.9; 1,500 ppm, 3.0; 5,000 ppm, 3.0; 15,000 ppm, 3.2). The increased severity of nephropathy in the 15,000 ppm male rats was accompanied by significantly increased incidences of mineralization of the blood vessels (4/52, 10/51, 6/51,17/52) and glandular stomach (8/52,13/51, 9/51, 23/52), parathyroid gland hyperplasia (14/51, 14/46, 12/49, 23/50), and fibrous osteodystrophy of the femur (12/52,14/51,12/51, 24/52). These lesions are manifestations of renal failure, uremia, and secondary hyperparathyroidism. The increased incidence of advanced renal disease caused reduced survival of the high-dose male rats. No increase in the incidence of neoplasms in male or female rats was attributed to the ingestion of diets containing manganese (II) sulfate monohydrate. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice received diets containing 0, 1,500, 5,000, or 15,000 ppm manganese (II) sulfate monohydrate. These levels resulted in an average daily ingestion of 160, 540, or 1,800 mg/kg body weight (males) or 200, 700, or 2,250 mg/kg (females). Nine or 10 mice from each group were evaluated at the 9-month and 15-month interim evaluations. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival rates of exposed male and female mice in the 2-year study were similar to those of the control groups. The mean body weights of exposed male mice were similar to that of the control group. Compared to controls, female mice had exposure related lower mean body weights after week 37, and the final mean body weights for the 1,500, 5,000, and 15,000 ppm groups were 6%, 9%, and 13% lower than that of the control group. Feed consumption by all exposure groups was similar to that by the control groups. No clinical findings were attributed to the administration of manganese (II) sulfate monohydrate. Hematology, Clinical Chemistry, and Tissue Metal Concentration Analyses No chemical-related differences between exposed and control groups occurred in hematology or clinical chemistry parameters. At the 9- and 15-month interim evaluations, tissue concentrations of manganese were significantly elevated in the livers of the 5,000 and 15,000 ppm groups. Hepatic iron levels were significantly lower in exposed females at the 9-month interim evaluation and in 5,000 and 15,000 males and all exposed females at the 15-month interim evaluation. Pathology Findings: Incidences of thyroid follicular dilatation and hyperplasia were significantly greater in 15,000 ppm male and female mice than in controls. Follicular cell adenomas occurred in one 15,000 ppm male at the 15-month interim evaluation and in three 15,000 ppm males at the end of the study but not in the lower exposure groups or the control group. Follicular cell adenomas also occurred in two control, one 1,500, and five 15,000 ppm female mice at the end of the study. It is uncertain if the slightly increased incidence of follicular cell adenoma is related to the ingestion of manganese (II) sulfate monohydrate. The incidences of focal hyperplasia of the forestomach epithelium were significantly greater in the 15,000 ppm male and exposed female groups. The hyperplasia was associated with ulcers and inflammation in some mice, particularly males. GENETIC TOXICOLOGY: Manganese (II) sulfate monohydrate was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9), and did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster. Tests for induction of sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells treated without S9 were positive; with S9, only the sister chromatid exchange test with manganese (11) sulfate monohydrate was positive. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of manganese (II) sulfate monohydrate in male or female F344/N rats receiving 1,500, 5,000, or 15,000 ppm. There was equivocal evidence of carcinogenic activity of manganese (II) sulfate monohydrate in male and female B6C3F1 mice, based on the marginally increased incidences of thyroid gland follicular cell adenoma and the significantly increased incidences of follicular cell hyperplasia. The ingestion of diets containing manganese (II) sulfate monohydrate was associated with an increased severity of nephropathy in male rats, focal squamous hyperplasia of the forestomach in male and female mice, and ulcers and inflammation of the forestomach in male mice. These studies were not designed to assess any neurotoxicity that might have been expected with chronic exposure to sufficiently high doses of manganese. Synonyms: Manganese sulfate; manganous sulfate; sulfuric acid. manganese2+ salt (1:1), monohydrate
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PMID:NTP Toxicology and Carcinogenesis Studies of Manganese (II) Sulfate Monohydrate (CAS No. 10034-96-5) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1261 3

N-Phenyl- 2- naphthylamine, formerly used as a antioxidant in the rubber industry, was selected for toxicology and carcinogenesis studies because at the time of nomination (1976) it had a large annual production and widespread human exposure. Additional reasons for selection included it structural similarity and possible metabolism to the known human urinary bladder carcinogen, 2-naphthylamine. Toxicology and carcinogenesis studies were conducted by feeding diets containing N-phenyl-2-naphthylamine (approximately 98% pure and containing less than 1 ppm 2-naphthylamine) at various concentrations to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: In 14-day studies, 3/5 male and 4/5 female rats that received 50,000 ppm N-phenyl-2-naphthylamine died before the end of the studies. Final mean body weights of rats that received 12,500 ppm or more were considerably lower (18%-57%) than those of the controls. Arched backs, rough coats, and diarrhea were observed for males that received 12,500 ppm or more and for females that received 25,000 or 50,000 ppm. All mice were alive at the end of the studies, and no compound-related clinical signs of toxicity were observed in mice given feed containing up to 20,000 ppm. In 13-week studies, deaths occurred in 4/10 male and 9/10 female rats that received the highest dose (40,000 ppm) of N-phenyl-2-naphthylamine. Final mean body weights of rats that received 5,000-40,000 ppm were 9%-60% lower than those of the controls. The liver weight to body weight ratios increased with increasing dose, with the ratios for male rats at 10,000 ppm or more and for female rats at 5,000 ppm being greater (P<0.05) than those of controls. A compound-related nephropathy occurred in rats and was characterized by renal tubular epithelial degeneration and hyperplasia. Other effects in rats included hematopoietic hypoplasia or atrophy of the femoral bone marrow, testicular hypospermatogenesis, lymphoid degeneration of the thymus, and lymphoid depletion of the spleen. In mice, 2/10 males and 7/10 females that received 40,000 ppm died before the end of the 13-week studies. The final mean body weights of mice that received 10,000, 20,000, or 40,000 ppm were 9%-32% lower than those of the controls. The liver weight to body weight ratios for mice increased with increasing dose. Those for male mice at 10,000 ppm or more and for female mice at 20,000 ppm or more were greater (P<0.05) than those for the controls. Nephropathywas observed at increased incidences and severity in dosed mice. Because of kidney lesions, liver enlargement, lower weight gain, and increased mortality in the shorter term studies, dietary concentrations of N-phenyl-2-naphthylamine selected for the 2-year studies in rats and mice were 0, 2,5000, and 5,000 ppm. Body Weight and Survival in the Two-Year Studies: The mean body weights of dosed rats were lower than those of the controls throughout the studies (12% and 16% lower for dosed males and 15% and 31% lower for dosed females at the end of the studies). The average daily feed consumption for rats was 94%-87% that of the controls for dosed males and 88% that of the controls for dosed females. The estimated average amount of N-phenyl-2-naphthylamine consumed per day was 100 mg/kg and 225 mg/kg for male rats and 120 mg/kg and 260 mg/kg for female rats. The survival of the high dose group of male rats was greater (P<0.05) than that of the controls after week 101 (male: control, 24/50; low dose, 28/50; high dose, 34/50; female: 26/50; 44/50; 38/50). Final mean body weights of high dose male and female mice were lower (male, 9%; female, 23%) than those of the controls. The estimated average daily feed consumption by dosed mice was within 10% that of the controls. The average amount of N-phenyl-2-naphthylamine consumed per day was approximately 500 or 1,000 mg/kg for male mice and 450 or 900 mg/kg for female mice. No significant differences in survival were observed between any groups of mice of either sex (male: control, 33/50; male mice. No significant differences in survival were observed between any groups of mice of either sex (male: control, 33/50; low dose, 36/50; high dose, 28/50; female: 36/50; 30/50; 35/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: As in the 13-week studies, the kidney was the principal target for toxic effects of N-phenyl-2-naphthylamine. Mineralization of the kidney, necrosis of the renal papilla, and epithelial hyperplasia and calculi of the kidney pelvis were observed at increased incidences in high dose female rats. Hydronephrosis, atrophy, fibrosis, and chronic focal inflammation of the kidney were observed at increased incidences in high dose female rats. Cysts and acute suppurative inflammation of the kidney were observed at increased incidences in dosed male and high dose female rats. No compound-related renal neoplasms were observed in rats. Nuclear enlargement of renal tubular epithelial cells and nephropathy were observed at increased incidences in high dose female mice. Atypical tubular cell hyperplasia occurred in two high dose female mice. A tubular cell adenoma was found in one high dose female mouse, and a tubular cell adenocarcinoma was found in another high dose female mouse. No renal neoplasms were observed in dosed male mice. Neoplasms of several organs occurred in rats with negative trends and/or at significantly lower incidences in high dose groups. These included thyroid gland C-cell neoplasms in males and females and mammary gland fibroadenomas, pituitary gland adenomas, and mononuclear cell leukemia in females. The lack of carcinogenicity in rats may be related to an inability to metabolize this compound to the known animal and human carcinogen 2-napththylamine. Genetic Toxicity: N-Phenyl-2-naphthylamine was not mutagenic in the Salmonella typhimurium/microsome assay with strains TA97, TA98, TA100, or TA1535 with or without induced hamster or rat liver S9. The chemical did not induce chromosomal aberrations in cultured Chinese hamster ovary (CHO) cells with or without metabolic activation. No increase in sister chromatid exchanges (SCEs) was observed in the absence of metabolic activation; in the presence of rat liver S9, the SCE results were judged to be equivocal. Data Audit: The data, documents, and pathology materials from the 2-year studies of N-phenyl-2-naphthylamine were audited at the NTP Archives. The audit findings show thatthe conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity for male or female F344/N rats fed diets containing 2,500 or 5,000 ppm N-phenyl-2-naphthylamine. Decreased incidences of several neoplasms were observed in dosed rats: thyroid gland C-cell neoplasms in males and females and mononuclear cell leukemia, pituitary gland adenomas, and mammary gland fibroadenomas in females. There was no evidence of carcinogenic activity for male B6C3F1 mice fed diets containing 2,500 or 5,000 ppm N-phenyl-2-naphthylamine. There was equivocal evidence of carcinogenic activity of N-phenyl-2-naphthylamine for female B6C3F1 mice as indicated by the occurrence of two rare kidney neoplasms. Chemical-related nonneoplastic lesions (nephropathy, karyomegaly, and hyperplasia) occurred in the kidney of rats and mice. Synonyms: N-(2-naphthyl)aniline; 2-naphthylphenylamine; b-naphthylphenylamine; 2-phenylaminonaphthalene; phenyl-b-naphthylamine; N-phenyl-b-naphthylamine Trade Names: Aceto PBN; Agerite Powder: Antioxidant 116; Neosone D; Neozon D; Nilox PBNA; Nonox D; PBNA; Stabilizator AR
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PMID:NTP Toxicology and Carcinogenesis Studies of N-Phenyl-2-naphthylamine (CAS No. 135-88-6) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1273 3

Villous adenoma comprises 5.6% of colon tumors. Adenomas of the colon could be divided into tubular, villous, and tubulovillous adenomas. Villous adenomas are not as common as tubular neoplasms; however, usually they are larger and could cause a depleting syndrome characterized by dehydration, hyponatremia, hypokalemia, hypochloremia, and metabolic acidosis. In severe cases, shock and renal failure in older patients could cause death. Case of villous adenoma is presented in this article. Seventy-eight-year-old male who suffered permanent diarrhea for few years followed with acute renal failure. Villous adenoma was diagnosed. The conservative treatment had short renal function improvement. Hemodialysis had to be performed. Renal function was completely recovered after radical tumor surgery.
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PMID:[Renal failure due to a villous adenoma]. 1276 20

The March COM. A 41-year-old woman presented in 1997 with diffuse abdominal pain, meteorism and intermittent diarrhea. Imaging studies revealed a focal rounded lesion in the liver. Although there was no history of progesterone or estrogen therapy, the radiographic appearance was considered to be suggestive of adenoma. The lesion was monitored by ultrasound until October 2000 when a resection was performed because of the presumed risk of a malignant transformation. H&E stained sections revealed an ectopic ependymoma that was strongly positive for GFAP. The surrounding hepatic tissue was negative for GFAP. An extensive search for a CNS manifestation or any other extraspinal localization was unrevealing. We believe we have encountered the first case of an ectopic ependymoma presenting as a solitary hepatic lesion in the absence of CNS disease. Ependymomas generally arise in the CNS in relation to the ventricular system. Extraneural metastasis from ependymomas may occasionally occur even years after detection and treatment of the primary lesion and have been the subject of several reports. In contrast, there are only anecdotal reports of primary extraneural "ectopic" ependymomas. So far those rare cases have only been found in close vicinity to the neural axis, eg, in the sacrococcygeal region, the posterior mediastinum or the ovaries and are there thought to originate from embryonic remnant cells around the neural tube. Distant metastases of ependymomas invading or arising within the extraneural lumbosacral soft tissue may occur in this situation. Here, we report what appears to be the first case of a primary ectopic ependymoma originating in the liver, with no signs of CNS or other systemic involvement.
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PMID:March 2003: a 41 -year-old female with a solitary lesion in the liver. 1294 33

We describe a 70-year-old woman who presented with watery diarrhea and was found to have gastric and colonic polyposis, cutaneous hyperpigmentation, alopecia and onychodystrophy (Cronkhite-Canada syndrome). Histology of a polyp from the stomach showed features of juvenile or retention type (hamartomatous) polyp. One colonic polyp revealed features of tubular adenoma, with moderate dysplasia. Another large pedunculated colonic polyp showed a tubulovillous adenoma with a focus of well-differentiated adenocarcinoma confined to the submucosa of the stalk. Adenomatous and carcinomatous epithelial changes can occur in Cronkhite-Canada syndrome.
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PMID:Cronkhite-Canada syndrome with adenomatous and carcinomatous transformation of colonic polyp. 1465 36

A 12-year-old, neutered male crossbred German shepherd presented with lethargy, inappetence, vomiting, and diarrhea. Bile duct carcinoma was diagnosed by cytological analysis of samples obtained by ultrasound-guided fine-needle aspiration. After surgical excision of the mass, the histologic diagnosis was hepatocellular adenoma.
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PMID:Hepatocellular adenoma in a 12-year-old crossbred German shepherd dog. 1514 8

We examined clinicopathologic associations and biopsy changes that suggested classic lymphocytic colitis (C-LC) but were less well developed in intensity or distribution in 19 cases, which we termed paucicellular LC (P-LC). We also studied clinicopathologic associations and prevalence of LC in 100 asymptomatic, non-gluten-sensitive adults who underwent screening surveillance colonoscopy for previous adenoma. The control group was 38 randomly selected morphologically C-LC cases. The features of P-LC were foci of mildly increased lamina propria lymphoplasmacytic inflammation and increased surface intraepithelial lymphocytes separated by foci or tissue fragments of normal mucosa. Mean age and rates of female sex, endoscopically normal appearing colon, abdominal pain, watery stools, weight loss, connective tissue diseases, and consistent ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) were similar for P-LC and C-LC patients. Of 100 asymptomatic patients, 26 (26%) had LC and 43 (43%) used NSAIDs daily. Of these 43 patients, 14 (33%) had P-LC or C-LC. Daily NSAID ingestion was associated significantly with LC (P = .024). P-LC patients had clinicopathologic relationships similar to those of C-LC patients, suggesting they should be considered part of the morphologic spectrum of LC. LC in asymptomatic adults might be more common than previously thought and might not be associated with watery diarrhea syndrome.
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PMID:Paucicellular and asymptomatic lymphocytic colitis: expanding the clinicopathologic spectrum of lymphocytic colitis. 1536 71

An 85 year old woman presented with a one month history of change in her bowel habits in the form of alternating diarrhoea and constipation. She also noted some rectal bleeding. Flexible sigmoidoscopy revealed a 1.5 cm polyp 30 cm from the anus. The polyp was removed during the sigmoidoscopy by electrocautery and sent for histological examination. The polyp was a tubular adenoma with mild dysplasia. The adenoma contained numerous foci of metaplastic bone. These consisted of irregular islands of mineralised osteoid bone rimmed by a layer of scattered osteoblasts. This is the first case of osseous metaplasia in a tubular adenoma of the colon to be reported.
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PMID:Osseous metaplasia in a tubular adenoma of the colon. 1567 48

The natural history of Crohn's disease (CD) is characterised by periods of remission followed by phases of flares. Persistent or intractable diarrhoea may be associated with ileal disease or arise following ileal resection, resulting in potassium depletion. Medical therapy with steroids presents troublesome side-effects (e.g. hypertension). Conn's syndrome, caused by unilateral aldosterone-producing adenoma, is characterised by clinical features including hypokalaemia and hypertension. Thus, CD and Conn's syndrome may have an overlap of manifestations, and up to now, the simultaneous occurrence of these conditions has not been described. We report here 2 cases of association between CD and Conn's syndrome.
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PMID:Association between Crohn's disease and Conn's syndrome. A report of two cases. 1598 78


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